Synthesis of (R)-2-methyl-4-deoxy and (R)-2-methyl-4,5-dideoxy analogues of 6-phosphogluconate as potential inhibitors of 6-phosphogluconate dehydrogenase.
The synthesis of (2R)-2-methyl-4,5-dideoxy and (2R)-2-methyl-4-deoxy analogues of 6-phosphogluconate is described. The synthetic strategy relies on the Evans aldol reaction for the installation of the chiral centres in the 2- and 3-positions. The selective phosphorylation at the primary alcohol function of (2R,3S)-3,6-dihydroxy-2-methylhexanoic acid benzyl ester (5) and (2R,3S,5S)-3,5,6-trihydroxy-2-methylhexanoic acid benzyl ester (20) was achieved with dibenzyl phosphochloridate and dibenzyl phosphoiodinate respectively, working at low temperature. (2R,3S)-3-Hydroxy-2-methyl-6-phosphonoxyhexanoic acid (9) was obtained in 25% overall yield from 4-benzyloxybutanol and (2R,3S,5S)-3,5-dihydroxy-2-methyl-6-phosphonoxyhexanoic acid (28) in 10% overall yield from L-malic acid.
Dardonville
Christophe
C
Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, UK CF10 3XF.
Gilbert
Ian H
IH
D000818:Animals; D003837:Deoxy Sugars / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005942:Gluconates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010734:Phosphogluconate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D014346:Trypanosoma brucei brucei / Q000201:enzymology
D003837:Deoxy Sugars; D004791:Enzyme Inhibitors; D005942:Gluconates; D010734:Phosphogluconate Dehydrogenase; C008884:6-phosphogluconic acid