Analogues of hepatotoxic pyrrolizidine alkaloids: synthesis and esterification of 1-methyl-2,3-bishydroxymethyl-pyrrolidines and -3-pyrrolines (synthanecines) and corresponding pyrrole derivatives

Abstract

Several 2,3-bishydroxymethyl-pyrrolidine and -3-pyrroline derivatives (synthanecines) have been prepared as monocyclic analogues of the bicyclic necine bases which constitute the alcohol portions of many pyrrolizidine alkaloids. Thus, reduction of 2,3-bisethoxycarbonyl-1-methyl-3-pyrroline (IX) and of 2,3-bisethoxycarbonyl-4-methoxy-1-methyl-3-pyrroline (XII) with lithium aluminium hydride gives mainly the pyrrolidine (XI)(synthanecine B) while reduction using di-isobutylaluminium hydride gives the pyrrolines (X) and (XIII)(synthanecines A and C, respectively). Some of the unsaturated synthanecine esters, such as the carbamate (XVII) have biological effects similar to those of the toxic pyrrolizidine alkaloid monocrotaline (IV). Dehydrogenation of the 3-pyrroline diesters (IX) and (XII) and reduction of the resulting pyrrole diesters (XXI) and (XXII) provides the corresponding bishydroxymethylpyrroles (XXIII) and (XXV), which behave as bifunctional alkylating agents.