Applications of ortho-quinone methide intermediates in catalysis and asymmetric synthesis

Abstract

Ortho-quinone methides are important synthetic intermediates and widely implicated in biological processes. In this Synopsis, recent advances concerning the synthesis and utility of these intermediates are discussed with a particular emphasis on metal-catalyzed formation of quinone methide intermediates. Additionally, applications of these intermediates as partners in asymmetric synthesis will be discussed including methods we have developed that involve the enantioselective Pd-catalyzed formation of ortho-quinone methides and the trapping of aforementioned intermediates with diverse nucleophiles.

Figure 1

Structural differences between ortho-quinone methide, ortho-quinone and ortho-quinone dimethide.

Figure 2

General modes of reactivity of ortho-quinone methides.

Figure 3

Proposed mechanism of action of anthracyclin antibiotics.

Figure 4

Pd-catalyzed total synthesis of carpanone, Chapman and coworkers, 1974.

Figure 5

Pd-catalyzed dialkoxylation of vinyl phenols, Sigman and coworkers, 2006.

Figure 6

Preliminary mechanistic experiments, Sigman and coworkers, 2006.

Figure 7

Effect of solvent in the Pd-catalyzed alkene functionalization of vinyl phenols, Sigman and coworkers, 2006.

Figure 8

Scope of Pd-catalyzed hydrofunctionalization of vinyl phenols using a sacrificial alcohol as the hydride source, Sigman and coworkers, 2007.

Figure 9

Evidence to support the proposed mechanism, Sigman and coworkers, 2007.

Figure 10

Hydrofunctionalization of styrene using n-butyl chloride as a sacrificial hydride source, Sigman and coworkers, 2011.

Figure 11

Diastereoselective reaction of chiral enol ethers with ortho-quinone methides, Pettus and coworkers, 2004.

Figure 12

Enantioselective reaction of ortho-quinone methides with ketene enolate using chiral ammonium fluoride pre-catalyst, Lectka and coworkers, 2009.

Figure 13

Enantioselective Pd-catalyzed dialkoxylation of vinyl phenols, Sigman and coworkers, 2007.

Figure 14

Scope of enantioselective Pd-catalyzed alkene difunctionalization reactions of vinyl phenols, Sigman and coworkers, 2009

Figure 15

Inverse electron demand Diels-Alder reaction with enol ether 22, Sigman and coworkers, 2009.

Figure 16

Scope of the enantioselective Pd-catalyzed alkene difunctionalization reaction of vinyl phenols with electron rich heteroaromatics, Sigman and coworkers, 2009.

Scheme 1

Proposed mechanism for Pd-catalyzed vinyl phenol dialkoxylation reaction, Sigman and coworkers, 2006.

Scheme 2

Proposed mechanism, Sigman and coworkers, 2007.

Scheme 3

Proposed mechanism, Sigman and coworkers, 2011.

Scheme 4

Proposed mechanism, Lectka and coworkers, 2009.

Scheme 5

Proposed mechanism of alkene difunctionalization, Sigman and coworkers, 2009