Asymmetric Synthesis of Isoquinoline Alkaloids: 2004â2015

Review pubs.acs.org/CR

Asymmetric Synthesis of Isoquinoline Alkaloids: 2004−2015 Maria Chrzanowska, Agnieszka Grajewska, and Maria D. Rozwadowska* Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland ABSTRACT: In the past decade, the asymmetric synthesis of chiral nonracemic isoquinoline alkaloids, a family of natural products showing a wide range of structural diversity and biological and pharmaceutical activity, has been based either on continuation or improvement of known traditional methods or on new, recently developed, strategies. Both diastereoselective and enantioselective catalytic methods have been applied. This review describes the stereochemically modified traditional syntheses (the Pictet−Spengler, the Bischler−Napieralski, and the Pomeranz−Fritsch− Bobbitt) along with strategies based on closing of the nitrogen-containing ring B of the isoquinoline core by the formation of bonds between C1−N2, N2−C3, C1−N2/N2−C3, and C1−N2/C4−C4a atoms. Methods involving introduction of substituents at the C1 carbon of isoquinoline core along with syntheses applying various biocatalytic techniques have also been reviewed.

CONTENTS 1. Introduction 2. Pictet−Spengler Cyclization 3. Bischler−Napieralski Cyclization/Reduction 3.1. Diastereoselective Synthesis 3.2. Catalytic Hydrogenation 3.2.1. Asymmetric Transfer Hydrogenation (ATH) 4. Pomeranz−Fritsch−Bobbitt Synthesis 5. Synthesis of the Tetrahydroisoquinoline NitrogenContaining Heterocyclic Ring by Formation of C1− N 2 , N 2 −C 3 , C 1 −N 2 /N 2 −C 3 , and C 1 −N 2 /C 4 −C 4a Bonds 5.1. Synthesis Involving C1−N2 Bond Formation 5.2. Synthesis Involving N2−C3 Bond Formation 5.3. Syntheses Involving Two Bonds Formation 5.3.1. C1−N2/N2−C3 Bond Formation 5.3.2. C1−N2/C4−C4a Bond Formation 5.4. Addition of Carbon Units to 3,4-Dihydroisoquinolines (C1−Cα Bond-Forming Synthesis) 5.4.1. Addition of Organometallic Compounds 5.4.2. Addition of Carbon Nucleophiles 5.5. C1−Cα Bond-Forming Synthesis via the Csp3− H Anionic Center of Tetrahydroisoquinolines 6. Biocatalytic Route to Isoquinoline Alkaloids 7. Conclusion Author Information Corresponding Author Notes Biographies Acknowledgments References

1. INTRODUCTION Isoquinoline alkaloids make a large family of natural products showing a wide range of structural diversity and biological activity. Over the past decade much effort has been directed toward development of efficient synthetic methodologies to obtain these alkaloids in chiral form. Different strategies based on diastereoselective or enantioselective catalytic methods have been employed. For a long time isoquinoline alkaloids have been important synthetic targets for organic synthesis not only to supply medicinally attractive products but also as an intellectual challenge. A great number of chiral natural alkaloids owe their chirality to the presence of a stereogenic center at the C-1 carbon of the tetrahydroisoquinoline moiety; thus, accessing this center in configurational integrity has been the subject of many synthetic attempts. Since the publication of our earlier articles1,2 on asymmetric synthesis of isoquinoline alkaloids, the number of new synthetic strategies and modifications of the traditional procedures has grown markedly; thus, a new compendium on this topic seemed to be appropriate. Several review articles on the asymmetric synthesis of isoquinoline alkaloids concerning, e.g., one class of alkaloids3−7 or the methods of their synthesis,8−12 as well as still important older classic works13−15 should be mentioned. The present review covers the literature from late 2004 to the middle of 2015. It begins with presentation of the stereochemically modified traditional methods [the Pictet−Spengler cyclization (P−S), the Bischler−Napieralski cyclization/reduction (B−N/[H]), and the Pomeranz−Fritsch−Bobbitt cyclization (P−F−B)]. Then strategies based on construction of the nitrogen-containing ring of tetrahydroisoquinoline by closing

A B AD AD AO AS AZ

BE BE BJ BN BN BR BS BS CA CD CF CK CK CK CK CK CL CL

Received: May 18, 2016

© XXXX American Chemical Society

A

DOI: 10.1021/acs.chemrev.6b00315 Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 1. Synthetic Strategies by Construction of Ring B in the Tetrahydroisoquinoline Skeleton

Scheme 2. Mechanism of Pictet−Spengler Condensation

bonds between C1−N2, N2−C3, C1−N2/N2−C3, and C1−N2/ C4−C4a atoms (Scheme 1) along with C1−Cα bond formation in tetrahydroisoquinoline derivatives are described. At the end a brief survey of syntheses based on biocatalytic methods has been included.

The Pictet−Spengler reaction has often been explored as a method of choice for the synthesis of a large family of important antitumor tetrahydroisoquinoline alkaloids, not only because of their intriguing molecular structures but also taking into regard a wide range of their biological activity. Although a number of elegant syntheses of these medicinally important alkaloids had been proposed, continuation of research toward the development of more efficient synthetic routes remains still a great challenge to the chemists specializing in this area. Within this family, several structural motifs may be found. They are represented, e.g., by ecteinascidin (Et-743) (1), saframycin A (2), cribrostatin 4 (3), lemonomycin (4), and quinocarcin (5) (Chart 1). These alkaloids are characterized by a basic tetracyclic (ABCD) or pentacyclic (ABCDE) carbon skeleton, which comprises one, two, or three tetrahydroisoquinoline units 6−8 (Chart 2) with a specific substitution pattern of the aromatic ring (usually 6-methyl, 7-methoxy, 8-hydroxy, or 6-methyl, 7,8methylenedioxy), in which ring A (E) of the tetrahydroisoquinoline core assumes either aromatic or quinoid form. Accordingly, alkaloids of the ecteinascidin type incorporate three units: 6, 7, and 6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline. Among the bisisoquinolines, the saframycin family contains two 9 fragments, while in cribrostatin both aromatic 8 and quinoid 9 elements are present. One tetrahydroisoquinoline

2. PICTET−SPENGLER CYCLIZATION In the past decade, the old but still useful Pictet−Spengler reaction16,17 has frequently been explored as a convenient method for the synthesis of tetrahydroisoquinoline derivatives and related heterocyclic systems. This reaction involves an acidcatalyzed condensation between β-arylethylamine and an aldehyde or their synthetic equivalents and is performed in a one-pot procedure. It is initiated by the formation of intermediate iminium ion which then undergoes cyclization to the nitrogen-containing heterocyclic ring by nucleophilic attack of the aryl group (Scheme 2). To adapt this method for the stereoselective synthesis, various modifications have been introduced to the stereo- and regioselective as well as inter- and intramolecular Pictet− Spengler reaction. Both diastereoselective and enantioselective modifications of the Pictet−Spengler reaction as well as enzymecatalyzed procedures have been worked out.8 In many of them generation of a C-1 stereogenic center in the tetrahydroisoquinoline core has been the crucial step. B


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Chart 1

Chart 2

Chart 3

ones or develop new approaches to the synthesis of these medicinally important compounds. In the synthetic strategy, based on the Pictet−Spengler method, the stereochemical outcome of the tetrahydroisoquinoline-forming step depended on the use of properly substituted chiral β-arylethylamines in the form of α-amino acids 10−12, aminoalcohols type 13, and aminoaldehyde acetal 14, precursors of tetrahydroisoquinolines 6−9 (Chart 3). Thus, access to the substrates has been a challenge since the beginning of studies in this area, and much effort has been made to solve this problem.

unit may be found in several alkaloids, represented, e.g., by lemonomycin (4) and quinocarcin (5). Construction of the cyclic framework of these alkaloids has been the pivotal point of their total synthesis. In a continuation of an earlier study, comprehensively reviewed by Scott and Williams18 in 2002 and by Mulzer et al.7 in 2008, many research groups around the world, headed by, e.g., Williams and Danishefsky in the United States, Liu and Chen in China, Fukuyama in Japan, and Zhu in France, to mentioned a few, have been engaged in the past decade to further improve the available C


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esterification, N-Boc-protection, O-methylation, LiBH4 reduction, and SOCl2-induced cyclization (Chart 5).

In general, three approaches have been chosen. Introduction of the appropriate substituents to the aromatic ring of natural amino acids of L-phenylalanine-type (L-tyrosine, L-DOPA), catalytic enantioselective alkylation of glycine synthons with properly substituted benzyl derivatives, or coupling of correctly functionalized benzene derivatives with equivalents of the chiral side chain. The L-tyrosine route to the highly functionalized amino acid 10, relying on the model study proposed by Schmidt et al.19 in 2004, was recognized as a very useful method, and it was further developed by others. The Schmidt’s procedure19 started with NBoc-L-tyrosine, which was subjected to a series of transformations to install the 3-hydroxy, 4-methoxy, and 5-methyl groups. The transformations included C-formylation of N-Boc-Ltyrosine to give 15 (R = H), iodination/methylation of the corresponding ester 15 (R = Me or Et) to afford 16, followed by O-methylation, Dakin oxidation, and finally O,N-deprotection to complete the synthesis of the desired amino acid 10, obtained in rather poor yield (Chart 4).

Chart 5

Williams and co-workers24,25 proposed a diastereoselective synthesis of tri- and tetrasubstituted β-arylethylamines through the reaction between oxazinone 23, used as chiral auxiliary/ building block, and trisubstituted or tetrasubstituted benzyl halides 21 or 22, respectively. The corresponding coupling products 24 or 25 were then converted into β-arylethylamines of type 10 or 12, respectively, by hydrolysis of the chiral auxiliary and removal of the N,O-protecting groups (Chart 6). The same authors,26 in another diastereoselective synthesis of (−)-cribrostatin 4 (3), employed cis-fused β-lactam 29 as the βarylethylamine substrate. It was prepared by the asymmetric Staudinger reaction between tetrasubstituted imine 26 and a ketene 27, generated in situ from chiral oxazolidinone 28 (Chart 6). The synthesis of aminoaldehyde acetal 14, used as a substrate for constructing Et-743 (1) pentacyclic core, has been performed in the laboratory of Fukuyama.27 The synthesis began with the known aldehyde 30 and involved Horner−Wadsworth− Emmons (HWE) reaction to give stereoselectively unsaturated ester 31, which on asymmetric catalytic hydrogenation {H2/ Rh[(cod)-(S,S)-Et-DuPHOS]OTf} afforded aminoester 32 of high enantiomeric purity. Transformation of 32 proceeded through Weinreb amide 33 and DIBAL reduction to the aldehyde 14, which was protected as an acetal (Scheme 3). Applying Corey’s28 procedure of catalytic enantioselective synthesis of highly substituted β-phenylethylamine derivatives, based on alkylation of N-(diphenylmethylene)glycine tert-butyl ester 34 by adequately substituted benzyl bromides, Zhu et al.29−32 carried out this reaction in the presence of cinchonidinederived chiral phase-transfer catalyst 35 and obtained amino alcohol 13 and amino esters 36−38 in high overall yield and high enantiomeric purity (≥90% ee) (Chart 7). Introduction of amino acid side chain into substituted benzene derivatives has been another way to reach the chiral, modified tyrosine derivatives. In several diastereoselective syntheses the (R)-Garner’s aldehyde 39 has been employed as chiral building block. It was particularly useful for the synthesis of βarylethylamines with a hydroxyl group at the benzylic position, important substrates for the synthesis of Et-743 (1). Zhu and coworkers,33,34 employing stereoselective phenolic aldol reaction between (R)-Garner’s aldehyde 39 and phenols 40 and 41, prepared syn-oxazolidines 42 and 43, respectively, in high yield (Chart 8). After allylic protection of the phenol OH group, followed by oxazolidine hydrolysis, ketalization, and protecting groups removal, intermediate syn-oxazolidines 42 and 43 were converted into syn-amino ketals 44 and 45. They were used for construction of the carbon framework of Et-743 (1)33 and for the total synthesis of (−)-cribrostatin 4 (3).34 On the other hand, Williams and Fishlock35 in their synthetic studies on Et-743 (1), carrying out a stereoselective aldol reaction between bromophe-

Chart 4

Several modifications to Schmidt’s procedure have been undertaken to improve the effectiveness of this method. Liu et al.20 used different protecting groups (N-Ac, O-Me) and different order of operations: formylation/reduction (to introduce Cmethyl group) followed by C-formylation/Bayer−Villiger oxidation prepared 10 in satisfactory overall yield along with its 6-bromo derivative. At the same time, the synthesis of amino alcohol 13, another important substrate for the synthesis of these alkaloids, has been reported by Zhu and co-workers.21 Their synthesis was initiated by Friedel−Crafts acetylation of N-Cbz-L-tyrosine to give acetophenone 17, which was subjected subsequently to iodination/methylation, Baeyer−Villiger oxidation, reduction and N-deprotection to supply the amino alcohol 13 in 50% overall yield. Chen and co-workers,22 starting with N-Cbz-protected Ltyrosine, prepared amino acid 10 and amino alcohol 13 in high yield by another modification to Schmidt’s procedure. The 3methyl substituent was installed by reduction of hydroxymethyl derivative 18, prepared by phenolic aldol condensation between N-Cbz-L-tyrosine with formaldehyde, while the 5-hydroxy group was introduced by the standard formylation/oxidation procedure. Reduction of the corresponding ester led to the amino alcohol 13. Lemaire and co-workers,23 in a model study, prepared oxazolidinone 20 by DDQ/RCOOH oxidation of 19, prepared in turn from L -DOPA in a 5-step synthesis involving D


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Chart 6

Scheme 3. Preparation of Aldehyde Acetal 14, the Substrate for the Synthesis of Et-743 (1)

Chart 7

two isoquinoline units have been coupled (A → E synthesis) or the opposite (E → A synthesis), has also been carried out. In this concept the Pictet−Spengler condensation has been explored at two stages. At the first one, the intermolecular Pictet−Spengler reaction was employed to assemble the 1,3-disubstituted tetrahydroisoquinolines (AB, ED units); at the second stage, the intramolecular version has been used for CD rings closure. Thus, with accessibility of the properly functionalized βarylethylamines, intermolecular Pictet−Spengler reaction with appropriate aldehydes has been carried out to supply 1,3disubstituted tetrahydroisoquinolines AB or ED. Benzyloxy acetaldehyde or glyoxylic acid esters have commonly been used to introduce the C-1 hydroxymethyl appendage, characteristic of the AB unit of a majority of those natural products. The configuration of the newly generated C-1 stereogenic center was strongly dependent on the aldehyde used. With benzyloxy acetaldehyde, the desired C-1 configuration for 1,3-syn arrangement of substituents was formed like in MY-336a38 (56), while the opposite 1,3-anti stereochemistry, as in 57,39 was produced in reactions with glyoxylic acid esters.25 Chiral aldehydes such as

nol 46 and (R)-Garner’s aldehyde 39, prepared anti-oxazolidine 47, isolated also in a satisfactory yield, which was converted into the anti-product 48. The reaction between Grignard reagent 49 and serinal-derived nitrone 50, which afforded aldehyde 52 via syn-hydroxylamine 51, has been described by Kaniskan and Garner36 in their synthetic approach toward cyanocyclines and bioxalomycines (Chart 9). To introduce a side chain into aryl bromide 53, Wu and Zhu37 employed chiral aziridine 55 as the coupling partner to prepare aminoester 37. Aziridine 55 was prepared from N-trityl-L-serine methyl ester 54 in high yield by MsCl-induced cyclization and N,O-protecting groups exchange (Chart 9). The known Ltyrosine derivative 37 was prepared in two steps and in high yield. Since the beginning of studies in this field the construction of the carbon skeleton of the alkaloids has been the crucial point of their synthesis. The most frequently explored strategy, essential for building of the fused rings system, started with ring A of βarylethylamine to which rings B, C, D, and E have been added stepwise (A → E synthesis). The convergent approach, in which E


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Chart 8

Chart 9

Chart 10

formyl aziridine 5837 and (S)-Garner’s aldehyde ent-3927,40 have also been used to build up rings ED of isoquinolines 59,37 60,40 61,27 respectively (Chart 10). Isoquinolines 60 and 61 have been applied by Zhu and co-workers40 and Fukuyama and coworkers,27 respectively, as substrates in the synthesis (E → A) of ecteinascidin 743 (1). The CD rings closure of the pentacyclic alkaloids has been achieved by the intramolecular Pictet−Spengler reaction. This process was based on N-acylation of the AB core with a second molecule of the β-arylethylamine introducing ring E, followed by coupling between the C-3 formyl substituent and the amino group of the β-arylethylamine introduced, thus completing the construction of carbon skeleton. The A → E strategy has been employed for a long time for total or partial syntheses of the many medicinally important pentacyclic alkaloids. It has been continued by a number of

research groups, introducing several modifications to the above scheme, e.g., using the C-3 substituent of the AB core at various oxidation states, different N,O-protecting groups, different reaction conditions and reagents, or routes for the final formation of the quinoid form of rings A and/or E. A retrosynthetic analysis of Williams’ asymmetric total synthesis25 of (−)-renieramycin G (62) is shown in Scheme 4 to illustrate the A → E approach en route to the pentacyclic alkaloids. The synthesis was characterized by three crucial steps: Nacylation of tetrahydroisoquinoline 63 with amino acid 64, oxidation of the O-deprotected primary alcohol, and cyclization of intermediate aldehyde 65 to give the pentacyclic core 66 of (−)-renieramycin G (62) (Chart 11). F


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Scheme 4. Retrosynthetic Analysis of Williams’ Asymmetric Total Synthesis of (−)-Renieramycin G (62)

Chart 11

Chart 12

several transformations of the β-lactam moiety and intramolecular Pictet−Spengler reaction afforded the pentacycle 72, converted to (−)-cribrostatin 4 (3) according to the established procedures (Chart 13). During the synthetic studies on the construction of the pentacyclic frameworks of the ecteinascidin−saframycin class of

According to Scheme 4 and Chart 11, the Williams’ group performed the total synthesis of 3-epi-renieramycin G (67), (−)-jorumycin (68), and 3-epi-jorumycin (69) (Chart 12).25 In their approach to (−)-cribrostatin 4 (3),26,39 two key building blocks, tetrahydroisoquinoline 70 and amino acid 64, were used to give N-acylation product 71 (R = OMe), which after G


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appendage with angelic acid and oxidation of ring A to the quinoid form. Stereoselective synthesis of ecteinascidin 743 (1)45 was performed according to a similar synthesis using tetrahydroisoquinoline 81, the methylenedioxy analogue of 77, and amino acid 78 to prepare the coupling product 82. In this synthesis, the C3−C-4 double bond in 83 was created prior to the Pictet− Spengler cyclization, affording the pentacyclic alkene 83. The 4hydroxyl group was installed stereoselectively to give 84 via an intermediate epoxide. The synthesis of the pentacyclic C-21 cyano derivative 86, the known precursor of Et-743 (1), was reached by ring opening of intermediate oxazolidine 85 upon exposure to KCN. Interchange of several protecting groups was needed to complete the synthesis (Scheme 6). Some of the synthetic aspects of ecteinascidins synthesis have been reviewed by Morris and Phillips.46 (−)-Lemonomycin (4) and (−)-quinocarcin (5) represent the alkaloids which incorporate only one tetrahydroisoquinoline unit. In many laboratories attempts have been made at constructing their tetracyclic framework, starting with the synthesis of AB rings. By N-acylation of the known tetrahydroisoquinoline 87 using amino acid 88, Zhu et al.31 obtained intermediate amide 89 containing all of the carbon atoms present in the molecule of lemonomycin aglycone and converted it into 92, the precursor of the alkaloid. The key steps of the synthesis included closing ring C of intermediate 89 via cyclization of in situ formed aldehyde obtained by reduction/Swern oxidation of the ester group to give 90, and formation of ring D via thioether 91, employing an intramolecular Mannich reaction. Finally, removal of N,Oprotecting groups and oxidation of hydroquinone to a quinone system completed the synthesis of lemonomycinone amide 92 in an overall yield of 12% (Scheme 7). Williams and co-workers47 transformed N-acylated isoquinoline 93 into the tetracyclic core of lemonomycin 96 through an intermediate iminium ion 94, formed by acid-catalyzed cyclization of 93. Treatment of 94 with tert-butyl acrylate afforded tetracyclic ester 95 as a 2.4:1 mixture, which was subjected to deacetylation, epimerization, and reduction

Chart 13

alkaloids, Williams and co-workers41 proved that the presence of a β-lactam moiety at the C-3 and C-4 positions of isoquinoline (e.g., as in 71, R = H) was essential for the regioselectivity of the second Pictet−Spengler step, securing the proper order of substituents in ring D41 (e.g., 72). In the formal synthesis of ecteinascidin 743 (1),42 coupling product 75, derived from isoquinoline 73 and amino acid chloride 74, after hydrolysis, Swern oxidation, and cyclization aforded 76, the precursor of the target alkaloid (Chart 14). In an earlier total synthesis of cribrostatin 4 (3), conducted by Danishefsky’s group,43,44 the key step of their strategy was based on the construction of a pentacyclic ring system by connecting two highly functionalized building blocks, tetrahydroisoquinoline 77 and amino acid 78 (Scheme 5). The resulting intermediate 79 was then subjected to oxidation of the Odeprotected primary alcohols and intramolecular Pictet− Spengler cyclization to supply the pentacyclic core 80. For the final architecture of the molecule, several manipulations of functional groups were carried out: introduction of a C-3−C-4 double bond, a C-14 carbonyl group, and the phenolic OH into the E ring, including final esterification of the C-1 hydroxymethyl Chart 14

H


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Scheme 5. Stereoselective Synthesis of Pentacyclic Core 80 of Cribrostatin 4 (3)

Scheme 6. Stereoselective Synthesis of Et-743 (1)

Kwon and Myers49 in a continuation of earlier study50 conducted the synthesis of (−)-quinocarcin (5) starting with the isoquinoline 102 and morpholino nitrile 103 to set up the tetracyclic core 105 via condensation product 104. The synthesis was completed by N,O-methylation, oxidative cleavage of the olefinic side chain, and formation of the oxazolidine ring by AgNO3 which induced cyclization of intermediate hydroxynitrile (Scheme 10). Wu and Zhu32 synthesized (−)-quinocarcin (5) in 16% overall yield carrying out a 22-step synthesis in which N-acylated tetrahydroisoquinoline 106 was the starting compound. It was converted into the tricyclic thioether 107 in several steps involving, among others, ester reduction/Swern oxidation,

followed by removal of N,O-protecting groups supplied the lemonomycin precursor 96 (Scheme 8). Mulzer’s synthesis48 of tetracyclic fragment 101 of (−)-lemonomycin (4) started with the reaction between tetrahydroisoquinoline 97 and silylated cyanohydrin 98 to provide amino nitrile 99. Acetylation of the phenolic OH group followed by deprotection of the O-TES function and oxidation of the liberated primary hydroxyl group led to tricyclic hemiacetal 100. After the action of trifluoroacetic acid, 100 was transformed into tetracyclic core 101 with all stereoceters required for the synthesis of (−)-lemonomycin (4) through a process which involved cyclization of intermediate iminium ion and Me3SiOTf elimination (Scheme 9). I


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Scheme 7. Stereoselective Synthesis of Lemonomycinone Aglycone 92

Scheme 8. Stereoselective Synthesis of Lemonomycin Precursor 96

Scheme 9. Stereoselective Synthesis of Tetracyclic Fragment 101 of (−)-Lemonomycin (4)

J


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Scheme 10. Stereoselective Synthesis of (−)-Quinocarcin (5) by Kwon and Myers49

Scheme 11. Stereoselective Synthesis of (−)-Quinocarcin (5) by Wu and Zhu32

Chart 15

111, after regioselective dioxane ring opening using hexane-1thiol and oxidation of the liberated primary alcohol, afforded aldehyde 112, which in a domino process was transformed into the pentacyclic core 113 and converted to the target natural product according to the established procedure (Chart 15). In a similar strategy, Zhu and co-workers33 in attempts to get ecteinascidin Et-743 (1) performed the synthesis of the pentacyclic core 118 using tetrahydroisoquinoline 114 and aldehyde 115 as advanced building blocks. The intermediate oxazolidine 116, formed when treated with TMSCN and (R)-NTroc-(S-trityl)cysteine, underwent acid-catalyzed macrocyclization with the formation of the sulfur-containing ring in 117.

cyclization of the intermediate aldehyde, reaction of intermediate carbinol amide with EtSH, and hydrolysis of O-TBS protection. Another Swern oxidation, the intramolecular Mannich reaction with EtSH elimination, supplied the pentacyclic core 108. The synthesis was completed by using the known chemistry (Scheme 11). The construction of the alkaloid pentacyclic carbon skeleton by connecting the AB end with the E end of the molecules has been studied by many research groups. A convergent total synthesis of (−)-cribrostatin 4 (3) by Nacylation of tetrahydroisoquinoline 109 with amino acid 110 has been described by Chen and Zhu.34 The major coupling product K


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Scheme 12. Stereoselective Synthesis of Pentacyclic Core 118, Precursor of Et-743 (1)

Chart 16

For the synthesis of (−)-saframycin A (2) obtained in 9.7% overall yield in 24 steps (from L-tyrosine), a series of operations was needed including, among others, closure of ring D, introduction of CN substituent to ring C, N-methylation, and oxidation of ring A. In a similar reaction pathway the tetracyclic precursor of renieramycin isomer 125 was prepared in 12 steps. Chen and co-workers55,56 in the synthesis of antitumor alkaloids, (−)-jorunnamycins A (129), C (130), and (−)-jorumycin (68), applied tetrahydroisoquinoline 126 and amino alcohol 13 to prepare the pentacyclic framework 128 of these alkaloids. Intermolecular Pictet−Spengler cyclization afforded intermediate 127 incorporating two isoquinoline moieties which was used as the common precursor in the synthesis of these alkaloids. For the synthesis of (−)-jorunnamycin A (129) compound 127 was subjected to Swern oxidation and intramolecular Strecker reaction to provide amino nitrile 128 with removal of protecting groups. The synthesis was completed by oxidation of A and E rings using atmospheric oxygen in the

Intramolecular Pictet−Spengler reaction, involving opening of the 10-membered ring, afforded the pentacyclic precursor 118 of Et-743 (1) (Scheme 12). The convergent synthesis employing combination of two building blocks, tetrahydroisoquinolines, as AB unit, and tyrosine-derived amino acids, as E unit, has recently been applied by Liu’s group for the synthesis of (−)-saframycin A (2)51 and analogues52 and for the construction of the renieramycin isomer skeleton 12553 and analogues,54 applying a common sequence of transformations. In the total synthesis of (−)-saframycin A (2), isoquinoline 119 and amino acid 120 were combined to give after O-deprotection of primary hydroxyl the coupling product 121, while for the synthesis of skeleton 125 of renieramycin isomer, isoquinoline 122 and amino acid 123 were employed. The so obtained coupling products, 121 and 124, were then converted to the final products by intramolecular Pictet−Spengler reaction as the key step at which closure of the central ring C took place (Chart 16). L


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Chart 17

Scheme 13. Retrosynthetic Analysis of Zhu’s Approach to the Synthesis of Et-597 (131) and Et-583 (132)

Accordingly, coupling of aminoaldehyde 134 with phenol 41 afforded tricyclic ED-A intermediate 135, which after a series of protecting group manipulations via intermolecular Pictet− Spengler condensation with O-Troc-protected hydroxyacetaldehyde was transformed into tetracyclic ED−AB ring system 136. Swern oxidation and intramolecular Strecker reaction furnished the pentacyclic core 137. The synthesis was advanced toward the target alkaloids via compound 138 in which the sulfur-containing macrocyclic lactone was installed by exchanging the O-Troc group for (R)-N-Troc-S-4,4′,4″-trimethoxytritylcysteine and liberating the SH group and cyclization using TMSBr (Scheme 14). Exploring the strategy outlined above, the same authors succeeded in the asymmetric total synthesis of other pentacyclic natural products: (−)-renieramycins M (133), G (62), (−)-jorunnamycin A (129), and (−)-jorumycin (68).37 As a result of the reaction between isoquinoline 59 containing at C-1 chiral aziridine (DE end) and Grignard reagent 49 bistetrahy-

presence of salcomine. (−)-Jorunnamycin C (130) and (−)-jorumycin (68) were achieved from (−)-jorunnamycin A (129) by simple functional group exchange (Chart 17). Another synthetic strategy toward the antitumor natural products started with the construction of a pentacyclic core from the E end of the molecule (E → A synthesis). A stimulating study of this approach has been carried out at the laboratory of Zhu, where the asymmetric total synthesis of ecteinascidins 597 (131), 583 (132),57 and 743 (1)40 along with (−)-renieramycins M (133), G (62), (−)-jorunnamycin A (129), and (−)-jorumycin (68)37 was performed. In their concept two processes were important: the stereoselective phenolic aldol condensation to connect rings ED with ring A, and the stereoselective, intermolecular Pictet−Spengler reaction to close ring B of the AB fragment. To illustrate this strategy a retrosynthetic analysis of the synthesis of ecteinascidins57 is shown in Scheme 13 (R represents various protecting groups or hydrogen). M


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Scheme 14. Stereoselective Synthesis of Et-597 (131) and Et-583 (132)

Chart 18

droisoquinoline 139 (DE, AB) was produced. Ring C was

synthesis of (−)-jorunnamycin A (129), jorumycin (68),

constructed after reduction/oxidation of the ester group, cyanohydrine formation, and intramolecular Pictet−Spengler

renieramycins G (62), and M (133). Isoquinoline 141 and bromo ester 142 have been used by Zhu

cyclization to give the pentacyclic ring system 140 (Chart 18).

et al.40 as components for the synthesis of ecteinascidin Et-743

Compound 140 was then used as a common intermediate in the

(1), while morpholinenone 143 and phenol 144 served as N


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Chart 19

Scheme 15. Stereoselective Synthesis of Pentacyclic Core 151 of Et-743 (1)

Chart 20

building blocks in the Fukuyama synthesis27 of the alkaloid precursor (Chart 19). A method based on the assembly of the pentacyclic core of Et743 (1), starting with the central ring C, to which ends ED and AB were successively added, has been realized in the laboratory of Fukuyama.58 Beginning with diketopiperazine 145, derived from L-glutamic acid, the synthesis of Et-743 (1) was carried out. First, the ED unit was prepared by the Perkin condensation between diketopiperazine 145 and 3,5-dibenzyloxy-4-methoxybenzaldehyde to give 146. The Pictet−Spengler cyclization (after reduction of the double bond) supplied tricyclic lactam 147 (CDE). It was then converted by decarboxylative cyclization to enamide 148. The AB isoquinoline unit was built up by

connecting enamide 148 with amine 149 to give the coupling product 150. Subjecting 150 to a series of reactions, involving among others the Pomeranz−Fritsch−Bobbitt cyclization, aforded the important intermediate 151, which was converted into Et-743 (1) according to a known procedure (Scheme 15). Some model study on the construction of analogues of the pentacyclic ring system has been carried out by French researchers.59,60 They prepared regioisomeric bistetrahydroisoquinolines 153 and 154 by the Pictet−Spengler reaction between N-Boc amino aldehyde 152 and L-DOPA methyl ester followed by O-methylation. Hydrolysis and intramolecular peptide coupling afforded pentacyclic amides 155 and 156, which were O


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Chart 21

Chart 22

Scheme 16. Stereoselective Synthesis of Diazabicyclononane 170, an Advanced Intermediate for the Synthesis of Et-743 (1)

Scheme 17. Diastereoselective Synthesis of (S)-Crispine A (ent-177) and (R)-Crispine A (177) from Chiral (S)-Amino Ester 171 as a Substrate

transformed into aminonitriles 157 and 158, potential anticancer agents (Chart 20).

Another model study directed toward the synthesis of diazabridged diastereomeric heterocycles 162 and 163, with feasible P


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applicability for the construction of EDC rings system of the pentacyclic natural products, has been performed by Grieco and co-workers.61 Their synthesis started with diastereomeric tetrahydroisoquinolines 160 and 161 prepared by the Pictet− Spengler condensation between L-DOPA methyl ester and NFmoc amino aldehydes 159, followed by intramolecular lactamization (Chart 21). Takemoto’s62 way to the CDE ring system of the pentacyclic alkaloids involved alkynyl amide 164 as an intermediate. The construction of C ring was achieved by intramolecular Au(I)catalyzed hydroamidation of 164 to tricyclic product 165, obtained as a single Z isomer. However, oxidative Friedel−Crafts cyclization was acompanied by Z/E isomerization of the enamide moiety, affording tetracycle 166 (Chart 22). More recently, Takemoto’s group63 developed a new route to Et-743 (1) in which a diazabicyclononane ring system 170 was used as an important intermediate. It was prepared by Au(I)catalyzed one-pot amidation of ketone 169 obtained by assembly of amine 167 and morpholinone 168. For the final ring B closing the Pomeranz−Fritsch−Bobbitt reaction was applied after adequate functionalization of the enamide double bond (Scheme 16). Several other types of tetrahydroisoquinoline alkaloids and analogues have been synthesized by the Pictet−Spengler methodology. Similarly to the synthesis of the important bioactive alkaloids mentioned above, chiral β-arylethylamines have been applied both as the amine components and as the source of chirality. Natural amino acids such as L-DOPA or (S)and (R)-3,4-dimethoxyphenylalanine derivatives as well as βarylethylamines bearing a chiral auxiliary attached to the nitrogen atom have frequently been explored. Herr and co-workers,64 using commercially available methyl esters of (S)- and (R)-3,4-dimethoxyphenylalanine (171 and ent171) and 4-chloro-1,1-dimethoxybutane (172) as substrates, synthesized the natural (R)-crispine A (177), a pyrroloisoquinoline alkaloid, and its (S)-enantiomer (ent-177) using the Pictet− Spengler methodology. Scheme 17 shows the three-step synthesis of the natural and unnatural alkaloids. During the Pictet−Spengler condensation, two successive cyclization steps were taking place, affording two diastereomeric tetrahydroisoquinolines: 1,3-cis-175 and 1,3-trans-175, which under optimized reaction conditions were produced in a 4.5:1 diastereomeric ratio. The prevailing 1,3-cis isomer 175 was postulated to be formed through a more stable E-iminium ion intermediate 173 being attacked by the aromatic ring from the si face and leading to intermediate (1S,3S)-tetrahydroisoquinoline 174. The synthesis was then completed by radical decarboxylation of the COOMe group via the corresponding methylselenyl ester 1,3-cis-176 affording (S)-crispine A (ent-177) in 31% overall yield. (R)Crispine A (177) was prepared in 8% overall yield from the minor diastereomer 1,3-trans-176 following the same procedure. The same reaction sequence was carried out starting from more expensive (R)-3,4-dimethoxyphenylalanine methyl ester (ent-171) leading to (R)-crispine A (177) with 32% overall yield. The natural amino acids, L-DOPA or L-3,4-dimethoxyphenylalanine methyl ester 171, in reactions with various aromatic and heteroaromatic aldehydes have been applied by Lemaire et al.65 for preparation of a series of new C-1-substituted tetrahydroisoquinolines. Isoquinolines 1,3-cis-178 and 1,3-trans-178 prepared from L-DOPA and benzaldehyde were obtained in a 80:20 cis/trans ratio in the reaction carried out in water (Chart 23). On the other hand, in experiments in which L-3,4-dimethoxyphenylalanine methyl ester 171 and other aryl aldehydes were used, the

Chart 23

diastereomeric composition of 1,3-cis-179/1,3-trans-179 was strongly dependent on the R substituent at the aromatic ring. For instance, a 87:13 cis/trans ratio was formed when aldehyde with a R = CN group was used, while no diastereoselectivity was observed for R = OMe (Chart 23). Liu et al.66 in the Pictet−Spengler reaction between L-DOPA methyl ester and highly functionalized aromatic aldehydes, carried out in acetic acid in the presence of anhydrous NaOAc, prepared a series of 1-substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl esters 180 achieving high yields and 1,3-cis selectivity, irrespective of the electronic nature of the R substituent (Table 1). Table 1. Preparation of 1-Substituted Tetrahydroisoquinoline-3-carboxylic Acid Methyl Esters

entry

R

Y (%)

cis/trans ratio

1 2 3 4 5

C6H5 3,4,5-(OMe)3C6H2 4-ClC6H4 4-(NO2)C6H4 3,4-(OCH2O)C6H3

90 95 90 80 95

10:1 20:1 13:1 11:1 15:1

Lactam 183, which has been prepared by Allin and coworkers67 from L-3,4-dimethoxyphenylalaninol (181) and racemic diketo acid 182, was used as the key intermediate in a formal synthesis of 3-demethoxyerythratidinone (186), an alkaloid of the Erythrina family. Lewis acid promoted Nacyliminium cyclization (a masked intramolecular Pictet− Spengler reaction) of 183 led to tetracyclic isoquinoline 184, which after removal of 3-hydroxymethyl side chain was transformed into the alkaloid’s precursor (−)-185 in high yield. The precursor of the natural dextrorotatory enantiomer (+)-ent-185 has also been prepared following the identical route using enantiomeric β-amino alcohol, ent-181, and diketo acid 182 as the substrates (Scheme 18). A straightforward way to a benzo[a]quinolizidine heterocyclic system, a structural motif of many isoquinoline alkaloids, has been proposed by Bosch et al.68−70 In their biosynthetic-like Q


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Scheme 18. Diastereoselective Synthesis of Tetracyclic Precursor (−)-185 of (+)-3-Demethoxyerythratidinone (186) Using Amino Alcohol 181 as a Substrate

Scheme 19. Stereoselective Synthesis of Enantiopure Benzo[a]quinolizidines 189a−c Using Amino Alcohol 181 as a Substrate

Scheme 20. Stereoselective Synthesis of cis- and trans-Pyrrolo[2.1-a]isoquinolines 192 from L-DOPA-Derived Imide Alcohol 190

compound in a ca. 2:1 diastereomer ratio and with 99% ee. When a protic acid was used in this step, the reversal of stereochemistry was observed, and this reaction afforded mainly the cis-isomer 192, also with 99% ee (Scheme 20). Recently, chiral N-sulfinyl β-arylethylamines have been employed as substrates for the asymmetric synthesis of isoquinoline alkaloids.72,73 The Mexican−Spanish team72 in a short and efficient synthesis of (+)-crispine A (177) applied sulfinamide 193, which was prepared from β-3,4-dimethoxyphenylethylamine and (S)-menthyl p-toluene sulfinate as the starting compounds. The Pictet−Spengler cyclization of 193 with 4chlorobutanal 194 led to isoquinoline 196 (via postulated iminium intermediate 195), which was produced as the only diastereomer (95% ee), thus proving the well-recognized great efficiency of the sulfinyl auxiliary as stereocontrolling factor. During removal of the sulfinyl auxiliary in acidic milieu a spontaneous cyclization of the intermediate aminochloro derivative 197 occurred, producing exclusively (R)-(+)-crispine

approach, a stereoselective cyclocondensation between racemic aldehyde esters 187a−c (secologanine-type synthetic equivalents) and L-3,4-dimethoxyphenylalaninol 181 afforded a mixture of diastereomeric lactams, from which enantiopure isomers 188a−c were isolated by chromatography. Intramolecular α-amidoalkylation of 188a−c induced by BF3·Et2O led to enantiopure benzo[a]quinolizidines 189a−c, isolated as single diastereomers, in satisfactory yield (Scheme 19). The hydroxymethyl appendage could be removed by oxidation to the carboxylic acid followed by radical reductive decarboxylation of the corresponding seleno ester. Lete et al.71 in their study on stereocontrolled intramolecular α-amidoalkylation have chosen L-DOPA-derived imide alcohol 190 as substrate for the synthesis of pyrrolo[2.1-a]isoquinolines cis- and trans-192. Under the action of methyl lithium, imide 190 was transformed into amide 191, which was subjected to Lewis acid induced N-acyliminium cyclization. Irrespective of the nature of the hydroxyl protecting group (TBDPS, Bn, Me) the trans-pyrroloisoquinoline 192 was produced as the major R


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Scheme 21. Short Diastereoselective Synthesis of (R)-(+)-Crispine A (177) Using Chiral Sulfinamide 193 as a Substrate

Scheme 22. Diastereoselective Synthesis of (−)-Lirinine (205) Using Sulfinamide 201 as a Chiral Intermediate

A (177) in 55% overall yield (Scheme 21). The synthesis of the alkaloid could also be performed as a one-pot process. Another alkaloid that has been synthesized using chiral sulfinylamide as the starting compound was (−)-lirinine (205), an aporphine alkaloid. Cuny and co-workers73 obtained it starting with chiral N-sulfinylamide 201, prepared by coupling of phenylacetaldehyde 198 with chiral sulfinylamide 199, followed by NaBH4 reduction of intermediate imine 200. The Pictet− Spengler reaction with o-bromophenylacetaldehyde 202 produced tetrahydroisoquinoline 203 with high diastereoselectivity (94:6 dr), in which the N-sulfinyl auxiliary was exchanged for a Ntosyl group to give 204. After hydrolysis of the benzylic ether, 204 was subjected to intramolecular phenolic arylation in the presence of Pd/XPhos precatalyst system and finally converted into the target (−)-lirinine (205) by tosyl group removal and Nmethylation (Scheme 22). Chiral imides 206 and 207, prepared from β-3,4-dimethoxyphenylethylamine and chiral dicarboxylic acids, (S)-malic acid and L-tartaric acid, respectively, have been employed as substrates for the stereoselective synthesis of pyrroloisoquinoline derivatives, alkaloids included (Chart 24). Simpkins and co-workers74 reported on the synthesis of (+)-demethoxyerythratidinone (186), which started with addition of but-3-enylmagnesium bromide to imide 206 (R =

Chart 24

Ac), readily available by condensation of β-3,4-dimethoxyphenylethylamine with (S)-malic acid, to afford hydroxylactam 208 (R = H) in good yield. Depending on the nature of the protecting group installed at the secondary hydroxyl in 208 (R = Ac, TIPS), the next step, the Pictet−Spengler reaction, occurring via Nacyliminium cyclization, supplied either lactam 209 (R = Ac) produced with a 3:1 diastereomer ratio or diastereomer 210, obtained with a 9:1 diastereomer ratio (Chart 25). To achieve the dextrorotatory natural product, the minor isomer 209 (R = TIPS), accompanying lactam 210, was isolated and subjected to a sequence of reactions: Wacker oxidation gave ketolactam 211, which on LiAlH4/AlCl3 reduction and Swern oxidation afforded diketo derivative 213 via diol 212. Final intramolecular aldol cyclization completed the synthesis of the natural (+)-demethoxyerythratidinone (186) (Scheme 23). S


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Chart 25

Enantiomeric (−)-ent-(186) was prepared from lactam 210 following the same sequence of transformations.

Chart 26

Scheme 23. Stereoselective Synthesis of (+)-Demethoxyerythratidinone (186) Using Chiral Lactam 209

cyclic hemiacetals, e.g., 217, which by intramolecular Cannizarro reaction followed by decarboxylation and subsequent hydrolysis of N-formyl derivative afforded β-amino alcohols 218 (R = Ph, Me). IBX oxidation gave N-formyl aldehyde 219 (R = Ph, Me, CCPh). The utility of these synthons has been demonstrated, e.g., in the synthesis of (+)-6-methoxysalsoline-1-carboxylic acid (220) and its 1-phenyl analogue 221. The synthesis started with hemiacetals 217 (R = Me) and 217 (R = Ph), respectively, which when subjected to Dess−Martin oxidation and hydrolysis in acidic solution were transformed into the salsoline-derived carboxylic acid 220 and 1-phenyl derivative 221, respectively, in satisfactory overall yields (Chart 26). Recently, in a continuation of their earlier investigations, the authors78 performed the asymmetric synthesis of (−)-erysotramidine (229), an unnatural erythrina alkaloid. The synthesis, illustrated in Scheme 25, began with the known L-tartaric acidderived imide 207 to which Grignard reagent 222 was added to afford tricyclic compound 223 via O-protecting groups exchange and BF3·Et2O-induced cyclization. AgNO3-promoted cyclization of 223 resulted in tetracyclic 224, and after reduction of the double bond, removal of the secondary hydroxyl group, and Odeprotection it afforded alcohol 225 as an enantiomerically pure compound. Swern oxidation and reaction with iodomethylene ylide of the intermediate aldehyde supplied (Z)-iodoolefin 226, which on treatment with TESOTf/TEA led to the elimination product 227. This product subjected to Heck cyclization and Omethylation supplied (−)-erysotramidine (229) via alcohol 228, thus completing the asymmetric synthesis of this alkaloid (Scheme 25).

Kałuża and co-workers75−78 conducted detailed studies on stereoselective synthesis of various tetrahydroisoquinoline derivatives with a quaternary C-1 stereogenic center, frequently present in a variety of natural products, and used C-10bsubstituted hexahydropyrroloisoquinolines, type 215, as key intermediates. A series of compounds 215 (R = alkyl, phenyl, alkynyl, vinyl) has been prepared from imide 207, derived from β-3,4-dimethoxyphenylethylamine and L-tartaric acid, upon treatment with the corresponding Grignard reagents. This process involved a one-pot N-acyliminium cyclization of intermediate lactams 214 to give pyrroloisoquinolines 215 (Scheme 24). Pyrroloisoquinolines 215 were produced in high yield and with high diastereoselectivity where the (10bS)/(10bR) ratio was dependent on the size of the R substituent and reaction conditions applied. The isomers were separated and used as building blocks for the syntheses of various tetrahydroisoquinoline derivatives. Palladium-catalyzed cyclization of diasteromeric mixture of 215 (R = CCPh) gave dihydrofuran derivative 216, isolated as a single (10bS) isomer in 82% yield (Chart 26). Glycolic cleavage of pyrroloisoquinolines 215 led to a mixture of

Scheme 24. Stereoselective Synthesis of Pyrroloisoquinoline Derivatives 215 with a Quaternary C-10b Stereocenter Using LTartaric Acid-Derived Imide 207 as a Substrate

T


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Scheme 25. Stereoselective Synthesis of (−)-Erysotramidine (229) Using L-Tartaric Acid-Derived Imide 207 as a Substrate

Chart 27

Scheme 26. Short Stereoselective Synthesis of Spirocyclic Skeleton (S,S)-233 of (+)-Erysotramidine (ent-229) from Chiral Keto Ester (S,S)-234

In their study Simpkins et al.79 prepared natural (+)-erysotramidine (ent-229) by a strategy in which the crucial point was based on desymmetrization of intermediate imide 230 taking place during C-silylation to give 231, carried out under the action of chiral base 232. Addition of Grignard reagent, pent-4enylmagnesium bromide, to 231 followed by Pictet−Spengler cyclization and retro-Diels−Alder reaction gave hydroxy lactam 233, which was converted to the alkaloid according to the known procedure (Chart 27). A short and efficient synthesis of the spirocyclic skeleton (S,S)233 of (+)-erysotramidine (ent-229) has been developed by Tietze et al.,80 who chose 3,4-dimethoxyphenylethylamine and keto ester (S,S)-234 as substrates for a domino-type reaction. Racemic keto ester 234 was prepared from cyclohexenone by stepwise addition of bis(dimethylphenylsilyl)zinc and ethyl bromoacetate and easily resolved by chiral HPLC to the (S,S)234 and (R,R)-234 with ≥99% ee. Reaction of (S,S)-234 with

3,4-dimethoxyphenylethylamine in the presence of AlMe3/ indium triflate led straightforward to the spirocyclic core 235 in a domino process that consisted of amidation, spirocyclization, iminium ion formation, and intramolecular Pictet−Spenglertype cyclization. For substitution of the silyl group by a hydroxyl group in the so prepared (S,S)-235, the Tamao−Fleming method was applied under microwave conditions to give the spirocyclic alcohol 233, the precursor of (+)-erysotramidine (ent-229), as a 9:1 mixture of epimers (Scheme 26). Commercially available chiral keto carboxylic acid 237 has been used by Goff81 as a synthon for construction of the C-1 stereogenic center of tetrahydroisoquinoline-containing azaspirocycles 239, a structural motif found in many naturally occurring alkaloids. The synthesis began with acid-catalyzed condensation between 3,4-dimethoxyphenylethylamine or phenethyl amines 236a,b and keto acid 237 to produce the corresponding enantiopure tetracyclic products 239 in two steps. U


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Chart 28

Scheme 27. Synthesis of Diasteromers of Norcryptostyline II (245) and (R)-246 by Galactosylatiof of Imines 240, 243, and Pictet− Spengler Cyclization

Scheme 28. Diastereoselective Total Synthesis of epi-Elwesine (251) using (S)-Phenylalaninol-Derived Amino Ether 248 as a Chiral Intermediate

(245), produced as a 65:35 mixture of enantiomers, with prevailing dextrorotatory isomer with (R) configuration, while isoquinoline (R)-246 was obtained from 244 in quantitative yield and in enantiomerically pure form (Scheme 27). The first asymmetric total synthesis of epi-elwesine (251), the natural product belonging to the family of crinane alkaloids, has been reported by French reserchers.83 The synthesis relied on the Pictet−Spengler reaction of azabicyclo[4.3.0]nonene 249 prepared in 6 steps from 1,3-cyclohexadione through olefin 247 and amine 248, which under the action of n-BuLi underwent hydroamination to form 249. Introduction of the hydroxyl group at C-3 occurred through oxy-mercuration to give alcohol 250, which on the second Pictet−Spengler reaction with formaldehyde afforded enantiomerically pure epi-elwesine (251) (Scheme 28). Another crinine-type alkaloid, (+)-amabiline (257) has been synthesized by Findlay and Banwell.84 The reaction between two

The condensation process involved acyliminium ion cyclization of intermediate hemiacetals, type 238, and acid-catalyzed cyclization to give tetracyclic nitro derivatives 239 (Chart 28). A stereoselective synthesis of 1-substituted tetrahydroisoquinoline via in situ activation/stereodifferentiation of the Pictet− Spengler imines by N-glycosylation has been described by Allef and Kunz.82 Several tetrahydroisoquinoline derivatives substituted at the C-1 by aryl (phenyl, 3,4-dimethoxyphenyl), benzyl, and other groups have been prepared, offering products in various yield and different diastereoselectivity. When for the synthesis of norcryptostyline II (245) imine 240 was used and subjected to the AgOTf-catalyzed cyclization in the presence of D-galactosyl bromide 241, isoquinoline 242 was formed yet in poor yield (27%) and low diastereoselectivity (36% de). On the other hand, imine 243 under the same reaction conditions afforded 244 in higher yield (74%) and with 98% de. Removal of the carbohydrate auxiliary in 242 led to norcryptostyline II V


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Scheme 29. Stereoselective Synthesis of (+)-Amabiline (257) Using Bioenzymatically Prepared Cyclohexene Derivative 252 as a Substrate

Scheme 30. Total Stereoselective Synthesis of Marine Alkaloids Schulzeine B (270) and Schulzeine C (271) with Coupling of Benzo[a]quinolizidine Subunit 265 with Carboxylic Acid 266 as the Key Step

building blocks, the known cyclohexene derivative 252 and boronic acid 253, afforded substitution product 254, which was converted into azide 255 by addition of the N,N-dimethylacetamide dimethyl acetal, reduction of the amide function to the primary alcohol, and conversion into azide 255 via intermediate

iodide. Azide 255 exposed to a Staundinger reaction underwent simultaneous cyclization to give indole derivative 256. Pictet− Spengler reaction with formaldehyde and reduction of the double bond and O-deprotection led to the target alkaloid 257 in 15 steps (Scheme 29). W


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Chart 29

Chart 30

Scheme 31. Preparation of Advanced Intermediate 286 for the Synthesis of (−)-Pancracine (287) Using Chiral Cyclohexene Derivative 280 as a Building Block

Diastereoselective synthesis of tetrahydroisoquinoline derivatives using chiral aldehydes as the components of the Pictet− Spengler reaction has not been often explored. Liu and Romo85 applied masked chiral aldehyde 259, derived from (R)-trichloromethyl-β-lactone 258, and O,O-dibenzyl catecholamine 260 to prepare isoquinoline building blocks 261 (R = H) and 262 in the total synthesis of marine alkaloids, schulzeines B (270) and C (271). The diastereomeric isoquinolines 261 (R = H) and 262 were obtained as ∼1:1

mixture of diastereomers. They were easily separated by chromatography, and the N-Boc-protected isoquinoline 261 (R = Boc), with stereochemistry required for the synthesis of schulzeine B (270), was subjected to the Corey−Link reaction to give azido acid 263. It was directly transformed to the tricyclic derivative 264 by N-Boc deprotection and lactamization (Scheme 30). Selective reduction of the azide group in 264 afforded the primary amine 265, which was coupled with carboxylic acid 266, prepared by condensation of allyl bromide X


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Scheme 32. Enantioselective Synthesis of Pentacyclic Core 295 of (−)-Pancracine (287) Starting with Proline 290-Catalyzed Addition of Cyclohexadione Derivative 288 to Nitrostyrene 289

characterized by a 5,11-methanomorphanthridine framework 279, has been reported by Hashimoto et al.89 (Scheme 31). To assemble the characteristic pentacyclic carbon skeleton 286 of this class of natural products, the synthesis began with optically active β-aminocyclohexene silyl ether 280, which on Nalkylation with 1-(bromoacetyl)-3,4-methylenedioxybenzene 281 provided the N,N-disubstituted β-amino silyl enol ether 282. Intermolecular Mukaiyama aldol reaction and subsequent dehydration provided optically pure bicyclic enone 283, which under Huthins’ reaction of tosylhydrazone 284 and NaBH3CN reduction provided alkene 285 as a major product with the desired regio- and stereochemistry. Finally, removal of the pNs group followed by the intermolecular Pictet−Spengler synthesis, using a CH2O/HCOOH reagents system, furnished the pentacyclic framework 286 with satisfactory overall yield. Another approach to the formal total synthesis of (−)-pancracine (287) has ben developed by Pansare et al.90 in which the pentacyclic enone 295 was prepared as an important intermediate. The synthesis started with γ-nitroketone 291 prepared by chiral addition of 1,4-cyclohexadione monoacetal 288 to nitrostyrene derivative 289 catalyzed by proline derivative 290. Stereoselective reduction of the carbonyl group in 291 using L-selectride afforded axial alcohol 292, which after Mitsunobu epimerization, reduction, and O-mesylation directly provided cisoctahydroindole 293 as a single diastereomer. Pictet−Spengler cyclization using formaldehyde led to the pentacyclic framework 294, which when subjected to DDQ oxidation provided enone 295 (Scheme 32). A synthesis of another montanine-type alkaloid, (+)-brunsvigine (301), has been reported by Banwell et al.91 Starting with chiral highly functionalized cyclohexene derivative 297 (X = Cl, Br), prepared from 1,2-dihydrocatechol in a multistep synthesis and aryl acetic acid derivative 296, the condensation product 298 was obtained as a 1:1 mixture of diastereomers. 298 (X = Cl) was then transformed into hexahydroindole lactam 299 (60%) by cleavage of the thiophenyl group and radical cyclization/halide elimination. After reduction of the amide carbonyl and several protecting groups exchange, amine 300 was obtained and subjected to intermolecular Pictet−Spengler condensation using CH2O/HCOOH as the aldehyde component, providing (+)-brunsvigine (301) after cleavage of cyclic carbonate (Scheme 33).

267 with methylacetoacetate (268), to introduce the side chain of the alkaloid. The synthesis of schulzeine B (270) was completed by cleavage of TES and benzyl protecting groups followed by sulfonation (SO3·pyridine complex) of the intermediate triol 269 to supply the alkaloid 270 of high purity. Schulzeine C (271) was synthesized from the diastereomeric isoquinoline 262 following the same reaction pathway. Another synthetic approach to schulzeines A (274), B (270), and C (271) has been applied by Bowen and Wardrop.86 The key 3-aminobenzo[a]quinolizidine subunit 265 was prepared from glutamate-derived β-arylethylamine 272 in a series of transformations involving oxidation of the primary hydroxyl group and Pictet−Spengler condensation of the intermediate aldehyde. Tetrahydroisoquinoline 265 was obtained as a mixture of cis/ trans diastereomers. They were separated by chromatography, and each one was used for the synthesis of the target alkaloids. (3S,11bR)-trans-265 isomer, after coupling with fatty acid 273 (R1 = Me, R2 = H), was converted into schulzeine A (274) and schulzeine C (271) using acid 273 (R1 = R2 = H), while (3S,11bS)-cis-265 and acid 273 (R1 = R2 = H) were used for the synthesis of schulzeine B (270). Syntheses of the alkaloids were completed by Sharpless dihydroxylation and persulfation (Chart 29). In a model study toward the tricyclic core of schulzeines, Kuntiyong et al.87 synthesized a methoxy analogue 278 of the key tetrahydroisoquinoline fragment 265. Thus, acylation of 3,5dimethoxyphenylethylamine with benzyl L-glutamate led to the formation of amide 275. Suprisingly, LAH reduction of 275 led straightforward to imide 276, apparently resulting from abstraction of the amide’s proton from nitrogen and subsequent attack to the benzyl ester carbonyl. DIBAL reduction afforded hydroxy lactam 277, which in intramolecular Pictet−Spengler cyclization led to the tricyclic core 278 as a 1:1.7 mixture of cis/ trans diastereomers. After N-deprotection they could be separated by chromatography via N-benzoyl derivatives (Chart 30). Synthetic approaches to schulzeine core have been reviewed by Morris and Phillips.88 Asymmetric synthesis of advanced intermediate 286 in the synthesis of (−)-pancracine (287), an alkaloid belonging to a small class of montanine-type amaryllidaceae natural products, Y


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Scheme 33. Diastereoselective Synthesis of (+)-Brunsvigine (301) Using Chiral Cyclohexene Derivative 297 as a Building Block

Scheme 34. Enantioselective Synthesis of Pentacyclic System 307, the Key Intermediate in Synthesis of Several Montanine-Type Amaryllidaceae Alkaloids

Enantioselective total synthesis of several montanine-type Amaryllidaceae alkaloids has been performed by Fan and coworkers.92 Following the biosynthetic pathway in which cherylline-type intermediate 306 was postulated, the synthesis began with a rhodium-catalyzed asymmetric conjugate addition of boronic acid 253 to nitrostyrene derivative 302, carried out in the presence of chiral ligand 303. The desired adduct 304 was obtained in high yield and with 95% ee. Reduction of the nitro group, O-desilylation, and introduction of COOEt groups on nitrogen and oxygen afforded carbamate 305, obtained as an enantiomerically pure compound. Intermolecular Pictet− Spengler cyclization using (CH2O)n/CF3COOH and removal of the protecting group gave the cherylline-type precursor 306. Next, a tandem process involving dearomatization and intramolecular aza-Michael addition afforded exclusively the pentacyclic core 307 with the desired regio- and stereochemistry (Scheme 34). Finally, the pentacyclic compound 307, comprising the basic framework of the montanine alkaloids, has been used as the key intermediate for the synthesis of several alkaloids, applying DIBAL reduction of the C-3 carbonyl group and further reduction of the C-2 ketal moiety, as shown in Scheme 35. The diastereoselective reduction of 307 led to diastereomeric products 308 and 309, which were separated and transformed

into two series of alkaloids differing in configuration at C-3 and C-2. (−)-Brunsvigine (ent-301) and its (−)-2-epimer 310 and (−)-manthidine (311) and its (−)-2-epimer 312 were obtained from intermediate 308, while (−)-cocinine (313), (−)-montanine (314), and (−)-pancracine (287) were prepared using diastereomer 309. Ku and Cuny93 performed a diastereoselective synthesis of 7oxygenated aporphine alkaloids, (−)-nornuciferidine (319), (−)-noroliveroline (320), (−)-oliveroline (321), and their analogues from a common precursor 318 (Scheme 36). Reaction between β-arylethylamine 315, (S)-(+)-2-chloromandelic acid methyl ester, and CDI afforded carbamate 316, which was transformed into oxazolidinone 317 via intermediate aldehyde (DIBAL reduction) and BF3·Et2O-mediated cyclization. The biaryl linkage in the prevailing anti-oxazolidinone 317 was constructed using XPhos precatalyst to give the pentacycle 318, transformed to the alkaloids (−)-nornuciferidine (319) by alkaline hydrolysis of the oxazolidinone ring. Alkaloids with methylenedioxy substituent in ring A (−)-noroliveroline (320) and (−)-oliveroline (321) were obtained from 318 by Odemethylation, 1,3-dioxole ring formation, and hydrolysis. Total synthesis of 7-deoxypancratistatin-1-carboxaldehyde 327 and carboxylic acid 328 has been reported by Hudlicky et al.94 The synthesis started with homochiral epoxy aziridine 322 Z


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Scheme 35. Synthesis of Montanine-Type Alkaloids 287, 301, and 310−314 Using Pentacyclic System 307 as an Advanced Intermediate

Scheme 36. Stereoselective Synthesis of Aporphine Alkaloids, (−)-Nornuciferidine (319), (−)-Noroliveroline (320), and (−)-Oliveroline (321) Using (S)-(+)-2-Chloromandelic Acid Methyl Ester as a Chiral Substrate

in which selective oxirane ring opening using the alkyne 323/nBuli, Me2AlCl system afforded addition product 324. Partial reduction of the triple bond and silica gel-catalyzed solvent-free cyclization followed by aziridine ring opening led to phenanthrene skeleton in 325. Oxidative cleavage of the double bond in 325 with simultaneous intramolecular cyclization led to hemiaminal 326. Further oxidation using IBX provided amide 327, in which the aldehyde function was oxidized to supply the carboxylic acid 328 (Scheme 37). Recently, catalytic enantioselective Pictet−Spengler reaction has been proposed to supply chiral tetrahydroisoquinoline

derivatives with the use of a chiral catalytic system, including organocatalysis. In a model study, Toda and Terada95 investigated intramolecular Pictet−Spengler cyclization of allylamides type 329 (R = Boc, P(O)Ph2; R1 = H, MeO; R2, R3 = H, Me) via isomeric enamines obtained by action of a binary catalytic system consisting of ruthenium hydride complex [RuClH(CO)(PPh3)3] and chiral phosphoric acid 330 (G = 9-anthryl). Several parameters of the process, which involved double bond isomerization, protonation, and cyclization of intermediate imine, have been investigated, and in the optimized reaction conditions tetrahydroisoquinolines of type 331 were produced AA


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Scheme 37. Stereoselective Synthesis of 7-Deoxypancratistatin-1-carboxaldehyde 327 and Carboxylic Acid 328 Using Epoxy Aziridine 322 as a Chiral Substrate

Scheme 38. Enantioselective Synthesis of 1-Substituted Tetrahydroisoquinoline 331 by Intramolecular Pictet−Spengler Reaction Catalyzed by Chiral Phosphoric Acid 330

Scheme 39. Preparation of Benzo[a]quinolizidines 335 and 336 in One-Pot Two-Step Organocatalytic Reaction Promoted by Proline Derivative 334

(89−98% ee) and diastereomeric ratio (62:38−83:17) (Scheme 39). The steric course of the synthesis, which led to major products with (2R) configuration, was postulated to arise from initially formed iminium ion 337 in which the re face was shielded by the proline bulky substituent, leaving the si face open for the conjugate addition of the β-arylethylamide followed by Pictet− Spengler cyclization of acyliminium ion 338. An organocatalytic enantioselective Pictet−Spengler approach to 1-substituted 1,2,3,4-tetrahydroisoquinoline alkaloids and congeners has been studied in the laboratory of Hiemstra.97,98 Part of their investigations was aimed at establishing factors

and isolated in good yield (50−87%) but with poor enantioselectivity (18−53% ee) (Scheme 38). In another model study, a short, efficient, one-pot, two-step synthesis of the benzo[a]quinolizidine system, present in a large number of naturally occurring alkaloids, has been developed by Franzen and Fisher.96 It relied on organocatalytic conjugate addition of α,β-unsaturated aldehydes to arylethylamide. Thus, reaction of amide 332 with cinnamic aldehydes 333 (R = H, NO2, OMe, OAc, Br), catalyzed by proline derivative 334, afforded a mixture of diastereomeric quinolizidines 335 and 336, obtained in good yield (53−71%) with high enantioselectivity AB


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Scheme 40. Organocatalytic Enantioselective Synthesis of Several 1-Substituted Isoquinoline Alkaloids Applying Pictet−Spengler Cyclization Catalyzed by (R)-TRIP 341

Scheme 41. Enantioselective Synthesis of 1-Benzyl-1,2,3,4-tetrahydroisoquinoline Alkaloids 350 by Pictet−Spengler Cyclization Catalyzed by (R)-TRIP 341/BINOL System

Table 2. Alkaloids 351−363 Synthesized from 350

a

entry

alkaloid

R1

R2

R3

R4

R5

R6

yield (%)

ee (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

(R)-norcoclaurine (351) (R)-coclaurine (352) (R)-norreticuline (353) (R)-reticuline (354) (R)-trimetoquinol (355) (R)-norarmepavine (356) (R)-armepavine (357) (R)-norprotosinomenine (358) (R)-protosinomenine (359) (R)-norlaudanosine (360) (R)-laudanosine (361) (R)-nor-5-methoxylaudanosine (362) (R)-5-methoxylaudanosine (363)

H H OH OH OMe H H OH OH OMe OMe OMe OMe

OH OH OMe OMe OMe OH OH OMe OMe OMe OMe OMe OMe

H H H H OMe H H H H H H OMe OMe

H Me Me Me H Me Me H H Me Me Me Me

H H H H H Me Me Me Me Me Me Me Me

H H H Me H H Me H Me H Me H Me

84 71 75 72 86 89 85 88 65 78 61 81 73

89 89 88 88 99a 85 85 83 83 86 86 99a 98a

After crystallization.

influencing the regio- and stereochemical outcome of the Pictet− Spengler reaction. It was found that the best results were achieved when the N-o-nitrophenylsulfenyl (Nps) substituent was present at the nitrogen in the starting β-arylethylamine, e.g., 339, and the reaction was carried out in the presence of BINOLderived chiral phosphoric acid [(R)-TRIP)] 341 used as the catalyst and (S)-BINOL as a cocatalyst. Aliphatic aldehydes

appeared to be more active then aromatic congeners (Scheme 40). On the basis of the above findings, several isoquinoline alkaloids and congeners have been obtained in high yields and enantioselectivity between 95% and 99%. In the synthesis of (R)(+)-crispine A (177), N-sulphinylamine 339 and tert-butyl 4oxobutanoate 340 (R = CH2CH2CH2COt-Bu) were used, and the Pictet−Spengler product obtained 342 (R = CH2CH2CO2tAC


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Scheme 42. Stereoselective Synthesis of (−)-α-Lycorane (368) from Chiral (S,S)-Aryl Cyclohexanol 365

Bu) was treated with HCl in refluxing toluene to remove the NNps protection. This process was accompanied by cyclization to give lactam 343, which on O-methylation and carbonyl reduction furnished (R)-(+)-crispine A (177). For the synthesis of (R)-(−)-calycotomine (344), phenylethylamine 339 and acetoxyacetaldehyde were selected and the isoquinoline 342 (R= CH2OCOCH 3) so obtained was converted into (R)-(−)-calycotomine (344) after protecting groups manipulation. (R)-(+)-Colchietine (345) and (R)(+)-almorexant precursor 346 were prepared from 339 and the corresponding arylacetaldehydes 340 (R = CH2CH2C6H4OMe) and 340 (R = CH2CH2C6H4CF3), respectively, via the corresponding tetrahydroisoquinolines 342 (R = p-methoxyphenylethyl) and 342 (R = p-trifluoromethylphenylethyl), respectively. (S)-(+)-AMPA-antagonist 347, was prepared from tetrahydroisoquinoline 342 (R = p-chlorophenyl) by Omethylation, N-Nps deprotection, and N-acetylation (Scheme 40). In another series of experiments, several biologically and pharmaceutically important alkaloids have been synthesized according to the strategy outlined above, starting with dopaminederived arylethylamine 348 and arylacetaldehydes 349, affording in one-step tetrahydroisoquinolines 350 in yields of 70−80% and with ee’s of 86−92% (Scheme 41). They were then transformed into the several alkaloids 351−363 in yields of 61−89% and with ee’s of 83−99% by standard exchange of functional and protecting groups (Table 2). A synthesis of (−)-α-lycorane (368) and (+)-γ-lycorane (372), the basic pentacyclic core of lycorane-type Amaryllidaceae alkaloids, has been performed by Chinese chemists.99,100 The synthesis of (−)-α-lycorane (368)99 started with chiral nonracemic (S,S)-aryl cyclohexanol 365, prepared with cis-selectivity by asymmetric hydrogenation of the corresponding cyclohexanone acetal using Ru-catalyst-type 364. Mitsunobu reaction of 365 using diphenylphosphoryl azide followed by hydrogenation led to amine 366, which on Pictet−Spengler reaction with formaldehyde afforded tetrahydroisoquinoline 367. NAcetylation with bromoacetic acid chloride of 367 and t-BuOKinduced cyclization followed by reduction of carbonyl groups led to (−)-α-lycorane (368) in 19.6% overall yield over 13 steps (Scheme 42). A different approach has been applied by the authors100 for the synthesis of (+)-γ-lycorane (372). The key intermediate was cis/ cis diol 370. It was prepared from racemic keto ester 369 by asymmetric hydrogenation using Ru-catalyst-type 364. Swern oxidation of diol 370 afforded keto aldehyde 371 (93% yield, 99.9% ee), which in Pictet−Spengler reaction conditions/

NaBH(OAc)3 underwent double cyclization to supply (+)-γlycorane (372) in 45% overall yield in 8 steps (Scheme 43). Scheme 43. Stereoselective Synthesis of (+)-γ-Lycorane (372) Using cis/cis-Diol 370 as Advanced Starting Material

A biocatalytic way to tetrahydroisoquinolines using Pictet− Spengler condensation has also been attempted and is described in section 6.

3. BISCHLER−NAPIERALSKI CYCLIZATION/REDUCTION In the asymmetric synthesis of isoquinoline alkaloids, the closing of the nitrogen-containing ring by generation of the C8a−C1 bond has most frequently been performed by the Bischler− Napieralski cyclization followed by stereoselective reduction. In the first step of this synthesis, cyclization of N-acyl βarylethylamine leads to 1-substituted 3,4-dihydroisoquinoline or a corresponding isoquinolinium salt, which, in the second step, is reduced to the 1,2,3,4-tetrahydroisoquinoline derivative (Scheme 44). In the stereoselective synthesis a stereogenic center at C-1 (R1 = alkyl, aryl) is generated during the reduction process, which is performed either in diastereoselective or in enantioselective synthesis. 3.1. Diastereoselective Synthesis

To control the steric outcome of the diastereoselective synthesis a chiral auxiliary-based strategy is employed in most cases. The auxiliary is placed either in the β-arylethyl amine moiety or at the N-acyl group. Hydride reduction or catalytic hydrogenation of chiral intermediates, the 1-substituted 3,4-dihydroisoquinolines or the corresponding 3,4-dihydroisoquinolinium salts, has been AD


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Napieralski cyclization followed by NaBH4 reduction of amides (S)-383 and (R)-383 gave amines 384, respectively, with 95% de, favoring S,S and R,R diastereomers. Catalytic hydrogenolysis of (S,S)-384 and (R,R)-384 afforded both enantiomers of Nnorlaudanidine (385 and ent-385), isolated as optically pure compounds after crystallization (Chart 32). Conversion of (S)-norlaudanidine (385) into (S)-corytenchine (386)103 was effected almost quantitatively through Ndeprotected (S)-384 and its N-formylation, followed by cyclization and NaBH3CN/acetic acid reduction in acetonitrile. Reduction using NaBH4 in methanol afforded a 7:3 mixture of (S)-corytenchine (386) and (S)-tetrahydropalmatrubine (387), from which both alkaloids were separated by preparative TLC. Benzylisoquinoline 388 (R = H), the bromo derivative of the known N-deprotected benzylisoquinoline (S)-384, has been used by Liu et al.104 for the synthesis of (S)-isocorydine (390) (R1 = H), an aporphine alkaloid. After Pd(OAc)2-catalyzed C−C coupling of N-methylated 388 (R = Me) the tetracyclic alkaloid’s core 389 was formed, in which cleavage of the benzyl ether completed the synthesis (Scheme 45). A convergent diastereoselective total synthesis of (S)(−)-stepholidine (394) has been described by Yang and coworkers105 (Scheme 46). The synthesis was based on the PEAassisted Bischler−Napieralski cyclization/reduction of amide 391 bearing a bromine atom at position 2 of the benzyl substituent to give tetrahydroisoquinoline 392, isolated as a single isomer after crystallization. Further transformations of 392 involving exchange of bromine for ester group and removal of the chiral auxiliary, which was accompanied by cyclization, afforded lactam 393, easily reduced and O-deprotected to give stepholidine (394) with 99% ee. An original approach to the synthesis of (S)-O-methylthalibrine (398), (S)-armepavine (ent-357), and (S)-O-methylarmepavine (399) has been undertaken by Nishiyama et al.106 By employing a stereocontrolled Bischler−Napieralski cyclization/ reduction methodology to the coupling product of the electrochemically prepared dicarboxylic acid 395 and two molecules of chiral amine 396, bisisoquinoline 397 was obtained (Scheme 47). After N-debenzylation of 397 and one-pot

Scheme 44. Mechanism of Bischler−Napieralski Cyclization/ ReductionSynthesis of 1,2,3,4-Tetrahydroisoquinoline Derivatives

found to give satisfactory to excellent yields of the tetrahydroisoquinoline products. Rodrigues et al.101 developed a new highly diastereoselective synthesis of cularine alkaloids, (+)-O-demethylcularine (376), (+)-cularine (377), (+)-sarcocapnine (378), (+)-sarcocapnidine (379) and their biosynthetic precursor, (+)-crassifoline (380), using chiral iminium salts (e.g., 373 or 374) as substrates (Chart 31). NaBH4 reduction of these chiral iminium salts, prepared from the corresponding 3,4-dihydroisoquinolines and (+)-8phenylmenthyl chloroacetate followed by phenolic coupling, led directly to the cularine alkaloids in high yield and with excellent enantiomeric excess (88−99% ee). Interestingly, during the reduction process, N-methylation occurred, due to simultaneous cleavage of the chiral auxiliary and reduction of the iminium species type 375. Georghiou et al.102,103 employed (S)- and (R)-α-methylbenzylamines 381 and acid chloride 382 for the synthesis of (S)and (R)-N-norlaudanidine (385 and ent-385), a minor opium alkaloid, which was further transformed into tetrahydroprotoberberine alkaloids: (S)-corytenchine (386) and (S)-tetrahydropalmatrubine (387). In this synthesis, the key intermediates, amides (S)-383 and (R)-383, were prepared from chiral amines (S)-381 and (R)-381 and acid chloride 382, which in turn both were synthesized from isovaniline in seven steps and five steps, respectively. Bischler− Chart 31

AE


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Chart 32

borohydride reduction resulted in direct and highly diastereoselective cyclization via intermediate acyliminium ion 401 to give tricyclic lactam (5S,10bR)-192, obtained as a single diastereoisomer. The synthesis was completed by oxidative removal of the hydroxymethyl side chain in (5S,10bR)-192 employing IBX oxidation/Rh-induced decarbonylation and final reduction of amide carbonyl. (R)-Crispine A (177) was obtained in 24% overall yield and with 95% ee (Scheme 48). A synthetic strategy in which glutamic acid was used both as a chiral auxiliary and as a chiral building block for construction of the tetrahydroisoquinoline moieties of schulzeines B (270) and C (271) has been reported by Gurjar et al.108 The key step of the synthesis was the Bischler−Napieralski reaction of amide 403, prepared from amine 260 and glutamic acid derivative 402. Hydride reduction of the cyclization product 404 followed by a second cyclization led to epimeric tricyclic derivatives cis-405 and trans-405 (2:3), which were separated by column chromatography, and each of them supplied amines cis265 and trans-265, respectively (Scheme 49).

Scheme 45. Synthesis of (S)-Isocorydine (390) by Pd(OAc)2Catalyzed C−C Coupling of 1-Benzyl Isoquinoline 388

reductive methylation, the desired (S)-O-methylthalibrine (398) was produced. Cleavage of the aryl ether in the alkaloid by Birch reduction led to (S)-armepavine (ent-357) and (S)-O-methylarmepavine (399), both showing 93:7 S/R ratio. In Allin’s107 synthesis of (R)-crispine A (177), enantiomerically pure imide 400, prepared from (2S)-2-amino-3-(3,4dimethoxyphenyl)propan-1-ol (181) and succinic anhydride, was used as the substrate. Subjecting imide 400 to sodium

Scheme 46. Diastereoselective Synthesis of (S)-(−)-Stepholidine (394) via Chiral 1-Benzyl-tetrahydroisoquinoline 392

AF


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Scheme 47. Diastereoselective Synthesis of Alkaloids 398, 357, and 399 Using Diaryl Ether 395 and Chiral β-Aryl Ethyl Amine 396 as Substrates

Scheme 48. Diastereoselective Synthesis of (R)-Crispine A (177) Using Imide Alcohol 400 as a Substrate

Scheme 49. Preparation of Isoquinoline Fragments cis-265 and trans-265 of Schulzeines B (270) and C (271) Using Glutamic Acid 402 as a Chiral Substrate

Scheme 50. Preparation of Fatty Acid Side Chain 408 of Schulzeines B (270) and C (271)

Naphthyltetrahydroisoquinoline alkaloids atropisomeric korupensamine A (416) and korupensamine B (ent-416) have been synthesized by Uemura et al.109 using biaryl chromium complexes 412 and ent-412, respectively, as building blocks (Scheme 52). Axially chiral chromium complex 412 was acquired by stereoselective Pd(0)-mediated cross-coupling of chiral benzaldehyde tricarbonyl chromium complex 410 with naphthyl boronic acid 411 to give the syn product 412 with axial stereochemistry corresponding to that of korupensamine A (416). Treatment of 412 with α-ethoxy vinyllithium followed by hydrolysis gave a hydroxy ketone 413 of 99:1 dr. The hydroxy ketone functionality was then converted into α-methylethylamine side chain in eight standard chemical operations to give primary amine 414. It was N-acetylated and subjected to the Bischler−Napieralski cyclization/reduction process to give

For the synthesis of schulzeines B (270) and C (271) the fatty acid side chain 408 was needed. It was prepared by Horner− Wadsworth−Emmons reaction between two fragments: 406 and 407 in a multistep reaction sequence using known chemistry (Scheme 50). Coupling of the tricyclic units cis-265 and trans-265 with the side chain 408 led to tetrahydroisoquinolines (11bS)-409 and (11bR)-409, respectively, precursors of schulzeines B (270) and C (271). The latter ones after O-deprotection and persulfation completed the synthesis of the alkaloids (Scheme 51). AG


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Scheme 51. Total Synthesis of Schulzeines B (270) and C (271) by Coupling of Acid Side Chain 408 with cis- and transBenzo[a]quinolizidines 265

Scheme 52. Stereoselective Synthesis of Atropisomeric Naphthyltetrahydroisoquinoline Alkaloids Korupensamine A (416) and Korupensamine B (ent-416) Employing Chiral Chromium Complex 410 as a Substrate

tetrahydroisoquinoline 415. Removal of O-protecting groups in 415 furnished the synthesis of the alkaloid korupensamine A (416). Similarly, the more stable anti-biaryl chromium complex ent-412, which was achieved by isomerization of the syn-isomer 412, was converted to korupensamine B (ent-416) according to the same reactions sequence.

Another approach to asymmetric total synthesis of korumpensamine B (ent-416) described by Lipshutz et al.110 involved Bischler−Napieralski cyclization of formamide 419, prepared in 3 steps from known (R)-TIPS-glycidol 417 via protected alcohol 418 to give the tetrahydroisoquinoline 420 with trans diastereoselectivity (20:1). N-Sulfonylation and subsequent AH


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Scheme 53. Stereoselective Synthesis of Korupensamine B (ent-416) Using Diol 418 as a Chiral Compound

Scheme 54. Total Stereoselective Synthesis of Ancistrocladidine (431) Using Chiral Biaryl Amine 430 as an Advanced Intermediate

Buchwald−Hartwig N-alkylation of (S)-1-aryl-2-aminopropane 434. Amine 434, prepared from L-alaninol-derived aziridine 432 and Grignard reagent 433, was reacted with bromonaphthalene derivatives 435 or 436 to supply amines 437 or 438, respectively. Bischler−Napieralski cyclization of N-acylated amines 437 or 438 afforded the target alkaloids, ancistrocladinium A (439) as a 2.5:1 mixture of atropdiastereomers in 43% overall yield, or ancistrocladinium B (440) as a 46:54 mixture of isomers (Scheme 55, only the main atropdiastereomers are shown). The Bischler−Napieralski ester methodology has been commonly applied for the construction of the AB-isocarbostiril fragment of pancratistatin-type alkaloids of the Amaryllidaceae group and analogues. Alonso et al.113 in the total synthesis of (+)-pancratistatin (448) utilized the enantioselective [3 + 3] annulation of dioxanone 441 with nitroenal 442 in the presence of (R)-2(methoxymethyl)pyrrolidine (443) to obtain the key intermediate 444 with five new stereocenters with 75% ee (99% ee after crystallization). Reduction of the nitro group in 444 and subsequent N-acylation afforded the required (4aR) methylcarbamate 445, which on stereoselective reduction of the keto group and protection group exchange resulted in formation of 446. Intramolecular Bischler−Napieralski reaction of carbamate 446 led to lactam 447, which after cleavage of the methyl ether

regiospecific iodination followed by esterification of the primary alcohol with 1-naphtoic acid provided iodinated derivative 421. Atropdiastereoselective Suzuki−Miyaura biaryl coupling between 421 and boronic acid 422 mediated by the Pd(OAc)2/ SPhos catalytic system afforded the naphthyltetrahydroisoquinoline 423 which after deoxygenation of the two side chains and removal of the N-tosyl group gave korumpensamine B (ent-416), Scheme 53. The first total synthesis of ancistrocladidine (431), a rare 7,3′linked naphthylisoquinoline alkaloid containing 3,4-dihydroisoquinoline unit, has been completed by Bungard and Morris111 (Scheme 54). The synthesis began with biaryl aldehyde 426, obtained by ortho-arylation of naphthol 424 with an aryllead triacetate 425. The formyl group in 426 was used to construct the amine side chain of 430 via allylic alcohol 427, epoxide 428, and secondary alcohol 429. The latter was transformed into amine 430 under Mitsunobu isomerization with phtalimide, setting the (S)-stereochemistry at C-3, which on hydrolysis followed by Nacetylation and Bischler−Napieralski cyclization afforded a 1:1 mixture of ancistrocladidine (431) and its atropisomer, which were separated by crystallization. A key step of Bringmann’s112 total synthesis of ancistrocladinium A (439) and ancistrocladinium B (440), representing N,Ccoupled naphthyldihydroisoquinolinium alkaloids, was based on AI


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Scheme 55. Stereoselective Synthesis of Ancistrocladinium A (439) and Ancistrocladinium B (440) Employing β-Aryl Amine 434 as a Substrate

Scheme 56. Enantioselective Total Synthesis of (+)-Pancratistatin (448) by Proline Derivative 443-Catalyzed Addition of Dioxanone 441 to Nitroenal 442

groups furnished (+)-7-deoxypancratistatin epimer (455) in 15% overall yield (Scheme 57). It should be noticed that intermediate-type 457, an analogue of 452, has earlier been synthesized by Nadein and Kornienko115 from D-xylose via diene 456 by ring-closing metathesis with Grubbs’ catalyst (Chart 33). In the total synthesis of (−)-lycorine (466) and (−)-2-epilycorine (467) accomplished by Tomioka et al.,116 chiral ligand 460 was applied to control asymmetric conjugate addition of aryllithium 458 to Michael acceptor 459, leading to cyclohexane derivative 462. In this step the formation of two C−C bonds and three stereogenic centers occurred in a one-pot cascade via enolate 461. Compound 462 was isolated as a major product with 92% ee enhanced to >99% ee after crystallization. After removal of the TMS substituent compound 462 was converted

and removal of the hydroxyl protecting groups was transformed into (+)-pancratistatin (448) (Scheme 56). Chavan and co-workers114 performed a highly stereocontrolled asymmetric total synthesis of (+)-7-deoxypancratistatin epimer (455) by a multistep synthesis using tricyclic derivative 453 as an advanced intermediate. It was prepared in seven steps from prochiral enone 449 by Sharpless asymmetric dihydroxylation via diol 450 and diene 451. Ring-closing metathesis of 451 affording cyclization product 452, which on reaction with Cl3CCN followed by Overman rearrangement and hydrogenolysis supplied oxazolidinone 453 as a single isomer. It was then converted into amide 454 by dihydroxylation and cleavage of carbamate ring in a process occurring with inversion of configuration at C-10b. Its cyclization according to the Bischler−Napieralski protocol followed by removal of protecting AJ


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Scheme 57. Total Synthesis of (+)-7-Deoxypancratistatin Epimer (455) Using Diol 450 as a Chiral Substrate and Ring-Closing Metathesis as the Key Step

(466) and (−)-2-epi-lycorine (467) through 7- and 8-step syntheses, respectively (Scheme 58). In a similar synthetic strategy (+)-β-lycorane (471) has been synthesized by Tomioka et al.117 in 33% overall yield over only 5 steps using diester 469 as an advanced intermediate. It was prepared by asymmetric conjugate addition of aryllithium 458 to unsaturated diester 468 mediated by chiral ligand 460 (Scheme 59). The nitrogen functionality was introduced by Curtius rearrangement of azide, prepared using diphenylphosphoryl azide (DPPA), of the selectively hydrolyzed ester 469, followed by Bischler−Napieralski cyclization to give lactam 470. Treatment of the latter with BF3·SMe2 in refluxing THF led to βlycorane (471) in one pot, involving three transformations:

Chart 33

to N-Boc amine 463 using standard operations. Hydrolysis of NBoc protection, cyclization to form the pentacyclic ring, and Nethoxy carbonylation aforded carbamate 464. Compound 464 was subjected to a Bischler−Napieralski ester reaction affording lactam 465 and transformed into (−)-lycorine

Scheme 58. Total Synthesis of (−)-Lycorine (466) and (−)-2-epi-Lycorine (467) by Chiral Ligand 460-Catalyzed Addition of Aryllithium 458 to Unsaturated Diester 459

AK


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Scheme 59. Total Synthesis of (+)-β-Lycorane (471) by Chiral Ligand 460-Catalyzed Addition of Aryllithium 458 to Unsaturated Diester 468

Scheme 60. Synthesis of (+)-α-Lycorane (ent-368) and (+)-Lycorine (ent-466) Starting with Addition of di-tert-Butyl Malonate to Nitro Derivative 472 Catalyzed by Organocatalyst 473

cyclization to octahydroindolone 477 (R = H). Bischler− Napieralski reaction of the corresponding uretane 477 (R = COOEt) supplied the desired key intermediate 478. Desulfurization followed by reduction of amide carbonyl afforded (+)-αlycorane (ent-368) in 1.9% overall yield. Hydrolysis of the thioketal group in 478 followed by reduction of the liberated ketone and dehydration of the so formed alcohol supplied the known precursor 479 of (+)-lycorine (ent-466) (Scheme 60). Recently,119 a stereoselective addition of aryl Grignard reagent 480 to Garner’s aldehyde ent-39 furnished a mixture of syn and anti benzylic alcohols 481 and epi-481 (1:6), which were used as substrates for the synthesis of (+)-3-epi-lycoricidine (489). The major epi-481 isomer was then O-benzylated and hydrolyzed to give amino alcohol 482, which via aldehyde 483 prepared by

lactam reduction, lactam formation (between amine and ester group), and its reduction. A Chinese group of chemists118 on a route to (+)-α-lycorane (ent-368) and (+)-lycorine (ent-466) synthesized lactam 478 as a common intermediate for the synthesis of both alkaloids. Its preparation started with asymmetric conjugate addition of ditert-butyl malonate to nitro derivative 472 catalyzed by chiral diamine 473·NiBr2 complex to produce enyne 474 in 91% yield and 93% ee. Treatment of 474 with a catalytic amount of TsOH in refluxing toluene led regioselectively to enone 475, which after esterification underwent intramolecular Michael addition to give enantiomerically enriched cyclohexanone 476 as a single diastereomer. Thioketalization and reduction of the nitro group followed by treatment with sodium methoxide induced AL


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Scheme 61. Stereoselective Synthesis of (+)-3-epi-Lycoricidine (489) Using Chiral Aminodiol 482 as an Advanced Substrate

Scheme 62. Total Synthesis of (+)-trans-Dihydronarciclasine (501) Applying Walphos 495-Catalyzed Nitroso Diels−Alder Reaction

AM


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Scheme 63. Enantioselective Total Synthesis of (−)-7-Deoxy-trans-dihydronarciclasine (510) Employing Nitromethane Addition to Enone 502 Catalyzed by Acid 503 as a Stereocontrolling Step

Scheme 64. Diastereoselective Synthesis of (−)-Quinocarcin (5) via Isoquinoline 516 as the Key Intermediate

Swern oxidation was converted into trans α,β-unsaturated ester 484. Compound 484 was then subjected to Sharpless asymmetric dihydroxylation reaction, giving dihydroxy derivative 485 with enantiomeric excess > 99%. Functional group transformations in 485, among others, ester and hydroxyl groups transformations into diketone 486, which on cyclization by intramolecular aldol condensation, followed by N-protecting group exchange furnished cyclohexenone 487. Bischler− Napieralski ester cyclization to give 488 followed by ether deprotection and reduction supplied (+)-3-epi-lycoricidine (489) in 7% overall yield in 20 steps (Scheme 61). The Bischler−Napieralski ester methodology has been applied by Studer and Jana120 for the construction of isocarbostiril AB fragment (+)-trans-dihydronarciclasine (501), a pancratistatintype alkaloid. The synthesis began with bromide 491 prepared from o-vanillin 490 in 3 steps, which in reaction with Fe-

complexed cyclohexadienyl cation 492 and subsequent decomplexation afforded diene 493. An enantioselective regiodivergent Diels−Alder reaction with 2-nitrosopyridine (494) catalyzed by Walphos (495) led to 496 in 48% yield with >99% ee. Reductive N−O bond cleavage supplied amino alcohol 497, which after dihydroxylation and O-silylation led to persilylated derivative 498. The pyridyl group was then cleaved by quaternization/basic hydrolysis to give urethane 499, which after Bischler− Napieralski reaction led to compound 500 easily O-deprotected into (+)-trans-dihydronarciclasine (501), isolated in 5.6% overall yield, over 17 steps (Scheme 62). In the stereoselective total synthesis of (−)-7-deoxy-transdihydronarciclasine (510) described by Kadas et al.121 the intermediate amino alcohol 506 was synthesized utilizing enantioselective (100%) nitromethane addition to benzylideneacetone 502 carried out in the presence of chiral catalyst 503 AN


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Scheme 65. Enantioselective Synthesis of Protoemetinol (522) and Protoemetine (523) Involving Proline 334-Catalyzed Addition of n-Butanal to Alkylidene Malonate 518 as the Key Stereocontrolling Step

Chart 34

to give nitropentanone 504. Cyclization of 504 to cyclohexanone 505 by aldol condensation with ethyl formate followed by protection of the keto group and reduction of the nitro group gave amino alcohol 506 with 39% overall yield. N-Acylation of 506 followed by deketalization, elimination of water, and stereoselective reduction gave allylic alcohol 507, which under Mitsunobu reaction conditions and subsequent cis-dihydroxylation and acetylation of hydroxyl groups led to urethane 508. Bischler−Napieralski ester cyclization aforded 509 in which removal of the protecting groups completed the synthesis of (−)-7-deoxy-trans-dihydronarciclasine (510) in 13% overall yield in 8 steps (Scheme 63). The key intermediate in the asymmetric total synthesis of (−)-quinocarcin (5), a tetrahydroisoquinoline antitumor antibiotic, reported by Allan and Stoltz,122 the isoquinoline derivative 515, was prepared by the fluoride-induced annulation reaction between silylaryl triflate 514-derived aryne and chiral N-acyl enamide 513. The latter was prepared in 3 steps from oxidopyrazinium betaine 511 and Oppolzer’s sultam acrylamide 512 (Scheme 64). Diastereoselective reduction of the isoquinoline ring systems in 515 was performed in two steps beginning with hydrogenation over Pd catalyst, followed by sodium cyanoborohydride reduction to afford a 3.3:1 mixture of separable tetrahydroisoquinolines 516. The stereochemistry of major diastereomer 516 corresponded to that of the target alkaloid. Further transformations of 516 involving cyclization, N- and O-debenzylation, and N-methylation provided tetracycle 517, which after ester

hydrolysis and closure of the oxazolidine ring was converted into target (−)-quinocarcin (5) in 10% overall yield for 11 steps (Scheme 64). Sun and Ma123 used the Michael reaction of n-butanal with alkylidene malonate 518 catalyzed with O-TMS-protected diphenylprolinol 334 to prepare the chiral intermediate 519 (81.6% ee) for the asymmetric synthesis of protoemetinol (522) and protoemetine (523). A reduction/lactonization/decarboxylation sequence of 519 afforded lactone 520, which was transformed into tricyclic intermediate 521 by condensation with 3,4-dimethoxyphenylethylamine and Bischler−Napieralski cyclization/reduction. Removal of the benzyl protecting group in 521 produced protoemetinol (522), which was oxidized to protoemetine (523) (Scheme 65). 3.2. Catalytic Hydrogenation

Recently, efforts in the field of catalytic enantioselective synthesis of isoquinoline alkaloids according to the Bischler−Napieralski cyclization/reduction approach have focused on the development of transition-metal-catalyzed enantioselective reduction of prochiral isoquinolines under either hydrogenation or transfer hydrogenation conditions. During the past decade a number of new catalytic systems as well as modifications of known ones have been developed. For enantioselective hydrogenation of isoquinolines to chiral 1-substituted 1,2,3,4-tetrahydroisoquinolines a variety of chiral metal catalysts, including Ir, Rh, and Ru complexes, have been successfully employed securing good to excellent enantioselectivities. AO


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Scheme 66. Synthesis of (S)-(−)-Carnegine (531) by Asymmetric Hydrogenation of Isoquinoline 527 Using [Ir(cod)Cl]2/(S)Segphos (524) as the Catalytic System

Scheme 67. Iridium-Catalyzed Enantioselective Hydrogenation of 3,4-Disubstituted Isoquinolines 532

Scheme 68. Preparation of 1- or 3-Substituted 1,2,3,4-Tetrahydroisoquinolines of Type 538 and 539 by Iridium-Catalyzed Hydrogenation of N-Benzyl Isoquinolinium Salts 536 and 537

Hydrogenation of isoquinolines 527 (R = H, R1 = Me) and 527 (R = OMe, R1 = Me) followed by LiAlH4 reduction of the intermediate dihydroisoquinolines type 528 (R2 = Me) and 529 (R2 = Me), obtained with 80% ee and 63% ee, respectively, gave tetrahydroisoquinoline (S)-(−)-530 and the naturally occurring alkaloid, (S)-(−)-carnegine (531), in moderate to good yield (Scheme 66). In another paper the enantioselective iridium-catalyzed hydrogenation of 3,4-disubstituted isoquinolines 532, employing 1-bromo-3-chloro-5,5-dimethylhydantoin (BCDMH) for catalyst activation, has been described by the same research group.126 When isoquinolines 532 were treated with [Ir(cod)Cl]2/(R)Synphos 525 (Chart 34), the corresponding chiral tetrahydroisoquinoline derivatives 533 were obtained with ee values as high as 96%. It was found that during the asymmetric hydrogenation of intermediate 3,4-disubstituted isoquinolines a dynamic kinetic resolution was involved. Thus, the enantioselectivity-controlling step of the reaction was the isomerization of partially hydrogenated intermediate enamine 534 to imine 535 and hydrogenation of the latter (Scheme 67). In another series of experiments127 the iridium-catalyzed hydrogenation of 1- and 3-substituted isoquinolinium N-benzyl salts 536 and 537 (Ar = Ph, 2-(i-PrCO2)C6H4), carried out in the presence of [Ir(cod)Cl]2 complexes with various bisphosphine ligands, e.g., ent-524, 525, and 526 (Chart 34), have been

Reduction of imines employing iridium complexes with chiral ligands, carried out in the presence of various additives, have been shown to be more potent catalytic systems than other transition-metal complexes. They have been frequently applied for the synthesis of isoquinoline alkaloids as well. Some of these methods have been reviewed by Glorius and Zhao in 2013.124 The Chinese research group headed by Yong-Gui Zhou125−127 developed a highly efficient catalytic system for enantioselective asymmetric hydrogenation of enamines, isoquinoline derivatives including using chiral iridium complexes with various chiral bidentate phosphine ligands (Chart 34). In their pioneering work on asymmetric hydrogenation of isoquinolines they employed chiral iridium complexes with (S)Segphos 524 to produce chiral tetrahydroisoquinolines in satisfactory yield and enantioselectivity (Scheme 66). A variety of 1-alkyl-substituted isoquinoline derivatives of type 527 were hydrogenated using [Ir(cod)Cl]2/(S)-Segphos 524 catalyst and chloroformates as the substrate-activating agents to afford 1,2dihydroisoquinoline derivatives, e.g., 528 and 529 with enantioselectivities up to 83% ee. The presence of the NCO2R2 (R2 = Me, Bn) group appeared to ensure good coordination between the substrate and the catalyst, being beneficial for control of the stereoselectivity of this process. The Chinese authors successfully applied this method for the asymmetric synthesis of several naturally occurring alkaloids. AP


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Scheme 69. Mechanism of Iridium-Catalyzed Hydrogenation of Isoquinolinium Salts

quinoline (552) (Chart 36) over [Ir(cod)Cl]2/(S)-P-phos 545 catalysis. This synthesis has been performed on a 200 g scale to give (S)-551 in 95% isolated yield and with 98% ee. Chiral iridium complexes based on spiro phosphoramidite ligands of type 546 have been employed by another Chinese research group of Qi-Lin Zhou130,131 for the asymmetric hydrogenation of unfunctionalyzed enamines of type 553 with an exocyclic double bond (Chart 37). The combination of excess iodine with complex [Ir(cod)Cl]2/(Sa,R,R)-546 (Chart 35) provided direct access to chiral N-alkyltetrahydroisoquinolines 554 in high yields with up to 98% ee. The catalyst [Ir(cod)Cl]2/(Sa,R,R)-546 has been successfully applied for the synthesis of (R)-crispine A (177) (97% yield, 90% ee) by hydrogenation of enamine 555.131 Zhang et al.132 reported the asymmetric hydrogenation of a wide range of 1-alkyl and 1-aryl-3,4-dihydroisoquinolines of type 556 getting appropriate tetrahydroisoquinolines 557 (R = H) with excellent conversion and enantioselectivities up to 99% ee (Chart 38) using dimeric iridium/(S,S)-(f)-(binaphane) 560 complex with iodine additive [{Ir(H)[(560)]}2(μ-I)3]+I− (Chart 39). This catalytic system offers highly efficient access to a variety of enantiomerically pure tetrahydroisoquinoline alkaloids, among others, enantiomerically pure (S)-(−)-norcryptostyline II (ent-245), (S)-(−)-norcryptostyline III (558), as well as the substructure 551 of the drug solifenacin (543). Several ruthenium complexes with chiral ligands have also been found to be useful for the enantioselective reduction of imines. Ruthenium complex (R,R)-Ph-BPM/RuCl2(S,S)-DPEN, prepared by reaction of (R,R)-1,2-bis(2,5diphenylphospholano)methane (561) (Ph-BPM) and RuCl2 (1,2-diphenylethylendiamine) [(S,S)-DPEN] (Chart 39), developed by Jackson and Lennon,133 has successfully been used for the reduction of prochiral imines of type 556 (R = OMe, R1 = Me) to produce (S)-(−)-salsolidine (559) with full conversion and selectivity of 89% ee. The 1,2-diamine-based chiral complex (R,R)-562 (Chart 40), developed by Fan and Guo,134 has been used for enantioselective hydrogenation of imines 556 (R = OMe, H, R1 = alkyl), carried out in neat imidazolium ionic liquid (Bmim)NTf2, to supply the corresponding tetrahydro derivatives with enantioselectivity between 93% and 99% ee. They used (R,R)-562 complex for

investigated, providing access to 1- and 3-substituted 1,2,3,4tetrahydroisoquinolines of type 538 and 539 with ee’s up to 96% when (Rax,S,S)-Tunephos 526 was applied (Scheme 68). The mechanistic studies undertaken indicated that the reaction involved a 1,2-hydride addition followed by isomerization of the intermediate enamine 540 to iminium salt 541, of which only 541 underwent hydrogenation (Scheme 69). To demonstrate the utility of this methodology, the authors127 performed the synthesis of the urinary antispasmodic drug, (+)-solifenacin (543), by N-debenzylation of the crystallizationenriched hydrogenation product 542, prepared from the corresponding isoquinolinium salt with 99% ee under the above-mentioned conditions and subsequent acylation with (R)quinuclidinol to furnish (+)-solifenacin (543) in 85% overall yield (Scheme 70). Scheme 70. Transformation of 2-Benzyl-1-phenyl-1,2,3,4tetrahydroisoquinoline (542) into (+)-Solifenacin (543)

Mashima et al.128 used iridium/(S)-difluorphos 544 complex [{Ir(H)(544)}2(μ-Cl)3]Cl (Chart 35) for direct asymmetric hydrogenation of 1- and 3-substituted isoquinolinum hydrochlorides 547 and 548 in a one-pot reaction. The corresponding tetrahydroisoquinolines 549 and 550 were produced in high enantiomeric excess (up to 98% ee), being isolated by a simple basic workup from their salts (Chart 36). It was speculated that by using isoquinolinium salts the substrate reactivity is enhanced by decreasing the aromaticity and inhibiting the coordination of the amine product to a metal center. In this catalytic system compound 551, with 96% ee, was prepared from isoquinolinium chloride 552 and transformed into solifenacin (543) with no loss of enantiomeric purity. Ružič and Zanotti-Gerosa,129 on route to solifenacin (543), demonstrated that 551 could also be synthesized via hydrogenation of the hydrochloride salt of 1-phenyl-3,4-dihydroisoChart 35

AQ


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Chart 36

Chart 37

Chart 38

Chart 39

Chart 40

Xiao and Li135 developed a cationic Rh(III)−diamine catalyst 564 derived from (R,R)-563 (Chart 40) with the bulky

reduction of dihydroisoquinoline 556 (R = OMe, R1 = Me) to prepare (S)-salsolidine (559) in 92% yield and with 99% ee. AR


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noncoordinating counteranion (SbF6−) and used it for the reduction of imines 556 (R = OMe, R1 = alkyl), carried out in ionic liquids. A variety of 1-alkyl tetrahydroisoquinolines with 91−99% ee have been prepared, among which (S)-salsolidine (559) was produced with 96% ee from dihydroisoquinoline 556 (R = OMe, R1 = Me). Iridium catalyst prepared from [Ir(cod)2]BArF [BArF = tetrakis(3,5-trifluoromethylphenyl)borate] and a monodentate phosphoramidite ligand (S)-PipPhos 565 (Chart 41) has been

well as polymer-bounded diamine ligands 570 have been explored as complexing ligands (Chart 42). In many syntheses the ATH methodology has been applied using Noyori’s catalysts of type 571 or their variants, securing 1,2,3,4-tetrahydroisoquinolines with high conversion and good to excellent selectivity (Chart 43). A six-membered transition state 572 has been postulated to operate in this process.141 Many research groups have chosen (S)- and (R)-salsolidine (559 and ent-559) as target compounds to test the effectiveness of the catalytic system applied. The enantioselectivity of these syntheses was high, ranging from 85% to 99%. Pikho et al.138 prepared (S)-salsolidine (559), achieving 90% yield and excellent 99% ee, by using the simple, unmodified Noyori’s catalyst (R,R)-571 (Ar = p-cymene; Ar1 = 4-MeC6H4; R = H) under aqueous conditions with sodium formate as the hydride source. Under similar reaction conditions, using the benzene complex (R,R)-571 (Ar = benzene; Ar1 = 4-MeC6H4; R = H) the authors obtained (S)-crispine A (ent-177) in moderate yield from the precursor iminium salt, 573, yet in this case activation of the catalyst with AgSbF4 was necessary (Scheme 71). The ruthenium complex [RuCl2(p-cymene)]2 developed by Haraguchi et al.139 with polymer-immobilized chiral TsDPEN 570 (R = H) in DME has been used to produce (S)-salsolidine (559) with full conversion and enantioselectivity of 92% ee. The use of an amphiphilic polymer 570 (R = p-C6H4SO3−Na+) allowed the reaction to be carried out in water (Chart 42). Various Ru(II) complexes of N-alkylated TsDPEN derivatives (R,R)-571 (Ar = benzene; Ar1 = 4-MeC6H4; R = alkyl, benzyl) have been investigated in the ATH reaction by Wills et al.140,141 In the synthesis of (S)-salsolidine (559) the best results (quantitative yield and 85% ee and 84% ee) were achieved using catalyst (R,R)-571 (Ar = benzene; Ar1 = 4-MeC6H4; R = Bn) and (R,R)-571 (Ar = 1,4-Me2C6H4; Ar1 = 4-MeC6H4; R = Bn), respectively. Earlier, Wills et al.142 worked out a one-pot conversion of N-Boc-protected aminoketones 574 and 575 into cyclic amines (S)-576 and (S)-577, respectively. The sequence of reactions involved N-deprotection, cyclization, and ATH catalyzed by (R,R)-571 (Ar = p-cymene; Ar1 = 4-MeC6H4; R = H) to afford (S)-benzo[a]quinolizidine 576 with 71% ee and Omethylbharatamine (577) with only 10% ee. In the latter case a better result (50% ee) was achieved when catalyst (R,R)-578 was used (Chart 44). Zhu, Deng, and co-workers143 in the ATH reaction of cyclic imines 556 (R1 = Me, Et, i-Pr) (Chart 38) or their iminium salts have obtained the corresponding tetrahydro derivatives in high yields and with high enantiomeric excess (90−95%). The reaction was carried out in water using cetyltrimethylammonium

Chart 41

synthesized and used by The Netherlands’ chemists136 for the hydrogenation of a wide range of acyclic N-aryl imines, producing the corresponding amines with high enantioselectivity. However, the asymmetric hydrogenation applied to cyclic imines, e.g., 556 (R = OMe, R1 = Me), under the abovementioned reaction conditions proceeded with low selectivity, giving, e.g., salsolidine of not determined configuration in low yield and only with 62% ee (Chart 38). Ratovelomanana-Vidal et al.137 demonstrated that the (R)-3,5diMe-Synphos 566 is an efficient ligand for the [Ir(cod)Cl]2catalyzed asymmetric hydrogenation of 1-aryl-3,4-dihydroisoquinolines 556 (R = 5-Me, 5-OMe, 6-Me, 6-OMe, 7-Me, 6,7(OMe)2, H, R1 = Ar) with in situ activation using TsCl. The corresponding N-tosyl 1-aryl tetrahydroisoquinolines 557 (R = Ts) (Chart 38) were produced in high yields and enantioselectivities ranging from 81% to 94% ee, which could be enhanced to 99% ee after a single crystallization. 3.2.1. Asymmetric Transfer Hydrogenation (ATH). During the past decade the enantioselective asymmetric transfer hydrogenation (ATH) of 3,4-dihydroisoquinoline derivatives of type 556 using a formic acid (or its salts)/triethyl amine azeotropic mixture as a source of hydrogen, catalyzed by Ru(II) and Rh(III) complexes with chiral diamine ligands, has been employed extensively in the synthesis of isoquinoline alkaloids. Enantiomerically pure N-tosylated-1,2-diphenylethane-1,2-diamine (TsDPEN) 567 and its derivatives, e.g., 568 and 569, as Chart 42

AS


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Chart 43

Scheme 71. Synthesis of (S)-Crispine A (ent-177) Using (R,R)-571 as a Catalyst

Chart 44

Scheme 72. Synthesis of (R)-Salsolidine (ent-559), (R)-O,O-Dimethylcoclaurine (581) and (S)-Norlaudanosine (ent-360) from C1-Substituted 3,4-Dihydroisoquinolines 556 Using ATH with (S,S)- or (R,R)-571 Catalyst

bromide (CTBA) as an additive and a water-soluble [RuCl2/(pcymene)2]2 complex with diamine (R,R)-568. Under the above reaction conditions, (S)-salsolidine (559) was isolated in 97% yield with 95% ee. The authors144 invented another watersoluble catalytic system containing rhodium(II) as the central metal. With the [Cp*RhCl2]2/(S,S)-569 complex, salsolidine (559) was produced in 95% yield and 93% ee. Another rhodium complex, [Cp*RhCl2]2 with (R,R)TsDPEN 567, described by Blackmond and co-workers,145 applied for the synthesis of (S)-salsolidine (559), afforded the alkaloid with 95% ee.

(R)-Salsolidine (ent-559), (S)-norlaudanosine (ent-360), and (R)-O,O-dimethylcoclaurine (581) have been synthesized by Opatz and co-workers146 by the ATH technique at the final step of the synthesis (Scheme 72). The synthesis started with 1cyano-tetrahydroisoquinoline 579, which upon C-1 deprotonation/C-1 alkylation using methyl, 3,4-dimethoxybenzyl and 4methoxybenzyl halides, afforded the corresponding C-1substituted isoquinolines 580 [R1 = CH3, 4-MeOC6H4CH2, 3,4-(MeO)2C6H3CH2], which underwent spontaneous HCN elimination to give the corresponding 3,4-dihydroderivatives of type 556 (R1 = CH3, 4-MeOC6H4CH2, 3,4-(MeO)2C6H3CH2), AT


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Chart 45

Chart 46

Scheme 73. Synthesis of 1-Benzyltetrahydroisoquinolines from the Corresponding 3,4-Dihydroisoquinolines 587 using ATH with 571 Catalyst

Chart 47

solution with moderate yields and selectivity. When this reaction was applied to salsolidine precursor 556 (R = OMe, R1 = Me) using complex 582 the alkaloid ent-559 was produced with 50% conversion and 88% ee. It was noticed that in this catalytic system the prochiral imines are preferentially reduced to the R enantiomers independently on the configurations of the chiral ligands used [e.g., (R,R)-582 and (S)-583]. These catalytic reactions involve CH/π interactions between the hydrogen atoms of the arene ligand of the ruthenium complex and the aryl substituent of the substrate in the hydrogen-bridged transition state 584. A French−Swiss group148 investigated the transfer hydrogenation process of 1-aryl-substituted 3,4-dihydroisoquinolines

respectively. After ATH reduction, using Noyori’s catalyst (S,S)571 (Ar1 = 4-MeC6H4; Ar = p-cymene; R = H), the alkaloids (R)salsolidine (ent-559) and (R)-O,O-dimethylcoclaurine (581) have been achieved in moderate yields (51% and 55%) and with an enantiomeric excess of 91% and 96% ee, respectively, whereas using enantiomeric (R,R)-571 catalyst, (S)-norlaudanosine (ent360) with 78% yield and 93% ee was obtained. Canivet and Süss-Fink147 developed a new family of cationic aqua ruthenium complexes of type [(arene)Ru(RSO2N∩NH2)(OH2)]+ based on chiral N-sulfonated 1,2-diamines (e.g., 582 with 1,2-diaminocyclohexane, 583 with aminomethylpyrrolidine) (Chart 45). The water-stable and environmentally friendly complexes catalyzed the ATH of ketones and imines in aqueous AU


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of type 556 catalyzed by (S,S)-571 (Ar = benzene; Ar1 = 4MeC 6 H 4 ; R = H) to give the corresponding 1,2,3,4tetrahydroisoquinoline derivatives with good to excellent enantiomeric excess up to 99%. Among a variety of differently substituted 1-aryl tetrahydroisoquinolines prepared, compound 585 was transformed into a potent AMPA receptor antagonist ent-347 in 93% yield for two steps and with 87% ee which could be enhanced to 98% ee after recrystallization (Chart 46). According to the above method they also prepared (S)(−)-norcryptostyline I (586) and (S)-(−)-norcryptostyline II (ent-245) (Chart 38) with 87% and 85% yield and with 82% ee and 75% ee, respectively.149 Asymmetric transfer hydrogenation of 1-benzyl-3,4-dihydroisoquinolines of type 587 (Scheme 73) using the catalytic systems based on Noyori’s catalysts 571 has been investigated by Blank and Opatz.150 The key step in the synthesis of (+)-O,Odimethylcoclaurine (581) and (S)-(−)-norlaudanosine (ent360) was the in situ reduction of imine 587 [Ar = 4-MeOC6H4 and 3,4-(MeO)2C6H3], respectively, carried out using (S,S)-571 and (R,R)-571 (Ar = p-cymene; Ar1 = 4-MeC6H4; R = H), respectively, affording 581 with 96% ee and ent-360 with 93% ee. On the other hand, N-methylbenzyltetrahydroisoquinolines, (+)-laudanidine (595), (+)-armepavine (ent-357), (+)-laudanosine (ent-361) as well as the tetrahydroprotoberberines: (−)-corytenchine (386) and tetrahydropseudoepiberberine (596) (Chart 47), have been prepared by the same authors150 from the corresponding 1-benzyl tetrahydroisoquinolines by either reductive N-methylation (of 588 and 589) or Pictet− Spengler cyclization (of ent-360 and 591). The tetrahydroisoquinolines ent-360 (Ar = 3,4-(MeO)2C6H3) and 590 (Ar = 4-BrC6H4),150 were used for the synthesis of two bisbenzylisoquinolines, (+)-tetramethylmagnolamine (597) and (+)-O-methylthalibrine (598), by employing a microwave accelerated Ullmann diaryl ether synthesis (Chart 48).

nolines 589, 593, and 594 (Scheme 73). Depending on the configuration of the catalysts used, both enantiomers of amines 589, 593, and 594 could be prepared (Scheme 73) and after ether deprotection transformed into both enantiomers of, e.g., (R)- and (S)-higenamine (norcoclaurine) (351 and ent-351) isolated as hydrobromides with ee > 99% as well as their naphthyl analogues (S)-599, (R)-ent-599, (S)-600, and (R)-ent-600 with ee > 98% (Scheme 74). The same catalytic system has been successfully applied by Chang154 for synthesis of the C-1 epimer of SCH71450 603, a glycoside of (R)-higenamine (351), a selective dopamine D4 receptor antagonist. The key step of the synthesis was the reduction of imine 601 with (S,S)-571 (Ar = p-cymene; Ar1 = 4MeC6H4; R = H) to give secondary amine 602 with 95% ee, which was transformed into 603 of (R)-configuration at C-1, thus proving the (S)-C-1 stereochemistry of the natural SCH71450 (Scheme 75). Cheng and Yang155 accomplished the first enantioselective synthesis of (S)-(−)-stepholidine (394) with the use of Noyori’s catalyst (R,R)-571 (Ar = p-cymene; Ar1 = 4-MeC6H4; R = H) for ATH of imine 605 prepared from amide 604 by Bischler− Napieralski cyclization. The so obtained chiral intermediate 606, after cyclization and protective group transformations, gave the target alkaloid 394 via chloride 607 with an ee value over 99% in a 4-step synthesis (Scheme 76). (S)-Stepholidine (394) and a series of tetrahydroprotoberberine derivatives have been synthesized by a Chinese group156 using dihydroisoquinolines 608 or 605 as the starting compounds. In the synthesis of (S)-stepholidine (394) dihydroisoquinoline 608 was reduced by ATH using Noyori’s catalyst (R,R)-571 (Ar = p-cymene; Ar1 = 4-MeC6H4; R = H) to give tetrahydro derivative 609, which through intermolecular Pictet−Spengler condensation with formaldehyde and removal of the protecting groups fulfilled the alkaloid 394 synthesis (Scheme 77). Noyori’s catalyst of type 571 has been used by Czarnocki et al.157−161 for ATH reduction of several imines and iminium salts for the synthesis of many types of isoquinoline alkaloids (Chart 49). Thus, (R,R)-coralydine (611)157 was prepared from iminium salt 610, (R)-crispine A (177),158 from 573, and (R)benzo[a]quinolizidine (ent-576)158 from precursor 612 with 63%, 87%, and 92% ee, respectively, using (S,S)-571 (Ar = benzene; Ar1 = 4-MeC6H4; R = H) (Chart 49). In the case of (R)crispine A (177) better results (ee > 99%) were obtained when 573 was isomerized to enamine 555 and then subjected to the reduction.159 The asymmetric synthesis of (S)-(−)-homoprotoberberine (615) and (S)-(+)-homoaporphine (616)157 was performed using tetrahydroisoquinoline 614 as the key intermediatete (Scheme 78). It was obtained as pure (S)-enantiomer in quantitative yield by ATH reduction of imine 613 in reaction catalyzed with the (R,R)-571 (Ar = benzene; Ar1 = 4-MeC6H4; R = H). It was then cyclized to enantiomerically pure alkaloids 615 and 616 by either intermolecular Pictet−Spengler reaction with formaldehyde to give 615 or N-methylation and C−C coupling catalyzed by Cr2O3 to give 616. The same authors161 carried out the first synthesis of guanidine-derived alkaloid: (+)-crispine E (619) applying the (S,S)-571 (Ar = p-cymene; Ar1 = 4-MeC6H4; R = H) for the reduction of imine 617. In the reduction step product 618 was prepared in enantiopure form upon a single recrystallization of crude product of 89% ee. Subsequent transformations of 618 involving imide hydrolysis, installing the guanidine fragment by

Chart 48

Various modifications of the catalyst of type 571 (e.g., Ar = pcymene, benzene; Ar1 = toluene, naphthalene, borneol; R = H) have been introduced by Kačer et al.151,152 and used for the synthesis of (R)-5′-methoxylaudanosine (363), a chiral precursor of Mivacurium chloride, sceletal muscle relaxant. The synthesis proceeded through asymmetric reduction of dihydroisoquinoline 587 [(Ar = 3,4,5-(MeO)3C6H2)] to intermediate 592 (Scheme 73, Chart 47) giving 363 with 95% ee. Lee and Yun-Choi153 used Noyori’s catalyst (S,S)-571 and (R,R)-571 (Ar = p-cymene; Ar1 = 4-MeC6H4; R = H) for the reduction of imines 587 (Ar = 4-OHC6H4, 1-naphthyl, 2naphthyl) in multigram quantities to prepare tetrahydroisoquiAV


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Scheme 74. Synthesis of (R)- and (S)-Higenamine (351 and ent-351) from the Corresponding 3,4-Dihydroisoquinolines 587 Using ATH with (S,S)-571 and (R,R)-571 Catalyst

Scheme 75. Synthesis of of C-1 Epimer of SCH71450 603 Applying ATH with (S,S)-571 Catalyst to 1-Benzyl 3,4Dihydroisoquinoline 601

Scheme 76. Synthesis of (S)-(−)-Stepholidine (394) by Applying ATH with (R,R)-571 Catalyst to 3,4-Dihydroisoquinoline 605

Scheme 77. Synthesis of (S)-(−)-Stepholidine (394) via Chiral Tetrahydroisoquinoline 609 Prepared from 3,4Dihydroisoquinoline 608 by ATH with (R,R)-571 Catalyst

reaction with N,N′-bis(Boc)-S-methylisothiourea and final NBoc deprotection, led to the enantiopure 619 in 38% overall yield (Chart 50).

The same group160 using the enantiomeric catalyst (R,R)-571 (Ar = benzene; Ar1 = 4-MeC6H4; R = H) synthesized (R)(−)-praziquantel (PZQ) (623), a drug of importance for the AW


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Chart 49

Scheme 78. Synthesis of (S)-(−)-Homoprotoberberine (615) and (S)-(+)-Homoaporphine (616) from 3,4-Dihydroisoquinoline 613 Using ATH with (R,R)-571 Catalyst

Chart 50

Scheme 79. Synthesis of (R)-(−)-Praziquantel (623) Employing ATH with (R,R)-571 Catalyst to 3,4-Dihydroisoquinoline Imide 620 as the Key Step

treatment of schistosomiasis and soil-transmitted helminthiasis. ATH of imine 620 led to amine 621, formed with only a moderate enantiomeric enrichment (62% ee). It was trans-

formed into enantiopure 623 with 50% overall yield via diamine 622, its N-acylation with cyclohexane carboxylic acid, and final cyclization using chloracetic acid chloride (Scheme 79). AX


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Scheme 80. Synthesis of (−)-Govadine (626) from 3,4-Dihydroisoquinoline 624 Using ATH with (R,R)-571 Catalyst as the Key Step

Scheme 81. Total Synthesis of Emetine (633), Tubulosine (634), and Benzoquinolizidine 636 from a Common Intermediate 631 Prepared by a Three-Component Domino Process

ATH of iminium salt 624 using (R,R)-571 (Ar = p-cymene; Ar1 = 4-MeC6H4; R = H) was the key step in the enantioselective synthesis of (+)- and (−)-govadine (626 and ent-626), the dopamine D1 and D2 receptor modulators, developed in Sammi’s group.162 The resulting tetrahydroisoquinoline 625, obtained with 99% ee after crystallization, was subjected to Mannich-type cyclization using aqueous formaldehyde and Odebenzylation to afford (−)-govadine (626), isolated as its hydrochloride salt. Using the opposite enantiomer of Noyori’s catalyst and minor modifications in the synthetic route, (+)-govadine (ent-626) was synthesized in comparable yields and enantioselectivities (Scheme 80). Tietze’s group163 synthesized the Ipecacuanha alkaloid emetine (633), the Alangium alkaloid tubulosine (634), and the novel benzoquinolizidine alkaloid 636 (Scheme 81) from a common intermediate 631. A three-component domino reaction of aldehyde 628, prepared from 3,4-dihydroisoquinoline 556 (R = OMe, R1 = CH2OTIPS) via tetrahydroderivative 627, Meldrum’s acid 629, and enol ether 630 afforded compound 631, which on treatment with K2CO3 (MeOH, Pd−C) in the second domino reaction afforded benzoquinolizidine 632. Enantiopure emetine (633) was then synthesized by N-acylation

of 3,4-dimethoxyphenylethylamine with intermediate 632 followed by Bischler−Napieralski cyclization and ATH of intermediate imine. The synthesis of tubulosine (634) procedeed through the same reactions sequence in which benzoquinolizidine 632 and 2-benzyloxytryptamine were coupled. The benzoquinolizidine 636 was obtained from 631 via benzoquinolizidine 635 and LiAlH4 reduction as a mixture of diastereomers with 95% de (Scheme 81). It is worthy to mention that a practical synthesis of enantiomerically pure alkaloids, (S)-(−)-norcryptostyline I (586), (S)-(−)-norcryptostyline II (ent-245), (R)-(+)-salsolidine (ent-559), and (S)-(−)-laudanosine (ent-360), via a resolution-racemization of their salts with organic acids has been described by Chinese authors.164 Ward, Baker, et al.165,166 prepared (S)-salsolidine (559) with 96% ee by applying artificial metalloenzymes for transfer hydrogenation of cyclic imines. It was based on hCA II (human Carbonic Anhydrase II) as protein scaffold with an affinity for an Ir-catalyst bearing an arylsulfonamide moiety 637, which was used for the asymmetric reduction of a cyclic imines 556 (R = OMe, R1 = Me) to afford (S)-salsolidine (559) in 59% yield and 96% ee (Chart 51). AY


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cleavage of the double bond of the five-membered ring, afforded isoquinoline 648 via in situ formed dialdehyde 647, Pomeranz− Fritsch−Bobbitt cyclization, and Red-Al reduction. The total synthesis of ecteinascidin 743 (1) was accomplished with 1.1% overall yield over 28 steps. In another approach to the synthesis of Et-743 (1),27 the known intermediate 650169 was acquired in an alternative way using tetrahydroisoquinoline 61 as the ED end of the molecule. It was prepared by the Pictet−Spengler reaction between amine 14 and aldehyde 649 and converted into 650 in a multistep synthesis in which the final step, the ring B closure, was realized by the Pomeranz−Fritsch−Bobbitt cyclization (Chart 53). Stereoselective synthesis of tetracyclic intermediates 658 and 659 en route to two alkaloids: (+)-naphthyridinomycin (644)167 and (−)-lemonomycin (4)168 was accomplished using chiral amine 651 as a common starting material and 4CC Ugi reaction to assemble all of the carbon framework of the alkaloids (Scheme 85). The multistep synthesis, in which a great number of steps relied on protecting group manipulations, involved dihydropyrazinones 652 and 653 and bicyclo[3.2.1]octane derivatives 654 and 655 as important intermediates. The exocyclic C-13 double bond of the latter compounds was then converted into the hydroxymethyl functionality by epoxidation/hydrolysis/reduction supplying alcohols 656 and 657, respectively, isolated as single isomers with the correct stereochemistry. The final process involved Dess−Martin periodinane oxidation of the primary hydroxyl group followed by Pomeranz−Fritsch-type cyclization of the intermediate aldehydes to supply precursors 658 and 659 of (+)-naphthyridinomycin (644) and (−)-lemonomycin (4), respectively (Scheme 85). Takemoto and co-workers63 applied the Pomeranz−Fritsch− Bobbitt cyclization as the final step of the synthesis of the pentacyclic core 661 on route to Et-743 (1) for closing the B ring in acetal 660 (Scheme 86). To prepare the chiral tetrahydroisoquinoline unit 666, for the synthesis of Et-743 (1) Zhu et al.170 started the synthesis with stereoselective phenolic Mannich reaction between phenol 144 and oxazine 663, prepared from (R)-serine-derived amino diol 662 and phenyl bromoacetate. Morpholinone 664 was prepared at a 10:1 diastereomer ratio and subjected to triflation of the phenol group, acid hydrolysis, protection of the primary alcohol as MOM ether, and NaBH4/LiCl reduction to give amino alcohol 665 in excellent overall yield. The triflate ester of 665 was then converted into a methyl group using Stille coupling, and a cyanomethyl group was introduced into nitrogen. Acetylation of the remaining primary hydroxyl group, selective removal of the TBDPS protective group, Swern oxidation of the resulting alcohol, and final Pomeranz−Fritsch-type cyclization supplied the tetrahydroisoquinoline 666 as a 3:2 mixture of diastereomers which were used in the next step of the synthesis without separation (Scheme 87). In another approach to the total synthesis of Et-743 (1) Zhu et al.40 applied the Pomeranz−Fritsch cyclization for construction of the ring B of the AB-tetrahydroisoquinoline unit in 667, thus

Chart 51

4. POMERANZ−FRITSCH−BOBBITT SYNTHESIS The term “Pomeranz−Fritsch−Bobbitt synthesis of tetrahydroisoquinoline derivatives” refers to a variety of synthetic strategies in which the nitrogen-containing heterocyclic ring was closed by the formation of a C4−C4a bond of benzylamines, bearing at the nitrogen atom a two-carbon C−C chain with a good leaving group. The original Pomeranz−Fritsch method involved cyclization of benzylidenoacetals to give 4-hydroxy-3,4-dihydroisoquinoline or fully aromatic isoquinoline derivatives. In the Bobbitt modification nucleophilic reagents (hydride ion or organometallics) were added to the benzylidenoacetals prior to acid-catalyzed cyclization followed by hydrogenolysis to supply tetrahydroisoquinolines (Scheme 82). It should be noted that the Pomeranz−Fritsch−Bobbitt strategy has not been explored as often as the Pictet−Spengler or the Bischler−Napieralski one. For instance, only a few reports on the synthesis of the isoquinoline motifs of the large group of antitumor antibiotics, employing stereocontrolled Pomeranz− Fritsch−Bobbitt cyclization, have been published. Danishefsky et al.,45 in their synthesis of the AB unit of ecteinascidin 743 (Et743) (1), applied this methodology. Starting with catechol 638, isoquinoline 81 was achieved in a multistep synthesis. The synthesis proceeded through bromine derivative 639, ketone 640, chiral alcohol 641, prepared through ATH of 640 with Noyori’s (R,R)-571 catalyst, azide 642, prepared using Mitsunobu reaction with diphenylphosphorylazide, benzylamine 167, and the key aminoacetal 643. Aminoacetal 643 subjected to acid-catalyzed cyclization afforded tetrahydroisoquinoline 81, which was further transformed toward the target alkaloid (Scheme 83). As a part of a continuation of the synthetic studies on the synthesis of antitumor alkaloids carried out at the laboratory of Fukuyama,27,58,167−169 the Pomeranz−Fritsch cyclization has been employed several times for the construction of the ring B of the tetrahydroisoquinoline AB fragment of ecteinascidin 743 (1),27,58 (+)-naphthyridinomycin (644),167 and (−)-lemonomycin (4)168 (Chart 52). In one of the syntheses58 of Et-743 (1) the key step involved the connection of two building blocks, diazonium salt 646 and enamide 148 (Scheme 84). They were prepared by multistep syntheses in which component 646 was obtained in six steps, starting with phenol 645, while tetracycle 148 was obtained from L-glutamic acid via diketopiperazine 145 in 10 steps. The condensation product 150 thus obtained, subjected to oxidative

Scheme 82. Mechanism of the Pomeranz−Fritsch−Bobbitt Synthesis of Tetrahydroisoquinolines

AZ


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Scheme 83. Preparation of Tetrahydroisoquinoline Fragment 81, an AB Component of Et-743, Applying ATH with (R,R)-571 Catalyst to Ketone 640 as the Stereocontrolling Step and the Final C4−C4a Bond Formation

Chart 52

Scheme 84. Fukuyama’s Total Synthesis of Et-743 (1) Involving Pomeranz−Fritsch−Bobbitt Cyclization for Ring Closure

omycin (4), a benzylisoquinoline alkaloid, and (S)-(+)-glaucine (673), an aporphine alkaloid, employing (S)-phenylglycinolderived imine 669 and Grignard regent 670 as starting material (Scheme 89). The addition product 672 prepared from 671 through N-alkylation with 2,2-diethoxyethyl bromide followed by N-methylation and acid-catalyzed cyclization/ionic hydro-

converting aldehyde 667 to the pentacyclic core 668 of the alkaloid (Scheme 88). Several other isoquinoline alkaloids have been synthesized using the Pomeranz−Fritsch−Bobbitt methodology for ring B closure. Badia et al.171 applied it in the diastereoselective synthesis of naphthyridinomycin (644)167 and (−)-lemonBA


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Chart 53

Scheme 85. Preparation of Tetracyclic Intermediates 658 and 659 as Precursors in the Synthesis of Naphthyridinomycin (644) and (−)-Lemonomycin (4)

methylmagnesium bromide to aldimine 674 providing αmethylamine (S,R)-676, the precursor of (S)-salsolidine (559), while the diastereomeric amine (R,R)-676, the precursor of (R)salsolidine (ent-559), was prepared by hydride reduction of ketimine 675. The two complementary syntheses were continued by removal of the chiral auxiliary, N-alkylation of enantiomeric amines (S)-677 and (R)-677 with 2,2-diethoxyethyl bromide to give enantiomeric acetals (S)-678 and (R)678. Final cyclization/hydrogenolysis of (S)-678 gave (S)salsolidine (559) in 24% overall yield with 98% ee, while (R)-678 afforded (R)-salsolidine (ent-559) in 20% overall yield with 96% ee (Scheme 90). (S)-N-tert-Butanesulfinimine, ent-674, has been applied by the same authors174 as a chiral substrate for the synthesis of (S)-Omethylbharatamine (577), a protoberberine alkaloid (Scheme 91). The key step of the synthesis involved addition of laterally lithiated N,N-diethyl o-toluamide 679 to aldimine ent-674 to give addition product 680. Removal of the N-sulfinyl auxiliary afforded amine 681, which was easily cyclized to isoquinolone 682 (n-BuLi). Hydride reduction of 682 followed by Nalkylation with bromoacetaldehyde diethyl acetal led to unstable “Pomeranz−Fritsch acetal” 683, which subjected to cyclization/ hydrogenolysis afforded (S)-O-methylbharatamine (577) in 24% overall yield with 88% ee, identical to that prepared earlier by Chrzanowska et al.175 (section 5.4.1).

Scheme 86. Preparation of Pentacyclic Core 661 for the Synthesis of Et-743 (1) by Final C4−C4a B Ring Closure

genation was then converted into enantiomerically pure (S)laudanosine (ent-361) in high yield. The final step, the C−C biaryl coupling in (S)-laudanosine (ent-361) promoted by PIFA reagent, completed the synthesis of (S)-(+)-glaucine (673) in 75% yield and with 94% ee. Grajewska and Rozwadowska performed diastereoselective total synthesis of both enantiomeric (S)-salsolidine (559)172 and (R)-salsolidine (ent-559)173 using chiral N-tert-butanesulfinylimines 674 and 675, as substrates, respectively, and Pomeranz− Fritsch−Bobbitt cyclization for the construction of tetrahydroisoquinoline ring system (Scheme 90). To prepare chiral αbenzylamines (S,R)-676 and (R,R)-676, two parallel reaction pathways were performed. One of them was based on addition of BB


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Scheme 87. Preparation of Tetrahydroisoquinoline Unit 666, a Building Block for the Synthesis of Et-743 (1), by C4−C4a Ring Closure in 665

An example of an enantioselective synthesis of precursor (−)-689 on route toward (S)-salsolidine (559) has been prepared by Głuszyńska and Rozwadowska177 by additions of methyllithium to the “Pomeranz−Fritsch imine” 684, carried out in the presence of several oxazoline chiral ligands, type 688. The aminoacetal 689 of known (S) configuration was obtained in yields ranging from 44 to 92% and up to 76% ee depending on the type of oxazoline 688 used (Scheme 93). Enantiomerically enriched 3,4-disubstituted tetrahydroisoquinolines 691 with trans stereoselectivity have been synthesized by Panda and Manna178 from chiral N-benzyl N-alkyl amino alcohols 690 derived from (S)-amino acids. The Friedel−Crafts reaction promoted by Lewis acid (AlCl3) led to 4-aryl and heteroaryl tetrahydroisoquinoline core 691, met in several natural products, in 65−79% yields and with high diastereoselectivity (Scheme 94). Recently, a new original approach to the synthesis of tetrahydroisoquinoline derivatives, employing a combination of two synthetic methods, that is, the Petasis synthesis of functionalized amines and the Pomeranz−Fritsch−Bobbitt synthesis of tetrahydroisoquinoline derivatives, has been developed by Rozwadowska et al.179−181 Following the earlier racemic version of this approach,179,180 a diastereoselective synthesis of (+)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline1-carboxylic acid 697, related to the simple isoquinoline alkaloids and important arylglycine analogues, has been performed. The stereoselectivity of this synthesis was based on chiral aminoacetaldehyde acetals of type 692, used as the amine components in the three-component (boronic acid, amine, carbonyl derivative) Petasis step to yield the Pomeranz−Fritsch−Bobbitt substrate in one simple operation (Scheme 95). Thus, reaction between 3,4-dimethoxyphenyl boronic acid 693, glyoxylic acid

Scheme 88. Preparation of Advanced Intermediate 668 for the Synthesis of Et-743 (1) by C4−C4a Ring Closure in Aldehyde 667

Chrzanowska and co-workers176 performed another total synthesis of both enantiomeric (S)- and (R)-O-methylbharatamine (577 and ent-577), employing the lateral metalation strategy in which chiral toluamides (S)-685 and (R)-685 incorporating chiral oxazolidine moiety were used as the building blocks and controllers of the steric course of the synthesis. There were prepared from o-toluoyl chloride and (S)- and (R)phenylalaninol, respectively. Addition of lithiated amides (S)685 and (R)-685 to the imine 684 gave enantiomeric isoquinolones (S)-686 and (R)-686, respectively, along with acyclic diastereomeric products 687, easily transformed into the corresponding isoquinolones 686 under the action of n-BuLi. The synthesis was completed by reduction of amides (S)-686 and (R)-686 followed by cyclization/hydrogenolysis to give (S)and (R)-O-methylbharatamine (577 and ent-577) in 32% and 37% overall yield and with 88% ee and 73% ee, respectively (Scheme 92).

Scheme 89. Diastereoselective Synthesis of (S)-Laudanosine (ent-361) and Glaucine (673) using Imine 669 as a Chiral Substrate

BC


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Scheme 90. Diastereoselective Synthesis of (S)- and (R)-Salsolidine (559 and ent-559) Using Sulfinylimines 674 and 675, Respectively, as Substrates

Scheme 91. Diastereoselective Synthesis of (S)-O-Methylbharatamine (577) Using Sulfinylimine ent-674 as a Substrate and Lateral Metallation Methodology as the Key Step

BINOL/Ti(Oi-Pr)4 catalytic system led to the homoallyl alcohol 698 transformed into homoallyl azide 699 with inversion of configuration using a complex generated from diphenylphosphoryl azide and DBU. Hydroboration−cycloalkylation of 699 led to pyrrolidine 700, which in Michael addition with phenyl vinyl sulfoxide in the presence of Et3N furnished N-alkylated product 701 in good yield. Pummerer cyclization in TFAA and DCM at room temperature led to tetrahydroisoquinoline 702 with de > 90%. Reductive elimination of the thiophenyl group using Bu3SnH catalyzed by AIBN yielded enantiomerically pure (+)-crispine A (177) in 22.4% overall yield (Scheme 96). Using the same set of reactions and (R)-BINOL/Ti(OiPr)4 catalyst, the unnatural enantiomer of (−)-crispine A (ent-177) was obtained with 19.7% overall yield. The synthesis of (+)-fortucine (707), a lycorine-type alkaloid, has been performed by Canesi et al.184 It started with L-tyrosine methyl ester and isovanillin-derived iodo acid chloride 703 and involved intermediate amide 704. Dearomatization/cyclization

694, and aminoacetaldehyde dimethyl acetals type 692 bearing chiral auxiliaries (α-phenylethyl, α-naphthylethyl, tetrahydronaphthyl, 1-indanyl) afforded acetals 695 in high yield as a mixture of diastereomers (from 79:21 to 56:44 dr), dependent on the chiral inductor applied. After removal of the chiral auxiliary, the N-deprotected amino acid 696, obtained in enantiomerically enriched form after recrystallization of crude reaction product, was then subjected to the cyclization/ hydrogenolysis procedure, supplying the target dextrorotatory amino acid 697 with 90% ee in three simple operations. The formation of the C 4 −C 4a bond leading to the tetrahydroisoquinoline system has been realized using Pummerer cyclization reaction. Chittiboyina et al.182 used this procedure in linear, stereoselective synthesis of both enantiomers of crispine A (177 and ent-177). The benzylic stereogenic center in 698 was formed by a Keck asymmetric allylation reaction183 using (R)- or (S)-BINOL/Ti(Oi-Pr)4 catalytic system. Reaction of allyltributyltin with veratraldehyde in the presence of the (S)BD


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Scheme 92. Diastereoselecive Synthesis of (S)- and (R)-O-Methylbharatamine (577 and ent-577) Using Oxazolidines (S)-685 and (R)-685 as Chiral Substrates with Lateral Metallation Methodology as the Key Step

Scheme 93. Enantioselective Synthesis of Precursor 689 of Salsolidine (559) by Addition of MeLi to Imine 684 Catalyzed by Chiral Oxazoline 688

Spengler condensation), C8a−C1 (the Bischler−Napieralski cyclization/reduction), and C4−C4a (the Pomeranz−Fritsch− Bobbitt cyclization). In the past decade, other strategies, based upon generation of C1−N2, N2−C3 one bond as well as two bonds C1−N2/N2−C3 and C1−N2/C4−C4a, have also been developed.

Scheme 94. Trans-Selective Synthesis of 4-Aryl and Heteroaryl 3-Substituted Tetrahydroisoquinoline Core 691 by Friedel−Crafts Cyclization of Chiral Amino Alcohols 690

5.1. Synthesis Involving C1−N2 Bond Formation

This type of the synthesis is based upon a stereoselective intramolecular amination (amidation) process involving the formation of the bond between β-arylethylamine nitrogen and the future C-1 carbon atom (alkenyl or carbonyl) present at the ortho position of the aromatic ring. This approach has been carried out in diastereoselective and enantioselective catalytic synthesis. Several isoquinoline alkaloids as well as pharmacologically useful tetrahydroisoquinoline congeners have been attained using chiral nonracemic allylic alcohols of type (S)708 or (R)-708 as the starting material through the intermediate 1-allyl-tetrahydroisoquinolines of type (S)-709 or (R)-709 (Chart 54). Such a diastereoselective synthesis, involving 1,3-transfer of chirality during the cyclization step, has been reported by Kawai, Uenishi, and co-workers.185−189 In this way, a total synthesis of several pyrroloisoquinoline188 and 1-phenethylisoquinoline189 alkaloids has been performed. The starting allylic alcohols, (S)708 and (R)-708 (R = OPiv, R1 = OMe, R2 = Boc, R3 = H), were prepared by Suzuki coupling of o-bromo-β-arylethylamine 710 (R = OPiv, R1 = OMe) and both enantiomers of boronate 711.

of 704 gave bicyclic system 705, which on intramolecular C−C coupling afforded tetracyclic system 706. Several manipulations of functional groups in the latter supplied (+)-fortucine (707) in 15 steps (Scheme 97).

5. SYNTHESIS OF THE TETRAHYDROISOQUINOLINE NITROGEN-CONTAINING HETEROCYCLIC RING BY FORMATION OF C1−N2, N2−C3, C1−N2/N2−C3, AND C1−N2/C4−C4A BONDS In the preceding sections of this review the classical methods of the synthesis of tetrahydroisoquinoline alkaloids adapted to the stereoselective synthesis have been reviewed. The crucial step of these syntheses involved closing the nitrogen-containing ring by generation of the following bonds: C1−C8a/C1−N2 (the Pictet− BE


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Scheme 95. Diastereoselective Synthesis of (+)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic Acid 697 Using Petasis/Pomeranz−Fritsch−Bobbitt Reaction Sequence

Scheme 96. Stereoselective Synthesis of (+)-Crispine A (177) Using Allylic Alcohol 698 as a Chiral Substrate with Pummerer Cyclization as the Key Step

Scheme 97. Stereoselective Synthesis of (+)-Fortucine (707) Starting with L-Tyrosine Methyl Ester and Acid Chloride 703

The addition products (S)-708 or (R)-708 (R = OPiv, R1 = OMe, R2 = Boc, R3 = H) were then subjected to Bi-catalyzed cyclization, affording tetrahydroisoquinolines (S)-709 or (R)709 (R = OPiv, R1 = OMe, R2 = Boc), respectively, in excellent yield with enantioselectivity up to 88% (Chart 54). The synthesis of (R)-(+)- and (S)-(−)-crispine A (177 and ent-177), (R)-(+)-oleracein E (715), and (S)-(−)-trolline (ent715)188 required the construction of the pyrroloisoquinoline carbon skeleton, represented by lactam 714, Chart 55. Thus, isoquinoline (S)-709 or (R)-709 (R = OPiv, R1 = OMe, R2 = Boc) was subjected to a series of transformations involving cleavage of the alkenyl bond, Wittig olefination of the

intermediate aldehyde 712, followed by hydrogenation to give ester 713. N-Deprotection and final cyclization of (S)-713 or (R)-713 afforded lactams (S)-714 or (R)-714 in 71% yield. Deprotection of the pivaloyl and methyl groups of (R)-714 led to (R)-(+)-oleracein E (715), while LAH reduction of (R)-714 followed by O-methylation of the resulting catechol gave (R)(+)-crispine A (177). (S)-(−)-Trolline (ent-715) and (S)(−)-crispine A (ent-177) were obtained from lactam (S)-714 in a similar series of transformation (Scheme 98). For the synthesis of 1-phenethyltetrahydroisoquinoline alkaloids, (+)-dysoxyline (718), (+)-colchiethanamine (719), and (+)-colchiethine (345),189 the corresponding isoquinolines BF


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Chart 54

replacement by methyl ether was followed by removal of N-Boc protecting group, and final reductive N-methylation supplied the target alkaloids in high yield in four- or five-step synthesis. Following the same strategy the Japanese authors190 reported the synthesis of benzo[a]quinolizidin-4-one 725, a tricyclic fragment of (−)-schulzeine B (270). The 17-step synthesis started with chiral allylic alcohol 720 and involved tetrahydroisoquinoline 721, unsaturated ester 722, hydroxy amide 723, and hydroxy lactam 724 as intermediates. The hydroxyl group in 724 was replaced with an amino group via O-tosylation, azide formation, and reduction (Chart 56). Pd-catalyzed enantioselective intramolecular alkene amidation using carbonates of type 726 of achiral allylic alcohols as substrates, carried out in the presence of axially chiral phosphoramidite (e.g., 728) or bisphosphonite (e.g., 729) ligands, has been reported by Ojima and co-workers.191,192 Several 1-vinyl tetrahydroisoquinolines of type 727, useful intermediates for the synthesis of isoquinoline alkaloids, have been achieved with excellent enantioselectivity (ee > 90%) (Chart 57). On the basis of the above strategy, the synthesis of the tricyclic core of schulzeines A−C has been performed employing two key processes: asymmetric allylic amination and Ru-catalyzed ringclosing metathesis.193 Thus, carbonate 726 (R = 3,5-diPMBO) was cyclized in the presence of a chiral Pd−diphosphonite system (R)-729 or (S)-729 to give (S)- or (R)-1-vinyltetrahydroisoquinoline 730. They in reaction with (S)-vinylglycinyl chloride 731 gave amide (S,S)-732 or (R,S)-732, which under the action of Grubbs’ catalyst afforded the (S,S)-733 or (R,S)-733 tricyclic core of the alkaloids, respectively. Using standard chemistry, diastereomer (S,S)-733 was converted into (S,S)-734, the precursor of the isoquinoline fragment of schulzeine B (270),

Chart 55

Scheme 98. Synthesis of Enantiomeric Pyrroloisoquinoline Alkaloids 715 and ent-715, as well as 177 and ent-177, by Transformation of Enantiomeric Lactams (R)-714 and (S)714

of type (S)-717, reduction products of styryl derivatives type (S)716, were used. The latter ones were in turn prepared from isoquinoline (S)-709 (R = OPiv, R1 = OMe, R2 = Boc) by ozonolysis and Wittig olefination using the corresponding benzyltriphenylphosphonium bromide or by Julia−Kocienski olefination (Scheme 99). Cleavage of the pivaloyl ether or its

Scheme 99. Synthesis of (+)-Dysoxyline (718), (+)-Colchiethanamine (719), and (+)-Colchiethine (345) from Chiral Allylic Isoquinoline (S)-709 via Styryl Derivatives (S)-716

BG


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Chart 56

Chart 57

Scheme 100. Preparation of Benzoquinolizidine Derivatives (S,S)-734 and (R,S)-734, Fragments of Schulzeines A−C, Using (S)or (R)-1-Vinytetrahydroisoquinoline 730 as Chiral Substrates with Ring-Closing Metathesis as the Key Step

afforded alkene 739. This on N-deprotection and N-alkylation with (S)-mandelate derivative 740 afforded 741 as a single isomer. Reduction of the double bond using the riboflavin/ hydrazine system completed the synthesis of enantiopure almorexant (742) (Scheme 101). Folowing earlier investigations196 Tomioka and co-workers197 reported on enantioselective synthesis of optically pure (S)laudanosine (ent-361) in 33% overall yield by butyllithiummediated catalytic asymmetric hydroamination of stilbene derivative 743, carried out in the presence of bisoxazoline 744. The starting compound 743 was prepared from 3,4-dimethoxystyrene and 6-bromoveratraldehyde in a 5 steps (Scheme 102). Recently, Pignataro and Ferraccioli198 in an evaluation of their newly discovered phthalaphos ligands (e.g., 746), efficient in promoting enantioselective transformations, have chosen 1-

while (R,S)-733 led to (R,S)-734, the key intermediates in the synthesis of schulzeines A (274) and C (271) (Scheme 100). Feringa and co-workers,194,195 in way similar to Ojima’s synthetic concept, performed the synthesis of 1-vinyltetrahydroisoquinolines reaching excellent yields and high enantioselectivity. The key step, the iridium-catalyzed enantioselective allylic amidation of carbonate type 735, was carried out in the presence of phosphoramidite ligands incorporating chiral binaphthyls, e.g., 736. This approach has been applied to the synthesis of the tetrahydroisoquinoline unit of almorexant (742), a potent antagonist of human orexin receptors. Thus, allyl carbonate 735 subjected to the intramolecular asymmetric allylic amidation catalyzed by [Ir(cod)Cl)]2/736 catalytic system led to 1-vinyltetrahydroisoquinoline 737 in 97% yield with 95% ee, which in the oxidative Heck reaction with boronic acid 738 BH


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Scheme 101. Enantioselective Synthesis of Almorexant (742) by Intramolecular Asymmetric Allylic Amidation of 735 Using [Ir(cod)Cl)]2/736 Catalytic System

Scheme 102. Enantioselective Synthesis of (S)-Laudanosine (ent-361) by Hydroamination of Stilbene Derivative 743 Carried Out in the Presence of Bisoxazoline 744/n-BuLi Complex

Scheme 103. Enantioselective Synthesis of 1-Vinyltetrahydroisoquinoline (R)-747 by Pd/746-Catalyzed Intramolecular Amidation of Allylic Alcohol 745

began the synthesis in which norlaudanosine (ent-360) was the advanced intermediate. A sequence of transformations involved hydrolysis of the N-acyl group in 748 (R = H), cyclization, and enantioselective reduction of intermediate 3,4-dihydroisoquinoline according to Noyori’s protocol using (R,R)-571 (Ar = pcymene; Ar1 = 4-MeC6H4; R = H) catalyst. Compound ent-360, isolated in 81% yield and 92% ee, after reductive N-methylation afforded (S)-(+)-laudanosine (ent-361), while after being subjected to the Pictet−Spengler condensation with formaldehyde it brought about (S)-(−)-xylopinine (749) (Scheme 104). An interesting example of the intramolecular amidation concept combined with ring-closing metathesis has been applied

vinyltetrahydroisoquinoline (R)-747 as a synthetic object. As a result of detailed study involving testing the efficiency of ligands, optimization of the reaction conditions, as well as the structure of the starting carbonate, (R)-1-vinyltetrahydroisoquinoline 747 was obtained in 81% yield and with 83% ee using N-tosyl tertbutyl carbamate 745 as the starting material and [Pd2(dba)3· CHCl3]/746 as the catalytic system (Scheme 103). (S)-(+)-Laudanosine (ent-361) along with (S)-(−)-xylopinine (749) have been synthesized by Mujahidin and Doyle,199 also taking advantage of the intramolecular hydroamidation process. A titanium-catalyzed cyclization of alkynyl derivative 748 (R = COCF3), prepared by Sonogashira coupling of N-trifluoroacetyl2-iodo-homoveratrylamine with 3,4-dimethoxyphenylacetylene, BI


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Scheme 104. Enantioselective Synthesis of (S)-(+)-Laudanosine (ent-361) and (S)-(−)-Xylopinine (749) from a Common Intermediate ent-360 Prepared from Amine 748 by Cyclization and ATH with (R,R)-571 Catalyst

Scheme 105. Stereoselective Synthesis of (+)-Tetrabenazine (755) Using Acid 751 as a Chiral Substrate and Ring-Closing Metathesis as the Key Step

Scheme 106. Preparation of Chiral Allyltetrahydroisoquinoline 758 by Allylation of Chiral N-Sulfinyl Aldimine 756

by Altmann and Johannes200 in their synthesis of (+)-tetrabenazine (755), a quinolizine structurally related to the protoberberine and to the emetine alkaloids. The synthesis of this therapeutically important drug for treatment of chorea associated with Huntington’s disease started with condensation of vinyl amine 750 with chiral acid 751 to give diene 752, which under the action of Hoveyda−Grubbs II catalyst was cyclized to macrolactam 753. Intramolecular acid-catalyzed cyclization of the latter supplied quinolizine 754, which on O-deprotection, LAH reduction, and TPAP oxidation led to the target compound (+)-755 in 27% overall yield (Scheme 105).

performed the synthesis of several isoquinoline alkaloids according to the N2−C3 bond-forming strategy. The synthesis of isoquinoline 758 began with reacting 2-(2-chloroethyl)-4,5dimethoxybenzaldehyde with (R)-tert-butanesulfinamide and treatment of the so prepared N-sulfinyl aldimine 756 (81% yield) with allylmagnesium bromide to produce addition product 757 in 80% yield and 9:1 dr. NaH-mediated ring closure of the major diastereomer 757 gave isoquinoline 758 in 76% yield (Scheme 106). For the synthesis of (−)-crispine A (ent-177)201 N-Bocprotected isoquinoline 759 was prepared from 758 by exchanging N-sulfinyl for the N-Boc group. Hydroboration of the terminal double bond in 759, O-mesylation of the intermediate primary alcohol 760, and final ring closure

5.2. Synthesis Involving N2−C3 Bond Formation

Using chiral 1-allyl-N-tert-butanesulfinyl-tetrahydroisoquinoline 758 as a starting material, Reddy and co-workers201−203 BJ


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Chart 58

Scheme 107. Diastereoselective Synthesis of Solifenacin (543) and AMPA-Antagonist 765 Starting with Sulfinimines 762 and 756, Respectively

Scheme 108. Total Synthesis of Almorexant (742) Starting with Allylation of Chiral Sulfinimine 756

mediated by NaH/DMF gave the target alkaloid ent-177 in 69% isolated yield (Chart 58). Following the same reaction scheme, (−)-salsolidine (559) was synthesized201 using N-sulfinyl aldimine 756, which in reaction with methylmagnesium bromide afforded addition product 761 (95:5 dr). NaH-induced cyclization of 761 and removal of the sulfinyl auxiliary supplied the alkaloid 559 in satisfactory yield (Chart 58).

After the successful synthesis of the above alkaloids, Reddy’s group202 has undertaken a synthesis of solifenacin (543), an antispasmodic agent and an AMPA antagonist 765, using the above synthetic strategy. As presented in Scheme 107, the synthesis of solifenacin (543) started with sulfinimine 762 to which phenylmagnesium bromide was added to give sulfinamide 763 in high yield and with 93:7 dr. An intramolecular cyclization (NaH/DMF) of the major diastereomer afforded tetrahydroiBK


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Scheme 109. Stereoselective Synthesis of (−)-Dihydrotetrabenazine (771) Using Chiral Aldehyde 766 and Chiral Oxazolidinone 768

Scheme 110. Diastereoselective Synthesis of (S)-(−)-Stepholidine (394) Applying Chiral Sulfinimine 772 as a Substrate with Lateral Metallation Methodology as the Key Step

Scheme 111. Diastereoselective Synthesis of Protoberberines 749, 778, and 779 Applying Chiral Sulfinyl Aldimines 775 and Chiral Toluene Derivatives 776 as Building Blocks and Lateral Metallation Methodology as the Key Step

soquinoline 764, which after exchanging N-protecting groups (NSOt-Bu → NH → NCOOEt) followed by reaction with (R)3-quinuclidinol supplied solifenacin (543) in high yield. The AMPA-antagonist 765 was prepared according to the above strategy. The starting known sulfinimine 756 was subjected to a similar synthetic pathway: addition of 4chlorophenylmagnesium bromide, intramolecular cyclization, removal of the sulfinyl auxiliary, and final N-acetylation to give 765 in satisfactory yield. The same authors demonstrated once again the versatile usefulness of the chiral sulfinimine 756 in the synthesis of various tetrahydroisoquinoline derivatives, including the total synthesis of almorexant (742).203 Addition of allylmagnesium bromide to imine 756 followed by cyclization, removal of the chiral auxiliary, and N-Boc protection supplied 1-allyltetrahydroisoquinoline 759. Oxidative cleavage of the terminal olefin led to the key

intermediate aldehyde 766, which on treatment with trifluoromethylphenylmagnesium bromide supplied hydroxyl derivative 767. Its deoxygenation, N-deprotection, and reaction with chiral amide 740 gave the target (−)-almorexant (742) in 9.7% yield over 11 steps (Scheme 108). The synthesis of (−)-dihydrotetrabenazine (771)204 relied also on the use of N-Boc isoquinoline 759 as a starting compound. Thus, oxidative cleavage of the olefin double bond and treatment of the intermediate aldehyde 766 with (R)oxazolidinone 768 afforded syn-aldol adduct 769. The NaOMemediated removal of oxazolidinone auxiliary and N-Boc protection was accompanied by cyclization to produce tricyclic lactam 770 (X = O), which finally was LAH reduced to complete the synthesis of (−)-dihydrotetrabenazine (771) (X = H2) (Scheme 109). BL


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Scheme 112. Total Synthesis of (−)-Quinocarcin (5) Starting with Chiral Building Blocks: Benzofurane Derivative 780 and Alkyne Derivative 781

Scheme 113. Preparation of (1R,3S)-1,2,3-Trimethyltetrahydroisoquinoline 788 via Lactam 785 Incorporating (R)Phenylglycinol Moiety

hensive study on the transition-metal-catalyzed intramolecular amination reactions. The key step of the synthesis of the alkaloid,208,209 the construction of the tetrahydroisoquinoline core, was realized by gold(I)-catalyzed intramolecular hydroamination of intermediate 782, prepared in a multistep synthesis by Sonogashira coupling of aryl iodide 780 and alkyne derivative 781, followed by NaBH3CN reduction to afford isoquinoline 783 with the desired 6-endo-dig stereochemistry. Acid-catalyzed cyclization of 783 led to the pentacyclic alkaloid’s skeleton 784. A crucial step of the last part of the synthesis was the successful Lewis-acid-mediated conversion of dihydrobenzofuran ring in 784 into oxazolidine, a characteristic feature of the (−)-quinocarcin (5) structure (Scheme 112). A synthesis of enantiopure (1R,3S)-1,2,3-trimethyltetrahydroisoquinoline 788, the amine component of naphthylisoquinoline alkaloids, has been reported by Amat et al.211 (Scheme 113). The key intermediate lactam 785, which was prepared by cyclocondensation of 2-acetyl-3,5-dimethoxyphenyl acetic acid and (R)-phenylglycinol, after removal of the chiral auxiliary followed by N-acylation afforded isoquinolone 786 (R = Boc or R = COOMe). Treatment of 786 (R = Boc) with Comins’ triflate afforded 1,2-dihydroisoquinoline 787 (R1 = OTf), which under the action of lithium methylcuprate yielded 3-methyl derivative 787 (R1 = Me). The latter was then hydrogenated with H2 and Pd/C then reduced with LiAlH4 to complete the synthesis of isoquinoline 788 with (1R,3S)-cis configuration, isolated in good overall yield.

Another example of the synthesis based on the addition of carbon nucleophiles to chiral N-tert-butanesulfinyl aldimines has been reported by Yang and co-workers.205 In the synthesis of (S)(−)-stepholidine (394), a potential antipsychotic drug, the reaction of laterally lithiated nitrile 773 with sulfinyl aldimine 772 led to addition product 774, which was converted into the protoberberine alkaloid 394 in 18.3% yield with >98% ee in 5 steps. They included removal of the N-sulfinyl auxiliary, exchange of O-Tos for O-TBS group, two subsequent cyclizations to form rings B and C, LAH reduction of lactam carbonyl, and final Odeprotection (Scheme 110). Mastranzo and co-workers206,207 for their short, three-step synthesis of protoberberine alkaloids, (S)-(−)-xylopinine (749),206 (S)-(−)-tetrahydropalmatine (778),207 and (S)(−)-canadine (779),207 employed two chiral building blocks, both containing chiral p-toluenesulfinyl auxiliary: sulfinyl aldimines (S)-775a or (S)-775b and toluene derivatives (S)776a or (S)-776b. Addition of the carbanion generated from toluene derivative (S)-776a or (S)-776b to the sulfinylimines (S)-775a or (S)-775b gave corresponding tetrahydroisoquinolines 777, which after N- and C-desulfinylation and Pictet− Spengler cyclization with formaldehyde afforded enantiopure alkaloids: (S)-(−)-xylopinine (749) in 52%, (S)-(−)-tetrahydropalmatine (778), and (S)-(−)-canadine (779) in 33% and 34% overall yields, respectively (Scheme 111). A multistep synthesis of (−)-quinocarcin (5), a potent antitumor alkaloid, has been reported by Fujii, Ohno, and coworkers208−210 as part of their recently reported210 compreBM


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Scheme 114. Enantioselective Total Synthesis of (R)-Crispine A (177) Using s-BuLi/(−)-Sparteine System for Substrate Coupling

Chart 59

Scheme 115. Synthesis of Oxazolotetrahydroisoquinolines 794 and 795 Using (R)-Phenylglycinol and Aromatic Aldehydes as Substrates

Scheme 116. Synthesis of (S)-(+)-Cryptostyline II (793) Using Chiral Oxazoloisoquinoline 794 and Arylmagnesium Bromide as Substrates

Enantioselective Pd-catalyzed α-arylation of N-Boc pyrrolidine, developed by Campos, O’Brien, and co-workers,212 was employed as the key step in the synthesis of several biologically active compounds, (R)-crispine A (177) included. The synthesis of the latter relied on deprotonation of N-Boc pyrrolidine using sBuLi/(−)-sparteine, transmetalation using ZnCl2, and Negishi coupling with methyl 2-bromo-4,5-dimethoxyphenylacetate to give adduct 789 in 70% yield and 96:4 er in a one-pot procedure. Cleavage of the N-Boc protecting group was accompanied by cyclization, leading to tricyclic lactam 790, which on borane reduction delivered (R)-crispine A (177) in 82% with 97:3 er (Scheme 114). Catalytic enantioselective synthesis of cryptostyline II (793) has been reported by Yamamoto and Miyaura213 as a part of their investigations concerning the addition of arylboronic acid to Nsulfonylimines catalyzed by rhodium complex with (R,R)-N-MeBIPAM. For the synthesis of cryptostyline II (793), enantioselective arylation of N-nosyl imine 791 with boronic

acid 693, catalyzed by Rh(acac)(C2H4)2/(R,R)-N-Me-BIPAM complex, afforded addition product 792 in 85% yield and 98% ee. Using routine procedures, cyclization, N-deprotection, Nmethylation, and carbonyl reduction (S)-(+)-cryptostyline II (793), was achieved in 5 steps (Chart 59). 5.3. Syntheses Involving Two Bonds Formation

Next to the synthetic strategies based on one bond formation to construct the nitrogen-containing heterocyclic ring of tetrahydroisoquinoline, there are also examples in which generation of two bonds has been involved. 5.3.1. C1−N2/N2−C3 Bond Formation. A pronounced synthetic potential of oxazolotetrahydroisoquinolines (e.g., 794, 795) for asymmetric synthesis of isoquinoline alkaloids, exemplifying the C1−N2/N2−C3 bond-forming strategy, has been demonstrated by Asao and co-workers214 and Amat and coworkers215 (Scheme 115). In Asao’s approach214 the key substrate, the oxazoloisoquinoline 794, was prepared in 72% yield as a 93:7 mixture of BN


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Scheme 117. Synthesis of Series of 1-Substituted Isoquinoline Alkaloids by Reaction of Oxazolotetrahydroisoquinolone 795 with Grignard Reagents

Chart 60

Stoltz and co-workers216 reported a synthesis of (+)-amurensinine (804), an isopavine alkaloid, by insertion of amine functionality into tricyclic hydroxy ester (−)-800 (90% ee), which was prepared by oxidative kinetic resolution of racemic (±)-800. Treatment of (−)-800 with (PhO)2P(O)N3 supplied intermediate azide 801 with inversion of configuration, which on catalytic hydrogenation was converted into lactam 802, the alkaloid’s precursor. The synthesis was completed by LAH reduction of the lactam carbonyl followed by N-methylation (Chart 60). Alternatively, enantiopure (+)-amurensinine (804) was prepared in a parallel series of transformations using diol (−)-803, prepared also by kinetic resolution of racemic diol (±)-803, a reduction product of hydroxy ester (±)-800. A tandem 1,2-addition/ring closure methodology involving generation of two C1−N2/N2−C3 bonds has been developed by Reisman and co-workers.217 In the synthesis of (−)-3demethoxyerythratidinone (ent-186), benzoquinone imine ketal 805, incorporating chiral N-tert-butanesulfinimine, and aromatic lithio derivative 806 were coupled to produce

diastereomers by cyclocondensation of 4,5-dimethoxy-2-vinylbenzaldehyde with (R)-phenylglycinol and was applied for the synthesis of (S)-(+)-cryptostyline II (793) (Scheme 115). Thus, the reaction of 794 with 3,4-dimethoxyphenylmagnesium bromide led to addition product 797, from which, after removal of the chiral inductor and N-methylation, the target alkaloid 793 was obtained with 96% ee in 57% overall yield (Scheme 116). Starting with with oxazolotetrahydroisoquinolone 795 prepared from aldehyde ester 796 and (R)-phenylglycinol in 58% yield (Scheme 115) Amat’s group215 used it as a substrate for the synthesis of C-1-substituted tetrahydroisoquinoline derivatives, alkaloids included. Thus, reaction of 795 with the appropriate Grignard reagents gave addition products 798, isolated as single isomers in 49−63% yield (Scheme 117). Removal of the N-chiral auxiliary led to lactam 799, in which reduction of the lactam carbonyl fulfilled the synthesis of five alkaloids: (−)-salsolidine (559), (−)-O,O-dimethylcoclaurine (ent-581), (−)-norcryptostyline II (ent-245), norcryptostyline III (558), and (−)-crispine A (ent-177). BO


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Scheme 118. Synthesis of (−)-3-Demethoxyerythratidinone (ent-186) Using Chiral Benzoquinone Imine Ketal 805 and Lithio Derivative 806 as Substrates

Scheme 119. Synthesis of 7-Deoxypancratistatin (epi-455) Starting with Chiral Iodofuranozides 810 and Olefin Metathesis as an Important Transformation

Scheme 120. Stereoselective Synthesis of (+)-Pancratistatin (448) via Intermediate Amide 818 Prepared by Coupling of PinitolDerived Amine 816 with Aryl Bromide 817

spirocycle 807 (74%), isolated as a single diastereomer. Then the reaction with enol ether 808 followed by the removal of the sulfinyl chiral auxiliary led to tetracyclic derivative 809, which

upon selective reduction (H2/Pd−C/CaCO3) furnished the target alkaloid ent-186 in 26% overall yield (Scheme 118). BP


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Scheme 121. Total Synthesis of Hexahydrobenzo[c]phenanthridine Alkaloids 825−829 Starting with Pd/(S)-Tol-Binap-Catalyzed Addition of Boronic Acids 820 to Azabicyclic Alkene 821

Scheme 122. Enantioselective Synthesis of (+)-Chelidonine (827) Starting with Pd-Catalyzed Ring-Opening Reaction of Azabenzonorbornadienes 821 with Iodobenzoate 831

trichloroacetamide group was installed via Overman rearrangement to give 815. Diastereoselective dihydroxylation of the double bond followed by closing of the lactam ring and protecting group removal completed the synthesis of 7deoxypancratistatin (epi-455) in 4.3% overall yield for 13 steps. A concise synthesis of (+)-pancratistatin (448), an important member of the Amaryllidaceae alkaloids, has been described by Li et al.219 A one-pot, phosgene-induced coupling reaction between pinitol-derived primary amine 816 and aryl bromide 817 afforded amide 818 in moderate yield. O- and N-MOM protection of 818 followed by opening of the cyclic sulfate ring by nucleophilic attack of arylcerium intermediate (formed in situ under the action of t-BuLi/CeCl3 reagents) accompanied by simultaneous cyclization gave lactam 819. After removal of all

The construction of the tetrahydroisoquinoline nitrogencontaining ring B in the synthesis of 7-deoxypancratistatin (epi455) has been undertaken by Madsen et al.218 The strategy was based on two key processes: zinc-mediated tandem reaction between iodofuranozides 810 (R + R1 = CMe2), piperonalderived allylic bromide 811, and benzylamine to give diene 812 and olefin metathesis affording cyclohexene derivative 813. This compound, obtained in very low yield, after O-deprotection, double bond epoxidation, hydrolysis, and N-debenzylation supplied 7-deoxypancratistatin (epi-455) in 1.4% overall yield for 11 steps (Scheme 119). In another series of experiments, to the allylic alcohol 814, formed by reaction between iodofuranoside 810 (R = TES, R1 = Bn) and allylic bromide 811 followed by olefin metathesis, a BQ


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Scheme 123. Diastereoselective Synthesis of Both Enantiomers of (S)- and (R)-Tetrahydropalmatine (778 and ent-778) Starting with SAMP or RAMP Hydrazones 835 and Lateral Metallation Methodology as the Key Step

Scheme 124. Enantioselective Synthesis of Fused Polycyclic Frameworks 843, an Intermediate in the Synthesis of Amaryllidaceae Alkaloids, by Allylic Amination of 838 with 839 Using Pd/(S)-840

nine (825), while treatment with H2O/BiCl3 prior to LAH reduction supplied (+)-chelamidine (826). The same strategy was then applied for the synthesis of (+)-chelidonine (827), (+)-chelamine (828), and (+)-norchelidonine (829) using boronic acid 820 (R + R = CH2) and alkene 821 (R = Cbz). Enantioselective, Pd-catalyzed ring-opening reaction of azabenzonorbornadienes of type 821 with iodobenzoates of type 831 using various chiral spirophosphine ligands and zinc as reducing agent has been investigated by Chinese researchers.222 It was shown to be a convenient method for the construction of the cis-dihydrobenzo[c]phenanthridine core of many isoquinoline alkaloids. As a result of the detailed study, aimed at optimization of reaction conditions, a synthesis of (+)-chelidonine (827) has been performed. Thus, the palladium/chiral phosphine 830-catalyzed asymmetric ring opening of azabenzonorbornadiene 821 (R = COOCHMe2) with methyl 6-iodo-2,3methylenedioxybenzoate (831) gave cis-addition product 832 in 88% yield and 82% ee. LAH reduction followed by N-Cbz protection afforded the known precursor 833, which could be transformed into (+)-chelidonine (827) using established methods (Scheme 122).

protecting groups in 819, (+)-pancratistatin (448) was produced in a 12-step synthesis (Scheme 120). 5.3.2. C1−N2/C4−C4a Bond Formation. The C1−N2/C4− C4a bond-forming strategy in construction of ring B in the synthesis of the B/C hexahydrobenzo[c]phenanthridine alkaloids has been employed by Lautens and co-workers.220,221 The synthesis was based on enantioselective Pd-catalyzed ring opening of azabicyclic alkenes by boronic acids to afford cis-1amino-2-aryl-dihydronaphthalene derivatives. The synthesis of (+)-homochelidonine (825) and (+)-chelamidine (826) is shown in Scheme 121 to illustrate this strategy. Addition of trisubstituted boronic acid 820 (R = Me) to azabicyclic alkene 821 (R = Cbz) catalyzed by Pd/(S)-tol-binap afforded addition product 822 in 90% yield and 91% ee. Construction of ring B was realized by hydrolysis of the O-MOM protection followed by exchanging of Br for OH group and NaH-induced cyclization to supply the pentacyclic intermediate 823 in 90% yield. Formation of syn-epoxide 824 occurred via the corresponding bromohydrin obtained by treatment of 823 with NBS/H2O. Epoxide 824 was then used as the key intermediate in the synthesis of both alkaloids. Thus, its LAH reduction led to the (+)-homochelidoBR


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Scheme 125. Synthesis of Benzazepine Heterocyclic System (S)-845 by Friedel−Crafts Cyclization of Chiral Precursor 844

Chart 61

Enders and Boudou223 described a stereoselective synthesis of both (S)- and (R)-enantiomers of tetrahydropalmatine (778 and ent-778) based on the addition of laterally lithiated toluamide 834 to SAMP or RAMP hydrazones 835, respectively. The intermediate addition/cyclization products 836 were obtained in high diastereomeric purity (de ≥ 96%) and in moderate yield (Scheme 123). Cleavage of the N−N bond of the chiral auxiliary in 836 and reduction of the lactam carbonyl followed by introduction of diethoxyethyl substituent to nitrogen yielded acetal (S)-837 or (R)-837. Finally, ring closure according to the Pomeranz−Fritsch−Bobbitt procedure completed the synthesis of (S)- and (R)-tetrahydropalmatine (778 and ent-778) with excellent enantioselectivity and in overall yields of 17% and 9%, respectively. Recently, in a continuation of an earlier study191−193 on asymmetric allylic amination catalyzed by Pd/chiral BOP ligands Zang and Ojima224 applied this method for the construction of fused polycyclic frameworks, e.g., 843 or 845, useful intermediates in the synthesis of Amaryllidaceae or montanine alkaloids. Carrying out a detailed study on optimization of the reaction conditions, versatile intermediates 841 (R = Ns, Ts, X = Br, H) were prepared in high yield and enantiopurity by reacting N-R derivative 838 (R = Ns, Ts, X = Br, H) with cyclohexenylcarbonate 839 in the presence of Pd/(S)-840. After several standard transformations of 841 (R = Ns, X = Br) a tetracyclic nitrile (−)-843 was prepared via, among others, the

intramolecular Heck reaction of the intermediate nitrile 842 (Scheme 124). Intermediate 841 (R = Ts, X = H) has been used for the synthesis of the benzazepine heterocyclic system (S)-845 by zinc-promoted Friedel−Crafts reaction of bromide 844, prepared from 841 (R = Ts, X = H) in two steps (Scheme 125). 5.4. Addition of Carbon Units to 3,4-Dihydroisoquinolines (C1−Cα Bond-Forming Synthesis)

In addition to the above-described methodologies in which construction of a nitrogen-containing heterocyclic ring was the critical point, addition of carbon units to 3,4-dihydroisoquinoline scaffolds, both in a diastereoselective and in a catalytic enantioselective manner, has been an important alternative approach to access various 1-substituted isoquinoline alkaloids. This strategy was most frequently realized by employing organometallic compounds (Grignard, organolithium, organozinc, alkynyl- and allylmetal reagents) as well as metal acetylides, enolates, and cyanide ions as the source of anionic carbon. 5.4.1. Addition of Organometallic Compounds. In the past decade the synthesis of several protoberberine alkaloids based upon addition of laterally lithiated chiral o-toluamides to 3,4-dihydroisoquinoline derivatives has been reported by Polish175,225−228 and Japanese229 researchers. Chrzanowska and co-workers175,225−227 developed a new aproach to a total asymmetric synthesis of protoberberine alkaloids, (S)-(−)- and (R)-(+)-O-methylbharatamine (577 and ent-577),175,225 (S)-(−)-gusanlung D (846) and (R)-(+)-2,3BS


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methylenedioxy-8-oxoberbine (ent-846),226 and (S)-(−)-8oxoxylopinine (847),227 using as building blocks 3,4-dihydroisoquinolines 848 or 849 and laterally metalated o-toluamides of type 850 or 851 with chirality controllers appended to the amide nitrogen (Chart 61). In initial experiments, amides of type 850, in which the amine part came from (1S,2S)-2-amino-1,3-propanediol derivatives 852, were used.175,225,226 The addition of laterally lithiated otoluamides 850 (X = SCH3, NO2, H) to 3,4-dihydroisoquinoline 848 or 849 afforded addition products 853 (R = Me) or 853 (R + R = CH2), respectively, however, in unsatisfactory yield and low diastereoselectivity (Chart 61). Diastereomers 853 (R + R = CH2, X = SMe) were separated by column chromatography, and each of them was converted into (S)-(−)-gusanlung D (846) and (R)-(+)-2,3-methylenedioxy-8-oxoberbine (ent-846) with 97% ee and 99% ee, respectively. In another series of experiments, o-toluamides of type 851, incorporating an oxazolidine moiety as part of the amine functionality, were tested. The oxazolidine-containing building blocks of type 851 were prepared from o-toluoyl chloride, 2,2dimethoxypropane, and chiral aminoalcohols, (R)- and (S)phenylalaninol to give (R)-685 and (S)-685,175 respectively, as well as from (1R,2S)-norephedrine to afford (R,S)-854.226 For the asymmetric synthesis of (S)-(−)-gusanlung D (846), oxazolidine 854 derived from (1R,2S)-norephedrine was chosen.226 During the reaction between lithiated oxazolidine 854 and 6,7-methylenedioxy-3,4-dihydroisoquinoline 849 an addition/cyclization process occurred affording (S)-(−)-gusanlung D (846) in a one-pot experiment. It was accompanied by a noncyclized product 855, which could be easily cyclized to the alkaloid 846 under the action of n-BuLi, raising the total yield up to 64% and ee up to 99% after single crystallization (Scheme 126).

According to this strategy, both enantiomers (S)-(−)- and (R)-(+)-O-methylbharatamine (577 and ent-577)175 were synthesized with high enantiomeric purity (ee > 99%) as a result of reactions between 6,7-dimethoxy-3,4-dihydroisoquinoline 848 and either oxazolidine (S)-685 or (R)-685, respectively. The addition step was accompanied by cyclization affording (S)and (R)-oxoberbines 856 in satisfactory yield with 92% ee and 82% ee, respectively, which could be increased to ee > 99% after a single crystallization. LAH reduction of oxoberbines (S)-856 or (R)-856 led to (S)-(−)- and (R)-(+)-O-methylbharatamine (577 and ent-577), respectively, without any loss of enantiopurity (Scheme 127). Recently, based on the above strategy, Meissner and Chrzanowska227 performed a one-pot synthesis of (S)-(−)-8oxoxylopinine (847) using as the starting material 3,4dihydroisoquinoline 848 and lithiated oxazolidines (S)-685 and (S)-857 prepared from (S)-phenylalaninol228 and (S)alaninol, respectively. The addition step was accompanied by simultaneous cyclization to give directly (S)-(−)-8-oxoxylopinine (847), isolated after one crystallization with 99% ee yet with low yield (13%) (Scheme 128). During the course of the study on addition of chiral, laterally metalated oxazolidines to 3,4-dihydroisoquinolines it was found that the configuration of the newly formed stereogenic center in protoberberine alkaloids was strongly dependent on the configuration of the C-4 carbon in the oxazolidine ring. In the presented studies, the (S)-configuration of oxazolidines generated the (S)-configuration of the newly created stereogenic center of the alkaloid in the same way as the (R)-configuration of oxazolidine led to (R)-configuration. Two other protoberberine alkaloids, xylopinine (749) and bharatamine (858), in both enantiomeric forms, have been synthesized by Fukudo and Iwao229 employing the lateral metalation strategy. Thus, (S)- and (R)-xylopinine (749 and ent749) were synthesized by treating 6,7-dimethoxy-3,4-dihydroisoquinoline 848 with laterally lithiated oxazoline 860 (R1 = OMe) to obtain diastereomeric addition product 861 (R = Me, R1 = OMe), which on chromatographic separation supplied diastereomers (S,S)-861 (52%) and (S,R)-861 (45%) with 95% de. Each of them was subjected to acid-catalyzed cyclization to gave 8-oxoxylopinine (S)-847 and (R)-847, respectively. The synthesis was completed by LAH reduction of the lactam carbonyl yielding (S)- and (R)-xylopinine (749 and ent-749) of high enantiomeric purity (Scheme 129). The same sequence of transformations was applied for the synthesis of (S)- and (R)-bharatamine (858 and ent-858). Dihydroisoquinoline 859 and oxazoline 860 (R1 = H) were used as substrates, and the synthesis was carried out as described

Scheme 126. Asymmetric Total Synthesis of (S)(−)-Gusanlung D (846) by Addition of Laterally Lithiated Chiral Oxazolidine 854 to 3,4-Dihydroisoquinoline 849

Scheme 127. Asymmetric Total Synthesis of (S)-(−)- and (R)-(+)-O-Methylbharatamine (577 and ent-577) by Addition of Laterally Lithiated Chiral Oxazolidine (S)-685 or (R)-685 to 3,4-Dihydroisoquinoline 848

BT


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Scheme 128. Asymmetric Synthesis of (S)-(−)-8-Oxoxylopinine (847) by Addition of Chiral Oxazolidines (S)-685 or (S)-857 to 3,4-Dihydroisoquinoline 848

Scheme 129. Asymmetric Synthesis of Both Enantiomers of (S)- and (R)-Xylopinine (749 and ent-749) and (S)- and (R)Bharatamine (858 and ent-858) by Addition of Laterally Lithiated Oxazoline 860 to 3,4-Dihydroisoquinolines 848 or 859

Scheme 130. Diastereoselective Synthesis of (−)-Argemonine (867) by Addition of Grignard Reagent to Chiral Isoquinolone 864 as the Key Step

dimethoxybenzylmagnesium chloride produced isoquinolinium chloride 865. Selective reduction of the CN+ bond (LAH/ THF, −78 °C) followed by acid-catalyzed cyclization led to the pavine tetracyclic carbon skeleton 866, isolated as a 93:7 mixture of separable diastereomers. Using the major isomer, (−)-866, the synthesis of (−)-argemonine (867) was completed by removal of the N-substituent followed by N-methylation (Scheme 130). There are many reports concerning the additions of organozinc reagents to 3,4-dihydroisoquinoline or its N-oxide derivative both in an enantioselective and in a diastereoselective manner.

above, involving chromatographic separation of diastereomeric addition product 861 (R = i-Pr, R1 = H). Cyclization of each diastereomer produced oxoberbine (S)-862 and (R)-862, respectively. The reduction of the lactam carbonyl and cleavage of isopropyl ether fulfilled the synthesis of (S)- and (R)bharatamine (858 and ent-858). Marazano and co-workers230 reported diastereoselective synthesis of (−)-argemonine (867), a pavine alkaloid, starting with isoquinolinium chloride 863, bearing a (S)-N-α-phenylethyl substituent as a chiral auxiliary. It was oxidized [K3Fe(CN)6] to form isoquinolinone 864, which on treatment with 3,4BU


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Suh’s research group,231−233 using 1-allyl-1,2,3,4-tetrahydroisoquinolines 870 and 871, which they prepared by enantioselective addition of allylzinc bromide to the corresponding 3,4dihydroisoquinolines type 868 catalyzed by chiral bisoxazolidine 869 (Scheme 131), performed a stereoselective syntheses of

generation catalyst. Aza-Claisen rearrangement of 874 led to the ring-expansion product 875, which underwent acid-catalyzed transannulation to alcohol 876, obtained as a single isomer with the desired configuration at C-11b. Final reduction of the amide carbonyl completed the synthesis of (−)-protoemetinol (522) in 17% overall yield through nine steps. The synthesis of the isoquinoline moiety 265 of the alkaloids schulzeines A and C, reported by Korean researchers,233 employed as advanced substrate 1-allyl-derivative (R)-871 of 90% enantiopurity. It was prepared by enantioselective addition of allylzinc bromide complex with chiral bisoxazolidine ligand ent-869 to 6,8-dibenzyloxy-3,4-dihydroisoquinoline 868 (R = R2 = OBn, R1 = H) according to the Nakamura procedure50 (Scheme 131). Compound (R)-871 was transformed into hydroxy azide 877 in a series of reactions involving N-acylation with azidoacetic acid, oxidative cleavage of the allylic double bond, and NaBH4 reduction of the intermediate aldehyde. Dehydration of the primary alcohol followed by reduction of the azide group resulted in vinyl amide 878, which subjected to the aza-Claisen rearrangement afforded macrolactam 879. Acidcatalyzed cyclization of 879 provided the desired benzoquinolizidine (11bR)-265 in 24% overall yield (Scheme 134). A diastereoselective synthesis of (S)-O,O-dimethylcoclaurine (ent-581) by N-galactosylation-induced addition of di(4methoxybenzyl)zinc to 6,7-dimethoxy-3,4-dihydroisoquinoline 848 carried out in the presence of galactosyl bromide 241 has been reported by Kunz and Allef82 (Scheme 135). The diastereomerically pure addition product 880, after hydrolytic removal of the N-chiral auxiliary, led to enantiomerically pure target alkaloid ent-581 in 53% yield. It should be mentioned that the enantioselective addition of organozinc reagents to 3,4-dihydroisoquinoline-N-oxides proposed by Seto and co-workers234,235, promoted by chiral ethylenediamine ligands incorporating natural amino acids, is worth consideration as the convenient method for constructing structural motifs of isoquinoline alkaloids and related biologically active compounds. This method is particularly useful for the preparation of 1-aryltetrahydroisoquinoline,234 although 1-allyl derivatives are also available.235 The synthesis of solifenacin (543), shown in Scheme 136, may serve as an illustrative example. Addition of PhZnEt reagent to 3,4-dihydroisoquinoline-N-oxide promoted by chiral N-Boc ethylenediamine ligand 881 afforded addition product 882 in 92% yield and with 98% ee. After reduction of the N-hydroxyl group in 882 (S)-1-phenyl-

Scheme 131. Enantioselective Synthesis of 1-Allyl-1,2,3,4tetrahydroisoquinolines 870 and 871 from 3,4Dihydroisoquinolines 868 by Addition of Allylzinc Bromide Catalyzed by Chiral Bisoxazolidine 869

isoquinoline alkaloids: (+)-tetrabenazine (755)231 and (+)-dihydrotetrabenazine (ent-771), (−)-protoemetinol (522),232 and isoquinoline fragment 265 of schulzeines A (274) and C (271).233 The synthesis of (+)-tetrabenazine (755), Scheme 132,231 a therapeutically important alkaloid and (+)-dihydrotetrabenazine (ent-771), its active metabolite, began with enantiomerically enriched (R)-1-allyltetrahydroisoquinoline 870. N-Acylation with 4-methylvaleric acid and oxidative cleavage of the allylic double bond afforded aldehyde 872. The crucial step of the synthesis was the successful aza-Claisen rearrangement of the desired E-enol ether of aldehyde 872, prepared using DBU/ TBSCl, thus producing the desired 10-membered lactam 753, isolated as a single diastereomer. Acid-catalyzed cyclization, accompanied by O-hydrolysis, provided benzo[a]quinolizidinone ent-770, which upon LAH reduction supplied (+)-dihydrotetrabenazine (ent-771) in 34% overall yield, easily oxidized to (+)-tetrabenazine (755) produced in 22% overall yield. A similar strategy has been applied for the synthesis of (−)-protoemetinol (522), a benzo[a]quinolizidine alkaloid,232 employing 1-allylisoquinoline 870 as a substrate (Scheme 133). The key synthetic intermediate amide 874 was prepared from vinyl amide 873 by subjecting it to cross-metathesis reaction with TBS-protected 3-buten-1-ol using Hoveyda−Grubbs’ second-

Scheme 132. Stereoselective Synthesis of (+)-Tetrabenazine (755) and Dihydrotetrabenazine (ent-771) Using Aldehyde 872 as a Chiral Substrate

BV


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Scheme 133. Synthesis of (−)-Protoemetinol (522) Using Chiral 1-Allyltetrahydroisoquinoline 870 as a Substrate

Scheme 134. Synthesis of Benzo[a]quinolizidine Moiety (11bR)-265 of Schulzeines A and C Using 1-Allylisoquinoline (R)-871 as a Substrate and the Aza−Claisen Rearrangement as the Key Step

Scheme 135. Diastereoselective Synthesis of (S)-O,O-Dimethylcoclaurine (ent-581) Starting with Three-Component Reaction Involving 3,4-Dihydroisoquinoline 848, Di(4-methoxybenzyl)zinc, and Galactosyl Bromide 241

1,2,3,4-tetrahydroisoquinoline (551) was produced and treated first with p-nitrophenyl chloroformate and then with (R)-3quinuclidinol to give the target solifenacin (543) in high overall yield. Catalytic asymmetric synthesis of isoquinoline alkaloids, crispine A (177), homolaudanosine (886), and isoquinoline frameworks of emetine and schulzeine A, based on the application of the known 1-allylisoquinolines 870 and 883, has been carried out by Itoh and co-workers.236,237 They prepared isoquinolines 870 and 883 by enantioselective allylation of 6,7dimethoxy-3,4-dihydroisoquinoline 848 and 6,8-dimethoxy-3,4dihydroisoquinoline 868, respectively, using allyltrimethoxysilane−Cu reagent in the presence of chiral phosphine ligands,

among which (R)- or (S)-dtbm-segphos and (R)-tol-binap were the most effective ones (Scheme 137). For the synthesis of (+)-crispine A (177),236 isoquinoline (R)759 was subjected to a hydroboration−oxidation process affording primary alcohol ent-760, which after N-deprotection was cyclized under Mitsunobu reaction conditions to give (R)(+)-crispine A (177) in 74% yield (Chart 62). In the synthesis of (S)-(+)-homolaudanosine (886),236 the key step involved addition of 3,4-dimethoxyphenylmagnesium bromide to aldehyde 884, prepared from (S)-870, by OsO4/ NaIO4 oxidative cleavage of the allylic double bond. The so obtained secondary alcohol 885 was treated successively with BW


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Scheme 136. Enantioselective Synthesis of Solifenacin (543) by Addition of PhZnEt to 3,4-Dihydroisoquinoline-N-oxide Promoted by Chiral N-Boc Ethylenediamine Ligand 881

steps. It was further converted to the alkaloid (−)-emetine (633) following a known procedure (Scheme 139). The tricyclic isoquinoline fragment (S,S)-725 of the alkaloid schulzeine A (274)236 was constructed from aldehyde 891, prepared by cleavage of the olefin double bond in N-Bocprotected 1-allylisoquinoline (R)-883. Horner−Wadsworth− Emmons olefination with phosphate derived from glycine afforded unsaturated ester 892 in high yield, which on asymmetric reduction, N-deprotection, and cyclization provided tricyclic amide 893 as a mixture of diastereomers. After column chromatography separation, the (S,S)-isomer 893 was used to prepare the desired isoquinoline (S,S)-725 (Scheme 140). Another example showing the usefulness of chiral 1allyltetrahydroisoquinolines to serve as building blocks for asymmetric synthesis of isoquinoline alkaloids has been developed by Wu and Chong.238 A series of chiral 1allyltetrahydroisoquinolines, among others (R)-870, have been prepared in good yield with high enantiomeric excess by enantioselective allylboration of 3,4-dihydroisoquinolines, e.g., 848 using stoichiometric amounts of allylboronates 894, incorporating chiral 3,3′-disubstituted binaphthols. By this approach a short, two-step synthesis of (+)-crispine A (177) in 57% yield was performed. It included hydroboration of (R)-870 to give amino alcohol 895 and intramolecular Mitsunobu reaction (Scheme 141). The direct oxidative cross-dehydrogenative coupling (CDC) between two C−H bonds applied for the formation of the C1−Cα bond in isoquinoline alkaloids has been found to be an effective strategy. It was postulated to involve 3,4-dihydroisoquinolinium salts as intermediates. Organocatalytic asymmetric oxidative cross-dehydrogenative coupling for functionalization of C-1-H in N-acyl-1,2,3,4tetrahydroisoquinolines with vinyl or aryl boronates has been developed by Liu et al.239 and applied for the synthesis of 1styryl-1,2,3,4-tetrahydroisoquinolines 901 or 1-aryl-1,2,3,4-

Scheme 137. Enantioselective Synthesis of 1Allyltetrahydroisoquinolines 870 and 883 by Cu-Catalyzed Allylation of 3,4-Dihydroisoquinolines 848 and 868 in the Presence of (R)-Tol-Binap

Chart 62

SOCl2 and LAH to give (S)-(+)-homolaudanosine (886) in 29% overall yield (Scheme 138). In another series of experiments the same authors237 described a formal total synthesis of (−)-emetine precursor 890 in which 1allylisoquinoline (S)-759 was employed as starting compound. The allylic chain of 759 was functionalized with ethyl acrylate by applying a cross-metathesis with Grubbs’ catalyst to give unsaturated ester 887 with high E-selectivity. Michael addition of acrolein to 887, followed by ring closure catalyzed by pyrrolidine, resulted in the formation of a tricyclic aldehyde 888 from which ethylene derivative 889 was prepared by Wittig olefination. The synthesis was completed by hydrogenation of the double bond, affording intermediate 890 in 21.5% yield in 8

Scheme 138. Synthesis of (S)-(+)-Homolaudanosine (886) from Chiral Tetrahydroisoquinoline 884 and 3,4Dimethoxyphenylmagnesium Bromide

BX


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Scheme 139. Formal Total Synthesis of (−)-Emetine Precursor 890 Using 1-Allylisoquinoline (S)-759 and Ethyl Acrylate as Substrates and Michael Addition of Acroleine to 887 as the Key Step

Scheme 140. Synthesis of Benzoquinolizidine Fragment (S,S)-725 of Schulzeine A (274) Starting with 1-Allylisoquinoline (R)-883 (R = Boc)

Scheme 141. Two-Step Synthesis of (R)-(+)-Crispine A (177) by Allylation of 3,4-Dihydroisoquinoline 848 with Chiral Allylboronate 894

tetrahydroisoquinolines 902 (Scheme 142). Thus, the reaction of tetrahydroisoquinolines of type 896 [R = H, 6,7-(OMe)2, 6,7OCH2O, R1 = Boc, Cbz] with either vinyl boronate 898 [R2 = H, 4-OMe, 3,4-(OMe)2] or aryl boronate 899 [R2 = 4-OMe, 3,4(OMe)2, 3,4-OCH2O], initiated by DDQ oxidation, catalyzed by tartaric acid derivatives, e.g., 900, afforded the corresponding 1substituted tetrahydroisoquinolines 901 or 902, respectively, via 3,4-dihydro intermediate 897 in high yield and with excellent enantioselectivity. The synthesis of homoprotoberberine (615) and the important intermediate 909 in the synthesis of emetine (633)

has been performed by adding terminal acetylenes 904 or 905, respectively, to N-Cbz-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 903 in the presence of 2,2,6,6-tetramethylpiperidine Noxide salt (T+BF4−) and PyBox ligand 906 (Scheme 143).240 One of the coupling products, 907, was subjected to catalytic hydrogenation to give 614, which on cyclization supplied homoprotoberberine (615) with 90% ee. The other acetylenic product, 908 through Bayer−Villiger oxidation and reduction, was smoothly converted to aldehyde 909, the emetine precursor. On the basis of the cross-dehydrative coupling reaction a series of optically active 1-alkynyl tetrahydroisoquinoline derivatives, BY


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Scheme 142. Synthesis of 1-Styryl-1,2,3,4-tetrahydroisoquinolines 901 and 1-Aryl-1,2,3,4-tetrahydroisoquinolines 902 by Oxidative Cross-Dehydrogenative Coupling of Tetrahydroisoquinoline 896 and Boronic Acids 898 and 899 Promoted by Tartaric Acid Derivative 900

Scheme 143. PyBox-Organocatalyzed Synthesis of Homoprotoberberine (615) by Cross-Dehydrogenative Coupling of Tetrahydroisoquinoline 903 and Terminal Alkyne 904

potential precursors en route to isoquinoline alkaloids, has been synthesized by Su et al.241 and Li et al.242 applying Cu/PyBoxcatalyzed enantioselective bond formation between terminal alkynes and N-aryl tetrahydroisoquinolines. This synthetic approach, carried out in the presence of TBHP or DDQ in solvent-free conditions with ball milling,241 afforded 1-alkynyl isoquinolines in good yield and enantioselectivity. Several examples of oxidative (t-BuOOOH) cross-dehydrative C−C coupling of tetrahydroisoquinoline derivatives with aldehydes catalyzed by complexes of chiral amines, e.g., (S)proline with CuBr2, have been described by Chi et al.243

Some of the examples of catalytic asymmetric functionalization of the α-Csp3−H bond of amines have been reviewed by Luo et al.244 Ma et al.245,246 developed a very efficient method for the synthesis of C-1,N-2-disubstituted chiral tetrahydroisoquinoline derivatives by Cu(I)/N-pinap ligands-catalyzed coupling of Nunprotected tetrahydroisoquinolines with aldehydes and terminal alkynes. The synthesis of two alkaloids (+)-dysoxyline (718) and (+)-crispine A (177) according to this method246 is shown in Scheme 144. BZ


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Scheme 144. Synthesis of Dysoxyline (718) and (+)-Crispine A (177) by Cu(I)/N-Pinap-Catalyzed Coupling of 6,7Dimethoxytetrahydroisoquinoline and Alkynes 910 and 911

Scheme 145. Synthesis of (S)- or (R)-Homolaudanosine (886 or ent-886) by (S)- or (R)-Quinap-Catalyzed Addition of Terminal Alkyne 914 to 3,4-Dihydroisoquinolinium Methiodide 848·MeI

treatment of 6,7-dimethoxy-3,4-dihydroisoquinolinium methiodide 848·MeI with 3,4-dimethoxyphenyl acetylene 914 in the presence of CuBr and (S)- or (R)-quinap to afford alkyne derivative (S)-915 or (R)-915, respectively, which on reduction were converted to (S)- or (R)-homolaudanosine (886 or ent886) in 76% yield with high enantiomeric purity. A catalytic asymmetric alkynylation of C-1-substituted azomethine imine of type 916, catalyzed by Cu(I)/Ph-pybox, useful in the synthesis of various C-1-alkynyltetrahydroisoquinolines, has been developed by Maruoka and co-workers.248 Several examples of catalytic addition of carbon-centered nucleophiles to nitrogen-containing aromatic heterocycles, isoquinolines included, have been reviewed by Ahamed and Todd.249 Sodeoka and co-workers,250,251 in their detailed mechanistic study on Pd(II)-catalyzed asymmetric addition of malonates to 3,4-dihydroisoquinolines (or in situ generated 3,4-dihydroisoquinolinium ions), applied, among others, (R)-DM-segphos as chiral ligand to form Pd(II)−malonate complex 917. Various 1substituted tetrahydroisoquinolines, alkaloids included, were

The reaction of 6,7-dimethoxytetrahydroisoquinoline with benzaldehyde and ethynyl benzodioxole 910 or propargyl acetate 911 afforded propargylic amines 912 (97% yield, 98% ee) or 913 (98% yield, 98% ee), respectively. (+)-Dysoxyline (718) was synthesized in 50% overall yield in 2 steps from 912 via Pd catalytic hydrogenation and N-methylation. The synthesis of (+)-crispine A (177) was achieved via alcohol 895 and SOCl2mediated cyclization in 39% overall yield in 4 steps. 5.4.2. Addition of Carbon Nucleophiles. Catalytic asymmetric addition reactions of carbon nucleophiles to isoquinolines, 3,4-dihydroisoquinolines, or isoquinolinium derivatives, catalyzed by external controllers of chirality, have been carried out in either metal-catalyzed or organocatalytic processes. Catalytic asymmetric addition of terminal alkynes to isoquinolinium and 3,4-dihydroisoquinolinium ions to produce 1-propargylisoquinolines in yields up to 95% and 99% ee, carried out in the presence of (S)- or (R)-quinap and catalytic amounts of CuBr, has been reported by Taylor and Schreiber247 (Scheme 145). This approach was applied for the synthesis of both enantiomers of homolaudanosine (886 and ent-886) by CA


Chemical Reviews

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Scheme 146. Enantioselective Synthesis of (R)-Calycotomine (344) Using Pd(II)−Malonate Complex 917 and 3,4Dihydroisoquinoline 848

quinoline 848 supplied the addition product ent-918, which by careful hydrolysis and decarboxylation provided monoester 925. DIBAL reduction of 925 afforded aldehyde ent-766, the key intermediate of the synthesis. It was then coupled with iodide 926, followed by direct oxidation of intermediate diastereomeric alcohols, to give α,β-unsaturated ketone 927. The synthesis was completed by acid-catalyzed cyclization of 927 to give (+)-tetrabenazine (ent-755) in 21% overall yield, which when subjected to NaBH4 reduction was transformed into (+)-dihydrotetrabenazine (ent-771), isolated in 16% overall yield in 9 steps (Scheme 148). It should be mentioned that earlier experiments of Jacobsen’s group,253 which were devoted to the addition of TBS-ketene acetals to isoquinoline in the presence of acylating agents and thiourea catalyst 928, leading to 1-substituted 1,2-dihydroisoquinoline derivatives type 929 in good yield with enantioselectivity up to 92%, may be useful for the synthesis of alkaloids as well (Scheme 149). Recently, Jacobsen et al.,254 in continuation of their study253 concerning the role of chiral thiourea catalysts in enantioselective additions of enones to cyclic imines, reported highly enantio- and diastereoselective synthesis of benzoquinolizidinones, potential building blocks for the synthesis of alkaloids. This concept was based on aza-Diels−Alder reaction between enones and cyclic imines. The synthesis of benzoquinolizidinone 932, which started with enone 930 and 6,7-dimethoxy-3,4-dihydroisoquinoline 848, was catalyzed by bifunctional aminothiourea catalyst 931, supplying the target compound 932 in one step as a 17:1 mixture of diastereomers, in yield > 99% with 92% ee (Scheme 150). The first enantioselective synthesis of (+)-13-methyltetrahydroprotoberberine alkaloid (938) (X = H2) using organocatalytic acyl-Mannich reaction of isoquinoline with phenyl acetaldehyde, promoted by chiral proline derivative 934, has been described by Cozzi et al.255 Addition of Boc2O to isoquinoline gave 1,2dihydroisoquinoline 933, which in reaction with phenyl acetaldehyde in the presence of proline derivative 934 afforded addition product 935 as a 78:22 anti/syn mixture of diastereomers. After hydrogenation of the 3,4-double bond, the diastereomeric alcohols were easily separated by chromatography, and the desired anti isomer was subjected to Mitsunobu reaction with MeCOSH followed by desulfuration with Raney nickel and N-deprotection to give the methyl derivative 936. Treatment of 936 with phosgene followed by Friedel−Crafts cyclization afforded lactam 937 (X = O), which after reduction

produced in yields up to 97% with enantioselectivity reaching 97% using this methodology. In Scheme 146 the synthesis of (R)calycotomine (344) is shown.250 Thus, in the reaction between 6,7-dimethoxy-3,4-dihydroisoquinoline 848, Pd(II)−enolate complex 917, and Boc2O, addition product 918 was obtained in 93% yield with 94% ee. It was then subjected to hydroxylation to give α-hydroxy derivative 919, which after hydrolysis and decarboxylation afforded ester 920, without racemization. LAH reduction followed by N-Boc group removal completed the synthesis of (R)-calycotomine (344). Applying the same ligand 917, benzoquinolizidinone 924, a tricyclic structural motif of various alkaloids, e.g., the ipecac alkaloids, was synthesized.251 Starting with N-acryloyl-tetrahydroisoquinoline 921 and malonate complex 917 addition product 922 was prepared in 74% yield and 86% ee via in situ generated iminium ion. Then the intramolecular Michael reaction afforded tricyclic amide ester 923, which on hydrolysis, decarboxylation, and esterification supplied benzoquinolizidinone 924, isolated as a single diastereomer (Scheme 147). Scheme 147. Synthesis of Benzoquinolizidinone 924 by Addition of Malonate Complex 917 to Tetrahydroisoquinoline 921

For the synthesis of tetrabenazine (ent-755) and dihydrotetrabenazine (ent-771), compounds important for their therapeutic activity, Rishel and co-workers252 used the Sodeoka’s Pdcatalyzed asymmetric malonate addition methodology.250,251 The reaction of Pd−malonate complex of type 917, incorporating (S)-DM-binap ligand, with 6,7-dimethoxy-3,4-dihydroisoCB


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Scheme 148. Synthesis of (+)-Tetrabenazine (ent-755) and (+)-Dihydrotetrabenazine (ent-771) Using ent-918 as an Advanced Substrate

Scheme 149. Enantioselective Thiourea 928-Catalyzed Synthesis of C-1-Substituted 1,2-Dihydroisoquinolines 929

Jørgensen et al.256 It was based on organocatalytic threecomponent reaction between 3,4-dihydroisoquinoline, α-bromo ester or α-bromo ketone, and α,β-unsaturated aldehyde catalyzed by chiral proline. In this approach, the formation of three novel bonds and four stereocenters occurred in one step. For instance, reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline 848, methyl α-bromopropionate, and cinnamic aldehyde, catalyzed by chiral proline derivative 334, in a [3 + 2]cycloaddition process followed by reaction with Ph3P CHCOOEt afforded optically active tricyclic product 939 in high yield, good diastereoselectivity, and excellent enantioselectivity of 95% ee (Scheme 152). A catalytic enantioselective Reissert-type reaction, involving hydrocyanation and N-acylation of 3,4-dihydroisoquinoline 848 using Jacobsen’s thiourea catalyst 940, leading to nitrile 941, has been developed by Itoh and co-workers257,258 and used for the

Scheme 150. Enantioselective Synthesis of Benzoquinolizidinone 932 by Amino Thiourea 931-Catalyzed Addition of Enone 930 to 3,4-Dihydroisoquinoline 848

afforded (+)-13-methyltetrahydroprotoberberine (938) (X = H2) in 18% overall yield and with ee of 95% (Scheme 151). The synthesis of a series of pyrroloisoquinolines, structural elements of many alkaloid families, has been developed by

Scheme 151. Proline 934-Mediated Asymmetric Synthesis of (+)-13-Methyltetrahydroprotoberberine (938) (X = H2) from 1,2Dihydroisoquinoline 933 and Phenyl Acetaldehyde

CC


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Scheme 152. Synthesis of Pyrroloisoquinoline 939 by Proline 334-Catalyzed Three-Component Organocatalytic Reaction

Chart 63

reaction with 1,3-bis(tert-butoxycarbonyl)guanidine under Mitsunobu reaction conditions afforded guanidine derivative 945, from which the N-Boc protecting group was removed to provide the alkaloid ent-619 in a 7-step reaction sequence (Scheme 155).

synthesis of simple and pyrroloisoquinoline alkaloids. Thus, 1cyano-6,7-dimethoxytetrahydroisoquinoline 941, obtained in 86% yield with 95% ee, was subjected to hydrolysis, esterification, and N-Boc protection to give ester 920 (Chart 63). It was then employed as the key intermediate for the synthesis of simple and pyrroloisoquinoline alkaloids. The synthesis of simple isoquinoline alkaloids,257 starting with LAH reduction of ester 920 and the so formed primary alcohol 942, was then converted into (R)-(−)-calycotomine (344) by removal of N-Boc protecting group, (S)-(−)-salsolidine (559) by O-tosylation, reduction, and N-deprotection and (S)-(−)-carnegine (531) by N-methylation of the latter (Scheme 153).

5.5. C1−Cα Bond-Forming Synthesis via the Csp3−H Anionic Center of Tetrahydroisoquinolines

Stereoselective synthesis of chiral nonracemic isoquinoline alkaloids involving C1−Cα bond formation, based on the introduction of electrophilic reagents to the deprotonated C-1 position of tetrahydroisoquinoline derivative, has been realized in both diastereoselective and catalytic enantioselective strategies. Gawley and Smith259 in a continuation of their earlier study260,261 carried out the synthesis of 1-benzylisoquinolines (R)-948 and (S)-949 (R = H), two building blocks for the synthesis of berbamunine (950), a bisbenzylisoquinoline alkaloid. Both compounds were prepared by C-1 asymmetric alkylation of C-1-deprotonated (t-BuLi) tetrahydroisoquinoline (S)-946 and (R)-946, respectively, controlled by (S)- and (R)oxazolines, attached to the nitrogen atom, by C−···Li+···:N coordination (Chart 64). Thus, lithiation/alkylation of C-1 of (S)-946 with t-BuLi/3bromo-4-benzyloxybenzyl chloride afforded isoquinoline (1R,4′S)-947 (R = Bn, X = Br), while treatment of (R)-946 with t-BuLi/4-methoxymethylbenzyl chloride led to isoquinoline (1S,4′R)-947 (R = MOM, X = H). The synthesis was completed by removal of oxazoline moieties in 947 followed by Nmethylation to give both target benzylisoquinolines (R)-948 and (S)-949 (R = H), respectively, isolated in high yield with high enantiomeric excess. The synthesis of berbamunine (950) by Ullman ether coupling of the two 1-benzylisoquinolines (R)-948 and (S)-949 (R = H) had earlier been reported by Kametani in 1969.262 Following Gawley’s concept based on chiral oxazolidines as stereochemistry controllers, Japanese authors263 performed the synthesis of pharmacologically active bisbenzylisoquinoline alkaloids, nelumboferine (951), neferine (952), and its stereoisomers, by Ullmann coupling between isoquinolines of type 948 and 949 or their stereomers. In the synthesis of nelumboferine (951), isoquinolines ent-949 (R = i-Pr) and 948 were coupled, while three stereoisomers of neferine were attained by various

Scheme 153. Synthesis of (R)-(−)-Calycotomine (344), (S)(−)-Salsolidine (559) and (S)-(−)-Carnegine (531) by LAH Reduction of Chiral Ester 920

To obtain the pyrroloisoquinoline alkaloids,258 aldehyde 943 was prepared by DIBAL reduction of α-aminoester 920 and subjected to Horner−Wadsworth−Emmons reaction to give α,β-unsaturated ester 944. After reduction of the double bond and N-Boc group removal using the TMSOTf/Et3N catalytic system, cyclization to tricyclic lactam ent-343 was taking place. It was then converted to (−)-trolline (ent-715) by O-demethylation and to (−)-crispine A (ent-177) by LAH reduction (Scheme 154). (−)-Crispine E (ent-619) was synthesized through alcohol 760 a reduction product of ester 944, which when subjected to CD


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Scheme 154. Synthesis of (−)-Trolline (ent-715) and (−)-Crispine A (ent-177) Using Chiral Ester 920 as a Substrate

Scheme 155. Asymmetric Synthesis of (−)-Crispine E (ent-619) Using Unsaturated Ester 944 as the Chiral Key Intermediate

Chart 64

al.264 using as substrates 1-cyanotetrahydroisoquinolines with chiral N-α-phenylethyl auxiliary, prepared by anodic cyanation of the corresponding tetrahydroisoquinoline 953. For the synthesis of (−)-crispine A (ent-177), (+)-nitrile 954, was converted to the target alkaloid in two ways depending on the alkylating iodide used 955 [R = (CH2)3OTHP)] or 956 {R = [(CH2)2CH(OCH2CH2O)]} (Scheme 156). Following the C-1 deprotonation of 954, either of the iodides 955 or 956 was used as alkylating agent to give isoquinolines 957 or 958, respectively, formed after reductive decyanation (NaBH4). The alcohol ent895 obtained after hydrolysis of O,N-protecting groups was subjected to NaOH-mediated cyclization via intermediate chloride ent-197 to afford (−)-crispine A (ent-177) with 90:10 er. Liberation of aldehyde from the cyclic acetal 958 along with N-deprotection led to (−)-crispine A (ent-177), obtained with 85:15 er, via intermediate iminium ion 959. (+)-Crispine A (177) was prepared in 58% overall yield with 90:10 er in 4 steps in a similar way to that of ent-177 using (−)-nitrile 954 as the substrate. Both enantiomers could be

combinations of coupling of 949 (R = Me) or ent-949 (R = Me) with 6,7-dimethoxy analogues of (R)-948 or (S)-948 (Chart 65). The usefulness of the stabilized α-amino carbanions formed by α-deprotonation of α-aminonitriles has found many applications in the synthesis of isoquinoline alkaloids. Diastereoselective total synthesis of both enantiomers of crispine A (177 and ent-177) has been performed by Hurvois et Chart 65

CE


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Scheme 156. Diastereoselective Synthesis of (S)-(−)-Crispine A (ent-177) via C-1-Deprotection/Alkylation of Chiral 1Cyanotetrahydroisoquinoline (+)-954

Scheme 157. Synthesis of (−)-Dihydrocodeine (964) by ATH of Intermediate 3,4-Dihydroisoquinoline 962 Using (S,S)-571 Catalyst

Scheme 158. Pictet−Spenglerase-Catalyzed Synthesis of (S)-Norcoclaurine (ent-351)

Several C1−Cα bond-forming reactions between tetrahydroisoquinolines and enolates or alkynes based on cross-dehydrative coupling, which proceeded through in situ generated dihydroisoquinoline, have been reported in section 5.4.1.

obtained in enantiomerically pure form by resolution of their salts with (−)-DBTA or (+)-DBTA. Catalytic enantioselective synthesis of intermediate 960 en route to (−)-dihydrocodeine (964) has been reported by Geffe and Opatz.265 The synthesis proceeded through 3,4-dihydroisoquinoline 962, obtained by C-1 deprotonation/C-1 alkylation of racemic 1-cyano-1,2,3,4-tetrahydroisoquinoline 960 with benzyl bromide 961, accompanied by simultaneous dehydrocyanation. Transfer hydrogenation of 962 using Noyori’s catalyst (S,S)-571 (Ar = p-cymene; Ar1 = 4-MeC6H4; R = H) supplied (R)tetrahydroisoquinoline 963 in 68% yield and 95% ee. (−)-Dihydrocodeine (964) was then prepared by a series of known transformations (Scheme 157).

6. BIOCATALYTIC ROUTE TO ISOQUINOLINE ALKALOIDS Within the past decade much attention has been paid to the role of biocatalysis in the asymmetric synthesis of alkaloids, isoquinoline alkaloids included.266,267 The enzymatic stereoselective Pictet−Spengler condensation using norcoclaurine synthase enzymes (NCS, one of the Pictet− Spenglerases) to catalyze this reaction has found a pronounced position among the enzymatic methods. Many research groups, CF


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Scheme 159. Mechanism of the Pictet−Spenglerase-Catalyzed Biosynthesis of (S)-Norcoclaurine (ent-351)

The NCS enzyme of Thalictrum f lavum has been used by Maresh et al.275 in a one-pot Pictet−Spengler condensation using dopamine and various aldehydes, which they prepared from the corresponding α-amino acids by oxidative decarboxylation using NaOCl in maleate buffer, getting the (S)-enantiomers of 1substituted tetrahydroisoquinolines. The chemoenzymatic version of the Pictet−Spengler condensation has recently been investigated at the University College London,276 employing two enzymes: transaminase (TAm) and norcoclaurine synthase (NCS). They elaborated a “two enzyme, one substrate, one-pot” cascade for the synthesis of chiral isoquinoline alkaloids. Reactions of 2 equiv of βphenylethylamines catalyzed by TAm/NCS catalysts conducted in the presence of 1 equiv of pyruvate supplied (S)benzyltetrahydroisoquinolines of type 965 with very good conversion and excellent enantioselectivity (Scheme 160).

following the biosynthetic pathway, have chosen (S)-norcoclaurine (ent-351) as a target and entry compound to other isoquinoline alkaloids. (S)-Norcoclaurine (ent-351) is produced under NCS catalysis from dopamine and 4-hydroxyphenylacetaldehyde, both arising from tyrosine, the 4-hydroxyphenylacetaldehyde by transamination and decarboxylation while dopamine by decarboxylation and hydroxylation (Scheme 158). In this context, several NCS-catalyzed syntheses of (S)norcoclaurine (ent-351) and other benzylisoquinolines have been reported.268−277 A significant contribution to this field has been made by Canadian268 and Italian269−271 researchers, who carried out a detailed study on both enzyme identification and the mechanism of this process (Scheme 158). Tanner and co-workers 268 for the synthesis of (S)norcoclaurine (ent-351) by condensation of dopamine with 4hydroxyphenylacetaldehyde used norcoclaurine synthase from Thalictrum f lavum overexpressed in Escherichia coli. They also carried out several experiments using various substrate analogues and proposed a mechanism for the Pictet−Spengler reaction catalyzed by norcoclaurine synthase to produce (S)-norcoclaurine (ent-351), which is shown in Scheme 159. In an analogous one-pot synthesis the Italian chemists269−271 synthesized enantiomerically pure (S)-norcoclaurine (ent-351) in 80% yield using 4-hydroxyphenylacetaldehyde, dopamine, and NCS enzyme, also of Thalictrum f lavum origin. On the basis of Xray measurements they were able to establish the structure of the enzyme. The Japanese group272 applied NCS isolated from Coptis japonica for the synthesis of (S)-norcoclaurine (ent-351). Recently, Hailes et al.273 developed a fluorescence assay to monitor the course of the enzymatic Pictet−Spengler reaction catalyzed by Coptis japonica NCS2 (CjNCS2) and evaluated the scope and limitation of this process. It was established that only a limited number of dopamine analogues were tolerated by CjNCS2, whereas various arylacetaldehydes as well as aliphatic aldehydes were excellent substrates. Several dopamine-derived 1substituted tetrahydroisoquinolines of (S)-configuration have been obtained in good to excellent yield with ee > 95%. Under similar reaction conditions O’Connor et al.274 by NCScatalyzed cyclization of dopamine with various aldehydes performed the synthesis of several C-1-substituted tetrahydroisoquinolines, including (S)-norcoclaurine analogues, yet in moderate yield and enantioselectivity.

Scheme 160. Chemoenzymatic Synthesis of Chiral (S)Benzyltetrahydroisoquinolines of Type 965 from Dopamine

In the synthesis of two regioisomers of (S)-tetrahydroprotoberberine, 966 and 967, shown in Scheme 161, a second Pictet− Spengler reaction with formaldehyde was used to close ring C in the intermediate (S)-1-benzyltetrahydroisoquinoline 965 (R = OH) affording the alkaloids in good yield and enantioselectivity. The Pictet−Spenglerase has been involved in the biosynthesis of tetrahydroisoquinoline antibiotics (e.g., saframycin) in which two succesive Pictet−Spengler reactions have been the key steps.277 Several methods concerning the acquisition of chiral nonracemic isoquinoline alkaloids from the racemic form using various biocatalytic methods have recently been developed and deserve some attention. CG


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Scheme 161. Synthesis of Two Regioisomers of (S)-Tetrahydroprotoberberine 966 and 967 from Dopamine, Catalyzed by TAm/ NCS

Scheme 162. Kinetic Resolution of Racemic Reticuline (±-354) to (S)-Scoulerine (968) and (R)-Reticuline (354), Catalyzed by BBE

The Austrian group led by Kroutil278−284 reported results of their detailed studies on Berbine bridge enzyme (BBE) from Californian poppy, which include enzyme structure determination, the mechanism of catalyst action, and the role of BBE in various stereoselective transformations within tetrahydroisoquinoline alkaloids. The BBE is involved in the biosynthesis of benzophenanthridine alkaloids in poppy plants. It catalyzes an intramolecular oxidative C−C bond formation between the Nmethyl group and the C-2 atom of the 1-benzyl substituent bearing a phenolic OH function in N-methyl tetrahydroisoquinolines, forming the “berbine bridge”. The most intensively studied reaction included the BBE-catalyzed kinetic resolution of racemic 1-(3′-hydroxybenzyl)-N-methyl-tetrahydroisoquinolines, which afforded regioselectively 9-functionalized berbine derivatives in good yield and excellent enantioselectivity.279−281 Scheme 162 illustrates the kinetic resolution of racemic reticuline (±-354) to give (S)-scoulerine (968) in 47% yield, leaving untouched (R)reticuline (354) in 37% yield, both compounds with ee > 97% (E >200).279 The BBE enzyme has been shown by Kroutil and coworkers281 to be able to enantioselectively N-dealkylate N-ethylor N-methyl-1-benzyltetrahydroisoquinolines to give the (S) Ndealkylated derivatives with ee > 99% and the remaining (R) Nalkyl derivatives in the range 21−80% ee. The regioselectivity of the formation of the berbine bridge in 1-(3′-hydroxybenzyl)-N-methyltetrahydroisoquinolines catalyzed by BBE has been investigated by Kroutil et al.282,282 They have shown that the regioisomer ratio favoring the 9hydroxy one could be inverted supplying the 11-hydroxy isomer in 99% yield by introducing fluorine into benzyl appendage at C1.283 Recently, Fülöp and co-workers285−287 carried out comprehensive studies on enzyme-catalyzed (Lipase PS) kinetic resolution of N-Boc-protected racemic tetrahydroisoquinoline alcohols 760, 942, and 969 employing either enzymatic Oacylation or enzymatic hydrolysis of the corresponding esters: decanoate 970 and acetates 971 and 972. They were transformed then into isoquinoline alkaloids: (R)-(+)- and (S)-(−)-crispine A (177 and ent-177),285 (R)-(−)-and (S)-(+)-calycotomine (344

and ent-344),286 and (R)-(−)-and (S)-(+)-homocalycotomine (973 and ent-973)287 (Chart 66). Chart 66

For the synthesis of (R)-(+)- and (S)-(−)-crispine A (177 and ent-177)285 enantiomeric alcohols (R)-(−)- and (S)-(+)-760 were used. They were prepared in two ways applying the Burkholderia cepacia lipase-catalyzed processes: either by Oacylation of racemic alcohol (±)-760 with vinyldecanoate or by hydrolysis of racemic decanoate ester (±)-970. Alcohol (R)(−)-760 (95% ee) was the unacylated product of (S)-selective Oacylation of (±)-760, while (S)-(+)-760 (96% ee) was the product of (S)-selective hydrolysis of decanoate ester (±)-970. The enantiomeric esters, (R)-(−)-970 and (S)-(+)-970, were hydrolyzed to the corresponding alcohols, (R)-(−)-760 and (S)(+)-760, which on direct ring-closing reaction furnished (R)(+)- and (S)-(−)-crispine A (177 and ent-177)285 in yields ≥ 21% and ee ≥ 94%. Excellent results as to the conversion and enantioselectivity were achieved in the synthesis of (R)-(−)-and (S)-(+)-calycotomine (344 and ent-344)286 and (R)-(−)-and (S)-(+)-homocalycotomine (973 and ent-973) 287 employing Candida CH


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Scheme 163. Enzymatic Resolution of Racemic Salsolidine (±)-559 by CALA-Catalyzed N-Acylation to (S)-Salsolidine (559) and (R)-Salsolidine Carbamate 974 further Transformed to (R)-Salsolinol (975)

Scheme 164. Kinetic Resolution of Racemic Tetrahydroberberrubine (±)-976 to (S)- and (R)-Enantiomers by Glycosylation Catalyzed by Gliocladium deliquescens NRRL 1080

derivatives, using an iridium-based catalyst coupled with Candida rugose lipase was developed by Page, Blacker, et al.290,291 This approach, based upon combination of enzymatic kinetic resolution with simultaneous racemization of the remaining amine, led finally to the formation of a single enantiomer. For instance, enzymatic resolution of salsolidine (±)-559 by N-npropoxycarbonylation catalyzed by Candida rugose lipase accompanied by racemization of the unchanged amine using {[IrCp*I2]2 } catalyst afforded carbamate 974 (R = n-Pr) in high yield and high enantiomeric purity. This reaction was performed at a 3 g scale. Kroutil’s group284 developed a new method of deracemization of racemic N-methyl-1-benzyltetrahydroisoquinolines getting optically pure berbines by applying a combination of two enzymes: MAO-N (MAO = monoamine oxidase) and BBE.283 These oxidases are able to transform only one of the enantiomers, thus producing only one enantiomeric product in a cyclic one-pot process. The MAO enzyme catalyzes oxidation of the (R)-enantiomer to give 3,4-dihydroisoquinolinium species, from which, after borane reduction, only the (S)enantiomer undergoes the BBE-induced cyclization leading to (S)-protoberberbine. This cyclic reaction sequence is shown in Scheme 165. A chemoenzymatic deracemization of racemic crispine A [(±)-177] to give the biologically active (R)-enantiomer 177 as the sole product was investigated by Turner and co-workers.292,293 Their approach was based upon a two-step, one-pot reaction involving a sequential oxidation/reduction process using enantiomer-specific monoamine oxidase (MAO-N) from Aspergillus niger and nonselective reduction agents (Chart 67).

antarctica lipase B (CAL-B). This enzyme-catalyzed Oacetylation of intermediate alcohols 942 and 969 using vinyl acetate was carried out on a preparative scale in a continuousflow system. O-Acetylation of (±)-942 afforded ester (S)-971, leaving unchanged alcohol (R)-942 in 43% and 46% yield, with ee 99%, respectively. N-Deprotection of alcohol (R)-942 and N,O-deprotection of ester (S)-971 completed the synthesis of (R)- and (S)-calycotomine (344 and ent-344). (R)- and (S)Homocalycotomine (973 and ent-973) was prepared according to the above strategy via acetate (R)-972 and alcohol (S)-969 with ee > 94%, respectively. Candida antarctica lipase A (CALA) was employed by Deng et al.288 to catalyze the enzymatic resolution of salsolidine (±)-559 by N-acylation using phenyl allyl carbonate as the acylating agent. The resulting (R)-enantiomer of N-allyloxycarbonyl salsolidine 974 (R = allyl) and the remaining (S)-salsolidine (559) were obtained with high conversion (50%) and with 98% ee. The (R)carbamate 974 (R = allyl) was further transformed into (R)salsolinol (975) by N-deprotection and O-demethylation (Scheme 163). A kinetic resolution of racemic tetrahydroberberrubine (±)-976 via O-glycosylation using whole cells of Gliocladium deliquescens NRRL 1080 has been worked out by Yu et al.289 It led to a 15:1 mixture of O-glycosylation products in which the (14S)diastereomer 977 was the major one. It was subjected to acid hydrolysis to afford (S)-tetrahydroberberrubine (976), while the minor diastereoisomer 978 was converted into the enantiomer (R)-976 via O-sulfation product 979 and subjected to enzymatic hydrolysis (Scheme 164). A highly efficient chemoenzymatic dynamic kinetic resolution of racemic secondary amines, including tetrahydroisoquinoline CI


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biometallic catalyst composed of the monoamine oxidase (MAO-N-D5)/Pd(0) system. It is worth mentioning that there are reports concerning the synthesis of chiral starting compounds for the synthesis of isoquinoline alkaloids acquired by biocatalytic methods. A stereoselective Bischler−Napieralski synthesis of (1S,3R)-1benzyl-2,3-dimethyltetrahydroisoquinolines 984 and 985, for which chiral β-phenylethylamines 982 and 983 were prepared by biocatalytic stereoselective reductive amination of prochiral ketones 980 and 981, has been developed by Kroutil and coworkers.297 This asymmetric amination controlled by the ωtransaminase (ω-TA)/AlaDH system gave primary amines 982 and 983 in high yield with ee > 99%. N-Methylation followed by condensation with 3-benzyloxyphenylacetic acid and subsequent reduction of the intermediate imine afforded alkaloids 984 and 985 without loss of enantioselectivity in overall yields of 30% and 14%, respectively, in 6 steps (Scheme 166). Finally, the pronounced achievements of the Australian group, led by Banwell,84,91,298−303 in the synthesis of chiral, nonracemic Amaryllidaceae alkaloids, although based only on chemoenzymatically prepared starting material, that is, the cis-1,2dihydrocatechols of general formula 986, deserves attention (Chart 68). Applying enantiomerically pure diols of type 986,

Scheme 165. Mechanism of Deracemization of Racemic NMethyl 1-Benzyltetrahydroisoquinolines to (S)Protoberberines by Two Enzymatic Systems MAO and BBE

Chart 67

Chart 68

readily available from the corresponding aromatics by chemoenzymatic transformations, was reviewed by Hudlicky.304 A diversity of alkaloid’s structures have been constructed, e.g., of lycorine-,298,300,301 crynine-,84,298 montanine-,91,302,303 as well as of pancratistatine-type305 natural and unnatural products. A tricyclic intermediate 987 for the synthesis of pancratistatin analogues has been prepared by Gonzales et al.306 through a sequence of transformations starting with enantiopure bromodiol 986 (X = Br) (Chart 68). The versatile utility of the cis-1,2-dihydrocatechol derivatives 986 for the synthesis of isoquinoline alkaloids can be illustrated by the synthesis of 10-aza-narciclasine (993), showing activity against a variety of cancer cell lines, reported by Hudlicky at al.307 The key feature of the synthesis involved the reaction between two building blocks: conduramine 988, prepared from diol 986

For instance, in initial experiments292 the MAO-N-5/borane system afforded the nonoxidizable (R)-enantiomer of crispine A (177) with 97% ee in 40 h. Later,293 the synthesis was improved using more active MAO-N-9C to give (R)-(+)-crispine A (177) within 2 h with 96% ee. It should be emphasized that the MAO-N D11/BH3−NH3 variant preferentially oxidizes (R)-enantiomers, affording (S)-isomeric products, which was demonstrated by the synthesis of solifenacin (543)294 and 1-benzyltetrahydroisoquinolines,295 all of (S)-configuration. Lloyd et al.296 obtained (R)-1-methyltetrahydroisoquinoline with 96% ee from the racemate by the oxidation/reduction protocol under microwave heating using an enantiomer-specific

Scheme 166. Synthesis of (1S,3R)-1-Benzyl-2,3-dimethyltetrahydroisoquinolines 984 and 985, Prepared from Chiral βPhenylethylamines 982 and 983 by Stereoselective Amination of Prochiral Ketones 980 and 981 Using the Catalytic ω-TA/AlaDH System

CJ


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Scheme 167. Synthesis of 10-Aza-Narciclasine (993) Using Conduramine 988 as a Chiral Substrate

(X = Br), and lithium salt of nicotinic acid 989. N-Boc-protection of the coupling product 990 resulted in imide 991, which by an intramolecular Heck reaction was transformed into tetracycle 992. Removal of N,O-protecting groups furnished 10-azanarciclasine (993) (Scheme 167). Several biocatalytically promoted syntheses of chiral substrates for the synthesis of tetrahydroisoquinoline derivatives have been described in various parts of this review.

purity. Usually the applied methodologies suffer from various limitations such as, e.g., moderate to poor yield, unsatisfactory regio- and stereoselectivity, multistep procedures, and costs of starting material and reagents. Therefore, the question of finding a more efficient and/or simpler synthetic strategy is still open.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

7. CONCLUSION Isoquinoline alkaloids form a large family of natural products showing a wide range of structural diversity and biological and pharmacological activity. Over the past decade much effort has been directed toward development of efficient synthetic methodologies to obtain these alkaloids in chiral nonracemic form. Different strategies based on diastereoselective or enantioselective catalytic methods have been employed. For a long time, isoquinoline alkaloids have been important synthetic targets for organic synthesis, not only to supply medicinally attractive products but also as an intellectual challenge. During the past decade the number of new synthetic strategies and modifications of the traditional procedures has grown markedly. The stereochemical modification of traditional Pictet− Spengler, Bischler−Napieralski, and Pomeranz−Fritsch−Bobbitt methods has been found to be still very useful and explored frequently. Strategies based on closing the nitrogen-containing ring B between bonds C1−N2, N2−C3, C1−N2/N2−C3, and C1− N2/C4−C4a along with introduction of a substituent at the C1 position of the isoquinoline core have been successfully continued as well. Several new syntheses based on biocatalytic methodologies have been recently developed and carried out in many laboratories. Among the natural products synthesized, the antitumor isoquinoline alkaloids have been frequently chosen as the target compounds. Thus, many research groups around the world have carried out detailed studies devoted to the construction of the complex structures of members of the family of the antitumor alkaloids. On the other hand, in many syntheses, crispine A (177 and ent-177) and salsolidine (559 and ent-559), rather simple alkaloids, have been chosen not only because of biological activity but also as reference compounds in assessing the efficiency of a new synthetic method introduced. However, there is no one general method that would secure preparation of all types of isoquinoline alkaloids with high optical

Notes

The authors declare no competing financial interest. Biographies Maria Chrzanowska, born in Poznań, Poland, graduated from the Poznan University of Technology (1981) and received her Ph.D. degree in Chemistry from Adam Mickiewicz University in Poznań under the supervision of Prof. Maria D. Rozwadowska. She was a postdoctoral fellow at the National Institutes of Health, NIDDK, LAC, Medicinal Chemistry Section, Bethesda, MD, USA (1986−1987), under the supervision of Dr. Arnold Brossi. After returning to Adam Mickiewicz University she obtained her habilitation degree in 2005, and in 2007 she got a professor position at the Faculty of Chemistry AMU. Her research has been focused on designing new methods for the synthesis of nonracemic tertiary amines and their further transformations into alkaloid’s system. She is interested in asymmetric synthesis of simple tetrahydroisoquinoline and protoberberine derivatives. Agnieszka Grajewska studied Chemistry at the Adam Mickiewicz University in Poznań, Poland. In 2007, she received her Ph.D. degree from the same institution under the supervision of Prof. Maria D. Rozwadowska. She then spent 1 year as a postdoctoral fellow in Prof. István Markó’s group at the Catholic University of Louvain. Next, she moved to the University of Münster as a Humboldt Postdoctoral Fellow with Professor Martin Oestreich. She is currently Assistant Professor at the Adam Mickiewicz University, Poznań. Her research interests include modern organic asymmetric synthesis and multicomponent reactions. Maria Danuta Rozwadowska is a Professor Emeritus at the Faculty of Chemistry of Adam Mickiewicz University in Poznań, Poland. During her academic carrier her research work concerned various aspects of organic syntheses, in particular, the synthesis of amines and isoquinoline alkaloids, both in racemic and in asymmetric forms. She is the author of two reviewing articles on asymmetric synthesis of isoquinoline alkaloids (published in 1994 and 2004). Her current research activities are focused on the asymmetric synthesis of tetrahydroisoquinoline CK


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(21) Demoulin, N.; Zhu, J. Synthesis of L-3-Hydroxy-4-methoxy-5methylphenylalanol. Synlett 2009, 466−468. (22) Chen, R.; Zhu, D.; Hu, Z.; Zheng, Z.; Chen, X. A New Approach to the Synthesis of L-3-Hydroxy-4-methoxy-5-methylphenylalanine Derivatives from L-Tyrosine. Tetrahedron: Asymmetry 2010, 21, 39−42. (23) Aubry, S.; Pellet-Rostaing, S.; Lemaire, M. Oxidative Nucleophilic Substitution (SNOx) of the Benzylic Position as a Tunable Synthesis of Tetrahydroisoquinoline Natural Alkaloid Analogues. Eur. J. Org. Chem. 2007, 5212−5225. (24) Jin, W.; Williams, R. M. Synthetic Studies on Ecteinascidin 743: Asymmetric Synthesis of the Versatile Amino Acid Component. Tetrahedron Lett. 2003, 44, 4635−4639. (25) Lane, J. W.; Chen, Y.; Williams, R. M. Asymmetric Total Syntheses of (−)-Jorumycin, (−)-Renieramycin G, 3-epi-Jorumycin, and 3-epi-Renieramycin G. J. Am. Chem. Soc. 2005, 127, 12684−12690. (26) Vincent, G.; Williams, R. M. Asymmetric Total Synthesis of (−)-Cribrostatin 4 (Renieramycin H). Angew. Chem., Int. Ed. 2007, 46, 1517−1520; Corrigendum. Angew. Chem., Int. Ed. 2011, 50, 8458. (27) Imai, T.; Nakata, H.; Yokoshima, S.; Fukuyama, T. Synthetic Studies toward Ecteinascidin 743 (Trabectedin). Synthesis 2012, 44, 2743−2753. (28) Corey, E. J.; Xu, F.; Noe, M. C. A Rational Approach to Catalytic Enantioselective Enolate Alkylation Using a Structurally Rigidified and Defined Chiral Quaternary Ammonium Salt under Phase Transfer Conditions. J. Am. Chem. Soc. 1997, 119, 12414−12415. (29) De Paolis, M.; Chen, X.; Zhu, J. A Short Enantioselective Synthesis of Protected L-3-Hydroxy-4-methoxy-5-methyl Phenylalanine and its Corresponding Aldehyde − A Common Subunit of Ecteinascidin-743, Safracin and Congeners. Synlett 2004, 729−731. (30) Couturier, C.; Schlama, T.; Zhu, J. Synthetic Studies towards (−)-Lemonomycin, Synthesis of Fused Tetracycles. Synlett 2006, 1691−1694. (31) Wu, Y.-C.; Bernadat, G.; Masson, G.; Couturier, C.; Schlama, T.; Zhu, J. Synthetic Studies on (−)-Lemonomycin: An Efficient Asymmetric Synthesis of Lemonomycinone Amide. J. Org. Chem. 2009, 74, 2046−2052. (32) Wu, Y.-C.; Liron, M.; Zhu, J. Asymmetric Total Synthesis of (−)-Quinocarcin. J. Am. Chem. Soc. 2008, 130, 7148−7152. (33) Chen, X.; Chen, J.; De Paolis, M.; Zhu, J. Synthetic Studies toward Ecteinascidin 743. J. Org. Chem. 2005, 70, 4397−4408. (34) Chen, X.; Zhu, J. Total Synthesis of the Marine Natural Product (−)-Cribrostatin 4 (Renieramycin H). Angew. Chem., Int. Ed. 2007, 46, 3962−3965. (35) Fishlock, D.; Williams, R. M. Synthetic Studies on Et-743. Asymmetric, Stereocontrolled Construction of the Tetrahydroisoquinoline Core via Radical Cyclization on a Glyoxalimine. Org. Lett. 2006, 8, 3299−3301. (36) Kaniskan, H. U.; Garner, P. An Efficient Synthetic Approach to Cyanocycline A and Bioxalomycin β2 via [C+NC+CC] Coupling. J. Am. Chem. Soc. 2007, 129, 15460−15461. (37) Wu, Y.-C.; Zhu, J. Asymmetric Total Syntheses of (−)-Renieramycin M and G and (−)-Jorumycin Using Aziridine as a Lynchpin. Org. Lett. 2009, 11, 5558−5561. (38) Liao, X. W.; Dong, W. F.; Liu, W.; Guan, B. H.; Liu, Z. Z. Total Synthesis of (−)-MY 336a from L-Tyrosine. J. Heterocycl. Chem. 2010, 47, 50−53. (39) Vincent, G.; Chen, Y.; Lane, J. W.; Williams, R. M. Formation of the C3-C4 Unsaturated Framework of Cribrostatin 4 via DEADMediated Oxidation of an Allylic Tertiary Amine. Heterocycles 2007, 72, 385−398. (40) Chen, J.; Chen, X.; Bois-Choussy, M.; Zhu, J. Total Synthesis of Ecteinascidin 743. J. Am. Chem. Soc. 2006, 128, 87−89. (41) Vincent, G.; Lane, J. W.; Williams, R. M. Regioselectivity of Pictet−Spengler Cyclization Reactions to Construct the Pentacyclic Frameworks of the Ecteinascidin-Saframycin Class of Tetrahydroisoquinoline Antitumor Antibiotics. Tetrahedron Lett. 2007, 48, 3719− 3722.

derivatives with employment of a combination of the two synthetic methods: the Petasis synthesis of amino acids and the Pomeranz− Fritsch−Bobbitt synthesis of isoquinoline derivatives. She is an Honorary Advisor to the Editorial Board of Heterocycles.

ACKNOWLEDGMENTS This work was supported by a research grant from the National Science Centre, Poland (NCN 2011/01/D/ST5/06627). REFERENCES (1) Chrzanowska, M.; Rozwadowska, M. D. Asymmetric Synthesis of Isoquinoline Alkaloids. Chem. Rev. 2004, 104, 3341−3370. (2) Rozwadowska, M. D. Recent Progress in the Enatioselective Synthesis of Isoquinoline Alkaloids. Heterocycles 1994, 39, 903−931. (3) Kaufman, T. S. Synthetic Pathways to Salsolidine. Tetrahedron: Asymmetry 2004, 15, 1203−1237. (4) Bracca, A. B. J.; Kaufman, T. S. Synthetic Approaches to Carnegine, a Simple Tetrahydroisoquinoline Alkaloid. Tetrahedron 2004, 60, 10575−10610. (5) Kaufman, T. S. Approaches to the Total Synthesis of Calycotomine, a Widespread 1-Hydroxymethyl-Substituted Simple Tetrahydroisoquinoline. Synthesis 2005, 339−360. (6) Pässler, U.; Knö lker, H.-J. The Pyrrolo[2,1-a]isoquinoline Alkaloids. The Alkaloids: Chemistry and Biology; Elsevier Inc., 2011; Vol. 70, pp 79−151. (7) Siengalewicz, P.; Rinner, U.; Mulzer, J. Recent Progress in the Total Synthesis of Naphthyridinomycin and Lemonomycin Tetrahydroisoquinoline Antitumor Antibiotics (TAAs). Chem. Soc. Rev. 2008, 37, 2676−2690. (8) Stöckigt, J.; Antonchick, A. P.; Wu, F.; Waldmann, H. The Pictet− Spengler Reaction in Nature and in Organic Chemistry. Angew. Chem., Int. Ed. 2011, 50, 8538−8564. (9) Liu, W.; Liu, S.; Jin, R.; Guo, H.; Zhao, J. Novel Strategies for Catalytic Asymmetric Synthesis of C1-Chiral 1,2,3,4-Tetrahydroisoquinolines and 3,4-Dihydrotetrahydroisoquinolines. Org. Chem. Front. 2015, 2, 288−299. (10) Zein, A. L; Valluru, G.; Georghiou, P. E. Recent Asymmetric Syntheses of Tetrahydroisoquinolines Using “Named” and Some Other Newer Methods. Studies in Natural Products Chemistry; Elsevier B.V., 2012; Vol. 38, pp 53−80. (11) Pesnot, T.; Gershater, M. C.; Ward, J. M.; Hailes, H. C. Phosphate Mediated Biomimetic Synthesis of Tetrahydroisoquinoline Alkaloids. Chem. Commun. 2011, 47, 3242−3244. (12) Leonard, E.; Runguphan, W.; O’Connor, S.; Prather, K. J. Opportunities in Metabolic Engineering to Facilitate Scalable Alkaloid Production. Nat. Chem. Biol. 2009, 5, 292−300. (13) Shamma, M. The Isoquinoline Alkaloids Chemistry and Pharmacology; Academic Press: New York, 1972. (14) Shamma, M.; Moniot, J. L. Isoquinoline Alkaloid Research 1972− 1977; Plenum Press: New York, 1979. (15) Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic Publishers: Amsterdam, 1998. (16) Pictet, A.; Spengler, T. Ü ber die Bildung von Isochinolinderivaten durch Einwirkung von Methylal auf Phenyl-äthylamin, Phenyl-alanin und Tyrosin. Ber. Dtsch. Chem. Ges. 1911, 44, 2030−2036. (17) Larghi, E. L.; Amongero, M.; Bracca, A. B. J.; Kaufman, T. S. The Intermolecular Pictet−Spengler Condensation with Chiral Carbonyl Derivatives in the Stereoselective Syntheses of Optically-Active Isoquinoline and Indole Alkaloids. ARKIVOC 2005, 98−153. (18) Scott, J. D.; Williams, R. M. Chemistry and Biology of the Tetrahydroisoquinoline Antitumor Antibiotics. Chem. Rev. 2002, 102, 1669−1730. (19) Schmidt, E. W.; Nelson, J. T.; Fillmore, J. P. Synthesis of Tyrosine Derivatives for Saframycin MX1 Biosynthetic Studies. Tetrahedron Lett. 2004, 45, 3921−3924. (20) Liao, X. W.; Liu, W.; Dong, W. F.; Guan, B. H.; Chen, S. Z.; Liu, Z. Z. Total Synthesis of (−)-Renieramycin G from L-Tyrosine. Tetrahedron 2009, 65, 5709−5715. CL


Chemical Reviews

Review

(42) Fishlock, D.; Williams, R. M. Synthetic Studies on Et-743. Assembly of the Pentacyclic Core and a Formal Total Synthesis. J. Org. Chem. 2008, 73, 9594−9600. (43) Chan, C.; Zheng, S.; Zhou, B.; Guo, J.; Heid, R. M.; Wright, B. J. D.; Danishefsky, S. J. The Solution to a Deep Stereochemical Conundrum: Studies toward the Tetrahydroisoquinoline Alkaloids. Angew. Chem., Int. Ed. 2006, 45, 1749−1754. (44) Chan, C.; Heid, R.; Zheng, S.; Guo, J.; Zhou, B.; Furuuchi, T.; Danishefsky, S. J. Total Synthesis of Cribrostatin IV: Fine-Tuning the Character of an Amide Bond by Remote Control. J. Am. Chem. Soc. 2005, 127, 4596−4598. (45) Zheng, S.; Chan, C.; Furuuchi, T.; Wright, B. J. D.; Zhou, B.; Guo, J.; Danishefsky, S. J. Stereoselective Formal Synthesis of Ecteinascidin 743. Angew. Chem., Int. Ed. 2006, 45, 1754−1759. (46) Morris, J. C.; Phillips, A. J. Marine Natural Products; Synthetic Aspects. Nat. Prod. Rep. 2008, 25, 95−117. (47) Jimenez-Somarribas, A.; Williams, R. M. Synthetic Studies on Lemonomycin: Construction of the Tetracyclic Core. Tetrahedron 2013, 69, 7505−7512. (48) Siengalewicz, P.; Brecker, L.; Mulzer, J. Stereocontrolled Synthesis of the Tetracyclic Core Framework of (−)-Lemonomycin. Synlett 2008, 2443−2446. (49) Kwon, S.; Myers, A. G. Synthesis of (−)-Quinocarcin by Directed Condensation of α-Amino Aldehydes. J. Am. Chem. Soc. 2005, 127, 16796−16979. (50) Myers, A. G.; Schnider, P.; Kwon, S.; Kung, D. W. Greatly Simplified Procedures for the Synthesis of α-Amino Acids by the Direct Alkylation of Pseudoephedrine Glycinamide Hydrate. J. Org. Chem. 1999, 64, 3322−3327. (51) Dong, W.; Liu, W.; Liao, X.; Guan, B.; Chen, S.; Liu, Z. Asymmetric Total Synthesis of (−)-Saframycin A from L-Tyrosine. J. Org. Chem. 2011, 76, 5363−5368. (52) Liu, Z. Z.; Wang, Y.; Tang, Y.-F.; Chen, S.-Z.; Chen, X.-G.; Li, H.Y. Synthesis and Antitumor Activity of Simplified EcteinascidinSaframycin Analogs. Bioorg. Med. Chem. Lett. 2006, 16, 1282−1285. (53) Liu, W.; Dong, W. F.; Liao, X. W.; Guan, B. H.; Liu, Z. Z. Synthesis of an Isomer of the Renieramycin Skeleton from L-Tyrosine. J. Heterocycl. Chem. 2011, 48, 414−418. (54) Liu, W.; Dong, W.; Liao, X.; Yan, Z.; Guan, B.; Wang, N.; Liu, Z. Synthesis and Cytotoxicity of (−)-Renieramycin G Analogs. Bioorg. Med. Chem. Lett. 2011, 21, 1419−1421. (55) Chen, R.; Liu, H.; Chen, X. Asymmetric Total Synthesis of (−)-Jorunnamycins A and C and (−)-Jorumycin from L-Tyrosine. J. Nat. Prod. 2013, 76, 1789−1795. (56) Liu, H.; Chen, R.; Chen, X. A Rapid and Efficient Access to Renieramycin-type Alkaloids featuring a Temperature-dependent Stereoselective Cyclization. Org. Biomol. Chem. 2014, 12, 1633−1640. (57) Chen, J.; Chen, X.; Willot, M.; Zhu, J. Asymmetric Total Syntheses of Ecteinascidin 597 and Ecteinascidin 583. Angew. Chem., Int. Ed. 2006, 45, 8028−8032. (58) Kawagishi, F.; Toma, T.; Inui, T.; Yokoshima, S.; Fukuyama, T. Total Synthesis of Ecteinascidin 743. J. Am. Chem. Soc. 2013, 135, 13684−13687. (59) Aubry, S.; Pellet-Rostaing, S.; Fenet, B.; Lemaire, M. Synthetic Investigations of (1,3′)-Bistetrahydroisoquinolines: toward Pentacyclic Analogues of Piperazine Core Alkaloids. Tetrahedron Lett. 2006, 47, 1319−1323. (60) Aubry, S.; Pellet-Rostaing, S.; Fournier Dit Chabert, J.; Ducki, S.; Lemaire, M. Synthesis and Inhibition of Cancer Cell Proliferation of (1,3′)-Bis-tetrahydroisoquinolines and Piperazine systems. Bioorg. Med. Chem. Lett. 2007, 17, 2598−2602. (61) Gomez-Monterrey, I. M.; Campiglia, P.; Bertamino, A.; Mazzoni, O.; Diurno, M. V.; Novellino, E.; Grieco, P. A Novel Approach to the Synthesis of Diaza-bridged Heterocyclic Derivatives. Tetrahedron 2006, 62, 8083−8088. (62) Obika, S.; Yasui, Y.; Yanada, R.; Takemoto, Y. Concise Synthesis of the CDE Ring System of Tetrahydroisoquinoline Alkaloids Using Carbophilic Lewis Acid-Catalyzed Hydroxyamination and Oxidative Friedel−Crafts Cyclization. J. Org. Chem. 2008, 73, 5206−5209.

(63) Enomoto, T.; Yasui, Y.; Takemoto, T. Synthetic Study toward Ecteinascidin 743: Concise Construction of the Diazabicyclo[3.3.1]nonane Skeleton and Assembly of the Pentacyclic Core. J. Org. Chem. 2010, 75, 4876−4879. (64) Gurram, M.; Gyimóthy, B.; Wang, R.; Lam, S. Q.; Ahmed, F.; Herr, R. J. Concise Enantiospecific, Stereoselective Syntheses of (+)-Crispine A and Its (−)-Antipode. J. Org. Chem. 2011, 76, 1605− 1613. (65) Aubry, S.; Pellet-Rostaing, S.; Faure, R.; Lemaire, M. Racemic and Diastereoselective Synthesis of Aryl and Heteroaryl Tetrahydroisoquinolines via the Pictet−Spengler Reaction. J. Heterocycl. Chem. 2006, 43, 139−148. (66) Wang, Y.; Liu, Z. Z.; Chen, S. Z.; Liang, X. T. Asymmetric Pictet− Spengler Reactions: Synthesis of Tetrahydroisoquinoline Derivatives from L-DOPA. Chin. Chem. Lett. 2004, 15, 505−507. (67) Allin, S. M.; Streetley, G. B.; Slater, M.; James, S. L.; Martin, W. P. A Formal Asymmetric Synthesis of both Enantiomers of the Erythrina Alkaloid 3-Demethoxyerythratidinone. Tetrahedron Lett. 2004, 45, 5493−5496. (68) Bassas, O.; Llor, N.; Santos, M. M. M; Griera, R.; Molins, E.; Amat, M.; Bosch, J. Biogenetically Inspired Enantioselective Approach to Indolo[2,3-a]- and Benzo[a]quinolizidine Alkaloids from a Synthetic Equivalent of Secologanin. Org. Lett. 2005, 7, 2817−2820. (69) Allin, S. M.; Duffy, L. J.; Page, P. C. B.; McKee, V.; Edgar, M.; McKenzie, M. J.; Amat, M.; Bassas, O.; Santos, M. M. M; Bosch, J. Complementary Routes for the Stereoselective Synthesis of Functionalized Benzoquinolizidine Targets. Tetrahedron Lett. 2006, 47, 5713− 5716. (70) Amat, M.; Santos, M. M. M; Bassas, O.; Llor, N.; Escolano, C.; Gomez-Esque, A.; Molins, E.; Allin, S. M.; McKee, V.; Bosch, J. Straighforward Methodology for the Enantioselective Synthesis of Benzo[a]- and Indolo[2,3-a]quinolizidines. J. Org. Chem. 2007, 72, 5193−5201. (71) Garcia, E.; Arrasate, S.; Lete, E.; Sotomayor, N. Diastereoselective Intramolecular α-Amidoalkylation Reactions of L-DOPA Derivatives. Asymmetric Synthesis of Pyrrolo[2,1-a]isoquinolines. J. Org. Chem. 2005, 70, 10368−10374. (72) Sánchez-Obregón, R.; Ortiz, B.; Mastranzo, V. M.; Yuste, F.; Ruano, J. L. G. Short Stereoselective Synthesis of (+)-Crispine A via an N-Sulfinyl Pictet−Spengler Reaction. Tetrahedron Lett. 2013, 54, 1893− 1896. (73) Hellal, M.; Singh, S.; Cuny, G. D. Monoligated Pd(0)-catalyzed Intramolecular ortho- and para-Arylation of Phenols for the Synthesis of Aporphine Alkaloids. Synthesis of (−)-Lirinine. Tetrahedron 2012, 68, 1674−1681. (74) Zhang, F.; Simpkins, N. S.; Wilson, C. An Enantiospecific Synthesis of (+)-Demethoxyerythratidinone from (S)-Malic Acid: Key Observations Concerning the Diastereocontrol in Malic Acid-derived N-Acyliminium Ion Cyclisations. Tetrahedron Lett. 2007, 48, 5942− 5947. (75) Mostowicz, D.; Wójcik, R.; Dołęga, G.; Kałuża, Z. Diastereoselective Synthesis of 10b-Substituted Hexahydropyrroloisoquinolines from L-Tartaric Acid. Creation of a Quaternary Carbon Stereocentre via N-Acyliminium Ion Cyclization. Tetrahedron Lett. 2004, 45, 6011−6015. (76) Kałuża, Z.; Mostowicz, D.; Dołęga, G.; Mroczko, K.; Wójcik, R. 10b-Substituted Hexahydropyrrolo-isoquinolines: Studies on Diastereoselective Formation of a Quaternary Carbon Stereocenter via NAcyliminium Ion Cyclization. Tetrahedron 2006, 62, 943−953. (77) Kałuża, Z.; Mostowicz, D.; Dołęga, G.; Wójcik, R. A New Route to Optically Pure Highly Functionalized Tetrahydro-isoquinolines with a Quaternary Carbon Stereocenter. Tetrahedron 2008, 64, 2321−2328. (78) Mostowicz, D.; Dygas, M.; Kałuża, Z. Heck Cyclization Strategy for Preparation of Erythrinan Alkaloids: Asymmetric Synthesis of Unnatural (−)-Erysotramidine from L-Tartaric Acid. J. Org. Chem. 2015, 80, 1957−1963. (79) Blake, A. J.; Gill, C.; Greenhalgh, D. A.; Simpkins, N. S.; Zhang, F. An Asymmetric Synthesis of (+)-Erysotramidine. Synthesis 2005, 3287− 3292. CM


Chemical Reviews

Review

Three Contigous Stereocenters. Angew. Chem., Int. Ed. 2013, 52, 593− 596. (101) Rodrigues, J. A. R.; Abramovitch, R. A.; de Sousa, J. D. F.; Leiva, G. C. Diastereoselective Synthesis of Cularine Alkaloids via Enium Ions and an Easy Entry to Isoquinolines by Aza-Wittig Electrocyclic Ring Closure. J. Org. Chem. 2004, 69, 2920−2928. (102) Zein, A. L.; Dakhil, O. O.; Dawe, L. N.; Georghiou, P. E. Enantioselective Syntheses and X-Ray Structures of (S)- and (R)-NNorlaudanidine: Trace Opium Constituents. Tetrahedron Lett. 2010, 51, 177−180. (103) Zein, A. L.; Dawe, L. N.; Georghiou, P. E. Enantioselective Total Synthesis and X-Ray Structures of the Tetrahydroprotoberberine Alkaloids (−)-(S)-Tetrahydropalmatrubine and (−)-(S)-Corytenchine. J. Nat. Prod. 2010, 73, 1427−1430. (104) Zhong, M.; Jiang, Y.; Chen, Y.; Yan, Q.; Liu, J.; Di, D. Asymmetric Total Synthesis of (S)-Isocorydine. Tetrahedron: Asymmetry 2015, 26, 1145−1149. (105) Gao, S.; Cheng, J.-J.; Ling, C.-Y.; Chu, W.-J.; Yang, Y.-S. A Practical Enantioselective Total Synthesis of (−)-(S)-Stepholidine. Tetrahedron Lett. 2014, 55, 4856−4859. (106) Kawabata, Y.; Naito, Y.; Saitoh, T.; Kawa, K.; Fuchigami, T.; Nishiyama, S. Synthesis of (+)-O-Methylthalibrine by Employing a Stereocontrolled Bischler−Napieralski Reaction and an Electrochemically Generated Diaryl Ether. Eur. J. Org. Chem. 2014, 2014, 99−104. (107) Allin, S. M.; Gaskell, S. N.; Towler, J. M. R.; Page, P. C. B; Saha, B.; McKenzie, M. J.; Martin, W. P. A New Asymmetric Synthesis of the Anti-Tumor Alkaloid (R)-(+)-Crispine A. J. Org. Chem. 2007, 72, 8972− 8975. (108) Gurjar, M. K.; Pramanik, C.; Bhattasali, D.; Ramana, C. V.; Mohapatra, D. K. Total Syntheses of Schulzeines B and C. J. Org. Chem. 2007, 72, 6591−6594. (109) Watanabe, T.; Tanaka, Y.; Shoda, R.; Sakamoto, R.; Kamikawa, K.; Uemura, M. Stereoselective Synthesis of Atropisomeric Korupensamines A and B Utilizing Planar Chiral Arene Chromium Complex. J. Org. Chem. 2004, 69, 4152−4158. (110) Huang, S.; Petersen, T. B.; Lipshutz, B. H. Total Synthesis of (+)-Korupensamine B via an Atropselective Intermolecular Biaryl Coupling. J. Am. Chem. Soc. 2010, 132, 14021−14023. (111) Bungard, C. J.; Morris, J. C. Total Synthesis of the 7,3′-Linked Naphthylisoquinoline Alkaloid Ancistrocladidine. J. Org. Chem. 2006, 71, 7354−7363. (112) Bringmann, G.; Gulder, T.; Hertlein, B.; Hemberger, Y.; Meyer, F. Total Synthesis of the N,C-Coupled Naphthylisoquinoline Alkaloids Ancistrocladinium A and B and Related Analogues. J. Am. Chem. Soc. 2010, 132, 1151−1158. (113) Cagide-Fagín, F.; Nieto-García, O.; Lago-Santomé, H.; Alonso, R. Enantioselective Synthesis of Protected Nitrocyclohexitols with Five Stereocenters. Total Synthesis of (+)-Pancratistatin. J. Org. Chem. 2012, 77, 11377−11382. (114) Chavan, P. S.; Garai, S.; Dey, C.; Gonnade, R. G. A Highly Stereocontrolled Asymmetric Total Synthesis of Epimer of (+)-7Deoxypancratistatin. Tetrahedron Lett. 2013, 54, 5562−5566. (115) Nadein, O. N.; Kornienko, A. An Approach to Pancratistatins via Ring-Closing Metathesis: Efficient Synthesis of Novel 1-Aryl-1deoxyconduritols F. Org. Lett. 2004, 6, 831−834. (116) Yamada, K.; Yamashita, M.; Sumiyoshi, T.; Nishimura, K.; Tomioka, K. Total Synthesis of (−)-Lycorine and (−)-2-epi-Lycorine by Asymmetric Conjugate Addition Cascade. Org. Lett. 2009, 11, 1631− 1633. (117) Nishimura, K.; Fukuyama, N.; Yasuhara, T.; Yamashita, M.; Sumiyoshi, T.; Yamamoto, Y.; Yamada, K.; Tomioka, K. A Short Synthesis of (+)-β-Lycorane by Asymmetric Conjugate Addition Cascade. Tetrahedron 2015, 71, 7222−7226. (118) Sun, Z.; Zhou, M.; Li, X.; Meng, X.; Peng, F.; Zhang, H.; Shao, Z. Catalytic Asymmetric Assembly of Octahydroindolones: Divergent Synthesis of Lycorine-type Amaryllidaceae Alkaloids (+)-α-Lycorane and (+)-Lycorine. Chem. - Eur. J. 2014, 20, 6112−6119.

(80) Tietze, L. F.; Tölle, N.; Kratzert, D.; Stalke, D. Efficient Formal Total Synthesis of the Erythrina Alkaloid (+)-Erysotramidine, Using a Domino Process. Org. Lett. 2009, 11, 5230−5233. (81) Goff, D. A. Diverse Alkaloid-like Structures from a Common Building Block. Tetrahedron 2013, 69, 242−256. (82) Allef, P.; Kunz, H. Glycosylation-Induced Asymmetric Synthesis of 1-Substituted Tetrahydroisoquinolines. Heterocycles 2007, 74, 421− 436. (83) Rousseau, G.; Lebeuf, R.; Schenk, K.; Castet, F.; Robert, F.; Landais, Y. Base-Catalyzed Intramolecular Hydroamination of Cyclohexa-2,5-dienes: Insights into the Mechanism through DFT Calculations and Applications to the Total Synthesis of epi-Elwesine. Chem. Eur. J. 2014, 20, 14771−14782. (84) Findlay, A. D.; Banwell, M. G. A Chemoenzymatic Total Synthesis of (+)-Amabiline. Org. Lett. 2009, 11, 3160−3162. (85) Liu, G.; Romo, D. Enantioselective Synthesis of Schulzeines B and C via a β-Lactone-Derived Surrogate for Bishomoserine Aldehyde. Org. Lett. 2009, 11, 1143−1146. (86) Bowen, E. G.; Wardrop, D. J. Total Synthesis of the α-Glucosidase Inhibitors Schulzeine A, B, and C and a Structural Revision of Schulzeine A. J. Am. Chem. Soc. 2009, 131, 6062−6063. (87) Kuntiyong, P.; Akkarasamiyo, S.; Eksinitkun, G. Short Synthetic Route toward the Tricyclic Core of Schulzeines. Chem. Lett. 2006, 35, 1008−1009. (88) Morris, J. C.; Phillips, A. J. Marine Natural Products: Synthetic Aspects. Nat. Prod. Rep. 2011, 28, 269−289. (89) Anada, M.; Tanaka, M.; Shimada, N.; Nambu, H.; Yamawaki, M.; Hashimoto, S. Asymmetric Formal Synthesis of (−)-Pancracine via Catalytic Enantioselective C-H Amination Process. Tetrahedron 2009, 65, 3069−3077. (90) Pansare, S. V.; Lingampally, R.; Kirby, R. L. Stereoselective Synthesis of 3-Aryloctahydroindoles and Application in a Formal Synthesis of (−)-Pancracine. Org. Lett. 2010, 12, 556−559. (91) Banwell, M. G.; Kokas, O. J.; Willis, A. C. Chemoenzymatic Approaches to the Montanine Alkaloids: A Total Synthesis of (+)-Brunsvigine. Org. Lett. 2007, 9, 3503−3506. (92) Bao, X.; Cao, Y.-X.; Chu, W.-D.; Qu, H.; Du, J.-Y.; Zhao, X.-H.; Ma, X.-Y.; Wang, C.-T.; Fan, C.-A. Bioinspired Total Synthesis of Montanine-Type Amaryllidaceae Alkaloids. Angew. Chem., Int. Ed. 2013, 52, 14167−14172. (93) Ku, A. F.; Cuny, G. D. Synthetic Studies of 7-Oxygenated Aporphine Alkaloids: Preparation of (−)-Oliveroline, (−)-Nornuciferidine, and Derivatives. Org. Lett. 2015, 17, 1134−1137. (94) Collins, J.; Drouin, M.; Sun, X.; Rinner, U.; Hudlicky, T. Total Synthesis of 7-Deoxypancratistatin-1-carboxaldehyde and Carboxylic Acid via Solvent-Free Intramolecular Aziridine Opening: Phenanthrene to Phenanthridone Cyclization Strategy. Org. Lett. 2008, 10, 361−364. (95) Toda, Y.; Terada, M. Relay Catalysis by a Ruthenium ComplexChiral Brønsted Acid Binary System for Ternary Reaction Sequence Involving Enantioselective Pictet−Spengler-Type Cyclization as the Key Step. Synlett 2013, 24, 752−756. (96) Franzen, J.; Fisher, A. Asymmetric Alkaloid Synthesis: A One-Pot Organocatalytic Reaction to Quinolizidine Derivatives. Angew. Chem., Int. Ed. 2009, 48, 787−791. (97) Mons, E.; Wanner, M. J.; Ingemann, S.; van Maarseveen, J. H.; Hiemstra, H. Organocatalytic Enantioselective Pictet−Spengler Reactions for the Syntheses of 1-Substituted 1,2,3,4-Tetrahydroisoquinolines. J. Org. Chem. 2014, 79, 7380−7390. (98) Ruiz-Olalla, A.; Würdemann, M. A.; Wanner, M. J.; Ingemann, S.; van Maarseveen, J. H.; Hiemstra, H. Organocatalytic Enantioselective Pictet−Spengler Approach to Biologically Relevant 1-Benzyl-1,2,3,4Tetrahydroisoquinoline Alkaloids. J. Org. Chem. 2015, 80, 5125−5132. (99) Li, G.; Xie, J.-H.; Hou, J.; Zhu, S.-F.; Zhou, Q.-L. Catalytic Asymmetric Hydrogenation of α-Arylcyclohexanones and Total Synthesis of (−)-α-Lycorane. Adv. Synth. Catal. 2013, 355, 1597−1604. (100) Liu, C.; Xie, J.-H.; Li, Y.-L.; Chen, J.-Q.; Zhou, Q.-L. Asymmetric Hydrogenation of α,α′-Disubstituted Cycloketones through Dynamic Kinetic Resolution: An Efficient Construction of Chiral Diols with CN


Chemical Reviews

Review

Simple Noyori-Type Catalysts in Aqueous Media. Chem. - Eur. J. 2009, 15, 12963−12967. (139) Haraguchi, N.; Tsuru, K.; Arakawa, Y.; Itsuno, S. Asymmetric Transfer Hydrogenation of Imines Catalyzed by a Polymer-immobilized Chiral Catalyst. Org. Biomol. Chem. 2009, 7, 69−75. (140) Martins, J. E. D.; Clarkson, G. J.; Wills, M. Ru(II) Complexes of N-Alkylated TsDPEN Ligands in Asymmetric Transfer Hydrogenation of Ketones and Imines. Org. Lett. 2009, 11, 847−850. (141) Martins, J. E. D.; Redondo, M. A. C.; Wills, M. Applications of N′-alkylated Derivatives of TsDPEN in the Asymmetric Transfer Hydrogenation of CO and CN Bonds. Tetrahedron: Asymmetry 2010, 21, 2258−2264. (142) Williams, G. D.; Wade, C. E.; Wills, M. One-pot Formation of Nitrogen-containing Heterocyclic Ring Systems Using a Deprotection− Cyclisation−Asymmetric Reduction Sequence. Chem. Commun. 2005, 4735−4737. (143) Wu, J.; Wang, F.; Ma, Y.; Cui, X.; Cun, L.; Zhu, J.; Deng, J.; Yu, B. Asymmetric Transfer Hydrogenation of Imines and Iminiums Catalyzed by a Water-Soluble Catalyst in Water. Chem. Commun. 2006, 1766− 1768. (144) Li, L.; Wu, J.; Wang, F.; Liao, J.; Zhang, H.; Lian, C.; Zhu, J.; Deng, J. Asymmetric Transfer Hydrogenation of Ketones and Imines with Novel Water-Soluble Chiral Diamine as Ligand in Neat Water. Green Chem. 2007, 9, 23−25. (145) Blackmond, D. G.; Ropic, M.; Stefinovic, M. Kinetic Studies of the Asymmetric Transfer Hydrogenation of Imines with Formic Acid Catalyzed by Rh-Diamine Catalysts. Org. Process Res. Dev. 2006, 10, 457−463. (146) Werner, F.; Blank, N.; Opatz, T. Synthesis of (−)-(S)Norlaudanosine, (+)-(R)-O,O-Dimethylcoclaurine, and (+)-(R)-Salsolidine by Alkylation of an α-Aminonitrile. Eur. J. Org. Chem. 2007, 2007, 3911−3915. (147) Canivet, J.; Süss-Fink, G. Water-Soluble Arene Ruthenium Catalysts Containing Sulfonated Diamine Ligands for Asymmetric Transfer Hydrogenation of α-Aryl Ketones and Imines in Aqueous Solution. Green Chem. 2007, 9, 391−397. (148) Wu, Z.; Perez, M.; Scalone, M.; Ayad, T.; Ratovelomanana-Vidal, V. Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of 1Aryl-Substituted Dihydroisoquinolines: Access to Valuable Chiral 1Aryl-Tetrahydroisoquinoline Scaffolds. Angew. Chem., Int. Ed. 2013, 52, 4925−4928. (149) Perez, M.; Wu, Z.; Scalone, M.; Ayad, T.; Ratovelomanana-Vidal, V. Enantioselective Synthesis of 1-Aryl-Substituted Tetrahydroisoquinolines Through Ru-Catalyzed Asymmetric Transfer Hydrogenation. Eur. J. Org. Chem. 2015, 2015, 6503−6514. (150) Blank, N.; Opatz, T. Enantioselective Synthesis of Tetrahydroprotoberberines and Bisbenzylisoquinoline Alkaloids from a Deprotonated α-Aminonitrile. J. Org. Chem. 2011, 76, 9777−9784. (151) Přech, J.; Václavík, J.; Šot, P.; Pechácě k, J.; Vilhanová, B.; Janušcǎ ḱ , J.; Syslová, K.; Pažout, R.; Maixner, J.; Zápal, J.; Kuzma, M.; Kačer, P. Asymmetric Transfer Hydrogenation of 1-Phenyl Dihydroisoquinolines Using Ru(II) Diamine Catalysts. Catal. Commun. 2013, 36, 67−70. (152) Vilhanová, B.; Matoušek, V.; Václavík, J.; Syslová, K.; Přech, J.; Pechácě k, J.; Šot, P.; Janušcǎ ḱ , J.; Toman, J.; Zápal, J.; Kuzma, M.; Kačer, P. Two Optimized Synthetic Pathways Toward a Chiral Precursor of Mivacurium Chloride and Other Skeletal Muscle Relaxants. Tetrahedron: Asymmetry 2013, 24, 50−55. (153) Pyo, M. K.; Lee, D.-H.; Kim, D.-H.; Lee, J.-H.; Moon, J.-C.; Chang, K. C.; Yun-Choi, H. S. Enantioselective Synthesis of (R)-(+)and (S)-(−)-Higenamine and their Analogues with Effects on Platelet Aggregation and Experimental Animal Model of Disseminated Intravascular Coagulation. Bioorg. Med. Chem. Lett. 2008, 18, 4110−4114. (154) Wu, H.-P.; Lu, T.-N.; Hsu, N.-Y.; Chang, C.-C. Absolute Stereochemical Assignment of SCH 71450, a Selective Dopamine D4 Receptor Antagonist, Through Enantioselective Epimer Synthesis. Eur. J. Org. Chem. 2013, 2898−2905. (155) Cheng, J.-J.; Yang, Y.-S. Enantioselective Total Synthesis of (−)-(S)-Stepholidine. J. Org. Chem. 2009, 74, 9225−9228.

(119) Bera, S.; Das, S. K.; Saha, T.; Panda, G. Total Synthesis of 3-epi(+)-Lycoricidine from Garner Aldehyde via Intramolecular Aldol Cyclization. Tetrahedron Lett. 2015, 56, 146−149. (120) Jana, C. K.; Studer, A. Total Synthesis of (+)-transDihydronarciclasine by a Catalytic Enantioselective Regiodivergent Nitroso Diels−Alder Reaction. Chem. - Eur. J. 2008, 14, 6326−6328. (121) Szántó, G.; Hegedű s, L.; Mattyasovszky, L.; Simon, A.; Simon, Á .; Bitter, I.; Tóth, G.; Tő ke, L.; Kádas, I. An Expedient Total Synthesis of ent-(−)-7-Deoxy-trans-dihydronarciclasine. Tetrahedron 2009, 65, 8412−8417. (122) Allan, K. M.; Stoltz, B. M. A Concise Total Synthesis of (−)-Quinocarcin via Aryne Annulation. J. Am. Chem. Soc. 2008, 130, 17270−17271. (123) Sun, X.; Ma, D. Organocatalytic Approach for the Syntheses of Corynantheidol, Dihydrocorynantheol, Protoemetinol, Protoemetine, and Mitragynine. Chem. - Asian J. 2011, 6, 2158−2165. (124) Zhao, D.; Glorius, F. Enantioselective Hydrogenation of Isoquinolines. Angew. Chem., Int. Ed. 2013, 52, 9616−9618. (125) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Asymmetric Hydrogenation of Quinolines and Isoquinolines Activated by Chloroformates. Angew. Chem., Int. Ed. 2006, 45, 2260−2263. (126) Shi, L.; Ye, Z.-S.; Cao, L.-L.; Guo, R.-N.; Hu, Y.; Zhou, Y.-G. Enantioselective Iridium-Catalyzed Hydrogenation of 3,4-Disubstituted Isoquinolines. Angew. Chem., Int. Ed. 2012, 51, 8286−8289. (127) Ye, Z.-S.; Guo, R.-N.; Cai, X.-F.; Chen, M.-W.; Shi, L.; Zhou, Y.G. Enantioselective Iridium-Catalyzed Hydrogenation of 1- and 3Substituted Isoquinolinium Salts. Angew. Chem., Int. Ed. 2013, 52, 3685−3689. (128) Iimuro, A.; Yamaji, K.; Kandula, S.; Nagano, T.; Kita, Y.; Mashima, K. Asymmetric Hydrogenation of Isoquinolinium Salts Catalyzed by Chiral Iridium Complexes: Direct Synthesis for Optically Active 1,2,3,4-Tetrahydroisoquinolines. Angew. Chem., Int. Ed. 2013, 52, 2046−2050. (129) Ružič, M.; Pečavar, A.; Prudič, D.; Kralj, D.; Scriban, C.; ZanottiGerosa, A. The Development of an Asymmetric Hydrogenation Process for the Preparation of Solifenacin. Org. Process Res. Dev. 2012, 16, 1293− 1300. (130) Yan, P.-C.; Xie, J.-H.; Hou, G.-H.; Wang, L.-X.; Zhou, Q.-L. Enantioselective Synthesis of Chiral Tetrahydroisoquinolines by Iridium-Catalyzed Asymmetric Hydrogenation of Enamines. Adv. Synth. Catal. 2009, 351, 3243−3250. (131) Hou, G.-H.; Xie, J.-H.; Yan, P.-C.; Zhou, Q.-L. Iridium-Catalyzed Asymmetric Hydrogenation of Cyclic Enamines. J. Am. Chem. Soc. 2009, 131, 1366−1367. (132) Chang, M.; Li, W.; Zhang, X. A Highly Efficient and Enantioselective Access to Tetrahydroisoquinoline Alkaloids: Asymmetric Hydrogenation with an Iridium Catalyst. Angew. Chem., Int. Ed. 2011, 50, 10679−10681. (133) Jackson, M.; Lennon, I. C. 1,2-Bis(2,5-diphenylphospholano)methane, a New Ligand for Asymmetric Hydrogenation. Tetrahedron Lett. 2007, 48, 1831−1834. (134) Ding, Z.-Y.; Wang, T.; He, Y.-M.; Chen, F.; Zhou, H.-F.; Fan, Q.H.; Guo, Q.; Chan, A. S. C. Highly Enantioselective Synthesis of Chiral Tetrahydroquinolines and Tetrahydroisoquinolines by RutheniumCatalyzed Asymmetric Hydrogenation in Ionic Liquid. Adv. Synth. Catal. 2013, 355, 3727−3735. (135) Li, C.; Xiao, J. Asymmetric Hydrogenation of Cyclic Imines with an Ionic Cp*Rh(III) Catalyst. J. Am. Chem. Soc. 2008, 130, 13208− 13209. (136) Mršić, N.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. Iridium/ Monodentate Phosphoramidite Catalyzed Asymmetric Hydrogenation of N-Aryl Imines. J. Am. Chem. Soc. 2009, 131, 8358−8359. (137) Berhal, F.; Wu, Z.; Zhang, Z.; Ayad, T.; Ratovelomanana-Vidal, V. Enantioselective Synthesis of 1-Aryl-tetrahydroisoquinolines through Iridium Catalyzed Asymmetric Hydrogenation. Org. Lett. 2012, 14, 3308−3311. (138) Evanno, L.; Ormala, J.; Pihko, P. M. A Highly Enantioselective Access to Tetrahydroisoquinoline and β-Carboline Alkaloids with CO


Chemical Reviews

Review

(156) Sun, H.; Zhu, L.; Yang, H.; Qian, W.; Guo, L.; Zhou, S.; Gao, B.; Li, Z.; Zhou, Y.; Jiang, H.; Chen, K.; Zhen, X.; Liu, H. Asymmetric Total Synthesis and Identification of Tetrahydroprotoberberine Derivatives as New Antipsychotic Agents Possessing a Dopamine D1, D2 and Serotonin 5-HT1A Multi-Action Profile. Bioorg. Med. Chem. 2013, 21, 856−868. (157) Szawkało, J.; Czarnocki, Z. Enantioselective Synthesis of Some Tetracyclic Isoquinoline Alkaloids by Asymmetric Transfer Hydrogenation Catalysed by a Chiral Ruthenium Complex. Monatsh. Chem. 2005, 136, 1619−1627. (158) Szawkało, J.; Czarnocki, S. J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.; Czarnocki, Z.; Drabowicz, J. Enantioselective Synthesis of Some Tetrahydroisoquinoline and Tetrahydro-βCarboline Alkaloids. Tetrahedron: Asymmetry 2007, 18, 406−413. (159) Szawkało, J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Drabowicz, J.; Czarnocki, Z. First Enantioselective Synthesis of the Antitumour Alkaloid (+)-Crispine A and Determination of its Enantiomeric Purity by 1H NMR. Tetrahedron: Asymmetry 2005, 16, 3619−3621. (160) Roszkowski, P.; Maurin, J. K.; Czarnocki, Z. Enantioselective Synthesis of (R)-(−)-Praziquantel (PZQ). Tetrahedron: Asymmetry 2006, 17, 1415−1419. (161) Czarnocki, S. J.; Wojtasiewicz, K.; Józw ́ iak, A. P.; Maurin, J. K.; Czarnocki, Z.; Drabowicz, J. Enantioselective Synthesis of (+)-Trypargine and (+)-Crispine E. Tetrahedron 2008, 64, 3176−3182. (162) Zhai, H.; Miller, J.; Sammis, G. First Enantioselective Syntheses of the Dopamine D1 and D2 Receptor Modulators, (+)- and (−)-Govadine. Bioorg. Med. Chem. Lett. 2012, 22, 1557−1559. (163) Tietze, L. F.; Rackelmann, N.; Müller, I. Enantioselective Total Syntheses of the Ipecacuanha Alkaloid Emetine, the Alangium Alkaloid Tubulosine and a Novel Benzoquinolizidine Alkaloid by Using a Domino Process. Chem. - Eur. J. 2004, 10, 2722−2731. (164) Zhu, R.; Xu, Z.; Ding, W.; Liu, S.; Shi, X.; Lu, X. Efficient and Practical Syntheses of Enantiomerically Pure (S)-(−)-Norcryptostyline I, (S)-(−)-Norcryptostyline II, (R)-(+)-Salsolidine and (S)-(−)-Norlaudanosine via a Resolution-Racemization Method. Chin. J. Chem. 2014, 32, 1039−1048. (165) Monnard, F. W.; Nogueira, E. S.; Heinisch, T.; Schirmer, T.; Ward, T. R. Human Carbonic Anhydrase II as Host Protein for the Creation of Artificial Metalloenzymes: the Asymmetric Transfer Hydrogenation of Imines. Chem. Sci. 2013, 4, 3269−3274. (166) Heinisch, T.; Pellizzoni, M.; Dürrenberger, M.; Tinberg, C. E.; Köhler, V.; Klehr, J.; Häussinger, D.; Baker, D.; Ward, T. R. Improving the Catalytic Performance of an Artificial Metalloenzyme by Computational Design. J. Am. Chem. Soc. 2015, 137, 10414−10419. (167) Mori, K.; Rikimaru, K.; Kan, T.; Fukuyama, T. Synthetic Studies on (+)-Naphthyridinomycin: Stereoselective Synthesis of the Tetracyclic Core Framework. Org. Lett. 2004, 6, 3095−3097. (168) Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Synthetic Studies on (−)-Lemonomycin: Stereocontrolled Construction of the 3,8Diazabicyclo[3.2.1] Skeleton. Chem. Commun. 2005, 394−396. (169) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. Total Synthesis of Ecteinascidin 743. J. Am. Chem. Soc. 2002, 124, 6552−6554. (170) Chen, X.; Chen, J.; Zhu, J. Synthetic Studies on Ecteinascidin 743 (Et 743): Asymmetric Synthesis of a Highly Oxygenated Tetrahydroisoquinoline via Key Phenolic Mannich Reaction. Synthesis 2006, 4081−4086. (171) Anakabe, E.; Carrillo, L.; Badia, D.; Vicario, J. L.; Villegas, M. Stereoselective Synthesis of Aporphinane Alkaloids Using a Hypervalent Iodine(III) Reagent-Promoted Oxidative Nonphenolic Biaryl Coupling Reaction. Total Synthesis of (S)-(+)-Glaucine. Synthesis 2004, 1093− 1101. (172) Kościołowicz, A.; Rozwadowska, M. D. Diastereoselective Pomeranz−Fritsch−Bobbitt Synthesis of (S)-(−)-Salsolidine using (R)N-tert-Butanesulfinylimine as a Substrate. Tetrahedron: Asymmetry 2006, 17, 1444−1448.

(173) Grajewska, A.; Rozwadowska, M. D. Total Synthesis of (R)(+)-Salsolidine by Hydride Addition to (R)-N-tert-Butanesulfinyl Ketimine. Tetrahedron: Asymmetry 2007, 18, 557−561. (174) Grajewska, A.; Rozwadowska, M. D. Diastereoselective Pomeranz−Fritsch−Bobbitt Synthesis of (S)-(−)-O-Methylbharatamine using (S)-N-tert-Butanesulfinimine as a Substrate. Tetrahedron: Asymmetry 2007, 18, 2910−2914. (175) Chrzanowska, M.; Dreas, A. The Asymmetric Synthesis of (R)(+)- and (S)-(−)-O-Methylbharatamine. Tetrahedron: Asymmetry 2004, 15, 2561−2567. (176) Chrzanowska, M.; Dreas, A.; Rozwadowska, M. D. Synthesis of (S)-(−)- and (R)-(+)-O-Methylbharatamine using a Diastereoselective Pomeranz−Fritsch−Bobbitt Methodology. Tetrahedron: Asymmetry 2005, 16, 2954−2958. (177) Głuszyńska, A.; Rozwadowska, M. D. Enantioselective Addition of Methyllithium to a Prochiral Imine−the Substrate in the Pomeranz− Fritsch−Bobbitt Synthesis of Tetrahydroisoquinoline Derivatives Mediated by Chiral Monooxazolines. Tetrahedron: Asymmetry 2004, 15, 3289−3295. (178) Manna, S. K.; Panda, G. Synthesis of Enantiomerically Enriched Indolines and Tetrahydroisoquinolines from (S)-Amino Acid-derived Chiral Carbocations: an Easy Access to (3R,4R)-Demethoxy-3isopropyl Diclofensine. Org. Biomol. Chem. 2014, 12, 8318−8324. (179) Chrzanowska, M.; Grajewska, A.; Meissner, Z.; Rozwadowska, M. D.; Wiatrowska, I. A Concise Synthesis of Tetrahydroisoquinoline-1carboxylic Acids using a Petasis Reaction and Pomeranz−Fritsch− Bobbitt Cyclization Sequence. Tetrahedron 2012, 68, 3092−3097. (180) Chrzanowska, M.; Grajewska, A.; Rozwadowska, M. D. Synthesis of Calycotomine and N-Methylcalycotomine using a Petasis Reaction − Pomeranz−Fritsch−Bobbitt Cyclizaton Sequence. Heterocycles 2012, 86, 1119−1127. (181) Bułyszko, I.; Chrzanowska, M.; Grajewska, A.; Rozwadowska, M. D. Synthesis of (+)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1carboxylic Acid, a Diastereoselective Approach. Eur. J. Org. Chem. 2015, 383−388. (182) Rotte, S. C. K.; Chittiboyina, A. G.; Khan, I. A. Asymmetric Synthesis of Crispine A: Constructing Tetrahydroisoquinoline Scaffolds Using Pummerer Cyclizations. Eur. J. Org. Chem. 2013, 2013, 6355− 6360. (183) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. Catalytic Asymmetric Allylation of Aldehydes. J. Am. Chem. Soc. 1993, 115, 8467−8468. (184) Beaulieu, M.-A.; Ottenwaelder, X.; Canesi, S. Asymmetric Synthesis of Fortucine and Reassignment of Its Absolute Configuration. Chem. - Eur. J. 2014, 20, 7581−7584. (185) Kurata, K.; Inoue, K.; Nishimura, K.; Hoshiya, N.; Kawai, N.; Uenishi, J. Synthesis of Optically Pure (R)- and (S)-Tetrahydroisoquinoline-1- and -3-Carboxylic Acids. Synthesis 2015, 47, 1238−1244. (186) Kawai, N.; Abe, R.; Uenishi, J. Lewis Acid-Catalyzed Intramolecular Amination via 1,3-Chirality Transfer. Tetrahedron Lett. 2009, 50, 6580−6583. (187) Kawai, N.; Abe, R.; Matsuda, M.; Uenishi, J. Synthesis of Chiral 1-Substituted Tetrahydroisoquinolines by the Intramolecular 1,3Chirality Transfer Reaction Catalyzed by Bi(OTf)3. J. Org. Chem. 2011, 76, 2102−2114. (188) Kawai, N.; Matsuda, M.; Uenishi, J. Stereoselective Synthesis of Tetrahydroisoquinoline Alkaloids: (−)-Trolline, (+)-Crispin A, (+)-Oleracein E. Tetrahedron 2011, 67, 8648−8653. (189) Reddy, R. J.; Kawai, N.; Uenishi, J. Synthesis of the 1Phenethyltetrahydroisoquinoline Alkaloids (+)-Dysoxyline, (+)-Colchiethanamine, and (+)-Colchiethine. J. Org. Chem. 2012, 77, 11101− 11108. (190) Hoshiya, N.; Noda, K.; Mihara, Y.; Kawai, N.; Uenishi, J. Synthesis of the Core Tricyclic Ring Domain of (−)-Schulzeine B. J. Org. Chem. 2015, 80, 7790−7796. (191) Shi, C.; Ojima, I. Asymmetric Synthesis of 1-Vinyltetrahydroisoquinoline through Pd-Catalyzed Intramolecular Allylic Amination. Tetrahedron 2007, 63, 8563−8570. (192) Chien, C.-W.; Shi, C.; Lin, C.-F.; Ojima, I. Enantioselective Synthesis of 1-Vinyltetrahydroisoquinolines via Pd-Catalyzed IntraCP


Chemical Reviews

Review

molecular Asymmetric Allylic Amination Reactions. Tetrahedron 2011, 67, 6513−6523. (193) Lin, H.-F.; Ojima, I. Formal Enantioselective Total Synthesis of Schulzeines A − C via Pd-Catalyzed Intramolecular Asymmetric Allylic Amination. J. Org. Chem. 2011, 76, 6240−6249. (194) Teichert, J. F.; Fananas-Mastral, M.; Feringa, B. L. IridiumCatalyzed Asymmetric Intramolecular Allylic Amidation: Enantioselective Synthesis of Chiral Tetrahydroisoquinolines and Saturated Nitrogen Heterocycles. Angew. Chem., Int. Ed. 2011, 50, 688−691. (195) Fananas-Mastral, M.; Teichert, J. F.; Fernandez-Salas, J. A.; Heijnen, D.; Feringa, B. L. Enantioselective Synthesis of Almorexant via Iridium-Catalysed Intramolecular Allylic Amidation. Org. Biomol. Chem. 2013, 11, 4521−4525. (196) Ogata, T.; Ujihara, A.; Tsuchida, S.; Shimizu, T.; Kaneshige, A.; Tomioka, K. Catalytic Asymmetric Intramolecular Hydroamination of Aminoalkenes. Tetrahedron Lett. 2007, 48, 6648−6650. (197) Ogata, T.; Kimachi, T.; Yamada, K.; Yamamoto, Y.; Tomioka, K. Catalytic Asymmetric Synthesis of (S)-Laudanosine by Hydroamination. Heterocycles 2012, 86, 469−485. (198) Pignataro, L.; Marelli, E.; Gennari, C.; Ferraccioli, R. Enantioselective Synthesis of 1-Vinyltetrahydroisoquinolines through Palladium-Catalysed Intramolecular Allylic Amidation with Chiral PhthalaPhos Ligands. Tetrahedron: Asymmetry 2014, 25, 844−850. (199) Mujahidin, D.; Doye, S. Enantioselective Synthesis of (+)-(S)Laudanosine and (−)-(S)-Xylopinine. Eur. J. Org. Chem. 2005, 2689− 2693. (200) Johannes, M.; Altmann, K.-H. A Ring-Closing Metathesis-Based Approach to the Synthesis of (+)-Tetrabenazine. Org. Lett. 2012, 14, 3752−3755. (201) Reddy, N. S. S.; Reddy, B. J. M.; Reddy, B. V. S. A Convergent and Stereoselective Total Synthesis of (−)-Crispine A, (−)-Benzo[a]quinolizidine and (−)-Salsolidine. Tetrahedron Lett. 2013, 54, 4228− 4231. (202) Babu, R. A.; Reddy, N. S. S.; Reddy, B. J. M.; Reddy, B. V. S. Stereoselective Total Syntheses of Solifenacin and N-Acetyl-1-(4chlorophenyl)-6,7-dimethoxytetrahydroisoquinoline. Synthesis 2014, 46, 2794−2798. (203) Reddy, N. S. S.; Reddy, B. V. S. Stereoselective Total Synthesis of Almorexant. Tetrahedron Lett. 2014, 55, 3157−3159. (204) Reddy, N. S. S.; Reddy, A. S.; Yadav, J. S.; Reddy, B. V. S. The Stereoselective Total Synthesis of (−)-Dihydrotetrabenazine. Tetrahedron Lett. 2012, 53, 6916−6918. (205) Cheng, J.; Fu, L.; Ling, C.; Yang, Y. Total Synthesis of (S)(−)-Stepholidine Using (S)-tert-Butanesulfinylimine. Heterocycles 2010, 81, 2581−2592. (206) Mastranzo, V. M.; Yuste, F.; Ortiz, B.; Sanchez-Obregon, R.; Toscano, R. A.; Ruano, J. L. G. Asymmetric Synthesis of (S)(−)-Xylopinine. Use of the Sulfinyl Group as an Ipso Director in Aromatic SE. J. Org. Chem. 2011, 76, 5036−5041. (207) Mastranzo, V. M.; Romero, J. L. O.; Yuste, F.; Ortiz, B.; SanchezObregon, R.; Ruano, J. L. G. Asymmetric Synthesis of (S)(−)-Tetrahydropalmatine and (S)-(−)-Canadine via a Sulfinyl-Directed Pictet−Spengler Cyclization. Tetrahedron 2012, 68, 1266−1271. (208) Chiba, H.; Oishi, S.; Fujii, N.; Ohno, H. Total Synthesis of (−)-Quinocarcin by Gold(I)-Catalyzed Regioselective Hydroamination. Angew. Chem., Int. Ed. 2012, 51, 9169−9172. (209) Chiba, H.; Sakai, Y.; Oishi, S.; Fujii, N.; Ohno, H. Lewis-AcidMediated Ring-Exchange Reaction of Dihydrobenzofurans and its Application to the Formal Synthesis of (−)-Quinocarcinamide. Tetrahedron Lett. 2012, 53, 6273−6276. (210) Ohno, H.; Chiba, H.; Inuki, S.; Oishi, S.; Fujii, N. The Synthesis of Alkaloids Using Transition-Metal-Catalyzed Intramolecular Amination Reactions. Synlett 2014, 25, 179−192. (211) Amat, M.; Subrizi, F.; Elias, V.; Llor, N.; Molins, E.; Bosch, J. Stereoselective Synthesis of cis-1,3-Dimethyltetrahydroisoquinolines: Formal Synthesis of Naphthylisoquinoline Alkaloids. Eur. J. Org. Chem. 2012, 5491−5497. (212) Barker, G.; McGrath, J. L.; Klapars, A.; Stead, D.; Zhou, G.; Campos, K. R.; O'Brien, P. Enantioselective, Palladium-Catalyzed α-

Arylation of N-Boc Pyrrolidine: In Situ React IR Spectroscopic Monitoring, Scope, and Synthetic Applications. J. Org. Chem. 2011, 76, 5936−5953. (213) Kurihara, K.; Yamamoto, Y.; Miyaura, N. An N-Linked Bidentate Phosphoramidite Ligand (N-Me-BIPAM) for Rhodium-Catalyzed Asymmetric Addition of Arylboronic Acids to N-Sulfonylarylaldimines. Adv. Synth. Catal. 2009, 351, 260−270. (214) Umetsu, K.; Asao, N. An Efficient Method for Construction of Tetrahydroisoquinoline Skeleton via Double Cyclization Process using ortho-Vinylbenzaldehydes and Amino Alcohols: Application to the Synthesis of (S)-Cryptostyline II. Tetrahedron Lett. 2008, 49, 2722− 2725. (215) Amat, M.; Elias, V.; Llor, N.; Subrizi, F.; Molins, E.; Bosch, J. A General Methodology for the Enantioselective Synthesis of 1Substituted Tetrahydroisoquinoline Alkaloids. Eur. J. Org. Chem. 2010, 4017−4026. (216) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. A Convergent and Enantioselective Synthesis of (+)-Amurensinine via Selective C−H and C−C Bond Insertion Reactions. J. Am. Chem. Soc. 2006, 128, 11752− 11753. (217) Chuang, K. V.; Navarro, R.; Reisman, S. E. BenzoquinoneDerived Sulfinyl Imines as Versatile Intermediates for Alkaloid Synthesis: Total Synthesis of (−)-3-Demethoxyerythratidinone. Chem. Sci. 2011, 2, 1086−1089. (218) Hakansson, A. E.; Palmelund, A.; Holm, H.; Madsen, R. Synthesis of 7-Deoxypancratistatin from Carbohydrates by the Use of Olefin Metathesis. Chem. - Eur. J. 2006, 12, 3243−3253. (219) Li, M.; Wu, A.; Zhou, P. A Concise Synthesis of (+)-Pancratistatin using Pinitol as a Chiral Building Block. Tetrahedron Lett. 2006, 47, 3707−3710. (220) Fleming, M. J.; McManus, H. A.; Rudolph, A.; Chan, W. H.; Ruiz, J.; Dockendorff, C.; Lautens, M. Concise Enantioselective Total Syntheses of (+)-Homochelidonine, (+)-Chelamidine, (+)-Chelidonine, (+)-Chelamine and (+)-Norchelidonine by a PdII-Catalyzed RingOpening Strategy. Chem. - Eur. J. 2008, 14, 2112−2124. (221) McManus, H. A.; Fleming, M. J.; Lautens, M. Enantioselective Total Synthesis of (+)-Homochelidonine by a PdII-Catalyzed RingOpening Reaction of a meso-Azabicyclic Alkene with an Aryl Boronic Acid. Angew. Chem., Int. Ed. 2007, 46, 433−436. (222) Huang, K.-L.; Guo, C.; Cheng, L.-J.; Xie, L.-G.; Zhou, Q.-L.; Xu, X.-H.; Zhu, S.-F. Enantioselective Palladium-Catalyzed Ring-Opening Reaction of Azabenzonorbornadienes with Methyl 2-Iodobenzoate: An Efficient Access to cis-Dihydrobenzo[c]phenanthridinones. Adv. Synth. Catal. 2013, 355, 2833−2838. (223) Boudou, M.; Enders, D. Asymmetric Synthesis of Tetrahydropalmatine via Tandem 1,2-Addition/Cyclization. J. Org. Chem. 2005, 70, 9486−9494. (224) Zang, Y.; Ojima, I. Pd-Catalyzed Asymmetric Allylic Amination with BOP Ligands and its Applications to the Synthesis of Fused Polycyclic Alkaloids. Tetrahedron Lett. 2015, 56, 3288−3292. (225) Chrzanowska, M.; Dreas, A. Addition Reaction of o-Toluamides with Chiral Auxiliary Derived from 2-Amino-1,3-propanediols to Imines. Heterocycles 2006, 69, 303−310. (226) Chrzanowska, M.; Dreas, A.; Rozwadowska, M. D. Asymmetric Synthesis of (R)-(+)- and (S)-(−)-2,3-Methylenedioxy-8-oxoberbine (Gusanlung D). Tetrahedron: Asymmetry 2004, 15, 1113−1120. (227) Meissner, Z.; Chrzanowska, M. Enantiospecific Synthesis of (S)(−)-8-Oxyxylopinine. Tetrahedron: Asymmetry 2015, 26, 225−229. (228) Chrzanowska, M.; Meissner, Z.; Chrzanowska, J. M.; Gzella, A. K. Synthesis and Crystal Structure of (4S)-4-Benzyl-3-(4,5-dimethoxy2-methylbenzoyl)-2,2-dimethyl-1,3-oxazolidine. Heterocycles 2015, 90, 730−739. (229) Fukuda, T.; Iwao, M. Synthesis of Both Enantiomers of Protoberberines via Laterally Lithiated (S)-4-Isopropyl-2-(o-Tolyl)oxazolines. Heterocycles 2007, 74, 701−720. (230) Youte, J.-J.; Barbier, D.; Al-Mourabit, A.; Gnecco, D.; Marazano, C. An Enantioselective Access to 1-Alkyl-1,2,3,4-tetrahydroisoquinolines. Application to a New Synthesis of (−)-Argemonine. J. Org. Chem. 2004, 69, 2737−2740. CQ


Chemical Reviews

Review

(231) Paek, S.-M.; Kim, N.-J.; Shin, D.; Jung, J.-K.; Jung, J.-W.; Chang, D.-J.; Moon, H.; Suh, Y.-G. A Concise Total Synthesis of (+)-Tetrabenazine and (+)-α-Dihydrotetrabenazine. Chem. - Eur. J. 2010, 16, 4623−4628. (232) Moon, H.; An, H.; Sim, J.; Kim, K.; Paek, S.-M.; Suh, Y.-G. Efficient Strategy for the Stereoselective Synthesis of 2,3-Disubstituted Benzo[α]quinolizidine Alkaloids: Concise Synthesis of (−)-Protoemetinol. Tetrahedron Lett. 2015, 56, 608−611. (233) Jang, J.; Jung, J.-W.; Ahn, J.; Sim, J.; Chang, D.-J.; Kim, D.-D.; Suh, Y.-G. Asymmetric Formal Synthesis of Schulzeines A and C. Org. Biomol. Chem. 2012, 10, 5202−5204. (234) Wang, S.; Onaran, M. B.; Seto, C. T. Enantioselective Synthesis of 1-Aryltetrahydroisoquinolines. Org. Lett. 2010, 12, 2690−2693. (235) Wang, S.; Seto, C. T. Enantioselective Addition of Vinylzinc Reagents to 3,4-Dihydroisoquinoline N-Oxide. Org. Lett. 2006, 8, 3979−3982. (236) Miyazaki, M.; Ando, N.; Sugai, K.; Seito, Y.; Fukuoka, H.; Kanemitsu, T.; Nagata, K.; Odanaka, Y.; Nakamura, K. T.; Itoh, T. Catalytic Asymmetric Allylation of 3,4-Dihydroisoquinolines and Its Application to the Synthesis of Isoquinoline Alkaloids. J. Org. Chem. 2011, 76, 534−542. (237) Itoh, T.; Miyazaki, M.; Fukuoka, H.; Nagata, K.; Ohsawa, A. Formal Total Synthesis of (−)-Emetine Using Catalytic Asymmetric Allylation of Cyclic Imines as a Key Step. Org. Lett. 2006, 8, 1295−1297. (238) Wu, T. R.; Chong, J. M. Asymmetric Allylboration of Cyclic Imines and Applications to Alkaloid Synthesis. J. Am. Chem. Soc. 2006, 128, 9646−9647. (239) Liu, X.; Sun, S.; Meng, Z.; Lou, H.; Liu, L. Organocatalytic Asymmetric C−H Vinylation and Arylation of N-Acyl Tetrahydroisoquinolines. Org. Lett. 2015, 17, 2396−2399. (240) Sun, S.; Li, C.; Floreancig, P. E.; Lou, H.; Liu, L. Highly Enantioselective Catalytic Cross-Dehydrogenative Coupling of NCarbamoyl Tetrahydroisoquinolines and Terminal Alkynes. Org. Lett. 2015, 17, 1684−1687. (241) Yu, J.; Li, Z.; Jia, K.; Jiang, Z.; Liu, M.; Su, W. Fast, Solvent-Free Asymmetric Alkynylation of Prochiral sp3 C−H Bonds in a Ball Mill for the Preparation of Optically Active Tetrahydroisoquinoline Derivatives. Tetrahedron Lett. 2013, 54, 2006−2009. (242) Li, Z.; MacLeod, P. D.; Li, C.-J. Studies on Cu-Catalyzed Asymmetric Alkynylation of Tetrahydroisoquinoline Derivatives. Tetrahedron: Asymmetry 2006, 17, 590−597. (243) Zhang, J. C.; Tiwari, B.; Xing, C.; Chen, X.; Chi, Y. R. Enantioselective Oxidative Cross-Dehydrogenative Coupling of Tertiary Amines to Aldehydes. Angew. Chem., Int. Ed. 2012, 51, 3649−3652. (244) Qin, J.; Lv, J.; Luo, S. Catalytic Asymmetric α-C(sp3)−H Functionalization of Amines. Tetrahedron Lett. 2014, 55, 551−558. (245) Lin, W.; Cao, T.; Fan, W.; Han, Y.; Kuang, J.; Luo, H.; Miao, B.; Tang, X.; Yu, Q.; Yuan, W.; Zhang, J.; Zhu, C.; Ma, S. Enantioselective Double Manipulation of Tetrahydroisoquinolines with Terminal Alkynes and Aldehydes under Copper(I) Catalysis. Angew. Chem., Int. Ed. 2014, 53, 277−281. (246) Lin, W.; Ma, S. Highly Efficient and General Enantioselective Synthesis of Naturally Occuring Isoquinoline Alkaloids. Org. Chem. Front. 2014, 1, 338−346. (247) Taylor, A. M.; Schreiber, S. L. Enantioselective Addition of Terminal Alkynes to Isolated Isoquinoline Iminiums. Org. Lett. 2006, 8, 143−146. (248) Hashimoto, T.; Omote, M.; Maruoka, K. Catalytic Asymmetric Alkynylation of C1-Substituted C,N-Cyclic Azomethine Imines by CuI/ Chiral Brønsted Acid Co-Catalyst. Angew. Chem., Int. Ed. 2011, 50, 8952−8955. (249) Ahamed, M.; Todd, M. H. Catalytic Asymmetric Additions of Carbon-Centered Nucleophiles to Nitrogen-Containing Aromatic Heterocycles. Eur. J. Org. Chem. 2010, 5935−5942. (250) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. Pd(II)Catalyzed Asymmetric Addition of Malonates to Dihydroisoquinolines. J. Am. Chem. Soc. 2006, 128, 14010−14011. (251) Dubs, C.; Hamashima, Y.; Sasamoto, N.; Seidel, T. M.; Suzuki, S.; Hashizume, D.; Sodeoka, M. Mechanistic Studies on the Catalytic

Asymmetric Mannich-Type Reaction with Dihydroisoquinolines and Development of Oxidative Mannich-Type Reactions Starting from Tetrahydroisoquinolines. J. Org. Chem. 2008, 73, 5859−5871. (252) Rishel, M. J.; Amarasinghe, K. K. D.; Dinn, S. R.; Johnson, B. F. Asymmetric Synthesis of Tetrabenazine and Dihydrotetrabenazine. J. Org. Chem. 2009, 74, 4001−4004. (253) Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Enantioselective Thiourea-Catalyzed Acyl-Mannich Reactions of Isoquinolines. Angew. Chem., Int. Ed. 2005, 44, 6700−6704. (254) Lalonde, M. P.; McGowan, M. A.; Rajapaksa, N. S.; Jacobsen, E. N. Enantioselective Formal Aza-Diels−Alder Reactions of Enones with Cyclic Imines Catalyzed by Primary Aminothioureas. J. Am. Chem. Soc. 2013, 135, 1891−1894. (255) Mengozzi, L.; Gualandi, A.; Cozzi, P. G. A Highly Enantioselective Acyl-Mannich Reaction of Isoquinolines with Aldehydes Promoted by Proline Derivatives: an Approach to 13Alkyltetrahydroprotoberberine Alkaloids. Chem. Sci. 2014, 5, 3915− 3921. (256) Fraile, A.; Scarpino Schietroma, D. M.; Albrecht, A.; Davis, R. L.; Jørgensen, K. A. Asymmetric Synthesis of Hexahydropyrrolo-isoquinolines by an Organocatalytic Three-Component Reaction. Chem. - Eur. J. 2012, 18, 2773−2776. (257) Kanemitsu, T.; Yamashita, Y.; Nagata, K.; Itoh, T. Catalytic Asymmetric Synthesis of (R)-(−)-Calycotomine, (S)-(−)-Salsolidine and (S)-(−)-Carnegine. Synlett 2006, 1595−1597. (258) Kanemitsu, T.; Yamashita, Y.; Nagata, K.; Itoh, T. Synthesis of (−)-Trolline, (−)-Crispine A and (−)-Crispine E. Heterocycles 2007, 74, 199−203. (259) Gawley, R. E.; Smith, G. A. Formal Synthesis of the Bisbenzylisoquinoline Alkaloid Berbamunine by Asymmetric Substitution of Chiral Organolithium Compounds. ARKIVOC 2011, 167−179. (260) Gawley, R. E.; Hart, G.; Goicoechea-Pappas, M.; Smith, A. L. Oxazoline-Mediated Asymmetric Alkylation of Amines. J. Org. Chem. 1986, 51, 3076−3078. (261) Rein, K.; Goicoechea-Pappas, M.; Anklekar, T. V.; Hart, G. C.; Smith, G. A.; Gawley, R. E. Chiral-Dipole Stabilized Anions: Experiment and Theory in Benzylic and Allylic System. Stereoselective Deprotonations, Pyramidal Inversions, and Stereoselective Alkylations of Lithiated (Tetrahydroisoquinoyl)oxazolines. J. Am. Chem. Soc. 1989, 111, 2211−2217. (262) Kametani, T.; Iida, H.; Sakurai, K. A Total Synthesis of Magnoline. J. Chem. Soc. C 1969, 500−501. (263) Nishimura, K.; Horii, S.; Tanahashi, T.; Sugimoto, Y.; Yamada, J. Synthesis and Pharmacological Activity of Alkaloids from Embryo of Lotus, Nelumbo nucifera. Chem. Pharm. Bull. 2013, 61, 59−68. (264) Louafi, F.; Moreau, J.; Shahane, S.; Golhen, S.; Roisnel, T.; Sinbandhit, S.; Hurvois, J.-P. Electrochemical Synthesis and Chemistry of Chiral 1-Cyanotetrahydroisoquinolines. An Approach to the Asymmetric Syntheses of the Alkaloid (−)-Crispine A and Its Natural (+)-Antipode. J. Org. Chem. 2011, 76, 9720−9732. (265) Geffe, M.; Opatz, T. Enantioselective Synthesis of (−)-Dihydrocodeine and Formal Synthesis of (−)-Thebaine, (−)-Codeine, and (−)-Morphine from a Deprotonated α-Aminonitrile. Org. Lett. 2014, 16, 5282−5285. (266) Schrittwieser, J. H.; Resch, V. The Role of Biocatalysis in the Asymmetric Synthesis of Alkaloids. RSC Adv. 2013, 3, 17602−17632. (267) Vick, J. E.; Schmidt-Dannert, C. Expanding the Enzyme Toolbox for Biocatalysis. Angew. Chem., Int. Ed. 2011, 50, 7476−7478. (268) Luk, L. Y. P.; Bunn, S.; Liscombe, D. K.; Facchini, P. J.; Tanner, M. E. Mechanistic Studies on Norcoclaurine Synthase of Benzylisoquinoline Alkaloid Biosynthesis: An Enzymatic Pictet−Spengler Reaction. Biochemistry 2007, 46, 10153−10161. (269) Ilari, A.; Franceschini, S.; Bonamore, A.; Arenghi, F.; Botta, B.; Macone, A.; Pasquo, A.; Bellucci, L.; Boffi, A. Structural Basis of Enzymatic (S)-Norcoclaurine Biosynthesis. J. Biol. Chem. 2009, 284, 897−904. (270) Bonamore, A.; Rovardi, I.; Gasparrini, F.; Baiocco, P.; Barba, M.; Molinaro, C.; Botta, B.; Boffi, A.; Macone, A. An Enzymatic, CR


Chemical Reviews

Review

Stereoselective Synthesis of (S)-Norcoclaurine. Green Chem. 2010, 12, 1623−1627. (271) Bonamore, A.; Barba, M.; Botta, B.; Boffi, A.; Macone, A. Norcoclaurine Synthase: Mechanism of an Enantioselective Pictet− Spengler Catalyzing Enzyme. Molecules 2010, 15, 2070−2078. (272) Minami, H.; Dubouzet, E.; Iwasa, K.; Sato, F. Functional Analysis of Norcoclaurine Synthase in Coptis japonica. J. Biol. Chem. 2007, 282, 6274−6282. (273) Pesnot, T.; Gershater, M. C.; Ward, J. M.; Hailes, H. C. The Catalytic Potential of Coptis japonica NCS2 Revealed − Development and Utilisation of a Fluorescamine-Based Assay. Adv. Synth. Catal. 2012, 354, 2997−3008. (274) Ruff, B. M.; Bräse, S.; O’Connor, S. E. Biocatalytic Production of Tetrahydroisoquinolines. Tetrahedron Lett. 2012, 53, 1071−1074. (275) Maresh, J. J.; Crowe, S. O.; Ralko, A. A.; Aparece, M. D.; Murphy, C. M.; Krzeszowiec, M.; Mullowney, M. W. Facile One-pot Synthesis of Tetrahydroisoquinolines from Amino Acids via Hypochlorite-Mediated Decarboxylation and Pictet−Spengler Condensation. Tetrahedron Lett. 2014, 55, 5047−5051. (276) Lichman, B. R.; Lamming, E. D.; Pesnot, T.; Smith, J. M.; Hailes, H. C.; Ward, J. M. One-pot Triangular Chemoenzymatic Cascades for the Syntheses of Chiral Alkaloids from Dopamine. Green Chem. 2015, 17, 852−855. (277) Koketsu, K.; Minami, A.; Watanabe, K.; Oguri, H.; Oikawa, H. Pictet−Spenglerase Involved in Tetrahydroisoquinoline Antibiotic Biosynthesis. Curr. Opin. Chem. Biol. 2012, 16, 142−149. (278) Resch, V.; Schrittwieser, J. H.; Siirola, E.; Kroutil, W. Novel Carbon−Carbon Bond Formations for Biocatalysis. Curr. Opin. Biotechnol. 2011, 22, 793−799. (279) Schrittwieser, J. H.; Resch, V.; Sattler, J. H.; Lienhart, W.-D.; Durchschein, K.; Winkler, A.; Gruber, K.; Macheroux, P.; Kroutil, W. Biocatalytic Enantioselective Oxidative C−C Coupling by Aerobic C− H Activation. Angew. Chem., Int. Ed. 2011, 50, 1068−1071. (280) Schrittwieser, J. H.; Resch, V.; Wallner, S.; Lienhart, W.-D.; Sattler, J. H.; Resch, J.; Macheroux, P.; Kroutil, W. Biocatalytic Organic Synthesis of Optically Pure (S)-Scoulerine and Berbine and Benzylisoquinoline Alkaloids. J. Org. Chem. 2011, 76, 6703−6714. (281) Gandomkar, S.; Fischereder, E.-M.; Schrittwieser, J. H.; Wallner, S.; Habibi, Z.; Macheroux, P.; Kroutil, W. Enantioselective Oxidative Aerobic Dealkylation of N-Ethyl Benzylisoquinolines by Employing the Berbine Bridge Enzyme. Angew. Chem., Int. Ed. 2015, 54, 15051−15054. (282) Resch, V.; Schrittwieser, J. H.; Wallner, S.; Macheroux, P.; Kroutil, W. Biocatalytic Oxidative C−C Bond Formation Catalysed by the Berbine Bridge Enzyme: Optimal Reaction Conditions. Adv. Synth. Catal. 2011, 353, 2377−2383. (283) Resch, V.; Lechner, H.; Schrittwieser, J. H.; Wallner, S.; Gruber, K.; Macheroux, P.; Kroutil, W. Inverting the Regioselectivity of the Berbine Bridge Enzyme by Employing Customized Fluorine-Containing Substrates. Chem. - Eur. J. 2012, 18, 13173−13179. (284) Schrittwieser, J. H.; Groenendaal, B.; Resch, V.; Ghislieri, D.; Wallner, S.; Fischereder, E.-M.; Fuchs, E.; Grischek, B.; Sattler, J. H.; Macheroux, P.; Turner, N. J.; Kroutil, W. Deracemization By Simultaneous Bio-oxidative Kinetic Resolution and Stereoinversion. Angew. Chem., Int. Ed. 2014, 53, 3731−3734. (285) Forró, E.; Schönstein, L.; Füllöp, F. Total Synthesis of Crispine A Enantiomers through a Burkholderia cepacia Lipase Catalysed Kinetic Resolution. Tetrahedron: Asymmetry 2011, 22, 1255−1260. (286) Schönstein, L.; Forró, E.; Füllöp, F. Continuous-Flow Enzymatic Resolution Strategy for the Acylation of Amino Alcohols with a Remote Stereogenic Centre: Synthesis of Calycotomine Enantiomers. Tetrahedron: Asymmetry 2013, 24, 202−206. (287) Schönstein, L.; Forró, E.; Füllöp, F. Enzymatic Reactions for the Preparation of Homocalycotomine Enantiomers. Tetrahedron: Asymmetry 2013, 24, 1059−1062. (288) Ding, W.; Li, M.; Dai, R.; Deng, Y. Lipase-Catalyzed Synthesis of the Chiral Tetrahydroisoquinoline (R)-Salsolinol. Tetrahedron: Asymmetry 2012, 23, 1376−1379. (289) Ge, H.-X.; Zhang, J.; Dong, Y.; Cui, K.; Yu, B.-Y. Unique Biocatalytic Resolution of Racemic Tetrahydroberberrubine via Kinetic

Glycosylation and Enantio-Selective Sulfation. Chem. Commun. 2012, 48, 6127−6129. (290) Stirling, M.; Blacker, J.; Page, M. I. Chemoenzymatic Dynamic Kinetic Resolution of Secondary Amines. Tetrahedron Lett. 2007, 48, 1247−1250. (291) Blacker, A. J.; Stirling, M. J.; Page, M. I. Catalytic Racemisation of Chiral Amines and Application in Dynamic Kinetic Resolution. Org. Process Res. Dev. 2007, 11, 642−648. (292) Bailey, K. R.; Ellis, A. J.; Reiss, R.; Snape, T. J.; Turner, N. J. A Template-based Mnemonic for Monoamine Oxidase (MAO-N) Catalyzed Reactions and its Application to the Chemo-enzymatic Deracemisation of the Alkaloid (±)-Crispine A. Chem. Commun. 2007, 3640−3642. (293) Rowles, I.; Malone, K. J.; Etchells, L. L.; Willies, S. C.; Turner, N. J. Directed Evolution of the Enzyme Monoamine Oxidase (MAO-N): Highly Efficient Chemo-enzymatic Deracemisation of the Alkaloid (±)-Crispine A. ChemCatChem 2012, 4, 1259−1261. (294) Ghislieri, D.; Green, A. P.; Pontini, M.; Willies, S. C.; Rowles, I.; Frank, A.; Grogan, G.; Turner, N. J. Engineering an Enantioselective Amine Oxidase for the Synthesis of Pharmaceutical Building Blocks and Alkaloid Natural Products. J. Am. Chem. Soc. 2013, 135, 10863−10869. (295) Schrittwieser, J. H.; Groenendaal, B.; Willies, S. C.; Ghislieri, D.; Rowles, I.; Resch, V.; Sattler, J. H.; Fischereder, E.-M.; Grischek, B.; Lienhart, W. D.; Turner, N. J.; Kroutil, W. Deracemisation of Benzylisoquinoline Alkaloids Employing Monoamine Oxidase Variants. Catal. Sci. Technol. 2014, 4, 3657−3664. (296) Foulkes, J. M.; Malone, K. J.; Coker, V. S.; Turner, N. J.; Lloyd, J. R. Engineering a Biometallic Whole Cell Catalyst for Enantioselective Deracemisation Reactions. ACS Catal. 2011, 1, 1589−1594. (297) Orden, A. A.; Schrittwieser, J. H.; Resch, V.; Mutti, F. G.; Kroutil, W. Controlling Stereoselectivity by Enzymatic and Chemical Means to Access Enantiomerically Pure (1S,3R)-1-Benzyl-2,3-dimethyl-1,2,3,4tetrahydroisoquinoline Derivatives. Tetrahedron: Asymmetry 2013, 24, 744−749. (298) Banwell, M. G.; Gao, N. Y.; Ma, X.; Petit, L.; White, L. V.; Schwartz, B. D.; Willis, A. C.; Cade, I. A. gem-Dibromocyclopropanes and Enzymatically Derived cis-1,2-Dihydrocatechols as Building Blocks in Alkaloid Synthesis. Pure Appl. Chem. 2012, 84, 1329−1339. (299) Banwell, M. G.; Lehmann, A. L.; Menon, R. S.; Willis, A. C. New Methods for the Synthesis of Certain Alkaloids and Terpenoids. Pure Appl. Chem. 2011, 83, 411−423. (300) Matveenko, M.; Kokas, O. J.; Banwell, M. G.; Willis, A. Chemoenzymatic Approaches to Lycorine-Type Amaryllidaceae Alkaloids: Total Syntheses of ent-Lycoricidine, 3-epi-ent-Lycoricidine, and 4Deoxy-3-epi-ent-lycoricidine. Org. Lett. 2007, 9, 3683−3685. (301) Jones, M. T.; Schwartz, B. D.; Willis, A. C.; Banwell, M. G. Rapid and Enantioselective Assembly of the Lycorine Framework Using Chemoenzymatic Techniques. Org. Lett. 2009, 11, 3506−3509. (302) Matveenko, M.; Banwell, M. G.; Willis, A. C. A Chemoenzymatic Total Synthesis of the Structure Assigned to the Alkaloid (+)-Montabuphine. Org. Lett. 2008, 10, 4693−4696. (303) Kokas, O. J.; Banwell, M. G.; Willis, A. C. Chemoenzymatic Approaches to the Montanine Alkaloids: a Total Synthesis of (+)-Nangustine. Tetrahedron 2008, 64, 6444−6451. (304) Hudlicky, T.; Reed, J. W. On the Merits of Biocatalysis and the Impact of Arene cis-Dihydrodiols on Enantioselective Synthesis. Synlett 2009, 685−703. (305) Hudlicky, T. Chemoenzymatic Synthesis of Complex Natural and Unnatural Products: Morphine, Pancratistatin, and Their Analogs. ARKIVOC 2006, 276−291. (306) de la Sovera, V.; Bellomo, A.; Gonzalez, D. Click Chemistry and Biocatalysis for the Preparation of Pancratistatin Analogs. Tetrahedron Lett. 2011, 52, 430−433. (307) Vshyvenko, S.; W’Giorgis, Z.; Weber, A.; Neverova, N.; Hedberg, B.; Hudlicky, T. Synthesis and Biological Activity of 10-Azanarciclasine. Adv. Synth. Catal. 2015, 357, 83−87.

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