Recent Advances in Organocatalytic Asymmetric …szolcsanyi/education/files/Chemia...Recent Advances in Organocatalytic Asymmetric Morita−Baylis− Hillman/aza-Morita−Baylis−Hillman

Recent Advances in Organocatalytic Asymmetric Morita−Baylis−Hillman/aza-Morita−Baylis−Hillman ReactionsYin Wei and Min Shi*

State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354Fenglin Road, Shanghai 200032, China

CONTENTS

1. Introduction 66592. Recent Mechanistic Insights into the MBH/aza-

MBH Reaction and Its Asymmetric Version 66612.1. Amine-Catalyzed Mechanism 66612.2. Phosphine-Catalyzed Mechanism 66642.3. Mechanistic Insights into the MBH/aza-MBH

Reaction Using Cocatalytic Systems orMulti-/Bifunctional Catalysts 6664

2.4. Stereoselectivity of MBH/aza-MBH Reaction 66653. Asymmetric Induction with Substrates 66664. Catalytic Asymmetric Induction with Chiral Lewis

Bases 66674.1. Catalytic Asymmetric Induction with Chiral

Amine Catalysts 66674.2. Catalytic Asymmetric Induction with Chiral

Phosphine Catalysts 66715. Catalytic Asymmetric Induction with Chiral Lewis

Acids 66736. Catalytic Asymmetric Induction with Chiral

Brønsted Acids 66746.1. Catalytic Asymmetric Induction with Chiral

Thioureas 66746.2. Catalytic Asymmetric Induction with Proline

Derivatives 66766.3. Catalytic Asymmetric Induction with Chiral

Thiols 66787. Recent Transformation of MBH Adducts Catalyzed

by Organocatalysts 66787.1. Allylic Substitution Reactions of MBH Ace-

tates and Carbonates 66787.2. Annulation of MBH Acetates and Carbonates

with Electron-Deficient Olefins 66828. Recent Developments in Asymmetric Rauhut−

Currier Reaction 66839. Conclusions 6685

10. Latest Developments 6685Author Information 6688

Corresponding Author 6688Notes 6688Biographies 6688

Acknowledgments 6688Abbreviations 6688References 6688

1. INTRODUCTIONThe carbon−carbon bond forming reactions is one of the mostimportant reactions in organic chemistry, and therefore has beenand remains an important and a fascinating area in organicsynthesis. Among these carbon−carbon bond forming reactions,the Morita−Baylis−Hillman (MBH) reaction has become one ofthe most useful and popular carbon−carbon bond formingreactions with enormous synthetic utility, promise, and potential.The classical MBH reaction can be broadly defined as theformation of α-methylene-β-hydroxycarbonyl compounds byaddition of α,β-unsaturated carbonyl compounds to aldehydescatalyzed by tertiary amine or phosphine (Scheme 1). Instead ofaldehydes, imines can also participate in the reaction if they areappropriately activated, and in this case the process is commonlyreferred to

Scheme 1

Scheme 2

Received: May 13, 2012Published: May 17, 2013

Review

pubs.acs.org/CR

© 2013 American Chemical Society 6659 dx.doi.org/10.1021/cr300192h | Chem. Rev. 2013, 113, 6659−6690

pubs.acs.org/CR

as the aza-Morita−Baylis−Hillman (aza-MBH) reaction. Theorigin of theMBH reaction can date back to 1968 to a pioneeringreport presented byMorita (phosphine-catalyzed reaction),1 andthen Baylis and Hillman described a similar amine-catalyzedreaction in 1972.2 Though this reaction is promising andfascinating, unfortunately, it has been ignored by organicchemists for almost a decade after its discovery. At the beginningof the 1980s, organic chemists such as Drewes, Hoffmann,Perlmutter, and Basavaiah started looking at this reaction andexploring various aspects of this important reaction.3 Inparticular, since the mid-1990s, particularly in recent decadesthis reaction and its applications have received remarkablegrowing interest, and the exponential growth of this reaction andthe importance of this reaction are evidenced by numerousresearch papers. The reasons for the fast growth of MBH/aza-

MBH reaction can be attributed to its several advantages asfollows: (i) the starting materials are commercially available andthe reaction is suitable for large-scale production; (ii) the atom-economic nature; (iii) the MBH adducts are flexible andmultifunctionalities which could be easily transformed to othersynthetically interesting products; (iv) it usually involves anucleophilic organocatalytic system without the heavy-metalpollution; (v) it can occur under mild reaction conditions.In recent years, several major reviews4 and mini reviews5 on

this fascinating reaction regarding the development of thisreaction and its applications have been published. SinceBasavaiah4e and Lamaty’s major review4d on MBH/aza-MBHreactions were published, which covers the advances of MBH/aza-MBH reactions before the end of 2008, there still has been aboom of research results on MBH/aza-MBH reactions in recent

Scheme 3

Scheme 4

Chemical Reviews Review

dx.doi.org/10.1021/cr300192h | Chem. Rev. 2013, 113, 6659−66906660

years. This review mainly focuses on the advances of asymmetricMBH/aza-MBH reactions from 2009 to 2011. We hope that thisreview will satisfy the expectations of readers who are interestedin the development of the field and looking for up-to-dateinformation on the chemistry of MBH/aza-MBH reactions.

2. RECENT MECHANISTIC INSIGHTS INTO THEMBH/AZA-MBH REACTION AND ITS ASYMMETRICVERSION

2.1. Amine-Catalyzed Mechanism

Although the elementary steps of the MBH reaction have beendescribed in the earliest publications,1a the exact reaction

mechanism, in particular those controlling the asymmetricinduction, has been debated frequently and remains as the core ofthe mechanistic discussion. The commonly accepted mechanismfor the MBH reaction was first proposed by Hoffmann3b andsupported by kinetic data studied by Hill and Isaacs6 in the late1980s and others.7 Their proposed mechanism is described inScheme 2. The catalytic cycle is initiated by the conjugateaddition of a tertiary amine 1 to an electron-deficient alkene 2,such as acrylonitrile, to generate the zwitterionic amine-acrylate3. In step II, the species 3 then attacks the aldehyde 4, leading toformation of the intermediate 5 via an aldolic addition reaction.The following intramolecular proton shifts within 5 to form 6 instep III, which subsequently generates the final MBH adduct andreleases the catalyst 1 via E2 or E1cb elimination in step IV.Through the kinetic studies by Hill and Isaacs, using acrylonitrileas an electron-deficient alkene and acetaldehyde as a carbonnucleophile for the MBH reaction, step II was initially suggestedas the MBH rate-determining step (RDS, Scheme 2), due to thelow kinetic isotopic effect (KIE = 1.03 ± 0.1). This suggestedmechanism was also supported by subsequent independentinvestigations including isolation of one intermediate in the

Scheme 5

Scheme 6

Scheme 7

Scheme 8

Scheme 9



catalytic cycle which was confirmed by X-ray analysis8 and theinterception of all key intermediates using electrospray ionizationwith mass and tandem mass spectrometry.9

However, McQuade et al.10 and Aggarwal et al.11 re-evaluatedthe MBH mechanism through kinetic and theoretical studies,focusing on the proton-transfer step and proposed the proton-transfer step as RDS. McQuade observed that the MBH reactionwas second order relative to the aldehyde and showed asignificant kinetic isotopic effect (KIE: kH/kD = 5.2 ± 0.6) inDMSO, and primary KIE (>2) was found in other tested solvents(DMF,MeCN, THF, CHCl3), indicating the relevance of protonabstraction on the RDS. On the basis of these kinetic data,McQuade proposed a new mechanism view for the proton-transfer step (Scheme 3), suggesting the proton transfer step asthe RDS. Aggarwal also proposed that the proton transfer stepwas the rate-determining step based on their kinetic studies, butonly at its beginning (≤20% of conversion), and then step II wasthe RDS when the product concentration built and protontransfer became increasingly efficient. They suggested that theMBH adducts 10 may act as a proton donor and therefore canassist the proton-transfer step via a six-membered intermediate(Scheme 3). This model also explained the autocatalytic effect ofthe product. More recently, Elberlin and Coelho performedcomplementary investigations on the MBH reaction mechanismvia electrospray ionization mass spectrometry (ESI-MS)(/MS).12 New key intermediates for the RDS of the MBHreaction have been successfully intercepted and structurallycharacterized, which provide strong experimental evidence that

both mechanisms proposed by McQuade et al. and Aggarwal etal. are possible.Besides kinetic studies, theoretical studies on the MBH

mechanism were conducted initially by Xu13 and Sunoj.14

Subsequently, Aggarwal and co-workers performed an extensivetheoretical study, which supported their own kinetic observa-tions and those of McQuade about the proton transfer step.15

Two distinct pathways leading to the products were proposed:(i) a second molecule of aldehyde participates the reaction toform a hemiacetal alkoxide hemi1 followed by rate-limitingproton transfer as proposed byMcQuade (non-alcohol-catalyzedpathway) and (ii) an alcohol acts as a shuttle to transfer a protonfrom the α-position to the alkoxide of int2 (Scheme 4). Inaddition, a few computational studies recently appeared in theliterature attempting to address mechanistic questions in theMBH reaction, including the addition of explicit water ormethanol molecules.16 However, some limitations exist in allthese studies. The popular B3LYP functional which may not beappropriate for this system was always used, and only potentialelectronic energies were employed to describe the energetics. Itshould be mentioned that Sunoj et al.14,17 have employedinteresting CBS-4 M and mPW1K methods to compute the freeenergies for the reaction pathways. However, they just comparedthe energetics of the direct proton transfer pathways (via a four-membered transition structure) and the 1,3-proton transferassisted by water and did not consider the possibility of theinfluences by a second molecule of aldehyde or other proticspecies. More recently, Cantillo and Kappe presented a detailedcomputational and experimental reinvestigation on the amine-catalyzed MBH reaction of benzaldehyde with methyl acrylate.18

They have proven that it was impossible to accelerate thereactions through variable-temperature experiments and MP2theoretical calculations of the reaction thermodynamics. Thecomplex reaction mechanism for the MBH reaction has beenrevisited using the M06-2X computational method. The resultsprovided by this theoretical approach are in agreement with allthe experimental/kinetic evidence such as reaction order,acceleration by protic species (methanol, phenol), andautocatalysis. They also pointed out that the suggested pathways(Aggarwal and McQuade pathways) are competing mechanisms,and either of two mechanisms is more favored depending on thespecific reaction conditions.Very recently, Eberlin and Coelho have investigated the

mechanism of aza-MBH via the ESI-MS(/MS) technique andproposed a rational mechanism for the aza-MBH reaction.19

They monitored the DABCO-catalyzed aza-MBH reaction of

Scheme 10

Figure 1.



methyl acrylate 2 with imine 12 by ESI-MS(/MS) spectrometryand intercepted the key intermediates 13, 15 and a unique bis-sulfonamide intermediate 14. On the basis of their results, theyproposed the mechanistic cycle for the aza-MBH reaction asdepicted in Scheme 5.

Miller and co-workers have performed kinetic studies on apyridylalanine-peptide catalyzed enantioselective coupling ofallenoates 16 andN-acyl imines 17 to investigate the mechanismof the aza-MBH reaction.20 In the catalytic cycle of a typicalMBH/aza-MBH reaction, the proton transfer step is often

Scheme 11. Proposed Catalytic Paths with Reaction Intermediates and Transition States Computationally for the L-Proline/Imidazole-Catalyzed Formation of (R)-32a

aFree energy (kJ mol−1) calculated at 0 °C at the B3LYP/6-31G(d,p) (plain text) and PCM B3LYP/6-31++G(d,p)B3LYP/6-31G(d,p) (italic) levelsof theory. The lowest-energy reaction path is indicated by bold arrows.



considered as the RDS. In comparison to typical MBH/aza-MBH reactions through mechanistic experiments, includingkinetics and hydrogen/deuterium kinetic isotope effects, theyhave found that the catalyst addition to allenoate becomes theRDS in this pyridylalanine-peptide catalyzed aza-MBH reaction(Scheme 6).2.2. Phosphine-Catalyzed Mechanism

The most likely mechanism of the MBH/aza-MBH reactioncatalyzed by tertiary phosphines is identical to that of the amine-catalyzed reaction via path a shown in Scheme 7, giving thenormal MBH/aza-MBH adducts 19. In principle, the initiallyformed zwitterionic intermediate 18 during the phosphine-catalyzed MBH/aza-MBH reaction can isomerize to phosphorusylide 20, which can then undergo aWittig reaction to give olefins21 (Scheme 7, path b). The latter process may require elevated

temperatures, since it is not observed in reactions such as theMBH reaction involving the more reactive α,β-unsaturatedketones under mild conditions.Sunoj and co-workers have also done theoretical studies on the

mechanism of the trimethylphosphine catalyzed aza-MBHreaction between acrolein and mesyl imine.17b They found thatthe relative energies of the crucial transition states for the PMe3-catalyzed reaction are lower than those of the correspondingNMe3-catalyzed reaction. The kinetic advantage of the PMe3-catalyzed reaction is also evident in the proton transfer step,where the energies of the transition states are much lower thanthose of the corresponding NMe3-catalyzed reaction. Thesepredictions are consistent with the available experimental reportswhere faster reaction rates are in general noticed for thephosphine-catalyzed aza-MBH reaction.21

Most recently, Tong et al. isolated a stable phosphonium−enamine zwitterion 22, which has long been postulated as one ofthe key intermediates in the aza-MBH reaction, from the PPh3-catalyzed reaction between propiolate and N-tosylimine(Scheme 8), which provides some experimental evidence tosupport the postulated reaction mechanism of the phosphine-catalyzed MBH reaction.22

2.3. Mechanistic Insights into the MBH/aza-MBH ReactionUsing Cocatalytic Systems or Multi-/Bifunctional Catalysts

Besides using traditional Lewis base catalysts in the MBH/aza-MBH reaction, the cocatalysts have been often used in theMBH/aza-MBH reaction to accelerate the reaction. Recently,

Scheme 12

Scheme 13



several mechanistic studies have been carried out to investigatethe mechanism of the MBH/aza-MBH reaction using cocatalyticsystems. Eberlin and Coelho studied the MBH reaction between2-thiazolecarboxaldehyde and methyl acrylate in the presence ofDABCO and thiourea by ESI-MS(/MS) and density functionaltheory (DFT) techniques.23 The key intermediates wereintercepted and characterized by ESI-MS(/MS) and suggestedthat thiourea 23 acted as an organocatalyst in all steps of theMBH reaction cycle shown in Scheme 9, including the rate-limiting proton-transfer step. The DFT calculations confirmedthis suggested a catalytic cycle and also revealed that the thioureadid not act as a proton shuttle in the rate-limiting proton-transferstep; instead, it acted as a Brønsted acid stabilizing the basicoxygen center being formed in the transition state and decreasedthe barrier of the RDS, thus accelerating the reaction.Sunoj and co-workers have identified the role of protic

cocatalysts such as water, methanol, and formic acid in theMBH/aza-MBH reaction by theoretical studies.17b They foundthat the protic cocatalysts had a profound influence in decreasingthe activation barriers associated with the key elementary stepsdue to the improved stabilization of the proton transfer transitionstate through a relay mechanism.The MBH/aza-MBH reaction involving proline as a catalyst

with imidazole as a cocatalyst was proposed to proceed throughan iminium ion intermediate. Recently, Santos and co-workershave studied the mechanism of proline-catalyzed and imidazole-co-catalyzed intramolecular MBH reaction by DFT calcula-tions.24 They first investigated the catalytic path for the MBHreaction of the α,β-unsaturated dialdehyde catalyzed by L-prolinein the absence of imidazole and found that water acted as animportant catalyst when imidazole was not present. Whenimidazole was used as a cocatalyst, water was still important in theimidazole addition step. Their results rationalized the exper-imental outcome of the intramolecular MBH reaction andprovided theoretical evidence to some mechanistic proposals.Oh and co-workers have performed the mechanistic

investigation on the proline-catalyzed asymmetric MBHreactions of vinyl ketones in the presence of brucine N-oxide24 as a cocatalyst.25 In this dual catalytic system, proline isbelieved to form iminium intermediatesAwith electron-deficientaryl aldehydes, while the N-oxide activates vinyl ketones toprovide enolates B through conjugate addition (Scheme 10).Upon the combination of these two intermediates, the MBHproducts with high enantioselectivities are obtained bycontrolling the RDS through the H-bridged chairlike transitionstate C.The bifunctional strategy has been successfully used to design

new organocatalysts for the MBH/aza-MBH reaction in recentyears. In the bifunctional strategy, a Lewis base and a Brønstedacid can be crafted onto one chiral backbone to act cooperativelyin theMBH reaction cycle. The Lewis base functionality serves toinitiate the Michael addition step of the reaction, and theBrønsted acidity is thought to stabilize the zwitterionicintermediates and promote the subsequent aldol and proton-transfer-elimination step. The first bifunctional catalyst, which isa hydroxylated chiral amine derived from cinchona alkaloids, forhigh enantioselective MBH reaction was reported by Hatakeya-ma in 1999.26 Subsequently, Shi and co-workers first reported abifunctional phosphorus catalyst bearing an artificial chiralbackbone for the high enantioselective aza-MBH reaction.27

Recently, Liu and co-workers developed this strategy andemployed a trifunctional catalyst 25 (Figure 1), which involvesthe phosphine Lewis base, the nitrogen Brønsted base, and the

phenolic Brønsted acid, in an asymmetric aza-MBH reaction.28

They have performed the kinetic experiments to investigate themechanism of asymmetric aza-MBH reaction catalyzed bytrifunctional catalyst. The catalysis was found to be first orderin the trifunctional catalyst with the Michael addition as the rate-limiting step.

2.4. Stereoselectivity of MBH/aza-MBH Reaction

The MBH/aza-MBH adduct has only one stereogenic center;however, several intermediates and transition states during thereaction process have more than one chiral center, which makesthe studies on the stereoselectivity of MBH/aza-MBH reactionmore complicated. Aggarwal first proposed models to accountfor the stereoselectivity of the MBH/aza-MBH reaction.15 Theysuggested that all four diastereomers of the intermediate alkoxideare formed in the reaction, but only one has the hydrogen-bonddonor suitably positioned to allow fast proton transfer, while theother diastereomers revert back to starting materials. Althoughseveral mechanistic studies also proposed similar transition statesto account for the stereoselectivity of the MBH/aza-MBHreaction, there are no studies to investigate the full reactionpathway of the enantioselective MBH/aza-MBH reaction untilrecently. Santos and co-workers have first investigated theproline-catalyzed and imidazole-co-catalyzed enantioselectiveintramolecular MBH reaction by DFT calculations.24 Theirresults indicated that proline played important role for selectivityin two different reaction steps, the cyclization and the addition ofimidazole (Scheme 11). They also demonstrated that theimidazole addition step was the rate-limiting step, and thecalculated results indicated that both imidazole addition andcyclization steps influenced overall selectivity of the reaction.Hu and co-workers investigated the mechanism of the MBH

reaction between formaldehyde and methyl vinyl ketone (MVK)catalyzed by N-methylprolinol using the DFT method.16c Theyfocused on the two reaction steps: C−C bond formation andhydrogen migration, which were commonly considered as theRDS under different reaction conditions, to investigate thestereoselectivity. In the presence of water, the hydrogenmigration occurs via a six-membered ring transition state, andthe corresponding energy barrier decreases dramatically, andtherefore the RDS is the C−C bond formation step. Thecalculations indicate that the C−C bond formation step controlsthe stereochemistry of the reaction. In this step, the hydrogenbonding induces the direction of the attack of enamine toaldehyde from the -OH group side of N-methylprolinol. Theenergy-favored transition states are mainly stabilized by hydro-gen bonding, while the chirality of the products is affected by thehydrogen bonding and the steric hindrance. The calculationscorrectly reproduce the major product in (R)-configuration,which is consistent with the experimental observation.In 2011, Chen and co-workers investigated the detailed

mechanism for the thiourea-tertiary amine-catalyzed enantiose-lective aza-MBH reaction of nitroalkene and N-tosylimine byDFT calculations.29 They proposed the mechanism as shown inScheme 12. The Lewis base catalyst 33 activates the nitroalkene34 by the tertiary amine moiety via a weak covalent bond,generating the zwitterionic intermediate Int0. The nucleophilicaddition of Int0 to N-tosylimine 35 affords Int2. Then theproton is transferred from the methyl group of 34 to theelectronegative nitrogen of 35, which is followed by thegeneration of β-nitro-γ-enamine 36 and the recovery of catalyst.The proton transfer from methyl group of nitroalkene to theelectronegative nitrogen of imine was identified as the rate-



limiting step via DFT calculations. The more favored TSs werestabilized by the noncovalent interactions (H-bonds, π−πstacking), leading to (3S,4R)-36 as the major product.

3. ASYMMETRIC INDUCTION WITH SUBSTRATES

Since 2009, considerable efforts have been devoted to develop-ment of asymmetric MBH/aza-MBH reactions. Either employ-ing chiral substrates or using chiral catalysts are straightforwardstrategies to achieve asymmetric MBH/aza-MBH reactions.Actually, only a few examples using chiral substrates to obtainasymmetric MBH/aza-MBH adducts were reported in recentyears, which are summarized in this section. Numerous reports

regarding organocatalytic asymmetric MBH/aza-MBH reactionswill be reviewed in the following sections.Krishna and co-workers first reported that chiral aldehydes

trans-(2R,3R) cyclopropanecarbaldehydes 37 underwent a facileMBH reaction with a variety of activated olefins in the presenceof a catalytic amount of DABCO to furnish the correspondingadducts 38 in good yields and selectivities (Scheme 13).30 It wasfound that the ring conformation and substituents played adecisive role in the stereoselection of the product. Subsequently,they reported an innovative synthesis of 3-deoxy sugars in both D

and L forms as exclusive products in high yield through asequential MBH reaction of sugar-derived aldehyde 39 or 42with ethyl acrylate and Lewis acid catalyzed reaction.31 It was

Scheme 14

Scheme 15

Scheme 16



demonstrated that sugar-derived aldehyde 39 or 42 with ethylacrylate underwent the DABCO-catalyzed MBH reaction,producing divinyl carbinols 40 or 43, which were furthertransformed to the corresponding 3-deoxy sugars 41 or 44 asexclusive isomers in high yields in the presence of Lewis acid(Scheme 14). These products could also be employed as valuablecomponents in the synthesis of sugar-modified nucleosides.Pinho eMelo et al. has demonstrated a DABCO-catalyzed aza-

MBH reaction of chiral allenes with imines to synthesize opticallyactive α-allenylamines and 2-azetine derivatives.32 The use of(1R)-(−)-10-phenylsulfonylisobornyl buta-2,3-dienoate 45 withimines 46 as starting materials underwent the DABCO-catalyzedaza-MBH reaction smoothly, affording aza-MBH adducts 47with S configuration and 2-azetine 48, whereas (1S)-(+)-10-phenylsulfonylisobornyl buta-2,3-dienoate 49 leads to aza-MBHadducts 50 with R configuration and 2-azetine 51 (Scheme 15).The yields of products and the ratios of products 47:48 and50:51 can be controlled by carefully selecting the reactionconditions or by tuning the electronic properties of the imines.

4. CATALYTIC ASYMMETRIC INDUCTION WITHCHIRAL LEWIS BASES

4.1. Catalytic Asymmetric Induction with Chiral AmineCatalysts

The chiral tertiary amine catalysts based on the quinidineframework such as β-ICD for asymmetric MBH/aza-MBH

reaction have been intensively investigated.5b Recent reportsdemonstrate that β-ICD is still an efficient chiral amine catalystwith good selectivity for asymmetric MBH/aza-MBH reaction

with respect to various substrates. Zhu’s group reported a β-ICD52a or β-ICD-amide 52b catalyzed aza-MBH reaction between

Scheme 17

Scheme 18

Scheme 19

Scheme 20

Scheme 21

Scheme 22

Scheme 23



N-sulfonylimines and alkyl vinyl ketones, affording (R)-enrichedproduct 53.33 This reaction was suitable for aromatic imines andaliphatic imines, affording the corresponding products inmoderate to good yields with excellent enatioselectivities.

Interestingly, they found that adding a catalytic amount of β-naphthol 54 led to the same reaction with reversed

Scheme 24

Scheme 25

Scheme 26

Scheme 27

Scheme 28



enantioselectivies, affording the product (S)-53 in excellentyields and enantioselectivities (Scheme 16). They hypothesizedthat theMannich-type coupling step may become the RDS in thepresence of achiral protic additive β-naphthol in this reaction,affording the (2S,3S) Mannich adduct 56 via a ternary Z-enolatecomplex 55. Subsequent β-naphthol-assisted β-elimination of(2S,3S) Mannich adduct 56 via a plausible six-membered cyclictransition state would then provide the observed (S)-aza-MBHadduct 53 (Scheme 17). They also performed a controlexperiment which indicated that both the amide-NH in 52band phenol-OH in 54 were important for the highenantioselectivity observed in this catalytic system. Subse-quently, Zhu’s group reported another β-ICD-amide catalyzedand β-naphthol cocatalyzed aza-MBH reaction using readilyavailable α-amidosulfones 57 as substrates to afford uniformlythe (S)-adducts 53 in high yields and excellent enantioselectiv-ities (Scheme 18).34 This is a domino process in which thecatalyst 52 served both as a base to trigger the in situ generationof N-sulfonylimine and then as a nucleophile to initiate the aza-MBH reaction. This reaction underwent smoothly with respectto various substrates under mild reaction conditions, whichprovided an easy access to α-methylene-β-amino-β-alkyl carbon-yl compounds with simple operations.Shi and co-workers almost simultaneously demonstrated the

similar asymmetric aza-MBH reaction of N-protected imines 58or N-protected α-amidoalkyl phenyl sulfones 57 with MVK orEVK catalyzed by β-ICD, affording highly enantioselective aza-MBH products 59 in good yields with high enantioselectivities(Scheme 19).35 Besides mild reaction conditions and operationalsimplicity since it avoided handing of unstable preformed imines,the reaction was found to be general with respect to various N-protected imines. Subsequently, Shi’s group reported a β-ICD-catalyzed asymmetric MBH reaction of isatin derivatives 60 withacrylates to afford 3-substituted 3-hydroxy-2-oxindoles 61 ingood yields with high enantioselectivities (Scheme 20).36 This isa first example to employ isatin derivatives as activated ketones inMBH reaction, which demonstrates an efficient syntheticmethod for the catalytic asymmetric construction of quaternarystereocenter. The obtained MBH adducts 3-substituted 3-hydroxy-2-oxindoles could be facilely transformed to 3-aryl-3-hydroxypyrrolidin-2-ones 62 with chirality remaining, whichwere precursors of promising drug candidates for treatment ofHIV-1 infection.Soon after Shi’s report, Lu’s group demonstrated the almost

same β-ICD-catalyzed asymmetric MBH reaction of isatinderivatives 63 with acrylates. They also showed that β-ICDwas an efficient catalyst for this reaction, affording 3-substituted3-hydroxy-2-oxindoles 64 in good yields with high enantiose-lectivities (Scheme 21).37 They pointed out that the C6′-OHgroup of β-ICD is probably to facilitate the key proton transferstep in the MBH reaction, via an intramolecular proton relayprocess. Meanwhile, Zhou and co-workers presented a β-ICDcatalyzed MBH reaction of isatin derivatives 65 and acrolein toprovide enantiomerically enriched 3-substituted 3-hydroxyox-

Scheme 29

Scheme 30

Scheme 31

Scheme 32

Figure 2. Proposed transition structures.



indoles 66, which could serve as valuable synthetic buildingblocks.38 They have shown that a variety of isatins worked wellwith acrolein to give the MBH adducts in good yields withexcellent ee’s (Scheme 22). The obtained MBH adducts could beeasily transformed into other compounds which can bepotentially used for the synthesis of the analogues of naturalproducts.In 2010, Connell and co-workers screened a series of chiral

amine nucleophiles 67−72 for the asymmetric MBH reaction ofaromatic and aliphatic aldehydes with cyclopentenone in thepresence of MgI2 as a cocatalyst (Scheme 23).39 They identifiedthat the Fu’s planar chiral DMAP catalyst 67 was the mostefficient catalyst for this asymmetric MBH reaction of a variety ofaromatic aldehydes or aliphatic aldehydes with cyclopentenone,affording the MBH products 74 in good to excellent yields andmoderate to excellent enantioslectivities. They have mentionedthat Lewis acid MgI2 as a cocatalyst could accelerate the reactionrate.Rouden and Maddaluno screened 20 new and easily prepared

diamines 75−94 for the asymmetric MBH reaction of MVK andsubstituted benzaldehydes (Scheme 24).40 Chiral nonracemic 3-(N,N-dimethylamino)-1-methylpyrrolidine 80 was found topromote efficiently the reaction of MVK with a variety ofortho- and para-substituted electron-deficient benzaldehydes,

affording the MBH products in good yields with enantiomericexcesses up to 73%.Liebscher and co-workers have demonstrated a novel dual

catalytic system composed of chiral α-guanidininoester 98 andtriphenylphosphine as an efficient catalytic system for theasymmetric MBH reaction (Scheme 25).41 This catalytic systemprovided the MBH products 99 in high yields with goodenantionselectivities up to 88% in the asymmetric MBHreactions of aromatic aldehydes with methyl acrylate. However,other Michael acceptors such as acrylonitrile or MVK were notsuitable for these asymmetric MBH reactions.Very recently, Terada reported an efficient guanidine/azole

cocatalytic system for theMBH reaction and achieved fairly goodenantioselectivies by using an axially chiral guanidine/azolebinary catalytic system.42 The MBH reaction was investigatedwith a series of aldehydes 100 and cyclic enones 101 usingtetramethylguanidine 102 and an azole 103 as the cocatalyticsystem in THF at room temperature (Scheme 26). A range ofaromatic aldehydes having different substituents underwent thereaction smoothly, giving the products 104 in moderate to highyields. The related enantioselective MBH reaction of 4-chlorobenzaldehyde and cyclpentenone was also investigatedusing chiral guanidine 105/azole 106 cocatalytic system,affording the product in high yield with moderate enantiose-lectivity (Scheme 26). The proposed mechanism is shown inScheme 27. In contrast to the generally accepted mechanism inwhich stable zwitterionic intermediates should be formed, theguanidine/azole binary system can be embedded into thecatalytic cycles of the MBH reaction without the formation ofzwitterionic intermediates, just through electrostatic interactionand hydrogen bonding.Takizawa and Sasai developed a new class of acid−base

bearing an imidazole unit chiral organocatalysts 107 and 108 foraza-MBH reaction of conjugated nitroalkenes 109 with imines110 (Scheme 28).43 They investigated the substrate scope under

Scheme 33

Scheme 34



the optimized reaction conditions. Regardless of whether thearomatic substituent R2 of imine 110 is electron-withdrawing orelectron-donating, organocatalysts 107 and 108 which includethe phenolic hydroxy groups as acidic functionalities and basicimidazole unit cooperatively activate nitroalkenes, promote thisaza-MBH reaction, affording the products 111 in good yieldswith moderate enantioselectivities. This reaction has limitationsfor some substrates, such as 4-methoxy-1-(2-nitrovinyl)benzene,2,4-dimethoxy-1-(2-nitrovinyl)benzene, (2-nitrovinyl)benzene,either leading to the desired products in low yields or withoutformation of the desired products.4.2. Catalytic Asymmetric Induction with Chiral PhosphineCatalysts

Chiral phosphines have been intensively used as efficientcatalysts inMBH/aza-MBH reactions.40 In a recent developmentof new chiral phosphines, the concept of multifunctional

catalysis, namely, the combination of Lewis basic and Brønstedacidic sites within one chiral backbone, has proved a powerfulstrategy for design of novel efficient catalysts in MBH/aza-MBHreactions and its related reactions.5c,44

In 2009, Liu’s group further developed and applied thismultifunctional strategy to design new chiral phosphines 25containing a Lewis base, a Brønsted base, and a Brønsted acidmoiety as shown in Figure 1. They first used these trifunctionalchiral phosphine catalysts 25 to catalyze an asymmetric aza-MBHreaction between N-tosylimines and MVK. The reactionsunderwent smoothly with fast reaction rates at room temper-ature, affording the corresponding products in good yields andenantioselectivities (Scheme 29).45 This catalytic systemrequired an acidic additive such as benzoic acid to confer itsenantioselectivity and rate improvement for both electron-richand electron-deficient imine substrates. They further rationalizedthe role of benzoic acid based on the hypothesis in which theyproposed the favored transition state involving formation ofhydrogen bonding and chiral ion pair between the catalyst andthe benzoic acid after protonation (Figure 2, proposed transitionstructures). In the disfavored transition structure, the desiredhydrogen bonding was not formed, and the rate of this pathwaydid not depend on the presence or absence of an ion pair. Acounterion-facilitated proton transfer process required the lowerenergy barrier, which allowed the substrates to pass through thispathway faster than other competing pathways and accounted for

Scheme 35

Scheme 36



the observation that the rate enhancement and enantioselectivityimprovement by using benzoic acid as an additive. Subsequently,

they developed a series of trifunctional chiral phosphine catalystsby tuning the acidity of the phenolic Brønsted acid group toimprove catalytic efficiency.46 They found that compared to thecatalyst 25a, the catalyst 25b with more acidic phenolic Brønstedacid group was more efficient for the aza-MBH reaction betweenN-tosylimines and MVK (Scheme 30). Furthermore, theydesigned and synthesized a series of new trifunctional catalysts112b−112e with a NH2 or NHTs Brønsted acid moiety andinvestigated their performance in generic aza-MBH reactions.47

Using catalyst 112d, better enantioselectivity was observed foraza-MBH reactions at relatively low catalyst loading (2.5 mol %)under facile conditions, and the substrate scope of catalyst 112dwas also investigated using a representative set of aryl imines andaryl aldehydes (Scheme 31). The para-substituted aryl iminescould undergo this reaction smoothly in the presence of catalyst

Scheme 37

Figure 3.

Scheme 38

Scheme 39



112d, giving the desired products in higher ee values. However,for the ortho-substituted ones, the corresponding products wereobtained in lower ee values, and for the aryl aldehydes, noreaction occurred under the standard conditions. They alsodemonstrated that the cooperativity between the counterion andtheNHTs Brønsted acid of the trifunctional catalyst was requiredfor good enantioselectivity and rate enhancement.Since Shi’s group first reported that 1,1′-bi-2,2′-naphthol

(BINOL)-derived chiral bifunctional phosphine 113 could beused as an effective catalyst in asymmetric aza-MBH reaction ofN-tosyl imines with MVK and phenyl acrylate,27 recently chiralbifunctional phosphine 113 has also been applied in aza-MBHwith respect to other substrates and its related reactions. Shi andco-workers demonstrated the asymmetric aza-MBH reaction ofN-protected α-amidoalkyl phenyl sulfones 114 with MVKcatalyzed by catalyst 113, affording highly enantioselective aza-MBH products 115 in good yields with high enantioselectivities(Scheme 32). Besides mild reaction conditions and operationalsimplicity since it avoided handling of unstable preformedimines, the reaction was found to be general with respect tovarious α-amidoalkyl phenyl sulfones.35 Sasai reported the firstdomino process based on the aza-MBH reaction catalyzed bybifunctional chiral phosphine (S)-113.48 On the basis of abifunctional strategy, they envisioned that chiral 1,3-disubsti-tuted isoindoline 118 could be acquired from enone 116 and N-tosylimine 117 with a Michael acceptor moiety at the orthoposition in the presence of a bifunctional chiral organocatalystbearing both Brønsted acid (BA) and Lewis base (LB) moieties.They proposed a catalytic cycle for the aza-MBH dominoreaction as shown in Scheme 33. Initially, the Michael addition ofthe bifunctional chiral phosphine to enone 116 generates chiralenolate I which is stabilized by the BA moiety of catalyst.Subsequently, chiral enolate I reacts with N-tosylimine 117 toform intermediate II. At this stage, the reaction may undergo twodivergent pathways. The first aza-MBH reaction pathwayinvolves proton-transfer from the α position of the carbonylgroup to the amine group and subsequent retro-Michael reactionof the organocatalyst, leading to the normal aza-MBH adduct119. In the second pathway, the nitrogen anion of intermediate IIcould further react with the attached Michael acceptorintramolecularly to afford intermediate III, which undergoesproton-transfer and subsequent retro-Michael reaction to furnishthe chiral isoindoline 118 along with regeneration of theorganocatalyst. They screened a series of commonly usedorganocatalysts for this enantioselective aza-MBH dominoreaction of enone with N-tosylimine, and they found that anacid−base organocatalyst (S)-113 was the most efficient catalystto mediate this reaction. After optimization of the reactionconditions, they investigated the scope of aza-MBH dominoreaction catalyzed by (S)-113, and the results are shown inScheme 34. The synthetic utility of the highly functionalized aza-MBH domino product was demonstrated through a variety oftransformations.Subsequently, Sasai and co-workers developed another

enantioselective aza-MBH domino process of α,β-unsaturatedcarbonyl compounds 122 and N-tosylimines 123 to affordtetrahydropyridine derivatives.49 They examined the catalyst (S)-113 and several other known chiral organocatalysts for this aza-MBH domino process (Scheme 35), and they found that theacid−base organocatalyst (S)-121 was the most efficient catalystfor this reaction, giving the product 124 or 125 in highenantioselectivity. The substrate scope under the optimizedreaction conditions was investigated. Regardless of whether the

aromatic substituent of 123 is electron-withdrawing or electron-donating, acid−base organocatalyst (S)-121 promotes thereaction, affording products 125 in moderate yields with goodto high enantioselectivities (Scheme 36). α,β-Unsaturated N-tosylimine was able to be used as a substrate for this reaction.?Wu and co-workers recently developed a new class of chiral

phosphine-squaramide catalysts to promote the asymmetricintramolecular MBH reactions of ω-formyleneones.50 They firsttested these new developed chiral phosphine-squaramidecatalysts 126 and several other related phosphine catalysts127−129 (Scheme 37) in this intramolecular MBH reaction.The chiral phosphine-squaramides 126a−c, containing differentalkoxyl scaffolds, all exhibited high catalytic activities, and theMBH adducts were obtained in very good yields andenantioselectivities. Subsequently, the substrate scope wasexplored in the presence of phosphine-squaramide 126a. Asshown in Scheme 37, the reactions worked well with acyclicsubstrates, bearing hydrogen, electron-withdrawing or electron-donating substituents on the phenyl group, to give the desiredadducts in good to high yield (64−98%) and excellentenantioselectivity (88−93% ee).More recently, Lu’s group designed and prepared a series of

novel bifunctional phosphine-sulfonamide organic catalysts130−135 from natural amino acids as shown in Figure 3,which were utilized to promote enantioselective aza-MBHreactions.51 L-Threonine-derived phosphine-sulfonamide 135bwas found to be the most efficient catalyst, and the reaction isapplicable to a wide range of aromatic imines, affording thedesired aza-MBH adducts in high yields and with excellentenantioselectivities (Scheme 38). Notably, the ortho-substitutedaromatic imines, which are well-known to be difficult substratesfor the aza-MBH reaction, were found to be suitable, and theproducts were obtained in nearly quantitative yields and with upto 97% ee. These results represent by far the bestenantioselectivities attainable for the ortho-substituted sub-strates in the aza-MBH reaction. In addition, imines withheterocyclic rings were also applicable. A less satisfactory resultwas obtained for a cyclohexyl imine.Sasai and co-workers have developed a new spiro-type

organocatalyst 136 having the Brønsted acid and Lewis basemoieties for the enantioselective aza-MBH reaction.52 Thisbifunctional spiro-phosphine catalyst was found to show highasymmetric induction to yield aza-MBH products (Scheme 39).

5. CATALYTIC ASYMMETRIC INDUCTION WITHCHIRAL LEWIS ACIDS

Ryu and co-workers reported a highly enantioselective and Z-stereocontrolled three-component coupling reaction of α,β-acetylenic esters, aldehydes, and trimethylsilyl iodide (TMSI)using chiral cationic oxazaborolidinium catalysts (Scheme 40).53

Both the enantiomers of (Z)-β-iodo MBH esters (R/S) could beobtained enantioselectively by using an S- or R-oxazaborolidi-nium salt (137 or 137′) which behaves as chiral Lewis acids andhas been proven to be an effective catalyst for Diels−Alderreactions, cyanosilylations, and Michael reactions. These esterscan be directly converted into the optically active (Z)-β-branched derivatives with retention of configuration. Theseresults are very useful in the synthesis of various optically active(Z)-β-branched MBH esters.Matsunaga, Berkessel, and Shibasaki found that La(O-iPr)3/

(S,S)-TMS-linked-BINOL 138 complex combined with acatalytic amount of DABCO could efficiently catalyze the aza-MBH reaction of a broad range of N-diphenylphosphinoyl



imines 139 with methyl acrylate.54 Aryl and heteroaryl imineswere all suitable for this reaction, affording the desired products140 in 77−99% yield and 81−95% ee. Alkenyl imines, theisomerizable alkyl imines, could be employed as well, givingproducts in 67−89% yield and 89−98% ee (Scheme 41). Kineticstudies pointed out the importance of both the nucleophilicity ofLa-enolate and the Brønsted basicity of a La-catalyst forpromoting the reaction.

6. CATALYTIC ASYMMETRIC INDUCTION WITHCHIRAL BRøNSTED ACIDS

6.1. Catalytic Asymmetric Induction with Chiral Thioureas

Nagasawa first reported a highly efficient chiral thiourea catalystfor enantioselective MBH reaction in 2004.55 Subsequently,Jacobsen reported a chiral thiourea catalyst for the highlyenantioselective aza-MBH reaction.56

In 2011, Ito found an efficient chiral biaryl-based bis(thiourea)organocatalyst 141 for asymmetric MBH reactions of 2-cyclohexen-1-one with aldehydes.57 Good yields and highenantioselectivities were achieved in the reaction of 2-cyclo-hexen-1-one with both aromatic aldehydes and aliphaticaldehydes (up to 86% yield, 96% ee) (Scheme 42).

Recently, Wu and co-workers developed a series of chiralbifunctional phosphinethioureas which were used as effectiveorganocatalysts in the enantioselective MBH/aza-MBH reac-tions. They first synthesized a series of chiral bifunctionalphosphinethioureas 142 (Scheme 43) and applied them to theenantioselective MBH reaction of aromatic aldehydes withacrylates.58 It is particularly noteworthy that this new catalyticsystem is suitable for various commercially available acrylates.With 8 mol % of phosphinothiourea 142e, the MBH reactioncould proceed in 5−24 h under mild conditions and afford thedesired products in moderate-to-excellent yields (up to 96%)with up to 77% ee (Scheme 43). Subsequently, they synthesized anew type of chiral bifunctional phosphinethioureas derived fromL-valine which were also efficient for the asymmetric MBHreaction of acrylates with aldehydes.59 They evaluated thesecatalysts 142b−c, 143 in the asymmetric MBH reaction of 4-nitrobenzaldehyde with methyl acrylate (Scheme 43) and foundthat catalyst 143a was the most efficient catalyst. Then, theyfound that theMBH reactions of various aldehydes with acrylatesoccurred smoothly in the presence of 10 mol % 143a, affordingthe desired product in moderate-to-excellent yields with goodenantioselectivities up to 83% ee (Scheme 43). Later, theyreported that these chiral cyclohexane-based phosphineureas andchiral bifunctional phosphinothioureas derived from L-amino

Scheme 40

Scheme 41

Scheme 42



acids were also efficient organocatalysts for the enantioselectiveintramolecular MBH reactions of ω-formyl-α,β-unsaturatedcarbonyl compounds.60,61 In the presence of 3 mol % of

phosphinothiourea 142c, various ω-formyl-enone substratesunderwent the enantioselective intramolecular MBH reactionsmoothly, giving the desired products in good-to-excellent yieldswith up to 98% ee under mild reaction conditions (Scheme 44).These bifunctional phosphinothioureas 143 synthesized startingfrom different amino acids, including L-valine, L-alanine, and L-phenylalanine could promote the enantioselective intramolecu-lar MBH reactions of ω-formyl-α,β-unsaturated carbonylcompounds, and the cyclic MBH products were obtained ingood to-excellent yields with up to 84% ee in dichloromethane atroom temperature (Scheme 44). More recently, they demon-strated that the chiral cyclohexane-based phosphineureas 142bwere also efficient to catalyze the enantioselective MBH reactionof acrylates with isatins.62 In the presence of 10 mol % ofphosphinothiourea 142b, the MBH reaction of acrylates withisatins could proceed smoothly to afford 3-substituted-3-

Scheme 43

Scheme 44

Scheme 45

Scheme 46



hydroxyl-oxindole derivatives in excellent yields (82−99%) andmoderate enatioselectivities (up to 69% ee) (Scheme 45).Lu and co-workers also developed a series of chiral

bifunctional phosphine-thiourea organocatalysts based onnatural amino acid scaffolds.63 They first synthesized L-threonine-derived bifunctional phosphine-thiourea catalyst 145and found that it was an effective catalyst for asymmetric MBHreactions of acrylates with aromatic aldehydes. A range ofaromatic aldehydes with different substituents were suitable forthis asymmetric MBH reaction, affording the desired MBHadducts in good yields with up to 90% ee. They also investigatedthe influences of various additives such as MeOH, PhOH, 2-naphthol, PhCOOH, and revealed that the hydrogen bondinginteractions play a key role in the enantioselectivity.In 2009, Xu and co-workers reported the first example of a

diastereo- and enantioselective aza-MBH-type reaction whichwas accomplished by the asymmetric synthesis of β-nitro-γ-enamines via a (1R,2R)-diaminocyclohexane thiourea derivativemediated tandem Michael addition and aza-Henry reaction.64 Inthe presence of catalyst 146, a variety of N-tosyl iminesunderwent this reaction smoothly, affording the desired products

in good yields (up to 95%) and high enantioselectivities (up to95% ee) and diastereoselectivities (up to 1:99 dr) (Scheme 47).

6.2. Catalytic Asymmetric Inductionwith ProlineDerivatives

Vesely have reported an organocatalytic highly enantioselectiveaza-MBH reaction of α,β-unsaturated aldehydes with in situgenerated N-Boc and N-Cbz imines from the correspondingsulfones under mild and easy conditions.65 They first screeneddifferent catalysts 147a−e shown in Figure 4, solvents and basesystems to achieve high enantioselectivities, diastereoselectiv-ities, and yields. The (S)-proline 147a with DABCO wasidentified as the best catalytic system for this reaction, and CHCl3was the best solvent choice. An excess amount of KF was alsoadded, which was crucial for enhancement of the diastereose-lectivity of the reaction. After the optimal reaction conditionswere obtained, they investigated the reaction scope by usingvarious α-amido sulfones and α,β-unsaturated aldehydes.Subsequently, the direct highly enantioselective addition ofα,β-unsaturated aldehydes 148 to bench-stable N-carbamate-protected α-amido sulfones 149 was investigated again, givingthe corresponding products 150 in good yields up to 87% withhigh enantioselectivities up to 99% ee (Scheme 48).66 They alsoreported a highly enantioselective organo-co-catalytic aza-MBHtype reaction between N-carbamate-protected imines and α,β-unsaturated aldehydes.66 Initially, they screened the cocatalyticsystems, and the combination of (S)-proline 147a and DABCOwas identified as the best cocatalytic system for this reaction.After optimization of reaction conditions, they investigated thescope of the catalytic entioselective addition of enals to N-Boc-protected imines. The corresponding β-amino aldehydes wereobtained in good yields with high ee’s (86−99%) (Scheme 49).In 2010, Aleman and co-workers reported the first highly

enantioselective oxa-Michael/aza-MBH tandem reaction be-tween 2-alkynals and tosylimines leading to optically active 4-amino-4H-chromenes using proline derivatives as organo-

Scheme 47

Figure 4.

Scheme 48



catalysts.67 A series of proline and its derivatives as shown inFigure 5 were screened for this reaction, and the results revealedthat 147f was the best catalyst. In order to check the scope of thereaction, they explored reactions of different aryl, alkyl, andalkenyl alkynals 151 with 152 under the optimized conditionswhich were to carry out with the reaction catalyzed by 20 mol %or 5 mol % 147f in the presence of toluene at room temperature,affording the desired products 153 (Scheme 50). The alkynal’s

aromatic ring having electron-donating substituents (p-Me, o-MeO, and p-MeO) did not affect the stereoselectivity, giving thecorresponding products with ee’s in the range of 94−98%;electron-withdrawing group at the alkynal’s aromatic ring alsogave the corresponding product with good enantioselectivity,however in low yield (55%). Decreasing the catalytic loading to 5mol % did not diminish the yield and stereoselectivity. Otheralkyl groups at para-position of alkynal’s aromatic ring, such asnPent and tBu also produced excellent ee’s with both 20 mol %and 5 mol % of catalyst. The reactions of alkynals bearing alkyl oralkenyl chains, instead of aryl ones, produced good stereo-selectivity and isolated yields.Ramachary and co-workers have demonstrated the proline

147h/thiourea 154 cocatalyzed asymmetric MBH-type reactionsfrom Hagemann’s esters 155 with nitroolefins 156 under

Scheme 49

Figure 5.

Scheme 50

Scheme 51

Scheme 52

Scheme 53



ambient conditions.68 This novel asymmetric MBH-typereaction was suitable for a range of nitroolefins, affording thecorresponding products 157 in fairly good yields with highenantioselectivities (Scheme 51). They also demonstrated theapplication of chiral MBH-type products in the synthesis ofhighly functionalized cyclohexenones.

6.3. Catalytic Asymmetric Induction with Chiral Thiols

More recently, Miller and co-workers reported that ortho-mercaptobenzoic acid and ortho-mercaptophenols 158 could beused as efficient thiol catalysts in both the intramolecular MBHand Rauhut−Currier (RC) reaction, and they also demonstratedthat chiral mercaptophenol afforded the reaction with low tomoderate enatioselectivities (Scheme 52).69 Under establishedoptimal reaction conditions, chiral catalysts (S)- and (R)-159afforded high yields and moderate asymmetric inductions in theMBH reactions. The obtained enantioselectivities was notaffected significantly by the amount of water and base added,catalyst loading, and substrate concentration but were markedlyinfluenced by the reaction temperature. Interestingly, bothincreasing and decreasing the temperature from the establishedvalue of 70 °C resulted in lower ee values. The catalyst (R)-160completely lost catalytic activity, indicating that a proticsubstituent in the ortho-position to the nucleophilic thiol playsa crucial role for catalytic activity.

7. RECENT TRANSFORMATION OF MBH ADDUCTSCATALYZED BY ORGANOCATALYSTS

The transformation of MBH adducts have attracted a lot ofattention from organic chemists since they are syntheticallyimportant synthons.70 Organic chemists have continued to maketheir efforts on transformation of MBH adducts based ondifferent strategies. Herein, we focus on recent reports fortransformation of MBH adducts catalyzed by organocatalysts.

7.1. Allylic Substitution Reactions of MBH Acetates andCarbonates

In 2001, Basavaiah first reported a SN2’ reaction on quinidiniumsalt of the Baylis−Hillman bromides to produce chiral Morita−Baylis−Hillman propargylic ethers.71 Recently, asymmetrictransformations of MBH adducts via substitution of MBHadducts by nucleophiles as described in Scheme 53 have beencommonly used and reported intensively.In 2004, Krische and co-workers reported the phosphine-

catalyzed intermolecular allylic substitution reactions of MBHacetates, wherein N- and C-nucleophiles such as 4,5-dichlor-ophthalimide and 2-trimethylsilyloxyfuran (TMSOF) wereutilized to generate allylic amines and γ-butenolides in highregioselectivities and in good yields, respectively.72 In 2008, Shi’sgroup developed catalyst 161, which was originally designed foraza-MBH reaction, achieved high yield and excellent ee for theallylic substitution of 2-trimethylsilyloxy furan, which is aneffective approach for the asymmetric synthesis of γ-butenolides(Scheme 54).73 The experimental observations revealed that theactive amide proton in 161 was critical to the catalytic reactivityand enantioselectivity. Subsequently, they designed andsynthesized a series of novel multifunctional, chiral amide−

Scheme 54

Scheme 55



phosphane organocatalysts 162 for the allylic substitution ofMBH acetate with 2-trimethylsilyloxyfuran for butenolidesynthesis, which were suitable for a wide range of substrates inabsolute MeOH or CH3CN, affording the desired products ingood to excellent yield (42−98%) and high ee (85−99%)

(Scheme 54).74 NMR tracing experiments were conducted to

identify the critical phosphonium intermediates in the catalytic

cycles. Computational studies were also carried out to account

for the origins of diastereo- and enantioselectivity, which

Scheme 56



revealed that the active proton of the amide moiety was thecritical factor for the catalyst to have high enantiofacial control.Shi’s group also developed a series of L-proline derived chiral

phosphine-amide catalysts and examined their performance.Using catalyst 163, they obtained the products in good yieldswith moderate ee’s, which could not be achieved successfully inprevious studies (Scheme 55).75 Their results demonstrated thatthe chirality of proline moiety had some influences on thereaction outcomes but did not show any significant match/mismatch between the chirality of binaphthol and proline.Replacing the active amino proton of proline byN-Boc group didnot decrease the yield and enantioselectivity significantly,

suggesting that the active amino proton of the proline moietymight be dispensable in this reaction.More recently, Shi’s group further developed a series of chiral

phosphine-thioureas 164−166, chiral amine 169 or used(DHQD)2PHAL 167, (DHQD)2PYR 168, as efficient organo-catalysts for asymmetric substitutions of MBH adducts withvarious prenucleophiles 170−176 (Scheme 56).76 High yieldsand good enatioselectivities were achieved under mild reactionconditions with respect to a wide range of MBH adducts andvarious prenucleophiles such as phthalimide, oxazolones,diphenyl phosphite, pyrrole derivatives, carbamates, tosylcarbamates, and isatins.

Scheme 57



Chen’s group has also developed a series of asymmetricsubstitutions of MBH adducts with various prenucleophiles177−183 catalyzed by modified cinchona alkaloids β-ICD,(DHQD)2PHAL 167, (DHQD)2PYR 168, and (DHQD)2AQN184 (Scheme 57).77 The corresponding products have beenobtained in high yields (up to 98%) with good-to-excellentenantioselectivities (up to 99% ee). The allylic substitutedproducts could be smoothly transformed into more complexcompounds in good yields without any racemization.

Wang’s group developed an asymmetric organocatalytic allylicsubstitution reaction of MBH carbonates with phosphine oxides185 or 186 using quinidine as a base catalyst.78 Thisorganocatalytic approach provides an easy and efficient methodfor the direct preparation of optically allylic phosphine oxideswith satisfactory yields and enantioselectivities (Scheme 58).More recently, they developed an asymmetric allylic substitutionreaction of MBH carbonates with allylamines 187, affording N-allyl-β-amino-α-methylene esters in high yields and enantiose-lectivities (Scheme 58).79

Scheme 58

Scheme 59



7.2. Annulation of MBH Acetates and Carbonates withElectron-Deficient Olefins

Among these transformations, annulation of MBH acetates andcarbonates with electron-deficient olefins is an extremely usefulsynthetic method to construct multifunctional cyclic compounds

because the in situ generated phosphorus ylides from MBHacetates and carbonates in the presence of tertiary phosphines arevery reactive 1,3-dipoles in a variety of annulations. Morerecently, Zhang, Huang, and He and co-workers have alsodeveloped several MBH acetates and carbonates involving [4 +1] annulations to give the corresponding annulation products inhigh yields, respectively (Scheme 59).80

In 2010, Tang and Zhou first reported the asymmetric versionof intramolecular [3 + 2] annulation using the derivative of MBHadducts. They utilized spirobiindane-based chiral phosphines ascatalysts to provide the corresponding products in good yieldsalong with high ee values (Scheme 60).81

Scheme 60

Scheme 61

Scheme 62

Scheme 63

Scheme 64

Scheme 65

Scheme 66

Scheme 67



In 2011, Shi’s group reported a phosphine-catalyzed highlyregio- and diastereoselective [3 +2] annulation of MBHcarbonates with isatylidene malononitriles to produce spirocy-clopenteneoxindoles in good yields under mild conditions(Scheme 61).82 They also demonstrated one example for anasymmetric version of the [3 + 2] annulation of MBH carbonatewith isatylidene malononitriles catalyzed by the chiral bifunc-tional thiourea phosphine catalyst 191, affording the desiredproduct in high yield with good enantioselectivity anddiastereoselectivity (Scheme 62).Barbas and co-workers reported a similar enantioselective

reaction of [3 + 2] annulation of MBH carbonates withmethyleneindolines.83 The best catalyst for this reaction waschiral diphosphine 192. This reaction afforded the finalspirocyclic products 193 in good yields with excellent stereo-selectivities (Scheme 63). The clear limitation of this reaction isthe low enantioselectivity obtained when alkyl MBH carbonateswere used. Barbas and co-workers believe that the seconddiphosphine has a major impact on the stereoselectivity.In 2011, Lu’s group developed a threonine-derived phosphine

thiourea catalyst 194 for the promotion of the stereoselective [3+ 2] cycloaddition process between the MBH carbonates andisatin-derived tetrasubstituted alkenes, giving the products inhigh yields with excellent enantioselectivities (Scheme 64).84

This strategy allows facile enantioselective preparation ofbiologically important 3-spirocyclopentene-2-oxindoles withtwo contiguous quaternary centers.Very recently, Shi and co-workers further developed a series of

multifunctional thiourea-phosphines derived from natural aminoacid and first applied them in asymmetric [3 + 2] annulations ofMBH carbonates with trifluoroethylidenemalonates.85 Themultifunctional thiourea-phosphine 195 was the best catalystfor this reaction, affording the highly functionalized trifluor-omethyl- or pentafluoroethyl-bearing cyclopentenes in excellentyield (up to >99%) and enantioselectivity (up to 96%) (Scheme65).Liu and co-workers reported a Me-DuPhos (196) catalyzed

efficient asymmetric [3 + 2] cycloaddition reaction betweenMBH carbonates of isatins and N-phenylmaleimide.86 They firstscreened a series of chiral diphosphine reagents and thenidentified that theMe-DuPhos (196), which was commonly usedas a ligand, was an efficient organocatalyst for [3 + 2]cycloaddition reaction between MBH carbonates of isatins andN-phenylmaleimide. A wide range of MBH carbonates derivedfrom substituted isatins were suitable for this asymmetric [3 + 2]cycloaddition reaction, giving the corresponding spirooxindolesin good yields (up to 89%) with excellent diastereoselectivitiesand high enantioselectivities (up to 99% ee) (Scheme 66).

8. RECENT DEVELOPMENTS IN ASYMMETRICRAUHUT−CURRIER REACTION

The Rauhut−Currier (RC) reaction, also known as vinylogousMBH reaction, involves the coupling of one active alkene/latentenolate to a second Michael acceptor, creating a new C−C bondbetween the α-position of one activated alkene and the β-position of a second alkene under the influence of a nucleophiliccatalyst.87 As a variant of MBH reaction, RC reaction, especiallyenatioselective RC reaction, has not been investigated intensivelyuntil now. Herein, we would like to overview the recentdevelopments in asymmetric RC reaction since it may becomeanother hot topic in the near future.The first enantioselective version of the intramolecular RC

reaction was presented by Miller’s group using cysteine-based

catalyst.88 They examined a variety of traditional MBH catalystsand cysteine-based catalysts for the intramolecular RC reaction.They found that cysteine-based catalysts were effective catalystsand identified the catalyst 197 exhibits extraordinary reactivityand enantiotopic control ability. After extensive screening ofreaction conditions, they demonstrated that electron-deficient

Scheme 68

Scheme 69

Scheme 70

Scheme 71



and electron-rich aryl symmetrical bis(enones) as well asaliphatic and heteroaromatic bis(enones) were viable substratesin the presence of catalyst 197 under optimal reaction conditions(Scheme 67). Mechanistic studies also provided insights on thepotential mechanism of the reaction and the suggested possibletransition states shown in Scheme 68 that provide an explanationfor the absolute stereochemistry formed in the observedproducts. More recently, Miller and co-workers showed thatthe aforementioned chiral thiol catalyst (R)-159 was also anefficient catalyst for intramolecular enantioselective RC reaction,

however, with low enantioselectivity (Scheme 69).69 Subse-quently, they further developed a cysteine-based catalyst 197catalyzed RC reaction, which was the key step in the quasi-biomimetic synthesis of natural product Sch-642305 and relatedanalogues (Scheme 70).89

In 2009, Christmann and co-workers developed anenantioselective organocatalytic RC-type cyclization of α,β-unsaturated aldehydes catalyzed by the commercially availableJørgensen−Hayashi catalyst 147d with AcOH.90 The iridoidproducts, cyclopentene derivatives bearing a tetra-substitutedolefin, were obtained in moderate to good yields (up to 73%yield) with good enantioselectivity (up to 96% ee) (Scheme 71).In 2011, Wu’s group also demonstrated an enantioselective

RC reaction catalyzed by chiral phosphinothiourea derived fromL-valine.91 A wide substrate scope with respect to bis(enones)with symmetrical substituents 198 underwent this RC reactionsmoothly, affording the desired products 199 in excellent yields(up to 99%) and enantioselectivities (90−99.4% ee) (Scheme 72,eq 1). In addition, the substrate 200 with unsymmetricalsubstituents, bearing both a strong electron-withdrawing groupand a strong electrondonating group, was also investigated(Scheme 72, eq 2). A regioisomeric mixture in favor of 201a wasobtained in total yield of 74%. Compared to the correspondingsymmetrical substrates, the enantioselectivity was remarkablydecreased. The results indicated that both the alkene activationby a nucleophilic catalyst and the coupling of an activated alkeneto a second Michael acceptor had influence on the RC reaction.Meanwhile, Gu, Xiao, and co-workers extended this intra-molecular RC reaction to nitroolefin enoates.92 The thioureaderivative 202 combined with achiral nucleophilic promoter 203was identified as an efficient hydrogen-bonding catalyst for thisintramolecular RC reaction with respect to a wide range ofsubstrates, affording the corresponding RC product in high yieldswith good enantioselectivities (Scheme 73).Soon after, Shi’s group reported the first example of chiral

amine catalyzed highly enantioselective intermolecular RCreaction of maleimides with allenoates and penta-3,4-dien-2-one.93 The traditional catalyst β-ICD for MBH reaction couldalso catalyze this intermolecular RC reaction with respect to awide range of substrates, affording the desired functionalizedallene derivatives in good to high yields with good to excellentenantioselectivities (Scheme 74).

Scheme 72

Scheme 73

Scheme 74

Scheme 75



Very recently, Sasai developed a highly atom-economical,chemo-, diastereo-, and enantioselective Rauhut−Currierreaction catalyzed by amino acid based chiral phosphine 133(Scheme 75).94a Aliphatic- and aromatic-substituted startingmaterials 204 were successfully cyclized to give the medicinallyimportant product α-alkylidene-γ-butyrolactones 205 in goodyields (up to 99%) with high enantioselectivities (up to 98% ee).Subsequently, they presented a report with more details on thishighly chemo-, diastereo-, and enantioselective RC reaction andgave a few examples of RC product transformations.94b

9. CONCLUSIONSDuring the past few years, different aspects of MBH/aza-MBHreactions, especially asymmetric MBH/aza-MBH reactions, havebeen studied intensively. In fact, significant developments havebeen made in the design of new chiral catalysts such as chiralamines, phosphines, and thioureas based on the concept of bi/multifunctionality for the asymmetric version of the MBH/aza-MBH reaction, and high enantioselectivities have been achieved.Although many important factors governing the reactions wereidentified, the present understanding of the basic factors, and thecontrol of reactivity and selectivity, remains incomplete. There isno one catalyst which is suitable for all substrates so far, and thusthe development of effective catalysts and catalyst diversity forasymmetric MBH/aza-MBH reactions that are applicable tomost of the common activated alkenes and electrophiles stillcontinues to be a challenging endeavor.

10. LATEST DEVELOPMENTSSince this manuscript was submitted for publication, several minireviews and new interesting reports on asymmetric MBH/aza-

MBH reactions and the applications of MBH/aza-MBH adductshave appeared in the literature. Hatakeyama reviewed theapplications of organocatalysts for enantioselective MBH/aza-MBH reactions,95 and Takemoto also briefly overviewed theapplications of bifunctional (thio)urea catalysts in aza-MBHreactions.96 Vasconcellos first highlighted the potentialities ofMBH adducts as a new class of bioactive compounds to thediscovery of new cheaper and efficient drugs.97

Wu’s group continually developed new chiral phosphine-squaramide catalysts 206 and employed them to catalyze theenantioselective MBH reaction of acrylates with isatins toconstruct 3-hydroxy-2-oxindoles with quaternary stereocen-ters.98 A variety of isatins and acrylates except for phenyl acrylateunderwent this reaction smoothly, affording chiral 3-hydroxy-2-oxindoles in good-to-excellent yields (up to 99%) with highenantioselectivities (up to 99% ee after a simple recrystallization)(Scheme 75). Very recently, they applied newly developedbifunctional phosphinothioureas 207 derived from saccharide topromote the enantioselective MBH reaction between acrylatesand aldehydes.99 The desired MBH adducts were obtained in upto 96% yield and 83% ee under mild reaction conditions in thepresence of glucose-based phosphineothiourea (Scheme 76).Zhou and co-workers first reported the asymmetric MBHreaction of aromatic aldehydes with acrolein catalyzed by β-ICDwith 2,6-dimethoxybenzoic acid. The aromatic aldehydes with

Scheme 76

Scheme 77

Scheme 78



electron-withdrawing substituents would facilitate this reaction,giving the desired products in up to 87% yield with up to 81% ee(Scheme 77).100 Rinaldi also demonstrated to synthesize the aza-MBH adducts mediated by cinchona alkaloids as promotors;101a

they recently reported that β-ICD and its derivatives wereefficient catalysts for MBH reactions of acrylates with aldehydes,and they also exploited the reaction mechanism throughexperimental and computational techniques.101b Shi’s groupdeveloped a new multifunctional chiral phosphine-amide typecatalyst 208 which combined with the BINOL derivative couldefficiently catalyze the asymmetric aza-MBH reaction of 5,5-disubstituted cyclopent-2-enones with N-sulfonated imines,affording the corresponding products in good to outstandingyields withmoderate to good ee’s undermild conditions (Scheme78).102 They also demonstrated a highly enantioselective aza-MBH reaction of isatin-derived ketimines with MVK catalyzedby chiral amine β-ICD or chiral phosphine 113.103

Lu’s group first applied phthalides in the asymmetric allylicalkylation (AAA) reaction with MBH carbonates to accessoptically enriched 3,3-disubstituted phthalides.104 By employingbifunctional chiral phosphines 194 or multifunctional tertiaryamine-thioureas 209 as the catalyst, γ-selective or β-selectiveallylic alkylation products were obtained, respectively, in highyields with excellent enantioselectivities (Scheme 79). Sub-

sequently, they developed AAA reaction of isatin-derived MBHcarbonates with nitroalkanes catalyzed by β-ICD, affording thedesired products in up to 92% yield with up to 92% ee (Scheme79).105 Rios also reported the AAA reaction of MBH carbonateswith 2-fluoromalonates catalyzed by β-ICD, affording the finalfluorinated products in good yields and enantioselectivities(Scheme 79).106

Lu’s group107 and Shi’s group108 almost simultaneouslyreported the catalytic asymmetric [3 + 2] annulation of MBHcarbonates with malaimides by using different chiral phosphinecatalysts. Lu’s group used L-Thr-L-Val-derived phosphine 210 ascatalyst to synthesize the functionalized bicyclic imides whichwere obtained in excellent yields, and with high diastereose-lectivities and nearly perfect enantioselectivities (Scheme 80).Shi’s group developed a multifunctional thiourea-phosphine 211which also efficiently catalyzed asymmetric [3 + 2] annulation ofMBH carbonates withmalaimides, affording the desired productsin moderate to excellent yields and excellent diastereo- andenantioselectivities (Scheme 80). Subsequently, they applied thismultifunctional thiourea-phosphine 211 in the asymmetric [3 +2] annulation reactions of 2-arylideneindane-1,3-diones withMBH carbonates, producing the corresponding quaternarycarbon centered spirocyclic cyclopentenes in moderate yields,

Scheme 79



with high diastereoselectivities and enantioselectivities undermild conditions (Scheme 80).109

Inspired by Lu’s work on chiral phosphine catalysts based onthe skeletons of natural amino acids,84 Zhong and Lohsynthesized the chiral phosphine catalysts derived from L-leucineand applied them on a catalytic asymmetric [4 + 2] annulationreaction initiated by an aza-RC reaction.110 A wide range of aryl1-aza-1,3-dienes underwent the [4 + 2] annulation process withMVK or EVK smoothly in the presence of 10 mol % chiralphosphine 212, generating tetrahydropyridine adducts withexclusively trans diastereoselectivity and excellent enantioselec-tivity in high to excellent chemical yields (Scheme 81). Chi andco-workers also employed an amino acid derived chiralphosphine 133 to achieve an intramolecular aza formal [2 + 4]reaction between α,β-unsaturated imines and electron-deficientalkenes through a tandem RC/SN2-substitution sequence.111

More recently, Shi’s group reported a catalytic asymmetricintramolecular RC reaction catalyzed a highly nucleophilic

multifunctional chiral phosphine.112 They demonstrated that ahighly nucleophilic multifunctional chiral phosphine 213 was anefficient catalyst for the asymmetric intramolecualr RC reactionof bis(enone)s, affording the corresponding cyclohexene 214and cyclopentene 215 products in moderate to good yields andwith good to high ee values under mild conditions (Scheme 82).

Scheme 80

Scheme 81 Scheme 82



AUTHOR INFORMATIONCorresponding Author

*E-mail: [email protected]. Fax: 86-21-64166128.

Notes

The authors declare no competing financial interest.

Biographies

Dr. Prof. Min Shi was born in Shanghai, China. He received his BS in1984 (Institute of Chemical Engineering of East China, now named asEast China University of Science and Technology) and PhD in 1991(Osaka University, Japan). He had his postdoctoral research experiencewith Prof. Kenneth M. Nicholas at University of Oklahoma (1995-6)and worked as an ERATO Researcher in Japan Science and TechnologyCorporation (JST) (1996-8). He is currently a group leader of the StateKey Laboratory of Organometallic Chemistry, Shanghai Institute ofOrganic Chemistry, Chinese Academy of Sciences (SIOC, CAS). Hisresearch interest is in photochemistry, total synthesis of naturalproducts, asymmetric synthesis, Morita-Baylis-Hillman reaction, fixationof CO2 using transition metal catalyst.

Dr. Yin Wei was born in 1977 in Henan (P. R. China). She received herPhD from Ludwig-Maximilians-Universitat in Munchen (Germany) in2009 under the direction of Professor Hendrik Zipse. Subsequently shejoined in Professor Min Shi’s group at Shanghai Institute of OrganicChemistry, Chinese Academy of Sciences (SIOC, CAS) as an assistantprofessor. She is currently working on the theoretical studies oforganocatalysis.

ACKNOWLEDGMENTSWe thank the Shanghai Municipal Committee of Science andTechnology (11JC1402600), the National Basic ResearchProgram of China (973)-2010CB833302, and the NationalNatural Science Foundation of China for financial support

(21072206, 20472096, 20872162, 20672127, 21121062,20732008, and 21102166).

ABBREVIATIONSAc acetylAr arylBn benzylBoc tert-butoxycarbonylBu butylB3LYP Becke-3-Lee−Yang−ParrCBS-4M Complete Basis Set-4MCbz carboxybenzylCy cyclohexylDABCO 1,4-diazabicyclo[2.2.2]octaneDBU 1,8-diazabicyclo[5.4.0]undec-7-eneDCE 1,2-dichloroethaneDMF dimethyl formamideDMSO dimethyl sulfoxideDppb 1,4-bis(diphenylphosphino)butaneE2 bimolecular eliminationE1cb 2-step, base-induced β-eliminationEt ethylEVK ethyl vinyl ketoneEWG electron withdrawing groupHex hexylβ-ICD β-isocupreidineLG leaving groupMe methylMP2 Møller−Plesset perturbation theory for second orderMs mesylMS Molecular sieveMVK methyl vinyl ketonePh phenylPMB para-methoxybenzylPr propylTBDPS tert-butyldiphenylsilylTBS tert-butyldimethylsilylTDS thexyldimethylsilyltert tertiaryTHF tetrahydrofuranTIPS triisopropysilylTMS trimethylsilylTr tritylTs tosylPMP para-methoxyphenyl

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