Colin Smith

L-(+)-swainsonine and other pyrrolidine inhibitors of naringinase: Through an enzymic looking glass from D-mannosidase to L-rhamnosidase?

Abstract The synthesis and inhibitory properties towards naringinase (L-rhamnosidase) of L-(+)-swainsonine and of a number of more highly oxygenated analogues, and of some monocyclic equivalents, are reported. L-(+)-swainsonine and 1,4,6-trideoxy-1,4-imino-L-mannitol are powerful and specific inhibitors of naringinase.

Tetrazoles of manno- and rhamno- furanoses

Abstract The synthesis of [3.3.0] bicyclic tetrazoles derived from D-manno and D-rhamnofuranose starting from D-mannose, and of L-rhamnofuranose starting from L-rhamnose is described. The key step in the formation of all three examples of this novel class of sugar mimics is an intramolecular [1,3]-dipolar cycloaddition of azide and nitrile moieties.

Tetrazoles of manno- and rhamno-furanoses

Abstract The synthesis of tetrazoles derived from D-mannofuranose and both enantiomers of rhamnofuranose provides the first examples of tetrazole analogues of carbohydrates in the furanose form. The D-furanotetrazoles are potential mannosidase inhibitors whereas the L-rhamnotetrazole may interfere with the biosynthesis of cell walls of mycobacteria and provide a strategy for the treatment of tuberculosis and leprosy.

Tetrazoles of manno- and rhamno-pyranoses: Contrasting inhibition of mannosidases by [4.3.0] but of rhamnosidase by [3.3.0] bicyclic tetrazoles

Abstract The synthesis of tetrazoles derived from D-manno and D-rhamnopyranose from L-gulonolactone and of L-rhamnopyranose from D-gulonolactone is described. These and other materials are assessed as inhibitors of glycosidases. The [4.3.0] tetrazoles of D-manno- and D-rhamnopyranose are inhibitors of human liver α-mannosidase. In contrast the D-furanose analogues show no inhibitory activity whilst the [3.3.0] L-rhamno furanotetrazole is a potent rhamnosidase inhibitor, a potential inhibitor of mycobacterial cell wall biosynthesis and as such may provide a strategy for the treatment of tuberculosis.

5-epi-Deoxyrhamnojirimycin is a potent inhibitor of an α-l-rhamnosidase: 5-epi-deoxymannojirimycin is not a potent inhibitor of an α-d-mannosidase

Abstract Whereas deoxyrhamnojirimycin (LRJ) 1 shows no significant inhibition of naringinase (an α- l -rhamnosidase), its C-5 epimer 2 is a potent and specific inhibitor of the enzyme and demonstrates the value of unambiguous chemical synthesis of such materials in the evaluation of their biological properties. In contrast, moderately weak inhibition towards an α- d -mannosidase is shown by both deoxymannojirimycin (DMJ) 5 and its C-5 epimer 6 . Mimics of l -rhamnose which are recognised by enzymes that synthesise or process l -rhamnose may inhibit either the biosynthesis of the sugar or its incorporation into mycobacterial cell walls, providing new strategies for the treatment of diseases such as tuberculosis and leprosy. Molecular modelling studies provide a rationale for the surprisingly potent activity of the C-5 epimer 2 compared with LRJ 1 and support a general hypothesis that potent piperidine glycosidase inhibitors mimic the 4 H 3 conformation of the relevant glycopyranosyl cation intermediate.

TETRAZOLES OF MANNO- AND RHAMNO-PYRANOSES : INHIBITION OF GLYCOSIDASES BY TETRAZOLES AND OTHER MANNOSE MIMICS

Abstract The synthesis of tetrazoles derived from D-mannopyranose and D-rhamnopyranose from L-gulonolactone is described. These and other materials are assessed as inhibitors of human liver glycosidases and delineate some structural features required for α- and β-mannosidase and α-fucosidase inhibition.

INHIBITION OF NARINGINASE (L-RHAMNOSIDASE) BY PIPERIDINE ANALOGUES OF L-RHAMNOSE: SCAFFOLDS FOR LIBRARIES INCORPORATING TRIHYDROXYPIPECOLIC ACIDS

Abstract L-Deoxyrhamnojirimycin 1 does not inhibit naringinase significantly but 5-epi-L-deoxyrhamnojirimycin 2 is a potent inhibitor. Conversely, α-C-glycosides of 1 are good inhibitors of L-rhamnosidase whereas those of 2 are not. Intermediate azabicyclic lactones are likely to be of use for the incorporation of a number of trihydroxypipecolic acids into peptide libraries.

A reductive aldol strategy for the synthesis of very highly substituted cyclopentanes from sugar lactones

Abstract Iodide ion induces a protected 5-formyl-2-iodo-1,5-lactone to undergo a reductive aldol condensation to give a fully substituted cyclopentane derivative in moderate yield; this strategy may provide a general synthesis of such highly functionalised carbocycles as mannostatins and allosamizolines.

High yield reduction of 2-O-trifluoromethanesulphonate esters of α-hydroxylactones to the corresponding 2-deoxylactones by lithium iodide trihydrate

Abstract Reaction of 2- O -trifluoromethanesulphonate esters of 1,4- and 1,5-α-hydroxy lactones with lithium iodide trihydrate in tetrahydrofuran gives good to excellent yields of the corresponding 2-deoxy lactones.

Synthesis of cyclopentane spirohydantoins by aldol cyclisations : an approach to highly substituted α-cyclopentane amino acids

Abstract Efficient but reversible aldol condensations of 2-azido-5-formyl-1,5-lactones provide short routes to precursors for α-cyclopentane amino acids, some aminopseudosugars and spirohydantoins of cyclopentanes with control of the stereochemistry at all 5 carbons bearing functional groups. The effects of some of the compounds on human liver-glycosidases are described.