C. W. Shoppee

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 XXXIV. 17β-Hydroxy-5β,14α,17α-pregnan-20-one and related compounds

5β,14α-Androstan-17-one was converted into the 17α-ethynyl derivative, which was hydrated to give 17β-hydroxy-5β,14α,17α-pregnan-20-one and its rearrangement product 17aα-hydroxy-17aβ-methyl-5β,14α-D-homoandrostan-17-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.

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.

Tetramethyl 2,2,4,4-tetramethoxycarbonylcyclobutane-1,3-dimalonate

The structure of the trans-1,3-dimalonate, named in the title, obtained in the self-condensation of methyl sodio-1,3-dicarboxyglutaconate with iodine, and of its cis-isomer have been established by n.m.r. spectroscopy.

Steroids and Walden inversion. Part LXV. Comparative experiments on the deamination of cis- and trans-4-t-butylcyclohexylamine

Deamination of trans-4-t-butylcyclohexylamine (NH2eq) in 50% acetic acid at 20° gives alcohols (63%) with 93% retention, and acetates (35%) with 73% retention; in acetic acid at 20° alcohols (42%) are formed with 95% retention, and acetates (52%) are formed with 78% retention. Very little elimination (2%, 6%) occurs. Deamination of cis-4-t-butylcyclohexylamine (NH2ax) in 50% acetic acid at 20° gives alcohols (35%) with only 54% retention, and acetates (18%) with only 41% retenion; in acetic acid at 20° alcohols (19%) are produced with 78% retention, whilst acetates (31%) are produced with only 44% retention. Considerable elimination (47% 50%) occurs.These results provide further evidence that the deamination is a complex reaction, greatly influenced by steric environment, and proceeding by a combination of SNi, SN2, and E2 mechanisms and mechanisms involving an intermediate solvated carbonium ion.

Steroids. Part XXIX. The structure of digacetigenin

Digacetigenin is shown to be 12β-acetoxy-3β,14β-dihydroxypregn-5-ene-15,20-dione, and has been converted into digacetigenone 3-acetate [3β-acetoxy-14β-hydroxypregn-5-ene-12,15,20-trone], also obtained from purprogenin [3β,14β,15α-trihydroxypregn-5-ene-12,20-dione]. Mass spectra of digacetigenin and its 3-acetate show that the compound, previously regarded as homogeneous, contains some 5α,6-dihydrodigacetigenin, from which it cannot be separated by thin-layer chromatography on alumina or on silica; re-examination of the nuclear magnetic resonance spectrum of digacetigenin and comparison with that of 5α,6-dihydrodigacetigenin shows that the proportion of the latter is 20–25%.