Total synthesis of ulocladol A and analogues alternariol 0-methyl ether and alternariol

Abstract

Ulocladol A is a natural product which has been shown to exhibit tyrosine kinase inhibitory activity against the enzyme Lck. It was isolated from the marine sponge Callyspongia vaginalis in 1999. Prior to the commencement of this project there had been three reported syntheses of ulocladol A, all of which started from intermediates prepared in the synthesis of graphislactones C and D. The routes were relatively long and did not provide much scope for analogous compounds.
We proposed it would be possible to prepare ulocladol A via a route which would allow for the synthesis of analogues. Any analogues prepared would be tested against five tyrosine kinases to determine whether any SAR could be elucidated.
This report details the use of Suzuki coupling methodology to prepare ulocladol A and eighteen analogues. Several different catalyst systems are reported due to the steric and electronic effects of the substrates used in the Suzuki reaction; also included in the report are the results of the biological testing. Two of the analogues, 2.47 and 2.60, exhibit greater inhibitory activity than ulocladol A and show good activity against four other tyrosine kinases.
In addition to the synthesis of ulocladol A and analogues, the report also details the synthesis of alternariol 9-methyl ether and alternariol in the shortest convergent synthesis to date

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