synthesis of some naturally occurring sesquiterpenes

Abstract

The thesis entitled "SYNTHETIC STUDIES IN SESQUITERPENES" consists of four chapters. Chapter I deals with the general introduction to the thesis, which outlines the broad classification of the sesquiterpenes and, in particular, the biogenetic origin of the tricyclic bridged sesquiterpenes namely zizaene (1) and cedrene (2) from the spiro[4.5]decane precursors. Examples of the spiro[4.5]decane sesquiterpenes include acorone (3) and ?-acoradiene (4). A brief illustration of the strategy for the synthesis of these biogenetically related sesquiterpenes starting from a common intermediate is presented. Chapter II deals with the synthetic investigations on zizaene and cedrene sesquiterpenes and is divided into three sections.

Section I: The chemistry of zizaene and cedrene is briefly reviewed, emphasizing their isolation, structure, biogenesis, and syntheses. Section II: Describes the formal total synthesis of zizaene. 2,3,4,7-Tetrahydro-5-methoxy-1-methyl-1H-indene (5), prepared from the corresponding aromatic precursor, underwent a cycloaddition with 2-chloroacrylonitrile to give the adduct regiospecifically, which on hydrolysis gave the tricyclic ketone (6). Reduction of the tricyclic ketone (6), followed by the solvolysis of the resulting alcohols (exo and endo), gave the skeletal rearranged products 7 and 8, which are the key intermediates for the synthesis of zizaene and cedrene respectively. The tricyclic enone (7) was transformed to the compounds 9 and 10 in two different routes. These two compounds (9 and 10) earlier have been transformed to zizaene, thus completing a formal total synthesis of zizaene. The tricyclic ketone (8) has the basic structural features and can be readily converted into cedrene by appropriate functionality. Section III: Describes the experimental details.

Chapter III deals with the general method developed for the stereospecific construction of the spiro asymmetric center in the spiro[4.5]decane and spiro[5.5]undecane sesquiterpenes. The utility of this method is successfully demonstrated in the syntheses of spiro[4.5]decane sesquiterpenes, namely, acorone (3) and ?-acoradiene (4). This chapter has been divided into three sections:

Section I: The chemistry of acorane group of spiro[4.5]decane sesquiterpenes is briefly reviewed with special emphasis on their isolation, structure, biogenesis, and syntheses of acorone (3) and related acoradienes. Section II: Deals with the construction of spiro[4.5]decane skeleton related to acorane group starting from the tricyclic ketone (6). Reduction of the ketone (6) with sodium borohydride afforded a mixture of endo- and exo-alcohols which was benzylated to the compound (11) and transformed into the spiro acid (12) by a two-step sequence. The key reaction in this sequence is the construction of a quaternary methyl group by the methylation of the enolate generated by the metal-ammonia reduction of an ?-methoxy carboxylic acid. The spiro acid (12) has been transformed to the mixture of key intermediates 13 and 14, which were earlier reported and have been elaborated to acorone and ?-acoradiene respectively, thus completing a formal total synthesis of these two spiro[4.5]decane sesquiterpenes. Section III: Deals with the complete experimental details.

Chapter IV deals with an efficient and general method for the preparation of [4.4.4]- and [4.4.3]-propellane (15, 16) and their derivatives and consists of three sections:

Section I: The chemistry of the propellanes and modhephene (17), a propellane sesquiterpene, is briefly reviewed. Section II: Describes the method of preparation of [4.4.4] propellane and 11-methyl-[4.4.3] propellane, by making use of the Oxy-Cope rearrangement as the key step. The tricyclic ketone (18), on treatment with vinylmagnesium bromide, gave a mixture of exo- and endo-allylic alcohols, of which the exo-alcohol underwent a smooth [3.3] sigmatropic shift to give the [4.4.4] propellane derivative (19). This compound (19) has been transformed to the [4.4.4] propellane (15). Similarly, starting from the ketone (6), 8-methoxy-11-methyl-[4.4.3] propellane (20) has been prepared, which was further transformed to the 11-methyl-[4.4.3] propellane. The compound (20) is a potent synthon for the synthesis of modhephene (17). Since [4.4.4] propellane is chiral, and the energy barrier for the conformational flip is rather low, the compound 19 with its functionality is expected to have a high energy barrier for the conformational flip and in theory could be resolvable. Section III: Describes the experimental details.

Arising out of the research investigations described in this thesis, the following papers have been published:

Zizaene and Cedrene Sesquiterpenes: Novel Synthesis of Tricyclic Intermediates for Their Preparation; K. Pramod and G. S. R. Subba Rao, J. Chem. Soc., Chem. Commun., 762 (1982). An Efficient General Method for Synthesis of [4.4.4] Propellane & 11-Methyl-[4.4.3] Propellane; K. Pramod and G. S. R. Subba Rao, Indian J. Chem., 21B, 984 (1982). Strategies of Synthesis Based on Dihydrobenzenes; G. S. R. Subba Rao and K. Pramod, Proc. Indian Acad. Sci. (Chem. Sci.), 93, 573 (1984). Stereospecific Synthesis of Spiro[4.5]Decane Sesquiterpenes; K. Pramod and G. S. R. Subba Rao, Communicated to J. Chem. Soc., Chem. Commun.