Development of Synthetic Methodologies via Catalytic

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Cite This: Acc. Chem. Res. 2018, 51, 1443−1454

Development of Synthetic Methodologies via Catalytic Enantioselective Synthesis of 3,3-Disubstituted Oxindoles Zhong-Yan Cao,† Feng Zhou,† and Jian Zhou*,†,‡,§ Shanghai Key Laboratory of Green Chemistry and Chemical Processes and ‡Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China § State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China Downloaded via UNIV OF CALIFORNIA SANTA BARBARA on June 19, 2018 at 06:52:03 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

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CONSPECTUS: 3,3-Disubstituted oxindoles are widely distributed in natural products, drugs, and pharmaceutically active compounds. The absolute configuration and the substituents on the fully substituted C3 stereocenter of the oxindole often significantly influence the biological activity. Therefore, tremendous efforts have made to develop catalytic enantioselective syntheses of this prominent structural motif. Research in this area is further fueled by the ever-increasing demand for modern probe- and drug-discovery programs for synthetic libraries of chiral compounds that are derived from privileged scaffolds with high structural diversity. Notably, the efficient construction of fully substituted C3 stereocenters of oxindole, tetrasubstituted or all-carbon quaternary, spirocyclic or not, also becomes a test ground for new synthetic methodologies. We have been engaged in developing efficient methods for diversity-oriented synthesis of chiral 3,3-disubstituted oxindoles from readily available starting materials. We have systematically developed catalytic enantioselective methods to prepare 3-substituted 3-hydroxyoxindoles, 3-aminooxindoles, and 3-thiooxindoles, quaternary oxindoles, and spirocyclic oxindoles. These protocols can be classified into six approaches: (1) enantioselective addition of nucleophiles to isatins or isatin ketimines; (2) unprotected 3-substituted oxindoles as nucleophiles; (3) functionalization of oxindole-derived tetrasubstituted alkenes; (4) desymmetrization of oxindole-based diynes; (5) spirocyclopropyl oxindoles as donor−acceptor (D−A) cyclopropanes; and (6) elaboration of diazooxindoles. By the use of these methods, chiral oxindoles with rich structural diversity are readily accessed with high to excellent enantioselectivity. Some methods have been used for the enantioselective formal or total synthesis of natural products, bioactive compounds, or their analogues. On the basis of these studies, we developed synthetic methodologies that have potential application. We designed phosphoramide-based bifunctional catalysts for the efficient construction of quaternary oxindoles: a cinchona-alkaloid-derived phosphoramide for the Michael addition of unprotected 3-substituted oxindoles to nitroolefins with broad substrate scope and a chiral 1,2-cyclohexanediamine-derived bifunctional phosphoramide for the activation of fluorinated enol silyl ethers for the addition to isatylidene malononitrile. The phosphoramide-based catalysts achieved better enantiofacial control than the analogous H-bond-donor-derived catalysts in these reactions, suggesting the potential of the former in new chiral catalyst development. We identified chiral Au(I) and Hg(II) catalysts for olefin cyclopropanation of diazooxindoles. We further disclosed the effective activation of spirocyclopropyl oxindoles by using electron-withdrawing N-protecting groups for enantioselective [3 + 3] cycloaddition, offering the promise of constructing a diverse range of spirocyclic oxindoles by the use of such monoactivated D−A cyclopropanes. We developed tandem sequences that allow the facile synthesis of 3,3-disubstituted oxindoles from simple starting materials in a one-pot operation, including a tandem Morita−Baylis−Hillman/bromination/ [3 + 2] annulation sequence, a hydrogenation/ketimine formation/asymmetric 6π electrocyclization sequence, a C−H functionalization/Michael addition or amination sequence, and an aza-Wittig/Strecker sequence. We designed oxindole-based diynes to realize a highly enantioselective Cu-catalyzed alkyne−azide cycloaddition (CuAAC), outlining the desymmetrization of prochiral diynes as an effective strategy to exploit asymmetric CuAAC. This Account focuses on the synthetic methodologies developed in our group for the catalytic enantioselective synthesis of 3,3-disubstituted oxindoles and provides an overview of our research on the design, development, and applications of these methods that will provide useful insights for the exploration of new reactions.

1. INTRODUCTION There is enormous demand for synthetic libraries of chiral molecules that replicate the structural features of privileged scaffolds that widely occur in natural products and drugs to © 2018 American Chemical Society

Received: March 7, 2018 Published: May 29, 2018 1443

DOI: 10.1021/acs.accounts.8b00097 Acc. Chem. Res. 2018, 51, 1443−1454

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Accounts of Chemical Research

Figure 1. Representative natural products and bioactive compounds.

adjacent all-carbon quaternary stereocenters6a,b or direct C−H bond functionalization.6c,d In 2010, we published a comprehensive review of the advances in the catalytic enantioselective synthesis of 3,3-disubstituted oxindoles, which has witnessed rapid development (cited 830 times to date).3a Meanwhile, it came to our attention that despite known elegant protocols, it remains highly desirable to develop efficient methods to access oxindoles with high structural diversity from readily available starting materials by using simple manipulations. Therefore, we initiated a program to exploit new chiral catalysts, new activation models, and tandem sequences for the catalytic enantioselective synthesis of 3,3-disubstituted oxindoles. This Account highlights our efforts and findings.

increase the returns of modern probe- and drug-discovery studies.1 3,3-Disubstituted oxindoles constitute one such class of scaffolds, and they form the core of many bioactive natural products (Figure 1). Drawing inspiration from these molecules, a number of new drugs and lead compounds have been developed.2 Intriguingly, the C3 carbon of oxindoles covers all kinds of fully substituted stereocenters, spiro or not, all-carbon quaternary or heteroatom-containing tetrasubstituted. This characteristic structural feature has aroused intense interest in the catalytic enantioselective synthesis of 3,3-disubstituted oxindoles3 because the efficient construction of tetrasubstituted4 and, in particular, quaternary5 carbon stereocenters remains difficult. Tremendous research effort has not only provided collections of structurally diverse oxindole derivatives for medicinal study, facilitating the discovery of more potent and selective analogues, but also contributed to the invention of new synthetic methodologies. Notably, this research has become a fruitful area in which to develop challenging catalytic enantioselective reactions6 involving highly stereoselective construction of

2. DEVELOPMENT OF CHIRAL CATALYSTS 2.1. Bifunctional Phosphoramide Amine Catalysts

The combination of H-bond donors with other functionalities is a powerful strategy for the design of bifunctional catalysts that enable highly enantioselective reactions that are unattainable by 1444


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Accounts of Chemical Research single catalysis.7 Whereas amides, sulfonamides, (thio)urea, and squaramides are popular H-bond donors for the design of new organocatalysts, phosphoramides (phosphinamides) have received less attention. We speculated that with two substituents as shielding groups from two directions, such phosphine-based H-bond donors would possess a unique advantage over other H-bond donors (Scheme 1). Changing the steric and electronic

Scheme 2. Asymmetric Strecker Reaction of Isatin Ketimines

Scheme 1. Design and Synthesis of Bifunctional Phosphoramide (Phosphinamide) Catalysts

Our bifunctional phosphoramides were subsequently found to be potent catalysts for the Michael addition of unprotected 3-substituted oxindoles to nitroolefins (Scheme 3).8b The resulting Scheme 3. Asymmetric Michael Addition

properties of the amide substituents would offer a convenient and effective way to tune the chiral environment and thereby to control the stereoselectivity and to alter the acidity of amide N−H bond for better electrophile activation. However, at the outset of our work, no reports were available to support our hypothesis. Considering the wide use of bifunctional tertiary amine catalysts7a,b originating from the capacity of tertiary amines as either Brønsted or Lewis bases to activate nucleophiles, we designed cinchona-alkaloid-derived bifunctional phosphoramide (phosphinamide) catalysts 3. These are easily accessed in one step from the corresponding primary amines and phosphinic chlorides (chlorophosphates), which are either commercially available or can be prepared in situ, and the products were obtained in moderate to good isolated yields (unoptimized).8a−d These catalysts were first applied in the Strecker reaction of N-aryl isatin ketimines with trimethylsilyl cyanide (TMSCN) (Scheme 2) because at that time the bifunctional tertiary-aminecatalyzed Strecker reaction was undeveloped,9a although Deng had reported a highly enantioselective chiral tertiary-aminemediated ketone cyanosilylation.9b Preliminary studies indicated that 10 mol % phosphinamide catalyst 3a afforded oxindolebased aminonitrile 5 with 68% ee.8a Despite the unsatisfactory result, the phosphinamide catalyst afforded clearly better enantioselectivity than analogous catalysts with amide or thiourea as the H-bond donor. This result encouraged us to examine their potency in other reactions and triggered subsequent research on catalytic enantioselective addition of nucleophiles to isatin ketimines for the synthesis of chiral 3-substituted 3-aminooxindoles.10

adducts are valuable synthons to access quaternary oxindole and indoline derivatives; however, previous studies relied on the use of highly active N-protected 3-substituted oxindoles and had limited substrate scope.3a Unprotected 3-substituted oxindoles were less reactive but more convenient and atom-efficient to prepare.8e The simple and easily available cinchonidine-derived phosphoramide 3b could be used to achieve high to excellent diastereo- and enantioselectivity in the desired reaction. Notably, both 3-aryl- and 3-alkyloxindoles as well as aryl- and alkyl-substituted nitroolefins are viable substrates, giving the desired quaternary oxindoles with excellent enantioselectivity.8b Later, with phosphoramide 3d having a bulky ester group, a highly enantioselective Michael addition of 3-alkylthio- and 3-arylthiooxindoles was developed, giving various 3-substituted 3-thiooxindoles with excellent ee values (Scheme 4).8c The reaction could be run on a gram scale with only 1.0 mol % catalyst. The phosphoramide was found to play an indispensable role in this reaction. When the N−H bond was protected with a methyl group, the resulting catalyst 14 lost almost all of its potency in 1445


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efficiently than commonly used rhodium, ruthenium, palladium, and copper salts (Scheme 6).13 Notably, this was the first

Scheme 4. Michael Addition of 3-Thiooxindoles

Scheme 6. Control Experiments

a

2.5 mol % was used. bNMR yield.

reported Hg(II)-catalyzed olefin cyclopropanation using diazo compounds. Spirocyclopropyl oxindoles not only are useful pharmacophores but also can serve as donor−acceptor (D−A) cyclopropanes for complexity-generating synthesis.2c,14 We attempted to develop enantioselective cyclopropanation. The use of chiral Difluorophos in combination with Hg(OTf)2 led to excellent dr and ee values in this reaction (Scheme 7).13a Both unprotected

terms of reactivity and stereoselectivity. Furthermore, the phosphoramide catalyst proved to be superior to the corresponding bifunctional amide, thiourea, and squaramide catalysts (Scheme 5). This result unambiguously showed that, as Scheme 5. Control Experiments

Scheme 7. Hg(II)-Catalyzed Asymmetric Olefin Cyclopropanation

a catalyst motif, phosphoramides have their own advantages over other H-bond donors and suggested the potential of phosphoramides for catalyst development.8c

and N-methyl diazooxindoles worked well to give the cyclopropanes with high enantioselectivity. Ligand acceleration effects were observed, as the use of 0.4 equiv of chiral ligand relative to Hg(OTf)2 afforded comparable outcomes. Furthermore, varying the counteranion enhanced the catalytic properties: whereas Difluorophos/Hg(PF6)2 achieved high activity in the cyclopropanation of disubstituted olefins, albeit with moderate enantioselectivity, Difluorophos/Hg(OTf)2 failed in these reactions. These results showed that it was possible to modulate the catalytic properties of Hg(II) by the use of ligands. To achieve high enantioselectivity in the cyclopropanation of di- and trisubstituted olefins, we then turned to Au(I) catalysis. In fact, because of the high sensitivity of metallocarbenes to the steric hindrance and geometry of alkenes, it is difficult to develop

2.2. Chiral Gold and Mercury Catalysis

Diazooxindoles, which can readily be prepared from isatins on a large scale, represent multifunctional cyclic diazo reagents for the diversity-oriented synthesis (DOS) of 3,3-disubstituted oxindoles through reagent-controlled catalytic diversification, including insertion, cyclopropanation, and cycloaddition reactions.11 Nevertheless, their use in catalytic enantioselective synthesis remained unexplored until 2013, possibly because of their lower reactivity compared with the corresponding acyclic diazo reagents.12 To address this problem, we investigated the use of soft acids to overcome the low reactivity of diazooxindoles (which are soft bases) and found that Hg(II) and Au(I) could catalyze the cyclopropanation of diazooxindole and styrene more 1446


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Accounts of Chemical Research a general catalyst for the full control of stereoselectivity in the cyclopropanation of trans- or cis-1,2-disubstituted and trisubstituted alkenes.13 Ding’s spiroketal bisphosphine-derived15 digold complex was identified as a powerful catalyst for highly stereoselective cyclopropanation with a broad range of alkenes, including monosubstituted, cis- and trans-1,2-disubstituted, 1,1disubstituted, and even trisubstituted alkenes (Scheme 8).13b

Scheme 9. DOS Based on Spirocyclopropyl Oxindoles

Scheme 8. Au(I)-Catalyzed Olefin Cyclopropanation

shown by the highly stereoselective [3 + 3] annulation with nitrones (Scheme 10). Both aryl and aliphatic nitrones worked Scheme 10. Enantioselective [3 + 3] Cycloaddition with Nitrones

3. NEW ACTIVATION MODELS 3.1. Activation of Spirocyclopropyl Oxindoles

The cycloaddition of doubly activated D−A cyclopropanes is a fruitful strategy for the enantioselective synthesis of cyclic compounds, but protocols were limited to 2-substituted cyclopropane-1,1-dicarboxylates or diketones.16 Spirocyclopropyl oxindoles are a type of monoactivated D−A cyclopropane. Whereas Carreira pioneered and demonstrated the usefulness of their cycloaddition with imines,2c,17 the low reactivity of these compounds hindered the development of new reactions and the corresponding catalytic enantioselective studies. We reported a strategy to activate spirocyclopropyl oxindoles by using an electronwithdrawing N-protecting group. This modification can effectively stabilize the negative charge developed at C3 of an oxindole through charge separation upon Lewis acid activation and allow the bidentate coordination of oxindoles to chiral metal complexes for better enantiofacial control (Scheme 9). By tuning of the electron-withdrawing N-protecting group, unprecedented reactions using spirocyclopropyl oxindoles as D−A cyclopropanes were realized.18 N-Diethoxyphosphoryl cyclopropanes, upon activation by a suitable Lewis acid, could undergo [3 + 3] cycloaddition with nitrone, cyclization with 1,4-dithiane-2,5-diol, and ring opening/cyclization with primary amine to give spirocyclic oxindoles 21a and 23 and 3,5-disubstituted pyrrolidinone 25. The N-benzoyl oxindole was superior in the [3 + 2] cycloaddition with aldehyde under Cu(OTf)2 catalysis (Scheme 9). These transformations did not take place when unprotected or N-methyl spirocyclopropyl oxindoles were used, demonstrating the unambiguous activation effects of electron-withdrawing N-protecting groups. The potency of this activation strategy in developing catalytic enantioselective reactions using spirocyclopropyl oxindoles is

well to give oxindole-based spirocyclic tetrahydro-1,2-oxazines with excellent dr and ee. Meanwhile, the kinetic resolution of cyclopropanes afforded chiral spirocyclopropyl oxindoles with good recovery and excellent ee. Remarkably, acetophenonederived ketonitrones are also viable substrates, allowing the highly stereoselective synthesis of spirooxindoles with adjacent quaternary and tetrasubstituted carbon stereocenters. Notably, enantioselective catalytic synthesis using ketonitrones was largely unexplored,19 and this approach represents the first example based on unactivated ketonitrones.18 3.2. Activation of Allyltrimethylsilane

Nontoxic allylsilanes are intensively used for allylation reactions to access valuable homoallylic alcohols or amines.20 In addition to strain-release-activated silane reagents,21 there are two major activation models for reaction development. One is acid activation of electrophiles, and the second is Lewis base activation of allylsilanes to react with electrophiles or to help the formation of reactive allylmetal species. Allyltrimethylsilane is the cheapest and most stable allylsilane, but its low activity prevents its wide application for ketone or ketimine allylation. By taking advantage of the excellent carbophilicity of Hg(II), we disclosed a conceptually different way to activate allyltrimethylsilane, using 1447


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3-allyl-3-hydroxyoxindoles. These products are very useful for the total synthesis of natural products such as CPC-1, donaxaridine, and dioxibrassinine.

Hg(II) to interact with the double bond of allyltrimethylsilane, leading to the generation of the more reactive nucleophile diallylmercury (Scheme 11).22 Inexpensive and easy-to-handle

3.3. Activation of Fluorinated Silyl Enol Ethers

Scheme 11. Activation of Allyltrimethylsilane by Hg(II)

The selective incorporation of a fluoroalkyl group into organic molecules is a routine strategy to modulate pharmaceutical properties.24 Therefore, oxindoles bearing a fluoroalkyl group at C3 are interesting targets for the development of medicinal agents and biological probes. However, whereas enantioselective trifluoromethylation has been intensively studied, methods for enantioselective mono- or difluoroalkylation remain undeveloped.25 With our efforts in selective fluoroalkylation, we wished to use readily available mono- and difluorinated silyl enol ethers26 to construct chiral carbons with an α-mono- or difluoromethylated ketone moiety as versatile synthetic handle because the corresponding α-fluorinated ketones are difficult to deprotonate under mild conditions. On the basis of our experience with the bifunctional tertiary-amine-catalyzed Strecker reaction using TMSCN,9a we found that amines could activate fluorinated silyl enol ethers (FSEEs) for enantioselective synthesis. Accordingly, a highly enantioselective quinine-derived urea-catalyzed Mukaiyama aldol reaction of isatins with difluoroenoxysilanes was developed, affording α-difluoroalkyl 3-hydroxyoxindoles with excellent ee (Scheme 13).27 The Lewis base activation of difluoroenoxysilanes Scheme 13. Mukaiyama-aldol Reaction of Difluoroenoxysilanes

Hg(ClO4)2·3H2O efficiently catalyzed the allylation of isatins or isatin ketimines with catalyst loadings as low as 0.1 mol %. Both cold-vapor atomic fluorescence spectroscopy and inductively coupled plasma mass spectrometry revealed that Hg contamination was low (ca. 3.0% Hg remained after single column chromatography). The use of 0.5−1 mol % Difluorophos/Hg(OTf)2 complex achieved high to excellent enantioselectivity in the allylation of unprotected isatins with allyltrimethylsilane (Scheme 12).23

by amines played an indispensable role, as shown by the control experiments indicated in Scheme 13. This method was then applied to the enantioselective synthesis of difluoro analogues of convolutamydine using a quinidinederived catalyst (Scheme 14).27 Because the bioactivities of convolutamydine A−E with different C3 side chains vary greatly, these difluoro analogues are interesting targets for medicinal research. The same strategy was applied to the Mukaiyama aldol reaction of isatins with monofluorinated silyl enol ethers for the highly stereoselective construction of hydroxyoxindoles bearing two adjacent tetrasubstituted carbon stereocenters (Scheme 15).28 Such bifunctional urea catalysts were also used to achieve a highly enantioselective Mannich reaction of cyclic N-sulfonyl ketimines and FSEEs.29 However, this catalysis failed to mediate the corresponding reaction of N-Boc isatin ketimines, which we found worked well under gold catalysis for the total synthesis of the difluoro analogue of the gastrin/CCK-B receptor antagonist AG-041R.30 In addition, cinchona-alkaloid-derived thiourea and squaramide both failed to achieve high enantioselectivity in the Michael reaction of isatylidene malononitrile (Scheme 16).

Scheme 12. Hg(II)-Catalyzed Asymmetric Allylation of Isatins

To further improve the enantioselectivity for the synthesis of unprotected 3-allyl-3-hydroxyoxindoles, we exploited a one-pot indirect yet convenient method using N-DMTr-protected isatins. Upon completion of the initial allylation, the reaction mixture was successively treated with acids to remove trimethylsilyl and 4,4′-dimethoxytrityl (DMTr) groups to give the unprotected 1448


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acetone (not anhydrous) as the solvent. Nevertheless, the benzyl substituent of the catalyst should be adjusted to achieve maximum enantioselectivity. Interestingly, both the secondary amine and phosphoramide moieties of the catalyst are indispensable for excellent enantioselectivity (Scheme 17). The corresponding tertiary amine

Scheme 14. Synthesis of Difluoro Analogues of Convolutamydines

Scheme 17. Superiority of Phosphoramide

Scheme 15. Reaction of FSEEs

catalyst afforded lower reactivity and enantioselectivity. When the phosphoramide was replaced with other H-bond donors, the enantioselectivity also decreased greatly. On the other hand, when the N−H bond of the phosphoramide was protected with a methyl group, the enantioselectivity was maintained, but the reactivity decreased slightly. This observation implied that the PO bond rather than N−H moiety of the phosphoramide played a key role in the reaction; the PO bond might cooperate with the secondary amine to activate silicon in a hexacoordinate fashion. These findings once again demonstrate the potential of phosphoramides in chiral catalyst development. Notably, significant fluorine effects were observed in these studies. Under bifunctional tertiary amine catalysis, both monoand difluorinated silyl enol ethers showed clearly higher reactivity than the nonfluorinated analogues (eqs 1 and 3 in Scheme 18),27,28

Scheme 16. Mukaiyama−Michael Addition

Scheme 18. Fluorine Effects

Since the use of tertiary amine activation of silyl enol ethers to construct all-carbon quaternary stereocenters might result in a sterically very congested transition state, secondary-amine-based catalysts were developed. 1,2-Diaminocyclohexane-derived bifunctional secondary amine−phosphoramide 44, readily available in two steps, could be used to construct quaternary oxindoles 45 featuring a C3 fluoroalkyl group with excellent stereoselectivity.31 Notably, both mono- and difluorinated silyl enol ethers worked well at room temperature using commercial

which is in contrast to the metal-catalyzed reactions.30 Fluorine substitution also had a beneficial influence on the stereoselectivity, 1449


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of spirocyclic oxindole−indolines (Scheme 20).36 This sequence nicely combined Pd-catalyzed hydrogenation of nitrobenzene,

which is significant in the case of difluoroenoxysilanes. In addition, it was found that fluorine substitution increased the reactivity of enol silyl ethers (eqs 1 and 3) but decreased the activity of the corresponding α-fluorinated ketones (eqs 2 and 4); the difluoromethyl phenyl ketone cannot be deprotonatively activated by tertiary amines (eq 2). The reasons for this are not clear at the present stage, but it may be due to the formation of C−F···H−N interactions between FSEEs and catalysts.32

Scheme 20. Asymmetric Triple Sequential Catalysis

4. SEQUENTIAL TANDEM REACTIONS An attractive strategy to improve the efficiency of synthesizing complex 3,3-disubstituted oxindoles is to combine multicatalytic reactions into one pot to develop asymmetric tandem sequences. This manipulation can effectively reduce the use of resources such as chemicals, energy, time, and labor, alleviate yield losses during the isolation of intermediates, and suppress waste generation.33 Taking advantage of the versatility of chiral tertiary amine catalysis, we developed tandem sequences for the efficient synthesis of spirocyclic and quaternary oxindoles. On the basis of our previously developed highly enantioselective β-isocupreidine-catalyzed Morita−Baylis−Hillman (MBH) reaction of isatins and acrolein,34 we exploited a novel MBH/bromination/annulation sequence consisting of three intermolecular reactions.35 This one-pot tandem reaction was initiated by the tertiary-amine-catalyzed MBH reaction, followed by bromination using HBr to afford oxindole-based tetrasubstituted alkenes II, which underwent a highly stereoselective [3 + 2] annulation with various activated ketones to furnish bis(spiro)oxindoles and spirocyclic oxindoles with adjacent quaternary/tetrasubstituted carbon stereocenters (Scheme 19).

Brønsted acid-mediated ketimine formation, and bifunctional tertiary-amine-catalyzed asymmetric 6π electrocyclization in one pot. The synthetic efficiency was greatly improved because the one-pot operation avoided the racemic cyclization of malonate− anilines 63 in the purification by column chromatography and severe yield losses associated with the purification of 63 and malonate−ketimines 64. The use of only 4 mol % TsOH to promote ketimine formation suppressed the background 6π electrocyclization and had minimum negative influence on the bifunctional tertiary-amine-mediated enantioselective reaction. This approach was recently utilized to develop a highly enantioselective one-pot Strecker reaction of fluoroalkyl ketones, anilines, and TMSCN.37 Because of the superiority of cationic Au(I) catalysis in olefin cyclopropanation of diazooxindoles,13b we exploited an unexplored sequential Au(I)/chiral tertiary amine catalysis as an attractive approach to develop diversity-oriented asymmetric tandem reactions, allowing the facile generation of scaffold diversity from diazooxindoles (Schemes 21 and 22).8d,38 Cationic Au(I) catalysis is known to be incompatible with tertiary amine catalysts; however, the success of these tandem reactions, resulting from the high activity of cationic Au(I) catalysis, allowed the use of only 1.0 mol % gold complex to realize these transformations of diazooxindoles. The remaining gold catalyst has little influence on the performance of the chiral tertiary amines, which are used at 10 mol %.8d For example, the merging of Au-catalyzed C−H functionalization with bifunctional-phosphoramide-catalyzed Michael addition efficiently furnished 3-aryl quaternary oxindoles with excellent enantioselectivity from diazooxindoles, weakly nucleophilic anisole or 3,4-dimethylthiophene, and nitroenynes.8d This sequence could be modularly tuned for the synthesis of 3,3-disubstituted oxindoles by varying the nucleophile used for functionalization of the diazooxindole or the electrophile used for the elaboration of the 3-substituted oxindole, as exemplified by the O−H insertion/Michael addition, C−H functionalization/amination, and O−H insertion/amination sequences (Scheme 21). In these protocols, the Au-catalyzed reaction affords the 3-substituted oxindole as the nucleophile, while the

Scheme 19. Asymmetric Triple Sequence

Trifluoropyruvates worked well in the [3 + 2] cycloaddition to provide trifluoromethylated spirocyclic oxindoles but could not be incorporated into the triple sequence. A rare example of asymmetric triple sequential catalysis was developed that allowed the highly enantioselective construction 1450


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potential in furnishing fully substituted carbon stereocenters remains unexplored. Helpfully, the high reactivities of isatins and isatin ketimines allow the potential of these difficult reactions to be investigated. For example, two reactions that we developed, namely, the MBH reaction of isatin and acrolein34 and the 6π electrocyclization of isatin ketimines,36 represent the first use of such reactions for enantioselective catalytic synthesis of tertiary alcohols and α-tertiary amines. We further developed two strategies for the construction of fully substituted carbon stereocenters. The Cu-catalyzed alkyne−azide cycloaddition (CuAAC) reaction has been applied in many areas of research; however, asymmetric studies in this area remain undeveloped.39 We considered a strategy to develop enantioselective CuAAC, namely, desymmetrization of prochiral diynes (Scheme 23).40 A highly

Scheme 21. Asymmetric Au(I)/Tertiary Amine Catalysis

Scheme 23. Asymmetric CuAAC Reactions

a

Michael addition using phosphoramide catalyst 3c; amination reaction of 3-aryl- or 3-ethoxyoxindole using 8a or quinine 2,5diphenyl-4,6-pyrimidinediyl diether as the catalyst, respectively.

chiral tertiary amine acts as a Brønsted base to deprotonatively activate the nucleophilic reaction partner of the Michael addition or amination reaction. Alternatively, integration of Au-catalyzed enone formation with tertiary-amine-mediated enantioselective cyanosilylation of ketones enabled a highly enantioselective synthesis of chiral 3-alkenyloxindoles from diazooxindoles, 2,5-disubstituted furans, and TMSCN (Scheme 22).38 Distinct from the above sequences, the Au-catalyzed reaction affords a 3-alkenyloxindole-based enone as the electrophile, while the tertiary amine functions as a Lewis base to activate TMSCN. enantioselective desymmetric CuAAC of oxindole-based 1,6heptadiynes was developed, furnishing quaternary oxindoles bearing a 1,2,3-triazole-containing moiety with 84−98% ee. This research also revealed that suppressing achiral diazole formation while achieving excellent enantioselectivity was very difficult, although we were fortunate to identify 2,6-hexadione as a solvent that could solve this problem in this case. The one-pot Strecker reaction of ketimines formed in situ from achiral ketones is an attractive strategy to improve the efficiency of accessing Cα-tetrasubstituted α-aminonitriles, which are valuable precursors of amino acids and diamines.41 However, successful precedents are rare because the conditions for ketimine formation are usually incompatible with the enantioselective catalytic cyanation reaction. We exploited a tandem aza-Wittig/ Strecker reaction of isatins, iminophosphorane, and TMSCN (Scheme 24).42 A cinchonidine-derived thiourea catalyzed the Strecker reaction of N-Boc isatin ketimines well, affording the desired adducts with high to excellent ee values. The corresponding oxindole-based α-aminonitriles were applied to the total synthesis of spirohydantoin, with potential use in suppressing pain.

Scheme 22. Au(I)/Tertiary Amine Nucleophilic Catalysis

6. CONCLUSIONS This Account outlines our results on the design, development, and applications of synthetic methodologies for the catalytic enantioselective construction of 3,3-disubstituted oxindoles. We have developed a variety of efficient protocols based on six

5. OTHERS Because of the difficulties in preparing tetrasubstituted and quaternary carbon stereocenters,4,5 although some reactions have been used to synthesize chiral tertiary carbons, their 1451


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Accounts of Chemical Research Scheme 24. One-Pot Strecker Reaction

guidance of Prof. Jian Zhou. Currently he is doing postdoctoral research with Prof. Paolo Melchiorre. Feng Zhou was born in Dezhou, P. R. China. He graduated from Sichuan Normal University in 2009, obtained his Ph.D. from ECNU in 2014 under the guidance of Prof. Jian Zhou, and became an associate professor at ECNU. He is interested in asymmetric synthesis using CO2 as a C1 synthon. Jian Zhou obtained his Ph.D. in 2004 from Shanghai Institute of Organic Chemistry 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 ECNU as a professor at the end of 2008. His research interests focus on the efficient and economical construction of tetrasubstituted or quaternary carbon stereocenters. He is now a member of the advisory boards of Acta Chimica Sinica, Organic & Biomolecular Chemistry, and Current Organocatalysis.

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ACKNOWLEDGMENTS The financial support from the National Natural Science Foundation of China (21725203) is appreciated.

approaches classified by the oxindole synthons involved, allowing facile access to oxindole derivatives with broad structural diversity. Through these studies, we have developed synthetic methodologies with a number of potential applications. The success of bifunctional phosphoramide−amine catalysts in Michael addition indicates that phosphoramides (phosphinamides) have some advantages over other H-bond donors, which is significant for the design of phosphoramide-based chiral bifunctional catalysts or ligands. The superiority of Au(I) in functionalization of diazooxindoles suggests that Au(I) catalysis is helpful for the development of enantioselective reactions involving diazo reagents that are unattainable using other metals.43 The observed ligand acceleration effect of Hg(II) will promote the future application of inexpensive mercury salts: they exhibit excellent performance in some transformations,44 but chiral mercury catalysis remains largely unexplored. The activation of spirocyclopropyl oxindoles by electron-withdrawing N-protecting groups opens a new pathway for the enantioselective synthesis of 3,3-disubstituted oxindoles. The Lewis base activation of FSEEs provides a useful method for enantioselective mono- or difluoroalkylation. Our new tandem sequences are suitable for one-pot complexity-generating syntheses from easily available starting materials. The desymmetrization of diynes has already emerged as a promising strategy to develop enantioselective CuAAC.39 We hope that this Account will bring to the attention of synthetic chemists these new catalysts, activation models, and methodologies. In the future, endeavors to extend the utilization of these synthetic methodologies to the valueadded synthesis of chiral scaffolds other than 3,3-disubstituted oxindoles will be the major focus of our research program.

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REFERENCES

(1) Sharma, I.; Tan, D. S. Drug discovery: Diversifying Complexity. Nat. Chem. 2013, 5, 157−158. (2) (a) Galliford, C. V.; Scheidt, K. A. Pyrrolidinyl-Spirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents. Angew. Chem., Int. Ed. 2007, 46, 8748−8758. (b) Lin, H.; Danishefsky, S. J. Gelsemine: A Thought-Provoking Target for Total Synthesis. Angew. Chem., Int. Ed. 2003, 42, 36−51. (c) Marti, C.; Carreira, E. M. Construction of Spiro[pyrrolidine-3,3′-oxindoles]Recent Applications to the Synthesis of Oxindole Alkaloids. Eur. J. Org. Chem. 2003, 2003, 2209−2219. (d) Trost, B. M.; Brennan, M. K. Asymmetric Syntheses of Oxindole and Indole Spirocyclic Alkaloid Natural Products. Synthesis 2009, 2009, 3003−3025. (e) Peddibhotla, S. 3-Substituted-3-Hydroxy-2-Oxindole, an Emerging New Scaffold for Drug Discovery with Potential Anti-Cancer and other Biological Activities. Curr. Bioact. Compd. 2009, 5, 20−38. (3) (a) Zhou, F.; Liu, Y.-L.; Zhou, J. Catalytic Asymmetric Synthesis of Oxindoles Bearing a Tetrasubstituted Stereocenter at the C-3 Position. Adv. Synth. Catal. 2010, 352, 1381−1407. (b) Shen, K.; Liu, X.; Lin, L.; Feng, X. Recent Progress in Enantioselective Synthesis of C3functionalized Oxindoles: Rare Earth Metals Take Action. Chem. Sci. 2012, 3, 327−334. (c) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740−751. (d) Dalpozzo, R. Recent Catalytic Asymmetric Syntheses of 3,3-Disubstituted Indolin-2-ones and 2,2-Disubstituted Indolin-3-ones. Adv. Synth. Catal. 2017, 359, 1772−1810. (e) Dalpozzo, R. Catalytic Asymmetric Synthesis of Heterosubstituted Oxindoles. Org. Chem. Front. 2017, 4, 2063−2078. (4) (a) 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. (b) Yu, J.S.; Huang, H.-M.; Ding, P.-G.; Hu, X.-S.; Zhou, F.; Zhou, J. Catalytic Enantioselective Construction of Sulfur-Containing Tetrasubstituted Carbon Stereocenters. ACS Catal. 2016, 6, 5319−5344. (5) (a) Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Natural Products as Inspiration for the Development of Asymmetric Catalysis. Nature 2008, 455, 323−332. (b) Quasdorf, K. W.; Overman, L. E. Catalytic Enantioselective Synthesis of Quaternary Carbon Stereocentres. Nature 2014, 516, 181−191. (c) Zeng, X.-P.; Cao, Z.-Y.; Wang, Y.-H.; Zhou, F.; Zhou, J. Catalytic Enantioselective Desymmetrization Reactions to AllCarbon Quaternary Stereocenters. Chem. Rev. 2016, 116, 7330−7396. (6) (a) Ohmatsu, K.; Ando, Y.; Ooi, T. Asymmetric Substitution at the Tetrasubstituted Chiral Carbon: Catalytic Ring-Opening Alkylation of Racemic 2,2-Disubstituted Aziridines with 3-Substituted Oxindoles. J.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhong-Yan Cao: 0000-0001-6669-8462 Feng Zhou: 0000-0002-6729-1311 Jian Zhou: 0000-0003-0679-6735 Notes

The authors declare no competing financial interest. Biographies Zhong-Yan Cao was born in Bozhou, P. R. China, and received his Ph.D. from East China Normal University (ECNU) in 2015 under the 1452


Article

Accounts of Chemical Research Am. Chem. Soc. 2013, 135, 18706−18709. (b) Zheng, J.-F.; Lin, L.; Dai, L.; Tang, Q.; Liu, X.-H.; Feng, X.-M. Nickel-Catalyzed Conjugate Addition of Silyl Ketene Imines to In Situ Generated Indol-2-ones: Highly Enantioselective Construction of Vicinal All-Carbon Quaternary Stereocenters. Angew. Chem., Int. Ed. 2017, 56, 13107−13111. (c) Shirai, T.; Ito, H.; Yamamoto, Y. Cationic Ir/Me-BIPAM-Catalyzed Asymmetric Intramolecular Direct Hydroarylation of a-Ketoamides. Angew. Chem., Int. Ed. 2014, 53, 2658−2661. (d) Frost, J. R.; Huber, S. M.; Breitenlechner, S.; Bannwarth, C.; Bach, T. Enantiotopos-Selective C− H Oxygenation Catalyzed by a Supramolecular Ruthenium Complex. Angew. Chem., Int. Ed. 2015, 54, 691−695. (e) Xiang, B.; Belyk, K. M.; Reamer, R. A.; Yasuda, N. Discovery and Application of Doubly Quaternized Cinchona-Alkaloid-Based Phase-Transfer Catalysts. Angew. Chem., Int. Ed. 2014, 53, 8375−8378. (f) Bai, X.; Zeng, G.; Shao, T.; Jiang, Z. Catalytic Enantioselective γ-Selective Additions of 2Allylazaarenes to Activated Ketones. Angew. Chem., Int. Ed. 2017, 56, 3684−3688. (7) (a) Takemoto, Y. Recognition and Activation by Ureas and Thioureas: Stereoselective Reactions Using Ureas and Thioureas as Hydrogen-Bonding Donors. Org. Biomol. Chem. 2005, 3, 4299−4306. (b) Connon, S. J. Asymmetric Catalysis with Bifunctional Cinchona Alkaloid-Based Urea and Thiourea Organocatalysts. Chem. Commun. 2008, 2499−2510. (c) Liu, X.; Lin, L.; Feng, X. Amide-Based Bifunctional Organocatalysts in Asymmetric Reactions. Chem. Commun. 2009, 6145−6158. (d) Wei, Y.; Shi, M. Multifunctional Chiral Phosphine Organocatalysts in Catalytic Asymmetric Morita−Baylis− Hillman and Related Reactions. Acc. Chem. Res. 2010, 43, 1005−1018. (e) Yu, J.-S.; Zhou, J. Asymmetric Multifunctional Catalysis. In Multicatalyst System in Asymmetric Catalysis; Zhou, J., Ed.; John Wiley & Sons: Hoboken, NJ, 2015; Chapter 3, pp 159−289. (8) (a) Liu, Y.-L.; Zhou, F.; Cao, J.-J.; Ji, C.-B.; Ding, M.; Zhou, J. A Facile Method for the Synthesis of Oxindole Based Quaternary. eAminonitriles via the Strecker Reaction. Org. Biomol. Chem. 2010, 8, 3847−3850. (b) Ding, M.; Zhou, F.; Liu, Y.-L.; Wang, C.-H.; Zhao, X.L.; Zhou, J. Cinchona Alkaloid-Based Phosphoramide Catalyzed Highly Enantioselective Michael Addition of Unprotected 3-Substituted Oxindoles to Nitroolefins. Chem. Sci. 2011, 2, 2035−2039. (c) Gao, W.-M.; Yu, J.-S.; Zhao, Y.-L.; Liu, Y.-L.; Zhou, F.; Wu, H.-H.; Zhou, J. Highly Enantioselective Michael Addition of 3-Arylthio- and 3Alkylthiooxindoles to Nitroolefins Catalyzed by a Simple Cinchona Alkaloid Derived Phosphoramide. Chem. Commun. 2014, 50, 15179− 15182. (d) Cao, Z.-Y.; Zhao, Y.-L.; Zhou, J. Sequential Au(I)/Chiral Tertiary Amine Catalysis: a Tandem C-H Functionalization of Anisoles or a Thiophene/Asymmetric Michael Addition Sequence to Quaternary Oxindoles. Chem. Commun. 2016, 52, 2537−2540. (e) Ding, M.; Zhou, F.; Qian, Z.-Q.; Zhou, J. Organocatalytic Michael Addition of Unprotected 3-Substituted Oxindoles to Nitroolefins. Org. Biomol. Chem. 2010, 8, 2912−2914. (9) (a) Liu, Y.-L.; Zhou, J. Catalytic Asymmetric Strecker Reaction: Bifunctional Chiral Tertiary Amine/Hydrogen-Bond Donor Catalysis Joins the Field. Synthesis 2015, 47, 1210−1226. (b) Tian, S.-K.; Deng, L. A Highly Enantioselective Chiral Lewis Base-Catalyzed Asymmetric Cyanation of Ketones. J. Am. Chem. Soc. 2001, 123, 6195−6196. (10) (a) Chauhan, P.; Chimni, S. S. Organocatalytic Asymmetric Synthesis of 3-Amino-2-Oxindole Derivatives Bearing a TetraSubstituted Stereocenter. Tetrahedron: Asymmetry 2013, 24, 343−356. (b) Yu, J.-S.; Zhou, F.; Liu, Y.-L.; Zhou, J. A Journey in the Catalytic Synthesis of 3-Substituted 3-Aminooxindoles. Synlett 2015, 26, 2491− 2504. (11) Cao, Z.-Y.; Wang, Y.-H.; Zeng, X.-P.; Zhou, J. Catalytic Asymmetric Synthesis of 3,3-Disubstituted Oxindoles: Diazooxindole Joins the Field. Tetrahedron Lett. 2014, 55, 2571−2584. (12) Chen, S.; Ma, J.; Wang, J. Palladium-Catalyzed Cyclopropanation of Electron-Deficient Olefins with Aryldiazocarbonyl Compounds. Tetrahedron Lett. 2008, 49, 6781−6783. (13) (a) Cao, Z.-Y.; Zhou, F.; Yu, Y.-H.; Zhou, J. A Highly Diastereoand Enantioselective Hg(II)-Catalyzed Cyclopropanation of Diazooxindoles and Alkenes. Org. Lett. 2013, 15, 42−45. (b) Cao, Z.-Y.; Wang, X.; Tan, C.; Zhao, X.-L.; Zhou, J.; Ding, K. Highly Stereoselective Olefin

Cyclopropanation of Diazooxindoles Catalyzed by a C2-Symmetric Spiroketal Bisphosphine/Au(I) Complex. J. Am. Chem. Soc. 2013, 135, 8197−8200. (14) Cao, Z.-Y.; Zhou, J. Catalytic Asymmetric Synthesis of Polysubstituted Spirocyclopropyl Oxindoles: Organocatalysis versus Transition Metal Catalysis. Org. Chem. Front. 2015, 2, 849−858. (15) Wang, X.; Han, Z.; Wang, Z.; Ding, K. Catalytic Asymmetric Synthesis of Aromatic Spiroketals by SpinPhox/Iridium(I)-Catalyzed Hydrogenation and Spiroketalization of sis’-Bis(2-hydroxyarylidene) Ketones. Angew. Chem., Int. Ed. 2012, 51, 936−940. (16) (a) Grover, H. K.; Emmett, M. R.; Kerr, M. A. Carbocycles from Donor-Acceptor Cyclopropanes. Org. Biomol. Chem. 2015, 13, 655− 671. (b) Schneider, T. F.; Kaschel, J.; Werz, D. B. A New Golden Age for Donor-Acceptor Cyclopropanes. Angew. Chem., Int. Ed. 2014, 53, 5504− 5523. (17) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M. Facile, Novel Methodology for the Synthesis of Spiro[pyrrolidin-3,3′oxindoles]: Catalyzed Ring Expansion Reactions of Cyclopropanes by Aldimines. Angew. Chem., Int. Ed. 1999, 38, 3186−3189. (18) Xu, P.-W.; Liu, J.-K.; Shen, L.; Cao, Z.-Y.; Zhao, X.-L.; Yan, J.; Zhou, J. Diastereo- and Enantioselective [3 + 3] Cycloaddition of Spirocyclopropyl Oxindoles Using Both Aldonitrones and Ketonitrones. Nat. Commun. 2017, 8, 1619. (19) (a) Shi, W.-M.; Ma, X.-P.; Su, G.-F.; Mo, D.-L. New Developments of Ketonitrones in Organic Synthesis. Org. Chem. Front. 2016, 3, 116−130. (b) Liu, R.-R.; Ye, S.-C.; Lu, C.-J.; Zhuang, G.L.; Gao, J.-R.; Jia, Y.-X. Dual Catalysis for the Redox Annulation of Nitroalkynes with Indoles: Enantioselective Construction of Indolin-3ones Bearing Quaternary Stereocenters. Angew. Chem., Int. Ed. 2015, 54, 11205−11208. (20) Hosomi, A. Characteristics in the Reactions of Allylsilanes and Their Applications to Versatile Synthetic Equivalents. Acc. Chem. Res. 1988, 21, 200−206. (21) Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L. Strained Silacycles in Organic Synthesis: A New Reagent for the Enantioselective Allylation of Aldehydes. J. Am. Chem. Soc. 2002, 124, 7920−7921. (22) Cao, Z.-Y.; Zhang, Y.; Ji, C.-B.; Zhou, J. A Hg(ClO4)2·3H2O Catalyzed Sakurai-Hosomi Allylation of Isatins and Isatin Ketoimines Using Allyltrimethylsilane. Org. Lett. 2011, 13, 6398−6401. (23) Cao, Z.-Y.; Jiang, J.-S.; Zhou, J. A Highly Enantioselective Hg(II)Catalyzed Sakurai-Hosomi Reaction of Isatins with Allyltrimethylsilanes. Org. Biomol. Chem. 2016, 14, 5500−5504. (24) (a) Ma, J.-A.; Cahard, D. Asymmetric Fluorination, Trifluoromethylation, and Perfluoroalkylation Reactions. Chem. Rev. 2004, 104, 6119−6146. (b) Zhang, C.-P.; Chen, Q.-Y.; Guo, Y.; Xiao, J.-C.; Gu, Y.C. Progress in Fluoroalkylation of Organic Compounds via Sulfinatodehalogenation Initiation System. Chem. Soc. Rev. 2012, 41, 4536−4559. (c) Ni, C.; Hu, J. The Unique Fluorine Effects in Organic Reactions: Recent Facts and Insights in Fluoroalkylations. Chem. Soc. Rev. 2016, 45, 5441−5454. (25) (a) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D. Advances in Catalytic Enantioselective Fluorination, Mono-, Di-, and Trifluoromethylation, and Trifluoromethylthiolation Reactions. Chem. Rev. 2015, 115, 826−870. (b) Liu, Y.-L.; Yu, J.-S.; Zhou, J. Catalytic Asymmetric Construction of Stereogenic Carbon Centers that Feature a gemDifluoroalkyl Group. Asian J. Org. Chem. 2013, 2, 194−206. (c) Valero, G.; Companyó, X.; Rios, R. Catalytic Asymmetric Organocatalytic Synthesis of Fluorinated Molecules. Chem. - Eur. J. 2011, 17, 2018− 2037. (26) Decostanzi, M.; Campagne, J.-M.; Leclerc, E. Fluorinated Enol Ethers: Their Synthesis and Reactivity. Org. Biomol. Chem. 2015, 13, 7351−7380. (27) Liu, Y.-L.; Zhou, J. Organocatalytic Asymmetric Synthesis of 3Difluoroalkyl 3-Hydroxyoxindoles. Chem. Commun. 2012, 48, 1919− 1921. (28) Liu, Y.-L.; Liao, F.-M.; Niu, Y.-F.; Zhao, X.-L.; Zhou, J. Highly Stereoselective Construction of Adjacent Tetrasubstituted Carbon Stereogenic Centres via an Organocatalytic Mukaiyama-aldol Reaction 1453


Article

Accounts of Chemical Research of Monofluorinated Silyl Enol Ethers to Isatins. Org. Chem. Front. 2014, 1, 742−747. (29) Yu, J.-S.; Zhou, J. Organocatalytic Enantioselective MukaiyamaMannich Reaction of Fluorinated Enol Silyl Ethers and Cyclic Nsulfonyl Ketimines. Org. Chem. Front. 2016, 3, 298−303. (30) Yu, J.-S.; Zhou, J. A Highly Efficient Mukaiyama-Mannich Reaction of N-Boc Isatin Ketimines and Other Active Cyclic Ketimines Using Difluoroenol Silyl Ethers Catalyzed by Ph3PAuOTf. Org. Biomol. Chem. 2015, 13, 10968−10972. (31) Yu, J.-S.; Liao, F.-M.; Gao, W.-M.; Liao, K.; Zuo, R.-L.; Zhou, J. Michael Addition Catalyzed by Chiral Secondary Amine Phosphoramide Using Fluorinated Silyl Enol Ethers: Formation of Quaternary Carbon Stereocenters. Angew. Chem., Int. Ed. 2015, 54, 7381−7385. (32) Yu, J.-S.; Liu, Y.-L.; Tang, J.; Wang, X.; Zhou, J. Highly Efficient “On Water” Catalyst-Free Nucleophilic Addition Reactions Using Difluoroenoxysilanes: Dramatic Fluorine Effects. Angew. Chem., Int. Ed. 2014, 53, 9512−9516. (33) Zhou, J. Recent Advances in Multicatalyst Promoted Asymmetric Tandem Reactions. Chem. - Asian J. 2010, 5, 422−434. (34) Liu, Y.-L.; Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.; Wang, C.; Zhou, J. Organocatalytic Asymmetric Synthesis of Substituted 3Hydroxy-2-oxindoles via Morita−Baylis−Hillman Reaction. J. Am. Chem. Soc. 2010, 132, 15176−15178. (35) Liu, Y.-L.; Wang, X.; Zhao, Y.-L.; Zhu, F.; Zeng, X.-P.; Chen, L.; Wang, C.-H.; Zhao, X.-L.; Zhou, J. One-Pot Tandem Approach to Spirocyclic Oxindoles Featuring Adjacent Spiro-Stereocenters. Angew. Chem., Int. Ed. 2013, 52, 13735−13739. (36) Yin, X.-P.; Zeng, X.-P.; Liu, Y.-L.; Liao, F.-M.; Yu, J.-S.; Zhou, F.; Zhou, J. Asymmetric Triple Relay Catalysis: Enantioselective Synthesis of Spirocyclic Indolines through a One-Pot Process Featuring an Asymmetric 6π Electrocyclization. Angew. Chem., Int. Ed. 2014, 53, 13740−13745. (37) Liu, Y.-L.; Yin, X.-P.; Zhou, J. Internally Reuse Waste: Catalytic Asymmetric One-Pot Strecker Reaction of Fluoroalkyl Ketones, Anilines and TMSCN by Sequential Catalysis. Chin. J. Chem. 2018, 36, 321−328. (38) Zhao, Y.-L.; Cao, Z.-Y.; Zeng, X.-P.; Shi, J.-M.; Yu, Y.-H.; Zhou, J. Asymmetric Sequential Au(I)/Chiral Tertiary Amine Catalysis: an Enone-Formation/Cyanosilylation Sequence to Synthesize Optically Active 3-Alkenyloxindoles from Diazooxindoles. Chem. Commun. 2016, 52, 3943−3946. (39) Brittain, W. D. G.; Buckley, B. R.; Fossey, J. S. Asymmetric Copper-Catalyzed Azide-Alkyne Cycloadditions. ACS Catal. 2016, 6, 3629−3636. (40) Zhou, F.; Tan, C.; Tang, J.; Zhang, Y.-Y.; Gao, W.-M.; Wu, H.-H.; Yu, Y.-H.; Zhou, J. Asymmetric Copper(I)-Catalyzed Azide-Alkyne Cycloaddition to Quaternary Oxindoles. J. Am. Chem. Soc. 2013, 135, 10994−10997. (41) Wang, J.; Liu, X.; Feng, X. Asymmetric Strecker Reactions. Chem. Rev. 2011, 111, 6947−6983. (42) Liu, Y.-L.; Zhou, J. Organocatalytic Asymmetric Cyanation of Isatin Derived N-Boc Ketoimines. Chem. Commun. 2013, 49, 4421− 4423. (43) Liao, F.-M.; Cao, Z.-Y.; Yu, J.-S.; Zhou, J. Highly Stereoselective Gold-Catalyzed Coupling of Diazo Reagents and Fluorinated Enol Silyl Ethers to Tetrasubstituted Alkenes. Angew. Chem., Int. Ed. 2017, 56, 2459−2463. (44) Nishizawa, M.; Imagawa, H.; Yamamoto, H. A New Catalyst for Organic Synthesis: Mercuric Triflate. Org. Biomol. Chem. 2010, 8, 511− 521.

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