Comparison of resolution methods for racemic 8-(phenylsulfinyl)-1-naphthoic acid

Despite of the fact that resolution is an extremely important process in the pharmaceutical and agrochemical industries, the development of the separation of enantiomers is still based on trial-and-error experiments. In order to compare the different procedures, the resolution of 8-(phenylsulfinyl)-1-naphthoic acid 1 was carried out by chiral organic bases using heat facilitated diastereomeric crystallization, enantioselective liquid–liquid extraction and chiroselective transport. The results give valuable information about the interactions in the racemate/resolving agent/solvent system, which helps with the understanding and development of resolution processes. Diastereomeric crystallization with brucine as a resolving agent afforded enantiomerically pure (?)-1.     

Preparation of single-enantiomer semiochemicals using 2-methoxy-2-(1-naphthyl)propionic acid and 2-methoxy-2-(9-phenanthryl)propionic acid

Enantioresolution of 3-octanol, 6-methyl-5-hepten-2-ol (sulcatol), and 1-octen-3-ol was conducted using (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid) and (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid (M9PP acid). In each case, the diastereomeric esters obtained were readily separated by HPLC. The stereochemistry of the esters could be assigned from their respective ¹H NMR analyses. Solvolyses of the esters gave enantiopure alcohols and acids. MαNP and M9PP acids displayed almost equivalent properties in ¹H NMR anisotropy. The chiral resolving ability of M9PP acid was slightly superior to that of MαNP acid in HPLC.     

Enantioresolution of 2-methoxy-2-(1-naphtyl)propionic acid using diastereomeric salt formation with chiral phenylethylamine

An enantioresolution of 2-methoxy-2-(1-naphtyl)propionic acid (MαNP acid) using the diastereomeric salt with chiral (R)-phenylethylamine was achieved to give enantiopure (R)-MαNP acid in 29% yield with >99% ee based on rac-MαNP acid. X-ray crystallographic analysis of diastereomeric salt revealed that (R)-MαNP acid was tightly arranged by four independent hydrogen bonds and one CH–π interaction with (R)-phenylethylamine.     

A convenient method for the kinetic resolution of racemic 2-hydroxyalkanoates using diphenylacetic anhydride (DPHAA) and a chiral acyl-transfer catalyst

Diphenylacetic anhydride (DPHAA) was found to be a useful reagent for the kinetic resolution of racemic 2-hydroxyalkanoates in the presence of a catalytic amount of (R)-benzotetramisole ((R)-BTM). The combined use of DPHAA and (R)-BTM effectively produced a variety of the optically active 2-hydroxyalkanoates and the corresponding 2-acyloxyalkanoates from racemic 2-hydroxyalkanoates (s-values = 42–177). A fairly broad substrate scope was demonstrated by this novel chiral induction system. We also revealed that the use of only 0.3 equiv of DPHAA is enough to provide the optically active 2-acyloxyalkanoates in good yields and with excellent ee’s by the added use of 0.3 equiv of pivalic anhydride for the kinetic resolution of the racemic 2-hydroxyalkanoates.     

A new method for production of chiral 2-aryl-2-fluoropropanoic acids using an effective kinetic resolution of racemic 2-aryl-2-fluoropropanoic acids

We report a new method for the preparation of chiral 2-aryl-2-fluoropropanoic acids, including 2-fluoroibuprofen, a fluorinated analogue of non-steroidal anti-inflammatory drugs (NSAIDs), by the kinetic resolution of racemic 2-aryl-2-fluoropropanoic acids using enantioselective esterification. By applying pivalic anhydride (Piv2O) as a coupling agent, bis(α-naphthyl)methanol [(α-Np)2CHOH] as an achiral alcohol, and (+)-benzotetramisole (BTM) as a chiral acyl-transfer catalyst, a series of racemic 2-aryl-2-fluoropropanoic acids were kinetically separated to afford the optically active carboxylic acids and the corresponding esters with good to high enantiomeric excesses. This technology can provide a convenient approach to furnish the chiral α-fluorinated drugs containing quaternary carbons at the α-positions in the 2-aryl-2-fluoropropanoic acid structure.     

Synthesis of new chiral Schiff bases from (+)-2-carene

New chiral Schiff bases were synthesized through tricyclic 2-azetidinones as key intermediate products which were obtained by reaction of (+)-2-carene with chlorosulfonyl isocyanate.     

Kinetic resolution of racemic 2-(2-furyl)-2-hydroxyethyl acetate in the presence of PS lipase

Kinetic resolution of racemic 2-(2-furyl)-2-hydroxyethyl acetate by transesterification with vinyl acetate in the presence of Amano PS lipase, yielding (1R)-1-(2-furyl)ethane-1,2-diol diacetate with 98% ee and (2S)-2-(2-furyl)-2-hydroxyethyl acetate with >99% ee, is described.     

A cyclic trimer of 2-(2-aminophenoxy)propionic acid with a bowl-shaped structure

A cyclic trimer of (R)-2-(2-aminophenoxy)propanoic acid, a δ-amino acid analogue, was synthesized. Molecular mechanics calculations on the cyclic trimer predicted that a concave network of sequential hydrogen bonds forms a C₃-symmetric bowl-shaped structure. Evidence for this conformation was found in the NMR spectra of the trimer in d-chloroform. Although the single-crystal structure of the cyclic trimer indicates that chloroform could be included in the bowl-shaped structure, the conformation was not C₃-symmetric and the hydrogen bonding network was of a different mode. These different conformations between solid and solution were reasonably clear from IR spectra.     

Kinetic resolution of racemic (cyclohexyl)(geranyl)acetic acid

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Kinetic resolution of racemic secondary alcohols catalyzed by chiral diaminodiphosphine-Ir(I) complexes

Chiral diaminodiphosphine-Ir(I) complexes were found to efficiently catalyze enantioselective oxidation of racemic secondary alcohols in acetone. In the presence of base, oxidative kinetic resolution of the alcohols proceeded smoothly with excellent enantioselectivity (up to 98% ee) under mild conditions. [reaction: see text].     

Synthesis and analytical properties of (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid

2-Methoxy-2-(9-phenanthryl)propionic acid was synthesized as a novel chiral resolving agent. The absolute configuration of (+)-2-methoxy-2-(9-phenanthryl)propionic acid was determined to be S by using X-ray structural analysis of the (1R,2S,5R)-menthyl ester. In the crystal, the methoxyl and carbonyl groups of the ester are in a syn-periplanar position. The syn-periplanar conformations of (1R,2S,5R)-menthyl esters were also observed by the NMR analyses in CDCl₃. The utility of (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid was exemplified by the resolution of (±)-3-octanol.     

Synthesis and mesomorphic properties of chiral liquid crystals derived from (S)-2-(6-hydroxy-2-naphthyl)propionic acid with a methyleneoxy linking group

Three homologous series of chiral materials derived from (S)-2-(6-hydroxy-2-naphthly)propionic acid with a methyleneoxy linking group were synthesized for the investigation of mesomorphic properties. All the materials displayed enantiotropic SmA* and SmC* phases. The spontaneous polarization (P _s) and optical tilt angles in the SmC* phase of the chiral materials were measured. The maximum spontaneous polarizations are in the range 12.3-19.1 nC cm^-2. No significant difference could be found in the P _s values with respect to the various alkyl chiral chain lengths, n. The maximum optical tilt angles are in the range 25-30°. The optical tilt angles decrease with the increase in alkyl chain length, n.     

Effect of the variation of swallow-tailed groups on the mesomorphic and electro-optical properties of chiral compounds derived from (S)-2-(6-hydroxy-2-naphthyl)propionic acid

Three homologous series of chiral swallow-tailed compounds, alkyl (S)-2-{6-[4-(4′-alkoxyphenyl)benzoyloxy]-2-naphthyl}propionates, (S)HNP(p,n,q) derived from (S)-2-(6-hydroxy-2-naphthyl)propionic acid in conjugation with a variety of swallow-tailed groups, attached to the external side of the chiral centre, have been synthesized and their mesomorphic and electro-optical properties studied. Both (S)HNP(p,1,2) and (S)HNP(p,1,3) exhibited an enantiotropic antiferroelectric SmC*_A phase. This implys that the swallow-tailed groups in the molecules favour zigzag pairing of the molecules in the smectic phase. The maximum P _S values of compounds (S)HNP(p,1,2) in the antiferroelectric phase were measured in the range 21–30 nC cm^-2; those of compounds (S)HNP(p,1,3) were in the range 15–23 nC cm^-2, indicating that these chiral compounds possess low polarity. The electro-optical response of the compounds in the antiferroelectric SmC*_A phase displayed thresholdless V-shaped switching.