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

In this paper we describe new asymmetric, catalytic strategies for the synthesis of biologically important a-methylene-d-lactones and d-lactams. The elaborated protocols utilize iminium-ion-mediated Michael addition of trimethyl phosphonoacetate to a,beta-unsaturated aldehydes catalyzed by (S)-(-)-a,a-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the key step. Enantiomerically enriched Michael adducts are employed in three different reaction pathways. Transformation into a-methylene-d-lactones is realized by a sequence of reactions involving chemoselective reduction of the aldehyde, followed by a trifluoroacetic acid (TFA)-mediated cyclization and HornerWadsworthEmmons 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 PictetSpengler reaction with tryptamine, followed by HornerWadsworthEmmons olefination. Finally, reductive amination of the Michael adducts by using methylamine and HornerWadsworthEmmons olefination of formaldehyde is demonstrated to give a-methylene-d-lactams. The developed strategies can be realized without the purification of intermediates, thus greatly increasing their practicality.