SYNTHESIS OF γ-KETOESTERS VIA ACID CATALYSED RING OPENING OF SUCCINIC ANHYDRIDE WITH SUBSTITUTED BENZYL ALCOHOLS

Abstract

The thesis consists of two parts. The part-I deals with the synthesis of γ-ketoesters using succinic anhydride as a starting material. The part-II is about extraction, isolation, purification and characterization of the chemical constituents from Coriandrum sativum Linn (Umbelliferae). It is an established fact that γ-ketoesters and their precursors are valuable synthons in synthetic organic chemistry. These intermediates have potential applications in the preparation of compounds of significant importance. In view of the important applications of γ-ketoesters, a three-step reaction approach has been employed for their synthesis via acid catalyzed ring opening of succinic anhydride with substituted benzyl alcohols. Step-1: Sixty (1-60) new monoesters of succinic acid were prepared using succinic anhydride and alcohols and toluene as a solvent. The catalyst employed was p-toluene sulfonic acid. Step-2: In this step the prepared monoesters on treatment with thionyl chloride were converted to corresponding acid chlorides (1a-60a). Step-3: Finally, using diethyl cadmium reagent, acid chlorides obtained in the step-2 were converted into corresponding novel γ-ketohexanoates (1b-60b). Diethyl cadmium was prepared by employing ethyl magnesium bromide and cadmium bromide. The final products were characterized by elemental analysis and spectroscopic techniques such as UV, IR, NMR (1H and C) 1D and 2D, COSY-45°, DEPT, HMQC, HMBC, NOE, ROESY, NOESY, mass spectrometry etc. Monoesters (1-29) were screened for biological activity against three fungi and three bacteria following disk diffusion protocol for inhibition zones and agar dilution method for minimum inhibitory concentrations. Their structure activity relationship is also discussed. All of the monoesters except nitro substituted were found to be active against fungi and bacteria. In Part-II seeds of Coriandrum sativum Linn (Umbelliferae) were hydrodistilled for essential oil and the obtained oil was analyzed by gas chromatograogy for its components. β-Linalool with retention time 16.575 min and %age 79.86 was identified as major component by GC-MS. The obtained essential oil was subjected to antifungal and antibacterial activity. Inhibition zones, minimum inhibitory concentrations (MICs) against fungi and bacteria were assessed. Results of these experiments showed that the essential oil was active against investigated microbes. The whole plant (seeds, leaves, stems, flowers) was extracted in 95% aqueous MeOH. The methanolic extract on solvent fractionation and repeated column chromatography on silica gel afforded a bio-active fraction. The fraction on repeated chromatotrax preparative TLC yielded most active fraction which under HPLC RP-18 fractionation afforded thirteen (1-13) compounds. According to our knowledge, since compounds 1-5 have not been reported earlier from plant kingdom and hence can be declared as new entities. The obtained compounds 1-13 were subjected to antifungal and antibacterial activity. Inhibition zones, minimum inhibitory concentrations (MICs) against fungi and bacteria were assessed. For isolates (6-13), cytotoxicity against cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW-480) was probed. IC50 of compounds 6-13 against human cancer cell lines HL-60 were also assessed. Compounds (1-3, 6- 13) displayed antimicrobial and cytotoxicity against used human cell lines. Among the tetra-hydroxysaponins (6-9) displayed IC50 =1.37± 0.02, 1.29 ± 0.02, 1.28 ± 0.02, and 1.07 ± 0.02, respectively, and compounds 10-13 displayed significant activity with IC50=1.27± 0.02, 1.02 ± 0.02, 1.02 ± 0.02, and 0.87 ± 0.02, respectively, standard (acarbose) showed IC50 0.82 μM. Structure and relative configuration of the compounds 1-13 was established after recording and analysis of spectroscopic data such as IR, 1D-NMR and 2D NMR (COSY-45, HOHAHA, HMQC, HMBC and ROESY) and mass measurements. The data revealed that isolated compounds are oleane triterpenoids and named as: 1-Oxo-11,21-dihydroxyoleane (1), 1-Oxo-11- hydroxy-21-O-acetyloleane (2), 1-Oxo-11-hydroxy-21-O-angeloyloleane (3), 1-Oxo-11-O-angelo yl-21-O-acetyloleane (4), 1-Oxo-11,21-O-dibenzoyloleane (5), 28-β-D-Glucopyranosyl 2α,3α, 19α,24-tetrahydroxy-12-ene-oleaenoate (6), 28-β-D-Glucopyranosyl 2β,3α,19α,24-tetrahydroxy- 12-ene-oleaenoate (7), 28-β-D-Glucopyranosyl 2α,3β,19α,24-tetrahydroxy-12-ene-oleaenoate (8), 28-β-D-Glucopyranosyl 2β,3β,19α,24-tetrahydroxy-12-ene-oleaenoate (9), 28-β-D-Glucopyrano- syl 2β,3β,19α,24-tetrahydroxy-12-ene-oleaenoate (10), 28-β-D-Glucopyranosyl 2α-O-acetyl ,3α,19α,24-tetrahydroxy-12-ene-oleaenoate (11), 28-β-D-Glucopyranosyl 3α-O-acetyl,2α,19α,24- tetrahydroxy-12-ene-oleaenoate (12) and 28-β-D-Glucopyranosyl 19α-O-acetyl,2α,3α,24-tetrahy- droxy-12-ene-oleaenoate (13).