Manaviazar, Soraya; (1995) Synthetic studies on the azinothricin family of antitumour antibiotics. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis consists of five sections. The first four discuss chemistry that is relevant to a total synthesis of the antitumour antibiotic A83586C that is being carried out in these laboratories. The fifth describes the preparation of some new pyranoid 5,6-glycals from methyl β-D-fructopyranoside. In the first section, we outline a method for preparing 2,3-O-cyclohexylidene-2-C-ethyl-(2R)-glyceraldehyde utilising Sharpless asymmetric dihydroxylation (AD) chemistry. This intermediate was then used for constructing the C(28)-C(47) segment of antibiotic A83586C. In the second section, we describe our studies on the Sharpless asymmetric dihydroxylation (AD) reactions of 1,1-disubstituted allyl alcohol and phenylsulfide derivatives. In the majority of systems examined, the product diols had ee's in the 11-91% range and possessed absolute stereochemistry opposite to that predicted by the Sharpless face-selection rule. The third chapter discusses a practical new asymmetric synthesis of both enantiomers of erythro-3-hydroxyleucine, that is again based on Sharpless AD chemistry. By this route, (2S,3S)-(+)-3-hydroxyleucine was obtained in 97% ee and 67% overall yield, while the (2R,3R)-(-)-enantiomer was isolated in 92% ee and 57% overall yield. In the fourth section, a new three-step asymmetric synthesis of (3R)-piperazic acid is described. The key steps in this route were the electrophilic hydrazination of a chiral bromovaleryl carboximide enolate with di-tert-butyl azodicarboxylate, and the subsequent intramolecular SN2 displacement of the bromide group to close the hydrazine ring system. The diastereoselectivity of this process was typically greater than 96%. (3R)-Piperazic acid is a key component of antibiotic A83586C. The final chapter discusses some new methodology for the efficient construction of pyranoside 5,6-glycal derivatives of methyl β-D-fructopyranoside.

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