synthetic studies in emmotins and related compounds

Abstract

The thesis entitled "SYNTHETIC STUDIES IN EMMOTINS AND RELATED COMPOUNDS" consists of seven chapters. Chapter 1, the total synthesis of emmotin-G (12), a sesquiterpene occurring in Emmotum nitens, is described. The intermediate 6-methoxy-1,4-dimethyltetralin (4) was first prepared by two routes: (i) Grignard reaction of 4-methoxyphenylmagnesium bromide with allylacetone gave the mixture of hexenol (1) and hexadiene (2). Birch reduction of the mixture afforded the arylhexene (3), which on cyclization using polyphosphoric acid gave the methoxy dimethyltetralin (4). (ii) 7'-Methoxy-4-methyl-1-tetralone (5), prepared from anisole, was subjected to Grignard reaction with methylmagnesium iodide to get the tetralol (6), which on hydrogenolysis gave the identical methoxy dimethyltetralin (4). The naphthaldehyde (10) required for elaboration to emmotin-G (12) was obtained next by two methods: (i) Methoxy dimethyltetralin (4), prepared as described above, was subjected to Vilsmeier reaction to get the aldehyde (9), the semicarbazone of which was dehydrogenated with DDQ and then hydrolysed to obtain the naphthaldehyde (10). (ii) The tetralol (6) itself, prepared as above, was subjected to Vilsmeier reaction and a mixture of formyldihydronaphthalenes (7) and (8) was obtained, the former giving the naphthaldehyde (10) on dehydrogenation with DDQ. Oxidation, followed by demethylation of the methoxynaphthaldehyde (10) gave the hydroxy naphthoic acid (11). Grignard reaction of its ester with excess methylmagnesium iodide afforded emmotin-G (12). Chapter 2 gives a discussion on the structure of the methoxy dimethyltetralin obtained from anisole via Friedel-Crafts reaction with allylacetone (13). The structure (4) reported in literature resulting from this reaction sequence has been shown to be incorrect. The correct isomeric structure (14) for the tetralin has been deduced from its dehydrogenation and demethylation to the known 5,8-dimethyl-1-naphthol (15), which has also been synthesized independently starting from p-xylene. Chapter 3 – Part I describes the synthesis of two ?-naphthol isomers (18) and (20) of emmotin-G (12). The half-ester (16), obtained by Stobbe condensation of 2,5-dimethylbenzaldehyde with diethyl succinate, was cyclodehydrated with NaOAc and Ac?O to the acetoxy ethyl naphthoate (17), which on subsequent Grignard reaction with CH?MgI gave the ?-naphthol isomer (18). The 2-acetyl derivative (19), obtained by acylation of 5,8-dimethyl-1-naphthol, gave the other ?-naphthol isomer (20) on treatment with CH?MgI. Part II describes the oxidation of the isomer (18) into emmotin-H (21a), a naturally occurring sesquiterpene isolated from Emmotum nitens, and emmotin-H acetate (21b) using iodoxybenzene, the reaction constituting a simple alternative synthesis of emmotin-H (21a). Chapter 4 gives an account of the synthesis of 3,6,9-trimethylnaphtho[1,2-b]furan (23) and 3,5,8-trimethylnaphtho[2,3-b]furan (29), naphthofurans related to emmotin-G (12). Cyclodehydration of the acetonyloxy derivative (22) with conc. H?SO? afforded the angular furan (23). Similar cyclodehydration of acetonyloxy dimethyltetralin (24) gave an inseparable mixture of tetrahydronaphthofurans (25) and (26). As even their dehydrogenation products proved inseparable, another route was followed. 7-Acetyl derivative (27) was first obtained as an exclusive product by the PPA-mediated acylation of 6-methoxy-1,4-dimethyltetralin (4). Demethylation of 27, followed by o-alkylation with ethyl bromoacetate gave the ethyl naphthoxyacetate (28a). Hydrolysis of the ester to the corresponding acid (28b), followed by treatment with NaOAc and Ac?O resulted in furanization accompanied by decarboxylation to get tetrahydronaphthofuran (25) exclusively, which on dehydrogenation gave the linear furan (29). Chapter 5 discusses the structure of an unusual product of alkylation obtained by the reaction of isobutyl 2-methylphenyl ketone (30) with ethyl bromoacetate. Though monoalkylated product (31) was obtained when alkylation was carried out with equimolar amounts of ethyl bromoacetate and NaH in benzene-DMF medium at 50°, the trisalkylated furanone diester (32) was the product when two molar equivalents each of the bromoester and the base were used under reflux. The non-equivalence of OCH? protons of the ester moiety and other spectral features of the furanone diester are discussed. Structure was further confirmed by the hydrolysis of 32 to the keto tricarboxylic acid (33). Chapter 6 deals with an approach towards the synthesis of emmotin-C (40). 3-Isopropyl-5-methyl-1,2-naphthoquinone (38), an intermediate envisaged for the synthesis of 40, was prepared and its conversion to emmotin-C (40) via the diacetate (39) was attempted. The ?,?-unsaturated ketone (34), obtained from 30, was converted to the cyano ketone (35), which on Wolff-Kishner reduction gave the acid (36). Cyclization of the acid (36) to the tetralone (37) was followed by oxidation with SeO? to obtain the 1,2-naphthoquinone (38). Reductive acetylation of the quinone (38) with zinc and acetic anhydride gave the diacetate (39). Attempted C? lithiation using n-BuLi followed in situ formylation with either DMF or CH(OEt)? to obtain emmotin-C (40) was unsuccessful. Chapter 7 deals with the synthesis of ar-occidol (43). Dehydrogenation of methyl ester (41) with DDQ gave the naphthoate (42), which on Grignard reaction with CH?MgI afforded ar-occidol (43). The transformation of the dimethylaryl carbinol (43) to the enal (44) was attempted, since its oxidation product eriofertinic acid (45) is a mechanistically interesting degradation product of the diacetate of eriofertin (46), a germacradienolide isolated from Eriphyllum confertiflorum.