Colin L. Hewett

Alkylated steroids. Part 2. 16α,17α-Dimethylpregnanes functionalised in ring C

An improved process for the preparation of 16α,17α-dimethylpregnanes (1b)–(9b) from pregn-16-en-20-ones has been developed and applied to ring C functionalised steroids (1a)–(9a) as a route to corticosteroid analogues. Good to excellent yields of the 16α,17α-dimethyl derivatives were achieved in all cases except with 11β-hydroxy-compounds and this was overcome by using the acetate. Two by-products, formed in variable amounts, were the 16α-methyl and 16α,17α,21-trimethyl derivatives (c) and (d) respectively.

18-Norandrosta-8,11,13-trienes. Part II. Aromatisation of 18-norandrost-13-enes by bromination and dehydrobromination

Bromination of 17,17-disubstituted-18-norandrost-13-enes (1) followed by dehydrobromination gave the corresponding 7,13-dienes (3), which on further bromination and dehydrobromination yielded the 8,11,13-trienes (8). The mechanism of the reaction including the involvement of the 17-substituents is discussed.

Alkylated steroids. Part 1. 16α-Substituted 17α-methylpregnanes

The sequential reaction of 3β-acetoxypregna-5,16-dien-20-one (1) with methylmagnesium bromide and then methyl iodide has been examined in detail. The major product (85%) was 3β-hydroxy-16α,17α-dimethylpregn-5-en-20-one (2). Other products identified were 3β-hydroxy-16α-methylpregn-5-en-20-one (4); the 21-methyl derivatives [(5) and (10)] of (2) and (4); the 21-(1-hydroxy-1-methylethyl) derivative (11) of (2); and a trace of the 21,21-dimethyl derivative (12) of (2). The scope of the reaction with regard to the range of substituents that can be introduced at positions 16 and 17 has been established by preparing a series of 16α-substituted 17α-methylpregnenolones with a variety of alkyl, aryl, and aralkyl groups. Some of these have been converted into the corresponding 16α,17α-disubstituted progesterones.

18-Norpregna-8,11,13-trienes: reaction of 16α,17α-epoxypregn-8-en-11-ones with Lewis acids

Treatment of 3β-acetoxy-16α,17α-epoxy-5α-pregn-8-ene-7,11,20-trione (6) with acetic anhydride gave 3β,17α-diacetoxy-5α-pregna-8,14-diene-7,11,20-trione (10) and 3β,16α-diacetoxy-11-hydroxy-17β-methyl-18-nor-5α,17α-pregna-8,11,13-triene-7,20-dione (8). Two competing mechanisms for the reaction are proposed. Similar attempts to aromatise 3β-acetoxy-16α,17α-epoxy-5α-pregn-8-ene-11,20-dione (4) were unsuccessful.

Formation of some novel 9β-methyl-19-norpregnane derivatives

The rearrangement of 9α,11α-epoxy-5α-pregnane-3β-20β-diyl diacetate (3) to 11-oxo-5α,9β-pregnane-3β,20β-diyl diacetate (4) and 11α-hydroxy-9β-methyl-19-norpregn-5(10)-ene-3β,20β-diyl diacetate (5) is reported. Treatment of the 5(10)-ene (5) with m-chloroperbenzoic acid in benzene affords 5β,10β-epoxy-11α-hydroxy-9β-methyl-19-norpregnane-3β,20β-diyl diacetate (11), whereas epoxidation with peracetic acid in acetic acid containing mineral acid (1% H2SO4) leads to 5α,11α-epoxy-10β-hydroxy-9β-methyl-19-norpregnane-3β,20β-diyl diacetate (12) by rearrangement of the initially formed 5β,10β-epoxide (11).

5,9-Methanobenzoannulenamines. Part 1. Improved synthesis of 11-amino-5,9-methanobenzo[8]annulenes

Reaction of 1-(3,4-dihydronapthalen-2-yl)pyrrolidine with acrylaldehyde gave an epimeric mixture of 8-hydroxy-5,6,7,8,9,10-hexahydro-5,9-methanobenzo[8]annulen-11-ones which was used for the synthesis of several 11 -amino derivatives.

18-Norandrosta-8,11,13-trienes. Part III. 1-Amino-derivatives

The syntheses of 1α-amino-17,17-dimethyl-18-nor-5α-androsta-8,11,13-triene (9e) and its N-methyl derivatives are described. Bromination–dehydrobromination of 1α-benzolyoxy-17,17-dimethyl-18-nor-5α-androst-13-ene (6b) gave 1α-benzoyloxy-17,17-dimethyl-18-nor-5α-androsta-7,13-diene (7), which on subsequent bromination–dehydrobromination and saponification gave 17,17-dimethyl-18-nor-5α-androsta-8,11,13-trien-1α-ol (9a). This was converted into the 1α-amino-derivatives via the ketone (8a). Reduction of 17,17-dimethyl-18-nor-5α-androsta-8,11,13-trien-1-one (8a) with sodium in alcohol gave a mixture of the 1α- and 1β-alcohols (9a) and (10), whereas reduction with lithium aluminium hydride gave the 1α-epimer (9a) stereospecifically. Both methods of reduction when applied to the corresponding 1-oxime (8b) gave entirely the 1α-amine (9e), a result which is explained in terms of steric interaction between positions 1 and 11. The corresponding 1β-amines could not be prepared.