A triply templated artificial β-sheet

Article abstract of DOI:10.1021/ja010220s

This paper describes the design, synthesis, and structural evaluation of a compound (4) comprising three molecular templates and a peptide strand that mimics a three-stranded protein β-sheet. Two of the templates mimic the hydrogen-bonding functionality o

Full text of DOI:10.1021/ja010220s

5176
J. Am. Chem. Soc. 2001, 123, 5176-5180
A Triply Templated Artificial â-Sheet
James S. Nowick,* Jennifer M. Cary, and James H. Tsai
Contribution from the Department of Chemistry, UniVersity of California, IrVine,
IrVine, California 92697-2025
ReceiVed January 25, 2001
Abstract: This paper describes the design, synthesis, and structural evaluation of a compound (4) comprising
three molecular templates and a peptide strand that mimics a three-stranded protein â-sheet. Two of the templates
mimic the hydrogen-bonding functionality of peptide â-strands and serve as the top and bottom strands by
embracing the peptide strand, which is located in the middle of the sheet. The remaining template holds the
three strands next to each other. The synthesis of artificial â-sheet 4 begins with the bottom template and
1
involves the sequential addition of the middle and top strands. H NMR chemical shift and NOE studies
establish that this compound folds to adopt a hydrogen-bonded â-sheetlike structure in CDCl3 solution. Chemical
shift studies indicate that triply stranded artificial â-sheet 4 is more tightly folded than its smaller doubly
stranded homologue, artificial â-sheet 1.
Over the past few years, our laboratory has sought to gain
insight into â-sheet structure and interactions and develop useful
peptidomimetic building blocks by designing, synthesizing, and
studying molecules that mimic protein â-sheets.1 In these
molecules, which we have termed artificial â-sheets, molecular
templates are combined with peptide groups to form the
characteristic conformations and hydrogen-bonding patterns of
protein â-sheets. Our efforts have complemented and built upon
the pioneering use of templates to stabilize â-sheet structure in
attached peptides by the research groups of Feigel,2 Kemp,3 and
Kelly4 and the ongoing efforts of groups such as Gellman5 and
Seebach,6 who create folded proteinlike structures in unnatural
peptides without using molecular templates. Collectively, these
studies are beginning to reveal how molecules that mimic the
structure and function of proteins can be designed and synthe-
sized.
One of our ongoing concerns has been the development of
larger and more complex designed molecules that begin to rival
the complex folding of proteins. We have previously reported
artificial â-sheets with â-strand mimics either along the upper
edge or along the lower edge. Artificial â-sheets 17 and 28
illustrate two of these structures. In artificial â-sheet 1, a
5-amino-2-methoxybenzoic hydrazide â-strand mimic and a
dipeptide strand are attached by urea linking groups to the upper
and lower nitrogen atoms of a 1,2-diaminoethane group. The
two urea groups hydrogen bond together to form a turnlike
“molecular scaffold”. In artificial â-sheet 2, the 5-amino-2-
methoxybenzoic hydrazide â-strand mimic resides on the lower
edge, rather than the upper, and the urea linking group has been
replaced by an oxalic acid group to achieve an appropriate
hydrogen-bonding pattern. To accommodate the oxalic acid
linking group, the peptide is elongated to a tripeptide.
In the present study, we sought to combine the elements of
these two doubly templated structures to form a triply templated
artificial â-sheet. Initially, we envisioned artificial â-sheet 3 as
embodying the combination of the types of structures repre-
sented by artificial â-sheets 1 and 2. In this structure, the diamine
has been extended to a triamine and the upper â-strand mimic
is extended by the addition of an amino acid to match a
tripeptide in length.9 Difficulties in synthesizing this compound
and concerns about its folded structure prompted us to design
and synthesize artificial â-sheet 4.10 Artificial â-sheet 4 contains
(1) Nowick, J. S. Acc. Chem. Res. 1999, 32, 287-296.
(2) (a) Wagner, G.; Feigel M. Tetrahedron 1993, 49, 10831-10842. (b)
Brandmeier V.; Sauer, W. H. B.; Feigel M. HelV. Chim. Acta 1994, 77,
70-85.
(3) (a) Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5077-
5080. (b) Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5081-
5082. (c) Kemp, D. S.; Bowen, B. R.; Muendel, C. C. J. Org. Chem. 1990,
55, 4650-4657.
(4) (a) Diaz, H.; Tsang, K. Y.; Choo, D.; Espina, J. R.; Kelly, J. W. J.
Am. Chem. Soc. 1993, 115, 3790-3791. (b) Tsang, K. Y.; Diaz, H.;
Graciani, N.; Kelly, J. W. J. Am. Chem. Soc. 1994, 116, 3988-4005.
(5) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180.
(6) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015-2022.
(7) Smith, E. M.; Holmes, D. L.; Shaka, A. J.; Nowick, J. S. J. Org.
Chem. 1997, 62, 7906-7907.
(8) Nowick, J. S.; Tsai, J. H.; Bui, Q.-C. D.; Maitra, S. J. Am. Chem.
Soc. 1999, 121, 8409-8410.
(9) Tsai, J. H.; Waldman, A. S.; Nowick, J. S. Bioorg. Med. Chem. 1999,
7, 29-38.
10.1021/ja010220s CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/09/2001

A Triply Templated Artificial â-Sheet
J. Am. Chem. Soc., Vol. 123, No. 22, 2001 5177
Scheme 1a
a Reagents: (a) EtO2CCOCl, Et3N/CH2Cl2 (91%). (b) 2-O2N-
C6H4SO2NH(CH2)3NH2/CH2Cl2 (44%). (c) BocNH(CH2)2Br, Cs2CO3/
DMF (52%). (d) PhSH, K2CO3/DMF (98%). (e) phenyalanylleucine
methyl ester isocyanate, Et3N/CH2Cl2 (82%). (f) CH3NH2/CH3OH
(86%). (g) (i) TFA/CH2Cl2; (ii) saturated aqueous K2CO3 (60%). (h)
CH2dCHCN/CH3OH:CHCl3 5:2 (81%). (i) 5-OCN-2-MeO-C6H3CON-
HNHCOi-Pr/CH2Cl2 (73%).
a dipeptide strand and a truncated lower â-strand mimic and is
smaller and easier to synthesize than 3. To allow the lower
â-strand mimic to better align with the peptide strand, artificial
â-sheet 4 incorporates a longer 1,3-diaminopropane group in
place of the lower 1,2-diaminoethane portion of the molecular
scaffold of 3.11 To mitigate synthetic difficulties associated with
the formation of the amide bond of the tertiary anilide group
and concerns about its conformational heterogeneity, it contains
a hydrogen in place of the phenyl group in its lower left-hand
corner.12,13 In this paper, we report the evaluation of this triply
templated design through synthetic and 1H NMR spectroscopic
structural studies of artificial â-sheet 4.
Results
Artificial â-sheet 4 was synthesized starting with the bottom
â-strand mimic (5-amino-2-methoxy-N-methylbenzamide) by
successively building up the triamine backbone and then adding
the middle peptide strand and the upper â-strand mimic (Scheme
1). 5-Amino-2-methoxy-N-methylbenzamide hydrochloride (5)14
was coupled with ethyl oxalyl chloride (EtO2COCOCl) in the
presence of triethylamine to form the corresponding ethyl
oxamate (6). Oxamate esters are especially reactive and can be
coupled with simple amines by simply mixing or by mixing
and warming; thus, oxamate 6 was coupled with N-(3-amino-
propyl)-2-nitrobenzenesulfonamide15 to give sulfonamide 7 by
mixing the two compounds in CH2Cl2 solution for 2 days at
room temperature.16 The triamine backbone was then generated
by alkylation of the sulfonamide group with tert-butyl N-(2-
bromoethyl)carbamate17 to give tertiary sulfonamide 8.18 Re-
moval of the sulfonyl group by treatment with benzenethiol and
K2CO3,18 followed by reaction of the resulting secondary
amine19 with phenylalanylleucine methyl ester isocyanate20 and
aminolysis of the ester group with methylamine, introduced the
(10) Preliminary studies suggest that artificial â-sheet 3 forms a well-
defined â-sheet structure in chloroform solution. For details, see: Tsai, J.
H. Ph.D. Dissertation, University of California, Irvine, 2000.
(11) Previous studies by our research group have shown that both the
1,2-diaminoethane group and the 1,3-diaminopropane group form turn
structures, but that the 1,2-diaminoethane turn is more stable and structurally
well defined. See: (a) Nowick, J. S.; Powell, N. A.; Martinez, E. J.; Smith,
E. M.; Noronha, G. J. Org. Chem. 1992, 57, 3763-3765. (b) Nowick, J.
S.; Abdi, M.; Bellamo, K. A.; Love, J. A.; Martinez, E. J.; Noronha, G.;
Smith, E. M.; Ziller, J. W. J. Am. Chem. Soc. 1995, 117, 89-99. (c) Nowick,
J. S.; Mahrus, S.; Smith, E. M.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118,
1066-1072.
(12) Simple oxalamides bearing phenyl and alkyl groups on one nitrogen
[RNHCOCON(Ph)R′ (R′ ) alkyl)] exhibit two conformers in the 1H NMR
spectrum at ambient temperatures. The observation of two conformers is
associated with the partial double-bond character of the CO-N(Ph)R′ bond.
Ureas bearing phenyl and alkyl groups on one nitrogen [RNHCON(Ph)R′
(R′ ) alkyl)] preferentially adopt a conformer in which the carbonyl oxygen
is cis to the alkyl group (R′) and trans to the phenyl group. The relatively
rapid rotation about the CO-N(Ph)R′ bond in these compounds precludes
the observation of discreet conformers by 1H NMR spectroscopy at ambient
temperatures.
(14) Holmes, D. L.; Smith, E. M.; Nowick, J. S. J. Am. Chem. Soc. 1997,
119, 7665-7669.
(15) Hidai, Y.; Kan, T.; Fukuyama, T. Tetrahedron Lett. 1999, 40, 4711-
4714.
(13) X-ray crystallographic and molecular modeling studies suggest that
the replacement of the tertiary amide group with a secondary group also
changes the preferred geometry of the oxalamide group from twisted (ca.
125° N-C-C-N torsion angle) to linear (ca. 180° N-C-C-N torsion
angle). This change in geometry makes the oxalamide group more
complementary to a peptide â-strand.
(16) The low yield of this step (44%) may result from incomplete
reaction; longer reaction times, higher concentrations, or heating may give
better yields.
(17) Beylin, V. G.; Goel, O. P. Org. Prep. Proc. Int. 1987, 19, 78-80.
(18) Fukuyama, T.; Jow, C.-K.; Cheung. M. Tetrahedron Lett. 1995, 36,
6373-6374.

5178 J. Am. Chem. Soc., Vol. 123, No. 22, 2001
Nowick et al.
Table 1. 1H NMR Chemical Shifts of NH Protons of Artificial â-Sheets and Controlsa
Ha
Hb
Hc
Hd
He
Hf
Hg
Hh
Hi
artificial â-sheet 1
artificial â-sheet 4
control 117
9.93
10.27
6.31
10.97
11.21
10.85
10.45
11.58
8.78
4.82
6.69
8.29
8.69
5.79
8.55
7.70
10.76
8.11
control 12
4.63
6.28
5.82
6.71
6.00
control 137
control 14
7.49
9.27
7.82
a Spectra were recorded in 1 mM CDCl3 solution at 298 K.
peptide strand and afforded urea 9. Removal of the Boc
protecting group and alkylation of the resulting primary amine
with acrylonitrile21 generated secondary amine 10. Coupling of
secondary amine 10 with the isocyanate 5-OCN-2-MeO-C6H3-
CONHNHCO-i-Pr14 introduced the upper â-strand mimic by
way of a urea linkage and completed the synthesis of artificial
â-sheet 4.
downfield of those of control 11,7 indicating that the protons
are hydrogen bonded in 4. Proton Hb appears at similar positions
in both 4 and 11, reflecting that it is intramolecularly hydrogen
bonded to the adjacent methoxy group in both compounds.23
Protons Hd and He of the peptide strand of 4 appear 2.06 and
2.41 ppm downfield of control 12,24 indicating that these protons
are hydrogen bonded in 4. Proton Hf of 4 appears 2.55 ppm
downfield of that of control 13,7 indicating it is also hydrogen
bonded.25 Proton Hh of artificial â-sheet 4 appears 1.49 ppm
downfield of that of control 14,26 indicating it is hydrogen
bonded in 4. Protons Hg and Hi are comparable in chemical
shift in both 4 and 14, reflecting that they have similar hydrogen-
bonding states in both compounds.27 Thus, the pattern and
magnitudes of the chemical shifts of NH protons Ha-Hi support
a model in which 4 is largely or wholly folded into a triply
stranded â-sheetlike structure.
1H NMR NOE studies provide compelling evidence that
artificial â-sheet 4 folds into a well-defined â-sheet structure
in CDCl3 solution.28 Because 4 is of intermediate size (MW )
999), these studies were performed in the rotating frame using
the transverse-ROESY (Tr-ROESY) method.29,30 These studies
reveal one prominent interstrand NOE between the proton at
the 6-position of the upper â-strand mimic and the R-proton of
the phenylalanine residue and a second prominent interstrand
NOE between the proton at the 6-position of the lower â-strand
mimic and the R-proton of the leucine residue. (Figure 1
illustrates these and other key interstrand NOEs graphically.)
Other key interstrand NOEs, which provide additional evidence
for a folded â-sheet structure, occur between the isobutyryl
methyl protons of the upper â-strand mimic and the methylamide
methyl group of the middle peptide strand, the urea proton (Hd)
of the middle peptide strand and the anilide proton (Hh) of the
lower â-strand mimic, the leucine methyl groups (δ-protons)
1H NMR chemical shift studies indicate that artificial â-sheet
4 is intramolecularly hydrogen bonded in CDCl3 solution and
provide a pattern of data consistent with a folded â-sheet
structure. In CDCl3 solution, NH protons that are hydrogen
bonded typically appear about 2 ppm downfield of similar types
of NH protons that are not hydrogen bonded. Non-hydrogen-
bonded peptide amide protons typically appear at about 6 ppm,
for example, while hydrogen-bonded peptide amide protons
typically appear at about 8 ppm. Comparison of the chemical
shifts of the NH protons of artificial â-sheet 4 to those of suitable
controls in dilute CDCl3 solution elucidates the hydrogen-
bonding states of the protons. For these studies, compound 117
serves as a control for the upper â-strand mimic of 4, compounds
12 and 137 serve as controls for the peptide strand, and
compound 14 serves as a control for the lower â-strand mimic.
1
(22) The H NMR spectra of these compounds were recorded at 1 mM
in CDCl3 solution at 298 K. Studies of the NH chemical shifts as a function
of concentration indicate no significant intermolecular association at this
concentration.
(23) The slight downfield shifting of Hb in 4 relative to 11 (∆δ ) 0.36
ppm) may reflect polarization of the amide group in 4 by hydrogen bonding
of the carbonyl.
(24) Control 12 was prepared by coupling of phenylalanylleucine methyl
ester isocyanate with diethylamine in CH2Cl2 to give Et2NCO-Phe-Leu-
OMe, followed by aminolysis with methylamine in CH3OH.
(25) The chemical shift of Hf of control 12 is 0.71 ppm downfield of
that of control 13. This downfield shifting may reflect that 12 can adopt a
â-turnlike conformation in which Hf is intramolecularly hydrogen bonded
to the urea carbonyl group. For this reason, 13 is likely a better control for
the chemical shift of Hf.
Table 1 summarizes the chemical shifts of the NH groups of
these compounds.22 Protons Ha and Hc of the upper â-strand
mimic of artificial â-sheet 4 appear 3.96 and 2.80 ppm
(19) It is not clear whether the free secondary amine or an indeterminate
salt or adduct is isolated after treatment of sulfonamide 8 with PhSH and
K2CO3. The 1H NMR and mass spectrum are consistent with the amine,
but do not preclude a salt or unstable adduct (such as that which might
form with CO2). Consistent with a salt or unstable adduct, the solubility of
this material in organic solvents is unexpectedly low, its melting point is
unexpectedly high, and it requires the addition of triethylamine to react
with phenylalanylleucine methyl ester isocyanate. The IR spectrum suggests
the presence of an amine salt.
(20) Nowick, J. S.; Holmes, D. L.; Noronha, G.; Smith, E. M.; Nguyen,
T. M.; Huang, S.-L. J. Org. Chem. 1996, 61, 3929-3934.
(21) (a) Bergeron, R. J.; Burton, P. S.; McGovern, K. A.; Kline, S. J.;
Synthesis 1981, 732-733. (b) Jasys, V. J.; Kelbaugh, P. R.; Nason, D. M.;
Phillips, D.; Rosnack, K. J.; Saccomano, N. A.; Stroh, J. G.; Volkmann, R.
A. J. Am. Chem. Soc. 1990, 112, 6696-6704.
(26) Control 14 was prepared by aminolysis of oxamate ester 6 with
ethylamine in CH3OH.
(27) The slight downfield shifting of Hg and Hi in 4 relative to 14 (∆δ
) 0.21 and 0.29 ppm, respectively) may reflect polarization of these amide
groups in 4 by hydrogen bonding of the carbonyl groups.
(28) Wu¨thrich, K. NMR of Proteins and Nucleic Acids; Wiley: New
York, 1986; pp 125-129.
(29) (a) Hwang, T. L.; Shaka, A. J. J. Am. Chem. Soc. 1992, 114, 3157-
3159. (b) Hwang, T. L.; Shaka, A. J. J. Magn. Reson. Ser. B 1993, 102,
155-165.
(30) The studies were performed at 10 mM with a mixing time of 350
ms and were run at 312 K to minimize overlap of key resonances.

A Triply Templated Artificial â-Sheet
J. Am. Chem. Soc., Vol. 123, No. 22, 2001 5179
Scheme 2
Figure 1. Key interstrand NOEs in artificial â-sheet 4. Studies were
performed in 10 mM CDCl3 solution at 312 K. Interstrand NOEs are
represented by arrows.
and the proton at the 6-position of the lower â-strand mimic,
the methylamide proton (Hf) of the middle peptide strand and
the proton at the 6-position of the lower â-strand mimic, and
the methylamide proton (Hf) of the middle peptide strand and
the methylamide methyl group of the lower â-strand mimic.
Additional evidence for a â-sheetlike conformation of 4
comes from the intrastrand NOEs of the peptide and peptido-
mimetic strands and the coupling constants of the peptide
strand.28 The peptide strand shows relatively strong interresidue
NOEs between the NH and R-protons and relatively weak
intraresidue NOEs between the NH and R-protons. Similarly,
the upper â-strand mimic shows a relatively strong NOE
between the NH proton Ha and the proton at its 6-position and
only a very weak NOE between this NH proton and the proton
at its 4-position; the lower â-strand mimic shows a relatively
strong NOE between the NH proton Hh and the proton at its
6-position and only a weak NOE between this NH proton and
hydrogen bonding in the folding of artificial â-sheet 4 and the
ability of competitive solvents to interrupt this folding.
Discussion
3
the proton at its 4-position. The JHNR coupling constants of
That artificial â-sheet 4 adopts a folded â-sheetlike conforma-
tion is noteworthy, considering all of the other conformations
that this large and complex molecule can adopt. The molecule
could adopt unfolded states, in which the â-strand mimics and
peptide strand are not hydrogen bonded (Scheme 2). It could
also adopt misfolded states with different hydrogen-bonding
patterns, such as the pairing of the â-strand mimics to the
exclusion of the peptide strand. Partially folded and aggregated
states are also possible. Despite the plethora of potential states,
all of the data described above are consistent with the folded
state and suggest that this state predominates.
To fold properly, artificial â-sheet 4 must form six hydrogen
bonds and restrict rotation about fifteen bonds (shown with
arrows in Scheme 2). Previous experience has shown us that in
chloroform solution each hydrogen bond is able to offset up to
roughly four degrees of rotational freedom. In doubly stranded
artificial â-sheets 1 and 2, rotation about three bonds must be
significantly constrained for each hydrogen bond formed:
Artificial â-sheet 1 has nine bonds about which substantial
rotation must be constrained to achieve its three hydrogen bonds;
artificial â-sheet 2 has twelve for its four hydrogen bonds. That
the ratio of restricted rotations to hydrogen bonds is smaller
for 4 than for 1 (2.5:1 vs 3:1) suggests that 4 could be better
folded than 1.
the peptide strand are 8.9 Hz (Phe) and 9.3 Hz (Leu).31
Collectively, these NOE and coupling constant data indicate
that the component peptide and strand mimics adopt â-strandlike
conformations.
1H NMR studies indicate that the â-sheetlike structure into
which 4 folds in the noncompetitive solvent CDCl3 is lost in
the competitive solvent CD3OD. Tr-ROESY studies in this
solvent show no NOEs between the protons at the 6-positions
of the aromatic rings of the â-strand mimics and the R-protons
of the phenylalanine and leucine residues.32 Additional evidence
for the loss of structure in this solvent comes from the chemical
shifts of the phenylalanine and leucine R-protons. In CDCl3
solution, these protons appear at 5.45 and 4.97 ppm, respec-
tively. These values are substantially (>0.5 ppm) downfield of
the typical random-coil values of Phe and Leu in proteins (4.66
and 4.17 ppm, respectively)33 and in control 12 (4.46 and 4.38
ppm, respectively). This downfield shifting should reflect the
anisotropic effects of the adjacent aromatic rings of the upper
and lower â-strand mimics, as well as the general propensity
of the R-protons of â-sheets to be shifted downfield.33 In CD3-
OD solution, the R-protons of the phenylalanine and leucine
residues show little downfield shifting, appearing at 4.75 and
4.41 ppm, respectively. These studies reflect the importance of
Comparison of the chemical shifts of the NH groups of 4 to
those of 1 reveals this to be the case. Notably, the chemical
shift of upper strand hydrazide proton Hc of triply stranded
artificial â-sheet 4 appears 1.13 ppm downfield of that of doubly
stranded artificial â-sheet 1. This dramatic difference may result
mainly from a greater hydrogen-bonded population of 4, stronger
(31) Wu¨thrich, K. NMR of Proteins and Nucleic Acids; Wiley: New
York, 1986; pp 166-168.
(32) NOEs involving the NH groups were not observed in CD3OD,
because the NH protons are lost by exchange with deuterium in this solvent.
(33) (a) Wishart, D. S.; Sykes, B. D.; Richards, F. M. J. Mol. Biol. 1991,
222, 311-333. (b) Wishart, D. S.; Sykes, B. D.; Richards, F. M.
Biochemistry 1992, 31, 1647-1651.

5180 J. Am. Chem. Soc., Vol. 123, No. 22, 2001
Nowick et al.
hydrogen bonds in 4, or both.34 The other NH groups that are
hydrogen bonded in both 4 and 1 (Ha, Hb, and He) are also
shifted downfield in 4, but the downfield shifting is considerably
less pronounced (0.24-0.40 ppm). These smaller differences
may reflect the polarization of these hydrogen-bonding groups
associated with their participation in hydrogen-bonded networks,
strengthening of the hydrogen bonds, or anisotropic effects
associated with small conformational differences between the
two molecules and are less significant than the dramatic
downfield shifting of Hc. Collectively, these shift data suggest
that the bottom â-strand mimic of 4 contributes cooperatively
to its folding and helps reduce fraying of the interface between
the upper â-strand mimic and the middle peptide strand.35
compound that folds to resemble a three-stranded protein â-sheet
in chloroform solution. This triply templated artificial â-sheet
(4) is more tightly folded than its smaller doubly stranded
homologue (1). These findings lend further support to our
modular approach to the creation of proteinlike structures and
bode well for the creation of even larger and more complex
molecules that begin to rival the complex folding of proteins.
Acknowledgment. The authors thank the NSF for grant
support (CHE-9813105). J.S.N. thanks the following agencies
for support in the form of awards: the Camille and Henry
Dreyfus Foundation (Teacher-Scholar Award), the Alfred P.
Sloan Foundation (Alfred P. Sloan Research Fellowship), and
the American Chemical Society (Arthur C. Cope Scholar
Award). J.M.C. thanks Allergan, Inc. for fellowship support.
J.H.T. thanks the Chao Family Comprehensive Cancer Center
Functional Genomics Program for training grant support.
Conclusion
The studies described herein establish that three molecular
templates can be combined with a peptide strand to form a
(34) (a) Mackay, J. P.; Gerhard, U.; Beauregard, D. A.; Westwell, M.
S.; Searle, M. S.; Williams, D. H. J. Am. Chem. Soc. 1994, 116, 4581-
4590. (b) Williams, D. H.; Maguire, A. J.; Tsuzuki, W.; Westwell, M. S.
Science 1998, 280, 711-714.
(35) (a) Sharman, G. J.; Searle, M. S. Chem. Commun. 1997, 1955-
1956. (b) Schenck, H. L.; Gellman, S. H. J. Am. Chem. Soc. 1998, 120,
4869-4870. (c) Das, C.; Raghothama, S.; Balaram, P. J. Am. Chem. Soc.
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Supporting Information Available: Synthetic procedures
1
and H NMR, TOCSY, and Tr-ROESY spectra of artificial
â-sheet 4 (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
JA010220S