Gold(I)-Catalyzed Activation of Alkynes for the Construction of Molecular Complexity

1.1. General Reactivity of Alkyne-Gold(I) Complexes 
For centuries, gold had been considered a precious, purely decorative inert metal. It was not until 1986 that Ito and Hayashi described the first application of gold(I) in homogeneous catalysis.1 More than one decade later, the first examples of gold(I) activation of alkynes were reported by Teles2 and Tanaka,3 revealing the potential of gold(I) in organic synthesis. Now, gold(I) complexes are the most effective catalysts for the electrophilic activation of alkynes under homogeneous conditions, and a broad range of versatile synthetic tools have been developed for the construction of carbon–carbon or carbon–heteroatom bonds. 
 
Gold(I) complexes selectively activate π-bonds of alkynes in complex molecular settings,4−10 which has been attributed to relativistic effects.11−13 In general, no other electrophilic late transition metal shows the breadth of synthetic applications of homogeneous gold(I) catalysts, although in occasions less Lewis acidic Pt(II) or Ag(I) complexes can be used as an alternative,9,10,14,15 particularly in the context of the activation of alkenes.16,17 Highly electrophilic Ga(III)18−22 and In(III)23,24 salts can also be used as catalysts, although often higher catalyst loadings are required. 
 
In general, the nucleophilic Markovnikov attack to η2-[AuL]+-activated alkynes 1 forms trans-alkenyl-gold complexes 2 as intermediates (Scheme 1).4,5a,9,10,12,25−29 This activation mode also occurs in gold-catalyzed cycloisomerizations of 1,n-enynes and in hydroarylation reactions, in which the alkene or the arene act as the nucleophile. 
 
 
 
Scheme 1 
 
Anti-Nucleophilic Attack to η2-[AuL]+-Activated Alkynes

For centuries, gold had been considered a precious, purely decorative inert metal. It was not until 1986 that Ito and Hayashi described the first application of gold(I) in homogeneous catalysis. 1 More than one decade later, the first examples of gold(I) activation of alkynes were reported by Teles 2 and Tanaka, 3 revealing the potential of gold(I) in organic synthesis. Now, gold(I) complexes are the most effective catalysts for the electrophilic activation of alkynes under homogeneous conditions, and a broad range of versatile synthetic tools have been developed for the construction of carbon−carbon or carbon−heteroatom bonds. Gold(I) complexes selectively activate π-bonds of alkynes in complex molecular settings, 4−10 which has been attributed to relativistic effects. 11 −13 In general, no other electrophilic late transition metal shows the breadth of synthetic applications of homogeneous gold(I) catalysts, although in occasions less Lewis acidic Pt(II) or Ag(I) complexes can be used as an alternative, 9,10,14,15 particularly in the context of the activation of alkenes. 16,17 Highly electrophilic Ga(III) 18−22 and In-(III) 23,24 salts can also be used as catalysts, although often higher catalyst loadings are required.
Structurally, Au(I) predominantly forms linear two-coordinate complexes, although higher coordination numbers are also possible. 30 A significant number of alkyne-gold complexes have been characterized 31, 32 and studied either in solution 32,33 or theoretically. 34 This selective activation of the alkyne moiety can explain a vast majority of the results experimentally observed for gold(I)-catalyzed cyclization of 1,n-enynes. Nevertheless, complexes of gold(I) with the alkene moiety of the enynes are also formed in equilibrium with the alkyne-gold complexes. 35 Indeed, well-characterized complexes of gold(I) with alkenes have been reported, 36 as well as with allenes 37 and 1,3-dienes. 38 Despite the fact that simple gold salts such as NaAuCl 4 or AuCl are active enough to catalyze several transformations, gold(I) complexes bearing phosphines or N-heterocyclic carbenes as ligands have found more wide-ranging applications. 39 The active species are often generated in situ by chloride abstraction from [LAuCl] upon treatment with a silver salt bearing a weakly coordinating anion.
Complexes [LAuY] only exist as neutral species when Y − is a coordinating anion (halides, carboxylates, sulfonates, and triflimide). The corresponding complexes with less coordinating anions, such as SbF 6 − , PF 6 − , or BF 4 − , are in most of the cases not stable. Although, species [AuL] + (also known as "naked gold complexes") are often suggested in mechanistic proposals, structural proof for their existence as stable, isolable species is still lacking. Here, for the sake of simplicity in mechanistic schemes throughout this review, LAu + is used as a surrogate of [LAuL′] + complexes, where L′ states for a relatively weakly bound ligand such as the substrate (alkyne or alkene), product, or solvent molecule.
It is important to remark that when the catalytically active species are generated in situ by chloride abstraction from complexes [LAuCl] in the absence of the alkyne or other unsaturated substrate, much less reactive chloride-bridged dinuclear species [LAuClAuL]Y are readily formed. 40 Formation of these dinuclear complexes could explain, at least partly, the erratic results that have been ascribed as the "silver effects" in reactions in which Ag(I) salts are used in situ to activate neutral gold(I) complexes [LAuY]. 41 Often, the most convenient catalysts for the activation of alkynes are complexes [LAuL′]X or [LAuX] bearing weakly coordinating neutral (L′) 42 or anionic ligand (X − ). 43 These complexes can enter catalytic cycles by ligand exchange with the unsaturated substrate, which proceed by associative mechanisms as observed for Au(I) and other diagonal d 10 metal centers. 44 Thus, large negative activation entropies characteristic of associative mechanisms have been determined for the rate determining ligand exchange reactions of substituted alkyne 45,46 and alkenes 36o on commonly used Au(I) catalysts. Although nitriles are frequently used as weakly coordinating neutral ligands, 1,2,3-triazole 46,47 or other related ligands 48 have also been employed.
The properties of gold(I) complexes can be easily tuned sterically or electronically depending on the ligand, consequently modulating their reactivity in the activation of alkynes, alkenes, and allenes. 27,29f,49 Thus, complexes containing more donating N-heterocyclic carbenes (3) are less electrophilic than those with phosphine ligands (4, 5) ( Figure  1). 28 Complexes with less donating phosphite ligands (6) and related species are the most electrophilic catalysts.
Gold(I) complexes bearing weak-coordinated ligands such as Me 2 S, thiodiglycol, or tetrahydrothiophene (tht) have been widely used for the preparation of soluble gold(I) complexes, commonly starting from a gold(III) source. 50 Complex [Au(tmbn) 2 ]SbF 6 (tmbn = 2,4,6-trimethoxybenzonitrile), in which gold(I) is supported by two nitrile ligands, can be used for the in situ preparation of a variety of chiral and achiral cationic complexes [LAu(tmbn)]SbF 6 , including complexes immobilized on a polymeric support. 42a Other immobilized gold(I) complexes have also been prepared. 51 The use of gold complexes bearing chiral ligands has led to the development of efficient asymmetric gold-catalyzed transformations. 52 Less common precatalysts used in gold(I)-catalyzed transformations are gold hydroxo complex IPrAuOH, which is activated in the presence of Brønsted acids, 53 open carbenes, 39c,54 and other related complexes, 55 which give rise to selective catalysts of moderate electrophilicity. Cyclopropenylylidene-stabilized phospenium cations, which behave similarly to classical triaryland trialkylphosphines, have also been used as ligands in goldcatalyzed reactions. 56 The effect of the counteranion has been studied in detail for several gold(I)-catalyzed transformations. 57,58 Thus, for the intermolecular reaction of phenylacetylene with 2-methylstyrene catalyzed by [t-BuXPhosAu(NCMe)]Y, it was found that yields increase depending on the counteranion in the order Y = OTf − < NTf 2 − < BF 4 − < SbF 6 − < BARF (BARF = 3,5,bis(trifluoromethyl)phenylborate). By using the bulky and noncoordinating anion BARF, yields are increased by 10−30% compared to those obtained when Y = SbF 6 − , probably due to a decrease in the formation of the unproductive σ,π-(alkyne)digold(I) complexes from the initial alkyne. 57

Scope and Organization of the Review
Homogeneous gold(I)-catalysis has experienced an outbreak in the past decade leading to the discovery of a remarkable amount of new synthetically useful transformations. Thus, in recent years many groups have used gold catalysis in key steps of total synthesis taking advantage of the unique catalytic ability of gold to build molecular complexity under mild reaction conditions. Several reviews have been published on gold(I)-catalyzed reactions of alkynes, enynes, and related substrates, 5,7,25−28,59 as well as on gold(I)-catalyzed reactions of allenes 60 and cascade gold-catalyzed reactions. 61 Moreover, specific reviews focused on gold-catalyzed carbon-heteroatom bond formation 62 and on the use of gold catalysis in total synthesis 63 have also been published. In this review, we will cover reactions of alkynes activated by gold(I) complexes, including recent applications of these transformations in the synthesis of natural products. According to the aim of this thematic issue, the main focus is on the application of gold(I)-catalyzed reactions of alkynes in organic synthesis, although reactions are organized mechanistically. Reactions of gold(I)-activated alkenes and allenes, as well as gold(III)-activated alkynes, will not be covered.
The discussion has been primarily organized based on the different reactions catalyzed by gold(I) complexes that alkynes can undergo. When possible, inter-and intramolecular processes, as well as the applications in total synthesis, are treated in specific subsections.

Addition of O-Nucleophiles to Alkynes
The effectiveness of gold(I) complexes for the activation of alkynes toward inter-and intramolecular nucleophilic attack has been demonstrated for a variety of heteronucleophiles. Due to relativistic effects, cationic gold complexes possess, besides a high π-acidity, a low oxyphilicity, 7 A well-known method for the addition of water and alcohols to alkynes uses toxic Hg(II) salts under acidic conditions. 64 Other less harmful although expensive transition-metal-based catalytic systems have also been described, 65 including the use of Au(III) salts. 66 The first examples of gold(I)-catalyzed addition of alcohols and water to alkynes were reported by the groups of Teles 2 and Tanaka, 3 respectively, employing air stable gold complexes [AuMe(L)] (L = phosphine, phosphite or arsine), which were activated in situ by protic acids to form acetals such as 7 or ketones 8 and 9 (Scheme 2). Markovnikov-type addition was observed in all cases, being reactive under these reaction conditions both terminal and internal alkynes. Despite its efficiency, this method suffers from several drawbacks, including the use of concentrated solutions of strong acids and relatively high catalyst loadings.
Although the catalytic hydration of alkynes with neutral Nheterocyclic carbene gold(I) chlorides or carboxylates in the presence of B(C 6 F 5 ) 3 was already demonstrated in 2003, 67 later in 2009 it was found that the use of gold(I) complexes bearing bulkier N-heterocyclic carbene ligands allowed to catalyze this process at loadings as low as <10 ppm under acid-free conditions (Scheme 3). 68 This catalytic system showed wide versatility, since both terminal and internal alkynes possessing any combination of alkyl and aryl substituents were suitable substrates. However, the reaction required high temperatures to proceed and for unsymmetrical internal alkynes only moderate regioselectivities were obtained. Alkynes can also be hydrated at room temperature without any acidic cocatalyst in the presence of gold(I)-phosphine complexes. 69 The regioselective hydration of haloalkynes was recently reported to afford α-halomethylketones 12 in excellent yields under very mild reaction conditions (Scheme 4). 70 This aldehyde or ketone under Brønsted acid conditions. When diols are added to alkynes in the presence of a gold(I) catalyst, cyclic acetals 13 are regioselectively formed instead of the unprotected carbonyls (Scheme 5). This reaction proceeds with complete regioselectivity in the case of terminal alkynes and with moderate selectivity for internal alkynes, yielding a mixture of cyclic acetals 13/13′. 72 The reaction can also be expanded to the preparation of acetals from 1,5-diols.
In a more recent example, α-bromo cyclic and acyclic acetals 14 and 15 were obtained from terminal alkynes and NBS (Scheme 6). 73 The reaction proceeded via formation of bromoacetylenes followed by addition of the O-nucleophiles to the triple bond.
The role of the anion in the intermolecular alkoxylation of alkynes catalyzed by N-heterocyclic carbene-based gold(I) complexes [(NHC)AuX] (X = BARF − , BF 4 − , OTf − , OTS − , TFA − , AcO − ) has recently been dissected, with the conclusion that both coordination ability and basicity have a great impact on this transformation. 74 The most important factor seems to be the ability to abstract the proton from the alcohol during the nucleophilic attack, which is directly related to the anion basicity.
Gold(I)-catalyzed intermolecular additions of alcohols to alkynes can be coupled with other tandem reactions, therefore increasing the degree of molecular complexity in the final product. 75 The addition of allylic alcohols to alkynes followed by a Claisen rearrangement of the resulting intermediates (16) has recently been developed, leading to the formation of γ,δunsaturated ketones 17 in an efficient one-pot procedure from simple starting materials (Scheme 7). 76 2.1.2. Intramolecular Addition of O-Nucleophiles to Alkynes. The high activity of gold(I) salts and complexes for C−O bond formation has been widely exploited intramolecularly to construct oxygen containing heterocycles. In this context, one of the most studied transformations is the intramolecular gold(I)-catalyzed cyclization of unactivated alkynols. 60b,77 As an example, alkynediols 18 underwent a gold(I)-catalyzed cyclization leading to furans 20 after elimination of H 2 O from intermediate 19 in the presence of very low catalyst loadings (Scheme 8). 78 The alcohol moiety may already be present in the precursor of the gold(I)-catalyzed transformation 79 or may be generated in situ from epoxides by ring opening. 80 Carbonyls can also act the nucleophiles. 81 Thus, alkynyloxiranes 21 were converted into trisubstituted furanes 22, 80b and alk-4-yn-1-ones 23 gave rise to 2,4,5-trisubstituted furans 24 or substituted 4H-pyranes 25 depending on the substitution pattern of the substrate (Scheme 9). 81b The reaction of alkynediols to give bicyclic acetals by gold(I)-catalyzed intramolecular hydroalkoxylation of terminal alkynes using bis-homopropargylic alcohols 31 was first described in 2005, opening a door to an interesting family of strained acetals 32 (Scheme 12). 85 Notably, the addition of methanol to alkene intermediates did not occur under the reaction conditions. Recently, the selective conversion of acetonide-tethered alkynes into bridged acetals through an analogous process using Ph 3 PAuCl and AgOTf in the presence of water was reported. 86 As described for intermolecular additions of O-nucleophiles, the intramolecular version can also be combined with subsequent tandem reactions in order to increase molecular complexity of the resulting products. One of the simplest examples is the tandem cycloisomerization/hydroalkoxylation of homopropargylic alcohols in the presence of an external alcohol to form tetrahydrofuranyl ethers 33 (Scheme 13). 87 Bishomopropargylic alcohols also react with gold(I) in a similar fashion, giving rise to methylene tetrahydrofuran motifs, which in the presence of an external nucleophile are the entry to a variety of structurally different products. 88 The formation of bicyclo[3.2.0]heptenes 35 was reported involving an intramolecular addition of an oxygen-containing nucleophile to a cyclopropyl alkyne 34 activated by gold(I) (Scheme 14). 89 The same group also developed an unprecedented gold(I)-catalyzed tandem reaction to form polysubstituted dihydrofurans from acetal-protected propargylic alcohols and carbonyl compounds. 90 The synthesis of tricyclic cage-like structures was described starting from diyne-diols by trapping the intermediate dienol ether, which results from a double intramolecular hydroalkoxylation with external nucleophiles. 91 The synthesis of 3-alkoxyfurans 37 from acetal-containing propargylic alcohols 36 has recently been reported. 92 Thus, these synthetically useful substrates can be easily prepared in two steps from readily available aldehydes, alcohols, and 3,3diethoxypropyne (Scheme 15).
In the case of alkynylketones or esters, the mechanism of the gold(I)-catalyzed hydration or alkoxylation involves the anchimeric assistance of the carbonyl group forming an intermediate that is opened back by one water or alcohol molecule leading to the final carbonyl compounds. 93 Diethynylketones 38 were converted into naphthol derivatives 40 by this ketone-assisted hydration followed by cyclization (Scheme 16).
In the formation of tricyclic spiroketones 44/44′ by tandem hydration/Conia-ene/aldol condensation, 93b the first step also takes place via anchimeric assistance of the carbonyl moiety to give intermediate 42 and not through direct addition of H 2 O to 41 (Scheme 17).
2-Alkynyl-1,5-diketones 45 undergo intramolecular oxygen transfer in the presence of AuCl via [4 + 2] cycloaddition to form cyclopentenylketones 48 (Scheme 18). 94 The mechanism of this transformation was proposed based on DFT calculations and also demonstrated by isotopic labeling experiments,  95 When Cu(OTf) 2 was used as the catalyst, 2,4cyclohexadienes 52 were formed, whereas in the presence of InCl 3 or gold(I) complexes, 1,3-cyclohexadienes 53 were obtained instead. The gold(I)-catalyzed transformation proceeds via intramolecular addition of the carbonyl to the alkyne, followed by a Diels−Alder reaction between the resulting pyrylium intermediate 50 and the alkene, and final demetalation.
Cascade-type sequences have also led to the formation of pyrane derivatives. 96 Tricyclic 2,3-benzopyranes 56 were synthesized by a tandem intramolecular hydroalkoxylation/ hydroarylation to obtain benzo-fused cyclic ethers. 97 Shortly later, a gold(I)-catalyzed tandem intramolecular hydroalkoxylation/Prins-type cyclization was described, affording oxygencontaining [3.3.2] bicyclic compounds 58 diastereoselectively (Scheme 20). 98 Spiroketals, which are key structural units in many biologically active natural products, can also be obtained by gold(I)-catalyzed intramolecular hydroalkoxylation of alkynediols and alkynetriols. 79,99 The use of an acetonide moiety to function as a regioselectivity regulator in the spiroketalization process has been proposed to address the possible regioselectivity issues in the formation of monounsaturated spiroketals. 100 The first multicomponent enantioselective gold(I)-catalyzed synthesis of spiroketals 59 has been recently described using a gold-phosphate catalytic system in a threecomponent coupling between alkynols, anilines, and glyoxylic acid (Scheme 21). 101 More recently, another synthesis of spiroketals has been reported combining a gold(I)-catalyzed cycloisomerization of an alkynol with an inverse-electrondemand hetero Diels−Alder mediated by Y(OTf) 3 . 102 Carboxylic acid derivatives, 103 carbonates, 104 carbamates, 105 sulfoxides, 106 boronic acids, 107 and related O-nucleophiles 108 can also add to alkynes (Scheme 22). Acetylenic carboxylic acids 60 undergo selectively an exo-cyclization providing functionalized γ-lactones 61. 103a Analogously, tert-butyl carbonates derived from homopropargyl alcohols 62 cyclize to afford cyclic enol carbonates 63 104b and N-Boc propargylamines 64 yield 1,3-oxazin-2-ones 65. 105b Gold(I) also promotes the rearrangement of homopropargyl sulfoxides 66 to give benzothiepinones 67 106a and the formation of boron enolates 70 from alkynes, which can be further transformed into other derivatives such as diols 71. 107 A gold(I)-catalyzed tandem sequence has been developed for the synthesis of dihydropyridones 76 from homopropargylic carboxamides 72 (Scheme 23). 109 After an intramolecular carbonyl addition of the homopropargylic amide to the alkyne, the formation of a σ-complex of the gold salt with the intermediate oxazine 73 promotes a nucleophilic addition of an external alcohol to form 74 followed by a Petasis-Ferrier rearrangement via 75. Based on this concept, a new protocol for the synthesis of benzyl alcohols has been described generating the benzylating agent upon treatment of N-Cbz-Nbenzyl-propargylamine with IPrAuNTf 2 . 110 This reaction takes place under very mild conditions and eliminates the need of base additives.

Addition of O-Nucleophiles to Alkynes in Total
Synthesis. The gold(I)-catalyzed formation of O-heterocycles is a powerful tool in the field of total synthesis of natural products. In the synthesis of (−)-atrop-abyssomicin C (82), 112 the bridged bicycle 81 was obtained via intramolecular 6-exodig cyclization of alkynol 80 (Scheme 25). Another remarkable example is found in the total synthesis of bryostatin 16 (85), 113 in which a gold(I)-catalyzed oxycyclization of alkynol 83 generates the dihydropyran cycle present in the natural product (Scheme 26). In the formal total synthesis of didemniserinolipid B, a gold(I)-catalyzed 6-endo-dig alkynol-cycloisomerization was considered as the key step to construct the bicyclic acetal skeleton. 114 Another example of gold(I)-promoted cycloisomerization of alkynols was recently reported in the total synthesis of (±)-cafestol. 115 In this work, the furan ring is constructed in a late-stage of the synthesis via intramolecular 5endo-dig cycloisomerization followed by dehydration.
The formation of spiroketal skeletons catalyzed by gold(I) has also been successfully applied in several total syntheses. 116 Okadic acid (86) is a natural occurring polyether containing three spiroketal motifs. The C15−C38 fragment was synthesized taking advantage of the high activity and selectivity of AuCl for the synthesis of spiroketals starting from alkynediols (Scheme 27). 117 The ability of carboxylic acid derivatives to add to alkynes in the presence of gold(I) complexes was exploited in the first total synthesis of neurymenolide A (94) 118 (Scheme 28) and in the synthesis of psymberin (97) 119 (Scheme 29).
A gold(I)-catalyzed tandem reaction of 1,7-diynes bearing a propargylic carboxylic acid was developed for the total synthesis of drimane-type sesquiterpenoids, 120 123 Another more recent example was developed using gold(I) complexes bearing 1,2,4-triazole-based N-heterocyclic carbene ligands for the formation of the corresponding ketimines from terminal alkynes and aniline derivatives. 124 125 These complexes are active catalysts for the regioselective intermolecular hydroamination of both internal and terminal alkynes under mild reaction conditions, showing a regioselectivity based on electronic rather than steric factors. This electronic control on the regioselectivity of alkyne hydroamination reactions had earlier been reported for the hydroamination of unsymmetrical electron-poor and electronrich alkynes with anilines (Scheme 31). 126 More challenging hydroaminations of less-reactive internal alkynes an unprotected aliphatic amines could be performed using a novel series of 1,2,3-triazole-based cationic gold(I) complexes, 47a which turned out to have a superior thermal stability than other catalysts previously reported.
Nowadays, as happens for the addition of O-nucleophiles to alkynes, gold(I)-catalyzed hydroamination of alkynes is not limited to the synthesis of imine or enamine products by formal addition of N−H reagents onto triple bonds. 123,127 Instead, a number of tandem sequences involving alkyne-hydroamination steps have been reported leading to the formation of more complex structures such as azaflavanones 101 128 or quinoline derivatives 102 129 (Scheme 32). Another example refers to a tandem intermolecular hydroamination/transfer hydrogenation catalyzed by gold(I) combined with a chiral Brønsted acid to form enantioenriched secondary amines 103 (Scheme 33). 130 This methodology tolerates a wide range of aryl, alkenyl, and aliphatic alkynes, as well as a range of anilines with different electronic properties.
An enantioselective tandem hydroamination/hydroarylation of alkynes has recently been reported using a gold(I)/chiral Brønsted acid binary system as catalyst. 131 In this transformation, the gold(I)-activated alkynes react with a range of pyrrole-based aromatic amines to give pyrrole-embedded aza- heterocyclic scaffolds bearing a quaternary center. Isoxazoles can also add to ynamides in the presence of gold(I) in a formal [3 + 2] cycloaddition to give polysubstituted 2-aminopyrroles. 132 The gold(I)-catalyzed intermolecular reaction between 2Hazirines and ynamides provides highly substituted pyrroles 105 in a formal [3 + 2] cycloaddition (Scheme 34). 133

Intramolecular Addition of N-Nucleophiles to
Alkynes. The intramolecular hydroamination of unactivated alkynes is a very useful tool to construct nitrogen-containing heterocycles. An efficient method to obtain pyrroles comes from the intramolecular dehydrative cyclization of amino-3alkyn-2-ols mediated by gold(I). 78b A similar catalytic system catalyzed a tandem direct amination/cycloisomerization from (Z)-2-en-4-yn-1-ols in the presence of an external amine to give substituted pyrroles under mild reaction conditions. 134 Alkynyl amidoalcohols undergo a gold(I)-catalyzed spiroamidoketalization giving rise to spiro-N,O-ketals with 5-and 6-membered rings presumably via tandem intramolecular 5-exo-dig hydroamidation/intramolecular oxycyclization. 135 Aryl-substituted N-tosyl alkynylaziridines 106 are prone to undergo a gold(I)-catalyzed ring expansion to form 2,5-(107) or 2,4-disubstituted pyrroles (108) depending on the solvent and the counterion of the gold complex (Scheme 35). 136 Similarly, the system Ph 3 PAuCl/AgOTf is able to catalyze the rearrangement of propargylic aziridines forming trisubstituted and cycloalkane-fused pyrroles. 137 This transformation involves an unusual tandem cyclization-opening/Wagner-Meerweein sequence. The selective formation of 2,5-disubstituted pyrroles catalyzed by the same Au(I)/Ag(I) system from acetylenyl aziridines was also described using THF as solvent, 138 finding that the presence of protic species such as MeOH increased the reaction rate and the yield of the pyrrole products.
A new method for the synthesis of substituted pyrroles 111 based on an intermolecular hydroamination process has recently been reported. 139 The reaction takes place by a tandem process consisting of an initial addition of a goldacetylide to an acetal moiety to form intermediate 110 followed The synthesis of N-heterocycles bearing −CN and −CF 3 groups at the α-position has been reported by intramolecular hydroamination coupled with the addition of external nucleophiles to the resulting enamine intermediate. 140 Depending on the relative position of the alkyne and the nucleophilic nitrogen, the cyclization can proceed by 5-exo-dig and 6-endo-dig pathways. In general, the electronic properties of the substituent of the alkyne play a crucial role in the control of regioselectivity. The presence of electron-donating substituents on the alkyne tends to favor 6-endo-dig cyclization pathway, whereas electron-withdrawing substituents favor the 5-exo-dig cyclization. One example of this regioselectivity reversal was reported in the cyclization of o-alkynylbenzyl carbamates 112 (Scheme 37). 141 However, other factors such as steric interactions have to be taken into account to predict the regiochemical outcome of intramolecular hydroaminations of internal alkynes having these two competing reaction pathways. In the case of terminal alkynes, most of the heterocyclizations afford 5-exo-dig products as a consequence of the better stabilization of the positive charge on the internal carbon of the triple bond.
Another example of exclusive formation of the 6-endo-dig cyclization product gave isoquinoline derivatives by a gold(I)mediated hydroamination of (2-alkynyl)benzyl carbamates. 142 Moreover, the hydroamination of alkynyl carbamates bearing an acetal or enone was applied to the synthesis of tetracyclic heterocycles such as 119 via a gold(I)-catalyzed tandem hydroamination/cyclization (Scheme 38).
Alkynylureas can also undergo intramolecular hydroamination processes in the presence of gold(I) catalysts. In general, oethynylarylureas bearing an internal alkyne lead to N1-attack-5endo-dig cyclizations, regardless of the gold(I) complex employed. In the case of 3-substituted 1-(o-alkynylphenyl)ureas 120, indole derivatives are formed (Scheme 39). O-Ethynylphenylureas can selectively undergo N3-attack-6-exodig cyclization when NHC-stabilized gold(I) complexes are used. 143 In contrast, in a similar gold(I)-catalyzed reaction previously reported, 1-(ortho-ethynylaryl)ureas bearing a terminal alkyne in aqueous media led exclusively to the corresponding indole under microwave heating through N1-5endo-dig cyclization. 144 This method provided indole-1carboxamides in moderate yields tolerating a variety of functional groups. 1H-Imidazol-[1,5-a]indol-3(2H)-ones were also prepared in the presence of a gold(I) catalyst starting from urea derivatives. 145 On the other hand, acyclic alkynylureas undergo O-attack-5exo-dig cyclization in the presence of gold(I). 146 This feature was exploited for the development of an asymmetric threecomponent tandem reaction from imines, terminal alkynes, and sulfonylisocyanates in which a single gold(I) species can catalyze both the alkynylation of aryl−aryl imines and the subsequent 5-exo-dig cyclization to afford enantioenriched fivemembered carbamimidates.

Addition of N-Nucleophiles to Alkynes in Total
Synthesis. The potential of gold(I) to construct nitrogen containing heterocycles has been demonstrated in several total synthesis. The intramolecular gold(I)-catalyzed alkyne hydroamination reaction provides an efficient entry to tetrahydroisoquinolines, as highlighted in the total synthesis of (−)-quinocarcin (127). 150 In the presence of [JohnPhosAu-(MeCN)]SbF 6 , 125 undergoes regioselectively a 6-endo-dig hydroamination forming the corresponding dihydroquinoline, which after reduction with NaBH 3 (CN) formed the desired tetrahydrosioquinoline 126 (Scheme 41). In another remarkable example, the key step in the total synthesis of (−)-rhazinicine (132) and (−)-rhazinilam (133) 151 was a gold(I)-catalyzed cascade cyclization of 128 initiated by an intramolecular 6-exo-dig nucleophilic addition of the nitrogen atom of the amide to the gold-activated alkyne to build the highly substituted indolizinone skeleton 131 (Scheme 42).

Addition of Other Heteronucleophiles to Alkynes
The gold(I)-catalyzed addition of heteronucleophiles to alkynes other than oxygen and nitrogen is by far a less developed transformation. Nevertheless, it has been described the attack of the sulfur atom of aryl thioethers to alkynes affording benzothiophenes 135 (Scheme 43). 152 This transformation has also been described in the presence of gold(III). 153 It was shown that aryl thiosilanes 136 can act as both sulfur nucleophiles and silicon electrophiles capturing the vinyl-gold intermediate in the gold(I)-catalyzed intramolecular reaction to afford 3-silylbenzothiophenes 138 (Scheme 44). 154 When enantiomerically pure o-alkynylphenyl-1-aryl ethyl sulfides were used as substrates for this transformation, complete chirality transfer was observed. 155 In an analogous transformation, the gold(I)-catalyzed alkoxyboration of alkynes provides a method for the preparation of O-heterocyclic boronic acid derivatives 140. 156 Moreover, in the presence of gold(I) complexes, dithiols can also add to alkynes to form cyclic thioacetals, 72 and homopropargylthiols bearing a propargylic alcohol lead to thiophenes after addition of the thiol to the gold-activated alkyne followed by dehydration. 78 A novel rearrangement was described for propargylic 1,3dithianes 141 when they were heated in the presence of Ph 3 PAuCl/AgSbF 6 . In this transformation, eight-membered dithiosubstituted cyclic allenes 142 were formed with good yields and remarkable stability (Scheme 45). 157 N-Heterocyclic carbene gold(I) bifluoride complexes have been shown to be efficient catalysts in the hydrofluorination of symmetrical and unsymmetrical alkynes. 158 This reaction proceeds in good to excellent yields with high stereo-and regioselectivity to afford fluorinated stilbene derivatives and fluorovinyl thioethers.

GOLD(I)-CATALYZED REACTIONS OF ALKENES WITH ALKYNES
3.1. Cycloisomerization of Enynes 3.1.1. General Mechanistic Aspects. Cycloisomerizations of 1,n-enynes are probably one of the most illustrative carbon− carbon bond forming reactions catalyzed by electrophilic metal complexes. These transformations are very useful in synthetic organic chemistry, since they provide access to complex molecular architectures from readily assembled starting materials through mechanistically complex, fully intramolecular processes.
The first example of electrophilic activation of enynes was reported back in the 1980s using palladium catalysts, 159 which promoted an intramolecular Alder-ene reaction. The Alder-ene cycloisomerization of enynes requires simultaneous coordination of both the alkyne and the alkene to the metal, followed by a two-electron oxidation of the metal, which is favorable for palladium(II) and also platinum(II). 160 However, the oxidation of gold(I) to form a gold(III) metallacycle is highly improbable under ordinary conditions. 161 In addition, [AuL] + cations are isolobal to H + , which makes the simultaneous coordination of the alkene and the alkyne highly unlikely. Therefore, in contrast to Pd(II) 159 and Pt(II), 162 gold(I)-catalyzed cycloisomerizations of enynes do not proceed via Alder-ene reaction. Instead, activation of the alkyne by gold(I) forms a (η 2 -alkyne)metal complex 143 that reacts as an electrophile with the alkene moiety either by 5-exo-dig or 6-endo-dig pathways to form the corresponding cyclopropyl gold carbenes 144 or 145 (Scheme 46), 45,163 which, in the absence of internal and external nucleophiles, evolve by different skeletal rearrangements. It is important to emphasize that these species show highly delocalized structures, which are intermediate between cyclopropyl gold(I) carbenes and gold(I)-stabilized cyclopropylmethyl/cyclobutyl/homoallyl carbocations. In general, π-backdonation from gold(I) to the carbene center is poor, 164,165 although it becomes more significant in complexes [LAuCR 2 ] + with highly donating N-heterocyclic carbene ligands. 166 Indeed, a few complexes with carbene-like structures showing relatively short Au(I)−C bonds have been structurally characterized. 167 The best-studied gold(I)-catalyzed reactions from a mechanistic point of view are cycloisomerizations of 1,6-enynes, which have often been used as model substrates for the discovery of new reactions and new catalysts activity. According to DFT calculations, the single-cleavage skeletal rearrangement occurs via opening of 144 to form η 2 -diene 146-gold(I) complexes in a single step by a 1,3-migration of the terminal carbon of the alkene to C(1) of the alkyne. 163b Six-membered ring compounds 147 arise from an alternative endo-type singlecleavage rearrangement in which the internal carbon of the double bond migrates toward C(1) of the alkyne. 168 Although formation of 1,3-dienes by single cleavage in metal-catalyzed cycloisomerization of enynes could also be explained by a conrotatory ring opening of cyclobutene intermediates 148, experimental evidence and theoretical calculations suggest that for enynes with di-and trisubstituted alkenes this transformation takes place by a direct reaction of cyclopropyl gold(I) carbenes bypassing the formation of cyclobutene intermediates. 163b Thus, the rearrangement of 1,6-enynes with two methyl groups at the alkene terminus proceeds smoothly at temperatures as low as −40 to −60°using cationic catalysts [(R 3 P)Au(MeCN)]SbF 6 , which would imply an abnormally low activation energy for the hypothetical conrotatory opening of a cyclobutene. 163b For the double-cleavage rearrangement, intermediates 144 can evolve by a formal insertion of the terminal carbon of the alkene into the alkyne carbons. These new carbenes 149 undergo α-proton elimination to afford dienes 150. In this process, both the alkene and the alkyne are cleaved in an intramolecular transformation.
On the other hand, intermediates 145 from 6-endo-dig cyclization can lead to bicyclo[4.1.0]hept-2-ene derivatives 151 by protodeauration, which are the products of an intramolecular cyclopropanation of the alkene by the alkyne. 161a,169 Alternatively, isomerization of gold(I) carbene 145 by ring expansion of the cyclopropane gives (η 2 -cyclobutene)-gold(I) complexes 152, which can isomerize to give cyclobutenes 153. Gold(I)-complexes of 152 have been observed by NMR spectroscopy, 170 and a bicyclo[3.2.0]hept-5-ene formed gold-(I)-catalyzed by cycloisomerization has been characterized by X-ray diffraction. 163c The opening of these gold(I) complexes can also form complexes 154, which are direct precursors of 1,3-dienes 146, the product of a single cleavage rearrangement. Analogously, 1,5-171 and 1,7-enynes undergo gold(I)-catalyzed rearrangements through somewhat related pathways. 163b, 172 3.1.2. Cycloisomerization of 1,6-and Higher Enynes. The pathway followed by a particular enyne is highly influenced by its substitution pattern. DFT calculations 173 support that the formation of 5-membered cyclic compounds is generally kinetically favored for terminal alkynes, while the formation of 6-membered rings becomes preferred for internal alkynes together with the ones with heteroatoms at the tether. Gold(I)catalyzed single-cleavage rearrangements of enynes proceed under very mild conditions to form 1,3-dienes. 43,161a,163a,b,174 Hence, enynes 155 bearing a terminal alkyne and a disubstituted alkene undergo a cycloisomerization reaction in the presence of Ph 3 PAuCl and AgBF 4 to give exclusive formation of single-cleavage rearrangement 1,3-dienes 156 (Scheme 47). 163a,b In most of the cases, these rearrangements are stereospecific processes in which the configuration of the alkene is retained. However, 1,6-enynes such as 157 bearing strongly electron-donating groups at the terminal alkene carbon lead to Z-configured 1,3-dienes 158 regardless the configuration of the starting enynes (Scheme 48). 175 1,6-Enynes 159 containing alkyl-substituted alkynes undergo double-cleavage rearrangements in the presence of Ph 3 PAuCl and AgBF 4 (Scheme 49). 161a,163b 1,6-Enynes bearing a terminal alkene and/or tethered with heteroatoms such as 161 and 164 provide six-membered rings 162 and 165 by endo-type single-cleavage rearrangement as the major products (Scheme 50). 161a 1,6-Enynes boronated at either the alkyne or the alkene react in a similar vein with Ph 3 PAuCl and AgSbF 6 . 176 Regarding gold(I)-catalyzed 6-endo-dig cyclizations, when 1,6-enynes are tethered by an ether or a sulfonamide group, A tandem allylation/cycloisomerization has been developed for the synthesis of 3-oxabicyclo[4.1.0]hept-4-ene derivatives using gold(I) catalysts. 178 The enantioselective synthesis of bicyclo[4.1.0]hept-4-enes has also been described with excellent enantioselectivities using (R)-DTBM-MeO-biphep-(AuCl) 2 /AgOTf 179 (DTBM = 4-MeO-3,5-(t-Bu) 2 C 6 H 2 ) or more recently gold(I) complexes with chiral phosphoramidite ligands. 52b,180 NHC-capped cyclodextrins coordinated to AuCl also catalyze the formation of 3-azabicyclo[4.1.0]hept-4-enes, although this catalyst provides only modest enantioselectivities. 181 3-Alkoxy-1,6-enynes in the presence of gold(I) form 1,4cycloheptadienes by a nucleophilic attack of the alkoxy group onto the alkyne presumably followed by a [3,3]-sigmatropic rearrangement. 182 O-Tethered 1,6-enynes 172 that contain a strained ring react with gold(I) by cycloisomerization followed by a 1,2-alkyl carbocationic shift resulting in ring expansion (Scheme 52). 183 A two-step method involving this transformation was developed for the synthesis of ketomacrolactones 174, which are scaffolds present in several natural products. The tricyclic skeleton of natural products crotobarin and crotogoudin has very recently been obtained via a 1,6enyne gold(I)-catalyzed cycloisomerization followed by intramolecular trapping of the resulting gold(I) carbene by a carboxylic acid. 184 A gold(I)-catalyzed polycyclization of linear dienediynes 175 has been developed for the construction of fused 5,7,6-tricyclic ring systems 177 in one step with high diastereocontrol (Scheme 53). 185 The polycyclization takes place through gold(I)-catalyzed intramolecular cyclopropanation of the diene with the diyne followed by Cope rearrangement to give strained allene intermediate 176, which subsequently undergoes a C−H activation, followed by 1,2-H and G-(H-or AcO) shifts.
The skeletal rearrangements of 1,7-enynes have been much less studied than those of 1,5-and 1,6-enynes. Gold(I) complexes are in general the best catalysts for the cycloisomerization of these substrates, leading to 1,3-dienes 179 through a single-cleavage process (Scheme 54). 172 Related enynes bearing aryl substituents at the alkene give mixtures of products of single-cleavage along with seven-membered ring compounds by an endo-type single-cleavage rearrangement. 186 Gold(I) complexes also catalyze Conia-ene reactions, which can be considered as cyclizations of 1,6-enynes via the corresponding enol tautomers (Scheme 55). 187 Thus, cyclopentane derivatives 180 were obtained in excellent yields and good diastereoselectivities. The reaction has also been efficiently carried out using a gold catalyst bearing a bulky phosphine ligand 188 or a catalyst generated in situ from a cyclic  189 The cyclization of aldehydes with alkynes in the presence of secondary amines proceeds analogously via the corresponding enamines generated in situ. 190 Silyl enol ether derivatives react with alkynes in a similar way. 191 Substrates featuring a 1,6-or 1,7-relationship between the silyl enol ether and the alkyne such as 181 undergo an exocyclization to form five- (182) or six-membered rings (183), respectively (Scheme 56). 192 However, it was found that it is possible to tune the exo-or endo-selectivity by changing the ligand on gold. 193 Thus, gold(I) complexes containing very bulky phosphine ligands favor the 6-endo-dig cyclization, whereas complexes with NHC ligands lead to 5-exo-dig cyclization products preferentially. Enantioselective versions of this reaction have been developed using chiral gold(I) complexes. 194 Conia-ene cyclizations have also been performed starting from 1,6-diynes that react first with methanol of another alcohol in the presence of gold(I) to form in situ the corresponding enol ethers, which then undergo the cycloisomerization process to afford the corresponding 5-memberedring products. 195 An analogous process has been developed by the intramolecular addition of other nucleophiles such as carboxylic acids or nitrogen nucleophiles to 1,6-diynes. 196 Gold(I)-complexes with a semihollow-shaped triethynylphosphine ligand promote a 7-exo-dig cyclization of 1,7-enynes bearing silyl enol ethers. 197 Related 1,8-enynes also give sevenmembered-ring products in the presence of this catalyst as a result of a 7-exo-dig cyclization. 198 The 8-endo-dig pathway to form eight-membered carbocycles could be promoted by using a modified triethynylphosphine-based ligand. 1,7-Enynes 184 also undergo a formal gold(I)-catalyzed 8endo-dig cyclization to give benzoxocines 187 (Scheme 57). 199 It has been proposed that the reaction proceeds through a 7endo-dig cyclization, followed by ring expansion to form the benzylic carbocation 186 that after elimination and protodeauration leads to the final product. As a proof of this mechanism, tricyclic compounds deriving from the protodeauration of 185 have been isolated in some cases as the minor products.

Intermolecular Reactions of Alkenes with Alkynes
Gold(I)-catalyzed intermolecular reactions between alkenes and alkynes constitute a real challenge since all the conceivable products are by themselves potential substrates for gold(I), which in consequence may compete with the initial alkene leading to oligomerization products. 59 The first reaction developed in this area was a formal [2 + 2] cycloaddition between terminal alkynes and substituted alkenes that led to the formation of cyclobutenes 261 (Scheme 78). 239 The regiochemical outcome of this process is in agreement with a reaction pathway through highly distorted cyclopropyl gold(I) carbenes 260 that finally undergo a ring expansion.
Interestingly, the intermolecular reaction of propiolic acid with alkenes does not form cyclobutenes. Instead, this reaction leads to 1,3-dienes (262) or lactones (263) depending on the nature of the alkenes (Scheme 79). 240 Asymmetrically substituted alkenes lead to the formation of lactones by attack of the carboxylic acid to the most substituted carbon of the alkene. On the other hand, alkenes with two electronically identical or very similar substituents afford stereospecifically 1,3-dienes by 1,3-migration, following a pathway that is similar to the one occurring in the single-cleavage rearrangement of 1,6-enynes.
Terminal ynamides react intermolecularly with enol ethers in the presence of gold(I) to give enamines 264 as a result of a [2 + 2 + 2] cycloaddition (Scheme 80). 243 Arylynamides react intermolecularly with alkenes forming a cyclopropyl gold(I) carbene, which is opened by a Friedel−Crafts attack of the aryl group forming 1,2-dihydronaphthalenes. 243

Addition of Heteronucleophiles to Enynes
Gold(I) complexes catalyze the addition of amines, alcohols, or water to enynes leading to products of amino-, alkoxy-, or hydroxycyclization under much milder conditions than other metal catalysts. 161a,163a,211,244 The overall process is an antiaddition of an electrophile (alkyne-gold(I) complex) and a heteronucleophile to a double bond in a stereospecific process.
3.3.1. Intermolecular Addition of Heteronuclephiles to Enynes. In the presence of an external heteronucleophile, the cyclopropyl gold(I) carbenes generated as intermediates in the cycloisomerization of 1,n-enynes are opened by attack to the cyclopropane ring. These additions take place following the Markovnikov regiochemistry, giving rise to products of exo-trig (266) or endo-trig cyclization (268) (Scheme 81). 161a,163a Similar results have been obtained using NHC-gold(I) or gold(III)-complexes as catalysts. 174a,244a, 245 The enantioselective hydroxy-and alkoxycyclization of 1,6-enynes catalyzed by a chiral biphosphine-gold complex 246 or by NHC-gold(I) complexes 247 proceeds with moderate to good enantioselectivities. 1,5-Enynes also react with alcohols or water in the presence of gold(I) catalysts to give the corresponding adducts. 244c The hydroxy-and alkoxycyclization of 1,7-enynes Scheme 77. Synthesis of (+)-Sieboldine A Scheme 78. [ 172 It is remarkable that the hydroxycyclization process is usually much faster than the direct addition of water to terminal alkynes to form the corresponding methyl ketones.
7-Substituted-1,6-enynes 269 bearing a fused aromatic ring at the tether undergo predominantly gold(I)-catalyzed hydroxycyclization by a 6-endo-dig pathway instead of the 5-exo-dig pathway usually observed for 1,6-enynes with trisubstituted alkenes to afford bicyclic compounds 270 (Scheme 82). 248 The reaction of allylsilylalkynes such as 271 catalyzed by gold(I) in the presence of external alcohols gives vinylsilanes. 249 Depending on the choice of the nucleophile, either cyclic or acyclic vinylsilanes were obtained (Scheme 83). DFT calculations suggest that this transformation takes place through silicenium cations 272 formed by a pericyclic reaction of the allylsilylalkynes coordinated to gold(I). 250 The attack of methanol to these intermediates gives cyclic vinylsilanes 273, whereas the attack of a weaker nucleophile such as phenol takes place at the silicon leading to acyclic vinylsilanes 274.
Propargyl vinyl ethers in the presence of gold(I) and water or alcohols undergo a Prins-type reaction affording dihydropyrans. 251 Furthermore, N-heteronucleophiles such as carbamates and anilines also react intermolecularly with 1,6-enynes to form amino-functionalized carbo-or heterocycles 275 (Scheme 84). 252 1,6-Enynes also react with aldehydes to give products of formal [2 + 2 + 2] cycloaddition 276 together with a metathesis-type reaction of the enyne with the aldehyde that forms 1,3-dienes 277 (Scheme 85). 253 1,7-Enynes also undergo a [2 + 2 + 2] cycloaddition with carbonyl compounds in the presence of gold(I) giving rise to analogous heterocyclic products. 254 Cyclopropenones react with enynes in a ring-expanding spiroannulation incorporating a molecule of water to afford spirocyclic cyclopentenones 278 by a mechanistically related process (Scheme 86). 255 1,6-Enynes bearing a monosubstituted alkene react with aldehydes and ketones in a different way, presumably via trapping of the rearranged carbene that results from the enyne to give intermediate 279, followed by Prins reaction, to afford tricyclic compounds 281 (Scheme 87). 256 In a similar vein, 1,5enynes also undergo intermolecular reactions with carbonyl compounds. 253 3.3.2. Intramolecular Addition of Heteronuclephiles to Enynes. The alkoxycyclizations can also take place intramolecularly starting from hydroxyl-1,6-enynes, 161a,244d and the resulting adducts may further evolve increasing molecular complexity. As an example, the synthesis of 4-oxa-6-azatricyclo[3.3.0.0 2,8 ]octanes 285 was reported by a complex gold-catalyzed cycloisomerization of alkynyl hydroxyallyl tosylamides 282 in the presence of Ph 3 PAuCl and AgSbF 6 (Scheme 88). 257 The intramolecular amino-or alkoxycyclization of amino-or hydroxyl-1,5-enynes 286 yields spirofused heterobicyclic compounds 287 (Scheme 89). 258 260 also undergo gold(I)-catalyzed tandem cyclizations in a mechanistically related transformation. The analogous reaction of 1,6-enynes bearing a carboxylic acid leads stereospecifically to lactones. 244d,261 Phenols can also add to 1,5-enynes in substrates of type 288 with a gold(I) catalyst to give tricycles 289 stereospecifically (Scheme 90). 262 The enantioselective version of the addition of phenols to 1,6enynes has also been described. 261 Similarly, the intramolecular reaction of hydroxypropargyl vinyl ethers 290 catalyzed by a trinuclear gold(I)-oxo complex leads to 5,6-and 6,6-spiroketals 291 and 292 with good stereocontrol (Scheme 91). 251 This transformation constrasts with the reactivity previously shown for propargyl vinyl ethers, which in the presence of the same trinuclear gold(I)-oxo complex underwent a Saucy-Marbet rearrangement giving rise to allenes. 263 Oxo-1,6-enynes such as 293 also react in the presence of gold(I) complexes to give oxatricyclic compounds 295 by a tandem sequence in which two C−C bonds are formed together with one C−O bond (Scheme 92). 264 This formal [2 + 2 + 2] alkyne/alkene/carbonyl cycloaddition proceeds by attack of the carbonyl to the cyclopropyl gold carbene intermediate followed by Prins cyclization to give 294, which forms the final oxatricyclic derivative after deauration. Oxo-1,5enynes also undergo an intramolecular reaction to give tricyclic derivatives. 265 Terminal alkynes and oxoalkenes undergo an analogous [2 + 2 + 2] cycloaddition reaction by intermolecular cyclization of the alkyne and the alkene followed by intramolecular attack of the carbonyl group to form 8-oxabicyclo[3.2.1]oct-3-enes 296 (Scheme 93). 266 Dienynes with a methoxy or other OR group at the propargylic position such as 297 react with gold(I) by an intramolecular 1,5-OR migration to form tricyclic compounds 299 (Scheme 94). 267 Substrates substituted with other OR groups at the propargyl position also undergo this 1,5migration. Ketoenyne (E)-300 in the presence of gold(I) reacted intramolecularly to give oxatricyclic compound 301, which was converted into (+)-orientalol F (302) in three additional steps (Scheme 95). 268 The key step of the synthesis of pubinernoid B (304) proceeded analogously starting from (Z)-300.

Addition of Heteronucleophiles to Enynes in
The stereospecific [2 + 2 + 2] alkyne/alkene/carbonyl cycloaddition was also applied to the synthesis of antitumor sesquiterpene (−)-englerin A (309) in two independent syntheses (Scheme 96). 269 It is remarkable that in both approaches an unprotected aldol subunit could be used as the substrate for the gold(I)-catalyzed reaction.
The formation of alkenylsilanes from allylsilylalkynes in the presence of an external alcohol 249 was used in the total synthesis of (−)-amphidinolide V. 270 Gold(I)-catalyzed reaction of 1,6-enyne 310 by cyclization followed by 1,5-acetoxy migration from 312 forms an α,βunsaturated carbene 314, 267 which reacts intermolecularly with alkene 311 to afford 315 with only 5% loss of enantiomeric excess (Scheme 97). 271 This transformation was reported as part of the total synthesis of antiviral sesquiterpene (+)-schisanwilsonene A (316). It is interesting that the cyclization/1,5-acetoxy migration is faster than the alternative 1,2-acyloxy migration, which would lead to racemization.
3.4.2. Friedel-Craft Arylation of Enynes. Electron-rich aromatic and heteroaromatic compounds such as indoles can undergo a stereospecific intermolecular addition to 1,6-enynes in the presence of gold(I) catalysts (Scheme 103). 252,265,277 This transformation proceeds by opening of the intermediate cyclopropyl gold(I) carbene in a process mechanistically related to the hydroxy-and alkoxycyclization of 1,6-enynes. The enantioselective version of this reaction has also been reported. 278 The enantioselective intramolecular addition leads to enantiomerically enriched complex ring systems in a single step. 261 1,6-Enynes bearing an aryl substituent at the alkyne such as 333 react stereospecifically with gold(I) in a formal [4 + 2] cycloaddition reaction under very mild reaction conditions (Scheme 104). 169b,244a,279 This reaction proceeds via initial exocyclization followed by opening of the cyclopropyl gold(I) carbene by a Friedel−Crafts-type reaction to provide 334. Related 1,6-enynes with 1-thienyl and 1-indolyl groups at the alkyne also undergo formal [4 + 2] cycloadditions catalyzed by gold(I) complexes bearing bulky biphenyl phosphine ligands. 280 In the presence of chiral phosphine gold(I) complexes 281 or gold(I) phosphite complexes 282 these [4 + 2] cycloadditions can be performed enantioselectively. Related cyclizations of alkynes with allenes 283 and diynes 284 have also been described. The endo-cyclization also takes place in certain cases, being the major pathway in the platinum(II)-or gold(I)-catalyzed cycloaddition of related arylalkynes bearing enesulfonamides or enamines. 285 1,5-Enynes 335 with an aryl substituent at the alkyne react with gold(I) to form dihydrobenzofluorenes 339 in a formal [3 + 3] cycloaddition by a 1,2-H shift in intermediate 337, followed by a Friedel−Crafts alkylation (Scheme 105). 286 3.4.3. Addition of Other C-Nucleophiles. 1,3-Dicarbonyl compounds can add to 1,6-enynes as C-nucleophiles through their enol tautomers, although some of them such as cyclohexane-1,3-dione and 2-oxocyclohexanecarboxaldehyde behave as O-nucleophiles. 277a In the presence of 1,3-diketones, N-tethered 1,6-enynes bearing an internal alkyne afford tetrahydropyridines 340 as a result of an endo-cyclization  297 The synthesis of substituted naphthalenes has been reported from propargylic esters by a gold(I)catalyzed sequence involving a 1,3-acyloxy migration followed by a 1,2-alkyl or aryl migration and subsequent hydroarylation. 298 Gold allenic intermediates 347 derived from 1,3-acyloxy migration (see Scheme 109) can be trapped by other functional groups to give of a range of different compounds. 299 In situ generated ketone-allene substrates 358 were used as substrates for a gold(I)-mediated tandem oxacyclization/[4 + 2] cycloaddition cascade to afford highly substituted oxacycles 359 with excellent stereocontrol (Scheme 112). 300 Nucleophilic allenes have also been generated in situ by a gold(I)-catalyzed rearrangement of propargylic esters and then used for intermolecular C(sp 3 )−C(sp 2 ) bond formation reactions. 301 In the presence of AuCl, ω-hydroxy propargylic acetates undergo a 1,3-acetoxy migration to form allenyl acetate 360, which is trapped intramolecularly to form tetrahydropyranes 361 containing an exocyclic enolacetate (Scheme 113). 302 This transformation proceeds with remarkable high Z-selectivity in the final alkenes and the retention of the configuration of diastereomerically pure substrates. 1,6-Diyne esters also react with gold(I) forming allenyl gold(I) intermediates, which can react with the pendant alkyne giving a variety of cyclized products. 303 The gold(I)-catalyzed acyloxy migration has been applied to the synthesis of 1-acetoxy-1H-indenes. 304 The mechanism of this transformation involves a 1,3-migration to form the allenyl intermediate that undergoes an intramolecular hydroarylation, followed by another final 1,3-acyloxy migration to generate a more stable substituted indene. The same reaction in the presence of water leads to α,β-unsaturated ketones.
Terminal halo-substituted propargyl carboxylates 362 react with Ph 3 PAuNTf 2 in anhydrous CH 2 Cl 2 to form 1-halo-2carboxy-1,3-dienes 363 by 1,2-migration of the ester (Scheme 114). 289f It has been recently reported that the same substrates in the presence of Ph 3 PAuCl/AgSbF 6 and H 2 O undergo a regioselective hydration to give α-acyloxy α′-halo ketones 364. 305 Gold(I) catalyzes the formation of alkenyl enol esters or carbonates from trimethylsilylmethyl-substituted propargyl esters/carbonates with excellent E-selectivity. 306 Alkynyloxiranes 365 bearing a propargylic ester rearrange to form divinyl ketones 366 (Scheme 115). 307 The mechanism of this transformation seems to proceed via anchimeric assistance of the propargyl ester moiety, although DFT calculations predict a complex mechanism involving several equilibriums.

Cyclizations of Arylalkynes
Electrophilic metal catalysts form, upon coordination to an alkyne, electrophilic complexes that undergo electrophilic aromatic substitution reactions with arenes. Gold(I)-complexes generally promote reactions according to this pathway. 338 The direct auration of electron-rich arenes and heteroarenes by gold(I) 339 and gold(III) 340 is a well-known process, but the resulting aryl-gold complexes are apparently not involved in subsequent C−C bond forming reactions with alkynes. The auration of electron-deficient arenes has also been achieved. 341 Aryl-gold(I) complexes only react with alkynes in the presence of a palladium(0) catalysts, or a palladium(II) precatalyst, to afford products of carboauration. 341c The gold-catalyzed intermolecular hydroarylation of alkynes leads to 1,1-disubstituted alkenes or 1,2-disubstituted derivatives in the case of alkynes bearing electron-withdrawing groups. 342 According to experimental and computational work on the cyclization of arylalkynes catalyzed by platinum(II), two pathways with very similar activation energies compete in intramolecular hydroarylations: a Friedel−Crafts alkenylation and a reaction proceeding through metal cyclopropyl carbenes. 343 However, comparing the results obtained for platinum(II)-catalyzed hydroarylation reactions such as the cyclization of N-propargyl-N-tosyl anilines, better yields and milder reaction conditions are obtained with cationic gold(I) catalysts (Scheme 127). 344 A detailed theoretical analysis of the cycloisomerization of phenyl propargyl ethers catalyzed by a Au 38 cluster has recently been reported. 345 N-Butynyl anilines also form 1,2-dihydroquinolines by 6-exo-dig cyclization followed by a proton-catalyzed isomerization of the exocyclic double bond. 346 These products could be rearranged into functionalized indole derivatives under photochemical conditions. The intramolecular hydroarylation of N-propargyl-N′phenylhydrazines gives cinnoline derivatives. 347 N-Aryl-2-alkenylpyrrolidine derivatives 402 formed in situ give rise to pyrrolo[1,2-a]quinolones 403 through a tandem sequence involving the attack to an external alkyne followed by an intramolecular hydroarylation (Scheme 128). 348 Unprotected propargylic and homopropargylic aniline derivatives in the presence of terminal alkynes undergo a tandem hydroamination/hydroarylation to give dihydroquinolines or quinolones. 129a, 349 The hydroarylation of iodo-substituted propargyl anilines 404 gives selectively 4-iododihydroquinolines 405 with more electrophilic gold(I) complexes, whereas 3-iododihydroquinolines 406 are obtained with more electron-rich gold(I) catalysts bearing NHC ligands (Scheme 129). 350 The cyclization of bromo-and iodopropargyl aryl ethers with IPrAuNTf 2 also proceeds with 1,2-halogen migration to give 3-halo-2Hchromenes. 351 The cyclization of propargyl aryl ethers takes place analogously yielding 2H-chromenes, even in the cases in which the aromatic ring bears electron-withdrawing groups. 163a, 343,344b,c,352 However, in the case of substrates containing both a 1,6-enyne and an aryl propargyl ether, the enyne cycloisomerization is favored, and no hydroarylation takes place. 353  355 Spiro [4.5]cyclohexadienones have been also obtained by a gold(I)-catalyzed carbocyclization of phenols with a terminal alkyne via intramolecular ipso-Friedel−Crafts. 356 Aryl alkynylphosphonates also undergo intramolecular gold(I)-catalyzed hydroarylation to give phosphacoumarins. 357 The intramolecular hydroarylation has also been applied in a complex transformation initiated by a rhodium(II)-catalyzed intramolecular cyclopropanation of α-aryldiazo ketones with alkenes to give products 411 that react with silver(I) to form alkynylhydrofurans 412, which in the presence of gold(I) afford benzo-fused dihydrofurans 413 (Scheme 131). 358 Alkynylaziridines with an aryl group rearrange in the presence of gold(I) to form spiro[isochroman-4,2′-pyrrolines] via allenylidene intermediates. 359 The cyclization of o-alkynyl biphenyl derivatives with gold(I), as happens with gold(III), platinum(II), and other metal catalysts, 360 proceeds preferentially by the endo-pathway leading to phenanthrenes 414. The use of a new strongly π-acidic phosphine-bound gold(I) catalyst has allowed to broaden the scope of this transformation, leading to excellent yields in short reaction times, even for 4,5-disubstituted phenanthrenes (Scheme 132). 361 Interestingly, o-haloalkynebiaryls react with AuCl to give phenanthrenes in which the halide has suffered a 1, 2-shift. 360c This type of transformation has been applied to the synthesis of 5,8-diiodo-and 6,13-diiodobenzo [k]tetraphenes 415 (Scheme 133), 362 as well as to the synthesis of benzo[a]phenanthridines from 3-alkynyl-4-arylisoquinolines. 363 It has been proposed that the most favored reaction pathway features an initial 6-endo-dig hydroarylation of the alkyne followed by 1,2-H shift and formation of a gold-carbene intermediate, which then undergoes a 1,2-halogen shift to finally give the rearranged product after deauration. 364 The reaction of (o-arylphenyl)alkynylselenides in the presence of gold(I) and gold(III) affords rearranged phenanthrenyl selenides very efficiently by migration of the selenide from the terminal to the internal position of the alkyne. 365 Gold(I)-catalyzed 6-exo-dig hydroarylation reactions are much less common. The synthesis of substituted anthracenes in the presence of gold(I) by exo-cyclization was achieved from o-alkynyldiarylmethanes. 366 In a mechanistically related transformation, the synthesis of functionalized phenanthrenes 416 has been described from o-propargylbiaryls (Scheme 134). 367 Dibenzocycloheptatrienes were obtained by a related transformation through a 7-exo-dig hydroarylation. 368 The gold(I)-catalyzed hydroarylation of alkyne-tethered fluorenes was applied to the synthesis of fluoranthenes and more complex polyarenes. 22 A gold(I)-catalyzed formation of benzofurans has been coupled with intramolecular hydroarylations to form polyaromatic ribbons. 369 5.2. Cyclizations of Heteroarylalkynes 5.2.1. Reactions of Indoles with Alkynes. The reaction of N-propargyl tryptophans or tryptamines 417 catalyzed by gold(I) or gold(III) leads to seven-and eight-membered rings, respectively (Scheme 135). 370 Eight-membered-ring products 419 are formed by an 8-endo-dig process, a type of cyclization that had not been observed in any other hydroarylation of alkynes or cyclization of enynes. These cyclizations have been coupled with other tandem reactions to obtain polycyclic indole-based structures. 371 The intermolecular reaction of indoles with (Z)-pent-2-en-4yn-1-ols gives intermediate (Z)-3-(pent-2-en-4-ynyl)indoles, which undergo a similar cyclization to afford sevenmembered-ring products. 372 Tetracyclic indole derivatives were synthesized enantioselectively by coupling a organocatalytic process with a gold(I)-catalyzed 7-endo-dig cyclization. 373 Indoles with the alkynyl chain tethered at the 2-position can undergo a gold(I)-catalyzed cyclization to form carbazoles. 374,375 The formation of indoles in situ by intramolecular hydroamination coupled with an intramolecular hydroarylation has been applied to the preparation of benzo-fused carbazoles, 148a,376 1,2,3,10-tetrahydroazepino [3,4-b]indoles, and related cyclic compounds. 148b Other gold(I)-catalyzed transformations that yield functionalized carbazoles are the gold(I)-catalyzed deactylative cyclization of 3-acylindole/ ynes 377 and the tandem hydroarylation/6-endo-dig cyclization of alkynes with 2-alkynylindoles. 378 In the case of indoles bearing a nucleophilic functional group, either at the 3-position (420) or on the alkynyl chain (422), the reaction leads to tetracyclic indolines (Scheme 136). 371,379 Other cascade processes initiated by cyclizations of indoles with alkynes have also been reported. 380 An Ugi four-component reaction of propargylamines with 3formylindoles, acids, and isonitriles can be coupled with a gold(I)-catalyzed cyclization of the resulting adducts 424 to furnish substituted spiroindolines 425 (Scheme 137). 381 The intramolecular gold(I)-catalyzed hydroarylation of alkynes with indole-3-carboxamides 426 proceeds by 1,2acyloxy shift to form dihydroindoloazepinones 428 (Scheme 138). 382 An unusual 1,2-indole migration has been observed in the gold(I)-catalyzed reaction of 3-propargylindoles. 383 The intermolecular reaction of homopropargyl alcohols with indoles in the presence of gold(I) catalysts proceeds differently forming first 2,3-dihydrofurans, which undergo the addition of two equivalents of the indole to the resulting enol ether to give bis(indolyl)alkanes 429 (Scheme 139). 384 5.2.2. Reactions of Furans with Alkynes. In contrast to the usual Friedel−Crafts type reaction of arenes with alkynes, furans usually undergo gold(I)-or gold(III)-catalyzed intramolecular reactions with alkynes to form phenols in good to excellent yields (Scheme 140). 91,385 According to experimental and theoretical studies, the phenol synthesis proceeds initially by a mechanism similar to that of the cyclization of 1,n-enynes from furans 430 giving intermediates 431 that evolve by ring opening, cyclization of the resulting carbene, demetalation, and final rearrangement to afford phenols 432. 385f,g,p,s, 386 Furans generated in situ from endiynes also undergo cyclization with alkynes to form phenols that feature the hydroxyl group at the meta position with respect to the ring junction. 387 The first example of synthesis of phenols by intermolecular reaction of a furan with an alkyne was reported using cationic binuclear complex [(Mes 3 PAu) 2 Cl]BF 4 as the catalyst, albeit the reaction is very slow and the resulting phenol was obtained in low yield. 388 Later it was reported that phenols 433 can be obtained by intermolecular reaction of furans and alkynes using gold(I) complexes bearing NHC ligands (Scheme 141). 389 Furan-yne systems 434 with aromatic tethers react with gold(III) to form phenol derivatives. However, in the presence of gold(I) these substrates react to form indene derivatives 435 by exo-cyclization followed by 1,4-furanyl migration and cyclization. 390 It has been recently described that the same substrates undergo an endo-selective cyclization with concomitant 1,5-migration of the furan group in the presence of unactivated molecular sieves to yield trisubstituted alkenes 436 (Scheme 142). 391 Arylated (Z)-enones 440 are obtained by intramolecular reaction of in situ formed intermediates 438 to give 439, which undergo ring opening and final aromatization (Scheme 143). 392 A related transformation leads to functionalized fulvenes with an enone or an enal moiety starting from furanynes with a twocarbon tether between the furan and the triple bond. 393 Furans 441 containing an alkynyl ether moiety in the presence of gold(I) undergo a furan-yne cyclization by a different reaction pathway by which, instead of phenols, tetracycles 443 containing two heteroatoms and two new stereocenters are formed (Scheme 144). 394 A more complex gold-catalyzed process initiated by an intermolecular reaction between 1,6-diyn-4-en-3-ols and furans leads to phenanthrene derivatives. 395 The gold(I)-catalyzed reaction of 4-silyloxy-4-furyl alkynes leads to benzofurans by a Friedel−Crafts mechanism. 396 This cyclization has been expanded for the synthesis of substituted benzo [b]-furans 445 by reaction with various external nucleophiles (Scheme 145). 397 Similarly, propargylic alcoholtethered furans are converted into benzofuran derivatives in moderate yields. 398 Internal alkynes 446 tethered to a furan through a protected benzylic alcohol react with gold(I) giving protected 1-naphthol derivatives 448 via formation of a cationic intermediate 447, followed by ring-opening of the furan ring and aromatization (Scheme 146). 399  ynes 449 bearing a propargylic alcohol moiety were subjected to an analogous reaction, an additional 1,2-rearrangement takes place, leading to substituted 1-naphthols 451 bearing an enal or enone moiety at the C-4 position. 400 5.2.3. Reactions of Pyrroles with Alkynes. The gold(I)catalyzed intramolecular post-Ugi hydroarylation of internal alkynes with pyrroles was developed for the synthesis of pyrrolopyridinones. 401 In the presence of platinum(II)-catalysts this reaction affords selectively pyrroloazepinones. Ugi-adducts 452 bearing a terminal alkyne give pyrrolopyridines 454 by 5exo-dig cyclization followed by 1,2-shift under very mild reaction conditions (Scheme 147). 402 The one-pot asymmetric synthesis of annulated pyrroles 455 has recently been reported combining cinchona-alkaloidderived primary amine and gold(I) catalysts (Scheme 148). 403 The analogous intramolecular reaction for β-yne-pyrrole derivatives provides access to fused cycloheptapyrroles in the case of internal alkynes and six-membered-ring fused pyrroles in the case of terminal alkynes via endo-and exo-selective cyclizations, respectively. 404 The intermolecular reaction of alkynes with pyrroles was also developed to form functionalized pyrrole derivatives 457 or 458 depending on the nature of the alkyne substituent, which could be useful scaffolds for additional annulation processes (Scheme 149).
A new synthesis of indoles 459 proceeds by formal gold(I)catalyzed intermolecular [4 + 2] cycloaddition between 1,3diynes and pyrroles (Scheme 150). 405 This reaction involves the hydroarylation of one of the alkyne moieties of the diyne with the pyrrole, followed by intramolecular hydroarylation to give 4,7-disubstituted indole. Carbazoles could also be obtained when indoles were used as the nucleophiles instead of pyrroles.

Hydroarylation and Hydroheteroarylation Reactions in Total Synthesis
An application of the formation of 2H-chromenes by intramolecular hydroarylation is found in the synthesis of the tetracyclic core of berkelic acid (462) (Scheme 151). 406 The cyclization of aryl propiolates gives coumarin derivatives, including the natural products pimpinellin (464) The cyclization of alkynylindoles bearing a nucleophile at the 3-position has been used in the formal total synthesis of the indole alkaloid minfiensine. 379a The gold(I)-catalyzed synthesis of carbazoles has recently been applied to the first total synthesis of naturally occurring alkaloid karapinchamine A 466 (Scheme 153). 375b An intramolecular gold(I)-catalyzed hydroarylation of a 3substituted furan is used as the key step of the total synthesis of furanosesquiterpenes crassifolone and dihydrocrassifolone. 408

Oxidative Reactions of Alkynes
The inter-or intramolecular oxidation of alkynes has been described using sulfoxides, 409 pyridine N-oxides, 410 nitrones, 411 nitroso-and nitrobenzenes, 412 as well as epoxides, 413 as the oxidizing agent. These processes have been proposed to proceed via α-oxo gold(I) carbenes 468, 414 although most likely gold(I) carbenoids 469 are involved by attack of the nucleophile to the highly reactive gold(I) carbene (Scheme 154). 415 The reaction of alkynes with pyridine-N-amidines to give 2,4,6-oxazoles has also been proposed to proceed through α-oxo gold(I) carbenes. 416 Nevertheless, a mechanism involving β-alkoxy alkenylgold(I) intermediates of type 467 rather than α-oxo gold(I) carbenes has been proposed in some of these oxidative reactions of alkynes. 417 In the case of terminal alkynes, the gold(I) carbene is always positioned at the terminal carbon of the alkyne. However, regioselectivity becomes a major challenge with internal alkynes. A highly regioselective oxidation of internal alkynes to α,β-unsaturated ketones was developed using IPrAuNTf 2 as the catalyst and 8-isopropylquinoline N-oxide as the oxidant. 410c The intermediate α-oxo gold(I) carbenes can be trapped intramolecularly by a nucleophile present in the starting alkyne increasing the molecular complexity of the final products. As an example, propargyl aryl ethers 470 in the presence of gold(I) and a pyridine N-oxide presumably form α-oxo gold(I) carbene 471, which undergoes an intramolecular Friedel−Crafts-type reaction to afford chroman-3-ones 472 (Scheme 155). 418 In a related transformation, propargylic and homopropargylic alcohols react with gold(I) in the presence of pyridine Noxides to give dihydrofuranones and oxetan-3-ones, respectively. 419 The related oxidative reaction of o-ethynylanilines gives 3-oxyindoles by intramolecular trapping of the intermediate gold(I) carbene. 420 The strong electrophilicity of the α-oxo gold(I) carbene also allows its intermolecular trapping. 2,5-Disubstituted oxazoles 474 were obtained by a formal [2 + 2 + 1] annulation using nitriles as the solvent via intermediates 473. 421 When carboxamides were used as the nucleophilic partners, 2,4disubstituted oxazoles 476 were obtained by a formal [3 + 2] annulation between terminal alkynes via intermediates 475 (Scheme 156). 422 Carboxylic acids are also suitable trapping agents for the in situ generated α-oxo gold carbenes, giving rise to carboxymethyl ketones. 423 The intermolecular trapping of α-oxo gold(I) carbenes by external nucleophiles such as indoles and anilines in aqueous media has been reported, revealing that water can dramatically suppress the undesired overoxidation of the alkyne. 424 A gold(I)-catalyzed tandem cycloisomerization/intermolecular trapping of an in situ generated α-oxo gold(I) carbene involving this transformation has been described to form functionalized indoles 477 from o-alkynyl anilines and ynamides (Scheme 157). 425 In this transformation, gold(I) serves dual catalytic roles to mediate both the cycloisomerization of o-alkynyl anilines and the intermolecular oxidation of ynamides.
Diynes bearing one terminal and one triarylmethylsubstituted alkyne were converted into benzofluorenone derivatives via a one-pot process involving a gold(I)-catalyzed generation of an α-oxo carbenoid at the terminal alkyne, followed by a photocyclization/oxidation. 426 The oxidative cyclization of 1,5-enynes in the presence of gold(I) and a range of oxidants is a well documented process. Thus, the reaction of 3,5-dien-1-ynes with pyridine N-oxides leads to cyclopropa[a]inden-6(1H)-ones 478 427 or cyclopentadienyl aldehydes 479 428 depending on the structure of the starting substrate or the particular oxidant used (Scheme 158). In a similar cyclization, N-allylyamides are converted into 3-aza-bicylo[3.1.0]hexan-2-ones. 429 The gold(I)-catalyzed reaction of 3,5-and 3,6-dienynes (480) with 8-alkylquinoline N-oxides results in an oxidative cycloaddition in which a quinoline framework is activated (Scheme 159). 430 The mechanism of this transformation probably involves an intermediate α-oxo pyridinium ylide 481, which undergoes a concerted [3 + 2] cycloaddition with the tethered alkene to form 482. Cycloalkanone-fused cyclopropanes have been recently obtained by a gold(I)-catalyzed oxidative cyclization from 1,5-ene-ynes. 431 Sulfoxides can also be employed in oxidative cyclization of enynes to afford rearranged products bearing a carbonyl moiety via gold(I)-carbenoid intermediates. 432 Enantiomerically enriched bicyclo[3.1.0]hexan-2-ones have recently been obtained by a tandem alkyne oxidation/ cyclopropanation in the presence of gold(I) complexes bearing a chiral phosphoramidite ligand. 433 Similarly, an enantioselective alkyne oxidation/cyclopropanation sequence of 1,5-enynes by gold(I) complexes bearing a P,N-bidentate ligand affords bicyclic cyclopropane products. 434 The intramolecular additions of azides to alkynes are somewhat mechanistically related transformations that give rise to pyrroles 486 (Scheme 160). 435,436 This reaction proceeds by nucleophilic attack of the azide in 483 to form intermediates 484, which loses N 2 in a processs reminiscent of the Schmidt reaction to form cationic α-imino gold(I)-carbene 485. Final 1,2-H shift and tautomerization lead to substituted pyrroles. In a similar reaction, 2-alkynyl arylazides have been converted into indoles, 437 whereas similar substrates bearing propargylic carboxylates give quinolines. 438 o-(Azido)ynamides 487 were efficiently converted into indoloquinolines 489 in the presence of gold(I) via α-imino gold(I)-carbenes 488 (Scheme 161). 439 Ynamides bearing a simple alkene instead of an allyl silane gave cyclopropane-fused derivatives.

Oxidative Reactions in Total Synthesis
An intramolecular oxidation of 490 through its N-oxide forms 4-piperidone 491, an intermediate in the total synthesis of the alkaloid (±)-decinine 492 (Scheme 162). 440 The gold(I)-catalyzed synthesis of optically active γ-lactams by tandem cycloisomerization/oxidation of homopropargyl amides was applied in the synthesis of (−)-bgugaine. 441 A similar strategy has been used in the total synthesis of (−)-irniine. 442 Interestingly, 3-coumaranones such as 493 can also be obtained by gold(I)-catalyzed oxidative cyclization of oethynylanisoles, which has been applied in the total synthesis of sulfuretin (494) (Scheme 163). 443 The gold(I)-promoted regioselective oxidation of alkynes 410c was applied on the total synthesis of alkaloids (−)-citrinadin A (497) 444 and (+)-citrinadin B (500) (Scheme 164). 445 The gold(I)-catalyzed oxidative cyclization of 1,5-enynes 427 has been recently used as the key step for a concise enantioselective total synthesis of the sesquiterpene (−)-nardoaristolone B (504) by reaction of dienyne 501 with IPrAuNTf 2 in the presence of 3,5-dichloropyridine N-oxide to form enone 502, along with the product of cycloisomerization 503 (Scheme 165). 446

CONCLUSIONS
Work carried out during the past decade has demonstrated that gold(I) complexes and, in particular, cationic complexes bearing bulky phosphines and NHC ligands are the most active and selective catalysts for the activation of enynes, even in complex polyfunctional settings. Mechanistically, reactions catalyzed by gold(I) are similar to those catalyzed by other electrophilic metal complexes or even Brønsted acids and resemble carbocation-mediated processes. However, gold(I) provides unique control on complex transformations by very selectively activating alkynes and by stabilizing the key carbocationic intermediates by weak, but still significant, metal to carbene π-back-donation. Although many goldcatalyzed reactions of alkynes and, in particular, enynes appear to proceed through gold(I) carbene-like species, the implication of α-oxo gold(I) carbenes in oxidative cyclizations has been recently questioned in several contexts. Further work on the mechanism of these reactions should shed light into the structure of the species involved in these transformations. Most of the work has been carried out in intramolecular processes leading to fiveor six-membered ring compounds, although smaller or larger ring systems can also be accessed by using gold(I)-catalysis. However, the regiochemical control in many cases is still essentially dependent on the substrate substitution pattern and not on the ligands on the gold(I) catalyst. Additionally, the structural characteristics of linear twocoordinated gold(I) complexes, in which the ligand is very distant from the nucleophilic addition site to the π-bound substrate, explains the slow development of general enantioselective transformations of alkynes. Finally, the developing of broad-scope intermolecular reactions of alkynes for the formation of carbon−carbon bonds still remains an important challenge in homogeneous gold(I) catalysis,

Notes
The authors declare no competing financial interest.