Eight pyrrolidine, five pyrrolizidine and one indolizidine analogue(s) of the known alpha-mannosidase inhibitor, the azafuranose, 1,4-dideoxy-1,4-imino-D-mannitol (DIM), have been tested for inhibition of the multiple forms of alpha-mannosidase in human liver in vitro. Substitution of the ring nitrogen markedly decreased or abolished inhibition, but loss of the C-6 hydroxy group, as in 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM, enhanced inhibition, particularly of the lysosomal alpha-mannosidase. Addition of the anomeric substituent-CH2OH decreased inhibition. To be a potent inhibitor of the lysosomal, Golgi II and neutral alpha-mannosidases, a polyhydroxylated pyrrolidine must have the same substituents and chirality as mannofuranose at C-2, C-3, C-4 and C-5. These four chiral centres can also be part of a polyhydroxylated indolizidine, e.g. swainsonine, but not of a pyrrolizidine, e.g. cyclized DIM, ring-contracted swainsonine or 1,7-diepi-australine. DIM did not inhibit lysosomal alpha-mannosidase intracellularly, but both 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM caused accumulation of partially catabolized glycans in normal human fibroblasts. Analysis of these induced storage products by h.p.l.c. showed that both compounds also inhibited Golgi alpha-mannosidase II and that 6-deoxy-6-fluoro-DIM was also a good inhibitor of the endoplasmic reticulum alpha-mannosidase and specific lysosomal alpha (1-6)-mannosidase. None of the mannofuranose analogues appeared to inhibit Golgi alpha-mannosidase I.

The stereoselective synthesis of both a-glucosides and bmannosides may be readily achieved by the use of N-iodosuccinimde, both to effect mixed ketal formation and subsequent intramolecular aglycon delivery (IAD).

N-Iodosaccharin is found to be a potent activator of armed thiophenyl glycosides.

Solvent incorporation between glycosyl donor and acceptor occurs during glycosylation reactions initiated by N-iodosaccharin (NISac) performed in acetone and cyclohexanone solvents to stereoselectively produce acetal linked a-glycosides. † Electronic supplementary information (ESI) available: spectral data for compounds 3, 6 and 8-10. See http://www.rsc.org/suppdata/cc/b1/ b104196g/ Scheme 1 Reagents and conditions: (i) NISac 1, MeOH (3 equiv.), acetone, 278 to 0 °C, 2.5 h, 76%.