A novel ring contraction: 3β-methyl-A-nor-5β-cholestan-5-ol-6-one from 3β-tosyloxy-5α-cholestane-5,6β-diol through an ene reaction of an unsaturated acyloin

A by-product of the reaction of 3β-tosyloxy-5α-cholestane-5,6β-diol with , 3β-methyl-A-nor-5β-cholestan-5-ol-6-one, is believed to arise from the intramolecular ene reaction of 4,5-seco-cholest-3-en-6β-ol-5-one.     

Metabolic studies of methenolone acetate in horses

Methenolone acetate (17β-acetoxy-1-methyl-5α-androst-1-en-3-one), a synthetic anabolic steroid, is frequently abused in human sports. It is preferred for its therapeutic efficiency and lower hepatic toxicity compared with its 17α-alkylated analogs. As with other anabolic steroids, methenolone acetate may be used to enhance performance in racehorses. Metabolic studies on methenolone acetate have been reported for humans, whereas little is known about its metabolic fate in horses. This paper describes the investigation of in vitro and in vivo metabolism of methenolone acetate in racehorses.Studies on the in vitro biotransformation of methenolone acetate with horse liver microsomes were carried out. Methenolone (M1, 1-methyl-5α-androst-1-en-17β-ol-3-one) and seven other metabolites (M2-M8) were detected in vitro. They were 1-methyl-5α-androst-1-ene-3,17-dione (M2), 1-methyl-5α-androst-1-en-6-ol-3,17-dione (M3) and two stereoisomers of 1-methylen-5α-androstan-2-ol-3,17-dione (M4 and M5), 1-methyl-5α-androst-1-en-16-ol-3,17-dione (M6) and monohydroxylated 1-methyl-5α-androst-1-en-17-ol-3-one (M7 and M8). After oral administration of Primobolan^® (80 tablets × 5 mg of methenolone acetate each) to two thoroughbred geldings, the parent steroid ester was not detected in the post-administration urine samples. However, seven metabolites, namely M1, M6-M8, two stereoisomers of M7 (M9 and M10) and 1-methyl-5α-androst-1-en-17α-ol-3-one (M11), could be detected. The metabolic pathway for methenolone acetate is postulated. This study has shown that metabolite M1 could be targeted for controlling the abuse of methenolone acetate in horses.     

Unusual Knoevenagel condensations of 16a-substituted-16-methylene-17-keto-steroids

A Knoevenagel condensation between 3β-acetoxy-16-pyrrolidinylmethylenandrost-5-en-17-one (8c) and an excess of malononitrile led unexpectedly to 3β-acetoxyandrost-5-eno-[17,16-c]-1′,6′-dicyanoaniline (12a) as the major product and 3β-acetoxy-16-pyrrolidinylmethylen-17-dicyanomethylenandrost-5-ene (11a) as the minor product. Knoevenagel reactions of other 16a-substituted-16-methylen-17-keto steroids were studied to evaluate the scope and mechanism of the reaction.     

Synthetic studies in steroidal sapogenins and alkaloids—XII : Synthesis of sceptrumgenin and isonuatigenin

The Michael adduct of 5-nitro-2,2-ethylene-dioxypentan-1-ol acetate with E-5,17(20)-pregnadien-3β-ol-16-one gave on reduction with sodium borohydride and deketalisation, spirost-5-en-3β-ol-25-one. This intermediate was converted to sceptrumgenin through reaction with triphenyl phosphonium methylide and to isonuatigenin by treatment with dimethyl oxosulfonium methylide followed by lithium aluminium hydride.     

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.     

Steroidal analogues of unnatural configuration—VII : Total synthesis of 17β-hydroxy-9-methyl-9β, 10α-oestr-4-en-3-one,a novel retrotestosterone isomer

Conjugate methylation of 17β-hydroxy-des-a-oestr-9-en-5-one (1) and the derived 4,5-seco-steroid (6b) afforded the respective 9β-methyl compounds. Base-catalysed alkylation of 17β-hydroxy-9-methyl-des-a-9/gb-oestran-5-one (3a) resulted in attack at C(6); this result was used to prepare the anthrasteroid (5). Ring closure of the 9β-methyl-4,5-seco-steroid (8) derived from 6b afforded 17β-hydroxy-9-methyl-9β,10α-oestr-4-en-3-one (9a). Conjugate methylation of 17β-hydroxyoestra-4,9-dien-3-one (11) resulted in 1,4-addition to the dienone system.     

Selectivity in cycloadditions: Crystal and molecular structure of (1a,4β,5a)-1,5-diacetyl-4-hydroxy-4-methylbicyclo[3.1.0]Hexan-2-one

The stereochemistry of (1a,4β,5a)-1,5-diacetyl-4-hydroxy-4-methylbicyclo[3.1.0]hexan-2-one, the main cycloadduct of 2,3-diacetyl-4-hydroxy-4-methylcyclopent-2-en-1-one and diazomethane, was unambiguously established from a single crystal X-ray analysis.     

Regio- and stereoselective introduction of 15β-hydroxy group and side chains to steroids by the palladium-catalyzed reaction of 1,3-diene monoepoxide

The Pd-catalyzed reaction of 1,3-diene monoepoxides with carbonucleophiles is applied to the regio- and stereoselective introduction of 15β-hydroxy group and side chains to steroid nuclei. 3β-Hydroxyandrost-5-en-17-one (15) was converted to 15,16β-epoxy-Δ¹⁷⁽²⁰⁾ isoheptylidene steroid 20 and ethylidene steroid 21. The former was subjected to the Pd-catalyzed reaction with dimethyl malonate and then converted to 15β-hydroxycholesterol (29). Similarly, 15β-hydroxyisocholesterol (32) was obtained from the ethylidene steroid 21 using the Pd-catalyzed reaction of methyl 3-oxo-5-methylhexanoate (24) as a key reaction.     

Synthesis,x-ray structure and molecular mechanics studies of the boar taint steroid (5α -androst-16-en-3-one)

5α-Androst-16-en-3-one has been prepared from 5α-androstan-3β-ol-17-one in an overall yield of 34% by the vinyl iodide route. Accurate molecular dimensions have been determined by X-ray crystal structure analysis and by molecular mechanics calculations. There is significant twisting of the angular methyl groups in the molecule.     

Epoxide compounds ofβ,β-dialkyl divinyl ketones and unsaturatedβ-methoxy ketones

By the epoxidation with alkaline hydrogen peroxide of 5-methylhepta-1,4-dien-3-one and 5-ethylhepta-1, 4-dien-3-one and the 3-methyl-7-methoxyhept-3-en-5-one and 3-ethyl-7-methoxyhept-3-en-5-one formed from them, we have obtained the mono- and diepoxy ketones corresponding to them with yields of 48–65%. It has been shown that under the influence of zinc chloride 4, 5-epoxy-3-methyl-7-methoxyheptan-5-one forms 3-methyl-7-methoxyheptane-4,5-dione and 3-methylhept-1-ene-3,4-dione. Under the same conditions, 4,5-epoxy-3-ethyl-7-methoxyheptan-5-one is converted into 3-ethyl-7-methoxyheptane-4,5-dione and 3-ethylhept-1-ene-3, 4-dione. 3-Methyl- and 3-ethylheptene-3,4-diones are also formed in the distillation of the methyl and ethyl methoxy diketones in the presence of p-toluenesulfonic acid. The IR spectra of the compounds synthesized have been recorded.     

厚皮树树皮的化学成分研究

采用各种柱色谱法从厚皮树(Lannea coromandelica)树皮的78%乙醇提取物中分离得到9个化合物。通过理化性质和波谱数据鉴定为:槲皮素-3-O-芸香糖苷(1),豆甾-4-烯-6β-醇-3-酮(2),蒲公英赛酮(3),蒲公英赛醇(4),乙酰蒲公英赛醇(5),5α-豆甾烷-3,6-二酮(6),β-谷甾醇(7),β-胡萝卜苷(8),香草醛(9)。除了化合物(7),其他化合物都是从该植物中首次分离得到。     

Synthesis of a transmembrane ionophore based on a C2-symmetric polyhydroxysteroid derivative

The synthesis of the C₂-symmetric bis-(20S)-5α-23,24-bisnorchol-16-en-3β,6α,7β-triol-22-terephthaloate (1), active as Na⁺-transporting transmembrane channel, has been achieved in 16 steps (10% overall yield) starting from the commercially available androst-5-en-3β-ol-17-one (3). The straightforward stereospecific functionalization of the side-chain, via the ‘ene’ reaction, and the successful regioselective terephthaloylation of the C-22 hydroxy group, illustrate the efficiency of the synthetic strategy.     

Diisophorone and related compounds. Part 12 Synthesis of 4-bromodiisophorones and their reactions with nucleophiles

4-Bromodiisophor-2(7)-en-1-ol-3-one (2) is accessible by the action of hydrobromic acid on 2,7-epoxydiisophoran-1-ol-3-one (1), and is convertible into the corresponding 1-carboxylic acid (9) by theKoch-Haaf reaction. Nucleophilic substitution displaces the halogen in both the 4-bromoketol (2) and the 4-bromoketo-acid (9). Amongst the products thus obtained, 4-hydroxy-1-carboxydiisophor-2(7)-en-3-one (11) is of special interest as a source of the 3,4-diketo-1-carboxylic acid (13).

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Diisophoron und verwandte Verbindungen, 12. Mitt.: Synthese von 4-Bromdiisophoronen und ihre Reaktion mit Nucleophilen

Zusammenfassung 4-Bromdiisophor-2(7)-en-1-ol-3-on (2) ist durch Einwirkung von Bromwasserstoffsäure auf 2,7-Epoxydiisophoran-1-ol-3-on (1) erhältlich und wird mittels derKoch-Haaf-Reaktion zur entsprechenden 1-Carbonsäure (9) umgesetzt. Durch nucleophile Reagenzien wird das Halogen sowohl im 4-Bromketol (2) als auch in der 4-Bromoketosäure (9) substituiert. Unter den so erhältlichen Produkten ist das 4-Hydroxy-1-carboxydiisophor-2(7)-en-3-on als Ausgangsmaterial für die 3,4-Diketo-1-säure (13) von zusätzlichem Interesse.

     

Total asymmetric syntheses of 3- and 4-deoxy-hexoses and derivatives

(1S,4S)-7-Oxabicyclo[2.2.1]hept-5-en-2-one ((−)-5, a “naked sugar”) has been converted to (−)-(1R,4S,6S)-6-endo-benzyloxy-2-bromo-7-oxabicyclo[2.2.1]hept-2-ene ((−)-12) in a highly stereoselective fashion. Double hydroxylation of the C=C double bond of (−)-12, followed by acetylation and Baeyer-Villiger oxidation of the resulting -acetoxyketone (−)-14 afforded (−)-5-O-acetyl-2-O-benzyl-3-deoxy-β-D-arabino-hexofuranurono-6,1-lactone ((−)-15). This compound was converted readily into (+)-methyl 3-deoxy--D-arabino-hexofuranoside ((+)-6 and (+)-methyl 3-deoxy-β-L-xylo-hexofuranoside ((+)-7) and partially protected derivatives. (−)-15 was also converted into 4-deoxy-D-lyxo-hexopyranose (34) and several partially protected derivatives such as (+)-methyl 4-deoxy-2,3-O-isopropylidene--D-lyxo-hexopyranoside ((+)-8).     

New derivatives of 4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrazole, 4,5-dihydro-1,2-oxazole,and pyrimidine prepared proceeding from (<Emphasis Type="Italic">E</Emphasis>)-3-[5-(4-methylphenyl)-1,2-oxazol-3-yl]-1-ferrocenylprop-2-en-1-one

Condensation of acetylferrocene with 5-phenyl(4-methylphenyl)-1,2-oxazole-3-carbaldehydes afforded (Е)-3-[5-phenyl(4-methylphenyl)-1,2-oxazol-3-yl]-1-ferrocenylprop-2-en-1-ones. Reactions of (Е)-3-[5-(4-methylphenyl)-1,2-oxazol-3-yl]-1-ferrocenylprop-2-en-1-one with semicarbazide, thiosemicarbazide, and hydroxylamine led to the formation of 5-[5-(4-methylphenyl)-1,2-oxazol-3-yl]-3-ferrocenyl-4,5-dihydro-1H-pyrazole- 1-carboxamide, 5-[5-(4-methylphenyl)-1,2-oxazol-3-yl]-3-ferrocenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide, and 5-(4-methylphenyl)-3'-ferrocenyl-4',5'-dihydro-3,5'-bi-1,2-oxazole respectively. Reactions of (Е)-3-[5-(4-methylphenyl)-1,2-oxazol-3-yl]-1-ferrocenylprop-2-en-1-one with guanidine and thiourea result in 4-[5-(4-methyl-phenyl)-1,2-oxazol-3-yl]-6-ferrocenylpyrimidin-2-amine and -2-thione respectively.     

Synthesis of potentially anti-inflammatory IPL576,092-contignasterol and IPL576,092-manoalide hybrids

The synthesis of two potentially anti-inflammatory steroidal hybrid compounds has been accomplished through a 16- and 17-step sequence, respectively, starting from commercially available androst-5-en-3β-ol-17-one. The synthetic strategies are based both on stereoselective side chains elaboration and high yielding functional group transformations.     

Reaction of trifluoromethyl-containing 1,3-dicarbonyl compounds with bis-hydrazides

Carbonic dihydrazide reacted with 2 equiv of trifluoroacetylacetone to give a compound containing 5-hydroxy-4,5-dihydropyrazole and keto enehydrazine fragments. Analogous 2 : 1 condensations of trifluoro-acetylacetone and 4-ethoxy-1,1,1-trifluorobut-3-en-2-one with oxalohydrazide and malonohydrazide afforded bis(5-hydroxy-4,5-dihydropyrazole) structures as two diastereoisomers.     

Reactions of Enone Ethylene Ketals with Methyl Diazomalonate/Bis(acetylacetonato)copper(II)

Several cyclic and acyclic enones and their ethylene ketals/acetals were reacted with dimethyl diazomalonate under bis(acetylacetonato)copper(II) catalysis. Cyclohex-2-en-1-one ( 1 ) yielded only C–H insertion products 2 and 3 , whereas but-3-en-2-one gave a cyclopropane albeit in very low yield. The ethylene ketals 6 of cyclopent-2-en-1-one and cyclohex-2-en-1-one gave the corresponding cyclopropanes 7 , which were in turn cleaved to the ketones 8 . The acetals 9 and 10 of crotonaldehyde ((E)-but-2-enal) and cinnamaldehyde ((E)-3-phenylprop-2-enal), respectively, yielded C–O insertion and [2,3]-sigmatropic rearrangement products 11b, c and 12b, c , as well as cyclopropanes 11a and 11b , all of which are polyfunctional and synthetically useful compounds.     

Quinazolines and 1,4-benzodiazepines. XLVI. Photochemistry of nitrones and oxaziridines

The cyclic nitrones 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5a ) and 1,3-dihydro-7-methylthio-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5b ) are photoisomerized to readily isolable oxaziridines, 7-chloro-4,5-epoxy-5-phenyl-1,3,4–5-tetrahydro-2H-1,4-benzodiazepin-2-one ( 6a ) and 4,5-epoxy-5-phenyl-1,3,4,5-tetrahydro-7-methylthio-2H-1,4-benzo-diazepin-2-one ( 6b ). Oxaziridine 6b upon further irradiation gave ring expansion and ring contraction products, 4,6-dihydro-2-phenyl-9-methylthio-5H-1,3,6-benzoxadiazocin-5-one ( 7b ) and 4-benzoyl-3,4-dihydro-6-methylthioquinoxalin-2(1H)-one ( 8b ) respectively. The ring contraction product, 4-benzoyl-6-chloro-3,4-dihydroquinoxalin-2(1H)-one ( 8a ), was obtained from irradiation of oxaziridine 6a .     

The formation of 3(or 5)-methylcyclopent-2-en-2-ol-1-one from acetone

The original observation that 3(or 5)-methylcyclopent-2-en-2-ol-1-one (I) was formed (in low yield) by the treatment of glycidaldehyde with acetone in the presence of aqueous alkali, and speculations concerning the reaction mechanism, led to the realization that the reaction could also be carried out with glyceraldehyde. This suggested an explanation for the previously known formation of I by drastic alkali-treatment of carbohydrates.