Chemoenzymatic synthesis of chiral 4-(N,N-dimethylamino)pyridine derivatives

Article abstract of DOI:10.1016/j.tetasy.2005.09.006

Chiral 4-(N,N-dimethylamino)pyridine derivatives have been prepared through a chemoenzymatic synthesis where the enzymatic kinetic resolution of a family of 4-chloro-2-(1-hydroxyalkyl)pyridines is the key step for the formation of potentially important chiral catalysts. Pseudomonas cepacia lipase (PSL) showed excellent enantioselectivity in the acylation of the (R)-enantiomers (E > 200) using vinyl acetate as acylating agent and THF as solvent, obtaining products and substrates enantiomerically pure and with excellent yields.

Full text of DOI:10.1016/j.tetasy.2005.09.006

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3427–3435
Chemoenzymatic synthesis of chiral
4-(N,N-dimethylamino)pyridine derivatives
*
´
Eduardo Busto, Vicente Gotor-Fernandez and Vicente Gotor
Departamento de Quı´mica Orga´nica e Inorga´nica, Universidad de Oviedo, 33071 Oviedo, Spain
Received 1 September 2005;accepted 8 September 2005
Available online 18 October 2005
Abstract—Chiral 4-(N,N-dimethylamino)pyridine derivatives have been prepared through a chemoenzymatic synthesis where the
enzymatic kinetic resolution of a family of 4-chloro-2-(1-hydroxyalkyl)pyridines is the key step for the formation of potentially
important chiral catalysts. Pseudomonas cepacia lipase (PSL) showed excellent enantioselectivity in the acylation of the (R)-enantio-
mers (E > 200) using vinyl acetate as acylating agent and THF as solvent, obtaining products and substrates enantiomerically pure
and with excellent yields.
ꢀ 2005 Published by Elsevier Ltd.
Me2N
1. Introduction
NMe2
N
NMe2
4-(N,N-Dimethylamino)pyridine DMAP, 1 is one of the
most versatile reagents, as it is known for its use in dif-
ferent processes such as acylation or silylation of alco-
hols and amines, for the formation of amides from
a-substituted carboxylic acids and isocyanates, transest-
erification of esters, and others.1 DMAP also has the
advantage of working under mild reaction conditions
thus avoiding, for example, racemization problems and
enhances the rate of reaction in several orders in com-
parison with the process in the absence of catalyst;
moreover, only a catalytic amount of catalyst is usually
required and can be recovered at the end of the process.
N
Fe
tBu
Me
Me
Me
Me
N
OMe
Me
DMAP 1
2
3
H
N
NEt2
N
H
Ph
N
4
5
Different examples of chiral 4-(N,N-disubstituted
amino)pyridine derivatives have been described over
the years allowing the development of enantioselective
processes (Chart 1). For example, Fu et al. introduced
the concept of Ôplanar-chiralÕ DMAP derivatives based
on the p-complexation of a heterocycle to a transition
metal, using these analogues in the enantioselective acyl-
ation of secondary alcohols and cyanosilylation of alde-
hydes.2 In addition, Vedejs et al. explored the possibility
of introducing the chirality in the DMAP-nucleus gener-
ating a 2-substituted DMAP derivative 3. The resulting
catalyst was successfully used in the enantioselective alk-
Chart 1. DMAP and other derivatives used as catalysts.
oxycarbonylation of secondary alcohols using chloro-
formates.3 Employing two chiral DMAP derivatives of
opposite stereochemistry, Vedejs and Chen introduced
the concept of a parallel kinetic resolution in order to
maximize the ee as well as the percent of conversion in
the resolution of racemic mixtures.4 The introduction
of chirality in the C-3 and C-4 position was also studied
years later achieving the formation of more reactive cat-
alysts than those substituted at the C-2 position.5
Biocatalysis is recognized as a powerful tool for the
enantioselective modification of very different chiral
building blocks under mild reaction conditions. Enzymes,
*
Corresponding author. Tel./fax: +34 985 103448;e-mail: vgs@fq.
uniovi.es
0957-4166/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.09.006

3428
E. Busto et al. / Tetrahedron: Asymmetry 16 (2005) 3427–3435
in particular lipases (E.C.3.1.1.3) have shown remark-
able chemoselectivity, regioselectivity, and enantioselec-
tivity toward a broad range of substrates over the last
few decades. In fact, the resolution of pyridyl-ethanols
was firstly achieved in 1992 by Schneider et al. by enzy-
matic hydrolysis or esterification of the corresponding
substrates using the lipase SAM II from Pseudomonas
sp.6
pyridine ring by reaction with the corresponding
organomagnesium derivative. However, there were sev-
eral difficulties in the isolation of the alkyl ketones due
to their volatility, so we decided to perform the reduc-
tion step over the crude of the reaction using NaBH4
in MeOH without further purification of the ketones.
Thus, alcohols were obtained in high isolated yields after
both steps (see Table 1).
The use of other acylating agents, exploration of the
complementary enzymatic hydrolysis reaction or the
use of other biocatalysts, has allowed an optimization
in the resolution of these interesting compounds and
other bipyridylethanols for their application in the syn-
thesis of enantiomerically pure oligopyridines.7 Also in
aqueous media, the reduction of acetylpyridines8 and
benzoylpyridines9 by asymmetric microbial reduction
using BakerÕs yeast, obtaining the corresponding enantio-
merically enriched alcohols was possible. Less studied
are the amine derivatives, which have also been success-
fully resolved using enzymatic methodologies.10 We
report herein the chemoenzymatic synthesis of a new
family of chiral catalysts based on the kinetic resolution
of 4-chloro-2-(1-hydroxyalkyl)pyridines as a key step in
the development of the analogues as that is the process
responsible of the introduction of chirality. The kinetic
resolution of these derivatives allows us to obtain cata-
lysts with potential application and with opposite ste-
reochemistry, which gives us the possibility to perform
complementary stereoselective processes.
Table 1. Transformation of 7 in different alcohols 8a–d
Entry
Product
R
X
Yield (%)a
1
2
3
4
8a
8b
8c
8d
Me
Et
Pr
I
77
76
76
74
Br
Br
Cl
Bu
a Isolated yield by flash chromatography.
Substitution of the chlorine atom for the dimethylamino
group at the 4-position of the pyridine ring was per-
formed by heating the corresponding substrate 8a–d
with a 40% aqueous solution of dimethylamine, thus
isolating the racemic potential catalysts in quantitative
yields.
Once that the synthesis of the racemic compounds was
achieved, we decided to obtain the potential catalyst in
the enantiopure form. For that reason, 9a was selected
as a model substrate and its kinetic resolution attempted
using PSL-C as biocatalyst, which has been described in
the literature as an ideal enzyme for the resolution of
pyridine derivatives.6,9 The data are summarized in
Table 2 (Scheme 2).
2. Results and discussion
4-Chloropyridine N-oxide 6 has been used for the prep-
aration of 4-chloro-2-cyanopyridine 7 as described by
Bisagni et al. by reaction with trimethylsilyl cyanide
and dimethylcarbamyl chloride affording 7 in 85% iso-
lated yield (Scheme 1).11
Table 2. Enzymatic acetylation of 9a using 3 equiv of 10 and PSL-C
Entry Solvent
T
t (h) eeP
eeS
c (%)b Ec
(ꢁC)
(%)a (%)a
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
MeCN
MeCN
MeCN
MeCN
MeCN
30
30
30
30
30
30
30
30
45
14.5
24
38
65
14.5
24
38
65
70
>99
>99
>99
>99
>99
>99
>99
95
52
69
76
71
42
46
59
62
49
34
41
43
42
30
31
37
39
38
>200
>200
>200
>200
>200
>200
>200
73
Cl
Me3SiCN
Cl
Me2NCOCl
CH2Cl2, rt
(85%)
N
O
+
-
N
CN
81
15
6
7
a Calculated by HPLC.
1) RMgX, Et2O
b c = eeS/(eeS + eep).
2) NaBH4, MeOH
0oC to rt
NH4Cl, HCl
c E = ln[(1 ꢀ c) · (1 ꢀ eeP)]/ln[(1 ꢀ c) · (1 + eeP)].
0 oC to rt
PSL-C showed an excellent selectivity toward the forma-
tion of acetate (+)-11a in 99% ee when the reaction was
carried out with 3 equiv of vinyl acetate at 30 ꢁC on
THF. This process was monitored by HPLC observing
34% conversion after 14.5 h (entry 1). Longer reaction
times gave higher yields without reached half conversion
in the first 65 h of the process, when a drop in the ee of
9a was observed. However (+)-11a was always detected
enantiomerically pure (entries 2–4).
NMe2
N
Cl
N
Me2NH
100 oC
R
R
OH
9a-d
OH
8a-d
R= Me, Et, Pr, Bu
Scheme 1. Chemical synthesis of DMAP derivatives.
The introduction of the cyano functionality allowed us
to synthesize different ketones at the 2-position of the
Using a more polar solvent as acetonitrile, low reactivity
was observed in comparison with THF but also with

E. Busto et al. / Tetrahedron: Asymmetry 16 (2005) 3427–3435
3429
NMe2
N
yields. This result overcomes the problems, which
appeared in the enzymatic resolution of 9a.
Different biocatalysts were used in the enzymatic trans-
esterification using vinyl acetate as the acyl donor and
THF as the solvent (Scheme 3).
NMe2
N
NMe2
N
OH
( )-9a
+
PSL-C
+
Solvent
O
T, 250 rpm
OAc
(+)-11a
OH
(_)-9a
Cl
O
10
N
Scheme 2. Enzymatic transesterification of 9a using vinyl acetate as
acyl donor and PSL-C as catalyst.
OAc
(+)-12a
Cl
N
Enzyme
+
+
10
THF
30 oC, 250 rpm
Cl
OH
( )-8a
excellent stereoselectivities, until 65 h when it started to
show a decrease in the enantioselectivity (entries 5–8).
More drastic conditions, for example, higher tempera-
tures, gave lower values of selectivity as it commonly
happens in biocatalysis (entry 9).
N
OH
(_)-8a
Scheme 3. Enzymatic transesterification of 8a using vinyl acetate as
the acyl donor and THF as solvent.
At this point, and before undertaking a further study of
all the parameters that influence the enzymatic catalysis,
we decided to turn our attention to the enzymatic reso-
lution of the synthon 8a, as 9a can easily be obtained
from those in quantitative yield. In addition, chlorinated
derivatives are also advantageous because of their great
versatility in organic synthesis. In this manner, we
focused our efforts trying to reach conversions close to
50% and 99% ee for substrate and product. Thus,
isolated yields could be higher and potential catalyst
obtained in enantiopure form in both stereochemistries.
Once that PSL-C was selected as the optimal biocatalyst
for the transesterification of 8a, this study was extended
to alcohols 8b–d in order to extend the family of catalyst
depending of the alkyl chain length (Scheme 4). The
results are summarized in Table 4.
Cl
Cl
Cl
PSL-C
+
+
10
Solvent
R1
R1
R
N
N
N
T, 250 rpm
The more significant results are shown in Table 3;both
Candida antarctica lipase type A (CAL-A) and the pro-
tease subtilisin (entries 1 and 2) did not show any activ-
ity toward 8a. However, different forms of C. antarctica
lipase type B (CAL-B), immobilized (Novozyme 435) or
supported (Chirazyme) stereoselectively acetylated 8a
(entries 3–5). Novozyme 435 showed a higher activity
but there was a loss of stereoselectivity after reaction
times longer than 2 days as a hydrolysis effect was ob-
served causing a decrease in the enantioselectivity of
the process before 50% conversion was reached (entry
4). The best conditions were achieved using immobilized
Pseudomonas cepacia lipase (PSL-C, entry 6) as after
14 h the reaction reached 50% conversion giving product
and starting material in 99% ee, isolating both with high
OAc
(+)-12a-d
OH
(_)-8a-d
OH
( )-8a-d
R= Me, Et, Pr, Bu
Scheme 4. Kinetic resolution of 8a–d with 10 catalyzed by PSL-C.
In all cases where values of E higher than 200 were
achieved, those processes were slower when the alkyl
group of the 4-chloro-[2-(1-hydroxyalkyl)]pyridine
derivative was longer. In this manner, 8b showed the
same activity as previously observed with 8a (entry 2),
and after 14.5 h, 50% conversion was reached affording
product and substrate enantiomerically pure and with
high yields. PSL-C showed a decrease in the activity
Table 3. Enzymatic acylation of 8a using 3 equiv of 10 in dry THF at 30 ꢁC, where values presented in brackets show the isolated yields
Entry
Enzyme
t (h)
eeP (%)a
eeS (%)a
c (%)b
Ec
1
2
3
4
5
6
CAL-A
Subtilisin
CAL-B (Novozyme)
CAL-B (Novozyme)
CAL-B (Chirazyme)
PSL-C
38
71
48
71
70
14.5
—
—
>99
96
>99
>99 (85)
—
—
82
81
70
>99 (88)
—
—
42
45
41
50
—
—
>200
149
>200
>200
a Calculated by HPLC.
b c = eeS/(eeS + eep).
c E = ln[(1 ꢀ c) · (1 ꢀ eeP)]/ln[(1 ꢀ c) · (1 + eeP)].

3430
E. Busto et al. / Tetrahedron: Asymmetry 16 (2005) 3427–3435
Table 4. Enzymatic transesterification of 8a–d using 10 as acyl donor and PSL-C as biocatalyst, isolated yields in brackets
Entry
Substrate
Solvent
T (ꢁC)
t (h)
eeP (%)a
eeS (%)a
c (%)b
Ec
1
2
3
4
5
6
8a
8b
8c
8c
8d
8d
THF
THF
THF
THF
THF
THF
30
30
30
30
30
30
14.5
14.5
14.5
38
14.5
60
>99 (85)
>99 (82)
>99
99 (97)
>99
>99 (88)
>99 (88)
88
>99 (89)
49
50
50
47
50
33
50
>200
>200
>200
>200
>200
>200
>99 (88)
>99 (89)
a Calculated by HPLC.
b c = eeS/(eeS + eep).
c E = ln[(1 ꢀ c) · (1 ꢀ eeP)]/ln[(1 ꢀ c) · (1 + eeP)].
Table 5. Dechlorination processes to obtain 14a–d
for the reaction with the propyl rest 8c but maintained
the enantiopreference, requiring 38 h to reach 50% con-
version (entries 3 and 4). The decrease in reactivity of
precursor 8d was observed in terms of reaction times
but 50% conversion was reached after 60 h with excel-
lent ee and isolated yields (entries 5 and 6). Biocatalysis
represents a very effective tool to selectively modify one
of the enantiomer of the racemic pyridine derivatives
and PSL-C shows a great versatility to accommodate
different substituted pyridines in its active site.
Entry
Substrate
Yield (%)a
1
2
3
4
5
(ꢀ)-8a
—
56
50
39
62
(+)-12a
(+)-12b
(+)-12c
(+)-12d
a Isolated yield by flash chromatography.
We then decided to use acetyl derivative (+)-12a
(Scheme 6), and after 4 h, (+)-13a was obtained with
43% yield (entry 2). Determination of the specific rota-
tion confirmed the (R)-configuration.13 Using the same
approach, the (R)-configuration of (+)-12b–d was also
assigned as (+)-13b–d and obtained in moderate yields.
The specific rotation of (+)-12b was in accordance with
previously published data (see also experimental part),14
meanwhile (+)-12c and (+)-12d were not described
before in the literature but the symbols of the optical
rotation were the same as the ones for (+)-12a and
(+)-12b, and the elution orders in the HPLC were the
same for all four compounds. Thus, all the cases are in
accordance with KazlauskasÕ rule.15
Substitution of the chlorine atom for the dimethylamino
group at the 4-position of the pyridine ring was achieved
heating the corresponding substrate (ꢀ)-8a–d with a
40% aqueous solution of dimethylamine, thus isolating
the potential catalyst (ꢀ)-9a–d in quantitative yields.
In all cases it was confirmed by HPLC that no racemiza-
tion occurred during the reaction.
One of the main advantages of this chemoenzymatic
synthesis is that potential catalysts of opposite stereo-
chemistry can be obtained. We have demonstrated the
access to (ꢀ)-9a–d but we also developed a one-step
route, which would lead to the corresponding enantio-
mers (+)-9a–d. The formation of (+)-9a was achieved
by refluxing (+)-12a in an aqueous solution of Me2NH,
the substitution of the chlorine atom for the dimethyl-
amino group at the same time showed that the acetate
was deprotected, thus forming the corresponding alco-
hol in 95% isolated yield (Scheme 5).
Cl
Pd(OAc)2
KF, PHMS
R
N
R
H2O, THF
rt
N
OH
OAc
(+)-12a-d
(+)-13a-d
R= Me, Et, Pr, Bu
Cl
NMe2
Scheme 6. Dechlorination of 4-chloropyridines to confirm their
stereochemistry.
Me2NH
100 o
(95%)
Me
Me
C
N
N
OAc
(+)-12a
OH
(+)-9a
3. Conclusions
Scheme 5. Synthesis of (+)-9a from (+)-12a by reaction with Me2NH.
In conclusion, we have synthesized a new family of
chiral catalysts derived from 4-(N,N-dimethylamino)-
pyridine using a chemoenzymatic approach. In this
manner, P. cepacia lipase has shown excellent stereo-
selectivity in the transesterification reaction of 4-chloro-
2-(1-hydroxyalkyl)pyridine derivatives. The kinetic
resolution using lipases as biocatalysts is an ideal tool
to obtain chiral synthons, which moreover we can syn-
thesize in both stereochemistries as alcohol and acetate
form. This easy methodology allows the preparation of
new chiral catalyst for use in asymmetric synthesis.
To confirm the configuration of the stereogenic centers,
the dechlorination of (ꢀ)-8a was attempted following
the procedure described by Maleczka Jr. et al. for
chloroarenes in order to obtain (ꢀ)-13a of known
stereochemistry.12 However when using polymethyl-
hydrosiloxane (PMHS) under palladium catalysis in
the presence of KF, no reaction was observed for alco-
hol (ꢀ)-8a after 24 h (Table 5, entry 1).

E. Busto et al. / Tetrahedron: Asymmetry 16 (2005) 3427–3435
3431
4. Experimental
addition was completed, 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
resulting mixture was stirred at room temperature for
additional 14 h. The solution was neutralized with NH3
aq and extracted with Et2O (3 · 15 mL). The solvent
was evaporated by distillation under reduced pressure
to obtain 2-acetyl-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 (1.36 g, 36.10 mmol) was
added in small portions. The clear solution was stirred
for 2 h at room temperature, then MeOH was evapo-
rated, and the resulting white solid was dissolved in water
and extracted with CH2Cl2 (3 · 10 mL). The organic
phases were combined, dried over Na2SO4, and evapo-
rated at reduced pressure. The crude of reaction was puri-
fied by flash chromatography (80% EtOAc/hexane)
yielding 880 mg as a white solid (77%). Rf (80% EtOAc/
hexane): 0.40. Mp: 73–75 ꢁC;IR (KBr): m 3195, 1582,
4.1. General
C. antarctica lipase type B (CAL-B, Novozyme 435,
7300 PLU/g) was a gift from Novo Nordisk Co. C. ant-
arctica 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. All other
reagents were purchased from Aldrich and used without
further purification. Solvents were distilled over an ade-
quate desiccant under nitrogen. Flash chromatographies
were performed using silica gel 60 (230–240 mesh). High
performance liquid chromatography (HPLC) analyses
were carried out in a Hewlett Packard 1100 chromato-
graph UV detector at 210 nm using a Daicel CHIRAL-
CEL OD or OB-H column (25 cm · 4.6 mm I.D.)
varying the conditions depending on the specific sub-
strate. Melting points were taken on samples in open
capillary tubes and are uncorrected. IR spectra were
recorded on using NaCl plates or KBr pellets in a
1
1555, 1390, 1132, 1082, 1020, 918, and 846 cmꢀ1; H
1
3
Perkin–Elmer 1720-X F7. H, 13C NMR, DEPT, and
NMR (CDCl3, 300.13 MHz): d 1.49 (d, JHH = 6.7 Hz,
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,
300.13 MHz and 13C, 75.5 MHz) or AV-400 (1H,
400.13 MHz and 13C, 100.6 MHz) spectrometers. The
chemical shifts are given in delta (d) values and the cou-
pling constants (J) in hertz (Hz). ESI+ using a HP1100
chromatograph mass detector, or EI with a Finigan
MAT 95 spectrophotometer were used to record mass
spectra (MS). Microanalyses were performed on a
Perkin–Elmer model 2400 instrument. Measurement of
the optical rotations were done in a Perkin–Elmer 241
polarimeter.
3H, H8), 4.50 (s, 1H, OH), 4.88 (q, JHH = 6.7 Hz, 1H,
3
3
4
H7), 7.21 (dd, JHH = 5.4, JHH = 2.0 Hz, 1H, H5), 7.34
4
3
(d, JHH = 2.0 Hz, 1H, H3), and 8.45 (d, JHH = 5.4,
1H, H6); 13C NMR (CDCl3, 100.6 MHz): d 23.9 (C8),
69.0 (C7), 120.1 (C3), 122.5 (C5), 144.8 (C4), 149.0 (C6),
and 165.1 (C2);MS (ESI +, m/z): 180 [(M35Cl+Na)+,
23%], 160 [(M37Cl+H)+, 33%], and 158 [(M35Cl+H)+,
100%]. Anal. Calcd (%) for C7H8NOCl: C, 53.35;H,
5.12;N, 8.89. Found: C, 53.4;H, 5.1;N, 8.9.
4.1.3. ( )-4-Chloro-2-(1-hydroxypropyl)pyridine 8b. Same
procedure as 8a, using ethylmagnesium bromide instead
of methylmagnesium iodide. Colorless oil (76% isolated
20
yield). Rf (80% EtOAc/hexane): 0.42; ½aŠ ¼ ꢀ29:4 (c 2,
D
4.1.1. 4-Chloro-2-cyanopyridine 7. To a solution of 4-
chloropyridine N-oxide (5.00 g, 38.6 mmol) in dry
CH2Cl2 (70 mL) were successively added trimethylsilyl
cyanide (4.92 mL, 39.3 mmol) and N,N-dimethylcarb-
amyl chloride in small portions. The resulting solution
was stirred at room temperature for 9 days, after which
time the solvent was evaporated at reduced pressure.
The crude of the reaction was purified by flash chroma-
tography (20% EtOAc/hexane) yielding 4.54 g as a white
solid (85%). Rf (20% EtOAc/hexane): 0.38. Mp: 83–
85 ꢁC;IR (KBr): m 3456, 3087, 2240, 1570, 1547, 1462,
CHCl3);IR (NaCl): m 3356, 2967, 2935, 2877, 2342, 1581,
1557, 1463, 1393, 1217, 1127, 1099, 984, 826, and
807 cmꢀ1 1H NMR (CDCl3, 400.13 MHz): d 0.95 (t,
;
3JHH = 7.5 Hz, 3H, H9), 1.67–1.94 (m, 2H, H8), 3.99 (s,
3
1H, OH), 4.68 (t, JHH = 7.5 Hz, 1H, H7), 7.21 (dd,
3JHH = 5.4, 4JHH = 1.6 Hz, 1H, H5), 7.33 (d,
3
4JHH = 1.6 Hz, 1H, H3), and 8.43 (d, JHH = 5.4 Hz, 1H,
H6); 13C NMR (CDCl3, 100.61 MHz): d 9.4 (C9), 31.1
(C8), 73.9 (C7), 120.8 (C3), 122.7 (C5), 144.7 (C4), 149.2
+
(C6), and 164.2 (C2);MS (ESI , m/z): 174 [(M37Cl+H)+,
33%] and 172 [(M35Cl+H)+, 100%]. Anal. Calcd (%) for
C8H10NOCl: C, 55.99;H, 5.87;N, 8.16. Found: C, 55.9;
H, 5.9;N, 8.1.
1382, 1288, 1214, 1108, 990, 886, and 847 cmꢀ1
;
1H
3
NMR (CDCl3, 300.13 MHz): d 7.54 (dd, JHH = 5.1,
4
4JHH = 1.7 Hz, 1H, H5), 7.71 (d, JHH = 1.7 Hz, 1H,
H3), and 8.63 (d, JHH = 5.1 Hz, 1H, H6); 13C NMR
4.1.4. ( )-4-Chloro-2-(1-hydroxybutyl)pyridine 8c. Same
procedure as 8a, using propylmagnesium bromide
instead of methylmagnesium iodide. Colorless oil (76%
isolated yield). Rf (20% EtOAc/hexane): 0.16;IR (NaCl):
m 3332, 2959, 2933, 2872, 2360, 2341, 1581, 1556, 1466,
3
(CDCl3, 100.6 MHz): d 116.1 (CN), 127.4 (C5), 128.8
(C3), 135.0 (C4), 145.3 (C2), and 151.9 (C6);MS (EI,
m/z): 140 [(M37Cl)+, 32%], 138 [(M35Cl)+, 100%], and
103 [(M-Cl)+, 61%]. Anal. Calcd (%) for C6H3N2Cl: C,
52.01;H, 2.18 N, 20.22. Found: C, 52.0 H, 2.2 N, 20.2.
1392, 825, and 706 cmꢀ1
400.13 MHz): d 0.96 (t, JHH = 7.4 Hz, 3H, H10), 1.40–
;
1H NMR (CDCl3,
3
4.1.2. ( )-4-Chloro-2-(1-hydroxyethyl)pyridine 8a. Over
a 3.0 M solution of methylmagnesium iodide in Et2O
(9.64 mL, 28.94 mmol) at 0 ꢁC under a nitrogen atmo-
sphere, a solution of 4-chloro-2-cyanopyridine (1.00 g,
7.24 mmol) in dry Et2O (25 mL) was added. Once the
1.51 (m, 2H, H9), 1.63–1.85 (m, 2H, H8), 3.89 (d,
3
3JHH = 4.8 Hz, 1H, OH), 4.73 (td, JHH = 7.4,
3JHH = 4.8 Hz, 1H, H7), 7.21 (dd, 3JHH = 5.4,
4
4JHH = 1.9 Hz, 1H, H5), 7.33 (d, JHH = 1.9 Hz, 1H,
3
H3), and 8.44 (d, JHH = 5.4 Hz, 1H, H6); 13C NMR

3432
E. Busto et al. / Tetrahedron: Asymmetry 16 (2005) 3427–3435
(CDCl3, 100.61 MHz): d 14.0 (C10), 18.5 (C9), 40.5 (C8),
72.7 (C7), 120.7 (C3), 122.6 (C5), 144.7 (C4), 149.2 (C6),
and 164.5 (C2);MS (ESI +, m/z): 188 [(M37Cl+H)+,
32%] and 186 [(M35Cl+H)+, 100%]. Anal. Calcd (%)
for C9H12NOCl: C, 58.23;H, 6.51;N, 7.54. Found: C,
58.3;H, 6.6;N, 7.6.
with CH2Cl2 (3 · 10 mL). The solvent was evaporated
and the crude of reaction purified by flash chromatogra-
phy (15–60% EtOAc/hexane) affording (S)-(ꢀ)-8b {88%
20
isolated yield and >99% ee, ½aŠ ¼ ꢀ29:4 (c 2, CHCl3)}
D
and (R)-(+)-12b {82% isolated yield and >99% ee,
20
½aŠ ¼ þ82:5 (c 2, CHCl3)}.
D
4.1.5. ( )-4-Chloro-2-(1-hydroxypentyl)pyridine 8d. Same
procedure as 8a, using butylmagnesium chloride instead
of methylmagnesium iodide. Colorless oil (74% isolated
yield). Rf (20% EtOAc/hexane): 0.22;IR (NaCl): m 3318,
2957, 2932, 2881, 1581, 1557, 1467, 1557, 1392, and
4.1.9. (R)-(+)-1-(4-Chloro-2-pyridinyl)propyl acetate
12b. Colorless oil; Rf (20% EtOAc/hexane): 0.30;IR
(NaCl): m 2973, 2938, 1738, 1578, 1558, 1465, 1394,
1372, 1234, 1022, 972, 829, and 709 cmꢀ1
;
1H NMR
3
(CDCl3, 400.13 MHz): d 0.91 (t, JHH = 7.4 Hz, 3H,
1
826 cmꢀ1; H NMR (CDCl3, 400.13 MHz): d 0.91 (t,
H9), 1.85–2.04 (m, 2H, H8), 2.15 (s, 3H, H11), 5.69
3JHH = 7.2 Hz, 3H, H10), 1.30–1.45 (m, 4H,
2H9+2H10), 1.65–1.88 (m, 2H, H8), 3.95 (d,
3JHH = 5.5 Hz, 1H, OH), 4.70–4.75 (m, 1H, H7), 7.22
(t, JHH = 6.7 Hz, 1H, H7), 7.21 (dd, JHH = 5.4,
3
3
4JHH = 1.6 Hz, 1H, H5), 7.31 (d, JHH = 1.6 Hz, 1H,
4
H3), and 8.47 (d, JHH = 5.4, 1H, H6); 13C NMR
3
3
4
(dd, JHH = 5.3, JHH = 1.9 Hz, 1H, H5), 7.33 (d,
(CDCl3, 100.61 MHz): d 9.6 (C9), 21.1 (C11), 27.9 (C8),
76.7 (C7), 121.3 (C3), 122.7 (C5), 144.7 (C4), 150.2
(C6), 161.4 (C2), and 170.4 (C10);MS (ESI +, m/z):
238 [(M37Cl+Na)+, 33%], 236 [(M35Cl+Na)+, 100%],
and 214 [(M35Cl+H)+, 5%]. Anal. Calcd (%) for
C10H12NO2Cl: C, 56.21;H, 5.66;N, 6.55. Found: C,
56.2;H, 5.6;N, 6.6.
4JHH = 1.9 Hz, 1H, H3), and 8.44 (d, JHH = 5.3 Hz,
3
1H, H6); 13C NMR (CDCl3, 100.61 MHz): d 14.0
(C11), 22.6 (C10), 27.4 (C9), 38.1 (C8), 72.9 (C7), 120.7
(C3), 122.7 (C5), 144.7 (C4), 149.2 (C6), and 164.5 (C2);
MS (ESI+, m/z): 224 [(M37Cl+Na)+, 32%], 222
[(M35Cl+Na)+, 100%], and [(M35Cl+H)+, 8%]. Anal.
Calcd (%) for C10H14NO2Cl: C, 60.15;H, 7.07;N,
7.01. Found: C, 60.2;H, 6.9;N, 7.2.
4.1.10. Kinetic resolution of ( )-8c. To a suspension of
8c (500 mg, 2.69 mmol) and PSL-C (431 mg) in dry THF
(27 mL) under a nitrogen atmosphere, vinyl acetate
(740 lL, 8.08 mmol) was added, and the reaction shaken
at 30 ꢁC and 250 rpm. Aliquots were regularly analyzed
by HPLC until 50% conversion was reached. The reac-
tion was then stopped and the enzyme filtered with
CH2Cl2 (3 · 10 mL). The solvent was evaporated and
the crude of reaction purified by flash chromatography
4.1.6. Kinetic resolution of ( )-8a. To a suspension of
8a (500 mg, 3.12 mmol) and PSL-C (500 mg) in dry
THF (31 mL) under a nitrogen atmosphere, vinyl ace-
tate (859 lL, 9.38 mmol) was added and the reaction
shaken at 30 ꢁC and 250 rpm. Aliquots were regularly
analyzed by HPLC until 50% conversion was reached,
then the reaction was stopped, and the enzyme filtered
with CH2Cl2 (3 · 10 mL). The solvent was evaporated
and the crude of the reaction purified by flash chroma-
(15–60% EtOAc/hexane) affording (S)-(ꢀ)-8c {89% iso-
20
lated yield and >99% ee, ½aŠ ¼ ꢀ41:7 (c 2, CHCl3)} and
D
tography (20–60% EtOAc/hexane) affording (S)-(ꢀ)-8a
(R)-(+)-12c {97% isolated yield and >99% ee,
20
20
{88% isolated yield and >99% ee, ½aŠ ¼ ꢀ36:1 (c 2,
½aŠ ¼ þ74:9 (c 2, CHCl3)}.
D
D
CHCl3)} and (R)-(+)-12a {85% isolated yield and
20
>99% ee, ½aŠ ¼ þ90:6 (c 2, CHCl3)}.
4.1.11. (R)-(+)-1-(4-Chloro-2-pyridinyl)butyl acetate
12c. Colorless oil; Rf (20% EtOAc/hexane): 0.37;IR
(NaCl): m 2961, 2935, 2874, 1739, 1578, 1557, 1372,
D
4.1.7.
(R)-(+)-1-(4-Chloro-2-pyridinyl)ethyl
acetate
12a. Colorless oil; Rf (20% EtOAc/hexane): 0.24;IR
(NaCl): m 3449, 1736, 1579, 1558, 1469, 1371, 1239,
1100, 1071, 1031, 949, and 828 cmꢀ1; 1H NMR (CDCl3,
300.13 MHz): d 1.57 (d, 3JHH = 6.7 Hz, 3H, H8), 2.14 (s,
1232, 1030, 828, and 709 cmꢀ1
400.13 MHz) d 0.91 (t, JHH = 7.3 Hz, 3H, H10), 1.23–
;
1H NMR (CDCl3,
3
1.43 (m, 2H, H9), 1.83–1.91 (m, 2H, H8), 2.12 (s, 3H,
3
3
H12), 5.75 (t, JHH = 7.0 Hz, 1H, H7), 7.17 (dd, JHH
=
3
3H, H10), 5.86 (q, JHH = 6.7 Hz, 1H, H7), 7.18 (dd,
5.3, 4JHH = 1.8 Hz, 1H, H5), 7.28 (d, 4JHH = 1.8 Hz, 1H,
3JHH = 5.4, 4JHH = 1.8 Hz, 1H, H5), 7.34 (d,
H3), and 8.45 (d, JHH = 5.3 Hz, 1H, H6); 13C NMR
3
3
4JHH = 1.8 Hz, 1H, H3), and 8.46 (d, JHH = 5.4 Hz,
(CDCl3, 100.61 MHz): d 13.7 (C10), 18.5 (C9), 21.0
(C12), 36.8 (C8), 75.9 (C7) 121.1 (C3), 122.9 (C5),
144.6 (C4), 150.2 (C6), 161.6 (C2), and 170.2 (C11);MS
(ESI+, m/z): 252 [(M37Cl+Na)+, 33%], 250 [(M35Cl+
Na)+, 100%], and 228 [(M35Cl+H)+, 4%]. Anal. Calcd
(%) for C11H14NO2Cl: C, 58.02;H, 6.20;N, 6.15.
Found: C, 58.0;H, 6.1;N, 6.1.
1H, H6); 13C NMR (CDCl3, 75.5 MHz): d 20.6 (C8),
21.1 (C10), 72.4 (C7), 120.6 (C3), 122.9 (C5), 145.2
+
(C4), 150.1 (C6), 162.0 (C2), and 170.0 (C9);MS (ESI
,
m/z): 222 [(M35Cl+Na)+, 7%], 202 [(M37Cl+H)+,
32%], and 200 [(M35Cl+H)+, 100%]. Anal. Calcd (%)
for C9H10NO2Cl: C, 54.15;H, 5.05;N, 7.02. Found:
C, 54.2;H, 5.0;N, 7.0.
4.1.12. Kinetic resolution of ( )-8d. To a suspension of
8d (500 mg, 2.50 mmol) and PSL-C (402 mg) in dry
THF (25 mL) under a nitrogen atmosphere, vinyl ace-
tate (690 lL, 7.50 mmol) was added and the reaction
shaken at 30 ꢁC and 250 rpm. Aliquots were regularly
analyzed by HPLC until 50% conversion was reached,
then the reaction was stopped, and the enzyme filtered
with CH2Cl2 (3 · 10 mL). The solvent was evaporated
4.1.8. Kinetic resolution of ( )-8b. To a suspension of
8b (500 mg, 2.91 mmol) and PSL-C (466 mg) in dry
THF (29 mL) under a nitrogen atmosphere, vinyl ace-
tate (800 lL, 8.74 mmol) was added and the reaction
shaken at 30 ꢁC and 250 rpm. Aliquots were regularly
analyzed by HPLC until 50% conversion was reached.
The reaction was then stopped and the enzyme filtered

E. Busto et al. / Tetrahedron: Asymmetry 16 (2005) 3427–3435
3433
3
and the crude of reaction purified by flash chromatogra-
1H, OH), 4.77 (q, JHH = 6.3 Hz, 1H, H7), 6.41–6.44
3
phy (15–55% EtOAc/hexane) affording (S)-(ꢀ)-8d {89%
(m, 2H, H3+H5), and 8.14 (d, JHH = 5.7 Hz, 1H, H6);
20
isolated yield and >99% ee, ½aŠ ¼ ꢀ45:8 (c 2, CHCl3)}
13C NMR (CDCl3, 75.5 MHz): d 24.4 (C8), 39.1 (C10),
68.9 (C7), 101.3 (C3), 105.5 (C5), 147.9 (C6), 154.9
(C4), and 163.2 (C2);MS (ESI +, m/z): 167 [(M+H)+,
100%]. Anal. Calcd (%) for C9H14N2O: C, 65.03;H,
8.49;N, 16.85. Found: C, 65.1;H, 8.5;N;16.9.
D
and (R)-(+)-12d {88% isolated yield and >99% ee,
20
½aŠ ¼ þ70:8 (c 2, CHCl3)}.
D
4.1.13. (R)-(+)-1-(4-Chloro-2-pyridinyl)pentyl acetate
12d. Colorless oil; Rf (20% EtOAc/hexane): 0.47;IR
(NaCl): m 2958, 2932, 2863, 1742, 1578, 1557, 1372,
4.1.17.
(R)-(+)-4-(N,N-Dimethylamino)-2-(1-hydroxy-
1
1233, and 1024 cmꢀ1; H NMR (CDCl3, 400.13 MHz):
ethyl)pyridine 9a. Same procedure as (ꢀ)-9a affording
3
d 0.89 (t, JHH = 6.9 Hz, 3H, H13), 1.26–1.38 (m, 4H,
(+)-9a from (+)-12a, as a colorless oil after 22 h
20
D
2H9+2H10), 1.79–1.95 (m, 2H, H8), 2.15 (s, 3H, H13),
(95%). ½aŠ ¼ þ34:1 (c 1, EtOH).
3
3
5.76 (t, JHH = 6.7 Hz, 1H, H7), 7.21 (dd, JHH = 5.3,
4JHH = 1.9 Hz, 1H, H5), 7.31 (d, JHH = 1.9 Hz, 1H,
4.1.18. (S)-(ꢀ)-4-(N,N-Dimethylamino)-2-(1-hydroxyprop-
yl)pyridine 9b. Same procedure as (ꢀ)-9a affording
4
H3), and 8.48 (d, JHH = 5.3 Hz, 1H, H6); 13C NMR
3
(CDCl3, 100.61 MHz) d 13.9 (C11), 21.1 (C13), 22.4
(C10), 27.4 (C9), 34.5 (C8), 76.2 (C7), 121.2 (C3), 122.9
(C5), 144.7 (C4), 150.2 (C6), 161.7 (C2), and 170.3
(C12);MS (ESI +, m/z): 264 [(M35Cl+Na)+, 7%], 244
[(M37Cl+H)+, 33%], and 242 [(M35Cl+H)+, 100%].
Anal. Calcd (%) for C12H16NO2Cl: C, 59.63;H, 6.67;
N, 5.79. Found: C, 59.9;H, 6.8;N, 5.6.
(ꢀ)-9b from (ꢀ)-8b, as a colorless oil after 24 h
20
D
(100%). ½aŠ ¼ ꢀ19:9 (c 1, EtOH); Rf (100% MeOH):
0.12;IR (NaCl): m 3344, 2959, 2361, 1643, 1558, 1514,
1443, 1401, 1228, and 1008 cmꢀ1
;
1H NMR (CDCl3,
3
200.13 MHz): d 0.95 (t, JHH = 7.4 Hz, 3H, H9), 1.66–
1.89 (m, 2H, H8), 3.01 (s, 6H, H10), 4.51–4.57 (m, 1H,
H7), 5.83 (br s, 1H, OH), 6.39–6.44 (m, 2H, H3+H5),
and 8.10 (d, 3JHH = 5.9 Hz, 1H, H6); 13C NMR (CDCl3,
75.5 MHz): d 9.64 (C9), 31.0 (C8), 39.1 (C10), 74.0 (C7),
102.5 (C3), 105.3 (C5), 146.8 (C6), 155.0 (C4), and
161.6 (C2);MS (ESI +, m/z): 182 [(M+H)+, 100%]. Anal.
Calcd (%) for C10H16N2O: C, 66.64;H, 8.95;N, 15.54
Found: C, 66.7;H, 9.0;N;15.5.
4.1.14. Kinetic resolution of ( )-9a. To a suspension of
9a (33.2 mg, 0.20 mmol) and PSL-C (32 mg) in dry sol-
vent (2 mL) under a nitrogen atmosphere, vinyl acetate
(55 lL, 0.60 mmol) was added and the reaction shaken
at 250 rpm. Aliquots were regularly analyzed by HPLC,
then the reaction was stopped and the enzyme filtered
with CH2Cl2 (3 · 2 mL). The solvent was evaporated
and the crude of reaction purified by flash chromatogra-
phy (15–100% MeOH/EtOAc) affording (R)-(+)-11a
and (S)-(ꢀ)-9a (see Table 2).
4.1.19.
butyl)pyridine 9c. Same procedure as (ꢀ)-9a affording
(S)-(ꢀ)-4-(N,N-Dimethylamino)-2-(1-hydroxy-
(ꢀ)-9c from (ꢀ)-8c, as a colorless oil after 24 h
20
D
(100%). ½aŠ ¼ ꢀ26:7 (c 1, EtOH); Rf (100% MeOH):
0.15;IR (NaCl): m 3473, 3215, 3103, 2968, 2361, 2343,
4.1.15. (R)-(+)-1-[4-(N,N-Dimethylamino)-2-pyridinyl]-
1645, 1602, 1597, 1004, and 984 cmꢀ1
;
1H NMR
20
3
ethyl acetate 11a. ½aŠ ¼ þ36:6 (c 0.8, CHCl3).
(CDCl3, 200.13 MHz) d 0.90 (t, JHH = 7.4 Hz, 3H,
H10), 1.37–1.47 (m, 2H, H9), 1.72–1.76 (m, 2H, H8),
3.01 (s, 6H, H11), 4.68–4.70 (m, 1H, H7), 6.45–6.52 (m,
2H, H3+H5), 6.89 (br s, 1H, OH), and 8.08 (d,
3JHH = 6.0 Hz, 1H, H6); 13C NMR (CDCl3,
75.5 MHz): d 13.8 (C10), 18.6 (C8), 39.4 (C11), 39.9
(C8), 71.8 (C7), 102.7 (C3), 105.3 (C5), 144.0 (C6),
155.8 (C4), and 160.6 (C2);MS (ESI +, m/z): 195
[(M+H)+, 100%]. Anal. Calcd (%) for C11H18N2O: C,
68.01;H, 9.34;N, 14.42. Found: C, 67.9;H, 9.3;N;
14.4.
D
Colorless oil; Rf (100% MeOH): 0.51;IR (NaCl):
m
3423, 2947, 1736, 1607, 1544, 1375, 1424, and
1070 cmꢀ1
;
1H NMR (CDCl3, 200.13 MHz) d 1.58
3
(d, JHH = 6.6 Hz 3H, H8), 2.12 (s, 3H, H10), 3.02 (s,
3
6H, H11), 5.80 (q, JHH = 6.6 Hz, 1H, H7), 6.42 (dd,
3JHH = 5.9, JHH = 2.7 Hz, 1H, H5), 6.52 (d, JHH
=
4
4
3
2.7 Hz, 1H, H5), and 8.23 (d, JHH = 5.9 Hz, 1H,
H6); 13C NMR (CDCl3, 75.5 MHz): d 20.6 (C8), 21.2
(C10), 39.1 (C11), 73.1 (C7), 103.0 (C3), 105.6 (C5),
148.7 (C6), 155.0 (C4), 159.6 (C2), and 170.2 (C9);MS
(ESI+, m/z): 209 [(M+H)+, 100%]. Anal. Calcd (%) for
C11H16N2O2: C, 63.42;H, 7.75;N, 13.46. Found: C,
63.4;H, 7.8;N;13.5.
4.1.20.
pentyl)pyridine 9d. Same procedure as (ꢀ)-9a affording
(S)-(ꢀ)-4-(N,N-Dimethylamino)-2-(1-hydroxy-
(ꢀ)-9d from (ꢀ)-8d, as a colorless oil after 48 h (100%).
20
4.1.16.
ethyl)pyridine 9a.
(S)-(ꢀ)-4-(N,N-Dimethylamino)-2-(1-hydroxy-
½aŠ ¼ ꢀ21:8 (c 1, EtOH); Rf (100% MeOH): 0.22;IR
A
mixture of (ꢀ)-8a (150 mg,
(NDaCl): m 3408, 2957, 1644, 1564, 1466, 1403, 1231,
1
0.95 mmol) and a 40% aqueous solution of Me2NH
(4 mL) was stirred in a sealed tube at 100 ꢁC until com-
plete consumption of the starting material (32 h). The
solvent was evaporated by distillation at a reduced pres-
sure and the resulting crude purified by flash chromato-
and 1005 cmꢀ1; H NMR (CDCl3, 200.13 MHz) d 0.90
3
(t, JHH = 7.0 Hz, 3H, H11), 1.26–1.46 (m, 4H,
2H9+2H10), 1.65–1.83 (m, 2H, H8), 3.00 (s, 6H, H11),
4.56–4.63 (m, 1H, H7), 6.40–6.43 (m, 2H, H3+H5), and
8.15 (d, JHH = 6.7 Hz, 1H, H6); 13C NMR (CDCl3,
3
graphy (80–100% MeOH/EtOAc) yielding 159 mg as a
75.5 MHz): d 14.0 (C11), 22.7 (C10), 27.5 (C9), 38.4
(C8), 39.1 (C12), 73.0 (C7), 102.3 (C3), 105.5 (C5), 148.0
(C6), 154.8 (C4), and 162.5 (C2);MS (ESI +, m/z): 209
[(M+H)+, 100%]. Anal. Calcd (%) for C12H20N2O: C,
69.19;H, 9.68;N, 13.45. Found: C, 69.2;H, 9.7;N;
13.4.
20
white solid (99%). ½aŠ ¼ ꢀ31:5 (c 1, EtOH); Rf (100%
D
MeOH): 0.10. Mp: 120–122 ꢁC;IR (KBr): m 3384,
2973, 2928, 1608, 1544, 1514, 1379, 1226, and
1
1000 cmꢀ1; H NMR (CDCl3, 300.13 MHz): d 1.48 (d,
3JHH = 6.3 Hz, 3H, H8), 3.01 (s, 6H, H10), 4.11 (br s,

3434
E. Busto et al. / Tetrahedron: Asymmetry 16 (2005) 3427–3435
4.1.21. (R)-(+)-2-(1-Hydroxyethyl)pyridine 13a. To a
suspension of (+)-12a (64 mg, 0.32 mmol) and palla-
dium acetate (II) (0.016 mmol, 3.6 mg) in dry THF
and under a nitrogen atmosphere were added succes-
sively potassium fluoride solution (0.64 mmol, 37 mg)
in degassed water (640 lL) and polyhydroxymethyl-
siloxane (77 mg, 1.28 mmol). The mixture was stirred
for 4 h at room temperature until complete disappear-
ance of the starting material. Excess of PMHS was
destroyed by adding 3 M NaOH solution (15 mL) and
stirring the mixture for 5 h. Then the solution was
extracted with Et2O (3 · 10 mL), the organic phases
combined, dried over Na2SO4, and finally the solvent
distilled under reduced pressure to obtain a crude of
reaction, which was purified by flash chromatography
(m, 2H, H3+H5), 7.64–7.69 (m, 1H, H4), and 8.52 (d,
3JHH = 4.5 Hz, 1H, H6); 13C NMR (CDCl3,
75.5 MHz): d (CDCl3, 75.5 MHz): d 13.9 (C11), 22.6
(C10), 27.3 (C9), 38.2 (C8), 72.7 (C7), 120.2 (C3), 122.1
+
(C5), 136.5 (C4), 148.1 (C6), and 162.4 (C2);MS (ESI
,
m/z): 188 [(M+Na)+, 100%], and 166 [(M+H)+, 85%].
Anal. Calcd (%) for C10H15NO: C, 72.69;H, 9.15;N,
8.48. Found: C, 72.7;H, 9.1;N;8.5.
Acknowledgments
We thank Novo Nordisk Co. for the generous gift of the
CAL-B (Novozyme 435). Financial support of this work
´
by the Spanish Ministerio de Educacion y Ciencia
(70% Et2O/hexane) isolating 22 mg as a colorless oil
(Project CTQ-2004-04185) is gratefully acknowledged.
V.G.-F. thanks MEC for a personal grant (Juan de la
Cierva Program). E.B. thanks MEC for a pre-doctoral
fellowship.
20
(43%). Rf (70% Et2O/hexane): 0.11; ½aŠ ¼ þ18:4 (c
D
20
1.0, EtOH), literature ½aŠ ¼ þ14:7 (c 4.4, EtOH);13 1H
NMR (CDCl3, 200 MHDz): d 1.51 (d, JHH = 6.7 Hz,
3H, H8), 4.51 (br s, 1H, OH), 4.90 (q, JHH = 6.7 Hz,
3
3
1H, H7), 7.17–7.31 (m, 2H, H3+H5), 7.65–7.74 (m, 1H,
3
4
H4), and 8.54 (dd, JHH = 4.9, JHH = 0.8 Hz); 13C
NMR (CDCl3, 75.5 MHz): d 24.2 (C8), 68.7 (C7), 119.7
(C3), 122.1 (C5), 136.7 (C4), 148.0 (C6), and 162.9 (C2).
References
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Chem. Res. 2000, 33, 412–420;(d) Fu, G. C. Acc. Chem.
Res. 2004, 37, 542–547.
3. Vedejs, E.;Chen, X. J. Am. Chem. Soc. 1996, 118, 1809–
1810.
4. Vedejs, E.;Chen, X. J. Am. Chem. Soc. 1997, 119, 2584–
2585.
4.1.22. (R)-(+)-2-(1-Hydroxypropyl)pyridine 13b. Same
procedure as (+)-13a affording (+)-13b from (+)-12b,
as a colorless oil (50%). Rf (70% Et2O/hexane): 0.13;
20
20
½aŠ ¼ þ11:7 (c 1.1, CHCl3), literature ½aŠ ¼ þ38:0 (c
D
D
1.68, EtOH);14 1H NMR (CDCl3, 200 MHz): d 0.96 (t,
3JHH = 7.4 Hz, 3H, H9), 1.62–2.00 (m, 2H, H8), 4.25
3
(br s, 1H, OH), 4.71 (t, JHH = 5.3 Hz, 1H, H7), 7.18–
7.28 (m, 2H, H3+H5), 7.66–7.74 (m, 1H, H4), and 8.56
3
(d, JHH = 5.1 Hz 1H, H6); 13C NMR (CDCl3,
75.5 MHz): d 9.3 (C9), 31.3 (C8), 73.6 (C7), 120.3 (C3),
5. See for example: (a) Spivey, A. C.;Fekner, T.;Spey, S. E.
J. Org. Chem. 2000, 65, 3154–3159;(b) Kawabata, T.;
Yamamoto, K.;Momose, Y.;Yoshida, H.;Nagaoka, Y.;
Fuji, K. Chem. Commun. 2001, 2700–2701;(c) Priem, G.;
Anson, M. S.;Macdonald, S. J. F.;Pelotier, B.;Campbell,
I. B. Tetrahedron Lett. 2002, 43, 6001–6003;(d) Shaw, S.
A.;Aleman, P.;Vedejs, E. J. Am. Chem. Soc. 2003, 125,
13368–13369.
122.1 (C5), 136.5 (C4), 148.1 (C6), and 161.9 (C2).
4.1.23. (R)-(+)-2-(1-Hydroxybutyl)pyridine 13c. Same
procedure as (+)-13a affording (+)-13c from (+)-12c,
as a colorless oil (39%). Rf (70% Et2O/hexane): 0.17;
20
½aŠ ¼ þ29:8 (c 0.5, CHCl3);IR (NaCl): m 3363, 1728,
D
1596, 1573, 1477, 1437, 1255, 1120, 1084, and
1019 cmꢀ1
;
1H NMR (CDCl3, 200 MHz): d 0.97 (t,
6. Seemayer, R.;Schneider, M. P. Tetrahedron: Asymmetry
1992, 3, 827–830.
3JHH = 7.2 Hz, 3H, H10), 1.29–1.50 (m, 2H, H9) 1.52–
1.98 (m, 2H, H8), 4.58 (br s, 1H, OH), 4.73 (t,
3JHH = 7.0 Hz, 1H, H7), 7.09–7.30 (m, 2H, H3+H5),
7. (a) Orrenius, C.;Mattson, A.;Norin, T.
Tetrahedron:
Asymmetry 1994, 5, 1363–1366;(b) Uenishi, J.;Nishiwaki,
K.;Hata, S. Tetrahedron Lett. 1994, 35, 7973–7976;(c)
Uenishi, J.;Hiraoka, T.;Hata, S.;Nishiwaki, K.;Yone-
mitsu, O. J. Org. Chem. 1998, 63, 2481–2487;(d) Bellezza,
3
7.61–7.71 (m, 1H, H4), and 8.49 (d, JHH = 4.7 Hz,
1H, H6); 13C NMR (CDCl3, 75.5 MHz): d 14.0 (C10),
18.4 (C9), 40.7 (C8), 72.5 (C7), 120.3 (C3), 122.1 (C5),
F.;Cipiciani, A.;Cruciani, G.;Fringuelli, F.
J. Chem.
+
136.5 (C4), 148.1 (C6), and 162.2 (C2);MS (ESI
,
Soc., Perkin Trans. 1 2000, 4439–4444;(e) Szatzker, G.;
m/z): 174 [(M+Na)+, 100%], and 152 [(M+H)+, 87%].
Anal. Calcd (%) for C9H13NO: C, 71.49;H, 8.67;N,
9.26. Found: C, 71.6;H, 8.5;N;9.3.
´
´
´
Moczar, I.;Kolonits, P.;Nova k, L.;Hustzthy, P.;Poppe,
L. Tetrahedron: Asymmetry 2004, 15, 2483–2490;(f)
Sigmund, A. E.;DiCosmio, R. Tetrahedron: Asymmetry
2004, 15, 2797–2799.
8. Takeshita, M.;Terada, K.;Akutsu, N.;Yoshida, S.;Sato,
T. Heterocycles 1987, 26, 3051–3054.
9. Takeshita, M.;Yoshida, S.;Sato, T.;Akutsu, N. Hetero-
cycles 1993, 35, 879–884.
4.1.24. (R)-(+)-2-(1-Hydroxypentyl)pyridine 13d. Same
procedure as (+)-13a affording (+)-13d from (+)-12d,
as a colorless oil (62%). Rf (70% Et2O/hexane): 0.18;
20
½aŠ ¼ þ20:7 (c 1.5, CHCl3);IR (NaCl): m 3385, 1643,
D
´
10. (a) Iglesias, L. E.;Sa nchez, V. M.;Rebolledo, F.;Gotor,
1596, 1478, 1437, 1255, 1121, 1084, 1018, and
V. Tetrahedron: Asymmetry 1997, 8, 2675–2677;(b)
Skupinska, K. A.;McEachern, E. J.;Baird, I. R.;Skerlj,
R. T.;Bridger, G. J. J. Org. Chem. 2002, 68, 3546–3551.
11. Bisagni, E.;Rautureau, M.;Huel, C. Heterocycles 1989,
29, 1815–1824.
1
905 cmꢀ1; H NMR (CDCl3, 300.13 MHz): d 0.88 (t,
3JHH = 7.1 Hz, 3H, H11), 1.28–1.44 (m, 2H, H10),
1.62–1.85 (m, 2H, H9), 1.62–1.84 (m, 2H, H8), 4.23 (br
3
s, 1H, OH), 4.72 (t, JHH = 4.5 Hz, 1H, H7), 7.16–7.26

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3435
12. Rahaim, R. J., Jr.;Maleczka, R. E., Jr. Tetrahedron Lett.
14. Okano, K.;Murata, K.;Ikariya, T.
2000, 41, 9277–9280.
Tetrahedron Lett.
2002, 43, 8823–8826.
13. Ziffer, H.;Kawai, K.;Kasai, M.;Imuta, M.;Froussios, C.
J. Org. Chem. 1983, 48, 3017–3021.
15. Kazlauskas, R. J.;Weissfoch, A. N. E.;Rappaport, A. T.;
Cuccia, L. A. J. Org. Chem. 1991, 56, 2656–2665.