A stereoselective and synthetically useful rearrangement reaction of 5alpha,8alpha-bridged 9,11alpha-epoxy steroids induced by boron trifluoride-diethyl ether is presented, in the preparation of a new class of 5alpha,9alpha-bridged 11alpha-hydroxy steroid derivatives in high yields. Lactones were prepared from several of the rearranged 11alpha-hydroxy compounds. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

The crystal structure of 14-oxo-13, 14-seco-5 alpha-cholest-13(18)-en-3 beta-yl acetate (2), obtained (ind addition to the (E)-Delta(12)-isomer 3) by oxidative fragmentation of the C(13)-C(14) bond of 14 alpha-hydroxy-5 alpha-cholestan-3 beta-yl acetate (1), was determined by X-ray analysis. In addition, the configurations of the acetoxy derivatives 4-6, formed by the thermal lead tetraacetate oxidation of 1, were deduced from the relevant H-1-NMR parameters.

The thermal and acid-catalyzed intramolecular rearrangement of the (Z)- and (E)-cyclodecene-1,4-dione compounds deriving from steroids, 2a,b and 3a,b, respectively, proceeds stereoselectively to give the corresponding configurationally different spiro-γ-lactone derivatives, the (5R,9R)-isomers 4a,b (from the (Z)-cyclodecenediones 2a,b) and the (5R,9S)-isomers 5a,b (from the (E)-cyclodecenediones 3a,b). The semiempirical MNDOAM1 and PM3 molecular orbital methods were applied to elucidate the possible mechanistic pathway of the observed intramolecular process leading to the spiro-γ-lactone structures.

The olefinic double bond in 17-oxo steroids 1, 5 and 7 is either reduced with diimide very slowly (compound 1) or it cannot be reduced at all (compounds 5 and 7), thus enabling hydrazine (accumulated by disproportionation of the diimide) to react with their respective 17-oxo groups to give hydrazones 3, 6 and 8.

A convenient synthesis (in seven steps) of the 14 alpha-hydroxy-5 alpha-cholestan-3 beta-yl acetate (8, Scheme 2) is described. The synthesis starts from cholesteryl acetate (1) and involves the following transformations: (i) bromination/dehydrobromination of cholesteryl acetate (1); (ii) partial hydrogenation of the Delta(5)-bond in the obtained 7-dehydrocholesteryl acetate (2); (iii) migration of the Delta(7)-double bond in the thus formed compound 3 to the Delta(8(14))-position; (iv) isomerisation of the Delta(8(14))-unsaturated product 4 to the Delta(14)-analogue 5 (v) epoxidation of the Delta(14)-bond in 5; (vi) lithium aluminium hydride reduction of the 14 alpha,15 alpha-epoxide 6; and (vii) partial acetylation of the 3 beta-hydroxyl function in the obtained diol 7 producing the final product 8. The total yield of the synthesis is ca. 18%.

The thermal and acid-catalyzed intramolecular rearrangement of the (Z)- and (E)-cyclodecene-1,4-dione compounds derived from steroids, 2a,b and 3a,b, respectively, proceeds stereoselectively to give the corresponding configurationally different spiro-gamma-lactone derivatives, the (5R,9R)-isomers 4a,b (from the (Z)-cyclodecenediones 2a,b) and the (5R, 9S)-isomers 5a,b (from the (E)-cyclodecenediones 3a,b). A possible mechanistic pathway of the observed intramolecular process leading to the spiro-gamma-lactone structures is discussed.

The two structurally similar 20-phenyl- and 20-(4-methoxyphenyl)-11-(nitrosooxy)pregnan-20-ol derivatives 4 and 7 behave differently under photolytic conditions, the former nitrous acid ester affording, as a main product, the benzo-fused hexacyclic compound 9, and the latter the 21-nitro derivative 12. Mechanistic aspects of these transformations are discussed.

transformation of (Z)- and (E)-5,10-secosteroidal alpha,beta-unsaturated oximes (2 and 3) with hydroxylamine hydrochloride to the corresponding dioximes 4 and 5 is reported and possible mechanistic pathways are discussed.

The structures 9 and 8 are proposed for the single isolated irradiation product of 5-oxo-5,10-secocholest-1(10)-en-3 beta-yl acetate (6) [2] and for the minor product of irradiation of 5-oxo-5,10-secocholest-1(10)-en-3 gamma-yl acetate (1) [3], respectively. These compounds are formed in an alternative reaction with respect to the originally observed intramolecular Paterno-Buchi photoprocess (transformation of 1 to oxetane 2). The formerly postulated 'active' conformations for 1 and 6 still allow explanation of their generation.

Upon heating in AcOH, the stereoisomeric (Z)- and (R)-6,9-dioxocyclodex-3-enyl derivatives, 5 and 6, respectively, obtained by HgO/I-2 oxidation of 5-hydroxy-8-oxo-8,14-seco-5 alpha-androstane-3 beta,17 beta-diyl diacetate (3), undergo an unusual intramolecular rearrangement to give the corresponding unsaturated (5R,9R)- and (5R,9S)-spiro-lactones 7 and 8, respectively. Hydroxylation of the C=C bond in 7 and 8, and subsequent glycol cleavage of the resulting diols 9 and 10 afforded the epimeric spiro-lactones (5R,9S)-11 and (5R,9R)-14, respectively,and in both cases, the ring-D-containing fragments 12 and 13.

Photochemically induced HgO/I-2 oxidation of cholest-5-en-3 alpha-ol (6) and cholest-5-en-3 beta-ol (7) afforded (Scheme 3) products arising from the corresponding alkoxy radicals (12, 13 and 14a,b) and from attack of the I2O intermediate at the olefinic double bond (epoxides 15a and 16a,b, respectively). With cholest-5-ene-1 alpha,3 beta-diol 3-acetate (8) and cholest-7-ene-3 beta,5 alpha-diol 3-acetate (9) the HgO/I-2 oxidation led to unresolvable complex mixtures (Sheme 5). With the same reagent cholest-5-en-3 alpha-ol acetate (10) and cholest-5-en-3 beta-ol acetate (11) underwent exclusively attack by I2O, to give epoxides 20a,b, iodohydrin 21, and rearranged products 19 and 22 (Scheme 7), in the case of 10, and predominantly epoxides 23a,b (Scheme 8), in the case of 11.

The Grignard reaction of 11 beta-hydroxy-3,3-(ethylenedioxy)-pregn-5-en-20-one (1) affords both epimers (20R) (2) and (20S) (3) of the hydroxy derivative. The configuration R at C20 is established for the predominant epimer by the determination of the X-ray structure of the deketalized analog 4. C27H36O3, M(r)=408.58, orthorhombic, P2(1)2(1)2(1), a = 30.009(11), b = 6.323(1), c = 12.182(9)Angstrom, V = 2312(2)Angstrom(3), Z=4,D-x=1.17 g.cm(-3), CuK alpha radiation (lambda = 1.5418 Angstrom). The final R indice is 0.079 for 2058 observed reflections.

The molecular structure of the title compound, which might be a possible intermediate in the synthesis of 5,10:8,9-diseco-steroids (=steroklastanes), was determined by X-ray analysis. Hydrogen bonding between the 5alpha-hydroxyl group and the 9-oxo function attached to the ten-membered ring, and the presence of two conformational forms of the side-chain in the solid state structure of 2 are established.

the molecular structure of the title compound, a 15-membered 9,10-epoxy-3-en-4-ol lactone, which is an important intermediate in the reaction sequence correlating steroid compounds with prostaglandin-like derivatives, was determined by X-ray analysis. The (E) stereochemistry around the double bond and the trans-(9R,10R)-configuration at the oxirane ring are established.

The molecular structure of the title compound, a steroidal isoxazolidine derivative, which is formed by transannular nitrone 1,3-dipolar cycloaddition in the reaction of (Z)-3beta-acetoxy-5,10-secocholest-1(10)-en-5-one with N-methylhydroxylamine, was determined by X-ray analysis, confirming the 1(2)-position of the double bond and the presence of a cis-3beta,5beta-epoxyimino bridge.

Catalytic hydrogenation of the DELTA-3-unsaturated (9R, 10R)- and (9S, 10S)-epoxyenol lactones 3a,b and 4a,b. respectively, affords, in addition to the expected saturated epoxylactones 5a, b and 7a, b, also open-chain products. i.e. the diastereoisomeric (9R, 10R)- and (9S, 10S)-9,10-epoxy-8-oxo-4,5-secosteroklastan-5-oic acids 6a, b and 8a, b. Alkaline hydrolysis of the lactone ring of compounds 5 and 7 and subsequent acetylation of the corresponding hydroxy derivatives give as the major products the open-chain, diastereoisomeric (9R, 10R)- and (9S, 10S)-4-acetoxy-9,10-epoxy-methyl esters 9a, b and 11a, b, respectively, and, but only in the androstane series, the tetrahydropyran derivatives 10a and 12a, as the minor components.

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Oxidative hydrolysis of N-methyl-1beta,5-epoxyimino-19-nor-5beta-androst-3-en-17beta-ol acetate 1 afforded the title compound 2, the molecular structure of which was determined by the X-ray diffraction technique. 2 : C20H26O3, Mr=314.42, orthorhombic, P2(1)2(1)2(1), a=9.636(3), b=11.307(5), c=16.099(5)angstrom, V=1754(1)angstrom3, Z=4, Dx=1.19g.cm-3, MoKalpha, lambda=0.71069angstrom, mu=0.84cm-1, F(000)=680, T=291K, R=0.060 for 1211 observed reflections. Ring A is slightly non planar, ring B is a half-chair and ring C a chair. The 5-membered ring D has a regular half-chair conformation.

Treatment of steroidal isoxazolidines 3a, 3b and 5b with N-methylhydroxylamine hydrochloride in boiling ethanol-pyridine (1:1) solution results in elimination of the CH3NH2fragment, affording products of oxidative hydrolysis 4a, 4b, and 6b, while acid-catalyzed reaction of isoxazolidines 2a, 3a and 5b leads to rearrangement involving the N-CH3 group with formation of the perhydro-3,1-oxazine derivatives 8a, 9a and 10b.

UV irradiation of the unsaturated (E)-5,10-secosteroidal ketones 1 and 6 results, in addition to (E/Z)-isomerization, in an intramolecular Paterno-Buchi reaction and, in the case of 1, in transannular cyclization (along with AcOH elimination). The stereochemistry of the observed intramolecular photoprocesses can be explained in terms of ground-state conformations of the (E)-seco-ketones 1 and 6 in solution.