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Towards the total synthesis of Miharamycin and related nucleoside antibiotics

Objective

The research program will focus on the total synthesis of the miharamycins, the development of synthetic approaches allowing access to these nucleoside antibiotics and a range of analogues, for biological testing purposes.

The miharamycins possess combined structural features of monosaccharides, nucleosides and peptides. Potent biological activity of nucleoside antibiotics has provoked a large amount of synthetic interest.

However the miharamycins themselves have not yet been synthesised and the absolute stereochemistry at one chiral centre is as yet unknown. The miharamycins are potent inhibitors of Pyricularia oryzae, which produces rice blast, and as such are important targets for the improvement of food production.

The synthetic studies will consist of three phases: the development of a new approach to the synthesis of the central carbohydrate portion by the use of a ring closing metathesis reaction; the development of methodology for a one carbon extension at C-6 and attachment of the amino acid portion; and finally glycosylation with a purine base to complete the total synthesis.

In addition to the total synthesis, a variety of structural analogues will be accessed in a parallel fashion as follows: variation of carbohydrate stereochemistry; variation of amino acid for coupling to C-6; variation of purine / pyrimidine base for installation at the anomeric centre.

These studies will provide the first total synthesis of miharamycin and thereby provide structural confirmation of the stereochemistry of the natural product at C-6. They will also produce an extremely interesting set of analogous materials for biological testing which will enable the deduction of structure activity relationships.

These studies will also entail the development of novel synthetic methodology that will find use more generally in the wider context of nucleoside synthesis, which will be of extreme importance for the development of the next generation of anti-virals and antibiotics.

Call for proposal

FP6-2002-MOBILITY-5
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Funding Scheme

EIF - Marie Curie actions-Intra-European Fellowships

Coordinator

CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Address
University Offices, Wellington Square
Oxford
United Kingdom