Self-assembling aromatic-bridged serine-based cyclodepsipeptides (serinophanes): A demonstration of tubular structures formed through aromatic π-π interactions

Article abstract of DOI:10.1021/ja982244d

A variety of 18-membered cyclodepsipeptides with alternating repeats of aromatic (phenyl or pyridyl) and Ser units in the ring have been synthesized and studied by X-ray crystallography for self-assembly patterns. Single- crystal structures of the macrocy

Full text of DOI:10.1021/ja982244d

VOLUME 120, NUMBER 42
OCTOBER 28, 1998
© Copyright 1998 by the
American Chemical Society
Self-Assembling Aromatic-Bridged Serine-Based Cyclodepsipeptides
(Serinophanes): A Demonstration of Tubular Structures Formed
through Aromatic π-π Interactions
Darshan Ranganathan,*,† V. Haridas,† R. Gilardi,‡ and Isabella L. Karle*,‡
Contribution from the DiscoVery Laboratory, Indian Institute of Chemical Technology,
Hyderabad - 500 007, India, and Laboratory for the Structure of Matter, NaVal Research Laboratory,
Washington, DC 20375-5341
ReceiVed June 26, 1998
Abstract: A variety of 18-membered cyclodepsipeptides with alternating repeats of aromatic (phenyl or pyridyl)
and Ser units in the ring have been synthesized and studied by X-ray crystallography for self-assembly patterns.
Single-crystal structures of the macrocycles showed similar, relatively flat-ring structures. Those molecules
containing one or two pyridine units showed self-assembly by stacking one over the other, thus creating tubular
structures using aromatic π-π interactions between Ph/Pyr or Pyr/Pyr as the main organizing force. The
cylindrical stacks are further stabilized by water molecules acting as bridges in intermolecular hydrogen bonding.
In both the macrocycle 4b, a hybrid of benzene and pyridine units connected through ester and amide bonds,
respectively, and the macrocycle 4d with two pyridine units, the molecules form parallel cylindrical stacks
wherein the aromatic rings interdigitate from one column to a neighboring one with a ∼3.5-Å separation
between the planes of the rings. Macrocycle 4a, with two phenyl rings, packs in a herringbone fashion and
does not form any tubes. Macrocycle 4a does not exhibit any internal hydrogen bonds. Only 4d forms a tube
with an inner space large enough to accommodate a water molecule.
Introduction
structure was provided by diketopiperazine,2 the smallest and
the simplest member of the cyclopeptide family. The two cis
amide bonds in the six-membered ring force the diketopiperazine
molecules to assemble into an infinite hydrogen-bonded tape
through NH‚‚‚OdC bonds with its neighbors. Interestingly, the
largest ring cis diamide with a known crystal structure to date
remains the eight-membered cyclo(di-â-alanyl), whose boat-
shaped molecules with both the amide groups on the same face
assemble to form a severely buckled hydrogen-bonded tape.3
Thus, while a tape or a layer was the most common motif
exhibited in the self-assembly of small-ring peptides containing
all cis amide bonds, the situation changes in larger ring peptides
where the amide groups prefer to adopt a trans conformation.
For example, while in a cyclic tetrapeptide containing 12 atoms
Conformationally constrained cyclopeptides constructed from
chiral amino acids represent an attractive class of macrocycles
that may be exploited to create functional self-assembly1 systems
through noncovalent interactions. Perhaps, the earliest example
of a cyclopeptide enforced into a well-defined supramolecular
* To whom correspondence should be addressed.
† Indian Institute of Chemical Technology.
‡ Naval Research Laboratory.
(1) Lehn, J.-M. Supramolecular Chemistry: Concepts and PerspectiVes;
VCH: Weinheim, Germany, 1995. Whitesides, G. M.; Simanek, E. E.;
Mathias, J. P.; Seto, C. T.; Chin, D. N.; Mammen, M.; Gordon, D. M. Acc.
Chem. Res. 1995, 28, 37. Lawrence, D. S.; Jiang, T.; Levett, M. Chem.
ReV. 1995, 95, 2229. Whitesides, G. M.; McDonald, J. C. Chem. ReV. 1994,
94, 2383.
(2) Degeilh, R.; Marsh, R. E. Acta Crystallogr. 1959, 12, 1007. Benedetti,
E.; Corradini, P.; Pedone, C. J. Phys. Chem. 1969, 73, 2891.
(3) White, D. N. J.; Dunitz, J. D. Isr. J. Chem. 1972, 10, 249.
(4) Konnert, J.; Karle, I. L. J. Am. Chem. Soc. 1969, 91, 4888.
10.1021/ja982244d CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/13/1998

10794 J. Am. Chem. Soc., Vol. 120, No. 42, 1998
Ranganathan et al.
Scheme 1
tion, a crucial requirement for vertical stacking,8 was achieved
by arranging D- and L-amino acids in an alternating sequence
in the ring.
Incorporation of small aromatic units into the backbone of a
cyclopeptide was considered by us an alternate approach to
create flat-ring peptides. It was envisaged that the aromatic
units if properly positioned would not only induce rigidity in
the structure but also help in stacking the peptide rings in a
cylindrical fashion by providing π-π interactions between the
rings.
In this article, we provide the first illustration of this strategy
and report on the design, synthesis, and crystal structure of
aromatic-bridged, serine-based 18-membered macrocycles, a
new class of cyclodepsipeptides, named serinophanes, containing
alternating repeats of serine and aromatic units (Ph or Pyr) in
the cyclic framework. The 18-membered peptide rings are
demonstrated to exhibit rigid conformation with all the carbonyl
groups oriented outward and amide NHs inward. Consequently,
there are no internal NH‚‚‚OdC bonds. The macrocycles show
a strong tendency to assemble, through intermolecular interac-
tions, into highly organized supramolecular structures. Par-
ticularly noteworthy features are the adoption of a relatively
flat conformation of amide-linked pyridine-containing macro-
cycles and their self-assembly into layers of parallel tubular
structures. Molecular modeling studies had suggested that direct
stacking of serinophanes to form discrete tubes may be
prevented by the projecting bulky carboxymethyl groups. The
aromatic units could however take up an alternating interdigi-
tating mode of stacking that may extend into layered structure
of tubular assemblies. This expectation was fully realized in
the crystal structure of 4b,d. To our knowledge this is the first
illustration of a tubular assembly formed in a cyclopeptide
through aromatic π-π interactions.
in the ring, two amide groups were shown4 in trans and two in
the cis conformation, the more flexible 14-membered cyclotet-
rapeptide exhibited5 all four amide groups in a trans conforma-
tion. Parenthetically, the self-assembly of the 14-membered
cyclotetrapeptide L-Ser(O-t-Bu)-â-Ala-Gly-L-â-Asp(OMe) pro-
vided the first example6 of a cylindrical structure formed through
vertical stacking of peptide rings through NH‚‚‚OdC bonds.
Rational design of cyclopeptides capable of self-assembling
into hollow tubular structures was considered particularly
important in the context of creating simple chemical models of
channel systems for simulating important biological functions
such as transport or catalysis. A beautiful illustration of tubular
self-assembly formed by vertical stacking of flat peptide rings
through antiparallel â-sheet-type intermolecular hydrogen bond-
ing between complementary amide groups was provided recently
in a series of papers by Ghadiri7 et al. The flat-ring conforma-
Results and Discussions
The 18-membered, serine-based cyclodepsipeptides 4a-e
were synthesized by a simple, two-step strategy (Scheme 1)
involving first the condensation of Z-Ser-OMe (2) with 1,3-
benzene (1a) or 2,6-pyridine (1b) dicarbonyl dichloride to give
the bis-Ser derivatives 3a,b, which after N-deprotection and
recoupling with 1 afforded the desired cyclodepsipeptides in
reasonable yields. The synthesis of adamantane-containing
aromatic-bridged macrocycles 4c,e not only showed the versatil-
ity of the design strategy but also provided models which could
act as controls in the stacking studies. In terms of ring size,
the macrocycles 4a-e can be considered as equivalent to six-
residue cyclopeptides. No unusual features were observed in
(5) Karle, I. L.; Handa, B. K.; Hassall, C. H. Acta Crystallogr. 1975, B
31, 555.
(6) Recently, the 16-membered cyclic tetramer of 3-aminobutanoic acid
has been shown, by powder diffraction data, to adopt a tubular structure
held together by NH‚‚‚OdC bonds, (Seebach, D.; Mathews, J. L.; Meden,
A.; Wessels, T.; Baerlocher, C.; McCusker, L. B. HelV. Chim. Acta 1997,
80, 173), as observed in ref 5.
(7) Ghadiri, M. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.;
Khazanovich, N. Nature 1993, 366, 324-327. Ghadiri, M. R.; Granja, J.
R.; Buehler, L. K. Nature 1994, 369, 301. Khazanovich, N.; Granja, J. R.;
McRee, D. E.; Milligan, R. A.; Ghadiri, M. R. J. Am. Chem. Soc. 1994,
116, 6011. Ghadiri, M. R.; Kobayashi, K.; Chadha, R. K.; McRee, D. E.
Angew. Chem., Int. Ed. Engl. 1995, 34, 93. Kobayashi, K.; Granja, J. R.;
Ghadiri, M. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 97. Hartgerink, J.
D.; Granja, J. R.; Milligan, R. A.; Ghadiri, M. R. J. Am. Chem. Soc. 1996,
118, 43.
(8) Although the prediction that alternating arrangement of D- and
L-amino acids in a cyclopeptide would create rings with a flat conformation
that may self-assemble through vertical â-sheet-like array of NH‚‚‚OdC
bonds into tube-like structures was made as early as 1974 (De Santis, P.;
Morosetti, S.; Rizzo, R. Macromolecules 1974, 7, 52), the first designs of
D,L-alternating cyclopeptides constructed from four, six, or eight Val, Leu,
or Phe residues proved to be too insoluble for obtaining any conclusive
evidence on their stacking profile (Tomasic, L.; Lorenzi, G. P. HelV. Chim.
Acta 1987, 70, 1012. Pavone, V.; Benedetti, E.; Di Blasio, B.; Lombardi,
A.; Pedone, C.; Tomasic, L.; Lorenzi, G. P. Biopolymers 1989, 28, 215).
In 1982, peptide nanotubes containing vertical hydrogen bonds had been
observed by the alternate stacking of the LLLL and LLDL isomers of cyclo-
[-Ala-Pro-Phe-Pro] (Chiang, C. C.; Karle, I. L. Int. J. Pept. Protein Res.
1982, 20, 133). In 1993, Ghadiri constructed peptide nanotubes through
the vertical stacking of an eight-residue cyclopeptide, cyclo[-(D-Ala-L-Glu-
D-Ala-L-Gln)2-].7
1
the H NMR spectra of 4a-e except the large downfield shift
(∼1.5 δ) of the amide NHs in pyridine-bridged macrocycles
4b,d as compared to rest of the macrocycles, suggesting
involvement of pyridyl amide NHs in intramolecular hydrogen
bonding with the ring N. The intramolecular NH‚‚‚N hydrogen
bonding in 4b,d was also supported by the syn orientation of
amide NHs as indicated by the absence of any cross-peaks
between amide NHs and aromatic protons in their ROESY NMR
spectra (Supporting Information). None of the 18-membered
macrocycles showed any significant features in their CD spectra,
indicating absence of secondary structural features as also
suggested by 1 H NMR and FT-IR studies. Final proof for the
open-ring structure in 4a-e was obtained by single-crystal X-ray
studies.
Suitable crystals were obtained from aqueous methanol for
4a,b,d. Attempted crystallization of 4c,e from a variety of
solvents (chloroform, methanol, ethyl acetate, or a mixture of

Aromatic-Bridged Serine-Based Cyclodepsipeptides
J. Am. Chem. Soc., Vol. 120, No. 42, 1998 10795
Figure 1. (a) Chemical structure of cyclo(Ph-Ser-)2 (4a). (b) Crystal structure of 4a, face-on view. Distances across the cavity are C1-C11, 5.24
Å; N1-O2G, 5.88 Å and N2-O1G, 5.58 Å. There are no intramolecular hydrogen bonds. (c) Side view of the molecule showing a crumpled ring
structure. Hydrogen atoms have been omitted in (c) for clarity.
Figure 2. (a) Two-dimensional layered self-assembly in 4a. Each molecule is surrounded by four neighbors to which it is bonded by NH‚‚‚O
bonds making an extended layer structure (projection is down the c axis). (b) Molecular packing diagram of 4a viewed edge-on to the layer
(projection is down the b axis).
polar and nonpolar solvents) was unsuccessful. Crystal struc-
tures showed that while 4b,d macrocycles had pairs of amide
NHs bonded to a ring N (NH‚‚‚N, 2.68 and 2.73 Å; H‚‚‚N,
2.30 and 2.35 Å), 4a had no internal hydrogen bonds. All
macrocycles showed an open-ring conformation with all car-
bonyl groups oriented outward and ring NHs facing inward,
thus ruling out any possibility of intramolecular NH‚‚‚OdC
hydrogen bonding.
The crystal structure of macrocycles 4b,d containing an
amide-linked pyridine unit revealed interesting features. Both
macrocycles exhibited intramolecular NH‚‚‚N (ring) hydrogen
bonds that should provide added rigidity to the macrocycles
4b,d. The diagrams in Figure 3 compare the planarity of the
macrocycles in 4a,b,d.
The structures of 4a and 4b are very similar, with 4a having
the two benzene rings in the same plane and 4b having the
benzene ring and pyridine ring in the same plane. In 4d, the
two pyridine rings are in planes that are inclined to each other
by 26°. The presence of the intramolecular NH‚‚‚N hydrogen
bonds in 4b,d is not correlated with the change, or lack thereof,
of the planarity of the macrocycle. Further, in each macrocycle,
the CR atoms are displaced ∼1 Å from the planes of the aromatic
rings. Torsional angles are listed in Table 2.
The macrocycle 4a with two phenyl units in the ring (Figure
1a) adopts a slightly crumpled structure in the solid state as
shown in Figure 1c. The amide NHs in this conformation are
available for participating in intermolecular hydrogen bonding,
creating an extended layer structure (Figure 2a), one molecule
thick, wherein each molecule is bonded to four neighbors
through NH‚‚‚OdC bonds (N(1)‚‚‚O(9), 2.934, H‚‚‚O, 2.13 Å;
N(2)‚‚‚O(8), 2.892, H‚‚‚O, 2.07 Å), Table 1. Figure 2b shows
the molecular packing diagram of the layer motif.
The crystal structure of 4b (Figure 4a,b) shows the presence
of two independent molecules, quite similar in conformation.

10796 J. Am. Chem. Soc., Vol. 120, No. 42, 1998
Ranganathan et al.
Table 1. Hydrogen Bonds
crystal
typea
donor
acceptor
D‚‚‚A (Å)
DHb‚‚‚A (Å)
4a
inter
inter
intra
intra
intra
intra
inter
inter
inter
inter
intra
N1
O9c
2.934
2.892
2.729
2.678
2.749
2.685
2.918
2.966
2.690
3.041
2.679
2.723
2.948
3.086
3.103
3.013
2.939
2.13
2.07
2.33
2.30
2.35
2.30
N2
O8d
4be
N1
N2
N1P
N1P
N1PA
N1PA
O8A
O16g
O8h
N1A
N2A
O1sf
O1s
O2sf
O2s
N1i
N2i
N1
O2
4d
N1P
N1P
W1
2.29
2.21
2.12
2.21
inter
inter
inter
inter
inter
N2
W1
W1
W1
W2
N11P
W2
O2g
a Intermolecular or intramolecular. b Hydrogen atoms placed in
idealized positions with N-H ) 0.90 Å and O-H ) 0.96 Å.
1
c Coordinates at symmetry equivalent 2 - x,
/ + y, 2 - z.
2
d Coordinates at symmetry equivalent 1 - x, -1/2 + y, 2 - z. e Two
independent molecules. Second molecule labeled A. f O1s and O2s are
water molecules. g Coordinates at symmetry equivalents 1 + x, y, z.
h Coordinates at symmetry equivalents -1 + x, y, z. i N1H and N2H
make bifurcated hydrogen bonds.
Table 2. Torsional Angles in the 18-Membered Macrocycle (deg)
4aa
4b(1)b
4b(2)b
4dd
C2X1C6C7
X1C6C7N1
C6C7N1C1a
-176
-31
+174
-103
-55
-135
-173
9
179
176
20
-173
-166
-57
-109
-178
-25
176
180
-22
-172
-105
-59
-133
-175
0
180
177
-1
-177
-140
-60
-117
-170
-18
177
176
-16
-173
-115
-61
-147
-179
8
178
177
+5
-180
-140
-63
-116
-170
-14
179
-177
-8
177
C7N1C1aC1b
N1C1aC1bO1g
C1aC1bO1gC9
C1bO1gC9C10
O1gC9C10X11
C9C10X11C12
C10X11C12C16
X11C12C16O2g
C12C16O2gC2b
C16O2gC2bC2a
O2gC2bC2aN2
C2bC2aN2C8
C2aN2C8C2
-115
-62
-135
-173
-11
179
178
-7
-180
-122
-62
-159
-178
+11
179
Figure 3. Diagrams showing projections of the conformations of 4a,b,d
viewed with the mean least-squares plane of the C(10) to C(15) ring
perpendicular to the page. Hydrogen bonds to a water molecule below
the cavity of 4d are indicated by dashed lines.
N2C8C2X1
C8C2X1C6
C7N1C1aC1′
129
136
123
115
N1C1aC1′O10
C1a C1′O10C10M
C8N2C2aC2′
N2C2aC2′O20
C2aC2′O20C20M
-45
-176
+120
+147
+168
-171
-174
+117
-163
-177
-167
-179
+121
-171
-174
+179
+177
+78
-151
-179
Molecules 1 and 2 stack in separate vertical columns with
pyridine and phenyl rings interdigitating from one column to
the other with a ∼3.5-Å separation between the planes of the
rings. Molecules 1 are connected through hydrogen bonds to
O2s (water 2). Molecules 2 are connected to molecules 1 by
hydrogen bonds to O1s (water 1). Vertical columns of π-π
stacks are formed without any hydrogen bonds to neighboring
stacks (Figure 5a,b). Figure 6a shows a schematic representation
of the interdigitated π-π stacks in 4b.
The macrocycle 4d (Figure 7a) containing alternating repeats
of pyridine and serine units, linked through ester and amide
bonds, is quite similar to 4b, except for the inclusion of a water
molecule W1 into the large ring and another water molecule
W2 above W1. Further, the aromatic rings in 4d are not
coplanar, but in separate planes, as shown in Figure 3.
Nevertheless, the molecules stack in columns with the pyridine
rings interdigitating from separate neighboring columns. The
separation between the planes of the pyridines is ∼3.4 Å. The
stacking of 4d (Figure 8a,b) is almost identical to that of 4b
(Figure 5a,b), despite a tilt of the pyridine rings in the vertical
π-π aromatic stack. A schematic representation of the inter-
digitated π-π stacks in 4d is shown in Figure 6b.
a X1 ≡ C1, X11 ≡ C11. b X1 ≡ N1P, X11 ≡ C11. d X1 ≡ N1P,
X11 ≡ N11P.
Although crystals of both 4b and 4d contain water molecules,
the water molecules in the lattice of 4b are between the sheets
of tubes (Figure 9), while in 4d, the water molecules are inside
the tubes (Figures 8 and 9). The aromatic stacks in 4b are
aligned along a straight line, parallel to the vertical axis in Figure
9, with the result that the tubules are filled with H atoms from
neighboring molecules on either side (the C4H‚‚‚HC14 distance
across the middle of a tubule is 2.35 Å). In 4d, however, the
tubules are rotated slightly so that the aromatic stacks form a
zigzag pattern in projection. The CH atoms of the pyridine
groups are directed away from the inside of the tubule, leaving
enough space to accommodate two water molecules inside the
tubule. Aside from hydrogen bonds, the closest approaches to
the water molecules are W1‚‚‚HC3a ) 3.19 Å, W1‚‚‚HC15a
) 3.10 Å, W2‚‚‚HC3a ) 2.35 Å, and W2‚‚‚HC14a ) 2.75 Å.
W1 is tetrahedrally hydrogen bonded to N1H, N2H, N11P, and

Aromatic-Bridged Serine-Based Cyclodepsipeptides
J. Am. Chem. Soc., Vol. 120, No. 42, 1998 10797
Figure 4. (a) Chemical structure of cyclo(Ph-Ser-Py-Ser-) (4b). (b) Crystal structure of 4b, Molecule 1. (c) Crystal structure of 4b, Molecule 2.
The NH protons are bonded to pyridine ring N. There are two water molecules associated with molecules 1 and 2 (the hydrogen atoms for the water
molecules were not located in the difference map).
Figure 5. (a) Vertical parallel stacks in the self-assembly of 4b. Molecules 1 and 2 stack in separate columns, but the pyridine and phenyl rings
interdigitate from one column to the other with a ∼3.5-Å separation between the planes of the rings. In the stacks, the molecules 1 are connected
by hydrogen bonds to O2s (water 2). Molecules 2 are connected to molecules 1 by hydrogen bonds to O1s (water 1). There are no direct hydrogen
bonds between the neighboring stacks. (b) Top view of a portion of a layer containing the interdigitated stacks in 4b.
W2. In turn, W2 also forms a hydrogen bond with O2 in the
same stack (Figure 10).
the functional properties of these assemblies are in progress in
our laboratories.
Conclusions
Experimental Section
The present work provides examples of cyclopeptides capable
of self-assembly into tubular structures through aromatic π-π
interactions. The tubes are not single but are part of a parallel
assembly in a sheet. The cylindrical stacks have interdigitated
aromatic rings from one column to another with 3.4-3.5 Å
separation between the planes of the rings. The pairs of
aromatic rings can be benzene/pyridine as in 4b or pyridine/
pyridine as in 4d, but the macrocycle 4a, that contains only a
pair of benzene rings, does not stack. The stacks in 4b,d are
further stabilized by some intermolecular hydrogen bonding
through water molecules acting as bridges. There are no direct
hydrogen bonds between the macrocycles. Studies related to
All amino acids used were of L-configuration. Melting points were
recorded on a Fisher-Johns melting point apparatus and are uncorrected.
1H NMR spectra were recorded on Bruker WM-300 and JEOL 90-
MHz instruments. The chemical shifts are reported in δ (parts per
million) with TMS at 0.00 as an internal reference. FAB-MS were
obtained on a JEOL SX-120/DA-6000 instrument using m-nitrobenzyl
alcohol as the matrix. Reactions were monitored wherever possible
by TLC. Silica gel G (Merck) was used for TLC, and column
chromatography was done on silica gel (100-200 mesh) columns which
were generally made from a slurry in hexane or a mixture of hexane
and ethyl acetate. Products were eluted with either a mixture of ethyl
acetate/hexane or chloroform/methanol.

10798 J. Am. Chem. Soc., Vol. 120, No. 42, 1998
Ranganathan et al.
3b: yield 86%; syrup; IR (KBr) 3375, 2962, 1730, 1586, 1533, 1453
1
cm-1
;
H NMR (90 MHz, CDCl3) δ 3.67 (s, 6H), 4.77 (m, 6H), 5.09
(s, 4H), 6.62 (d, J ) 7.5 Hz, 2H), 7.32 (s, 10 H), 7.95 (t, J ) 7.8 Hz,
1H), 8.23 (brd, 2H).
Preparation of 18-Membered Cyclodepsipeptides 4a-e. General
Procedure: (a) N-Deprotection of Aryl-Supported Bis-NrZ-Ser
Depsipeptides (3a,b). A solution of bis-NR Z peptide (3a,b, 1 mmol)
in dry ethyl acetate (∼10 mL) was admixed with Pd/C, 5% (peptide/
catalyst 1:0.5 w/w), and hydrogenolyzed using a Parr hydrogenation
apparatus. The reaction mixture after complete NR deprotection (TLC)
was filtered through a sintered funnel, the residue washed with dry
ethyl acetate (20 mL), and the filtrate directly used for the coupling
reaction in the next step.
(b) Condensation of Nr-Deprotected Aryl-Supported Bis-Ser
Depsipeptides (3a,b) with 1. To a well-stirred and ice-cooled solution
of NR-deprotected bis-Ser depsipeptide (1 mmol in ∼100 mL of dry
EtOAc) and NEt3 (2 mmol) was added dropwise a solution of freshly
prepared 1,3-benzene or 2,6-pyridine dicarbonyl dichloride (1 mmol
in 50 mL of dry CH2Cl2) over a period of 0.5 h, and the mixture was
stirred at room temperature for 12 h. The solvents were removed in
vacuo, the residue taken up in CH2Cl2 (∼100 mL) and washed,
sequentially, with 20 mL each of the ice-cold 2 N H2SO4, H2O, and
5% aqueous NaHCO3. The organic layer was dried over anhydrous
MgSO4 and evaporated in vacuo, and the residue was purified on a
column of silica gel using either a mixture of EtOAc/hexane or CHCl3/
MeOH as eluents to afford aromatic-bridged Ser cyclodepsipeptides
4a-e in good yields.
1
4a: yield 51%; mp 234-236 °C; H NMR (200 MHz, CDCl3) δ
3.76 (s, 6H), 4.42 (dd, J ) 3.4, 11.2 Hz, 2H), 5.21 (m, 2H), 5.34 (dd,
J ) 2.1, 11.4 Hz, 2H), 7.07 (d, J ) 8.1 Hz, 2H), 7.62 (m, 2H), 8.03 (s,
1H), 8.10 (dd, J ) 2.0, 9.5 Hz, 2H), 8.29 (dd, J ) 2.0, 9.5 Hz, 2H),
8.49 (brs, 1H); FAB-MS: m/z (%): 499 (100) (MH)+.
Figure 6. Schematic representation of the multiple π-π stacks in the
self-assembly of (a) 4b and (b) 4d.
General Procedure for the Preparation of 1,3-Benzene or 2,6-
Pyridine Bis-Ser Depsipeptides 3a,b. A solution of 1,3-benzene or
2,6 pyridine dicarbonyl dichloride (1, 1 mmol) in dry CH2Cl2 (10 mL)
was added dropwise over a period of 0.5 h to a well-stirred and ice-
cooled solution of NRZ-Ser-OMe (2 mmol) in dry CH3CN (30 mL)
containing N,N′-dimethyl-4-aminopyridine (DMAP, 2 mmol) and the
mixture stirred at room temperature for 12 h. Solvents were evaporated
in vacuo, and the residue was triturated with ethyl acetate (∼100 mL),
the extract washed sequentially, with 20 mL each of ice cold 2 N H2-
SO4, H2O, and 5% aqueous NaHCO3, and the organic layer dried over
anhydrous MgSO4 and evaporated in vacuo. The residue was purified
on a short column of silica gel using a mixture of ethyl acetate and
hexane as eluents to afford the bis-Ser peptides 3a,b in nearly
quantitative yields.
1
4b: yield 50%; mp 227-230 °C; H NMR (300 MHz, CDCl3) δ
3.76 (s, 6H), 4.36 (dd, J ) 3.0, 8.4 Hz, 2H), 5.26 (m, 2H), 5.50 (dd,
J ) 1.5, 9.9 Hz, 2H), 7.61 (t, J ) 7.8 Hz, 1H), 8.10 (t, J ) 7.8 Hz,
1H), 8.29 (dd, J ) 1.5, 6.3 Hz, 2H), 8.44 (d, J ) 7.8 Hz, 2H), 8.53 (d,
J ) 9.3 Hz, 2H), 8.68 (s, 1H); FAB-MS: m/z (%): 500 (100%) (MH)+.
4c: yield 52%; mp 240-242 °C; [R]25 +87.26 (c, 3.0 in CHCl3);
H NMR (200 MHz, CDCl3) δ 1.55-2.31 (m, 14H), 3.79 (s, 6H),
D
1
4.55 (dd, J ) 3.42, 7.73 Hz, 2H), 4.97 (m, 4H), 6.47 (d, J ) 8.0 Hz,
2H), 7.59 (t, J ) 7.5 Hz, 1H), 8.28 (dd, J ) 1.9, 7.5 Hz, 2H), 8.37
(brs, 1H); FAB-MS: m/z (%): 557 (100%) (MH)+.
1
4d: yield 28%; mp 236-237 °C; H NMR (300 MHz, CDCl3) δ
3.76 (s, 6H), 4.47 (brd, 2H), 5.35 (m, 4H), 8.06 (t, 2H), 8.38 (m, 4H),
9.75 (d, J ) 7.8 Hz, 2H); FAB-MS: m/z (%): 501 (100) (MH)+.
3a: yield 95%; syrup; IR (KBr) 3375, 2952, 1729, 1521, 1434 cm-1
H NMR (90 MHz, CDCl3) δ 3.68 (s, 6H), 4.65 (brs, 4H), 4.80 (m,
;
1
1
4e: yield 22%; semisolid; H NMR (300 MHz, CDCl3) δ 1.60-
2H), 5.10 (s, 4H), 6.27 (d, J ) 7.5 Hz, 2H), 7.32 (10 H, brs), 7.55 (t,
1H), 8.20 (dd, J ) 2.0, 9.5 Hz, 2H), 8.57 (brs, 1H).
2.20 (m, 14H), 3.78 (s, 6H), 4.18 (d, J ) 11.3 Hz, 2H), 5.04 (d, J )
8.9 Hz, 2H), 5.16 (d, J ) 9.0 Hz, 2H), 8.09 (t, J ) 7.9 Hz, 1H), 8.26
Figure 7. (a) Chemical structure of cyclo(Py-Ser-)2 (4d). (b) Crystal structure of 4d.

Aromatic-Bridged Serine-Based Cyclodepsipeptides
J. Am. Chem. Soc., Vol. 120, No. 42, 1998 10799
Figure 8. (a) Tubular self-assembly in 4d. The molecules of 4d stack one over the other and are connected by hydrogen bonds to two water
molecules in a row. The main organizing force for the self-assembly is provided by the π-π interactions between the pyridine rings. (b) Top view
of a portion of a layer containing the interdigitated stacks in 4d. Compare to Figure 5a,b.
Figure 9. Comparison of the packing and π-π stacking in 4b (left) and 4d (right). In 4b water molecules occur between the layers, while in 4d
water molecules occur within the tubules created by the macrocyles. In each case the projection is down the a axis.
(d, J ) 8.9 Hz, 2H), 8.43 (d, J ) 7.8 Hz, 2H); FAB-MS: m/z (%): 558
(100) (MH)+, 580 (73) (M + Na+).
X-ray Diffraction Analysis. X-ray structure analysis of 4a:
C24H22N2O10, P21, a ) 11.058(1) Å, b ) 9.290(0) Å, c ) 11.111(1) Å,
â ) 92.920°, dcalc ) 1.452 g/cm3, R ) 3.91%. X-ray structure analysis
of 4b: C23H19N3O10‚H2O, P21, a ) 7.135(1) Å, b ) 22.751(3) Å, c )
14.759(2) Å, â ) 90.10(1)°, dcalc ) 1.379 g/cm3, R ) 12.0%. X-ray
structure analysis of 4d: C23H20N3O10‚2H2O, P21, a ) 7.002(0) Å, b
) 15.562(2) Å, c ) 11.202(1) Å, â ) 93.19(1)°, dcalc ) 1.464 g/cm3,
R ) 5.35%.
For 4a,d, X-ray data were collected on a Siemens automated
diffractometer in the θ/2θ mode, constant scan speed of 10 deg/min,
2° scan width, and 2θmax ) 116° (resolution 0.9 Å for Cu KR radiation).
Full-matrix anisotropic least-squares refinement was performed on the

10800 J. Am. Chem. Soc., Vol. 120, No. 42, 1998
Ranganathan et al.
to which each was bonded. For 4b, the crystals were in the form of
extremely fine needles. After a number of trials, the acicular crystal
that provided sufficient scattering power to measure observable data
up to 2θ ) 100° was 0.10 × 0.04 mm in cross section. The profiles
of the diffracted spots were broad, indicating either a bundle of needles
with almost identical alignment, rather than a single crystal, or perhaps,
some undetectable twinning since the â angle is very near 90°. The
high R factor could be attributed to either of the above conditions. A
structure could not be found in space groups with higher symmetry.
Although the two independent molecules are quite similar, the
environment around each molecule is different, thus precluding higher
symmetry space groups.
Acknowledgment. We are most grateful to Professor S.
Ranganathan for valuable advice. Financial assistance from DST
New Delhi and from the office of Naval Research and the
National Institutes of Health (USA) Grant-30902 is acknowl-
edged.
Supporting Information Available: ROESY spectra of
4a-c and X-ray coordinates, bond lengths, bond angles,
anisotropic thermal parameters, and coordinates for hydrogen
atoms (28 pages, print/PDF). See any current masthead page
for ordering information and Web access instructions.
Figure 10. Side view of a partial stack of molecules of 4d showing
water molecules in the tubule. Not shown are neighboring molecules
(in front and back) with their pyridine moieties inserted halfway between
the pyridine moieties shown that provide π-π interactions.
parameters for all the atoms except the H atoms. The H atoms were
placed in idealized positions and allowed to ride with the C or N atom
JA982244D