Knoevenagel condensation of α,βunsaturated aromatic aldehydes with barbituric acid under non-catalytic and solvent-free conditions

An efficient route for the synthesis of 5-(arylpropenylidine)-2,4,6-pyrimidinetrione 3 from an appropriateα,β-unsaturated aromatic aldehydes 1 and barbituric acid 2 under both non-catalytic and solvent-free microwave irradiation conditions was described.In this way,a range of biologically important compounds 3 was obtained in good to excellent yields (86-98%) in a very short reaction time (30-80s).     

Synthesis of new peptidic glycoclusters derived from β-alanine

The synthesis of an asymmetric glycocluster 1 has been achieved by coupling of a sugar unit with the β-alanine polypeptide, the principal chain, and combining a carbohydrate chain with the side chain causing it to branch from the N terminal. The synthesis of this side chain multivalent ligands is based on the scaffolding of some ω-amino acid (glycine, β-alanine, and GABA) derivatives. This method facilitated the synthesis of the cluster, of which the length of each unit differs.     

The first example of α-organoseleno arsonium ylides and its Wittig-type reaction

α-Organoseleno arsonium ylide 3 was synthesized for the first time by a phenylselenenylation-transylidation reaction. It has sufficient activity to carry out the Wittig-type reaction, affording a novel method for the stereoselective synthesis of (Z)-α-phenyl-seleno-α, β-unsaturated esters 6.     

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.     

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.     

Steroids from sponges

The sponges Stelleta clarella Tethya aurantia, Lissodendoryx noxiosa, Haliclona permollis and Haliclona sp. were examined for steroids. All sponges contained C₂₇-C₂₉, Δ⁵, mono and diunsaturated sterols. In addition, the sponge Tethya aurantia contained Z - 24 - propylidene - cholest - 5- en -3β-ol (19) and the 5α,8α-peroxides of cholesta - 5,7 - dien - 3β - ol, ergosterol, ergosta - 5,7,24(28) - trien - 3β - ol and 24ξ - ethyl - cholesta - 5,7 - dien - 3β - ol (29, 30, 31 and 32). The sponge Stelleta clarella also contained 24 - nor - cholesta - 4,22 - dien - 3 - one (21), cholesta - 4,22 - dien - 3 - one (22), 24ξ - methyl - cholesta - 4,22 - dien - 3 - one (24), ergosta - 4,24(28) - dien - 3 - one (25), (E) - stigmasta - 4,24(28) - dien - 3 - one (28), 5α - cholestanol (5), 5α - ergostanol (7) and 5α - poriferastanol (9) The possible biosynthetic significance of these hitherto undescribed peroxides and enones from marine sources is discussed. A synthesis of 19 is also described.     

Group 9 half-sandwich complexes containing the unique P,P′-diphenyl-1,4-diphospha-cyclohexane ligand: Synthesis, X-ray structure analyses and spectroscopic studies

We wish to report the synthesis and characterization of Group 9 metal complexes with the novel P,P′-diphenyl-1,4-diphospha-cyclohexane (dpdpc) ligand. The complexes are readily prepared by direct ligand substitution reactions from the dichloro-bridged binuclear complexes, [{η⁵-Cp*M(Cl)₂}₂]. The complexes include: [η⁵-Cp*Rh(Cl)₂]₂(μ-dpdpc) (1), [η⁵-Cp*Ir(Cl)₂]₂(μ-dpdpc) (2), and [η⁵-Cp*Rh(Cl)(dpdpc)]PF₆ (3). The structures for all three complexes are supported by ¹H, ¹³C{¹H}, and ³¹P{¹H} NMR spectroscopy as well as elemental analysis. The molecular structures of 1 and 3 have also been established by single-crystal X-ray analysis.     

Synthesis of 2-deoxy-α-DAH based on diazo chemistry by insertion reactions of 2-diazo-3-deoxy- -arabino-heptulosonate derivatives mediated by rhodium(II)

The synthesis of 2-deoxy-α-DAH (2) is described based on the use of diazo chemistry as previously reported by us during the synthesis of the corresponding 2-deoxy-KDO. Initially, the -arabino-aldehydo sugar derivative 3 was reacted with ethyl diazoacetate, using diethyl zinc as promoter. The corresponding β-hydroxy-α-diazo ester 4, obtained in very good yield, was transformed into the corresponding 2-diazo-3-deoxy-heptulosonate derivative 10, which was subjected to the action of rhodium(II). However, the major compound obtained in this reaction was the C-glycofuranoside 12 by the interaction of the benzyl protecting group employed at the OH of C-4 with the carbenoid generated at C-2. To avoid this undesired insertion reaction, aldehyde 13 was selected as a suitable starting material and, following the same chemistry than for 3, diazo 19 was efficiently synthesized. Finally, the intramolecular OH insertion mediated by rhodium(II) of 19 provided the targeted 2-deoxy-DAH derivative 21 in a reasonable good yield, which was finally transformed into the potassium salt of 2-deoxy-α-DAH 2.     

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.     

A practical synthesis of trifluorophenyl R-amino acid: The key precursor for the new anti-diabetic drug sitagliptin

Sitagliptin is the first new anti-diabetic drug in DPP-IV inhibitor class. The general synthesis of sitagliptin is by coupling of the β-amino acid fragment with the heterocycle fragment. Though the specific β-amino acid can be easily made from the corresponding R-amino acid by Arndt-Eistert homologation, the optically pure precursor R-amino acid is difficult to prepare. We herein reported a practical protocol to make the trifluorophenyl substituted R-amino acid 4 in >99.9% ee and 40.3% yield by the enzymatic resolution employing enantioselective hydrolysis and a general separation procedure. This protocol requires only cheap starting materials and friendly reaction condition. The procedure not only allows people to prepare the drug substance, but also provides an alternative method for prepareing the rare α-amino acid and the subsequent β-amino acid.     

A practical and enantiospecific conversion of d-galactose to a substituted α,β-unsaturated δ-lactone synthon

A multi-gram synthesis of a substituted α,β-unsaturated δ-lactone synthon, 1, was developed from commercially available d-galactose. The use of a Horner–Wadsworth–Emmons reaction was able to furnish, with Z selectivity, the enone ester that spontaneously lactonised to provide enantiomerically pure 1.     

Total synthesis of ganglioside GQ1b and the related polysialogangliosides

The first total synthesis of ganglio-series gangliosides GQ1b, GT1b and GD1b, which contain α-sialyl-(2→8)-α-sialic acid residue in the structure, will be described. Glycosylation of 2-(trimethylsilyl)ethyl O-(2-acetamido-6-O-benzyl-2-deoxy-3,4-O-iso-propylidene-β- -galactopyranosyl)-(1→4)-O-(2,6-di-O-benzyl-β- -galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-glucopyranoside (7) with methyl [phenyl 5-acetamido-8-O-(5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy- -glycero-α- -galacto-2-nonulopyranosylono-1′,9-lactone)-4,7-di-O-acetyl-3,5-dideoxy-2-thio- -glycero- -galacto-2-nonulopyranosid]onate (8) using N-iodosuccinimide (NIS)-trifluoromethanesulfonic acid (TfOH) in acetonitrile gave the protected GD2 pentasaccharide 9, which was converted into the pentasaccharide acceptor 10 by de-O-isopropylidenation. Glycosylation of 10 with methyl thioglycoside derivatives 18, 26, 34 by use of dimethyl(methylthio)sulfonium triflate (DMTST) gave the protected ganglioside oligosaccharides 19, 27 and 35, respectively. Compounds 9, 19, 27 and 35 were transformed into the corresponding α-trichloroacetimidates 13, 22, 30 and 38, via reductive removal of benzyl groups, O-acetylation, selective removal of 2-(trimethylsilyl)ethyl group, and treatment of trichloroacetonitrile. Condensation of the imidates 13, 22, 30 and 38 with (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol (14) gave the corresponding β-glycosides 15, 23, 31 and 39, which were converted, via selective reduction of azido group, coupling with octadecanoic acid, de-O-acylation, and saponification of methyl esters and lactone groups, into the corresponding gangliosides GD2 (17), GD1b (25), GT1b (33) and GQ1b (41).     

Electrooxidation of tigogenin acetate

Electrooxidation of tigogenin acetate afforded two products: 3β-acetoxy-16β-hydroxy-23,24-dinor-5α-cholanoic acid lactone (2) and 20-epitigogenin acetate (3). The structure of the latter compound was confirmed by an X-ray analysis. The tentative mechanism of reaction is proposed.     

Syntheses and structures of doubly tucked-in titanocene complexes with tetramethyl(aryl)cyclopentadienyl ligands

Titanocene–bis(trimethylsilyl)ethyne complexes [Ti(η⁵-C₅Me₄R)₂(η²-Me₃SiCCSiMe₃)], where R=benzyl (Bz, 1a), phenyl (Ph, 1b) and p-fluorophenyl (FPh, 1c), thermolyse at 150–160°C to give products of double C---H activation [Ti(η⁵-C₅Me₄Bz){η³:η⁴-C₅Me₃(CH₂)(CHPh)}] (2a), [Ti(η⁵-C₅Me₄Bz){η³:η⁴-C₅Me₂Bz(CH₂)₂}] (2a′), [Ti(η⁵-C₅Me₄Ph){η³:η⁴-C₅Me₂Ph(CH₂)₂}] (2b), and [Ti(η⁵-C₅Me₄FPh){η³:η⁴-C₅Me₂FPh(CH₂)₂}] (2c). In the presence of 2,2,7,7-tetramethylocta-3,5-diyne (TMOD) the thermolysis affords analogous doubly tucked-in compounds bearing one η³:η⁴-allyldiene and one η⁵-C₅Me₄R ligand having TMOD attached by its C-3 and C-6 carbon atoms to the vicinal methylene groups adjacent to the substituent R (R=Bz (3a), Ph (3b), and FPh (3c)). Compound 3a is smoothly converted into air-stable titanocene dichloride [TiCl₂{η⁵-C₅Me₂Bz(CH₂CH(t-Bu)CH=CHCH(t-Bu)CH₂)}(η⁵-C₅Me₄Bz)] (4a) by a reaction with hydrogen chloride. Yields in both series of doubly tucked-in complexes decrease in the order of substituents: BzPh>FPh. Crystal structures of 1c, 2a, 2b, and 3b have been determined.     

ααTwo new eudesmane sesquiterpenes from Lactuca sativa var. anagustata L

Two new eudesmane sesquiterpene lactones were isolated from the stalk of Lactuca sativa var.anagustata L and their structureswere elucidated by means of spectroscopic methods,including 2D NMR(~1H-~1H COSY,HMBC and NOESY) as 1β-O-β-D-glucopyranosyl-4α-hydroxyl-5α,6β,11βH-eudesma-12,6α-olide(1) and 1β-hydroxyl-15-O-(p-methoxyphenylacetyl)-5α,6β,11βH-eudesma-3-en-12,6α-olide(2).     

Manganese(III)-based oxidative free-radical reaction of α-allyl-β-keto ester with molecular oxygen

Oxidative reactions of α-allyl-β-keto esters 5 with Mn(OAc)₃·2H₂O give the δ-hydroxy-β-,γ-unsaturated-α-keto esters 6 in good yields. The mechanism of this reaction is discussed.     

Synthesis of tadalafil (Cialis) from l-tryptophan

The first synthesis of tadalafil 1 (Cialis) from l-tryptophan is described. The title compound 1 was synthesized via seven steps from l-tryptophan methyl ester hydrochloride in 42.3% overall yield. Two characteristic steps involved in this synthesis are the base-catalyzed epimerization of the C-3 position of (1S,3S)-1,2,3-trisubstituted-tetrahydro-β-carboline 3a and the acid-catalyzed epimerization of the C-1 position of (1S,3R)-1,3-disubstituted-tetrahydro-β-carboline 5. The (S)-configurations at C-1 and C-3 were inverted to (R)-configurations during the epimerization reactions. The base-catalyzed epimerization of C-3 of (1S,3S)-1,2,3-trisubstituted-tetrahydro-β-carbolines 3a–3e was also studied in detail.     

Supramolecular assemblies based on some new methyl-substituted cucurbit[5]urils through hydrogen bonding

Three supramolecular assemblies based on three new partial methyl-substituted cucurbit[5]urils, which are tetramethylcucurbit[5]uril (α,γ-TMeQ[5]), hexamethyl cucurbit[5]uril (α,β,δ-HMeQ[5]), Nonamethylcucurbit[5]uril (NMeQ[5]), were synthesized and structurally characterized by single-crystal X-ray diffractions. For the comparison with these new Q[5]s, crystal structure of an assembly constructing with normal Q[5] and K₂PtCl₆ was also reported. They are (α,γ-TMeQ[5])·15(H₂O) (1), (α,β,δ-HMeQ[5])·2Cl⁻·2(H₃O)⁺·7(H₂O) (2), (NMeQ[5])·14(H₂O) (3), (4). In the corresponding crystal structures, the molecular encapsulates included a water molecule and lidded water molecules at both of the portals were observed. Moreover, these molecular encapsulates are connected through hydrogen bonding and formed supramolecular chains or joined in pair.     

Total synthesis of (±)-dihydroactinidiolide using selenium-stabilized carbenium ion

A new, short total synthesis of dihydroactinidiolide 1 is described using selenium carbenium ion-promoted carbon–carbon bond formation as the key step. Our synthetic strategy starts with a lactonization reaction between 1,3,3-trimethylcyclohexene 13 and α-chloro-α-phenylseleno ethyl acetate 14, affording the key intermediate, α-phenylseleno-γ-butyro lactone 15, which reacted via a selenoxide elimination to the target compound 1.     

Reactivity of AlMe3 with titanium(IV) Schiff base complexes: X-ray structure of [Ti{(μ-Br)(AlMe2)}{(μ-Br)(AlMe2X)}(salen)] · C7H8 (X=Me or Br) and reactivity studies of mono-alkylated [Ti(Me)X(L)] complexes

[TiCl₂(salen)] (1) reacts with AlMe₃ (1:2) to give the heterometallic Ti(III) and Ti(IV) complexes [Ti{(μ-Cl)(AlMe₂)}{(μ-Cl)(AlMe₂X)}(salen)] (X=Me or Cl) (2) and [TiMe{(μ-Cl)(AlCl₂Me)}(salen)] (3). Addition of diethyl ether to 3 affords [Ti(Me)Cl(salen)] (4). The analogous reaction of [TiBr₂(salen)] (5) gives the crystallographically characterised [Ti{(μ-Br)(AlMe₂)}{(μ-Br)(AlMe₂X)}(salen)] (X=Me or Br) (6) and [Ti(Me)Br(salen)] (7) in a single step, whilst the comparable reaction of [TiCl₂{(3-MeO)₂salen}] (8) with AlMe₃ yields [Ti(Me)Cl{(3-MeO)₂salen}] (9) with no evidence of titanium(III) species. Reactivity of both halide and methyl groups of 4 has been probed using magnesium reduction, SbCl₅ and AgBF₄ halide abstraction and SO₂ insertion reactions. Hydrolysis of [Ti(Me)X(L)] complexes affords μ-oxo species [TiX(L)]₂(μ-O) [X=Cl, L=salen (13); X=Br, L=salen (14); X=Cl, L=(3-MeO)₂salen (15)].