Enantioselective merged gold/organocatalysis

Abstract

Gold complexes, because of their unique carbophilic nature, have evolved as efficient catalysts for catalyzing various functionalization reactions of C–C multiple bonds. However, the realization of enantioselective transformations via gold catalysis remains challenging due to the geometrical constraints and coordination behaviors of gold complexes. In this context, merged gold/organocatalysis has emerged as one of the intriguing strategies to achieve enantioselective transformations which could not be possible by using a single catalytic system. Historically, in 2009, this field started with the merging of gold with axially chiral Brønsted acids and chiral amines to achieve enantioselective transformations. Since then, based on the unique reactivity profiles offered by each catalyst, several reports utilizing gold in conjunction with various chiral organocatalysts such as amines, Brønsted acids, N-heterocyclic carbenes, hydrogen-bonding and phosphine catalysts have been documented in the literature. This article demonstrates an up-to-date development in this field, especially focusing on the mechanistic interplay of gold catalysts with chiral organocatalysts.

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Chayanika Pegu

Chayanika Pegu was born in 1998 in Jonai (Assam), India. She received her MSc degree (2022) in Organic Chemistry from Tezpur University, Assam. In January 2023, she started her PhD at IISER Bhopal under the supervision of Dr Nitin T. Patil, where she is focusing on the development of new strategies based on gold catalysis.

Bidisha Paroi

Bidisha Paroi is currently pursuing her doctoral studies under the supervision of Dr Nitin T. Patil. She was born in 1993 in Kolkata (West Bengal), India. She received her Master's degree (2016) in organic chemistry from the University of Calcutta. Her research interest includes development of new synthetic methodologies based on Au(I)/Au(III) catalysis.

Nitin T. Patil

Nitin T. Patil was born in Jalgaon (Maharashtra), India, in 1975. He completed his doctoral studies at the University of Pune in 2002 under the supervision of Prof. Dilip D. Dhavale. Subsequently, he joined Prof. Christoph Schneider's group as a postdoctoral fellow at the University of Goettingen, Germany. In November 2002, he moved to Tohoku University, Japan, as a JSPS postdoctoral fellow to work with Prof. Yoshinori Yamamoto, where later on he was appointed as an Assistant Professor. In June 2006, he joined Prof. K. C. Nicolaou's laboratory at ICES, Singapore, and later moved to The Scripps Research Institute, USA. He began his independent career in September 2008 at CSIR-IICT, Hyderabad, and subsequently moved to CSIR-NCL, Pune, in August 2013. In July 2017, he joined IISER Bhopal as an Associate Professor and he attained the rank of Professor in October 2023. His research group focuses on understanding the unique reactivities of gold complexes and their utilization in developing organic transformations.

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1. General introduction

The development of asymmetric catalysis to synthesize highly enantiopure compounds has been regarded as one of the sought-after research topics.¹ Substantial progress in the field of asymmetric synthesis has been accomplished by relying on transition metal catalysis² and organocatalysis.³ Besides these conventional approaches, the concept of dual catalysis has garnered remarkable attention as an innovative tool for developing a diverse array of enantioselective transformations.⁴ The foundation for dual catalysis has been laid based on the utilization of two catalysts in one-pot, working in synchronization to enable a single synthetic transformation. In this regard, several dual catalytic systems merging metal–metal,⁵ organo–organo⁶ and metal–organocatalysts⁷ have been devised to achieve unique molecular scaffolds with excellent levels of chemo-, regio- and stereoselectivity. Among these merged catalytic systems, the strategy involving the combination of transition metals and chiral organocatalysts has been enormously applied in the realm of asymmetric organic synthesis.⁷

Gold catalysts have gained considerable interest owing to their unique π affinity for carbon–carbon multiple bonds. Leveraging the carbophilic mode of activation, a variety of reactions have been achieved under gold catalysis.⁸ Primarily, these transformations are based on the π–complexation of gold to the C–C multiple bonds which then triggers the nucleophilic attack followed by protodeauration. Capitalizing on this carbophilic character of gold, significant efforts have been directed towards the advancement of enantioselective gold catalysis (Scheme 1a).⁹ However, most of the developed strategies rely on the employment of chiral Au(I) complexes. The main challenge encountered in achieving enantiocontrol originates from the remote placement of the chiral ligand from the reaction site at the Au(I) center. As a result, imparting high enantioinduction to Au(I) catalysis usually requires (a) bulky dinuclear species;^9j (b) mononuclear gold(I) complexes having bulky chiral ligands or helical ligands^9f,9k and (c) chiral counterions.¹⁰ Additionally, other enantioinducting modes involving chiral Au(III) catalysis^9k and Au(I)/Au(III) redox catalysis^9k,11 have been developed to realize asymmetric transformations. In the ongoing pursuit of advancing asymmetric gold catalysis, the scientific community has successfully utilized the well-established concept of metal-based dual catalysis (bimetallic and metal-organocatalysis) as a powerful tool for achieving numerous enantioselective reactions.

Scheme 1 (a) State of the art in enantioselective gold catalysis; (b) this review: enantioselective merged gold/organocatalysis; and (c) schematic representation of sequential, relay and cooperative modes of catalysis. ^† The catalytic sequence can be reversed.

The prospect of merging gold with organocatalysis has evolved as a promising strategy to induce enantioselectivity in gold-catalyzed asymmetric transformations (Scheme 1b). This is mainly because of the advantages, such as: (a) utilization of the complementary reactivities offered by gold and organocatalysts depending on the chemoselective activation of specific functional groups; (b) access to different reactivities and selectivities which are not possible to achieve by either of the catalysts alone. However, this strategy is associated with some challenges, such as: (a) catalyst inhibition due to undesired coordination between gold and organocatalysts; (b) synchronization between the two catalytic cycles to avoid mismatch in the individual kinetic rates of both cycles. In addition, another significant challenge lies in the identification of the reaction conditions essential for both catalysts to work in a synergistic fashion. Despite these difficulties, owing to the complementary reactivities of gold and organocatalysts, several enantioselective transformations have been reported over the years. The origin of this field can be traced back to the utilization of gold with chiral Brønsted acids and amine in the reports from the groups of Dixon,¹² Gong,¹³ Che,¹⁴ Krause and Alexakis¹⁵ in 2009. Following these reports, a diverse array of chiral organocatalysts including amine, Brønsted acid, N-heterocyclic carbene (NHC), hydrogen-bonding and phosphine catalysts have been successfully applied in combination with gold catalysts.

As a part of our continuous research interest in the field of gold catalysis, we endeavored to provide an authoritative review on merged gold/organocatalysis. Reviews addressing the advancements in this concept have already been summarized a long back.¹⁶ However, significant progress achieved in the subsequent period has prompted a need for an up-to-date compilation of the reports in this field. Herein, we report an overview focusing on the state of the art in the field of enantioselective merged gold/organocatalysis. It should be noted that the reports regarding the combination of gold catalysis with enzyme catalysis¹⁷ remains out of the scope of our discussion. For a better understanding of the operating catalytic modes, the transformations are discussed based on our previous proposition on sequential, relay and cooperative catalysis (Scheme 1c).¹⁸ This article has been categorized into five sections, according to the type of chiral organocatalysts employed, which are as follows:

(1) Enantioselective merged gold/amine catalysis.

2) Enantioselective merged gold/Brønsted acid catalysis.

(3) Enantioselective merged gold/NHC catalysis.

4) Enantioselective merged gold/H-bonding catalysis.

(5) Enantioselective merged gold/phosphine catalysis.

2.1. Enantioselective merged gold/amine catalysis

In 2009, Krause, Alexakis and co-workers reported the merging of gold catalysis with chiral amine catalysis to carry out sequential Michael addition and acetalization/cyclization (Scheme 2).¹⁵ At first, isovaleraldehyde 2b undergoes Michael addition with nitroenyne 2a in the presence of chiral pyrrolidine 2c to deliver aldehyde 2d with excellent diastereoselectivity (up to 97 : 3 dr for syn : anti) and enantioselectivity (up to >99% ee). After the completion of Michael addition, aldehyde 2d undergoes gold-catalyzed tandem acetalization/cyclization in the presence of alcohol to furnish tetrahydrofuranyl ether 2e (77–86% yield and up to 93 : 7 dr for cis/trans). Mechanistically, the cationic Au(I) complex would coordinate with the oxygen atom of aldehyde 2d (cf. 2f), thereby promoting the nucleophilic attack of an alcohol to form a hemiacetal intermediate 2g. A subsequent oxyauration (cf. 2h) generates a vinyl gold intermediate 2i, which upon protodeauration forms 2e. The authors mentioned that p-TsOH is required to prevent the quenching of the gold catalyst by amine 2c but using in excess (100 mol%) leads to epimerization of 2d giving an anti-adduct. Usage of p-TsOH in slight excess (25 mol%), relative to 10 mol% 2c, slows down the epimerization as compared to acetalization, providing the optimal result.

Scheme 2 Gold/chiral amine-catalyzed enantioselective Michael addition and tandem acetalization/cyclization. [*] dr value corresponds to the cis/trans relationship between the stereogenic centers labeled as (a) and (b).

In 2010, Jørgensen and co-workers demonstrated the carbocyclization of enals 3a with alkyne-tethered malononitrile 3b, with high enantioselectivity (ee up to 96%), by exploiting mutual cooperativity of Ph₃AuNTf₂ and chiral pyrrolidine amine 3j (Scheme 3).¹⁹ The proposed mechanism involves the initial activation of enal 3a by chiral pyrrolidine 3j to deliver the corresponding iminium ion 3d which then undergoes a nucleophilic attack from 3b, forming 3e. Subsequently, the alkyne activation by gold in 3e initiates the nucleophilic attack from tethered enamine, leading to the 5-exo-dig cyclization. The generated vinyl gold intermediate 3g produces the iminium ion 3hvia protodeauration which then undergoes hydrolysis followed by isomerization to furnish α,β-unsaturated cyclopentene carbaldehyde 3c. This dual catalytic cascade protocol can be also achievable under Cu(I) and Cu(II) catalysis but such catalytic systems suffer from the disadvantages of requiring additional phosphine and an inert atmosphere, unlike gold catalysis.

Scheme 3 Gold/chiral amine-catalyzed enantioselective carbocyclization of α,β-unsaturated aldehydes with propargylated malononitrile.

In 2012, Dixon and co-workers documented a sequential catalysis protocol utilizing the combination of Takemoto's catalyst 4d and Echavarren's gold(I) catalyst.²⁰ A diastereo- and enantioselective synthesis of tetrahydropyridine derivatives 4cvia a nitro-Mannich/hydroamination reaction sequence between N-protected aldimines 4a and nitro-alkynes 4b has been achieved in 96% ee (Scheme 4a). At first, the nitro-Mannich reaction between 4a and 4b under chiral amine (4d) catalysis delivers chiral β-nitroamine 4e. In the subsequent reaction, Au(I) catalyzes the intramolecular hydroamination of 4e, resulting in 6-exo-dig cyclization (cf. 4f). The generated vinyl gold intermediate 4g on protodeauration followed by isomerization gives 4c. After the completion of the first reaction, DPP was added to prevent the quenching of the subsequent gold catalysis process.

Scheme 4 Gold/chiral amine-catalyzed enantioselective nitro-Mannich/hydroamination cascade reaction.

Later, in 2014, the same group utilized the above-mentioned sequential strategy involving a chiral amine 4d catalyzed asymmetric nitro-Mannich reaction followed by gold-catalyzed hydroamination to afford trisubstituted pyrrolidine derivatives 4k in 96% ee from N-Cbz protected aldimines 4i and nitro-allene 4j (Scheme 4b).²¹

In 2012, Bandini and co-workers developed a cooperative catalytic system by merging [JhonPhosAu(MeCN)]SbF₆ with chiral imidazolidinone 5c to perform enantioselective intramolecular α-allylic alkylation of enolizable aldehydes 5a with allyl alcohols (Scheme 5).²² In this reaction, five or six-membered cyclic aldehydes 5b are obtained in dr up to 99 : 1 E : Z (trans) with excellent enantioselectivities (up to 98% ee). The mechanism was proposed to initiate with the condensation between 5a and 5c in the presence of benzoic acid, generating chiral enamine 5d. For the gold-catalyzed nucleophilic allylic substitution process, a stepwise anti/anti S_N2′-mechanism was suggested by the authors. The activation of the C–C double bond (cf. 5e) by the gold complex facilitates the intramolecular nucleophilic attack from chiral enamine, favouring anti-carboauration (cf. 5f) over the sterically more hindered syn-carboauration (cf. A). Subsequently, the intermediate 5g undergoes anti-β-hydroxy elimination followed by hydrolysis of the resulting iminium ion 5h to generate 5b. The authors proposed that in the anti-β-hydroxy elimination step, a steric interaction between the methyl substituent of the Re-face of the iminium intermediate and the alkyl group (R) of secondary alcohol determines the E : Z ratio of the allylic double bond (compare intermediates B and C).

Scheme 5 Gold/chiral amine-catalyzed enantioselective intramolecular α-allylic alkylation of aldehydes.

Later, in 2013, Jiang, Liu and co-workers utilized the combination of the gold complex and chiral amine 6e to synthesize spiro[pyrrolidin-3,2′-oxindole] derivatives 6c in 56–91% yields with enantiomeric excess up to 97%. The protocol involves a chiral amine-catalyzed Mannich reaction and a subsequent gold-catalyzed intramolecular hydroamination reaction (Scheme 6a).²³ Under the catalysis of chiral Cinchona alkaloid 6e, oxindole imines 6a reacts with propargylated malononitrile 6b producing adduct 6f. Then, BF₃·OEt₂ was added to quench 6e prior to the introduction of gold catalysis. Subsequently, Au(I) activates the C–C triple bond in 6f towards the nucleophilic attack from secondary amine (cf. 6g). The resulting vinyl gold(I) species 6h on protodeauration affords exo product 6c.

Scheme 6 Gold/chiral amine-catalyzed enantioselective Mannich/hydroamination cascade reaction.

Along the same line, Vaselý and co-workers in 2021 employed the above-mentioned sequential catalytic system for the enantioselective synthesis of bispiro[oxindole-pyrrolidine-pyrazolones] 6l (Scheme 6b).²⁴ During the chiral amine 6k catalyzed Mannich reaction, the squaramide part of 6k activates the oxindole imines 6i through H-bonding with the carbamate group. In addition, the basic quinuclidine moiety of 6k increases the nucleophilic character of the enol form of the alkyne tethered pyrazolones 6j (cf. 6m). The observed enantioselectivity has been attributed to the sterically favourable nucleophilic attack from the activated enol on the Re-face of the imine in the H-bonded transition state. A subsequent gold-catalyzed hydroamination step leads to the construction of 6l in 99% ee.

Enders’ group, in 2014, employed a sequential catalytic system consisting of JohnPhosAuCl and chiral cinchona-alkaloid-derived primary amine 7d, for the dialkylation of pyrrole at C-2 and C-3 positions (Scheme 7).²⁵ Pyrroles 7a and enones 7b upon treatment with amine 7d followed by JhonPhosAuCl provide access to an enantiopure seven-membered ring containing 2,3-annulated pyrrole 7c (up to 94% ee). Mechanistically, the reaction initiates with condensation of 7b with amine 7d in the presence of TFA. The generated iminium ion then binds to 7avia H-bonding through trifluoroacetate from the quinuclidine backbone (cf. 7e). The nucleophilic attack from the C-2 position of pyrrole on the α,β-unsaturated iminium ion in the rigid H-bonded intermediate 7e was proposed to determine the enantioselectivity of the reaction. The ensuing enamine 7f hydrolyzes to form a ketone 7g. Next, 7g upon alkyne activation by gold undergoes a nucleophilic attack from the C-2 position of pyrrole, resulting in 6-endo-dig cyclization. The resulting non-aromatic spirocycle 7i then rapidly rearranges to a seven-membered cationic intermediate 7j, which after rearomatization followed by protodeauration delivers 7c in 70–99% yields.

Scheme 7 Merged gold/chiral amine-catalyzed enantioselective C–H functionalization of the C-2 and C-3 positions of pyrroles.

In the same year, by taking advantage of the mutual cooperativity of the gold(I) catalyst and Cinchona alkaloid-based amine 8d, Wu and co-workers reported the asymmetric synthesis of [6,5,6]-carbotricyclic compounds in excellent ee up to >99% and high dr up to >20 : 1 (Scheme 8).²⁶ The reaction proceeds with the condensation between alkynylenones 8a and amine 8d generating dienamine 8e, which then undergoes a formal Diels–Alder reaction with maleimide 8b to furnish enamine 8f. Next, intermediate 8f engages in an intramolecular carboannulation reaction under Au(I) catalysis (cf. 8g), forming a vinyl gold intermediate 8h. Subsequent hydrolysis and protodeauration of 8h leads to the generation of 8c.

Scheme 8 Gold/chiral amine-catalyzed enantioselective Diels–Alder/carboannulation cascade reaction.

Zhou and co-workers, in 2016, developed a sequential process consisting of Au(I)-catalyzed C–H functionlizaton²⁷ and a chiral tertiary amine-catalyzed Michael addition reaction (Scheme 9a).²⁸ In the presence of 1.5 mol% Ph₃PAuOTf,²⁹ diazooxindole 9a undergoes C–H insertion with the aromatic compounds 9b to form 3-aryloxindoles 9c. After the completion of aromatic C–H functionalization, nitroenynes 9d and chiral amine 9e were added. The activation of intermediate 9c through deprotonation by 9e facilitates Michael addition with 9d to furnish the quaternary oxindoles 9f in 44–99% yields with excellent ee (up to 99%).

Scheme 9 Gold/chiral amine-catalyzed (a) enantioselective C–H functionalization/Michael addition reaction and (b) enantioselective formal allylation/Michael addition reaction.

In 2021, Dong, Wu, Zhou and co-workers combined Au(I)-catalyzed allylation of diazo (thio)oxindoles 9g with chiral amine-catalyzed Michael addition in a sequential manner (Scheme 9b).³⁰ The authors hypothesized the mechanism to involve Au(I)-catalyzed cyclopropanation/elimination of 9g with allyltrimethylsilane 9h (cf. 9i and 9j), delivering 3-allyl (thio)oxindoles 9k. In the next step, the asymmetric Michael addition of 9k to nitroolefins 9l in the presence of amine 9e, yields chiral 3,3-disubstituted (thio)oxindoles 9m in 93% ee.

Zhou and co-workers, in 2016, demonstrated a binary catalytic system comprising gold/chiral amine to execute an enantioselective enone formation/cyanosilylation of diazooxindoles 10avia a sequential mode of catalysis. Synthesis of 3-alkenyloxindole-based cyanohydrins 10d has been achieved in 40–87% yield and up to 96% ee (Scheme 10).³¹10a reacts with furan 10b in the presence of PPh₃AuCl to produce 3-alkenyl oxindole based enones 10e. Thereafter, an asymmetric cyanosilylation of 10e was carried out using TMSCN under the catalysis of amine 10c, which acts as a nucleophilic activator.

Scheme 10 Gold/chiral amine-catalyzed enantioselective enone formation/cyanosilylation cascade reaction.

In 2016, the research groups of González and López independently demonstrated the enantioselective intermolecular α-allylation of aldehydes 11b with N-allenamides 11a under the cooperative catalysis of IPrAuNTf₂ and chiral diphenylprolinol silyl ether 11d (Scheme 11).³² In the gold(I) catalytic cycle, López and co-workers proposed the formation of a zwitterionic electrophilic species 11e through the interaction of IPrAuNTf₂ and 11a, while González proposed gold(I)-coordinated N-allenamide species 11f as the key intermediate. Simultaneously, the reaction of 11b with amine 11d leads to enamine 11g which subsequently captures the electrophilic 11e or 11f, resulting in the adduct 11h. The protodeauration of 11h followed by hydrolysis of the resulting 11i forms 11c. Of note, López and co-workers suggested that the presence of BPy (2,2′-bipyridine) can facilitate the decoordination of amine from the gold catalyst.

Scheme 11 Gold/chiral amine-catalyzed enantioselective intermolecular α-allylation of aldehydes with N-allenamides.

In 2017, synthesis of bicyclic (5,6- or 6,6-fused) O,O-acetals was achieved in 99% ee under a sequential catalysis of gold and chiral diphenylprolinol silyl ether 12d by the research group of Liu (Scheme 12).³³ The reaction commences with the activation of the racemic lactol 12a by amine 12d to form the corresponding enamine. Subsequently, the enamine undergoes a Si-face attack to nitroenyne 12b, resulting in the formation of substituted lactol 12g. Next, gold-catalyzed oxyauration of 12g generates a vinyl gold intermediate 12i which upon protodeauration provides two separable bicyclic acetal epimers 12c and 12c′ in 65–79% yields with excellent diastereo- and enantioselectivity.

Scheme 12 Gold/chiral amine-catalyzed enantioselective [3 + 3] process leading to bicyclic O,O-acetals. [*] dr value corresponds to stereogenic centers labeled as (a) and (b).

Shi and co-workers, in 2018, demonstrated a cooperative catalytic system comprising of the gold complex and chiral amine 13d for the enantioselective α-arylation of aldehydes 13a using 2-indolylmethanols 13b as an arylating agent (Scheme 13).³⁴ Chiral α-arylated aldehydes 13c were synthesized in 40–69% yield and with ee up to 82%. The Au(I) complex activates 13b by coordinating to the double bond between the C-2 and C-3 positions. Such a metal complexation in the presence of TFA (cf. 13e) promotes the formation of a delocalized carbocation 13fvia dehydration. Simultaneously, enamine 13g was formed from 13a in the presence of 13d and TFA. Next, the nucleophilic attack from 13g on the carbocation 13f leads to the formation of adduct 13h which on rearomatization followed by hydrolysis furnishes 13c.

Scheme 13 Gold/chiral amine-catalyzed enantioselective α-arylation of aldehydes.

In 2021, Moreau and co-workers reported an enantioselective gold and chiral diphenylprolinol silyl ether 14d catalyzed sequential cycloisomerization/cycloaddition strategy to synthesize 4,5,6,7-tetrahydrofuro[2,3-b]pyridines 14c in 99% ee (Scheme 14).³⁵ The reaction begins with the gold-catalyzed 5-endo-dig cycloisomerization (cf. 14e) of ynamide 14a, leading to the formation of α,β-unsaturated N-sulfonyl ketimine 14f. In the next step, 14d undergoes condensation with α-H containing aldehydes 14b, generating chiral enamine 14g. At this stage, two plausible mechanisms have been proposed. Path A involves the nucleophilic attack of 14g on intermediate 14f, leading to the formation of a conjugate adduct 14i. Subsequently, 14i undergoes hydrolysis to generate aldehyde 14j, followed by the formation of hemiaminal 14c. In path B, 14f and 14g react through an Aza-Diels–Alder reaction, resulting in aminal 14h, which upon hydrolysis, leads to the formation of 14c. Furthermore, an alternative path C involves the direct formation of aminal 14h from 14i, followed by hydrolysis to yield 14c.

Scheme 14 Gold/chiral amine-catalyzed enantioselective cycloismerization/cycloaddition reaction to access furan-fused tetrahydropyridines.

In the same year, Hu, Xu and co-workers disclosed the gold/chiral amine cooperative catalysis in the asymmetric allylation of isatins 15b and isatin-derived ketimines 15b′ by using N-propargylamides 15a (Scheme 15).³⁶ This methodology provides an access to 2,5-disubstituted alkylideneoxazolines (15e/15e′) in 99% ee, using quinine-derived squaramides (QN-SQA) 15c and 15d as chiral amine catalysts. Mechanistically, the reaction commences with 5-endo-dig cyclization (cf. 15f) of 15a under Au(I) catalysis, generating a (E)-vinyl gold intermediate 15g. The authors proposed that 15g transforms into the key alkyl gold species 15h through H-shift driven by aromatization. Then, 15h undergoes a formal hetero-ene reaction with 15b′ under the chiral QN-SQA catalysis, delivering 15e′. Within the transition state 15i, QN-SQA 15d associates with 15b′ through double H-bonding with squaramide hydrogens and simultaneously coordinates to the Au(I) center of 15h with the N-atom of the quinoline part of 15d. In this transition state, nucleophilic addition occurs preferably to the Re-face of 15b′ which results in high enantioselectivity.

Scheme 15 Gold/chiral amine-catalyzed enantioselective allylation of isatins and isatin-derived ketimines.

Next, Wennemers and co-workers developed a combination strategy of a gold catalyst with peptide catalysts (H–_DPro–Pro–Glu–NHC₁₂H₂₅16d and H–_DPro–Pro–Asp–NHC₁₂H₂₅16e) for enantioselective addition of branched alkyl-aryl and alkoxy-aryl aldehydes (16a and 16b) to allenamides (16c) under cooperative mode of catalysis. This protocol affords various γ,δ-enamide aldehydes bearing a fully substituted benzylic stereocenter (16f and 16g) in high ee up to 99% (Scheme 16).³⁷ The plausible mechanism depicts the formation of an enamine 16h from 16a in the presence of the peptide 16d. 16h then reacts with an electrophilic allenamide-gold(I) complex 16m, generated through ligand exchange between Au–DMAP complex 16k (or Au–TFA complex 16l) and 16c. This C–C bond-forming step is proposed to be the stereodetermining step where the reaction at 16m takes place from the upper, less sterically hindered face of 16h (cf. 16o). The resulting vinyl gold iminium 16i then undergoes protodeauration followed by hydrolysis to furnish 16f. Balancing the concentrations of DMAP and TFA is crucial for achieving the optimal reaction rate with suppression of undesired side reactions, forming 16n and other oligomers.

Scheme 16 Gold/chiral amine-catalyzed enantioselective addition of branched aldehydes to allenamides.

2.2 Enantioselective merged gold/Brønsted acid catalysis

Chiral Brønsted acids (BH) have exhibited remarkable compatibility as an organocatalyst with the gold complexes in expanding the horizon of enantioselective merged gold/organocatalysis. In this regard, a comprehensive review on merged gold/Brønsted acid catalysis has been published by our research group in 2014.^16c Therefore, this discussion exclusively concentrates on Au(I)/chiral BH-catalyzed enantioselective reactions reported subsequent to that period. Of note, reports regarding the asymmetric counterion directed catalysis (ACDC) via the formation of a gold–phosphate complex^10,38 and tethered-counterion directed catalysis (TCDC) where chiral phosphate counterion is covalently tethered to gold via a ligand,³⁹ are beyond the scope of this review.

In advancing the field of merged metal/organocatalysis, the group of Gong and co-workers has contributed significantly over the years.^7a,13 In 2014, the authors developed a relay catalytic cascade hydrosiloxylation and asymmetric hetero-Diels–Alder reaction under the binary catalytic system of Au(I) and chiral N-triflyl BINOL-based phosphoramide 17d (Scheme 17).⁴⁰ An efficient access to tetrahydrobenzo-pyrano-oxasiline carboxylates 17c from enynyldiphenylsilanols 17a and fluorenyl glyoxylates 17b has been achieved with excellent enantiomeric excess up to 93%. Mechanistically, the gold(I) complex triggers an intramolecular hydrosiloxylation of 17a, generating diene 17e. Next, under the stereochemical control of 17d, an oxo-hetero-Diels–Alder reaction of 17e with 17b provides intermediate 17f. Subsequent isomerization leads to the more stabilized conjugated product 17c.

Scheme 17 Gold/chiral Brønsted acid-catalyzed enantioselective hydrosiloxylation/hetero-Diels–Alder cascade reaction.

In 2015, Jia and co-workers described an enantioselective redox annulation reaction of nitroalkynes 18a with indoles 18b under the cooperative catalysis of gold and chiral phosphoric acid (CPA) 18d (Scheme 18).⁴¹ This transformation afforded indolin-3-one derivatives 18c bearing a quaternary stereocenter at the C2 position with high enantiopurity (up to 96% ee). At first, π-activation of 18a by the gold catalyst promotes an intramolecular nucleophilic attack from the O-atom of the nitro group, yielding α-oxo gold carbenoid intermediate 18e. Afterwards, two mechanistic possibilities have been proposed for the formation of 18c. The path a showcases the interception of 18e with 18b, generating a zwitterionic intermediate 18f. Subsequent cyclization via intramolecular nucleophilic attack from the gold enolate on the nitroso group (cf. 18f) in the presence of CPA delivers 18c. Whereas, path b depicts an intramolecular trapping of the carbenoid species by the nitroso group resulting in the generation of 18g. A subsequent protonation of 18g with CPA 18d, followed by the attack of 18b delivers 18c.

Scheme 18 Gold/chiral Brønsted acid-catalyzed enantioselective redox annulation of nitroalkynes with indoles.

In 2016, Han and co-workers reported a hydroamination/Michael addition cascade under the relay catalysis of a gold complex and chiral Brønsted acid 19c to afford enantiopure tetrahydrocarbazoles 19b (Scheme 19).⁴² Mechanistically, the reaction proceeds with gold(I)-catalyzed intramolecular hydroamination of 2-ethynylanilines 19a leading to indole 19d. Later, 19d undergoes a CPA-catalyzed asymmetric intramolecular Michael addition reaction, yielding 19b with excellent enantioselectivity (up to 99% ee).

Scheme 19 Gold/chiral Brønsted acid-catalyzed enantioselective synthesis of tetrahydrocarbazoles.

In 2017, the group of Luo and Gong employed a relay catalytic system consisting of XPhosAuNTf₂ and chiral Brønsted acid 20d for synthesis of γ-keto esters 20c (Scheme 20).⁴³ The reaction mechanism initiates with the interaction between α-diazoester 20a and XPhosAuNTf₂, leading to the generation of gold carbenoid species (20e or 20e′). The highly electrophilic Au(I) carbenoid then engages in an aza-ene-type reaction with the nucleophilic enamide 20b, furnishing the adduct 20f. Next, an intramolecular proton transfer from the iminium functionality within intermediate 20f results in the formation of an enol species 20hvia the gold enolate species 20g. Subsequent stereoselective protonation of 20h with CPA 20d (cf. 20i) generates imine 20j which on hydrolysis delivers 20c with enantiomeric excess up to 97%.

Scheme 20 Gold/chiral Brønsted acid-catalyzed enantioselective aza-ene-type reaction of enamides with α-diazoesters.

In 2018, Chan and co-workers developed a sequential chiral Brønsted acid-catalyzed dehydrative Nazarov-type electrocyclization (DNE) and gold-catalyzed hydroamination, leading to the synthesis of 1,8-dihydroindeno[2,1-b]pyrroles 21b from β-amino-1,4-enynols 21a (Scheme 21).⁴⁴ At first, chiral N-triflyl BINOL-based phosphoramide 21c results in the dehydration of 21a with the formation of an ion-pair 21d. The precise stereochemical environment in 21d, aided by H-bonding interactions between the amino group and CPA anion facilitates the enantioselective Nazarov-type electrocyclization, generating chiral 1H-indene 21e. Next, under the gold(I) catalysis, 21e undergoes a 5-endo-dig cyclization, forming vinyl gold intermediate 21g which on protodeauration affords 21b in 99% ee.

Scheme 21 Gold/chiral Brønsted acid-catalyzed enantioselective dehydrative Nazarov-type electrocyclization/hydroamination reaction.

In 2018, Hu, Xu and co-workers developed the cooperative catalysis of gold(I) and chiral phosphoric acid (CPA) to achieve an enantioselective Mannich-type reaction of 3-butynols 22a and nitrones 22b, affording dihydrofuran-3-ones 22c in 96% ee (Scheme 22a).⁴⁵ The plausible reaction mechanism involves the gold-catalyzed oxidation of 22a in the presence of 22b, resulting in an electrophilic α-oxo gold carbenoid 22f formation along with the elimination of imine 22g. Subsequently, an intramolecular attack of the tethered hydroxyl group on gold carbenoid species 22f generates the gold associated oxonium ylide 22h or its enolate form 22i. Next, 22i undergoes Mannich-type addition with the eliminated 22g under CPA catalysis to deliver 22c. The observed high enantioselectivity originates from the dual H-bonding of CPA with both reactive species in the Mannich-type addition step (cf. 22j).

Scheme 22 Gold/chiral Brønsted acid-catalyzed enantioselective oxidative cyclization of alkynes/Mannich-type addition cascade.

Along the same line, in 2021, the group of Hu, Ke and Xu employed the cooperative catalysis of gold/CPA 22n to achieve the intermolecular three-component enantioselective multifunctionalization of terminal alkynes 22k with nitrones 22l and alcohols (Scheme 22b).⁴⁶ Of note, gold catalyzed multicomponent reactions (MCRs) have evolved as an important branch, giving access to different molecular frameworks in a single step.⁴⁷ Herein, an alkyne oxidation/ylide formation/Mannich-type addition sequence has been successfully performed, affording α-alkoxy-β-amino-ketones 22m in 98% ee. A similar mechanistic paradigm as described in Scheme 22a has been proposed for this case as well, only differing in the ylide formation through an intermolecular attack of external alcohol on the α-oxo gold carbenoid. For the gold-associated Mannich-type addition step, the authors proposed two possible intermediates: (a) 22o, where the gold complex binds to the initial carbonyl oxygen atom, and (b) 22p, where gold interacts to the ether oxygen atom. DFT calculations suggested the more stable gold enolate species 22o as the key intermediate involved in the enantioselective C–C bond formation step.

In 2021, Cheng, Liu and co-workers reported the asymmetric [3 + 2]-annulation of tetrasubstituted alkenes 23b with α-aryl diazoketones 23c under the cooperative catalysis of gold and chiral Brønsted acid 23d, affording bicyclic 2,3-dihydrofurans 23e (Scheme 23).⁴⁸ Vinyl-allenes 23a have been utilized as precursors for 23b under Au(I) catalysis. Using the L’AuCl catalyst and CPA 23h, the free energy profile of the reaction has been studied through DFT calculations. Based on DFT calculations, the authors proposed the mechanism to involve the nucleophilic attack from the more substituted alkene of 23b on the α-oxo gold carbene 23f, generated from 23c under Au(I) catalysis. This regioselective attack leads to the generation of gold enolate intermediate 23g bearing a highly stabilized allylic cation. Next, the CPA associates with both gold enolate and the allylic cation part of 23gvia a dual H-bonding interaction. Under this rigid stereochemical environment, a subsequent ring closure affords the [3 + 2]-annulation product 23e with high enantioselectivity (up to 92% ee).

Scheme 23 Gold/chiral Brønsted acid-catalyzed enantioselective [3 + 2]-annulations of α-aryl diazoketones with cyclopentadienes.

Two research groups, led by Zhang/Sun⁴⁹ and by Liu,⁵⁰ independently employed gold/chiral Brønsted acid (24f/24g) relay catalysis for an enantioselective C–H insertion reaction (Scheme 24). The two groups reported the insertion of α-aryl-α-diazoesters 24a into the para-C–H bond of alkyloxy arenes 24b and alkyl arenes 24c, affording chiral 1,1-diaryl esters 24d and 24e, respectively. As per the proposed reaction mechanism by Zhang and Sun, the electrophilic Au(I) carbene 24h, generated from the diazoester 24a′ under gold catalysis, triggers a para-C–H insertion reaction of alkyloxy arene 24b′ to form cation 24i. Subsequently, 24i generates E- or Z-enol species 24k through an intramolecular proton transfer (cf. 24j). This step is indicated as the rate-determining step by DFT analysis. The energetically favorable E-enol species 24k (due to the stabilized interaction between hydroxyl and methoxy groups) furnishes 24d′ with high enantioselectivity via a CPA assisted proton transfer process (cf. 24l). Mechanistic investigations performed by Liu's research group also support the similar catalytic cycle.

Scheme 24 Gold/chiral Brønsted acid-catalyzed enantioselective para-C(sp²)–H bond functionalization of arenes with α-aryl-α-diazoesters.

2.3. Enantioselective merged gold/N-heterocyclic carbene catalysis

In the realm of merged gold/organocatalysis, amines and Brønsted acids as organocatalysts have witnessed a significant development for the enantioselective synthesis of a diverse range of organic compounds. In contrast, reports demonstrating merged gold/N-heterocyclic carbene (NHC) catalysis are relatively scarce, probably due to the inherent strong coordinating ability of NHC ligands to gold complexes, causing catalyst inhibition.

In 2020, the first report of merging gold and chiral NHC catalysis in a diastereo- and enantioselective cycloisomerization/azadiene-Diels–Alder reaction was disclosed by the group of Pan and Chi (Scheme 25).⁵¹ Ynamides 25a and enals 25b react together in the cooperative catalysis mode of the PPh₃AuCl complex and NHC precatalyst 25d to generate furan-fused six-membered lactams 25c. Mechanistically, Au(I) catalyzes 5-endo-dig cyclization of 25a through an intramolecular oxyauration, resulting in the formation of vinyl gold intermediate 25e. Next, an intramolecular proton transfer in 25e leads to the generation of α,β-unsaturated N-sulfonyl ketimine 25f. Parallelly, 25b reacts with the active NHC catalyst to generate the Breslow intermediate 25g which further isomerizes to an azolium enolate intermediate 25h through a proton transfer process. Finally, the reaction between two key intermediates 25f and 25h furnishes 25c in high enantiomeric excess (up to 99%).

Scheme 25 Gold/chiral NHC-catalyzed enantioselective cycloisomerization/cyclization reaction of ynamides and enals.

Later, in 2022, Lu and co-workers reported the gold and NHC relay catalysis in the formal [3 + 3] cycloaddition between α-amino-ynones 26a and enals 26b to afford enantioenriched pyrrole-fused lactones 26c (Scheme 26).⁵² The proposed mechanism involves gold catalyzed intramolecular hydroamination to generate furyl gold intermediate 26f. Subsequent protodeauration of 26f leads to the formation of pyrrolin-4-one 26g. Chiral NHC reacts with 26b, generating Breslow intermediate 26i which on oxidation with DQ (3,3′,5,5′,-tetra-tert-butyl-4,4′-diphenoquinone) produces α,β-unsaturated acylazolium 26j. Next, an enolate 26h, formed via proton abstraction from 26g, undergoes a conjugate addition to 26j and a subsequent alkoxide cyclization. The resulting cyclic intermediate 26k delivers 26c in 96% ee with the NHC elimination.

Scheme 26 Gold/chiral NHC-catalyzed enantioselective annulation of α-amino-ynones and enals.

Very recently, in 2023, Lv, Zhou and co-workers utilized a relay catalysis strategy involving Au(I)/chiral NHC for the asymmetric synthesis of spirofuro[2,3-b]azepine-5,3′-indoline derivatives 27c from enyne-amides 27a and isatin-derived enals 27b (Scheme 27).⁵³ Mechanistically, the alkynophilic activation (cf. 27e) by the Au(I) species of 27a leads to 5-endo-dig cyclization, thereby forming a furyl-Au(I) intermediate 27f. Following this, dihydrofuran-fused azadiene 27g is generated through an isomerization and protodeauration of 27f. In another catalytic cycle, the interaction between enal 27b and chiral NHC produces Breslow intermediate 27h, which then isomerizes to the azolium homoenolate species 27i. Next, 27i undergoes conjugate addition to 27g, leading to the formation of adduct 27j which via intramolecular N-acylation delivers 27c in 96% ee.

Scheme 27 Gold/chiral NHC-catalyzed enantioselective cycloisomerization/formal [4 + 3]-cycloaddition reaction of enyne-amides and isatin-derived enals.

2.4 Enantioselective merged gold/hydrogen-bonding catalysis

In addition to the amine, Brønsted acid and NHC, the merger of hydrogen-bonding catalysis involving chiral bifunctional H-bonding organocatalysts with gold catalysis has appeared as an innovative tool to achieve excellent enantiocontrol. However, this strategy has seen limited development which could be due to their strong coordination tendencies to the gold center leading to catalyst deactivation.

In 2010, Jørgensen and co-workers first reported a one-pot sequential catalysis involving thiourea-based hydrogen-bonding organocatalyst 28d and Ph₃PAuNTf₂. By employing this catalyst combination, 2,3,3,5-tetrasubstituted 2,3-dihydro-1H-pyrrole derivatives 28c were enantioselectively synthesised from N-Boc protected imines 28a and propargylated malononitriles 28b (Scheme 28).⁵⁴ The initial step involves the Mannich-type reaction between 28a and 28b to generate a chiral intermediate 28e. The authors proposed that the observed enantioselectivity stems from the simultaneous activation of 28avia the H-bonding from the thiourea moiety and the activation of 28bvia the base-catalysis from one of the basic sites of 28d. In the next step, Au(I) catalyzes 5-exo-dig cyclization of 28e, forming a vinyl gold intermediate 28g which then undergoes protodeauration followed by isomerization to yield 28c in 88% ee.

Scheme 28 Enantioselective synthesis of 2,3-dihydropyrroles under gold/H-bonding catalysis.

Later, in 2011, Enders and co-workers developed a H-bonding organo/gold-catalyzed double Friedel–Crafts type reaction in a sequential manner, affording an asymmetric C2/C3-annulation of indoles (Scheme 29).⁵⁵ Synthesis of tetracyclic indole derivatives 29c has been achieved from indoles 29a and nitrostyrenes 29b in excellent ee up to 99%. The first Friedel–Crafts type reaction involves the simultaneous activation of 29a and 29b in the presence of a H-bonding organocatalyst 29d, producing an adduct 29f. This step exhibits excellent stereocontrol by locking both reactants with the organocatalyst in a rigid transition state (cf. 29e) through multiple H-bonding interactions and thereby favouring the Si-face attack of indole on nitrostyrene 29b. In the next step, 29f undergoes another intramolecular Friedel–Crafts type reaction under the gold catalysis. Gold-activated C–C triple bond of 29f undergoes 6-endo-dig cyclization via the nucleophilic attack from the C3-position of indole. The generated spirocyclic intermediate 29h then undergoes a 1,2-alkyl shift to produce a seven-membered ring containing carbocation 29i which after rearomatization and protodeauration delivers 29c.

Scheme 29 Enantioselective synthesis of tetracyclic indoles under gold/H-bonding catalysis.

2.5 Enantioselective merged gold/phosphine catalysis

Phosphine catalysis has found extensive utilization in Morita–Baylis–Hillman (MBH) and aza-Morita–Baylis–Hillman (aza-MBH) reactions, providing multiple functional groups containing complex molecular architectures from simple substrates. Despite significant advances in phosphine-mediated MBH reactions, realization of these reactions under merged gold/phosphine catalysis poses a specific challenge. The strong coordination between phosphines and gold complexes leads to the quenching of both the catalysts. In 2016, an enantioselective sequential catalysis involving a chiral phosphine catalyst 30d and a gold catalyst was developed by Shi and co-workers to afford enantio-enriched dihydroisoquinoline derivatives 30c (up to 99% ee) (Scheme 30).⁵⁶ At first, under the phosphine catalysis, the asymmetric aza-MBH reaction between aromatic sulphonated imine tethered alkynes 30a and vinylketones 30b delivers an intermediate 30e. A subsequent 6-endo-dig cyclization of the Au(I)-activated alkyne (cf. 30f) produces a vinyl gold intermediate 30g which upon protodeauration affords 30c in 73–91% yields.

Scheme 30 Gold/chiral phosphine-catalyzed enantioselective synthesis of dihydroisoquinolines.

3. Conclusion and Outlook

The field of gold catalysis has garnered remarkable interest capitalizing on its carbophilic activation mode; however, the developments in asymmetric gold catalysis have been comparatively modest. The linear geometry of the dicoordinated Au(I) species poses a challenge in efficiently transferring the chiral information from the ligand to the substrate. In the continuing endeavor for developing strategies to realize enantioselective transformations, the merger of gold catalysts with chiral organocatalysts has emerged as one of the efficient techniques for achieving gold-catalyzed asymmetric synthesis. In this review, we have summarized the progress in the field of enantioselective merged gold/organocatalysis. The categorization of the reports has been made based on the type of chiral organocatalysts such as amine, Brønsted acid, N-heterocyclic carbene, H-bonding and phosphine catalysts. Through exploiting their complementary reactivities, merged gold/organo-catalyzed asymmetric transformations have unlocked the reactivities that remain beyond the reach of individual catalysts. As discussed, notable advancements have been accomplished in merging gold catalysis with amine and Brønsted acid catalysis. In contrast, the merging of gold catalysis with NHC, phosphine and H-bonding catalysis is underdeveloped which could be due to their compatibility issues with gold complexes.

It is worth noting that most of the reports on the merged gold/organocatalysis employed Au(I) catalysts for the activation of C–C multiple bonds. Considering the recent surge in the development of Au(I)/Au(III) redox catalysis,⁵⁷ the combination of this catalytic mode with chiral organocatalysis is expected to uncover new enantioselective reactions in the future. As fundamental knowledge of both gold and organocatalysts has expanded over the years, we foresee the realization of several fascinating transformations utilizing the concept of merged catalysis. It is our belief that this review will not only provide the foundation for further development of enantioselective merged gold/organocatalysis but also stimulate the interest of the scientific community in exploring different mergers to expand the horizon of dual catalysis.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Generous financial support by SERB, New Delhi (CRG/2022/000195, SCP/2022/000063 and JCB/2022/000052), is gratefully acknowledged. We also acknowledge the financial assistance from BRNS (58/14/30/2022-BRNS/37101). CP thanks CSIR and BP thanks IISER Bhopal for fellowships.

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Footnote

† These two authors have contributed equally to this manuscript.

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