Deoxymannojirimycin

The asymmetric syntheses of (-)-ADMJ and (+)-ADANJ, the 2-deoxy-2-amino analogues of (-)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin, are described herein. Methodology for the ring-closing iodoamination of bishomoallylic amines followed by in situ ring-expansion (via intramolecular ring-opening of the corresponding aziridinium intermediates with a tethered carbamate moiety) to give oxazolidin-2-ones was initially optimized on a model system. Subsequent application of this methodology to two enantiopure bishomoallylic amines (which were produced via aminohydroxylation of an α,β-unsaturated ester, partial reduction, and reaction of the corresponding aldehyde with vinylmagnesium bromide) also proceeded with concomitant N-debenzylation to afford the corresponding diastereoisomerically pure (>99:1 dr) oxazolidin-2-ones. Subsequent deprotection of these enantiopure templates gave (-)-ADMJ and (+)-ADANJ as single diastereoisomers in 16% and 24% overall yield, respectively.

Three different Mitsunobu reactions have been investigated for the synthesis of 1-deoxymannojirimycin (1-DMJ) from d-fructose. The highest yielding and most practical synthesis can be undertaken on a 10 g scale with minimal chromatography. In the key step, N,O-di-Boc-hydroxylamine reacts with methyl 1,3-isopropylidene-α-d-fructofuranose under Mitsunobu conditions to give 14. Acidic hydrolysis affords nitrone 15, which reduces quantitatively via catalytic hydrogenolysis to afford 1-DMJ (4) in 55% overall yield from d-fructose (cf. 37% for azide route and 29% for nosyl route).

The asymmetric syntheses of (-)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin are described herein. The ring-closing iodoamination of two epimeric bishomoallylic amines to give the corresponding 5-iodomethylpyrrolidines was followed by in situ ring-expansion to give two diastereoisomerically pure (>99:1 dr) cyclic carbonates. Subsequent deprotection gave (-)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin as single diastereoisomers in 7.4 and 3.3% overall yield, respectively, from commercially available starting materials.