Chirality and template-mediated induction of helical preferences in achiral β-peptides

Article abstract of DOI:10.1002/chem.201201892

This study describes chirality- or template-mediated helical induction in achiral β-peptides for the first time. A strategy of end capping β-peptides derived from β-hGly (the smallest achiral β-amino acid) with a chiral β-amino acid that possesses a carbo

Full text of DOI:10.1002/chem.201201892

DOI: 10.1002/chem.201201892
Chirality and Template-Mediated Induction of Helical Preferences in
Achiral b-Peptides
Gangavaram V. M. Sharma,*[a] Srinivas Reddy Kodeti,[a] Samit K. Dutta,[b]
Subash Velaparthi,[a] Kongari Narsimulu,[b] Gonuguntla Anjaiah,[a]
Shaik Jeelani Basha,[b] and Ajit C. Kunwar*[b]
Dedicated to Professor C. L. Khetrapal on the occasion of his 75th birthday
Abstract: This study describes chirality-
or template-mediated helical induction
in achiral b-peptides for the first time.
A strategy of end capping b-peptides
derived from b-hGly (the smallest achi-
ral b-amino acid) with a chiral b-amino
acid that possesses a carbohydrate side
chain (b-Caa; C-linked carbo b-amino
acid) or a small, robust helical template
derived from b-Caas, was adopted to
investigate folding propensity. A single
chiral (R)-b-Caa residue at the C- or
N-terminus in these oligomers led to a
preponderance of right-handed 12/10-
helical folds, which was reiterated
more strongly in peptides capped at
both the C- and N-terminus. Likewise,
the presence of a template (a 12/10-hel-
ical trimer) at both the C- and N-termi-
nus resulted in a very robust helix. The
propagation of the helical fold and its
sustenance was found in a homo-oligo-
meric sequence with as many as seven
b-hGly residues. In both cases, the in-
duction of helicity was stronger from
the N terminus, whereas an anchor at
the C terminus resulted in reduced hel-
ical propensity. Although these oligo-
to favor a 12/10-mixed helix in apolar
solvents, this study provides the first
experimental evidence for their exis-
tence. Diastereotopicity was found in
both the methylene groups of the b-
hGly moieties due to chirality. Addi-
tionally, the b-hGly units have shown
split behavior in the conformational
space to accommodate the 12/10-helix.
Thus, end capping to assist chiralty- or
template-mediated helical induction
and stabilization in achiral b-peptides
is a very attractive strategy.
AHCTUNGTRENNmGUN ers have been theoretically predicted
Keywords: diastereotopicity · end
capping · helical structures · pep-
AHCTUNGTREGtNNUN ides · template
Introduction
terest.[2] The early work of Toniolo et al.[3] on achiral Aib
(amino isobutyric acid) oligomers showed that the direction
of the helical handedness is dependent on the position of
the chiral guest residue. A further systematic study by Inai
et al.[4] showed the influence of a chiral residue at either the
C- or N-terminus, or both, on the induction of helical screw
sense in achiral peptides with a propensity to form a 310
helix. Though a single l-Leu residue is adequate to initiate
left-handed helical folding, Ousaka and Inai[7] observed that
oligomeric l-Leu (two or more residues) at the N terminus
promotes a right-handed helical propensity. The phenomen-
on has been described as a domino effect[5,6] because a
single chiral residue infers a profound influence to provide a
distinct structure in the peptide. Interestingly, the generation
of left-handed helices by a monomeric l-Leu terminal resi-
due conforms with the observations of Shellman.[8] Chiral
helical induction in aromatic foldamers instigated by a ter-
minal chiral residue was also demonstrated by Huc et al.[9]
Further research endeavors from Clayden et al.[10] resulted
in the development of various NMR spectroscopic methods
that utilized remote diastereotopic “reporter” groups to un-
derstand, both qualitatively and quantitatively, the handed-
ness of the helical conformations that are rapidly intercon-
verting. Such studies have provided evidence and rationale
Template-nucleated helices in chiral a peptides, in which in-
duction has been achieved by introduction of a few residues
fixed in a helical conformation by covalent or metal-sup-
ported side-chain–side-chain bridges have been extensively
studied.[1]Likewise, the concept of induction of helical screw
sense in achiral peptides that contain rapidly interconverting
left- and right-handed helices has evinced a great deal of in-
[a] Dr. G. V. M. Sharma, Dr. S. R. Kodeti,+ Dr. S. Velaparthi, G. Anjaiah
Organic and Biomolecular Chemistry Division
CSIR-Indian Institute of Chemical Technology
Hyderabad 500 007 (India)
E-mail: esmvee@iict.res.in
[b] Dr. S. K. Dutta,+ Dr. K. Narsimulu, S. J. Basha, Dr. A. C. Kunwar
Centre for Nuclear Magnetic Resonance
CSIR-Indian Institute of Chemical Technology
Hyderabad 500 007 (India)
E-mail: kunwar@iict.res.in
[+] These authors have contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201892. It contains NMR
spectra, CD spectra, details of the MD calculations, and experimental
details for compounds 4–6, 11–12, 18, 21–23, 26, 28–33, 36–37, 39, 42,
45, and 48.
16046
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16046 – 16060

FULL PAPER
for the role of the terminal/internal chiral residue, bound co-
valently or noncovalently, in the control of the helical screw
sense.
the peptides, derived from alternating chiral b-amino acids
and b-hGly. The conformational preference to such foldings
is attributed to the influence of the neighboring chiral[15,16]
b-amino acid residues.
Recent studies by Gellman et al.[11] in their chimeric
design of the a/b+a-peptide family, reported that the a/b-
peptide template (in this case, a 14/15-helical motif) facili-
tates the nucleation of a right-handed a-helical fold in the
a-peptide region. More recently, we have demonstrated that
a variety of compatible helical templates can be combined
to generate a novel hybrid helical fold, which consists of up
to three different helix types.[12]
Based on the findings on the induction of helicity/screw
sense[2,4–7,9–12] in achiral oligomers and the behavior of b-
hGly, it was proposed that b-hGly oligomers, which do not
reveal well-defined structures, could be persuaded to have
helical folding. Thus, we planned to adopt the strategy of
end capping the b-peptide oligomers formed from b-hGly,
either with a chiral amino acid (b-Caa)[27] residue or with a
robust template[28] derived from b-Caas (Figure 1), at the
peptide termini to stimulate a secondary structure. This phi-
losophy of anchoring the termini by two helical fragments
Although all the above studies present different designs
to induce helical screw sense in the achiral a peptides, such
endeavors in the domain of achiral b-peptides are unex-
plored. Thus, it is imperative to
investigate the induction of
helicity in oligomers of achiral
b-amino acids. The archetype
of such b-peptidic homo-
oligomers can be constructed
from an achiral b-alanine, b-
hGly (the simplest b-amino
acid). b-hGly permits both syn-
and anti-periplanar dihedral
[13]
ꢀ
angles about Ca Cb.
Gell-
man et al.[14] predicted en-
hanced folding propensity in
the oligomers of b-hGly very
early from FTIR studies and
attributed it to the repulsive
interaction of the amide
groups.[15,16] Interestingly, from
NMR spectroscopic studies on
polyACHTUNGTRENNUNG(b-hGly), Glickson and
Applequist[17] inferred that
these peptides are disordered
and possess little intermolecu-
lar hydrogen bonding. Further,
Bode and Applequist have the-
oretically explored various
types of helices in (b-
hGly)12.[17c,18] Pavone et al.[19]
have shown that the cyclic pep-
tides that contain b-hGly adopt
a well-defined 10-membered-
ring hydrogen bond unit due to
a gauche configuration. The ab
initio quantum mechanical cal-
culations by Hofmann et al.[20]
and Wu and Wang[21] and co-
workers predicted a variety of
ordered secondary structures[22]
in b-peptides. Though the b-
hGly residue is known to de-
stabilize the helices,[23] several
groups[24–26] reported the pres-
ence of 12/10- and 14-helices in
Figure 1. Structures of monomers 1–3 and peptides 4–15 (Boc=tert-butoxycarbonyl).
Chem. Eur. J. 2012, 18, 16046 – 16060
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16047

G. V. M. Sharma, A. C. Kunwar et al.
was also adopted by Huc et al.[29] in probing the helix-form-
ing propensity of monomers. The present report more spe-
cifically describes our attempts towards the synthesis and in-
vestigation of the helix-forming potential of achiral b-pep-
ACHTUNGTRENNUNGtides rich in b-hGly residues by NMR and circular dichroism
(CD) spectroscopy and molecular dynamics (MD) studies.
Results and Discussion
Peptide synthesis: The peptides 4–7 (Scheme 1), 8–11
(Scheme 2), 12–15, and 29–32 (Scheme 3) were prepared
from b-hGly 1, b-Caas 2 and 3, and standard peptide cou-
pling reagents 1-ethyl-3-(3-dimethylaminopropyl)carbodi-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Scheme 1. Synthesis of peptides 4—7. Reagents and conditions: a) 1-hy-
droxybenzotriazole (HOBt; 1.2 equiv), 1-ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide
(EDCI;
1.2 equiv),
N,N-diisopropylethylamine
Scheme 3. Synthesis of peptides 13–15 and 29—32. Reagents and condi-
tions: a) HOBt (1.2 equiv), EDCI (1.2 equiv), DIPEA (2 equiv), dry
CH2Cl2, 08C–RT; b) 4n NaOH (aq), MeOH, 08C–RT; c) CF3COOH, dry
CH2Cl2, 08C–RT.
(DIPEA; 2 equiv), dry CH2Cl2, 08C–RT; b) 4n NaOH (aq), MeOH,
08C–RT, 2 h; c) CF3COOH, dry CH2Cl2, 2 h; d) N,N-dicyclohexylcarbo-
diimide (DCC), 4-dimethylaminopyridine (DMAP), CH2Cl2, 08C–RT.
Synthesis of peptides 4–7: The synthesis of peptides 4–7 is
outlined in Scheme 1. Accordingly, peptide coupling of acid
16 with the HCl salt of b-hGly-OMe (16a) gave dipeptide
17 (82%). Hydrolysis of 17 with 4n NaOH (aq) furnished
acid 17a, whereas reaction of 17 with CF3COOH in CH2Cl2
afforded salt 17b. Coupling of acid 17a with 16a gave tri-
peptide 4 (65%). Esterification of acid 17a with galactose
diacetonide, [(3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyl
ACHTUNGTRENNUNGper-
A
R
ACHTUNGTRENNUNG
presence of N,N-dicyclohexylcarbodiimide (DCC) and 4-di-
methylaminopyridine (DMAP) in CH2Cl2 gave ester 18
(83%).
Exposure of dipeptide 18 to CF3COOH in CH2Cl2 gave
salt 18a, which, on further reaction with acid 16 in the pres-
ence of EDCI, HOBt, and DIPEA in CH2Cl2, afforded tri-
peptide 5 (62%). Similarly, acid 17a furnished tetrapeptide
6 (70%) on peptide coupling with salt 18a. Treatment of 6
with CF3COOH in CH2Cl2 gave salt 19, which on further
condensation (EDCI, HOBt, and DIPEA) with 16 in
CH2Cl2 furnished pentapeptide 7 (56%) [Scheme 1].
Scheme 2. Synthesis of peptides 8—11. Reagents and conditions: a) 4n
NaOH (aq), MeOH, 08C–RT; b) CF3COOH, dry CH2Cl2, 08C–RT;
c) HOBt (1.2 equiv), EDCI (1.2 equiv), DIPEA (2 equiv), dry CH2Cl2,
08C–RT.
16048
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16046 – 16060

Induction of Helical Preferences in Achiral b-Peptides
FULL PAPER
Synthesis of peptides 8–11: The synthesis of peptides 8–11 is
outlined in Scheme 2. Accordingly, hydrolysis of ester 2 with
4n NaOH (aq) afforded acid 20a, whereas exposure of 2 to
CF3COOH in CH2Cl2 gave salt 20. Peptide coupling of acid
17a with salt 20 furnished tripeptide 21 (82%). Reaction of
peptide 21 with CF3COOH in CH2Cl2 gave salt 21a, which
afforded pentapeptide 8 (76%) on further coupling with
acid 17a under standard peptide coupling conditions.
Reaction of acid 20a with salt 17b in the presence of
EDCI, HOBt, and DIPEA in CH2Cl2 afforded tripeptide 22
(82%). Base hydrolysis of peptide 22 gave acid 22a, which
furnished peptide 9 (79%) on further coupling with salt 17b
under standard conditions.
On reaction with salt 20 in the presence of EDCI, HOBt,
and DIPEA in CH2Cl2, acid 16 gave peptide 23 (87%).
Treatment of peptide 23 with CF3COOH in CH2Cl2 furnish-
ed salt 23a, which afforded peptide 10 (79%) on further
coupling with acid 22a under standard conditions. Similarly,
hydrolysis of 9 with 4n NaOH (aq) gave acid 24, which gave
peptide 11 (66%) after coupling with salt 23a in CH2Cl2.
general, in both 4 and 5, the amide protons were found to
not be hydrogen bonded (deduced from the chemical shifts
d<7 ppm and very large changes in their chemical shifts of
Dd>1.00 ppm detected by solvent titration studies).[31,32]
Peptide 6 behaved similarly to 5 and no structural features
1
could be deciphered from its H NMR spectrum, which may
be due to its small size and fraying in the terminal residues.
1
However, the H NMR spectrum of 7[32] supported the pres-
ence of two isomeric species in a ratio of 70:30, inferred
from an extensive array of exchange peaks in the ROESY
spectrum. Although both isomers showed the presence of
hydrogen bonding, suggested by distinctive
d and Dd
values,[31,32] the broadening of resonances that arises due to
exchange between the isomers prevented deduction of more
meaningful information on their structures. Diastereotopici-
ty was also observed for the methylene protons of the C-ter-
minal b-hGly residue linked to d-galactose in peptides 6 and
7. This finding is unlike the report of Clayden et al.,[33] who
have shown diastereotopicity due to a single chiral center
propagating as far as 60 bonds away.
The above results indicate the role of chiral induction by
a carbohydrate residue, but also open up several possibili-
ties. To investigate further, peptide 8 with a C-terminal (R)-
b-Caa residue[26,28] (a b-amino acid with a carbohydrate side
Synthesis of peptides 12–15 and 29–32: Peptide coupling of
acid 20a with salt 25 (prepared by tert-butoxycarbonyl (Boc)
deprotection of 3) afforded dipeptide 26 (88%). Base hy-
drolysis [4n NaOH (aq)] of ester 26 gave acid 26a, which
furnished tripeptide 12 (87%) on peptide coupling with salt
20.[28] Further peptide coupling of acid 16 with salt 27a gave
tetrapeptide 28 (71%), which afforded salt 28a after treat-
ment with CF3COOH in CH2Cl2. Peptide coupling of acid
17a with salt 27a furnished pentapeptide 29 (70%). Treat-
ment of 29 with CF3COOH in CH2Cl2 gave salt 29a. Peptide
coupling of acid 17a with 29a under standard coupling con-
ditions afforded heptapeptide 30 (Scheme 3).
Similarly, acid 27 reacted with 17b in the presence of
EDCI, HOBt, and DIPEA in CH2Cl2 and gave pentapeptide
31 (93%), which subsequently afforded acid 31a after base
hydrolysis. Peptide coupling of acid 31a with salt 28a fur-
nished peptide 13 (70%). Likewise, reaction of acid 31a
with 17b in the presence of EDCI, HOBt, and DIPEA gave
32 (89%). Hydrolysis of peptide 32 with 4n NaOH (aq) af-
forded acid 32a, which furnished peptides 14 (70%) and 33
(63%) after coupling with either salt 28a or 16a, respective-
ly, in the presence of EDCI, HOBt, and DIPEA in CH2Cl2.
Peptide 33 gave acid 33a after hydrolysis with 4n NaOH
(aq), which reacted with 29a in the presence of EDCI,
HOBt, and DIPEA in CH2Cl2 to afford peptide 15 (68%)
[Scheme 3].
1
chain) was synthesized and investigated. The H NMR spec-
trum of 8 displayed diastereotopicity for the methylene pro-
tons of all of the b-hGly residues. The spectrum showed the
presence of two isomers in a 1:2 ratio. A careful study re-
vealed the involvement of the last four amide protons (d>
7.19 ppm and Dd<0.60 ppm) in hydrogen bonding for the
3
major isomer. The J
N
tive for the last three residues (for the third and fourth resi-
dues the values are J=5.2 and 7.1 Hz, respectively, whereas
for the fifth residue J=8.2 Hz), although their values seem
to suggest some degree of constraint about f (C(O)-N-Cb-
Ca)[34] with preponderance of jfjꢁ1208 (Figure 2).
Figure 2. Definition of the dihedral angles in b-amino acids.
The above facts, as well as several discrete medium-range
nOe correlations [for example, CbH(1)
R), CbH(1)(pro-R)/NH(3), CbH(3)(pro-R)/NH(5), CbH(3)-
(pro-R)/CaH(5)(pro-R)], along with sequential correlations
CbH(1)(pro-R)/NH(2), CaH(1)(pro-S)/NH(2), NH(2)/
CaH(3)(pro-R), CaH(2)(pro-R)/NH(3), CbH(3)(pro-R)/
NH(4), CaH(3)(pro-S)/NH(4), NH(4)/CaH(5)(pro-R),
CaH(4)(pro-R)/NH(5), and NH(4)/NH(5), provide emphat-
ACHUTGTNRENN(GU pro-R)/CaH(3)ACHTUNGTRENNUNG(pro-
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
1
Conformational analysis: H NMR spectroscopic studies on
A
R
ACHTUNGTRENNUNG
peptides 4–15 and 29–32 were carried out in CDCl3 (c=3–
A
ACHTUNGTRENNUNG
1
7 mm). The H NMR spectrum of 5, unlike achiral peptide 4,
ACHTUNGTRENNUNG
revealed the signatures of chiral induction in the form of
distinctly different chemical shifts for both the Ca protons
(d=2.53 and 2.63 ppm) and Cb protons (d=3.39 and
3.68 ppm) for the third b-hGly residue, whereas the protons
of other b-hGly residues did not display diastereotopicity.
Despite the observation of diastereotopic protons in 5, in
ic support for the presence of a 12/10-helix.[26,28] These find-
ings are very important; they not only provide unmistakable
evidence for the induction of a helical preference in achiral
peptides, but also provide the first unequivocal experimental
proof for the theoretically predicted preference for the 12/
10-helix in b-peptides in apolar solvents.[20,21]
Chem. Eur. J. 2012, 18, 16046 – 16060
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16049

G. V. M. Sharma, A. C. Kunwar et al.
MD calculations were undertaken by using the distance
constraints obtained from the ROESY data, and two spin
approximations were employed. Dihedral angle constraints
were not used in these calculations, although starting ge
ACHTUNGERTNoNUNG m-
ACHTUNGTRENNUNGetries were consistent with the data. Twenty superimposed
low-energy structures[32] very clearly showed a right-handed
12/10-helix with average root-mean-square deviation
(RMSD) values for the backbone and heavy atoms of 0.70
and 0.98 ꢁ, respectively. Significant fraying at the peptide
termini can be noticed. This result clearly demonstrates that
the chirality end capping by (R)-b-Caa with a furanoside
side chain induced right-handed helicity in the achiral b-
hGly oligomer 8.
Like the major isomer of 8, the minor isomer displayed
diastereotopicity for each of the methylene protons for all
of the b-hGly residues. The minor isomer of 8 showed very
distinct signatures of hydrogen bonding of the amide pro-
tons [d=6.99, 7.99, 7.62, and 8.13 ppm for the second to
Figure 3. Stereoviews of the superimposition of the 20 lowest-energy
structures of peptide 9 determined on the basis of NMR spectroscopic
measurements in solution in CDCl3 (hydrogen bonds are shown as dotted
lines).
fifth amide protons, respectively, and Dd <0.71 ppm]. In ad-
3
dition, the J
G
coupling information could be obtained for most of them.
Prochirality of the methylene groups was assigned with help
of the exchange peaks between the analogous protons of the
major isomer.
b-hGly (J>8.2 Hz or J<4.6 Hz) residues were consistent
with jfjꢁ1208. For the minor isomer of 8, nOe correlations
NH(1)/NH(2) and NH(1)/NH(3) were also observed in the
ROESY spectrum. However, due to lack of sufficient nOe
constraints, deduction of the structure was not possible. In
addition, though theoretically a 14-helix is an energetically
favored conformation, the above data does not support the
presence of such a structure for the minor isomer.
Having observed remarkable induction of a right-handed
helical structure prompted by the chirality of a carbohydrate
side chain in peptide 8, peptide 9, with an N-terminal (R)-b-
Caa residue, was investigated. The inference from NMR
spectroscopic studies of 9 in CDCl3 was found to be very
similar to 8. A 12/10-helical pattern, as discussed below, was
observed with a slightly larger population (ꢁ70%) for the
major isomer. The involvement of the amide protons of last
four residues in hydrogen bonding is supported (d>
7.19 ppm and DdNH <0.70 ppm). A large number of ob-
served couplings in 9 provided emphatic support for the
As in the case of the minor isomer of peptide 8,
3
3J
3J
(HN,HCb)ꢂ4.5 Hz and J
N
3
large and one small value for J
ACHTUNGTRENNUNG
qꢁ608. Also, the nOe correlations NH(1)/NH(2) and
NH(1)/NH(3) were present, as shown in the expansion of
the amide region in the ROESY spectrum (Figure 4).
Though the above information and the absence of an
NH(2)/NH(3) nOe correlation in the minor isomer indicate
some departure from a 12/10-helical pattern at the N termi-
nus, we still failed to decipher the structure.
The findings for achiral b-peptide 9, which show the pres-
ence of a higher population of the 12/10-helix, further sup-
port stronger induction from the N terminus, as was ob-
served for achiral a-peptides.[4,10] Though the revelation of
major isomers with right-handed 12/10 helices in 8 and 9 is
quite an encouraging result and reflects the important role
played by the chiral side chain in helical induction in b-hGly
oligomers, the presence of a sizeable population of the other
isomer reflects the compromised robustness of the helix.
Thus, it was felt worthwhile to adopt the strategy of end
capping the b-hGly oligomers at both the C- and N-terminus
with an (R)-b-Caa residue.
As envisaged, the NMR spectrum of 10 showed enhanced
population of the major isomer (95%) with all the signa-
tures of a robust 12/10-helix.[32] The involvement of the
amide protons of the last four residues in hydrogen bonding
was supported (d>7.54 ppm and Dd=0.12 to ꢀ0.60 ppm).
All of the derived couplings that involved the backbone sup-
port a fairly robust helical pattern. A large number of the
observed couplings provided emphatic support for con-
constrained values for f and q. For b-hGly, 3J
4.7 Hz or 3J(HN,HCa)>7.8 Hz and 3J
(HCa,HCb)>11 Hz or
3J
(HCa,HCb)<4.5 Hz are consistent with |f|ꢁ1208 and q
ꢁ608. The nOe correlations CbH(1)/NH(3), CbH(1)/
CaH(3)(pro-R), NH(2)/CaH(3)(pro-R), NH(2)/NH(3),
CbH(3)(pro-R)/NH(5), CbH(3)(pro-R)/CaH(5)(pro-R),
NH(4)/CaH(5) (pro-R), and NH(4)/NH(5), besides the ob-
servations mentioned above, strongly support a 12/10-helix
in 9. Twenty superimposed structures from the MD calcula-
tions (Figure 3) with backbone and heavy atom RMSD
values of 0.65 and 0.83 ꢁ, respectively, also support the
above findings for 9.
ACHTUNGTRENNUNG
E
A
The results for the minor isomers are very similar to those
for 7 and 8.[32] All of the amide protons, except NH(1), ap-
peared at d>6.92 ppm, which, along with Dd<0.75 ppm de-
termined by solvent titration studies, confirms their involve-
A
ACHTNUGTNER(NGNU HN,HCa)>9.5 Hz or
ment in hydrogen bonding. The H NMR spectrum was well
A
ACHTUNGTRENNUNG
dispersed; all of the protons could be assigned properly and
ACHTUNGTRENNUNG
16050
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16046 – 16060

Induction of Helical Preferences in Achiral b-Peptides
FULL PAPER
signatures of the 12/10-helix and the robustness of the helix
is further supported by the MD data.[32]
It was reassuring to be able to induce a helical structure
with a preference to exist as right-handed 12/10-helix in
achiral b-peptides 8–11 by end capping with (R)-b-Caa. Al-
though the populations of the major isomers increased sub-
stantially when both the peptide termini were anchored with
(R)-b-Caa, all of the peptides studied above showed the
presence of sizeable populations of other structures. Conse-
quently, we decided to explore helix motif 12,[28] based on
the concept of hybrid helices, for the induction of enhanced
helical propensities in b-hGly oligomers and prepared pepti-
des 13–15.
For peptide 13, a highly dispersed 1H NMR spectrum[32]
infers the existence of a well-defined structure. The ROESY
spectrum displayed several exchange peaks that implied the
1
presence of two isomers. However, the H NMR spectrum
did not reveal significant signatures of the minor isomer,
which suggested a minuscule population (possibly <1%).
All of the amide protons, except NH(1), had d>7.94 ppm
and only a very small change in their chemical shifts (Dd=
0.01 to ꢀ0.32 ppm) was detected by solvent titration studies
(Figure 6),[32] which provided adequate support for their in-
volvement in intramolecular hydrogen-bonded structures.
This indicates that the helical structures are retained in the
terminal tripeptide fragments, which also ensures induction
and continuity of the helical fold in the b-hGly segment. It
was observed that the backbone dihedral angles of b-Caa as
well as b-hGly residues are constrained, reflected by the
coupling constants.[32] All six of the b-Caa residues at the
Figure 4. Expansion of the amide region in the ROESY spectrum of pep-
tide 9 to show NH–NH nOe correlations (black) and exchange peaks
(red) between the two isomers. 1a, 2a, and 3a refer to the peaks of the
minor isomer for the amide protons of residues 1, 2, and 3, respectively.
The nOe correlations,[32] coupling constants, and MD data,
support a very robust 12/10-helix compared to oligomers 8
and 9 capped at only the C- or N-terminus, respectively.
Twenty superimposed structures of 10 with backbone and
heavy atom RMSD values of 0.64 and 0.81 ꢁ, respectively,
are shown in Figure 5. However, the structure of the minor
isomer was unresolved.
termini have 3J
ACTHNUTRGNEN(UG HN,HCb)>9.0 Hz, which corresponds to dihe-
dral angles fꢁꢀ1208 and 1208 for (R)-b-Caa and (S)-b-Caa,
respectively. This implies an anti-periplanar arrangement of
NH and CbH. One small and one large coupling constant
(3J
G
for q of about 608 or 1808. These couplings, as well as one
Figure 5. Stereoviews of the superimposition of the 20 lowest-energy
structures of peptide 10 determined on the basis of NMR spectroscopic
measurements in solution in CDCl3 (hydrogen bonds are shown as dotted
lines).
Heptapeptide 11 showed a trend similar to that displayed
by 10, with a population of about 92% for the major
isomer. The last six amide protons appear to be hydrogen
bonded (d>7.63 ppm and DdNH =0.09 to ꢀ0.82 ppm). The
derived couplings that involve the backbone protons imply
constrained dihedral angles (b-hGly: 3J
or 3J(HN,HCa)>8.5 Hz and 3J
(HCa,HCb)>9.3 Hz or
3J
(HCa,HCb)<4.3 Hz). The nOe correlations contain distinct
ACHTNUGNERT(NGNU HN,HCa)<4.2 Hz
Figure 6. Solvent dependence of NH chemical shifts at varying concentra-
tion of [D6]-DMSO in CDCl3 (600 mL) from titration studies of peptide
13.
G
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Chem. Eur. J. 2012, 18, 16046 – 16060
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16051

G. V. M. Sharma, A. C. Kunwar et al.
strong and another medium intensity inter-residue nOe cor-
relation that involves CaH and NH supported qꢁ608. Simi-
larly, for (S)-b-Caa, two small coupling constants (3J-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(pro-R) specifies yꢁꢀ1008 for (S)-b-
Caa. The terminal capping sequences also display medium
range nOe correlations [CbH(1)/NH(3), CbH(1)/CaH(3)-
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
NH(8)/NH(9)], which additionally qualifies a mixed 12/10-
helix for the tripeptide motifs at the peptide termini.
The b-hGly fragment in 13 also displayed signatures of a
Figure 7. Stereoviews of the superimposition of the 20 lowest-energy
structures of peptide 13 determined on the basis of NMR spectroscopic
measurements in solution in CDCl3 (hydrogen bonds are shown as dotted
lines).
structure that corresponds to a mixed 12/10-helix.[32] Due to
3
spectral overlap, only a few of the J
N
stants could be obtained, however, all of them had extreme
values (3J(HCa,HCb)>12.5 Hz or 3J(HCa,HCb)<4.5 Hz ; 3J-
(HN,HCb)>8.4 Hz or J(HN,HCb)<4.1 Hz). The nOe correla-
tions [CbH(3)/NH(4), CbH(3)/NH(5), CbH(3)/CaH(5)(pro-
R), NH(4)/CaH(3)(pro-S), NH(4)/CaH(5)(pro-R), NH(4)/
NH(5), CbH(5)(pro-R)/NH(6), CbH(5)(pro-R)/NH(7),
NH(6)/CaH(5)(pro-S), and NH(6)/CaH(7)(pro-R)], along
A
ACHTUNGTRENNUNG
3
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
with the structural features already elaborated, confirm the
continuity of a mixed helical structure. Thus, the peptide 13
has a 12/10-helix with a (12/10)4 hydrogen-bonded arrange-
ment. Terminal helical motifs nucleate these folds, which ef-
fectively regulate and propagate the helix throughout the
length of the oligomer. In this helical organization, it was re-
markable to note that the b-hGly residues in the fourth and
sixth positions behave differently compared to that in the
fifth position. For b-hGly(4) and b-hGly(6), the observed se-
Figure 8. The nOe correlations required to establish a right-handed 10/
12-helical pattern in b-peptides (R)-b-Caa (R=sugar, R'=H), (S)-b-Caa
(R=H, R'=sugar), and b-hGly (R=R'=H). 1) NH(i)/CaH
2) NH(i)/CaH(i+1)(pro-R); 3) NH(i)/NH(i+1); 4) NH(i+1)/CaH
(pro-R); 5) NH(i+1)/CaH(i)(pro-R); 6) CbH
(iꢀ1)*/NH(i); 7) CbH-
(iꢀ1)*/NH(i+1); 8) CbH(iꢀ1)*/CaH(i+1)(pro-R). NH(i) participates in
10-membered-ring hydrogen bonding with CO(i+1) and NH(i+1) forms
12-membered-ring hydrogen bonding system with CO
(iꢀ2). *For
b-hGly, CbH (iꢀ1)(pro-R).
(iꢀ1) is replaced by CbH
A
ACHTUNGTRENNUNG
quential nOe correlations NH(i)/CaH
NH(i)/CaH(pro-R)(i+1) [i=4, 6] are noticed for the amide
protons of (S)-b-Caa, whereas for b-hGly(5), the nOe corre-
lation NH(5)/CaH(pro-R)(4) is similar to that for the amide
A
N
A
E
E
N
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
E
N
ACHTUNGTRENNUNG
A
E
E
N
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
a
ACHTUNGTRENNUNG
protons of (R)-b-Caa. This interesting split behavior of the
b-hGly residues, which span two different conformational
spaces, is a consequence of the alternating chirality in the
helix design of peptide 13 and is an elegant demonstration
of the accommodative nature of b-hGly in the mixed-helical
folds. Similar split behavior is observed in all of the peptides
studied above.
Twenty superimposed low-energy structures of 13 ob-
tained from the MD calculations are shown in the Figure 7.
The average RMSD values of the backbone and heavy
atoms are 0.52 and 0.68 ꢁ, respectively.
A
R
ACHTUNGTRENNUNG
R), CbH
CaH(i+1)
bonding of NH
rich in b-hGly, the relations modify nominally. Specifically,
A
E
E
G
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
we need to replace CbH
hGly residues.
(iꢀ1) with CbH
E
ACHTUNGTREN(NUNG pro-R) for b-
Further NMR spectroscopic studies of 14 and 15, with
five and seven b-hGly residues, respectively, helix capped by
the (R,S,R) template at both the C- and N-terminus,[28] indi-
cated the propagation of the 12/10-mixed-helical pattern. In
14, it very clearly emerged that the (b-hGly)5 segment end
capped between the two 12/10-helices at the termini is ac-
commodated in an elongated helix with a (12/10)5 hydrogen-
bonded configuration. However, for peptide 15 although
there was a severe overlap, most of the characteristic cou-
Close scrutiny of the above nOe correlations reveals that
in b-peptides with an alternation of (R)- and (S)-b-Caa resi-
dues the nOe correlations required to establish a right-
handed 12/10-helical pattern can be generalized (Figure 8).
The nOe correlations NH(i)/CaH
(i+1)(pro-R), and NH(i)/NH(i+1) support formation of 10-
membered-ring hydrogen bonding of NH(i) with CO(i+1),
(i+1)/CaH(i)(pro-
A
ACHTUNGTREN(NUNG pro-S), NH(i)/CaH-
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
whereas NH
16052
G
E
E
G
ACHTUNGTRENNUNG
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16046 – 16060

Induction of Helical Preferences in Achiral b-Peptides
FULL PAPER
plings and nOe correlations, along with the derived hydro-
gen-bonding information, provided unmistakable signatures
of the 12/10-helix. Thus, similar propagation of the helix in
peptide 15 further shows that as many as seven consecutive
b-hGly residues are held in a 12/10-helical fold by end cap-
ping with two robust helices.
its helical fold and induce helicity, and suggests that 13 con-
tains a substantial population of disordered structures in sol-
ution in methanol. This conclusion was further supported by
the ROESY data obtained in CD3OH,[32] which, despite
severe overlap, showed the presence of weak nOe cross
peaks [NH(2)/NH(3), NH(8)/NH(9), and CbH(1)/NH(3)]
Twenty superimposed low-energy structures for 14 de-
duced from MD studies[32] have shown the average RMSD
of the backbone and heavy atoms are 0.63 and 0.96 ꢁ, re-
spectively. However, for 15, due to severe overlap of the
nOe cross peaks in the ROESY spectrum,[32] it was difficult
to deduce the volume integrals and, hence, the distance con-
straints, which restricted the use of MD studies.
that corresponded to the 12/10-helical folds of the templates.
3
Coupling constants of J
N
Caa residues (except for the seventh residue) provided addi-
tional evidence for the structure. Although the Ca and Cb
protons of all the b-hGly residues displayed diastereotopici-
ty, only the sixth residue had two distinct coupling constants
(3J(HN,HCb =5.2 and 6.5 Hz). These observations show that
helical induction in methanol is significantly weaker than
that observed in CDCl3.
The above observations on induction and propagation of
helicity in achiral b-peptides (R,S,R) helix-capped at both
the C- and N-terminus, along with the findings of Gellman
et al.,[11a] naturally led us to study single-capped peptides 29
and 30 (capped at the C terminus) and 31 and 32 (capped at
the N terminus).
The CD spectra[32] of peptides 8–11 (Figure 9a), 13–15
(Figure 9b), and 29–32 (Figure 9c) were obtained from solu-
tions in methanol (c=0.2 mm). Peptides 13–15 and 29–32
showed distinct maxima at about 202 nm, with positive
molar ellipticity (q) values above 195 nm, which is consistent
with a 12/10-helix.[26,28,35] These results, as indicated from the
NMR spectroscopic studies, show that as the b-hGly se-
quence becomes longer, the value of q decreases, which im-
plies that integrity of the helical folds is being challenged
and, thus, the robustness of the 12/10-helix is compromised.
However, the observed lower molar ellipticity values[32]
for peptides 8–11, with maxima less-than-half as intense
compared to 13–15, may be attributed to weak helical induc-
tion by a single chiral amino acid residue relative to tem-
plate-mediated induction by 12 (see reference [28] for the
CD spectrum). In addition, the CD data is consistent with
the NMR spectroscopic observations for stronger helical in-
duction from the N terminus.[32]
The CD spectra of all of the peptides, except for 8,
showed similar q maxima that corresponded to a 12/10-
helix. As already discussed, a comparison of the NMR spec-
troscopic data of 8 and 9 in CDCl3 indicated the presence of
a 12/10-helix in peptide 8, although the induction was shown
to be stronger in 9. Consistent with NMR spectroscopic ob-
servations, the CD spectrum of 9 in methanol reflects a
better definition of the 12/10-helix, with a maxima at q=
204 nm. However, for 8, the CD spectrum looked different,
which suggested very weak 12/10-helical folding (Figure 9a).
Having observed a rather distinctive helical induction by
end capping b-hGly oligomers with (R)-b-Caa, we thought it
was meaningful to explore the generality of this induction
with other b-amino acids. To extend the study, cyclic and
acylic b-amino acids trans-3-aminopyran-2-carboxylic acid
(APyC) 34[36] and b-hPhe 35 were utilized for the synthesis
of end-capped pentapeptides 36 and 37 (Figure 10), respec-
tively, to further understand the helical induction.
1
From the H NMR spectrum of 29 and 30, two isomers
were found in equilibrium, in ratios of 70:30 and 75:25, re-
spectively. The results show that the major isomers contain
all the signatures of a 12/10-helix.[32] For the minor isomers,
although several hydrogen-bonded amide protons were ob-
served, it was not possible to get many structural details.
The MD structure for the major isomer of 29 confirmed the
12/10-helix,[32] whereas for 30 such calculations could not be
undertaken due to spectral overlap and broadening of the
resonances.
Similarly, both peptides 31 and 32, end capped with a
single (R,S,R) helix at the N terminus, displayed all the char-
acteristic signatures for the presence and propagation of a
mixed 12/10-helix. The exchange peaks in the ROESY spec-
tra of 31 and 32 imply an equilibrium between two isomers,
in which the populations of the minor isomers was too small
to be determined (probably <1%), unlike in 29 and 30.
It was gratifying to learn that 12/10-helical folds were in-
duced in oligomers rich in b-hGly residues (13–15 and 29–
32) by the robust terminal (R,S,R)-helical segments. The ob-
servation that a helix at either the C- or N-terminus is ade-
quate to induce the desired helical fold in the achiral b-hGly
oligomer is notable. All four peptides 29–32 generated a
mixed 12/10-helix as the major isomer, although the pep-
ACHTUNGTRENNUNGtides capped at the N terminus have shown one isomer
almost excusively and, thus, appear to have more robust
helices.
To evaluate the effectiveness of helical induction by (R)-
b-Caa in polar solvents, NMR spectroscopic studies were
also carried out on 13 in deuterated methanol (c=3–5 mm);
a 98:2 ratio of major/minor isomer was detected. H/D ex-
change studies of the amide protons are typically used to
obtain information on hydrogen bonding in CD3OD. For
peptide 13 it was observed that the amide protons of the
fourth to sixth b-hGly residues exchange rapidly (within a
minute), whereas all the protons of the (R,S,R)-helical
motifs, except NH(1), were present for about an hour.[32]
This implies that the template has a weak tendency to retain
Synthesis of peptides 36 and 37: The synthesis of the pepti-
des 36 and 37 is outlined in Scheme 4. Accordingly, coupling
of acid 16b with salt 38 (prepared from 34[36] in the presence
of EDCI, HOBt, and DIPEA in CH2Cl2) furnished dipep-
tide 39 (88%), which on reaction with CF3COOH in CH2Cl2
Chem. Eur. J. 2012, 18, 16046 – 16060
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16053

G. V. M. Sharma, A. C. Kunwar et al.
Figure 10. Structures of monomers 34 and 35 and peptides 36 and 37.
Scheme 4. Synthesis of peptides 36 and 37. Reagents and conditions:
a) HOBt (1.2 equiv), EDCI (1.2 equiv), DIPEA (2 equiv), dry CH2Cl2,
08C–RT; b) CF3COOH, dry CH2Cl2, 2 h; c) 4n NaOH (aq), MeOH,
08C–RT, 2 h.
HOBt, DIPEA) with salt 44 (prepared from 35) in CH2Cl2
to give tripeptide 45 (75%), which afforded salt 46 on expo-
sure to CF3COOH in CH2Cl2. Likewise, coupling of acid 47
(prepared from 35) with salt 16a under standard peptide
coupling conditions furnished dipeptide 48 (71%), which
gave acid 49 after hydrolysis with 4n NaOH (aq). Finally,
treatment of 49 with salt 46 in the presence of EDCI,
HOBt, and DIPEA in CH2Cl2 furnished pentapeptide 37
(29%).
Figure 9. a) CD spectra of peptides 8, 9, 10, and 11 in MeOH; b) CD
spectra of peptides 13, 14, and 15 in MeOH; c) CD spectra of peptides
29, 30, 31, and 32 in MeOH.
gave salt 40. Coupling of acid 41 (prepared from 34)[36] with
salt 17b under standard conditions afforded tripeptide 42
(79%). Hydrolysis of 42 with 4n NaOH (aq) afforded acid
43. Finally, treatment of 43 with salt 40, in the presence of
EDCI, HOBt, and DIPEA in CH2Cl2 furnished pentapep-
tide 36 (60%).
1
Conformational analysis of 36 and 37: The H NMR spec-
Similarly, synthesis of peptide 37 was achieved from 35 as
shown in Scheme 4. Thus, acid 17a was coupled (EDCI,
trum of 36 in CDCl3 (293 K)[32] showed a well-dispersed
spectrum, which implied the presence of secondary structure
16054
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16046 – 16060

Induction of Helical Preferences in Achiral b-Peptides
FULL PAPER
(>99% population). Except NH(1), all of the amide pro-
tons resonated at d> 7 ppm, which indicated their participa-
tion in hydrogen bonding. This was further confirmed by the
small Dd value detected from solvent titration studies[31]
(Dd<0.38 ppm). For the (S,S)-APyC residues, coupling con-
NH(1), resonated at d>7.2 ppm, which indicated their par-
ticipation in hydrogen bonding. The small Dd value detected
from solvent titration studies[31] (Dd<0.39 ppm) further con-
firmed the presence of hydrogen bonding. In the major
isomer, the large coupling constant (3J
ACTHNUGTRNE(UNG HN,HCb)>8.5 Hz) for
3
3
stants J(HN,HCb >9.1 Hz and J
N
b-hPhe shows an anti-periplanar arrangement of NH and
CbH. Due to severe spectral overlap, many of the coupling
constants could not be obtained, especially for the b-hGly
residues. However, the presence of characteristic nOe corre-
lations [CbH(1)/NH(3), CbH(3)/NH(5), CbH(1)/CaꢂH(3),
CbH(3)/CaꢂH(5), NH(4)/NH(5), NH(2)/CaꢂH(3), and
NH(4)/CaꢂH(5)] provides sufficient evidence for the pres-
ence of a 12/10-helix.
sistent with fꢁꢀ1208 and qꢁ608. Strong nOe correlations
for NH(i)/CaH(i) support the deduced value of q. For the b-
3
hGly residues coupling constants of J
(HN,HCb)>9.4 Hz or
3J
ACHTUNGTRENNUNG ACHTUNGTRENNUGN
(HN,HCb)<2.7 Hz and 3J(HCa,HCb)>12.5 Hz or 3J-
ACHTUNGTRENNUNG
careful examination of the coupling constants suggests that
they are consistent with angles of fꢁꢀ1208 for b-hGly(2)
and b-hGly(4) and fꢁ1208 for b-hGly(3). The data further
indicates that qꢁ608 for all the b-hGly residues. Additional-
ly, the nOe correlations CbH(1)/NH(3), CbH(1)/CaH(3)-
In the case of the minor isomer,[32] the amide protons
NH(3) and NH(5) resonate at d>7.8 ppm and, additionally,
a small Dd value supports their involvement in hydrogen
A
E
N
bonding (Dd<0.23 ppm). For b-hPhe, the coupling constant
3
N
value of J(HN,HCb)>8.5 Hz suggests the anti-periplanar ar-
G
NH(4)/NH(5), along with the values of the coupling con-
stants, emphatically support the propagation of a 12/10-helix
along the length of the oligomer. These results are compara-
ble with those derived for the analogous peptide 10, end
capped with (R)-b-Caa. Twenty superimposed low-energy
structures of 36 obtained from the MD calculations[32] are
shown in Figure 11. The average RMSD values of the back-
bone and heavy atoms are 0.31 and 0.56 ꢁ, respectively. The
CD spectrum in methanol supports the presence of a secon-
dary structure.[32]
rangement of NH and CbH. Lack of sufficient information
for the coupling constants and nOe correlations prevented
the elucidation of the structure of the minor isomer, as was
the case with other peptides.
The above analyses on peptides 36 and 37 amply demon-
strates that chiral induction of a 12/10-helix in achiral b-pep-
tides can be achieved by b-amino acids other than b-Caa.
The preorganized cyclic b-amino acid 34 almost exclusively
generated
weaker for the unconstrained b-amino acid 35 with a pro-
teinogenic side chain.
We performed variable temperature (VT) NMR studies
a 12/10-helix, whereas induction was much
NMR spectroscopic studies on peptide 36 were also car-
ried out in deuterated methanol;[32] a ratio of 94:6 for the
major/minor populated isomers was detected in CD3OH. H/
D exchange studies in CD3OD showed that all of the amide
proton resonances disappeared within 1 h, suggestive of
weak helical induction. Observation of only a few nOe cor-
relations [NH(1)/NH(2), NH(2)/NH(3), and CbH(1)/NH(3)]
further supported the presence of a weak helical structure
and the substantial population of disordered structures.
A
ACHTUNGTRENNUNG
1
on 37 because of the very good quality of the H NMR spec-
trum, with sharp resonances, as well as the largest popula-
tion of the minor isomer among the peptides investigated. A
study between T=223 K and 298 K showed that the popula-
tion of the minor isomer is practically unchanged (33ꢄ2%
at 223 K and 37ꢄ2% at 298 K). From the populations of
the two isomers, it was inferred that the major isomer is en-
ergetically more favored by ꢁ0.3 kcalmolꢀ1 relative to the
minor isomer.[32] The energy differences between the major
and minor isomers of all the peptides are provided in the
Supporting Information.
1
The H NMR spectra of peptide 37 in CDCl3 (273 K)[32]
showed the presence of two isomers in equilibrium in a ratio
of 63:37. For the major isomer all the amide protons, except
Finally, it is pertinent to mention that all of the peptides,
whether end capped with chiral residues or templated, have
shown the induction of helicity and distereotopicity in the b-
hGly residues. Diastereotopicity was observed for the Ca
and Cb protons of all the b-hGly residues in the peptides
end capped with (R)-b-Caa or the tripeptide helical tem-
plate, which enables them to be used as reporter groups to
indicate chiral induction in an achiral b-peptide.[10,33] Inter-
estingly, the peptides with a d-galactose protecting group do
not induce such universal diastereotopicity, which highlights
that the chemical environment in the helical backbone re-
sults in very significant asymmetry.
Yet another important finding of the study, as already dis-
cussed for peptide 13, emanates from the presence of a 12/
10-helical structure in most of the peptides. This implies that
b-hGly residues do not occupy the same conformational
Figure 11. Stereoviews of the superimposition of the 20 lowest-energy
structures of peptide 36 determined on the basis of NMR spectroscopic
measurements in solution in CDCl3 (hydrogen bonds are shown as dotted
lines).
Chem. Eur. J. 2012, 18, 16046 – 16060
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16055

G. V. M. Sharma, A. C. Kunwar et al.
[degcm2 dmolꢀ1 residueꢀ1]. Restraint molecular dynamics (MD) studies
were carried out by using the INSIGHT-II Discover module. The con-
straints were derived from the volume integrals obtained from the
ROESY spectra by using a two-spin approximation and a reference dis-
tance of 1.8 ꢁ for the geminal protons. The upper and lower bounds of
the distance constraints were obtained by enhancement and reduction of
the derived distance by 10%.
space, which infers the split behavior. Thus, the amide pro-
tons of the even-numbered b-hGly residues participated in
hydrogen bonding with the CO moiety of the subsequent
residue [NH(i)···COACHTUNGTRNEUNG(N i+1)], whereas the amide protons of
the odd-numbered residues [except NH(1)] participated in
hydrogen bonding with the carbonyl group located three
Peptide 17:
A solution of 16 (1.2 g, 6.34 mmol), HOBt (1.02 g,
residues behind [NH(i)···CO
(iꢀ3)]. Thus, it is important to
7.61 mmol), and EDCI (1.46 g, 7.61 mmol) in CH2Cl2 (25 mL) was stirred
at 08C under N2 atmosphere for 15 min, then treated sequentially with
amine salt 16a (0.88 g, 6.34 mmol) and DIPEA (2.18 mL, 12.6 mmol) and
stirred at RT for 8 h. The reaction mixture was quenched at 08C with a
saturated aqueous solution of NH4Cl (15 mL). After 10 min, the reaction
mixture was diluted with CHCl3 (20 mL), washed with 1n HCl (15 mL),
water (15 mL), a saturated aqueous solution of NaHCO3 (15 mL), and
brine (15 mL). The organic layer was dried (Na2SO4), evaporated, and
the residue was purified by column chromatography (60–120 mesh silica
gel, 55% EtOAc/petroleum ether) to give 17 (1.42 g, 82%) as a white
solid. M.p. 143–1458C; 1H NMR (500 MHz, CDCl3): d=6.18 (m, 1H;
NH-2), 5.16 (m, 1H; NH-1), 3.70 (s, 3H; COOCH3), 3.53 (m, 2H; CbH-
2), 3.38 (m, 2H; CbH-1), 2.54 (m, 2H; CaH-2), 2.37 (m, 2H; CaH-1),
1.43 ppm (s, 9H; Boc); 13C NMR (100 MHz, CDCl3): d=172.5, 171.4,
156.0, 78.9, 51.3, 36.5, 36.2, 34.9, 33.9, 28.3 ppm (3C); IR (KBr): n˜ =3290,
3080, 2927, 2854, 2355, 1734, 1638, 1536, 1293, 1174, 1107 cmꢀ1; MS
(FAB): m/z calcd (%) for C12H22N2O5: 275 (52) [M+H]+, 175 (100)
[M+HꢀBoc]+.
Peptide 7: A mixture of 16 (0.2 g, 0.76 mmol), HOBt (0.12 g, 0.92 mmol),
and EDCI (0.17 g, 0.92 mmol) in CH2Cl2 (15 mL) was stirred at 08C for
15 min then treated with 19 [prepared from 6 (0.44 g, 0.76 mmol) and
CF3COOH (0.5 mL) in CH2Cl2 (4 mL)] and DIPEA (0.26 mL,
1.53 mmol)] under N2 atmosphere for 8 h. Workup as described for 17
and purification by column chromatography (60–120 mesh silica gel,
4.2% methanol/CHCl3) gave 7 (0.31 g, 56%) as a white solid. M.p. 228–
2308C; [a]2D5 =ꢀ60.0 (c=0.1 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
7.29 (m, 1H; NH-5), 7.21 (m, 1H; NH-3), 7.19 (m, 1H; NH-2), 6.98 (m,
1H; NH-4), 5.57 (d, J=5.0 Hz, 1H; C1H), 5.44 (m, 1H; NH-1), 4.64 (dd,
J=2.5, 8.1 Hz, 1H; C3H), 4.37 (dd, J=2.5, 5.0 Hz, 1H; C2H), 4.34 (dd,
J=8.7, 11.8 Hz, 1H; C6H), 4.25 (m, 1H; C4H), 4.25 (m, 1H; C6H), 4.08
(ddd, J=1.9, 3.1, 8.7 Hz, 1H; C5H), 3.66 (m, 1H; CbH-5), 3.58 (m, 2H;
CbH-3), 3.54 (m, 2H; CbH-2), 3.52 (m, 2H; CbH-4), 3.48 (m, 2H; CbH-
1), 3.44 (m, 1H; CbH-5), 2.63 (m, 1H; CaH-5), 2.58 (m, 1H; CaH-5),
2.42 (m, 2H; CaH-1), 2.41 (m, 2H; CaH-3), 2.36 (m, 2H; CaH-4), 2.34
(m, 2H; CaH-2), 1.52 (s, 3H; CH3), 1.46 (s, 6H; 2ꢃCH3), 1.34 (s, 3H;
CH3), 1.43 ppm (s, 9H; Boc); 13C NMR (150 MHz, CDCl3): d=172.3,
172.1, 172.0, 171.9, 171.6, 156.2, 109.8, 108.9 (2C), 96.2 (2C), 79.3, 70.8,
70.4, 66.0, 63.8, 37.1, 36.6, 36.3, 36.0, 35.9, 35.8, 35.5, 34.5, 29.7, 28.3 (3C),
25.8 (2C), 24.8, 24.3 ppm; IR (KBr): n˜ =3301, 3080, 2929, 1743, 1638,
1544, 1544, 1257, 1071, 1006, 800, 699 cmꢀ1; HRMS (ESI): m/z calcd for
C32H53N5O13Na: 738.3537 [M+Na]+; found: 738.3515.
note that to accommodate a mixed 12/10-helix, b-hGly resi-
dues participate in alternate 10- and 12-membered-ring hy-
drogen bonding, which implicates split behavior.
Conclusion
The present account delineates that chirality from a single
chiral b-amino acid [(R)-b-Caa] can efficiently induce helici-
ty (12/10-mixed helix) in achiral b-peptides derived from b-
hGly residues. It was also demonstrated that the nucleation
of helicity mediated by template capping of peptides with
short and robust preorganized motifs is an elegant strategy.
In addition, it was evident that induction from the N termi-
nus led to more robust helical patterns relative to those
capped at the C terminus. Chiral induction was inferred by
the observed diastereotopicity of the Ca and Cb protons of
the b-hGly residues in all of the peptides studied. The pres-
ence of a minor folded structure was noticed for all of the
peptides, in which several amide protons were hydrogen-
bonded, yet it was not possible to exactly decipher the fold-
ing pattern. The generality of the chiral induction was fur-
ther reiterated by the studies on peptides end capped with
(S,S)-APyC and b-hPhe. Stronger helical induction was ob-
served by end capping with a preorganized b-amino acid,
relative to the b-amino acids with less-constrained side
chains. This study also exemplifies the split behavior of b-
hGly; alternating b-hGly units participate in 12- and 10-
membered-ring hydrogen bonding to form robust 12/10 heli-
ces. These results provide, for the first time, the experimen-
tal evidence for the reported theoretical predictions of the
preference for a 12/10-helical fold in b-peptides in apolar
solvents. It establishes that proper nucleation plays a pivotal
role in defining the helix formation and stability in oligo-
Peptide 8:
A mixture of 17a (0.1 g, 0.38 mmol), HOBt (0.06 g,
ACHTUNGTRENNUNG
0.46 mmol), and EDCI (0.09 g, 0.46 mmol) in CH2Cl2 (5 mL) was stirred
at 08C for 15 min then treated with 21a [prepared from 21 (0.2 g,
0.38 mmol) and CF3COOH (0.2 mL) in CH2Cl2 (2 mL)] and DIPEA
(0.13 mL, 0.76 mmol) under N2 atmosphere at RT for 8 h. Workup was as
described for 17 and purification by column chromatography (60–120
mesh silica gel, 2.5% methanol/CHCl3) gave 8 (0.19 g, 76%) as a white
solid. M.p. 1858C; [a]2D5 =+207.33 (c=0.1 in CHCl3); IR (KBr): n˜ =3310,
ACHTUNGTRENNUNG
might facilitate further novel conformations.
Experimental Section
3017, 1658, 1514, 1440, 1216, 759, 670 cmꢀ1
.
Major isomer: 1H NMR (600 MHz, CDCl3): d=7.58 (d, J=8.1 Hz, 1H;
NH-5), 7.30 (t, J=6.1 Hz, 1H; NH-2), 7.24 (dd, J=5.2, 7.1 Hz, 1H; NH-
3), 7.19 (dd, J=5.2, 7.1 Hz, 1H; NH-4), 5.39 (t, J=6.3 Hz, 1H; NH-1),
4.89 (s, 1H; C1H-5), 4.77 (dd, J=3.5, 6.0 Hz, 1H; C3H-5), 4.70 (ddt, J=
4.6, 7.2, 8.1 Hz, 1H; CbH-5), 4.54 (d, J=6.0 Hz, 1H; C2H-5), 4.02 (dd,
J=3.5, 7.2 Hz, 1H; C4H-5), 3.81 (m, 1H; CbH(pro-R)-3), 3.72 (m, 1H;
CbH(pro-S)-2), 3.70 (m, 1H; CbH(pro-S)-4), 3.70 (s, 3H; COOCH3), 3.58
General: NMR spectra (1D and 2D experiments) for all the peptides
were obtained in CDCl3 at 500, 600, and 700 MHz (1H), and at 100, 150,
and 175 MHz (13C). Chemical shifts (d) are reported in ppm with respect
to an internal tetramethylsilane reference. IR spectra were recorded with
a FTIR spectrometer as KBr pellets in the range n˜ =400–4000 cmꢀ1
.
Melting points were determined in open capillaries and were not correct-
ed. The CD spectra were obtained with a spectropolarimeter by using
rectangular fused quartz cells of 0.2 cm path length as solutions in metha-
nol (200 mm). The binomial method was used to smooth the spectra. The
values are expressed in terms of the total molar ellipticity (q)
(dddd, J=4.2, 6.3, 8.6, 13.5 Hz, 1H; CbH(pro-R)-1), 3.39 (m, 1H; CbH(pro-S)
-
3), 3.39 (m, 1H; CbH(pro-S)-1), 3.33 (m, 1H; CbH(pro-R)-4), 3.33 (m, 1H;
CbH(pro-R)-2), 3.30 (s, 3H; OCH3), 2.86 (dd, J=4.6, 14.2 Hz, 1H; CaH(pro-
16056
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16046 – 16060

Induction of Helical Preferences in Achiral b-Peptides
FULL PAPER
R)-5), 2.63 (dd, J=8.1, 14.2 Hz, 1H; CaH(pro-S)-5), 2.46 (m, 1H; CaH(pro-S)
-
(dt, J=13.3, 3.3 Hz, 1H; CaH(pro-R)-3), 2.48 (ddd, J=4.5, 9.7, 13.8, 1H;
CaH(pro-S)-5), 2.44 (dt, J=5.0, 13.3, 1H; CaH(pro-S)-3), 2.40 (t, J=12.5 Hz,
1H; CaH(pro-R)-1), 2.25 (ddd, J=3.1, 3.9, 13.5 Hz, 1H; CaH(pro-R)-2), 2.21
(m, 1H; CaH(pro-S)-4), 2.19 (m, 1H; CaH(pro-R)-4), 2.06 (ddd, J=3.1, 11.8,
13.5 Hz, 1H; CaH(pro-S)-2), 1.51 (s, 3H; CH3), 1.49 (s, 3H; CH3), 1.43 ppm
(s, 9H; Boc).
1), 2.46 (m, 1H; CaH(pro-R)-3), 2.37 (m, 1H; CaH(pro-S)-3), 2.37 (m, 1H;
CaH(pro-R)-1), 2.30 (m, 1H; CaH(pro-S)-4), 2.30 (m, 1H; CaH(pro-S)-2), 2.30
(m, 1H; CaH(pro-R)-4), 2.30 (m, 1H; CaH(pro-R)-2), 1.49 (s, 3H; CH3), 1.43
(s, 9H; Boc), 1.31 ppm (s, 3H; CH3); 13C NMR (150 MHz, CDCl3): d=
173.9, 173.0, 172.2, 172.0, 171.6, 156.2, 112.7, 106.7, 84.7, 79.5, 79.4, 78.8,
54.7, 52.2, 46.1, 39.2, 37.6, 37.3, 37.2, 36.9, 36.7, 36.3, 36.2, 35.9, 28.3 (3C),
25.9, 24.4 ppm.
Minor isomer: 1H NMR (600 MHz, CDCl3): d=8.13 (d, J=8.5 Hz, 1H;
NH-5), 7.99 (dd, J=3.5, 9.0 Hz, 1H; NH-3), 7.62 (dd, J=4.6, 8.2 Hz, 1H;
NH-4), 6.99 (dd, J=3.6, 9.1 Hz, 1H; NH-2), 6.38 (dd, J=1.9, 8.4 Hz, 1H;
NH-1), 4.89 (s, 1H; C1H-5), 4.77 (dd, J=3.5, 6.0 Hz, 1H; C3H-5), 4.70
(m, 1H; CbH-5), 4.54 (d, J=6.0 Hz, 1H; C2H-5), 4.03 (m, 1H; CbH-3),
3.98 (dd, J=3.5, 7.8 Hz, 1H; C4H-5), 3.91 (m, 1H; CbꢂH-2), 3.81 (m,
1H; CbꢂH-4), 3.74 (m, 1H; CbꢂH-1), 3.70 (s, 3H; COOCH3), 3.32 (m,
1H; CbꢂH-3), 3.30 (s, 3H; OCH3), 3.28 (m, 1H; CbH-1), 3.27 (m, 1H;
CbH-2), 3.23 (m, 1H; CbH-4), 3.00 (dd, J=3.5, 13.3 Hz, 1H; CaH-5),
2.54 (dd, J=9.3, 13.3 Hz, 1H; CaꢂH-5), 2.51 (m, 1H; CaH-3), 2.49 (m,
1H; CaH-1), 2.46 (m, 1H; CaꢂH-3), 2.36 (m, 1H; CaꢂH-1), 2.23 (m, 1H;
CaꢂH-4), 2.23 (m, 1H; CaH-4), 2.22 (m, 1H; CaH-2), 2.10 (ddd, J=3.0,
10.5, 13.5 Hz, 1H; CaꢂH-2), 1.49 (s, 3H; CH3), 1.31 (s, 3H; CH3),
1.43 ppm (s, 9H; Boc); HRMS (ESI): m/z calcd for C29H49N5O12Na:
682.3275 [M+Na]+; found: 682.3286.
Peptide 10:
A solution of ester 22 (0.2 g, 0.38 mmol) in methanol
(1.5 mL) was treated with 4n NaOH (1.5 mL) at 08C–RT for 2 h.
Workup as described for 17a gave the acid 22a.
A mixture of 22a (0.15 g, 0.29 mmol), HOBt (0.04 g, 0.35 mmol), and
EDCI (0.06 g, 0.35 mmol) in CH2Cl2 (5 mL) was stirred at 08C for 15 min
then treated with 23a [prepared from 23 (0.13 g, 0.29 mmol) and
CF3COOH (0.15 mL) in CH2Cl2 (1 mL)] and DIPEA (0.1 mL,
0.59 mmol) under N2 atmosphere at RT for 8 h. Workup as described for
17 and purification by column chromatography (60–120 mesh silica gel,
2% methanol/CHCl3) gave 10 (0.19 g, 79%) as a white solid. M.p.
1408C; [a]2D5 =ꢀ174.66 (c=0.1 in CHCl3); 1H NMR (600 MHz, CDCl3):
d=8.51 (dd, J=3.3, 9.8 Hz, 1H; NH-3), 8.47 (d, J=8.8 Hz, 1H; NH-5),
8.06 (dd, J=3.6, 9.5 Hz, 1H; NH-2), 7.54 (dd, J=4.0, 9.5 Hz, 1H; NH-4),
5.90 (d, J=10.3 Hz, 1H; NH-1), 4.93 (s, 1H; C1H-1), 4.89 (s, 1H; C1H-
5), 4.78 (dd, J=3.4, 5.8 Hz, 1H; C3H-5), 4.74 (dd, J=3.5, 5.8 Hz, 1H;
C3H-1), 4.70 (m, 1H; CbH-5), 4.70 (m, 1H; CbH-1), 4.54 (d, J=5.8 Hz,
1H; C2H-5), 4.54 (d, J=5.8 Hz, 1H; C2H-1), 4.15 (dddd, J=3.3, 9.8,
12.8, 13.1 Hz, 1H; CbH(pro-R)-3), 4.00 (ddt, J=9.5, 13.7, 4.0 Hz, 1H;
CbH(pro-S)-2), 3.96 (dd, J=3.5, 5.1 Hz, 1H; C4H-1), 3.91 (m, 1H; CbH(pro-
S)-4), 3.90 (dd, J=3.4, 8.1 Hz, 1H; C4H-5), 3.70 (s, 3H; COOCH3), 3.30
(s, 3H; OCH3), 3.29 (s, 3H; OCH3), 3.20 (ddt, J=4.3, 13.1, 3.3 Hz, 1H;
CbH(pro-S)-3), 3.10 (dddd, J=2.4, 3.6, 4.0, 12.0 Hz, 1H; CbH(pro-R)-4), 3.06
(dd, J=3.7, 13.1 Hz, 1H; CaH(pro-S)-5), 2.99 (dddd, J=2.6, 3.6, 12.1,
13.7 Hz, 1H; CbH(pro-R)-2), 2.67 (dd, J=2.6, 12.5 Hz, 1H; CaH(pro-S)-1),
2.51 (dt, J=13.0, 3.3 Hz, 1H; CaH(pro-S)-3), 2.46 (dd, J=9.3, 13.1 Hz, 1H;
CaH(pro-R)-5), 2.40 (ddd, J=4.3, 12.8, 13.0 Hz, 1H; CaH(pro-R)-3), 2.35 (dd,
J=12.1, 12.5 Hz, 1H; CaH(pro-R)-1), 2.31 (ddd, J=3.6, 12.1, 12.5 Hz, 1H;
CaH(pro-R)-4), 2.27 (ddd, J=4.0, 12.1, 12.4 Hz, 1H; CaH(pro-R)-2), 2.16
(ddd, J=2.4, 4.3, 12.5 Hz, 1H; CaH(pro-S)-4), 2.13 (ddd, J=2.6, 4.0,
12.4 Hz, 1H; CaH(pro-S)-2), 1.52 (s, 3H; CH3), 1.49 (s, 3H; CH3), 1.31 (s,
3H; CH3), 1.30 (s, 3H; CH3), 1.43 ppm (s, 9H; Boc); 13C NMR
(150 MHz, CDCl3): d=174.3, 173.6, 173.0, 171.8, 170.7, 157.0, 112.8,
112.7, 107.0, 106.5, 84.9, 84.7, 80.2 (2C), 54.6, 52.4, 51.2, 51.0, 50.2, 46.3,
40.4, 39.2, 38.8, 37.8, 37.6, 37.0, 36.8, 36.7, 36.3, 28.4, 28.2 (3C), 26.0, 25.6,
24.8, 24.3 ppm; IR (KBr): n˜ =3302, 3088, 2984, 2938, 1740, 1646, 1550,
1441, 1372, 1240, 1169, 1103, 1017, 857, 590 cmꢀ1; HRMS (ESI): m/z
calcd for C37H61N5O16Na: 854.4113 [M+Na]+; found: 854.4142.
Peptide 9: A solution of ester 22 (0.2 g, 0.38 mmol) in methanol (1.5 mL)
was treated with 4n NaOH (1.5 mL) at 08C–RT for 2 h. Workup as de-
scribed for 17a gave acid 22a.
A mixture of acid 22a (0.15 g, 0.29 mmol), HOBt (0.05 g, 0.35 mmol),
and EDCI (0.06 g, 0.35 mmol) in CH2Cl2 (10 mL) was stirred at 08C for
15 min then treated with 17b [prepared from 17 (0.08 g, 0.29 mmol) and
CF3COOH (0.1 mL) in CH2Cl2 (1 mL)] and DIPEA (0.1 mL, 0.59 mmol)
under N2 atmosphere at RT for 8 h. Workup as described for 17 and puri-
fication by column chromatography (60–120 mesh silica gel, 2.5% metha-
nol/CHCl3) gave 9 (0.15 g, 79%) as a white solid. M.p. 188–1908C;
[a]2D5 =+167.50 (c=0.25 in CHCl3); IR (KBr): n˜ =3312, 3017, 2360, 1653,
1440, 1215, 1099, 759, 669 cmꢀ1; HRMS (ESI): m/z calcd for C29H50N5O12
:
660.3455 [M+H]+; found: 660.3473.
Major isomer: 1H NMR (500 MHz, CDCl3): d=8.35 (dd, J=3.7, 9.2 Hz,
1H; NH-3), 8.11 (dd, J=4.5, 7.8 Hz, 1H; NH-5), 7.92 (dd, J=4.0, 9.0 Hz,
1H; NH-2), 7.19 (dd, J=4.7, 8.5 Hz, 1H; NH-4), 5.91 (d, J=6.6 Hz, 1H;
NH-1), 4.92 (s, 1H; C1H-1), 4.75 (dd, J=3.6, 6.0 Hz, 1H; C3H-1), 4.68
(m, 1H; CbH-1), 4.54 (d, J=6.0 Hz, 1H; C2H-1), 4.02 (m, 1H; CbH(pro-
R)-3), 3.97 (dd, J=3.6, 5.0 Hz, 1H; C4H-1), 3.94 (m, 1H; CbH(pro-S)-2),
3.89 (dddd, J=3.8, 7.8, 8.7, 13.3 Hz, 1H; CbH(pro-R)-5), 3.82 (m, 1H;
CbH(pro-S)-4), 3.70 (s, 3H; COOCH3), 3.33 (ddt, J=6.2, 13.2, 4.5 Hz, 1H;
CbH(pro-S)-5), 3.28 (s, 3H; OCH3), 3.27 (ddt, J=3.7, 13.1, 4.0 Hz, 1H;
CbH(pro-S)-3), 3.20 (m, 1H; CbH(pro-R)-4), 3.07 (dddd, J=3.0, 4.0, 11.6,
Peptide 13:
A solution of ester 31 (0.4 g, 0.39 mmol) in methanol
(1.6 mL) was treated with 4n NaOH (1.6 mL) at 08C–RT for 2 h.
Workup as described for 17a gave the acid 31a.
13.2 Hz, 1H; CbH(pro-R)-2), 2.69 (ddd, J=3.8, 6.2, 14.3 Hz, 1H; CaH(pro-S)
-
A mixture of 31a (0.07 g, 0.07 mmol), HOBt (0.01 g, 0.09 mmol), and
EDCI (0.02 g, 0.09 mmol) in CH2Cl2 (10 mL) was stirred at 08C for
15 min then treated with 28a [prepared from 28 (0.07 g, 0.07 mmol) and
CF3COOH (0.07 mL) in CH2Cl2 (0.5 mL)] and DIPEA (0.02 mL,
0.14 mmol) under N2 atmosphere at RT for 8 h. Workup as described for
17 and purification by column chromatography (60–120 mesh silica gel,
2.5% methanol/CHCl3) gave 13 (0.09 g, 70%) as a white solid. M.p.
1508C; [a]2D5 =+386.1 (c=0.5 in CHCl3); 1H NMR (600 MHz, CDCl3):
d=9.19 (dd, J=3.4, 9.1 Hz, 1H; NH-4), 9.09 (J=9.5, Hz 1H; NH-7),
8.97 (d, J=9.4 Hz, 1H; NH-3), 8.81 (dd, J=4.1, 9.0 Hz, 1H; NH-6), 8.79
(dd, J=3.3, 8.4 Hz, 1H; NH-5), 8.72 (d, J=9.5 Hz, 1H; NH-9), 8.51 (d,
J=9.6 Hz, 1H; NH-2), 7.94 (d, J=9.4 Hz, 1H; NH-8), 5.96 (d, J=9.4 Hz,
1H; NH-8), 5.96 (d, J=10.3 Hz, 1H; NH-1), 5.10 (dd, J=3.3, 5.9 Hz,
1H; C3H-8), 5.01 (dd, J=3.3, 5.9 Hz, 1H; C3H-2), 4.93 (s, 1H; C1H-2),
4.90 (s, 1H; C1H-1), 4.89 (s, 1H; C1H-9), 4.88 (s, 1H; C1H-8), 4.86 (s,
1H; C1H-7), 4.83 (s, 1H; C1H-3), 4.79 (dd, J=3.4, 5.8 Hz, 1H; C3H-9),
4.75 (m, 1H; CbH-9), 4.74 (dd, J=3.0, 5.7 Hz; C3H-7), 4.72 (m, 1H;
CbH-1), 4.71 (dd, J=3.4, 5.9 Hz, 1H; C3H-1), 4.69 (dd, J=3.2, 5.9 Hz,
1H; C3H-3), 4.66 (m, 1H; CbH-7), 4.65 (m, 1H; CbH-3), 4.61 (m, 1H;
CbH-2), 4.58 (d, J=5.9 Hz, 1H; C2H-2), 4.56 (d, J=5.7 Hz; C2H-9), 4.53
(d, J=5.7 Hz; C2H-7), 4.53 (d, J=5.9 Hz, 1H; C2H-1), 4.52 (d, J=
5.9 Hz, 1H; C2H-3), 4.50 (m, 1H; CbH-8), 4.45 (d, J=5.9 Hz, 1H; C2H-
5), 2.66 (dd, J=2.8, 12.6 Hz, 1H; CaH(pro-S)-1), 2.46 (ddd, J=4.5, 8.7,
14.3 Hz, 1H; CaH(pro-R)-5), 2.43 (m, 1H; CaH(pro-S)-3), 2.40 (ddd, J=4.0,
11.8, 13.2 Hz, 1H; CaH(pro-R)-3), 2.40 (dd, J=11.5, 12.6 Hz, 1H; CaH(pro-
R)-1), 2.34 (ddd, J=3.8, 11.1, 13.2 Hz, 1H; CaH(pro-R)-4), 2.28 (ddd, J=3.8,
11.6, 12.6 Hz, 1H; CaH(pro-R)-2), 2.20 (ddd, J=2.8, 4.3, 13.2 Hz, 1H;
CaH(pro-S)-4), 2.19 (ddd, J=3.0, 4.2, 12.6 Hz, 1H; CaH(pro-S)-2), 1.51 (s,
3H; CH3), 1.49 (s, 3H; CH3), 1.43 ppm (s, 9H; Boc); 13C NMR
(150 MHz, CDCl3): d=173.6, 172.9, 172.4, 172.2, 170.5, 156.6, 112.7,
106.5, 84.7, 80.2, 79.9, 79.6, 54.5, 52.0, 49.4, 39.8, 37.4, 37.3, 36.7, 36.4,
36.0, 35.7, 35.5, 34.4, 28.3 (3C), 25.5, 24.3 ppm.
Minor isomer: 1H NMR (500 MHz, CDCl3): d=8.25 (dd, J=2.5, 9.7 Hz,
1H; NH-3), 8.17 (dd, J=4.5, 7.7 Hz, 1H; NH-5), 7.40 (dd, J=4.3, 9.0 Hz,
1H; NH-4), 6.92 (dd, J=2.6, 10.3 Hz, 1H; NH-2), 6.59 (d, J=9.9 Hz,
1H; NH-1), 4.85 (s, 1H; C1H-1), 4.70 (dd, J=3.1, 5.7 Hz, 1H; C3H-1),
4.56 (m, 1H; CbH-1), 4.51 (d, J=5.7 Hz, 1H; C2H-1), 4.17 (dddd, J=3.5,
9.7, 13.3, 13.5 Hz, 1H; CbH(pro-S)-3), 4.05 (m, 1H; CbH(pro-R)-2), 3.99 (m,
1H; CbH(pro-S)-5), 3.89 (dddd, J=3.2, 4.3, 9.0, 12.5 Hz, 1H; CbH(pro-R)-4),
3.70 (s, 3H; COOCH3), 3.69 (dd, J=3.1, 8.3 Hz, 1H; C4H-1), 3.28 (s,
3H; OCH3), 3.26 (m, 1H; CbH(pro-R)-5), 3.17 (m, 1H; CbH(pro-R)-3), 3.15
(m, 1H; CbH(pro-S)-4), 3.13 (m, 1H; CbH(pro-S)-2), 2.73 (dd, J=2.8,
12.6 Hz, 1H; CaH-1), 2.70 (ddd, J=4.0, 6.7, 13.8 Hz, 1H; CaH-5), 2.52
Chem. Eur. J. 2012, 18, 16046 – 16060
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16057

G. V. M. Sharma, A. C. Kunwar et al.
8), 4.30 (ddt, J=3.3, 13.9, 8.4 Hz, 1H; CbH(pro-R)-5), 4.08 (dd, J=3.3,
10.5 Hz, 1H; C4H-8), 4.06 (dd, J=3.3, 10.5 Hz, 1H; C4H-2), 4.04 (dd,
J=3.2, 9.7 Hz, 1H; C4H-3), 3.98 (m, 1H; CbH(pro-S)-4), 3.96 (dd, J=3.4,
9.2 Hz, 1H; C4H-9), 3.94 (dd, J=3.4, 9.5 Hz, 1H; C4H-1), 3.94 (m, 1H;
CbH(pro-S)-6), 3.70 (s, 3H; COOCH3), 3.34 (s, 3H; OCH3), 3.32 (s, 6H; 2ꢃ
OCH3), 3.31 (s, 3H; OCH3), 3.23 (s, 3H; OCH3), 3.22 (s, 3H; OCH3),
3.13 (dt, J=13.9, 3.3 Hz, 1H; CbH(pro-S)-5), 3.05 (dd, J=2.9, 12.3 Hz, 1H;
CaH-3), 3.02 (dd, J=3.5 Hz, 12 Hz, 1H; CaH(pro-S)-7), 2.96 (dd, J=2.6,
12.4 Hz, 1H; CaH(pro-S)-9), 2.96 (m, 1H; CbH(pro-R)-5), 2.94 (m, 1H;
CbH(pro-R)-6), 2.74 (dd, J=2.0, 12.8 Hz, 1H; CaH-1), 2.65 (dt, J=12.5,
3.3 Hz, 1H; CaH-3), 2.56 (dd, J=3.0, 12.9 Hz, 1H; CaH-2), 2.47 (m, 1H;
CaH(pro-R)-7), 2.46 (m, 1H; CaH(pro-R)-8), 2.45 (m, 1H; CaH(pro-R)-6), 2.44
(m, 1H; CaH(pro-S)-5), 2.43 (t, J=12.4 Hz, CaH(pro-R)-9), 2.40 (m, 1H;
CaH(pro-S)-8), 2.37 (m, 1H; CaH(pro-R)-1), 2.27 (dt, J=4.5, 12.5 Hz;
CaH(pro-R)-4), 2.21 (t, J=12.3 Hz, 1H; CaH-3), 2.17 (t, J=12.5 Hz;
CaH(pro-R)-7), 2.10 (dt, J=12.6, 3.6 Hz, 1H; CaH(pro-S)-7), 2.08 (m, 1H;
CaH(pro-S)-4), 1.52 (s, 3H; CH3), 1.49 (s, 3H; CH3), 1.48 (s, 6H; 2ꢃCH3),
1.43 (s, 3H; CH3), 1.40 (s, 3H; CH3), 1.31 (s, 3H; CH3), 1.30 (s, 6H; 2ꢃ
CH3), 1.28 (s, 6H; 2ꢃCH3), 1.27 (s, 3H; CH3), 1.42 ppm (s, 9H; Boc);
13C NMR (150 MHz, CDCl3): d=174.2, 173.1 (2C), 172.4, 171.4, 170.8
(2C), 169.7, 169.3, 157.0, 112.9, 112.8 (2C), 112.4, 112.3 (2C), 112.2 (2C),
108.0, 107.7, 107.3, 106.9, 106.6, 106.5, 85.1 (2C), 84.9, 84.8 (2C), 81.6,
81.2, 80.4, 79.8, 79.6 (2C), 79.5, 79.2 (2C), 78.9, 55.2 (2C), 54.9, 54.3 (2C),
54.2, 54.1, 52.3 (2C), 50.2, 47.7, 46.7, 46.3, 46.2, 45.9, 42.4, 41.8, 40.6, 39.5
(2C), 38.5, 37.3, 37.2, 36.9, 36.8, 36.5, 36.4, 29.7, 28.3 (3C), 26.4, 26.2, 26.1
(2C), 26.0, 25.7, 25.1, 25.0, 24.8, 24.6, 24.3, 24.1 ppm; IR (KBr): n˜ =3300,
CaH(pro-R)-7), 2.23 (m, 1H; CaH(pro-R)-3), 2.22 (m, 1H; CaH(pro-R)-9), 2.12
(m, 1H; CaH(pro-S)-8), 2.10 (m, 1H; CaH(pro-S)-4), 2.08 (m, 1H; CaH(pro-S)
-
6), 1.52 (s, 3H; CH3), 1.49 (s, 3H; CH3), 1.48 (s, 3H; CH3), 1.47 (s, 3H;
CH3), 1.42 (s, 3H; CH3), 1.40 (s, 3H; CH3), 1.31 (s, 3H; CH3), 1.29 (s,
6H; 2ꢃCH3), 1.28 (s, 6H; 2ꢃCH3), 1.27 (s, 3H; CH3), 1.42 ppm (s, 9H;
Boc); 13C NMR (150 MHz, CDCl3): d=174.1, 173.6, 173.1, 173.0, 172.8,
172.3, 172.0, 171.5, 170.9 (2C), 169.7, 169.3, 156.9, 112.8 (2C), 112.7 (2C),
112.4, 112.3 (2C), 112.2, 107.9, 107.3, 107.2, 106.9, 106.5 (2C), 106.4, 85.0,
84.9, 84.8 (2C), 81.1 (2C), 80.3, 79.8, 79.6, 79.5, 79.4, 79.3, 79.2, 79.1, 79.0,
78.9, 55.1, 54.7, 54.3, 54.2 (2C), 54.1, 52.4, 50.2, 47.5, 46.7, 46.3, 46.2, 45.8,
42.0, 41.7, 40.5, 39.5, 39.3, 39.0, 38.8, 38.5, 37.3, 37.2, 37.1, 36.8, 36.7, 36.4,
36.3, 28.3 (3C), 26.3 (2C), 26.1 (2C), 25.6, 25.0 (2C), 24.8 (2C), 24.5,
24.2 ppm (2C); IR (KBr): n˜ =3292, 3089, 2986, 2940, 1650, 1533, 1444,
1377, 1206, 1100, 1026, 966, 516 cmꢀ1; HRMS (ESI): m/z calcd for
C87H141N11O38: 973.9714 [M+2H]2+; found: 973.9717.
Peptide 15: A solution of ester 33 (0.07 g, 0.04 mmol) in methanol
(0.3 mL) was treated with 4n NaOH (0.3 mL) at 08C–RT for 2 h.
Workup as described for 17a gave the acid 33a.
A mixture of 33a (0.06 g, 0.04 mmol), HOBt (0.01 g, 0.05 mmol), and
EDCI (0.01 g, 0.05 mmol) in CH2Cl2 (5 mL) was stirred at 08C for 15 min
then treated with 29a [prepared from 29 (0.05 g, 0.04 mmol) and
CF3COOH (0.05 mL) in CH2Cl2 (0.4 mL)] and DIPEA (0.01 mL,
0.09 mmol) under nitrogen atmosphere at RT for 8 h. Workup as descri-
bed for 17 and purification by column chromatography (60–120 mesh
silica gel, 5% methanol/CHCl3) gave 15 (0.07 g, 68%) as a white solid.
M.p. 2108C; [a]2D5 =+191.9 (c=0.25 in CHCl3); 1H NMR (600 MHz,
CDCl3): d=9.07 (dd, J=2.7, 9.8 Hz, 1H; NH-7), 9.04 (dd, J=4.1, 9.5 Hz,
1H; NH-4), 9.04 (d, J=9.5 Hz, 1H; NH-11), 8.97 (d, J=9.5 Hz, 1H; NH-
3), 8.91 (dd, J=3.0, 9.8 Hz, 1H; NH-9), 8.89 (dd, J=3.5, 9.8 Hz, 1H;
NH-5), 8.87 (dd, J=3.8, 9.4 Hz, 1H; NH-10), 8.77 (dd, J=4.0, 9.1 Hz,
1H; NH-8), 8.71 (d, J=9.8 Hz, 1H; NH-13), 8.59 (dd, J=4.1, 9.2 Hz,
1H; NH-6), 8.46 (d, J=9.7 Hz, 1H; NH-2), 7.93 (d, J=9.2 Hz, 1H; NH-
12), 5.99 (d, J=10.2 Hz, 1H; NH-1), 5.10 (dd, J=3.3, 5.9 Hz, 1H; C3H-
12), 4.97 (dd, J=3.3, 5.8 Hz, 1H; C3H-2), 4.90 (s, 1H; C1H-1), 4.90 (s,
1H; C1H-2), 4.89 (s, 1H; C1H-13), 4.88 (s, 1H; C1H-12), 4.85 (s, 1H;
C1H-11), 4.84 (s, 1H; C1H-3), 4.79 (dd, J=3.6, 5.9 Hz, 1H; C4H-13),
4.78 (m, 1H; CbH-13), 4.74 (dd, J=3.0, 6.0 Hz, 1H; C4H-11), 4.72 (dd,
J=3.0, 6.3 Hz, 1H; C3H-3), 4.72 (m, 1H; CbH-1), 4.70 (m, 1H; CbH-3),
4.69 (dd, J=3.0, 5.9 Hz, 1H; C3H-1), 4.69 (m, 1H; CbH-11), 4.60 (dddd,
J=3.2, 4.5, 9.7, 10.0 Hz, 1H; CbH-2), 4.56 (d, J=5.9 Hz, 1H; C3H-13),
4.53 (d, J=5.9 Hz, 1H; C2H-1), 4.52 (d, J=3.9 Hz, 1H; C3H-12), 4.51
(d, J=6.0 Hz, 1H; C3H-11), 4.50 (m, 1H; CbH-12), 4.48 (d, J=5.8 Hz,
1H; C2H-2), 4.45 (d, J=6.3 Hz, 1H; C2H-3), 4.42 (m, 1H; CbH(pro-R)-7),
4.41 (m, 1H; CbH(pro-R)-5), 4.39 (m, 1H; CbH(pro-R)-9), 4.08 (dd, J=3.3,
10.2 Hz, 1H; C4H-12), 4.04 (dd, J=3.3, 10.3 Hz, 1H; C4H-2), 4.03 (dd,
J=3.0, 9.3 Hz, 1H; C4H-3), 4.00 (m, 1H; CbH(pro-S)-4), 3.99 (m, 1H;
CbH(pro-S)-6), 3.96 (m, 1H; CbH(pro-S)-10), 3.96 (dd, J=3.6, 9.0 Hz, 1H;
CbH-13), 3.96 (dd, J=3.0, 9.0 Hz, 1H; C4H-1), 3.86 (dd, J=3.1, 8.9 Hz,
1H; CbH-11), 3.70 (s, 3H; COOCH3), 3.33 (s, 3H; OCH3), 3.31 (s, 6H;
2ꢃOCH3), 3.30 (s, 3H; OCH3), 3.24 (s, 3H; OCH3), 3.22 (s, 3H; OCH3),
3.22 (m, 1H; CbH(pro-S)-7), 3.20 (m, 1H; CbH(pro-S)-9), 3.03 (m, 1H;
3090, 2987, 2939, 1650, 1554, 1445, 1377, 1272, 1099, 880, 593 cmꢀ1
;
HRMS (ESI): m/z calcd for C81H131N9O36: 902.9343 [M+2H]2+; found:
902.9343.
Peptide 14: A solution of ester 32 (0.17 g, 0.14 mmol) in methanol
(0.6 mL) was treated with 4n NaOH (0.6 mL) at 08C–RT for 2 h.
Workup as described for 17a gave the acid 32a.
A mixture of 32a (0.06 g, 0.05 mmol), HOBt (0.01 g, 0.06 mmol), and
EDCI (0.01 g, 0.06 mmol) in CH2Cl2 (5 mL) was stirred at 08C for 15 min
then treated with 28a [prepared from 28 (0.05 g, 0.05 mmol) and
CF3COOH (0.05 mL) in CH2Cl2 (0.5 mL)] and DIPEA (0.02 mL,
0.1 mmol) under N2 atmosphere at RT for 8 h. Workup as described for
17 and purification by column chromatography (60–120 mesh silica gel,
3% methanol/CHCl3) gave 14 (0.07 g, 70%) as a white solid. M.p.
1558C; [a]2D5 =+477.2 (c=0.5 in CHCl3); 1H NMR (600 MHz, CDCl3):
d=9.05 (d, J=9.6 Hz, 1H; NH-9), 9.02 (dd, J=3.9, 9.6 Hz, 1H; NH-4),
8.96 (dd, J=3.2, 10.1 Hz, 1H; NH-7), 8.93 (d, J=9.4 Hz, 1H; NH-3),
8.86 (dd, J=3.5, 9.6 Hz, 1H; NH-5), 8.84 (dd, J=3.9, 9.4 Hz, 1H; NH-8),
8.69 (d, J=9.4 Hz, 1H; NH-11), 8.65 (dd, J=4.0, 9.1 Hz, 1H; NH-6),
8.44 (d, J=9.8 Hz, 1H; NH-2), 7.91 (d, J=9.3 Hz, 1H; NH-10), 5.97 (d,
J=10.3 Hz, 1H; NH-1), 5.10 (dd, J=3.3, 5.7 Hz, 1H; C3H-10), 4.97 (dd,
J=3.2, 5.7 Hz, 1H; C3H-2), 4.90 (s, 1H; C1H-1), 4.90 (s, 1H; C1H-2),
4.89 (s, 1H; C1H-11), 4.88 (s, 1H; C1H-10), 4.85 (s, 1H; C1H-9), 4.84 (s,
1H; C1H-3), 4.79 (dd, J=3.2, 5.7 Hz; C3H-11), 4.77 (m, 1H; CbH-11),
4.73 (dd, J=3.3, 5.7 Hz, 1H; C3H-1), 4.72 (dd, J=3.0, 5.7 Hz, 1H; C3H-
3), 4.71 (m, 1H; CbH-1), 4.69 (m, 1H; CbH-3), 4.69 (dd, J=3.0, 5.7 Hz,
1H; C3H-9), 4.66 (m, 1H; CaH-9), 4.59 (ddt, J=3.2, 4.5, 9.8 Hz, 1H;
CbH-2), 4.55 (d, J=5.7 Hz; C2H-11), 4.53 (d, J=5.7 Hz, 1H; C2H-1),
4.52 (d, J=5.7 Hz, 1H; C2H-3), 4.51 (d, J=5.7 Hz, 1H; C3H-9), 4.50 (m,
CaH(pro-S)-3), 3.00 (t, J=12.6 Hz, 1H; CaH-11), 2.98 (m, 1H; CbH(pro-R)
-
10), 2.98 (m, 1H; CbH(pro-R)-8), 2.91 (m, 1H; CbH(pro-R)-4), 2.96 (m, 1H;
CaH(pro-S)-13), 2.95 (m, 1H; CbH(pro-R)-6), 2.74 (m, 1H; CaH(pro-S)-1), 2.72
(ddd, J=2.8, 5.8, 13.0 Hz, 1H; CaH-7), 2.72 (m, 1H; CaH(pro-S)-9), 2.63
(dt, J=12.8, 2.8 Hz, 1H; CaH-5), 2.57 (dd, J=3.0, 13.0 Hz, 1H; CaH-2),
2.48 (m, 1H; CaH(pro-R)-2), 2.45 (m, 1H; CaH(pro-R)-12), 2.45 (m, 1H;
CaH(pro-R)-6), 2.45 (m, 1H; CaH(pro-R)-5), 2.45 (m, 1H; CaH(pro-S)-12), 2.43
(m, 1H; CaH(pro-R)-13), 2.40 (m, 1H; CaH(pro-R)-1), 2.34 (m, 1H; CaH(pro-
R)-10), 2.33 (m, 1H; CaH(pro-R)-6), 2.30 (m, 1H; CaH(pro-R)-9), 2.30 (m,
1H; CaH(pro-S)-11), 2.29 (m, 1H; CaH(pro-R)-8), 2.23 (m, 1H; CaH(pro-R)-3),
2.22 (dt, J=6.0, 12.6 Hz, 1H; CaH(pro-R)-4), 2.12 (m, 1H; CaH(pro-S)-4),
2.12 (m, 1H; CaH(pro-S)-10), 2.11 (m, 1H; CaH(pro-S)-6), 2.11 (m, 1H;
CaH(pro-S)-8), 1.52 (s, 3H; CH3), 1.50 (s, 3H; CH3), 1.49 (s, 3H; CH3),
1.48 (s, 3H; CH3), 1.40 (s, 3H; CH3), 1.31 (s, 3H; CH3), 1.30 (s, 3H;
CH3), 1.29 (s, 3H; CH3), 1.28 (s, 3H; CH3), 1.27 (s, 6H; 2ꢃCH3),
1.42 ppm (s, 9H; Boc); 13C NMR (150 MHz, CDCl3): d=174.1, 173.6,
173.0, 172.9, 179.8 (2C), 172.3, 172.1, 171.5, 170.9, 170.8, 169.7, 169.3,
156.9, 112.8, 112.7, 112.4, 112.3, 112.2, 107.9, 107.3, 107.2, 106.9, 106.5,
1H; CbH-10), 4.45 (d, J=5.7 Hz, 1H; C2H-10), 4.37 (m, 1H; CbH(pro-R)
-
7), 4.36 (m, 1H; CbH(pro-R)-5), 4.08 (dd, J=3.3, 10.3 Hz, 1H; C4H-10),
4.04 (dd, J=3.0, 9.4 Hz, 1H; C4H-3), 4.03 (dd, J=3.2, 8.4 Hz, 1H; C4H-
2), 3.98 (m, 1H; CbH(pro-S)-6), 3.97 (m, 1H; CbH(pro-S)-4), 3.97 (dd, J=3.3,
9.2 Hz, 1H; C4H-1), 3.95 (dd, J=3.2, 9.2 Hz, 1H; CbH-11), 3.95 (m, 1H;
CbH(pro-S)-8), 3.86 (dd, J=3.0, 8.8 Hz, 1H; C4H-9), 3.70 (s, 3H;
COOCH3), 3.29 (s, 6H; 2ꢃOCH3), 3.24 (s, 6H; 2ꢃOCH3), 3.22 (s, 6H;
2ꢃOCH3), 3.20 (m, 1H; CbH(pro-S)-5), 3.14 (m, 1H; CbH(pro-S)-7), 2.96 (m,
1H; CaH(pro-S)-11), 2.96 (m, 1H; CbH(pro-R)-4), 2.95 (m, 1H; CbH(pro-R)-8),
2.92 (m, 1H; CbH(pro-R)-6), 2.73 (m, 1H; CaH(pro-R)-1), 2.72 (m, 1H;
CaH(pro-S)-7), 2.62 (dt, J=12.8, 3.0 Hz, 1H; CaH(pro-S)-5), 2.57 (dd, J=3.0,
12.9 Hz, 1H; CaH(pro-S)-2), 2.47 (m, 1H; CaH(pro-R)-2), 2.45 (m, 1H;
CaH(pro-R)-5), 2.45 (m, 1H; CaH-10), 2.44 (m, 1H; CaH(pro-R)-11), 2.42
(m, 1H; CaH(pro-R)-6), 2.42 (m, 1H; CaH-10), 2.40 (m, 1H; CaH(pro-S)-1),
2.33 (m, 1H; CaH(pro-R)-8), 2.29 (m, 1H; CaH(pro-R)-4), 2.27 (m, 1H;
16058
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16046 – 16060

Induction of Helical Preferences in Achiral b-Peptides
FULL PAPER
106.4, 85.0 (2C), 84.9, 84.8 (2C), 81.1, 80.3, 79.8, 79.5 (2C), 79.4, 79.3,
79.2, 78.8, 55.1 (2C), 54.7 (2C), 54.3 (2C), 54.2 (2C), 54.1 (2C), 52.4 (2C),
50.2, 47.5, 46.7, 46.3, 46.2, 45.8, 42.0, 41.7, 40.5, 39.5, 39.3, 39.0, 38.8, 38.5,
37.3 (2C), 37.2, 37.0, 36.9, 36.8, 36.7, 36.4, 28.2 (3C), 26.3 (2C), 26.1 (2C),
26.0, 25.6, 25.0, 24.9, 24.8, 24.5, 24.2 ppm (2C); IR (KBr): n˜ =3294, 3090,
2986, 2938, 1649, 1553, 1443, 1376, 1272, 1208, 1099, 1026, 965, 878,
3712–3715; e) R. A. Brown, T. Marcelli, M. D. Poli, J. Sola, J. Clay-
den, Angew. Chem. Int. Ed. 2012, 51, 1395–1399.
[11] a) J. D. Sadowsky, M. A. Schmitt, H. S. Lee, N. Umezawa, S. Wang,
Y. Tomita, S. H. Gellman, J. Am. Chem. Soc. 2005, 127, 11966–
11968; b) J. D. Sadowsky, W. D. Fairlie, E. B. Hadley, H. S. Lee, N.
Umezawa, Z. Nikolovska-Coleska, S. Wang, D. C. S. Huang, Y.
Tomita, S. H. Gellman, J. Am. Chem. Soc. 2007, 129, 139–154;
c) W. S. Horne, S. H. Gellman, Acc. Chem. Res. 2008, 41, 1399–
1408; d) E. F. Lee, J. D. Sadowsky, B. J. Smith, P. E. Czabotar, K. J.
Peterson-Kauman, P. M. Colman, S. H. Gellman, W. D. Fairlie,
Angew. Chem. 2009, 121, 4382–4386; Angew. Chem. Int. Ed. 2009,
48, 4318–4322.
593 cm-1; HRMS (ESI): m/z calcd for C93H151N13O40
[M+2H]2+; found: 1045.5118.
: 1045.5101
[12] G. V. M. Sharma, N. Chandramouli, C. Madavi, P. Nagendar, K. V. S.
Ramakrishna, A. C. Kunwar, P. Schramm, H.-J. Hofmann, J. Am.
Chem. Soc. 2009, 131, 17335–17344.
[13] a) A. Aubry, M. Marraud, Biopolymers 1989, 28, 109–122; b) C. To-
niolo, Int. J. Peptide Protein Res. 1990, 35, 287–305.
[14] a) G. P. Dado, S. H. Gellman, J. Am. Chem. Soc. 1994, 116, 1054–
1162; b) M. Marraud, J. Neel, J. Polym. Sci. Polym. Symp. 1975, 52,
271–282.
Acknowledgements
The authors are thankful for financial support from CSIR, New Delhi,
grant number MLP-0010. S.R.K., S.K.D., S.V., K.N., G.A., and S.J.B. are
thankful to UGC and CSIR, New Delhi, for financial support in the form
of fellowships.
[15] E. Navarro, C. Aleman, J. Piggali, J. Am. Chem. Soc. 1995, 117,
7307–7310.
[1] a) M. Siedlecka, G. Goch, A. Ejchart, H. Sticht, A. Bierzynski, Proc.
Natl. Acad. Sci. USA 1999, 96, 903–908 and references cited there-
in; b) A. Patgiri, A. L. Jochim, P. S. Arora, Acc. Chem. Res. 2008, 41,
1289–1300.
[16] a) R. Kishore, Tetrahedron Lett. 1996, 37, 5747–5750; b) A. K.
Thakur, R. Kishore, Tetrahedron Lett. 1998, 39, 9553–9556; c) A. K.
Thakur, R. Kishore, Tetrahedron Lett. 1999, 40, 5091–5094.
[17] a) J. D. Glickson, J. Applequist, Macromolecules 1969, 2, 628–634;
b) J. Applequist, J. D. Glickson, J. Am. Chem. Soc. 1971, 93, 3276–
3280; c) K. A. Bode, J. Applequist, Macromolecules 1997, 30, 2144–
2150.
[18] J. M. Fernꢆndez-Santꢇn, J. Ayamami, A. Rodriguez-Galan, S.
Munoz-Guerra, J. A. Subirana, Nature 1984, 311, 53–54.
[19] a) V. Pavone, A. Lombardi, X. Yang, C. Pedone, B. Di Blasio, Bio-
polymers 1990, 30, 189–196; b) B. Di Blasio, A. Lombardi, X. Yang,
C. Pedone, V. Pavone, Biopolymers 1991, 31, 1181–1188.
[2] a) E. Yashima, K. Maeda, H. Iida, Y. Furusho, K. Nagai, Chem. Rev.
2009, 109, 6102–6211; b) K. Maeda, E. Yashima, Top. Curr. Chem.
2006, 265, 47–88; c) T. Nakano, Y. Okamoto, Chem. Rev. 2001, 101,
4013–4038; d) S. Hecht, I. Huc, (Eds.), Foldamers: Structure, Prop-
erties and Applications, Wiley-VCH: Weinheim, Germany, 2007;
e) D. J. Hill, M. J. Mio, R. B. Prince, T. S. Hughes, J. S. Moore,
Chem. Rev. 2001, 101, 3893–4011; f) S. H. Gellman, Acc. Chem. Res.
1998, 31, 173–180; g) E. W. Meijer, A. R. A. Palmans, Angew.
Chem. 2007, 119, 9106–9126; Angew. Chem. Int. Ed. 2007, 46, 8948–
8968; h) M. M. Green, C. Andreola, B. Munoz, M. P. Reidy, K.
Zero, J. Am. Chem. Soc. 1988, 110, 4063–4065; i) M. M. Green,
N. C. Peterson, T. Sato, A. Teramoto, R. Cook, S. Lifson, Science
1995, 268, 1860–1866; j) M. Tanaka, K. Anan, Y. Demizu, M. Kuri-
hara, M. Doi, H. Suemune, J. Am. Chem. Soc. 2005, 127, 11570–
11571; k) M. Tanaka, Y. Demizu, M. Doi, M. Kurihara, H. Suemune,
Angew. Chem. 2004, 116, 5474–5477; Angew. Chem. Int. Ed. 2004,
43, 5360–5363; l) M. Nagano, M. Tanaka, M. Doi, Y. Demizu, M.
Kurihara, H. Suemune, Org. Lett. 2009, 11, 1135–1137; m) S. Royo,
W. M. Borggraeve, B. De, C. Peggion, F. Fernando, M. Crisma, A. I.
Jimenez, C. Cativiela, C. Toniolo, J. Am. Chem. Soc. 2005, 127,
2036–2037; n) T. A. Martinek, F. Fꢄlçp, Chem. Soc. Rev. 2012, 41,
687–702.
[3] B. Pengo, F. Formaggio, M. Crisma, C. Toniolo, G. M. Bonora, Q. B.
Broxterman, J. Kamphuis, M. Savioano, R. Iacovino, F. Rossi, E.
Beneditti, J. Chem. Soc. Perkin Trans. 2 1998, 1651–1657.
[4] Y. Inai, Y. Kurokawa, T. Hirabayashi, Biopolymers 1999, 49, 551–
564.
[5] Y. Inai, K. Tagawa, A. Takasu, T. Hirabayashi, T. Oshikawa, M. Ya-
mashita, J. Am. Chem. Soc. 2000, 122, 11731–11732.
[6] a) Y. Inai, Y. Ishida, K. Tagawa, A. Takasu, T. Hirabayashi, J. Am.
Chem. Soc. 2002, 124, 2466–2473; b) N. Ousaka, Y. Inai, J. Org.
Chem. 2009, 74, 1429–1439.
[7] N. Ousaka, Y. Inai, J. Am. Chem. Soc. 2006, 128, 14736–14737.
[8] C. Shellman, In Protein Folding; Jaenicke, R., Ed.; Elsevier: Am-
sterdam, 1980; pp. 53–64.
[9] a) H. Jiang, C. Dolain, J.-M. Leger, H. Gornitzka, I. Huc, J. Am.
Chem. Soc. 2004, 126, 1034–1035; b) C. Dolain, H. Jiang, J.-M.
Leger, P. Guionneau, I. Huc, J. Am. Chem. Soc. 2005, 127, 12943–
12951.
[10] a) J. Clayden, L. Lemiegre, G. A. Morris, M. Pickworth, T. J. Snape,
L. H. Jones, J. Am. Chem. Soc. 2008, 130, 15193–15202; b) J. Solꢅ,
M. Helliwell, J. Clayden, J. Am. Chem. Soc. 2010, 132, 4548–4549;
c) J. Solꢅ, S. P. Fletcher, A. Castellanos, J. Clayden, Angew. Chem.
2010, 122, 6988–6991; Angew. Chem. Int. Ed. 2010, 49, 6836–6839;
d) J. Solꢅ, G. A. Morris, J. Clayden, J. Am. Chem. Soc. 2011, 133,
[20] a) K. Mçhle, R. Gꢄnther, M. Thormann, N. Sewald, H.-J. Hofmann,
Biopolymers 1999, 50, 167–184; b) R. Gꢄnther, H.-J. Hofmann,
Helv. Chim. Acta 2002, 85, 2149–2168; c) C. Baldauf, R. Gꢄnther,
H.-J. Hofmann, Helv. Chim. Acta 2003, 86, 2573–2588; d) C. Bal-
dauf, R. Gꢄnther, H.-J. Hofmann, Angew. Chem. 2004, 116, 1621–
1624; Angew. Chem. Int. Ed. 2004, 43, 1594–1597; e) C. Baldauf, R.
Gꢄnther, H.-J. Hofmann, J. Org. Chem. 2004, 69, 6214–6220; f) C.
Baldauf, R. Gꢄnther, H.-J. Hofmann, Biopolymers 2005, 80, 675–
687.
[21] a) Y.-D. Wu, D.-P. Wang, J. Am. Chem. Soc. 1998, 120, 13485–
13493; b) Y.-D. Wu, D.-P. Wang, J. Am. Chem. Soc. 1999, 121, 9352–
9362; c) Y.-D. Wu, J.-Q. Lin, Y.-L. Zhao, Helv. Chim. Acta 2002, 85,
3144–3161; d) Y.-D. Wu, W. Han, D.-P. Wang, Y. Gao, Y. L. Zhao,
Acc. Chem. Res. 2008, 41, 1418–1427.
[22] a) D. Seebach, J. L. Matthews, Chem. Commun. 1997, 2015–2022;
b) R. P. Cheng, S. H. Gellman, W. F. DeGrado, Chem. Rev. 2001,
101, 3219–3232; c) J. Venkatraman, S. C. Shankaramma, P. Balaram,
Chem. Rev. 2001, 101, 3131–3152; d) T. A. Martinek, F. Fꢄlçp, Eur.
J. Biochem. 2003, 270, 3657–3666; e) D. Seebach, A. K. Beck, D. J.
Bierbaum, Chem. Biodiversity 2004, 1, 1111–1239; f) C. M. Good-
man, S. Choi, S. Shandler, W. F. DeGrado, Nat. Chem. Biol. 2007, 3,
252–262; g) S. Hanessian, X. H. Luo, R. Schaum, S. Michnick, J.
Am. Chem. Soc. 1998, 120, 8569–8570; h) S. Hanessian, X. H. Luo,
R. Schaum, Tetrahedron Lett. 1999, 40, 4925–4929; i) P. G. Vasudev,
N. Shamala, K. Ananda, P. Balaram, Angew. Chem. 2005, 117, 5052–
5055; Angew. Chem. Int. Ed. 2005, 44, 4972–4975; j) C. Grison, P.
Coutrot, C. Geneve, C. Didierjean, M. Marraud, J. Org. Chem. 2005,
70, 10753–10764; k) L. Szabo, B. L. Smith, K. D. McReynolds, A. L.
Parrill, E. R. Morris, J. Gervay, J. Org. Chem. 1998, 63, 1074–1078.
[23] D. Seebach, P. E. Ciceri, M. Overhand, B. Jaun, D. Rigo, Helv.
Chim. Acta 1996, 79, 2043–2066.
[24] a) S. A. W. Gruner, V. Truffault, G. Voll, E. Locardi, M. Stçckle, H.
Kessler, Chem. Eur. J. 2002, 8, 4365–4376; b) S. Chandrasekhar,
S. M. Reddy, B. N. Babu, B. Jagadeesh, A. Prabhakar, B. Jagannadh,
J. Am. Chem. Soc. 2005, 127, 9664–9665.
Chem. Eur. J. 2012, 18, 16046 – 16060
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16059

G. V. M. Sharma, A. C. Kunwar et al.
[25] a) D. Seebach, M. Overhand, F. N. M. Kuhnle, B. Martinoni, L.
Oberer, U. Hommel, H. Widmer, Helv. Chim. Acta 1996, 79, 913–
941; b) D. H. Appella, L. A. Christianson, I. L. Karle, D. R. Powell,
S. H. Gellman, J. Am. Chem. Soc. 1996, 118, 13071–13072.
[26] a) G. V. M. Sharma, K. R. Reddy, P. R. Krishna, A. R. Sankar, K.
Narsimulu, S. K. Kumar, P. Jayaprakash, B. Jagannadh, A. C.
Kunwar, J. Am. Chem. Soc. 2003, 125, 13670–13671; b) G. V. M.
Sharma, K. R. Reddy, P. R. Krishna, A. R. Sankar, K. Narsimulu,
S. K. Kumar, P. Jayaprakash, B. Jagannadh, A. C. Kunwar, Angew.
Chem. 2004, 116, 4051–4055; Angew. Chem. Int. Ed. 2004, 43, 3961–
3965.
[27] G. V. M. Sharma, V. G. Reddy, A. S. Chander, K. R. Reddy, Tetrahe-
dron: Asymmetry 2002, 13, 21–24.
[28] G. V. M. Sharma, V. Subash, K. Narsimulu, A. R. Sankar, A. C.
Kunwar, Angew. Chem. 2006, 118, 8387–8390; Angew. Chem. Int.
Ed. 2006, 45, 8207–8210.
[31] Solvent titration studies were carried out by sequentially adding up
to 33%v/v of [D6]-DMSO to solutions of the peptides in CDCl3
(600 mL).
[32] See the Supporting Information.
[33] J. Clayden, A. Castellanos, J. Sola, G. A. Morris, Angew. Chem.
2009, 121, 6076–6079; Angew. Chem. Int. Ed. 2009, 48, 5962–5965.
[34] The 3J
ACTHNUGTRNE(UNG HN,HCb) values for the third and fourth residue are J=5.2
and 7.1 Hz, whereas for the fifth residue J=8.2 Hz, which suggets a
dihedral angle of fꢁ1208.
[35] D. Seebach, K. Gademann, J. V. Schreiber, J. L. Matthews, T. Hinter-
mann, B. Jaun, L. Oberer, U. Hommel, H. Widmer, Helv. Chim.
Acta 1997, 80, 2033–2037.
[36] G. V. M. Sharma, K. Srinivas Reddy, S. Jeelani Basha, K. Ravinder
Reddy, A. V. S. Sharma, Org. Biomol. Chem. 2011, 9, 8102–8111.
[29] C. Dolain, J.-M. Leger, N. Delsuc, H. Gornitzka, I. Huc, Proc. Natl.
Acad. Sci. USA 2005, 102, 16146–16151.
[30] a) L. C. Chan, G. B. Cox, J. Org. Chem. 2007, 72, 8863–8869; b) M.
Bodanszky, Peptide Chemistry: A Practical Textbook, Springer: New
York, 1988.
Received: May 30, 2012
Revised: August 20, 2012
Published online: October 30, 2012
16060
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16046 – 16060