Stereocomplexity and stereoselective synthesis of triamine molecules bearing four chiral carbon centers: Stereodifferentiated preparation of all 10 stereoisomers of 2,6-bis[1-(1-phenylethylamino)ethyl]pyridines

Article abstract of DOI:10.1021/jo061729e

Compounds (S,S)-2,6-bis(1-hydroxyethyl)pyridine, (R,R)-2,6-bis(1- acetoxyethyl)pyridine, and (1R,1′S)-2-(1-acetoxyethyl)-6-(1′- hydroxyethyl)pyridine were obtained by lipase-catalyzed kinetic acetylation of 2,6-bis(1-hydroxyethyl)pyridine as enantiomerica

Full text of DOI:10.1021/jo061729e

Stereocomplexity and Stereoselective Synthesis of Triamine
Molecules Bearing Four Chiral Carbon Centers:
Stereodifferentiated Preparation of All 10 Stereoisomers
of 2,6-Bis[1-(1-phenylethylamino)ethyl]pyridines
Jun’ichi Uenishi,* Sachiko Aburatani, and Taro Takami
Kyoto Pharmaceutical UniVersity, Misasagi, Yamashina, Kyoto 607-8412, Japan
juenishi@mb.kyoto-phu.ac.jp
ReceiVed August 21, 2006
Compounds (S,S)-2,6-bis(1-hydroxyethyl)pyridine, (R,R)-2,6-bis(1-acetoxyethyl)pyridine, and (1R,1′S)-
2-(1-acetoxyethyl)-6-(1′-hydroxyethyl)pyridine were obtained by lipase-catalyzed kinetic acetylation of
2,6-bis(1-hydroxyethyl)pyridine as enantiomerically pure forms. The stereospecific replacement of hydroxy
groups with (R)-phenylethylamine or (S)-phenylethylamine via its methanesulfonate or toluenesulfonate
simultaneously or stepwise afforded all the stereoisomers of 1. Stereospecific preparation of all the 10
possible stereoisomers of 2,6-bis[1-(1-phenylethylamino)ethyl]pyridines 1a-f was achieved. Triamine
1b reacted with ZnCl2 to form Zn-triamine complex 16, the structure of which was determined by
X-ray crystallographic analysis.
Introduction
stereoselective synthesis is undertaken. Although remarkable
technical advances and developments in separation of organic
compounds3 allow us to isolate one enantiomer or diastereo-
mer in complex molecules, this still remains difficult for spe-
cific compounds. In such cases, stereoselective synthesis is
highly desired with a combination of effective separation
techniques.
We have been interested in such symmetric and asymmetric
organic molecules possessing multichiral centers. In this paper,
we report the stereodefined synthesis of 10 2,6-bis[1-(1-
phenylethylamino)ethyl]pyridines 1a-f in a stereochemically
pure form.
The chirality and stereocomplexity of natural and unnatural
molecules have attracted much attention.1 Related to them, the
molecular symmetry and asymmetry of organic compounds have
been an important subject in organic chemistry.2 When the
molecule possesses multiple n-chiral centers, 2n of stereoisomers
are present. If we wish to obtain only one of the stereoisomers,
chromatographic separation by HPLC, recrystallization or
(1) (a) Lough, W. J.; Wainer, I. W. Chirality in Natural and Applied
Science; Blackwell Science Ltd.: Oxford, 2003. (b) Denmark, S. E.; Siegel,
J. Materials Chirality. In Topics in Stereochemistry; John Wiley & Sons,
Inc.: Hoboken, 2003; Vol. 24.
(2) (a) Nakazaki, M. The Synthesis and Stereochemistry of Chiral Organic
Molecules with High Symmetry. In Topics in Stereochemistry; Wiley: New
York, 1984; Vol. 15, pp 199-251. (1984). (b) Flapan, E. When Topology
Meets Chemistry: A Topological Look at Molecular Chirality; Cambridge
University Press: Cambridge, 2000.
(3) (a) Subramanian, G. Chiral Separation Techniques: A Practical
Approach; Wiley-VCH: Weinheim, 2001. (b) Gu¨bitz, G.; Schmid, M. G.
Chiral Separations: Methods and Protocols in Methods in Molecular
Biology; Humana Press, Inc.: Totowa, 2004.
10.1021/jo061729e CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/09/2006
132
J. Org. Chem. 2007, 72, 132-138

Stereocomplexity and StereoselectiVe Synthesis of Triamine Molecules
SCHEME 1
could not be separated completely by HPLC or GPC. Therefore,
we decided to try to stereoselectively synthesize them.
Tactics for the Construction of Chiral Centers and
Synthetic Strategy for 1a-f. Previously, we reported that the
substitution reaction of chiral 1-(2-pyridinyl)ethyl methane-
sulfonates with amine nucleophiles5 proceeds stereospecifically
to give the stereoinversion product via an SN2 process exclu-
sively, as shown in Scheme 1. Various kinds of optically pure
1-(2-pyridinyl)ethylamines were synthesized from the corre-
sponding optically pure alcohol in two steps: (i) methansulfo-
nylation and (ii) stereospecific substitution at the benzylic
position. The starting chiral alcohol could be prepared very
efficiently by lipase-catalyzed kinetic acetylation of racemic
alcohol.6
FIGURE 1. Ten stereoisomers of 2,6-bis[1-(1-phenylethylamino)ethyl]-
pyridine.
Therefore, if we can obtain chiral 2,6-bis(1-hydroxyethyl)-
pyridines, (R,R)-2, (S,S)-2, meso-2, and (1′R,1′′S)-2-(1′-ac-
etoxyethyl)-6-(1′′-hydroxyethyl)pyridine (ROAc,SOH)-4 by
lipase-catalyzed kinetic acetylation7 and they are subject to the
stereospecific substituted reaction via their methanesulfonates,
compounds 1a-f will be synthesized stereoselectively, as shown
in Scheme 2. Namely, their starting materials will be these chiral
(R,R)-2, (S,S)-2, (ROAc,SOH)-4, and meso-2. Substitution
reactions of the corresponding mesylate with (S)-(-)-phenyl-
ethylamine (X in Scheme 2) or (R)-(+)-phenylethylamine (Y
in Scheme 2) give 1a-f stepwise or simultaneously.
Preparation of 2,6-Bis(1-hydroxyethyl)pyridines.7 A dias-
tereomixture of 2,6-bis(1-hydroxyethyl)pyridine 2 was prepared
by reduction of 2,6-bisacetylpyridine with NaBH4. A kinetic
acetylation of 2 with vinyl acetate in the presence of Candida
antarctica lipase gave diacetate (R,R)-3 in 23% yield, mono-
acetate (ROAc,SOH)-4 in 45% yield and the recovery of (S,S)-2
in 23% yield. Potassium carbonate promoted methanolysis of
(R,R)-3 gave diol (R,R)-2 in quantitative yield. On the other
hand, methanolysis of monoacetate (ROAc,SOH)-4 gave me-
so-2 in 79% yield (Scheme 3).
Preparation of 1a-c from (R,R)-2 and 1a′, 1b′, and 1c′
from (S,S)-2. Mesylation of (R,R)-2 in CH2Cl2 gave dimesylate
(R,R)-5 in quantitative yield. Substitution of the mesylate with
(S)-phenylethylamine in the presence of N,N′-diisopropylethy-
FIGURE 2. Structures of 1a-f.
(5) (a) Uenishi, J.; Takagi, T.; Ueno, T.; Hiraoka, T.; Yonemitsu, O.;
Tsukube, H. Synlett 1999, 41-44. (b) Uenishi, J.; Hamada, M.; Aburatani,
S.; Matsui, K.; Yonemitsu, O.; Tsukube, H. J. Org. Chem. 2004, 69, 6781-
6789.
Results and Discussion
Since four chiral centers exist in 1, 16 (24) stereoisomers are
available theoretically.4 However, due to the symmetry of the
molecule, eight chiral diastereoisomers involving 4 enantiomeric
pairs of 1a,a′, 1b,b′, 1c,c′, and 1d,d′ and two meso isomers 1e
and 1f actually exist, the structures of which are shown in
Figures 1 and 2. Although all of the diastereomers and
enantiomers of 1 were prepared by three steps, including the
nonselective reduction of 2,6-bisacetylpyridine with NaBH4,
mesylation with methanesulfonyl chloride, and the substitution
of mesylate with racemic 1-phenylethylamine. However, they
(6) Uenishi, J.; Hiraoka, T.; Hata, S.; Nishiwaki, K.; Yonemitsu, O.;
Nakamura, K.; Tsukube, H. J. Org. Chem. 1998, 63, 2481-2487.
(7) Preparation by asymmetric reduction or hydrogen transfer reaction:
(a) Ramachandran, P. V.; Chen, G.; Lu, Z.; Brown, H. C. Tetrahedron Lett.
1996, 37, 3795-3798. (b) Ohkuma, T.; Koizumi, M. Yoshida, M.; Noyori,
R. Org. Lett. 2000, 2, 1749-1751. (c) Okano, K.; Murata, K.; Ikariya, T.
Tetrahedron Lett. 2000, 41, 9277-9280. Preparation by enzymatic reduc-
tion: (d) Bailey, D.; O’Hagan, D.; Dyer, U.; Lamont, R. B. Tetrahedron:
Asymmetry 1993, 4, 1255-1258. (e) Garrett, M. D.; Scott, R.; Sheldrake,
G. N. Tetrahedron: Asymmetry 2002, 13, 2201-2204. Preparation by lipase-
catalyzed kinetic acetylation: (f) Wallance, J. S.; Baldwin, B. W.; Morrow,
C. J. J. Org. Chem. 1992, 57, 5231-5239. (g) Persson, B. A.: Huerta, F.
F.; Backvall, J.-E. J. Org. Chem. 1999, 64, 5237-5240. (h) Szatzker, G.;
Moczar, I.; Kolonits, P.; Novak, L.; Huszthy, P.; Poppe, L. Tetrahedron:
Asymmetry 2004, 15, 2483-2490.
(4) Eliel, E. L.; Wilen, S. H.; Mander L. N. Stereochemistry of Organic
Compounds; Wiley-Interscience: New York, 1994.
J. Org. Chem, Vol. 72, No. 1, 2007 133

Uenishi et al.
SCHEME 2. Synthetic Plan for 1a-f
SCHEME 3
Preparation of meso-Isomers 1e and 1f from (ROAc,
SOH)-4. The synthesis of a meso-isomer with four chiral centers
is rather complicated. Although a mixture of dl- and meso-
isomers can be easily prepared by a nonstereoselective method,
stereocontrolled synthesis of the meso-isomer is as difficult as
that of the chiral isomer. Stepwise and stereospecific replace-
ment reactions are required in both sides on the 2- and
6-positions of the pyridine ring. First, an (S)-alcohol of
(ROAc,SOH)-4 was mesylated and the resulting mesylate 11
was replaced with (S)-phenylethylamine inducing (R)- and (S)-
chiral centers on the right of the pyridine ring to afford 12 in
88% yield (Scheme 6). The acetate of 12 was hydrolyzed, and
the resulting alcohol was tosylated to give 13 in 78% yield in
two steps. Finally, substitution of the tosylate with (R)-
phenylethylamine gave meso-isomer 1e in 84% yield. No
specific rotation of 1e was observed. The proton NMR chart
became quite simple. Two sets of methine protons appeared at
3.84 and 3.76 ppm as a quartet. Four methyl groups were
observed at 1.37 ppm as a doublet. On the other hand, the
synthesis of another meso-isomer 1f was performed in four steps
from 11. Treatment of 11 with (R)-phenylethylamine gave 14
in 84% yield. Then methanolysis of 14, followed by tosylation
gave 15 in 70% yield in two steps. The substitution of 15 with
(S)-phenylethylamine eventually gave 1f in 83% yield. This
compound also showed no specific rotation. In its proton NMR,
characteristic peaks appeared at 1.30 ppm for 6 protons of two
methyl groups as a doublet and at 1.29 ppm for 6 protons of
the other two methyl groups as a doublet. At 3.59 and 3.48
ppm, two of each methine protons appeared as a quartet.
Structures of Six Diastereomers of 1a-f. In all compounds
1a-f, no diastereomer can be observed in their proton and
carbon NMR spectra, clearly indicating the high purity of the
stereoisomers. Patterns of proton NMR chemical shifts of the
2,6-side chain part are characteristic for 1a-f. The chemical
shifts of four methyl groups and four methine groups are listed
in Table 1. It is interesting that two 1,3-methine and two 1,3-
methyl groups existing in syn-relation for 1b, 1e, and part of
1c and 1d, and those existing in an anti-relation for 1a, 1f, and
part of 1c and 1d are easily identified. The chemical shifts of
lamine in CH3CN at 60 °C afforded 1a in 70% yield, while
that with (R)-phenylethylamine afforded 1b in 75% yield.
Tosylation of (R,R)-2 was carried out at room temperature in
CH2Cl2 to give 6 in 44% yield selectively at 50% conversion
of the reaction, though the formation of ditosylate was increased
when reaction time was prolonged. Substitution of the tosylate
with (R)-phenylethylamine gave 7 in 99% yield. Replacement
of the remaining hydroxy group with (S)-phenylethylamine was
performed via the corresponding tosylate 8 to give 1c in 61%
yield in two steps. In a similar manner, enantiomers of 1a′ and
1b′ were synthesized via dimesylate (S,S)-5 in 81% and 97%
yields respectively. Compound 1c′ was derived from (S,S)-2 in
four steps. The enantiomer 6′ derived from (S,S)-2 by mono-
tosylation reacted with (R)-phenylethylamine to give 9 in 91%
yield. After tosylation of the remaining alcohol, the substitution
of the tosylate 10 with (S)-phenylethylamine afforded 1c′ in
68% yield in two steps (Scheme 4).
Preparation of 1d and 1d′ from meso-2. The synthesis of
1d and 1d′ from meso-2 is shown in Scheme 5. Dimesylation
of meso-2 gave meso-5 quantitatively. Substitution of the
mesylates with (S)-phenylethylamine and with (R)-phenylethy-
lamine in the presence of N,N′-diisopropylethylamine in CH3-
CN at 60 °C gave optically pure 1d and 1d′ in 75% and 63%
yields, respectively.
134 J. Org. Chem., Vol. 72, No. 1, 2007

Stereocomplexity and StereoselectiVe Synthesis of Triamine Molecules
SCHEME 4a
SCHEME 6a
a Reagents and conditions: (a) MsCl (3 equiv), Et3N (5 equiv), CH2Cl2,
i
rt; (b) (S)-phenylethylamine (3 equiv), Pr2NEt (5 equiv), CH3CN, 60 °C;
(c) K2CO3 (3 equiv), MeOH; (d) TsCl (1.2 equiv), Et3N (1 equiv), DMAP
i
(0.6 equiv), CH2Cl2, rt; (e) (R)-phenylethylamine (3 equiv), Pr2NEt (5
equiv), CH3CN, 60 °C.
TABLE 1. Chemical Shifts of Methine and Methyl Protons for
1a-f
entry
compd
methine protons (ppm)
methyl protons (ppm)
1
2
3
1a
1b
1c
3.58a
3.84a
3.87
3.56
3.86
3.56
3.84a
3.59a
3.45a
3.72a
3.74
3.42
3.76
3.43
3.76a
3.48a
1.30b
1.36c
1.40
1.28
1.40
1.27
1.37c
1.30b
1.28b
1.39
1.26
1.39
1.19
4
1d
5
6
1e
1f
1.29b
a Two protons. b Six protons. c Twelve protons.
a Reagents and conditions: (a) MsCl (3 equiv), Et3N (5 equiv), CH2Cl2,
chain of 1 takes an extended conformation in CDCl3 solution.
However, when a metal ion is added to 1, triamine is able to
coordinate with the metal ion to form a metal-triamine ligand
complex. If the complex is formed, the molecule would take a
holding conformation. In fact, when ZnCl2 was added to the
CDCl3 solution of 1b, these symmetric methyl and methine
protons of 1b shifted down to be 4.57 and 3.94 ppm for two
kinds of two methines and 1.58 and 1.43 ppm for two kinds of
two methyl groups. ZnCl2-1b complex 16 was produced as
nice crystals in 65% yield by the reaction of 1b with ZnCl2 in
ethanol. The NMR spectrum of the resulting crystals in CDCl3
exactly matched that observed in the mixture of 1b and ZnCl2.
X-ray crystalographical analysis of the single-crystal clearly
supported the holding structure of 16, an ORTEP view of which
is shown in Figure 3. It is found that the complex has a pincer-
type structure with two newly generated (S)-chiral centers on
the nitrogen atoms. Chiral pyridines have been recognized as
an important ligand not only for asymmetric synthesis but also
functional materials.8 These chiral pyridine diamines will be
expected to have such functional properties.
i
rt; (b) (S)-phenylethylamine (3 equiv), Pr2NEt (5 equiv), CH3CN, 60 °C;
(c) (R)-phenylethylamine (3 equiv), iPr2NEt (5 equiv), CH3CN, 60 °C; (d)
TsCl (1.2 equiv), Et3N (1 equiv), DMAP (0.6 equiv), CH2Cl2, rt.
SCHEME 5
two methines in syn-relation appear in the range of 3.72-3.87
ppm and those in anti-relation appear in the range of 3.42-
3.59 ppm. On the other hand, the chemical shifts of 1,3-dimethyl
groups in syn-relation appear between 1.36 and 1.40 ppm and
those in anti-relation appear between 1.19 and 1.30 ppm.
Because compounds 1c and 1d have no C2 symmetry, their four
methines as well as their four methyls show different chemical
shifts, while compounds having C2 symmetry such as 1a and
1b or meso-compounds 1e and 1f indicate two kinds of methine
protons. These proton NMR spectra suggest that the carbon
Conclusion
In summary, we have succeeded in stereodifferentiated
synthesis of all the stereoisomers of 2,6-bis[1-(1-phenylethy-
J. Org. Chem, Vol. 72, No. 1, 2007 135

Uenishi et al.
(1′S,1′′S)-2,6-Bis(1-hydroxyethyl)pyridine ((S,S)-2): colorless
oil; Rf ) 0.51 (EtOAc); [R]32D -59 (c 0.9, acetone), [R]29D -25 (c
1
1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 7.70 (t, J ) 7.7 Hz,
1H), 7.21 (d, J ) 7.7 Hz, 2H), 4.90 (q, J ) 6.6 Hz, 2H), 3.89 (brs,
2H), 1.51 (d, J ) 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 162.0
(2C), 137.7, 118.3 (2C), 69.1 (2C), 24.0 (2C); IR (film, cm-1) 3366.
(1′R,1′′S)-2-(1′-Acetoxyethyl)-6-(1′′-hydroxyethyl)pyridine
((ROAc,SOH)-4): colorless oil; Rf ) 0.67 (EtOAc); [R]29D +48 (c
1
0.7, acetone), [R]29 +89 (c 1.0, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 7.69 (t, J ) 7.7 Hz, 1H), 7.24 (d, J ) 7.7 Hz, 1H), 7.17
(d, J ) 7.7 Hz, 1H), 5.93 (q, J ) 6.6 Hz, 1H), 4.87 (q, J ) 6.6 Hz,
1H), 4.48 (brs, 1H), 2.13 (s, 3H), 1.59 (d, J ) 6.6 Hz, 3H), 1.49
(d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.0, 162.5,
158.5, 137.4, 118.9, 118.2, 72.6, 68.5, 23.9, 20.9, 20.4; IR (film,
cm-1) 3418, 1737.
Preparation of (R,R)-2 and meso-2. A mixture of (R,R)-3 or
(ROAc,SOH)-4 (1.0 mmol) and K2CO3 (3.0 mmol) was stirred in
MeOH (10 mL) for 10 min at room temperature. The mixture was
then diluted with water and extracted with CHCl3. The organic
extract was washed with brine, and dried over MgSO4. After
removal of the solvent, the residue was purified by column
chromatography on silica gel eluted with EtOAc to give (R,R)-2
in quantitative yield or meso-2 in 79% yield.
FIGURE 3. Synthesis and crystal structure of Zn complex 16.
lamino)ethyl]pyridines 1a-f. The synthesis involving stepwise
or simultaneous stereospecific substitution of pyridinylethyl
methansulfonate or toluenesulfonate with (R)- or (S)-phenyl-
ethylamine is highly efficient with high enantio- and diastereo
selectivities to provide optically pure triamine molecules, which
is found to exist as an extended conformation. Chiral Zn-
triamine complex 16 was prepared and the absolute structure
was revealed by the X-ray analysis. The approach for the
stereoselective preparation of 1 is a good example of the
systematic synthesis of complex molecules having multiple
chiral centers.
(1′R,1′′R)-2,6-Bis(1-hydroxyethyl)pyridine ((R,R)-2): colorless
oil; [R]26D +27 (c 0.4, CHCl3), [R]24D +62 (c 0.7, acetone). All of
the spectroscopic data including 1H NMR, 13C NMR, IR, and MS
are exactly same as those of (S,S)-2 except specific rotation.
meso-2,6-Bis(1-hydroxyethyl)pyridine (meso-2): white powder;
1
mp 69-71 °C (EtOH). All of the spectroscopic data including H
NMR, 13C NMR, IR, and MS are exactly same as those of (S,S)-2.
General Method for Mesylation: Preparation of 5. To a stirred
solution of 2 (250 mg, 1.5 mmol) in CH2Cl2 (15 mL) were added
Et3N (1.05 mL, 7.5 mmol) and MsCl (0.35 mL, 4.5 mmol) at 0 °C.
The mixture was stirred for 10 min at room temperature, diluted
with water, and extracted with CHCl3. The organic extract was
washed with brine and dried over MgSO4. After removal of the
solvent, the residue was purified by column chromatography on
silica gel eluted with 30% EtOAc in hexane to give 5 in quantitative
yield.
Experimental Section
Mixture of dl- and meso-2,6-Bis(1-hydroxyethyl)pyridine (2).7
To a solution of 2,6-bisacetylpyridine (13.0 g, 79.7 mmol) in MeOH
(150 mL) was added NaBH4 (2.00 g, 52.9 mmol) at 0 °C, and the
mixture was stirred for 1 h at room temperature. The reaction
mixture was quenched with water and extracted with CHCl3 a few
times. The combined organic extracts were washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The crude
residue was distilled to give 2 (12.7 g) in 95% yield: colorless oil;
(1′R,1′′R)-2,6-Bis(1-methanesulfonyloxyethyl)pyridine ((R,R)-
5): white powder; mp 75-77 °C (EtOH); Rf ) 0.28 (50% EtOAc
in hexane); [R]24 +121 (c 0.5, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.82 (t, J ) 7.9 Hz, 1H), 7.45 (d, J ) 7.9 Hz, 2H), 5.78
(q, J ) 6.6 Hz, 2H), 2.98 (s, 6H), 1.76 (d, J ) 6.6 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 158.0 (2C), 138.3, 120.4 (2C), 80.1 (2C),
38.7 (2C), 21.6 (2C); IR (KBr, cm-1) 1353, 1173; MS(CI) m/z 324
(M + H+); HRMS calcd for C11H18NO6S2 (M + H+) 324.0575,
found m/z 324.0569. Anal. Calcd for C11H17NO6S2: C, 40.80; H,
5.47; N, 4.18. Found: C, 40.86; H, 5.30; N, 4.33.
1
Rf ) 0.29 (70% EtOAc in hexane); bp 120-121 °C/2 mmHg; H
NMR (300 MHz, CDCl3) δ 7.70 (t, J ) 7.7 Hz, 1H), 7.22 (d, J )
7.7 Hz, 2H,), 4.90 (q, J ) 6.6 Hz, 2H), 3.92 (brs, 2H), 1.51 (d, J
) 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 162.0 (2C), 137.7,
118.3 (2C), 69.1 (2C), 24.1 (2C); IR (film, cm-1) 3292.
Lipase-Catalyzed Kinetic Acetylation of 2,6-Bis(1-hydroxy-
ethyl)pyridine. A mixture of 2,6-bis(1-hydroxyethyl)pyridine (2)
(4.48 g, 26.8 mmol), Cal (Novozym 435) (2.69 g), MS 4A (8.8 g),
(1′S,1′′S)-2,6-Bis(1-methanesulfonyloxyethyl)pyridine ((S,S)-
i
5): white powder; mp 75-77 °C (EtOH); [R]26 -112 (c 0.1,
D
and vinyl acetate (9.3 mL, 118 mmol) was stirred in Pr2O (350
CHCl3). All of the spectroscopic data including 1H NMR, 13C NMR,
IR, and MS are exactly same as those of (R,R)-5 except specific
rotation.
mL) for 10 h at room temperature. The mixture was passed through
a Celite pad, and the filtrate was condensed under reduced pressure.
The crude residue was purified by column chromatography on silica
gel eluted with 20% EtOAc in hexane to give (R,R)-3 in 23% yield,
with 50% EtOAc in hexane to give (ROAc,SOH)-4 in 45% yield,
and with EtOAc to give (S,S)-2 in 23% yield.
(1′R,1′′R)-2,6-Bis(1-acetoxyethyl)pyridine ((R,R)-3): colorless
oil; Rf ) 0.82 (EtOAc); [R]29D +138 (c 1.8, acetone), [R]29D +151
(c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.66 (t, J ) 7.8 Hz,
1H), 7.21 (d, J ) 7.8 Hz, 2H), 5.91 (q, J ) 6.6 Hz, 2H), 2.13 (s,
6H), 1.58 (d, J ) 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 169.9
(2C), 159.7 (2C), 137.2, 118.7 (2C), 72.8 (2C), 21.0 (2C), 20.5
(2C); IR (film, cm-1) 1740.
meso-2,6-Bis(1-methanesulfonyloxyethyl)pyridine (meso-5):
white powder; mp 48-49.5 °C (EtOH). All of the spectroscopic
1
data including H NMR, 13C NMR, IR, and MS are exactly same
as those of (R,R)-5.
General Substitution Reaction of Mesylate with (S)- and (R)-
Phenylethylamine: Reaction of 5. A mixture of 5 (1.0 mmol),
iPr2NEt (5.0 mmol), and (S)- or (R)-phenylethylamine (3.0 mmol)
in CH3CN (5.0 mL) was heated at 60 °C for 23-36 h. After the
reaction was completed, the mixture was diluted with water and
extracted with CHCl3. The organic extract was washed with
saturated aq NaHCO3 and dried over Na2SO4. After removal of
the solvent, the residue was purified by column chromatography
on silica gel eluted with 50% EtOAc in hexane to give 1a, 1b, 1d,
or their enantiomers.
(8) (a) Schulz, E. Top. Organomet. Chem. 2005, 15, 93-148. (b)
Mamula, O.; von Zelewsky, A. Coord. Chem. ReV. 2003, 242, 87-95. (c)
Chelucci, G. Tetrahedron: Asymmetry 2005, 16, 2253-2383.
136 J. Org. Chem., Vol. 72, No. 1, 2007

Stereocomplexity and StereoselectiVe Synthesis of Triamine Molecules
(1′S,1′′S)-2,6-Bis{1-[(S)-1-phenylethyl]aminoethyl}pyridine (1a):
70% yield; colorless oil; Rf ) 0.30 (EtOAc); [R]28D -249 (c 0.20,
oil; Rf ) 0.16 (EtOAc); [R]26D -26 (c 0.2, CHCl3); 1H NMR (300
MHz, CDCl3) δ 7.59 (t, J ) 7.7 Hz, 1H), 7.27-7.17 (m, 5H), 7.11
(d, J ) 7.7 Hz, 1H), 7.07 (d, J ) 7.7 Hz, 1H), 4.84 (q, J ) 6.6 Hz,
1H), 3.88 (q, J ) 6.6 Hz, 1H), 3.77 (q, J ) 6.6 Hz, 1H), 2.04 (brs,
1H), 1.48 (d, J ) 6.6 Hz, 3H), 1.39 (d, J ) 6.6 Hz, 3H), 1.38 (d,
J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.8, 162.1, 145.5,
137.2, 128.4 (2C), 126.9, 126.6 (2C), 119.7, 117.8, 68.4, 56.0, 55.3,
24.2, 23.4, 21.8. IR (film, cm-1) 3315; MS(CI) m/z 271 (M + H+);
HRMS calcd for C17H23N2O (M + H+) 271.1810, found m/z
271.1808. Its diasrtereomer 9 was obtained from 6′ with (R)-
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.52 (t, J ) 7.6 Hz, 1H),
7.34-7.21 (m, 10H), 6.92 (d, J ) 7.6 Hz, 2H), 3.58 (q, J ) 6.6
Hz, 2H), 3.45 (q, J ) 6.6 Hz, 2H), 1.89 (s, 2H), 1.30 (d, J ) 6.6
Hz, 6H), 1.28 (d, J ) 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
164.2 (2C), 145.5 (2C), 136.4, 128.4 (4C), 126.9 (4C), 126.9 (2C),
120.0 (2C), 56.2 (2C), 55.8 (2C), 25.1 (2C), 23.6 (2C); IR (film,
cm-1) 3319; MS (FAB) m/z 374 (M + H+); HRMS calcd for
C25H32N3 (M + H+) 374.2596, found m/z 374.2603.
phenylethylamine in 91% yield: colorless oil; Rf ) 0.30 (EtOAc);
(1′R,1′′R)-2,6-Bis{1-[(R)-1-phenylethyl]aminoethyl}pyridine
1
[R]25 +159 (c 0.3, CHCl3); H NMR (300 MHz, CDCl3) δ 7.62
(1a′): 81% yield; colorless oil; [R]26 +240 (c 0.07, CHCl3).
D
D
(t, J ) 7.7 Hz, 1H), 7.34-7.25 (m, 5H), 7.12 (d, J ) 7.7 Hz, 1H),
7.00 (d, J ) 7.7 Hz, 1H), 4.89 (q, J ) 6.4 Hz, 1H), 3.62 (q, J )
6.6 Hz, 1H), 3.46 (q, J ) 6.6 Hz, 1H), 1.51 (d, J ) 6.4 Hz, 3H),
1.32 (d, J ) 6.6 Hz, 3H), 1.29 (d, J ) 6.6 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 163.1, 162.5, 145.5, 137.1, 128.4 (2C), 126.9 (2C),
126.8, 120.2, 117.8, 68.4, 56.0, 55.6, 25.1, 24.3, 23.3; IR (film,
cm-1) 3315; MS(CI) m/z 271 (M + H+); HRMS calcd for
C17H23N2O (M + H+) 271.1810, found m/z 271.1818.
(1′S,1′′S)-2,6-Bis{1-[(R)-1-phenylethyl]aminoethyl}pyridine (1b):
75% yield; colorless oil; Rf ) 0.30 (EtOAc); [R]28 -60 (c 0.30,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.49 (t, J ) 7.7 Hz, 1H),
7.25-7.06 (m, 10H), 7.01 (d, J ) 7.7 Hz, 2H), 3.84 (q, J ) 6.6
Hz, 2H), 3.72 (q, J ) 6.6 Hz, 2H), 2.01 (s, 2H), 1.36 (d, J ) 6.6
Hz, 12H). 13C NMR (75 MHz, CDCl3) δ 163.6 (2C), 145.7 (2C),
136.6, 128.3 (4C), 126.8 (2C), 126.8 (4C), 119.2 (2C), 55.9 (2C),
55.2 (2C), 23.1 (2C), 22.0 (2C); IR (film, cm-1) 3314; MS (FAB)
m/z 374 (M + H+); HRMS calcd for C25H32N3 (M + H+) 374.2596,
found m/z 374.2593.
(1′S,1′′R)-2-{1′′-[(R)-1-Phenylethyl]aminoethyl}-6-[1′-(p-tolu-
enesulfonyloxy)ethyl]pyridine (8). A tosylation of 7 and 9 was
carried out in a manner similar to that described for the synthesis
of 6 and 6′. Elution of the crude mixture with 50% EtOAc in hexane
(1′R,1′′R)-2,6-Bis{1-[(S)-1-phenylethyl]aminoethyl}pyridine
(1b′): 97% yield; colorless oil; [R]26 +62 (c 0.07, CHCl3).
D
for column chromatography on silica gel gave 8 in 77% yield. 8:
(1′R*,1′′S*)-2,6-Bis{1-[(S)-1-phenylethyl]aminoethyl}-
1
colorless oil; Rf ) 0.52 (EtOAc); [R]24 -61 (c 0.06, CHCl3); H
pyridine (1d): 75% yield; colorless oil; Rf ) 0.36 (EtOAc); [R]23
D
D
1
NMR (300 MHz, CDCl3) δ 7.65 (d, J ) 8.3 Hz, 2H), 7.43 (t, J )
7.7 Hz, 1H), 7.16-7.08 (m, 8H), 6.97 (q, J ) 7.7 Hz, 1H), 5.51
(q, J ) 6.6 Hz, 1H), 3.74 (q, J ) 6.6 Hz, 1H), 3.63 (q, J ) 6.6 Hz,
1H), 2.31 (s, 3H), 1.51 (d, J ) 6.6 Hz, 3H), 1.30 (d, J ) 6.6 Hz,
3H), 1.24 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 163.3,
157.8, 144.5 (2C), 137.1, 134.0, 129.6 (2C), 128.4 (2C), 127.8 (2C),
126.9, 126.7 (2C), 120.6, 118.5, 80.9, 60.4, 55.9, 55.4, 23.0, 21.9,
21.6; IR (film, cm-1) 3319, 1364, 1177; MS(CI) m/z 425 (M +
H+); HRMS calcd for C24H29N2O3S (M + H+) 425.1899, found
m/z 425.1908. Its diastereomer 10 was obtained from 9 in 75%
yield: colorless oil; Rf ) 0.65 (EtOAc); [R]23D +62 (c 0.42, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.77 (t, J ) 8.4 Hz, 2H), 7.57 (t, J
) 7.7 Hz, 1H), 7.34-7.24 (m, 8H), 7.00 (d, J ) 7.7 Hz, 1H), 5.63
(q, J ) 6.6 Hz, 1H), 3.60 (q, J ) 6.4 Hz, 1H), 3.43 (q, J ) 6.4 Hz,
1H), 2.41 (s, 3H), 1.63 (d, J ) 6.6 Hz, 3H), 1.32 (d, J ) 6.4 Hz,
3H), 1.29 (d, J ) 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 163.9,
158.3, 145.3, 144.5, 137.0, 134.0, 129.6 (2C), 128.4 (2C), 127.8
(2C), 126.9, 126.8 (2C), 121.0, 118.4, 80.9, 56.0, 55.7, 24.9, 23.5,
21.7, 21.6; IR (film, cm-1) 3418, 1364, 1190, 1177; MS(CI) m/z
425 (M + H+); HRMS calcd for C24H29N2O3S (M + H+) 425.1899,
found m/z 425.1897.
-86 (c 0.10, CHCl3); H NMR (300 MHz, CDCl3) δ 7.49 (t, J )
7.7 Hz, 1H), 7.33-7.17 (m, 10H), 7.04 (d, J ) 7.7 Hz, 1H), 6.89
(d, J ) 7.7 Hz, 1H), 3.86 (q, J ) 6.6 Hz, 1H), 3.76 (q, J ) 6.6 Hz,
1H), 3.56 (q, J ) 6.8 Hz, 1H), 3.43 (q, J ) 6.4 Hz, 2H), 2.35 (s,
2H), 1.40 (d, J ) 6.6 Hz, 3H), 1.39 (d, J ) 6.6 Hz, 3H), 1.27 (d,
J ) 6.8 Hz, 3H), 1.19 (d, J ) 6.4 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 163.9, 163.8, 145.8, 145.6, 136.5 (3C), 128.3 (2C), 126.9
(2C), 126.8 (2C), 126.6 (2C), 119.8, 119.2, 56.1, 55.7, 55.7, 55.2,
25.1, 23.6, 23.5, 21.9; IR (film, cm-1) 3320; MS (FAB) m/z 374
(M + H+); HRMS calcd for C25H32N3 (M + H+) 374.2596, found
m/z 374.2602.
(1′R*,1′′S*)-2,6-Bis{1-[(R)-1-phenylethyl]aminoethyl}-
pyridine (1d′): 63% yield; colorless oil; [R]24 +83 (c 0.50,
D
CHCl3).
(1′R,1′′R)-2-(1′-Hydroxyethyl)-6-[1′′-(p-toluenesulfonyloxy)-
ethyl]pyridine (6). To a solution of (R,R)-2 (670 mg, 4.0 mmol)
in CH2Cl2 (40 mL) were added Et3N (0.56 mL, 4.0 mmol), DMAP
(294 mg, 2.4 mmol), and TsCl (917 mg, 4.8 mmol) at room
temperature. The mixture was stirred for 45 min at room temper-
ature, quenched with water, and extracted with CHCl3. The organic
extract was washed with brine and dried over MgSO4. After removal
of the solvent, the residue was purified by column chromatography
on silica gel eluted with 50% EtOAc in hexane to give 6 (558 mg)
in 44% yield. Elution with hexane gave 7% of ditosylate and that
with EtOAc gave a recovery of (R,R)-2 in 50% yield: colorless
oil; Rf ) 0.41 (50% EtOAc in hexane); [R]26D +82 (c 0.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.73 (d, J ) 8.3 Hz, 2H), 7.65 (t,
J ) 7.9 Hz, 1H), 7.29-7.24 (m, 3H), 7.14 (d, J ) 7.9 Hz, 1H),
5.61 (q, J ) 6.6 Hz, 1H), 4.80 (q, J ) 6.6 Hz, 1H), 4.17 (brs, 1H),
2.41 (s, 3H), 1.61 (d, J ) 6.6 Hz, 3H), 1.44 (d, J ) 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 162.3, 156.9, 144.7, 137.8, 133.9,
129.7 (2C), 127.8 (2C), 119.2, 119.2, 80.4, 68.3, 24.0, 21.6, 21.5;
IR (film, cm-1) 3411, 1362, 1176; MS (CI) m/z 322 (M + H+);
HRMS calcd for C16H20NO4S: 322.1113, found m/z 322.1104. Its
enantiomer 6′ was obtained from (S,S)-2 in 38% yield along with
7% of ditosylate and 35% of (S,S)-2: colorless oil; [R]26D -78 (c
0.3, CHCl3).
(1′S,1′′S)-2-{1-[(R)-1-Phenylethyl]aminoethyl}-6-{1-[(S)-1-
phenylethyl]aminoethyl}pyridine (1c). The reaction of 8 (95 mg,
0.2 mmol) with (S)-phenylethylamine (0.10 mL, 0.66 mmol) was
carried out by the general substitution method of mesylate.
Purification by column chromatography eluted with 50% EtOAc
in hexane gave 1c (74 mg) in 79% yield: colorless oil; Rf ) 0.42
(EtOAc); [R]27D -153 (c 0.30, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 7.50 (t, J ) 7.7 Hz, 1H), 7.34-7.21 (m, 10H), 7.03 (d, J ) 7.7
Hz, 1H), 6.89 (d, J ) 7.7 Hz, 1H), 3.87 (q, J ) 6.6 Hz, 1H), 3.74
(q, J ) 6.6 Hz, 1H), 3.56 (q, J ) 6.9 Hz, 1H), 3.42 (q, J ) 6.6 Hz,
1H), 2.15 (s, 2H), 1.40 (d, J ) 6.6 Hz, 3H), 1.39 (d, J ) 6.6 Hz,
3H), 1.28 (d, J ) 6.9 Hz, 3H), 1.26 (d, J ) 6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 163.9 (2C), 145.6 (2C), 136.5, 128.4 (4C),
126.9 (4C), 126.7 (2C), 119.9, 119.3, 56.1, 56.0, 55.7, 55.3, 25.2,
23.7, 23.1, 22.0; IR (film, cm-1) 3317; MS(FAB) m/z 374 (M +
H+); HRMS calcd for C25H32N3 (M + H+) 374.2596, found m/z
374.2602. Its enantiomer 1c′ was obtained from 10 with (S)-
phenylethylamine in 91% yield: colorless oil; [R]27D +151 (c 1.2,
CHCl3).
(1′R,1′′S)-2-(1′-Hydroxyethyl)-6-{1′′-[(R)-1-phenylethyl]-
aminoethyl}pyridine (7). The substitution reaction was performed
by the general substitution method of mesylate. (R)-Phenylethy-
lamine was used, and the reaction time was 10 h. An 80% EtOAc
in hexane solution was used as an eluent for silica gel column
chromatography. Compound 7 was obtained in 99% yield: colorless
(1′R,1′′S)-2-(1′-Acetoxyethyl)-6-[1′′-(methanesulfonyloxy)eth-
yl]pyridine (11). Mesylation of (ROAc,SOH)-4 (1.0 g, 4.8 mmol)
was carried out by the general substitution method of mesylate.
J. Org. Chem, Vol. 72, No. 1, 2007 137

Uenishi et al.
Purification by silica gel column chromatography eluted with 50%
EtOAc in hexane gave 11 (1.4 g) in quantitative yield: colorless
oil; Rf ) 0.54 (50% EtOAc in hexane); [R]30D +3 (c 0.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.74 (t, J ) 7.7 Hz, 1H), 7.37 (d,
J ) 7.7 Hz, 1H), 7.30 (d, J ) 7.7 Hz, 1H), 5.89 (q, J ) 6.6 Hz,
1H), 5.77 (q, J ) 6.6 Hz, 1H), 2.94 (s, 3H), 2.13 (s, 3H), 1.76 (d,
J ) 6.6 Hz, 3H), 1.57 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.0, 160.0, 157.4, 137.7, 119.7, 119.3, 80.5, 72.6, 38.5,
21.4, 21.0, 20.4; IR (film, cm-1) 1733, 1358, 1176; MS (CI) m/z
288 (M + H+). HRMS calcd for C12H18NO5S (M + H+) 288.0905,
found m/z 288.0906.
6.6 Hz, 3H), 1.20 (d, J ) 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 163.6, 158.1, 144.9, 144.3, 136.9, 133.9, 129.5 (2C), 128.3 (2C),
127.7 (2C), 126.8, 126.7 (2C), 120.9, 118.4, 80.9, 55.9, 55.5, 24.8,
23.2, 21.6, 21.4; IR (film, cm-1) 3420, 1365, 1196; MS(CI) m/z
425 (M + H+); HRMS calcd for C24H29N2O3S (M + H+) 425.1899,
found m/z 425.1902.
Synthesis of 1e and 1f from 13 and 15. Substitution of 13 with
(R)-phenylethylamine and that of 15 with (S)-phenylethylamine
were carried out by general substitution method of mesylate.
Purification by column chromatography eluted with EtOAc gave
1e in 84% yield and 1f in 83% yield, respectively.
Substitution of 11 with (S)-Phenylethylamine and (R)-Phe-
nylethylamine. The reactions of 11 with (S)-phenylethylamine and
(R)-phenylethylamine were carried out by the general substitution
method of mesylate. Purification by column chromatography eluted
with 80% EtOAc in hexane gave 12 in 88% yield and 14 in 84%
yield, respectively.
(1′R*,1′′S*)-2-{1′-[(S)-1-Phenylethyl]aminoethyl}-6-{1′′-[(R)-
1-phenylethyl]aminoethyl}pyridine (1e): colorless oil; [R]25
0
D
(c 0.80, CHCl3); Rf ) 0.30 (EtOAc); 1H NMR (300 MHz, CDCl3)
δ 7.48 (t, J ) 7.7 Hz, 1H), 7.34-7.18 (m, 10H), 7.02 (d, J ) 7.7
Hz, 2H), 3.84 (q, J ) 6.6 Hz, 2H), 3.76 (q, J ) 6.6 Hz, 2H), 2.24
(brs, 2H), 1.37 (d, J ) 6.6 Hz, 12H); 13C NMR (75 MHz, CDCl3)
δ 163.5 (2C), 145.7 (2C), 136.6, 128.4 (4C), 126.8 (2C), 126.7
(4C), 119.0 (2C), 55.8 (2C), 55.1 (2C), 23.4 (2C), 21.8 (2C); IR
(film, cm-1) 3317; MS(FAB) m/z 374 (M + H+); HRMS calcd for
C25H32N3 (M + H+) 374.2596, found m/z 374.2590.
(1′R,1′′R)-2-(1′-Acetoxyethyl)-6-{1′′-[(S)-1-phenylethyl]-
aminoethyl}pyridine (12): colorless oil; [R]26 +85 (c 0.2,
D
1
CHCl3); Rf ) 0.21 (50% EtOAc in hexane); H NMR (300 MHz,
CDCl3) δ 7.56 (t, J ) 7.7 Hz, 1H), 7.27-7.18 (m, 5H), 7.14 (d, J
) 7.7 Hz, 1H), 7.08 (d, J ) 7.7 Hz, 1H), 5.90 (q, J ) 6.6 Hz, 1H),
3.85 (q, J ) 6.6 Hz, 1H), 3.75 (q, J ) 6.6 Hz, 1H), 2.12 (s, 3H),
2.07 (s, 1H), 1.57 (d, J ) 6.6 Hz, 3H), 1.38 (d, J ) 6.6 Hz, 3H),
1.36 (d, J ) 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.2,
163.7, 159.6, 145.6, 136.9, 128.3 (2C), 126.7, 126.7 (2C), 119.9,
117.9, 73.1, 55.9, 55.2, 23.2, 22.0, 21.2, 20.6; IR (film, cm-1) 3324,
1736; MS (CI) m/z 313 (M + H+); HRMS calcd for C19H25N2O2
(M + H+) 313.1916, found m/z 313.1922.
(1′R*,1′′S*)-2-{1-[(R)-1′-Phenylethyl]aminoethyl}-6-{1′′-[(S)-
1-Phenylethyl]aminoethyl}pyridine (1f): colorless oil; [R]27
0
D
(c 0.50, CHCl3); Rf ) 0.67 (EtOAc); 1H NMR (300 MHz, CDCl3)
δ 7.51 (t, J ) 7.7 Hz, 1H), 7.35-7.24 (m, 10H), 6.90 (d, J ) 7.7
Hz, 2H), 3.59 (q, J ) 6.8 Hz, 2H), 3.48 (q, J ) 6.6 Hz, 2H), 2.34
(s, 2H), 1.30 (d, J ) 6.8 Hz, 6H), 1.29 (d, J ) 6.6 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ: 164.1 (2C), 145.4 (2C), 136.4, 128.4
(4C), 127.0 (4C), 126.9 (2C), 120.0 (2C), 56.1 (2C), 55.8 (2C),
25.2 (2C), 23.6 (2C).; IR (film, cm-1) 3319; MS(FAB) m/z 374
(M + H+); HRMS calcd for C25H32N3 (M + H+) 374.2596, found
m/z 374.2582.
(1′R,1′′R)-2-(1′-Acetoxyethyl)-6-{1′′-[(R)-1-phenylethyl]-
aminoethyl}pyridine (14): colorless oil; [R]30 +206 (c 0.9,
D
1
CHCl3); Rf ) 0.63 (EtOAc); H NMR (300 MHz, CDCl3) δ 7.59
(t, J ) 7.7 Hz, 1H), 7.33-7.22 (m, 5H), 7.18 (d, J ) 7.7 Hz, 1H),
6.98 (d, J ) 7.7 Hz, 1H), 5.93 (q, J ) 6.6 Hz, 1H), 3.58 (q, J )
6.6 Hz, 1H), 3.43 (q, J ) 6.6 Hz, 1H), 2.14 (s, 3H), 1.98 (brs, 1H),
1.60 (d, J ) 6.6 Hz, 3H), 1.27 (d, J ) 6.6 Hz, 3H), 1.36 (d, J )
6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.3, 163.8, 160.1,
145.2, 136.9, 128.4 (2C), 126.4 (3C), 120.6, 118.1, 73.2, 56.2, 55.8,
24.9, 23.4, 21.3, 20.7; IR (film, cm-1) 3422, 1734; MS (CI) m/z
313 (M + H+); HRMS calcd for C19H25N2O2 (M + H+) 313.1916,
found m/z 313.1920.
Conversion of Acetates 12 and 14 to Tosylates 13 and 15.
Compound 12 was treated with K2CO3 in methanol as described
for the methanolysis of (R,R)-3 and (ROAc,SOH)-4 and tosylations
of the resulting alcohols by the same manner described for the
synthesis of 6 gave 13 in 78% yield and 15 in 70% yield
respectively. Purification was made by silica gel column chroma-
tography eluted with 50% EtOAc in hexane.
Preparation of 16. A mixture of 1b (100 mg, 0.27 mmol) and
ZnCl2 (36 mg, 0.27 mmol) in EtOH (2.0 mL) was stirred at room
temperature for 12 h. After evaporation of the solvent, 16 was
isolated in 65% yield (88 mg) as colorless crystals.
η3-{(1′S,1′′S)-2,6-Bis[1-((R)-phenylethylamino-κN)ethyl]-
pyridine}zinc(II) chloride (16): mp 293-296 °C (EtOH-CH2-
Cl2); [R]25 D -80 (c 0.29, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ
7.78 (t, J ) 7.7 Hz, 1H), 7.40-7.24 (m, 10H), 7.09 (d, J ) 7.7
Hz, 2H), 4.57 (brq, J ) 6.8 Hz, 2H), 3.94 (q, J ) 6.8 Hz, 2H),
2.74 (brs, 2H), 1.58 (d, J ) 6.8 Hz, 6H), 1.43 (d, J ) 6.8 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 161.8 (2C), 142.5 (2C), 141.0, 128.9
(4C), 127.5 (2C), 126.7 (4C), 121.2 (2C), 55.2 (2C), 53.1 (2C),
22.2 (2C), 21.8 (2C); IR (KBr, cm-1) 3446; MS(FAB) m/z 508 (M
+ H+); HRMS calcd for C25H32N3Cl2Zn (M + H+) 508.1265, found
m/z 508.1264. Anal. Calcd for C25H31Cl2N3Zn: C, 58.90; H, 6.13;
N, 8.24. Found: C, 58.54; H, 6.19; N, 8.12.
Crystallographic Data: empirical formula, C25H31Cl2N3Zn;
crystal system, monoclinic; space group, C2 (#2); lattice parameters,
a ) 11.689(1) Å, b ) 9.363(1) Å, c ) 11.234(1) Å, â ) 99.153-
(7)°; V ) 1213.8(2) Å3; Z value, 2; Dcalc, 1.395 g/cm3; (Cu KR),
35.51 cm-1; residuals, R ) 0.043; Rw ) 0.068.
(1′R,1′′R)-2-{1′-[(S)-1-Phenylethyl]aminoethyl}-6-[1′′-(p-tolu-
enesulfonyloxy)ethyl]pyridine (13): colorless oil; [R]27 +68 (c
D
1
0.40, CHCl3); Rf ) 0.29 (50% EtOAc in hexane); H NMR (300
MHz, CDCl3) δ 7.72 (d, J ) 8.3 Hz, 2H), 7.50 (t, J ) 7.7 Hz,
1H), 7.26-7.20 (m, 7H), 7.16 (d, J ) 7.7 Hz, 1H), 7.05 (d, J )
7.7 Hz, 1H), 5.59 (q, J ) 6.6 Hz, 1H), 3.79 (q, J ) 6.6 Hz, 1H),
3.72 (q, J ) 6.6 Hz, 1H), 2.38 (s, 3H), 2.18 (s, 1H), 1.58 (d, J )
6.6 Hz, 3H), 1.36 (d, J ) 6.6 Hz, 3H), 1.30 (d, J ) 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 163.6, 157.8, 145.4, 144.6, 137.1,
134.1, 129.6 (2C), 128.3 (2C), 127.8 (2C), 126.9, 126.8 (2C), 120.5,
118.4, 81.0, 55.9, 55.4, 23.2, 21.9, 21.7, 21.5; IR (film, cm-1) 3422,
1364, 1189, 1177; MS(CI) m/z 425 (M + H+); HRMS calcd for
C24H29N2O3S (M + H+) 425.1899, found m/z 425.1919.
Acknowledgment. This work was supported in part by a
Special Grant for Cooperative Research administered by the
Japan Private School Promotion Foundation and by the 21st
COE Program from the Ministry of Education, Science and
Culture of Japan.
(1′R,1′′R)-2-{1′-[(R)-1-Phenylethyl]aminoethyl}-6-[1′′-(p-tolu-
1
Supporting Information Available: Copies of the H and/or
enesulfonyloxy)ethyl]pyridine (15): colorless oil; [R]24D +153 (c
13C NMR spectra for compounds 1a-f, (R,R)-5, 6-8, meso-5, and
9-16. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
0.30, CHCl3); Rf ) 0.29 (50% EtOAc in hexane); H NMR (300
MHz, CDCl3) δ 7.75 (d, J ) 8.3 Hz, 2H), 7.54 (t, J ) 7.7 Hz,
1H), 7.32-7.19 (m, 8H), 6.95 (d, J ) 7.7 Hz, 1H), 5.63 (q, J )
6.6 Hz, 1H), 3.51 (q, J ) 6.8 Hz, 1H), 3.34 (q, J ) 6.6 Hz, 1H),
2.39 (s, 3H), 1.95 (s, 1H), 1.61 (d, J ) 6.6 Hz, 3H), 1.25 (d, J )
JO061729E
138 J. Org. Chem., Vol. 72, No. 1, 2007