PROCEDE D'OBTENTION D'ESTERS D'ACIDES HYDROXYCARBOXYLIQUES OPTIQUEMENT ACTIFS

PROCESS FOR PRODUCING OPTICALLY ACTIVE .alpha.- HYDROXYCARBOXYLIC ACID ESTER

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
An optically active .alpha.-hydroxycarboxylic acid ester is
produced by asymmetric hydrogenation of an .alpha.-ketocarboxylic acid
ester in the presence of a rhodium complex having a phosphine
ligand having an optically active substituent group which present
is derived from natural sources.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing an optically active .alpha.-
hydroxy-carboxylic acid ester which comprises the asymmetric
hydrogenation under a hydrogen pressure of 1 to 50 atmospheres
of an .alpha.-ketocarboxylic acid ester selected from a pyruvic
acid ester, a benzoylformic acid ester, an alkylglyoxylic acid
ester and an .alpha.-ketolactone in the presence of a rhodium complex
with a phosphine ligand having an optically active substituent
group which is derived from natural sources, the phosphine
being selected from a dioxolan having optically active positions
at least at 2- and 3-positions which has the formula
<IMG>
wherein the asterisk (*) represents an optically active position;
R1 to R4 respectively represent an alkyl or aryl group; and R5
and R6 respectively represent hydrogen atom, an alkyl, aryl,
alkoxy, amino, carbonyl, carboxyl, ester, cyano, alkylthio or
arylthio group, and a pyrrolidine having optically active
positions at least at 2- and 3-positions which has the formula
<IMG>
wherein the asterisk (*) represents an optically active position;
R1' to R4' respectively represent alkyl or aryl group; R5' and R6'
respectively represent hydrogen atom or an alkyl or aryl group;
R7' represents hydrogen atom or an alkyl, aryl, ester, amino,
carboxyl or cyano group.

2. A process as claimed in claim 1, in which the
dioxolan is selected from (2R, 3R)-2,3-0-3R)-2,3-0-isoropylidene-2,3-
dihydroxy-1-4-bis(diphenylphosphino) butane and (2S, 3S)-2,3-0-
isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butane;
(2R, 3R) or (2S, 3S)-2,3-0-isopropylidene-2,3-dihydroxy-1,4-bis
(dibenzophosphoryl butane; (2R, 3R) or (2S, 3S)-2,3-0-isopropyli-
dene-2,3-dihydroxy-1,4-bis(di-o-tolylphosphino) butane; (2R, 3R)
or (2S, 3S)-2,3-0-isopropylidene-2,3-dihydroxy-1,4-bis(di-m-tolyl-
phosphino) butane; (2R, 3R) or (2S, 3S)-2,3-0-isopropylidene-2,3-
dihydroxy-1,4-bis(di-2,5-xylylphosphino) butane; (2R, 3R) or
(2S, 3S)-2,3-0-benzylidene-2,3-dihydroxy-1,4-bis(diphenylphos-
phino) butane; (2R, 3R) or (2S, 3S)-2,3-0-cyclohexylidene-2,3-
dihydroxy-1,4-bis(diphenylphosphino) butane; (2R, 3R) or (2S, 3S)-
2,3-0-cyclopentylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)
butane; and (2R, 3R) or (2S, 3S)-2,3-0-cyclohexylidene-2,3-di-
hydroxy-1,4-bis(cyclohexylphenylphosphino) butane.
3. A process as claimed in claim 1, in which the
pyrrolidine is selected from (2S, 4S)-N-t-butoxycarbonyl-4-diphenyl-
phosphino-2-diphenylphosphinomethyl pyrrolidine; (2S, 4S)-N-
methoxycarbonyl-4-diphenylphosphinomethyl pyrrolidine; and
(2S, 4S)-4-diphenylphosphino-2-diphenylphosphinomethyl pyrroli-
dine.
4. A process as claimed in claim 1, 2 or 3 in which
the .alpha.-ketocarboxylic acid ester is selected from methyl pyruvate
and propyl pyruvate, ethyl phenyl glyoxylate, cyclohexyl gly-
oxylate methyl pentylglyoxylate, ethyl octylglyoxylate; and .alpha.-
keto-.beta.,.beta.-dimethyl-?-butyrolcatone.
5. A process according to claim 1 wherein the.
reaction is carried out by dissolving the .alpha.-ketocarboxylic acid
ester in a solvent.
6. A process according to claim 5, wherein the solvent
is an aromatic hydrocarbon, an alcohol, an ether or a mixture
thereof.
11

7. A process according to claim 1, 2 or 3 wherein the
.alpha.-ketocarboxylic acid ester is a pyruvic acid ester, to obtain an
optically active lactic acid ester.
8. A process according to claim 1, 2 or 3 wherein the
.alpha.-ketocarboxylic acid ester is .alpha.-keto-.beta.,.beta.-dimethyl-?-butyrolactone
to obtain an optically active pantoyl lactone.
12

Description

The present invention relates to a process for pro-
ducing an optically active ~-hydroxycarboxylic acid ester. More
particularly, it relates to a process for producing an optically
active ~-hydroxycarboxylic acid ester by asymmetric hydrogenation
of an ~-ketocarboxylic acid ester in the presence of a rhodium
complex having a phosphine ligand having an optically active
substituent group which is derived from natural sources.
The optically active ~-hydroxycarboxylic acid esters
are physiologically active compounds in natural materials such
as lactic acid esters, mandelic acid ester and pantoyl lactones.
It is well-known that optically active D-(-)-pantoyl
lactone is an important intermediate for producing pantothenic
acid, pantetheine and Coenzyme A. Calcium pantothenate has been
produced on an industrial scale as one of the vitamins. Panto-
thenic acid is a component of Coenzyme A and has coenzymatic
activity. Pantothenyl alcohol and pantothenyl ethyl ether as
the derivatives of pantothenic acid have been produced in an
industrial scale. Calcium pantothenate can be produced by
reacting pantolactone with calcium salt of ~-alanine without a
racemization (E.H. Wilson, J. Weijlard and M. Tishler, J. Amer.
Chem. Soc., 76 5177 (1954) ). In the production, it is impor-
tant to consider how to produce D-(-)-pantoyl lactone. In the
production of pantetheine, pantothenyl alcohol and pantothenyl
ethyl ether, it is also important to consider the same problem.
The products of the present invention are important as inter-
mediates for the synthesis of amino acids and derivatives thereof.
It is known to produce the optically active ~-hydroxy-
carboxylic acid ester from an ~-ketocarboxylic acid ester by the
hydrogenation in the presence of a catalyst, as follows.
1) A method of hydrogenation of an optically active
~-ketocarboxylic acid ester in the presence of a catalyst
(A. McKenzie, J. Chem. Soc., 87, 1373 (1905); Mitsui and Kanai J.

4~79
Japanese Chem. Soc., _, 179 (1966).
2. A method of asymmetric hydrogenation in the pre-
sence of a rhodium complex having an optically active phosphine
ligands having ferrocenyl group (Mise, Hayashi and Kumada Chem.
Soc. Japan, 35th Annual Meeting Abstract lK-20 (1976)).
However, in the method 1), an equivalent amount or more
of the optically active compound is required as the starting
material in the asymmetric synthesis whereas in the present
invention only a catalytic amount of the optically active com-
pound is used to obtain the desired compound. Accordingly, themethod 1) is disadvantageous.
In method 2) the optically active phosphine is a com-
pound having complicated structure and metal component, which
is not easily produced because the synthesis includes an optical
resolution and the optical yield is low.
Heretofore, D-(-)-pantoyl lactone has been produced
by optical resolution of pantonyl lactone in racemic form with
e.g. quinine and ephedrine. In accordance with the method,
only maximum 50% of the yield can be obtained. Since L-(+)-
pantonyl lactone has no physiological activity, it must be
~ converted to pantonyl lactone in racemic form by severeracemization otherwise it is wasted.
The present invention provides an indusLrial process
for obtaining an optically active ~-hydroxycarboxylic acid este
having high optical purity at high yield.
The present invention to produce an optically active
~ -hydroxycarboxylic acid ester by using a complex having
optically active ligands which is derived from natural sources
and have high optical purity and easily obtained as ligand of the
catalyst.
According to the present invention there is provided a
process for producing an optically active ~-hydroxycarboxylic
- 2 -

7~
acid ester which comprises asymmetric hydrogenation at a
hydrogen pressure of 1 to 50 atmospheres of an ~-keto-
- 2a -

1~9~7~
-arboxylic acid ester in the presence of a rhodlum complex with
a phosphine ligand having an optically active substituent group
which is derived from natural sources.
Suitable ~-ketocarboxylic acid ester for use in the
process of the present invention include pyruvic acid esters
such as methyl pyruvate and n-propyl pyruvate; benzoylformic acid
esters such as ethyl phenylglyoxylate and cyclohexyl phenylgly-
oxylate; alkyl chain type ~-ketocarboxylic acid esters such as
methyl pentylglyoxylate and ethyl octylglyoxylate; and c~-ketolac-
tones such as ~-keto-R,~-dimethyl-~-butyrolactone.
The catalyst for use in the process of the present
invention is rhodium complex with a phosphine ligand having an
optically active substituent group which is derived from a natur- -
al source. The phosphines having an optically active substituent
group which is derived from a natural source can be dioxolans
having the formula
R5 / PR R
~ ~ 3 4
R6 O -- PR R
wherein the asterisk (*) represents an optically active position
and Rl to R4 respectively represent an alkyl or aryl group and
R5 and R6 represent hydrogen atom, an alkyl, aryl, alkoxy,
aminocarbonyl, carboxyl, ester, cyano alkylthio or arylthio
group, or pyrrolidines having the formula
Rl R2 P - ~ ~ R6 ...................... (II)
7'
R
wherein the asterisk (*) represents an optically active position
and R to R respectively represent an alkyl or aryl group;
R5 and R6 respectively represent hydrogen atom or an alkyl or

l7~
aryl group; R represents hydrogen atom or an alkyl, aryl, ester,
amino, carboxyl or cyano group.
Suitable dioxolans having the formula (I) include
(2R, 3R)-2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphos-
phino) butane and (2S, 3S)-2,3-O-isopropylidene-2,3-dihydroxy-1,
4-bis(diphenylphosphino) butane; (2R, 3R) or (2S, 3S)-2,3-O-iso-
propylidene-2,3-dihydroxy-1,4-bis-(dibenzophosphoryl) butane;
(2R, 3R) or (2S, 3S)-2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis
(di-o-tolylphosphino) butane; (2R, 3R) or (2S, 3S)-2,3-O-isopro-
pylidene-2,3-dihydroxy-1,4-bis(di-m-tolylphosphino) butane;
(2R, 3R) or (2S, 3S)-2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis
(di-2,5-xylylphosphino) butane; (2R, 3R) or (2S, 3S)-2,3-O-
benzylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butane;
(2R, 3R) or (2S, 3S)-2,3-O-cyclohexylidene-2,3-dihydroxy-1,4-
bis(diphenylphosphino) butane; (2R, 3R) or (2S, 3S)-2,3-O-
cyclopentylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino) butane;
and (2R, 3R) or (2S, 3S)-2,3-O-cyclohexylidene-2,3-dihydroxy-
1,4-bis(cyclohexylphenylphosphino) butane.
Suitable pyrrolidines having the formula (II) include
(2S, 4S)-N-t-butoxycarbonyl-4-diphenylphosphino-2-diphenylphos-
phino-methyl pyrrolidine; (2S, 4S)-N-methoxycarbonyl-4-diphenyl-
phosphino-2-diphenylphosphino-methyl pyrrodine; and (2S, 4S)-4-
diphenylphosphino-2-diphenylphosphino-methyl pyrrolidine.
In the process of the presentiinvention, it is prefer-
able to use a solvent. Suitable solvents include aromatic
hydrocarbons such as benzene, toluene and xylene; alcohols such
as methanol and ethanol; ethers such as tetrahydrofuran, mono-
glyme and mixtures thereof.
In the process of the present invention, the starting
material of ~-ketocarboxylic acid ester is dissolved in a solvent
and the rhodium complex catalyst is added at a catalytic amount
of 0.01 to 1.0 mole % and the reaction is carried out in hydrogen
- 4 -

under atmos~)heric r)ressure or hi(lher pressure. The reac~ion is
;moothly performed at room temperature without using the special
heating or coolin~ means and the product can ~e obtained at sub- -
stantially stoichiometric yield. Tn order to reduce the reaction
time, it is preferable to perform the reaction under higher
pressure such as several to several -tens atms, and at higher
temperatures.
The present invention will be further illustrated by
the following Examples.
EX~MPLE 1:
Under argon atmosphere, 38 mg of [Rh(1,5-cyclooctadiene)
CQ]2 and 100 mg of (2S, 4S)-N-butoxycarbonyl-4-diphenylphosphino
-2-diphenylphosphinomethyl pyrrolidine (hereinafter referring to
as BPPM) were dissolved in 8 ml of tetrahydrofuran to prepare a
solution of the catalyst.
In an autoclave, the solution of the catalyst and 3.90
g of n-propyl pyruvate were charged and the reaction was carried
out under hydrogen at a pressure of 20 atm. at 20C for 24 hours
with stirring to complete the reaction. The solvent was distilled
off from the reaction mixture and the product was distilled to
obtain 3.76 g of n-propyl (+)- lactate having a boiling point of
62C/ll mmllg, [(~]D + 9.17 (neat) and an optical purity of 76%
(yield: 95%).
EXAMPLES 2 to 15:
In accordance with the process of Example 1 except
various ~-ketocarboxylic acid esters, optically active ligands
and solvents, the optically active ~-hydroxycarboxylic acid esters t
were produced. The results are shown in Table 1.
In Table 1, the optically active ligand (-)-DIOP means
(2R, 3R)-2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis (diphenyl-
phosphino) butane and (+)- DIOP means (2S, 3S)-2,3-O-isopropyli-
dene-2,3-dihydroxy-1,4-bis (diphenylphosphino) butane.

11~947~
EXAMPL~ 16:
In accordance with the process of Example 1, 19 mg of
[Rh(1,5-cyclooctadiene) CQ]2 and 50 mg of an optically active
ligand of BPPM were dissolved in 4 ml of tetrahydrofuran to pre-
pare a solution of the catalyst.
In an autoclave, the solution of the catalyst and 1.92 g of ~-
keto-R,~-dimethyl-~-butyrolactone were charged and the reaction
was carried out under hydrogen of 50 atm. at 20C for 24 hours
with stirring to complete the reaction.
The solvent was distilled off from the reaction mixture and the
product was purified by passing through a short silica gel chroma-
tography column using n-hexane-ether as elute to obtain 1.89 g of
(-)-pantoyl lactone having a melting point of 89 to 91C and
[~]D5 -25.3 (C.2.00; H2O) and an optical activity of 50%
(yield: 97%).
; EXAMPLES 17 and 18:
In accordance with the process of Example 16 except
using various optically active ligands and solvents, the optically
active (-)-pantoyl lactone was produced. The results are also
shown in Table 1.
Note: BPPM, (-)-DIOP,(+)-DIOP are defined above.
PhH: benzene
THF: tetrahydrofuran
MeOfl: methanol
Monoglyme: 1,2-dimethoxyethane
EXAMPLE 19:
In accordance with the process of Example 16, 24.2 mg
of [Rh(1,5-cyclooctadiene CQ]2 and 60.2 mg of BPPM were dissolved
in 8 ml of benzene to prepare the solution of the catalyst. In
an autoclave, the solution of the catalyst and 1.28 g of ~-keto-
~,~-dimethyl-~-butyrolactone were charged and the reaction was r
carried out under initial hydrogen pressure of 50 atm at 30C for

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48 hours with st:irring in a thermostat-tcmperature-controlled
bath. The reaction was completed at a conversion of 100%. The
solvent ancl the catalyst were separated as the process of
Example 16 to obtain 1.28 g of (-)-pantoyl lactone having
[~]D -42.5 (C.2.046-H20) and an optical purity of 83.9%
(yield: 98.4~).
EXAMPLE 20:
In accordance with the process of Example 19 except
varying the reaction temperature to 40C and the initial hydrogen
pressure to 20 atm the reaction was carried out and the reaction
mixture was distilled under a reduced pressure without separating
the catalyst to obtain 1.20 g of (-) pantoyl lactone having a
boiling point of 92C/4 mmllg a melting point of 89 to 91C, [~]D
-43.3 (C.2.033:H20) and an optical purity of 85.4% (yield: 92.3%).
EXAMPLE 21:
In accordance with the process of Example 19 except
varying the reaction temperature to 50C, the reaction and the
separation were carried out to obtain 1.23 g of (-) pantoyl
lactone having [~]25 _43.0o (C. 2.042 : ~12) and an optical purity
of 84.8% (yield: 94.6%).
EX~MPLE 22:
In accordance with the process of Example 20 except
varying the reaction temperature to 70C, the reaction and the
separation were carried out to obtain 1.18 g of (-) pantoyl lac-
tone having [~]D5 -39.1 (C. 2.128 : H2O) and an optical purity
of 77.1% (yield: 90.7%).
EXAMPLE 23:
In accordance with the process of Example 21 except
using 8 ml of toluene as the solvent; the reaction and the separ-
ation were carried out to obtain 1.25 g of (-) pantoyl lactone
having [~]D5 ~39 4 (C. 2.032 : 112O) and an optical purity of
77.7~ (yield: 96.2%).
g