An approach to 8 stereoisomers of homonojirimycin from (D)-glucose via kinetic & thermodynamic azido-γ-lactones.

Crystal structures were obtained for the two C2 epimeric azido-γ-lactones 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-ido-heptono-1,4-lactone and 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-gulo-heptono-1,4-lactone prepared from kinetic and thermodynamic azide displacements of a triflate derived from d-glucoheptonolactone. Azido-γ-lactones are very useful intermediates in the synthesis of iminosugars and polyhydroxylated amino acids. In this study two epimeric azido-heptitols allow biotechnological transformations via Izumoring techniques to 8 of the 16 possible homonojirimycin analogues, 5 of which were isolated pure because of the lack of stereoselectivity of the final reductive amination. A side-by-side glycosidase inhibition profile of 11 of the possible 16 HNJ stereoisomers derived from d-glucose and d-mannose is presented.

Eight stereoisomers of homonojirimycin from D-mannose.

Although there are 32 6-azidoheptitols, there are only 16 homonojirimycin (HNJ) stereoisomers. Two epimeric azidoalditols derived from d-mannose allow the synthesis in water of eight stereoisomers of HNJ.

4-C-Me-DAB and 4-C-Me-LAB - enantiomeric alkyl-branched pyrrolidine iminosugars - are specific and potent α-glucosidase inhibitors; acetone as the sole protecting group.

The syntheses of 4-C-Me-DAB [1,4-dideoxy-1,4-imino-4-C-methyl-d-arabinitol] from l-erythronolactone and of 4-C-Me-LAB [from d-erythronolactone] require only a single acetonide protecting group. The effect of pH on the NMR spectra of 4-C-Me-DAB [pK(a) of the salt around 8.4] is discussed and illustrates the need for care in analysis of both coupling constants and chemical shift. 4-C-Me-DAB (for rat intestinal sucrase K(i) 0.89 µM, IC(50) 0.41 µM) is a competitive - whereas 4-C-Me-LAB (for rat intestinal sucrase K(i) 0.95 µM, IC(50) 0.66 µM) is a non-competitive - specific and potent α-glucosidase inhibitor. A rationale for the α-glucosidase inhibition by DAB, LAB, 4-C-Me-DAB, 4-C-Me-LAB, and isoDAB - but not isoLAB - is provided. Both are inhibitors of endoplasmic reticulum (ER) resident α-glucosidase I and II.

2,6-Dide-oxy-2,6-imino-l-glycero-d-ido-heptitol.

The title mol-ecule, C(7)H(15)NO(5), the major product from selective enzymatic oxidation followed by hydrogeno-lysis of the corresponding azido-heptitol, was found by X-ray crystallography to exisit in a chair conformation with three axial hydroxyl groups. One of the hydroxymethyl groups is disordered over two sets of sites in a 0.590 (3):0.410 (3) ratio. In the crystal, O-H⋯O, O-H⋯(O,O), O-H⋯N and N-H⋯O hydrogen bonding occurs.