Azasteroid

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David W. Russell - One of the best experts on this subject based on the ideXlab platform.

  • human osteoblast like cells express predominantly steroid 5α reductase type 1
    The Journal of Clinical Endocrinology and Metabolism, 2002
    Co-Authors: Sedika Issa, David W. Russell, Doris Schnabel, Maritta Feix, Lutz Wolf, Hans E Schaefer, H U Schweikert
    Abstract:

    In previous studies we established that human bone and human osteoblast-like cells (hOB cells) cultured from bone express 5α-reductase (5α-R) activity, as demonstrated by the conversion of testosterone and androstenedione to their corresponding 5α-reduced metabolites, 5α-dihydrotestosterone (DHT) and 5α-androstanedione. Two 5α-R isozymes (types 1 and 2) have been identified in various tissues. As their nature in bone is unknown, we investigated which isozymes were expressed in first passage hOB cells cultured from bone specimens obtained from six donors (five women and one man). For comparison, 5α-reductase isozyme expression in genital skin fibroblasts cultured from foreskin of three males was determined. Pharmacological and biochemical studies using selective inhibitors of the 5α-R isozymes were performed, and gene expression was assessed by RT-PCR. In hOB cells, LY191704, a potent nonsteroidal selective inhibitor of 5α-R type 1, and the 4-Azasteroid 17β-(N,N,-diethyl-carbamoyl)-4-methyl-4-aza-5α-andros...

  • ly191704 a selective nonsteroidal inhibitor of human steroid 5 alpha reductase type 1
    Proceedings of the National Academy of Sciences of the United States of America, 1993
    Co-Authors: Kenneth Steven Hirsch, Charles David Jones, James E Audia, Stefan Andersson, Loretta Ames Mcquaid, Nancy B Stamm, Blake Lee Neubauer, Pam Pennington, Richard E Toomey, David W. Russell
    Abstract:

    Abstract Androgens, in particular dihydrotestosterone (DHT), play a key role in differentiation, growth, and maintenance of the mammalian prostate. Production of DHT from testosterone is catalyzed by two distinct membrane-bound steroid 5 alpha-reductase [5 alpha-reductase; 3-oxo-5 alpha-steroid delta 4-dehydrogenase; 3-oxo-5 alpha-steroid:(acceptor) delta 4-oxidoreductase, EC 1.3.99.5] isozymes designated types 1 and 2. Benign prostatic hyperplasia (BPH), a disease that occurs almost universally in males, is characterized by obstructive and irritative urinary voiding symptoms and has been associated with an overproduction of DHT. Recently, steroidal inhibitors of 5 alpha-reductase type 2 have been used successfully for treatment of BPH. Described here is a nonsteroidal inhibitor of 5 alpha-reductase type 1, LY191704 (8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octaahydro-benzo[f]quinol in-3(2H)-one). This compound was identified based on its capacity to inhibit 5 alpha-reductase activity in a human genital skin fibroblast cell line (Hs68). Surprisingly, LY191704 is inactive when tested in freshly isolated prostate cells obtained from subjects with BPH, whereas previously described 4-Azasteroids are active. LY191704 is, however, a potent inhibitor of the 5 alpha-reductase activity of BPH cells that have been maintained in culture. Analysis of human and rat 5 alpha-reductases expressed from transfected cDNAs in simian COS cells indicates that LY191704 is a specific noncompetitive inhibitor of the human 5 alpha-reductase type 1. Taken together, the results suggest that prostate cells have the capacity to express both 5 alpha-reductase isozymes and that LY191704 may be useful in treatment of human endocrine disorders associated with overproduction of DHT by 5 alpha-reductase type 1.

  • tissue distribution and kinetic characteristics of rat steroid 5 alpha reductase isozymes evidence for distinct physiological functions
    Journal of Biological Chemistry, 1992
    Co-Authors: Karl Normington, David W. Russell
    Abstract:

    Abstract The enzyme steroid 5 alpha-reductase (5 alpha-reductase) catalyzes the reduction of delta 4,5 double bonds in a variety of substrates and is thought to play both catabolic and anabolic roles in steroid hormone metabolism. Here, we describe the isolation and characterization of a cDNA encoding the rat type 2 isozyme of 5 alpha-reductase and compare the kinetic properties and tissue-specific expression patterns of this isozyme with those of the type 1 isozyme. The type 2 isozyme has apparent Km values in the nanomolar range for steroid substrates, whereas the type 1 isozyme has micromolar affinities. The isozymes differ in their inhibition by various 4-Azasteroids with the type 2 isozyme showing exquisite sensitivity (Ki = 40 pM) to 21,21-pentamethylene-4-aza-5 alpha-pregn-1-ene-3,20-dione. Messenger RNAs encoding the type 2 isozyme are more abundant than type 1 mRNAs in most male reproductive tissues, whereas the type 1 mRNAs predominate in peripheral tissues. Both 5 alpha-reductase mRNAs are more efficiently induced by dihydrotestosterone than by testosterone in the regenerating prostate. The differences in substrate affinities and tissue distributions of the 5 alpha-reductase isozymes suggest that type 2 plays an anabolic role and type 1 a catabolic role in the metabolism of androgens and other steroid hormones.

  • four amino acid segment in steroid 5 alpha reductase 1 confers sensitivity to finasteride a competitive inhibitor
    Journal of Biological Chemistry, 1992
    Co-Authors: Anice E. Thigpen, David W. Russell
    Abstract:

    Abstract The 4-Azasteroid 17 beta-(N-t-butyl)carbamoyl-4-aza-5 alpha-androst-1-en-3-one (finasteride) is 100-fold more potent as a competitive inhibitor of the rat NADPH:delta 4-3-oxosteroid-5-alpha- oxidoreductase (steroid 5 alpha-reductase) type 1 enzyme (Ki = 3-5 nM) than of the human type 1 enzyme (Ki greater than or equal to 300 nM). In this study, we exploit this differential sensitivity to map a major determinant of finasteride sensitivity in steroid 5 alpha-reductase. Chimeric steroid 5 alpha-reductase cDNAs composed of different combinations of rat and human exon sequences were created by genetic engineering, expressed in human embryonic kidney 293 cells, and assayed for their sensitivity to finasteride. Hybrid proteins containing sequences encoded by rat exon 1 were found to be as sensitive to finasteride as the parental enzyme. The exchange of progressively smaller protein segments encoded within exon 1 identified a tetrapeptide sequence (Val-Ser-Ile-Val) in the rat enzyme that conferred sensitivity to finasteride. The analogous sequence in the human enzyme (Ala-Val-Phe-Ala) conferred partial resistance to the drug. Finasteride was a competitive inhibitor of the native and all chimeric enzymes tested, suggesting that the tetrapeptide segments form a portion of the substrate-binding domain of steroid 5 alpha-reductase.

Hansulrich Reisig - One of the best experts on this subject based on the ideXlab platform.

  • nitrogen containing tricyclic and tetracyclic compounds by stereoselective samarium diiodide promoted cyclizations of quinolyl substituted ketones a new access to Azasteroids
    European Journal of Organic Chemistry, 2008
    Co-Authors: Francesca Aulenta, Irene Brudgam, Ulrike K Wefelscheid, Hansulrich Reisig
    Abstract:

    In this report, we describe our experiments dealing withsamarium diiodide promoted cyclizations of quinolyl-substituted ketones 6–12 and also the attempted reductive cyclization of carbazole-containing ketone 13. These precursors were prepared by Heck-type coupling reactions of the corresponding hetaryl nonaflates with adequately substituted olefins as a key step. The cyclization of compounds 7–12 led to nitrogen-containing tri- and tetracyclic compounds 23–28 in moderate to good yields and generally proceeded in a highly diastereoselective fashion. The azatetracycles present steroid-like skeletons but with unnatural cis–cis annulation of rings B, C and D. We also describe the chemical modification of the styrene-type double bond of these products, which provided highly functionalized steroid-type compounds such as 29, 30 and 32.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

  • a new efficient and stereoselective synthesis of tricyclic and tetracyclic compounds by samarium diiodide induced cyclisations of naphthyl substituted arylketones an easy access to steroid like skeletons
    Chemistry: A European Journal, 2007
    Co-Authors: Francesca Aulenta, Mathias Berndt, Irene Brudgam, Hans Hartl, Sebastian Sorgel, Hansulrich Reisig
    Abstract:

    In this report, we present the application of samarium diiodide induced cyclisations of naphthyl-substituted ketones towards an easy and stereoselective access to tri- and tetracyclic-functionalised compounds. Typical naphthalene derivatives were studied to investigate the scope and limitations of this novel cyclisation process. The model substrates studied demonstrate that the samarium ketyl cyclisations are essentially restricted to the formation of six-membered rings. The diastereoselectivity of these reactions is strongly influenced by the connection of the alkyl side chain to the naphthalene core. Gamma-naphth-1-yl-substituted ketones furnished cyclisation products, such as 17 or 22-26, as single diastereomers, whereas gamma-naphth-2-yl-substituted precursors gave mixtures of diastereomers--as demonstrated by the conversion of model compound 10 into tricyclic products 18 a/18 b, or that of cyclohexanone derivative 33 into tetracyclic diastereomers 34 a/34 b. Cyclic ketones as ketyl precursors furnished steroid-like tetracyclic skeletons; however, due to the cis/cis fusion of rings B/C and C/D these products have an "unnatural" bowl-like shape. Several of the cyclisation products have been identified by X-ray analyses, which not only proved the constitutions, but also the relative configurations and the preferred conformations. Steroid analogue 23 was subjected to subsequent transformations, which demonstrate that the styrene-like double bond of such compounds can be used for further structural diversification. First attempts to synthesise related Azasteroids by incorporating nitrogen atoms into the ketone moiety are also reported. Thus, pyrrolidine derivatives 44 and 47 as well as piperidine derivatives 50 and 52 were subjected to samarium diiodide induced cyclisations. The expected tetracyclic products 48, 49 a/49 b, 51 and 53 a/53 b were obtained in moderate to good yields. The stereoselectivities observed follow the rules already established for the all-carbon precursors. The resulting products, bearing a nitrogen atom in ring D, are interesting Azasteroid analogues with "unnatural" configuration.

Joana Filipa Monteiro De ,sousa - One of the best experts on this subject based on the ideXlab platform.

  • Rastreio virtual na descoberta de possíveis inibidores da 5a-redutase
    2013
    Co-Authors: Joana Filipa Monteiro De ,sousa
    Abstract:

    Dissertação de Mestrado em Química Farmacêutica Industrial apresentada à Faculdade de Farmácia da Universidade de CoimbraA 5α-redutase é uma proteína microssomal, que converte a testosterona em dihidrotestosterona (DHT) um androgénio mais potente que tem como função induzir a diferenciação durante o desenvolvimento do feto que conduz ao desenvolvimento dos genitais externos masculinos. Quando ocorrem distúrbios no desempenho desta enzima, podem surgir distúrbios como o pseudo-hermafroditismo, a calvície, a hiperplasia benigna e o cancro da próstata, entre outras. O cancro da próstata e a hiperplasia benigna da próstata são doenças que têm vindo a aumentar nos últimos anos. Existindo apenas dois fármacos comercializados, a finasterida e a dutasterida, que possuem no entanto efeitos colaterais, sendo por isso necessário o desenvolvimento de melhores inibidores para esta enzima. Neste trabalho procedeu-se numa primeira etapa à tentativa de se obter informações relevantes sobre a possível estrutura da enzima 5α-redutase utilizando a técnica de modelação de proteínas por homologia. Numa segunda etapa tentou-se obter informação sobre a atividade dos inibidores desta enzima, de modo a contribuir para o desenvolvimento de antagonistas mais potentes, seletivos e menos tóxicos. Para esta etapa foram utilizando métodos computacionais de rastreio virtual baseados em ligandos (LBVS) entre as quais, técnicas de aprendizagem de máquina – numa tentativa de compreender como as características físico-químicas de inibidores já conhecidos contribuem para a definição da sua atividade. Por fim, numa terceira etapa, foram analisadas as subestruturas máximas comuns entre os inibidores das duas isoenzimas. Estas subestruturas foram posteriormente utilizadas para a pesquisa de novos possíveis inibidores da 5α.redutase, e a sua atividade foi prevista utilizando os métodos desenvolvidos na etapa anterior. Na primeira etapa do trabalho, com a utilização da técnica de modelação de proteínas por homologia não foi possível obter informações relevantes sobre a possível estrutura da 5α- redutase, com os dados estruturais atualmente disponíveis. Na segunda etapa do trabalho, os resultados obtidos pelos métodos de aprendizagem de máquina mostraram que as características físico-químicas (descritores moleculares) mais importantes para a construção de inibidores da 5α-R2 parecem ser as propriedades aromáticas dos compostos enquanto que para a 5α-R1 surgem propriedades como o LogP, ASA+, volume e área de superfície. A análise das subestruturas máximas comuns obtidas nas diferentes isoenzimas demonstrou que os esteroides 4-Azasteroides e 6-Azasteroides são bons inibidores de ambas as isoenzimas.The 5α-reductase is a microsomal protein that converts testosterone into dihydrotestosterone (DHT), a more potent androgen with the function of inducing differentiation during fetal development that leads to the development of the male external genitalia. When disturbances occur in the performance of this enzyme may arise disorders such as pseudohermaphroditism, baldness, benign hyperplasia and prostate cancer, among others. Prostate cancer and benign prostatic hyperplasia are diseases that have been increasing in recent years. There are only two marketed drugs, finasteride and dutasteride, which have side effects, which therefore stresses the need for the development of better inhibitors for this enzyme. This work presented here was developed in three major steps. In a first step, an attempt was made to obtain relevant information about the possible structure of the enzyme 5α- reductase, using homology protein modeling techniques. In a second step, we tried to obtain information about activity the inhibitors of this enzyme, in order to contribute to the development of more powerful, selective and less toxic antagonists. In this step, we applied ligand based computational methods, the virtual screening (LBVS) computational methods – among which machine learning techniques – in an attempt to understand how the physicochemical characteristics of the known inhibitors contribute to their activity. Finally, in a third step, the maximum common substructures among the inhibitors of both enzymes were analyzed. These substructures we then used to search to search in chemical databases for potential new inhibitors of 5α-reductase, and their activity predicted using the methods developed in the previous step. In the first step of our work, using homology modeling techniques, it was not possible to obtain relevant information about the possible structure of 5α-reductase with structural data currently available. In the second step of our work, the results obtained by the machine learning methods showed that the physic-chemical characteristics (molecular descriptors) most important for the construction of inhibitors of 5α-R2 seem to be the aromatic properties of the compound, while for the 5α-R1 the results suggest that the most important properties as LogP, ASA +, volume and surface area. The analysis of the maximum common substructure obtained with the analysis of compounds for the two isoenzymes showed that 4-Azasteroids and 6-Azasteroids are good inhibitors of both isoenzymes

  • Rastreio virtual na descoberta de possíveis inibidores da 5 α-redutase
    2013
    Co-Authors: Joana Filipa Monteiro De ,sousa
    Abstract:

    Dissertação de mestrado em Química Farmacêutica Industrial, apresentada à Faculdade de Farmácia da Universidade de CoimbraA 5α-redutase é uma proteína microssomal, que converte a testosterona em dihidrotestosterona (DHT) um androgénio mais potente que tem como função induzir a diferenciação durante o desenvolvimento do feto que conduz ao desenvolvimento dos genitais externos masculinos. Quando ocorrem distúrbios no desempenho desta enzima, podem surgir distúrbios como o pseudo-hermafroditismo, a calvície, a hiperplasia benigna e o cancro da próstata, entre outras. O cancro da próstata e a hiperplasia benigna da próstata são doenças que têm vindo a aumentar nos últimos anos. Existindo apenas dois fármacos comercializados, a finasterida e a dutasterida, que possuem no entanto efeitos colaterais, sendo por isso necessário o desenvolvimento de melhores inibidores para esta enzima. Neste trabalho procedeu-se numa primeira etapa à tentativa de se obter informações relevantes sobre a possível estrutura da enzima 5α-redutase utilizando a técnica de modelação de proteínas por homologia. Numa segunda etapa tentou-se obter informação sobre a atividade dos inibidores desta enzima, de modo a contribuir para o desenvolvimento de antagonistas mais potentes, seletivos e menos tóxicos. Para esta etapa foram utilizando métodos computacionais de rastreio virtual baseados em ligandos (LBVS) entre as quais, técnicas de aprendizagem de máquina – numa tentativa de compreender como as características físico-químicas de inibidores já conhecidos contribuem para a definição da sua atividade. Por fim, numa terceira etapa, foram analisadas as subestruturas máximas comuns entre os inibidores das duas isoenzimas. Estas subestruturas foram posteriormente utilizadas para a pesquisa de novos possíveis inibidores da 5α.redutase, e a sua atividade foi prevista utilizando os métodos desenvolvidos na etapa anterior. Na primeira etapa do trabalho, com a utilização da técnica de modelação de proteínas por homologia não foi possível obter informações relevantes sobre a possível estrutura da 5α- redutase, com os dados estruturais atualmente disponíveis. Na segunda etapa do trabalho, os resultados obtidos pelos métodos de aprendizagem de máquina mostraram que as características físico-químicas (descritores moleculares) mais importantes para a construção de inibidores da 5α-R2 parecem ser as propriedades aromáticas dos compostos enquanto que para a 5α-R1 surgem propriedades como o LogP, ASA+, volume e área de superfície. A análise das subestruturas máximas comuns obtidas nas diferentes isoenzimas demonstrou que os esteroides 4-Azasteroides e 6-Azasteroides são bons inibidores de ambas as isoenzimas.The 5α-reductase is a microsomal protein that converts testosterone into dihydrotestosterone (DHT), a more potent androgen with the function of inducing differentiation during fetal development that leads to the development of the male external genitalia. When disturbances occur in the performance of this enzyme may arise disorders such as pseudohermaphroditism, baldness, benign hyperplasia and prostate cancer, among others. Prostate cancer and benign prostatic hyperplasia are diseases that have been increasing in recent years. There are only two marketed drugs, finasteride and dutasteride, which have side effects, which therefore stresses the need for the development of better inhibitors for this enzyme. This work presented here was developed in three major steps. In a first step, an attempt was made to obtain relevant information about the possible structure of the enzyme 5α- reductase, using homology protein modeling techniques. In a second step, we tried to obtain information about activity the inhibitors of this enzyme, in order to contribute to the development of more powerful, selective and less toxic antagonists. In this step, we applied ligand based computational methods, the virtual screening (LBVS) computational methods – among which machine learning techniques – in an attempt to understand how the physicochemical characteristics of the known inhibitors contribute to their activity. Finally, in a third step, the maximum common substructures among the inhibitors of both enzymes were analyzed. These substructures we then used to search to search in chemical databases for potential new inhibitors of 5α-reductase, and their activity predicted using the methods developed in the previous step. In the first step of our work, using homology modeling techniques, it was not possible to obtain relevant information about the possible structure of 5α-reductase with structural data currently available. In the second step of our work, the results obtained by the machine learning methods showed that the physic-chemical characteristics (molecular descriptors) most important for the construction of inhibitors of 5α-R2 seem to be the aromatic properties of the compound, while for the 5α-R1 the results suggest that the most important properties as LogP, ASA +, volume and surface area. The analysis of the maximum common substructure obtained with the analysis of compounds for the two isoenzymes showed that 4-Azasteroids and 6-Azasteroids are good inhibitors of both isoenzymes

A L Mikhalchuk - One of the best experts on this subject based on the ideXlab platform.

  • spectral and kinetic properties of an immunoactive 8 Azasteroid and a product of its photochemical transformation in aqueous solutions
    Optics and Spectroscopy, 2008
    Co-Authors: V L Dubovskiĭ, A L Mikhalchuk, S A Tikhomirov, O V Gulyakevich, T F Raĭchenok, G. B. Tolstorozhev
    Abstract:

    The spectral and kinetic properties of an immunoactive 8-Azasteroid and a product of its photochemical transformation are studied by the methods of steady-state and transient spectroscopy. It is found that the spectral features of the studied compounds in solvents of different nature are determined by a high sensitivity of the electronic structure of the aminovinyldicarbonyl fragment to intermolecular interactions of the donor-acceptor type. This leads to the existence in solutions of several mesomeric-tautomeric forms that are in a dynamic equilibrium controlled by the experimental conditions. Based on the analysis of the dynamics of the transient spectra of induced absorption and of the spectral and luminescent properties of the extracted photoproduct, the conclusion is made on the direction of the photochemical transformation of 2,3-dimethoxy-8-azagona-1,3,5(10),13-tetraene-12,17-dione and the final product is identified as 6,7-dehydroderivative of the parent compound.

  • photochemical processes in aqueous solutions of immunoactive 8 Azasteroid
    Journal of Applied Spectroscopy, 2003
    Co-Authors: N A Borisevich, A L Mikhalchuk, S A Tikhomirov, V L Dubovskii, T F Raichenok, G. B. Tolstorozhev
    Abstract:

    Based on an analysis of the absorption, fluorescence excitation, and fluorescence spectra, and the duration of the excited states of an aqueous solution (pH 7.4) of 2,3-dimethoxy-8-azagona-1,3,5(10),13-tetraen-12,17-dione molecules, the existence of two centers emitting longwave (L centers) and shortwave (S centers) fluorescence has been established. Irradiation of the solution accelerates the accumulation of L centers and considerably reduces the quantity of S centers that represent the initial molecule. Analysis of the induced-absorption spectra and their kinetics with picosecond time resolution shows that ionization of the molecule studied is the initial photochemical act and formation of a dehydro derivative of the initial molecule or protonation of carbonyl groups is the next act.

  • phosphorescence of 8 Azasteroid in solid solution
    Journal of Fluorescence, 2002
    Co-Authors: S A Bagnich, V N Knyukshto, N N Khropik, A L Mikhalchuk
    Abstract:

    This paper presents the results of the investigation of delayed luminescence of 2,3-methoxy-8-azagona-1,3,5(10),13-tetraene-12,17-dione classed with 8-Azasteroids in ethanol solution at 77 K. Dual phosphorescence with maxima in the region of 400 and 500 nm, depending on the excitation wavelength, has been discovered. It is shown that the short-wavelength luminescence is due to the radiation transition from second triplet state. The possible mechanisms of emergence of dual phosphorescence in the compound investigated are considered.

  • dual phosphorescence of 8 Azasteroid in ethanol solid solution
    Chemical Physics, 2001
    Co-Authors: S A Bagnich, N N Khropik, V N Knykshto, A L Mikhalchuk
    Abstract:

    Abstract This paper presents the results of the investigation of delayed luminescence of 2,3-dimethoxy-8-azagona-1,3,5(10),13-tetraene-12,17-dione classed with 8-Azasteroids in ethanol solution at 77 K. Dual phosphorescence with maxima in the region of 400 and 500 nm depending on the excitation wavelength has been discovered. It is shown that the short-wavelength luminescence is due to the radiation transition from second triplet state. The possible mechanisms of emergence of dual phosphorescence in the compound investigated are considered.

  • exciton luminescence of 8 Azasteroid microcrystals
    Journal of Applied Spectroscopy, 1999
    Co-Authors: A. A. Akhrem, O. V. Gulyakevich, N A Borisevich, A L Mikhalchuk, S A Tikhomirov, V N Knyukshto, G. B. Tolstorozhev
    Abstract:

    Luminescence of microcrystals of 2,3-methoxy-8-azagon-1,3,5(10),13-tetraene-12,17-dion of the class of molecules of biologically active steroids is detected at room temperature (293 K). It represents fast fluorescence of free and self-localized excitons and prolonged phosphorescence of triplet excitons.

Francesca Aulenta - One of the best experts on this subject based on the ideXlab platform.

  • nitrogen containing tricyclic and tetracyclic compounds by stereoselective samarium diiodide promoted cyclizations of quinolyl substituted ketones a new access to Azasteroids
    European Journal of Organic Chemistry, 2008
    Co-Authors: Francesca Aulenta, Irene Brudgam, Ulrike K Wefelscheid, Hansulrich Reisig
    Abstract:

    In this report, we describe our experiments dealing withsamarium diiodide promoted cyclizations of quinolyl-substituted ketones 6–12 and also the attempted reductive cyclization of carbazole-containing ketone 13. These precursors were prepared by Heck-type coupling reactions of the corresponding hetaryl nonaflates with adequately substituted olefins as a key step. The cyclization of compounds 7–12 led to nitrogen-containing tri- and tetracyclic compounds 23–28 in moderate to good yields and generally proceeded in a highly diastereoselective fashion. The azatetracycles present steroid-like skeletons but with unnatural cis–cis annulation of rings B, C and D. We also describe the chemical modification of the styrene-type double bond of these products, which provided highly functionalized steroid-type compounds such as 29, 30 and 32.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

  • a new efficient and stereoselective synthesis of tricyclic and tetracyclic compounds by samarium diiodide induced cyclisations of naphthyl substituted arylketones an easy access to steroid like skeletons
    Chemistry: A European Journal, 2007
    Co-Authors: Francesca Aulenta, Mathias Berndt, Irene Brudgam, Hans Hartl, Sebastian Sorgel, Hansulrich Reisig
    Abstract:

    In this report, we present the application of samarium diiodide induced cyclisations of naphthyl-substituted ketones towards an easy and stereoselective access to tri- and tetracyclic-functionalised compounds. Typical naphthalene derivatives were studied to investigate the scope and limitations of this novel cyclisation process. The model substrates studied demonstrate that the samarium ketyl cyclisations are essentially restricted to the formation of six-membered rings. The diastereoselectivity of these reactions is strongly influenced by the connection of the alkyl side chain to the naphthalene core. Gamma-naphth-1-yl-substituted ketones furnished cyclisation products, such as 17 or 22-26, as single diastereomers, whereas gamma-naphth-2-yl-substituted precursors gave mixtures of diastereomers--as demonstrated by the conversion of model compound 10 into tricyclic products 18 a/18 b, or that of cyclohexanone derivative 33 into tetracyclic diastereomers 34 a/34 b. Cyclic ketones as ketyl precursors furnished steroid-like tetracyclic skeletons; however, due to the cis/cis fusion of rings B/C and C/D these products have an "unnatural" bowl-like shape. Several of the cyclisation products have been identified by X-ray analyses, which not only proved the constitutions, but also the relative configurations and the preferred conformations. Steroid analogue 23 was subjected to subsequent transformations, which demonstrate that the styrene-like double bond of such compounds can be used for further structural diversification. First attempts to synthesise related Azasteroids by incorporating nitrogen atoms into the ketone moiety are also reported. Thus, pyrrolidine derivatives 44 and 47 as well as piperidine derivatives 50 and 52 were subjected to samarium diiodide induced cyclisations. The expected tetracyclic products 48, 49 a/49 b, 51 and 53 a/53 b were obtained in moderate to good yields. The stereoselectivities observed follow the rules already established for the all-carbon precursors. The resulting products, bearing a nitrogen atom in ring D, are interesting Azasteroid analogues with "unnatural" configuration.