First synthesis of a phosphonothiashikimic acid derivative† Montserrat Heras, Mihaela Gulea and Serge Masson* Laboratoire de Chimie Moléculaire et Thioorganique (UMR CNRS, 6507), ISMRA-Université de Caen et CNRS, 6 boulevard du Maréchal Juin, F-14050 Caen, France. E-mail: serge.masson@ismra.fr Received (in Cambridge, UK) 30th January 2001, Accepted 21st February 2001 First published as an Advance Article on the web 13th March 2001 A new phosphono and thio analogue of shikimic acid ester has been synthesised from a thiopyranic derivative obtained via a [4 + 2] cycloaddition involving a phosphonodithio- formate as heterodienophile. Shikimic acid 1 I (Scheme 1) is an important intermediate in the biosynthesis of aromatic amino acids from carbohydrates in plants and microorganisms. Therefore, increasing effort has been directed towards the synthesis of its analogues as potential enzyme inhibitors in this biological pathway. Several modifica- tions of the shikimic acid structure were described, including the functionalisation of the cyclohexene ring, 2 the substitution of the carboxylic function by a phosphono group 3 (phosphono shikimic acid II) or the replacement of the methylene group involved in the shikimate pathway by a sulfur atom (thia- shikimic acid III). We report here the first synthesis of a new racemic derivative of compound IV which is both a phosphono and thio analogue of shikimic acid. As for the preparation of thiashikimic acid ester, 4 we used a hetero Diels–Alder cycloaddition for the first step of our synthesis (Scheme 2). However, instead of the unknown and probably very unstable thioaldehyde-phosphonate (analogue of a thioxoacetate) we used a very stable and readily accessible phosphonodithioformate 1 (very recently described by our group as a new heterodienophile 5 ). Although relatively slow (7 days), the reaction of (E,E)-1,4-diacetoxybutadiene with this dithioester in refluxing THF led to the functionalized dihy- drothiopyranic derivative 2 as a mixture of diastereomers 2a and 2b in a 2+1 ratio and 87% yield (use of a Lewis acid to accelerate the reaction 5 was excluded because it induced some undesirable degradation of the cycloadduct). These isomers were easily separated by chromatography on silica gel. By comparison with the reaction of the thioxoacetate, 4 we could expect for the major isomer 2a (58%) resulting from a preferential phosphonyl-endo cycloaddition, a cis configuration as far as the two acetoxy and the phosphono groups are concerned. The structures assumed for 2a and 2b were indeed found in accordance with the observed coupling constants between phosphorus and protons on C 3 and C 6 : large equato- rial–equatorial or axial–axial coupling (torsion angle F ~ 0 or ~ 180°) and almost null equatorial–axial coupling (F ~ 90°) 6 (Scheme 3). Each isomer was then desulfanylated using Bu 3 SnH–AIBN in refluxing benzene and, as expected from our preliminary study, 5 the heterocyclic sulfur atom is not affected by the reaction. A mixture of 2,3-cis 3a and 2,3-trans 3b isomers was respectively obtained in a 2+1 ratio from 2a (85%) and in a 5+3 ratio from 2b (75%). The favoured formation of isomer 3a could be explained by the preferential reduction of the anomeric radical on the opposite side to the C 3 acetoxy groups through an axial attack. 7 The stereochemistry of these diastereomers was deduced from the 3 J H2–H3 = 6.1 (for 3a) and 10.7 Hz (for 3b) coupling constants. † Electronic supplementary information (ESI) available: experimental. See http://www.rsc.org/suppdata/cc/b1/b101050f/ Scheme 1 Scheme 2 Reagents and conditions: i: THF, rt, 7 d; ii: Bu 3 SnH–AIBN, refluxing benzene, 2 h; iii: OsO 4 –Py, rt, 2 h. Scheme 3 Relative configurations of cycloadducts 2 (one conformer of each isomer is represented). This journal is © The Royal Society of Chemistry 2001 DOI: 10.1039/b101050f Chem. Commun., 2001, 611–612 611 Published on 13 March 2001. Downloaded by Temple University on 26/10/2014 16:51:15. View Article Online / Journal Homepage / Table of Contents for this issue