Alkaloids mimicking the structures of monosaccharides are now believed to be widespread in plants and microorganisms, and these sugar mimics inhibit glycosidases because of a structural resemblance to the sugar moiety of the natural substrate. Naturally occurring sugar mimics with a nitrogen in the ring are classified into five structural classes: polyhydroxylated piperidines, pyrrolidines, indolizidines, pyrrolizidines and nortropanes. Glycosidases are involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. The realization that alkaloidal sugar mimics might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes has led to increasing interest and demand for these compounds. Most of these effects can be shown to result from the direct or indirect inhibition of glycosidases. The glycosphingolipid (GSL) storage diseases are relatively rare hereditary disorders that are severe in nature and frequently fatal. Possible strategies for the treatment of these lysosomal storage diseases include enzyme replacement therapy, gene therapy and substrate deprivation. Recently, quite a new therapy for lysosomal storage diseases has been reported, namely a ‘chemical chaperone therapy’ for Fabry disease. In this report, the structural basis for the specificity of inhibition of alkaloidal sugar mimics and their current and potential application to biomedical problems will be reviewed.

Sugar-mimic glycosidase inhibitors: natural occurrence, biological activity and prospects for therapeutic application

Polyhydroxylated alkaloids -- natural occurrence and therapeutic applications.

The total syntheses of the potent glycosidase inhibitors castanospermine ((+)-1), 6-epicastanospermine ((+)-2), australine ((+)-3), and 3-epiaustraline ((+)-4) are described. The syntheses of indolizidine alkaloids (+)-1 and (+)-2 were accomplished in eight steps and in 18% and 24% overall yields from 2,5-dihydrofuran while the pyrrolizidine alkaloids (+)-3 and (+)-4 were obtained in a nine-step sequence in 17% and 22% overall yields from the same starting material. These four natural products are derived from a single common intermediate, nitroso acetal (−)-31, which is created in the key step by the asymmetric tandem [4 + 2]/[3 + 2] cycloaddition between silaketal nitro olefin 18 and chiral vinyl ether (+)-23. The ability to access both 5,5- and 5,6-fused bicyclic systems was a result of a successful in situ N-alkylation strategy during the hydrogenolysis of four highly functionalized nitroso acetals. A novel silaketal tether provided exceptional levels of diastereocontrol and the ideal combination of p...

Enantioselective Total Syntheses of (+)-Castanospermine, (+)-6-Epicastanospermine, (+)-Australine, and (+)-3-Epiaustraline

The first synthesis of (+)-casuarine ((+)-6), a pentahydroxy pyrrolizidine alkaloid of the alexine/australine subclass, is described. The key step is a tandem [4 + 2]/[3 + 2] nitroalkene cycloaddition involving nitrobenzoate 13, chiral vinyl ether 16c, and vinyl silane 10, which establishes five of the six stereocenters present in this potent glycosidase inhibitor. The completion of the synthesis requires only four additional steps to deliver the final product in 20% overall yield.

Synthesis of (+)-Casuarine

α-Homonojirimycin [2,6-dideoxy-2,6-imino-d-glycero-l-gulo-heptitol] from omphalea diandra L.: isolation and glucosidase inhibtion

Isolation from and x-ray crystal structure of 3,8-diepialexine, (1r,2r,3s,7s,8r)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine [(2s,3r,4r,5s,6r)-2-hydroxymethyl-1-azabicyclo[3.3.0]octan-3,4,6-triol]

Isolation from Castanospermum australe and X-Ray Crystal Structure of 3,8-Diepialexine, (1R,2R,3S,7S,8R)-3-Hydroxymethyl-1,2,7-trihydroxypyrrolizidine ((2S,3R,4R,5S,6R)-2-Hydroxymethyl-1-azabicyclo(3.3.0)octan-3,4,6-triol).

A. C. Plant

Papers

Isolation from and x-ray crystal structure of 3,8-diepialexine, (1r,2r,3s,7s,8r)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine [(2s,3r,4r,5s,6r)-2-hydroxymethyl-1-azabicyclo[3.3.0]octan-3,4,6-triol]

Isolation from Castanospermum australe and X-Ray Crystal Structure of 3,8-Diepialexine, (1R,2R,3S,7S,8R)-3-Hydroxymethyl-1,2,7-trihydroxypyrrolizidine ((2S,3R,4R,5S,6R)-2-Hydroxymethyl-1-azabicyclo(3.3.0)octan-3,4,6-triol).