Synthesis, characterization and anticancer activity of new chiral Pd(II)-complexes derived from unsymmetrical α-diimine ligands

A set of new diastereopure unsymmetrical α-diimine ligands 2a-d derived from methylglyoxal and optically pure primary amines 1a-d afforded the new chiral Pd(II)-complexes (S,S)-3a, (S,S)-3b, (S,S)-3c, and (1S, 2S, 3S, 5R)-3d. All compounds have been characterized by IR, ¹H, and ¹³C NMR spectroscopies along with MS-FAB⁺ spectrometry. The crystal and molecular structure for the complexes 3a, 3b and 3d have been fully confirmed by single-crystal X-ray studies. Likewise, complexes 3a-d have also been screened for their in vitro cytotoxicity against different classes of cancer: leukemia (K-562 CML), colon cancer (HCT-15), human breast adenocarcinoma (MCF-7), central nervous system (U-251 Glio) and prostate cancer (PC-3) cell lines.     

Synthesis and characterization of a series of chiral NHC–Pd complexes derived from l-phenylalanine

The synthesis of a series of chiral Pd(L)PyBr₂ (3a–3e) and Pd(L)PyCl₂ (4d and 4e) complexes from l-phenylalanine is presented (L = (S)-3-allyl-4-benzyl-1-(2,6-diisopropylphenyl)-imidazolin-2-ylidene (a), (S)-4-benzyl-1-(2,6-diisopropylphenyl)-3-(naphthalen-2-ylmethyl)imidazolin-2-ylidene (b), (S)-4-benzyl-3-(biphenyl-4-ylmethyl)-1-(2,6-diisopropylphenyl)imidazolin-2-ylidene (c), (S)-4-benzyl-1-(2,6-diisopropylphenyl)-3-(naphthalen-1-ylmethyl)imidazolin-2-ylidene (d) or (S)-4-benzyl-1-(2,6-diisopropylphenyl)-3-(2,4,6-trimethylbenzyl)imidazolin-2-ylidene (e). The complexes were characterized by physicochemical and spectroscopic methods, and the X-ray crystal structures of 3a–3c and 4d are reported. In each case, there is a slightly distorted square-planar geometry around palladium, which is surrounded by imidazolylidene, two trans halide ligands and a pyridine ligand. There are π–π stacking interactions in the crystal structures of these complexes. Complex 3a showed good catalytic activity in the Cu-free Sonogashira coupling reaction under aerobic conditions.     

Practical and highly stereoselective method for the preparation of several chiral arylsulfinamides and arylsulfinates based on the spontaneous crystallization of diastereomerically pure N-benzyl-N-(1-phenylethyl)-arylsulfinamides

A novel and simple process for the preparation of enantiomerically pure (S_S)-benzenesulfinamide (S_S)-3a, (S_S)-p-toluenesulfinamide (S_S)-3b, (S_S)-p-chloro-benzenesulfinamide (S_S)-3c and (S_S)-p-fluorobenzenesulfinamide (S_S)-3d has been developed. The treatment of arylsulfinyl chlorides with (R)-N-benzyl-1-phenylethanamine in the presence of excess triethylamine gave diastereomeric mixtures of N-benzyl-N-(1-phenylethyl)-arylsulfinamides 1, which underwent spontaneous crystallization to furnish diastereomerically pure (R,S_S)-N-benzyl-N-(1-phenylethyl)-arylsulfinamides (R,S_S)-1a-1d in 28%, 29%, 27% and 31% yields, respectively. The diastereomerically pure compounds (R,S_S)-1 were then converted into four enantiopure (R_S)-methyl arylsulfinates (R_S)-2, and finally into four enantiopure (S_S)-arylsulfinamides (S_S)-3 in good yields.     

Optically active 1-(benzofuran-2-yl)ethanols and ethane-1,2-diols by enantiotopic selective bioreductions

Enantiotopic selective reduction of 1-(benzofuran-2-yl)ethanones 1a–d, 1-(benzofuran-2-yl)-2-hydroxyethanones 4a–c and 2-acetoxy-1-(benzofuran-2-yl)ethanones 3a–c was performed by baker's yeast for preparation of optically active (benzofuran-2-yl)carbinols [(S)-5a–d, (S)-6a–c and (R)-6a–c, enantiomeric excess from 55 to 93% ee].     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Stereoselective intramolecular cycloadditions of homochiral N-alkenoyl aryl azides

Starting from the commercially available (S)-1-phenylethylamine and l-alanine benzylester, we synthesised the homochiral N-alkenoyl aryl azides 2a–2d. The intramolecular cycloaddition of unsubstituted 2a and 2b gave enantiopure 3,3a-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepine-4(6H)-ones 3a, 3b, 4a and 4b, while phenyl-substituted 2c and 2d gave enantiopure 1,1a-dihydro-2H-azirino[2,1-c][1,4]benzodiazepine-4(6H)-ones 5c, 5d, 6c and 6d.     

Resolution of 1-arylalkylamines with 3-O-hydrogen phthalate glucofuranose derivatives: role of steric bulk in a family of resolving agents

The development of three new acidic resolving agents which are hydrogen phthalates of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose 1, 1,2:5,6-di-O-cyclohexylidene-α-d-glucofuranose 2 and 1,2-O-cyclohexylidene-5,6-O-diphenylmethylidene-α-d-glucofuranose 3 is shown for the resolution of 1-arylalkylamines 7a–k. The salts between 1, 2 and (RS)-1-arylalkylamines 7a–k selectively crystallize 1·(S) 7a–j and 2·(S) 7a–h salts, allowing us to recover the corresponding bases (S) 7a–j and (S) 7a–h, respectively, in good yield and enantiomeric excess (73–95% ee). Whereas, the salts between 3 and (RS)-1-arylalkylamines 7a–c,g–i,k selectively crystallize 3·(S)-7a–c,g–i salts to recover the corresponding bases (S)-7a–c,g–i in poor enantiomeric excess (4–35% ee). The difference between the resolving ability of 1 and 2 for 1-arylalkylamines 7a–h is very slight, but there is considerable difference compared to ortho-substituted 1-arylalkylamines 7i and 7j. The role of substituents on a family of resolving agents 1, 2 and 3 is also discussed to interpret their resolving ability.     

Trichloro- and methyldichlorogermyl monochelates and dibromo- and dichlorogermyl bischelates derived from N,N-disubstituted amides of 2-hydroxycarboxylic acids

The reactions of GeCl₄, GeBr₄, and MeGeCl₃ with O-trimethylsilyl derivatives of N,N-disubstituted amides of 2-hydroxycarboxylic acids afforded pentacoordinate and hexacoordinate neutral (O,O)-mono- and (O,O)-bischelates. The reactions of glycolic acid derivatives with GeX₄ produced bischelates X₂Ge[OCH₂C(O)NR²R³]₂ 7a,c,d (X = Cl, R² = R³ = Me (a), (CH₂)₅ (c), (CH₂CH₂)₂O (d)) and 8a (X = Br). By contrast, the reactions of lactic and mandelic acid derivatives with GeCl₄ and MeGeCl₃ gave monochelates Cl₃Ge[OCH(R¹)C(O)NR²R³] (S)-9a–c (R¹ = Me) and Cl₂MeGe[OCH(R¹)C(O)NR²R³] 10a (R¹ = H), (S)-11a,b (R¹ = Me), and (S)-12a (R¹ = Ph) (R²R³ = (CH₂)₄ (b)), respectively. According to the X-ray diffraction data, the Ge atom in bischelates 7c,d and 8a has a coordination number 6, and its coordination polyhedron can be described as a slightly distorted octahedron. In monochelates (S)-9a-c, 10a, (S)-11a,b, and (S)-12a, the Ge atom has a coordination number 5, and its coordination polyhedron can be described as a trigonal bipyramid with two halogen atoms or one halogen atom and one ethereal oxygen atom in equatorial positions and the halogen atom and the amide oxygen atom in the axial positions. The bonds in the axial positions are somewhat longer than the corresponding bonds in tetracoordinate Ge compounds.     

Diastereoselective intramolecular acyl transfer of 5-(α-methylbenzyl)amino-1,3-dioxan-2-one to 4-hydroxymethyl-2-oxazolidinones

Intramolecular acyl transfer of (R)-5-(α-methylbenzyl)amino-1,3-dioxan-2-one (2) by treatment with DBU in CD₂Cl₂, CDCl₃, C₆D₆, CD₃CN, CD₃NO₂, DMSO-d₆, DMF, THF-d₈, ⁱPrOH, and ^tBuOH at room temperature afforded (4S,αR)-4-hydroxymethyl-3-α-methylbenzyl-2-oxazolidinone [(4S)-3] in moderate to quantitative yields with 58-94% de via an asymmetric desymmetrization process. Treatment of 2 with DBU and Cs₂CO₃ in MeOH and EtOH gave (4S)-3 and (4R)-3 without diastereoselectivities. Acidic treatment of 2 using HCO₂H, AcOH, EtCO₂H, ⁱPrCO₂H, ^tBuCO₂H, and C₆F₅OH in CDCl₃ gave (4S)-3 in moderate diastereoselectivities (26-52% de). First-order kinetics were observed in the reaction of 2 to (4S)-3 with DBU in CDCl₃ and THF-d₈.     

Structural control in palladium(II)-catalyzed enantioselective allylic alkylation by new chiral phosphine-phosphite and pyridine-phosphite ligands

The ligands 6-[(diphenylphosphanyl)methoxy]-4,8-di-tert-butyl-2,10-dimethoxy-5,7-dioxa-6-phosphadibenzo[a,c]cycloheptene, 1, (S)-4-[(diphenylphosphanyl)methoxy]-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4a′]dinaphthalene, (S)-2, and (S)-4-[(diphenylphosphanyl)methoxy]-2,6-bis-trimethylsilanyl-3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalene, (S)-3, (S)-2-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yloxymethyl)pyridine, (S)-4, and (S)-2-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-a′]dinaphthalen-4-yloxy)pyridine, (S)-5, have been easily prepared.The cationic complexes [Pd(η³-C₃H₅)(L-L′)]CF₃SO₃ (L–L′=1–(S)-5) and [Pd(η³-PhCHCHCHPh)(L–L′)]CF₃SO₃ (L–L′=(S)-2–(S)-4) were synthesized by conventional methods starting from the complexes [Pd(η³-C₃H₅)Cl]₂ and [Pd(η³-PhCHCHCHPh)Cl]₂, respectively. The behavior in solution of all the π-allyl- and π-phenylallyl-(L–L′)palladium derivatives 6–14 was studied by ¹H, ³¹P{¹H}, ¹³C{¹H} NMR and 2D-NOESY spectroscopy. As concerns the ligands (S)-4 and (S)-5, a satisfactory analysis of the structures in solution was possible only for palladium–allyl complexes [Pd(η³-C₃H₅)((S)-4)]CF₃SO₃, 11, and [Pd(η³-C₃H₅)((S)-5)]CF₃SO₃, 12, since the corresponding species [Pd(η³-PhCHCHCHPh)((S)-4)]CF₃SO₃, 13, and [Pd(η³-PhCHCHCHPh)((S)-5)]CF₃SO₃, 14, revealed low stability in solution for a long time. The new ligands (S)-2–(S)-5 were tested in the palladium-catalyzed enantioselective substitution of (1,3-diphenyl-1,2-propenyl)acetate by dimethylmalonate. The precatalyst [Pd(η³-C₃H₅)((S)-2)]CF₃SO₃ afforded the allyl substituted product in good yield (95%) and acceptable enantioselectivities (71% e.e. in the S form). A similar result was achieved with the precatalyst [Pd(η³-C₃H₅)((S)-3)]CF₃SO₃. The nucleophilic attack of the malonate occurred preferentially at allylic carbon far from the binaphthalene moiety, namely trans to the phosphite group. When the complexes containing ligands (S)-4 and (S)-5 were used as precatalysts, the product was obtained as a racemic mixture in high yield. The number of the configurational isomers of the Pd-allyl intermediates present in solution in the allylic alkylation and the relative concentrations are considered a determining factor for the enantioselectivity of the process.     

Non-enzymatic diastereoselective asymmetric desymmetrization of 2-benzylserinols giving optically active 4-benzyl-4-hydroxymethyl-2-oxazolidinones: asymmetric syntheses of α-(hydroxymethyl)phenylalanine,N-Boc-α-methylphenylalanine,cericlamine and BIRT-377

A reaction of (S)-2-benzyl-2-(α-methylbenzyl)amino-1,3-propanediol (S)-4a and 2-chloroethyl chloroformate, and the subsequent addition of DBU gave (4R,αS)-4-benzyl-4-hydroxymethyl-3-(α-methylbenzyl)-2-oxazolidinone (4R)-5a (92% de) via a diastereoselective asymmetric desymmetrization process. Debenzylation of (4R)-5a using trifluoromethanesulfonic acid and anisole in MeNO₂ gave (R)-4-benzyl-4-hydroxymethyl-2-oxazolidinone (R)-15a, which was converted into (R)-(α-hydroxymethyl)phenylalanine (7) in two steps. N-Boc-α-methylphenylalanine (8), cericlami0ne (9) and BIRT-377 (10) were also synthesized using these asymmetric desymmetrization and debenzylation.     

Aluminum and zinc complexes supported by functionalized phenolate ligands: Synthesis, characterization and catalysis in the ring-opening polymerization of ε-caprolactone and rac-lactide

A series of aluminum and zinc complexes supported by functionalized phenolate ligands were synthesized and characterized. Reaction of 2-(3,5-R₂C₃N₂)C₆H₄NH₂ (R = Me, Ph) with salicylaldehyde or 3,5-di-tert-butylsalicylaldehyde afforded 2-((2-(1H-pyrazol-1-yl)phenylimino)methyl)phenol derivatives 2a-2d. Treatment of 2a-2d with an equiv. of AlR²₃ (R² = Me, Et) gave corresponding aluminum aryloxides 3a-3e, while reaction with an equiv. of ZnEt₂ afforded zinc aryloxides 4a-4d. Treatment of 2c with 0.5 equiv. of ZnEt₂ formed diphenolato zinc complex 5. All new compounds were characterized by ¹H and ¹³C NMR spectroscopy and elemental analyses. The structures of complexes 3a, 4a and 5 were further characterized by single crystal X-ray diffraction techniques. The catalytic activity of complexes 3-5 toward the ring-opening polymerization of ε-caprolactone was studied. The zinc complexes (4a-4d) exhibited higher catalytic activity than the aluminum complexes (3a-3e). The diphenolato zinc complex 5 showed lower catalytic activity than the ethylzinc complexes 4a-4d. The aluminum complex (3b) is inactive to initiate the ROP of rac-lactide, while the zinc complex (4d) is active initiator for the ROP of rac-lactide, giving atactic polylactide.     

Synthesis and properties of bis(heteroazulen-3-yl)methyl cations and bis(heteroazulen-3-yl)ketones

The synthesis and properties of a novel type of bis(heteroazulen-3-yl)methyl cations, bis(2-oxo-2H-cyclohepta[b]furan-3-yl)methyl cation salt and nitrogen analogues, (9a-c·PF₆⁻) and (9a-c·BF₄⁻), as well as bis(heteroazulen-3-yl)ketones (12a-d) are studied. The synthetic method was based on a TFA-catalyzed electrophilic aromatic substitution on the heteroazulenes (6a-d) with paraformaldehyde to afford the corresponding disubstituted methane derivatives 7a-d, followed by oxidative hydrogen abstraction with DDQ, and subsequent exchange of the counter-anion by using aq. HPF₆ or aq. HBF₄. In addition, the reaction of 7a-d with 2.2 equiv. amounts of DDQ afforded carbonyl compounds 12a-d. The delocalization of the positive charge of 9a-c was evaluated by the ¹H and ¹³C NMR spectral data. The thermodynamic stability of cations 9a-c was evaluated to be in the order 9a<9b<9c on the basis of their reduction potentials measured by cyclic voltammetry (CV) and pK_R+ values (2.6-10.3) obtained spectrophotometrically. The reduction waves of cations 9a-c were irreversible, suggesting the dimerization of the radical species generated by one-electron reduction. This was demonstrated by the reduction of 9a·BF₄⁻ with Zn powder to give dimerized product 14a. In addition, the quenching of 9a·BF₄⁻ with MeOH/NaHCO₃ gives ether derivative 15a, which is proposed for the precursor for synthesizing tris(heteroazulene)-substituted methyl cations bearing two different heteroazulene-units.     

Synthesis and structure of {{amino(triorganosilyl)carbene}pentacarbonyltungsten(0)} complexes and attempted synthesis of {[2-bis(trimethylsilyl)methyl-3-triorganosilyl-2H-azaphosphirene-κP]pentacarbonyltungsten(0)}

First examples of tungsten aminocarbene complexes [(OC₅)W{C(SiR¹_nR²_3-n)NH₂}] 2a-d (R¹ = Ph, R² = Me) were synthesized via ammonolysis of the corresponding methoxycarbene complexes 1a-d. They were characterized by NMR spectroscopy, MS, IR, UV/Vis and elemental analysis, and in the case of the C-triphenylsilyl derivative 2a by single-crystal X-ray structure analysis. The reaction of P-chloro alkylidenephosphane 3 with complexes 2a-d, meant to give 2H-azaphosphirene complexes, was monitored by ³¹P NMR spectroscopy to reveal the formation of the products 4-7, which were presumably formed via decomposition of the transient complexes 10a-d.     

Synthetic access to optically active isoflavans by using allylic substitution

A general approach to the (S)- and (R)-isoflavans was invented, and efficiency of the method was demonstrated by the synthesis of (S)-equol ((S)-3), (R)-sativan ((R)-4), and (R)-vestitol ((R)-5). The key step is the allylic substitution of (S)-6a (Ar¹=2,4-(MeO)₂C₆H₃) and (R)-6b (Ar¹=2,4-(BnO)₂C₆H₃) with copper reagents derived from CuBr·Me₂S and Ar²-MgBr (7a, Ar²=4-MeOC₆H₄; 7b, 2,4-(MeO)₂C₆H₃; 7c, 2-MOMO-4-MeOC₆H₃), furnishing anti S_N2′ products (R)-8a and (S)-8b,c with 93-97% chirality transfer in 60-75% yields. The olefinic part of the products was oxidatively cleaved and the Me and Bn groups on the Ar¹ moieties was then removed. Finally, phenol bromide 9a and phenol alcohols 9b,c underwent cyclization with K₂CO₃ and the Mitsunobu reagent to afford (S)-3 and (R)-4 and -5, respectively.     

Kinetic resolution of 1-(benzofuran-2-yl)ethanols by lipase-catalyzed enantiomer selective reactions

Kinetic resolution of racemic 1-(benzofuran-2-yl)ethanols rac-1a–d was performed by lipase-catalyzed enantiomer selective acylation (E≫100) yielding (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a–d and (1S)-1-(benzofuran-2-yl)ethanols (S)-1a–d in highly enantiopure form. The degree of enantiomer selectivity for enzymatic alcoholysis/hydrolysis processes starting from racemic 1-acetoxy-1-(benzofuran-2-yl)ethane rac-2 was also tested under various conditions including supercritical CO₂ medium. Racemization-free lipase-catalyzed ethanolysis of the (1R)-1-acetoxy-1-(benzofuran-2-yl)ethanes (R)-2a–d yielded almost quantitatively the enantiopure (1R)-1-(benzofuran-2-yl)ethanols (R)-1a–d.     

Heterocycles 35. CaL-B mediated synthesis of enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates

Herein we present the lipase catalyzed synthesis of four new enantiomerically pure (R)- and (S)-ethyl 3-(2-arylthiazol-4-yl)-3-hydroxypropanoates and their butanoates by enzymatic enantioselective acylation of the racemic alcohols rac-1a–d and by ethanolysis of the corresponding racemic esters rac-2a–d mediated by lipase B from Candida antarctica (CaL-B) in organic solvents. In terms of stereoselectivity and activity, both procedures, the acylation and alcoholysis, are successful (50% conversion, E ≫ 200). The absolute configuration of the resolution products was determined by a detailed ¹H NMR study of the Mosher’s derivatives of (S)-1a.     

Synthesis and dynamics of atropisomeric (S)-N-(α-phenylethyl)benzamides

The synthesis of atropisomeric 2-substituted benzamides 2a-e, 3a-e, and 4a-e, and characterization by X-ray structure analysis of 2d, 2e, 3c, 3e, 4c, and 4e are reported. Dynamic ¹H NMR spectroscopic studies of benzamides 2b-d, 3b-d, and 4b-d indicate that only two of the four possible rotamers are present in solution, with population ratios ranging between 1.5:1 and 4.1:1. The measured free energy of activation to interconversion of the rotamers ranged from 12.4 to 18.9 kcal mol⁻¹. Benzamides ArCON[(S)-phenethyl]₂ (2e, 3e, and 4e), exhibited atropisomer ratios between 1.7:1 and 1:1, and free energies of interconversion of the rotamers ranged from 11.5 to 17.6 kcal mol⁻¹. The highest rotation barriers were observed for the ortho-nitro derivatives 2a-e. Molecular calculations at the semiempirical level (PM3MM) gave free energies of activation for benzamides 2e and 3e of 23.6 and 12.4 kcal mol⁻¹, respectively, which are comparable to the experimental values.     

Asymmetric transfer hydrogenation of aromatic ketones with the ruthenium(II) catalyst derived from C2 symmetric N,N′-bis[(1S)-1-benzyl-2-O-(diphenylphosphinite)ethyl]ethanediamide

Asymmetric transfer hydrogenation of ketones with chiral molecular catalysts is realized to be one of the most magnificent tools to access chiral alcohols in organic synthesis. A new chiral phosphinite compound N,N′-bis[(1S)-1-benzyl-2-O-(diphenylphosphinite)ethyl]ethanediamide (1), has been synthesized by the reaction of chlorodiphenylphosphine with N,N′-bis[(1S)-1-benzyl-2-hydroxyethyl]ethanediamide under argon atmosphere. The oxidation of 1 with aqueous hydrogen peroxide, elemental sulfur or grey selenium in toluene gave the corresponding oxide 1a, sulfide 1b and selenide 1c, respectively. Pd, Pt and Ru complexes were obtained by the reaction of 1 with [MCl₂(cod)] (M: Pd 1d, Pt 1e) and [Ru(p-cymene)Cl₂]₂1f, respectively. All these new complexes were characterized by using NMR, FT-IR spectroscopies and microanalysis. Additionally, as a demonstration of their catalytic reactivity, the ruthenium complex 1f was tested as catalyst in the asymmetric transfer hydrogenation reactions of acetophenone derivatives with iPrOH was also investigated.     

New chemical and chemo-enzymatic routes for the synthesis of (RS)- and (S)-enciprazine

The chemo-enzymatic synthesis of racemic and enantiopure (RS)- and (S)-enciprazine 1, a non-benzodiazepine anxiolytic drug, is described herein. The synthesis started from 1-(2-methoxyphenyl) piperazine 3, which was treated with 2-(chloromethyl) oxirane (RS)-4 using lithium bromide to afford a racemic alcohol, 1-chloro-3-(4-(2-methoxyphenyl) piperazin-1-yl) propan-2-ol (RS)-6 in 85% yield. Intermediate (S)-6 was synthesized from racemic alcohol (RS)-6 using Candida rugosa lipase (CRL) with vinyl acetate as the acyl donor. Various reaction parameters such as temperature, time, substrate, enzyme concentration, and the effect of the reaction medium on the conversion and enantiomeric excess for the transesterification of (RS)-6 by CRL were optimized. It was observed that 10 mM of (RS)-6, 50 mg/mL of CRL in 4.0 mL of toluene with vinyl acetate (5.4 mmol) as acyl donor at 30 °C gave good conversion (C = 49.4%) and enantiomeric excess (ee_P = 98.4% and ee_S = 96%) after 9 h of reaction. Compound (S)-6 is a key intermediate for the synthesis of enantiopure (S)-1. The (RS)- and (S)-enciprazine drug 1 was synthesized by treating (RS)- and (S)-6 with 3,4,5-trimethoxyphenol 5 using MeCN as a solvent and K₂CO₃ as a base.