A Chiral Phosphorous Derivatizing Agent for the Determination of the Enantiomeric Excess of Chiral Alcohols, Amines by ~(31)P NMR

The suitable chiral derivatizing agent (CDA) is the essential factor for the determination of the optical purity of the enantiomeric substances by NMR method. Among different kinds of CDAs, the chiral phosphorous derivatizing agents1 have become very popular. In this paper, we report a simple and highly efficient 31P NMR method for the ee determination of chiral alcohols and amines, based on the phosphorous CDA 12. R1R2XH+X=O, NH+123A3BOOPClXR1R2HOOPOOPXR1R2H The po…     

Optically Active Phenyl-t-Butylphosphinothioic Acid as a Useful CSA for the Enantiomeric Excess Determination of Alcohols,Aminoalcohols and Related Compounds

Abstract

There are rather few methods for determination of the enantiomeric excess of chiral alcohols, amines, thiols and related compounds.¹ All these methods consist in the formation of. diastereomeric derivatives of the samples investigated with various chiral derivatizing agents (the CBA method) followed by the quantitative determination of their diastereomer composition using NMR or other techniques.     

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.     

A chiral phosphazane reagent strategy for the determination of enantiomeric excess of amines

Methods for measuring enantiomeric excess (ee) of organic molecules by NMR spectroscopy provide rapid analysis using a standard technique that is readily available. Commonly this is accomplished by chiral derivatisation of the detector molecule (producing a chiral derivatisation agent, CDA), which is reacted with the mixture of enantiomers under investigation. However, these CDAs have almost exclusively been based on carbon frameworks, which are generally costly and/or difficult to prepare. In this work, a methodology based on the readily prepared inorganic cyclodiphosph(iii)azane CDA ClP(μ-N^tBu)₂POBorn (Born = endo-(1S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) is shown to be highly effective in the measurement of ee’s of chiral amines, involving in situ reaction of the chiral amines (R*NH₂) with the P–Cl bond of the CDA followed by quaternization of the phosphorus framework with methyl iodide. This results in sharp ³¹P NMR signals with distinct chemical shift differences between the diastereomers that are formed, which can be used to obtain the ee directly by integration. Spectroscopic, X-ray structural and DFT studies suggest that the NMR chemical shift differences between diastereomers is steric in origin, with the sharpness of these signals resulting from conformational locking of the bornyl group relative to the P₂N₂ ring induced by the presence of the P(v)-bonded amino group (R*NH). This study showcases cheap inorganic phosphazane CDAs as simple alternatives to organic variants for the rapid determination of ee.

The simple inorganic cyclodiphosph(iii)azane chiral derivatisation agent ClP(μ-^tBuN)₂POBorn (Born = endo-(1S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) is shown to be effective in the measurement of ee’s of chiral amines using ³¹P NMR spectroscopy.     

PtCl3(C2H4)]-[AmH]+ complexes containing chiral secondary amines: use as chiral derivatizing agents for the enantiodiscrimination of unsaturated compounds by 195Pt NMR spectroscopy and NMR stereochemical investigation.

Ionic complexes [PtCl3(C2H4)]-[AmH]+, containing chiral secondary amines, constitute a versatile class of chiral derivatizing agents (CDAs) for the enantiomeric purity determination of chiral unsaturated compounds via 195Pt NMR spectroscopy. The NMR conformational analysis allows us to search for the stereochemical basis of their enhanced versatility.     

O-Methylatrolactic acid as a new reagent for determination of the enantiomeric purity and absolute configuration of chiral alcohols and amines

Easily available in both enantiomeric forms, O-methylatrolactic acid (MAA) was successfully used as a new chiral derivatizing agent. Enantiomeric purities and the absolute configurations of chiral secondary alcohols and amines were determined using the observed differences in ¹H NMR chemical shifts. The Mosher’s stereochemical model explains the conformational preferences of the respective diastereomeric MAA esters and amides. This was confirmed by the results of DFT calculations for the respective conformers.     

Methylphosphonic dichloride as reagent for the determination of the enantiomeric excess of chiral thiols. scope and limitations

Methylphosphonic dichloride, CH₃P(=O)Cl₂ , reacts cleanly and quantitatively with thiols to form dialkylthiophosphonates, CH₃P(=O) (SR)₂. From the ratio of the integrations of the ³¹P absorptions in the NMR spectra, the enantiomeric excesses of the thiols can be obtained for the cases that R is chiral. The effect of structural change in the phosphorus derivatizing reagent on the separation of peaks in the ³¹P NMR spectra has been examined, especially the effects of variations in electronegativity and/or steric bulk. The effect of the temperature on the peak separation was also studied.     

Preparation and use of (S)-O-acetyllactyl chloride (Mosandl's reagent) as a chiral derivatizing agent

(S)-O-Acetyllactyl chloride is used as a versatile chiral derivatizing agent for the chromatographic determination of the enantiomeric excesses of alcohols or amines. However, some precautions must be taken to avoid its racemization during preparation and use. In addition, the racemic counterpart of this reagent can be used to determine the best analytical separation conditions.     

P*-Chiral phosphapalladacycle as derivatizing agent for enantiomeric purity determination of α-amino acids by means of 31P NMR spectroscopy

A P*-chiral cyclopalladated complex was shown to be an efficient chiral derivatizing agent for enantiomeric excess determination of α-amino acids by ³¹P NMR technique. The main advantages of this type of reagent are discussed.     

In situ Synthesis of Rosin Derived Chiral Derivatizing Agents for 31P NMR Assays of Amine and Alcohol Enantiomers

Chiral alcohols(3, 5) were synthesized in optically pure forms from easily available rosin acid in short-steps. A comprehensive protocol for the enantiomeric excess assays of mono-or difunctional-grouped chiral secondary amine or alcohol has been established with them used as chiral auxiliary for chiral phosphorus derivatizing agents(CPDAs) in ³¹P NMR tests. Chemical shift difference(Δδ_P) values ranging from 4.5 to 0.15 between two diastereoisomers of the CPDAs and the aryl substrates were obtained. Positive Δδ_R-S was observed for all the tested alcohol P(III) and P(V) derivatives, while negative Δδ_R-S was observed for all the amines.     

Signal separation and determination of the enantiomeric purity of primary amines with (-)-myrtenal--a 13C NMR study

The applicability of (-)-myrtenal as a chiral derivatizing agent in combination with (13)C NMR spectroscopy was investigated. (13)C NMR was found to be a valuable tool for the identification and enantiomer differentiation of primary amines including beta-amino alcohols and vicinal diamines. The enantiomeric excess could be determined via automated deconvolution and integration, and was found to be in good accordance with the expected values even in the cases, when enantiomer differentiation was not possible in (1)H NMR spectra.     

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.     

Determination of the absolute configuration of chiral cyclic alcohols using diamine derivatizing agents by 31P NMR spectroscopy

The absolute configuration and enantiomeric excess of chiral cyclic alcohols can be predicted from the ³¹P NMR spectra of the two diastereoisomers obtained with organophosphorus diamino-derivatizing agents (CDAs) and the chiral secondary alcohol, according to a simplified model taking into account the spatial location of the substituents of the chiral alcohol center and the ³¹P NMR signals of the two diastereoisomers.     

Application of deuterated THENA for assigning the absolute configuration of chiral secondary alcohols

The structure of a constrained bicyclic chiral derivatizing agent (CDA), 1,2,3,4-tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid, THENA 1, was modified by replacing both exo-methylene protons with deuterium atoms. The modified CDA, THENA-d₂2, could be used to assign the absolute configuration of chiral secondary alcohols with good reliability. Compared with THENA, the multiplicity of the methylene proton signals in the ¹H NMR spectra of THENA-d₂ derivatives is less complicated and the new CDA thus offers simpler NMR spectra for data interpretation.     

31P NMR assays for rapid determination of enantiomeric excess in catalytic hydrosilylations and transfer hydrogenations

Chiral chlorophosphine (S)-(1,1′-binaphthalen-2,2′-dioxy)chlorophosphine (S)-2 was tested for its performance as a chiral-derivatizing agent (CDA) using solutions of various alcohols, amines, and N-BOC amino acids. Based on ³¹P NMR spectroscopy, the enantiomeric excess was determined within less than 5 min per sample, reaching an accuracy of ±1%. One-pot procedures for a combination of the method with typical homogenous catalytic transformations of prochiral ketones were established. Hydrosilylation products may be analyzed after conversion into alcohols using HF bound to PS-vinyl pyridine co-polymer beads. Transfer hydrogenations simply require solvent evaporation prior to the use of the CDA.     

Triphenylethanediol-Derived 2-Chloro-1,3,2- dioxaphospholane: Synthesis,Structure, and Reaction with Chiral Alcohols

The reaction of (S)-1,1,2-triphenylethanediol (3) with phosphorus trichloride leads to the diastereoselective formation of (S _C,R _P)-2-chloro-1,3,2-dioxaphospholane (2). Its configuration has been determined by single crystal X-ray diffraction. When reacted with racemic secondary alcohols, diastereomeric phosphites are obtained, which display substantial shift differences in the ³¹P NMR spectra. Thus, chlorodioxaphospholane 2 can serve as derivatizing reagent for chiral secondary alcohols permitting to determine their enantiomeric excess.     

NMR in chiral polypeptide liquid crystals: the problem of amines

It is shown that lyotropic liquid crystal mixtures made of poly-γ-benzyl-l-glutamate (PBLG) dissolved in N,N-dimethylformamide (DMF) are efficient anisotropic NMR solvents to distinguish the enantiomers of chiral amines through the effects of the differential ordering of enantiomers. This type of solvent overcomes problems often encountered when dissolving amines into the more conventional PBLG/CHCl₃ or PBLG/CH₂Cl₂ liquid crystals. Furthermore, it is shown that perdeuterobenzyl chloride is an excellent achiral deuterated derivatizing agent for enantiomeric excess measurements of chiral amines in conjunction with the PBLG/DMF solvent.     

Michael addition to a chiral non-racemic 2-phosphono-2,3-didehydrothiolane S-oxide

The Michael addition of selected sulfur and nitrogen nucleophiles to a chiral non-racemic 2-phosphono-2,3-didehydrothiolane S-oxide is fully diastereoselective. The enantiomeric excesses of the adducts obtained could be determined by ³¹P NMR spectroscopy using (R)-(+)-tert-butyl(phenyl)phosphinothioic acid as a chiral solvating agent. The addition of thiophenol was monitored by ³¹P NMR spectroscopy which made it possible to observe the formation and evolution of the kinetic and thermodynamic adducts in the reaction mixture. The structures of both enantiomeric thiophenol adducts have been determined by X-ray analysis.     

用于芳香胺和醇NMR对映体检测的松香基膦试剂的合成

以松香为原料通过三步反应高产率合成手性二醇3和手性单醇6,将它们用作手性助剂现场制备有机膦衍生试剂,分别对单官能团手性底物(单胺、单醇)和双官能团底物(双胺、双醇及氨基醇)进行衍生,通过31P NMR测定,其芳基底物非对映体衍生物的膦化学位移差异值(Δδp)在3.08～0.10之间,均能够在测定条件下实现对映体峰的基线分离.用于α-萘乙胺和1,1’-联二萘酚(BINOL)样品对映体过量值测定,相对误差小于±2%.     

Acide fluoro-2 phenyl-2 acetique: Synthesis,configuration absolute et emploi comme agent chiral de derivation

2-Fluoro-2-phenyl acetic acid was synthetized from phenylglycine through a fluorodeamination reaction in a HF : pyridine mixture or from ethylmandelate through fluorodehydroxylation using the reagent fluoroamine (FAR). The specific rotation of S-2-fluoro-2-phenyl acetic acid is [α] ²⁰_D = + 153° in chloroform at concentration c = 1,25 g/100 ml. This acid can be used as a derivatizing chiral agent : the enantiomers can be distinguished and the enantiomeric excess of secondary alcohols can be determined by ¹⁹F NMR spectra of the corresponding esters.