First optically active P*-chiral phosphapalladacycle

The first cyclopalladated complex containing an asymmetric P^*-donor atom in the phosphapalladacycle has been prepared in an enantiomerically pure state via resolution of diastereomeric (S)-prolinate derivatives of the racemic dimer. The absolute configuration of the P^*-stereocenter (S_P) and the geometric configuration of the palladium environment (Z) were determined by an X-ray diffraction investigation of the less soluble diastereomer of the (S)-prolinate adduct.     

A planar chiral non-metallocenic analogue of the most popular N,N-dimethylbenzylaminate palladacycle

A racemic planar chiral tertiary amine pCp-CH₂NMe₂ (HL¹, pCp = [2.2]paracyclophane-4-yl) was prepared by aminomethylation of the bromide pCp-Br with Eschenmoser’s salt. Direct cyclopalladation of this new ligand with palladium(II) acetate results in the formation of the racemic CN-dimer rac-3 in a moderate yield of 64%. The enantiomerically pure dimer (S_pl, S_pl)-3 was obtained by the standard procedure of racemic palladacycle resolution using (S_C)-prolinate as a chiral derivatising agent. The ortho-palladated structure, absolute configuration of the chiral plane and stereochemical peculiarities of the new CN-palladacycle were established by means of NMR spectroscopy and an X-ray diffraction study of its (S_C)-prolinate derivative.     

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.     

Chiral,non-racemic α-hydroxyphosphonates and phosphonic acids via stereoselective hydroxylation of diallyl benzylphosphonates

Chiral, non-racemic α-hydroxyphosphonates have been prepared in high enantiomeric excess (96–98% ee), via stereoselective oxaziridine-mediated hydroxylation of diallyl benzylphosphonates. The enantiomeric purity and absolute configuration of the α-hydroxyphosphonates was established from ¹H and ³¹P NMR spectroscopy of the (S)-O-methylmandelate esters. Deprotection of the diallyl α-hydroxyphosphonates under neutral conditions furnished the corresponding free phosphonic acids, retaining a high degree of stereochemical purity (90 to >98% ee).     

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.     

Enantiomerically pure cyclopalladated diazaphospholidine

Enantiomerically pure (S)-2-(anilinomethyl)pyrrolidine (S)-2 was obtained from (S)-proline using a modified four-step procedure in a total yield of 56%. Diamine (S)-2 was converted to diazaphospholidine (S)-1 using ^oTolP(NMe₂)₂. The enantiomeric purity of ligand (S)-1 and diamine (S)-2 was determined by ³¹P and ¹H NMR spectroscopy, respectively, using a CN-palladacycle for their chiral derivatization. Direct cyclopalladation of (S)-1, using Pd(OAc)₂ in toluene under mild conditions regioselectively afforded the cyclopalladated complex with the (sp²)C–Pd bond. The aromatic C–H bond activation was confirmed by NMR spectral data and X-ray diffraction study of the PPh₃ derivative of the new P¹,C¹,N¹-chiral phosphapalladacycle.     

First enantiopure phosphapalladacycle with planar chirality. X-Ray study of the racemic dimer and (Spl,SCSN)-diastereomer of its prolinate derivative

The first P,C-cyclopalladated complex with planar chirality was prepared by direct cyclopalladation of prochiral di-tert-butyl(ferrocenylmethyl)phosphine. Resolution of the racemic dimer was achieved through separation of its diastereomeric (S)-prolinate derivatives. The palladacycle structure was confirmed by the ¹H NMR spectra of the dimer and its triphenylphosphine adduct and an X-ray diffraction study of the racemic dimeric complex. The absolute configuration of the planar chirality was determined by an X-ray diffraction investigation of one of two diastereomers of the (S)-prolinate derivative.     

An approach to the synthesis and assignment of the absolute configuration of all enantiomers of ethyl hydroxy(phenyl)methane(P-phenyl)phosphinate

Ethyl butyryloxy(phenyl)methane(P-phenyl)phosphinate was hydrolyzed using four bacterial species as biocatalysts. In all cases the reaction was stereoselective and isomers bearing an α-carbon atom with an (S)-configuration were hydrolyzed preferentially. Also a lack of stereoselectivity toward the phosphorus atom was observed. Hydrolysis of one enantiomeric mixture, namely mixture of (S_P,R) and (R_P,S) configuration afforded enantiomerically pure ethyl (R_P,S)-hydroxy(phenyl)methane(P-phenyl)phosphinate, configuration of which was established by X-ray crystallography. The observed ¹H and ³¹P NMR chemical shifts of Mosher esters of ethyl hydroxy(phenyl)methane(P-phenyl)phosphinate were correlated with the configurations of both stereogenic centers of all four stereoisomers.     

(18-Crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent for determining the enantiomeric purity and absolute configuration of β-amino acids

(18-Crown-6)-2,3,11,12-tetracarboxylic acid is an excellent chiral NMR solvating agent for cyclic β-amino acids and acyclic derivatives with aliphatic, aromatic, and heterocyclic aromatic moieties. The β-amino acids are mixed with the crown ether in methanol-d₄ in either their neutral or protonated form. Substantial enantiomeric discrimination typically occurs for the resonances of the α-methylene and β-methine hydrogen atoms. Resonances of the substituent group of the β-amino acid often exhibit enantiomeric discrimination. The enantiomeric discrimination of the α-methylene and β-methine resonances of specific groups of compounds shows consistent patterns that correlate with the absolute configuration.     

New chiral organophosphorus derivatizing agent for the determination of enantiomeric composition of chloro- and bromohydrins by 31P NMR spectroscopy

The synthesis of a new chiral organophosphorus derivatizing agent prepared from (S)-2-anilinomethylpyrrolidine 1 and its successful use in the determination of enantiomeric composition of various halohydrins by ³¹P NMR spectroscopy is described.     

Deracemisation of aromatic β-hydroxy esters using immobilised whole cells of Candida parapsilosis ATCC 7330 and determination of absolute configuration by 1H NMR

Deracemisation of aryl and substituted aryl β-hydroxy esters using immobilised whole cells of Candida parapsilosis ATCC 7330 yields the corresponding (S)-enantiomer in >99% enantiomeric excess and good yield (up to 68%). The absolute configuration of ethyl 3-(2,4-dichlorophenyl)-3-hydroxy propanoate and ethyl 3-hydroxy-5-phenyl-pent-4-enoate as determined by ¹H NMR using MTPA chloride was found to be ‘S’. The chemical shifts of the methoxy groups of the two diastereomeric MTPA esters were used as diagnostic signals to determine the absolute configuration.     

A resolution of the monodentate P*-chiral phosphine PButC6H4Br-4 and its NMR-deduced absolute configuration

Both enantiomers of the monodentate phosphine PBu^tC₆H₄Br-4 were obtained in an enantiopure state by chromatographic separation of their diastereomeric adducts with a new homochiral ortho-palladated resolving agent derived from α-tert-Bu-substituted tertiary benzylamine. The conformation of the palladacycle and the absolute configuration of the phosphine were determined using ¹H NMR spectroscopy (including NOE technique) and confirmed by an X-ray diffraction study of both diastereomeric complexes. The enantiomers of the resolved phosphine were displaced from the individual diastereomers of the palladium(II) complexes with recovery of the starting resolving agent, and trapped in the form of binuclear coordination complexes of palladium(II).     

FICA,a new chiral derivatizing agent for determining the absolute configuration of secondary alcohols by 19F and 1H NMR spectroscopies

Optically active 1-fluoroindan-1-carboxylic acid (FICA) was designed and prepared as its methyl ester for determining the absolute configuration of chiral molecules by both ¹H and ¹⁹F NMR spectroscopies. Enantiomerically pure isomers of FICA methyl esters (FICA Me esters) were obtained by chromatographic separation using HPLC with a Daicel Chiralcel OJ-H column. The absolute configuration of the (+)-FICA Me ester was deduced to be (S) by X-ray crystallographic analysis of the (+)-FICA amide of (R)-α-phenethylamine. Both enantiomers were derived to the diastereomeric esters of chiral secondary alcohols by an ester exchange reaction. In the ¹H NMR spectra, the signs of Δδ_H (δ_R ? δ_S) were consistent on each side of the FICA molecular plane. Therefore, the concept of the modified Mosher’s method could be successfully applied to the FICA-based procedure. Moreover, the consistency in the signs of Δδ_F (δ_R ? δ_S) values suggests that the FICA method would be reliable in assigning the absolute configurations of secondary alcohols based on ¹⁹F NMR spectroscopy.     

Application of 1H NMR?Eu(fod)3?shifted spectra for the determination of the enantiomeric composition and absolute configuration of secondary alcohols,using (−)-ω-camphanic esters

The diastereomeric differences (Δδ) were measured for a series of 11 (?)-ω-camphanic esters of secondary alcohols of known absolute configuration, using ¹H NMR spectroscopy with Eu(fod)₃ as shift reagent. This method is convenient and useful for the measurement of enantiomeric compositions, whereas additional assumptions must be applied in determining the absolute configuration related to the signs of the diastereomeric differences.     

Pt(II) stereoisomeric complexes with serine

There have been synthesized Pt(II) stereoisomeric complexes with hydroxy-α-amino acid serine (SerH = NH₂CH(CH₂OH)COOH is α-amino-β-hydroxypropionic acid): trans-[Pt(S-SerH)₂Cl₂], trans-[Pt(R-SerH)(S-SerH)Cl₂] with monodentately (through NH₂ group ) bound SerH and cis-, trans-[Pt(R-Ser)(S-Ser)], trans-[Pt(S-Ser)₂] with bidentately bound (through groups NH₂ and COO) ligands (R, S is the absolute configuration of asymmetric carbon atom). The successive phases in the synthesis of Pt(II) stereoisomeric complexes with serine were studied by ¹⁹⁵Pt NMR spectroscopy. To identificate the compounds synthesized the method of elemental analysis, IR and NMR (¹⁹⁵Pt, ¹³C, ¹H) spectroscopy were used. For trans-[Pt(R-Ser)(S-Ser)] the X-ray diffraction data were obtained.     

Biocatalytic deracemization of alkyl-2-hydroxy-4-arylbut-3-ynoates using whole cells of Candida parapsilosis ATCC 7330

Racemic alkyl-2-hydroxy-4-arylbut-3-ynoates were deracemized to the (S)-alkyl-2-hydroxy-4-arylbut-3-ynoates in excellent enantiomeric excesses (up to >99%) and good isolated yields (up to 81%) with the biocatalyst Candida parapsilosis ATCC 7330. The absolute configuration of the resulting enantiomer was assigned by ¹H NMR using Mosher’s method.     

Enantiomeric NMR signal separation mechanism and prediction of separation behavior for a praseodymium (III) complex with (S,S)-ethylenediamine-N,N-disuccinate

Because choice of chiral nuclear magnetic resonance (NMR) shift reagents and concentration conditions have been made empirically by trials and errors for chiral NMR analyses, the prediction of NMR signal separation behavior is an urgent issue. In this study, the separation of enantiomeric and enantiotopic ¹H and ¹³C NMR signals for α-amino acids and tartaric acid was performed by using the praseodymium(III) complex with (S,S)-ethylenediamine-N,N′-disuccinate ((S,S)-EDDS). All the present D-amino acids exhibited larger downfield shift of their α-protons and α-carbons compared with those for the corresponding L-amino acids in common. This regularity is applicable to absolute configurational assignment and determination of optical purity of amino acids. The chemical shifts of β-protons of d - and l -alanine fully bound with the Pr(III) ((S,S)-EDDS) complex (δ_bs) and the adduct formation constants of both enantiomers (Ks) were obtained by dependences of the observed downfield shifts of the β-protons on the total concentrations of the respective enantiomers in the presence of a constant concentration of the Pr(III) complex. The difference in the K values was found to be predominant determining factor for the enantiomeric signal separation. The chemical shifts of both enantiomers (δs) and the enantiomeric signal separations (Δδs) under given conditions could be calculated from the δ_b and K values. Furthermore, prediction of the signal separation behavior was enabled by using the calculated δ values and the signal broadening obtained by dependences of the half-height widths of the observed signals on the bound/free substrate concentration ratios for the respective enantiomers.     

Application of phosphorylated reagents derived from N,N′-di-[(S)-α-phenylethyl]-cyclohexane-1,2-diamines in the determination of the enantiomeric purity of chiral alcohols

The synthesis of two new N-[(S)-α-phenylethyl] substituted P-chloro-1,3-diazaphospholidines derived from C₂-symmetric trans-1,2-diaminocyclohexanes, and their application as chiral derivatizing agents in the determination of enantiomeric purities of chiral alcohols by means of ³¹P NMR spectroscopy is described.     

Lipase-catalyzed resolution of 5-acetoxy-1,2-dihydroxy-1,2,3,4-tetrahydronaphthalene. Application to the synthesis of (+)-(3R,4S)-cis-4-hydroxy-6-deoxyscytalone, a metabolite isolated from Colletotrichum acutatum

(+)-cis-4-Hydroxy-6-deoxyscytalone, a natural product bio-synthesized by Colletotrichum sp., has been prepared and its absolute configuration confirmed as 3R,4S, the key step being a kinetic racemic resolution of a cis-diol easily obtained from commercial 1,2,3,4-tetrahydronaphthalen-1,5-diol. Four lipases and different reaction conditions were tested in order to obtain the best yield and enantiomeric excess. Confirmation of absolute configuration was made by NMR using a single-derivatization low-temperature procedure and MPA as the auxiliary reagent.     

Enantiodifferentiation of aminophosphonic and aminophosphinic acids with α- and β-cyclodextrins

Cyclodextrins were used as chiral selectors for the ³¹P NMR determination of the enantiomeric excess of aminoalkanephosphonic and aminoalkanephosphinic acids. Most of these acids form inclusion complexes with α- and/or β-cyclodextrin and upon increasing the cyclodextrin to aminophosphonic acid molar ratio ³¹P NMR signals for (R)- and (S)-enantiomers separate. ROESY spectra allowed the determination of structures of the inclusion complexes.