Indium-Catalyzed Conia-Ene Reaction for Alkaloid Synthesis (Report‪)‬

INTRODUCTION The importance of nitrogen-containing heterocycles as drugs and other various chemical entities continues to inspire the development of tactical methods for their synthesis. In connection with a project [1-4] directed toward the synthesis of biologically intriguing natural products [5] having a highly functionalized pyrrolidinone core such as lactacystin, salinosporamide A, and neooxazolomycin, we became interested in developing a novel approach which relied upon Conia-ene reaction of amidomalonate 1 to give 3 via 2 (Scheme 1). We envisaged that the suitably functionalized pyrrolidinone skeletons useful for the synthesis of the above-mentioned alkaloids would be accessible from 3 by the discrimination of the geminal esters and stereoselective functionalization of the exo olefin. However, Conia-ene reactions [6] usually require harsh conditions so that racemization of the product and isomerization of the exo olefin from the [beta],[gamma]- to [alpha],[beta]-position are serious matters of concern. Recently, in place of the original thermal Conia-ene reaction, a number of metal-catalyzed reactions that are carried out under mild conditions have been devised for the preparation of carbocycles [7,8] as well as heterocycles [9,10], although the latter are largely limited to 3-methylene-pyrrolidines and tetrahydrofurans. However, it was unknown whether metal-catalyzed versions of the Conia-ene reaction would be applicable to our envisaged transformation. This paper describes a new route to pyrrolidinones and other heterocycles based on In-catalyzed Conia-ene type cyclization of nitrogen- and oxygen-tethered acetylenic malonic esters. This paper also demonstrates the utility of this methodology by its application to the synthesis of (-)-salinosporamide A [3,4] and (+)-neooxazolomycin [2,4].