Gold-Catalyzed Rearrangements and Beyond

Abstract

Cycloisomerizations of enynes are probably the most representative carbon–carbon bond forming reactions catalyzed by electrophilic metal complexes. These transformations are synthetically useful because chemists can use them to build complex architectures under mild conditions from readily assembled starting materials. However, these transformations can have complex mechanisms. In general, gold(I) activates alkynes in the presence of any other unsaturated functional group by forming an (η2-alkyne)–gold complex. This species reacts readily with nucleophiles, including electron-rich alkenes. In this case, the reaction forms cyclopropyl gold(I) carbene-like intermediates. These can come from different pathways depending on the substitution pattern of the alkyne and the alkene. In the absence of external nucleophiles, 1,n-enynes can form products of skeletal rearrangement in fully intramolecular reactions, which are mechanistically very different from metathesis reactions initiated by the [2 + 2] cycloaddition of a Grubbs-type carbene or other related metal carbenes.In this Account, we discuss how cycloisomerization and addition reactions of substituted enynes, as well as intermolecular reactions between alkynes and alkenes, are best interpreted as proceeding through discrete cationic intermediates in which gold(I) plays a significant role in the stabilization of the positive charge. The most important intermediates are highly delocalized cationic species that some chemists describe as cyclopropyl gold(I) carbenes or gold(I)-stabilized cyclopropylmethyl/cyclobutyl/homoallyl carbocations. However, we prefer the cyclopropyl gold(I) carbene formulation for its simplicity and mnemonic value, highlighting the tendency of these intermediates to undergo cyclopropanation reactions with alkenes.We can add a variety of hetero- and carbonucleophiles to the enynes in the presence of gold(I) in intra- or intermolecular reactions, leading to the corresponding adducts with high stereoselectivity through stereospecific anti-additions. We have also developed stereospecific syn-additions, which probably occur through similar intermediates. The attack of carbonyl groups at the cyclopropyl carbons of the intermediate cyclopropyl gold(I) carbenes initiates a particularly interesting group of reactions. These trigger a cascade transformation that can lead to the formation of two C–C and one C–O bonds. In the fully intramolecular process, this stereospecific transformation has been applied for the synthesis of natural sesquiterpenoids such as (+)-orientalol F and (−)-englerin A.Intra- and intermolecular trapping of cyclopropyl gold(I) carbenes with alkenes leads to the formation of cyclopropanes with significant increase in the molecular complexity, particularly in cases in which this process combines with the migration of propargylic alkoxy and related OR groups. We have recently shown this in the stereoselective total synthesis of the antiviral sesquiterpene (+)-schisanwilsonene by a cyclization/1,5-acetoxy migration/intermolecular cyclo...

Meeting the Challenge of Intermolecular Gold(I)‐Catalyzed Cycloadditions of Alkynes and Allenes

“…This reaction required the use of sterically hindered gold(I) complex [ t BuXPhosAu(NCMe)]SbF 6 as catalyst, a member of a family of highly reactive cationic gold(I) complexes such as [JohnPhosAu(NCMe)]SbF 6 , which circumvent the addition of any silver salt to catalyze a wide range of synthetically useful transformations 1m. 9 The reaction required arylacetylenes, although cyclopropylacetylene could also be used.…”

“…1, 2 These intermediates could then undergo ring expansion to form a stabilized tertiary carbocation and finally the cyclobutene after demetalation (Scheme 2). …”

“…The development of gold(I)-catalyzed reactions relied on intramolecular reactions of 1,n-enynes and their allene analogues 1. 2 Much less attention was given initially to the corresponding intermolecular reactions, which, in principle, are more challenging.…”

Gold(i)-catalyzed addition of aldehydes to cyclopropylidene bearing 6-aryl-1,5-enynes

“…1–7 The effectiveness of electrophilic gold(I) complexes for activating unsaturated carbon-carbon bonds 8 is key to initiating and guiding the reactivity of these fragments. Coupling enyne cycloisomerization processes to the addition of heteronucleophiles, including alcohols 9–11 and aldehydes, 12–16 in enyne cycloisomerization reactions has created new transformations that multiply the molecular complexity of the products.…”

A simple Ag(I)-enyne cation

“…A plethora of gold(I) complexes and enyne substrates have been employed to access a variety of products with increased molecular complexity under very mild reaction conditions. [1][2][3][4][5][6] The mechanism is presumed to proceed via initial coordination of the gold(I) moiety to the alkyne which enhances its electrophilicity allowing for subsequent nucleophilic attack from the alkene. [7][8] However, low temperature NMR spectroscopy investigations indicated no preference between alkyne and alkene coordination, suggesting that the procedure may be kinetically rather than thermodynamically controlled.…”