The synthesis of 1-hydroxy phosphonates of high enantiomeric excess using sequential asymmetric reactions: Titanium alkoxide-catalyzed P-C bond formation and kinetic resolution

Article abstract of DOI:10.1016/S0957-4166(01)00303-2

Titanium alkoxide-catalyzed asymmetric phosphonylation of aldehydes yields hydroxy phosphonates in moderate to good enantiomeric excess (e.e.s ～70%). The hydroxy phosphonates were acetylated and the acetates were subjected to enzyme-catalyzed kinetic resolution. The non-racemic acetates 2 (predominantly (R)-enantiomer) were hydrolyzed with an (R)-enantiomer-selective lipase, resulting predominantly in the hydrolysis of the (R)-isomer (at 85% conversion) to give the alcohols 3 with high e.e. Alternatively, hydrolysis of the minor enantiomeric (S)-acetate to approximately 20% conversion left the enriched (R)-configured acetate with improved e.e. (>90%). The moderate enantioselectivities obtained in the catalytic P-C bond formation are enhanced during the enzymatic hydrolysis. Furthermore, availability of the non-racemic phosphonates permits the use of less selective enzymes, resulting in higher yields in comparison with the standard resolution of racemic materials.

Full text of DOI:10.1016/S0957-4166(01)00303-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1701–1708
The synthesis of 1-hydroxy phosphonates of high enantiomeric
excess using sequential asymmetric reactions: titanium
alkoxide-catalyzed PꢀC bond formation and kinetic resolution
Bradley J. Rowe and Christopher D. Spilling*
Department of Chemistry and Biochemistry, University of Missouri-St. Louis, 8001 Natural Bridge Road, St. Louis,
MO 63121, USA
Received 30 April 2001; accepted 21 June 2001
Abstract—Titanium alkoxide-catalyzed asymmetric phosphonylation of aldehydes yields hydroxy phosphonates in moderate to
good enantiomeric excess (e.e.s ꢀ70%). The hydroxy phosphonates were acetylated and the acetates were subjected to
enzyme-catalyzed kinetic resolution. The non-racemic acetates 2 (predominantly (R)-enantiomer) were hydrolyzed with an
(R)-enantiomer-selective lipase, resulting predominantly in the hydrolysis of the (R)-isomer (at 85% conversion) to give the
alcohols 3 with high e.e. Alternatively, hydrolysis of the minor enantiomeric (S)-acetate to approximately 20% conversion left the
enriched (R)-configured acetate with improved e.e. (>90%). The moderate enantioselectivities obtained in the catalytic PꢀC bond
formation are enhanced during the enzymatic hydrolysis. Furthermore, availability of the non-racemic phosphonates permits the
use of less selective enzymes, resulting in higher yields in comparison with the standard resolution of racemic materials. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
reacting under a given set of conditions is characterized
by the enantioselectivity ratio, E, which is related to the
ratio of the rates for the fast and slow reacting enan-
tiomers. In general for successful resolutions, an E of
>100 is required. However, it was shown that enzymes
with low E values could still be useful by cycling the
materials through multiple enzymatic hydrolysis reac-
tions, where each cycle leads to an increase in e.e.7 It
appeared evident from these recycling experiments that
enzymatic hydrolysis of non-racemic substrates would
allow the use of less selective enzymes and result in
higher conversion and selectivity when compared to a
similar resolution of racemic materials. Thus, it was
proposed that an additional enzyme-mediated resolu-
tion could be used to enhance the e.e. of the non-
A major emphasis in the development of new organic
reactions is the control of absolute stereochemistry via
chiral catalysts. While there are some truly outstanding
systems, many others fall short of the desired levels of
enantioselectivity when applied to a wide range of
substrates.1
For almost ten years there has been an interest in the
asymmetric synthesis of hydroxy phosphonates,2 pre-
cipitated not only by their biological activity,3 but also
because they are attractive precursors to other a- and
g-substituted phosphonates.4 Hammerschmidt et al.
have investigated enzymatic routes to hydroxy phos-
phonates extensively,5 while ourselves and others have
studied asymmetric catalysis.6 Both methods have
attained varying levels of success, but a general, repro-
ducible, high yielding and highly selective method is
still unavailable.
racemic
1-hydroxy
phosphonates
formed
by
asymmetric catalysis.
Although it has been recognized8 that the coupling of
two asymmetric reactions9 or an asymmetric reaction
and a resolution10 can lead to the efficient formation of
compounds with high e.e., this combination of tech-
niques has not been widely applied. We report herein
In 1982, Sih et al. reported a set of equations for
describing the course of an enantioselective enzyme-cat-
alyzed hydrolysis.7a The substrate–enzyme combination
that
a combination of asymmetric catalysis and
enzyme-catalyzed kinetic resolution (Scheme 1) leads to
the first reliable, high yielding synthesis of 1-hydroxy
phosphonates with high enantiopurity.
* Corresponding author. Tel.: 314-516-5314; fax: 314-516-5342;
e-mail: cspill@umsl.edu
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00303-2

1702
B. J. Rowe, C. D. Spilling / Tetrahedron: Asymmetry 12 (2001) 1701–1708
O
P
and good reaction rates were used to treat the non-
O
P
MeO
MeO
i
H
R
MeO
MeO
1. Diol, Ti(OPr)4, Et2O
R
racemic substrates. The amount of enzyme used was
adjusted to achieve complete reaction in a reasonable
period of time, but no further effort was made to
optimize the reaction conditions. While it would have
been more efficient to combine asymmetric catalysis
with an enantioselective enzyme-catalyzed acetylation,
an efficient enzyme system for acylating 1-hydroxy
phosphonates was not found.12
R
2. polyvinylpyridine
AcCl, CH3CN
O
1
OAc
OAc
2 (R), major
2 (S), minor
O
O
t-BuOMe, pH 7.0 buffer
lipase
MeO
MeO
P
R
P
R
MeO
MeO
OH
OAc
3
2
Ph
The non-racemic hydroxy phosphonates were prepared
in 70–95% isolated yields and e.e.s of 60–77% by the
titanium alkoxide-catalyzed addition of dimethyl phos-
phite to the aldehyde (Scheme 1) using either cyclohex-
anediol or dimethyl tartrate as the chiral ligands.6a,13 It
was expected that reaction of the non-racemic acetates
2 ((R)-predominant) with an (R)-enantiomer-selective
lipase would result predominantly in the hydrolysis of
the (R)-isomer (at 85% conv.) to give the alcohols 3
with high e.e. A 0.1 mmol sample of acetate 2a ((R)-
enantiomer, 65% e.e.) was treated with lipase from
Pseudomonas sp. The reaction (Fig. 2) was followed by
HPLC. The data points14 follow closely to the theoreti-
cal prediction. In a similar preparative scale hydrolysis
of acetate 2a (73% e.e.), the reaction was stopped at
80% conversion to give, after chromatographic separa-
tion, the hydroxy phosphonate 3a in 99% e.e. The
acetates 2b, 2c, and 2d were treated similarly (Table 1)
to give hydroxy phosphonates in e.e. of 92–99%.
a, R =
b, R =
c, R =
d, R =
e, R =
Ph
n-C5H11
f, R =
CH3
CH3
g, R =
Ph
n-C5H11
Scheme 1.
2. Results and discussion
An initial screening was used to identify an optimal
enzyme system for each phosphonate. Racemic hydroxy
phosphonates11
were
acetylated
with
AcCl/
polyvinylpyridine in CH3CN (>90% yield). A bank of
33 lipase enzymes was screened with the acetate deriva-
tives 2 for enantioselective hydrolysis. The screening
was performed on a 0.1 mmol (:25 mg) sample in 7
mL vials with 16 units of enzyme. Three to five samples
of each reaction were taken over a 64 hour period and
the results derived directly from HPLC analysis on the
crude samples. The data obtained from HPLC were
plotted over a graph of the theoretical reaction profiles7
to estimate values of E and reaction rates (Fig. 1).
Enzyme systems exhibiting good enantioselectivities
Since enzymes are selective for a single enantiomer it
was necessary to examine cases where the minor isomer
was hydrolyzed preferentially. It was expected that
hydrolysis of the (S)-acetate (approx. 20% conv.)
would leave the enriched (R)-acetate with improved e.e.
Figure 1. A comparison of the theoretically derived curves and experimental data points for enzyme-catalyzed kinetic resolution
of racemic acetoxy phosphonate 2a with four enzymes.

B. J. Rowe, C. D. Spilling / Tetrahedron: Asymmetry 12 (2001) 1701–1708
1703
Figure 2. Theoretical and experimental data for an enzyme-catalyzed kinetic resolution of non-racemic acetoxy phosphonate 2a
(65% e.e. (R)) with an enzyme selective for the major (R)-enantiomer.
Table 1. Hydrolysis of the major enantiomer
Figure 3. Experimental data for an enzyme-catalyzed kinetic resolution of non-racemic acetoxy phosphonate 2a (67% e.e. (R))
with an enzyme selective for the minor (S)-enantiomer.

1704
B. J. Rowe, C. D. Spilling / Tetrahedron: Asymmetry 12 (2001) 1701–1708
Table 2. Hydrolysis of the minor enantiomer
(>90%). A sample of acetate 2a (67% e.e.) was treated
with lipase from Penicillium roqueforte (E=7). The e.e.
(from HPLC) for both the acetoxy phosphonate 2a and
the hydroxy phosphonate 3b were plotted against con-
version (Fig. 3). The graph clearly shows the expected
enhancement in the e.e. of the acetate 2a. On a prepar-
ative scale, the acetate 2a (73% e.e.) was treated with a
more active lipase (from Rhizopus arrizhus), and reac-
tion stopped at 20% conversion. Separation of the
acetate 2a and alcohol 3a by chromatography gave the
acetoxy phosphonate in 70% yield and greatly
improved enantiopurity (91%). Other examples (Table
2) proved equally successful with the more selective
enzymes (e.g. 2e) giving the higher e.e.
Regis (S,S)-Whelk-O 1 column or a Daicel Chiralpak
AS column. Optical rotations were determined using a
Rudolf Research Autopol III automatic polarimeter set
at 589 nm. Mass spectral analyses were performed
using a JEOL MStation (JMS-700) mass spectrometer.
Microanalyses were performed by Atlantic Microlab,
Inc., Norcross, GA. The enzymes were purchased from
Fluka chemical Co (basic and extended lipase kits:
Aspergillus niger, Candida antartica, Candida cylin-
dracea, Mucor miehei, Pseudomonas cepacia, Pseu-
domonas fluorescens, Rhizopus arrihzus, Rhizopus niveus,
hog pancreas, Aspergillus oryzae, Candida lipolytica,
Mucor javanicus, Penicillium roqueforti, Pseudomonas
fluorescens (purified), Rhizomucor miehei, wheat germ,
Chromobacterium viscosum, Pseudomonas sp., and
Pseudomonas sp., type B). Additional enzymes were
generously donated by Amano Co. ltd., USA (lipases
F-AP15, R, A, G, M, AY, AK, PS, CHE, and PGE,
Newlase F, and immobilized lipases PS-CI, PS-CII,
PS-DI).
In summary, in this synthesis of 1-hydroxy phospho-
nates, the moderate enantioselectivities encountered in
the catalytic PꢀC bond formation are enhanced by the
enzymatic hydrolysis. Furthermore, the availability of
the non-racemic phosphonates allows for the use of less
selective enzymes and results in higher yields than those
achieved with the standard resolutions of racemic
materials.
The racemic hydroxy phosphonates were prepared by
reacting dimethyl phosphite with an aldehyde using
either triethylamine11 or titanium iso-propoxide as cata-
lyst. Non-racemic hydroxy phosphonates were prepared
by the titanium alkoxide-catalyzed addition of dimethyl
phosphite to the aldehyde using either cyclohexa-
nediol6a or dimethyl tartrate as the chiral ligands.13
3. Experimental
3.1. General experimental procedures
1H, 13C and 31P NMR spectra were recorded on a
Varian XL-300, a Varian UNITY-plus 300 or a Bruker
3.2. Preparation of ( )-hydroxy phosphonates
1
ARX-500 spectrometer in CDCl3. H NMR spectra are
referenced to internal tetramethylsilane (TMS, l=
0.00), 13C NMR spectra to the center line of CDCl3
(77.23 ppm) and 31P NMR spectra to external 85%
H3PO4. Coupling constants, J, are reported in Hz.
Infrared spectra were recorded on a Perkin–Elmer
Model 1600 FT-IR spectrometer. Enantiomer ratios
were measured by chiral stationary-phase HPLC on a
Distilled Ti(OiPr)4 (20 mol%) was added to a solution
of dimethyl phosphite (2 equiv.) in freshly distilled
CH2Cl2 at 0°C. The solution was stirred for 30 min,
then the aldehyde (1 equiv.) was added. When the
reaction was complete, as indicated by TLC (SiO2,
EtOAc:hexane, 50:50), the mixture was diluted further
with CH2Cl2 and washed with H2O. The layers were

B. J. Rowe, C. D. Spilling / Tetrahedron: Asymmetry 12 (2001) 1701–1708
1705
separated and the H2O layer was re-extracted with
3.5. ( )–Dimethyl (1-hydroxy-2-methyl-3-phenyl-2E-
CH2Cl2. The combined CH2Cl2 extracts were washed with
H2O, dried (MgSO4) and evaporated in vacuo to give the
crude hydroxy phosphonates. Purification by column
chromatography (SiO2, gradient EtOAc:hexanes,
50:50 to 100% EtOAc) gave the pure a-hydroxy phospho-
nates.
propenyl) phosphonate 3b6d
1
87% yield, mp 73–75°C; H NMR (CDCl3) l 7.38–7.22
(m, 5H), 6.68 (dd, JHH=1.3, JHP=5.0 Hz, 1H), 4.57 (d,
J
J
HP=12.8 Hz, 1H), 3.84 (d, JHP=10.5 Hz, 3H), 3.83 (d,
HP=10.4 Hz, 3H), 2.03 (dd, JHP=3.0, JHH=1.3 Hz, 3H);
13C NMR (CDCl3) l 137.0, 133.3 (d, JCP=4.7 Hz), 129.2
(d, JCP=2.7 Hz), 128.5 (d, JCP=12 Hz), 128.3, 127.0, 74.0
(d, JCP=156 Hz), 54.1 (d, JCP=6.8 Hz), 53.8 (d, JCP=7.3
Hz), 15.62 (d, J=2.2 Hz); 31P NMR (CDCl3) l 24.6.
3.3. General procedures for the preparation of the non-
racemic hydroxy phosphonates
3.6. ( )-Dimethyl (1-hydroxy-2E-butenyl) phosphonate
Method A:6a To a solution of anhydrous (1S,2S)-trans
1,2-cyclohexanediol (49.9 mg, 430 mmol) in freshly dis-
tilled Et2O (3.5 mL) was added distilled Ti(OiPr)4 (116
mL, 391 mmol). The mixture was stirred for 30 min to
insure complete complexation (diol dissolves). The alde-
hyde (2 mmol) was added, followed by distilled dimethyl
phosphite (216 mL, 2.4 mmol). The flask was placed in
a freezer (approx. −15°C). When the reaction was com-
plete, as indicated by TLC (SiO2, EtOAc:hexane, 50:50),
the reaction mixture was diluted with CH2Cl2 (50 mL)
and washed with deionized H2O (60 mL). The CH2Cl2
layer was collected and the aqueous layer was extracted
further with CH2Cl2 (50 mL). The extracts were combined
and washed with deionized H2O (50 mL), dried (MgSO4)
and evaporated in vacuo. Purification by column chro-
matography (SiO2, gradient EtOAc:hexanes, 1:1 to 100%
EtOAc) gave the pure a-hydroxy phosphonates.
3e5
89% yield, pale yellow oil; 1H NMR (CDCl3) l 5.90 (m,
1H), 5.62 (m, 1H), 4.45 (m, 1H), 3.85 (d, JHP=10.4 Hz,
3H), 3.84 (d, JHP=10.4 Hz, 3H), 1.76 (m, 3H); 13C NMR
(CDCl3) l 129.9 (d, J=14 Hz), 125.5, 69.0 (d, J=162 Hz),
53.6 (d, J=7.2 Hz), 53.5 (d, J=7.2 Hz), 18.1; 31P NMR
(CDCl3) l 24.8.
3.7. ( )-Dimethyl (1-hydroxy-2E-octenyl) phosphonate
3f4a
84% yield, yellow oil; 1H NMR (CDCl3) l 5.88–5.76 (m,
1H), 5.58–5.48 (m, 1H), 4.40–4.34 (m, 1H), 3.74 (d, JHP
=
9.6 Hz, 3H), 3.74 (d, JHP=10.6 Hz, 3H), 3.36 (brd s, 1H),
2.06–1.98 (m, 1H), 1.36–1.19 (2m, 6H), 0.81 (t, JHH=6.9
Hz, 3H); 13C NMR (CDCl3) l 135.8 (d, JCP=13.3 Hz),
123.8 (d, JCP=3.7 Hz), 69.3 (d, JCP=161 Hz), 53.7 (d,
Method B:13 To a solution of dimethyl-
L-tartrate (20
J
J
CP=7.0 Hz), 53.6 (d, JCP=7.2 Hz), 32.4, 31.4, 28.6 (d,
mol%) in freshly distilled diethyl ether (total conc.=0.06
M) was added distilled Ti(OiPr)4 (20 mol%). The mixture
was stirred at −15°C for 30 minutes to ensure complete
complexation. The aldehyde (40 mmol) was added and
the mixture was stirred for an additional 15 minutes.
Dimethyl phosphite (80 mmol) was added and the
reaction mixture was placed in the freezer (approx.
−15°C). After the reaction was complete, as indicated by
TLC (SiO2, EtOAc:hexane, 1:1), the reaction mixture was
treated with deionized H2O and extracted with CH2Cl2.
The combined extracts were dried (Na2SO4) and concen-
trated in vacuo to give crude product. Purification by
column chromatography (SiO2, gradient EtOAc:hexanes,
1:1 to 100% EtOAc) gave the pure a-hydroxy phospho-
nates.
CP=2.8 Hz), 22.6, 14.1; 31P NMR (CDCl3) l 24.8.
3.8. ( )-Dimethyl (1-hydroxy-oct-2-ynyl) phosphonate
3c4a
82% yield, yellow oil; 1H NMR (CDCl3) l 4.69 (m, 1H),
3.89 (d, JHP=10.2 Hz, 3H), 3.88 (d, JHP=10.5 Hz, 3H),
2.25 (m, 2H), 1.53 (m, 2H), 1.42–1.27 (m, 4H), 0.90 (t,
J
HH=7.2 Hz, 3H); 13C NMR (CDCl3) l 89.4 (d, JCP=11.5
Hz), 74.1, 58.8 (d, JCP=171.2 Hz), 54.4 (d, JCP=7.1 Hz),
54.2 (d, JCP=7.0 Hz), 30.9, 28.0 (d, JCP=2.6 Hz), 22.1,
18.8 (d, JCP=2.6 Hz), 13.9; 31P NMR (CDCl3) l 20.6.
3.9. ( )-Dimethyl (phenylhydroxymethyl) phosphonate
3d5,6,11
1
93% yield, mp 102°C; literature1 102–103°C; H NMR
(CDCl3) l 7.50–7.27 (m, 2H), 7.40–7.25 (m, 3H), 5.06 (d,
3.4. ( )-Dimethyl (1-hydroxy-3-phenyl-2E-propenyl)
phosphonate 3a6,11,15
J
J
J
HP=11.2 Hz, 1H), 3.70 (d, JHP=10.5 Hz, 3H), 3.67 (d,
HP=10.3 Hz, 3H); 13C NMR (CDCl3) l 136.5 (d,
CP=1.8 Hz), 128.5 (d, JCP=2.6 Hz), 128.3 (d, JCP=3.2
Hz), 127.2 (d, JCP=5.8 Hz), 70.8 (d, JCP=159 Hz), 54.1
(d, JCP=7.0Hz), 54.0(d, JCP=7.5Hz); 31P NMR (CDCl3)
l 24.3.
89%yield, mp101°C;literature1 101°C;1HNMR(CDCl3)
l 7.42–7.38 (m, 2H), 7.34–7.22 (m, 3H), 6.80 (ddd,
J
HH=15.6, 1.5 Hz, JHP=4.9 Hz, 1H), 6.35 (ddd, JHH
=
15.9, 6.2 Hz, JHP=5.6 Hz, 1H), 4.73 (ddd, JHH=12.9, 1.6,
J
J
J
HP=6.2 Hz, 1H), 3.85 (d, JHP=10.3 Hz, 3H), 3.81 (d,
HP=10.3 Hz, 3H); 13C NMR (CDCl3) l 136.1 (d,
CP=2.9 Hz), 132.2 (d, JCP=13 Hz), 128.4, 127.8, 126.5,
3.10. ( )-Dimethyl [(1-cyclopentenyl)-hydroxymethyl]
phosphonate 3g
123.5 (d, JCP=4.3 Hz), 69.2 (d, JCP=161 Hz), 53.9 (d,
CP=7.1 Hz), 53.7 (d, JCP=7.4 Hz); 31P NMR (CDCl3)
l 23.8.
J
65% yield, pale yellow oil; 1H NMR (CDCl3) l 5.87 (m,
1H), 4.64 (d, JHP=12.7 Hz, 1H), 3.80 (d, JHP=10.4 Hz,

1706
B. J. Rowe, C. D. Spilling / Tetrahedron: Asymmetry 12 (2001) 1701–1708
3H), 3.79 (d, JHP=10.4 Hz, 3H), 2.55–2.33 (m, 4H),
1.91 (m, 2H); 13C NMR (CDCl3) l 139.5 (d, JCP=3.1
Hz), 128.9 (d, JCP=11.5 Hz), 67.9 (d, JCP=160 Hz),
53.61 (d, JCP=8.0 Hz), 53.60 (d, JCP=8.0 Hz), 32.6 (d,
3.15. Dimethyl (1-acetoxy-2E-octenyl) phosphonate 2f
91% yield, pale yellow oil. IR (NaCl neat) 1751 cm−1;
1H NMR (CDCl3) l 5.97–5.85 (m, 1H), 5.69–5.63 (m,
1H), 5.57–5.47 (m, 1H), 3.81 (d, JHP=10.7 Hz), 3.78 (d,
J
CP=11.6 Hz), 32.5 (d, JCP=11.5 Hz), 23.4; 31P NMR
(CDCl3) l 24.5.
JHP=10.6 Hz), 2.14 (s, 3H), 2.13–2.09 (m, 2H), 1.42–
1.26 (2m, 6H), 0.88 (t, JHH=6.6 Hz, 3H); 13C NMR
(CDCl3) l 169.2 (d, JCP=8.0 Hz), 138.6 (d, JCP=12.6
Hz), 120.6 (d, JCP=4.0 Hz), 69.2 (d, JCP=170 Hz), 53.9
(d, JCP=7.0 Hz), 53.8 (d, JCP=6.4 Hz), 32.6, 31.5, 28.6,
22.7, 21.2, 14.3; 31P NMR (CDCl3) l 21.4.
3.11. General procedure for the acetylation of a-
hydroxy phosphonates
To a cooled (ice bath), stirred suspension of poly
(4-vinyl) pyridine (1.2 equiv.) in dry CH3CN (10 mL)
was added acetyl chloride (2.0 equiv.) followed by
hydroxy phosphonate. The suspension was stirred at
room temperature until the reaction was complete, as
indicated by TLC (SiO2, EtOAc). The reaction was
filtered to remove the polymer and the solvent was
removed in vacuo. The residue was adsorbed onto SiO2
and filtered through a short plug of SiO2 eluting with
EtOAc to give, after evaporation of the solvent in
vacuo, the pure acetates.
3.16. Dimethyl (1-acetoxy-2-octynyl) phosphonate 2c
90% yield, pale yellow oil. IR (NaCl neat) 1756 cm−1;
1H NMR (CDCl3) l 5.81 (dt, JHH=2.3, JHP=16.2 Hz,
1H), 3.90 (d, JHP=10.7 Hz, 3H), 3.86 (d, JHP=10.7 Hz,
3H), 2.28–2.20 (m, 2H), 2.16 (s, 3H), 1.60–1.45 (m, 2H),
1.40–1.28 (m, 4H), 0.89 (t, JHH=7.0 Hz, 3H); 13C
NMR (CDCl3) l 169.0 (d, JCP=7.8 Hz), 90.4 (d, JCP
=
9.3 Hz), 71.2 (d, JCP=6.1 Hz), 58.8 (d, JCP=177 Hz),
54.6 (d, JCP=8.0 Hz), 54.5 (d, JCP=6.3 Hz), 31.2, 28.1,
22.3, 20.9, 19.1, 14.2; 31P NMR (CDCl3) l 17.1.
3.12. Dimethyl (1-acetoxy-3-phenyl-2E-propenyl)
3.17. Dimethyl phenyl(acetoxy)methyl phosphonate 3d
phosphonate 2a
1
90% yield, colorless oil; H NMR (CDCl3) l 7.50–7.46
99% yield, colorless oil; IR (NaCl neat) 1747 cm−1; H
(m, 2H), 7.40–7.30 (m, 3H), 6.17 (d, JHP=13.5 Hz, 1H),
3.75 (d, JHP=10.7 Hz, 3H), 3.64 (d, JHP=10.6 Hz, 3H),
2.17 (s, 3H); 13C NMR (CDCl3) l 169.0 (d, JCP=8.7
Hz), 133.1 (d, JCP=1.9 Hz), 128.4 (d, JCP=2.8 Hz),
128.1 (d, JCP=2.2 Hz), 127.4 (d, JCP=5.7 Hz), 69.7 (d,
1
NMR (CDCl3) l 7.41–7.23 (m, 5H), 6.76 (ddd, JHH
16, 1.1, JHP=4.2 Hz, 1H), 6.30–6.20 (ddd, JHH=16,
6.2, JHP=5.3 Hz, 1H), 5.89 (ddd, JHH=7.5, 1.1, JHP
13.9 Hz, 1H), 3.82 (d, JHP=10.7 Hz, 3H), 3.80 (d,
HP=10.6 Hz, 3H) 2.18 (s, 3H); 13C NMR (CDCl3) l
=
=
J
JCP=169 Hz), 53.9 (d, JCP=7.1 Hz), 53.8 (d, JCP=7.4
169.0 (d, JCP=7.7 Hz), 135.4, 135.3 (d, JCP=12.9 Hz),
128.5, 128.4, 126.8, 119.6 (d, JCP=4.6 Hz), 70.0 (d,
Hz), 20.5; 31P NMR (CDCl3) l 20.5.
J
CP=170 Hz), 53.8 (d, JCP=6.5 Hz), 53.7 (d, JCP=6.9
3.18. Dimethyl [(1-cyclopentenyl)acetoxymethyl]
phosphonate 2g
Hz), 20.9; 31P NMR (CDCl3) l 20.7.
3.13. Dimethyl (1-acetoxy-2-methyl-3-phenyl-2E-
propenyl) phosphonate 2b
93% yield, pale yellow oil; IR (NaCl neat) 1732 cm−1;
1H NMR (CDCl3) l 5.88–5.82 (m, 2H), 3.82 (d, JHP
=
10.6 Hz, 3H), 3.78 (d, JHP=10.7 Hz, 3H), 2.50–2.34 (m,
4H), 2.15 (s, 3H), 1.97–1.86 (m, 2H); 13C NMR
(CDCl3) l 169.30 (d, JHP=8.0 Hz), 136.0 (d, JCP=4.1
Hz), 131.1 (d, JCP=10.6 Hz), 67.8 (d, JCP=169 Hz),
53.9 (d, JCP=7.0 Hz), 53.7 (d, JCP=6.5 Hz), 33.0 (d,
1
98% yield, colorless oil; IR (NaCl neat) 1748 cm−1; H
NMR (CDCl3) l 7.36–7.21 (m, 5H), 6.77 (d, JHP=4.8
Hz, 1H), 5.71 (dd, JHH=0.9, JHP=14.2 Hz, 1H), 3.85
(d, JHP=10.7 Hz, 3H), 3.81 (d, JHP=10.7 Hz, 3H) 2.19
(s, 3H), 2.05 (dd, JHH=1.38, JHP=3.1 Hz, 3H); 13C
NMR (CDCl3) l 169.2 (d, JCP=8.8 Hz), 136.5 (d,
J
CP=2.5 Hz), 32.7 (d, JCP=2.2 Hz), 23.3, 21.0; 31P
NMR (CDCl3) l 20.6.
J
CP=2.5 Hz), 130.5 (d, JCP=4.2 Hz), 130.4 (d, JCP=
11.6 Hz), 129.1, 129.0, 128.3, 127.2, 73.2 (d, JCP=168
Hz), 54.1 (d, JCP=7.1 Hz), 54.0 (d, JCP=6.5 Hz), 21.1,
15.82 (d, JCP=2.3 Hz); 31P NMR (CDCl3) l 20.8.
3.19. Lipase activity screen on racemic hydroxy
phosphonates
The lipase enzymes were weighed into 7 mL vials and
dissolved in pH 7.0 phosphate buffer (1.8 mL). Stock
solutions of the racemic acetates were prepared by
dissolution in t-butyl methyl ether (0.25 M). To each
vial was added a sample of the acetate solution (0.4 ml).
The vials were shaken and the pH was adjusted to 7.0
with either aqueous 1 M NaOH or 1 M K2PO4 solu-
tion. The vials were agitated on a rotating shaker, and
aliquots were removed by dipping the tip of a glass
pipette into the solution and allowing a small amount
of the organic phase to be drawn up. The aliquots were
diluted with EtOH and analyzed directly by HPLC.
3.14. Dimethyl (1-acetoxy-2E-butenyl) phosphonate 2e
96% yield, pale yellow oil. IR (NaCl neat) 1748 cm−1;
1H NMR (CDCl3) l 6.00–5.87 (m, 1H), 5.69–5.51 (m,
2H), 3.81 (d, JHP=10.7 Hz, 3H), 3.79 (d, JHP=10.7 Hz,
3H), 2.14 (s, 3H), 1.76 (m, 3H); 13C NMR (CDCl3) l
169.1 (d, JCP=7.9 Hz), 133.3 (d, JCP=12.9 Hz), 121.9
(d, JCP=4.0 Hz), 68.9 (d, JCP=170 Hz), 53.8 (d, JCP
=
7.0 Hz), 53.7 (d, JCP=6.5 Hz), 20.9, 18.1 (d, JCP=1.5
Hz); 31P NMR (CDCl3) l 21.3.

B. J. Rowe, C. D. Spilling / Tetrahedron: Asymmetry 12 (2001) 1701–1708
Table 3. Preparative scale reaction conditions and results
1707
Compd.
Amount
(mg)
Enzyme
(Units/mg)
Amount
mg (Units)
Yield
mg (%)
E.e. (%)
[h]D, conc. solvent (at 20°C in EtOH)
3a
500
Pseudomonas sp.
(1500)
30 (45,000)
290 (68)
99
+38.5, c=1 {+23.0, c=1, CHCl3, Ref. 14}
3b
3c
3d
270
350
250
Lipase PSCII (30)
Lipase AY (42)
Pseudomonas sp.
type B (160)
Rhizopus arrizhus
(0.002)
200 (6000)
250 (10,500)
15 (2400)
175 (75)
175 (59)
150 (72)
99
92
99
+4.0, c=0.5
+25.9, c=1
+39.4, c=1
2a
2c
505
500
350 (0.7)
300 (70)
302 (74)
90
90
+58.2, c=1
+42.1, c=1
Rhizopus arrizhus
(0.002)
868 (1.74)
2e
2f
2g
331
250
258
F-AP15 (150)
F-AP15 (150)
F-AP15 (150)
300 (45,000)
300 (45,000)
300 (45,000)
213 (79)
157 (74)
155 (72)
97
95
79
+29.3, c=1
+23.4, c=2.0
+16.0, c=1
The e.e.s of the hydroxy and acetoxy phosphonate products were determined by HPLC; compounds 2a and 3a on a Whelk-O column with
EtOH:hexanes, 1:4 (1 mL/min) detected at 254 nm; 3b on a Whelk-O column with EtOH:hexanes, 1:9 (1 mL/min) detected at 254 nm; 2c, 2e,
i
3c, and 3g on a Spherisorb silica column in tandem with a ChiralPak AS column with PrOH:hexanes, 1:4 (1 mL/min) detected at 205 nm; 2f
on a ChiralPak AS column with EtOH:hexanes, 1:9 (0.5 mL/min) detected at 205 nm; and 3d on a Whelk-O column with EtOH:hexanes, 1:9
(1 mL/min) detected at 210 nm. The enantiomers of acetate 2g were not separable by HPLC on either the ChiralPak AS or Whelk-O columns.
The acetate was hydrolyzed using the non-selective lipase from wheat germ and the e.e. of the product hydroxy phosphonate was determined
by 31P NMR spectroscopy using quinine as the shift reagent.16
References
3.20. Kinetic resolution of non-racemic acetoxy
phosphonates
1. For examples, see: (a) Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, 1993; (b) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; John Wiley
and Sons: New York, 1994; (c) Cervinka, O. Enantiose-
lective Reactions in Organic Chemistry; Ellis Horwood:
New York, 1995; (d) Asymmetric Synthesis; Morrison, J.
D., Ed.; Vol. 5 Chiral Catalysis; Academic Press: New
York, 1985.
A solution of the acetates (200–500 mg) in t-BuOMe
(2–3 mL) was added to a solution of the enzyme
(300–1500 U) in pH 7.0 phosphate buffer (2–3 mL) (see
Table 1 for quantities). The mixture was agitated on a
rotating shaker at room temperature (40°C for Amano
enzymes) and the conversion and % e.e. were monitored
by HPLC. When approximately 80% of the acetate (or
20–25% for S selective enzymes) had been hydrolyzed
the reaction mixture was extracted with CH2Cl2 (5×20
mL). The combined CH2Cl2 extracts were dried and
evaporated in vacuo. The products were isolated by
column chromatography (SiO2, EtOAc) and the e.e.
was re-determined by HPLC (Table 3).
2. Wiemer, D. F. Tetrahedron 1997, 53, 16609.
3. For examples, see: (a) Patel, D. V.; Rielly-Gauvin, K.;
Ryono, D. E. Tetrahedron Lett. 1990, 31, 5587; (b)
Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.;
Ruppert, D. Tetrahedron Lett. 1992, 33, 6625.
4. For example, see: (a) Shabany, H.; Spilling, C. D. Tetra-
hedron Lett. 1998, 39, 1465; (b) De la Cruz, M. A.;
Shabany, H.; Spilling, C. D. Phosphorus, Sulfur Silicon
1999, 146, 181; (c) Zhu, J.; Lu, X. Tetrahedron Lett. 1987,
28, 1897; (d) Zhu, J.; Lu, X. J. Chem. Soc., Chem.
Commun. 1987, 1318; (e) Cooper, D.; Trippett, S. J.
Acknowledgements
8
Chem. Soc., Perkin Trans. 1 1981, 2127; (f) Ohler, E.;
8
Kotzinger, S. Synthesis 1993, 497; (g) Ohler, E.; Kanzler,
We are grateful to the National Science Foundation
(CHE-9628820) and the Donors of the Petroleum
Research Fund administered by the American Chemical
Society (34428-AC1) for financial support of this pro-
ject. We are also grateful to the National Science
Foundation, the US Department of Energy and the
University of Missouri Research Board for grants to
purchase the NMR spectrometers (CHE-856671, CHE-
9318696, DE-FG02-92-CH10499) and mass spectrome-
ter (CHE-9708640) used in this work. We thank
Anchalee Thanavaro for providing some of the hydroxy
phosphonates and Amano USA for a generous gift of
enzymes.
S. Liebigs Ann. 1997, 1437.
5. (a) Heisler, A.; Rabiller, C.; Douillard, R.; Goalou, N.;
Ha¨gele, G.; Levayer, F. Tetrahedron: Asymmetry 1993, 4,
959; (b) Li, Y.-F.; Hammerschmidt, F. Tetrahedron:
Asymmetry 1993, 4, 109; (c) Drescher, M.; Li, F.-Y.;
Hammerschmidt, F. Tetrahedron 1995, 51, 4933; (d)
Drescher, M.; Hammerschmidt, F.; Kahlig, H. Synthesis
1995, 1267; (e) Eidenhammer, G.; Hammerschmidt, F.
Synthesis 1996, 748; (f) Drescher, M.; Hammerschmidt,
F. Tetrahedron 1997, 53, 4627; (g) Wuggenig, F.; Ham-
merschmidt, F. Monatsh. Chem. 1998, 129, 423; (h) Ham-
merschmidt, F.; Wuggenig, F. Tetrahedron: Asymmetry
1999, 10, 1709.

1708
B. J. Rowe, C. D. Spilling / Tetrahedron: Asymmetry 12 (2001) 1701–1708
6. (a) Groaning, M. D.; Rowe, B. J.; Spilling, C. D. Tetra-
Chem. 1985, 50, 1143; (e) Hoye, T. R.; Suhadolnik, J. C.
J. Am. Chem. Soc. 1985, 107, 5312; (f) Schreiber, S. L.;
Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987,
109, 1525.
hedron Lett. 1998, 39, 5485; (b) Rath, N. P.; Spilling, C.
D. Tetrahedron Lett. 1994, 35, 227; (c) Yokomatsu, T.;
Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry 1993,
4, 1783; (d) Sasai, H.; Bougauchi, M.; Arai, T.;
Shibasaki, M. Tetrahedron Lett. 1997, 38, 2717; (e) Yoko-
matsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron:
Asymmetry 1993, 4, 1779; (f) Yokomatsu, T.; Yamagishi,
T.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1 1997, 1527;
(g) Arai, T.; Bougauchi, M.; Sasai, H.; Shibasaki, M. J.
Org. Chem. 1996, 61, 2926; (h) Duxbury, J. P.; Cawley,
A.; Thorton-Pett, M.; Wantz, L.; Warne, J. N. D.;
Greatrex, R.; Brown, D.; Kee, T. P. Tetrahedron Lett.
1999, 40, 4403; (i) Yamagishi, T.; Yokomatsu, T.; Sue-
mune, K.; Shibuya, S. Tetrahedron 1999, 55, 12125.
7. (a) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294; (b) Wang, Y.-F.; Chen,
C.-S.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1984,
106, 3695.
8. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry
of Organic Compounds; Wiley: New York, 1994; p. 381.
9. For examples of the coupling of two asymmetric reac-
tions, see: (a) Roush, W. R.; Straub, J. A.; VanNieuwen-
hze, M. S. J. Org. Chem. 1991, 56, 1636; (b) Kogure, T.;
Eliel, E. L. J. Org. Chem. 1984, 49, 567; (c) Merifield, E.;
Steel, P. G.; Thomas, E. J. J. Chem. Soc., Chem. Com-
mun. 1987, 1826; (d) Midland, M. M.; Gabriel, J. J. Org.
10. For an example of the coupling of an asymmetric reac-
tion and enzyme-catalyzed amide deprotection, see: Tay-
lor, S. J. C.; Holt, K. E.; Brown, R. C.; Keene, P. A.;
Taylor, I. N. In Stereoselective Biocatalysis; Patel, R. N.,
Ed. Choice of biocatalyst in the development of industrial
biotransformations. Marcel Dekker: New York, 2000,
pp. 397–413.
11. (a) Textier-Boullet, F.; Foucaud, A. Synthesis 1982, 165;
(b) Baraldi, P. G.; Guarneri, M.; Moroder, F.; Pollini, G.
P.; Simoni, D. Synthesis 1982, 653.
12. We are aware of only one example of an enzyme-cata-
lyzed acetylation of a 1-hydroxy phosphonate. Patel, R.
N.; Banerjee, A.; Szarka, L. J. Tetrahedron: Asymmetry
1997, 8, 1055
13. Rowe, B. J.; Spilling, C. D.; Thanavaro, A., manuscript
in preparation.
14. There is some error (1–2%) in the measurement of e.e. on
the crude samples due to noise and some baseline drift.
15. Blazis, V. J.; Koeller, K. J.; Spilling, C. D. J. Org. Chem.
1995, 60, 931.
16. Zymanczyk-Duda, E.; Skwarczynski, M.; Lejczak, B.;
Karfarski, P. Tetrahedron: Asymmetry 1996, 7, 1277.
.