A-L-fucosidase inhibitors

A L-/wco-related analogue (71) of isofagomine [61], which was recently prepared from D-ribose by Ichikawa et al. following previously established chemistry [63,121], was found to be an a-L-fucosidase inhibitor with Kj 8 pmol/1. No inhibition was found with tetrazole derivatives such as (72) [ 122] obtained from L-gulonolactone. 

Chem. Soc. Chem. Commun. 1983, 835-836. Witczak, Z. J. Boryczewski, D. Thiosugars IV design and synthesis of S-linked fiicoside analogs as a new class of a-L-fucosidase inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 3265-3268. Kim, K. S. Hurh, E. Y. Youn, J. N. Park, J. I. Dialkyl (l-hydroxyiminoalkyl)phosphonates from 1-bromo-l-nitroalkanes and trialkyl phosphites./. Org. Chem. 1999, 64, 9272-9274. 

Fleet, G W J, Shaw, A N, Evans, S V, Fellows, L E, Synthesis from D-glucose of 1,5-dideoxy-1,5-imino-L-fucitol, a potent a-L-fucosidase inhibitor, J. Chem. Soc. Chem., Commun., 841-842, 1985. 

Defoin et al. has developed the synthesis of hydroxy-ethane derivative 148, a nanomolar a-L-fucosidase inhibitor, starting from chiral nitrone 145, an analog of 5-deoxy-L-lyxose that was derived from o-ribose [67]. Nitrone 145 reacted easily in C2CI4 at 50 °C with phenyl vinyl ether to give cycloadducts 146a and 146b quantitatively in a 85 15 ratio (Fig. 34). The major isomer 146a was converted via pyrrolidine 147 to the C-a-L-fucoside 148 in four steps in an overall yield of 59%. 

Vasella and Peer have developed a regioselective synthesis of the protected six-membered cyclic L-fucose-derived nitrone 157 in view of the synthesis of a-L-fucosidase inhibitors [70]. The nitrone 157 has been transformed into the indolizidines 160 and 161 via a cycloaddition to an acrylate (Fig. 37). The reaction proceeded regioselectively and led to a 60 40 mixture of the diastereomeric isoxazoHdines 158 (55%) and 159 (34%) by exclusively axial C - C bond formation. Reductive cleavage of the N - O bond of the isoxazoHdines 158 and 159, followed by reduction with BH3 in THF with subsequent hydrogenolytic debenzylation in MeOH/HCl, afforded the indoUzidines 160 and 161 as their hydrochlorides. 

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