A chemoenzymatic dynamic kinetic resolution approach to enantiomerically pure (R)- and (S)-duloxetine

Article abstract of DOI:10.1021/jo2003665

The synthesis of (R)-duloxetine is described. Dynamic kinetic resolution of β-hydroxynitrile rac-1 using Candida antarctica lipase B (CALB, N435) and ruthenium catalyst 6 afforded β-cyano acetate (R)-2 in high yield and in excellent enantioselectivity (98% ee). The subsequent synthetic steps were straightforward and (R)-duloxetine was isolated in 37% overall yield over 6 steps. The synthetic route also constitute a formal total synthesis of (S)-duloxetine.

Full text of DOI:10.1021/jo2003665

ARTICLE
pubs.acs.org/joc
A Chemoenzymatic Dynamic Kinetic Resolution Approach to
Enantiomerically Pure (R)- and (S)-Duloxetine
Annika Tr€aff, Richard Lihammar, and Jan-E. B€ackvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
S Supporting Information
b
ABSTRACT: The synthesis of (R)-duloxetine is described.
Dynamic kinetic resolution of β-hydroxynitrile rac-1 using
Candida antarctica lipase B (CALB, N435) and ruthenium
catalyst 6 afforded β-cyano acetate (R)-2 in high yield and in
excellent enantioselectivity (98% ee). The subsequent synthetic
steps were straightforward and (R)-duloxetine was isolated in
37% overall yield over 6 steps. The synthetic route also
constitute a formal total synthesis of (S)-duloxetine.
’ INTRODUCTION
chemoenzymatic DKR an enzyme is employed as catalyst for the
resolution while, e.g., a transition metal catalyst is employed for
the racemization. Our group has successfully applied the concept
of DKR to several substrate classes such as secondary alcohols,6
amines,7 diols,8 amino alcohols,9 and β-hydroxynitriles.10
Herein we report on the enantioselective synthesis of duloxetine
via a DKR. The strength of the synthetic route described lies in
utilizing DKR in the enantiodetermining step where we take
advantage of the high selectivity of enzyme catalysis while
circumventing the limitation of a normal kinetic resolution by
converting the slow-reacting enantiomer to the fast reacting one.
Duloxetine is an antidepressant drug targeting the presynaptic
cell. It is a dual inhibitor preventing the reuptake of serotonin as
well as norepinephrine. In addition to being an important
pharmaceutical in the short term treatment of major depressive
disorders, it can be used to treat urinary incontinence and
obsessive compulsive disorder. Duloxetine is sold in its (S)-form
as a hydrochloride salt under the name Cymbalta.1
’ RESULTS AND DISCUSSION
Synthetic routes toward duloxetine utilizing β-hydroxynitrile as a
chiral intermediate are not as well explored as those with γ-chloro
ketones, and only a few syntheses are reported.3d,4d β-Hydroxyni-
triles are versatile intermediates since they give access to both
β-hydroxy acids and γ-amino alcohols through simple transforma-
tions.10 We envisioned starting from a readily available and in-
expensive starting material such as 2-thiophene carboxaldehyde.
Subjecting the β-hydroxynitrile to DKR would give the enantio-
merically pure β-cyano acetate. The latter compound could easily
be reduced to give the γ-hydroxyamine, which subsequently could
be protected with ethyl chloroformate. Reduction of the carbamate
followed by a nucleophilic aromatic substitution to introduce the
naphthyl would give (R)-duloxetine (Scheme 3). As described in
the literature (S)-duloxetine is also available by subjecting Boc-
protected (R)-4 to a Mitsunobu reaction.4d
In 1992 the U.S. Food and Drug Administration and the
European Committee for Proprietary Medicinal Products deter-
mined that each enantiomer of a potential drug has to be
characterized for their individual physiological action.2 This
demand calls for simple and straightforward preparation of both
enantiomers with high degree of purity, which can be a challenge.
For duloxetine the (S)-enantiomer has been found to be twice as
potent as the (R)-enantiomer, whereas for norduloxetine the
(R)-enantiomer was found more potent than the (S)-enantiomer
as reuptake inhibitor of the human serotonin transporter.1c
Different methods have been reported for the enantioselective
synthesis of duloxetine where asymmetric reduction3 and kinetic
resolution4 are most commonly employed.
Dynamic kinetic resolution is the concept of combining a
kinetic resolution (KR) with in situ racemization and is a growing
research area of great importance (Scheme 1).5 In a KR, a chiral
catalyst, for example, an enzyme, transforms one enantiomer of a
racemate much faster than the other enantiomer. By combining
this with a continuous racemization of the substrate, a theoretical
yield of 100% of the enantiopure product can be obtained. In a
By starting from 2-thiophene carboxaldehyde the β-hydroxyni-
trile was obtained in 91% yield through a condensation reaction with
acetonitrile. The following transformation to acquire the enantio-
merically enriched β-cynao acetate requires a successful DKR.
To find suitable conditions the KR and racemization was studied
Received: February 18, 2011
Published: March 31, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
ARTICLE
Scheme 1. Schematic Picture of Dynamic Kinetic Resolution
Table 2. Racemization of (S)-β-Hydroxynitrile at Room
Temperature, 50, 70, and 80 °C13
entry
T (°C)
t (min)
eea (%)
1
2
3
4
rt
50
70
80
120
20
5
57
0
Table 1. Investigating the Selectivity of Different Enzymes in
Kinetic Resolution of β-Hydroxynitrile 113
0
5
0
a Measured by chiral HPLC.
Scheme 2. DKR of 1
conv
% ee % ee
entry
enzyme
PS-IM
T (°C) t (h) (1)a (%) (1)b (2)b
Ec
1
2
3
4
5
6
7
8
9d
rt
3
3
35
44
33
38
6
52
76
54
51
6
97
96
98
82
110 (R)
112 (R)
170 (R)
16 (R)
PS-C
rt
PS-D
rt
2
PS-D
80
rt
2
CALB N435
CALB N435
CALB N435
CALB N435
CALB-W104Ae
6
>99 >200 (R)
50
70
80
50
38
50
4
21
23
35
14
41
23
25 >99 >200 (R)
2
27
56
14
5
98
96
81
8
128 (R)
86 (R)
10 (S)
1.2 (S)
1.5 (S)
4
good selectivity but more importantly higher activity (entries
6ꢀ8). The (S)-selective enzymes employed (entries 9ꢀ11)
showed very low selectivity.
24
4
10d subtilisinf
11d subtilisinf
5
6
18
The racemization of β-hydroxynitrile was investigated at room
temperature, 50, 70, and 80 °C employing ruthenium complex 6.
From the results it was clear that an elevated temperature was
necessary for the racemization to be sufficiently efficient in a
DKR (Table 2). The ee of the (S)-β-hydroxynitrile only
decreases to 57% within 2 h at room temperature (entry 1). At
higher temperature the rate of racemization was sufficient
(entries 2ꢀ4) and at g70 °C (S)-β-hydroxynitrile was fully
racemized within 5 min (entries 3, 4).
From these individual studies it seemed that the optimal condi-
tions for a successful DKR would be to run the reaction at a
temperature above 70 °C employing CALB for the resolution.
However, when the DKR was run at 70 °C, the ee of the acetate
decreased with time and as much as 20% elimination product was
observed. Running a control experiment where the enzyme was
excluded showed that a background reaction of chemical acylation
was taking place, which lowers the ee of the acetate. It was also found
that water increased the amount of elimination product. In the
presence of water, the acyl donor and the acetate (R)-2 can be
hydrolyzed forming acetic acid. If the heterogeneous Na2CO3
does not neutralize the acid immediately, these slightly acidic
conditions will promote protonation of the product, which in turn
initiates elimination. By careful optimization it was found that by
increasing the amount of enzyme as well as the acyl donor
(isopropenyl acetate) and running the reaction at 50 °C the
elimination was kept to a minimum (Scheme 2). Under these
reaction conditions the DKR reached 93% conversion within 25 h
and only 2% elimination product was observed. Cyanoacetate
(R)-2 was isolated in 87% yield in 98% ee.
a Measured by 1H NMR. b Measured by chiral HPLC. c Calculated
values. d The (S) form of the acetate was obtained. A mutated form
e
of CALB proven to be (S)-selective.14 f 1:4:4 subtilisin:Brij:octyl-β-D-
glucopyranoside.
separately before being combined in a DKR. In non-aqueous media
(e.g., toluene), lipases catalyze transesterification of a wide range of
substrates such as carboxylic acids, alcohols, amines, or esters. The
reaction usually proceeds with high regio- and/or enantioselectivity,
and as a result, lipases have attracted considerable attention. In
agreement with Kazlauskas’ rule,11 lipases display (R)-selectivity in
transesterification reactions, whereas serine porteases (e.g., Subtilisin
Carlsberg) display (S)-selectivity. The selectivity of different en-
zymes was initially determined (Table 1). From our previous work it
was known that enzymatic resolution of β-hydroxynitriles with
Candida antarctica lipase B (CALB) works very well.10 In the litera-
ture, however, Burkholderia cepacia lipase (previously Pseudomonas
cepacia lipase) is most commonly used in the KR of rac-1.4d,12 The
enantioselectivity (E value) of the kinetic resolution was measured
in toluene using isopropenyl acetate or trifluoroethyl butyrate as acyl
donor. Both (R)- and (S)-selective enzymes were investigated for
their selectivity.
Burkholderia cepacia lipase (PS-IM, PS-C, PS-D) and CALB
show high selectivity at room temperature (entries 1ꢀ3, 5) with
PS-D giving an E value of 170 (entry 3), whereas CALB gave an
E value >200 (entry 5). However the activity of CALB at room
temperature was extremely low with only 6% conversion after
6 h. At higher temperature the selectivity of PS-D dropped
considerably (entry 4), while CALB still showed excellent to
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The Journal of Organic Chemistry
ARTICLE
Scheme 3. Synthesis of Duloxetine
By reducing the nitrile and subsequently protecting it as a
carbamate, the hydroxyl amide (R)-3 was formed. Different
conditions were tried for this two-step transformation, and it
used as purchased. The enantiomeric excess of the compounds was
determined by chiral HPLC using racemic compounds as references.
Racemic acetate (rac-2) was obtained from the racemic alcohol (rac-1)
by standard acylation. Silica column chromatography was performed
with chromatographic silica (0.035ꢀ0.070 mm) for separation and
purification applications.
HPLC samples were run on HPLC with a photodiode array detector.
1H and 13C NMR were recorded at 400 and 100 MHz, respectively.
Optical rotation was measured with a polarimeter equipped with a Na
lamp. HR-MS was recorded on an ESI MS. Ruthenium complex 6
(η5C5Ph5)Ru(CO)2Cl was synthesized according to a literature
procedure.6a CALB (Novozym 435), PS-IM, PS-C, and PS-D are
commercially available. CALB-W104A was obtained according to ref
14c. The subtilisin used was prepared according to ref 16.
was found that subjecting the nitrile to 3.8 equiv of BH3 SMe2
3
and subsequently quenching with MeOH, followed by immedi-
ate treatment of the crude product with ethyl chloroformate in
CH2Cl2/NaHCO3 (aq), gave the desired product ((R)-3) in
67% yield over two steps. This was followed by a LiAlH4
reduction, which afforded the amino alcohol (R)-4 in 87% yield.
The final step in the synthesis toward (R)-duloxetine was a
nucleophilic aromatic substitution. Deprotonation of the amino
alcohol (R)-4 and subsequent substitution with 1-fluoronaphtha-
leneyielded(R)-5 in80% yield(Scheme 3). The opticalpuritywas
maintained at a high level throughout the synthesis (>96% ee).15
Prolonged reaction time and increased temperature during the
nucleophilic aromatic substitution decreased the enantiomeric
excess of the final product. This scheme also provides a formal
total synthesis of (S)-5, since the transformation of (R)-4 to (S)-5
has previously been described.4d
3-Hydroxy-3-(thiophen-2-yl)propanenitrile (rac-1). To a
solution of diisopropylamine (1.5 mL, 11 mmol) in 10 mL of dry
THF under an argon atmosphere at ꢀ78 °C was added dropwise n-BuLi
(2.5 M in hexanes, 4 mL, 10 mmol). After 0.5 h acetonitrile (0.5 mL, 10
mmol) in 5 mL of dry THF was added dropwise. The mixture was stirred
for an additional 0.5 h at ꢀ78 °C before 2-thiophenecarboxaldehyde
(0.94 mL, 10 mmol) dissolved in 5 mL of dry THF was added. After 18 h
of stirring, the reaction was quenched by addition of 30 mL of saturated
aqueous NH4Cl solution. The water phase was extracted with Et2O (3 ꢁ
30 mL), and the combined organic phases were dried over MgSO4,
filtered, and evaporated. The crude product was purified by flash
chromatography (SiO2, pentane/EtOAc 4:1) yielding 1 (1.4 g, 9.1
mmol, 91%) as a yellow oil. Spectral data were in accordance with those
reported in the literature.12 1H NMR (400 MHz, CDCl3): δ 7.33 (dd, J =
5.1 Hz, 1.2 Hz, 1H), 7.10 (dt, J = 3.6 Hz, 1.1 Hz, 1H), 7.01 (dd, J = 5.1
Hz, 3.6 Hz, 1H), 5.31 (app t, J = 6.2 Hz, 1H), 2.89 (dd, J = 6.3 Hz, 1.8 Hz,
2H), 2.48 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 144.4, 127.1, 125.7,
124.7, 116.9, 66.2, 28.2. HPLC: Chiralpak OJ column, i-hexane/i-PrOH,
’ CONCLUSION
We have reported a direct and efficient synthetic route for
(R)-duloxetine as well as a formal total synthesis of (S)-duloxetine.
By employing DKR in the enantiodetermining step the β-cyano
acetate, (R)-2, was obtained in high yield and excellent enantios-
electivity (98% ee). Further elaboration, via the γ-amino alcohol
(R)-4, afforded (R)-duloxetine ((R)-5). The target molecule
(R)-5 was obtained in 37% overall yield from thiophene carbox-
aldehyde over six steps in high enantiomeric excess (>96%).15
85:15 for80 min, 0.5 mL minꢀ1, 25 °C, UVat230 nm, tR1= 40 min (S)-1,
’ EXPERIMENTAL SECTION
3
tR2 =44 min (R)-1.
General. KR, DKR, and racemization reactions were carried out
under dry argon atmosphere using standard Schlenk technique. The
racemic 3-hydroxy-3-(thiophen-2-yl)propanenitrile (rac-1) was dried
over molecular sieves (4 Å) before using it in DKR. Isopropenyl acetate
was dried over CaCl2 and distilled before use. Dry THF and toluene
were obtained from a VAC solvent purifier. Acetonitrile was dried
through distillation over CaH. All other chemicals and solvents were
General Procedure for KR of rac-1. The corresponding enzyme
(see Table 3 for the appropriate amount) and Na2CO3 (53 mg, 0.5
mmol) were added to a vial. The rac-3-hydroxy-3-(thiophen-2-yl)pro-
panenitrile (rac-1) (77 mg, 0.5 mmol) dissolved in dry toluene (1 mL)
was added to the vial, and the mixture was stirred. After a few minutes
isopropenyl acetate (see Table 3 for the appropriate amount) was added to
the reaction mixture. Samples for HPLC analysis were collected with a
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ARTICLE
Table 3. Kinetic Resolution of rac-1
entry
enzyme
enzyme (mg/mmol)
OAca (equiv)
T (°C)
t (h)
conv (1)b (%)
% ee (1)c
% ee (2)c
Ed
1
PS-IM
50
50
2
2
rt
3
3
35
44
33
38
6
52
76
54
51
6
97
96
98
82
>99
>99
98
98
98
96
81
8
110 (R)
112 (R)
170 (R)
16 (R)
2
PS-C
rt
3
PS-D
50
2
rt
2
4
PS-D
50
2
80
rt
2
5
CALB N435
CALB N435
CALB N435
CALB N435
CALB N435
CALB N435
CALB-W104Ae
subtilisinf
50
2
6
>200 (R)
>200 (R)
158 (R)
152 (R)
128 (R)
86 (R)
6
50
2
50
50
50
70
80
50
38
50
4
21
33
32
23
35
14
41
23
25
47
44
27
56
14
5
7
100
100
50
2
4
8
3
4
9
2
2
10
11
12
13
50
2
4
100
100
100
3
24
4
10 (S)
3g
3g
1.2 (S)
subtilisinf
5
6
18
1.5 (S)
a OAc = isopropenyl acetate. b Measured by 1H NMR. c Measured by chiral HPLC. d Calculated values. The selectivity displayed by the enzyme is given in
parentheses. e A mutated form of CALB proven to be (S)-selective.14 f 1:4:4 subtilisin:Brij:octyl-β-D-glucopyranoside. g Trifluoroethyl buturate was used
as acyl donor.
syringe after 0.5, 2, 3, 4, 5, 6, and 24 h. HPLC: Chiralpak OJ column,
i-hexane/i-PrOH, 85:15 for 80 min, 0.5 mL min-1, 25 °C, UV at 230 nm, tR1
under gas formation. After 2 h the reaction was quenched by slow addition of
4 mL of MeOH at 0 °C followed by addition of 2 mL of H2O. After filtration
the organic solvent was evaporated, and the crude product obtained was used
in the next step without further purification. If purification is desirable it can be
done with flash chromatography (EtOAc/MeOH/NH4OH 9:1:0.2) yielding
the pure amino alcohol as a clear oily solution. 1H NMR (400 MHz D2O):
δ 7.34ꢀ7.32 (m, 1H), 7.00ꢀ6.96 (m, 2H), 5.04ꢀ5.00 (m, 1H), 3.02ꢀ2.88
(m, 2H), 2.12ꢀ2.06 (m, 2H).
=
3
40 min (S)-1, tR2 = 44 min (R)-1, tR3 = 57 min (S)-2, tR4 = 62 min (R)-2.
General Procedure for Racemization of (S)-1. Ruthenium
complex 6, (η5C5Ph5)Ru(CO)2Cl (9.5 mg, 0.015 mmol), and Na2CO3
(32 mg, 0.3 mmol) were added to a Schlenk tube. Dry toluene (0.3 mL)
was added, and the resulting yellow solution was stirred. A THF solution
of t-BuOK (30 μL, 0.5 M in dry THF, 0.015 mmol) was added to the
reaction mixture. The reaction turned orange. After approximately 6 min
of stirring (R)-3-hydroxy-3-(thiophen-2-yl)propanenitrile ((R)-1) (46
mg, 0.3 mmol), dissolved in dry toluene (0.3 mL), was added to the
reaction mixture, and the reaction was heated to the appropriate
temperature. Samples for HPLC analysis were collected with a syringe
after 5, 15, 30, 60, and 120 min. HPLC: Chiralpak OJ column, i-hexane/
(R)-Ethyl 3-Hydroxy-3-(thiophen-2-yl)propylcarbamate
((R)-3). To a solution of crude (R)-3-amino-1-(thiophen-2-yl)propan-1-ol
(originated from 0.45 mmol (R)-2) in CH2Cl2 (4 mL) was added 4 mL
of saturated aqueous NaHCO3 solution. Ethyl chloroformate (0.10 mL,
0.1 mmol) was added dropwise to the two phase mixture. After 1 h of
stirring the product was extracted with CH2Cl2 (3 ꢁ 5 mL), dried over
MgSO4, filtered and concentrated. Purification by flash chromatography
(SiO2, pentane/EtOAc 3:1) yielded (R)-3 as a colorless oil (69 mg, 0.3
mmol, 67% over two steps, 98% ee). Spectral data were in accordance
with those reported in the literature.3c 1H NMR (400 MHz CDCl3): δ
7.24 (dd, J = 4.5 Hz, 1.8 Hz, 1H), 6.96ꢀ6.93 (m, 2H), 5. 09 (br s, 1H),
5.01ꢀ4.98 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.54ꢀ3.46 (m, 1H),
i-PrOH, 85:15 for 80 min, 0.5 mL minꢀ1, 25 °C, UV at 230 nm, tR1 = 40
3
min (S)-1, tR2 = 44 min (R)-1.
2-Cyano-1-(thiophen-2-yl)ethyl Acetate ((R)-2). Ruthenium
complex 6 (η5C5Ph5)Ru(CO)2Cl (16 mg, 0.025 mmol), CALB (50 mg,
100 mg/mmol substrate), and Na2CO3 (53 mg, 0.5 mmol) were added
to a Schlenk tube. Dry toluene (0.5 mL) was added, and the resulting
yellow solution was stirred. A THF solution of t-BuOK (50 μL, 0.5 M in
dry THF, 0.025 mmol) was added to the reaction mixture. The reaction
turned orange. After approximately 6 min of stirring, rac-1 (77 mg, 0.5
mmol) dissolved in dry toluene (0.5 mL) was added to the reaction
mixture. After an additional 4 min, isopropenyl acetate (165 μL, 1.5
mmol) was added. The reaction was heated to 50 °C. After 25 h the
reaction mixture was filtered and concentrated. Purification by column
chromatography (SiO2; pentane/Et2O 4:1) afforded 85 mg (0.435
mmol, 87%) of (R)-2 in 98% ee. Spectral data were in accordance with
those reported in the literature.12 1H NMR (400 MHz CDCl3): δ 7.33
(dd, J = 5.1 Hz, 1.2 Hz, 1H), 7.16 (dt, J = 3.6 Hz, 1.1 Hz 1H), 7.00 (dd, J =
5.1 Hz, 3.6 Hz, 1H), 6.26 (app t, J = 6.3 Hz, 1H), 2.99 (dd, J = 6.3 Hz,
1.8 Hz, 2H), 2.12 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.4,
139.3, 127.0, 126.5, 126.4, 115.7, 66.2, 25.6, 20.8. [R]20D = þ94 (c 1.16,
MeOH), [R]20 = þ96 (c 0.93, CHCl3); lit.12 [R]20 = þ94 (c 1,
3.29ꢀ3.21 (m, 1H), 2.02ꢀ1.96 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H). 13
C
NMR (100 MHz, CDCl3): δ 157.5, 148.1, 126.7, 124.5, 123.4, 67.7,
61.1, 39.5, 37.8, 14.6. HPLC: Chiralpak OD-H column, i-hexane/
i-PrOH, 97:3 for 120 min, 1.0 mL minꢀ1, 30 °C, UV at 230 nm, tR1
3
= 85 min (R)-3, tR2 = 97 min (S)-3.
3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol ((R)-4). A
flame-dried two-necked round bottomed flask was charged with LiAlH4
(330 mg, 8.7 mmol) and (R)-3 (570 mg, 3.3 mmol) dissolved in 35 mL
of dry THF was added. The suspension was heated to reflux and stirred
for 14 h. 500 μL of ethylenediamine, 600 μL of aq. NaOH (10 w%), and
600 μL of H2O was added subsequently with 10 min intervals. The gray
mixture was filtered through a thin pad of Celite and washed with 50 mL
of THF. The organic solvent was stripped off at reduced pressure. The
aqueous phase was diluted and extracted with Et2O (3 ꢁ 30 mL). The
combined organic phases were dried over Na2SO4, filtered and con-
centrated in vacuo. The residue was purified by flash chromatography
(SiO2, gradient eluent from 100% CH2Cl2 to 90:15:2 CH2Cl2/MeOH/
NH4OH) yielding (R)-4 (491 mg, 2.87 mmol, 87%) as a clear oil that
crystallized upon standing. Spectral data were in accordance with those
reported in the literature.3c,17 1H NMR (400 MHz CDCl3) δ 7.21 (dd, J =
5.12 Hz, 1.33 Hz, 1H), 6.98ꢀ6.96 (m, 1H), 6.92 (dt, J = 3.5 Hz, 1.1 Hz,
1H), 5.20 (dd, J = 8.4 Hz, 3.3 Hz, 1H), 2.97 (ddd, J = 12.3 Hz, 5.9 Hz,
D
D
CHCl3, 95% ee (R)-enantiomer). HPLC: Chiralpak OJ column, i-
hexane/i-PrOH, 85:15 for 80 min, 0.5 mL minꢀ1, 25 °C, UV at
3
230 nm, tR1 = 57 min (S)-2, tR2 = 62 min (R)-2.
(R)-3-Amino-1-(thiophen-2-yl)propan-1-ol. BH3 Me2S (1 mL,
3
2.0 mmol, 2 M in THF) was added to a two-necked round bottomed flask
and heated to 80 °C for 30 min. Acetate (R)-2 (87 mg, 0.45 mmol) was
dissolved in 2 mL of dry THF and was then added dropwise to the mixture
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ARTICLE
3.4 Hz,1H), 2.87 (ddd, J = 12.3 Hz, 9.6 Hz, 3.4 Hz, 1H), 2.44 (s, 3H),
2.03ꢀ1.94 (m, 1H), 1.94ꢀ1.84 (m, 1H). 13C NMR (100 MHz CDCl3):
δ 149.5, 126.6, 123.8, 122.6, 71.0, 49.6, 37.1, 35.8.
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M. S.; Shaik, A. A.; Azeeza, S. J. Mol. Catal. B: Enzym. 2009, 58, 132–137.
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B€ackvall, J.-E. Chem. Soc. Rev. 2001, 30, 321–331. (b) Kim, M.-J.; Ahn,
Y.; Park, J. Curr. Opin. Biotechnol. 2002, 13, 578–587. (c) Pꢀamies, O.;
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1015.
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related efficient DKR of secondary alcohols, see: P€aivi€o, M.; Mavrynsky,
D.; Leino R.; Kanerva, L. T. Eur. J. Org. Chem. 2011, 1452ꢀ1457.
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2010, 132, 15182–15184.
(R)-N-Methyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)-
propan-1-amine ((R)-5). To a solution of (R)-4 (45 mg, 0.26 mmol)
dissolved in 1.7 mL of dry DMSO was added NaH (60% in mineral oil,
16 mg, 0.39 mmol)). The white suspension formed was stirred at
ambient temperature for 30 min followed by an increase of reaction
temperature to 50 °C and addition of 1-fluoronaphthalene (44 μL, 0.34
mmol). A red suspension was initially generated, which turned green
after a few minutes of stirring. After 1 h the mixture was cooled to room
temperature, and 4 mL of aq NaOH (1 M) was added in order to quench
the reaction. The product was extracted with EtOAc (3 ꢁ 10 mL), and
the combined organic phases were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The remaining DMSO was
removed by Kugelrohr distillation (0.6 mmHg, 45 °C). Purification by
flash chromatography (SiO2, CH2Cl2/MeOH/NH4OH 19:1:0.1)
afforded (R)-5 (61 mg, 0.21 mmol, 80%) as a colorless oil in >96% ee
(determined by chiral HPLC). Spectral data were in accordance with
those reported in the literature.3c 1H NMR (400 MHz, CDCl3):
δ 8.37ꢀ8.33 (m, 1H), 7.80ꢀ7.77 (m, 1H), 7.51ꢀ7.46 (m, 1H), 7.42
(d, J = 8.2 Hz, 1H), 7.29ꢀ7.25 (m, 1H), 7.21 (dd, J = 5.0 Hz, 1.0 Hz,
1H), 7.06 (d, J = 3.3 Hz, 1H), 6.94 (dd, J = 4.9 Hz, 3.5 Hz, 1H), 6.86 (d,
J = 7.7 Hz, 1H), 5.79 (dd, J = 7.6 Hz, 5.2 Hz, 1H), 2.87ꢀ2.81 (m, 2H),
2.51ꢀ2.40 (m, 1H), 2.44 (s, 3H), 2.28ꢀ2.16 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ 153.3, 145.2, 134.6, 127.5, 126.6, 126.3, 126.2,
125.7, 125.3, 124.7, 124.6, 122.1, 120.6, 107.0, 74.7, 48.2, 38.8, 36.4.
[R]21D = ꢀ114.3 (c 1, MeOH); lit.3d [R]20D = þ110.5 (c 1.1, MeOH,
95% ee (S)-enantiomer). HPLC: Chiralpak OJ column, i-hexane/
(10) (a) Pꢀamies, O.; B€ackvall, J.-E. Adv. Synth. Catal. 2001,
343, 726–731. Correction: see ref 10b.(b) Pꢀamies, O.; B€ackvall, J.-E.
Adv. Synth. Catal. 2002, 344, 947–952.
EtOH/diethylamine, 90:10:0.1 for 40 min, 1.0 mL minꢀ1, 25 °C, UV
3
at 229 nm, tR1 = 19 min (S)-5, tR2 = 24 min (R)-5
(11) (a) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.;
Cuccia, L. A. J. Org. Chem. 1991, 56, 2656–2665. (b) Kazlauskas, R. J.;
Weissfloch, A. N. E. J. Mol. Catal. B: Enzym. 1997, 3, 65–72.
(12) Turcu, M. C.; Perki€o, P.; Kanerva, L. T. ARKIVOC
2009, 251–263.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra. This
S
b
material is available free of charge via the Internet at http://pubs.
acs.org.
(13) See the Experimental Section for experimental details.
(14) (a) Magnusson, A. O.; Rotticci-Mulder, J. C.; Santagostino, A.;
Hult, K. ChemBioChem 2005, 6, 1051–1056. (b) Magnusson, A. O.;
Takwa, M.; Hamberg, A.; Hult, K. Angew. Chem., Int. Ed. 2005,
44, 4582–4585. (c) Engstr€om, K.; Vallin, M.; Syrꢁen, P.-O.; Hult, K.;
B€ackvall, J.-E. Org. Biomol. Chem. 2011, 9, 81–82.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jeb@organ.su.se.
(15) [R]21D = ꢀ114.3 (c 1, MeOH); lit.3d [R]20D = þ110.5 (c 1.1,
MeOH, 95% ee (S)-5)
(16) Borꢁen, L.; Martín-Matute, B.; Xu, Y.; Cꢁordova, A.; B€ackvall, J.-E.
Chem.—Eur. J. 2006, 12, 225–232.
(17) Panunzio, M.; Tamanini, E.; Bandini, E.; Campana, E.; D’Aurizio,
A.; Vicennati, P. Tetrahedron 2006, 62, 12270–12280.
’ ACKNOWLEDGMENT
The authors wish to acknowledge Dr. Allan Svendsen, Novozymes
A/S for a generous gift of CALB (Novozym 435). We thank
Dr. Yoshihiko Hirose, Amano Enzyme Inc. Gifu R&D Center for
kindly providing us with enzymes (PS-IM, PS-C, PS-D). Financial
support from INTENANT is gratefully acknowledged.
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