Process for preparing asymmetric compound by using metal complex

A process for producing an asymmetric compound using a metal complex containing no rare earth metal element is disclosed. The process affords an optically active compound having high optical purity. Optically active binaphthol having the chemical formula ##STR1## and lithium aluminum hydride are reacted, or the optically active binaphthol, a dialkyl aluminum hydride, and a base containing an alkali metal (or a base containing alkaline earth metal) are reacted to prepare a metal complex comprising optically active binaphthol, aluminum, and alkali metal (or alkaline earth metal). This metal complex can be used as a catalyst to perform an asymmetric Michael reaction, an asymmetric phosphonylation reaction, or the like, to obtain, in a high yield, an asymmetric compound having high optical purity.

FIELD OF THE INVENTION 
The present invention relates to a metal complex which can be used in the 
preparation of an asymmetric compound useful in the fields of medicines, 
agricultural chemicals, perfumes, liquid crystals, and the like. More 
particularly, it relates to a metal complex by which an optically active 
reaction product having high optical purity can be obtained in high yield 
when it is used as a catalyst for asymmetric Michael addition reaction, 
asymmetric hydrophosphonylation reaction, or the like, as well as a 
process for producing an asymmetric compound using a solution of the metal 
complex. 
BACKGROUND OF THE INVENTION 
The present inventors previously studied an asymmetric synthesis reaction 
using a metal complex catalyst of a rare earth metal element and, as a 
result, found that a metal complex prepared by a method of mixing 
lanthanum chloride (LaCl.sub.3) and optically active dilithium 
binaphthoxide in tetrahydrofuran and adding water and sodium hydroxide 
thereto, or by a method of successively adding optically active 
binaphthol, water, and lithium chloride to a solution of La.sub.3 
(O-tC.sub.4 H.sub.9).sub.9 (lanthanum t-butoxide) in tetrahydrofuran 
containing sodium tert-butoxide, can catalyze an asymmetric nitroaldol 
reaction to afford a nitroaldol product having high optical purity (J. Am. 
Chem. Soc., Vol. 114, p. 4418 (1992)). 
In addition, the present inventors revealed that a complex prepared by 
adding 1 mole equivalent of optically active binaphthol to La(O-iC.sub.3 
H.sub.7).sub.3 (lanthanum isopropoxide) can catalyze an asymmetric Michael 
reaction to afford a Michael adduct having high optical purity (J. Synth. 
Org. Chem., Jpn., Vol. 51, p. 972 (1993); J. Am. Chem. Soc., Vol. 116, p. 
1571 (1994)). 
Further, the present inventors found that a metal complex, i.e., 
La--K-Binol (LPB), can act as an effective catalyst in 
imine-hydrophosphonylating reaction to afford a hydrophosphonyl compound 
having high optical purity (J. Org. Chem., Vol. 60, p. 6656 (1995)). 
In addition, it was found that a metal complex, La--Li-Binol (LnLB), can 
act as an effective catalyst in an aldehyde-hydrophosphonylating reaction 
to afford an asymmetric hydrophosphonylated compound (Tetrahedron: 
Asymmetry, Vol. 4, p. 1783 (1993); Tetrahedron Lett., Vol. 35, p. 227 
(1994)). 
However, lanthanum, which is a rare earth metal element contained in the 
aforementioned metal complexes, is difficult to obtain and, thus, the 
development of metal complex catalysts without using a rare earth metal is 
desired. However, such metal complex catalysts are not yet known. 
On the other hand, an asymmetric Michael reaction product and an asymmetric 
.alpha.-hydrophosphonylated compound are both known as useful asymmetric 
compound reaction products. Particularly, a hydroxy phosphorylated 
compound has potent bioactivity and is expected to act effectively as an 
enzyme inhibitor for a synthesis enzyme such as renin, EPSP synthase, HIV 
protease, and the like and, thus, the development of an optically 
selective process for synthesizing these asymmetric phosphorylated 
compounds is desired. However, even when the above metal complex, 
Ln--Li-Binol (LnLB), is used in this application, either optical purity or 
yield of the resulting phosphorylated compound is not satisfactory. In 
addition, a reaction at an extremely low temperature is inevitably 
required. Thus, the above application has suffered many unsolved problems 
as an industrial process for preparing the above compounds. 
SUMMARY OF THE INVENTION 
The present invention provides a metal complex, or a solution of the metal 
complex, that can be used as a catalyst in an asymmetric Michael reaction 
and in an asymmetric hydrophosphonylation reaction, contains no rare earth 
metal element, and can afford an optically active compound having high 
optical purity at high yield. The present invention also provides a 
process for producing an asymmetric compound by an asymmetric Michael 
reaction and an asymmetric hydrophosphonylation reaction using such the 
metal complex. 
The present inventors further studied an asymmetric synthesis catalyst 
using optically active binaphthol and a derivative thereof and found that, 
although the chemical structure is not clear, a metal complex prepared 
using an aluminum compound, without using a rare earth metal compound, 
acts as an extremely effective catalyst in the asymmetric Michael reaction 
and the asymmetric hydrophosphonylation reaction, and produces, at high 
yield, a Michael adduct and an asymmetric hydrophosphonylated compound 
having high optical purity. 
That is, a metal complex of the present invention is characterized by the 
fact that it can be obtained by reacting optically active binaphthol, or a 
derivative thereof, with an alkali metal aluminum hydride or an alkali 
metal aluminum hydride compound. 
In addition, a metal complex of the present invention is characterized by 
the fact that it can be obtained by reacting optically active binaphthol, 
or a derivative thereof, with dialkylaluminum hydride, and a base 
containing an alkali metal or a base containing an alkaline earth metal. 
As the optically active binaphthol or derivative thereof that can be used 
for preparing a metal complex of the present invention, a compound 
represented by the following general formula 1 can be used: 
Chemical formula 1 
##STR2## 
wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are, independently, a group 
selected from the group consisting of a hydrogen atom, a lower alkyl 
group, a lower alkoxy group, halogen, cyano, and nitro. R.sub.1 to R.sub.4 
can be the same or different from each other. 
As the alkali metal aluminum hydride that can be used in preparation of a 
metal complex of the present invention, lithium aluminum hydride is a 
typical example. In addition, as the alkali metal aluminum hydride 
compound which can be used in preparation of a metal complex of the 
present invention, a compound that can be easily obtained, such as 
sodium-bis(methoxyethoxy) aluminum hydride, diisobutylaluminum hydride, 
and the like can be used. A preferable molar ratio of the optically active 
binaphthol or a derivative thereof and the alkali metal aluminum hydride 
in the preparation of a metal complex is in a range of 1-4:1, preferably 
1.5-2.5:1, and more preferably 2:1. 
As the dialkylaluminum hydride that can be used in the preparation of a 
metal complex of the present invention, there are diethylaluminum hydride, 
diisopropylaluminum hydride, diisobutylaluminum hydride, and the like. 
From among them, diisobutylaluminum hydride is preferably used. 
In addition, as the base containing an alkali metal, there are sodium 
methylate, sodium ethylate, sodium isopropoxide, sodium tert-butoxide, 
lithium hydride, potassium hydride, sodium borohydride, lithium 
tert-butoxide, butyllithium, and the like. From among them, sodium 
tert-butoxide is preferably used. As the base containing an alkaline earth 
metal, barium tert-butoxide and the like can be used. An equivalent ratio 
of the optically active binaphthol or a derivative thereof, the 
dialkylaluminum hydride, and the base containing an alkali metal or an 
alkaline earth metal is 1-4:0.5-2:1. The use at an equivalent ratio of 
1.5-2.5:0.5-1.5:1 is preferable and the use at an equivalent ratio of 
2:1:1 is more preferable. 
In addition, various organic solvents can be used in the preparation of the 
above metal complex. Particularly, ethereal solvents are preferable. From 
among them, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 
dioxane, and mixtures thereof are particularly preferable, although 
solvents such as toluene, hexane, heptane, and the like can be used. An 
organic solution, in which a metal complex is prepared, can be used as 
such for synthesizing an asymmetric compound without isolation of the 
metal complex therefrom. 
The metal complex of the present invention, or a solution thereof, can be 
suitably used in an asymmetric Michael reaction and is particularly useful 
in a reaction of cyclopentenone or cyclohexenone with a malonic diester or 
an alkylmalonic diester. 
Further, in asymmetric Michael reaction using the metal complex of the 
present invention or a solution thereof, an optically active compound 
having the following general formula 2 can be obtained by adding an 
aliphatic or an aromatic aldehyde thereto. 
Chemical formula 2 
##STR3## 
In the above formula, R.sub.1 is a residue of an aliphatic compound or an 
aromatic compound, R.sub.2 is hydrogen or an alkyl group, and R.sub.3 is 
an alkyl group or an aralkyl group. 
The metal complex of the present invention, or a solution thereof, can be 
suitably used in an asymmetric hydrophosphonylation reaction. A reaction 
solvent for performing this asymmetric hydrophosphonylation reaction is 
not limited to specified solvents, and preferably is benzene, toluene, or 
xylene. 
The process for producing an asymmetric hydrophosphonylated compound of the 
present invention can be suitably used to obtain an asymmetric 
hydrophosphonylated compound shown by the following general formula 5 by 
reacting an aldehyde shown by the following general formula 3 with a 
phosphonic diester compound shown by the following general formula 4. 
Chemical formula 3 
##STR4## 
Chemical formula 4 
##STR5## 
Chemical formula 5 
##STR6## 
In the chemical formulas 3 to 5, R.sub.1 is a hydrogen atom, a halogen 
atom, an alkyl group having 1-4 carbon atoms, an alkoxy group having 1-4 
carbon atoms, a nitro group, an amino group, an alkylamino group, or a 
dialkylamino group, and R.sub.2 is an alkyl group having 1-8 carbon atoms, 
an arylalkyl group, or a silylalkyl group. The symbol * represents an 
asymmetric carbon atom. 
In addition, the process for producing an asymmetric hydrophosphonyl 
compound of the present invention can be suitably used to obtain an 
asymmetric hydrophosphonyl compound shown by the following general formula 
8 by reacting an aldehyde shown by the following general formula 6 with a 
phosphonic diester compound shown by the following general formula 7. 
Chemical formula 6 
##STR7## 
Chemical formula 7 
##STR8## 
Chemical formula 8 
##STR9## 
In the chemical formulas 6 to 8, R.sub.3, R.sub.4, and R.sub.5 are, 
independently, a hydrogen atom, a phenyl group, a lower alkyl-substituted 
phenyl group, a lower alkoxy-substituted phenyl group, or an alkyl group 
or an alkoxy group each having 1-8 carbon atoms, or R.sub.3 and R.sub.4, 
or R.sub.4 and R.sub.5, can form a ring. In addition, R.sub.6 is an alkyl 
group having 1-8 carbon atoms, an arylalkyl group, or a silylalkyl group, 
and the symbol * represents an asymmetric carbon atom. 
Further, the process for producing an asymmetric hydrophosphonyl compound 
of the present invention can be suitably used to obtain an asymmetric 
hydrophosphonyl compound shown by the following general formula 11 by 
reacting an aldehyde shown by the following general formula 9 with a 
phosphonic diester compound shown by the following general formula 10. 
Chemical formula 9 
EQU R.sub.1 --CHO 
Chemical formula 10 
##STR10## 
Chemical formula 11 
##STR11## 
In the chemical formulas 9 to 11, R.sub.1 is a linear or branched alkyl 
group having 1-8 carbon atoms, or a cyclic alkyl group having 3-10 carbon 
atoms. In addition, R.sub.2 is an alkyl group having 1-8 carbon atoms, an 
arylalkyl group, or a silylalkyl group, and the symbol * represents an 
asymmetric carbon atom. 
In the present invention, the asymmetric hydrophosphonylation reaction can 
be carried out at the temperature of -70.degree. C. to 45.degree. C. 
However, from a viewpoint of optical purity, the reaction temperature 
preferably is -20.degree. C. to -60.degree. C., more preferably 
-30.degree. C. to -45.degree. C., and most preferably -40.degree. C. 
In the asymmetric hydrophosphonylation reaction of the present invention, 
various organic solvents can be used. From among them, aromatic 
hydrocarbons such as xylene, toluene, benzene, and mixtures thereof are 
particularly preferable. However, aliphatic hydrocarbons, such as hexane, 
heptane, and the like, ether compounds, such as tetrahydrofuran, diethyl 
ether, methyl tert-butyl ether, dioxane, and the like can be used. 
PREFERRED EMBODIMENTS OF THE PRESENT INVENTION 
The following Examples illustrate a process for preparing a metal complex 
of the present invention, and a process for producing an asymmetric 
compound by an asymmetric Michael reaction and an asymmetric 
hydrophosphonylation reaction using the metal complex as a catalyst, but 
the present invention is not limited by these disclosures.

EXAMPLE 1 
Preparation of Al--Li--(R)-binaphthol complex 
Lithium aluminum hydride (114 mg, 3.0 mmol) was dissolved in anhydrous 
tetrahydrofuran (15 ml) under an argon atmosphere. To this solution was 
added, dropwise, a solution of (R)-binaphthol in anhydrous tetrahydrofuran 
(1.72 g, 6.0 mmol/THF 15 ml) at 0.degree. C., which was stirred at room 
temperature for 12 hours. The supernatant was used as a solution of 
Al--Li--(R)-binaphthol complex in tetrahydrofuran (0.1M). 
EXAMPLE 2 
Preparation of Al--Na--(R)-binaphthol complex 
To a solution of (R)-binaphthol in anhydrous tetrahydrofuran (0.1M, 2.0 ml) 
was added, dropwise, a solution of diisobutylaluminium hydride in 
tetrahydrofuran (1.0M, 0.1 ml) at 0.degree. C., which was stirred for 15 
minutes. Thereafter, a solution of sodium tertiary butoxide in 
tetrahydrofuran (0.8M, 0.12 ml) was added thereto, which was stirred at 
room temperature for another 30 minutes to obtain a solution of 
Al--Na--(R)-binaphthol complex in tetrahydrofuran. 
EXAMPLE 3 
Preparation of Al--Ba--(R)-binaphthol complex 
To a solution of (R)-binaphthol in anhydrous tetrahydrofuran (0.1M, 2.0 ml) 
was added a solution of diisobutylaluminum hydride in tetrahydrofuran 
(0.1M, 0.1 ml) at 0.degree. C., which was stirred for 15 minutes. 
Thereafter, a solution of barium dibenzyl malonate in tetrahydrofuran 
(1.0M, 0.1 ml), which had been prepared by prereacting 2 equivalents of 
dibenzyl malonate and barium tertiary butoxide (Ba(O-tC.sub.4 
H.sub.9).sub.2), was added thereto, which was stirred at room temperature 
for another 30 minutes to obtain a solution of Al--Ba--(R)-binaphthol 
complex in tetrahydrofuran. 
EXAMPLE 4 
Preparation of Al--Li--(R)-6,6'-dibromobinaphthol 
The same procedure as shown in Example 1 was used, except that 
(R)-6,6'-dibromobinaphthol (obtained from Kankyokagaku Center Co., Ltd.) 
was used in place of the (R)-binaphthol of Example 1 to afford 
Al--Li--(R)-6,6'-dibromobinaphthol. As Reference Example, a process for 
synthesizing (R)-6,6'-dibromobinaphthol is shown below. 
Reference Example 
Synthesis of (R)-6,6'-dibromobinaphthol 
(R)-binaphthol (750 mg, 2.6 mmol) was dissolved in 20 ml of methylene 
chloride, which was cooled to -78.degree. C. To this solution was added, 
dropwise, bromine (0.32 ml, 6.3 mmol), which was stirred at -78.degree. C. 
for 30 minutes and then at room temperature for 2 hours. After completion 
of the reaction, the reaction mixture was treated with sodium thiosulfate 
to obtain 6,6'-dibromobinaphthol (the following structural formula 12). 
Chemical formula 12 
##STR12## 
EXAMPLE 5 
Preparation of Al--Li--(R)-6,6'-dicyanobinaphthol 
Preparation of 6,6'-dicyanobinaphthol 
(1) The reaction was carried out according to the same procedure as shown 
in Example 4, except that the purification step after treatment with 
sodium thiosulfate was omitted, to obtain crude 6,6'-dibromobinaphthol 
which was used in the next step without further purification. 
(2) Crude 6,6'-dibromobinaphthol was dissolved in dimethylformamide (5 ml, 
abbreviated as DMF hereinafter). This solution was added to a suspension 
of sodium hydride (800 mg) in DMF (30 ml) under ice-cooling, which was 
stirred for 30 minutes. After methoxymethyl chloride (hereinafter 
abbreviated as MOMCl) (1.2 ml) was added thereto, the mixture was stirred 
at room temperature for 3 hours. The reaction solution was poured into 
water. The mixture was extracted with ethyl acetate, and the solvent was 
distilled off to obtain crude Br--MOM protected compound (the following 
structural formula 13). 
Chemical formula 13 
##STR13## 
(3) The crude Br--MOM protected compound obtained in the above step (2) was 
dissolved in benzene and azeotropic dehydration was carried out three 
times. Thereafter, the solution was dissolved in 30 ml of tetrahydrofuran 
(hereinafter abbreviated as THF), which was cooled to -78.degree. C. under 
argon atmosphere. Then, n-butyllithium (4.3 ml, 1.05 equivalents to the 
Br--MOM protected compound) was added thereto to stir for 1 hour. 
Thereafter, 500 .mu.l of dry DMF was added thereto to stir at room 
temperature for 5 hours. The reaction was poured into water, and the 
mixture was extracted with ethyl acetate, then the solvent was distilled 
off to obtain crude OHC--MOM protected compound (the following structural 
formula 14). 
Chemical formula 14 
##STR14## 
The results of an analysis of this compound are shown in Table 1. 
TABLE 1 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
3.19(s, 6H), 5.13(d, J=7.0Hz, 2H), 
(.delta.) 5.23(d, J=7.0Hz, 2H), 7.27 
(d, J=8.9Hz, 2H), 7.77 
(d, J=8.9Hz, 4H), 8.20 
(d, J=9.2Hz, 2H), 8.46(s, 2H), 10.20 
(s, 2H) 
______________________________________ 
(4) The crude OHC--MOM protected compound obtained in the above step (3) 
was dissolved in methyl alcohol (80 ml), then sodium bicarbonate (10 g) 
and hydroxylamine hydrochloride (4.1 g) were added thereto. After stirring 
at room temperature for 1 hour, a majority of methyl alcohol was distilled 
off, and the remainder was poured into water. The mixture was extracted 
with ethyl acetate, and the combined extracts were concentrated to obtain 
a crude dioxime-MOM protected compound (the following structural formula 
15). This compound was used in the next step without further purification. 
Chemical formula 15 
##STR15## 
The results of an analysis of this compound are shown in Table 2. 
##STR16## 
(5) The compound obtained in the above step (4) was suspended in 80 ml of 
methylene chloride, and 1,8-diazabicyclo5.4.0.!undec-7-ene (DBU) (3.2 ml) 
was added thereto to complete dissolution. To this solution was added 
p-toluenesulfonyl chloride (2.0 g) at room temperature. After stirring at 
room temperature for 30 minutes, the mixture was poured into water. The 
mixture was extracted with ethyl acetate. The combined extracts were 
washed with aqueous sodium carbonate solution, and concentrated. The 
residue was purified by column chromatography (flash chromatography on 
silica (SiO.sub.2)) to obtain dicyano-MOM protected compound (1.1 g (wet 
weight)) (the following structural formula 16). 
Chemical Formula 16 
##STR17## 
The results of an analysis of this compound are shown in Table 3. 
TABLE 3 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
3.12(s, 6H), 4.98(d, J=6.9Hz, 2H), 
(.delta.) 5.03(d, J=6.9Hz, 2H), 7.08 
(d, J=8.9Hz, 2H), 7.20 
(dd, J=1.7, 8.6Hz, 2H), 7.65 
(d, J=8.9Hz, 2H), 7.97 
(d, J=8.9Hz, 2H), 8.21(d, J=1.7Hz, 2H) 
______________________________________ 
(6) The dicyano-MOM protected compound obtained in the above step (5) was 
dissolved in a mixed solvent of THF (20 ml) and concentrated hydrochloric 
acid (15 ml). After stirring at room temperature for 2 hours. Completion 
of the reaction was confirmed by thin layer chromatography. The reaction 
solution was poured into water, and the mixture extracted with ethyl 
acetate. The combined extracts were concentrated. The residue was 
recrystallized from a mixed solvent of ethyl acetate/hexane (ethyl 
acetate:hexane=2:3 to 1:2) at room temperature to obtain 
(R)-6,6'-dicyanobinaphthol (500 mg). 
The overall yield based on the raw material binaphthol used was 51%. 
Recrystallization was carried out again with the above mother liquor to 
obtain further 160 mg (yield 16%), with a total yield of 660 mg of 
(R)-6,6'-dicyanobinaphthol (the following structural formula 17). The 
overall yield from (R)-binaphthol was 67%. 
Chemical formula 17 
##STR18## 
The results of an analysis of this compound are shown in Table 4. 
TABLE 4 
______________________________________ 
.sup.1 H NMR 7.13(d, J=8.0Hz, 2H), 7.46 
(CDCl.sub.3 +CD.sub.3 OD) 
(dd, J=1.7, 8.9Hz, 2H), 7.52 
(.delta.) (d, J=8.9Hz, 2H), 8.07 
(d, J=8.9Hz, 2H), 8.29 
(d, J=1.7Hz, 2H) 
Optical purity 99% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AD manufactured by 
Daicel Chemical Industries Co., 
Ltd., isopropanol/hexane = 1/9, 
detection: 254 nm, flow rate: 
1.0 ml/min. 
______________________________________ 
(7) Preparation of Al--Li--(R)-6,6'-dicyanobinaphthol was achieved using 
the same procedure as shown in Example 1, except that the 
(R)-6,6'-dicyanobinaphthol obtained in the above steps (1) to (6) was used 
in place of (R)-binaphthol in Example 1 to afforded 
Al--Li--(R)-6,6'-dicyanobinaphthol. 
EXAMPLE 6 
Asymmetric Michael reaction 
Cyclohexenone (96 mg, 1.0 mmol) and dibenzyl malonate (250 mg, 1.0 mmol) 
were added to a solution of Al--Li--(R)-binaphthol complex in 
tetrahydrofuran (0.1M, 1.0 ml), which was stirred at room temperature for 
48 hours to carry out an asymmetric Michael reaction shown by the 
following chemical formula 18. The reaction was stopped by adding 1N 
hydrochloric acid (HCl) aqueous solution (3 ml) to the reaction solution. 
The mixture was extracted with ethyl acetate (15 ml.times.three times) and 
the combined extracts were dried over sodium sulfate (Na.sub.2 SO.sub.4). 
The solvent was distilled off, and the residue was purified by flash 
column chromatography (acetone/hexane=1/10) using SiO.sub.2 to obtain the 
Michael reaction product of a final compound in a yield of 91%. 
Chemical formula 18 
##STR19## 
The results of an analysis of the reaction product in this Example are 
shown in Table 5. 
TABLE 5 
______________________________________ 
IR (KBr) 1740 cm.sup.-1, 1261 cm.sup.-1 
Melting point 43.degree. C. 
.sup.1 H NMR (CDCl.sub.3) 
1.46(dddd, J=3.0, 11.5, 11.5, 
(.delta.) -11.5Hz, 1H), 1.62(dddd, J=2.2, 2.4, 
-12.3, 12.3, 12.3Hz, 1H), 1.84-2.08 
(m, 2H), 2.12-2.64(m, 5H), 3.41 
(d, J=7.6Hz, 1H), 5.14(s, 2H), 5.16 
(s, 2H), 7.25-7.36(m, 10H) 
.sup.13 C NMR (CDCl.sub.3) 
24.4, 28.6, 38.0, 40.9, 45.0, 56.6, 
(.delta.) 67.2, 128.2, 128.4, 128.5, 135.0, 
167.4, 167.5, 209.3 
MS m/z 289(M.sup.+--Bn), 91(base peak) 
HRMS for C.sub.23 H.sub.24 O.sub.5 (M.sup.+ --Bn) 
cal'd C, 72.61; H, 6.36! 
measured C, 72.40; H, 6.13! 
.alpha.!.sub.p.sup.24 
+1.24.degree. (c 1.02, CHCl.sub.3) 
Optical purity 
98% e.e. HPLC analysis conditions: 
(HPLC analy- CHIRALPAK AS manufactured by Daicel 
sis) Chemical Industries Co., Ltd., iso- 
propanol/hexane = 1/9, detection: 
254 nm, flow rate: 1.0 ml/min. 
______________________________________ 
EXAMPLE 7 
Asymmetric Michael reaction 
According to the same reaction conditions and operations as used in Example 
6, cyclohexenone and diethyl malonate were subjected to the asymmetric 
Michael reaction to obtain the reaction product of the structural formula 
19 in a yield of 87%. 
Chemical formula 19 
##STR20## 
An analysis was carried out on this reaction product in same manner as in 
Example 6, the results are shown in Table 6. 
TABLE 6 
______________________________________ 
IR (KBr) 1731 cm.sup.-1, 1230 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
1.20(t, J=7.3Hz, 3H), 1.21(t, J= 
(.delta.) -7.3Hz, 3H), 1.44(dddd, J=3.2, 12.1, 
-12.1, 12.1Hz, 1H), 1.62(ddddd, 
J=3.2, 5.0, 12.1, 12.1, 12.1Hz, 1H), 
1.83-1.95(m.1H), 1.95-2.07(m, 1H), 
2.11-2.28(m, 2H), 2.28-2.54(m, 3H), 
3.23(d, J=7.9Hz, 1H), 4.13 
(q, J=7.3Hz, 2H), 4.14(q, J=7.3Hz, 2H) 
.sup.13 C NMR (CDCl.sub.3) 
14.0, 24.5, 28.7, 38.0, 40.9, 45.0, 
(.delta.) 56.8, 61.5, 167.7, 167.8, 209.6 
MS m/z 256(M.sup.+), 211(M.sup.+ --OMe), 97(base 
peak) 
HRMS for C.sub.13 H.sub.20 O.sub.5 
cal'd C, 60.92; H, 7.87! 
measured C, 60.64; H, 7.62! 
.alpha.!.sub.p.sup.24 
+3.33.degree.(c2.09, CHCl.sub.3) 
Optical purity 
95% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., iso- 
propanol/hexane = 1/9, detection: 
differential refraction, 254 nm, 
flow rate: 1.0 ml/min.) 
______________________________________ 
EXAMPLE 8 
Asymmetric Michael reaction 
According to the same reaction conditions and operations as used in Example 
6, cyclohexenone and dimethyl malonate were subjected to the asymmetric 
Michael reaction to obtain the reaction product of the structural formula 
20 in a yield of 90%. 
Chemical formula 20 
##STR21## 
The analysis was carried out on this reaction product in same manner as in 
Example 6, and the results are shown in Table 7. 
TABLE 7 
______________________________________ 
IR (neat) 1732 cm.sup.-1, 1259 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
1.46(dddd, J=2.6, 12.2, 12.2, 12.2Hz, 
(.delta.) -1H), 1.62(ddddd, J=2.6, 4.2, 12.2, 12.2, 
12.2Hz, 1H), 1.86-1.97(m, 1H), 1.98- 
2.11(m, 1H), 2.15-2.31(m, 2H), 2.31- 
2.59(m, 3H), 3.32(d, J=7.9Hz, 1H), 
3.71(s, 3H), 3.72(s.3H) 
.sup.13 C NMR (CDCl.sub.3) 
24.4, 28.7, 37.9, 38.0, 40.9, 45.0, 
(.delta.) 52.5, 56.5, 168.1, 168.2, 209.4 
MS m/z 228(M.sup.+), 197(M.sup.+ --OMe), 97(base 
peak) 
HRMS for C.sub.17 H.sub.16 O.sub.5 
cal'd C, 57.88; H, 7.07! 
measured C, 57.70; H, 7.01! 
.alpha.!.sub.p.sup.24 
+3.73.degree.(c1.00, CHCl.sub.3) 
Optical purity 
93% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., iso- 
propanol/hexane = 1/9, detection: 
differential refraction, flow rate: 
1.0 ml/min. 
______________________________________ 
EXAMPLE 9 
Asymmetric Michael reaction 
According to the same reaction conditions and operations as used in Example 
6, cyclopentenone and dibenzyl malonate were subjected to the asymmetric 
Michael reaction to obtain the reaction product of the structural formula 
21 in a yield of 93%. 
Chemical formula 21 
##STR22## 
The analysis was carried out on this reaction product in the same manner as 
in Example 6, and the results are obtained shown in Table 8. 
TABLE 8 
______________________________________ 
IR (neat) 1740 cm.sup.-1, 1211 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
1.51-1.72(m, 1H), 1.99(dd, J=11.2, 
(.delta.) -18.5Hz, 1H), 2.06-2.38(m ,3H), 2.45 
(dd, J=7.9, 18.5Hz, 1H), 2.78-2.97(m, 1H), 
3.45(d, J=9.6Hz, 1H), 5.14(s, 2H), 5.16 
(s, 2H), 7.25-7.37(m, 10H) 
.sup.13 C NMR (CDCl.sub.3) 
27.4, 36.3, 38.1, 42.7, 56.4, 67.3, 
(.delta.) 67.3, 128.2, 128.5, 128.6, 135.0, 
135.1, 167.7, 167.8, 216.9 
MS m/z 275(M.sup.+ --Bn), 91 (base peak) 
HRMS for C.sub.15 H.sub.15 O.sub.5 (M.sup.+ --Bn) 
cal'd 275.0919! 
measured 275.0931! 
.alpha.!.sub.p.sup.24 
+35.0.degree.(c1.20, CHCl.sub.3) 
Optical purity 
91% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., isopro- 
panol/hexane = 1/9, detection: 254 nm, 
flow rate: 1.0 ml/min. 
______________________________________ 
EXAMPLE 10 
Asymmetric Michael reaction 
According to the same reaction conditions and operations as used in Example 
6, cyclopentenone and diethyl methylmalonate were subjected to the 
asymmetric Michael reaction to obtain the reaction product of structural 
formula 22 in a yield of 84%. 
Chemical formula 22 
##STR23## 
The analysis was carried out on this reaction product in the same manner as 
in Example 2, and the results are obtained shown in Table 9. 
TABLE 9 
______________________________________ 
IR (neat) 2984 cm.sup.-1, 1730 cm.sup.-1, 1262 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
1.25(t, J=7.0Hz, 3H), 1.26 
(.delta.) (t, J=7.0Hz, 3H), 1.44(s, 1H) 
1.60-1.84(m, 1H), 2.07-2.49 
(m, 5H), 2.78-2.94(m, 1H), 4.19 
(q, J=7Hz, 2H), 4.21(q, J=7Hz, 2H) 
.sup.13 C NMR (CDCl.sub.3) 
14.0, 17.8, 24.6, 38.5, 40.8, 
(.delta.) 41.4, 55.4, 61.4, 171.2, 171.3, 
217.7 
MS m/z 257(M+1), 288(M+1 --Et), 174 
(base peak) 
HRMS for C.sub.13 H.sub.20 O.sub.5 
cal'd C, 60.92;H, 7.87! 
measured C, 60.66;H, 7.76! 
.alpha.!.sub.p.sup.24 
+54.9.degree.(c3.34, CHCl.sub.3) 
Optical purity 91% e.e. HPLC analysis 
(HPLC analysis) 
conditions: CHIRALPAK AS manu- 
factured by Daicel Chemical In- 
dustries Co., Ltd., isopro- 
panol/hexane = 1/9, detection: 
254 nm, flow rate: 1.0 ml/min. 
______________________________________ 
EXAMPLE 11 
Asymmetric Michael reaction 
Cyclohexenone (96 mg, 1.0 mmol) and dibenzyl malonate (250 mg, 1.0 mmol) 
were added to the solution obtained in Example 2. After stirring at room 
temperature for 48 hours, 1N HCl aqueous solution (3 ml) was added to the 
reaction solution to stop the reaction. The mixture was extracted with 
ethyl acetate (15 ml.times.three times) and the combined extracts were 
dried over Na.sub.2 SO.sub.4. The solvent was distilled from the reaction 
solution, and the residue was purified by flash column chromatography 
(acetone/hexane=1/10, on SiO.sub.2) to obtain the Michael reaction product 
of a final compound in a yield of 44%. The optical purity by HPLC analysis 
was 97% e.e. (HPLC analysis conditions were the same as those in Example 
6). 
EXAMPLE 12 
Asymmetric Michael reaction 
Cyclohexenone (96 mg, 1.0 mmol) and dibenzyl malonate (250 mg, 1.0 mmol) 
were added to the solution obtained in Example 3. After stirring at room 
temperature for 6 hours. A 1N HCl aqueous solution (3 ml) was added to the 
reaction solution to stop the reaction. The mixture was extracted with 
ethyl acetate (15 ml.times.three times) and the combined extracts were 
dried over Na.sub.2 SO.sub.4. The solvent was distilled from the reaction 
solution, and the residue was purified by flash column chromatography 
(acetone/hexane=1/10, on SiO.sub.2) to obtain the Michael reaction product 
of a final compound in a yield of 100%. The optical purity of the product 
was 87% e.e as analyzed by HPLC. (HPLC analysis conditions were the same 
as those in Example 6). 
EXAMPLE 13 
Three-component combination type reaction 
Cyclopentenone (84 mg, 1.0 mmol), diethyl methylmalonate (138 mg, 1.0 
mmol), and hydrocinnamaldehyde (158 mg, 1.2 mmol) were added to a solution 
of Al--Li--(R)-binaphthol complex obtained in Example 1 (0.1M, 1.0 ml). 
The stirring was continued at room temperature for 36 hours to carry out 
the reaction below. 
Chemical formula 23 
##STR24## 
After 1N HCl aqueous solution (3 ml) was added to this reaction solution to 
stop the reaction, the mixture was extracted with ethyl acetate (15 
ml.times.three times). The combined extracts were dried over Na.sub.2 
SO.sub.4. After the solvent was distilled, the residue was purified by 
flash column chromatography (acetone/hexane=1/10, on SiO.sub.2) to afford 
the three-component combination type reaction product of a final compound 
in a yield of 64%. An analysis was performed on this reaction product in 
same manner as in Example 6 to obtain the results shown in Table 10. 
TABLE 10 
______________________________________ 
IR (neat) 3518 cm.sup.-1, 3085 cm.sup.-1, 1728 cm.sup.-1, 
1253 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
1.19(t, J=7.0Hz, 3H), 1.22 
(.delta.) (t, J=7.0Hz, 3H), 1.40(s, 3H), 1.68- 
1.87(m, 2H), 2.01-2.19(m, 2H), 
2.24(t, J=8.4Hz, 2H), 2.35(dd, 
J=3.8, 6.3Hz, 1H), 2.57-2.70(m, 2H), 
2.76-2.899(m, 1H), 2.97 
(dt, J=6.3, 8.0Hz, 1H), 3.75 
(dt, J=3.8, 9.6Hz, 1H), 4.06 
(q, J=7.0Hz, 1H), 4.11 
(q, J=7.0Hz, 1H), 4.13 
(q, J=7.0Hz, 2H), 7.13-7.40(m, 5H) 
.sup.13 C NMR (CDCl.sub.3) 
13.9, 14.0, 18.6, 22.9, 32.5, 
(.delta.) 36.1, 38.5, 42.4, 43.3, 55.9, 
56.9, 57.0, 61.6, 72.0, 125.9, 
128.4, 128.5, 141.8, 171.6, 171.8, 
218.9 
MS m/z 391(M.sup.+), 373(M.sup.+ --H.sub.2 O), 175(base 
peak) 
HRMS for C.sub.22 H.sub.36 O.sub.6 
cal'd C, 67.67;H, 7.74! 
measured C, 67.41;H, 7.70! 
.alpha.!.sub.p.sup.24 
+18.34.degree.(c0.66, CHCl.sub.3) 
Optical purity 
91% e.e. HPLC analysis conditions: 
(HPLC analy- CHIRALPAK AS manufactured by 
sis) Daicel Chemical Industries Co., 
Ltd., isopropanol/hexane = 1/9, 
detection: 254 nm, flow rate: 
1.0 ml/min. 
______________________________________ 
EXAMPLE 14 
Three-component combination-type reaction 
Cyclopentenone (84 mg, 1.0 mmol), diethyl methylmalonate (138 mg, 1.0 
mmol), and benzaldehyde (122 mg, 1.2 mmol) were added to the solution of 
Al--Li--(R)-binaphthol complex obtained in Example 1 (0.1M, 1.0 ml). The 
stirring was continued at room temperature for 72 hours to carry out the 
reaction below. 
Chemical formula 24 
##STR25## 
Then, the workup was performed as in Example 13 to obtain the three 
component combination compound of a final product in a yield of 82%. In 
order to analyze this reaction product in the same manner as in Example 6, 
the product was oxidized with pyridinium chlorochromate (hereinafter 
abbreviated as PCC) to obtain the diketone compound as shown in chemical 
formula 25. The results of the analysis of this diketone compound are 
shown in Table 11. According to the HPLC analysis results shown in this 
Table, the optical purity of the diketone compound was 89% e.e. Therefore, 
it is considered that the optical purity of the three-component 
combination-type reaction product in this Example is also 89% e.e. 
Chemical formula 25 
##STR26## 
TABLE 11 
______________________________________ 
IR (neat) 3468 cm.sup.-1, 1728 cm.sup.-1, 1677 cm.sup.-1, 
1260 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
1.04(t, J=7.3Hz, 3H), 1.21 
(.delta.) (t, J=7.3Hz, 3H), 1.49(s, 3H), 1.03- 
2.03(m, 1H), 2.26-2.48(m, 3H), 
3.55-3.68(m, 1H), 3.87 
(dq, J=7.3, 10.9Hz, 1H), 4.03(dq, 
J=7.3, 10.9Hz, 1H), 4.13 
(q, J=7.3Hz, 2H), 4.77 
(d, J=8.6Hz, 1H), 7.45-7.52(m, 2H), 
7a.55-6.62 (m, 1H), 8.00-8.05 
(m, 1H) 
.sup.13 C NMR (CDCl.sub.3) 
13.6, 13.9, 19.7, 22.7, 38.9, 
(.delta.) 44.4, 55.6, 59.4, 61.4, 128.5, 
129.4, 133.3, 136.5, 171.1, 195.1, 
211.0 
MS m/z 361(M.sup.+), 360(M.sup.+ --H.sub.2 O), 105(base 
peak) 
HRMS for C.sub.20 H.sub.24 O.sub.6 
cal'd C, 66.65;H, 6.71! 
measured C, 66.38;H, 6.65! 
.alpha.!.sub.p.sup.24 
22.00.degree.(c1.02, CHCl.sub.3) 
Optical purity 
89% e.e. A diketone compound which 
(HPLC analysis) 
had been oxidized with pyridinium 
chlorochromate in methylene chlo- 
ride was subject to HPLC analysis. 
HPLC analysis conditions: 
CHIRALCEL OJ manufactured by 
Daicel Chemical Industries Co., 
Ltd., isopropanol/hexane = 1/4, 
detection: 254 nm, flow rate: 
0.5 ml/min. 
______________________________________ 
EXAMPLE 15 
Asymmetric hydrophosphonylation reaction 
The solution of the Al--Li--(R)-binaphthol complex (hereinafter abbreviated 
as ALB) obtained in Example 1 in tetrahydrofuran (0.1M, 0.36 ml) was 
concentrated at room temperature for 1 hour under reduced pressure, then 
0.4 ml of toluene was added thereto under an argon atmosphere. To this 
solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring for 30 minutes, the reaction vessel was cooled 
to -40.degree. C. After it was maintained at this temperature for 15 
minutes, benzaldehyde (0.48 mmol) was added thereto. After reacting for 90 
hours, 1N hydrochloric acid was added thereto to stop the reaction. The 
mixture was extracted with ethyl acetate (10 ml.times.three times), and 
the combined extracts were washed with brine and dried over Na.sub.2 
SO.sub.4. The solvent was distilled, and the residue was purified by flash 
column chromatography (acetone/hexane=1/5, on SiO.sub.2) to obtain 
dimethyl (S)-hydroxyphenylmethylphosphonate as a final product in a yield 
of 95%. The chemical reaction in this Example is shown in chemical formula 
26. 
Chemical formula 26 
##STR27## 
The results of an analysis of this reaction product are shown in Table 12. 
TABLE 12 
______________________________________ 
IR (neat) 3261 cm.sup.-1, 1235 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
3.30(dd, J=4.0, 5.3Hz, 1H), 3.61 
(.delta.) (d, J=9.9Hz, 3H), 3.63 
(d, J=9.9Hz, 3H), 4.98 
(dd, J=5.0, 9.9Hz, 1H), 7.2-7.5 
(m, 5H) 
.sup.13 C NMR (CDCl.sub.3) 
53.6(J=7.3Hz), 53.9 
(.delta.) (J=7.3Hz), 70.6(J=159.9Hz), 
127.0(J=159.9Hz), 128.2 
(J=3.7Hz), 128.4(J=2.5Hz), 
136.3 
MS m/z 216(M.sup.+) 
HRMS for C.sub.9 H.sub.13 O.sub.4 P.sub.1 
cal'd C, 50.00;H, 6.06! 
measured C, 49.80;H, 6.05! 
Optical purity 90% e.e. HPLC analysis condi- 
(HPLC analysis) 
tions: CHIRALPAK AS manufac- 
tured by Daicel Chemical In- 
dustries Co., Ltd., isopropa- 
nol/hexane = 1/4, detection: 
254 nm, flow rate: 0.9 
ml/min. 
______________________________________ 
EXAMPLE 16 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring for 30 minutes, the reaction vessel was cooled 
to -40.degree. C., and it was maintained at this temperature for 15 
minutes. Benzaldehyde (0.40 mmol) then was added thereto. After reacting 
for 51 hours, 1N hydrochloric acid was added thereto to stop the reaction. 
The mixture was extracted with ethyl acetate (10 ml.times.three times). 
The combined extracts were washed with brine and dried over Na.sub.2 
SO.sub.4. The solvent was distilled, and the residue was purified by flash 
column chromatography (acetone/hexane=1/5, on SiO.sub.2) to obtain 
dimethyl (S)-hydroxy-phenylmethylphosphonate as final product in a yield 
of 90%. The chemical reaction in this Example is shown in chemical formula 
27. 
Chemical formula 27 
##STR28## 
The results of an analysis of this reaction product are shown in Table 13. 
TABLE 13 
______________________________________ 
IR (KBr) 3261 cm.sup.-1, 1235 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
3.30(dd, J=4.0, 5.3Hz, 1H), 3.61 
(.delta.) (d, J=9.9Hz, 3H), 3.63 
(d, J=9.9Hz, 3H), 4.98 
(dd, J=5.0, 9.9Hz, 1H), 7.2-7.5 
(m, 5H) 
.sup.13 C NMR (CDCl.sub.3) 
53.6(J=7.3Hz), 53.9 
(.delta.) (J=7.3Hz), 70.6(J=159.9Hz), 
127.0(J=159.9Hz), 128.2 
(J=3.7Hz), 128.4(J=2.5Hz), 
136.2 
MS m/z 216(M.sup.+) 
HRMS for C.sub.9 H.sub.13 O.sub.4 P.sub.1 
cal'd C, 50.00;H, 6.06!, 
measured C, 49.80;H, 6.05! 
.alpha.!.sub.p.sup.24 
-44.3.degree.(c1.0, CHCl.sub.3) 
Optical purity 85% e.e. HPLC analysis condi- 
(HPLC analysis) 
tions: CHIRALPAK AS manufac- 
tured by Daicel Chemical In- 
dustries Co., Ltd., isopropa- 
nol/hexane = 1/4, detection: 
254 nm, flow rate: 0.9 
ml/min. 
______________________________________ 
EXAMPLES 17-20 
Asymmetric hydrophosphonylation reaction 
Further, the same reactions were carried out as in chemical formula 27 by 
changing the reaction solvents to obtain analysis results shown in Table 
14. 
TABLE 14 
______________________________________ 
Reaction Optical 
Example time Yield 
purity 
No. Solvent (hr) (%) (%) 
______________________________________ 
17 Tetrahydro- 
36.5 61 73 
furan 
18 Toluene 36.5 88 83 
19 Methylene 36.5 49 80 
chloride 
20 Ethyl ether 
36.5 58 78 
______________________________________ 
EXAMPLE 21 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring for 30 minutes, the reaction vessel was cooled 
to -40.degree. C., and it was maintained at this temperature for 15 
minutes. Then p-chlorobenzaldehyde (0.40 mmol) was added thereto. After 
reacting for 38 hours, 1N hydrochloric acid was added thereto to stop the 
reaction. The mixture was extracted with ethyl acetate (10 ml.times.three 
times), and the combined extracts were washed with brine and dried over 
Na.sub.2 SO.sub.4. The solvent was distilled, and the residue was purified 
by flash column chromatography (acetone/hexane=1/5, on SiO.sub.2) to 
obtain dimethyl (S)-hydroxy(p-chlorophenyl)methylphosphonate as a final 
product in a yield of 90%. The chemical reaction in this Example is shown 
in chemical formula 28. 
Chemical formula 28 
##STR29## 
The results of the analysis of this reaction product are shown in Table 15. 
TABLE 15 
______________________________________ 
IR (KBr) 3257 cm.sup.-1, 1233 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
2.95(dd, J=4.6, 10.6Hz, 1H), 3.62 
(.delta.) (d, J=10.6HZ, 3H), 3.64 
(d, J=10.6HZ, 3H), 5.05 
(dd, J=5.0, 10.9Hz, 1H), 7.35 
(d, J=8.5Hz, 2H), 7.43 
(dd, J=3.0, 8.5Hz, 2H) 
.sup.13 NMR (CDCl.sub.3) 
53.6(J=7.4Hz), 54.1(J=7.4Hz), 
(.delta.) 70.0(J=159.9Hz), 128.4 
(J=6.0Hz), 128.5(J=2.4Hz), 133.9 
(J=3.7Hz), 135.1(J=2.4Hz) 
MS m/z 250(M.sup.+) 
HRMS for C.sub.9 H.sub.12 C.sub.11 O.sub.4 P.sub.1 
cal'd C, 43.13;H, 4.83! 
measured C, 42.88;H, 4.80! 
.alpha.!.sub.p.sup.24 
-49.1.degree.(c1.0, CHCl.sub.3) 
Optical purity 83% e.e. HPLC analysis 
(HPLC analysis) 
conditions: CHIRALPAK AS manu- 
factured by Daicel Chemical In- 
dustries Co., Ltd., isopropa- 
nol/hexane = 1/4, detection: 254 
nm, flow rate: 0.5 ml/min. 
______________________________________ 
EXAMPLE 22 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring at room temperature for 30 minutes, the 
reaction vessel was cooled to -40.degree. C., and it was maintained at 
this temperature for 15 minutes. Then p-methylbenzaldehyde (0.40 mmol) was 
added thereto. After reacting for 92 hours, 1N hydrochloric acid was added 
thereto to stop the reaction. The mixture was extracted with ethyl acetate 
(10 ml.times.three times), and the combined extracts were washed with 
brine and dried over Na.sub.2 SO.sub.4. The solvent was distilled, and the 
residue was purified by flash column chromatography (acetone/hexane=1/5, 
on SiO.sub.2) to obtain dimethyl 
(S)-hydroxy(p-methylphenyl)methylphosphonate as a final product in a yield 
of 82%. The chemical reaction in this Example is shown in chemical formula 
29. 
Chemical formula 29 
##STR30## 
The results of the analysis of this reaction product are shown in Table 16. 
TABLE 16 
______________________________________ 
IR (KBr) 3250 cm.sup.-1, 1256 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
2.28(d, J=1.6, 3H), 2.80 
(.delta.) (bs, 1H), 3.63(d, J=10.8Hz, 3H), 
3.65(d, J=10.8Hz, 3H), 4.93 
(d, J=10.6Hz, 1H), 7.12 
(d, J=7.9Hz, 2H), 7.30 
(dd, J=2.0, 7.9Hz, 2H) 
.sup.13 C NMR (CDCl.sub.3) 
21.2, 53.6(J=7.3Hz), 53.9 
(.delta.) (J=7.3Hz), 70.5(J=159.9Hz), 
126.9(J=6.1Hz), 129.1 
(J=2.4Hz), 133.3, 138.0 
(J=2.4Hz) 
MS m/z 230(M.sup.+) 
HRMS for C.sub.10 H.sub.15 O.sub.4 P.sub.1 
cal'd C, 52.18;H, 6.57! 
measured C, 52.17;H, 6.45! 
.alpha.!.sub.p.sup.24 
-49.5.degree.(c1.0, CHCl.sub.3) 
Optical purity 86% e.e. HPLC analysis condi- 
(HPLC analysis) 
tions: CHIRALPAK AS manufac- 
tured by Daicel Chemical Indus- 
tries Co., Ltd., isopropa- 
nol/hexane = 1/4, detection: 
254 nm, flow rate: 0.5 ml/min. 
______________________________________ 
EXAMPLE 23 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring for 30 minutes at room temperature, the 
reaction vessel was cooled to -40.degree. C., and it was maintained at 
this temperature for 15 minutes. Then, p-methoxybenzaldehyde (0.40 mmol) 
was added thereto. After reacting for 115 hours, 1N hydrochloric acid was 
added thereto to stop the reaction. The mixture was extracted with ethyl 
acetate (10 ml.times.three times), and the combined extracts were washed 
with brine and dried over Na.sub.2 SO.sub.4. The solvent was distilled, 
and the residue was purified by flash column chromatography 
(acetone/hexane=1/5, on SiO.sub.2) to obtain dimethyl 
(S)-hydroxy(p-methoxyphenyl)methylphosphonate as a final product in a 
yield of 88%. The chemical reaction in this Example is shown in chemical 
formula 30. 
Chemical formula 30 
##STR31## 
The results of the analysis of this reaction product are shown in Table 17. 
TABLE 17 
______________________________________ 
IR (KBr) 3338 cm.sup.-1, 1236 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
3.19(bs, 1H), 3.63 
(.delta.) (d, J=10.4Hz, 3H), 3.65 
(d, J=10.4Hz, 3H), 3.74(s, 3H), 4.91 
(d, J=9.9Hz, 1H), 6.85 
(d, J=8.3Hz, 2H), 7.34(dd, J=2.0, 
8.3Hz, 2H) 
.sup.13 C NMR (CDCl.sub.3) 
53.5(J=7.3Hz), 53.8(J=7.3Hz), 
(.delta.) 55.2, 70.0(J=162.4Hz), 113.8, 
128.4, 159.5(J=2.5Hz) 
MS m/z 246(M.sup.30 ) 
HRMS for C.sub.10 H.sub.15 O.sub.5 P.sub.1 
cal'd C, 48.79;H, 6.19! 
measured C, 48.81;H, 6.07! 
.alpha.!.sub.p.sup.24 
-38.7.degree. (c1.0, CHCl.sub.3) 
Optical purity 78% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by 
Daicel Chemical Industries Co., 
Ltd., isopropanol/hexane = 1/4, 
detection: 254 nm, flow rate: 
1.0 ml/min. 
______________________________________ 
EXAMPLE 24 
Asymmetric hydrophosphonylation reaction 
Dimethyl phosphite (37 .mu.l, 0.40 mmol) was added to the solution of ALB 
in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 at room 
temperature. After stirring at room temperature for 30 minutes, the 
reaction vessel was cooled to -78.degree. C., and it was maintained at 
this temperature for 15 minutes. Then p-nitrobenzaldehyde (0.40 mmol) was 
added thereto. After the temperature was raised to room temperature, the 
stirring was continued for 12 hours. Hydrochloric acid (1N) was added 
thereto to stop the reaction, and the mixture was extracted with ethyl 
acetate (10 ml.times.three times). The combined extracts were washed with 
brine and dried over Na.sub.2 SO.sub.4. The solvent was distilled, and the 
residue was purified by flash column chromatography (acetone/hexane=1/5, 
on SiO.sub.2) to obtain dimethyl 
(S)-hydroxy(p-nitrophenyl)methylphosphonate as a final product in a yield 
of 81%. The chemical reaction in this Example is shown in chemical formula 
31. 
Chemical formula 31 
##STR32## 
The results of the analysis of this reaction product are shown in Table 18. 
TABLE 18 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
3.85(d, J=10.9Hz, 3H), 3.87 
(.delta.) (d, J=10.9Hz, 3H), 5.30 
(d, J=11.6Hz, 1H), 7.77 
(dd, J=2.0, 8.0Hz, 2H), 8.34 
(d, J=8.0Hz, 2H) 
Optical purity 23% e.e. HPLC analysis Conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by 
Daicel Chemical Industries Co., 
Ltd., isopropanol/hexane = 1/9, 
detection: 254 nm, flow rate: 
1.0 ml/min. 
______________________________________ 
EXAMPLE 25 
Asymmetric hydrophosphonylation reaction 
Dimethyl phosphite (37 .mu.l, 0.40 mmol) was added to the solution of ALB 
in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 at room 
temperature. After stirring at room temperature for 30 minutes, the 
reaction vessel was cooled to -40.degree. C., and it was maintained at 
this temperature for 15 minutes. p-Dimethylaminobenzaldehyde (0.40 mmol) 
was added thereto. After reacting for 48 hours, 1N hydrochloric acid was 
added thereto to stop the reaction. The mixture was extracted with ethyl 
acetate (10 ml.times.three times), and the combined mixture were washed 
with brine and dried over Na.sub.2 SO.sub.4. The solvent was distilled, 
and the residue was purified by flash column chromatography 
(acetone/hexane=1/5, on SiO.sub.2) to obtain dimethyl (S)-hydroxy 
(p-dimethylaminophenyl)methylphosphonate as a final product in a yield of 
71%. The chemical reaction in this Example is shown in chemical formula 
32. 
Chemical formula 32 
##STR33## 
TABLE 19 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
2.96(s, 6H), 3.64(d, J=10.2Hz, 3H), 
(.delta.) 3.74(d, J=10.6Hz, 3H), 4.92 
(dd, J=5.0, 9.9Hz, 1H), 6.72 
(d, J=8.9Hz, 2H), 7.35 
(dd, J=2.0, 8.9Hz, 2H) 
Optical purity 
15% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., 
isopropanol/hexane = 1/2, 
detection: 254 nm, flow rate: 1.0 
ml/min. 
______________________________________ 
Example 26 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added diethyl phosphite (0.40 mmol) at room temperature. 
After stirring at room temperature for 30 minutes, the reaction vessel was 
cooled to -40.degree. C., and it was maintained at this temperature for 15 
minutes. Then, benzaldehyde (0.40 mmol) was added thereto. After reacting 
for 90 hours, 1N hydrochloric acid was added thereto to stop the reaction. 
The mixture was extracted with ethyl acetate (10 ml.times.three times), 
and the combined extracts were washed with brine and dried over Na.sub.2 
SO.sub.4. The solvent was distilled, and the residue was purified by flash 
column chromatography (acetone/hexane=1/5, on SiO.sub.2) to obtain diethyl 
(S)-hydroxy-phenylmethylphosphonate as a final product in a yield of 39%. 
The chemical reaction in this Example is shown in chemical formula 33. 
Chemical formula 33 
##STR34## 
EXAMPLE 27 
Asymmetric hydrophosphonylation reaction 
The same procedure as shown in Example 26 was used, except that dibutyl 
phosphite was used in place of the diethyl phosphite used in Example 26 to 
afford dibutyl (S)-hydroxy-phenylmethylphosphonate as a final product in a 
yield of 42%. 
The analysis results of this reaction product are shown in Table 21. 
TABLE 21 
______________________________________ 
Optical purity 67% e.e. HPLC analysis 
(HPLC analysis) 
conditions: CHIRALPAK AS manu- 
factured by Daicel Industries 
Co., Ltd., isopropanol/hexane = 
1/9, detection: 254 nm, flow 
rate: 1.0 ml/min. 
______________________________________ 
EXAMPLE 28 
Asymmetric hydrophosphonylation reaction 
The same manner as shown in Example 26 was adopted except that dibenzyl 
phosphite was used in place of diethyl phosphite used in Example 26 and 
that the reaction was performed at room temperature for 6.5 hours to 
afford dibenzyl (S)-hydroxy-phenylmethylphosphonate of a final product in 
a yield of 60%. The analysis results on this reaction product are shown in 
Table 22. 
TABLE 22 
______________________________________ 
Optical purity 8.4% e.e. HPLC analysis 
(HPLC analysis) 
conditions: CHIRALPAK AS manu- 
factured by Daicel Industries 
Co., Ltd., isopropanol/hexane = 
1/9, detection: 254 nm, flow 
rate: 1.0 ml/min. 
______________________________________ 
EXAMPLE 29 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring at room temperature for 30 minutes, the 
reaction vessel was cooled to -40.degree. C., and it was maintained at 
this temperature for 15 minutes. Then, cinnamaldehyde (0.40 mmol) was 
added thereto. After reacting for 81 hours, 1N hydrochloric acid was added 
thereto to stop the reaction. The mixture was extracted with ethyl acetate 
(10 ml.times.three times), and the combined extracts were washed with 
brine and dried over Na.sub.2 SO.sub.4. The solvent was distilled, and the 
residue was purified by flash column chromatography (acetone/hexane=1/5, 
on SiO.sub.2) to obtain dimethyl 
(S,E)-1-hydroxy-3-phenyl-2-propenylphosphonate as a final product in a 
yield of 85%. The chemical reaction in this Example is shown in chemical 
formula 34. 
Chemical formula 34 
##STR35## 
The results of the analysis of this reaction product are shown in Table 23. 
TABLE 23 
______________________________________ 
IR (KBr) 3258 cm.sup.-1, 1243 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
3.77(d, J=10.3Hz, 3H), 3.78 
(.delta.) (d, J=10.3Hz, 3H), 4.64 
(ddd, J=1.7, 6.3, 12.9Hz, 1H), 6.26 
(dt, J=5.6, 15.8Hz, 1H), 6.73 
(dd, J=5.0, 15.8Hz, 1H), 7.30(m, 5H) 
.sup.13 C NMR (CDCl.sub.3) 
53.7(J=7.3Hz), 53.9(J=7.3Hz), 
(.delta.) 69.3(J=2.5Hz) 
MS m/z 242(M.sup.+) 
HRMS for C.sub.11 H.sub.15 O.sub.4 P.sub.1 
cal'd C, 54.55;H, 6.24! 
measured C, 54.28;H, 5.96! 
.alpha.!.sub.p.sup.24 
-21.4.degree.(c1.0, CHCl.sub.3) 
Optical purity 
82% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., iso- 
propanol/hexane = 1/4, detection: 
254 nm, flow rate: 1.2 ml/min. 
______________________________________ 
EXAMPLE 30 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring at room temperature for 30 minutes, the 
reaction vessel was cooled to -40.degree. C., and it was maintained at 
this temperature for 15 minutes, then (E)-.beta.-methylcinnamaldehyde 
(0.40 mmol) was added thereto. After reacting for 81 hours, 1N 
hydrochloric acid was added thereto to stop the reaction. The mixture was 
extracted with ethyl acetate (10 ml.times.three times), and the combined 
extracts were washed with brine and dried over Na2SO.sub.4. The solvent 
was distilled, and the residue was purified by flash column chromatography 
(acetone/hexane=1/5, on SiO.sub.2) to obtain dimethyl 
(S,E)-1-hydroxy-3-methyl-3-phenyl-2-propenylphosphonate as a final product 
in a yield of 93%. The chemical reaction in this Example is shown in 
chemical formula 35. 
Chemical formula 35 
##STR36## 
The results of the analysis of this reaction product are shown in Table 24. 
TABLE 24 
______________________________________ 
IR (KBr) 3245 cm.sup.-1, 1031 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
2.14(dd, J=1.0, 3.3Hz, 3H), 3.10 
(.delta.) (bs, 1H), 3.82(d, J=10.6Hz, 3H), 
3.84(d, J=10.6Hz, 3H), 4.89 
(t, J=9.2, 10.6Hz, 1H), 5.87 
(dt, J=7.2, 15.5Hz, 1H), 7.36 (m, 5H) 
.sup.13 C NMR (CDCl.sub.3) 
16.8, 53.6, (J=7.4Hz), 53.8 
(.delta.) (J=7.3Hz), 66.3(J=163.5Hz), 122.0 
(J=3.7Hz), 126.0, 127.7, 128.3, 
140.9(J=13.5Hz), 142.4 
MS m/z 256(M.sup.+) 
HRMS for C.sub.12 H.sub.17 O.sub.4 P.sub.1 
cal'd C, 56.25;h, 6.69! 
measured C, 54.02;H, 6.91! 
.alpha.!.sub.p.sup.24 
12.8.degree. (c1.0, CHCl.sub.3) 
Optical purity 89% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by 
Daicel Chemical Industries Co., 
Ltd., isopropanol/hexane = 5/95, 
detection: 254 nm, flow rate: 
1.0 ml /min. 
______________________________________ 
EXAMPLE 31 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring at room temperature for 30 minutes, the 
reaction vessel was cooled to -40.degree. C., and it was maintained at 
this temperature for 15 minutes. Then 3-methyl-2-butenal (0.40 mmol) was 
added thereto. After reacting for 81 hours, 1N hydrochloric acid was added 
thereto to stop the reaction. The mixture was extracted with ethyl acetate 
(10 ml.times.three times), and the combined extracts were washed with 
brine and dried over Na.sub.2 SO.sub.4. The solvent was distilled, and the 
residue was purified by flash column chromatography (acetone/hexane=1/5, 
on SiO.sub.2) to obtain dimethyl 
(S)-1-hydroxy-3-methyl-2-butenylphosphonate as a final product in a yield 
of 72%. The chemical reaction in this Example is shown in chemical formula 
36. 
Chemical formula 36 
##STR37## 
The results of the analysis of this reaction product are shown in Table 25. 
TABLE 25 
______________________________________ 
IR (KBr) 3274 cm.sup.-1, 1052 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
1.71(dd, J=1.3, 3.0Hz, 3H), 1.81 
(.delta.) (dd, J=1.0, 4.0Hz, 3H), 3.18(bs, 1H), 
3.80(d, J=10.5Hz, 3H), 3.82 
(d, J=10.5Hz, 3H), 4.66 
(dt, 5.5, 9.1, 9.2, 1H), 5.33(m, 1H) 
.sup.13 C NMR (CDCl.sub.3) 
18.5, 25.9, 53.4(J=6.1Hz), 53.5 
(.delta.) (J=7.4Hz), 65.5(J=163.6Hz), 119.4 
(J=2.4Hz), 139.6(J=14.6Hz) 
MS m/z 191(M.sup.+) 
HRMS for C.sub.7 H.sub.15 O.sub.4 P.sub.1 
cal'd C, 43.30;H, 7.79! 
measured C, 43.01;H, 7.80! 
.alpha.!.sub.p.sup.24 
-54.4.degree.(c0.65, CHCl.sub.3) 
Optical purity 
68% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., iso- 
propanol/hexane = 1/4, detection: 
differential refraction 
______________________________________ 
EXAMPLE 32 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring at room temperature for 30 minutes, the 
reaction vessel was cooled to -40.degree. C., and it was maintained at 
this temperature for 15 minutes. Then 2-hexenylaldehyde (0.40 mmol) was 
added thereto. After reacting for 39 hours, 1N hydrochloric acid was added 
thereto to stop the reaction. The mixture was extracted with ethyl acetate 
(10 ml.times.three times), and the combined extracts were washed with 
brine and dried over Na.sub.2 SO.sub.4. The solvent was distilled, and the 
residue was purified by flash column chromatography (acetone/hexane=1/5, 
on SiO.sub.2) to obtain dimethyl (E,S)-1-hydroxy-2-hexenylphosphonate as a 
final product in a yield of 53%. The chemical reaction in this Example is 
shown in chemical formula 37. 
Chemical formula 37 
##STR38## 
The results of the analysis of this reaction product are shown in Table 26. 
TABLE 26 
______________________________________ 
IR (KBr) 3299 cm.sup.-1, 1237 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
0.91(d, J=7.3Hz, 3H), 1.43 
(.delta.) (dt, J=7.3, 7.6Hz, 2H), 2.07(m, 2H) 
3.79(d, J=10.2Hz, 3H), 3.81 
(d, J=10.2Hz, 3H), 4.46 
(dd, J=7.3, 10.6Hz, 1H), 5.60(m, 1H) 
5.90(m, 1H) 
.sup.13 C NMR (CDCl.sub.3) 
13.6, 22.0, 34.4, 53.5(J=7.3Hz), 
(.delta.) 53.7(J=7.3Hz), 69.2(J=162.3Hz), 
124.2(J=3.6Hz), 135.4(J=12.2Hz) 
MS m/z 208(M.sup.+) 
.alpha.!.sub.p.sup.24 
-9.7.degree.(c0.95, CHCl.sub.3) 
Optical purity 
55% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., iso- 
propanol/hexane = 1/4, flow rate: 
1.0 ml/min., detection: differential 
refraction 
______________________________________ 
EXAMPLE 33 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring at room temperature for 30 minutes, the 
reaction vessel was cooled to -40.degree. C., and it was maintained at 
this temperature for 15 minutes. Then (E)-.alpha.-methylcinnamaldehyde 
(0.40 mmol) was added thereto. After reacting for 61 hours, 1N 
hydrochloric acid was added thereto to stop the reaction. The mixture was 
extracted with ethyl acetate (10 ml.times.three times), and the combined 
extracts were washed with brine and dried over Na.sub.2 SO.sub.4. The 
solvent was distilled, and the residue was purified by flash column 
chromatography (acetone/hexane =1/5, on SiO.sub.2) to obtain 
dimethyl-(E)-(S)-1-hydroxy-2-methyl-3-phenyl-2-propenyl phosphonate as a 
final product in a yield of 47%. The chemical reaction in this Example is 
shown in chemical formula 38. 
Chemical formula 38 
##STR39## 
The results of an analysis of this reaction product are shown in Table 27. 
TABLE 27 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
1.96(dd, J=1.3, 3.3Hz, 3H), 3.76 
(.delta.) (d, J=10.8Hz, 3H), 3.78 
(d, J=10.6Hz, 3H), 4.47 
(dd, J=4.3, 12.5Hz, 1H), 6.63 
(d, J=4.6Hz, 1H), 7.21(m, 5H) 
Optical purity 56% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by 
Daicel Chemical Industries Co., 
Ltd., isopropanol/hexane = 1/4, 
detection: 254 nm, flow rate: 
0.5 ml/min. 
______________________________________ 
EXAMPLE 34 
Asymmetric hydrophosphonylation reaction 
The same procedure as shown in Example 33 was used, except that 
2-methylpropenal was used in place of the (E)-.alpha.-methylcinnamaldehyde 
(0.40 mmol) used in Example 33 and that the reaction was carried out for 
35 hours to afford dimethyl (S,E)-1-hydroxy-2-methyl-2-propenylphosphonate 
as a final product in a yield of 65%. The chemical reaction in this 
Example 15 is shown in chemical formula 39. 
Chemical formula 39 
##STR40## 
The results of an analysis of this reaction product are shown in Table 28. 
TABLE 28 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
1.83(t, J=1.3, 1.0Hz, 3H)3.12 
(.delta.) (dd, J=5.6, 10.2Hz, 1H), 3.75 
(d, J=10.5Hz, 3H), 3.76 
(d, J=10.5Hz, 3H), 4.38 
(dd, J=5.0, 12.5Hz, 1H), 5.02 
(t, J=1.3Hz, 1H), 5.13(d, J=4.6Hz, 1H) 
Optical purity 
56% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK As manufactured by Daicel 
Chemical Industries Co., Ltd., 
isopropanol/hexane = 1/4, 
detection: differential re- 
fraction, flow rate: 0.5 ml/min. 
______________________________________ 
EXAMPLE 35 
Asymmetric hydrophosphonylation reaction 
The same procedure as shown in Example 33 was used, except that 
cyclohexylidene-.DELTA..sup.1 .alpha.-acetaldehyde was used in place of 
the (E)-.alpha.-methylcinnamaldehyde (0.40 mmol) used in Example 33 and 
the reaction was carried out for 47 hours to afford 
dimethyl-(S)-cyclohexylidene-.DELTA..sup.1 
.alpha.-1-hydroxyethylphosphonate in a yield of 65%. The chemical reaction 
in this Example is shown in chemical formula 40. 
Chemical formula 40 
##STR41## 
The results of an analysis of this reaction product are shown in Table 29. 
TABLE 29 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
1.45(bs, 6H), 2.11(bs, 2H), 3.05 
(.delta.) (bs, 1H), 3.74(d, J=10.6Hz, 3H), 
3.75(d, J=10.6Hz, 3H), 4.70 
(m, 1H), 5.21(m, 1H) 
Optical purity 60% e.e. HPLC analysis 
(HPLC analysis) 
conditions: CHIRALPAK AS manu- 
factured by Daicel Chemical In 
dustries Co., Ltd., isopropa- 
nol/hexane = 1/4, detection: 254 
nm, flow rate: 1.0 ml/min. 
______________________________________ 
EXAMPLE 36 
Asymmetric hydrophosphonylation reaction 
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 
1 was concentrated at room temperature for 1 hour under reduced pressure, 
then 0.4 ml of toluene was added thereto under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol) at room 
temperature. After stirring at room temperature for 30 minutes, the 
reaction vessel was cooled to -40.degree. C., and it was maintained at 
this temperature for 15 minutes. Then 2-methylpropionaldehyde (0.40 mmol) 
was added thereto. After reacting for 38 hours, 1N hydrochloric acid was 
added thereto to stop the reaction. The mixture was extracted with ethyl 
acetate (10 ml.times.three times), and the combined extracts were washed 
with brine and dried over Na.sub.2 SO.sub.4. The solvent was distilled, 
and the residue was purified by flash column chromatography 
(acetone/hexane=1/5, on SiO.sub.2) to obtain dimethyl 
(S)-1-hydroxy-2-methylpropylphosphonate as a final product in a yield of 
95%. The chemical reaction in this Example is shown in chemical formula 
41. 
Chemical formula 41 
##STR42## 
The results of an analysis of this reaction product are shown in Table 30. 
##STR43## 
EXAMPLE 37 
Asymmetric hydrophosphonylation reaction 
The same procedure as shown in Example 36 was used, except that hexanal was 
used in place of the 2-methylpropionaldehyde used in Example 36 and the 
reaction was carried out for 20 hours to afford dimethyl 
(S)-1-hydroxyhexylphosphonate as a final compound in a yield of 90%. The 
chemical reaction in this Example is shown in chemical formula 42. 
Chemical formula 42 
##STR44## 
The results of an analysis of this reaction product are shown in Table 31. 
TABLE 31 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
0.97(t, J=6.3, 3H), 1.40(m, 4H), 
(.delta.) 1.80(m, 4H), 3.87 
(d, J=10.2Hz, 3H), 3.88 
(d, J=10.2Hz, 3H), 3.92(m, 1H) 
Optical purity 3% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by 
Daicel Chemical Industries Co., 
Ltd., isopropanol/hexane = 1/4, 
detection: 254 nm, flow rate: 
0.5 ml/min. 
______________________________________ 
EXAMPLE 38 
Asymmetric hydrophosphonylation reaction 
The same procedure as shown in Example 36 was used, except that 
cyclohexanal was used in place of the 2-methylpropionaldehyde used in 
Example 36 and the reaction was carried out for 43 hours to afford 
dimethyl (S)-1-hydroxyhexyl phosphonate in a yield of 91%. The chemical 
reaction in this Example is shown in chemical formula 43. 
Chemical formula 43 
##STR45## 
The results of an analysis of this reaction product are shown in Table 32. 
TABLE 32 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
1.20(m, 6H), 1.78(m, 4H), 1.98 
(.delta.) (d, J=11.9Hz, 1H), 2.52 
(t, J=6.9Hz, 1H), 3.71 
(q, J=6.9, 12.5Hz, 2H), 3.80 
(d, J=10.6Hz, 3H), 3.82 
(d, J=10.6Hz, 3H) 
Optical purity 
24% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., 
isopropanol/hexane = 1/4, 
detection: differential refrac- 
tion, flow rate: 0.5 ml/min. 
______________________________________ 
EXAMPLE 39 
Asymmetric hydrophosphonylation reaction using 
Al--Li--(R)-6,6'-dibromobinaphthol (hereinafter abbreviated as ALB--Br) 
The solution of ALB--Br in tetrahydrofuran (0.1M, 0.40 ml) obtained in 
Example 4 was concentrated at room temperature for 1 hour under reduced 
pressure, then 0.4 ml of toluene was added under an argon atmosphere. To 
this solution was added dimethyl phosphite (37 .mu.l, 0.40 mmol). After 
stirring at room temperature for 30 minutes, the reaction vessel was 
cooled to -40.degree. C., and it was maintained at this temperature for 15 
minutes. Then benzaldehyde (0.40 mmol) was added thereto. After reacting 
for 59 hours, 1N hydrochloric acid was added to stop the reaction. The 
mixture was extracted with ethyl acetate (10 ml.times.three times), and 
the combined extracts were washed with brine and dried over Na.sub.2 
SO.sub.4. The solvent was distilled, and the residue was purified by flash 
column chromatography (acetone/hexane=1/5, on SiO.sub.2) to obtain 
dimethyl (S)-hydroxy-phenylmethyl phosphonate as a final product in a 
yield of 91%. The chemical reaction in this Example is shown in chemical 
formula 44. 
Chemical formula 44 
##STR46## 
The results of an analysis of this reaction product are shown in Table 33. 
TABLE 33 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
3.30(dd, J=4.0, 5.3Hz, 1H), 3.61 
(.delta.) (d, J=9.9Hz, 3H), 3.63 
(d, J=9.9Hz, 3H), 4.98 
(dd, J=5.0, 9.9Hz, 1H), 7.2-7.5(m, 5H) 
Optical purity 
68% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., 
isopropanol/hexane = 1/4, 
detection: 254 nm, flow rate: 0.5 
ml/min. 
______________________________________ 
EXAMPLE 40 
Asymmetric hydrophosphonylation reaction using ALB--Br 
The same procedure as shown in Example 39 was used, except that 
p-methoxybenzaldehyde was used in place of the benzaldehyde used in 
Example 39 to afford dimethyl (S)-hydroxy(p-methoxyphenyl)methylphosphate 
as a final product in a yield of 72%. The chemical reaction in this 
Example is shown in chemical formula 45. 
Chemical formula 45 
##STR47## 
The results of an analysis of this reaction product are shown in Table 34. 
TABLE 34 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
3.19(bs, 1H), 3.63(d, J=10.4Hz, 3H), 
(.delta.) 3.65(d, J=10.4Hz, 3H), 3.74(s, 3H), 
4.91(d, J=9.9Hz, 1H), 6.85 
(d, J=8.3Hz, 2H), 7.34 
(dd, J=2.0, 8.3Hz, 2H) 
Optical purity 
35% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., 
isopropanol/hexane = 1/4, 
detection: 254 nm, flow rate: 1.1 
ml/min. 
______________________________________ 
EXAMPLE 41 
Asymmetric hydrophosphonylation reaction using 
Al--Li--(R)-6,6'-dicyanobinaphthol (hereinafter abbreviated as ALB--CN) 
The solution of ALB--CN in tetrahydrofuran (0.1M, 0.40 ml) obtained in 
Example 5 was concentrated at room temperature for 1 hour under reduced 
pressure, then 0.4 ml of toluene was added thereto under an argon 
atmosphere. To this solution was added dimethyl phosphite (37 .mu.l, 0.40 
mmol) at room temperature. After stirring at room temperature for 30 
minutes, the reaction vessel was cooled to -40.degree. C., and it was 
maintained at this temperature for 15 minutes. Then p-methoxybenzaldehyde 
(0.40 mmol) was added thereto. After reacting for 59 hours, 1N 
hydrochloric acid was added to stop the reaction. The mixture was 
extracted with ethyl acetate (10 ml.times.three times), and the combined 
extracts were washed with brine and dried over Na.sub.2 SO.sub.4. The 
solvent was distilled, and the residue was purified by flash column 
chromatography (acetone/hexane=1/5, on SiO.sub.2) to obtain dimethyl 
(R)-hydroxy(p-methoxyphenyl)methylphosphonate as a final product in a 
yield of 25%. The chemical reaction in this Example is shown in chemical 
formula 46. 
Chemical formula 46 
##STR48## 
The results of an analysis of this reaction product are shown in Table 35. 
TABLE 35 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
3.19(bs, 1H), 3.63(d, J=10.4Hz, 3H), 
(.delta.) 3.65(d, J=10.4Hz, 3H), 3.74(s, 3H), 
4.91(d, J=9.9Hz, 1H), 6.85 
(d, J=8.3Hz, 2H), 7.34 
(dd, J=2.0, 8.3Hz, 2H) 
Optical purity 
35% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., 
isopropanol/hexane = 1/4, 
detection: 254 nm, flow rate: 1.1 
ml/min. 
______________________________________ 
EXAMPLE 42 
Asymmetric hydrophosphonylation reaction using ALB--CN 
The same procedure as shown in Example 41 was used, except that 
2-methylpropionaldehyde was used in place of the p-methoxybenzaldehyde 
used in Example 41 to afford dimethyl 
(S)-1-hydroxy-2-methylpropylphosphonate as a final product in a yield of 
66%. The chemical reaction in this Example is shown in chemical formula 
47. 
Chemical formula 47 
##STR49## 
The results of an analysis of this reaction product are shown in Table 36. 
TABLE 36 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
1.15(dd, J=2.0, 6.9Hz, 6H), 2.19 
(.delta.) (m, 1H), 2.95(t, J=6.6Hz, 1H), 3.79 
(dd, J=9.3, 12.2Hz, 1H), 3.89 
(d, J=10.6Hz, 3H), 3.90 
(d, J=10.6Hz, 3H) 
Optical purity 
29% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daicel 
Chemical Industries Co., Ltd., 
isopropanol/hexane = 1/4, detection: 
differential refraction, flow rate: 
0.5 ml/min. 
______________________________________ 
EXAMPLE 43 
Asymmetric hydrophosphonylation reaction using ALB--CN 
The same procedure as shown in Example 41 was used, except that 
3-methyl-2-butenal was used in place of the p-methoxybenzaldehyde used in 
Example 41 to afford dimethyl (R)-1-hydroxy-3-methyl-2-butenylphosphonate 
as a final product in a yield of 34%. The chemical reaction in this 
Example is shown in chemical formula 48. 
Chemical formula 48 
##STR50## 
The results of an analysis of this reaction product are shown in Table 37. 
TABLE 37 
______________________________________ 
.sup.1 H NMR (CDCl.sub.3) 
1.71(dd, J=1.3, 3.0Hz, 3H), 1.81 
(.delta.) (dd, J=1.0, 4.0Hz, 3H), 3.18(bs, 1H) 
3.80(d, J=10.5Hz, 3H), 3.82 
(d, J=10.5Hz, 3H), 4.66 
(dt, 5.5, 9.1, 9.2, 1H), 5.33(m, 1H) 
Optical purity 
47% e.e. HPLC analysis conditions: 
(HPLC analysis) 
CHIRALPAK AS manufactured by Daic- 
el Chemical Industries Co., Ltd., 
isopropanol/hexane = 5/95, 
detection: differential 
refraction, flow rate: 0.5 
ml/min. 
______________________________________ 
Reference Example 
Reduction of unsaturated bond 
Dimethyl (S)-1-hydroxy-3-methyl-2-butenylphosphonate obtained in Example 31 
(68% e.e., 54 mg) was dissolved in 10 ml of methanol, and 10% Pd/C (16 mg) 
was added thereto. The mixture was stirred at room temperature for 3 hours 
under hydrogen atmosphere. The reaction mixture was filtered through 
Celite and the filter cake was washed with ethyl acetate. The solvent was 
distilled under reduced pressure and the residue was purified by flash 
column chromatography (acetone/hexane=1/4, on SiO.sub.2) to obtain 
dimethyl (S)-1-hydroxy-3-methylbutylphosphonate as a final product in a 
yield of 98%. This compound is known to be useful as a raw material for 
medicines and the like. The chemical reaction in this Reference Example is 
shown in chemical formula 49. 
Chemical formula 49 
##STR51## 
The results of an analysis of this reaction product are shown in Table 38. 
TABLE 38 
______________________________________ 
IR (neat) 3320 cm.sup.-1 
.sup.1 H NMR (CDCl.sub.3) 
0.90(d, J=6.6Hz, 3H), 0.95 
(.delta.) (d, J=6.6Hz, 3H), 1.47(m, 1H), 1.73 
(m.1H), 1.95(m,JH), 3.78 
(d, J=10.2Hz, 3H), 3.79 
.sup.13 C NMR (CDCl.sub.3) 
21.0, 23.4, 24.0(J=14.6Hz), 39.9, 
(.delta.) 53.2(J=4.9Hz), 53.3(J=6.1Hz), 
65.5(J=161.1Hz) 
MS m/z 196 9M.sup.+) 
.alpha.!.sub.p.sup.25 
+16.4.degree.(c1.0, CHCl.sub.3) 
Optical purity 
68% e.e. HPLC analysis conditions: 
(HPLC analy- CHIRALPAK AS manufactured by Daic- 
sis) el Chemical Industries Co., Ltd., 
isopropanol/hexane = 1/4, flow 
rate: 1.0 ml/min., detection: 
differential refraction 
______________________________________ 
INDUSTRIAL APPLICABILITY 
The process for producing an asymmetric compound of the present invention 
is suitable for obtaining, in a high yield, an optically active compound 
having high optical purity, which is useful as an intermediate for 
medicines, by an asymmetric Michael reaction and an asymmetric 
hydrophosphonylation reaction although the process uses, as a catalyst, a 
metal complex containing no rare earth metal element.