A Concise, Economical, and Diastereoselective Synthesis of Methyl DGJ Isopropylidene: An Iminocyclitol Molecule Core for Analogue Synthesis

Abstract

A six-step synthesis of the title compound starting from l-lyxonolactone 2,3-isopropylidene (6) is described. The synthesis is achieved by conversion of 6 to the C5-triflate or C5-mesylate 7a or 7b and their displacement by sodium azide to yield the C5 azido compound 8. Addition of methylmagnesium bromide and catalytic hydrogenation during which the azide group is reduced to the amine followed by an intramolecular cyclization yields the imine 15. Concomitant reduction of the imine occurs stereoselectively to yield methyl DGJ isopropylidene (5) which is isolated via the succinic acid salt and its further neutralization with ammonia. It was found that changing the synthetic sequence, namely, instead of 7a → 8 → 9, the methylmagnesium bromide could be added first to the mesylate 7b, 7b → 11 followed by azide ion displacement 11 → 9. This modification proved advantageous from the viewpoint of cost, use of methanesulfonyl chloride rather than trifluoromethylsulfonyl chloride, ease of operation, and yield. Methyl DGJ isopropylidene (5) is an important azasugar precursor because it can undergo N-alkyl substitution via reductive amination and be derivatized at C2 via the secondary hydroxyl group. The synthesis reported herein allows for the production of mutikilogram amounts of this important key iminocyclitol core.