synthetic investigations in terpenoids

Abstract

The object of the present investigation is to develop a new strategy for the synthesis of 1-methylcyclohexa-1,3-diene derivatives, which are required for the construction of bicyclo[2.2.2]octane ring systems with bridgehead methyl and/or alkyl groups via Diels–Alder reaction. This strategy is applied towards the total synthesis of two natural products. The thesis entitled “SYNTHETIC INVESTIGATIONS IN TERPENOIDS” is divided mainly into four chapters. The literature pertaining to the various synthetic methodologies developed for the construction of bicyclo[2.2.2]octane ring systems and their use in natural product synthesis has been reviewed in Chapter I. Chapter II describes the synthesis of bicyclo[2.2.2]oct-2-ene derivatives with a bridgehead methyl group, a potential carbocyclic framework. This is further divided into three sections:

Section (i): Various procedures available for the preparation of 1-methylcyclohexa-1,3-diene derivatives, including the metal-ammonia reduction of toluic acids, are described.

Section (ii): Deals with the preparation of 1-methylcyclohexa-1,3-diene carboxylic acids. Dihydrotoluic acids (1 and 2) on treatment with sodium methoxide in methanol afforded conjugated dienes (5 and 6), whereas the esters (3 and 4) on treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in benzene gave (7 and 8) respectively.

Section (iii): Investigations on the [4+2] cycloaddition reaction of these 1-methylcyclohexa-1,3-diene carboxylic acids with various dienophiles, in particular the regiochemistry of addition, are described. Thus, 1-methylcyclohexa-1,3-diene-3-carboxylic acid (5) and methyl 1,2-dimethylcyclohexa-1,3-diene-3-carboxylate (7) afforded selectively only one regiomer (9 and 10 respectively), whereas 1-methylcyclohexa-1,3-diene-2-carboxylic acid (6) and methyl 1,4-dimethylcyclohexa-1,3-diene-2-carboxylate (8) gave a mixture of regiomers (11, 12 and 13, 14 respectively). These adducts were characterised by spectral analysis and analytical data. The regiochemistry of the adducts was confirmed by chemical transformations.

Chapter III describes an efficient, highly stereoselective total synthesis of (+)-seychellene, a tricyclic sesquiterpene isolated from patchouli oil. The allyl alcohol (15) was prepared by the reaction of vinylmagnesium bromide with compound (6), which on treatment with phosphorus tribromide afforded the allyl bromide (16) in good yield. Attempts to convert compound (16) to the tricyclic system using tributyltin hydride were not successful. Similarly, coupling of the ?-carbons of two proximal enones in the model system (17) was also unsuccessful. The acetylenic ester (18), prepared by the reaction of compound (16) with propargylmagnesium bromide, on treatment with tributyltin hydride yielded the tricyclic system (19) in good yield. Oxidation of compound (19) afforded the keto ester (20), whose conversion to seychellene (21) was successfully accomplished. Chapter IV comprises the synthesis of the tricyclic skeleton (29), which serves as a key intermediate for the total synthesis of (+)-eremolactone (30), a diterpene isolated from Eremophila fraseri F. and E. freelingii F. A similar strategy described in Chapter II was adopted for the construction of tricyclo[5.2.2.0^2,6]undecane nucleus. The indane carboxylic acid (25) was chosen as the aromatic precursor, which in turn was prepared from 2-acetylbenzoic acid via the lactone (22), the dicarboxylic acid (23), and the indanone (24). Sodium-ammonia reduction of indane carboxylic acid (25) resulted in the dihydro compound (26), which on esterification and isomerisation yielded the diene (27). Diels–Alder reaction of (27) with 2-chloroacrylonitrile resulted in the chloro-nitrile (28) regioselectively, which was hydrolysed and methylated to the keto ester (29) in good yield. Further elaboration of ketone (29) into eremolactone (30) has been attempted.