DOI: 10.1002/cctc.201000070

Recent Advances in Asymmetric Gold CatalysisSujata Sengupta and Xiaodong Shi*[a]

The first decade of the 21st century evidenced the explosivegrowth of homogeneous gold catalysis. The unique versatilityand efficiency of gold metal complexes are clearly indicated bythe numerous reports regarding their application in various or-ganic transformations.[1] Key to the success of homogeneousgold catalysis is the ability of gold(I) and gold(III) to act as softcarbophilic Lewis acids towards C�C multiple bonds. This highcarbophilicity translates to a relatively low oxophilic characterand a kinetically labile carbon-metal bond, which allows effi-cient catalyst turnover. In addition, the high oxidation potentialbetween gold(I) and gold(III) makes the gold catalysts inertfrom air oxidation. Therefore, compared with other transitionmetal catalysts, gold complexes could catalyze reactions undervery mild conditions (tolerates air or moisture), giving excellentchemoselectivity, wide functional group compatibility and highefficiency.

However, despite its high efficiency in alkyne and alleneactivation, gold catalysts, like many other transition metal com-plexes, inherit some limitations that prevent them from being“perfect.” Two clearly identified challenges in gold catalysis area) rather poor thermal stability due to disproportionation ofthe metal cation and b) difficulty in asymmetric transforma-tions. In the past several years, efforts have been made byvarious research groups to overcome these challenges.[2] Sig-nificant progress has been made, which has given this very hottopic in catalytic research strong momentum for an even morepromising future. Major breakthroughs in asymmetricgold catalysis are certainly expected in the coming decadeand this Minireview, by highlighting recent advances, aims tofacilitate progress in this fascinating field of research.

Introduction

Although AuI and AuIII catalysts have shown similar reactivity inmany reactions, asymmetric transformations using these twocatalysts are very different. AuIII complexes usually have fourcoordination sites and exist as square planar complexes. TheAuI cation, on the other hand, has only two coordination siteswith a 1808 bond angle. Therefore, different spatial controlstrategies are required for these two catalysts.

With four possible coordination sites around the metalcatalytic center, AuIII has long been the intuitive choice forasymmetric gold catalysis, since it should be easy to build theneeded spatial control around the reaction center. Althoughseveral AuIII complexes bound by chiral ligands have been re-ported, successful asymmetric syntheses involving chiral AuIII

catalysts are very few. Moreover, among the limited examples,the AuIII cation has usually served as a regular Lewis acid in-stead of as a characteristic carbophilic p-bond promoter. For

example, it has been reported that pyridine ONN-pincer AuIII

complexes promote asymmetric hydrogenation with modestto good stereoselectivity (up to 80 % ee),[3] and that a chiralpyridine NNN-pincer ligand-bound AuIII catalyst promotesasymmetric olefin epoxidation, albeit with poor enantioselec-tivities (8–32 % ee).[4] To date, no examples of allene, alkyne, oralkene asymmetric activations using chiral AuIII complexes havebeen reported. Meanwhile, albeit with some debate, it is still ageneral belief that AuI complexes possess two binding sites.This linear geometry makes asymmetric catalysis extremely dif-ficult since special strategies or chiral ligands were needed todeliver spatial arrangements to the opposite site of the metalcation. Herein we focus only on recent progress achieved inasymmetric transformations by gold-promoted carbon–carbonmultiple bond activation.

Asymmetric Induction through ChiralityTransfer

Whereas employing chiral ligands to control the enantio-selectivity is challenging, chirality transfers from allenes andpropargyl alcohols have been applied as an efficientalternative strategy to achieve asymmetric Au catalysis.

Allenes as source for chirality transfer

Homogeneous gold catalysis involving the transfer of chiralityfrom the substrate to the product has emerged as a powerfultool for the stereoselective synthesis of complex organic mole-cules. In this context, the inherent axial chirality of allenes andits high reactivity towards p activation makes them excellentsubstrates for stereoselective gold catalysis.

In one of the earliest works highlighting chirality transferfrom the substrates to the product, Krause and co-workersreported the endo-cycloisomerization of both a- andb-hydroxyallenes with both gold(I) and gold(III) chloride salts(Scheme 1).[5] The reactions represent a mild and efficientmethod for the synthesis of dihydrofuran and pyran derivativeswith complete axis-to-center chirality transfer. Both reactionsoffer a large substrate scope and the products were obtainedin good to excellent yields. In both the cases, vinyl–goldspecies were formed as active intermediates. More recently,both Hegedus and Krause have reported that gold(I) salts alsocatalyze the cycloisomerization of a-hydroxyallenes.[6]

[a] S. Sengupta, Prof. Dr. X. ShiDepartment of Chemistry, West Virginia UniversityMorgantown, WV 26506 (USA)Fax: (+ 1) 304-293-4904E-mail : Xiaodong.Shi@mail.wvu.edu

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Krause and Morita later extended the application of thegold-catalyzed procedure to the cycloisomerization ofa-aminoallenes to provide easy access to chiral 3-pyrrolines.[7]

For example, treatment of diastereomerically pure a-amino-allene 3 with gold(III) chloride in dry dichloromethane at roomtemperature produced 3-pyrroline 4 with complete transfer ofchirality (Scheme 2). Although the reaction tolerated a wide

substrate scope, the chirality transfer was dependent on thenature of the N-protecting group; unprotected a-aminoallenesunderwent cycloisomerization with complete transfer ofchirality.

In addition to the gold-catalyzed cycloisomerization of a-hy-droxyallenes and a-aminoallenes, Krause and Morita reportedthe stereoselective cycloisomerization of a-thioallenes to 2,5-dihydrothiophenes, representing one of the first examples of agold-catalyzed carbon–sulfur bond formation (Scheme 3).[8]

Although both gold(I) and gold(III) salts were suitable for thereaction, the highest yields were obtained by employing eitherAuCl or AuI. The reaction tolerated a large substrate scope andall of the corresponding 2,5-dihydrothiophenes were obtainedin moderate to high yields with a complete axis-to-centerchirality transfer.

In a more recent investigation towards the hydrofunctional-ization of allenes, Yamamoto and Nishina reported a gold(III)-

catalyzed intermolecular hydroamination of allenes with aniline(Scheme 4).[9] The reaction proceeded with a high degree ofaxis-to-center chirality transfer and provided the allylic amines

in good to excellent yields. Furthermore, in a separate study,Yamamoto reported the intramolecular hydroamination ofallenes in the presence of gold(I) or gold(III) to give corresp-onding 2-vinyl pyrrolidines and piperidines in high yields.[10]

For example, enantiomerically enriched aminoallene 9(99 % ee), synthesized from (S)-(�)-1-octyne-3-ol, was convertedinto the corresponding pyrrolidine 10 in 99 % yield with94 % ee, indicating an almost complete transfer of chirality(Scheme 4).

Propargyl alcohols as source of chirality transfer

Propargyl alcohols are readily available building blocks, whichcan be prepared with high enantioselectivity. Therefore, theyhave also been applied as good chiral precursors for gold-promoted asymmetric transformations. In a series of reportson gold-catalyzed transformations involving propargyl ethers,Toste and co-workers demonstrated the AuI catalyzed [3,3]Claisen rearrangement to give homoallenic alcohols withexcellent diastereoselectivity and complete chirality transfer(Scheme 5).[11] In this case, the [(Ph3PAu)3O]BF4 was identifiedas the optimal catalyst in giving the best performance com-pared to other Au catalysts. The same group also reported therearrangement of enantiomerically enriched ethers to affordfunctionalized pyrans with excellent retention of chirality.[12]

With this strategy, chiral spiroketals were synthesized withhigh efficiency and good enantioselectivity (Scheme 5).

Later, Toste and co-workers reported another gold(I)-cata-lyzed diastereoselective rearrangement of propargyl esters toform cyclopentenones. Treatment of propargyl pivalates withcationic gold(I) underwent a Rautenstrauch rearrangement toafford cyclopenten-2-ones with good yields.[13] Interestingly,when enantiomerically enriched propargyl esters were applied,excellent chirality transfers were obtained and enantiomericallyenriched cyclopentenones were prepared with excellentstereoselectivity (Scheme 6). According to the authors, thereaction proceeds through an active vinyl gold species,where the C�C bond is formed prior to the cleavage of thestereogenic C�O bond.

Scheme 1. Gold-catalyzed cycloisomerization of allenyl carbinols withaxis-to-center chirality transfer.

Scheme 2. Gold(III)-catalyzed cycloisomerization of a-aminoallenes withtransfer of chirality.

Scheme 3. Gold(I)-catalyzed cycloisomerization of a-thioallenes to2,5-dihydrothiophenes with complete transfer of chirality.

Scheme 4. Gold(I)- and gold(III)-catalyzed intra-/intermolecularhydroamination of allenes with transfer of chirality.

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Recently, Toste’s group further extended the chirality transferstrategy to allylic alcohols through a gold(I)-catalyzed intramo-lecular carboalkoxylation of propargyl benzylic ethers.[14] Thereaction proceeded with excellent chirality transfer, therebyproviding easy access to functionalized indenyl ethers. Forexample, treatment of enantiomerically enriched alkyne 19(82 % ee) with [(p-CF3C6H4)3PAu]BF4 in methylene chloride atroom temperature gave indenyl ether 20 in 99 % yield with81 % ee, highlighting the complete chirality transfer of thisattractive stereoselective transformation (Scheme 7).

Enantioselective p-Activation with Chiral AuI

Catalysts

Although the first example of an enantioselective gold-cata-lyzed reaction was reported by Ito and Hayashi in 1986 for the

asymmetric carbonyl activation with a gold cation as the Lewisacid,[15] much of the progress regarding Au-catalyzed enantio-selective carbon–carbon multiple bond activation has onlybeen achieved during the past few years.

Asymmetric activation of alkynes

Alkynes are by far the most popular reaction partners inhomogeneous gold catalysis. During the past few years, theelectrophilic activation of alkynes by either gold(I) or gold(III)species towards a variety of nucleophiles has become an ex-tremely successful tool for the synthesis of complex organicmolecules.[16] Recent reports involving the cycloisomerizationof enynes and the desymmetrization of dialkynes provide ex-amples of the emerging role of alkynes in enantioselectivegold catalysis.

In 2005, Echavarren and co-workers developed chiral goldcomplexes bearing mono- and bidentate phosphine ligandsfor the enantioselective alkoxycyclization of enynes.[17] Thisprocedure was one of the first examples of chiral bis-gold(I)complexes being applied for enantioselective gold catalysis.Utilizing various enantiopure ferrocenylphosphine and binolderivatives, the authors synthesized and characterized a varietyof chiral bis-gold(I) complexes. Ligand optimization revealedthat employing a 1.6:2 catalytic mixture of [(R)-L1(AuCl)2] (L1 =

tol-binap; binap = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl ;Scheme 8) and AgI salt produced the best results for the asym-metric alkoxycyclization (Scheme 8). Presumably, under such anAu/Ag ratio a highly active monocationic gold complex wasformed, providing the highest efficiency and enantioselectivity.Although the reaction suffered from a limited substrate scopeand the enantioselectivities were moderate (94 % ee in onesingle example), the reaction was possible at room tempera-ture unlike its PtII variant which required higher temperatures.More recently, Michelet and co-workers have also reported theefficient preparation of enantiomerically enriched functional-ized alcohols and ethers via hydroxy- and alkoxycyclizationreaction. (R)-4-MeO-3,5-(tBu)2-MeObiphep (biphep = 2,2’-bis(di-phenylphosphino)biphenyl) was found to be the best chiralinductor, providing moderate to good enantioselectivities (upto 78 % in single case).

Scheme 6. Gold(I)-catalyzed Rautenstrauch reaction for synthesis of chiralcyclopentenones. Piv = pivaloyl.

Scheme 7. Gold(I)-catalyzed intramolecular carboalkoxylation of alkynesinvolving transfer of chirality.

Scheme 8. Enantioselective alkoxycyclization of enynes. (R)-tol-binap = (R)-(+)-2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl.

Scheme 5. Gold-catalyzed rearrangements with transfer of chirality.TIPS = triisopropylsilyl.

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Michelet and co-workers recently developed an enantiose-lective cyclization of 1,6-enynes to afford functionalized cyclicalkenes.[18] Employing bis-gold(I) complexes with electron richand sterically hindered chiral ligands, such as (R)-4-MeO-3,5-(tBu)2-MeObiphep, provided the best enantioselectivity (up to88 % ee compared to only 20 % ee with binap). For example,treatment of enyne 23 a with [(R)-L2(AuCl)2] (L2 = 4-MeO-3,5-(tBu)2-MeObiphep; Scheme 9) and AgOTf in diethyl ether led

to the formation of product 24 a in 99 % yield with 83 % ee(Scheme 9). The reaction tolerated a wide substrate scope, pro-viding the cyclic alkenes in excellent yields and high enantiose-lectivities (up to 98 % ee). Interestingly, the authors detectedan increase in the enantioselectivity with an increase in thesize of the tether group on the enyne. Furthermore, anenantioselective intramolecular hydroarylation/cyclizationreaction was also possible, affording the tricyclic product 26 in99 % yield with 93 % ee.

In a more recent example of their continuing work ongold(I)-catalyzed reactions, Michelet et al. reported an asym-metric gold-catalyzed cycloisomerization of heteroatom-teth-ered 1,6-enynes to afford functionalized bicyclo[4.1.0]heptenederivatives in moderate yields and with excellent enantioselec-tivities (up to 98 % ee).[19] For example, treatment of substituted1,6-enyne 27 with [(R)-L2(AuCl)2] and AgOTf in toluene atroom temperature furnished heptene derivative 28 in 56 %yield with 96 % ee (Scheme 10). Furthermore, the cycloisomeri-zation was not limited exclusively to oxygen-tethered enynesbut could also be applied successfully to nitrogen-tetheredenynes.

Tomioka and co-workers recently reported chiral C2-symmet-ric N-heterocyclic carbene (NHCs) complexes for the gold(I)-cat-alyzed cycloisomerization of 1,6-enynes to the correspondingcyclopentane derivatives.[20] NHC�AuCl complexes bearing abis(2,5-dimethylphenyl)methyl substituent were found to bemost effective, providing the chiral cyclopentanes in high

yields but moderate enantioselectivities (up to 59 % ee ;Scheme 11).

Hashmi and co-workers reported the application ofdiastereotopic dialkynes in asymmetric gold(I)-catalyzedphenol synthesis.[21] Initial studies with chiral bis-gold(I) ferro-cenyl complexes employed by Ito and Hayashi indicated highreactivities but low enantioselectivities (up to 41 % ee withMandyPhos ligand).[21] The highest enantioselectivity was ob-tained by employing the popular chiral bis-gold(I) complex,[(R)-L2(AuCl)2] , and AgBF4 (55 % ee ; Scheme 12). Unlike certainreports of enantioselective gold(I) catalysis, the influence ofthe counterions on the reaction was found to be minimal. Theauthors were successful in obtaining X-ray crystallographicdata for a few of the bis-gold(I) complexes, all of which indicat-ed a nearly linear P�Au�Cl bond angle (1758) and a large

Scheme 9. Enantioselective gold(I)-catalyzed cyclization of 1,6-enynes.

Scheme 10. Enantioselective gold(I)-catalyzed synthesis of bicyclo-[4.1.0]heptene derivatives.

Scheme 11. Enantioselective cycloisomerization of 1,6-enynes with chiral[NHC(AuCl)] .

Scheme 12. Enantioselective gold(I)-catalyzed phenol synthesis.

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distance between the two gold centers, thereby minimizingthe chance for any type of aurophilic interactions.

Later, Wilckens and Czekelius developed an enantioselectivegold(I)-catalyzed cyclization of diynamides to oxazepine deriva-tives using chiral gold(I) complexes (Scheme 13).[22] Althoughgold complexes employing chiral N-heterocyclic carbene (NHC)ligands gave low enantioselectivity, chiral bis-gold(I) complex[(R)-L2(AuCl)2] provided the resulting oxazepine derivative witha much-improved enantioselectivity (60 % ee).

Asymmetric addition to allenes

The electrophilic p activation of allenes by gold was amongthe earliest reactions investigated and, to date, allenes remaina very popular synthon for homogeneous gold catalysis. Al-though allenes are more reactive towards gold than alkenes,problems associated with the chemo-, diastereo-, andregioselectivity exist.[23] However as a result of their inherentprochirality, numerous enantioselective reactions of alleneswith chiral gold(I) complexes have been reported during thepast few years.

Based upon their success in the hydrofunctionalization ofallenes with achiral gold(I) catalysts,[24] Widenhoefer andco-workers reported a bis-gold(I) complex-catalyzed enantio-selective hydroarylation of achiral 2-allenyl indoles to tetra-hydrocarbazoles.[25] Treatment of 2-(4,5-hexadienyl)indole 37 awith a 1:2 catalytic mixture of [(S)-L2(AuCl)2] and AgBF4 in tolu-ene at �10 8C afforded 4-vinyltetrahydrocarbazole 38 a in 88 %yield with 92 % ee (Scheme 14). The enantioselectivity of the re-action was dependent upon the choice of the counteranion,solvent, and phosphine ligand. Substituents on the benzenering of the indole moiety and on the alkyl tether were well tol-erated but provided only modest enantioselectivity. Terminallydisubstituted allenyl indoles 37 b and even 2-(5,6-hepta-dienyl)indole 39 underwent enantioselective hydroarylationwith high yields and excellent enantioselectivity. The stereo-selectivity of the hydroarylation was completely substrate-

controlled and involved an outer-sphere attack of the arene onthe activated gold–allene intermediate.

Kleinbeck and Toste reported the first example of anenantioselective gold(I)-catalyzed 1,2-alkyl migration based ona Wagner–Meerwein alkyl shift.[26] Employing chiral bis-gold(I)complex, [(R)-L3(AuCl)2] (L3 = 4-MeO-dimethylbiphep;Scheme 15), with sodium tetrakis[3,5-bis(trifluoromethyl)phe-nyl]borate (NaBArF) at �30 8C, various 1-allenylcyclopropanolsunderwent asymmetric ring expansion to provide cyclobuta-nones with a vinyl-substituted quaternary center. A loading ofonly 0.5 mol % of the air- and moisture-stable chiral gold(I)catalyst was sufficient to provide cyclobutanone 42 in 88 %yield with 89 % ee, even on a gram scale (Scheme 15). Initialcoordination of the cationic gold(I) species to the internaldouble bond of the allene followed by a Wagner–Meerwein1,2-alkyl shift generated the intermediate vinyl–gold(I) species.Subsequent protodeauration then released the catalyst toprovide the cyclobutanone.

Recently, Gagn� and co-workers reported the asymmetricgold(I)-catalyzed cycloisomerization of eneallenes to vinylcyclo-hexene derivatives.[27] Based upon the recent success of chiralbiarylphosphine ligands in asymmetric gold(I) catalysis, [(R)-

Scheme 13. Enantioselective gold(I)-catalyzed intramolecularhydroamination of diynamides.

Scheme 14. Enantioselective gold(I)-catalyzed hydroarylation of indoles.

Scheme 15. Enantioselective gold(I)-catalyzed 1,2-alkyl migration and itsproposed mechanism. NaBArF = sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate; DCE = dichloroethane.

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L4(AuCl)2] (L4 = 3,5-xylyl-binap; Scheme 16) was found to bethe most effective catalyst. For example, treatment ofeneallene 43 with [(R)-L4(AuCl)2] and AgOTf in nitromethane at

room temperature, afforded the regioisomeric vinylcyclo-hexenes 44 and 45 in 83 % combined yield and 72 % ee(Scheme 16). However, both the regioselectivity and the enan-tioselectivity of the products were dependent on the choice ofthe solvent and the counterion. Nitromethane was identifiedas the best solvent and employing OTs� as counterion provid-ed the highest regioselectivity (10:1 with 65 % ee), whereasOTf� as counterion gave the best enantioselectivity (72 % eewith 4:1 regioselectivity). Although the enantioselectivitieswere moderate in all cases, substrates with substitution on thealkene terminus and functional groups on the alkyl tether be-tween the alkene and allene functionalities were well tolerated.Most interestingly, the authors were able to obtain X-ray crys-tallographic data for the bis-gold(I) precatalyst [(R)-L4(AuCl)2] .A strong p–p stacking interaction between the twophosphorus-bound aryl groups is believed to be responsiblefor determining the chiral environment for the complex in thesolid state.

Toste and co-workers developed the transition metal-catalyzed enantioselective [2+2] cycloaddition of eneallenes toalkylidene-cyclobutanes.[28] For example, by employing a 1:2catalytic mixture of [(R)-L5(AuCl)2] (L5 = DTBM-segphos;DTBM-segphos = 5,5’-bis{di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino}-4,4’-bi-1,3-benzodioxole; Scheme 17) and AgBF4,eneallene 46 afforded cyclobutane derivative 47 in 92 % yieldwith 95 % ee (Scheme 17). Allenenes with various substitutedstrenyl groups and substitutions on the alkyl tether betweenthe allene and alkene moiety were well tolerated, providingthe cyclobutane derivatives in moderate yields but excellentenantioselectivities. According to the authors, nucleophilicattack of the gold(I)-activated allene generated cis-disubstitut-ed vinyl–gold(I) intermediate 48. Subsequent, reaction of thevinyl–gold species with the benzylic carbocation intermediatethen afforded the cyclobutane 47 (Scheme 17).

In a more recent example of enantioselective gold(I)-cata-lyzed intramolecular [4+2] cycloaddition of allenedienes, Mas-

carenas and co-workers reported the use of chiral phosphor-amidite gold complexes. A catalyst loading of only 2 mol %was required to afford the cycloadducts in excellent yields (upto 93 %) and enantioselectivities (up to 92 % ee ; Scheme 18).[29]

Furthermore, the chirality of the bis(phenylethyl)amine moietyon the chiral phosphoramidite was found to dictate the abso-lute stereochemical outcome of the cycloadduct. The reactionrepresents one of the first examples of an asymmetric reactioninvolving a mononuclear phosphorus-based carbophilic gold(I)complex.

Toste and co-workers also reported the enantioselectivegold(I)-catalyzed intramolecular [4+2]-cycloaddition of alleneswith dienes to afford trans-hexahydroindenes and pyrroli-dines[30] with the use of C3-symmetric monodentate phosphitegold(I) and o-arylphosphoramidite gold(I) complexes(Scheme 19). The reaction tolerated substitution on both thediene and the allene moiety in all examples. The trans-fusedbicyclic compounds were obtained exclusively. Interestingly,

Scheme 16. Gold(I)-catalyzed cycloisomerization of eneallenes.Scheme 17. Enantioselective gold(I)-catalyzed [2+2] cycloaddition reactionand its proposed mechanism.

Scheme 18. Enantioselective gold(I)-catalyzed [4+2] cycloaddition reaction.

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the gold catalyst could be recovered during the purification ofthe product through column chromatography and reapplied inthe cycloaddition reaction.

In one of the earliest examples of N-nucleophilic addition toallenes, Toste and co-workers reported the enantioselectiveintramolecular hydroamination of N-allenyl sulfonamides usingchiral bis-gold(I) biarylphosphine complex [(R)-L4(AuCl)2] .[31]

Interestingly, detailed studies indicated the enantioselectivityof the reaction to be highly dependent on the counteranioninvolved and a dramatic increase in the enantioselectivity wasbrought about by the use of sterically coordinating counter-ions, such as benzoate (up to 98 % ee ; Scheme 20). However,

the best results were obtained by employing preformedbis-gold(I) complex [(R)-L4(AuOPNB)2] , which led to increasedyields (up to 88 %), shorter reaction time (17 h), and high enan-tioselectivity (98 % ee). The reaction offered a large substratescope, with a variety of g-allenyl sulfonamides being suitablefor the reaction. By modifying the choice of the chiralbis-gold(I) complex, chiral piperidines were also obtained inexcellent enantioselectivities (up to 97 % ee).

However, hydroamination of allenes was not limited toN-allenyl sulfonamides. Based upon their success in the hydro-arylation of allenes with chiral bis-gold(I) complexes of thetype [(P

_P)(AuX)2] (P

_P = bidentate biarylphosphine, X = anion),

Widenhoefer and co-workers reported the enantioselectivehydroamination of N-allenyl carbamates (Scheme 21).[32] Initialinvestigations of the treatment of N-allenyl carbamate 55 awith a 1:2 catalytic mixture of [(S)-L2(AuCl)2] and AgOTs in tolu-

ene for nearly six days furnished 2-vinylpyrrolidine in 97 %yield with 65 % ee. Similar to the findings of Toste, both the ef-ficiency and the selectivity of the reaction was dependentupon the nature of the counteranion. Substitution of AgOTswith AgClO4 led to nearly a 1000-fold increase in the reactionrate without much effect on the enantioselectivity. Thereaction was effective for a variety of carbamate groups andtolerated terminal disubstitution on the allenyl moiety but washighly sensitive to substitution on the C2 position of the alkylchain tethered to the allenyl moiety. Axially chiral N-allenyl car-bamates formed pyrrolidines with high diastereoselectivity butpoor enantioselectivity.

More recently, Widenhoefer reported that axially chiralallenes underwent dynamic kinetic enantioselective hydro-amination (DKEH) to predominantly form only one of fourpossible 2-vinyl pyrrolidine stereoisomers.[33] For example, thereaction of trisubstituted allenyl carbamate 57 with a catalytic1:2 mixture of [(S)-L2(AuCl)2] and AgClO4, under the sameconditions as above, gave a 3.1:1 mixture of (Z)-58 and(E)-58 in 94 % combined yield with 96 % and 76 % ee,respectively (Scheme 22).

With their recent success in the asymmetric hydroarylationand hydroamination of allenes, Widenhoefer and Zhangreported the enantioselective gold(I)-catalyzed intramolecularexo-hydroxylation of g- and d-hydroxyallenes to 2-vinyl tetra-hydrofurans.[34] For example, treatment of g-hydroxyallene 59with a 1:2 catalytic mixture of chiral bis-gold(I) complex[(S)-L2(AuCl)2] and AgOTs at �20 8C gave tetrahydrofuran 60 in67 % yield with 93 % ee (Scheme 23). Hydroxyallenes withaxially chiral allenyl moieties were just as effective, providingthe tetrahydrofurans in high yields and excellent enantioselec-tivities (up to 95 % ee). Furthermore, substitution on the alkyltether was crucial for high enantioselectivity as unsubstitutedalkoxyallenes provided the diastereomeric tetrahydrofurans inexcellent yield but poor enantioselectivity (<40 % ee). Interest-ingly, the configuration of the sp3 stereocenter in the product

Scheme 19. Ligand-enhanced enantioselective gold(I)-catalyzed [4+2] cyclo-addition reaction.

Scheme 20. Gold(I)-catalyzed enantioselective intramolecularhydroamination of N-allenyl sulfonamides. OPNB = p-nitrobenzoate.

Scheme 21. Enantioselective gold(I)-catalyzed hydroamination of N-allenylcarbamates. Cbz = carbobenzyloxy.

Scheme 22. Gold(I)-catalyzed dynamic kinetic enantioselectivehydroamination of N-allenyl carbamates.

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was completely dependent on the absolute configuration ofthe chiral catalyst. This protocol was further applied to thecyclization of d-hydroxyallenes to form the correspondingsubstituted tetrahydropyran 64 in 96 % yield with88 % ee (Scheme 23).

Asymmetric alkene activation

Although cationic Au-activated alkene hydroamination hasbeen reported,[35] later studies regarding HOTf catalysis for sim-ilar transformations generated concern as to whether cationicAu complexes were effective catalysts for alkene activation.[36]

As a result, very few asymmetric alkene activation exampleshave been reported.

Very recently, Bandini and Eichholzer reported the synthesisof enantiomerically enriched vinyltetrahydrocarbazoles fromunactivated alkenes through a gold(I)-catalyzed ring-closingFriedel–Crafts alkylation reaction of indolyl alcohols.[37] Reactionof indolyl alcohol 65 with chiral bis-gold(I) biarylphoshphinecomplex [(S)-L2(AuCl)2] and AgOTf provided 1-vinyltetrahydro-carbazole 66 in 78 % yield with 88 % ee (Scheme 24). Thechoice of counterion was crucial for both the efficiency andenantioselectivity of the reaction, with OTf� acting as the bestcounterion. Both 3- and 2-indolyl alcohols were found to besuitable for the reaction, affording the 1- and 4-vinyltetrahy-drocarbazoles, respectively. A wide range of functional groupson the indolyl moiety were tolerated, providing the tetrahydro-carbazoles in good yields and high enantioselectivities (up to92 % ee). Although conclusive mechanistic evidence was notobtained, the authors proposed the simultaneous activation of

the alkene and hydroxy group by gold(I) followed by an outer-sphere attack of the nucleophile. This method was one of thefirst examples of a gold(I)-catalyzed transformation involvingunactivated alkenes.

Although successful examples of Au-catalyzed asymmetricalkene activation were rare, asymmetric additions to alkene bychiral Au catalysts have been reported recently. Toste andco-workers reported the catalytic enantioselective 1,3-dipolarcycloaddition of m�nchnones (mesoionic azomethine ylides)with electron-deficient alkenes.[38] Interestingly, the previouslyemployed binap–AuI benzoate complexes gave only modestyields, whereas planar chiral segphos complexes containingsubstitution on the phosphine aryl rings with more electron-rich substituents, such as DTBM and Cy, proved to be most ef-fective. For example, treatment of chiral bis-gold(I) complex,[(S)-L9(AuCl)2] (L9 = Cy-segphos) with azomethine ylide 67 andN-phenylmaleimide in a 10:1 ratio of THF and fluorobenzeneprovided substituted pyrroline 68 in 76 % yield with 95 % ee(Scheme 25). The reaction tolerated a large substrate scopeand a variety of electron-deficient alkenes and azalactoneswere found to be suitable. In all cases, only the exo-adductwas formed with excellent diastereo- and regioselectivity.

According to the authors, the reaction proceeded throughthe formation of a N-aurated 1,3-dipole generated by the de-protonation of the gold(I)-activated azalactone species, whichthen underwent cycloaddition with the electron-deficientalkene to give cycloadduct 69. Subsequent C�O bondcleavage and deprotonation provided the pyrroline product(Scheme 26).

Based upon their initial success in the intermolecular hydro-amination of terminal alkenes with cyclic ureas, Widenhoeferand co-workers reported an enantioselective variant of this re-action by employing chiral bis-gold(I) complexes of the generalformula [(P

_P)(AuCl)2] (P

_P = chiral biaryl bisphosphine ligand).[39]

For example, treatment of 1-methylimidazolidin-2-one 70 with1-octene with a 1:2 catalytic mixture of [(S)-L2(AuCl)2] andAgOTf in m-xylene at 100 8C for 48 h afforded 1-methyl-3-(octan-2-yl)imidazolidin-2-one 71 in 86 % yield with 76 % ee(Scheme 27). Various substituted imidazolidin-2-ones and ter-

Scheme 23. Enantioselective gold(I)-catalyzed intramolecular hydroalkoxyla-tion of g- and d-hydroxyallenes.

Scheme 24. Enantioselective gold(I)-catalyzed intramolecular allylic alkylationof indoles.

Scheme 25. Enantioselective gold(I)-catalyzed 1,3-cycloaddition.

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S. Sengupta and X. Shi

minal alkenes were found to be suitable, forming the exclusiveMarkovnikov hydroamination products with good yields andmoderate enantioselectivities. This result provides goodevidence for Au activation of alkenes, although othercoordination mechanisms cannot be ruled out at this moment.

In extension of their works on cationic gold(I)-catalyzedreactions of propargyl esters, Toste and co-workers reportedan enantioselective intermolecular cyclopropanation of vinylarenes with propargyl esters (Scheme 28).[40] Treatment ofpropargyl acetate 72 and styrene with a 1:2 catalytic mixtureof [(R)-L5(AuCl)2] and AgSbF6 provides cyclopropane 73 in 72 %yield with 60 % ee in greater than 20:1 diastereomeric ratio.Furthermore, by changing to more sterically hindered pivalate

esters and more-bulky substituent groups on the aromaticring, enantioselectivities as high as 94 % ee were achieved.

In a more recent example, Toste and co-workers carried outenantioselective intramolecular alkene cyclopropanation forthe synthesis of medium-sized rings with chiral gold(I) com-plexes.[41] This procedure clearly extends the scope of transitionmetal-catalyzed enyne cycloisomerization reactions, which areotherwise limited to the synthesis of 5- and 6-membered-ringcarbocycles (Scheme 29).

In continuation of this work, the same group later reportedan enantioselective carboalkoxylation reaction of propargylesters to give benzopyrans containing an all-carbon quaternarycenter with excellent enantioselectivity.[42] The efficiency andselectivity of the carboalkoxylation reaction were dependenton the substituents on the phosphine aryl ring of the chiralligand employed. For example, [(R)-L2(AuCl)2] provided benzo-pyran in 74 % yield with 97 % ee, whereas [(R)-L3(AuCl)2]provided afforded the same product with only 35 % ee(Scheme 30). Although substitution on the aryl ring was welltolerated, substrates with bulky substituents in the propargylposition gave lower yields, but the enantioselectivity remainedhigh.

A possible mechanism for the carboalkoxylation involves aninitial gold(I)-promoted 1,2-acyl migration to give a vinyl–gold(I) carbenoid followed by nucleophilic attack from theether oxygen to generate an oxonium intermediate. Subse-quent reaction between the allyl cation and allyl–gold(I) inter-mediates generated from the vinyl–gold(I) species affords thebenzopyran derivative 77 (Scheme 31).

Enantioselective AuI Catalysts with ChiralCounteranions

The majority of gold(I)-catalyzed enantioselective transforma-tions described in the previous sections relied on the applica-

Scheme 26. Proposed mechanism for the 1,3-cycloaddition reaction.

Scheme 27. Enantioselective bis-gold(I)-catalyzed intermolecularhydroamination of unactivated alkenes.

Scheme 28. Enantioselective gold(I)-catalyzed olefin cyclopropanation.

Scheme 29. Intramolecular enantioselective gold(I)-catalyzed olefin cyclopro-panation.

Scheme 30. Enantioselective gold(I)-catalyzed carboalkoxylation.

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Recent Advances in Asymmetric Gold Catalysis

tion of chiral ligands bound to the gold metal center forasymmetric induction. However, as a result of the linear twocoordinate geometry adopted by gold(I) complexes, the chiralligand is often placed far from the substrate and enantioselec-tivities are usually low. Toste and co-workers recentlyemployed chiral counteranions to induce enantioselectivity inthe gold(I)-catalyzed intramolecular hydrofunctionalization ofallenes as a very attractive alternative approach in conductingasymmetric gold catalysis.

In their previous reports on the intramolecular hydroamina-tion of N-allenyl sulfonamides, the enantioselectivities werefound to be significantly dependent upon the counteranionemployed. As a result, the authors investigated a completelydifferent approach by employing chiral counterions, wherebyinteractions between the cationic gold(I) metal center with thechiral counteranion would induce asymmetry.[43] Initial studiesof the intramolecular hydroalkoxylation of allenol 78 with[Ph3PAuCl] and chiral binapththol-derived phosphate silver salt(Ag[(R)-X1] ; Scheme 32) in dichloromethane, produced product79 in 89 % yield with 48 % ee. The enantioselectivity could befurther improved with the use of dinuclear gold(I) complexes

with bis(diphenylphosphinomethane) ligand (dppm) and em-ploying nonpolar solvents such as benzene (up to 97 % ee).The results clearly indicate the formation of an ion pair wherethe enantioselectivity is dependent upon the proximity be-tween the active gold(I) metal center and the chiral anion. Thisstrategy was not limited to hydroalkoxylation and could alsobe applied to the intramolecular hydroamination reactions ofallenes, where enantioselectivities as high as 99 % ee could beachieved.

Furthermore, simple combination of the chiral gold(I) com-plexes with chiral counterions led to an excellent enhancementin the enantioselectivity for challenging substrates. For exam-ple, employing chiral bis-gold(I) complex [(R)-binap(AuCl)2] andchiral counteranion (R)-X1, the highly challenging hydrocarbox-ylation of allenes was achieved with enantioselectivity as highas 83 % ee (Scheme 33). Interestingly, however, when the mis-matched combination of the chiral phosphine and chiral coun-teranion was employed, the product was obtained with lessthan 5 % ee, suggesting a strong synergistic effect between thechiral ligand and counteranion towards the asymmetric induc-tion. These results clearly represent the promising potential ofchiral phosphates in enantioselective gold(I)-catalyzed reac-tions. Noting that this method is not limited exclusively tochiral phosphates or to cationic gold(I) complexes, it may serveas a very powerful approach in chiral counterion-mediatedtransition metal catalysis.

Outlook

Even though homogeneous gold catalysis first originated withan enantioselective aldol reaction, it was only during the lastfew years that considerable success has been achieved. As pre-sented herein, enantioselective gold catalysis developed todate has either involved the transfer of chirality or employedthe use of enantiomerically pure gold complexes or counter-ions. When employing chiral gold complexes, bis-gold(I) com-plexes of the general formula [(P

_P)(AuX)2] (P

_P = axially chiral

biaryl bisphosphine ligand, X = counterion) have typically beenthe catalyst of choice, often incorporating chiral segphos andbiphep ligands and their derivatives, whereupon the high elec-tron density and added steric hindrance associated with bulkyalkyl groups have been shown to improve both the reactivityand selectivity of the reactions. More recently, researchers havebegun to stray from this family of biaryl bisphosphines toidentify new ligands such as chiral phosphates, and these ap-proaches may very likely lead to the development of newenantioselective transformations. As an alternative approach,

Scheme 31. Mechanism of chiral gold(I)-catalyzed carboalkoxylation.

Scheme 32. Enantioselective gold(I)-catalyzed hydrofunctionalization ofallenes based on chiral anions.

Scheme 33. Enantioselective gold(I)-catalyzed carboalkoxylation.

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S. Sengupta and X. Shi

the chiral counterions strategy indicated a fundamentally newapproach in facilitating asymmetric Au catalysis, representing avery powerful tool for researchers in this field.

Although great success has been achieved in the enantio-selective gold catalysis, key challenges still remain. Exactmechanistic details relating to enantioselective bis-gold(I) com-plex-catalyzed transformations are still lacking. Although X-raycrystallographic data for the bis-gold complexes indicate astrong p–p stacking interaction, which was believed to deter-mine the chiral environment in the solid state, whether theseinteractions still exist in solution or in the cationic gold(I) com-plexes is unclear. A greater understanding of these catalystswould clearly allow for a rational catalyst design, thereby lead-ing to increased reactivity and enantioselectivity of futuregold(I)-catalyzed transformations. Furthermore, whether boththe gold centers play an active role in catalysis is still unclear.A general model to explain the stereoinduction would behighly beneficial to future researchers in this field. Eventhough employing chiral counteranions for gold(I)-catalyzedhydrofunctionalization of allenes has proven quite successful,its applicability as a general approach in enantioselective goldcatalysis remains unknown.

Keywords: asymmetric catalysis · chirality · enantioselectivity ·gold · homogeneous catalysis

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Received: March 15, 2010Published online on May 18, 2010

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Recent Advances in Asymmetric Gold Catalysis