Process for preparing optically active threonine

A process for preparing optically active threonine is disclosed, which comprises asymmetrically hydrogenating a 2-N-acylaminoacetoacetic ester represented by formula (I): ##STR1## wherein R.sup.1 represents a lower alkyl group, a phenyl group, a phenyl group substituted with a lower alkyl group or a lower alkoxy group, a benzyl group, or a benzyl group substituted with a lower alkyl group or a lower alkoxy group; R.sup.2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a phenyl group, a phenyl group substituted with a lower alkyl group or a lower alkoxy group, a benzyloxy group, or a benzyloxy group substituted with a lower alkyl group or a lower alkoxy group, in the presence of a ruthenium-optically active phosphine complex as a catalyst to obtain an optically active threonine derivative represented by formula (II): ##STR2## wherein R.sup.1 and R.sup.2 are as defined above, and then hydrolyzing the compound of formula (II). The 2-N-acylaminoacetoacetic ester intermediate can be selectively prepared in a high yield. Either natural type threonine or non-natural type threonine can be prepared selectively by selecting the absolute configuration of the ligand of the ruthenium-optically active phosphine complex.

FIELD OF THE INVENTION 
This invention relates to a process for preparing optically active 
threonine which is important as an essential amino acid and also useful as 
an intermediate for synthesizing pharmaceuticals, by asymmetric 
hydrogenation of a 2-N-acylaminoacetoacetic ester in the presence of a 
ruthenium-optically active phosphine complex as a catalyst, followed by 
hydrolysis. The process of this invention can make a distinction of the 
product between natural type threonine and non-natural type threonine by 
properly selecting the absolute configuration of the ligand of the 
ruthenium-optically active phosphine complex used. 
BACKGROUND OF THE INVENTION 
There have been proposed many processes for preparing optically active 
threonine. The typical one comprises synthesizing DL-threonine and then 
optically resolving the racemate with an enzyme to obtain the desired 
isomer, the undesired isomer being reused through racemization, as 
described in Fodor, et al., J. Biol. Chem., Vol. 178, 503 (1949). 
A problem in the conventional synthesis of threonine lies in the difficulty 
of selectively synthesizing a threo form. That is, the product obtained 
generally comprises a mixture of a threo form and an erythro form at a 
ratio of 8 to 2. Another problem is that since each of the threo form and 
the erythro form comprises optical isomers (antipodes), isolation of the 
respective desired isomers cannot be achieved without racemic resolution. 
This means that the whole process involves a step for separating and 
purifying the isomer and a step for racemizing the undesired isomer, thus 
leading to an increase of production cost. 
SUMMARY OF THE INVENTION 
As a result of extensive investigations with the purpose of settling the 
above-described problems and meeting demands in the art, the inventors 
have found that an optically active N-acylthreonine can be synthesized 
selectively in high yield by hydrogenation of a 2-N-acylaminoacetoacetic 
ester in the presence of a ruthenium-optically active phosphine complex as 
a catalyst. This process has been confirmed capable of synthesizing either 
natural type threonine or non-natural type threonine arbitrarily by 
selecting the absolute configuration of the ligand of the 
ruthenium-optically active phosphine complex. The present invention has 
been completed based on these findings. 
The present invention relates to a process for preparing optically active 
threonine which comprises asymmetrically hydrogenating a 
2-N-acylaminoacetoacetic ester represented by formula (I): 
##STR3## 
wherein R.sup.1 represents a lower alkyl group, a phenyl group, a phenyl 
group substituted with a lower alkyl group or a lower alkoxy group, a 
benzyl group, or a benzyl group substituted with a lower alkyl group or a 
lower alkoxy group; R.sup.2 represents a hydrogen atom, a lower alkyl 
group, a lower alkoxy group, a phenyl group, a phenyl group substituted 
with a lower alkyl group or a lower alkoxy group, a benzyloxy group, or a 
benzyloxy group substituted with a lower alkyl group or a lower alkoxy 
group, in the presence of a ruthenium-optically active phosphine complex 
as a catalyst to obtain an optically active threonine derivative 
represented by formula (II): 
##STR4## 
wherein R.sup.1 and R.sup.2 are as defined above, and then hydrolyzing the 
compound of formula (II). 
DETAILED DESCRIPTION OF THE INVENTION 
The 2-N-acylaminoacetoacetic ester represented by formula (I) which can be 
used in the present invention as a starting compound can be obtained by 
known processes, for example, the process described in Shulgin, et al., J. 
Am. Chem. Soc., Vol. 74, 2427 (1952) and Attenburrow, et al., J. Chem. 
Soc., 310 (1948). Specific but non-limiting examples of the compound of 
formula (I) includes methyl 2-N-accetamidoacetoacetate, ethyl 
2-N-acetamidoacetoacetate, n-butyl 2-N-acetamidoacetoacetate, t-butyl 
2-N-acetamidoacetoacetate, benzyl 2-N-acetamidoacetoacetate, 
p-methoxybenzyl 2-N-acetamidoacetoacetate, p-methylbenzyl 
2-N-acetamidoacetoacetate, methyl 2-N-benzamidoacetoacetate, ethyl 
2-N-benzamidoacetoacetate, benzyl 2-N-benzamidoacetoacetate, ethyl 
2-N-benzyloxycarbonylamidoacetoacetate, methyl 
2-N-ethoxycarbonylamidoacetoacetate, ethyl 
2-N-t-butoxycarbonylamidoacetoacetate, benzyl 2-N-benzyloxycarbonylamido 
acetoacetate, methyl 2-N-formamidoacetoacetate, benzyl 
2-N-formamidoacetoacetate, and t-butyl 2-N-formamidoacetoacetate. 
The ruthenium-optically active phosphine complex to be used as a catalyst 
includes those represented by the following formulae (III), (V), (VI), and 
(VII): 
EQU Ru.sub.x H.sub.y Cl.sub.z (R.sup.3 -BINAP).sub.2 (T).sub.p (III) 
wherein R.sup.3 -BINAP represents a tertiary phosphine represented by 
formula (IV): 
##STR5## 
wherein R.sup.3 represents a hydrogen atom, a methyl group, or a t-butyl 
group; T represents a tertiary amine; when y represents 0, x represents 2, 
z represents 4, and p represents 1; and when y represents 1, x represents 
1, z represents 1, and p represents 0. 
EQU RuH.sub.u (R.sup.3 -BINAP).sub.v]Y.sub.w 
wherein R.sup.3 -BINAP is as defined above; Y represents ClO.sub.4, 
BF.sub.4 or PF.sub.6 ; when u represents 0, v represents 1, and w 
represents 2; and when u represents 1, v represents 2, and w represents 1. 
##STR6## 
wherein R.sup.3 -BINAP is as defined above; and R.sup.4 represents a lower 
alkyl group or a trifluoromethyl group. 
EQU [Ru(R.sup.3 -BINAP)MCl.sub.k ].sub.l X.sub.m (VII) 
wherein R.sup.3 -BINAP is as defined above; M represents Zn, Al, Ti, or Sn; 
X represents N(C.sub.2 H.sub.5).sub.3 or CH.sub.3 CO.sub.2 ; when X is 
N(C.sub.2 H.sub.5).sub.3, l is 2, m is 1, and k is 4 when M is Zn, 5 when 
M is Al, or 6 when M is Ti or Sn; and when X is CH.sub.3 CO.sub.2, l is 1, 
m is 2, and k is 2 when M is Zn, 3 when M is Al, or 4 when M is Ti or Sn. 
The complex of formula (III) can be obtained by the process disclosed in T. 
Ikariya, et al., J. Chem. Soc., Chem. Commun., 922-924 (1985) and 
JP-A-61-63690 (the term "JP-A" as used herein means an "unexamined 
published Japanese patent application"). More specifically, the complex of 
formula (III) wherein y is 0 can be prepared by reacting 1 mole of 
[RuCl.sub.2 (COD)].sub.n (wherein COD represents cycloocta-1,5-diene, 
hereinafter the same), which is obtainable by reacting ruthenium chloride 
and COD in an ethanol solution, and 1.2 mols of a 2,2'-bis(di-p-R.sup.3 
-phenylphosphino)-1,1'-binaphthyl (R.sup.3 -BINAP) by heating in a solvent 
(e.g., toluene, ethanol) in the presence of 4 moles of a tertiary amine 
(e.g., triethylamine). The complex of formula (III) wherein y is 1 can be 
prepared by reacting 1 mole of [RuCl.sub.2 (COD)].sub.n, 2.25 moles of 
R.sup.3 -BINAP, and 4.5 moles of a tertiary amine. 
The complex of formula (V) wherein u is 0, v is 1, and w is 2 can be 
prepared by reacting Ru.sub.2 Cl.sub.4 (R.sup.3 -BINAP).sub.2 (NEt.sub.3) 
(wherein Et represents an ethyl group, hereinafter the same), which is 
obtained by the above-described process, with a salt represented by 
formula (VIII): 
EQU MY (VIII) 
wherein M represents Na, K, Li, Mg, or Ag; and Y is as defined above, in a 
solvent system comprising water and methylene chloride in the presence of 
a quaternary ammonium salt or quaternary phosphonium salt represented by 
formula (IX): 
EQU R.sup.5 R.sup.6 R.sup.7 R.sup.8 AB (IX) 
wherein R.sup.5, R.sup.6, R.sup.7, and R.sup.8 each represents an alkyl 
group having from 1 to 16 carbon atoms, a phenyl group, or a benzyl group; 
A represents a nitrogen atom or a phosphorus atom; and B represents a 
halogen atom, as a phase transfer catalyst. The reaction can be carried 
out by adding the reactants and the phase transfer catalyst of formula 
(IX) to a mixed solvent of water and methylene chloride and stirring the 
system. The amounts of the salt of formula (VIII) and the phase transfer 
catalyst of formula (IX) to be added range from 2 to 10 moles (preferably 
5 moles) and from 1/100 to 1/10 mole, respectively, per mole of ruthenium. 
The reaction sufficiently proceeds by stirring at a temperature of from 
5.degree. to 30.degree. C. for a period of from 6 to 18 hours, usually 12 
hours. Examples of the phase transfer catalyst of formula (IX) are 
described in literature, e.g., W. P. Weber and G. W. Gokel, Sokan Ido 
Shokubai (Japanese translation), 1st Ed., Kagaku Dojinsha (1978). After 
completion of the reaction, the reaction mixture is allowed to stand 
still, and the aqueous layer is removed by liquid-liquid separation. The 
methylene chloride solution thus separated is washed with water, and the 
methylene chloride is removed by distillation under reduced pressure to 
obtain the desired compound. 
The complex of formula (V) where u is 1, v is 2, and w is 1 can be prepared 
by reacting RuHCl(R.sup.3 -BINAP).sub.2 with the salt of formula (VIII) in 
a mixed solvent of water and an organic solvent, e.g., methylene chloride, 
in the presence of the phase transfer catalyst of formula (IX). The 
amounts of the salt of formula (VIII) and the phase transfer catalyst of 
formula (IX) range from 2 to 10 moles (preferably 5 mole) and from 1/100 
to 1/10 mole, respectively, per mole of ruthenium. This reaction 
sufficiently proceeds by stirring at a temperature of from 5.degree. to 
30.degree. C. for a period of from 6 to 18 hours, usually 12 hours. 
The complex of formula (VI) can be prepared by reacting Ru.sub.2 Cl.sub.4 
(R.sup.3 -BINAP).sub.2 (NEt.sub.3) with a carboxylic acid salt in an 
alcohol solvent, e.g., methanol, ethanol, and t-butanol, at a temperature 
of from about 20.degree. to 110.degree. C. for 3 to 15 hours. After the 
reaction, the solvent is removed by distillation, and the residue is 
extracted with a solvent, e.g., diethyl ether, ethanol, etc., to obtain 
the desired complex, followed by concentration to dryness to obtain a 
crude complex. Recrystallization of the crude product from ethyl acetate, 
etc., gives a purified product. The acyloxy group (R.sub.4 =alkyl group) 
to be introduced can be determined by selecting the carboxylic acid to be 
used. For example, when sodium acetate is used as a carboxylic acid salt, 
Ru(R.sup.3 -BINAP)(OCOCH.sub.3).sub.2 is yielded. The complex of formula 
(VI) having a trifluoroacetyl group (R.sup.4 =trifluoromethyl group) can 
be obtained by reacting the above-prepared diacetate complex with 
trifluoroacetic acid in methylene chloride at about 25.degree. C. for 
about 12 hours. 
The complex of formula (VII) can be prepared by starting with Ru.sub.2 
Cl.sub.4 (R.sup.3 -BINAP).sub.2 (NEt.sub.3) or Ru(R.sup.3 
-BINAP)-(OCOCH.sub.3)2. That is, Ru.sub.2 Cl.sub.4 (R.sup.3 
-BINAP).sub.2(NEt.sub.3) is reacted with a Lewis acid selected from zinc 
chloride, aluminum chloride, titanium tetrachloride, and tin tetrachloride 
in a solvent, e.g., methylene chloride, at 10.degree. to 25.degree. C. for 
2 to 20 hours, and the solvent is removed by distillation, followed by 
drying to solidify to obtain the desired compound. Ru(R.sup.3 
-BINAP)(OCOCH.sub.3).sub.2 is reacted with the above-recited Lewis acid in 
a solvent, e.g., methylene chloride, at 10.degree. to 25.degree. C. for 2 
to 20 hours, and the solvent is removed by distillation, followed by 
drying to solidify to obtain the desired compound. 
In the processes stated above, an optically active ruthenium-phosphine 
complex can be obtained by using R.sup.3 -BINAP having the corresponding 
optical activity. 
Specific examples of the ruthenium-optically active phosphine complex 
according to the present invention are shown below. 
Ru.sub.2 Cl.sub.4 (BINAP).sub.2 (NEt.sub.3) 
[BINAP represents 2,2'-bis(diphenylphosphino)1,1'-binaphthyl, hereinafter 
the same) 
Ru.sub.2 Cl.sub.4 (T-BINAP).sub.2 (NEt.sub.3) 
[T-BINAP represents 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl] 
Ru.sub.2 Cl.sub.4 (t-Bu-BINAP).sub.2 (NEt.sub.3) 
[t-Bu-BINAP represents 2,2'-bis(di-p-t-butyl-phenylphosphino)-1,1'- 
binaphthyl] 
RuHCl(BINAP).sub.2 
RuHCl(T-BINAP).sub.2 
RuHCl(t-Bu-BINAP).sub.2 
[Ru(BINAP)](ClO.sub.4).sub.2 
[Ru(T-BINAP)](ClO.sub.4).sub.2 
[Ru(t-Bu-BINAP)](ClO4).sub.2 
[Ru(BINAP)](BF.sub.4).sub.2 
[Ru(T-BINAP)](BF.sub.4).sub.2 
[Ru(t-Bu-BINAP)](BF.sub.4).sub.2 
[Ru(BINAP)](PF.sub.6).sub.2 
[Ru(T-BINAP)](PF.sub.6).sub.2 
[RuH(BINAP).sub.2 ]ClO.sub.4 
[RuH(T-BINAP).sub.2 ]ClO.sub.4 
[RuH(BINAP).sub.2 ]BF.sub.4 
[RuH(T-BINAP).sub.2 ]BF.sub.4 
[RuH(BINAP).sub.2 ]PF.sub.6 
[RuH(T-BINAP).sub.2 ]PF.sub.6 
Ru(BINAP)(OCOCH.sub.3).sub.2 
Ru(BINAP)(OCOCF.sub.3).sub.2 
Ru(T-BINAP)(OCOCH.sub.3).sub.2 
Ru(BINAP)(OCO-t-Bu).sub.2 
(t-Bu represents a t-butyl group) 
Ru(T-BINAP)(OCOCF.sub.3).sub.2 
Ru(t-Bu-BINAP)(OCOCH.sub.3).sub.2 
[Ru(BINAP)ZnCl.sub.4 ].sub.2 (NEt.sub.3) 
[Ru(BINAP)A;Cl.sub.5 ].sub.2 (NEt.sub.3) 
[Ru(BINAP)SnCl.sub.6 ].sub.2 (NEt.sub.3) 
[Ru(BINAP (NEt.sub.3) 
[Ru(T-BINAP)ZnCl.sub.4 ].sub.2 (NEt.sub.3) 
[Ru(T-BINAP)AlCl.sub.5 ].sub.2 (NEt.sub.3) 
[Ru(T-BINAP) NEt.sub.3) 
[Ru(T-BINAPTiCl.sub.6 ].sub.2 NEt.sub.3) 
[Ru(BINAP)ZnCl.sub.2 ](OCOCH.sub.3).sub.2 
[Ru(BINAP)AlCl.sub.3 ](OCOCH.sub.3).sub.2 
[Ru(BINAP)SnCl.sub.4 ](OCOCH.sub.3).sub.2 
[Ru(BINAP)TiCl.sub.4 ](OCOCH.sub.3).sub.2 
[Ru(T-BINAP)ZnCl.sub.2 ](OCOCH.sub.3).sub.2 
[Ru(T-BINAP)AlCl.sub.3 ](OCOCH.sub.3).sub.2 
[Ru(T-BINAP)SnCl.sub.4 ](OCOCH.sub.3).sub.2 
[Ru(T-BINAP)TiCl.sub.4 ](OCOCH.sub.3).sub.2 
In carrying out the present invention, a solution of a 
2-N-acylaminoacetoacetic ester dissolved in an equivalent amount to ten 
times the volume of a solvent, e.g., methanol, ethanol, isopropanol, etc., 
is charged in an autoclave in a nitrogen stream, and from, 1/50 to 1/1000 
mole of a ruthenium-optically active phosphine complex is added thereto 
per mole of the substrate. The hydrogenation reaction is effected at a 
temperature of from 25.degree. to 50.degree. C. at a hydrogen pressure of 
from 10 to 100 kg/cm.sup.2 for a period of from 15 to 48 hours to thereby 
obtain an N-acyl-threonine. The resulting compound is then subjected to 
hydrolysis in a hydrochoric acid aqueous solution in a usual manner, 
followed by purification to obtain optically active threonine.

The present invention is now illustrated in greater detail with reference 
to Reference Examples and Examples, but it should be understood that the 
present invention is not deemed to be limited thereto. 
REFERENCE EXAMPLE 1 
Synthesis of Ru.sub.2 Cl.sub.4 [(+)-BINAP].sub.2 (NEt.sub.3) (di[.sub.2,2 
'-bis(diphenylphosphino)-1,1'-binaphthyl]tetrachloro-diruthium 
triethylamine): 
To 100 ml of toluene were added 1 g (3.56 mmoles) of [RuCl.sub.2 
(COD)].sub.n, 2.66 g (4.27 mmoles of (+)-BINAP, and 1.5 g of triethylamine 
in a nitrogen atmosphere, and the mixture was heat-refluxed for 10 hours. 
The solvent was removed from the reaction mixture by distillation under 
reduced pressure, and the residual solid was dissolved in methylene 
chloride, followed by filtration through Celite. The filtrate was 
concentrated to dryness to obtain 3.7 g of the entitled compound as a deep 
brown solid. 
Elemental Analysis for C.sub.94 H.sub.79 Cl.sub.4 NP.sub.4 Ru.sub.2 : 
Calcd. (%): Ru 11.96; C. 66.85; H 4.71; P 7.33. Found (%): Ru 11.68; C. 
67.62; H 4.97; P 6.94. 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 1.30-1.50 (t, 6H, NCH.sub.2 
CH.sub.3), 3.05-3.30 (q, 4H, NCH.sub.2 CH.sub.3). 6.40-8.60 (m, 32H, Ar-H) 
REFERENCE EXAMPLE 2 
Synthesis of [Ru((-)-T-BINAP)](ClO.sub.4).sub.2 
([2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl]ruthenium perchlorate) 
In a 250 ml-volume Schlenk's tube was charged 0.54 g (0.30 mmole) of 
Ru.sub.2 Cl.sub.4 [(-)-T-BINAP].sub.2 (NEt.sub.3). After thorough 
displacement of the atmosphere with nitrogen gas, 60 ml of methylene 
chloride was added thereto, and then a solution of 0.73 g (6.0 mmoles) of 
sodium perchlorate in 60 ml of water and a solution of 16 mg (0.06 mmole) 
of triethylbenzylammonium bromide in 3 ml of water were added to the 
mixture. The mixture was stirred at room temperature for 12 hours. After 
completion of the reaction, the reaction mixture was allowed to stand, and 
the aqueous layer was removed. The methylene chloride was removed from the 
organic layer by distillation under reduced pressure, and the residue was 
dried under reduced pressure to obtain 0.59 g (99.6%) of the entitled 
compound as a deep brown solid. 
Elemental Analysis for C.sub.48 H.sub.40 Cl.sub.2 P.sub.2 Ru: Calcd. (%): 
Ru 10.32; C. 58.90; H 4.12; P 6.33. Found (%): Ru 10.08; C. 58.61; H 4.53; 
P 5.97. 
.sup.31 P NMR (CDCl.sub.3) .delta. ppm: 12.920 (d, J=41.1 Hz). 61.402 (d, 
J=41.1 Hz) . 
REFERENCE EXAMPLE 3 
Synthesis of Ru[(-)-BINAP](OCOCH.sub.3).sub.2 
([2,2'-bis(diphenyl-phosphino)-1,1'-binaphthyl]ruthenium-diacetate): 
In a 250 ml-volume Schlenk's tube were charged 1.43 g (0.85 mmole) of 
Ru.sub.2 Cl.sub.4 [(-)-BINAP].sub.2 (NEt.sub.3) and 3.06 g (37 mmoles) of 
sodium acetate. After thorough displacement of the atmosphere with 
nitrogen, 100 ml of t-butanol was added thereto. The mixture was heated at 
reflux for 12 hours. After completion of the reaction, t-butanol was 
removed by distillation under reduced pressure of 20 mmHg, and the 
residual solid was extracted twice with 10 ml portions of ethyl ether. The 
ethyl ether was removed from the extract by distillation, and the 
resulting solid was further extracted twice with 10 ml portions of 
ethanol. The extract was concentrated to dryness to obtain 1.50 g of crude 
Ru[(-)-BINAP](OCOCH.sub.3).sub.2. Recrystallization of the crude product 
from ethyl acetate gave 0.79 g (52%) of the entitled compound as a 
yellowish brown solid. 
Melting Point: 180.degree.-181.degree. C. (with decomposition) Elemental 
Analysis for C.sub.48 H.sub.38 O.sub.4 P.sub.2 Ru: Calcd. (%): Ru 12.01; 
C. 68.48; H 4.55; P 7.36. Found (%): Ru 11.85; C. 68.35; H 4.61; P 7.28. 
31P-NMR (CDCl.sub.3) .delta. ppm: 65.00 (s). 
.sup.1 H-NMR (CDCl.sub.3) .delta. ppm: 
1.75 (s, 6H, 
##STR7## 
6.5-7.8 (m, 32H, naphthyl ring and phenyl proton). 
REFERENCE EXAMPLE 4 
Synthesis of [Ru((-)-T-BINAP)SnCl.sub.6 ].sub.2 NEt.sub.3) 
(bis[ruthenium(2,2'-bis(di-p-tolylphosphino)-1,- 
.1)hexachlorotin]triethylamine): 
In a 80 ml-volume Sohlenk's tube was charged 0.52 g (0.3 mmole) of Ru.sub.2 
Cl.sub.4 [(-)-T-BINAP].sub.2 (NEt.sub.3). After thorough displacement of 
the atmosphere with nitrogen, 20 ml of methylene chloride and 0.16 g (0.6 
mmole) of SnCl.sub.4 were added thereto, followed by stirring at room 
temperature for 15 hours. After completion of the reaction, the methylene 
chloride was removed by distillation under reduced pressure, and the 
residue was dried to solidify to obtain 0.68 g (100%) of the entitled 
compound as a deep brown solid. 
Elemental Analysis for C.sub.102 H.sub.95 Cl.sub.12 NP.sub.4 Sn.sub.2 
Ru.sub.2 : Found (%): P 5.91; C. 53.48; H 4.36; Cl 17.56. Calcd. (%): P 
5.33 C. 52.72; H4.12; Cl 18.31. .sup.31 P-NMR (CDCl.sub.3) .delta. ppm: 
14.14 (d, J=41.7 Hz). 62.57 (d, J=41.7 Hz). 
In the foregoing Reference Examples, .sup.31 P-NMR spectra were measured by 
means of AM400 Model (161 MHz) manufactured by Bruker Co., and the 
chemical shift was determined by using 85% phosphoric acid as an external 
standard. 
EXAMPLE 1 
In a 500 ml-volume stainless steel autoclave whose atmosphere had been 
replaced with nitrogen was added a solution of 29 g (0.12 mole) of ethyl 
2-N-benzamidoacetoacetate and 582 mg (0.33 mmole) of Ru.sub.2 Cl.sub.4 
[(-)-BINAP].sub.2 (NEt.sub.3) prepared according to Reference Example 1 in 
100 m; of methylene dichloride, and the solution was stirred at room 
temperature at a hydrogen pressure of 40 kg/cm.sup.2 for 80 hours to 
effect hydrogenation. The solvent was removed by distillation, and the 
residue was subjected to silica gel column chromatography (eluent =7:3 
mixture of hexane:isopropanol) to remove the catalyst and to obtain 23.0 g 
of N-benzoyl-D-threonine ethyl ester, which was crystallized from a 2'1 
mixed solvent of ethyl ether and n-hexane to obtain 15.0 g of crystals. 
Recrystallization was from a 2:1 mixed solvent of benzene and ethyl ether 
to obtain 12.0 g (41.4%) of a pure product. 
Melting Point: 85-86.5.degree. C. 
[.alpha.].sub.d .sup.25 =-29.5.degree. (chloroform, c=3.225) 
Then, 3.6 g of the resulting ester was refluxed in 10% hydrochloric acid 
for 3 hours to obtain a uniform solution. The solution was allowed to 
stand under ice-cooling for 1 hour, followed by filtration to remove 
benzoic acid crystals. The filtrate was concentrated to dryness, and the 
residue was dissolved in 10 ml of water. After adjusting to a pH of 7.0 
with 28% aqueous ammonia, the solution was subjected to recrystallization 
from a 1:2 mixed solvent of water and ethanol to obtain 1.2 g (71%) of 
D-threonine. 
[.alpha.].sub.D.sup.25 =+27.6.degree. (H.sub.2 O, c=1.23). 
Optical Yield: 97.2% ee. 
.sup.1 H-NMR (D.sub.2 O) .delta. ppm: 4.18 (1H), 3.55 (lH, J=4.86 Hz), 1.25 
(3H, J=6.78 Hz). 
EXAMPLE 2 
In a 500 ml-volume stainless steel autoclave whose atmosphere had been 
replaced with nitrogen was charged a solution of 20.7 g (0.11 mole) of 
ethyl 2-N-acetamidoacetoacetate and 444 mg (0.25 mmole) of Ru.sub.2 
Cl.sub.4 [(-)-T-BINAP].sub.2 (NEt.sub.3) prepared according to Reference 
Example 1 in 200 ml of methylene dichloride, and the mixture was stirred 
at 50.degree. C. at a hydrogen pressure of 100 kg/cm.sup.2 for 24 hours to 
effect hydrogenation. The solvent was removed by distillation, and the 
residue was subjected to silica gel column chromatography (eluent =7:3 
mixture of hexane and isopropanol) to remove the catalyst and to obtain 
19.5 g (93%) of N-acetyl-D-threonine ethyl ester. 
Then, 4.4 g of the resulting ester was refluxed in 10% hydrochloric acid 
for 3 hours to prepare a uniform solution. The solution was concentrated 
to dryness, and 10 ml of water was added to the residue. The solution was 
adjusted to a pH of 7 with 28% aqueous ammonia and then recrystallized 
from a 1:2 mixed solvent of water and ethanol to obtain 2.2 g (79%) of 
D-threonine. 
[.alpha.].sub.D .sup.25 =+28.0.degree. (H.sub.2 O c=1.85). 
Optical Yield: 98.6%ee. 
.sup.1 H-NMR (D.sub.2 O): The same as in Example 1. 
EXAMPLE 3 
In 50 ml of methanol were dissolved 17.3 g (0.1 mole) of methyl 
2-N-acetamidoacetoacetate and 422 mg (0.25 mmole) of Ru.sub.2 Cl.sub.4 
[(+)-BINAP].sub.2 (NEt.sub.3)as synthesized in Reference Example 1, and 
the solution was charged in an autoclave in a nitrogen stream. The 
solution was subjected to hydrogenation at 35.degree. C. at a hydrogen 
pressure of 40 kg/cm.sup.2 for 24 hours. The methanol was removed by 
distillation, and 72 ml of 10% hydrochloric acid was added to the residue, 
followed by heat-refluxing for 3 hours to obtain a uniform solution. The 
solution was concentrated to dryness, and 50 ml of water was added 
thereto. The solution was adjusted to a pH of 7 with 28% aqueous ammonia. 
The precipitated crystals were collected and dried to obtain 8.1 g (0.07 
mol, 68%) of L-threonine. 
[.alpha.].sub.D.sup.25 =-27.8.degree. (H.sub.2 O, c=2.0). 
Optical Yield: 97.9%ee. 
EXAMPLE 4 
In 50 ml of ethanol were dissolved 18.7 g (0.1 mole) of ethyl 
2-N-acetamidoacetoacetate and 461 mg (0.5 mmole) of 
[Ru((+)-BINAP)](ClO.sub.4).sub.2 prepared according to Reference Example 
2, and the solution was charged in an autoclave in a nitrogen stream. The 
solution was subjected to hydrogenation at 25.degree. C. and at a hydrogen 
pressure of 70 kg/cm.sup.2 for 40 hours. The ethanol was removed from the 
reaction mixture by distillation under reduced pressure, and to the 
residue was added 70 ml of 10% hydrochloric acid, followed by 
heat-refluxing for 4 hours. The solution was concentrated to dryness, and 
47 ml of water was added to the residue. The solution was adjusted to a pH 
of 7 with 28% aqueous ammonia, and the precipitated crystals were 
collected and dried to obtain 8.56 g (72%) of L-threonine. 
[.alpha.].sub.D.sup.25 =-27.degree. (H.sub.2 O c=1.5). 
Optical Yield: 95%ee. 
EXAMPLE 5 
In 80 ml of ethanol were dissolved 28 g (0.1 mole) of ethyl 
2-N-benzyloxycarbonylamidoacetoacetate and 1,105 mg (0.5 mmole) of 
[Ru((-)-BINAP)SnCl.sub.6 ].sub.2 (NEt.sub.3) as synthesized in Reference 
Example 4, and the solution was charged in an autoclave in a nitrogen 
stream. The solution was subjected to hydrogenation at 30.degree. C. and 
at a hydrogen pressure of 50 kg/cm.sup.2 for 30 hours. The ethanol was 
removed from the reaction mixture by distillation under reduced pressure, 
and 70 ml of 10% hydrochloric acid was added to the residue, followed by 
heat-refluxing for 3 hours. The solution was concentrated to dryness, and 
50 ml of water was added to the residue. The solution was adjusted to a pH 
of 7 with 28% aqueous ammonia. The thus precipitated crystals were 
collected and dried to obtain 8.33 g (70%) of D-threonine. 
[.alpha. .sub.D.sup.25 =+25.6.degree. (H.sub.2 O c=2.1). 
Optical Yield: 90%ee. 
EXAMPLE 6 
In 54 ml of ethanol were dissolved 18.7 g (0.1 mole) of ethyl 
2-N-acetamidoacetoacetate and 89.7 g (0.1 mmole) of 
Ru[(-)-T-BINAP](OCOCH.sub.3).sub.2 prepared according to Reference Example 
3, and the solution was charged in an autoclave in a nitrogen stream. The 
solution was subjected to hydrogenation at 30.degree. C. and at a hydrogen 
pressure of 70 kg/cm.sup.2 for 35 hours. The ethanol was removed from the 
reaction mixture by distillation, and to the residue was added 70 ml of 
10% hydrochloric acid, followed by heat-refluxing for 3 hours. The 
solution was concentrated to dryness. To the residue was added 50 ml of 
water, and the solution was adjusted to a pH of 7 with 28% aqueous 
ammonia. The precipitated crystals were collected and dried to obtain 8.9 
g (72%) of D-threonine. 
[.alpha.].sub.D.sup.25 =+27.degree. (H.sub.2 O c=1.7). 
Optical Yield: 88%ee. 
EXAMPLES 7 to 14 
The same procedure of Examples 1 to 6 was repeated, except for altering the 
substrate, catalyst and reaction conditions as shown in Table 1. The 
reaction results are shown in Table 1. 
3 TABLE 1 
Reaction Product Reaction Conditions Optical Substrate Hydrogen 
Temper- Rotation Optical Example Catalyst Pressure ature Time Yield 
[.alpha.].sub.D.sup.25 Yield No. Substrate Catalyst mole/mole Solvent 
(kg/cm.sup.2) (.degree.C.)(hr) (%) (.degree.) (% ee) 
7 benzyl 2-N--acetamidoaceto- Ru.sub.2 Cl.sub.4 [(+)-BINAP].sub.2 
(NEt.sub.3) 50 methylene 70 30 15 93 -26.4 93 acetate chloride 8 
benzyl 2-N--benzyloxycarbo- Ru.sub.2 Cl.sub.4 [(-)-T-BINAP].sub.2 - 100 
ethanol 50 25 24 95 +27.0 95 nylamidoacetoacetate (NEt.sub.3) 9 methyl 
2-N--t-butyloxy- Ru.sub.2 Cl.sub.4 [(-)-BINAP].sub.2 (NEt.sub.3) 200 
methanol 45 25 40 98 +27.8 98 carbonylamidoacetoacetate 10 ethyl 
2-N--ethoxycarbonyl- Ru.sub.2 Cl.sub.4 [(-)-BINAP].sub.2 (NEt.sub.3) 200 
ethanol 45 25 40 93 +25.8 91 amidoacetoacetate 11 methyl 2-N--acetamido- 
Ru[(-)-T-BINAP](OCOCF.sub.3).sub.2 100 methanol 60 30 24 94.5 +25.27 89 
acetoacetate 12 methyl 2-N--acetamido- Ru[(-)-t-Bu-BINAP]- 50 methanol 
70 30 30 94.7 +24.13 85 acetoacetate (OCOCH.sub.3).sub.2 13 methyl 
2-N--acetamido- [Ru((+)-BINAP)](BF.sub.4).sub.2 100 methanol 50 25 24 
95.1 -26.11 92 acetoacetate 14 methyl 2-N--acetamido- [Ru((-)-T-BINAP)Zn 
Cl.sub.4 ].sub.2 - 100 methanol 65 25 24 94 +27.25 96 acetoacetate 
(NEt.sub.3) 
As described above, the present invention provides a process for preparing 
optically active threonine, which is important as an essential amino acid 
and also useful as an intermediate for pharmaceuticals, by asymmetric 
hydrogenation of a 2-N-acylaminoacetoacetic ester using a cheap 
ruthenium-optically active phosphine complex as a catalyst and then 
hydrolyzing the product. According to the present invention, either of 
natural type threonine or non-natural type threonine can be selectively 
synthesized by selecting the absolute configuration of the ligand of the 
ruthenium-optically active phosphine complex. Therefore, the process of 
the present invention is industrially superior. 
While the invention has been described in detail and with reference to 
specific embodiments thereof, it will be apparent to one skilled in the 
art that various changes and modifications can be made therein without 
departing from the spirit and scope thereof.