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Total synthesis of acetoxyodontoschismenol

Total synthesis of acetoxyodontoschismenol
Total synthesis of acetoxyodontoschismenol

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 SN2' 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.

University of Southampton
Baldwin, Ian Robert
Baldwin, Ian Robert

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 SN2' 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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Published date: 1998

Identifiers

Local EPrints ID: 463552
URI: http://eprints.soton.ac.uk/id/eprint/463552
PURE UUID: 54dc9225-1503-49b5-b053-990775020612

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Date deposited: 04 Jul 2022 20:53
Last modified: 04 Jul 2022 20:53

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Contributors

Author: Ian Robert Baldwin

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