An efficient route to chiral α- and β-hydroxyalkanephosphonates

Article abstract of DOI:10.1021/jo026888m

Enzymatic kinetic resolution of α- and β-hydroxyphosphonates in combination with ruthenium-catalyzed alcohol isomerization led to a successful dynamic kinetic resolution. A variety of racemic hydroxyphosphonates were efficiently transformed to the corresponding enantiomerically pure acetates (ee up to 99% and yield up to 87%).

Full text of DOI:10.1021/jo026888m

An Efficien t Rou te to Ch ir a l r- a n d â-Hyd r oxya lk a n ep h osp h on a tes
Oscar Pa`mies* and J an-E. Ba¨ckvall*
Arrhenius Laboratory, Department of Organic Chemistry, Stockholm University,
SE-10691 Stockholm, Sweden
jeb@organ.su.se; pamies@organ.su.se
Received December 20, 2002
Enzymatic kinetic resolution of R- and â-hydroxyphosphonates in combination with ruthenium-
catalyzed alcohol isomerization led to a successful dynamic kinetic resolution. A variety of racemic
hydroxyphosphonates were efficiently transformed to the corresponding enantiomerically pure
acetates (ee up to 99% and yield up to 87%).
In tr od u ction
phonates by lipase-catalyzed transesterification6b,8 and
hydrolysis of the corresponding acetates6b,9 have been
reported. The former studies have shown that hydroxy-
alkanephosphonates are transesterified at good reaction
rates and good selectivity.
During recent years, there has been a growing interest
in chiral hydroxyalkanephosphonates due to their pres-
ence in bioactive molecules (e.g., peptide analogues,
haptens of catalytic antibodies, phosphonic acid-based
antibiotics, and enzyme inhibitors).1 Moreover, they are
also useful intermediates for a variety of organophos-
phorus derivatives.2 The known chemical approaches to
these synthetically valuable compounds include the
enantio- and diastereoselective addition of dialkyl phos-
phites to aldehydes,3 the Lewis acid-catalyzed ring open-
ing of 1,3-dioxane acetals with phosphites,4 and the
asymmetric reduction of ketophosphonates.5 However, of
all these chemical approaches only the asymmetric
stoichoimetric boron reduction of ketophosphonates pro-
vides access to chiral R-, â-, and γ-hydroxyalkanephos-
phonates.5d Bioconversions also provide access to the
required diversity of chiral hydroxyalkanephosphonates.
In particular, the microbial and enzymatic reduction of
ketophosphonates has been successfully applied.6 Lipase-
catalyzed kinetic resolutions can be useful alternatives,
especially because coenzyme regeneration, an inherent
problem of enzymatic redox reactions, is not required.7
Thus, during the past decade, several studies dealing
with the kinetic resolution (KR) of hydroxyalkanephos-
A major drawback with KR is that the yield is limited
to a maximum of 50%. An efficient use of all racemate
can be achieved by applying dynamic kinetic resolution
(DKR). We and others have recently developed proce-
dures for DKR of alcohols in which the traditional
enzymatic kinetic resolution is combined with an in situ
racemization of the substrate using a ruthenium hydrogen-
transfer catalyst.10 As a part of our ongoing project on
chemoenzymatic DKR of different functionalized alcohols,
which would lead to interesting building blocks for the
synthesis of high-value compounds (e.g., pharmaceuti-
cals, natural products, etc.),11 we now report on the
synthesis of enantiopure acetoxyalkanephosphonates via
DKR (Scheme 1).
Resu lts a n d Discu ssion
Syn th esis of Hyd r oxyp h osp h on a tes. Two different
routes were employed for the synthesis of starting
materials (Scheme 2). Thus, R-hydroxyphosphonates
1a -h were prepared efficiently by reaction of the corre-
(1) See for instance: (a) Guiannousis, P. P.; Barlett, P. A. J . Med.
Chem. 1987, 30, 1603. (b) Heilmann, J .; Maier, W. F. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 471. (c) Hirschmann, R.; Smith, A. B., III;
Taylor, C. M.; Benkovic, P. A.; Taylor, S. D.; Yager, K. M.; Sprengeler,
P. A.; Benkovic, S. J . Science 1994, 265, 234.
(2) See, for example: (a) Dhawm, B.; Redmore, D. Phosphorus Sulfur
1987, 32, 119. (b) Laschat, H.; Kunz, H. Synthesis 1992, 90.
(3) (a) Gordon; N. G.; Evans, S. A. J . Org. Chem. 1993, 58, 5293. (b)
Rath, N. P.; Spilling, C. D. Tetrahedron Lett. 1994, 35, 227. (c) Balzis,
V. J .; Kobler, K. J .; Spilling, S. J . Org. Chem. 1995, 60, 931. (d) Arai,
T.; Bougauchi, M.; Sasai, H.; Shibasaki, M. J . Org. Chem. 1996, 61,
2926.
(7) Engel, K. H.; Boh Nen, M.; Dobe, M. Enzyme Microb. Technol.
1991, 13, 655.
(8) (a) Zurawinski, R.; Nakamura, K.; Drabowicz, J .; Kielbasinski,
P.; Mikolajczyk, M. Tetrahedron: Asymmetry 2001, 12, 3139. (b) Zhang,
Y.; Yuan, C.; Li, Z. Tetrahedron 2002, 58, 2973.
(9) See, for instance: (a) Li, Y. F.; Hammerschmidt, F. Tetrahe-
dron: Asymmetry 1993, 4, 109. (b) Drescher, M.; Hammerschmidt, F.;
Ka¨hlig, H. Synthesis 1995, 1267. (c) Drescher, M.; Hammerschmidt,
F. Tetrahedron 1997, 53, 4627. (d) Hammerschmidt, F.; Wuggenig, F.
Tetrahedron: Asymmetry 1999, 10, 1709.
(10) See, for instance: (a) Larsson, A. L. E.; Persson, B. A.; Ba¨ckvall,
J .-E. Angew. Chem., Int. Ed. Engl. 1997, 36, 1211. (b) Persson, B. A.;
Larsson, A. L. E.; LeRay, M.; Ba¨ckvall, J .-E. J . Am. Chem. Soc. 1999,
121, 1645. (c) Choi, J . H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; Kim, M.
J .; Park, J . Angew. Chem., Int. Ed. 2002, 41, 2373. (d) Dijksman, A.;
Elzinga, J . M.; Li, Y. X.; Arends, I. W. C. E.; Sheldon, R. A.
Tetrahedron: Asymmetry 2002, 13, 879.
(4) Yokomatsu, T.; Shibuya, S. Tetrahedron: Asymmetry 1992, 3,
377.
(5) For hydrogenation examples, see: (a) Kitamura, M.; Tokunaga,
M.; Noyori, R. J . Am. Chem. Soc. 1995, 117, 2931. (b) Gautier, I.;
Ratovelomanana-Vidal, V.; Savignac, P.; Geneˆt, J . P. Tetrahedron Lett.
1996, 43, 7721. For borane reduction, see, for instance: (c) Gadja, T.
Tetrahedron: Asymmetry 1994, 5, 1965. (d) Meier, C.; Laux, W. H. G.
Tetrahedron 1996, 52, 589.
(6) (a) Zymanczyk-Duda, E.; Lejczak, B.; Kafarski, P.; Grimaud, J .;
Fischer, P. Tetrahedron 1995, 51, 11809. (b) Mikolajczyk, M.; Luczak,
J .; Kielbasinski, P. J . Org. Chem. 2002, 67, 7872.
(11) (a) Huerta, F. F.; Laxmi, Y. R. S.; Ba¨ckvall, J .-E. Org. Lett. 2000,
2, 1037. (b) Huerta, F. F.; Ba¨ckvall, J .-E. Org. Lett. 2001, 3, 1209. (c)
Runmo, A.-B. L.; Pa`mies, O.; Fabert, K.; Ba¨ckvall, J .-E. Tetrahedron
Lett. 2002, 43, 2983. (d) Pa`mies, O.; Ba¨ckvall, J .-E. J . Org. Chem. 2002,
67, 1261. (e) Pa`mies, O.; Ba¨ckvall, J .-E. Adv. Synth. Catal. 2001, 343,
726. (f) Pa`mies, O.; Ba¨ckvall, J .-E. J . Org. Chem. 2001, 66, 4022.
10.1021/jo026888m CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/17/2003
J . Org. Chem. 2003, 68, 4815-4818
4815

Pa`mies and Ba¨ckvall
TABLE 1. Kin etic Resolu tion of 1a a n d 1ia
SCHEME 1
SCHEME 2. P r ep a r a tion of Hyd r oxyp h osp h on a tes
1 (R ) Me, Et; R′ ) Me, Et)
yield of
% ee
% ee
entry
substrate
lipaseb
2c (%)
of 2d
of 1d
1
2
3
4
5
6
1a
1a
1a
1i
1i
1i
PS-C
AK
CALB
PS-C
AK
49
45
50
26
5
>99
>99
>99
>99
>99
>99
96
82
99
35
5
CALB
49
96
a
Reactions were carried out on a 0.1 mmol scale with 10 mg
of enzyme and 3 equiv of 3 in 1 mL of toluene at 60 °C for 5 h.
b
PS-C ) P. cepacia lipase; CALB ) C. antarctica lipase B
(Novozym-435); AK ) Pseudomonas fluorescens lipase. c Deter-
mined by NMR. % ee determined by GC.
d
sponding aldehydes with different dialkyl phosphites in
the presence of DBU in THF at room temperature. The
use of DBU as base turned out to be advantageous
compared to other bases used.12 â-Hydroxyphosphonates
1i-k were prepared by reaction of the corresponding
lithium salt of dialkyl methyl phosphonate, generated in
situ, with different aldehydes.13
that the change of size in the phosphonate substituents
does not affect the enantiopreference of the lipase for
these substrates (entries 1-3). However, the activity
decreases considerably when a bulky diisopropyl phos-
phonate moiety is present (entry 3). On the other hand,
Pseudomonas cepacia lipase (PS-C) showed good activity
and enantioselecitivity for the ethyl-substituted phos-
phonate 1d (entry 4).16 However, the acylation of diethyl
(1-hydroxyallyl)phosphonate (1e) proceeded with better
enantiopreference with CALB than with PS-C lipase
(entry 5 vs entry 6). R-Hydroxyphosphonates containing
propyl (1f) and 2-propenyl (1g) moieties could also be
acetylated with good enantiopreference using PS-C lipase
(entries 7 and 8).17 However, the PS-C transesterification
of dimethyl (hydroxyphenylmethyl)phosphonate (1h ) pro-
ceeded very slowly (entry 9).
For (2-hydroxypropyl)phosphonates 1i and 1j excellent
activities and enantioselectivies were obtained using C.
antarctica lipase B (entries 10 and 11). The transesteri-
fication of diethyl (2-hydroxybutyl)phosphonate (1k ) also
proceeded with good enantiomeric ratio, but the reaction
rate was low (entry 12).
On the basis of these preliminary results on KR, we
next combined the enzymatic KR of hydroxyphosphonates
1 with a ruthenium-catalyzed racemization process via
hydrogen transfer employing catalyst 4.18 A feature of
this catalyst is that no addition of external base is needed
as a cocatalyst.19 This is an important advantage to other
potential base-induced ruthenium-catalyzed racemiza-
tions.20
Kin etic Resolu tion a n d Dyn a m ic Kin etic Resolu -
tion of Hydr oxyp h osp h oph on a tes. A primary require-
ment for a successful DKR is that the KR conditions are
compatible with the racemization process. Therefore, in
a first set of experiments, the efficiency of different
commercially available lipases to catalyze the transes-
terification of chiral R- and â-hydroxyphosphonates 1 was
investigated. For this purpose, racemic diethyl (1-hy-
droxyethyl)phosphonate (1a ) and diethyl (2-hydroxypro-
pyl)phosphonate (1i) were chosen as model substrates
and treated with 3 equiv of 4-chlorophenyl acetate (3) in
toluene at 60 °C in the presence of different lipases. 3
was used as acyl donor since it is known to be compatible
with ruthenium-catalyzed racemization of alcohols.14
Toluene was chosen as a solvent since the efficiency of
the DKR is higher in toluene than in other solvents.15
The results are summarized in Table 1. In all cases, the
enantioselectivity of the acetate was excellent, but the
activity varied, and Candida antarctica lipase B (CALB,
Novozym-435) showed the highest activity (entries 3 and
6). The other lipases examined (lipase from porcine
pancreas, Candida rugosa, Candida cylindracea, and
Aspergillus sp.) gave either very low conversion (<5%)
or no reaction after 48 h.
To investigate how the different substituents affect the
lipase-catalyzed transesterification, we extended our
study to other substrates. The results are shown in Table
2. The effect of different substituents in the phosphonate
moiety was studied using substrates 1a -c with C.
antarctica lipase B as the enzyme. The results indicate
(12) Other bases such as triethylamine, pyridine, and sodium
methoxide also gave access to the desired R-hydroxyphosphonates, but
either the reaction times were substantially longer or the reactions
conditions were less convenient.
(13) Genov, D. G.; Tebby, J . C. J . Org. Chem. 1996, 61, 2454.
(14) The use of vinyl acetate, commonly used as acyl donor, results
in the formation of acetaldehyde after the acyl-transfer process, which
interferes with the ruthenium hydrogen-transfer catalysts usually
employed in the DKR; see ref 10b.
In a first set of experiments the DKR of different
R-hydroxyphosphonates were carried out using 4 mol %
(16) The KR of 1d using CALB proceeded with low activity (<5%
after 5 h).
(17) Substrates with a medium-sized substituent larger than ethyl
are not suitable for CALB-catalyzed transesterification. See, for
instance: Rottichi, D.; Halffner, F.; Orrenius, C.; Norin, T.; Hult, K.
J . Mol. Catal. B 1998, 5, 267.
(15) The solubility of the Ru catalyst 4 in toluene is higher than in
ethers and other solvents, and this results in higher racemization rates;
see ref 11f.
4816 J . Org. Chem., Vol. 68, No. 12, 2003

A Route to R- and â-Hydroxyalkanephosphonates
TABLE 2. Kin etic Resolu tion of 1a
yield of
% ee
% ee
entry
substrate
R
n
R′
lipaseb
2c (%)
of 2d
of 1d
Ee
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1e
1f
1g
1h
1i
Me
Me
Me
Et
CH2dCH
CH2dCH
0
0
0
0
0
0
0
0
0
1
1
1
Et
CALB
CALB
CALB
PS-C
CALB
PS-C
PS-C
PS-C
PS-C
50
50
2
45
39
43
16
15
2
>99 (+)
>99 (+)
>95
98 (+)
99 (+)
84 (+)
99 (+)
ndf (-)
>95
99 (-)
99 (-)
2
90 (-)
65 (-)
60 (-)
15 (-)
14 (+)
3
>500
>500
ndf
300
390
Me
iPr
Et
Et
Et
Et
Et
Me
Et
Me
Me
21
Pr
230
CH3CHdCH
ndf
Ph
Me
Me
Et
ndf
10
11
12g
CALB
CALB
CALB
49
47
12
99 (+)
>99 (+)
>99 (+)
98 (+)
90 (+)
13 (+)
>500
>500
>225
1j
1k
a
b
Reactions were carried out on a 0.1 mmol scale with 10 mg of enzyme and 3 equiv of 3 in 1 mL of toluene at 60 °C for 5 h. PS-C )
P. cepacia lipase; CALB ) C. antarctica lipase B (Novozym-435). c Determined by NMR. % ee determined by GC. Absolute configura-
d
tion in parentheses. e Enantiomeric ratio determined from the ee values of the alcohol and acetate. f Not determined. Determined after
g
24 h.
TABLE 3. Dyn a m ic Kin etic Resolu tion of
reaction times did not improve the yields of the acetoxy-
phosphonates. We believe that this is due to the coordi-
nation of the phosphonate to the 16-electron intermediate
4b at low alcohol concentration, which causes decomposi-
tion of the ruthenium catalyst 4.22 This hypothesis is
based on the following:
r a c-r-Hyd r oxyp h osp h on a tesa
(i) No catalyst deactivation was observed when alcohol
and 4 were premixed for 24 h.
T
yield of
entry substrate
R
R′ enzyme (°C) 2b,c (%) % eed
(ii) The addition of 0.5 equiv of 2,4-dimethyl-3-pentanol
(6), as a bulky competing alcohol that cannot be acety-
lated, after 10 h, inhibited the catalyst deactivation.23
The DKR of â-hydroxyphosphonates was studied under
“standard” conditions (i.e., 4 mol % 4, 3 equiv of 3, and
100 mg of lipase/mmol of 1). The results are summarized
in Table 4. In contrast to the DKR results on R-hydroxy-
phosphonates, the formation of large amounts of the
corresponding ketone 5, formed during the hydrogen-
transfer process, was observed.24 Interestingly, the tem-
perature screening indicated that the ratio (R)-2/5 was
best at 70 °C (entry 2 vs entries 1 and 3).
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1b
1d
Me Et
Me Et
Me Et
Me Et
Me Et
Me Me
CALB
CALB
CALB
PS-C
PS-C
CALB
PS-C
60
70
80
60
80
80
80
70
76
86
69
>99
>99
>99
>99
>99
>99
99
87 (74)e
83 (69)e
85 (73)e
Et
Et
a
Conditions: 0.2 mmol of rac-1, 0.6 mmol of 3, 4 mol % 4, 20
b
mg of lipase and 2 mL of toluene. Yield measured by NMR after
24 h. c A high product selectivity for (R)-2 was obtained with <1%
d
of the corresponding ketone as determined by GC. Enantiomeric
excess measured by GC. e Isolated yields from reactions performed
on a 0.6 mmol scale.
Several attempts to increase the efficiency of the
process by reducing the amount of ketone were done.
Thus, hydrogen gas (1 bar) and 6 were tested as hydrogen
sources with the aim to push the equilibrium back to the
alcohol. The addition of hydrogen gas (1 bar) or 2,4-
dimethyl-3-pentanol (0.5 equiv) inhibited the formation
of ketone completely (entries 4 and 5). However, the DKR
efficiency is highly reduced in both cases. In the former
case, this is mainly due to a decrease of the racemization
rate under 1 bar of hydrogen. In the latter case, the lower
DKR efficiency can be attributed to the competition
between alcohols 6 and 1 in the transfer hydrogenation
4, 3 equiv of 3, and 100 mg of lipase/mmol of 1. The
results are summarized in Table 3. In all cases, traces of
the corresponding ketophosphonate (<1%), formed during
the hydrogen-transfer process, were observed by GC. A
temperature screening indicated that the efficiency of the
DKR is higher at 80 °C than at low temperature (entries
1-5). This is due to the faster racemization rates at
higher temperature.11f
Under these conditions, good yields (∼85%) of the cor-
responding acetoxyphosphonates in excellent enantiose-
lectivities (>99%) were obtained after 24 h for substrates
1a , 1b, and 1d (entries 3 and 5-7).21 However, longer
(22) The Ru decomposition triggers, at the same time, the progres-
sive deactivation of the enzyme. Similar behavior has been recently
observed when DKR on â-bromo alcohols was attempted; see: Pa`mies,
O.; Ba¨ckvall, J .-E. J . Org. Chem. 2002, 67, 9006.
(23) The addition of 6 also reduces the efficiency of the DKR. Thus,
the corresponding acetate was obtained in only 53% yield (>99% ee)
after 24 h. This is attributed to the competition between alcohols 6
and 1 in the transfer hydrogenation process.
(18) Menasche, N.; Shvo, Y. Organometallics 1991, 10, 3885.
(19) Pa`mies, O.; Ba¨ckvall, J .-E. Chem.sEur. J . 2001, 7, 5052.
(20) The presence of base can cause undesired side reactions in the
substrate and/or product. Moreover, the basicity and quantity of base
have to be carefully tuned to not affect the enzyme.
(21) Similar results were obtained by adding only 1.2 equiv of acyl
donor 3.
(24) The amount of ketone 5 increased when the amount of acyl
donor added was lowered to 1.2 equiv.
J . Org. Chem, Vol. 68, No. 12, 2003 4817

Pa`mies and Ba¨ckvall
TABLE 4. Dyn a m ic Kin etic Resolu tion of
TABLE 5. 31P {1H} Ch em ica l Sh ift a n d Reten tion Tim es
of Com p ou n d s 1 a n d 2
r a c-â-Hyd r oxyp h osp h on a tesa
δ(31P)
R′ (ppm)
a
a
substrate
R
n
tR
tR
1a
2a
1b
2b
1c
2c
1d
2d
1e
2e
1f
Me
Me
Me
Me
Me
Me
Et
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
Et
Et
26.38 33.62 (-) 33.81 (+)
22.23 23.22 (-) 23.82 (+)
Me 28.35 33.74
33.74
H
T
yield of yield of
Me 24.82 16.11 (-) 16.54 (+)
entry substrate
R
R′ source (°C) 2b (%) 5 (%) % eec
iPr 24.34 27.52
iPr 20.05 26.35
28.46
27.02
1
2
3
4
1i
1i
1i
1i
1i
1i
1j
Me Et
Me Et
Me Et
Me Et
Me Et
Me Et
Me Me
60
70
80
70
70
70
70
54
65
69
53
57
69
62
18
10
19
0
0
1
>99
>99
>99
>99
>99
>99
>99
Et
Et
25.72 35.59 (-) 36.42 (+)
21.64 29.20 (-) 30.59 (+)
Et
H2
6
6
CH2dCH
CH2dCH
Pr
Pr
CH3CHdCH
CH3CHdCH
Ph
Ph
Me
Me
Me
Me
Et
Me 22.00 35.37 (-) 36.32 (+)
Me 18.38 29.52 (-) 20.62 (+)
Et
Et
Et
Et
5
6d
7
26.05 38.39 (-) 39.17 (+)
21.76 35.59 (-) 35.85 (+)
22.90 38.45 (+) 39.19 (-)
16
2f
1g
2g
1h
2h
1i
2i
1j
2j
1k
2k
a
Conditions: 0.2 mmol of rac-1, 0.6 mmol of 3, 4 mol % 4, 20
19.43 36.23
36.23
47.92
44.71b
b
mg of CALB, and 2 mL of toluene. Yield measured by NMR after
Me 24.07 47.51
24 h. c Enantiomeric excess measured by GC. 6 (0.5 equiv) added
d
Me 20.66 44.67b
after 24 h. Yield measured after 48 h.
Et
Et
30.80 26.94 (+) 27.52 (-)
27.37 36.43 (-) 36.70 (+)
Me 33.18 25.54 (+) 25.61 (-)
Me 29.72 34.34 (-) 34.97 (+)
Me 34.15 33.13 (+) 33.49 (-)
Me 30.59 36.65 (-) 36.86 (+)
process. To minimize this competitive reaction, we de-
cided to add 6 after 24 h. Despite the fact that ketone
5 was reduced back to the alcohol, the yield of the de-
sired acetate 2i did not substantially increase (entry 6
vs entry 2).
Et
a
b
Absolute configuration in parentheses. No baseline separa-
tion.
The DKR of dimethyl (2-hydroxypropyl)phosphonate
(1j) followed the same trend as observed for substrate
1i. Thus, a moderate yield but in excellent enantioselec-
tivity (99% ee) was obtained (entry 7).
aqueous HCl (2 N), and the organic phase was dried with
Na2SO4 and evaporated.25 The residue was purified by bulb-
to-bulb distillation26 to yield 3.06 g (84%) of rac-1a as a
colorless liquid.
Gen er a l P r oced u r e for th e KR of Hyd r oxyp h osp h o-
n a tes. Dieth yl (R)-(1-Acetoxyeth yl)p h osp h on a te ((R)-2a ).
In a typical experiment, C. antarctica lipase B (Novozym-435)
(10 mg) was added to a solution of 1a (15.4 mg, 0.1 mmol) and
3 (51 mg, 0.3 mmol) in dry toluene (1 mL) under argon. The
resulting reaction mixture was stirred at 60 °C for 5 h. The
enzyme was then filtered off and washed with toluene (3 × 5
mL). The combined toluene phases were evaporated, and the
residue was analyzed. The product (S)-2a was obtained in 50%
conversion and in >99% ee.
Gen er a l P r oced u r e for th e DKR of Hyd r oxyp h osp h o-
n a tes. (R)-2a . In a typical experiment, ruthenium catalyst 4
(30.6 mg, 4 mol %) and C. antarctica lipase B (Novozym-435)
(60 mg) were placed in a Schlenk flask under argon. A solution
of 1a (109.2 mg, 0.6 mmol) and 3 (306 mg, 1.8 mmol) in dry
toluene (6 mL) under argon (2 min of argon bubbling) was
transferred to the ruthenium catalyst and the enzyme. The
resulting reaction mixture was stirred at 80 °C for 24 h. The
enzyme was then filtered off and washed with toluene (3 × 5
mL), the solvent was evaporated, and the product was purified
by flash chromatography (ethyl acetate) to yield 99 mg (74%)
of (S)-2a in >99% ee.
Exp er im en ta l P r oced u r es
Gen er a l Exp er im en ta l P r oced u r es. All reactions were
carried out under a dry argon atmosphere in oven-dried
glassware. Solvents were purified by standard procedures.
Compounds 1i-k were prepared according to literature pro-
cedures.13 Racemic acetoxyphosphonates 2 were prepared from
the corresponding alcohols 1 by reaction with acetic anhydride
and pyridine under standard conditions. Acyl donor 3 was
prepared according to a literature procedure.10b Ruthenium
catalyst 4 was synthesized according to a literature procedure11a
and recrystallized from CH2Cl2/pentane prior to use. Lipases
PS-C and AK were a generous gift from Amano Pharmaceuti-
cal Co. Ltd., J apan. All other reagents are commercially
available and were used without further purification.
1H, 13C, and 31P NMR spectra were recorded in CDCl3 at
300, 75, and 121 MHz, respectively. Solvents for extraction
and chromatography were technical grade and distilled before
use. The enantiomeric excess of compounds 1 and 2 was
determined by GC analysis on a CP-Chirasil-Dex CB column
using racemic compounds as references (Table 5). The oven
parameters were 100 °C for 30 min and then 5 °C/min up to
200 °C. The absolute configuration was determined by pola-
rimetry using chloroform as solvent (Table 5).
Gen er a l P r oced u r e for th e P r ep a r a tion of r a c-r-
Hyd r oxyp h osp h on a tes 1a -i. r a c-Dieth yl (1-Hyd r oeth yl)-
p h osp h on a te (1a ). To a solution of diethyl phosphite (2.58
mL, 20 mmol) and acetaldehyde (1.12 mL, 20 mmol) in THF
(20 mL) under an argon atmosphere at 0 °C was added DBU
(1.62 mL, 20 mmol). The mixture was stirred for 3 min at 0
°C and then warmed to room temperature. After 10 min, the
solvent was removed in vacuo and the residue was dissolved
in dichloromethane. The solution was washed with 20 mL of
Ackn owledgm en t. Financial support from the Swed-
ish Foundation for Strategic Research is gratefully
acknowledged.
J O026888M
(25) For substrate 1b, the addition of HCl causes decomposition of
the product. Therefore, it was purified by column chromatography
using ethyl acetate as eluent and then by bulb-to-bulb distillation.
(26) Alternatively, the product can also be purified by column
chromatography using ethyl acetate as eluent with similar yields.
4818 J . Org. Chem., Vol. 68, No. 12, 2003