Synthetic investigations in terpenoids: total synthesis of (+)-allo-cedrol (Khusiol) and Illudinine

Abstract

The thesis entitled "SYNTHETIC INVESTIGATIONS IN TERPENOIDS: TOTAL SYNTHESIS OF (±)—ALLO-CEDROL [KHUSIOL] AND ILLUDININE" consists of two chapters.

The Chapter I deals with the total synthesis of the sesquiterpene (+)-allo-cedrol 1, which possesses the tricyclo[5.2.2.0^1,6] undecane framework with a bridgehead methyl group, and is divided into three sections. (+)-allo-Cedrol was isolated from Juniperus risida Sieb. et Zucc and is enantiomeric with (-)-khusiol, isolated from Vetiveria zizanioides of Indian origin.

Section I contains a brief introduction to the various methods of construction of the tricyclo[5.2.2.0^1,6]undecane framework.

Section II describes the synthesis of methyl 2,7-dimethyl tricyclo[5.2.2.0^1,6]undec-5-en-6-carboxylates 7, 8, and 9, which are considered intermediates for the total synthesis of allo-cedrol 1.

Thus, 6-methoxy-8-methyltetral-1-one 2, prepared from 3-methylanisole, was converted into the indanone 3 by oxidative cleavage followed by recyclisation. The acid 4, prepared from indanone 3 upon Birch reduction followed by esterification, gave the dihydro ester 5, which was converted into a (1:1) mixture of dihydro esters 5 and 6 on treatment with DBU. This mixture of dienes, when subjected to Diels-Alder reaction with 2-chloroacrylonitrile followed by hydrolysis, gave the ketone 7. On the other hand, cycloaddition with methyl vinyl ketone afforded a regioisomeric mixture of adducts 8 and 9.

Since compounds 7 and 8 yielded an inseparable mixture of products on further chemical transformations, their conversion into (±)-allo-cedrol was abandoned in favour of other stereoselective approaches, described in Section III.

Section III describes a methodology for bridgehead substitution of the adducts 10 and 17 and its elaboration to the total synthesis of (±)-allo-cedrol.

Acid-catalysed rearrangement of ketone 10, prepared from 6-methoxytetralin, gave a (3:1) mixture of enones 13 and 14.

Reaction of enone 13 with methyl lithium gave the allylic alcohol, which upon treatment with perchloric acid afforded ketone 11.

Conversion of ketone 10 to 12 was carried out in an analogous way through allylic alcohol 16.

Similar transformations on ketone 17 afforded ketones 18 and 19.

Total synthesis of (+)-allo-cedrol was then attempted by three different approaches:

First approach: Reduction of ketone 19, followed by acetylation and allylic oxidation, gave enones 21, which upon treatment with diazomethane followed by pyrolysis of the pyrazoline derivative gave enone 22. Conjugate addition on enone 22 gave ketoacetate 23, which was converted into ketone 24. Comparison of the spectral data of ketone 24 with that derived from khusiol showed it to be different, having the unnatural configuration at C-5.

Second approach: Enone 20, prepared from 17, was subjected to Woodward methylation resulting in an inseparable mixture of ketones 25 and 26. Wittig reaction of this mixture with methyl triphenylphosphonium iodide followed by Lewis acid-catalysed rearrangement gave ketones 27 and 28. Allylic oxidation of the acetates derived from ketones 27 and 28 gave enones 29 and 30, which were readily separated by chromatography. Enone 29 was transformed into ketone 31, isolated as an epimeric mixture at C-2 and C-5. These isomers could not be separated, although ^1H NMR indicated the presence of (±)-khusione.

Third approach: This approach controlled stereochemistry at C-2 and C-5 in allo-cedrol.

Gem-dimethylation of enone 13 gave ketone 32, converted into ketone 33 after reduction and protection as the benzyl ether.

Dieckmann cyclisation of the diester derived from ketone 33 gave ketoester 34, transformed into benzyl ether 35 after introduction of the methyl group at C-2.

Deprotection and oxidation of benzyl ether 35 afforded ketone, which was converted to compound 36 via Wittig olefination followed by Lewis acid-catalysed rearrangement.

This ketone 36 was identical with that obtained by oxidation of khusiol. Reduction of 36 with lithium in liquid ammonia in the presence of ammonium chloride afforded (+)-allo-cedrol and (+)-8-epi-allo-cedrol, which were separated by chromatography and identified by comparison with authentic samples.

Chapter II describes the total synthesis of illudinine 37, a natural terpenoid product isolated from the fungus Basidiomycete Clitocybe illudens.

Synthesis starts from hydrocarbon 38, prepared from 6-methoxytetralin.

Regiospecific benzylic oxidation of 38 to 39, followed by oxidative cleavage of the cyclohexanone ring, gave the diacid, which was cyclised to ketoester 40.

Indanone 40 was smoothly transformed into illudinine 37 through the Schmidt rearrangement, based on earlier experiments on exclusive conversion of indanones 41 into isocarbostyrils 42 using sodium azide and sulphuric acid.

Isocarbostyrils 42 were converted into isoquinolines 44 through tetrahydroisoquinolines 43 by known methods.

Application of this strategy on ketoester 40 gave illudinine methyl ester, which was hydrolysed to illudinine 37, completing the total synthesis.