Studies in the synthesis of the higher terpenes

In the introduction to this Thesis recent progress in the biogenesis of triterpenes is discussed with particular reference to the dammarene diols (XI a and b). This example is also taken to illustrate the techniques now used in the elucidation and determination of such complex structures. There follows a survey of the methods used in the total synthesis of pentacyclic triterpenes. Because of difficulties presented by both the structure and the stereochemistry of such molecules the approaches have necessarily been limited to three main courses of attack, the acid-catalysed cyclisation of aqualene (XII), the combination of two decalin derivatives to provide rings AB and DE of the pentacyclic system, and the combination of a of a tricyclic ABC moiety with a monocyclic unit to provide ring E.
The main body of this Thesis is divided into two sections (A and B). In the first a detailed investigation la made into a previously reported route from elemadienolic acid (I) to a possible ABC tricyclic intermediate (I→IX) with particular emphasis being placed on yields and reproducibility. It is shown that the route has several undesirable features and a superior alternative is offered (X→XI→IX). In connection with this work two potential monocyclic ring E precursors have been synthesised (XIIIa and XIVa) and an attempted electrolytic coupling of (XIIIa) and (IX) has been carried out.
The second section represents a continuation of the work of Littlehailes and is devoted to the synthesis of a hydroxylated bicyclic AB unit (XV) which could be utilised in alkylating the decalone (XVI) with the aim of constructing a pentacyclic triterpene of the amyrin series.
Section A.
The tricyclic intermediate (IX) was first isolated by the route illustrated (I→IX) in quantities sufficient for little more than characterisation purposes. More recently Ryback has made a preliminary investigation into the practical utilisation of such a route with special regard to the isolation of (IX) in large enough quantities for use in further synthetic operations. However his results were not conclusive and it was decided to reinvestigate some of the operations involved.
As supplies of tirucallenediol (II) were at hand it was decided to look first at its conversion into isotirucallenyl acetate (VIIa). It was found that although diacetylation went in high yield, the yield from the semi-hydrolysis of the diacetate (III) was not reproducible and was often poor necessitating a laborious fractional recrystallisation and recycling procedure in order to obtain quantities of the monoacetate (IV). The formation of the methanesulphonyl derivative (V), its reduction with lithium aluminium hydride to give tirucallenyl acetate (VI) and the subsequent acid isomerisation to isutirucallenyl acetate (VIIa) all went in high yield. Oxidation of (VIIa) with t-butyl chromate gave a reproducible 50% conversion to the αβ-unsaturated ketone (VIIIa).
The cleavage of the Δ13(17) double bond in the unsaturated ketone (VIIIa) was attempted by ozonolysis, osmium tetroxide and lead tetraacetate, alkaline peroxide and the Lemieux periodate/permanganate oxidation. Only ozone caused fission to occur giving the tricyclic keto acid (IX) in poor yield. A summary of the results of these experiments and a discussion of the implications is presented.
The demonstration that at least two stages in this route were unsatisfactory, the difficulty of isolating elemadienonic acid (XVII) in a high degree of purity, and the many stages involved in the conversion of elemadienolic acid (I) to the tricyclic intermediate (IX), instigated the search for an alternative source of (IX). This was afforded by the isolation of the epimeric mixture of dammarene diols (XI a and b) and the related ketones (X a and b) from Dammar resin. Reduction of the ketone content of the mixture to alcohol by lithium aluminium hydride followed by acetylation, hydrogenation and acid-catalysed dehydration gave a further mixture which contained isotirucallenyl acetate (VIIa) and isocuphenyl acetate (VIIb). Oxidation of this mixture with t-butyl chromate followed by ozonolysis of the resultant αβ-unsaturated ketones (VIII a and b) gave the tricyclic intermediate (IX), in the manner already described for isotirucallenyl acetate (VIIa) alone. The tricyclic intermediate (IX) could now be effectively and efficiently isolated from a natural source as the end product of a route containing only four major operations.
Two cyclohexane keto-esters (XIIIb) and (XIVb) were synthesised for the purpose of coupling with the tricyclic intermediate (IX). Each was derived from dimedone. In one case, dimedone was converted into the enol-chloride (XVIII) which was hydrogenated to the cyclohexanone (XIX), and carbethoxylated to give the keto-ester (XIVb). In the second case, dimedone was alkylated first with methyl iodide and then ethyl bromoacetate to give (XXI). Eliminating one of the ketone groups via the thioketal and reduction with Raney nickel gave the keto-ester (XIIIb).
It was attempted to electrolytically couple the tricyclic intermediate (IX) with the monocyclic keto-acid (XIIIa) but only the bis-cyclohexyl ethane derivative (XXII) could be isolated.
Both isotirucallenyl acetate (VIIa) and isoeuphenyl acetate (VIIb) were converted into the 1,5-diketones (XXIIIa) and (XXIIIb) in good yields with osmium tetroxide and lead tetraacetate. Attempts to recyclise the 1,5-diketones by a pinacolic reduction succeeded, albeit in poor yield, when the forcing conditions of molten sodium in xylene were employed.
An attempted Baeyer-Villiger oxidation of the 1,5-diketone (XXIIIa), however, was unsuccessful.
In anticipation of the products to be obtained from the coupling of the monocyclic and tricyclic intermediates (XIIIa) and (IX) attempts were made to hydroxylate and fission the Δ13(18) double bond in δ-amyrin acetate (XXIV), but these proved unsuccessful. The δ-amyrin acetate (XXIV) was obtained from β-amyrin (XXVa) by successive acetylation, selenium dioxide dehydrogenation and partial re-hydrogenation. β-Amyrin (XXVa) was itself isolated as its benzoate from the fractional crystallisation of a mixture of &alpha-; and β-amyrin benzoates, (XXVI) and (XXVb).
Also included in this section is a discussion of further methods of converting the tricyclic intermediate (IX) into a pentacyclic triterpene.
Section B.
The base catalysed condensation of ethyl 2-oxo-3-carbethoxy-butyrate and ethyl vinyl ketone gave the 1,3-diketone (XXVIII), which after acid-catalysed cyclisation and esterification gave the αβ-unsaturated keto-ester (XXIX) in high overall yield. As difficulties were both anticipated and realised in the alkylation of (XXIX), a second monocyclic keto-ester (XXX) was synthesised in order to make comparative studies of their alkylation. The keto-ester (XXX) was synthesised in high yield via the base-catalysed condensation of ethyl α-methyl-β-oxoadipate and methyl vinyl ketone, ring-closure and esterification.
Unsuccessful attempts were made to convert the unsaturated keto-ester (XXIX) into a bicyclic precursor (XL) for rings A and B by a Robinson ring extension and by a Michael addition with acrylonitrile. However, the discovery (see below) that the substance (XXIX) could be alkylated suggested that the same result might be indirectly achieved by alkylating it with a β-halobutan-3-one ketal and then splitting the ketal and cyclising the resultant 1,5-diketone.
With the object of preparing a β-halobutan-3-one ketal several vain attempts were made to add methanol in the presence of mercuric chloride/boron trifluoride etherate catalyst to several related ω-substituted but-1-ynes (XXXI a, b and c). Finally the object was realised by converting ethyl acetoacetate into its ketal derivative (XXXIIa), which was reduced with lithium aluminium hydride to the ketal alcohol (XXXIIb), this in turn giving the toluene-p-sulphonate (XXXIIc) and iodide (XXXIId).
A wide variety of conditions were employed in attempts to alkylate the monocyclic keto-esters (XXIX and XXX) with both the β-ketal toluene-p-sulphonate (XXXIIc) and iodie (XXXIId) but as no alkylated product was ever isolated it appeared that the β-ketal detivatives (XXXIIc) and (XXXIId) were either too unstable or too inactive to accomplish substitution.
However, the monocyclic intermediates (XXIX) and (XXX) were alkylated in several ways. The unsaturated keto-ester (XXIX) was alkylated with methyl iodide and potassium t-butoxide, and the homologous keto-ester (XXX) was alkylated by ethyl bromoacetate using sodium triphenylmethide as base. Both (XXIX) and (XXX) were alkylated with 1,3-dichlorobut-2-ene in the presence of sodium t-amyloxide but no bicyclic ring closure compounds could be obtained on treatment of the chlorocrotyl derivatives (XXXIII) and (XXXIV) with concentrated sulphuric acid. In fact the latter regressed to the keto-ester (XXX) and the former isomerised to give a solid crystalline product which could not be identified.
Finally, ring extension was achieved by first reducing the olefinic bond in the monocyclic αβ-unsaturated keto-ester (XXIX) with lithium in liquid ammonia and condensing the resultant saturated keto-ester (XXXV) with the methiodide of 1-diethylaminobutan-3-one using sodamide as base. The octalone (XXXVI) was isolated and a gem-dimethyl group was introduced to give (XXXVII).
A description of the continuation of this work is given and also included is a variation involving the preparation of the diester (XXXVIII) by a base-catalysed ring closure of the 1,5-diketone (XXXIX), itself derived from the base-catalysed condensation of ethyl β-oxoadipate and methyl vinyl ketone. Ways in which this latter compound can be utilised are also presented.