Novel methodologies for the construction of polyether libraries

Abstract

Polyether antibiotics are a class of natural products obtained by the fermentation of Streptomyces sp. They display a broad range of biological properties and are of commercial importance in the veterinary field as anticoccidial agents and growth promoters. Due to the complexity of their structures, the discovery of new leads and access to analogues is restricted to semi-synthetic modifications of the natural products. This thesis describes an iterative approach aimed at the synthesis of unnatural polyether libraries. A new method of O-alkylation using cyclic sulfate chemistry has been developed. Reaction of resin bound 1,4-benzenedimethanol with representative 1,2-, 1,3- and 1,4-cyclic sulfates gave the ether products in satisfactory yields. The scope of the reaction was shown to be limited by the predisposition of some cyclic sulfates to elimination. Good regioselectivity was obtained. Hydrolysis of the intermediate sulfate ester under mild acidic conditions allowed the regeneration of the hydroxyl group and was shown to proceed with retention of configuration. The methodology was successfully applied to the synthesis of tetramer library using two 1,2-cyclic sulfates and a trimer library using 4 cyclic sulfates by multiple parallel synthesis. Cyclic sulfate chemistry was shown to be a convenient method for solid phase 0-alkylation and polyether synthesis, allowing activation of the hydroxyl group while at the same time avoiding the synthesis of monoprotected diols and bifunctionalised building blocks.

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