Enantiospecific Approaches To Komarovispiranes

Abstract

Among Nature's creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionalities. This phenomenal structural diversity of terpenes makes them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The thesis entitled “Enantiospecific approaches to komarovispiranes” describes the utility of the monoterpene α-campholenaldehyde as chiral starting material in the enantiospecific synthesis of a variety of bi- and tricyclic compounds, and enantiospecific first total synthesis of spiro diterpenes komarovispiranes. For convenience the results are described in two different sections, viz., (a) Chiral synthons from α-campholenaldehyde; and (b) Enantiospecific synthesis of a komarovispirane. In the thesis, the compounds are sequentially numbered (bold) and the references are marked sequentially as superscripts and listed in the last section of the thesis. Complete details of the experimental procedures and the spectroscopic data were provided in the experimental section. A brief introduction is provided wherever appropriate to keep the present work in proper perspective. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. Monoterpenes are widely used as chiral auxiliaries, but their potential as chiral synthons has not been properly exploited. In the present thesis, utility of α-campholenaldehyde, which is readily available from α-pinene in two steps, as chiral synthon has been demonstrated in the enantiospecific synthesis of a few bi- and tricarbocyclic frameworks as well as spiroditerpenes komarovispiranes. To begin with, synthesis of several bi- and tricyclic compounds, namely bicyclo[3.3.0]octan-3-one; bicyclo[3.2.1]octan-2-one; bicyclo[3.2.1]octan-3-one; 3-cyclopentylcyclopentanone; bicyclo[4.3.0]non-3-one; spiro[4.4]non-2-one; tricyclo[6.3.0.02,6]undecan-6-ol; and spiro[4.5]decan-2-one; have been accomplished employing an intramolecular rhodium carbenoid C-H insertion, intramolecular type II carbonyl ene cyclisation, intramolecular acid catalysed diazoketone cyclisation reactions and ring-closing metathesis (RCM) reaction as the key steps. Komarovispirone is a tricyclic spiro diterpene isolated from Dracocephalum komarovi Lipsky, a perennial semishrub available in Uzbekistan and exhibits trypanocidal activity. The novel diterpene containing an unusual carbon framework, cyclohexane spiro fused to bicyclo[4.3.0]nonane, coupled with the potential biological activity have made komarovispirone, and its analogues interesting and challenging synthetic targets. Initially, as a model study, enantiospecific synthesis of a bis-norkomarovispirane was developed employing 7,8,8-trimethylbicyclo[3.3.0]oct-6-en-3-one as the starting material, which was readily available from campholenaldehyde. A Claisen rearrangement and RCM reaction based methodology was developed for the spiroannulation of a cyclohexane ring at the C-3 position of the bicyclo[3.3.0]octan-3-one. For the enantiospecific first total synthesis of komarovispiranes, the AB-trans ring system was generated via ring expansion of 7,8,8-trimethylbicyclo[3.3.0]oct-6-en-3-one employing ozonolytic cleavage followed by an intramolecular aldol condensation reaction of the resultant keto aldehyde. For the generation of the ABC ring system of the komarovispiranes, initially, a Claisen rearrangement and intramolecular type II carbonyl ene reaction based methodology was developed for the spiroannulation of a cyclohexane ring at the C-8 position of the bicyclo[4.3.0]nonan-8-one. Subsequently, an alternate Claisen rearrangement-RCM reaction based methodology was also developed for the spiroannulation, and extended it to the first total synthesis of a komarovispirane.