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1,4-Diazabicyclo[3.3.1]nonanes (aza-morphans) represent conformationally constrained piperazine derivatives. Herein, we report a six-step synthesis of the benzyl and allyl substituted bicyclic ketones 3a and 3b, which represent interesting building blocks for the synthesis of conformationally restricted receptor ligands. The key steps of the synthesis are the regioselective addition of ethyl acrylate to the piperazine 8, the sodium hexamethyldisilazide-induced Dieckmann cyclization of the diesters 10, and the decarboxylation of the enol esters 11 with dilute HCl. The complete sequence is only successful when a benzyl (10a) or allyl moiety (10b) is attached to N-1, since the tosyl derivative 10f failed to give a Dieckmann cyclization product, and the decarboxylation failed with the acyl derivatives 11c and 11d. [ABSTRACT FROM AUTHOR]

Starting with (S)-aspartate, methyl (S)-2-[1-allyl-4-(4-methoxybenzyl)-3,6-dioxopiperazin-2-yl]acetate 10 was synthesized in a four-step synthesis. Deprotonation of 10 and subsequent trapping of the first cyclization product led to the bicyclic mixed acetal 13 in 15% yield. The low yield of 13, compared with the yield of the corresponding glutamate derivatives, is explained by the higher energy (strain) of the bicyclo[2.2.2]octane system and the lower conformational flexibility of the shorter acetate side chain. The formation of a six-membered Na+-chelate 12 as intermediate is responsible for the high diastereoselectivity of the cyclization step. [ABSTRACT FROM AUTHOR]