Abstract
2‐Methylisocitrate (=3‐hydroxybutane‐1,2,3‐tricarboxylic acid) is an intermediate in the oxidation of propanoate to pyruvate (=2‐oxopropanoate) via the methylcitrate cycle in both bacteria and fungi (Scheme 1). Stereocontrolled syntheses of (2__R__,3__S__)‐ and (2__S__,3__R__)‐2‐methylisocitrate (98% e.e.) were achieved starting from (R)‐ and (S)‐lactic acid (=(2__R__)‐ and (2__S__)‐2‐hydroxypropanoic acid), respectively. The dispiroketal (6__S__,7__S__,15__R__)‐15‐methyl‐1,8,13,16‐tetraoxadispiro[5.0.5.4]hexadecan‐14‐one (2a) derived from (R)‐lactic acid was deprotonated with lithium diisopropylamide to give a carbanion that was condensed with diethyl fumarate (Scheme 3). The configuration of the adduct diethyl (2__S__)‐2‐[(6__S__,7__S__,14__R__)‐14‐methyl‐15‐oxo‐1,8,13,16‐tetraoxadispiro[5.0.5.4]hexadec‐14‐yl]butanedioate (3a) was assigned by consideration of possible transition states for the fumarate condensation (cf. Scheme 2), and this was confirmed by a crystal‐structure analysis. The adduct was subjected to acid hydrolysis to afford the lactone 4a of (2__R__,3__S__)‐2‐methylisocitrate and hence (2__R__,3__S__)‐2‐methylisocitrate. Similarly, (S)‐lactic acid led to (2__S__,3__R__)‐2‐methylisocitrate. Comparison of 2‐methylisocitrate produced enzymatically with the synthetic enantiomers established that the biologically active isomer is (2__R__,3__S__)‐2‐methylisocitrate.