Recent Advances in Metal-Catalyzed Asymmetric 1,4-Conjugate

Review Cite This: Chem. Rev. 2018, 118, 7586−7656

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Recent Advances in Metal-Catalyzed Asymmetric 1,4-Conjugate Addition (ACA) of Nonorganometallic Nucleophiles Ke Zheng, Xiaohua Liu, and Xiaoming Feng*

Chem. Rev. 2018.118:7586-7656. Downloaded from pubs.acs.org by UNIV OF KENTUCKY on 08/22/18. For personal use only.

Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. China ABSTRACT: The metal-catalyzed asymmetric conjugate addition (ACA) reaction has emerged as a general and powerful approach for the construction of optically active compounds and is among the most significant and useful reactions in synthetic organic chemistry. In recent years, great progress has been made in this area with the use of various chiral metal complexes based on different chiral ligands. This review provides comprehensive and critical information on the enantioselective 1,4-conjugate addition of nonorganometallic (soft) nucleophiles and their importance in synthetic applications. The literature is covered from the last 10 years, and a number of examples from before 2007 are included as background information. The review is divided into multiple parts according to the type of nucleophile involved in the reaction (such as C-, B-, O-, N-, S-, P-, and Sicentered nucleophiles) and metal catalyst systems used.

CONTENTS 1. Introduction 2. C−C Bond Formation by Metal-Catalyzed ACA Reactions 2.1. Conjugate Addition of 1,3-Dicarbonyl Compounds 2.1.1. Using Chiral Diamines as Ligands 2.1.2. Using Chiral Bisoxazolines as Ligands 2.1.3. Using Chiral N,N′-Dioxides as Ligands 2.1.4. Using Chiral Schiff Bases as Ligands 2.1.5. Other Chiral Ligands 2.2. Conjugate Addition of Nitroalkanes or Malononitrile 2.2.1. Using Chiral Bisoxazolines as Ligands 2.2.2. Using Chiral N,N′-Dioxides as Ligands 2.2.3. Other Chiral Ligands 2.3. Conjugate Addition of Aldehydes and Ketones 2.3.1. Using Chiral Diamines as Ligands 2.3.2. Using Chiral Bisoxazolines as Ligands 2.3.3. Using Chiral Amino Acids as Ligands 2.3.4. Other Chiral Ligands 2.4. Conjugate Addition of Amino Acid Derivatives 2.4.1. Using Chiral Bisoxazolines as Ligands 2.4.2. Using Chiral Ferrocenyl Phosphines as Ligands 2.4.3. Other Chiral Ligands 2.5. Conjugate Addition of Oxindoles 2.5.1. Using Chiral Schiff Bases as Ligands 2.5.2. Using Chiral N,N′-Dioxides as Ligands 2.5.3. Other Chiral Ligands 2.6. Conjugate Addition of Cyanides © 2018 American Chemical Society

2.7. Conjugate Addition of Alkynes 2.8. Conjugate Addition of Vinylogous Nucleophiles and Indoles 2.9. Conjugate Addition of Other Carbon Nucleophiles 2.10. Summary 3. C−Heteroatom Bond Formation by Metal-Catalyzed ACA Reactions 3.1. Conjugate Addition of Boron Nucleophiles 3.1.1. Using Chiral Phosphines as Ligands 3.1.2. Using Chiral NHCs as Ligands 3.1.3. Other Chiral Ligands 3.2. Conjugate Addition of Oxygen Nucleophiles 3.3. Conjugate Addition of Sulfur Nucleophiles 3.4. Conjugate Addition of Nitrogen Nucleophiles 3.5. Conjugate Addition of Phosphorus Nucleophiles 3.5.1. Chiral P−C−P, N−C, and P−C Palladacycle Catalysts 3.5.2. Chiral P−C−N and N−C−N Palladacycle Catalysts 3.5.3. Other Chiral Catalysts 3.6. Conjugate Addition of Silicon Nucleophiles 4. Summary and Perspective Author Information Corresponding Author ORCID Author Contributions Notes

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Received: November 15, 2017 Published: July 26, 2018 7586

DOI: 10.1021/acs.chemrev.7b00692 Chem. Rev. 2018, 118, 7586−7656

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Figure 1. Asymmetric conjugate addition (ACA) reactions.

Figure 2. Chiral ligands in metal-catalyzed ACA reactions: an overview of selected milestones.

Biographies Acknowledgments References

been frequently used as key steps in the construction of biologically active chiral molecules and natural products.20 Two types of nucleophiles are commonly used in asymmetric conjugate addition reactions (Figure 1): organometallic nucleophiles (hard nucleophiles, which are small with high charge density) and nonorganometallic nucleophiles (soft nucleophiles, which are large with low charge density). The ACA reactions of organometallic nucleophiles, such as Grignard, organozinc, organoaluminum, organoborane, organocopper, and organolithium reagents, have been welldocumented, and for a comprehensive summary of such methodologies one can refer to a review paper by Heravi in 2016.18 For nonorganometallic nucleophiles, including carbonic nucleophiles (e.g., malonates, 1,3-dicarbonyl nucleophiles, nitroalkanes, aldehydes, ketones, and amino acid derivatives, etc.) and heteronucleophiles, enormous research efforts have also contributed to the considerable progress made in this area, along with the development of well-defined catalytic organometallic complex systems. The evolution of metal-complex catalysis in the ACA of nonorganometallic nucleophiles dates back to the original discovery of the diamine−Co(II) complexes in 1984,21 and the development of the multifunctional metal−BINOL catalyst by Shibasaki et al.

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1. INTRODUCTION The addition of various nucleophiles to electron-deficient alkenes (conjugate addition reactions) represents one of the most useful synthetic tools for the construction of C−C or C− heteroatom bonds. Since their initial discovery by Komnenos1 in 1883 and the subsequent pioneering works of Michael in 1887,2 the conjugate addition reaction has been widely studied and has become an extremely useful method in organic chemistry. In particular, the catalytic asymmetric conjugate addition (ACA) reaction is a direct and efficient approach for the synthesis of optically active compounds.3−5 However, it took almost a century from the discovery of this reaction to the first catalytic asymmetric version, which was reported in 1975.6 Together with the well-developed organocatalytic ACA reactions,7−16 significant breakthroughs also have been made in metal-catalyzed ACA reactions over the last four decades, along with the development of a number of chiral metalcatalyst systems.17−19 Moreover, these transformations have 7587


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Scheme 1. ACA of 1,3-Dicarbonyl Compounds to Nitroalkenes

catalyzed ACA reactions using nonorganometallic carbon nucleophiles will be discussed. This part is organized by different types of carbon nucleophiles (such as 1,3-dicarbonyl compounds, nitroalkanes, aldehydes, ketones, and amino acid derivatives) and chiral ligands. In the second part, C− heteroatom bond formation via ACA reaction using nucleophiles based on a range of heteroatoms is discussed and organized into C−B, C−O, C−N, C−S, C−P, and C−Si bond formation categories. Since there is a large amount of relevant literature on metal-catalyzed ACA reactions, there will inevitably be a slight overlap with other review articles and book chapters.

marked a milestone in this area at the end of the 20th century.22,23 Later, following the emergence of the first asymmetric version using chiral bisoxazolines24 and chiral Schiff bases25 as ligands in 1996 and 1999, respectively, a major advance was made in the 21st century with the introduction of different metals.26,27 Chiral N,N′-dioxide− metal complexes have also demonstrated their high efficiency in many types of ACA reactions,28 and Meggers recently reported that octahedral metal complexes29 are especially important as these enable new ACA chemistry with aldehydes and radicals as the nucleophiles. The major advancements of using different chiral ligands in metal-catalyzed ACA reactions are summarized in Figure 2. Moreover, several challenging ACA reactions were achieved with high yields and selectivities, such as using alkynes and radicals as the nucleophiles, as well as C−O, C−S, and C−Si bond-forming processes. Together with the development of ACA reactions, some aspects of this topic have been briefly mentioned in several reviews.17−19,30−40 Herein, we present a systematic summary of the recent achievements related to metal-catalyzed asymmetric 1,4conjugate addition of nonorganometallic nucleophiles published within the last ten years (from 2007 to 2017), as well as mechanistic studies and their synthetic applications. Although the review mainly focuses on references that appeared after 2007, some earlier studies are also included as background information to gain a better understanding of the history of developments in this area. The asymmetric 1,6- or 1,8conjugate addition to extended Michael acceptors has been recently summarized17 and falls outside the scope of this review. The review is divided into two parts according to the type of nucleophile. In the first part, C−C bond formation by metal-

2. C−C BOND FORMATION BY METAL-CATALYZED ACA REACTIONS The formation of C−C bonds by metal-catalyzed ACA reactions using soft carbon nucleophiles is known as one of the most useful methods in organic synthesis and has developed rapidly in recent years.1,35 A wide variety of nonorganometallic nucleophiles including malonates, nitroalkanes, aldehydes, ketones, and amino acid derivatives have been successfully applied in the ACA reaction. 2.1. Conjugate Addition of 1,3-Dicarbonyl Compounds

Of the prevalent nonorganometallic carbonic nucleophiles used in catalytic ACA reactions, malonates and the related 1,3dicarbonyl nucleophiles are the most studied objects in chiral Lewis acid catalysis due to the fact that the two carbonyl groups can chelate with a metal center to form a stable sixmembered transition state structure. Over the last two decades, significant effort has been made to realize enantioselective 1,4conjugate additions with electron-deficient alkenes by using 7588


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Scheme 2. ACA of Other 1,3-Dicarbonyl Compounds to Nitroalkenes

Scheme 3. ACA of 1,3-Dicarbonyl Compounds to Other Nitroalkene Derivatives

β-diketones) to a wide range of nitroalkenes catalyzed by readily prepared chiral Ni(II) complexes based on trans-1,2diaminocyclohexane derivatives L1 and L2, delivering the adducts with good enantiocontrol (up to 95% ee; Scheme 1b). When β-diketones were used under the optimized conditions, slightly lower ee’s were obtained. Significantly, this methodology exhibited potential for the synthesis of enantioenriched products on a large scale. Later, the application of diamine− Ni(II) complex catalysts was extended to the enantioselective decarboxylative Michael addition of nitroalkenes with βketoacids, resulting in good to high yields and ee values (up to 94% ee; Scheme 1a).42 A detailed mechanistic study of chiral diamine−Ni(II)-complex-catalyzed ACA reactions is

1,3-dicarbonyl compounds as the nucleophiles, and as a result, various well-defined metal-catalyst systems with new chiral ligands have been employed for these transformations. 2.1.1. Using Chiral Diamines as Ligands. Since the first enantioselective ACA reactions catalyzed by chiral metal diamine complexes, reported by Brunner and co-workers in 1984 (up to 66% ee in the reaction between methyl vinyl ketone and methyl 1-oxo-2-indanecarboxylate),21 a large number of chiral metal-diamine complexes have been developed, and one of the most important advances was made by the Evans group. From 2005 to 2007, Evans and coworkers41,42 reported asymmetric additions of various 1,3dicarbonyl compounds (including malonates, β-ketoesters, and 7589


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Scheme 4. ACA of 1,3-Dicarbonyl Compounds to Enones

Scheme 5. ACA of 1,3-Dicarbonyl Compounds to Enones Catalyzed by Sulfonamide−Metal Complexes

shown in Scheme 1. The dicarbonyl compound first displaces one diamine ligand and coordinates to the Ni center, giving the chiral enolate I. Then, the coordination of the nitroalkene to the metallic center forms the intermediate II, where the active enolate nucleophile attacks the nitroalkene to afford the initial 1,4-addition intermediate III. Subsequent intermolecular proton transfer gives the Michael adduct and displacement of the product with another molecule of the dicarbonyl substrate regenerates I. Highlighting the utility of this method, a version of this ACA reaction served as the key step in the synthesis of (−)-stenine by Zhang and co-workers.43 The Kim group further extended the application of the Evans diamine−Ni(II) complexes to the enantioselective 1,4addition of 2-fluoromalonates to aromatic nitroalkenes, giving desired products in both high yields and ee’s (Scheme 2a).44,45 Interestingly, using 2-bromomalonates as the nucleophiles and L3−Ni(II) as the chiral catalyst, nitrocyclopropanes were obtained as the final products in high yields and ee’s (up to 99% ee) via a successive process involving 1,4-addition and a base-induced cyclization (Scheme 2b).46 Reznikov et al. successfully developed L1−Ni(II)-promoted ACA of nitrioalkenes with β-oxo phosphonates, which provided an efficient method for the synthesis of valuable synthetic intermediates, achieving α-nitroalkyl-substituted β-oxo phosphonates with good selectivity (up to 99% ee; Scheme 2c).47,48 Later studies by the Kim group showed that the α-fluoro-β-ketophospho-

nates could be successfully employed as the nucleophiles for reaction with nitroalkenes under suitable conditions (R2 = F; Scheme 2c).49 The addition of various azaarylacetates and acetamides to nitroalkenes was also explored by Lam and coworkers (Scheme 2d). The corresponding adducts were obtained in high yields with high diastereo- and enantioselectivities (up to 12/1 dr and 99% ee for esters; up to 19/1 dr and 99% ee for amides).50 Chiral Ni(II) complexes of 1,2-diaminocyclohexane derivatives were also efficient for the addition of cyclic nitroalkenes with malonates. High yields and ee values were obtained for the only anti-products in the presence of 5 mol % of complex L1−Ni(II) (Scheme 3a).51 In 2012, Shao and co-workers reported the first examples of ACA reactions of nitroenynes with malonates, β-ketoesters, or β-diketones.52 A range of nitroenynes was investigated, and 1,4-selective adducts were observed in high yields and ee’s in the presence of complex L2−Ni(II) (Scheme 3b). This method was used in the synthesis of diverse functional molecules and useful building blocks. Similarly, 1,4-selective adducts were aso obtained from the reaction of conjugated nitrodienynes, and the enantioenriched 1,3-enynes were obtained in up to 95% yield and 94% ee (Scheme 3b).53 Moreover, none of the 1,6- or 1,8-addition products were observed under the optimized conditions in either of these two cases. It is noteworthy that reversed stereoinduction was observed by replacing the diaminocyclo7590


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Interestingly, the complex prepared from a L7−NiBr2 (1:1) mixture was found to be efficient for the reaction and the enantioselectivity increased significantly to 90% ee with high yield. In comparison, the complex L7−Ni(II) was inferior to L8−Ni(II) in terms of stereocontrol. Although the highest enantioselectivities were observed for the transformation with L8 at 80 °C, it is noteworthy that even at 120 °C, the enantiomeric excess was still excellent (90% ee). Gladysz and co-workers attempted the asymmetric conjugate addition of malonates to nitroalkenes catalyzed by chiral Co(III)−Werner complexes [L9a− and L9b−Co(III)] (Scheme 7).65−67 In these cases, a series of alkyl- and arylnitroalkenes, including 1-naphthyl and 2-furyl moieties were tolerable, giving the corresponding addition products in good yields and ee’s (up to 99% yield and 99% ee). In general, dimethyl malonates yielded higher ee’s in comparison with diethyl or dibenzyl malonate. In addition, chiral bifunctional 2guanidinobenzimidazole cyclopentadienyl complexes L9c− Ru(I) were also successfully employed in the ACA reaction of malonates to nitroalkenes (48−99% yields and up to 99% ee).68 Most recently, Bellemin-Laponnaz and co-workers applied an efficient self-supported catalyst based on diamine ligand L10 and nickel(II) in the asymmetric Michael addition of 1,3dicarbonyl compounds to nitroalkenes (Scheme 8). Under the optimized conditions, a series of β-ketoesters and β-diketones with aryl-nitroalkenes were tolerated with low catalyst loading. The catalyst could be recovered easily and recycled more than ten times without any loss of efficiency.69 2.1.2. Using Chiral Bisoxazolines as Ligands. Bisoxazoline ligands were successfully employed in metal-catalyzed ACA reactions dating back to 1996.24,26,70−73 The most recent related work comes from the Kanemasa group, who demonstrated that ACA of α,β-unsaturated amides with nitromethane is possible in the presence of a chiral bisoxazoline L11−Ni(II)-based catalyst system.70 Many nucleophiles performed the additions well, allowing for the synthesis of a small library of chiral compounds in excellent yields and enantioselectivities. The enantioselective Michael addition of dimedones to α,β-unsaturated amides afforded the corresponding enol lactones in good to excellent yields and ee values (Scheme 9a).72,74 More recently, the Xu group75 established a L12a−Cu(II)-catalyzed asymmetric Michael addition of 2-substituted benzofuran-3(2H)-ones (Scheme 9b). Under the optimized conditions, a series of α,βunsaturated ketones was tested and the corresponding adducts were obtained with up to 95% yield and 99% ee. Alkaline earth metal salts have gradually attracted increasing attention due to their abundance and low toxicity and have been successfully employed in ACA reactions of 1,3-dicarbonyl compounds.76 The most recent related work comes from the Kobayashi lab77 and involves the use of a pybox(L13a)− Ca(OAr)2 catalyst system. Various 1,3-dicarbonyl compounds and a series of nitroalkenes worked well, generating enantioenriched 1,4-addition products in high yields and ee’s at −20 °C in toluene (Scheme 10a). In particular, they found that methyl or ethyl malonates with less steric hindrance tended to give higher yields and high ee’s. In contrast, only 18% ee and 50% yield was obtained when tert-butyl malonate was used as the nucleophile. Moreover, aromatic nitroalkenes with ortho-substitution gave only moderate enantioselectivity due to steric constraints (65% ee). In the case of β-ketoesters as nucleophiles, good enantiocontrol was observed for both

hexane ligand L2 with chiral 1,2-diphenylethanediamine derivative L4b (Scheme 4). Kantam et al. revealed in 2007 that nanocrystalline MgO complexed with chiral 1,2-diphenylethylene diamine L4a could also act as an excellent chiral catalyst for asymmetric conjugate addition of malonate derivatives to cyclic enones and chalcones. In the presence of 5 mol % of complex L4a− MgO at −20 °C, up to 96% yield and 96% ee were observed for the addition products (Scheme 4).54 Later, Xu and coworkers reported the combination of iron(III) salts with diamine L4a for the ACA of enones.55 In 2008, an efficient catalytic system based on alkaline earth metal salts was disclosed by Kobayashi and co-workers56 for the asymmetric conjugate addition of malonates to a series of aromatic enones (Scheme 5a). The complex prepared from Sr(OiPr)2 and chiral bis(sulfonamide) ligand L5 proved efficient, and the corresponding adducts were obtained with high enantiomeric purity in excellent yield (up to 99% ee). It should be noted that the catalyst loading could be reduced to 0.5 mol % without any significant loss in efficiency. Nevertheless, Ca- or Ba-based catalysts were inferior in terms of reactivity and enantioselectivity. Subsequently, this methodology was extended to the ACA reaction of both acyclic and cyclic enone derivatives.57 Interestingly, it was found that using Sr(HMDS)2 as the metal source is more efficient than Sr(OiPr)2, resulting in better ee’s and yields in most cases under mild conditions. The sulfonamide−Ru(II) complex was also suitable for the ACA reaction of α,β-unsaturated cyclic ketones (Scheme 5b). Ikariya and co-workers applied chiral Ru(II) catalysts of sulfonamide to asymmetric Michael additions of α,β-unsaturated cyclic ketones with various nucleophiles (such as malonates, ketoesters, or nitroacetates).58−61 The chiral complex L6−Ru(II) enabled the formation of chiral β-substituted cyclic ketones in up to 99% ee and excellent yields at low catalyst loadings (S/C up to 1000).62 On the basis of the flexible DPEN framework L4a, rigidified cyclic diamines L7 and L8 were constructed by the Xia group63 and the Czekelius group,64 respectively (Scheme 6). The conformational rigidity was increased by two cyclic backbones, which restrains the free rotation of the phenyl groups. In the case of the complex L7−Ni(II) (2:1), the reaction proceeded smoothly with full conversion but low enantioselectivity (only 10% ee) by using N-methylmorpholine (NMM) as an additive. Scheme 6. ACA of 1,3-Dicarbonyl Compounds to Nitroalkenes Catalyzed by Diamine−Ni(II) Complexes

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Scheme 7. ACA of 1,3-Dicarbonyl Compounds to Nitroalkenes Reported by the Gladysz Group

the complex III, which reacts with malonate to regenerate I. Recently, a similar pybox(L14)−CaCl2 system was developed by Kanger and co-workers for the catalytic asymmetric Michael addition of various malonates with α,β-unsaturated carbonyl compounds,78 resulting in good yields and ee’s (Scheme 10b). However, the rate of the reaction was slow and substratedependent for the reaction of chalcones, and other phenylsubstituted α,β-unsaturated ketones needed 3−7 days with an additional base additive. In 2011, the Singh group79 described an efficient catalyst system for asymmetric Michael addition to 2-enoylpyridine Noxide substrates, employing a chiral bisoxazoline complex L15−Zn(OTf)2 as catalyst (Scheme 11a). A range of β-aryl- or alkyl-substituted enone derivatives were tolerated well, and the corresponding products were obtained with high enantiopurity (up to 99% ee). However, no product was detected after 100 h when a sterically hindered tert-butyl substituted substrate (R1 = t Bu) was used under the optimized conditions, and only 60% yield with 16% ee was obtained when using tBu-malonate as the nucleophile. Aliphatic cyclic 1,3-dicarbonyl compounds were also examined as suitable nucleophiles for the ACA reaction catalyzed by complex L15−Zn.80 In 2013, Pedro, Blay, and co-workers81 disclosed the asymmetric conjugate addition of dimethyl malonate to α,β-unsaturated Ntosylimines in the presence of complex L13b−La(III), and the corresponding E-enamines were obtained in high yields with up to 94% ee (Scheme 11b). Further extending the utility of this ligand, complex L16−Cu(OTf)2 was also applied to the

Scheme 8. ACA of 1,3-Dicarbonyl Compounds to Nitroalkenes Catalyzed by Self-Supported Ni(II) Complexes

diastereoisomers. As shown in Scheme 10, a reasonable catalytic cycle was proposed to elucidate the reaction process. The malonate first coordinates with the calcium pybox complex to give chiral calcium enolate I. Then, the activated enolate I attacks the nitroalkene to afford the initial 1,4addition intermediate II. Subsequent intermolecular proton transfer by a phenol derivative gives the Michael adduct and 7592


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Scheme 9. ACA of 1,3-Dicarbonyl Compounds Catalyzed by Bisoxazoline−Metal Complexes

enantioselective Michael reaction of β-trifluoromethyl α,βunsaturated N-tosylimines, yielding the products with good enantiocontrol.82 In 2015, Nagorny and co-workers83 developed a chiral bisoxazoline−Cu(II)-catalyzed asymmetric Michael addition of cyclic ketoesters and enones (Scheme 12). A modified procedure using sterically bulky enones in the presence of L17−Cu(SbF6)2 under neat conditions afforded the desired addition products with good outcomes (up to 95% yield, 20:1 dr, and 99% ee). No reaction was observed when using bisoxazoline L18 or L19 as a ligand, indicating the ligand play a significant role to reach high reactivity. Furthermore, both natural and unnatural steroid skeletons could be synthesized by subsequent base-promoted diastereoselective aldol reactions. Significantly, this catalyst system exhibited great potential for the synthesis of enantioenriched steroidal scaffolds on a large scale. 2.1.3. Using Chiral N,N′-Dioxides as Ligands. The Feng group utilized chiral N,N′-oxides in metal-complex-promoted conjugate additions and other reactions.28,84 Different kinds of nucleophiles, such as malonates, nitroalkanes, β-ketoesters, and thioglycolates could react with nitroalkenes and enones catalyzed by N,N′-dioxide−metal complexes (Scheme 13).85−91 For instance, N,N′-dioxide L20a derived from Lramipril acid and benzylamine coordinated with Sc(OTf)3 showed superior performance in the Michael reaction of malonates with chalcone derivatives.92 The application of this system was further extended to the Michael reaction of α,βunsaturated ketones and esters with α-chloromalonates and βdiketones.93 The Michael addition of malonates to α,βunsaturated enones was achieved by the use of the chiral Y(OTf)3 complex of N,N′-dioxide L22c derived from Lpipecolic acid (Scheme 13a), whereas only trace amount of products were obtained with Sc(OTf)3 complexes.87 The cobalt- or nickel-N,N′-dioxide complexes with ligands L22b, L22c, and L22e were also tested as catalysts for the Michael

reaction of 4-hydroxycoumarin,94 nitroalkenes, and alkynones,95 delivering the adducts in good yields and ee’s (Scheme 13a). Most recently, this methodology was used for the synthesis of chiral trisubstituted 1,2-allenyl ketones from enynes using complex L22d−Sc(OTf)3 as the catalyst, providing the corresponding products in good to excellent yields with good enantiocontrol (up to 99% yield, 95:5 dr, and 99% ee).96 A tandem asymmetric Michael/ring-closure reaction of α,β-unsaturated pyrazoleamides and amidomalonates was also developed, and a series of chiral glutarimides were synthesized in excellent yield with high enantiomeric purity (up to 99% yield and 94% ee) in the presence of complex L22a−Y(OTf)3 (Scheme 13b). The potential of this reaction was illustrated in the synthesis of the antidepressant drug (−)-paroxetine.97 2.1.4. Using Chiral Schiff Bases as Ligands. In addition to the chiral ligands mentioned above, Schiff bases have also been successfully employed in metal-catalyzed ACA reactions.25 Second-generation variants of these catalysts, bifunctional bimetallic catalysts, have been developed by Matsunaga, Shibasaki, and co-workers using complexes derived from metals and Schiff base ligands27,98−102 and were applied to the asymmetric 1,4-addition of β-ketoesters to nitroalkenes and alkynones (Scheme 14).103 The homodinuclear complex L23a−Co2 proved most efficient after investigation of the metal sources (including Cu, Pd, Ni, Zn, Co, and lanthanides), delivering the addition products in excellent yield with moderate enantioselectivity (up to 52% ee). Better results were achieved by using a tBu-β-ketoester instead of a Me-βketoester and iPr2O as a solvent. With these modifications, both alkynones and nitroalkenes104 were found to be suitable substrates, resulting in up to >30:1 dr and 99% ee. It should be noted that the reaction still proceeds well with as little as 0.1 mol % catalyst loading under solvent-free conditions. A proposed transition state was proposed by the authors, as shown in Scheme 14, whereby one metal (M2) works as a 7593


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Scheme 10. ACA of 1,3-Dicarbonyl Compounds Catalyzed by Bisoxazoline−Ca Complexes

Scheme 11. ACA of Malonates Catalyzed by Bisoxazoline−Metal Complexes

Brønsted base to coordinate with a 1,3-dicarbonyl substrate and the other (M1) acts as a Lewis acid to control the position

of the nitroalkene. The activated enolate then attacks the nitroalkene to afford the desired adduct. The decarboxylative 7594


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Michael addition to nitroalkenes with malonic acid halfthioesters afforded the corresponding adducts with high yields and enantiomeric purities using heterobimetallic L23b−Ni−La as the catalyst (up to 99% yield and 94% ee).105 Later, βketoesters and N-Boc oxindoles were successfully employed for the reaction under suitable conditions by using L23b−Ni2 as the catalyst.106 A tandem asymmetric Michael addition/cyclization reaction of cyclohexane-1,3-dione or dimedone to 2-cyanoacrylate derivatives was reported by Feng and co-workers (Scheme 15a).107 The corresponding adducts were obtained with moderate to good yields and up to 89% ee in the presence of complex L24−Co(II). High yields with up to 93% ee for the corresponding products were achieved by using complex L25− Ru(II) as the catalyst when employing 1,3-dicarbonyl compounds and methyl vinyl ketone as the substrate (Scheme 15b).108 The use of oxygen-containing cosolvents was crucial for both reactivity and enantioselectivity, which might be due to their ability to deprotonate the intermediate in its transient state.

Scheme 12. ACA of 1,3-Dicarbonyl Compounds Catalyzed by Bisoxazoline−Cu(II) Complexes

Scheme 13. ACA of 1,3-Dicarbonyl Compounds Catalyzed by N,N′-Dioxide−Metal Complexes

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Scheme 14. ACA of 1,3-Dicarbonyl Compounds Catalyzed by Cooperative Bimetallic Complexes

Scheme 15. ACA of 1,3-Dicarbonyl Compounds Catalyzed by L24−Co or L25−Ru Complexes

catalysis27,109 and have proven efficient for the ACA reaction.110−114 In 2007, Shibasaki and co-workers115 reported asymmetric Michael additions of malonates to acyclic α,βunsaturated N-acylpyrroles catalyzed by the (S,S)-Ph-linked-

2.1.5. Other Chiral Ligands. Bifunctional catalysts based on heterobimetallic combinations of rare earth and alkali metals, along with BINOL ligands, were demonstrated as a class of powerful and versatile catalyst systems in asymmetric 7596


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Scheme 16. ACA of 1,3-Dicarbonyl Compounds Catalyzed by BINOL−Metal Complexes

Scheme 17. ACA of Malonates to Enones Catalyzed by Chiral α- or β-Amino Acid Lithium Salts

BINOL complex L26−La(OiPr)3, furnishing the addition products with excellent outcomes (up to 96% ee; Scheme 16). Later, a stereoselective synthesis of HIV-1 protease inhibitor GRL-06579A was achieved, utilizing this method as the key step.116 Rare earth heterobimetallic frameworks based on Shibasaki’s REMB complex also proved efficient for the addition of dibenzyl malonate to cyclohexenone.117 Belokon and co-workers118 successfully developed a L27−Li-promoted ACA of malonates or β-ketoesters to cyclic enones and nitroalkenes, yielding the adducts in high conversions and moderate enantioselectivities. Most recently, other types of chiral lithium binaphtholate complexes such as L28a−Li and L28b−Li were also studied for their ability to catalyze ACA reactions by Nakajima and co-workers.119,120 Yoshida and co-workers121 described a detailed study using natural α-amino acids and their derivatives as chiral catalysts for the ACA of malonates to enones (Scheme 17). The best results (up to 87% ee and 96% yield) were achieved in the

presence of 30 mol % of complex L29a−Li based on TBDPSO-protected L-serine. No product was detected with tBumalonate, presumably due to its steric hindrance, and a chalcone gave only 10% enantioselectivity under the optimized conditions. Later, better results were obtained using the catalyst derived from β-amino acid L29b (Scheme 17).122 Unfortunately, chalcone substrates still gave very low ee’s. Subsequent studies indicated that β-ketoesters are suitable substrates, achieving the corresponding Michael adducts in high yields with excellent enantiocontrol.123−125 Some other Li complexes were developed for the Michael addition of malonate derivatives to various chalcones by Naka et al.,126 affording the corresponding adducts in high yields with up to 89% ee. The addition of a cyclic β-ketoester to MVK was tested by using a NHC−Pd(II) complex as the catalyst, but a low ee was obtained.127 In 2007, the Roelfes group reported the first example of an enantioselective Michael addition using L30-st-DNA−Cu7597


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of α,β-unsaturated acylimidazoles with various nucleophiles proceeded well to furnish the desired adducts in high yields with up to 99% ee (Scheme 19a). Later studies by Kang and co-workers133 indicated that the complex L33a−Rh(III) could also be successfully employed in the decarboxylative Michael addition of α,β-unsaturated imidazoles or pyridines with β-keto acids (94−98% yields and 88−96% ee’s; Scheme 19b). The catalyst loading could be reduced to 0.05 mol % for a gram scale reaction without a significant decrease in yield or enantioselectivity. Most recently, a cascade Michael-alkylation reaction utilizing chiral complex L31−Rh(III) as catalyst was also discovered (Scheme 19c),134 giving the chiral cyclopropane derivatives with 70−99% yields and 93−99% ee’s.

(dmbipy)(NO3)2 as a catalyst in water (Scheme 18). A range of α,β-unsaturated 2-acylimidazoles was successfully converted Scheme 18. ACA of α,β-Unsaturated 2-Acylimidazoles Catalyzed by L30-st-DNA−Cu(II) in Water

2.2. Conjugate Addition of Nitroalkanes or Malononitrile

2.2.1. Using Chiral Bisoxazolines as Ligands. The ACA of nitroalkanes to electron-deficient olefins (the nitro-Michael reaction) is one of the most useful processes in organic synthesis and has developed rapidly in recent years. The bisoxazoline ligand L12b was successfully applied by Du and co-workers135 to the Zn-catalyzed ACA of nitroalkanes to nitroalkenes with good results (Scheme 20a). Later, α-hydroxy enones and α,β-unsaturated amides were successfully employed for this reaction under suitable conditions by the Palomo136 and Kanemasa74 groups, respectively. Most recently, a similar system involving complex L34a−La(III) was developed for the catalytic asymmetric Michael addition of nitroalkanes to azachalcones by Blay, Pedro, and co-workers, 137 yielding the products in moderate yield and enantiocontrol (Scheme 20b).

into the corresponding products with up to 99% ee. Only 54% conversion and a racemic product was obtained from the reaction when using Cu(dmbipy)(NO3)2 as catalyst but in the absence of DNA, indicating that the DNA plays a significant role in achieving both high reactivity and selectivity.128 Meggers and co-workers introduced a new class of octahedral chiral-at-metal Rh(III) and Ir(III) complexes for asymmetric reactions,29,129,130 including asymmetric conjugate additions.131,132 By using Rh(III) or Ir(III) complexes containing L31 or L32 as the catalysts, the Michael addition

Scheme 19. ACA Reaction Catalyzed by Chiral-at-Metal Rh(III) and Ir(III) Complexes

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Scheme 20. ACA of Nitroalkanes Catalyzed by Bisoxazoline−Metal Complexes

Scheme 21. ACA of Nitroalkanes Catalyzed by N,N′-Dioxide−Metal Complexes

2.2.2. Using Chiral N,N′-Dioxides as Ligands. The Feng group also extended the application of their N,N′-dioxide− metal catalyst system to the enantioselective 1,4-addition of nitroalkanes (Scheme 21a).138−141 In the presence of 10 mol % of complex L21a−La(III) and a catalytic amount of imidazole, the corresponding 1,3-dinitro products were obtained in high yields with up to 93:7 dr and 97% ee.138 However, the isopropyl-substituted nitroalkene (R = iPr; Scheme 21a) gave a low yield with an acceptable ee (22% yield and 83% ee). Further studies showed that the metal source for the N,N′dioxide−metal complex plays a significant role in this reaction.139 For the enones, L20b−Sc(OTf)3 promoted the

reaction with low catalyst loadings under neat conditions, yielding the desired adducts with high enantioselectivities, whereas the La(OTf)3 complex gave low yields and ee’s under similar conditions. A range of α,β-unsaturated amides were tolerated well and gave good results with complex L22c− Ga(OTf)3 as catalyst (53−99% yields and 93−99% ee’s).141 The nitrile-stabilized carbanions (arylacetonitriles) were also found to be suitable substrates in the presence of complex L20b−Zn(NTf2)2, giving the corresponding adducts in high yields with up to 99:1 dr and 99% ee (Scheme 21b).140 2.2.3. Other Chiral Ligands. Early in 2006, Jacobsen et al. reported the ACA reaction of β-silyl-α,β-unsaturated imides 7599


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cyanocarbonyl compounds (Scheme 24a). The metal source had a decisive effect on the enantioselectivity, and complex L37−Y(OiPr)3 generally gave superior results (54−98% yield and 69−98% ee’s). Deng et al.146 revealed that complex L4a− Ru(II) was efficient for the ACA of malononitrile to α,βunsaturated ketones. Under the optimized conditions, a range of α,β-unsaturated ketones were examined and high yields with up to 82% ee were observed for the addition products (Scheme 24b). However, no product was detected when using the substrate bearing an aliphatic substituent (R2 = Me) adjacent to the carbonyl group. Various bispalladacycle complexes were exploited as soft Lewis acid catalysts by Peters and co-workers,147−155 which have proven to have good catalytic properties in the asymmetric Michael addition of α-cyanoacetates to vinyl ketones.150 The best results (80−99% yields, 76−95% ee’s; Scheme 25a) were achieved when the reaction was promoted with 0.1−1 mol % of the complex L38a−Pd2. Later, the application of these catalyst systems was extended to the addition of cyclic enones, and the corresponding adducts were obtained with high enantioselectivities under low catalyst loading.156 Interestingly, different diastereomers were obtained by using chiral mono- or bimetallic catalysts. While (R,R) diastereomers were obtained in the presence of the bimetallic catalyst L38−Pd2, the monometallic complex L39−Pd gave (S,R) diastereomers as the major products (Scheme 25, panels b and c). Generally, compared to the major diastereomers, the minor diastereomers were achieved with significantly lower enantioselectivity in both cases. It should be mentioned that the undesired β-elimination of the intermediate δ-alkyl Pd complex in the catalytic cycle was completely suppressed by using HOAc as a cocatalyst. Wang et al.157 demonstrated that the catalyst generated from chiral ligand L40 and [Cu(CH3CN)4]BF4 was efficient for the ACA reaction of ethyl nitroacetate to β,γ-unsaturated αketoesters (Scheme 26a). Feng and co-workers158 developed the simple quinine complex L41−Al(OiPr)3 as catalyst for addition of malonitrile to chalcones (Scheme 26b). Later, a dual activation mechanism was revealed by Kim and coworkers for this reaction.159 In 2015, the Ghosh group160 reported an example of enantioselective Michael addition of αmethylcyano esters to alkyl vinyl ketones and acrylonitrile under base-free conditions using chiral complex NHC(L42)− Ni(II) as a bifunctional catalyst (Scheme 26c).

using an aluminum salen complex as catalyst and applied this to the total synthesis of the natural product (+)-lactacystin.142 The most recent related work comes from the laboratory of Wang143 and involves the use of complexes L35−Sc(III), derived from C2−symmetric Schiff base ligands, as catalysts and the combination of nitroalkanes and a series of 2-enoylpyridine N-oxides, generating enantioenriched 1,4-addition products with high enantiomeric purity in excellent yield (up to 25:1 dr and 98% ee; Scheme 22). It is noteworthy that the reversal of enantioselectivity was possible by changing the metal source from Sc(OTf)3 to Cu(OTf)2. Scheme 22. ACA of Nitroalkanes Catalyzed by Schiff Base− Sc(III) Complexes

Shibasaki and co-workers144 described a detailed study using α,β-unsaturated thioamides as substrates for the Michael addition of nitroalkanes (Scheme 23). Good results (up to Scheme 23. ACA of Nitroalkanes Catalyzed by Complex L36a−Cu

2.3. Conjugate Addition of Aldehydes and Ketones

2.3.1. Using Chiral Diamines as Ligands. Sodeoka and co-workers achieved ACA reactions of α-ketoesters (R2 = OtBu) to nitroalkenes using a combination of Ni(OAc)2 and diamine L1, which led to the corresponding anti-adducts (up to 30:1 dr) with enantioselectivities of up to 94% ee and high yields (Scheme 27a).161 The acetate anion of Ni(OAc)2 played a significant role in this reaction; without it only trace amounts of product were observed under the same reaction conditions (when using NiBr2 as metal source). Meanwhile, a small amount of Et3N was added to trap the generated acetic acid, which accelerated the reaction. The usefulness of this method was further demonstrated in the synthesis of a biologically interesting kainic acid analogue with high yield and ee. Later studies showed that the diamine complex L43−Cu(II) could be successfully applied to the reaction under suitable conditions, which led to the anti-adducts in moderate to good yields with up to 84% ee.162 Recently, Shibasaki and co-

97% yield, 93/7 dr, and 98−99% ee’s) were obtained when the reactions were carried out in the presence of 5 mol % of complex L36a−Cu. It is worth noting that only thioamides reacted with the nitroethane when more electrophilic substrates, such as α,β-unsaturated amide, ester, and even an α,β-unsaturated ketone, were added to the reaction mixture. Nitrile-stabilized carbanions derived from active methylene compounds, such as cyanoacetate esters, malononitrile, and cyano-ketones, have also been utilized in ACA reactions. Shibasaki et al.145 explored rare earth metal complexes derived from chiral amide-based ligands for ACA reactions of these α7600


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Scheme 24. ACA Reaction Catalyzed by L37−Y(III) and L4a−Ru(II) Complexes

Scheme 25. ACA Reaction Catalyzed by Pd Complexes

workers163 successfully exploited their homodinuclear complex L44−Ni2 to the 1,4-addition of α-ketoanilides (R2 = NHPh) with nitroalkenes. In this case, the syn-adducts were obtained with 72−98% ee’s by using 1,4-dioxane as a solvent and 5 Å MS as well as hexafluoroisopropanol (HFIP) as an additive (Scheme 27b). A cascade Michael-Henry reaction between diones and nitroalkenes catalyzed by chiral diamine complex L2− Ni(OAc)2 was reported by Wang et al.164 (Scheme 28). Both acyclic and cyclic diketones were found to be suitable

substrates, and various polyfunctionalized bicyclooctane adducts with four consecutive stereogenic centers were obtained in high yields with good enantiocontrol (up to 50:1 dr and 99% ee). It should be mentioned that the base-catalyzed isomerization165 of the products was not observed in this weakly basic catalyst system, even when the reaction time was prolonged from 6 to 48 h. However, the ee value was diminished when 1,2-cyclopentanedione was used as a nucleophile (51% ee). 7601


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Scheme 26. ACA Reaction Catalyzed by L40−Cu, L41−Al, and L42−Ni Complexes

Scheme 27. ACA of α-Ketoesters and α-Ketoanilides to Nitroalkenes

enantioselectivities (65−82% ee’s) were obtained for β-alkylsubstituted nitroalkenes. Most recently, Fu at el.167 revealed an example of Michael addition of 2-acetyl azaarene to β,βdisubstituted nitroalkenes for constructing trifluoromethylated all-carbon quaternary stereocenters using the chiral complex L46−Ni(acac)2, affording the products with good outcomes (up to 99% ee). In this case, the ortho substituent on the phenyl ring of the nitroalkene greatly affected the reactivity, especially for ortho-methyl- or ortho-methoxy-substituted nitroalkenes, whereby no products were observed. Later, the chiral bisoxazoline complex L48−Co(II) was also applied to this reaction by Song and co-workers.168 Generally, good to high yields with up to 98% ee were obtained for most substrates (Scheme 29). 2.3.3. Using Chiral Amino Acids as Ligands. Early in 2007, the Feng group169 reported the first example of Michael addition of ketones to nitroolefins catalyzed by the chiral salt

Scheme 28. ACA of Diketones to Nitroalkenes

2.3.2. Using Chiral Bisoxazolines as Ligands. Catalysts based on chiral bisoxazoline ligands were also employed for the ACA of ketones (Scheme 29). For instance, the Ni(II)catalyzed asymmetric Michael addition of 2-acetylazaarenes to nitroalkenes, carried out in the presence of bisoxazoline ligand L45, was reported by Lam and co-workers in 2013,166 which furnished the corresponding products with up to 99% ee. Compared to the β-aryl-substituted nitroalkenes, lower 7602


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Scheme 29. ACA of Ketones to Nitroalkenes Catalyzed by Chiral Bisoxazoline−Metal Complexes

Scheme 30. ACA of Aldehydes and Ketones to Nitroalkenes Catalyzed by Chiral K or Li Salts

Scheme 31. ACA Reaction Catalyzed by a Chiral L52−Cu(I) Complex

properties in the asymmetric Michael addition of isobutyraldehyde to β-nitroalkenes. The best results (up to 96% yield and 99% ee) were achieved when the reaction was promoted with 20 mol % of the complex L50−Li. Wang and co-

L49−K and the corresponding products were obtained in high yields with up to 96:4 syn/anti ratios and 95% ee (Scheme 30). The lithium salt of phenylalanine was used as a catalyst by Yoshida and co-workers170,171 and showed good catalytic 7603


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workers172 demonstrated that the addition of aldehydes to nitroolefins can be achieved with excellent outcomes (13/1− 96/1 dr and up to 99% ee) in the presence of complex L51−Li (Scheme 30). A small amount of water was essential for achieving better yield and enantioselectivity. Generally, better enantiocontrol was obtained when using aldehydes with bulkier substituents. 2.3.4. Other Chiral Ligands. Utilizing thioamides as pronucleophiles for the ACA reaction, Kumagai, Shibasaki, and co-workers173 achieved a direct approach to the catalytic asymmetric intramolecular conjugate addition of thioamides to α,β-unsaturated esters (Scheme 31). A series of chiral optically active five- and six-membered carbocyclic products were achieved in up to a 99% yield with up to 20:1 dr and 96% ee in the presence of complex L52−Cu(I). The substituents on the benzene-type tether greatly affected the reactivity and stereoselectivity of the reaction, especially for an electrondonating methoxy substituent on the phenyl ring, with which only trace product was observed. A novel bifunctional catalyst based on enamine formation with chiral amine L53 and Lewis acid Zn(SbF6)2 was developed by the group of Wang174 for the ACA of ketones to alkylidene malonates, which led to the corresponding products with satisfactory outcomes (up to >99% ee and >99:1 dr; Scheme 32). However, only moderate ee was achieved

were synthesized in good yields with good enantiocontrol (10:1 dr and 75−98% ee’s). Interestingly, while the antiproducts were obtained for most substrates, the syn-products were observed as the major products with moderate enantioselectivities for substrates with a substituent at the 2position of the aromatic ring (R2 = 2-ClC6H4, 2-BrC6H4). In 2016, a chiral L31−Rh(III)-β-PHE-based catalyst system was disclosed by Meggers and co-workers for the addition of α,α-disubstituted aldehydes to α,β-unsaturated 2-acyl imidazoles (Scheme 34).176 Both complex L31−Rh(III) and βphenylalanine generated in situ from the decomposition of complex L31−Rh(III)-β-PHE played important roles in this reaction, and only trace amounts of product were obtained when they were used individually. Aside from the orthosubstituted substrate 2-(2-methylphenyl) propanal (71% yield and 89% ee), the corresponding adducts were obtained in moderate to high yields and up to 99% ee. A similar catalyst system based on the combination of a rhodium complex and amine (Et3N) was employed by Kang and co-workers177 for this reaction, providing the addition products with excellent outcomes. 2.4. Conjugate Addition of Amino Acid Derivatives

2.4.1. Using Chiral Bisoxazolines as Ligands. Kobayashi and co-workers178−180 extended the application of their bisoxazoline−calcium complexes to the ACA of α-amino acid derivatives (Scheme 35). Under the optimal conditions (10 mol % catalyst L55−Ca(OiPr)2, 4 Å MS in THF at −30 °C), the addition of a range of α,β-unsaturated esters and Weinreb amides led to the corresponding adducts with good enantiocontrol. When methyl crotonate (R1 = Me) and α,βunsaturated amides were employed, the [3 + 2] cycloaddition products were observed rather than the prospective 1,4addition products. However, later studies indicated that when one Ph group in the α-amino acid derivatives was replaced by the tBu group (R4 = tBu), only 1,4-addition products were obtained in high yields with up to 99:1 dr and 99% ee in the presence of complex L56−Ca(OiPr)2.180 The complexes L57− Ca(OiPr)2, L14−Ca(OiPr)2, and L58−CaCl2 also proved efficient, yielding the corresponding 1,4-addition adducts with good selectivity (up to 99% ee).181,182 2.4.2. Using Chiral Ferrocenyl Phosphines as Ligands. Ferrocenyl-phosphine ligands were successfully employed for the metal-catalyzed ACA of α-amino acid derivatives (Scheme 36). Fukuzawa and co-workers183 revealed that the complex L59−AgOAc was efficient for the ACA of glycine imino esters to various nitroalkenes. The 1,4-addition products were exclusively obtained with satisfactory outcomes (up to 97% yield and 99% ee; Scheme 36b) when the glycine imino methyl ester (R = Me) was used as a substrate with Et3N as an additive. However, for the tert-butyl ester (R = tBu), the

Scheme 32. ACA of Ketones Catalyzed by a Chiral Enamine−Zn(II) Complex

when using acetone as a substrate, and a very low yield was detected for acetophenone. This method was further applied to allylidene malonates, delivering exclusively 1,4-addition products with up to >98% ee but low stereoselectivities. Recently, the dinuclear complex L54−ZnEt2 was applied to the domino Michael/hemiketalization addition of α-hydroxyacetophenone with β,γ-unsaturated α-ketoesters (Scheme 33).175 The best conditions were identified as 2−10 mol % of L54−Zn2Et complex, 0.25 mmol α-hydroxyacetophenone, and 0.275 mmol of β,γ-unsaturated α-ketoesters in DCM at 0 °C, under which the multisubstituted chiral tetrahydrofurans

Scheme 33. ACA of α-Hydroxyacetophenone Catalyzed by a Chiral L54−ZnEt2 Complex

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Scheme 34. ACA of Aldehydes Catalyzed by a Chiral L31−Rh(III) Complex

Scheme 35. ACA Reactions Catalyzed by Bisoxazoline−Ca Complexes

cycloadducts formed as major products without added base (up to 99% yield and 98% ee; Scheme 36a). The application of this catalyst system was further extended to the reaction of α,βunsaturated malonates, α-enones, and arylidene diphosphonates, furnishing a range of syn-adducts in high yields with up to 97:3 dr and 99% ee (Scheme 36, panels c and d).184,185 The Cu-catalyzed ACA of aromatic nitroalkenes using glycine derivatives as nucleophiles, carried out in the presence of catalysts based on (S,Sp)-FOXAP L60a and L60b, was developed by Hou and co-workers.186 The copper salt Cu(ClO4)2 was identified as the best metal source for the reaction (72−99% yields, up to 98:2 dr and 86−98% ee’s; Scheme 37a). However, for the aliphatic nitroalkene, no target product was obtained and the reaction only gave the cyclcoadduct. The resulting products were easily converted to their β-substituted-α,γ-diaminobutyric acid derivatives in high yields (79%) without loss of stereochemistry. The Zajac group187 realized the ACA of glycine derivatives to α,βunsaturated ketones using complex L60c−Cu(I) in THF with

1 mol % DBU as additive (up to 98% ee; Scheme 37b). The product was obtained without any loss of yield or enantioselectivity, even at low catalyst loadings (0.5 mol %) in gram-scale syntheses. Most recently, a similar catalyst system was applied to the addition of ketiminoesters to βtrifluoromethyl β,β-disubstituted enones by Zhang and coworkers (Scheme 37c).188 In the presence of complex L60c− CuOAc, highly functionalized 1-pyrrolines bearing a trifluoromethylated all-carbon quaternary stereocenter were obtained in high yields with up to 98% ee via hydrolytic cyclization. Most recently, the Fukuzawa group189−191 showed that the complex L59−AgOAc can promote the ACA of 1-pyrroline esters (X = C) to nitroalkenes with anti-products (up to 98% yield, 99:1 anti/syn and 98% ee; Scheme 38).189 On the contrary, the L60d−CuOAc complex gave syn-adducts in good yields with up to 99% ee when using pyridine as additive. The application of this catalyst system was further extended to the ACA of 2-oxazoline- and 2-thiazoline-4-carboxylates (X = O or S). While the electron-poor ligand L60a led to anti products, 7605


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Scheme 36. ACA Reactions Catalyzed by Ferrocenyl-Phosphine−Ag(I) Complexes

Scheme 37. ACA of α-Amino Acid Derivatives Catalyzed by Ferrocenyl-Oxazoline−Cu(I) Complexes

unnatural α-amino acid derivatives containing bisphosphonates with up to 99% ee. Later, the application of this catalyst system was further extended to the addition of cyclic ketimino esters to alkylidene malonates (Scheme 39b).193 The Oh group194 demonstrated that the ACA of glycine aldimines with nitroalkenes can proceed smoothly using the strychnos-alkaloid-derived amino alcohol complex L62−Cu(I) as the catalyst, furnishing the syn-adducts in good yields with high ee’s (up to 91% yield and 99% ee; Scheme 40a). Conversely, for the glycine ketimine, the anti-products were

the syn-adducts were obtained in good yields and stereoselectivities in the presence of electron-neutral or electron-rich chiral P,N-ligands (L60c or L60e, respectively).190 Later, they also employed complex L59−Ag(I) for the same reactions, which afforded the anti-adducts in both high yields and ee’s.191 2.4.3. Other Chiral Ligands. An efficient catalyst generated from CuBF4 and L61 was developed for the enantioselective Michael addition of azomethine ylides with β-substituted alkylidene bisphosphates by Wang and coworkers (Scheme 39a),192 delivering the corresponding 7606


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Scheme 38. ACA Reaction Catalyzed by Ferrocenyl-Phosphine−Metal Complexes

Scheme 39. ACA Reaction Catalyzed by an L61−Cu(I) Complex

Scheme 40. ACA Reaction Catalyzed by an L62−Cu(I) Complex

exclusively obtained with good outcomes (up to 89% yield and 90% ee; Scheme 40b) in the presence of L62−CuOTf and DBU in THF using 2-phenyl-2-propanol as cosolvent. The exo- and endo-cyclization products could be easily obtained from the syn- and anti-products, respectively, by a baseinduced cyclization. Interestingly, when 10 mol % L62−CuCl and DBU were employed in the reaction, the [3 + 2]

cycloaddition products were obtained rather than 1,4-addition products. In 2014, Schiff base−Co(III) complexes were also found to be suitable catalysts for the ACA of glycine ketimines to activated olefins by Belokon and co-workers.195 A mono- or bimetallic catalyst system derived from palladium and chiral ferrocenyl imidazoline ligands was successfully developed by Peters and co-workers.147,196,197 7607


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Scheme 41. ACA Reaction Catalyzed by Pd Complexes

achievements in the field of catalytic enantioselective conjugate addition of oxindoles up to 2016 have already been comprehensively summarized and discussed by Dalpozzo,205 in this review we describe only a few representative examples in detail. 2.5.1. Using Chiral Schiff Bases as Ligands. The Shibasaki group206 described the asymmetric 1,4-addition reaction of 3-substituted oxindoles to nitroalkenes using cooperative bimetallic complexes as catalysts (Scheme 43). Aside from the complex L23a−Mn2, with which the best outcomes (up to 99% yield, > 30:1 dr and 96% ee) were achieved, other dimetallic Schiff base complexes (such as Cu, Pd, Ni, Co, or Zn) only gave moderate to high yields with low diastereo- and enantioselectivities, indicating that the two manganese atoms play a significant role in achieving both high reactivity and selectivity. Yuan and co-workers207 revealed a similar reaction with the use of a L64−Ni(OAc)2 complex. Good yields with up to 99:1 dr and 97% ee were achieved for a broad range of aromatic nitroalkenes. However, no product was detected when aliphatic nitroalkenes were subjected to the catalytic reaction. Polyfunctional Ni(II) complexes based on L65 and L66 were applied to the conjugate addition of 3substituted oxindoles to aromatic nitroolefins by Peters and coworkers,208,209 furnishing the adducts in high yields with up to 97% ee. It is noteworthy that reversal of enantioselectivity was achieved by replacing the ligand L65 with L66. 2.5.2. Using Chiral N,N′-Dioxides as Ligands. Recently, the Feng group reported a catalyst system based on the complex L21b−Sc(OTf)3 for achieving the ACA of alkynes with 3-substituted-2-oxindoles,210 affording the corresponding products in high yields with up to 99% ee and >95:5 Z/E selectivity (Scheme 44a). Later,211 this methodology was extended to the synthesis of a new family of chiral succinimides bearing adjacent quaternary and tertiary stereocenters using L20c−Sc(OTf)3 as catalyst (up to >19/1 dr and 99% ee; Scheme 44b). 2.5.3. Other Chiral Ligands. In 2011, Antilla and coworkers successfully developed a chiral calcium phosphate complex (L67−Ca)-promoted ACA of 3-aryl-substituted-NBoc oxindoles to methyl vinyl ketone (MVK), which provided the corresponding adducts in excellent yields with up to 95% ee (Scheme 45a).212 In 2014, Arai and co-workers213 reported a chiral ACA of 3′-indolyl-3-oxindole to nitroalkenes catalyzed by imidazoline−aminophenol nickel complex L68−Ni(II), which led to addition products with high enantiomeric purity in moderate to high yields (up to 95% ee and 30−95% yields; Scheme 45b). Significantly, this methodology exhibited great potential in the synthesis of the bioactive chiral compound 3indolyl cyclotryptamine in three steps without any loss of

The application of this catalyst system (L38a−Pd2 or L39−Pd; Scheme 25) was extended to the catalytic asymmetric conjugate addition of azlactones to enones, giving the desired products in high yields with up to >98/2 dr and 99% ee (Scheme 41a).153,198−201 Later, the authors further demonstrated that the [FBIP-Cl]2 (L38a−Pd2) precatalyst was efficient for the asymmetric 1,4-addition (and a subsequent Nef-type reaction) of N-benzoyl alanines with nitroolefins in nhexane (Scheme 41b).202 It is noteworthy that AgOTf is essential for activation of the catalyst to generate the monomeric complex FBIP-OTf, which is vital for high enantioselectivities. A range of N-benzoyl α-amino acids and nitroolefins furnished target products with high diastereo- and enantioselectivities (up to 50/1 dr and 96% ee). This methodology provides a facile route to the synthesis of biologically interesting α-alkyl-α-aminosuccinimides. Inspired by their previous work on asymmetric [3 + 2] cycloadditions based on a Michael-addition-initiated cyclization reaction,203 Xu et al.204 reported the Michael addition of glycine aldimino esters to chalcones using the Ag(I)/XingPhos (L63−AgOAc) catalyst, providing excellent outcomes (up to >20:1 dr and 97% ee; Scheme 42). The cyclization Scheme 42. ACA of Glycine Aldimino Esters to Chalcones Catalyzed by an L63−Ag(I) Complex

products were obtained with cis-isomers when the 1,4-addition products were further treated with HCl, which could be easily transformed to the trans-isomers under alkaline conditions. 2.5. Conjugate Addition of Oxindoles

Oxindoles are important structural motifs in the library of natural products and biologically active drugs. Since the 7608


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Scheme 43. ACA of Oxindoles to Nitroalkenes Catalyzed by Schiff Base−Metal Complexes

Scheme 44. ACA of Oxindoles Catalyzed by N,N′-Dioxide−Sc(III) Complexes

spirooxindoles) were synthesized in good to excellent yields (38−98%).

enantioselectivity (59% yield and 92% ee). Most recently, Nishiyama and co-workers214 promoted these reactions using a combination of Ni(OAc)2 with chiral N,N,O-tridentate phenanthroline ligand L69, which led to the corresponding adducts with up to 87% ee (Scheme 45c). A cascade Michael addition/cyclization reaction of 3-nitro2H-chromenes and 3-isothiocyanato oxindoles was demonstrated by the Xiao group215 using a complex L12a−Zn(OTf)2 as catalyst. A series of chiral polycyclic spirooxindoles with three consecutive stereocenters were obtained in good to high yields with excellent enantiocontrol (up to 95:5 dr and 99% ee; Scheme 46a). Recently, Trost et al.216 realized a tandem Michael addition/transesterification of 3-hydroxyoxindoles with β-substituted enoates using dinuclear complex L70− Et2Zn as catalyst (Scheme 46b). Using this method, a range of highly versatile synthetic building blocks (chiral polycyclic

2.6. Conjugate Addition of Cyanides

After Jacobsen and co-workers first demonstrated the asymmetric conjugate cyanation of α,β-unsaturated imides using the chiral complex L72−AlIII as catalyst,217 the authors further exploited covalently linked dinuclear salen−AlIII2 complexes for this reaction.218 Interestingly, they found that the dinuclear catalyst L73−AlIII2 is more efficient than mononuclear analogue L72−AlIII, resulting in better yields and ee’s within shorter reaction time (Scheme 47a). Especially for β-substituted α,β-unsaturated imides, the reactions were complete within several hours using L73−AlIII2 at lower catalyst loadings, while longer reaction times (over 2 days) were required for high conversion with L72−AlIII. It should be 7609


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Scheme 45. ACA of Oxindoles Catalyzed by L67−, L68− and L69−Metal Complexes

Scheme 46. Cascade Michael Addition/Cyclization Reaction Catalyzed by Zn-Complexes

47b).222 To enhance the activity of the catalyst, Weck and coworkers223−225 immobilized the salen unit on polynorbornenes to generate a polymer-supported salen−Al catalyst, which could be easily recovered and reused without any loss of efficiency. Shibasaki and co-workers described an asymmetric conjugate cyanation of α,β-unsaturated imides by using Gd(OiPr)3 and chiral D-glucose-derived ligand L74a (X = O) as catalyst in 2005.226 Recently, they found that the polymetallic complex

noted that several particular substrates that were completely unreactive with the mononuclear L72−AlIII catalyst system were tolerated well under the optimized conditions. The titanium(IV),219 vanadium(V),220 and AlIII complexes221 based on L72 also proved efficient for the asymmetric cyanation of nitroalkenes, delivering the corresponding adducts in high yields with up to 90% ee (Scheme 47b). Most recently, the application of these systems was extended to the enantioselective cyanation of β-CF3-substituted nitroalkenes (Scheme 7610


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Scheme 47. Asymmetric Conjugate Cyanation Reaction Catalyzed by a Salen−AlIII Complex

L74b−Gd(III) was also efficient for the conjugate addition of TMSCN to α,β-unsaturated N-acylpyrroles, providing the addition products in high yields with up to 98% ee (Scheme 48a).227 Interestingly, the opposite enantiomers were obtained by using L74a and L74b, which have the same chirality. Later, this catalyst system228 was employed for the ACA of TBSCN to enones (Scheme 48b). A range of enones, such as methyl, linear, branched, aryl, and cyclic examples were converted to the corresponding products in both high yields and enantioselectivities in the presence of complexes L74−Gd(III) or L75−Gd(III). Unsatisfactory results for the reaction with HCN indicated that the silyl group of TBSCN might play a significant role in the reaction, especially in their regio- and enantioselectivities. Interestingly, the 1,4-addition product can be achieved with up to 85% ee through the irreversible asymmetric rearrangement of the racemic 1,2-addition product cyanohydrin. Later,229 the complex L76−Sr(OiPr)2 was utilized for the ACA of TBSCN to β,β-disubstituted α,βunsaturated carbonyl compounds (Scheme 48c). The corresponding adducts were obtained with opposite configuration for the E- or Z-isomers in high yields with excellent enantiocontrol (R-configuration adducts with 89−99% ee’s

for E-isomers and S-configuration adducts with 97−99% ee’s for Z-isomers). In 2011, Ohkuma et al.230 revealed that the complex L77− Ru could also act as an excellent chiral catalyst for the ACA of HCN to α,β-unsaturated ketones (Scheme 49). Under the optimized conditions, the corresponding chiral β-cyano ketones were obtained in high yields with up to 99% ee values. Subsequently, the application of this catalyst system was further extended to the cyanation of α,β-unsaturated Nacylpyrroles by using CH3OLi instead of C6H5OLi.231 Recently, the Wang group used the binuclear complex L70− MgBu2 for the ACA of TMSCN to α,β-unsaturated ketones (Scheme 50a).232 A broad range of β-alkyl, β-aryl, and βheteroaromatic-substituted enones (R = alkyl, aryl) were tolerated, affording the corresponding adducts with good results (up to 95% yield and 97% ee). Ar-BINMOL-derived functional catalysts have proven efficient for the enantioselective 1,2-addition reactions of organometallic reagents to aldehydes.233,234 Xu and co-workers235 extended the application of a multifunctional Py-BINMOL(L78)−MgBu2 catalyst to the ACA of TMSCN to chalcones, providing desired products in 67−91% yields with up to 92% ee (Scheme 50b). 7611


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Scheme 48. Asymmetric Conjugate Cyanation Reaction Catalyzed by Gd or Sr Complexes

Scheme 49. Asymmetric Conjugate Cyanation Reaction Catalyzed by a (phgly)2(binap)−Ru Complex

The Feng group236 reported that a modular catalyst based on Ti(IV), which was generated from Ti(OiPr)4, cinchonidine L79, and achiral biphenol, catalyzed the ACA of diethyl alkylidenemalonate with CNCOOEt (Scheme 51), delivering the adducts in moderate to high yields with 74−94% ee’s. Notably, the corresponding products could readily be converted to useful enantioenriched building blocks such as γ-aminobutyric acid. An efficient chiral sodium phosphate salt catalyst system was also developed to catalyze the 1,4-addition of TMSCN to aromatic enones by Chen and co-workers.237

Scheme 50. Asymmetric Conjugate Cyanation Reaction Catalyzed by MgBu2 Complexes

2.7. Conjugate Addition of Alkynes

The asymmetric conjugate addition of terminal alkynes to electron-deficient alkenes is a highly efficient method to obtain versatile chiral building blocks with triple bonds. Enantioselective procedures for the alkynylation of enones and related compounds that have been carried out by using preformed alkynyl-organometallic reagents will not discussed in this review. Herein, we will review the literature on the convenient approach of directly using terminal alkynes as nucleophiles. The first examples of the ACA reaction of terminal alkynes (phenylacetylene and aliphatic alkynes) on acceptors derived from Meldrum’s acid were reported by the Carreira group in 2005 (Scheme 52).238 In the presence of water and Na(+)-ascorbate, the readily prepared complex L80−Cu(OAc)2 delivered addition products with good enantiocontrol (82− 7612


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Among the developments in the ACA of alkynes, excellent work has been achieved by Hayashi and co-workers. In 2008,241 the complex L36a−Rh(I) was applied to synthesize βalkynylketones through the ACA of (triisopropylsilyl)acetylene to α,β-unsaturated ketones (Scheme 53a), resulting in high yields with up to 97% ee. Interestingly, the steric bulk present in (triisopropylsilyl)acetylene and ligand L36a was integral in obtaining higher conversion due to lower amounts of dimerization. The use of complex [Rh(OH)((R)-binap)]2 can also produce the corresponding alkynylation products in good results with a wide scope of enones.242 The application of this catalyst system was further extended to α,β-unsaturated aldehydes (Scheme 53b).243 A range of useful natural products, such as ciguatoxin, frondosin B, and goniodomin A could be easily synthesized from the enantioenriched β-alkynyl aldehyde products. The L83c−Co(OAc)2 complex was effective for the ACA of silylacetylenes to α,β-unsaturated ketones and led to the generation of alkynylation products with excellent outcomes (up to 91% ee; Scheme 53d).244 Phenylacetylene and 1-octyne were not applicable in this reaction due to their unexpected alkyne oligomerization. High yields with excellent enantiocontrol were obtained for the corresponding 1,6addition products by using complexes L83a− and L83b− Co(OAc)2 as catalysts, when employing the α,β,γ,δ-unsaturated carbonyl compounds as substrates (Scheme 53c).245 Most recently,246 the complex [(R,R)-L84−RhCl]2 was revealed to be an efficient catalyst for the ACA of diphenyl[(triisopropylsilyl)ethynyl]methanol to cyclic α,βunsaturated carbonyl compounds (up to 98% ee; Scheme 54a). The bulky iPr3Si group at the acetylene terminus improved the yield remarkably. The Dou group247 also described a similar reaction for β,γ-unsaturated α-ketoesters using L85−[Rh(OH)(cod)]2 as catalyst. A broad range of γaryl-β,γ-unsaturated α-ketoesters were smoothly converted to the adducts in good yields with up to 93% ee (Scheme 54b). Soft Lewis acid/hard Brønsted base cooperative catalyst systems based on copper salts and ligands L81b/A1 or L36a/

Scheme 51. Asymmetric Conjugate Cyanation Reaction Catalyzed by a Cinchonidine−Ti(IV) Complex

97% ee’s). The Fillion group239 successfully developed the catalyst L81a−Rh(I) for the ACA reaction of 5-benzylidene Meldrum’s acids with TMS-acetylene (Scheme 52), yielding the corresponding products in moderate to high yields with up to 99% ee. However, no products were detected when using 2Me- or 4-MeO-substituted acceptors (R2 = 2-MeC6H4, 4OMeC6H4). Most recently, Aponick and co-workers240 employed the five-membered chiral biaryl heterocyclic scaffold L82 to construct the efficient catalyst L82−Cu(OAc)2. Various nucleophiles, such as protected propargyl alcohols and amines, TMS-acetylene, and alkyl alkynes were tolerated in the reaction.

Scheme 52. ACA of Terminal Alkynes Catalyzed by L80−, L81a−, and L82−metal complexes

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Scheme 53. ACA of Alkynes to Enones Catalyzed by Bisphosphine−Metal Complexes

Scheme 54. ACA of (Triisopropylsilyl)acetylene to Enones Catalyzed by Rh Complexes

of β-trifluoromethyl α,β-enones using complex L86−Cu(I) as catalyst (28−99% yields and 70−99% ee’s; Scheme 56b).251 In this case, aliphatic enones generally displayed less reactivity than the aromatic enones, especially for the n-Bu-substituted examples, where no reaction was observed. Subsequently, similar results were achieved for the corresponding 1,4addition products by using copper(I) complex L81c−Cu(I) as catalyst when employing 1,3-diynes as alkynylation reagents (Scheme 56c).252,253 The catalyst L87−Et2Zn, based on the transition metal zinc and ligand L87, was developed for the ACA of phenylacetylene to enones by Blay, Pedro, and co-workers254 (up to 80% yield and 93% ee; Scheme 57a). However, while good results were obtained for the arylacetylenes, low yields and enantioselectivities were obtained when using 1-butyne as substrate under the optimized conditions. Later, the authors demonstrated that the substituted dihydrocoumarins provided the corresponding 1,4addition products in good yields with moderate to excellent

A2 were adopted for the ACA of the terminal alkynes to α,βunsaturated thioamides (Scheme 55).248 In this case, a series of phenylacetylene and saturated aliphatic terminal alkynes were tolerated, resulting in moderate to high yields (43−98%) with good enantiocontrol (up to 98% ee). Later, this method was employed for the synthesis of a potent GPR40 agonist (AMG837), and the desired product was obtained with up to 91% ee.249 Pedro and co-workers250 first employed 1,1-difluoro-1(phenylsulfonyl)-3-en-2-ones, which are regarded as ester/ amide surrogates, in the ACA reaction. A range of terminal alkynes with variously substituted 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones were tolerated well in the presence of complex L81c−Cu(I), yielding the corresponding products with excellent outcomes (up to 90% yield and 99% ee; Scheme 56a). The potential of this reaction was illustrated in the synthesis of some fluorinated pharmaceuticals and agrochemicals. Later, this methodology was extended to the ACA 7614


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Scheme 55. ACA of Alkynes to α,β-Unsaturated Thioamides Catalyzed by Cu Complexes

Scheme 56. ACA of Alkynes to Enones Catalyzed by Cu(I) Complexes

ee’s by using complex L88−Et2Zn as catalyst (Scheme 57b).255 Most recently,256 the complex L89a−Et2Zn, generated from the 3,3′-bis(perfluorophenyl) BINOL ligand L89a, ZnEt2, and bis(hydroxyamide), proved efficient for the ACA of terminal alkynes to β-aryl-β-trifluoromethyl enones, yielding the corresponding trifluoromethylated ketones bearing a propargylic quaternary stereocenter with up to 90% ee (Scheme 57c). However, no adducts were observed when using 4nitrophenylacetylene or alkyl-acetylene as substrates.

after that date and only present a few representative examples in detail. Optically active butenolide-containing compounds display an impressive biological activity in a wide range of natural products.260 In the metal-catalyzed ACA of butenolides, the Lewis acid or base can deprotonate butenolides to generate highly active metal enolate intermediates (Scheme 58), which could react with electrophiles at different positions (γ- or αpositions). Usually, nucleophiles react at the γ-position rather than at the α-position as the activity of the γ-position of the enolate intermediate is higher than the α-position. In 2014, the Shibasaki group261 showed that the soft Lewis acid/Brønsted base cooperative catalyst L36b−Cu(I) was applicable to the ACA of α,β- or β,γ-unsaturated butyrolactones to α,βunsaturated thioamides (51−97% yields and up to 99% ee; Scheme 58). However, only a 19% yield, with lower diastereoand enantioselectivity, was obtained when using an α,β-

2.8. Conjugate Addition of Vinylogous Nucleophiles and Indoles

As achievements in the field of ACA, reactions using vinylogous nucleophiles have already been discussed by Chabaud, Guillou, and Schneider in 2014,257,258 and since the enantioselective conjugate addition of indoles reported before 2016 have been covered in a review by Jia,259 in this review, we will mainly focus on the related literature appearing 7615


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Scheme 57. ACA of Terminal Alkynes Catalyzed by Zn Complexes

unsaturated ketone as substrate. The α-vinylidene malonate exhibited high reactivity but gave only a racemic product. No products were observed with electron-deficient olefins such as α,β-unsaturated ester, amide, imide, and tosylated amide. α,βUnsaturated thioester and the N-acylpyrrole gave less than 10% yield under the optimized conditions. Although full conversion of an α,β-unsaturated nitrile was detected, an unknown product was obtained. A transition state was postulated by the authors, as shown in Scheme 58, whereby a metal enolate is generated from unsaturated butyrolactones by using a tertiary amine and complex L36b−Cu(I). Subsequent coordination of the α,β-unsaturated thioamide to the tetracoordinate metal center produces the transition state, where the active enolate nucleophile attacks the α,βunsaturated thioamide to afford the 1,4-addition product. The Feng group89 revealed that the N,N′-dioxide− scandium(III) complex L22f−Sc(OTf)3 was efficient for the ACA of β,γ-unsaturated butenolides to α,β-unsaturated γketoesters, delivering the γ,γ-disubstituted butenolide products with good outcomes (up to >19:1 dr and 97% ee; Scheme 59a). Most recently, the application of this catalyst system was extended to the ACA of butenolides to alkynones (Scheme 59, panels b and c).262 When using β-ester-substituted alkynones as substrates, the desired adducts were obtained in moderate to high yields with 49−95% ee’s in the presence of 5 mol % of L22c−Sc(OTf)3. However, the complex L20b−Sc(OTf)3 gave better results for terminal alkynones, delivering the corresponding products with excellent enantiocontrol (up to >19:1 E/Z and 99% ee). The substrates containing electronwithdrawing groups generally gave higher reactivities and enantioselectivities. However, no addition products were obtained under the same conditions when the acyl group on the terminal alkynone was replaced by an ester or amide.

Wang and co-workers263 successfully used complexes L89b−Al(OiPr)3 or −La(OiPr)3 for the ACA of γ-phenylsubstituted butenolides to enones, leading to the corresponding adducts in fair to high yields with excellent enantioselectivities (Scheme 60). A lower yield with slightly higher enantioselectivity was obtained by using L89b−Al(OiPr)3, while L89b−La(OiPr)3 gave the opposite results. Bolm and co-workers found that the complex L47− Cu(ClO4)2 was an efficient catalyst for the ACA of siloxy furans to unsaturated α-keto phosphonates (Scheme 61a).264 The position of the methyl group on the siloxy furans played a significant role in the reaction, especially on the reactivity. While an 82% yield with 98% ee was achieved for the 3methyl-substituted siloxy furans, the 4- or 5-substituted siloxy furans gave only 56% yield with 91% ee, and 27% yield with 70% ee, respectively, under the same conditions. However, the aldol addition product was obtained as a major product when the 4-methoxy-substituted siloxy furan was used as a nucleophile. The Nakada group265 developed a similar system for the ACA of silyl enol ethers to cyclic α-alkylidene β-oxo imides using complex L90a−Cu(OTf)2 as catalyst (Scheme 61b). They further extended the application of this catalyst system to cyclic α-alkylidene β-oxo phosphates and phosphine oxides by using complex L90b−Cu(II) as catalyst (Scheme 61c).266 It is worth noting that the potential of this method was illustrated in the synthesis of (R)-homosarkomycin. Most recently, the Singh group267 found that the ACA of silyloxyfurans to α,β-unsaturated 2-acyl imidazoles proceeded in the presence of chiral pybox complexes L14−Sc(III) or − Er(III) (Scheme 61d). After screening of solvent, catalyst loading, reaction temperature and additives, the optimal conditions were identified as 10 mol % catalyst, CHCl3 as solvent, and HFIP as additive. A broad range of β-furyl or substituted furyl α,β-unsaturated 2-acyl imidazoles were 7616


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Scheme 58. ACA of Butenolides to α,β-Unsaturated Thioamides Catalyzed by an L36b−Cu(I) Complex

atures (0−30 °C, up to 99% ee), the (R)-enantiomers were obtained as the major products when the reaction was performed at temperatures below −30 °C (up to 96% ee). Moreover, two plausible alternative catalytic cycles were proposed by the authors to explain the relationship between the reaction conditions and enantioselectivity. The Kobayashi group270 reported an ACA of indoles to α,βunsaturated ketones catalyzed by a L93−palladium(II) complex (Scheme 64). The reaction was carried out in water by adding a certain amount of surfactant and good yields with up to 91% ee were obtained for most substrates. However, α,βunsaturated ketones with aromatic groups at the β-position (R2 = Ph), or alkyl groups adjacent to the carbonyl group (R1 = t Bu), retarded the reaction and gave low enantioselectivities. Moreover, indoles with electron-donating substituents (R4 = 2Me or 7-Me) or N-methylindole only gave racemic products (12% ee for 7-methylindole) in high yields.

tolerated, giving the corresponding addition products in good yields with up to >20:1 dr and 98% ee. In 2015, Wang and co-workers described268 a C−C-bondforming conjugate addition reaction in asymmetric dearomatization of β-naphthols with propargylic ketones catalyzed by complex L91−MgBu2 (Scheme 62). A range of β-naphthols with alkyl or aryl groups, as well as halogens substituted at C3 of the naphthyl ring, were converted to the desired adducts with Z-configured C−C double bonds (15:1 Z/E) with good results (up to 97% ee). However, a low yield (32%) was observed when using C3-TMS-substituted β-naphthol as nucleophile, even under higher catalyst loading. Most recently, the Carmona group269 developed the complex L92−Rh for the enantioselective Michael-type Friedel−Crafts reaction between N-methyl-2-methylindole and trans-β-nitroolefins (Scheme 63). Interestingly, the enantiocontrol was found to be strongly temperature-dependent: while (S)-enantiomers were obtained at higher temper7617


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Scheme 59. ACA of Butenolides Catalyzed by N,N′-Dioxide−Metal Complexes

amino butyric acid pregabalin. Later, Scheidt et al.278 reported a conjugate addition of silyloxyallenes279,280 to alkylidene malonates. Using (R,R)-Ph-Pybox L13b as the chiral ligand provided a moderate yield and ee (72% yield and 70% ee; Scheme 67b). Recently, Lam et al.281 demonstrated that the ACA of alkylazaarenes282 to nitroalkenes is possible in the presence of a chiral L45−Pd(II)-based catalyst system, furnishing the corresponding syn products in high yields with up to 99% ee (Scheme 67c). Shibasaki et al.283 successfully developed the ACA of allyl cyanide to α,β-unsaturated thioamides promoted by complex L36a−[Cu(CH3CN)4]BF4 (Scheme 68), which provided the corresponding α,β-unsaturated nitriles with excellent enantiomeric purity in high yield. Moreover, various bioactive isothiazoles were successfully synthesized when the products were further treated with CuOTf/Li(OC6H4-p-OMe), in which CuOTf acted as a redox catalyst. The thiolactams were successfully employed as the nucleophiles under suitable conditions (up to 83% yield, anti/syn = 96/4 and 99% ee).284 Feng and co-workers revealed in 2015 that the complex L22c−Yb(OTf)3 acted as an excellent chiral catalyst for the ACA of 3-alkylidene oxindoles to chalcones (Scheme 69a).90 A range of chalcones with electron-withdrawing or electrondonating substituents on the aromatic ring were evaluated and gave target products with excellent outcomes (66−96% yields, 84−98% ee’s, and 78:22−91:9 Z/E). A gram-scale synthesis was also attempted, and the product was obtained without any loss of enantioselectivity. Most recently, silyl ketene imines (SKIs) were found to be suitable nucleophiles for the ACA of in situ generated indol-2-ones.285 In the presence of complex L22g−Ni(BF4)2 and iPrNEt in EtOAc at −20 °C, the desired products were obtained in high yields with excellent enantiocontrol (up to 90% yield, 23:1 dr, and 98% ee; Scheme 69b). However, while good results were obtained for most SKIs, only trace amounts of the racemic adduct were obtained when using a cyclohexane-derived SKI as substrate. Recently, photochemically generated α-amino radicals have proven to be suitable nucleophiles in ACA reactions.286−289 Yoon and co-workers290 realized the highly enantioselective conjugate addition of α-amino radicals to α,β-unsaturated carbonyl compounds by combining a transition metal complex with a photocatalyst (Scheme 70). The chloride salts play a significant role in achieving high enantioselectivities, and the

Scheme 60. ACA of Butenolides to Enones

The Roelfes group271 also extended the application of the L30-st-DNA−Cu(dmbipy)(NO3)2 catalyst system to the enantioselective Friedel−Crafts conjugate addition protonation reaction of indoles (Scheme 65). A range of indoles with enone groups were successfully converted into the corresponding products with reasonable outcomes (up to 84% ee). Almost no conversion was obtained for the reaction without DNA when using Cu(dmbipy)(NO3)2 as a catalyst, indicating that DNA had a crucial effect on the reaction process. In addition, the reaction at higher pH (>5) values also resulted in a significant decrease in enantioselectivity. Most recently, Meggers and co-workers272 reported a new class of chiral-at-metal biscyclometalated iridium(III) catalyst tethered to polystyrene, which was efficient for the asymmetric Friedel−Crafts conjugate addition of indoles to α,β-unsaturated 2-acyl imidazoles (up to 98% ee; Scheme 66). Interestingly, the amide-linked catalyst L94−Ir(III) was very stable and could be reused more than ten times without any significant loss of efficiency. In addition, this catalyst system was extended to enantioselective Diels−Alder reactions with good results. The complex L95−Ir(III) was also successfully used by Shibata and co-workers273 for the asymmetric C−H conjugate addition of acetanilides to β-substituted acrylates. 2.9. Conjugate Addition of Other Carbon Nucleophiles

In addition to the nucleophiles described above, other nucleophiles have also been employed in metal-catalyzed ACA reactions. Lassaletta and co-workers274 reported an example of the ACA of 1-methyleneamino pyrrodine to αhydroxy enones,275−277 employing chiral complex L47− Zn(OTf)2 as the catalyst (Scheme 67a). The best enantioselectivity was achieved when the reaction was carried out in toluene at rt or 5−10 °C. It is worth noting that the potential of this method was illustrated in the synthesis of bioactive γ7618


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Scheme 61. ACA of Siloxy Furans and Silyl Enol Ethers

Scheme 62. Asymmetric Dearomatization of β-Naphthols with Propargylic Ketones Catalyzed by an L91−MgBu2 Complex

Scheme 63. Michael-Type Friedel−Crafts Reaction Catalyzed by an L92−Rh Complex

optimal conditions were identified as 2 mol % Ru(bpy)3Cl2, 15 mol % Sc(OTf)3, 20 mol % (S,S)-L34b, and 30 mol % Bu4N+Cl− in degassed MeCN (0.05 M) with a 23 W compact fluorescent light bulb. A range of N-aryl amines and α,βunsaturated carbonyl compounds were combined to give the corresponding adducts with excellent outcomes (up to 96% yield and 96% ee). In 2016, Meggers and co-workers291,292 reported an example of a photoinduced asymmetric Michael addition of alkyl radicals293 to enones catalyzed by complex L32−Rh(III) (up

to 97% yield and 99% ee; Scheme 71a). Only a trace product was obtained without addition of photosensitizer or visible light. The application of this catalyst system was extended to the enantioselective alkylation reaction employing complex 7619


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Scheme 64. ACA of Indoles Catalyzed by an L93−Pd(II) Complex

Scheme 65. ACA of Indoles Catalyzed by an L30-st-DNA−Cu(II) Complex in Water

Scheme 66. ACA Reactions Catalyzed by Ir(III) Complexes

L31−Rh(III) as the catalyst (Scheme 71b).294 The presence of electron-donating or aliphatic groups on the double bond of the Michael-acceptor (R2 = 4-MeOC6H4, Me or n-Pr) almost completely prevented the reaction. Most recently, the complex

L33b−Rh(III) was also successfully applied to the photoinduced enantioselective Michael addition of α-amino radicals by the Kang group (Scheme 71c). The catalyst acted not only as a Lewis acid but also as a photosensitizer.295 7620


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Scheme 67. ACA Reactions Catalyzed by Bisoxazoline−Metal Complexes

Scheme 68. ACA Reactions of α,β-Unsaturated Thioamides

2.10. SUMMARY

bisoxazoline ligands have proven more successful than others. As shown in Figure 3a, more than 72 publications related to chiral bisoxazoline ligands appeared between 1996 and 2017. The multifunctional alkali-metal-lanthanide-BINOL catalysts developed by Shibasaki et al. and their second-generation variants (using linked BINOLs as ligands) were praised as a milestone in metal-catalyzed ACA reactions, although most of these were developed before 2007 and are thus not included in this review (Figure 3b, brown dashed line). A closer inspection of Figure 3b reveals that another major advance was achieved at the beginning of the 21th century (2001−2009) with the application of chiral bisoxazoline ligands, which have brought

Given the broad diversity of chemistry demonstrated above, it is evident that the ACA reaction of soft nucleophiles has had a broad impact on the field of asymmetric synthesis. Since the first enantioselective ACA reactions catalyzed by chiral metal diamine complexes, reported by Brunner and co-workers in 1984, numerous research groups have attempted to find more efficient catalyst systems, and as a result, a large number of chiral ligands have been applied in this area. The popularity of different classes of chiral ligands for the ACA reaction since 1993 is shown in Figure 3. The results show that chiral 7621


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Scheme 69. ACA Reactions Catalyzed by N,N′-Dioxide−Metal Complexes

Scheme 70. ACA of α-Amino Radicals to α,β-Unsaturated Carbonyl Compounds Catalyzed by an L34b−Sc(III) Complex

Scheme 71. ACA of Radicals to Enones Catalyzed by Rh(III) Complexes

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Figure 3. Recent publication frequency of several classes of chiral ligands (publications in Scifinder Scholar about the metal-catalyzed ACA of nonorganometallic nucleophiles between 1993 and 2017, not including patents).

activated, including heterobimetallic BINOL complexes (Table 1, entry 2), bimetallic Schiff base catalysts (Table 1, entry 4), and parts of chiral diamine−metal complexes (Table 1, entry 1) and (2) via monoactivation, where just one reaction partner is activated by the catalyst, such as chiral bisoxazolines (Table 1, entry 3), chiral Schiff bases (Table 1, entry 4), chiral N,N′dioxides (Table 1, entry 5), and Meggers octahedral metal complexes (Table 1, entry 6).

about a huge development of novel enantioselective metalcatalyzed transformations (Figure 3b, green line). Following their introduction in 1999 for the ACA reaction, chiral Schiff bases and their bimetallic scaffolds (reported by the Shibasaki group in 2009) were shown to be key to the development of highly regio-, diastereo-, and enantioselective reactions (Figure 3b, purple line). Inspired by the success of diamine−Co(II) complexes in 1984, an large number of chiral metal diamine complexes have been developed. The most spectacular advances were reported by the Evans group in 2005 by using diamine−Ni(II) complexes as catalysts (Figure 3b, mazarine dashed line). Especially in the last 10 years, chiral N,N′dioxide−metal complexes have demonstrated their high efficiency as Lewis acids, becoming catalysts of choice for many types of ACA reactions generally performed under mild reaction conditions (Figure 3b, blue dashed line). The central metals, nucleophiles and transition states that have been used or proposed in the ACA reaction for the representative chiral ligands are summarized in Table 1. Selecting a metal−ligand combination, as well as the choice of target reactions, is critical to achieving high stereoselectivity and enantioselectivity. As shown in Table 1, each kind of ligand has a most effective metal (the metal used most often is marked in red, Table 1). For example, heterobimetallic BINOL complexes work best with rare earth metals and alkali metals, while diamines work best with nickel. The chiral bisoxazoline− Cu(II), Schiff base−Al(III), and N,N′-dioxide−Sc(III) catalysts are remarkable systems for their high levels of enantioselective induction in ACA reactions. Rhodium and iridium were effective in Meggers octahedral metal complexes catalyst systems. For Michael acceptors, compared to the α,βunsaturated enones (such as chalcones and their derivatives, which are the most often used in the ACA reactions), the other Michael acceptors (such as α,β-unsaturated ester, lactone, imide, and thioester substrates) are often less reactive and need either more active nucleophiles or more competent catalysts to achieve the best results. For nucleophiles, almost all carbonic nucleophiles and some heteroatom nucleophiles have been combined with the catalysts mentioned in Table 1, and Meggers octahedral metal complexes proved advantageous for the ACA reaction using aldehydes and radicals as nucleophiles. Moreover, the mechanistic model for the metal-catalyzed ACA reaction can be classified into two main pathways: (1) via dualactivation, where both reaction partners are simultaneously

3. C−HETEROATOM BOND FORMATION BY METAL-CATALYZED ACA REACTIONS The asymmetric conjugate addition of heteroatom-based nucleophiles is a valuable tool for the introduction of a functional group into the β-position of α,β-unsaturated acceptors. In this section, research progress in the use of different heteroatom nucleophiles (such as B, O, S, N, P, and Si) is summarized, involving various metal-complex catalysts based on chiral ligands, including bisphosphines, N-heterocyclic carbenes, and others. 3.1. Conjugate Addition of Boron Nucleophiles

The metal-catalyzed asymmetric conjugate borylation reaction has emerged as a useful method to afford a variety of organoboron compounds, which are very useful building blocks in organic synthesis.296−298 Over the past decade, significant efforts have been made in this area by using bis(pinacolato)diboron (B2pin2) as the nucleophile. 3.1.1. Using Chiral Phosphines as Ligands. In 2008, Yun and co-workers reported the first example of Cu(I)catalyzed β-borylation of α,β-unsaturated nitriles, esters,299 and amides300 using CuCl and Josiphos L97 as the catalyst, along with a base as an additive. A series of α,β-unsaturated nitriles, esters, and amides were converted to the corresponding addition products in good yields with high to excellent ee values. This methodology was successfully extended to tolerate linear301 and cyclic302 enones, allowing for the synthesis of a small library of chiral organoboron compounds (Scheme 72). Notable are the essential and related roles of the addition of a catalytic amount of base and an excess of alcohol. Controlling the amount of alcohol according to its size was important to obtain high ee’s. Later, Gómez Arrayás, Carretero, and coworkers demonstrated that α,β-unsaturated sulfones could be tolerated,303 affording the corresponding β-hydroxy sulfones in good yields with 77−96% ee’s by subsequent oxidation. In this 7623


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Table 1. Comparison of Several Representative Chiral Ligands

case, the electron-rich aromatic substituents at the β-position of sulfones generally gave better outcomes. In contrast, no product was detected when using a 4-trifluoromethylphenyl βsubstituted sulfone. A similar system was also used to achieve the β-borylation of α,β-unsaturated phosphine oxides by Feringa and co-workers (Scheme 72).304 Generally, α,βunsaturated phosphine oxides with linear aliphatic substituents displayed higher reactivities and enantioselectivities, but β-aryland trimethylsilyl-substituted substrates gave lower yields and ee’s. Most recently, this catalytic strategy was further applied to the asymmetric borylation of β-trifluoromethyl-α,β-unsaturated ketones.305 A range of chiral products bearing both CF3 and organoboron functional groups were prepared with good results. DFT calculations on the reaction were disclosed by Marder and Lin,306 and catalytic cycles for these reactions were proposed. As shown in Scheme 72, the catalytic cycle commences with the coordination of the in situ generated

complex I to the double bond of the alkene substrate, forming the complex II, and subsequent insertion of its CC bond into the copper−boron bond of complex II, generating the intermediate III. The copper enolate III undergoes proteolytic cleavage by an alcohol forming the protonated product V and a copper alkoxide IV. Subsequently, intermediate IV reacts with B2pin2 regenerating I. Cu(I)-catalyzed domino conjugate borylation/aldol cyclization using enone diones as substrates, carried out in the presence of Josiphos L97, was reported by Lam and coworkers (Scheme 73).307 The optimal conditions were identified to be 5 mol % of complex L97−CuCl (molar ratio: 1.1/1), 7.5 mol % NaOtBu, and 2 equiv iPrOH or t BuOH in THF at RT, under which the corresponding highly functionalized chiral bicyclic products were synthesized with high diastereo- and enantioselectivities (>95/5 dr and 99% ee). 7624


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Scheme 72. Asymmetric Conjugate Borylation Catalyzed by Ferrocenyl-Phosphine−Cu(I) Complexes

Cu(O t Bu) (complex I) with B 2 pin 2 to generate the intermediate II. Then, coordination of the intermediate II with methylindole-2-carboxylate 2 gives the intermediate III, which isomerizes to the enolate IV with concomitant C−B bond formation via conjugate addition. Assisted by the bulky t BuOH additive, the resulting enolate IV subsequently undergoes a diastereoselective protonation via six-membered cyclic transition state V, affording borylation products and the L83d−Cu(OtBu) precatalyst I. In 2009, the Shibasaki group described a highly enantioselective conjugate borylation of β-substituted cyclic enones for the synthesis of enantiomerically enriched tertiary organoboronates.309 Utilizing the P-chiral (R,R)-QuinoxP ligand L98 and Cu(I) as central metal, a series of tertiary boronates were obtained in high yields with 70−98% ee’s (Scheme 75a). In contrast to the previous work described above, this reaction does not require an alcohol as a protic additive. Later, a similar methodology was applied to the βsubstituted linear esters by Yun and co-workers.310 In this case, chiral phosphine ligand (S,S)-MeDuphos (L83a), bearing a short tether between the two phosphines, gave better results (Scheme 75b), while Josiphos and BINAP ligands led to very poor conversions. In 2011, Fernández and co-workers successfully developed a one-pot three-step borylation/reduction/oxidation of α,βunsaturated imine starting materials using Cu(I) complexes based on chiral phosphorus ligands, providing an efficient route for the synthesis of γ-amino alcohols, valuable synthetic intermediates, in good yields with up to 99% ee (Scheme

Scheme 73. Asymmetric Domino Conjugate Borylation/ Aldol Cyclization of Enone Diones

Ito and co-workers applied chiral bisphosphine ligands to the Cu(I)-catalyzed asymmetric borylation of methylindole-2carboxylates.308 A modified procedure using Cbz-protected methylindole-2-carboxylates in the presence of (R,R)-L83d− Cu(OtBu), Na(OtBu), and tBuOH, the latter acting as a proton source, afforded the desired products in moderate to good yield with excellent enantiocontrol (up to 76% yield, 97/3 dr and 97% ee; Scheme 74). The Cbz protecting group of methylindole-2-carboxylate was required for reactivity, while the Boc-protected indole gave only a 13% yield. The authors circumvented this problem by using the less sterically hindered ligand (R,R)-L83c (Scheme 74), affording the desired products in high yield with good stereoselectivity (93:7 dr and 86% ee). Moreover, only trace products were observed when using Fmoc- and Me-protected indoles, as well as 2-methylindole, as substrates. In accordance with the proposed mechanism (shown in Scheme 74), the first step of this copper(I)catalyzed dearomative borylation is reaction of L83d− 7625


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Scheme 74. Asymmetric Borylative Dearomatization of Heteroaromatic Compounds

complex L60c−Cu(I) in the reaction of β-substituted αdehydroamino acid derivatives with B2Pin2 in MeOH, generating enantioenriched β-boronate-α-amino acid derivatives in high yields with excellent ee’s (91−98% ee’s for synisomers, 92−98% ee’s for anti-isomers; Scheme 77a) but low diastereoselectivity (1:1).315 Interestingly, the geometry of the double bond played a crucial role in the reactivity as only trace product was obtained when the E-substrate was employed under the standard conditions (Scheme 77b). Having β-alkyl substitution on the double bond affected the enantioselectivity, where less than 30% ee was obtained under the standard conditions. However, a significant improvement in the enantioselectivity with reversed chiral induction was obtained

76a).311,312 Most recently, Whiting and co-workers disclosed the synthesis of chiral homoallylic boronates with high ee’s by an efficient one-pot methodology (the imine is formed in situ from its respective α,β-unsaturated aldehyde, followed by catalytic borylation in the presence of complex L85−Cu(I) and workup). The unstable borylation products could easily be transformed to stable compounds by either a subsequent Wittig olefination to give homoallylic boronates or subsequent CN reduction and C−B oxidation reactions to yield γ-amino alcohols (Scheme 76b).313,314 In addition to P,P-chelating ligands, P,N-chelating ligands were also successfully employed in Cu-catalyzed asymmetric conjugate borylation reactions. The most recent work in this area comes from the group of Lin and involves the use of the 7626


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Scheme 75. Asymmetric Conjugate Borylation of β-Substituted Enones

Scheme 76. Asymmetric Conjugate Borylation of α,β-Unsaturated Aldehydes and Imines

Scheme 77. Asymmetric Conjugate Borylation Catalyzed by Ferrocenyl-Oxazoline−Cu(I) Complexes

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esters, giving the corresponding products with reasonable stereoselectivities (Scheme 80a).321 Later, Hoveyda and coworkers reported the first asymmetric borylation of trisubstituted acyclic α,β-unsaturated esters, ketones, and thioesters using a chiral monodentate NHC L104−Cu(I) complex as the catalyst. Under the optimized conditions, the corresponding products with β-substituted quaternary stereocenters were obtained in up to 98% yield and 98% ee (Scheme 80b).322 However, while excellent results were obtained for most aryland alkyl-substituted α,β-unsaturated esters, yields of only 31% with 6% ee were obtained for ortho-methylaryl-substituted substrates. α,β-Unsaturated ketones and thioesters were tolerated but resulted in slightly lower ee’s. On the basis of mechanistic studies, as shown in Scheme 80, a transition state was proposed by the authors, indicating that the size of the Nsubstituent of the ligand plays a significant role in achieving high selectivity due to the steric hindrance. Interestingly, Sawamura et al.323 demonstrated that the chiral ligand L105 bearing a phosphate moiety is also suitable for Cu-catalyzed borylation reactions. Ma, Song, and co-workers published a series of works on NHC−Cu(I)-catalyzed asymmetric conjugate borylation reactions (Scheme 81).324−328 In 2011, they successfully developed a chiral NHC (L106a)−Cu(I)-based catalyst system for the enantioselective conjugate β-borylation of enones to furnish the corresponding products in high yields with up to 84% ee.325 This methodology was successfully applied to the borylation of α,β-unsaturated esters (up to 95% yield and 97% ee; Scheme 81).326 In addition to α,βunsaturated ketones and esters, the authors demonstrated that α,β-unsaturated N-acyloxazolidinones provided the corresponding adducts in high yields with excellent enantiocontrol (97−99% ee’s) in the presence of complex L106b− Cu(I).328 Subsequent studies showed that ligands L106c and L106d are also efficient for the borylation of acylic enones and α,β-unsaturated ketones, respectively.324,327 However, a low ee (47% ee) was obtained when benzalacetone (R2 = Me) was used as a substrate. It should be noted that the catalyst loading could be reduced to 0.1 mol % for a gram-scale reaction without any significant loss in efficiency (95% ee). In addition to the NHC ligands described above, several other chiral NHC ligands have been employed in asymmetric conjugate borylation reactions.329−332 As shown in Scheme 82a, Hong et al. achieved the conjugate borylation of α,βunsaturated amides using complex L107−Cu(I) as the catalyst. After treating with NaBO3 in THF at room temperature, the corresponding hydroxyl compounds were obtained with good results (up to 92% yield and 87% ee). The geometry of the double bond played an important role in the reaction as the Eisomers generally gave higher yields and ee’s.329 Later studies by the McQuade group330 showed that the chiral sixmembered annulated N-heterocyclic carbene (6-NHC) copper complex L108−Cu(I) was also efficient for the reaction of α,βunsaturated esters (Scheme 82b). It should be noted that a particularly high catalytic performance was observed with as little as 0.01 mol % catalyst loading (93% yield and 88% ee in 100 min). Recently, Wang, Sun, and co-workers demonstrated331,332 that complexes L109− and L110−Cu(I) were suitable catalysts for the borylation of α,β-unsaturated esters (Scheme 82c). In Sun’s case, the reaction temperature had a crucial influence on the reactivity and selectivity, and the best results were observed at −55 °C.

Scheme 78. Asymmetric Conjugate Borylation of Enones Catalyzed by an L100−CuCl Complex

Scheme 79. Asymmetric Conjugate Borylation of α,βUnsaturated Esters Catalyzed by an L102−CuCl Complex

when using (R,R)-Ph-BPE (L99) as a ligand (up to 92% ee; Scheme 77c). The Li group successfully developed an efficient catalyst system for asymmetric borylation of α-substituted α,βunsaturated substrates, employing aminophosphine (S,R)ppfa L100 as ligand (up to 70:1 dr and 98% ee; Scheme 78).316 A range of functional moieties (alkyl, NHR, OMe, and halogen) on the α-position were tolerated well, and notably, additives such as AgNTf2 and alcohols played an important role in achieving high reactivity as well as diastereo- and enantioselectivity. Compared to most Cu(I)-catalyzed asymmetric boron reactions, which are performed under alkaline conditions, the nonalkaline conditions were tolerated well by this catalyst system. Similar work was described by the same group for the asymmetric borylation of α,β-unsaturated ketones and esters.317 A new class of axially chiral P,N-chelating ligands L102 based on Quinap-type ligands with steric bulk at the 2-position were introduced to the asymmetric borylation of α,βunsaturated esters by Guiry and co-workers (up to 79% ee; Scheme 79).318 Later, Č asar and co-workers disclosed a Cu(II)-complex catalyst system that was also efficient for the borylation of α,β-unsaturated esters by using water as the solvent.319 They evaluated a range of chiral P,P-chelating and P,N-chelating ligands that gave the borylation products with reasonable enantioselectivities. In addition to the Cu complexes, Fernández and co-workers revealed in 2009 that palladium or nickel complexes with chiral P−P or P−N ligands could also act as excellent chiral catalysts for the borylation of α,β-unsaturated esters.320 3.1.2. Using Chiral NHCs as Ligands. Transition metal complexes bearing a range of N-heterocyclic carbene (NHC) ligands have also demonstrated efficiency in asymmetric borylation reactions (Scheme 80). In 2009, Fernández and co-workers demonstrated that the complex L103−Cu(I) was competent in catalyzing the β-borylation of α,β-unsaturated 7628


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Scheme 80. Asymmetric Conjugate Borylation Catalyzed by NHC−Cu(I) Complexes

3.1.3. Other Chiral Ligands. Kobayashi and co-workers333−337 employed their complex L93−Cu in the asymmetric conjugate borylation of α,β-unsaturated compounds, as well as α,β,γ,δ-dienones and dienoesters (Scheme 83). In 2012, they realized an efficient route to achieve the asymmetric conjugate borylation of α,β-unsaturated carbonyl compounds with B2pin2 in water (Scheme 83a).336 A range of acyclic, cyclic, and β,βdisubstituted enones, α,β-unsaturated esters, amides, nitriles, α,β,γ,δ-unsaturated ketones delivered the 1,4-addition products in high yields with up to 99% ee. The application of the catalyst system was further extended to the asymmetric conjugate borylation of α,β,γ,δ-unsaturated dienones and dienoesters (Scheme 83b).335 Interestingly, the counteranions play a decisive role in the regioselectivity of the reaction (i.e., 1,4- or 1,6-addition). For the acyclic α,β,γ,δ-unsaturated dienones and dienoesters, regardless which catalyst system [Cu(OH)2 with L93, Cu(OH)2 and acetic acid with L93, or Cu(OAc)2 with L93] was employed, the 1,4-addition products were obtained exclusively with good results. However, for the cyclic α,β,γ,δ-unsaturated dienones, the heterogeneous catalyst system generated from Cu(OH)2 and L93 afforded the 1,6-

addition products in both good yields and ee’s. In contrast, the homogeneous catalyst system derived from Cu(OH)2 and acetic acid with L93, or Cu(OAc)2 with L93, furnished the 1,4addition products (Scheme 83b). Later, a catalyst based on Cu powder and L93 was demonstrated to be suitable for the borylation of α,β-unsaturated enones.333 α,β-Unsaturated imines were also tolerated well under this catalyst system (Scheme 83c).334 Except for substrates with electron-withdrawing substituents at the β-position, excellent enantioselectivities were observed (up to 99% ee). Later, the efficacy of this catalyst system was further demonstrated in organic solvents.337 In Et2O with 1 equiv MeOH as a proton source, a range of α,β-unsaturated enones were converted to the corresponding adducts with excellent outcomes. It should be noted that the catalyst loading could be decreased to as little as 0.005 mol % (TOF = 31200 h−1) with maintained efficiency. Bisoxazoline ligands were successfully employed for the metal-catalyzed asymmetric borylation of α,β-unsaturated carbonyl compounds by Nishiyama and co-workers.338,339 In the presence of complex L111−Rh(III), a range of α,βunsaturated carbonyl compounds including esters, ketones, 7629


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asymmetric conjugate borylation of β,β-disubstituted acyclic enones for the synthesis of enantiomerically enriched tertiary organoboronates (Scheme 84b). Utilizing chiral diamine complex L112−Cu(I) as the catalyst, a series of tertiary boronates was obtained in high yields with excellent enantiopurities (90−99% ee’s). It is worth noting that addition of iPrOH remarkably improved the yield with maintained enantioselectivities. Fernández et al.341 investigated the asymmetric conjugate borylation of isobutyl crotonate, cinnamaldehyde, cinnamonitrile, and α,β-unsaturated imines with a diverse set of chiral phosphoramidites and phosphite ligands using a high-throughput screening method; the complex L113−Cu(I) was found to be the best catalyst for the borylation of α,β-unsaturated imines with up to 95% ee (Scheme 84c). Most recently, an efficient catalytic asymmetric borylation of α,β-unsaturated amides has been developed by Molander and co-workers (Scheme 85). 342 Employing B 2 (OH) 4 or B2(NMe2)4 as nucleophiles, as well as complex L114−Cu(I) as the catalyst, a range of enantioenriched potassium βtrifluoroboratoamides were achieved in good yields with high enantioselectivities (up to 96% ee). The borylation products could be easily transformed to chiral aryl-substituted compounds by cross-coupling reactions with aryl and heteroaryl chlorides in high yields with maintained enantioselectivities.

Scheme 81. Asymmetric Conjugate Borylation Catalyzed by L106−Cu(I) Complexes

3.2. Conjugate Addition of Oxygen Nucleophiles

The ACA of oxygen nucleophiles to electron-deficient olefins has been a significant challenge in organic synthesis, owing to its low reactivity and the reversibility of the reaction.343−346 Thus far, most reports have focused on organocatalytic procedures, and only a small number of metal-catalyzed oxaMichael reactions have been reported. Since the first example of catalytic asymmetric intermolecular oxa-Michael addition was disclosed by the Jacobsen group using (salen)aluminum catalysts in 2004,347 Feng and co-

and amides were tolerated well (up to 95% yield and 97% ee; Scheme 84a). However, when lactones, β,β-disubstituted acrylates, cyclic enones, and N-methoxy cinnamate were used as substrates, no reaction was observed under the standard conditions. In 2010, the Shibasaki group340 reported an

Scheme 82. Asymmetric Conjugate Borylation Catalyzed by NHC (L107−L110)−Cu(I) Complexes

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Scheme 83. Asymmetric Conjugate Borylation Catalyzed by L93−Cu Complexes

L115 and st-DNA, resulting in good enantioselectivities (up to 82% ee). The syn-addition product could still be achieved using only Cu(II) salts as the catalyst without DNA or ligand. It is worth noting that the DNA sequence is the source of chirality for the reaction. Later, this catalyst system was further extended to the conjugate addition of methanol and npropanol to enones with similar results (up to 86% ee).354 In 2012, the Zhou group355 reported an efficient asymmetric tandem hydrogenation/oxa-Michael cyclization of acrylatecontaining arylketones catalyzed by chiral complex L116− Ru(II). As shown in Scheme 88, a series of 2,6-cisdisubstituted tetrahydropyrans were generated in high yields with excellent diastereo- and enantioselectivities through a one-pot process at low catalyst loadings (S/C = 2000, up to 99:1 dr and 99% ee). The potential of this reaction was illustrated in the enantioselective synthesis of (−)-centrolobine (68.8% yield in three steps from the product of the ACA reaction).

workers described an asymmetric intramolecular oxa-Michael addition of the phenol group to activated enones catalyzed by chiral complexes L20d−Ni(II) (Scheme 86a),85 generating the corresponding enantiopure flavanones in 90−99% yields and 80−99% ee’s. Later studies showed that the chiral N,N′dioxide−iron(II) complexes (L21e−Fe) could be successfully applied to the intermolecular oxa-Michael addition of oximes to α,β-unsaturated aldehydes, which led to the corresponding adducts in moderate to good yield with up to 76% ee (Scheme 86b).348 In terms of oxygen nucleophiles, water would be the best choice. The direct enantioselective 1,4-addition of water to α,β-unsaturated acceptors is a significant challenge in asymmetric catalysis.349−351 The first example of nonenzymatic catalytic enantioselective addition of water to enones in an aqueous solvent was reported by Feringa, Roelfes, and coworkers (Scheme 87);352,353 this reaction was catalyzed by a L115-st-DNA−Cu(II) complex derived from achiral ligand 7631


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Scheme 84. Asymmetric Conjugate Borylation of α,β-Unsaturated Compounds

Inspired by the work of Fuwa and co-workers,356 You et al. developed an asymmetric cascade cross-metathesis/oxoMichael addition employing chiral phosphoric acid L117 and Hoveyda−Grubbs II as the catalyst (Scheme 89). Under the optimized conditions, a series of benzofuran and benzoxazine derivatives were successfully converted to the corresponding adducts with reasonable outcomes (up to 75% yield and 81% ee).357

Scheme 85. Asymmetric Conjugate Borylation Catalyzed by an L114−Cu(I) Complex

3.3. Conjugate Addition of Sulfur Nucleophiles

Since the first report by Kanemasa et al. on ACA reactions of thiols to 3-(2-alkenoyl)-2-oxazolidinones catalyzed by a DBFOX/ph−Ni(II) complex in 1999,358 great progress has been made in this area.359−362 On the basis of their previous work,362 Koskinen and co-workers disclosed the asymmetric conjugate reaction of thiols to 3-crotonoyl-2-oxazolidinones catalyzed by chiral complex Pybox (L13a)−Sc(III) (Scheme 90a), achieving the corresponding sulfides in good yield with high enantiomeric purity (up to 95% yield and 92% ee).363 At the same time, the Fe(II) catalysts based on Pybox L34c were demonstrated as suitable for this reaction by Kawatsura, Itoh, and co-workers.364,365 The salt Fe(BF4)2 was identified as the best metal source to furnish sulfa-Michael adducts in enantioselectivities of up to 95% ee (Scheme 90b). It should be noted that the complex L34c−Co(II) also gave similar results with up to 95% ee. The Shibasaki group366 disclosed the complex L36a− mesitylcopper as a suitable catalyst for the ACA of thiols to α,β-unsaturated thioamides (Scheme 91). Under the optimized conditions, a range of thiols with α,β-unsaturated thioamides was successfully converted to the corresponding products (up to 99% ee). The β-alkyl (R1 = Me)-substituted thioamide showed outstanding reactivity at lower temperatures (90% yield and 97% ee within 2 h at −40 °C). A competition reaction indicated that only the thioamide gave the addition product in the presence of other substrates such as α,βunsaturated amides, esters, and thioesters.

Scheme 86. Asymmetric oxa-Michael Addition Catalyzed by N,N′-Dioxide−Metal Complex

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Scheme 87. Asymmetric oxa-Michael Addition Catalyzed by an L115-st-DNA−Cu(II) Complex

Scheme 88. Asymmetric Tandem Hydrogenation/oxa-Michael Cyclization

proceed under very low catalyst loading (0.01 mol %). Besides thioglycolate, other thiols such as tBuSH, EtSH, PhSH, and PhCH2SH exhibited low reactivity under the same conditions. Later, a similar catalyst system was reported by Govender and co-workers368 using tetrahydroisoquinoline N,N′-dioxides as ligands. Most recently, the Feng group91 successfully extended their catalyst system to the sequential sulfa-Michael-cyclization reaction using complex L20b−Yb(OTf)3 as the catalyst (Scheme 92b), allowing for the synthesis of optically active NH-free 2,3-dihydro-1,5-benzothiazepinones with excellent enantiopurity. Later studies showed that the domino Michael/aldol reaction of 1,4-dithiane-2,5-diol with 3alkenyloxindoles led to the corresponding spirocyclic oxindole-fused tetrahydrothiophenes with good outcomes in the presence of N,N′-dioxide−Ni(II) complexes (up to >19:1 dr and 98% ee).369 Early in 2011, Lewis-acid-catalyzed enantioselective sulfaMichael additions in water were reported by the Vaccaro370 and Kobayashi groups.371 Under neutral conditions, the complex L93−Sc(OTf)3 efficiently converted enones to βketo sulfides in high yields with up to 97% ee (Scheme 93). However, the enantioselectivity decreased significantly when employing thiophenol as a nucleophile due to its high acidity. It should be noted that this catalyst, as well as the aqueous medium, could be easily recovered and reused more than three

Scheme 89. Asymmetric Cascade Cross-Metathesis/oxoMichael Addition

The efficient N,N′-dioxide complex L21c−La(OTf)3 was successfully applied to the ACA reaction of chalcones with thioglycolate by Feng and co-workers (up to 99% yield and 99% ee; Scheme 92a).367 A remarkable asymmetric amplification was observed in this reaction, allowing the reaction to 7633


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Scheme 90. Asymmetric sulfa-Michael Addition Catalyzed by Bisoxazoline−Metal Complexes

Scheme 91. Asymmetric sulfa-Michael Addition Catalyzed by an L36a−Cu Complex

Scheme 92. Asymmetric sulfa-Michael Addition Catalyzed by N,N′-Dioxide−Metal Complexes

On the basis of a bicyclo[2.2.2]octane scaffold, an iron(III)salen complex was successfully employed by White and coworkers373 in the ACA of thiols to enones (Scheme 94a). The optimal reaction conditions were established as 20 mol % L118−Fe(III) at −5 °C in DCE, under which the corresponding adducts were obtained in high yields with up to 98% ee. When using an α-substituted ketone as substrate, the reaction predominantly generated the syn-adducts. Later, the catalyst L119−Fe(III) was applied to the ACA of thiols to acyclic α,β,γ,δ-unsaturated dienones,374 delivering the 1,6addition products as the main products with good outcomes (up to 98% ee; Scheme 94b). A chiral ruthenium Lewis acid catalyst (L120−Ru) was reported for asymmetric 1,4-addition reactions of aryl thiols to enones by the Kündig group (Scheme 95).375 The substituents on the aryl thiols and the ring size of the cyclic enones had a large effect on the reactivity and enantioselectivity. While only racemic product was obtained with 2,6-dichlorothiophenol, 2,6-dimethylthiophenol gave the addition product with satisfactory outcomes (94% yield and 82% ee). Interestingly, 2-cyclopenten-1-one (n = 1) and acyclic enones generated the opposite enantiomers in moderate yields with poor enantioselectivities.

Scheme 93. Asymmetric sulfa-Michael Addition Catalyzed by Bipyridine-Sc(III) Complex

times without any loss in efficiency. Later, a similar system was also applied to asymmetric Michael/protonation reactions of thiols with enones, delivering the corresponding adducts with good enantiocontrol (up to 94% ee).372 7634


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Scheme 94. Asymmetric sulfa-Michael Addition Catalyzed by a Salen−Fe(III) Complex

torcetrapib, providing the important intermediates with high enantiomeric purity in excellent yield.395,396 The mechanisms of these reactions were also systematically investigated by Xray crystallography, mass spectrometry, NMR, and UV−vis spectroscopy, as well as kinetic studies.397 Later, Kim and coworkers further extended the application of these catalysts to the asymmetric aza-Michael addition of aromatic amines to fumarate derivatives.398 In the presence of 5 mol % of complex L121a−Pd, a wide variety of primary arylamines were combined with fumaryl pyrrolidinone derivatives, providing the addition products with up to 96% ee. Fadini et al.399 successfully developed the L122−Ni(II)promoted asymmetric hydroamination of α,β-unsaturated esters and α,β-unsaturated nitriles (reaction in ionic liquids provided good yields but low enantioselectivities; Scheme 97).400 Recently, Zhang et al.401 reported the use of a new pincer-type P-stereogenic Ni complex based on diphosphine ligand L123a as catalyst for aza-Michael reactions of α,βunsaturated nitriles, affording the desired products in good yields with poor enantioselectivities (up to 46% ee).

Scheme 95. Asymmetric sulfa-Michael Addition Catalyzed by an L120−Ru Complex

3.4. Conjugate Addition of Nitrogen Nucleophiles

The asymmetric aza-Michael reaction is one of the most significant methods for constructing valuable chiral nitrogencontaining molecules.376,377 In recent decades, diverse chiral metal-complex catalysts377−389 have been applied to this reaction (Scheme 96). For instance, impressive achievements have been made by the Hii and Sodeoka groups using palladium-phosphine complexes (L121−Pd) as the catalysts.390−394 The usefulness of this method was further demonstrated in the synthesis of the optically active molecule

Scheme 96. Asymmetric aza-Michael Addition Catalyzed by Phosphine−Pd(II) Complexes

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bromoamination of α,β-unsaturated aromatic ketones was achieved with particularly good outcomes in the presence of 0.05 mol % of L22i−Sc(OTf)3 (up to 99% yield, 99% ee, and 99:1 dr; Scheme 98d).86 On the basis of a mechanistic study, a chiral-bromonium-based mechanism and transition state were proposed by the authors. A series of metal complexes based on chiral oxazoline ligands were also employed for asymmetric aza-Michael reactions.405 In 2007, Yamazaki et al.406 disclosed the enantioselective conjugate addition of aromatic amines to ethenetricarboxylates catalyzed by complex L47−Cu(OTf)2 (up to 91% yield and 87% ee; Scheme 99a). However, near-racemic products were obtained when using aniline and primary aniline derivatives as nucleophiles under the same conditions. Sibi et al.407 revealed that the complex L15−Mg(ClO4)2 was efficient for the addition of hydrazines to α,β-unsaturated imides (Scheme 99b), generating pyrazolidinones with excellent outcomes. It is worth noting that the temperature greatly affected the chemoselectivity of the reaction, and a significant improvement was achieved when the temperature was decreased from RT to −50 °C (A: B from 59:41 to 98:2). Most recently, asymmetric hydroxyamination of α,β-unsaturated imidazoles catalyzed by the chiral-at-metal complex L31−Rh(III) was reported by Kang et al.408 A series of N-protected hydroxyl amines and α,βunsaturated imidazoles were tolerated, providing the corresponding adducts in both high yields and ee’s (up to 91% yield and 99% ee; Scheme 99c). Collin and co-workers409,410 successfully developed a simple samarium-iodobinaphtholatepromoted addition of aromatic amines and O-benzylhydroxylamine to α,β-unsaturated N-alkenoyloxazolidinones (up to 88% ee).

Scheme 97. Asymmetric aza-Michael Addition Catalyzed by a Phosphine−Ni(II) Complex

Sc(III) complexes based on chiral N,N′-dioxide ligands were also demonstrated to be highly efficient catalysts in a series of aza-Michael reactions (Scheme 98).28,402−404 For instance, using chalcones as the Michael acceptors, the asymmetric addition of benzoyl hydrazide was carried out in the presence of complex L21c−Sc(OTf)3, giving the addition products in acceptable yields with good enantiocontrol (up to 97% ee; Scheme 98a).402 Later, the application of this catalyst system was extended to the addition of pyrazoles to α-aryl-substituted vinyl ketones using ScCl3 as metal source and L22c as ligand (up to 99% yield and 94% ee; Scheme 98b).404 The addition of 1H-benzotriazole to chalcones was realized by employing complex L22h−Sc(OTf)3 as the catalyst (Scheme 98c).403 The

3.5. Conjugate Addition of Phosphorus Nucleophiles

3.5.1. Chiral P−C−P, N−C, and P−C Palladacycle Catalysts. The ACA of phosphorus nucleophiles to electrondeficient olefins is one of the most valuable methods for the synthesis of optically active chiral phosphines, which are very

Scheme 98. Asymmetric aza-Michael Addition Catalyzed by N,N′-Dioxide−Sc(III) Complexes

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Scheme 99. Asymmetric aza-Michael Addition Catalyzed by Bisoxazoline−metal Complexes

Scheme 100. Asymmetric Hydrophosphination Catalyzed by L123−Pd Complexes

conjugate addition of diarylphosphines to α,β-unsaturated enones,414 esters,415,416 N-acylpyrroles,417 and aldehydes,418 as well as the nitroalkenes419 and α,β,γ,δ-dienoesters420,421 (Scheme 100). It is worth noting that the catalyst loading was reduced to 0.05 mol % without any significant loss in efficiency when using α,β-unsaturated aldehydes as substrates.418 The 1,6-addition products were observed when employing α,β,γ,δ-unsaturated sulfonic esters421 and bi-

useful in the fields of asymmetric catalysis, pharmaceutical chemistry, and materials.40,411,412 Early in 2010, the Duan group reported the first example of an enantioselective hydrophosphination reaction catalyzed by PCP−pincer Pd complexes. In the presence of 2 mol % of complex L123a−Pd, the reaction proceeded smoothly to give the desired products in high yields with up to 99% ee (Scheme 100).413 They have since adapted this catalyst system further to facilitate the 7637


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1,4-addition products were achieved with good enantiocontrol (up to 99% ee) when using L123b as the ligand. Zhang and coworkers425,426 successfully employed a similar PCP−pincer Pd complex (L123c−Pd) for the 1,4-addition of diarylphosphines to α,β-unsaturated esters and nitroalkenes, yielding the desired products with high enantioselectivities (up to 93% ee). In addition to PCP−pincer Pd complexes, N−C- or P−Ctype palladacycle complexes were also successfully employed in ACA reactions of diphenylphosphine. In 2010, Leung et al. reported an asymmetric hydrophosphination of enones using N−C-type palladacycle (R)-L124a−Pd as the catalyst,427 affording the desired products in high yields with moderate to high enantioselectivities (up to 99% yield and 86% ee; Scheme 101a). The ee value was significantly improved when the ligand (R)-L124a was replaced by the P−C-type ligand (R)-L124b (92−99% ee’s).428 Racemic secondary phosphines were also tolerated well, providing the corresponding tertiary phosphines with two chiral centers in high yields with reasonable enantiocontrol (up to 82% ee and 91:9 dr). Later, the application of this methodology was extended to the asymmetric hydrophosphination of dienones, yielding chiral bis-phosphines or tertiary P-heterocycles with excellent stereoselectivities (up to 99:1 dr and 99% ee; Scheme 101a).429,430 Later studies showed that a range of α,βunsaturated substituted alkenylisoxazoles, esters, and amides


sphosphate esters420 under suitable conditions. Most recently, a similar system was applied to the addition of diarylphosphines to α,β,γ,δ-unsaturated carbonyl compounds by Leung and co-workers (Scheme 100).422−424 In this case, the 7638


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Scheme 103. Asymmetric 1,4-Addition of Phosphites and Phosphine Oxides Catalyzed by Dinuclear Zn Complexes

Scheme 104. Asymmetric Hydrophosphination Catalyzed by L126−, L127−, and L128−metal Complexes

were suitable substrates for this reaction.431−435 Most recently, the authors successfully developed a (S)-124a−Pd-promoted ACA of diphenylphosphine to ferrocenyl enones, which provided an efficient route to valuable chiral ferrocenyl phosphapalladacycle catalysts (Scheme 101b).436 It is noteworthy that the substituent on the double bond of the

ferrocenyl enones greatly affected the reactivity. As shown in Scheme 101b, while the reactions with 2-furyl-substitutedenones were completed within 2 h, the aryl- or alkylsubstituted enones required more than 3 days for full conversion. 7639


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Scheme 105. ACA of PhMe2SiBpin to Enones and Lactones Catalyzed by BINAP−Rh(I) Complex

3.5.2. Chiral P−C−N and N−C−N Palladacycle Catalysts. PCN pincer palladium and nickel complexes based on L125a and L125b were evaluated in the ACA of diphenylphosphine to chalcones by Song and co-workers (Scheme 102).437,438 Generally, the enones containing β-aryl groups bearing electron-withdrawing groups gave better results. However, for bis(4-methoxyphenyl) phosphine, only 35% yield and 40% ee were obtained. The bis(imidazoline) NCN pincer palladium complex L125c−Pd(II) was also demonstrated to be an efficient catalyst for the hydrophosphination of enones.439,440 3.5.3. Other Chiral Catalysts. In 2009 and 2010, Wang et al. revealed that dinuclear Zn complexes (L70−Et2Zn and L71−Et2Zn) were efficient for the ACA of diethyl phosphites and dialkyl phosphine oxides to enones (Scheme 103).441,442 Under the optimized conditions, the corresponding adducts were achieved with excellent outcomes (up to 99% yield and 99% ee). α,β-Unsaturated N-acylpyrroles and imines were found to be suitable substrates under this catalyst system.443,444 Recently, the complex L71−Et2Zn was also employed for the ACA of dialkylphosphine oxides to β,β-disubstituted α,βunsaturated carbonyl compounds,445 resulting in high yields and enantioselectivities (up to 99% ee). In addition to the catalysts described above, Namboothiri et al. demonstrated that the ACA of dialkyl phosphites to nitroalkenes is possible under the (S)-L126a−Al catalyst system (Scheme 104a).446 Except for diphenyl phosphite (98% ee and >98:2 dr; Scheme 106a). Moreover, this method was applied to the synthesis of the key intermediate for the natural product (+)-erysotramidine in 92% yield and 95% ee. Subsequently,458 the application of this catalyst system was further extended to the ACA of PhMe2SiBpin to dienones and dienoates (Scheme 106b). The results indicated that if the dienone or dienoate lacked substitution at the β-position (R = H), 1,4-addition products were exclusively obtained in both high yields and ee values (up to 98% ee). In contrast, 1,6-addition products with Z-selectivity were obtained in high yields and ee’s with βsubstituted (R = Me) acyclic α,β,γ,δ-unsaturated dienones or cyclic α,β,γ,δ-unsaturated dienones. The complex L130e− Cu(I) was developed for the ACA of PhMe2SiBpin to

successfully extended to the Z-acyclic α,β-unsaturated esters (up to 99% ee). However, the E-substrate gave a product with only 17% ee, and no products were observed for Z-methyl thioesters, α,β-unsaturated amides, and α,β-unsaturated nitriles under the same conditions.454 The usefulness of this method was further demonstrated in the synthesis of the C7−C16 fragment of (+)-neopeltolide and C17−C25 fragment of dermostatin A.455,456 7641


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Scheme 108. ACA of PhMe2SiBpin to α,β-Unsaturated Compounds Catalyzed by an L93−Cu(II) Complex

the synthesis of chiral compounds and is among the most significant and useful reactions in organic chemistry. As summarized in this review, great progress has been made in this area in the last two decades with the use of a wide range of nonorganometallic nucleophiles: not only 1,3-dicarbonyl compounds, nitroalkanes, aldehydes, ketones, or amino acid derivatives but also more exotic substrates such as oxindoles, radical nucleophiles, and heteroatom-based nucleophiles (B, O, N, S, P, and Si). A steadily growing number of chiral metal complexes based on various chiral ligands have also been developed for ACA reactions, including chiral diamine ligands, chiral bisoxazoline ligands, chiral N,N′-dioxide ligands, chiral Schiff base ligands, chiral binaphtholate ligands, and many more. In some cases, high catalytic capability could be achieved with very low catalyst loading and the catalysts are recyclable without loss of catalytic efficiency, showing a great potential for large scale and industrial use. Looking ahead, despite the substantial number of contributions made and results obtained, many challenges remain: (1) the main challenge remaining for the ACA reaction is the use of α,β-unsaturated aldehydes as substrates, which are considered the most challenging Michael acceptors and nucleophiles owing to their higher reactivity (1,4- vs 1,2-addition). Although several examples exist, the catalyst systems are only specific to certain substrates, thus, more research in this area is required. (2) Compared with asymmetric 1,4-conjugate additions, the regiocontrol of the conjugate addition to extended Michael acceptors is still an open issue, since 1,6- or 1,8-addition may lead to an undesired mixture of adducts. (3) Catalysts based on Cu, Pd, and Rh are still the most widely used catalyst systems in ACA reactions. Thus, the exploration of other inexpensive metal catalysts is still a major goal. Utilizing radicals as nucleophiles in the ACA reaction might be a good opportunity to solve some complex problems, and this field is still in its infancy; new reactions with broader substrate scopes, especially more challenging substrates (such as aldehydes and extended Michael acceptors), should be explored in the future to make this reaction more valuable and applicable. Moreover, development of a simple and robust catalyst having a wide substrate scope for more challenging substrates (such as radical nucleophiles, O-, S-, and Si-based nucleophiles) is an important research goal for the future. To conclude, although considerable progress has been achieved in metal-catalyzed ACA reactions in the past decade, there is still room for improvement to make the ACA reaction

unsaturated lactones of various sizes by Procter and co-workers (Scheme 106c).459,460 β-Silyl adducts could be achieved from a series of 5-, 6-, and 7-membered α,β-unsaturated lactones in good yields with up to 93% ee. This methodology provided a facile route to the synthesis of (+)-blastmycinone. α, βUnsaturated lactams and amides were also tolerated well,461 providing the corresponding adducts in moderate to high yields with high ee’s (up to 90% yield and 92% ee for lactams; up to 87% yield and 84% ee for amides). It should be noted that, for lactams, the substituents on nitrogen and the ring size of the lactams have significant effects on the reactivity and enantioselectivity. The usefulness of this method was further demonstrated in the synthesis of a nootropic drug (R)oxiracetam. Córdova and co-workers462 revealed that a catalyst system based on CuCl and chiral amine L131 was efficient for the ACA of PhMe2SiBpin to α,β-unsaturated aldehydes (Scheme 107). In this case, a series of alkyl and aryl aldehydes including naphthyl moieties were tested and gave corresponding addition products in good results (65−80% yields and 72−94% ee’s). Moreover, the β-methyl-substituted substrate (R2 = Me) was also tolerated with acceptable outcomes (67% yield and 76% ee). Following the achievements in ACA reactions using catalysts based on copper and chiral bipyridine ligands, the Kobayashi group463 extended this concept to the enantioselective 1,4addition of PhMe2SiBpin to α,β-unsaturated acceptors using complex L93−Cu(II) as the catalyst (Scheme 108). Interestingly, this reaction only proceeded smoothly in water, and both yields and ee’s were significantly decreased even in mixed solvents. α,β-Unsaturated nitriles and β-nitroolefins were also found to be suitable substrates for this reaction, achieving the corresponding products with excellent outcomes. Meanwhile, 1,6-addition products were observed when cyclic α,β,γ,δunsaturated dienones were employed. It should be noted that, due to the convenience of separation and recovery of the catalyst as well as the use of water as solvent, this heterogeneous reaction system is highly consistent with the concept of green chemistry.

4. SUMMARY AND PERSPECTIVE The metal-catalyzed asymmetric conjugate addition of nonorganometallic (soft) nucleophiles is a powerful approach to 7642


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(2) Michael, A. Ueber Die Addition Von Natriumacetessig- Und Natriummalonsäureäthern Zu Den Aethern Ungesättigter Säuren. J. Prakt. Chem. 1887, 35, 349. (3) Córdova, A. Catalytic Asymmetric Conjugate Reactions; WileyVCH: Weinheim, Germany, 2014; pp 1−439. (4) Mauduit, M.; Baslé, O.; Clavier, H.; Crévisy, C.; DenicourtNowicki, A. Metal-Catalyzed Asymmetric Nucleophilic Addition to Electron−Deficient Alkenes; Wiley-VCH: Weinheim, Germany, 2014; pp 189−341. (5) Vicario, J. L.; Reyes, E.; Carrillo, L.; Uria, U. Organocatalytic Asymmetric Nucleophilic Addition to Electron−Deficient Alkenes; WileyVCH: Weinheim, Germany, 2014; pp 119−188. (6) Wynberg, H.; Helder, R. Asymmetric Induction In The AlkaloidCatalysed Michael Reaction. Tetrahedron Lett. 1975, 16, 4057−4060. (7) Vicario, J. L.; Badía, D.; Carrillo, L.; Reyes, E. Organocatalytic Enantioselective Conjugate Addition Reactions: A Powerful Tool for the Stereocontrolled Synthesis of Complex Molecules; Royal Society of Chemistry: Cambridge, 2010; pp 1−354. (8) Vicario, J. L.; Reyes, E.; Carrillo, L.; Uria, U. Organocatalytic Asymmetric Nucleophilic Addition to Electron-Deficient Alkenes; WileyVCH: Weinheim, Germany, 2014; pp 119−188. (9) Hiemstra, H.; Wynberg, H. Addition of Aromatic Thiols to Conjugated Cycloalkenones, Catalyzed by Chiral β-Hydroxy Amines. A Mechanistic Study on Homogeneous Catalytic Asymmetric Synthesis. J. Am. Chem. Soc. 1981, 103, 417−430. (10) Sulzer-Mossé, S.; Alexakis, A. Chiral Amines as Organocatalysts for Asymmetric Conjugate Addition to Nitroolefins and Vinyl Sulfones via Enamine Activation. Chem. Commun. 2007, 3123−3135. (11) Tsogoeva, S. B. Recent Advances in Asymmetric Organocatalytic 1,4-Conjugate Additions. Eur. J. Org. Chem. 2007, 2007, 1701−1716. (12) Almaşi, D.; Alonso, D. A.; Nájera, C. Organocatalytic Asymmetric Conjugate Additions. Tetrahedron: Asymmetry 2007, 18, 299−365. (13) Chauhan, P.; Chimni, S. S. Recent Advances in Asymmetric Organocatalytic Conjugate Addition of Arenes and Hetero-Arenes. RSC Adv. 2012, 2, 6117−6134. (14) Nguyen, T. N.; May, J. A. Enantioselective Organocatalytic Conjugate Addition of Organoboron Nucleophiles. Tetrahedron Lett. 2017, 58, 1535−1544. (15) Mondal, A.; Bhowmick, S.; Ghosh, A.; Chanda, T.; Bhowmick, K. C. Advances on Asymmetric Organocatalytic 1,4-Conjugate Addition Reactions in Aqueous and Semi-Aqueous Media. Tetrahedron: Asymmetry 2017, 28, 849−875. (16) Alonso, D. A.; Baeza, A.; Chinchilla, R.; Gómez, C.; Guillena, G.; Pastor, I. M.; Ramón, D. J. Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes. Molecules 2017, 22, 895−946. (17) Schmid, T. E.; Drissi-Amraoui, S.; Crévisy, C.; Baslé, O.; Mauduit, M. Copper-Catalyzed Asymmetric Conjugate Addition of Organometallic Reagents to Extended Michael Acceptors. Beilstein J. Org. Chem. 2015, 11, 2418−2434. (18) Heravi, M. M.; Dehghani, M.; Zadsirjan, V. Rh-Catalyzed Asymmetric 1,4-Addition Reactions to α,β-Unsaturated Carbonyl and Related Compounds: An Update. Tetrahedron: Asymmetry 2016, 27, 513−588. (19) Hayashi, M.; Matsubara, R. Recent Topics on Catalytic Asymmetric 1,4-Addition. Tetrahedron Lett. 2017, 58, 1793−1805. (20) Hui, C.; Pu, F.; Xu, J. Metal-Catalyzed Asymmetric Michael Addition in Natural Product Synthesis. Chem. - Eur. J. 2017, 23, 4023−4036. (21) Brunner, H.; Hammer, B. Enantioselective Michael Additions with Optically Active CoII/Diamine Catalysts. Angew. Chem., Int. Ed. Engl. 1984, 23, 312−313. (22) Sasai, H.; Arai, T.; Shibasaki, M. Catalytic Asymmetric Michael Reactions Promoted by a Lithium-Free Lanthanum-BINOL Complex. J. Am. Chem. Soc. 1994, 116, 1571−1572.

more convenient, practical, economical, and efficient. We are convinced of a bright future for this useful enantioselective transformation, which will inevitably become more widely applied in organic synthesis.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Xiaohua Liu: 0000-0001-9555-0555 Xiaoming Feng: 0000-0003-4507-0478 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest. Biographies Ke Zheng was born in Zhejiang, China, in 1983. He received his B.S. degree from Sichuan University in 2007 and Ph.D. from the same university in 2012 under the supervision of Professor Dr. Xiaoming Feng. He then worked as a postdoctoral fellow and a research scientist at The Scripps Research Institute, TSRI (USA), and the University of Michigan, Ann Arbor (USA). He then moved to Sichuan University and was appointed as Professor in 2016. His research interests lie in asymmetric catalysis, the synthesis of bioactive compounds and medicinal chemistry. Xiaohua Liu received her B.S. degree in 2000 from Hubei Normal University and her M.S. degree in 2003 and Ph.D. in 2006 from Sichuan University. She joined the faculty of Prof. Feng’s group at Sichuan University, where she is now a Professor. Her current research interests include asymmetric catalysis of chiral guanidines and organic synthesis. Xiaoming Feng was born in 1964. He received his B.S. degree in 1985 and M.S. degree in 1988 from Lanzhou University. He then worked at Southwest Normal University from 1988 to 1993, becoming an Associate Professor in 1991. In 1996, he received his Ph.D. from the Chinese Academy of Sciences (CAS) under the supervision of Professors Zhitang Huang and Yaozhong Jiang. He then moved to the Chengdu Institute of Organic Chemistry, CAS, from 1996 to 2000 and was appointed Professor in 1997. In 1998−1999, he performed postdoctoral research at Colorado State University with Professor Yian Shi and then in 2000 moved to Sichuan University to take up a professorship. He was selected as an Academician of the Chinese Academy of Sciences in 2013. His research is focused on the design of chiral catalysts, the development of new synthetic methods, and the synthesis of bioactive compounds.

ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Grants 21432006 and 21602142) and Sichuan University for financial support. REFERENCES (1) Komnenos, T. Ueber Die Einwirkung Von Fettaldehyden Auf Malonsäure Und Aethylmalonat. Lieb. Ann. Chem. 1883, 218, 145− 167. 7643


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