synthetic investigations in terpenoids

Abstract

The thesis entitled "SYNTHETIC INVESTIGATIONS IN TERPENOIDS: STRATEGIES OF SYNTHESIS OF ILLUDININE, EREMOLACTONE AND KHUSIOL" is mainly divided into two chapters. Chapter I deals with the synthetic studies on the fungal metabolites illudinine (1), illudalic acid (2) and illudacetalic acid (3), isolated from the basidiomycete Clitocybe illudens. The isolation and elucidation of structures (1), (2) and (3) are discussed. A new, formal total synthesis of illudinine, illudalic acid and illudacetalic acid is described. Earlier, Woodward and Hoye synthesized these metabolites (1), (2) and (3) from the ketone (4), which was prepared from indane. In their synthesis, the ketone (4) was converted into the olefin (6) via the alcohol (5). Oxidative cleavage of the double bond in (6) afforded the intermediate dialdehyde (7), which was converted into the three natural products (1), (2) and (3). An alternative method for the synthesis of the ketone (4) is now developed and the results of these investigations are discussed. The present methodology employs the construction of an indanone carboxylic acid from a dicarboxylic acid obtained by the oxidative cleavage of a six-membered ketone. Model system studies were carried out to investigate the feasibility of this methodology. Thus, 6-methoxy-1-tetralone (8) was converted into its furfurylidene derivative (9) which, on treatment with ozone followed by oxidative work-up, gave 6-(2-carboxy-5-methoxyphenyl)propionic acid (10). This was cyclised with thionyl chloride/aluminium chloride to afford the keto acid (11a), which was esterified with ethereal diazomethane to give 4-carbomethoxy-7-methoxyindan-1-one (11b). This strategy was employed in the synthesis of the key intermediate (4). Thus, 6-methoxy-1,2,3,4-tetrahydronaphthalene (12), on Vilsmeier reaction, gave the aldehyde (13). Knoevenagel reaction of (13) with malonic acid in pyridine afforded the ?,?-unsaturated acid (14), which, on reduction with sodium in liquid ammonia, yielded the compound (15). Conversion of the acid (15) into its acid chloride and intramolecular Friedel–Crafts acylation resulted in the ketone (16). Treatment of (16) with sodium hydride and methyl iodide in dimethylformamide gave the dimethyl ketone (17), which on Clemmensen reduction gave the hydrocarbon (18). Jones oxidation of (18) yielded the ketone (19), which afforded the furfurylidene derivative (20) on treatment with furfural in the presence of 20% aqueous sodium hydroxide. Oxidative cleavage of (20) by ozonolysis led to the dicarboxylic acid (21), which was converted into the key intermediate (4) via its acid chloride. Since the ketone (4) is earlier converted into illudinine (1), illudalic acid (2) and illudacetalic acid (3), this method constituted a formal synthesis of these metabolites. All the new compounds have been characterised by analytical and spectral methods. ________________________________________ The second chapter deals with the development of a new strategy for the construction of a bicyclo[2.2.2]octane framework with a bridgehead alkyl group and elaboration of this skeleton to the synthesis of some natural products. The required bicyclo[2.2.2]octane moieties were prepared from suitable aromatic precursors via metal-ammonia reduction, base-catalysed conjugation of the resulting unconjugated dienes, and subsequent Diels–Alder reaction with a variety of dienophiles. The different aspects of metal-ammonia reduction and its use in synthetic organic chemistry are briefly described in the introduction to Chapter II, which is subdivided into two sections. Section I deals with the attempts to utilise the above general strategy in the synthesis of diterpenes eremolactone (22) and isoeremolactone (23). Eremolactone was isolated from Eremophila fraseri F. Muell and E. freelingii F. and contains the novel tricyclo[5.2.2.0^2,6]undecane moiety. A new synthesis of methyl tricyclo[5.2.2.0^2,6]undeca-4-one-9-carboxylate (26) from simple aromatic precursors is described. 6-(2-carboxyphenyl)propionic acid (30) was prepared from 6-naphthol (28) via o-carboxycinnamic acid (29). Sodium-liquid ammonia reduction of (30) gave the 1,4-dihydro compound (31), which was converted into the conjugated diene (32) by refluxing with 20% aqueous sodium hydroxide. Diels–Alder reaction of (32) with methyl acrylate followed by esterification with methanol-sulfuric acid gave the regiomeric adducts (33) and (34) in a 2:1 ratio. The structural assignment of these products was done on the basis of chemical and spectral studies. It was anticipated that the regiomer (33) on Dieckmann condensation would afford the 6-ketoester (35), which would be transformed to the ketoester (36) and finally to the ester (24). Conversion of the ester (24) into isoeremolactone (23) via the aldehyde (25) had already been described in the literature. Thus, construction of (24) would accomplish a formal total synthesis of the novel diterpenes eremolactone (22) and isoeremolactone (23). However, Dieckmann condensation of the regiomeric adduct (33) gave the 6-ketoester (37), which was decarboxylated to give (38). Hydrogenation of the ketoester (38) yielded the compound (26), which was closely related to (27), a possible precursor of isoeremolactone and synthesized by Kraus et al. during their synthetic investigations on eremolactone. Having failed to obtain the required key intermediate (24) by the above method, it was planned to design an alternative route. Thus, the triester (40) was prepared from the regiomer 33 via the pyrazoline 39. Conversion of 40 into 42 by 1,4- Grignard addition using lithium dimethylcuprate or methylmagnesium iodide-cuprous chloride followed by Dieckmann cyclisation would result in the 6 -ketoester 43 which could easily be transformed into the key intermediate 24. However, attempts to introduce a methyl group at the C-3 position in 40 by conjugate addition of lithium dimethylcuprate were unsuccessful. Dieckmann condensation of 40 afforded the 6 - ketoester 41 in good yield. Section-II describes the synthetic investigations on khusiol (44), a sesquiterpene alcohol isolated from vetiver oil. Since 1,5-dimethylindane-4-carboxylic acid (45) was envisaged as the important aromatic precursor for the construction of the bicyclo[2 .2 .2 .]octane moiety present in khusiol, several attempts were made to prepare the acid from readily available starting materials. These methods' include (i) carbonation of 1,5-dimethyl indan-3-ol (46) using nbutyllithium and ethyl chloroformate and (ii) degradation of the furfurylidene derivative obtained from 8 -methyl-2 -tetralone (47). All these attempts failed to yield any of the desired compounds.