Synthetic investigations on B-Ventivone

Abstract

The synthetic studies described in this thesis entitled "Synthetic Investigations on ?-Vetivone – Syntheses of 5,6-dimethylcyclohept-2-enone, 8-isopropylidene-cis-bicyclo[4,3,0]non-5-ene, and 2-acetoxydecahydroazulen-6-one", were started before Marshall revised the azulenic structure of ?-vetivone to the spiro structure. The subject matter of this thesis has been divided into two chapters. Chapter I is a comprehensive review of the chemistry of ?-vetivone. Chapter II deals with the candidate's work. This chapter has a brief introduction, describing the two earlier unsuccessful attempts to synthesize the azulenic structure of ?-vetivone and our projected scheme to achieve the same objective, and has been subdivided into three sections: A, B, and C.

Section A describes the conversion of cycloheptanone (I) to 3,6-dimethylcyclohept-2-enone (II) as a model experiment. Cyclohepta-2,6-dienone (III) was prepared by following the procedure of Garbisch; earlier attempts to prepare this compound by DDQ dehydrogenation of cycloheptanone (I) failed. Conjugate addition of methylmagnesium iodide to the aforementioned dienone furnished 3,6-dimethylcycloheptanone (IV), which in turn was successfully converted to 3,6-dimethylcyclohept-2-enone (II) through a sequence of reactions involving enol acetylation, bromination, and dehydrobromination.

Section B describes another model experiment involving the conversion of cis-bicyclo[4,3,0]non-3-ene-8-one (V) to 8-isopropylidene-cis-bicyclo[4,3,0]non-3-ene (VI). cis-1,2-bis(cyanomethyl)cyclohex-4-ene (VII), prepared from cis-??-tetrahydrophthalic anhydride (VIII) in an improved yield by effecting suitable modifications of various steps of the earlier procedure, was subjected to Thorpe cyclisation (KOBu^ and benzene) to give cis-bicyclo[4,3,0]non-3-ene-8-one (V). The bicyclic unsaturated ketone (V) was reduced with sodium borohydride to yield 8-hydroxy-cis-bicyclo[4,3,0]non-3-ene (IX), which on treatment with phosphorus tribromide and pyridine furnished 8-bromo-cis-bicyclo[4,3,0]non-3-ene (X). The Grignard reagent prepared from the latter on interaction with acetone furnished cis-bicyclo[4,3,0]non-3-enyl-8-dimethylcarbinol (XI), which on dehydration with acetic acid and acetic anhydride followed by rigorous chromatographic purification of the resulting mixture of dienes through silver nitrate impregnated silica gel gave the pure 8-isopropylidene-cis-bicyclo[4,3,0]non-3-ene (VI). The structure of this diene was confirmed by IR and NMR spectral data and elemental analysis.

Section C deals with the synthesis of 2-acetoxydecahydroazulen-6-one (XII). 3,4-Bis(methoxycarbonyl)cyclopentanone (XIII), prepared from cis-??-tetrahydrophthalic anhydride (VIII) via the known intermediates namely, meso-butane-1,2,3,4-tetracarboxylic acid (XIV) and tetramethyl meso-butane-1,2,3,4-tetracarboxylate (XV), was converted into its ethylene ketal (XVI), which on lithium aluminium hydride reduction gave 3,4-bis(hydroxymethyl)cyclopentanone (XVII). Tosylation of this diol followed by ketalisation afforded the ethylene ketal of the ditosylate of 3,4-bis(hydroxymethyl)cyclopentanone (XVIII), which on condensation with diethyl sodiomalonate furnished 3,3-diethoxycarbonylbicyclo[3,3,0]octan-7-one (XIX). The ketal ditosylate (XVIII) was next condensed with potassium cyanide to yield the ethylene ketal of 3,4-dicyanomethylcyclopentanone (XX), which on treatment with methanolic hydrogen chloride afforded dimethylcyclopentanone-3,4-diacetate (XXI). This keto diester was converted to the corresponding ethylene ketal (XXII), which was reduced with lithium aluminium hydride to furnish 3,4-bis(hydroxyethyl)cyclopentanone (XXIII). Tosylation of this diol followed by ketalisation yielded the ethylene ketal of the ditosylate of 3,4-bis(hydroxyethyl)cyclopentanone (XXIV), which was condensed with potassium cyanide to furnish the ethylene ketal of 3,4-di-?-cyanoethylcyclopentanone (XXV). The aforementioned ketal dinitrile was deketalised to give 3,4-di-?-cyanoethylcyclopentanone (XXVI), which on reduction with sodium borohydride furnished 3,4-di-?-cyanoethylcyclopentanol (XXVII), and the acetate (XXVIII) of the latter was subjected to Thorpe cyclisation with n-BuLi/N-methylanilide under high dilution conditions to afford 2-hydroxydecahydroazulen-6-one (XXIX), which on acetylation gave 2-acetoxydecahydroazulen-6-one (XII).