Gold Catalysts

Chemfiles Volume 6 Article 2

Prior to the 1980s, gold was regarded as having little catalytic activity. Recent advancements, spearheaded by F. Dean Toste (University of California, Berkeley) and others, have propelled gold into the forefront of transition metal catalysis. In particular, phosphine-ligated gold(I) complexes have recently emerged as powerful C–C bond forming catalysts, capable of performing a variety of reactions under mild conditions. The list of useful C–C bond construction methods includes cyclopropanations, enyne isomerizations, Rautenstrauch rearrangements, ene reactions, and ring expansions. Typically, the catalyst system relies on a phosphine gold(I) chloride complex in combination with a silver salt co-catalyst to generate the active species in situ (Scheme 1).

Scheme 1

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Toste and co-workers successfully demonstrated that a variety of olefins undergo stereoselective cyclopropanation with propargyl esters in the presence of Ph3PAuSbF6 (generated in situ from PPh3AuCl and AgSbF6, Scheme 2).1 This reaction shows a preference for cis-selectivity and therefore complements the transselectivity observed in transition metal-catalyzed cyclopropanation of olefins using α-diazoacetates. A diverse set of complex vinylcyclopropanes was synthesized using this methodology (Figure 1).

Scheme 2

Figure 1

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Isomerization of 1,5-Enynes

In the presence of gold(I), a range of 1,5-enynes rearrange to give bicyclo[3.1.0]hexenes in a high-yielding, stereocontrolled fashion.2 The isomerization conditions accommodate diverse substitution patterns about the enyne, and moreover, can be conducted under “open-flask” conditions. The catalyst system utilizes Ph3PAuCl in combination with AgBF4, AgPF6, or AgSbF6 co-catalysts. While this method allows for access to simple bicyclic hydrocarbons (Scheme 3), complex heteroatom-rich cyclopropanes can also be prepared in high-yield and with superb diastereocontrol (Scheme 4). This latter example also illustrates the efficient chirality transfer that takes place in the isomerization process.

Scheme 3

Scheme 4

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Rautenstrauch Rearrangement

The Rautenstrauch rearrangement of 1,4-enynes provides efficient access to a diverse portfolio of functionalized cyclopentenones. Historically, the Pd-catalyzed reaction was limited to the preparation of achiral cyclopentenones, substituted at the 2 and 3 positions. Recent advances in gold(I) catalysis by Toste and co-workers have significantly broadened the scope of this synthetically useful rearrangement.3 For example, chiral 1-ethynyl- 2-propenyl pivalates efficiently rearrange in an enantioselective fashion and under mild conditions (Scheme 5). For optically pure pivalates, the in situ-generated catalyst Ph3PAuSbF6 is most effective for transfer of the resident substrate chirality to the cyclopentenone product. Ph3PAuOTf (also generated in situ) is adequate for Rautenstrauch rearrangement of racemic pivalates.

Scheme 5

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Conia-Ene Reactions

The thermal cyclization of ε-acetylenic carbonyl compounds (Conia-ene reaction) provides access to methylenecyclopentanes without the need for deprotonation. However, the synthetic utility of this reaction is limited due to the high temperatures required. Toste has reported a mild catalytic version of this reaction that proceeds under neutral conditions at ambient temperatures.4 The treatment of β-ketoesters containing tethered alkynes with Ph3PAuOTf rapidly provides the corresponding vinylidenecyclopentanes in excellent conversion (Scheme 6, Table 1). This isomerization can also be performed at reduced catalyst loadings by using the oxonium catalyst, [(Ph3PAu)3O]BF4, in the presence of acid. This methodology was applied to the synthesis of a variety of architecturally intriguing cyclopentanes (Scheme 7).

Scheme 6

Table 1

Scheme 7

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5-endo-dig Carbocyclizations

While the gold(I)-catalyzed Conia-ene cycloisomerization is limited to terminal ε-alkynes, the related 5-endo-dig reaction allows for cyclization onto nonterminal δ-alkynes providing cyclopentene derivatives.5 While this synthetic methodology can be applied to simple bicyclic molecules, it can also be used in the preparation of N-heterocycles and halogenated cyclopentenes (Scheme 8).

Scheme 8

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Propargyl Claisen Rearrangement

The Claisen rearrangement is one of the most powerful methods for C–C bond formation in the organic chemist’s toolbox. The isolable oxonium gold catalyst, [(Ph3PAu)3O]BF4, provides access to a variety of homoallenic alcohols via a rapid two-step, one-pot sequence of a Claisen rearrangement of a propargyl vinyl ether, followed by reduction of the aldehyde functionality (Scheme 9, Table 2).6 The reactions are generally high-yielding, and additionally, the catalyst system also shows a good ability to relay resident substrate chirality into the allene products (Scheme 10).

Scheme 9

Table 2

Scheme 10

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Other Gold-Catalyzed Reactions

The facile and high-yielding ring expansion of 1-alkynylcycloalkanols to the corresponding 2-alkylidenecycloalkanones is catalyzed by several gold catalysts, including in situ-generated Ph3PAuSbF6. Treatment of 1-(phenylethynyl)cyclopropanol with Ph3PAuSbF6 gives exclusively the (E)-benzylidenecyclobutanone in high yield (Scheme 11).7 Using the same catalyst, pyrroles can be prepared by an intramolecular acetylenic Schmidt reaction of homopropargyl azides (Scheme 12).8

Scheme 11

Scheme 12

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  1. Toste, F. D. et al. J. Am. Chem. Soc. 2005, 127, 18002.
  2. Toste, F. D. et al. J. Am. Chem. Soc. 2004, 126, 10858.
  3. Toste, F. D. et al. J. Am. Chem. Soc. 2005, 127, 5802.
  4. (a) Toste, F. D. et al. J. Am. Chem. Soc. 2004, 126, 4526; (b) Toste, F. D. et al. J. Am. Chem. Soc. 2005, 127, 17168.
  5. Toste, F. D. et al. Angew. Chem. Int. Ed. 2004, 43, 5350.
  6. Toste, F. D. et al. J. Am. Chem. Soc. 2004, 126, 15978.
  7. Toste, F. D. et al. J. Am. Chem. Soc. 2005, 127, 9708.
  8. Toste, F. D. et al. J. Am. Chem. Soc. 2005, 127, 11260.

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