La formation de sels augmente-t-elle la fréquence des dédoublements spontanés?

The resolution by entrainment which allows the pure enantiomers to be obtained by direct crystallization of the racemate is possible only when the racemate is a conglomerate (eutectic mixture). Spontaneous resolutions exist to an extent less than 10% of the crystalline racemates. Considering a family of racemic salts formed by a racemic acid or racemic base and a racemic or an achiral counterion, we show by a statistical analysis, which has required the preparation of more than 500 salts, that the probability of finding spontaneous resolution is 2 or 3 times greater than in the family of covalent racemates. The preparation of some phosphonic acids, which could be useful as new resolving agents is described.     

Syntheses of (S)-(+)-trihexyphenidyl hydrochloride and (S)-(+)-procyclidine hydrochloride, two anticholinergics, using (S)-(-)-3-cyclohexyl-3-hydroxy-3-phenylpropanoic acid as chiral synthon

The absolute configuration of the more active (-)-enantiomer of the anticholinergic trihexyphenidyl hydrochloride has been established as (R) by syntheses of (S)-(+)-procyclidine hydrochloride, whose absolute configuration has been established previously, and (S)-(+)-trihexyphenidyl hydrochloride from the same chiral building block, viz. (S)-(-)-cyclohexyl-3-hydroxy-3-phenylpropanoic acid. Both enantiomers of this chiral synthon were prepared by optical resolution of the corresponding racemate, employing (R)- and (S)-1-phenylethylamine, respectively, as resolving agents.     

Resolution of Racemates: Did You Say “Classical”?

A successful “family approach” is already being used in industry for large-scale enantiomeric resolutions. In this method, racemates are resolved by formation of salts with mixtures of three structurally related resolving agents instead of a single one. Although the physical chemistry behind this is still largely unexplored, successful resolution is more likely and resolution efficiency is often improved over that of classical resolution.     

Sub- and supercritical chiral separation of racemic compounds on columns with stationary phases having different functional groups

Separation of the enantiomers of each of three different racemates, neutral rac-alpha-tetralol, acidic rac-2-phenylpropionic acid, and basic rac-1-phenylethylamine, using subcritical and supercritical fluid chromatography with two different chiral stationary phases, heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (Sumichiral OA-7500 column) and tris(3,5-dimethylphenylcarbamate) of amylose (Chiralpak AD-H column), was compared. The elution order of the enantiomers of the three racemates was determined, and the effects of the type of alcohol modifier, column oven temperature, mobile phase composition, flow rate, and pressure were examined. The most appropriate column oven temperature depended on both the type of alcohol modifier and the compound analyzed. Lower alcohol content improved the peak separation of both rac-alpha-tetralol on the Sumichiral OA-7500 column and rac-1-phenylethylamine on the Chiralpak AD-H column, while the same phenomenon was not observed with either rac-alpha-tetralol or rac-2-phenylpropionic acid on the Chiralpak AD-H column. Decreasing outlet pressure improved the peak separation obtained with rac-2-phenylpropionic acid, but had little effect on either rac-alpha-tetralol or rac-1-phenylethylamine.     

An amylopectin tris(phenylcarbamate) chiral stationary phase for high performance liquid chromatography

Amylopectin tris(phenylcarbamate) has been evaluated as a chiral stationary phase for HPLC; the influence on its cptical resolving capabilities of mobile phase composition and nature of the alcohol used as modifier has been studied. Separation and resolution of twelve arylalcohol racemates were examined. In most instances, the stationary phase exhibited high optical resolving capacity.     

Resolution of enantiomers of [α-hydroxy-(o-chlorophenyl)methyl]phosphinic acid via diastereomeric salt formation with enantiopure 1-phenylethylamines

The resolution of racemic α-hydroxy-H-phosphinic acid with enantiopure 1-phenylethylamines via diastereomeric salt formation was investigated. X-Ray crystallographic analysis of the salt revealed that (R)-1-phenylethylamine to be efficient resolving agent for obtaining a single enantiomer of [α-hydroxy-(o-chlorophenyl)methyl]phosphinic acid. Resolving racemic α-hydroxy-H-phosphinic acid with (S)-2-phenylethylamine also gave access to (S)-α-hydroxyalkylphosphinic acid in good yield.     

“Dutch”拆分研究进展

本文综述了第一代Dutch拆分、第二代Dutch拆分及反义Dutch拆分的拆分机理和研究进展,并展望了Dutch拆分的应用前景。Dutch拆分能以高收率和近于100％ee值与所有的实验消旋体迅速形成非对映体的结晶。第一代Dutch拆分中Family拆分试剂在形成非对映体晶体过程是典型的固溶体行为。在第二代Dutch拆分中,成核抑制剂改变了非对映异构体的亚稳区宽度,溶解度较大的非对映体盐比溶解度较小的非对映体盐的结晶温度下降得更多,使溶解度较小的非对映体盐更容易析出。     

Optical resolution of N-formylphenylalanine succeeds by crystal growth rate differences of diastereomeric salts

Optical resolution of racemic-phenylalanine through its N-formyl derivative with a 1-phenylethylamine resolving agent is an effective procedure. Differential scanning calorimetry, single crystal X-ray diffraction and optical microscopy were used in the investigation of the resolution process. It was found that the thermodynamic properties of the given system would not allow the efficient enantiomer separation. Kinetic effects during the crystal formation have been discovered by the comparison of the crystal morphologies of the two diastereomers. The crystal structure of the less soluble diastereomer (S)-(−)-1-phenylethylammonium (S)-(+)-N-formylphenylalaninate salt has been determined and discussed.     

Ordered binary crystals via cocrystallisation of quasiracemic Pd(II) complexes in a borderline regime between inertness and lability

Square planar complexes of the type [2-(1-aminoethyl)phenyl-kappa(2)C(1),N]chloro(py-kappaN)palladium(II)(py = pyridine derivative) have been prepared by cyclopalladation of 1-phenylethylamine. When opposite enantiomers of the chiral amine and different pyridine ligands were coordinated to the metal, quasiracemic complexes were obtained. The racemisation speed of solutions containing equimolar amounts of such quasiracemic complexes was used to test the compounds for inertness: slow ligand exchange was found for methylated pyridines. Enantiomerically pure complexes of opposite chirality with the electron rich ligands 2,6-collidine and 2,4,6-lutidine were successfully cocrystallised: they form a well-ordered binary solid in which four independent molecules, two of each constituent, are related by pseudo symmetry operations. This quasiracemate as well as its components and the true racemates of the latter were characterised by single crystal X-ray diffraction. The heterochiral crystals, both the cocrystal as well as the racemates, show better space filling than the homochiral solids.     

Solvent dependency though not solvate formation in the derivative–derivative resolution of N-formylphenylalanine

The efficiency of the resolution of N-formylphenylalanine was remarkably improved using (S)-(+)-2-benzylaminobutanol resolving agent in acetone. The efficiency of the resolution strongly depended on the quality of the solvent. Nevertheless, solvate formation did not occur during the process. The nature of the solvent-dependence was studied. The solid-melt binary phase diagram of the diastereomeric salts formed during the resolution by (S)-(+)-2-benzylaminobutanol was measured and discussed. It was recognized that the (S)-(+)-benzylaminobutanol (S)-(+)-N-formylphenylalanine salt exists in two polymorphic modifications.The effect of structurally related chiral and achiral auxiliary reagents in the above resolution was also studied. Thus, (S)-(+)-2-benzylaminobutanol was applied together with an (R)-(+)-1-phenylethylamine auxiliary resolving agent and benzylamine was used as a half-equivalent achiral basic reagent in a Pope–Peachey type resolution of N-formylphenylalanine by (S)-(+)-2-benzylaminobutanol. The results are compared to those obtained by the structurally related (R)-(+)-1-phenylethylamine chiral auxiliary.     

The Family Approach to the Resolution of Racemates

The resolution of racemates is revolutionized with the method presented here, in which mixtures (“families”) of structurally and stereochemically related resolving agents are used to precipitate salts of acidic or basic racemates rapidly and dependably. The racemate is usually separated in a single operation into enantiomers—the enantiomeric excesses and yields are good to excellent. Reagent mixtures with racemic or achiral components have also been developed.     

Racemic compound formation-conglomerate formation

The phenomena of conglomerate formation-racemic compound formation were investigated in a series of five (N-alkyl)-2,6-pipecoloxylidides. The optically active enantiomers were prepared by optical resolution of the racemates using 2R,3R-tartaric acid and 0,0-dibenzoyl-2R,3R-tartaric acid as resolving agent. By DSC measurement of the racemates and the enantiomer the binary phase diagrams were determined.Among the four racemic molecular compounds the N-methyl derivative is the more stable. By increasing the length of the alkyl chain the stability of the racemic compound decreased, and in case of the longest -butyl-chain conglomerate formation was observed.Part 3. D. Kozma, Zs. Böcskei, Cs. Kassai, K. Simon and E. Fogassy: Racemic Compound Formation-Conglomerate Formation. Part 3. Investigation of the Acidic Salts of -phenylethylamine by Achiral Dicarboxylic Acids. Optical Resolution by Preferential Crystallization and a Structural Study of R--phenylethylammonium hydrogen ithaconate, J. Chem. Soc. Perkin Trans. 2 (1996) 1511.The authors are grateful for financial support to OTKA foundation (grant numbers: F14851 (D. K.), T14887 (E. F.)) and for the Z. Magyary award for D. K.     

异噁唑啉及异噁唑烷类化合物在多糖衍生物类柱上的手性拆分

在ＣｈｉｒａｌｃｅｌＯＤ，ＣｈｉｒａｌｃｅｌＯＪ及ＣｈｉｒａｌｐａｋＡＤ等３种多糖类手性固定相上，以各种配比的正己烷－异丙醇为洗脱剂，对７种异口恶唑啉及异口恶唑烷类化合物的对映体进行了手性拆分。考察了这些外消旋物在这些手性柱上的色谱行为。实验结果表明，手性固定相上葡萄糖片段构型的差异和它们高级结构的不同以及手性固定相上的二甲基苯基氨基甲酸酯或对甲基苯甲酸酯等功能团与样品的极性基团之间的相互作用，可能是支配手性拆分的主要原因。方法已用于不对称１，３－偶极环加成反应产物的光学纯度鉴定。     

Synthesis of Aristotelia-Type Alkaloids. Part III. (3R,4R)- and (3R,4S)-1-p-menthene-3,8-diol and the corresponding racemates: Preparation and assignment of configuration

A 1:1 mixture of the racemic trans- and cis-1-p-menthene-3,8-diols ((±)- 3 and (±)- 4 , resp.) was readily prepared in 3 steps starting from 3-methyl-2-cyclohexen-1-one. The relative configuration of the diols, purified via the corresponding cyclocarbonates, was assigned by ¹H-NMR spectroscopy and found to be at variance with tentative claims in the literature. Optically active samples of 3 and 4 were prepared by resolution of the racemates with (R)-1-phenylethylamine. The absolute configuration of the resulting diols was determined by chemical correlation with standards of known absolute configuration.     

Mechanism of Optical Resolutions via Diastereoisomeric Salt Formation. Part 7 Role of the solvents in the optical resolution of α-phenylethylamine by 2R,3R-tartaric acid

The optical resolution of α-phenylethylamine (1) by 2R,3R-tartaric acid (2) was studied in different solvents, the precipitated salts were subjected to thermoanalytical measurements and X-ray powder diffraction. The most efficient resolution can be accomplished by using methanol, the precipitate, an unsolvated salt containing the S-(-)-1⋅2R,3R-(+)-2 salt in abundance, is not a simple mixture of the diastereoisomeric salt pair, but a new modification. In water, ethanol and acetonitrile a reversed, but less effective resolution can be accomplished by precipitation of a hydrate which contains the R-(+)-1 in abundance. The precipitates from water and ethanol also proved to be new modifications. Only the precipitate from acetonitrile is the mixture of the diastereoisomeric salt pair, which can be expected in fractional crystallization of an eutectic forming diastereoisomeric salt pair. The number of different modifications found by changing the solvent in case of this particular salt pair seems surprisingly high, but may occur for other diastereoisomeric salt pairs, too. The existing but not investigated polymorphism can be the explanation for the sometimes very poor reproducibility of the preparative resolutions. This revised version was published online in July 2006 with corrections to the Cover Date.     

Nucleation inhibition in attrition-enhanced Pope-Peachey type of diastereomeric resolutions

The resolution of racemic 1-(3-methoxyphenyl)ethylamine with (S)-mandelic acid by diastereomeric salt formation can be made more economical by application of the Pope-Peachey method. This resolution was further improved upon by the addition of small amounts of a nucleation inhibitor, which prevents the formation of crystals of the more soluble diastereomer. The mandelic acid left in the solution is then used for further crystal growth of the less soluble diastereomer, furnishing high yields and diastereomeric excesses. Slow cooling and grinding of the crystals formed lead to increased secondary nucleation and thus to more consumption of the less soluble diastereomer and even better results.     

‘Easy-on,easy-off’ resolution of chiral 1-phenylethylamine catalyzed by Candida antarctica lipase B

An ‘easy-on, easy-off’ process for the effective resolution of (±)-1-phenylethylamine was designed using the lipase B of Candida antarctica. This two step lipase-catalyzed process for the resolution of a chiral arylalkylamine involves a high-conversion enantioselective condensation of (R)-(+)-1-phenylethylamine with capric acid (conversion 99%, <24 h), followed by the hydrolysis of the corresponding synthesized (R)-(+)-amide (conversion 98%, 48 h). As a result, this efficient enzymatic process yields both (R)- and (S)-enantiomers of 1-phenylethylamine in high enantiomeric purity.     

Stereoselective Synthesis and Resolution of P-Chiral Phosphine Chalcogenides.

Abstract

New synthetic methods and resolution procedures securing ready access to the resolved P-chiral phosphinoylethenes, phosphinoylacetates and secondary phosphine oxides of diversified structures have been developed. The methods are based on processes employing stereoselective nucleophilic displacement at phosphorus, asymmetric deprotonation, immolative vinyl and chirality transfer from sulfur to phosphorus, chemical and enzymatic kinetic resolution, resolution via covalent diastereoisomers, as well as direct resolution of racemates by classical resolving agents and by chromatography on chiral stationary phases.     

Optically-active polyurethanes containing coumarin dimer component: Synthesis,characterization, and chiral recognition ability

Optically-active polyurethanes ( 2a-2c ) were prepared by polyaddition reaction of diamide ( 1a, 1b ) and diester ( 1c ) derivatives of chiral coumarin dimer with 4,4′-diphenylmethane diisocyanate (MDI) in chloroform and methyl ethyl ketone, respectively. The inherent viscosity of the polyurethanes are between 0.13 and 0.21 dL/g in N,N-dimethylacetamide (DMAc) at 30°C. Treated silica gels were absorbed with ca. 25 wt % of the polyurethanes, and packed as chiral stationary phases for direct optical resolution of 16 racemates with aromatic groups by high-performance liquid chromatography (HPLC). Polyurethanes 2a and 2b , obtained from diamide derivatives, show efficient resolution ability to some of the racemates (α = 1.06-1.79), especially the atropic ( R5 ) and trans ( R6-R9 ) isomers. The recognition ability of the polyurethanes can be attributed to the simultaneous aromatic stacking and hydrogen-bonding interactions with racemates. © 1992 John Wiley & Sons, Inc.     

Stereocomplexity and stereoselective synthesis of triamine molecules bearing four chiral carbon centers: Stereodifferentiated preparation of all 10 stereoisomers of 2,6-bis[1-(1-phenylethylamino)ethyl]pyridines

Compounds (S,S)-2,6-bis(1-hydroxyethyl)pyridine, (R,R)-2,6-bis(1-acetoxyethyl)pyridine, and (1R,1'S)-2-(1-acetoxyethyl)-6-(1'-hydroxyethyl)pyridine were obtained by lipase-catalyzed kinetic acetylation of 2,6-bis(1-hydroxyethyl)pyridine as enantiomerically pure forms. The stereospecific replacement of hydroxy groups with (R)-phenylethylamine or (S)-phenylethylamine via its methanesulfonate or toluenesulfonate simultaneously or stepwise afforded all the stereoisomers of 1. Stereospecific preparation of all the 10 possible stereoisomers of 2,6-bis[1-(1-phenylethylamino)ethyl]pyridines 1a-f was achieved. Triamine 1b reacted with ZnCl2 to form Zn-triamine complex 16, the structure of which was determined by X-ray crystallographic analysis.