Catalytic Enantioselective Aldol‐type Reaction of β‐Ketosters with Acetals

Abstract

Optically active β-oxycarbonyl compounds are useful intermediates in synthetic organic chemistry, and great efforts have been devoted to the development of catalytic asymmetric aldol reactions. Excellent methods have been developed with chiral Lewis acids and chiral secondary amines, in which ketones and their silyl derivatives react with aldehydes in a highly enantioselective manner. In contrast, readily enolizable 1,3-dicarbonyl compounds, such as β-keto esters and malonates have rarely been used as nucleophiles, probably because of insufficient nucleophilicity of the metal enolates of such compounds, although a plausible alternative explanation is that the products are unstable and readily undergo retro-aldol reaction (Scheme 1). Because of these general difficulties, there are only a few examples of the synthesis of optically active β-oxymalonates using π-allyl Pd chemistry, aldol reaction, and oxy-Michael reaction. As for catalytic aldol reactions of 1,3-dicarbonyl compounds, we recently reported a catalytic asymmetric hydroxymethylation of β-keto esters using paraformaldehyde as a C1 unit. However, reactions with less reactive aldehydes were difficult (vide infra), and we found no precedents in the literature. Previously, we showed that chiral Pd enolates were formed by the reaction of chiral Pd-bisphosphine complexes 1 with β-keto esters, being accompanied with the formation of a protic acid (Scheme 1). We envisaged that this proton might activate O,O-acetals to give an oxonium intermediate, so that aldol-type reactions with β-keto esters would proceed smoothly. Since the product is O-protected, we expected that the undesired retro-aldol reaction would be suppressed. The use of O,O-acetals as a synthetic equivalent of aldehydes has been extensively investigated in Lewis acid-mediated or catalyzed aldol-type reactions with silyl enolates. A general principle of these reactions is that chiral induction is hard to achieve, since the chiral Lewis acid interacts only weakly with the prochiral electrophile (Scheme 2). To our knowledge, no asymmetric version of such reactions has been reported. Here, we disclose the first example of a catalytic asymmetric aldol-type reaction of O,O-acetals using chiral Pd and Pt complexes, in which the chiral metal enolates of prochiral β-keto esters are the key intermediates.