Robert Thomas Logan

Alkylated steroids. Part 3. The 21-alkylation of 20-oxopregnanes and synthesis of a novel anti-inflammatory 16α,17α,21-trimethyl steroid (Org 6216)

The development of a 21-alkylation reaction which proceeds via the lithium 20(21)-enolate is described and its scope demonstrated by the preparation of a variety of 21-alkylpregnane derivatives. Application of this process to 11β-acetoxy-16α,17α-dimethyl-5α-pregnane-3,20-dione (28a) and its 5β-analogue (28b) led to the corresponding 16α,17α,21-trimethyl derivatives. Several routes from these saturated trimethylpregnane-3,20-diones to 11β-hydroxy-16α,17α,21-trimethylpregna-1,4-diene-3,20-dione (Org 6216) were explored. The best method gave Org 6216 in 75% yield.

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.

Alkylated steroids. Part 5. Formation of 17β-acetylenic steroids from hindered 20-oxo-compounds via Grignard derived enolates

Treatment of methyl 3β-acetoxy-16α,17α-dimethyl-5α-androst-9(11)-ene-l7-carboxylic acid (1), or 3β-hydroxy-16α,17α-dimethyl-5α-pregn-9(11)-en-20-one (4), with methylmagnesium halide in refluxing anisole gives the 20-yne (3). Similarly 3β-acetoxy-16α,17α-dimethylpregn-5-en-20-one (5) gives the 20-yne (6). The mechanism of the reaction is discussed in terms of the steric hindrance due to the 16- and 17-methyl groups. Acetylenes (3) and (6) are converted into compounds of potential pharmacological interest.

Amino-steroids. Part 6. Stereospecific syntheses of eight, isomeric, steroidal vicinal 2,3-amino-alcohols

The seven possible 3-amino-2-hydroxy and 2-amino-3-hydroxy isomers of the anti-arrhythmic steroid, 3α-amino-2β-hydroxy-5α-androstan-17-one, were prepared from 5α-androst-2-en-17-one. The intermediate 2α, 3α- and 2β,3β-epoxides and aziridines were cleaved to vicinal trans-diaxial amino- and azido-alcohols, which, in turn yielded the isomers by a series of functional group inversions and transformations.

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.

Rapid, efficient regeneration of steroidal ketones from thioacetals by periodic acid

Periodic acid smoothly regenerates a variety of steroidal ketones from their thioacetals at room temperature in common solvents and generally in high yield.

Alkylated steroids. Part 4. An unusual Favorskii rearrangement

Favorskii rearrangement of the mixed 17ξ-bromo-16α-methyl-20-oxo-5α-pregn-9(11)-en-3β-yl acetates (5) and (6)(9 : 1) gives methyl 3β-hydroxy-16α,17α-dimethyl-5α-androst-9(11)-ene-17-carboxylate (7) and methyl 3β-hydroxy-16α-methyl-5α-pregn-9(11)-en-21-oate (9) as the major components. Only a small amount of the isomeric 16α,17β-dimethyl-17-carboxylate (8) is formed. The structures of the esters (7) and (9) are confirmed by synthesis, and an explanation for the unexpected formation of (9) is advanced.