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. 2010 Mar 1;2010(5):675-691.
doi: 10.1055/s-0029-1219369.

A Reactivity-Driven Approach to the Discovery and Development of Gold-Catalyzed Organic Reactions

Nathan D Shapiro  1 , F Dean Toste
Affiliations

A Reactivity-Driven Approach to the Discovery and Development of Gold-Catalyzed Organic Reactions

Nathan D Shapiro et al. Synlett. .

Abstract

Approaches to research in organic chemistry are as numerous as the reactions they describe. In this account, we describe our reactivity-based approach. Using our work in the area of gold-catalysis as a background, we discuss how a focus on reaction mechanism and reactivity paradigms can lead to the rapid discovery of new synthetic tools.

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Figures

Figure 1
Figure 1
A comparison of calculated sizes and energies of Au 6s and 5d orbitals with and without consideration of relativistic effects.
Figure 2
Figure 2
Calculated bond-distances and relative natural orbital populations for three cationic Au(I)-carbene complexes.
Figure 3
Figure 3
A bonding-model for Au-carbene complexes.
Scheme 1
Scheme 1
(a) The mechanism, which has subsequently been disproved, originally proposed by Teles and coworkers for the addition of alcohols to alkynes mediated by Au(I) complexes. (b) A reaction reported in 1974 showing the carboauration of β-ketoesters. These reports prompted us to investigate the Au-catalyzed addition of β-ketoesters to alkynes.
Scheme 2
Scheme 2
Mechanistic proposals in the gold(I)-catalyzed Conia-ene reaction. Experimental results support a mechanism involving trans addition.
Scheme 3
Scheme 3
Transition metal catalyzed enantioselective Conia-ene reaction. (a) Effect of transition metal and ligand on enantioselectivity. (b) A comparison of (R)-DTBM-SEGPHOS-Pd(OTf)2 and (R)-BINAP(AuCl)2 complexes showing the effect of metal geometry on the proximity of the ligand and substrate. (tert-butyl groups and OTf counteranions in the Pd complex have been removed for clarity).
Scheme 4
Scheme 4
(a) Development of a gold(I)-catalyzed asymmetric hydroamination reaction. (b) A possible rationale for the observed counteranion effects.
Scheme 5
Scheme 5
The first report of a highly enantioselective, chiral counteranion-controlled asymmetric reaction.
Scheme 6
Scheme 6
(a) A potential mechanism for pro-nucleophile activation by Au (I). (b) Au(I)-catalyzed enantioselective 1,3-dipolar cycloaddition initiated by formation of a Au-coordinated Münchnone.
Scheme 7
Scheme 7
Au(I)-catalyzed cyclopropanol ring expansion reactions.
Scheme 8
Scheme 8
(a) and (b) Mechanistic possibilities for the in situ generation of reactive electrophiles and subsequent trapping of vinyl Au moieties. (c) Application to the synthesis of enantioenriched indenyl ethers.
Scheme 9
Scheme 9
A typical catalytic cycle for the Au(I)-catalyzed addition of protic nucleophiles to alkynes.
Scheme 10
Scheme 10
(a). Re-catalyzed synthesis of 1,5-enynes and subsequent Au-catalyzed cycloisomerization. (b) Stereospecific cycloisomerizations.
Scheme 11
Scheme 11
Proposed 1,5-enyne cycloisomerization mechanism.
Scheme 12
Scheme 12
A few possible routes to gold-carbenoids from ylide-tethered alkynes. Nu = nucleophile, LG = leaving group.
Scheme 13
Scheme 13
Gold(I)-catalyzed intramolecular acetylenic Schmidt reaction.
Scheme 14
Scheme 14
Gold(I)-catalyzed sulfoxide rearrangements.
Scheme 15
Scheme 15
(a) Pd-catalyzed Rautenstrauch rearrangement. (b) The gold-catalyzed variant allows for efficient chirality transfer. In order to account for this observation, we proposed a cyclic transition state. Calculations later showed that the C-O breaking and C-C bond forming events occur separately, while the chirality is retained in a helically chiral intermediate.
Scheme 16
Scheme 16
(a) Demonstrating that Au(I)-catalyzed cyclopropanation is stereospecific. (b) An enantioselective variant.
Scheme 17
Scheme 17
The effect of the ancillary ligand (L) on the reactivity of Au(I)-carbene complexes.
Scheme 18
Scheme 18
Observed products resulting from intramolecular rearrangement of cationic intermediates.
Scheme 19
Scheme 19
Gold(I)-catalyzed 1,3-allene cycloisomerization.
Scheme 20
Scheme 20
Observed reaction products and possible reactive intermediates in the Au-catalyzed reactions of allene L1.
Scheme 21
Scheme 21
Initial experimental observations and mechanistic hypothesis in ligand-directed, Au-catalyzed [4 + 3] and [4 + 2] cycloadditions.
Scheme 22
Scheme 22
Calculated structures and transition state energies for intermediates in Au-catalyzed [4 + 3] and [4 + 2] cycloadditions.
Scheme 23
Scheme 23
Observed products resulting from intermolecular trapping of intermediate A′.
Scheme 24
Scheme 24
Proposed mechanism of Au(III)-catalyzed azepine synthesis.
Scheme 25
Scheme 25
Transition-metal catalyzed (a), and mediated (b) annulations of α,β-unsaturated imines.
Scheme 26
Scheme 26
Isolobal analogies of (a) alkenyl Fischer carbenes and (b) alkenyl metal carbenoids lead to predictions of distinct regioselectivity in the reaction of these species with 1,3-dipoles.
Scheme 27
Scheme 27
Gold(I)-catalyzed tandem cyclization reactions.
Scheme 28
Scheme 28
Tandem propargyl-Claisen/cyclization reactions.
See this image and copyright information in PMC

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