Hidemoto Kurokawa

OPTICAL RESOLUTION BY PREFERENTIAL CRYSTALLIZATION OF DL-METHIONINE HYDROCHLORIDE

DL-Methionine hydrochloride (DL-Met·HCl) was found to exist as a conglomerate, based on the infrared spectrum, solubility, and melting point. The optical resolution of DL-Met·HCl was successfully achieved by preferential crystallization into D-and L-Met·HCl. Treatment of the purified D- and L-Met·HCl with triethylamine gave D- and L-methionine of 100% optical purities. Chirality, 9;48–51, 1997.

Synthesis of Optically Active 1,4-Thiazane-3-carboxylic Acid via Optical Resolution by Preferential Crystallization of (RS)-2-Amino-3-[(2-chloroethyl)sulfanyl]propanoic Acid Hydrochloride

Optically active 1,4-thiazane-3-carboxylic acid [TCA] was synthesized from cysteine via optical resolution by preferential crystallization. The intermediate (RS)-2-amino-3-[(2-chloroethyl)sulfanyl]propanoic acid hydrochlo-ride [(RS)-ACS•HCl] was found to exist as a conglomerate based on its melting point, solubility and IR spectrum. (RS)-ACS•HCl was optically resolved by preferential crystallization to yield (R)- and (S)-ACS•HCl. (R)- and (S)-ACS•HCl thus obtained were recrystallized from a mixture of hydrochloric acid and 2-propanol, taking account of the solubility of (RS)-ACS•HCl, efficiently yielding both enantiomers in optically pure forms. (R)- and (S)-TCA were then respectively synthesized by the cyclization of (R)- and (S)-ACS•HCl in ethanol in the presence of triethylamine.

Optical Resolution by Preferential Crystallization of (RS)-2-Amino-3-(2-carboxyethylthio)propanoic Acid.

Electrophilic additions of DL- and L-Cys to propenoic acid afforded (RS)- and (R)-2-amino-3-(2-carboxyethylthio)propanoic acids [(RS)- and (R)-ACE], respectively. (RS)-ACE was found to exist as a conglomerate based on its melting point, solubility, and infrared spectrum. (RS)-ACE was optically resolved by preferential crystallization to yield (R)- and (S)-ACE. The obtained (R)- and (S)-ACE were efficiently recrystallized from water, taking account of the solubility of (RS)-ACE, to give them in optically pure form.

Optical resolution by preferential crystallization of (RS)-2-amino-3-chloropropanoic acid hydrochloride

The racemic structures of (RS)-2-amino-3-chloropropanoic acid [(RS)-ACP] and (RS)-2-amino-3-chloropropanoic acid hydrochloride [(RS-ACP·HCl] were examined to obtain (R)- and (S)-ACP via optical resolution by preferential crystallization. The melting point, infrared spectrum, solubility, and ternary solubility diagram suggested that (RS)-ACP·HCl exists as a conglomerate and that (RS)-ACP forms a racemic compound. Optical resolution by preferential crystallization of (RS)-ACP·HCl was successfully achieved to yield (R)- and (S)-ACP·HCl. Optically pure (R)- and (S)-ACP were obtained from the purified (R)-and (S)-ACP·HCl, respectively.

Optical resolution by the replacing crystallization of DL-threonine with L-alanine as an optically active cosolute

DL-Threonine (DL-Thr) was optically resolved by replacing crystallization with L-alanine (L-Ala) as an optically active cosolute. D-Thr was preferentially crystallized from a supersaturated aqueous solution of DL-Thr in the presence of L-Ala. Optical resolution was successfully achieved to afford D-Thr with an optical purity of 96-98% and L-Thr of 91-95%. The partially resolved D- and L-Thr were recrystallized from water, taking account of the solubility of DL-Thr, to efficiently yield both enantiomers in an optically pure form.

Optical resolution by preferential crystallization of (2RS,3SR)‐2‐amino‐3‐chlorobutanoic acid hydrochloride

(2RS,3SR)-2-Amino-3-chlorobutanoic acid hydrochloride [(2RS,3SR)-ACB · HCl] was found to exist as a conglomerate based on the melting point, infrared spectrum, and solubility. Optical resolution by preferential crystallization of (2RS,3SR)-ACB · HCl was achieved to yield both (2R,3S)- and (2S,3R)-ACB · HCl of 80–100% optical purities. The obtained (2R,3S)- and (2S,3R)-ACB · HCl were recrystallized, taking into account the solubility of (2RS,3SR)-ACB · HCl, to give efficiently optically pure (2R,3S)- and (2S,3R)-ACB · HCl. Treatment of the purified (2R,3S)- and (2S,3R)-ACB · HCl with triethylamine gave optically pure (2R,3S)- and (2S,3R)-2-amino-3-chlorobutanoic acid, respectively. Chirality 9:656–660, 1997.

Synthesis of Four Stereoisomers of 1,4-Thiazane-3-carboxylic Acid 1-Oxide via the Asymmetric Transformation (combined isomerization-preferential crystallization) of 1,4-Thiazane-3-carboxylic Acid

In order to synthesize four stereoisomers of 1,4-thiazane-3-carboxylic acid 1-oxide (TCA•SO), (S)-1,4-thiazane-3-carboxylic acid [(S)-TCA], which is one of the precursors, was prepared by the asymmetric transformation (combined isomerization-preferential crystallization) of (RS)-TCA. This asymmetric transformation was used (2R, 3R)-tartaric acid [(R)-TA] as a resolving agent and salicylaldehyde as the epimerization catalyst in propanoic acid at 110°C to afford a salt of (S)-TCA with (R)-TA in 100% de with a yield of over 90%. Optically pure (S)-TCA was obtained by treating the salt with triethylamine in methanol in a yield of over 80%, based on (RS)-TCA as the starting material. In addition, asymmetric transformation of (R)-TCA gave (S)-TCA in a yield of 60-70%. (S)-TCA was oxidized by hydrogen peroxide in dilute hydrochloric acid to selectively crystallize (1S, 3S)-TCA•SO. (1R, 3S)-TCA•SO of 70% de from the filtrate was allowed to form a salt with (R)-TA after a treatment with triethylamine to give (1R, 3S)-TCA•SO as a single diastereoisomer. (1R, 3R)- and (1S, 3R)-TCA•SO were also prepared by starting from (R)-TCA that had been synthesized from L-cysteine.

Preparation and isolation of 2-methylamino-3-phenylpropanoic acid enantiomers using selective crystallization

First, (RS)-2-chloro-3-phenylpropanoic acid [(RS)-CPP] was optically resolved using ethyl (S)-phenylalaninate as a resolving agent, aiming at preparation of optically active 2-methylamino-3-phenylpropanoic acid (MPP). The (R)-CPP obtained as the sodium salt monohydrate was reacted with methylamine to give (S)-2-methylamino-3-phenylpropanoic acid [(S)-MPP]. Next, the optical resolution of (RS)-MPP was also attempted via molecular compound formation with optically active mandelic acid (MAN). The molecular compound of (R)-MPP with (S)-MAN [(R)-MPP (S)-MAN] was obtained as the less soluble diastereomeric compound, while the (S)-MPP (S)-MAN compound was found to be the more soluble one. Recrystallization of (R)-MPP (S)-MAN compound from water, followed by treatment with acetone, gave optically pure (R)-MPP in 79% yield, based on a half amount of the starting (RS)-MPP. The (S)-MPP obtained from (S)-MPP (S)-MAN compound was again subjected to formation of molecular compound with (R)-MAN to give optically pure (S,)-MPP in 66% yield. Chirality 9:386–389, 1997.

Preparation of (2S,4R)‐2,4‐thiazolidinedicarboxylic acid by separation of diastereoisomeric salts with organic amines

L-Cysteine was condensed with glyoxylic acid monohydrate in acetic acid at 30°C to give (4R)-2,4-thiazolidinedicarboxylic acid [(4R)-TDA] as a mixture of two diastereoisomers, (2R,4R)- and (2S,4R)-TDA. An attempt was made to separate (2S,4R)-TDA from the diastereoisomeric salts of (4R)-TDA with 1-propylamine, 2-methyl-2-propylamine, benzylamine, and (R)- and (S)-1-phenylethylamines [(R)- and (S)-PEA]. The salts of (2S,4R)-TDA were preferentially crystallized as less soluble diastereoisomeric salts. When the salt with (R)-PEA was employed, the separation was successfully achieved to afford optically pure (2S,4R)-TDA in a yield of 41%, based on the starting amount of the diastereoisomeric mixture of (4R)-TDA. Chirality 11:326–329, 1999.