Catalytic Enantioselective Desymmetrization Reactions to All-Carbon

Review pubs.acs.org/CR

Catalytic Enantioselective Desymmetrization Reactions to All-Carbon Quaternary Stereocenters Xing-Ping Zeng,† Zhong-Yan Cao,† Yu-Hui Wang,† Feng Zhou,† and Jian Zhou*,†,‡ †

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P. R. China ‡ State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China ABSTRACT: This Review summarizes the advances in the construction of all-carbon quaternary stereocenters via catalytic enantioselective desymmetrization of prochiral and meso-compounds, highlights the power and potential of this strategy in the total synthesis of natural products and biologically active compounds, and outlines the synthetic opportunities still available.

CONTENTS 1. INTRODUCTION 2. DESYMMETRIZATION OF PROCHIRAL 1,3-DIKETONES 2.1. Desymmetric Aldol-type Reactions 2.2. Desymmetric Reduction 2.3. Desymmetric Domino Reactions 3. DESYMMETRIZATION OF PROCHIRAL DIENES 3.1. Desymmetric Cross-Coupling Reactions 3.2. Desymmetric Ring-Closing Metathesis 3.3. Desymmetric Intramolecular Hydroamination 3.4. Miscellaneous 4. DESYMMETRIZATION OF PROCHIRAL gem-DIARYL COMPOUNDS 5. DESYMMETRIZATION OF PROCHIRAL PRIMARY DIOLS 5.1. Desymmetric Transesterification 5.2. Desymmetric Bromoetherification 5.3. Miscellaneous Reactions 6. DESYMMETRIZATION OF PROCHIRAL DICARBOXYLIC ACID DERIVATIVES 6.1. Prochiral Diesters 6.2. Prochiral Diamides 6.3. Prochiral Anhydrides 7. DESYMMETRIZATION OF PROCHIRAL SMALL-RING SYSTEMS 7.1. Prochiral Cyclopropenes 7.1.1. Enantioselective Addition to the C−C Double Bond 7.1.2. Enantioselective Ring-Opening/Crossmetathesis 7.2. Prochiral Cyclobutanols © 2016 American Chemical Society

7.3. Prochiral Cyclobutanones 7.4. Prochiral Cyclopropanes and Cyclobutanes 7.5. Prochiral Oxetanes and Azetidines 8. DESYMMETRIZATION OF PROCHIRAL ENONES 8.1. Prochiral Cyclohexa-2,5-dienones 8.2. Prochiral Cyclopentene-1,3-diones 9. DESYMMETRIZATION OF PROCHIRAL DIALKYNES 10. MISCELLANEOUS SUBSTRATES 11. SUMMARY AND OUTLOOK Author Information Corresponding Author Notes Biographies Acknowledgments References

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1. INTRODUCTION When the remaining hydrogen atom on a tertiary carbon is replaced by any other atom or group, fully substituted carbons are produced with great structural diversity. Those featuring four carbon neighbors are defined as quaternary carbons,1,2 whereas those bearing heteroatom substitutions are referred to tetrasubstituted carbons, as observed in tertiary alcohols or thiols, α-tertiary amines, and so on.3 When the four substituents differ, quaternary or tetrasubstituted carbon stereogenic centers are generated, which exist widely in natural products, drugs, and bioactive compounds. Because of their structural diversity and enhanced conformational constraints as compared with the corresponding tertiary carbon stereocenters, an effective strategy

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Received: February 5, 2016 Published: June 2, 2016 7330

DOI: 10.1021/acs.chemrev.6b00094 Chem. Rev. 2016, 116, 7330−7396

Chemical Reviews

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Figure 1. Synthetic strategies to all-carbon quaternary stereogenic centers.

of prochiral molecules with a prochiral quaternary carbon or meso-compounds with preexisting stereogenic quaternary carbons; and (iii) kinetic resolution reaction of racemic compounds bearing quaternary stereocenters. Obviously, prochiral carbons to construct quaternary carbon stereocenters must be fully substituted by carbon groups, while in contrast, those that make tertiary stereocenters are substituted by a hydrogen atom. This poses two particular challenges: (i) the increased steric repulsion resulting from replacing hydrogen, the smallest atom, by a carbon substituent raises difficulties for the two reaction partners to approach each other and renders the transition state more congested; and (ii) the lesser steric dissimilarity of two carbon substituents on the prochiral center compared with that between a carbon substituent and a H atom makes it hard to achieve excellent enantiofacial discrimination (or enantiotopic group discrimination). Accordingly, it is a challenging task to create quaternary carbon stereocenters efficiently from simple starting materials, in a stereocontrollable and operationally friendly fashion; this is regarded as a testing ground for new catalysts and new synthetic strategies to demonstrate their value.16 Among these strategies, catalytic enantioselective desymmetrization17 of prochiral compounds or meso-compounds is a promising and attractive strategy that separates the task of C−C formation from the task of its enantiofacial discrimination. This strategy may have some unique advantages. First, in principle, it puts all types of catalytic reactions to use for enantioselective synthesis, as a quaternary carbon stereocenter is simultaneously formed no matter what kind of reaction takes place at one of the two identical functional groups attached to the preexisting quaternary carbon. In contrast, enantioselective C−C bondforming reactions must involve the conversion of a sp2 prochiral carbon. Second, as the reaction proceeds at the tethered functionality rather than at the existing quaternary carbon, unfavorable steric repulsion is alleviated to some extent because the reactive site is at least one covalent bond away from the existing quaternary carbon, if no additional quaternary carbon stereocenter is generated. Third, the theoretical yield of the desymmetric reaction is 100%, while the yield of the kinetic resolution reaction cannot exceed 50%. Fourth, the symmetric substrates are often easy to prepare. Fifth, by using preorganized substrates, it is possible to construct quaternary carbon stereocenters bearing a functionality that is difficult to introduce

in drug design is to modify organic compounds by introducing fully substituted carbon stereocenters to improve biological activity. For example, spirocyclic systems have found increasing utility in drug discovery, as the conformational restriction imposed by spiro ring fusion reduces the conformational entropy penalty upon interacting with a protein target.4 In addition to playing a special role in the design of new peptide-based therapeutic agents,5 enantiopure Cα-tetrasubstituted α-amino acids are sources of small-molecule drugs, as exemplified by two drugs, α-methyldoba6 and eflornithine,7 which were rationally designed by introducing a methyl or CF2H group to the α position of L-3,4-dihydroxyphenylalanine and ornithine, respectively. Notably, the absolute configuration of fully substituted carbon stereocenters often greatly influences the pharmaceutical properties of related drug molecules.8−10 This implies a vast demand for catalytic enantioselective methods for efficient construction of fully substituted carbon stereocenters, to allow facile access and modification of related bioactive compounds while creating synthetic libraries for structure−activity relationship studies.11 Tremendous attention therefore has been devoted to the development of efficient methods for the stereocontrolled construction of quaternary and tetrasubstituted carbon stereocenters.12−14 Despite remarkable advances, catalytic enantioselective creation of quaternary carbon stereocenters, bonded by four different carbon substituents, is still a long-term challenge.13−17 As Quasdorf and Overman pointed out recently,15 although molecules bearing a quaternary carbon stereocenter comprise 12% of the top 200 prescription drugs sold in the United States in 2011, the synthesis of these drugs relies on the use of natural product precursors to provide the quaternary stereocenters. The almost lack of approved drugs containing chemically synthesized chiral quaternary carbon stereocenters clearly shows that reliable methods for constructing such structural motifs are highly desirable. The challenges associated with enantioselective creation of quaternary carbon stereocenters can be fully understood by examining known synthetic strategies. As shown in Figure 1, there are three major strategies to furnish quaternary carbon stereocenters: (i) C−C bond-forming reactions on an sp2hybridized prochiral carbon, as found in organic compounds such as 1,1-disubstituted olefins, fully substituted metal carbenoids, enolates, and their equivalent; (ii) desymmetrization 7331


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Scheme 1. Desymmetric Reactions Based on the Conversion of a Prochiral sp2 Carbon

via an enantioselective C−C bond-forming reaction on an sp2prochiral carbon (an ethynyl group, for example). In addition, the desymmetrization of meso-compounds allows the formation of multiple quaternary carbon stereocenters at the same time. With these advantages, there is ever-increasing interest in developing enantioselective desymmetrizing reactions to furnish quaternary carbon stereocenters. The fruitfulness of this strategy has been demonstrated by a number of impressive protocols, along with their application in the enantioselective total synthesis of natural products and biologically active compounds. However, although catalytic enantioselective creation of quaternary carbon stereocenters has been independently reviewed by Overman and co-workers,15,18 Trost and Jiang,19 and Stoltz and co-workers,20 only a few examples of catalytic enantioselective desymmetrizing reactions are offered in these reviews. Therefore, this Review aims to give a comprehensive summarization of achievements in this field from 1971 to the end of 2015,21 show the latest achievements, highlight the power and potential of this strategy, and outline the synthetic opportunities still available. As multifunctional symmetric substrates play an important role in designing new catalytic enantioselective desymmetric reactions, this Review is organized by substrate class, and each section is further subdivided by reaction types. Attention is also paid to the application of these protocols to facilitate the enantioselective synthesis of natural products or important scaffolds. To help newcomers to enantioselective catalysis, the mechanisms of reactions catalyzed by chiral metal complexes or small organic molecules, along with a brief discussion on the advantages and limitations, are also introduced where necessary. It should be mentioned that this Review focuses on enantioselective desymmetrizing reactions of prochiral or mesocompounds with preexisting quaternary carbons. There are some special desymmetrizing reactions that indeed convert symmetric substrates to optically active products bearing a quaternary carbon stereocenter; however, the quaternary stereocenters are derived from the sp2-hybrized prochiral carbon imbedded in the

starting materials. For example, in the Pd-catalyzed catalytic Wagner−Meerwein shift reaction developed by Trost and Yasukata (eq 1, Scheme 1),22 the vinylogous α-ketol rearrangement by Tu and co-workers (eq 2),23 and the Cu-catalyzed borylative cyclization of 1,6-enynes by Tian, Lin, and co-workers (eq 3),24 the quaternary carbon stereocenters of the final products 3, 6, and 9 are all derived from the sp2 prochiral carbon of the corresponding substrates. According to the above discussion, these desymmetric protocols are not within the scope of this Review, although they are elegant and attractive.

2. DESYMMETRIZATION OF PROCHIRAL 1,3-DIKETONES Given the versatility of carbonyl groups, cyclic or acyclic symmetric 1,3-diketones with two different substituents at the prochiral carbon are very attractive scaffolds for reaction design for two reasons: (i) the α methylene group of 1,3-diketones can easily be activated by deprotonation to install various types of tethered functionalities for the facile construction of cyclic or polycyclic compounds via single or tandem reactions and (ii) ketone carbonyl groups can undergo a broad range of transformations, which is very helpful for the exploitation of new reactions. By enantioselectively modifying one of the two enantiotopic ketone units, the resulting chiral ketones bearing a quaternary carbon stereocenter are often valuable synthetic building blocks. Therefore, the enantioselective desymmetrization of prochiral 1,3-diketones has been studied extensively, and the known protocols are divided into aldol-type or reduction reactions. 2.1. Desymmetric Aldol-type Reactions

The Hajos−Parrish−Eder−Sauer−Wiechert reaction of prochiral 1,3-diketones with an α-tethered ketone moiety is probably the most famous desymmetric reaction; it is regarded as the origin of enantioselective catalysis by small organic molecules. It allows the facile synthesis of enantioenriched Hajos−Parrish 7332


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Scheme 2. Hajos−Parrish−Eder−Sauer−Wiechert Reaction

Scheme 3. Enantioselective Synthesis of Estrone and 19-Norsteroid

tones to HP or WM ketone in 92/8 and 85.5/14.5 er, respectively.26 Almost 30 years later, List, Lerner, and Barbas reported that the proline catalyst is viable for the intermolecular aldol reaction of aldehydes and ketones.27 This seminal work triggered enormous enthusiasm for exploring enantioselective enamine catalysis.28 Today, it is generally believed that such an aldol reaction starts from the formation of enamine intermediate I, followed by the attack of enamine to ketone moiety controlled by carboxylic acid through an H-bonding interaction, to form an iminium intermediate III that hydrolyzes to give the aldol adduct IV and release the amine catalyst.29 It should be noted that not only proline, with a secondary amine moiety, but also primary amine-based α-amino acids can serve as powerful bifunctional catalysts for the desymmetric aldol reaction with triketones. For example, in 1976, Danishefsky and

(HP) ketones and Wieland−Miescher (WM) ketones as versatile building blocks for numerous natural products. In 1971, when enantioselective catalysis was in its infancy, two groups of industrial chemists independently realized the intramolecular aldol reaction of triketones 10a and 12a catalyzed by L-proline (Scheme 2). Hajos and Parrish from Hoffmann La Roche found that, in the presence of 3 mol % proline, the initial intramolecular aldolization of triketone worked well in N,Ndimethylformamide (DMF) at room temperature to give βhydroxyketone IV, followed by an acid-catalyzed dehydration to afford HP ketone 11a in 96.5/3.5 enantiomeric ratio (er), or WM ketone 13a in 87/13 er.25 Meanwhile, Eder, Sauer, and Wiechert at Schering AG developed an aldol condensation procedure by using a large amount of proline in combination with HClO4 as cocatalyst, which directly converted the corresponding trike7333


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Scheme 4. Selected Enamine Catalysts for Enantioselective H−P−E−S−W Reaction

Scheme 5. Selected Natural Products Synthesized from WM Ketone

dimethylformamide (DMF) and dimethylsulfoxide (DMSO) that are difficult to remove. Therefore, much effort has gone into the development of new chiral bifunctional enamine catalysts to improve the efficiency of this important desymmetric reaction. Some notable catalysts are shown in Scheme 4, including βamino acid cispentacin 17,31 N-substituted bimorpholine derivatives 18,32 benzimidazole pyrrolidine 19,33 prolinamide 20,34 proline-based tripeptide 21,35 multifunctional N-tosyl-(S)binam-L-prolinamide 22,36 L-prolinethioamide 23,37 1,2-cyclohexanediamine-derived primary amine 24,38 and the trifluor-

Cain disclosed that, in the presence of 1.2 equiv of Lphenylalanine 15 and 0.5 equiv of HClO4, the intramolecular annulation of cyclopentane-l,3-dione derivatives 14 worked well to give the desired functionalized HP-type ketone 11b in 82% yield and 93/7 er, paving the way for the enantioselective total synthesis of estrone and Δ5(10)-19-norsteroid (Scheme 3).30 While the use of natural amino acids as catalysts is costeffective, the corresponding protocols have ample room for improvement in terms of enantioselectivity, catalyst loading, and substrate scope. In addition, to dissolve α-amino acids well, it is often necessary to use toxic, hydrophilic, aprotic solvents such as 7334


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Scheme 6. Selected Natural Products Synthesized from HP Ketone and Its Derivatives

Scheme 7. Phosphoric Acid-Catalyzed Desymmetrization of Prochiral Triketones

omethanesulfonic salt of a primary amine 25.39,40 For a detailed introduction, see the good review by Moyano and Rios.41 The enantioenriched WM ketone, along with HP ketone and their analogues, have found wide application in the total synthesis of natural products, especially terpenoids and steroids. As exemplified in Scheme 5, both enantiomers of WM ketone, obtained by catalytic enantioselective desymmetrization of triketone 12a, have been used for the total synthesis of (+)-halenaquinol,42 (+)-paspalinine,43 (−)-glaucarubolone,44 taxol,45 (−)-penitrem D,46 and (−)-scabronine G.47 For a recent summarization on the application of WM ketones in the synthesis of natural products, see the recent review by Bradshaw and Bonjoch.48 The value of proline-catalyzed desymmetrization of triketone 10a to HP ketone 11a is also exhibited in the enantioselective total synthesis of variecolin,49 cortistatin A,50 aplykurodinone1,51 and (−)-nitidasin52 (Scheme 6). On the other hand, the synthesis of some natural products requires the enantioselective desymmetric synthesis of HP ketone analogues with different

substituents at the 2′ or 9′ positions. In such circumstances, proline often proves to be insufficient, although it was used by Corey and Huang in the synthesis of HP ketone 11c bearing an ethyl group at the 9′ position for the total synthesis of desogestrel.53 For example, in the synthesis of estrone, Danishefsky and Cain identified that L-phenylalanine was more powerful than proline in the desymmetric synthesis of HP ketone 11b.30 In the total synthesis of wortmannin, Shibasaki and coworkers found that using L-phenylalanine in combination with pyridinium p-toluenesulfonate (PPTS) could achieve 95.5/4.5 er in desymmetrizing prochiral triketone 11e for the synthesis of HP ketone bearing a C4 terminal ester group.54 This protocol was further applied by De Paolis and co-workers to the synthesis of aplykurodinone-1.55 During the enantioselective total synthesis of (−)-jiadifenolide, Theodorakis and co-workers disclosed that D-prolinamide was a highly enantioselective catalyst for the synthesis of an HP ketone analogue 11d bearing an allyl group at the 2′ position.56 7335


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Scheme 8. N-Heterocyclic Carbene-Catalyzed Desymmetrization

Scheme 9. Total Synthesis of (−)-Bakkenolides S, I, and J

enones 28 (Scheme 7).57 In the presence of 5−10 mol % chiral phosphoric acid 27, indanone-based chiral cyclohexenones 28, for which chiral amino catalysts had not been considered, were obtained in excellent enantioselectivity, although the results in the synthesis of MW and HP ketones were not impressive. It was remarkable that the weak and noncovalent H-bonding interaction between chiral phosphoric acid and a ketone substrate could achieve such a high level of enantioselectivity, comparable with that by covalent enamine catalysis. The conversion of a tethered ketone moiety at the prochiral carbon of 1,3-diketone to other functionalized groups offers the possibility of developing other aldol-type desymmetric reactions.

The highly efficient and cost-effective synthesis of optically active WM ketone, HP ketone, and their analogues as key synthons for a broad range of bioactive natural products is very impressive and fully illustrates the power of enantioselective desymmetrization of prochiral triketones via intramolecular aldol condensation. Notably, this enantioselective variant of the Robinson annulation serves as the cornerstone of modern enamine catalysis, as primary and secondary amines have proven to be efficient catalysts for these transformations. In addition to enamine catalysis, Akiyama and co-workers showed that chiral phosphoric acid catalysis was also a viable tool for the desymmetric aldol condensation of triketones 26 to cyclic 7336


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Scheme 10. Desymmetric Aldol Lactonization of Keto Acid

Scheme 11. Total Synthesis of (−)-Curcumanolide A and (−)-Curcumalactone

In 2007, Scheidt and co-workers reported that N-heterocyclic carbenes (NHCs) catalyzed the highly enantioselective desymmetric aldol reaction of acyclic 1,3-diketone-based enal 29 to the fused bicyclic β-lactone 31 or α,α-disubstituted cyclopentenes 32 (Scheme 8).58 The authors proposed a possible pathway for this transformation as follows. The treatment of 10 mol % chiral triazolium salt 30 with i-Pr2NEt generates the real carbene catalyst, which reacts with 29 to form intermediate I, followed by a β-protonation to produce enol II, which undergoes an aldol reaction to β-hydroxy ketone intermediate III. The following intramolecular acylation of tertiary alcohol species III regenerates the chiral catalyst and affords β-lactone 31, which then loses a molecule of CO2 to give cyclopentenes 32. When aliphatic substituted diketones (R = alkyl) were used, β-lactone products 31a−b were isolated in 51−65% yield and 96.5/3.5−98/2 er, while aromatic diketones (R = aryl) readily provided α,αdisubstituted cyclopentenes 32a−c in 60−80% yield and 91.5/ 8.5−96.5/3.5 er.

The authors later applied this method to enantioselective total synthesis of (−)-bakkenolides S, I, and J, which belong to the class of sesquiterpene natural products containing a characteristic cis-fused 6,5-bicyclic core (Scheme 9).59 Starting from 1,3diketone 29a, a 5.0-g-scale synthesis of β-lactone ent-31a was achieved in 69% yield, 20/1 dr, with 99/1 er, using 5 mol % of the opposite enantiomer of chiral triazolium salt 30. The key building block ent-31a thus obtained was converted into (−)-bakkenolides S in 15 steps with a total yield of 7.2%. A further acylation of (−)-bakkenolides S could deliver (−)-bakkenolides I and J in 69% and 64% yields, respectively. With the high synthetic value of tricyclic β-lactones 34, Romo and co-workers exploited a nice organocatalytic intramolecular aldol lactonization via desymmetric biscyclization of prochiral diketoacids 33, to construct this motif efficiently (Scheme 10).60 Under optimized conditions using 20 mol % of chiral Lewis base homobenzotetramisole derivative (HBTM), in the presence of 1.0 equiv Lewis acid LiCl and 1.25 equiv p-TsCl as carboxylic acid 7337


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Scheme 12. NHC-Catalyzed Intramolecular Crossed Benzoin Reaction

Scheme 13. Enantioselective Monoreduction of 2-Allyl-2-methyl-1,3-cyclopentanedione

In 2009, starting from symmetric cyclic diketones 38 tethered with a terminal aldehyde group, a highly enantioselective NHCcatalyzed desymmetric crossed benzoin reaction was developed by Ema, Sakai, and co-workers, allowing access to tertiary alcohols 40 featuring adjacent quaternary and tetrasubstituted carbon stereocenters at the two bridgehead positions (Scheme 12).62 Because of the challenge in the construction of adjacent fully substituted chiral carbons, this protocol involved the use of 20−30 mol % of carbene precursor 39 and 20−30 mol % of Cs2CO3 or Et3N as the base, affording a variety of bicyclic compounds 40 with different ring sizes in moderate to high yield, excellent dr values, and good to excellent er values. In general, the substituent at the prochiral center of the starting materials and the ring size greatly affected reaction outcomes, so the reaction conditions must be carefully optimized for a given substrate to maximize the reaction outcome.63

activating agents, the aldol lactonization of diketoacids 33 worked well to deliver the desired tricyclic β-lactones 34 in 70− 93% yield, 93.5/6.5−98/2 er. Notably, the presence of LiCl played a crucial role in obtaining high yield. The authors proposed that this aldol lactonization starts with the generation of the more active electrophilic intermediate I from diketoacid 33 and p-TsCl, followed by a nucleophilic addition−elimination to give intermediate ammonium enolate II, which further undergoes an aldol-type reaction to give the tricyclic β-lactones 34. The presence of LiCl possibly has a dual role: to organize a favorable bicyclic chairlike transition state III via Li−S chelation and to activate the ketone moiety to facilitate the addition reaction. The efficient synthesis of tricyclic β-lactone 34a was further applied to the enantioselective total synthesis of (−)-curcumanolide A and (−)-curcumalactone by the same group (Scheme 11).61 Under the conditions described above, a gram-scale synthesis of 34a from 33a was achieved in 65% yield and excellent stereoselectivity. A further Baeyer−Villiger oxidation readily converted 34a to a fused bislactone 35 bearing both βand δ-lactone moieties, which underwent a TMSOTf-catalyzed dyotropic rearrangement to give spirocyclic, bridged γbutyrolactones 36. This novel dyotropic rearrangement reaction, developed by the Romo group, possibly proceeds via an unprecedented stereospecific 1,2-acyl migration to give δ-lactone 36, which is further transformed in five steps to a common intermediate 37 for the total synthesis of the two target natural products.

2.2. Desymmetric Reduction

The enantioselective desymmetrization of α,α-disubstituted 1,3diketones via stereoselective reduction of one of the two enantiotopic ketone moieties is a useful approach to furnish quaternary hydroxyketones of high synthetic value. Early attempts relied on the use of biocatalysis.64 For example, 2allyl-2-methyl-3-hydroxycyclopentanone 42 is an attractive chiral synthon (Scheme 13). During their efforts toward the synthesis of coriolin and anguidine,65 Brook and co-workers discovered that the use of actively fermenting baker’s yeast (Saccharomyces 7338


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Scheme 14. Enzymatic Desymmetric Reduction to Hemiacetals

Scheme 15. Total Synthesis of (+)-Crotogoudin

Scheme 16. Total Synthesis of (+)-Paspaline

cerevisiae) could stereoselectively reduce one of the two enantiotopic homomorphic ketone moieties of 2-allyl-2methyl-1,3-cyclopentanedione 41 to provide (2S,3S)-42 in 75% yield with >99/1 er, along with a minor isomer in a 10:1 ratio.66 The ketol product (2S,3S)-42 could be converted to enedione 43, a key synthon in the total synthesis of coriolin by Trost and Curran.67 The authors also utilized (2S,3S)-42 to prepare lactone 44 for the total synthesis of anguidine.68 Later, Fujii and co-workers disclosed an improved protocol to access this valuable chiral synthon. It was found that the reduction of diketone 41 by Geotrichum candidum NBRC 4597 under anaerobic conditions gave (2S,3S)-42 in 83% yield, >99.5/ 0.5 dr, and >99.5/0.5 er value, whereas G. candidum NBRC 5767 gave (2R,3S)-42 in 75% yield and >99.5/0.5 er (Scheme 13).69 In 2003, Sugai and co-workers reported the enantioselective reduction of prochiral triketones 45 mediated by a yeast strain, Torulaspora delbrueckii IFO 10921 (Scheme 14).70 The adducts were isolated as cyclic hemiacetals 46a−c in good yield and excellent stereoselectivity. Interestingly, the reduction worked well even when using air-dried, long-term preservable whole cells of this yeast.

A notable recent example of enzymatic reductive desymmetrization of diketones was disclosed by Breitler and Carreira in the enantioselective total synthesis of (+)-crotogoudin (Scheme 15).71 It was found that, when treated with a broth of baker’s yeast and sugar in water, prochiral diketone 47 was readily converted to the desired quaternary hydroxyketone 48 in 77% yield with >99.5/0.5 er. The remaining ketone moiety of compound 48 served as a necessary synthetic handle for the synthesis of the δ-lactone and chair-cyclohexane ring in the natural product (+)-crotogoudin. Most recently, in the total synthesis of paspaline, Sharpe and Johnson utilized an enzymatic enantioselective monoreduction of prochiral 1,3-diketone 49 (Scheme 16).72 In the presence of Saccharomyces cerevisiae (YSC-2), hydroxyketone 50 was obtained in 66% yield, 10/1 dr, and >99/1 er, which was then converted to paspaline with further transformations including a gram-scale local desymmetrization as the key step. In addition to biocatalysis, synthetic catalysts have been shown to be powerful in the desymmetric reduction of prochiral diketones, even in some cases unattainable by enzymes. A remarkable example was reported by the Corey group in the enantioselective synthesis of estrone from Torgov diketone.73 In 7339


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Scheme 17. Total Synthesis of (+)-Estrone Methyl Ether

Scheme 18. Enantioselective Synthesis of the Pentacyclic Core of the Cortistatins

Scheme 19. Desymmetric Transfer Hydrogenation

the presence of 20 mol % oxazaborolidine (S)-55a and 40 mol % N,N-diethylaniline, the use of catecholborane as the reductant allowed stereoselective reduction of Torgov diketone 54a to give cyclopentanol 56 in 86% yield and 96/4 er, which was then enriched to >99.5/0.5 after a single recrystallization (Scheme 17). The following aldol condensation and oxidation gave Torgov diene 57a, which afforded (+)-estrone methyl ether after

two steps. This reduction was also a rare example of orthogonal activation,74 wherein both chiral catalyst 55a and catecholborane were activated by catecholborane and aniline, respectively. 2Benzyl-2-methylcyclopentane-1,3-dione also worked well under these conditions to give the corresponding product in 73% yield and 97/3 er. 7340


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Scheme 20. Catalytic Desymmetric Tandem Conjugate Addition−Aldol Cyclization

Scheme 21. Desymmetric Borylative Aldol Cyclization of Cyclohexane-1,3-dione

This method was further applied by Liu and Chiu in the synthesis of the pentacyclic core of cortistatins A and J, but (S)CBS-B-Me 55b was used as the optimal chiral catalyst (Scheme 18).75 (2R,3R)-2-Allyl-2-methyl-3-hydroxycyclopentanone 42 was obtained in 78% yield, 6.1/1 dr, and 97/3 er from the reduction of cyclopentanedione 41. With this chiral synthon, the synthesis of the pentacyclic core 61 of cortistatins A and J was

realized in 8.6% yield by a 12-step sequence including a Lewis acid-catalyzed intramolecular [4 + 3] cycloaddition as the key step. Chiu, Metz, and co-workers reported a remarkable example of stereoselective reduction of prochiral diketone 62 by Noyori transfer hydrogenation, in which the use of baker’s yeast resulted in no conversion.76 Gratifyingly, by using 11 mol % [(S,S)7341


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Scheme 22. Desymmetric Reductive-Aldol Cyclization of Prochiral Diketones

Scheme 23. Desymmetrization of Unsaturated Thioester Derivatives of 1,3-Diones

prochiral carbon of the diketone first undergoes a transformation to produce an active nucleophilic intermediate that can react with one of the two ketone carbonyls to create the quaternary carbon stereocenter.77 A very attractive feature of such a process is that it readily increases stereochemical complexity, as multiple stereocenters can be constructed simultaneously with the formation of multiple covalent bonds. In 2004, Krische and co-workers reported a remarkable highly stereoselective tandem Michael addition/aldol cyclization of prochiral diones 68 bearing a tethered enone moiety, allowing the facile synthesis of cyclic compound 70 with four contiguous carbon stereogenic centers, including a quaternary one (Scheme

TsDPEN]Ru(p-cymene) 63 as the catalyst and i-PrOH as the hydrogen source, the desired monoreduction product 64 was obtained in 81% yield, 12/1 dr, and 96.5/3.5 er (Scheme 19). The product 64 thus obtained could be converted to vinylsulfonate 66 for a subsequent rhodium-catalyzed carbene cyclization cycloaddition cascade reaction to give the polycyclic compound 67. 2.3. Desymmetric Domino Reactions

While the above examples are based on the direct stereoselective transformation of one of the two enantiotopic homomorphic ketone moieties, it is also possible to develop desymmetric tandem reactions in which a preorganized functionality at the 7342


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Scheme 24. Iridium-Catalyzed Desymmetric Arylative Cyclization

Scheme 25. Brønsted Acid-Catalyzed Torgov Cyclization of Prochiral Diketones

20).78 In the presence of (S)-BINAP-derived chiral Rh catalyst, the initial addition of aryl boronic acid to the α,β-unsaturated enone moiety of prochiral substrate 68 produced the Rh-enolate I, which underwent an aldol cyclization to give polysubstituted cyclic products 70 in 65−97% yield, >99.5/0.5 dr, and 92.5/7.5− 97/3 er. This method had a broad substrate scope, as both acyclic and cyclic prochiral diketones bearing five- or six-membered ring systems were viable substrates. Interestingly, this domino sequence paved the way for the concise construction of seco-B ring steroids bearing a cis-fused C−D ring junction with a bridgehead hydroxyl group, which is present in natural cardiotonic steroids derived from digitalis. For example, the blue part of compound 70a resembles the structural features of the natural products digitoxin and digitoxigenin. Inspired by Krische’s work, Lam and co-workers further developed a highly stereoselective tandem conjugate borylation/

aldol cyclization of enone−diones 68, to access the highly functionalized bicyclic compounds 73 with four contiguous stereocenters (Scheme 21).79 In the presence of a chiral Josiphos 72-derived Cu(I) catalyst, along with the use of t-BuONa to activate B2(pin)2, the initial borylation produced a Z-enolate II, followed by an aldol cyclization in a chairlike Zimmerman− Traxler transition state in which the B(pin) substituent occupies a pseudoequatorial position in the tether connecting the dione and enolate components. This tandem synthesis readily afforded hydrindane 73b and decalins 73c−e with excellent diastereo- and enantioselectivity. The diquinane derivative 73a was also obtained in 96/4 er, but with moderate 1.5/1 dr value. Similar to the conjugate addition/aldol cyclization process, reductive-aldol cyclization can also generate a metal enolate for aldol cyclization via the conjugate addition of a metal hydride species.80 In 2009, Riant and co-workers reported a domino 7343


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Scheme 26. Desymmetric Wittig Reaction of Prochiral 1,3-Diketones

the presence of a newly developed chiral disulfonimide 85, the cyclization of diketones 54 worked well to afford Torgov diene 57a and its analogues in good yield and enantioselectivity (Scheme 25).86 Mechanistically, this acid-catalyzed sequence involves four steps. Upon treatment with acid catalyst, diketones 54 are first isomerized to intermediate I, which undergoes an intramolecular Prins reaction to give stabilized carbocation III. The following deprotonation and dehydration affords dienone 57a. This good protocol was conducted on a gram-scale process for the concise synthesis of (+)-estrone; this is the shortest route available to date. The cyclization of Torgov diketone 54a catalyzed by 5 mol % 85 was conducted on a 1.8-g scale to give 1.61 g of 57 in 95% yield and 96.4/3.6 er, which was enriched to >99.9/0.1 er after a recrystallization in 88% yield. Then (+)-estrone was reached after selective hydrogenation and subsequent demethylation. By desymmetrizing diketones with an α-bromethyl ketone moiety tethered to the prochiral carbon, Werner and co-workers recently disclosed the first catalytic enantioselective Wittig reaction (Scheme 26).87 After screening several chiral phosphines, two different reaction conditions were developed for the desymmetrization of 1,3-dione 86. Using 5 mol % of phosphine 87 as the chiral source, along with the use of HSi(OMe)3 and Na2CO3, the reaction ran in toluene at 125 °C gave the desired enone 43 in up to 95/5 er, albeit with 98:2 dr, and 99/1 er. The formation of all-cis products as the major diastereomer was rationalized by a chairlike transition state for the aldol cyclization. Prochiral diones bearing an alkyne group can also be utilized for the development of tandem sequences. In 2014, Lam and coworkers described a desymmetrization of prochiral alkynones 82 through an iridium-catalyzed arylative cyclization using aryl boronic acid as the nucleophile (Scheme 24).85 Through the use of chiral (R)-difluorophos 83/Ir(I) complex, polycyclic compounds 84 were obtained in 32−62% yield with excellent er values. Mechanistically, an aryliridium species I is first produced via transmetalation from the arylboronic acid, followed by the insertion of an alkyne moiety into the aryliridium species to give alkenyliridium species II, which undergoes an unprecedented 1,4-iridium migration to give aryliridium intermediate III, which enantioselectively reacts with one carbonyl group, leading to the final product. Intrigued by the facile construction of the tetracyclic architecture of steroids via desymmetrizing prochiral diketones, synthetic chemists continue to develop new methods to make the process more efficient. In this context, the female sex hormone estrone is a prime target. In addition to Corey’s desymmetric reduction protocol (Scheme 17), List and co-workers exploited a more practical method using chiral Brønsted acid-catalyzed Torgov cyclization for the concise synthesis of (+)-estrone. In

3. DESYMMETRIZATION OF PROCHIRAL DIENES The alkene functionality can undergo many catalytic transformations that allow preorganized prochiral dienes to be particularly attractive frameworks for the design of new enantioselective desymmetric reactions. Moreover, the resulting optically active products still contain a tethered alkene group, attaching to the quaternary carbon stereocenter, as a useful synthetic handle for further elaboration. Notably, by desymmetrizing prochiral dienes, it is possible to develop enantioselective versions of CC functionalization reactions that are otherwise unable to produce chiral quaternary carbons. For example, the first catalytic enantioselective Heck reaction was developed via 7344


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Scheme 27. Catalytic Enantioselective Desymmetric Coupling of Dienes and its Application

Scheme 28. Desymmetric Heck Reaction−Carbanion Capture Process

conditions for each substrate should be optimized case by case. The improved conditions enabled the synthesis of cis-decalin derivative 89a in 93/7 er, contributing to the enantioselective total synthesis of (+)-vernolepin,90 and its absolute stereochemistry was accordingly determined. Such an intramolecular desymmetric Heck reaction was further coupled with a carbanion capture process to form a good tandem reaction in 1996 by the same group (Scheme 28).91 The desymmetric Heck process mediated by (S)-BINAP-derived palladium catalyst proceeded well to give a chiral metallic complex, which was captured in situ by the nucleophilic carbanion 92 to afford the final bicyclo[3.3.0]octane derivatives 93 with high enantioselectivity. It should be noted that this report represented an unprecedented Heck reaction−carbanion capture process. Using compound 93a as the building block, the first catalytic enantioselective total synthesis of (−)-Δ9(12)capnellene from commercially available starting material was achieved. Bräse and co-workers further attempted a desymmetric Heck reaction of a meso-bicyclic system 94 to furnish tricyclic system 95 (Scheme 29).92 After screening a variety of ligands, a planar-

the desymmetrization of prochiral dienes by Shibasaki and coworkers in 1989. This strategy has been used successfully to construct quaternary carbon stereogenic centers and has demonstrated its value in the total synthesis of natural products. 3.1. Desymmetric Cross-Coupling Reactions

With their interest in the synthesis of (+)-vernolepin, Shibasaki and co-workers designed an enantioselective desymmetrization of prochiral dienes via an intramolecular Heck reaction to obtain the key building blocks, cis-decalin derivatives 89 (Scheme 27). Their early attempts revealed that the desymmetrization of vinyl iodide 88 afforded the desired product 89 in good yield and up to 73/27 er through the use of a chiral Pd(0) catalyst formed in situ from 3.0 mol % Pd(OAc)2 and 9.0 mol % (R)-BINAP.88 Further optimization of the conditions resulted in an improved protocol that involved the cross-coupling of alkenyl triflate 90.89 The replacement of Ag2CO3 by K2CO3 as the base allowed the desired products 89 to be obtained in 96/4 er with 51% yield when using 1,2-dichloroethane as solvent and 1.0 equiv of pinacol as additive. It was also found that KOAc could serve as an additive to improve the reaction outcome. However, the reaction 7345


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Scheme 29. Catalytic Desymmetric Coupling of Bicyclic System

Scheme 30. Desymmetric Intermolecular Cross-Coupling of Ditriflates

Scheme 31. Palladium-Catalyzed Enantioselective Carbonylation Reaction

prochiral dienes. For example, Willis’s group reported an enantioselective desymmetric intermolecular Suzuki coupling of prochiral cyclopentadiene-based ditriflate 96 with aryl boronic acid 69 in 2004 (Scheme 30).93 In the presence of 10 mol % chiral palladium catalyst derived from (S)-97 and Pd(OAc)2, a variety of aryl boric acids worked well with ditriflate 96 to afford the corresponding monotriflates 98 in up to 66% yield and 86/ 14−93/7 er. Because of the presence of the triflate group as a valuable synthetic handle, monotriflates 98a could be further functionalized by a range of palladium-catalyzed reactions. Later in 2010, Willis and co-workers further realized an enantioselective desymmetric carbonylation reaction of prochiral

chiral Josiphos ligand (S,R)-72 was found to be the most effective ligand, allowing the synthesis of the corresponding tricyclic product 95 in 92/8 er and 92% yield. Notably, while catalytic desymmetric Heck coupling of prochiral dienes proved to be a good strategy to construct ring systems via intramolecular reactions of cyclic substrates, this protocol is limited to cyclic dienes and intramolecular reactions. How to employ acyclic systems and how to develop intermolecular desymmetric coupling reactions are still challenges in this context. Besides Heck reactions, other coupling reactions have also been employed for enantioselective desymmetrization of 7346


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Scheme 32. Catalytic Desymmetric Ring-Closing Metathesis of Trienes

Scheme 33. Enantioselective Total Synthesis of (+)-Quebrachamine

cyclic bisalkenyltriflates 101 (Scheme 31).94 In the presence of 10 mol % chiral monophosphine ligand 102-coordinated Pd(II) complex, the desired monoesters 103 were obtained in high to excellent enantioselectivity, albeit with unsatisfactory yield because of the generation of diester byproducts. Despite ample room for further improvement, this represented the first desymmetric enantioselective carbonylation to a quaternary center.

prepared in up to 97/3 er with 94% yield, whereas poor enantioselectivity was observed for product 106e bearing a bulky cyclohexyl group. A plausible transition state was proposed, including the formation of a more Lewis-acidic anti-Mo alkylidene by reaction of chiral catalyst 105 with the lesssubstituted enol ether olefin, which enables an enantiotopic discrimination of one of the two unsaturated side chains. To reduce the high catalyst loading and extend the substrate scope of enantioselective alkene metathesis, Schrock, Hoveyda, and co-workers further developed a powerful Mo-based catalyst 108 (Scheme 33).99 Accordingly, a highly efficient enantioselective desymmetrization of prochiral trienes was developed, catalyzed by only 1−3 mol % of the newly developed, enantiopure but diastereomerically enriched, stereogenic-atmetal complex 108, for the synthesis of nitrogen- or oxygencontaining heterocycles bearing a tetrasubstituted carbon stereocenter in high to excellent yield and er value. Furthermore, the power of this catalyst was nicely demonstrated in the total synthesis of (+)-quebrachamine featuring a quaternary carbon stereocenter. In the presence of only 1 mol % of 108, enantioselective desymmetrization of indole-based triene 107 could complete within only 1 h to give the desired compound 109 in 84% yield and 98/2 er, which was further converted to the target natural product in 97% yield via hydrogenation.

3.2. Desymmetric Ring-Closing Metathesis

Catalytic enantioselective olefin metathesis has attracted much attention and found application in natural product synthesis since the pioneering works of Chauvin, Grubbs, and Schrock. Both chiral Ru- and Mo-based complexes are routine catalysts for this reaction,95−97 but Mo-based chiral catalysts are commonly used for the desymmetrization to quaternary carbon stereocenters. In 2006, Hoveyda and co-workers achieved the first example of catalytic enantioselective ring-closing metathesis of enol ethers to quaternary carbon stereogenic centers, in which the desymmetrization strategy was elegantly applied (Scheme 32).98 Through the use of 15 mol % chiral Mo-based complex 105, enol ether 104 bearing an aryl group at the prochiral carbon was desymmetrized to give optically active six-membered pyran derivatives 106a−c in 91−97% yield with up to 93.5/6.5 er. Product 106d, with an ester at the quaternary center, could be 7347


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Scheme 34. Representative Catalysts for Hydroamination of Aminodialkene 110

Scheme 35. Zirconium-Catalyzed Desymmetrization of Aminodialkenes

3.3. Desymmetric Intramolecular Hydroamination

111 was obtained in 82% yield with up to 96/4 er for the major diastereomer, albeit with only moderate 2.3/1 dr.103 In 2011, Sadow and co-workers developed a cyclopentadienylbis(oxazolinyl)borato zirconium complex 115, enabling the synthesis of both diastereomers in excellent enantioselectivity, although the diastereoselectivity was still poor.104 In their subsequent studies, they found that the use of chiral catalyst 115 provided access to either cis or trans products with excellent enantioselectivity simply by varying the substrate concentration and reaction temperature. Generally, low concentrations and high temperatures favored the generation of cis products, while high concentrations and low temperatures benefited the formation of trans products (Scheme 35).105 For example, in the presence of 10 mol % complex 115, cis-117 was obtained in 94% yield and 98/2 er, with an 8.9/1 cis/trans ratio, when the concentration of 116 was 5.45 mM at room temperature. In contrast, when a high concentration of 116 (327 mM) was used, the reaction at −30 °C provided trans-117 in 95% yield, 99.5/0.5 er, and a trans/cis ratio of 4.5/1. To account for the reversal of diastereoselectivity by concentration, two distinct working models I and II were proposed. The difference is that, at high concentrations of substrate, one more molecule of aminodialkene is coordinated to the complex to form a transition state II, which allows the synthesis of trans-117 in high enantioselectivity at low temperature. This mechanistic insight was supported because the addition of propyl amine could improve the ratio of trans/cis

The addition of an amine N−H bond to alkenes, the so-called hydroamination reaction, is an atom-economical route to valueadded nitrogen-containing compounds. Therefore, vast endeavors have been devoted to developing the corresponding enantioselective versions.100 In this scenario, the desymmetric hydroamination of prochiral aminodialkenes to prepare Ncontaining heterocycles has been widely studied. In particular, the intramolecular cyclization of 2-allyl-2-methylpent-4-en-1amine 110 to optically active substituted pyrrolidine 111 has become a testing ground for new catalysts (Scheme 34). In 2006, Hultzsch and co-workers reported that the use of 5 mol % dimeric proline-derived diamidobinaphthyl dilithium salt 112 could mediate the hydroamination of 110 well to give the desired pyrrolidine 111 bearing an allyl-substituted quaternary carbon stereocenter in 79% yield and moderate stereoselectivity (Scheme 34).101 Notably, this allowed the main group metal based catalysts to join the field of enantioselective hydroamination of aminodialkenes. They further identified a chiral 3,3′-bis(triphenylsilyl)-substituted binaphtholate scandium complex 113 as a more efficient catalyst for this reaction. The use of 2 mol % complex 113 catalyzed the reaction well to give product 111 in 93% yield, 2.7/1 dr, and 94/6 er for the major diastereomer.102 Later in 2007, Schafer and co-workers disclosed a chiral neutral amidate zirconium complex 114 as a highly enantioselective catalyst for cyclohydroamination of aminodialkenes. In the desymmetrization of aminodialkene 110, the desired pyrrolidine 7348


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synthesis of (−)-myriocin110 from cyclic diene derivative 122a by a four-step sequence. Despite advances, successful desymmetric reactions based on prochiral dienes are still limited in terms of reaction types and substrate scope, considering the rich chemistry of alkene functionality. Nevertheless, this approach offers ample synthetic opportunities for further development.

from 4.5/1 to 6/1 while the concentration of 116 was kept at 327 mM. 3.4. Miscellaneous

In addition to the aforementioned transformations, symmetric dienes bearing other tethered functionalities at the prochiral sp3hybridized carbon permit other types of desymmetric reactions to convert one of the two enantiotopic homomorphic alkene functionalities. In 2000, Tanaka, Suemune, and co-workers reported the use of 10 mol % chiral Rh complex derived from (R)-BINAP to mediate hydroacylation of prochiral diene 118 for the synthesis of trisubstituted cyclopentanones 119 (Scheme 36).106 Dienes 118 with a methyl or ethyl group at the prochiral carbon were converted to cyclopentanones 119a−c in 75−83% yield, with up to 98/2 dr and >97.5/2.5 er.

4. DESYMMETRIZATION OF PROCHIRAL GEM-DIARYL COMPOUNDS Symmetrical gem-diaryl compounds, bearing two identical aryl groups at the prochiral carbon, are interesting platforms for the development of enantioselective aromatic C−H functionalization reactions. While few such reactions can construct quaternary carbon stereocenters, except for the coupling of an aromatic C− H bond with a tertiary carbon with three different carbon substituents, the enantioselective desymmetric strategy offers the promise of employing all kinds of C−H functionalization reactions for reaction design. Advances accumulated to date have clearly shown that both intra- and intermolecular C−H functionalization reactions can fulfill the task of enantioselective construction of quaternary carbon stereocenters. Enantioselective intramolecular C−H insertion reactions of diazo compounds catalyzed by a chiral metal complex are an established tool to construct cyclic compounds.111−113 In 1995, Hashimoto and co-workers attempted desymmetric intramolecular aromatic C−H insertion reactions of prochiral α,αdiaryl-α′-diazoketones 124. In the presence of 2 mol % Rh2[(S)PTPA]4 125a, a variety of (S)-l-alkyl-L-phenyl-2-indanones 126 containing a chiral quaternary carbon atom were prepared in up to 97.5/2.5 er (Scheme 39).114 The mechanism of this formal aromatic C−H insertion is believed to be an electrophilic aromatic substitution process. Later, the same group reported an enantioselective desymmetric intramolecular C−H insertion of α-diazo β-keto ester 127a catalyzed by 2 mol % Rh2[(S)-PTTL]4 125b, and the desired cyclic indanone-based β-keto ester 128a was obtained in 87% yield and 96.5/3.5 er (eq 1, Scheme 40).115 With 128a at hand, they further developed a new route for the total synthesis of FR115427, a noncompetitive NMDA receptor antagonist, in eight steps with a total yield of 22%. With their continuing interest in chiral dirhodium(II) catalystmediated formal C−H insertion reactions, the Hashimoto group further extended the scope of the above intramolecular C−H insertion of diazo reagents by developing a more efficient dirhodium catalyst, Rh2[(S)-TFPTTL]4 125c (eq 2, Scheme 40).116 For example, the use of 2 mol % 125c enabled the reaction of 127a to finish within 2 min to give 128a in 90% yield and 98.5/1.5 er in CH2Cl2 at 0 °C, while 1 h was required for 125b to afford 128a in 89% yield and 96/4 er under identical conditions. Moreover, after reducing the catalyst loading of 125c to 0.001 mol %, the transformation of diazo compound 127a to

Scheme 36. Desymmetric Intramolecular Hydroacylation of Prochiral Diene

In 2001, Spivey and co-workers found that meso-tertiary diallylic alcohols 120 could be desymmetrized to give epoxide 121, which was a pivotal intermediate to prepare the core structure of polyhydroxylated celastraceae sesquiterpene (Scheme 37).107 Under a Zr-modified Sharpless epoxidation process using t-BuOOH as the oxidant, epoxide 121 was synthesized in 59% yield with >97.5/2.5 er. In 2012, Hamashima, Kan, and co-workers employed 10−20 mol % of (DHQD)2PHAL to realize a highly enantioselective desymmetrization of prochiral cyclic dienes 122 using Nbromosuccinimide (NBS) as the brominating reagent, via the halolactonization of unsaturated carboxylic acids,108 enabling a facile access to β- or γ-lactones 123 with multiple contiguous chiral stereogenic centers, including a quaternary one (Scheme 38).109 However, the enantioselectivity and yield were found to be sensitive to the structure of the substrate, and only sixmembered cyclic dienes were examined. This methodology was applied to the synthesis of the key intermediate for the total

Scheme 37. Desymmetric Epoxidation of Tertiary Diallylic Alcohol

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Scheme 38. Desymmetric Halolactonization of Prochiral Cyclic Diene

Scheme 39. Dirhodium Carboxylate-Mediated Desymmetric C−H Insertion

Scheme 40. Intramolecular C−H Insertion of Acceptor−Acceptor Diazo Compounds

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Scheme 41. Pd(II)-Catalyzed Enantioselective C(sp2)−H Olefination

Scheme 42. Pd(II)-Catalyzed Enantioselective C(sp2)−H Activation/C−O Cyclization

indanone-based β-keto ester 128a could still complete within 48 h to afford 98% yield and 98.5/1.5 er. Apart from enantioselective functionalization of an aromatic C−H bond via carbenoid insertion, Yu and co-workers successfully exploited the use of a chiral Pd(II) complex to induce enantioselective cleavage of one of the two enantiotopic C−H bonds of diaryl groups attached to the prochiral carbon, for the construction of quaternary carbon stereogenic centers. In 2010, they used a chiral Pd(II) catalyst derived from N-Bocprotected α-amino acids 131, a type of potent ligand developed by their group for C−H functionalization, to accomplish a highly enantioselective intermolecular C−H olefination of sodium α,αdiphenylacetates 130 with styrenes (Scheme 41).117 In the presence of 5 mol % of chiral Pd catalyst, along with 5 mol % 1,4benzoquinone (BQ) as the oxidant and 50 mol % KHCO3 as the base, a variety of α,α-diarylacetates 132 were obtained in 35− 74% yield and up to 98.5/1.5 er. The authors proposed that the σ-chelation of the carbonyl oxygen of the carboxylate salt with Pd(II) leads to the enantioselective C−H cleavage that is facilitated by the complex-induced proximity effect, resulting in a chiral carbon−Pd intermediate I that undergoes olefination to

give product 132. In addition to styrene as the coupling partner, this catalytic system also showed promising results using acrylates as the coupling partners. In 2013, Wang, Yu, and co-workers reported that a chiral Pd(II) complex ligated by Boc-Ile-OH 134 could mediate an enantioselective C−H activation/C−O bond formation sequence starting from symmetric α,α-diarylacetic acids 133, giving α,α-disubstituted benzofuran-2-ones 135 in 37−86% yield and 94.5/5.5−98/2 er; this prominent structural motif is widely present in natural products and drugs (Scheme 42).118 This protocol could tolerate the presence of substituents such as methyl, thiomethyl, methoxy, and chloro groups on the p- or mposition of phenyl rings, and the corresponding products were all obtained in excellent er value. Mechanistically, this reaction is initiated by the enantioselective C−H cleavage by the chiral Pd(II) coordinated to the carboxylate of prochiral substrates to give a six-membered palladacycle I, which is subsequently oxidized to a Pd(IV) cyclometalated intermediate II, followed by a reductive elimination to afford the final product. Notably, this reaction 7351


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Scheme 43. Palladium-Catalyzed Intramolecular Arylation of Dibenzazepinones

Scheme 44. Lipase-Catalyzed Transesterification of 1,3-Diols

represents the first example of enantioselective C−H functionalization via a Pd(II)/Pd(IV) redox catalytic cycle. In 2013, Saget and Cramer developed an enantioselective Pdcatalyzed intramolecular arylation of o-bromoaniline-derived α,α-diaryl-substituted amides 136 for highly enantioselective synthesis of functionalized quaternary dibenzazepinones 138, a class of nitrogen-containing compounds with interesting biological properties (Scheme 43).119 This work represented a rare example of construction of seven-membered rings via intramolecular C−H functionalization, which requires the formation of a difficult eight-membered palladacycle intermediate III. In the presence of 1.5 equiv of Cs2CO3 as the base and 30 mol % pivalic acid as additive, and chiral phosphoramidite 137/Pd(0) complex as the catalyst, a number of dibenzazepinones 138 were readily prepared in 78−99% yield and up to 97.5/2.5 er, with good

functional group compatibility. Another important feature of this work was that this catalytic system showed complete selectivity for C(sp2)−H activation over the competing C(sp3)−H activation, which could give five- or six-membered rings.

5. DESYMMETRIZATION OF PROCHIRAL PRIMARY DIOLS Symmetric diols bearing two enantiotopic, homomorphic free terminal hydroxy groups can be prepared smoothly from readily available materials such as malonates and active methylene compounds. Optically active alcohol derivatives could be readily prepared via the enantioselective transformation of one of the two enantiotopic hydroxy groups intramolecularly with a tethered functional group at the prochiral carbon, or intermolecularly with an appropriate reaction partner. Because 7352


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Scheme 45. Enantioselective Transesterification of 1,3-Diols Using 1-Ethoxyvinyl 2-Furoate

Scheme 46. Lipase-Catalyzed Desymmetrization of Prochiral Oxindole-Based 1,3-Diols

power in the synthesis of valuable disubstituted 3-acetoxypropanols as building blocks for a number of natural product syntheses. A useful early example was reported in 1997 by Fadel and Arzel for the construction of benzylic quaternary carbon stereocenters (Scheme 44).121 They found that, in the presence of lipase from Pseudomonas cepacia immobilized on Hyflo Super Cell (PSL/ HSC), the desymmetrization of malonate-derived prochiral diol 140 using isopropenyl acetate gave product (R)-141 in 86% yield and 85.5/14.5 er, which could be converted to tetralinic alcohol (R)-142 as a key intermediate to natural products bearing a benzomorphan moiety.122 The use of lipase from Candida antarctica (CAL) mediated the transesterification of the dihydronaphthalene-based diol 143 using isopropenyl acetate to provide the corresponding monoester (S)-144 in 94% yield

of the high synthetic value of the resulting products, the desymmetrization of prochiral primary diols has been studied intensively. 5.1. Desymmetric Transesterification

Although significant attention has been paid to enantioselective desymmetrization of 1,3-diols via transesterification,120 highly enantioselective protocols for the creation of quaternary carbon stereocenters only emerged at the end of the last century. A formidable challenge in this research is how to suppress racemization of the chiral products, as the remaining free primary alcohol group is highly nucleophilic and undergoes an intramolecular acyl-transferring reaction. Nevertheless, much progress has been made by using enzymes or metal complexes as catalysts, and the desymmetrization of prochiral α,α-disubstituted 1,3-propanediols via transesterification has shown its 7353


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Scheme 47. Lipase-Catalyzed Desymmetrization of Difluorinated Prochiral Diols

Scheme 48. CAL-B-Catalyzed Desymmetrization of α,α-Bishydroxymethylated α-Tetralone

Scheme 49. Lewis Acid-Catalyzed Enantioselective Monobenzoylation

and 87.5/12.5 er after 3.5 days, which could be used for the synthesis of (+)-eptazocine. Interestingly, in the presence of PSL/HSC with the addition of a small amount of Et3N, the transesterification of diol 143 using vinyl acetate afforded the opposite enantiomer (R)-144 in 89% yield and 96.5/3.5 er, which could be converted to tetralinic alcohol (R)-142 for the synthesis of (−)-aphanorphine. To improve the reactivity and to suppress possible racemization of chiral monoester via intramolecular acyl group migration associated with the use of common acyl donors such as vinyl acetate and isopropenyl acetate, Kita and co-workers developed a new acyl donor, 1-ethoxyvinyl 2-furoate 146, for the desymmetrization of prochiral 1,3-diols 145 (Scheme 45).123 It was found that lipase MY (from Candida rugosa, Meito) mediated the desymmetrization of cyclic diols 145 and 146 via transesterification to give the desired monoesters 147 in moderate to excellent yield and er value, while lipase from CRL (C. rugosa, Sigma Type VII), immobilized on Hyflo Super Cell, allowed the transesterification of acyclic diols to provide the desired products 147 in high to excellent enantioselectivity. By using the newly developed acyl donor 146, all reactions could finish within 5 h; in sharp contrast, other aroyl donors required at least 1 day and generally more than 4 days to

consume the diols. This method was applied to the total synthesis of fredericamycin A in 2005 by the same group.124 In a 10:1 mixture of iPr2O and MeCN at 40 °C, it took 8 days for the desymmetrization of 1,3-diol 145a mediated by lipase MY to afford the corresponding monoester 147a in 57% yield and 91.5/ 8.5 er, with 40% of diol 145a recovered. The er value of 147a could be further enriched to 98.5/1.5 by a lipase-catalyzed kinetic resolution. On the basis of the optically active monoester 147a, a total synthesis of the potent antitumor antibiotic fredericamycin A was then achieved. The Kita group further developed a desymmetric transesterification of oxindole diols 148 to construct quaternary oxindoles 149, using C. rugosa lipase (Scheme 46).125 This represents an early example of highly enantioselective synthesis of quaternary oxindoles, a privileged scaffold widely present in many bioactive natural products and drugs; its catalytic synthesis is of great current interest.126 The group found that N-protected oxindole diols 148 reacted with 1-ethoxyvinyl 2-furoate 146 in a mixed wet solvent of iPr2O and tetrahydrofuran (THF) to give the (R)-enantiomer of quaternary oxindole 149 in good yield and excellent enantioselectivity. Interestingly, under the same reaction, the hydrolysis of oxindole-derived diesters 150 afforded the opposite enantiomer (S)-149 in excellent er values. The 7354


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Scheme 50. Lewis Base-Catalyzed Enantioselective Benzoylation of 1,3-Diols

Scheme 51. Chiral DMAP-Catalyzed Monoacylation of meso-Diols

derivatives of α-tetralone and chromanone. The initial study showed it was quite challenging to develop a highly enantioselective version, possibly because the intramolecular acyl migration led to racemization of the product (Scheme 48).131 The best result achieved in desymmetrizing α-tetralone diol 155 was up to 70% yield and 79/21 er for the corresponding monoester 156, in the presence of C. antarctica lipase B (CALB). Despite significant advances in the lipase-catalyzed desymmetrization of 2,2-disubstituted 1,3-propanediols to furnish quaternary carbon stereocenters, the substrate scope of these methods is limited, and high enantioselectivity was often realized using cyclic framework-based prochiral diols. The exploration of synthetic chiral catalysts to enlarge substrate scope is therefore receiving considerable attention. A remarkable advance was made by Kang and co-workers in 2011. They identified a pyridinebisoxazoline (Pybox) 158-derived Cu(II) complex as a powerful catalyst for the general and highly enantioselective desymmetric transesterification of acyclic 2,2-disubstituted prochiral 1,3-diols 157 (Scheme 49).132 In the presence of 10 mol % 158/CuCl2 and 1.1 equiv of Et3N, the monobenzoylation of a variety of acyclic and cyclic diols readily afforded the desired products 159, with different functionalities at the quaternary

resulting monoester 149a could be converted to the key synthon 151 for the total synthesis of natural products (−)-esermethole and (−)-physostigmine.127 This is a notable example of obtaining both enantiomers of a product by modifying the substrates, even with the same chiral catalyst. 1-Aminocyclopropane-1-carboxylic acid (ACC)128 is present in many plants and shows interesting biological activities. Its difluoromethylated analogue is an attractive synthetic target, as the replacement of a methylene group by a difluoromethylene one (CF2) may not only modulate the properties of ACC but introduce chirality. However, catalytic enantioselective synthesis of cyclopropanes featuring a CF2 group is still very challenging.129 Kirihara and co-workers reported an indirect method for enantioselective synthesis of chiral difluoromethylated cyclopropane derivatives via lipase-catalyzed desymmetrization of difluoromethylated cyclopropane-based prochiral diol 152 (Scheme 47).130 The lipase PS from Pseudomonas cepacia (Amano) mediated monoacetylation of diol 152 to give the difluorinated quaternary cyclopropane 153 in 96% yield and 95.5/4.5 er, which was then converted to the difluorinated analogue of ACC (R)-154. In 2008, Nanda and co-workers attempted the enzymatic enantioselective desymmetrization of α,α-bishydroxymethylated 7355


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Scheme 52. Lewis Basic Sulfide-Catalyzed Enantioselective Bromocyclization

Scheme 53. Desymmetric Bromoetherification of Diolefinic Diols

presence of achiral Hünig’s base, with a similar tertiary amine moiety to the chiral catalyst 161, might cause severe background racemic reactions. While the above desymmetric transesterification reactions only furnished a single quaternary carbon stereocenter at a time, Chuzel, Bressy, and co-workers recently achieved a rare example of simultaneous generation of two stereogenic all-carbon quaternary centers (Scheme 51).135 In the presence of 2 mol % Fu’s planar-chiral catalyst 164,136 the monoacylation of mesodiols 163 by acetic anhydride readily gave tetrahydro-2H-pyran derivatives 165 with five continuous carbon stereocenters including two quaternary ones, in good yield and moderate to excellent er value. The authors also showed that the high level of enantioselectivity during the symmetry-breaking process originates from the combination of a desymmetrization and a kinetic resolution that consumes the minor enantiomer of 165 to form meso-diacetate 166. The success of this method may because the chiral N,N-dimethylpyridin-4-amine (DMAP)-type catalyst 164

carbon stereocenter, in generally high to excellent yield and er value. It was proposed that two hydroxyl groups of diols bind to a copper center at the 1,3-positions, while the benzyl chloride weakly interacts with the copper to facilitate the monobenzoylation. As the prostereogenic center of 157 is located far from the chiral sphere of the ligand in the 1,3-chelated complex, only ligand 158, modified by two n-butyl groups at the α-position of oxygen atom of both oxazoline rings to form a deep chiral cave, was capable of achieving efficient enantiotopic differentiation. Nucleophilic tertiary amine catalysis is a powerful tool for developing enantioselective acylation of alcohols via desymmetrization or kinetic resolution,133 but the application of this strategy to construct quaternary carbon stereocenters has been very limited. In 2012, Fujimoto and co-workers utilized a chiral tertiary amine 161 as a nucleophilic catalyst to mediate desymmetric benzoylation of prochiral 1,3-diol 157a using 4tert-butylbenzoyl chloride 160, and product 162 was obtained in only 55% yield and 71/29 er in the presence of i-Pr2NEt (Scheme 50).134 The moderate er value of 162 was not surprising, as the 7356


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Scheme 54. Enantioselective Intramolecular Desymmetrization of Diols

Scheme 55. Chiral Phosphoric Acid Catalyzed Desymmetric Intramolecular Transacetalization

is much more nucleophilic than i-Pr2NEt, so the background reaction failed to compete with the enantioselective pathway.

were well-tolerated to give the corresponding products in good to high stereoselectivity. This work represented the first monofunctional sulfide-catalyzed enantioselective bromocyclization reactions. It was proposed that the chiral cyclic sulfide catalyst 168 activates NBS through a Lewis acid−base interaction to give an activated species I, which then enantioselectively delivers the Br to the olefin to form a bromonium ion, and a subsequent SN2 reaction gives the corresponding products with the regeneration of the sulfide catalyst 168. Meanwhile, Yeung’s group also reported a highly diastereoand enantioselective desymmetric bromoetherification of diolefinic diols 170 catalyzed by bifunctional aminothiocarbamate 172, to give tetrahydrofurans 173 bearing two fully substituted chiral carbons in high to excellent yield and good to high dr and er values (Scheme 53).139 Diols with two identical or different unsaturated functional groups at the α position were all viable substrates under these conditions. Interestingly, after the initial bromoetherification, a further diastereoselective halocyclization of the products 173 thus obtained provided a facile

5.2. Desymmetric Bromoetherification

With the rapid development of halofunctionalization of olefins in the past few years, the application of this method for enantioselective desymmetrization of prochiral olefinic alcohols via intramolecular bromoetherification has emerged as an attractive strategy for the synthesis of optically active tetrahydrofuran derivatives.137 The use of prochiral α,αdisubstituted 1,3-diols bearing an alkene functionality allows the synthesis of substituted tetrahydrofurans with a quaternary carbon stereocenter via the intramolecular bromoetherification. In 2014, Yeung and co-workers demonstrated the viability of this concept and developed a C2-symmetric cyclic sulfide catalyst 168 that readily converts 2-benzyl-2-allyl-1,3-diols 167 to tetrahydrofurans 169 bearing two fully substituted chiral carbon atoms, including a quaternary carbon stereocenter (Scheme 52).138 A variety of olefin substituents at the prochiral center 7357


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Scheme 56. CPA-Catalyzed Desymmetric Oxidative Cleavage of Benzylidene Acetals

Scheme 57. Copper-Catalyzed Intramolecular Desymmetric Aryl C−O Coupling

cyclic acetals bearing two stereocenters in excellent yield and dr and er values (Scheme 55).142 A seeming challenge was that the desired products 180 would undergo a further cyclization to form achiral bicyclic acetal, so the identification of a suitable chiral acid was very important. After intensive screening, chiral phosphoric acid 179 bearing a spiro backbone turned out to be the best choice, furnishing the desired reaction with excellent stereoselectivity at 0 °C in the presence of 4 Å molecular sieves. By varying the length of the linker between the acetal moiety and the prochiral carbon, both tetrahydrofurans (THFs) and tetrahydropyrans (THPs) bearing a quaternary carbon stereocenter can be obtained readily. The products thus obtained can be reduced to chiral THF or THP derivatives or oxidized to lactones. The reaction might proceed via a SN1-type or a SN2-type mechanism in which chiral phosphoric acid 179 acts as a bifunctional catalyst to interact with both the free hydroxy group and the acetal moiety of the substrate. The extension of the protocol to the synthesis of six-membered pyran-derived acetals was also achieved in a highly enantioselective manner by using an analogue of 179 (Ar = 9-phenanthryl). In 2014, Houk, Zheng, and co-workers reported a remarkable desymmetrization of prochiral diols via oxidative cleavage of benzylidene acetals (Scheme 56).143 This protocol was workable for both cyclic and acyclic 1,3-diols with different substituents at

method to construct spirocyclic compounds. For example, 174 was obtained in 96% yield and 94:6 dr in the presence of 10 mol % Ph3PS. 5.3. Miscellaneous Reactions

By installing other functional groups at the α position of prochiral 1,3-propanediols, it is possible to develop other types of desymmetric reactions using prochiral diols. For example, during their studies of the Co-catalyzed regio- and enantioselective cyclization of epoxy alcohols, Jacobsen and co-workers reported in 1999 an example of desymmetrization of meso-1,3-diol 175 via an intramolecular ring-opening reaction of epoxide, giving bicyclic ring system 177 in 86% yield and 97.5/2.5 er (Scheme 54).140 As both rate acceleration and increased er values were observed when using the dimeric analogue of the Co-complex in which two [Co(salen)] units were covalently tethered for the ring-opening reaction of epoxy alcohols, the authors proposed a preferred bimetallic cyclization step for the ring closure, in which both the epoxide and the alcohol group were simultaneously activated by two Co(III) groups.141 In 2013, Chen and Sun achieved a chiral phosphoric acidcatalyzed intramolecular transacetalization reaction for the desymmetrization of prochiral 1,3-propanediols 178 bearing an acetal moiety at the α position, which represented a new reaction type for 1,3-diol desymmetrization and provided facile access to 7358


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Scheme 58. Gold(I)-Catalyzed Desymmetric Intramolecular Hydroalkoxylation

Scheme 59. Lipase-Catalyzed Enantioselective Hydrolysis of Prochiral 1,3-Diesters

the α position. On the basis of theoretical calculations, it was proposed that the reaction proceeds through the formation of an “ortho-ester” species via oxidation of 2,2-disubstituted 1,3-diol benzylidene acetals 181 by dimethyldioxirane 182, followed by an enantioselective proton transfer catalyzed by (S)-TRIP to give the final product 183 in 83−96% yield and high to excellent enantioselectivity. Theoretical studies also revealed that the oxidation of acetal by 182 is the rate-determining step, and the attractive aryl−aryl interactions between substrates and catalyst play a key role in achieving the high enantioselectivity, as the replacement of the p-methoxyphenyl (PMP) group of the acetal by a methyl group would dramatically lower the enantioselectivity. During their efforts with the catalytic desymmetric aryl C−O coupling reaction of prochiral diols, Cai and co-workers recently reported an intramolecular aryl C−O coupling reaction of 2,2disubstituted 1,3-diols 184 to chiral dihydrobenzofurans 186, which is a common structural motif in many natural products and pharmaceutically active compounds (Scheme 57).144 They found that a cyclic chiral diamine 185 in combination with CuI achieved excellent enantioselective discrimination of two enantiotopic hydroxymethyl groups of 2,2-disubstituted 1,3diols 184 to deliver the corresponding chiral 2,3-dihydrobenzofurans 186 bearing a quaternary carbon stereocenter in 81−95% yield and up to 92/8 er. Various functionalized alkyl groups such as allyl, acetyl, and amine were all tolerated and may be useful for a variety of transformations. With their continuing efforts in gold-catalyzed hydrofunctionalization of allenes enabled by a chiral counteranion strategy,145 Toste and co-workers most recently achieved a gold(I)-catalyzed desymmetric hydroalkoxylation of 1,3-diols featuring an allene moiety (Scheme 58).146 In the presence of 5 mol % of (R)-C8TRIP-derived silver salt 188 and 2.5 mol % 3-F-dppe(AuCl)2 189, the intramolecular hydroalkoxylation of allenic 1,3-diols

187 worked well to afford the multisubstituted tetrahydrofuran derivatives 190 in good yield with high to excellent diastereo- and enantioselectivity. Both alkyl and aryl substituents at the prochiral center could be tolerated, but the aryl-substituted products were generally obtained with higher er than the alkylsubstituted ones. In addition, this protocol can also synthesize tetrahydropyran derivatives, albeit with modest stereoselectivity.

6. DESYMMETRIZATION OF PROCHIRAL DICARBOXYLIC ACID DERIVATIVES Prochiral dicarboxylic acid derivatives such as diesters, diamides, and meso-cyclic anhydrides have been utilized to develop enantioselective desymmetric reactions. However, because the activities of these carboxylic derivatives are usually lower than those of ketones, there are relatively limited reaction types available for the design of desymmetric reactions. For example, prochiral diesters mainly participate in desymmetric hydrolysis or ester-exchange reactions, while prochiral diamides are involved in enantioselective C−N bond formation reactions by taking advantage of a free N−H bond of the amide group. Nevertheless, the corresponding desymmetric processes provide facile access to optically active quaternary carboxylic acid derivatives. 6.1. Prochiral Diesters

Complementary to transesterification of prochiral 1,3-diols, desymmetrizing prochiral 2,2-disubstituted 1,3-diesters through hydrolysis or ester exchange is also an effective pathway to construct quaternary carbon centers. An early example was reported by Tanaka and Suemune: the desymmetric hydrolysis of prochiral 3,3-bis(acyloxymethyl)-2-oxindole 150 to quaternary oxindole 191, in the presence of cholinesterase from electric eels. Although up to 97.5/2.5 er was achieved for the methoxymethyl (MOM)-protected oxindole diol 191, the yield was only 38% (eq 7359


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Scheme 60. Enantioselective Desymmetric Hydrolysis of Prochiral 1,3-Diesters

Scheme 61. CPA-Catalyzed Intramolecular Transesterification of Diesters

Scheme 62. CPA-Catalyzed Intermolecular Transesterification of Diesters

1, Scheme 59).147 Later, as mentioned in Scheme 46, Kita and coworkers tried to improve this reaction by using 1-ethoxyvinyl-2furoate (146) as the acyl donor, with a C. rugosa lipase (Meito

OF) as the catalyst; however, this method still suffered from unsatisfactory yield of the products 149 (eq 2),125 considering 7360


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Scheme 63. CPA-Catalyzed Intramolecular Lactamization

Scheme 64. Enantioselective Desymmetric Buchwald−Hartwig Reaction

the importance of quaternary oxindole derivatives in medicinal research. During the synthesis of orthogonally protected (R)- and (S)-2methylcysteine, naturally occurring amino acids present in the thiazoline rings of natural products such as mirabazoles A−C and tantazoles A−F, Kedrowski identified pig-liver esterase (PLE) as a powerful catalyst for the enantioselective desymmetric hydrolysis of malonate derivative 192, giving the desired product 193 in 97% yield and 95.5/4.5 er (eq 1, Scheme 60).148 The 193 thus obtained could undergo a further Curtius rearrangement to give (R)-2-methylcysteine in two steps with 63% overall yield. One year later, Back and Wulff applied this method to the enantioselective synthesis of a key building block for the stereodivergent synthesis of (−)-virantmycin (eq 2, Scheme 60).149 The PLE-catalyzed desymmetric hydrolysis of functionalized prochiral diester 194 afforded the hemiacid ester 195 in 89% yield and 97.5/2.5 er. The efficient synthesis of

enantioenriched 195 provided facile access to both enantiomers of virantmycin, a natural product possessing strong inhibitory activity against RNA, DNA, and viruses as well as antifungal activity. The nonenzymatic enantioselective desymmetric hydrolysis of prochiral diesters has also been developed, and chiral phosphoric acid catalysis has proved to be a powerful tool. In 2014, Wilent and Petersen reported a highly enantioselective desymmetrization of hydroxy di-tert-butyl diester 196 bearing a terminal hydroxyl group via (S)-TRIP-catalyzed intramolecular transesterification (Scheme 61).150 In the presence of 5 mol % chiral acid (S)-TRIP 27, a variety of differently substituted diesters 196 worked well to give five- or six-membered lactones 197, with a chiral quaternary carbon center, in high to excellent yield and enantioselectivity. Dimethyl-4-ethyl-4-formylpimelate 200a, introduced by Kuehne,151 is a valuable synthon for the synthesis of natural 7361


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Scheme 65. Desymmetric Intramolecular N-Arylation of Diamide

Scheme 66. Enantioselective Synthesis of the Cyclopentyl Core of the Axinellamines

synthetic utility of this novel desymmetrization has been demonstrated in the total synthesis of (+)-melodinine E and (−)-leuconoxine.

monoterpene indole alkaloids such as vincamine, 8-oxovincatine, and vincadifformine. However, the enantioselective synthesis of this useful building block via desymmetrization of prochiral pimelate is unprecedented and challenging. During their efforts in the divergent synthesis of (−)-rhazinilam and (−)-leucomidine B, Zhu and co-workers developed a chiral phosphoric acidcatalyzed desymmetrization of bicyclic bislactone surrogates 198 for the highly enantioselective synthesis of this important intermediate, after they failed to desymmetrize the corresponding acyclic diesters and eight-membered cyclic anhydride. They found that, in the presence of 10 mol % chiral imidodiphosphoric acid 199, bislactone 198 with different substituents at the prochiral carbon readily reacted with aliphatic alcohols to give enantioenriched 4-substituted 4-formylpimelate monoacids 200 in good to excellent yield and enantioselectivity (Scheme 62).152 With this good protocol, the authors further achieved a concise total synthesis of (−)-rhazinilam and the first total synthesis of (−)-leucomidine B. Apart from transesterification, the desymmetrization of prochiral diesters via lactamization also emerged quite recently. Aiming at the enantioselective total synthesis of (−)-leuconoxine, Higuchi, Kawasaki, and co-workers developed a chiral phosphoric acid-catalyzed desymmetric lactamization of diester 202 to enable the enantioselective synthesis of optically active lactam 204 (Scheme 63).153 However, this reaction turned out to be quite challenging. After they carefully examined a number of chiral phosphoric acids, they found that, in the presence of 10 mol % of a highly hindered phosphoric acid 203, the intramolecular lactamization of 202 afforded 204 in 94% yield and 87/13 er after 4 days at 80 °C. Although there is ample room for further improvement in terms of enantioselectivity, the

6.2. Prochiral Diamides

The enantioselective desymmetrization of prochiral 1,3-diamides via Pd-catalyzed intramolecular N-arylation (Buchwald−Hartwig reaction) is an interesting strategy to access optically active lactams. Two groups independently reported their results in 2009. Sasai and co-workers disclosed an intramolecular double N-arylation of malonamides 206 bearing two 2-bromoarylmethyl groups to give C2-symmetric spirobi(3,4-dihydro-2-quinolone) derivatives 207 in up to 99% yield and 85/15 er, catalyzed by 6.6 mol % chiral Pd(0) complex derived from (S)-BINAP (eq 1, Scheme 64).154 This N-arylation reaction is believed to be initiated by the oxidative addition of Pd(0) complex to one of the two bromoarenes in 206 to give Pd(II) complex I, which undergoes an enantioselective C−N bond-forming step to give palladacycle II. The following reductive elimination yielded monocyclized compound III and regenerated the Pd(0) catalyst. A subsequent intramolecular N-arylation of III could furnish the spirobilactams 207. Concurrently, Porosa and Viirre reported an intramolecular cross-coupling of malonamides 208 with only one 2bromobenzyl group at the prochiral center, mediated by (R)MOP/Pd(OAc)2 complex, which gave quinolinone products 209 in 54−99% yield with up to 88/12 er (eq 2, Scheme 64).155 A plausible reason why the enantioselectivity was unsatisfactory in Sasai and Viirre’s work is that the two amide groups might chelate to the palladium catalyst to cause racemic background reactions, an inherent challenge in enantioselective desymmetrization of two identical amide groups. To address this 7362


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Scheme 67. Desymmetric Ring-Opening of Bisquaternary meso-Anhydride

Scheme 68. Desymmetric Z-Selective EROCM of Norbornene-Derived Anhydride

gave half-ester 216 in 88% yield and 85/15 er. This important result suggests that it is possible to use catalytic amounts of chiral tertiary amines to develop enantioselective desymmetrization of meso-anhydrides. Alternatively, the use of 100 mol % of quinine could improve the er value to 88.5/11.5. The monoester 216 thus obtained was readily converted to the carbocyclic core of zoanthenol 217 after 13 steps with a total yield of 5.4%. This represents a rare example of a desymmetric reaction enabling simultaneous construction of two continuous quaternary stereogenic centers, a formidable challenge in enantioselective catalysis.161 Later in 2013, Hartung and Grubbs developed a new homochiral stereogenic-at-ruthenium complex 220 as a Zselective enantioselective ring-opening/cross-metathesis (EROCM) catalyst. In this research, the desymmetric Z-selective EROCM reaction of dimethyl-substituted norbornene anhydride 219 with allyl acetate 218 was examined. Through the use of 1 mol % 220, chiral cyclic anhydride 221 with two vicinal quaternary stereocenters was obtained in 65% yield, 96/4 Z/E selectivity, and 97.5/2.5 er (Scheme 68).162 This process was proposed to start from the cross-metathesis of 220 with a molecule of allyl acetate, which results in epimerization at the ruthenium center to give an intermediate I, which then reacts with 219 to give a ruthenium carbene intermediate II to afford product 221 after an additional metathesis with allyl acetate.

problem, Huo, Cai, and co-workers recently optimized a chiral copper catalyst for the enantioselective desymmetrization of 2benzyl-2-(2-iodobenzyl)malonamides 210 (Scheme 65).156 Chiral 1,2-diamine 211 in combination with CuI was identified as a promising catalyst in preparing six-membered quinolinone derivatives 212 in 52−98% yield and up to 90/10 er. 6.3. Prochiral Anhydrides

The desymmetrization of meso-cyclic anhydrides to optically active building blocks has a long and continuing history;157,158 however, the utilization of this strategy for the construction of quaternary carbon centers has rarely been explored. In 2000, Carreira et al. found that, in the presence of 1.1 equiv of quinine and 3.0 equiv of MeOH, the desymmetrization of meso-bicyclic anhydride 213 worked well to afford methyl ester acid 214 in quantitative yield with 96.5/3.5 er. Starting from hemiacid ester 214, enantioselective total synthesis of the fully functionalized cyclopentyl core of the axinellamines was achieved (Scheme 66).159 In 2009, during their efforts toward efficient and enantioselective construction of the challenging carbocyclic core of zoanthenol, Stoltz and co-workers meaningfully demonstrated that it is possible to desymmetrize a bisquaternary mesoanhydride 215 by using a catalytic amount of a chiral source (Scheme 67).160 In the presence of 10 mol % quinine, together with the use of 1 equiv of pempidine, the methanolysis of 215 7363


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Scheme 69. Rhodium-Catalyzed Desymmetric Hydroboration of Cyclopropenes

Scheme 70. Cu(I)-Catalyzed Desymmetric Hydroboration of Cyclopropenes

Scheme 71. Copper-Catalyzed Desymmetric Hydroboration of Cyclopropenes

7.1. Prochiral Cyclopropenes

7. DESYMMETRIZATION OF PROCHIRAL SMALL-RING SYSTEMS

As the smallest unsaturated cyclic molecules, the high ring strain of 3,3-disubstituted prochiral cyclopropenes makes them highly reactive. Therefore, they have been used as starting materials for various transformations to afford synthetically useful building blocks.163 To date, two basic desymmetric methods have been developed based on the reaction of the C−C double bond within the three-membered ring to alleviate the ring strain. One is the enantioselective addition reactions to prepare cyclopropanes derivatives with a quaternary carbon stereocenter, which are present in many natural products and pharmaceuticals;164 their enantioselective synthesis has attracted intensive research interest. The other is ring-opening metathesis to synthesize compounds with acyclic quaternary stereogenic centers. 7.1.1. Enantioselective Addition to the C−C Double Bond. Cyclopropyl boronic derivatives represent a class of

Prochiral small-ring systems such as 3,3-disubstituted cyclopropenes, 1,1-disubstituted cyclopropanes, cyclobutanes, oxetanes, and azetidines are attractive scaffolds for the development of enantioselective desymmetric reactions. On the one hand, optically active three- or four-membered small-ring systems are prominent structural motifs in bioactive compounds that are interesting targets in chemistry, biology, and medicinal research, and the diverse syntheses of these privileged frameworks in stereocontrollable fashion is of current interest. On the other hand, such small-ring systems are valuable building blocks capable of undergoing various ring-opening reactions. Therefore, enantioselective desymmetric functionalization of small-ring systems has received ever-increasing attention. 7364


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Scheme 72. Rhodium-Catalyzed Desymmetric Hydrostannation of Cyclopropenes

Scheme 73. Rhodium-Catalyzed Desymmetric Hydroformylation

without an ester group at the prochiral center (Scheme 71).167 In the presence of 10 mol % chiral biphosphine ligand 230/CuCl catalyst, cyclopropylboronates 231 with different substituents on the quaternary carbon stereocenter were synthesized in up to 98/ 2 er and >98:2 dr. This Cu-catalyzed enantioselective desymmetrization of cyclopropenes with no directing group well complemented the above two protocols for the synthesis of cyclopropylboronates. Apart from hydroboration, Gevorgyan’s group also developed the first example of catalytic stereoselective hydrostannation of cyclopropenes 229 to optically active cyclopropylstannanes 232 of high synthetic value (Scheme 72).168 Trost ligand (R,R)-2 in combination with [Rh(COD)Cl]2 as catalyst allowed the hydrostannation of differently substituted prochiral cyclopropenes 229 to give the corresponding cyclopropylstannanes 232 in up to 98.5/1.5 er. Notably, in their previous report on Rh-catalyzed hydroboration of cyclopropenes (Scheme 69), the installation of an ester group or alkoxymethyl substituent at the prochiral carbon was important: it might act as a directing group to improve the enantioselectivity. However, this hydrostannation reaction was free from the use of a directing group and was more general with respect to substituents. In addition, this protocol afforded transcyclopropylstannane derivatives as the major products, complementary to the previous cis-hydroboration process. Rh-catalyzed desymmetrization of prochiral cyclopropenes 233 via hydroformylation was also developed by Sherrill and Rubin in 2008, providing an efficient synthesis of optically active cyclopropylcarboxaldehydes, arguably some of the most sought after chiral small cyclics. They found that a (R)-C3-Tunephos 234-derived rhodium complex catalyzed the hydroformylation of

enticing building blocks for synthetic organic chemistry. The desymmetrization of prochiral cyclopropenes via hydroboration provides a facile method for the synthesis of cyclopropylboronates bearing a quaternary carbon stereocenter. In 2003, Gevorgyan and co-workers reported the first Rh-catalyzed desymmetric hydroboration of 3,3-disubstituted cyclopropenes 222 to afford optically active cis-cyclopropylboronates 224 bearing an ester group at the quaternary carbon in excellent stereoselectivity using the readily available chiral ligand BINAPderived Rh(I) complex (Scheme 69).165 The corresponding boric acid 225 of boronates 224 could undergo Suzuki crosscoupling reactions using aryl or vinyl iodides to provide 1,1,2trisubstituted cyclopropanes 226 in good yield. Although only limited examples were reported, this work opened new opportunities in desymmetric reactions. In 2014, Tian, Lin, and co-workers disclosed that transcyclopropylboronic derivatives 228 could be obtained from the desymmetric hydroboration of cyclopropenes 227 with an ester group, through the use of a BINAP-derived Cu(I) complex (Scheme 70).166 They proposed that, with the facilitation of tBuONa, the transmetalation of a (pinacolato)boron group from boron to chiral copper catalyst forms a borylated copper species I, which is subsequently added to the C−C double bond in a syn fashion to afford the corresponding trans products, as the low coordination between copper and the carbonyl group could not overcome the high hindrance of the methyl ester group. This method allowed the synthesis of 12 examples of transcyclopropylboronates in 55−86% yield, up to 97.5/2.5 er and excellent diastereoselectivity. Concurrently, Tortosa and co-workers reported a desymmetric hydroboration of 3,3-disubstituted cyclopropenes 229, 7365


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Scheme 74. Rhodium-Catalyzed Desymmetric Hydroacylation of Cyclopropenes

Scheme 75. NHC-Catalyzed Desymmetric Hydroacylation of Cyclopropenes

Scheme 76. Substrate-Controlled AROM/CM Reaction of Cyclopropene

Catalytic hydroacylation has also been successfully applied to enantioselective desymmetrization of 3,3-disubstituted cyclopropenes, which not only furnished a quaternary carbon stereocenter but introduced a versatile ketone substituent for further elaboration. While the intermolecular hydroacylation was generally difficult because of competing decarbonylation, the

233 well, affording optically active cyclopropylcarboxaldehydes 235 in 54−86% yield and up to 91.5/8.5 er, with catalyst loading as low as 0.13 mol % (Scheme 73).169 In addition, the substituents at the prochiral carbon of cyclopropenes 233 influenced the enantioselectivity significantly. 7366


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Scheme 77. Desymmetric Z-Selective AROM/CM of Cyclopropene

Scheme 78. Palladium-Catalyzed Enantioselective Arylation of tert-Cyclobutanol

group were used. This is an advantage over the previous Rhcatalyzed protocol (Scheme 74). 7.1.2. Enantioselective Ring-Opening/Cross-metathesis. In addition to the synthesis of chiral quaternary cyclopropane derivatives, it is also possible to develop an enantioselective desymmetric olefin metathesis of 3,3-disubstituted cyclopropenes to access acyclic compounds with a quaternary carbon stereocenter. In 2007, Giudici and Hoveyda reported a Rucatalyzed asymmetric ring-opening/cross-metathesis (AROM/ CM) of cyclopropenes 232, to afford highly functionalized products 244 in high to excellent er values (Scheme 76).172 In the presence of 5 mol % 243, enoates 242 bearing a range of unsaturated carbonyl groups worked well with cyclopropenes 232 to give acyclic 1,4-dienes 244 in 63−83% yield with up to 7/ 1 E/Z and up to 99/1 er. Interestingly, the functional group of the cross-partner olefin was found to significantly influence the enantioselectivity. After screening, they found that, when styrene was used, (R)-245 was obtained in 90% yield and 96.5/3.5 er with >20:1 E/Z selectivity; when the enoate 242a was used as cross-partner, (S)-244a was provided in 77% yield and 92.5/7.5 er under identical conditions. As illustrated in the proposed transition state, the authors proposed that the presence of the additional enoate of the intermediate I from 242 could coordinate with the Ru center and thus lead to an opposite

release of ring-strain energy by reduction was in favor of the desired transformation. In 2010, Dong and co-workers disclosed that, in the presence of 5 mol % Josiphos ligand 237-derived rhodium complex, the desymmetric hydroacylation of cyclopropenes 233 using salicylaldehydes 236 proceeded smoothly to afford trisubstituted cyclopropyl ketones 238 bearing vicinal tertiary and quaternary carbon stereogenic centers in up to 99% yield, high diastereoselectivity, and up to 99.5/0.5 er under mild conditions (Scheme 74).170 Substituted salicylaldehydes were used as the hydroacylation reagents because their phenolic oxygen was known to be able to coordinate to rhodium and accelerate hydroacylation. Later, in 2011, Glorius and co-workers disclosed a remarkable organocatalytic desymmetric hydroacylation of prochiral cyclopropenes (Scheme 75).171 The newly developed triazolium salt 240, with a highly electron-rich 2,6-dimethoxyphenyl N1 substituent, was found to be superior to known catalysts in the enantioselective hydroacylation of cyclopropenes 233. In the presence of 20 mol % salt 240 as precatalyst and 1.5 equiv of K3PO4 as the base, a variety of different substituted aromatic aldehydes reacted readily with cyclopropenes 233 to afford the desired acyl cyclopropanes 241 in 50−93% yield, up to >20/1 dr, and up to 98/2 er. Notably, excellent enantioselectivity was achieved when aromatic aldehydes without an ortho directing 7367


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Scheme 79. Rhodium-Catalyzed Desymmetric C−C Cleavage

Scheme 80. Desymmetrization of Allenyl tert-Cyclobutanols

participating in various reactions, with the release of ring strain.175 Such a C−C bond-cleavage process offers the promise to exploit new reactions,176 including the construction of quaternary carbon stereogenic centers by using 3,3-disubstituted cyclobutanols. In 2003, Uemura and co-workers exploited a novel Pdcatalyzed enantioselective arylation, vinylation, and allenylation of tert-cyclobutanol, taking advantage of the alkylmetallic species produced via selective insertion of palladium catalyst into one of the two enantiotopic C−C bonds (Scheme 78).177 It was found that, in the presence of 5 mol % N,P-bidentate ligand 251-derived chiral Pd(II) catalyst, along with the use of Cs2CO3 as the base, the enantioselective arylation of cis-3-methyl-1,3-diphenylcyclobutanol 250a afforded ketone (−)-252a with a β-acyclic quaternary carbon in 83% yield and 95/5 er. The authors proposed that this reaction possibly starts from the coordination of tert-cyclobutanol 250 to the in situ-formed aryl palladium intermediate with the assistance of Cs2CO3, to give a palladium(II) alcoholate I. A subsequent β-carbon elimination produces an alkyl palladium intermediate II, which undergoes a reductive elimination to deliver the final product and

sense of enantioselectivity, as compared with that of the styrenederived intermediate II. While the Ru-catalyzed protocol gave E isomers of chiral 1,4diene as the major products, Hoveyda and co-workers further developed a Z-selective Mo-catalyzed olefin metathesis of cyclopropenes, and two examples allowed the construction of quaternary carbon stereocenters (Scheme 77).173 In the presence of 3 mol % Mo catalyst 247, the AROM/CM of 3-methyl-3phenylcyclopropene 232a and vinyl ethers 246 afforded the desired Z products 248a−b in 71−79% yield with up to 96.5/3.5 er. 7.2. Prochiral Cyclobutanols

The inherent strain and convenient availability of cyclobutanederived prochiral tertiary alcohols make them an attractive substrate class for the development of enantioselective C−C bond activation via desymmetric processes, which could provide facile access to optically active acyclic or cyclic β-substituted ketones.174 In the presence of transition metal catalysts, cyclobutanolates derived from the ligand exchange of tertcyclobutanol with the metal complex tend to undergo a β-carbon elimination to form an active alkyl metal species capable of 7368


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Scheme 81. Desymmetric C−C/C−H Activation Sequence

Scheme 82. Enantioselective C−C Bond Cleavage Reactions of tert-Cyclobutanols

regenerate the catalyst. It should be noted that trans-250a was converted to (+)-252a in only 77.5/22.5 er, although with comparable yield under the same conditions. Moreover, the presence of an aryl group at the 1-position of cyclobutanol was essential to secure high yield and enantioselectivity, as the butylsubstituted cis-250b substrate afforded the corresponding product (−)-252b in a much inferior fashion (50% yield and 57.5/42.5 er). During their efforts to explore the potential of such a C−C bond-activation strategy in constructing quaternary carbon

stereocenters, Seiser and Cramer developed a highly enantioselective synthesis of acyclic β-quaternary ketones from 3,3disubstituted cyclobutanols (Scheme 79).178 In this case, rhodium intermediate II generated via β-carbon elimination was protonated to give ketones 254 bearing a methyl-substituted quaternary stereogenic center. In the presence of 6 mol % 230 and 2.5 mol % [Rh(OH) (cod)]2, 11 examples of acyclic or cyclic β-quaternary ketones were prepared in high to excellent yield with excellent er values. Even (R)-4-ethyl-4-methyloctan-2-one 254a was synthesized in 96.5/3.5 er; it could be converted to the 7369


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Scheme 83. Enantioselective Ring-Expansion Reaction of tert-Cyclobutanols

give 259. Difluorphos 83 was the optimum ligand for this reaction, allowing the synthesis of a variety of indanol derivatives bearing a quaternary chiral carbon with two different aryl groups or one alkyl and one aryl group, in 63−98% yield, up to 20/1 dr and 99.5/0.5 er. Meanwhile, Murakami’s group also worked on this reaction using the same catalyst system. They found that the reaction temperature could be lowered to 80 °C when conducted in 1,4dioxane with the addition of 1.5 equiv of Cs2CO3. Six examples of 259 were reported in 79−98% yield, up to 9/1 dr, and 99.5/0.5 er.181 By installing a bromo or triflate group on the ortho position of a C3 phenyl substituent of tert-cyclobutanols, the alkyl rhodium intermediate II could undergo an oxidative addition to give benzorhoda(III)cyclopentenes, which were employed by Cramer and co-workers for the synthesis of chiral quaternary β-tetralones 262 or benzobicyclo[2.2.2]octanones 263 (Scheme 82).182 If intermediate II has an enone moiety, the oxidative addition gives a cyclic rhodium intermediate III coordinating with the C−C double bond, followed by an alkyl insertion and reductive elimination sequence to deliver 263 in 48−67% yield with up to 98.5/1.5 er. On the other hand, if intermediate II has a methyl ketone moiety, a possible intramolecular 1,5-rhodium shift occurs, giving a new alkylrhodium species V that finally transforms to β-tetralones 262 with 63−89% yield and up to 99/ 1 er via an oxidative addition and reductive elimination sequence.

simplest quaternary hydrocarbon by reducing the methyl ketone moiety to a propyl group. The broad substrate scope of this protocol is of high potential application, considering the significance of methyl-substituted quaternary chiral carbons in natural products. The potential of this strategy in facile synthesis of chiral cyclic ketones was further explored by harnessing the alkylmetallic species generated in situ from the β-carbon elimination. In 2008, Seiser and Cramer developed a highly enantioselective synthesis of quaternary cyclohexenones from α-allenyl prochiral tertcyclobutanols 255 (Scheme 80).179 With 2.5 mol % chiral biphosphine (R)-256-derived rhodium complex, the desymmetrization of 255 worked well to give the desired optically active cyclohexenones 257 in 57−99% yield and up to 99.5/0.5 er. This protocol had a good substrate scope, as both terminal and internal allenyl substituents could be tolerated, as well as a broad scope of two aryl or alkyl groups at the prochiral quaternary carbon of tert-cyclobutanols. It was proposed that the generation of seven-membered metallacycle II via β-carbon elimination simultaneously furnishes the quaternary carbon stereocenter. Cramer’s group further developed an enantioselective Rhcatalyzed C−C/C−H activation sequence for the synthesis of indanols from tert-cyclobutanols (Scheme 81).180 Starting from tert-cyclobutanols 258 with a C3 aryl group, the β-carbon elimination produces an alkyl rhodium intermediate I that undergoes a 1,4-rhodium shift to afford a more stable aryl rhodium species II, which then reacts with the ketone moiety to 7370


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Scheme 84. Desymmetric Intramolecular Addition/Ring-Opening Process of Cyclobutanones

Scheme 85. Desymmetric Addition/Ring-Opening Process of Cyclobutanones

derivatives. It is worth mentioning that, while enantioselective C−C activation of tert-cyclobutanols is mostly based on intramolecular transformations, this work suggests it is possible and promising to couple additional reaction partners to this Rhcatalyzed C−C activation process to develop new reactions.

Most recently, Murakami and co-workers disclosed that the in situ-generated alkyl rhodium intermediate could be utilized to decompose diazo compounds for further elaboration (Scheme 83).183 Chiral biphosphine ligand (S)-230/Rh complex facilitated the desymmetric ring expansion of prochiral 3,3disubstituted cyclobutanols 264 to cyclopentanols 266 bearing three carbon stereocenters, including a quaternary one in 34− 50% yield and 99.5/0.5 er. In this transformation, the alkyl rhodium intermediate II from the β-carbon elimination could decompose the in situ-produced diazo compound to furnish an (alkyl)(carbene)rhodium complex III, followed by an alkyl migration onto the carbenoid carbon to form intermediate IV, which further undergoes a 5-exo intramolecular addition to the carbonyl group, leading to polysubstituted cyclopentane

7.3. Prochiral Cyclobutanones

Prochiral 3,3-disubstituted cyclobutanones are versatile for enantioselective desymmetric C−C single-bond activation reactions.184 In 2006, Murakami and co-workers reported an (S)-261/rhodium complex-catalyzed intramolecular addition/ ring-opening reaction of boryl-substituted cyclobutanones 268, affording 2,3-dihydro-1H-inden-1-ones 269 bearing a chiral benzylic quaternary carbon in 81−96% yield and up to 97.5/2.5 er (Scheme 84).185 Such an enantioselective desymmetric 7371


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Scheme 86. Ni-Catalyzed Intramolecular Alkene Insertion of Cyclobutanones

Scheme 87. Rh-Catalyzed Intramolecular Alkene Insertion of Cyclobutanones

carbonyl group to give a rhodium cyclobutanolate II. The enantioselective β-carbon elimination generates an alkyl rhodium intermediate III, which might undergo a further 1,4rhodium shift to give a more stable rhodium species IV and finally produce 272 after protonolysis. The intermediate IV was capable of reacting with adscititious electron-poor olefins to give alkylated dihydrocoumarins 273 in 65−93% yield and up to 98.5/1.5 er. In addition to Rh-catalysis, Murakami’s group also exploited a nickel-catalyzed enantioselective intramolecular alkene insertion reaction of 3-(2-styryl)cyclobutanone 274 for the atom- and step-economical synthesis of chiral benzobicyclo[2.2.2]octenone 276 from an achiral precursor (Scheme 86).188 A chiral phosphoramidite ligand 275-derived chiral Ni(0) complex allowed access to 276 in excellent 96% yield and 91/9 er. This Ni-catalyzed process starts from intramolecular oxidative cyclization between the vinyl group and the cyclobutanone carbonyl group onto the chiral Ni(0) complex. This enantiodetermining step generates a tricyclic oxanickelacyclopentane II, which undergoes a β-carbon elimination to give bicyclic

process was presumably initiated by a transmetalation to give aryl rhodium intermediate I, which reacts with the carbonyl group to give the rhodium cyclobutanolate II. The following enantioselective β-carbon elimination produces an alkyl rhodium intermediate III that was ultimately converted to 269 after protonolysis. This enantioselective desymmetric reaction was then applied to the formal synthesis of (−)-α-herbertenol. Under the standard conditions, functionalized cyclobutanone 268a was converted to 269d in 84% yield and 97/3 er. A further six-step transformation produced 270 in 39% yield, which was the key synthon to (−)-α-herbertenol by Mukherjee’s route.186 Murakami and co-workers further used this Rh-catalyzed addition/ring-opening process to synthesize 3,4-dihydrocoumarins 272 enantioselectively from 3-(2-hydroxyphenyl)cyclobutanone 271 (Scheme 85).187 In the presence of (R)Tol-BINAP/[RhOH(cod)]2, both 3,3-diaryl and 3-alkyl-3arylcyclobutanones were successfully desymmetrized to give the desired products 272 in 68−92% yield and up to 97.5/2.5 er. According to the proposed mechanism, the binding of the hydroxy group of 271 to the chiral rhodium complex forms a rhodium aryloxide I that can be captured by the intramolecular 7372


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Scheme 88. Rhodium-Catalyzed Desymmetric Carbonyl Carboacylation

Scheme 89. Chiral Phosphoric Acid-Catalyzed Enantioselective Baeyer−Villiger Oxidation

By varying the tethered alkene functionality of prochiral cyclobutanones to an aldehyde or ketone moiety, Souillart and Cramer further extended the above chiral Rh-catalysis system to a remarkable enantioselective carbonyl carboacylation process, enabling the highly efficient and enantioselective synthesis of complex bicyclic lactones 280, ubiquitous motifs in natural products and pharmaceuticals (Scheme 88).190 In this case, the binding of the chiral Rh catalyst to two carbonyl groups of substrates gave complex I, wherein the stronger Lewis acidity of Rh(I) might induce enolization, leading to a side intramolecular aldolization, as side products 281 were observed when [Rh(cod)I]2 was used. Chiral biphosphine ligand 230-derived Rh(I) catalyst achieved the highest selectivity in the oxidative addition to one of the two enantiotopic acyl−carbon bonds to give intermediate II, which then underwent insertion of the carbonyl group into the Rh(III)−alkyl bond to give the rhodabicycle III. The following reductive elimination furnished the desired benzo[c]oxepinone framework. In addition to transitional metal catalysts, organocatalytic enantioselective C−C single-bond cleavage of cyclobutanones

nickelacycle III, and a further reductive elimination delivered the final product. Distinct from Murakami’s sequence, wherein the enantiodetermining step was the oxidative cyclization step, Cramer and co-workers reported in 2014 a Rh-catalyzed enantiotopic C−C single-bond cleavage of cyclobutanones involving an enantiodetermining oxidative addition step (Scheme 87).189 Initially, the tethered olefin of cyclobutanones binds to the chiral Rh catalyst derived from axially chiral biphosphine (R)-230 to form a complex I, which organizes a favorable transition state for the enantioselective oxidative addition of Rh into cyclobutanones to give a five-membered acyl rhodium species II. The subsequent migratory insertion leads to a bicyclic acyl rhodium species III, followed by a reductive elimination to the desired bicycloheptanones. Products 278 were readily constructed in 73−96% yield with excellent er values. Moreover, cyclobutanones bearing a dior trisubstituted trans-olefin moiety, which had not been explored in previously reported Ni-catalyzed protocol, all worked well under these rhodium-catalyzed conditions. 7373


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Scheme 90. Enantioselective C(sp3)−H Activation of Cyclopropanecarboxylic Amides

Scheme 91. Enantioselective C−H Functionalization of Cyclopropylmethylamines

also joined the field. Ding and co-workers identified chiral phosphoric acid 284 as a powerful catalyst for the enantioselective desymmetric Baeyer−Villiger oxidation of 3-substituted cyclobutanones, giving the desired lactones in high to excellent enantioselectivity. The oxidation of 3-methyl-3-phenylcyclobutanone 283 was also tried, giving the corresponding quaternary lactone 285 in 99% yield, albeit with 80.5/19.5 er (Scheme 89).191 This work represents the first chiral Brønsted acidcatalyzed enantioselective Baeyer−Villiger transformation.

H bonds, originating from the orbital rehybridization imposed by the geometry of the cyclopropane ring, permits the C(sp3)−H functionalization of cyclopropane. Accordingly, the decoration of a preexisting cyclopropyl moiety via enantioselective functionalization of cyclopropyl C−H bonds recently emerged as a promising strategy to prepare optically active cyclopropanes, which is conceptually different from enantioselective cyclopropanation reactions. In 2011, Yu and co-workers accomplished the first Pdcatalyzed enantioselective cyclopropyl C(sp3)−H activation/ organoboron cross-coupling reaction (Scheme 90).194 Intensive screening revealed that N-protected α-amino acid 288 in combination with Pd(OAc)2 allowed the cross-coupling reactions of prochiral cyclopropane 286 with coupling partners 287 such as 1-cyclohexenyl-BPin, Ph-BPin, and n-butyl-BF3K to afford the desired cyclopropanes 289 in up to 81% yield and 96/4 er. This reaction was proposed to undergo a Pd(0)/Pd(II) catalytic cycle, initiated by the binding of 286 to chiral Pd(II)

7.4. Prochiral Cyclopropanes and Cyclobutanes

Prochiral cyclopropanes and cyclobutanes are attractive substrates to exploit enantioselective C(sp3)−H functionalizations. It is well-known that the direct functionalization of C(sp3)−H bonds, which involves the formation of a transient M−C species, is much more difficult than that of C(sp2)−H bonds because of their weak ability to coordinate to the metal centers.192,193 However, the enhanced acidity of cyclopropyl C− 7374


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Scheme 92. Intramolecular C(sp3)−H Activation of Cyclopropylmethyl Anilines

Scheme 93. Pd(0)-Catalyzed Intramolecular C(sp3)−H Functionalization of Cyclopropane

catalyst. The following C(sp3)−H activation gives palladacycle II, and the transmetalation of II with organoboron reagents and subsequent reductive elimination gives the final product 289 and Pd(0) catalyst, which is oxidized to Pd(II) by benzoquinone (BQ). In the above work, an acidic N-arylamide group tethered to cyclopropanes served as a weakly coordinating directing group to facilitate C(sp3)−H cleavage. Yu and co-workers further reported an intermolecular C(sp3)−H arylation of cyclopropylmethylamines 290, wherein the triflyl-protected amine acted as a weak coordinating directing group for C(sp3)−H activation. Chiral Pd(II) complex derived from Boc-Val-OH 292

enabled the highly enantioselective arylation of cyclopropyl C− H bonds using p-iodotoluene, which represented the first enantioselective C−H arylation via a Pd(II)/Pd(IV) catalytic cycle (Scheme 91).195 Quaternary cyclopropyl β-amino acid derivatives 293 were prepared in up to 99% yield and up to 99.7/ 0.3 er. Similar to the above Pd(0)/Pd(II) catalytic cycle, the proposed Pd(II)/Pd(IV) cycle for this reaction starts from the coordination of cyclopropylmethylamine to Pd catalyst, which facilitates the C(sp3)−H activation. The oxidative addition of aryl iodide to the Pd catalyst produces a Pd(IV) species III, which undergoes a reductive elimination to provide product 293 and regenerate the Pd(II) catalyst. 7375


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Scheme 94. Enantioselective C(sp3)−H Activation of Cyclobutanecarboxylic Amides

Scheme 95. Rh(I)-Catalyzed Intramolecular [3 + 2] Cycloaddition of Vinylcyclopropane

cleavage to form a seven-membered palladacycle II, which finally produces the desired tetrahydroquinolines via reductive elimination. Most recently, Cramer and co-workers expanded the substrate scope of this Pd(0)-catalyzed intramolecular process (Scheme 93).197 Using a similar catalyst system, cyclopropanecarboxamide 297 and aminocyclopropane 299 were readily desymmetrized via enantioselective C−H arylation to give dihydroquinolones 298 and dihydroisoquinolones 300 in reasonable to excellent yield and er values, respectively. They further attempted the enantioselective C−H arylation of the heavily substituted indole 301, which involved the formation of an eight-membered palladacycle intermediate, to construct the seven-membered ring of the cyclopropyl indolobenzazepine core of BMS-791325, a hepatitis C virus NS5B replicase inhibitor. The use of phosphonite 302 as chiral ligand gave the product 303 in 94.5/5.5 er with 80% yield.

Meanwhile, Cramer and co-workers explored the enantioselective desymmetric C(sp3)−H decoration of prochiral cyclopropanes to furnish chiral heterocyclic compounds with a fused cyclopropyl group. In 2012, they reported that the use of only 2 mol % of chiral Pd(0) complex derived from chiral phosphoramidite 295 enabled the direct intramolecular C(sp3)−H functionalization of unbranched cyclopropylmethyl anilines 294 (Scheme 92).196 A variety of cyclopropane tetrahydroquinolines 296 were obtained in 86−99% yield and up to 97/3 er; these are important structural subunits of natural products and biologically active compounds. Both aryl and alkyl substituents at the prochiral center could be tolerated, and the high efficiency of this catalytic system allowed the reaction to proceed on a gram scale with a catalyst loading of 1 mol % without loss of yield or er value. As proposed, the reaction is initiated by an oxidative addition to form a chiral Pd(II) intermediate I, followed by an enantioselective C−H bond 7376


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Scheme 96. Salen/Co(III)-Catalyzed Intramolecular Ring Opening of Oxaetane

Scheme 97. CPA-Catalyzed Intermolecular Ring Opening of Oxaetanes

Enantioselective C(sp3)−H functionalization of the methylene group of prochiral cyclobutanes has also been realized by Yu and co-workers via a Pd-catalyzed desymmetric cross-coupling based on cyclobutanecarboxylic amides 304 (Scheme 94).198 NBoc α-amino-O-methylhydroxamic acid 306-derived Pd(II) complex was found to be crucial in achieving high enantioselectivity of the cross-coupling of 304 with arylboron reagents 305. A number of chiral cyclobutanecarboxylates 307 were readily accessed in 49−77% yield and up to 97.5/2.5 er. Interestingly, the authors further used an analogous L-tertleucine-derived α-amino-O-methylhydroxamic acid as the ligand to achieve the more challenging enantioselective C(sp3)−H functionalization of acyclic α,α-dimethyl amides with aryltrifluoroborate, giving the quaternary amides in up to 61% yield and promising 90:10 er. In addition to C−H functionalization, it is possible to desymmetrize prochiral cyclopropanes via a C−C cleavage process. Following their interest in the chemistry of vinylcyclopropane derivatives, Yu and co-workers reported a highly enantioselective intramolecular [3 + 2] cycloaddition of 1-yne-

vinylcyclopropane derivatives 308 to construct bicyclo[3.3.0] compounds 310, bearing a quaternary carbon stereocenter at the bridgehead (Scheme 95).199 The Takasago BINAP (R)-309 derived chiral rhodium complex was identified as the catalyst for this reaction, allowing nitrogen-, oxygen-, and gem-diestertethered substrates bearing either an internal or terminal alkyne moiety to be cyclized to the desired bicyclic compounds in 40− 90% yield and up to 99.5/0.5 er. From density functional theory calculations, they proposed that this [3 + 2] cycloaddition is initiated by the interaction of substrate and chiral catalyst to form a 16-electron Rh(I) complex (S)-I, with both the vinyl and cyclopropane moieties binding to the rhodium center, followed by the cyclopropane cleavage and alkyne insertion to provide (S)-III, which easily undergoes reductive elimination to afford the product−catalyst complex (S)-IV. The complexation step is believed to be the first stereogenerating step, i.e., the chirality in complex (S)-I can be transferred to the final (S)-product. 7.5. Prochiral Oxetanes and Azetidines

Symmetric 3,3-disubstituted oxetanes and azetidines are also intriguing substrates for exploiting enantioselective desymmetric 7377


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Scheme 98. CPA-Catalyzed Intermolecular Ring-Opening of Azetidine

Scheme 99. Desymmetric Intramolecular Michael Reaction

room for further improvement, this reaction identified a new direction in desymmetrizing oxaetanes for the construction of quaternary carbon stereocenters. More recently, the same group further developed a highly enantioselective desymmetric ring-opening reaction for more challenging substrates, azetidines 319 (Scheme 98).203 Although this protocol focused mainly on the buildup of tertiary chiral carbon stereocenters, one example of highly enantioselective desymmetrization of 3,3-disubstituted azetidine 319 to furnish quaternary carbon stereocenter was achieved, affording chiral amine 321 in 97% yield and 98.5/1.5 er in the presence of 5 mol % phosphoric acid 320. On the basis of DFT calculation results, a bifunctional role of the phosphoric acid was proposed in the transition state, wherein H-bonding interactions play a crucial role in organizing a favorable transition state.

reactions, as they are apt to undergo a ring-opening reaction to release strain energy. Importantly, by organizing two different carbon substituents on the prochiral centers of oxetanes and azetidines, the inter- or intramolecular desymmetric ringopening processes not only offer the promise of constructing quaternary carbon stereocenters but provide facile access to highly functionalized cyclic or acyclic chiral building blocks featuring a terminal hydroxy group or amine group.200 In 2009, Loy and Jacobsen reported a highly enantioselective intramolecular ring opening of oxaetane 311 to build up quaternary tetrahydrofurans 314, catalyzed by salen/Co(III) complexes 312 or 313 (Scheme 96).201 The oligomeric salen/ Co(III) complex 313 was more active than the monomer 312. For example, the use of only 0.01 mol % 313 could achieve excellent yield and enantioselectivity in the syntheses of 314a,b, comparable with those obtained by the use of 1 mol % catalyst 312b. In addition, this protocol allowed the synthesis of enantioenriched quaternary dihydrobenzofuran 314c, although the catalyst loading must be increased. In 2013, Sun and co-workers developed an intermolecular desymmetric ring opening of prochiral oxaetanes 315, using 2mercaptobenzothiazole 316a as a nucleophile (Scheme 97).202 The use of 2.5−5 mol % of chiral phosphoric acid 317 facilitated this ring-opening reaction to afford the benzothiazole thioethers 318 in excellent yield with up to 88.5/11.5 er. Despite ample

8. DESYMMETRIZATION OF PROCHIRAL ENONES There are two types of prochiral enones available for enantioselective desymmetric reactions to construct quaternary carbon stereogenic centers: 4,4-disubstituted cyclohexadienones and 2,2-disubstituted cyclopentene-1,3-diones. The two classes of substrates are relatively highly electrophilic, and their electrondeficient olefin functionality permits the use of a broad range of nucleophiles to develop desymmetric conjugate addition, 7378


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Scheme 100. Total Synthesis of (−)-Mesembrine

Scheme 101. Desymmetric Tandem Aminolysis/aza-Michael Addition

dienones 322 featuring a 3-formylpropyl group to construct bicyclo[4.3.0]nonene carbon skeletons 324, a prominent structural motif in natural products (Scheme 99).205 The enamine catalysis, realized by 10 mol % trifluoroacetic salt of cysteine-derived aminocatalyst 323, allowed this transformation to proceed well at 0 °C, giving the desired cis-324 in 89−100% yield, up to 96/4 dr and 97.5/2.5 er for the cis isomer. Notably, the cis-selectivity achieved by this work is complementary to other protocols capable of synthesizing trans-bicyclo[4.3.0]nonene carbon skeletons.206 By installing an amine moiety on the C4 substituent of prochiral cyclohexadienones, Gu and You developed a nice desymmetric intramolecular aza-Michael addition to furnish optically active nitrogen-containing heterocyclic compounds (Scheme 100).207 In the presence of 5 mol % cinchonine-derived bifunctional thiourea 326, a variety of differently substituted dienones worked well to afford the enantioenriched pyrrolidine derivatives in high to excellent yield and er value. Nevertheless,

cycloaddition, and tandem reactions, which readily afford multisubstituted cyclohexane or cyclopentane derivatives bearing a quaternary carbon stereogenic center. In addition, by preorganizing a suitable functionality tethered to the prochiral carbon, it is possible to construct both bicyclic and polycyclic compounds, whether or not these cyclic compounds contain heteroatoms. 8.1. Prochiral Cyclohexa-2,5-dienones

4,4-Disubstituted cyclohexadienones have been widely employed for the construction of six-membered cyclic compounds featuring a quaternary carbon stereocenter, privileged scaffolds widely present in natural products and pharmaceutically active compounds. While the use of prochiral cyclohexadienones for desymmetric Michael additions dates back to the pioneering work of Feringa and co-workers in 1999,204 Hayashi and coworkers were the first to attempt to utilize this framework to construct quaternary carbon stereocenters. They reported a desymmetric intramolecular Michael reaction of prochiral 7379


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Scheme 102. Desymmetric Intermolecular Sulfa-Michael Reaction

Scheme 103. Desymmetric Intermolecular Michael Reaction

reaction using malonates under high pressure (Scheme 103).210 The merger of chiral primary amine−thiourea 339 and 4-(pyrrolidin-1-yl)pyridine (PPY) (30 mol %, each) was identified as the choice of catalyst system, allowing the synthesis of functionalized cyclohexenones 340 with adjacent tertiary and quaternary carbon stereocenters in a highly stereoselective manner. They proposed that high pressures could accelerate both the catalyst−substrate interactions and C−C bond-forming reactions, thus increasing the overall reaction rate.

only one example involved the creation of a quaternary carbon stereocenter, where the desymmetrization of 325 proceeded well to give product 327 in 91% yield and 98.5/1.5 er, paving the way to the concise total synthesis of (−)-mesembrine in 5 steps with a 32% total yield. Most recently, Fan and co-workers merged the desymmetric intramolecular aza-Michael addition of prochiral enone with an aminolysis, to achieve a remarkable tandem reaction for the construction of densely functionalized hydrocarbazole scaffolds 332, which are widely present in bioactive alkaloid compounds (Scheme 101).208 Starting from spirocyclic para-dienoneimides 329, an intermolecular aminolysis by an additional primary amine afforded the key intermediate I, which underwent the subsequent enantioselective desymmetric aza-Michael addition to ultimately give hydrocarbazole synthons 332. Bifunctional tertiary amine−thiourea 331 was identified as a powerful catalyst for this reaction, affording the desired hydrocarbazoles 332 in up to 95% yield with up to 98/2 er. This remarkable tandem protocol was also applied to the total synthesis of (+)-limaspermidine and (+)-deethylibophyllidine, which began with the intramolecular aza-Michael addition of product 332a (95/5 er) to give key intermediate 333 in 85% yield. In 2013, Wang and co-workers designed oxindole-based spirocyclic cyclohexadienones 334 and achieved a highly enantioselective desymmetric sulfa-Michael reaction to provide facile access to spirocyclic oxindoles bearing a C3 quaternary stereogenic center (Scheme 102).209 They found that, in the presence of 5 mol % catalyst 336, the desymmetrization worked well to give spirocyclic oxindoles 337 in 77−95% yield with up to 97.5/2.5 er and excellent dr values. In 2014, Kotsuki and co-workers reported a diastereo- and enantioselective desymmetrization of 4,4-disubstituted cyclohexadienones 338 via the intermolecular Michael addition

8.2. Prochiral Cyclopentene-1,3-diones

Prochiral 2,2-disubstituted cyclopentene-1,3-diones 341, readily prepared by the Lewis acid-catalyzed reaction of 1,2-bis[(trimethylsilyl)oxy]cyclobutene and ketones,211 are highly active substrates for the synthesis of optically active quaternary cyclopentanes and cyclopentenes, which are basic structures of many natural products and bioactive compounds.212 In 2012, Mikami and co-workers first used this scaffold for enantioselective desymmetric reactions. Since the reaction site was far from the prochiral center, the use of a chiral ligand 343 bearing a deep chiral cave and the installation of a coordinating benzyloxy group were the keys to achieving excellent stereoselectivity. In the presence of 343-derived Cu(II) complex, the Michael addition of dialkylzinc reagents to 1,3-diones 341 bearing both aryl and alkyl substituents at the prochiral center worked well to afford functionalized cyclopentane derivatives 344 in high to excellent stereoselectivity (Scheme 104).213 The catalyst loading could be reduced to 0.5 mol %. Furthermore, the in situ-formed zinc enolate could be employed for tandem reactions. For example, in the synthesis of key intermediate 347 to madindolines B, the zinc enolate produced from the addition of ZnMe2 to 341a reacted with butyraldehyde to give 345 with excellent diastereo- and enantioselectivity. With this methodology, the 7380


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Scheme 104. Cu(II)-Catalyzed Desymmetric Intermolecular Michael Reaction

Scheme 105. Vinylogous Addition of Deconjugated Butenolides to Cyclopentenediones

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Scheme 106. Desymmetric Alkylation of Prochiral Cyclopentenediones

Scheme 107. Desymmetric [3 + 2] Cycloaddition of Prochiral Cyclopentenedione

synthesis of 347 was realized within five steps with a total yield of 32%, which was superior to the literature synthesis involving 13 steps starting from Evans’ oxazolidinone with a total yield of only 8%.214 To develop organocatalytic desymmetrization of prochiral cyclopentene-1,3-diones 341 to cyclopentanes bearing a quaternary carbon stereocenter, Manna and Mukherjee attempted a vinylogous nucleophilic addition using deconjugated butenolides (Scheme 105).215 In the presence of 10 mol % bifunctional tertiary amine 349, a variety of chiral cyclopentanes 350 were obtained in 72−99% yield, up to >20/1 dr, and 99/1 er. Interestingly, they noticed that the free N−H bond of the side amide chain played an important role in achieving excellent stereoselectivity. Control experiments indicated that the optimal catalyst 349 could afford 94% yield, >20:1 dr, and 99/1 er for 350a; the catalyst 351, with the amide N−H bond masked by a methyl group, afforded obviously poorer results. The authors

proposed that the N−H bond of the side amide chain of the catalyst might have a dual role: (1) cooperating with thiourea N− H bonds to form an oxyanion hole that effectively stabilizes the negative charge developed in the transition state and (2) organizing a more favorable transition state in which the chiral information on the catalyst would communicate with the remote reaction site in a better way. These results suggested that multifunctional small-molecule catalysts with H-bonding interactions as secondary controlling factors are promising in achieving excellent remote enantiofacial control in the desymmetrization of prochiral cyclopentene-1,3-diones. Later, in 2015, the authors further reported a remarkable enantioselective desymmetric formal C(sp2)−H alkylation of prochiral 1,3-diones 341 using nitroalkanes as alkylating agents (Scheme 106).216 This formal alkylation reaction possibly proceeded via a conjugate addition/elimination/isomerization pathway. Dihydroquinine-derived bifunctional urea 352 was 7382


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Scheme 108. Au(I)-Mediated Desymmetrization to Methylene Pyrrolidines

Scheme 109. Desymmetric Bromolactonization of Prochiral Dialkynes

product 357a thus obtained could be further oxidized to give chiral bicyclic pyrroles 358.

optimized as the choice of catalyst, along with Na2CO3 as an achiral base to neutralize HNO2, which enabled this tandem process to work well to afford chiral cyclopentenes 353 in 51− 92% yield and up to 98/2 er. The product 353 thus obtained could undergo a second alkylation with a different nitroalkane to give cyclopentene-1,3-diones containing unsymmetrical tetrasubstituted olefins using Cs2CO3 as the base. This novel double alkylation allowed highly efficient synthesis of 354, the core structure of (+)-madindoline B, via the enantioselective methylation of 1,3-dione 341b in 96/4 er. Recently, Singh and co-workers disclosed a desymmetric [3 + 2] cycloaddition reaction of prochiral 1,3-dione 341 with azomethine ylides 355 to construct highly substituted bicyclic pyrrolidines 357 (Scheme 107).217 Through the use of 2 mol % of chiral ferrophox 356-derived Ag(I) as the catalyst, both benzyl- and allyl-substituted cyclopentenediones readily reacted with azomethine ylides to afford the corresponding pyrrolidines 357 in 35−76% yield, up to 83/17 dr, and up to 99/1 er. The

9. DESYMMETRIZATION OF PROCHIRAL DIALKYNES Symmetric dialkyne systems are useful synthons for the construction of complex molecules, including cyclic, polycyclic, and spirocyclic compounds, owing to the versatility of the carbon−carbon triple bond in organic synthesis. The desymmetrization of prochiral dialkynes offers the possibility of developing enantioselective reactions based on the functionalization of C−C triple bonds, a well-recognized vexing challenge in organic synthesis.218 Attractive features of this approach include the facile synthesis of various types of prochiral dialkynes and the installation of an alkyne-containing moiety on the resulting chiral carbons after selective conversion of an alkyne group. However, the linear shape of the alkyne moiety makes the desymmetrization of prochiral diynes quite challenging in achieving good enantioselectivity while inhibiting bifunctional7383


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Scheme 110. Pd(II)-Catalyzed Desymmetric Lactonization of Prochiral Dialkynes

Scheme 111. Desymmetric Hydroamination of Nonterminal Prochiral Dialkynes

catalysts with a chiral counteranion in the desymmetrization of prochiral terminal alkynes, as the same group reported previously that an axially chiral biphosphine ligand-derived gold complex could only afford up to 80/20 er and 23% yield in the desymmetrizing prochiral diynamide to tetrahydrooxazepine.222 In 2013, Hennecke and co-workers employed an organocatalytic bromolactonization reaction to enantioselectively desymmetrize prochiral α,α-disubstituted diynoic acids to construct quaternary chiral carbon centers (Scheme 109).223 This represented the first enantioselective halocyclization of simple nonconjugated alkynes. Through the use of 10 mol % of dimeric cinchona alkaloid derivative (DHQD)2PHAL, 5-exobromolactonization diynoic acids 362 using inexpensive NBS as a bromine source gave optically active bromoenol lactones 363 in high to excellent yield and er value. Regardless of the aryl or alkyl group on the prochiral center, diynoic acids with internal alkyne groups generally afforded the desired products in higher enantioselectivity; however, diynoic acids with terminal alkynes gave lower er values. By control experiments and NMR studies,

ization. Therefore, most attention has been paid to the desymmetric intramolecular cyclization of prochiral diynes to furnish cyclic compounds219 since the pioneering work of Fu and co-workers,220 with limited intermolecular examples reported. Nevertheless, the desymmetrization of prochiral dialkynes has been proved a useful strategy to construct tetrasubstituted carbon stereocenters, including quaternary carbon stereocenters. In 2012, Czekelius and co-workers disclosed a chiral phosphoric acid-derived gold complex 360-catalyzed enantioselective desymmetric cycloisomerization of 1,4-diynamides 359 to methylene pyrrolidines 361, which are common scaffolds in natural products (Scheme 108).221 Under standard conditions, the cyclization of diynes bearing aryl groups at the prochiral center could finish within 24 h in the presence of only 5 mol % catalyst to give the desired products in high yield and er value. In contrast, alkyl-substituted prochiral diynes were much less reactive, and even in the presence of 15 mol % gold complex 360, the corresponding products were obtained in only moderate yield after 7 days. This result showed the potential of gold 7384


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Scheme 112. Desymmetric CuAAC of Oxindole-based 1,6-Heptadiynes

Scheme 113. Desymmetric CuAAC of Prochiral Acyclic 1,6-Bisalkynes

to higher enantioselectivity to some extent without loss of yield. For example, for product 367b, only 85.5/14.5 er was obtained when the reaction was conducted with a concentration of 65.4 mM, whereas 88.5/11.5 er could be achieved under standard conditions. They proposed that the amine moiety of the substrates first coordinates to the catalyst, accompanied by the loss of two molecules of HNMe2, followed by enantioselective hydroamination to give enamine intermediate II, which then undergoes a proton transfer to provide the final product. In general, the catalytic desymmetrization reactions of prochiral dialkynes were based on intramolecular reactions; the corresponding intermolecular processes are largely unexplored and have proved very challenging. Apart from the difficulty in realizing excellent enantiotopic group discrimination, a daunting challenge in the development of enantioselective desymmetrization via intermolecular reaction is how to suppress the formation of undesired achiral difunctionalized products, particularly when terminal alkynes are involved. Because of the linear structure of the alkyne group, and because the conversion of one alkyne moiety into other groups will not produce enough steric hindrance to differentiate the alkyne group of the desired product strongly from that of prochiral dialkynes, it is not hard for the chiral monofunctionalized product to be converted to undesired difunctionalized achiral products. This issue has been fully exemplified by the investigation into the desymmetrization of prochiral dialkynes via Cu(I)-catalyzed azide−alkyne cycloaddition (CuAAC). Since Kolb, Finn, and Sharpless introduced the concept of click chemistry, CuAAC has been intensively studied and has found applications in many research areas.225 However, no successful highly enantioselective CuAAC reactions had been developed before our group disclosed the first enantioselective desymmetrization of prochiral dialkynes on the basis of an intermolecular CuAAC reaction. With our ongoing interest in oxindole chemistry, we designed oxindole-based 1,6-heptadiynes

the authors proposed that (DHQD)2PHAL worked as a bifunctional catalyst to achieve excellent yield and enantiofacial control; the tertiary amine moiety of the catalyst activates the NBS to form halirenium ion reversibly with one of the two alkyne groups to form a stereogenic center remote from where the halogenation takes place. Simultaneously, the pyridazine part of the catalyst activated the carboxylic acid for an attack on one of the two possible enantiomeric halirenium ions generated in equilibrium. Concurrently, Sridharan, Sasai, and co-workers studied the Pdcatalyzed enantioselective intramolecular desymmetrization of α,α-disubstituted diynoic acids 362. After screening a variety of chiral ligands, they found that Zhou’s SDP ligand 364 in combination with Pd(OAc)2 could catalyze this 5-exo-dig cyclization reaction at room temperature to afford dihydrofuran-2(3H)-one 365 in up to 96% yield with 85.5/14.5 er (Scheme 110).224 The authors proposed that the cyclization starts from the binding of chiral SDP/Pd(II) to diynoic acid 362 to form cationic chiral palladium intermediate I, with the generation of HOAc, followed by the 5-exo-dig nucleopalladation of the activated species I to generate Pd(II) species II with the simultaneous formation of the stereogenic center. The final protonation of II gives the desired product 365 and releases the chiral catalyst. Because of difficulties in controlling enantiotropic discrimination, there is still ample room for further improvement in terms of enantioselectivity and generality of the substrate scope. During their study of the desymmetric hydroamination of prochiral dienes (Scheme 35), Sadow and co-workers also examined the hydroamination of nonterminal prochiral diynes 366 catalyzed by 10 mol % of zirconium complex 115. The desired 1,2-didehydropyrrolidine (367a), 1,2-didehydropiperidine (367b), and 1,2-didehydroazepane (367c) were obtained in 89−95% yield and up to 95.5/4.5 er value (Scheme 111).105 They observed that lower substrate concentrations contributed 7385


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Scheme 114. Desymmetric CuAAC of Maleimide-Based Bis(alkynes)

Scheme 115. Enantioselective Total Synthesis of Quadrigemine C and Psycholeine

368 for the study of enantioselective CuAAC (Scheme 112).226 While optimizing conditions, we found that the desired product 371 could be obtained in high er value when using 10 mol % PyBox 370/CuCl as catalyst and CH2Cl2 as the solvent. However, the achiral ditriazole 372 was obtained as the major product (371/372 = 1:4), even if the corresponding azide and dialkyne were used in equal amounts. Fortunately, further screening revealed that, by using the uncommon 2,5-hexanedione as the solvent, the ratio of 371/372 could be raised from 1:4 to 1:1 under identical conditions. With a slight excess of dialkyne over azide and increasing the catalyst loading to 15 mol %, the ratio of 371/372 could be greatly enhanced to 12:1 at 0 °C. Accordingly, a variety of differently substituted oxindole dialkynes and azides were subjected to the reaction, affording the desired chiral quaternary oxindoles 371 in up to 99/1 er with up to 82% yield. The remaining propargyl group on the C3 position of oxindole

allowed the resulting products to be elaborated further to increase the structural diversity. In addition, a strong (−)-NLE (non-linear effect) was observed in this reaction, providing further proof to support the involvement of a dinuclear copper intermediate of the postulated mechanism of CuAAC.227 Stephenson et al. further explored this reaction using dialkyne in an acyclic system, using various chiral ligand-coordinated Cu(I) compounds as the catalyst (Scheme 113).228 The desymmetric CuAAC of dialkyne 373 with benzyl azide was found to be quite challenging. Among the ligands they tried, (S)t-Bu-BOX afforded relatively higher conversion, but only 51.5/ 48.5 er was obtained with the formation of a considerable amount of the undesired difunctionalized product 375. (R,R)NORPHOS gave 34% conversion with 52/48 er, and (S)-tolBINAP could afford 59/41 er but with only 6% conversion. 7386


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Scheme 116. Total Synthesis of Hodgkinsine B

Scheme 117. Palladium-Catalyzed Intramolecular Arylation to Indanes

An elegantly preorganized framework, meso-dibutenanilide 380, was devised for the development of enantioselective desymmetric reactions. During their efforts in enantioselective total synthesis of quadrigemine C and psycholeine, Overman and co-workers pioneered this good protocol and found that the use of stoichiometric amounts of chiral palladium complex derived from (R)-Tol-BINAP and Pd(OAc)2 could achieve 62% yield and 95/5 er in the desymmetric double Heck cyclization of mesodibutenanilide 380 at 80 °C (Scheme 115).230 A remarkable feature of this protocol was the simultaneous installation of two peripheral quaternary carbon stereocenters. Considering the wide occurrence of pyrrolidinoindoline units in natural bioactive alkaloids, this desymmetrization strategy would be attractive in the related total syntheses. Later, in 2011, Willis and co-workers exploited an enantioselective desymmetric allylation of meso-chimonanthine 382 for the total synthesis of hodgkinsine B (Scheme 116).231 Using Trost ligand 2 in combination with [Pd(allyl)Cl]2 as the catalyst, along with Et3N as the base, the desymmetrization proceeded well on a multigram scale to afford the Nallylchimanthonine 383 (ca. 3 g) in 76% yield and >99.5/0.5 er as essentially a single enantiomer. The high efficiency and practicability of this desymmetric allylation was very impressive, considering the complexity of meso-chimonanthine. In particular,

These results further demonstrate the great challenges of this reaction. Most recently, Xu and co-workers reported an enantioselective desymmetrization of maleimide-based bis(alkynes) 376 to give optically active succinimides 379 bearing both a propargyl and a triazole moiety at the quaternary carbon stereocenter (Scheme 114).229 They found that the presence of a bulky trimethylsilyl and a diphenylphosphine group adjacent to the two hydroxy groups of the ligand played an important role in achieving high chemoselectivity (the ratio of mono- to bistriazole was above 12:1 in all cases). Finally, through the use of 15 mol % ligand 378derived Cu(II) complex, the desired monotriazoles 379 were achieved in good yield with high enantioselectivity. This work showed that it is possible to use suitable ligands to suppress the undesired bistriazole formation, which is a crucial issue in this field.

10. MISCELLANEOUS SUBSTRATES Apart from the above-mentioned prochiral or meso-compounds, there are some other types of symmetric substrates that have been invented and found initial utility in developing novel enantioselective reactions to furnish quaternary carbon stereogenic centers. We summarize these interesting protocols in this section. 7387


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Scheme 118. Desymmetric Copper-Catalyzed Intramolecular N-Arylation Reaction

Scheme 119. Desymmetric Enantioselective Benzylic C−H Bond Oxidation

and 4-piperidone derivatives were all viable substrates in this C(sp2)−H bond arylation reaction, giving the desired products in high to excellent er value. Acyclic prochiral vinyl triflates also worked well, albeit with moderate enantioselectivity. α,α-Di(iodobenzyl)-substituted prochiral nitriles 387 were harnessed by Cai, Zhang, and co-workers to develop an enantioselective desymmetric intramolecular N-arylation reaction, to prepare tetrahydroquinolines 389 bearing a C3 cyanosubstituted quaternary carbon stereocenter (Scheme 118).233 A highly hindered 3,3′-disubstituted BINOL derivative 388 in combination with CuI was optimized as a powerful catalyst for this N-arylation process, providing the desired quaternary tetrahydroquinoline derivatives 389 in 60−98% yield and up to 97/3 er. Both aryl iodides and bromides were workable in this reaction, but higher reaction temperatures were required for the less-reactive bromides. The cyano group at the prochiral center of 387 was found to be essential for maintaining excellent enantioselectivity, because the use of other functional groups, such as amide, hydroxyl, and carbonyl groups, resulted in inferior enantioselectivity. Bach and co-workers realized symmetric spirocyclic oxindole derivatives 390 by desymmetric enantioselective oxygenation of

desymmetric protocols based on the transformations of amine functionality are very limited because of the inherent reactivity profiles of amines as compared with alcohols. The product Nallylchimonanthine 383 thus obtained was used as a key intermediate in the catalytic enantioselective total synthesis of hodgkinsine B, which exhibits a broad range of biological activities. In 2009, Albicker and Cramer designed α,α-dibenzylsubstituted ketone-derived vinyl triflates 384 for the development of enantioselective intramolecular arylation reactions via C(sp2)−H activation (Scheme 117).232 They found that, in the presence of 5 mol % chiral Pd(II) catalyst derived from a new chiral phosphoramidite 385, the direct intramolecular arylation of vinyl triflates 384 worked well at room temperature to afford optically active indanes 386 in 70−98% yield and up to 99/1 er. The reaction was proposed to start from the oxidative addition of the Pd(0) with the vinyl triflates to give a vinyl palladium species I, which could undergo a concerted deprotonation/metalation of the aryl group of 384 to afford a six-membered ring intermediate III. Subsequent reductive elimination would give 386 with the regeneration of the chiral palladium catalyst. Phenyl groups with different substituents, heteroaromatic rings such as thiophenyl, 7388


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Scheme 120. Enantioselective Activation of Primary and Secondary C−H Bonds

Scheme 121. Desymmetric Hydroboration−Oxidation Reaction

reaction well at 90 °C with a catalyst loading of only 1−5 mol %. Both primary and cyclic secondary C−H bonds could be activated for the synthesis of fused cyclopentanes, and even polycyclic products 396 containing three adjacent stereocenters were achieved as single diastereoisomers in good to excellent enantioselectivity. During mechanistic studies, the authors observed a linear correlation between the er value of ligand 395 and indane product 396, which suggested the presence of a monoligated Pd species in the enantioselective C−H bond activation. On the basis of DFT calculations, they proposed an intermediate II for the enantio-determining C−H activation step. Symmetric cyclopentene-based γ,δ-unsaturated amides 397 were employed by Takacs and co-workers for enantioselective desymmetrization via Rh-catalyzed carbonyl-directed hydroboration (Scheme 121).236 In the presence of chiral rhodium catalyst derived from phosphoramidite ligand 399 and [Rh(nbd)2]BF4, the desymmetric addition of 4,4,6-trimethyl-1,3,2dioxaborinane 398 to the C−C double bond of 397 afforded chiral secondary organoboronates in up to 97/3 er, which underwent a subsequent oxidation to give cis chiral cyclopentanols 400 with up to 78% yield for the two steps. Both phenyl amides and benzyl amides bearing alkyl, aryl, and CF3 substituents at the prochiral center were well-tolerated.

benzylic C−H bonds (Scheme 119).234 In the presence of 1 mol % chiral ruthenium metalloporphyrin complex 392, the C−H oxidation reaction using 2,6-dichloropyridine N-oxide 391 as an external oxidant could afford the desired optically active spirocyclic oxindoles 393 in 42−70% yield with up to 97/3 er after a further oxidation under pyridinium chlorochromate (PCC) or Swern oxidation conditions. The second oxidation step was employed to improve the yield of the desired spirocyclic oxindole, as the intermediate alcohol I was not completely oxidized under the reaction conditions, although the conversion of the starting material 390 was perfect. Therefore, a challenge in this study was to find a suitable oxidation to convert the intermediate alcohol to the final product 393 while avoiding the possible retroaldol reaction that would lead to decreased er values. On the basis of DFT calculations, a double hydrogen-bonding model between the substrate and the catalyst was proposed, in which the catalyst binds the substrate through hydrogen bonds at one site and performs the desired oxygenation reaction at another site. Most recently, Baudoin and co-workers developed a highly diastereo- and enantioselective intramolecular arylation via activation of primary and secondary C(sp3)−H bonds of symmetric α,α-dialkylated nitriles 394 (Scheme 120).235 An axially chiral monophosphine ligand 395 with a P-ferrocenyl substituent-derived chiral palladium complex could catalyze the 7389


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11. SUMMARY AND OUTLOOK Recent decades have witnessed the exploitation of a number of remarkable desymmetric transformations, allowing the facile conversion of prochiral or meso-compounds bearing one or two preexisting quaternary carbons to the corresponding optically active molecules with high enantioselectivity. Many of these protocols have demonstrated their value by facilitating the enantioselective total synthesis of natural products and drugs. This research not only becomes the platform for new chiral catalysts to demonstrate their value but has its roots deeply cultivated by the latest achievements of synthetic chemistry, as evidenced by some impressive examples of enantioselective C(sp2)−H or C(sp3)−H functionalizations to furnish quaternary stereocenters. Nevertheless, despite tremendous achievements, this research field is still full of opportunities for future development. First, while much attention has been paid to intramolecular desymmetric reactions of acyclic compounds or intermolecular desymmetric reactions of cyclic compounds to construct cyclic compounds, methods allowing successful intermolecular desymmetrization of acyclic molecules to furnish quaternary carbon stereocenters in acyclic molecules are still very limited. Second, the catalytic enantioselective desymmetrization of meso-compounds to quaternary stereogenic centers is largely undeveloped, with very limited examples reported,107,135,140,160−162,230,231 despite the potential of this strategy in the simultaneous construction of multiple quaternary carbon stereocenters, even adjacent quaternary stereocenters. Third, the critical challenge remains to develop ideal catalytic enantioselective desymmetric reactions by using inexpensive and readily available catalysts to accomplish excellent yield and enantioselectivity, with a broad scope of substrates under mild conditions. Nevertheless, with the development of new powerful chiral catalysts and new multicatalyst systems,237 it can be anticipated that new and efficient enantioselective desymmetric reactions will continue to be exploited and find utility in facile incorporation of quaternary carbon stereocenters in organic molecules for use in chemistry, biology, medicinal research, agriculture, and other areas where high-value enantioenriched organic compounds play indispensable roles.

where she obtained her bachelor’s degree in 2013. Then she joined Prof. Jian Zhou’s group as a Ph.D. student at the same university. Feng Zhou was born in 1987 in Dezhou, Shandong province of P. R. China. After he obtained his bachelor’s degree in 2009 from Sichuan Normal University, he joined Professor Jian Zhou’s group in East China Normal University. He has been a lecturer at East China Normal University since he received his Ph.D. degree in 2014. His research interest focuses on the catalytic asymmetric construction of tetrasubstituted stereogenic centers by chiral metal- and organocatalysis. Jian Zhou obtained his Ph.D. in 2004 from Shanghai Institute of Organic Chemistry, CAS, under the guidance of Prof. Yong Tang. After postdoctoral research with Professor Shu̅ Kobayashi at the University of Tokyo and Professor Benjamin List at Max-Planck-Institut für Kohlenforschung, he joined East China Normal University as a Professor from the end of 2008. His research interests include the development of new chiral catalysts and enantioselective reactions for the construction of tetrasubstituted carbon stereocenters. He has received the “Thieme Chemistry Journal Award 2011”. He is now the member of the Advisory Board of Acta Chimica Sinica, Organic & Biomolecular Chemistry, and Current Organocatalysis.

ACKNOWLEDGMENTS We are grateful for financial support from the 973 program (2015CB856600) and NSFC (21472049). REFERENCES (1) Fuji, K. Asymmetric Creation of Quaternary Carbon Centers. Chem. Rev. 1993, 93, 2037−2066. (2) Christoffers, J.; Mann, A. Enantioselective Construction of Quaternary Stereocenters. Angew. Chem., Int. Ed. 2001, 40, 4591−4597. (3) Shibasaki, M.; Kanai, M. Asymmetric Synthesis of Tertiary Alcohols and α-Tertiary Amines via Cu-Catalyzed C−C Bond Formation to Ketones and Ketimines. Chem. Rev. 2008, 108, 2853− 2873. (4) Zheng, Y.; Tice, C. M.; Singh, S. B. The Use of Spirocyclic Scaffolds in Drug Discovery. Bioorg. Med. Chem. Lett. 2014, 24, 3673−3682. (5) Cativiela, C.; Díaz-de-Villegas, M. D. Stereoselective Synthesis of Quaternary α-Amino Acids. Part 1: Acyclic Compounds. Tetrahedron: Asymmetry 1998, 9, 3517−3599. (6) Saari, W. S.; Halczenko, W.; Cochran, D. W.; Dobrinska, M. R.; Vincek, W. C.; Titus, D. C.; Gaul, S. L.; Sweet, C. S. 3-Hydroxy-αMethyltyrosine Progenitors, Synthesis and Evaluation of Some (2-Oxo1,3-dioxol-4-yl)methyl Esters. J. Med. Chem. 1984, 27, 713−717. (7) Bey, P.; Gerhart, F.; Van Dorsselaer, V.; Danzin, C. α(Fluoromethyl)dehydroornithine and α-(Fluoromethyl)dehydroputrescine Analogues as Irreversible Inhibitors of Ornithine Decarboxylase. J. Med. Chem. 1983, 26, 1551−1556. (8) Hong, C. Y.; Kado, N.; Overman, L. E. Asymmetric Synthesis of Either Enantiomer of Opium Alkaloids and Morphinans. Total Synthesis of (−)- and (+)-Dihydrocodeinoneand (−)- and (+)-Morphine. J. Am. Chem. Soc. 1993, 115, 11028−11029. (9) Hayashi, M.; Rho, M.-C.; Enomoto, A.; Fukami, A.; Kim, Y.-P.; Kikuchi, Y.; Sunazuka, T.; Hirose, T.; Komiyama, K.; O̅ mura, S. Suppression of Bone Resorption by Madindoline A, a Novel Nonpeptide Antagonist to Gp130. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 14728−14733. (10) Zhou, F.; Liao, F.-M.; Yu, J.-S.; Zhou, J. Catalytic Asymmetric Electrophilic Amination Reactions to Form Nitrogen-Bearing Tetrasubstituted Carbon Stereocenters. Synthesis 2014, 46, 2983−3003. (11) Sharma, I.; Tan, D. S. Drug discovery: Diversifying complexity. Nat. Chem. 2013, 5, 157−158. (12) Riant, O.; Hannedouche, J. Asymmetric Catalysis for the Construction of Quaternary Carbon Centres: Nucleophilic Addition of Ketones and Ketimines. Org. Biomol. Chem. 2007, 5, 873−888.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Xing-Ping Zeng was born in Ganzhou, Jiangxi province of P. R. China, in 1988. He obtained his bachelor’s degree in chemistry from Jiangxi Normal University in 2010. Later, he joined Prof. Jian Zhou’s group in East China Normal University as a Ph.D. student in 2011, focusing on the study on enantioselective ketone cyanosilylation. Zhong-Yan Cao was born in Bozhou, P. R. China, and received his B.Sc. from East China Normal University in 2010. He continued on to graduate studies under the guidance of Prof. Jian Zhou at the same university, focusing on the development of soft Lewis acids for constructing tetrasubstituted carbon centers. He completed his Ph.D. this year and is going to join the Laboratory of Prof. Paolo Melchiorre with the support of MSCA-IF-2015 Fellowship. Yu-Hui Wang was born in 1990 in Suzhou, Jiangsu province of P. R. China. She studied applied chemistry at East China Normal University, 7390


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