Synthetic studies in B-Nonsteroids

Abstract

Chapter I Describes the objectives of the present work.

Chapter II Embodies the syntheses of the key intermediates for the synthesis of several B-norsteroids: (i) 4,7-dimethoxy-3,3-dimethylindanone (2.1), (ii) 4,7-dimethoxyindanone (2.2), (iii) 5,6-dimethoxy-3,3-dimethylindanone (2.3), and (iv) 4?-methoxy-2-dehydroisovalerophenone (2.4).

Several schemes were attempted for the synthesis of indanone 2.1. The successful synthesis involved fusion of 6-methoxy-2,2-dimethylchromanone with a melt of anhydrous AlCl? and NaCl, followed by methylation with dimethyl sulfate of the resulting 4,7-dihydroxy-3,3-dimethylindanone.

A similar approach for indanone 2.2 is described: fusion of 6-methoxychromanone with AlCl?/NaCl gave 4,7-dihydroxyindanone, which on methylation afforded indanone 2.2.

Section 2.3 describes preparation of indanone 2.3 by a known method.

Section 2.4 deals with the attempted synthesis of 5-methoxy-3,3-dimethylindanone (2.5). Friedel–Crafts reaction of anisole with p,p-dimethylacryloyl chloride gave quantitatively the unsaturated ketone 2.4 instead of the reported indanone 2.5. Further, reaction of ketone 2.4 with PPA did not yield indanone 2.5 but afforded 4,4?-dimethoxybenzophenone. However, ketone 2.4 itself could be employed for the synthesis of B-norsteroid analogs.

Chapter III Describes the conversion of intermediates 2.1–2.4 to the corresponding B-norestra-1,3,5(10),8,14-pentaen-17-ones.

Section 3.1: Synthesis of 1,4-dimethoxy-6,6-dimethyl-B-norestra-1,3,5(10),8,14-pentaen-17-one (3.3). Indanone 2.1 was treated with vinylmagnesium bromide; the resulting vinyl alcohol was condensed with 2-methylcyclopentane-1,3-dione (3.1) to obtain seco-dione 3.2. Cyclodehydration of 3.2 using acetic acid/HCl gave pentaenone 3.3.

Sections 3.2 and 3.3: Similar syntheses of 1,4-dimethoxy-B-norestra-1,3,5(10),8,14-pentaen-17-one (3.4) and 2,3-dimethoxy-6,6-dimethyl-B-norestra-1,3,5(10),8,14-pentaen-17-one (3.5).

Section 3.4: Synthesis of 3-methoxy-6,6-dimethyl-B-norestra-1,3,5(10),8,14-pentaen-17-one (3.6). Ketone 2.4 was treated with vinylmagnesium bromide to give vinyl alcohol 3.7. Condensation with dione 3.1 yielded diketone 3.8. Cyclodehydration with conc. H?SO? gave pentaenone 3.6 plus by-products, including a hydroxyketone tentatively assigned the structure of a dibenz[ e,g ]azulene derivative based on PMR and NMR spectra.

Chapter IV Concerns the transformation of B-norestra-1,3,5(10),8,14-pentaen-17-ones (3.3–3.6) to the corresponding B-norestra-1,3,5(10)-trien-17?-ols.

Section 4.1: Transformation of pentaenone 3.3 to trien-17?-ols 4.2 and 4.3. SBH reduction gave tetraenol 4.1, which underwent metal–ammonia reduction to yield trienols 4.2 and 4.3. Oxidation with CrO?–pyridine gave trienones 4.4 and 4.5, tentatively assigned 8?,9? and 8?,9? configurations.

Section 4.2: SBH reduction of pentaenone 3.4 gave tetraenol 4.7. Metal–ammonia reduction afforded trienol 4.9, tentatively assigned 8? configuration.

Sections 4.3 and 4.4: Syntheses and configuration assignments of (i) 2,3-dimethoxy-6,6-dimethyl-B-norestra-1,3,5(10)-trien-17?-ols and (ii) 3-methoxy-6,6-dimethyl-B-norestra-1,3,5(10)-trien-17?-ols.

Section 4.5: Probable mechanisms of stereoselective reductions of B-norestratetraenols are discussed.