Robert Gibson Roy

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 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.