Strategies of synthesis based on methoxyclohexadienes: synthesis of some polyketides

Abstract

The thesis entitled “STRATEGIES OF SYNTHESIS BASED ON METHOXYCYCLOHEXADIENES: SYNTHESIS OF SOME POLYKETIDES” consists of two chapters. The first chapter deals with a general introduction to the thesis and is divided into two sections. In Section I, a brief review on the preparation of methoxycyclohexadienes by the metal–ammonia reduction of aromatic ethers and their application in the synthesis of natural products has been presented. Section II deals with cycloaddition reactions and is divided into two parts. A brief introduction to Diels–Alder and Alder–Rickert reactions forms the first part. The reactions have been discussed in detail with respect to their importance in organic synthesis. In the second part, the scope of the Alder–Rickert reaction involving methoxycyclohexadienes and acetylenic dienophiles as a realistic approach to the synthesis of several aromatic polyketides is outlined. The second chapter deals with synthetic investigations on aromatic polyketides and consists of five sections. A novel synthetic route to dihydroisocoumarins is presented in Section I. Total synthesis of two biologically active dihydroisocoumarins: mellein (1) and 6?methoxy?mellein (2) is described. The acetylenic ester (5) underwent regiospecific cycloaddition reaction with substituted methoxycyclohexadienes (4a,b) to form adducts which aromatised spontaneously to give the products (7a,b). Cyclisation followed by demethylation furnished mellein and 6?methoxymellein. Application of this method to the synthesis of 5?methylmellein (3) using the diene (4c) resulted in the formation of a benzofuran (8), indicating an inversion of regiochemistry during cycloaddition in this particular case. Investigations leading to the synthesis of macrolide polyketides, curvularin (9) and lasiodiplodin (10), have been discussed in Section II. Alkaline hydrolysis of 2?acetylcyclohexanone gave the ketoacid (11). Esterification followed by ketalisation gave the ketal (12). Lithium aluminium hydride reduction of (12) gave the alcohol (13) which on oxidation with pyridinium dichromate furnished the aldehyde (14). This on reaction with the lithio derivative of the acetylenic ether (15) followed by oxidation with pyridinium dichromate afforded the acetylenic ketone (16). Reaction of the ketone (16) with the diene (4b) furnished the aromatic alcohol (17a). Further transformation of the alcohol through the acid (17b) to curvularin (9) has been attempted through conventional methods. The hydroxy acid (19a) which was obtained by an Arndt–Eistert reaction on the acid chloride (18) was esterified and the methyl ester (19b), on treatment with dihydropyran in the presence of catalytic amount of p?toluenesulphonic acid, furnished the ester (19c). Lithium aluminium hydride reduction of (19c) gave the alcohol (20a). This on tosylation followed by treatment with lithium bromide in acetone afforded the bromide (20b). Addition of the bromide (20b) to sodium acetylide yielded the acetylenic compound (21) which on treatment with n?butyllithium followed by ethyl chloroformate gave the acetylenic ester (22). Cycloaddition of the diene (4b) with the acetylenic ester (22) followed by aromatisation and hydrolysis gave the hydroxy acid (23) which has been earlier converted into lasiodiplodin. In Section III, a novel and highly efficient synthesis of 2,5?dialkylresorcinols using methoxycyclohexadienes and acetylenic dienophiles has been presented. By using this method, the antifungal antibiotic DB?2073 (24) and its isomer (25) have been synthesised. The diene (26a) underwent cycloaddition with the acetylenic aldehyde (27a) to form the adduct which spontaneously aromatised to the benzaldehyde (28a). Decarbonylation with tris(triphenylphosphine)rhodium chloride followed by demethylation afforded DB?2073 identical with the natural product. Similar reactions involving the diene (26b) and the dienophile (27b) led to the isomer of DB?2073 (25). Section IV deals with an attempted total synthesis of mycophenolic acid (31b), an important antitumour antibiotic isolated from Penicillium brevicompactum. Attempts to prepare the intermediate (31a) by using the reaction between the diene (29b) and dimethylacetylene dicarboxylate are described. The regiochemistry of the isomerisation of 1,5?dimethoxy?4?methylcyclohexadiene (29a) has been explored under different conditions and the results are reported in this section. Section V deals with the experimental and references.