The new way to synthesize ethyl 1-butyryloxy-1-phenylmethane(P-phenyl)phosphinate and whole-cell biocatalysis by Escherichia coli and Pseudomonas fluorescens

Abstract

A new compound, ethyl 1-carboxy-1-hydroxy-1-phenylmethane(P-phenyl)phosphinate, was synthesized and the configuration of its diastereoisomers was described using NMR spectroscopy. Acylation with butyryl chloride gave an unexpected product, ethyl butyryloxy(phenyl)methane(P-phenyl)phosphinate, which was then hydrolyzed using two bacterial species as biocatalysts. Good results were achieved for biocatalytic hydrolysis performed by Escherichia coli cells, giving optically active products with 84% enantiomeric excess, and enantioselectivity of 25.8 for one pair of enantiomers. Better results were obtained when the biocatalytic reaction was carrying out for a longer period and the conversion degree reached 71%, the enantiomeric excess of unreacted substrate was >99% and enantioselectivity increased to 32.1. In all cases, isomers bearing α–carbon atom of S configuration were hydrolyzed preferentially.     

Diastereoselective synthesis of (2S)-2-[(R)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one

Double asymmetric induction in Michael reactions has been studied. Enantioselective alkylation of a cyclic ketone (1-indanone) with α-phenyl-nor-gramine was carried out. The relative configuration of (2S^∗)-2-[(R^∗)-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-one was established by X-ray diffraction. The relative configuration of (R^∗,R^∗,S^∗)- and (S^∗,R^∗,S^∗)-2-1H-indol-3-yl(phenyl)methyl]-2,3-dihydro-1H-inden-1-ols was established by ¹H NMR studies.     

Reaction of 5-oxo-2-phenyl-4,4-bis(trifluoromethyl)-4,5-dihydro-1,3,2-benzodioxaphosphepine with chloral. The synthesis and spatial structure of 5-carbaphosphatrane containing a four-membered ring

Phosphorylation of 2-hydroxyphenyl 2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl ketone with dichloro(phenyl)phosphine gave 5-oxo-2-phenyl-4,4-bis(trifluoromethyl)-4,5-di-hydro-1,3,2-benzodioxaphosphepine. Heating of the latter initiated an intramolecular interaction of the P atom with the carbonyl group. Hydrolysis of the intermediate product yielded 3-hydroxy-2-oxo-2-phenyl-3-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2,3-di-hydro-1,2λ⁵-benzo[d]oxaphosphole. The reaction was highly stereoselective (P_RC_S/P_SC_R). The reaction of the starting phosphepine with chloral proceeded highly stereoselectively (P_RC_SC_S/P_SC_RC_R) to give a 5-carbaphosphatrane derivative containing a four-membered ring, namely, 1-phenyl-3-trichloromethyl-10,10-bis(trifluoromethyl)-6,7-benzo-2,4,8,9-tetraoxa-1λ⁵-phosphatricyclo[3.3.2.0¹,⁵]decene. The trigonal bipyramid of the 5-carbaphosphatrane derivative is made up of the equatorial O atoms and the apical C atoms.     

Enzymatic resolution of α-hydroxyphosphinates with two stereogenic centres and determination of absolute configuration of stereoisomers obtained

The use of quinine as a chiral solvating agent allows us to determine a tentative absolute configuration at the phosphorus atom of hydroxyphosphinates with two stereogenic centres (at the phosphorus and α-carbon atoms). Two ethyl butyryloxyalkane(P-phenyl)phosphinates were hydrolysed using various lipases. In all cases isomers possessing α-carbon atom with an (S)-configuration were hydrolysed preferentially. The absolute configuration of both chiral centres of obtained α-hydroxyphosphinates was determined by using (S)-(+)-MTPA-Cl and quinine. The mode of chiral discrimination of α-hydroxyphosphinates by quinine was studied by means of computational chemistry, which confirmed the experimental findings that the signals in ³¹P NMR spectra of compounds with an (R_P)-configuration are situated upfield when compared with the respective (S_P) isomers.     

Hemilability and structural considerations in complexes of platinum(II) comprising bis(diphenylphosphanyl)methane monoxide,monosulfide, and monoselenide

The structure of a platinum(II) complex containing (R)-(dimethylamino)ethylnapthyl and bis(diphenylphosphanyl)methane monosulfide ligands, namely, {(R)-1-[1-(dimethylamino)ethyl]napthyl-κ²N,C²}[(diphenylphosphanylmethyl)diphenylphosphine sulfide-κ²P,S]platinum(II) hexafluoridoantimonate dichloromethane monosolvate, [Pt(C₁₄H₁₆N)(C₂₅H₂₂P₂S)][SbF₆]·CH₂Cl₂, was determined. The structural features are compared with analogous platinum bis(diphenylphosphanyl)methane monoxide [dppm(O)] and bis(diphenylphosphanyl)methane monoselenide [dppm(Se)] complexes in relation to their potential hemilability and stereochemical nonrigidity.     

Optically active transition-metal compounds: XXII. Stereochemistry and crystal structure determination of (η5-C5H5)CoI(NC4H3C(R)=N(S)-CH(CH3)(C6H5)) (R = H,CH3)

The crystal structures and absolute configurations of (η⁵-C₅H₅)-CoI(NC₄H₃-C(R)=N(S)-CH(CH₃)(C₆H₅)) (R = H, compound I; R = CH₃, compound II) have been determined by single crystal X-ray diffraction. Crystals of compound I are orthorhombic, with a 11.084(6), b 12.107(6) and c 13.121(7) Å, space group ^P2₁2₁2₁ and d (calcd, Z = 4) 1.69 g cm^?3 The structure was solved by the Patterson technique and refined with use of full matrix least-squares methods to R(F) = 0.031 and R_w(F) = 0.028. Compound II is nearly isomorphous and isostructural; a 11.246(6), b 11.923(6) and c 13.370(7) Å, d(calc., Z = 4) 1.71 g cm^?3 and was refined to the final agreement factors of R(F) = 0.044 and R_w(F) = 0.035. The Co atom has a distorted tetrahedral coordination, with Co-I 2.595(2) for I and 2.607(2) Å for II; Co-(η⁵-C₅H₅ ring centroid) 1.681(4) and 1.703(5) Å; Co-N(pyrrole) 1.905(9) and 1.885(9) Å; Co-N(imine) 1.971(8) and 2.003(9) Å, all the parameters being well within values found in the literature. The configuration around the chiral carbon of the phenylethylamine is S for both compounds, whereas the configuration around the metal is R in I and S in II. The different metal configurations in I and II have their origin in the two different substituents (R = H, CH₃) at the imine carbon atoms of the chelate ring, which induce completely different conformations of the (S)-CH(CH₃)(C₆H₅) moiety in the two complexes. For both compounds the thermodynamically less stable isomer is enriched upon crystallization. Also, for compound I the solution and solid state conformations are almost opposite to each other, the conformation in the solid reflecting intramolecular interactions (phenyl/C₅H₅ attraction).     

Enantioselective addition of β-keto phosphinate to ω-nitrostyrene in the presence of optically active nickel(II) complex

Synthesis was performed of individual methyl [(S,2R,3S)-4-nitro-1-oxo-1,3-diphenylbutan-2-yl]-(phenyl)phosphinate from racemic β-keto phosphinate and ω-nitrostyrene under the catalysis by nickel(II) complex with (1R,2R)-N,N'-dibenzylcyclohexane-1,2-diamine.     

Absolute configuration of the four stereoisomers of valnoctamide (2-ethyl-3-methyl valeramide), a potentially new stereospecific antiepileptic and CNS drug

Valnoctamide (2-ethyl-3-methyl valeramide, Nirvanil^®, VCD), a mild tranquilizer endowed with anticonvulsant properties, exhibits diastereoselective and enantioselective pharmacokinetics in healthy subjects and epileptic patients. The purpose of this paper is to assign the absolute configuration of the four VCD stereoisomers and to describe the stereoselective synthesis used to prepare two-key VCD stereoisomers. We have synthesized two out of the four stereoisomers, with high diastereomeric excess, by two different synthetic methods. In both methods the (S) configuration at C-3 of VCD was fixed by synthesizing (S)-3-methyl valeric acid from l-isoleucine. In the first method the diastereomeric mixture (2RS,3S)-VCD was prepared. This mixture gave one of the diastereomers via repeated crystallizations, and its absolute configuration (2R,3S)-VCD, was established by X-ray crystallography using a single crystal. The absolute configuration of all four VCD stereoisomers, separated by chiral gas chromatography, was established on the basis of diastereomeric and enantiomeric correlations. In order to assess stereoselective pharmacodynamic properties of VCD, the single stereoisomers have to be synthesized. Stereoselective synthesis of (2R,3S)-VCD and (2S,3S)-VCD was accomplished by using chiral oxazolidinone auxiliaries. These diastereomers were obtained in 99.6% diastereomeric excess.     

Chloro(η6‐p‐cymene)(phosphoramidite)ruthenium(II), a 16‐Electron Fragment Stabilized by an η2‐Aryl–Metal Interaction,and Its Use in Asymmetric Cyclopropanation

Chloride abstraction from the half‐sandwich complexes [RuCl₂(η⁶‐p‐cymene)(P*‐κP)] ( 2a : P* = (S_a,R,R)‐ 1a = (1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl bis[(1R)‐1‐phenylethyl)]phosphoramidite; 2b : P* = (S_a,R,R)‐ 1b = (1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl bis[(1R)‐(1‐(1‐naphthalen‐1‐yl)ethyl]phosphoramidite) with (Et₃O)[PF₆] or Tl[PF₆] gives the cationic, 18‐electron complexes dichloro(η⁶‐p‐cymene){(1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl {(1R)‐1‐[(1,2‐η)‐phenyl]ethyl}[(1R)‐1‐phenylethyl]phosphoramidite‐κP}ruthenium(II) hexafluorophosphate ( 3a ) and [Ru(S)]‐dichloro(η⁶‐p‐cymene){(1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl {(1R)‐1‐[(1,2‐η)‐naphthalen‐1‐yl]ethyl}[(1R)‐1‐(naphthalen‐1‐yl)ethyl]phosphoramidite‐κP)ruthenium(II) hexafluorophosphate ( 3b ), which feature the η²‐coordination of one aryl substituent of the phosphoramidite ligand, as indicated by ¹H‐, ¹³C‐, and ³¹P‐NMR spectroscopy and confirmed by an X‐ray study of 3b . Additionally, the dissociation of p‐cymene from 2a and 3a gives dichloro{(1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl [(1R)‐(1‐(η⁶‐phenyl)ethyl][(1R)‐1‐phenylethyl]phosphoramidite‐κP)ruthenium(II) ( 4a ) and di‐μ‐chlorobis{(1S_a)‐[1,1′‐binaphthalene]‐2,2′‐diyl [(1R)‐1‐(η⁶‐phenyl)ethyl][(1R)‐1‐phenylethyl]phosphoramidite‐κP}diruthenium(II) bis(hexafluorophosphate) ( 5a ), respectively, in which one phenyl group of the N‐substituents is η⁶‐coordinated to the Ru‐center. Complexes 3a and 3b catalyze the asymmetric cyclopropanation of α‐methylstyrene with ethyl diazoacetate with up to 86 and 87% ee for the cis‐ and the trans‐isomers, respectively.     

Absolute configurations of organometallic compounds : V. X-ray study of (−)578-(η5-C5H5)Mo(CO)2SC(CH3NR′ with R′ = (S-CH(CH3)(C6H5)

The structure and absolute configuration of the thioamido complex (?)₅₇₈-(η⁵-C₅H₅Mo(DO)₂SC(CH₃NR′ with R′ = (S)CH(CH₃)(C₆H₅) have been determined by single-crystal X-ray diffraction. The substance crystallizes in the orthorhombic system; space group P2₁2₁2₁ with cell constants of a = 8.314(1), b = 9.020(1), and c = 22.352(2) Å, and Z = 4 molecules/unit cell. The absolute configuration was determined using Bijvoet's method. Refinement of the data using the anomalous scattering contributions of Mo and S yields a final R(F = 0.036 for 2715 independent reflections having I > 3σ(I). The distorted square pyramidal coordination of the Mo atom is defined by two carbonyl carbons and the S and N atoms of the thioamido ligand occupying the four basal plane sites and the five carbons of the η⁵-C₅C₅ ligand in the axial position. The Mo—ligand distances and most of the bond lengths and angles within the ligands are normal and compare closely with those of recent structure determinations. However, the distances and angles within the thioacetamide ligand show, distinctly, the effect of chelate binding to the Mo atom. In particular, the angles at the central thioacetamide carbon differ markedly from those of free thioacetamide and monodentate, S-bound metal thioacetamido complexes. The Mo atom is 1.041 Å above the plane formed by the four basal ligands. The conformation of the (S)-α-phenylethyl group with respect to the ligand plane, defined by the thioamido system and the Mo atom, is discussed. The configuration at the metal atom in the (?)₅₇₈-isomer of (η⁵-C₅H₅)Mo(CO)₂SC(CH₃)NR′ is specified as (S).     

Studies on the configuration of nitrogenous stereogenic centres in adducts of rhodium(II) tetraacylates with chiral amines: the application of 1H and 13C NMR spectroscopy

The ¹H and ¹³C NMR spectra of enantiomerically pure amines (S)-N,N-dimethyl-1-phenylethylamine, (S)-N-methyl-1-phenylethylamine, (S)-N-ethyl-1-phenylethylamine and (S)-N-ethyl-N-methyl-1-phenylethylamine in the presence of a twofold molar excess of dirhodium(II) tetratrifluoroacetate and dirhodium(II) Mosher’s acid derivatives [(4S) and (4R)] were measured in CDCl₃ as a solvent. The amines having various substituents at the nitrogen atom (H, CH₃ and CH₂CH₃) formed in such conditions as an equilibrium mixture of C_SN_R and C_SN_S 1:1 adducts. The signals of both diastereoisomers were observed in NMR spectra at either room temperature (303 K) or moderately decreased temperatures (263–273 K). The rates of mutual diastereoisomer conversion were estimated by selective inversion recovery experiments and varied from less than 0.1 to ca. 10 s^?1, depending on the ligand and temperature. Analysis of ¹³C NMR data and NOE experimental data resulted in the unambiguous determination of the configuration at the nitrogen atom with respect to the carbon stereogenic centre.Modelling of adduct structures and calculations of molecular energy and NMR parameters (GIAO) using Density Functional Theory (DFT) were performed in order to support the experimental findings. The calculations were carried out using 3-21G//B3LYP (structure optimizing) and 311G(2d,p)/LanL2DZ//B3LYP theory levels (molecular energy and NMR shielding).     

Acid-catalyzed enzymatic hydrolysis of 1-methylcyclohexene oxide

Limonene-1,2-epoxide hydrolase from Rhodococcus erythropolis DCL14, an enzyme involved in the limonene metabolism of this microorganism, catalyzes the enantioselective hydrolysis of 1-methylcyclohexene oxide. (1R,2S)-1-Methylcyclohexene oxide was the preferred substrate and it was mainly hydrolyzed to (1S,2S)-1-methylcyclohexane-1,2-diol, while (1S,2R)-1-methylcyclohexene oxide was converted more slowly and mainly yielded (1R,2R)-1-methylcyclohexane-1,2-diol. The reaction proceeded with a high regioselectivity (C1:C2, 85:15). H₂¹⁸O-labelling experiments confirmed that the nucleophile was mainly incorporated at the most substituted carbon atom, suggesting that limonene-1,2-epoxide hydrolase uses an acid-catalyzed enzyme mechanism.     

Stereospecific synthesis of P-epimeric (Rp1, Rp2)-bis-[O-l-menthylphenylphosphonothionyl] diselenide. A new variant of the stereoselective Staudinger reaction

An efficient procedure is described that leads to pure (S_P)- O -l-menthylphenylthiophosphinate. The absolute configuration of this diastereomer was assigned by chemical correlation and confirmed by X-ray crystallography. The reaction of the isomer with phenyl azide, leading to amidate, is a new variant of the stereoselective Staudinger reaction. Addition of elemental selenium to the (S_P)-thiophosphinate led to diastereomeric O-l-menthylphenylselenophosphonothioic acid, which was finally oxidized to the diastereomeric (R_P1,R_P2)-bis-[O-l-menthylphenylphosphonothionyl] diselenide. The diselenide structure was unambiguously confirmed by ³¹P NMR spectroscopy.     

Synthesis and resolution of an α-phenyl substituted ortho-palladated matrix

A novel ortho-palladated benzylaminate matrix bearing phenyl substituent at the α-carbon stereocenter was prepared in the racemic state by direct intramolecular palladation of tertiary diphenylmethylamine with palladium(II) acetate; its structure and palladacycle conformation were determined by ¹H NMR studies of the mononuclear triphenylphosphine adduct. The resolution of the dimeric complex was performed via recrystallization of its diastereomeric (S)-prolinate derivatives. The absolute configuration (R_C,R_C) of the enantiopure dimer thus obtained was determined by an X-ray diffraction investigation of the less soluble (R_C,S_CS_N)-diastereomer of its (S)-prolinate adduct.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Synthesis and preliminary studies on novel enantiopure crown ethers containing an alkyl diarylphosphinate or a proton-ionizable diarylphosphinic acid unit

This paper reports the synthesis, characterization and electronic circular dichroism (ECD) spectroscopic studies of a new type of crown ethers and their achiral analogues containing a tetrahedral phosphorous centre. The synthetic routes to the two chiral phosphinate derivatives [(R,R)-10 and (R,R)-11] were similar, starting from the earlier reported ethyl bis(2-hydroxyphenyl)phosphinate and the unreported methyl bis(2-hydroxyphenyl)phosphinate, respectively. The enantiopure crown ether containing phosphinic acid unit (R,R)-14 was obtained by hydrolysis of the phosphinates (R,R)-10 and (R,R)-11, respectively. ECD spectroscopy was used for investigation of the chiroptical properties as well as complex formation ability of the novel enantiopure ligands. Owing to the presence of the aryl substituents the ECD spectra are rich in bands in the ¹B_b, ¹L_a and ¹L_b regions (190-250 nm and 260-330 nm, respectively). In the case of (R,R)-14, a solvent dependent conformational behaviour was observed due to the strong dimer or aggregate forming ability of the POOH groups. This finding was supported by theoretical calculation of the monomer and the dimer forms. Phosphinates (R,R)-10 and (R,R)-11 form complexes with α-phenylethylammonium perchlorate (PEA) and α-(1-naphthyl)ethyl ammonium perchlorate (NEA) but do not discriminate between their enantiomers. All three chiral crown ethers bind strongly cations of ionic radii <∼1 Å.     

Stereoselective synthesis of (1′S,3R,4R)-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone

A stereoselective synthesis of (1′S,3R,4R)-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone as a new fluorine-containing intermediate towards β-lactams, is described. The synthetic key step relies upon the dynamic kinetic resolution (DKR) of ethyl 2-benzamidomethyl-4-fluoro-3-oxo-butanoate via asymmetric transfer hydrogenation catalyzed by [Ru(η⁶-arene)(S,S)-R₂NSO₂DPEN].     

Synthesis of (R)- and (S)-4-hydroxyisophorone by ruthenium-catalyzed asymmetric transfer hydrogenation of ketoisophorone

The first synthesis of (R)- and (S)-4-hydroxyisophorone by catalytic transfer hydrogenation of ketoisophorone is reported. Ruthenium catalysts containing commercially available chiral amino alcohols afforded 4-hydroxyisophorone in up to 97% selectivity and 97% ee. (R)- or (S)-4-Hydroxyisophorones with >99% ee were isolated by crystallization. The catalyst precursors [RuCl₂((S,R)-ADPE)(η⁶-p-cymene)] ((S,R)-ADPE=(1S,2R)-amino-1,2-diphenylethanol-N) and (R_Ru)-[RuCl((S,R)-ADPE⁻¹)(η⁶-p-cymene)] (ADPE⁻¹=amino-1,2-diphenylethanolato-N,O) were isolated for the first time and the X-ray crystal structure of the latter determined.     

Stabilization of the labile metal configuration in halfsandwich complexes [CpRh(PN)Hal]X

PN ligands 3 and 4, derived from 2-diphenylphosphanylmethylpyridine 2a, were synthesized, to which in the backbone a tether to a cyclopentadiene system and for comparison an ⁱPr substituent were attached. The chiral compounds were resolved by introduction of a menthoxy substituent into the 2-position of the pyridine system and/or palladium complexes with enantiomerically pure co-ligands. The tripod ligand 3b contains three different binding sites (Cp, P, N) connected by a resolved chiral carbon atom. (S_C)-configuration of this tripod ligand enforces (R_Rh)-configuration at the metal atom in the halfsandwich rhodium complex (L_Ment,S_C,R_Rh)-7b. The opposite metal configuration is inaccessible. Substitution of the chloro ligand in (L_Ment,S_C,R_Rh)-7b by halide (Br, I) or pseudohalide (N₃, CN, SCN) ligands occurs with retention of configuration to give complexes 8b-11b. However, in the reaction of (L_Ment,S_C,R_Rh)-7b with PPh₃ the pyridine arm of the tripod ligand in compound 13b becomes detached from the metal atom. In the Cp*Rh and CpRh compounds of the bidentate PN ligands 4a and 4b both metal configurations are accessible and in complexes 14a-17a and 14b-17b they equilibrate fast. The stereochemical assignments are corroborated by 9 X-ray analyses.     

Stereoselective reduction,methylation, and phenylation of the 13-carbonyl group in chlorophyll derivatives

Regioselective reduction of the 13-carbonyl group on the five-membered exo-ring of methyl pyropheophorbide-a, one of the chlorophyll-a derivatives, with sodium borohydride gave an epimeric mixture of (13¹R/S)-hydroxy-chlorins. The stereoselectivity was controlled by the steric effect of the (17S)-methoxycarbonylethyl group to afford the (13¹S)-rich secondary alcohol (25% de). The use of sterically large lithium tri(sec-butyl)borohydride as the reductant enhanced the stereoselectivity to 55% de. The regio- and stereoselective methylation and phenylation of the 13-CO of pyropheophorbide-a were observed using methyl and phenyl lithium, respectively. The major diastereomer of the tertiary alcohols obtained had the same configuration at the 13¹-stereogenic center as in the reduced product. All of the anion species (H^?, CH₃^?, and C₆H₅^?) favorably attacked the 13¹-carbon atom from the reverse side of the 17-propionate residue, that is, the less sterically crowded face of the 13-CO plane.