Chiral N-Heterocyclic Carbene Catalyzed Annulations of Enals and Ynals with Stable Enols: A Highly Enantioselective Coates-Claisen Rearrangement

Abstract

A combination of a chiral N-heterocyclic carbene catalyst and α,β-unsaturated aldehyde leads to a catalytically generated α,β-unsaturated acyl azolium, which participates in a highly enantioselective annulation to give dihydropyranone products. This full account of our investigations into the scope and mechanism of this reaction reveals the critical role of both the type and substitution pattern of the chiral triazolium precatalyst in inducing and controlling the stereochemistry. In an effort to explain why stable enols such as naphthol, kojic acid, and dicarbonyl are uniquely efficient, we have postulated that this annulation occurs via a Coates-Claisen rearrangement that invokes the formation of a hemiacetal prior to a sigmatropic rearrangement. Detailed kinetic investigations of the catalytic annulation are consistent with this mechanistic postulate.

Figure 1

Wender’s elaboration of Kojic acid

Figure 2

The catalytic cycle for NHC-catalyzed Claisen rearrangement from ynal and an enol

Figure 3

The activation parameters for Coates-Claisen reaction and the NHC-catalyzed variant

Figure 4

An investigation on non-linear effect.

Scheme 1

Selected variant of Claisen rearrangement

Scheme 2

An NHC-catalyzed Claisen rearrangement

Scheme 3

Stereoselective generation of α,β-unsaturated acyl azoliums

Scheme 4

Competing pathways of hemiacetal intermediate

Scheme 5

Catalytic, enantioselective couplings with other enol partners

Scheme 6

Catalytic generation of α,β-unsaturated acyl azolium from enal via the oxidation of the Breslow intermediate

Scheme 7

A conjugate addition of 1-methylindole to α,β-unsaturated acyl azolium

Scheme 8

Ynals reactivity comparison

Scheme 9

Catalyst-controlled product selectivity: Claisen reaction vs. esterification