Chiral amino alcohols derived from (S)-6-chloronicotine as catalysts for asymmetric synthesis

Article abstract of DOI:10.1016/j.tetlet.2009.02.012

Commercially available (S)-nicotine was converted in two or three synthetic steps to various chiral amino alcohols. These nicotine derivatives were evaluated as potential chiral ligands for metal-catalyzed asymmetric reactions by using the addition of die

Full text of DOI:10.1016/j.tetlet.2009.02.012

Tetrahedron Letters 50 (2009) 1806–1808
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chiral amino alcohols derived from (S)-6-chloronicotine as catalysts
for asymmetric synthesis
*
Sonja S. Capracotta, Daniel L. Comins
Department of Chemistry, North Carolina State University, Raleigh, NC 2769-8204, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Commercially available (S)-nicotine was converted in two or three synthetic steps to various chiral amino
alcohols. These nicotine derivatives were evaluated as potential chiral ligands for metal-catalyzed asym-
metric reactions by using the addition of diethylzinc to aldehydes as a screen. Several reactions pro-
ceeded with a high degree of enantioselectivity providing good yields of secondary alcohols of high
enantiopurity.
Received 11 December 2008
Revised 26 January 2009
Accepted 2 February 2009
Available online 8 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Currently there is considerable interest in the synthesis of chiral
ligands for metal-catalyzed asymmetric reactions.1 Although
numerous enantiopure chelating ligands have been prepared, there
is still a need for new types obtainable by concise syntheses from
inexpensive starting materials. (S)-Nicotine is a commercially
available enantiopure amine that has been underutilized in organic
synthesis. Recently in our laboratories,2 we have been developing
methods for the substitution of natural nicotine with the goal of
producing analogues as potential therapeutics for central nervous
system (CNS)-related disorders.3 As a spin-off of this program, a
study on the application of our nicotine substitution methods to
the preparation of novel ligands for asymmetric synthesis was ini-
tiated. Since amino alcohols are well established as an effective
class of ligands for asymmetric reactions,4 they were chosen as
our first synthetic targets. Herein is reported the preparation of
novel chiral amino alcohols in two to three steps from natural
(S)-nicotine.
In addition to the above ligands, the C-2 tertiary alcohol 9 was
prepared from iodide 88, and the C2 symmetric alcohol 11 was pre-
pared from aldehyde 108 as shown in Scheme 2.
With the synthesized ligands in hand, their ability to transfer
chirality was screened using the asymmetric addition of diethyl-
zinc to benzaldehyde.9 Initially, reactions were run with 20% cata-
lyst loading in toluene at 0 °C for 24 h (Table 2). The C-4 secondary
alcohol 5a (entry 2) provided both a better yield and enantioselec-
tivity for the asymmetric reaction than the C-2-substituted ligand
9 (entry 1). Both diastereomers of the secondary alcohol ligands (5
and 6) were examined as catalysts in the diethylzinc reaction as
shown in entries 2–9. Interestingly, only the nicotine ligands con-
taining a C-4 phenylmethanol unit of the R configuration provided
good enantioselectivity. Compound 6d gave the highest enantio-
meric excess for this class of ligands (entry 9); however, the
1-naphthyl-substituted ligand 6c provided a similar ee of 76% with
an 83% yield. In the case of 6d, the electron-withdrawing effect of
(S)-Nicotine (1) can be converted to 6-chloronicotine (2) in one
step by directed lithiation5 using n-BuLi-LiDMAE.6 Subsequent
metalation at C-4 of 2 with n-BuLi gives a 4-lithio intermediate
which on addition of electrophiles affords the desired 4,6-disubsti-
tuted nicotines7 (Scheme 1). This methodology can be used to pro-
vide C-4 substituted amino-alcohol ligands in two steps from
nicotine. The addition of an aryl aldehyde to 6-chloro-4-lithionico-
tine gave approximately a 1:1 mixture of diastereomers 5 and 6 as
shown in Table 1 (entries 1–4). The diastereomers were separated
by silica gel chromatography to afford pure alcohols in moderate
yields. The relative stereochemistry of 5a was determined by single
crystal X-ray analysis.7 The use of symmetrical ketones (4) as
electrophiles avoided diastereomer separation and provided an
increase in yield of the desired amino alcohols 7 (entries 5–8).
n-BuLi-LiDMAE,
hexanes, -20 oC
N
N
N
Cl
N
C2Cl6, -78 oC
1
2
E
1. 1.1 n-BuLi,
THF, -78 oC
N
2. E+
Cl
N
3
* Corresponding author. Tel.: +1 919 515 2911; fax: +1 202 513 8757.
E-mail address: daniel_comins@ncsu.edu (D.L. Comins).
Scheme 1. Directed lithiation of nicotines 1 and 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.012

S. S. Capracotta, D. L. Comins / Tetrahedron Letters 50 (2009) 1806–1808
1807
Table 1
Table 2
Formation of secondary and tertiary alcohols at the C-4 position of 2
Screening of nicotine-derived ligands in the catalytic asymmetric addition of
diethylzinc to benzaldehyde
R2
O
R1 OH
Li
N
N
O
OH
*
R1 R2
2.2 Et Zn , 20 % catalyst
2
4
n-BuLi
N
H
2
o
toluene, 0 C, 24 h
(1.2 equiv)
Cl
Cl
N
Entry
Catalyst
Yield (%)
eea (%)
5 R1 = H, R2 = Ar
6 R1 = Ar, R2 = H
7 R1 = R2 = Ar
1
2
3
4
5
6
7
8
9
10
11
12
13
14
9
42
82
64
13
73
90
83
64
48
78
83
72
66b
91
2 (R)
5a
6a
5b
6b
5c
6c
5d
6d
7a
7b
7c
7d
11
14 (R)
64 (R)
2 (S)
64 (R)
10 (S)
76 (R)
7 (R)
79 (R)
79 (R)
83 (R)
66 (R)
95 (R)
67 (R)
Entry
4
Yield 5 (%) Yield 6 (%) Yield 7 (%)
1
Benzaldehyde
2-Naphthaldehyde
1-Naphthylaldehyde
Pentafluorobenzaldehyde
Benzophenone
5aa, 31
5b, 21
5c, 12
5d, 25
—
6aa, 37
6b, 25
6c, 14
6d. 35
—
—
—
—
—
7a, 68
7b, 50
7c, 39
2b
3b
4b
5
6
7
Di-naphthalen-2-yl methanone
Bis-(4-tert-butylphenyl)
methanone
—
—
—
—
8
Decafluorobenzophenone
—
—
7d. 51
a
a
Determined by chiral HPLC on column Chiralcel OD, 10% i-propanol/hexanes as
Known compound.
b
the eluent and a flow rate of 1.00 mL/min.
The absolute stereochemistry at the C-4 position of 5 and 6 was determined by
b
Lower yield due to difficulties in purification.
the X-ray diffraction of and comparison to 5a.
The –Cl and –OCH3 substituents on the aromatic ring did not
seem to have a significant effect on the enantioselectivity of the
reaction (entries 5 and 6) and afforded similar results; however,
the yield of the reaction was lower with chlorobenzaldehyde as
the substrate. When cinnamaldehyde and hydrocinnamaldehyde
1) 1.1 n-BuLi ,
THF, -78
C
N
N
OH
Ph
2) benzophenone
N
Cl
I
N
Cl
Ph
Table 3
Et2Zn addition to aldehydes catalyzed by 7d
8
33%
9
Entry
RCHO
7d, mol %
Yielda (%)
eeb (%) (R)
1
2
3
4
5
6
7
8
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
p-Chlorobenzaldehyde
p-Methoxybenzaldehyde
Hydrocinnamaldehyde
Cinnamaldehyde
20
10
5
2
5
5
5
5
66
55
89
83
57
78
43
88
96
95
95
89
94
94
69
72
N
1) 1.1 n-BuLi ,
THF, -78 C
N
N
OH
Cl
2) CHO
N
N
Cl
N
2
a
N
Lower yield due to difficulties in purification.
Determined by chiral HPLC on column Chiralcel OD with k = 219 nm, 2–10%
Cl
N
Cl
b
10
74%
i-propanol/hexanes as the eluent and a flow rate of 0.8–1.00 mL/min.
11
Scheme 2. Synthesis of ligands 9 and 11.
Ph
the fluorines on the aromatic ring created an increase in chirality
transfer as compared to the phenyl derivative 6a.
OH
1) 1.1 n-BuLi ,
Ph
Cl
Cl
Cl
THF, -78
C
In general, the C-4 tertiary alcohols (entries 10–13) enhanced
the enantioselectivity of the catalytic asymmetric reaction more
than the secondary alcohols. The decafluoro tertiary alcohol 7d
provided the best enantioselectivity (95% ee) overall. Surprisingly,
the increased bulkiness of the tert-butyl groups on compound 7c
did not improve the selectivity over that afforded by 7a and even
caused a decrease in asymmetric induction.
N
N
2) benzophenone
30%
Cl
N
N
12
13
After discovering that 7d was the most effective catalyst at
20 mol % loading, the asymmetric reaction parameters were opti-
mized by varying the amount of catalyst (Table 3). When going
from 20% to 10% of catalyst (7d), only a slight change in yield
and ee was observed. Much to our delight, the reaction was more
efficient and successful when 5% of catalyst 7d was employed in
the reaction; however, when lowering to 2% of 7d a decrease in
selectivity was observed (Table 3, entry 4). Using the optimized
conditions, 7d was used to catalyze the addition of diethylzinc to
other aldehyde substrates as shown in Table 3.
Ph
Ph
Ph
Ph
OH
OH
Pd(OH)2, H2
N
N
NaOH, MeOH, rt, 1 h
Cl
N
N
99%
14
7a
Scheme 3. Preparation of ligands 13 and 14.

1808
S. S. Capracotta, D. L. Comins / Tetrahedron Letters 50 (2009) 1806–1808
Table 4
References and notes
Effect of chlorine substituentsa
1. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994;
(b) Catalytic Asymmetric Synthesis, 2nd ed., Wiley-VCH, New York, 2000.; (c)
Pfaltz, A. Chimia 2004, 58, 49; (d) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol.
Chem. 2006, 4, 393.
2. Review: (a) Wagner, F. F.; Comins, D. L. Tetrahedron 2007, 63, 8065; (b)
Ondachi, P. W.; Comins, D. L. Tetrahedron Lett. 2008, 49, 569.
3. (a) Karlin, A. Nat. Rev. Neurosci. 2002, 3, 102; (b) Lloyd, G. K.; Williams, M. J.
Pharmacol. Exp. Ther. 2000, 292, 461; (c) Tonder, J. E.; Olesen, P. H. Curr. Med.
Chem. 2001, 8, 651; (d) Jensen, A. A.; Frolund, B.; Liljefors, T.; Krogsgaard-
Larsen, P. J. Med. Chem. 2005, 48, 4705.
Entry
Catalyst
mol %
Yield (%)
ee (%)
1
2
3
4
5
7a
13
13
14
14
20
20
5
20
5
78
61
91
69
36
79 (R)
95 (R)
92 (R)
63 (R)
60 (R)
a
Reactions were run at 0 °C for 24 h in toluene.
4. (a) Anaya de Parrodi, C.; Juaristi, E. Synlett 2006, 2699; (b) Vicario, J. L.; Badía,
D.; Carillo, L.; Reyes, E.; Etxebarria, J. Curr. Org. Chem. 2005, 9, 219; (c)Transition
Metals for Organic Synthesis; Beller, M., Bolm, C., Eds., 2nd ed.; Wiley VCH:
Weinheim Germany, 2004.
5. Février, F. C.; Smith, E. D.; Comins, D. L. Org. Lett. 2005, 7, 5457.
6. Review: Gros, P.; Fort, Y. Eur. J. Org. Chem. 2002, 2375.
7. Crystallographic data (excluding structure factors) for the structure 5a have
been deposited with the Cambridge Crystallographic Data Center as
supplementary publication numbers CCDC 713132. Copies of these data can
be obtained free of charge on application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK.
were employed in the reaction, a decrease in enantioselectivity oc-
curred. In an attempt to discover a way to bring the selectivity up
for these aldehydes, a few different reaction conditions were tested
but no improvement was observed. Overall, the novel nicotine-
based decafluorocatalyst demonstrates good yields and high
enantioselectivities when employed in the catalytic asymmetric
addition of diethylzinc to aromatic aldehydes.
8. Wagner, F. F.; Comins, D. L. Eur. J. Org. Chem. 2006, 3562.
9. For recent examples and leading references, see: (a) Park, J. K.; Lee, H. G.; Bolm,
C.; Kim, B. M. Chem. Eur. J. 2005, 11, 945; (b) Lin, R.-X.; Chen, C. J. Mol. Catal. A:
Chem. 2006, 243, 89; (c) Milburn, R. R.; Hussain, S. M. S.; Prien, O.; Ahmed, Z.;
Snieckus, V. Org. Lett. 2007, 9, 4403.
Finally, to investigate the effect of the C-6 chlorine substituent
on the nicotine-based catalysts during the asymmetric reaction,
compounds 13 and 14 were synthesized from 12 and 7a as shown
in Scheme 3 and compared to 7a. This comparison was intended to
provide insight as to whether or not the C-4 substituted nicotine-
based catalysts could be modified to enhance enantioselectivity
in the asymmetric reaction by adding or removing chlorine substit-
uents on the pyridine ring. Addition of a chlorine substituent to the
C-5 position of the catalyst, as shown with compound 13, increased
the selectivity from 79% to 95% ee at 20 mol %, but at 5 mol % a
slight decrease in selectivity was observed (Table 4, entries 2 and
3). In contrast, catalyst 14, with no chlorine substituents, effected
a decrease in observed selectivity as compared to ligand 7a (entries
4 and 5). This study showed that it is necessary to have at least one
chlorine substituent on the pyridine portion of the catalyst in order
to maintain adequate enantioselectivity in the asymmetric addi-
tion of organozinc reagents to aldehydes.
Although further study is needed to understand how the sub-
stituents affect the degree of chirality transfer, it appears that a
C-6 electron-withdrawing group may be needed to reduce the ba-
sicity, and thus the coordinating ability, of the pyridyl nitrogen.
In summary, novel chiral amino alcohol catalysts have been
prepared in two to three steps from natural (S)-nicotine.10 The
ability of these catalysts to transfer chirality was determined by
using the asymmetric addition of diethylzinc to aldehydes as a
screen. A high degree of enantioselectivity was obtained in several
examples. The effectiveness of these catalysts in other asymmetric
reactions and the synthesis of other types of ligands from commer-
cially available (S)-nicotine are under study in our laboratories.
10. General procedure for the preparation of the nicotine-derived ligands: To
a
solution of (S)-6-chloronicotine (2, 200 mg, 1.02 mmol) in THF (2 mL) was
added n-BuLi (0.68 mL, 1.12 mmol) at ꢀ78 °C. After 1 h, a solution of the
aldehyde or ketone (1.2 equiv) in toluene (2 mL) kept over molecular sieves
was cannulated into the reaction. The mixture was stirred for 30–60 min at
ꢀ78 or ꢀ42 °C after which it was quenched with aqueous saturated sodium
bicarbonate (2 mL). After warming to room temperature, the organic layer was
separated. The aqueous layer was extracted with methylene chloride
(2 ꢁ 10 mL). The combined organic layers were dried over potassium
carbonate, filtered, and concentrated in vacuo. The crude product was
purified by radial PLC (silica gel).
Spectral data: [5-((2S)-1-Methylpyrrolidin-2-yl)-2-chloro(4-pyridyl)]bis(2,3,4,5,6-
pentafluorophenyl)methan-1-ol (7d). The crude product was purified using
radial PLC (5% TEA/hexanes; then CH2Cl2) to afford 146 mg (51%) of 7d as a
white solid, mp 38–40 °C; ½a D32
ꢂ
ꢀ16.9 (c 1.1, CH2Cl2); IR (thin film) 3380, 2963,
2924, 2856, 1650, 1578, 1524, 1484, 1122, 1005 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) d 12.82 (s, 1H), 8.36 (s, 1H), 6.93 (s, 1H), 3.54–3.49 (m, 1H), 3.35–3.30
(m, 1H), 2.49–2.41 (m, 1H), 2.27 (s, 3H), 2.24–2.17 (m, 1H), 2.13–1.96 (m, 2H),
1.93–1.85 (m, 1H); 13C NMR (75 MHz, CDCl3) d 154.3, 153.2, 152.5, 146.7,
143.4, 142.9, 139.8, 139.7, 136.7, 136.5, 132.6, 125.3, 79.5, 71.4, 56.3, 39.7,
32.7, 22.4; 19F NMR (282 MHz, CDCl3) d ꢀ133.2 (d, J = 18.6 Hz, 2F), ꢀ133.9 (d,
J = 18.6 Hz, 2F), ꢀ149.7 (m, 2F), ꢀ157.4 (m, 4F); HRMS calcd for C23H13ClF10N2O
([M+H]+) 559.0635, found 559.0654.
Bis[5-((2S)-1-methylpyrrolidin-2-yl)-2-chloro-4-pyridyl]methan-1-ol (11). The
crude product was purified using radial PLC (1% TEA/30% EtOAc/hexanes) to
afford 249 mg (74%) of 11 as a white solid, mp 80–82 °C; ½a D31
ꢀ101 (c 0.95,
ꢂ
CH2Cl2); IR (thin film) 3238, 2967, 2876, 2840, 2787, 1582, 1455, 1372, 1146,
1092 cmꢀ1 1H NMR (400 MHz, CDCl3) d 8.92 (s, 1H), 8.54 (s, 1H), 8.24 (s, 1H),
;
7.67 (s, 1H), 6.41 (s, 1H), 6.31 (s, 1H), 3.46–3.42 (m, 1H), 3.38–3.32 (m, 1H),
3.10–3.06 (m, 1H), 2.89–2.85 (m, 1H), 2.51–2.41 (m, 2H), 2.33–2.20 (m, 4H),
2.16–2.03 (m, 3H), 1.98 (s, 3H), 1.92–1.79 (m, 1H), 1.69–1.56 (m, 3H); 13C NMR
(75 MHz, CDCl3) d 154.1, 152.4, 151.6, 151.3, 150.7, 135.1, 133.6, 123.6, 122.7,
69.8, 67.0, 66.3, 57.3, 57.1, 40.7, 40.6, 34.5, 31.9, 24.6, 22.9; HRMS calcd for
C21H26Cl2N4O (M+) 421.1556, found 421.1554.
5-((2S)-1-Methylpyrrolidin-2-yl)-2,3-dichloro(4-pyridyl)diphenylmethan-1-ol (13).
The crude product was purified using radial PLC (1% TEA/2% EtoAc/hexanes;
Acknowledgments
then CH2Cl2) to afford 46 mg (30%) of 13 as a white solid, mp 170–172 °C; ½a D32
ꢂ
ꢀ164.5 (c 1.1, CH2Cl2); IR (thin film) 3321, 3057, 3027, 2957, 2784, 1550, 1489,
This work was supported in part by Targacept, Inc. We thank Dr.
Paul Boyle (NCSU) for X-ray crystallographic analysis of 5a. NMR,
X-ray analysis, and mass spectra were obtained at NCSU instru-
mentation laboratories, which were established by grants from
the North Carolina Biotechnology Center and the National Science
Foundation (Grant CHE-0078253).
1447, 1310, 1219, 1057 cmꢀ1 1H NMR (400 MHz, CDCl3) d 10.19 (s, 1H), 8.30 (s,
;
1H), 7.41–7.31 (m, 5H), 7.26–7.21 (m, 3H), 7.12–7.10 (m, 2H), 3.48–3.43 (m, 1H),
3.12–3.08 (m, 1H), 2.64–2.55 (m, 1H), 2.34–2.28 (m, 1H), 2.26–2.19 (m, 1H),
2.12–2.00 (m, 1H), 1.89–1.83 (m, 1H), 1.64 (s, 3H); 13C NMR (100 MHz, CDCl3) d
157.4, 150.4, 147.4, 143.2, 136.7, 129.0, 128.2, 128.0, 127.9, 127.8, 127.1, 84.8,
73.2, 56.5, 39.4, 34.8, 22.0; HRMS calcd for C23H22Cl2N2O (M+) 413.1181, found
413.1173.