Synthesis and unusual beckmann fragmentation reaction of syn-3-Methoxy-6α,17β-Dihydroxyestra-1,3,5(10)-trien-7-one oxime

Sodium borohydride reduction of anti-3-methoxy-17β-hydroxyestra-1,3,5(10)-trien-6,7-dione 7-oxime (4a) afforded syn-3-methoxy-6α,17β-dihydroxyestra-1,3,5(10)-trien-7-one oxime (5), which in thionyl chloride at −18 °C undenvent Beckmann fragmentation reaction to the unexpected 3-methoxy-6-oxo-17β-hydroxy-6.7-secoestra-1.3.5(10)-trien-7-nitrile (6). A mechanism of this fragmentation process was proposed.     

Chemo-, stereo- and regioselective hydrogenolysis of carbohydrate benzylidene acetals. Synthesis of benzyl ethers of benzyl α- -, methyl β-D-mannopyranosides and benzyl α-D-rhamnopyranoside by ring cleavage of benzylidene derivatives with the LiAlH4-AlCl3 reagent

Treatment of benzyl α-(1) and methyl β- -mannopyranoside (2) with α,α-dimethoxytoluene gave the exo and endo isomers (3,5 and 4,6) of the dibenzylidene derivatives of 1 and 2. Hydrogenolysis of the exo isomers (3 and 5) with a molar equivalent of AlH₂Cl gave the 3-0-benzyl-4,6-0-benzylidene derivatives (7 and 21), whereas the endo isomers (4 and 6) gave the 2-0-benzyl-4,6-0-benzylidene compounds (8 and 22). The 2-0-allyl ether 9 of 7, the 3-0-allyl derivative (10) of 8 and compounds 21 and 22 were treated with an additional molar equivalent of AlH₂Cl at reflux and the products were the 4-0-benzyl-6-hydroxyl derivatives (11, 12, 23 and 24), whereas in the case of 22 the 6-0-benzyl-4-hydroxyl isomer (25) was also isolated. By deallylation of 11 and 12, 3,4-(13) and 2,4-di-0-benzyl (14) ethers of 1 were prepared. Tosylation of 11 and 12, and subsequent reduction of the products (15 and 16) made possible the preparation of the partially protected benzyl α- -rhamnopyranoside derivatives (17–20). The structures of the compounds synthesized were characterized by ¹H and ¹³C NMR spectroscopic investigation and by chemical methods.     

Biosynthesis of aristeromycln: Evidence for the intermediacy of a 4β-hydroxymethyl-1α, 2α, 3α-trihydroxycyclopentanetriol.

Evidence for the intermediacy of a 4β-hydroxymethyl-1α, 2α, 3α-trihydroxycyclopentanetdol (5 or6) in the biosynthesis of the nucleoside antibiotic aristeromycin (1) has been obtained by administration of doubly-labeled forms of D-glucose to the fermentation broth ofStreptomyces citricolor followed by trapping of the tetrol5 using isotope dilution methods.     

Syntheses of methyl α-dl-mycaminoside, methyl α-dl-oleandroside, methyl β-dl-cymaroside, methyl α-dl-tyveloside and methyl α-dl-chromoside C

Five rare hexoses, which are components of antibiotics or cardiac glycosides, have been synthesized as methyl glycosides through a common intermediate methyl 2,3-dehydro-2,3,6-trideoxy-α-dl glucopyranoside (7). Epoxidation and subsequent treatment with dimethylamine of7 afforded methyl α-dl-mycaminoside (9). The addition reaction of MeOH to12 gave methyl α-dl-oleandroside (15) and methyl β-dl-cymaroside (17). The hydroxymercuration and subsequent reduction of12 afforded methyl α-dl-chromoside C (19) and methyl β-dl-tyveloside (25).     

Synthetic studies towards (±)-phthalascidin 650: synthesis of a fully functionalized N-protected-α-amino-aldehyde

An efficient synthesis of fully functionalized N-protected α-amino-aldehyde (±)-13 as synthetic precursor of the tetrahydroisoquinoline alkaloid phthalascidin 650 is reported. Starting from sesamol 6, 11 steps are required to give rise to the desired N-protected α-amino-aldehyde (±)-13 in 25% overall yield. This synthetic strategy involves the elaboration of fully functionalized aromatic aldehyde 7 and its transformation into an α-amino-alcohol through a Knoevenagel condensation. The phthalimidomethyl derivative (±)-11 was then synthesised from 8 by a Bischler–Napieralski reaction, a diastereoselective hydrogenation of the resultant dihydroisoquinoline and transformed into the corresponding N-protected α-amino-aldehyde (±)-13.     

Additive Pummerer reactions of vinylic sulfoxides. Synthesis of γ-hydroxy-α,β-unsaturated esters, α-hydroxyketones, and 2-phenylsulfenyl aldehydes and primary alcohols

Treatment of β-monosubstituted vinylic sulfoxides 1 with trifluoroacetic anhydride in dichloromethane gave excellent yields of 1,2-bis(trifluoroacetoxy)thioethers 6. Mildly basic methanolysis of 2-alkyl-substituted 6 gave α-hydroxyaldehydes 11 as monomer-dimer mixtures; similar treatment of the 2-aryl analogues afforded aryl (hydroxymethyl) ketones 12. Compounds 11 underwent Wittig reactions with methoxycarbonylmethylenetriphenylphosphorane to give high yields of γ-hydroxy-α,β-unsaturated esters 13, predominantly as the E-isomers. β-Monosubstituted vinylic sulfoxides 1 possessing a β-aryl group, and β-disubstituted vinylic sulfoxides 3 reacted with trifluoromethanesulfonic anhydride-sodium acetate in acetic anhydride to give 2-(phenylsulfenyl)acylals 14. These gave 2-phenylsulfenyl aldehydes 15 upon basic methanolysis, and the corresponding primary alcohols 16 on reduction with sodium borohydride. Reaction of both geometric isomers of enantiomerically pure vinylic sulfoxide 1o with TFAA gave racemic 6o as a mixture of diastereomers. Reaction of optically pure (E)- and (Z)-1p with trifluoromethanesulfonic anhydride-sodium acetate in acetic anhydride gave acylal 19 in 10.5 and 23% e.e., respectively.     

A Flexible Stereoselective Synthesis of the Spirosesquiterpenes (±)-β-Acorenol, (±)-β-Acoradiene, (±)-Acorenone-B and (±)-Acorenone via an Intramolecular Ene-Reaction

The racemic spirosesquiterpenes β-acorenol ( 1 ), β-acoradiene ( 2 ), acorenone-B ( 3 ) and acorenone ( 4 ) (Scheme 2) have been synthesized in a simple, flexible and highly stereoselective manner from the ester 5 . The key step (Schemes 3 and 4), an intramolecular thermal ene reaction of the 1,6-diene 6 , proceeded with 100% endo-selectivity to give the separable and interconvertible epimers 7a and 7b . Transformation of the ‘trans’-ester 7a to (±)- 1 and (±)- 2 via the enone 9 (Scheme 5) involved either a thermal retro-ene reaction 10 → 12 or, alternatively, an acid-catalysed elimination 11 → 13 + 14 followed by conversion to the 2-propanols 16 and 17 and their reduction with sodium in ammonia into 1 which was then dehydrated to 2 . The conversion of the ‘cis’-ester 7b to either 3 (Scheme 6) or 4 (Scheme 7) was accomplished by transforming firstly the carbethoxy group to an isopropyl group via 7b → 18 → 19 → 20 , oxidation of 20 to 21 , then alkylative 1,2-enone transposition 21 → 22 → 23 → 3 . By regioselective hydroboration and oxidation, the same precursor 20 gave a single ketone 25 which was subjected to the regioselective sulfenylation-alkylation-desulfenylation sequence 25 → 26 → 27 → 4 .     

Preparation of α- or β-trifluoromethylated vinylstannanes and their cross-coupling reactions

α- or β-Trifluoromethylated vinylstannanes 1, 2a, 3 and 4 were prepared form 1,1-bis(phenylthio)-2,2,3,3,3-pentafluoropropylbenzene (5) via several steps. The cross-coupling arylation reactions of 1–4 with aryl iodides bearing a bromo, methoxy, methyl, nitro or trifluoromethyl group on para- or meta-position of benzene ring afforded the corresponding coupling products in good yields. Compounds 1, 2a and 4 underwent the acylation reaction with various types of acyl chlorides to give the corresponding trifluoromethylated enone derivatives in good yields. Reduction of trifluoromethylated enone derivatives with LiAlH₄, followed by Fridel-Craft’s type of cyclization with AlCl₃ provided trifluoromethylated indene derivatives in good yields.     

Total Synthesis of (±)-3-Deoxy-7,8-dihydromorphine, (±)-4-Methoxy-N-methylmorphinan-6-one and 2,4-Dioxygenated (±)-Congeners

A total synthesis of racemic 3-deoxy-7,8-dihydromorphine ((±)- 2 ) and 4-me-thoxy-ALmethylmorphinan-6-one ((±)- 3 ) is described. The key intermediate was 2,4-dihydroxy-N-formylmorphinan-6-one (11) , obtained from 3,5-dibenzyloxy-phenylacetic acid (4) in 41.8% overall yield. Bromination of 11 , and treatment with aqueous N_aOH-solution afforded, after N-deblocking and reductive N-methylation with concomitant removal of the aromatic bounded Br-atom, the morphinanone 14. Elimination of the HO–C(2) group in 14 was accomplished by hydrogenolysis of its N-phenyltetrazolyl ether 15 , to give 3-deoxy-6,0-didehydro-7,8-dihydromorphine (16). Reduction of 16 with L-Selectride at low temperature provided (±)- 2 in high yield. The ether 15 directly afforded, under more vigorous reduction conditions, 4-hydroxy-N-methylmorphinan-6-one (17). and after O-methylation of 17 , the methyl ether (±)- 3 was obtained. A (1:l)-mixture of 4-hydroxy-2-methoxy-N-methylmor-phinan-6-one (28) and its 2-hydroxy-4-methoxy isomer 30 svere obtained by Grewe-cyclization of a mono-methoxylated aromatic precursor similar to that which afforded 11. The 2,4-dioxygenated N-methylmorphinan-6-ones 29 , 31 and 38 were also prepared and characterized.     

Highly stereocontrolled boron-mediated synthesis of β-hydroxy-α-amino acids and dipeptides. Part 2

The chiral synthons 1(a–d) were submitted to boron-mediated asymmetric aldol condensation with acetaldehyde and benzaldehyde providing, in high diastereomeric excess (>95%), R,R-configured aldols 2(a–f) which are useful intermediates to enantiomerically pure β-hydroxy-α-amino acids.     

α-Fluoro decalones as chiral epoxidation catalysts: fluorine effect

Three rigid monofluorinated trans-decalones 4a, 5e, and 6e (90% ee) have been synthesized from commercially available (−)-(R)-methyl naphthalenone (90% ee). Their structures have been fully characterized (NMR, X-ray): ketones 4a and 5e are Me,F-disubstituted α to the carbonyl with the fluorine axial and equatorial, respectively, while ketone 6e is F-monosubstituted α to the carbonyl with the fluorine equatorial. The use of these ketones as chiral catalysts for the epoxidation of trans-olefins (such as stilbene, β-methylstyrene and p-methoxy cinnamate) through the formation of dioxiranes shows (i) that dioxiranes with an equatorial fluorine α to the dioxirane ring are less reactive and provide lower ee’s than dioxiranes with an axial fluorine and having the same chirality and (ii) that an axial methyl α to the dioxirane ring is significantly less efficient than a fluorine. The results corroborate Armstrong and Houk’s theoretical model and our first hypothesis to rationalize the inverted enantioselectivities observed using α-fluorinated cyclohexanones having the same chirality, i.e.: rapid ring inversion (Curtin–Hammett principle) allows the dioxirane conformation to have the fluorine axial (even if less populated than the other) to contribute significantly to the epoxidation reaction.     

Chlorotrimethylsilane promoted asymmetric Michael reaction of chiral enamines of α-alkyl β-keto esters

By the promotion of chlorotrimethylsilane, asymmetric Michael reaction of the chiral enamines (2) of α-alkyl β-keto esters (1) with methyl vinyl ketone and ethyl acrylate proceeded to afford, after hydrolysis, either enantiomer of the corresponding adducts (4) in a good enantioselectivity.     

Die reaktion von 4-(α-hydroxyalkyliden)-Δ-5-isoxazolonen mit bifunktionellen stickstoffbasen

The 4-(α-hydroxyalkylidene)-Δ²-5-isoxazolones2 exist in the β-ketoenol form (“vinyloge car☐ylic acids”),2a,c react with guanidine and amidines to give only the enolates4, whereas they react both with hydrazines and 1,2-diamines to form the enamines6 and9 (“vinyloge amids”). The 4-(α-ethoxyalkylidene)-Δ²-5-isoxazolones 7 (“vinyloge esters”) condense with guanidine, benzamidine, and urea to affort the enamines8. Attempted ring-opening by bases failed whilst catalytic hydrogenation of the enamines6 and8 yielded the pyrazoles10,11 and diazepines12. The structures of the compounds have been elucidated by NMR and IR-spectra.     

New series of platinum group metal complexes bearing η- and η-cyclichydrocarbons and Schiff base derived from 2-acetylthiazole: Syntheses and structural studies

The mononuclear complexes [(η⁶-arene)Ru(ata)Cl]PF₆ {ata = 2-acetylthiazole azine; arene = C₆H₆ [(1)PF₆]; p-ⁱPrC₆H₄Me [(2)PF₆]; C₆Me₆ [(3)PF₆]}, [(η⁵-C₅Me₅)M(ata)]PF₆ {M = Rh [(4)PF₆]; Ir [(5)PF₆]} and [(η⁵-Cp)Ru(PPh₃)₂Cl] {η⁵-Cp = η⁵-C₅H₅ [(6)PF₆]; η⁵-C₅Me₅ (Cp^*) [(7)PF₆]; η⁵-C₉H₇ (indenyl); [(8)PF₆]} have been synthesised from the reaction of 2-acetylthiazole azine (ata) and the corresponding dimers [(η⁶-arene)Ru(μ-Cl)Cl]₂, [(η⁵-C₅Me₅)M(μ-Cl)Cl]₂, and [(η⁵-Cp)Ru(PPh₃)₂Cl], respectively. In addition to these complexes a hydrolysed product (9)PF₆, was isolated from complex (4)PF₆ in the process of crystallization. All these complexes are isolated as hexafluorophosphate salts and characterized by IR, NMR, mass spectrometry and UV–Vis spectroscopy. The molecular structures of [2]PF₆ and [9]PF₆ have been established by single-crystal X-ray structure analyses.     

Non-chair six-membered-ring conformations. Preference for a twist-boat (or skew) structure in α- -sorbopyranose derivatives

The conformational preferences for 2,3-O-isopropylidene-α- -sorbopyranose derivatives 3–6 were determined by using ¹H NMR data and empirical force field calculations. Proton NMR studies of 3–6 indicate that a twist-boat (or skew) conformation (³S₀) prevails over possible chair forms for each compound. Force-field calculations (MM2, MNDO, AM1) on a model 2,3-O-isopropylidene-α- -sorbopyranose system (18) indicate that the ³S₀ conformation is among the low-energy structures. X-Ray crystallographic analysis of α- -sorbopyranose sulfamate 3, a compound with potent anticonvulsant activity, demonstrates that the ³S₀ skew conformation is manifested in the solid state, as well.     

η-Pentamethylcyclopentadienylruthenium(II) complexes containing η-coordinated α-amino acids

Reaction of [Cp* RuCl₂]₂ with -alanine ( -alaH) in methanol at room temperature in the presence of NaOMe yields the complex Na[Cp* RuCl( -ala)] (1), which contains a five-membered N,O-coordinated chelate ring. The analogous complex Na[Cp* RuCl( -phe)] (2) is obtained under similar conditions but at 0°C in 90% yield. At temperatures above 20°C both 2 and the η⁶-coordinated complex [Cp* Ru( -pheH)]Cl (4) are obtained, with the proportion of the latter increasing with temperature. Compound 4 is obtained in 88% yield by refluxing [Cp* RuCl₂]₂ and -phenylalanine ( -pheH) in CH₃OH/CH₃ONa followed by separation from 2. The analogous ruthenium(II) sandwich complexes 5–10 were obtained from -tyrosine and -tryptophane and various derivatives. [Cp* Ru( -met)] (3), prepared by the reaction of [Cp* RuCl₂]₂ with -methionine ( -metH) in CH₃OH/CH₃ONa, displays N,O,S-coordination.     

Synthesis and structure of the unsymmetrical β-diimine precursor: The β-iminoamine

The reaction of benzoylacetone with ortho-substituted aniline derivatives gives the unsymmetrical β-iminoamine ligands (5–8) with high yields. A convenient synthesis is described. These compounds have been characterized by NMR and IR spectroscopies. The structure of the β-iminoamine 5, 3-N-(2,6-diisopropylphenylamino)-1-phenyl-1N-(2,6-diisopropylphenylimino)but-2-ene, was solved by X-ray diffraction methods.     

Platinum(IV) complexes with α,ω-bis(pyrazol-1-yl) alkanediyl and diethyl ether/thioether ligands. Crystal structures of dibromodimethyl[1,2-bis(pyrazol-1-yl)ethane]platinum(IV) and trimethyl-bis[2-(pyrazol-1-yl)ethyl]etherplatinum(IV) tetrafluoroborate

Reactions of the flexible α,ω-bis(pyrazol-1-yl) compounds 1,2-bis(pyrazol-1-yl)ethane (L1), 1,8-bis(pyrazol-1-yl)-n-octane (L2), bis[2-(pyrazol-1-yl)ethyl]ether (L3) and bis[2-(pyrazol-1-yl)ethyl]thioether (L4) with precursor organometallic platinum complexes ([(PtBr₂Me₂)_n], [(PtIMe₃)₄] and [(PtMe₂(cod)]/I₂) are described herein. The spectroscopic characterization of the platinum(IV) products of these reactions [PtBr₂Me₂{pz(CH₂)_mpz}], m = 2 (1) or 8 (2), [PtI₂Me₂{pz(CH₂)₂pz}] (3), [PtMe₃(pzCH₂CH₂OCH₂CH₂pz)][BF₄] (4) and [PtMe₃(pzCH₂CH₂SCH₂CH₂pz)][CF₃SO₃] (5), where ‘pz’ is pyrazol-1-yl, is discussed. Furthermore, solid state structures of 1, a complex with a seven-membered chelate ring, and 4, a complex bearing the neutral κ²N,N′,κO ligand bis[2-(pyrazol-1-yl)ethyl]ether (L3) are reported.     

Highly stereoselective aziridine ring-opening with phenylselenide anion and selective intramolecular aldol closure for the enantiopure synthesis of γ-aminocyclopentene derivatives

A practical and enantiopure synthesis for the preparation of key intermediates of conformationally locked γ-amino acid and nucleoside analogues is described. First, a highly stereoselective aziridine ring-opening reaction with phenylselenide anion was employed for the stereoselective synthesis of the chiral aminoselenide (1S,2S,1′S)-8, which after N-benzylation was transformed into the corresponding allyl amine (1S,1′S)-7 by oxidation with H₂O₂. Then, dihydroxylation–dehomologation of (1S,1′S)-7 with (OsO₄/NMO, NaIO₄) selectively afforded the desired γ-aminocyclopentene aldehyde (S)-1 and its corresponding γ-amino acid (S)-2 via an intramolecular selective aldol-condensation catalyzed by an internal base.     

A novel method for the synthesis of (Z)-α-selenyl-α,β-unsaturated ketones via acylation of (E)-α-selanylvinylstannanes

The (E)-α-selenylvinylstannanes react with acyl halides in presence of a catalytic amount of Pd(PPh₃)₄ to give the corresponding (Z)-α-selenyl-α,β-unsaturated ketones in good yield.