Macrocyclic pyrrolizidine alkaloid analogues. Synthesis and stereochemistry of (12R,14S)- and (12S,14R)-12,14-dimethyl-1,2-didehydrocrotalanine. X-Ray molecular structure of the (12S,14R)-isomer

Abstract

Treatment of (+)-retronecine (1) with meso-2,4-dimethylglutaric anhydride followed by lactonisation via the pyridine-2-thiol esters yielded(12R,14S)-(3) and (12S,14R)-dimethyl-1,2-didehydrocrotalanine (4). These pyrrolizidine alkaloid analogues were separated by column chromatography. The absolute configuration of the acid portion of each analogue was established by a sequence of two chemoselective reactions to afford optically active tetrahydro-3,5-dimethyl-2H-pyran-2-one. An X-ray crystal structure analysis confirmed the structure and stereochemistry of the (12S,14R)-isomer (4). The ester carbonyl groups of compound (4) are synparallel and directed below the plane of the macrocyclic ring.