Biosynthetic studies on the polyether and macrolide antibiotics

O'Hagan, David (1985) Biosynthetic studies on the polyether and macrolide antibiotics. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

A study aimed at establishing stereochemical aspects of iso-butyrate metabolism in the monensin A producing strain Streptomyces cinnamonensis was carried out. [1-¹³C], [3,3-¹³C₂], 2(S)-[3-¹³C], 2(S)-[3-²H₃] and 2(R)-[3-²H₃]Na iso-butyrates were prepared. The chiral iso-butyrates were synthesised using the enantioselective epoxidation of Sharpless. Incorporation into monensin A was studied using ¹³C-n.m.r. and ²H-n.m.r. spectroscopy. The pro-(S) methyl carbon of iso-butyrate is incorporated only into C-16 of monensin A. Tylactone, produced by a mutant of Streptomyces fradiae (the parent strain produces tylosin), was used to study the origin of the aglycone oxygen atoms of tylosin. On incorporation of [1-¹³C,1-¹⁸0₂]Na acetate, propionate and butyrate into tylactone, analysis of the resultant ¹³C-n.m.r. spectrum in each case revealed that each of the oxygen atoms arose from the carboxylate group of one of these precursors. [1-¹³C,1-¹⁸0₂]Na butyrate also labelled the propionate carboxylate derived atoms with ¹³C-¹⁸0. From this study a mechanism for macrocyclic ring closure was proposed. The synthesis of a fully functionalised open chain methyl ester derivative of tylactone was studied by synthetic modification from tylactone. Tylactone was protected as its isopropylidene derivative and then reduced with NaBH₄. Hydrolysis and treatment with diazomethane followed by oxidation with MnO₂ gave an isopropylidene methyl ester. Deprotection with Me₂BBr gave a product which is consistent with the desired product, however rigorous characterisation of this compound has not been accomplished. A study aimed at the synthesis of two key compounds, for the preparation of a range of possible Co-enzyme-A intermediates in tylactone biosynthesis, was carried out. (D72864/87)