Bicyclic sigma receptor ligands by stereoselective Dieckmann analogous cyclization of piperazinebutyrate

Starting from racemic 2-aminoadipic acid (6) the piperazinedione 10 with a butyrate side chain was synthesized in four reaction steps. The four-carbon bridge was established upon deprotonation of 10 with LHMDS and subsequent trapping of the lithium alcoholate with Me(3)SiCl to give diastereoselectively the mixed methyl silyl ketal 12 in 94% yield. The relative configuration of the new center of chirality was determined by X-ray crystal structure analysis of 12. The high diastereoselectivity during the conversion of the butyrate 10 into the mixed methyl silyl ketal 12 supports the formation of the lithium alcoholate 11 as central intermediate. Stereoselective reduction of the ketone 13 with LiBH(4) led to the alcohol 14, which was benzylated and reduced to provide the final bicyclic products 16 and 17. Whereas the alcohol 16 shows only moderate affinity to both sigma receptor subtypes, the benzyl ether 17 represents a potent and selective sigma(1) receptor ligand (K(i) = 47 nM). Comparison of the sigma receptor affinities of 16 and 17 with the smaller homologues 5a and 5c clearly indicates that the size of the bridge and the O-substituent determines subtype selectivity.