Dedicated to Professor Dieter Hoppe on the occasion of his 65th birthday 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 cis/trans mixtures. Electrophiles bearing a psystem favored the trans-products 9. Some isolated cis-and trans-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).Introduction. -In contrast to the well-known Schçllkopf bislactim-ether method for the synthesis of a-amino acids [1 -3], the alkylation of monolactim ethers has been rarely reported in the literature [4 -6]. Recently, we have published the preparation of tricyclic diketopiperazines with an annulated tetrahydroisoquinoline moiety via diastereoselective alkylation of the corresponding monolactim ethers and subsequent hydrolysis [7].Several secondary metabolites of microorganisms with interesting biological properties such as deoxybrevianamide E (1) [8], tryprostatins A and B (2a, b) [9], spirotryprostatin A (3) [10], and fumitremorgin C (4) [11] contain a proline-derived diketopiperazine as part of their molecular skeleton. Furthermore, this type of compound has been found in the bitter flavor of roasted coffee [12]. The diketopiperazine structural motif in these natural products was prepared in most cases by cyclocondensation [8 -11] [13] [14]. However, we were interested to synthesize related proline-based diketopiperazines via alkylation of the bicyclic lactim ether 5, followed by acidic hydrolysis. The results of our investigation are reported in this paper.

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