Highly enantioselective CALB-catalyzed kinetic resolution of building blocks for β-blocker atenolol

Article abstract of DOI:10.1016/j.tet.2016.02.018

Both enantiomers of 4-(3-chloro-2-hydroxypropoxy)phenyl)acetamide has been synthesized in 98.5–99% enantiomeric excess by use of lipase B from Candida antarctica as catalyst. The R-alcohol is a building block for the cardioselective β-blocker (S)-atenolol ((S)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide. Performing kinetic resolutions of 3-chloro-1-phenoxy-2-propanol and 3-bromo-1-phenoxy-2-propanol with vinyl butanoate as acyl donor and the same CALB enzyme, but a different preparation, showed higher E-values than previously reported.

Full text of DOI:10.1016/j.tet.2016.02.018

Tetrahedron xxx (2016) 1e5
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly enantioselective CALB-catalyzed kinetic resolution of
building blocks for b-blocker atenolol
Ingvild T. Lund, P ꢀa l L. Bøckmann, Elisabeth E. Jacobsen *
Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, N-7491 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Both enantiomers of 4-(3-chloro-2-hydroxypropoxy)phenyl)acetamide has been synthesized in 98.5e99%
enantiomeric excess by use of lipase B from Candida antarctica as catalyst. The R-alcohol is a building
Received 15 October 2015
Received in revised form 18 January 2016
Accepted 4 February 2016
Available online xxx
block for the cardioselective
b-blocker (S)-atenolol ((S)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)
phenyl)acetamide. Performing kinetic resolutions of 3-chloro-1-phenoxy-2-propanol and 3-bromo-1-
phenoxy-2-propanol with vinyl butanoate as acyl donor and the same CALB enzyme, but a different
preparation, showed higher E-values than previously reported.
Keywords:
Ó 2016 Elsevier Ltd. All rights reserved.
Chiral building blocks
Kinetic resolution
Atenolol
Chiral chromatography
E-value
5
1
. Introduction
become more controversial in recent years. Atenolol is also used
6
in the treatment of angina and myocardial infarction. Atenolol is
sold both enantiomerically pure as the S-enantiomer as Atpure
and racemic as Mylan , but it has been found that only the S-en-
antiomer has the desired effect. The S-enantiomer has been found
to lack the reported side effect of a lowered heart rate sometimes
encountered with the racemate.
Several researchers have used biocatalysis in order to obtain
enantiopure atenolol, however ee’s of the building blocks have not
reached 99%. A recent paper reports kinetic resolution of 4-(3-
chloro-2-hydroxypropoxy)phenyl)acetamide with lipase from
Candida antarctica in toluene with an E-value of 142 producing
Ò
The amount of approved new racemic drugs, so-called New
Molecular Entities (NME’s), has decreased in the past 20 years.
This can be explained by increased knowledge of the difference in
the biological effects of the two enantiomers, in addition to im-
proved asymmetric synthesis. In the years between 1992 and 2011
the amount of racemic NME’s approved by The US Food and Drug
Administration (FDA) decreased from 21% to 5%. Globally no ra-
cemic NME’s were approved in 2011, and almost 70% of the ap-
proved drugs were enantiomerically pure. The rest were achiral
compounds. In the US the number of enantiopure NME’s were
lower, and a few racemates were also approved by FDA for the
American market.1 Although there is an increasing demand for
enantiopure drugs, still several drugs are being sold as the race-
Ò
7
8
,9
A
10
enantiomers of the compound. However, optical rotations of
these enantiomer products have not been reported previously. (S)-
Atenolol has also been made from (R)-epichlorohydrin.
,2
11
mate. In 2010 there were still more
b
-blockers sold as the race-
Previously, we have achieved 99% ee of product enantiomers of
mate, however, mostly the S-enantiomers are the active
secondary phenoxy alcohols with a halogen as a leaving group in 3-
3
enantiomer (eutomer). Some of the R-enantiomers can even have
position in the side chain in kinetic resolutions using lipase B from
4
12,13
adverse effects, rather than any effect at all. Atenolol is a car-
C. antarctica (CALB),
and it was desirable to prepare enantio-
dioselective
b
-blocker, which means that it is selective towards
b
1
merically pure building blocks for atenolol using the same enzyme.
We have used the computer program E&K Calculator 2.1b0 PCC
for calculations of the E-value based on 5e7 ee-values for a kinetic
receptors found in the heart. For a long time atenolol has been
a popular choice for treatment of high blood pressure, but has
14
resolution. Resolutions of racemic compounds catalyzed by li-
pases react by a ping-pong bi-bi mechanism and in this program
calculations of E and Keq based on both the ping-pong bi-bi and uni-
*
Corresponding author. Tel.: þ47 73 59 62 56 (office), þ47 98 84 35 59 (mobile);
15e20
e-mail address: elisabeth.e.jacobsen@ntnu.no (E.E. Jacobsen).
uni kinetic models can be performed.
http://dx.doi.org/10.1016/j.tet.2016.02.018
0
040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
I.T. Lund et al. / Tetrahedron xxx (2016) 1e5
2
. Results and discussion
enantiomers of 1b (or the acetate enantiomers of 1) on the OD-H
column (one column from 2004 and one from 2014) or other
Chiralcel columns.
2
.1. Synthesis of racemic compounds
It was obvious from the chromatograms of resolutions of 1 that
only one alcohol peak was decreasing. The formed butanoate 1b
was hydrolyzed in phosphate buffer by CALB in order to obtain
correct ee-values for calculation of the E-value. Scheme 4. The S-
alcohol (S)-1 was produced in 98.5% ee, thus we present 1b as (S)-
1b in Scheme 4. Optical rotation (o.r.) values of (R)-1 (99.0% ee)
Racemic 4-(3-chloro-2-hydroxypropoxy)phenyl)acetamide (1)
was synthesized from epichlorohydrin and 2-(4-hydroxyphenyl)
acetamide in 2.5 M NaOH. A mixture of 1 (70%) and the epoxide 2
2 4
30%) was obtained. In order to open the epoxide 2 Li CuCl in
(
tetrahydrofuran was applied as a complexing agent. Scheme 1. NMR
spectra were in accordance with previously reported data.1 Prob-
lems with the extraction resulted in lower total yield than pre-
0
23
D
23
D
is½
a
ꢂ
¼ꢁ3.0 (c 1.0, MeOH). O. r. for (S)-1 (98.5% ee) is ½
a
ꢂ
¼þ3.0 (c
1.0, MeOH). Optical rotation values for these compounds have not
been reported previously.
12
viously reported by us in similar reactions.
Scheme 1. Synthesis of 4-(3-chloro-2-hydroxypropoxy)phenyl)acetamide, 1.
3
-Chloro-1-phenoxy-2-propanol (3) was synthesized in high
2.3. Improvement of enantiomeric ratio (E) with new CALB
preparation
yield and purity by opening benzyl glycidyl ether with conc.
21
hydrochloric acid in dichloromethane according to Chini et al. 3-
Bromo-1-phenoxy-2-propanol (4) was synthesized in high yield
and purity by opening benzyl glycidyl ether by addition of LiBr in
acetic acid according to Bajwa et al. Scheme 2. NMR spectra for
both compounds were in accordance with previously reported
As model substrates for comparison of E-values in CALB reso-
lutions of the series of secondary halogenated aryl alcohols 3-
chloro-1-phenoxy-2-propanol (3) and 3-bromo-1-phenoxy-2-
propanol (4) (Scheme 5), have been synthesized and resolved by
another batch of CALB (with vinyl butanoate as acyl donor in dry
hexane) than previously reported by us.
2
2
13,21e23
data.
Scheme 2. Synthesis of 3-chloro-1-phenoxy-2-propanol, 3, and 3-bromo-1-phenoxy-2-propanol, 4.
2
.2. Kinetic resolution of 4-(3-chloro-2-hydroxypropoxy)
The E-value in resolution of 3 increased from E¼11 with the
1 23
ꢁ
phenyl)acetamide (1) by CALB
previous CALB preparation (PLU 7000 g , no lot information) to
E¼220 with the new enzyme preparation (Novozym 435, PLU
ꢁ
1
Resolution of 1 with CALB (Novozym 435) was performed in dry
10000 g , batch no LC200204). The E-value in the resolution of 4
acetonitrile with vinyl butanoate as acyl donor. The reaction was
incubated at 30 C and stirred at 200 rpm for 27 h. (R)-1 was pro-
duced in 99% ee in 16% yield, and the butanoate (S)-1b was obtained
in 18% yield. the E-value was 238. Scheme 3 and Fig. 1.
increased from E¼58 with the previous CALB preparation (PLU
ꢀ
ꢁ1 23
7000 g
)
to E¼278 with the new enzyme preparation. Chro-
matographic analyses (GLC) of 3 and 4 have been performed on
similar Chirasil DEX columns with the same conditions as pre-
viously reported. Different water content in the reaction medium
The alcohol enantiomers from the transesterification of 1 was
analyzed on Daicel Chiralcel OD-H HPLC columns with baseline
2
4,25
may affect the E-value.
The water content of the old enzyme
ꢁ
1
separation (hexane:2-propanol, 83:17, 1.00 mL min
,
UV
preparation was 2.16%, the water content of the newer preparation
is 2.0%. Molecular sieve has been used in all reactions. We have
2
54 nm). However, we were not able to separate the butanoate
Scheme 3. CALB catalyzed kinetic resolution of 1 with vinyl butanoate in acetonitrile.
Please cite this article in press as: Lund, I. T.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.018

I.T. Lund et al. / Tetrahedron xxx (2016) 1e5
3
3
3
. Experimental
.1. General
Analytical grade chemicals and solvents were purchased from
SigmaeAldrich, Oslo, Norway. For HPLC-analyses solvents with
HPLC grade from SigmaeAldrich were used. CALB was a gift from
Novozymes AS, Bagsværd, Denmark. Enzyme specifications:
Novozym 435 (CALB) immobilized on macroporous acrylic resin,
ꢁ
1
activity 10000 PLU g , batch nr. LC200204. Flash chromatography
was performed with silica gel from SigmaeAldrich, Oslo, Norway
ꢀ
(
pore size 60 A, 230e400 mesh, 40e63
mm particle size).
The enzyme catalyzed kinetic resolutions were performed in
ꢀ
a New Brunswick G24 Environmental Incubator Shaker at 30 C and
ꢀ
200 rpm. Optical rotations ([
a
]
D
) were determined at 23 C using
a Perkin-Elmer 243 B instrument, concentrations are given in g/
00 mL. NMR spectra were recorded with a Bruker Avance DPX 400
1
1
13
instrument operating at 400 MHz for H and 100 MHz for C, re-
spectively. Chemical shifts are in ppm rel to TMS and coupling
d
Fig. 1. The enantiomeric excess (ee) of kinetic resolution of 1 in acetonitrile with CALB
and vinyl butanoate as acyl donor, E¼238. Circles: ee of butanoate ((S)-1b in excess).
Squares: ee of remaining alcohol ((R)-1 in excess).
constants are in Hertz (Hz). Accurate mass determination in posi-
tive and negative mode was performed on a WatersSynapt G2-S Q-
TOF instrument with WatersÔ Software (Masslynx V4.1 SCN871).
Samples were ionized by use of ASAP probe (APCI). Infrared spec-
troscopy was performed on a Nexus FTIR instrument.
3.2. Chiral analyses
3.2.1. Chiral HPLC-analyses. Chiral HPLC analyses of 1 were per-
formed on an Agilent 1100 HPLC instrument with manual injector
Rheodyne 77245i/Agilent, 10 L-loop, UV 254 nm. The column was
Chiralcel OD-H column (25 cm, i.d 4.6 mm, film density 5 m) from
Daicel, Chiral Technologies Europe. Eluent 1: Hexane:2-propanol,
m
Scheme 4. CALB catalyzed hydrolysis of (S)-1b in phosphate buffer.
m
Scheme 5. CALB catalyzed kinetic resolution of 3 and 4.
previously resolved the secondary alcohols 3 and 4 with the older
CALB preparation with vinyl butanoate as acyl donor in toluene
83:17, flow rate 1.00 mL minꢁ1. R
1¼37.70 min, R (R)-142.75 min, R
of 1: R
(S)-1b¼21.83 min, (butanoate enantiomers were not sep-
arated at R 23.48 min (from 1 derivatized with butyric anhydride).
After hydrolysis of the butanoate 1b it was shown that only one
butanoate enantiomer had been produced in the transesterification
t
alcohol enantiomers of 1: R
t
(S)-
t
S
¼1.84. R butanoate enantiomers
t
with fixed water activity (a
ranging from 33 to 21 for 3 depending on the water activity of the
medium, and from 12 to 16 for 4 depending on the a
w
) (a
w
¼0.18e0.65), resulting in E-values
t
t
1
2
w
.
2
2
Optical rotation (S)-3 (96% ee) ½ ꢂ ¼þ5.3 (c 1.71, EtOH). Re-
a
D
20
D
26
ported previously for 97% ee of (S)-3: ½
a
ꢂ
¼þ3.6 (c 0.56, CHCl
3
).
reaction (giving R
t
(S)-1¼36.91).
2
2
(
S)-4b (93% ee) ½ ꢂ ¼þ14.4 (c 1.71, EtOH). O. r. of (S)-4 (96% ee)
a
D
2
2
½
a
ꢂ
¼þ5.26 (c 1.71, EtOH) corresponded with previously reported
2,22
3.2.2. Chiral GLC-analyses. Chiral GLC-analyses of 3 and 4 were
D
1
o. r.
See Table 1 for E-values, ee’s and optical rotation values for
performed on a Varian 3380 gas chromatograph with a Varian CP-
ꢀ
enantiomers of 1, 3 and 4.
8410 autoinjector and a split injector (200 C) and flame ionization
Table 1
E-values from kinetic resolutions of secondary alcohols 1 and 3e4 with CALB (Novozym 435) and vinyl butanoate as acyl donor. For further details, see Experimental section
2
3
23
D
Substrate, X
E-value
Alcohol, % ee
(R)-1, 99
½
a
ꢂ
Butanoate, % ee
½
a
ꢂ
Rx time to 50% conv. (h)
27
D
1
3
4
, Cl
, Cl
, Br
238
ꢁ3.0, (MeOH)
þ3.0, (MeOH)
þ5.3, (EtOH)
(
S)-1, 98.5
(S)-3, 96
S)-3, 97
(S)-4, 96
220
278
23
10
26
(
þ3.6 (CHCl
3
)
þ5.26, (EtOH)
(S)-4b, 93
þ14.0 (EtOH)
Please cite this article in press as: Lund, I. T.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.018

4
I.T. Lund et al. / Tetrahedron xxx (2016) 1e5
ꢀ
detector (FID, 250 C). The secondary chloro alcohol 3 and the cor-
responding butanoate 3b were separated on a Varian CP Chirasil DEX
3.5. Kinetic resolutions of racemic compounds
column (25 m, i.d. 0.25 mm, film density 0.25
flow 7.5 psi, split flow 60 mL min , temp program: 110e120 C/
m
m). Carrier gas H
2
5.0,
3.5.1. Small scale transesterifications. Transesterification reactions
ꢁ1
ꢀ
ꢀ
were performed in a New Brunswick Incubator Shaker at 30
C
ꢀ
ꢁ1
ꢀ
ꢀ
ꢁ1
ꢀ
ꢀ
ꢁ1
ꢁ4
2
C min , 120e140 C/1 C min , 140e150 C/0.5 C min , R
cohol (R)-3¼38.13 min, R (S)-3 38.67 min. R ¼1.50. R butanoates: R
R)-3b¼63.57 min and R (S)-3b¼64.55 min. R ¼2.30.
The bromo alcohol 4 and the corresponding butanoate 4b were
separated on the same column with H 5.0 carrier gas, flow 9 psi,
t
al-
agitating at 200 rpm. Racemic alcohols 1 and 3e4 (1.31ꢃ10 mol)
ꢁ
4
t
S
t
t
and vinyl butanoate (6.5ꢃ10 mol) were mixed in solvent (ace-
tonitrile, hexane and DCM/hexane, respectively) and the reactions
started by addition of immobilized lipase (20 mg) and were in-
cubated for 10e27 h before the enzyme was filtered off and the
solvent removed. Two replicates of each reaction were performed.
The enantiomers were separated by column chromatography.
(
t
S
2
ꢁ
1
ꢀ
ꢀ
ꢁ1
split flow 80 mL min , temp program: 105e115 C/2 C min ,
ꢀ ꢀ ꢀ ꢀ
ꢁ1
ꢁ1
1
1
4
4
15e130 C/1 C min , 130e140 C/0.5 C min (5 min hold),
ꢀ
ꢀ
ꢁ1
40e150 C/0.5 C min . R
t
alcohols: R
butanoates: R
(R)-4b¼67.53 min and R
¼2.40.
t
(R)-4¼51.10 min R
t
(S)-
(S)-
Chiral GLC and HPLC analyses gave ee
the degree of conversion was calculated according to c¼ee
(ee ). The E-values were calculated using the program E&K
S P
- and ee -values from which
¼51.60 R
S
¼1.80. R
t
t
t
S
/
b¼67.92 min. R
S
S
þee
P
14
Calculator 2.1b0 PCC. In control experiments under the same re-
action conditions but without enzyme, no acylation was observed.
3
.3. Assignment of absolute configurations
The absolute configuration of the faster reacting enantiomer in
3.6. Large scale transesterifications
lipase catalyzed resolution was determined by the known enan-
tiopreference of CALB27 and by comparing the elution orders of the
enantiomers with GLC elution orders of similar enantiopure com-
pounds synthesized from (S)-epichlorohydrin. In chiral HPLC
analyses, the enantiomers eluted in the opposite order compared to
chiral GLC.
3.6.1. (R)-2-(4-(3-Chloro-2-hydroxypropoxy)phenyl)acetamide, (R)-
1. Alcohol 1 (0.56 g, 2.3 mmol) and vinyl butanoate (1.43 g,
12.5 mmol) was added to a flask with dry acetonitrile (40 mL) and
molecular sieve. CALB (0.71 g) was added and the reaction was
incubated at 30 C and 200 rpm for 27 h in an incubator shaker. The
enzyme and molecular sieve was filtered off and the solvent was
removed under reduced pressure. The ester (S)-1b and the alcohol
12
ꢀ
(
R)-1 were separated on a silica column with ethyl acetate as eluent.
(S)-1b was isolated in 99% ee and 18% yield (0.13 g, 0.41 mmol). (R)-
was isolated in 99% ee and 16% yield (0.090 g, 0.37 mmol).
3
.4. Synthesis of racemic substrates
1
.4.1. 4-(3-Chloro-2-hydroxypropoxy)phenyl)acetamide (1).10,11 2-
½ ꢂ ¼ꢁ3.0 (c 1.0, MeOH).
a
23
3
D
(
4-Hydroxyphenyl)acetamide (2.52 g, 16.6 mmol) and epichloro-
hydrin (13 mL) was mixed and transferred to a solution of sodium
hydroxide (0.50 g, 12.3 mmol) and water (5 mL). The reaction was
stirred for 48 h at rt. TLC chromatography (DCM:MeOH, 4:1) showed
that both alcohol 1 and the epoxide 2 was produced. The white solid
3.6.2. (S)-2-(4-(3-Chloro-2-hydroxypropoxy)phenyl)acetamide, (S)-
1. Butanoate 1b (0.092 g, 0.29 mmol) and phosphate buffer (0.1 M,
pH¼7, 4.0 mL) was mixed in a reaction vessel. CALB (0.8 g) was added
and the reaction was incubated for 48 h. The enzyme was filtered off
and the mixture was extracted with ethyl acetate (5ꢃ2 mL). The
solvent was removed under reduced pressure and gave (S)-1 in 48%
was washed with DCM and filtrated, then Li
2 4
CuCl in THF (0.1 M,
3
0 mL) was added. The reaction mixture was stirred for 24 h under
2
3
inert atmosphere. Sodium phosphate buffer (0.1 M, 30 mL) was
added. THF was removed and the residue was extracted with ethyl
acetate (5ꢃ20 mL) and washed with a satd sodium chloride solution
yield (0.034 g, 0.14 mmol) 98.5% ee, ½ ꢂ ¼þ3.0 (c 1.0, MeOH).
a
D
3.6.3. (S)-3-Chloro-1-phenoxy-2-propanol, (S)-3 from butanoate (S)-
3b. Alcohol 3 (1.00 g, 4.2 mmol) was dissolved in dry hexane
(100 mL) with molecular sieve. Vinyl butanoate (3.02 g, 26.4 mmol)
(
1
2ꢃ20 mL). Ethyl acetate was removed under reduced pressure and
ꢀ
1
was isolated in 22% yield (0.901 g, 3.70 mmol), mp 129e132 C. H
ꢀ
NMR (MeOD): 7.23e7.21 (m, 2H, aromatic), 6.92e6.90 (m, 2H, aro-
matic), 4.13e4.10 (m, 1H, eCHe), 4.06e4.02 (m, 2H, eOeCH e),
). C NMR:
and CALB (1.00 g) was added. The suspension was incubated at 30 C
2
at 200 rpm for 23 h. The enzyme was filtered off and the mixture
was extracted with ethyl acetate (5ꢃ2 mL). The solvent was re-
moved under reduced pressure and after separation of the enan-
13
3
2 2 2
.77e3.66 (m, 2H, eCH eCl), 3.44 (s, 2H, eCH eCONH
1
77.4, 159.2,131.3 (2C), 129.4, 115.7 (2C), 71.0, 70.2, 46.8, 42.5. HRMS
þ
(
APCI/ASAP, m/z): 244.0744 [MþH] , (calcd. C11
H14NO
3
Cl, 243.654).
tiomers on silica column (S)-3b was hydrolyzed by CALB and gave
ꢁ1
22
IR (cm ): 3349, 1633, 1241, 706.
(S)-3 in 96% ee, optical rotation ½ ꢂ ¼þ5.3 (c 1.71, EtOH).
a
D
3
.4.2. 3-Chloro-1-phenoxy-2-propanol (3).21 HCl (37%, 50 mL) was
added to a flask with a solution of 1,2-epoxy-3-phenoxypropane
3.6.4. (S)-3-Bromo-1-phenoxy-2-propanol (S)-4 and butanoate (S)-
4b. Alcohol 4 (1.26 g, 5.5 mmol) was dissolved in dry hexane
(100 mL) with molecular sieve. Vinyl butanoate (3.15 g, 27.5 mmol)
(3.31 g, 22.0 mmol) and DCM (25 mL). The reaction mixture was
ꢀ
ꢀ
stirred at0 C.TLCshowedfull conversionof the substrate after30 min
and CALB (0.85 g) was added. The suspensionwas incubated at 30 C
(
DCM:acetonitrile, 40:1,R
f
¼0.42). The organicphasewas concentrated
at 200 rpm for 10 h. The enzyme was filtered off and the mixture was
extracted with ethyl acetate (5ꢃ2 mL). The solvent was removed
under reduced pressure and after separation of the enantiomers on
silica column (S)-4b was produced in 57% yield (0.81 g, 3.2 mmol)
under reduced pressure and purified on a silicagel flash column
(
(
6
DCM:acetonitrile, 40:1). The colorlessfluid 3 wasisolated in76% yield
1
3.11 g, 16.7 mmol). H NMR (CDCl
.98e6.96 (m, 1H, aromatic), 6.91e6.89 (m, 2H, aromatic), 4.21e4.17
m, 1H, eCHe), 4.08e4.03 (m, 2H, eOeCH e), 3.77e3.68 (m, 2H,
eCl), 2.81e2.80 (d, 1H, OH; J¼6.0). C NMR: 158.3, 129.7 (2C),
21.5, 114.6 (2C), 70.0, 68.5, 46.0. HRMS (APCI/ASAP, m/z): 169.0424
3
) 7.29e7.27 (m, 2H, aromatic),
2
2
ee¼93%, ½ ꢂ ¼þ14.4 (c 1.71, EtOH). CALB catalyzed hydrolysis of (S)-
a
D
22
D
(
2
4b gave (S)-4 in 96% ee, optical rotation ½ ꢂ ¼þ5.26 (c 1.71, EtOH)
a
13
eCH
1
2
corresponded with previously determined o. r. of this compound in
2
2
13,23
96% ee, which was ½ ꢂ ¼þ5.3 (c 1.71, EtOH).
a
D
þ
ꢁ1
[MꢁOH] , (calcd. C
H O
9 11 2
Cl, 186.628). IR (cm ): 3405, 751, 690.
4. Conclusion
3
.4.3. 3-Bromo-1-phenoxy-2-propanol
(4).22,23 3-Bromo-1-
phenoxy-2-propanol (4) was synthesized and characterized as
previously described in 99% purity (GLC) and in 82% yield.
An efficient process for synthesis of both enantiomers (S)-1 and
(R)-1 (in 98.5 and 99% ee, respectively) as building blocks for the
b-
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I.T. Lund et al. / Tetrahedron xxx (2016) 1e5
8. Bevinakatti, H. S.; Banerji, A. A. J. Org. Chem. 1992, 57, 6003e6005.
5
blocker atenolol has been developed using CALB as catalyst and
9
. Barbosa, O.; Ortiz, C.; Torres, R.; Fernandez-Lafuente, R. J. Mol. Catal. B: Enzym.
2
vinyl butanoate as acyl donor. All enantiopure compounds have
been extensively characterized. Different preparations of CALB
Novozym 435) show different enantioselectivity in trans-
esterification reactions of the halo alcohols 3 and 4 with the same
reaction conditions as in resolutions previously performed by us,
which indicates that model reactions should be performed with
new enzyme preparations.
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Acknowledgments
1
1
We thank Novozymes AS, Denmark, for gifts of several prepa-
rations of Novozym 435 and Professor Thorleif Anthonsen for
valuable discussions. COST Action CM1303 Systems Biocatalysis is
thanked for funding.
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Please cite this article in press as: Lund, I. T.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.018