Approaches to the synthesis of herbimycin

Hirst, Gavin Charles (1987) Approaches to the synthesis of herbimycin. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

This thesis describes two entirely different approaches to the synthesis of the C₃-C₁₁ fragment of herbimycin. The first approach discussed centres around a fragmentation of a suitably substituted bicyclic lactone, prepared by an intramolecular Diels-Alder (IMDA) reaction of a suitable triene. If successful, the approach would set up two double bond geometries and three relative stereocentres. Numerous attempts to prepare 3-trimethylsilylprop-2(Z)-enoic acid proved unsuccessful, although the TBS analogue could be prepared. Coupling with the model dienol 4-methyl-3(E),5-dienol was achieved by a Mitsonobu coupling. Unfortunately the resulting triene failed to undergo an IMDA reaction so we were never able to study the fluoride induced key fragmentation step. An advanced intermediate RS-(1l,2u3u,4l6u)-2-[2'-(t-butyldi-methylsilyloxy)ethyl-3-[(t-butyldimethylsilyloxy)methyl]-1-methyl-7-oxa-4-(phenylsulphonyl)bicyclo[4.1.0]heptane, which possessed a sulphonyl moiety in place of the silyl function was readily prepared by a Diels-Alder reaction and further elaboration. Although an anionic/Lewis acid catalysed fragmentation failed to present the required dienol, some interesting results were obtained. Anion formation followed by BF₃.OEt₂ gave RS-(1l,2u,3l4l,5u)-3-[2'(t-butyldimethylsilyloxy)ethyl]-4-[(t-butyldimethylsilyloxy)methyl]-2-methyl-5-(phenylsulphonyl)bicyclo[3.1.0]hexan-2-ol whereas trimethylsilyl triflate catalysis gave RS-(1l,2u,4l,5u,6u)-6-[2'-(t-butyldimethylsilyloxy)ethyl]-5-[(t-butyldimethylsilyloxy)methyl]-1-methyl-4-(phenylsulphonyl)bicyclo[2.2.0]hexan-2.ol. The second approach involved a Lewis acid mediated cyclocondensation between 1-(t-butyldimethylsilyloxy)-4-methoxybuta-1(E),3(E)-diene and (4S)-(+)-3-[(2'S)-2',4'-dimethyl-5-oxopent-3'(E)-enoyl]-4-(2-propyl)-oxazolidin-2-one. Initial cyclocondensation studies proved promising.