Pyrrolizidine alkaloids. The synthesis and absolute configuration of all stereoisomers of monocrotalic acid.

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All stereoisomers (3a, b–6a, b) of monocrotalic acid have been synthesized. Methylation of (±)-cis-2,3,4-trimethyl-2-pentenedioic acid with diazomethane followed by cis-hydroxylation with potassium permanganate afforded two epimeric γ-lactone esters in a ratio of ca. 1:5. These esters were then hydrolyzed with dilute hydrochloric acid to the corresponding acids, (±)-3 and racemic monocrotalic acid (4). Optical resolution of (±)-3 with brucine afforded 3a (2R,3R,4S) and 3b (2S,3S,4R). The racemic monocrotalic acid was also resolved by means of brucine to give natural monocrotalic acid (4a: 2R,3R,4R) and its enantiomer (4b: 2S,3S,4S). Subsequently, (±)-trans-2,3,4-trimethyl-2-pentenedioic acid was resolved with cinchonidine to give 8a and 8b, whose stereochemistry was assigned respectively as S- and R-configuration by correlation to the known (R)-(−)-2-phenylpropanoic acid. Methylation of 8a followed by cis-hydroxylation and hydrolyses afforded γ-lactone acids, 5a (2R,3S,4S) and 6b (2S,3R,4S). Similarly, the enantiomer 8b was also converted into the corresponding acids, 5b (2S,3R,4R) and 6a (2R,3S,4R). The stereochemical course of the above hydroxylations with potassium permanganate was well explained by a modification of Gram's rule of asymmetric induction. The CD spectra of 3a,b–6a,b were also discussed.
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