John M. Midgley

Unsaturated steroids. Part 6. A route to cholesta-5,7-diene-1α,3β-diol; preparation of steroidal 4,6,8(14)-trienes

Bromination of 5α-cholest-7-en-3-one to give the corresponding 2ζ,4ζ-dibromo-derivative followed by dehydro-bromination gives cholesta-1,4,7-trien-3-one (3). The corresponding cholesta-1,3,5,7-tetraen-3-yl acetate (4) was converted by the method of Kaneko et al. into the adduct of cholesta-1,5,7-trien-3β-ol with 4-phenyl-1,2,4-triazoline-3,5-dione. The corresponding dimethyl-t-butylsilyl ether was transformed into the 1α,2α-epoxide, which was readily converted into cholesta-5,7-diene-1α,3β-diol (8). Treatment of the adduct from a steroidal 5,7-dien-3-one and 4-phenyl-1,2,4-triazoline-3,5-dione with boron trifluoride–ether yields the corresponding 4,6,8(14)-trien-3-one (10).

Unsaturated steroids. Part 12. Synthesis of 1α,3β-dihydroxy-24-nor-9,10-secochola-5,7,10(19)trien-23-oic (calcitroic) acid and of the cholic-and 25-homocholic acid analogues

The three title compounds have been synthesized by the same general method. Thus, methyl 3β-hydroxy-24-nor-5α-chol-7-en-23-oate (3; R = CO2Me), derived from 3β-acetoxypregn-7-ene-22-carbaldehyde (2), gave methyl 3-oxo-24-nor-5α-chol-7-en-23-oate (4; R = H,R′= CH3). Bromination of this to the 2ξ,4ξ-dibromo derivative (4; R = Br, R′= Me) followed by dehydrobromination formed the corresponding 1,4,7-triene-3-one (5). The corresponding enol acetate (6) was reduced to the 1,5,7-triene (7) which was converted into the adduct (8; R = H) with 4-phenyl-1,2,4-triazoline-3,5-dione; the 3β-dimethyl-t-butylsilyl ether of (8;R = H)gave the 1α,2α-epoxide(9; R = Me2ButSi). Removal of the silyl ether group with acid, and then of the triazoline residue with pyridine–1,5-diazabicyclo[4.3.0] non-5-ene gave methyl 3β-hydroxy-1α,2α-epoxy-24-norchola-5,7-dien-23-oate (10; R = Me). Reduction of the corresponding acid (10; R = H) gave 1α,3β-dihydroxy-24-norchola-5,7-dien-23-oic acid (11; R = H). Photolysis/thermolysis of the corresponding methyl ester (11; R = Me) followed by saponification gave 1α,3β-dihydroxy-24-nor-9,10-secochola-5,7,10(19)trien-23-oic acid (calcitroic acid)(1; R = H, n= 1). The analogous cholic (1; R = H, n= 2) and 25-homocholic acid (1; R = H, n= 3) derivatives were similarly synthesized.

Unsaturated steroids. Part 3. Synthesis of steroidal 22,24(28)-dienes, ergosta-5,7,22,24(28)-tetraen-3β-ol, and cholesta-5,7,22-trien-3β-ol

Dehydrobromination of 22,23-dibromo-5β-ergostane with 1,5-diazabicyclo[3.4.0]non-5-ene (DBN) gives 5β-ergosta-22,24(28)-diene (3). This structure has been confirmed by partial synthesis.Ergosteryl acetate is readily regenerated from its adduct (8) with 4-phenyl-1,2,4-triazoline-3,5-dione by the action of warm DBN. The adduct reacts with bromine to yield the 22,23-dibromo-derivative, which forms ergosta-5,7,22,24(28)-tetraen-3β-ol (7) directly, in high yield, when heated with DBN.The structure (9)(cholesta-5,7,22-trien-3β-ol) assigned to a metabolite of the protozoan, Tetrahymena pyriformis, has been confirmed by partial synthesis from stigmasterol.

Conformational studies. Part 8. Crystal and molecular structure of 17β-iodoacetoxy-4,4-dimethylandrostan-5-en-3-one

Crystals of the title complex (2) are monoclinic, space group P21, a= 6.394(2), b= 11.303(4), c= 15.566(4)A, β= 92.92(2)°, Z= 2. The structure has been refined by full-matrix least-squares calculations to a final R of 0.046 for 1 065 observed reflections. The conformations of the rings are: A, skewed boat; B, half-chair; C, chari; and D, half-chair distroted towards a C(13) envelope.

Conformational studies. Part 7. Crystal and molecular structure of 17β-bromoacetoxy-19-nor-5α-androstan-3-one and 17β-bromoacetoxy-5α-androstan-3-one

The crystal and molecular structures of the title compounds have been determined by X-ray crystallography. Whereas the 19-nor-derivative (1) C20H29BrO3, crystallises in the orthorhombic system, space group P212121 with Z= 4 in a unit cell of dimensions a= 6.134(1), b= 12.580(2), and c= 25.297(3)A, the other (2) C21H31BrO3, crystallises in the monoclinic space group P21 with Z= 2 in a unit cell a= 12.972(2), b= 7.321(1), c= 10.580(2)A, β= 99.71(1)°. Both structures were solved by the heavy-atom method and refined by full-matrix least-squares calculations from three-dimensional diffractometer data, to R 0.961 for 1 057 reflections (1), and R 0.042 for 1 075 reflections (2). The conformation of ring A in both molecules is affected by intramolecular packing effects. Ring A in (1) is abnormally flattened whereas in (2) it is more puckered than expected. Bond lengths and angles are normal.

Conformational studies. Part 10. Crystal and molecular structure of 17β-iodoacetoxy-4,4-dimethyl-5α-androst-7-en-3-one

The crystal and molecular structure of the title compound, (2), C23H33O3I, has been determined by single-crystal X-ray techniques. Crystals are trigonal, space group P32, with six molecules per unit cell (two independent molecules per asymmetric unit) of dimensions a= 22.982(3) and c= 7.547(1)A. The structure was solved by the heavy-atom method and refined by least-squares calculations to R 0.064 for 1 686 observed reflections. The steroid frameworks of both molecules have essentially the same conformations, the only differences being in the orientations of the 17β-iodoacetoxy-side-chains. Ring A of the steroid skeleton has a very flattened chair conformation, ring B is a distorted half-chair, ring C a flattened chair, and ring D a distorted envelope.

Unsaturated steroids. Part 2. A novel route to anthrasteroids: X-ray crystal structure of 1(10 → 6)abeo-cholesta-5,7,9-trien-3-yl p-bromobenzoate

Treatment of the adduct from a steroidal 5,7-diene and 4-phenyl-1,2,4-triazoline-3,5-dione with boron trifluoride–diethyl ether gives the corresponding anthrasteroid. The structure of the product derived from cholesta-5,7-dien-3β-ol has been determined by X-ray crystallography. Oxidation of the anthrasteroid with the Moffat reagent furnishes the corresponding 3-ketone, which can be dehydrogenated with tri-N-methylanilinium perbromide to the corresponding naphthol. The various anthrasteroids are oxidised by dichlorodicyano-1,4-benzoquinone to the corresponding 14-enes.

Conformational studies. Part 2. Synthesis of 17β-hydroxy-4,4-dimethyl-5α-androstan-3-one, and of the 19-nor-analogue

Prepared from 17β-hydroxy-5α-androstan-3-one by C-4 methylation of 17β-(tetrahydropyran-2-yloxy)-2,2-trimethylenedithio-5α-androstan-3-one, 17β-hydroxy-4,4,dimethyl-5α-androstan-3-one (1; R1= Me, R2= H), exhibited a negative o.r.d. curve, and was identical with the hydrogenation product of 17β-hydroxy-4,4-dimethyl-androst-5-en-3-one (2; R1= Me, R2= H). 17β-Hydroxy-4,4-dimethyl-19-nor-5α-androstan-3-one (1; R1= R2= H) was similarly synthesised from 17β-hydroxy-19-nor-5α-androstan-3-one and also had a negntive o.r.d. curve. However, contrary to previous reports, hydrogenation of 17β-hydroxy-4,4-dimethyl-19-nor-androst-5-en-3-one (2; R1= R2= H) did not furnish the androstane (1; R1= R2= H) but a mixture of (1; R1= R2= H) and the 5β-diastereoisomer which was difficult to separate; both these products exhibit negative o.r.d. curves. The physical constants of various cognate derivatives of (1; R1= R2= H), reported values of which are probably those of mixtures, have been clarified. B-Nortestosterone has been converted into 17β-hydroxy-4,4-dimethyl-B-nor-5α-androstan-3-one. The preparation of various steroidal 2-butylthiomethylene-3-ones is reported.

Conformational studies. Part 5. Functionalisation of methyl groups in 4,4-dimethyl steroids

Hydroboration of 3,3-ethylenedioxy-4,4-dimethylandrost-5-ene (6; R1= Me, R2= H2) gave (a) the 5α-androstan-6α-ol (9; R1= Me, R2= H), (b) the 5β-androstan-6β-ol (10; R1= Me, R2= H), and (c) the 5α-androstan-7α-ol (7). Oxidation of 3,3-ethylenedioxy-4,4-dimethyl-5α-androstan-6α-ol (9; R1= Me, R2= H) furnished the 5α-6-ketone (12; R = Me), which on reduction with lithium aluminium hydride gave the 6β-ol (11; R1= Me, R2= H). Oxidation of 3,3-ethylenedioxy-4,4-dimethyl-5β-androstan-6β-ol (10; R1= Me, R2= H) afforded the corresponding 5β-6-ketone (13). Deacetalisation of (12; R = Me) and of (13) gave 4,4-dimethyl-5α-androstane-3,6-dione (15; R = Me) and 4,4-dimethyl-5β-androstane-3,6-dione (16), respectively, which were interconverted by acid.Oxidation of 3,3-ethylenedioxy-4,4-dimethyl-5α-androstan-7α-ol (7) gave the 7-ketone (17), which was also synthesised from 3,3-ethylenedioxy-4,4-dimethylandrost-5-ene (6; R1= Me, R2= H2) as starting material.3,3-Ethylenedioxy-4,4-dimethyl-19-norandrost-5-ene (6; R1= H, R2= H2) was hydroborated to afford the 19-nor-5α-androstan-6α-ol (9; R1= R2= H) in high yield; this alcohol was oxidised to the 5α-6-ketone (12; R = H), reduction of which gave the corresponding 6β-ol (11; R1= R2= H).The nitrites of 6α- and 6β-hydroxy-3,3-ethylenedioxy-4,4-dimethyl-5α-androstane, of 4,4-dimethyl-3-oxo-5α-androstan-6α-ol, of 6α- and 6β-hydroxy-3,3-ethylenedioxy-4,4-dimethyl-19-nor-5α-androstane, and of 6α- and 6β-hydroxy-4,4-dimethyl-3-oxo-19-nor-5α-androstane were irradiated (u.v.) and the products characterised. The results are interpreted in terms of the conformations of the substrates.

Unsaturated steroids. Part 5. Synthesis of 4α-methylcholest-8(9)-en-3β-ol

4α-Methylcholest-8(9)-en-3β-ol (1) has been synthesised from 5α-cholest-8-en-3-one by way of 2,2-trimethylenedithio-5α-cholest-8-en-3-one (4; R = H) and the corresponding 4α-methyl derivative (4; R = Me). Alternatively 5α-cholesta-8,14-dien-3-one (5; R = H2) was converted into the 2,2-trimethylenedithio-derivative (8; R = H), which was monomethylated at C-4. Removal from this 4-methyl compound of the dithio-substituent and subsequent hydrogenation of the 14(15)-double bond gave 4α-methylcholest-8(9)-en-3β-(and 3α-) ol.