Biocatalytic preparation of optically active 4-(N,N-dimethylamino)pyridines for application in chemical asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2006.03.018

4-Chloro-2-(1-hydroxybenzyl)pyridine and 4-chloro-2-(1-hydroxyalkyl)pyridines were obtained with moderate to excellent enantiomeric excesses and high isolated yields by bioreduction with Baker's yeast of the corresponding ketones. The resulting optically active alcohols were transformed into adequate DMAP derivatives, which have been applied in asymmetric catalytic processes as nucleophilic catalysts in the stereoselective chemical alkoxycarbonylation of 1-phenylethanol or as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde.

Full text of DOI:10.1016/j.tetasy.2006.03.018

Tetrahedron: Asymmetry 17 (2006) 1007–1016
Biocatalytic preparation of optically active
4-(N,N-dimethylamino)pyridines for application in
chemical asymmetric catalysis
*
´
Eduardo Busto, Vicente Gotor-Fernandez and Vicente Gotor
Departamento de Quı´mica Orga´nica e Inorga´nica, Instituto de Biotecnologie de Asturias, Universidad de Oviedo,
33071 Oviedo (Asturias), Spain
Received 2 March 2006; accepted 14 March 2006
Abstract—4-Chloro-2-(1-hydroxybenzyl)pyridine and 4-chloro-2-(1-hydroxyalkyl)pyridines were obtained with moderate to excellent
enantiomeric excesses and high isolated yields by bioreduction with Baker’s yeast of the corresponding ketones. The resulting optically
active alcohols were transformed into adequate DMAP derivatives, which have been applied in asymmetric catalytic processes as nucleo-
philic catalysts in the stereoselective chemical alkoxycarbonylation of 1-phenylethanol or as chiral ligands in the enantioselective addition
of diethylzinc to benzaldehyde.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
mentation processes of heteroaryl-alkyl and heteroaryl-aryl
ketones like a,b,c-acetylpyridines, a-acetylfuran,9 benzoyl-
pyridine N-oxides,10 and benzoylpyridines10b with Baker’s
yeast were studied by Takeshita et al. achieving, in some
cases, the corresponding alcohols with high enantioprefer-
ences. Successful enantioselective reductions of 2,6-diacet-
ylpyridine11 and other diacetylaromatics12 have also been
described. Other biocatalysts have been employed in recent
years in the bioreduction of pyridine ketone derivatives
such as immobilized cells of Daucus carota,13 Geotrichum
candidum,14 Camellia sinensis,15 Rhizopus arrhizus,16 Pseu-
domonas putida,17 Rhodococcus species18 or Candida visw-
anathii,19 while some recombinant strains have shown
activity toward these substrates.20
4-(N,N-Dimethylamino)pyridine (DMAP) has become one
of the most popular catalysts for different processes such as
acylations, alkylations, silylations, Baylis–Hillman reaction
and nucleophilic substitutions of alcohols and amines.1 The
development of chiral DMAP derivatives has received
considerable attention, since they have been successfully
employed as chiral nucleophilic catalysts in a wide range of
asymmetric synthetic processes.1b,2 There are many different
strategies for the preparation of DMAP analogues, for
instance Ruble and Fu introduced the concept of ‘planar
chirality’,3 and a few examples of ferrocene-fused DMAP
complexes have been described in the literature, which have
been used in stereoselective processes.4 The synthesis of
atropoisomeric biaryl complexes,5 2-,6 3-,7 and 4-substituted
DMAP derivatives8 have also been described, some of which
have been applied to different asymmetric processes showing
different degrees of reactivity and stereoselectivity.
Herein, we report the development of a new chemoenzy-
matic route for the synthesis of chiral 2-substituted DMAP
derivatives where the key step for the introduction of
chirality is the bioreduction of ketones catalyzed by differ-
ent oxidoreductases. The preparation and application of
adequate chiral DMAP analogues in asymmetric catalytic
processes have also been studied.
Enzymes are recognized as valuable tools for the synthesis
of optically active compounds. The use of oxidoreductases,
in particular Baker’s yeast (Saccharomyces cerevisiae), has
attracted significant attention because it provides very effi-
cient access to important optically enriched products. Fer-
2. Results and discussion
Recently, we described the chemoenzymatic synthesis of
enantiomerically pure 4-(N,N-dimethylamino)-2-(1-hydr-
oxyalkyl)pyridines, where Pseudomonas cepacia lipase
*
Corresponding author. Tel./fax: +34 985 103448; e-mail: vgs@fq.
uniovi.es
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.018

1008
E. Busto et al. / Tetrahedron: Asymmetry 17 (2006) 1007–1016
(PSL-C) played a fundamental role in the introduction of
chirality, which was possible through transesterification
reactions of 4-chloro-2-(1-hydroxyalkyl)pyridines 2a–d
using 3 equiv of vinyl acetate as the acyl donor and THF
as the solvent (Scheme 1).21
ity; for that reason we reacted 4-chloro-2-cyanopyridine 1
with different organomagnesium derivatives (Table 1 and
Scheme 2) and the isolation steps after flash chromatogra-
phy were carried out taking as many precautions as possi-
ble. For example, by assuring that the bath temperature of
the rotary evaporator was always below 25 ꢁC, avoiding
later use of the vacuum pump, and storing the products
at cold temperature. In this manner ketones 6a–e were
obtained with good yields (75–87%).
Cl
Cl
R
N
OH
2a-e
Table 1. Synthesis of ketones 6a–e
N
CN
Entry
R2
X
Yielda (%)
1
1
2
3
4
5
Me
Et
Pr
Bu
Ph
I
87
81
79
85
75
Cl
N
Cl
N
Cl
N
Br
Br
Cl
Br
Enzyme
O
+
+
R
R
R
O
3
Solvent, T
OH
OAc
(R)-4a-e
OH
(S)-2a-e
a Isolated yield by flash chromatography.
2a-e
2a: R=Me, 2b: R=Et, 2c: R=Pr, 2d: R=Bu, 2e: R=Ph
Scheme 1. Synthesis and lipase-catalyzed resolution of 4-chloro-2-
(substituted)pyridines.
R1
R1
R1
N
R2MgX
Baker's Yeast
H2O
R2
Et2O
0 ºC to rt
*
R2
N
N
CN
In all cases, PSL-C showed excellent stereoselectivities in
the acylation of these 4-chloro derivatives (E >200). Our
next goal was the extension of these results to the enzy-
matic resolution of 4-chloro-2-(1-hydroxybenzyl)pyridine
2e, which was synthesized from 4-chloro-2-cyanopyridine
1 in 75% yield. Initially we carried out the enzymatic
transesterification of 2e under the same conditions than
the ones used in the kinetic resolution of 2a–d, however
no reaction was observed and neither at 60 ꢁC. Other
enzymes such as Candida antarctica lipase A (CAL-A)
and C. antarctica lipase B (CAL-B) were also tested but
the final product could not be detected. Finally, we decided
to carry out the process using vinyl acetate as solvent and
acyl donor at 60 ꢁC and after 166 h, 42% conversion was
reached affording enantiomerically enriched product (82%
ee) and substrate (59% ee).
OH
O
1: R1=Cl
6a: R1=Cl, R2=Me, 6b: R1=Cl, R2=Et,
6c: R1=Cl, R2=Pr, 6d: R1=Cl, R2=Bu,
6e: R1=Cl, R2=Ph, 6f: R1=NMe2, R2=Me
(S)-2a-d
(R)-2e
(S)-7a
5: R1=NMe2
Scheme 2. Synthesis of ketones 6a–f and bioreduction using Baker’s yeast
as biocatalyst.
For the formation of 2-acetyl-4-(N,N-dimethylamino)pyr-
idine 6f we first tried to react 1 with a 40% aqueous
solution of dimethylamine at 100 ꢁC, isolating 2-cyano-4-
(N,N-dimethylamino)pyridine 5 in 71% yield, however, this
substrate was not soluble in the diethyl ether solution of the
organomagnesium derivative, so we decided to prepare 6f
from 6a instead of 1 by simple substitution of the
chlorine atom by the dimethylamino group which occurred
with moderate yield (53%) as reaction by-products
appeared during the process.
Previously we have described the resolution of substrates
2a–d, which led to the formation of the corresponding
acetates (R)-4a–d, whose stereochemistries follow the ones
expected for Kazlauskas’ rule.22 To determine the configu-
ration of substrate 2e and product 4e from the enzymatic
transesterification of racemic 2e, we applied Kelly’s
empirical method,23 which is described below.
Bioreduction of ketones 6a–f was carried out in an aqueous
solution of glucose, shaking the corresponding mixtures at
30 ꢁC (Table 2). All conversions were up to 75% after 60 h
except for the case of 6f due to solubility problems. Com-
paring the alkanoyl substrates 6a–d, a decrease in the con-
version occurred when the size of the alkyl chain length was
increased from the methyl substitution 6a to bulkier groups
2.1. Bioreduction of 2-alkanoyl-4-chloropyridines and
2-benzoyl-4-chloropyridine using Baker’s yeast
Table 2. Bioreduction of ketones 6a–f using Baker’s yeast as a biocatalyst
Due to the low enantioselectivity obtained in the enzymatic
transesterification of 2e (E = 18), we started to investigate
new enzymatic routes for the synthesis of enantiomerically
pure 4-chloro-2-(1-hydroxysubstituted)pyridines. By tak-
ing into account the excellent selectivities achieved in the
bioreduction of pyridine ketone derivatives using Baker’s
yeast,9–12 we turned our attention to this type of processes.
Entry
R1
R2
t (h)
ca (%)
eeb (%)
1
2
3
4
5
6
Cl
Cl
Cl
Cl
Cl
NMe2
Me
Et
Pr
Bu
Ph
Me
60
60
60
60
60
100 (76)
90 (71)
79 (73)
84 (72)
88 (84)
58 (40)
98
91
81
80
97
98
168
a Calculated by 1H NMR of the reaction crude. Isolated yields in brackets.
b Calculated by HPLC.
The synthesis of 2-alkanoyl-4-chloropyridines is not an
easy task because they present serious problems of volatil-

E. Busto et al. / Tetrahedron: Asymmetry 17 (2006) 1007–1016
1009
such as ethyl, propyl or butyl 6b–d. Nevertheless, the iso-
lated yields of all reactions reached similar values. Better
yields were obtained for 6e (entry 5) as the phenyl substitu-
ent made the molecule more hydrophobic and could be eas-
ily extracted in the purification step. In the case of 6f longer
reaction times were needed in order to afford significant
conversions to 7a (entry 6).
they require the inconvenient use of the NADPH cofactor,
there is advantage of affording alcohol derivatives with
opposite stereochemistry than the ones obtained from the
reduction with Baker’s yeast. Bioreduction processes were
carried out in a TRIS/HCl buffer solution of pH 7 and
the results are summarized in Table 3.
Table 3. Reduction of ketones 6a–e using T-ADH and LB-ADH
Importantly, alcohols 2a–e and 7a were obtained with
moderate to excellent ee (80–98%), up to 95% with
R2 = Me or Ph and decreasing when the alkyl chain was
elongated. Enzymatic reduction of the ketones afforded
the (S)-alcohols, except in the case of the phenyl derivative,
which gave (R)-2e. Synthesis, using yeast of enantiomeri-
cally enriched alcohol 2e (R2 = Ph) represents a great
advantage in comparison, with lipase-catalyzed transesteri-
fication which occurs with low enantioselectivity. More-
over, isolated yields can exceed 50%, which is generally
the main limitation of a kinetic resolution.
Entry
6
ADH
t (h)
ca (%)
eeb (%)
Conf.
1
2
3
4
5
6
7
8
9
a
a
b
b
c
c
d
d
e
e
T
LB
T
LB
T
LB
T
LB
T
LB
38
38
47
100 (89)
100 (87)
100 (94)
100 (91)
—
—
—
—
—
>99
>99
>99
>99
—
—
—
—
—
S
R
S
47
R
168
168
168
168
168
168
—
—
—
—
—
—
10
—
—
a Calculated by 1H NMR of the reaction crude. Isolated yields in brackets.
b Calculated by HPLC.
The absolute stereochemistries of alcohols 2a–d and 7a–d
were assigned by comparing the values of the specific rota-
tion with those previously described.21 To determine the
stereochemistry of the products obtained in the lipase-cat-
alyzed transesterification reaction, the optically enriched
acetate (R)-4e was converted in the alcohol (R)-2e using so-
dium hydroxide in MeOH, and later to the Mosher’s ester
observing clearly a major signal, which corresponds to the
(R,R)-diastereoisomer (d = 8.50 ppm, Fig. 1).
Both enzymes were only active with the less hindered
ketones 6a–b, and no reaction was observed with bulkier
substrates. Fortunately, these two alcohol dehydrogenases
were completely enantioselective, showing opposite stereo-
selections. In this manner, T-ADH produced (S)-alcohols
similar to Baker’s yeast; meanwhile LB-ADH allowed the
formation of enantiomerically pure (R)-alcohols. Isolated
yields were higher than the ones obtained with Baker’s
yeast as the reaction work-ups for the isolation of the final
product were easier (see Section 4).
(R,R)
(R,S)
H2
H2
H2
Ph
F3C
N
OMe
O
(R,R) + (R,S)-diasterioisomers
1
H
R
M
N
AV600
Cl
Cl
Cl
2.2. Synthesis of a chiral catalyst and application in
asymmetric catalysis
8
.
7
6
8
.
7
2
8
.
6
8
8
.
6
4
8
.
6
0
8
.
5
6
8
.
5
2
8.48
)
8
.
4
4
8
.
4
0
8
.
3
6
8
.
3
2
8
.
2
8
8
.
2
4
(ppm
Ph
O
H
(R,R)
(R,R)-diasterioisomer from
lipase-catalyzed
transesterification reaction
Ph
F3C
N
OMe
O
(R,S)
Once the reduction processes of the ketones were success-
fully achieved, the chloro derivatives (S)-2a–d and (R)-2e
were converted into the corresponding 4-N,N-dimethyl-
amino products, using the same procedure for the transfor-
mation of 1 into 5.
8
.
7
6
8.72
8.68
8
.
6
4
8.60
8
.
5
6
8
.
5
2
8
.
4
8
8.44
8
.
4
0
8
.
3
6
8
.
3
2
8
.
2
8
8
.
2
4
Ph
O
(
p
m
)
H
1
H
R
M
N
AV600
(R,R)
Ph
F3C
N
(R,R)-diasterioisomer
from bioreduction
OMe
O
(R,S)
For the benzyl derivative, we used the product obtained in
the bioreduction process as previously described, because
this reaction led to the formation of the product (R)-2e
in 97% ee. However, as not all the enzymatic reductions
of the alkyl derivatives occurred with complete selectivity,
and in order to compare the selectivity factor(s) in the
application of these catalysts to chemical asymmetric pro-
cesses,24 we decided to use those obtained through the
lipase-catalyzed transesterification of the corresponding
alcohols, that were previously isolated enantiomerically
pure.21 It is also noteworthy that the alkyl catalysts 8a–d
have an (S)-configuration and the benzyl derivative 8e
has (R)-configuration, which explains the opposite configu-
ration of substrates and products obtained in the chemical
alkoxycarbonylation depending upon the catalyst used in
the reaction.
Ph
O
H
8
.
7
6
8
.
7
2
8
.
6
8
8
.
6
4
8
.
6
0
8
.
5
6
8
.
5
2
8
.
4
8
8
.
4
4
8
.
4
0
8
.
3
6
8
.
3
2
8
.
2
8
8
.
2
4
(ppm
)
Figure 1. Structure of (R)-MTPA esters derivatives of 2e.
The reason for these spectra is that the hydrogen atom at
the 2-position of the pyridine ring is not shielded by the
phenyl group of the Mosher’s reagent. The same stereo-
chemistry was assigned for the alcohol obtained in the bio-
reduction, as the same order of peaks was observed in the
1H NMR spectrum.
In spite of the good results obtained in the bioreduction of
pyridine ketones using Baker’s yeast, we explored the use
of other oxidoreductases such as alcohol dehydrogenases
from Thermoanaerobacter species (T-ADH) or from Lacto-
bacillus brevis (LB-ADH) that present complementary
enantiopreferences; T-ADH catalyses the enantioselective
reduction of prochiral ketones to (S)-alcohols meanwhile
LB-ADH allow the production of (R)-alcohols. Although
To apply these synthons to catalytic asymmetric processes,
protection of the oxygen of the hydroxyl group was

1010
E. Busto et al. / Tetrahedron: Asymmetry 17 (2006) 1007–1016
Table 4. Nonenzymatic kinetic resolution of 1-phenylethanol at room
temperature during 60 h
required in order to avoid the formation of reaction
by-products during the development of the asymmetric
processes. For this process, potassium hydride was used
as a base and methyl iodide as the electrophilic agent
(Scheme 3), obtaining the O-methylated compounds (S)-
8a–d and (R)-8e in good yields (70–76%). No racemization
occurred in these nucleophilic substitution steps as (R)-7e
and (R)-8e were injected in an HPLC and compared with
the corresponding racemates.
b
Entry
R1
R2
ca (%)
eesb (%)
eep (%)
sc
1
2
3
4
5
6
Me
Et
Pr
Bu
Ph
Me
Me
Me
Me
Me
Me
Bu
32
34
37
34
50
36
28
34
43
38
46
36
60
65
73
75
46
65
5.5
6.5
9.6
10.1
4.2
6.7
a c = ees/(ees + eep).
b Calculated by chiral HPLC.
c s = ln[(1 ꢀ c) · (1 ꢀ eep)]/ln[(1 ꢀ c) · (1 + eep)].
NMe2
NMe2
1. KH, THF, -78 ºC
R
R
2. MeI, 18-crown-6, THF, -60 ºC
N
N
times as it would be necessary. On the other hand, it is
noteworthy that the production of enantiomerically pure
1-phenylethanol is more likely through other chemical or
enzymatic procedures, however, these results are encourag-
ing for the application of these novel catalysts in other
asymmetric catalytic processes.
OH
OMe
(S)-8a-d
(R)-8e
(S)-7a-d
(R)-7e
R=Me, Et, Pr, Bu, Ph
Scheme 3. Synthesis of O-methylated derivatives (8a–e).
Vedejs et al. developed the chemical synthesis of a chiral
DMAP substituted at the 2-position of the pyridine ring
with a structure similar to that of compounds 8a–e having
a tert-butyl substituent instead of an alkyl or phenyl substi-
tutions.6a They tested the selectivity of the catalyst in the
alkoxycarbonylation of 1-phenylethanol using 2,2,2-tri-
chloro-1,1-dimethylethyl chloroformate 10 as an alkoxy-
carbonylating reagent. At this point, we decided to use
our catalysts in this model reaction with NEt3 as base
and ZnCl2 as a Lewis acid (Scheme 4).
Once the potential of chiral DMAP derivatives as nucleo-
philic catalysts had been demonstrated, we studied their
role as chiral ligands in the enantioselective addition of
diethylzinc to benzaldehyde, one of the most effective meth-
ods for the production of chiral secondary alcohols.25 Tra-
ditionally, amino alcohols are considered as excellent
ligands for the enantioselective addition of organometallic
reagents to aldehydes.26 For that reason, we decided to
examine the behavior of (S)-7a, (S)-7d, and (R)-7e (Scheme
5).
Carboxyl transfer occurred with moderate selectivities
(Table 4, s = 4.2–10.1) which increased when the alkyl
chain became longer (entries 1–4). However, the use of
8e, where the phenyl substitution is present, gave the lowest
selectivity factors (entry 5).
ZnEt2 (2eq.)
6% catalyst
H
Toluene
*
Additionally, the synthesis and later application of the O-
butyl derivative (S)-9 was performed using 1-iodobutane
in order to compare the influence of the substituent on
the oxygen atom of the catalyst. Interestingly slightly better
results were observed for the bulkier substrate in compari-
son with the O-methylated compound (entries 1 and 6).
OH
O
15
14
R1
catalyst
(S)-7a: R1=NMe2, R2=Me
(S)-7d: R1=NMe2, R2=Bu
(R)-7e: R1=NMe2, R2=Ph
(S)-16: R1=H, R2=Me
* R2
N
OH
One advantage of these catalysts is that although it is nec-
essary to use them in stoichiometric amounts, they can be
recovered at the end of the process and reused as many
Scheme 5. Enantioselective addition of ZnEt2 to benzaldehyde promoted
by chiral DMAP ligands.
OH
O
NMe2
O
NMe2
Cl3C
O
10
Cl
OH
12
O
*
O
CCl3
R1
*
+
R1
*
N
ZnCl2
Et3N
CH2Cl2
*
N
OR2
OR2
Cl3C
O
O
(S)-8a-d, R2=Me
(R)-8e, R2=Me
(S)-11a-d
(R)-11e
(S)-11f
(R)-13 with (S)-11a-d and (S)-11f
(S)-13 with (R)-11e
(S)-12 with (R)-11a-d and (R)-11f
(R)-13 with (S)-11e
(S)-9, R1=Me, R2=Bu
11a: R1=Me, R2=Me; 11b: R1=Et, R2=Me
11c: R1=Pr, R2=Me; 11d: R1=Bu, R2=Me
11e: R1=Ph, R2=Me; 11f: R1=Me, R2=Bu
Scheme 4. Stereoselective carboxylation of 1-phenylethanol catalyzed by chiral DMAP analogues.

E. Busto et al. / Tetrahedron: Asymmetry 17 (2006) 1007–1016
1011
Reactions were performed using 2 equiv of ZnEt2 and tol-
uene as solvent isolating 1-phenylpropan-1-ol in 100% con-
version and with moderate ee (Table 5), which overcome
the ee observed when no substitution was present at the
4-position of the pyridine ring (entry 4) in comparison with
(S)-7a (33%).27
300.13 MHz and 13C, 75.5 MHz), AV-400 (1H, 400.13
MHz and 13C, 100.6 MHz) or AV-600 (1H, 600.15 MHz
and 13C, 150.9 MHz) spectrometers. The chemical shifts
are given in delta (d) values and the coupling constants
(J) in hertz (Hz). ESI+ using a HP1100 chromatograph
mass detector, or EI+ with a Finigan MAT 95 spectrometer
were used to record mass spectra (MS). Microanalyses
were performed on a Perkin–Elmer model 2400 instrument.
Measurement of the optical rotation was done in a Perkin–
Elmer 241 polarimeter.
Table 5. Use of chiral DMAP derivatives in the enantioselective addition
of ZnEt2 to benzaldehyde
Entry
Chiral ligand
Yield (%)
eea (%)
Conf. (15)
4.1.1. 4-Chloro-2-cyanopyridine 1. The preparation of 1
was carried out according to the procedure reported before
from 4-chloropyridine N-oxide in 85% yield.21
1
2
3
4
(S)-7a
(S)-7d
(R)-7e
(S)-16
80
79
83
75
33
31
35
27
S
S
R
S
a Calculated by chiral HPLC.
4.1.2. 4-Chloro-[2-(1-hydroxybenzyl)]pyridine] 2e. To a
phenylmagnesium bromide 3.0 M solution in Et2O
(4.81 mL, 14.43 mmol) at 0 ꢁC and under a nitrogen atmo-
sphere, a solution of 4-chloro-2-cyanopyridine (500 mg,
3.61 mmol) in dry Et2O (13 mL) was added. Once the addi-
tion was complete, the mixture was stirred at room temper-
ature for 4 h, after which the solution was added to a
saturated ammonium chloride solution at 0 ꢁC (20 mL),
adding HCl concd until pH = 1. The resulting mixture
was stirred at room temperature for an additional 14 h.
The solution was neutralized with NH3 aq and extracted
with Et2O (3 · 50 mL). The solvent was evaporated by dis-
tillation under reduced pressure obtaining 2-benzoyl-4-
chloropyridine which was used for the next step without
further purification. This resulting crude was dissolved in
MeOH (60 mL) and cooled at 0 ꢁC, moment when NaBH4
(683 mg, 18.04 mmol) was added in small portions. The
clear solution was stirred for 2 h at room temperature, after
which MeOH was evaporated and the resulting white solid
dissolved in water and extracted with CH2Cl2 (3 · 5 mL).
The organic phases were combined, dried over Na2SO4
and evaporated at reduced pressure. The crude of the
reaction mixture was purified by flash chromatography
(30–40% EtOAc/hexane) yielding 597 mg of a white
solid (75%). Rf (40% EtOAc/hexane): 0.32; IR (KBr): m
3204, 3063, 2894, 1654, 1637, 1579, 1556, 1456, 1437,
3. Conclusions
In conclusion, a new family of chiral catalysts derived from
DMAP has been obtained through a straightforward
chemoenzymatic synthesis where the stereoselective reduc-
tion of a broad range of ketones has been achieved with
high enantiomeric excesses using Baker’s yeast as the bio-
catalyst. Moreover, the corresponding analogues have
shown some degree of enantiopreference as nucleophilic
catalysts in the nonenzymatic kinetic resolution of 1-phenyl-
ethanol, while their use as chiral ligands in the addition of
diethylzinc to benzaldehyde has also been demonstrated.
4. Experimental
4.1. General
C. antarctica lipase type B (CAL-B, Novozyme 435, 7300
PLU/g) was a gift from Novo Nordisk Co. C. antarctica
lipase type A (CAL-A, Chirazyme L-5, c-f, lyophilized,
1000 U/g using tributyrin) was acquired from Roche. P.
cepacia lipase (PSL-C, 783 U/g) was obtained from Amano
Pharmaceutical Co. Baker’s yeast (type II from S. cerevi-
siae) was purchased from Sigma. Alcohol dehydrogenases
T. species (T-ADH, 378 U/mL) and L. brevis (LB-ADH,
1388, 1311, 1216, 1095, 1056, 898, 824, 741 cmꢀ1
;
1H
3
NMR (CDCl3, 400.13 MHz): d 4.97 (d, JHH = 4.0 Hz,
3
1H, OH), 5.73 (d, JHH = 4.0 Hz, 1H, H7), 7.22–7.37
(m, 7H, H3+H5+2H9+2H10+H11), 8.44 (d, 3JHH = 5.4 Hz,
1H, H6); 13C NMR (CDCl3, 100.6 MHz): d 75.1 (C7),
121.6 (C3), 123.0 (C5), 127.0 (2C9), 128.2 (C11), 128.8
(2C10), 142.4 (C8), 145.0 (C4), 148.9 (C6), 163.0 (C2); MS
(EI+, m/z): 221 [(M37Cl)+, 33%], 220 [(M37ClꢀH)+, 18%],
219 [(M35Cl)+, 100%] 218 [(M35ClꢀH)+, 53%], 184 [(Mꢀ
Cl)+, 7%], 144 [(M37ClꢀPh)+, 20%], 142 [(M35ClꢀPh)+,
67%]. Anal. Calcd (%) for C12H10NOCl: C, 65.61; H,
4.59; N, 6.38. Found: C, 65.6; H, 4.5; N, 6.4.
1300 U/mL) were obtained from Julich Fine Chemicals.
¨
Chemical reagents were commercialized by Aldrich, Fluka
or Lancaster. Solvents were distilled over an appropriate
desiccant under nitrogen. Flash chromatographies were
performed using silica gel 60 (230–240 mesh). High perfor-
mance liquid chromatography (HPLC) analyses were car-
ried out in a Hewlett–Packard 1100 chromatograph UV
detector at 210 nm using a Daicel CHIRALCEL OD or
OB-H column (25 cm · 4.6 mm I.D.) varying the condi-
tions depending on the specific substrate. Melting points
were taken on samples in open capillary tubes and are
uncorrected. IR spectra were recorded using NaCl plates
or KBr pellets in a Perkin–Elmer 1720-X F7. 1H, 13C
NMR, DEPT, 1H–1H homonuclear experiments, and
1H–13C heteronuclear experiments were obtained using
AC-200 (1H, 200.13 MHz and 13C, 50.3 MHz), AC-300
(1H, 300.13 MHz and 13C, 75.5 MHz), DPX 300 (1H,
4.1.3. Enzymatic resolution of 4-chloro-[2-(1-hydroxybenz-
yl)]pyridine] 2e. A suspension of compound 2e (55 mg,
0.25 mmol) and PSL-C (40 mg) in vinyl acetate (2.5 mL,
27.1 mmol) under a nitrogen atmosphere was shaken at
250 rpm and 60 ꢁC taking regularly aliquots that were ana-
lyzed by HPLC. Reaction was stopped when the reaction
reached 42% conversion, the enzyme was filtered and
washed with CH2Cl2 (3 · 10 mL). Solvent was evaporated

1012
E. Busto et al. / Tetrahedron: Asymmetry 17 (2006) 1007–1016
under reduced pressure obtaining a crude that was purified
by flash chromatography (5–20% EtOAc/CH2Cl2) afford-
[(M35Cl+H)+, 38%]. Anal. Calcd (%) for C7H6NOCl: C,
54.04; H, 3.89; N, 9.00. Found: 54.0; H, 3.9; N, 8.9.
20
ing (S)-(+)-2e [91% isolated yield and 59% ee, ½aꢁD
¼
þ22:3 (c 2, CHCl3)], and (R)-(ꢀ)-4e {94% isolated yield
4.1.6. 4-Chloro-2-propanoylpyridine 6b. Same procedure
as that used for 6a, using ethylmagnesium bromide instead
of methylmagnesium iodide. Colorless oil (81% isolated
yield). Rf (10% EtOAc/hexane): 0.31; IR (NaCl): m 2979,
20
and 82% ee, ½aꢁD ¼ ꢀ60:3 (c 2, CHCl3)}. (R)-(ꢀ)-1-
(4-Chloro-2-pyridinyl)benzyl acetate 4e. White solid; Rf
(15% EtOAc/hexane): 0.26. Mp: 56–58 ꢁC; IR (KBr): m
2969, 2364, 2344, 1752, 1577, 1558, 1392, 1373, 1220,
1
2361, 1704, 1571, 1555, 1581, 1461, 1400, 1225 cmꢀ1; H
1028, 826 cmꢀ1; H NMR (CDCl3, 400.13 MHz): d 2.21
NMR (CDCl3, 400.13 MHz): d 1.22 (t, JHH = 7.2 Hz,
1
3
3
3
(s, 3H, H13), 6.80 (s, 1H, H7), 7.19 (dd, JHH = 5.1,
3H, H9), 3.22 (q, JHH = 7.2 Hz, 2H, H8), 7.47 (dd,
4JHH = 2.0 Hz, 1H, H5), 7.30–7.44 (m, 6H, H3+2H9+
3JHH = 5.2, JHH = 2.0 Hz, 1H, H5), 8.03 (d, JHH
=
4
4
2H10+H11), 8.47 (d, JHH = 5.1 Hz 1H, H6); 13C NMR
2.0 Hz, 1H, H3), 8.57 (d, JHH = 5.2 Hz, 1H, H6); 13C
NMR (CDCl3, 100.6 MHz): d 7.8 (C9), 31.4 (C8), 122.2
(C3), 127.0 (C5), 145.4 (C4), 150.0 (C6), 154.6 (C2), 201.3
(C7); MS (ESI+, m/z): 194 [(M37Cl+Na)+, 25%], 192
[(M35Cl+Na)+, 95%], 172 [(M37Cl+H)+ 30%], 170
[(M35Cl+H)+ 100%]. Anal. Calcd (%) for C8H8NOCl: C,
56.65; H, 4.75; N, 8.26. Found: C, 56.7; H, 4.7; N, 8.2.
3
3
(CDCl3, 100.6 MHz): d 21.2 (C13), 77.4 (C7), 121.2 (C3),
123.0 (C5), 127.4 (2C9), 128.5 (C11), 128.7 (2C10), 138.4
(C8), 144.9 (C4), 150.4 (C6), 161.0 (C2), 170.0 (C12); MS
(ESI+, m/z): 286 [(M37Cl+Na)+, 32%], 284 [(M35Cl+Na)+,
100%], 262 [(M35Cl+H)+, 13%]. Anal. Calcd (%)
for C14H12NO2Cl: C, 68.44; H, 4.92; N, 5.70. Found: C,
68.6; H, 4.7; N, 5.9.
4.1.7. 2-Butanoyl-4-chloropyridine 6c. Same procedure as
that used for 6a, using propylmagnesium bromide instead
of methylmagnesium iodide. Colorless oil (79% isolated
yield). Rf (10% EtOAc/hexane): 0.33; IR (NaCl): m 2963,
4.1.4. 2-Cyano-4-(N,N-dimethylamino)pyridine 5. A mix-
ture of 1 (200 mg, 1.44 mmol) and a 40% aqueous solution
of Me2NH (1.78 mL) were stirred in a sealed tube at 100 ꢁC
until complete consumption of the starting material (20 h).
The solvent was evaporated by distillation at reduced pres-
sure and the resulting crude purified by flash chromatogra-
phy (10% MeOH/EtOAc) yielding 150 mg of a white solid
(71%). Rf (10% MeOH/EtOAc): 0.23. Mp: 190 ꢁC (decom-
position); IR (KBr) m 1700, 1664, 1609, 1541, 1508, 1463,
1
2935, 2361, 1701, 1570, 1555, 1340, 1217 cmꢀ1; H NMR
(CDCl3, 300.13 MHz): d 0.95 (t,3JHH = 7.4 Hz, 3H, H10),
3
1.71–1.96 (m, 2H, H9), 3.12 (t, JHH = 7.4 Hz, 2H, H8),
3
4
7.41 (dd, JHH = 5.1, JHH = 2.0 Hz, 1H, H5), 7.96 (d,
4JHH = 2.0 Hz, 1H, H3), 8.52 (d, 1H, JHH = 5.1, 1H,
3
H6); 13C NMR (CDCl3, 100.6 MHz): d 13.7 (C10), 17.2
(C9), 39.6 (C8), 122.1 (C3), 126.9 (C5), 145.3 (C4), 149.7
(C6), 154.6 (C2), 200.7 (C7); MS (ESI+, m/z): 186
[(M37Cl+H)+, 32%], 184 [(M35Cl+H)+, 100%]. Anal. Calcd
(%) for C9H10NOCl: C, 58.87; H, 5.49 N, 7.63. Found: C,
58.7; H, 5.5; N, 7.6.
1383, 1225, 1066, 1000, 870, 814, 789 cmꢀ1 1H NMR
;
(CDCl3, 300.13 MHz): d 3.03 (s, 6H, H7), 6.54 (dd,
4
4
3JHH = 5.7, JHH = 2.8 Hz, 1H, H5), 7.44 (d, JHH
=
2.8 Hz, 1H, H3), 8.14 (d, JHH = 5.7 Hz, 1H, H6); 13C
NMR (CDCl3, 100.6 MHz): d 39.1 (2C7), 105.2 (C3),
108.2 (C5), 148.3 (C6), 149.6 (C2), 155.1 (C4), 167.9 (CN);
MS (ESI+, m/z): [(M+H2O+H)+, 100%]. Anal. Calcd (%)
for C8H9N3: C, 65.29; H, 6.16; N, 28.55. Found: C, 65.3;
H, 6.2; N, 28.6.
3
4.1.8. 4-Chloro-2-pentanoylpyridine 6d. Same procedure
as that used for 6a, using butylmagnesium chloride instead
of methylmagnesium iodide. Colorless oil (85% isolated
yield). Rf (10% EtOAc/hexane): 0.34; IR (NaCl): m 3318,
4.1.5. 2-Acetyl-4-chloropyridine 6a. Over a methylmagne-
sium iodide 3.0 M solution in Et2O (9.64 mL, 28.94 mmol)
at 0 ꢁC and under a nitrogen atmosphere, a solution of 1
(1.00 g, 7.24 mmol) in dry Et2O (20 mL) was added. Once
the addition was complete, the mixture was stirred at room
temperature for 4 h, after which time the solution was
poured onto a saturated ammonium chloride solution at
0 ꢁC (23.9 mL) adding HCl concd until pH = 1. The result-
ing mixture was stirred at room temperature for an addi-
tional 14 h. The solution was neutralized with NH3 aq
and extracted with Et2O (3 · 100 mL). The organic phases
were dried over Na2SO4 and the solvent evaporated by dis-
tillation at reduced pressure and the resulting crude puri-
fied by flash chromatography (20% EtOAc/hexane)
yielding 987 mg of a colorless oil (87%). Rf (20% EtOAc/
hexane): 0.36; IR (NaCl): m 3445, 1701, 1570, 1554, 1398,
2957, 2932, 2881, 1581, 1557, 1467, 1557, 1392, 826 cmꢀ1
;
3
1H NMR (CDCl3, 300.13 MHz): 0.95 (t, JHH = 7.1 Hz,
3H, H11), 1.24–1.31 (m, 2H, H10), 1.54–1.59 (m, 2H, H9)
3
3
3.05 (t, JHH = 7.1 Hz, 2H, H8), 7.33 (dd, JHH = 5.4,
4JHH = 2.0 Hz, 1H, H5), 7.85 (d, JHH = 2.0 Hz, 1H, H3),
4
8.44 (d, 1H, JHH = 5.4, 1H, H6); 13C NMR (CDCl3,
3
75.5 MHz): d 13.5 (C11), 22.0 (C10), 25.5 (C9), 37.0 (C8),
121.5 (C3), 126.4 (C5), 144.8 (C4), 149.4 (C6), 154.2 (C2),
200.0 (C7); MS (ESI+, m/z): 222 [(M37Cl+Na)+, 11%],
220 [(M35Cl+Na)+, 60%], 200 [(M37Cl+H)+, 35%], 198
[(M35Cl+H)+, 100%]. Anal. Calcd (%) for C10H12NOCl:
C, 60.76; H, 6.12; N, 7.09. Found: C, 60.9; H, 6.3; N, 7.2.
4.1.9. 2-Benzoyl-4-chloropyridine 6e. Same procedure as
that used for 6a, using phenylmagnesium bromide instead
of methylmagnesium iodide. White solid (75% isolated
yield). Rf (10% Et2O/hexane): 0.28. Mp: 82–84 ꢁC; IR
(KBr): m 1654, 1596, 1570, 1553, 1452, 1394, 1322, 1283,
1353, 1281, 1258, 1235 cmꢀ1
;
1H NMR (CDCl3,
3
300.13 MHz): d 2.71 (s, 3H, H8), 7.47 (dd, JHH = 5.2,
4
1
4JHH = 2.1 Hz, 1H, H5), 8.03 (d, JHH = 2.1 Hz, 1H, H3),
1162, 1216, 1095 cmꢀ1; H NMR (CDCl3, 400.13 MHz):
3
8.58 (d, JHH = 5.2, 1H, H6); 13C NMR (CDCl3,
d 7.42–7.68 (m, 4H, 2H10+H11+H5), 8.05–8.10 (m, 3H,
3
75.5 MHz): d 25.6 (C8), 122.1 (C3), 127.1 (C5), 145.4 (C4),
149.9 (C6), 154.7 (C2), 198.8 (C7); MS (ESI+, m/z): 180
[(M37Cl+Na)+, 20%], 178 [(M35Cl+Na)+, 70%], 156
H3+2H9), 8.63 (d, JHH = 5.0 Hz, 1H, H6); 13C NMR
(CDCl3, 100.6 MHz): d 125.1 (C3), 126.3 (C5), 128.3
(C10), 131.0 (C9), 133.3 (C11), 135.8 (C8), 145.5 (C4),

E. Busto et al. / Tetrahedron: Asymmetry 17 (2006) 1007–1016
1013
149.5 (C6), 156.3 (C2), 192.5 (C7); MS (ESI+, m/z): 242
[(M37Cl+Na)+, 33%], 240 [(M35Cl+Na)+, 100%], 218
[(M35Cl+H)+, 20%]. Anal. Calcd (%) for C12H8NOCl: C,
66.22; H, 3.70; N, 6.44. Found: C, 66.2; H, 3.8; N, 6.4.
4.1.16. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-(1-hydroxyethyl)-
pyridine 7a by bioreduction with Baker’s yeast. Same pro-
cedure as that of (S)-2a, using 6f as starting material
instead of 6a (see Table 2). White solid (40% isolated yield
and 98% ee). Spectroscopic data are in accordance with the
ones previously described in the literature.21
4.1.10. 2-Acetyl-4-(N,N-dimethylamino)pyridine 6f.
A
mixture of 6a (100 mg, 0.64 mmol) and a 40% aqueous
solution of Me2NH (700 lL) were stirred in a sealed tube
at 100 ꢁC until complete consumption of the starting mate-
rial (24 h). The solvent was evaporated by distillation at
reduced pressure and the resulting crude purified by flash
chromatography (20–40% MeOH/EtOAc) yielding 60 mg
of a colorless oil (53%). Rf (20% MeOH/EtOAc): 0.30;
IR (NaCl): m 1700, 1570, 1558, 1458, 1400, 1304,
4.1.17. Typical procedure for the bioreduction of ketones
using alcohol dehydrogenases. The corresponding ketone
6a–e (0.32 mmol) was dissolved in 2-propanol (0.54 mL)
and a TRIS/HCl buffer solution of pH 7 (2.56 mL) was
added. Finally NADP (0.56 mg, 6.4 · 10ꢀ4 mmol) and
T-ADH (16 U, 44 lL) or LB-ADH (16 U, 12 lL) were
added. The resulting mixture was shaken at 30 ꢁC for the
required time. The reaction was extracted with CH2Cl2
(3 · 15 mL) and the organic phases combined. The solvent
was then distilled under reduced pressure. The reaction
crude was purified by flash chromatography (20–80%
EtOAc/hexane) yielding alcohols 2a–b or ketones 6c–e
(see Table 3).
1217 cmꢀ1
;
1H NMR (CDCl3, 200.13 MHz): d 2.70 (s,
3
3H, H8), 3.06 (s, 6H, H9), 6.63 (dd, JHH = 6.3,
4JHH = 3.1 Hz, 1H, H5), 7.30 (d, JHH = 3.1 Hz, 1H, H3),
4
3
8.30 (d, JHH = 6.3 Hz, 1H, H6); 13C NMR (CDCl3,
75.5 MHz): d 25.9 (C8), 39.0 (2C9), 104.3 (C3), 109.0 (C5),
148.9 (C6), 153.6 (C4), 154.6 (C2), 201.0 (C7); MS (ESI+,
m/z): 165 [(M+H)+, 100%]. Anal. Calcd for C9H12N2O:
C, 65.83; H, 7.37; N, 17.06. Found: C, 65.8; H, 7.4; N, 17.0.
4.1.18. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-(1-hydroxyethyl)-
pyridine 7a by chloro substitution. The preparation of 7a
was carried out according to the procedure reported be-
fore, from (S)-(ꢀ)-4-chloro-2-(1-hydroxyethyl)pyridine.21
4.1.11. (S)-(ꢀ)-4-Chloro-2-(1-hydroxyethyl)pyridine 2a.
A
suspension of 6a (500 mg, 3.21 mmol) and Baker’s yeast
(25 g) in 210 mL of an aqueous solution of glucose
(25 mg/mL) was shaken at 30 ꢁC and 250 rpm. Aliquots
were regularly analyzed by TLC, until complete consump-
tion of the starting material (60 h). After that time, the
mixture was centrifuged to separate the yeast, and the solu-
tion extracted with CH2Cl2 (3 · 100 mL). The organic
phases were combined and dried over Na2SO4 and the sol-
vent distilled under a reduced pressure to obtain a crude
mixture, which was purified by flash chromatography
(60–80% EtOAc/hexane) to yield 383 mg of (S)-2a (76%)
with 98% ee as a white solid. Spectroscopic data are in
accordance with the ones previously described in the
literature.21
4.1.19. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-(1-hydroxypropyl)-
pyridine 7b. The preparation of 7b was carried out
according to the procedure reported before from (S)-(ꢀ)-
4-chloro-2-(1-hydroxypropyl)pyridine.21
4.1.20. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-(1-hydroxybutyl)-
pyridine 7c. The preparation of 7c was carried out accord-
ing to the procedure reported before from (S)-(ꢀ)-4-
chloro-2-(1-hydroxybutyl)pyridine.21
4.1.21. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-(1-hydroxypentyl)-
pyridine 7d. The preparation of 7d was carried out
according to the procedure reported before from (S)-(ꢀ)-
4-chloro-2-(1-hydroxypentyl)pyridine.21
4.1.12. (S)-(ꢀ)-4-Chloro-2-(1-hydroxypropyl)pyridine 2b.
Same procedure as that of (S)-2a, using 6b as starting mate-
rial instead of 6a (see Table 2). Colorless oil (71% isolated
yield and 91% ee). Spectroscopic data are in accordance
with the ones previously described in the literature.21
4.1.22. (R)-(ꢀ)-4-(N,N-Dimethylamino)-2-(1-hydroxybenzyl)-
pyridine 7e. Same procedure as that of (ꢀ)-7a, using (ꢀ)-
2e as starting material (24 h). Colorless oil (91% isolated
yield). Rf (100% MeOH): 0.28; IR (NaCl): m 3343, 2927,
4.1.13. (S)-(ꢀ)-4-Chloro-2-(1-hydroxybutyl)pyridine 2c.
Same procedure as that of (S)-2a, using 6c as starting mate-
rial instead of 6a (see Table 2). Colorless oil (73% isolated
yield and 81% ee). Spectroscopic data are in accordance
with the ones previously described in the literature.21
1602, 1543, 1513, 1436, 1378, 1255, 966, 909, 732 cmꢀ1
;
1H NMR (CDCl3, 200.13 MHz): d 2.93 (s, 6H, H12), 5.34
(br s, 1H, OH), 5.66 (s, 1H, H7), 6.34–6.43 (m, 2H,
H3+H5), 7.29–7.45 (m, 5H, 2H9+2H10+H11), and 8.15 (d,
3JHH = 5.5 Hz, 1H, H6); 13C NMR (CDCl3, 75.5 MHz): d
39.0 (2C12), 74.8 (C7), 103.2 (C3), 105.7 (C5), 126.8 (C10),
127.3 (C11), 128.2 (C9), 143.7 (C8), 147.3 (C6), 154.8 (C4),
and 160.9 (C2); MS (ESI+, m/z): 229 [(M+H)+, 100%].
Anal. Calcd (%) for C14H16N2O: C, 73.66; H, 7.06; N,
12.27. Found: C, 73.6; H, 7.1; N; 12.3.
4.1.14. (S)-(ꢀ)-4-Chloro-2-(1-hydroxypentyl)pyridine 2d.
Same procedure as that of (S)-2a, using 6d as starting mate-
rial instead of 6a (see Table 2). Colorless oil (72% isolated
yield and 80% ee). Spectroscopic data are in accordance
with the ones previously described in the literature.21
4.1.23. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-[(1-methoxyethyl)-
pyridine] 8a. To a solution under a nitrogen atmosphere
of (S)-7a (100 mg, 0.60 mmol) in dry THF (10 mL) at
ꢀ78 ꢁC was added a 30% dispersion of KH in mineral oil
(100 mg, 0.75 mmol). The resulting suspension was stirred
at ꢀ60 ꢁC for 2 h, after which time the mixture was cooled
4.1.15. (R)-(ꢀ)-4-Chloro-2-(1-hydroxybenzyl)pyridine 2e.
Same procedure as that of (S)-2a, using 6e as starting mate-
rial instead of 6a (see Table 2). White solid (84% isolated
yield and 97% ee). Rf (5% EtOAc/CH2Cl2): 0.19;
20
½aꢁD ¼ ꢀ43:4 (c 2, CHCl3).

1014
E. Busto et al. / Tetrahedron: Asymmetry 17 (2006) 1007–1016
3
to ꢀ78 ꢁC, adding successively 18–6 crown ether (155 mg,
0.59 mmol) and MeI (47 lL, 0.75 mmol). The mixture
was stirred at ꢀ60 ꢁC for 3 h. The reaction was stopped
by adding 4 mL of H2O and 1 mL of a NaOH (4 M) solu-
tion and extracted with CH2Cl2 (3 · 10 mL). The organic
phases were combined and dried over Na2SO4, and the sol-
vent evaporated under reduced pressure affording a crude
mixture, which was purified by flash chromatography
H8), 3.00 (s, 6H, H13), 3.30 (s, 3H, H12), 4.14 (t, JHH =
3
4
6.5 Hz, 1H, H7), 6.39 (dd, JHH = 6.0, JHH = 2.5 Hz, 1H,
4
3
H5), 6.58 (d, JHH = 2.5 Hz, 1H, H3), 8.15 (d, JHH
=
6.0 Hz, 1H, H6); 13C NMR (CDCl3, 75.5 MHz): d 13.8
(C11), 22.5 (C10), 27.8 (C9), 36.7 (C8), 39.0 (2C13), 57.0
(C12), 85.2 (C7), 102.2 (C3), 105.3 (C5), 148.8 (C6), 154.9
(C4), 162.2 (C2); MS (ESI+, m/z): 223 [(M+H)+, 100%].
Anal. Calcd (%) for C13H22N2O: C, 70.23; H, 9.97; N,
12.60. Found: C, 69.9; H, 9.9; N, 12.5.
(100% hexane–20% MeOH/EtOAc) affording 81 mg of a
20
colorless oil (75%). Rf (80% EtOAc/MeOH): 0.19; ½aꢁD
¼
ꢀ100:2 (c 2.1, CHCl3); IR (NaCl): m 2931, 2630, 2342,
4.1.27. (R)-(ꢀ)-4-(N,N-Dimethylamino)-2-[(1-methoxybenz-
yl)pyridine] 8e. Same procedure as that of (ꢀ)-8a, using
1605, 1545, 1378, 1225, 994 cmꢀ1
;
1H NMR (CDCl3,
3
300.13 MHz): d 1.46 (d, JHH = 6.7 Hz, 3H, H8), 3.03 (s,
6H, H10), 3.34 (s, 3H, H9), 4.33 (q, JHH = 6.7 Hz, 1H,
H7), 6.41 (dd, JHH = 5.9, JHH = 2.0 Hz, 1H, H5), 6.61
(ꢀ)-7e as starting material. Colorless oil (73%). Rf (20%
20
3
MeOH/EtOAc): 0.34; ½aꢁD ¼ ꢀ62:9 (c 1.5, CHCl3); IR
3
4
(NaCl) m 2932, 1604, 1542, 1513, 1452, 1378, 1094,
4
3
(d, JHH = 2.0 Hz, 1H, H3), 8.18 (d, JHH = 5.9 Hz, 1H,
H6); 13C NMR (CDCl3, 75.5 MHz): d 22.4 (C8), 39.1
(2C10), 56.8 (C9), 80.9 (C7), 101.8 (C3), 105.4 (C5), 148.8
(C6), 155.1 (C4), 162.9 (C2); MS (ESI+, m/z): 181
[(M+H)+, 100%]. Anal. Calcd (%) for C10H16N2O: C,
66.64; H, 8.95; N, 15.55. Found: C, 66.7; H, 9.0; N, 15.7.
1007 cmꢀ1 1H NMR (CDCl3, 300.13 MHz): d 2.98 (s,
;
6H, H13), 3.43 (s, 3H, H12), 5.27 (s, 1H, H7), 6.36 (dd,
4
4
3JHH = 6.0, JHH = 2.3 Hz, 1H, H5), 6.72 (d, JHH
=
2.3 Hz, 1H, H3), 7.22–7.45 (m, 5H, 2H9+2H10+H11), 8.14
(d, JHH = 6.0 Hz, 1H, H6); 13C NMR (CDCl3,
3
75.5 MHz): d 39.0 (2C13), 57.1 (C12), 86.6 (C7), 102.7
(C3), 105.4 (C5), 126.8 (2C10), 127.4 (C11), 128.2 (2C9)
141.2 (C8), 149.0 (C6), 155.0 (C4), 161.2 (C2); MS (ESI+,
m/z): 265 [(M+Na)+, 3%], 243 [(M+H)+, 100%]. Anal.
Calcd (%) for C15H18N2O: C, 74.35; H, 7.49; N, 11.56.
Found: C, 74.3; H, 7.5; N; 11.5.
4.1.24. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-[(1-methoxypropyl)-
pyridine] 8b. Same procedure as that of (ꢀ)-8a, using (ꢀ)-
7b as starting material. Colorless oil (79%). Rf (20%
20
MeOH/EtOAc): 0.21; ½aꢁD ¼ ꢀ80:6 (c 1.1, CHCl3); IR
(NaCl) m 2996, 2932, 2361, 1603, 1545, 1509, 1376, 1223,
1
1127, 1092, 998 cmꢀ1; H NMR (CDCl3, 300.13 MHz): d
4.1.28. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-[(1-butoxyethyl)-
pyridine] 9. Same procedure as that of (ꢀ)-9a, using 1-
3
0.91 (t, JHH = 7.0 Hz, 3H, H9), 1.69–1.83 (m, 2H, H8),
3
3.00 (s, 6H, H11), 3.30 (s, 3H, H10), 4.07 (t, JHH = 7.0 Hz,
iodobutane instead of methyl iodide. Colorless oil (68%).
20
1H, H7), 6.38 (dd,3JHH = 5.9,4JHH = 2.7 Hz, 1H, H5), 6.58
(d,4JHH = 2.7 Hz, 1H, H3), 8.15 (d,3JHH = 5.9 Hz, 1H, H6);
13C NMR (CDCl3, 75.5 MHz): d 10.0 (C9), 29.7 (C8), 39.0
(2C11), 57.0 (C10), 86.5 (C7), 102.5 (C3), 105.4 (C5), 148.9
(C6), 154.9 (C4), 161.9 (C2); MS (ESI+, m/z): 195
[(M+H)+, 100%]. Anal. Calcd (%) for C11H18N2O: C,
68.01; H, 9.34; N, 14.42. Found: C, 68.0; H, 9.2; N, 14.5.
Rf (80% MeOH/EtOAc): 0.18; ½aꢁD ¼ ꢀ107:3 (c, 2.5,
CHCl3); IR (NaCl): m 3376, 2958, 2871, 1602, 1543, 1509,
1375, 1224, 1224, 1102, 993 cmꢀ1 1H NMR (CDCl3,
;
300.13 MHz): d 0.89 (m, 3H, H12), 1.33–1.67 (m, 4H,
H10+H11), 1.44 (d, JHH = 6.5 Hz, 1H, H8), 3.00 (s, 6H,
H13), 3.40 (m, 3H, H9), 4.40 (q, JHH = 6.5 Hz, 1H, H7),
3
3
3
4
6.38 (dd, JHH = 6.0, JHH = 2.9 Hz, 1H, H5), 6.66 (d,
4JHH = 2.9 Hz, 1H, H3), 8.15 (d, JHH = 6.0 Hz, 1H, H6);
3
4.1.25. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-[(1-methoxybutyl)-
pyridine] 8c. Same procedure as that of (ꢀ)-8a, using
13C NMR (CDCl3, 75.5 MHz): d 13.9 (C12), 19.4 (C8),
22.8 (C11), 32.0 (C10), 39.1 (C13), 68.9 (C9), 79.3 (C7),
101.7 (C3), 105.3 (C5), 148.9 (C6), 155.0 (C4), 163.9 (C2);
MS (ESI+, m/z): 223 [(M+H)+, 100%]. Anal. Calcd (%)
for C13H22N2O: C, 70.23; H, 9.97; N, 12.60. Found: C,
70.1; H, 9.9; N, 12.6.
(ꢀ)-7c as starting material. Colorless oil (72%). Rf (20%
20
MeOH/EtOAc): 0.25; ½aꢁD ¼ ꢀ73:9 (c 1.1, CHCl3); IR
(NaCl) m 2958, 2931, 2360, 1605, 1544, 1508, 1377, 1223,
1
1091, 996 cmꢀ1; H NMR (CDCl3, 300.13 MHz): d 0.84
3
(t, JHH = 7.5 Hz, 3H, H10), 1.17–1.70 (m, 4H, H9+H8),
3
2.93 (s, 6H, H12), 3.60 (s, 3H, H114), 4.09 (t, JHH = 6.5 Hz,
4.1.29. Catalytic resolution of 1-phenylethanol 12. To a
solution of the corresponding catalyst 8a–e or 9
3
1H, H7), 6.33 (dd, JHH = 6.2, JHH = 2.7 Hz, 1H, H5),
4
3
6.53 (d, JHH = 2.7 Hz, 1H, H3), 8.09 (d, JHH = 6.2 Hz,
1H, H6); 13C NMR (CDCl3, 75.5 MHz): d 13.8 (C10),
18.8 (C9), 39.0 (C8), 39.0 (2C12), 57.0 (C11), 85.0 (C7),
102.2 (C3), 105.3 (C5), 148.8 (C6), 154.9 (C4), 162.1 (C2);
MS (ESI+, m/z): 209 [(M+H)+, 100%]. Anal. Calcd (%)
for C12H20N2O: C, 69.18; H, 9.68; N, 13.45. Found: C,
69.0; H, 9.7; N, 13.5.
(0.15 mmol) in dry CH2Cl2 (1.5 mL) at 0 ꢁC was added
ZnCl2 of a 1.0 M solution in Et2O (300 lL, 0.30 mmol),
and the mixture stirred for 10 min at room temperature.
Finally 12 (37 mg, 0.30 mmol) and NEt3 (63 lL, 0.45
mmol) were added successively. The resulting mixture
was stirred for an additional 60 h, after which CH2Cl2
was distilled out under reduced pressure and the residue
was purified by flash chromatography (5–20% EtOAc/
hexane) yielding 27 mg of 12 and 13 with different yields
and ee (see Table 4). Catalyst 8 or 9 was quantitatively
recovered by flushing with 20% MeOH/EtOAc.
4.1.26. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-[(1-methoxypentyl)-
pyridine] 8d. Same procedure as that of (ꢀ)-8a, using (ꢀ)-
7d as starting material. Colorless oil (76%). Rf (20% MeOH/
20
EtOAc): 0.28; ½aꢁD ¼ ꢀ77:5 (c 1.0, CHCl3); IR (NaCl): m
1
2931, 2871, 2360, 1602, 1545, 1507, 1376, 1093 cmꢀ1; H
4.1.30. 1,1,1-Trichloro-2-methylpropan-2-yl-1-phenylethyl
carbonate 13. Rf (5% EtOAc/hexane): 0.21. Mp: 72–
74 ꢁC; IR (KBr): m 1744, 1458, 1388, 1371, 1338, 1274,
3
NMR (CDCl3, 300.13 MHz): d 0.86 (t, JHH = 7.1 Hz,
3H, H11), 1.27–1.35 (m, 4H, H9+H10), 1.71–1.74 (m, 2H,

E. Busto et al. / Tetrahedron: Asymmetry 17 (2006) 1007–1016
1015
1212, 1163, 1055, 824, 784 cmꢀ1
200.13 MHz): d 1.64 (d, JHH = 6.7 Hz, 3H, H6), 1.90
;
1H NMR (CDCl3,
J. Am. Chem. Soc. 2003, 125, 4050–4051; (j) Fu, G. C. Acc.
Chem. Res. 2004, 37, 542–547; (k) Wilson, J. E.; Fu, G. C.
Angew. Chem., Int. Ed. 2004, 43, 6358–6360; (l) Mermerian,
A. H.; Fu, G. C. Angew. Chem., Int. Ed. 2005, 44, 949–952.
5. (a) Spivey, A. C.; Kekner, T.; Spey, S. E.; Adams, H. J. Org.
Chem. 1999, 64, 9430–9443; (b) Spivey, A. C.; Maddaford,
A.; Fekner, T.; Redgrave, A. J.; Frampton, C. S. J. Chem.
Soc., Perkin Trans. 1 2000, 3460–3468; (c) Spivey, A. C.;
Fekner, T.; Spey, S. E. J. Org. Chem. 2000, 65, 3154–3159; (d)
Spivey, A. C.; Maddaford, A.; Leese, D. P.; Redgrave, A. J.
J. Chem. Soc., Perkin Trans. 1 2001, 1785–1794; (e) Spivey, A.
C.; Zhu, F.; Mitchell, M. B.; Davey, S. G.; Jarvest, R. L. J.
Org. Chem. 2003, 68, 7379–7385; (f) Spivey, A. C.; Leese, D.
P.; Zhu, F.; Davey, S. G.; Jarvest, R. L. Tetrahedron 2004, 60,
4513–4525; (g) Spivey, A. C.; Arseniyadis, S.; Fekner, T.;
Maddaford, A.; Leese, D. P. Tetrahedron 2006, 62, 295–301.
6. (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809–
1810; (b) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119,
2584–2585.
7. (a) Jeong, K.-S.; Kim, S.-H.; Park, H.-J.; Chang, K.-J.; Kim,
K. S. Chem. Lett. 2002, 1114–1115; (b) Shaw, S. A.; Aleman,
P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368–13369; (c)
Yamada, S.; Misono, T.; Iwai, Y. Tetrahedron Lett. 2005, 46,
2239–2242; (d) Poisson, T.; Penhoat, M.; Papamicae¨l, C.;
Dupas, G.; Dalla, V.; Marsais, F.; Levacher, V.; Marsais, F.
Synlett 2005, 2285–2288; (e) Shaw, S. A.; Aleman, P.; Christy,
J.; Kampf, J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006,
128, 925–934.
3
3
(s, 3H, H9), 1.98 (s, 3H, H6), 5.75 (c, JHH = 6.7 Hz, 1H,
H5), 7.30–7.45 (m, 5H, H1+2H2+2H3); 13C NMR (CDCl3,
75.5 MHz): d 21.1 (C9), 22.5 (C6), 77.4 (C5), 89.6 (C8),
105.5 (C10), 125.7 (C3), 128.5 (C1), 128.5 (C2), 141.0 (C4),
151.8 (C7); MS (ESI+, m/z): 325 [(M+H)+, 100%]. Anal.
Calcd (%) for C13H15O3Cl3: C, 47.95; H, 4.64; Found: C,
47.9; H, 4.6.
4.1.31. Typical experimental procedure for the enantioselec-
tive addition of ZnEt2 to benzaldehyde in the presence of
chiral catalysts (S)-7a, (S)-7d, (R)-7e or (S)-16. A solution
of catalyst (0.06 mmol) in toluene (1 mL) was cooled at
0 ꢁC and stirred for 5 min under nitrogen atmosphere.
After this time, a 1 M ZnEt2 solution in hexane (2.1 mL,
2.1 mmol) was slowly added over 5 min and the resulting
mixture stirred at room temperature during 30 min. This
solution was cooled at 0 ꢁC and benzaldehyde (106 lL,
1.1 mmol) was added. The reaction mixture was stirred at
room temperature for an additional 20 h. At this time,
the reaction was quenched with HCl 1 N (4 mL) and ex-
tracted with EtOAc (3 · 15 mL). The organic phases were
combined and the solvent distillated under reduced pres-
sure. The crude was purified by flash chromatography
(20% EtOAc/hexane) to yield optically active 15 (see Table
5).
8. (a) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am.
Chem. Soc. 1997, 119, 3169–3170; (b) Kawabata, T.;
Yamamoto, K.; Momose, Y.; Yoshida, H.; Nagaoka, Y.;
Fuji, K. Chem. Commun. 2001, 2700–2701; (c) Priem, G.;
Anson, M. A.; MacDonald, S. J.; Pelotier, B.; Campbell, I. B.
Tetrahedron Lett. 2002, 43, 6001–6003; (d) Kawabata, T.;
Stragies, R.; Fukaya, T.; Fuji, K. Chirality 2003, 15, 71–76;
(e) Priem, G.; Pelotier, B.; McDonald, S. J. F.; Anson, M. S.;
Campbell, I. B. J. Org. Chem. 2003, 68, 3844–3848; (f)
Kawabata, T.; Stragies, R.; Fukaya, T.; Nagaoka, Y.;
Schedel, H.; Fuji, K. Tetrahedron Lett. 2003, 44, 1545–1548;
Acknowledgements
We thank Julich Fine Chemicals, for the generous gift of the
¨
alcohol dehydrogenases from Thermoanaerobacter species
(T-ADH) and L. brevis (LB-ADH). Financial support of
this work by the European Project EU-04-LSHB-2003-
503017 is gratefully acknowledged. V.G.-F. thanks Minis-
´
(g) Dalaigh, C. O.; Hynes, S. J.; Maher, D. J.; Connon, S. J.
´
terio de Educacion y Ciencia, for a personal Grant (Juan
´
Org. Biomol. Chem. 2005, 3, 981–984; (h) Dıez, D.; Gil, M. J.;
de la Cierva Program). E.B. thanks MEC, for a pre-doc-
toral fellowship.
Moro, R. F.; Garrido, N. M.; Marcos, I. S.; Basabe, P.; Sanz,
F.; Broughton, H. B.; Urones, J. G. Tetrahedron: Asymmetry
2005, 16, 2980–2985; (i) Pelotier, B.; Priem, G.; Macdonald,
S. J. F.; Anson, M. S.; Upton, R. J.; Cambell, I. B.
Tetrahedron Lett. 2005, 46, 9005–9007.
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