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.     

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.     

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.     

Design of Peptides with α,β-Dehydro Residues: Synthesis,Crystal Structure and Molecular Conformation of a Peptide N-Boc-Phe-ΔPhe-Ile-OCH<Subscript>3</Subscript>

To develop a complete set of design rules with α,β-dehydro residues, a tripeptide N-Boc-Phe-ΔPhe-Ile-OCH₃ was synthesized. The synthesis was carried out in solution phase using azlactone procedure. The three-dimensional structure of the peptide was determined by X-ray diffraction method and refined to an R-factor of 0.085. The structure contains three peptide molecules in the asymmetric unit. In all the three crystallographically independent molecules ΔPhe residue adopts one of the three conformations that have been reported for a ΔPhe residue. The overall conformations of three peptide molecules in the asymmetric unit are not similar. Two out of three crystallographically independent molecules adopt type II β-turn conformations whereas the third molecule is found having the characteristic S-shaped conformation in which the values of dihedral angles φ, ψ have opposite signs alternately. One of these two types of conformations has been observed when a ΔPhe is introduced at (i+2) position of a tetrapeptide. The β-turn conformation is stabilized by a 4→1 hydrogen bond where the hydrophobic side chains of residues at (i+1) and (i+3) positions stabilized the unfolded conformation with van der Waals interactions. The three independent molecules are locked together by three hydrogen bonds between molecules A and B and two hydrogen bonds between molecules B and C.     

Synthesis and catalytic properties of novel ruthenium N-heterocyclic-carbene complexes

The reaction of [RuCl₂(p-cymene)]₂ with 1,3-dialkylimidazolinium salts 1a–f in the presence of a small excess of cesium carbonate yields chelated η⁶-arene, η¹-carbene ruthenium complexes 2a–f. All synthesised compounds were characterized by elemental analysis, NMR spectroscopy. The catalytic activity of RuCl₂(η⁶-arene, η¹-imidazolinylidene) complexes 2a–f was evaluated in the direct arylation of 2-phenylpyridine with chlorobenzene derivatives.     

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.     

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.     

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.     

EPR spectra of γ-irradiated dl-α-alanine supported on molecular sieves

The aim of the work was to collect information concerning boundary effects which are suspected in α-alanine dosimeters consisted of powdered microcrystalline α-alanine and binders. In our experiments the conventional binders were replaced by molecular sieves (MS). MS are inorganic porous materials (host structures) with well organized and uniform intra-crystalline pore systems of nano-scale size. The guest molecules can be either physically adsorbed on very large inner MS surface, or chemically bound to the active sites. They can be also encapsulated inside the intracrystalline cavities. The EPR spectra of gamma irradiated dl-α-alanine supported on NaY, CeY, SOD, mordenite, ZSM-5 and ALPO₄-5 were very similar to that one observed for irradiated microcrystalline dl-α-alanine. In the case of alanine supported on HY an initial EPR spectrum was different and only after some weeks it made resemble to the well known quintet observed in microcrystalline samples. In sodalites synthesized in the presence of dl-α-alanine EPR signal appeared in non-irradiated sample was very low and structureless. The irradiated sample showed a distinct spectrum which was quite different from that one observed for crystalline dl-α-alanine.     

An efficient method for the stereoselective synthesis of cis-3-substituted prolines: conformationally constrained α-amino acids

An efficient synthesis of enantiomerically pure cis-3-substituted prolines is reported. Key steps involve the stereoselective organocuprate addition to the (E)-α,β-unsaturated ester 1, obtained from the Garner's aldehyde, and expedient oxidation–cyclization sequences.     

Design,Synthesis and Molecular Docking Study of Novel 3-Phenyl-β-Alanine-Based Oxadiazole Analogues as Potent Carbonic Anhydrase II Inhibitors

Carbonic anhydrase-II (CA-II) is strongly related with gastric, glaucoma, tumors, malignant brain, renal and pancreatic carcinomas and is mainly involved in the regulation of the bicarbonate concentration in the eyes. With an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of twelve novel 3-phenyl-β-alanine 1,3,4-oxadiazole hybrids (4a–l), characterized by ¹H- and ¹³C-NMR with the support of HRESIMS, and evaluated for their inhibitory activity against CA-II. The CA-II inhibition results clearly indicated that the 3-phenyl-β-alanine 1,3,4-oxadiazole derivatives 4a–l exhibited selective inhibition against CA-II. All the compounds (except 4d) exhibited good to moderate CA-II inhibitory activities with IC₅₀ value in range of 12.1 to 53.6 µM. Among all the compounds, 4a (12.1 ± 0.86 µM), 4c (13.8 ± 0.64 µM), 4b (19.1 ± 0.88 µM) and 4h (20.7 ± 1.13 µM) are the most active hybrids against carbonic CA-II. Moreover, molecular docking was performed to understand the putative binding mode of the active compounds. The docking results indicates that these compounds block the biological activity of CA-II by nicely fitting at the entrance of the active site of CA-II. These compounds specifically mediating hydrogen bonding with Thr199, Thr200, Gln92 of CA-II.     

A directly ring-to-ring linked ferrocene–pseudotitanocene complex

Addition of excess ferrocenylacetylene (FcCCH) to [η⁵-(C₅H₅)Ti][μ:η²:η²-C₂(SiMe₃)₂]₂[η⁵-(C₅H₅)Mg] (1) affords the novel ferrocene–pseudotitanocene complex [η⁵-1,2,5,6-tetrakis(trimethylsilyl)-4-ferrocenylcyclohexa-1,4-dienyl](η⁵-cyclopentadienyl)titanium(II), [η⁵-(Me₃Si)₄FcC₆H₂]Ti(η⁵-C₅H₅) (2), as the sole isolated titanium-containing product. Its structure was established by EI MS, NMR and UV–vis spectroscopy. The formation of 2 follows the general reaction route of terminal acetylenes with 1.     

New approach to the stereoselective synthesis of the [4.5] spiroketal moiety of papulacandins

An efficient approach for the stereoselective construction of the spiroketal moiety of papulacandins, based on the condensation of the protected derivative of D-arabino-1,4-lactone 2 with the α-lithiated carbanion of β-phenylsulfonyl dihydrofuran 1, is described.     

Tetramethylammonium hydroxide (TMAH) thermochemolysis of 2-arylcoumaran lignin model compounds

Phenolic 2-arylcoumarans 1–6 were used to examine the behaviors of β-5 subunits in lignin during tetramethylammonium hydroxide (TMAH) thermochemolysis. Products were monitored by gas chromatography/mass spectrometry. The process predominantly provided dimeric products with the opened hydrofuran ring. Substituent changes at the γ-position of ring A and at the 5-position of ring B had a large effect on the product compositions. 2-Arylcoumarans 1 and 6 with the γ-CH₂OH substituent predominantly gave 2,3,3′,4′-tetramethoxystilbenes involving the elimination of the γ-CH₂OH substituent, while 2–5 with the γ-CH₃ substituent gave a mixture of 2,3,3′,4′-tetramethoxy-α-methylstilbenes and α-methoxy-α-(3′,4′-dimethoxyphenyl)-β-(2,3-dimethoxyphenyl)propanes. Substituent –CHCHCH₃ on ring B remained unaffected. Substituents –CHCHCH₂OH and –COOH on ring B produced the corresponding methyl ether and ester, respectively, by methylation. The –CHCHCHO substituent on ring B was converted to the –CHO substituent.     

Crystal structure and IR spectrum of 1-O-α- -glucopyranosyl- -mannitol–ethanol (2/1)

1-O-α- -Glucopyranosyl- -mannitol–ethanol (2/1), (C₁₂H₂₄O₁₁)₂–C₂H₅OH, crystallizes in the monoclinic space group P2₁ with unit cell dimensions a=11.4230(8) Å, b=9.525(4) Å, c=15.854(2) Å, β=102.751(7)° and V=1682.4(7) ų, Z=2, D_x=1.45 Mg m⁻³, λ (Mo-K_α)=0.71069 Å, μ=0.128 mm⁻¹, F(000)=788 and T=293(2) K. The structure was solved by direct methods and refined by least-squares calculations on F² to R₁=0.0371[I>2σ(I)], and 0.0930 (all data, 3542 independent reflections, R_int=0.021). There are two molecules of glucopyranosylmannitol (GPM) and one ethanol molecule in the asymmetric unit, and the glucopyranosyl ring adopts a chair conformation in both GPM molecules. Bond lengths and angles accord well with the mean values of related structures. The conformation along the mannitol side chain for one of the GPM molecules was the same as for the known polymorphs of -mannitol, while the conformation of the other molecule was different, indicating different conformational arrangements in the terminal carbon atoms of the mannitol side chains of the two GPM molecules. The structure in 1-O-α- -glucopyranosyl- -mannitol–ethanol (2/1) is held together by a very complex hydrogen bonding system, which consists of an infinte chain propagating along the b-axis and a discontinuous chain, which binds the ethanol molecule to the structure. The FTIR spectra for anhydrous GPM, GPM dihydrate and GPM–ethanol (2/1) were recorded. Both IR and X-ray results indicate the extensive hydrogen bonding in crystalline state.     

Influence of substituted groups on the binding ability of benzoyl-modified β-cyclodextrins

A series of substituted benzoyl modified β-cyclodextrins, including mono-6-O-(p-methylbenzoyl)-β-CD (1), mono-6-O-(m-methylbenzoyl)-β-CD (2), mono-6-O-(o-methylbenzoyl)-β-CD (3), mono-6-O-(p-methoxylbenzoyl)-β-CD (4), mono-6-O-(m-methoxylbenzoyl)-β-CD (5), mono-6-O-(o-methoxylbenzoyl)-β-CD (6), mono-6-O-(m, p-dimethoxylbenzoyl)]-β-CD (7), mono-6-O-(o,m-dimethoxylbenzoyl)-β-CD (8), and mono-(6-O-benzoyl)-β-CD (9) were synthesized and their inclusion properties were studied by using fluorescence spectroscopy. The binding constants (K_a) of the modified β-CD derivatives with 2-p-toluidinylnaphthalene-6-sulfonate (TNS) were determined on the basis of the fluorescence spectroscopy. The effect of types and location of substituted groups of the benzene ring of the modified β-cyclodextrins on the binding property was discussed. Results indicated that the substituents had significant influences on the binding abilities of modified β-cyclodextrins.     

Lithiated γ-O-functionalized propyl phenyl sulfides and sulfones of the type Li[CH(SOxPh)CH2CH2OR] (x = 0, 2). [Li{CH(SPh)CH2CH2Ot-Bu}(tmeda)] – A structurally characterized organolithium inner complex

Lithiation of O-functionalized alkyl phenyl sulfides PhSCH₂CH₂CH₂OR (R = Me, 1a; i-Pr, 1b; t-Bu, 1c; CPh₃, 1d) with n-BuLi/tmeda in n-pentane resulted in the formation of α- and ortho-lithiated compounds [Li{CH(SPh)CH₂CH₂OR}(tmeda)] (α-2a–d) and [Li{o-C₆H₄SCH₂CH₂CH₂OR)(tmeda)] (o-2a–d), respectively, which has been proved by subsequent reaction with n-Bu₃SnCl yielding the requisite stannylated γ-OR-functionalized propyl phenyl sulfides n-Bu₃SnCH(SPh)CH₂CH₂OR (α-3a–d) and n-Bu₃Sn(o-C₆H₄SCH₂CH₂CH₂OR) (o-3a–d). The α/ortho ratios were found to be dependent on the sterical demand of the substituent R. Stannylated alkyl phenyl sulfides α-3a–c were found to react with n-BuLi/tmeda and n-BuLi yielding the pure α-lithiated compounds α-2a–c and [Li{CH(SPh)CH₂CH₂OR}] (α-4a–b), respectively, as white to yellowish powders. Single-crystal X-ray diffraction analysis of [Li{CH(SPh)CH₂CH₂Ot-Bu}(tmeda)] (α-2c) exhibited a distorted tetrahedral coordination of lithium having a chelating tmeda ligand and a C,O coordinated organyl ligand. Thus, α-2c is a typical organolithium inner complex.Lithiation of O-functionalized alkyl phenyl sulfones PhSO₂CH₂CH₂CH₂OR (R = Me, 5a; i-Pr, 5b; CPh₃, 5c) with n-BuLi resulted in the exclusive formation of the α-lithiated products Li[CH(SO₂Ph)CH₂CH₂OR] (6a–c) that were found to react with n-Bu₃SnCl yielding the requisite α-stannylated compounds n-Bu₃SnCH(SO₂Ph)CH₂CH₂OR (7a–c). The identities of all lithium and tin compounds have been unambiguously proved by NMR spectroscopy (¹H, ¹³C, ¹¹⁹Sn).     

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).     

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.