Diastereoselective alkylation of a proline-derived bicyclic lactim ether

Abstract

N-Boc-protected L-proline (6) was converted into the bicyclic lactim ether (8aS)-6,7,8,8a-tetrahydro-1-methoxypyrrolo[1,2-a]pyrazin-4(3H)-one (5) in four steps (Scheme 1). Deprotonation with LDA or LHMDS and subsequent alkylation resulted in the diastereoisomeric products cis- and trans-9. The diastereoselectivity was mainly dependent on the electrophile. Whereas small alkyl halides gave preferably cis-9, sterically more-demanding alkyl halides resulted in cisltrans mixtures. Electrophiles bearing a π-system favored the trans-products 9. Some isolated cis- and tranx-lactim ethers 9 were converted to the corresponding diketopiperazines cis- and trans-10 by acid hydrolysis. The structures and configurations of several compounds were confirmed by NMR and NOE experiments, as well as by X-ray crystallography (Figs. 1-4). © 2006 Verlag Helvetica Chimica Acta AG.