Recent advances in the gold-catalyzed additions to C–C multiple bonds

C–O, C–N and C–C bonds are the most widespread types of bonds in nature, and are the cornerstone of most organic compounds, ranging from pharmaceuticals and agrochemicals to advanced materials and polymers. Cationic gold acts as a soft and carbophilic Lewis acid and is considered one of the most powerful activators of C–C multiple bonds. Consequently, gold-catalysis plays an important role in the development of new strategies to form these bonds in more convenient ways. In this review, we highlight recent advances in the gold-catalyzed chemistry of addition of X–H (X = O, N, C) bonds to C–C multiple bonds, tandem reactions, and asymmetric additions. This review covers gold-catalyzed organic reactions published from 2008 to the present.


Introduction
Gold-catalyzed reactions have emerged as a powerful synthetic tool in modern organic synthesis. This past decade has been the boom time for homogeneous gold catalysis, which was rather limited in organic synthesis until the advantages of gold complexes as catalysts were discovered [1]. In comparison to other transition-metal catalysts, most gold-catalyzed reactions are atom-economic, remarkably mild with regard to reaction conditions, and most importantly, have a different reaction scope [2][3][4].
One of the most important fundamental reactions in goldcatalyzed synthesis is the addition of X-H (X = O, N, C) bonds to C-C multiple bonds, which features diverse functional group tolerance and the easy formation of carbon-carbon and carbon-heteroatom bonds [1,4,5]. Furthermore, the rapid growing area of tandem reactions has allowed chemists to assemble diverse complex molecular frameworks more conveniently. Although various research efforts have led to goldcatalyzed addition reactions, the area of asymmetric addition has only recently been pioneered. Currently, a broad range of chiral gold catalysts (or gold combined with chiral ligands) has been developed and screened. However, only limited success has been achieved. The most notable example is the chiral BIPHEP-based catalyst, which has been successfully employed in several asymmetric cycloadditions.
Several early reviews have summarized well the progress of gold-catalyzed reactions up to 2008 [6][7][8][9][10][11][12][13][14][15][16]. Since then, the expansion of this field has continued unabated as evidenced by more than 500 publications to be found in the literature. Herein, we summarize the new research efforts that cover several aspects of gold-catalyzed additions to unsaturated bonds: (i) X-H (X = O, N, C) bonds to C-C multiple bonds; (ii) tandem reactions; and (iii) gold-catalyzed asymmetric additions. The literature published from 2008 up to the February of 2011 is covered. Only the most important recent studies have been selected to demonstrate the significance of gold catalysis.

Gold-catalyzed C-O bond formations
The carbon-oxygen bond is one of the most widespread types of bonds in nature. Gold catalytic addition of oxygen nucleophiles to electronically non-activated C-C multiple bonds represents an attractive approach to the synthesis of functionalized ethers and ketones. In particular, the intramolecular addition of oxygen nucleophile to C-C multiple bonds has become a very effective tool in the synthesis of oxygen heterocycles from readily available starting materials [11].
The intramolecular addition of a hydroxy group to a carbon-carbon triple bond is an effective strategy to construct furan analogues. Du et al. reported a highly efficient Au-catalyzed cyclization of (Z)-enynols that proceeded under mild reaction conditions. This methodology provided rapid access to substituted furans 6 and stereo-defined (Z)-5-ylidene-2,5-dihydrofurans 7 in a regioselective manner from suitably substituted (Z)-2-en-4-yn-1-ols 5 [20]. A similar strategy has been applied to an efficient formation of substituted furans 9 through gold-catalyzed selective cyclization of enyne-1,6-diols 8 [21]. Nucleophilic attack of the hydroxy oxygen atom on 1-position to a gold-coordinated C-C triple bond formed the vinyl-gold complex. Surprisingly, no other cyclic compound formed by nucleophilic attack of the hydroxy oxygen atom on C-6-position to a gold-coordinated C-C triple bond was formed. A new efficient route to furans 11 by gold-catalyzed intramolecular nucleophilic attack of readily available heteroatom-substituted propargyl alcohols 10 has been developed by Aponick and co-workers [22]. For the formation of tetrahydropyran analogs 13 and 15, the gold(I)-catalyzed cyclization of monoallylic diols 12 and 14 is an efficient method (Scheme 2) [23,24].
In addition to common organic solvents, an attractive alternative is the use of ionic liquids as the reaction solvent, which often affords inexpensive, recyclable (and therefore environmentally benign), and sustainable catalyst systems. For example, Aksin et al. demonstrated that ionic liquids were highly suitable reaction media for the gold-catalyzed cycloisomerization of α-hydroxyallenes 16 to 2,5-dihydrofurans 17 (Scheme 3) [25]. The best system was found to be AuBr 3 in 6 ]. The cycloisomerization of various alkyl-or arylsubstituted α-hydroxyallenes gave corresponding 2,5-dihydrofuran with complete axis-to-center chirality transfer.
Rüttinger et al. reported a gold-catalyzed synthetic route for the preparation of enynes (Scheme 4) [26]. The gold-catalyzed cyclization provided the corresponding exo-enol ethers 19 in moderate to high yield with complete regioselectivity. By contrast, Wilckens et al. reported the gold-catalyzed endocyclizations of 1,4-diynes 20 to seven-membered ring heterocycles 21 [27]. The cyclization occurs exclusively in an endo-Scheme 2: Gold-catalyzed cycloaddition of alcohols. fashion under mild conditions and provides access to dihydrodioxepines and tetrahydrooxazepines.
The dioxabicyclo[4.2.1] ketal 23 and its further transformation product tetrahydropyran 24 were produced by an efficient gold(I) chloride catalyzed cycloisomerization of 2-alkynyl-1,5diol 22 [28]. A plausible mechanism for the gold-catalyzed transformation of dioxabicyclo[4.2.1]ketal 25 to tetrahydropyran 31 is outlined in Scheme 5. The gold catalyst activates one of the oxygen atoms to form the intermediates 26 or 27, which then rearrange to yield the oxonium intermediates 28 or 29, respectively. Gold(I)-catalyzed intramolecular cyclization of monopropargylic triols 32 has been reported to be a novel and mild ap-proach [29] for producing olefin-containing spiroketals 33 (and enantiomer) in excellent yields (Scheme 6). A range of variously substituted triols was prepared which were cyclized to give substituted 5-and 6-membered ring spiroketals. Similarly, the synthesis of the bisbenz-annelated spiroketal core 35 of natural bioactive rubromycins via a gold-catalyzed double intramolecular hydroalkoxylation was reported by Zhang and co-workers [30]. A tandem cyclization mechanism was proposed by the authors.
The first example of gold-catalyzed ring-opening addition of cyclopropenes has been developed by Lee's group [31,32]. The reaction of alkyl-disubstituted cyclopropene 36 with a series of alcohols generated the corresponding tert-allylic ethers 37 with high regioselectivity. Gold(I) catalysts were found to be unique and superior in terms of reactivity and regioselectivity. A notable observation in some of these studies is that gold(I) catalyzed rearrangement to furanones 39 and indenes 40 is observed upon introduction of ester and phenyl substituents on the cyclopropene (Scheme 7). AuPR 3 NTf 2 complexes (PR 3 = 41-45) are selective catalysts for the intermolecular Scheme 6: Gold-catalyzed cycloaddition of glycols and dihydroxy compounds. hydroalkoxylation of electron-poor alkynes of type R−C≡C−EWG and dimethyl acetylenedicarboxylate [33]. In reactions of phenylacetylene the ratio of vinyl ether 47 to ketal 48 can be controlled by the choice of catalyst (Scheme 8).
Scheme 11: Preparation of unsymmetrical ethers from alcohols.
Furthermore, it is possible to couple the 6-endo-dig cyclization with iodination and bromination of the presumed vinyl-gold intermediate. However, attempted alkoxychlorination with N-chlorosuccinimide failed. Intermolecular hydroalkoxylation of non-activated olefins catalyzed by the combination of gold(I) and electron deficient phosphine ligands has been developed [35]. Gold-catalyzed hydroalkoxylations of non-activated olefins 52 and simple aliphatic alcohols 53 gave unsatisfactory results. However, a significant improvement of reaction efficiency was observed by employing alcohol substrates bearing coordination functionalities. In addition, the catalyst system with electron deficient phosphines was also found to catalyze the desired reaction effectively (Scheme 10).
An efficient approach [36] for the preparation of unsymmetrical ethers from alcohols has been developed by utilizing  Ye et al. reported an expedient gold-catalyzed synthesis of dihydrofuran-3-ones 63, in which terminal alkynes 62 were used as equivalents of α-diazo ketones to generate α-oxo gold carbenes (Scheme 12) [37]. The α-oxo gold carbenes were produced via gold-catalyzed intermolecular oxidation of 62. This provides improved synthetic flexibility in comparison with the intramolecular strategy and offers a safe and economical alternative to those based on diazo substrates.
A number of interesting gold-catalyzed glycosylations have appeared in recent years. Ph 3 PAuOTf is reported to be a superior catalyst (yield increases by >20%) compared to convention- β-galactosides 69 stereoselectively and in much higher yields compared to those obtained with 2,3,4,6-tetra-O-acetyl-α-Dgalactopyranosyl bromide [40]. Subsequently, a method to activate the propargyl 1,2-orthoesters 70 selectively in the presence of propargyl glycosides and propargyl ethers was developed [41]. Recently, Li et al. reported the gold(I)-catalyzed glycosylation with glycosyl ortho-alkynylbenzoates 73 as donors [42]. This glycosylation protocol was used in an efficient synthesis of a cyclic triterpene tetrasaccharide 74, which demonstrated its versatility and efficacy. Another study [43] showed that 1,6anhydro sugars 76 and 78 could be synthesized by utilizing salient features of gold-catalyzed glycosidations.

Carboxylates as nucleophiles
Seraya has reported the gold-catalyzed rearrangement of cyclopropenylmethyl acetates as a route to (Z)-acetoxydienes [48]. Thus, treatment of 4-nitrobenzaldehyde derived cyclopropene 90 with a catalytic amount of PPh 3 AuNTf 2 in DCM led to quantitative formation of acetoxy diene 91 with a 4:1 Z:E selectivity within 5 min at −50 °C. Wang et al. developed an efficient method for the preparation of polysubstituted C-vinyl butyrolactones through a gold-catalyzed highly diastereoselective cyclization of malonate substituted allylic acetates [49]. 96 in 85% yield (Scheme 17) [50]. This result could provide the experimental evidence required to support the postulated mechanism of Au-catalyzed reactions.
Dual-catalyzed rearrangement reactions have been reported by Shi and co-workers for the preparation of substituted butenolides 101 and isocoumarins [51]. In this study, the authors employed a carbophilic Lewis acidic Au(I) catalyst to catalyze the cross-coupling reactivity of a second Lewis basic Pd catalyst in order to functionalize vinyl-gold intermediates arising from intramolecular substrate rearrangements (Scheme 18).
Mechanistically, it was proposed that the enones 103 were produced through two pathways (Scheme 19).

Gold-catalyzed C-N bond formations
Many organic compounds containing nitrogen exhibit important biological and pharmaceutical properties. As with goldcatalyzed C-O bond formation, the directly catalytic addition of a nitrogen nucleophile to a C-C multiple bond represents an attractive approach to the formation of C-N bonds [55]. This is a direct and efficient procedure for the synthesis of nitrogen containing compounds of industrial importance.

Alkyl-and aromatic amines as nucleophiles
Imines and oximes are versatile synthetic intermediates for the preparation of dyes, pharmaceuticals, and agricultural chemicals. Sun et al. have reported a multi-task Au/hydroxyapatite reagent for the heterogeneous catalyzed oxidation of alcohols and amines to imines or oximes [56]. N-alkylation of primary amines is an important reaction in organic synthesis. He et al. developed an efficient gold-catalyzed one-pot selective N-alkylation of amines with alcohols [57]. In their study, gold nanoparticles supported on titania act as an efficient heterogeneous catalyst for the reaction to give the N-alkylated amines in excellent yields (Scheme 21).
Zeng and co-workers reported that cationic gold(I) complexes promote the addition of all types of non-tertiary amines 120 to a variety of allenes 121 to afford allylic amines 122 in good to excellent yields [58]. Importantly, the Markovnikov adduct was obtained in all cases. A similar Markovnikov hydroamination [59] could also be achieved via an intermolecular hydroamination of allenamides 123 with arylamines under mild AuPPh 3 OTf catalysis conditions to furnish allylamino (E)enamides stereoselectively (Scheme 22).
Hesp and co-workers have identified a gold pre-catalyst 125 featuring a P,N-ligand that has significantly extended the substrate scope and synthetic utility of alkyne hydroamination [60]. The hydroamination of unsymmetrical internal aryl acetylenes 126 with dialkylamines 127 has been achieved with synthetically useful regioselectivities. In addition to intermolecular addition, Mukherjee and Widenhoefer recently reported a gold(I)-
Huang et al. has developed an efficient gold-catalyzed method to access piperidinyl enol esters 155 and piperidinyl ketones 156 under mild reaction conditions from ε-N-protected propargylic esters 154 [71]. This intramolecular piperidine cyclization methodology shows different reactivity and substrate applicability compared with the former intermolecular nucleophilic addition. The mechanism speculated by the authors involves a goldcatalyzed intramolecular rearrangement followed by nucleophilic attack of the Boc-protected nitrogen atom. A similar method to synthesize the 2-vinylpiperidin-3-ol 158 by a highly stereoselective gold-catalyzed allene cyclization has been reported (Scheme 27) [72].
The ring expansion of cyclopropane derivatives provides a powerful method to construct synthetically useful fourmembered carbocycles. Ye et al. reported a new type of gold(I)catalyzed ring expansion of an non-activated alkynylcyclopropane/sulfonamide to obtain (E)-2-alkylidenecyclobutanamines [73]. For example, treatment of alkynylcyclopropane 159 with TsNH 2 and 5 mol % PPh 3 AuCl/5 mol % AgOTf in dichloroethane at 80 °C gave alkylidenecyclobutanamine 160 in 65% yield as a single olefin isomer (Scheme 28).  The formation of tri-and tetrasubstituted pyrroles 163 [74] via cationic N-heterocyclic carbene-gold(I) complex catalyzed amino Claisen rearrangement of N-propargyl-β-enaminone derivatives 161 and the cyclization of α-allenyl-β-enaminone intermediates has been developed by Saito and co-workers (Scheme 29) [75]. Toste's group has reported a novel gold(III)catalyzed [3 + 3]-annulation of azomethine imines 165 with propargyl esters 164. Substitution of the β-position of the pyrazolidinone generally provides the bicyclic product 166 with high cis selectivity, which is determined during ring closing rather than in the formation of allyl-gold intermediate [76].
A simple, convenient, and green synthetic approach to diverse fused xanthines 182 has also been developed by gold-complex catalyzed intramolecular hydroamination of terminal alkynes 181 under microwave irradiation in aqueous media (Scheme 33). This transformation is atom-economical and has high functional group tolerance [83].

Gold-catalyzed C-C bond formations
The formation of carbon-carbon bonds by using various transition metals such as Pd, Ni, Ru, Rh has been extensively investigated and is well documented in the literature. Recent years have witnessed a tremendous growth in the number of gold-catalyzed highly selective chemical transformations. Although gold was considered to be an inert metal for a long time, its ability to behave as a soft Lewis acid has only been recently recognized. Such a property allows it to activate unsaturated functionalities such as alkynes, alkenes, and allenes, to create C-C bonds under extremely mild conditions [15].

Intermolecular coupling
An unprecedented homogeneous gold-catalyzed oxidative cross-coupling which leads to α-arylenones 190 from propargylic acetates 189 and arylboronic acids has been developed by Zhang's group (Scheme 35) [86]. This cross-coupling reaction reveals the synthetic potential of Au(I)/Au(III) catalytic cycles. allenamide and 1-methylindole with 5.0 mol % of PPh 3 AuNTf 2 in CH 2 Cl 2 at room temperature gave the corresponding enamide in 83% yield.
Gold-catalyzed direct carbon-carbon bond coupling reactions have been less explored [88,89]. In 2008, Li et al. reported a gold(I) iodide catalyzed Sonogashira reaction [88]. Terminal alkynes 197 reacted smoothly with aryl iodides and bromides 198 in the presence of 1 mol % AuI and 1 mol % dppf to generate the corresponding cross-coupling products 199 in good to excellent yields (Scheme 37). Another direct carbon-carbon bond coupling reaction was reported by Tarselli and co-workers [90]. In their study, the addition of nucleophilic methoxyarenes 200 to allenes 201 proceeded at room temperature in dichloromethane with a catalytic amount of phosphite-gold(I) pre-catalyst and a silver additive. Notably, the addition is regioselective for the allene terminus, and generates (E)-allylation products 202.
The direct C-H functionalization of indoles or pyrroles is an efficient method for the introduction of vinyl and aryl groups. A gold-catalyzed direct alkynylation of indole and pyrrole heterocycles 204 with a benziodoxolone-based hypervalent iodine reagent 203 has been developed [91]. The functional group tolerance was greatly increased when compared with direct alkynylation of indoles reported previously. Kar  ates a wide range of functional groups [92]. All halogens survive the reaction, which provides the potential for further reactions.

Rearrangements and ring enlargement
A gold-catalyzed rearrangement of 6-alkynylbicyclo[3.1.0]hexen-2-enes 209 has been developed [93]. In this reaction, divergent structural rearrangements are observed in the absence/presence of nucleophiles. The process results in a novel five-to-six-membered ring expansion that involves cleavage of the bridging C-C bond and a formal [1,2]-alkynyl shift. Li et al. reported the first gold-catalyzed reaction of propargylcyclopropene systems 212 which affords benzene derivatives 213 in high yields [94] (Scheme 39).
Only few efficient methods have emerged for the synthesis of cyclobutane derivatives, which are important structural units in several natural products. Li et al. reported a novel goldcatalyzed oxidative ring-expansion of non-activated cyclopropylalkynes using Ph 2 SO as an oxidant [95]. Various alkynylcyclopropane derivatives 214 have been converted to cyclobutenyl ketones 215 in moderate to high yields under optimal conditions. Zou et al. has developed a versatile approach to 5-, 6-, and 7-membered carbocycles via the goldcatalyzed cycloisomerization of cyclopropyl alkynyl acetates [96]. The homo-Rautenstrauch rearrangement of 1-cyclopropylpropargylic esters 216 gave cyclohexenones 217 under mild conditions. Toste's group reported a gold(I)-catalyzed sequential cycloisomerization/sp 3  (Scheme 39) of 1,5-enynes 218 and 1,4-enallenes to yield tetracyclododecane 219 and tetracyclotridecane derivatives, respectively [97]. These transformations represent rare examples of sp 3 C-H bond insertion via a cationic gold(I)-carbenoid intermediate.

Cycloadditions
Intramolecular [M + N]-type cycloaddition reactions are powerful tools for accessing complex molecular frameworks [98]. Several gold-catalyzed [ [3 + 2] cycloadditions to afford cis-fused dihydrobenzo[a]fluorenes 221 efficiently and selectively [99]. As pointed out by the researchers, the reactions proceeded with the initial formation of trans/cis mixtures of 2-alkyl-1-isopropyl-2phenyl-1,2-dihydronaphthalene cations, which were converted into the desired cis-fused cycloadducts through the combined action of a gold catalyst and a Brønsted acid. Gung and co-workers developed a 3,3-rearrangement/transannular [4 + 3] cycloaddition reaction (Scheme 40) in the presence of either a Au(I) or Au(III) catalyst [109]. In these reactions, the regiochemistry of the product 223 is controlled by the position of the acetoxy group in the starting material 222, while the stereochemistry of the reaction depends on the ring size.
Cheong and co-workers demonstrated that 1,5-allenynes 242 could be transformed to cross-conjugated trienes 243 via rearrangement with [(Ph 3 PAu) 3 O]BF 4 as the catalyst [121]. Computational results indicated that the ene-reaction proceeded through a unique nucleophilic addition of an allene double bond to a cationic phosphine-gold(I)-complexed phosphine-gold(I) acetylide, followed by a 1,5-hydrogen shift (Scheme 44).
A range of indole based cycloaddition products were obtained by concerting the initial regioselective site-selective indole attack (C3 position) to the C-C multiple bonds [132][133][134]. In the case of gold(I)-catalyzed reactions initiated by 1,2-indole migrations [132], the starting material, indole 247, was converted to an intermediate with [AuNTf 2 (Ph 3 P)]. Intramolecular attack of the indole on the activated alkyne gives the vinyl-gold complex, which is transformed into the gold carbene complex through a 1,2-migration of the indole. Further intramolecular nucleophilic attack of the phenyl group on the carbene carbon center, followed by a re-aromatization step and subsequent protodemetalation, affords 248 as the final product. Treatment of N-tethered 2,3-butadienyl-1H-indole 249 with di-tert-butyl(o-biphenyl)phosphine and AuNTf 2 led to 6-endo cyclization [133]. The methodology was applied in a direct synthesis of the relevant 6,9-dihydropyrido[1,2-a]-1H-indole core 250. A similar strategy was adopted by Ferrer and co-workers [134], who prepared the 1H-azocino [5,4-b]indole skeleton 252 of the lundurines by the 8-endo-dig cyclization of the alkynylindole 251 using gold(III) chloride as the catalyst (Scheme 45).
Insertion of a C-H bond into a metal-carbenoid is a highly useful method for forming a new carbon-carbon bond. An atypical gold-carbenoid induced cleavage of a sp 3 -hybridized C-H bond can be achieved by undergoing 1,3-addition to a vinyl-carbenoid intermediate [142]. The bicyclo[3.2.1]oct-6-en-2-ones 265 and 267 could be synthesized stereoselectively by this method. Deuterium labeling experiments indicated the cyclization involved an unprecedented 1,3-addition of a sp 3hybridized C-H bond to the vinyl-carbenoid moiety (Scheme 47).

Gold-catalyzed tandem reactions
Tandem catalysis refers to the synthetic strategies of modular combination of catalytic reactions into one synthetic operation with minimum workup or change in conditions [143]. The goldcatalyzed tandem reactions have allowed chemists to assemble diverse complex molecular frameworks more conveniently.

Sequential inter-and intramolecular reactions
Phenanthrenyl ketones are very important subunits in material science and also occur in numerous natural products. A goldcatalyzed cascade Friedel-Crafts/furan-yne cyclization/ heteroenyne metathesis was developed for the highly efficient construction of phenanthrene derivatives 270 [144]. Both AuCl 3 and PPh 3 AuCl are effective catalysts for all the processes in the reaction and a variety of diyne substrates 271 could be used (Scheme 48). Similar strategies [145,146] were applied to synthesize arylated (Z)-enones, -enals or dihydrocyclohepta[b]indole skeletons 277 by gold-catalyzed cascade Friedel-Crafts/furan (or indole)-alkyne cycloisomerizations (Scheme 48).
The polysubstituted butenolides 281 could be obtained through a gold-catalyzed multi-component tandem reaction that  An intermolecular hetero-dehydro-Diels-Alder reaction between captodative 1,3-dien-5-ynes 282 and non-activated nitriles was introduced by Barluenga and co-workers [148]. The sequence is promoted by both, gold(I) and gold(III) catalysts and leads to the regioselective formation of tetrasubstituted pyridines 289. The initial coordination of the triple bond to the gold catalyst forms intermediate 284, followed by the regioselective nucleophilic attack of the nitrile, leading to the formation of 285. Cyclization may occur through resonance structure 286 or 287 followed by final metal de-coordination (Scheme 50).

Sequential intramolecular reactions
Sequential intramolecular reactions result in the formation of multi-ring products from a single substrate [149]. In 2010, a concise synthetic method for the generation of fused indoles (291-293), by a gold-catalyzed cascade cyclization of diynes 290 was developed by Hirano and co-workers [150]. The reaction gave aryl annulated[a]carbazoles, dihydrobenzo[g]indoles, and azepino-or oxepinoindole derivatives through an intramolecular cascade 5-endo-dig hydroamination followed by a 6-or 7-endo-dig cycloisomerization. Dudnik et al. reported a gold(I)catalyzed cycloisomerization of propargylic esters 294 which led to unsymmetrically substituted naphthalenes 296 [151]. This cascade reaction involves a tandem sequence of 1,3-and 1,2migration of two different migrating groups. Jin and Yamamoto prepared the fused tri-and tetracyclic enones 298 through an efficient gold(III)-catalyzed tandem reaction, heteroenyne metathesis, and Nazarov cyclization of 1,3-enynyl ketones 297 [152]. The gold(III) catalyst exhibits dual roles for activating both the alkyne and carbonyl moieties (Scheme 51).
More recently, Liu et al. developed a gold(III)-catalyzed tandem rearrangement/cyclization reaction of β-phenoxyimino ketone 299 (produced from O-arylhydroxylamines with 1,3-dicarbonyl compounds in situ) to give 3-carbonylated benzofuran derivatives 300 [153]. Trisubstituted isoxazoles 303 were obtained from alkynyl oxime ether 301 through a gold-catalyzed domino reaction involving cyclization and subsequent Claisen-type rearrangement [154]. The presence of additional substituents on the allyl moiety required an increase in catalyst loading and a prolonged reaction time for complete consumption of the substrate (Scheme 52).
Liu et al. has developed two highly stereoselective cationic gold(I)-catalyzed tandem cyclization reactions of alkynylindoles 322 [160]. The reaction proceeds with remarkable retention of chirality and allows the efficient enantioselective synthesis of polycyclic indolines 327 from the corresponding enantiomerically enriched alkynylindole 326 (Scheme 55). Scheme 55: Gold(I)-catalyzed tandem cyclization approach to tetracyclic indolines.
The catalytic conversion of C(sp 3 )-Au bonds into C(sp 3 )-C(sp 2 ) bonds is an ongoing challenge. In 2010, Zhang's group reported the first example in an intermolecular oxidative cross-coupling manner [167]. In their pioneering work, carboamination, carboalkoxylation and carbolactonization of terminal alkenes 341 was achieved via oxidative gold catalysis and provided expedient access to various substituted Nor O-heterocycles (344-351) (Scheme 57). Deuterium labeling experiments were carried out to unveil the reaction mechanism. The results established the anti nature of the alkene functionalization and the indispensable role of Au(I)/Au(III) catalysis. Toste's group and Russell's group subsequently reported the aminoarylation and oxyarylation of alkenes (352 and 355) following a similar protocol [168,169]. In the gold-catalyzed intramolecular aminoarylation of alkenes, ligand and halide effects played a dramatic role for the addition to alkenes. The experimental studies suggest that the C-C bond-forming reaction occurs through a bimolecular reductive elimination. Furthermore, a gold-catalyzed three-component coupling was also developed for the oxidative oxyarylation of alkenes 358 via a similar strategy [170].
From the discovery and development of metal-carbenoids in cycloadditions with alkenes, as well as the internal redox reactions on alkynes, a further extensive investigation was focused on the new redox/cycloaddition cascades on alkynes to obtain azacyclic compounds 363 [171]. The central cores of the products were constructed through a formal [2 + 2 + 1] cycloaddition that involved α-carbonyl-carbenoids, nitroso species and external alkenes (Scheme 58).
A gold(I)-catalyzed cascade cyclization/oxidative crosscoupling process has been devised to prepare β-alkynyl-γbutenolides 366 directly from allenoates 364 and various terminal alkynes [172]. The González group developed an intermolecular reaction of internal alkynes and imines, in which the propargyl tosylates 367 react with N-tosylaldimines 368 to afford cyclopent-2-enimines 369 [173]. The final product was achieved through a 1,2-migration of the tosylate followed by the interaction with the imine and a Nazarov-like cyclization. Barluenga et al. reported a gold-catalyzed cascade reaction involving an unusual intramolecular redox process in which 5-heteroaryl-substituted ketone derivatives 372 were obtained from secondary 5-hexyn-1-ols 370 (Scheme 59) [174]. The first step is supposed to be an intramolecular addition of the hydroxy group to the internal carbon of the triple bond, which is similar to the mechanism mentioned above [161,163]. 6 Gold-catalyzed asymmetric addition reactions The chiral ligand used for the transition metal-catalyzed reactions are the main determinant of enantioselectivity. Although asymmetric catalysis using chiral organometal complexes and chiral organomolecules have shown many advantages and a range of catalytic asymmetric reactions have been well documented [175], gold-catalyzed asymmetric addition reactions do not feature often. More recently this situation has been changing with significant progress being made in this area. To date, a broad range of chiral catalysts have been developed. Despite the large amount of chiral ligands used, only a few provided good to high enantioselectivities. The best ee values have been obtained with thiourea-cinchonine [176], chiral carbene [177], BINAP [178][179][180], and BIPHEP [181][182][183][184][185][186][187][188][189][190] analogs.
In the study of enantioselective cyclization, for example, of 1,6enynes 381 for the synthesis of cyclopentane derivatives 382, Matsumoto and co-workers found chiral carbene-AuCl catalyst precursor 380 gave moderate enantioselectivity of up to 59% (Scheme 61) [177].  Gold(I)-catalyzed asymmetric cyclization of 1,3-dihydroxymethyl-2-alkynylbenzene chromium complexes 389 gave planar chiral isochromene-chromium complexes 390 with high enantioselectivity [179]. Enantioselectivities of the cyclized isochromene-chromium complexes are largely dependent on the combination of gold pre-catalysts and silver salts. The use of AgSbF 6 resulted in excellent enantioselectivities, regardless of the nature of the gold pre-catalyst (Scheme 63). Julolidine derivatives 396 were obtained via a highly enantioselective three-component (393-395) cascade reaction which involved an enantioselective [4 + 2] cycloaddition reaction catalyzed by a chiral phosphoric acid and a subsequent catalytic intramolecular hydroamination by a gold(I) complex (Scheme 64) [180]. Further studies revealed that the Brønsted acid is both a chiral catalyst for the asymmetric cycloaddition and assists to facilitate the gold complex catalyzed hydroamination.
Muratore et al. have reported an interesting example of C-N bond formation for the construction of chiral nitrogencontaining fused heterocycles 400 [191]. In this case, different alkynoic acids 397 were treated with Ph 3 PAuCl/AgOTf and tryptamines 398 in the presence of (R)-3,3'bis(triphenylsilyl)BPA 399. The multi-catalyst cascade products were isolated in good yields and with high ee values (Scheme 65).
BIPHEP is the most extensively used chiral atropisomeric biaryl diphosphine ligand in the gold catalytic enantioselective addi- tion. Although the gold catalysis has been well developed, the use of non-activated olefinic C-C double bonds is still largely unexplored due to the intrinsic inertness of C=C (with respect to allenes and alkynes) in taking part in nucleophilic addition reactions assisted by π-electrophilic activation [183]. The first example of a direct catalytic enantioselective Friedel-Crafts allylic alkylation reaction with alcohols was reported by Bandini's group [182]. In terms of stereo-induction, 3,5-(t-Bu) 2 -4-MeO-MeOBIPHEP 401 (Scheme 66) gave the best results. Their method exploits the unprecedented capability of chiral gold(I) catalysts to activate selectively prochiral π-activated alcohols 402 toward aromatic functionalization in a highly enantioselective manner. On the basis of the above results, the same group extended the substrate scope of the 3,5-(t-Bu) 2 -4-MeO-MeOBIPHEP-Au-catalyzed Friedel-Crafts-type alkylation to indolyl alcohols 404 bearing an unsaturated side chain at the C2 position of the indole [183]. 1,6-Enyne derivatives and their analogs are the most frequently used substrates for gold-catalyzed cycloisomerization. Chao et al. discovered that the combination of atropisomeric electron-rich and hindered chiral ligand 3,5-(t-Bu) 2 -4-MeO-MeOBIPHEP 401 with Au(I) and silver salts promoted the enantioselective hydroarylation/cyclization reaction of 1,6-enynes 406 under mild conditions [181]. Treatment of enynes with catalytic amount of 3,5-(t-Bu) 2 -4-MeO-MeOBIPHEP(AuCl) 2 and AgOTf in Et 2 O at room temperature for 15-20 hours led to the desired arylated products with ee values up to 98%. A similar strategy was also applied by the same group in the asymmetric Au(I)-catalyzed synthesis of bicyclo[4.1.0]heptene derivatives 410 via a cycloisomerization process of 1,6-enynes 409 [184].
Due to the strength of sp 3 C-H bonds and because it can be difficult for the metal to reach sterically hindered C-H bonds, direct functionalization of sp 3 C-H bonds remained a challenge for a long time. Recently, however, Zhang's group have presented the first example of an enantioselective redox-neutral domino reaction catalyzed by gold(I) that results in the direct functionalization of unreactive sp 3 C-H bonds. Furan-fused azepine derivatives 419 (including 420-422) have been obtained from enyne 418 with high enantioselectivities (Scheme 68) [185].
Toste's group developed the first example of a highly enantioselective polyene (423, 425, 427, 429) cyclization reaction in which transition metal-promoted alkyne activation serves as the cyclization initiating event [186]. The reactions of the enyne with the monocationic gold(I) complexes and AgSbF 6 were carried out in the presence of sterically encumbered phosphines.  [188]. Notably, the amount of catalyst could be reduced without significant loss of enantioselectivity or yield.

Conclusion
In this account, we have presented a summary of the recent gold catalysis which involves the addition of X-H (X = O, N, C) bonds to C-C multiple bonds, tandem reactions, and asymmetric additions. The variety of reactions reflects that gold catalysis has become a very innovative synthetic tool in modern organic chemistry. What is particularly worth mentioning is that the design or choice of chiral ligands together with gold catalysts is the key to attaining high asymmetric induction. Up to now, only a small proportion of the chiral ligands have been successfully introduced to gold-catalyzed reactions. Consequently, the development of new and efficient chiral ligands or chiral gold complexes is still a major challenge for the future.