studies in natural products

Abstract

The thesis entitled “Studies in Natural Products: Essential Oil of Ageratum conyzoides and Transformation of One of Its Constituents to ?-Norsteroid Derivatives” consists of two parts.

Part I

Chapter I deals with the isolation of a few more constituents of the oil of Ageratum conyzoides, of Indian origin. From the hydrocarbon fraction, p-caryophyllene has been separated and characterized. The oxygenated fraction has been shown to contain coumarin, in addition to the already reported ageratochromene and 6-demethoxyageratochromene.

Chapter II discusses the results obtained in the course of studies of the dimerisation of ageratochromene. Dimerisation of ageratochromene with different reagents gave, in addition to the naturally occurring dimer of ageratochromene, viz., 6,7,6',7'-tetramethoxy-2,2,2',2'-tetramethyl-3,4-dehydro-3f,4-bichroman, another dimer, for which the structure, 5,6,6a,6b,7,12b-hexahydro-1,2,10,11-tetramethoxy-5,5,1,1-tetramethylcyclopenta[1,2-c;5,4,3-d’e’]bis[ibenzopyran], has been assigned.

Chapter II is subdivided into three sections.

Chapter IIa is a review of the chemistry of ?-norsteroids with special emphasis on their syntheses and biological properties.

Chapter IIb embodies the successful transformation of naturally occurring 7-methoxy-2,2-dimethylochromene to ?-norsteroid derivatives. The transformation has been achieved in three stages:

The first stage involves the conversion of 7-methoxy-2,2-dimethylochromene to the key intermediate, 2,4-dimethoxy-2-dehydroisovalerophenone.

In the second stage, this unsaturated ketone is converted to l-(2,5-diketo-1-methylcyclopentyl)-3-(2,4-dimethoxyphenyl)-5-methylhex-2-ene (seco dione-1) by Grignard reaction with vinyl magnesium bromide followed by condensation with 2-methylcyclopenta-1,3-dione. Similarly, 2,4-dimethoxyisovalerophenone, obtained by hydrogenation of the aforementioned unsaturated ketone, was transformed to l-(2,5-diketo-1-methylcyclopentyl)-3-(2,4-dimethoxyphenyl)-5-methylhex-2-ene (seco dione-2). Cyclodehydration of these seco diones with different reagents produced several products:

Seco dione-1 with methanolic HOI gave 2-(2,4-dimethoxyphenyl)-2-(isobut-1-enyl)-5-methylbicyclo[3,2,1]octane-6,8-dione.

Seco dione-2 gave two isomeric compounds tentatively assigned as exo- and endo-isopropyl derivatives of 2-(2,4-dimethoxyphenyl)-2-isopropyl-5-methylbicyclo[3,2,1]octane-6,8-dione.

Cyclodehydration of seco dione-1 with concentrated H?SO? gave 1,3-dimethoxy-6,6-dimethyl-5-norestra-1,3,5(10),8,14-pentaen-17-one, which was confirmed by spectral data and comparison with an authentic sample. Reduction of this compound with NaBH? gave the 17?-alcohol. Stereoselective reduction of the 14,15-double bond in this alcohol in the presence of 2% Pd–BaSO? catalyst gave 1,3-dimethoxy-6,6-dimethyl-8-is?-?-norestra-1,3,5(10)-trien-17?-ol. Catalytic hydrogenation of the 8,9-double bond in this tetraenol with 10% Pd–C catalyst gave mainly a single isomer, 1,3-dimethoxy-6,6-dimethyl-8-is?-?-norestra-1,3,5(10)-trien-17?-ol. Metal-ammonia reduction of the 8,9-double bond in the above tetraenol in the presence of aniline gave a single product, assigned the structure 1,3-dimethoxy-6,6-dimethyl-?-norestra-1,3,5(10)-trien-17?-ol. Both trienols were oxidized to the corresponding keto derivatives using CrO?–pyridine complex.

Chapter III focuses on the preparation of 4,6-dimethoxy-3,3-dimethylindan-1-one, required for the synthesis of ?-norsteroid derivatives.

Reaction of 3-(2,4-dimethoxyphenyl)-propionic acid with POCl? followed by treatment with AlCl? did not give the expected indanone but afforded two chloro ketones. Their structures were determined to be 3-(2,4-dimethoxy-5-chlorophenyl)-propiophenone and 3-[2,4-dimethoxy-5-(1-keto-3-(2,4-dimethoxy-5-chlorophenyl)-propyl)]-phenylpropiophenone.

Similar treatment of 3-(2,4-dimethoxyphenyl)-isovaleric acid gave 4,4-dimethyl-6-chloro-7-methoxy-dihydrocoumarin.

Nuclear halogenation of several dimethoxybenzene derivatives using POCl? was carried out.

The required indanone was successfully synthesized starting from 3,5-dimethoxycinnamic acid. Grignard reaction of ethyl 3-(3,5-dimethoxyphenyl)-propionate with methyl magnesium iodide, followed by cyclodehydration, gave 4,6-dimethoxy-3,3-dimethylindane, which on oxidation with CrO?–pyridine complex yielded the indanone in good yield