Access to optically pure β-hydroxy esters via non-enzymatic kinetic resolution by a planar-chiral DMAP catalyst

Article abstract of DOI:10.3390/molecules190914273

The development of new approaches to obtain optically pure β-hydroxy esters is an important area in synthetic organic chemistry since they are precursors of other high value compounds. Herein, the kinetic resolution of racemic β-hydroxy esters using a planar-chiral DMAP derivative catalyst is presented. Following this procedure, a range of aromatic β-hydroxy esters was obtained in excellent selectivities (up to s = 107) and high enantiomeric excess (up to 99% ee). Furthermore, the utility of the present method was demonstrated in the synthesis of (S)-3-hydroxy-N-methyl-3-phenylpropanamide, a key intermediate for bioactive molecules such as fluoxetine, tomoxetine or nisoxetine, in its enantiomerically pure form.

Full text of DOI:10.3390/molecules190914273

Molecules 2014, 19, 14273-14291; doi:10.3390/molecules190914273
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Access to Optically Pure β-Hydroxy Esters via Non-Enzymatic
Kinetic Resolution by a Planar-Chiral DMAP Catalyst
Alba E. Díaz-Álvarez 1,†, Laura Mesas-Sánchez 1,† and Peter Dinér 1,2,
*
1
Department of Chemistry-BMC, Uppsala University, Box 576, Uppsala SE-75123, Sweden;
E-Mails: albaestrella.diaz@csic.es (A.E.D.-A.); laura.mesas@kemi.uu.se (L.M.-S.)
Department of Chemistry-Organic Chemistry, KTH Royal Institute of Technology,
Stockholm SE-100 44, Sweden
2
†
These authors contributed equally to this work.
* Author to whom correspondence should be addressed; E-Mail: diner@kth.se;
Tel.: +46-8-790-81-39.
Received: 15 July 2014; in revised form: 26 August 2014 / Accepted: 27 August 2014 /
Published: 11 September 2014
Abstract: The development of new approaches to obtain optically pure β-hydroxy esters is
an important area in synthetic organic chemistry since they are precursors of other high
value compounds. Herein, the kinetic resolution of racemic β-hydroxy esters using a
planar-chiral DMAP derivative catalyst is presented. Following this procedure, a range of
aromatic β-hydroxy esters was obtained in excellent selectivities (up to s = 107) and high
enantiomeric excess (up to 99% ee). Furthermore, the utility of the present method was
demonstrated in the synthesis of (S)-3-hydroxy-N-methyl-3-phenylpropanamide, a key
intermediate for bioactive molecules such as fluoxetine, tomoxetine or nisoxetine, in its
enantiomerically pure form.
Keywords: non-enzymatic kinetic resolution; β-hydroxy esters; planar-chiral DMAP
catalyst; ferrocenyl catalyst
1. Introduction
In the recent decades, the development of methods for asymmetric synthesis of organic molecules
has gained increasing importance [1]. As a representative example, the development of approaches to

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achieve optically pure β-hydroxy esters has emerged as an important issue in synthetic organic
chemistry [2], since these chiral derivatives have received special attention due to their importance as
intermediates in the synthesis of a variety of important chemicals, such as β-lactams, pheromones and
carotenoids [3,4]. In addition, β-hydroxy esters are also precursors to norepinephrine or serotonin
reuptake inhibitors that are an important class of drugs. For example, fluoxetine (Prozac), which is
formulated as a racemate, is one of the most widely prescribed antidepressants. It has been shown that
the different enantiomers display different pharmacological properties [5–7] and therefore the
enantioselective synthesis of enantiopure compounds is of interest [8–12]. Several routes to produce
optically pure 1,3-hydroxy esters have been explored, including asymmetric aldol reaction [13–16], the
Reformatsky reaction [17–22], or regioselective epoxide ring opening [23–26]. The most widely studied
method to achieve this kind of derivatives is asymmetric reduction, using either biocatalysts [4,27–30] or
organometallic complexes [31–36] (Scheme 1).
Scheme 1. Different asymmetric approaches to β-hydroxy esters.
In comparison, kinetic resolution (KR) of β-hydroxy esters has been less studied. There are four
different kinetic resolution approaches to prepare β-hydroxy esters including: hydrolytic KR [37–40],
oxidative KR [41,42], acylation reactions [43–45], and dehydrative KR [46] (Scheme 2a–d).
Scheme 2. Kinetic resolution alternatives of β-hydroxy esters: (a) hydrolytic KR; (b)
oxidative KR, (c) acylative KR and (d) dehydrative KR.
With the exception of oxidative KR, which takes place in the presence of a palladium complex
containing (−)-sparteine ligand [41,42], and the dehydrative KR, in which a chiral aminoalcohol in the

Molecules 2014, 19
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presence of a zinc complex dehydrates the chiral alcohol [46], the remaining examples described in
bibliography to date are enzymatic processes [37–40,43–45].
In the last decade, several organocatalysts for the enantioselective acylation of alcohols have been
developed as an alternative to enzymes [47]. In 1996, Vedejs and Chen described the first example of a
chiral DMAP derivative catalyst for the kinetic resolution of secondary aryl alcohols [48,49].
Independently, Fu and co-workers developed the synthesis of planar-chiral ferrocenyl DMAP
analogues, e.g., (−)-1, which catalyzed the kinetic resolution of secondary aryl [50,51], allylic [52] and
propargylic [53] alkyl alcohols with good selectivity factors. In addition, Fu and co-workers recently
reported the compatibility of (−)-1 with a ruthenium-based racemization catalyst representing the first
highly selective non-enzymatic dynamic kinetic resolution (DKR) of secondary alcohols [54,55].
The advantages of using the planar-chiral ferrocene DMAP derivative are that both (S)-(−)-1 and
(R)-(+)-1 enantiomers are commercially available providing an easy access to both enantiomers of the
substrates. Further, the kinetic resolution can be performed with low loading of the planar-chiral
DMAP catalyst (1–2 mol %), the catalyst can easily be recovered after the reaction by simple flash
chromatography [50,51], and it is possible to combine it with a racemization catalyst for an appealing
DKR [54,55]. We have focused our effort in expanding the substrate scope of the KR by (−)-1 to sec-aryl
alcohols that contains an additional heteroatom-containing functional group in the alkyl moiety [56,57]
(Scheme 3), which includes aromatic β-azido alcohols and β-hydroxy phosphonate alcohols, that are
important intermediates for the synthesis of bioactive molecules.
Scheme 3. Kinetic resolution of secondary aryl alcohol catalyzed by planar-chiral DMAP
derivative (−)-1.
Previous work
OH
OH
(−)-1 (2 mol %)
Ac2O
Ar
R
Ar
R
Me2N
t-amyl alcohol
N
Ph
0 °C
Fe
Ph
Ph
Work performed in our group
Ph
Ph
(−)-1
OH
OH
(−)-1 (1-2 mol %)
FG
FG
Ac2O
Ar
Ar
t-amyl alcohol
0 °C
-FG = -N3 with s up to 45
-FG = -P(O)(OR)2 with s up to 68
-FG = -COOR with s up to 107
This work
In this study, we wish to present the non-enzymatic kinetic resolution of a variety of β-hydroxy
esters with good to excellent selectivities, using the planar-chiral ferrocenyl DMAP catalyst (−)-1.
Furthermore, the utility of the present method could be demonstrated in the synthesis of the
(S)-3-hydroxy-N-methyl-3-phenylpropanamide, which is a key intermediate for highly selective
norepinephrine or serotonin reuptake inhibitor aryloxyphenylpropylamine derivatives, such as fluoxetine,
tomoxetine or nisoxetine, in their enantiomerically pure forms.

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2. Results and Discussion
2.1. Substrate Screening
In accordance with previous studies [51,56,57], the kinetic resolution of secondary alcohols
catalyzed by the planar-chiral DMAP catalyst (−)-1 proceeds in an efficient and selective way in
tert-amyl alcohol and in the presence of acetic anhydride (0.75 equiv.) as acylation agent. Employing
these conditions, the influence of the temperature and addition of triethylamine was investigated in the
kinetic resolution of rac-(2a), which was used as a model substrate in order to find the best conditions
for the selectivity of the reaction. Using the standard conditions, it was found that the selectivity factor
increases when the reaction was performed at lower temperature, but at the expense of the reaction rate
with a subsequent increase of the reaction times. Previously, the addition of triethylamine increased the
rate of the reaction [50–52]. Unfortunately, triethylamine catalyzed the unselective acetylation of the
more reactive β-hydroxy esters, resulting in a decrease of the selectivity. For this reason, the rest of the
kinetic resolution studies of the β-hydroxy esters were performed at a lower temperature (0 °C) and
without addition of base.
Next, we wanted to explore the influence of the bulkiness of the substituent in the β-position to the
hydroxyl group on the selectivity of the kinetic resolution. Kinetic resolutions were performed for the
substrates (2a–i) containing either ethyl or the bulkier tert-butyl carboxylate group using the standard
conditions. The selectivity factor was determined from the enantiomeric excess of the chiral alcohol
and the acetylated product after 3 h of reaction (Entries 1 to 9, Table 1).
Table 1. Selectivity for the kinetic resolution of β-hydroxy-β-aryl esters (rac-2) by (−)-1 a.
Ac2O
OH
OH
OAc
(−)-1 (2 mol %)
+
COOR
COOR
COOR
Ar
Ar
Ar
t-amyl alcohol
0 °C
rac-2a−i
(S)-2a−i
(R)-3a−i
Entry
R
Ar
Time/h eeROH (%) b eeROAc (%) b Conv. (%) c s c
1
2
3
4
5
6
7
8
9
Et
Et
Ph (2a)
3
3
3
3
3
3
3
3
3
32.4
84.2
39.8
28.8
88.4
39.4
83.4
75.0
40.4
95.4
92.8
94.6
95.2
93.6
96.0
95.2
95.2
96.6
25.4
44.6
29.6
23.2
48.6
29.1
46.7
44.1
29.5
58
71
53
54
89
72
107
92
86
4-NO2-Ph (2b)
4-MeO-Ph (2c)
Ph (2d)
Et
tert-Bu
tert-Bu
tert-Bu
4-NO2-Ph (2e)
4-MeO-Ph (2f)
tert-Bu 2-Naphthyl (2g)
tert-Bu
4-Cl-Ph (2h)
tert-Bu
2,6-Cl2-Ph (2i)
a: Reaction conditions: rac-(2) (0.15 mmol), Ac2O (0.75 equiv.), (−)-1 (0.003 mmol, 2 mol %) in 0.6 mL of
b
c
tert-amyl alcohol at 0 °C; : Determined by HPLC; : Selectivity and conversion calculated using the
following equations: s = ln[(1 − c)(1 − eeROH)]/ln[(1 − c)(1 + eeROH)] and c = eeROH/(eeROH + eeROAc).
In general, the substrates bearing the bulkier tert-butyl group show higher selectivity than the
substrates with the ethyl substituents. The largest difference is seen for the substrates containing the

Molecules 2014, 19
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electron donating methoxy group or an electron-withdrawing nitro group in the para position (Entries 1–6,
Table 1). The tendency that kinetic resolutions of substrates with more bulky alkyl substituents lead to
higher selectivity is in agreement with the results previously reported by Fu for secondary benzylic
alcohols with a bulky aliphatic substituent (the tert-butyl compared to the methyl substituent) [51] as
well as for secondary β-hydroxyl-β-aryl phosphonates [57].
We also wanted to explore the influence of electronic effects of the substitution on the aromatic
ring. The replacement of the phenyl group with an aryl containing an extended π-system led to a higher
selectivity (selectivity factor of 107) and a faster reaction rate compared to the parent compound (entry 4
vs. entry 7, Table 1). This is consistent with a suggested π–cation interaction between the cationic
acylated catalyst and the aromatic substituent, which has previously been suggested for other catalytic
systems [58–60]. In general, substrates with additional substituents gave a higher selectivity than the
parent compound. For example, the compound with an electron donating methoxy group in the para
position (2f) (entry 4 vs. entry 6, Table 1) and substrates with electron withdrawing groups in the
phenyl ring led to higher selectivity compared to the parent compound. The results follow the previous
trend [56,57] that electron-withdrawing substituents in the aromatic ring lead to a higher selectivity.
This suggests that the electronic properties affect the interactions between the aromatic ring of the
substrate and the acylated catalyst.
The kinetic resolutions were also performed with longer reaction times (24 h) in order to be able to
access the remaining alcohol in high enantiomeric excess (Table 2). We were able to isolate all the
alcohols 2a–f in high enantiomeric excess (95%–99% ee) and in good to moderate yield (23%–45%).
Table 2. Substrate screening for the kinetic resolution of β-hydroxy-β-aryl esters (rac-2)
by (−)-1 a.
Ac2O
OH
OH
OAc
(−)-1 (2 mol %)
+
COOR
COOR
COOR
Ar
Ar
Ar
t-amyl alcohol
0 °C
rac-2a−i
(S)-2a−i
(R)-3a−i
Entry
R
Ar
Conv. (%) c Yield (%) d eeROH (%) e
1
2
Et
Ph (2a)
57
79
55
56
66
55
54
65
63
41
23
32
39
33
41
45
34
31
99
99 f
99 f
95
Et
4-NO2-Ph (2b)
4-MeO-Ph (2c)
Ph (2d)
3
Et
4 b
5
tert-Bu
tert-Bu
tert-Bu
tert-Bu
tert-Bu
tert-Bu
4-NO2-Ph (2e)
4-MeO-Ph (2f)
2-Naphthyl (2g)
4-Cl-Ph (2h)
2,6-Cl2-Ph (2i)
99 f
99
6
7
98
8
9 b
99 f
99 f
a: Reaction conditions: rac-2 (0.25 mmol), Ac2O (0.75 equiv.), (−)-1 (0.005 mmol, 2 mol %) in 1 mL of
b
c
tert-amyl alcohol at 0 °C, 24 h unless otherwise specified; : 48 h; : Conversion calculated using the
d
e
following equation: c = eeROH/(eeROH + eeROAc); : Isolated yield base on rac-2; : Determined by HPLC;
f: A single peak was judged as 99% ee.

Molecules 2014, 19
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2.2. Assignment of the Absolute Configuration of 2e and 2i after KR
The absolute configuration of the optically pure β-hydroxy esters was assigned by comparing the
sign of the optical rotation with literature values. Ethyl (S)-3-(4-nitrophenyl)-3-hydroxypropanoate
(S)-2e and ethyl (S)-3-(2,6-dichlorophenyl)-3-hydroxypropanoate (S)-2i were the two substrates whose
specific rotations are not reported in the literature and had to be determined. In order to confirm the
absolute configuration of these two substrates after KR, the secondary alcohol was derivatized with a
chiral auxiliary of already known absolute configuration (Scheme 4).
Scheme 4. Synthesis of the Mosher’s esters using (R)-MTPA chloride as chiral derivatization agent.
Ph
Ph
MeO
MeO
CF3
CF3
OH
O
O
O
O
+
COOtBu
COOtBu
COOtBu
Ar
Ar
Ar
MeO CF3
(S)-2g-(R)-MTPA
(S)-2e,i-(R)-MTPA
(R)-2g-(R)-MTPA
(R)-2e,i-(R)-MTPA
rac-2g
rac-2e,2i
Cl
Ph
O
Ph
(R)-MTPA-Cl
MeO
CF3
DMAP, DCM
r.t., 1.5 h
OH
O
O
COOtBu
COOtBu
Ar
Ar
(S)-2g
(S)-2e,2i
(S)-2g-(R)-MTPA
(S)-2e,i-(R)-MTPA
Numerous chiral derivatizing reagents have been described and used to assign the absolute
configuration of chiral secondary alcohols [61]. The most common are the aryl-containing carboxylic
acids (R)-(+) and (S)-(−)-α-methoxy-α-trifluoromethylphenylacetic acid (MTPA, Mosher’s reagent;
(4) [62]. Chadha et al., reported the assignment of the absolute configuration of β-hydroxy esters using
a single enantiomer of Mosher’s acid chloride [63–65].
Firstly, the Mosher’s ester of the racemic mixture and the (S)-enantiomer of the substrate tert-butyl
1
3-hydroxy-3-(2-naphthyl)propanoate (2g) were prepared and used to validate the method. The H-NMR
spectrum of the mixture of diastereomers formed shows that the chemical shift difference between the
methoxy signals is significant enough to be used for the differentiation of the diastereomers
(Figure 1a), as reported by Padhi and Chadha [64]. This chemical shift difference in the diastereomer
originates from the fact that the methoxy group and the aromatic ring of the β-hydroxy ester are on the
same side of the MTPA plane (i.e., (S)-2g-(R)-MTPA) and that the signal for the methoxy group
protons is shielded due to the diamagnetic effect of the aromatic ring and appears at a lower chemical
shift (3.42 ppm) (see Figure 1). The signal from the methoxy protons of the other diastereomer (i.e.,
(R)-2g-(R)-MTPA) appears downfield (3.56 ppm) because they are less shielded. In the same manner,
the signals of the CF3 group allow the assignment by 19F-NMR and eliminate the possibility of
overlapping signals (Figure 1b). The signal at −71.68 ppm belongs to the diastereomer that has the CF3
group and the aromatic ring on the same side of the MTPA plane (i.e., (R)-2g-(R)-MTPA), whereas the
signal at −71.31 ppm belongs to the other diastereomer that has these two groups in opposite sides of
the plane (i.e., (S)-2g-(R)-MTPA) (see Figure 1).

Molecules 2014, 19
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1
Figure 1. (a) H-NMR of the methoxy region of (R)-MTPA esters of rac-2g (above) and
(R)-MTPA ester of (S)-2g (below); (b) 19F-NMR of (R)-MTPA esters of rac-2g (above)
and (R)-MTPA ester of (S)-2g (below).
Therefore, the analysis of the 1H and 19F-NMR spectrum of the known enantiomer of (S)-2g allows
us to conclude that obtained enantiomer has (S)-configuration which is in agreement with the
previously reported sign of the optical rotation. The same method was used to determine the absolute
configuration of the enantiomerically pure unknown enantiomers of 2e and 2i obtained after kinetic
resolution. The 1H-NMR analysis of the Mosher’s esters (Figures 2a and 3b) shows that the signals of
the methoxy protons are shielded (3.43 and 3.49 ppm for the Moshers esters of enantiopure 2e and 2i
respectively). This supports the fact that the formed diastereomers have the methoxy group and the
aromatic ring in the same side of the MTPA plane, i.e., the β-hydroxy esters have (S)-configuration.
The same conclusion can be drawn from the 19F-NMR spectrum. The fluorine signal obtained
belongs to the (S)-2e-(R)-MTPA (−71.29 ppm, Figure 2b) and (S)-2i-(R)-MTPA (−71.49 ppm, Figure 2b)
because it appears in the deshielded region and this it indicates that the CF3 group and the aromatic
ring are not in the same side of the plane as previously observed.
1
The H-NMR and 19F-NMR analyses confirm that the absolute configuration of ethyl (S)-3-(4-
nitrophenyl)-3-hydroxypropanoate (S)-2e and ethyl (S)-3-(2,6-dichlorophenyl)-3-hydroxypropanoate
(S)-2i is S.

Molecules 2014, 19
14280
1
Figure 2. (a) H-NMR of the methoxy region of (R)-MTPA esters of rac-2e (above) and
(R)-MTPA ester of (S)-2e (below); (b) 19F-NMR of (R)-MTPA esters of rac-2e (above)
and (R)-MTPA ester of (S)-2e (below).
1
Figure 3. (a) H-NMR of the methoxy region of (R)-MTPA esters of rac-2i (above) and
(R)-MTPA ester of (S)-2i (below); (b) 19F-NMR of (R)-MTPA esters of rac-2i (above) and
(R)-MTPA ester of (S)-2i (below).
2.3. Synthesis of (S)-3-Hydroxy-N-methyl-3-phenylpropanamide
In order to demonstrate the synthetic applicability of the present method, the synthesis of the
enantiomerically pure intermediate (S)-3-hydroxy-N-methyl-3-phenylpropanamide was carried out
(Scheme 5). First, the kinetic resolution of ethyl 3-hydroxy-3-phenylpropanoate, rac-2a (547.6 mg,

Molecules 2014, 19
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2.8 mmol) was performed, recovering 62% of the (S)-enantiomer (32% yield, 99% ee). The subsequent
treatment of the β-hydroxy esters with aqueous methylamine gave access to the β-hydroxy amide (S)-4
in 85% yield and with retention of the configuration (99% ee). The β-hydroxyamide (S)-4 can then be
reduced by lithium aluminium hydride in THF to the corresponding amine, followed by an aromatic
nucleophilic substitution by 4-chlorobenzotrifluoride using sodium hydride in DMF, in order to yield
(S)-fluoxetine [8–12].
Scheme 5. Synthesis of (S)-3-hydroxy-N-methyl-3-phenylpropanamide.
OH
O
OH
O
OH O
(i)
(ii)
Ph
OEt
Ph
OEt
Ph
NHMe
rac-2a
(S)-2a
(S)-4
R
Ref. 8-12
O
Ph
NHMe
R= 4-CF3 (S)-fluoxetine
R= 2-Me (S)-tomoxetine
R= 2-OMe (S)-nisoxetine
Reagents and conditions: (i) rac-(2a) (2.8 mmol), Ac2O (0.75 equiv.), (−)-1 (0.005 mmol, 2 mol %)
in 1 mL of tert-amyl alcohol at 0 °C, 24 h. (ii) MeNH2 (40% aq), r.t, 3 h.
3. Experimental Section
3.1. General Information
Commercially available reagents were purchased from Sigma-Aldrich Co. and used without further
purification. Thin layer chromatography (TLC) was performed on ALUGRAM® SIL G/UV254 plates
(0.2 mm), using UV-light (254 nm) for visualization. Flash column chromatography was performed
1
using Merck silica gel (0.04–0.06 mm). H and 13C{1H} NMR spectra were recorded on a Varian
Mercury 300 MHz, Varian Unity 400 MHz or Varian Unity 500 MHz spectrometer. The chemical shift
values (δ) are given in parts per million (ppm) and are referred to the residual peak of the deuterated
solvent used (CDCl3). Chemical shifts and literature NMR shifts were used as references in
identification and characterization of the optically pure synthesized compounds. Characterization data
1
for these compounds are as follows (copies of the HPLC chromatograms, H- and 13C{1H}-NMR
spectra are included in the Supplementary data). IR spectra were recorded on a PerkinElmer Spectrum
One (ATR Technique). High-resolution mass spectra were recorded by Aleh Yahorau, Department of
Pharmaceutical Biosciences, Uppsala University, Sweden.
3.2. Preparation of the Racemic Substrates
3.2.1. General Procedure
The racemic substrates 2a–c and 4a–f were prepared following the procedure described by Xu and
Yuan [43]. The racemic acetates 3a–c and 5a–f were prepared, as a references for the measurement of
the HPLC retention times, by routine acetylation of the corresponding alcohols in dichloromethane at

Molecules 2014, 19
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r.t. in the presence of catalytic amounts of DMAP and triethylamine. Chemical shifts and literature
NMR shifts were used as references in identification and characterization of the synthesized
compounds [43,66–71]. For the new substrates (4b and 4f) the IR and HRMS data are included in the
characterization data.
3.2.2. Characterization Data
Ethyl 3-hydroxy-3-phenylpropanoate (2a) [43]
1H-NMR (CDCl3) δ 7.28–7.17 (m, 5H, Ar-H), 5.04 (dd, J = 7.8, 4.2 Hz, 1H, CH), 4.10 (m, J = 6.9 Hz, 2H,
13
CH2), 3.22 (bs, 1H, OH), 2.64-2.50 (m, 2H, CH2), and 1.17 (t, J = 6.9 Hz, 3H, CH3). C{1H}-NMR
(CDCl3) δ 172.6, 142.8, 128.8 (2C), 128.0, 125.9 (2C), 70.6, 61.1, 43.6 and 14.4.
Ethyl 3-hydroxy-3-(4-nitrophenyl)propionate (2b) [43]
1H-NMR (CDCl3) δ 7.87 (d, 2H, Ar-H), 7.46 (d, 2H, Ar-H), 5.25 (dd, J = 7.8, 4.2 Hz, 1H, CH), 4.29–4.11
(m, 2H, CH2), 3.62 (bs, 1H, OH), 2.71 (q, J = 6.9 Hz, 2H, CH2) and 1.24 (t, J = 6.9 Hz, 3H, CH3).
13C{1H}-NMR (CDCl3) δ 172.0, 149.9, 147.4, 126.2 (2C), 123.9 (2C), 69.2, 61.3, 43.1 and 14.1.
Ethyl 3-hydroxy-3-(4-metoxyphenyl)propionate (2c) [66]
1H-NMR (CDCl3) δ. 7.29 (d, 2H, J = 7.5 Hz, Ar-H), 6.86 (d, 2H, J = 7.5 Hz, Ar-H), 5.08 (dd, J = 8.8,
4.0 Hz, 1H, CH), 4.19–4.09 (m, 2H, CH2), 3.80 (s, 3H, OCH3), 2.76–2.69 (m, 2H, CH2) and 1.27 (t,
J = 6.9 Hz, 3H, CH3). 13C{1H}-NMR (CDCl3) δ 172.3, 159.1, 134.8, 126.9 (2C), 113.8 (2C), 69.9, 60.7,
55.2, 43.3 and 14.1.
t-Butyl 3-hydroxy-3-phenylpropionate (2d) [67]

Molecules 2014, 19
14283
1H-NMR (CDCl3) δ 7.39–7.22 (m, 5H, Ar–H), 5.07 (dd, 1H, J = 7.8, 4.2 Hz, CH), 3.42 (bs, 1H, OH),
2.67 (dd, 1H, J = 16.0, 4.8 Hz, CH2), 2.61 (dd, 1H, J = 16.0, 4.8 Hz, CH2) and 1.43 (s, 9H, 3 CH3).
13C{1H}-NMR (CDCl3) δ 171.9, 142.6, 128.4 (2C), 127.6, 125.7 (2C), 81.5, 70.4, 44.3 and 28.0.
t-Butyl 3-hydroxy-3-(4-nitrophenyl)propionate (2e) [68]
1H-NMR (CDCl3) δ 8.20 (d, 2H, J = 8.1 Hz, Ar-H), 7.55 (d, 2H, J = 8.1 Hz, Ar-H), 5.18 (dd, J = 8.3,
13
4.1 Hz, 1H, CH), 2.73–2.57 (m, 2H, CH2) and 1.49 (s, 9H, 3 CH3). C{1H}-NMR (CDCl3) δ 171.3,
150.0, 147.3, 126.5 (2C), 123.6 (2C), 82.1, 69.4, 43.8 and 28.0. IR (neat): v(cm−1) 3438, 2941, 2977,
+
2903, 1700, 1510, 1343, 1148, 843. HRMS (ESI, m/z) Calcd for C13H18NO5 [M+H+]: 268.1185,
found: 268.1189.
t-Butyl 3-hydroxy-3-(4-methoxyphenyl)propionate (2f) [69]
1H-NMR (CDCl3) δ 7.29 (d, 2H, J = 7.5 Hz, Ar-H), 6.86 (d, 2H, J = 7.5 Hz, Ar-H), 5.01 (dd, J = 8.8,
4.0 Hz, 1H, CH), 3.78 (s, 3H, OCH3), 3.15 (bs, 1H, OH), 2.71–2.54 (m, 2H, CH2) and 1.44 (s, 9H, 3
13
CH3). C{1H}-NMR (CDCl3) δ 171.9, 159.1, 134.9, 127.0 (2C), 113.8 (2C), 81.4, 70.0, 55.2, 44.3,
and 28.0.
t-Butyl 3-hydroxy-3-(2-naphthyl)propionate (2g) [70]
1H-NMR (CDCl3) δ 7.85–7.81 (m, 4H, Ar-H), 7.50–7.26 (m, 3H, Ar-H), 5.26 (dd, J = 7.3, 5.5 Hz, 1H,
CH), 2.76–2.74 (m, 2H, CH2) and 1.46 (s, 9H, 3 CH3). 13C{1H}-NMR (CDCl3) δ 171.9, 140.1, 133.3,
133.0, 128.3, 128.0, 127.7, 126.1, 125.9, 124.5, 123.9, 81.6, 70.5, 44.3 and 28.1.
t-Butyl 3-hydroxy-3-(4-chloro)propionate (2h) [69]

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1H-NMR (CDCl3) δ 7.34–7.31 (m, 4H, Ar-H), 5.09–5.05 (m, 1H, CH), 2.63–2.60 (m, 2H, CH2) and
1.45 (s, 9H, 3 CH3). 13C{1H}-NMR (CDCl3) δ 171.7, 141.1, 133.3, 128.6 (2C), 127.1 (2C), 81.7, 69.7,
44.1 and 28.0.
t-Butyl 3-hydroxy-3-(2',6'-dichlorophenyl) propionate (2i)
1H-NMR (CDCl3) δ 7.32–7.12 (m, 3H, Ar-H), 5.90 (dd, 1H, J = 10.5, J = 4.2 Hz, 1H, CH), 3.23–2.62
(m, 2H, CH2) and 1.46 (s, 9H, 3 CH3). 13C{1H}-NMR (CDCl3) δ 170.5, 136.2, 134.6, 129.4 (2C),
129.2 (2C), 81.3, 68.2, 40.7 and 28.0. IR (neat): v(cm−1) 3514, 2987, 2938, 1700, 1561, 1144, 766.
+
HRMS (ESI, m/z) Calcd for C13H17Cl2O3 [M+H+]: 291.0555, found: 291.0551.
3.3. General Procedure for the Kinetic Resolution
3.3.1. Selectivity Factor for the KR of 2a–i after 3 h
Catalyst (−)-1 (2.0 mg, 0.003 mmol), β-hydroxy ester 2a–i (0.15 mmol) and t-amyl alcohol
(0.6 mL) were sequentially added to a vial. The vial was capped and stirred at room temperature to
help dissolve the catalyst. The reaction mixture was cooled to 0 °C in an ice-water bath and stirred for
15 min. Then, acetic anhydride (11 μL, 0.11 mmol) was added. After 3 h, a sample (0.2–0.3 mL) was
quenched by the addition of methanol. The resulting solution was filtered through a short plug of silica
using ether as eluent and then it was concentrated. The enantiomeric excess of the unreactive alcohol
and the acetate were determined by HPLC (Table 1) using the appropriate chiral column and
conditions. The chromatograms are attached in Supplementary section 1.
The selectivity s was calculated using the Equation (1), where C is the conversion (calculated using
the Equation (2), eeROH and eeROAc are the enantiomeric excess for the unreactive alcohol and the
resulting acetate respectively determined by HPLC [47]:
ln[(1 − C)(1 − ee )] ln[1 − C(1 + ee )]
ROH
ROAc
S =
=
(1)
(2)
ln[(1 − C)(1 + ee )] ln[1 − C(1 − ee )]
ROH
ROAc
ee
ROH
C =
ee + ee
ROH
ROAc
3.3.2. Synthesis of Optically Pure Alcohols
Catalyst (−)-1 (3.3 mg, 0.005 mmol), β-hydroxy ester 2a–i (0.25 mmol) and t-amyl alcohol (1.0 mL)
were sequentially added to a vial. The vial was capped and stirred at room temperature to help dissolve
the catalyst. The reaction mixture was cooled to 0 °C, and then acetic anhydride (18 μL, 0.19 mmol)
was added. After the appropriate amount of time, the reaction mixture was quenched by the addition of
a large excess of methanol. The resulting solution was concentrated, and the unreactive alcohol, the
acetate and the catalyst were separated by flash chromatography using increasing polarity mixtures of

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pentane/ethyl acetate as eluent. The enantiomeric excess of the unreactive alcohol and the acetate were
determined by HPLC (Table 2). The chromatograms are attached in Supplementary section 2.
Chemical shifts and literature NMR shifts were used as references in identification and
characterization of the optically pure synthesized compounds 2a–i. The 1H and 13C{1H}-NMR spectra
are attached in Supplementary section 3.
Ethyl (S)-3-hydroxy-3-phenylpropanoate ((S)-2a) [43]. Colorless oil (21.8 mg, 41% yield); ee 95%,
Kromasil 5-CellCoat, n-hexane/i-PrOH = 95:05, 0.5 mL/min, 220 nm, tR[(S)/(R)] = 20.5/28.5 min;
[α]2D5 : −45.3 (c 3.7, CDCl3) (Lit. [71] [[α]D25 : = −46.5 (c 1.04, CHCl3)). H-NMR (CDCl3) δ 7.28–7.17
1
(m, 5H, ArH), 5.04 (dd, J = 7.8, 4.2 Hz, 1H, CH), 4.10 (m, J = 6.9 Hz, 2H, CH2), 3.22 (bs, 1H, OH),
13
2.64–2.50 (m, 2H, CH2), and 1.17 (t, J = 6.9 Hz, 3H, CH3). C{1H}-NMR (CDCl3) δ 172.6, 142.8,
128.8 (2C), 128.0, 125.9 (2C), 70.6, 61.1, 43.6 and 14.4.
Ethyl (S)-3-hydroxy-3-(4-nitrophenyl)propanoate ((S)-2b) [43]. Colorless oil (13.8 mg, 23% yield);
ee 99%, Chiralpack AD, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 220 nm, tR[(S)/(R)] = 26.6/28.4 min.
[α]2D0 : −58.0 (c 0.23, CHCl3) (Lit. [64] [α]D25 : −59.5 (c 1.5, CHCl3)). H-NMR (CDCl3) δ 7.87 (d, 2H,
1
ArH), 7.46 (d, 2H, ArH), 5.25 (dd, J = 7.8, 4.2 Hz, 1H, CH), 4.29–4.11 (m, 2H, CH2), 3.62 (bs, 1H,
OH), 2.71 (q, J = 6.9 Hz, 2H, CH2) and 1.24 (t, J = 6.9 Hz, 3H, CH3). 13C{1H}-NMR (CDCl3)
δ 172.0, 149.9, 147.4, 126.2 (2C), 123.9 (2C), 69.2, 61.3, 43.1 and 14.1.
Ethyl (S)-3-hydroxy-3-(4-methoxyphenyl)propanoate ((S)-2c) [66]. Yellow oil (18.0 mg, 32% yield);
ee 99%, Reprosil chiral NR, n-hexane/i-PrOH = 80:20, 0.5 mL/min, 220 nm, tR[(S)/(R)] = 15.9/18.7 min.
[α]2D0 : −45.9 (c 0.75, CHCl3) (Lit. [71] [α]D26 : −28.6 (c 1, CHCl3)). H-NMR (CDCl3) δ 7.29 (d, 2H,
1
J = 7.5 Hz, ArH), 6.86 (d, 2H, J = 7.5 Hz, ArH), 5.08 (dd, J = 8.8, 4.0 Hz, 1H, CH), 4.19–4.09 (m, 2H,
13
CH2), 3.80 (s, 3H, OCH3), 2.76–2.69 (m, 2H, CH2) and 1.27 (t, J = 6.9 Hz, 3H, CH3). C{1H}-NMR
(CDCl3) δ 172.3, 159.1, 134.8, 126.9 (2C), 113.8 (2C), 69.9, 60.7, 55.2, 43.3 and 14.1.
tert-Butyl (S)-3-hydroxy-3-phenylpropanoate ((S)-2d) [67]. Pale yellow oil (21.6 mg, 39% yield); ee
95%, Reprosil Chiral NR, n-hexane/i-PrOH = 99:01, 1.0 mL/min, 220 nm, tR[(S)/(R)] = 11.4/15.6 min.
[α]2D0 : −85.0 (c 0.1, CHCl3) (Lit. [71] [α]2D5 : −37.7 (c 1.2, CHCl3)). H-NMR (CDCl3) δ 7.39–7.22 (m,
1
5H, ArH), 5.07 (dd, 1H, J = 7.8, 4.2 Hz, CH), 3.42 (bs, 1H, OH), 2.67 (dd, 1H, J = 16.0, 4.8 Hz, CH2),
2.61 (dd, 1H, J = 16.0, 4.8 Hz, CH2) and 1.43 (s, 9H, 3 CH3). 13C{1H}-NMR (CDCl3) δ 171.9, 142.6,
128.4 (2C), 127.6, 125.7 (2C), 81.5, 70.4, 44.3 and 28.0.
tert-Butyl (S)-3-hydroxy-3-(4-nitrophenyl)propanoate ((S)-2e) [68]. Yellow oil (18.0 mg, 32% yield);
ee 99%, Reprosil Chiral NR, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 220 nm, tR[(S)/(R)] = 14.5/15.5 min.
[α]2D0 : −31.4 (c 0.19, CHCl3). H-NMR (CDCl3) δ 8.20 (d, 2H, J = 8.1 Hz, ArH), 7.55 (d, 2H,
1
J = 8.1 Hz, ArH), 5.18 (dd, J = 8.3, 4.1 Hz, 1H, CH), 2.73–2.57 (m, 2H, CH2) and 1.49 (s, 9H, 3 CH3).
13C{1H}-NMR (CDCl3) δ 171.3, 150.0, 147.3, 126.5 (2C), 123.6 (2C), 82.1, 69.4, 43.8 and 28.0. IR
(neat): v(cm−1) 3438, 2941, 2977, 2903, 1700, 1510, 1343, 1148, 843. HRMS (ESI, m/z) Calcd for
+
C13H18NO5 [M+H+]: 268.1185, found: 268.1189.

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tert-Butyl (S)-3-hydroxy-3-(4-methoxyphenyl)propanoate ((S)-2f) [69]. Yellow oil (26.0 mg, 41%
yield); ee 99% after acetylation with DMAP, Chiralpak AD, n-hexane/i-PrOH = 90:10, 0.5 mL/min,
220 nm, tR[(S)/(R)] = 24.8/11.9 min. [α]2D0 : −34.5 (c 1.6, CHCl3) (Lit. value for the (R)-enantiomer [46]
[α]2D0 : +28.0 (c 0.15, CHCl3)). 1H-NMR (CDCl3) δ 7.29 (d, 2H, J = 7.5 Hz, ArH), 6.86 (d, 2H, J = 7.5 Hz,
ArH), 5.01 (dd, J = 8.8, 4.0 Hz, 1H, CH), 3.78 (s, 3H, OCH3), 3.15 (bs, 1H, OH), 2.71–2.54 (m, 2H,
13
CH2) and 1.44 (s, 9H, 3 CH3). C{1H}-NMR (CDCl3) δ 171.9, 159.1, 134.9, 127.0 (2C), 113.8 (2C),
81.4, 70.0, 55.2, 44.3, and 28.0.
tert-Butyl (S)-3-hydroxy-3-(2-naphthyl)propanoate ((S)-2g) [70]. Yellow oil (30.3 mg, 45% yield); ee
96%, Kromasil 5-CellCoat, n-hexane/i-PrOH = 99:01, 1.0 mL/min, 220 nm, tR[(S)/(R)] = 26.4/29.6 min.
[α]2D0 : −36.9 (c 0.42, CHCl3) (Lit. [21] [α]D20 : −24.8 (c 1.1, CHCl3)). 1H-NMR (CDCl3) δ 7.85–7.81 (m,
4H, ArH), 7.50–7.26 (m, 3H, ArH), 5.26 (dd, J = 7.3, 5.5 Hz, 1H, CH), 2.76–2.74 (m, 2H, CH2) and
13
1.46 (s, 9H, 3 CH3). C{1H}-NMR (CDCl3) δ 171.9, 140.1, 133.3, 133.0, 128.3, 128.0, 127.7, 126.1,
125.9, 124.5, 123.9, 81.6, 70.5, 44.3 and 28.1.
tert-Butyl (S)-3-(4-chlorophenyl) 3-hydroxypropanoate ((S)-2h) [69]. Colorless oil (22.0 mg,
33% yield); ee 99%, Reprosil Chiral NR, n-hexane/i-PrOH = 90:10, 0.5 mL/min, 220 nm, tR[(S)/(R)] =
10.7/12.2 min. [α]2D0 : −34.1 (c 1.9, CHCl3) (Lit. [21] [α]2D3 : −25.4 (c 2.0, CHCl3)). H-NMR (CDCl3)
1
δ 7.34–7.31 (m, 4H, ArH), 5.09–5.05 (m, 1H, CH), 2.63–2.60 (m, 2H, CH2) and 1.45 (s, 9H, 3 CH3).
13C{1H}-NMR (CDCl3) δ 171.7, 141.1, 133.3, 128.6 (2C), 127.1 (2C), 81.7, 69.7, 44.1 and 28.0.
tert-Butyl (S)-3-(2,6-dichlorophenyl) 3-hydroxypropanoate ((S)-2i). Colorless oil (23.0 mg, 31% yield); ee
99%, Kromasil 5-CellCoat, n-hexane/i-PrOH = 99.5:0.5, 1.0 mL/min, 220 nm, tR[(S)/(R)] = 10.7/16.1 min.
[α]2D0 : +21.8 (c 2.0, CHCl3). H-NMR (CDCl3) δ 7.32–7.12 (m, 3H, ArH), 5.90 (dd, 1H, J = 10.5,
1
J = 4.2 Hz, 1H, CH), 3.23–2.62 (m, 2H, CH2) and 1.46 (s, 9H, 3 CH3). 13C{1H}-NMR (CDCl3) δ 170.5,
136.2, 134.6, 129.4 (2C), 129.2 (2C), 81.3, 68.2, 40.7 and 28.0. IR (neat): v(cm−1) 3514, 2987, 2938,
+
1700, 1561, 1144, 766. HRMS (ESI, m/z) Calcd for C13H17Cl2O3 [M+H+]: 291.0555, found: 291.0551.
3.3.3. Methods Used to Determine Enantiomeric Excess
The enantiomeric separations of β-hydroxy esters 2a–i were performed by high performance liquid
chromatography (HPLC) with a Young Lin 9100 instrument using the appropriate chiral column at 25 °C
with n-hexane and isopropanol as eluents. The enantiomeric separation of 2f was achieved converting
the alcohol to the corresponding acetate using DMAP and triethylamine in DCM. The selectivity
(S)-factors were calculated with the equation: S = ln[(1 − c)(1 − eeROH)]/ln[(1 − c)(1 + eeROH)].
3.4. Synthesis of (S)-3-Hydroxy-N-methyl-3-phenylpropanamide ((S)-4)
Catalyst (−)-1 (37 mg, 0.0056 mmol), racemic substrate 2a (2.8 mmol) and tert-amyl alcohol (11 mL)
were sequentially added to a vial. The vial was capped and stirred at room temperature to help dissolve
the catalyst. The reaction mixture was cooled to 0 °C, and then acetic anhydride (200 μL, 2.1 mmol)
was added. After 24 h, the reaction mixture was quenched by the addition of a large excess of
methanol. The resulting solution was concentrated, and the unreactive alcohol was separated from the
acetate and the catalyst by flash chromatography using increasing polarity mixtures of pentane/ethyl

Molecules 2014, 19
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acetate as eluent (175 mg, 32% yield, 99% ee). The β-hydroxy ester (S)-2a was treated with a 40%
aqueous solution of methylamine (1.56 mL, 18 mmol) at r.t. during 3 h. Beige solid was obtained
(137.8 mg, 85.3% yield, 99% ee). Chemical shifts and literature NMR shifts were used as references in
identification and characterization of the optically pure synthesized compound (S)-4 [36]. Beige solid
(138 mg, 85% yield); ee 99%, Chiralpak AD, n-hexane/i-PrOH = 98:02, 1.0 mL/min, 220 nm,
tR[(R)/(S)] = 41/51 min. [α]2D0 : −26.7 (c 1.0, CH3OH) (Lit. [36] [α]D23 : −26.2 (c 1.25, CH3OH)).
1H-NMR (CDCl3) δ 7.49–7.14 (m, 5H, ArH), 5.82 (br s, 1H, NH), 5.16-5.05 (m, 1H, CHOH), 2.82 (d,
J = 4.5 Hz, 3H, NHCH3), 2.59–2.52 (m, 2H, CH2). 13C{1H}-NMR (CDCl3) δ 172.56, 143.16, 128.67,
127.84, 125.71, 71.07, 44.72, 26.37.
4. Conclusions
In summary, we have demonstrated that the planar-chiral DMAP derivative catalyst (−)-1 catalyzes
the kinetic resolution for a range of aromatic β-hydroxy esters with excellent selectivities (selectivity
factor up to 107) and high enantiomeric excess (up to 99% ee) of the remaining alcohol. To the best of
our knowledge, these results represent the first example of the kinetic resolution of this family of
substrates employing a chiral DMAP derivative as catalyst.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/9/14273/s1.
Acknowledgments
This work was supported by Vetenskapsrådet and The Carl Trygger Foundation.
Author Contributions
P.D. conceived the project. A.E.D.A. and L.M.S. designed the experiments and executed the chemical
synthesis. All authors wrote the paper, discussed the results and commented on the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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