Donald Stevenson

Synthesis of (E)- and (Z)-pulvinones

Two new routes to pulvinones have been developed, one of which involves a novel Wittig reaction. For the first time, members of the E-series, including the parent (E)-pulvinone, are reported and the structural elucidation of the geometric isomers is described. A method for quantitatively converting (E)-pulvinones into (Z)-pulvinones is presented, together with a technique for differentiating between the isomers.

Novel water soluble 2,6-dimethoxyphenyl ester derivatives with intravenous anaesthetic activity.

A number of water soluble bis-amino-2,6-dimethoxyphenyl ester derivatives were found to exhibit improved anaesthetic activity in mice relative to propofol 1. Of the analogues disclosed, 44 was further profiled in rodents and found to be a superior agent to propofol for the induction and maintenance of anaesthesia.

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.

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.

Novel α-amino-acid phenolic ester derivatives with intravenous anaesthetic activity

A novel series of α-amino-acid phenolic ester derivatives containing sulphide, sulphoxide, sulphone, ester and amide side chains were prepared and shown to display potent intravenous anaesthetic activity.