Ruth E. Lack

Steroids. Part XXVII. Modification of 14α-methyl group in 4,4,14α-trimethylsteroids

Lanost-8-enyl acetate has been converted via 3β-acetoxy-5α-lanostane-7,11-dione to 3β-acetoxy-7α-hydroxy-5α-lanostan-11-one which by the Barton reaction on the nitrite ester, followed by dehydration gave 3β-acetoxy-11-oxo-5α-lanost-8-en-14α-nitrile, which resisted hydrolysis to the corresponding acid. Lead tetra-acetate and iodine converted the 7α-hydroxy-11-ketone to the 7α-acetoxy-14α→ 7α-lactone and the 7α-acetoxy-7α,14α-ether. This ether was cleaved with pyridinium hydrochloride, which gave 3β-acetoxy-4,4-dimethyl-5α-cholest-8-en-11-one by rearrangement, together with the 3β,32-diacetoxy-11-oxo-5α-lanost-7-ene which was hydrolysed and oxidised to give the 4,4-dimethyl-5α-cholest-8-en-3,11-dione as the major product.

Steroids. Part XXXV. Removal of the 4-methyl groups in 4,4,14α-trimethyl-steroids: conversion of lanosterol into 14α-methylcholest-4-en-3-one

3,4-Seco-5α-lanost-4(30)-en-3-onitrile, obtained by ‘second-order’ Beckmann cleavage of 3-hydroxyimino-5α-lanostane, has been used as an intermediate in the conversion of lanosterol into 14α-methylcholest-4-en-3-one.

Steroids. Part XXXV. Preparation of the epimeric 2-hydroxy-19-nor-5α-cholestanes

2β,19-Epoxy-5α-cholestane, readily obtained from 5α-cholestan-2β-ol by treatment with lead tetra-acetate, on acetolysis with acetic anhydride catalysed by pyridinium hydrochloride or by boron trifluoride gave a variety of products, from which were derived 5α-cholestan-19-oic acids, 5α-cholest-1- and -2-en-19-aldehydes, and 5α-cholestan-19-ols. 2α-Acetoxy- and 2α-methoxy-5α-cholestan-19-oic acids resisted decarboxylation; the inseparable mixture of 5α-cholest-1- and-2-en-19-als when irradiated underwent decarbonylation to give 19-nor-5α-cholest-1-ene.An improved preparation of 19-nor-5α-cholest-1-ene from 5α-cholest-1-ene was devised. Conversion of the latter into 1α-bromo-5α-cholestan-2β-ol followed by treatment with lead tetra-acetate gave 1α-bromo-2β,19-epoxy-5α-cholestane. This was converted with zinc–ethanol into 5α-cholest-1-en-19-ol, which was oxidised to 5α-cholest-1-en-19-al with Jones reagent. Irradiation of this aldehyde gave 19-nor-5α-cholest-1-ene, converted by hydroboration (bis-3-methyl-2-butylborane) into 19-nor-5α-cholestan-2α-ol (56%), 19-nor-5α-cholestan-2β-ol (28%), and the isomeric 19-nor-1α-ol (4%) and 19-nor-1β-ol (12%), which were separated by column chromatography, followed by preparative t.l.c.

Intramolecular electrocyclic reactions. Part I. Structure of ‘bromohydroxyphorone’: 3-bromo-5-hydroxy-4,4,5,5-tetramethylcyclopent-2-enone

αα′-Dibromophorone (3,5-dibromo-2,6-dimethylhepta-2,5-dien-4-one) as the conjugate acid undergoes intramolecular electrocyclic addition to give 3-bromo-5-hydroxy-4,4,5,5-tetramethylcyclopent-2-enone. The reactions of this substance, its bromine-free analogue and their derivatives, recorded by Ingold and Shoppee in 1928, are clarified and reinterpreted.

Autoxidation of 2α-hydroxy-5α-cholestan-3-one in methanolic potassium hydroxide

2α-Acetoxy-5α-cholestan-3-one in methanolic potassium hydroxide or in an excess of methanolic potassium carbonate at 20° for 16 hours is converted into a mixture of the monomethyl esters of 2,3-seco-5α-cholestane-2,3-dicarboxylic acid. 5α-Cholestane-2,3-dione is isolated as an intermediate and is probably formed by autoxidation of 2α-hydroxy-5α-cholestan-3-one through 2-hydroperoxy-2-hydroxy-5α-cholestan-3-one.

Steroids. Part XXXIII. Attempted preparation of 19-nor-5α-cholestanes via 2β-hydroxy-5α-cholestan-19-oic acid

5α-Cholestan-2β-ol (I) and lead tetra-acetate–iodine with irradiation gave the 2β,19-epoxide (II)(10%) and the 2β,19-hemiacetal (III)(50%), which was oxidised to the 19 → 2β-lactone (IV). This, on hydrolysis gave the 2β-hydroxy-acid (VIa), whose methyl ester by oxidation afforded the 2-keto-ester (VIIb), which was hydrolysed to an equilibrium mixture of the 2-keto-acid and the lactol [(VIIa)⇌(IXa)], from which the 2-keto-acid chloride (VIIc) could not be obtained, the product being the chloro-lactone (IXc). Reduction with sodium borohydride of the 2-keto-ester (VIIb) gave the 2α-hydroxy-ester (X)(75%) and the 2β-hydroxy-ester (VIb). Attempted decarboxylation of the 2β-methoxy-acid (VIc) and of the equilibrium mixture (VIIa)⇌(IXa) was unsuccesful. Dehydration of the 2β-hydroxy-ester (VIb), or treatment of its toluene-p-sulphonate with refluxing s-colidine, gave a mixture of the Δ1- and Δ2-19-methyl esters represented by (XI), which resisted alkaline hydrolysis, but on reduction with lithium aluminium hydride gave a mixture of the Δ1- and Δ2-19-ols represented by (XII), which could be oxidised to a mixture of the related aldehydes. Structures assigned are supported by u.v., i.r., and n.m.r. spectroscopy.

Steroids. Part XXXI. Attempted modification of the 14α-methyl group in 4,4,14α-trimethyl steroids

5α-Lanost-8-en-3β-yl acetate was converted by way of 3β-acetoxy-5α-lanost-8-en-7-one into 3β-acetoxy-7α-hydroxy-5α-lanost-8-ene, which as the 7α-nitrite did not undergo the Barton reaction, and which with lead tetra-acetate–iodine gave 3β-acetoxy-5α-lanosta-7,9(11)-diene. 3β-Acetoxy-5α-lanost-9(11)-en-7-one, when hydrogenated over platinum in ethyl acetate–perchloric acid gave only 3β-acetoxy-5α-lanosta-7,9(11)-diene, whilst use of sodium borohydride yielded mainly 3β-acetoxy-7β-hydroxy-5α-lanost-9(11)-ene. Reductive cleavage of the 7β,8β-epoxide of 3β-acetoxy-5α-lanosta-7,9(11)-diene also yielded a 7β-hydroxy-5α-lanost-9(11)-ene; the 7α,8α-epoxide of 3β-acetoxy-5α-lanosta-7,9(11)-diene could not be prepared.

Steroids and Walden inversion. Part LX. Some reactions of the epimeric 5α-cholestan-1-ols and the solvolysis of their toluene-p-sulphonates

5α-Cholestan-1a-ol with phosphorus pentachloride or thionyl chloride gives a mixture of 5α-cholest-1-ene, 1β-methyl-19-norcholest-5(10)-ene, and 1β-methyl-19-nor-5α-cholest-9-ene, whilst solvolysis of 5α-cholestan-1α-yl toluene-p-sulphonate in buffered aqueous acetone at 65° gives a similar mixture of the same three olefins and some 5α-cholestan-1α-ol. 5α-Cholestan-1β-ol with the same reagents gives a single crystalline olefin, 9aζ A-nor-B-homo-19-norcholest-5(10)-ene, whilst solvolysis of 5α-cholestan-1β-yl toluene-p-sulphonate yields mainly the non-crystalline 9a-methylene-A-nor-B-homo-19-nor-5α-cholestane, and some 5α-cholestan-1β-ol.

The chemical shifts of protons γ to a halogen atom in steroids

The chemical shifts of protons γ to the halogen atoms in 3β-acetoxy-6β,19-epoxy-5α-halogenocholestane (IVb) and the 3β-hydroxy-derivatives (IVa; X = F, Cl, Br, or H) have been measured in dilute carbon tetrachloride solution. Dependence of chemical shift on the stereochemistry has been observed since the signal of one of the 19-methylene protons, which has a W stereochemistry with the halogen atom, shows a small increase in chemical shift with the electronegativity of the halogen atom whilst the other, broadened by long-range coupling with the 9α-proton, shows a downfield shift in the order Br = F > Cl > H and appears to be influenced more by anisotropy and field effects. The 3α-protons, which have a 1,3-diaxial stereochemistry, follow the order Br > Cl > F > H and appear to be mainly influenced by effects other than electronegativity.

19-Nor and aromatic steroids. Part 1. The cleavage of 3-oxygenated-2β,19-ethers in the cholestane series

Acetolysis of 2β,19-epoxy-5α-cholestan-3-one, catalysed by boron trifluoride, gave mainly 2α, 19-diacetoxy-5α-cholestan-3-one which was partially hydrolysed with methanolic sodium hydroxide at 20° for 10 min. to 19-acetoxy-2α-hydroxy-5α-cholestan-3-one which resisted dehydration. Acetolysis of 2β,19-epoxycholest-4-en-3-one with acetic anhydride and boron trifluoride was complicated by enolacetylation of the 3-carbonyl group and subsequent addition of acetic anhydride to the Δ-5 double bond: however, 4α-bromo-2β,19-epoxy-5α-cholestan-3-one was slowly cleaved with acetic anhydride and boron trifluoride to give only 2α,19-diacetoxy-4α-bromo-5α-cholestan-3-one which was readily converted by treatment with calcium carbonate in dimethylacetamide into 2α,19-diacetoxycholest-4-en-3-one; the latter compound was hydrolysed with methanolic hydrochloric acid to give 3-hydroxy-19-norcholesta-1,3,5(10)-triene.3α-Acetoxy-2β,19-epoxy-5α-cholestane was cleaved with boron trifluoride in acetic anhydride, probably involving an intermediate 2α,3α-acetoxonium ion, to give mainly 3α,19-diacetoxy-5α-cholestan-2α-ol which was readily dehydrated to 3α,19-diacetoxy-5α-cholest-1-ene; this was then hydrolysed, oxidised, and decarboxylated to give 19-nor-5α-cholest-1(10)-en-3-one.