Synthesis and conformational study of homo-peptides based on (S)-Bin, a C2-symmetric binaphthyl-derived Cα,α-disubstituted glycine with only axial chirality

Article abstract of DOI:10.1016/S0957-4166(03)00285-4

We synthesised the [(S)-Bin]_n (n=2-5) homo-peptides by solution methods. Only the acid fluoride derivative Fmoc-(S)-Bin-F could be efficiently coupled with H-[(S)-Bin]_n-OMe (n=2-4). Spectroscopic experimental analyses of the [(S)-Bin

Full text of DOI:10.1016/S0957-4166(03)00285-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1879–1893
Synthesis and conformational study of homo-peptides based on
a,a
(S)-Bin, a C2-symmetric binaphthyl-derived C -disubstituted
glycine with only axial chirality
Jean-Paul Mazaleyrat,a Karen Wright,a Anne Gaucher,a Michel Wakselman,a Simona Oancea,b
Fernando Formaggio,b Claudio Toniolo,b,* Vladimir Setnicˇka,c Josef Kapita´nc and
Timothy A. Keiderlingc
aSIRCOB, UMR CNRS 8086, Baˆt. Lavoisier, University of Versailles, F-78035 Versailles, France
bInstitute of Biomolecular Chemistry, CNR, Department of Organic Chemistry, University of Padua, I-35131 Padua, Italy
cDepartment of Chemistry, University of Illinois at Chicago, Chicago, IL 60607-7061, USA
Received 21 March 2003; accepted 1 April 2003
Abstract—We synthesised the [(S)-Bin]n (n=2–5) homo-peptides by solution methods. Only the acid fluoride derivative
Fmoc-(S)-Bin-F could be efficiently coupled with H-[(S)-Bin]n-OMe (n=2–4). Spectroscopic experimental analyses of the
[(S)-Bin]n homo-peptides in solution performed by CD, FT-IR absorption, and VCD, supported by VCD calculations, confirmed
the (S) configuration of the Bin residues and identified the most largely populated secondary structures as right-handed b-turns
which eventually evolve to 310-helices in the highest oligomers. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
set of model peptides based on 2%,1%:1,2;1%%,2%%:3,4-
dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid
(Bip)4,5 and 2%,1%:1,2;1%%,2%%:3,4-dinaphthcyclohepta-1,3-
diene-6-amino-6-carboxylic acid (Bin)4,6 (Fig. 1), in
combination with Ala, Gly or Aib (a-aminoisobutyric
acid) residues. The [Bip]n homo-oligomers are also
folded into 310-helices.5 Herein we report the synthesis
of the corresponding [(S)-Bin]n homo-peptides to the
pentamer level and their conformational study by elec-
tronic CD, FT-IR absorption, and VCD (vibrational
CD) spectroscopy. The Bip and Bin residues combine
structural features of Dbzg and Ac7c. Both are C2-sym-
metric and possess a chiral axis (atropoisomerism)
along their 1-1% bond.
The conformationally constrained Ca,a-symmetrically
disubstituted glycines are among the simplest and most
widely used structural units in the construction of pep-
tides with a predetermined secondary structure.1 In
particular, it has been shown that peptides based on
Ca,a-dibenzylglycine (Dbzg)2 (Fig. 1) strongly prefer to
adopt a fully-extended (C5) conformation,1k,1l whereas
those rich in 1-aminocycloheptane-1-carboxylic acid
3
(Ac7c)
exhibit a very high tendency to fold into
b-turns and 310-helices.1d A conformational preference
for b-turns and 310-helical structures, in the crystal state
as well as in solution, was also demonstrated for a large
Figure 1. Chemical structures of the axially chiral (R)-Bin and (S)-Bin residues, compared to those of Ac7c, Dbzg and Bip.
* Corresponding author. Fax: (+39)-049-827-5239; e-mail: claudio.toniolo@unipd.it
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00285-4

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J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
However, in contrast with the Bip residue, which is
conformationally labile with non-isolable (R) and (S)
interconverting enantiomers resulting from rotation
along the 1-1% bond of the biphenyl moiety (the rota-
tional energy barrier is about 14 kcal mol−1),4b,5b the
Bin residue can be isolated in an enantiomerically pure
state and has a very high enantiomeric stability,4b,6 as
expected.7g A variety of similar 2,2%-disubstituted 1,1%-
binaphthyl systems with highly stable, chiral, C2-sym-
metric configurations have been extensively exploited as
chiral auxiliaries in enantioselective organic synthesis,
in the preparation of chiral hosts for molecular recogni-
tion studies, and in the construction of new materials.7
In this connection our targeted [(S)-Bin]n homo-pep-
tides present several interesting properties: (i) access to
a new class of 1,1%-binaphthyl oligomers as potential
chiral catalysts7g and photoactive fluorophores,8 (ii) syn-
thetic challenge concerning the coupling of highly hin-
dered Bin residues, (iii) conformational study of unique
peptide homo-oligomers with only axial chirality, more
specifically determination of their preferred secondary
structure and its comparison with that of the conforma-
tionally labile [Bip]n series previously investigated,5 and
(iv) analysis of the relationship between binaphthyl axial
chirality and peptide helix handedness.
Saponification of the methyl ester function of 2b, which
was expected to present some difficulties,9b failed in our
hands to afford the desired N-protected dipeptide Z-
[(S)-Bin]2-OH 2c. No reaction occurred using aqueous
1N NaOH in MeOH at 60°C for 8 h, while either under
similar experimental conditions with dioxane and tolu-
ene added for complete solubilisation, or when using
tetrabutylammonium hydroxide as
a
base,12 only
unidentified decomposition products were obtained.
Therefore, we turned to an alternative strategy of cou-
plings from the C-terminus, starting with N-deprotec-
tion of 2b by hydrogenolysis, which gave
H-[(S)-Bin]2-OMe 2a in 96% yield (Fig. 3).
However, when coupling of 1c with 2a by the CIP/
HOAt method, successfully employed for the coupling
of 1c with 1a (vide supra), was attempted, only recov-
2. Results
2.1. Synthesis
Our initial strategy was to apply the same synthetic
methodology previously employed with success for the
synthesis of the Z-[Bip]n-OtBu (Z, benzyloxycarbonyl;
OtBu, tert-butoxy) series,5b i.e. the use of the pivaloyl
mixed anhydride coupling method for the homo-dipep-
tide [(S)-Bin]2 and then successive C-deprotections and
couplings from the N-terminus involving carboxyl
group activation through the 5(4H)-oxazolone interme-
diates.9 Therefore, our starting material, the amino
ester H-(S)-Bin-OMe (OMe, methoxy) 1a (Fig. 2), pre-
viously obtained in an enantiomerically pure state by
resolution,6a was first treated with N-(benzyloxycar-
bonyloxy) succinimide (Z-OSu) in acetonitrile at room
temperature to give Z-(S)-Bin-OMe 1b (87%). Saponifi-
cation of the ester function of 1b with a large excess of
aqueous 1N NaOH in MeOH, conducted for 24 h at ca
75°C, a relatively high temperature usually required for
basic hydrolysis of Ca,a-disubstituted amino esters,4b,10
afforded the N-protected amino acid Z-(S)-Bin-OH
1c4b in high yield (91%).
Activation of 1c as its pivaloyl (Piv) mixed anhydride
Z-(S)-Bin-OPiv (not isolated), followed by reaction
with H-(S)-Bin-OMe 1a in toluene at 60°C for 18 h,5b,9
led to the dipeptide Z-[(S)-Bin]2-OMe 2b in 59% yield
(Fig. 3). Interestingly, the yield could be raised to 84%
under even simpler experimental conditions, by apply-
ing the CIP (2-chloro-1,3-dimethylimidazolidinium
Figure 2. Synthesis of the activated and/or protected (S)-Bin
residues used as building blocks, from H-(S)-Bin-OMe 1a. (i)
Z-OSu; CH3CN; rt; 48 h; (ii) Boc2O; CH3CN; rt; 3 days; (iii)
aq. 1N NaOH; MeOH; 75°C; 24 h; (iv) TFA/CH2Cl2 1:1; rt;
4 h; (v) Fmoc-OSu; DIEA; CH3CN/CH2Cl2; 60°C; 10 h; (vi)
cyanuric fluoride; pyridine; CH2Cl2; −15°C (1 h) to rt; 3 h.
hexafluorophosphate)/HOAt
(7-aza-1-hydroxy-1,2,3-
benzotriazole) coupling procedure.11

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
1881
CH2Cl2 by cyanuric fluoride13–15 at −15°C to room
temperature, gave Fmoc-(S)-Bin-F 1g in 58% yield.
Because of its low stability, the acid fluoride 1g was
purified only on one occasion by chromatography and
1
then characterised by H NMR. In the next coupling
steps it was always freshly prepared in large excess
relative to the amino component, identified by TLC
and the crude solution used directly. Thus, coupling of
crude 1g (ca 2 equiv.) with the dipeptide 2a gave
Fmoc-[(S)-Bin]3-OMe 3h in 51% yield (Fig. 4). N-
Deprotection of the Fmoc group with a 10% solution
(vol/vol) of diethylamine (Et2NH) in CH3CN at room
temperature for a few hours led to H-[(S)-Bin]3-OMe
3a in 73% yield. In the same manner, acylation of 3a by
crude 1g (ca 3 equiv.) gave Fmoc-[(S)-Bin]4-OMe 4h in
66% yield. However, for unclear reasons, when H-[(S)-
Bin]4-OMe 4a, obtained in 87% yield after cleavage of
Figure 3. Synthesis of the protected [(S)-Bin]2 dipeptides. (i)
(1) TEA; Piv-Cl; toluene; −10°C to rt; 3h, (2) 1a; toluene;
60°C; 18 h, (ii) CIP; HOAt; DIEA; CH2Cl2; rt; 3 days, (iii)
aq. 1N NaOH; MeOH; 60°C; 8 h, (iv) aq. 2N NaOH; MeOH;
toluene; dioxane; 70°C; 8 h, (v) nBu4N+OH−; THF; rt; 4 days,
(vi) H2/Pd-C; MeOH; rt; 5 h.
ered 2a (40%) and several unidentified compounds
could be isolated, but no desired tripeptide Z-[(S)-Bin]3-
OMe. Finally, according to the well demonstrated
efficiency of the amino acid fluoride activation for the
coupling of hindered a-amino acids,13 particularly those
involving consecutive Ca,a-disubstituted glycines,14,15 we
considered the use of Fmoc-(S)-Bin-F (Fmoc, fluoren-
9-ylmethyloxycarbonyl) 1g (Fig. 2).16 This compound
was readily synthesised from resolved H-(S)-Bin-OMe
1a, which was first N-protected by means of Boc2O
(Boc, tert-butyloxycarbonyl) in CH3CN at room tem-
perature, to give Boc-(S)-Bin-OMe 1d (86%).17 The
ester function of 1d was saponified as above for 1b (Fig.
2), to afford Boc-(S)-Bin-OH 1e4b in 94% yield. The
Boc group of 1e was then cleaved by trifluoroacetic acid
(TFA) in CH2Cl2 and the resulting crude H-(S)-Bin-
OH·TFA was N-acylated with Fmoc-OSu in the pres-
ence of a large excess of DIEA (N,N-diisopro-
pylethylamine), in CH3CN and CH2Cl2 at 60°C for
several hours, to afford Fmoc-(S)-Bin-OH 1f in 74%
yield. Treatment of a solution of 1f and pyridine in
Figure 4. Synthesis of the protected homo-peptides Fmoc-
[(S)-Bin]n-OMe and H-[(S)-Bin]n-OMe (n=3–5). (i) NMM;
CH2Cl2; rt; 10–14 days, (ii) 10% Et2NH in CH3CN; rt.

1882
J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
the Fmoc protecting group of 4h, was reacted with
crude 1g (ca 3 equiv.), the desired pentapeptide Fmoc-
[(S)-Bin]5-OMe 5h was isolated in only 18% yield. The
deprotected amino ester H-[(S)-Bin]5-OMe 5a was
obtained from 5h in 38% yield, but chain elongation
could not be pursued because of the lack of a sufficient
amount of pentamer.
In Figure 6 the electronic CD spectra of the terminally
protected (S)-Bin lowest homo-oligomers are reported.
As already shown with simple Bin model peptides,6b the
Cotton effects are extremely intense and dominated by
the contribution of the split 1Bb band (p“p* transition)
of the binaphthyl chromophore.18 For this transition a
positive band at longer wavelength ($232 nm) and a
negative band at shorter wavelength ($218 nm) are
typical of a binaphthyl moiety of (S) absolute configu-
ration. No information can be extracted on the peptide
secondary structure preference nor on the most popu-
lated screw sense of the putative turn/helix conforma-
tion. The spectra of the longest oligomers (n=4 and 5)
are not shown in Figure 6 in view of the limited
solubility of these two peptides in MeOH. In any case,
qualitatively, their CD patterns closely resemble those
of the lowest oligomers. Removal of the Z or Fmoc
Na-protection does not change the overall shape of the
CD curves [in the 1:9 (v/v) CHCl3/TFE mixture, for
solubility reasons; spectra not shown].
For the longest, Na-protected (Fmoc) or unprotected
peptides Fmoc(or H)-[(S)-Bin]n-OMe (n=3–5), all
1
homogeneous by TLC, H NMR was not informative
for structural identification. However, the expected
chemical structures were clearly confirmed by ES+ MS
of the Fmoc derivatives, with a single peak of correct
m/z (M+H)+ seen in each spectrum (Fig. 5).
Figure 6. CD spectra in the 200–250 nm region of Z-(S)-Bin-
OMe (Z1), Z-[(S)-Bin]2-OMe (Z2), and Fmoc-[(S)-Bin]3-OMe
(F3) in MeOH solution. Peptide concentration: 1.0 mM.
The FT-IR absorption spectra of the Na-deprotected
di- (n=2), tri- (n=3), and tetrapeptide (n=4) esters in
the 98:2 (v/v) CDCl3/TFE-OD solvent mixture over the
spectral region 1780–1840 cm−1 are shown in Figure 7.
The band at 1737–1739 cm−1 is assigned to the w(CꢀO)
vibration of the C-terminal protecting ester group. The
amide I (CꢀO stretch) bands lie between 1700 and 1640
cm−1 with maxima at 1675, 1678, and 1669 cm−1 for
n=2, 3, and 4, respectively. Contrary to what one
expects for a uniform helical (or any repeating) peptide
structure, the amide I absorption band for this series
broadens with increasing peptide chain length and,
most importantly, three distinct components are
observed for the tetramer. Such a pattern indicates a
dominant contribution from non-uniform secondary
structures.19
Figure 5. Mass spectra (ES+) of the homo-peptides Fmoc-
[(S)-Bin]n-OMe (n=3–5).
2.2. Solution conformational analysis
The conformational preferences of the (S)-Bin homo-
peptides were evaluated in structure supporting solvents
(MeOH, CHCl3 and CHCl3/TFE mixtures) (TFE is
2,2,2-trifluoroethanol) by electronic CD, FT-IR absorp-
tion, and VCD techniques.
To get another point of view from the IR absorption
results, the spectra in the N–H stretching (amide A)
region are shown in Figure 8 for the N- and C-pro-
tected peptide series in CDCl3 solution. The spectra of

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
1883
the highest oligomers are characterised by main bands
at 3440–3428 cm−1 (free, solvated N–H groups) and at
3360–3348 cm−1 (H-bonded N–H groups).20 The inten-
sity of the low-frequency band relative to the high-fre-
quency band increases as the peptide main chain is
elongated. This effect is quite remarkable on going
from the dimer to the trimer. We were also able to
demonstrate that, even at 10 mM concentration, only
quite limited changes take place in the spectra of the
various oligomers. Therefore, the band at 3360–3348
cm−1 should be interpreted as arising almost exclu-
sively from intramolecular CꢀO···HꢁN interactions.
This study provided convincing evidence that main-
chain length dependent intramolecular H-bonding is a
factor of paramount importance influencing the con-
formation of (S)-Bin peptides in CDCl3 solution. The
dramatic enhancement in the intensity of the band of
H-bonded N–H groups from dimer to trimer is a
strong indication of the onset of a significant popula-
tion of b-turns in the conformational equilibrium mix-
ture of the latter peptide. It is reasonable to assume
that this propensity will propagate into a 310-helix1d
for the longer oligomers, characterised by a steady
increase in the intensity of the same band. However,
the occurrence of other bands in the tetramer and
pentamer points to the co-existence of other confor-
mations in these peptides. More specifically, we
observe concentration-independent shoulders at 3387–
3388 cm−1, present in both compounds but more evi-
dent in the tetramer and usually assigned to the
fully-extended (C5) conformation,1k,1l,19 and at about
3320 cm−1 in the pentamer, probably related to a
different type of folded conformation.
Figure 7. FT-IR absorption spectra (1780–1480 cm−1) in the
98:2 (v/v) CDCl3/TFE-OD solvent mixture of the H-[(S)-
Bin]n-OMe homo-peptides: n=2 (dotted line), n=3 (dashed
line), n=4 (full line). Peptide concentration: 18 mg mL−1
.
The side-chain contributions to the spectra are evident
in the strong IR absorption band at 1510 cm−1 (Fig. 7)
consisting mainly of w(CꢀC) stretching and l(CꢁH)
bending modes of the aromatic rings, which are over-
lapped by the broad amide II band to higher fre-
quency. Other binaphthyl w(CꢀC) vibrations are seen
at 1620 and 1595 cm−1. These assignments are confi-
rmed by a comparison of the H-[(S)-Bin]4-OMe exper-
imental IR absorption and VCD spectra [again in the
98:2 (v/v) CDCl3/TFE-OD solvent mixture] to the cal-
culated spectra for just the binaphthyl side chains
(Fig. 9). The VCD sign patterns and frequencies agree
very well for these binaphthyl centred modes [espe-
cially taking into account the typical deviation to
higher values for density functional theory (DFT)
force fields (FFs)]. The VCD spectra of the n=2 and 3
peptides (data not shown) reveal almost the same
shape, positions, and intensities for VCD bands in the
region of 1620–1400 cm−1 as are shown for n=4 in
Figure 9. The negative signs of the 1501 and 1465
cm−1 VCD bands are common to all these cases and
agree well with those of the calculated spectra. Finally,
we note that the amide I VCD is a positive couplet
(centred at about 1670 cm−1), a sign pattern normally
associated with a right handed helical conformation
(see Fig. 9).21
Figure 8. FT-IR absorption spectra (3550–3200 cm−1 region)
in CDCl3 solution of Z-(S)-Bin-OMe (Z1), Z-[(S)-Bin]2-OMe
(Z2), Fmoc-[(S)-Bin]3-OMe (F3), Fmoc-[(S)-Bin]4-OMe (F4),
and Fmoc-[(S)-Bin]5-OMe (F5). Peptide concentration: 1.0
mM.
2.3. Computational modelling
The fully optimised structure of the binaphthyl side
chain was obtained as a single geometry minimum due
to the bridge between the 1,1%-positions. IR absorption
and VCD spectra computed for this side chain with or
without methyl groups on the bridge 6-carbon atom
were nearly identical (aside from specific -CH3 modes)
and agree well with observed spectra which do not
change much among the oligopeptides studied in the
1620–1400 cm−1 region, suggesting that there is not
strong intramolecular stacking interaction between
binaphthyl aromatic side chains (Fig. 9). Lack of
interactions justifies our calculating molecular property
tensors for peptide backbone and aromatic side chains
separately and suggests that transfer of the Cartesian
FF, APT (atomic polar tensor) and AAT (atomic axial
tensor) values from these segments onto the final tetra-
peptide geometry will be satisfactorily accurate.

1884
J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
These findings are close to the calculation error (as
judged by the variation between methods), so it is not
possible to reliably predict a single conformation that is
most favourable from the MM results alone. However,
some conformations were consistently low in all the
MM calculations, and those were the focus of our
follow-up spectral simulations.
Some binaphthyl stacking interactions were also
observed, this being most apparent for distorted strand
structures started from the b-sheet. This unique struc-
ture had also the lowest energy among all conforma-
tions, but was so ‘encased’ in interacting side chains,
that only single-stranded species would be possible,
thus effectively preventing H-bond formation between
strands, but allowing two H-bonded 7-membered rings
to form within the strand. Other promising low-energy
geometries were the right-handed 31-helix, and left- and
right-handed, distorted 310-helices. These conforma-
Table 1. MM minimised energies for H-[(S)-Bin]4-OMe
using the Cerius2 and InsightII programs
Starting
Force fieldb
conformationa
Cerius2
InsightII
CFF91 CVFF
CFF91
CVFF300
Figure 9. Experimental (full lines) VCD (upper frame) and
FT-IR absorption (lower frame) spectra (1780–1400 cm−1) in
the 98:2 (v/v) CDCl3/TFE-OD solvent mixture of H-[(S)-
Bin]4-OMe (peptide concentration: 18 mg mL−1) and calcu-
lated spectra (dashed lines) of the simplified model compound
2%,1%:1,2:1%%,2%%:3,4-dinaphthcyclohepta-1,3-diene.
a-Helix [right
handed (RH)]
a-Helix [left
handed (LH)]
Poly (Pro)n II
(RH)
5
7
19
1
15
9
26
16
12
17
−1
2
4
6
Poly (Pro)n II
(LH)
4
7
To find possible low-energy conformations of the H-
[(S)-Bin]4-OMe molecule, a series of molecular mechan-
ics (MM) energy minimisation calculations were started
from various regular geometries, including a-, 31 [poly
(Pro)n II] and p-helices for both left- and right-handed
forms. The final conformational features are mainly
determined by the relatively large side chains, which,
due to steric interference, prevent formation of some
regular structures, such as regular 310-helix and b-sheet
structures. To address this problem, some starting
structures were based on distorted conformations,
including b-sheet structures and 310-helices with ends
distorted so that the side chains do not collide. Finally,
simulations for H-[(S)-Bin]4-OMe, started as b-turns of
type I, II, I% and II%, were allowed to minimise the
energy by geometry optimisation. MM simulations
were performed in both CFF91 and CVFF force fields
(they were carried out using both the Cerius2 and
InsightII programs). Due to small differences in the
convergence algorithms and the implementation of the
parametre sets, most of these conformations converged
to slightly different minima with each method. All the
minimised conformations differed from the starting
geometries, the final states tending to have irregular
structures and often developing distorted ends, with
relative energies that lie within a range of 10 kcal mol−1
for CFF91 and 18 kcal mol−1 for CVFF (Table 1).
p-Helix (RH)
p-Helix (LH)
b-Turn I22
5
2
9
8
3
7
14
11
11
9
1
10
15
10
14
12
12
12
26
18
23
19
21
23
b-Turn I%
b-Turn II
b-Turn II%
Modified structures
b-Sheet: „1=−29,
ƒ4=−157
b-Sheet: „1=151,
ƒ4=−157
b-Sheet: „1=−29,
ƒ4=23
b-Sheet: „1=151,
ƒ4=23
6
2
3
1
1
8
0
2
6
12
5
7
11
0
17
23
0
15
16
4
4
22
21
16
14
12
310-Helix 1 RH:
10
9
„1=−116
310-Helix 1 LH:
„1=60
310-Helix 2 RH:
„1=30
0
8
3
10-Helix 2 LH:
9
5
„1=−90
a Although all MM calculations in a given row were started with the
same geometries, the final structures with different FF were not
always the same (thus, comparison can be difficult). Therefore, the
list primarily serves to identify low-energy conformations.
b Relative molecular energies in [kcal mol−1].

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
1885
Figure 10. Comparison of experimental (left) and calculated (right) VCD (top) and IR absorption (bottom) spectra (1780–1400
cm−1) of H-[(S)-Bin]4-OMe. Experimental spectra were measured in CDCl3 solution at a peptide concentration of 18 mg mL−1
.
Table 2. Backbone torsion angles for H-[(S)-Bin]4-OMe in
tions were sources for the ƒ, „ torsion angles used to
constrain the DFT calculation of the backbone of the
model tetrapeptide H-(Aib)4-OMe, while all other inter-
nal coordinates (including the ꢀ torsion angles) were
relaxed. Then, the geometry of H-[(S)-Bin]4-OMe for
simulations was obtained by overlapping the H-(Aib)4-
OMe backbone and the side-chain binaphthyls, both
optimised on the same DFT level, and eliminating the
redundant atoms. Cartesian force field and intensity
tensors of backbone and side chains were then trans-
ferred to the final geometry.
a distorted right-handed 310-helixa
Residue
ƒ (°)b
„ (°)b
ꢀ (°)c
(S)-Bin1
(S)-Bin2
(S)-Bin3
(S)-Bin4
14.9
−35.0
−13.6
−82.6
−160.8 (−167.1)
−171.8 (−180.0)
−173.4 (175.5)
177.9 (178.3)
−57.7
−64.5
−1.3
a Structure obtained from MM with the CFF force field.
b
ƒ and „ torsion angles were fixed.
c ꢀ values in parentheses are ab initio optimised for the H-(Aib)4-
OMe peptide backbone.
The best agreement with experiment is found for one of
the consistently low-energy structures, the right-handed
310-helix, whose choice is justified below. Figure 10
shows a comparison of the experimental IR absorption
and VCD spectra of H-[(S)-Bin]4-OMe in CDCl3 with
the results of the simulated spectra in a distorted,
right-handed 310-helical structure. The shape and the
band assignment of the IR absorption spectrum are
similar to those presented in Figure 9. There is a clear
positive couplet for the amide I VCD and a large
negative VCD correlated to the amide II. This latter is
discriminated from the binaphthyl modes by both the
calculated results and the lower VCD intensity seen
experimentally for the amide II mode when the
molecule is partially deuterated (as also seen in Figure
9). Table 2 lists the MM energy-optimised ƒ, „, and ꢀ
torsion angles for this most promising 310-helical
conformation.
3. Discussion
We have successfully synthesised by solution methods a
novel series of [(S)-Bin]n homo-peptides to the pen-
tamer level by use of acid fluoride C-activation, the
only efficient methodology in our hands for the 1+2,
1+3 and 1+4 couplings of these extremely sterically
hindered peptide bonds. Indeed, the CIP/HOAt proce-
dure, which gave the highest yield in the 1+1 coupling,
failed in peptide bond formation with amino compo-
nents longer than the amino acid derivative.
Peptide structure is most often studied with NMR and
X-ray diffraction techniques for atomic resolution and
with electronic CD in the UV region or IR absorption
for average conformational determination. For the
binaphthyl substituted peptides investigated in this

1886
J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
work, these classical techniques become impossible or
very difficult as series of large Bin side chains inhibit
crystallisation and limit solubility. Due to their homo-
oligopeptide nature, NMR resolution would also be
compromised. The p–p* transitions of the binaphthyls
and their intrinsic chirality have prevented any use of the
electronic CD technique to determine the peptide sec-
ondary structure. Finally, normal IR absorption frequen-
cies will not be very useful with both Ca,a-disubstituted
peptides and aromatic side chains, in addition to the high
probability of their being in distorted structures.21a,23
However, MM calculations can address any of these
compounds and with DFT techniques we can simulate
their vibrational spectra. IR absorption and VCD spectra
of the amide I and II bands do have the ability to focus
on the peptide backbone and to sense regularity in the
structure and the handedness of any helical form that is
developed.
II is nonetheless still quite intense (Fig. 10), which would
be consistent with the peptide forming a more tightly
wound (increased number of H-bonds) structure like a
310-helix.19,21a,b,24a In this respect we further note that the
a-helix energies were consistently calculated to be quite
high in our MM optimisations (Table 1).
As stated above, the experimental VCD spectra of
H-[(S)-Bin]4-OMe are consistent: there is a positive
couplet dominating the amide I and a negative broad
amide II (at 1524 cm−1), when measured in CDCl3 or
CDCl3/TFE (data not shown), the latter being compara-
ble in intensity to the negative component of the amide
I. In CDCl3/TFE the amide I positive couplet has the
same shape and it is shifted for about 4 cm−1 to higher
wavenumbers in comparison to the couplet of H-[(S)-
Bin]4-OMe in CDCl3/TFE-OD with a minimum at 1691
cm−1 and a maximum at 1664 cm−1. The intensity of the
amide II band is significantly higher in CDCl3 and
CDCl3/TFE than in CDCl3/TFE-OD, reflecting the
effects of N-deuteration in the latter sample (Fig. 9). In
addition, the spectra of the tetrapeptide at a five times
lower concentration (i.e. 3.6 mg mL−1) are perfectly
consistent in terms of shape, band positions, and even
intensity to those plotted in Figure 10, indicating that no
aggregation effects are operative. When the experimental
spectra are compared (Fig. 10) to our simulated results,
the agreement is particularly gratifying. While detailed
intensities vary, the overall sign pattern and relative
intensities are reproduced well for both the amides I and
II as well as the major binaphthyl-based bands. Some
level of disagreement between experiment and theory is
expected for a distorted structure, since one is unlikely
to predict its spectra correctly and the tetrapeptide is
likely to sample many local conformations around the
distorted segment. The results in Figure 10 fall well
within the variation of the method itself. Since they were
also consistently predicted to have relatively low MM
energies, we also calculated the IR absorption and VCD
spectra for a distorted left-handed 310-helix, a b-sheet
structure with stacked side chains and a right-handed
poly(Pro)n-type helix backbone. None of these secondary
structures gave simulated spectra in qualitative agree-
ment with the experiments, leaving the distorted, right-
handed 310-helix (Fig. 11) as yielding the optimal
simulated spectra.
Several observations come to bear on our attempt to use
optical spectra (IR absorption and VCD) to determine
the solution conformation of the tetrapeptide H-[(S)-
Bin]4-OMe and the consequent effort to discriminate
among the large number of possible computed structures.
The amide A absorption spectra of the Na-protected
oligomers, showing the band at $3350 cm−1 to increase
in relative intensity with peptide main-chain length,
indicates occurrence of intramolecularly H-bonded
amide N–H groups. The multiple component amide I
absorption band for the n=4 oligomer suggests develop-
ment of a distorted structure. Finally, the sign pattern of
its amide I VCD favours a right-handed helical structure.
Among our calculated most stable structures, the first
observation discourages consideration of the b-sheet and
31-helix structures, which at best (in the b-sheet) would
have weak H-bonds (interaction between NꢁH and CꢀO
groups of the same residue in the sequence). The second
observation eliminates regular a- or p-helices and favours
either distorted helices or turn structures. Finally, the last
observation favours a right-handed turn or helix. This
logic and the shape of the VCD spectrum led us to
explore the spectra for the distorted 310-helix, which was
one of the low-energy structures in all our MM calcula-
tions. Considering all these approximations, its spectra
prove to be an excellent match to what we observe
experimentally (Fig. 10) as discussed below.
The most conformationally sensitive part of the IR
absorption or VCD spectra of peptides is the amide I
region, where side-chain vibrations do not appear (Fig.
9) and inter-residue coupling dominates the spectral
character (IR absorption frequency and VCD sign pat-
tern). The positive couplet (positive to low frequency)
amide I VCD spectrum of H-[(S)-Bin]4-OMe in CDCl3
(Fig. 10) reflects published amide I results for right-
handed 310- or a-helical structures.19,21,23b,c,24 The nega-
tive amide II VCD signal at 1524 cm−1 is overlapped by
two narrow, oppositely signed (couplet) VCD negative
bands to lower frequency (seen best in Fig. 9, due to
partial N–D deuteration weakening of the amide II
band). The relative amide I and amide II intensities,
which are useful for discrimination between 310-helix and
a-helix, are complicated by this overlap, but the amide
It is worth pointing out that our present conclusion on
the conformation preferentially adopted by the Bin-rich
peptides (distorted b-turn/310-helix) is not surprising in
view of the Ca-tetrasubstituted nature of this a-amino
acid.1 Indeed, it was already proposed on the basis of an
investigation of simpler model peptides containing one
or two such residues.6b,8
4. Experimental
4.1. General experimental
Melting points were determined by means of a capillary
tube immersed in an oil bath (Tottoli apparatus, Bu¨chi)
with a final temperature raise of 3°C min−1, and are

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
1887
MeOH–90% CH2Cl2 (V); 2.5% EtOAc (ethyl acetate)–
97.5% CH2Cl2 (VI); 5% EtOAc–95% CH2Cl2 (VII); 20%
EtOAc–80% CH2Cl2 (VIII). UV light (u=254 nm)
allowed visualisation of the spots after TLC runs for all
compounds, even at low concentration.
4.2. (S)-Methyl 2%,1%:1,2;1%%,2%%:3,4-dinaphthcyclohepta-
1,3-diene-6-benzyloxycarbonylamino-6-carboxylate,
Z-(S)-Bin-OMe 1b
To a mixture of resolved H-[(S)-Bin]-OMe 1a (0.280 g;
0.76 mmol), containing traces of H-[(S)-Bin]-O-(CH2)2-
O-(CH2)2-OH,6a and Z-OSu (0.209 g; 0.84 mmol), was
added CH3CN (10 mL). The resulting clear colourless
solution was stirred at room temperature for 48 h and
evaporated to dryness in vacuo. The residue was chro-
matographed on a 2.3×60 cm column of silica gel with
eluents (I), then (II), to give 0.335 g (87%) of analyti-
1
cally pure 1b as a white, solid foam. Rf=0.50 (II). H
NMR (CDCl3): l 7.96 [m, 4H, ArH], 7.54–7.36 [m,
11H, ArH], 7.28 [m, 2H, ArH], 5.26 [s, 1H, NH],
5.24–5.16 [d-d (broad), Jꢀ12.3–12.1, 1H-1H, CH2 Z],
3.77 [s (broad), 3H, OMe], 3.35–2.46 [d-d, J=13.2–
13.2, 1H-1H, ArCH2b], 3.25–3.15 [d (broad)-d, Jꢀ
14.0–14.1, 1H-1H, ArCH2b%]. 13C NMR (CDCl3): l
172.8 (CꢀO Bin), 155.0 (CꢀO Z), 136.1, 134.2, 134.1,
134.0, 133.6, 133.0, 132.8, 131.6, 131.5, 128.4, 128.2,
128.1, 128.05, 127.98, 127.92, 127.70, 126.96, 125.8,
125.7, 125.2 (CAr), 69.6 (Ca), 66.7 (CH2 Z), 52.4
25
25
25
(OCH3), 41.7 (Cb), 38.2 (Cb%). [h] +8; [h] +8; [h]
589
578
546
25
436
25
365
+4; [h] −66; [h] −715 (c 0.2; MeOH). Anal. calcd
for C33H27NO4·0.5H2O (510.562): C, 77.63; H, 5.53; N,
2.74. Found: C, 77.85; H, 5.61; N, 2.54%.
4.3. (S)-2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-
diene-6-benzyloxycarbonylamino-6-carboxylic acid,
Z-(S)-Bin-OH 1c
To a clear solution of 1b (0.242 g; 0.48 mmol) in MeOH
(100 mL) was added aqueous 1N NaOH (50 mL). The
resulting white suspension was stirred at 75°C, which
gradually led to solubilisation of the precipitate. The
obtained clear colourless solution was stirred for 24 h.
Methanol was evaporated under reduced pressure with
portions of water added. The resulting solution was
ice-cooled and acidified by addition of a large excess of
aq. 1N HCl. The resulting fine precipitate was filtered
on a Bu¨chner funnel, washed with water and air dried.
The collected white solid was dried in vacuo at 80°C for
Figure 11. (Top) side view of the MM energy optimised,
distorted, right-handed 310-helical conformation of H-[(S)-
Bin]4-OMe that shows the peptide main chain through the
middle of the binaphthyl side chains. (Bottom) end view
emphasising the triangular shape of the ternary 310-helix
continuing to the distorted C-terminus (ester group) and the
steric interference of the binaphthyl groups.
uncorrected. 1H NMR and 13C NMR spectra were
recorded at 300 MHz and 77 MHz, respectively, the
solvent CDCl3 being used as internal standard (l=7.27
2 h to afford 0.214 g (91%) of pure 1c, identical to an
25
589
authentic sample.4b Mp=150–180°C (indefinite). [h]
25
578
25
546
25
25
+22, [h] +22, [h] +22, [h] −40, [h] −696 (c 0.5;
436
25
365
25
25
546
MeOH). {Lit.4b Mp 167°C. [h] +15, [h] +15, [h]
1
ppm for H and 77.00 ppm for 13C). Splitting patterns
589
578
25
436
25
365
+13, [h] −56, [h] −712 (c 0.5; MeOH)}.
are abbreviated as follows: (s) singlet, (d) doublet, (t)
triplet, (q) quartet, (m) multiplet. The optical rotations
were measured with an accuracy of 0.3%, in a 1 dm
thermostated cell. Analytical TLC and preparative
column chromatography were performed on Kieselgel
F 254 and Kieselgel 60 (0.040–0.063 mm) (Merck)
respectively, with the following eluent systems: CH2Cl2
(I); 1% MeOH–99% CH2Cl2 (II); 2.5% MeOH–97.5%
CH2Cl2 (III); 5% MeOH–95% CH2Cl2 (IV); 10%
4.4. (S)-Methyl 2%,1%:1,2;1%%,2%%:3,4-dinaphthcyclohepta-
1,3-diene-6-tert-butyloxycarbonylamino-6-carboxylate,
Boc-(S)-Bin-OMe 1d
To a mixture of Boc2O (0.654 g; 3.00 mmol) and
resolved H-(S)-Bin-OMe 1a (0.736 g; 2.00 mmol) con-
taining traces of H-(S)-Bin-O-(CH2)2-O-(CH2)2-OH,6a
was added CH3CN (30 mL). The resulting clear colour-

1888
J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
less solution was stirred at room temperature for 3 days
and evaporated to dryness in vacuo. The residue was
chromatographed on a 2.3×53 cm column of silica gel
with eluents (I), then (II), to give 0.807 g (86%) of
analytically pure 1d as a white, crystalline powder.
Mp=100–130°C (indefinite). Rf=0.40 (I). 1H NMR
(CDCl3): l 7.93 [m, 4H, ArH], 7.49 [m, 4H, ArH], 7.27
[m, 2H, ArH], 4.81 [s, 1H, NH], 3.76 [s, 3H, OMe],
3.35–2.41 [d-d, J=13.0–13.0, 1H-1H, ArCH2b], 3.16–
3.08 [d (broad)-d, Jꢀ13.8–13.6, 1H-1H, ArCH2b%], 1.48
[s, 9H, Boc]. 13C NMR (CDCl3): l 173.2 (CꢀO Bin),
154.5 (CꢀO Boc), 134.5, 134.2, 134.0, 133.1, 133.0,
131.73, 131.68, 128.4, 128.23, 128.20, 128.1, 128.01,
127.97, 127.1, 125.9, 125.7, 125.4, 125.3 (CAr), 80.3
(C-O Boc), 69.6 (Ca), 52.4 (OCH3), 42.0 (Cb), 38.7
residue taken up in CH2Cl2 (ca. 350 mL by portions)
and 0.5N HCl (ca. 100 mL by portions) with stirring.
The decanted CH2Cl2 solution was washed with more
0.5N HCl (100 mL), then water (2×100 mL), dried
(MgSO4), filtered and evaporated in vacuo. The residue
was chromatographed on a 2.3×32 cm column of silica
gel with eluents (IV), then (V), to afford 0.437 g (74%)
of pure 1f as a pale brown, amorphous solid. Mp=
160–210°C (indefinite). Rf=0.43 (V). 1H NMR
(CDCl3): l 7.96 [m, 1H, ArH], 7.85 [m, 1H, ArH], 7.72
[m, 4H, ArH], 7.46 [m, 4H, ArH], 7.36–7.12 [m, 10H,
ArH], 5.85 [s (broad), 1H, COOH], 4.94 [s (broad), 1H,
NH], 4.53–4.21 [m (broad)-m (broad), 1H-1H, CH2
Fmoc], 4.12 [m (broad), 1H, CH Fmoc], 3.21–2.19 [m
(broad)-m (broad), 1H-1H, ArCH2b], 3.07 [m (broad),
2H, ArCH2b%]. 13C NMR (CDCl3): l 176.9 (CꢀO Bin),
155.4 (CꢀO Fmoc), 143.7, 143.6, 141.3, 141.2, 134.5,
134.4, 134.1, 133.8, 133.0, 132.9, 131.7, 131.5, 128.2,
128.0, 127.6, 127.2, 127.0, 125.8, 125.6, 125.3, 125.2,
25
25
25
(Cb%), 28.2 (CH3 Boc). [h] +39; [h] +40; [h] +41;
589
578
546
25
436
25
[h]
+4; [h]
−562 (c 0.5; MeOH). Anal. calcd for
365
C30H29NO4·1.2H2O (489.159): C, 73.66; H, 6.47; N,
2.86. Found: C, 73.39; H, 5.99; N, 2.74%.
125.1, 124.9, 119.9 (CAr), 69.8 (Ca), 66.4 (CH2 Fmoc),
25
589
47.2 (CH Fmoc), 41.6 (Cb), 38.1 (Cb%). [h]
+101;
4.5. (S)-2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-
diene-6-tert-butyloxycarbonylamino-6-carboxylic acid,
Boc-(S)-Bin-OH 1e
25
578
25
546
25
436
[h]
+101; [h]
+113; [h]
+132 (c 0.2; CH2Cl2).
Anal. calcd for C39H29NO4·1.5H2O (602.654): C, 77.72;
H, 5.35; N 2.32. Found: C, 77.96; H, 5.28; N, 2.05%.
To a clear solution of 1d (0.673 g; 1.44 mmol) in MeOH
(100 mL) was added aqueous 1N NaOH (50 mL). The
resulting milky solution clarified upon stirring at 75°C.
After 24 h, the clear colourless solution was evaporated
under reduced pressure with portions of water added in
order to remove methanol. The obtained solution was
ice-cooled, acidified by addition of a large excess of aq.
1N HCl, and extracted with CH2Cl2 (250 mL in three
portions). The organic phase was washed with water
(2×100 mL), dried (MgSO4), filtered and evaporated.
The collected white solid was dried in vacuo at 80°C for
2 h to afford 0.614 g (94%) of pure 1e, identical to an
4.7. (S)-2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-
diene-6-(9-fluorenylmethyloxycarbonyl-amino)-6-carb-
oxylic acid fluoride, Fmoc-(S)-Bin-F 1g
To a solution of 1f (0.044 g; 0.076 mmol) in CH2Cl2 (2
mL) was added pyridine (0.013 mL; 0.15 mmol). The
solution was stirred under argon at ca. −15°C (ice-salt
bath) and cyanuric fluoride (0.065 mL; 0.77 mmol) was
added by syringe through a septum. The resulting
suspension was stirred from −15°C to −5°C during 1 h
and then at room temperature for 3 h. The mixture was
diluted with CH2Cl2 and the solution was extracted
twice with iced water, dried (MgSO4), filtered and evap-
orated in vacuo at 40°C. The resulting crude product
presented a main spot corresponding to 1g on TLC,
with traces of several other spots of unidentified com-
pounds. Flash chromatography on a 1.5×23 cm column
of silica gel with eluent (IV) led to 0.026 g (58%) of 1g
which was obtained as a white, amorphous solid after
precipitation from CH2Cl2/hexane, but still presented
several minor extra spots on TLC because of some
decomposition occurring on silica gel. Rf=0.75 (IV).
1H NMR (CDCl3): l 7.94 [m, 4H, ArH], 7.80 [m, 2H,
ArH], 7.62 [m, 2H, ArH], 7.51–7.26 [m, 12H, ArH],
4.93 [s (broad), 1H, NH], 4.76–4.48 [dd-m (broad),
J=5.9; 10.9-not seen, 1H-1H, CH2 Fmoc], 4.26 [dd
(t-like), Jꢀ5.9, 1H, CH Fmoc], 3.26–2.47 [d (broad)-d
(broad), Jꢀ12.8–12.8, 1H-1H, ArCH2b], 3.12 [m
(broad), 2H, ArCH2b%]. 19F NMR (CDCl3): l 18.53.
25
25
authentic sample.4b Mp=259–263°C. [h]
+45, [h]
589
578
25
546
25
436
25
+46, [h]
+48, [h]
+9, [h]
−639 (c 0.5; MeOH).
365
25 25
25
589
{Lit.4b Mp 264°C. [h]
+46, [h]
+47, [h]
+50°,
546
578
25
436
25
365
[h] +9, [h] −644 (c 0.5; MeOH)}.
4.6. (S)-2%,1%:1,2;1%%,2%%:3,4-Dinaphthcyclohepta-1,3-
diene-6-(9-fluorenylmethyloxycarbonyl-amino)-6-carb-
oxylic acid, Fmoc-(S)-Bin-OH 1f
To a solution of 1e (0.468 g; 1.10 mmol) in CH2Cl2 (10
mL) was added TFA (10 mL). The solution was stirred
at room temperature for 4 h and evaporated to dryness
in vacuo at 40°C. The residue was repeatedly dissolved
in CH2Cl2 and the solution evaporated in vacuo to
yield crude TFA.H-(S)-Bin-OH (not characterised)
which was directly used in the next step. This com-
pound was dissolved in CH3CN (25 mL) and DIEA
(0.550 mL; 3.16 mmol) was added. A heavy white
precipitate formed. Addition of CH2Cl2 (ca. 40 mL)
gave a milky solution to which Fmoc-OSu (0.100 g)
was added. The mixture was magnetically stirred at
60°C for 4 h, with more Fmoc-OSu (0.330 g) added in
portions every hour, then at room temperature for 3
days, then at 60°C again for 6 h, after addition of 0.024 g
more Fmoc-OSu (for a total of 0.454 g; 1.34 mmol).
The reaction mixture was evaporated in vacuo, and the
4.8. Z-[(S)-Bin]2-OMe 2b
4.8.1. By the pivaloyl mixed anhydride method. To a
solution of Z-(S)-Bin-OH 1c (0.083 g; 0.17 mmol) in
toluene (2 mL) was added TEA (0.030 mL; 0.21 mmol).
The solution was stirred under argon at ca. −10°C
(ice-salt bath) and pivaloyl chloride (0.021 mL; 0.17

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
1889
mmol) was added by syringe through a septum.
Theresulting suspension was stirred from ca. −10°C to
ca. +10°C for 1 h, and then at room temperature for 2
h. A solution of H-(S)-Bin-OMe 1a (0.069 g; 0.19
mmol) in toluene (1 mL) was then added, the mixture
was stirred in an oil bath at 60°C for 18 h, and
evaporated in vacuo. The residue was solubilised in
EtOAc (100 mL), and the solution was successively
extracted with 0.5N HCl (2×50 mL), water (100 mL),
5% aq. NaHCO3 (2×50 mL), water (2×100 mL), dried
(MgSO4), filtered and evaporated in vacuo. The residue
was chromatographed on a 2.3×30 cm column of silica
gel with eluent (VII) to afford 0.084 g (59%) of pure 2b.
could possibly be due to the insolubility of 2b in
MeOH/aq. 1N NaOH, the experiment was repeated
with a solution of 2b (0.021 g; 0.025 mmol) in MeOH
(10 mL), aq. 2N NaOH (1 mL), toluene (1 mL) and
dioxane (10 mL), which was stirred at 70°C for 8 h.
Extraction as above gave a crude product in which
several compounds were present, with no, or only traces
of, starting material 2b. Preparative TLC on silica gel
with eluent (V) gave fractions of 0.0043 g (Rf=0.70),
0.0012 g (Rf=0.54), 0.0016 g (Rf=0.37) and 0.0067 g
(Rf=0.03), of four unidentified compounds. In another
experiment, a clear colourless solution of 2b (0.013 g;
0.015 mmol) and aq. 40% tetrabutylammonium hydrox-
ide (0.030 mL; 0.045 mmol) in THF (1 mL), was stirred
at room temperature for 4 days, diluted with CH2Cl2
(75 mL), acidified with a large excess of 0.5N HCl (50
mL), extracted as above and chromatographed on a
1×23 cm column of silica gel with eluent (V) to give
0.0053 g of an unidentified compound. Rf=0.37 (V).
4.8.2. By the CIP/HOAt method. To a solution of 1c
(0.071 g; 0.14 mmol), 1a (0.054 g; 0.14 mmol), HOAt
(0.022 g; 0.16 mmol) and CIP (0.055 g; 0.20 mmol) in
CH2Cl2 (2.5 mL), was added DIEA (0.100 mL; 0.57
mmol). The mixture was magnetically stirred at room
temperature for 3 days. Addition of EtOAc (100 mL),
followed by extraction of the organic phase as above,
and then by preparative TLC of the crude product on
silica gel with eluent (VII) gave 0.103 g (84%) of pure
2b, obtained as a white, amorphous solid. Mp=186–
4.10. H-[(S)-Bin]2-OMe 2a
To a warm solution (heating was necessary for solubili-
sation) of 2b (0.145 g; 0.17 mmol) in MeOH (75 mL)
was added 10% palladium on charcoal (0.125 g) under
an argon stream. The mixture was hydrogenated in a
Parr apparatus at ca. 50 psi for 5 h at room tempera-
ture and filtered through paper. The solution was evap-
orated in vacuo at 40°C and the crude product was
dissolved in CH2Cl2 (100 mL). The solution was
washed with water (100 mL), dried (MgSO4), filtered
and evaporated in vacuo after addition of hexane to
afford 0.116 g (95%) of pure 2a, obtained as a white,
amorphous solid after precipitation from CH2Cl2/hex-
ane. Mp=185–230°C (indefinite). Rf=0.18 (VII). 1H
NMR (CDCl3): l 7.96–7.88 [m, 8H, ArH], 7.72 [s, 1H,
NH Bin2], 7.68–7.18 [m, 16H, ArH], 3.75 [s, 3H, OMe],
3.51–2.34 [d-d, J=13.4–13.2, 1H-1H, ArCH2b Bin],
3.33–2.46 [d-d, J=13.1–13.1, 1H-1H, ArCH2b Bin],
3.22–3.14 [d-d, J=13.8–14.2, 1H-1H, ArCH2b% Bin],
3.07–2.38 [d-d, J=13.2–13.2, 1H-1H, ArCH2b% Bin].
13C NMR (CDCl3): l 172.9, 172.4 (CꢀO Bin), 134.5,
134.4, 134.0, 133.8, 133.1, 133.0, 132.8, 131.8, 131.7,
1
188°C. Rf=0.54 (VII). H NMR (CDCl3): l 7.96–7.83
[m, 8H, ArH], 7.71 [d (broad), Jꢀ7.7, 1H, ArH], 7.61
[d (broad), Jꢀ7.4, 1H, ArH], 7.57 [d, J=8.2, 1H,
ArH], 7.48–7.32 [m, 13H, ArH], 7.29–7.20 [m, 5H,
ArH], 6.99 [s (broad), 1H, NH Bin2], 5.12–4.85 [d
(broad)-d, Jꢀ11.6–12.3, 1H-1H, CH2 Z], 3.76 [s, 3H,
OMe], 5.24–5.16 [d-d (broad), Jꢀ12.3–12.1, 1H-1H,
CH2 Z], 4.94 [s, 1H, NH Bin1 (Z)], 3.73 [s, 3H, OMe],
3.52–2.37 [d-d, J=12.8–13.0, 1H-1H, ArCH2b Bin],
3.52–2.44 [d-d (broad), Jꢀ12.8–13.0, 1H-1H, ArCH2b
Bin], 3.36–2.91 [d (broad)-d (broad), Jꢀ13.4–13.2, 1H-
1H, ArCH2b% Bin], 3.13 [s, 2H, ArCH2b% Bin]. 13C
NMR (CDCl3): l 172.9, 171.3 (CꢀO Bin), 155.2 (CꢀO
Z), 136.0, 134.7, 134.4, 134.1, 134.0, 133.8, 133.1, 133.0,
132.9, 131.8, 131.7, 131.6, 131.5, 128.8, 128.5, 128.4,
128.3, 128.2, 128.1, 127.9, 127.7, 127.3, 127.2, 127.1,
127.0, 125.9, 125.6, 125.34, 125.26, 125.21 (CAr), 70.4,
69.3 (Ca Bin), 66.9 (CH2 Z), 52.4 (OCH3), 41.9, 41.0
25
25
(Cb Bin), 39.1, 37.2 (Cb% Bin). [h]
+27; [h]
+26;
578
589
25
546
25
436
25
365
[h] +23; [h] −76; [h] −986 (c 0.1; MeOH). Anal.
calcd for C57H44N2O5·0.5 H2O (845.946): C, 80.92; H,
128.4, 127.3, 127.2, 125.9, 125.4 (CAr), 69.6, 69.2 (Ca
25
589
Bin), 52.7 (OCH3), 43.0, 41.6, 38.1 (Cb Cb% Bin). [h]
25
25
25
25
5.36; N, 3.31. Found: C, 81.14; H, 5.57; N 3.17%.
−19; [h] −22; [h] −33; [h] −203; [h] −1293 (c
578 546 436 365
0.1; MeOH). Anal. calcd for C49H38N2O3·0.5H2O
(711.818): C, 82.67; H, 5.52; N, 3.93. Found: C, 82.62;
H, 6.01; N, 3.61%.
4.9. Attempts at saponification of 2b
To a clear warm solution of 2b (0.226 g; 0.27 mmol) in
MeOH (100 mL) was added aqueous 1N NaOH (25
mL). The resulting white suspension was stirred at 60°C
for 8 h, but did not solubilise. The mixture was
decanted at room temperature and the absence of start-
ing material 2b in the supernatant was checked by TLC.
Methanol was partly evaporated in vacuo, the suspen-
sion was magnetically stirred, cooled by addition of
crushed ice, acidified by addition of a large excess of
aq. 1N HCl, and extracted with CH2Cl2 (ca. 200 mL in
three portions). The organic phase was washed with
water, dried (MgSO4), filtered and evaporated in vacuo,
to afford 0.214 g of a crude product consisting of
starting material 2b by TLC. As the absence of reaction
4.11. Attempt at coupling Boc-(S)-Bin-OH 1e with H-
[(S)-Bin]2-OMe 2a by the CIP/HOAt method
To a solution of 1e (0.046 g; 0.10 mmol), 2a (0.070 g;
0.10 mmol), HOAt (0.017 g; 0.12 mmol) and CIP (0.034
g; 0.12 mmol) in CH2Cl2 (3 mL), was added DIEA
(0.070 mL; 0.40 mmol). The mixture was magnetically
stirred at room temperature for 24 h, a TLC control
showing a main spot corresponding to the starting
material 2a. Acetonitrile (3 mL) was added and the
solution was stirred in an oil bath at 75°C (CH2Cl2
evaporated) for 8 h. Extraction as for the preparation
of 2b (vide supra), followed by preparative TLC of the

1890
J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
obtained crude product on silica gel with eluent (VII),
gave 0.028 g (40%) of recovered 2a and a mixture of
several minor unidentified compounds.
CH3CN and the solution was again evaporated in
vacuo at 40°C. The crude product was chro-
matographed on a 1.5×40 cm column of silica gel with
eluent (VII) (elution of dibenzofulvene and traces of
impurities of high Rf), then (VIII), to afford 0.103 g
(73%) of pure 3a, as a white, amorphous solid. Mp=
240–243°C. Rf=0.20 (VII); 0.80 (VIII). 1H NMR
(CDCl3): l 8.06–7.18 [m, 38H, 36 ArH and 2 NH
Bin2,3], 3.70 [s, 3H, OMe], 3.72 [d (partly masked), 1H],
3.67 [d (partly masked), 1H], 3.57 [d, J=13.3, 1H], 3.20
[d, Jꢀ12.8, 1H], 3.16 [d, Jꢀ12.8, 1H], 3.10–3.04 [d-d,
Jꢀ13.8–13.8, 1H-1H], 2.86 [d, J=13.6, 1H], 2.47 [d,
4.12. Fmoc-[(S)-Bin]3-OMe 3h
A solution of 1f (0.230 g; 0.40 mmol) and pyridine
(0.070 mL; 0.82 mmol) in CH2Cl2 (10 mL), was treated
with cyanuric fluoride (0.180 mL; 2.13 mmol) under
argon at ca. −15°C to −5°C (1 h) and then at room
temperature (2 h), under the same experimental condi-
tions and work-up as described earlier, to give Fmoc-
(S)-Bin-F 1g (vide supra). The extracted crude 1g was
not purified by flash chromatography, but directly
treated with a solution of H-[(S)-Bin]2-OMe 2a (0.140
g; 0.20 mmol) and NMM (N-methylmorpholine) (0.050
mL; 0.45 mmol) in CH2Cl2 (4 mL). The resulting clear
orange–brown solution was stirred at room tempera-
ture for 10 days, diluted with CH2Cl2 (150 mL), succes-
sively extracted with 0.5N HCl (2×50 mL), water (100
mL), 5% aq. NaHCO3 (2×50 mL), water (2×100 mL),
dried (MgSO4), filtered and evaporated in vacuo. The
crude product was chromatographed on a 2.3×50 cm
column of silica gel with eluent (VI) to afford 0.130 g
(51%) of pure 3h, as a white, amorphous solid. Mp=
226–230°C. Rf=0.27 (VI); 0.56 (VII). 1H NMR
(CDCl3): l 7.97–7.88 [m, 8H, ArH], 7.83–7.56 [m, 8H,
ArH], 7.61 [s, 1H, NH Bin], 7.32–7.09 [m, 27H, ArH],
6.76 [d, J=8.3, 1H, ArH], 6.62 [s, 1H, NH Bin], 4.56 [s,
1H, NH Bin1 (Fmoc)], 3.99–3.86 [dd-d, Jꢀ11.0; 5.2–
13.0, 1H-1H, CH2 Fmoc], 3.71 [dd (t-like), Jꢀ5.2, 1H,
CH Fmoc], 3.49 [s, 3H, OMe], 3.39 [d, Jꢀ13.4, 1H],
3.37 [d, Jꢀ12.7, 1H], 3.36 [d, Jꢀ12.1, 1H], 3.28 [d,
J=14.0, 1H], 3.18 [d (partly masked), 1H], 3.15 [s, 2H],
2.96 [d-d (t-like), Jꢀ12.5, 2H], 2.74 [d, J=13.1, 1H],
2.37 [d, J=13.2, 1H], 2.01 [d, J=12.9, 1H], [ArCH2bb%
Bin1,2,3]. 13C NMR (CDCl3): l 172.8, 171.7, 170.8 (CꢀO
Bin), 155.4 (CꢀO Fmoc), 143.4, 142.9, 141.4, 141.2,
135.5, 135.4, 134.7, 134.44, 134.42, 134.3, 134.1, 133.9,
133.5, 133.45, 133.38, 133.1, 133.0, 132.9, 132.8, 132.7,
131.80, 131.76, 131.71, 131.6, 131.5, 131.3, 129.5, 129.2,
128.6, 128.4, 128.35, 128.27, 128.18, 128.11, 128.06,
127.9, 127.8, 127.7, 127.6, 127.5, 127.3, 127.2, 126.9,
126.8, 126.7, 126.0, 125.8, 125.7, 125.5, 125.4, 125.34,
125.29, 125.22, 125.0, 124.5, 119.8 (CAr), 70.6, 70.3,
69.8 (Ca Bin), 65.4 (CH2 Fmoc), 52.3 (OCH3), 47.1
(CH Fmoc), 42.0, 41.8, 41.0, 39.6, 38.4, 37.3 (Cb Cb%
J=13.3, 1H], 2.38 [d, Jꢀ13.4, 1H], 2.34 [d, Jꢀ13.4,
25
589
1H], 2.17 [d, J=13.3, 1H], [ArCH2bb% Bin1,2,3]. [h]
25
578
25
546
25
436
25
365
−109; [h] −128; [h] −160; [h] −534; [h] −2430
(c 0.1; CH2Cl2). Anal. calcd for C73H55N3O4·H2O
(1056.210): C, 83.01; H, 5.44; N, 3.98. Found: C, 83.11;
H, 5.35; N, 3.84%.
4.14. Fmoc-[(S)-Bin]4-OMe 4h
A solution of 1f (0.111 g; 0.19 mmol) and pyridine
(0.035 mL; 0.41 mmol) in CH2Cl2 (5 mL), was treated
with cyanuric fluoride (0.100 mL; 1.18 mmol), under
the same experimental conditions and work-up as
described earlier, to give crude Fmoc-(S)-Bin-F 1g (vide
supra), which was directly treated with a solution of
H-[(S)-Bin]3-OMe 3a (0.067 g; 0.064 mmol) and NMM
(0.025 mL; 0.23 mmol) in CH2Cl2 (2 mL). The resulting
solution was stirred at room temperature for 12 days.
Work-up as in the preparation of 3h (vide supra),
followed by chromatography of the obtained crude
product on a 1.5×41 cm column of silica gel with eluent
(VI) afforded 0.068 g (66%) of pure 4h, as a white,
1
amorphous solid. Mp=260–262°C. Rf=0.65 (VII). H
NMR (CDCl3): l 8.28 [d, J=8.3, 1H], 8.09 [d, J=8.3,
1H], 8.05 [d, J=8.3, 1H], 7.96–7.76 [m, 15H], 7.68 [d,
J=7.4, 1H], 7.53 [m (t-like), J=7.2, 2H], 7.49–7.28 [m,
19H], 7.23–7.06 [m, 15H], 7.00–6.89 [m, 2H], 6.59 [m
(broad), 1H], [56 ArH and 2 NH Bin], 6.04 [s, 1H, NH
Bin], 4.86–5.51 [m (dd-like)-m (dd-like), 1H-1H, CH2
Fmoc], 4.39 [s, 1H, NH Bin1 (Fmoc)], 4.19 [m (t-like),
1H, CH Fmoc], 3.47 [s, 3H, OMe], 4.15 [d (partly
masked), 1H], 3.86 [d, J=13.4, 1H], 3.46 [d (partly
masked), 1H], 3.31–3.14 [m, 5H], 2.94 [d, J=13.1, 1H],
2.63 [d, J=13.2, 1H], 2.33 [d, J=13.6, 1H], 2.20 [m,
2H], 1.85 [m (broad), 1H], 1.82 [d, J=13.2, 1H], 1.45
[d, Jꢀ12.5, 1H], [ArCH2bb% Bin1,2,3,4]. 13C NMR
(CDCl3): l 173.2, 173.1, 171.8, 170.8 (CꢀO Bin), 155.3
(CꢀO Fmoc), 143.9, 143.3, 141.5, 141.4, 137.4, 135.9,
135.8, 135.1, 134.7, 134.6, 134.3, 134.2, 134.1, 134.0,
133.8, 133.2, 133.0, 132.95, 132.92, 132.83, 132.79,
132.6, 131.9, 131.84, 131.79, 131.75, 131.6, 131.5, 131.3,
130.8, 130.7, 130.5, 129.2, 128.7, 128.6, 128.4, 128.2,
128.1, 127.8, 127.76, 127.66, 127.60, 127.4, 127.3, 127.2,
127.1, 127.0, 126.9, 126.8, 126.7, 126.3, 126.0, 125.9,
125.7, 125.5, 125.1, 125.0, 124.7, 124.6, 120.0 (CAr),
70.5, 70.3, 69.8, 68.9 (Ca Bin), 65.3 (CH2 Fmoc), 52.1
(OCH3), 47.3 (CH Fmoc), 41.6, 41.4, 40.9, 40.6, 38.1,
25
25
25
25
Bin). [h] −123; [h] −132; [h] −159; [h] −422;
589
578
546
436
25
365
25
[h]
−1608 (c 0.1; MeOH; sparingly soluble). [h]
589
25 25 25 25
−45; [h] −57; [h] −76; [h] −292; [h] −1516 (c
578
546
436
365
0.1; CH2Cl2). ESI+ MS m/z: 1260.5 [M+H]+ (see Fig.
5). Anal. calcd for C88H65N3O6·1.5 H2O (1287.448): C,
82.09; H, 5.32; N, 3.26. Found: C, 82.13; H, 5.41; N,
3.32%.
4.13. H-[(S)-Bin]3-OMe 3a
A suspension of 3h (0.126 g; 0.10 mmol) in CH3CN (18
mL) was heated for a few minutes in order to obtain a
clear solution which was allowed to cool to room
temperature. Diethylamine (2 mL) was added, the
resulting solution was stirred for 5 h and then evapo-
rated to dryness in vacuo. The residue was dissolved in
25
25
25
36.6 (Cb Cb% Bin). [h] −116; [h] −133; [h] −159;
589
578
546
[h] −462; [h] −1806 (c 0.1; CH2Cl2). ESI+ MS m/z:
25
436
25
365
1595.6 [M+H]+ (see Fig. 5). Anal. calcd for
C112H82N4O7·2 H2O (1631.840): C, 82.43; H, 5.31; N,
3.43. Found: C, 82.53; H, 5.31; N, 3.24%.

J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
25 25
1891
25
25
4.15. H-[(S)-Bin]4-OMe 4a
(VII). [h] −122; [h] −142; [h] −176; [h] −526;
589 578 546 436
25
[h]
−2162 (c 0.1; CH2Cl2). ESI+ MS m/z: 1907.8
365
A solution of 4h (0.059 g; 0.037 mmol) in CH3CN (9
mL) and diethylamine (1 mL) was stirred at room
temperature for 5 h. Work-up as in the preparation of
3a (vide supra), followed by chromatography of the
obtained crude product on a 1.5×38 cm column of silica
gel with eluent (VII), then (VIII), afforded 0.044 g
(87%) of pure 4a, as a white, amorphous solid. Mp=
240–260°C (indefinite). Rf=0.10 (VII). 1H NMR
(CDCl3): l 8.06–6.90 [m, 51H, 48 ArH and 3 NH
Bin2,3,4], 3.46 [s, 3H, OMe], 3.87 [d, J=13.4, 1H], 3.77
[d, Jꢀ13.4, 1H], 3.72 [d, Jꢀ13.4, 1H], 3.43 [d (partly
masked), 1H], 3.19 [d, J=13.2, 1H], 3.01–2.76 [m, 6H],
2.83 [m, 3H], 2.10 [d, J=12.9, 1H], 1.68 [d, Jꢀ13.6,
1H], [ArCH2bb% Bin1,2,3,4]. 13C NMR (CDCl3): l 177.0,
173.0, 172.8, 172.1 (CꢀO Bin), 134.0, 133.9, 133.7,
133.6, 133.4, 133.1, 132.94, 132.90, 132.85, 132.81,
131.9, 131.8, 131.73, 131.68, 131.6, 131.5, 131.4, 129.5,
128.8, 128.7, 128.5, 128.4, 128.2, 128.1, 127.9, 127.8,
127.66, 127.7, 127.6, 127.5, 127.2, 127.0, 126.0, 125.8,
125.6, 125.5, 125.4, 125.3, 125.26, 125.20, 125.1, 125.0
(CAr), 71.4, 71.2, 69.6, 68.4 (Ca Bin), 52.1 (OCH3),
45.1, 43.1, 41.4, 41.1, 40.9, 39.6, 39.0, 37.2 (Cb Cb%
[M+H]+, 854.9 [M+2H]2+.
4.18. Electronic circular dichroism
Electronic CD spectra were recorded on a Jasco model
J-715 spectropolarimeter. Cylindrical, fused quartz cells
of 1.0 and 0.2 mm path lengths were employed. The
data are expressed in terms of [q]T, the total molar
ellipticity (deg cm−2 dmol−1). Spectrograde MeOH
(Fluka), TFE (Acros), and CHCl3 (Fluka) were used as
solvents.
4.19. FT-IR absorption
The solution IR absorption spectra of the Na-protected
(S)-Bin derivative and peptide esters in the 3550–3200
cm−1 region were recorded at UP using a Perkin–Elmer
model 1720X FT-IR spectrophotometer, nitrogen
flushed, equipped with a sample-shuttle device, at 2
cm−1 nominal resolution, averaging 100 scans. Solvent
(baseline) spectra were obtained under the same condi-
tions. Cells with path lengths of 0.1, 1.0, and 10 mm
(with CaF2 windows) were used. Spectrograde deutero-
chloroform (99.8% d) was purchased from Fluka.
25
25
25
25
Bin). [h] −122; [h] −142; [h] −176; [h] −526;
589
578
546
436
25
365
[h]
−2162 (c 0.1; CH2Cl2). Anal. calcd for
C97H72N4O5·1.5 H2O (1400.602): C, 83.18; H, 5.40; N,
4.00. Found: C, 83.27; H, 5.88; N, 3.55%.
Samples of the Na-deprotected (S)-Bin peptide esters
for IR absorption spectroscopy in the 1780–1480 cm−1
region were dissolved in deuterochloroform at both
$3.6 and 18 mg mL−1 concentration and placed in a
demountable cell (Specac) constructed of two CaF2
windows separated by a 500 mm Teflon spacer. Addi-
tional experiments were performed in 98:2 (v/v) CDCl3/
TFE-OD (deuterated TFE). The spectra were recorded
at UIC on a Digilab FTS-60 FT-IR spectrophotometer
as an average of 256 scans at 4 cm−1 resolution with a
zero filling factor of 4.
4.16. Fmoc-[(S)-Bin]5-OMe 5h
A solution of 1f (0.034 g; 0.059 mmol) and pyridine
(0.011 mL; 0.13 mmol) in CH2Cl2 (2 mL), was treated
with cyanuric fluoride (0.030 mL; 0.35 mmol), under
the same experimental conditions and work-up as
described earlier, to give crude Fmoc-(S)-Bin-F 1g (vide
supra), which was directly treated with a solution of
H-[(S)-Bin]4-OMe 4a (0.0266 g; 0.019 mmol) and
NMM (0.008 mL; 0.073 mmol) in CH2Cl2 (2 mL). The
resulting solution was stirred at room temperature for
14 days. Work-up as in the preparation of 3h (vide
supra), followed by chromatography of the obtained
crude product on a 1.5×37 cm column of silica gel with
eluent (VI), then (VII), gave 0.0133 g (50%) of starting
4a and 0.0094 g of the desired pentapeptide, which was
further purified by preparative TLC on silica gel with
eluent (VI) to afford 0.0069 g (18%) of pure 5h, as a
pale brown, amorphous solid. Mp=250–270°C
4.20. Vibrational circular dichroism
For the VCD spectroscopic study of the Na-deprotected
(S)-Bin peptide esters, the same solutions were used as
those described above for the FT-IR absorption investi-
gation. VCD spectra over the amide I and II regions
were obtained on the UIC dispersive VCD spectropho-
tometer, the design and the use of which have been
previously described in detail.25 Spectra were recorded
at 10 cm−1 resolution and 10-s time constant, collected
under the same experimental conditions, averaged for
base line correction and subsequently subtracted from
the averaged sample spectra.
25
25
578
(indefinite). Rf=0.46 (VII). [h]
−185; [h]
−208;
589
25
25
25
[h]
−246; [h]
−621; [h]
−2177 (c 0.1; CH2Cl2).
546
436
365
ESI+ MS m/z: 1930.9 [M+H]+ (see Fig. 5). Anal. calcd
for C136H99N5O8·4 H2O (2003.256): C, 81.54; H, 5.38;
N, 3.49. Found: C, 81.81; H, 6.13; N, 3.02%.
4.21. Calculations
4.17. H-[(S)-Bin]5-OMe 5a
A series of MM energy minimisation calculations of the
target molecule H-[(S)-Bin]4-OMe were performed
using the CFF and CVFF force fields as provided in
the Cerius2 and InsightII program packages from MSI
(San Diego, CA). These force fields are applicable to
systems including peptide backbone and aromatic side
chains. These MM calculations were used to determine
possible equilibrium conformations of the tetrapeptide
A solution of 5h (0.0060 g; 0.003 mmol) in CH3CN (9
mL) and diethylamine (1 mL) was stirred at room
temperature for 5 h. Work-up as in the preparation of
3a (vide supra), followed by preparative TLC of the
obtained crude product on silica gel with eluent (VII),
afforded 0.0020 g (38%) of pure 5a, as a white, amor-
phous solid. Mp=200–260°C (indefinite). Rf=0.40

1892
J.-P. Mazaleyrat et al. / Tetrahedron: Asymmetry 14 (2003) 1879–1893
ester molecule in vacuo. A large number of conformers,
based on standard secondary structural types, were
used as starting conformations for minimisations. The
tetrapeptide ester structure consists of 178 atoms for
which it was not possible for us to calculate the IR
absorption and VCD spectra directly on an ab initio
quantum mechanical level. However, it could be done
in parts, peptide chain and side chains, and the results
transferred to the complete molecule using our estab-
lished techniques.26 To simulate spectra for the back-
bone, ab initio calculations of the FF and intensity
parameters (APT and AAT) were performed by means
of DFT at the BPW91/6-31G** level using the Gaus-
sian 98 program package.27 Simulations were carried
out for the H-(Aib)4-OMe tetrapeptide ester as a model
of the H-[(S)-Bin]4-OMe backbone, but constrained to
fixed ƒ, „ angles from the most favourable conforma-
tion found in the MM calculations. All the remaining
structural parameters were relaxed (including the ꢀ
angles). Separate DFT calculations were performed at
the same level with full optimisation, for 6,6-dimethyl-
Karle, I. L. Biopolymers 1996, 40, 157–180; (i) Karle, I. L.
Acc. Chem. Res. 1999, 32, 693–701; (j) Andrews, M. J. I.;
Tabor, A. B. Tetrahedron 1999, 55, 11711–11743; (k)
Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C.
Biopolymers (Peptide Sci.) 2001, 60, 396–419; (l) Toniolo,
C.; Benedetti, E. In Molecular Conformation and Biological
Interactions; Balaram, P.; Ramaseshan, S., Eds.; Indian
Academy of Sciences: Bangalore, 1991; pp. 511–521.
2. (a) Valle, G.; Crisma, M.; Bonora, G. M.; Toniolo, C.; Lelj,
F.; Barone, V.; Fraternali, F.; Hardy, P. M.; Langran-
Goldsmith, A.; Maia, H. L. S. J. Chem. Soc., Perkin Trans.
2 1990, 1481–1487; (b) Crisma, M.; Valle, G.; Bonora, G.
M.; Toniolo, C.; Lelj, F.; Barone, V.; Fraternali, F.; Hardy,
P. M.; Maia, H. L. S. Biopolymers 1991, 31, 637–641.
3. (a) Valle, G.; Crisma, M.; Toniolo, C.; Rao, R. B.;
Sukumar, M.; Balaram, P. Int. J. Peptide Protein Res. 1991,
38, 511–518; (b) Toniolo, C.; Crisma, M.; Formaggio, F.;
Benedetti, E.; Santini, A.; Iacovino, R.; Saviano, M.; Di
Blasio, B.; Pedone, C.; Kamphuis, J. Biopolymers 1996, 40,
519–522; (c) Benedetti, E.; Di Blasio, B.; Iacovino, R.;
Menchise, V.; Saviano, M.; Pedone, C.; Bonora, G. M.;
Ettorre, A.; Graci, L.; Formaggio, F.; Crisma, M.; Valle,
G.; Toniolo, C. J. Chem. Soc., Perkin Trans. 2 1997,
2023–2032.
2%,1%:1,2:1%%,2%%:3,4-dinaphthcyclohepta-1,3-diene,
with
two methyls on the central bridge carbon (equivalent to
the Bin Ca atom), which was designed to mimic the
electronic environment of the Bin side-chain group, to
determine the spectral properties of the H-[(S)-Bin]4-
OMe peptide side-chain. Previously, it was shown that
the BPW91 functional provides reliable simulations of
IR absorption and VCD for larger spectral
molecules21a,28 as well as other systems.29 The Cartesian
FF, APT and AAT values from these binaphthyl side-
chain and H-(Aib)4-OMe backbone calculations were
transferred onto appropriate position and with the
proper orientation to match the complete H-[(S)-Bin]4-
OMe oligopeptide geometry using the previously
described property tensor transfer technique.26 Theoret-
ical IR absorption and VCD spectra were simulated by
placing Lorentzian bands with a half-bandwidth of 7
cm−1 on each transition scaled with the appropriate
dipole (D) or rotational (R) strength, respectively.
4. (a) Mazaleyrat, J.-P.; Gaucher, A.; Wakselman, M.; Tch-
ertanov, L.; Guilhem, J. Tetrahedron Lett. 1996, 37,
&
2971–2974; (b) Mazaleyrat, J.-P.; Gaucher, A.; Savrda, J.;
Wakselman, M. Tetrahedron: Asymmetry 1997, 8, 619–631;
(c) Mazaleyrat, J.-P.; Gaucher, A.; Wakselman, M.;
Toniolo, C.; Crisma, M.; Formaggio, F. In Peptides 1996;
Ramage, R.; Epton, R., Eds.; Mayflower Scientific:
Kingswinford, UK, 1998; pp. 623–624.
5. (a) Formaggio, F.; Crisma, M.; Toniolo, C.; Mazaleyrat,
J.-P.; Wakselman, M. In Peptides 1998; Bajusz, S.; Hudecz,
F., Eds.; Akade´miai Kiado: Budapest, 1999; pp. 352–353;
(b) Formaggio, F.; Crisma, M.; Toniolo, C.; Tchertanov,
L.; Guilhem, J.; Mazaleyrat, J. P.; Gaucher, A.; Waksel-
man, M. Tetrahedron 2000, 56, 8721–8734.
6. (a) Mazaleyrat, J.-P.; Boutboul, A.; Lebars, Y.; Gaucher,
A.; Wakselman, M. Tetrahedron: Asymmetry 1998, 9,
2701–2713; (b) Formaggio, F.; Peggion, C.; Crisma, M.;
Toniolo, C.; Tchertanov, L.; Guilhem, J.; Mazaleyrat, J.
P.; Goubard, Y.; Gaucher, A.; Wakselman, M. Helv. Chim.
Acta 2001, 84, 481–501.
Acknowledgements
7. For reviews on synthesis, molecular recognition, asymmet-
ric catalysis and new materials involving 1,1%-binaphthyl
monomers, dimers, oligomers and polymers, see: (a) Cram,
D. J. Angew. Chem., Int. Ed. Engl. 1988, 27, 1009–1020;
(b) Whitesell, J. K. Chem. Rev. 1989, 89, 1581–1590; (c)
Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345–350;
(d) Rosini, C.; Francini, L.; Raffaelli, A.; Salvadori, P.
Synthesis 1992, 503–517; (e) Blaser, H.-U. Chem. Rev.
1992, 92, 935–952; (f) Shibasaki, M.; Sasai, H.; Arai, T.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1236–1256; (g) Pu,
L. Chem. Rev. 1998, 98, 2405–2494; (h) Putala, M. Enan-
tiomer 1999, 4, 243–262.
8. The Bin residue has been used as fluorophore in photo-
physical studies involving intramolecular energy transfer
(fluorescence quenching) and intramolecular spin polarisa-
tion (CIDEP) effects in designed, rigid peptide-based
systems: (a) Toniolo, C.; Formaggio, F.; Crisma, M.;
Mazaleyrat, J. P.; Wakselman, M.; George, C.;
Deschamps, J. R.; Flippen-Anderson, J. L.; Pispisa, B.;
Venanzi, M.; Palleschi, A. Chem. Eur. J. 1999, 5, 2254–
One of the authors (T.A.K.) wishes to thank the
Donors of the Petroleum Research Fund, administered
by the American Chemical Society, for a grant in
partial support of this work. Thanks are due to Dr. P.
Bour for discussion of the theoretical modelling.
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removed and replaced by a Fmoc group in the next steps.
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(CH2)2-OH.6a
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