Approaches to pseudopeptidic ergopeptines. Part 3.1 Consequences of the incorporation of an α-azaphenylalanine residue into the ergotamine oxa-cyclolic system

Abstract

In the context of a research program aimed at synthesizing pseudopeptidic ergopeptines, the incorporation of an α-azaPhe residue into the peptidic moiety of ergotamine has been studied. Acylation of cyclo(-azaPhe-Pro-) 6 with (+)-(S)-2-benzyloxy-2-methylmalonyl monoethyl ester monochloride 5 gives the (E)-isoimide 7 as the predominant reaction product; contrary to expectation the conversion of 7 into the desired imide isomer 8 proceeds with difficulty and is accompanied by decomposition. Hydrogenolysis of 8 leads stereospecifically to the pseudopeptidic oxa-cyclol ethyl ester 9. Subsequent rearrangement of the corresponding oxa-cyclol acyl-azide 11 in the presence of benzyl alcohol fails to give the pseudopeptidic ergotamine oxa-cyclol. The new stable pseudopeptidic aza-cyclol 12 containing the residue of the didehydroalanine has been isolated together with a comparable amount of the imino aza-cyclol derivative 13. The mechanism of the formation of the new products 12 and 13 and the unexpected stability of the (E)-isoimide 7 are discussed.