Organophosphorus Reagents in Organocatalysis: Synthesis of Optically Active α-Methylene-δ-lactones and δ-Lactams

Abstract

In this paper we describe new asymmetric, catalytic strategies for the synthesis of biologically important α-methylene-δ-lactones and δ-lactams. The elaborated protocols utilize iminium-ion-mediated Michael addition of trimethyl phosphonoacetate to α,β-unsaturated aldehydes catalyzed by (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the key step. Enantiomerically enriched Michael adducts are employed in three different reaction pathways. Transformation into α-methylene-δ-lactones is realized by a sequence of reactions involving chemoselective reduction of the aldehyde, followed by a trifluoroacetic acid (TFA)-mediated cyclization and Horner–Wadsworth–Emmons olefination of formaldehyde. On the other hand, indolo[2, 3-a]quinolizine-framework-containing products can be accessed when enantiomerically enriched Michael adducts are employed in a Pictet–Spengler reaction with tryptamine, followed by Horner–Wadsworth–Emmons olefination. Finally, reductive amination of the Michael adducts by using methylamine and Horner–Wadsworth–Emmons olefination of formaldehyde is demonstrated to give α-methylene-δ-lactams. The developed strategies can be realized without the purification of intermediates, thus greatly increasing their practicality.