General Synthesis of Unsymmetrical Norbornane Scaffolds As Inducers for Hydrogen Bond Interactions in Peptides

Article abstract of DOI:10.1021/jo030295+

Starting from readily accessible endo-cis-(2S,3R)-norbornene dicarboxylic acid benzyl monoester, a general and efficient synthetic approach toward unsymmetrical two-stranded peptidic structures was developed. In these structures the peptide strands are or

Full text of DOI:10.1021/jo030295+

Gen er a l Syn th esis of Un sym m etr ica l Nor bor n a n e Sca ffold s a s
In d u cer s for Hyd r ogen Bon d In ter a ction s in P ep tid es†,‡
Christian P. R. Hackenberger, Ingo Schiffers, J an Runsink, and Carsten Bolm*
Institut fu¨r Organische Chemie der RWTH Aachen, Prof.-Pirlet-Str. 1, D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received September 23, 2003
Starting from readily accessible endo-cis-(2S,3R)-norbornene dicarboxylic acid benzyl monoester,
a general and efficient synthetic approach toward unsymmetrical two-stranded peptidic structures
was developed. In these structures the peptide strands are oriented in a parallel geometry. Their
synthesis is easily applicable to a variety of amino acids and peptides. Specifically, a norbornane
template as molecular scaffold induces hydrogen bonding between the adjacent peptide strands.
The specific hydrogen bonding patterns between these strands were revealed by detailed NMR
analysis including TOCSY/NOE experiments.
In tr od u ction
bornene scaffolds, which have been studied by Ranga-
nathan et al.11 and by North and co-workers,12 are
considered to orient two peptide strands attached to the
endo-cis-(2S,3R)-norbornene-dicarbonyl substituents in
the same direction, thus leading to hydrogen bonding
patterns between the strands. However, the synthetic
routes to these useful norbornene derivatives have severe
limitations, as either unsymmetrical scaffolds are inac-
cessible or proline is required in one of the peptide
strands. Therefore we initiated a study on searching for
a novel strategy that allows the incorporation of almost
any amino acid or peptide into the endo-norbornene
framework.
The synthesis of compounds with defined secondary
structures has recently become an emerging field in
modern organic chemistry.1 Along these lines, the desire
for efficient procedures to assemble stable secondary
structures has increased considerably.2 Particular atten-
tion has been focused on the synthesis and structural
investigation of â-sheets and â-hairpins.3 The latter are
considered to represent the smallest possible sheet
structure and have been studied extensively as â-sheet
model systems.4 Several examples of such model systems
as well as sheet mimetics are known to date,5 which can
be aligned in a parallel6 or antiparallel fashion.7
A
common approach uses a molecular scaffold,8 which
preorients adjacent peptide strands and initiates nonco-
valent interactions and hydrogen bonds between them.9
Besides covalent molecular scaffolds, a noncovalent
linked framework has been reported recently.10 Many of
these systems are easily accessible and display stable
sheetlike structures. However, they sometimes bear
disadvantages in terms of general applicability since their
syntheses allow only derivatives with equal peptidic side
chains, which are attached to the molecular scaffold.
Our studies have focused on parallel peptide scaffolds
containing a norbornene or norbornane motif. Nor-
(5) (a) Schneider, J . P.; Kelly, J . W. Chem. Rev. 1995, 95, 2169. (b)
Nowick, J . S. Acc. Chem. Res. 1999, 32, 287. (c) Nowick, J . S.; Mahrus,
S.; Smith, E. M.; Ziller, J . W. J . Am. Chem. Soc. 1996, 118, 1066. (d)
Nowick, J . S.; Chung, D. M.; Maitra, K.; Maitra, S.; Stigers, K. D.;
Sun, Y. J . Am. Chem. Soc. 2000, 122, 7654; Correction: Nowick, J . S.;
Chung, D. M.; Maitra, K.; Maitra, S.; Stigers, K. D.; Sun, Y. J . Am.
Chem. Soc. 2001, 123, 1545. (e) Nowick, J . S.; Brower, J . O. J . Am.
Chem. Soc. 2003, 125, 876. (f) Nowick, J . S.; Cary, J . M.; Tsai, J . H. J .
Am. Chem. Soc. 2001, 123, 5176. (g) Nowick, J . S.; Lam, K. S.;
Khasanova, T. V.; Kemnitzer, W. E.; Maitra, S.; Mee, H. T.; Liu, R. J .
Am. Chem. Soc. 2002, 124, 4972. (h) Huck, B. R.; Fisk, J . D.; Gellman,
S. H. Org. Lett. 2000, 2, 2607. (i) Belvisi, L.; Gennari, C.; Madder, A.;
Mielgo, A.; Potenza, D.; Scolastico C. Eur. J . Org. Chem. 2000, 695.
(k) Moriuchi, T.; Nomoto, A.; Yoshida, K.; Hirao, T. J . Organomet.
Chem. 1999, 589, 50. (j) Moriuchi, T.; Nomoto, A.; Yoshida, K.; Ogawa,
T.; Hirao, T. J . Am. Chem. Soc. 2001, 123, 68.
* To whom correspondence should be adressed. Phone: +49 241 809
4675. Fax: +49 241 809 2391.
(6) For a recent contribution, see: Langenhan, J . M.; Guzei, I. A.;
Gellman, S. H. Angew. Chem., Int Ed. 2003, 42, 2402.
(7) Fisk, J . D.; Gellman, S. H. J . Am. Chem. Soc. 2001, 123, 343.
(8) For early examples on this approach, see: (a) Kemp, D. S.;
Bowen, B. R. Tetrahedron Lett. 1988, 29, 5077. (b) Kemp, D. S.; Bowen,
B. R. Tetrahedron Lett. 1988, 29, 5081. (c) Kemp, D. S.; Bowen, B. R.;
Muendal, C. C. J . Org. Chem. 1990, 55, 4650.
(9) For recent studies on noncovalent interactions in â-hairpin or
â-sheet systems, see: (a) Tatko, C. D.; Waters, M. L. J . Am. Chem.
Soc. 2002, 124, 9372. (b) Nowick, J . S.; Chung, D. M. Angew. Chem.,
Int. Ed. 2003, 42, 1764.
(10) Zeng, H.; Yang, X.; Flowers, R. A., II; Gong, B. J . Am. Chem.
Soc. 2002, 124, 2903.
† This work is part of the Ph.D. thesis of C.P.R.H.
‡ Dedicated to Professor Dr. H.-J . Reich on the occasion of his 60th
birthday.
(1) (a) Hill, D. J .; Mio, J .; Prince, R. B.; Hughes, T. S.; Moore, J . S.
Chem. Rev. 2001, 101, 3893. (b) Gellman, S. H. Acc. Chem. Res. 1998,
31, 173. (c) Stigers, K. D.; Soth, M. J .; Nowick, J . S. Curr. Opin. Chem.
Biol. 1999, 3, 714. (d) Burgess, K. Acc. Chem. Res. 2001, 34, 826.
(2) (a) Fletcher, M. D.; Campbell, M. M. Chem. Rev. 1998, 98, 763.
(b) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244.
(3) (a) Smith, C. K.; Regan, L. Acc. Chem. Res. 1997, 30, 153. (b)
Blanco, F.; Ramirez-Alvarado, M.; Serano, L. Curr. Opin. Struct. Biol.
1998, 8, 107. (c) Lacroix, E.; Kortemme, T.; de la Paz, M. L.; Serano,
L. Curr. Opin. Struct. Biol. 1999, 9, 487. (d) Karle, I. L. Acc. Chem.
Res. 1999, 32, 693.
(11) Ranganathan, D.; Haridas, V.; Kurur, S.; Thomas, A.; Madhusud-
anan, K. P.; Nagaraj, R.; Kunwar, A. C.; Sarma, A. V.; Karle, I. L. J .
Am. Chem. Soc. 1998, 120, 8448.
(4) (a) Gellman, S. H. Curr. Opin. Chem. Biol. 1998, 2, 717. (b)
Serrano, L. Adv. Protein Chem. 2000, 53, 49. (c) Searle, M. S. J . Chem.
Soc., Perkin Trans. 2 2001, 1011.
(12) (a) Hibbs, D. E.; Husthouse, M. B.; J ones, I. G.; J ones, W.;
Malik, K. M. A.; North, M. J . Org. Chem. 1998, 63, 1496. (b) J ones, I.
G.; J ones, W.; North, M. J . Org. Chem. 1998, 63, 3, 1505.
10.1021/jo030295+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/25/2003
J . Org. Chem. 2004, 69, 739-743
739

Hackenberger et al.
SCHEME 1. Kn ow n Syn th etic Ap p r oa ch es tow a r d
P ep tid es Con ta in in g a Nor bor n en e Molecu le
F IGURE 1. Hydrogen bonding patterns in unsymmetrical
norbornene peptides.12,17
conformations,18 which mainly results in intrastrand
interactions as depicted in Figure 1, where the two major
conformers of a norbornene heptapeptide 3c are il-
lustrated.19 This picture points to another goal of our
studies, since we intended to search for other noncovalent
interactions and especially interstrand hydrogen bonding
patterns that can be initiated by such bicyclic scaffolds.
We assumed those to be dependent on the kind of amino
acids in the norbornene or norbornane peptide backbone.
The known synthetic approaches toward endo-nor-
bornene-containing peptides start out from norbornene
anhydride 1 (Scheme 1). Ranganathan et al. produced a
parallel C2-symmetric peptide framework with two equiva-
lent peptide strands (Scheme 1, left) by ring opening of
1 with primary amino acids or peptides to yield acid 2a
as a 1:1 mixture of diastereomers. To avoid difficult
separations, the acid 2a was symmetrized via coupling
with the same amino acid or peptide to give the C2-
symmetric peptide 3a . It was shown by CD measure-
ments as well as X-ray studies that these norbornene
templates initiate a â-sheet-like orientation.13
The approach by North led to the first example of an
unsymmetrical norbornene template (Scheme 1, right).
The key step in his procedure is a desymmetrization
reaction of the norbornene anhydride 1.14 In contrast to
the previous example the ring opening was performed
with an ester of the seondary amino acid L-proline,15
which gave acid 2b in high yields and excellent diaste-
reoselectivities.16 Subsequent coupling steps led to stru-
cutural defined pseudopeptides 3b with up to six amino
acids attached.12,17 The main disadvantage in this route,
however, is the requirement of proline at the first position
of one peptide strand. Unfortunately, proline cannot be
cleaved and exchanged to other amino acids under
conditions that are desirable for peptidic systems. This
lack of variation is even more important in the context
of the peptides secondary structures as proline in com-
bination with other amino acids is known to favor turn
Resu lts a n d Discu ssion
As outlined in the Introduction, our first aim was to
generalize the synthetic approach to unsymmetrical
norbornene peptides aligned in a parallel orientation. We
started our investigation by applying another desymme-
trization procedure, which circumvents the synthetic
disadvantages mentioned above, i.e., the alkaloid-medi-
ated desymmetrization of anydrides with alcohols.20
When performed with methanol this protocol leads to
enantiomerically pure norbornene hemimethylester 4 in
high yields (Scheme 2). We envisioned 4 as the starting
point in our synthesis of unsymmetrical parallel â-sheets.
First, norbornene hemiester 4 was coupled with vari-
ous C-terminal protected amino acids, yielding in all
cases norbornene amino acids 5a -e in very good yields
(Scheme 2 and Table 1).21 Especially noteworthy is the
fact that a possible alternative product, imide 6, was not
detected even in the conformationally flexible glycine
analogue 5e. Imide formation was the major side reaction
in related systems with an anthracene backbone22 and
the one described by Ranganathan et al.11 Next, the
selective cleavage of one of the two ester functionalities
in 5 was envisaged. Unfortunately, under various condi-
tions this transformation remained unsuccessful. Base-
mediated cleavage of 5b led almost exclusively to imide
6a with a free acid functionality (R3 ) H). The attempt
to transform 5b directly to the corresponding amide using
a NaCN-catalyzed transamidation, as previously used for
(13) Ranganathan, D.; Haridas, V.; Kurur, S.; Nagaraj, R.; Bik-
shapathy, E.; Kunwar, A. C.; Sarma, A. V. S.; Vairamani, M. J . Org.
Chem. 2000, 65, 365.
(14) For reviews on desymmetrization protocols, see: (a) Willis, M.
C. J . Chem. Soc., Perkin Trans. 1 1999, 1765. (b) Spivey, A. C.;
Andrews, B. I. Angew. Chem., Int. Ed. 2001, 40, 3131. (c) Chen, Y.;
McDaid, P.; Deng, L. Chem. Rev. 2003, 103, 2965.
(18) (a) Branden, C.; Tooze, J . Introduction to Protein Structure, 2nd
ed.; Garland: New York, 1998. (b) See also: Stanger, H. E.; Gellman,
S. H. J . Am. Chem. Soc. 1998, 120, 4236.
(19) Structural analysis was carried out using detailed NMR
analysis and X-ray data of shorter norbornene peptides. For further
information, see ref 12.
(15) In this paper, all natural R-amino acid derivatives have
(20) (a) Bolm, C.; Schiffers, I.; Dinter, C. L.; Gerlach A. J . Org. Chem.
2000, 65, 6984. (b) Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999,
3, 471.
(21) This transformation yielding endo,endo norbornene-dicarbonyl
systems 5 is particularly noteworthy in the light of a recent investiga-
tion of epimerzations to endo,exo norbornene-dicarbonyl systems
containing sulfoximidoyl moieties. Hackenberger, C. P. R.; Raabe, G.,
Bolm, C. Manuscript in preparation.
L-configuration.
(16) (a) Hibbs, D. E.; Husthouse, M. B.; J ones, I. G.; J ones, W.;
Malik, K. M. A.; North, M. J . Org. Chem. 1999, 64, 5413. (b) Albers,
T.; Biagini, S. C. G.; Hibbs, D. E.; Husthouse, M. B.; Malik, K. M. A.;
North, M.; Uriarte, E.; Zagotto, G. Synthesis 1996, 393. (c) North, M.;
Zagotto, G. Synlett 1995, 639. (d) J ones, I. G.; J ones, W.; North, M.;
Teijeira, M.; Uriarte, E. Tetrahedron Lett. 1997, 38, 889.
(17) North, M. J . Pept. Sci. 2000, 6, 301.
(22) Turk, J . A.; Smithrud, D. B. J . Org. Chem. 2001, 66, 8328.
740 J . Org. Chem., Vol. 69, No. 3, 2004

Unsymmetrical Norbornane Templates
TABLE 2. Dep r otection of Ben zyl Ester s u n d er
Hyd r ogen a tion Con d ition sa
SCHEME 2. Syn th esis of Un sym m etr ica l P a r a llel
Nor bor n a n e Con ta in in g P ep tid esa
entry
benzyl ester
R1
PG1
product
yield [%]
1
2
3
8a
8b
8c
H
Me
Bn
tBu
Me
tBu
9a
9b
9c
85
97
99
a
The reactions were performed with H2 (1 atm) at room
temperature in ethyl acetate (0.25 M solution). The conversions
were monitored by TLC.
choice. During the hydrogenation of the benzyl esters we
expected the norbornene double bond to be reduced
affording the analogous norbornane derivatives. How-
ever, because both bicyclic scaffolds have similar rigidi-
ties, only a minor influence on the sheet inducing
propensities should result.23
The coupling of norbornene benzylester 7 with various
amino acids to norbornene amino acids 8a -c proceeded
with similar high yields as in the methyl ester cases
(Scheme 2 and Table 1, entries 6-10). Entries 7 and 9
are particularly noteworthy because in these reactions
EDC (instead of DCC) was the coupling reagent and the
workup by aqueous acidic extraction led to almost
quantitative product yields without further purification
by column chromatography.
Consequently, compounds 8a -c were hydrogenated
with Pd/C as catalyst, giving rise to the corresponding
norbornane acids 9a -c in very good yields (Scheme 2 and
Table 2). Attempts to retain the norbornene double bond
by shorter reaction times failed.
a
Conditions: (i) HXaa1OPG1 (see Table 1), DCC, DMAP,
CH2Cl2; (ii) 1 N NaOH, MeOH (product 6a ) or NaCN, HYaa2OPG2,
MeOH (product 6b); (iii) H2, Pd/C; (iv) HYaa2OPG2 (see Table 3),
DCC, HOBt, DMAP, CH2Cl2.
TABLE 1. Ca r bod iim id e Cou p lin g of Nor bor n en e
Hem iester s w ith Am in o Acid sa
entry
hemiester
amino acid
product
yield [%]
1
2
3
4
4
HPheOBn
HPheOBn
HPheOtBu
HLeuOBn
HGlyOtBu
HGlyOtBu
HGlyOtBu
HAlaOMe
HAlaOMe
HPheOtBu
5a
5b
5c
5d
5e
8a
8a
8b
8b
8c
74
71
96
99
93
70
98
76
94
85
ent-4
4
4
4
7
7
7
7
7
5
6
Acids 9b and 9c were then coupled under DCC/HOBt
conditions to give bis(amino acid diesters) 10 in good
yields, which demonstrated the general approach toward
unsymmetrical norbornane peptides 10. Starting form
norbornene anydride 1 this synthetic route yields peptide
derivatives with overall yields >72% over four steps
(Scheme 2 and Table 3). Additionally, the mild cleavage
conditions of the benzyl ester allows an applicability of
this reaction sequence to almost any amino acid with no
racemization or side reaction in the peptide chain.
Having established the general synthetic strategy, we
adressed the questions of how these bis(amino acid
diesters) behave in terms of structural orientation and
if they show any significant difference from the known
7b
8
9b
10
a
The reactions were performed at room temperature for 12 h
using 1 equiv of C-terminal protected amino acid, 1 equiv of HOBt,
b
0.1 equiv of DMAP, and 1.1 equiv of DCC in CH2Cl2. As coupling
reagent EDC was used instead of DCC.
the synthesis of endo/ exo amino alcohol amides,23 re-
sulted in imide formation as well. This time, however,
the benzyl ester (R3 ) Bn) remained intact and imide 6b
was formed.
Because the approach toward the unsymmetrical bi-
cyclic scaffolds using desymmetrized norbornene hemi-
methylesters 4 was not successful, we revised our strat-
egy and chose the norbornene hemibenzylester 7 as
starting material. As recently described by our laboratory
this hemiester can be prepared in 92% yield and 97% ee
by an analogous anhydride opening in the presence of
an alkaloid using benzyl alcohol as nucleophile.24 This
change in the ester functionality allows a mild ester
cleavage by simple hydrogenation. The amino acids
should then be protected as inert C-terminal esters in
the first coupling step, and commercially available methyl
and tert-butyl esters would be starting materials of
1
norbornene proline derivatives. Investigations of the H
NMR amide proton shifts of derivatives 10a -c revealed
signals between 6.26 and 6.90 ppm (see Supporting
Information), which have also been observed in the
related systems by North.12 Generally, these amide
hydrogens, which are close to the bicyclic scaffold, do not
seem to be involved in hydrogen bonding to a major
extend. We therefore decided to search for interstrand
molecular interactions in longer peptides and prepared
norbornane peptide 13. The synthesis proceeded analo-
gously to the one of norbornane peptides 10 and involved
a carbodiimide coupling of norbornene hemiester 7 with
HPheAlaOMe to 11, subsequent hydrogenation, and final
coupling of the resulting acid 12 with HPheGlyOBn to
13 in good overall yields (Scheme 3).
(23) A disadvantage of the resulting saturated bicyclic scaffold is
that it does not allow a direct access to interesting ROMP-peptide
polymers or further chemical transformations as shown in related
studies. For examples see ref 16 and (a) Bedekar, A. V.; Koroleva, E.
B.; Andersson, P. G. J . Org. Chem. 1997, 62, 2518. (b) Ho¨gberg, T.;
Stro¨m, P.; Ebner, M.; Ra¨msby, S. J . Org. Chem. 1987, 52, 2033. (c)
Bolm, C.; Dinter, C. L.; Schiffers, I.; Defre`re, L. Synlett 2001, 1875
and references therein.
1H NMR analysis of compound 13 in CDCl3 showed
four amide proton signals at 5.97, 6.66, 7.74, and 7.82
(24) Bolm, C.; Schiffers, I.; Atodiresei, I.; Hackenberger, C. P. R.
Tetrahedron: Asymmetry 2003, 14, 3455.
J . Org. Chem, Vol. 69, No. 3, 2004 741

Hackenberger et al.
yield
TABLE 3. Cou p lin g of Nor bor n a n e Acid s to Un sym m etr ica l P a r a llel Bis(a m in o a cid d iester s) 10a
norbornane
entry
acid
R1
PG1
amino acid
product
R2
PG2
[%]b
1
2
3
9b
9c
9c
Me
Bn
Bn
Me
tBu
tBu
HPheOtBu
HLeuOBn
HPheOMe
10a
10b
10c
Bn
iBu
Bn
tBu
Bn
Me
79 (72)
85 (72)
91 (77)
a
The reactions were performed at room temperature for 12 h using 1 equiv of C-terminal protected amino acid, 1 equiv of HOBt, 0.1
b
equiv of DMAP, and 1.1 equiv of DCC in CH2Cl2. Values in parentheses refer to overall yields after four steps starting from anhydride 1.
respectively). To determine the exact nature of the
interstrand interactions, a number of selective DPFGSE-
NOE and -TOCSY and a pseudo 3D TOCSY-NOE se-
quence were used.26 Strong NOEs between NH2 and Ha′
and NH3 and Hc revealed the connection of the amides
and the norbornane units. Furthermore, the transoid
orientation of the two connecting amide carbonyl groups
was indicated. Two more NOEs were found between the
two peptide strands. Both involved the CH at the
stereogenic center of phenylalanine. One NOE was
detected between this group and the alanine methyl and
the other between the CH and amide proton NH1 (Figure
2, left). This observation confirmed the formation of a
hydrogen bond between NH1 and the carbonyl of the
F IGURE 2. Interstrand NOEs in norbornane peptide 13 and
second amino acid, which was already indicated by the
downfiled shift of amide proton NH1. Taking the inter-
strand NOEs as molecular constraints, a molecular
dynamics simulation of the norbornene peptide 13 with
the program INSIGHT II using the force field AMBER27
was carried out.28 The resulting structure, which has a
preferred conformation with an interstrand H-bond in-
volving the amide proton NH1, is shown in Figure 2. In
comparison with norbornene peptide 3c by North12,17
bearing two proline residues in the peptide chain the
observed hydrogen pattern in 13 differs significantly.
Whereas in molecule 3c mainly interactions within the
peptide strands are observed, 13 clearly displays an
interstrand hydrogen bond.
In contrast to NH1 no interstrand NOE was observed
for amide NH.4 Thus the origin of the downfield shift of
NH4 could not be explained thoroughly. The molecular
dynamic studies indicated that this effect could be a
result of a positive anisotropic effect due to the aromatic
residues of the phenylalanine side chain.
structure of 13 after molecular dynamics using the AMBER
force field.
SCHEME 3. Syn th esis of P ep tid e 13a
a
Conditions: (i) HPheAlaOMe, DCC, HOBt, DMAP, CH2Cl2
(71%); (ii) H2, Pd/C (96%); (iii) HPheGlyOBn, DCC, HOBt, DMAP,
CH2Cl2 (71%).
TABLE 4. 1H NMR Am id e P r oton Sign a ls in
Nor bor n en e P ep tid e 13a
shift value
[ppm]
signal
∆ shift
entry
(coupling constant) [ppm]b correlation
1
2
3
4
5.97
6.66
7.74
7.82
doublet (J ) 8.0 Hz)
doublet (J ) 8.8 Hz)
triplet (J ) 5.5 Hz)
doublet (J ) 7.4 Hz)
1.07
1.50
0.27
0.35
NH2
NH3
NH4
NH1
Con clu sion
a
The 1H NMR data were recorded at 500 MHz in CDCl3 and
b
A general and mild synthetic procedure for the prepa-
ration of unsymmetrical template molecules that inititate
a hydrogen bonding pattern between two adjacent pep-
tide strands was developed. It takes advantage of the
readily accessible norbornene anydride 1 and its efficient
alkaloid-mediated asymmetric anhydride opening with
benzyl alcohol to give desymmetrized benzyl ester 7.
Currently we are investigating further applications of the
are given relative to TMS as internal standard. DMSO (12 vol
%) was added; ∆δ CHCl3 ) 0.37 ppm.
ppm. A triplet at 7.74 ppm corresponded to the R-position
to the methylene glycine moiety. Further correlations
were made by NOE, TOCSY, and gHSQC spectra analy-
ses (Table 4 and Figure 2).
As revealed by the data listed in Table 4, the signals
of the remote amide protons NH1 and NH4 were signifi-
cantly shifted downfield with respect to protons NH2 and
NH3 in the proximity to the norbornane scaffold, indicat-
ing the presence of an interstrand hydrogen bond pattern
involving the first two amide protons. Evidence for such
interaction was also obtained from a DMSO titration
experiment. Whereas NH2 and NH3 shifted significantly
upon addition of 12 vol % of DMSO (∆δ ) 1.07 and 1.50
ppm, respectively), the shift values for NH1 and NH4 were
effected to a much lower extend (∆δ ) 0.35 and 0.27 ppm,
(25) Biagini, S. C. G.; Davies, R. G.; Gibson, V. C.; Giles, M. R.;
Marshall, E. L.; North, M.; Robson, D. A. Chem. Commun. 1999, 235.
(26) Parella, T. Magn. Reson. Chem. 1996, 34, 329.
(27) (a) Weiner, S. J .; Kollman, P. A.; Case, D. A.; Singh, U. C.; Ghio,
C.; Alagona, G.; Profeta, S., J r.; Weiner, P. J . Am. Chem. Soc. 1984,
106, 765. (b) Weiner, S. J .; Kollman, P. A.; Nguyen, D. T.; Case, D. A.
J . Comput. Chem. 1986, 7, 230.
(28) For the molecular simulation 1000 iterations with the steepest
descent were performed, followed by molecular dynamics (AMBER,
10000 steps at 300 K, 1ps each step). The resulting structure was again
simulated with 1000 iterations.
(29) Albrich, H.; Vahrenkamp, H. Chem. Ber. 1994, 127, 1223.
742 J . Org. Chem., Vol. 69, No. 3, 2004

Unsymmetrical Norbornane Templates
norbornane templates in larger â-sheet mimetics in both
parallel and antiparallel orientations.
Exp er im en ta l Section
Gen er a l. Solvent purification, suppliers, instruments, and
workup procedures, as well as the general procedures for the
carbodiimide couplings (GP-A1 and GP-A2 for the DCC- and
the EDC-coupling, respectively) and the deprotection of benzyl
ester derivatives to acids under hydrogenation conditions
(GP-B), are described in the Supporting Information.
(2S,3R)-3-en do-[1-(1-Meth oxycar bon yl-eth ylcar bam oyl)-
2-ph en yl-eth ylcar bam oyl]-bicyclo[2.2.1]h ept-5-en e-2-en do-
ca r boxylic a cid ben zyl ester (11) was obtained from 7 by
coupling with HPheAlaOMe according to GP-A1 as a colorless
Hz, H-C17), 2.23 (2 H, m, H-C1, H-C4), 2.59 (1 H, d, J )
10.7 Hz, H-C3), 2.86 (1 H, dd, J ) 4.6, 11.4 Hz, H-C2), 2.96/
3.18 (2 H, dAB-system, J ) 9.0, 14.0 Hz, H-C22), 3.08/3.32
(2 H, dAB-system, J ) 5.5, 13.8 Hz, H-C10), 3.64 (3 H, s,
H-C19), 3.97/4.13 (2 H, dAB-system, J ) 5.5, 12.9 Hz,
H-C29), 4.50 (1 H, qn, J ) 7.2 Hz, H-C16), 4.58 (1 H, q, J )
6.0 Hz, H-C9), 4.75 (1 H, dt, J ) 5.8, 8.8 Hz, H-C21), 5.10 (2
H, s, H-C31), 5.97 (1H, d, J ) 8.0 Hz, NH-2), 6.66 (1 H, d, J
) 8.8 Hz, NH-3), 7.16-7.36 (15 H, m, H-C11-14, H-C23-
27, H-C32-36), 7.74 (1 H, t, J ) 5.5 Hz, NH-4), 7.82 (1H, d,
J ) 7.4 Hz, NH-1); 13C NMR (100 MHz, CDCl3) δ 17.3 (C-17),
23.1 (C-5), 25.3 (C-6), 36.3 (C-10), 37.3 (C-22), 38.7 (C-4), 40.7
(C-7), 41.5 (C-1), 41.6 (C-29), 47.4 (C-2), 48.5 (C-16), 49.9 (C-
3), 52.4 (C-19), 53.6 (C-21), 53.7 (C-9), 67.0 (C-31), 126.7 (C-
aryl), 126.9 (C-aryl), 128.2 (C-aryl), 128.4 (C-aryl), 128.4 (C-
aryl), 128.6 (C-aryl), 128.7 (C-aryl), 129.2 (C-aryl), 129.3 (C-
aryl), 135.4 (C-aryl), 137.0 (C-aryl), 137.1 (C-aryl), 169.9
(CdO), 170.9 (CdO), 171.8 (CdO), 172.3 (CdO), 172.7 (CdO),
173.7 (CdO); IR (CHCl3) ν 3400, 3282, 3064, 2929, 2876, 2851,
1741, 1642, 1541, 1501, 1454, 1383, 1192, 753, 701 cm-1; MS
(EI, DIP) m/z 710 (1, [M+]), 463 (1), 462 (7), 461 (25), 399 (24),
398 (16), 268 (44), 131 (37), 120 (100).
solid in 71% yield: mp 80 °C; [R]25 -34.1 (c 0.50, CHCl3); Rf
D
1
) 0.20 (PE/EE 1:1 v/v); H NMR (400 MHz, CDCl3) δ 1.32 (1
H, d, J ) 10.4 Hz), 1.34 (3 H, d, J ) 7.1 Hz), 1.46
(1 H, td, J ) 1.7, 10.4 Hz), 2.91 (1 H, dd, J ) 7.2, 13.9 Hz),
3.01-3.04 (1 H, m), 3.10-3.18 (2 H, m), 3.20/3.32 (2 H, dAB-
system, J ) 3.2, 10.1 Hz), 3.69 (3 H, s), 4.45 (1 H, qn, J ) 7.1
Hz), 4.56 (1 H, td, J ) 6.0, 7.4 Hz), 4.92/5.08 (2 H, AB-system,
J ) 12.4 Hz), 5.93 (1 H, dd, J ) 2.9, 5.7 Hz), 6.05 (1 H, d, J )
7.4 Hz), 6.34 (1 H, dd, J ) 2.9, 5.7 Hz), 6.52 (1 H, d, J ) 7.1
Hz), 7.18-7.30 (10 H, m); 13C NMR (100 MHz, CDCl3) δ 17.8,
37.5, 46.1, 46.9, 48.3, 48.7, 49.3, 50.1, 52.4, 54.2, 66.4, 127.0,
128.1, 128.3, 128.5, 128.7, 129.4, 133.4, 136.0, 136.5, 136.7,
170.5, 171.6, 172.7, 172.8; IR (CHCl3) ν 3294, 3065, 2978, 2935,
1745, 1646, 1544, 1453, 1382, 1340, 1211, 1165, 744, 699 cm-1
;
MS (EI, DIP) m/z 505 (7, [M+ + H]), 504 (22, [M+]), 396 (41),
234 (13), 210 (14), 174 (24), 91 (100); HRMS calcd for
C
29H32N2O6 504.226037, found 504.226070.
(2S,3R)-3-en do-[1-(1-Meth oxycar bon yl-eth ylcar bam oyl)-
2-p h en yl-eth ylca r ba m oyl]-bicyclo[2.2.1]h ep ta n e-2-en d o-
ca r boxylic a cid (12) was obtained from 11 according to GP-B
as a colorless solid in 96% yield: mp 93 °C; [R]25 -26.0 (c
D
1
0.50, CHCl3); H NMR (400 MHz, CDCl3) δ 1.33 (3 H, d, J )
7.1 Hz), 1.39-1.44 (2 H, m), 1.52-1.72 (2 H, m), 1.88-1.98 (2
H, m), 2.43-2.49 (1 H, m), 2.53-2.56 (1 H, m), 2.88 (1 H, dd,
J ) 3.0, 11.9 Hz), 2.93 (1 H, dd, J ) 3.7, 11.9 Hz), 3.08 (2 H,
dAB-system, J ) 6.4, 13.9 Hz), 3.68 (3 H, s), 4.44 (1 H, qn, J
) 7.1 Hz), 4.74 (1 H, td, J ) 6.4, 8.0 Hz), 6.74 (1 H, d, J ) 8.0
Hz), 6.98 (1 H, d, J ) 7.1 Hz), 7.18-7.28 (5 H, m), 8.05 (1 H,
br s); 13C NMR (100 MHz, CDCl3) δ 17.8, 23.7, 24.5, 37.8, 40.1,
40.3, 41.7, 47.5, 48.1, 48.3, 52.4, 54.3, 126.9, 128.5, 129.4, 136.5,
171.0, 172.9, 173.1, 176.0; IR (CHCl3) ν 3307, 3065, 3031, 2955,
Ack n ow led gm en t. This work was supported by the
Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (DFG) within the Collabora-
tive Research Center (SFB) 380 “Asymmetric Synthesis
by Chemical and Biological Methods”. C.P.R.H. is grate-
ful to the Fonds der Chemischen Industrie and the
BMBF for a predoctoral stipend. We also thank Nicole
Brendgen, Susi Gru¨nebaum, and Marc Hans for experi-
mental contributions, Dr. Marc Nitz for helpful discus-
sions, Dr. Eugenio Vazques for help during the modeling
studies, and Prof. Dr. Barbara Imperiali for the use of
her modeling facilities.
2878, 1741, 1648, 1543, 1453, 1293, 1212, 1157, 744, 700 cm-1
;
MS (EI, DIP) m/z (%) 416 (1, [M+]), 398 (12, [M+ - H2O]), 159
(16), 120 (100), 66 (24); HRMS calcd for C22H28N2O6 - H2O
398.183172, found 398.183125.
(2S,3R)-[2-({3-en d o-[1-(Ben zyloxyca r bon yl-m eth ylca r -
bam oyl)-2-ph en yl-eth ylcar bam oyl]-bicyclo[2.2.1]h eptan e-
2-en d o-ca r bon yl}-a m in o)-3-p h en yl-p r op ion yla m in o]-p r o-
pion ic acid m eth yl ester (13) was obtained from 12 according
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details for all new compounds and spectral characterization
(1H NMR, 13C NMR, gMQCOSY) of 5c, 8c, 9c, 10a , 10b, 10c,
and 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
to GP-A1 as a colorless solid in 71% yield: mp 78 °C; [R]25
D
1
-23.5 (c 0.20, CHCl3); Rf 0.45 (EE/PE/AcOH 90:9:1 v/v/v); H
NMR (500 MHz, CDCl3) δ 1.05/1.20 (2 H, m, H-C6), 1.26/1.50
(2 H, m, H-C5), 1.33 (2 H, m, H-C7), 1.41 (3 H, d, J ) 7.2
J O030295+
J . Org. Chem, Vol. 69, No. 3, 2004 743