Synthetic studies in terpenes synthesis of the cis, trans-C-11 acid : The degradation product of agathic acid

Abstract

The thesis entitled "Synthetic Studies in Terpenes – Synthesis of the cis/trans-C-11 Acid, the Degradation Product of Agathic Acid" is divided into two chapters. Chapter I is a comprehensive review of the chemistry of the C-11 acid and the part played by it in diterpenoid chemistry. In Chapter II, the synthesis of the cis,trans-(racemic)-C-11 acid, viz. 1,3-dimethylcyclohexane-1,2,3-tricarboxylic acid (XIIIa) by an unambiguous stereoselective route (outlined in the chart) is described. 1-Methyl-1-carbomethoxycyclohex-2-ene-2-carboxylic acid (I) was prepared from cyclohexanone in eight steps following the procedure of Linstead and Millidge. The unsaturated acid (IX) was converted into 1-methyl-1-carbomethoxy-2-acetylcyclohex-2-ene (III) by the malonic ester synthesis, earlier attempts to prepare this compound by alternate routes having failed. Addition of hydrogen cyanide to the unsaturated ketone (III) gave 1-methyl-1-carbomethoxy-2-acetyl-3-cyanocyclohexane (IV). Treatment of this compound with ethylene glycol furnished the ketal-nitrile-ester (V) which was alkylated with triphenylmethyl sodium and methyl iodide to give the ethylene ketal of 1,3-dimethyl-1-carbomethoxy-2-acetyl-3-cyanocyclohexane (VI). Deketalisation of the methylated product (VI) furnished 1,3-dimethyl-1-carbomethoxy-2-acetyl-3-cyanocyclohexane (VII) which was converted into the corresponding furfurylidene derivative (VIII) and subjected to ozonolysis, followed by periodic acid oxidation to afford 1,3-dimethyl-1-carbomethoxycyclohexane-2,3-dicarboxylic acid (IX). Attempts to degrade the ketonitrile-ester (VII) by other methods were unsuccessful. Acid hydrolysis of the diacid-ester (IX) gave 1,3-dimethylcyclohexane-1,2,3-tricarboxylic acid (X) which was esterified with diazomethane to obtain 1,3-dimethyl-1,2,3-tricarbomethoxycyclohexane (Xa). A comparative study of the nuclear magnetic resonance spectra of the ketonitrile-ester (IV), the ketal-nitrile-ester (V), the corresponding methylated analogues (VI and VII), and the triester (Xa) led to the assignment of definite conformations to the intermediates IV, V, VI and VII and the cis,trans-(racemic)-configuration (XIIIa) to the triacid (X). Independent chemical evidence for these assignments was furnished by the observation that hydrolysis of the ketonitrile-ester (V) and its methylated analogue (VII) gave the dilactone and lactol-acid respectively. Two isomeric triacids of gross structure (X) were synthesised by Banerjee and Balasubrahmanyam of our laboratory by an alternate route, one of which was identified as the trans-meso-isomer (Xb), the degradation product of abietic acid, by direct comparison with an authentic specimen. The method of synthesis by the above authors did not throw any light on the steric configurations of their products. The second isomer was shown to have the cis-trans-configuration (XIIIa) on the basis of the identity of its trimethyl ester with the triester presently synthesised. A comparison of the nuclear magnetic resonance spectra of the two isomeric triesters (XIIIb and XIVb) furnished unequivocal proof in favour of the trans-meso-configuration of the abietic acid degradation product.