Transformations of kurchi alkaloids—I The action of nitrous acid on holarrhimine

Holarrhimine (I), 18-hydroxy-3β,20-diamino-5-pregnene, was treated with nitrous acid under different conditions. From the reaction mixtures several crystalline products were isolated and characterized as 3β-hydroxy-18-20β-oxido-5-pregnene (II), the nitrate ester of II (III), 3β-nitro-18-20β-oxido-5-pregnene (IV), 6-methoxy-18-20β-oxido-3,5-cyclopregnane (V) and 3β,18-dihydroxy-20-amino-5-pregnene (VII). On treatment with boron trifluoride and acetic anhydride compounds II, IV, V and an unidentified compound (VI) gave the same triacetate 3β,18,20-triacetoxy-5-pregnene (VIII).     

Comparison of calculated DFT/B3LYP and experimental C and O NMR chemical shifts, ab initio HF/6-31G* optimised structures, and single crystal X-ray structures of some substituted methyl 5β-cholan-24-oates

Single crystal X-ray structures (monoclinic space group P2₁) for methyl 3-oxo-5β-cholan-24-oate and methyl 3,12-dioxo-5β-cholan-24-oate have been solved and compared with HF/6-31G* optimised structures. In the crystalline packings the side chains are connected with weak OC(sp³)HO-type of interactions between C25–H and C24–O–C25 and the keto ends with weak C(sp³)HO=C-type of interactions between C4–H and O=C3. The orientations of the side chains, which steric configurations are of great importance to the biological activity of the molecules, are compared with the experimental structure of methyl 3-hydroxy-5β-cholan-24-oate. Probable reasons for the observed differences are discussed. In addition, ¹³C and ¹⁷O NMR chemical shifts of methyl 3-oxo-5β-cholan-24-oate and methyl 3,12-dioxo-5β-cholan-24-oate as well as the epimeric methyl 3-hydroxy-5β-cholan-24-oate and methyl 3β-hydroxy-5β-cholan-24-oate have been calculated (DFT/B3LYP/6-311G*) and compared with the experimental values by linear regression analyses. In general, the correspondence between the theoretical and experimental parameters is good or excellent.     

Unusual sulfated marine steroids from the ophiuroid ophioderma longicaudum

Polar extracts of the ophiuroid Ophioderma longicaudun contain unusual sterol sulfates together with a mixture of common 3β-hydroxysterol sulfates. The more polar compound has been shown to be 5β-cholestane-3, 4,11β,12β,21-pentol 3,21-disulfate 1. A second group of unusual compounds are disulfated 3,21-dihydroxysteroids. After solvolysis to remove the sulfate groups they have been identified as : (20R)-5-cholestane-3, 21-diol 4a, (20R)-cholest-5-ene-3,21-diol 5a, (20R22E)-cholest-5,22-diene-3,21-diol 6a and (20R)-24-methylcholest-5,24(28)-diene-3,21-diol 7a. Analysis of the “non-sulfated” sterol fractions has shown the presence of common 3β-hydroxy sterols.     

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.     

Steroids and sex hormones. The synthesis of 1-beta, 4-beta-oxido-3-aza-17-beta-hydroxy-A-homo-5-alpha-androstane

A sterically controlled transformation of 3-oxo-17β-acetoxy-Δ^1?-α-androstene ( 2 ) into 1β,4β-oxido-3-aza-17β-hydroxy-A-homo-5α-androstane ( 16 ) is described. With the exception of two conversions [ 14 → 15 (60%); 15 → 16 (50%)], the yields of the remaining seven steps are higher than 75% each. The reaction sequence will serve as a model for an analogous partial synthesis of samandarine ( 1 ).     

Fused sulfur-containing pyridine systems. 1. Synthesis and structures of tetrahydropyridothienopyridinone and tetrahydropyridothiopyranopyridinone derivatives

The reactions of N-methylmorpholinium 4-aryl(hetaryl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates with malononitrile and acetone in ethanol afforded substituted tetrahydropyridothienopyridinones. In the absence of acetone, tetrahydropyridothiopyranopyridinones were isolated as the major reaction products. The latter were also synthesized independently by the reactions of the above-mentioned thiolates with 2-amino-1,1,3-tricyanopropene. The structure of 2,4-diamino-10-(2-chlorophenyl)-3-cyano-5-imino-8-oxo-7,8,9,10-tetrahydro-5H-pyrido[2",3":2,3]thiopyrano[4,5-b]pyridine was established by X-ray diffraction analysis.     

20, 21-Azirdin-Steroide: Reaktion von Derivaten der Oxime von 5-Pregnen-20-on,9β,10α-5-Pregnen-20-on und 9β,10α-5,7-Pregnadien-20-on mit Lithiumaluminiumhydrid und von 3β-Hydroxy-5-pregnen-20-on-oxim mit Grignard-Verbindungen

20, 21-Aziridine Steroids: Reaction of Derivatives of the Oximes of 5-Pregnen-20-one, 9β, 10α-5-Pregnen-20-one and 9β, 10α-5,7-Pregnadiene-20-one with Lithium Aluminium Hydride, and of 3β-Hydroxy-5-pregnen-20-one Oxime with Grignard Reagents. Reduction of 3β-hydroxy-5-pregnen-20-one oxime ( 2 ) with LiAlH₄ in tetrahydrofuran yielded 20α-amino-5-pregnen-3β-ol ( 1 ), 20β-amino-5-pregnen-3β-ol ( 3 ), 20β, 21-imino-5-pregnen-3β-ol ( 6 ) and 20β, 21-imino-5-pregnen-3β-ol ( 9 ). The aziridines 6 and 9 were separated via the acetyl derivatives 7 and 10 . The reaction of 6 and 9 with CS₂ gave 5-(3β-hydroxy-5-androsten-17β-yl)-thiazolidine-2-thione ( 8 ). Treatment of the 20-oximes 12 and 15 of the corresponding 9β,10α(retro)-pregnane derivatives with LiAlH₄ gave the aziridines 13 and 16 , respectively. Their deamination led to the diene 14 and triene 17 , respectively. Reduction of isobutyl methyl ketone-oxime with LiAlH₄ in tetrahydrofuran yielded 2-amino-4-methyl-pentane ( 19 ) as main product, 1, 2-imino-4-methyl-pentane ( 22 ) as second product and the epimeric 2,3-imino-4-methyl-pentanes 20 and 21 as minor products. – 3β-Hydroxy-5-pregnen-20-one oxime ( 2 ) was transformed by methylmagnesium iodide in toluene to 20α, 21-imino-20-methyl-5-pregnen-3β-ol ( 23 ) and 20β, 21-imino-20-methyl-5-pregnen-3β-ol ( 26 ). Acetylation of these aziridines was accompanied by elimination reactions leading to 3β-acetoxy-20-methylidene-21-N-acetylamino-5-pregnene ( 30 ) and 3β-acetoxy-20-methyl-21-N-acetylamino-5,17-pregnadiene ( 32 ). The reaction of oxime 2 with ethylmagnesium bromide in toluene gave 20α, 21-imino-20-ethyl-5-pregnen-3β-ol ( 24 ) and 20α,21-imino-20-ethyl-5-pregnen-3β-ol ( 27 ). Acetylation of 24 and 27 led to 3β-acetoxy-20-ethylidene-21-N-acetylamino-5-pregnene ( 31 ), 3β-acetoxy-20-ethyl-21-N-acetylamino-5,17-pregnadiene 33 and 3β, 20-diacetoxy-20-ethyl-21-N-acetylamino-5-pregnene ( 37 ). With phenylmagnesium bromide in toluene the oxime 2 was transformed to 20β, 21-imino-20-phenyl-5-pregnen-3β-ol ( 25 ) and 20β,21-imino-20-phenyl-5-pregnen-3β-ol ( 28 ). Acetylation of 25 and 28 yielded 3β-acetoxy-20-phenyl-21-N-acetylamino-5, 17-pregnadiene ( 34 ) and 3β,20-diacetoxy-20-phenyl-21-N-acetylamino-5-pregnene ( 39 ). LiAlH₄-reduction of 39 gave 3β, 20-dihydroxy-20-phenyl-21-N-ethylamino-5-pregnene ( 41 ). – The 20, 21-aziridines are stable to LiAlH₄. Consequently they are no intermediates in the formation of the 20-amino derivatives obtained from the oxime 2 .     

Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related alpha-amino acids

The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 degrees C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).     

Determination of critical micellar concentrations of cholic acid and its keto derivatives

The critical micellar concentration (CMC) values of keto derivatives of cholic acid (3,12-dihydroxy-7-oxo-5β-cholanoic acid, 3,7-dihydroxy-12-oxo-5β-cholanoic acid, 12-hydroxy-3,7-dioxo-5β-cholanoic acid, 3-hydroxy-7,12-dioxo-5β-cholanoic acid, 3,7,12-triketo-5β-cholanoic acid) and cholic acid itself, were determined. Replacement of hydroxyl groups in cholic acid molecule with keto groups yields the derivatives whose CMC values increase with increase in the number of keto groups introduced. The CMCs of derivatives with the same number of keto groups but at different positions do not differ significantly. The relationship between the number of keto groups in the molecule of cholic acid keto derivatives and CMC value can be described by the following equation: CMC = 43 number of keto groups + 14.667. The effect of NaCl concentration on CMC increases with increase in the number of keto groups.     

Über die Herstellung von substituierten 2,3,4,5-Tetrahydro-1,2,4-triazin-6-carbonitrilen und einige ihrer Abwandlungsreaktionen

Preparation of substituted 2,3,4,5-Tetrahydro-1,2,4-triazine-6-carbonitriles and some of its Derivatives. The synthesis of 4-substituted 2-aryl-2,3,4,5-tetrahydro-5-imino-3-oxo-1,2,4-triazine-6-carbonitriles ( 3 ), 2-aryl-2,3,4,5-tetrahydro-3, 5-dioxo-1,2,4-triazine-6-carbonitriles ( 4 ) and some 3-thioxo-derivatives thereof by a novel approach is described. In addition some possibilities for the derivatisation of these compounds are given.     

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.     

The reaction of 1,3-dibutyl-2-ethoxy-4,5-dimethyl-2-oxo-1,3,2-diazaphosphol-4-ene with tetracyanoethylene

The reaction of 1,3-dibutyl-2-ethoxy-4,5-dimethyl-2-oxo-1,3,2-diazaphosphol-4-ene with tetracyanoethylene gives 6-amino-1,3-dibutyl-5-cyano-2-ethoxy-4-(1-imino-2-cyanoethyl)-2-oxo-1,3,2-diazaphosphindane.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 303–305, February, 1994.     

Synthesis of 5-[2-(Phenoxy)ethyl] Derivatives of 6-Methyluracil, 6-Methyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one,and 2-Imino-6-methyl-2,3-dihydro-1H-pyrimidin-4-one

A synthesis of novel derivatives of 6-methyluracil, 6-methyl-2-thioxo-, and 2-imino-6-methyl-2,3-dihydro-1H-pyrimidin-4-one containing a 2-(phenoxy)ethyl substituent at position 5 of the pyrimidine ring has been carried out. It was found that 5-[2-(phenoxy)ethyl] derivatives of 6-methyl-2-thioxo- and 2-imino-6-methyl-2,3-dihydro-1H-pyrimidin-4-one are obtained by the condensation of the corresponding ethyl 3-oxo-2-(2-phenoxyethyl)butanoates with thiourea or guanidine. 6-Methyl-5-[2-(phenoxy)ethyl]uracils can be prepared by treating 6-methyl-5-[2-(phenoxy)ethyl]-2-thioxo-2,3-dihydro-1H-pyrimidin-4-ones with an excess of aqueous monochloroacetic acid solution. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1213–1217, August, 2005.     

Synthesis of nitrogen-containing heterocycles. 7 Reaction of aliphatic diaminomethylenehydrazones with hindered ethoxymethylenecyanoacetate

Aliphatic diaminomethylenehydrazones 1 were reacted with ethyl 2-cyano-3-ethoxy-2-pentenoate 2 to give a number of heterocycles in low to moderate yields, according to the substitution pattern and the size of substituent. When 1 carried a single methyl group on the terminal nitrogen, it gave preferentially 6-oxo-1,6-dihydropyrimidines 4 incorporating N(4) into the ring. In contrast, the reaction between 1c or 1d and 2 led to 6-imino- and 6-oxo-1, 6-dihydropyrimidines 7 and 8 along with 3 . When the alkylidene moiety was bulky, 1e and 1f , the similar reaction gave 3 in high yields without any cyclized product. Upon exposure to acid, compound 3 yielded 6-oxo-1,6-dihydropyrimidines 6 , [1,2,4]triazolo[1,5-c]pyrimidine-8-carboxylate 5 and N-alkenyl-1,2,4-triazoles 9 in addition to 7 and 8 in proportions dictated by the nature of the substituents of 1 . The structural assignment and reaction mechanism are discussed.     

Synthesis of trichloro-1,4-benzoquinonyl-substituted 2,2′-bithiazoles

2,2-Bi[5-(2,5-dihydroxy-3,4,6-trichlorophenyl)thiazole] and 6-(2,5-dihydroxy-3,4,6-trichlorophenyl)-2-imino-3,4-dihydro-4H-1,4-thiazin-3-thione are synthesized from 2,5-dihydroxy-3,4,6,7-tetrachloro-2,3-dihydrobenzo[b]furan and dithiooxalyldiamide. The products are oxidized by FeCl₃ to the corresponding trichloro-1,4-benzoquinonyl-substituted sulfur-containing heterocycles. N-Methylation of 2,2-bithiazole by dimethyl sulfate gives 2,2-bi[5-(2,5-dihydroxy-3,4,6-trichlorophenyl)-3-methylthiazolium] bismonomethyl sulfate. The last compound is readily transformed to 2,2-bi[5-(2-hydroxy-5-oxido-3,4,6-trichlorophenyl)-3-methylthiazolium] bisbetaine.Riga Technical University, Riga LV-1048, Latvia, Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 988–992, July, 1999.     

Synthesis of nitrogen-containing heterocycles 6. Formation and structures of imidazolinones and related compounds through cyclization of diaminomethylenehydrazones with dimethyl acetylenedicarboxylate

Diaminomethylenehydrazones 1 of aromatic and aliphatic carbonyl compounds react with dimethyl acetylenedicarboxylate (DMAD) at room temperature to give four types of heterocycles, (5-oxoimidazolin-4-ylidene) acetates 2, 3 and 6 , (2-imino-5-oxoimidazolidin-4-ylidene) acetate 4 and 6-oxo-1,6-dihydropyrimidine-4-carboxylates 5 according to the substitution patterns of 1 in moderate to high yields. Amino (N,N-dimethylamino)methylenehydrazones of ketones give exclusively (5-oxoimidazolin-4-yl-idene) acetates, both (Z)- and (E)-isomers 2 and 3 about the exocyclic alkenic linkage, with the (Z)-isomer 2 generally being predominant, while those of aldehydes give 5 . Diamino- and amino (N-methylamino)methylenehydrazones produce 5 and/or 6 and di (N-methylamino) methylenehydrazone gives (2-imino-5-oxoimidazolidin-4-ylidene) acetate 4 as the sole cyclized product.     

FIVE NEW DITERPENES FROM EUPHORBIA SIEBOLDIANA

Five new diterpenes were isolated from Euphorbia sieboldiana and identified as atis-16-en-13(S)-hydroxy-3, 14-dione(Ⅰ), atis-16-en-14-oxo-13(S), 3 β-diol(Ⅱ), atisane-3-oxo-16α, 17-diol(Ⅳ), atisane-3β, 16α, 17-triol(Ⅴ)and atisane-3β-acetyl-16α, 17-diol(Ⅵ)based on the chemical, spectral evidences and X-ray diffraction.     

Chelating diphos ligands with inorganic backbones. Crystal structure of [PtCl2{(PPh2O)2SiPh2}]

The metallo-phosphaalkenes (η⁵-C₅Me₅)(CO)₂FeP=C(R)(SiMe₃) (Ia: R = SiMe₃, Ib: R = Ph) and MeO₂C---CC---CO₂Me undergo a dipolar [3+2]-cycloaddition to afford the metallo-heterocycles [(η⁵-C₅Me₅)(CO)

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=C(R)SiMe₃] (IIIa,b) with exocyclic P=C double bonds.     

Isolation of a diketone species that is allylically bound to tungsten, and its relationship to a tungsten η-ketone complex

The diketone complex [W(CO)₂(η-C₅H₄Me){η³-

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(H)---C(O)---C₅Me₅}] (3) was isolated from the reaction of PhC₂H with a mixture of [Ni(CO)I(η-C₅Me₅)] and [W(CO)₃(η-C₅H₄Me)]⁻. Complex 3 contains an organic diketone fragment that is bound in a π-allyl fashion to a tungsten atom. It was fully characterized by standard spectroscopic techniques and by a single-crystal X-ray diffraction study. The relationship of complex 3 to a structurally characterized cyclopentadienyl tungsten η²-ketone species 1, and the likelihood that 3 and the methylcyclopentadienyl analog of 1 share common intermediates, are discussed.     

Synthesen mit Nitrilen. 34. Mitteilung. Phenylhydrazone des Dicyanmethylenindandions: Photolyse von 2-Dicyanmethylen-1,3-indandion-monophenylhydrazon in Methylenchlorid

Photolysis of 2-dicyanomethylene-1, 3-indandione-monophenylhydrazone 1 during several days yielded 3-(N-chlorimino)-5-oxo-2-phenyl-2.3-dihydro-5H-indeno[1.2-c]pyridazine-4-carbonitrile 2 . Isomerization to 3-imino-5-oxo-2-phenyl-2.3-dihydro-5H-indeno[1.2-c]pyridazine-4-carbonitrile 4 was also observed. Radical formation from the first triplet state leads to chlorine abstraction from the solvent and to formation of 2 . The same reaction occurs from the first triplet state of 4 .