Gilbert F. Woods

Specificities of antisera against estrogens linked to albumin at different positions (c6, c11, c16, c17)

Antisera were raised in rabbits using conjugates of albumin with 11-hemisuccinates of 11α-OH E1 and 11α-OH E2. These antisera were compared with antisera to 6-oxo E2 6-CMO-, E2 17-succinyl- and E3 16, 17-disuccinyl-BSA by radioimmunoassay using a statistically designed three-point assay. Sheep anti-(rabbit γ-globulin) coupled to cellulose was used for the separation of antibody-bound and free labeled hapten. Antisera obtained with haptens linked to the carrier at the 17(16) position poorly discriminated between the various estrogens. Antisera obtained with 6- and 11-conjugates showed a much better specificity. In addition the specificity was influenced by using either estrone, estradiol or estriol as tritiated labels. This gives the possibility to determine different parameters by employing different labeled hormones.

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.

18-Norpregna-8,11,13-trienes. Part 2. Preparation from 17β-methyl-17α-pregn-13-enes

17,17-Dimethyl-18-nor-5β-androsta-8,11,13-trien-3α-yl acetate (6) has been prepared from 9α,11α-epoxy-17α-methyl-5β-androstane-3α,17β-diol 3-acetate (5) in good yield. An attempt to repeat the aromatisation with the analogous 9α,11α-epoxy-5β-pregnane-3α,17α,20β-triol 3,20-diacetate (10) did not give the expected product. However, a number of ring-C-aromatic pregnanes have been successfully prepared from derivatives of 5β-preganane-3α,11β,17α,20β-tetraol (21). Attempts to aminate some of these aromatic pregnanes at the 3- and 20-positions are described.

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.

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.

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).

Cyclisation studies of O-benzylhydroxyguanidines: synthesis of N-hydroxyimidazolines and N-hydroxypyrimidones

Two new classes of N-hydroxy heterocycles, N-hydroxy-2-imidazolines and N-hydroxypyrimidones, were synthesized by chemoselective intramolecular cyclisations.

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.