Toggle Main Menu Toggle Search

Open Access padlockePrints

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

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

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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


Altmetrics

Altmetrics provided by Altmetric


Share