Synthetic investigations on morellin

Abstract

The thesis entitled "Synthetic Investigations on Morellin" is divided into three sections. Morellin (1), a polyisoprenylated xanthone, was isolated from Garcinia morella and shown to possess high antistaphylococcal activity. Morellin and its congeners possess a unique structure having an oxatricyclo[4.3.1.0^3,7]decan-2-one moiety. By a retrosynthetic analysis, we arrived at the pyranoxanthone (37) and the oxatricyclo moiety (10c) as key intermediates for the synthesis of morellin. The first section deals with the chemistry of morellin with reference to its isolation, structure, biogenesis, and synthesis. It includes a discussion of our synthetic efforts aimed at elaborating the oxatricyclo[4.3.1.0^3,7]decan-2-one moiety (10), from the bicyclooctene intermediate (3). The compound (3) was obtained from the dihydroaromatic compound (2), which is readily available by the metal-ammonia-alcohol reduction of anisole. Two routes, one involving halocyclisation and the other involving an oxidative cyclisation, have been developed for the construction of the oxatricyclo system. A brief overview of the different methods available for the construction of the bicyclo[2.2.2]octane ring and tetrahydrofurans is also presented in this section. Diels–Alder reaction of methyl acrylate with dihydroanisole (2a) afforded the bicyclo[2.2.2]octene adduct (3a). The t-alcohol (4a), obtained by the reaction of the adduct (3a) with methylmagnesium iodide, when subjected to treatment with N-bromosuccinimide, underwent bromoetherification to afford the compound (5a). Solvolysis of the bromoether (5a) with silver acetate in acetic acid afforded a mixture of the desired acetate (6a), the cyclopropyl compound (7a) and the rearranged acetate (8a). Hydrolysis of the acetate (6a) gave the alcohol (9a), which on oxidation with PCC afforded the tricyclic ketone (10a). Before attempting the synthesis of the tricyclic ketone (10c), the moiety present in morellin, by the halocyclisation route, it was felt appropriate to check its feasibility by its application to the synthesis of the oxatricyclo moiety (10b). Thus, 6-butyl-1-methoxycyclohexa-1,4-diene (2b), obtained by the alkylation of 1-methoxycyclohexa-1,4-diene (2a) with n-butyl bromide in the presence of potassamide in ammonia, was elaborated to the bromoether (5b) in a way similar to that outlined for dihydroanisole (2a). Reaction of the bromoether (5b) with silver acetate in acetic acid afforded the desired acetate (6b), the cyclopropyl compound (7b), the rearranged acetates (8b) and (11a), and a ketone (12). Hydrolysis of the acetate (6b) afforded the alcohol (9b), which underwent smooth oxidation to afford the tricyclic compound (10b). We next focused our attention on the synthesis of the oxatricyclo moiety (10c) employing the above methodology. Alkylation of 1-methoxycyclohexa-1,4-diene (2a) with prenyl bromide in the presence of potassamide in ammonia afforded predominantly the product of thermodynamic alkylation (13) and very little of the desired dihydro compound (2c). Alkylation of 1-methoxycyclohexa-1,4-diene (2a) was next attempted with 2-(2-bromoethyl)-1,3-dioxolane to afford the dihydro compound (2d), which was elaborated to the bromoether (5d) in a manner similar to that outlined for the dihydro compound (2a). Solvolysis of the bromoether with silver acetate in acetic acid gave a complex mixture of products, none of which analysed for the desired acetate (6d). Two products were isolated and characterised: the cyclopropyl compound (7d) and the rearranged acetate (11b). Since the halocyclisation route to the tricyclo compound (10c) resulted only in the rearranged products, an alternative route involving the oxidative cyclisation of the compound (3) has been developed for the synthesis of the oxatricyclo systems (10a) and (10c). Hydrolysis of the adduct (3a) afforded the acid (14a), which on reaction with performic acid gave the epoxy acid (15a). Grignard reaction of the corresponding tetrahydropyranyl ether (16) afforded the diol (17), which when exposed to catalytic amounts of PTS in dry benzene underwent cyclisation and deprotection of the tetrahydropyranyl group to afford the compound (9a). Hydrolysis of the adduct (3d) afforded the acid (14d), which on treatment with MCPBA afforded the epoxide (15d). Hydrolysis of the acetal functionality in the compound (15d) with pyridinium para-toluenesulfonate (PPTS) gave the hemiacetal (18), which on reaction with methanol in the presence of catalytic amounts of PTS afforded the acetal (19). Reaction of 19 with methyllithium gave the diol (20), which cyclised on treatment with PTS to afford the compound (21). Hydrolysis of 21 with PPTS gave the hemiacetal (22), which was oxidised using PCC to the lactone (23). Grignard reaction gave the diol (24), which was oxidised with PCC to the keto alcohol (25). Dehydration of the compound (25) with phosphoryl chloride and pyridine afforded a mixture of the tricyclic ketones (10c) and (26); the mixture without separation was subjected to treatment with rhodium chloride in isopropanol to afford the oxatricyclo compound (10c). The second section deals with the synthesis of the pyranoxanthone (37). Our efforts to elaborate the pyranoxanthone (37) from the key intermediates (28), (29), and (30) failed. A novel general route has been developed for the synthesis of the dihydropyranoxanthone (32) and this has been used for the synthesis of 37. 1,3-Dihydroxyxanthone (27), obtained by employing the Grover, Shah and Shah conditions, from salicylic acid and phloroglucinol, when treated with prenyl bromide in the presence of potassium carbonate, afforded the 3-O-prenyl ether (31). The compound (31) on heating in xylene in the presence of catalytic amounts of zinc chloride gave a mixture of the linear (32) and the angular dihydropyranoxanthone (33). Acetylation of the compound (32) with acetic anhydride and pyridine gave the compound (34), which on bromination followed by dehydrobromination, afforded the pyranoxanthone (35). Reaction of 35 with prenyl bromide and potassium carbonate afforded the prenyl ether (36), which when heated in N,N-dimethylaniline smoothly underwent a Claisen rearrangement to afford the xanthone (37). The third section deals with the preparation of 5,8-dihydro-1,3-dimethoxyxanthene (43) as this is required for further elaboration to an analogue of morellin (44). The compound (43) can obviously be prepared by the metal–ammonia reduction of 1,3-dimethoxyxanthone (40) through the reduction of the carbonyl group followed by the reduction of the less substituted aromatic ring. Since no report on the metal–ammonia reduction of xanthones is available in the literature, we have investigated the reduction of xanthone (38) and 1,3-dimethoxyxanthone (40) with metal–ammonia solutions. The results are reported in this section. Reduction of xanthone (38) with lithium and t-butanol in ammonia afforded 1,4-dihydroxanthene (39). A similar reduction of 1,3-dimethoxyxanthone (40) using lithium and t-butanol in ammonia however afforded the demethylated dihydroxanthene (41). Hence the carbonyl group in 1,3-dimethoxyxanthone (40) was first reduced with diborane to afford 1,3-dimethoxyxanthene (42), which was then reduced with lithium and t-butanol to afford 5,8-dihydro-1,3-dimethoxyxanthene (43). Presently, efforts are underway to elaborate the oxatricyclo moiety (10c) on the dihydroxanthene (43) by the oxidative cyclisation methodology towards the total synthesis of desoxymorellin (45).