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Stereocontrolled Synthesis of (2R,3S)-2-Methylisocitrate, a Central Intermediate in the Methylcitrate Cycle

Lookup NU author(s): Emeritus Professor Bill Clegg, Dr Ross Harrington, Professor Bernard Golding

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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 (2R,3S)- and (2S,3R)-2-methylisocitrate (98% e.e.) were achieved starting from (R)- and (S)-lactic acid (=(2R)- and (2S)-2-hydroxypropanoic acid), respectively. The dispiroketal (6S,7S,15R)-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 (2S)-2-[(6S,7S,14R)-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 (2R,3S)-2-methylisocitrate and hence (2R,3S)-2-methylisocitrate. Similarly, (S)-lactic acid led to (2S,3R)-2-methylisocitrate. Comparison of 2-methylisocitrate produced enzymatically with the synthetic enantiomers established that the biologically active isomer is (2R,3S)-2-methylisocitrate.


Publication metadata

Author(s): Darley DJ, Selmer T, Clegg W, Harrington RW, Buckel W, Golding BT

Publication type: Article

Publication status: Published

Journal: Helvetica Chimica Acta

Year: 2003

Volume: 86

Issue: 12

Pages: 3991-3999

ISSN (print): 0018-019X

ISSN (electronic): 1522-2675

Publisher: Verlag Helvetica Chimica Acta

URL: http://dx.doi.org/10.1002/hlca.200390332

DOI: 10.1002/hlca.200390332


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