Preparation of Optically Active Allothreonine via Optical Resolution by Replacing Crystallization.

Abstract

D-and L-Allothreonine [D-and L-aThr; (2R,3R)-and (2S,3S)-2-amino-3-hydroxybutanoic acid] are useful as chiral reagents in asymmetric syntheses.1) However, D-and L-aThr, non-proteinogenic a-amino acids, are difficult to produce commercially in large quantities. Therefore, synthetic DLaThr 2-4) has been subjected to optical resolution by separating the diastereoisomeric salts of DL-aThr derivatives to obtain the enantiomers. 5,6) In our previous paper, 7) DL-aThr was found to exist as a conglomerate and to be optically resolved by preferential crystallization and replacing crystallization of DL-aThr. The optical resolution by replacing crystallization is a procedure for obtaining an enantiomer from a conglomerate, and is achieved by allowing an optically active co-solute to coexist in a racemic supersaturated solution.8) DL-aThr was optically resolved using 4-hydroxy-L-proline (L-Hyp) as the optically active cosolute, and D-aThr was allowed to preferentially crystallize from a supersaturated solution of DL-aThr.7) Although L-aThr will be preferentially crystallized from the racemic solution in the presence of D-Hyp, L-Hyp is expensive and D-Hyp is not commercially available. Therefore, we selected D-and L-Ala, which are commercially available and are the most inexpensive optically active a-amino acids, as the optically active cosolutes in optical resolution by replacing crystallization of DL-aThr (Chart 1).Optical resolution by replacing crystallization is based on different interactions between enantiomers and the optically active co-solute. Therefore, the solubilities (mole fractions) of D-, L-, and DL-aThr were first measured in the presence of L-Ala (16.0 mmol) in 100 cm 3 of water at 10°C; these values are summarized in Table 1

An Efficient Route to Both Enantiomers of allo‐Threonine by Simultaneous Amino Acid Racemase‐Catalyzed Isomerization of Threonine and Crystallization

“…Separation of allo-Thr from Thr in our approach is performed by simultaneous crystallization in a simple batch reactor. In contrast to replacing crystallization [23,24] or dynamic kinetic resolution processes, where enzymatic racemization is combined with preferential crystallization of single enantiomers from a saturated racemic solution, [25] the crystallization of allo-Thr is based on its lower solubility limit compared to Thr in water.…”

Preparation of Optically Active Allothreonine by Separating from a Diastereoisomeric Mixture with Threonine

“…In addition, D-and L-aThr serve as useful chiral building blocks in asymmetric syntheses. 4) D-and L-aThr have been obtained by an asymmetric synthesis, 5) optical resolution of DL-aThr, [6][7][8] enzymatic resolution of N-acylated and O-methylated 9) and selective enzymatic hydrolysis of a mixture of N-acetylated and O-benzylated L-Thr and D-aThr. 10) Of these methods, optical resolution by separating the diastereoisomers by crystallization seemed to be a simple and efficient procedure.…”

“…However, such optical resolution would require an optically active compound such as a resolving agent in separating the diastereoisomeric salts, 6) seed crystals in preferential crystallization, 7) and an optically active cosolute in replacing crystallization. 8) We have already reported the preparation of aThr by replacing crystallization with alanine as a cosolute. 8) We report in the present work a procedure to obtain D-and L-aThr from diastereoisomeric mixtures of Thr and aThr, which were given by epimerizing Thr, by a simpler and more efficient procedure without employing such a chiral factor as alanine.…”

“…8) We have already reported the preparation of aThr by replacing crystallization with alanine as a cosolute. 8) We report in the present work a procedure to obtain D-and L-aThr from diastereoisomeric mixtures of Thr and aThr, which were given by epimerizing Thr, by a simpler and more efficient procedure without employing such a chiral factor as alanine.…”

“…The epimerization of D-Thr also gave a mixture of D-Thr and L-aThr in a molar ratio of 1:0.7. As L-Thr is more soluble than D-aThr in water, 8,12) we first attempted to separate aThr from the diastereoisomeric mixtures by recrystallizing from water. However, separation seemed to be difficult even by repeated recrystallization.…”