synthetic investigations in terpenoids

Abstract

The thesis entitled “Synthetic Studies in Terpenoids” consists of seven chapters.

Chapter 1 Chapter 1 describes the first total synthesis, by two different routes, of 8?methoxycalamenene (1.6), a sesquiterpene of marine origin. Polyphosphoric?acid cyclodehydration of the carbinol (1.2), prepared from the arylbutanoic acid (1.1) by standard reactions, gave 8?methoxycalamenene (1.6). Simple dehydration with p?toluenesulphonic acid of the carbinol (1.2) gave the methyl ether (1.3) of curcuphenol (1.4), a constituent of another marine gorgonian. In the second route, polyphosphoric?acid cyclodehydration of the secondary alcohol corresponding to ketone (1.5), also prepared from acid (1.1), afforded 8?methoxycalamenene (1.6).

Chapter 2 Chapter 2 presents the first total synthesis of 5?hydroxycalamenene (1.8), a phenolic sesquiterpene from Bazzania tricrenata. Polyphosphoric?acid cyclodehydration of the secondary alcohol (1.7), prepared from o?cresol by a multistep procedure, is the key step in this synthesis. Hydrobromic acid in acetic acid also gave the natural product (1.8) with concurrent cyclodehydration–demethylation.

Chapter 3 Chapter 3 deals with the first synthesis of methyl nidiorellaurinate (1.10), a newly isolated sesquiterpene ester with an isoprenyl moiety unusually linked to p-cymene. A convenient one?pot procedure was developed for converting a tertiary alcohol to an ?,??unsaturated aldehyde with E geometry by selenium?dioxide oxidation in dimethyl sulfoxide. The resulting enal (1.9) was transformed into methyl nidiorellaurinate (1.10) in one step by Corey’s procedure.

Chapter 4 Chapter 4 describes a new approach for an economical synthesis of ??himachalenoids. The strategy involves intermolecular electrophilic attack of suitably substituted aromatic substrates on 6?methylhept?5?en?2?one, a readily available retro?aldol fragment of citral. Benzosuberone derivatives (1.11 and 1.12), key intermediates in the synthesis of ??himachalene and its hydroxy derivative, were prepared in two steps from the Friedel–Crafts reaction products of toluene and o-cresol methyl ether with 6?methylhept?5?en?2?one. The methyl ether (1.13) of himaphenolone, a secosesquiterpene phenolic ketone biogenetically related to p-himachalene, was synthesised in one step. Cumene was elaborated to the tetralin (1.14), an industrially important compound.

Chapter 5 Chapter 5 deals with the revision of structure (to 1.16) of an aromatic monoterpene isolated from Piqueria trinervea, earlier assigned structure (1.15). Unambiguous syntheses of 2?methyl?3?isopropenyl? and 2?isopropenyl?3?methyl anisoles (1.15 and 1.16), followed by comparison of their spectral data with those reported for the natural product, suggest that the natural product’s structure should be represented by (1.16).

Chapter 6 Chapter 6 discusses the oxidation of acetoxy? and alkoxy?alkyl arenes using a new oxidant, benzyltriethylammonium permanganate (BTAP), and the convenient synthesis of some natural products based on this reaction. A brief survey of benzyl oxidations by well?known oxidants precedes the discussion. Part 1 BTAP is shown to be useful for regiospecific oxidation of the arylmethyl moiety of acetoxy?alkyl arenes, leading to convenient preparation of the corresponding arylcarboxylic acids and several new thymol derivatives (1.18, 1.19, 1.20). Hydrolysis of the acetoxy acid (1.17), obtained via BTAP oxidation of thymyl acetate, furnished 3?hydroxy?4?isopropylbenzoic acid (1.18), a natural thymol derivative. Lithium aluminium hydride reduction of acid (1.17), followed by treatment with isobutyryl chloride of the dimagnesio derivative of the resulting diol, furnished 7?isobutanoyloxythymol isobutanoate (1.19), another naturally occurring thymol derivative. The third derivative synthesised was hydroxy acid (1.20), again involving BTAP oxidation as the key step. Part 2 This part presents a new inexpensive synthesis of espeleton (1.21), a natural isoprenyl aromatic diketone, using BTAP-mediated benzylic oxidation. 5?Ethyl?2?methoxyisovalerophenone, obtained by acylation of 4?ethyl anisole using isovaleric acid and polyphosphoric acid, was oxidised with BTAP to give espeleton (1.21). Part 3 BTAP oxidation was applied to various alkyl arenes, leading to convenient syntheses of alkylarylcarboxylic acids and the optically active natural product ar?pseudotsugonal (1.23). Model studies on oxidation of xylenes, mesitylene, and p-cymene produced corresponding alkylbenzoic acids. Oxidation of (+) (S)?ar?dihydroturmerone (1.22) gave, in two steps, (+)(S)?ar?pseudotsugonal (1.23).

Chapter 7 Chapter 7 presents the synthesis of 2,2,3?trimethyl?(2??methoxy?4??methylphenyl)propanoic acid (1.25), a synthon envisaged for elaboration to cuparenoid sesquiterpenes. Lewis?acid rearrangement of epoxide (1.24), prepared from acid (1.1) in four steps, followed by Jones oxidation, gave synthon (1.25). The rearrangement mechanism is discussed, and attempts to elaborate the acid (1.25) into cuparenoids are outlined.