Catalytic C–C Bond-Forming Multi-Component Cascade or Domino

Review pubs.acs.org/CR

Catalytic C−C Bond-Forming Multi-Component Cascade or Domino Reactions: Pushing the Boundaries of Complexity in Asymmetric Organocatalysis Chandra M. R. Volla, Iuliana Atodiresei, and Magnus Rueping* Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany 4.2. Michael/Henry/Michael/Aldol Condensation Sequences 4.3. Friedel−Crafts-Type/Michael/Michael/Aldol Condensation Sequences 4.4. Michael/Michael/Michael/Aldol Condensation Sequences 4.5. Hydrogenation/Michael/Michael/Aldol Condensation Sequences 4.6. Aza-Michael/Michael/Michael/Aldol Sequences 5. Conclusions Author Information Corresponding Author Notes Biographies References

CONTENTS 1. Introduction 2. Double Cascade Reactions 2.1. Michael/Aldol and Michael/Aldol Condensation Sequences 2.2. Michael/Henry Sequences 2.3. Michael/Michael Sequences 2.4. Michael/Alkylation Sequences 2.5. Miscellaneous Double Cascade Reactions 2.5.1. Michael/Morita−Baylis−Hillman Sequences 2.5.2. Michael/Knoevenagel Sequences 2.5.3. Michael/Wittig Sequences 2.5.4. Knoevenagel/Diels−Alder Sequences 2.5.5. Michael/Cyclization Sequences 2.5.6. Michael/Mannich Sequences 2.5.7. Mannich/Michael Sequences 2.5.8. Cationic Polycyclizations 2.5.9. Diels−Alder/Cyclization Sequences 2.5.10. Diels−Alder/Conjugate Addition Sequences 3. Triple Cascade Reactions 3.1. Michael/Michael/Aldol Condensation Sequences 3.2. Knoevenagel/Michael/Cyclization Sequences 3.3. Knoevenagel/Michael/Michael Sequences 3.4. Michael/Nitro-Mannich/Cyclization Sequences 3.5. Michael/Michael/Henry Sequences 4. Quadruple Cascade Reactions 4.1. Oxa-Michael/Michael/Michael/Aldol Condensation Sequences

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1. INTRODUCTION The construction of carbon−carbon bonds, along with the creation of stereogenic carbon centers, continues to be an appealing and demanding area of research, and processes in which compounds are synthesized in optically active form are of growing interest. This statement is best reflected by the steadily increasing number of publications devoted to the development of asymmetric synthetic routes for the synthesis of compounds with stereogenic carbon centers. In particular, asymmetric catalysis1−30 has surpassed the use of chiral auxiliaries31 for the preparation of enantiopure materials, as these systems avoid the lengthy and costly removal and recovery of chiral auxiliary reagents. Also, an efficient chiral catalyst can be used many times, in relatively small amounts, enabling the preparation of large quantities of optically pure products. In this context, in addition to processes catalyzed by metals1−4 and enzymes,5 organocatalyzed transformations6−30 revolutionized synthetic organic chemistry in the past two decades. New and highly enantioselective processes were developed using organocatalysts, expanding the scope of asymmetric organic synthesis. Furthermore, these methods utilize inexpensive and readily available organic compounds as catalysts. They are compatible with many different functional groups and provide high and predictable enantioselectivities for a wide range of substrates. As a whole, organocatalysis has become an important synthetic tool in the hands of organic chemists.7−30

X Z Z AA AA AA AB AB AC AC AC AC AF AG AG AG AH AH

Received: April 22, 2013

© XXXX American Chemical Society

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Scheme 1. Amine-Derived Catalysts Applied in Organocatalyzed Cascade Reactions

More recently, research has focused on the development of cascade32−43 and multicomponent44−48 reactions, particularly organocatalyzed reactions in which small organic molecules catalyze multiple chemical transformations in a one-pot, consecutive fashion. Nature uses this principle for the efficient construction of multiple bonds in the biosynthesis of many natural products with the aid of enzymes. In this regard, organocatalytic cascade reactions49−54 resemble natural biosynthetic processes that are highly chemo-, regio-, and stereoselective.55 According to Tietze, a domino reaction is a process in which two or more bond-forming events occur under the same reaction conditions based on the functionalities formed in the previous step.33b Fogg and dos Santos illustrated the nomenclature of one-pot reactions based on the number of mechanisms and catalysts required.56 Domino or cascade reactions constitute a powerful subgroup of the broader category of one-pot reactions. These transformations are atom-economical and avoid time-consuming protection/deprotection steps and isolation of intermediates. In addition, they are recognized as processes with minimal waste generation. In this way, cascade reactions fall under the category of green

chemical transformations. In contrast to classical multistep sequences, in the case of cascade reactions, numerous pathways are possible. These pathways can compete, leading to undesired routes; nevertheless, by careful selection of the catalyst, exceptional levels of control can be achieved, as only a few of these possible pathways are facilitated, resulting in high selectivities for the overall transformation. Organocatalysis provides an alternative to metal- and enzyme-catalyzed cascade reactions for creating molecular complexity from simple starting materials in an expedient manner. Organocatalytic cascade reactions are distinguished especially by the fact that a single organocatalyst activates relatively unreactive organic molecules such as carbonyl compounds. Organocatalytic cascade or domino reactions were found to be an efficient synthetic tool for the synthesis of chiral cyclic derivatives. However, for the development of successful asymmetric organocatalytic cascade sequences, many crucial issues have to be addressed. The compatibility of different reagents is one of the main concerns. Also, the presence of these stoichiometric reagents can either erode or affect the overall stereoselectivity induced by the catalyst. B

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Scheme 2. (a) Cinchona Alkaloid-Derived Organocatalysts and (b) Chiral BINOL−Phosphoric Acid

highly selective organocatalyzed methodologies that involve the stereoselective construction of at least two carbon−carbon bonds. Transformations in which a carbon−heteroatom bond is formed, in addition to at least two carbon−carbon bonds, are also included in this review, in which we cover the literature through the end of 2012. The cascades illustrated thereby are organized according to the number of reactions involved in the process, and the newly formed bonds are bold and highlighted in red. Many excellent diastereoselective transformations and asymmetric cascade reactions in which a single carbon−carbon bond is constructed along with additional carbon−heteroatom bonds or in which two different carbon−heteroatom bonds are formed51,54 are not addressed in the present review. These transformations have, nevertheless, been compiled in numerous excellent reviews that can be consulted by the readers to broaden their expertise in this challenging area. Asymmetric organocatalytic concerted cycloadditions have been reviewed recently by Moyano and Rios,27 Pellissier,28 and Merino et al.29 and are not covered in the present review.

Organocatalytic cascade reactions in which a single organocatalyst is used for several transformations should be clearly distinguished from organomulticatalysis,30 in which multiple organocatalysts are used to catalyze the reaction sequence. In contrast to organomulticatalysis, organocatalytic cascade reactions take advantage of the multifunctional nature of the catalyst. Efforts have been made by various research groups to develop new and improved organocatalysts useful for cascade or domino reactions. For a better overview, the organocatalysts employed in the domino reactions presented in this review are summarized in Schemes 1 and 2. Scheme 1 provides an outline of amine-derived catalysts 1−24 applied frequently in organocatalyzed cascade reactions. The structures of the most common cinchona alkaloid-derived organocatalysts 25−39 and chiral 1,1′-bi-2-naphthol (BINOL)−phosphoric acid 40 are depicted in Scheme 2. It should be noted that the chemical community has recognized the great potential of asymmetric organocatalyzed domino reactions, and several excellent general reviews covering developments in this area have been published.27,49−54 The goal of the present review is to provide an overview of C

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the field of asymmetric organocatalyzed domino reactions saw breathtaking growth with developments in two directions, namely, new catalysts and novel reaction sequences. More recently, additional Wieland−Miescher ketone analogues74 43b−d (R = Et, n-Pr, n-Bu) were also easily prepared using proline catalysis.75 Another one-pot Michael addition/intramolecular aldol reaction was described by Swaminathan and coworkers (Scheme 4b). In this case, the L-proline-catalyzed reaction between methyl vinyl ketone (41) and 2-methylcyclopentane-1,3-dione (44) afforded ketol 45, which was subjected to dehydration to give the Wieland−Miescher ketone 46 in up to 70% yield and >76% ee (>98% ee after recrystallization).76 Regarding the mechanism of the L-proline-catalyzed Robinson annulation, in a first step, L-proline activates both reaction partners for the first carbon−carbon bond-forming reaction. As depicted in Scheme 5, methyl vinyl ketone (41) is

2. DOUBLE CASCADE REACTIONS The field of double cascade reactions is dominated by the use of secondary amines as catalysts because of their ability to accommodate different activation modes for nucleophiles as well as electrophiles through enamine- and iminium-ion catalysis, respectively (Scheme 3).57−65 By combining these Scheme 3. Main Activation Modes in Aminocatalysis

two different activation modes in one protocol, the transformation of simple starting materials into complex architectures is facilitated. Notably, the structure of the catalysts allows fine-tuning of their electronic and steric properties, so that the most suitable structure for a given reaction can be obtained. Accordingly, considerable progress has been achieved, and various classes of cyclic compounds relevant for the synthesis of natural products and biologically active compounds can easily be accessed in an enantioselective manner. Moreover, intensive research has led to the design of different catalytic systems and the disclosure of other activation modes that have broadened the application field of organocatalyzed domino reactions.

Scheme 5. Proposed Mechanism for Organocatalyzed Robinson Annulation

2.1. Michael/Aldol and Michael/Aldol Condensation Sequences

Although proline and its derivatives were used as catalysts for the enantioselective Michael and aldol reactions in the early 1970s,66−68 their use as promoters for domino reactions was first realized three decades later.69,70 Based on the principle that the antibody aldolase Ab38C2 catalyzes both steps of a Robinson annulation reaction,71 Barbas and co-workers studied several chiral secondary amines as catalysts for the annulation sequence.69,72 With methyl vinyl ketone (41) and 2methylcyclohexane-1,3-dione (42a: R = Me) as substrates, the condensation product 43a (R = Me) was isolated in 49% yield and 76% enantiomeric excess (ee) when the reaction was performed in the presence of L-proline73 (1) (Scheme 4a). Investigation of the structure/catalytic activity relationship showed that the pyrrolidine-type secondary amine and the carboxylate functionality are both important for catalyzing the two steps of the Robinson annulation. After these initial results,

activated through the formation of an iminium ion and 2alkylcyclohexane-1,3-dione (42) through hydrogen bonding, enabling the Michael addition, which gives rise to intermediate 50. Isomerization of the resulting enamine intermediate 50 provides enamine 51, which undergoes an intramolecular aldol reaction through Zimmerman−Traxler-type transition state 52, as proposed by Houk and co-workers.77 Dehydration of

Scheme 4. Organocatalyzed Robinson Annulation

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in most solvents giving the corresponding Michael/aldol product 57a (R1 = Ph, R2 = Bn, R3 = Ph, R4 = H) in excellent enantioselectivities, yields were strongly dependent on the solvent. Protic solvents gave the best results in terms of both yield and selectivity. Interestingly, no chromatography was required, and the optically active cyclohexanone 57a was obtained as a single diastereomer by simple filtration and washing. In general, both aromatic- and heteroaromatic-substituted α,β-unsaturated ketones 55/56 were successfully reacted with aromatic β-ketoesters to afford the corresponding cyclohexanones 57/58 in good yields (up to 85%) and excellent enantioselectivities (83−99% ee). The whole sequence involves the formation of up to four new stereogenic centers. The initial Michael reaction led to a mixture of syn and anti diastereomers A/B, which are in equilibrium with each other (Scheme 7). However, the final Michael/aldol adduct was isolated as a single diastereomer. This has been explained by the assumption that, under the reaction conditions, only syn isomer A undergoes an intramolecular aldol reaction to give the more stable cyclohexanone with all large substituents in equatorial positions. The potential of this domino Michael/aldol reaction was further illustrated by the functionalization of adduct 57a to give access to several classes of compounds such as cyclohexenone 59 and cyclohexanediol 60, as well as ε- and γ-lactones 61 and 62, respectively (Scheme 8). Very recently, readily available chiral primary aminoalcohols and chiral diamine catalysts were evaluated, in the presence of various achiral acid cocatalysts, in the domino Michael/aldol reaction of benzyl benzoylacetate (54a: R1 = Ph, R2 = Bn) and benzylideneacetone (55a: R3 = Ph, R4 = H) and afforded the desired cyclohexanone product 57a or ent-57a in low to good yields and good selectivities (28−77% yield and 56−86% ee for 57a; 55−71% yield and 63−80% ee for ent-57a).81b Theoretical calculations were also performed to explain the stereochemical outcome of the Michael addition product. In addition to β-ketoesters, Jørgensen and co-workers reported the use of other Michael donors, such as 1,3-diketones and β-ketosulfones, for the Michael/aldol sequence (Scheme 9).82,83 With the same catalyst 22, halogenated solvents proved to be superior, providing the products in good yields and enantioselectivities. Different aromatic- and heteroaromaticsubstituted α,β-unsaturated ketones 55/56 were reacted with 2phenylsulfonylacetophenone (63) and dibenzoylmethane (65a) to give the corresponding optically active cyclohexanones 64 and 66, respectively. In the same manner as above, the adducts 64 and 66 were isolated as single diastereomers in analytically pure form after filtration. Aliphatic-substituted diketones and ketosulfones were found to react sluggishly, and only trace amounts of products were obtained. The proposed reaction mechanism implies three different roles for the imidazolidinone catalyst 22: activator of both the Michael acceptor and donor by iminium-ion formation and

intermediate 53 followed by hydrolysis affords the bicyclic product 43 and regenerates the catalyst. Various transition states have been proposed in the literature (Scheme 6), to Scheme 6. Proposed Transition States for the Intramolecular Aldol Reaction

explain the stereoselectivity of the intramolecular aldol reaction with 2-methyl-2-(3′-oxobutyl)-cyclopentan-1,3-dione (47) as the substrate. Whereas Hajos and Parrish proposed transition state A in which L-proline activates one of the two enantiotopic carbonyl acceptor groups by forming a carbinol amine,67 Agami et al. proposed transition state B in which two proline molecules are involved in the activation through enamine formation and hydrogen bonding.78 In their study on the intramolecular aldol reaction, Swaminathan and co-workers suggested that this reaction is a heterogeneous catalyzed reaction, taking place at the surface of crystalline proline.79 Based on extensive theoretical investigations, Houk and coworkers proposed Zimmerman−Traxler-type transition state D, which accounts for the selectivity of the reaction.77,80 The first highly general enantio- and diastereoselective organocatalytic domino Michael/aldol reaction was reported by Jørgensen and co-workers.81a Optically active cyclohexanone derivatives 57/58 with up to four stereogenic centers were obtained in excellent enantioselectivities by the reaction of βketoesters 54 and α,β-unsaturated ketones 55/56 (Scheme 7). Scheme 7. Michael/Aldol Cascade Reaction According to Jørgensen and Co-workers

The best results for the reaction of benzyl benzoylacetate (54a: R1 = Ph, R2 = Bn) and benzylideneacetone (55a: R3 = Ph, R4 = H) were observed in the presence of phenylalanine-derived imidazolidinone catalyst 22. Although the reaction proceeded

Scheme 8. Functionalization of the Michael/Aldol Cascade Reaction Products

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Scheme 9. Michael/Aldol Cascade Reaction with Different Michael Donors

reaction parameters showed that the enantioselectivity was better at higher temperatures and lower catalyst loadings. Use of 10 mol % tetramethylsilane- (TMS-) protected diphenylprolinol (20a)87 in chloroform at 45 °C was found to give a high level of stereocontrol for the reaction. Interestingly, use of acetonitrile as the solvent gave the opposite enantiomer with high diastereoselectivity and lower enantioselectivity. Under the optimized conditions, differently substituted 2-cyanocinnamic esters 69 bearing aromatic and heteroaromatic residues reacted with glutaraldehyde (68) and gave the corresponding cyclohexane derivatives 70 having cyano, formyl, hydroxy, and ester functionalities as a mixture of diastereomers. However, the minor isomer could be easily separated from the reaction mixture by column chromatography. In addition, use of microwave irradiation slightly improved the diastereoselectivity. Very recently, other groups were also interested in exploiting the ability of glutaraldehyde (68) in Michael/aldol cascade reactions using isatin-derived alkenes 71 as Michael acceptors.88 A series of functionalized spirocyclohexane oxindoles 72 with three stereogenic centers were prepared using 10 mol % TMSprotected diphenylprolinol catalyst ent-20a in dichloromethane at room temperature (Scheme 11b). The protocol can also be run on the gram scale without affecting either the yield or the selectivity. An enantioselective formal [3 + 3] annulation reaction cascade was described by Tang and co-workers.89 The Michael/ aldol cascade involves the reaction of cyclic ketones 73 and enones 74 to give bicyclic compounds 75 having four stereogenic centers (Scheme 12). Notably, the reaction

deprotonation, respectively, and base for the intramolecular aldol reaction. Alternatively, the third step might involve an enamine mechanism that is responsible for the high diastereoselectivity obtained in the intramolecular aldol reaction. In 2006, a more elaborated reaction protocol was developed.84 In contrast to the above-mentioned cases, βketoesters substituted with a chlorine atom at the γ-position act as double Michael donors. They can react with Michael acceptors such as α,β-unsaturated aldehydes in the presence of secondary amines to afford Michael/aldol adducts. This principle was applied to a one-pot Michael/aldol/SN2 reaction to generate optically active epoxy cyclohexanones. An enantioselective protocol involving acyclic 1,3-diketones 65 and methyl vinyl ketone (41) using secondary amines as catalysts for the synthesis of 3-hydroxycyclohexanones 67 (Scheme 10) was reported by Gryko.85 Initial results showed Scheme 10. Michael/Aldol Cascade Reaction of 1,3Diketones with Methyl Vinyl Ketone

that L-proline (1) catalyzes the reaction between dibenzoylmethane (65a: R1 = R2 = Ph) and methyl vinyl ketone (41) in different solvents with moderate to good selectivities. Subsequently, several 1,3-diketones took part in the reaction with methyl vinyl ketone to give the corresponding products 67 in good yields and moderate selectivities. In 2009, Córdova and co-workers developed a highly enantioselective domino Michael/aldol sequence for the synthesis of cyclohexane derivatives 70 with an all-carbon quaternary stereocenter (Scheme 11a).86 Screening of several

Scheme 12. Michael/Aldol Cascade Reaction According to Tang and Co-workers

Scheme 11. Michael/Aldol Cascade Reaction with Glutaraldehyde generates two new C−C bonds and four new stereogenic centers. Several pyrrolidine derivatives were screened for the reaction of cyclohexanone (73a: X = CH2) and (E)-methyl-4phenyl-2-oxabut-3-enoate (74a: R1 = Me, R2 = Ph), and it was found that pyrrolidine 4 having a trifluoromethanesulfonamide group gave the best enantiocontrol at room temperature (89% conversion, 90% ee). Acid additives were found to have a positive influence on the yield without affecting the enantiocontrol. For example, 20 mol % 4-methoxybenzoic acid (76) improved the conversion to 99%, whereas the enantioselectivity remained unchanged. Under these optimized conditions, cyclohexanone 73a (X = CH2) reacted with β-arylsubstituted enones 74 to provide the bicyclic products 75 in F

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good yields and high enantioselectivities (56−90% yield, 87− 94% ee). The enantioselectivity varied only slightly with the substituents on the enone benzene ring. Other six-memberedring ketones, such as tetrahydropyran-4-one (73b: X = O) and 1-methylpiperidine-4-one (73c: X = NMe), were also tested in the domino reaction, providing access to different classes of heterocyclic compounds with good enantioselectivities (90% and 80% ee, respectively). Cyclopentanone and acetone were found to be unsuitable substrates, as they provided the corresponding products in lower ee’s although in excellent yields. The authors proposed a bifunctional mode of activation for the sulfonamide catalyst 4, which involves the activation of both ketone and enone substrates by formation of an enamine and a hydrogen bond, respectively. Rueping and co-workers also reported an asymmetric protocol for the synthesis of polyfunctionalized bicyclic derivatives 79.90 They investigated the reaction of 1,2cyclohexanedione (77) with α,β-unsaturated aldehydes 78 in the presence of catalytic amounts of TMS-protected diphenylprolinol (20a) to gain access to bicyclo[3.2.1]octanes 79 (Scheme 13) by an iminium/enamine activation path

Scheme 15. Proposed Mechanism for the Michael/Aldol Cascade Reaction

Enders and co-workers also exploited the use of α,βunsaturated aldehydes in asymmetric domino nitro-Michael/ aldol condensation sequences (Scheme 16).91a Chiral cyclohexenes 88 were synthesized by the reaction of γ-nitroketones 87 and α,β-unsaturated aldehydes 78 in the presence of TMSprotected diphenylprolinol (20a).87 Differently substituted aromatic and heteroaromatic enals 78 reacted under the optimized reaction conditions (20 mol % 20a, 20 mol % benzoic acid, toluene, 9 °C) to give cyclohexenes 88 in good to high enantioselectivities (67−96% ee). Nevertheless, the enantioselectivities could be improved to >99% by single recrystallization. Aliphatic enals afforded the products in very low yields. Later, the sequence was extended to other nucleophiles such as 2-(nitromethyl)benzaldehyde (89).91b A wide range of aliphatic, aromatic, and heteroaromatic enals reacted under the optimized conditions to give 3,4dihydronaphthalene derivatives 90 in moderate to good yields and good to excellent enantio- and diastereoselectivities [from 91 to >99% ee, >98% diastereomeric excess (de)]. For the reaction mechanism, it was assumed that the catalyst, TMSprotected diphenylprolinol (20a), activates the enal 78 through the formation of iminium ion 84 (Scheme 17). Michael addition of the nitroalkane to the iminium ion generates enamine 91, which can undergo intramolecular aldol addition and subsequent hydrolysis to give the corresponding alcohol and regenerate the catalyst. The alcohol undergoes dehydration to afford the final cyclohexene and 3,4-dihydronaphthalene derivatives 88 and 90.92 Synthetically important chiral bicyclic decalin structures 95 were prepared by Chen and co-workers following a similar domino nitro-Michael/aldol reaction (Scheme 18).93 They employed chiral γ-nitroketones 94 in reaction with α,βunsaturated aldehydes 78 in the presence of TMS-protected diphenylprolinol (20a) to obtain functionalized bicyclo[4.4.0]decalins 95 in excellent diastereo- and enantioselectivities [up to 99:1 diastereomeric ratio (dr) and >99% ee]. Acid additives enhanced the diastereoselectivity maintaining the same enantioselectivity, whereas basic additives improved the chemical yield with a decrease in enantioselectivity. Finally, a combination of acid and base was found to be optimal for a high yield and selectivity. Importantly, in the presence of stoichiometric amounts of base, only trace amounts of the Michael/aldol adducts were obtained with low selectivities (56% vs 90% de and 65% vs >99% ee). This clearly rules out

Scheme 13. Michael/Aldol Cascade Reaction According to Rueping and Co-workers

(Scheme 15). Protic solvents were found to promote both the reaction rate and the enantiocontrol. Under the optimized conditions, a wide range of aromatic α,β-unsaturated aldehydes having both electron-donating and electron-withdrawing substituents were successfully used. 2-Heptenal as an aliphatic aldehyde also reacted with 1,2-cyclohexanedione to give the corresponding derivative with good selectivity, although in lower yield (44% yield, 98% ee). The bicyclic compound 79a (R = Ph) derived from 78a (R = Ph) was subsequently converted into either diol 80 or triol 81 by selective reduction, which was completely stereoselective in the case of triol. Furthermore, 79a (R = Ph) was easily transformed into other synthetically useful chiral building blocks such as functionalized tetrahydrochroman 82 and cycloheptanone 83 (Scheme 14). Scheme 14. Functionalization of the Michael/Aldol Cascade Reaction Products

Regarding the mechanism of the domino Michael/aldol reaction, diphenylprolinol ether 20a reacts with the α,βunsaturated aldehyde 78 to generate iminium ion 84. Michael addition of the tautomeric structure of 1,2-cyclohexanedione to iminium ion gives adduct 85, which undergoes an intramolecular aldol reaction to give intermediate 86. Hydrolysis gives the bicyclic product 79 and regenerates the catalyst (Scheme 15). G

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Scheme 16. Nitro-Michael/Aldol Condensation Cascade Reaction According to Enders and Co-workers

nitroketones and enals, only catalyst 20a showed good reactivity in toluene as the solvent using acetic acid as an additive, and the products were isolated in moderate to good yields. Cyclopentenes 97 having the R1 and R2 substituents trans to the nitro group were isolated, implying that, under the reaction conditions, the base-sensitive aromatic-derived 2-alkyl3-nitroalkanone 96 undergoes kinetic resolution. This hypothesis is further supported by the fact that the recovered excess of β-nitroketone 96 was optically active. To circumvent the problem of catalyst inactivation, the catalyst was added in several portions during the reaction, leading to improved yields. It is noteworthy that the β-nitroketones 96 were prepared by intermolecular Stetter reaction of aromatic aldehydes and nitroalkenes. Later, the same group demonstrated the use of heteroaromatic-substituted β-nitroketones 96 (R3 = 2-pyridinyl, 2-quinolinyl, 2-furanyl) instead of aromatic β-nitroketones. However, in this case, Michael/aldol cascade adducts 98 were isolated.95 In the presence of excess acetic acid and a more polar solvent, fully substituted cyclopentanes 98 bearing a quaternary carbon and five contiguous stereogenic centers were achieved. The authors proposed that intramolecular H-bonding between the heteroaromatic group and the alcohol is responsible for the stability of the aldol product 98. Interestingly, in contrast to cyclopentenes 97, products 98 bearing the opposite configuration at the stereogenic center resulting from the kinetic asymmetric transformation were observed. Thus, derivatives 98 bearing the substituents at the 2and 3-positions in a cis relation were observed. Cyclohexenedicarbaldehydes 100 were obtained in good yields (58−69%) and excellent enantioselectivities (89−99% ee) by the reaction of various aromatic enals 78 (R1 = Aryl) with glutaraldehyde (68) and 5-oxohexanal (99) as Michael donors (Scheme 20).96 The reaction of glutaraldehyde (68) and 5-oxohexanal (99) with the furanyl derivative (78b: R1 = 2furanyl) afforded the products in lower yields (55% and 53%, respectively) and lower selectivities (74% and 92% ee, respectively). Carefully designed imidazole derivatives 101 were employed by Ye and co-workers as substrates in a one-pot domino Michael/aldol reaction with α,β-unsaturated aldehydes 78

Scheme 17. Proposed Mechanism for the Nitro-Michael/ Aldol Condensation Cascade Reaction

Scheme 18. Synthesis of the Chiral Bicylo[4.4.0]decalin System According to Chen and Co-workers

chirality transfer from the chiral Michael donor and supports the participation of the chiral catalyst in iminium-ion activation. Under similar conditions, Hong and co-workers employed βnitroketones instead of γ-nitroketones and obtained functionalized cyclopentenes 97 in moderate yields but with excellent selectivities (Scheme 19).94 In a comparison of several chiral amine catalysts for the Michael/aldol cascade cyclization of βScheme 19. Synthesis of Cyclopentenes and Cyclopentanes

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temperature provided the spirocyclic derivatives 105 in high to excellent yields and selectivities for both aromatic- and heteroaromatic-substituted enones (70−99% yield, 83−96% ee). Functionalized chiral cyclopentenes were successfully prepared using a Michael/aldol-condensation cascade (Scheme 23).99 Dimethyl 2-oxoethylmalonate (106) served as a Michael

Scheme 20. Synthesis of Cyclohexenedicarbaldehydes by a Michael/Aldol Condensation Reaction

Scheme 23. Synthesis of Cyclopentanecarbaldehydes by a Michael/Aldol Condensation Reaction

(Scheme 21).97 Although the imidazole derivative 101 has two nucleophilic sites, the carbon atom bearing the keto group was Scheme 21. Michael/Aldol Cascade Reaction with Imidazole Derivatives

donor and as a latent electrophile for the secondary-aminecatalyzed cascade reaction with α,β-unsaturated aldehydes 78. The main challenge for this iminium/enamine cascade was that the aldehyde groups of both substrates 78 and 106 could react with the diarylprolinol silyl ether catalyst, leading to a variety of undesired transformations. Sterically hindered diphenylprolinol triethylsilyl (TES) ether (21a) was used as a catalyst to minimize the possible undesired side reactions. The use of NaOAc as a base greatly improved both the yield and selectivity. These optimized conditions were applied to the reaction of 106 with various aromatic and heteroaromatic enals 78 to obtain the products 107 in good yields (63−89%) and excellent enantioselectivities (91−97% ee). In contrast, almost no reaction occurred with less reactive aliphatic enals. A highly enantioselective method for the synthesis of functionalized cyclohexenones was devised by Zhao and coworkers utilizing a Michael/aldol-condensation cascade reaction (Scheme 24).100 The catalytic system consisting of 20 mol

more acidic than the carbon atom of the imidazole ring. The first step consists of the Michael addition of the nucleophile to the iminium ion generated by the reaction of the unsaturated aldehyde with the catalyst. In the second step, the imidazole ring acts as the enamine and undergoes aldol reaction with the aldehyde to generate the final assembly. The final imidazole product 102a (R1 = R2 = R4 = Ph, R3 = Me), which has three newly formed stereogenic centers, was obtained with good enantioselectivity (95% ee) but in low yield (54% conversion) using 20 mol % catalyst 20a. Acid additives have a profound effect on the reactivity. Using 20 mol % 2-nitrobenzoic acid 103a, the product 102a was formed with higher enantiocontrol and yield (98% ee, >99% conversion). Aromatic aldehydes with different substitution patterns undergo Michael/aldol reaction to afford products 102 in good yields (76−95%) and excellent enantioselectivities (98−99% ee). In contrast, aliphaticsubstituted aldehydes provided the corresponding products in moderate yields (65−67%) and good to high ee’s (87−95% ee). Most Michael/aldol condensation double cascade reactions involve an aldehyde−ketone aldol reaction. Examples for asymmetric ketone−ketone aldol reactions are relatively scarce in organocatalysis. This is due to the lower reactivity of ketones as electrophiles in comparison to aldehydes. Wang and coworkers demonstrated the application of primary amines as excellent activators in asymmetric domino Michael/ketone− aldol condensation reaction for the synthesis of spirocyclic oxindoles 105 by the reaction of 104 and enones 55 (Scheme 22).98 9-Amino-9-deoxy-epi-cinchonine (27, 20 mol %) and 40 mol % trifluoroacetic acid (TFA) in 1,4-dioxane at room

Scheme 24. Chiral Cyclohexenones through a Michael/Aldol Condensation Cascade Reaction

Scheme 22. Michael/Ketone Aldol Condensation Reaction % diamine 9 having both primary and secondary amine groups and 20 mol % N-Boc-D-phenylglycine (109) was found to be very efficient for catalyzing the cascade reaction between different β-ketoesters 54 and enones 55. Both aromatic enones having different substituents on the ring and heteroaromatic enones performed well to generate the cyclohexenone skeleton 108 with excellent enantioselectivities but moderate diasterI

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isomerization yields intermediate C. After the intramolecular Mannich-type addition, the resulting adduct D will undergo hydrolysis and elimination to form the desired cyclohexenone 113. This hypothesis was supported by the isolation of bicyclo[2.2.2]octane derivative 115, which cannot undergo elimination, when cyclohexenone 114 was used instead of the acyclic enone 55. Application of Michael/aldol cascade reaction to more complex motifs was described by Barbas and co-workers (Scheme 27a).106 The protocol deals with the synthesis of

eoselectivities. Fluorinated cyclohexenones 111 having a fluorinated quaternary stereogenic center were also prepared using a similar methodology employing α-fluoro-β-ketoesters 110 instead of β-ketoesters 54.101 A Michael/aldol-condensation reaction for the synthesis of enantiomerically pure cyclohexenones 113 was also described by Carter and co-workers (Scheme 25).102,103 They studied the Scheme 25. Cyclohexenones through a Domino Michael/ Aldol Condensation Reaction

Scheme 27. Synthesis of Spirooxindole Derivatives

sophisticated bis-spirooxindole moieties having four stereogenic centers, three of which are quaternary. Cinchona alkaloid catalyst 39 having thiourea and tertiary and primary amine functionalities catalyzed the domino Michael/aldol reaction between 3-substituted oxindoles 116 and methyleneindolinones 117 to give the corresponding domino products 118. High levels of diastereo- and enantioselectivities were achieved using a catalyst having an S-binapthyl unit in dichloromethane at room temperature. Wide ranges of both aromatic and heteroaromatic substituents on the methyleneindolinone unit were compatible under the reaction conditions. Interestingly, applying the catalyst with the same S-binaphthyl unit and opposite configuration at the thiourea and tertiary amine groups gave the opposite enantiomer ent-118 with excellent selectivity. As proposed by the authors, a dual activation model, in which the thiourea unit activates the 3-substitued oxindole by multiple H-bond interactions and the primary amine coordinates the carbonyl group of methyleneindolinone, might be responsible for the high selectivity of the reaction. Subsequently, they developed another strategy for preparing spirooxindole derivatives 120 employing an iminium/enamine activation mode (Scheme 27b).107 The cascade was catalyzed by the TMS-protected diphenylprolinol (20a) and consists of the reaction of 3-substituted oxindoles 119 and α,β-unsaturated aldehydes 78. Both alkyl- and aryl-substituted enals 78 were well tolerated under the reaction conditions. When prop-2-enal was used (78c: R4 = H), the product was isolated in 96% yield but with considerably lower enantioselectivity (23% ee).

use of α,α-disubstituted aldehydes 112 as Michael donors in reaction with enones for the preparation of cyclohexenones having an all-carbon quaternary center. Proline aryl sulfonamide catalyst 3a bearing a lipophilic side arm was found to be the optimal catalyst. Interestingly, the reaction required the addition of 1.0 equiv of benzyl amine additive, the absence of which leads to no reaction. In contrast to most organocatalyzed transformations, the reaction needs addition of molecular sieves for improved yields and selectivities. Accordingly, cyclohexenone derivatives 113 bearing different functionalized or unfunctionalized substituents have been obtained.104,105 It is believed that the chiral catalyst 3a activates the enones by forming an iminium ion and the achiral amine activates the aldehyde toward Michael addition by forming an enamine (Scheme 26). Michael addition with subsequent enamine Scheme 26. Proposed Mechanism for the Domino Michael/ Aldol Condensation Reaction

2.2. Michael/Henry Sequences

Diarylprolinol silyl ethers were reported independently by Hayashi et al. and Jørgensen and co-workers as useful organocatalysts for domino Michael/Henry reactions.108−110 Hayashi and co-workers used commercially available aqueous 2,6-dihydroxytetrahydropyran solution as a surrogate for J

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pentane-1,5-dial (68), which reacted with trans-β-nitrostyrene 121a (R = Ph) in the presence of 10 mol % TMS-protected diphenylprolinol (20a) (Scheme 28).108 The reaction gen-

Scheme 30. Proposed Mechanism for the Domino Michael/ Henry Reaction

Scheme 28. Domino Michael/Henry Reactions

erated four new stereogenic centers, two in each of the carbon− carbon bond-forming step. Although the cyclohexane product was isolated as a mixture of four diastereomers, the major diastereomer was obtained in good yield and excellent enantiopurity (88% yield, 99% ee). Furthermore, the diastereomeric ratio was highly dependent on the solvent, with tetrahydrofuran (THF) providing the best product ratio. The reaction can also be performed on a large scale with lower catalyst loading (2 mol %) to obtain the product 122a (R = Ph) in 67% yield and 99% ee. The rate of the reaction was greatly influenced by the substituents on the aromatic ring of the nitroolefin: Electron-withdrawing groups accelerated the reaction, whereas electron-donating groups showed the opposite effect. However, the observed enantioselectivity was independent of the substituents on the aromatic ring. More importantly, the major diastereomer was subjected to different isomerization conditions to obtain access to complete formation of other diastereomers in good enantioselectivities. Whereas, under weak acidic conditions, the major isomer 122a turns into more stable diastereomer 123a, which has the formyl group in an equatorial position, under basic conditions, 122a transforms into 124a, which has all substituents in equatorial positions (Scheme 29). Deprotonation/protonation and retroHenry/Henry reaction sequences were suggested for the isomerization under basic conditions.

% benzoic acid as an additive, and in contrast to Hayashi et al.’s protocol, 123 was the major diastereomer. The application of catalyst 20d in the double cascade was illustrated using different aromatic- or heteroaromatic-substituted nitroolefins 121 and 1,5-pentanedial to prepare functionalized cyclohexanes in good yields and excellent enantioselectivities in aqueous i-propanol (64−85% yield, 98−99% ee). In addition, the catalyst can be recycled up to four times to achieve comparable results (79− 82% yield, 98% ee) and up to seven times to obtain products in lower yields with good ee’s (40−82% yield, 95−98% ee). Jørgensen and co-workers designed an elegant approach for the synthesis of highly substituted optically active cyclohexanols 130 by an intermolecular reaction between 1,3-dinitroalkanes 129 and α,β-unsaturated aldehydes 78 catalyzed by prolinol ethers (Scheme 31).110 They investigated the reaction between Scheme 31. Domino Michael/Henry Reaction According to Jørgensen and Co-workers

Scheme 29. Isomeric Products in the Domino Michael/ Henry Reaction

2-pentenal (78d: R1 = Et) and 1-(1,3-dinitropropan-2yl)benzene (129a: R2 = Ph) in the presence of 20 mol % silyl-protected prolinol ether 20c to obtain the pentasubstituted cyclohexane 130a (R1 = Et, R2 = Ph). The reaction was less influenced by the solvent but dependent on the amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) used in the reaction. Using 20 mol % TMS-protected prolinol 20c and 10 mol % DABCO in dichloromethane, the major diastereomer was isolated in moderate yield and good enantioselectivity (45% yield, 90% ee). Remarkably, the reaction generates five new stereogenic centers in one step. Interestingly, when the unprotected prolinol was employed as the catalyst, the opposite enantiomer was obtained. The authors rationalized that the opposite enantioselectivity might be due to hydrogen-bonding interactions between the free OH group of the catalyst and the dinitro compound 129. Under the optimized conditions, a wide range of β-alkyl-substituted unsaturated aldehydes reacted with

The authors proposed that the catalyst activates the Michael donor by enamine formation, which reacts with the nitroalkene to generate the zwitterions 127 with syn selectivity (Scheme 30). An intramolecular Henry reaction with the other carbonyl group provides the intermediate 128. This is hydrolyzed under the reaction conditions to give the product and the catalyst to continue the reaction. Consequently, the asymmetric domino Michael/Henry reaction of 1,5-pentanedial and nitroolefins was investigated by Ni and co-workers in aqueous solvents using the watersoluble and recyclable organocatalyst 20d (Scheme 28).111 Use of water as a safe, economical, nontoxic, and environmentally benign solvent in organocatalysis has been gaining more and more prominence in recent years. The reaction requires 60 mol K

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the dinitro nucleophiles to form cyclohexane products 130 with moderate diastereoselectivity and good enantioselectivity. The enantioselectivity increases with increasing steric bulk of the alkyl substituent. The major diastereomer in all cases can be separated by column chromatography. Both aromatic- and heteroaromatic-substituted dinitro compounds are compatible for the reaction with unsaturated aldehydes. Although the electronic and steric properties of the nucleophile did not affect the enantioselectivity, the diastereoselectivity was slightly influenced in favor of the major isomer. In contrast to Hayashi et al.’s protocol, the reaction was initiated by iminium-ion activation of the α,β-unsaturated aldehyde (Scheme 32). The

Scheme 33. Cinchona Alkaloid-Catalyzed Domino Michael/ Henry Reactions

Scheme 32. Proposed Mechanism for the Domino Michael/ Henry Reaction

activates the nucleophile by deprotonation has been proposed for this Michael/Henry cascade reaction (Scheme 34A). After the initial Michael addition, the carbanion generated attacks the Si face of the keto group to afford the final cyclohexane products. Later, the same protocol was applied to prepare functionalized cyclopentane derivatives 137 having four stereogenic centers in excellent selectivities.113 The initial screening using catalyst 33 showed that the reaction was highly dependent on the substituent R4 of the acceptor ketone. In contrast to cyclohexane synthesis, aromatic ketones 136 (R4 = Ph) were required in this case for higher selectivities. After screening different primary-amine-based catalysts, they found that the same catalyst, 9-amino-9-deoxy-epi-quinine (29), catalyzes the reactions between ethyl-2-acetyl-4-oxo-4-phenylbutanoate (136a: R3 = Et, R4 = Ph) and different nitrostyrenes in toluene at 4 °C. Interestingly, different substituents on the aromatic ring of nitrostyrenes had a very slight impact on the enantioselectivity and yield. It is worth mentioning that only one highly substituted cyclopentane diastereomer was isolated in all cases, which further supports a very rigid transition state involving a network of H-bonds. Subsequently, the same Michael/Henry domino sequence was applied to cyclic-1,4-diketones 138 to prepare bicyclo[3.2.1]octane derivatives 139 having four stereogenic centers in excellent yields and selectivities (Scheme 35).114 Cinchona-based catalysts have been studied for the reaction between nitrostyrene (121a: R1 = Ph) and methyl-2,5-dioxocyclohexanecarboxylate (138a: R2 = Me). Thiourea catalyst 34 gave the bicyclic product 139a in highest yield and selectivity in benzonitrile as the solvent. Evaluation of different catalysts showed that the thiourea moiety has an accelerating effect on the reaction. Lowering either the temperature or the catalyst loading did not improve the selectivity. Under the optimized conditions (5 mol % 34, benzonitrile, room temperature), both aromatic- and heteroaromatic-substituted nitroolefins 121 reacted with diketoesters 138 to afford the corresponding bicyclic products 139. Regarding the reaction mechanism, a dual activation mode in that both thiourea and tertiary amine simultaneously activate the nitro and dicarbonyl groups was proposed by the authors (Scheme 34B). However, density functional theory (DFT) calculations provided a new and different picture for the activation mode. The calculations also supported a dual activation mode having multiple H-bond interactions between the substrates and the catalyst (Scheme 34C).115 In the first case, the tertiary amine is protonated by reaction with the

achiral base deprotonates the nitroalkane to generate the nucleophile. This nucleophile reacts from the less hindered Re face of the iminium ion to give intermediate 132, which, upon hydrolysis, undergoes an intramolecular nitroaldol reaction to afford the product. X-ray analysis of the major diastereomer implied that the intramolecular aldol reaction takes place from the Si face of the carbonyl group, suggesting no catalyst involvement in the stereoselection of the Henry reaction. In addition to the proline-based derivatives, other catalysts have also been studied for the domino Michael/Henry reaction. For example, readily available cinchona alkaloid derivatives have been used by Zhong and co-workers for the reaction between diketoesters and nitroolefins to generate functionalized cyclohexanes having four stereogenic centers, two of which are quaternary stereocenters (Scheme 33a).112 Using 15 mol % 9amino-9-deoxy-epi-quinine (29) in diethyl ether at room temperature, excellent selectivity (96% de, >99% ee) was obtained for the reaction of ethyl 2-acetyl-5-oxohexanoate (134a: R2 = Et) and β-nitrostyrene (121a: R1 = Ph). Under the optimized conditions, differently substituted nitrostyrenes 121 were employed to generate the corresponding cyclohexanols 135 in good to excellent yields (85−94%) with excellent enantio- and diastereoselectivities (97−99% ee, 80−98% de). Of note, only one Michael/Henry adduct was isolated in 97% ee when α,β-γ,δ-nitrodiene (121b: R1 = CHCHPh) was used. Therewith, the authors reported the first organocatalytic asymmetric Henry reaction of common ketones. A dual activation mode in which the primary amine activates the nitrostyrene by multiple H-bonds and the tertiary amine L

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Scheme 34. Proposed Activation Modes for the Cinchona Alkaloid Derivatives

substituted nitrostyrenes 121 (R2 = H) were reacted with cyclohexane-1,2-dione under these optimized conditions to provide the corresponding products 141 in good enantioselectivities and moderate diastereoselectivities. The kinetically favored conformer has the nitro and aromatic groups in the syn configuration and is the major product. The low diastereoselectivites observed in the reaction were because of the baseinduced epimerization of 141 to 142 under the reaction conditions. The occurrence of this process was supported by the fact that electron-withdrawing substituents on the aromatic ring of the nitroolefins reversed the diastereoselectivity. When α,β-disubstituted nitroolefins 140 were employed in reaction, the corresponding products were isolated with high levels of diastereo- and enantioselectivities. In these cases, the baseinduced epimerization of 141 to 142 is not possible because of the lack of a proton at the nitrocarbon. However, an alternative epimerization pathway consisting of a retro-Henry/Henry reaction can take place. This pathway is probably slow, which accounts for the high diastereoselectivities in these cases. Similar results were observed by Zhao and co-workers, who employed 15 mol % quinine-derived thiourea catalyst 33 for the same reaction.117 The better diastereoselectivities observed in their case are most probably due to the high catalyst loading and longer reaction times, which accelerate the epimerization and provide the thermodynamically more stable diastereomer 142 (67−90% yield, 72:28−95:5 dr, 92−99% ee). The application of 3-substituted oxindoles as versatile nucleophiles in the Michael/Henry cascade was realized by Barbas and co-workers (Scheme 37).118 They designed a

Scheme 35. Domino Michael/Henry Reaction with a Cinchona Alkaloid-Based Thiourea Catalyst

nucleophile. The protonated tertiary amine then activates the nitro group of the olefin by H-bonding, and thiourea interacts with the enol form of the nucleophile. More importantly, the calculations showed a H-bond interaction between the C−H proton of the phenyl ring of the thiourea unit and the ester group. The presence of two CF3 groups on the phenyl ring of the thiourea unit increases its acidity, enabling it to interact with the O atom of the ester moiety. Interesting methods for the synthesis of bicyclo[3.2.1]octanes 141/142 were later independently described by the groups of Rueping and Zhao using a Michael/Henry reaction sequence between cyclohexane-1,2-dione (77) and nitroolefins 121 and 140.116,117 The potential of cyclohexane-1,2-dione (77) as a useful substrate in enantioselective cascade reactions was previously demonstrated in the Michael/aldol sequence (Scheme 13).90 Based on this reactivity, the authors envisioned a Michael/Henry cascade reaction (Scheme 36).116 The results Scheme 36. Synthesis of [3.2.1]Bicyclic Compounds through a Domino Michael/Henry Reaction

Scheme 37. Spirooxindoles by a Michael/Henry Cascade Reaction

from the initial screening of different Brønsted base catalysts for the reaction led to the conclusion that bifunctional catalysts were crucial for the success of the reaction. Optimization of different parameters such as substrate concentration, catalyst loading, and temperature revealed that 1 mol % epicinchonidine-based catalyst 32 at room temperature in 0.2 M toluene solution was sufficient for good yields and enantioselectivities. Bicyclic Michael/Henry adducts 141 having four stereogenic centers were formed in excellent yields and selectivities using only 1 mol % catalyst 32. As expected, the opposite enantiomer was isolated by employing the pseudoenantiomeric epi-cinchonine catalyst. A wide range of β-

cinchona alkaloid-catalyzed Michael/Henry cascade reaction between 3-substituted oxindoles 119 and nitrostyrenes 121 to afford spirooxindole derivatives 143 in excellent yields and selectivities under mild reaction conditions. The cascade reaction involves the formation of two C−C bonds accompanied by the creation of four consecutive stereogenic centers. Sterically hindered 9-anthracenylmethyl-protected cinchona alkaloid 26 gave the best results in terms of yield and diastereoselectivity. Also, the phenolic hydroxyl group on the aromatic ring of the catalyst and the Boc protecting group M

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on oxindole were found to be crucial for the success of the reaction. The optimized conditions (10 mol % 26 in dichloromethane at 0 °C) were used to explore the scope of the Michael/Henry cascade reaction.119 Whereas electrondonating groups on nitrostyrene provided products with slightly lower diastereo- and enantioselectivities, electronwithdrawing groups gave products with excellent selectivities. Heteroaromatic-substituted nitroalkenes were also found to be useful substrates under the optimized conditions. In their efforts to synthesize polysubstituted tetrahydroquinolines, Xu and co-workers reported that bifunctional thiourea catalyst 36 derived from dihydroquinine efficiently catalyzes the Michael/aza-Henry reaction sequence between chalcone 144 and nitromethane 145 (Scheme 38).120 Tetrahydroquinolines

Scheme 39. Synthesis of Cyclopentane Derivatives

longer reaction time. Different substituents on the malonic ester have very small effects on the selectivity. Aromatic- and aliphatic-substituted aldehydes were successfully tested for the cascade reaction to prepare the corresponding products in good yields and excellent selectivities. Very recently, a similar approach was also studied for the synthesis of cyclohexane skeletons having four stereogenic centers using ethyl (E)-7-oxohept-2-enoate instead of 147 in reaction with enals 78.131 Highly functionalized cyclopentanes 150 were achieved by Córdova and co-workers using a nitro-Michael/Michael cascade reaction (Scheme 39b).132 Easily available α,β-unsaturated esters 149 bearing a nitro group at the δ-position were reacted with enals 78 in the presence of 20 mol % TMS-protected diphenylprolinol (20a) in chloroform at room temperature. Acidic additives increased the rate of the reaction but decreased the selectivity, and hence, basic additives were tested for the reaction, with DABCO giving the best results in terms of both yield and selectivity. Different functional groups on the enal were tolerated, allowing the preparation of products 150 with very high selectivities (97−99% ee). Furthermore, the products were subjected to different functional group transformations. At the same time, Zhong and co-workers developed a similar enantioselective double Michael cascade addition reaction that generates two new C−C bonds and four contiguous stereogenic centers including one quaternary center (Scheme 40).133 Cinchona alkaloids have been widely used as organocatalysts for the asymmetric Michael reactions of nitroalkenes. Based on this principle, Zhong and co-workers studied cinchona-based catalysts for the Michael/Michael domino reaction sequence between 121 and 151 bearing an unsaturated ester moiety and an enolizable ketoester at the δ-position. After screening several catalysts, they found 9-amino-9-deoxy-epi-quinine (29) to be the best choice for promoting the reaction between diethyl-5acetylhex-2-enedioate (151a) and nitrostyrene, providing only one diastereomer. Further solvent screening led to the conclusion that the reaction proceeds with high diastereoand enantioselectivities in diethyl ether. Under the optimized conditions, differently substituted nitroolefins were reacted with 151 to give the corresponding functionalized cyclopentanes 152 in good yields and excellent stereoselectivities. Heteroaromatic-substituted nitroolefins were also well tolerated under the reactions conditions. Interestingly, a different ratio of E/Z isomers in the starting material had no effect on the selectivity. Also notable is the fact that α,β-γ,δ-nitrodiene 121b (R1 = CHCHPh) selectively reacted at the β-position, showing the regioselectivity of the method. A mechanism that involves the dual activation of both nitro group and Michael donor by the primary-amine catalyst as presented in Scheme 34A was

Scheme 38. Synthesis of Tetrahydroquinolines through a Domino Michael/Aza-Henry Reaction

146 having three stereogenic centers were obtained in excellent yields and selectivities using a 20 mol % catalyst loading in toluene at room temperature. Whereas aromatic imines furnished the products in good yields, aliphatic imines provided the products in low yields only. Control experiments were carried out to investigate the preference of Michael addition of nitromethane to chalcone over the aza-Henry reaction. 2.3. Michael/Michael Sequences

Efficient asymmetric domino double-Michael reactions121 have been achieved starting from chiral precursors122−125 or using chiral auxiliaries.126,127 Recently, organocatalyzed Michael/ Michael domino reactions have appeared. For these protocols, two distinct α,β-unsaturated systems with different reactivities that can react in a sequential manner without interfering with each other are necessary. The reactivity of one system should be low enough not to compete with the second system in the first Michael reaction and high enough to be able to undergo the second Michael addition. Furthermore, the activity of the existing carbon nucleophile should allow its participation only in the first Michael addition. Following these considerations, successful approaches for the organocatalyzed Michael/Michael domino reactions have been designed. The first organocatalytic asymmetric double Michael addition reaction128−130 was developed by Wang and co-workers to synthesize functionalized chiral cyclopentanes having three stereogenic centers (Scheme 39a).130 Their method relied on the fact that iminium ions generated by the reaction of α,βunsaturated aldehydes and secondary amines react with the malonate nucleophile at a higher rate than unsaturated esters. They designed substrate 147 having an unsaturated ester along with an enolizable malonic ester as the reacting partner. Upon the screening of different chiral amines, they found that 20 mol % catalyst 20a gives cyclopentane 148a (R1 = p-MeO−C6H4, R2 = Me) in excellent yield (95%) and enantioselectivity (99% ee) in ethanol at room temperature for the reaction of 78e (R1 = p-MeO−C6H4) and 147a (R2 = Me). Similar results were observed when 10 mol % catalyst was used, although with a N

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Scheme 40. Synthesis of Cyclopentane Derivatives According to Zhong and Co-workers

Scheme 41. Synthesis of Cyclopentanone Derivatives According to Ma and Co-workers

clearly showed that the minor diastereomer formed in most cases was the 2-epimer of 155. Theoretical calculations were carried out at the DFT level to probe more details of the mechanism and rate-limiting step of the catalytic cycle. Michael addition of β-ketoester to iminium ion was proposed to be the rate-limiting step in the sequence.136 Most double Michael cascade reactions involve either the activation of enals with secondary amines or the activation of 1,3-dicarbonyl compounds with tertiary amines, but cascade reactions dealing with simple enones have been less investigated. This is because of the inherent difficulties arising for the formation of suitable covalent intermediates from the secondary amines and ketones to efficiently control the stereoselectivity. Melchiorre and co-workers137 came up with an interesting solution to circumvent the problem of activating α,β-unsaturated ketones toward an enamine/iminium cascade.138 Simple chiral primary amines derived from natural cinchona alkaloids were tested for the reaction of acyclic enones with nitrostyrenes to give formal [4 + 2] cycloadducts (Scheme 42). A catalytic system consisting of 20 mol % 9-amino-9deoxy-epi-hydroquinine (30) and 30 mol % 2-fluorobenzoic

proposed. A slightly modified unsaturated ester having an enolizable diester at the ε-position was used in a reaction with a nitroolefin in the construction of the tetracyclic core of lycorine-type alkaloids.134 Based on the same principles, an interesting and highly efficient double Michael reaction protocol was developed by Ma and co-workers for the synthesis of highly substituted skeletons having a cyclopentanone core (Scheme 41).135 They employed modified Nazarov reagents 154 as bifunctional substrates in reaction with α,β-unsaturated aldehydes 78 and 153 in the presence of TMS-protected diphenylprolinol (20a) as the catalyst. It was assumed that the catalyst activates the enal by forming an iminium ion, which is attacked by the βketoester nucleophile. The thereby formed enamine undergoes intramolecular Michael addition reaction onto the activated olefin moiety, creating the second C−C bond. As expected, high levels of diastereo- and enantiocontrol were observed for the reaction of substrate 154 with cinnamaldehyde 78a (R1 = R3 = H, R2 = Ph) in most solvents using 2 mol % catalyst, with toluene being superior and providing the cyclopentanone 155a product in 77% yield and >99.9% ee. The diverse array of functional groups present in the product allows further functionalization into useful derivatives, making this protocol highly valuable. Even a 2 mol % catalyst loading was sufficient to allow for the completion of the reaction in 2 h. This behavior was probably due to the highly electron-deficient olefin present in the β-ketoester. Under the optimized conditions, a wide range of substituted cinnamaldehydes 78 (R1 = R3 = H, R2 = Aryl) were reacted with 154 to obtain the desired products with high diastereo- and enantioselectivities. When less reactive aliphatic enals 78 (R1 = R3 = H, R2 = Alkyl) were used, a slight increase in the catalyst loading (5 mol %) was required for complete conversions in 1−2 h. The protocol has also been extended to α,β- and β,β-disubstituted α,β-unsaturated aldehydes 153. Use of disubstituted aldehydes is not as common in organocatalysis because of their lower reactivity caused by the increased steric hindrance. Although a slight increase in the temperature was required when using α,βdisubstituted enals, the obtained selectivities were still in good range. Moderate diastereoselectivities and excellent enantioselectivities were obtained when β,β-disubstituted enals were employed. Fused bicyclic and spiro derivatives were also prepared using suitable aldehydes. When both diastereomers of reduced 155b (R1 = Me, R2 = Ph, R3 = H) were benzoylated under basic conditions, only one isomer was isolated, which

Scheme 42. Entry to Cyclohexanones through Domino Double Michael Reactions

O

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Scheme 43. Proposed Mechanism for the Cinchona Alkaloid-Derived Amine-Catalyzed Domino Michael/Michael Reaction

Scheme 44. Domino Double Michael Reactions in the Synthesis of Cyclohexene Derivatives

unsaturated conjugated β-ketoesters with α,β-unsaturated aldehydes to obtain fused carbocycles 166. Using 20 mol % TMS-protected diphenylprolinol (20a), the product α-/β-166a (R1 = p-NO2−C6H4, R2 = Et) was obtained in only 13% yield after a long reaction time (10 days). Different acidic and basic additives were investigated to accelerate the reaction. Whereas basic additives had no beneficial effect, benzoic acid accelerated the reaction to give the bicyclic product α-/β-166a in good diastereoselectivity and excellent enantioselectivity in dichloroethane (DCE) as the solvent. Acceleration effects were also observed in polar solvents such as EtOH. Finally, the best results were obtained with 10 mol % catalyst 20a at room temperature in trifluoroethanol without the need for benzoic acid additive to give the product as a mixture of two epimers α-/β-166. Both epimers were obtained with excellent selectivity. Under the optimized conditions, aromatic-, heteroaromatic-, and ester-substituted α,β-unsaturated aldehydes were employed to obtain the corresponding fused bicycles in good yields and excellent selectivities (Scheme 44a).141,142 More recently, the same group extended their originally applied conditions (10 mol % 20a in CF3CH2OH as the solvent at room temperature) to linear alkyl-substituted unsaturated β-ketoesters 168 as Michael donors (Scheme 44b).143 Under the previously optimized conditions, reaction of p-nitrocinnamaldehyde 78f (R1 = p-NO2−C6H4) with 168a (R3 = n-Bu) gave the corresponding cyclohexene product α-/β169a (R1 = p-NO2−C6H4, R3 = n-Bu) in 87% yield, along with 13% of the Michael/Morita−Baylis−Hillman product. A higher diastereoselectivity of 4:1 for 169 to 170 was observed. The two epimers α- and β-169a were isolated in a 1:8 ratio favoring the β-epimer, β-169a, with both epimers being obtained with good enantioselectivities.

acid 161 efficiently catalyzed the cascade reaction to give highly substituted cyclohexanes 156 having three or four stereogenic centers in good yields and excellent diastereo- and enantioselectivities (Scheme 42a). The reaction was expanded to trans-α-cyanocinnamate 157a to prepare cyclohexanes 158 having an all-carbon quaternary center (Scheme 42b).137 Other electrophiles such as N-protected maleimides were also explored to obtain interesting fused bicyclic adducts 160 (Scheme 42c). The mechanism of the cascade reaction has been proposed to follow an enamine/iminium activation for the double Michael sequence (Scheme 43). Condensation of primary-amine catalyst 30 with α,β-unsaturated ketone 56 generates enamine 162, which can undergo Michael addition with the unsaturated olefin. The resulting iminium intermediate 163 selectively undergoes intramolecular Michael addition to generate the cyclic adducts 156/158. As mentioned above in regard to Schemes 39a and 41, Wang and Ma and co-workers illustrated double Michael reactions based on the principle of activating the enal with secondary amines to undergo nucleophilic addition with β-ketoesters, followed by an intramolecular Michael addition of enamines to activated olefins. However, attempts to use unsubstituted Nazarov reagents as bifunctional substrates in double Michael reactions led to the unexpected Michael/Morita−Baylis− Hillman cascade reaction (vide infra, Scheme 73).139 Later, Gong and co-workers reported that β-aryl-substituted Nazarov reagents undergo a domino Michael/acetalization sequence (vide infra, Scheme 45a).140 Taking into account these considerations, Brenner and co-workers assumed that βketoesters 165 having the conjugated alkene in a carbocyclic moiety would undergo the second Michael addition rather than the Morita−Baylis−Hillman reaction or acetalization.141 They studied differently substituted prolinol ethers for the reaction of P

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Moreover, their conditions seemed to work well for βketoesters with aryl groups in the 2-position,143 which is in strong contrast to the work of Gong and co-workers, who reported a Michael/acetalization sequence with those substrates (Scheme 45a).140 Using 10 mol % TMS-protected diphenyl-

solvents and additives (Scheme 45b). In nonpolar solvents, such as dichloromethane, the intermediate arising from the first Michael addition of the β-dicarbonyl compound and the enal undergoes a keto−enol equilibrium to form the more stable enol isomer (because of extended conjugation, route A), which undergoes an intramolecular acetalization to provide the dihydropyrans 171. In contrast, the keto−enol equilibrium is disrupted in stronger hydrogen-bonding solvents such as trifluoroethanol, and the protic solvent activates the Michael acceptor (route B) toward nucleophilic addition by hydrogen bonding to give the cyclohexanones 169. In analogy with the Michael/aldol-condensation sequence of β-nitroketones and enals using secondary-amine catalysts (Scheme 19),94 Hong and co-workers designed a Michael/ Michael cascade sequence for the synthesis of polysubstituted cyclopentane and cyclohexanecarbaldehydes having multiple stereogenic centers by the reaction of 172a and 172b, respectively, with α,β-unsaturated aldehydes 78 (Scheme 46).144 The reagents 172a and 172b were prepared in around 60% ee by chiral thiourea-catalyzed conjugate addition of phosphorus ylides to nitroalkenes followed by Wittig reaction with either formaldehyde or ethyl glyoxalate.145 They were subjected to double Michael addition reaction with enals 78 to give the corresponding products anti-173 and anti-174 as major diastereomers with high to excellent enantioselectivities (95− 99% ee for anti-173 and 93−97% ee for anti-174, Scheme 46). In 2009, Cobb and co-workers reported the application of bifunctional thiourea derivatives to the enantioselective Michael addition of nitronates to conjugated esters.146 In subsequent studies, they extended the scope of the reaction by designing a Michael/Michael cascade reaction between nitrohex-4-enoates and nitroolefins using the same class of catalysts (Scheme 47).147 For the reaction between (E)-ethyl 6-nitrohex-2-enoate (175) and nitrostyrene (121a: R = Ph), excellent enantioselectivities were observed using catalyst 33 irrespective of the solvent, although the diastereoselectivity and yield were dependent on solvent. Under the optimized conditions, (E)ethyl 6-nitrohex-2-enoate (175) undergoes double Michael addition with the generation of four contiguous stereocenters in high enantio- and diastereoselectivities. Additionally, when 2substituted nitroesters were employed, multisubstituted cyclohexanes having five contiguous stereogenic centers were obtained. The authors proposed that the cyclization step would be faster than the protonation of the nitronate formed after the first Michael addition, as no detectable amount of

Scheme 45. (a) Domino Michael/Acetalization Reaction and (b) Comparison of the Mechanisms of the Domino Michael/ Michael and Michael/Acetalization Reactions

prolinol (20a) in trifluoroethanol as the solvent, β-dicarbonyl compounds 168 having electronically different aromatic substituents at the 5-position led to the corresponding products α- and β-169 in good yields, excellent enantioselectivities of 91−99% ee for β-169, and moderate to high diastereoselectivities (1:2 to 1:11 for α-169 to β-169 and 2:1 to 10:1 for 169 to 170). As in the case of alkyl-substituted β-dicarbonyl compounds, the β-epimer was the major product in all cases (Scheme 44b). The preference for different products using the same starting materials and catalyst was attributed to the effect of different

Scheme 46. Synthesis of Polysubstituted Cyclopentanes and Cyclohexanes

Q

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enamine and iminium activation and efficiently combined both activation modes into a single mechanism. Spirooxindolic cyclohexane derivatives 183 have been synthesized by the reaction of unprotected methyleneindolinones 182 and enones 55/56 in the presence of 20 mol % 9-amino-9-deoxy-epihydroquinine (30) and 30 mol % 2-fluorobenzoic acid (161) in toluene at 60 °C (Scheme 49). Different substituents on both

Scheme 47. Michael/Michael Cascade Reaction between Nitrohex-4-enoates and Nitroolefins

Scheme 49. Entry to Spirocyclic Compounds through a Domino Double Michael Reaction

single Michael addition product was observed. The proposed model B for the cyclization involved the coordination of the thiourea unit simultaneously to both nitronate and ester groups. Hong and co-workers explored the double Michael addition of dicarbonyl derivatives with α,β-unsaturated aldehydes, which involved the formation of two C−C bonds and the creation of four stereogenic centers.148 This transformation was subsequently successfully applied to the synthesis of (+)-galbulin (181), a natural product having a tetrahydronaphthalene carbon skeleton (Scheme 48).149 TMS-protected diphenylpro-

the methyleneindoline and enone were compatible, and the corresponding products were isolated in good yields and excellent enantioselectivities. Although the reaction gives a mixture of two diastereomers, the major diastereomer was easily isolated by column chromatography. Highly congested bicyclo[2.2.2]octanes 184a/b having a spirooxindole moiety were prepared by employing cyclohexenone derivatives. Based on the stereochemical outcome of the spirocyclic oxindoles 183 and bicyclo[2.2.2]octanes 184, the authors proposed that the reaction proceeds through a stepwise double Michael addition rather than an alternative Diels−Alder pathway, which should provide products with a different configuration. The same activation principle was later applied to benzofuranone derivatives to obtain spirobenzofuranone cyclohexane derivatives 186 having three stereogenic centers (Scheme 50).151 The reaction creates two new C−C bonds

Scheme 48. Double Michael Addition in the Asymmetric Synthesis of (+)-Galbulin

Scheme 50. Synthesis of Spirobenzofuranone Cyclohexane Derivatives

linol (20a) catalyzed the reaction between (E)-3-(3,4dimethoxyphenyl)acrylaldehyde (177) and racemic (E)-3methyl-7-oxooct-5-enal (178) to afford the key intermediate 180 in 82% yield and 99% ee as a single diastereomer after aldol condensation in the presence of p-toluenesulfonic acid (pTsOH). The authors proposed that, under the reaction conditions, kinetic asymmetric transformation (KAT) of racemic (±)-178 is taking place and only (S)-178 is undergoing the double Michael addition to give cyclohexanecarbaldehyde derivative 179 having all five substituents in equatorial positions.149 An asymmetric method for the synthesis of spirooxindole derivatives was described by Melchiorre and co-workers.150 They took advantage of the ability of a single chiral primaryamine catalyst to activate unsaturated ketones toward both

along with three stereogenic centers in the presence of catalytic amounts of 9-amino-9-deoxy-epi-hydroquinine (30) and 2fluorobenzoic acid (161) in toluene at 60 °C. A variety of spiro derivatives were prepared in good diastereomeric and enantiomeric ratios. The interesting bifunctional nature of Nazarov reagents was also exploited by Gong and co-workers in reactions with methyleneindolinones 187 to synthesize spiro[4-cyclohexanone-1,3′-oxindoline] derivatives 188 (Scheme 51).152 They assumed that bifunctional catalysts having Brønsted acidic− Lewis basic functionalities would simultaneously activate both the Michael acceptor and Michael donor by H-bonding R

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spiro[cyclohexane-1,3′-indoline]-2′,4-dione unit,150−152 a regioselectively different spiro[cyclohexane-1,3′-indoline]-2′,3dione moiety was realized by the reaction of methyleneindolinones 189 with α,β-unsaturated ketones 55. The synergistic combination154 of quinidine-based primary amine 28 and simple BINOL−phosphoric acid 40 proved to be an efficient catalytic system for the double Michael addition to afford spirocyclohexanone oxindoles 190 in good yields and excellent selectivities. Although the product was isolated in good yield with 98:2 dr and 98% ee for the room-temperature reaction between 2-(2-oxoindoline-3-ylidene)malononitrile 189a (R2 = H) and benzylideneacetone (55a: R1 = Ph), the reaction was very slow. Interestingly, the reaction proceeded faster (1.5−4 h) at high temperature (80 °C) without affecting either selectivity or yield. Different mono- and disubstitution on the oxindole unit was compatible under the reaction conditions. Regarding the α,β-unsaturated ketones, both aromatic and heteroaromatic groups at the β-positions were viable. A mechanism similar to that of Melchiorre and co-workers (Scheme 43) involving formation of a dienamine intermediate by the reaction of ketone with the primary amine was proposed. Selective attack at the 3-C position of isatylidene moiety affords a Michael adduct that subsequently undergoes an intramolecular Michael addition to furnish the final product. More recently, Shao and co-workers employed the double Michael addition strategy to the preparation of biologically interesting spirocyclopentaneoxindoles (Scheme 53).155 Newly designed bifunctional thiourea catalyst 19 having an axially chiral binaphthyl unit promoted the reaction of oxindoles 192 and nitrostyrenes 121 in dichloromethane at room temperature, giving the corresponding densely functionalized spirocyclopentanes 193 in good yields and excellent selectivities. The desired bifunctional oxindoles 192 were reached by the ruthenium-catalyzed metathesis reaction on easily available 3-allyloxindoles 191. Substituted nitrostyrenes were applied in the primary-aminecatalyzed domino double Michael addition by Xu and coworkers in the preparation of complex tetracyclic molecules (Scheme 54).156 Nitrostyrenes 194 having an enoate in the ortho position were utilized to obtain tetracyclic chroman skeletons 195 having a bicyclo[2.2.2]octane structural unit. After the double Michael addition, the base deprotonates the proton next to the nitro group to generate the corresponding carbanion, which triggers an intramolecular Michael addition/ aldol cascade reaction. It is noteworthy that only a single isomer of the tetracyclic molecule having six stereogenic centers was isolated. Most double Michael additions generally involve the reaction of a substrate having both a nucleophilic center and a Michael acceptor with another Michael acceptor. Recently, reports on conceptually different double Michael additions, those having two Michael acceptors in the same molecule, have appeared. These reactions require the activation of a dienone toward a nucleophile, and primary-amine catalysis proved successful in these cases. The double Michael addition of malononitrile 197 to dienones 196 to obtain tetrasubstituted cyclohexanones was presented by Yan and co-workers (Scheme 55).157 Different Hbonding catalysts were tested for the reaction of malononitrile and dibenzylidene acetone, and it was found that 9-amino-9deoxy-epi-quinine (29) generates the chiral cyclohexane 198a (R1 = R2 = Ph) in moderate yield and high selectivity (53% yield, 18:1 dr, 94% ee). Acidic additives further improved the rate and the selectivity of the reaction. Under the optimized

Scheme 51. Formal [4 + 2] Cycloaddition

interaction toward the nucleophilic addition. The generated carbanion would undergo a second conjugate addition to furnish the spirooxindole structural unit. Thiourea and urea catalysts having a tertiary amine moiety were tested for the reaction of (E)-1-acetyl-3-benzylideneindolinone (187a: R1 = Ph, R2 = H) and Nazarov reagent 168a (R3 = Et, R4 = Ph) and found that the electronically poor aryl substituent on the thiourea and urea moiety was important for good selectivities. Although substitution on the Lewis basic tertiary amine did not improve the selectivity, a good enhancement in diastereo- and enantioselectivities was observed using urea surrogates at room temperature in dichloromethane as the solvent. Further tuning of the solvent, temperature, and concentrations led to the best conditions, which gave the product 188a in 90% yield and 96% ee at 10 °C in dichloromethane using 4-Å molecular sieves. Under the optimized conditions, a wide range of 3-substituted methyleneindolinones were reacted with Nazarov reagent 168 to obtain the corresponding spirooxindole products 188 in good yields and excellent selectivities. In the case of 3arylsubstituted methyleneindolinones, although the electronic factors did not influence the enantioselectivity, the diastereoselectivity was slightly varied. As expected, methyleneindolinones having electron-deficient substituents were more reactive, and excellent enantioselectivities were achieved even at −30 °C. Differently substituted Nazarov reagents were also found to be excellent substrates to provide the corresponding products in excellent diastereo- and enantioselectivities. Tolerance of halogen substituents on the indoline moiety further illustrates the scope of this double Michael addition reaction. A complementary approach for the synthesis of spirocyclohexanone oxindoles was developed by Wang and co-workers (Scheme 52).153 Whereas similar strategies were employed by Melchiorre and Gong and co-workers for the synthesis of the Scheme 52. Double Michael Addition According to Wang and Co-workers

S

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Scheme 53. Spirocyclopentaneoxindoles by a Domino Double Michael Reaction

based primary-amine catalyst 28 together with (S)-BINOL− phosphoric acid 40.159 Protecting groups on the nitrogen of oxindole were found to be detrimental for the reactivity of the methylene of oxindole. Under the reaction conditions (20 mol % 28, 40 mol % 40, THF, 30 °C), both electron-donating and electron-withdrawing substituents on the dienone were tolerated, and no significant difference in selectivity was observed with the pattern of substitution. Oxindoles substituted on the aromatic ring also gave the corresponding spiro derivatives 202 in excellent enantioselectivities. More recently, Wang and co-workers reported a double Michael addition reaction between divinyl ketones and Nunprotected oxindoles 200 or N-phenyl protected pyrazolones 201 using slightly modified conditions (Scheme 56).160 Using 20 mol % catalyst 29 and 40 mol % N-Boc-D-phenylglycine (109) as an acid additive in toluene at 40 °C, they reported a [5 + 1] double Michael addition cascade between dibenzylidene acetones and various unprotected oxindoles in good yields and selectivities. Under the same catalytic conditions [20 mol % 29, 40 mol % N-Boc-D-phenylglycine (109)] in chloroform at room temperature, N-phenyl pyrazolone 201 was also found to be a good binucleophile. An interesting application of nitroallylic esters in organocatalysis was realized in 2009 by Li and co-workers.161 Previously, in 1990, Seebach et al. described the use of nitroallylic esters in reaction with chiral enamines derived from prolinol in a formal [3 + 3] carbocyclization to afford chiral bicyclic [3.3.1] and [3.2.1] systems.162 Catalytic methods were described much later (2009) by Li and co-workers, who employed bifunctional pyrrolidine thiourea catalysts along with cocatalytic amounts of benzoic acids for the reaction of nitroallylic esters with cyclic ketones.161 The planned Michael/ elimination/Michael cascade afforded bicyclic [3.3.1] skeletons having four or five stereogenic centers. Optimization of different catalysts and solvents was carried out with (E)-2nitroallylic acetate 205a (R = H) and cyclohexanone (73a: X = CH2) at room temperature, which led to the conclusion that the cascade reaction generates product 206a (R = H, X = CH2) as a single diastereomer in good yield and excellent enantioselectivity in the presence of 20 mol % thiourea catalyst 13 and an equal amount of 4-methoxybenzoic acid (76) under solvent-free conditions (Scheme 57). The generality of the reaction was investigated with cyclohexanone and differently substituted nitroallylic esters, and the corresponding products 206 were isolated in moderate to good yields and excellent selectivities (56−78% yield, 94−98% ee). Also, tetrahydropyran-4-one (73b: X = O) gave the bicyclic product in excellent selectivity. When 1-methylpiperidin-4-one (73c: X = NMe) was employed, the desired heterocycle was isolated in good selectivity (97% ee) but in low yield (27%). In the case of cyclopentanone, the corresponding product was obtained in 94% yield and 93% ee. Attempts to use other ketones such as

Scheme 54. Domino Double Michael Reaction in the Synthesis of Complex Tetracyclic Molecules

Scheme 55. Synthesis of Tetrasubstituted Cyclohexanones by a Domino Double Michael Reaction

conditions (20 mol % 29, 40 mol % TFA, chloroform at room temperature), different benzylideneacetones 196 were reacted with malononitrile. Substrates having electron-donating groups on the aromatic ring proved to react better than those with electron-withdrawing substituents. A single example of an unsymmetrical benzylideneacetone was also presented. In addition to malononitrile, nitroacetate and cyanoacetate were also used as successful nucleophiles. Similar results (32−68% yield, from 16:1 to >50:1 dr, 80−86% ee for ent-198) were published by Lattanzi and co-workers independently using quinine as catalyst.158 Dienones 196 were also tested in reaction with 3unsubstituted oxindoles under primary-amine catalysis to afford spirocyclic oxindoles 202 (Scheme 56). Double iminium/ iminium activation of dienones was achieved by the cinchonaScheme 56. Access to Spirocyclic Compounds

T

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mechanism rather than a [4 + 2] Diels−Alder reaction based on the isolation of intermediates and reactivity. Later, the same group employed α,β-unsaturated aldehydes 78 as electrophiles in reaction with 2-vinylindoles 207 to synthesize optically pure tetrahydrocarbazoles 209 having an aldehyde functionality.165 Whereas sterically hindered imidazolidinone-based catalysts led to Friedel−Crafts alkylation products, prolinol-based catalysts gave cyclized products in the presence of Brønsted acid cocatalysts. The authors proposed a secondary-amine-catalyzed Friedel−Crafts alkylation/Michael addition/aromatization cascade mechanism for the reaction. The optimal conditions were found by screening different prolinol catalysts, solvents, acid cocatalysts, and protecting groups. Under the optimized conditions (20 mol % 20c, 20 mol % HClO4 in acetonitrile), both aliphatic- and aromatic-substituted enals were tested in reaction with 2-vinylindoles. Regarding the indole moiety, both electron-donating and electron-withdrawing groups were compatible on the aromatic ring. The use of either (Z)-hex-2enal or (E)-hex-2-enal led to a product with the same configuration, which rules out a Diels−Alder mechanism for the reaction.

Scheme 57. Bicyclic [3.3.1] Systems through a Formal [3 + 3] Cyclization

cycloheptanone and acetone as well as aliphatic-derived nitroallylic esters did not lead to the desired product.163 Regarding the mechanism of the reaction, both the amine and Brønsted acid functionalities of the bifunctional catalyst were found to be crucial for the reactivity and selectivity of the cascade reaction. As shown in Scheme 58, the pyrrolidone Scheme 58. Proposed Mechanism for the Formal [3 + 3] Carbocyclization

2.4. Michael/Alkylation Sequences

The cyclopropane motif is a common structural unit found in a wide range of natural products and biologically active compounds.166 After the seminal report of Corey and Chaykovsky167 on the cyclopropanation of α,β-unsaturated aldehydes and ketones using stabilized ylides, an immense number of research works were devoted to the creation of the cyclopropane architecture using α-halocarbanions as well as sulfur, phosphorus, arsenium, and tellurium ylides. Enantioselective cyclopropanation of electron-poor olefins by organocatalysis was accomplished using cinchona alkaloids as organocatalysts by Gaunt and co-workers.168 Their methodology was based on the in situ generation of chiral ammonium ylides from α-bromocarbonyl compounds. In this context, Kunz and MacMillan reported in 2005 an elegant enantioselective organocatalytic cyclopropanation reaction using a Michael/ alkylation cascade reaction (Scheme 60).169 Based on iminium-

moiety reacts with the cyclic ketone and forms enamine A, which undergoes a first Michael addition with the nitroallylic ester that is in close proximity because of the coordination of nitro group with the thiourea moiety. Elimination of the acetate and tautomerization of iminium ion B gave another Michael acceptor and enamine C. Intramolecular addition of enamine to the nitroolefin in C generates the bicyclic product 206 and the catalyst after hydrolysis. The proposed reaction mechanism is in agreement with the stereochemical outcome of the reaction and is supported by DFT calculations. Other hydrogen-bonding catalysts have also been studied for the synthesis of highly substituted tetrahydrocarbazoles 208 by a double Michael cascade addition and aromatization (Scheme 59).164 Wang et al. found that chiral bissulfonamide 8 catalyzes the reaction of 2-propenylindoles 207 (R3 = Me) and nitroolefins 121, generating three consecutive stereogenic centers in a one-pot operation. They proposed a stepwise

Scheme 60. Cyclopropanation of Enals with Ylides

Scheme 59. Chiral Tetrahydrocarbazoles through Domino Double Michael Reactions

ion catalysis, various conditions for the reaction between α,βunsaturated aldehydes 78 and dimethylsulfonium ylides 210 were explored. Although imidazolidinone-based catalysts did not lead to the corresponding products, L-proline proved to be a promising catalyst for the reaction between 2-hexenal and dimethylphenylacyl sulfonium ylide (210a, R2 = Ph) providing product 211a with 72% conversion and 46% ee. The best catalyst was found to be (S)-indoline-2-carboxylic acid (5), which gave the cyclopropane products 211 in good yields and excellent diastereo- and enantioselectivities. The catalyst design and the proposed mechanism were based on directed electrostatic activation. Whereas the amine group activates the enal toward nucleophilic attack by forming an iminium ion, the carboxylate group directs the incoming sulfonium ylide by electrostatic attraction to attack from the top face of the iminium ion, thus providing the enantiofacial U

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Scheme 63. Cyclopropanation of β,γ-Unsaturated αKetoesters with Sulfur Ylides

discrimination (A, Scheme 61). Also, (S)-indoline-2-carboxylic acid 5 predominantly forms the (Z)-zwitterionic iminium ion to Scheme 61. Proposed Catalytic Cycle for the Cyclopropanation Reaction

electron-rich β,γ-unsaturated α-ketoesters 74, providing the corresponding cyclopropanes 214. Organocatalysts were also studied for the enantioselective cyclopropanation of enals and enones employing bromonitromethane. However, the use of alkyl halides instead of stabilized ylides in the Michael/alkylation cascade was found to be more challenging. Ley and co-workers reported in 2006 their studies on the nitrocyclopropanation of cyclohexenone using pyrrolidone-based catalysts (Scheme 64).175 After careful and minimize the van der Waals interaction between the substrate olefin and the aryl hydrogen. This accounts for the higher degree of enantiodiscrimination when using catalyst 5 in comparison to L-proline. The enamine B generated after the initial Michael addition undergoes an intramolecular alkylation to give the final cyclopropane 211 after hydrolysis. An improved catalytic system based on catalyst 6 in which the carboxylic group was replaced by a tetrazole group was reported by Arvidsson and Hartikka.170 In most cases, an enantioselectivity of 99% ee was observed for the cyclopropanated products 211 using this new catalyst, which is proposed to be due to the increased steric bulk of the tetrazole group in comparison to the carboxylic acid group. Sulfonamide derivatives 7 were also reported to catalyze the same reaction and afford products 211 in low to moderate yields (16−50% and 21−58% for catalysts 7a and 7b, respectively) but with high levels of selectivity (95−97% de and 88−95% ee for 7a; 94− 98% de and 88−99% ee for 7b).171 Zhao and co-workers developed an asymmetric cyclopropanation reaction between enals and arsonium ylides using TMS-protected diphenylprolinol (20a) as the catalyst under mild basic conditions.172 The corresponding products 211 were obtained in good yields (51− 80%) and moderate to excellent diastereo- and enantioselectivities (from 2:1 to >99:1 dr, 78−98% ee). An alternative method for the enantioselective preparation of cyclopropanes was developed very recently by replacing the stabilized ylides 210 with chloroacetophenones 212 (Scheme 62).173

Scheme 64. Nitrocyclopropanation of Cyclohexenone

systematic optimization of different reaction parameters such as solvent, concentration, catalyst, time, and base for the reaction between cyclohexenone (114) and bromonitromethane (215), they obtained the bicyclic nitro derivative 216 as a single diastereomer in 80% yield and 77% ee. Their best conditions were found to be 1.2 equiv of cyclohexenone and 15 mol % 5-(pyrrolidin-2-yl)-1H-tetrazole (2) in dichloromethane at room temperature for 24 h using 1.0 equiv of morpholine as the base. Later, Córdova and co-workers described an enantioselective nitrocyclopropanation of α,β-unsaturated aldehydes using bromonitromethane in the presence of TMS-protected diphenylprolinol (20a).176,177 Although a significant level of enantioinduction (91−98% ee) was observed for the Michael/ alkylation cascade, the diastereoselectivity was low (1:1−3:1 dr). Bifunctional catalysts were studied by Bencivenni and coworkers for the asymmetric nitrocyclopropanation of oxindoles to prepare optically pure spiro-3,3′-cyclopropyl oxindoles 219 and 220 (Scheme 65).178 Michael/alkylation cascade reaction of bromonitroalkane and Boc-protected 3-alkylidene oxindoles

Scheme 62. Cyclopropanation Reaction with Chloroacetophenones

Scheme 65. Nitrocyclopropanation of Oxindoles

Xiao and co-workers reported the asymmetric cyclopropanation of more challenging β,γ-unsaturated α-ketoesters 74 using sulfur ylides 210 (Scheme 63).174 Although only moderate enantioselectivities of up to 80% ee were obtained using C2-symmetric urea derivatives as catalysts, the protocol provides new insights into the asymmetric cyclopropanation reaction. Both aromatic- and heteroaromatic-derived sulfur ylides 210 were tested in the reaction with electron-poor and V

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enantioinduction were achieved for products 226 using 10 mol % 35 under basic conditions.181 Córdova and co-workers also investigated the cyclopropanation of α,β-unsaturated aldehydes 78 with bromomalonates 227 (Scheme 68a).182,183 Using 20 mol % TMS-protected prolinols

218 was catalyzed by 5 mol % 9-epi-thiourea-9-deoxydihydroquinidine (37) in MTBE (methyl tert-butyl ether) as the solvent at room temperature. The use of 1.0 equiv of Na2CO3 was found to be crucial for the success of the reaction. Oxindoles having an activated double bond gave the corresponding products 219 with high diastereoselectivities and enantioselectivities. Substitution on the aromatic ring of oxindole had no impact on the selectivity of the reaction. The corresponding enantiomeric products ent-219 were obtained by employing the pseudoenantiomeric catalyst 36. Moreover, spirooxindoles 220 having two adjacent quaternary stereogenic centers were prepared using the pseudoenantiomeric catalyst 36 for the reactions using bromonitroethane in good enantioselectivities albeit low diastereoselectivities. A dual activation mechanism in which the thiourea moiety activates the imide unit of the oxindole by H-bonding and the tertiary amine activates the Michael donor was proposed for the cascade reaction. An interesting and mechanistically different Michael/ alkylation cascade for nitrocyclopropanation of oxindoles was reported by Dou and Lu, who employed β-bromo-β-nitroolefins as C2 synthons (Scheme 66).179 The application of β-

Scheme 68. Cyclopropanation of Enals with Bromomalonates

20a or 20b as catalysts in chloroform at room temperature provided the cyclopropanes 228 in good yields and selectivities. The use of triethylamine was found to be essential for good reactivity. Different aromatic- and aliphatic-substituted enals 78 were successfully used as substrates under the optimized conditions to afford the corresponding formyl cyclopropanes 228. At the same time, Wang and co-workers also developed similar conditions for the cyclopropanation of enals with halomalonates.184 In the presence of 10 mol % TMS-protected diphenylprolinol (20a) and using 2,6-lutidine as a base, electronically different substituted enals were reacted with bromomalonate to obtain the corresponding highly functionalized chiral cyclopropanes 228 in good enantioselectivities (93−99% ee). Their mechanism is based on the ambiphilic nature of the bromomalonate, which acts as a nucleophile in the Michael addition and as an electrophile in the alkylation (Scheme 69). The amine activates the enal by forming the

Scheme 66. Nitrocyclopropanation of Oxindoles with βBromo-β-nitroolefins

bromo-β-nitroolefins as C2 synthons was previously independently described by the groups of Rueping et al. and Xie and coworkers.180 Quinine-based thiourea catalysts incorporating an amino acid moiety were tested for the reaction between N-Bocprotected oxindole 221a (R1 = H) and β-bromo-β-nitrostyrene 222a (R2 = Ph). After careful evaluation of different reaction parameters, the optimized conditions were applied to differently substituted oxindoles 221 and bromonitrostyrenes 222, providing the corresponding cyclopropanes 223 in good yields, diastereoselectivities of up to 90% de, and enantioselectivities of up to 99% ee. The low diastereoselectivities in Bencivenni and co-workers’ protocol in accessing spirocyclopropanes with two adjacent quaternary centers prompted Malkov and co-workers to study the spirocyclopropanation of oxindoles 224 using 2-chloro-1,3dicarbonylcompounds 225 (Scheme 67).181 The drawbacks were addressed by designing a new quinine-based thiourea catalyst 35 having bulky i-propyl groups in the ortho positions of the aromatic unit. High levels of diastereo- and

Scheme 69. Proposed Mechanism for the Cyclopropanation of Enals with Bromomalonates

Scheme 67. Spirocyclopropanation of Oxindoles Using 2Chloro-1,3-dicarbonyl Compounds iminium ion 84, in which the Si face is effectively shielded by the bulky TMS-protected diphenyl ether unit. Attack from the Re face onto the iminium ion by bromomalonate generates the enamine, which undergoes intramolecular alkylation to produce the cyclopropane and regenerate the catalyst after hydrolysis. Further application of organocatalysis to the synthesis of chiral cyclopropanes 230 having three contiguous stereocenters was W

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Scheme 70. Synthesis of Cyclopentanones through a Domino Michael/Alkylation Reaction

of 20 mol % 20a, the desired product 235 was obtained as a mixture of cis and trans isomers, the ratio of which varied with the steric bulk on the aldehyde. The importance of the protocol was illustrated by synthesizing cyclic α-amino acids in just two steps from the diastereomerically pure cyclopentanes 235. In analogy to the approach of Barbas and co-workers (Scheme 27)106 for the synthesis of bis-spirocyclic oxindoles through a Michael/aldol cascade reaction, Wang and coworkers recently reported a Michael/alkylation cascade for the construction of the same skeleton (Scheme 72).191 Squaramides offer useful advantages in hydrogen-bond catalysis and have been found to be complementary to urea- or thioureabased catalysts.192,193 In this context, bifunctional catalyst 18 with a squaramide backbone was reported to be an efficient catalyst for the reaction between methyleneindolines 224 and 3-substituted oxindoles 238. After careful optimization of different parameters such as solvent, base, catalyst loading, and temperature, the best results obtained were successfully demonstrated in the synthesis of differently substituted spirocyclopentane bisoxindoles 239. The products were obtained in good to very high yields (70−98%) with high diastereo- and enantioselectivities (6.2:1:1−13.7:1:1 dr, 90− 96% ee). On the basis of nuclear magnetic resonance (NMR) and mass spectrometry (MS) experiments, the authors proposed that the catalyst simultaneously activates both reacting partners toward the cascade reaction. It was also demonstrated that both the tertiary amine functionality on the catalyst and the protecting group on methyleneindoline 224 were very important for the reactivity.

achieved using 2-bromo-3-oxoesters 229 in reaction with enals 78 (Scheme 68b).185 Cyclopropanes 230 were obtained in high yields (76−95%) and moderate to excellent selectivities (from 2.4:1 to >25:1 dr, 63−99% ee). Moreover, Campagne and co-workers developed a useful protocol for the Michael/alkylation cascade reaction of more challenging α-substituted α,β-unsaturated aldehydes.186 Cyclopropane derivatives having a quaternary carbon stereocenter in the cyclopropane ring were thereby prepared in moderate to good yields (35−81%) and good to high selectivities (85−97% ee). More recently, the secondary-amine-catalyzed iminium/ enamine cascade for the cyclopropanation reaction was performed in water to yield products 228 (five examples: R1 = Aryl, HetAryl) in good yields (56−84%) and high selectivities (>10:1 dr, 92−99% ee).187 In addition to cyclopropanes, the domino Michael/alkylation reaction was also used in the construction of cyclopentanones. Córdova and co-workers183,188 reported the TMS-protected prolinol-catalyzed Michael/alkylation reaction between 4bromoacetoacetates 231 and α,β-unsaturated aldehydes 78 to generate functionalized cyclopentanones 232 (Scheme 70).189 This is in strong contrast to the domino Michael/aldol condensation reaction reported by Jørgensen and co-workers for the reaction between 4-chloroacetoacetate and enals.84 The choice of the base was crucial for the cascade reaction, as inorganic bases such as K2CO3, KOH, and NaOAc led to the products in good yields whereas organic bases such as Et3N gave no conversion. A different activation strategy for the domino Michael/ alkylation reaction to prepare cyclopentanes was described by Enders and co-workers (Scheme 71).190 They took advantage

2.5. Miscellaneous Double Cascade Reactions

As illustrated above, organocatalytic domino reactions have been widely applied in the synthesis of various complex structures, all benefiting from at least one stereoselective Michael addition in the course of the reaction. In this context, the recently developed domino Michael/Morita−Baylis−Hillman, Michael/Knoevenagel, Knoevenagel/Diels−Alder, Diels− Alder/cyclization, and polycyclization reactions broaden the application field of cascade reactions. 2.5.1. Michael/Morita−Baylis−Hillman Sequences. In an attempt to develop a tandem Michael/Michael reaction of α,β-unsaturated aldehydes 78 with Nazarov reagents 240, Jørgensen and co-workers observed the formation of unexpected products 242 arising from a domino Michael/ Morita−Baylis−Hillman reaction (Scheme 73).139 They reported for the first time the use of chiral secondary amines as organocatalysts in an asymmetric Morita−Baylis−Hillman reaction. The authors proposed a mechanism in which the chiral catalyst is involved in two different cycles for the formation of products 242 (Scheme 74). In the first cycle, the catalyst activates the α,β-unsaturated aldehydes 78 by the known iminium-ion formation 84. Michael addition of Nazarov reagent 240 on this iminium ion generates intermediate 247, which undergoes hydrolysis instead of intramolecular Michael reaction to form 248 and regenerates the catalyst. In the second

Scheme 71. Domino Michael/Alkylation Reaction in the Synthesis of Cyclopentanes

of the secondary-amine-catalyzed Michael addition of carbonyl compounds to nitroalkenes and designed ω-iodonitroalkene 234 as a bielectrophile. Michael addition of aldehyde 233 to nitroalkene 234 generates the intermediate 236, which can undergo two different pathways leading to either 235 or 237. However, under the reaction conditions, iodide was attacked selectively by enamine to give 235. The reaction is strongly dependent on the polarity of the solvent, and dimethyl sulfoxide (DMSO) was found to be optimal. In the presence X

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Scheme 72. Domino Michael/Alkylation According to Wang and Co-workers

Scheme 73. Domino Michael/Morita−Baylis−Hillman Reaction

Scheme 74. Proposed Mechanism for the Michael/Morita−Baylis−Hillman Cascade Reaction

Scheme 75. Michael/Knoevenagel Cascade Reaction

nucleophilic catalysts including the secondary amine 20a gave the product 242 in almost same enantio- and diastereoselectivities. This result further confirmed that the intramolecular Morita−Baylis−Hillman reaction is diastereoselective and that the selectivity depends on the stereogenic center formed in the first step.

cycle, the chiral amine acts as a nucleophilic catalyst and promotes the intramolecular Morita−Baylis−Hillman reaction to give products 242. To support their mechanism, they isolated the intermediate product 248 of the Michael addition as a 1:1 diastereomeric mixture at low temperature and subjected it to different conditions. Whereas no product was isolated in the absence of a catalyst, both chiral and nonchiral Y

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Scheme 76. Domino Michael/Knoevenagel Reaction According to Hayashi et al.

Scheme 77. Domino Michael/Wittig Reaction

Scheme 78. Three-Component Domino Knoevenagel/Diels−Alder Reaction

the domino reaction to occur. Furthermore, the synthetic potential of the products was demonstrated by converting them into cyclohexene and cyclohexane derivatives containing up to four stereogenic centers. A closely related approach was independently developed by Hayashi and co-workers using tricarbonyl derivatives in the domino Michael/Knoevenagel condensation reaction (Scheme 76).195 They used sterically hindered TBS-protected diarylprolinol 21b as a catalyst for the reaction between dimethyl-3oxopentanedioate (254) and aromatic-substituted enals 78. The molar ratio of the two reactants was very important, as different side reactions were possible under the reaction conditions. Although the selectivities were very good in the absence of any additive, the reaction was very slow. Acidic additives accelerated the reaction without significantly changing the selectivity. Aromatic- and heteroaromatic-substituted enals were found to undergo the domino reaction, but aliphatic enals did not give any product. 2.5.3. Michael/Wittig Sequences. Formal [3 + 3] annulations were previously demonstrated for the synthesis of c y c l o h e x e n o n e s k e le t o n s u s i n g ( 3 - c a r b e t h o x y - 2 oxopropylidene)triphenylphosphorane and α,β-unsaturated aldehydes under basic conditions.196 Chen and co-workers employed newly designed chiral secondary-amine catalyst 20e for the reaction between 78 and 256 giving the corresponding 6-carboxycyclohex-2-en-ones 257 in good yields (56−85%) and excellent diastereo- and enantioselectivities (from 3:1 to >50:1 dr, 86−99% ee). The protocol requires 20 mol % LiClO4 and 40 mol % DABCO as additives for better reactivities (Scheme 77).197

A wide range of functional groups including aromatic, heteroaromatic, ester, and alkyl functionalities were compatible on the α,β-unsaturated aldehyde 78 for the domino reaction, giving the products in good yields and high enantio- and diastereoselectivities (3:2−9:1 dr, 86−98% ee). In addition, products 242 were further functionalized into important synthetic intermediates 243−246. A different reaction sequence was reported by Gong and co-workers for the reaction of unsaturated aldehydes with substituted Nazarov reagents.140 2.5.2. Michael/Knoevenagel Sequences. Jørgensen and co-workers reported a TMS-protected prolinol-catalyzed domino Michael/Knoevenagel condensation reaction between ethyl 4-diethoxyphosphoryl-3-oxobutanoate (252) and α,βunsaturated aldehydes 78 for the synthesis of optically active 6substituted 3-diethoxyphosphoryl-2-oxocyclohex-3-enecarboxylates 253 (Scheme 75).194 As expected, the Michael adduct obtained by the nucleophilic addition of ethyl-4-diethoxyphosphoryl-3-oxobutanoate to the iminium ion undergoes a spontaneous Knoevenagel condensation. The domino reaction proceeds nicely in most solvents, but dichloromethane was found to provide the optimum yield and selectivity in the presence of 10 mol % benzoic acid as a cocatalyst. Under the optimized conditions, cinnamaldehydes bearing either electrondonating or electron-withdrawing substituents on the aromatic ring were used in the domino reaction with ethyl-4diethoxyphosphoryl-3-oxobutanoate to afford the corresponding products 253 in good yields and excellent diastereo- and enantioselectivities. Aliphatic enals were found to be unreactive under the optimized conditions, and different additives were further tested to improve the reactivity. A cocatalytic amount of dihydroquinine was required in the case of aliphatic enals for Z

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2.5.4. Knoevenagel/Diels−Alder Sequences. Although the Knoevenagel/Diels−Alder and Knoevenagel/hetero-Diels− Alder cascade reactions have been widely studied and frequently applied to the synthesis of natural products and biologically active compounds,198 a generally applicable organocatalyzed diastereo- and enantioselective version did not appear until 2003.199,200 Barbas and co-workers reported the first asymmetric domino Knoevenagel/Diels−Alder reaction for the construction of highly substituted spiro[5.5]undecane-1,5,9-triones from the three-component reaction of enones 55, aldehydes 258, and Meldrum’s acid 259 (Scheme 78). It was anticipated that the chiral amino acid would catalyze the Knoevenagel condensation reaction between aldehydes 258 and Meldrum’s acid 259 to provide the alkylidene derivatives of Meldrum’s acid 264. Diels−Alder cycloaddition from the exo face of this intermediate with 2-amino-1,3-butadiene 263 generated by the reaction of enone 55 with the amino acid would then lead to a spirocyclic system in a highly diastereoselective and enantioselective manner. L-Proline catalyzed the three-component reaction between trans-4phenyl-3-buten-2-one (55a: R1 = Ph), 4-nitrobenzaldehyde (258a: R2 = p-NO2−C6H4), and Meldrum’s acid (259) to give the desired product 260a in 85% yield and 60% ee in methanol. The solvent was found to be crucial for the domino reaction, as aprotic nonpolar solvents provided the product in low yields and good enantioselectivities whereas polar solvents produced the desired product in excellent yields but in moderate to good enantioselectivities. Polar/protic solvents tend to accelerate the reaction as a result of the enhanced stabilization of charged intermediates. Remarkably, the cascade generates three new C− C bonds and two stereogenic centers. Further screening of different pyrrolidine-based catalysts led to 5,5-dimethylthiazolidinium-4-carboxylate (24) as the best catalyst. Good enantiocontrol was observed for the spirocyclic products in the reaction between different enones and aldehydes with Meldrum’s acid. In most of the cases, formation of the desired products was accompanied by the formation of small amounts of the corresponding acetals 262. Prochiral spirotriones 261 were also isolated in some cases in low yields. Under amine catalysis, the aldehyde undergoes aldol condensation with the acetone produced in situ to give enones, which can compete for the 2-amino-1,3-butadiene formation and result in the formation of 261. A diastereoselective triple domino reaction taking advantage of the in situ formation of the enone through either aldol condensation or a Wittig reaction has also been described.201 2.5.5. Michael/Cyclization Sequences. A cascade reaction involving a domino Michael/cyclization reaction was reported by Wang and co-workers for the synthesis of 3,3′thiopyrrolidonyl spirooxindole skeleton.202 Bifunctional thiourea catalysts were screened for the reaction between N-protected methyleneindolinones 224 and α-isothiocyanato amides or esters 266 to generate products 267 with three contiguous stereocenters (Scheme 79). The authors envisioned that a Lewis base activates the α-isothiocyanato imide nucleophile toward Michael addition to thiourea-activated methyleneindolinones. Subsequent addition of the resulting anion to the electron-deficient carbon atom generates the 3,3′-thiopyrrolidonyl spirooxindole unit. Different bifunctional thioureas were investigated for the cascade, and rosin-derived tertiary amine thiourea catalyst 17 was found to be efficient in catalyzing the reaction. The scope of the protocol was illustrated with a large number of examples. Electronically and sterically different

Scheme 79. Domino Michael/Cyclization Reaction

functional groups on the aromatic ring and protecting groups on the nitrogen were compatible in the reaction to provide the products in excellent yields and selectivities. Furthermore, benzofuranone and benzothiophenone skeletons can also be realized in good yields. Also, the thiolactam group can be selectively converted into either a lactam or pyrrolidine skeleton by either oxidation or reduction. The strategy of Michael/cyclization cascade reaction was also studied by Xie and co-workers for the synthesis of chiral benzopyran derivatives 270−272.203 Bifunctional thiourea catalyst 31 derived from quinine and having a simple phenylsubstituted thiourea was found to be the optimal catalyst for the reaction between 3-nitro-2H-chromenes 268 and α,α-dicyano olefins 269 (Scheme 80). The cascade reaction proceeds with high chemo-, diastereo-, and enantioselectivities using 20 mol % catalyst 31 in dichloromethane to give a mixture of domino Michael/cyclization adduct 270 and its tautomer 271 in moderate yields. Importantly, when 270 was heated to reflux in dichloromethane, 271 was obtained in almost quantitative yields. In addition to the formation of three stereogenic centers for derivative 271a (R1 = Ph, R2 = H), the cascade also generates a fourth stereogenic center by kinetic resolution of chromene 268a, which was isolated with 55% ee after reaction. Interestingly, when β-phenyl α,α-dicyano olefins (R3 = Aryl and R4 = H) were employed, only benzannulation products 272 resulting from the kinetic resolution were isolated. 2.5.6. Michael/Mannich Sequences. Another interesting Michael/cyclization cascade for the synthesis of indole derivatives 274 was described by You and co-workers employing primary-amine catalysis (Scheme 81).204 They studied the intramolecular Michael/Mannich cascade reaction of indolyl methyl enones 273 to synthesize the complex tetracyclic core 274. The reaction of tryptamine derivatives was catalyzed by 20 mol % 9-amino-9-deoxy-epi-quinine catalyst (29) along with 40 mol % 2-nitrobenzoic acid (103a) to give the tetracyclic moiety having three stereogenic centers in good to moderate yields and excellent selectivities. Carbon-tethered indolyl enones 273 (X = CH2) were also found to be useful substrates in the cascade cyclization. Regarding the scope, both electron-donating and electron-withdrawing groups on the indole ring were compatible with providing the skeleton in good yields. When an ethyl ketone derivative was used, a fourth stereogenic center was generated, and a 1:1 mixture of two diastereomers was isolated. The usefulness of the methodology was demonstrated by preparing a key fragment used in the synthesis of (+)-kreysiginine. The proposed mechanism of the reaction involves activation of enone by forming the iminium ion with the primary amine. Indole undergoes an intramolecular Michael addition to give intermediate 276. Tautomerization and enamine catalysis of the primary amine generates the tetracyclic skeleton and catalyst after hydrolysis. To support the mechanism, intermediate 278a was prepared using a Brønsted acid catalyst and subjected to the optimized AA

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Scheme 80. Michael/Cyclization Cascade Reaction According to Xie and Co-workers

Scheme 81. Michael/Mannich Cascade Reaction

conditions, good levels of diastereoinduction and excellent levels of enantioinduction were observed for the tetrahydroquinoline products. Based on kinetic experiments, the authors proposed that the Mannich reaction was faster than the Michael reaction and so formulated a Mannich/Michael cascade. The cascade reaction can also be performed by the three-component reaction of 2-alkenyl aniline, benzaldehyde, and malononitrile under the standard conditions although with lower diastereoand enantioselectivities (279a: R1 = R2 = Ph, R3 = H: 85% yield, 3.5:1 dr, and 62% ee for the three-component reaction vs 97% yield, 7.5:1 dr, and >99% ee for the two-component reaction). 2.5.8. Cationic Polycyclizations. Cationic polycyclizations are widely used in the synthesis of polycyclic skeletons in terpene and steroid chemistry. Until recently, asymmetric versions relied on the use of chiral auxiliaries or chiral starting materials.206 In 1999, Yamamoto and co-workers reported the first enantioselective biomimetic cyclization using Lewis-acidassisted chiral Brønsted acid catalysis.207 Later, Ishihara and coworkers reported an enantioselective halocyclization of polyprenoids for the synthesis of tricyclic molecules using stoichiometric amounts of chiral promoters.208 More recently, Jacobsen and co-workers reported the first metal-free organocatalytic thiourea-catalyzed cationic polycyclization using

reaction conditions. As expected, tetracyclic skeleton 274a was formed in good yield under these conditions. 2.5.7. Mannich/Michael Sequences. Wang and coworkers reported an efficient protocol for the synthesis of highly functionalized tetrahydroquinoline skeletons 279 employing a Mannich/Michael cascade reaction (Scheme 82).205 The protocol is complementary to the Michael/azaScheme 82. Mannich/Michael Cascade Reaction

Henry cascade reaction presented by Xu and co-workers (Scheme 38).120 The authors used malononitrile as a dual nucleophile in reaction with (E)-3-{2-[(E)-benzylideneamino]phenyl}-1-phenylpro-2-en-1-one (144a) in the presence of bifunctional tertiary-amine catalysts. Specifically designed indane amine-thiourea catalyst 14 was found to be optimal for catalyzing the cascade reaction. Under the optimized AB

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hydroxylactams (Scheme 83).209,210 The reaction proceeds through the formation of an N-acyliminium intermediate. It was

2.5.10. Diels−Alder/Conjugate Addition Sequences. A similar strategy was also followed more recently for the synthesis of the tetracyclic unit 293 using 2-(vinyl-1selenomethyl)tryptamine derivative 289, instead of the corresponding sulfur analogue 282 (Scheme 85).212 This tetracyclic moiety was the key intermediate in the total synthesis of complex indole alkaloids belonging to the Strychnos, Aspidosperma, and Kopsia families. Based on the propensity of methyl selenide to undergo β-elimination, a conceptually different cascade reaction consisting of Diels− Alder/conjugate addition was realized. The combination of endo-selective Diels−Alder cycloaddition of propynal to vinyl indole, elimination, and cyclization was efficiently catalyzed using 20 mol % ent-23 to give the spiroindoline unit 293 in 82% yield and 97% ee. This complex unit was then transformed in the collective total synthesis of six natural products in an efficient manner.

Scheme 83. Cationic Polycyclization Reaction

envisaged that treatment of hydroxylactam with hydrochloric acid would result in the formation of a chlorolactam intermediate. In the presence of an anion-binding catalyst, the intermediate generates a chloride iminium ion pair that can undergo enantioselective cyclization. Screening of different thiourea catalysts for the cyclization of substrate 280 revealed that 2-arylpyrrolidine catalysts bearing larger aromatic groups on the 2-position were crucial for good asymmetric induction, and in turn, thiourea catalyst 16 bearing 4-pyrenyl substitution was found to be the optimal catalyst in MTBE as the solvent at −30 °C in the presence of 4 Å molecular sieves. Cation−π interactions were proposed to be the key for good asymmetric induction. Under the optimized conditions, different arene groups acted as nucleophiles in the asymmetric polyene cyclization to give the tetracyclic moieties 281 in good yields and selectivities. An Eyring plot analysis was conducted using different catalysts, which also revealed that the enantioselectivity was enthalpically controlled and that the differential enthalpy increased with increasing arene size. 2.5.9. Diels−Alder/Cyclization Sequences. The advantages associated with domino reactions have also been exploited by some research groups in the total syntheses of natural products. One such excellent report came from the group of MacMillan and co-workers, who applied the organocatalyzed domino Diels−Alder/cyclization strategy in a very efficient manner for the construction of a key intermediate in the synthesis of (+)-minfiensine 288 (Scheme 84).211 Imidazolidinone salt 23·TBA (TBA = tribromoacetic acid) catalyzed the double cascade reaction between vinylindole 282 and propynal (283) to provide the key tetracyclic core 287 in 87% yield and 96% ee. Subsequent conversion of pyrrolindoline tetracycle 287 into (+)-minfiensine (288) was achieved in five further steps.

3. TRIPLE CASCADE REACTIONS The ability of secondary amines to activate both electrophiles and nucleophiles through iminium and enamine catalysis led scientists to study more complex triple and quadruple cascade reactions. The choice of the substrates and their reactivity are crucial for the good execution of the complex cascade reactions involving the formation of three or more bonds. Triple cascade reactions involving the creation of either three consecutive C− C bonds or one C−heteroatom and two C−C bonds are the most commonly studied. 3.1. Michael/Michael/Aldol Condensation Sequences

The breakthrough in the field of organocatalyzed triple cascade reactions came from the group of Enders.213,214 They reported a highly diastereo- and enantioselective three-component domino reaction using the simple TMS-protected diphenylprolinol catalyst 20a (Scheme 86). The cascade reaction consists of three consecutive C−C bond-forming events for the creation of four stereogenic centers in a very efficient manner. The chiral secondary amine catalyzes a Michael/Michael/aldol condensation sequence between linear aldehydes 233, nitroalkenes 121, and α,β-unsaturated aldehydes 78 by enamine/ iminium/enamine activation. It was anticipated that, in the first step, the catalyst activates the linear aldehyde 233 by enamine formation. Subsequent reaction with the nitroalkene 121, the more reactive Michael acceptor in the reaction, yields intermediate 297 after hydrolysis of intermediate 296. The regenerated catalyst then activates the α,β-unsaturated aldehyde

Scheme 84. Domino Reaction in the Total Synthesis of (+)-Minfiensine

AC

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Scheme 85. Domino Diels−Alder/Conjugate Addition Reaction as a Key Step in the Total Synthesis of Indole Alkaloids

consequence of the first Michael addition reaction, which is known to occur with great stereoselectivity. The optimized conditions involve the use of almost stoichiometric quantities of the three reagents (233/121/78 = 1.20:1.00:1.05) and 20 mol % TMS-protected diphenylprolinol (20a) catalyst in toluene from 0 °C to room temperature. Under these optimized conditions, a wide range of cyclohexenecarbaldehydes 294 having either three or four stereogenic centers were prepared in moderate yields and excellent selectivities. Both aromatic- and heteroaromatic-substituted nitroalkenes were useful substrates, but aliphatic nitroalkenes gave the products in only trace amounts. In the case of α,βunsaturated aldehydes, both aromatic and aliphatic residues were compatible. Linear aldehydes containing simple and sterically hindered groups can be employed as substrates. The efficient variation of the three residues allows easy synthesis of diverse derivatives. In addition, acrolein can be employed as the α,β-unsaturated aldehyde to furnish trisubstituted cyclohexenecarbaldehyde with excellent enantiomeric induction (>99% ee). Furthermore, functional groups, such as acetals or protected alcohols, were found to be compatible on the aldehyde substrate. The scope of the protocol was further illustrated by the selective derivatization of the products. Subsequently, the triple cascade reaction was also reported in water as the solvent with a wide array of substrates in the presence of 10 mol % acid additive (N-Boc-D-phenylglycine) and a surfactant [10 mol % sodium dodecyl benzene sulfonate (SDBS)] using 10 mol % dithienylprolinol silyl ether catalyst (20f).216 In this case, the cyclohexenecarbaldehyde products 294 were obtained in low to good yields (16−56%), good diastereoselectivities (76:24−90:10 dr), and excellent enantioselectivities (>99% ee). In addition, a domino Michael/Michael/aldol/Diels−Alder quadruple cascade reaction to synthesize complex tricyclic cores was attempted. Unfortunately, under the reaction conditions, the cyclohexenecarbaldehydes 294 did not undergo spontaneous intramolecular Diels−Alder (IMDA) reaction, but the products were obtained by employing a Lewis acid to promote the IMDA reaction. Remarkably, the sequence consisting of the triple cascade followed by Diels−Alder cycloaddition provided tricyclic carbon frameworks (decahydrophenalene derivatives) containing eight stereogenic centers in good overall yields (52− 56%) and excellent selectivities (10:1−15:1 dr and >99% ee).217 Similar principles were employed in the synthesis of highly substituted thiadecalins (40−57% yield, from 85:15 to >97:3 dr, >99% ee) by utilizing the triple cascade reaction followed by base-mediated sulfa-Michael reaction.218 Details

Scheme 86. First Organocatalyzed Triple Cascade Reaction

78 by iminium-ion formation, enabling the addition of nitroalkane 297 and giving rise to intermediate 298 (Scheme 87). This intermediate now undergoes an intramolecular aldol Scheme 87. Proposed Mechanism for the Triple Cascade Reaction Evolving through Enamine/Iminium/Enamine Activation

condensation reaction to give the cyclohexenecarbaldehyde product 294 after hydrolysis of intermediate 299 and regenerates the catalyst. 213−215 The high chemo- and enantioselectivities observed were attributed to the high reactivity of nitroalkenes as Michael acceptors in comparison to α,β-unsaturated aldehydes. Astonishingly, the cascade gives rise to just two diastereomers of 16 possible stereoisomers, and the major diastereomer can be separated easily by flash chromatography. The high stereoselectivity observed is a AD

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about the mechanism of this complex triple cascade reaction were probed by means of electronspray ionization mass spectrometry (ESI-MS) studies. Important information about the short-lived intermediates was obtained using these techniques to support the proposed mechanism.219 After the initial success of Enders and co-workers in synthesizing cyclohexenecarbaldehydes through a triple cascade reaction (Scheme 86), several groups were interested in preparing similar structures by exploiting the ability of secondary amines to activate carbonyl compounds by either enamine or iminium activation. A conceptually different strategy, based on iminium/iminium/enamine activation mode, for the synthesis of functionalized carbaldehydes was independently reported by the groups of Jørgensen and Enders (Scheme 88).220,221 Using α,β-unsaturated aldehydes 78 and

Scheme 89. Proposed Mechanism for the Triple Cascade Reaction Evolving through Iminium/Iminium/Enamine Activation

Scheme 88. Different Approaches to Cyclohexenecarbaldehydes

Cyclohexene derivatives having two different substituents (R1 ≠ R2) were also investigated by employing two different α,βunsaturated aldehydes. α,β-Unsaturated aldehydes having sterically different substituents were used for this purpose. Based on NMR spectroscopic studies, it was reasoned that, if the first enal had a sufficiently low reactivity that it reacted slowly in the second cycle, the second aldehyde could be added sequentially after the consumption of the first enal. This reactivity pattern could allow for the synthesis of carbaldehydes having two different substituents. The idea was achieved using isopropyl acrolein as the first Michael acceptor in reaction with malononitrile. Subsequent addition of either crotonal or cinnamaldehyde provided the corresponding products in 51− 52% yield with 97−99% ee. The reaction involves the formation of three consecutive C−C bonds and two stereogenic centers. Furthermore, the reaction was also studied using activated methylene compounds 300 having two different electron-withdrawing groups. In this case, an additional stereogenic quaternary center was formed during the second Michael addition of intermediate 307 to the iminium ion. When isopropyl cyanoacetate was used as the Michael donor, the corresponding products were obtained with good diastereocontrol and excellent enantiocontrol (from 90:10 to >98:2 dr, from 99 to >99% ee). Later, Enders and co-workers reported conditions for the iminium/iminium/enamine activation mode sequence using nitromethane (145) as the nucleophile. Simple conditions such as 20 mol % TMS-protected diphenylprolinol (20a) in chloroform at room temperature provided the corresponding trisubstituted carbaldehydes 304 having three stereogenic centers in moderate yields (Scheme 88). Although low diastereoselectivities for the products were observed in different solvents, the enantioselectivities for the major diastereomer were high for aromatic- and heteroaromatic-substituted aldehydes. In contrast, aliphatic enals did not lead to any product.

Michael donors in the presence of catalytic amounts of prolinol-based catalysts, trisubstituted carbaldehydes 301−304 were obtained in moderate to good yields and excellent selectivities. The mechanism of the reaction begins with the Michael addition of activated methylene compound to the activated enal to give adducts 305/306, which, after hydrolysis, give rise to 307 and regenerate the catalyst (Scheme 89). The regenerated catalyst then enters the second cycle by activating the second enal molecule by iminium-ion formation. Subsequent reaction of intermediate 307 with the iminium ion generates the enamines 308/309, which undergo intramolecular aldol condensation to furnish the products 301−304 and the catalyst. Crotonaldehyde (78g: R1 = R2 = Me) and malononitrile (197) were chosen as reacting partners in the presence of TMS-protected diarylprolinol catalyst 20c, and it was found that, in either chlorinated or aromatic solvents, the reaction gave a single diastereomer of the product with excellent optical purity (Scheme 88). Using malononitrile as the active methylene compound, the scope of the reaction was studied by employing aliphatic-, aromatic-, and heteroaromaticsubstituted enals with R1 = R2. Whereas aliphatic enals provided the product as a single diastereomer in good yields, aromatic- and heteroaromatic-substituted enals gave the product in slightly lower yields in the presence of 10 mol % catalyst 20c and 10 mol % benzoic acid as an additive in toluene at room temperature. AE

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protected diphenylprolinol (20a), 10 mol % 2-fluorobenzoic acid (161) in toluene at room temperature], different trisubstituted carbaldehydes 316 were prepared in moderate yields and diastereoselectivities with excellent enantioselectivities for the major diastereomer (34−42% yield, 2.5:1−5.5:1 dr, 98−99% ee), the minor diastereomer being the epimer at the quaternary center. The reaction was extended toward the synthesis of tetra-substituted carbaldehydes by employing transα-cyanocinnamates 157 as the Michael acceptor. Interestingly, a higher level of diastereocontrol was observed using aliphatic enals in comparison to aromatic enals. A remarkable threecomponent domino reaction having two all-carbon quaternary stereocenters was also described (Scheme 91). When an α,αdisubstituted aldehyde such as 2-phenylpropanal (318) was used as the aldehyde under standard conditions, the highly functionalized cyclohexane derivative 319 having five stereocenters was isolated. Spirocyclic oxindole derivatives 320 were synthesized using olefinic oxindoles 181 as Michael acceptors in a Michael/ Michael/aldol-condensation triple cascade reaction with enals 78 and aldehydes 233 (Scheme 92).151,225 The method relies on prolinol-catalyzed enamine/iminium/enamine activation of aldehydes in the presence of acidic additives to afford complex spirocyclic moieties in a procedure complementary to the double Michael reaction presented in Schemes 49 and 50. The conditions were also applied to olefinic benzofuranones 184151 and pyrazolones 322226 to obtain the corresponding spirocyclic benzofuranone and pyrazolone derivatives having four stereogenic centers (Scheme 92). A combined bifunctional thiourea/secondary-amine catalytic system was studied for the synthesis of functionalized cyclohexanes starting from enals 78, nitroolefins 121, and malonate esters 324 through a Michael/nitro-Michael/aldol triple cascade reaction (Scheme 93).227 Despite excellent enantioselectivity for the major products 325 (from 98 to >99% ee), only a moderate level of diastereoselection was observed, and 325 was obtained together with two further diastereomeric products 326 and 327.

The iminium/iminium/enamine activation sequence using heterocyclic systems was exploited by Melchiorre and coworkers for the synthesis of enantiomerically pure spirobenzofuranone cyclohexene derivatives using benzofuranone (312) as the active methylene compound (Scheme 90). Products 313 Scheme 90. Spirocyclic Derivatives through a Triple Cascade Reaction

were isolated in good yields with excellent diastereo- and enantioselectivities at room temperature in the presence of 5 mol % catalyst 20a.151 Spiro compounds 314 and 315 with different heterocyclic skeletons (oxindoles, pyrazolones) were described by Rios and co-workers (Scheme 90).222,223 The reaction between diverse enals as Michael acceptors and various heterocyclic systems as Michael donors follows a Michael/ Michael/aldol condensation sequence and takes place through an iminium/iminium/enamine activation mode, leading to various spiro compounds 314 and 315 with excellent selectivity (Scheme 90). An organocatalytic triple cascade reaction for a one-pot synthesis of tri- and tetra-substituted cyclohexenecarbaldehydes 316 and 317 having three and four stereogenic centers, respectively, was developed by Melchiorre and co-workers (Scheme 91).224 The protocol involves the creation of an allcarbon quaternary stereogenic center. The identification of cyanoacrylates as a new type of Michael acceptor in asymmetric conjugate addition of aldehydes through enamine catalysis is the basis for the triple cascade reaction. Using cyanoacrylate instead of nitroalkenes in the triple domino cascade reaction of Enders and co-workers, the authors achieved the synthesis of multisubstituted carbaldehydes having a stereogenic quaternary center. Under the optimized conditions [10 mol % TMS-

3.2. Knoevenagel/Michael/Cyclization Sequences

Enantioselective triple cascade reactions were also extended to reactions involving the formation of C−X (X = O, N) bonds along with C−C bonds.228−233 Yuan and co-workers developed a three-component domino Knoevenagel/Michael/cyclization sequence catalyzed by cupreine (25) to prepare stereochemically complex spiro[4H-pyran-3,3′-oxindoles] 329 in excellent

Scheme 91. Triple Cascade Reactions According to Melchiorre and Co-workers

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Scheme 92. Spirocyclic Compounds through a Triple Domino Reaction

Scheme 93. Polysubstituted Cyclohexanes through a Michael/Nitro-Michael/Aldol Triple Cascade Reaction

yields and good to excellent enantioselectivities (Scheme 94).229 Using protected isatins 328, malononitrile (197), and

Scheme 95. Domino Knoevenagel/Michael/Michael Reaction

Scheme 94. Domino Knoevenagel/Michael/Cyclization Sequence

Scheme 96. Combined Catalytic System for the Assembly of Piperidines 1,3-dicarbonyl compounds 65, a wide range of spiro derivatives 329 was prepared. Whereas acyclic 1,3-diketones gave the products with good selectivities, cyclic 1,3-diketones gave the corresponding products in nearly racemic form. 3.3. Knoevenagel/Michael/Michael Sequences

Spirocyclic cyclohexane derivatives 332 were obtained by a three-component domino Knoevenagel/Michael/Michael reaction between ynones 330, aldehydes 258, and indane-1,3dione 331 that was performed with a catalytic system consisting of 20 mol % 9-amino-9-deoxy-epi-hydroquinine (30) and 30 mol % 2-fluorobenzoic acid (161) (Scheme 95).234

the aldehyde and the nitroalkene by enamine activation and Hbond catalysis, respectively. The bifunctional thiourea catalyst also promotes the nitro-Mannich reaction. Finally, under the reaction conditions, the adduct undergoes cyclization to afford functionalized piperidines as a mixture of α- and β-epimers. The protocol also demonstrated the flexibility of the system, as different functional groups were tolerated. Furthermore, optically pure pyrrolidines and tetrahydropyridine derivatives can easily be prepared by functionalization of the products.

3.4. Michael/Nitro-Mannich/Cyclization Sequences

Fully substituted, optically active piperidines 334 were synthesized by a three-component cascade reaction of aldehydes 233, nitroalkenes 121, and protected aldimines 333 using a bicatalytic system consisting of a Lewis base and a bifunctional thiourea (Scheme 96). The Michael/nitroMannich/cyclization sequence was efficiently promoted using a combination of the prolinol catalyst 21a and thiourea-derived catalyst 15.235 It was envisaged that the two catalysts activate

3.5. Michael/Michael/Henry Sequences

A relay Michael/Michael/Henry reaction cascade236−238 was achieved by the group of Wang,236 who reported a mixture of 20a and quinine thiourea 33 as a matched combination to AG

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diphenylprolinol (20a), several different solvents and acidic additives were screened. Good yields and excellent selectivities were observed for the product 338a (R1 = R3 = Ph, R2 = R4 = H) in solvents such as dichloromethane, toluene, and chloroform using acetic acid as an additive. Remarkably, only one diastereomer of the product from among the 32 theoretically possible stereoisomers was obtained. The authors proposed that the high stereoselectivity observed for the product is due to the first oxa-Michael addition reaction, which is known to proceed with very high selectivity. The stereogenic center formed then controls the stereochemistry of the subsequent reactions. The reaction begins with the addition of phenol to the activated iminium ion to generate the C−O bond and the first stereogenic center. The resulting enamine undergoes intramolecular Michael addition with the nitroolefin functionality to give a nitroalkane of type 339 that acts as Michael donor reacting with a second iminium ion. The resulting enamine reacts intramolecularly with the aldehyde to furnish the final chromene skeleton after hydrolysis. Under the optimized conditions, different cinnamaldehydes were reacted with 336 to obtain the corresponding products 338 in excellent diastereo- and enantioselectivities (one diastereomer, >99% ee). A high degree of enantioinduction was reported for both electron-donating and electron-withdrawing substituted aldehydes. In contrast, the reaction of 336 with 3-methylbut-2-enal, a β-disubstituted aldehyde, proceeded very rapidly (30 min) to afford predominantly the domino oxaMichael/Michael adduct 339, and no further reaction was observed even after prolonged stirring or addition of excess aldehyde. This might be due to steric hindrance of the gemdimethyl groups. The authors took advantage of this reactivity and designed a crossed quadruple cascade reaction to obtain structurally more complex products using 3-methylbut-2-enal and substituted cinnamaldehyde in the same pot. Furthermore, the domino oxa-Michael/Michael/Michael/aldol-condensation reaction was applied in the total synthesis of (+)-conicol (Scheme 99). The key fragment 342 was obtained in 55% yield and >99% ee using (E)-2-(2-nitrovinyl)-benzene-1,4-diol (340), 3-methylbut-2-enal (337a), and aldehyde 341. In a few more steps, this skeleton was converted into (+)-conicol (343).240−242 Interesting results in quadruple cascades came at the same time from the group of Gong, who described an asymmetric organocatalytic four-component quadruple cascade reaction for the synthesis of chiral cyclohexenecarbaldehydes (Scheme 100).243 The authors presented a TMS-protected diphenylprolinol-catalyzed domino oxa-Michael/Michael/Michael/aldol condensation sequence between alcohols, acrolein, and nitroolefins. Whereas , 5 mol % catalyst 20a led to products with good selectivities, 25 mol % benzoic acid accelerated the reaction to obtain the compounds in moderate yields and excellent selectivities. Different alcohols such as primary,

catalyze the reaction between simple aliphatic aldehydes and nitroolefins to afford hexasubstituted cyclohexane skeletons 335 with all six contiguous stereocenters (Scheme 97).238 Scheme 97. Synthesis of Hexasubstituted Cyclohexane Skeletons through a Michael/Michael/Henry Cascade Reaction

Control experiments clearly demonstrated that the two catalysts act independently. The prolinol catalyst promotes the first Michael addition between aldehyde and nitroolefin by enamine catalysis to yield a Michael adduct. In the presence of hydrogen-bonding catalyst 33, this adduct reacts with a second molecule of nitroolefin to give a nitroalkane. This species can subsequently undergo base-promoted intramolecular Henry reaction to furnish the hexasubstituted cyclohexanes 335.

4. QUADRUPLE CASCADE REACTIONS The excellent results obtained in the field of double and triple cascade reactions led chemists to study more complex higherorder cascade reactions. With the careful design of substrates and matching arrangement of functional groups in the molecule, multicomponent quadruple cascade reactions have been achieved to prepare molecules of tremendous complexity. Again, the central element to the development of quadruple cascade reactions is the capability of the secondary-amine catalysts to activate both electrophiles and nucleophiles by iminium and enamine activation, respectively. 4.1. Oxa-Michael/Michael/Michael/Aldol Condensation Sequences

The first asymmetric organocatalytic quadruple cascade reaction came in 2009 from the group of Hong, who devised an efficient protocol for the synthesis of tetrahydro-6Hbenzo[c]chromenes 338 (Scheme 98).239 This skeleton is found in some naturally occurring biologically active compounds. The three-component cascade reaction involves the TMS-protected-prolinol-catalyzed reaction of 2-((E)-2nitrovinyl)phenol (336) and α,β-unsaturated aldehydes 337. The reaction proceeds with the formation of three C−C and one C−O bonds to generate multifunctionalized chromene moiety 338 having five contiguous stereogenic centers on the basis of a domino oxa-Michael/Michael/Michael/aldol condensation reaction. For the optimization reaction between 2((E)-2-nitrovinyl)phenol and cinnamaldehyde 78a (R1 = R3 = Ph, R2 = R4 = H) in the presence of TMS-protected

Scheme 98. Oxa-Michael/Michael/Michael/Aldol Condensation Sequence According to Hong and Co-workers

AH

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Scheme 99. Domino Oxa-Michael/Michael/Michael/Aldol Reaction in the Synthesis of (+)-Conicol

Scheme 100. Oxa-Michael/Michael/Michael/Aldol Sequence According to Gong and Co-workers

Scheme 102. Quadruple Cascade Reaction According to Enders and Co-workers

secondary, and functionalized alcohols were used in the reaction. In addition, phenols also served as O-nucleophiles. Both aromatic- and heteroaromatic-substituted nitroalkenes were found to be useful Michael acceptors. Moreover, the reaction can be performed on a larger scale without affecting the yield or selectivity. The proposed mechanism involves the formation of iminium ion 346 by the reaction of secondaryamine catalyst with acrolein, which will be attacked by the hard O-nucleophile alcohol to give intermediate 347 (Scheme 101). This enamine intermediate undergoes Michael addition with nitroalkene 121 to provide nitroalkane 348, which will react in a second cycle with iminium ion to provide 349. Finally, aldol condensation leads to product 345.

β-aryl-substituted nitroalkenes in the presence of 20 mol % catalyst 20a require 2.0 equiv of water and microwave irradiation at 60 °C. Although the diastereoselectivity was low, the major product could be separated by flash chromatography. In contrast to the above-mentioned quadruple cascade reactions, the present reaction proceeds through an enamine/ iminium/enamine/enamine activation sequence. In the first step, the enamine derived from acetaldehyde undergoes Michael addition to nitroolefin, generating a nitroalkane with a stereogenic center. Henry condensation of this nitroalkane with a second molecule of acetaldehyde produces another nitroalkene which acts as second Michael acceptor. Hydrolysis leads to a dialdehyde, which undergoes amine-catalyzed aldol condensation to yield the product and regenerate the catalyst. The proposed mechanism is supported by additional experiments and ESI-MS studies.

4.2. Michael/Henry/Michael/Aldol Condensation Sequences

Quadruple cascade reactions involving the formation of four consecutive C−C bonds and multiple stereogenic centers were also investigated.244,245 Enders and co-workers reported an organocatalytic domino Michael/Henry/Michael/aldol condensation sequence for the reaction between 3.0 equiv of acetaldehyde 258b and nitroalkene 121 to obtain trisubstituted cyclohexenecarbaldehydes 350 (Scheme 102).244 The optimal conditions for the reaction between acetaldehyde and different

4.3. Friedel−Crafts-Type/Michael/Michael/Aldol Condensation Sequences

Later, Enders and co-workers devised another quadruple domino reaction for the synthesis of indole derivatives using an iminium/enamine/iminium/enamine activation se-

Scheme 101. Proposed Mechanism for the Domino Oxa-Michael/Michael/Michael/Aldol Reaction

AI

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quence.246 The reaction between indoles 351, acrolein 78c, and nitroalkenes 121 proceeds in the presence of prolinol catalyst 20a in chloroform to yield the corresponding products 352 with good diastereoselectivity and excellent enantioselectivity (Scheme 103). To improve the yields of the cascade product,

Scheme 105. Hydrogenation/Michael/Michael/Aldol Cascade Reaction

Scheme 103. Synthesis of Indole Derivatives through a Quadruple Cascade Reaction enzyme-catalyzed reactions in the cells, as selective double versus quadruple cascade products were achieved by varying the concentration of substrates. They performed the reaction of α,β-unsaturated aldehydes 78, nitrostyrenes 121, and Hantzsch ester 355 in a 4.0:1.0:2.2 ratio using 20 mol % TMS-protected prolinol (20a) as the catalyst in chloroform to furnish the enantiomerically enriched cyclohexenecarbaldehydes 356 in moderate yields and excellent enantioselectivities.

slow addition of acrolein by a syringe pump was needed. Under the optimized conditions, indoles with different substitution patterns reacted with nitrostyrene and acrolein and afforded the products in moderate yields. Regarding the nitroalkene, the scope is limited to aromatic and heteroaromatic substituents on the β-position. The electronic nature of the substituents did not affect the selectivity but influenced the yield, a substantial increase being observed in the case of the electron-rich piperonyl substituent.

4.6. Aza-Michael/Michael/Michael/Aldol Sequences

More recently, a quadruple cascade reaction leading to tetracyclic indole derivatives249,250 was described by Enders and co-workers by the secondary-amine-catalyzed threecomponent reaction between indole-2-methylene malononitriles 357 and α,β-unsaturated aldehydes 78 (Scheme 106).250 The cascade reaction is based on enantioselective N-alkylation of 2-substituted indole derivatives and consists of a domino azaMichael/Michael/Michael/aldol reaction. The sequence begins with the aza-Michael addition of indoles to iminium ions formed by the reaction of enals with the secondary-amine catalyst. Intramolecular Michael addition of the corresponding enamine gives the tricyclic derivative, which can undergo Michael addition again with a second molecule of aldehyde. Final aldol reaction furnishes the doubly annulated indole derivatives 358. Overall, the reaction generates four new bonds and six new stereogenic centers. The optimized conditions consist of 15 mol % 20a in chloroform at room temperature. Differently substituted aromatic- and heteroaromatic-derived aldehydes were successfully employed under the reaction conditions to afford the corresponding products in excellent diastereo- and enantioselectivities. In contrast, use of aliphatic aldehydes resulted in no product formation.

4.4. Michael/Michael/Michael/Aldol Condensation Sequences

Complex hydroindane derivatives were prepared by Chen and co-workers on the basis of an asymmetric three-component quadruple cascade reaction between (E)-4-(1-methyl-2-oxoindolin-3-ylidene)-3-oxobutanoates 353 and α,β-unsaturated aldehydes 78 (Scheme 104).247 Four C−C bonds and six Scheme 104. Spirocyclic Oxindoles through a Quadruple Cascade Reaction

5. CONCLUSIONS In summary, we have highlighted the different advantages associated with organocatalytic cascade reactions and presented the classification of various cascade reactions useful for carbon− carbon bond formation, based on the number of transformations. As illustrated, these processes have gained a great deal of interest in recent years as useful tools for the efficient construction of complex molecular structures as well as chiral cyclic derivatives. Complex molecular architectures can be easily accessed from simple and readily available starting materials. These methods are highly valuable for the formation of chiral carbo- and heterocyclic compounds with multiple stereocenters that are relevant for the pharmaceutical and medicinal chemistry and useful in the synthesis of various natural products. The benefits of organocatalytic cascade reactions include high atom-economy, reduced waste generation and synthetic efficiency. Regarding the disadvantages of the organocatalyzed domino reactions and organocatalysis in general, relatively high catalyst loadings (10−20 mol %) and an excess of one of the reagents are the two main drawbacks. In addition, the frequent use of chlorinated solvents, the tedious

contiguous stereogenic centers were formed in the prolinolcatalyzed reaction to afford spirocyclic oxindole framework. In contrast to the reaction having two identical enal molecules, reactions involving two different enal molecules require the sequential addition of the less reactive aldehyde followed by the more reactive aldehyde. Although excellent enantioselectivities were observed in most cases, the yield of the reaction was strongly dependent on the enal substitution. Whereas aromatic and heteroaromatic enals led to products in good yields, aliphatic enals and reactions involving two different enals yielded the products in moderate yields. 4.5. Hydrogenation/Michael/Michael/Aldol Condensation Sequences

Based on the selective reduction of α,β-unsaturated aldehydes over nitrostyrenes in the presence of secondary-amine catalysts using Hantzsch ester as reducing agent, Rueping and coworkers reported a quadruple cascade reaction consisting of a hydrogenation/Michael/Michael/aldol-condensation cascade reaction (Scheme 105).248 The cascade is reminiscent of AJ

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Scheme 106. Domino Aza-Michael/Michael/Michael/Aldol Condensation Reaction

purification of the products by column chromatography and the need to recover and reuse of a relatively large amount of catalyst used call for the design of improved, more flexible, and sustainable strategies in organocatalytic cascade or domino reactions. Although the field of organocatalyzed cascade reactions is relatively new, it has experienced a rapid and astonishing development in a short period of time, now offering a complementary approach to metal and biocatalyzed cascade reactions. We are confident that more robust and effective catalytic systems that could find industrial application in the preparation of chiral organic compounds and drug development will soon emerge. Iuliana Atodiresei was born in Radauti, Romania, in 1977. She studied chemistry at the Al. I. Cuza University of Iaşi, Romania, and TU Braunschweig, Brunswick, Germany. After obtaining her M.Sc. in 2001, she joined the group of Professor C. Bolm at the RWTH Aachen University, Aachen, Germany, where she carried out her doctoral studies in the field of asymmetric anhydride desymmetrization. In 2005, she joined the group of Professor G. Raabe, focusing on computational and theoretical chemistry. Currently, she is a research scientist in the group of Professor M. Rueping and is also involved in the structure elucidation and determination of the absolute configuration of organic molecules.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Chandra M. R. Volla was born in Parvathipuram, India, in 1983. He received his M.Sc. in chemistry in 2005 from University of Hyderabad, Hyderabad, India. He graduated with a Ph.D. in organic chemistry from École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland, working under the guidance of Prof. Pierre Vogel. In 2010, he joined the group of Prof. Magnus Rueping at RWTH Aachen University, Aachen, Germany, as a Swiss National Science Foundation Fellow. He is also a recipient of Alexander von Humboldt fellowship for conducting postdoctoral studies for the period 2011−2013. Since the beginning of 2013, he has been pursuing postdoctoral studies in the group of Prof. Jan-E. Bäckvall funded by the Wenner−Gren Foundation at Stockholm University, Stockholm, Sweden. His research interests include the study and development of different activation modes in metal and organocatalysis and their application in dual catalysis.

Magnus Rueping studied at the Technical University of Berlin, Trinity College Dublin, and ETH Zürich. He conducted doctoral studies with Professor Dieter Seebach and obtained his Ph.D. in 2002 from ETH Zürich. He then moved to Harvard University to work with Professor David A. Evans. In August 2004, he was directly appointed to a C3associate professorship, the Degussa Endowed Professorship of Synthetic Organic Chemistry, at the Goethe University Frankfurt. After four years in Frankfurt, he accepted a Chair and Full Professorship of Organic Chemistry at RWTH Aachen University. His group’s research activities are directed toward the development and simplification of synthetic catalytic methodology and technology and their application in the rapid synthesis of diverse functional molecules. AK

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