Preparation of optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolution

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1), (2RS,3SR)-2-benzoylamino-3-hydroxy-3-phenylpropanoic acid [(2RS,3SR)-2] was first optically resolved using (1S,2S)- and (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol as the resolving agents to afford (2R,3S)- and (2S,3R)-2 in yields of 73% and 66%, based on half of the starting amount of (2RS,3SR)-2. Next, the racemic structures of ammonium and some organic ammonium salts of (2RS,3SR)-2 were examined based on melting point, solubility, and infrared spectrum, with the aim of optical resolution by preferential crystallization. The benzylammonium salt of (2RS,3SR)-2 was suggested to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization of the racemic salt afforded the (2R,3S)- and (2S,3R)-salts with optical purities of 90-97%. The (2R,3S)- and (2S,3R)-2 obtained from the purified salts were hydrolyzed by reflux in hydrochloric acid to give (2R,3S)- and (2S,3R)-1.     

Preparation of optically active (2RS,3SR)-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolutions by replacing and preferential crystallization

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1) via optical resolutions by replacing and preferential crystallization, the racemic structure of (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1.HCl] was examined based on the melting point, solubility, and infrared spectrum. (2RS,3SR)-1.HCl was indicated to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. When, in optical resolution by replacing crystallization, L-phenylalanine methyl ester hydrochloride (L-2) was used as the optically active co-solute, (2R,3S)-1.HCl was preferentially crystallized from the supersaturated racemic solution; the use of D-2 as the co-solute afforded (2S,3R)-1.HCl with an optical purity of 95%. In addition, optical resolution by preferential crystallization was successfully achieved to give successively (2R,3S)- and (2S,3R)-1.HCl with optical purities of 90-92%. The (2R,3S)- and (2S,3R)-1.HCl purified by recrystallization from 1-propanol were treated with triethylamine in methanol to give optically pure (2R,3S)- and (2S,3R)-1.     

Optical resolution by preferential crystallization of (1RS,3RS)-1,2,3,4-tetrahydro-6,7-dihydroxy-1-methyl-3-isoquinolinecarboxylic acid

The racemic structure of (1RS,3RS)-1,2,3,4-tetrahydro-6,7-dihydroxy-1-methyl-3-isoquinolinecarboxylic acid [(1RS,3RS)-1] was examined based on the melting point, solubility, and IR spectrum, with the aim of optical resolution by preferential crystallization. (1RS,3RS)-1 was indicated from these results to exist as a conglomerate. The successive optical resolution by preferential crystallization of (1RS,3RS)-1 yielded (1S,3S)- and (1R,3R)-1 with optical purities of 85--95% at 66--81% degrees of resolution, which were fully purified by recrystallization.     

The practical synthesis of (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthylamine via optical resolution of 2-(3-methoxybenzyl)succinic acid

We describe the practical synthetic route for (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthylamine 1(2S)-2-amino-7-methoxytetraline; (S)-AMT]. (2R)-2-(3-Methoxybenzyl)succinic acid [(R)-1] was obtained by the optical resolution of 2-(3-methoxybenzyl)succinic acid (1) as the salt of (1R,2S)-2-(benzylamino)cyclohexylmethanol (7), and (R)-1 was converted to the optically active (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthoic acid [(S)-2] by the intramolecular Friedel-Crafts reaction followed by catalytic hydrogenation. (S)-AMT was obtained from the acid (S)-2 by Hofmann rearrangement without racemization.     

Studies on the Synthesis of (2R,4′R,8′R)-α-Tocopherol Alternative Syntheses of 2-Chroman-acetic Acid Intermediates

As an extension of previous studies on the total synthesis of (2R,4′R,8′R)-α-tocopherol ( 1 ) [1] [2], (S)-(?)-2-(6-benzyloxy-2,5,7,8-tetramethylchroman)acetic acid ( 6 ), a pivotal intermediate, possessing the absolute configuration required for construction of 1 was prepared by optical resolution of the racemic modification 11 . the latter substance was obtained by two routes, one emanating from the hydroxy acetal 7 [1] and the other based upon the Lewis acid mediated cycloaddition of trimethylhydroquinone to rac.-3-hydroxy-3-methylpent-4-en-l-yl acetate ( 16 ) giving rac. ethyl 2-(6-hydroxy-2,5,7,8-tetramethyl-chroman)acetate ( 12 ).     

Novel enantioselective fluorinating agents, (R)- and (S)-N-fluoro-3-tert-butyl-7-nitro-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxides

Enantioselective fluorinating agents, (R)- and (S)-,N-fluoro-3-tert-butyl-7-nitro-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxides (BNBT-F, 2) are readily prepared in 3 steps from racemic 3-tert-butyl-7-nitro-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxides (5) via optical resolution and fluorination. These agents make accessible both enantiomers of optically active quaternary alpha-fluoro carbonyl compounds in modest to high enantioselectivities. X-ray crystallographic analysis of chiral 2 reveals a unique structure wherein the nitrogen atom is highly pyramidalized and fluorine occupies an axial position.     

Preparation,characterization, and porperties of optically active poly(α-methyl-α-ethyl-β-propiolactones)

S(?) and R(+) enantiomers of α-methyl-α-ethyl-β-propiolactone (MEEPL) were prepared in an eight-step synthesis with respective optical purities of 99 and 97% determined by ¹H-NMR (250 MHz) spectroscopy. Polymers (PMEPL) of different enatiomeric compositions were prepared with an anionic-type initiator. Substantial differences in physical properties were observed between the racemic and optically pure polymers; for example, the melting point of the latter is 42°C higher than that of the former. Chiroptical properties of PMEPLs are reported. The ¹³C-NMR (100.62 MHz) spectra of the polymers indicated that the distribution of configurational units in the macromolecular chain is random.     

酶催化拆分制备手性2-氯-1-(2,4-二氟苯基)乙醇及 光学活性抗真菌药物的合成

用Pseudomonas stutzeri脂肪酶催化转酯化反应动力学拆分外消旋体法制备高对映体纯的手性2-氯-1-(2,4-二氟苯基)乙醇, 得到95.8% ee值的(R)-异构体和94.5% ee值的(S)-异构体, 以此手性醇为关键中间体合成了4种具有抗真菌活性的光学活性化合物α-氯代苄氧基-β-(1-咪唑基)-2,4-二氟乙苯硝酸盐. 纸片扩散法测试体外抗真菌活性结果表明, 对各种念珠菌(Candida species) (R)-5a和(R)-5b具有与氟康唑相当的抗菌活性, 特别是对氟康唑耐药的烟曲霉菌(Aspergillus fumigatus), 5a, 5b及其两种光学活性异构体均有优异的抗菌活性, 而且(R)-异构体的活性明显高于(S)-异构体和外消旋体.     

四氢糠酸的拆分工艺改进

利用非对映异构体盐在溶剂中溶解度的不同,以(1S,2R)-1-氨基-2-茚醇(1)为手性拆分剂,拆分四氢糠酸［(RS)-THFA, (RS)-2］获得高光学纯的(S)-2,其结构经¹H NMR, ¹³C NMR和HPLC确证。探究了不同溶剂量和投料比对拆分效果的影响。结果表明较佳拆分条件为：以4-甲基-2-戊酮(3)作溶剂,n［(RS)-2］: n(1)=2.2 : 1,一次拆分得91.7% ee (S)-2;再以n［91.7% ee (S)-2］: n(1)=6 : 5进行二次拆分得99.0% ee (S)-2。拆分剂的回收率提高至92.0%,同时对拆分母液中的非目标对映体成功地进行消旋化,回收率为89.0%,实现了四氢糠酸的循环拆分。     

Lipase-catalyzed kinetic resolution of cyclic trans-1,2-diols bearing a diester moiety: synthetic application to chiral seven-membered-ring alpha,alpha-disubstituted alpha-amino acid

Chiral cycloalkane-trans-1,2-diols (+/-)-3 and (+/-)-8 having a diester moiety have been prepared from dimethyl dialkenylmalonate using olefin metathesis by Grubbs catalyst, followed by epoxidation and acidic hydrolysis. Kinetic resolution of racemic cyclopentane-trans-1,2-diol (+/-)-3 by lipase-catalyzed transesterification afforded an optically active monoacetate (-)-5 of 95% ee in 46% yield and the recovered diol (-)-3 of 92% ee in 51% yield, and that of cycloheptane-trans-1,2-diol (+/-)-8 gave a monoacetate (+)-10 of 95% ee in 51% yield and the diol (-)-8 of >99% ee in 43% yield, respectively. The enantiomer selectivity of racemic cyclic trans-1,2-diols bearing a diester moiety by lipases (Amano PS and Amano AK) was opposite to that of the reported simple racemic cycloalkane-trans-1,2-diols. To explain the lipase-catalyzed enantiomer selectivity, computer modeling of lipase-substrate complexes was performed. Furthermore, the optically active diester (-)-8 could be efficiently converted into an optically active seven-membered-ring alpha,alpha-disubstituted amino acid (4R,5R)-(-)-15.     

Synthesis, Resolution, and Enantiomeric Purity Assay of 2-n-Butylbutanedioic Acid 4-t-Butyl Esters

Introduction2-Substituted enantiomerically pure succinic acidderivatives have attracted a considerable interest in re-cent years,mainly because of their importance as chiralbuilding blocks and peptidomimetics in the field ofpharmaceutical design[1—3].Mos…     

Asymmetric synthesis of (1R,2S,3R)-gamma-methyl-cis-pentacin by a kinetic resolution protocol

The asymmetric synthesis of (1R,2S,3R)-3-methyl-2-amino-cyclopentane carboxylic acid has been achieved via kinetic resolution of racemic tert-butyl 3-methyl-cyclopentene-1-carboxylate with homochiral lithium (S)-N-benzyl-N-alpha-methylbenzylamide.     

Synthesis and polymerization of racemic and optically active substituted ß-propiolactones. V. α-methyl ß-propiolactone

R(+) and S(?) enantiomers of α-methyl β-propiolactone (MPL) have been synthesized from the corresponding α-methyl β-hydroxymethylpropionates and racemic MPL from methyl methacrylate. The optical purity and absolute configuration of these lactones were determined using ¹H-NMR spectroscopy after complexation with a chiral compound: 2,2,2-trifluoro-1-(9-anthryl)-ethanol. Optical purities of 100% were obtained for both the S(?) ([α₀] = ?10.4°, c = 1.3 g/dL in CHCl₃) and the R(+) ([α₀] = +10.5°, c = 1.0 g/dL in CHCl₃) enantiomers. The corresponding racemic and optically active polylactones [poly(MPL)] were prepared by anionic polymerization, in bulk and in solution, as well as poly(MPL)s of intermediate optical purities. The polymers thus obtained are optically active ([α₀] = 16.2° in CHCl₃ for the optically pure polymer, S configuration) and exhibit significant differences. For example, the racemic poly(MPL) is soluble in several organic solvents such as tetrahydrofuran, benzene, CCl₄, CH₂Cl₂, hexafluoroisopropanol, and CHCl₃, whereas the optically active poly(MPL)s are soluble in CHCl₃ and hexafluoroisopropanol only. Moreover, racemic poly(MPL) is amorphous whereas optically active poly(MPL)s are semicrystalline for optical purities larger than 51%. Melting temperatures and enthalpies of fusion of the semicrystalline polylactones vary with optical purity whereas glass transition temperatures remain invariant for all polymers, at about ?28°C. The poly(MPL) of highest optical purity exhibits a melting temperature of 95°C and an enthalpy of fusion of 61 J/g.     

用循环拆分法制备手性萘乙胺

研究了1-(1-萘基)乙胺[(RS)-1]和1-(2-萘基)乙胺[(RS)-2]的循环拆分方法。以D-酒石酸为拆分剂,分别拆分(RS)-1和(RS)-2得到了(R)-1-(1-萘基)乙胺(收率31%,98%ee)和(R)-1-(2-萘基)乙胺(收率30%,98%ee),并对母液中的非目标对映异构体成功的进行了消旋化,实现了循环拆分。     

Phase Diagram of R(+)-S(-) Efaroxan Hydrochloride

The phase diagram of R(+)-S(-) efaroxan hydrochloride (T_fus.(R)=245.1±0.3°C. ΔH_fus.(R)=119.6±3.0 J g^-1) shows a racemic compound. The melting temperature and melting enthalpy of the compound are: T_fus.(RS)=247.8±0.2°C and ΔH_fus. (RS)=124.6±2.4 J g^-1. A solid ↔ solid transformation takes place at T_trs.=180±1°C, ΔH_trs.=15.0±0.4 J g^-1. This transition is observed between 3 and 97% R(+). The stability of the racemic compound already established in a previous study was confirmed by the value of Petterson's coefficient (i=1.19). The two eutectic positions at 20 and 80% R(+) that define the range over which the racemic compound is found, exclude the use of resolution methods by preferential crystallization. This revised version was published online in July 2006 with corrections to the Cover Date.     

A Chemo-enzymatic Route for the Preparation of Chiral （S）-3-Hydroxy-3-phenylpropanoic Acid

（S）-3-Hydroxy-3-phenylpropanoic acid is a potential progenitor of optically pure tomoxetine hydrochlo- ride and fluoxetine hydrochloride which are currently available antidepressant drugs. We report here the chemical synthesis of racemic substrate （R,S）-ethyl 3-hydroxy-3-phenylpropanoate and enzymatic preparation of S-isomer of the substrate by employing Porcine pancreas lipase（PPL） as a biocatalyst. Optimum enzyme-catalyzed reaction con- ditions, such as the effects of the temperature, pH and solvents on conversion degree and enantiomeric excess, were studied. An optimal temperature of 35 ℃ and pH=7.5 are the best for the resolution of （R,S）-ethyl 3-hydroxy-3- pheylpropanoate by PPL when 0.1 mol/L phosphate buffer solution acts as a medium. This work provides a practi- cally chemo-enzvmatic oreoaration of chiral β-hvdroxv acid by PPL.     

Microbial enantioselective ester hydrolysis for the preparation of optically active 4,1-benzoxazepine-3-acetic acid derivatives as squalene synthase inhibitors

Microbial enantioselective ester hydrolysis for the preparation of optically active (3R,5S)-(-)-5-phenyl-4,1-benzoxazepine-3-acetic acid derivatives as potent squalene synthase inhibitors was investigated. Pseudomonas diminuta and Pseudomonas taetrolens hydrolyzed the racemic ethyl ester of the 5-(2-chlorophenyl) analogue to yield the (-)-carboxylic acid with excellent enantiomeric excess (>99% ee). We found that the (-)-enantiomer was an active inhibitor. Bulkiness of the ester moiety did not affect the enantioselectivity but did affect reactivity. The racemic ethyl ester of the 5-(2-methoxyphenyl) analogue, 5-(2,3-dimethoxyphenyl) analogue and 5-(2,4-dimethoxyphenyl) analogue were also hydrolyzed with Pseudomonas taetrolens to afford enantiomerically pure (-)-carboxylic acids in large scale. As another route to (3R,5S)-(-)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid [(-)-1c], the earlier intermediate (-)-2-amino-5-chloro-alpha-(2,3-dimethoxyphenyl)benzyl alcohol [(-)-12] was successfully obtained by asymmetric hydrolysis of (+/-)-5-chloro-alpha-(2,3-dimethoxyphenyl)-2-pivaloylaminobenzyl acetate with Pseudomonas sp. S-13 with >99% ee in kilogram scale followed by alkaline treatment. The product (-)-12 was converted to (-)-1c without racemization.     

Configurational studies on 2-[∝-(2-ethoxyphenoxy)benzyl] morpholine fce 20124

The relative configuration of the two diastereoisomers of (±)2-[?-(2-ethoxyphenoxy)benzyl] morpholine is determined by a synthesis involving regio and stereo specific reactions. (RS,RS) diastereoisomer FCE 20124 was separated into its (+) and (-) enantiomers both by crystallization of the optically active mandelate salt and by a multi-step synthesis from (+)-(2S,3R)-3-phenylglycidic acid.     

Copper(II)-mediated resolution of alpha-halo carboxylic acids with chiral O,O'-dibenzoyltartaric acid: spontaneous racemization and crystallization-induced dynamic resolution

Herein we present a new example of coordination-mediated resolution of racemic acids by a chiral acid. The reaction of copper(II) acetate monohydrate, optically pure O,O'-dibenzoyltartaric acid (DBTA) and racemic alpha-bromo-2-chlorophenylacetic acid (HL1) in acetonitrile solution afforded a binuclear copper(II) complex with D-DBTA dianion, alpha-bromo-2-chlorophenylacetate and acetate as ligands. After decomposition of the complex with acid, the optically active acid ((R)-HL1) was obtained. Similarly, alpha-bromo-2-fluorophenylacetic acid (HL2), alpha-bromo-2-bromophenylacetic acid (HL3), alpha-chloro-2-chlorophenylacetic acid (HL4), alpha-chloro-2-fluorophenylacetic acid (HL5), alpha-bromophenylacetic acid (HL6), alpha-bromo-4-chlorophenylacetic acid (HL7), 2-bromopropionic acid (HL8) and 2-chloropropionic acid (HL9) were resolved by the same method. Satisfactory results were obtained for HL2 to HL5. For HL6 and HL7, only racemic acids were obtained. For the two alpha-halo aliphatic acids (HL8 and HL9), poor enantioselectivity was obtained. It is more interesting that three acids (HL1, HL2 and HL3) could spontaneously racemize in acetonitrile solution, which resulted in crystallization-induced dynamic resolution (CIDR) with greater than 50% yield.     

Synthesis of the enantiomers of 5-hexadecanolide,the pheromone of the queen of the oriental hornet,vespa orientalis,employing enzymic resolution of (±)-2-aminotridecanoic acid as the key-step

Optical resolution of(±)-2-chloroacetylaminotridecanoic acid with amino acylase gave (S)-2-aminotridecanoic add, which was converted into highly optically pure (S)-5-hexadecanolide (the pheromone of Vespa orientalls). Similarly (R)-2-chloroacetylammotridecanoic acid recovered after the enzymic hydrolysis yielded (R)-5-hexadecanolide. The existing methods for the preparation of the enantiomers of 5-hexadecanolide were critically surveyed to point out basic requisites for an effective chiral synthesis.