- Tetrapropylammonium perruthenate as a mild and efficient oxidant for sensitive steroidal alcohols
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Tetrapropylammonium perruthenate N-methylmorpholine N-oxide oxidation of steroidal alcohols is described. The reagent combination is mild and gave good yields of the corresponding ketones. Although the oxidation can generate ketones from 3-, 11-, 15-, 17-, and 20-hydroxy steroids, the oxidation of homoallylic alcohols proceeds in low yields. Finally, we observed that the oxidation reagents will convert 17α-hydroxy-2-keto steroids to 17-keto systems in excellent yields.
- Acosta, C. Kirk,Rao, Pemmaraju N.,Kim, Hyun K.
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- Side chain removal from corticosteroids by unspecific peroxygenase
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Two unspecific peroxygenases (UPO, EC 1.11.2.1) from the basidiomycetous fungi Marasmius rotula and Marasmius wettsteinii oxidized steroids with hydroxyacetyl and hydroxyl functionalities at C17 - such as cortisone, Reichstein's substance S and prednisone
- Ullrich, René,Poraj-Kobielska, Marzena,Scholze, Steffi,Halbout, Claire,Sandvoss, Martin,Pecyna, Marek J.,Scheibner, Katrin,Hofrichter, Martin
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- A straightforward chemical synthesis of 17-ketosteroids by cleavage of the C-17-dihydroxy acetone side chain in corticosteroids
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A facile and convenient approach to 17-ketosteroids is described. Treatment of steroids containing the C-17-dihydroxy acetone side chain with an excess of sodium methoxide in dry 1,4-dioxane under reflux, affords high yields of the corresponding 17-ketosteroids that are recovered as pure products, without the need of further purification.
- Le Pera, Adolfo,Leggio, Antonella,Siciliano, Carlo,Di Gioia, Maria L.,Napoli, Anna,Sindona, Giovanni,Liguori, Angelo
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- Electrochemically Enabled One-Pot Multistep Synthesis of C19 Androgen Steroids
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The synthesis of many valuable C19 androgens can be accomplished by removal of the C17 side chain from more abundant corticosteroids, followed by further derivatization of the resulting 17-keto derivative. Conventional chemical reagents pose significant drawbacks for this synthetic strategy, as large amounts of waste are generated, and quenching of the reaction mixture and purification of the 17-ketosteroid intermediate are typically required. Herein, we present mild, safe, and sustainable electrochemical strategies for the preparation of C19 steroids. A reagent and catalyst free protocol for the removal of the C17 side chain of corticosteroids via anodic oxidation has been developed, enabling several one-pot, multistep procedures for the synthesis of androgen steroids. In addition, simultaneous anodic C17 side chain cleavage and cathodic catalytic hydrogenation of a steroid has been demonstrated, rendering a convenient and highly atom economic procedure for the synthesis of saturated androgens.
- Sommer, Florian,Kappe, C. Oliver,Cantillo, David
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- A simple two-step method for the conversion of [3H]cortisol to [3H]- 11-ketotestosterone
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Despite the existence of several protocols, problems appear to persist in the small scale chemical synthesis of radiolabeled 11-ketotestosterone from cortisol. We investigated the possibilities of using the mild oxidant pyridinium dichromate for the oxidative cleavage of the dihydroxyacetone side chain of cortisol and 17β-hydroxysteroid dehydrogenase for the subsequent reduction of the resulting 17-keto group. Our protocol has resulted in consistently high yields of both the intermediate, adrenosterone (70-80%), and the product, 11-ketotestosterone (up to 60%). This, taken together with the convenience and relatively low cost of our method, recommends the protocol for its use for the synthesis of [3H]-11-ketotestosterone for endocrine studies.
- Lokman, P. Mark,Irwin, Jacob L.,Blackwell, Leonard F.,Davie, Peter S.,Thomas, Mervyn,Young, Graham
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- Iodine-promoted cleavage of the C-17-dihydroxyacetone side chain of corticosteroids in aqueous ammonia water
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A convenient approach to 17-ketosteroids by the iodine-promoted cleavage of the C-17-dihydroxy acetone side chain of corticosteroids is described. Treatment of steroids containing the C-17-dihydroxyacetone side chain with iodine and an excess of aqueous ammonia in acetonitrile at 50°ffords high yields of the corresponding 17-ketosteroids.
- Sun, Liang,Geng, Xin,Liu, Lanhai,Jiang, Chenggang,Wang, Cunde
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- HYDROXYSTEROID COMPOUNDS, THEIR INTERMEDIATES, PROCESS OF PREPARATION, COMPOSITION AND USES THEREOF
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The present invention relates to novel steroidal compounds of formula (I), process for preparation of the same and composition comprising these compounds.
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Page/Page column 50; 51
(2016/02/09)
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- Biotransformation of dehydro-epi-androsterone by Aspergillus parasiticus: Metabolic evidences of BVMO activity
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The research on the synthesis of steroids and its derivatives is of high interest due to their clinical applications. A particular focus is given to molecules bearing a D-ring lactone like testolactone because of its bioactivity. The Aspergillus genus has been used to perform steroid biotransformations since it offers a toolbox of redox enzymes. In this work, the use of growing cells of Aspergillus parasiticus to study the bioconversion of dehydro-epi-androsterone (DHEA) is described, emphasizing the metabolic steps leading to D-ring lactonization products. It was observed that A. parasiticus is not only capable of transforming bicyclo[3.2.0]hept-2-en-6-one, the standard Baeyer-Villiger monooxygenase (BVMO) substrate, but also yielded testololactone and the homo-lactone 3β-hydroxy-17a-oxa-d-homoandrost-5-en-17-one from DHEA. Moreover, the biocatalyst degraded the lateral chain of cortisone by an oxidative route suggesting the action of a BVMO, thus providing enough metabolic evidences denoting the presence of BVMO activity in A. parasiticus. Furthermore, since excellent biotransformation rates were observed, A. parasiticus is a promising candidate for the production of bioactive lactone-based compounds of steroidal origin in larger scales.
- Mascotti, M. Laura,Palazzolo, Martín A.,Bisogno, Fabricio R.,Kurina-Sanz, Marcela
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- Identification of new substrates for the CYP106A1-mediated 11-oxidation and investigation of the reaction mechanism
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Abstract CYP106A1 from Bacillus megaterium DSM319 was recently shown to catalyze steroid and terpene hydroxylations. Besides producing hydroxylated steroid metabolites at positions 6β, 7β, 9α and 15β, the enzyme displayed previously unknown 11-oxidase activity towards 11β-hydroxysteroids. Novel examples for 11-oxidation were identified and confirmed by 1H and 13C NMR for prednisolone, dexamethasone and 11β-hydroxyandrostenedione. However, only 11β-hydroxyandrostenedione formed a single 11-keto product. The latter reaction was chosen to investigate the kinetic solvent isotope effect on the steady-state turnover of the CYP106A1-mediated 11-oxidation. Our results reveal a large inverse kinetic isotope effect (～0.44) suggesting the involvement of the ferric peroxoanion as a reactive intermediate.
- Kiss, Flora Marta,Khatri, Yogan,Zapp, Josef,Bernhardt, Rita
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p. 2320 - 2326
(2015/08/18)
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- Development of a concise synthesis of ouabagenin and hydroxylated corticosteroid analogues
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The natural product ouabagenin is a complex cardiotonic steroid with a highly oxygenated skeleton. This full account describes the development of a concise synthesis of ouabagenin, including the evolution of synthetic strategy to access hydroxylation at the C19 position of a steroid skeleton. In addition, approaches to install the requisite butenolide moiety at the C17 position are discussed. Lastly, methodology developed in this synthesis has been applied in the generation of novel analogues of corticosteroid drugs bearing a hydroxyl group at the C19 position.(Chemical Equation Presented).
- Renata, Hans,Zhou, Qianghui,Dünstl, Georg,Felding, Jakob,Merchant, Rohan R.,Yeh, Chien-Hung,Baran, Phil S.
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supporting information
p. 1330 - 1340
(2015/02/19)
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- Bismuth(III) triflate-catalyzed direct conversion of corticosteroids into highly functionalized 17-ketosteroids by cleavage of the C17-dihydroxyacetone side chain
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(Chemical Equation Presented) The use of bismuth(III) triflate as catalyst for the direct conversion of corticosteroids into highly functionalized 17-ketosteroids by cleavage of the C17-dihydroxyacetone side chain is reported. This catalytic process is very chemoselective, since functionalities of the starting corticosteroids, such as Δ4-3-keto, Δ1,4-3-keto, 11β-hydroxyl, and 9β,11β-epoxide, remained intact.
- Pinto, Rui M. A.,Salvador, Jorge A. R.,Le Roux, Christophe,Paixao, Jose A.
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supporting information; experimental part
p. 8488 - 8491
(2010/02/28)
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- Selective 1,4-reduction of unsaturated carbonyl compounds using Co2(CO)8-H2O
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α,β-Unsaturated ketones and aldehydes were selectively reduced to the corresponding saturated carbonyl compounds by Co2(CO)8-H2O system. The current reducing system also offered a chemoselective reduction of less substituted unsaturated carbonyl groups.
- Lee, Hee-Yoon,An, Mihyun
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p. 2775 - 2778
(2007/10/03)
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- Steroid transformations with Fusarium oxysporum var. cubense and Colletotrichum musae
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The utility of two locally isolated fungi, pathogenic to banana, for steroid biotransformation has been studied. The deuteromycetes Fusarium oxysporum var. cubense (IMI 326069, UAMH 9013) and Colletotrichum musae (IMI 374528, UAMH 8929) had not been examined previously for this potential. In general, F. oxysporum var. cubense effected 7α hydroxylation on 3β-hydroxy- Δ5-steroids, 6β, 12β, and 15α hydroxylation on steroidal-4-ene-3-ones, side-chain degradation on 17α,21-dihydroxypregnene-3,20-diones, and 15α hydroxylation on estrone. Both strains were shown to perform redox reactions on alcohols and ketones.
- Wilson, Maureen R.,Gallimore, Winklet A.,Reese, Paul B.
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p. 834 - 843
(2007/10/03)
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- A new strategy for the preparation of 11-oxygenated steroids synthesis of (±)-adrenosterone
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Conjugate 1,4-addition of 1-[(tert-butyldimethylsilyl)oxy]-2-methyl- 1,3-cyclohexadiene (5) to 2-methyl-cyclopentenone in highly polar media and subsequent alkylation of the resultant silyl enol ether (4) with phenylthiodienyl carbonate 10 in 5.0 M LiClO4·Et2O provides substrate 2. Exposure of 2 to TMSOTf/TMSOCH2CH2OTMS affords tetracyclic bis-ketal 3, which is converted into (±)-adrenosterone (1) in four steps.
- Grieco, Paul A.,May, Scott A.,Kaufman, Michael D.
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p. 7047 - 7050
(2007/10/03)
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- Synthesis of 11-substituted androstenediones and testosterones as human decidual cell growth inhibitors
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11α-Hydroxytestosterone (1a), 11β-hydroxytestosterone (1b), 11α- methoxytestosterone (1c), 11β-methoxytestosterone (1d), 11-ketotestosterone (1e), and Δ(9(11))-testosterone (1f) were synthesized from hydrocortisone (4b) or 11-epi-hydrocortisone (4a). The six target compounds, together with 11α-methoxyandrostenedione (2c), 11β-methoxyandrostenedione, (2d) and their lead compound, testosterone (1), were found to effectively inhibit the growth and differentiation of human decidual cells in culture. There is no observable binding of these compounds to estrogen receptor of rabbit uterus. The introduction of a polar group (e.g., hydroxyl and carbonyl) to C-11 of androstenes decreases both the relative binding affinities to progesterone receptor and the inhibitory effects on human decidual cell growth, while the methylation of 11-hydroxyl group minimizes these effects. The similar effects of a polar group at C-11 of testosterone (1) on the inhibitory effects on human decidual cell growth and the relative binding affinities to progesterone receptor of rabbit uterus may suggest that one of the mechanisms of human decidual cell growth inhibition by these compounds is the anti- progestational activity of these androgens.
- Zhao, Qinjian,Li, Zhensu
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p. 190 - 195
(2007/10/02)
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- Photochemical Studies, 64. - Photostability of Glucocorticoids in the Solid State
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Most of the pharmacopoeia require that the glucocorticoids hydrocortisone (1), cortisone (2), hydrocortisone 21-acetate (3) and cortisone 21-acetate (4) must be protected from light during storage.The present study shows that irradiation of these compounds in the solid state leads to the loss of the side chain at C-17.Two-17-ketosteroids, 11β-hydroxy-4-androstene-3,17-dione (6) and 4-androstene-3,11,17-trione (7), were obtained as photoproducts (yields 3percent and 4percent, respectively).Key Words: Hydrocortisone / Cortisone / Steroids / Photochemistry
- Reisch, Johannes,Iranshahi, Lotfollah,Ekiz-Guecer, Nurten
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p. 1199 - 1200
(2007/10/02)
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- Total Synthesis of ( +/-)-Cortisone. Double-Hydroxylation Reaction for Corticoid Synthesis
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Total syntheses of (+/-)-cortisone and (+/-)-adrenosterone have been achieved in 18 steps with the aid of metal-assisted new synthetic sequences in particular, ene reaction and homoenolate chemistry.A novel double-hydroxylation reaction of enol silyl ethers leading to a single step construction of the dihydroxyacetone side chain in corticoids has been developed and applied to the synthesis of cortisone, cortexolone, and 16α-methylcortexolone.
- Horiguchi, Yoshiaki,Nakamura, Eiichi,Kuwajima, Isao
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p. 6257 - 6265
(2007/10/02)
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- 1H NMR Analyses, Shielding Mechanisms, Coupling Constants, and Comformations is Steroids Bearing Halogen, Hydroxy, Oxo Groups, and Double Bonds
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The 1H NMR analyses of 16 5αH-androstanes and one progesterone analogue furnish shifts and coupling constants for the basic steroid skeleton and substituent-induced shifts (SIS) for oxo, hydroxy, and halogen groups as well as for a Δ double bond.It is shown how a single 2D experiment complemented by a NOE difference spectrum can lead to complete assignments even with the most complicated spin systems compirising, e.g., 29 strongly coupled protons within only 1 ppm; the accurancy of information from 2D techniques is evaluated by comparison to some 1D and computer-simulated spectra.On the basis of up to six simultaneously observable couplings, a special approach is used to scan the conformational space of particularly flexible parts.Intermediate conformations between half-chair and twist are obtained with a torsional C14-C15-C16-C17 angle of φ ca. 20 deg for the D ring with a sp2 (17-oxo) carbon and of φ ca. 10 deg with only sp3 carbon atoms; the observed flat profiles, however, allow also for mixtures of different conformations, which is supported by MM2 calculations.For the Δ-3-oxo A ring, a sofa conformation is favored compared to a half-chair geometry.The observed shielding effects of heterosubstituents are partially at variance with the few earlier observations, which were mostly based on polysubstituted compounds.Classical shielding mechanisms were evaluated with the program SHIFT, based on force-field-minimized structures.Steric-induced shielding dominates in the hydrocarbon, leading to upfield shifts increasing with the number of 1,3-diaxial interactions.Linear electric-field effects predict, e.g., the shielding difference between equatorial and axial protons vicinal to C-Hal bonds and the deshielding observed for diaxial C-Hal/C-H bond arrangements.A combination of anisotropy and electric-field effects explains all shifts observed in the ketones with the exception of protons vicinal to C=O; a multilinear regression analysis leads to Δχ1C=O = -36 (-27) and Δχ2C=O = -24 (-21) (10-3 cm3/molecule, old ApSimon values in parentheses); it is, however, demonstrated, that an analysis on the basis of NMR shifts alone leads to broad ranges of parameters.Parallels between 1H and 13C NMR shifts are drawn, particularly at γ and θ positions to C-Hal bonds.
- Schneider, Hans-Joerg,Buchheit, Ulrich,Becker, Norman,Schmidt, Guenter,Siehl, Ulrich
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p. 7027 - 7039
(2007/10/02)
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- INTRAMOLECULAR DIELS-ALDER REACTION WITH FURAN-DIENE. TOTAL SYNTHESIS OF (+/-)-11-KETOTESTOSTERONE AND (+/-)-ADRENOSTERONE.
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A novel D BCD ABCD route to 11-keto steroids is reported involving a high yield stereoselective intramolecular Diels-Alder reaction of furan-diene 12 in water as a key-step.The dienophilic side chain is readily introduced starting from 8 via a sequence involving alkylation with ethyl (E)-3-ethoxy-4-iodo-2-butenoate, reduction and acid hydrolysis.The reduced adduct 14 is further converted into (+/-)-adrenosterone (6) via 24, the dienediolate equivalent of which is a known intermediate in corticosteroid synthesis.
- Royen, Luc A. Van,Mijngheer, Roelant,Clercq, Pierre J. De
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p. 4667 - 4680
(2007/10/02)
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- CHEMISTRY OF DIHYDRO-1,4-DIOXIN III. A NEW METHOD FOR THE PREPARATION OF α,α'-DIHYDROXY KETONES FROM KETONES AND ALDEHYDES
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Title compounds, 7, were prepared from ketones and aldehydes via the intermediate 3 by methanolic peracid epoxidation followed by NaBH4 reduction and acidic hydrolysis.Application of this method to the preparation of the unnatural corticoid side chain was reported.
- Fetizon, Marcel,Goulaouic, Pierre,Hanna, Issam
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p. 4925 - 4928
(2007/10/02)
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- INTRAMOLECULAR DIELS-ALDER REACTION WITH FURAN DIENE. A NEW SYNTHESIS OF 11-KETO STEROIDS
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A novel D BCD ABCD route to 11-keto steroids is reported involving a high yield stereoselective intramolecular Diels-Alder reaction of furan-diene 5a in water as a key-step.The dienophilic side chain is readily introduced starting from 2 via a sequence involving alkylation with ethyl 4-iodo-3-ethoxycrotonate, reduction and acid hydrolysis.The reduced adduct 8a, obtained in 24 percent overall yield from 2-methyl-1,3-cyclopentanedione, is converted into (+/-)-adrenosterone (16) via base-opening to 9 and further transformation to 13, the dienediolate equivalent of which is a known intermediate in corticosteroid synthesis.
- Royen, Luc A. Van,Mijngheer, Roelant,Clercq, Pierre J. De
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p. 3145 - 3148
(2007/10/02)
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- Radiolytic degradation scheme for 60Co-irradiated corticosteroids
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The cobalt 60 radiolytic degradation products have been identified in the following corticosteroids: cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone sodium succinate, isoflupredone acetate, methylprednisolone, methylprednisolone acetate, prednisolone, prednisolone acetate, and prednisone. Two major types of degradation processes have been identified: loss of the corticoid side chain the D-ring to produce the C-17 ketone and conversion of the C-11 alcohol, if present, to the C-11 ketone. Minor degradation products derived from other changes affecting the side chain are also identified in several corticosteroids. These compounds are frequently associated in corticosteroids as process impurities or degradation compounds. No new radiolytic compounds unique to 60Co-irradiation have been found. The majority of corticosteroids have been shown to be stable to 60Co-irradiation. The rates of radiolytic degradation ranged from 0.2 to 1.4%/Mrad.
- Kane,Tsuji
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- 4-(Dimethylamino)pyridinium Chlorochromate, a New Selective Reagent for the Oxidation of Allylic and Benzylic Alcohols
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4-(Dimethylamino)pyridinium chlorochromate (3) is a mild selective reagent for the oxidation of complex allylic and benzylic alcohols to the corresponding carbonyl compounds.
- Guziec, Frank S.,Luzzio, Frederick A.
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p. 1787 - 1789
(2007/10/02)
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- Process for preparing 11-keto steroids
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A process for preparing an 11-keto steroid consists essentially of heating the corresponding 9α-halo-11β-hydroxy steroid, to 180°-350° C. in an inert, aprotic, high-boiling solvent.
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