Conformations of the Ten-membered Ring in 5, 10-Secosteroids. III: (Z)-3β- and (Z)-3α-Hydroxy-5, 10-seco-1 (10)-cholesten-5-one Esters and (Z)-5, 10-seco-1 (10)-Cholestene-3, 5-dione

(Z)-3β-Acetoxy- and (Z)-3 α-acetoxy-5, 10-seco-1 (10)-cholesten-5-one ( 6a ) and ( 7a ) were synthesized by fragmentation of 3β-acetoxy-5α-cholestan-5-ol ( 1 ) and 3α-acetoxy-5β-cholestan-5-ol ( 2 ), respectively, using in both cases the hypoiodite reaction (the lead tetraacetate/iodine version). The 3β-acetate 6a was further transformed, via the 3β-alcohol 6d to the corresponding (Z)-3β-p-bromobenzoate ester 6b and to (Z)-5, 10-seco-1 (10)-cholestene-3, 5-dione ( 8 ) (also obtainable from the 3α-acetate 7a ). The ¹H-and ¹³C-NMR. spectra showed that the (Z)-unsaturated 10-membered ring in all three compounds ( 6a , 7a and 8 ) exists in toluene, in only one conformation of type C ₁, the same as that of the (Z)-3β-p-bromobenzoate 6b in the solid state found by X-ray analysis. The unfavourable relative spatial factors (interdistance and mutual orientation) of the active centres in conformations of type C ₁ are responsible for the absence of intramolecular cyclizations in the (Z)-ketoesters 6 and 7 ( a and c ).     

5α-androstano [3,2-b]pyridines, 5α-androstano[17,16-b]pyridines and androst-4 and 5-eno[17,16-b]pyridines

A new synthesis of 5α-androstano[3,2-b]pyridin-17β-ol acetate (VIa) and 17-methyl-5α-androstano[3,2-b]pyridin-17β-ol (VIb), first reported by Shimizu, Ohta, Ueno, and Takegoshi, was achieved. The analogous 5α - androstano[17,16-b]pyridin-3β-ol (XII), 5α-androstano[17,16-b]pyridin-3-one (XIVa), and androst-4-eno[17,16-b]pyridin-3-one (XIVb) were also prepared. An illustration of the method follows. Condensation of 3β-hydroxy-5α-androstan-17-one (VIIa) with 3-(2-furyl)acrolein afforded 16-[3-(2-furyl)-2-propenylidene]-3β-hydroxy-5α-androstan-17-one (VIIIa), the oxime (IXa) of which was thermally cyclized to 5α-androstano[17,16-b]-6′-(2-furyl)pyridin-3β-ol (Xa). 3β-Hydroxy-5α-androstano[17,16-b]pyridine-6′-carboxylic acid (XI) was obtained by ozonolysis of Xa. Thermal decarboxylation of XI gave XII. Cinnamaldehyde was used in place of 3-(2-furyl)acrolein to give the corresponding phenylpyridines.     

Photochemical Rearrangement of a Steroidal α,β-Epoxylactone. Photochemical reactions,XI [1]

The UV. irradiation of 17β-acetoxy-4α, 5α-epoxy-2-oxaandrostan-3-one ( 7 ) yields 17β-acetoxy-2-oxa-10(5 → 4)abeo-4ζ (H)-androsta-3,5-dione ( 11 ). A non-photochemical synthesis of 11 , proceeding in lower yield, is also described.     

Oxetane from A-nor-steroides: 2-alpha, 5-oxido-A-nor-5-alpha-cholestane, 2-beta, 5-oxido-A-nor-5-beta-cholestane and 2-alpha-ethyl-2-beta,2'-oxido-A-nor-5-alpha-cholestane

Treatment of 2β-tosyloxy-A-nor-5α-cholestane-5-ol ( 2 ) with t-butoxide in t-butanol gave 2α, 5-epoxy-A-nor-5α-cholestane ( 3 ) in quantitative yield. When A-nor-5β-cholestane-2α, 5-diol ( 4 ) was treated with tosyl chloride in pyridine 2β-chloro-A-nor-5β-cholestane-5-ol ( 7 ) and 2α-tosyloxy-A-nor-5β-cholestane-5-ol ( 8 ) were obtained. Whereas the chloride 7 was resistant to t-butoxide the tosylate 8 was transformed into an 1 : 1 mixture of 2α, 5-epoxy-5β-cholestane ( 10 ) and 2ξ-t-butoxy-A-nor-5β-cholestane-5-ol ( 11 ). In 2α-tosyloxy-A-nor-5α-cholestane-5-ol ( 12 ) substitution occurred as the only reaction. Both oxetanes 3 and 10 isomerize after heating above 50° and in polar or protic solvents to form A-nor-Δ³⁽⁵⁾-cholestene-2α-ol ( 6 ) and -2β-ol ( 14 ) respectively. Also, 2, 5-diols are encountered. 2α-Ethyl-2β, 2′-epoxy-A-nor-5α-cholestane ( 23 ) was synthesized starting from A-nor-5α-cholestane-2-one ( 17 ). The intermediates were the ester 16 , the diol 18 , the hydroxy-tosylate 19 and the chlorhydrin 20 . The spirocyclic oxetane 23 was reduced by LiAlH₄ in dioxane (not in ether). By chromatography on silica gel 23 was isomerized to the homoallylic alcohol 21 and transformed into 2-methylene-A-nor-5α-cholestane ( 24 ) by fragmentation. The IR. and NMR. spectra of the new oxetanes were compared with those of a series of known oxetanes.     

The Crystal and Molecular Structure of 3-Oxo-17β-acetoxy-Δ4-14α-methyl-8α, 9β, 10α, 13α-estrene

The crystal and molecular structure of 3-oxo-17β-acetoxy-Δ⁴-14α-methyl-8α, 9β, 10α, 13α-estrene, C₂₁H₃₀O₃, has been determined by X-ray diffraction analysis. The crystals belong to the orthorhombic space group P2₁2₁2₁, with the cell dimensions a = 12.093 Å, b = 19.667 Å, c = 7.746 Å; Z = 4. Intensity data were collected at room temperature with an automatic four-circle diffractometer. The structure was solved by direct methods and the parameters were refined by least-squares analysis. All the hydrogen atoms were included in the refinement. The final R value was 0.038 for 1413 observed reflections. The conformation of ring A is intermediate between a half-chair and a 1, 2-diplanar form. The hydrogens at C(9) and C(10) are anti, the B/C ring junction is trans, and rings B and C adopt chair conformations. Ring D is cis fused and is halfway between C₂ and C_s forms.     

Dissimilar behaviour of 3β, 16α-dihydroxy-5α-androstan-17-one Diacetate under Basic and Acidic Conditions

The base-catalysed rearrangement of 3β, 16α-dihydroxy-5α-androstan-17-one diacetate ( 1 ) in (D₆)benzene/ CD₃OD to 3β, 17β-dihydroxy-5α-androstan-16-one ( 3 ) is followed by ¹³C-NMR spectroscopy. By the same procedure, it is determined that in (D₆)benzene/CD₃OD, but under acid catalysis, 1 does not rearrange to 3 but yields the intermediate product 3β, 16α-dihydroxy-5α -androstan-17-one 17α -methyl hemiacetal ( 5 ).     

Synthese von 5-Methyl-3-oxa-A-nor-5β-cholestan und 3-Oxa-Δ4-cholesten-2-on

2, 3-seco-Δ⁴-Cholestene-2, 3-dicarboxylic acid ( 5 ) was prepared in 30% yield from 2-hydroxymethylene-Δ⁴-cholestene-3-one ( 1 ) by ozonolysis under special conditions. Pyrolysis of the pure di-acid 5 gave A-nor-Δ³⁽⁵⁾-cholestene-2-one ( 6 ), the anhydride 2 and 5-methyl-3-oxa-A-nor-5β-cholestane-2-one ( 8 ). Pyrolysis of amorphous acidic material obtained by the ozonolysis of 1 yielded the enol-lactones 7 and 9 as additional products. LiA1H₄-reduction of the γ-lactone 8 gave the diol 10 , which was transformed into 5-methyl-3-oxa-A-nor-5β-cholestane ( 13 ) by treatment with tosyl chloride in pyridine.     

Totalsynthese von Steroiden. 1. Mitteilung. rac-17β-Hydroxydes-A-androst-9-en-5-on

In connection with earlier work on the synthesis of 9β, 10α-steroids, a new and practical synthesis of rac-17α-hydroxy-des-A-androst-9-en-5-one ( 19 ) has been developed, based on a novel stereoselective condensation of 7-hydroxy-1-nonen-3-one ( 3 ) with 2-methyl-cyclopentane-1, 3-dione ( 9 ) and subsequent transformations of the resulting tricyclic diene ether 12 .     

Synthese von 4-[3β, 14-Dihydroxy-5β, 14β-androstan-17β-yl]-3-pyrrolin-2-on (Hothesimogenin). Partialsynthetische Versuche in der Reihe der Herzgifte, 11. Mitteilung

Synthesis of 4-[3β, 14-Dihydroxy-5β, 14β-androstan-17β-yl]-3-pyrrolin-2-one (hothesimogenin) We describe the synthesis of 4-[3β, 14-Dihydroxy-5β, 14β-androstan-17β-yl]-3-pyrrolin-2-one (24-aza-24-desoxa-digitoxigenin) (7) , starting from 3-O-acetyl-digitoxigenin (1) .     

9, 10-Secocholesta-(5Z)-5,8(14), 10(19)-trien-3β-ol und 18-Nor-14β-methyl-9,10-secocholesta-(5E)-5, 10(19), 13(17)-trien-3β-ol,zwei neue Doppelbindungsisomere des Vitamins D3. Strukturelle Abwandlungen am Vitamin D3: 5. Mitteilung [1]

9,10-Secocholesta-(5 Z )-5,8(14),10(19)-triene-3β-ol and 18-Nor-14β-methyl-9,10-secocholesta-(5 E )-5,10(19), 13(17)-trien-3β-ol, two new double bond isomers of vitamin D₃ . Structural modifications of vitamin D₃: 5. Communication [1] The present paper reports the synthesis and structure elucidation of the two title compounds. Treatment of the 4-phenyl-1,2,4-triazolin-3,5-dione adducts of vitamin D₃ with BF₃O (C₂H₅)₂ and KOH/butanol yields these two new vitamin D₃ double bond isomers.     

Steroidal quinoxalines

The treatment of 3β-hydroxy-16α-bromo-5α-androstan-17-one, 3β-acetoxy-16α-bromo-5-androsten-17-one and 21-bromo-5-pregnen-3β-ol-20-one with 4,5-dimethyl-o-phenylenediamine gave substituted quinoxalines. Hydrolysis of 3β-acetoxy-5-androsteno[16,17-b]-6′,7′-dimethylquinoxaline produced the corresponding 3β-hydroxy compound. 3-Oxo-4-androsteno[16,17-b]-6′,7′-dimethylquinoxaline was obtained by Oppenauer oxidation of the corresponding alcohol.     

Herstellung von 3-Oxo-17β-hydroxy-1,19-cyclo-5α-androstan. Über Steroide, 219. Mitteilung

Under the influence of radical anions generated from lithium and biphenyl, 3-oxo-17β-acetoxy-19-mesyloxy-Δ¹-5α-androstane was converted into 3-oxo-17β-acetoxy-1, 19-cyclo-5α-androstane.     

Tordanone,un stéroïde replié avec une jonction de cycle A/B β-cis (5β) et B/C α-cis(8α)

Tordanone, a Twice Bent Steroid Structure with Ring A/B β-cis(5β)- and Ring B/C α-cis(8α)-Fused The 3β, 14α, 25-trihydroxy-5β, 8α-cholestan-6-one ( = tordanone; 4 ) has been prepared by stereospecific hydrogenation of 3β, 14α, 25-trihydroxy-5β-cholesta-7,22ξ-dien-6-one ( 5 ). This is the first stereospecific synthesis of a B/C cis-fused steroid belonging to the 5β, 8α -cholestane group with a H-atom at positions 5β (A/B cis-fused) and 8α. The resulting twice bent structure shows a particularly strong steric hindrance of the β-face where CH₃(18) at the C/D ring junction and H_β? C(7) of the B ring are very close to each other. Structural features and mechanistic aspects of the hydrogenation are discussed.     

Synthesis of the 2,5-dioles of A-nor-5-alpha-cholestanes and A-nor-5-beta-cholestanes

Treatment of A-nor-Δ³⁽⁵⁾-cholestene-2-one ( 1 ) with alkaline hydrogen peroxide gave 3β,5-epoxy-A-nor-cholestane-2-one ( 2 ) and the epoxylactone 3 (BAEYER -VILLIGER reaction). LiAlH₄-reduction of 2 yielded A-nor-5β-cholestane-2β,5-diol( 4 ) (main product) and A-nor-5β-cholestane-2α,5-diol ( 5 ). LiAlH₄-reduction of 1 led mainly to A-nor-Δ³⁽⁵⁾-cholestene-2α-ol ( 8 ). Catalytic hydrogenation of 8 gave the known A-nor-5α-cholestane-2α-01 ( 10 ), A-nor-5β-cholestane-2α-01 ( 11 ) (main product), A-nor-5β-cholestane ( 9 ) and A-nor-5β-cholestane-2-one ( 12 ). By LiAlH₄-reduction of the ketones 12 and 13 the two additional alcohols 14 and 15 were obtained.     

A novel fragmentation of trimethylsilyl ethers of 3β-hydroxy-Δ5-steroids

An ion formed by loss of 56 mass units from the molecular ion is often seen in mass spectra of trimethylsilyl ethers of C₁₉ and C₂₁ steroids having a 3β-hydroxy-Δ⁵ structure and an oxo group at C-17 or C-20. The nature of this fragment was investigated by the use of perdeuteriotrimethylsilyl ether derivatives and of [4-¹⁴C], [3-¹⁸O], [4,4-²H₂] and [2,2,4,4-²H] labelled derivatives of 3β-hydroxy-5-androsten-17-one and 3β-hydroxy-5-pregnen-20-one. Evidence is presented to show that the neutral fragment of mass 56 is composed of carbon atoms 1, 2 and 3, the oxygen at C-3 and four hydrogen atoms. During the fragmentation process, the trimethylsilyl group and one of the hydrogens at C-2 are transferred to the fragment that carries the charge.     

The synthesis of β-heteroarylamino-α,β-dehydro-α-amino acid and β-heteroarylamino-α-amino acid derivatives

From heteroarylaminomethyleneoxazolones 4 , obtained from N-heteroarylformamidines 2 and 2-phenyl-5-oxo-4,5-dihydro-1,3-oxazole ( 3 ), the following β-heteroarylamino-α,β-dehydro-α-amino acid derivatives were prepared: methyl 8 and ethyl esters 9 , amides 10 and 11 , hydrazides 12 , and azides 15 . By catalytic hydrogenation the compounds 4 were converted into β-heteroarylamino substituted amides 18 and β-heteroarylamino-α-amino acids 20 .     

Synthese und Eigenschaften von 2-(α-Hydroxyalkyl)-und 2-(α-alkoxycarbonyl)-substituierten 4-Methyl-5-(β-hydroxyäthyl)-thiazolen und -thiazoliumsalzen

Condensation of the tetrahydropyranyl ether of the α-hydroxyalkyl-thioamides with 3-bromo-4-hydroxy-2-pentanones yields DL -2-(α-hydroxyalkyl)-4-methyl-5-(β-hydroxyethyl)-thiazoles. By oxidation with chromic anhydride 2-hydroxymethyl-4-methyl-5-(β-acetoxyethyl)-thiazole yields the corresponding 2-formyl derivative. The latter compound reacted with GRIGNARD complexes gives the homologous DL -2-(α-hydroxyalkyl)-4-methyl-5-(β-hydroxyethyl)-thiazoles. This is a general method for the synthesis of the thiazole part of the «active aldehydes». 2-Acetyl-4-methyl-5-(β-hydroxyethyl)-thiazole is also obtained by chromic oxidation of the suitable methylthiazol-2-yl-carbinol. The condensation of the thioamides obtained from the α-ethoxycarbonyl-nitriles with 3-bromo-5-acetoxy-2-pentanone results in the DL -2-(α-ethoxycarbonyl-alkyl)-4-methyl-5-(β-acetoxyethyl)-thiazoles. The α-hydroxyl function is introduced into the 2-(α-ethoxycarbonyl-alkyl) group by chlorination with sulfuryl chloride and replacement of the introduced chlorine by acetate. The latter compounds are the esters of the thiazole part of the «active α-oxo-carboxylic acids» (e.g. active pyruvate, etc.). The reaction of 2-(α-hydroxyalkyl)-4-methyl-5-(β-hydroxyethyl)-thiazoles and 2-(α-ethoxycarbonyl-α-acetoxy-alkyl)-4-methyl-5-(β-acetoxyethyl)-thiazoles, respectively, with alkyl, alkenyl and aralkyl haloids, or with 2-methyl-4-amino-5-bromomethyl-pyrimidine hydrobromide results in the quaternary thiazolium compounds belonging to the group of the active aldehydes, active α-oxo-carboxylic acids, etc. According to this method 2-hydroxymethyl-thiamine bromide hydro-bromide has been synthesized, which can be considered as the pyrophosphate-free «active formal-dehyde». The 2-α-hydrogen atom in 2-(α-hydroxyalkyl)-thiazolium compounds cannot be replaced by deuterium under conditions similar to those used for the H → D exchange in thiamine. The main peaks in the mass spectra of 2-(α-hydroxyalkyl) substituted thiazoles and thiazolium quaternary salts are listed.     

Photochemical Rearrangement of a Steroidal α, β-Epoxylactam. Photochemical reactions,XII [1]

The UV. irradiation of 17β-hydroxy-4α, 5α-epoxy-2-azaandrostan-3-one ( 1 ) yields 17β-hydroxy-2-aza-10 (5 → 4-abeo)-4ζ (H)-androsta-3,5-dione ( 3 ).     

Umwandlung von Cardenoliden durch Mikroorganismen VI. 7β, 11α-Dihydroxydigitoxigenin und Abbau von 7β-Hydroxy-digitoxigenin zum 3β, 7β-Diacetoxy-14-hydroxy-5β, 14β, 17αH-ätiansäure-methylester. Mitteilung über Reaktionen mit Mikroorganismen [1]

Digitoxigenin ( 3 ) was transformed by a Fusarium spec. to 7β-hydroxydigitoxigenin ( 1 ) 1β, 7β-dihydroxydigitoxigenin ( 4 ) and to the hitherto unknown 7β, 11α-dihydroxydigitoxigenin ( 9 ). 7β-acetoxy-digitoxigenin ( 2 ) was degraded to methyl 3β, 7β-diacetoxy-14-hydroxy-5β, 14β, 17αH-etianate ( 11 ).     

Gas-Chromatographie und Massenspektrometrie der Trimethylsilyl-enoläther von 5α- und 5β-Cholestan-3-on

Trimethylsilyl-enolethers of 5α- and 5β-cholestan-3-on were investigated by gas chromatography and mass spectrometry. These derivatives are readily prepared and well suited for gas chromatographic analysis. In the mass spectrum they show fairly intense fragmentation, which appears to be characteristic for some structural elements in the surroundings of the functional group (excluding stereochemistry). This fragmentation may be useful for the structure elucidation of 3-oxo-steroids and related compounds. For comparison purposes the corresponding enolacetates were also investigated.