Investigation of steroids. XLII. Transformation of 17-alpha-pseudostrophanthidins to 19-hydroxy-8,19-epoxy-14-beta,17-alpha-cortexone and 8-hydroxy-19-nor-14-beta,17-alpha-cortexone

The synthesis of a structural isomer of aldosterone, viz. 19-hydroxy-8, 19-epoxy-(11-) de(s)oxycorticosterone (= 19-hydroxy-8, 19-epoxy-cortexone), and a number of related compounds was reported earlier from this laboratory [1]. It appeared desirable to prepare the corresponding compounds of the 17α-series also, such as 19-hydroxy-8, 19-epoxy-14 β, 17 (βH)-deoxycorticosterone ( 28 ). 17 α-Pseudostrophanthidin ( 2 ), which has not yet been described in the literature, was considered as starting material for the synthesis of 28. 2 has now been prepared by heating a solution of pseudostrophanthidin ( 1 ) in dimethylformamide in the presence of sodium p-toluenesulfonate and anhydrous sodium acetate. 2 was characterized as the 3, 19-diacetate ( 7 ), the 19-methylal ( 8 ) and the 3-monoacetat ( 9 ). 9 was also obtained by acetylating the methylal 8 and demethylating the resulting reaction product 10. To support the structures assigned to 9 and, by implication, to 2 , a series of further reactions were carried out.     

Fluordiazadiphosphetidine, 17. Mitt.

The reactions of (CH₃NPF₃)₂ and F₃P(CH₃N)₂PF₂OCH₃ with lithium-1,1,1-trimethyl-N-(trimethylsilyl)-silanamide yield two new dispiro-compounds:XF₂P(CH₃N)₂PF(NSiCH₃)₂PF(CH₃N)₂PF₂ X withX=F, OCH₃. Synthesis, mass-spectra and X-ray structures are discussed.

Herrn Prof. Dr.K. L. Komarek zum 60. Geburtstag gewidmet.     

Oxydative Umwandlung von 17-Alkoxy-aspidospermidin-Derivaten in 17, 17-Dialkoxy-17, 18-dihydro-1, 18-dehydro-aspidospermidine

Treatment of 17-alkoxy-aspidospermidine derivatives with iodine and sodium hydroxide in methanolic or ethanolic solution yields the corresponding 17, 17-dialkoxy-17, 18-dihydro-1, 18-dehydro-aspidospermidine. Hence compounds 1 and 2 in methanol give the oxidation products 8 and 3 , respectively. In ethanol, 4 is converted to 5 , 2 to a mixture of 6 and 7 ; 4 in methanol yields a mixture of 6 and 7 in a different ratio.     

Tetracyanoquinodimethane complexes of copper and a 17-membered N,O-donor macrocycle

An axially elongated copper(II) complex, CuL¹Cl₂, has been obtained by reaction of copper(II) chloride with a 17-membered N,O-donor macrocyclic ligand (L¹). In an attempt to prepare the complex from copper(II) perchlorate, crystals of L¹ suitable for X-ray were obtained as its diperchlorate salt, [H₂L¹][ClO₄]₂. Further reaction of CuL¹Cl₂ with LiTCNQ and Et₃NH(TCNQ)₂ furnished the charge transfer copper(I) complexes CuL¹(TCNQ)₂·3H₂O and CuL¹(TCNQ)₃, with TCNQ carrying partially reduced charge. The presence of a diamagnetic metallic centre was confirmed by EPR and magnetic measurements.     

73GE, 17O, 13C NMR Spectra of alkoxygermanes

¹³C, ¹⁷O and ⁷³Ge NMR spectra of seven tetraalkoxygermanes have been investigated. ⁷³Ge resonance signals in these compounds are more sensitive to structure variations than those of ²⁹Si in isostructural alkoxysilanes. ¹⁷O and ¹³C NMR spectra of alkoxygermanes Me_4-n Ge(OR)_n (R = Et, Pr, Bu, i-Bu, s-Bu, CH₂CHCH₂, CH₂CH₂OMe, CH₂CF₃; n = 1–3) have been studied.It has been shown that the magnitude of (p—d)_τ-bonding in the GeO bond is smaller than in the SiO bond, but variation in the extent of (p—d)_τ-overlapping in alkozygermanes with different substituents is similar to that in the isostructural alkoxysilanes.     

Structure of 7, 8, 17, 18-Tetrabromo-5,10,15, 20-Tetraphenylporphinatozinc(Ⅱ)

1mrnODUCTIONRecentlywereportedthestructureof7,8,17,18--tetrabromo--5,10,15,20--tetraphenylporphinatozinc(H,TPPBr.)ill.Inordertoobservetheeffectofthefoulelectron--withdrawingbromogroupsonthestructureofametalcomplexofthisPOrphyrin,thetitlecompoundwaspreparedbyanestablishedmethod[Ziandthecrysta:wasobtained,whichissuitableforstructureanalysisbylayeringasolutioninCHCI,withpetroleum(60--90C)--piperidine.2EXPERIMENTALThetitlecomplexwassynthesizedbyreactionofH,TPPBr.andZn(CH,COO):.ZH…     

Synthesis of (2s, 3r, 7rs)-stegobinone [2,3-dihydro-2,3,5-trimethyl-6-(1-methyl-2- oxobutyl)-4h-pyran-4-one] and its (2r, 3s, 7rs)-isomer : The pheromone of the drugstore beetle

Reaction of acetaldehyde with the trianion of 4,6-dimethylnonane-3,5,7-trione followed by acidification yielded a stereoisomeric mixture of stegobinone, the pheromone of Stegobium paniceum L. Acylation of the dianion derived from 4-methylheptane-3,5-dione with a mixed anhydride prepared from (2R, 3S)-3-hydroxy-2-methylbutanoic acid or its enantiomer led to (2S,3R,7RS)- or (2R, 3S, 7RS)-stegobinone. The natural pheromone possesses (2S,3R)-stereochemistry.     

Synthesis of 6α-methyl-16α, 17α-cyclohexanoprogesteronevia γ-methylenation of 16α, 17α-cyclohexanopregn-4-ene-3,20-dione

6-Methylene-16α, 17α-cyclohexanopregn-4-ene-3,20-dione 2 has been synthesized by the reaction of Δ⁴-3-ketone1 with CH₂(OEt)₂ and POCl₃ in the presence of AcONa in 55% yield. Reduction of the product2 in the presence of 5% Pd/C gives 6α-methyl-16α, 17α-cyclohexanoprogesterone3 in a yield exceeding 70%. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1234–1236,June, 1997.     

Cardenolides ofStrophanthus kombe III. 17α-Strophadogenin

17α-Strophadogenin, which is 3β,5,14,16β-tetrahydroxy-19-oxo-5β,14β-card-17βH-20(22)-enolide has been obtained in the pure form for the first time and has been studied.     

Non-Alcoholic Fatty Liver Disease in Long-Term Type 2 Diabetes: Role of rs738409 PNPLA3 and rs499765 FGF21 Polymorphisms and Serum Biomarkers

Fibroblast growth factor 21 (FGF21) signaling and genetic factors are involved in non-alcoholic fatty liver disease (NAFLD) pathogenesis. However, these factors have rarely been studied in type 2 diabetes mellitus (T2D) patients from admixed populations such as in those of Brazil. Therefore, we aimed to evaluate rs738409 patanin-like phospholipase domain-containing protein (PNPLA3) and rs499765 FGF21 polymorphisms in T2D, and their association with NAFLD, liver fibrosis, and serum biomarkers (FGF21 and cytokeratin 18 levels). A total of 158 patients were included, and the frequency of NAFLD was 88.6%, which was independently associated with elevated body mass index. Significant liver fibrosis (≥F2) was detected by transient elastography (TE) in 26.8% of NAFLD patients, and was independently associated with obesity, low density lipoprotein, and gamma-glutamyl transferase (GGT). PNPLA3 GG genotype and GGT were independently associated with cirrhosis. PNPLA3 GG genotype patients had higher GGT and AST levels; PNPLA3 GG carriers had higher TE values than CG patients, and FGF21 CG genotype patients showed lower gamma-GT values than CC patients. No differences were found in serum values of FGF21 and CK18 in relation to the presence of NAFLD or liver fibrosis. The proportion of NAFLD patients with liver fibrosis was relevant in the present admixed T2D population, and was associated with PNPLA3 polymorphisms.     

17O-enriched α-azohydroperoxides: 17O NMR spectroscopy, 17O-labeling reagents

¹⁷O-enriched α-azohydroperoxides, prepared by autoxidation, are efficient ¹⁷O-labeling reagents; ¹⁷O NMR (CD₃CN) of 2 showed broad signals at δ 254 and 204 PPM; the solvent dependence of the ¹⁷O chemical shifts and the kinetics of ionic oxidations are interrelated.     

Further studies on the stereochemistry of sparteine, its isomers and derivatives : Part. I. Synthesis, structure and properties of 16,17-endo-methylene-lupaniumm perchlorate, 17-β-methyllupanine and 17-β-methylsparteine

The reduction of the product (V) obtained from the reaction of δ^16,17-dehydro- lupaninium perchlorate with diazomethane leads to 17-β-methyllupanine (III) (NaBH₄- reduction) or to 17-β-methylsparteine (X) (LiAlH₄-reduction). The structures of III and X were determined by spectroscopic methods (NMR and IR) and further proved by chemical methods. The β-methyl group at C-17 has a pronounced effect on the basicity of III and X. The basicity of in is higher than that of its parent lupanine by about 1.5 pK^*_MCSunits which can be explained by additional stabilization of the C/D boat-chair conformation in III and better solvation conditions than in lupanine. The same effect leads to a decrease of the δpK^*_MCS-value of the diamine X with reference to that of sparteine by ca. 2.6 units. The methyl group in X stabilizes the C/D boat-chair conformation and hinders the formation of an intramolecular hydrogen bond in monoprotonated X, consequently the addition of a second proton is favoured and it is assumed that the diprotonated cations of X and sparteine have different conformations. The reaction intermediate 16,17-endo-methylenelupaninium perchlorate (V) was isolated and its structure was determined.     

One-electron reduction of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin: a pulse radiolysis study

Geldanamycin, a benzoquinone ansamycin antibiotic, is a natural product inhibitor of Hsp90 with potent and broad anticancer properties but with unacceptable levels of hepatotoxicity. Consequently, numerous structural analogs, which differ only in their 17-substituent, have been synthesized including the water-soluble and less toxic 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG, Alvespimycin). It has been suggested that the different hepatotoxicity reflects the redox active properties of the quinone moiety. The present pulse radiolysis study was aimed at studying the one-electron reduction of 17-DMAG. The UV-visible spectrum of the semiquinone radical, its pK(a), and the second-order rate constants for the reactions of 17-DMAG with CO(2)(?-) and (CH(3))(2)C(?)OH have been obtained. The reduction potential of 17-DMAG has been determined to be -194 ± 6 mV (vs NHE) using oxygen, 1,4-naphthoquinone, and menadione as electron acceptors. This reduction potential is lower than that of O(2) demonstrating that thermodynamically the semiquinone radical can reduce O(2) to superoxide, particularly since the concentration of O(2) is expected to exceed that of the drug in cells and tissues.     

Direct Electrochemical Investigations of 17-Electron Complexes of CpM(CO)(3)(*) (M = Mo, W, and Cr)

Photolysis of complexes of the type M(2)(CO)(6)(RC(5)H(4))(2) (where M = W, Mo, Cr and R = H (Cp) or CH(3) (Cp')) leads to the production of short lived 17-electron radicals. Direct electrochemical characterization of these intermediates has been achieved using a technique known as photomodulated voltammetry (PMV). The results from PMV analysis are in excellent agreement with literature estimates for CpMo(CO)(3)(*) and CpCr(CO)(3)(*). However, CpW(CO)(3)(*) is found to be shifted oxidatively 115 mV relative to previous literature estimates. The change in the value for the tungsten complex changes previous estimates to the bond dissociation energy for tungsten metal hydrides by 3.0 +/- 0.9 kcal/mol. Lifetime information on the radicals is also reported based on the phase shift of the electrochemical signal observed by PMV under limiting current conditions.     

Ring-borylated 15-electron and 17-electron ansa-chromocene complexes, their physical properties and molecular structures

A detailed study of the thermal decomposition of the zwitterionic, ring-borylated ansa-chromocene hydrido carbonyl complex [Cr(CO)H{Me(4)C(2)(C(5)H(4))[C(5)H(3)B(C(6)F(5))(3)]}] (2) is described. This complex is formed in the reaction between [Cr(CO){Me(4)C(2)(C(5)H(4))(2)}] (1) and B(C(6)F(5))(3) in toluene at -78 degrees C. Above -25 degrees C, 2 decomposes to a 50:50 mixture of the low-spin, 17e Cr(III) complexes [Cr(CO){Me(4)C(2)(C(5)H(4))[C(5)H(3)B(C(6)F(5))(3)]}] (3b) and [Cr(CO){Me(4)C(2)(C(5)H(4))(2)}][HB(C(6)F(5))(3)] (4). Carbon monoxide elimination from 3 b generates high-spin, 15 e [Cr{Me(4)C(2)(C(5)H(4))[C(5)H(3)B(C(6)F(5))(3)]}] (3a), which coordinates two other electron-donating ligands, such as xylyl isocyanide, PMe3, and PPh(2)Me to form the low-spin, 17 e electron complexes 3c, 3d, and 3e, respectively. High-spin, 15 e [Cr{Me(4)C(2)(C(5)H(4))(2)}][HB(C(6)F(5))(3)] (5) is generated by heating 3 b in toluene at 100 degrees C and periodically removing the evolved CO. Efforts to isolate more than a few X-ray quality crystals of 5 were thwarted by its tendency to form an insoluble precipitate (6) with the same molecular formula. Heating the solution of 5 at 120 degrees C results in its partial conversion (ca. 28 %) to 3a, thereby allowing the formation of 3a in yields as high as 74 % from the reaction between 1 and B(C(6)F(5))(3). The X-ray crystal structures of 3 b-e and 5 are described. Cyclic voltammetry measurements on 3 a-e reveal a dramatic reduction in the redox potentials of the complexes relative to their non-borylated analogues. DFT calculations show that this is due primarily to electrostatic stabilization of the oxidized species by the negatively charged borylate group. EPR and 19F NMR spectroscopy allow 3a to be distinguished from its Lewis base adducts 3 b-e and reveal the relative affinities of different Lewis bases for the chromium.     

Mass spectrometry of steroid glucuronide conjugates. II-Electron impact fragmentation of 3-keto-4-en- and 3-keto-5alpha-steroid-17-O-beta glucuronides and 5alpha-steroid-3alpha,17beta-diol 3- and 17-glucuronides

The steroid glucuronide conjugates of 16,16,17-d(3)-testosterone, epitestosterone, nandrolone (19-nortestosterone), 16,16,17-d(3)-nortestosterone, methyltestosterone, metenolone, mesterolone, 5alpha-androstane-3alpha,17beta-diol, 2,2,3,4,4-d(5)-5alpha-androstane-3alpha,17beta-diol, 19-nor-5alpha-androstane-3alpha,17beta-diol, 2,2,4,4-d(4)-19-nor-5alpha-androstane-3alpha,17beta-diol and 1alpha-methyl-5alpha-androstane-3alpha/beta,17beta-diol were synthesized by means of the Koenigs-Knorr reaction. Selective 3- or 17-O-conjugation of bis-hydroxylated steroids was performed either by glucuronidation of the corresponding steroid ketole and subsequent reduction of the keto group or via a four-step synthesis starting from a mono-hydroxylated steroid including (a) protection of the hydroxy group, (b) reduction of the keto group, (c) conjugation reaction and (d) removal of protecting groups. The mass spectra and fragmentation patterns of all glucuronide conjugates were compared with those of the commercially available testosterone glucuronide and their characterization was performed by gas chromatography/mass spectrometry and nuclear magnetic resonance spectroscopy. For mass spectrometry the substances were derivatized to methyl esters followed by trimethylsilylation of hydroxy groups and to pertrimethylsilylated products using labelled and unlabelled trimethylsilylating agents. The resulting electron ionization mass spectra obtained by GC/MS quadrupole and ion trap instruments, full scan and selected reaction monitoring experiments are discussed, common and individual fragment ions are described and their origins are proposed.     

Brominations of steroidal hormone having alpha,beta-unsaturated ketone, 17-O-acetyltestosterone, in the presence of silver triflate

Bromination of 17-O-acetyltestosterone (17beta-acetoxyandrost-4-en-3-one) (1) was performed with 1, 5, and 10 eq of Br2 in AcOH-Et2O at room temperature. In all cases 2alpha,6beta- (2) and 2alpha,6beta-dibromo-17beta-acetoxyandrost-4-en-3-one (3) were obtained, although the yields were dependent upon the conditions used. Bromination of compound 1 with 10 eq of Br2 in the presence of silver trifluoromethanesulfonate (silver triflate, AgOTf) at room temperature for 12 h gave 2,7alpha-dibromo- (4) and 2,4,7alpha-tribromo-17beta-acetoxy-3-hydroxy-1-methylestra-1,3,5(10)-triene-6-one (5). The formations of the products were inferred on the basis of products obtained under controlled brominations of 1 in the presence of AgOTf, and of those obtained by the brominations of compounds 9-13 also in the presence of AgOTf.     

Neue Komplexe der Lanthanoiden mit zweizähnigen Liganden. Die Strukturen von [(C17H17N2)GdBr2(thf)2] und [(C17H17N2)3Ln] (L = Sm,Gd)

New Complexes of the Lanthanoides with Bidentate Ligands. The Crystal Structures of [(C₁₇H₁₇N₂)GdBr₂(thf)₂] and [(C₁₇H₁₇N₂)₃Ln] (L = Sm, Gd) Reaction of [(AIP)Li] with GdBr₃ leads to a new mononuclear complex [(AIP)GdBr₂(thf)₂] 1 . In contrast to this with SmI₂ the compound [(AIP)₃Sm] 2 is build up. Such complexes are also formed with Gd(OR^*)₃ (R^* = O^tBu₂C₆H₃) and [(AIP)Li] in a 1:3 ratio, [(AIP)₃Gd] 3 . The structures of 1–3 were characterized by X-ray single crystal structure analysis ( 1 : space group Pna2₁ (No. 33), Z = 4, a = 1 972.7(9) pm, b = 984.7(5) pm, c = 1 425.0(8) pm, α = β = γ = 90°; 2 · 2 THF: space group C2/c (No. 15), Z = 8, a = 3 644.4(9) pm, b = 1 437.5(5) pm, c = 2 334.4(7) pm, β = 1 21.07(6)°; 3 : space group P2(1)/c (No. 14), Z = 4, a = 1 872.9(1) pm, b = 1 064.6(1) pm, c = 2 282.4(2) pm, β = 103.75(8)°).     

Synthesis of 17E- and 17Z-Cheilanthene-13α, 19-diols

cis- and trans-Cheilanthene-3α, 19-diols — structurally close analogues of the parent of the cheilanthane sesterterpenoids cheilantha-6α,13α,19-triol and substances related to it — have been synthesized.     

Crystal and Molecular Structure of 17-(1-Adamantyl)amino-6,7,9,10-tetrahydro-17H-dibenzo[d, m]-[1,3,6,9,12,2]pentaoxaphosphacyclotetradecine-17-oxide

The crystal structure of 17-(1-adamantyl)amino-6,7,9,10-tetrahydro-17H-dibenzo[d, m][1,3,6,9,12,2]pentaoxaphosphacyclotetradecine-17-oxide, C₂₆H₃₂NO₆P (I), was determined by single crystal X-ray diffraction. The monoclinic structure of I (space group P2₁ /n; a=10.951(2), b=16.730(3), c=13.255(3) , =99.22(2)°, Z=4) was solved by direct methods and refined anisotropically by the full-matrix least-squares method; R=0.042 for all independent 4197 reflections (CAD-4 automatic diffractometer, MoK). The geometrical parameters of molecule I (bond lengths and bond and torsion angles) were determined with a good accuracy.