Synthetic applications of gold-catalyzed ring expansions

The development of new methodologies catalyzed by late transition metals involving cycloisomerizations of strained rings can open new venues for the synthesis of structurally complex molecules with interesting biological activities. Herein we summarize, from both a synthetic as well as a mechanistic point of view, the most recent developments in gold-catalyzed ring expansions.


Introduction
Over the past twenty years, the image of gold has evolved, from being considered a dead-entity in terms of chemical reactivity, to playing a key role in catalytic processes. The vast array of gold-mediated transformations reported so far share a common feature: The ability of gold(I) and gold(III) species to activate unsaturated moieties due to the strong relativistic effects governing its coordination behavior [1][2][3][4][5][6]. However, beyond its Lewis acidity properties towards alkynes, allenes or alkenes, gold has also proved to be extremely powerful in triggering ring-expansion processes to introduce structural complexity into organic molecules. The gold-catalyzed ring expansion of strained rings is viewed nowadays as a flexible synthetic tool in organic synthesis [7][8][9].
In this review, we aim to summarize the most recent developments in gold-catalyzed ring expansions, from both a synthetic and a mechanistic point of view. A deeper understanding of the processes governing gold-chemistry allows organic chemists to become more creative in designing novel processes, which might provide access to architectures that were so far inaccessible.
Only four years later, de Meijere reported a gold-catalyzed rearrangement of strained small ring hydrocarbons [12]. Although heterogeneous catalysis seemed to be operating in this case, homogeneous complexes such as AuCl(DCP) (DCP = dicyclopentadiene) were able to trigger the quantitative rearrangement of diademane (8) to snoutene (9) and, at least partially, the rearrangement of the latter into basketene (10) (Scheme 2).
Although the structures of the final products in these transformations are rather simple and the low selectivities limit the synthetic potential of these methods, the fact that gold was able to activate strained ring systems opened up a new research area that is still highly active to date, as will be shown in the following sections of this review.
Both processes were rationalized as a result of the π-activation of the alkyne in the presence of gold, followed by migration of the C-C bond, and a final 1,4-H shift (Scheme 4) [20]. Interestingly, the use of internal alkynyl cyclobutanols such as 15, reported in 2007 by Chung and co-workers [21], led to a completely different outcome (Scheme 5). This transformation did not lead to the expected cyclopentanones. Instead, α,βunsaturated ketones 16 were isolated in good yields. The proposed mechanism (Scheme 5) involves nucleophilic attack by a molecule of water on the activated alkyne moiety, followed by dehydration to give the cumulene intermediate 17.
Attack on 17 by a second water molecule regenerates the catalyst with the formation of intermediate 18, which then tautomerizes to afford the observed product. 1-Allenyl cyclopropanols 19 can be transformed into cyclobutanones 20 with absolute stereocontrol at the quaternary stereogenic center generated during the reaction by the use of a binuclear chiral gold-phosphine complex, as shown in Scheme 6 [22]. Bicyclic cyclopentanones can also be obtained in a related transformation starting from allenyl cyclobutanols [23].

Cyclopropylmethanols
Cyclopropyl methanols can be used, alternatively, as pre-electrophiles in gold-catalyzed reactions. In 2008 Chan and co-workers developed an efficient synthetic route to pyrrolidines via a tandem amination/ring expansion of these substrates in the presence of sulfonamides [24]. Phenylcyclopropylalcohol 21 was efficiently transformed into sulfonyl pyrrolidine 23 in the presence of 5 mol % of the cationic complex AuOTf (Scheme 7). The reaction was applicable to a wide range of activated and non-activated cyclopropylmethanols, sulfonamides containing electron-withdrawing, electron-donating, and sterically demanding substituents. This transformation is thought to proceed through activation of the substituted cyclopropylmethanol by the gold catalyst, which leads to the ionization of the alcohol followed by the subsequent cyclopropyl ring opening and trapping of the carbocation by the sulfonamide. Subsequent intramolecular hydroamination gave the pyrrolidine products.

Oxiranes
As an oxophilic Lewis acid, gold can activate epoxides towards the attack of nucleophiles. A good example is the AuCl 3 catalyzed ring opening of aryl alkyl epoxide 24 to give 3-chromanol 25, which was reported by He and co-workers in 2004 (Scheme 8) [25]. The same year, Hashmi and co-workers described the first example of a gold-catalyzed conversion of alkynyl epoxides 26 into furans 27 [26,27]. Mechanistic studies performed later by Pale and co-workers [28] seem to rule out the usually proposed mechanism, that is, via the intramolecular nucleophilic addition of the oxirane oxygen on the π-metal-alkyne complex (Scheme 9, upper row). Instead, the reaction seems to proceed through a cascade initiated by an internal or external nucleophilic (the hydroxy group in the substrate or adventitious water or alcohol present in the reaction media) opening of the three membered ring, followed by metal activation of the triple bond to trigger the cyclization (Scheme 9, lower row). In both cases, aromatization and protodeauration would afford the observed products.
Epoxy alkynes can also be transformed with high stereoselectivity into ketals in the presence of catalytic amounts of gold and an external nucleophile such as water or an alcohol (Scheme 11) [32]. The reaction seems to commence with the epoxide ring opening in the presence of the nucleophile to give intermediate 33 (as already proposed in Scheme 9) followed by activation of the alkyne and intramolecular nucleophilic attack of the alcohol function to give 34. Reactivation of the olefin and subsequent incorporation of a second molecule of nucleophile (intramolecularly in the case of water, intermolecularly in the case of alcohols) affords ketals 35 and 36, respectively. The reaction can also proceed in an intramolecular manner, if the substrate contains an alcohol functionality [33,34].

Ring expansions involving cyclopropyl alkynes
The metal-catalyzed ring expansion of cyclopropyl alkyne derivatives represents a versatile method to access a wide range of building blocks [35][36][37][38]. Upon gold activation of the triple bond in 37 two possible pathways can arise. In the first, the cyclobutyl cation 38 is formed by ring expansion, which is subsequently trapped by an external nucleophile (Scheme 12,  path a). In 2010, the group of Yu developed a new route for the synthesis of cyclobutanamines 39 according to this reaction mode [39]. Alternatively, in the presence of an external oxidant, a nucleophilic addition can occur to form carbene 40, which rearranges to cyclobutenone 41 (Scheme 12, path b). Liu recently reported the use of diphenylsulfoxide as an external nucleophilic oxidant in this context [40].
The gold-catalyzed intramolecular nucleophilic attack of heteroatoms on alkynes, followed by ring expansion, represents an appropriate method for the synthesis of furans and pyrroles. In 2006, Schmalz and co-workers reported a gold-catalyzed cascade reaction of alkynyl cyclopropyl ketones 42, which makes use of the carbonyl group as a nucleophile, and yields substituted furans 43 (Scheme 13) [41]. Toste and co-workers reported an intramolecular acetylenic Schmidt reaction using azides as internal nucleophiles to give substituted pyrroles (Scheme 15) [42]. Gold activation of the alkyne in 48, addition of the azide moiety followed by a loss of dinitrogen affords a gold-stabilized cationic intermediate 49. A subsequent 1,2-H shift gave, after tautomerization, the 1H-pyrrole 50. Epoxides can also be used as nucleophiles for the preparation of heterocarbocycles via gold-catalyzed ring expansion of 1-oxiranyl-1-alkynylcyclopropanes [43,44].
An alternative method for obtaining disubstituted pyrroles via gold-catalyzed ring expansion was reported by Davies and co-workers who employed alkynyl aziridines 51 as intramolecular nucleophiles [45]. Ring expansion from the aziridines onto  [46]. The process resulted in a five-tosix-membered ring expansion which involves the cleavage of the bridging C-C bond and a formal [1,2]-alkynyl shift. A mixture of regioisomers resulted due to an unexpected equilibration of the starting material 53 to 53' via 6-endo cyclization of the olefin with the gold-activated alkyne.

Ring expansions of cyclopropenes
Highly strained cyclopropenes can undergo a wide variety of transformations in the presence of Lewis acids. Shi and co-workers reported in 2008 a gold-catalyzed cycloisomeriza-tion of aryl vinyl cyclopropenes to produce, selectively, 2-vinyl-1H-indene derivatives in high yields (Scheme 18). Upon activation of the cyclopropene, cation 55 is formed. C-C bond cleavage of the cyclopropyl ring followed by a Friedel-Crafts reaction affords, after recovery of aromaticity, the observed products [47].
of the analogous gold-catalyzed transformations has remained, until recently, largely unexplored. Usually, 1,n-dipoles are elusive intermediate species, which can undergo many side reactions preceding the desired annulation/cyclization processes. Zhang envisioned that if the negative terminus of the dipole could be stabilized in the presence of gold, a better handling of these species could be achieved to trigger [n + m] annulation processes. In fact, the cationic end of the dipole was proposed to react in a bimolecular process in the presence of a dipolarophile, such that the nucleophilic C-Au bond could intercept the newly generated delta positive charge (Scheme 19).

Scheme 19: Gold-catalyzed [n + m] annulation processes.
This concept, successfully applied to self cyclization processes [50], could be enforced in its intermolecular version by generation of gold-1,4-dipoles, which minimize self cyclization events [51]. 1-(1-Alkynyl)cyclopropyl ketones 56 proved to be versatile building blocks for this purpose and gave, in the presence of indoles 57 as dipolarophiles, tetracyclic furans 58 in excellent yields (Scheme 20, reaction 1). NHC carbenes are preferred as ancillary ligands on the metal center. Upon coordination of the metal to the alkyne 59, the 1,4-dipole 61 can be formed from oxocarbenium 60. Carbonyl compounds and carbonyl derivatives, such as imines or silyl enol ethers, can also be used as dipolarophiles to generate bicyclic furans 62 in fairly good yields (Scheme 20, reaction 2). Nitrones also reacted as dipolarophiles in the presence of AuCl 3 , even if in some cases copper catalysts were found to be more effective at triggering the corresponding annulations [52].
By contrast, when alkoxy vinyl ethers were employed as dipolarophiles, the cycloaddition takes place prior to the formation of the 1,4-furan dipole (Scheme 21). In fact, a resonance structure of 60 can be envisaged entailing a gold-carbene and a carbonyl ylide 63. Upon 1,3-dipolar cycloaddition with the alkoxy vinyl ether, bridged bicycle 64 is formed. 1,2-Alkyl migration and bridge opening produces a spiro cation 66, such that a consecutive cyclopropyl ring expansion affords the bicyclic [3.2.0]heptane skeleton 68 in excellent yield and selectivity [53]. Treatment of 68 with a protic acid in water should activate the enone system triggering the nucleophilic attack of water to give hydroxy ketones 69. The synthetic utility of the method can be easily recognized by an examination of the structure of natural products such as repraesentin F, whose core largely comprises the structural motifs generated in this goldcatalyzed cascade.

Ring expansions involving enynes
The gold-catalyzed heteroatom-assisted 1,2-shift already summarized in section 1 of this review, can offer further syn-thetic potential in combination with 1,6-enyne substrates. non-concerted process takes place, then cyclopropyl carbene 73 evolves towards cyclopropyl cation 76, which upon non-stereospecific ring expansion and cyclization could explain the formation of both cis and trans reaction products 71 and 72, respectively.
Toste and co-workers also reported a remarkable synthetic application of a gold-catalyzed ring expansion of cyclopropanols in enynic substrates [55]. Vinyl cyclopropanol 77 reacts with Ph 3 PAuBF 4 via cyclization, followed by a selective semi-pinacol shift via carbocationic intermediate 78, to give cyclobutanone 79, which is readily transformed into the angular triquinane ventricosene in six steps (Scheme 23).
A mechanistic rationale for these transformations is shown in Scheme 26. Cyclopropanes 85a are generated in situ by intermolecular cyclopropanation of enyne 84 and a carbene resulting from the rearrangement of propargyl ester 83. When tertiary propargyl esters are used, the 5-endo-dig cyclization generates the carbocation 89. Migration of the pivaloyloxy group affords the allylic cations 90 and 91 by delocalization of the positive charge onto gold. The aromatic intermediate 92 is probably converted, via 93, into 86 and 87 by E1 and S N 1 mechanisms, respectively. When secondary esters are employed, 6-endo-dig cyclization occurs to give 94, which forms the cycloheptatriene derivate 88 upon cyclopropyl ring expansion.
In addition, 3-and 1-substituted cyclopropyl propargylic acetates 98 and 99 have also been intensively studied and provide access to 5-and 6-membered ring enones, respectively (Scheme 29) [62][63][64]. In the former substrates, experimental as well as computational evidence was gathered which proved the reversible nature of the [3,3]-rearrangement in these cyclopropane probes. However, these transformations proved to be stereospecific in nature through gold-stabilized non-classical carbocations 100 and 100', even if the stereochemical information transfer to the product is sometimes incomplete. This may arise due to a competitive gold-promoted cyclopropyl ring opening/epimerization/ring closure, both in cis and trans-cyclo-propyl settings, which competes with the cyclization event, thus eroding the overall transfer of stereochemical information.

Conclusion
From the early examples reported by Gassman and de Meijere, the field of gold-catalyzed ring expansions has experienced a continuous and sustained growth. Recently, the development of chiral gold catalysts, and the implementation of highly stereocontrolled transformations, has opened up the avenue for the application of these methodologies into more complex settings, such as natural product synthesis. In summary, gold-catalyzed ring expansions of strained rings can now be considered a mature tool for the construction of molecular complexity and thus are to be incorporated in to the toolbox of the synthetic organic chemist.