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Prevalence of Diarylprolinol Silyl Ethers as Catalysts in Total Synthesis and Patents Gabriel J. Reyes-Rodríguez, Nomaan M. Rezayee, Andreu Vidal-Albalat, and Karl Anker Jørgensen*

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Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark ABSTRACT: Diarylprolinol silyl ethers are among the most utilized stereoselective organocatalysts for the construction of complex molecules. With their debut in 2005, these catalysts have been applied in numerous method developments primarily leveraging enamine and iminium-ion catalysis. These strategies have extended into the preparation of complex molecules in both academic and industrial settings. This Review intends to give an overview of the application of the diarylprolinol silyl ether catalysts in total synthesis. Furthermore, integration of these catalysts in patent literature is also disclosed highlighting the versatility of the catalytic system.

CONTENTS 1. Introduction 2. Activation Modes 2.1. Enamine Activation 2.2. Iminium-Ion Activation 3. Enamine Catalysis 3.1. Michael Additions 3.2. Mannich Reactions 3.3. Oxylations 3.4. Cycloadditions 3.5. Multicatalytic Systems 4. Iminium-Ion Activation 4.1. Michael Additions 4.2. Epoxidations 4.3. Aziridinations 4.4. Cyclopropanations 4.5. Cycloadditions 4.6. Multicatalytic Systems 5. Vinylogous Iminium-Ion Catalysis 5.1. Michael Additions 6. Diarylprolinol Silyl Ethers in Patent Literature 6.1. Synthesis of Drugs, Drug Candidates, And Intermediates in Drug Synthesis 6.1.1. Enamine Catalysis 6.1.2. Iminium-Ion Catalysis 6.2. Synthesis of Chiral Molecular Building Blocks 6.2.1. Enamine Catalysis 6.2.2. Iminium-Ion Catalysis 7. Conclusion and Outlook Author Information Corresponding Author ORCID © XXXX American Chemical Society

Notes Biographies Acknowledgments References

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1. INTRODUCTION Within the last two decades, organocatalysis has established itself as an integral concept in asymmetric catalysis.1−4 The growth in the field of organocatalysis arises from inherent advantages such as ease of handling and breadth of chiral pool. Its application, based on chiral organic molecules such as amino acids, alkaloids, and their derivatives, as well as other classes of small organic molecules, has opened new possibilities of novel stereoselective transformations.1,5−8 Organocatalysis involves a number of different activation concepts such as covalent- and hydrogen-bonding, Brønsted acid, and Brønsted base. The subfield of aminocatalysis relies on the catalytic activation of aldehydes and ketones by amines through covalently bonded intermediates and provides a series of stereoselective carbon−carbon and carbon−heteroatom bond forming reactions based on enamine and iminium-ion activation modes.5,9−18 The impact of aminocatalysis on asymmetric methods would be difficult to overstate, especially one such class of synthetic chiral organic amines introduced to the field in 2005,19−21 which are now among the most used stereoselective organocatalysts: the diarylprolinol silyl ethers (Figure 1). Evidenced by the remarkable increase in reported synthetic applications, these rationally designed catalysts have distinguished them-

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Received: September 24, 2018

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Figure 1. Diarylprolinol silyl ethers employed in the total syntheses and patents presented in this Review (Ar = 3,5-bis(trifluoromethyl)phenyl).

iminium-ion, the multifaceted activation roles of the catalyst for the design of combined enamine/iminium-ion activation strategies such as multicatalytic systems will be presented. The total synthesis sections will be outlined in the following manner: the diarylprolinol silyl ether catalytic asymmetric reaction applied, the molecule and/or fragment of the molecule to be discussed will be presented, as well as the chiral center(s) formed (highlighted in red). This will be followed by the synthesis of the chiral fragment, and a discussion of the role of the diarylprolinol silyl ether, as well as other aspects of the synthesis. The syntheses involving enamine catalysis applying aldehydes will be presented first, and discussions will include the application of aminocatalytic Michael additions, Mannich reactions, oxylations, and cycloadditions. Then, the activation of α,β-unsaturated aldehydes leading to iminium-ion intermediates will be discussed for reactions based on this activation mode such as Michael additions, epoxidations, aziridinations, cyclopropanations, and cycloadditions. The next activation mode will include the vinylogous iminium-ion. The application of multicatalytic systems in total synthesis will also be disclosed. While this, no doubt, is only a fraction of the copious examples of methodologies using these activation strategies, for the purpose of this Review, only the methods applied in total synthesis and/or patent literature will be discussed. In the sections discussing the application of the diarylprolinol silyl ethers in patent literature, the first part will be devoted to a brief discussion of the difference in scientific literature in chemical scientific journals and the statements in patent applications. The synthesis of drugs, drug candidates, and intermediates in drug synthesis will be presented next. This will be followed by the synthesis of chiral molecular building blocks through the application of the diarylprolinol silyl ether as catalysts. Finally, some general remarks will be disclosed. This Review may have its most consequential impact by describing the prevalence and applicability of diarylprolinol silyl ethers in total syntheses and patents. In order to limit the scope of this Review, we have decided only to include total syntheses and patents published within the past decade.

selves as privileged catalysts exhibited in their versatility.4,17,18,22−26 Consequently, the number of chiral compounds accessible via aminocatalysis has increased extensively. The unique properties of diarylprolinol silyl ethers have been expanded further by the introduction of novel activation modes such as dienamine, trienamine, tetraenamine, vinylogous iminium-ion, and bis-vinylogous iminium-ion, generated by their reaction with different types of aldehydes and conjugated aldehydes.2−4,14,18,22,23,26−30 This class of catalysts can activate different types of aldehydes to act as both nucleophiles and electrophiles, and complementary activation modes have allowed for novel and unprecedented reactions in asymmetric catalysis, which have been documented in numerous articles and summarized in a large number of reviews, accounts, perspectives, etc.2,7,31−36 These complementary activation strategies have been expanded to more complex one-pot transformations, cascade reactions, and synergistic catalysis using transition metals and photoredox catalysts.8,25,28,30,37−39 The reactivity properties and high efficacy of the diarylprolinol silyl ethers in organocatalysis have also been highlighted in a number of mechanistic investigations, based on both experimental and computational studies,11,15−17,32 and applied in total synthesis for the asymmetric construction of important fragments of complex molecules.6,7,38,40,41 Furthermore, the application of these catalysts for the synthesis of chiral drugs, bioactive molecules, and synthetic building blocks, considered solely within the purview of academia, are also starting to be pushed to production scales in drug syntheses and applied in patent applications. Development of asymmetric methodologies using these aminocatalysts have provided the impetus for diverse chemical libraries for drug discovery. It is of particular importance to note that asymmetric aminocatalysis was discovered in the industrial setting,42 and it continues to be fueled by its industrial relevance and applications. The demand for stereocontrolled transformations using a robust and general catalyst, and the pursuit for less toxic processes continues to persist. Ease of operation, and their stability and potential recovery43 make these catalysts an attractive solution in the industrial setting. In the prominent world of drug development, processes that encompass the use of diarylprolinol silyl ethers have taken center stage. In this Review, we will cover the application of the diarylprolinol silyl ethers in total synthesis and patent applications. After a brief introduction of the different activation modes: enamine, iminium-ion, and vinylogous

2. ACTIVATION MODES 2.1. Enamine Activation

Ideal substrates for the HOMO-raising strategy are enolizable carbonyl-containing compounds and typically forge bonds B

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from the α-position of the carbonyl. Following the canonical mode of activation, the diarylprolinol silyl ether initially condenses with the carbonyl containing moiety forming an iminium ion (Scheme 1). The highly electron-withdrawing

Scheme 2. LUMO-Lowering Mode of Activation for the Direct Aminocatalytic Enantioselective β-Functionalization of α,β-Unsaturated Aldehydes

Scheme 1. HOMO-Raising Mode of Activation for the Direct Aminocatalytic Enantioselective α-Functionalization of Aldehydes

ion catalysis has flourished allowing for asymmetric functionalizations to generate C−H, C−C, and C−heteroatom bonds. Despite opposing reactivity in the inherent nature of enamine and iminium-ion catalysis, the seemingly conflicting modes of activation, in fact, converge and are integral intermediates for turnover of the aminocatalyst. For example, upon α-addition of the enamine to electrophile following the HOMO-raising strategy, the resulting iminium-ion is hydrolyzed, releasing the aminocatalyst. While this specific example deals with an iminium-ion during the enamine catalytic cycle, the converse is also true where enamine intermediates are involved in the iminium-ion mode of activation. Showcasing the versatility and complementarity of the aminocatalyst, cascade reactions have been performed wherein a single catalyst was used for both enamine and iminium-ion catalysis. The dual activation modes have been leveraged in concert to perform, for example, enantioselective epoxidations, aziridinations, and cyclopropanations of α,β-unsaturated aldehydes, which will be discussed in their respective sections. Elements of the complementary bifurcated activation modes have been further applied to extended conjugated systems, allowing for the application of established methodologies according to the principle of vinylogy.

nature of the iminium-ion makes the α-C−H more acidic. Subsequent deprotonation provides the neutral enamine species. Unlike the keto−enol tautomerization, the iminiumion-enamine equilibrium thermodynamically favors the nucleophilic enamine, effectively increasing the population of the reactive species. Through this HOMO-raising mode of activation, the concentration of the nucleophilic enamine is regulated by the catalyst loading of the aminocatalyst, thus minimizing unproductive side reactions. The stereochemical outcome upon addition of the electrophile to the enamine is governed by the steric shielding of the aminocatalyst. This is complementary to L-proline-catalyzed reactions where the electrophile is directed via hydrogen bonding to the reactive intermediate.

3. ENAMINE CATALYSIS

2.2. Iminium-Ion Activation

3.1. Michael Additions

Initial condensation of the aminocatalyst with a carbonylcontaining compound provides an iminium-ion. This makes the enolizable C−H bond more acidic leading to the enamine, as discussed in the previous section. However, if the formation of the enamine is not possible, as in the case of nonenolizable α,β-unsaturated aldehydes, the resulting iminium-ion lowers the LUMO of the compound through electronic effects allowing for nucleophilic attack at the β-position of the α,βunsaturated aldehydes (Scheme 2). Seminal reports utilizing iminium-ion catalysis harnessed the increased electrophilicity to activate substrates toward addition and cycloaddition reactions. Since then, the field of iminium-

In the context of enamine catalysis, the Michael addition consists of the addition of the catalytically formed enamine to an electrophilic olefin, such as nitroolefins or α,β-unsaturated carbonyl compounds. Thus, allowing the stereoselective formation of C−C bonds under mild conditions. The Hayashi group has employed the enamine strategy for the synthesis of prostaglandin A1 (1) and E1 (2) methyl esters (Figure 2).44 Prostaglandins (PGs) are a family of lipid compounds that act as hormones in diverse physiological processes in humans and other animals.45 Derivatives of their core scaffold have been investigated in order to design C

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Figure 3.

Figure 2.

The nakinadine alkaloid family contains an α-phenyl-βamino acid moiety in their structure. These are isolated from Okinawan Amphimedon marine sponges,49 and they present a broad spectrum of interesting biological properties.50,51 Pandey and co-workers reported the total synthesis of 12 (Figure 4) starting from commercially available substrates by using enantioselective aminocatalysis in the first step.52 The treatment of nitrostyrene 13 with acetaldehyde 10 in the presence of catalyst I followed by the reduction of the resulting aldehyde with NaBH4 afforded the corresponding adduct 14 in 75% yield and 96% ee (Scheme 5). Further transformations allowed the synthesis of 12 in 28% overall yield. Isoketals (IsoKs) are formed in the human body from arachidonic acid 15 under oxidative stress (Scheme 6).53 Besides their role as biomarkers in some pathological processes, exogenous IsoKs have also shown diverse biological activities on cultured cells.54 Candy et al. reported the total synthesis of 5-D2-IsoK 17 with a versatile approach that allowed for the introduction of different side chains.55 The first step of their synthesis involved a Michael addition between aldehyde 18 and nitroolefin 19 mediated by catalyst I (Scheme 7), which resulted in excellent yield and enantioselectivity (97% yield, 90% ee). The poor diastereoselectivity (3:1 d.r.) was remedied by selectively epimerizing a downstream intermediate into the desired diastereomer 20. Aflatoxins are a family of natural products that are wellknown for their tetrahydrofuro[2,3-b]benzofuran moiety, abundance in nature, and potent biological activities.56 Aflatoxin B2 21 (Figure 5) has garnered the most interest since it is found as a contaminant in improperly stored food.57−59 Many synthetic approaches for this compound rely on the formation of (−)-dihydroaflatoxin D2 22. Huang et al. reported a one-pot methodology for the synthesis of tetrahydrofuro[2,3-b]benzofuran moieties (Scheme 8).60 They reported multiple examples with moderate overall yields (50−65% over 5 steps), excellent enantioselectivities (90 to 99% ee), and substrate-dependent diastereose-

therapeutics to treat diseases with higher efficacy than the native PGs.46 Therefore, development of an efficient synthesis that facilitates accessibility to this broad family of molecules with high degree of stereoselectivity is desired. An 8-step synthesis of 2 in three one-pot sequences was presented, while also obtaining 1 as an intermediate in the overall process.44 The first one-pot sequence consisted in the formation of the 5-membered ring scaffold by employing catalyst II (Scheme 3). The initial reaction involved a Michael addition of nitroolefin 3 to the enamine derived from succinaldehyde 4. Then, i-Pr2EtN was added to promote an intramolecular Henry reaction to construct the cyclopentane ring of 6, followed by the addition of the corresponding phosphonate to perform a Horner-Wadsworth-Emmons (HWE) reaction. This one-pot sequence fostered the construction of the 5membered ring with four consecutive stereocenters in good yield and moderate diastereoselectivity. Moreover, performing the HWE in the same one-pot sequence avoided the epimerization of the α-carbon of the aldehyde. Further transformations allowed for the total synthesis of 1 and 2 in 25% and 14% overall yield, respectively. Meng et al. reported the synthesis of chiral β-alkynyl acids via enamine catalysis,47 where one of the examples of their scope was further transformed into the alkaloid (+)-α-lycorane 8 (Figure 3). The reaction described consisted of a Michael addition between nitroolefin 9 and acetaldehyde 10 mediated by catalyst I (Scheme 4). After in situ reduction of the addition product using NaBH4, the corresponding alcohol 11 was obtained in 65% yield and 95% ee. To proceed with the targeted synthesis of (+)-α-lycorane 8, a one-pot Michael addition-Pinnick oxidation was performed followed by TsOH-mediated alkyne hydration. The resulting intermediate has been previously accessed by the same research group in the first-generation synthesis of 8.48

Scheme 3. Synthesis of Prostaglandin Precursor 7 via Three One-Pot Sequences Starting from Succinaldehyde 4 and Nitroolefin 3

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Scheme 4. Michael Addition between Nitroolefin Precursor of Lycorane 9 and Acetaldehyde 10

starting from a racemic compound can be challenging, the authors observed that the isomer shown in 31 is mainly formed and isolated in 40% yield, >99% ee and >19:1 dr. In order to rationalize this impressive stereoselectivity, the authors suggest that the starting aldehyde may undergo kinetic resolution during the catalytic process; however, evidence for this was not disclosed.64 In a recent publication Fischer et al. reported the synthesis of elevenol 32 and (+)-przewalskin 33, two natural products belonging to a group of 7−20 oxa-bridged diterpenes and dinorditerpenes (Figure 7).65 Elevenol 32 was isolated from the roots of the tropical plant Flueggea virosa and has shown promising activity against the hepatitis C virus.66 The authors envisioned a total synthesis of 32 that would access a modular intermediate, which could be further modified to provide diverse 7−20 oxa-bridged analogues such as 33. Their retrosynthetic analysis was divided into two key steps, namely C−C bond formations by intramolecular arylation and intramolecular Michael addition-Tischenko reactions. The aldehyde precursor 35 was prepared using a Dess-Martin periodinane (DMP) oxidation of alcohol 34 and used immediately without purification. The Michael addition was catalyzed by I, the only catalyst able to give the desired trans-isomer intermediate. Utilizing the Tischenko transformation, lactone 36 was obtained in an excellent diastereomeric ratio of >20:1. The full sequence, oxidationMichael addition-Tischenko lactonization, proceeded in 50% overall yield (Scheme 10). Lactone 36 could be transformed into 32 after further transformations, including an intramolecular arylation followed by TBS-deprotection. (−)-GB17 37 (Figure 8) is an alkaloid isolated from the bark of Galbulimima genus rainforest trees,67 whose piperidine ring and a trans-decalin carbocylic core spark interest as a therapeutic agent to treat Alzheimer’s disease.68 In 2012, Thomson et al. reported the stereoselective synthesis of this tetracyclic alkaloid, where part of the construction of its naphthoquinolizinone skeleton was achieved by a catalyst-controlled intramolecular Michael addition of aldehyde 38 (Scheme 11).69 The authors were able to conduct this reaction on a 5 g scale using catalyst I,

Figure 4.

Scheme 5. Asymmetric Michael Addition for the Construction of Key Intermediate 14

lectivities. The first step consisted of a Michael addition of aliphatic aldehydes 25 to nitrostyrenes 24, catalyzed by I. Various substitution patterns were shown to be tolerated. Using the appropriate substituents in the starting materials, the authors reported the synthesis of 27 (R1 = 3-OMOM; R2 = OTBS) using the sequence shown in Scheme 8 in 53% overall yield and 90% ee. The synthesis of (−)-microminutinin 23 required further transformations to obtain the optically active compound with 93% ee, which led to a revision of the absolute configuration of the native natural product.61,62 Atropurpuran 28 (Figure 6) is a natural compound, isolated from the Aconitum species, which is commonly used in Chinese traditional medicine.63,64 The molecule shows a complex scaffold that contains a highly functionalized cyclohexanone moiety fused with diverse rings. The Qin group published a synthetic approach to scaffold 29, which formed the three fused 6-membered rings.64 The use of catalyst I was integrated in the early stage of the synthesis, where an intramolecular Michael addition was performed on intermediate 30 to form bicyclic system 31 containing a cyclohexenone moiety (Scheme 9). While generating a molecule with four contiguous stereocenters

Scheme 6. Biological Pathway for the Synthesis of 5-D2-IsoK 17 from Arachidonic Acid 15 through Isoprostane (IsoP) Intermediate 16

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Scheme 7. Michael Addition between Aldehyde 18 and Nitroolefin 19

Figure 5.

Scheme 8. One-Pot Synthesis of Scaffolds 27 for the Synthesis of Functionalized Aflatoxin Systems such as 21−23

The presence of the dithiane moiety on aldehyde 38 was pivotal for the enhanced stereoselectivities, since poor results were obtained in the absence of this specific functional group. The authors interpreted the enhanced selectivity as arising from favorable Thorpe-Ingold effects.69 3.2. Mannich Reactions

The Mannich reaction is, typically, a three-component transformation which involves the condensation of a primary or secondary amine to a nonenolizable aldehyde, followed by the addition of an enolate to achieve C−C bond formation. Preformation of the imine simplifies the ternary system allowing for greater stereocontrol. This approach is compatible with the diarylprolinol silyl ether catalysts. Kumaraswamy et al. reported the synthesis of the nonproteinogenic amino acid (2S,3R,4S)-4-hydroxyisoleucine 40 and its stereoisomers (Figure 9).70 Isomers of this uncommon amino acid were isolated as free acids from fenugreek seeds,71 and isomer 41 was found in the Mexican tree Cacahuaxochitl as a component of the natural product funebrine 43.72 In their reports, Kumaraswamy et al. detailed the conditions for the Mannich reaction that allowed the synthesis of the presented stereoisomers with excellent stereocontrol. Starting from commercially available propanal 45 and the furfuralderived Boc-protected imine 44, reactions underwent in an anti-selective fashion when catalyst I or II were employed in water as the solvent. The amino acid precursors 46 and 47, respectively, were obtained in good yields and excellent stereoselectivities (Scheme 12). Isomers 40, 42, and ent-42 of the uncommon amino acid were afforded with this approach after further synthetic transformations. Complementarily, when L-4-TBDPSO-proline and R-proline were used as catalysts, the syn-products were formed with

Figure 6.

Scheme 9. Intramolecular Michael Addition of Aldehyde 30 Applied to the Synthesis of Atropurpuran 28

Figure 7.

which afforded intermediate 39 in near quantitative yield and excellent level of diastereo- and enantiocontrol. F

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Scheme 10. Synthesis of Lactone Fragment 36, a Precursor of Elevenol 32

Scheme 12. Synthesis of 4-Hydroxyisoleucine Precursors 46 and 47 for the Preparation of Uncommon Amino Acids 40, 42, and ent-42

Figure 8.

Scheme 11. Gram-Scale Intramolecular Michael Addition for the Synthesis of trans-Cyclohexane 39

excellent yield and diastereo- and enantioselectivities. After further transformations, isomers 41 and ent-41 were achieved. Another example of a Mannich reaction employing enamine catalysis is found in the synthesis of a Dolastatin 16 subunit reported by Umezawa and co-workers.73 Dolastatin 16 (48) presents unusual amino acids in its structure such as the dolamethylleuine unit 49 (Figure 10). The anti-Mannich reaction between aminosulfone 50 and propanal 45 catalyzed by VI afforded the dolamethylleuine precursor 51 (Scheme 13). Although this reaction was previously reported by Hayashi et al.,74,75 the authors encountered reproducibility issues when working on a gramscale. Upon optimization, they found that the reaction

Figure 10.

proceeded more efficiently when tetrahydrofuran (THF) was used instead of 1,4-dioxane and 40 mol % of catalyst loading

Figure 9. G

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Park et al. targeted the synthesis of (−)-(5R,6S)-6-acetoxy5-hexadecanolide 59 using enamine catalysis in a benzyloxylation step.80,81 This molecule is a mosquito oviposition attractant pheromone and an attractive synthetic target due to its physiological properties (Figure 12).82−88

Scheme 13. Gram-Scale Synthesis of Dolamethylleuine Precursor 51

instead of 10 mol % as originally reported. The optimized conditions afforded product 51 in 75% yield, >95:5 d.r. and 98% ee. 3.3. Oxylations

Figure 12.

Catalytic enamine formation can also be employed to form stereoselective C−O bonds. The catalytically formed enamine can perform an asymmetric nucleophilic attack of the α-carbon of a ketone or aldehyde to an electrophilic oxygen atom. This class of reactions is often described as oxylations. An example of enamine-based benzyloxylation for the synthesis of natural products is found in the total synthesis of cardenolides such as 19-hydroxysarmentogenin 52 and its epimer trewianin aglycone 53 (Figure 11).76 Cardenolides are

After exploring the reaction conditions, it was found that the benzyloxylation between the aliphatic aldehyde 60 and benzoyl peroxide proceeded with excellent enantioselectivity when catalyst II was employed. The authors also described a one-pot benzyloxylation followed by the addition of allyl bromide and stoichiometric metallic indium to afford the corresponding adduct 62 in 44% overall yield, 95% ee, and 86:14 d.r. (Scheme 15). The product was further transformed to achieve the naturally occurring pheromone 59. 3.4. Cycloadditions

According to the IUPAC definition, a cycloaddition is a reaction in which two or more sites of unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity.89 In the context of this section, the aminocatalyst allows the formation of the reactive enamine and, thus, the reaction with the unsaturated partner. Beraprost 64 (Figure 13) is a prostaglandin-like drug developed by Toray Industries Inc. in order to circumvent the instability that the natural prostaglandin I 2 63 presents.90−92 The synthetic drug is presented as a mixture of four isomers that show more stability and less cytotoxicity than the natural analogs. The Hayashi group reported the total synthesis of the most biologically active beraprost isomers 64a,b.93 The synthesis of the cyclopentane ring in 64a,b was synthesized by a formal [3 + 2]-cycloaddition reaction between succinaldehyde 4 and nitroolefin 65, catalyzed by I via enamine activation (Scheme 16). The cycloaddition was followed by protection of the aldehyde intermediate 66, which also promoted epimerization to afford adduct 67 as a single diastereoismer in 62% overall yield and 93% ee, as measured upon further transformations. This fragment was used for the synthesis of tricyclic fragment 68 in a seven-pot sequence.

Figure 11.

plant-derived steroids which have shown important physiologic activities such as inhibition of the Na+/K+ ATPase pump.77−79 Nagorny et al. designed the key intermediate 54 for the synthesis of a family of cardenolides, which proved to be useful for the preparation of both 19-hydroxysarmentogenin and trewianin aglycone, 52 and 53, respectively. The authors envisioned the use of enamine catalysis to carry out an oxylation reaction in an early stage of the total synthesis (Scheme 14). Even though this reaction could have been performed in a later stage, the stereoselective benzyloxylation proved to be a critical step as the newly formed stereocenter offered great stereocontrol in the subsequent steps. The reaction to form 58 proceeded in a three-step one-pot sequence in which the benzyloxylation reaction between cyclopentanedione 55 and acrolein was mediated by catalyst I, followed by a Wittig olefination to afford key intermediate 58.

3.5. Multicatalytic Systems

Multicatalytic systems/synergistic catalysis is a synthetic strategy wherein both the nucleophile and the electrophile

Scheme 14. Early Stage Asymmetric Benzoxylation for the Synthesis of Intermediate 58

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Scheme 15. One-Pot Benzyloxylation-Allylation Protocol Toward the Synthesis of Pheromone 59

Figure 14.

The first step of their synthesis controlled the stereochemistry of the two chiral centers of the natural product. The reaction consisted of an allylation reaction using synergistic catalysis (Scheme 17). Aldehyde 72 was activated via enamine catalysis, while allylic alcohol 71 was activated by an iridiumphosphine ligand complex. With the right combination of the diarylprolinol silyl ether catalyst (V or VI) and ligand ((R)-L or (S)-L), the four different stereoisomers 73−76 could be obtained in moderate yields, good diastereoselectivity, and excellent enantioselectivity, starting from achiral materials. Further transformations allowed the synthesis of the natural product stereoisomers with a uniform synthetic sequence of steps.

Figure 13.

are simultaneously activated by two separate and distinct catalysts to afford a single chemical transformation.94 In the context of enamine catalysis, a secondary amine such as a diarylprolinol silyl ether activates the nucleophile, meanwhile another catalyst simultaneously activates the electrophile. In the following example, catalytic iridium is employed to activate the electrophile. Δ9-Tetrahydrocannabinol (THC) belongs to the family of cannabinoids, which are commonly found in the flowering tops of female plants of Cannabis sativa L. varieties.95−98 These can be found as two different diastereomers, 69 and 70 (Figure 14). The trans-isomer 69 (the more abundant of the two) is currently employed as an antinauseant for patients undergoing chemotherapy99 and for the management of naturopathic pain.100,101 Carreira’s group developed a stereodivergent synthesis that gives rise to the four possible stereoisomers.102

4. IMINIUM-ION ACTIVATION In contrast to the HOMO-raising strategy exploited with the enamine intermediate, formation of an iminium-ion intermediate represents a LUMO-lowering strategy, facilitating reactivity of a variety of nucleophiles toward α,ß-unsaturated aldehydes.2,4,6

Scheme 16. Synthetic Sequence for the Synthesis of Beraprost Fragment 68, Highlighting a Formal [3 + 2]-Cycloaddition Reaction between Succinaldehyde 4 and Nitroolefin 65

I

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Scheme 17. Stereodivergent Strategy for the Synthesis of Δ9-THC Stereoisomers 69 and 70

4.1. Michael Additions

applying HWE. Finally, beraprost isomers 64a,b were synthesized in excellent diastereoselectivity through a total of 17 pots. Several estrane steroids have been successfully synthesized by employing organocatalytic methods.103 An illustrative example is the enantioselective total synthesis of estradiol methyl ether 80 (Figure 16) accomplished by Hayashi et al.104

The ability of diarylprolinol silyl ethers to promote both HOMO-raising and LUMO-lowering activation modes makes it a valuable tool to consider from a synthetic design point of view. Thus, the synthesis of different fragments of a natural product can be envisioned using both strategies. This is the case for the preparation of beraprost isomers 64a,b (Figure 15)

Figure 16.

Their strategy included a total of five reaction vessels with four purification steps, where the key reaction involved the use of catalyst I to mediate a Michael addition of commercially available nitroalkane 81 to 3-(4-methoxyphenyl)propenal 82. Subsequent intramolecular desymmetrization resembling a Hajos-Parrish-Eder-Sauer-Wiechert-type reaction afforded the bicyclo[4.3.0]nonane structure 83 as a single isomer with excellent enantioselectivity (Scheme 19). The five stereocenters required for the tetracyclic molecular scaffold were achieved in the first pot with full diastereo- and enantiocontrol bearing the desired conformation including the stereoselective addition of the cyanide anion to the aldehyde moiety. Finally, this pot-economy protocol proved to be general for the synthesis of other steroid derivatives.105

Figure 15.

by Hayashi and co-workers.93 A key fragment (presented in section 3.4, Scheme 16) was prepared via enamine activation. A second key fragment was also prepared using a diarylprolinol silyl ether, this time by iminium-ion catalysis. The method involved a Michael addition of nitromethane to crotonaldehyde 77 using catalyst IV to afford adduct 78 in 82% yield and 90% ee (Scheme 18). Further transformations allowed the synthesis of the phosphonate compound 79 for additional connection to key fragment 68 (Scheme 16)

Scheme 18. Synthesis of Key Fragment 79 for the Convergent Synthesis of Beraprost Isomers 64a,b

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Scheme 19. Five-Reaction Sequence for the Preparation of Key Intermediate 83 Toward the Synthesis of Estradiol Methyl Ether 80, Highlighting a Domino-Michael Desymmetrization Reaction

L-Pyrrolysine 84 is an α-amino acid produced by some bacteria and methanogenic archaea through the assembly of two molecules of L-lysine (Figure 17).106,107

Figure 17.

Figure 18.

In the chemical laboratory, only a few synthetic approaches for the preparation of 84 have been developed, and these often suffer from low yields over multistep protocols.108,109 In 2013, Wang et al. developed a concise synthesis, which was inspired by their previous work on the enantioselective synthesis of trans-3-substituted prolines.110,111 The key step of their synthesis included an organocatalytic asymmetric Michael addition of nitroalkane 85 to α,β-unsaturated aldehyde 77 for the construction of the C-4 stereogenic center of the pyrroline ring (Scheme 20). The methodology was showcased in the synthesis of the acetal 87 formed in 96% yield and with excellent enantioselectivity on an 89.5 mmol scale in a one-pot operation with only 1 mol % of catalyst V. The total synthesis of 84 was accomplished in a total of six steps with a 16% overall yield. (−)-Nakadomarin A 88 (Figure 18) is a marine alkaloid isolated from the sponge Amphimedon species.112 This molecule presents a complex structure with several fused heterocyclic moieties of different ring sizes. Takemoto et al. reported the synthesis of the pentacyclic core ABCDE as a synthetic approach to the natural product.113 The authors started from the C-ring to build the ABC skeleton. The first step consisted of a Michael addition of dimethylmalonate 89 to 3-furanacrolein 90 mediated by catalyst VII (Scheme 21). The reaction resulted in 91 with a 78% yield and 97% ee using water as solvent and a remarkably low catalyst loading (2 mol %).

Debromoflustramine E 92 (Figure 19) is an alkaloid isolated from an Australian myobatrachid frog,114 known to exhibit antibacterial activity against vancomycin-resistant Enterococci and methicillin-resistant Staphylococcus aureus.115,116 In 2013, Liu and Zhang developed an enantioselective synthesis of 3,3′-disubstituted oxindoles by conjugate addition of malonate 89 to isatylidene-3-acetaldehyde 95 using iminium-ion catalysis (Scheme 22).117 This transformation was readily scaled to the gram scale for the asymmetric total synthesis of debromoflustramine E 92 in high yield and excellent enantioselectivity. The authors claimed this was the first example of the use of β-carbonyl-substituted α,βunsaturated aldehydes to construct a quaternary stereocenter. The same year, Liu and Zhang used this robust transformation to develop the first example of an organocatalytic asymmetric conjugate addition of indole 97 to isatylidene-3acetaldehyde 95, which provided access to oxindoles bearing all-carbon quaternary stereocenters with high enantioselectivity.118 The transformation was used for the gram scale enantioselective formal total synthesis of dimeric hexahydropyrroloindole alkaloid (−)-chimonanthine 93 and the core structure construction of fungal-derived marine alkaloid (+)-gliocladin C 94 (Figure 19). Highlights include the use of the same starting material (Scheme 23) and catalysts VI and V for the synthesis of substructures 98 and 99, respectively. Finally, the authors observed that buffered conditions influenced the enantioselectivity. In 2015, Weng et al. disclosed a short enantioselective total synthesis of epoxyisoprostane EC methyl ester 100 (Figure

Scheme 20. One-Pot Asymmetric Michael Addition/Acetalization for the Construction of Key Intermediate 87

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Scheme 21. Early-Stage Enantioselective Michael Addition as Strategy for the Construction of the Pentacyclic Core of 88

Figure 19.

Scheme 22. Gram-Scale Aminocatalytic Michael Addition Applied for the Construction of the Quaternary Center of 96

Figure 20.

The Lycopodium alkaloids are an extensive family of natural compounds that exhibit intricate polycyclic scaffolds, which show interesting biological properties.120−136 These products are isolated from diverse sources.137−140 Lei et al. focused on the total synthesis of four of these alkaloids namely, (−)-huperzine Q 105, (+)-lycopladine B 106, (+)-lycopladine C 107, and the 4-epimer of (−)-lycopladine D 108 (Figure 21).141 In an initial attempt for the total synthesis of the aforementioned alkaloids, the authors sought for a synthetic strategy that would afford a common intermediate. Their first synthetic approach afforded the desired intermediate after 15 steps. However, the synthetic pathway was found to be low yielding. After a few changes in their synthetic strategy, including an asymmetric iminium-ion catalyzed Robinson

20), a promising anti-inflammatory agent whose free acid is released by phospholipases during lipid hydrolysis in inflammatory responses.119 The success of this total synthesis relied on the use of catalyst V to promote an enantioselective Michael addition between α,β-unsaturated aldehyde 101 and ketoester 102 to provide aldehyde 103 in excellent yield and enantioselectivity (Scheme 24). Two steps could also be performed in a one-pot sequence to minimize purification operations, namely the organocatalytic Michael-Wittig olefination. This two-step sequence improved the overall yield of Z-alkene 104.

Scheme 23. Gram-Scale Michael Additions of Indole 97 for the Construction of Chimonantine and Gliocladin Precursors, Highlighting the Formation of Quaternary Centers with Stereocontrol

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Scheme 24. One-Pot Asymmetric Michael Addition/Wittig Olefination Sequence for the Construction of Intermediate 104

Figure 21.

Figure 22.

annulation, the common intermediate 112 was obtained in 7 steps from commercially available substrates 109 and 110 (Scheme 25). Bradshaw and Bonjoch targeted the total synthesis of two other Lycopodium alkaloids, namely lycoposerramine Z 113 and (−)-cermizine B 114 (Figure 22). Their synthetic approach included the rapid asymmetric assembly of azabicyclic intermediate 117, and their success relied on the use of catalyst VIII to achieve a one-pot organocatalyzed Michael reaction followed by a domino Robinson annulation/ intramolecular aza-Michael reaction promoted by LiOH. In their first report,142 the authors achieved a 10-step synthesis of 113 from commercially available reagents, highlighting the organocatalyzed Michael addition of β-keto ester 115 and crotonaldehyde 77 to generate adduct 116 from which the tandem cyclization conditions were applied (Scheme 26). The addition of lithium acetate was crucial for obtaining high yield and enantioselectivity. Further recrystallization provided adduct 117 in >99% ee. In their second report,143 the authors achieved the enantioselective total synthesis of 114 on a gram-scale using series of tandem reactions and principles of pot economy. The improvement of the aminocatalyzed Michael reaction included a loading reduction of catalyst VIII (5 mol %) and the replacement of workup procedures with a sulfonic acid resin that allowed the capture and recovery of VIII in 93% yield and a 75% overall yield of decahydroquinoline 117 with 90% ee. Finally, the authors expanded the potential of this methodology, thus providing access to a range of different nitrogen bicyclic scaffolds in enantiopure form, such as morphans144 and octahydroindoles.145

Very recently, Thomson et al. developed a powerful reaction sequence for the preparation of polycyclic scaffolds, and its utility was demonstrated by the formal synthesis of (+)-7,20diisocyanoadociane 118 (Figure 23), a complex antimalarial marine diterpene containing ten contiguous stereogenic centers distributed among a tetracyclic backbone.146 Their methodology involved a stereoselective oxidative coupling of cyclic ketones via silyl bis-enol ethers followed by ring-closing metathesis. The synthesis commenced with the preparation of enones 121 and 123 from enantioenriched βTMS enones 120 and 122, respectively (Scheme 27). The latter were prepared on a 2-step 10 g scale protocol using an aminocatalytic Robinson annulation previously developed.147 This one-pot reaction sequence by which β-ketoester 110 reacts with a silyl-substituted α,β-unsaturated aldehyde 119 highlighted the use of both enantiomers of the catalyst (V and VI) for stereocontrol. Katsumadain A 125 (Figure 24) is a naturally occurring influenza virus neuraminidase inhibitor isolated from a Chinese herbal drug and used as an antiemetic and stomachic agent.148 Following their previously reported biomimetic total synthesis of katsumadain C,149 Tang’s group reported the first total synthesis of 125 by employing iminium-ion catalysis.150 The key element of their synthesis included an organocatalytic enantioselective 1,4-conjugate addition of pyranone 127 to cinnamaldehyde 126 affording adduct 128 in high yield and excellent enantioselectivity (Scheme 28). The authors also synthesized (+)-katsumadain A (ent-125) in a similar fashion by simply replacing catalyst I with enantiomer II. Finally, due to the high efficiency and flexibility of their synthetic route, this transformation was applicable to the syntheses of katsumadain A analogues.

Scheme 25. Synthesis of Common Intermediate 112 as Synthetic Strategy for the Synthesis of Alkaloids 105−108

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Scheme 26. One-Pot Asymmetric Robinson Annulation/Intramolecular aza-Michael Biscyclization Sequence for the Construction of Key Decahydroquinoline Intermediate 117

Figure 24.

quinolizidine skeleton (Scheme 30).156 This aminocatalyzed sequence highlighted the use of catalyst II in the presence of diketene 142, 6-methoxytryptamine 143, acrolein derivative 145, and acetyl chloride to achieve quinolizidine derivative 146 through intermediate 144 in good yield and excellent enantioselectivity. Finally, this work provided a concise strategy for the asymmetric synthesis of bioactive spirooxindole alkaloids such as 147 in only two steps from commercially available reagents. A similar strategy to build quinolizidine scaffolds was employed by Zhang et al. in the total synthesis of diverse alkaloids from the ipecac and corynantheine families.157 The group reported the total synthesis of natural products (−)-protoemetinol 148, (−)-protoemetine 149, (−)-dihydrocorynantheol 154, (−)-corynantheol 155, (−)-(15S)-hydroxydihydrocorynantheol 156, (−)-dihydrocorynantheal 157, (−)-corynantheal 158, and (+)-hirsutinol 160, as well as some of their corresponding epimers and analogues. Formal syntheses of (−)-emetine 150, (−)-cephaeline 151, (−)-tubulosine 152, (−)-deoxytubulosine 153, and (+)-dihydrocorynantheine 159 were also reported (Figure 27). Starting from the easily accessible α,β-unsaturated aldehyde 145 and β-ketoamide 161, the synthesis of a common quinolizidine scaffold 162 was achieved by employing catalyst II (Scheme 31). Interestingly, applying thermodynamic

Figure 23.

The Nauclea species have been used as medicinal plants in different tropical regions of Africa and Asia.151 A considerable amount of indole alkaloids have been isolated from this genus, and some of them have exhibited diverse bioactivity profiles.152,153 Recent work from Jia and co-workers described the synthesis of eight different natural products through common intermediate 133 (Figure 25).154 The authors reported the synthesis of common intermediate 133 by employing catalyst III. The catalyst controls a regioselective Michael addition of 138 to the α,β-unsaturated aldehyde 139 via iminium-ion activation to afford an E-/Zmixture of isomers of 140 after the Pictet-Spengler reaction (Scheme 29). Subsequent treatment of the E-isomer with 1 M HCl promoted cyclization to achieve intermediate 133 upon purification. (−)-Strychnofoline 141 (Figure 26) is a natural product of the spirooxindole alkaloid family isolated from the leaves of a Strychnos shrub and another attractive target for chemical synthesis due to its antitumor activities.155 Its most recent synthesis was achieved in only nine steps by Xu and co-workers and includes a one-pot acylation/Michael addition/Pictet-Spengler reaction for the construction of its

Scheme 27. Synthesis of Enantioenriched Silane Intermediates 120 and 122 under Iminium-Ion Catalysis, Targeting the Synthesis of Intermediate 124

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Scheme 28. Aminocatalytic Conjugate Addition/Hemiketalization Sequence Toward the Synthesis of Natural Product 125

Figure 25.

Scheme 29. Synthesis of Common Intermediate 133, Highlighting a Michael Addition/Pictet-Spengler Reaction Sequence

formed with an 82:18 ratio. Kinetic/thermodynamic control was found to depend on the choice of acid when quenching the reaction. The two different epimers constituted the starting materials for the aforementioned natural products; their nonnatural isomers were constructed in high yields and excellent stereoselectivities. Moreover, these reactions allowed for multigram scale conditions and one-pot procedures. Communesin F belongs to a family of polycyclic bis-aminal alkaloids (Figure 28). This family of compounds shows interesting cytotoxic and insecticide properties.158−162 The complexity of its chemical structure represents a synthetic challenge, which has been recently tackled in the literature.163 Among these examples, Park and co-workers reported the

Figure 26.

conditions afforded solely the epimer α-162, while using kinetic conditions and the same catalyst, the β-epimer was O

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Scheme 30. Synthesis of Quinolizidine Derivative 146 via One-Pot Acylation/Michael Addition/Pictet-Spengler Sequence

Figure 27.

α,β-unsaturated aldehyde was generated in situ, followed by its coupling with the corresponding nucleophilic oxindole 166. Finally, aldehyde reduction afforded the corresponding adduct 167 in 55% yield and 86% ee. Interestingly, control of diastereoselectivity was not observed. Upon closer inspection, the authors noted that the different diastereomers coexisted in

synthesis of communesin F 163 and putative communesins 164a,b via iminium-ion catalysis.81 Catalyst III was used for the enantioselective construction of the C−C bond between the two indole subunits (Scheme 32). Methoxy oxindole 165 was employed as a masked α,βunsaturated aldehyde. Under the given reaction conditions, the P

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Scheme 31. Enantio- and Diastereoselective One-Pot Preparation of Quinolizidine Skeletons for the Total or Formal Syntheses of Ipecac and Corynantheine Alkaloids

Figure 29. Figure 28.

tetracyclic spirondoline products (Scheme 33). Leveraging the LUMO-activation strategy imposed by catalyst V, asymmetric addition of indole 170 to aldehyde 171, followed by an enantioselective aza-Michael addition afforded ester intermediate 172. Finally, an enamine-catalyzed cyclization with spontaneous dehydration yielded the tetracyclic spiroindoline core 173.176 These reactions proceeded with moderate yields but excellent enantioselectivity leading to a single diastereomer. This scaffold served as a template for the complete synthesis of both 168 and 169, highlighting the potential of cascade sequences mediated by diarylprolinol silyl ethers. Córdova et al. has disclosed a general strategy for the concise synthesis of tropane alkaloids, which include (−)- and (+)-cocaine (174 and ent-174) as well as their analogs: (+)-ferruginine 175, (−)-1-methylcocaine 176, and (+)-methylecgonine 177 (Figure 30).177 Their total syntheses were achieved using an organocatalytic strategy, which proved to be general and highlighted the use of catalysts I and II. The transformation involved a one-pot, three-component aza-Michael/Wittig tandem reaction between acetal-functionalized α,β-unsaturated aldehydes 179 or 182, hydroxylamine 178, and phosphonium ylide 180 (Scheme 34) to afford the corresponding α,β-unsaturated δ-

equilibrium under the reaction conditions. Fortunately, the desired diastereoisomer was isolated by column chromatography. The undesired diastereoisomer was subjected to DessMartin oxidation and recycled by applying the original reaction conditions to promote the epimerization and increase the amount of the desired diastereoisomer. A yield of 42% was reported using this approach. Further transformations involved azide reduction-intramolecular condensation, titanium-catalyzed indole ring fusion, and C−H activation to obtain products 163, 164a,b. The total synthesis of a series of polycyclic system bearing an encaged bicyclo[2.2.2]octane core, such as kopsinine 168 and aspidofractine 169, has been pursued as synthetic targets due to their biological activities (Figure 29). Originally isolated from the genus Kopsia, 168 and related monoterpene indole alkaloids have shown promising antileishmanial, antitumoral, antimitotical, and antitussive activities.164−166 As such, great effort has been dedicated for the synthesis of these class of alkaloids. Typical strategies invoked to construct the bicyclo[2.2.2]octane substructure has squarely relied on the Diels−Alder reaction.167−175 Wu et al. pursued an alternative route where an organocatalyzed cascade sequence was applied to provide the

Scheme 32. Iminium-Ion Activation Strategy for the Coupling of Indole Subunits 165 and 166 Toward the Synthesis of Communesins 163, 164a,b

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Scheme 33. Asymmetric Michael/aza-Michael/Cyclization Cascade Sequence for the Construction of Spiroindoline Cores Found in Alkaloids 168 and 169

Figure 31.

35). The authors suggested that epimerization occurs during the aminocatalytic Michael addition of hydroxylamine 185 to Scheme 35. Aminocatalytic aza-Michael Addition to Cyclic α,β-Unsaturated Aldehydes Toward the Synthesis of Cispentacin 184

Figure 30.

amino acid derivatives 181 and 183 in good yields and excellent enantio- and diastereoselectivities. In 2013, Pou and Moyano developed an organocatalytic enantioselective aza-Michael/cyclization reaction of a hydroxylamine with α-branched α,β-unsaturated aldehydes for the synthesis of the antifungal and antibiotic cispentacin 184 (Figure 31).178 Prior to this work organocatalytic aza-Michael additions to α,β-unsaturated aldehydes had been mainly limited to simple β-substituted α,β-unsaturated aldehydes. Their methodology highlighted the use of catalyst II and cyclopentene-1carbaldehyde 186, as the cyclized isoxazolidine 187 was obtained as a single diastereomer in excellent yields (Scheme

186, which leads to the selective formation of the desired cisisomer 187. Since the primary product of the Michael addition would have been obtained as a cis/trans diastereomeric mixture, the isoxazolidinone 188 was obtained in a 96% ee after oxidation. Upon catalytic hydrogenation, the authors obtained 184 with a known (1S,2R) configuration.

Scheme 34. One-Pot aza-Michael/Wittig Reaction Sequence As a General Strategy for the Synthesis of Tropane Alkaloids 174−177

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The first enantioselective total synthesis of the marine meroterpene (+)-conicol 189 (Figure 32) was described by

and then the corresponding enamine intermediate performs the ring-closure in a stepwise fashion.184,185 However, recent studies have elucidated an alternative mechanism which operates via an SN2′ pathway. A key distinction is the addition of the nucleophilic oxygen at the β-position leading to the expulsion of H2O from the hemiaminal intermediate. Thus, the iminium-ion is suggested to be an off-cycle intermediate.185 A few examples of organocatalyzed epoxidations in total synthesis are presented herein. As presented in section 4.1, Weng et al. disclosed a short enantioselective total synthesis of epoxyisoprostane EC methyl ester 100 (Figure 20 and 34).119 The synthesis of a key fragment for its preparation was also envisioned using an organocatalytic strategy, again highlighting the versatility of diarylprolinol silyl ethers for the synthesis of different fragments of a natural product. Their synthetic route also featured the use of catalyst I for the preparation of the α-side chain of 100 using an asymmetric epoxidation reaction of aldehyde 198, affording epoxyaldehyde 199 in moderate yield with excellent enantioselectivity (Scheme 38). Finally, this synthesis not only featured the multiple use of diarylprolinol silyl ethers but also featured a phase-transfer catalyzed intramolecular aldol reaction (not shown), further highlighting the application of organocatalysis in total synthesis. Hirsutellone B 200 (Figure 35) is a fungal secondary metabolite which exhibits high inhibitory effect for the tuberculosis pathogen Mycobacterium tuberculosis.186−188 Nicolaou et al. reported the total synthesis of 200 employing diverse cascade reaction sequences.189 In the early stages of the synthesis of 200, the authors employed iminium-ion catalysis to build the three-fused ring backbone. Specifically, the organocatalytic epoxidation reaction of 203 was carried out using catalyst I (Scheme 39). The epoxide moiety in 204 provided a useful tool which allowed for further synthetic elaborations to promote the ring closure followed by an intramolecular Diels−Alder reaction to form the three fused rings. The group of Nicolaou also developed the total synthesis of the trioxacarcin DC-45-A2 205 (Figure 36) using iminium-ion catalysis to perform an asymmetric epoxidation of an α,βunsaturated aldehyde.190 DC-45-A2 205 is a precursor for many compounds from the trioxacarcin family. In addition, it also presents antitumoral and antibacterial properties.191−194 The epoxidation step was performed in an advanced stage of the total synthesis. Despite the diverse collection of sensitive protecting groups, the epoxidation of the core scaffold 206 was carried out, using the urea-hydrogen peroxide complex as

Figure 32.

Hong et al.179 This natural product was obtained via an organocatalytic domino oxa-Michael/Michael/Michael/aldol condensation, a transformation that further expands the synthetic application of diarylprolinol silyl ethers in total synthesis. The approach started with an oxa-Michael/Michael sequence between nitrovinylbenzene diol 190 and α,βunsaturated aldehyde 191 to afford aldehyde 192, followed by a domino Michael/aldol condensation with aldehyde 101 to provide hexahydro-6H-benzo[c]chromene 193 bearing four contiguous centers (Scheme 36). Both transformations mediated by catalyst I proceeded in good yields and excellent enantioselectivities (>99% ee). The two reactions could also be achieved in a one-pot fashion to give 193 without the isolation of 192 in a 55% overall yield. Finally, the authors successfully assigned the absolute configuration of 189, which they presume had previously been unknown. Nicolaou et al. reported the total synthesis of thailanstatin A 194 and its methyl ester analogue 195 (Figure 33).180,181 This natural product was isolated from the Gram-negative bacillus Thailandensis burkholderia, which has shown promising activity toward diverse human cancer cell lines.182,183 The construction of one of the tetrahydropyran rings was performed via an intramolecular oxa-Michael addition (Scheme 37). The substrate 196 was activated by catalyst VII and benzoic acid as cocatalyst to promote an intramolecular 1,4-addition of the hydroxy group to the electrophilic carbon atom. 4.2. Epoxidations

In the context of this Review, epoxidation reactions can be visualized as an oxa-Michael reaction followed by ring closure. A general and simplified mechanism catalyzed by diarylprolinol silyl ethers is the use of iminium-ion catalysis. Following the LUMO-lowering activation of α,β-unsaturated aldehydes, a nucleophilic oxygen atom attacks the activated double bond

Scheme 36. Asymmetric Quadruple Domino Reaction Applied for the Synthesis of (+)-Conicol 189

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Figure 33.

Scheme 37. Construction of Key Tetrahydropyran Intermediate 197 through an Intramolecular oxa-Michael Reaction Applied to the Synthesis of Thalilanstatins 194 and 195

Figure 36.

Hillman, and TMS-protection reactions (Scheme 40). Even though the epoxidation proceeded with an excellent degree of enantioselectivity, the desired product 208 was obtained as a 3:1 diastereomeric ratio due to the Baylis-Hillman step involving enone 207. The diarylprolinol silyl ether catalytic epoxidation reaction has also been employed in the total synthesis of bacilosarcins A and B (209 and 210, respectively) reported by Kuwahara et al.195 These natural products (Figure 37) were isolated from a culture of Bacillus subtilis, which is a bacterium found in intestinal contents of some sardine species.196 Curiously, bacilosarcins 209 and 210 showed remarkable activity as herbicides.197 An organocatalytic epoxidation procedure allowed the synthesis of acid fragment 213 for subsequent construction of structures 209 and 210 through a peptide coupling. The authors followed a previously reported procedure by Córdova et al. to achieve the enantiomerically pure epoxide 212 starting from aldehyde 211 (Scheme 41).184,198 This epoxide was then subjected to a five-step sequence to afford the targeted fragment 213 in a 20% overall yield. Paecilonic acid A 214 (Figure 38) is a fatty acid which was recently isolated, among other metabolites, from the marine fungi Paecilomyces varioti.199 Even though biological properties have not been described yet for 214, the development of synthetic tools to construct this natural product scaffold could facilitate possible future applications. Fürstner et al. recently reported the first total synthesis of acid 214 employing a novel methodology for the late-stage formation of ketones, acyloins, and aldols.200 The authors employed catalyst II in an early stage of this total synthesis by performing an epoxidation on commercially available enal 215, followed by an alkaline ring opening to generate the

Figure 34.

Scheme 38. Construction of Epoxyisoprostane EC Methyl Ester 100 Fragment by Employing an Asymmetric Epoxidation Reaction

Figure 35.

oxidant and catalyst I with high chemoselectivity. The developed method was robust and tolerated a one-pot sequence of three reactions, namely, epoxidation, Baylis-

Scheme 39. Enantioselective Construction of Epoxy Ester Iodide 204 Toward the Total Synthesis of Metabolite 200

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Scheme 40. Synthesis of Epoxyketone 208, Highlighting the Asymmetric Epoxidation Reaction in a Late-Stage of the Synthesis of Trioxacarcin 205

Figure 38. Figure 37.

Scheme 42. Asymmetric Epoxidation/Dihydroxylation/ Acetalization Reaction Sequence for the Construction of Diol 216 Applied in the Synthesis of Fatty Acid 214

corresponding 1,2-diol 216 in 59% yield and 97% ee (Scheme 42). In a later step, the two newly installed oxygen atoms would be integrated in the bicyclic system of the natural product 214. 4.3. Aziridinations

Aziridinations consist in an aza-Michael addition to a LUMOactivated α,β-unsaturated aldehyde, followed by ring closure. To facilitate the second step, the amine is attached to a leaving group (e.g., tosylate), which is displaced during the cyclization step. To the best of our knowledge, there is only one example of aziridination in the literature that fits the criteria of the present Review. In early 2018, a formal synthesis of (−)-aurantioclavine 217 was described by Hamada and co-workers (Figure 39).201 This ergot-derived alkaloid has attracted interest from the synthetic community due to its role as a biosynthetic precursor of the complex polycyclic alkaloids of the communesin family (e.g., communesin F; see Figure 28). Several syntheses of 217 have been previously achieved, but the present one is noteworthy given that the key step of the synthesis includes an aminocatalytic asymmetric aziridination of an α,β-unsaturated aldehyde for the construction of the stereogenic center (Scheme 43). The general aziridination method was previously developed by the same group202,203 and relies on the use of catalyst IX and tert-butyl p-toluenesulfonyloxy carbamate 218 as a nucleophile to afford chiral aziridine derivatives such as 220. A subsequent transformation to afford β-amino ester derivative 222 was performed in a one-pot sequence by adding catalytic amounts of triazolium salt 221 and methanol to the reaction mixture, affording N-Bocprotected amine 222 in excellent yield and enantioselectivity (Scheme 43).

Figure 39.

This work successfully demonstrates the synthetic utility of the aziridination method which aims at developing synthetic methods for 3,4-fused tricyclic indole derivatives and further highlights the use of diarylprolinol silyl ether catalysts in the construction of three-membered rings beyond epoxides. 4.4. Cyclopropanations

Cyclopropanation refers to any chemical reaction that forms cyclopropanes. Since cyclopropanes present high levels of strain and energy, highly reactive species are required. In the examples presented in this Review, the chemical partner of the LUMO-activated α,β-unsaturated aldehyde is a 1,3-dicarbonyl

Scheme 41. Preparation of Acid Fragment 213 Starting with an Asymmetric Epoxidation Reaction of Aldehyde 211

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Scheme 43. Synthesis of N-Boc-Protected Amine 222 Employing an Aminocatalytic Asymmetric Aziridination on Enal 219

identification of a diverging pathway for stereoinduction. Application of catalysts I and II for the asymmetric synthesis of each enantiomerically pure intermediate provided this pathway. The use of catalyst I for the cyclopropanation of the cinnamaldehyde derivative 230 using bromomalonate 224 afforded the optically active diester 231 in 91% yield and 95% ee (Scheme 45). This intermediate was further functionalized to complete the unprecedented total syntheses of (+)-podophyllic aldehydes 227−229. Exhibiting its versatility, catalyst II was also applied for the cyclopropanation reaction to afford the opposing enantiomer, ent-231, in 88% yield with 95% ee, thus providing access to both enantiomers of the podophilic aldehydes.

compound with an halide in the nucleophilic position. Thus, the halide acts as a leaving group in the ring-closure step, after the nucleophilic attack of the carbon atom to which the halide is attached. Virgatusin 223 (Figure 40) is a natural product that belongs to the lignan family of compounds, and it was first isolated from Phyllantus virgatus.204

4.5. Cycloadditions

Complementary to what it has been exposed for enamine catalysis (see section 3.4), diarylprolinol silyl ethers can also provide cycloaddition reactions via LUMO-lowering strategies as a consequence of iminium-ion formation. Herein, we present two examples of iminium-ion-activated cycloadditions applied in total synthesis. The diarylprolinol silyl ethers have also been applied for the synthesis of chiral piperidines. This was illustrated in the total synthesis of (+)-α-skytanthine 232 (Figure 42), a monoterpene piperidine alkaloid isolated from Skytanthus actus (Apocynaceae).224 (+)-α-Skytanthine 232 features four contiguous stereogenic centers on a 3-azabicyclo[4.3.0]nonane core and has shown promising hypotensive activity.225 Due to these biological attributes, several total syntheses of 232 have been reported.226−230 The total synthesis of 232, reported by Ishikawa et al., utilized an organocatalytic pathway to access the chiral piperidine moiety.231 Typical proline-based aminocatalysts require 10−20 mol % loading; however, Ishikawa’s et al. approach underscored incredibly low loadings of catalyst IV (0.1 mol %) in a formal aza-[3 + 3]-cycloaddition (Scheme 46). Interestingly, the selection of nucleophile dramatically affected the formal cycloaddition reaction. Competitive

Figure 40.

The Johnson group published the total synthesis of 223 using a formal [3 + 2]-cycloaddition between a donor− acceptor cyclopropane and an α,β-unsaturated aldehyde to construct the tetrahydrofuran ring (Scheme 44).205 In order to achieve this transformation, the authors prepared the optically active precursor by using aminocatalysis. Catalyst I mediated the cyclopropanation reaction through an iminium-ion activated Michael addition between bromomalonate 224 and enal 225 followed by enamine-activated alkylation to form 226. (−)-Podophyllic aldehydes A, B, and C, (227, 228, and 229, respectively), a subset of dihydronapthalene-type lignans, have received increased interest due to their biological activity and abundance in nature (Figure 41).206−217 These natural products have displayed notable antineoplastic cytotoxicity and apoptosis-inducing qualities.218−222 While total synthesis of (−)-podophyllic aldehydes have been reported, the synthesis and activity of their enantiomeric series has not been previously disclosed. For structure and activity studies, investigation of both optically pure enantiomers is sensible. Nishii et al. sought to develop a route for facile access to series of enantiomeric partners.223 Pertinent to this was the

Scheme 44. Aminocatalytic Michael/Intramolecular Alkylation for the Preparation of Formylcyclopropane 226, a Key Intermediate for the Synthesis of Virgatusin 223

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Figure 41.

Scheme 45. Aminocatalytic Michael/Intramolecular Alkylation for the Preparation of the Enantiomeric Pair of Formylcyclopropane Intermediates 231 and ent-231

Overall, key intermediate 236 was prepared over the course of five steps in 53% yield with 91% ee. The laboratories of Chen and Yang undertook the daunting task of synthesizing the nortriterpenoid, (+)-propindilactone G 237 (Figure 43).232,233 Bearing a unique pentacyclic core Figure 42.

dienamine formation from the aliphatic α,β-unsaturated aldehyde 233 led to decomposition through self-condensation. Hence, strong nucleophiles, such as 234, would add and outcompete the iminium-ion before acidification/deprotonation to the dienamine. Using catalyst IV, formal aza-[3 + 3] cycloaddition was achieved, affording intermediate 235.

Figure 43.

Scheme 46. Synthesis of Intermediate 236, Highlighting an Asymmetric Formal aza-[3 + 3] Cycloaddition for the Construction of the Piperidine Ring of Skytanthine 232

W

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Scheme 47. Construction of Bromoenone Intermediate 241, Highlighting a Multigram-Scale Asymmetric Diels-Alder Reaction Applied in the Synthesis of Propindilactone G 237

Another tandem strategy employing iminium-ion catalysis is found in the total synthesis of (1R)-suberosanone 247 (Figure 45) reported by Ren et al.255 Suberosanone 247 belongs to a small family of compounds called quadranes, which present cytotoxic activities and are found in both terrestrial and marine organisms.256 In the first step of their synthesis, the authors generated the bicyclic core by combining iminium-ion and carbene catalysis (Scheme 49). The addition of catalyst V promoted the βalkylation of the corresponding enal 77, followed by an intramolecular aldol reaction mediated by the carbene catalyst 250. Sphingoid-bases safingol 251 and D-threo-clavaminol 252 are characterized by the 2-amino-1,3-diol moiety in a long aliphatic chain (Figure 46). This feature is common in a large number of bioactive compounds.257−259 For example, 251 is used in combination of cisplatin for treatment of advanced tumors.260 Weng et al. reported the synthesis of optically active 251 and 252, applying oxime 253 and achiral aliphatic α,β-unsaturated aldehydes, such as 254, as starting materials.261 They developed a one-pot cascade strategy employing catalyst V, which initially promoted the oxa-Michael reaction via iminiumion activation, followed by α-amination via enamine activation (Scheme 50). The dual role of the catalyst allowed for the synthesis of both natural products with high optical purity. Córdova et al. have also disclosed the first example of an enantioselective β-alkylation of α,β-unsaturated aldehydes by combination of aminocatalysis and transition-metal catalysis.262 This cocatalyzed asymmetric 1,4-addition was used as the key step for the total synthesis of three bisabolane sesquiterpenes: (S)-(+)-tumerone 257, (S)-(+)-curcumene 258, and (S)-(+)-3-dehydrocurcumene 259 (Figure 47). These natural products exhibit anticancer and antimicrobial activities and are used as additives in perfumes, flavors, and cosmetics.263−271 Using catalyst I in combination with a copper salt, the authors achieved a catalytic asymmetric addition of dimethylzinc reagent to the α,β-unsaturated aldehyde 260 to afford the corresponding β-alkyl aldehyde 261 in good yield and excellent enantioselectivity (Scheme 51). On the basis of the absolute configuration of aldehyde 261 and previous DFT calculations,272 they proposed an in situ generated copper(II)-alkyl complex which selectively adds to an iminium-ion intermediate. Finally, hydrolysis of the iminium-ion regenerates the catalyst I as well as the elusive active copper-catalyst complex.

including seven stereogenic centers in which three are quaternary centers, compound 237 was first isolated from various species of the Schisandraceae family.234 Owing to the use of this species as a traditional herb with medicinal properties,235 further biological investigation has garnered increased interest for its anti-HIV activity, thus necessitating a general approach for its total synthesis.236 The approach by Chen and Yang for this synthetic challenge centered on the initial construction of the pentacyclic core, followed by an oxidative heterocoupling of enolsilanes.232 Key asymmetric reactions for the synthesis of this nortripenoid scaffold started with an aminocatalyzed Diels−Alder reaction mediated by catalyst X, successfully performed on a 100 g scale (Scheme 47). Cycloadduct 240 was obtained in high yield (88%) and excellent enantioselectivity (98% ee). Further transformations afforded 241, setting the stereochemistry of the bridged BC-ring system (Scheme 47). Through this 20step synthesis, the authors identified a structural inconsistency from previously reported analyses leading to a correction of (+)-propindilactone G 237.234 The originally proposed structure was reassigned as C17-epi-(+)-propindilactone G. 4.6. Multicatalytic Systems

While the diarylprolinol silyl ethers catalysts have been shown to participate in multicatalytic systems exploiting the enamine activation concept (section 3.5), these catalysts can also be employed in multicatalytic systems using LUMO-lowering systems. Alkaloids from the Amaryllidaceae family have shown interesting biological activities, such as antiviral and anticancer.237−253 The chemical structure of this family of compounds is characterized by densely functionalized aminocyclitol cores, such as (+)-trans-dihydrolycoricidine 242 (Figure 44).249−253

Figure 44.

McNulty et al. reported the total synthesis of 242 employing a tandem iminium-ion/chiral-base catalyzed sequence for the construction of the highly functionalized 6-membered ring (Scheme 48).254 The use of catalyst II allowed the formation of the Michael adduct 246, which in the presence of cinchona alkaloid 245 underwent an intramolecular aldol reaction to afford the 6-membered ring with 20:1 d.r. and 98% ee.

5. VINYLOGOUS IMINIUM-ION CATALYSIS The expansion of the HOMO-raising and LUMO-lowering strategies have been accomplished by the combination of the vinylogous concept with aminocatalysis.13,14 The ability of diarylprolinol silyl ethers to propagate electronic effects and X

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Scheme 48. Enantioselective Michael/Aldol Sequence Applied in the Synthesis of Alkaloid 242

Figure 46. Figure 45.

6. DIARYLPROLINOL SILYL ETHERS IN PATENT LITERATURE The maturity of the diarylprolinol silyl ethers in asymmetric catalysis has been extended to multiple applications in the patent literature. The literature shows that the organocatalysts have mainly been applied for the enantioselective functionalization of aldehydes and α,β-unsaturated aldehydes toward the formation of drugs, drug candidates, and important chiral scaffolds. Patents may vary in content compared to a scientific publication, and it is important to have this in mind when integrating patents and patent applications in the present Review. A patent is a temporary government-granted monopoly right on something made by an inventor. The historical purpose of the patent system was to encourage the development of new inventions and, in particular, to encourage the disclosure of those new inventions. For applicants, patents are an attractive way to gain exclusivity or to earn licensing income, although patents are also used as bargaining chips (e.g., in cross-licensing).275 The experimental details disclosed in a patent can in many cases be compared to and have the same quality as required for a chemical journal; however, less

relay stereoinduction through conjugate π-systems has provided new opportunities to functionalize polyconjugated carbonyl compounds, further highlighting the versatility of this class of catalysts in the synthetic community. More specifically, the emergence of iminium-ion catalysis with the concept of vinylogy transmits the LUMO-lowering effect within the extended π-system of 2,4-unsaturated carbonyls for functionalization of δ-positions.13,14 Herein, we present one example of this concept applied in total synthesis. 5.1. Michael Additions

(+)-Dactylolide 262 (Figure 48) is a cytotoxic 20-membered macrolide isolated from the Vanuatu sponge Dactylospongia sp. by Riccio et al.,273 which has shown modest tumor cell growth inhibitory activities in leukemia and ovarian cancer cell lines.273 Highlights of its synthesis include an organocatalytic 1,6-oxa conjugate addition reaction for the stereoselective synthesis of tetrahydropyran subunit 264.274 Application of catalyst I for the 1,6-oxa conjugate addition of ω-hydroxy-2,4-dienal 263, the authors were able to obtain subunit 264 with excellent stereoselectivity (>20:1 d.r.) and 98% yield (Scheme 52).

Scheme 49. Dual Organocatalytic System for the Direct Enantioselective Construction of Bridged Bicyclo[3.2.1] Ring System of Suberosanone 247

Y

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Scheme 50. One-Pot oxa-Michael/α-Amination Reaction Sequence Applied in the Synthesis of Safingol 251 and Clavaminol 252

Figure 47.

Scheme 51. Co-Catalyzed Asymmetric β-Alkylation of α,βUnsaturated Aldehyde 261 for Further Synthesis of Sesquiterpenes 257−259, Highlighting the Use of Copper Salts, Dialkylzinc Reagents, And Diarylprolinol Silyl Ethers

intention of this Review to provide a complete overview of patents in which these catalysts have been used but rather to present some examples where the catalysts have been integrated in the synthesis of drugs, drug candidates and intermediates in drug synthesis, and in the synthesis of chiral molecular building blocks. 6.1. Synthesis of Drugs, Drug Candidates, And Intermediates in Drug Synthesis

A number of patents have applied the diarylprolinol silyl ethers as catalysts for the formation of an important intermediate in the process for obtaining drug molecules. 6.1.1. Enamine Catalysis. The pharmaceutical company Lundbeck has disclosed a patent on compounds having betasecretase activity, BACE1 inhibitors, for the treatment of neurodegenerative and cognitive disorders.276 The patent covers the synthesis of a large number of stereoisomers of compounds 265 (Figure 49). Furthermore, the patent also includes many variations in substituent patterns.

Figure 48.

Scheme 52. Vinylogous Iminium-Ion Activation for Intramolecular 1,6-oxa Conjugate Addition of 263 to Provide Subunit 264 Figure 49.

A key-step for the formation of the BACE1 inhibitors 265 is the enantioselective introduction of a fluorine atom as the R3substituent. The enantioselective fluorination was achieved by reacting the aldehyde precursor 266 with NFSI as the fluorinating reagent in the presence of catalyst V (25 mol %) providing intermediate 267. Intermediate 267 was not isolated, but directly converted to 268 and isolated in 42% yield as a mixture of diastereomers (Scheme 53). More recently, a team including researchers from Eli Lilly and Company showed that it was also possible to apply D-proline as a catalyst for introduction of the fluorine atom.277 Novartis has, in a very well-documented patent, described a novel process, novel process steps, and novel intermediates useful in the synthesis of aliskiren 269 (Figure 50).278 Aliskiren 269 is an antihypertensive compound on the market developed

extensive experimental details can also be found in patents in various situations. In the following section, we present a limited number of examples of patents and patent applications in which the diarylprolinol silyl ethers have been disclosed. It is not the Z

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Scheme 53. Enantioselective Fluorination of Aldehyde Intermediate 266 for the Synthesis of Optically Active BACE1 Analogues Catalyzed by V

to interfere with the renin-angiotensin system at the beginning of the angiotensin II biosynthesis.

Figure 51.

A number of publications by Hayashi et al.105,280−284 have documented the successful application of the diarylprolinol silyl ethers as catalyst for the stereoselective synthesis of Tamiflu/oseltamivir 274 as alternative process to that published by Roche,285 Corey,286 and Trost.287 A patent by Ma et al. disclosed the formation of the chiral amino fragment 275 as a key intermediate for the synthesis of 274 and some enantiopure 3-aminopyrrolidines that have potential application for the synthesis of clinically used drugs (Scheme 55).288 In the patent, the diphenylprolinol silyl ethers (both I and II have been applied) are used to prepare 275 having different stereochemical composition and a number of substituent variations. A synthesis of a number of intermediate products 275 in excellent yields and enantioselectivities, as a mixture of diastereoisomeres, are described in the patent based on different combinations of aldehydes and nitroolefins. It should also be noted that in the claims, several of the original claims have been canceled. 6.1.2. Iminium-Ion Catalysis. The reaction of α,βunsaturated aldehydes with diarylprolinol silyl ethers which generates an iminium-ion intermediate that allows for an enantioselective nucleophilic attack at the β-position of the α,β-unsaturated aldehyde is also a concept which has been integrated into patent literature. One such example is the synthesis of telaprevir 278 (Figure 52) disclosed by the company Sandoz, which requires a 3amino-2-hydroxyhexanamide containing vicinal stereocenters as an intermediate.289 Telaprevir 278 is a drug that is a protease inhibitor used for the treatment of hepatitis C. Known processes for the stereochemical synthesis of telaprevir intermediates are based on the use of organometallic catalysts to perform an epoxidation reaction, which, as stated, results in metal impurities in the final compound.289 An alternative process patented for the stereoselective synthesis of the 3-amino-2-hydroxyhexanamine intermediate 285 (Scheme 56) is based on the organocatalytic epoxidation of transhexanal 279 with hydrogen peroxide in the presence of the catalyst I (no yield, and diastereo- and enantiomeric details are given).290 Subsequent oxidation of the aldehyde to the carboxylic acid by TEMPO and sodium hypochlorite followed by opening of the epoxide with sodium azide yields 282. Intermediate 285 is formed by reaction of cyclopropylamine

Figure 50.

The patent focuses on the preparation of the C-8 lactam lactone 273, a key intermediate for the synthesis of 269, and a variety of different procedures are covered in the patent. The process is based on enamine activation, formed by condensing an aldehyde, preferably isovaleraldehyde 270, with an aminocatalyst, preferentially a diarylprolinol silyl ether, reacting with an in situ generated nitroethene (Scheme 54). In one Scheme 54. Novartis Process for the Formation of Lactam Lactone 273, a Key Intermediate for the Synthesis of Renin Inhibitors Such As Aliskiren 269

particular example (no yields are given), 270 was reacted with 2-nitrobenzoate 271 in the presence of catalyst III (8 mol %) and the desired product 272 was obtained with 91% ee. This is followed by a Nef reaction of 272 and a nitroaldol reaction using a second equivalent of 272, reduction, and Bocprotection of the amino group. Hydrogenation of the protected alcohol and then oxidation catalyzed by tetrapropyl ammonium perruthenate (TPAP) and N-methyl morpholine-N-oxide (NMO) as the oxidation reagent provides 273 (Scheme 54). Tamiflu 274 (Figure 51), also known as oseltamivir, is a highly effective compound that can block the pyrolysis of sialic acid residues on the surface of virus infected cells, which is caused by the influenza virus, thus inhibiting the newly formed virus to be released from host cells.279 AA

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Scheme 55. Overall Process Concept for the Preparation of the Key Intermediate 276 in the Synthesis of Tamiflu® by Reaction of Various Aldehydes with Nitroolefins in the Presence of Diphenylprolinol Silyl Ethers

Figure 52. Figure 53.

283 in the presence of i-Pr2EtN and cleavage of the N−N bond in the azide by hydrogen over Pd/C. Telaprevir 278 is finally formed by coupling of the primary amine in intermediate 285 with the carboxylic acid of the peptide fragment. Paroxetine 286 (Figure 53) is a compound marketed under the trademark Paxil for the treatment of depression. It has also been shown useful in the treatment of obsessive compulsive disorder, panic disorder, and social anxiety disorder. The inventors argued that their process, based on the use of a diarylprolinol silyl ether as a catalyst, was an improved process that addressed the problems associated with the production reported in the prior art.290 It was stated that the problems included the use of toxic and/or costly solvents, which were eliminated with the process described in the patent. Furthermore, the process did not require additional purification steps and critical workup procedures which provide marked improvements such as a simple, efficient, cost-effective, environmentally friendly, and commercially scalable process for large scale preparations. By the application of III as the catalyst for the reaction of 4-fluorocinnamaldehyde 287 with methyl-3-(methylamino)-3-oxopropanoate 288, the inventors were able to obtain intermediate 289 in ∼46% yield and >99% ee across two steps (Scheme 57), from which paroxetine can be easily prepared.

Scheme 57. One-Pot Stereoselective Synthesis of the Paroxetine Intermediate 289 by Reaction of 4Flourocinnamaldehyde 287 with Methyl-3-(methylamino)3-oxopropanoate 288

It is interesting to compare this patented process with the synthetic procedure found in the scientific literature for the synthesis of 289 which was disclosed in the first paper where diarylprolinol silyl ethers were introduced as catalysts for conjugate additions to α,β-unsaturated aldehydes.291 In that work, the synthesis of 289 was described by a similar organocatalytic process using malonate followed by a reductive amination-cyclization sequence, rather than methyl-3-(methyl-

Scheme 56. Formation of the β-Amino Acid Derivative 285 by Epoxidation of trans-Hexenal 279 Catalyzed by Catalyst I

AB

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amino)-3-oxopropanoate 288, and prepared in slightly lower yield than in the patent. Telcagepant 290 (Figure 54) is a peptide receptor antagonist compound developed by the company Merck, Figure 55.

In a series of patents, Gellman et al. have demonstrated the generality of the diarylprolinol silyl ethers as catalysts for the formation various types of chiral amino acids derivatives and peptides.294−296 The formation of chiral α-substituted β-amino acids was based on an aldehyde aminomethylation, which involved a Mannich reaction between an aldehyde, such as 300, and N,N-dibenzylamine-derived N,O-acetal 302 to give, in the presence of catalyst I and after reduction of the aldehyde, amino alcohols 303 as presented in Scheme 60. The reaction showed great diversity in substitution pattern and proceeded in good yields and >90% ee. The benzyl groups could be removed, and the amino group was reprotected by a Boc-group in a one-pot procedure with >65% yield. The Bocamino alcohol was then oxidized to the corresponding β2amino acid in >85% yield. In the patent, the developed organocatalytic procedure for the formation of β2-amino acids was compared to Seebachs β2-amino acid synthesis strategy which requires eight steps and allows for a final yield of approximately 10%, which is significantly lower than the developed procedure.297 This reaction concept has been extended to provide elegant protocols for the formation constrained cyclic α-substituted-γnitro-aldehydes. These can easily be converted to the corresponding protected γ-amino acid derivatives. The two different concepts are based on enamine and iminium-ion activation with the application of the diphenylprolinol silyl ether (Scheme 61). For the reaction of aldehydes 304 with 1nitrocyclohexene 305, the reaction proceeded in high yields and diastereoselectivity and excellent enantioselectivity of the isolated alcohol product 307. The patent also disclosed the conversion to useful Boc-protected γ-amino α-substituted αamino acids, such as 309. For the cyclic α,β-unsaturated aldehydes 306, catalyst I was an efficient catalyst for the addition of nitromethane providing γ-nitro-aldehydes, which were isolated in high yields and excellent stereoselectivities after reduction to the corresponding alcohols 308. An interesting aspect of the organocatalytic procedures for the synthesis of constrained cyclic γ-nitro-aldehydes in the

Figure 54.

Sharp, and Dohme for the treatment of migraines and cluster headaches. A central moiety in the synthesis of 290 is the caprolactam fragment.292 The stereoselective formation of the caprolactam fragment is based on the addition of nitromethane to the difluorocinnamaldehyde 291 applying catalyst I (Scheme 58).292 Product 292 underwent an organocatalyzed Knoevenagel condensation catalyzed by pyrrolidine providing 294, followed by treatment with a base to give 295 in 48% overall yield. Compound 295 was then converted into telcagepant 290. 6.2. Synthesis of Chiral Molecular Building Blocks

The application of the diarylprolinol silyl ethers as catalysts have also played an important role in the formation of chiral building blocks of interest in, for example, life sciences. 6.2.1. Enamine Catalysis. Hayashi has filed a patent that provided a process for the formation of five-membered cyclic compounds 296 and ent-296 (Figure 55) by reaction of nitroolefins with 1,4-butanediones in the presence of a diarylprolinol silyl ether.293 The intermediates resemble the crucial intermediates involved in the total synthesis described in Schemes 3 and 16. The invention in the patent relates to the synthesis of five-membered cyclic compounds serving as pharmaceutically active components of the prostaglandin type. In the patent it is demonstrated that, for example, succinaldehyde 4 reacts with nitrostyrene 13 in the presence of catalyst I in a stoichiometric amount relative to 4, affording the five-membered cyclic compounds 297 in 71% yield. Dehydration applying acetic anhydride and pyridine leads to intermediate 298 in 75% yield and 95% ee, which opened up for the synthesis of various types of prostaglandin analogues (Scheme 59).

Scheme 58. Formation of the Chiral Fragment in Telcagepant by Enantioselective Addition of Nitromethane to Difluorocinnamaldehyde 291 Catalyzed by I

AC

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Scheme 59. Method for the Construction of Intermediate 298 for the Synthesis of Prostaglandin Analogues

Scheme 60. Gellman’s Process for the Formation of β2Amino Alcohols 303

products described in the patent were characterized as white solids with the same yield (52%) and d.r. (95:5). 6.2.2. Iminium-Ion Catalysis. Catalytic enantioselective activation of α,β-unsaturated aldehydes by diarylprolinol silyl ethers have also been applied for the formation of chiral building blocks of interest in, for example, life science and molecules with potential bioactivity. A Chinese patent has demonstrated the application of the diphenylprolinol silyl ethers as a very efficient catalyst for the stereoselective synthesis of dihydrochromones having multiple stereocenters.299 It was stated that the reason for filing the patent was due to the importance of the compounds described as useful intermediates for the formation of medicines. The mechanism for the formation of dihydrochromones 323 probably involved a dienamine intermediate generated from the α,β-unsaturated aldehyde 321 and catalyst I. The patent also disclosed further interesting transformations of the dihydrochromones obtained by the organocatalytic steps (Scheme 64). Wang has filed a patent for an invention that provides direct processes and related organocatalysts for the one-pot syntheses of trisubstituted chiral pyrrolidines, piperidines, tetrahydrothiophenes, and thianes by a highly enantio- and diastereoselective cascade Michael/Michael reactions of α,β-unsaturated aldehydes with trans-γ-protected amino and mercapto α,β-unsaturated esters (Scheme 65).300 The obtained products, such as the substituted chiral pyrrolidines and piperidines, were claimed to be “privileged” structures and are ubiquitous structural components of numerous naturally occurring alkaloids, neuroexcitatory amino acids, and biologically active synthetic substances such as promising new anticancer agents

patent was the application of the chiral products to prepare αand γ-peptide foldamers that adopt specific helical conformations. Scheme 62 presents the synthesis of one of several examples for the synthesis of a peptide based on the Bocprotected γ-amino α-substituted α-amino acid. First the Cterminus is protected as a benzyl ester, followed by deprotection of the N-terminus. A coupling with Boc-proteced D-Ala gave dipeptide 314 which by hydrogenation over Pd/C or by deprotection of the N-terminus gave Boc-(D)Ala(Et)ACAB−OH 315 or NH2-(D) Ala-(Et)ACAH-OBn 316, respectively [(Et)ACHA stands for cyclic γ-amino acids residue]. The two latter peptides were then coupled to provide the final product 317 (no yields are given in the patent). A simple procedure for the synthesis of chiral lactones containing a quaternary stereocenter obtained by the reaction of mixing aldehydes and α,β-unsaturated aldehydes in the presence of catalyst I was disclosed in a Chinese patent (Scheme 63).298 The scope of the reaction was demonstrated for a variety of different aromatic, heteroaromatic, and α,βunsaturated aldehydes, and seems to give high diastereo- and enantioselectivity. However, it was remarkable that all the

Scheme 61. Formation of Constrained Cyclic α-Substituted-γ-Nitro-Aldehydes Based on the Reaction of Either Cyclic Nitroolefins 305 or α,β-Unsaturated Aldehydes 306, with Aldehydes 304 or Nitromethane, Respectively

AD

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Scheme 62. Synthesis of α- and γ-Peptide Foldamers Based on the Organocatalyzed Reactions of the Constrained Cyclic γNitro-Aldehydes

Scheme 65. Cascade Michael/Michael Reactions of α,βUnsaturated Aldehydes for the Formation of, for Example, Substituted Chiral Pyrrolidines

Scheme 63. Formation of Lactones by Reaction of Aldehydes with α,β-Unsaturated Aldehydes Catalyzed by I

and influenza drugs.301 The patented reaction concept was demonstrated in a number of examples to proceed in high yields and excellent stereoselectivities. The synthesis of chiral trans-α,β-epoxy carboxylic acids by reaction of α,β-unsaturated aldehydes with hydrogen peroxide in the presence of catalyst XI has been disclosed (Scheme 66).302 The trans-α,β-epoxy carboxylic acids have been claimed to be important intermediates for natural products with a wide range of applications in drug synthesis. The organocatalytic epoxidation reaction provided trans-epoxy aldehydes 329 as intermediates, from which the chiral trans-α,β-epoxy carboxylic acids 330 are prepared by reacting intermediate 329 with

sodium carbonate and NBS. For a series of aromatic α,βunsaturated aldehydes, the chiral trans-α,β-epoxy carboxylic acids were synthesized in good yields and >90% ee. A method for the synthesis of β-indole aldehydes 332 have been patented by the reaction of α,β-unsaturated aldehydes 326 with indoles 331 in the presence of catalyst I.303 The scope of the reaction was demonstrated by the formation of a series of indole aldehydes in >66% yield and >94% ee (Scheme 67).

Scheme 64. Synthesis of Chiral Dihydrochromones Applying Catalyst I

AE

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Scheme 66. Asymmetric Epoxidation of α,β-Unsaturated Aldehydes for the Synthesis of Chiral trans-α,β-Epoxy Carboxylic Acids

ORCID

Gabriel J. Reyes-Rodríguez: 0000-0002-0566-0820 Nomaan M. Rezayee: 0000-0002-9622-6324 Andreu Vidal-Albalat: 0000-0002-8514-6580 Karl Anker Jørgensen: 0000-0002-3482-6236 Notes

The authors declare no competing financial interest. Biographies Gabriel J. Reyes-Rodrı ́guez received his Ph.D. in 2013 at the University of California, San Diego, under the direction of Professor Charles L. Perrin. From 2015 to 2017, he worked as a postdoctoral researcher under the direction of Professor David B. Collum at Cornell University. In 2017, he joined the research group of Professor Karl Anker Jørgensen as a postdoctoral fellow, where his current interest includes a mechanistic approach for the enhancement of aminocatalytic oxidative couplings with improved control over yield and stereoselectivity.

Scheme 67. β-Indole Aldehydes Prepared by Reaction of Indoles with α,β-Unsaturated Aldehydes in the Presence of Catalyst I

Nomaan M. Rezayee received his B.S. degree with honors in Chemistry from Pepperdine University in 2012 with the guidance of Professor Joseph M. Fritsch. He pursued graduate studies at the University of Michigan under the mentorship of Professor Melanie S. Sanford. Following the completion of his Ph.D. work, he joined the lab of Professor Karl Anker Jørgensen at Aarhus University as a postdoctoral researcher. Current research interests entail the development of novel catalysts to perform diverse sets of transformations.

7. CONCLUSION AND OUTLOOK Within the past decade, a substantial paradigm shift in synthetic and patent literature has been observed. Since the initial disclosure of the diarylprolinol silyl ether catalysts, their use have manifested as a key strategy to construct complex chiral molecules. Their versatility and stereoselectivity have singled these aminocatalysts out as a privileged general catalyst. Affirming the impact to the field of asymmetric catalysis is the transition of the developed methodologies from simple small molecules in the academic setting to the early stage production of intricate, three-dimensional pharmaceuticals. This Review, spanning works published since 2008, highlights a key uptick in integration of the diarylprolinol silyl ether in total synthesis and patent literature. The rise in application may be attributed to the maturation of wellestablished methodologies. Academics have invested in the development of activation strategies to access valuable synthons which have flourished to bear fruitful applications in practical circumstances. The combination of enamine and iminium-ion activation modes have provided a robust method for the asymmetric formation of C−X bond(s) through the Michael, Mannich, oxylation, cycloaddition, epoxidation, aziridination, cyclopropanation, and vinylogous reactions. While the incorporation of the diarylprolinol silyl ether catalysts on full-scale production sites underscore their value, the application of these catalysts in an industrial setting remain in its infancy. Since this Review is limited to examples in total synthesis and patent literature, significant collections of novel methods were omitted. It is fully anticipated that during the course of the following years, new methods such as photocatalytic, oxidative, and reductive strategies will be implemented in the synthesis and production of complex molecules to stimulate further development and growth.

Andreu Vidal-Albalat completed his Ph.D. in Organic Chemistry in 2016 under the supervision of Professor Florenci V. González at Universitat Jaume I de Castelló (Spain). Afterward, he joined Professor Karl Anker Jørgensen’s group as a postdoctoral researcher. Now, he is employed as a postdoctoral researcher at Umeå University (Sweden) under the supervision of Professor Anna Linusson. His current research interests focus on the application of organocatalytic methodologies for the synthesis of inhibitors for the tropical disease vector control. Karl Anker Jørgensen received his Ph.D. from Aarhus University in 1984. He was a postdoctoral researcher with Roald Hoffmann at Cornell University (1985). In 1985, he became Assistant Professor at Aarhus University, and in 1992, he was promoted to Professor. His research interests are the development, understanding, and application of asymmetric catalysis mainly in the field of organocatalysis.

ACKNOWLEDGMENTS The work was made possible by generous support of grants from Carlsberg Foundation’s “Semper Ardens” programme, FNU, and Aarhus University. REFERENCES (1) List, B. The Ying and Yang of Asymmetric Aminocatalysis. Chem. Commun. 2006, 819−824. (2) Dondoni, A.; Massi, A. Asymmetric Organocatalysis: from Infancy to Adolescence. Angew. Chem., Int. Ed. 2008, 47, 4638−4660. (3) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Asymmetric AminocatalysisGold Rush in Organic Chemistry. Angew. Chem., Int. Ed. 2008, 47, 6138−6171. (4) Bertelsen, S.; Jørgensen, K. A. OrganocatalysisAfter the Gold Rush. Chem. Soc. Rev. 2009, 38, 2178−2189. (5) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Asymmetric Enamine Catalysis. Chem. Rev. 2007, 107, 5471−5569.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. AF

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DOI: 10.1021/acs.chemrev.8b00583 Chem. Rev. XXXX, XXX, XXX−XXX