An Expeditious Synthesis of Sialic Acid Derivatives by Copper(I)-Catalyzed Stereodivergent Propargylation of Unprotected Aldoses

Abstract

We developed a copper(I)-catalyzed stereodivergent anomeric propargylation of unprotected aldoses as a facile synthetic pathway to a broad variety of sialic acid derivatives. The soft allenylcopper(I) species, catalytically generated from stable allenylboronic acid pinacolate (2), is unusually inert to protonolysis by the multiple hydroxy groups of the substrates and thereby functions as a carbon nucleophile. The key additive B(OMe)3 facilitated ring-opening of the nonelectrophilic cyclic hemiacetal forms of aldoses to the reactive aldehyde forms. The chirality of the catalyst, and not the internal stereogenic centers of substrates, predominantly controlled the stereochemistry of the propargylation step; i.e., the diastereoselectivity was switched simply by changing the catalyst chirality. This is the first nonenzyme catalyst-controlled stereodivergent C-C bond elongation at the anomeric center of unprotected aldoses, which contain multiple protic functional groups and stereogenic centers. The propargylation products can be expeditiously transformed into naturally occurring and synthetic sialic acid derivatives in a simple three-step sequence. This synthetic method, which requires no protecting groups, can be performed on a gram-scale and thus offers general and practical access to various sialic acid derivatives from unprotected aldoses.

Figure 1

(a) Representative sialic acids and (b) protecting group-free and stereodivergent synthesis of sialic acid derivatives (this work).

Figure 2

Proposed catalytic cycle for the catalyst-controlled stereodivergent propargylation of unprotected aldoses.

Scheme 1. Stereodivergent Propargylation of β-d-Lactose