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We developed a stereocontrolled route allowing potential access to the eight isomers of 4-benzylaminohex-5-ene-1,2,3-triol in two or four steps and ca. 50% yield from readily available chiral nonracemic cis- or trans-alpha,beta-epoxyimine precursors. A new (NH(4))(2)CO(3)-based carboxylation/intramolecular cyclization sequence allowed regio- and stereocontrolled C-3 epoxide opening while neat C-2 hydrolysis was ensured by simple aqueous acidic treatment.

New endoperoxides, related to the natural phytohormones known as G factors (G1, G2, G3), were modified on the side chain and the ketalic position. An unexpected rearrangement, specific to one diastereoisomer was observed in the deprotection step of O-silylated compounds and attributed to a hexacoordinated fluorosilicon intermediate. The reduction potential of these new peroxides was determined. They exhibited good to moderate antimalarial activity, greatly related to the presence of peroxyketal function.

(-)-Lentiginosine and its pyrrolizidinic analogue have been prepared in a straightforward five-step sequence from a versatile chiral cis-alpha,beta-epoxyamine.

Cinnamyl alcohol dehydrogenase is one of the enzymes controlling the first two committed steps of lignification. Using a 3-dimensional similarity model of this enzyme, a series of novel phosphonates (1-5) was designed as potential inhibitors. Phosphonates 1-5 were synthesized in good yield by reaction of the corresponding cinnamaldehydes with tetraethylmethylene diphosphonate. Monophosphonic acids 6 and 7 were obtained by basic hydrolysis of the corresponding phosphonates while phosphonamidate 8 was synthesized by reacting benzylamine with the iminium salt intermediate of the monophosphonic acid. Using recombinant cinnamyl alcohol dehydrogenase (CAD, EC 1.1.1.195) the inhibitory activity of these compounds was evaluated and compared with that of the carbonyl analogues. Inhibition kinetic studies showed compounds 2 and 3 to be mixed type linear inhibitors while compound 4 was uncompetitive. 1H NMR studies of inhibitor 2, for which Ki and Ki' were 20 and 86 microM, respectively, in the presence of CAD based on selective line-broadening showed an increased interaction of the 3-OMe group of the aromatic ring of the inhibitor with the active site of the CAD. A transferred nuclear overhauser effect spectroscopy (TRNOESY) experiment for inhibitor 2 with CAD was used to determine the conformation of this compound bound to CAD. These results were found to be consistent with the 3-dimensional structural model of the enzyme.

The synthesis of the thymidine 2-deoxypolyoxin C analogue 10 from a noncarbohydrate precursor was achieved in 10 steps and 9% yield starting from a chiral gamma,delta-epoxy-beta-hydroxy ester 11 readily available from cis-2-butene-1,4-diol. The main steps concern the stereo- and regioselective opening of the epoxide ring by an azide anion, the stereoselective introduction of the thymine base, and the transformation of the primary alcohol to the acid functionality of the final product. Two other approaches have also been investigated.

The plant aromatic alcohol dehydrogenase, cinnamyl alcohol dehydrogenase (CAD2 from Eucalyptus) was found by sequence analysis of its cloned gene to be homologous to a range of dehydrogenases including alcohol dehydrogenases, L-threonine-3-dehydrogenase, D-xylose reductase and sorbitol dehydrogenase. A homology model of CAD2 was built using the X-ray crystallographic coordinates of horse-liver alcohol dehydrogenase to provide the template, with additional modelling input from other analogous regions of structure from similar enzymes where necessary. The structural model thus produced rationalised the Zn-binding properties of CAD2, indicated the possession of a Rossmann fold (GXGXXG motif), and explained the class A stereospecificity (pro-R hydrogen removal from substrate alcohol) and aromatic substrate specificity of the enzyme. A range of potential ligands was designed based on the homology model and tested as inhibitors of CAD2 and horse liver alcohol dehydrogenase.