Lipase-catalyzed kinetic resolution of α-hydroxy-H-phosphinates

Article abstract of DOI:10.1016/j.tetlet.2004.07.066

A chiral synthesis of α-hydroxy-H-phosphinates was achieved via lipase-catalyzed hydrolysis of acetate precursors.

Full text of DOI:10.1016/j.tetlet.2004.07.066

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6713–6716
Lipase-catalyzed kinetic resolution of a-hydroxy-H-phosphinates
Takehiro Yamagishi, Tetsuya Miyamae, Tsutomu Yokomatsu* and Shiroshi Shibuya
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 28 May 2004; revised 13July 2004; accepted 16 July 2004
Available online 3August 2004
Abstract—A chiral synthesis of a-hydroxy-H-phosphinates was achieved via lipase-catalyzed hydrolysis of acetate precursors.
Ó 2004 Elsevier Ltd. All rights reserved.
a-Heteroatom substituted phosphinic acids are of much
interest due to their usefulness both in the development
of catalytic antibodies1 and pharmacologically active
substances.2 Some a-hydroxyphosphinic acids function
as GABA antagonists3 and significant intermediates
for inhibitors of human renin4 as well as HIV protease.5
However, very little investigation has been undertaken
on a chiral synthesis of this class of compounds.6 We
have previously succeeded in the first chiral synthesis
of a-hydroxy-H-phosphinates, useful synthetic interme-
diates for a-hydroxyphosphinates, through the addition
of methyl phosphinate to aldehydes utilizing
AlLibis(binaphthoxide) (ALB)7 as the catalyst.8 This
methodology afforded adducts as a mixture of diastere-
omers arising from the chirality of the phosphinate
group. Enantioselectivity concerning the a-position
was moderate (up to 85% ee) in reactions of aromatic
aldehydes, whereas low enantiomeric ratio resulted in
the case of aliphatic aldehydes. To overcome the limita-
tions of optical purity and generality, we envisioned
exploring a new method utilizing an enzymatic proce-
dure for the resolution of a-hydroxy-H-phosphinates.
Kielbasinski et al. successfully applied lipase-catalyzed
kinetic resolution for a chiral hydroxymethylphosphi-
nate possessing an asymmetric center at phosphorus
atom.9 Quite recently, Shioji et al. accomplished the
kinetic resolution of a-hydroxy(phenyl)phosphinates
containing two stereogenic centers at the phosphorus
and a-carbon atom through lipase-catalyzed acylation.10
In this letter, we wish to report a new chiral synthesis of
a-hydroxy-H-phosphinates having two chiral centers via
HO
O
P
R
H
OEt
Figure 1.
lipase-catalyzed hydrolysis reactions of the correspond-
ing racemic acetates (Fig. 1). The present reactions
could provide products as a single diastereomer with
high enantio purity starting from not only diastereo-
merically pure racemic acetates but also a mixture of
diastereoisomers.
The requisite a-acetoxy-H-phosphinates 3a–e in the
study were prepared as shown in Scheme 1. The hydro-
phosphinylation of aldehydes with phosphinate 111 in
the presence of 20mol% of PhOLi, according to our pre-
vious procedure,12 provided adducts 2a–e in 61–86%
yield. Acetylation of 2a–e followed by treatment with
TMSCl and EtOH gave 3a–e as a mixture of diastereo-
mers. Although individual diastereomers of 3a were not
separated by silica gel column chromatography, employ-
ing preparative HPLC made it possible to isolate
*
*
(R*,RP )-3a and (R*,SP )-3a in pure states.
*
To verify the relative stereochemistry of (R*,SP )-3a, the
chemical transformations shown in Scheme 2 were
performed. Tanaka and co-workers have recently
elucidated that chiral alkenylphosphinates possessing
an asymmetric center at phosphorus atom could be pre-
pared via palladium-catalyzed stereospecific hydrophos-
phinylation of alkynes, which proceeded with
retention of configuration at the phosphorus.13 When
Keywords: Phosphinic acids and derivatives; Lipase; Kinetic
resolution.
*
the reaction of (R*,SP )-3a with 4-ethynyltoluene
*
was carried out based upon TanakaÕs protocol,
alkenylphosphinate 4 was formed in 65% yield without
Corresponding author. Tel./fax: +81-426-76-3239; e-mail: yokomatu@
ps.toyaku.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.066

6714
T. Yamagishi et al. / Tetrahedron Letters 45 (2004) 6713–6716
1) Ac2O, pyridine,
HO
AcO
O Me
P
RCHO
O Me
P
O
DMAP
H
OEt
R
OEt
R
PH
OEt
PhOLi
(20 mol %)
2) TMSCl, EtOH
(46-64%)
EtO OEt
EtO OEt
1
3a-e
2a-e
(61-86%)
a: R=4-Me-C6H4; b: R=Ph; c: R=4-Cl-C6H4; d: R=PhCH2; e: R=n-C5H11
Scheme 1.
Ar
AcO
Me2Pd(PPh2Me)2,
Ph2P(O)OH
AcO
1) OsO4, NaIO4
2) NaBH4
O
P
O
H
Ar
Ar
P
Ar
toluene, 70 ˚C
Ar=4-Me-C6H4
3) Ac2O, pyridine,
DMAP
OEt
(R*,SP*)-3a
OEt
4 (65%)
AcO
OAc
AcO
OAc
O
O
O
O
1) Et3N, MeOH
O
P
+
Ar
P
Ar
Ar
P
Ar
Ar
Ar
2) Me2C(OMe)2,
CSA
OEt
OEt
OEt
5 (27%)
6 (40%)
7
Me
Me
O
H
O
O
P
O
H
CH3
selected NOESY correlation of 7
Scheme 2.
*
detection of any diastereomer. Sequential oxidative
cleavage of the olefin moiety of 4 with OsO4–NaIO4,
reduction with NaBH4, and acetylation gave racemic
diacetate 5 and meso diacetate 6. Stereochemistry of
the meso product 6 was determined after converting to
the acetonide 7. The NOESY correlation suggested the
Having obtained diastereomerically pure (R*,RP )-3a
*
and (R*,SP )-3a, enzyme-catalyzed hydrolysis reaction
of each isomer was investigated (Scheme 4). Upon treat-
ment of (R*,RP )-3a (384mg, 1.5mmol) with 75mg of
*
lipase PS (Pseudomonas cepacia) in hexane/t-BuOMe
in the presence of 0.067M phosphate buffer (pH7.0) at
25°C for 30h, the desired reaction did not proceed
and the crude starting material (76mg) was recovered.14
HPLC analysis using a column with a chiral stationary
phase (DAICEL CHIRALPAK AS column, hexane–
*
relative stereochemistry of 7 to be R*,SP ,R*.
The assignment was further confirmed by spectroscopic
*
comparison with (R*,RP ,R*)-isomer 9, prepared from
*
*
(R*,SP )-3a (Scheme 3). The PhOLi-catalyzed hydro-
EtOH = 85:15) revealed the recovered (R*,RP )-3a was
racemate. On the other hand, when (R*,SP )-3a was sub-
*
*
phosphinylation of p-tolualdehyde with (R*,SP )-3a
and acetylation gave products 5, 6, and 8. After separa-
tion, 8 was converted into 9 through removal of the
acetyl group with Et3N in MeOH followed by
acetonidation.
mitted to similar conditions, the reaction was completed
within 4h as verified by TLC monitoring, providing the
alcohol (R,SP)-10a in 18% yield along with recovered
acetate (S,RP)-3a in 33% yield.15 Optical purity of
1) PhOLi (20 mol %),
ArCHO
AcO
AcO
OAc
O
P
O
P
H
5
6
+
+
Ar
Ar
Ar
2) Ac2O, pyridine,
DMAP
OEt
OEt
8
(R*,SP*)-3a Ar=4-Me-C6H4
Me
O
Me
O
O
O
H
O
P
1) Et3N, MeOH
O
Ar
P
Ar
2) Me2C(OMe)2,
CSA
O
OEt
H
H
H
9
CH3
selected NOESY correlation of 9
Scheme 3.

T. Yamagishi et al. / Tetrahedron Letters 45 (2004) 6713–6716
6715
AcO
HO
AcO
O
P
O
P
O
P
lipase PS
H
H
H
+
hexane, t-BuOMe,
phosphate buffer,
25 ˚C, 30 h
OEt
OEt
OEt
Me
Me
Me
Me
Me
Me
(R*,RP*)-3a
(R,RP)-10a
(S,SP)-3a
AcO
O
HO
O
AcO
O
lipase PS
H
H
H
+
P
P
P
hexane, t-BuOMe,
phosphate buffer,
25 ˚C, 4 h
OEt
OEt
OEt
(R,SP)-10a
(S,RP)-3a
(R*,SP*)-3a
18%, 99% ee
33%, 94% ee
Scheme 4.
(R,SP)-10a and (S,RP)-3a was determined to be 99% and
94% ee, respectively.16 The results indicated that lipase
enantiopurity in >99% and 90% ee, respectively (entries
2 and 3). In comparison to using 3a–c, decrease in the
optical purity was observed in the reaction of 3d and
3e having an aliphatic group (entries 4 and 5). In view
of the level of optical purity, the methodology using
the lipase-catalyzed hydrolysis proved to be superior
to reported ALB-catalyzed hydrophosphinylation of
aldehydes (43–85% ee).17
*
PS led to hydrolysis of only one diastereomer (R*,SP )-
3a and highly selective conversion of one enantiomer
(R,SP)-3a into the corresponding alcohol in preference
to (S,RP)-3a.
On the basis of the above results, we next examined
lipase-catalyzed hydrolysis of a-acetoxy-H-phosphinates
composed of four kinds of stereoisomers. In these reac-
tions, one isomer would be hydrolyzed selectively to give
the a-hydroxy-H-phosphinates with high optical purity
in 25% maximum yield. The results from these experi-
ments are summarized in Table 1.
The relative stereochemistry of (R,SP)-10b–e was
estimated analogously to (R,SP)-10a, whose relative config-
uration has already been determined. The absolute
configuration at the a-position of (R,SP)-10a–e was veri-
fied after their conversion to known a-hydroxyphospho-
nates 11a–e through acetylation, oxidation with DMSO
and I2,18 esterfication with diazoethane, and deacetyl-
ation (Scheme 5). By comparing the optical rotation of
The hydrolysis reaction of 3a, a mixture of diastereo-
mers in a ratio of 1.3:1, in the presence of lipase PS
afforded (R,SP)-10a in 14% yield as a single diastereomer
with recovering 3a (39% yield) as a diastereomixture in a
ratio of 2.0:1 (entry 1). The high optical purity of (R,SP)-
10a (>99% ee) demonstrated that only one isomer was
reacted selectively among four kinds of stereoisomeric
acetates through differentiation of both enantiomer
and diastereomer by lipase PS. Similar reactions were
carried out using 3b–e for probing the scope of the sub-
strates. Reactions of 3b and 3c possessing an aromatic
group also gave (R,SP)-10b and (R,SP)-10c with high
1) Ac2O, pyridine, DMAP
HO
HO
O
P
O
P
2) DMSO, I2
H
OEt
R
R
3) CH3CHN2
4) Et3N
OEt
OEt
(R,SP)-10a-e
11a-e
a: R=4-Me-C6H4; b: R=Ph; c: R=4-Cl-C6H4; d: R=PhCH2; e: R=n-C5H11
Scheme 5.
Table 1. Hydrolysis reactions of a-acetoxy-H-phosphinates in the presence of lipase PS
HO
AcO
R
AcO
R
O
P
O
O
lipase PS
H
+
R
PH
OEt
PH
OEt
hexane, t-BuOMe,
phosphate buffer,
25 ˚C, 4 h
OEt
3a-e
(R,SP)-10a-e
3a-e
a: R=4-Me-C6H4; b: R=Ph; c: R=4-Cl-C6H4; d: R=PhCH2; e: R=n-C5H11
Entry
3 (dra)
(R,SP)-10a–e
Recovered 3a–e
Yield (%)
Yield (%)
ee (%)b
Dra
1
2
3
4
5
a (1.3:1)
b (1.5:1)
c (1.2:1)
d (1.3:1)
e (1.2:1)
14
17
10
14
9
>99
>99
90
39
45
32
76
54
2.0:1
2.8:1
2.2:1
1.4:1
1.5:1
74
76
a Diastereomeric ratio.
b Determined by 31P NMR (121MHz, CDCl3) analysis of corresponding MTPA esters.

6716
T. Yamagishi et al. / Tetrahedron Letters 45 (2004) 6713–6716
11a–e with those reported,19 the absolute stereochemis-
try of 11a–e was determined to be R configuration.
P.; Albrycht, M.; Luczak, J.; Mikolajczyk, M. Tetrahe-
dron: Asymmetry 2002, 13, 735.
10. Shioji, K.; Tashiro, A.; Shibata, S.; Okuma, K. Tetrahe-
dron Lett. 2003, 44, 1103.
11. Baylis, E. K. Tetrahedron Lett. 1995, 36, 9385.
12. Yamagishi, T.; Kusano, T.; Kaboudin, B.; Yokomatsu,
T.; Sakuma, C.; Shibuya, S. Tetrahedron 2003, 59, 767.
13. Han, L.-B.; Zhao, C.-Q.; Onozawa, S.; Goto, M.; Tanaka,
M. J. Am. Chem. Soc. 2002, 124, 3842.
In conclusion, we have developed a new method for pre-
paring chiral a-hydroxy-H-phosphinates through lipase-
catalyzed hydrolysis of the corresponding racemic
acetates. From a mixture of four kinds of stereoisomers
of a-acetoxy-H-phosphinates, one isomer of a-hydroxy-
H-phosphinates was obtained selectively.
14. No by-products were detected by 1H and 31P NMR
analysis of the crude recovered starting materials. Thus,
low yield of recovered (R*,RP*)-3a might be associated
with partial hydrolysis of their phosphinate moiety in the
reaction mixture.
Acknowledgements
15. Lipase PS-catalyzed hydrolysis reaction of (R*,SP*)-3a
(512mg, 2mmol) gave the corresponding crude products
(378mg) and performing silica gel column chromatogra-
phy afforded (R,SP)-10a (77mg, 0.36mmol) and (S,RP)-3a
(171mg, 0.66mmol). It was apparent that the amount
yield of (R,SP)-10a and (S,RP)-3a was relatively low
compared to that of crude products. Any by-products
were not detected by 1H and 31P NMR analysis of the
corresponding crude materials. Thus, low chemical yields
of (R,SP)-10a and (S,RP)-3a might be associated with both
loss at the purification step and partial hydrolysis of their
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Cul-
ture, Sports, Science, and Technology, Japan. We are
also grateful to Amano Pharmaceutical Co., Ltd for
providing lipase PS, AY-30, AS, and F-AP 15.
References and notes
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phosphinate moiety in the reaction mixture.
20
16. Compound (R,SP)-10a: an oil; ½aŠ þ59:4 (c 1.4, CHCl3);
D
1H NMR (400MHz, CDCl3): d 7.32–7.30 (2H, m), 7.21–
7.19 (2H, m), 6.90 (1H, d, J = 532.6Hz), 4.92 (1H, s),
4.17–4.10 (2H, m), 2.35 (3H, s), 1.32 (3H, t, J = 7.0Hz);
31P NMR (162MHz, CDCl3): d 33.38; IR (neat) 3227,
1201cmꢀ1; ESIMS m/z 215 (MH+). HRMS calcd for
C10H16O3P (MH+): 215.0837; found: 215.0833. Com-
20
pound (R,SP)-3a: an oil; ½aŠ ꢀ 43:0 (c 1.4, CHCl3); 1H
ˆ
Karlsson, G.; Klebs, K.; Maıtre, L.; Marescaux, C.;
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J = 9.0Hz), 4.13–4.04 (2H, m), 2.35 (3H, s), 1.28 (3H, t,
J = 7.0Hz); 31P NMR (162MHz, CDCl3): d 27.58; IR
(neat) 1751, 1226cmꢀ1; ESIMS m/z 279 (MNa+). HRMS
calcd for C12H17O4NaP (MNa+): 279.0762; found:
279.0773.
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17. We also examined reactions of 3b with other enzymes such
as lipase AY-30 (Candida rugosa), lipase AS (Aspergillus
nieger), lipase F-AP 15 (Rhizopus oryzae). While the
desired reaction did not proceed in the presence of lipase
AY-30, employing lipase AS gave the hydrolysis product
(36% yield) as a mixture of diastereomers (1:2.1). The
reaction in the presence of lipase F-AP 15 provided the
product as a diastereomixture (1:2.4) in low yield (5%).
Thus, lipase PS proved to be the optimum enzyme among
those examined for resolving a-hydroxy-H-phosphinates.
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