Synthesis of bifunctional P-chiral hydroxy phosphinates; Lipase-catalyzed stereoselective acylation of ethyl (1-hydroxyalkyl)phenylphosphinates

Article abstract of DOI:10.1016/S0040-4039(02)02716-8

Lipase-catalyzed acylation of ethyl (1-hydroxyalkyl)phenylphosphinates afforded a single diastereomer in high enantiomeric excess. The substituent effect of the alkyl group toward the acylation using Candida antractica (CAL) was larger than that of an imm

Full text of DOI:10.1016/S0040-4039(02)02716-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1103–1105
Synthesis of bifunctional P-chiral hydroxy phosphinates;
lipase-catalyzed stereoselective acylation of ethyl
(1-hydroxyalkyl)phenylphosphinates
Kosei Shioji,* Aya Tashiro, Sanae Shibata and Kentaro Okuma
Department of Chemistry, Faculty of Science, Fukuoka University, Jonan-ku, Fukuoka 814-0180, Japan
Received 17 September 2002; revised 20 November 2002; accepted 22 November 2002
Abstract—Lipase-catalyzed acylation of ethyl (1-hydroxyalkyl)phenylphosphinates afforded a single diastereomer in high enan-
tiomeric excess. The substituent effect of the alkyl group toward the acylation using Candida antractica (CAL) was larger than that
of an immobilized lipase from Pseudomonas fluorescens lipase (lipase AK). © 2003 Elsevier Science Ltd. All rights reserved.
The synthesis, stereochemistry, and utility of P-chiral
phosphorus compounds possessing a stereocenter at the
phosphorus are of current interest.1 Phosphorus com-
pounds having other optically active functionalities
such as hydroxyl and amino groups are useful for
homogeneous asymmetric metal catalysis in the
reaction2 and as chiral auxiliaries in the synthesis of
allylic alcohols3 and oxazolidinones.4 Warren et al.
synthesized P-chiral 1,2-hydroxyphosphine oxides as
precursors of optically active alcohol.5 Recently,
Granell et al. reported the synthesis and resolution of a
P-chiral benzyl(a-hydroxybenzyl)phenylphosphine by
palladium metallacycles.6 Lipase-catalyzed optical reso-
lution is a most powerful method for the synthesis of
optically pure alcohols and esters. Kielbasinski et al.
have reported that P-chiral methyl a-hydroxy-
methylphosphinate was a good substrate of lipase-cat-
alyzed kinetic resolution (E=ꢀ51).7 We have also
reported lipase-catalyzed optical resolution of primary
alcohol-type phosphine oxides (E=ꢀ95).8 However,
there is no report on the optical resolution of phosphi-
nates with two stereogenic centers. We describe here the
synthesis and kinetic resolution of phosphinates con-
taining two stereogenic centers, the phosphorus and
a-carbon atom, via lipase-catalyzed acylation.
The preparation of racemic phosphinates 1 was carried
out by a slightly modified Haynes’s method.9,10 The
nucleophilic addition of lithiated ethyl phenylphosphi-
nate to appropriate aldehydes gave the major and
minor products (Scheme 1).
The products ratios depended on reaction temperature.
The ratio of major 1a to minor product was 2:1 at
Table 1. The reaction of lithiated ethyl phenylphosphinate
with aldehydes at −78°C
Substrate
R
Yield (%)
Major:minora
1a
1b
1c
Me
Et
52
58
69
4:1
5:1
6:1
Pri
a Determined by 1H NMR.
Scheme 1.
* Corresponding author. E-mail: shioji@fukuoka-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02716-8

1104
K. Shioji et al. / Tetrahedron Letters 44 (2003) 1103–1105
−15°C, whereas it was 1:1 at 0°C. The yields and
products ratios of the reactions at −78°C are summa-
rized in Table 1.
85% yield. The obtained optically pure diastereomer 1a
was converted into Mosher’s MTPA ester 3a* using
(R)-MTPA chloride in 90% yield.11 The absolute
configuration of reacting 1a was assumed by comparing
1
the H NMR spectrum of (R)-MTPA esters 3a* with
The kinetic separation of the major phosphinates (SP,S)
and (RP,R)-1 was carried out by CAL and lipase AK-
catalyzed acylation using vinyl acetate as an acyl donor.
The acylation of a mixture of (SP,S) and (RP,R)-1
afforded the corresponding enantiomerically pure esters
2 (Scheme 2). These results are shown in Table 2. Using
CAL, hydroxy phosphinates 1a and b were esterified to
give acetyl phosphinates 2 with high optical purity
(>98%). Using lipase AK, each methyl and ethyl deriva-
tive 1a,b also reacted to reach 50% conversion with
high enantioselectivity. After being stirred for 48 h, the
yield of recovered phosphinates 1a was 50% with >98%
enantiomeric excess. Thus, perfect resolution was
achieved in the present acylation. Methyl derivative 1a
was acylated rapidly by using CAL compared with
lipase AK. Lipase AK acylated isopropyl derivative 1c,
which was not acylated by using CAL. Thus, the differ-
ence of acylation rates of 1 using CAL was larger than
those using lipase AK. The difference in the sensitivity
toward substituent R indicates that the hydrophobic
pocket of lipase AK was much flexible than that of
CAL.
that of MTPA esters of (RP,R) and (SP,S)-1a. 1H NMR
chemical shifts of the methyl group of 3a were observed
at 1.54 and 1.44 ppm. The methyl group of ester 3a*
was observed at 1.44 ppm. The methyl signal of the (S)
conformer was upfield shifted by the anisotropic effect
of the phenyl group relative to the (R) conformer.
Thus, acylating hydroxy phosphinate 1a has (SP,S)
configuration (Fig. 1). The Cotton effect of other opti-
cally active hydroxy phosphinates, which were resolved
by lipase-catalyzed acylation, was similar to that of
(RP,R)-1a. In view of these results, lipase AK and CAL
favored (SP,S)-1 rather than the (RP,R)-diastereomer.
There is an empirical rule for the enantiopreference of
lipase-catalyzed optical resolution toward secondary
alcohols.12
The reacting optically pure diastereomer 2a was
hydrolyzed in the presence of a small amount of H2SO4
in methanol to give optically pure diastereomer 1a in
Figure 1. Configurational correlation model for (R)-MTPA
esters 3a.
Scheme 2.
Table 2. Lipase-catalyzed kinetic resolution of 1a
Substrate
Lipaseb
Time (h)
Conv. (%)
Ee (%) of recovered 1c
Ee (%) of esters 2c
1a
1b
1c
1a
1a
1b
1c
CAL
CAL
CAL
AK
AK
AK
1
32
50
17
\98
28
\98
\98
No reaction
\98d
\98
\98f
2
8
48
29
75
50
50
50
9
\98e
\98
\98g
\98
AK
a
,
Lipase (20 mg) was added to a mixture of (SP,S) and (RP,R)-1 (0.023 mmol), vinyl acetate (0.165 mmol) and 3 A molecular sieves (20 mg) in
diisopropyl ether (2.0 ml) at 36°C.
b AK; Pseudomonas fluorescens lipase (Amano AK), CAL; immobilized lipase from Candida antractica (Chirazyme® L-2, cf. C2, lyo.).
c Enantiomeric excess (ee%) was determined by HPLC (CHIRALPAK AD, Daicel).
d [h]D +15.4 (c=2.7, CHCl3).
e [h]D −8.82 (c=1.0, CHCl3).
f [h]D +11.5 (c=0.21, CHCl3).
g [h]D −4.65 (c=0.16, CHCl3).

K. Shioji et al. / Tetrahedron Letters 44 (2003) 1103–1105
1105
Scheme 3.
The obtained phosphinates 1 and 2 are converted into
P-chiral phosphine oxides by several organomagnesium
reagents without racemization.13 We then tried substitu-
tion of the ethoxy ligand of P-chiral phosphinate
(RP,R)-1a to a vinyl group.
12, 3139; (c) Kielbasinski, P.; Omelanczuk, J.; Mikola-
jczyk, M. Tetrahedron: Asymmetry 1998, 9, 3283.
8. Shioji, K.; Ueno, Y.; Kurauchi, Y.; Okuma, K. Tetra-
hedron Lett. 2001, 42, 6569.
9. Haynes, R. K.; Lam, W. W.-L.; Yeung, L.-L. Tetra-
hedron Lett. 1996, 37, 4729.
Reaction of TBS ether (RP,R)-4a, which was prepared
from (RP,R)-1a with tert-butyldimethylsilyl chloride
(TBSCl), with vinylmagnesium bromide afforded the
corresponding vinylphosphine oxide (RP,R)-5a in 48%
10. The major products (SP,S) and (RP,R)-1 were purified by
preferential crystallization from ethyl acetate–hexane.
Satisfactory elemental analyses were obtained for all new
compounds. Ethyl (1-hydroxyethyl)phenylphosphinate
(1a); major products; 1H NMR (400 MHz, CDCl3) l=
1.33 (dd, J=6.8, 16.8 Hz, 3H), 1.36 (t, J=6.8 Hz, 3H),
3.97–4.22 (m, 3H) 7.45–7.85 (m, 5H); 13C NMR (100
MHz, CDCl3) l=16.4 (JPC=5.0 Hz), 16.97 (JPC=3.2
Hz), 61.5 (JPC=7.5 Hz), 65.9 (JPC=116.0 Hz), 128.4,
128.6, 128.8, 132.4, 132.5, 132.6, 132.7; 31P NMR (162
MHz, CDCl3) l=42.4. Ethyl (1-hydroxypropyl)-
phenylphosphinate (1b); major products; 1H NMR (400
MHz, CDCl3) l=1.03 (t, J=7.4 Hz, 3H), 1.35 (t, J=6.8
Hz, 3H), 1.50–1.77 (m, 2H), 3.86–4.00 (m, 1H), 4.01–4.21
(m, 2H), 7.49–7.86 (m, 5H); 13C NMR (100 MHz,
CDCl3) l=10.50 (JPC=12.5 Hz), 16.5 (JPC=4.9 Hz),
24.2, 61.4 (JPC=5.8 Hz), 71.7 (JPC=87.1 Hz), 127.8,
128.4, 128.5, 132.4, 132.5, 132.6, 132.7; 31P NMR (162
MHz, CDCl3) l=41.4. Ethyl (1-hydroxy-2-methyl-
propyl)phenylphosphinate (1c); major products; 1H
NMR (400 MHz, CDCl3) l=1.02 (d, J=2.0 Hz, 6H),
1.34 (t, J=7.0 Hz, 3H) 1.92–2.04 (m, 1H), 3.73–3.78 (m,
1H), 3.94–4.22 (m, 2H) 7.47–7.87 (m, 5H); 13C NMR
(100 MHz, CDCl3) l=16.5 (JPC=5.8 Hz), 17.3 (JPC=5.8
Hz), 20.2 (JPC=10.0 Hz), 29.4, 75.2 (JPC=109.0 Hz),
128.6, 128.7, 129.9, 132.1, 132.3, 132.4, 132.5; 31P NMR
(162 MHz, CDCl3) l=40.7.
1
yield (Scheme 3). H NMR and HPLC analysis of 5a
indicated that racemization did not occur in the course
of substitution. Thus, the optically active vinyl phos-
phine oxide, which is used as precursor of other func-
tional phosphine oxides, was obtained.1
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