Synthetic studies towards herbimycin

Watkins, Alison Jane (1991) Synthetic studies towards herbimycin. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Synthetic studies towards the C-7 to C-15 fragment of the herbimycins are presented. An enantioselective aldol reaction between acrolein and (4R, 5S)-(+)-4-methyl-3-(l'-oxopropyl)-5-phenyl-2-oxazolidinone was used to establish the correct absolute stereochemistry at C-10 and C-ll. lodolac-tonisation of the resultant 3-hydroxy acid under both thermodynamic and kinetic conditions gave exclusively a butyrolactone containing the unde-sired (R) stereochemistry at C-12; a rationale for this result is described. Attempts to form a cii-fused 5,6-dilactone by intramolecular 6-exo-trig radical cyclisation onto an acrylate ester of the butyrolactone failed. Similarly, investigations into 6-exo-trig radical cyclisations using allyl carbonate derivatives of the lactone were unsuccessful. The ring also failed to close via intramolecular nucleophilic displacement of iodide ion from the butyrolactone using the ester enolates of various ester derivatives.

Wittig reaction of the lactol, derived by reduction of the aforementioned butyrolactone, with (carbethoxyethylidene)triphenylphosphorane in the presence of silver (I) oxide gave ethyl (45, 5R, 6R-(2E))-(-)-5-[(fm-butyldimethylsilyl)oxyl]-6,7-epoxy-2,4-dimethyl-2-heptenoate which had the correct herbimycin C-8-C-9 (E) olefin geometry. Propionate formation from the free hydroxy derivative gave a diester which subequently failed to undergo an intramolecular anionic ester enolate-mediated 6-endo cyclisation onto the epoxide.

A successful 6-exo-trig intramolecular radical cyclisation was finally achieved by very slow addition of tri-n-butyltin hydride to an allyl ether derivative of the lactone. (3/?, 3afl, 6R/S, 7aK)-(+)-3,6-Dimethyl-dihydro-2(3//)-furanono[3,2-fe]tetrahydropyran was generated in which the newly formed stereocentre existed as a 4:1 mixture of respective R and S chirality.

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