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.

GRAPHICAL ABSTRACT

Keywords:

• Carbohydrates
• diacetone-D-glucose
• (2S,4S)-4-hydroxy-L-proline
• reductive debenzylation
• reductive deoxygenation