Ag+-Specific Pyridine Podands: Effects of Ligand Geometry and Stereochemically Controlled Substitution on Cation Complexation and Transport Functions

Article abstract of DOI:10.1021/jo9721148

A new series of acyclic podands was designed so that three pyridine moieties cooperatively bind a guest Ag⁺. Liquid-liquid extraction, NMR binding, and computer calculation experiments reveal that podands with three pyridine donors in a proper geometry exhibit a perfect Ag⁺ specificity. They selectively extracted Ag⁺ in the presence of equimolar Pb²⁺, Cu²⁺, Ni²⁺, Co²⁺, and Zn²⁺. Introduction of two chiral centers close to the pyridine binding sites surprisingly influences the Ag⁺-binding ability of the podand. Fourteen new pyridine podands were evaluated as carriers in a liquid membrane transport system. A combination of ligand geometry and stereocontrolled substitution provides excellent Ag⁺-speeific transport.

Full text of DOI:10.1021/jo9721148

3884
J . Org. Chem. 1998, 63, 3884-3894
Ag+-Sp ecific P yr id in e P od a n d s: Effects of Liga n d Geom etr y a n d
Ster eoch em ica lly Con tr olled Su bstitu tion on Ca tion Com p lexa tion
a n d Tr a n sp or t F u n ction s
Hiroshi Tsukube,*,† Satoshi Shinoda,† J un’ichi Uenishi,*,‡ Takao Hiraoka,‡
Takahiro Imakoga,‡ and Osamu Yonemitsu‡
Department of Chemistry, Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi-ku,
Osaka 558-8585, J apan, and Department of Chemistry, Faculty of Science, Okayama University of
Science, Ridai-cho, Okayama 700-0005, J apan
Received November 18, 1997
A new series of acyclic podands was designed so that three pyridine moieties cooperatively bind a
guest Ag+. Liquid-liquid extraction, NMR binding, and computer calculation experiments reveal
that podands with three pyridine donors in a proper geometry exhibit a perfect Ag+ specificity.
They selectively extracted Ag+ in the presence of equimolar Pb2+, Cu2+, Ni2+, Co2+, and Zn2+
.
Introduction of two chiral centers close to the pyridine binding sites surprisingly influences the
Ag+-binding ability of the podand. Fourteen new pyridine podands were evaluated as carriers in
a liquid membrane transport system. A combination of ligand geometry and stereocontrolled
substitution provides excellent Ag+-specific transport.
Synthetic podands are a family of linear multidentate
1). Ag+-selective binders are of great utility in 111Ag-
based radioimmunotherapy and photographic techniques,
as well as in the separation of Ag+ from natural source
or wastewater.6 Ag+ usually has a linear bidentate
coordination mode but occasionally forms tridentate or
highly coordinated complexes.7 We chose pyridine ni-
trogen atoms as soft donor groups and placed three
pyridine rings in the acyclic skeleton to form a selective
and stable Ag+ complex. The newly designed pyridine
podands were found to exhibit perfect Ag+ selectivity via
1:1 complexation. We further introduced two CH3 sub-
stituents close to the pyridine binding sites in a stereo-
chemically controlled fashion and noted remarkable
differences in extraction and transport abilities between
certain stereoisomers. The stereocontrolled substitution
enhanced the Ag+-binding ability of the podand. Thus,
a proper combination of ligand geometry and stereospe-
cific substitution led to the development of Ag+-selective
podands.
ligands which includes acyclic polyethers. They generally
form complexes with smaller stability constants than
those of corresponding macrocyclic complexes and thus
are usually regarded as poor ligands.1 In contrast, there
are many excellent podands in nature. For example,
naturally occurring polyether antibiotics, such as mon-
ensin and lasalocid, selectively bind several metal cations
and effectively transport them across a biomembrane.2
Although they have acyclic podand-type structures, geo-
metrical and stereochemical arrangements of cation-
ligating donors in the acyclic skeleton provide specific
cation-binding properties. Lasalocid typically has a
salicylate anion and several oxygen donor atoms located
in the pseudocyclic skeleton. It has 10 asymmetric
carbons and exhibits higher cation binding ability than
nonbiological stereoisomers.3 Synthetic podands have
advantages over these biological podands, in terms of
facile synthesis and versatility of molecular structure.
Since the number of synthetic podands showing specific
binding abilities is still limited,1 there are many things
to learn from biological podand systems.4
Resu lts a n d Discu ssion
Design of P yr id in e P od a n d s. Molecular design of
new specific ligands has usually included empirical “trial-
and-error” exercises, but computational methods are
expected to provide a rational basis for their design.8 We
performed modeling experiments to optimize the struc-
tures of Ag+ complexes with pyridine podands. Computer
Here, we present a new series of specific podands based
on geometrical and stereochemical optimizations of the
ligand structure.5 We systematically prepare Ag+-specific
podands which have three pyridine donors as binding
sites and two asymmetric centers close to them (Chart
† Osaka City University.
‡ Okayama University of Science.
(5) Preliminary communications: (a) Tsukube, H.; Uenishi, J .;
Kojima, N.; Yonemitsu, O. Tetrahedron Lett. 1995, 36, 2257-2260. (b)
Tsukube, H.; Uenishi, J .; Hiraoka, T.; Yonemitsu, O. Enantiomer 1997,
2, 281-285.
(1) (a) Tsukube, H. In Crown Ethers and Analogous Compounds;
Hiraoka, M., Ed.; Elsevier: New York, 1992; pp 100-197. (b) Gokel,
G. W.; Murillo, O. In Molecular Recognition: Receptors for Cationic
Guests; Comprehensive Supramolecular Chemistry, Vol. 1; Pergamon
Press: New York, 1996; pp 1-33.
(2) (a) Tsukube, H. In Cation Binding by Macrocycles; Inoue, Y.,
Gokel, G. W., Eds.; Marcel Dekker: New York, 1991; pp 497-522. (b)
Dobler, M. In Molecular Recognition: Receptors for Cationic Guests;
Comprehensive Supramolecular Chemistry, Vol. 1; Pergamon Press:
New York, 1996; pp 267-313.
(3) Still, W. C.; Hauck, P.; Kempt, D. Tetrahedron Lett. 1987, 28,
2817-2820.
(4) (a) Tsukube, H.; Sohmiya, H. Supramol. Chem. 1993, 1, 297-
304. (b) Lindoy, J . F. Coord. Chem. Rev. 1996, 148, 349-368.
(6) (a) Parker, D. Chem. Soc. Rev. 1990, 19, 271-291. (b) Bakker,
W. I. I.; Verboom, W.; Reinhoudt, D. N. J . Chem. Soc., Chem. Commun.
1994, 71-72.
(7) (a) Kang, H. C.; Hanson, A. W.; Eaton, B.; Boekelheide, V. J .
Am. Chem. Soc. 1985, 107, 1979-1985. (b) Heirtzer, F. R.; Hopf, H.;
J ones, P. G.; Bubenitschek, P.; Lehne, V. J . Org. Chem. 1993, 58,
2781-2784.
(8) (a) Wipff, G.; Troxler, L. In Computational Approaches in
Supramolecular Chemistry; Wipff, G., Ed.; Kluwer Academic Press:
The Netherlands, 1994; pp 319-348. (b) Tsukube, H. Coord. Chem.
Rev. 1996, 148, 1-17.
S0022-3263(97)02114-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/22/1998

Ag+-Specific Pyridine Podands
J . Org. Chem., Vol. 63, No. 12, 1998 3885
Ch a r t 1. Tr id en ta te P yr id in e P od a n d s a n d Rela ted Com p ou n d sa
a
Pal ) CO(CH2)14CH3.
F igu r e 1. Optimized structures of pyridine podand-Ag+ complexes.
modeling and energy calculations were performed using
Spartan SGI version 4.0.1 (ab initio, STO-3G). In the
calculations, the effects of counteranion and the tail group
were neglected. Figure 1 illustrates the optimized struc-
tures of Ag+ complexes with three kinds of pyridine
podands: 1a , SS-2a , and m eso-2a . These have three
pyridine donors in the acyclic skeletons, but the orienta-
tion of the pyridine rings is slightly altered in the Ag+
complexes. For podand 1a , Ag+ is very nicely coordinated
by three pyridine nitrogen atoms, indicating that the
three nitrogen donors are arranged so as to converge on
the guest Ag+. The calculated distances between the
nitrogen atoms of terminal pyridines and Ag+ are 1.93
Å, while that between the nitrogen atom of central
pyridine and Ag+ is 2.44 Å. Both are comparable to those
observed in solid-state structures for other types of
pyridine-Ag+ complexes.9 Although the oxygen atoms
of the ester moieties are located near the Ag+, their lone
pair electrons did not point to it. Thus, the three pyridine
nitrogens were indicated as the potential binding sites.
For chiral SS-2a and its meso-form, there are interesting
differences in the calculated structures and energies of
their Ag+ complexes. SS-2a has a symmetrical arrange-
ment of the three pyridine rings for binding of Ag+, and
the Ag+ is equally coordinated by the two terminal
(9) Engelhardt, L. M.; Pakawatchai, C.; White, A. H.; Healy, P. C.
J . Chem. Soc., Dalton Trans. 1985, 117-123.

3886 J . Org. Chem., Vol. 63, No. 12, 1998
Tsukube et al.
Ch a r t 2. P yr id in eeth a n ols for Syn th esis of
pyridine rings. Distances between the two nitrogen
atoms and Ag+ are the same (1.94 Å). In contrast, m eso-
2a forms a different type of Ag+ complex in which two
terminal pyridine nitrogen atoms coordinate with Ag+ in
an asymmetrical fashion. Distances between nitrogen
atoms of terminal pyridines and Ag+ are calculated to
be 1.91 and 1.96 Å, respectively. Thus, introduction of
two CH3 substituents significantly modifies the coordina-
tion mode of Ag+. These structural features also influ-
ence the stability of the Ag+ complex. In energy calcu-
lations the stabilized energy of the SS-2a complex is
larger by 3.46 kcal/mol than that of the m eso-2a complex.
Thus, proper stereocontrolled substitution of the pyridine
podand is calculated to enhance Ag+-binding ability.
Syn th esis of P yr id in e P od a n d s. Three kinds of
pyridine podands were prepared: 1a -f have three py-
ridine rings in the podand skeletons; 2a -c have two
additional CH3 substituents in the middle of the chain;
and 3a -c also have two substituents on the tails (see
Chart 1). We obtained stereoisomers having the SS- and
meso-configurations of podands 2a -c, while meso-
isomers of podands 3a -c were not prepared. Because
these podands had stereocontrolled substituents as well
as three pyridine donors, we compared their cation-
binding properties to determine the effects of stereocon-
trolled substitution. Different types of podands 4a ,b and
5 were also synthesized for comparison. Podands 4a ,b
have one benzene and two pyridine rings, and 5 has
different linkages between the pyridine units from those
in podands 1-4. Compounds 6 and 7 are common
pyridine ligands for heavy and transition-metal cations,
while 8 was reported to be a Ag+-specific ionophore.10
We developed a new synthetic route to the optically
pure pyridine precursors for preparation of podands 2-4
(Chart 2), because the reported synthetic reactions of
chiral or bifunctional pyridine derivatives included reac-
tion sequences and procedures for scale-up which were
too complicated.11 Our synthetic strategy was to resolve
the enantiomers of the pyridine building block via
enzymatic reaction. Lipase-catalyzed acetylation pro-
vided ready access to multigram quantities of the opti-
cally pure pyridineethanol derivatives.12 Kinetic reso-
lution of racemic pyridineethanol 18 was typically
performed by Candida antarctia lipase with vinyl acetate
in diisopropyl ether. We obtained both enantiomers with
99% ee or better in good yields.
P yr id in e P od a n d s
Sch em e 1a
a
Reagents and conditions: (a) PalCl, Et3N, THF-CH2Cl2 (1:
1), rt; (b) TrCl, Et3N, THF-CH2Cl2 (10:1), rt; (c) NaH, PhCH2Br,
THF-DMF (2:5), rt; (d) K2CO3, MeOH-CH2Cl2 (3:2), rt.
For the synthesis of pyridine podands 1-4, a variety
of achiral and chiral pyridine alcohols were required.
Their structures are depicted in Chart 2, and syntheses
are shown in Schemes 1-3. Scheme 1 describes the
preparation of unsymmetrically substituted pyridinemeth-
anols 12, 14, and 15. Palmitoylation of one of the
hydroxyl groups of 2,6-pyridinedimethanol with palmitoyl
chloride in the presence of triethylamine gave 12 in 70%
yield, while monotrityl ether 15 was obtained by trity-
lation in 64% yield. Monobenzyl ether 14 was derived
from 15 via 24 in the following steps: (i) benzyl ether
formation of the other hydroxyl group with benzyl
bromide and NaH (93%) and (ii) deprotection of the trityl
group with hydrochloric acid (96%).
Scheme 2 shows the synthetic routes to optically active
pyridineethanols S-19, S-21, S-22, and S-23 from S-18,
which was obtained in an enantiomerically pure form by
C. antarctica lipase-catalyzed acetylation of racemic 18.12
Desilylation of S-18 with Bu4NF gave S-25 in 96% yield.
Palmitoylation of the primary alcohol of S-25 with
palmitoyl chloride afforded S-19 in 94% yield. Acetyla-
tion of S-25 with acetic anhydride, silylation of the
remaining secondary alcohol with TBDMSCl, and depro-
tection of the acetate provided S-22 in 90% yield via S-26
and S-27 in three steps. Pyridinemethanols S-21 and
S-23 were derived from S-18 in two steps: acetylation
of S-18 gave S-28 in 94% yield, which upon treatment
(10) (a) Izatt, R. M.; Pawlak, K.; Bradshaw, J . S.; Bruening, R. I.
Chem. Rev. 1991, 91, 1721-2085. (b) Lerch, M.; Reitter, E.; Simon,
W.; Pretsch, E. Anal. Chem. 1994, 66, 1713-1717.
(11) Some optically active pyridine derivatives have been prepared
as the chiral auxiliary: (a) Soai, K.; Niwa, S.; Kobayashi, T. J . Chem.
Soc., Chem. Commun. 1987, 801-802. (b) Bolm, C.; Eward, M.;
Zehnder, M.; Neuburger, M. A. Chem. Ber. 1992, 125, 453-458. (c)
Nishiyama, H.; Yamaguchi, S.; Park, S. B.; Itoh, K. Tetrahedron:
Asymmetry 1993, 4, 143-150.
(12) (a) Uenishi, J .; Nishiwaki, K.; Hata, S.; Nakamura, K. Tetra-
hedron Lett. 1994, 35, 7973-7976. (b) Uenishi, J .; Hiraoka, T.; Hata,
S.; Nishiwaki, K.; Yonemitsu, O.; Nakamura, K.; Tsukube, H. J . Org.
Chem. 1998, 63, 2481-2487.

Ag+-Specific Pyridine Podands
Sch em e 2a
J . Org. Chem., Vol. 63, No. 12, 1998 3887
Ta ble 1. Cou p lin g Rea ction of P yr id in eeth a n ols w ith
2,6-P yr id in ed ica r bon yl a n d 1,3-Ben zen ed ica r bon yl
Dich lor id es
acid
chloride
yield
(%)
entry
pyridineethanol
product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9b
9b
10
11
12
13
14
15
S-16
S-18
S-19
S-21
S-22
S-23
10
1a
1b
1c
1d
1e
1f
SS-2a
SS-2b
SS-2c
SS-3a
SS-3b
SS-3c
4a
75
92
70
87
72
95
80
87
95
88
94
90
86
86
S-23
SS-4b
m eso-2a , m eso-2b, and m eso-2c, in contrast, were
synthesized by stepwise coupling with the S-alcohol and
then the R-alcohol in one pot (Scheme 5). Successive
Sch em e 5. Syn th esis of m eso-P yr id in e P od a n d s
a
Reagents and conditions: (a) Bu4NF, THF, rt; (b) Ac2O, Et3N,
CH2Cl2, rt; (c) TBDMSCl, imidazole, DMF, rt; (d) K2CO3, MeOH,
rt; (e) PalCl, Et3N, CH2Cl2, rt.
with Bu4NF gave S-21 in 97% yield. In the same reaction
sequence, palmitoylation of S-18 followed by desilylation
afforded S-23 in 75% yield.
As shown in Scheme 3, R-19 and R-20 were prepared
by acetylation and tritylation of R-25 in 95% and 78%
yields, respectively.
Sch em e 3
These pyridine alcohols were coupled with 2,6-py-
ridinedicarbonyl dichloride (9a ) or 1,3-benzenedicarbonyl
dichloride (9b) to afford pyridine podands 1a -f, chiral
2a -c, chiral 3a -c, and chiral 4a ,b (Scheme 4). The
results are summarized in Table 1. The yields were
generally excellent, and the obtained podands were
mostly solids.
Sch em e 4. Syn th esis of P yr id in e P od a n d s
additions of equivalent amounts of S-17 and R-16 to 9a
produced unsymmetric podand 30 in 64% yield together
with symmetric pyridine podand 2a in 9% yield. Hydro-
genolysis of bromide 30 with Bu3SnH gave exclusively
m eso-2a in 60% yield. Podand m eso-2b was assembled
from the three components, S-18, R-20, and 9a , in the
same manner described for the synthesis of m eso-2a . The
coupling provided unsymmetrical podand 31 in 36% yield
together with SS-2b in 11% yield. Deprotection of the
trityl group with ZnBr2 followed by silylation of the
resulting hydroxyl group with TBDMSCl afforded m eso-
2b in 81% yield in two steps. Using the same reaction
sequence, m eso-2c was obtained from reaction of S-18

3888 J . Org. Chem., Vol. 63, No. 12, 1998
Tsukube et al.
Ta ble 2. Ca tion -Extr a ction P r op er ties of P yr id in e
P od a n d s
and R-19 with 9a . The three components were coupled
in 68% yield giving 33, which afforded m eso-2c through
34 in 30% yield in two steps. Podands 3a -c with a SS-
configuration were prepared from the corresponding
optically pure pyridineethanols, while statistical mixtures
of SS-, RR-, and meso-isomers were derived from racemic
pyridineethanols. Since SS-, RR-, and meso-isomers of
each podand were not separable by any chromatographic
technique or recrystallization, independent synthesis of
the chiral and meso-podands was necessary. The ob-
tained chiral podands 2a -c and 3a -c had sufficient
optical purities to allow for evaluation of the stereochem-
ical effect on the cation complexation, and their cation-
binding behaviors were compared with those of corre-
sponding meso-isomers and statistical mixtures of SS-,
RR-, and SR-isomers.
extraction percentagea
podand
1a
Ag+
Pb2+
Cu2+
Ni2+
Co2+
Zn2+
b
80
52
b
b
<3
<3
b
b
<3
<3
b
b
<3
<3
b
b
<3
<3
b
b
<3
<3
b
1b
1cc
1d
1e
1f
97
80
96
76
79
90
77
72
73
47
60
57
54
79
73
59
62
<3
<3
b
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
b
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
b
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
b
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
b
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
b
SS-2a c
m eso-2a
2a d
SS-2b
m eso-2b
2bd
SS-2c
m eso-2c
2cd
Ca tion Extr a ction . Cation-binding abilities of the
newly prepared pyridine podands were assessed by
solvent extraction of heavy and transition-metal cations.13
A total of 14 pyridine podands 1-5 were examined
together with the three reference ligands 6-8. The
extraction ability was estimated on the basis of partition
of metal perchlorates between methylene chloride and
an aqueous solution. Typical results for the competitive
extraction experiments are summarized in Table 2.
These results were obtained for extraction of an aqueous
mixture of equimolar Ag+, Pb2+, Cu2+, Ni2+, Co2+, and
SS-3a
3a d
SS-3b
3bd
SS-3c
3cd
SS-4b
4bd
5
6c
<3
62
67
<3
<3
5
21
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
<3
7
8
Zn2+
.
a
Aqueous layer: AgClO4, Pb(ClO4)2, Cu(ClO4)2, Ni(ClO4)2,
Co(ClO4)2, and Zn(ClO4)2, 0.030 mmol each in 3 mL of H2O.
Organic phase: podand, 0.030 mmol in 3 mL of CH2Cl2. b Insoluble
The pyridine podands exhibit perfect Ag+ selectivity
in the presence of equimolar Pb2+, Cu2+, Ni2+, Co2+, and
Zn2+, and some of them extracted Ag+ more efficiently
than the common Ag+-specific ligands 7 and 8 (see Table
2). For a series of podands 1a -f, ether and silyl ether
derivatives 1b,e, and f exhibited higher extractabilities
for Ag+ than ester derivative 1c. Since unsubstituted
and bromide derivatives 1a ,d produced considerable
amounts of insoluble materials under the extraction
conditions, the nature of the tail group (X or Y in Chart
1) is judged to greatly influence extraction behavior of
the podand. Podand 4b was also employed but gave
negligible extraction for all the metal cations. Since this
podand has one benzene and two pyridine rings, cooper-
ativity of the three pyridine rings is clearly demonstrated.
When the aqueous phase contained a mixture of Ag+, Li+,
Na+, and K+, podands with three pyridine rings were also
found to extract Ag+ selectively. Thus, the present type
of pyridine podands exhibits highly Ag+-selective extrac-
tion.
d
material appeared. c Turbidity appeared. A statistical mixture
of SS-, RR-, and meso-isomers (1:1:2).
the concentrations of Ag+ in the aqueous phase prior to
and after extraction. Their values are Kex ) 50 100 for
SS-2a , 1300 for m eso-2a , 8600 for SS-2b, 1500 for m eso-
2b, 1000 for SS-2c, and 170 for m eso-2c. Interestingly,
SS-2b has a 5.7 times larger Kex value than m eso-2b.
Since the latter had a similar Kex value to that of
unsubstituted podand 1b (Kex ) 2000), stereocontrolled
substitution remarkably enhanced the Ag+ extraction
ability of the pyridine podand. Much larger enhancement
(ca. 38.5 times) was observed between the stereoisomers
of podand 2a , although the corresponding unsubstituted
podand 1a gave precipitate under the same conditions.
Podands 3a -c also have two CH3 substituents on the tail
groups. However, their stereoisomers showed almost the
same Ag+ extraction efficiencies, which were also similar
to those of corresponding unsubstituted podands 1a -c
(see Table 2). Therefore, both the location and stereo-
chemistry of the introduced substituents are found to be
important factors in determining Ag+ extraction ef-
ficiency in these pyridine podand systems.14 Terpyridine
6, which is known to be a strong chelating reagent for
several metal cations, extracted Cu2+ moderately under
the employed conditions. Thus, the geometrical arrange-
ment of three pyridine rings in the podand skeleton
creates a unique cation recognition profile.
Podands 2a -c and 3a -c which have additional sub-
stituents exhibited Ag+-specific extraction, but their two
CH3 substituents introduced close to the pyridine binding
sites affected Ag+ extraction efficiency. There were
marked differences in the extraction percentages between
the stereoisomers of 2a -c, whereas only slight effects
were observed with podands 3a -c. Kex values were
estimated for podands 2a -c. These were defined as
[podand-Ag+]org/[Ag+]aq × [podand]org and calculated from
NMR Stu d ies of Ag+ Bin d in g. Further detailed
information on the Ag+-binding behaviors of the pyridine
(13) Recent examples of pyridine-containing receptors: (a) West-
mark, P. R.; Gardiner, S. J .; Smith, B. D. J . Am. Chem. Soc. 1996,
118, 11093-11100. (b) Hasenknopf, B.; Lehn, J . M.; Kneisel, B. O.;
Baum, G.; Fenske, D. Angew. Chem., Int. Ed. Engl. 1996, 35, 1838-
1840. (c) Habata, Y.; Bradshaw, J . S.; Zhang, X. X.; Izatt, R. M. J .
Am. Chem. Soc. 1997, 119, 7145-7146. (d) Kelly, T. R.; Lee, Y. J .;
Mears, R. J . J . Org. Chem. 1997, 62, 2774-2781. (e) Santos, O.; Lajmi,
A. R.; Canary, J . W. Tetrahedron Lett. 1997, 38, 4383-4386. (f)
Takeuchi, M.; Yamamoto, M.; Shinkai, S. J . Chem. Soc., Chem.
Commun. 1997, 1731-1732.
(14) The effect of stereochemically controlled substitution on the
metal cation-binding property of a ligand was reported in a few cases:
(a) Erickson, S. D.; Still, W. C. Tetrahedron Lett. 1990, 31, 4253-4256.
(b) Sasaki, S.; Naito, H.; Maruta, K.; Kawahara, E.; Maeda, M.
Tetrahedron Lett. 1994, 35, 3337-3340. (c) Shibutani, Y.; Mino, S.;
Long, S. S.; Moriuchi-Kawakami, T.; Yakabe, K.; Shono, T. Chem. Lett.
1997, 49-50.

Ag+-Specific Pyridine Podands
J . Org. Chem., Vol. 63, No. 12, 1998 3889
F igu r e 2. Ag+ ion-induced 13C NMR spectral changes of podands 3c and 4b.
Ta ble 3. Ca tion -Tr a n sp or t P r op er ties of P yr id in e
P od a n d s
podands was obtained using NMR spectroscopy. Figure
2 illustrates the Ag+-induced changes in the 13C NMR
chemical shifts of the selected carbon signals in SS-3c
and SS-4b, which have three and two pyridine rings,
respectively. The addition of AgClO4 to a solution
(CDCl3-CH3OH, 4:1) of each podand caused significant
and continuous spectral changes. Since these titration
curves had clear breaks at [Ag+]/[podand] ) 1.0, 1:1
complexation was confirmed in both podand systems.
When podand SS-3c was employed, significant shifts
were observed in the signals for carbons of the three
pyridine rings. Since the ester carbon signal on the tail
shifted only slightly, the three pyridine rings predomi-
nantly and cooperatively bound the Ag+. Podand SS-4b
is suggested to form a 1:1 Ag+ complex in a different
fashion. Signals for the two pyridine rings shifted,
although those for benzene and ester moieties showed
little change. Thus, podand 4b formed a bidentate
complex with Ag+, while podand 3c wrapped around the
Ag+ via cooperativity of the three pyridine donors. 1H
NMR binding experiments provided parallel results to
those in 13C NMR experiments: cooperative binding of
the pyridine rings and 1:1 complexation. Since these
experimental results are consistent with those of the
computer calculations (see Figure 1), a proper arrange-
ment of the three pyridine donors is shown to be effective
in accommodating Ag+ and offering high Ag+ specificity.
Ca tion Tr a n sp or t a cr oss a Liqu id Mem br a n e.
Results of the cation-binding and extraction experiments
suggest that the present type of pyridine podands has
potential as effective carriers of Ag+. Competitive cation-
transport experiments were carried out in a CH2Cl2 liquid
membrane system.13 Table 3 summarizes the transport
results for various pyridine podands when a mixture of
AgClO4, Pb(ClO4)2, Cu(ClO4)2, Ni(ClO4)2, Co(ClO4)2, and
Zn(ClO4)2 was employed as the aqueous source phase.
Pyridine podands 1a -f, 2a -c, and 3a -c exhibit perfect
Ag+ selectivity in the transport process as well as in the
extraction, while bidentate podand 4b was an inefficient
carrier. Podands 3a -c showed higher Ag+-transport
efficiencies than the corresponding podands 1a -c and
2a -c. Podand SS-3c exhibited a 2-fold higher transport
rate than corresponding podand SS-2c,
transport rate 106 (mol/h)a
podand
1a
Ag+
Pb2+
Cu2+
Ni2+
Co2+
Zn2+
0.6
4.8
2.3
1.5
3.1
1.9
2.1
2.6
2.0
2.8
2.6
2.8
5.7
3.8
4.6
7.1
3.9
5.5
5.9
5.3
0.2
0.2
1.0
<0.1
4.6
5.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
0.2
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
<0.1
1b
1d b
1e
1f
SS-2a
m eso-2a
2a c
SS-2b
m eso-2b
2bc
SS-2c
m eso-2c
2cc
SS-3a
3a c
SS-3b
3bc
SS-3c
3cc
SS-4b
4bc
5
6
7
8
<0.1
<0.1
a
Aqueous source phase: AgClO4, Pb(ClO4)2, Cu(ClO4)2, Ni-
(ClO4)2, Co(ClO4)2, and Zn(ClO4)2, 0.50 mmol each in 5 mL of H2O.
Membrane: podand, 0.0186 mmol in 12 mL of CH2Cl2. Aqueous
b
receiving phase: 5 mL of H2O. Insoluble material appeared. c A
statistical mixture of SS-, RR-, and meso-isomers (1:1:2).
although both have the same palmitoyl moiety. The
location and stereochemistry of the substituent in the
podand significantly influenced the transport behavior.
Podands m eso-2 generally offered higher transport rates
than the SS-2 isomers. Since the latter extracted Ag+
much more effectively than the former, the release of the
complexed Ag+ into the aqueous receiving phase is an
important process in determining the overall transport
rate. Figure 3 shows the relationship between the
extraction percentage (Table 2) and the transport rate
for all ligands. This plot shows an inverse relationship
between the transport rate and extraction percentage.

3890 J . Org. Chem., Vol. 63, No. 12, 1998
Tsukube et al.
stirring for 10 min at the same temperature and for an
additional 30 min at room temperature, the reaction mixture
was diluted with CH2Cl2 (35-300 mL). The solution was
evaporated in vacuo, and the residue was purified by column
chromatography on silica gel. The following solvent systems
were used as eluents: 1a , EtOAc-CH2Cl2 (4:1); 1b, EtOAc-
CH2Cl2 (1:4); 1c, EtOAc-CH2Cl2 (1:4); 1e, EtOAc-CH2Cl2 (3:
7); 1f, EtOAc-hexane (2:3); SS-2a , EtOAc-hexane (4:1); SS-
2b, EtOAc-hexane (1:4); SS-2c, EtOAc-hexane (3:7); SS-3a ,
EtOAc-hexane (4:1); SS-3b, EtOAc-hexane (3:7); SS-3c,
EtOAc-hexane (3:7). Due to the poor solubility of 1d , the
reaction mixture was diluted with a large volume of CH2Cl2
(ca. 1000 mL) and then refluxed for 1 h. After cooling, the
precipitate was collected and recrystallized from CH2Cl2. For
the synthesis of 4a ,b, 9b was used instead of 9a . As eluents,
EtOAc-hexane (7:3) and EtOAc-hexane (1:4) were used in
the purification of 4a ,b, respectively.
1a : colorless crystals; mp 171-172 °C (EtOAc); Rf ) 0.50
(MeOH-EtOAc, 1:9); IR (KBr) 1740 cm-1; 1H NMR (400 MHz,
CDCl3) δ 8.61 (2H, dm, J ) 5.1 Hz), 8.36 (2H, d, J ) 7.7 Hz),
8.04 (1H, t, J ) 7.7 Hz), 7.70 (2H, td, J ) 7.7 and 1.8 Hz),
7.53 (2H, d, J ) 7.7 Hz), 7.25 (2H, dd, J ) 5.1 and 1.8 Hz),
5.58 (4H, s); 13C NMR (100 MHz, CDCl3) δ 164.1, 155.4, 149.4,
148.2, 138.3, 136.8, 128.3, 122.9, 121.8, 68.0; HRMS (FAB)
calcd for C19H16N3O4; MH+, 350.1141, found m/z 350.1160.
Anal. Calcd for C19H15N3O4: C, 65.32; H, 4.33; N, 12.03.
Found: C, 65.55; H, 4.35; N, 11.78.
1b: colorless crystals; mp 151-152 °C (hexane); Rf ) 0.29
(EtOAc-CH2Cl2 , 1:9); IR (KBr) 1745 cm-1; 1H NMR (400 MHz,
CDCl3) δ 8.34 (2H, d, J ) 7.7 Hz), 8.02 (1H, t, J ) 7.7 Hz),
7.70 (2H, t, J ) 7.7 Hz), 7.47 (2H, d, J ) 7.7 Hz), 7.38 (2H, d,
J ) 7.7 Hz), 5.53 (4H, s), 4.84 (4H, s), 0.96 (18H, s), 0.12 (12H,
s); 13C NMR (100 MHz, CDCl3) δ 164.2, 161.3, 154.2, 148.3,
138.3, 137.5, 128.2, 119.8, 119.2, 68.1, 65.9, 25.9, 18.3, -5.4;
MS (FAB) m/z 638 (MH+). Anal. Calcd for C33H47N3O6Si2: C,
62.13; H, 7.43; N, 6.59. Found: C, 61.93; H, 7.54; N, 6.64.
1c: colorless crystals; mp 138-139 °C (EtOAc); Rf ) 0.20
(EtOAc-CH2Cl2, 1:9); IR (KBr) 1745, 1735 cm-1; 1H NMR (400
MHz, CDCl3) δ 8.37 (2H, d, J ) 7.9 Hz), 8.05 (1H, t, J ) 7.9
Hz), 7.71 (2H, t, J ) 7.7 Hz), 7.47 (2H, d, J ) 7.7 Hz), 7.30
(2H, d, J ) 7.7 Hz), 5.58 (4H, s), 5.23 (4H, s), 2.42 (4H, t, J )
7.6 Hz), 1.73-1.63 (4H, m), 1.40-1.18 (48H, m), 0.88 (6H, t, J
) 6.8 Hz); 13C NMR (75 MHz, CDCl3) δ 173.4, 164.1, 155.8,
155.1, 148.1, 138.4, 137.6, 128.3, 120.8, 120.7, 67.9, 66.4, 34.2,
31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 24.9, 22.7, 14.1; MS
(FAB) m/z 887 (MH+). Anal. Calcd for C53H79N3O8: C, 71.83;
H, 8.98; N, 4.74. Found: C, 71.87; H, 9.18; N, 4.60.
1d : colorless crystals; mp 248-249 °C (CH2Cl2); Rf ) 0.20
(MeOH-EtOAc, 2:3); IR (KBr) 1745 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.37 (2H, d, J ) 7.7 Hz), 8.06 (1H, t, J ) 7.7 Hz),
7.57 (2H, t, J ) 7.7 Hz), 7.51 (2H, d, J ) 7.7 Hz), 7.45 (2H, d,
J ) 7.7 Hz), 5.54 (4H, s); MS (FAB) m/z 510, 508, 506 (MH+).
Anal. Calcd for C19H13Br2N3O4: C, 45.00; H, 2.58; N, 8.29.
Found: C, 45.07; H, 2.86; N, 8.05.
1e: colorless crystals; mp 157-158 °C (hexane); Rf ) 0.40
(EtOAc-CH2Cl2, 3:7); IR (KBr) 1750 cm-1; 1H NMR (400 MHz,
CDCl3) δ 8.34 (2H, d, J ) 7.8 Hz), 8.02 (1H, t, J ) 7.8 Hz),
7.70 (2H, t, J ) 7.8 Hz), 7.46 (2H, d, J ) 7.8 Hz), 7.42 (2H, d,
J ) 7.8 Hz), 7.40-7.28 (10H, m), 5.55 (4H, s), 4.69 (4H, s),
4.66 (4H, s); 13C NMR (100 MHz, CDCl3) δ 164.2, 158.5, 154.7,
148.3, 138.3, 137.9, 137.4, 128.4, 128.2, 127.8, 127.8, 120.6,
120.3, 73.0, 72.9, 68.1; MS (FAB) m/z 590 (MH+). Anal. Calcd
for C35H31N3O6: C, 71.29; H, 5.30; N, 7.13. Found: C, 71.39;
H, 5.42; N, 6.85.
F igu r e 3. Plot of transport rate vs extraction percentage: O,
podand 1; 4, podand 2; 2, podand 3; b, podands 4-8.
As reported before,15 podands which moderately bind the
guest Ag+ effectively transport it.
Thus, we have presented an interesting series of
podands capable of specific extraction and transport of
Ag+. Although several macrocycles have been developed
as Ag+-specific ligands,16 the present type of podands
have a unique sequence of three pyridine rings which is
suitable for Ag+ binding. Furthermore, stereocontrolled
substitution significantly enhances the Ag+-binding abil-
ity of the pyridine podand. The stereoisomers can, in
principle, be considered different ligands of metal cations,
but only a few papers have described the effects of
stereochemistry of the ligand on metal cation binding.14
Still et al. prepared certain stereoisomers of the biological
ionophore lasalocid with 10 asymmetric substituents in
the podand skeleton.3 They demonstrated that the
isomer with the natural configuration formed a more
stable complex with Na+ than the other stereoisomers.
Our podands have only two chiral substituents, but the
effect of stereochemically controlled substitution on the
cation-binding properties was clearly observed. Thus,
guest-targeted ligand geometry and stereochemically
controlled substitution provide a new possibility for the
development of specific podand-type ligands, not only for
chiral guests but also for achiral metal cations.
Exp er im en ta l Section
Syn th esis of P yr id in e P od a n d s. Cou p lin g of P yr id in e
Alcoh ol a n d Acid Ch lor id e (Sch em e 4). To an ice-cooled,
stirred solution of pyridine alcohol (1 mmol) and DMAP (244
mg, 2 mmol) or Et3N (0.28 mL, 2 mmol) in anhydrous CH2Cl2
(5-30 mL) was dropped a solution of 9a (102 mg, 0.5 mmol)
in anhydrous CH2Cl2 (1 mL) during a 3-min period. After
(15) (a) Lamb, J . D.; Christensen, J . J .; Oscarson, J . L.; Nielson, B.
L.; Asay, B. W.; Izatt, R. M. J . Am. Chem. Soc. 1980, 102, 6820-6824.
(b) Behr, J . P.; Kirch, M.; Lehn, J . M. J . Am. Chem. Soc. 1985, 107,
241-246.
(16) (a) Frensdorff, H. K. J . Am. Chem. Soc. 1971, 93, 600-606. (b)
Tsukube, H.; Takagi, K.; Higashiyama, T.; Iwachido, T.; Hayama, N.
Tetrahedron Lett. 1985, 26, 881-882. (c) Oue, M.; Akama, K.; Kimura,
K.; Tanaka, M.; Shono, T. J . Chem. Soc., Perkin Trans. 1 1989, 1675-
1678. (d) Craig, A. S.; Kataky, R.; Parker, D.; Adams, H.; Bailey, N.;
Schneider, H. J . Chem. Soc., Chem. Commun. 1989, 1870-1872. (e)
Tsukube, H.; Minatogawa, M.; Munakata, M.; Toda, M.; Matsumoto,
K. J . Org. Chem. 1992, 57, 542-547. (f) Nabeshima, T.; Tsukada, N.;
Nishijima, K.; Ohshiro, H.; Yano, Y. J . Org. Chem. 1996, 61, 4342-
4350. (g) Kumar, S.; Hundal, G.; Kaur, N.; Hundal, M. S.; Singh, H.
Tetrahedron Lett. 1997, 38, 131-132. (h) Vogtle, F.; Ibach, S.; Nieger,
M.; Chartroux, C.; Kruger, T.; Stephan, H.; Gloe, K. J . Chem. Soc.,
Chem. Commun. 1997, 1809-1810.
1f: syrup; Rf ) 0.26 (EtOAc-hexane, 2:3); IR (KBr) 1730
1
cm-1; H NMR (300 MHz, CDCl3) δ 8.31 (2H, d, J ) 7.8 Hz),
7.98 (1H, t, J ) 7.8 Hz), 7.78 (2H, d, J ) 7.8 Hz), 7.76 (2H, t,
J ) 7.8 Hz), 7.55-7.47 (12H, m), 7.40 (2H, d, J ) 7.8 Hz),
7.35-7.19 (18H, m), 5.48 (4H, s), 4.37 (4H, s); 13C NMR (75
MHz, CDCl3) δ 164.1, 159.2, 154.2, 148.1, 143.7, 138.3, 137.5,
128.6, 128.2, 127.9, 127.1, 120.0, 119.9, 77.2, 68.0, 66.6; HRMS
(FAB) calcd for C59H48N3O6; MH+, 894.3543, found m/z 894.3514.
SS-2a : colorless crystals; mp 78-79 °C (hexane); Rf ) 0.45
(EtOAc-hexane, 7:3); [R]26 +54.7 (c 1.59, CHCl3); IR (KBr)
D
1740 cm-1; H NMR (300 MHz, CDCl3) δ 8.61 (2H, dm, J )
1

Ag+-Specific Pyridine Podands
J . Org. Chem., Vol. 63, No. 12, 1998 3891
5.0 Hz), 8.32 (2H, d, J ) 7.8 Hz), 8.00 (1H, t, J ) 7.8 Hz), 7.70
(2H, td, J ) 7.8 and 1.2 Hz), 7.60 (2H, d, J ) 7.8 Hz), 7.22
(2H, ddd, J ) 7.8, 5.0, and 1.2 Hz), 6.23 (2H, q, J ) 6.6 Hz),
1.80 (6H, d, J ) 6.6 Hz); 13C NMR (100 MHz, CDCl3) δ 163.7,
160.0, 149.2, 148.5, 138.1, 136.8, 127.9, 122.7, 120.5, 74.9, 20.8;
MS (EI) m/z (rel intensity) 377 (M+, 48), 228 (60), 210 (41),
106 (base). Anal. Calcd for C21H19N3O4: C, 66.83; H, 5.07;
N, 11.13. Found: C, 66.99; H, 5.18; N, 10.84.
C20H16N2O4: C, 68.96; H, 4.63; N, 8.04. Found: C, 69.22; H,
4.75; N, 7.75.
SS-4b: colorless crystals; mp 82-83 °C (EtOAc); Rf ) 0.53
(EtOAc-hexane, 1:4); [R]25 -37.3° (c 1.94, CHCl3); IR (KBr)
D
1730 cm-1; H NMR (400 MHz, CDCl3) δ 8.84 (1H, t, J ) 1.6
1
Hz), 8.33 (2H, dd, J ) 7.8 and 1.6 Hz), 7.71 (2H, t, J ) 7.8
Hz), 7.58 (1H, t, J ) 7.8 Hz), 7.34 (2H, d, J ) 7.8 Hz), 7.28
(2H, d, J ) 7.8 Hz), 5.92 (2H, q, J ) 6.7 Hz), 5.51 (4H, s), 2.38
(4H, t, J ) 7.5 Hz), 1.68-1.61 (4H, m), 1.56 (6H, d, J ) 6.7
Hz), 1.39-1.20 (48H, m), 0.88 (6H, t, J ) 7.3 Hz); 13C NMR
(100 MHz, CDCl3) δ 172.9, 165.2, 160.5, 155.2, 137.4, 134.2,
131.0, 130.5, 128.7, 120.2, 119.2, 72.7, 67.4, 34.5, 31.9, 29.6,
29.6, 29.6, 29.4, 29.3, 29.2, 29.1, 24.9, 22.6, 20.8, 14.1; MS
(FAB) m/z 914 (MH+). Anal. Calcd for C56H84N2O8: C, 73.65;
H, 9.27; N, 3.07. Found: C, 73.65; H, 9.52; N, 3.03.
SS-2b: colorless crystals; mp 86-87 °C (hexane); Rf ) 0.30
(EtOAc-hexane, 1:4); [R]29 +39.4 (c 1.49, CHCl3); IR (KBr)
D
1740 cm-1; H NMR (400 MHz, CDCl3) δ 8.29 (2H, d, J ) 7.7
1
Hz), 7.99 (1H, t, J ) 7.7 Hz), 7.69 (2H, t, J ) 7.7 Hz), 7.44
(2H, d, J ) 7.7 Hz), 7.43 (2H, d, J ) 7.7 Hz), 6.17 (2H, q, J )
6.6 Hz), 4.83 (4H, s), 1.76 (6H, d, J ) 6.6 Hz), 0.94 (18H, s),
0.11 (12H, s); 13C NMR (100 MHz, CDCl3) δ 163.7, 161.0, 158.9,
148.5, 138.1, 137.4, 127.9, 119.0, 118.2, 75.0, 66.0, 25.9, 21.0,
18.3, -5.4; MS (FAB) m/z 666 (MH+). Anal. Calcd for
C35H51N3O6Si2: C, 63.12; H, 7.72; N, 6.31. Found: C, 62.92;
H, 7.71; N, 6.27.
P r ep a r a tion of 5. To a mixture of 2,6-pyridinedimethanol
(300 mg, 2.16 mmol) and ethyl picolinate (0.874 mL, 6.47
mmol) in toluene (25 mL) was added anhydrous K2CO3 (50
mg). After refluxing for 1 h and cooling, dry ether (80 mL)
was added and the mixture was filtered. The filtrate was
evaporated in vacuo, and the residue was chromatographed
on silica gel with EtOAc as eluent to give 5 (527 mg) in 70%
yield: colorless crystals; mp 138-140 °C (ether); Rf ) 0.37
(MeOH-EtOAc, 1:9); IR (KBr) 1740 cm-1; 1H NMR (300 MHz,
CDCl3) δ 8.80 (2H, dm, J ) 7.8 Hz), 8.20 (2H, d, J ) 7.8 Hz),
7.88 (2H, td, J ) 7.8 and 1.8 Hz), 7.74 (2H, d, J ) 7.8 Hz),
7.52 (2H, ddd, J ) 7.8, 4.8, and 1.2 Hz), 7.43 (2H, d, J ) 7.8
Hz), 5.59 (4H, s); 13C NMR (100 MHz, CDCl3) δ 164.7, 155.3,
149.9, 147.6, 137.6, 137.0, 127.1, 125.4, 120.8, 67.6; MS (FAB)
m/z 350 (MH+). Anal. Calcd for C55H83N3O8: C, 65.32; H, 4.33;
N, 12.03. Found: C, 65.29; H, 4.33; N, 11.92.
SS-2c: colorless crystals; mp 61-62 °C (hexane); Rf ) 0.55
(EtOAc-hexane, 2:3); [R]25 +14.3 (c 1.96, CHCl3); IR (KBr)
D
1740 cm-1; H NMR (400 MHz, CDCl3) δ 8.32 (2H, d, J ) 7.8
1
Hz), 8.02 (1H, t, J ) 7.8 Hz), 7.70 (2H, t, J ) 7.8 Hz), 7.52
(2H, d, J ) 7.8 Hz), 7.26 (2H, d, J ) 7.8 Hz), 6.24 (2H, q, J )
6.7 Hz), 5.24 (4H, s), 2.42 (4H, t, J ) 7.6 Hz), 1.78 (6H, d, J )
6.7 Hz), 1.67-1.65 (4H, m), 1.32-1.18 (48H, m), 0.88 (6H, t, J
) 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 173.2, 163.7, 159.8,
155.6, 148.5, 138.0, 137.4, 127.8, 120.3, 119.1, 74.8, 66.4, 34.1,
31.8, 29.6, 29.5, 29.5, 29.4, 29.2, 29.2, 29.1, 24.9, 22.6, 20.8,
14.0; MS (FAB) m/z 915 (MH+). Anal. Calcd for C55H83N3O8:
C, 72.25; H, 9.15; N, 4.60. Found: C, 72.12; H, 9.33; N, 4.65.
SS-3a : colorless crystals; mp 138-139 °C (hexane); Rf )
Syn th esis of m eso-P od a n d s (Sch em e 5). P r ep a r a tion
of 30. To a mixture of 9a (299 mg, 1.47 mmol) and Et3N (410
µL, 2.94 mmol) in anhydrous CH2Cl2 (10 mL) was added a
solution of S-17 (297 mg, 1.47 mmol) in anhydrous CH2Cl2 (3.5
mL) at -78 °C under Ar atmosphere. The mixture was
warmed slowly to -15 °C during 30 min, and then a solution
of R-16 (181 mg, 1.47 mmol) in CH2Cl2 (3.5 mL) was added.
The mixture was stirred for 10 min at the same temperature,
then diluted with CH2Cl2 (180 mL), and worked up. The
residual oil was purified by chromatography on silica gel with
EtOAc-hexane (3:2) as eluent to give 30 (428 mg) in 64% yield
along with symmetrical coupling product (73 mg) in 9% yield.
30: colorless crystals; mp 56-57 °C (hexane); Rf ) 0.45
25
0.53 (EtOAc-hexane, 4:1); [R]
-80.2 (c 1.02, CHCl3); IR
D
(KBr) 1740 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.36 (2H, d, J
) 7.8 Hz), 8.05 (1H, t, J ) 7.8 Hz), 7.68 (2H, t, J ) 7.8 Hz),
7.43 (2H, d, J ) 7.8 Hz), 7.28 (2H, d, J ) 7.8 Hz), 5.91 (2H, q,
J ) 6.7 Hz), 5.58 (4H, s), 2.13 (6H, s), 1.58 (6H, d, J ) 6.7
Hz); 13C NMR (100 MHz, CDCl3) δ 170.2, 164.1, 160.1, 155.0,
148.3, 138.3, 137.5, 128.2, 120.4, 119.3, 72.9, 67.9, 21.2, 20.7;
MS (FAB) m/z 522 (MH+). Anal. Calcd for C27H27N3O8: C,
62.18; H, 5.22; N, 8.06. Found: C, 62.30; H, 5.30; N, 7.98.
SS-3b: colorless crystals; mp 137-138 °C (hexane); Rf )
0.40 (EtOAc-hexane, 3:7); [R]28 -43.4 (c 1.42, CHCl3); IR
D
(KBr) 1740 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.34 (2H, d, J
) 7.7 Hz), 8.02 (1H, t, J ) 7.7 Hz), 7.67 (2H, t, J ) 7.7 Hz),
7.48 (2H, d, J ) 7.7 Hz), 7.36 (2H, d, J ) 7.7 Hz), 5.54 (4H, s),
4.94 (2H, q, J ) 6.6 Hz), 1.44 (6H, d, J ) 6.6 Hz), 0.91 (18H,
s), 0.07 (6H, s), 0.01 (6H, s); 13C NMR (100 MHz, CDCl3) δ
165.7, 164.2, 153.9, 148.3, 138.3, 137.4, 128.1, 119.6, 118.5,
72.0, 68.1, 25.8, 25.6, 18.2, -4.8, -5.0; MS (EI) m/z (rel
intensity) 608 (M+ - 57, base), 373 (34), 313 (6), 275 (19). Anal.
Calcd for C35H51N3O6Si2: C, 63.12; H, 7.72; N, 6.31. Found:
C, 62.86; H, 7.79; N, 6.41.
(EtOAc-hexane, 7:3); [R]26 +11.7 (c 1.99, CHCl3); IR (KBr)
D
1735 cm-1; H NMR (300 MHz, CDCl3) δ 8.61 (1H, dm, J )
1
4.8 Hz), 8.34 (1H, d, J ) 7.7 Hz), 8.33 (1H, d, J ) 7.7 Hz),
8.04 (1H, t, J ) 7.7 Hz), 7.70 (1H, td, J ) 7.7 and 1.7 Hz),
7.60 (1H, d, J ) 7.7 Hz), 7.58 (1H, d, J ) 7.7 Hz), 7.55 (1H, t,
J ) 7.7 Hz), 7.41 (1H, d, J ) 7.7 Hz), 7.23 (1H, ddm, J ) 7.7
and 4.9 Hz), 6.23 (1H, q, J ) 6.7 Hz), 6.18 (1H, q, J ) 6.7 Hz),
1.81 (3H, d, J ) 6.7 Hz), 1.79 (3H, d, J ) 6.7 Hz); 13C NMR
(75 MHz, CDCl3) δ 163.6, 163.6, 161.5, 159.8, 149.2, 148.4,
148.2, 141.4, 139.2, 138.2, 136.9, 128.1, 128.0, 127.1, 122.8,
120.5, 119.1, 74.8, 74.1, 20.8, 20.8; HRMS (EI) calcd for
C21H18BrN3O4, M+, 455.0481 and 457.0460, found m/z 455.0456
and 457.0431.
SS-3c: colorless crystals; mp 118-119 °C (CH2Cl2-hexane,
1:19); Rf ) 0.45 (EtOAc-hexane, 2:3); [R]25 -35.7 (c 1.25,
D
CHCl3); IR (KBr) 1740, 1730 cm-1; 1H NMR (400 MHz, CDCl3)
δ 8.36 (2H, d, J ) 7.8 Hz), 8.05 (1H, t, J ) 7.8 Hz), 7.68 (2H,
t, J ) 7.8 Hz), 7.43 (2H, d, J ) 7.8 Hz), 7.28 (2H, d, J ) 7.8
Hz), 5.92 (2H, q, J ) 6.6 Hz), 5.57 (4H, s), 2.38 (4H, t, J ) 6.8
Hz), 1.70-1.60 (4H, m), 1.58 (6H, d, J ) 6.6 Hz), 1.38-1.20
(48H, m), 0.88 (6H, t, J ) 7.0 Hz); 13C NMR (100 MHz, CDCl3)
δ 172.9, 164.1, 160.4, 155.0, 148.3, 138.2, 137.4, 128.2, 120.3,
119.2, 72.7, 68.0, 34.5, 31.9, 29.6, 29.6, 29.6, 29.4, 29.3, 29.2,
29.1, 24.9, 22.6, 20.8, 14.1; MS (FAB) m/z 915 (MH+). Anal.
Calcd for C55H83N3O8: C, 72.25; H, 9.15; N, 4.60. Found: C,
72.15; H, 9.44; N, 4.76.
P r ep a r a tion of m eso-2a . To a degassed anhydrous ben-
zene solution (2.5 mL) of 30 (201 mg, 0.44 mmol) and Bu3SnH
(142 µL, 0.53 mmol) was added triethylborane (88 µL of 1.0 M
hexane solution) at room temperature. The mixture was
stirred for 2 h at room temperature, and then the reaction was
quenched with saturated aqueous NaHCO3 (1 mL). The
mixture was diluted with CH2Cl2 (40 mL) and worked up. The
residue was chromatographed on silica gel with EtOAc-
hexane (7:3) as eluent to give m eso-2a (100 mg) in 60% yield:
1
4a : colorless crystals; mp 69-70 °C (hexane); Rf ) 0.49
colorless crystals; mp 98-99 °C (hexane). Rf value, H NMR,
(EtOAc); IR (KBr) 1720 cm-1; H NMR (400 MHz, CDCl3) δ
13C NMR, IR, and MS spectral data were exactly the same as
those of SS-2a .
1
8.81 (1H, t, J ) 1.8 Hz), 8.60 (2H, ddd, J ) 4.8, 1.8, and 0.7
Hz), 8.30 (2H, dd, J ) 7.7 and 1.8 Hz), 7.70 (2H, td, J ) 7.7
and 1.8 Hz), 7.55 (1H, t, J ) 7.7 Hz), 7.43 (2H, d, J ) 7.7 Hz),
7.23 (2H, ddd, J ) 7.7, 4.8, and 0.7 Hz), 5.49 (4H, s); 13C NMR
(100 MHz, CDCl3) δ 165.3, 155.6, 149.5, 136.8, 134.2, 131.0,
130.3, 128.7, 122.9, 121.8, 67.5; MS (EI) m/z (rel intensity) 348
(MH+, 5), 347 (base), 240 (25), 213 (50). Anal. Calcd for
P r ep a r a tion of 31. To a mixture of 9a (676 mg, 3.31 mmol)
and Et3N (1.38 mL, 9.94 mmol) in anhydrous CH2Cl2 (30 mL)
was added a solution of S-18 (886 mg, 3.31 mmol) in anhydrous
CH2Cl2 (10 mL) at -78 °C under Ar atmosphere. The mixture
was warmed slowly to -15 °C during 30 min, and then a
solution of R-20 (1.31 g, 3.31 mmol) in CH2Cl2 (10 mL) was

3892 J . Org. Chem., Vol. 63, No. 12, 1998
Tsukube et al.
added. The mixture was stirred for 10 min at the same
temperature, then allowed to warm to room temperature, and
stirred for 7 h. The reaction mixture was diluted with CH2Cl2
(100 mL) and worked up. The crude product was purified by
column chromatography on silica gel with EtOAc-hexane (3:
2) as eluent followed by HPLC purification (silica gel, EtOAc-
hexane (7:13)) to give 31 (943 mg) in 36% yield along with
SS-2b (243 mg) in 11% yield. 31: colorless oil; Rf ) 0.38
66.5, 66.0, 34.2, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 29.2,
25.9, 24.9, 22.7, 21.0, 21.0, 18.3, 14.1, -5.4; HRMS (FAB) calcd
for C45H68N3O7Si, MH+, 790.4827, found m/z 790.4849.
P r ep a r a tion of 34. To a THF solution (4 mL) of 33 (365
mg, 0.46 mmol) was added Bu4NF (0.46 mL of a 1 M THF
solution) at room temperature. The mixture was stirred for
40 min, diluted with EtOAc (70 mL), and worked up. The
crude product was purified by column chromatography on
silica gel with EtOAc-hexane (7:3) as eluent to give 34 (102
mg) in 33% yield. A compound with the palmitoyl group
hydrolyzed was formed as a side product. 34: colorless oil; Rf
(EtOAc-hexane, 3:7); [R]26 -0.44 (c 1.47, CHCl3); IR (neat)
D
1
1750 and 1730 cm-1; H NMR (400 MHz, CDCl3) δ 8.29 (1H,
dd, J ) 7.8 and 1.1 Hz), 8.28 (1H, dd, J ) 7.8 and 1.1 Hz),
7.97 (1H, t, J ) 7.8 Hz), 7.73 (1H, t, J ) 7.8 Hz), 7.70 (1H,
dm, J ) 7.8 Hz), 7.68 (1H, t, J ) 7.8 Hz), 7.53-7.49 (6H, m),
7.47 (1H, d, J ) 7.8 Hz), 7.44 (1H, d, J ) 7.8 Hz), 7.43 (1H, d,
J ) 7.8 Hz), 7.34-7.21 (9H, m), 6.18 (1H, q, J ) 6.7 Hz), 6.14
(1H, q, J ) 6.7 Hz), 4.84 (2H, s), 4.29 (1H, s), 4.28 (1H, s),
1.77 (3H, d, J ) 6.7 Hz), 1.72 (3H, d, J ) 6.7 Hz), 0.96 (9H, s),
0.12 (6H, s); 13C NMR (75 MHz, CDCl3) δ 163.7, 163.7, 160.9,
159.2, 159.0, 158.9, 148.4, 143.7, 138.1, 137.5, 128.6, 127.9,
127.9, 127.1, 119.6, 118.9, 118.3, 118.1, 87.1, 75.0, 66.7, 65.9,
25.9, 21.1, 21.0, 18.3, -5.4; HRMS (FAB) calcd for C48H52N3O6Si,
MH+, 794.3626, found m/z 794.3641.
25
) 0.35 (EtOAc- hexane, 7:3); [R]D -0.46 (c 2.47, CHCl3); IR
(neat) 3400, 1740, 1720, 1710 cm-1; 1H NMR (300 MHz, CDCl3)
δ 8.33 (1H, d, J ) 7.8 Hz), 8.33 (1H, d, J ) 7.8 Hz), 8.02 (1H,
t, J ) 7.8 Hz), 7.70 (1H, d, J ) 7.8 Hz), 7.68 (1H, d, J ) 7.8
Hz), 7.50 (1H, t, J ) 7.8 Hz), 7.50 (1H, t, J ) 7.8 Hz), 7.26
(1H, d, J ) 7.8 Hz), 7.16 (1H, d, J ) 7.8 Hz), 6.24 (1H, q, J )
6.7 Hz), 6.22 (1H, q, J ) 6.7 Hz), 5.24 (2H, s), 4.77 (2H, s),
2.42 (2H, t, J ) 6.4 Hz), 1.81 (3H, d, J ) 6.7 Hz), 1.79 (3H, d,
J ) 6.7 Hz), 1.72-1.62 (2H, m), 1.38-1.20 (24H, m), 0.88 (3H,
t, J ) 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 173.4, 163.8,
163.7, 159.8, 158.8, 158.5, 155.6, 148.5, 148.4, 138.2, 137.5,
128.0, 128.0, 120.4, 119.5, 119.2, 118.9, 74.9, 74.6, 66.4, 63.8,
34.2, 31.9, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 24.9, 22.6,
20.9, 20.8, 14.1; HRMS (FAB) calcd for C39H54N3O7, MH+,
676.3962, found m/z 676.3959.
P r ep a r a tion of 32. A mixture of 31 (385 mg, 1.1 mmol)
and ZnBr2 (1.09 g, 4.85 mmol) in CH2Cl2 (8 mL) was stirred
for 10 min at room temperature. The mixture was diluted with
CH2Cl2 (90 mL) and worked up. The crude product was
purified by column chromatography on silica gel with EtOAc-
hexane (3:2) as eluent to give 32 (231 mg) in 88% yield: syrup;
P r ep a r a tion of m eso-2c. Palmitoyl chloride (32 mg, 0.157
mmol) was added to a mixture of 34 (96 mg, 0.143 mmol) and
DMAP (88 mg, 0.072 mmol) in anhydrous CH2Cl2 (2 mL) at
room temperature. The mixture was stirred for 5 min,
quenched with water (5 mL), and extracted with EtOAc-
hexane (1:1, 30 mL). The crude product was purified by silica
gel chromatography with EtOAc-hexane (2:3) as eluent to give
m eso-2c (120 mg) in 91% yield: colorless crystals; mp 54-55
°C (hexane). Rf value, 1H NMR, 13C NMR, IR, and MS spectral
data were exactly the same as those of SS-2c.
Rf ) 0.33 (EtOAc-hexane, 7:3); [R]26 -1.28 (c 1.93, CHCl3);
D
IR (KBr) 3300, 1740 cm-1; H NMR (300 MHz, CDCl3) δ 8.32
1
(1H, d, J ) 7.8 Hz), 8.32 (1H, d, J ) 7.8 Hz), 8.01 (1H, t, J )
7.8 Hz), 7.69 (1H, t, J ) 7.8 Hz), 7.67 (1H, t, J ) 7.8 Hz), 7.47
(1H, d, J ) 7.8 Hz), 7.44 (1H, d, J ) 7.8 Hz), 7.41 (1H, d, J )
7.8 Hz), 7.15 (1H, d, J ) 7.8 Hz), 6.23 (1H, q, J ) 6.7 Hz),
6.17 (1H, q, J ) 6.7 Hz), 4.84 (2H, s), 4.75 (2H, d, J ) 4.8 Hz),
4.16 (1H, t, J ) 4.8 Hz), 1.80 (3H, d, J ) 6.7 Hz), 1.77 (3H, d,
J ) 6.7 Hz), 0.95 (9H, s), 0.11 (6H, s); 13C NMR (75 MHz,
CDCl3) δ 163.8, 163.7, 161.1, 158.8, 158.7, 158.6, 148.4, 148.4,
138.2, 137.6, 137.5, 128.1, 128.1, 119.6, 119.1, 119.1, 118.3,
75.1, 74.6, 65.9, 63.8, 25.9, 21.0, 20.8, 18.3, -5.4; HRMS (FAB)
calcd for C29H38N3O6Si, MH+, 552.2530, found m/z 552.2514.
P r ep a r a tion of m eso-2b. t-BuMe2SiCl (97 mg, 0.64 mmol)
was added to a mixture of 32 (231 mg, 0.43 mmol) and DMAP
(105 mg, 0.86 mmol) in CH2Cl2 (3 mL) at room temperature.
After being stirred for 30 min, the reaction mixture was diluted
with CH2Cl2 (100 mL) and worked up. The crude product was
purified by silica gel chromatography with EtOAc-hexane (3:
2) as eluent to give m eso-2b (265 mg) in 93% yield: colorless
Syn th esis of P yr id in em eth a n ol P r ecu r sor s (Sch em e
1). P r ep a r a tion of 12. A mixture of 2,6-pyridinedimethanol
(765 mg, 5.5 mmol), palmitoyl chloride (1.36 g, 4.95 mmol),
and Et3N (1.15 mL, 8.25 mmol) was stirred in 120 mL of THF-
CH2Cl2 (1:1) for 1.5 h at room temperature. Then the solvent
was removed in vacuo, and the residue was dissolved in CH2Cl2
(120 mL) and worked up. The crude product was purified by
column chromatography on silica gel with EtOAc-hexane (2:
3) as eluent to give 12 (1.3 g) in 70% yield along with the
dipalmitate (531 mg) in 17% yield. 12: colorless crystals; mp
69-70 °C (hexane); Rf ) 0.50 (EtOAc-hexane, 2:3); IR (KBr)
1
3380, 1735 cm-1; H NMR (300 MHz, CDCl3) δ 7.71 (1H, t, J
crystals, mp 99-100 °C (hexane). The Rf value, 1H NMR, 13
C
) 7.7 Hz), 7.26 (1H, d, J ) 7.7 Hz), 7.20 (1H, d, J ) 7.7 Hz),
5.23 (2H, s), 4.76 (2H, s), 3.95 (1H, br s), 2.42 (2H, t, J ) 7.5
Hz), 1.67 (2H, m), 1.40-1.17 (24H, m), 0.88 (3H, t, J ) 6.7
Hz); 13C NMR (75 MHz, CDCl3) δ 173.4, 158.7, 154.9, 137.4,
120.1, 119.6, 66.2, 63.8, 34.2, 31.9, 29.7, 29.6, 29.4, 29.3, 29.2,
29.1, 24.9, 22.7, 14.1; MS (FAB) m/z 378 (MH+). Anal. Calcd
for C23H39NO3: C, 73.17; H, 10.41; N, 3.71. Found: C, 73.30;
H, 10.29; N, 3.62.
NMR, IR, and MS spectral data were exactly the same as those
of SS-2b.
P r ep a r a tion of 33. To a mixture of 9a (195 mg, 0.95 mmol)
and Et3N (400 µL, 2.86 mmol) in anhydrous CH2Cl2 (6 mL)
was added a solution of S-18 (255 mg, 0.95 mmol) in anhydrous
CH2Cl2 (2 mL) at -78 °C under Ar atmosphere. The mixture
was warmed slowly to -15 °C during 30 min, and then a
solution of R-19 (299 mg, 0.763 mmol) in CH2Cl2 (2 mL) was
added. After stirring for 1 h at the same temperature and for
1 h at room temperature, the reaction mixture was diluted
with CH2Cl2 (50 mL) and worked up. The crude product was
purified by column chromatography on silica gel with EtOAc-
hexane (3:7) as eluent followed by HPLC purification (silica
gel, EtOAc-hexane (1:3) as eluent) to give 33 (408 mg) in 68%
yield along with SS-2c (48 mg) in 8% yield. 33: colorless oil;
P r ep a r a tion of 15. A mixture of 2,6-pyridinedimethanol
(100 mg, 0.72 mmol), trityl chloride (1.36 g, 0.72 mmol), and
Et3N (0.3 mL, 2.16 mmol) was stirred in 5.5 mL of THF-
CH2Cl2 (1:10) for 7 h at room temperature. Then, the solvent
was removed in vacuo, and the residue was dissolved in EtOAc
(100 mL) and worked up. The crude product was purified by
column chromatography on silica gel with EtOAc-hexane (3:
7) as eluent to give 15 (174 mg) in 64% yield along with the
ditrityl product (24 mg) in 5% yield. 15: colorless crystals;
mp 115-116 °C (hexane); Rf ) 0.49 EtOAc-hexane (1:1); IR
Rf ) 0.26 (EtOAc-hexane, 3:7); [R]25 +0.71 (c 1.39, CHCl3);
D
IR (neat) 1745, 1730 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.31
(2H, d, J ) 7.7 Hz), 8.00 (1H, t, J ) 7.7 Hz), 7.69 (1H, t, J )
7.7 Hz), 7.68 (1H, t, J ) 7.7 Hz), 7.53 (1H, d, J ) 7.7 Hz), 7.44
(2H, d, J ) 7.7 Hz), 7.25 (1H, d, J ) 7.7 Hz), 6.21 (1H, q, J )
6.7 Hz), 6.18 (1H, q, J ) 6.7 Hz), 5.23 (2H, s), 4.84 (2H, s),
2.41 (2H, t, J ) 7.5 Hz), 1.78 (3H, d, J ) 6.7 Hz), 1.77 (3H, d,
J ) 6.7 Hz), 1.69-1.64 (2H, m), 1.29-1.16 (24H, m), 0.95 (9H,
s), 0.87 (3H, t, J ) 6.8 Hz), 0.12 (6H, s); 13C NMR (100 MHz,
CDCl3) δ 173.4, 163.8, 161.0, 159.9, 159.0, 155.6, 148.6, 148.5,
138.1, 137.5, 137.5, 128.0, 120.4, 119.2, 119.0, 118.2, 75.1, 74.9,
1
(KBr) 3230 cm-1; H NMR (400 MHz, CDCl3) δ 7.70 (1H, t, J
) 7.6 Hz), 7.65 (1H, d, J ) 7.6 Hz), 7.51 (6H, d, J ) 7.4 Hz),
7.30 (6H, t, J ) 7.4 Hz), 7.23 (3H, t, J ) 7.4 Hz), 7.08 (1H, d,
J ) 7.6 Hz), 4.66 (2H, s), 4.34 (2H, s), 3.78 (1H, br s); 13C NMR
(100 MHz, CDCl3) δ 158.2, 157.9, 143.8, 137.3, 128.6, 127.9,
127.1, 119.3, 118.6, 87.3, 66.8, 63.8; MS (FAB) m/z 382 (MH+).
Anal. Calcd for C26H23NO2: C, 81.86; H, 6.08; N, 3.67.
Found: C, 81.97; H, 6.11; N, 3.75.

Ag+-Specific Pyridine Podands
J . Org. Chem., Vol. 63, No. 12, 1998 3893
P r ep a r a tion of 24. To a DMF (16 mL) suspension of NaH
(120 mg, 3 mmol, 60% in mineral oil) was added 15 (956 mg,
2.51 mmol) in 12 mL of DMF-THF (2:1) at 0 °C. The mixture
was stirred for 30 min, and benzyl bromide (0.36 mL, 3.01
mmol) was added. The ice bath was removed after 30 min,
and stirring was further continued for 12 h. The mixture was
diluted with 120 mL of EtOAc-hexane (3:7) and worked up.
The crude product was purified by silica gel chromatography
with EtOAc-hexane (1:4) as eluent to give 24 (1.09 g) in 93%
yield: colorless crystals; mp 115-117 °C (hexane); Rf ) 0.23
(EtOAc-hexane, 1:9); 1H NMR (400 MHz, CDCl3) δ 7.76 (1H,
t, J ) 7.7 Hz), 7.70 (1H, dm, J ) 7.7 Hz), 7.51-7.48 (6H, m),
7.07 (1H, d, J ) 7.7 Hz), 4.93 (1H, q, J ) 6.5 Hz), 4.72 (2H, s),
4.12 (1H, br s), 1.44 (3H, d, J ) 6.5 Hz), 0.91 (9H, s), 0.08 (3H,
s), 0.01 (3H, s); 13C NMR (75 MHz, CDCl3) δ 164.7, 157.3,
137.3, 118.3, 117.8, 71.8, 63.7, 25.8, 25.4, 18.2, -4.8, -5.0;
HRMS (FAB) calcd for C14H26NO2Si, MH+, 268.1733, found m/z
268.1725.
P r ep a r a tion of S-19. To an ice-cooled solution of S-25 (153
mg, 1 mmol) and Et3N (0.21 mL, 1.5 mmol) in CH2Cl2 (10 mL)
was dropped palmitoyl chloride (275 mg, 1 mmol) in CH2Cl2
(1 mL). The mixture was stirred for 15 min at 0 °C and diluted
with EtOAc (70 mL). The crude product was chromatographed
on silica gel with EtOAc-hexane (2:3) as eluent to give 19 (368
mg) in 94% yield: colorless crystals; mp 35-36 °C (hexane);
7.37-7.20 (15H, m), 4.61 (2H, s), 4.59 (2H, s), 4.35 (2H, s); 13
C
NMR (100 MHz, CDCl3) δ 158.8, 157.5, 143.8, 138.0, 137.3,
128.7, 128.4, 127.9, 127.8, 127.7, 127.1, 119.6, 119.3, 87.3, 73.1,
72.9, 66.9; MS (FAB) m/z 472 (MH+). Anal. Calcd for
Rf ) 0.28 (EtOAc-hexane, 3:7); [R]25 -1.72 (c 2.00, CHCl3);
D
IR (KBr) 3420, 1740 cm-1; H NMR (400 MHz, CDCl3) δ 7.70
1
(1H, t, J ) 7.7 Hz), 7.24 (1H, d, J ) 7.7 Hz), 7.20 (1H, d, J )
7.7 Hz), 5.23 (2H, s), 4.88 (1H, q, J ) 6.6 Hz), 3.90 (1H, br s),
2.42 (2H, t, J ) 7.6 Hz), 1.73-1.62 (2H, m), 1.50 (3H, d, J )
6.6 Hz), 1.38-1.18 (24H, m), 0.88 (3H, t, J ) 6.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 173.4, 162.7, 154.6, 137.5, 119.9, 118.8,
68.5, 66.3, 34.2, 31.9, 29.7, 29.6, 29.6, 29.4, 29.3, 29.2, 29.1,
24.9, 24.2, 22.7, 14.1; MS (EI) m/z (rel intensity) 391 (M+, base),
376 (22), 348 (9), 279 (22), 256 (35). Anal. Calcd for
C
33H29NO2: C, 84.05; H, 6.20; N, 2.97. Found: C, 83.85; H,
6.29; N, 3.08.
P r ep a r a tion of 14. To a stirred solution of 24 (420 mg,
0.89 mmol) in 10 mL of MeOH-CH2Cl2 (3:2) was added
concentrated HCl (10 mL) at 0 °C. After stirring for 20 min
at room temperature, saturated aqueous NaHCO3 (100 mL)
was added, and the solvent was removed in vacuo. The residue
was dissolved in water (5 mL) and extracted with CH2Cl2 (70
mL). The crude product was chromatographed on silica gel
with EtOAc-hexane (1:1) as eluent to give 14 (196 mg) in 96%
yield: colorless oil; Rf ) 0.30 (EtOAc-hexane, 3:2); IR (neat)
C
24H41NO3: C, 73.61; H, 10.55; N, 3.58. Found: C, 73.47; H,
10.76; N, 3.61. R-19 was obtained exactly in the same manner
described for S-18 but starting from R-25.
P r ep a r a tion of S-28. S-28 was obtained by acetylation
of S-18 in 94% yield. The method was the same as described
for S-26 except EtOAc-hexane (1:9) was employed as eluent
for column chromatography: colorless oil; Rf ) 0.55 (EtOAc-
1
3380 cm-1; H NMR (400 MHz, CDCl3) δ 7.67 (1H, t, J ) 7.7
Hz), 7.42-7.26 (6H, m), 7.14 (1H, d, J ) 7.7 Hz), 4.72 (2H, s),
4.66 (2H, s), 4.63 (2H, s), 4.15 (1H, br s); 13C NMR (100 MHz,
CDCl3) δ 158.5, 157.5, 137.8, 137.3, 128.4, 127.7, 119.8, 119.1,
72.8, 72.7, 64.0; HRMS (FAB) calcd for C14H16NO2, MH+,
230.1181, found m/z 230.1198.
hexane, 1:4); [R]D26 -61.9 (c 2.02, CHCl3); IR (neat) 1740 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.69 (1H, t, J ) 7.7 Hz), 7.42
(1H, d, J ) 7.7 Hz), 7.18 (1H, d, J ) 7.7 Hz), 5.86 (1H, q, J )
6.7 Hz), 4.83 (2H, s), 2.11 (3H, s), 1.56 (3H, d, J ) 6.7 Hz),
0.95 (9H, s), 0.12 (6H, s); 13C NMR (100 MHz, CDCl3) δ 169.9,
160.9, 159.2, 137.1, 118.7, 118.1, 73.0, 66.0, 25.8, 21.1, 20.7,
18.2, -5.5; HRMS (FAB) calcd for C16H28NO3Si, MH+, 310.1839,
found m/z 310.1858.
Syn t h esis of Ch ir a l P yr id in eet h a n ol P r ecu r sor s
(Sch em es 2 a n d 3). P r ep a r a tion of S-26. To an ice-cooled
solution of S-25 (507 mg, 3.31 mmol) and Et3N (0.69 mL, 4.96
mmol) in CH2Cl2 (33 mL) was added acetic anhydride (0.32
mL, 3.4 mmol). The mixture was stirred for 2 h at 0 °C. Ice
water (20 mL) was added, and the mixture was extracted with
EtOAc (150 mL). The crude product was purified by silica gel
column chromatography with EtOAc-hexane (1:1) as eluent.
Oily acetate 26 (582 mg) was obtained in 96% yield: colorless
P r ep a r a tion of S-21. S-21 was obtained in 97% yield by
desilylation of S-28 with Bu4NF. The method was the same
as described for S-25 except using EtOAc-hexane (7:3) as the
eluent for column chromatography: colorless oil; Rf ) 0.30
oil; Rf ) 0.35 (EtOAc-hexane, 1:1); [R]26 -3.89 (c 1.97,
(EtOAc-hexane (1:1)); [R] D -93.3 (c 1.85, CHCl3); IR (neat)
26
D
CHCl3); IR (neat) 3420, 1740 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.72 (1H, t, J ) 7.8 Hz), 7.26 (1H, d, J ) 7.8 Hz), 7.24 (1H,
d, J ) 7.8 Hz), 5.23 (2H, s), 4.90 (1H, q, J ) 6.6 Hz), 4.45 (1H,
br s), 2.18 (3H, s), 1.50 (3H, d, J ) 6.6 Hz); 13C NMR (75 MHz,
CDCl3) δ 170.6, 162.7, 154.2, 137.5, 119.9, 118.9, 68.5, 66.5,
24.1, 20.9; HRMS (FAB) calcd for C10H14NO3, MH+, 196.0973,
found m/z 196.0957.
3410, 1740 cm-1; H NMR (300 MHz, CDCl3) δ 7.69 (1H, t, J
1
) 7.7 Hz), 7.25 (1H, d, J ) 7.7 Hz), 7.17 (1H, d, J ) 7.7 Hz),
5.91 (1H, q, J ) 6.7 Hz), 4.75 (2H, s), 4.16 (1H, br s), 2.13 (3H,
s), 1.59 (3H, d, J ) 6.7 Hz); 13C NMR (75 MHz, CDCl3) δ 170.2,
159.1, 158.4, 137.4, 119.3, 118.7, 72.8, 63.7, 21.2, 20.6; HRMS
(EI) calcd for C10H13NO3, M+, 195.0896, found m/z 195.0911.
P r ep a r a tion of S-29. S-29 was obtained in 95% yield by
acylation of S-18 with palmitoyl chloride. The synthetic
method was the same as described for S-19 except using
EtOAc-hexane (1:19) as the eluent for column chromatogra-
phy: colorless oil; Rf ) 0.47 (EtOAc-hexane, 1:9); [R]25D -34.9
P r ep a r a tion of S-27. A mixture of 26 (583 mg, 3.18 mmol),
imidazole (650 mg, 9.55 mmol), and t-BuMe2SiCl (528 mg, 3.5
mmol) in DMF (5 mL) was stirred for 1 h at room temperature.
The reaction mixture was diluted with 200 mL of EtOAc-
hexane (3:7) and worked up. The crude product was purified
by silica gel column chromatography with EtOAc-hexane (1:
4) as eluent to give 27 (953 mg) in 98% yield: colorless oil; Rf
(c 1.05, CHCl3); IR (neat) 1740 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.67 (1H, t, J ) 7.7 Hz), 7.40 (1H, d, J ) 7.7 Hz),
7.16 (1H, d, J ) 7.7 Hz), 5.87 (1H, q, J ) 6.6 Hz), 4.81 (2H, s),
2.35 (2H, t, J ) 7.3 Hz), 1.64-1.60 (2H, m), 1.54 (3H, d, J )
6.6 Hz), 1.27-1.24 (24H, m), 0.94 (9H, s), 0.86 (3H, t, J ) 6.6
Hz), 0.10 (6H, s); 13C NMR (100 MHz, CDCl3) δ 172.7, 160.8,
159.4, 137.1, 118.6, 117.9, 72.7, 65.9, 34.3, 31.8, 29.5, 29.4, 29.3,
29.2, 29.0, 29.0, 29.0, 25.7, 24.8, 22.5, 20.8, 18.1, 13.9, -5.6;
HRMS (FAB) calcd for C30H56NO3Si, MH+, 506.4030, found m/z
506.4045.
P r ep a r a tion of S-23. S-23 was obtained in 79% yield by
desilylation of S-29 with Bu4NF. The synthetic method was
the same as described for S-25 except using EtOAc-hexane
(3:7) as eluent for column chromatography: colorless crystals;
) 0.25 (EtOAc-hexane, 1:9); [R]27 -38.5 (c 2.62, CHCl3); IR
D
(neat) 1750 cm-1; H NMR (300 MHz, CDCl3) δ 7.65 (1H, t, J
1
) 7.7 Hz), 7.44 (1H, d, J ) 7.7 Hz), 7.14 (1H, d, J ) 7.7 Hz),
5.14 (2H, s), 4.90 (1H, q, J ) 6.6 Hz), 2.10 (3H, s), 1.40 (3H, d,
J ) 6.6 Hz), 0.87 (9H, s), 0.03 (3H, s), -0.04 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 170.5, 165.7, 154.1, 137.2, 119.6, 118.3,
71.8, 66.8, 25.7, 25.5, 20.8, 18.1, -4.9, -5.1; HRMS (FAB) calcd
for C16H28NO3Si, MH+, 310.1838, found m/z 310.1841.
P r ep a r a tion of S-22. To a methanol solution of 27 (681
mg, 2.2 mmol) was added anhydrous K2CO3 (608 mg, 4.4
mmol), and the mixture was stirred for 30 min. After the
solvent was removed, water (5 mL) was added to the residue
and the mixture was extracted with EtOAc (70 mL). The crude
product was purified by chromatography on silica gel with
EtOAc-hexane (3:7) as eluent to give 22 (566 mg) in 96%
yield: colorless oil; Rf ) 0.45 (EtOAc-hexane, 3:7); [R]27D -44.7
mp 78-79 °C (hexane); Rf ) 0.22 (EtOAc-hexane, 3:7); [R]25
D
-40.2 (c 0.92, CHCl3); IR (KBr) 3180, 1730 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.67 (1H, t, J ) 7.7 Hz), 7.24 (1H, d, J ) 7.7
Hz), 7.12 (1H, d, J ) 7.7 Hz), 5.93 (1H, q, J ) 6.7 Hz), 4.75
(2H, s), 3.92 (1H, br s), 2.38 (2H, t, J ) 6.8 Hz), 1.68-1.61
(2H, m), 1.59 (3H, d, J ) 6.7 Hz), 1.30-1.25 (24H, m), 0.88
(3H, t, J ) 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 173.0, 159.5,
(c 1.97, CHCl3); IR (neat) 3400 cm-1
;
1H NMR (300 MHz,
CDCl3) δ 7.66 (1H, t, J ) 7.7 Hz), 7.43 (1H, d, J ) 7.7 Hz),

3894 J . Org. Chem., Vol. 63, No. 12, 1998
Tsukube et al.
158.4, 137.3, 119.2, 118.7, 72.5, 63.8, 34.5, 31.9, 29.7, 29.7, 29.6,
29.5, 29.4, 29.2, 29.1, 25.0, 22.7, 20.7, 14.1; HRMS (EI) calcd
for C24H41NO3, M+, 391.3087, found m/z 391.3100. Anal.
Calcd for C24H41NO3: C, 73.61; H, 10.55; N, 3.58. Found: C,
73.39; H, 10.63; N, 3.68.
aqueous receiving phase, which were determined spectroscopi-
cally (at Exlan Technical Center Co., Okayama). We confirmed
that no metal salt was transported in the absence of carrier
(transport rate < 0.3 × 10-6 mol/h).
NMR Stu d ies of Ag+ Bin d in g. 13C NMR binding experi-
ments were carried out with a J EOL 90 A spectrometer. Each
podand was dissolved in CDCl3-CH3OH (4:1) at a concentra-
tion of 0.05 mol/L.
P r ep a r a tion of R-20. R-20 was obtained in 78% yield by
tritylation of R-25 with trityl chloride. The synthetic method
was the same as described for 15 except using EtOAc-hexane
Com p u ta tion a l Meth od . The calculations were carried
out using Spartan SGI version 4.0.1 (ab initio, STO-3G).
Acyclic podands are generally flexible so it is very difficult to
search all of the stationary points of their geometries and
obtain global minima for their structures. We made initial
geometries of complexed podands on the basis of semiempirical
calculations. Due to a lack of a parameter for Ag+, Li+
complexes were first optimized using the Spartan PM3 pro-
gram. The geometries obtained were adopted as the starting
structures for optimization. The metal cation of the Li+
complex was replaced with Ag+ to provide a starting structure
for the Ag+ complex. Although we determined the parameters
for Ag+ for calculations via an ab initio method, we could not
estimate quantitative stabilization energies due to the complex
formation. However we did obtain qualitative insight into the
effect of ligand geometry and stereochemically controlled
substitution on Ag+ binding by the podand.
(3:7) as eluent for column chromatography: colorless oil; Rf )
26
0.33 (EtOAc-hexane, 3:7); [R]
-1.57 (c 1.92, CHCl3); IR
D
(neat) 3410 cm-1; H NMR (300 MHz, CDCl3) δ 7.75 (1H, t, J
) 7.6 Hz), 7.68 (1H, dm, J ) 7.6 Hz), 7.56-7.48 (6H, m), 7.36-
7.20 (9H, m), 7.12 (1H, dm, J ) 7.6 Hz), 4.81 (1H, qd, J ) 6.6
and 4.4 Hz), 4.42 (1H, d, J ) 4.4 Hz), 4.34 (2H, s), 1.45 (3H, d,
J ) 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 161.7, 157.7, 143.7,
137.4, 128.6, 127.9, 127.1, 119.1, 117.9, 87.1, 68.3, 66.6, 24.2;
HRMS (FAB) calcd for C27H26NO2, MH+, 396.1964, found m/z
396.1966.
1
Extr a ction Exp er im en ts. Extraction experiments were
carried out by adding a CH2Cl2 solution of the podand (0.015
mmol, 1.5 mL) to an aqueous solution of six metal perchlorates
(0.015 mmol each, 1.5 mL). After the mixture had been stirred
for 2 h, the aqueous phase was separated. The concentrations
of metal cations were determined by atomic absorption or
flame spectroscopy (performed at Exlan Technical Center Co.,
Okayama) and used to calculate the extraction percentage and
apparent extraction equilibrium constant Kex (L/mol).
Tr a n sp or t Exp er im en ts. Transport experiments were
performed at room temperature (ca. 20 °C) in a U-tube glass
cell (2.0-cm i.d.).17 The carrier, dissolved in CH2Cl2, was placed
in the base of the U-tube, and the two aqueous phases were
placed in the tube arms, floating on the membrane phase. The
membrane phase was stirred constantly with a magnetic
stirrer. The transport rates listed in Table 3 were calculated
from the initial rates of appearance of metal cation into the
Ack n ow led gm en t. This research was supported in
part by Grant-in-Aids for Scientific Research (Nos.
08454205 and 09238249) from the Ministry of Educa-
tion, Science, Sports and Culture, J apan.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
compounds lacking elemental analyses (35 pages). This mate-
rial is contained in libraries on microfiche, immediately follows
this article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(17) Tsukube, H. In Liquid Membrane: Chemical Applications;
Araki, T., Tsukube, H., Eds.; CRC Press: Boca Raton, FL, 1990; pp
20-50.
J O9721148