Stereocontrolled Domino Reactions - Chemical Reviews (ACS

REVIEW pubs.acs.org/CR

Stereocontrolled Domino Reactions H
elene Pellissier* Aix-Marseille Universit
e, UMR CNRS 7313 Institut des Sciences Mol
eculaires de Marseille Equipe Chirosciences, Case 561, Campus Saint J
er^ome Avenue Esc. Normandie-Niemen, 13397 Marseille Cedex 20, France

3.5. Multicomponent Mannich Reactions 3.6. Multicomponent Reactions Initiated by an Allylation Reaction 3.7. Multicomponent Passerini Reactions 3.8. Multicomponent Biginelli Reactions 3.9. Multicomponent Petasis Reactions 3.10. Miscellaneous Multicomponent Reactions 3.10.1. Metal-Catalyzed Multicomponent Reactions 3.10.2. Other Multicomponent Reactions 4. Conclusion Author Information Biography Abbreviations References

CONTENTS 1. Introduction 2. One- and Two
Component Domino Reactions 2.1. Anionic Primary Step 2.1.1. Domino Reactions Initiated by the Michael Reaction 2.1.2. Domino Reactions Initiated by Other Anionic Reaction 2.2. Cationic Sequences 2.3. Domino Reactions Initiated by a Pericyclic Primary Step 2.4. Carbene Sequences 2.5. Palladium-Catalyzed Domino Reactions 2.6. Ruthenium-Catalyzed Domino Reactions 2.7. Gold-Catalyzed Domino Reactions 2.8. Miscellaneous Domino Reactions 2.8.1. Domino Reactions Initiated by an Oxidation 2.8.2. Domino Reactions Initiated by a Ring-Opening Reaction 2.8.3. Domino Reactions Initiated by an Isomerization 2.8.4. Other Domino Reactions 3. Multicomponent Reactions 3.1. Multicomponent Reactions Initiated by the Michael Reaction 3.1.1. Multicomponent Reactions Initiated by a Classical Michael Reaction 3.1.2. Multicomponent Reactions Initiated by a Hetero-Michael Reaction 3.2. Multicomponent Hantzsch Reactions 3.3. Multicomponent Ugi Reactions 3.4. Multicomponent Strecker Reactions r XXXX American Chemical Society

A G G G

BH BI BK BM BN BP BP BT BZ BZ CA CA CA

O

1. INTRODUCTION A domino reaction has been defined by Tietze as a reaction involving two or more bond-forming transformations that take place under the same reaction conditions, without adding additional reagents and catalysts, and in which the subsequent reactions result as a consequence of the functionality formed by bond formation or fragmentation in the previous step.1 It must be noted, however, that there is a relatively narrow distinction between domino and consecutive cascade or tandem reactions. From the point of view of an experimentalist, the only difference between the two lies in the point along the sequence at which one or more catalysts or reagents had to be added to effect either the initiation of a sequence (that is, domino reaction) or propagation to the next step (that is, consecutive reaction). Nicolaou has pointed out that the descriptors domino, cascade, and tandem are often used indistinguishably from one another in the literature.2 Indeed, a variety of opinions exist on how such reactions should be classified. According to Tietze, a domino reaction is strictly defined as a process in which two or more bond-forming transformations occur based on functionalities formed in the previous step. Furthermore, no additional reagents, catalysts, or additives can be added to the reaction vessel, nor can reaction conditions be changed.1 Denmark and Thorarensen further posited, however, that most domino reactions, as defined by Tietze, fell under the broader category of tandem processes.3 Other tandem reactions that are not cascades involve the isolation of intermediates, a change in reaction conditions, or the

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Scheme 1. Synthesis of Salvinorin A through Domino Michael/Michael Reaction

Scheme 2. Synthesis of Ouabain through Domino Michael/Michael Reaction

this review, the definition according to Tietze is suitable. Domino reactions are classified according to the mechanism of the

addition of reagents or coupling partners. Others classified domino reactions with even stricter conditions;4 however, for the sake of B

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Scheme 3. Synthesis of (
)-Chokol A through Domino Michael/Dieckmann Reaction

Scheme 4. Synthesis of Key Intermediate in the Synthesis of Himbacine through Domino Michael/Dieckmann Reaction

individual steps, which may be of the same or different type. The quality and importance of a domino reaction can be correlated to the number of bonds generated in such a process and the increase

in complexity. Its goal is the emulation of Nature in its highly selective sequential transformations. The reactions can be performed as single-component, two-component, and multicomponent C

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Scheme 5. Synthesis of Both Enantiomers of α-(Hydroxymethyl)glutamic Acid through Domino Michael/Dieckmann Reaction

Scheme 6. Domino Michael/Mannich/Mannich Reaction

D

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Scheme 7. Synthesis of Pheromone through Domino Michael/Intramolecular Alkylation Reaction

Scheme 9. Domino Michael/Acetal Ring-Opening Reaction

Scheme 8. Domino Michael/Intramolecular Alkylation Reaction

should be clearly differentiated from other one-pot processes, such as tandem or cascade reactions, and in general from all processes that involve the reaction between two reagents to yield an intermediate that is captured by the successive addition of a new reagent (sequential component reactions). This review is based on the definition of multicomponent reactions as convergent chemical processes that involve the well-defined coupling of more than two reactants to form a product that contains significant portions of all reactants, ideally all atoms.5b Moreover, no additional reagents, catalysts, or additives can be added to the reaction vessel, nor can reaction conditions be changed as in domino processes according to Tietze. The use of one-component, twocomponent domino, and multicomponent domino reactions in organic synthesis is increasing constantly. Such single-step reactions allow the rapid synthesis of a wide range of complex

transformations. Multicomponent reactions are defined as domino reactions involving at least three substrates and, consequently, constitute a subgroup of domino reactions.4a,5 It must be noted that there are also some confusing ideas among chemists about the definition of a multicomponent reaction. According to Ramon and Yus,5c this type of reaction E

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Scheme 10. Intra- and Intermolecular Domino Michael/ Ylide Epoxidation Reactions

Scheme 11. Domino Michael/Ylide Cyclopropanation Reaction

molecules, including natural products and biologically active compounds such as pharmaceuticals and agrochemicals, in an economically favorable way by using processes that are reasonably simple.6 Indeed, domino reactions have gained wide acceptance, because they increase synthetic efficiency by decreasing the number of laboratory operations required and the quantities of chemicals and solvents used.7 The proliferation of these reactions is evidenced by the number of recent reviews covering the literature through 1992.1,4,5,8 Although asymmetric synthesis is sometimes viewed as a subdiscipline of organic chemistry, actually this topical field transcends any narrow classification and pervades essentially all of Chemistry. 9 Of the methods available for preparing chiral compounds, asymmetric synthesis from chiral substrates still attracts a lot of attention. Indeed, it remains the method most employed in the total synthesis of optically active compounds playing an important role in medicine and materials as well as natural products, in spite of the explosive growth of organocatalysis in the past decade, 8m
p,t,10 and its application in the synthesis of a number of chiral products. 11 The goal of this review is to cover the last efforts of the chemical community in the development of novel stereocontrolled domino reactions of chiral substrates and their wide applications in total synthesis published since the beginning of 2006, since this field was most recently

reviewed in 2006 by Tietze in a book and by this author in a review, covering the literature until the beginning of 2006. 1e,8l Moreover, it must be noted that, very recently, Orru and co-workers reported a review on asymmetric multicomponent reactions. 8u This review deals with stereocontrolled domino reactions, including both asymmetric domino reactions based on the use of removable chiral auxiliaries and asymmetric domino reactions of chiral reagents in which the source of chirality is within the substrates and associated stereogenic centers that need to remain an integral part of the products. The domino reactions are catalogued on the basis of the reaction types involved in the first synthetic step. To facilitate presentation, the review has been divided into two parts. The first part deals with asymmetric domino reactions involving one and F

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Scheme 12. Domino Michael/Wittig Reaction

Scheme 13. Synthesis of Oseltamivir through Domino Michael/Horner
Wadsworth
Emmons Reaction

examples in which it has been applied as a key strategic transformation in total synthesis. As a consequence, in recent years, many different versions of this important transformation have been reported, using a wide variety of nucleophiles and conjugate acceptors.14 In particular, the Michael/Michael domino reaction is a powerful tool in forging ring systems common to many natural products. A number of asymmetric double Michael reactions have been reported in the past few years, often applied to the total synthesis of important products. As an example, Scheerer et al. reported the first asymmetric synthesis of the naturally occurring neoclerodane diterpene salvinorin A, which is a potent k opioid receptor agonist, the only nonalkaloid psychoactive substance, and the most potent natural hallucinogen.15 The key step of the synthesis was a transannular double Michael reaction cascade of chiral bisenone macrocycle 1 promoted by tetra-n-butylammonium fluoride (TBAF). The corresponding tricycle 2, arising from the domino reaction, was obtained in quantitative yield as a single diastereomer, as shown in Scheme 1. The process delivered two quaternary methyl stereocenters at C5 and C9 in a 1,3-diaxial alignment from the corresponding β,βdisubstituted enones, moieties commonly known to possess poor reactivity toward conjugate addition. Scheme 1 provides a rationale for the observed stereoselectivity in the domino

two components, while the second part includes multicomponent (domino) reactions involving at least three substrates.

2. ONE- AND TWO
COMPONENT DOMINO REACTIONS 2.1. Anionic Primary Step

2.1.1. Domino Reactions Initiated by the Michael Reaction. 2.1.1.1. Domino Reactions Initiated by a Classical Michael Reaction. The nucleophilic 1,4-addition of stabilized carbon nucleophiles to electron-poor olefins, generally α,βunsaturated carbonyl compounds, is known as the Michael addition, although it was first reported by Komnenos in 1883.12 Michael-type reactions can be considered as one of the most powerful and reliable tools for the stereocontrolled formation of carbon
carbon and carbon
heteroatom bonds,13 as has been demonstrated by the huge number of G

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Scheme 14. Synthesis of ABT-341 through Domino Michael/Horner
Wadsworth
Emmons Reaction

reaction. Conformational analysis of bisenone macrocycle 1 suggested that the three stereocenters, in pseudoequatorial positions, mutually reinforced the diastereoselectivity. This analysis also suggested that enolization favored the Z-enolate. The key enantiopure tricycle 2 was further converted into expected salvinorin A through seven supplementary steps in 41% overall yield. The first and long-awaited total synthesis of the natural cardioactive glycosylated steroid ouabain has been developed by Deslongchamps and co-workers on the basis of a polyanionic cyclization strategy, providing a tricyclic domino intermediate 3, which is depicted in Scheme 2.16 This intermediate arose from an asymmetric domino Michael/Michael reaction occurring between chiral cyclohexenone 4 and chiral Nazarov substrate 5 in the presence of Cs2CO3. This key tricyclic product 3 was obtained in 85% yield and subsequently submitted to decarboxylation to give product 6 as a single diastereomer in 92% yield. Finally, this polyfunctionalized tricyclic compound 6 was converted into expected ouabain. A novel asymmetric domino Michael/Dieckmann cyclization reaction was employed by Groth et al. as key step in a total synthesis of naturally occurring fungitoxic (
)-chokol A, in 2006.17 As shown in Scheme 3, the condensation of a higherorder cuprate 7 derived from the corresponding vinyl bromide to chiral α,β-unsaturated ester 8 derived from (
)-phenylmenthol provided, after a Michael addition followed by a Dieckmann cyclization, the corresponding cyclic β-keto ester 9 in 93% yield combined with an excellent diastereoselectivity of >98% de. This chiral product was further converted into expected (
)-chokol A through a five-step sequence with an overall yield of 29%. In the course of developing a novel synthesis of natural and biologically active himbacine, Casey and McCarthy have found that a domino Michael/Dieckmann reaction of enantioenriched α,β-unsaturated furanone 10 (ee = 70%) with a racemic diester 11 led to the corresponding tricyclic product 12, which constituted a key intermediate for the proposed synthesis.18 Actually, the process generated the domino product as a mixture of three diastereomers, 12, 120 , and 1200 , among which the major one, 12, was separated by chromatography with 46% yield (Scheme 4). This enantiopure tricyclic product constituted a useful intermediate for a short enantioselective synthesis of himbacine and derivatives.

Scheme 15. Synthesis of Precursor of (
)-Pumiliotoxin C through Domino Aza-Michael/Michael Reaction

Another asymmetric domino Michael/Dieckmann reaction was demonstrated by Avenoza and co-workers to be an efficient entry to both enantiomers of α-(hydroxymethyl)glutamic acid.19 As shown in Scheme 5, the reaction of methyl acrylate with L-serine-derived bicyclic N,O-acetal (3S,7R,7aS)-13 provided, through a sequence of a Michael addition followed by a Dieckmann reaction promoted by the participation of the cyclic carbamate group, the domino product 14 as a 39:61 mixture of (3S,6R,7aS)- and (3S,6S,7aS)-diastereomers. This mixture was further submitted to 6N HCl aqueous solution under reflux to achieve the (S)-enantiomer of α-(hydroxymethyl)glutamic acid H

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Scheme 16. Domino Thia-Michael/Aldol Reaction of Chiral 3-Cinnamoyloxazolidine-2-thione with Aromatic Aldehydes

from bicyclic N,O-acetal (3R,7R,7aS)-13 derived from D-serine, as shown in Scheme 5. In 2011, Qin and co-workers reported a novel domino Michael/Mannich/Mannich reaction of tryptamine derivative 16 with chiral amidinobenzodiene 17, which was in situ generated from the corresponding isatin-derived chloride 18.20 Surprisingly, the process led, in the presence of 2 equiv of AgBF4, to a 3:1 diastereomeric mixture of complex products 19 and 190 possessing a polycyclic skeleton of 2,3,4,5-diindolinohexahydropyrrole in 76% yield. The authors assumed that the formation of these products was explained through a three-step cascade reaction beginning with the attack of indole on the benzodiene, which gave the corresponding indolinium 20 (Scheme 6). This intermediate 20 was susceptible to addition of its imidate group to afford the corresponding iminium intermediate 21. A final Mannich addition of the amide group in 21 to the iminium moiety provided the final products 19 and 190 . The stereochemistry of the chiral formed products was established by X-ray crystal-structural analysis. In another context, the Michael reaction has also been combined to intramolecular alkylation reaction. As an example, the synthesis of a pheromone was achieved by Reddy and coworkers on the basis of a domino Michael/intramolecular

Scheme 17. Domino Aza-Michael/Cyclization Reaction of Lithium (R)-N-(α-methylbenzyl)amide with Benzylidene Imines

15. In the same way as that described for the synthesis of this (S)-enantiomer, the authors have achieved the corresponding (R)-enantiomer of α-(hydroxymethyl)glutamic acid 15 starting I

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Scheme 18. Intramolecular Domino Hetero-Michael/Mannich-type Reaction

Scheme 19. Domino Hetero-Michael/Intramolecular Alkylation Reaction

Scheme 21. Domino Nucleophilic Addition/Aza-Michael Reaction

Scheme 20. Synthesis of (
)-Mearsine through Domino Aza-Michael/Imine Formation Reaction

in Scheme 8. It must be noted that, in all cases of substrates studied, the products were produced in good yields and as single diastereomers. Furthermore, the scope of the reaction was applied to malonitrile as nucleophile, yielding the corresponding enantiopure carbocycle in 68% yield, as shown in Scheme 8. Very recently, Roscales and Csaky developed a nice route to enantiopure polyfunctionalized tetrahydropyrans based on asymmetric domino Michael/acetal ring-opening reaction promoted by trifluoroacetic anhydride.23 This sequence consisted of the metal-free conjugate addition of boronic acids to chiral acetals 26 performed in the presence of 3 equiv of trifluoroacetic anhydride, providing the corresponding tetrahydropyrans 27 in good to high yields and high to excellent diastereoselectivities of up to >96% de. A mechanism accounting for the diastereoselective formation of these products is

alkylation reaction of chiral α,β-unsaturated ester 22 derived from (R)-pantolactone with Me2CuLi.21 Indeed, the resulting enolate arising from the Michael addition of this cuprate to α,β-unsaturated ester 22 subsequently cyclized to furnish the corresponding chiral cyclopentane derivative 23 as a single diastereomer in 94% yield, as shown in Scheme 7. This product was further converted into the expected sex pheromone depicted in Scheme 7. Another type of asymmetric domino Michael/intramolecular alkylation reaction was developed by Atta and Pathak to achieve a range of chiral six-membered heterocycles and carbocycles bearing three contiguous stereocenters.22 In this case, the domino reaction occurred between chiral vinyl sulfone 24 derived from ribose and dialkyl malonates, which provided the corresponding enantiopure cyclohexane derivatives 25, as shown J

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Scheme 22. Domino Imino
Aldol/Aza-Michael Reaction

Scheme 23. Domino Nucleophilic Addition/Nucleophilic Aromatic Substitution Reaction

depicted in Scheme 9. Reaction of trifluoroacetic anhydride with boronic acid could give a mono- or a diacylboronate intermediate 28, in which the Lewis acidity of the boron atom was enhanced with respect to boronic acid. Coordination of this species with the γ-oxygen of acetal 26 led to intermediate 29. The subsequent intramolecular delivery of the R1 group was facilitated by the lone pair on the δ-oxygen, providing intermediate 30. Intramolecular ring-closure finally accounted for the formation of products 27. The stereochemistry has

been found to depend on both the substrate and reagent structures. Indeed, a highly selective trans relative disposition between R 1 and OH groups in the final products 27 was found, which was consistent with a substrate-controlled chelated syn Michael addition step, as depicted on intermediate 29. The final cyclization could be envisioned by an approach of the enolate to the sp 2 carbon of the electrophilic moiety in a chairlike transition state 31. The pseudoequatorial disposition of the substituents minimized the steric K

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33 with α,β-unsaturated enones depicted above could be switched to give rise to enantioenriched vinylcyclopropanes.25 Indeed, when the reaction was performed in the presence of a strong base, such as t-BuOK in THF, it selectively afforded the corresponding vinylcyclopropanes 36 instead of the cyclohexadiene epoxides 35 obtained by using a weak base such as K2CO3 in MeCN. As shown in Scheme 11, a range of trisubstituted chiral vinylcyclopropanes 36 were achieved in good yields and excellent enantioselectivities of up to >99% ee in almost all cases of substrates studied. Moreover, the diastereoselectivity of the process was found to be in a range of >92 to >98% de for all the substrates studied. A possible mechanism to account for the observed results of the asymmetric tunable ylide-initiated reaction is depicted in Scheme 11. The sulfur ylide 33 has two major contributing resonances 33A and 33B, and the latter one underwent Michael addition with unsaturated kenone to form intermediate 37. In the presence of a weak base such as Cs2CO3, the base could not remove the proton smoothly on the α-position of the ester group in intermediate 37, and consequently, the proton transferred to enolate to form 38, allowing the intramolecular ylide epoxidation to afford cyclohexadiene epoxide 35 as a major product. In the presence of a strong base and under a low-temperature condition, intermediate 37 disfavored a proton-transfer process to form ketone 38, and as a consequence, a normal ylide cyclopropanation between ylide 33A and unsaturated ketone was preferred to afford vinylcyclopropane 36 as a major product. The same authors have developed an asymmetric domino Michael/Wittig reaction of crotonate-derived chiral phosphonium salts 39 with α,β-unsaturated enones in the presence of Cs2CO3.26 This domino process provided the corresponding enantiomerically enriched functionalized cyclohexa-1,3-diene derivatives 40 in moderate to good yields and enantioselectivities (25
90% ee) when using (R)-2-MeO-MeOBIPHEP-derived phosphonium salt as chiral auxiliary. As depicted in Scheme 12, the chiral phosphonium salt 39 generated the corresponding chiral phosphorus ylide 41, which underwent Michael addition to the α,β-unsaturated enone to give an enolate 42. This enolate generated a novel phosphorus ylide 43, which underwent intramolecular Wittig olefination to give the final cyclohexadiene 40.

interaction between R1 and benzyl groups in tetrahydropyrans 27. In 2008, Tang and co-workers reported a remarkable synthesis of a collection of enantiopure, highly functionalized cyclohexadiene epoxide derivatives through asymmetric intramolecular as well as intermolecular domino Michael/ylide epoxidation reactions.24 As shown in Scheme 10, when the two types of chiral allylic sulfonium salts 32 and 33 derived from camphor were treated with K2CO3, they afforded the corresponding cyclohexadiene epoxides 34 and 35, respectively, as single products in good yields and general excellent enantioselectivities of >91% ee in both intramolecular and intermolecular reactions with α,β-unsaturated enones. In addition to being highly functionalized and enantiopure, it must be noted that these products exhibited three stereocenters. Further studies of the same authors have revealed that the intermolecular reaction of chiral camphor-derived sulfonium salt Scheme 24. Synthesis of (
)-PNU-286607 through Domino Knoevenagel/[1,5]-Hydrogen Shift/Cyclization Reaction

Scheme 25. Synthesis of (+)-Chinensiolide B through Domino Allylboration/Lactonization Reaction

L

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Scheme 26. Synthesis of Alkaloids through Domino Horner
Wadsworth
Emmons/Isomerization/Claisen Rearrangement Reaction

chiral cis-cyclohexene 48 as a single diastereomer in 87% yield. This product could be transformed into the expected ABT341 in four steps. 2.1.1.2. Domino Reactions Initiated by a Hetero-Michael Reaction. In marked contrast with the Michael addition of carbon nucleophiles, the addition of noncarbon nucleophiles (hetero-Michael addition), such as amines,14a thiols,29 phosphorus,30 and alcohols,31 has gained considerably less interest in the past few decades. Several nice examples of asymmetric domino reactions initiated by hetero-Michael reactions of chiral substrates have been reported, however, in the past few years. As an example, Garrido et al. have developed an expeditious asymmetric synthesis of a precursor of natural product (
)-pumiliotoxin C, based on an asymmetric domino aza-Michael/Michael reaction.32 This process was initiated by a highly diastereoselective aza-Michael addition of a chiral lithium amide 49 to nona-2,7-diendioic diester 50, followed by a 6-exo-trig cyclization of the thus formed enolate 51. As shown in Scheme 15, the expected chiral cyclohexane domino product 52 was achieved in 80% yield as a single diastereomer

In 2010, Lu and co-workers reported a practical and azide-free synthetic approach to the antiviral agent oseltamivir (Tamiflu) from diethyl D-tartrate.27 The key step of this synthesis was a domino nitro-Michael
/Horner
Wadsworth
Emmons reaction of chiral nitroalkane 44, which allowed the cyclohexene ring of the antiviral product to be constructed, since the domino product 45 was obtained in 61% yield as a 3:1 mixture of diastereomers, as shown in Scheme 13. This diastereomeric mixture was further converted into oseltamivir in three steps. In the same context, another asymmetric domino Michael/ Horner
Wadsworth
Emmons reaction has constituted the key step in a synthesis of dipeptidyl peptidase IV-selective inhibitor ABT-341, which was reported by Hayashi and co-workers in 2011.28 In this case, the chiral starting material of the domino reaction was another chiral nitroalkane, such as substrate 46, which is depicted in Scheme 14. The process evolved through the formation of Michael product 47, which was subsequently submitted to Horner
Wadsworth
Emmons reaction, affording the corresponding M

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Scheme 27. Domino Amidation/Cyclization Reaction Followed by Intramolecular Electrophilic Aromatic Substitution

compounds 55 and 550 were presumably formed along the reaction pathways shown in Scheme 16. BF3 3 Et2O coordinated with the carbonyl oxygen of the N-cinnamoylthiocarbamate 54, allowing the enone moiety to be activated. The intramolecular thia-Michael addition of the thione group to the enone moiety proceeded via intermediate 56 and afforded the boron enolate
iminium salt 57. An aldol reaction between the boron enolate moiety and aldehyde yielded the aldol product 58, which cyclized to afford the final tricyclic products 55 and 550 . In 2009, Davies et al. demonstrated that the condensation of chiral lithium (R)-N-(α-methylbenzyl)amide 59 to a range of benzylidene imines 60 provided the corresponding almost diastereo- and enantiopure domino aza-Michael/cyclization products 61 in good to excellent yields, as shown in Scheme 17.34 This process opened a novel and powerful access to enantiopure 2-aryl-4-aminotetrahydroquinoline-3-carboxylic acid derivatives bearing three contiguous stereogenic centers with general diastereo- and enantioselectivities of >98% de and >98% ee, respectively. In addition to being readily applicable to the preparation of libraries of chiral 4-aminotetrahydroquinolines for biological screening, this approach has been shown to be useful to prepare corresponding chiral diamino esters through simple hydrogenolysis of the domino products, which occurred without compromising the diastereo- and enantiopurity. In 2007, Nagasaka and co-workers reported the first domino hetero-Michael addition/Mannich-type reaction using a TiCl4/ tetra-n-butylammonium iodide (TBAI) system and occurring intramolecularly between α,β-unsaturated carbonyl compounds 62, which bore an Evans oxazolidinone as a chiral moiety and in situ-generated N-acyliminium ion intermediates.35 The cyclization of the chelated iodo titanium enolate intermediates 63, arising from the Michael addition of iodide, afforded the corresponding chiral indolizidines 64 bearing three stereogenic centers in moderate to good diastereoselectivities of up to 80% de, as shown in Scheme 18. In this study, the use of mixed solvents, such as AcOEt and CH2Cl2, was shown to be the most effective.

Scheme 28. Domino Ethanolysis/Dehydrobromation/ Aziridination Reaction

that bore three contiguous stereocenters. This chiral product 52 was subsequently converted into the required chiral precursor 53 of (
)-pumiliotoxin C through a three-step sequence, involving successively a Cope elimination, a selective hydrolysis of the less steric demanding ester, and an efficient Barton decarboxylation. In 2006, Kataoka and co-workers investigated the reaction of chiral 3-cinnamoyloxazolidine-2-thione 54 with aromatic aldehydes in the presence of BF3 3 Et2O.33 The reaction evolved through an asymmetric domino thia-Michael/aldol process, providing diastereoselectively the corresponding tricyclic products, which incorporated a bridgehead carbon bound to four heteroatoms. These products were produced as mixtures of two diastereomers 55 and 550 with moderate to high diastereoselectivities of up to 90% de, as shown in Scheme 16. It must be noted that this process generated four stereocenters. The chiral domino products achieved in good to high yields could be further transformed into the corresponding enantiopure propane-1,3-diols bearing three contiguous stereocenters through acid hydrolysis, allowing the chiral auxiliaries to be recovered. The structurally rare N

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Scheme 29. Domino Ireland
Claisen Rearrangement/Michael Reaction

Another type of asymmetric domino hetero-Michael/intramolecular alkylation reaction was developed by Atta and Pathak to achieve a range of chiral six-membered heterocycles and carbocycles bearing three contiguous stereocenters.22 In this case, the domino reaction occurred between chiral vinyl sulfone 65 derived from ribose and Na2S, which provided the corresponding enantiopure cyclic sulfide 66a in 72% yield, as shown in Scheme 19. This highly efficient methodology was applied to a series of other nucleophiles, such as primary amines, leading to the corresponding piperidine derivatives 66b
e. Remarkably, in all cases of substrates studied, the products were produced in good to high yields and as single diastereomers. The synthetic utility of many of these chiral products was demonstrated by converting the sulfonylated piperidine derivatives into functionalized olefinic piperidines, for example. In another context, an asymmetric domino aza-Michael/imine formation reaction was reported by Taylor and co-workers,

allowing the synthesis of the alkaloid (
)-mearsine to be achieved.36 As shown in Scheme 20, treatment of chiral diketone 67 with 35% aqueous ammonia in methanol initiated the domino reaction with the Michael addition of ammonia to enone, providing intermediate 68, which further underwent intramolecular imine formation reaction to give the required (
)-mearsine in 82% yield combined with an enantioselectivity of 81% ee. 2.1.2. Domino Reactions Initiated by Other Anionic Reaction. 2.1.2.1. Domino Reactions Initiated by a Nucleophilic Addition to an Imine. Domino reactions involving the formation of anionic intermediates in their first step constitute the largest family of domino processes. In reactions of this type, the primary step is the formation of an anion or a nucleophile as for the domino reactions initiated by a Michael addition discussed in section 2.1.1. This family of domino reactions has been used extensively in total synthesis. A number of anionic reactions other than the Michael addition O

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Ghorai et al. on the basis of an asymmetric domino imino
aldol/aza-Michael reaction with α-arylmethylidene-β-keto esters.38 The required chiral sulfinyl imines were readily prepared from commercially available (1R,2S,5R)-(
)menthyl (S)-p-toluenesulfinate, lithium bis(trimethylsilyl)amide, and aromatic aldehydes, according to Davis0 s protocol.39 As shown in Scheme 22, the reaction of chiral 2-aryl-N-sulfinylaldimines 71 with (E)-ethyl 2-benzylidene3-oxobutanoate 72 led to the corresponding 2,6-disubstituted piperidines 73 as single diastereomers in good yields and remarkable enantioselectivities of >98% ee. A nice one-pot synthesis of optically pure fluorinated indolines was reported by Fustero and co-workers on the basis of a novel asymmetric domino reaction including a nucleophilic addition of the carbanion of chiral 2-p-tolylsulfinyl alkylbenzenes 74, generated in the presence of lithium diisopropylamide (LDA) as a base, to fluorinated aldimines and ketimines 75, which was followed by an intramolecular nucleophilic aromatic substitution of the p-tolylsulfinyl group by the amine anion, providing the corresponding fluorinated indolines 76 containing one or two stereogenic centers in good yields and diastereoselectivity of >96% de in all cases of substrates studied (Scheme 23).40 2.1.2.2. Domino Reactions Initiated by a Nucleophilic Addition to a Carbonyl Compound. In 2007, Cho and Romo reported a concise total synthesis of the biologically active natural product (
)-belactosin C and derivatives based on a diastereoselective domino Mukaiyama aldol/lactonization reaction of chiral dipeptide glyoxamide or a novel tartrate-derived chiral glyoxylate with chiral silyl ketene acetals.41 These processes allowed the construction of the pharmacophoric β-lactone moiety of these proteasome inhibitors to be achieved in a single process, albeit in zero to moderate diastereoselectivities. On the other hand, Hurd and co-workers have developed a practical twostep asymmetric synthesis of the (
)-enantiomer of PNU286607, which is a promising member of a novel class of antibacterial agents.42 The key step of the synthesis consisted of a domino Knoevenagel/[1,5]-hydrogen shift/cyclization reaction, occurring between chiral aldehyde 77 and barbituric acid when heated at 117 °C in n-butanol. As shown in Scheme 24, the process began with the Knoevenagel condensation between the two substrates, producing alkylidene intermediate 78. This intermediate then underwent a [1,5]hydrogen shift to give zwitterion 79, which finally cyclized to afford in 74% yield the enantiopure (
)-PNU-286607 as a single enantiomer. An important natural and biologically active product, (+)chinensiolide B, was recently synthesized on the basis of an asymmetric domino allylboration/lactonization reaction starting from chiral aldehyde 80 derived from (R)-carvone, as depicted in Scheme 25.43 When this aldehyde was treated by a Z/E mixture of allylboronate 81 in the presence of BF3 3 Et2O, it provided the corresponding trans-γ-lactone product 82 in remarkable yield of 87% and diastereoselectivity of >90% de. This chiral product was further converted into (+)-chinensiolide B in nine supplementary steps, as shown in Scheme 25. In another context, Wilson and Brimble have developed a flexible asymmetric synthesis of the tetracyclic core of berkelic acid, an extremophile natural product with selective activity against ovarian cancer, which was based on a domino Horner
Wadsworth
Emmons/oxa-Michael reaction of a α-ketophosphonate with a

Scheme 30. Domino Wittig Rearrangement/Aldol Reaction and Domino Wittig Rearrangement/Mannich Reaction

have been incorporated as first steps in asymmetric domino reactions in the past few years. As an example, Fustero et al. have developed a new domino reaction consisting of the addition of fluorinated nucleophiles to (R)-N-(tert-butanesulfinyl)imines 69, followed by an intramolecular aza-Michael addition.37 As shown in Scheme 21, this asymmetric process has been applied to the synthesis of various chiral fluorinated 1,3-disubstituted isoindolines 70 in moderate to high yields and excellent diastereoselectivities of up to 98% de. The removal of the tert-butanesulfinyl group was achieved by treatment of isoindolines 70 with 4 M HCl in dioxane, yielding the corresponding free amines after basification with 2.2 M NaOH. To make the domino methodology synthetically more useful, its scope was expanded to partially fluorinated nucleophiles, such as nucleophilic fluoroalkylating agent PhSO2CF2H. In this case, the reaction was performed at
78 °C in THF in the presence of 1.1 equiv of LiHMDS as a base and provided the corresponding domino product in 63% yield as a single diastereomer. In 2010, a highly efficient synthesis of enantiopure, highly functionalized piperidines from chiral sulfinyl imines was achieved by P

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Scheme 31. Domino SN2/Michael Reactions

chiral lactone.44 The domino process provided the corresponding isochroman as an approximately 1:1 mixture of cis/trans chiral diastereomers in 80% yield. This mixture constituted the key intermediate in the synthesis of the tetracyclic benzannulated spiroketal core of berkelic acid. In the same area, Kawasaki and co-workers have used an asymmetric domino Horner
Wadsworth
Emmons/isomerization/Claisen rearrangement reaction as the key step in the synthesis of biologically active marine indole alkaloids, such as (
)-flustramines A and B, (
)-flustramides A and B, (
)-fructigenine A, and (
)-5-N-acetylardeemin.45 As shown in Scheme 26, the domino process occurred between diethyl cyanomethylphosphonate and a diastereoisomer mixture of substituted N-acetylindolin-3-ones 83 in the presence of t-BuOK to provide the corresponding Horner
Wadsworth
Emmons products 84, which subsequently isomerized into intermediates 85. Intermediates 85 subsequently underwent a Claisen rearrangement to afford the final almost enantiopure oxindoles 86. These key products were further converted into natural pyrrolo[2,3-b]indole alkaloids, such as (
)-flustramines A and B, (
)-flustramides A and B, (
)-fructigenine A, and (
)-5-Nacetylardeemin. Enantioselective total syntheses of biologically active lyconadin alkaloids A and B have been achieved by Beshore and Smith on the basis of an asymmetric domino intramolecular aldol/

Michael reaction of a chiral diketo aldehyde, allowing the formation of an enantiopure tricyclic key product bearing three stereogenic centers in 84% yield.46 This key product could be further converted into (+)-lyconadin A and (
)-lyconadin B. In 2009, Tietze et al. reported an efficient formal total synthesis of the erythrina alkaloid (+)-erysotramidine by using a domino process consisting of an amidation of chiral ketoester (S,S)-87 with primary amine 88 to provide amide 89. This amide reacted with the carbonyl moiety through intramolecular cyclization to give iminium ion 90, which constituted the domino amidation/cyclization product.47 Under treatment with TfOH, the iminium ion 90 underwent an intramolecular electrophilic aromatic substitution to give the spirocyclic skeleton of (+)-erysotramidine 91 as a 4:1 mixture of diastereomers, as shown in Scheme 27. It must be noted that starting chiral ketoester 87 was prepared according to a method developed by Oestreich and Weiner,48 which consisted of conjugate addition of dimethylphenyl silyl zincate to cyclohexenone in the presence of a catalytic amount of CuI, followed by quenching with ethyl bromoacetate to give racemic substrate 87 as a single trans-diastereomer. This racemic compound was subsequently resolved on a chiral stationary phase to afford required (S,S)-87 along with (R,R)87 with enantioselectivity of g99% ee. Q

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Scheme 29, the reaction of Baylis
Hillman adducts 94a
d with chiral lithium amide 59 afforded the corresponding chiral γ-substituted δ-amino acids 95a
d in moderate to good yields combined with both high diastereo- and enantioselectivities of up to >95% de and ee, respectively. It is reasonable to think that deprotonation of 94 was favorable over initial Michael addition to a trisubstituted double bond, so a rearrangement probably through transition state 96 gave rise to transition state 97 leading to intermediate 98, which underwent Michael addition with chiral lithium amide 59 to finally afford product 95. This methodology was applied to the total synthesis of the nonpeptidic neurokinin NK1 receptor antagonists (+)-L-733,060 and (+)-CP-99,994.51 Moreover, these authors have shown that, when benzaldehyde was used as the starting material in the Baylis
Hillman adduct (R1 = Ph
CHdCH, R2 = OMe), the domino nucleophilic addition
nucleophilic aromatic substitution reaction of the corresponding domino substrate 94e was preceded by an allylic acetate rearrangement to give the corresponding chiral δ-amino acids 95e and 95e0 as a 63:37 diastereoisomeric mixture, along with diastereoisomeric byproducts 99e and 99e0 arisen from double addition reaction (Scheme 29). Products 95e and 95e0 were further converted into biologically active chiral cis- and trans-piperidine dicarboxylic acids 100e and 100e0 , respectively.52 In another area, Wolfe and co-workers have described asymmetric domino Wittig rearrangement/aldol reactions, occurring between chiral O-benzyl- and O-allylglycolate esters of trans-2phenylcyclohexanol 101 and aldehydes.53 The reactions proceeded through Z-boron ester enolates and afforded the corresponding syn-α-alkyl-α,β-dihydroxy esters 102 in good yields, enantioselectivities of up to 95% ee, and >95:5 syn/anti diastereoisomeric ratio after cleavage of the 2-phenylcyclohexanol chiral auxiliary achieved by treatment with LiAlH4, as shown in Scheme 30. The scope of this methodology was extended by the same authors to asymmetric domino Wittig rearrangement/ Mannich reactions by using imines instead of aldehydes.54 As shown in Scheme 30, the reaction of the same chiral auxiliaries 101 with a range of imines provided the corresponding α-alkylα-hydroxy-β-amino esters 103 in good yields. It must be noted that the reaction of N-benzylimines derived from aromatic aldehydes led stereoselectively to the corresponding syn-domino products, whereas the reaction of N-benzylimines derived from unbranched aliphatic aldehydes failed to undergo the Mannich reaction. Moreover, the reaction of N-Boc imines or enamides derived from aliphatic aldehydes also failed to undergo the domino process. On the other hand, the authors have demonstrated that N-Boc-2-(phenylsulfonyl)amines 104 stereoselectively reacted with O-benzyl- and O-allylglycolate esters of trans-2-phenylcyclohexanol 101 to give the corresponding anti-α-alkyl-α-hydroxy-β-amino esters 105 in good yields and diastereoselectivities of >90% de in all cases of substrates studied. After cleavage of the chiral auxiliaries by treatment with LiAlH4, the corresponding anti-amino alcohols were achieved with enantioselectivities ranging from 90 to 96% ee, as shown in Scheme 30. 2.1.2.4. Other Domino Reactions. A SN2 reaction was also employed by Gharpure and Reddy as a first step in a diastereoselective domino reaction allowing the construction of 2,3,3,6-tetrasubstituted tetrahydropyrans to be achieved.55 As shown in Scheme 31, the domino SN2/Michael reaction of active methylene compounds 106a
e with vinylogous carbonates

Scheme 32. Domino Intramolecular Azetidine RingOpening/Closing Reaction

Scheme 33. Domino Elimination/1,6-Addition Reaction

In addition, a novel total synthesis of (
)-oseltamivir was reported by Fukuyama and co-workers, in which the building of the cyclohexene skeleton was achieved through an asymmetric domino reaction, evolving successively through ethanolysis of chiral N-Boc lactam 92, dehydrobromination, and aziridine formation via an SN2 reaction to provide the corresponding enantiopure, highly functionalized cyclohexene 93 in 87% yield, as shown in Scheme 28.49 This key product was further converted into (
)-oseltamivir in four steps. 2.1.2.3. Domino Reactions Initiated by a Rearrangement. In 2008, Garrido et al. reported a novel asymmetric domino process, involving a diastereoselective Ireland
Claisen rearrangement followed by a Michael addition, allowing the first practical and efficient one-pot route to optically active γ-substituted δ-amino acids to be achieved.50 As shown in R

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Scheme 34. Synthesis of (
)-Dysibetaine PP through Domino Cyclization Reaction

domino intramolecular azetidine ring-opening/closing reaction.56 The key step of this process was an intramolecular SN2-type ringopening of TMSOTf-activated azetidine rings by silyl ketene acetals generated by treatment with TMSOTf and triethylamine. As shown in Scheme 32, the reaction of azetidine 111 in the presence of TMSOTf and triethylamine led to the corresponding functionalized 5-azaspiro[2.4]heptane derivative 112 in good yield and relative diastereoselectivity of >98% de. The key step of the process was an SN2-type ring-opening of the TMSOTfactivated azetidine ring by the silyl ketene acetal generated by treatment with TMSOTf and triethylamine (TEA). The formed amino ester 113 finally underwent an intramolecular cyclization to afford five-membered lactam 112 through the reaction of the amine function with the ester group in the γ-position, as depicted in Scheme 32. Remarkably, in this process TMSOTf played a triple role by generating the reactive nucleophilic intermediate (silyl ketene acetal), by activating the azetidine for the nucleophilic ring-opening, and by activating the carbonyl group of the tertiary ester group for the final amide bond formation. The scope of this methodology was found, however, to be limited because substrates such as corresponding tert-butyl ester or corresponding lactam, N-Tos or N-Boc related azetidines, and azetidines bearing substituents in the α- or β-position did not provide the expected corresponding spirocyclopropyl γ-lactams. In 2011, Metz and co-workers described the first total synthesis of the macrodiolide antibiotic pamamycin-649B by using as the key step an asymmetric domino elimination/alkoxidedirected 1,6-addition of ethyllithium reaction of chiral sulfone 114 induced by BF3 3 Et2O.57 In spite of a moderate yield of 36%, the corresponding enantiopure bicyclic sulfone 115 exhibiting four stereogenic centers was produced as a single stereoisomer, as shown in Scheme 33. Finally, Ma and coworkers reported a novel domino cross-Rauhut
Currier/ acetalization reaction occurring between 2-bromo-cyclohexenal and (
)-menthyl ester, which provided, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-en (DBU), the corresponding

Scheme 35. Synthesis of Schweinfurthin G through Domino Epoxide-Opening/Cyclization Reaction

107a
h performed in the presence of cesium carbonate as a base led to the corresponding substituted tetrahydropyran derivatives 108a
p in good to high yields and relative diastereoselectivities of up to >90% de. Symmetrical active methylene compounds, such as dimethyl malonate or malononitrile, as well as unsymmetrical active methylene compounds, such as sulfone nitrile, sulfone ester, or ethyl cyanoacetate, gave good results. Interestingly, better diastereoselectivities were obtained when using unsymmetrical nucleophiles rather than symmetrical nucleophiles. The scope of this methodology was extended to the synthesis of fused bicyclic tetrahydropyrans starting from iodide 109 derived from tri-O-acetyl-(D)-glucal, which was reacted with sulfone nitrile 106e to give the corresponding bistetrahydropyran 110 in 64% yield and excellent relative diastereoselectivity of >90% de, as shown in Scheme 31. It must be noted that this type of product is applicable in polycyclic ether fragments of ladder toxins. In 2011, Compain and co-workers developed the synthesis of spirocyclopropyl γ-lactams on the basis of a diastereoselective S

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Scheme 36. Synthesis of (+)-Stachyflin through Domino Epoxide-Opening/Rearrangement/Cyclization Reaction

diastereoselectivities of up to 88% de in favor of the trans-isomer. This methodology was applied to chiral dipeptide 116e derived from L-allysine to give the corresponding amine 117e, which was further converted into (
)-dysibetaine PP. A BF 3 3 Et 2 O-mediated asymmetric domino cationic epoxide-opening/cyclization reaction was developed by Wiemer and co-workers in the course of synthesizing natural and biologically active tetracyclic schweinfurthins. 60 As shown in Scheme 35, the cascade sequence was initiated by BF 3 3 Et 2 O-promoted opening of chiral epoxide 118 and terminated by cationic cyclization of one of the phenolic oxygens to give the corresponding chiral tricyclic product 119 in 52% yield along with tricyclic product 120 in 30% yield, both exhibiting the hexahydroxanthene core of schweinfurthins. The usefulness of this methodology was demonstrated in a total synthesis of schweinfurthin G starting from tricyclic product 119. In the same area, the first enantioselective total synthesis of a potential anti-influenza A virus agent (+)-stachyflin was

functionalized spiro-3,4-dihydropyran in 74% yield, albeit combined with a low diastereoselectivity of 11% de.58 2.2. Cationic Sequences

Cationic-mediated reactions constitute one of the oldest known subsets of domino reactions. In these processes, a carbocation is formed, either formally or in reality. This carbocation can be formed by elimination or by addition of a positive particle such as a proton. The carbocation then reacts with a nucleophile to form a new carbocation that undergoes one or more comparable further transformations in a cationic
cationic process, finally being trapped by a nucleophile or stabilized by elimination of a proton. A diastereoselective cationic domino cyclization was employed by Blaauw and co-workers as the key step in a total synthesis of natural product (
)-dysibetaine PP.59 As shown in Scheme 34, treatment of various enantiopure dipeptides 116a
d by a catalytic amount of TsOH underwent the formation of the corresponding bicyclic N,N-acetals 117a
d through cascade cationic cyclizations in good yields and T

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Scheme 37. Domino Prins/Friedel
Crafts Reaction

Scheme 38. Oxidative Domino Prins/Pinacol Reaction

U

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Scheme 39. Domino Intramolecular Diels
Alder Cycloaddition/1,3-Dipolar Cycloaddition Reaction

the undesired epimer 1220 (C3 α-OH), which was isolated in 66% yield. The major epimer 1220 (C3 α-OH) could be converted in 96% yield into the desired β-OH epimer 122 by successive oxidation with Dess
Martin periodinane and reduction with LiAlH(Ot-Bu)3. This domino sequence evolved in a stepwise manner through the carbocation intermediates 123, 124, and 125 (Scheme 36). Thus, the first coordination-activation between the Lewis acid and the epoxide moiety of epoxide 121 led to an epoxide ring-opening and the formation of intermediate 123, which further produced intermediate 124 through migration of the C5 methyl group to the C4 carbocation center. Intermediate 124 underwent a 1,2-hydride shift from the C10 position to the C5 carbocation center on the α-face of the molecule to provide intermediate 125, wherein the C10 carbocation center was trapped by the inner phenolic hydroxyl group to deliver, after elimination of the Lewis acid, the desired cyclized products 122 and 1220 . Separated chiral product 122 was transformed into (+)-stachyflin through two supplementary steps. A domino Prins/Friedel
Crafts reaction of chiral enal 126 derived from L-serine was successfully employed by Aub
e and coworkers to achieve a key chiral intermediate 127 in a formal synthesis of biologically active alkaloid (
)-haouamine A.62 This domino product 127 was produced in 65% yield as a 1.5:1 mixture of two C2 α/β-OH epimers. This mixture was further oxidized into the corresponding ketone, which was subsequently submitted to hydrogenolysis to provide the expected key product 128, as shown in Scheme 37. Consequently, the required indenotetrahydropyridine was constructed in 13 steps from L-serine. Finally, Canesi and co-workers have reported a diastereoselective oxidative domino Prins/pinacol process mediated by a hypervalent iodine reagent, such as PhI(OAc)2, performed in a mixture of hexafluoroisopropanol (HFIP) and dichloromethane as the solvent.63 As shown in Scheme 38, the reaction involved various phenols 129 bearing a terminal alkene as an internal nucleophile to trigger the oxidative Prins process followed by a semipinacol-type rearrangement to produce the main corresponding polyfunctionalized spiro[4.5]decanyl compounds 130

Scheme 40. Domino Intramolecular Ynamide Benzannulation Reaction

achieved by Katoh and co-workers on the basis of an asymmetric domino epoxide-opening/rearrangement/cyclization reaction, which stereoselectively formed the requisite pentacyclic ring system.61 As shown in Scheme 36, treatment of tetracyclic chiral epoxide 121 by BF3 3 Et2O led to the corresponding domino product as a mixture of two C3 epimers 122 and 1220 , which could be readily separated by chromatography. The desired epimer 122 (C3 β-OH) was isolated in 9% yield along with V

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Scheme 41. Domino Oxy-Cope/Claisen/Ene Reaction

Scheme 42. Domino Retro-Diels
Alder Cycloaddition/ Diels
Alder Cycloaddition Reactions

in moderate to good yields and relative diastereoselectivities of 90
95% de. It was assumed that during the umpolung activation, mediated by a single-electron transfer, the phenoxonium ion 131 generated was trapped via an oxidative Prins process by the double bond, possibly through a cyclic chairlike transition state, as depicted in Scheme 38. Then, a stereocontrolled ring contraction occurred with retention of configuration of the emerging quaternary center. Moreover, a single diastereomer of tricyclic product 132 bearing contiguous tertiary and quaternary centers was obtained in 42% overall yield starting from the corresponding trans-cycloether 133. The domino product 134 was isolated in 70% yield as a mixture of anomers, which was subsequently oxidized by treatment with Dess
Martin periodinate into the corresponding keto aldehyde 132 in 60% yield as a single diastereomer. As a first application of this novel diastereoselective domino process, a formal synthesis of important antibiotic agent (
)-platensimycin was achieved. 2.3. Domino Reactions Initiated by a Pericyclic Primary Step

Pericyclic reactions, such as the Diels
Alder, ene, Claisen, Cope, or electrocyclic reactions, are by themselves extremely useful transformations. By combining two or more pericyclic reactions, however, the effect can be multiplied. There have been considerable advances in the use of pericyclic processes to initiate both inter- and intramolecular sequences.64 In particular, asymmetric domino sequences involving cycloaddition reactions are highly effective processes for the rapid elaboration of complex polycyclic systems, since each cycloaddition event generates a new ring and two new covalent bonds. Most of the asymmetric pericyclic sequences include a Diels
Alder reaction most of the time in the first step. As an example, Boger and co-workers have developed an asymmetric domino reaction of chiral 1,3,4-oxadiazole 135 bearing a tethered trisubstituted olefin with an electron-donating substituent to activate dienophile for participation in an inverse electron-demand intramolecular Diels
Alder reaction with the electron-deficient 1,3,4-oxadiazole as the first step of the domino process.65 The stereochemistry of this [4 + 2]-cycloaddition was controlled by the chiral substituent on the tether linking the dienophile, providing a diazo compound 136, which subsequently reacted through 1,3-dipolar cycloaddition to give the corresponding cascade cycloadduct 137 possessing six stereocenters, as shown in Scheme 39. This complex chiral product was further applied as a key intermediate in the

total synthesis of vindorosine, vindoline, and key vinblastine analogues. W

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Scheme 43. Domino Diels
Alder Cycloaddition/Sulfoxide Elimination Reactions

benzannulation reaction followed in a second step by a ringclosing metathesis.66 The domino benzannulation step was based on the reaction of cyclobutenones with ynamides. This cascade process proceeded via a sequence of four successive pericyclic reactions, such as four-electron electrocyclic cleavage, [2 + 2]-cycloaddition, four-electron electrocyclic cleavage, and six-electron electrocyclic closure, as depicted in Scheme 40. This sequence furnished multiply substituted aniline derivatives. The authors have applied this powerful methodology to chiral ynamide 138, which afforded, by reaction with 3-methoxymethylcyclobutenone 139, the corresponding enantiopure aniline 140 in 88
94% yield. This product was subsequently submitted to ring-closing metathesis to give a key benzazocine core of the anticancer agent (+)-FR900482. In 2007, Barriault and co-workers investigated the asymmetric domino oxy-Cope/Claisen/ene reaction of chiral allyl 1,2-divinylcyclohexanol ethers 141, providing through microwave irradiation and heating the corresponding domino decalin cycloadducts 142 in high yields and moderate to high diastereoselectivities of up to 92% de, combined with excellent enantioselectivities of >98% ee, as shown in Scheme 41.67 The observed conservation of enantiomeric excess was taken by the authors as evidence that the ring inversion of the intermediary enol ether did not occur before the Claisen reaction. In addition, Porco and co-workers have accomplished an enantioselective synthesis of (+)-chamaecypanone, which is

Scheme 44. Domino Carbonyl Ylide Formation/1,3-Dipolar Cycloaddition Reaction

On the other hand, Danheiser and co-workers have reported the synthesis of polycyclic benzofused nitrogen heterocycles via a strategy that involved a domino ynamide X

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Scheme 45. Domino Carbonyl Ylide Formation/1,3-Dipolar Cycloaddition Reaction

retro-Diels
Alder reaction of its dimeric form. Later, these authors improved and extended the scope of this type of domino reaction by using microwave irradiation in the presence of thermal susceptors or sensitizers, such as silicon carbide (SiC).69 In this work, the authors have accomplished a parallel screen of cycloaddition partners for ortho-quinols using a plate-based microwave system. A range of alkene partners including dienes and dienophiles were demonstrated to react with chiral o-quinol dimer 143, providing the corresponding domino products 144 as single diastereomers in high to excellent yields in all cases of substrates studied, as shown in Scheme 42. Indeed, complete diastereoselectivity was observed by using a range of alkene partners, which could be normal-demand dienophiles, such as methylvinylketone, indene, and 4-methoxystyrene, as well as inverse-demand dienophiles, such as dihydrofuran and vinylene carbonate. In addition, the authors have extended the scope of this methodology to other ortho-quinol precursors 145, which led, under the same reaction conditions, to the corresponding cycloadducts 146 as single diastereomers in good to excellent yields (78
93%), as shown in Scheme 42. Among the number of chiral products generated by using this powerful process, a bicyclo[2.2.2]octenone was found to be a novel inhibitor of activator protein-1 (AP1), an oncogenic transcription factor. Another asymmetric domino sequence, including a Diels
Alder cycloaddition followed by sulfoxide elimination, was used by Urbano and co-workers as the key step in a total synthesis of rubiginones A2 and C2, as well as their 11-methoxy regioisomers, which are angucyclinone-type natural products.70 The domino reaction occurred between enantiopure vinyl cyclohexene 147 and a racemic methoxy-substituted sulfinylnaphthoquinone, such as 5-methoxy-2-(p-tolylsulfinyl)-1,4naphthoquinone 148, providing by heating in dichloromethane the corresponding enantiopure tetracyclic quinine 149 as a sole regioisomer and pure diastereomer in 52% yield, as shown in Scheme 43. This tetracyclic product resulted from a regioselective Diels
Alder cycloaddition, followed by the spontaneous elimination of p-tolylsulfenic acid, which

Scheme 46. Domino Carbonyl Ylide Formation/1,3-Dipolar Cycloaddition Reaction and Total Synthesis of Pseudolaric Acid A

an anticancer agent, on the basis of an asymmetric domino retro-Diels
Alder cycloaddition/Diels
Alder cycloaddition reaction.68 This key step of the synthesis involved a Diels
Alder cycloaddition between a diarylcyclopentadienone, which was generated in situ, and a chiral ortho-quinol derived from a Y

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Scheme 47. Domino Ammonium Ylide Formation/[2,3]-Rearrangement Reaction

Scheme 48. Domino Aldol/Cyclization/β-Hydride Shift Reaction and Domino Aldol/Cyclization/Oxo-Ylide Formation/β-Silyl Fragmentation

regenerated the quinonic double bond. It was further converted into C4 oxygenated angucyclinones rubiginones C2 and A2. In addition, enantiopure vinyl cyclohexene 147 reacted with racemic 5-methoxy-3-(p-tolylsulfinyl)-1,4-naphthoquinone 150 to give under similar conditions the corresponding tetracyclic quinine 151 in 76% yield. This domino product also resulted from the spontaneous elimination of the sulfoxide in the initially formed Diels
Alder cycloadduct 152 (Scheme 43), which was formed in a completely regio- and diastereoselective way. The regiochemistry of the initial cycloadduct 152, resulting from 5-methoxy-3-(p-tolylsulfinyl)-1,4-naphthoquinone 150 bearing the sulfoxide at C3, must be the opposite to that of adduct 153 arisen from reaction of 5-methoxy-2-(p-tolylsulfinyl)-1,4-naphthoquinone 148 with the sulfoxide at C2. Tetracyclic product 151 was further converted into regioisomeric angucyclinones.

these processes, the catalytic domino carbonyl ylide formation/ 1,3-dipolar cycloaddition offers an elegant route to highly substituted oxygen-containing heterocycles.71c,72 This powerful methodology has been extensively advanced by the Padwa group, in particular.71c,73 In 2006, a diastereoselective version of this type of domino reaction was used by Hashimoto and coworkers as the key step in the first total syntheses of squalene synthase inhibitors zaragozic acids A and C.74 As shown in Scheme 44, the rhodium-catalyzed domino carbonyl ylide formation/1,3-dipolar cycloaddition reaction of chiral α-diazo ester carbonyl ylide precursor 154, derived from di-tertbutyl D-tartrate, with 3-butyn-2-one 155 afforded the corresponding cycloadduct 156 as a single diastereomer in 72% yield. This chiral domino product was further converted into zaragozic acids A and C. In addition, an intramolecular version of a comparable strategy was applied by the same authors to synthesize biologically active natural products (
)-polygalolides A and B.75 In 2007, Schaus and co-workers developed a nice intermolecular domino carbonyl ylide formation/1,3-dipolar cycloaddition reaction of chiral dihydropyrimidones 157 with maleimide 158, which afforded, in the presence of rhodium(II) acetate, the corresponding cycloadducts 159 in 91
93% yield as a single stereoisomer, as shown in Scheme 45.76

2.4. Carbene Sequences

Cascade reactions initiated from carbene intermediates have been a productive area of discovery during the past 15 years. Carbenes and carbenoids can react with a series of functional groups, and a more reactive intermediate (ylide) is frequently formed that can undergo further subsequent reactions, allowing the synthesis of many complex molecules to be achieved.71 Of Z

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Scheme 49. Domino Carbopalladation/Heck Reaction and Domino Carbopalladation/Stille Reaction

1620 . The major diastereomer 162 was separated and then converted into pseudolaric acid A through 10 steps. It must be noted that the use of achiral dirhodium catalysts, such as rhodium(II) acetate, favored the formation of the undesired diastereomer 1620 , because in this case the ratio of 162/1620 was 1:3 combined with a 61% yield. In 2009, Saba and co-workers developed concise syntheses of novel chiral tricyclic alkaloids, starting from readily available (S)1,2,3,4-tetrahydroisoquinoline carboxylic acid methyl ester 163 as chiral substrate, which underwent a domino ammonium ylide formation/[2,3]-rearrangement reaction, affording the corresponding key pyrrolo benzoazacyclononenone 164, as shown in Scheme 47.79 The process, mediated by copper, first provided a Cu(acac)2-generated metallo carbenoid species, which cyclized to give the corresponding spirocyclic ammonium ylide 165. This ylide then underwent a [2,3]-rearrangement to afford the final chiral tricyclic product 164 as a single stereoisomer in 70% yield.

The process evolved through the in situ formation of dipole 160 by treatment of substrate 157 with rhodium(II) acetate dimer in refluxed benzene. In the presence of maleimine as a dipolarophile, the dipole intermediate 160 underwent 1,3-dipolar cycloaddition to generate final domino product 159 (Scheme 45). In the same area, Chiu and co-workers have reported total syntheses of natural and biologically active pseudolaric acid A77 and (
)-indicol on the basis of rhodium-catalyzed intramolecular domino carbonyl ylide formation/1,3-dipolar cycloaddition reactions of chiral α-diazoketones derived from commercially available glycidol derivatives, which allowed the core bicyclo[5.4.0]undecane skeleton to be assembled.78 As shown in Scheme 46, treatment of chiral α-diazoketone 161 with a catalytic amount of chiral catalyst [Rh2{(S)-bptv}4] in benzotrifluoride at
40 °C afforded the corresponding domino product in 82% yield as a 1.6:1 mixture of two diastereoisomers 162 and AA

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Scheme 50. Domino Heck/Lactonization Reaction

Scheme 51. Domino Heck/Aza-Michael Reaction

The domino process resulted in a three-carbon expansion of the starting amine ring moiety. In 2010, Li et al. reported an expedient synthesis of Δ4oxocene cores of (+)-laurencin and (+)-prelaureatin on the basis of a diastereoselective domino aldol-type condensation/ cyclization/fragmentation reaction of chiral tetrahydrofuran 166 with ethyl diazoacetate.80 This cascade reaction was mediated by SnCl2 and provided the corresponding enantiopure eightmembered cyclic ether 167 as minor product in low yields (20
25%), along with major product β-keto ester 168, arising

from a diastereoselective domino aldol-type condensation/ cyclization/β-hydride shift reaction. As shown in Scheme 48, from the initial Sn2+-mediated aldol reaction, the diastereomeric adduct 169 subsequently lost N2 to give the carbene intermediate 170. This resulting carbene 171 underwent a β-hydride shift to provide β-keto ester 168 (pathway a, Scheme 48). In the second plausible pathway, a tricyclic oxo-ylide transition state 171 was stereoselectively formed via an oxo-carbenoid insertion by the oxygen atom from the tetrahydrofuran ring in 170. In this highly organized hydrindane-type transition state 171, the enforcing AB

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proximity of three reacting partners accounted for the observed stereoselectivity in product 167. Intermediate 171 was subsequently submitted to a β-silyl fragmentation sequence to give the final product 167 in 20
25% yield, which constituted the Δ4-oxocene cores of (+)-laurencin and (+)-prelaureatin. Even if the process achieving required product 167 began with an aldol-type reaction, it was decided to situate this domino reaction in the section dealing with carbene sequences.

2.5. Palladium-Catalyzed Domino Reactions

Transition-metal-catalyzed transformations are of increasing importance in synthetic organic chemistry. Over the past 40 years, a wide number of new reactions have been uncovered, and activity in this area has remained high. Among the increasing number of asymmetric domino processes starting with a transition metal-catalyzed reaction, the asymmetric palladium-catalyzed domino transformations have seen an astounding development over the past few years. Indeed, because palladium has the advantage of being compatible with many functional groups, it constitutes an ideal catalyst for domino reactions.81 Although palladium-catalyzed domino processes have only recently been extensively reported in the literature,82 the concept of sequential palladium-mediated transformations was actually pioneered some time before the word “domino” was coined. The discovery of the ability of this transition metal to interact with organic moieties, to connect inter- or intramolecularly alkenes, alkynes, carbon monoxide, etc. in cascading processes, is certainly a breakthrough in organometallic synthesis. It must be remembered that the astonishing simplicity of achieving many complex polycyclizations is sometimes directly proportional to the labor required for the synthesis of the cyclization precursor. The possible modes by which an organopalladium complex can be engaged in consecutive bond formations, or the manner in which two sequential palladium-catalyzed processes can be coupled by using a single catalytic system, is only limited by the chemist’s imagination. The Heck reaction is an important way to couple aryl and vinyl systems in the presence of palladium83 and has been recently exploited as key step of many total syntheses of natural products. 84 Furthermore, it forms the keystone of many domino reactions. 85 As a recent example, Tietze et al. have reported the synthesis of new chiral photochromic switches based on helical alkenes through asymmetric domino processes consisting of either a carbopalladation of an alkyne and a Heck reaction or a combination of a carbopalladation and a Stille reaction. 86 As shown in Scheme 49, the palladium-catalyzed domino carbopalladation/Heck reaction of chiral alkynes 172 provided the corresponding tetrasubstituted helical alkenes 173 as single diastereomers in high yields. Although enantiopure syn-diastereomers provided good results, the reaction of anti-diastereomers did not achieve the corresponding domino helical alkenes. The authors have explained the induced diastereoselectivity by

Scheme 52. Domino Wacker/Heck Reaction

Scheme 53. Synthesis of (
)-Panacene through Domino Alkoxycarbonylation/Lactonization Reaction

AC

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Scheme 54. Syntheses of (+)-Lysergic Acid, (+)-Lysergol, and (+)-Isolysergol through Domino Cyclization Reaction

an interaction of the Pd-atom and the hydroxyl group in the primarily assembled Pd-intermediate 174, which forced the alkyne moiety to lie below the naphthalene skeleton and thus controlled the selective insertion into the triple bond via intermediate 175. This intermediate subsequently underwent Heck reaction to afford the final domino product 173. Moreover, these authors have developed domino palladiumcatalyzed carbopalladation/Stille reaction of enantiopure organotin compounds 176, which afforded the corresponding chiral tetrasubstituted helical alkenes 177 in good yields, evolving through corresponding intermediates 178 and 179. In 2009, Roy and co-workers reported a convenient regioselective synthesis of enantiopure 3-C-linked mannopyranosyl coumarins on the basis of a domino Heck/lactonization reaction.87 As shown in Scheme 50, the reaction of chiral β-Cmannopyranosyl acrylate 180 with 2-iodophenol led to the corresponding chiral 3-C-mannopyranosyl coumarin derivative

181 in 86% yield through a domino Heck/lactonization process, while chiral α-C-mannopyranosyl acrylate 182 provided a mixture of the corresponding domino product 183 in 77% yield, along with the intermediary Heck product 184 as minor product (Scheme 50). This intermediary Heck product could be further converted by treatment with NaOMe in methanol into the domino product 183 in 83% yield. An analogous chiral α-C-mannopyranosyl acrylate 185 was also submitted to the same conditions, providing a 1:2 mixture of the corresponding Heck product 186, and the corresponding chiral domino 3-C-mannopyranosyl coumarin 187 in 71% yield (Scheme 50). The intermediary Heck product 186 was also further transformed by treatment with tetra-n-butylammonium bromide (TBAB) and NaHCO3 in dimethylformamide (DMF) into the corresponding domino product 187 in 38% yield. Another asymmetric domino reaction based on the Heck reaction has been very recently reported by Pfeffer and AD

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Scheme 55. Synthesis of 1α,25-Dihydroxyvitamin D3 through Domino Cyclization/Suzuki Coupling Reaction

Scheme 56. Domino Oxa-Michael/Tsuji
Trost Reaction

co-workers.88 In this process, chiral 1,3-disubstituted tetrahydroisoquinolines 189 were achieved in good yields from the domino Heck reaction of the enantiopure phenylalanine derivative 188 with α,β-unsaturated carbonyl compounds, followed by an intramolecular aza-Michael addition. Moderate

to high diastereoselectivities (85
92% de, Scheme 51) were obtained for the corresponding domino products 189, while the extension of this methodology to indole substrates provided the corresponding C1-substituted tetrahydro-β-carbolines in moderate diastereoselectivities (e60% de). AE

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Scheme 57. Domino Olefin Cross-Metathesis/Intramolecular Aza-Michael Reaction

Scheme 59. Domino Ring-Closing Metathesis/CrossMetathesis Reaction

Scheme 60. Domino Ring-Opening/Ring-Closing Metathesis Reactions

Scheme 58. Domino Olefin Cross-Metathesis/Intramolecular Oxa-Michael Reaction

A novel palladium-catalyzed oxy-carbopalladation process was developed by Gouverneur and co-workers, allowing the orchestrated union of hydroxy ynones with ethyl acrylate.89 With enantiopure β-hydroxy ynones 190, the domino Wacker/Heck reaction provided the corresponding dihydropyranones 191 with excellent enantioselectivities of 96% ee

with no detectable racemization, as shown in Scheme 52. The importance of this efficient methodology was highlighted by the fact that these compounds were unknown. A plausible mechanism for this domino process is depicted in Scheme 52. It involved the initial coordination of the metal to the triple AF

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Scheme 61. Domino Ring-Opening/Ring-Closing Metathesis Reaction

Scheme 62. Domino Ring-Opening/Ring-Closing Metathesis Reaction

bond, resulting in intramolecular nucleophilic attack by the proximal hydroxy group (oxypalladation). This led to the formation of a σ-alkenyl palladium intermediate, which could not undergo β-hydride elimination. This intermediate further reacted in a subsequent carbopalladation process with ethyl acrylate present in large excess. After β-hydride elimination, the trisubstituted dihydropyranone was formed with concomitant formation of a palladium hydride species, which could upon reductive elimination allow Pd(0) to reenter the catalytic cycle after oxidation by molecular oxygen. The first total synthesis of natural biologically active (
)panacene was accomplished by Snieckus and co-workers on the basis of a key asymmetric domino alkoxycarbonylation/ lactonization reaction of chiral phenol 192 with retention of enantioselectivity, as shown in Scheme 53.90 The formed tricyclic product 193 was further converted into (
)-panacene in seven steps. In 2011, Ohno and co-workers described the enantioselective total syntheses of (+)-lysergic acid, (+)-lysergol, and (+)-isolysergol through palladium-catalyzed domino cyclization of chiral allenes bearing amino and bromoindolyl groups.91 This key domino reaction enabled the direct construction of the C/D ring system of the ergot alkaloids skeleton, as well as the creation of the C5 stereogenic center with transfer of the allenic axial chirality to the central chirality. As shown in Scheme 54, the domino process of chiral allenic amide 194 (88% de) provided the corresponding expected tetracyclic product 195 in 76% yield and diastereoselectivity of 84% de. This chiral key product was further converted into alkaloids (+)-lysergic acid, (+)-lysergol, and (+)-isolysergol. To explain these results, the authors have proposed the mechanism depicted in Scheme 54. The process began with the aminopalladation of indolylpalladium bromide 196, formed by oxidative addition of 194 to Pd(0), which proceeded through conformation 197 to produce alkenylpalladium(II) intermediate 198 stereoselectively. This was followed by reductive elimination, leading to final product 195 as the major isomer. An expeditious route to 1α,25-dihydroxyvitamin D3 was reported by Mourino and co-workers through an aqueous domino palladium-catalyzed cyclization/Suzuki coupling reaction.92 As depicted in Scheme 55, the process consisted of a highly stereoselective intramolecular cyclization of chiral enol triflate 199, allowing ring A of 1α,25-dihydroxyvitamin D3 to

Scheme 63. Synthesis of Kempene-2, Kempene-1, and 3-epi-Kempene-1 through Domino Enyne Metathesis Reaction

be built, followed by a Suzuki
Miyaura coupling of the resulting palladium intermediate with chiral alkenyl boronic ester 200. The domino product 201 was further submitted to deprotection of the silyl ether to give the expected α,25-dihydroxyvitamin D3 in 81% yield (for the two steps, domino and desilylation reactions). Finally, Menche and co-workers have developed a novel diastereoselective palladium-catalyzed domino reaction allowing a concise synthesis of tetrahydropyrans to be achieved.93 The process involved as the first step of the sequence an oxa-Michael addition of chiral homoallylic alcohol 202 to a α-substituted nitroalkene 203, which provided the corresponding intermediate enolate 204. In the presence of a catalytic amount of [{Pd(allyl)Cl}2] combined with a base such as LiHMDS, this enolate produced a π-allyl complex 205, which was subsequently trapped in an intramolecular fashion through an allylic substitution reaction to finally afford the corresponding polysubstituted AG

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Scheme 64. Domino Cyclization Reaction

tetrahydropyran 206 as a mixture of two diastereomers. The authors carried out the domino process with several chiral homoallylic alcohols 202 differentiated by the nature of the carbonate function born at position C5. Methyl and tert-butyl carbonates proved to be the best leaving groups of those evaluated, providing low to good yields of up to 72% combined with moderate to good relative diastereoselectivities of up to 82% de (Scheme 56). In spite of these moderate diastereoselectivities, this domino oxa-Michael/Tsuji
Trost reaction constituted a conceptually novel methodology for the synthesis of functionalized tetrahydropyrans.

208 with methyl vinyl ketone in the presence of Hoveyda
Grubbs second-generation catalyst led to the corresponding chiral protected 2,5-substituted pyrrolidines 208 in good to high yields (76
98%) combined with moderate diastereoselectivities (50
72% de). These authors have also demonstrated the utility of a closely related methodology by achieving the total synthesis of the piperidine natural product (
)-pinidinol.96 In this case, the nitrogen nucleophiles were chiral N-sulfinyl secondary amines that provided, through domino olefin cross-metathesis/ intramolecular aza-Michael reaction, the corresponding 2-substituted pyrrolidines and piperidines in low to high yields (10
92%) and moderate to good diastereoselectivities (40
84% de). Another diastereoselective domino olefin cross-metathesis/ aza-Michael reaction was more recently reported by Cho and co-workers and applied to the asymmetric formal synthesis of pyrrolopiperazinone natural products.97 In this case, the domino reaction occurred between acrolein and chiral tertiary allyl amides derived from the condensation of 4,5-dibromo-1H-pyrrole-2-carboxylic acid to (R)-N-allyl-1arylethylamine. It furnished the corresponding 2-((S)-6,7dibromo-1-oxo-2-((R)-1-arylethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetaldehydes as mixtures of two diastereomers with low to moderate diastereoselectivities ranging from 14 to 54% de. On the other hand, Fuwa et al. have developed highly diastereoselective synthesis of chiral 2,6-cis-disubstituted tetrahydropyrans 209 via asymmetric domino olefin crossmetathesis/intramolecular oxa-Michael reaction of chiral

2.6. Ruthenium-Catalyzed Domino Reactions

Olefin metathesis represents one of the most powerful and attractive tools in polymer science and organic synthesis for the formation of carbon
carbon double bonds.94 Moreover, the combination of two or more metathesis reactions has increased its efficiency immensely; in particular, the domino ring-opening/ ring-closing metathesis has been widely used. Indeed, a wide number of asymmetric domino reactions include a rutheniumcatalyzed olefin ring-closing metathesis, ring-opening metathesis, enyne metathesis, or cross-metathesis, which can be associated in domino processes to various other reactions. In 2007, Fustero et al. reported the first example of domino olefin crossmetathesis/intramolecular aza-Michael reaction.95 The scope of this novel methodology was extended to an asymmetric variant by using chiral Cbz-protected secondary amines 207 as starting materials. As shown in Scheme 57, the reaction of chiral amines AH

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Scheme 65. Domino Allylation/Enyne Cycloisomerization Reaction

Scheme 66. Domino 1,3-Migration/[2 + 2]-Cycloaddition Reaction

6-hydroxy alkenes 210 with α,β-unsaturated aliphatic and aromatic ketones.98 As shown in Scheme 58, a range of substituted tetrahydropyrans 209 could be achieved on the basis of this powerful methodology using Hoveyda
Grubbs second-generation catalyst. These chiral products were produced in good to excellent yields (77
97%) combined with diastereoselectivities of >90% de in all cases of substrates studied. A closely related methodology was recently employed by Hong and co-workers to achieve an efficient formal synthesis of biologically active SCH 351448.99 On the other hand, asymmetric domino enyne ring-closing metathesis/cross-metathesis processes have been developed by several groups. As an example, Martin and co-workers have reported an enantioselective synthesis of natural product

(+)-8-epi-xanthatin on the basis of enyne metathesis/crossmetathesis reaction of chiral enyne 211 with methyl vinyl ketone in the presence of a phosphine-free ruthenium catalyst, which provided the corresponding enantiopure seven-membered bicyclic (+)-8-epi-xanthatin 212 in 83% yield (Scheme 59).100 In the same area, Li and Lee have developed a total synthesis of AI

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Scheme 67. Domino Cyclization Reaction and Synthesis of Marasmene

Scheme 68. Au-Catalyzed Cyclization Reaction

Scheme 69. Domino Oxidation/Oxa-Michael Reaction

another naturally occurring and biologically active product, (+)-panepophenanthrin, by using an asymmetric domino enyne ring-closing metathesis/cross-metathesis reaction, occurring between a chiral linear enyne and 2-buten-3-ol.101 The process was catalyzed by Hoveyda
Grubbs second-generation catalyst and yielded the corresponding key chiral cyclohexene in 51% yield combined with moderate diastereoselectivity of 34% de. Another type of asymmetric ruthenium-catalyzed domino reactions, such as domino ring-opening/ring-closing metathesis, has been reported by Henderson and Phillips to be applied to the syntheses of several natural tetramic acid containing macrolactams, such as aburatubolactam A,102 and cylindramide A.103 In the case of the synthesis of aburatubolactam A, the process involved the domino ring-opening/ring-closing metathesis of a chiral functionalized bicyclo[2.2.1]heptene 213 performed in the presence of ethylene upon catalysis by first-generation Grubbs' catalyst. The reaction afforded the expected bicyclo[3.3.0]octene 214 in 90% yield as a

single stereoisomer, as shown in Scheme 60. Moreover, the same authors have reported the total synthesis of biologically active natural product norhalichondrin B, which also involved a domino ring-opening/ring-closing metathesis of a chiral highly functionalized substrate 215 under almost similar conditions, providing the corresponding chiral key pyranopyran 216 in 71% yield, as shown in Scheme 60. 104 A novel asymmetric approach to a densely functionalized lactarane skeleton in enantiomerically pure form, involving a domino ring-opening/ring-closing metathesis of a chiral norbornene derivative, was reported by Ghosh and co-workers in 2008.105 As shown in Scheme 61, the reaction of chiral substrate 217 with ethylene in the presence of firstgeneration Grubbs0 catalyst afforded the corresponding enantiopure hydroazulene derivative 218 in 65% yield as a single product. Another chiral norbornene derivative, such as 219, was involved by the same authors to produce the corresponding AJ

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Scheme 70. Syntheses of α-Cedrene, sec-Cedrenol, and α-Pipitzol through Domino Oxidative Dearomatization/Intramolecular [5 + 2]-Cycloaddition Reaction

Scheme 71. Domino Dihydroxylation/Lactonization Reactions

Scheme 72. Synthesis of (
)-Codonopsinine through Domino Epoxidation/Cyclization Reaction

enantiopure tricycle through asymmetric domino ring-opening/ ring-closing metathesis reaction under comparable reaction conditions.106 As shown in Scheme 62, the enantiopure domino product 220 was nicely produced in 94% yield as a single stereoisomer. This product constituted the CDE core of

nortriterpenoid schintrilactones A and B, which are naturally occurring anti-HIV agents. An intramolecular domino metathesis reaction of chiral dienyne 221 was used by Schubert and Metz as the key step in a total synthesis of diterpenes, such as kempene-2, kempene-1, and 3-epi-kempene-1.107 The process catalyzed by Hoveyda
Grubbs second-generation catalyst provided the corresponding enantiopure tetracyclic product 222 in 92% yield, as shown in Scheme 63. On the other hand, Trost et al. have reported ruthenium-catalyzed domino alkyne
enone AK

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Scheme 73. Domino Oxidation/Intramolecular Hetero-Diels
Alder Cycloaddition Reaction and Synthesis of 1-epi-Pathylactone A and Domino Oxidation/Intramolecular Hetero-Diels
Alder Cycloaddition/Ring-Expansion/SN2 Reaction

coupling/Michael reaction.108 Indeed, the reaction of chiral propargylic alcohols with β,γ-enones in the presence of [CpRu(MeCN)3][PF6] provided the corresponding 2,6-cisdihydropyrans as major diastereomers in moderate to good yields (31
80%). The cis/trans ratios ranged from 5:1 to 8:1. The process was demonstrated to be compatible with a variety of alcohol protecting groups. One of the formed products was used as the key chiral intermediate in the syntheses of ring A and B subunits of the bryostatins. With the aim of synthesizing chiral benzo[d]xanthene tetracyclic core of anti-influenza active sesquiterpene natural products, Cramer and co-workers have investigated the asymmetric ruthenium(III)-catalyzed domino cyclization reaction of a chiral phenol 223.109 As shown in Scheme 64, treatment of this functionalized phenol with cationic ruthenium(III) complexes promoted its cascade cyclization to form the corresponding tetracycle 224 as a 93:7 mixture of trans- and

cis-diastereomers in 74% yield. The authors have shown, however, that it was possible to favor the diastereoselective formation of the cis-required product through treatment of substrate 223 with triflic acid in nitromethane, albeit in low yield (20%). The authors have not proposed a mechanism for the formation of 224; nevertheless, a plausible one is depicted in Scheme 64. First, ruthenium precursor reacted with AgOTf to give a cationic ruthenium species. This cationic Ru(III) species had some TfO
, ligand, and/or solvent molecules. The CdC double bond of cyclohexene coordinated to this cationic ruthenium to give a Ru
olefin complex, which allowed reaction with phenolic oxygen in a nucleophilic fashion intramolecularly to give a cyclized intermediate. At this stage, the counteranion held the phenolic proton, and the resulting TfOH reacted with carbon
ruthenium σ-bond by cyclization to the second CdC double bond to give after protonolysis the final product 224. AL

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Scheme 74. Domino Epoxide-Opening/Oxidative Cleavage/Cyclization Reaction

Scheme 75. Synthesis of Hirsutellone B through Al-Catalyzed Domino Epoxide-Opening/Diels
Alder Reaction

Ph3PAuNTf2 and was found to follow another route when employing terminal propargylic alcohols 228 because, in this case of substrates, tetrahydrofurans 229 were produced as single diastereomers in high yields, as shown in Scheme 65. To explain the two different routes to products 227 and 229, the authors have proposed the mechanism depicted in Scheme 65. Enyne ether intermediates 230, in situ generated from intermolecular allylation, underwent subsequent cycloisomerization to yield a series of oxygen heterocycles. In the second

2.7. Gold-Catalyzed Domino Reactions

In 2010, Chen et al. reported a novel gold-catalyzed diastereoselective domino allylation/enyne cycloisomerization reaction occurring between allylic acetates 225 and nonterminal propargylic alcohols 226.110 Remarkable levels of relative diastereoselectivities of >94% de in combination with good yields were achieved in all cases of substrates studied in the formation of a range of densely functionalyzed oxygen heterocycles 227, as shown in Scheme 65. The reaction was catalyzed by 5 mol % of AM

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Scheme 76. Cu-Catalyzed Domino Aziridine-Opening/ Cyclization Reaction

Scheme 77. Pt-Catalyzed Domino Enyne Isomerization/ Diels
Alder Cycloaddition Reactions

Scheme 78. Fe-Catalyzed Domino Isomerization/Mannich Reaction

step, trapping the gold-activated triple bond by the alkene group was favored to proceed through transition state 231, in which the allylic R1 group pointed away from the alkyne bond to avoid the steric hindrance between R1 and gold complexes. The stereochemistry of bicyclo[4.1.0]heptylidene gold(I) carbene 233 (route I) and bicyclo[3.1.0]hexylidene gold(I) carbene 234 (route II) was then determined by the favored transition state 231. Product 227 was obtained from intermediate 233 by β-hydrogen elimination. Trapping intermediate 234 with terminal propargylic alcohols 228 afforded products 229. In 2011, Chan and co-workers demonstrated the gold(I)catalyzed domino 1,3-migration/[2 + 2]-cycloaddition reaction of 1,7-enyne benzoates to be a regioselective and stereoconvergent strategy for the construction of highly functionalized chiral azabicyclo[4.2.0]oct-5-enes.111 Indeed, when chiral 1,7-enyne benzoates 235 were treated with a catalytic amount of Au(I) complex 236 at 80 °C, they led to the corresponding enantiopure domino products 237 as single diastereomers irrespective of whether it started from a single

or diastereomeric mixture of the substrate. As shown in Scheme 66, the process was shown to tolerate a diverse set of 1,7-enyne substrates 235 and furnished stereochemically a range of enantiopure cyclobutane-fused pyridines 237 bearing up to four stereogenic centers, which constituted key starting materials for the synthesis of natural and biologically interesting products. A tentative mechanism for this novel domino AN

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Scheme 79. Ni-Catalyzed Domino Isomerization/Aldolization Reaction

group and formation of allenene 238. To avoid unfavorable steric interactions between the gold complex and the substituents on the allene moiety, the catalyst selectively coordinated to the alkene bond of the newly formed allenene to give intermediate 239. This intermediate then underwent a [2 + 2]-cycloaddition to give the piperidine adduct 240. A subsequent nucleophilic addition of the Au
C(sp 3 ) bond to the carbonyl carbon center of the benzoyl cationic moiety generated from this initial intramolecular cyclization step then delivered final product 237, as depicted in Scheme 66. In addition, Li and co-workers have developed total syntheses of drimane-type sesquiterpenoids on the basis of a gold-catalyzed domino reaction of 1,7-diynes 241 involving both internal and external nucleophiles. 112 This domino process allowed the formation of three bonds, two rings, and two stereogenic centers. The reaction began with a 5-endo-dig addition of oxygen to an alkyne to give a polarized olefin functionality 242, which functioned as the nucleophile in the following 6-exo-dig cyclization (Scheme 67). The reaction was terminated by an external nucleophile as an alcohol, affording tricyclic domino product 243. Indeed, when 1,7-diynes 241 were treated by 5 mol % of catalyst system [(IPr)AuCl]/AgSbF 6 in the presence of an alcohol as external nucleophile, they led to the corresponding tricyclic domino products 243 in low to excellent yields (26
96%) and relative diastereoselectivities of >90% de in all cases of substrates studied. The utility of this methodology was applied to the synthesis of natural C15 oxygenated drimane-type sesquiterpenoid marasmene. Finally, a gold(I)-catalyzed domino cyclization approach to tetracyclic indolines was reported by Wang and coworkers.113 The scope of this methodology was applied to an enantioenriched alkynylindole 244 bearing a secondary propargyl alcohol, which provided the corresponding tetracyclic indoline 245 with quantitative retention of chirality (81% ee) at the secondary propargyl alcohol, which should be useful for the synthesis of complex indoline alkaloids. As shown in Scheme 68, the first cyclization catalyzed by Ph3AuSbF6 led to the formation of intermediate 246 containing a secondary alcohol, which served as an internal nucleophile in the second cycization step to afford the final tetracyclic indoline 245.

Scheme 80. Domino (Di)bromination/Cyclization Reactions

process was proposed by the authors, in which activation of the alkyne moiety of the 1,7-enyne substrate by the gold(I) catalyst resulted in syn-1,3-migration of the carboxylic ester AO

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Scheme 81. Domino 1,3-H
1,7-H Shift/6π Electron Pericyclic Ring-Closure/[4 + 2]-Cycloaddition Reaction

Scheme 82. Synthesis of Solandelactones A, B, E, and F through Ti-Catalyzed Domino Petasis/Claisen Lactonization Reaction

Efficient novel syntheses of the most biologically active members of the cedranoic family, α-cedrene, α-pipitzol, and sec-cedrenol, have been achieved by Green and Pettus, beginning with the oxidative dearomatization of curcuphenol, which was followed by an intramolecular [5 + 2]-cycloaddition of the phenoxonium intermediate across the tethered olefin (Scheme 70).115 In this asymmetric domino reaction, the benzylic stereocenter effectively guided the formation of the first two stereocenters during the [5 + 2]-cycloaddition. The sequence then terminated with the selective incorporation of acetic acid to generate a third stereocenter, setting it apart from other previous cationic [5 + 2]-cycloaddition. As shown in Scheme 70, the scope of this domino process could be extended to several chiral substrates 249, providing the corresponding domino products 250 as single diastereomers in moderate to good yields, opening the route to the enantiopure sesquiterpenes. In 2012, Bull and co-workers reported a novel method of preparing enantiopure hydroxyl-γ-butyrolactones containing up to four stereocenters in high yields and moderate to excellent diastereoselectivities.116 This process, performed in the presence

2.8. Miscellaneous Domino Reactions

2.8.1. Domino Reactions Initiated by an Oxidation. A number of other asymmetric domino reactions have been reported in the last years, among which a number are catalyzed by metals other than palladium, ruthenium, and gold. Among them are several asymmetric Michael-terminated processes involving chiral substrates. As an example, Hong and co-workers have recently combined an oxidation to an oxa-Michael addition in an asymmetric domino sequence, which constituted the key step of a formal synthesis of leucascandrolide A.114 Indeed, the domino oxidation/oxa-Michael reaction of allylic alcohol 247 (Scheme 69) led, in the presence of MnO2, to the corresponding 2,6-cis-tetrahydropyran aldehyde 248 in 86% yield and relative diastereoselectivity of >90% de. This product constituted a potent key precursor of leucascandrolide A. In addition, these authors have extended the scope of this methodology to another chiral allylic alcohol, which afforded, through domino oxidation/ oxa-Michael reaction, the corresponding chiral 2,6-cis-tetrahydropyran aldehyde in 90% yield and >90% de. This product was used as the key intermediate in a formal synthesis of SCH 351448, which is a potent agent against hypercholesterolemia. AP

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of β-alkenyl-β-hydroxy-N-acyloxazolidin-2-ones 251, which provided the corresponding enantiopure hydroxyl-γ-butyrolactones 252 in high yields and diastereoselectivities of up to >96% de, as shown in Scheme 71. It was found that 1-substituted, 1,1-disubstituted, (E)-1,2-disubstituted, (Z)1,2-disubstituted, and 1,1,2-trisubstituted alkenes underwent dihydroxylation with anti-diastereoselectivity to their β-hydroxyl groups, whereas 1,2,2-trisubstituted alkene 253 led to syn-diastereomer 254. The synthetic utility of this novel methodology has been demonstrated with a short synthesis of 2-deoxy-D-ribonolactone. On the other hand, an asymmetric domino epoxidation/cyclization reaction was used by Chandrasekhar et al. as the key step of a highly stereoselective approach to the total synthesis of biologically active alkaloid (
)-codonopsinine.117 In this process, chiral allylic alcohol 255, bearing a Boc-protected amino group in the α-position of the hydroxy group, was submitted to epoxidation by treatment with MCPBA to directly furnish the corresponding pyrrolidine diol 256 in 89% yield and diastereoselectivity of 80% de in favor of the anti-diol, as shown in Scheme 72. The first formed epoxide was subsequently submitted to a regioselective opening with the internal nitrogen nucleophile in an endo fashion facilitated by the 4-methoxy phenyl group, which allowed facile benzylic cleavage to produce the final diol 256. The major anti-diol was subsequently converted into (
)-codonopsinine through reduction of the Boc group into a methyl group in 83% yield. Moreover, PhI(OAc)2 was also employed by Aseniyadis et al. to mediate another asymmetric domino reaction beginning with the oxidation of chiral 1,2-diol 257 into the corresponding dialdehyde 259 (Scheme 73), which underwent an intramolecular hetero-Diels
Alder cycloaddition to give the corresponding cyclic ene
acetal 258 in 72% yield as a single stereoisomer, as shown in Scheme 73. 118 This chiral product was applied as the key intermediate in an enantioselective total synthesis of a natural Ca 2+ antagonist, 1-epi-pathylactone A. As an extension of this methodology, these authors have demonstrated that using Pb(OAc)4 as the oxidant instead of PhI(OAc)2 and under microwave irradiation and heating made it so that the intermediate Diels
Alder cycloadduct 260 further evolved through ring-expansion during the domino process, providing iodonium intermediate 261, which was subsequently submitted to an SN 2 opening with the reagent’s

of 10 mol % of osmium tetroxide (OsO4) and N-methylmorpholine-N-oxide (NMO), consisted of the diastereoselective domino dihydroxylation/lactonization reaction of a range Scheme 83. Cu-Catalyzed Domino Kinugasa Cycloaddition/ Rearrangement Reaction

Scheme 84. Three-Component Domino Double Michael/Ring-Closure Reaction of Sodium Anion of (S)-N-(α-Methylbenzyl)allylamine and 2 Equiv of tert-Butyl Cinnamate

AQ

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Scheme 85. Three-Component Domino Michael/Aldol/ Retro-Dieckmann Reaction of 2-Oxo-cyclopentanecarboxylate Methyl Esters, α,β-Unsaturated Aldehydes, and Methanol

Scheme 86. Three-Component Domino Michael/Mannich Reaction of Chiral N-Sulfinimines, Cyclic Enones, and Dialkylzincs

acetate, resulting in a ring-system interchange to finally afford final product 262 (Scheme 73).119 As shown in Scheme 73, a range of chiral ring-expanded domino products 262 could be prepared in high yields starting from the corresponding hydrindene
diols 263. 2.8.2. Domino Reactions Initiated by a Ring-Opening Reaction. An efficient synthesis of enantiopure lactols 265 was described by Kita and co-workers on the basis of a domino reaction of chiral cis-2,3-epoxy-1-alcohols 264 with a hypervalent iodine(III) reagent, such as PhI(OCOCF 3)2, in the presence of H2O.120 In this process, the nucleophilic addition of water causing the oxirane ring-opening first occurred at the C3 position (Scheme 74). In the reaction, PhI(OCOCF3)2 reacted with the hydroxy function, which accelerated the reaction rate and the nucleophilic addition at the C3 position. Cleavage at the C1
C2 bond by forming a five-membered transition state then gave the hydroxy keto aldehyde, in

which automatic lactol formation occurred to produce final lactol 265. As shown in Scheme 74, several lactols were achieved in good to high yields and complete diastereoselectivity and were subsequently converted into enantiopure lactones 266 by treatment with Jones reagent. The utility of this efficient novel asymmetric domino epoxide-opening/ oxidative cleavage/cyclization reaction was applied to the total synthesis of (+)-tanikolide, an antifungal marine natural product. In 2009, Nicolaou et al. developed a stereoselective aluminumcatalyzed domino epoxide-opening/Diels
Alder cycloaddition reaction, which constituted the key step in a total synthesis of naturally occurring and biologically active hirsutellone B.121 Indeed, the treatment of enantiopure epoxide 267 derived from (R)-(+)-citronellal by Et2AlCl led to the corresponding tricyclic domino product 268 in 50% yield as a single diastereomer, as shown in Scheme 75. The cascade of reactions depicted in Scheme 75 could explain the formation of this key enantiopure product, which was subsequently converted into hirsutellone B in 17 steps. In 2010, Ghorai and Tiwari described a remarkable synthesis of enantiopure functionalized γ-lactams on the basis of a highly stereoselective copper-catalyzed domino aziridineopening/cyclization reaction.122 As shown in Scheme 76, monosubstituted aziridines 269 reacted, in the presence of Cu(OTf)2 as catalyst and NaH as base, with active methylene carbon nucleophiles, such as diethyl malonate or ethyl acetoacetate, to afford the corresponding enantio- and diastereopure γ-lactams 270 in good to excellent yields (64
99%). These products arose from the Cu-catalyzed SN2-type AR

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Scheme 87. Three-Component Domino Aza-Michael/Michael Reaction of α,β-Unsaturated Esters, Alkylidene Malonates, and Lithium (S)-N-Benzyl-N-α-methylbenzylamide

Scheme 88. Three-Component Domino Double Aza-Michael/Nitroaldol Reaction of Chiral Amino esters, Nitroalkene, and Enone

ring-opening of aziridines with enolates followed by intramolecular cyclization. The scope of this methodology could be extended to trans-N-tosyl-2,3-disubstituted aziridines 271, which led to the corresponding enantiopure trisubstituted γ-lactams 272 as single diastereomers in comparable high yields (Scheme 76). 2.8.3. Domino Reactions Initiated by an Isomerization. In 2010, Helmchen and co-workers reported a novel route to highly enantioenriched complex heterocycles on the basis of asymmetric domino platinum-catalyzed enyne isomerization/Diels
Alder cycloaddition reaction of enantiopure 1,6-enynes.123 As shown in Scheme 77, heating a mixture of these 1,6-enynes 273a,b and various dienophiles 274a
d in the presence of PtCl2 in toluene led to the corresponding domino bi- or tricyclic cycloadducts 275a
e in moderate to good yields as single diastereomers in all cases of substrates studied.

A novel route toward chiral aminocyclopentanols was reported by Gr
ee and co-workers in 2011.124 It was based on an iron-catalyzed domino isomerization/Mannich reaction of chiral N-tert-butanesulfinamide. As shown in Scheme 78, this process was performed by using Fe(CO)5 as the catalyst with full stereocontrol, because diastereomer 276 yielded the corresponding cyclopentanone 277 as a single diastereomer in 85% yield and diastereomer 2760 led to corresponding cyclopentanone 2770 in 84% yield, as shown in Scheme 78. These products were further converted into biologically interesting chiral aminocyclopentitols, such as mannostatin A analogues. Nickel catalysts have also been employed to promote asymmetric domino reactions.125 As an example, Gr
ee and co-workers have developed a stereoselective synthesis of functionalized 1,3diols on the basis of the domino isomerization/aldolization reaction of a 4:1 diastereomeric mixture of allylic alcohol 278 AS

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bearing a chiral imidazolidine group with benzaldehyde.126 The process was catalyzed by NiHCl(dppe) associated to MgBr2 and led to the corresponding bicyclic aldol product 279 as a mixture

of three diastereomers in 70% yield and moderate diastereoselectivity of e40% de, as shown in Scheme 79. It began with the isomerization of the starting allylic alcohol into its corresponding Z-enol 280 (Scheme 79), which subsequently reacted with benzaldehyde through aldol condensation to afford the final product. 2.8.4. Other Domino Reactions. A novel domino stereoselective electrophile bromation/cyclization reaction of tryptophan-derived α-amino nitriles was described by Herranz and co-workers in 2007.127 As shown in Scheme 80, treatment of enantiopure tryptophan-derived α-amino nitrile 281 by 1 equiv of N-bromosuccinimide (NBS) in 10% aqueous trifluoroacetic acid (TFA) in dichloromethane at
40 °C led to the corresponding chiral monobrominated product 282 in 91% yield, whereas the use of 2 equiv of NBS provided the corresponding enantiopure dibrominated derivative 283 in 94% yield. Attempts of corresponding iodocyclization of this α-amino nitrile were unsuccessful, while the corresponding chlorocyclization led to a 4:1 mixture of diastereoisomeric monochlorides. Moreover, these authors have shown that this α-amino nitrile could also be allylated at the same position as that for the monobromination through treatment with prenyl bromide and Mg(NO3)2 3 6H2O in AcOH/AcONa buffer with complete stereoselectivity in 45% yield. These novel domino processes allowed an easy entry to chiral indole alkaloid analogues to be achieved. In another context, Hsung and co-workers have reported a remarkable asymmetric quadruple domino process, consisting of 1,3-H
1,7-H shift
6π electron pericyclic ring-closure
[4 + 2]cycloaddition reaction, allowing a rapid assembly of chiral complex tricycles from simple chiral allenamides to be achieved.128 As shown in Scheme 81, heating enantiopure α-substituted allenamides 284, bearing an E-alkene moiety, provided the corresponding chiral amide-substituted 1,3,5-hexatrienes 285 through 1,3-H
1,7-H shift, which underwent a 6π-electron ring-closure to give the corresponding cyclohexadienes 286 as single stereoisomers. Furthermore, the authors have shown that this sequence could be followed by a [4 + 2]-cycloaddition, affording the corresponding tricyclic products as almost single stereoisomers (de >90%) in good yields (48
55%). On the other hand, White et al. have reported total syntheses of natural solandelactones A, B, E, and F by exploiting an asymmetric titanium-catalyzed domino Petasis/Claisen

Scheme 89. Three-Component Domino Aza-Michael/Aldol Reaction and Three-Component Domino Aza-Michael/ Michael/Aldol Reaction of N-Benzyl-2(R)-methoxy-(+)-10bornylamine

Scheme 90. Three-Component Domino Aza-Michael/Nucleophilic Addition Reaction of Chiral N-Sulfinimines, t-Butyl Acrylate, and Magnesium Thiolates

AT

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deprotonation of 290 led to the dinuclear copper(I) complex 294 that, in the presence of nitrone, underwent stepwise or concerted cycloaddition leading to 297. In the case of a stepwise process, which should be more plausible in the case of the metalcatalyzed reaction, it could proceed through intermediates 295 and 296. Then, six-membered copper metallocycle 296 contracted to five-membered isoxazoline 297 and rearranged to enolate 298. Finally, protonation of 298 gave the final 2-azetidinone and released the copper catalyst. The domino process has allowed a range of chiral carbapenams to be achieved in acceptable yields even in the presence of a catalytic amount of copper salt.

Scheme 91. Remote Group-Aza-Michael-Based ThreeComponent Reaction of Chiral Amino Amides, Aldehydes, and Enones

3. MULTICOMPONENT REACTIONS One of the challenges in organic synthesis is to implement various reaction strategies in a multicomponent reaction, which is a domino reaction involving at least three substrates,5b,8k to achieve multibond formation in a single reaction vessel, forming a new product that contains portions of all the components. Multicomponent reactions convert more than two educts directly into their product by one-pot reactions. The starting materials for this kind of chemical transformation are rich in functional groups. Typically, multicomponent reactions lead to very complex products by reacting structurally simple starting materials. The multicomponent reaction proceeds according to the domino principle, because subsequent transformations are a consequence of the functionalities produced in the previous transformation. These reactions are highly flexible, (chemo)selective, convergent, and atom-efficient processes of high exploratory power. Inspired by the mode of action of nature, they have brought the concept of ideal synthesis closer to reality.131 Indeed, this strategy is atomeconomical and avoids the necessity of protecting groups and isolation of intermediates. Its goal is the emulation of Nature in its highly selective sequential transformations. Even though the history of multicomponent reactions dates back to the second half of 19th century with the reactions of Strecker, Hantzsch, and Biginelli, it was only in the last decades with the work of Ugi and co-workers that the concept of the multicomponent reaction has emerged as a powerful tool in synthetic chemistry.132

lactonization reaction.129 As shown in Scheme 82, Petasis methylenation of enantiopure cyclic carbonate 287 in tandem with a Claisen rearrangement generated the corresponding chiral octenalactone portion of solendelactone 288 as a single stereoisomer in 60
65% yield. This chiral product was further converted into a mixture of expected solandelactones A, B, E, and F. In 2010, Chmielewski and co-workers reported copper-catalyzed domino Kinugasa cycloaddition/rearrangement reaction of chiral acetylene 289 derived from D-glyceraldehyde and propargyl aldehyde with nitrone 290, affording the corresponding chiral cis-β-lactam 291 in moderate to good yields and cis/trans ratios of up to >90% de.130 One of the best results is depicted in Scheme 83. The authors assumed that the process evolved via formation of a rigid dinuclear copper(I) complex in which each copper ion was coordinated to one or both oxygen atoms in the acetylene molecule and to both triple bonds. They have proposed the catalytic cycle depicted in Scheme 83, which began with the coordination of the alkyne to Cu(I) species 292 to form π-complex 293 in which the copper ion was also linked to other nucleophilic centers (oxygen atom/atoms, phenyl ring). The

3.1. Multicomponent Reactions Initiated by the Michael Reaction

3.1.1. Multicomponent Reactions Initiated by a Classical Michael Reaction. Several asymmetric multicomponent reactions employing chiral substrates and initiated by Michael additions of carbon nucleophiles have been recently reported. As an example, a novel diastereoselective domino double Michael/ring-closure reaction sequence was developed by Andrews and co-workers in 2007.133 This three-component process consisted of the reaction of the sodium anion of (S)N-(α-methylbenzyl)allylamine 299 with 2 equiv of tert-butyl cinnamate 300, resulting in a remarkable domino double Michael addition/ring-closure reaction, affording the corresponding chiral aminocyclohexane 301 containing six new vicinal stereogenic centers with an excellent level of stereocontrol of >90% de and 44% yield. The authors have proposed the mechanism depicted in Scheme 84 in which the sequence began with the first Michael addition of (S)-N-(α-methylbenzyl)allylamine 299 to 1 equiv of tert-butyl cinnamate 300, providing the corresponding imine (Z)-enolate 302. AU

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Scheme 92. Synthesis of 1,4-Dihydropyridine C-Glycoconjugate through Three-Component Hantzsch Reaction

reaction, the authors have found that the use of of α-substituted acroleins provided, by reaction with Dieckmann ester 304a and methanol, the corresponding dehydrated cycloheptenes 306a
f in good to high yields and complete relative diastereoselectivity, as shown in Scheme 85. Remarkably, the crude did not require purification because a simple acidic workup allowed pure products to be achieved. As depicted in Scheme 85, the sequence began with the Michael addition of the β-ketoesters to the α,β-unsaturated aldehydes, providing intermediate aldehydes 307, which underwent an intramolecular aldol reaction to give the corresponding 8-oxo-bicyclo[3.2.1]octanes 308. Then, a retro-Dieckmann-type fragmentation of these bicyclic compounds led to seven-membered products 305a
f or, after a supplementary dehydration, to products 306a
f. The further extension of the scope of the process to related five-membered β-ketosulfones allowed the corresponding cycloheptanols to be afforded in good to high yields albeit moderate relative diastereoselectivities (34
66% de). In addition, Lhommet and co-workers have reported the asymmetric three-component condensation of various dicarbonyl compounds, acrolein, and (S)-2-phenylglycinol, providing the corresponding chiral 6-carbonyl-3-phenyl-2,3,8,8a-tetrahydro-7H-[1,3]oxazolo[3,2-a]pyridines in low to moderate yields

This enolate subsequently added to another equivalent of tert-butyl cinnamate 300 through a second Michael addition to give a novel imine (Z)-enolate 303, which finally underwent an intramolecular 6-exo-trig cyclization of the enolate fragment onto its imino functionality, resulting in the formation of the final cyclohexane derivative 301. In 2008, Rodriguez and co-workers reported a diastereoselective domino Michael/aldol/retro-Dieckmann reaction of β-ketoesters with α,β-unsaturated aldehydes in methanol as solvent and third component, allowing functionalized seven-membered rings to be achieved under mild reaction conditions.134 Thus, a range of substituted cycloheptanols 305a
f was regio- and diastereoselectively synthesized through the reaction of β-substituted acroleins with 2-oxo-cyclopentanecarboxylate methyl esters 304a,b in the presence of DBU as a base in methanol at room temperature. These products, containing up to five stereogenic centers, were produced in moderate to high yields and relative high diastereoselectivities of >92% de, as shown in Scheme 85. Furthermore, by starting from enantiopure 5-methyl-2-oxo-cyclopentanecarboxylate methyl ester 304b (R1 = R2 = Me) derived from (+)-pulegone and crotonaldehyde in methanol, the reaction led to the corresponding chiral cycloheptanol 305f as a single stereoisomer in 43% yield (Scheme 85). Investigating the scope of the AV

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Scheme 93. Synthesis of Highly Functionalized Amines through Four-Component Ugi Reaction

three-component couplings of α,β-unsaturated esters and alkylidene malonates initiated by chiral lithium amide conjugate addition, which proceeded with high levels of 2,3-antidiastereoselectivity of >90% de.137 As shown in Scheme 87, the domino reaction began with the Michael addition of lithium (S)-N-benzyl-N-α-methylbenzylamide 490 to α,βunsaturated esters, providing the corresponding enolates, which further reacted with alkylidene malonates according to a second Michael addition, furnishing the final β-amino esters 311 in moderate to good yields and cis-diastereoselectivities. Investigating the scope of the reaction has shown that higher yields and diastereoselectivities were observed with β-aryl substituents in both ester and malonate components, although the reaction successfully tolerated both β-alkyl and β-alkenyl functionality. The utility of this process was demonstrated by the conversion of the chiral formed products into polysubstituted piperidinones through hydrogenolysis. A one-pot synthesis of chiral substituted piperidines was developed by Shi and co-workers on the basis of a threecomponent reaction occurring between a nitroalkene, chiral aminoester 312, and an enone.138 As depicted in Scheme 88, the process began with the aza-Michael addition of the chiral amine to the nitroalkene to give a nitroalkane, which underwent a second aza-Michael addition to the enone, providing a novel nitroalkane. This nitroalkane then cyclized according to a nitroaldol reaction to give the corresponding substituted piperidine 313. The reaction provided the corresponding enantiopure piperidines in good yields and moderate diastereoselectivities

(19
63%) and zero to good diastereoselectivities of up to 80% de.135 This domino reaction involved the Michael addition of dicarbonyl compounds to acrolein, followed by condensation of chiral amine (S)-2-phenylglycinol, with the resulting tricarbonyl compounds providing the final chiral bicyclic functionalized tetrahydropyridines. It must be noted that this simple procedure allowed the concomitant formation of four bonds and two stereogenic centers. Although only limited success was achieved in terms of reactivity and selectivity, various β-ketoesters and β-diketones were tolerated in the process. Furthermore, the utility of this domino process was illustrated by its application in a total synthesis of quinolizidine alkaloid (
)-lupinine. Other asymmetric multicomponent domino reactions initiated by a Michael addition have been developed, such as domino Michael/Mannich reactions of dialkylzincs, cyclic enones, and chiral N-sulfinimines 309, which were reported by Yus and co-workers in 2008.136 In this work, a double induction by using a chiral copper catalyst in addition to the chiral N-sulfinimine auxiliary 309 was necessary to obtain the corresponding chiral β-aminocyclohexanones 310 as single stereoisomers. Indeed, the use of both a chiral catalyst and a chiral N-sulfinimine allowed the enantiopure domino Michael/Mannich products to be achieved in good to high yields, as shown in Scheme 86. This process could be applied to a wide range of substrates and was especially efficient when enolizable t-BuS imines were used. 3.1.2. Multicomponent Reactions Initiated by a HeteroMichael Reaction. In 2007, Davies et al. reported asymmetric AW

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Scheme 94. Four-Component Ugi Reaction of (
)-N-Allyland N-Propargyl-3-amino-7-oxa-[2.2.1]-bicyclohept-5-ene-2carboxylic Acids with Isocyanides, Aldehydes, and Methanol

Scheme 95. Three-Component Ugi Reactions of Chiral β-Amino Acids with Isocyanides and Aldehydes in Water

(50
72% de) with only C4 isomers observed, as shown in Scheme 88. On the other hand, Node and co-workers have investigated asymmetric domino three-component reactions initiated by the aza-Michael addition of a chiral amine, such as N-benzyl2(R)-methoxy-(+)-10-bornylamine 314, to α,β-unsaturated esters.139 For example, the asymmetric domino aza-Michael/ aldol reaction of this chiral amine with an α,β-unsaturated ester and an aldehyde occurred in the presence of a base, such as n-BuLi, to give the corresponding domino products 315 in moderate to good yields and diastereoselectivities of up to 80% de. Another asymmetric domino three-component reaction initiated by the aza-Michael addition of the same chiral amine 314 to α,β-unsaturated esters was developed by these authors. In that case, the three components were chiral amine 314, an aldehyde, and a diester, such as di-tert-butyl 2,6octadien-1,8-dioate, which reacted through a domino azaMichael/Michael/aldol reaction, providing the corresponding highly functionalized domino products 316 bearing five contiguous stereocenters. The process was performed in the presence of a base, such as n-BuLi, and provided moderate to good yields (40
67%) and diastereoselectivities of up to 50% de. In spite of these moderate stereoselectivities, this process constituted the first method of amination that could build up to five contiguous stereocenters in one pot. The best results of these two domino processes are collected in Scheme 89.

Kamimura et al. have shown that optically active N-sulfinimines 317 underwent a stereoselective domino aza-Michael/nucleophilic addition reaction triggered by magnesium thiolate to give the corresponding α-phenylthiomethyl-β-(N-sulfinylamino) esters 318 in good to high diastereoselectivities (62
94% de).140 As shown in Scheme 90, the major syn-products were obtained in good to quantitative yields. These products could be further converted into useful corresponding aza-Baylis
Hilman adducts. In 2010, Wang and co-workers reported the first example of dynamic kinetic aza-Michael addition, allowing the convenient AX

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Scheme 96. Four-Component (Thio)-Ugi Reaction of (S)-α-Methylbenzylamine, Isobutyraldehyde, Isocyanide, and (Thio)benzoic Acid

synthesis of an important class of chiral heterocyclic compounds, which are imidazolidin-4-ones.141 Indeed, it is known that these products exhibit a range of biological activities and constitute key chiral building blocks for the total synthesis of medicinally important compounds.142 The pyridyl moiety of chiral amino amide 319 activated the Michael acceptor under acidic conditions, while acting as a remote directing group to position the enone and the secondary amine in a favorable orientation for the azaMichael addition, as depicted in Scheme 91. The importance of the nitrogen position in the protonated pyridyl directing group was illustrated by failure of the Michael addition

reaction with regioisomeric pyridyl derivatives of 319. Both intermediate diastereomers trans-320 and cis-320 provided the corresponding cis-products 321 as the reaction outcome of the final Michael addition reaction. The authors assumed the occurrence of a dynamic kinetic pathway in which the reaction of cis-320 was faster due to reduced steric hindrance. Although electron-poor aromatic aldehydes afforded the Michael products in moderate to good yields (64
90%) and good to excellent diastereoselectivities (84
96% de) in the presence of trifluoroacetic acid, electron-rich aromatic aldehydes required the use of a stronger Bronsted acid, such as p-toluenesulfonic acid (TsOH), to provide acceptable AY

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Scheme 97. Three-Component Ugi Reaction of Chiral 2-(2-Formyl-1-H-pyrrol-1-yl)acetic Acids, tert-Butylisocyanide, and Primary Amines

Scheme 98. Three-Component Ugi Reaction of Chiral D-lyxo-Derived Pyrroline, Isocyanides, and Carboxylic Acids

results (63
70% yields, 72
86% de's). Furthermore, electron-rich aliphatic aldehydes required elevated temperatures (80 °C) to achieve better yields (46
53%) and diastereoselectivities (92
94% de) in the aza-Michael addition-based three-component process. 3.2. Multicomponent Hantzsch Reactions

A venerable and old multicomponent reaction is the so-called Hantzsch reaction, which was first reported in 1882,143 allowing the synthesis of 1,4-dihydropyridines through the reaction of enamines, aldehydes, and 1,3-dicarbonyl compounds. Dihydropyridines are well-known for exhibiting activity against calcium channels, multidrug inflammatory targets in addition to their usefulness as tools for reducing imines to amines. The harsh reaction conditions usually applied to carry out the Hantzsch reaction have significantly decelerated the development of asymmetric versions of this reaction. In comparison with the other asymmetric multicomponent reactions, the asymmetric Hantzsch process has probably known the greatest progress in the last six years. In 2006, Dondoni and co-workers reported the synthesis of chiral 1,4-dihydropyridines through the three-component Hantzsch reaction between chiral aldehydes bearing a N-Boc benzyl glycinate group, β-keto esters, and enamino esters, which led to the corresponding chiral 1,4-dihydropyridines.144 The scope of this methodology was extended by the same authors to the synthesis of a variety of enantiopure C-glycosylmethyl pyridylalanines starting from the corresponding chiral aldehydes.145 A collection of eight novel C-glycosylmethyl pyridine amino acids were achieved in 55
68% yields with total preservation of the stereocenter integrity and functional group protection. Furthermore, the same authors have developed the first organocatalyzed three-component Hantzsch reaction occurring between C-glycosyl aldehyde 322, β-diketone 323, and enamine 324, to provide the corresponding enantiopure substituted 1,4-dihydropyridine C-glycoconjugate 325 in 50% yield and excellent diastereoselectivity of >95% de, as shown in Scheme 92.146 This method, based on a double asymmetric induction, arising from the use of a chiral substrate associated to a chiral organocatalyst, allowed the synthesis of biologically

relevant C-nucleosides, which were not accessible through uncatalyzed procedures, to be achieved. 3.3. Multicomponent Ugi Reactions

The modern concept of a multicomponent reaction is intimately related to the reactions developed with isocyanide reagents.147 The Ugi four-component reaction is the reaction of a carbonyl compound (usually an aldehyde), an amine, an isocyanide, and a carboxylic acid (or an alcohol) to yield α-amino acid derivatives. Its general mechanism involves in situ formation of an imine from the aldehyde or ketone and the primary amine, followed by α-addition of the isocyanide component to this imine and carboxylic acid and subsequent rearrangement to furnish diversely substituted α-amino acid derivatives. This reaction, first described in 1959, has been more widely studied and used than any other multicomponent reaction.132a In their early work, Ugi and co-workers determined that the use of a chiral acid or isonitrile in the reaction did not provide any degree of stereoselectivity.148 In contrast, chiral ferrocenylamine inputs resulted in the synthesis of nonracemic amino acid derivatives with low to modest levels of diastereoselectivity.149 Kunz et al. have developed more versatile chiral auxiliaries for the Ugi reaction using carbohydrate derivatives.150 High enantioselectivities (>90% ee) of (R)-amino acids were obtained in reactions using a galactosylamine derivative.150a A drawback of this asymmetric Ugi reaction was that high levels of stereoselectivity were only observed for reactions using tert-butyl isonitrile. The asymmetric synthesis of (S)-amino acids via the AZ

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Scheme 99. Four-Component Ugi Reaction of Chiral 7-Aza-norbornene trans-Dicarboxylic Acid, Isocyanides, Aldehydes, and Methanol

O-acylaldopyranosylamides used by Kunz et al.151a On the other hand, the Ugi three-component is a variant of the general reaction in which either two of the usual groups are included in the same reagents or the condensation of the carbonyl compound with the amine takes place before the addition of the isocyanide and acid derivatives. Even though the imine condensation could be performed in a one-pot process and its isolation was not necessary, it must be included in this category. A number of diastereoselective versions of both three-component and four-component Ugi reactions have been successfully developed. In 2006, Dyker and coworkers reported an interesting and novel route to highly functionalized chiral dihydroisoquinolines and isoindoles based on a two-step sequence including an asymmetric four-component Ugi reaction using an amino acid, such as 152 L -valine 326, as chiral auxiliary. Indeed, the Ugi reaction between L-valine 326, t-butyl isocyanide, methanol, and benzaldehydes 327 as source of the alkyne moiety proceeded somewhat sluggishly at room temperature within 6
9 days, building up the corresponding highly functionalized amines 328, finally with satisfactory yields (68
71%) and diastereoselectivities e82% de, as shown in Scheme 93. These chiral products were further submitted to a gold-catalyzed intramolecular hydroamination to provide a series of important chiral heterocycles, such as isoindoles and dihydroisoquinolines. In the same year, Guanti and co-workers developed the synthesis of complex chiral fused polycyclic scaffolds containing up to eight stereogenic centers on the basis of a sequence of reactions beginning with a four-component asymmetric Ugi reaction of optically pure (
)-N-allyl-3-amino-7-oxa-[2.2.1]bicyclohept-5-ene-2-carboxylic acid 329.153 As shown in Scheme 94, the reaction of this chiral substrate with different combinations of aldehydes and isocyanides in methanol at room temperature for 2
4 days resulted in the formation of the corresponding Ugi products 330 in moderate to good yields (46
71%) and as single diastereomers. These products were subsequently submitted to a ring-opening/ ring-closing metathesis to give a range of enantiopure, highly functionalized tricyclic products bearing five stereocenters. In addition, the scope of the Ugi methodology was extended to another optically pure bicyclic amino acid 331 bearing a

Scheme 100. Synthesis of Substituted Prolyl Peptides through Three-Component Ugi Reactions

Ugi reaction was achieved using an arabinosylamine derivative, but the stereoselectivity was not as high as that observed in the synthesis of the corresponding (R)-enantiomer.150b A single variant on the chemistry developed by Kunz has been reported by Goebel and co-workers.151 In 1991, these authors showed that 2,3,4,6-tetra-O-alkyl-β-D-glucopyranosylamines used as chiral amine components were as favorable as the BA

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Scheme 101. Synthesis of Telaprevir through Three-Component Ugi Reaction

Scheme 102. Synthesis of Core Fragment of Massidine through Four-Component Ugi Reaction

Scheme 103. Synthesis of α-Arylglycines through Three-Component Strecker Reaction

propargyl group instead of an allylic group as in substrate 330. In spite of the fact that a propargyl group is less bulky than an allylic group, the corresponding Ugi products resulting from the reaction of 331 with various aldehydes and

isocyanides were unexpectedly achieved as mixtures of diastereomers 332a,b. In one case of product 332b derived from tert-butyl isocyanide and p-chlorobenzaldehyde, however, the stereoselection was satisfactory (80% de) and the major BB

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Scheme 104. Synthesis of C-Glycosyl α,α-Dimethyl β-Amino Esters through Three-Component Mannich Reactions

of protein
protein interactions involved in apoptotic processes. 155 Water as a solvent is not only inexpensive and environmentally benign but may allow good reactivity. In this context, F€ul€op and co-workers have developed modified three-component Ugi reaction of various β-amino acids with isocyanides and aldehydes in water to construct β-lactam libraries.156 In addition to requiring shorter reaction times, these experimental procedures presented the advantage that the final products insoluble in water could be isolated by simple filtration. As shown in Scheme 95, this benefit could be exploited when less water-soluble amino acids, such as norbornene- and norbornane-based β-amino acids 333a,b and 335, were employed as substrates to give the corresponding Ugi products 334a
d and 336a
c, respectively, in good yields and moderate to complete relative diastereoselectivities. The mechanism of the reaction is depicted in Scheme 95. In the first step, the β-amino acid was reacted with the appropriate aldehyde, resulting in the formation of protonated Schiff base 339, followed by addition of the isocyanide to afford final β-lactam via intramolecular cyclization and rearrangement. Furthermore, other cyclic β-amino acids, such as cis-aminocyclopentane carboxylic acid 337a and cis-aminocyclohexane carboxylic acid 337b, provided under the same conditions the corresponding Ugi products 338a,b in moderate to good yields and complete relative diastereoselectivity when cyclohexylisocyanide was used. The authors have studied the same reactions performed in methanol

Scheme 105. Synthesis of Aminonaphthols through Mannich-type Reaction

diastereomer was separated by chromatography. This enantiopure product 332b was then submitted to a sequence of ring-opening/ring-closing metathesis and Diels
Alder cycloaddition to afford complex highly functionalized triand tetracyclic enantiopure products bearing up to eight stereocenters. More recently, the same authors combined this four-component Ugi reaction with a subsequent palladium-catalyzed ring-opening to transform oxabicycloheptene-based β-amino acids into two families of regioisomeric polyfunctionalized cyclohexenols. 154 The whole process was found to be completely stereoselective, and enantiomerically pure products were obtained in high overall yields. Interestingly, this diversity-oriented approach has been recently exploited to discover novel inhibitors BC

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Scheme 106. Synthesis of (S)-Anabasine through Three-Component Vinylogous Mannich Reaction

Scheme 107. Three-Component Allylation of Ketones

Scheme 96. Carboxylic acids formed salts with imine 3440 (mechanism B) without further nucleophilic addition to the iminium center. Thereafter, an isocyanide attack occurred from the less sterically hindered side, and Ugi product 343 having the S-configuration was formed as the major diastereomer. In the case of the thio-Ugi reaction (mechanism A), the much more nucleophilic thiocarboxylate attacked imine 344 from the less sterically hindered side, and the intermediate (R)-345 was formed. Furthermore, an SN2-type nucleophilic substitution with inversion of configuration of the formed stereocenter resulted in intermediate 346 as the (R)-isomer. Therefore, thioamide (R)-342 was formed as the major diastereomer. Moreover, chiral thioamide (R)-342 were treated with ammonia to afford the corresponding substituted amidine 347, which could be cyclized to imidazole derivative 348 in aqueous HCl (Scheme 96). Among these chiral imidazoles, one constituted a key synthon in the synthesis of SB203386, which is a naturally occurring orally bioactive HIV-1 protease inhibitor. In the same year, the first diastereoselective threecomponent Ugi reaction performed without chiral amines was reported by Nenajdenko et al.158 Indeed, the use of chiral

instead of water and found that the yields were slightly better in water than in methanol, while the diastereoselectivities were comparable. In 2007, Nenajdenko and co-workers reported the first example of a diastereoselective thio-Ugi reaction using (S)-αmethylbenzylamine 340 as chiral auxiliary, affording thioamides which constitute amide bond surrogates in a number of biologically active peptides and incorporated into various natural molecules.157 As shown in Scheme 96, chiral substrate 340 reacted with thiobenzoic acid, isobutyraldehyde, and isocyanide 341 to give the corresponding thioamide 342 as a 2:1 mixture of two diastereomers from which major (R)-342 was separated by chromatography in 35% yield. Unexpectedly, the authors observed inversion of the stereoselectivity of the reaction upon replacement of thiobenzoic acid by benzoic acid, which furnished the corresponding Ugi product (S)-343 as the major diastereomer in 80% yield and 55% de. To explain the preferable formation of the (R)-diastereomer in the thio-Ugi reaction with (S)-α-methylbenzylamine and that of (S)-diastereomer in the Ugi reaction with the same substrate, the authors have proposed that the thio-Ugi and Ugi reactions followed different mechanisms A and B, respectively, which are depicted in BD

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Scheme 108. Three-Component Allylation of Aldehydes

diastereoselective three-component Ugi reaction of carboxylic acids, isocyanides, and D-lyxo-derived pyrroline 351 as the chiral imine component was reported by Overkleeft and coworkers in 2008.160 During this sequential one-pot procedure, the imine component 351 was generated in situ through a Staudinger reduction of an L-ribose-derived 4-azido aldehyde with trimethylphosphine, followed by an intramolecular azaWittig reaction with the aldehyde. The subsequent threecomponent Ugi reaction was directed toward the formation of 2,3-trans-configured pyrrolidines 352 through the addition of 3 equiv of a Lewis acid such as InCl3, performing the reaction at 0 °C and working in dilute solution (Scheme 98). On the other hand, the formation of the corresponding 2,3-cis-configured pyrrolidines was promoted in apolar solvents, such as MeCN, as well as by omitting the Lewis acid. The control of the diastereoselectivity of the process was found to be highly dependent on the nature of 351, carboxylic acid, and isocyanide involved, providing the corresponding carbohydratederived pyrrolidines 352 in poor to reasonable yields (20
72%) and diastereoselectivities of 0 to 80% de for the trans-adduct. 7-Aza-norbornene trans-dicarboxylic acid 353 was used as chiral reagent by Basso et al. in a diastereoselective

2-(2-formyl-1-H-pyrrol-1-yl)acetic acids 349, derived from natural L-amino acids, as chiral substrates in the Ugi reaction with tert-butylisocyanide and primary amines, provided the corresponding chiral pyrroloketopiperazines 350 in good yields and moderate diastereoselectivities of up to 60% de, as shown in Scheme 97. The low diastereoselectivity observed could be explained by the almost planar structure of the heterocyclic fragment in the target molecules. To improve the diastereoselectivity, the authors have carried out the reaction in the presence of chiral amines; however, it did not improve the diastereoselectivity of the process significantly due to the structural peculiarities of pyrroloketopiperazines. Only modest success with diastereoselectivities e36% de was achieved by Guanti and co-workers for a three-component Ugi reaction occurring between a chiral pyrroline as preformed imine, various isocyanides, and carboxylic acids.159 On the other hand, the corresponding enantiomerically pure N-acyl2,5-disubstituted pyrrolidines were produced in moderate to high yields (47
85%). These products were employed as key intermediates in the synthesis of two series of enantiopure bicyclic derivatives, namely, hexahydro pyrrolo-oxazocinediones and -diazepinediones. A slightly more consistent BE

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asymmetric synthesis of alkaloid-like polycyclic compounds through a tandem MAO-N oxidation/three-component Ugi reaction/Pictet
Spengler-type cyclization sequence. 166 The process occurred between biocatalytically desymmetrized pyrroline 357, α-ketocarboxylic acids, and homoveratryl isocyanide or 2-(indol-3-yl)ethyl isocyanide, providing the corresponding Ugi products in good yields (75
83%) and both remarkable diastereo- and enantioselectivities of >98% de and >99% ee, respectively. These products were subsequently submitted to a Pictet
Spengler-type cyclization to give polycyclic 2,5-diketopiperazines in generally good yields (40
92%) and poor to excellent diastereoselectivities (14
96% de). It must be noted that these products are structurally similar to naturally occurring alkaloids displaying a broad range of biological activities.167 Moreover the biocatalytic desymmetrization/three-component Ugi reaction sequence of pyrroline 356 was also investigated by Turner and co-workers. 168 The scope of the Ugi reaction was explored with several carboxylic acids and isocyanides, affording the corresponding prolyl peptides 358 in high diastereoselectivities (84
86% de) and excellent enantioselectivities (94
97% ee). It was demonstrated that the stereochemical outcome of the process, providing stereoselectively the 2,3-trans isomers in all cases of substrates studied, was solely determined by the configuration of the chiral imine. In addition, these authors used a related sequence constituted by a biocatalytic desymmetrization followed by a three-component Ugi reaction as the key step in a highly efficient synthesis of telaprevir, which is a potent peptidic hepatitis C virus NS3 protease inhibitor.169 As shown in Scheme 101, the reaction occurred between a readily available enantiopure carboxylic acid 360, isocyanide 361, and chiral cyclic imine 356 previously desymmetrized by treatment with monoamine oxidase-N, to afford the corresponding key intermediate 362 in 76% yield. The latter compound was further converted in two steps into expected drug candidate telaprevir, which constituted the major isomer of an 83:13:4 mixture of diastereomers in 80% overall yield. This novel synthetic route to telaprevir represented impressive improvement over previous strategies, as minimization of the use of protective groups as well as a highly shortened procedure was achieved. On the other hand, D€omling and co-workers have reported a four-component version of the thiazole
Ugi reaction, using for the first time in this reaction (R)-4-methoxyphenylethylamine as the chiral auxiliary to react with acetaldehyde, thioacetic acid, and 2,4-dimethoxybenzylamine. The reaction led, however, to a 1:1 mixture of two diastereomers in 65% yield, which could be further separated through chromatography. After cleavage of the chiral auxiliary, the corresponding (R)-amide could be converted into naturally occurring (
)bacillamide C.170 In addition, Carreira and co-workers have recently reported the total synthesis of the core fragment of natural and biologically active massadine in which the key step was an asymmetric four-component Ugi reaction using chiral norbornenone 363 as the chiral auxiliary.171 As shown in Scheme 102, the reaction of this chiral norbornene with 2-nitrophenylisonitrile, trifluoroacetic acid, and 2,4-dimethoxybenzylamine led to the corresponding Ugi-product 364 as a single stereoisomer in 79% yield. This key product

Scheme 109. Synthesis of (R)-(+)-Orizaterpenyl Benzoate through Three-Component Allylation Reaction

intramolecular four-component Ugi reaction in 2009.161 The resulting unnatural amino acid derivatives 354 constitute valuable building blocks in drug discovery, because they can be applied for the synthesis of various peptidomimetics.162 Interestingly, the alkylated bridgehead nitrogen atom showed abnormally high barriers for nitrogen inversion 163 due to the so-called bicyclic effect.164 As expected, the seven-membered ring intermediates 355 in this Ugi process was attacked by methanol to afford the corresponding azabicycloheptanes 354 in moderate to good yields (34
76%) and low to excellent diastereoselectivities (2
99% de), as shown in Scheme 99. The endo-configured carboxylic acid group was unable to participate in the Ugi reaction and provided an interesting handle for postcondensation transformations. Various isocyanides were tolerated, showing no particular difference in reactivity while the influence of the nature of aldehydes was found to be more important. Acetone was demonstrated to be incompatible to the process. As there is a lack of methods to introduce complex alkyl substituents onto bridgehead nitrogen atoms, this methodology is very useful for the preparation of polyfunctionalized azabicyclic peptidomimetics. More recently, Orru and co-workers have developed a highly stereoselective synthesis of chiral substituted prolyl peptides by using as the key step an asymmetric threecomponent Ugi reaction.165 As shown in Scheme 100, the three-component Ugi reaction of two types of chiral cyclic imines, such as 356 and 357, provided under mild conditions the corresponding almost enantiopure prolyl peptides 358 and 359 in high yields and high to complete diastereoselectivities. The starting chiral 3,4-cis-substituted 1-pyrrolines 356 and 357 arose from the biocatalytic desymmetrization of the corresponding 3,4-cis-substituted meso-1-pyrrolines with engineered monoamine oxidase-N (MAO-N) from Aspergillus niger. The utility of this powerful three-component Ugi reaction was demonstrated by its application in a rapid BF

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Scheme 110. Synthesis of Jerangolid D through Three-Component Sakurai Reaction

was further converted into the chiral core fragment of massadine in 14 steps.

often use expensive chiral catalysts or require multistep syntheses of chiral ligands. Moreover, many of these catalytic methodologies require the use of trimethylsilyl cyanide as a nucleophile, which is expensive in addition to being a toxic reagent. Finally, the substrate-specificity profile of a number of catalytic processes is often limited. Consequently, an alternative approach to asymmetric catalysis is to use enantiopure amines as chiral auxiliaries to perform diastereoselective Strecker reactions. As a recent example, James and co-workers have developed the synthesis of enantiopure α-arylglycines through an asymmetric three-component Strecker reaction of various aryl aldehydes, sodium cyanide in solution, and (S)1-(4-methoxyphenyl)ethylamine 365 as the chiral auxiliary.174 As shown in Scheme 103, the process afforded the corresponding crystalline α-aminonitriles 366 in good yields and as single stereoisomers after fractional recrystallization of the

3.4. Multicomponent Strecker Reactions

The asymmetric Strecker reaction, discovered in 1850,172 is one of the most widely used methods for synthesizing α-aminonitriles that can be further hydrolyzed to give α-amino acids.173 The Strecker reaction is a three-component coupling between carbonyl derivatives, amines, and a cyanide source, such as hydrogen cyanide, to give the corresponding α-aminonitriles. The mechanism of the Strecker reaction involves the initial formation of an imine by condensation of the carbonyl and amine components, after which addition of the cyanide component to the imine intermediate follows. Although many enantioselective catalytic protocols using either metal-based catalysts or organocatalysts have been shown to afford enantiopure α-arylaminonitriles, they BG

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Scheme 111. Three-Component Passerini Reaction of Chiral Carbohydrate-Derived Aldehydes, Carboxylic Acids, and TosMIC

C-glycosyl aldehydes, such as 368 and 369, as chiral reagents in the Mannich reaction with p-methoxybenzylamine 370, and commercially available ketene silyl acetal 1-methoxy-2methyl-1-trimethylsilyloxypropene 371. 144 This process was promoted by InCl 3 and provided the corresponding chiral C-glycosyl α,α-dimethyl β-amino esters 372 and 373, respectively, in high yields and complete diastereoselectivity in all cases of substrates studied, as shown in Scheme 104. In 2007, a solvent-free diastereoselective Mannich-type reaction was described by Petrini and co-workers. 179 This process occurred between β-naphthol, amines, and chiral functionalized aldehyde 374 to afford the corresponding chiral aminonaphthols 375 in moderate yields (24
62%) and diastereoselectivities (24
78% de). As shown in Scheme 105, the best diastereoselectivities were reached when using a chiral amine in addition to the chiral aldehyde. A subsequent deprotection of the formed products 375 by acid hydrolysis (aqueous HCl/THF) allowed the

crude from Et2O in almost all cases of substrates studied. A further heating of these products in 6 M aqueous HCl at reflux resulted in the cleavage of their chiral auxiliary fragments and hydrolysis of their nitrile groups to afford enantiopure (S)-αarylglycines 367. 3.5. Multicomponent Mannich Reactions

The classic direct Mannich reaction discovered in 1912 175 is an aminoalkylation of carbonylic compounds involving ammonia (or a primary or secondary amine derivative), a nonenolizable aldehyde (usually formaldehyde) or a ketone, and an enolizable carbonyl compound, leading to β-aminocarbonyl derivatives. 176 In addition to enantioselective catalytic Mannich reactions, 177 all of the possibilities of using chiral starting materials for this asymmetric multicomponent reaction have been reported. In their aim of discovering novel glycopeptide-based drugs for the treatment of bacterial and viral infections, cancer, and inflammatory processes, 178 Dondoni and Massi have used a range of chiral BH

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piperidinones, including the biologically active and natural alkaloid (S)-anabasine.

Scheme 112. Three-Component Passerini Reaction of Chiral 2,3-Epoxy Aldehyde, Chiral Carboxylic Acids, and TosMIC

3.6. Multicomponent Reactions Initiated by an Allylation Reaction

Stereoselective allylations of carbonyl compounds, such as aldehydes and ketones, are useful but challenging reactions in organic chemistry. The resulting chiral secondary and tertiary homoallylic alcohols or ethers are valuable building blocks in the synthesis of a number of biologically active natural compounds. Although researchers have developed several methods for the stereoselective allylation of aldehydes, that of allylation of ketones still poses a severe problem. In this context, Tietze et al. have developed a highly diastereoselective domino threecomponent allylation reaction of ketones and allyltrimethyl silane, using the trimethylsilyl ether of norpseudoephedrine 379 as the chiral auxiliary, which provided the corresponding ethers 380 in good yields and diastereoselectivities of up to 96% de, as shown in Scheme 107.181 The reaction was performed in the presence of a catalytic amount of trifluoromethanesulfonic acid and led to the corresponding tertiary ethers. To determine the origin of the stereoselectivity of the reaction, these authors have undertaken density functional theory (DFT) calculations.182 Computational investigations on the allylation of butanone have suggested an SN1-type mechanism via the attack of allyltrimethylsilane to an intermediately formed oxocarbenium ion from butanone and silyl ether (Scheme 107). The identification of preferred transition states led to a straightforward rationalization of the observed selectivity. A screening process based on B3LYP//AM1 energies allowed for the narrowing down of the number of potentially relevant transition states. The predicted selectivities were in good agreement with experimentally determined ones. The procedure could also be used for the allylation of aliphatic aldehydes with diastereoselectivities of up to >98% de, as shown in Scheme 108. It must be noted that ketones led to the corresponding 4,10 -syn products, while aldehydes yielded products 381 bearing two stereogenic centers with anti-diastereoselectivity of >98% de. The homoallylic ethers formed in the domino multicomponent processes can be used in further transformations. Indeed, the auxiliary can serve as a protecting group or can be cleaved reductively to give the corresponding homoallylic alcohols. The reaction was catalyzed by TMSOTf, which was sufficient to initiate the reaction, whereas reactions of ketones required the use of TfOH as catalyst. The authors have proposed that the domino reaction evolved via the formation of a mixed acetal species 382, which was transformed into an oxocarbenium ion 383 bearing the organic part of the silyl ether residue at its oxygen atom (Scheme 108). Intermediate 383 was then intercepted by the weak nucleophile trimethylallyl silane to give the carbenium ion 384, which in the following step was attacked by the trimethylsilyloxide anion to yield the final homoallylic product 381. The utility of these methodologies was illustrated by their application as key steps of the total syntheses of several natural products, such as (
)-hydroxymyoporone, 5,6dihydrocineromycin B, polyoxygenated cembrene,181a and (R)-(+)-orizaterpenyl benzoate. 183 As shown in Scheme 109, the key step of the synthesis of (R)-(+)-orizaterpenyl benzoate consisted of an asymmetric three-component

Scheme 113. Synthesis of Telaprevir through ThreeComponent Passerini Reaction

corresponding enantiopure aminodiols to be achieved in high yields. A novel stereoselective approach to chiral 6-alkylated piperidinones and 2-piperidines was recently reported by Yang et al. on the basis of a three-component vinylogous Mannich reaction involving a chiral amine as chiral auxiliary.180 As shown in Scheme 106, the reaction of (R)-(+)-1-naphthalen1-yl-ethylamine 376 with various aldehydes and a silylketene acetal, such as (1-methoxy-buta-1,3-dienyloxy)trimethylsilylsilane 377, provided, in the presence of 1 equiv of Sn(OTf)2, the corresponding chiral amines 378 in good yields and moderate to good diastereoselectivities ranging from 66 to 80% de. These products could be readily converted through hydrogenation into the corresponding cyclized 6-alkylated BI

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Scheme 114. Three-Component Biginelli Reaction of Unprotected Chiral Aldoses, (Thio)ureas, and Mercaptoacetylating Active Methylene Building Block

allylation reaction of 6-methyl-2-heptanone 385, using chiral trimethylsilyl ether 386, which was easier to prepare than the norpseudoephedrine derivative 379. The corresponding tertiary homoallylic ether 387 was obtained in 85% yield as a 90:10 mixture of two diastereomers. The major isomer was further converted into (R)-(+)-orizaterpenyl benzoate. In another context, Pospisil and Marko have reported the first total synthesis of natural product jerangolid D by using an asymmetric three-component Sakurai reaction.184 This domino process occurred between allyl trimethyl silane,

chiral aldehyde 388, and chiral ether 389 in the presence of a catalytic amount of TMSOTf, which afforded the corresponding syn
syn-ether 390 as a single stereoisomer in 80% yield, as shown in Scheme 110. This product was further converted into jerangolid D. The authors have proposed the mechanism depicted in Scheme 110, in which intermediate 391 was supposed to be generated under the reaction conditions and equilibrated with the starting aldehyde 388 and the silylated alcohol 389. The diastereoselectivity observed during this reaction could be broadly rationalized by invoking an SN 1-type mechanism, which BJ

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Scheme 115. Petasis Reaction of (S)-α-Methylbenzyl Amine, Chiral Boronate, and Glyoxylic Acid Monohydrate

Anh transition state 392, thus delivering the final 2,3-synadduct.

Scheme 116. Petasis Reactions of Chiral Lactol, Chiral Amino Esters, and Boronate

3.7. Multicomponent Passerini Reactions

The Passerini three-component reaction, discovered in 1921, involves the condensation of carbonyl compounds, carboxylic acids, and isocyanides to afford the corresponding α-acyloxy carboxamides.185 Among several advantages are the mildness of the reaction conditions, the broad scope, and the high variability of the inputs.186 In spite of a number of investigations about the mechanism of the Passerini reaction, the exact intermediates involved in this reaction are still discussed.147,187 Several chiral auxiliaries or reagents have been applied to control the stereochemical outcome of the diastereoselective Passerini reaction. This reaction has been performed with the chiral version of each of the components before 2006. 188 It must be noted that, in the last 6 years, only a few novel examples of diastereoselective Passerini processes have been described. Among them, an interesting Passerini reaction, using (p-toluenesulfonyl)methylisocyanide (TosMIC) for the first time in such reaction as the isonitrile component, was reported by Krishna et al. in 2006.189 As shown in Scheme 111, the process employed carbohydrate-derived aldehydes 393a
d as the chiral auxiliaries to react with TosMIC and carboxylic acids, providing the corresponding products 394a
e as mandelamides in moderate to good yields (40
90%) and anti-diastereoselectivities (30
90%). The highest diastereoselectivities of up to 90% de were reached by employing Garner’s aldehyde 393d as the chiral auxiliary. The use of a chiral carboxylic acid in this reaction did not allow the stereoselectivity of this reaction to be enhanced. Later, the same authors investigated the use of chiral 2,3epoxy aldehydes as chiral auxiliaries in the Passerini reaction with TosMIC and carboxylic acids as the two other components.190 As shown in Scheme 112, densely substituted products 395 were achieved in moderate to good yields and lower diastereoselectivities (40
86% de) than those obtained by using carbohydrate-derived aldehydes 393a
d. The best results were obtained through double asymmetric induction by using chiral epoxide 396 in combination with chiral carboxylic acids 397a,b. Interestingly, the use of trans-epoxy

involved the oxocarbenium 391. The addition of the allyltrimethyl silane then occurred according to the Felkin
BK

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Scheme 117. Petasis Reactions of Chiral Aminophosphonic Esters, Glyoxylic Acid Monohydrate, and Boronic Acids

Scheme 118. Petasis Reaction of L-Xylose with Allylamine and (E)-Styrene Boronic Acid

Scheme 119. Petasis-Type Reaction of Chiral Tartaric Acid, Styrylboronic Acid, and Ammonia

aldehydes resulted in syn-adducts formation, whereas antiisomers were obtained by employing cis-epoxy aldehydes. The stereochemical outcome can be explained by invoking the well-established mechanism cited for the classical Passerini reaction (as in the previous scheme), which involves the reaction of the isonitrile with loosely bound adducts 398 and 399 (Scheme 112), initially formed by the reaction of the carboxylic acid with the aldehyde. These adducts might also be seen as tight ion pairs resulting from protonation of the aldehyde by the carboxylic acid. Consequent to their formation, the isomeric bias may be explained by the following transition state models as

depicted in Scheme 112. There is a diastereofacial preference for the entering isonitrile from the less-hindered side for both the acid chelated cis- and trans-epoxy aldehydes, i.e., from the Re face to ensure a syn product (major) for the trans-epoxy aldehyde and from the Si face to afford an anti product (major) for the cis-epoxy aldehyde. Finally, a diastereoselective three-component Passerini reaction was used in a total synthesis of potent peptidic hepatitis C virus NS3 protease inhibitor telaprevir, in addition to the diastereoselective Ugi reaction depicted in Scheme 113.169 This Passerini reaction occurred between chiral aldehyde 400, acetic acid, and cyclopropyl isocyanide to provide the corresponding Passerini adduct 401 in 56% yield as a 78:22 mixture of diastereomers, as shown in Scheme 113. BL

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Scheme 120. Rh-Catalyzed Three-Component Carbonyl Ylide-Formation/1,3-Dipolar Cycloaddition Reaction

Scheme 121. Rh-Catalyzed Three-Component Domino Oxonium Ylide Formation/Nucleophilic Addition Reaction

The production of enantiopure dihydropyrimidines has mostly been based on chemical resolution and diastereoselective Biginelli reactions of chiral auxiliaries or reagents. 193 As a recent and nice example, Yadav et al. developed a novel efficient version of a diastereoselective Biginelli reaction that involved a mercaptoacetylating active methylene building block 402, unprotected aldoses 403a,b as biorenewable aldehyde components, and ureas or thioureas 404. 194 As shown in Scheme 114, the process allowed a range of thiosugar-annulated multifunctionalized dihydropyridine scaffolds of pharmaceutical potential, 405 and 406, arisen from the use of D-xylose and D-glucose as aldoses, respectively. This reaction was performed without solvent under microwave irradiation at 90 °C in the presence of Montmorillonite K-10

3.8. Multicomponent Biginelli Reactions

The Biginelli reaction, discovered in 1893, is a threecomponent reaction allowing the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones or -thiones by reacting urea or thiourea, a 1,3-dicarbonyl derivative, and an aldehyde. 191 The heterocyclic pyrimidinone products are known to exhibit a wide range of important pharmacological properties and make up a large family of medicinally relevant compounds. Consequently, the asymmetric version of the Biginelli reaction is of significant contemporary interest. The accepted mechanism for the Biginelli multicomponent reaction involves intermediate imine formation between the aldehyde and urea components, followed by a Mannich-type reaction with the enol derivative of the 1,3-dicarbonyl derivative.192 BM

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Scheme 122. Rh-Catalyzed Three-Component Domino Hydroformylation/Cyclization Reactions

nanoclay and provided these important chiral products in high general yields combined with high diastereoselectivities of up to 96% de.

investigated the effect of chirality of the amine and organoboron species on the stereochemical outcome of the Petasis reaction. 198 The best results were achieved by using chiral secondary amines, such as (S)-α-methylbenzyl amine 407, which was reacted with chiral boronate 408 and glyoxylic acid monohydrate 409 to afford the corresponding Petasis product 410 in moderate yields (50
60%) and excellent diastereoselectivities of >90% de, as shown in Scheme 115. Because both enantiomers of anti-boronate 408 produced the same diastereomer of product 410, it can be concluded that the stereochemical outcome of this reaction was dominated by the stereochemical configuration of the amine. In the same year, Schreiber and co-workers reported a remarkable combination of L-phenylalanine derivative 411 with boronate 412 and enantiopure lactol 413 as the aldehyde

3.9. Multicomponent Petasis Reactions

The Petasis multicomponent reaction was discovered in 1993 195 and involves the condensation of amines, carbonyl derivatives, and aryl- or vinylboronic acids for the synthesis of amine derivatives, 196 such as α-amino acids, when using glyoxylic acid as the aldehyde component. 197 Advantages such as mild reaction conditions and high accessibility of the reagents have contributed to render the Petasis reaction a powerful synthetic tool in the past decade. Generally, secondary amines gave better yields than primary amines, and vinylboronic acids are more reactive than arylboronic acids. In 2006, Hutton and co-workers BN

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Scheme 123. Ni-Catalyzed Four-Component Domino Reformatsky Reactions

Scheme 124. Ni-Catalyzed Three-Component Domino Aldehydes
Alkynes Reductive Coupling Reaction

Scheme 125. Ni-Catalyzed Three-Component Domino Aldehydes
Ynamides Reductive Coupling Reaction

component.199 The corresponding Petasis product 414 was achieved as the almost enantiopure stereoisomer in 85% yield, as shown in Scheme 116. Opposite enantiopreference was observed by using either (S)-lactol 413 or its (R)-enantiomer, while L-phenylalanine derivative 411 was used in both cases. To account for this result, a secondary hydroxyl group adjacent to the intermediate imine was assumed to direct the stereochemical outcome of the process. Therefore, the directing effect of the stereocenter of L-phenylalanine derivative 411 was inferior to that of the aldehyde component in this case. The scope of this powerful methodology could be extended to other amino acid derivatives, such as 415 and 416, which were reacted under the same reaction conditions with boronate 412 and (S)-lactol 413, providing the

corresponding Petasis products 417 and 418, respectively, as almost single stereoisomers in high yields, as shown in Scheme 116. Later, the scope of the boronate component was further broadened by Kukhar et al. in the Petasis reaction of glyoxylic acid monohydrate 409, various boronic acids, and chiral aminophosphonic esters 419a,b instead of amino esters.200 Electron-rich boronic acid components were successful in this Petasis process, particularly in combination with aminophosphonate 419a, because the corresponding Petasis products 420a were obtained in good to excellent yields (69
95%) and high diastereoselectivities of up to >90% de, as shown in Scheme 117. On the other hand, the use of primary BO

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which was subsequently transformed into the desired pyrrolizidine alkaloids uniflorine A, casuarine, australine, and 3-epiaustraline. In addition, Wissinger and co-workers have developed the synthesis of various other heterocyclic chiral frameworks on the basis of a diastereoselective Petasis reaction of chiral β-amino amides with boronic acids and hydroxyaldehydes.203 This key step furnished the corresponding Petasis products in high yields (83
96%), but no precision about the diastereoselectivity of the process was given, because this crude product was directly transformed to provide a range of chiral bi- and tetraheterocyclic products. A Petasis-type aminocyclization reaction can be applied to generate biologically interesting iminocyclitols, as reported by Wong and co-workers in 2009.204 The oxocarbenium ion-like transition state of carbohydrate-processing enzymes is mimicked by iminocyclitols, which are metabolically inert carbohydrates.205 The various biological properties as anticancer, antiviral, and antidiabetic agents of iminocyclitols render the synthesis of these key products through one-step Petasis-type reaction highly desirable.206 An unexpected diastereoselectivity of up to >98% de was achieved by Wong and co-workers in their elegant Petasis-type reaction of chiral sugar-derived tartaric acid 422 with styrylboronic acid 423 and ammonia as the amine donor, which provided the corresponding almost enantiopure pyrrolidine 424 in 70% yield, as shown in Scheme 119. Iminocyclitol 425 and analogues could be further produced through ozonolysis of 424 in acidic solution and subsequent reduction with sodium borohydride. Furthermore, the scope of this methodology could be extended to the synthesis of chiral six-membered iminocyclitols by using commercially available 1,2- or 2,3-O-isopropylideneprotected D-glucose, D-mannose, D-galactose, and D-allose as starting materials. The intermediate corresponding sixmembered Petasis-type products of these sugar derivatives were achieved in comparable almost complete diastereoselectivity and, however, in slightly lower yields ranging from 55 to 65% yields.

Scheme 126. Ag- and Cu-Catalyzed Three-Component Domino Imine Formation/1,3-Dipolar Cycloaddition [C + NC + CC] Processes

3.10. Miscellaneous Multicomponent Reactions

3.10.1. Metal-Catalyzed Multicomponent Reactions. 3.10.1.1. Rhodium-Catalyzed Multicomponent Reactions. In 2006, Torssell and Somfai reported a rhodium(II)-catalyzed diastereoselective three-component 1,3-dipolar cycloaddition of in situ-generated carbonyl ylides with chiral imines as chiral auxiliaries to construct chiral highly functionalized oxazolines. 207 When chiral α-methylbenzylimines 426 were reacted with benzaldehyde and ethyl diazoacetate 427 in the presence of a catalytic amount of Rh 2 (OAc)4 , they provided the corresponding oxazolines 428 in good yields and moderate to good diastereoselectivities of up to 60% de, as shown in Scheme 120. These products could readily be hydrolyzed by treatment with TsOH to afford syn-α-hydroxy-β-amino esters 429, which constitute interesting building blocks in the synthesis of natural products and biologically important compounds. 208 Furthermore, these motifs can be applied to the synthesis of various chiral ligands and auxiliaries.209 This methodology was also used as the key step in a short asymmetric synthesis of paclitaxel side-chain. In 2007, Hu and co-workers described an efficient trapping of oxonium ylides, generated in situ from phenyldiazoacetates and

amine-containing phosphonic acid 419b resulted in both lower yields (43
76%) and diastereoselectivities (e80% de) for the corresponding Petasis products 420b, as summarized in Scheme 117. The asymmetric Petasis reaction has been applied by Ritthiwigrom et al. as the key step in total syntheses of natural products, such as (
)-uniflorine A,201 and related casuarine, australine, and 3-epi-australine, which are biologically active pyrrolizidine alkaloids.202 All these syntheses employed as the key intermediate a chiral tetraol that arose from the asymmetric Petasis reaction of L-xylose with allylamine and (E)styrene boronic acid. As shown in Scheme 118, the Petasis key product 421 was achieved in 92% yield as a single stereoisomer. This enantiopure tetraol was further converted into corresponding chiral 2-substituted-2,5-dihydropyrrole, BP

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Scheme 127. Synthesis of A-315675 through Cu-Catalyzed Three-Component Domino [C + NC + CC] Coupling Process

alcohols, by imines through a highly diastereoselective threecomponent domino reaction.210 As shown in Scheme 121, the reaction of chiral N-(tert-butylsulfinyl)imines 430 with methyl phenyldiazoacetate 431 and a range of alcohols provided the corresponding almost enantiopure β-amino-α-hydroxyesters 432 in moderate to good yields combined with exceptionally high diastereoselectivities of >96% de in all cases of substrates studied. Enantioselective syntheses of 2-substituted pyrrolidines from allylamines through rhodium-catalyzed domino hydroformylation/ reductive amination reaction have been reported by Helmchen and co-workers.211 It must be noted that the outcome of the hydroformylation reaction was found to be controlled by the nature of the substituent at nitrogen, and not by the substituent at carbon. In the case of N-alkylallylamines 433, an in situ reduction to the corresponding almost enantiopure pyrrolidines 434 occurred (first reaction of Scheme 122), whereas with N-sulfonyl- and N-acyl derivatives 435, the corresponding hemiaminals 436 were generated (second reaction of Scheme 122) and, with unprotected primary amines 437, the corresponding cyclic imines 438 were formed (third reaction of Scheme 122). In all these cases of substrates studied, the yields were moderate to good and the enantioselectivities were generally excellent, up to 98% ee, as shown in Scheme 122. 3.10.1.2. Nickel-Catalyzed Multicomponent Reactions. Diastereoselective nickel-catalyzed asymmetric four-component domino Reformatsky reactions have been developed by Dondoni and co-workers with the aim of achieving chiral C-glycosyl β-amino esters.144 As shown in Scheme 123, an in situ initial coupling of chiral C-glycosyl aldehydes 439 or 440 with p-methoxybenzylamine gave the corresponding imines, which reacted with a bromozinc enolate, which was in situ generated from dimethylzinc and ethyl bromoacetate, providing the

corresponding chiral Reformatsky products 441 and 442, respectively, in moderate to good yields and as single diastereomers in all cases of substrates studied. Another type of nickel-catalyzed asymmetric multicomponent domino reaction was reported by Sa-ei and Montgomery in 2006.212 In this case, the reaction consisted of a three-component coupling of chiral α-silyloxyaldehydes 443 with an alkynylsilanes 444 in the presence of (i-Pr)3SiH as the reducing agent. This domino aldehyde
alkyne reductive coupling process, performed in the presence of Ni(cod)2 and N-heterocyclic carbene generated from imidazolium, afforded the corresponding protected allylic alcohols 445 in excellent yields and diastereoselectivities of up to 96% de, as shown in Scheme 124. These chiral products could be easily converted into the corresponding anti-1,2-diols with conservation of the enantioselectivity by treatment with n-Bu4NF. The mechanistic basis for the outstanding results has been qualified as unclear by the authors. More recently, Sato and co-workers have reported the asymmetric synthesis of γ-siloxyenamides 446 through diastereoselective coupling of chiral oxazolidinone-derived ynamides 447, aldehydes, and triethylsilane mediated by a nickel catalyst.213 As shown in Scheme 125, both excellent yields and diastereoselectivities were achieved in the formation of the corresponding chiral coupling products. The authors assumed that the process proceeded through the formation of oxanickelacycles to afford γ-siloxyenamide derivatives in a highly regio- and stereoselective manner. 3.10.1.3. Multicomponent Reactions Catalyzed by Metals Other than Rhodium and Nickel. In 2006, Garner et al. reported a silver-catalyzed three-component [C + NC + CC] coupling domino process, allowing a variety of highly functionalized chiral pyrrolidines 448 to be synthesized at ambient temperature in good to high yields (58
94%) and diastereoselectivities ranging BQ

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Scheme 128. Pd-Catalyzed Three-Component Domino Aminoacetal Formation/Stille
Migita Coupling/6π-Azaelectrocyclization/ Aminoacetal Formation Reaction

from 73 to 90% de. 214 The domino reaction began with the formation of a chiral imine 449 from the reaction between an aldehyde and chiral glycyl sultam 450. This imine then formed a metalated azomethine ylide 451, which underwent a 1,3-dipolar cycloaddition with an activated alkene to give the final pyrrolidine 448. Later, these authors showed that, by varying the metal catalyst and the chiral auxiliary, the domino process provided direct access to four of the eight possible pyrrolidine stereoisomers. 215 For example, by mediating the reaction with copper catalyst, such as CuOAc in THF, instead of silver catalyst such as AgOAc in dimethylsulfoxide (DMSO), the process led to diastereomers 452, different than those obtained by using AgO Ac as catalyst, in good to excellent yields (60
97%) and

diastereoselectivities of up to >99% de, as shown in Scheme 126. In 2011, these authors illustrated the utility of this asymmetric three-component [C + NC + CC] coupling domino reaction by developing a novel entry to the naphthyridinomycin natural product family of tetrahydroisoquinoline antibiotics. 216 Indeed, this methodology constituted the key step in total synthesis of cyanocycline A and bioxalomycin β2. Very recently, the same authors have applied this methodology to an efficient synthesis of the neuramidase inhibitor A-315675.217 As shown in Scheme 127, the fully functionalized core of this target was assembled in a single process through a copper-catalyzed exo-selective asymmetric threecomponent domino [C + NC + CC] coupling reaction of BR

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Scheme 129. Syntheses of (
)-Dendroprimine, (
)-Corynantheidine, and (
)-Epiuleine

Scheme 130. Ti-Catalyzed Three-Component Reaction of Phenyldihydrofuran, N-Tosylimino Ethyl Ester, and Silane Reagents

chiral α-acetamidoaldehyde 453, chiral glycylsultam 450, and ethyl thioacrylate 454. This process afforded the corresponding highly functionalized pyrrolidine 455 in 76% yield and diastereoselectivity of 90% de. This chiral product was further converted into neuramidase inhibitor A-315675 in five steps. Another type of asymmetric three-component domino process was reported by Katsumara and co-workers in 2006.218 It dealt with a palladium-catalyzed domino aminoacetal formation/Stille
Migita coupling/6π-azaelectrocyclization/aminoacetal formation reaction of vinylstannanes 456, vinyliodides 457, and chiral cis-aminoindanol derivative 458. As shown in Scheme 128, the sequence began with the in situ formation of an aminoacetal 459 from chiral cisaminoindanol derivative 458 and vinyliodide 457. This aminoacetal formation protected the unstable aldehyde moiety in vinyliodide, thus successfully achieving the subsequent Stille
Migita coupling with vinyl stannane 456. The coupling product 460 was in equilibrium with a 1-azatriene 461, which spontaneously cyclized into the corresponding dihydropyridine 462. The reactive enamine moiety in this dihydropyridine was then trapped by the proximal hydroxyl group of cisaminoindanol, giving rise to the observed product 463. The scope of this methodology was extended to a range of vinylstannanes, and tri- as well as tetrasubstituted vinyliodides, providing a variety of chiral 2,4-disubstituted 1,2,5,6tetrahydropyridines and 2,4,5-trisubstituted 2,5-tetrahydropyridines 463 in good yields and diastereoselectivities of up to 100% de (Scheme 128).

This powerful methodology was applied to the total synthesis of three natural indole alkaloids, such as (
)-dendroprimine,219 (
)-corynantheidol,220 and (
)-20-epiuleine,221 as depicted in Scheme 129. Asymmetric titanium-catalyzed domino reactions have also been described. As an example, Ghosh et al. have successfully developed the synthesis of chiral substituted pyrrolidine and proline derivatives on the basis of a diastereoselective titaniumcatalyzed three-component domino reaction, occurring between chiral phenyldihydrofuran 464, N-tosylimino ester 465, and various silane reagents.222 As shown in Scheme 130, a range of chiral functionalized pyrrolidines 466 were stereoselectively produced in good yields and excellent diastereoselectivities of up to 98% de by using a variety of silane reagents. To explain the formation of these products, the authors have proposed that the domino process began with the reaction of chiral phenyldihydrofuran 464 with N-tosylimino ester 465 in the presence of TiCl4 to give the corresponding oxocarbenium ion 467. This intermediate reacted with the silane reagent to provide the corresponding tetrahydrofuran 468, which was then activated by TiCl4 to produce a novel oxonium ion 469. The SN2 nucleophilic attack of sulfonamide nucleophile (NTs) to this oxonium ion provided the final pyrrolidine 466, as depicted in Scheme 130. In 2007, Young and Kerr reported the total synthesis of natural product (+)-nakadomarin A, which constitutes BS

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Scheme 131. Synthesis of (+)-Nakadomarin A through Yb-Catalyzed Three-Component Reaction of Chiral Cyclopropane Derivative, p-Methoxybenzylhydroxylamine, and a Furfural Derivative

one of the most architecturally beautiful classes of alkaloids.223 An asymmetric ytterbium-catalyzed three-component domino reaction, occurring between chiral cyclopropane 470, p-methoxybenzylhydroxylamine 471, and furfural derivative 472, was the key step of this synthesis, allowing an enantiopure highly functionalized tetrahydro-1,2-oxazine 473 to be achieved in both excellent yield and enantioselectivity, as shown in Scheme 131. The reaction began with the in situ formation of a nitrone from p-methoxybenzylhydroxylamine 471 and aldehyde 472. Then, this nitrone underwent a homo [3 + 2]cycloaddition224 with cyclopropane 470 to afford the final almost enantiopure cycloadduct 473, which was further converted into expected (+)-nakadomarin A in 21 steps. It must be noted that, even if ytterbium is a lanthanide, it was decided to situate this work in this section dealing with metal-catalyzed multicomponent reactions for commodity.

Finally, Che and co-workers have described asymmetric gold(III)-catalyzed three-component coupling reactions of chiral prolinol derivatives 474, alkynes, and aldehydes, providing the corresponding chiral propargylamines 475 in good to excellent yields and diastereoselectivities of up to 98% de, as shown in Scheme 132.225 These processes were promoted by a salen gold(III) complex in water, which could be repeatedly used for 10 reaction cycles, leading to an overall turnover number of 812. A proposed mechanism for the three-component coupling reaction of aldehyde, amine, and alkyne is illustrated in Scheme 132. Aldehyde was first condensed in situ with the secondary amine to give an iminium ion, while the gold(III) complex activated the C
H bond of terminal alkyne to generate a gold acetylide intermediate. The gold acetylide intermediate further underwent a nucleophilic attack on the iminium ion to give the final propargylamine. 3.10.2. Other Multicomponent Reactions. 3.10.2.1. Multicomponent Reactions of Chiral Diamines. In 2006, BT

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Scheme 132. Gold-Catalyzed Three-Component Reaction of (S)-Prolinol Derivatives, Alkynes, and Aldehydes

multicomponent reaction occurring between β-ketoamides 482, aromatic aldehydes, and cyclic or acyclic 1,2-diamines 483.227 The 1,4-diazepine derivatives 484 were achieved in low to excellent yields with a complete relative diastereoselectivity in all cases of substrates studied, as shown in Scheme 134. In some cases, better results were obtained by simply heating the mixture of substrates at 120 °C without solvent than by performing the reaction in toluene at 110 °C in the presence of molecular sieves. Later, the authors extended this methodology to β-ketoesters, which were reacted with aromatic aldehydes and cyclic 1,2-diamines to provide the corresponding 1,4-diazepine derivatives in low to good yields (e56%) and complete relative diastereoselectivity.228 A possible mechanistic pathway is depicted in Scheme 134, involving the formation of an intermediate with imine and enamino ester functionalities 485, which could lead to the final product 484 via an intramolecular Mannichtype condensation.

Kita and co-workers described asymmetric three-component domino aminal formation/bromation reaction of cyclohexa-2,5-dienyl-1-methylaldehyde 476 with optically pure 1,2-di(4-methoxyphenyl)-1,2-diamine 477 and NBS. 226 This process provided the corresponding enantiopure tricyclic domino product 478 in 57% yield as a single stereoisomer, through discrimination of the two olefins of cyclohexa2,5-dienyl-1-methylaldehyde, as shown in Scheme 133. The utility of this methodology was illustrated by converting this enantiopure product into natural product (
)-γ-lycorane. A plausible mechanism is shown in Scheme 133. First, it involved the formation of bromonium ion 479 by attack of NBS to alkene, followed by cyclization of the nitrogen atom to the bromonium ion, affording intermediate 480. The aminal unit in 480 was quite easily oxidized in the presence of NBS to give the final dihydroimidazole 478 via intermediate 481. In 2008, Rodriguez and co-workers reported a diastereoselective synthesis of 1,4-diazepines on the basis of a BU

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Scheme 133. Synthesis of (
)-γ-Lycorane through Three-Component Domino Aminal Formation/Bromation Reaction

γ-amino-β-hydroxy amide 494 with good yields and high levels of diastereoselectivity of up to 86% de, as shown in Scheme 136.230 The authors have demonstrated that subsequent exposure of γ-amino-β-hydroxy amides to microwave irradiation and acidic conditions promoted a cyclization to form the corresponding γ-lactam 489 in high enantiomeric excesses of 87% ee (Scheme 136). Because a wide number of biologically active products include γ-lactam moieties, the importance of this novel methodology, allowing chiral highly substituted γ-lactams to be achieved, was demonstrated. 3.10.2.3. Multicomponent Reactions of Chiral Sulfoxides and Derivatives. A three-component reaction between sulfonylimidates 495, silyl glyoxylates 496, and chiral N-tert-butanesulfinyl aldimines 497 was developed by Yao and Lu in 2011.231 This process promoted the formation of two contiguous stereogenic centers, two C
C bonds, one C
N bond, and one O
Si bond, together with the cleavage of the chiral auxiliary, in one-pot. It afforded the corresponding chiral substituted cyclic sulfonylamidines 498 in good to high yields and diastereoselectivities of >90% de in all cases of substrates studied, combined with remarkable enantioselectivities, as shown in Scheme 137. The domino reaction was supposed to begin with the addition of the lithium aza-enolate of sulfonylimidate 495 to the silyl

3.10.2.2. Multicomponent Reactions of Chiral Amides. In 2007, Beller and co-workers reported the diastereoselective three-component reaction of (S)-methyl pyroglutamate 486 with aldehydes and dienophiles, such as N-methyl maleimide or maleic anhydride, which led to a range of chiral substituted 1-amido-2-cyclohexenes 487.229 As shown in Scheme 135, these bicyclic products were formed in moderate to good yields and as single diastereomers. A possible mechanism of this reaction is depicted in Scheme 135 in which the domino reaction began with the formation of 1-(N-acylamino)-1,3-butadienes 488 as key intermediates, which were generated through the condensation of aldehydes to amides. These intermediates were further trapped by dienophiles through a subsequent Diels
Alder cycloaddition. In another context, Scheidt and co-workers have developed a stereoselective synthesis of chiral, highly substituted β-hydroxy-γ-lactam 489 by using chiral β-silyloxy homoenolate 490 that could be accessed from (L)-phenylalaninolderived acetamide enolates of 491 and acylsilane 492. As shown in Scheme 136, the acylsilanes acted sequentially as an electrophilic/nucleophilic moiety in this process by undergoing a 1,2-silyl group migration (1,2-Brook rearrangement). The unconventional nucleophilic species 490 subsequently underwent addition to imine 493 to provide the BV

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Scheme 134. Three-Component Reaction of Chiral 1,2-Amines, β-Ketoamides, and Aromatic Aldehydes

Scheme 135. Three-Component Reaction of Chiral Amide, Aldehydes, and Dienophiles

BW

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Scheme 136. Three-Component Reaction of Chiral Amide, Acylsilane, and Imine

glyoxylate 496, which triggered a Brook rearrangement, providing a novel enolate 499. This enolate further underwent addition to chiral N-tert-butanesulfinyl aldimine 497, in which the imine participated as the second electrophile, providing intermediate 500. The anionic nitrogen-induced cyclization into 501 and subsequent desulfinylation by nucleophilic attack by the extruding ethoxide led to the final product 498. A novel family of chiral fluorinated 1,4-dihydropyridines have been generated by Fustero et al. on the basis of an asymmetric Hantzsch-type process, occurring between alkyl propiolates 502, fluorinated nitriles 503, and (R)-(+)-allyl p-tolyl sulfoxyde 504 as chiral reagent.232 The reaction began with the formation of enamino sulfoxides 505 by reaction of (R)-(+)-allyl p-tolyl sulfoxyde 504 through the γ-position with fluorinated nitriles 503. These enamino sulfoxides 505 subsequently underwent an aza-Michael addition with alkyl propiolates 502 to give the corresponding enolates 506, which then cyclized through an intramolecular Michael addition, as shown in Scheme 138. The reaction took place with complete selectivity, allowing the formation of a variety of enantiopure fluorinated 1,4-dihydropyridines 507 to be achieved as single stereoisomers in moderate to good yields. 3.10.2.4. Multicomponent Reactions of Other Chiral Reagents. The key step of a total synthesis of naturally occurring and biologically active (
)-dibromophakellstatin, which was reported by Lindel and co-workers, consisted of an asymmetric three-component imidazolidinone

annulation reaction of chiral tricycle enamide 508 with 2 equiv of EtO 2 CNHOTs in the presence of CaO. 233 As shown in Scheme 139, this domino process provided the corresponding tetracycle 509 in 50% yield as a single stereoisomer. This key enantiopure product was subsequently converted into the expected (
)-dibromophakellstatinin in 4 steps. In 2010, Barluenga et al. reported an enantioselective synthesis of 4-hydroxy-2-cyclohexenones 510 through a four-component reaction, occurring between aryl- and heteroarylcarbene chromium complexes 511, in situ-prepared lithium enolate of (S)-3-acetyl-4-benzyl-2-oxazolidinone 512, and 2 equiv of propargylic organomagnesium bromides 513. 234 This remarkable domino process afforded the corresponding almost enantiopure densely functionalized 2-cyclohexenones 510 containing two quaternary stereogenic centers at the α- and γ-positions. As shown in Scheme 140, these products were produced in moderate to high yields as single stereoisomers in all cases of substrates studied. The authors assumed that the process began with the initial addition of the imide lithium enolate 512 to the carbene carbon atom of the chromium complex 511, which led to the corresponding lithium alkylpentacarbonylchromate intermediate 514. A subsequent double addition of the organomagnesium derivative 513 to the exocyclic carbonyl group of the N-acyl-2-oxazolidinone moiety 512, which entailed an unprecedented removal of this chiral auxiliary group, proceeded regioselectively BX

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Scheme 137. Three-Component Reaction of Chiral N-Tertbutanesulfinyl Aldimines, Sulfonylimidate, and Silyl Glyoxylates

Scheme 138. Three-Component Reaction of (R)-(+)-Allyl p-Tolyl Sulfoxyde, Alkyl Propiolates, and Fluorinated Nitriles

Scheme 139. Synthesis of (
)-Dibromophakellstatin through Three-Component Imidazolidinone Annulation Reaction

incorporating two allenyl units and provided intermediate 515. Insertion of CO into C(sp 3 )
Cr σ bond of intermediate 515 afforded allenyl substituted lithium acyltetracarbonylchromate complex 516. A final intramolecular carbometalation reaction of the terminal CdC bond of one of the allene groups produced allylchromate intermediate 517, which was finally protonated to give the final product 510. Finally, Bella and co-workers have described a novel three-component domino reaction occurring between L -proline lithium salt 518, 2-cyclohexen-1-one 519, and aliphatic aldehydes, which afforded the corresponding chiral 4-alkylidene-2-cyclohexen-1-ones 520 with four stereogenic centers. 235 In all cases of aldehydes studied, the reaction gave a single stereoisomer with >98% de combined with moderate yields, as shown in Scheme 141.

To explain these results, the authors have proposed that the chiral lithium salt 518 reacted with aldehyde to give the corresponding iminium salt 521. This iminium ion gave the corresponding enamine 522, which deprotonated 2-cyclohexen-1-one 520, providing the formation of an activated diene 523. Then, the cycloaddition reaction of this diene with enamine occurred, affording the final bicyclic cycloadduct 520. BY

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Scheme 140. Four-Component Reaction of (S)-3-Acetyl-4benzyl-2-oxazolidinone Enolate, Carbene Chromium Complexes, and 2 Equiv of Propargylic Organomagnesium Bromides

Scheme 141. Three-Component Reaction of L-Proline Lithium Salt, Aliphatic Aldehydes, and 2-Cyclohexen-1-one

favorable manner by avoiding the use of costly and timeconsuming protection
deprotection processes, as well as purification procedures of intermediates. It must be noted that it was difficult to locate all the published examples of stereocontrolled domino reactions involving chiral auxiliaries or chiral reagents, because many are incorporated in total syntheses advertised under different keywords. The cases cited in this review have been selected to highlight the most promising applications of asymmetric domino reactions to organic synthesis.

4. CONCLUSION This review illustrates the power and diversity of asymmetric domino reactions based on the use of chiral substrates, which have quickly become a powerful, fascinating, and highly efficient tool in organic synthesis. The concept of domino sequences has allowed easily reaching high molecular complexity with very often excellent levels of stereocontrol with simple operational procedures, as well as advantages of savings in solvent, time, energy, and costs. The use of one-component, two-component, and multicomponent domino reactions in asymmetric synthesis is increasing constantly. Such single-step reactions allow the synthesis of a wide range of structurally diverse and complex chiral molecules from simple substrates in an economically

AUTHOR INFORMATION Corresponding Author

*Tel.: +33 4 91 28 27 65. E-mail: [email protected]. The authors declare no competing financial interest. BZ

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BIOGRAPHY

NAPH naphthyl NBS N-bromosuccinimide NF nonaflate NMO N-methylmorpholine-N-oxide NS nosyl NU nucleophile PHTH phthalimido PIN pinacol PY pyridine TBAB tetra-n-butylammonium bromide TBAF tetra-n-butylammonium fluoride TBAI tetra-n-butylammonium iodide TBAT tetrabutylammonium triphenyldifluorosilicate TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TEA triethylamine TES triethylsilyl TF trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TMP 2,2,6,6-tetramethylpiperidide TMS trimethylsilyl TOL tolyl TOSMIC (p-toluenesulfonyl)methylisocyanide TS 4-toluenesulfonyl (tosyl) XANTPHOS 4,5-bis(diphenylphosphino)-9,9dimethylxanthene

H
elene Pellissier carried out her Ph.D. under the supervision of Dr. G. Gil in Marseille (France) in 1987. The work was focused on the reactivity of isocyanides. In 1988, she entered the Centre National de la Recherche Scientifique as a researcher. After a postdoctoral period in Professor K. P. C. Vollhardt’s group at the University of California, Berkeley, she joined the group of Professor M. Santelli in Marseille in 1992, where she focused on the chemistry of BISTRO and its application to the development of novel, very short total syntheses of steroids starting from 1,3-butadiene and benzocyclobutenes.

ABBREVIATIONS ACAC acetylacetone ALLOC allyloxycarbonyl AR aryl BIPHEP 2,20 -bis(diphenylphosphino)-1,10 -biphenyl BIPHEPHOS 6,60 -[(3,30 -di-tert-butyl-5,50 -dimethoxy-1,10 -biphenyl-2,20 -diyl)bis(oxy)bis(dibenzo[d,f][1,3,2]dioxaphosphepin)] BN benzyl BOC tert-butoxycarbonyl BOM π-benzyloxymethyl BZ benzoyl COD cyclooctadiene CY cyclohexyl CBZ benzyloxycarbonyl CY cyclohexyl DBA (E,E)-dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene de diastereomeric excess DME dimethoxyethane DMF dimethylformamide DMSO dimethylsulfoxide DPPB 1,4-bis(diphenylphosphino)butane DPPF 1,10 -bis(diphenylphosphanyl)ferrocene ee enantiomeric excess FMOC 9-fluorenylmethoxycarbonyl HFIP hexafluoroisopropanol HMDS hexamethyldisilazide L ligand LA Lewis acid LDA lithium diisopropylamide MCPBA meta-chloroperbenzoic acid MES mesyl MOM methoxymethyl

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