Total synthesis of acetoxyodontoschismenol

Baldwin, Ian Robert (1998) Total synthesis of acetoxyodontoschismenol. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

The first total synthesis of the naturally occurring dolabellane diterpenoid, acetoxyodontoschismenol, is outlined. The dolabellanes are characterised by a trans-bicyclo [9.3.0] tetradecane carbon skeleton, and acetoxyodontoschismenol possesses moderate growth-inhibitory activity on a series of plant pathogenic fungi.

A desmethyldeshydroxydesisopropyl analogue was synthesised and synthesis optimised. The key step was zirconocene mediated co-cyclisation of 1,6 heptadiene followed by sequential tandem insertion of methallyl carbenoid and (E)-4-[1-(tert-butyl)-1,1- dimethylsilyl]oxy-3-methyl-2-butenal and iodine quench. The reaction formed three new carbon-carbon bonds and a carbon-iodine bond and assembled all the carbons needed for the model dolabellane skeleton in a single pot and 80% yield. Macrocyclisation to form the trans-bicyclo [9.3.0] tetradecane nucleus was achieved by an α-lithiosulphone displacement of an allylic chloride in 82% yield.

The elaborate diene, ethoxy(4-methyl-1-vinyl-4-pentenyl)diphenylsilane, required for the total synthesis, was synthesised by a S_N2' displacement of an allylic chloride, which resulted in a 22 : 1 separable mixture of regioisomers. The presence of the bulky silyl group controlled the relative stereochemistry of C-11 and reversed the expected ratio of isomers at C-1 to give the desired trans relative stereochemistry as the major product. The silyl group also acted as a masked hydroxyl group removing the problem of allylic rearrangement in the zirconocene co-cyclisation step. The diastereoisomers at C-6 were separated after macrocyclisation and the subsequent introduction of the isopropyl group was controlled by the methyl group at C-1 and the methylene group at C-10. Overall, the synthesis of acetoxyodontoschismenol and its C-6 epimer was achieved in 18 steps and 1.5% overall yield from triethylorthoformate and 2-methyl-2-propen-1-ol.

The α-lithiosulphone macrocyclisation technique was extended to the displacement of propargylic chlorides. The reaction formed trans-bicyclo [9.3.0] tetradecane skeletons which, after functional group manipulation, furnished compounds suitable for investigation in a radical transannular cyclisation. This represents a possible novel route towards the synthesis of the dolastanes.

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