Process for preparing optically active 2-aminopropanal

A process for preparing an optically active 2-aminopropanal through oxidative cleavage of the corresponding optically active 3-amino-1,2-butanediol of the following formula (2): ##STR1## wherein R1 is a hydrocarbon group having 3 to 6 carbon atoms; R2 and R3 are each a hydrogen atom, or separately or together represent an N-protecting group; and the configuration at the *1 position is S or R. An optically active 2-aminopropanal of high purity can be obtained in a high yield by the process.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a process for preparing an optically 
active 2-aminopropanal, which is widely used as a starting material for 
synthesis of intermediates of drugs, examples of which include an 
intermediate of bestatin as a carcinostatic, an intermediate of a renin 
inhibitor as a hypotensor and an intermediate of an HIV protease 
inhibitor. 
2. Description of the Related Art 
Two general processes are known for preparing an optically active 
2-aminopropanal using an a-amino acid as a starting material. According to 
one process, an .alpha.-amino acid is reduced to the corresponding 
.alpha.-amino alcohol, which is then oxidized to the corresponding 
aldehyde (see Japanese Patent Laid-Open No. 23,4071/1987). According to 
another process, an .alpha.-amino acid is esterified, and the resulting 
ester is reduced to the corresponding aldehyde under mild conditions. 
In the first-mentioned process comprising reduction of an .alpha.-amino 
acid to the corresponding .alpha.-amino alcohol and subsequent oxidation 
thereof to the corresponding aldehyde, a relatively mild oxidation 
reaction is carried out from the viewpoint of problems of oxidation to an 
unstable aldehyde and epimerization thereof. Examples of such a mild 
oxidation reaction include oxidation with chromium oxide-pyridine and 
oxidation with dimethyl sulfoxide [see Journal of Organic Chemistry, 52, 
1487 (1987)]. Further, oxidation with pyridinium dichromate is known. 
According to any one of these reactions, however, by-product(s) is formed, 
while there is a possibility that epimerization of the amino group might 
occur because the liquid systems involved in the reaction and 
post-treatments are not always neutral. 
On the other hand, in the second-mentioned process comprising 
esterification of an .alpha.-amino acid and subsequent reduction of the 
resulting ester, a mild reduction reaction is carried out from the 
viewpoint of reduction to an unstable aldehyde as well. Reduction with 
diisobutylaluminum hydride may be mentioned as a general mild reduction 
method (see, for example, Journal of Organic Chemistry, 52, 1487 (1987), 
wherein an example of synthesis is described). 
According to this process as well, however, delicate control of the 
equivalent number of a reducing agent and a reaction temperature as low as 
-60.degree. to -78.degree. C. are necessary because reduction of the ester 
must be terminated just when the aldehyde is formed. Further, this process 
involves a problem that, even when the equivalent number of the reducing 
agent is controlled, unreacted matter remains and an alcohol is formed as 
a result of further reaction. As described hereinabove, an optically 
active .alpha.-amino aldehyde is one of the aldehydes which are difficult 
to synthesize, because such an aldehyde is unstable in itself and 
characteristically subject to epimerization of the amino group thereof at 
the .alpha.-position because of the influence thereon of the aldehyde 
group. 
SUMMARY OF THE INVENTION 
An object of the present invention is to provide a process for preparing an 
optically active 2-aminopropanal with the foregoing problems solved. 
As a result of intensive investigations with a view to solving the 
foregoing problems, the inventors of the present invention have completed 
the present invention. 
In accordance with one aspect of the present invention, there is provided a 
process for preparing an optically active 2-aminopropanal represented by 
the following general formula (1): 
##STR2## 
wherein R1 is a hydrocarbon group having 3 to 6 carbon atoms; R2 and R3 
are each a hydrogen atom, or separately or integrally an N-protecting 
group; and the configuration at the position *1 is S or R: 
comprising oxidative cleavage of an optically active 3-amino-1,2-butanediol 
represented by the following general formula (2): 
##STR3## 
wherein R1, R2, R3, and the configuration at the position *1 are each as 
defined above. 
In accordance with another aspect of the present invention, there is 
provided a process for preparing an optically active 2-aminopropanal 
represented by the following general formula (1): 
##STR4## 
wherein R1 is a hydrocarbon group having 3 to 6 carbon atoms; R2 and R3 are 
each a hydrogen atom, or separately or integrally an N-protecting group; 
and the configuration at the position *1 is S or R: 
comprising reduction of an optically active 3-amino-2-hydroxybutyric acid 
or ester represented by the following general formula (3): 
##STR5## 
wherein R1, R2, R3, and the configuration at the position *1 are each as 
defined above; and R4 is a hydrogen atom or an ester residue; and 
oxidative cleavage of the resulting optically active 3-amino-1,2-butanediol 
represented by the following general formula (2): 
##STR6## 
wherein R1, R2, R3, and the configuration at the position *1 are each as 
defined above. 
DETAILED DESCRIPTION OF THE INVENTION 
In the present invention, the compound of the formula (2) can be obtained 
by reducing to an alcohol group the carboxyl or carboxylate group of an 
optically active 3-amino-2-hydroxybutyric acid or ester represented by the 
formula (3): 
##STR7## 
wherein R1 is a hydrocarbon group having 3 to 6 carbon atoms; R2 and R3 are 
each a hydrogen atom, or separately or integrally an N-protecting group; 
R4 is a hydrogen atom or an ester residue; and the configuration at the 
position *1 is S or R. 
In the present invention, the hydrocarbon group having 3 to 6 carbon atoms 
as R1 in the formula (1) to (3) may be any of saturated and unsaturated 
cyclic and acyclic groups. Examples of the cyclic hydrocarbon group 
include phenyl and cyclohexyl groups, while those of the acyclic 
hydrocarbon group include propyl, butyl and pentyl groups. 
All known amino-protecting groups can be used as the N-protecting group 
which R2 and/or R3 stands for in the formula (1) to (3), and R2 and R3 may 
be bonded to each other to form a single N-protecting group. Preferred 
examples of the N-protecting group include acyl type protecting groups 
such as formyl, acetyl, trifluoroacetyl, and substituted and unsubstituted 
benzoyl; urethane-forming type protecting groups such as substituted and 
unsubstituted benzyloxycarbonyl, alkoxycarbonyl with the alkoxy having 1 
to 6 carbon atoms, and cycloalkanoxycarbonyl; and other protecting groups 
including alkoxyalkyl groups such as methoxymethyl, arylalkyl groups such 
as benzyl and trityl, aryl groups, substituted and unsubstituted 
arylsulfonyl groups, a phthalyl group, and an o-nitrophenylsulfenyl group. 
Examples of the ester residue which R4 stands for in the formula (3) 
include alkyl groups having 1 to 4 carbon atoms, aryl groups, and 
arylalkyl groups. Specific examples of the alkyl groups having 1 to 4 
carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, and 
isobutyl. Specific examples of the aryl group include phenyl and naphthyl, 
while those of the arylalkyl group include benzyl. The above-mentioned 
groups may be substituented. 
The reduction of the carboxyl or carboxylate group to the alcohol group to 
obtain the diol compound of the formula (2) from the butyric acid or ester 
compound of the formula (3) may be carried out according to any one of 
customary methods of reducing a carboxyl or carboxylate group to an 
alcohol group, preferred examples of which include a method wherein use is 
made of a boron hydride compound or an aluminum hydride compound, a method 
wherein use is made of diborane, and the Birch reduction method wherein 
use is made of sodium or lithium. In general, however, the method wherein 
use is made of a boron hydride compound or an aluminum hydride compound is 
employed. 
In the case where a boron hydride compound is used as a reducing agent, the 
reactivity thereof is so low that when the reduction reaction is carried 
out under mild conditions, the reactive group of the compound of the 
formula (3) must be an ester group, though the N-protecting group is not 
particularly restricted. Examples of the boron hydride compound to be used 
in the reaction include sodium borohydride, calcium borohydride, and 
lithium borohydride. The amount of the boron hydride compound to be used 
in carrying out the reaction may be 1 to 10 equivalents, preferably 2 to 4 
equivalents, based on the reaction substrate. The boron hydride compound 
may be added either as such in a solid state or in the form of a solution 
to the reaction system. Alternatively, the boron hydride compound may 
sometimes be formed in the reaction system and used for the reaction. In 
the case of sodium borohydride, the reaction is carried out using as a 
solvent a lower alcohol such as methanol, ethanol or propanol at a 
temperature of -20.degree. C. to the reflux temperature of the solvent, 
preferably 10.degree. to 40.degree. C. In the case of calcium borohydride, 
a solution of calcium chloride may sometimes be added to a solution of 
sodium borohydride to form, in the reaction system, calcium borohydride, 
which is then used for the reaction. The solvents of such solutions are 
preferably the same as the reaction solvent. The reaction solvent, though 
not particularly restricted, is usually a lower alcohol such as methanol, 
ethanol or propanol, which may be used in carrying out the reaction at a 
temperature of -20.degree. C. to room temperature, preferably -10.degree. 
to 10.degree. C. In the case of lithium borohydride, an ether such as 
diethyl ether or tetrahydrofuran may be used as a solvent wherein the 
reaction is carried out at a temperature of room temperature to the reflux 
temperature of the solvent, preferably the reflux temperature of the 
solvent, at which the reaction proceeds rapidly. After the completion of 
the reaction, customary post-treatments may be carried out to obtain the 
diol compound of the formula (2). 
In the case where an aluminum hydride compound is used as a reducing agent, 
the reactive group of the compound of the formula (3) may be any of the 
carboxyl and carboxylate groups, though usable examples of the 
N-protecting group is restricted to arylalkyl groups, alkoxyalkyl groups, 
aryl groups, arylsulfonyl groups, and the like, which are not reactive 
with the reducing agent. In this case, specific examples of the 
N-protecting group include methoxymethyl, benzyl and trityl groups. The 
amount of the reducing agent to be used in carrying out the reaction may 
be 1 to 10 equivalents, preferably 2 to 4 equivalents, based on the 
reaction substrate. 
Examples of the aluminum hydride compound include (a) dialkylaluminum 
hydride compounds with each alkyl group having 3 to 6 carbon atoms, such 
as diisobutylaluminum hydride; and (b) alkali metal aluminum hydride 
compounds such as lithium aluminum hydride and sodium aluminum hydride. In 
the case of the aluminum hydride compound, usable reaction solvents 
include ethers such as diethyl ether and tetrahydrofuran; aromatic 
hydrocarbons such as benzene and toluene; and saturated hydrocarbons such 
as pentane, hexane, and cyclohexane. In this case, the reaction may be 
carried out at a temperature of 0.degree. to 60.degree. C., preferably 
10.degree. to 40.degree. C. 
After the completion of the reaction, customary post-treatments may be 
carried out to obtain the diol compound of the formula (2). 
In the case of lithium aluminum hydride, an ether such as diethyl ether or 
tetrahydrofuran is usually used as the reaction solvent, wherein the 
reaction may be carried out at a temperature of -10.degree. C. to the 
reflux temperature of the solvent. In this case, the reaction is 
preferably carried out at a temperature of 0.degree. C. to room 
temperature (about 30.degree. C.) where the reactive group of the compound 
of the formula (3) is an ester group, and at a temperature of 10.degree. 
C. to the reflux temperature of the solvent where the reactive group of 
the compound of the formula (3) is a carboxyl group. After the completion 
of the reaction, customary post-treatments may be carried out to obtain 
the diol compound of the formula (2). 
Examples of the aforementioned sodium aluminum hydride compounds include 
bis(lower alkoxy or lower alkyl)aluminum hydrides such as sodium 
bis(2-methoxyethoxy)aluminum hydride and sodium diethylaluminum hydride. 
In the case where use is made of a sodium aluminum hydride compound, 
usable reaction solvents include ethers such as diethyl ether and 
tetrahydrofuran; and aromatic hydrocarbons such as benzene and toluene. In 
this case, the reaction may be carried out at a temperature of 0.degree. 
C. to the reflux temperature of the solvent. Somewhat like in the case of 
lithium aluminum hydride, the reaction is carried out preferably at around 
room temperature where the reactive group of the compound of the formula 
(3) is an ester group, and preferably at around the reflux temperature of 
the solvent (e.g., 60.degree. to 120.degree. C.) where the reactive group 
of the compound of the formula (3) is a carboxyl group. After the 
completion of the reaction, customary post-treatments may be carried out 
to obtain the diol compound of the formula (2). 
The oxidative cleavage reaction of the diol compound of the formula (2) 
thus obtained may be carried out according to a method wherein use is made 
of a periodic acid compound such as periodic acid or a salt thereof, or a 
method wherein use is made of lead tetraacetate. The method wherein use is 
made of a periodic acid compound is preferred from the viewpoint of waste 
disposal, little formation of by-product(s), etc. Further preferred is a 
method wherein use is made of a salt of periodic acid, according to which 
the reaction can be carried out under such neutral conditions as not to 
cause epimerization, etc. 
Preferred examples of the salt of periodic acid that may be used in the 
reaction include alkali metal periodares such as sodium periodate and 
potassium periodate. The amount of the salt of periodic acid that may be 
used in the reaction may be 1 to 5 equivalents, preferably 1 to 3 
equivalents. The reaction may be carried out in a solvent mixture mainly 
composed of water and an organic solvent. Examples of the organic solvent, 
though not particularly restricted so long as they can dissolve the 
reaction substrate, include lower alcohols such as methanol, ethanol, and 
propanol; ethers such as diethyl ether and tetrahydrofuran; aliphatic 
hydrocarbons such as pentane, hexane, and heptane; lower alkyl halides 
with each alkyl having 1 to 5 carbon atoms, such as methylene chloride and 
chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; 
and petroleum ether. The reaction temperature may be about -10.degree. C. 
to around room temperature, preferably -10.degree. to 10.degree. C. at 
which no side reactions occur. The reaction is preferably carried out 
under such neutral conditions as not to cause epimerization, etc. After 
the completion of the reaction, water may further be added to the reaction 
mixture to dissolve therein inorganic salts, followed by operations of 
extraction with an extractant, washing, drying and distilling off the 
extractant to obtain the 2-aminopropanal of the formula (1). 
Examples of the ester compound of the formula (3) that may be used as the 
starting material in the present invention are as follows: 
(1) isopropyl 
(2R,3S)-3-(N-benzyloxycarbonyl)-amino-4-cyclohexyl-2-hydroxybutyrate; 
(2) ethyl (2R,3S)-3-(N-benzoyl)-amino-4-phenyl-2-hydroxybutyrate; and 
(3) isopropyl 
(2R,3S)-3-(N-butoxycarbonyl)-amino-4-cyclohexyl-2-hydroxybutyrate. 
The compound of the formula (3) is obtained according to the method 
disclosed in Japanese Patent Publication No. 21,466/1986 or a similar 
method by catalytic reduction of an N-protected 
threo-3-amino-2-hydroxy-4-oxo-4-hydrocarbyl (having 3 to 6 carbon atoms, 
such as phenyl or cyclohexyl)butyric acid or ester in the presence of a 
catalyst such as a palladium catalyst or a Raney nickel catalyst, removal 
of the amino-protecting group if necessary, and subsequent optical 
resolution of the resulting product. Alternatively, the compound (3) is 
obtained by introducing an amino-protecting group into a 
2(R)-hydroxy-3-(S)-amino-4-hydrocarbylbutyric acid or ester disclosed in 
Japanese Patent Laid-Open No. 183,551/1988. 
Examples of the diol compound of the formula (2) to be used in the present 
invention are as follows: 
(1) (2R,3S)-3-(N-benzyloxycarbonyl)-amino-4-cyclohexyl-1,2-butanediol; 
(2) (2R,3S)-3-(N-benzoyl)-amino-4-phenyl-1,2-butanediol; and 
(3) (2R,3S)-3-(N-butoxycarbonyl)-amino-4-cyclohexyl-1,2-butanediol. 
Examples of the 2-aminopropanal compound of the formula (1) to be obtained 
according to the present invention are as follows: 
(1) 2S-(N-benzyloxycarbonyl)-cyclohexylalaninal; 
(2) 2S-(N-benzoyl)-phenylalaninal; and 
(3) 2S-(N-butoxycarbonyl)-cyclohexylalaninal. 
The following Examples will specifically illustrate the present invention, 
but should not be construed as limiting the scope of the invention.