Kinetic resolution of 2-hydroxy-2-aryl-ethylphosphonates by a non-enzymatic acylation catalyst

Article abstract of DOI:10.1016/j.tet.2014.03.102

Optically pure hydroxyphosphonates are widely used as derivatizable compounds that can be incorporated into a variety of synthetic strategies for the preparation of other high value organic products. A non-enzymatic kinetic resolution procedure to obtain chiral 2-hydroxy-2-arylethylphosphonates from the easily available racemic counterparts is described. A range of 2-hydroxy-2-arylethylphosphonates was efficiently resolved employing a planar-chiral DMAP derived catalyst with good selectivities (up to S=68). The chiral hydroxyphosphonates were isolated in good yields and high enantiomeric excess (>94% ee).

Full text of DOI:10.1016/j.tet.2014.03.102

Tetrahedron 70 (2014) 3807e3811
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Kinetic resolution of 2-hydroxy-2-aryl-ethylphosphonates
by a non-enzymatic acylation catalyst
a
a
a
a,b,
ꢀ
*
ꢀ
ꢀ
Laura Mesas-Sanchez , Alba E. Díaz-Alvarez , Petr Koukal , Peter Diner
a Department of Chemistry e BMC, Uppsala University, Box 576, SE-75123 Uppsala, Sweden
b Department of Chemistry, KTH-Royal Institute of Technology, Teknikringen 30, SE-10044 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically pure hydroxyphosphonates are widely used as derivatizable compounds that can be in-
corporated into a variety of synthetic strategies for the preparation of other high value organic products.
A non-enzymatic kinetic resolution procedure to obtain chiral 2-hydroxy-2-arylethylphosphonates from
the easily available racemic counterparts is described. A range of 2-hydroxy-2-arylethylphosphonates
was efficiently resolved employing a planar-chiral DMAP derived catalyst with good selectivities (up
to S¼68). The chiral hydroxyphosphonates were isolated in good yields and high enantiomeric excess
(>94% ee).
Received 15 January 2014
Received in revised form 20 March 2014
Accepted 31 March 2014
Available online 4 April 2014
Keywords:
Non-enzymatic kinetic resolution
2-Hydroxy-2-arylethylphosphonates
Planar chiral DMAP derivative catalyst
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 1),7 which involve the asymmetric reduction of the cor-
responding 2-ketophosphonates3,8 and kinetic resolution.6,9 The
The synthesis of enantiomerically pure compounds has
emerged as one of the most important fields of organic chemistry.1
Chiral secondary alcohols are undoubtedly one of the most im-
portant broad classes of building blocks available for the synthesis
of pharmaceuticals and other fine chemicals.2 In addition, hydroxy-
phosphonic acids and their esters are important precursors for bi-
ologically active compounds, such as aminophosphonic esters,
which have received significant attention due to their ability to
mimic their carboxylic counterparts.3 Particularly, 2-amino-2-
arylethylphosphonates analogues have attracted considerable
attention due to their wide range of potential applications, such as
enzyme inhibitors4 or pharmacologic agents.5 For instance, 2-
amino-2-arylethylphosphonic acids are reported to be potential
GABAB receptor antagonists,5a,c and therefore, the development of
asymmetric synthesis of these compounds is important. Current
stereoselective approaches to 2-amino-2-aryl-ethylphosphonates
involve the synthesis of chiral 2-hydroxy-2-arylethylphosphonates
by enzymatic catalysis,4b,6 followed by the substitution of the hy-
droxyl by an azide group with inversion of configuration under
Mitsunobu reaction conditions, and subsequent reduction of the
azide to the amine.
asymmetric reduction of 2-ketophosphonates can occur via chiral
metal complexes,3,8aec chirally modified metal hydrides,8d,e chiral
reagents8d,e or by biotransformation.8f,g Several studies of kinetic
resolution by lipase-catalyzed hydrolysis of the corresponding
acetates6,9a,b have been reported. Although many lipases were ex-
plored for acylative kinetic resolution of 2-hydroxy-2-
arylethylphosphonates, none proved to be fruitful, probably due
to the bulkiness of the phosphonate group.9a,b So far, the only ex-
ample of acylative kinetic resolution is described by Onomura and
co-workers,9d who reported a method for the kinetic resolution of
2-hydroxyalkane-phosphonates by 2-fluorobenzylation in the
presence of a copper (II) triflate/(R,R)-Ph-BOX catalyst system with
good selectivities (up to S¼21) (Scheme 1).
During the last two decades, a variety of organic small-molecule
catalysts for the acylative kinetic resolution of secondary alcohols
10d
have been developed.10 Schreiner and Muller
classified these
€
organocatalysts into six distinct groups: phosphines and phos-
phinites, N-alkylimidazoles, amidines, vicinal diamines, N-hetero-
cyclic carbenes, and 4-aminopyridines derivates (DMAP
analogues). The first member of the ‘chiral DMAP’ family11 was
introduced by Vedejs and Chen in 199612 and they demonstrated its
efficiency in the kinetic resolution of secondary benzylic alcohols12
using stoichiometric amounts of their chiral DMAP analogue in the
presence of 2 equiv of a Lewis acid. In the same year, Fu and co-
workers developed the synthesis of planar-chiral ferrocenyl
DMAP derivates.13 The DMAP analogue (ꢀ)-1 catalysed the kinetic
resolution of secondary aryl alkyl alcohols.14 This catalytic system
Several synthetic routes for the preparation of enantioenriched
2-hydroxy-2-arylethylphosphonates
have
been
developed
* Corresponding author. Tel.: þ46 8 7903891; fax: þ46 8 7912333; e-mail ad-
ꢀ
dress: diner@kth.se (P. Diner).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.102

ꢀ
L. Mesas-Sanchez et al. / Tetrahedron 70 (2014) 3807e3811
3808
period to avoid Nuclear Overhauser Effect (NOE) enhancements
(see Experimental section for more details). Upon addition of qui-
nine (molar ratio quinine-hydroxy phosphonate 5:1),20 the chem-
ical shift differences of the (R)- and (S)-alcohols were relatively
large (Dd¼0.30e0.44 ppm, in CDCl3) for all the substrates (2aej)
(Fig. 1a and b).21
Scheme 1. Synthetic routes to enantiopure 2-hydroxy-2-arylethylphosphonates.
was also very efficient in the kinetic resolution of propargylic15 and
allylic16 alkyl alcohols. Recently, Fu and co-workers reported the
first non-enzymatic dynamic kinetic resolution of secondary alco-
hols and demonstrated the compatibility of (ꢀ)-1 with a ruthe-
nium-based racemization catalyst.17
In our effort to expand the applicability of the planar chiral
DMAP catalyst (ꢀ)-1, we have previously studied the kinetic reso-
lution of sec-alcohols that contain an additional heteroatom-
containing functional group in the alkyl moiety. Recently, we
demonstrated that the catalyst (ꢀ)-1 promotes the kinetic resolu-
tion for a range of aromatic 1,2-azidoalcohols with good selectivity
factors (up to S¼45) and high enantiomeric excess (up to 99% ee) of
the remaining alcohol.18 Herein, we wish to present the non-
enzymatic kinetic resolution of
a variety of 2-hydroxy-2-
Fig. 1. 31P NMR spectra of racemic dimethyl (2-hydroxy-2-phenylethyl)phosphonate,
rac-2a (a) in the absence, (b) in the presence of 5 equiv of quinine, and (c) enantiopure
dimethyl (R)-(2-hydroxy-2-phenylethyl)phosphonate, (R)-2a, in the presence of
quinine.
arylethylphosphonates using the planar-chiral ferrocenyl DMAP
derivate (ꢀ)-1 as a catalyst with excellent selectivities (up to S¼68)
(Scheme 1, bottom).
2. Results and discussion
The kinetic resolution of diethyl (2-hydroxy-2-phenylethyl)
phosphonate (2d) was performed following the conditions pre-
viously reported14b,18 using the racemic alcohol 2d (0.25 mmol),
acetic anhydride (0.75 equiv), triethylamine (0.75 equiv), and (ꢀ)-1
(0.0025 mmol, 1 mol %) in tert-amyl alcohol (1.0 mL) at 0 ꢁC. After
24 h, the conversion was 53% and the selectivity factor (S) was 20.
When the reaction was performed in the absence of base, the se-
lectivity improved significantly (S¼37), but the reaction slowed
down. We finally decided to compromise the speed of the reaction
in favour of the selectivity, excluding triethylamine in the succes-
sive experiments.
Previous work has shown that the bulky base, triethylamine,
catalyses the acetylation of some sec-alcohols,15 and therefore, we
studied how the presence or the absence of this base affects the
selectivity of the system under study.
The enantiomeric excess (ee) and the conversion were de-
termined by 31P NMR spectroscopy using quinine as a chiral sol-
vating agent. 31P NMR spectroscopy is a convenient tool for the
determination of the enantiomeric excess of phosphorus-
containing compounds due to the large chemical shift dispersion
and the simplicity of the 31P NMR spectra.19 In order to obtain
undistorted 31P signal intensities for an accurate integration, long
relaxation times (30 s) were used without irradiation during this
In the first stage of the study, the selectivity factor of the kinetic
resolution of rac-2aej was determined after 4 h of reaction in order
to easily compare the efficiency of the kinetic resolution

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L. Mesas-Sanchez et al. / Tetrahedron 70 (2014) 3807e3811
3809
methodology of the different substrates. The reaction was carried
out using racemic alcohol (0.25 mmol), acetic anhydride
(0.75 equiv), and (ꢀ)-1 (0.0025 mmol, 1 mol %) in tert-amyl alcohol
(1.0 mL) at 0 ꢁC (Table 1). Initially, the effect of the size of the
phosphonate ester substituents was evaluated using either the di-
methyl- or diethylhydroxyphosphonates.
In the second stage of the study, the kinetic resolutions of the
different substrates (rac-2a and rac-2cej) were performed with
longer reaction times, under the general conditions, in order to
isolate the enantiomerically pure hydroxyarylphosphonates and to
demonstrate the practical use of this methodology (Table 2). As
previously mentioned, the enantioselectivity of the reaction was
determined by 31P NMR spectroscopy using quinine as the solvating
agent. Integral ratios ranging from 1:99 to 0:100 were judged as
>95% ee, even in cases where only one peak was observed. In
general, all the substrates were obtained with very high enantio-
meric excess (>95% ee) and good yields (29e49%). For instance, the
larger 2-naphthyl derivate 2g was isolated enantiomerically pure
(>95% ee) in 32% yield after only 24 h (entry 6). For the less reactive
parent compound (R)-2d, longer reaction times were necessary
(96 h) in order to obtain the product in high ee (>95%) (Table 2,
entry 3). On the contrary, substrates having halogens in the aro-
matic ring ((R)-2h and (R)-2j) show a lower selectivity compared to
the parent compound, but are more reactive and could be isolated
with high ee after shorter reaction time (48 h) (Table 2, entries
7 and 9).
Table 1
Selectivity factor of kinetic resolution of 2-hydroxy-2-arylethylphosphonates by
(ꢀ)-1a
Entry
Ar
R
eeROH (%)b
Conv. (%)b
Sc
1
2
3
4
5
6
7
8
9
Ph (2a)
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
38
23
36
32
31
22
55
35
15
43
31
16
31
25
25
20
37
28
14
38
24
5
4-NO2-Ph (2b)
3-MeO-Ph (2c)
Ph (2d)
4-NO2-Ph (2e)
3-MeO-Ph (2f)
2-Naphthyl (2g)
2,4-diCl-Ph (2h)
4-Me-Ph (2i)
4-F-Ph (2j)
16
43
62
19
68
35
25
11
Table 2
Synthesis of (R)-2-hydroxy-2-arylethylphosphonates by means of kinetic
,b
resolutiona
10
a
Reaction conditions: 2 (0.25 mmol), Ac2O (0.75 equiv), (ꢀ)-1 (0.0025 mmol,
1 mol %) in tert-amyl alcohol (1.0 mL) at 0 ꢁC for 4 h.
b
Determined by 31P NMR spectroscopy using quinine as the chiral solvating
agent. The value given is an average of two runs.
Entry
R
R
Time/h Integral ratioc,d eeROH (%)d Yield (%)e
c
The best selectivity of two runs.
1
2
3
4
5
6
7
8
9
Ph (2a)
3-MeO-Ph (2c)
Ph (2d)
4-NO2-Ph (2e)
3-MeO-Ph (2f)
2-Naphthyl (2g) Et 24
2,4-diCl-Ph (2h) Et 51
Me 72
Me 68
Et 96
Et 45
Et 70
1:99
>95
>95
>95
>95
>95
>95
>95
94
30 (60)
35 (70)
41 (82)
33 (66)
31 (62)
32 (64)
29 (58)
49 (98)
44 (88)
0:100
0:100
0:100
0:100
0:100
0:100
3:97
The compounds investigated included the parent compounds 2a
and 2d (entries 1 and 4), compounds 2b and 2e with the electron
withdrawing nitro group in the 4-position (entries 2 and 5), and
compounds 2c and 2f with the electron donating methoxy group in
the 4-position (entries 3 and 6). The substrates bearing the larger
ethyl group in the phosphonate ester, 2def (entries 4e6), show
significantly higher selectivity than the dimethyl hydrox-
yphosphonates 2aec (entries 1e3). These results are in accordance
with the previous result reported by Fu for secondary benzylic al-
cohols with a bulky aliphatic substituent.14b The significantly lower
selectivity (ten times lower) obtained for dimethyl (2-hydroxy-2-
(4-nitrophenyl)ethyl)-phosphonate 2b (S¼5, entry 2) could also be
a consequence of its poor solubility in t-amyl alcohol. With these
results in hand, we continued with the study of the effect of dif-
ferent substituents in the aromatic ring among diethyl phospho-
nates. The larger 2-naphthyl derivate 2g gave better results in terms
of both selectivity and reactivity (S¼68, 37% conv.). The electron
withdrawing nitro group in the 4-position also increases the se-
lectivity (S¼62) compared to the parent compound 2d (S¼43). The
presence of an electron donating group in the phenyl ring, such as
a methyl or methoxy group (entries 6 and 9) decreases the selec-
tivity compared to the parent compound 2d, and it can also be
observed that the reactivity decreases for substrate 2i (entry 8). In
the case of the alcohol 2h, having two chloro substituents in the 2-
and 4-position of the aromatic ring, the selectivity obtained was
slightly lower (S¼35) compared to the corresponding parent
compound 2d. The decrease in the selectivity is even larger in the
case of the 4-fluoro derivate (S¼11). In general, it could be observed
that substrates having electron withdrawing substituents show
a higher selectivity than the substrates having electron donating
4-Me-Ph (2i)
4-F-Ph (2j)
Et 96
Et 48
0:100
>95
a
Reaction conditions: 2 (0.25 mmol), Ac2O (0.75 equiv), (ꢀ)-1 (0.0025 mmol,
1 mol %) in tert-amyl alcohol (1.0 mL) at 0 ꢁC.
b
The absolute configuration was assigned by comparison of the optical rotation
sign of (R)-2a and (R)-2d with literature.
c
Integral ratio.
d
Determined by 31P NMR spectroscopy using quinine as the solvating agent;
integral ratios between 1:99 to 0:100 were judged as >95% ee.
e
Isolated yields based on rac-2-hydroxy-2-arylethanephosphonate. In paren-
thesis: % recovered (R)-isomer.
Finally, in order to demonstrate the applicability of the current
method for synthetic purposes, the reaction was scaled up. The
kinetic resolution of the hydroxyphosphonate rac-2d (using
3 mmol scale) was performed following the general procedure,
obtaining compound (R)-2d in good yield (258 mg, 1.0 mmol, 33%
yield) with high enantiomeric excess (>95% ee) after 96 h.
3. Conclusion
In summary, we have demonstrated that the chiral DMAP de-
rivative catalyst (ꢀ)-1 catalysed the kinetic resolution of a range of
aromatic 2-hydroxyphosphonates with good selectivities (selec-
tivity factor up to 68) and high enantiomeric excess (>95% ee) of
the remaining alcohol. The 2-hydroxy-2-aryl-phosphonates with
the more bulky ethyl substituent in the phosphonate ester show in
general a higher selectivity than the less bulky methylsubstituted
phosphonate ester. To the best of our knowledge, these results
represent the first example of kinetic resolution of 2-hydroxy-2-
arylethylphosphonates using a non-enzymatic nucleophilic chiral
catalyst.
substituents. Previously,
pep-stacking between the catalysts and
the aromatic group of the substrates is suggested to be involved in
the rate-determining step of these acylation reactions, which could
also be the case for the Fu catalyst.22

ꢀ
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L. Mesas-Sanchez et al. / Tetrahedron 70 (2014) 3807e3811
20
4. Experimental section
[
d
a
]
ꢀ30.7 (c 1.6, CDCl3). 1H NMR (500 MHz, CDCl3, 25 ꢁC)
D
¼7.28e7.25 (m, 1H, ArH), 6.97e6.94 (m, 2H, ArH), 6.83e6.81
4.1. General
(m, 1H, ArH), 5.12e5.07 (m, 1H, CHOH), 3.81 (s, 3H, ArOCH3), 3.78
(d, J¼10.8 Hz, 3H, OCH3), 3.74 (d, J¼10.9 Hz, 3H, OCH3), 2.29e2.15
Unless otherwise stated, all reagents were purchased from
commercial sources and used without further purification. Thin
Layer Chromatography (TLC) was performed on ALUGRAMÒ SIL G/
UV254 plates (0.2 mm), using UV-light (254 nm) for visualization.
Flash chromatography was performed using Merck silica gel
(0.04e0.06 mm). 1H, and 13C spectra were recorded on a Varian
Mercury 300 MHz, Varian Unity 400 MHz or Varian Unity 500 MHz.
31P NMR spectra were recorded on a Varian Mercury 300 MHz. The
(m, 2H, CH2). 13C{1H} NMR (126 MHz, CDCl3, 25 ꢁC)
d¼160.0, 145.2
(d, J¼16.6 Hz), 129.8, 117.8, 113.6, 111.0, 68.8, 55.4, 52.8 (d, J¼5.6 Hz),
52.6 (d, J¼5.6 Hz), 35.2 (d, J¼136.1 Hz). 31P NMR (121 MHz, CDCl3,
25 ꢁC)
d
¼32.8. IR (neat):
n
(cmꢀ1)¼3340, 2958, 1588, 1213, 1020.
HRMS (ESI) Calcd for C11H18O5Pþ [MþHþ]:25 261.0892, found:
261.0894.
4.2.3. (Diethyl (R)-(2-hydroxy-2-phenylethyl)phosphonate ((R)-
20
chemical shifts values (
d
) are given in parts per million (ppm) rel-
2d)).9d Colourless oil (26.5 mg, 41% yield, >95.0% ee); [
a
]
D
ꢀ40.0
20
ative to TMS and referred to and internally referenced to the re-
sidual undeuterated peak of solvent used (CHCl3: dH¼7.26 ppm,
dC¼77.16 ppm) or externally to H3PO4 (85%). J values are given in
Hertz. Abbreviations used are s (singlet), d (doublet), t (triplet), q
(quartet), and m (multiplet). IR spectra were recorded on a Per-
kineElmer Spectrum One (ATR Technique). High-resolution mass
spectra were recorded by Dr. Aleh Yahorau, Department of Phar-
maceutical Biosciences, Uppsala University, Sweden.
(c 1.4, CDCl3); [
a]
ꢀ10.8 (c 1.1, acetone, 41% ee).9d 1H NMR
D
(300 MHz, CDCl3, 25 ꢁC)
d
¼7.41e7.26 (m, 5H, ArH), 5.14e5.07
(m, 1H, CHOH), 4.17e4.02 (m, 4H, 2OCH2CH3), 2.25e2.16 (m, 2H,
CH2), 1.34 (d, J¼7.1 Hz, 3H, OCH2CH3), 1.29 (t, J¼7.1 Hz, 3H,
OCH2CH3). 13C{1H} NMR (75 MHz, CDCl3, 25 ꢁC)
d¼143.6
(d, J¼16.2 Hz), 128.6, 127.8, 125.6, 68.9 (d, J¼4.6 Hz), 62.2
(d, J¼6.4 Hz), 62.1 (d, J¼6.7 Hz), 36.0 (d, J¼136.0 Hz), 16.6
31
(d, J¼2.7 Hz), 16.5 (d, J¼2.9 Hz). P NMR (121 MHz, CDCl3, 25 ꢁC)
The enantiomeric excesses of 2aej were determined by 31P NMR
spectroscopy with quinine as the chiral solvating agent. In order to
obtain undistorted 31P signal intensities for an accurate integration,
an inverse gated decoupling pulse sequence was always used to
obtain proton-decoupled spectra with no NOE enhancement. The
decoupler is switched off before the excitation pulse so that the
NOE enhancement is not allowed to develop. Proton decoupling is
provided since the decoupler is switched on during the excitation
pulse and the acquisition time. Spectra were collected using 128
transients with long relaxation time (30 s). Integral ratios between
1:99 and 0:100 were judged as >95% ee. The selectivity (S) values
were calculated with the equation: S¼ln[(1ꢀc)(1ꢀeeROH)]/ln
[(1ꢀc)(1þeeROH)].23
d
¼30.2.
4.2.4. Diethyl (R)-(2-hydroxy-2-(4-nitrophenyl)ethyl)-phosphonate
((R)-2e).24 Yellowish oil (25.9 mg, 33% yield, >95% ee); [
a
]
20 ꢀ36.8
D
(c 1.4, CDCl3). 1H NMR (300 MHz, CDCl3, 25 ꢁC)
d
¼8.22 (d, J¼8.7 Hz,
2H, ArH), 7.59 (d, J¼8.7 Hz, 2H, ArH), 5.25e5.16 (m, 1H, CHOH),
4.20e4.07 (m, 4H, 2OCH2CH3), 2.22e2.11 (m, 2H, CH2), 1.38
(t, J¼7.0 Hz, 3H, OCH2CH3), 1.31 (t, J¼7.1 Hz, 3H, OCH2CH3). 13C{1H}
NMR (75 MHz, CDCl3, 25 ꢁC)
d¼150.6, 126.5, 123.9, 100.3, 69.8e66.8
(m), 62.5 (dt, J¼7.6, 4.5 Hz), 35.9 (d, J¼137.1 Hz), 16.6 (d, J¼5.9 Hz),
31
16.5 (d, J¼5.9 Hz). P NMR (121 MHz, CDCl3, 25 ꢁC)
¼29.3.
d
4.2.5. Diethyl (R)-(2-hydroxy-2-(3-methoxyphenyl)ethyl)-phospho-
20
nate ((R)-2f). Colourless oil (22.3 mg, 31% yield, >95% ee); [a]
D
4.2. General procedure for the kinetic resolution of racemic
2-aryl-2-hydroxyethylphosphonates rac-2aej
ꢀ25.5 (c 2.3, CDCl3). 1H NMR (500 MHz, CDCl3, 25 ꢁC)
¼7.37e7.23
d
(m, 1H, ArH), 7.08e6.92 (m, 2H, ArH), 6.91e6.78 (m, 1H, ArH),
5.25e5.01 (m, 1H, CHOH), 4.30e3.99 (m, 4H, 2OCH2CH3), 3.86
(s, 3H, ArOCH3), 2.39e2.06 (m, 2H, CH2), 1.40 (t, J¼7.1 Hz, 3H,
OCH2CH3), 1.35 (t, J¼7.0 Hz, 3H, OCH2CH3). 13C{1H} NMR (126 MHz,
Catalyst (ꢀ)-1 (1.65 mg, 0.0025 mmol), racemic 2-aryl-2-
hydroxyethylphosphonates rac-2aej (0.25 mmol), and tert-amyl al-
cohol (1.0 mL) were sequentially added to a vial. The vial was capped
and stirred at room temperature in order to dissolve the catalyst. The
CDCl3, 25 ꢁC)
d¼159.9, 145.3 (d, J¼16.5 Hz), 129.7, 117.9, 113.5, 111.0,
68.8 (dd, J¼4.8, 2.1 Hz), 62.2 (d, J¼6.3 Hz), 62.1 (d, J¼6.7 Hz), 55.4,
reaction mixture was cooled to 0 ꢁC, and then acetic anhydride (18
mL,
36.1 (d, J¼136.0 Hz), 16.5 (dt, J¼10.2, 5.6 Hz). 31P NMR (121 MHz,
0.19 mmol) was added. After an appropriate amount of time, the re-
action mixture was quenched by the addition of a large excess of
methanol. The resulting solution was concentrated, and the unreac-
tive alcohol, the acetate, and the catalyst were separated by flash
chromatography using DCM (1% EtOH) as eluent. All the previously
describedcompounds were confirmed by NMR spectroscopy. All new
compounds and for those compounds where no NMR data was re-
ported, were also confirmed by IR and HRMS spectroscopy. Charac-
terization data for these compounds are as follows (copies of the 1H,
13C, and 31P NMR spectra are included in Supplementary data).
CDCl3, 25 ꢁC)
d¼30.2. IR (neat):
n
(cmꢀ1)¼3292, 2982, 1594, 1206,
1018. HRMS (ESI) Calcd for C13H22O5Pþ [MþHþ]: 289.1205, found:
289.1202.
4.2.6. Diethyl (R)-(2-hydroxy-2-(naphthalen-2-yl)ethyl)-phospho-
20
nate ((R)-2g).9b Colourless oil (24.7 mg, 32% yield, >95% ee); [
a]
D
ꢀ31.7 (c 1.4, CDCl3). 1H NMR (500 MHz, CDCl3, 25 ꢁC)
¼7.87e7.38
d
(m, 4H, ArH), 7.50e7.46 (m, 3H, ArH), 5.31e5.26 (m, 1H, CHOH),
4.20e4.07 (m, 4H, 2OCH2CH3), 2.32e2.26 (m, 2H, CH2), 1.36
(t, J¼7.0 Hz, 3H, OCH2CH3), 1.29 (t, J¼7.0 Hz, 3H, OCH2CH3). 13C{1H}
NMR (75 MHz, CDCl3, 25 ꢁC)
d¼141.0 (d, J¼16.1 Hz), 133.4, 133.1,
4.2.1. Dimethyl (R)-(2-hydroxy-2-phenylethyl)phosphonate ((R)-
128.5, 128.2, 127.8, 126.3, 126.1, 124.4, 123.7, 69.1 (d, J¼3.1 Hz), 62.3
2a).3,9d Colourless oil (17.3 mg, 30% yield, >95% ee); [
a
]
D
ꢀ10.0
(d, J¼6.5 Hz), 62.2 (d, J¼7.6 Hz), 36.1 (d, J¼136.0 Hz), 16.6
20
25
31
(c 0.5, CDCl3), lit. [
a
]
ꢀ21.1 (CH3OH, c 1.26, 95% ee).3 1H NMR
(d, J¼5.4 Hz), 16.5 (d, J¼5.6 Hz). P NMR (121 MHz, CDCl3, 25 ꢁC)
D
(300 MHz, CDCl3, 25 ꢁC)
d
¼7.42e7.28 (m, 5H, ArH), 5.17e5.09
d
¼30. 4. IR (neat):
n
(cmꢀ1)¼3321, 2987, 1209, 1070, 1020, 961.
(m, 1H, CHOH), 3.78 (d, J¼10.9 Hz, 3H, OCH3), 3.73 (d, J¼11.0 Hz 3H,
HRMS (ESI) Calcd for C16H22O4Pþ [MþHþ]: 309.1256, found:
OCH3), 2.28e2.18 (m, 2H, CH2). 13C{1H} NMR (75 MHz, CDCl3, 25 ꢁC)
309.1253.
d
¼143.6 (d, J¼15.9 Hz), 128.7, 128.0, 125.6, 68.9 (d, J¼4.8 Hz), 52.8
(d, J¼6.3 Hz), 52.6 (d, J¼6.6 Hz), 35.2 (d, J¼136.4 Hz). 31P NMR
4.2.7. Diethyl (R)-(2-(2,4-dichlorophenyl)-2-hydroxyethyl)-phospho-
20
(121 MHz, CDCl3, 25 ꢁC)
d¼32.8.
nate ((R)-2h).4b,9b Yellowish oil (23.7 mg, 29% yield, >95% ee); [
a]
D
ꢀ42.6 (c 2.0, CDCl3). 1H NMR (300 MHz, CDCl3, 25 ꢁC)
¼7.64
d
4.2.2. (Dimethyl
(R)-(2-hydroxy-2-(3-methoxyphenyl)ethyl)phos-
(d, J¼8.4 Hz, 1H, ArH), 7.34 (d, J¼2.1 Hz, 1H, ArH), 7.30 (dd, J¼8.4,
2.1 Hz, 1H, ArH), 5.41e5.33 (m, 1H, CHOH), 4.24e4.06 (m, 4H,
phonate ((R)-2c)). Yellowish oil; (22.8 mg, 35% yield, >95% ee);

ꢀ
L. Mesas-Sanchez et al. / Tetrahedron 70 (2014) 3807e3811
3811
Yamakawa, R.; Terashima, Y.; Imura, S.; Ishigaki, K.; Kinjo, M.; Ando. J. Chem.
Ecol. 2013, 39, 28e36 Application in liquid crystal field: (i) Parra, M.; Vergara, J.;
Hidalgo, P.; Barbera, J.; Sierra, T. Liq. Cryst. 2006, 33, 739e745.
2OCH2CH3), 2.34e2.27 (m, 1H, CH2), 2.03e1.98 (m, 1H, CH2), 1.39
(t, J¼7.1 Hz, 3H, OCH2CH3), 1.30 (t, J¼7.1 Hz, 3H, OCH2CH3). 13C{1H}
ꢀ
NMR (75 MHz, CDCl3, 25 ꢁC)
d
¼139.7 (d, J¼17.1 Hz), 134.0, 131.8,
3. Kitamura, M.; Tokunaga, M.; Noyori. J. Am. Chem. Soc. 1995, 117, 2931e2932.
4. (a) Maier, L.; Diel, P. J. Phosphorus, Sulfur Silicon Relat. Elem. 1995, 107, 245e255;
(b) Xu, C.; Yuan, C. Eur. J. Org. Chem. 2004, 4410e4415.
5. (a) Hara, N.; Natsume, Y.; Hara, Y.; Goto, Y. Eur. J. Pharmacol. 1990, 179, 17e23;
(b) Ong, J.; Kerr, D. I. B.; Abbenante, J.; Prager, R. H. Eur. J. Pharmacol. 1991, 205,
319e322; (c) Abbenante, G.; Hughes, R.; Prager, R. H. Aust. J. Chem. 1997, 50,
523e527; (d) Ong, J.; Marino, V.; Parker, D. A. S.; Kerr, D. I. B. Naunyn-
Schmiedeberg’s Arch. Pharmacol. 1998, 357, 408e412.
129.3, 128.2, 127.8, 65.6 (d, J¼4.5 Hz), 62.6 (d, J¼6.3 Hz), 62.4
(d, J¼6.5 Hz), 34.0 (d, J¼135.6 Hz), 16.7 (d, J¼5.9 Hz), 16.6
31
(d, J¼6.0 Hz). P NMR (121 MHz, CDCl3, 25 ꢁC)
d
¼29.8. IR (neat):
n
(cmꢀ1)¼3304, 2991, 1563, 1383, 1210, 1028, 950. HRMS (ESI) Calcd
for C12H18Cl2O4Pþ [MþHþ]: 327.0320, found: 327.0325.
6. Woschek, A.; Lindner, W.; Hammerschmidt, F. Adv. Synth. Catal. 2003, 345,
4.2.8. Diethyl (R)-(2-hydroxy-2-(p-tolyl)ethyl)phosphonate ((R)-
1287e1298.
20
2i).4b,25 Yellowish oil (33.4 mg, 49% yield, 94% ee); [
a
]
ꢀ33.4
7. For review on asymmetric synthesis of hydroxyphosphonates: Kolodiazhnyi, O.
I. Tetrahedron: Asymmetry 2005, 16, 3295e3340.
8. Selected examples of asymmetric reduction of
chiral metal complexes: (a) Madec, J.; Pfister, X.; Phansavath, P.; Ratoveloma-
nana-Vidal, V.; Genet, J. P. Tetrahedron 2001, 57, 2563e2568; (b) Chavez, M. A.;
Vargas, S.; Suarez, A.; Alvarez, E.; Pizzano, A. Adv. Synth. Catal. 2011, 353,
2775e2794; (c) Tao, X.; Li, W.; Ma, X.; Li, X.; Fan, W.; Zhu, L.; Xie, X.; Zhang, Z. J.
Org. Chem. 2012, 77, 8401e8409 Chirally modified metal hydrides: (d) Meier, C.;
Laux, W. H. G. Tetrahedron: Asymmetry 1995, 6, 1089e1092 Chiral reagents: (e)
Nesterov, V. V.; Kolodiazhnyi, O. I. Tetrahedron 2007, 63, 6720e6731 Bio-
transformation: (f) Zymanczyk-Duda, E.; Brzezinska-Rodak, M.; Klimek-Ochab,
M.; Latajka, R.; Kafarski, P.; Lejczak, B. J. Mol. Catal. B: Enzym. 2008, 52e53,
74e77; (g) Zymanczyk-Duda, E.; Lejczak, B.; Kafarski, P.; Grimaud, J.; Fischer, P.
Tetrahedron 1995, 51, 11809e11814.
D
(c 2.3, CDCl3). 1H NMR (300 MHz, CDCl3, 25 ꢁC)
d
¼7.29 (d, J¼8.1 Hz,
b-ketophosphonates: using
2H, ArH), 7.16 (d, J¼8.1 Hz, 2H, ArH), 5.13e5.05 (m, 1H, CHOH),
4.13e4.06 (m, 4H, 2OCH2CH3), 2.34 (s, 3H, ArCH3), 2.26e2.15
(m, 2H, CH2), 1.35 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.31 (t, J¼7.0 Hz, 3H,
ꢀ
ꢀ
ꢀ
OCH2CH3). 13C{1H} NMR (75 MHz, CDCl3, 25 ꢁC)
d
¼140.7
(d, J¼16.3 Hz), 137.5, 129.3, 125.6, 68.8 (dd, J¼4.7, 1.3 Hz), 62.2
(d, J¼6.6 Hz), 62.0 (d, J¼6.8 Hz), 36.0 (d, J¼135.7 Hz), 21.2, 16.5
31
(d, J¼5.8 Hz), 16.5 (d, J¼5.8 Hz). P NMR (121 MHz, CDCl3, 25 ꢁC)
d¼30.3.
9. Kinetic resolution of 2-hydroxy-2-arylethylphosphonates. Hydrolytic kinetic
resolution, selected examples: (a) Zhang, Y.; Yuan, C.; Li, Z. Tetrahedron 2002,
58, 2973e2978; (b) Zhang, Y.; Li, Z.; Yuan, C. Tetrahedron Lett. 2002, 43,
4.2.9. Diethyl (R)-(2-(4-fluorophenyl)-2-hydroxyethyl)-phosphonate
((R)-2j).9b Yellowish oil (30.7 g, 44% yield, >95% ee); [
a
]
ꢀ32.7
20
D
(c 2.3, CDCl3). 1H NMR (300 MHz, CDCl3, 25 ꢁC)
d
¼7.38e7.33 (m, 2H,
ꢂ
€
3247e3249; (c) Pamies, O.; Backvall, J.-E. J. Org. Chem. 2003, 68, 4815e4818
Acylative kinetic resolution: (d) Moriyama, A.; Matsumura, S.; Kuriyama, M.;
Onomura, O. Tetrahedron: Asymmetry 2010, 21, 810e824 Diastereomeric
ArH), 7.06e7.00 (m, 2H, ArH), 5.13e5.05 (m, 1H, CHOH), 4.18e4.03
(m, 4H, 2OCH2CH3), 2.21e2.12 (m, 2H, CH2), 1.35 (t, J¼6.9 Hz, 3H,
OCH2CH3), 1.30 (t, J¼6.9 Hz, 3H, OCH2CH3). 13C{1H} NMR (75 MHz,
ꢀ
methods: (e) Rojas-Cabrera, H.; Fernandez-Zertuche, M.; García-Barradas, O.;
~
~
ꢀ~
Munoz-Muniz, O.; Ordonez, M. Tetrahedron: Asymmetry 2007, 18, 142e148.
10. For review on kinetic resolution, see: (a) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N.
Adv. Synth. Catal. 2001, 343, 5e26 For review on non-enzymatic kinetic reso-
lution, see: (b) Robinson, D. E. J. E.; Bull, S. D. Tetrahedron: Asymmetry 2003, 14,
1407e1446; (c) Pellissier, H. Adv. Synth. Catal. 2011, 353, 1613e1666 For a recent
CDCl3, 25 ꢁC)
d
¼162.3 (d, J¼245.6 Hz), 139.5 (d, J¼16.8 Hz), 127.4
(d, J¼8.1 Hz), 115.4 (d, J¼21.4 Hz), 68.3 (d, J¼3.9 Hz), 62.3
(d, J¼6.2 Hz), 62.1 (d, J¼6.7 Hz), 36.1 (d, J¼136.2 Hz), 16.7
€
review on non-enzymatic acylative kinetic resolution, see: (d) Muller, C. E.;
31
(d, J¼5.6 Hz), 16.6 (d, J¼5.7 Hz). P NMR (121 MHz, CDCl3, 25 ꢁC)
Schreiner, P. R. Angew. Chem., Int. Ed. 2011, 50, 6012e6042.
11. For a recent review on chiral DMAP derivatives, see: Wurz, R. P. Chem. Rev. 2007,
107, 5570e5595.
12. (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809e1810; (b) Vedejs, E.;
Chen, X. J. Am. Chem. Soc. 1997, 119, 2584e2585.
d¼29.9. IR (neat):
n
(cmꢀ1)¼3333, 2984, 1604, 1509, 1217, 1020, 957,
836. HRMS (ESI) Calcd for C12H19FO4Pþ [MþHþ]: 277.1005, found:
277.1008.
13. Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230e7231.
14. (a) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492e1493; (b)
Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794e2795.
15. Tao, B.; Ruble, J. C.; Hoic, D. A.; Fu. J. Am. Chem. Soc. 1999, 121, 5091e5092.
16. Bellemin-Laponnaz, S.; Tweddell, J.; Ruble, J. C.; Breitling, F. M.; Fu, G. C. Chem.
Commun. 2000, 1009e1010.
Acknowledgements
ꢁ
The authors thank Vetenskapsradet (621-2009-4018) and The
Carl Trygger Foundation (CTS12:105) for financial support.
17. (a) Lee, S. Y.; Murphy, J. M.; Ukai, A.; Fu, G. C. J. Am. Chem. Soc. 2012, 134,
ꢀ
ꢀ
ꢀ
15149e15153; (b) Díaz-Alvarez, A. E.; Mesas-Sanchez, L.; Diner, P. Angew. Chem.,
Supplementary data
Int. Ed. 2013, 52, 502e504.
ꢀ
ꢀ
ꢀ
18. Mesas-Sanchez, L.; Díaz-Alvarez, A. E.; Diner, P. Tetrahedron 2013, 69, 753e757.
19. For a recent review on assignment of absolute configuration using chiral re-
agents and NMR spectroscopy, see: (a) Wenzel, T. J.; Chisholm, C. D. Chirality
2011, 23, 190e214 For a selected example where quinine is used as a chiral
solvating agent, see: (b) Maly, A.; Lejczak, B.; Kafarski, P. Tetrahedron: Asym-
metry 2003, 14, 1019e1024.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.102.
References and notes
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