Synthesis of (2S,4S)-4-Hydroxyproline from D-Glucose

Abstract

Diacetone-D-glucose 1 gives 3- O -methylxanthate 2 on reaction with NaH/Me I. Reductive deoxygenation of compound 2 by Bu3SnH gives the corresponding 3-deoxy glucose derivative 3 and on acid-catalyzed regioselective deprotection of C-5,6-acetonide gives the diol 4. The diol on oxidative cleavage with NaIO4 gives the aldehyde 5, which on further condensation with benzylamine followed by reduction with NaBH4 gives the amine 7. Z-Protection of the amine followed by methanolysis gives methyl furanoside 9. Reaction of 9 with methanesulfonyl chloride/Et3N gives the corresponding C-3-O-mesylate derivative 10. Catalytic hydrogenation of compound 10 (Pd/C/H2/MeOH 3 kg) gives bicyclic oxaazo compound 11, due to deprotection of the N-benzyl- and Z-protecting groups and intramolecular nucleophilic displacement of the C-2- O-mesylate by the C-5 amine in a one-pot reaction. Z-Protection of the amine 11 followed by acid-catalyzed hydrolysis gives acetal 13. Reduction of acetal by use of NaBH4 gives Z-prolinol 14. Selective oxidation of diol 14 by (2,2,6,6-tetramethylpiperidin-1-yl)-oxyl (TEMPO)/[(bis)(acetoxy)iodo]benzene (BAIB) and NaClO2/NaH2PO4, followed by Z-deprotection, gives the title compound I in 3.5% overall yield from D-glucose.