The design of α/β-peptides: Study on three-residue turn motifs and the influence of achiral glycine on helix and turn

Article abstract of DOI:10.1002/asia.201000438

Novel three-residue helix-turn secondary structures, nucleated by a helix at the N terminus, were generated in peptides that have 'β-Caa-L-Ala-L-Ala, ' 'β-Caa-L-Ala-γ-Caa,' and 'β-Caa-L-Ala-γ-Caa' (in which β-Caa is C-linked carbo-β-amino acid, γ-Caa is C-linked carbo-γ-amino acid, and γ-Caa is C-linked carbo-γ-amino acid) at the C terminus. These turn structures are stabilized by 12-, 14-, and 15-membered (mr) hydrogen bonding between NH(i)/CO(i+2) (i+2 is the last residue in the peptide) along with a 7-mr hydrogen bond between CO(i)/NH(i+2). In addition, a series of α/β-peptides were designed and synthesized with alternating glycine (Gly) and (S)-β-Caa to study the influence of an achiral α-residue on the helix and helix-turn structures. In contrast to previous results, the three 'β-α-β' residues at the C terminus (α-residue being Gly) are stabilized by only a 13-mr forward hydrogen bond, which resembles an α-turn. Extensive NMR spectroscopic and molecular dynamics (MD) studies were performed to support these observations. The influence of chirality and side chain is also discussed. A turn for the better: α/β-Peptides with novel turns (12/7-, 14/7-, and 15/7-) at the C terminus were prepared. Similarly, the design with glycine gave an opportunity to study the influence of achiral α-residues on helix formation and stability. This study also resulted in a new 13-membered 'turn' in the forward direction, which resembles the α-turn (see picture). Copyright

Full text of DOI:10.1002/asia.201000438

FULL PAPERS
DOI: 10.1002/asia.201000438
The Design of a/b-Peptides: Study on Three-Residue Turn Motifs and the
Influence of Achiral Glycine on Helix and Turn
Gangavaram V. M. Sharma,*[a] Nagula Chandramouli,[a] Shaik Jeelani Basha,[b]
Pendem Nagendar,[a] Kallaganti V. S. Ramakrishna,[b] and Akella V. S. Sarma*[b]
84
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 84 – 97

Abstract: Novel three-residue helix-
turn secondary structures, nucleated by
a helix at the N terminus, were gener-
ated in peptides that have ꢁb-Caa-l-
Ala-l-Ala,ꢂ ꢁb-Caa-l-Ala-g-Caa,ꢂ and
ꢁb-Caa-l-Ala-d-Caaꢂ (in which b-Caa is
C-linked carbo-b-amino acid, g-Caa is
C-linked carbo-g-amino acid, and d-
Caa is C-linked carbo-d-amino acid) at
the C terminus. These turn structures
are stabilized by 12-, 14-, and 15-mem-
bered (mr) hydrogen bonding between
NH(i)/CO
in the peptide) along with a 7-mr hy-
drogen bond between CO(i)/NH(i+2).
In addition, a series of a/b-peptides
were designed and synthesized with al-
ternating glycine (Gly) and (S)-b-Caa
to study the influence of an achiral a-
G
residue on the helix and helix-turn
structures. In contrast to previous re-
sults, the three ꢁb–a–bꢂ residues at the
C terminus (a-residue being Gly) are
stabilized by only a 13-mr forward hy-
drogen bond, which resembles an a-
turn. Extensive NMR spectroscopic
and molecular dynamics (MD) studies
were performed to support these obser-
vations. The influence of chirality and
side chain is also discussed.
Keywords: amino acids · foldamers ·
glycine
·
helical structures
·
peptides
Introduction
turns, which involve four residues by forming a hydrogen
bond between CO(i) and NH(i+3), are well studied, the re-
AHCTUNGTRENNUNG
Oligomers of nonproteinogenic amino acids, which are re-
ferred to as foldamers, form a variety of stable secondary
structures such as helices, sheets, and turns stabilized by
noncovalent interactions.[1] b-Peptides[2] are the most exten-
sively studied foldamers. They form a variety of helical
folds.[3] Most foldamers reported so far have homogeneous
backbones. Because of their well-defined folding propensi-
ties, a/b-peptides[4–8] with heterogeneous backbones that
contain a- and b-residues have received a lot of attention
and have been studied extensively.[4e] These hybrid peptides
have shown a variety of helical patterns including mixed hel-
ical structures.[6c] The a/b-peptide series with alternating
proteinogenic a- and cyclic b-residues, disclosed by Gellman
et al.,[4a] showed the propensity of an 11-helix and 14/15-
helix.[7] Sharma et al.[6a] have observed that a/b-peptides
with alternating l-Ala and C-linked carbo-b-amino acid (b-
Caa) that contain ꢁa–b–aꢂ residues at the C terminus display
a robust 11/9-mixed helix. Recently, Gellman et al.[9] have
reported the crystallographic characterization of oligomers
that contain 2:1 and 1:2 a/b-peptides, which can adopt a hel-
ports on turns that encompass three residues are limited.
Balaram et al.[12] have designed and studied a turn that con-
tains a central three-residue loop in a nine-residue natural
peptide. The turn is stabilized by a backward 13-membered
(mr) hydrogen bond between CO(3) and NH(7). Pavone
et al.,[13] by using a simple molecular model, studied an iso-
lated 13-membered a-turn with all trans peptide bonds. An
a-turn that consists of five amino acid residues, is stabilized
by an intramolecular hydrogen bond between the CO group
and the NH group of the first and fifth residues, respectively.
Very recently it was demonstrated[14] that a three-residue
turn with 1:1 a/b-peptides that terminates with ꢁb–a–bꢂ
shows a 13-mr turn at the C terminus by forming a forward
hydrogen bond between the NH of residue nÀ2 and CO of
the nth residue, which was further stabilized by a 7-mr turn
with a backward hydrogen bond between the CO of residue
nÀ2 and the NH of the nth residue. In this peptide series,
the b-residue was (S)-b-Caa and the a-residue was l-Ala/l-
Leu/l-Val. In the present study, we propose to explore a
new family of turns that contain ꢁb–a–a,ꢂ ꢁb–a–g,ꢂ and ꢁb–a–
dꢂ sequences at the C terminus initiated by a helix at the N
terminus. In this direction, the peptides 1, 2, 2a, and 2b
(Scheme 1) were designed with the intent to generate new
turn motifs. In the present work, we have also studied the
role of achiral a-amino acids such as glycine (Gly) for un-
derstanding the impact of the lack of a side chain in the a-
amino acid on the stability of helix and helix-turn structures.
For this purpose, the peptides 3–9 (Schemes 2 and 3) with
alternating a- and b-amino acids were designed, synthesized,
and studied. Furthermore, this study provides an opportuni-
ty to understand the effect of Gly when it is incorporated as
one of the three residues of the turn region at the C termi-
nus.
À
À
ical conformation that contains CO(i) NH
ACHTUNGTREN(NUNG i+3) and CO(i)
NH(i+4) hydrogen bonds depending upon the presence of
ACHTUNGTRENNUNG
a-amino acid residues in the foldamer backbone. The same
group has also reported[10] that a/b-peptides show binding
affinity towards the proapoptotic proteins of the Bcl-2
family. In addition to helices, the other secondary structures
that exist in peptides and proteins are reverse turns.[11]
Though b-turns are more frequently found, and reverse
[a] Dr. G. V. M. Sharma, N. Chandramouli, Dr. P. Nagendar
Organic Chemistry Division III
Indian Institute of Chemical Technology
Hyderabad 500 607 (India)
Fax : (+91)40-27160387/27193108
E-mail: esmvee@iict.res.in
[b] S. J. Basha, Dr. K. V. S. Ramakrishna, Dr. A. V. S. Sarma
Centre for Nuclear Magnetic Resonance
Indian Institute of Chemical Technology
Hyderabad 500 607 (India)
Results and Discussion
Synthesis of Peptides
The peptides 1, 2, 2a, 2b (Scheme 4), and 3–9 (Scheme 5)
were prepared from a-amino acids (l-Ala, Gly), b-amino
acids (b-hGly (b-alanine) and b-Caa),[15a,b] C-linked carbo-g-
E-mail: ssav@iict.res.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000438.
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85

G. V. M. Sharma, A. V. S. Sarma et al.
FULL PAPERS
in the presence of EDCI,
HOBt, and DIPEA in CH2Cl2,
furnished the heptapeptides 2a
(55%) and 2b (67%), respec-
tively.
The synthesis of the peptides
3–9 is outlined in Scheme 5.
Reaction
of
14
with
CF3COOH gave the salt 14a,
which, on treatment with com-
mercially available acid Boc-
Gly-OH 15a in the presence
of EDCI, HOBt, and DIPEA
in CH2Cl2, afforded the dipep-
tide 16 (89%). Independently,
on treatment with base (aq. 4n
NaOH) and CF3COOH, ester
16 gave the acid 16a and the
salt 16b, respectively. Peptide
coupling of acid 16a in the
presence of EDCI, HOBt, and
DIPEA with commercially
available HCl·HGly-OMe 15b
gave tripeptide 3 (78%). Simi-
larly, salt 3a, prepared from 3
and CF3COOH in CH2Cl2, on
coupling reaction with acid
16a furnished pentapeptide 4
(47%).
Reaction of acid 14b (pre-
pared from 14 by hydrolysis
with aq. 4n NaOH) with salt
15b in the presence of EDCI,
HOBt, and DIPEA in CH2Cl2
gave the dipeptide 17 (75%).
Hydrolysis of 17 with aq. 4n
NaOH furnished the acid 17a,
which, on coupling with salt
14a in CH2Cl2, afforded the
tripeptide 18 (77%). Further,
18 on base hydrolysis with aq.
4n NaOH gave acid 18a, and,
on exposure to CF3COOH fur-
nished the salt 18b. Coupling
Scheme 1. Structures of peptides 1, 2, 2a, and 2b (arrows indicate the hydrogen-bonding pattern).
amino acid (g-Caa),[15c] and C-linked carbo-d-amino acid (d-
Caa)[15d] by standard peptide coupling methods[16] using 1-
ethyl-3-(N,N-dimethylamino-1-propyl)carbodiimide (EDCI),
1-hydroxybenzotriazole (HOBt), and N,N-diisopropylethyl-
amine (DIPEA) in the solution phase.
(EDCI, HOBt, DIPEA) of acid 18a with salt 3a in CH2Cl2
gave the hexapeptide 5 in 45% yield. Likewise, peptide cou-
pling (EDCI, HOBt, DIPEA) of acid 15a with salt 18b fur-
nished the tetrapeptide 6 (52%), whereas reaction of acid
18a with salt 16b in the presence of EDCI, HOBt, and
DIPEA afforded the pentapeptide 7 (70%). Similarly, acid
3b (prepared from 3 and aq. 4n NaOH), on treatment with
salt 18b in the presence of EDCI, HOBt, and DIPEA in
CH2Cl2, gave the hexapeptide 8 in 59% yield.
Likewise, reaction of acid 15a with salt 15c (commercially
available; prepared from b-alanine) in the presence of
EDCI, HOBt, and DIPEA in CH2Cl2 afforded the dipeptide
19 (76%). Treatment of 19 with CF3COOH gave the salt
Peptide coupling of acid 10[14] with salt 11 in the presence
of EDCI, HOBt, and DIPEA in CH2Cl2 for 8 h afforded the
pentapeptide 1 in 63% yield. On exposure to CF3COOH
for 2 h, ester 12 gave the salt 12a, which, on reaction with
acid 13[14] in the presence of EDCI, HOBt, and DIPEA in
CH2Cl2, gave the tetrapeptide 2 in 54% yield. Peptide
13a[6a] on treatment with base (aq. 4n NaOH) gave the acid
13b, which, independently upon reaction with 12a and 12b
86
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Chem. Asian J. 2011, 6, 84 – 97

The Design of a/b-Peptides
NOE
correlations
NH(1)/
NH(2) and CaH(2)/NH(4) are
the distinctive NOEs that sup-
port the nucleation of 11/9-hy-
drogen bonding at the N termi-
nus. Further, the NOE correla-
tions NH(3)/NH(4), NH(4)/
NH(5),
NH(3)/NH(5),
and
CaH(2)/NH(5) have been used
to provide ample support for a
turn at the C terminus. The mo-
lecular dynamics (MD) studies
(see the Supporting Informa-
tion) on 1 very clearly indicated
the presence of a new turn sup-
ported by a 12-membered (mr)
hydrogen bond, which is further
stabilized by a 7-mr hydrogen
bond. The superposition of
twenty lowest-energy structures
with average pairwise heavy
atom and backbone root mean
square
deviation
(RMSD)
values of 0.43 and 0.31 ꢃ, re-
spectively, are shown in Fig-
ure 1a in which the 9- and 11-
mr hydrogen bonds at the N
terminus and an unusual
pseudo a-turn at the C termi-
nus are clearly visible.
An interesting continuation
of this idea is the presence of a
similar turn in peptide 2 with a
ꢁb–a–gꢂ sequence at the C ter-
minus, which is stabilized by 14-
mr hydrogen bonding between
Scheme 2. Structures of peptides 3 to 5 (arrows indicate the hydrogen-bonding pattern).
À
NH(2) CO(4) and 7-mr hydro-
À
19a, which, on coupling with acid 20[14] under standard con-
ditions, afforded the hexapeptide 9 (31%).
gen bonding between CO(2) NH(4). The NOE correlations
and hydrogen-bonding information from solvent titration[17]
and MD studies support the above observation (see the Sup-
porting Information). The turn structure is nucleated by 11-
mr hydrogen bonding at the N terminus. The propagation of
the helix structure at the N terminus with 14-mr hydrogen
bonding and its further stabilization by 7-mr hydrogen bond-
ing is observed in peptide 2a. This observation was support-
ed by the NOE correlations CaH(2)/NH(4), CaH(4)/NH(6),
NH(1)/NH(2), NH(3)/NH(4), NH(5)/NH(6), NH(6)/NH(7),
NH(5)/NH(7), and CaH(4)/NH(7). The stereoviews of pep-
tides 2 and 2a are displayed in Figure 1b and c with average
pairwise heavy-atom and backbone RMSD values of 0.36
and 0.29 ꢃ for the peptide 2 and 0.65 and 0.30 ꢃ for peptide
2a. But owing to spectral overlap, MD studies for the pep-
tide 2b were not possible. The CD spectra of peptides 1, 2a,
and 2b, as displayed in Figure 2, show a positive maximum
around 199 nm and a small broad signal around 221 nm,
which indicates the signature for a helix with no separate
signature for turn.
Conformational Analysis of Peptides
1
All the H NMR spectroscopic studies were undertaken as
2–3 mm solutions in CDCl3 (see the Supporting Informa-
tion). The proton NMR spectrum of peptide 1 is very well
dispersed, and NH(3), NH(4), and NH(5) display a chemical
shift (d) greater than 7 ppm. Solvent titration studies[17]
show a small change in chemical shift (Dd) value for all
amide protons except NH(2), thereby supporting their par-
ticipation in hydrogen bonding. Further, for b(1) and b(3)
3
residues, the JCaH,CbH ꢀ5.5 Hz coupling constant suggests
À
predominantly a single rotamer population about the Ca
3
Cb bond with a q of approximately 608. The JNH,CaH for a-
3
residues and JNH,CbH for b-residues are considerably varied
when compared to a/b-peptides with ꢁa–b–aꢂ at the C termi-
ni, but are in agreement with those values observed for a/b-
peptides with ꢁb–a–bꢂ at the C terminus. The characteristic
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87

G. V. M. Sharma, A. V. S. Sarma et al.
FULL PAPERS
tration study,[17] which showed a
small change in chemical shift
(DdNH) for NH(3). The ob-
served medium range NOE cor-
relations,
CaH(1)/NH(3),
CbH(2)/NH(3), NH(2)/NH(3),
which are distinctive, in con-
junction with the above infor-
mation correspond to the pre-
ponderance of a nascent 11/9-
helix. It is very interesting to
note that the tripeptide that has
an achiral a-amino acid such as
Gly has resulted in a folded
conformation. For a better un-
derstanding of the underlying
structure, peptides 4 and 5 were
studied in detail. For peptide 4
(in CDCl3), many of the amide
resonances appeared at d>
7.0 ppm, which, along with
DdNH<0.5 ppm in the solvent
titration studies,[17] provided
emphatic support for their in-
volvement in hydrogen bonding
(see the Supporting Informa-
tion), whereas the large DdNH
value indicates the free nature
of NH(1) and NH(4). For b-
Caa (2) and b-Caa (4), the
3JNH,CbH values of 9.0 and 8.8 Hz
as well as small values of
3JCaH,CbH (<5.4 Hz) are consis-
tent with fꢁ1008 and qꢁ608.
3JNH,CaH values of approximately
6.0 Hz for Gly residues are not
distinctive and do not provide
any specific information. The
handedness of the structure was
derived by distinguishing the
CaH protons of b-Caa and Gly
on the basis of NOE correla-
tions. The NOEs CaH(1)/
NH(3), CaH(3)/NH(5), NH(2)/
NH(3), and NH(4)/NH(5) sup-
port a right-handed mixed helix
with
pattern (Scheme 2). Peptide 4
was also investigated in
CD3OH (see the Supporting In-
a 11/9-hydrogen-bonding
Scheme 3. Structures of peptides 6 to 9 (arrows indicate the hydrogen-bonding pattern).
In a further study on a/b-peptides to understand the influ-
ence of achiral a-residue on the helix and helix-turn motifs,
peptides 3–9 that contain Gly have been studied. The a/b-
tripeptide 3 displayed a dNH very close to 7 ppm for NH(2)
and NH(3), thus suggesting a significant population of con-
formations that take part in hydrogen bonding. Further,
confirmation for the same was derived from the solvent ti-
formation), wherein it displayed characteristic NOE correla-
tions of a 11/9-mixed helix that were observed in CDCl3.
However, the NOE correlations show considerably weak
cross-peak intensities, thereby implying reduced preponder-
ance of the ordered structures.
Peptide 5 displayed further propagation of mixed helical
structure as observed in 4. All the characteristic NOE corre-
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Chem. Asian J. 2011, 6, 84 – 97

The Design of a/b-Peptides
sistent with those reported for a right-handed 11/9-mixed
helix (see the Supporting Information).
MD studies further confirmed the presence of an 11/9-
helix in these peptides. Figure 3 shows a stereoview of
twenty minimum-energy structures of peptide 4 with aver-
age pairwise heavy-atom and backbone RMSD values of
0.19 and 0.10 ꢃ, respectively. The sugar moieties were re-
placed with methyl groups for clarity after the energy mini-
mization. Similar observations of mixed-helical structures
have been made on peptides from alternating b-Caa/l-Ala
with an ꢁa–b–aꢂ sequence at the C termini.[6a] The study
amply inferred that the chiral (S)-b-Caa thus has shown an
efficient ꢁdesignꢂ control in peptides 3–5 to display robust
11/9-mixed helices, although still accommodating the achiral
Gly residues well.
In a further study to learn the impact of Gly in the turn
region, peptides 6–8 were analyzed. The proton NMR spec-
trum (in CDCl3) of tetrapeptide 6 revealed a dNH> 7 ppm
for NH(2) and NH(3), and small DdNH (<0.6 ppm) in sol-
vent titration study,[17] thereby
Scheme 4. Synthesis of peptides 1, 2, 2a, and 2b. Reagents and condi-
tions: a) aq. 4n NaOH, MeOH, 08C to RT; b) CF3CO2H, dry CH2Cl2;
c) HOBt (1.2 equiv), EDCI (1.2 equiv), DIPEA (1.5 equiv), dry CH2Cl2,
08C to RT.
suggesting their involvement in
hydrogen bonding (see the Sup-
porting Information), whereas
the free nature of NH(1) and
NH(4) is confirmed by large
DdNH. In addition to the NOE
correlations CaH(1)/NH(3) and
CbH(2)/NH(3), which are dis-
tinguishing features of an 11-
helix, NH(2)/NH(3), NH(3)/
NH(4), NH(2)/NH(4), CaH(1)/
NH(4), and C4H(2)/NH(4)
seem to suggest a variation in
the structure compared to pep-
tides 3–5. These signatures sup-
port the presence of an unusual
three-residue turn stabilized by
13-mr hydrogen bonding be-
À
tween
NH(2) CO(4)
(Scheme 3), unlike in the a/b-
peptides reported.[14] Further,
the 13-mr turn in 6 was found
to be different from the a-turn
observed by Balaram et al.[12] in
an a-peptide as well as by
Pavone et al.[13] from their
model-building studies.
To confirm the above infor-
mation, higher oligomers 7 and
8 were analyzed. The proton
NMR spectrum of peptide 7 (in
CDCl3) showed dispersion in
Scheme 5. Synthesis of peptides 3 to 9. Reagents and conditions: a) CF3CO2H, dry CH2Cl2; b) HOBt
(1.2 equiv), EDCI (1.2 equiv), DIPEA (1.5 equiv), dry CH2Cl2, 08C to RT; c) aq. 4n NaOH, MeOH, 08C to
RT.
lations, coupling constants, and hydrogen-bonding informa-
tion revealed a secondary structure with alternating 11/9-hy-
drogen-bonded structure (Scheme 2). The CD spectra of the
peptides 3–5 show a positive maximum around 198 nm as
well as a broad and weaker maxima at 227 nm, which is con-
the amide region and lowfield dNH values as well as small
DdNH values in solvent titration study confirmed that
NH(1), NH(3), and NH(4) participate in hydrogen bonding
(see the Supporting Information). For b-Caa (1), b-Caa (3),
3
and b-Caa (5), the large value of JNH,CbH (>8 Hz) is consis-
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G. V. M. Sharma, A. V. S. Sarma et al.
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Figure 2. CD profiles of peptides 1, 2a, and 2b.
Figure 3. Stereoview of peptide
4 (sugars are replaced with methyl
groups for clarity after calculations).
NOEs. Further, the NOEs CaH(2)/NH(4) and NH(1)/
NH(2) are characteristic features of a helical structure with
À
an 11-mr hydrogen bond between CO(1) NH(4) as well as
À
a 9-mr hydrogen bond between NH(1) CO(2) at the N ter-
minus, respectively. In addition, the NOEs C4H(3)/NH(5),
CaH(2)/NH(5), NH(3)/NH(4), NH(4)/NH(5), and NH(3)/
NH(5) that involve C terminal ꢁb–a–bꢂ residues confirm the
presence of a three-residue turn, which is stabilized by 13-
À
mr hydrogen bonding between NH(3) CO(5), thereby pro-
ducing a super secondary structure with an 11/9-mixed helix
followed by a 13-mr turn (Scheme 3).
Figure 1. a) Stereoview of peptide 1 (sugars are replaced with methyl
groups for clarity after calculations). b) Stereoview of peptide 2 (sugars
are replaced with methyl groups for clarity after calculations). c) Stereo-
view of peptide 2a (sugars are replaced with methyl groups for clarity
after calculations)
In a similar study, propagation of the mixed helix with an
11/9/11-hydrogen-bonding pattern was observed in peptide 8
at the N terminus. The expansions of ROESY spectrum
(Figure 4) of peptide 8 show characteristic features of a
helix as well as a turn structure. The exchange peaks in the
ROESY spectrum indicate the presence of two isomers with
the major isomer population being 95%. For the major
isomer, the NOE correlations C4H(4)/NH(6), CaH(3)/
3
tent with a fꢁ1008 and small values of JCaH,CbH (<5.4 Hz)
imply a qꢁ608. The CaH(pro-R) and CaH(pro-S) protons of b-
Caa and Gly residues were distinguished on the basis of
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Chem. Asian J. 2011, 6, 84 – 97

The Design of a/b-Peptides
Figure 4. Expansions of ROESY spectrum of peptide 8 showing the signatures of an 11/9-helix and 13-membered turn structure (* represents exchange
peaks).
NH(6), NH(4)/NH(5), NH(5)/NH(6), and NH(4)/NH(6)
confirm the presence of a 13-mr turn stabilized by forward
present study that contain a three-residue turn motif ꢁb–
Caa–Gly–b–Caaꢂ with achiral Gly, resulted in a new helix-
turn motif with an 11/9-helix followed by a 13-mr turn at the
C terminus.
À
hydrogen bonding between NH(4) CO(6) (Scheme 3) at the
C terminus. Restrained MD studies (Figure 5) on peptide 8
showed the presence of an 11/9/11-mixed helix followed by
a 13-mr hydrogen-bonded turn at the C terminus with the
average pairwise heavy-atom and backbone RMSDs of 0.63
and 0.60 ꢃ, respectively. The backbone dihedral angles that
characterize the turn structure are given in Table 1. Thus,
unlike in the earlier a/b-peptides,[14] peptides 6–8 in the
To investigate the effect of the chiral side chain of b-Caa
in the turn region, peptide 9 was designed with three ꢁb–
hGly–Gly–b–hGlyꢂ (b-hGly is referred as b-alanine or b-ho-
moglycine) residues at the C terminus. The NMR spectrum
of peptide 9 (in CDCl3) showed amide protons NH(2),
NH(3), NH(4), and NH(5) at lowfield, thus indicating their
participation in hydrogen bonding, which was further con-
firmed by solvent titration studies.[17] The first and last
amide protons do not seem to participate in hydrogen bond-
ing. The NOE correlations suggested that the 13-mr turn is
À
stabilized by hydrogen bonding between NH(4) CO(6) at
the C terminus (Scheme 3), whereas CD and MD studies
further confirm the above observation. Figure 6 displayed
overlaid CD spectra of peptides 6–9. Further, the molar el-
lipticity of peptide 9 is smaller than peptides 7 and 8, which
may be attributed to the absence of side chains in the b-resi-
dues at the C terminus.
The peptides with ꢁb–a–a,ꢂ ꢁb–a–g,ꢂ and ꢁb–a–dꢂ at the C
terminus showed new types of turns with 12/7-mr, 14/7-mr,
and 15/7-mr hydrogen bonding, respectively. This observa-
tion is found to be similar to our earlier results on the three-
residue turn with 13/7-mr hydrogen bonding.[14] Further-
more, the peptides studied with ꢁb–a–bꢂ at the C terminus
with achiral Gly residue showed a novel 13-mr turn struc-
ture. The new 13-mr hydrogen bonding (Figure 7C) resem-
bles the a-turn (Figure 7A) and the turn (Figure 7B) ob-
served in peptides reported by Balaram et al.,[12] with a dif-
ference in the directionality of hydrogen bonding. The ab-
sence of 7-mr hydrogen bonding in these peptides with an
Figure 5. Stereoview of peptide 8 (sugars are replaced with methyls for
clarity after calculations).
Chem. Asian J. 2011, 6, 84 – 97
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
91

G. V. M. Sharma, A. V. S. Sarma et al.
FULL PAPERS
Table 1. Backbone dihedral angles [8] representing turns in peptides that contain a C terminus b–a–a, b–a–g,
and b–a–b sequence (i+2 is the last residue in the sequence).
dues in the peptide design that
resulted in new turn and helix-
Peptide
1
2
6
7
8
9
turn peptides would contribute
residue(i)
f
q
76Æ1
62Æ1
89Æ1
68Æ1
85Æ1
69Æ1
82Æ2
68Æ1
74Æ2
68Æ1
73Æ2 to the further development of
65Æ2
À88Æ2
À120Æ1
82Æ1
foldamers. It provides an oppor-
tunity to create skeletal diversi-
ty with unsubstituted amino
acid residues in the backbones,
wherein the chirality of one or
more amino acid residues
would help in the creation of
conformational diversity.
y
f
y
f
q
À106Æ1
À98Æ1
66Æ1
À90Æ1
À102Æ1
68Æ2
À89Æ1
À127Æ2
78Æ1
À89Æ3
À120Æ1
81Æ2
À88Æ2
À118Æ2
77Æ2
residue
residue
ACHTUNGTRENNUNG
A
157Æ1
125Æ1
116Æ2
61Æ1
89Æ1
78Æ3
105Æ2
67Æ2
[a]
–
68Æ2
66Æ2
y
130Æ2
94Æ3
91Æ2
108Æ2
99Æ6
93Æ3
[a] q1 =À(70Æ2)8, q2 =(167Æ2)8.
C
Experimental Section
Samples for NMR spectroscopy were prepared by dissolving the peptides
in deuterated chloroform (0.6 mL) to maintain a concentration of 2–
3 mm of each peptide. NMR spectroscopic experiments were performed
with Varian INOVA-500 and Bruker AVANCE II-600 NMR spectrome-
ters at an ambient temperature depending upon the resolution of the
proton spectrum. Double quantum filtered correlation spectroscopy
(DQF COSY), total correlation spectroscopy (TOCSY), and rotating-
frame Overhauser effect spectroscopy (ROESY) were performed for in-
traresidue and interresidue resonance assignments. A mixing time of
80 ms in TOCSY and 150, 200, and 300 ms in ROESY experiment were
used. All the experiments were run using standard system pulse sequen-
ces and processed with Varian/Bruker software. Solvent titration studies
were done by adding [D6]DMSO sequentially up to a total DMSO con-
centration of 33% v/v.
Figure 6. CD profiles of peptides 6–9.
The CD spectra were acquired with a Jasco J-810 spectropolarimeter at
room temperature by using rectangular fused quartz cells of 0.02 cm path
length. The sample concentration was maintained at 200 mm in methanol
solvent. The binomial method was used for smoothing the spectra. The
values are expressed in terms of q, the total molar ellipticity
(degcm2 dmolÀ1).
Restrained MD studies were performed with a Silicon Graphics Inc.
(SGI) workstation using the Discover module of INSIGHT-II. The con-
straints were obtained from the volume integrals of a ROESY spectrum
using a two-spin approximation. A reference distance of 1.8 A is used
from the geminal protons.
Boc-(S)-b-Caa-l-Ala-(S)-b-Caa-l-Ala-l-Ala-OMe (1): A solution of 10[14]
(0.1 g, 0.13 mmol), HOBt (0.02 g, 0.16 mmol), and EDCI (0.04 g,
0.16 mmol) in CH2Cl2 (2 mL) was stirred at 08C under an N2 atmosphere
for 15 min and treated with 11 (0.02 g, 0.16 mmol) in CH2Cl2 (0.5 mL)
and DIPEA (0.05 mL, 0.26 mmol) under an N2 atmosphere for 8 h. The
reaction mixture was quenched at 08C with a sat. NH4Cl solution (5 mL).
After 10 min, it was diluted with CHCl3 (5 mL), washed with 1n HCl
(5 mL), water (5 mL), aq. sat. NaHCO3 solution (5 mL), and brine
(5 mL). The organic layer was dried (Na2SO4), evaporated, and the resi-
due purified by column chromatography (silica gel, 3.2% MeOH in
Figure 7. Ball-and-stick models of turns: a) a helix, b) d-Pro-l-Pro-d-
Ala,[12] and c) b-Caa-Gly-b-Caa.
achiral Gly residue may be attributed to some deviation in
the orientation of the bonds in these peptides compared to
the helix-turn peptides already studied.
CHCl3) to afford 1 (0.07 g, 63%) as a solid. M.p. 234–2368C; [a]D27
=
À23.6 (c=0.1, CHCl3); 1H NMR (500 MHz, CDCl3, 303 K): d=7.70 (d,
1H, J=8.3 Hz, NH-3), 7.37 (d, 1H, J=6.7 Hz, NH-4), 6.95 (d, 1H, J=
4.8 Hz, NH-5), 6.59 (d, 1H, J=7.6 Hz, NH-2), 5.93 (d, 1H, J=3.4 Hz,
C1H-1), 5.88 (d, 1H, J=3.8 Hz, C1H-3), 5.42 (d, 1H, J=7.3 Hz, NH-1),
4.62 (m, 1H, CaH-5), 4.58 (m, 2H, C2H-1, 3), 4.39 (m, 1H, CaH-4), 4.38
(m, 1H, CbH-3), 4.26 (m, 1H, CbH-1), 4.22 (dd, 1H, J=2.8, 8.6 Hz, C4H-
1), 4.18 (dd, 1H, J=2.8, 9.3 Hz, C4H-3), 4.16 (m, 1H, CaH-2), 4.01 (d,
1H, J=2.8 Hz, C3H-3), 3.76 (s, 3H, COOMe), 3.74 (d, 1H, J=2.8 Hz,
C3H-1) 3.39 (s, 3H, OMe), 3.37 (s, 3H, OMe), 2.71 (dd, 1H, J=4.5,
13.6 Hz, CaH(pro-R)-3), 2.58 (dd, 1H, J=4.9, 14.6 Hz, CaH(pro-R)-1), 2.43
(dd, 1H, J=5.5, 14.6 Hz, CaH(pro-S)-1), 2.24 (dd, 1H, J=3.7, 13.6 Hz,
CaH(pro-S)-3), 1.47 (s, 3H, Me), 1.45 (m, 1H, Me-4), 1.44 (s, 3H, Me), 1.43
(s, 9H, Boc), 1.39 (m, 6H, Me-2, 5), 1.31 (s, 3H, Me), 1.30 ppm (s, 3H,
Me); 13C NMR (150 MHz, CDCl3): d=174.0, 173.0, 172.4, 171.1, 170.4,
Conclusion
The present study resulted in new three-residue turn motifs
in ꢁb–a–a,ꢂ ꢁb–a–g,ꢂ and ꢁb–a–dꢂ with novel turn at the C ter-
minus. Likewise, the report amply demonstrates that the ab-
sence of chirality in a-residue does not affect the formation
of a stable helix and helix-turn structures in a/b-peptides.
However, the effect of the same culminated in novel 13-mr
hydrogen bonding in the turn region at the C terminus in
helix-turn peptides. It is thus pertinent to mention that the
above studies on the new turns and the use of achiral resi-
92
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 84 – 97

The Design of a/b-Peptides
155.9, 111.6, 111.5, 104.9, 104.8, 84.2, 83.5, 81.4, 81.3, 81.2, 80.1, 79.8, 57.5,
57.3, 51.7, 50.3, 47.9, 47.8, 47.2, 39.0, 37.9, 29.7, 28.4 (3C), 26.8, 26.7, 26.4,
26.3, 18.4, 17.3, 17.1 ppm; IR (KBr): n˜ =3459, 3281, 2984, 2936, 1743,
6.1, 14.4 Hz, CaH(pro-S)-1), 2.42 (m, 1H, CaH(pro-R)-7), 2.38 (m, 1H,
CaH(pro-S)-7), 2.16 (m, 1H, CaH(pro-S)-5), 2.14 (m, 1H, CaH(pro-S)-3), 1.98 (m,
1H, CbH-7), 1.84 (m, 1H, Cb’H-7), 1.48 (s, 6H, 2ꢄMe), 1.45 (s, 3H, Me),
1.44 (s, 3H, Me), 1.43 (s, 9H, Boc), 1.39 (d, 3H, J=7.1 Hz, Me-2), 1.37
(d, 3H, J=7.1 Hz, Me-6), 1.36 (d, 3H, J=7.1 Hz, Me-4), 1.31 (s, 3H,
Me), 1.30 (s, 3H, Me), 1.29 ppm (s, 6H, 2ꢄMe); 13C NMR (150 MHz,
CDCl3): d=174.8, 174.0, 173.4, 172.9, 171.7, 171.3, 170.6, 156.1, 111.6,
111.4, 111.3 (2C), 105.1, 104.9, 104.7 (2C), 84.4, 84.0, 83.5, 81.5, 81.3 (2C),
81.2, 80.1, 79.5, 72.7, 71.8, 70.1, 57.6, 57.5, 57.3, 57.2, 55.2, 51.7, 51.6, 49.9,
48.2, 48.1, 47.4, 46.9, 38.0, 31.9, 30.8, 30.3, 29.7, 29.3, 28.4 (3C), 27.1, 26.6
(2C), 26.5, 26.2, 26.1, 26.0, 22.7, 17.1, 16.7, 16.4 ppm; IR (KBr): n˜ =3285,
2927, 2856, 1738, 1694, 1645, 1546, 1518, 1458, 1375, 1249, 1217, 1169,
1081, 1022 cmÀ1; HRMS (ESI): m/z: calcd for: C60H97N7O26: 1354.6380
[M+Na]+; found: 1354.6385.
1667, 1646, 1551, 1454, 1377, 1234, 1171, 1080, 1021, 859, 665, 577 cmÀ1
;
HRMS (ESI): m/z: calcd for C37H61N5NaO16: 854.4006 [M+Na]+; found:
854.4028.
Boc-l-Ala-(S)-b-Caa-l-Ala-(S)-g-Caa-OMe (2):
A
solution of 12[15d]
(0.08 g, 0.20 mmol) and CF3COOH (0.1 mL) in CH2Cl2 (0.5 mL) was
stirred at room temperature for 1 h. After completion of reaction, solvent
was evaporated under reduced pressure, dried under high vacuum, and
the resulting H-g-Caa-OMe·CF3COOH (12a) was used as such for the
next reaction.
As described for the synthesis of 1, a mixture of 13[14] (0.1 g, 0.20 mmol),
HOBt (0.03 g, 0.24 mmol), and EDCI (0.04 g, 0.24 mmol) in CH2Cl2
(2 mL) was stirred at 08C for 15 min and treated with the above salt 12a
and DIPEA (0.06 mL, 0.29 mmol) under an N2 atmosphere for 8 h.
Workup and purification by column chromatography (silica gel, 2.2%
MeOH in CHCl3) afforded 2 (0.08 g, 54%) as a solid. M.p. 199–2018C;
[a]2D7 =À65.8 (c=0.1, CHCl3); 1H NMR (500 MHz, CDCl3, 293 K): d=
7.43 (d, 1H, J=7.2 Hz, NH-3), 7.21 (d, 1H, J=8.2 Hz, NH-2), 6.43 (d,
1H, J=8.2 Hz, NH-4), 5.99 (d, 1H, J=3.8 Hz, C1H-4), 5.88 (d, 1H, J=
3.8 Hz, C1H-2), 5.08 (d, 1H, J=6.2 Hz, NH-1), 4.57 (d, 2H, J=3.8 Hz,
C2H-2, 4), 4.47 (m, 1H, CbH-2), 4.38 (m, 1H, CaH-3), 4.30 (dd, 1H, J=
3.3, 9.6 Hz, C4H-2), 4.25 (dd, 1H, J=3.1, 5.9 Hz, C4H-4), 4.12 (m, 1H,
CgH-4), 4.02 (d, 1H, J=3.1 Hz, C3H-2), 4.01 (m, 1H, CaH-1), 3.72 (s, 3H,
COOMe), 3.66 (d, 1H, J=3.1 Hz, C3H-4), 3.39 (s, 3H, OMe), 3.37 (s,
3H, OMe), 2.62 (dd, 1H, J=5.1, 13.5 Hz, CaH(pro-R)-2), 2.40 (m, 2H,
CaH-4), 2.28 (dd, 1H, J=2.7, 13.5 Hz, CaH(pro-S)-2), 1.94 (m, 1H, CbH-4),
1.87 (m, 1H, Cb’H-4), 1.48 (s, 3H, Me), 1.46 (s, 3H, Me), 1.44 (s, 9H,
Boc), 1.37 (d, 3H, J=7.2 Hz, Me-3), 1.35 (d, 3H, J=7.2 Hz, Me-1),
1.31 ppm (s, 6H, 2ꢄMe); 13C NMR (150 MHz, CDCl3): d=173.7, 173.2,
172.9, 170.4, 155.8, 111.4, 111.3, 104.9, 104.7, 84.5, 83.7, 81.6, 81.3, 80.2,
79.9, 79.7, 57.6, 57.3, 51.7, 50.9, 49.7, 48.1, 47.0, 38.3, 30.3, 28.3 (3C), 27.3,
26.7, 26.6, 26.2, 26.1, 17.8, 16.8 ppm; IR (KBr): n˜ =3423, 2984, 2936, 1727,
Boc-(S)-b-Caa-l-Ala-(S)-b-Caa-l-Ala-(S)-b-Caa-l-Ala-(S)-d-Caa-OMe
(2b): As described for the synthesis of 1, a mixture of 13b (0.06 g,
0.06 mmol), HOBt (0.01 g, 0.07 mmol), and EDCI (0.014 g, 0.07 mmol) in
CH2Cl2 (3 mL) was stirred at 08C for 15 min and treated with 12b
(0.025 g, 0.06 mmol) in CH2Cl2 (1 mL) and DIPEA (0.016 mL,
0.09 mmol) under an N2 atmosphere for 8 h. Workup and purification by
column chromatography (silica gel, 3.1% methanol in CHCl3) afforded
2b (0.056 g, 67%) as a solid. M.p. 209–2118C; [a]2D7 =À18.5 (c=0.1,
CHCl3); 1H NMR (600 MHz, CDCl3, 303 K): d=8.03 (br, 1H, NH-4),
7.84 (d, 1H, J=7.4 Hz, NH-6), 7.77 (d, 1H, J=9.4 Hz, NH-3), 7.33 (d,
1H, J=7.5 Hz, NH-5), 6.66 (d, 1H, J=8.1 Hz, NH-7), 6.46 (br, 1H, NH-
2), 6.02 (d, 1H, J=3.9 Hz, C1H-7), 5.89 (d, 1H, J=3.9 Hz, C1H-1), 5.88
(d, 1H, J=3.9 Hz, C1H-5), 5.87 (d, 1H, J=3.9 Hz, C1H-3), 5.52 (d, 1H,
J=8.1 Hz, NH-1), 4.57 (d, 1H, J=3.9 Hz, C2H-7), 4.55 (d, 1H, J=3.9 Hz,
C2H-1), 4.55 (d, 1H, J=3.9 Hz, C2H-3), 4.55 (d, 1H, J=3.9 Hz, C2H-5),
4.48 (m, 1H, CbH-3), 4.38 (p, 1H, J=7.4 Hz, CaH-6), 4.34 (m, 1H, C4H-
5), 4.34 (m, 1H, C4H-7), 4.32 (m, 1H, CbH-5), 4.26 (dd, 1H, J=3.2,
7.8 Hz, C4H-1), 4.22 (dd, 1H, J=3.2, 9.7 Hz, C4H-3), 4.20 (m, 1H, CaH-
2), 4.16 (m, 1H, CbH-1), 4.15 (m, 1H, CaH-4), 4.02 (d, 1H, J=2.9 Hz,
C3H-5), 3.93 (d, 1H, J=3.2 Hz, C3H-3), 3.92 (m, 1H, CdH-7), 3.74 (d,
1H, J=3.2 Hz, C3H-1), 3.66 (s, 3H, COOMe), 3.62 (d, 1H, J=3.2 Hz,
C3H-7), 3.39 (s, 3H, OMe), 3.37 (s, 6H, 2ꢄOMe), 3.32 (s, 3H, OMe),
2.67 (dd, 1H, J=4.3, 13.0 Hz, CaH(pro-R)-5), 2.56 (dd, 1H, J=5.2, 12.6 Hz,
CaH(pro-R)-3), 2.54 (dd, 1H, J=5.1, 14.4 Hz, CaH(pro-R)-1), 2.45 (dd, 1H, J=
6.1, 14.4 Hz, CaH(pro-S)-1), 2.33 (m, 1H, CaH(pro-R)-7), 2.33 (m, 1H,
CaH(pro-S)-7), 2.14 (dd, 1H, J=5.8, 13.0 Hz, CaH(pro-S)-5), 2.13 (dd, 1H, J=
5.9, 12.6 Hz, CaH(pro-S)-3), 1.76 (m, 1H, CgH-7), 1.74 (m, 1H, CbH-7), 1.62
(m, 1H, Cb’H-7), 1.48 (s, 3H, Me), 1.47 (s, 3H, Me), 1.44 (s, 3H, Me),
1.43 (m, 1H, Cg’H-7), 1.43 (s, 9H, Boc), 1.39 (m, 3H, Me-2), 1.38 (m, 3H,
Me-6), 1.36 (m, 3H, Me-4), 1.30 (s, 6H, 2ꢄMe), 1.29 (s, 6H, 2ꢄMe),
1.24 ppm (s, 3H, Me); 13C NMR (150 MHz, CDCl3): d=175.0, 173.9,
173.1, 172.8, 171.8, 171.2, 170.5, 156.0, 111.6, 111.4, 111.3 (2C), 105.1,
105.0, 104.7 (2C), 84.4, 83.9, 83.4, 81.5, 81.3, 81.2, 81.1, 80.1, 80.0, 79.8,
79.5, 79.4, 57.5 (2C), 57.3, 57.2, 51.6, 51.5, 51.0, 49.8, 48.8, 47.8, 47.4, 46.9,
38.7, 38.0, 37.9, 33.5, 30.7, 29.7, 28.4 (3C), 26.7 (2C), 26.6 (2C), 26.2, 26.1
(2C), 26.0, 20.9, 17.1, 16.7, 16.2 ppm; IR (KBr): n˜ =3288, 2984, 2933,
1655, 1528, 1457, 1375, 1253, 1216, 1166, 1079, 1023, 890, 857, 639 cmÀ1
;
HRMS (ESI): m/z: calcd for C35H58N4NaO15: 797.3791 [M+Na]+; found:
797.3808.
Boc-(S)-b-Caa-l-Ala-(S)-b-Caa-l-Ala-(S)-b-Caa-l-Ala-(S)-g-Caa-OMe
(2a): A cooled (08C) solution of 13a (0.15 g, 0.14 mmol) in methanol
(4 mL) was treated with aq. 4n NaOH solution (4.2 mL) and stirred at
room temperature. After 2 h, methanol was removed and adjusted to
pH 2–3 with aq. 1n HCl solution at 08C and extracted with ethyl acetate
(2ꢄ10 mL). The organic layers were dried (Na2SO4) and evaporated to
give Boc-b-Caa-l-Ala-b-Caa-l-Ala-b-Caa-l-Ala-OH (13b; 0.13 g, 90%)
as a solid, which was used as such in the next reaction.
As described for the synthesis of 1, a mixture of 13b (0.06 g, 0.06 mmol),
HOBt (0.01 g, 0.07 mmol), and EDCI (0.014 g, 0.07 mmol) in CH2Cl2
(3 mL) was stirred at 08C for 15 min and treated with 12a (0.024 g,
0.06 mmol) in CH2Cl2 (1 mL) and DIPEA (0.016 mL, 0.09 mmol) under
an N2 atmosphere for 8 h. Workup and purification by column chroma-
tography (silica gel, 3.2% methanol in CHCl3) afforded 2a (0.045 g,
1735, 1643, 1536, 1453, 1375, 1215, 1166, 1116, 1079, 1020, 858, 755 cmÀ1
;
HRMS (ESI): m/z: calcd for C61H99N7O26: 1368.6537 [M+Na]+; found:
1
55%) as a solid. M.p. 197–1998C; [a]2D7 =À22.0 (c=0.1, CHCl3); H NMR
1368.6533.
(600 MHz, CDCl3, 300 K): d=8.01 (br, 1H, NH-4), 7.87 (d, 1H, J=
6.5 Hz, NH-6), 7.79 (d, 1H, J=8.8 Hz, NH-3), 7.40 (d, 1H, J=8.0 Hz,
NH-5), 6.53 (d, 1H, J=7.4 Hz, NH-7), 6.48 (br, 1H, NH-2), 6.00 (d, 1H,
J=3.8 Hz, C1H-7), 5.89 (d, 1H, J=3.8 Hz, C1H-1), 5.89 (d, 1H, J=
3.8 Hz, C1H-5), 5.88 (d, 1H, J=3.8 Hz, C1H-3), 5.51 (d, 1H, J=7.9 Hz,
NH-1), 4.57 (d, 1H, J=3.8 Hz, C2H-3), 4.56 (d, 1H, J=3.8 Hz, C2H-1),
4.56 (d, 1H, J=3.8 Hz, C2H-5), 4.56 (d, 1H, J=3.8 Hz, C2H-7), 4.50 (m,
1H, CbH-3), 4.37 (m, 1H, CbH-5), 4.35 (m, 1H, C4H-5), 4.34 (m, 1H,
CaH-6), 4.29 (dd, 1H, J=3.2, 7.9 Hz, C4H-7), 4.27 (dd, 1H, J=3.1,
8.1 Hz, C4H-1), 4.23 (m, 1H, C4H-3), 4.21 (m, 1H, CaH-2), 4.18 (m, 1H,
CaH-4), 4.17 (m, 1H, CbH-1), 4.03 (m, 1H, CgH-7), 4.02 (d, 1H, J=
3.1 Hz, C3H-5), 3.93 (d, 1H, J=3.1 Hz, C3H-3), 3.74 (d, 1H, J=3.1 Hz,
C3H-1), 3.68 (s, 3H, COOMe), 3.65 (d, 1H, J=3.2 Hz, C3H-7), 3.39 (s,
3H, OMe), 3.37 (s, 3H, OMe), 3.36 (s, 3H, OMe), 3.33 (s, 3H, OMe),
2.65 (dd, 1H, J=4.2, 12.8 Hz, CaH(pro-R)-5), 2.56 (dd, 1H, J=5.1, 13.0 Hz,
CaH(pro-R)-3), 2.54 (dd, 1H, J=4.9, 14.4 Hz, CaH(pro-R)-1), 2.46 (dd, 1H, J=
Boc-Gly-(S)-b-Caa-OMe (16): As described for the synthesis of 1, a mix-
ture of 15a (0.23 g, 1.33 mmol), HOBt (0.21 g, 1.59 mmol), and EDCI
(0.30 g, 1.59 mmol) in CH2Cl2 (10 mL) was stirred at 08C for 15 min,
treated with 14a [prepared from 14 (0.5 g, 1.33 mmol) and CF3COOH
(0.5 mL) in CH2Cl2 (2 mL)], and DIPEA (0.51 mL, 2.94 mmol), and
stirred for 8 h. Workup and purification by column chromatography
(silica gel, 60% EtOAc in pet. ether) afforded 16 (0.51 g, 89%) as a
syrup. [a]2D7 =À38.3 (c=0.1, CHCl3); 1H NMR (400 MHz, CDCl3, 298 K):
d=6.67 (d, 1H, J=8.3 Hz, NH-2), 5.89 (d, 1H, J=3.9 Hz, C1H-2), 5.21
(t, 1H, J=5.9 Hz, NH-1), 4.57 (d, 1H, J=3.9 Hz, C2H-2), 4.59 (m, 1H,
CbH-2), 4.37 (dd, 1H, J=3.3, 7.0 Hz, C4H-1), 3.80 (dd, 1H, J=5.9,
16.7 Hz, CaH-1), 3.74 (dd, 1H, J=5.9, 16.7 Hz, Ca’H-1), 3.68 (s, 3H,
COOMe), 3.37 (s, 6H, OMe), 2.70 (dd, 1H, J=5.9, 16.2 Hz, CaH-2), 2.61
(dd, 1H, J=5.3, 16.3 Hz, Ca’H-2), 1.48 (s, 3H, Me), 1.45 (s, 9H, Boc),
1.31 ppm (s, 3H, Me); 13C NMR (100 MHz, CDCl3): d=171.6, 168.9,
155.7, 111.6, 104.7, 84.2, 81.2, 79.9, 79.2, 57.4, 51.6, 45.4, 44.2, 35.9, 28.2
Chem. Asian J. 2011, 6, 84 – 97
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
93

G. V. M. Sharma, A. V. S. Sarma et al.
FULL PAPERS
(3C), 26.6, 26.1 ppm; IR (KBr): n˜ =3373, 2939, 1722, 1670, 1534, 1457,
1375, 1216, 1162, 1119, 1078, 1019, 853, 639, 542 cmÀ1; HRMS (ESI): m/z:
calcd for C19H32N2NaO9: 455.2012 [M+Na]+; found: 455.2016.
104.8, 83.4, 83.2, 81.2, 81.1, 80.1, 79.9, 79.8, 57.4, 57.3, 52.3, 47.3, 46.8,
44.7, 44.4, 41.4, 37.7, 37.5, 28.2 (3C), 26.7, 26.5, 26.3, 26.1 ppm; IR (KBr):
n˜ =3384, 3079, 2984, 2936, 1746, 1664, 1535, 1441, 1375, 1250, 1217, 1166,
1118, 1079, 1020, 958, 888, 603, 539 cmÀ1; HRMS (ESI): m/z: calcd for
C34H55N5NaO16: 812.3541 [M+Na]+; found: 812.3512.
Boc-Gly-(S)-b-Caa-Gly-OMe (3): As described for 13b, a solution of 16
(0.5 g, 1.15 mmol) in methanol (4 mL) was treated with aq. 4n NaOH so-
lution (4.2 mL) and stirred at room temperature and worked up to give
16a (0.45 g, 93%) as a solid, which was used as such for the next reac-
tion.
Boc-(S)-b-Caa-Gly-OMe (17): As described for the synthesis of 13b, a
solution of 14 (0.6 g, 1.6 mmol) gave 14b (0.49 g, 85%) as a solid, which
was used as such for the next reaction.
As described for the synthesis of 1, a solution of 14b (0.90 g, 2.49 mmol),
HOBt (0.40 g, 2.98 mmol), and EDCI (0.57 g, 2.98 mmol) in CH2Cl2
(15 mL) was stirred at 08C under an N2 atmosphere for 15 min and treat-
ed with 15b (0.37 g, 2.98 mmol) in CH2Cl2 (2 mL) and DIPEA (0.64 mL,
3.74 mmol) under an N2 atmosphere for 8 h. Workup and purification by
column chromatography (silica gel, 65% EtOAc in petroleum ether) af-
forded 17 (0.8 g, 75%) as a solid. M.p. 156–1588C; [a]2D7 =À44.1 ( c=0.1
CHCl3); 1H NMR (400 MHz, CDCl3, 300 K): d=6.90 (t, 1H, J=5.7 Hz,
NH-2), 5.90 (d, 1H, J=3.8 Hz, C1H-1), 5.30 (d, 1H, J=7.7 Hz, NH-1),
4.58 (d, 1H, J=3.8 Hz, C2H-1), 4.30 (d, 1H, J=3.3, 7.7 Hz, C4H-1), 4.20
(m, 1H, CbH-1), 4.04 (dd, 1H, J=5.7, 17.9 Hz, CaH-2), 3.98 (dd, 1H, J=
5.7, 17.9 Hz, Ca’H-2), 3.74 (d, 1H, J=3.3 Hz, C3H-1), 3.74 (s, 3H,
COOMe), 3.37 (s, 6H, OMe), 2.61 (dd, 1H, J=5.6, 15.3 Hz, CaH-1), 2.55
(dd, 1H, J=5.9, 15.3 Hz, Ca’H-1), 1.48 (s, 3H, Me), 1.43 (s, 9H, Boc),
1.32 ppm (s, 3H, Me); 13C NMR (100 MHz, CDCl3): d=170.8, 170.1,
155.9, 111.5, 104.6, 83.8, 81.3, 80.1, 79.4, 57.3, 52.0, 47.7, 41.0, 38.7, 28.2
(3C), 26.6, 26.1 ppm; IR (KBr): n˜ =3385, 2934, 1747, 1677, 1533, 1455,
1375, 1216, 1162, 1118, 1080, 1020, 853, 644, 540 cmÀ1; HRMS (ESI): m/z:
calcd for C19H32N2NaO9: 455.2032 [M+Na]+; found: 455.2005.
A suspension of 15b (0.16 g, 1.29 mmol; prepared from Gly in methanol-
ic HCl) in CH2Cl2 (2 mL) was treated with DIPEA (0.28 mL, 1.62 mmol)
at 08C and stirred for 15 min to give free amine, H-Gly-OMe, which was
used as such for further reaction.
As described for the synthesis of 1, a mixture of 16a (0.45 g, 1.07 mmol),
HOBt (0.17 g, 1.29 mmol), and EDCI (0.25 g, 1.29 mmol) in CH2Cl2
(5 mL) was stirred at 08C for 15 min, treated with the above amine, and
stirred for 8 h. Workup and purification by column chromatography
(silica gel, 1.5% methanol in CHCl3) afforded 3 (0.41 g, 78%) as a solid.
1
M.p. 75–788C; [a]2D7 =À25.6 (c=0.1, CHCl3); H NMR (500 MHz, CDCl3,
298 K): d=7.06 (dd, 1H, J=4.7, 6.6 Hz, NH-3), 6.94 (d, 1H, J=8.1 Hz,
NH-2), 5.89 (d, 1H, J=3.9 Hz, C1H-2), 5.27 (dd, 1H, J=5.9, 6.5 Hz, NH-
1), 4.59 (d, 1H, J=3.9 Hz, C2H-2), 4.47 (m, 1H, CbH-2), 4.35 (dd, 1H,
J=3.3, 8.9 Hz, C4H-2), 4.19 (dd, 1H, J=6.6, 17.7 Hz, CaH(pro-R)-3), 3.89
(d, 1H, J=3.3 Hz, C3H-2), 3.81 (dd, 1H, J=4.7, 17.7 Hz, CaH(pro-S)-3),
3.75 (dd, 1H, J=6.5, 16.3 Hz, CaH(pro-R)-1), 3.73 (s, 3H, COOMe), 3.69
(dd, 1H, J=5.9, 16.3 Hz, CaH(pro-S)-1), 3.39 (s, 3H, OMe), 2.66 (dd, 1H,
J=5.4, 14.1 Hz , CaH(pro-R)-2), 2.46 (dd, 1H, J=4.1, 14.1 Hz, CaH(pro-S)-2),
1.48 (s, 3H, Me), 1.43 (s, 9H, Boc), 1.31 ppm (s, 3H, Me); 13C NMR
(150 MHz, CDCl3): d=171.2, 170.1, 169.9, 156.5, 111.8, 104.8, 83.5, 81.2,
80.2, 79.8, 57.4, 52.3, 46.9, 44.7, 41.3, 37.8, 28.2 (3C), 26.3, 26.7 ppm; IR
(KBr): n˜ =3383, 3079, 2984, 2935, 1745, 1664, 1535, 1438, 1375, 1233,
1217, 1166, 1118, 1078, 1020, 889, 854, 639, 549, cmÀ1; HRMS (ESI): m/z:
calcd for C21H35N3NaO10: 512.2215 [M+Na]+; found: 512.2237.
Boc-(S)-b-Caa-Gly-(S)-b-Caa-OMe (18): As described for the synthesis
of 13b, a solution of 17 (0.5 g, 1.15 mmol) gave 17a (0.47 g, 97%) as a
solid, which was used as such for the next reaction.
As described for the synthesis of 1, a mixture of 17a (0.4 g, 0.95 mmol),
HOBt (0.15 g, 1.14 mmol), and EDCI (0.22 g, 1.14 mmol) in CH2Cl2
(5 mL) was stirred at 08C for 15 min and treated with salt 14a [prepared
from 14 (0.35 g, 0.95 mmol) and CF3COOH (0.4 mL) in CH2Cl2 (1 mL)]
and DIPEA (0.25 mL, 1.43 mmol) under an N2 atmosphere for 8 h.
Workup and purification by column chromatography (silica gel, 90%
EtOAc in petroleum ether) afforded 18 (0.5 g, 77%) as a solid. M.p. 87–
898C; [a]2D7 =À76.5 (c=0.1, CHCl3); 1H NMR (500 MHz, CDCl3, 303 K):
d=6.72 (t, 1H, J=5.4 Hz, NH-2), 6.58 (d, 1H, J=8.1 Hz, NH-3), 5.90 (d,
2H, J=3.8 Hz, C1H-1 & C1H-3), 5.24 (d, 1H, J=7.7 Hz, NH-1), 4.58 (m,
1H, CbH-3), 4.57 (d, 1H, J=3.8 Hz, C2H-3), 4.56 (d, 1H, J=3.8 Hz, C2H-
1), 4.36 (dd, 1H, J=3.3, 6.6 Hz, C4H-3), 4.32 (dd, 1H, J=3.3, 6.6 Hz,
C4H-1), 4.15 (m, 1H, CbH-1), 3.92 (dd, 1H, J=5.4,16.1 Hz, CaH-2), 3.84
(dd, 1H, J=5.4, 16.1 Hz, Ca’H-2), 3.75 (d, 1H, J=3.3 Hz, C3H-1), 3.68 (d,
1H, J=3.8 Hz, C3H-3), 3.68 (s, 3H, COOMe), 3.37 (s, 6H, OMe), 2.68
(dd, 1H, J=6.0, 16.1 Hz, CaH-3), 2.59 (dd, 1H, J=5.8, 14.5 Hz, CaH-1),
2.54 (dd, 1H, J=5.6, 14.5 Hz, Ca’H-1), 2.26 (dd, 1H, J=5.7, 16.1 Hz,
Ca’H-3), 1.48 (s, 3H, Me), 1.43 (s, 9H, Boc), 1.31 ppm (s, 3H, Me);
13C NMR (150 MHz, CDCl3,): d=171.7, 170.9, 168.5, 156.1, 111.7, 111.6,
104.8, 104.7, 84.2, 83.7, 81.2, 81.1, 80.2, 79.6, 79.2, 57.5, 57.4, 51.9, 47.9,
45.5, 43.2, 38.8, 35.9, 28.3 (3C), 26.7, 26.6, 26.2, 26.1 ppm; IR (KBr): n˜ =
3385, 2933, 1729, 1678, 1655, 1547, 1541, 1374, 1254, 1220, 1166, 1118,
Boc-Gly-(S)-b-Caa-Gly-(S)-b-Caa-Gly-OMe (4): As described for the
synthesis of 1, a mixture of 16a (0.18 g, 0.43 mmol), HOBt (0.07 g,
0.51 mmol), and EDCI (0.1 g, 0.51 mmol) in CH2Cl2 (4 mL) was stirred at
08C for 15 min and treated with 3a [prepared from 3 (0.21 g, 0.43 mmol)
and CF3COOH (0.2 mL) in CH2Cl2 (0.5 mL)] and DIPEA (0.11 mL,
0.64 mmol) under an N2 atmosphere for 8 h. Workup and purification by
column chromatography (silica gel, 2.9% methanol in CHCl3) afforded 4
(0.16 g, 47%) as a solid. M.p. 112–1148C; [a]2D7 =+85.7 (c=0.1, CHCl3);
1H NMR (600 MHz, CDCl3, 303 K): d=7.73 (dd, 1H, J=4.8, 7.6 Hz, NH-
5), 7.68 (t, 1H, J=6.1 Hz, NH-3), 7.62 (d, 1H, J=9.0 Hz, NH-2), 7.17 (d,
1H, J=8.8 Hz, NH-4), 5.90 (d, 1H, J=3.8 Hz, C1H-4), 5.88 (d, 1H, J=
3.9 Hz, C1H-2), 5.40 (dd, 1H, J=6.0, 6.2 Hz, NH-1), 4.61 (d, 1H, J=
3.8 Hz, C2H-4), 4.58 (d, 1H, J=3.9 Hz, C2H-2), 4.49 (m, 1H, CbH-2), 4.43
(m, 1H, CbH-4), 4.34 (dd, 1H, J=7.6, 17.7 Hz, CaH(pro-R)-5), 4.31 (dd, 1H,
J=3.3, 9.9 Hz, C4H-4), 4.27 (dd, 1H, J=3.3, 9.3 Hz, C4H-2), 3.99 (d, 1H,
J=3.3 Hz, C3H-4), 3.91 (d, 1H, J=3.3 Hz, C3H-2), 3.91 (dd, 1H, J=6.0,
15.8 Hz, CaH(pro-R)-3), 3.84 (dd, 1H, J=6.2, 16.1 Hz, CaH(pro-R)-1), 3.72 (s,
3H, COOMe), 3.71 (dd, 1H, J=4.8, 17.7 Hz, CaH(pro-S)-5), 3.66 (dd, 1H,
J=6.1, 15.8 Hz, CaH(pro-S)-3), 3.56 (dd, 1H, J=6.0, 16.1 Hz, CaH(pro-S)-1),
3.39 (s, 6H, OMe), 2.69 (dd, 1H, J=5.2, 13.1 Hz , CaH(pro-R)-4), 2.66 (dd,
1H, J=5.3, 13.2 Hz, CaH(pro-R)-2), 2.26 (m, 1H, CaH(pro-S)-2), 2.25 (m, 1H,
CaH(pro-S)-4), 1.48 (s, 3H, Me), 1.45 (s, 3H, Me), 1.41 (s, 9H, Boc), 1.32 (s,
3H, Me); 1.30 ppm (s, 3H, Me); 1H NMR (500 MHz, CD3OH, 298 K):
d=8.27 (t, 1H, J=6.1 Hz, NH-5), 8.17 (t, 1H, J=6.1 Hz, NH-3), 8.04 (d,
1H, J=8.9 Hz, NH-2), 8.00 (d, 1H, J=8.9 Hz, NH-4), 6.82 (t, 1H, J=
6.1 Hz, NH-1), 5.82 (d, 1H, J=3.8 Hz, C1H-4), 5.81 (d, 1H, J=3.9 Hz,
C1H-2), 4.68 (m, 1H, C2H-4), 4.67 (m, 1H, C2H-2), 4.45 (m, 1H, CbH-2),
4.44 (m, 1H, CbH-4), 4.32 (dd, 2H, J=3.3, 8.9 Hz, C4H-2,4), 3.95 (d, 2H,
J=6.1 Hz, CaH-5), 3.84 (dd, 1H, J=6.1, 16.6 Hz, CaH(pro-R)-3), 3.80 (d,
2H, J=2.9 Hz, C3H-2,4), 3.78 (dd, 1H, J=6.1, 16.6 Hz, CaH(pro-S)-3), 3.71
(s, 3H, COOMe), 3.70 (dd, 1H, J=6.2, 16.1 Hz, CaH(pro-R)-1), 3.67 (dd,
1H, J=6.1, 16.7 Hz, CaH(pro-S)-1), 3.40 (s, 6H, OMe), 2.54 (m, 1H,
CaH(pro-R)-2), 2.53 (m, 1H, CaH(pro-R)-4), 2.46 (dd, 1H, J=6.0, 14.7 Hz,
CaH(pro-S)-4), 2.42 (dd, 1H, J=6.1, 14.2 Hz, CaH(pro-S)-2), 1.43 (s, 6H, 2ꢄ
Me), 1.42 (s, 9H, Boc), 1.29 ppm (s, 6H, 2ꢄMe); 13C NMR (CDCl3,
150 MHz): d=172.4, 171.9, 171.2, 170.2, 170.1, 156.8, 111.8, 111.5, 104.9,
1079, 1020, 890, 630, 538 cmÀ1
; HRMS (ESI): m/z: calcd for
C30H49N3NaO14: 698.3107 [M+Na]+; found: 698.3122.
Boc-(S)-b-Caa-Gly-(S)-b-Caa-Gly-(S)-b-Caa-Gly-OMe (5): As described
for the synthesis of 13b, a solution of 18 (0.11 g, 0.16 mmol) gave 18a
(0.10 g, 94%) as a solid, which was used as such for the next reaction.
As described for the synthesis of 1, a mixture of 18a (0.1 g, 0.15 mmol),
HOBt (0.02 g, 0.18 mmol), and EDCI (0.03 g, 0.18 mmol) in CH2Cl2
(2 mL) was stirred at 08C for 15 min and treated with 3a [prepared from
3 (0.07 g, 0.15 mmol) and CF3COOH (0.1 mL) in CH2Cl2 (0.5 mL)] and
DIPEA (0.03 mL, 0.23 mmol) under an N2 atmosphere for 8 h. Workup
and purification by column chromatography (silica gel, 3.1% methanol in
CHCl3) afforded 5 (0.07 g, 45%) as a solid. M.p. 132–1348C; [a]D27
=
+18.3 (c=0.1, CHCl3); 1H NMR (600 MHz, CDCl3, 303 K): d=7.95 (dd,
1H, J=4.6, 7.5 Hz, NH-6), 7.84 (dd, 1H, J=5.3, 5.9 Hz, NH-4), 7.79 (d,
1H, J=8.6 Hz, NH-3), 7.34 (d, 1H, J=8.7 Hz, NH-5), 7.18 (t, 1H, J=
5.9 Hz, NH-2), 5.90 (d, 2H, J=3.7 Hz, C1H À1, 5), 5.88 (d, 1H, J=
94
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 84 – 97

The Design of a/b-Peptides
3.7 Hz, C1H-3), 5.30 (d, 1H, J=8.1 Hz, NH-1), 4.61 (d, 1H, J=3.7 Hz,
C2H-5), 4.58 (d, 1H, J=3.7 Hz, C2H-3), 4.57 (d, 1H, J=3.7 Hz, C2H-1),
4.48 (m, 1H, CbH-3), 4.41 (m, 1H, CbH-5), 4.35 (dd, 1H, J=7.5, 17.5 Hz,
CaH(pro-R)-6), 4.33 (dd, 1H, J=3.1, 10.1 Hz, C4H-5), 4.24 (m, 2H, CbH-1
& C4H-3), 4.18 (dd, 1H, J=2.9, 10.0 Hz, C4H-1), 3.99 (d, 1H, J=3.1 Hz,
C3H-5), 3.93 (dd, 1H, J=5.8, 16.0 Hz, CaH(pro-R)-2), 3.91 (d, 1H, J=
3.1 Hz, C3H-3), 3.89 (dd, 1H, J=5.9, 15.8 Hz, CaH(pro-R)-4), 3.73 (m, 1H,
CaH(pro-S)-6), 3.72 (d, 1H, J=2.9 Hz , C3H-1), 3.72 (s, 3H, COOMe) 3.69
(m, 1H, CaH(pro-S)-2), 3.67 (m, 1H, CaH(pro-S)-4), 3.39, (s, 6H, OMe), 3.37
(s, 6H, OMe), 2.65 (dd, 1H, J=4.9, 13.4 Hz, CaH(pro-R)-5), 2.64 (m, 1H,
CaH(pro-R)-3), 2.54 (dd, 1H, J=4.5, 14.5 Hz, CaH(pro-R)-1), 2.42 (dd, 1H, J=
6.7, 14.5 Hz, CaH(pro-R)-1), 2.25 (dd, 1H, J=3.6, 13.4 Hz, CaH(pro-S)-5), 2.22
(m, 1H, CaH(pro-S)-3), 1.48, (s, 3H, Me), 1.47 (s, 3H, Me), 1.46 (s, 3H,
Me), 1.43 (s, 9H, Boc), 1.31 (s, 6H, 2ꢄMe), 1.30 ppm (s, 3H, Me);
13C NMR (150 MHz, CDCl3,): d=172.5, 172.4, 171.9, 171.1, 170.2, 169.3,
156.2, 111.8, 111.6, 111.5, 104.8 (2C), 104.7, 83.7, 83.3, 83.2, 81.2 (2C),
81.0, 80.3, 80.0, 79.9, 79.3, 57.5, 57.4, 57.3, 52.3, 47.7, 47.2, 46.9, 44.5, 44.3,
41.4, 39.2, 37.8, 37.6, 28.3 (3C), 26.7, 26.6, 26.5, 26.3, 26.1, 26.0 ppm; IR
(KBr): n˜ =3341, 3079, 2985, 2936, 1747, 1664, 1536, 1457, 1375, 1216,
1166, 1118, 1079, 1021, 889, 853, 642, 549 cmÀ1; HRMS (ESI): m/z: calcd
for C45H73N6O21: 1033.4823 [M+H]+; found: 1033.4842.
2.58 (dd, 1H, J=5.4, 16.3 Hz, CaH(pro-S)-5), 2.52 (m, 2H, CaH), 2.35 (dd,
1H, J=5.4, 13.9 Hz, CaH(pro-S)-3), 1.48, (s, 6H, Me), 1.46 (s, 3H, Me), 1.43
(s, 9H, Boc), 1.32 (s, 6H, 2ꢄMe), 1.31 ppm (s, 3H, Me); 13C NMR
(150 MHz, CDCl3): d=172.3, 171.8, 171.0, 169.6, 169.4, 156.0, 111.6, 111.5
(2C), 104.8, 104.7, 104.6, 83.5 (2C), 83.3, 81.1, 81.0, 80.8, 80.1, 79.8, 79.5,
79.2, 57.4, 57.3, 52.1, 47.7, 47.1, 45.9, 44.2, 43.7, 38.4, 37.5, 35.1, 29.7, 28.3
(3C), 26.6, 26.5 (2C), 26.2, 26.1, 26.0 ppm; IR (KBr): n˜ =3387, 2933,
1731, 1677, 1659, 1547, 1530, 1441, 1377, 1253, 1216, 1166, 1118, 1079,
1020, 890, 855, 603, 540 cmÀ1
;
HRMS (ESI): m/z: calcd for
C43H69N5NaO20: 998.4428 [M+Na]+; found: 998.4454.
Boc-Gly-(S)-b-Caa-Gly-(S)-b-Caa-Gly-(S)-b-Caa-OMe (8): As described
for the synthesis of 13b, a solution of 3 (0.11 g, 0.22 mmol) gave 3b
(0.11 g, 93%) as a solid, which was used as such for the next reaction.
As described for the synthesis of 1, a mixture of 3b (0.1 g, 0.21 mmol),
HOBt (0.03 g, 0.25 mmol), and EDCI (0.05 g, 0.25 mmol) in CH2Cl2
(3 mL) was stirred at 08C for 15 min and treated with 18b [prepared
from 18 (0.11 g, 0.22 mmol) and CF3COOH (0.15 mL) in CH2Cl2
(1.5 mL)] and DIPEA (0.05 mL, 0.31 mmol) under an N2 atmosphere for
8 h. Workup and purification by column chromatography (silica gel,
3.2% methanol in CHCl3) afforded 8 (0.13 g, 59%) as a solid. M.p. 134–
1368C; [a]2D7 =+19.0 (c=0.1, CHCl3); 1H NMR (600 MHz, CDCl3,
278 K): d=7.98 (d, 1H, J=9.1 Hz, NH-2), 7.95 (dd, 1H, J=5.3, 7.4 Hz,
NH-5), 7.85 (dd, 1H, J=5.7, 6.4 Hz, NH-3), 7.81 (d, 1H, J=8.5 Hz, NH-
4), 6.95 (d, 1H, J=8.2 Hz, NH-6), 6.01 (d, 1H, J=3.9 Hz, C1H-6), 5.90
(d, 2H, J=3.8 Hz, C1H-2, 4), 5.43 (t, 1H, J=6.1 Hz, NH-1), 4.62 (d, 1H,
J=3.8 Hz, C2H-4), 4.61 (d, 1H, J=3.9 Hz, C2H-6), 4.60 (d, 1H, J=
3.8 Hz, C2H-2), 4.54 (dd, 1H, J=3.2, 8.6 Hz, C4H-6), 4.51 (m, 1H, CbH-
2), 4.42 (m, 1H, CbH-4), 4.37 (m, 1H, CbH-6), 4.33 (dd, 1H, J=3.1,
10.1 Hz, C4H-4), 4.26 (dd, 1H, J=3.1, 9.3 Hz, C4H-2), 4.22 (dd, 1H, J=
7.4, 15.8 Hz, CaH(pro-R)-5), 4.02 (d, 1H, J=3.1 Hz, C3H-4), 3.94 (d, 1H,
J=3.1 Hz, C3H-2), 3.93 (dd, 1H, J=5.7, 16.1 Hz, CaH(pro-R)-3), 3.85 (dd,
1H, J=6.1, 16.1 Hz, CaH(pro-R)-1), 3.71 (s, 3H, COOMe), 3.68 (dd, 1H,
J=6.4, 16.1 Hz, CaH(pro-S)-3), 3.64 (d, 1H, J=3.2 Hz, C3H-6), 3.55(dd, 1H,
J=5.3, 15.8 Hz, CaH(pro-S)-5), 3.54 (dd, 1H, J=6.1, 16.1 Hz, CaH(pro-S)-1),
3.40 (s, 3H, OMe), 3.39 (s, 3H, OMe), 3.37 (s, 3H, OMe), 2.70 (m, 1H,
CaH(pro-R)-4), 2.69 (m, 1H, CaH(pro-R)-6), 2.66 (m, 1H, CaH(pro-S)-2), 2.64
(m, 1H, CaH(pro-S)-6), 2.24 (dd, 1H, J=3.5, 13.2 Hz CaH(pro-S)-2), 2.19 (dd,
1H, J=3.2, 13.1 Hz CaH(pro-S)-4), 1.48 (s, 3H, Me), 1.47 (s, 3H, Me) 1.45
(s, 3H, Me), 1.41 (s, 9H, Boc), 1.31 (s, 6H, 2ꢄMe); 1.30 ppm (s, 3H,
Me); 1H NMR (CD3OH, 313 K, 500 MHz): d=8.04 (t, 1H, J=6.1 Hz,
NH-3), 7.99 (d, 1H, J=8.7 Hz, NH-4), 7.93 (t, 1H, J=6.1 Hz, NH-5),
7.88 (d, 1H, J=8.8 Hz, NH-6), 7.83 (d, 1H, J=8.5 Hz, NH-2), 6.65 (t,
1H, J=6.1 Hz, NH-1), 5.84 (d, 1H, J=3.7 Hz, C1H-6), 5.82 (d, 1H, J=
3.7 Hz, C1H-4), 5.81 (d, 1H, J=3.7 Hz, C1H-2), 4.66 (d, 1H, J=3.8 Hz,
C2H-2, 4, 6), 4.50 (m, 1H, CbH-6), 4.49 (m, 1H, CbH-2), 4.46 (m, 1H,
CbH-4), 4.35 (m, 1H, C4H-4), 4.33 (m, 1H, C4H-2), 4.32 (m, 1H, C4H-6),
3.90 (dd, 1H, J=6.1, 16.6 Hz, CaH(pro-R)-5), 3.85 (dd, 1H, J=6.1, 16.4 Hz,
CaH(pro-R)-3), 3.83 (d, 1H, J=3.1 Hz, C3H-4), 3.81 (d, 1H, J=3.1 Hz,
C3H-2), 3.71 (m, 1H, CaH(pro-R)-1), 3.78 (dd, 1H, J=5.4, 16.6 Hz,
CaH(pro-S)-5), 3.77 (dd, 1H, J=6.1, 16.4 Hz, CaH(pro-S)-3), 3.70 (d, 1H, J=
2.9 Hz, C3H-6), 3.68 (m, 1H, CaH(pro-S)-1), 3.66 (s, 3H, COOMe), 3.40 (s,
3H, OMe), 3.40 (s, 6H, OMe), 3.39 (s, 3H, OMe), 2.61 (dd, 1H, J=4.7,
15.4 Hz, CaH(pro-R)-6), 2.55 (dd, 1H, J=4.5, 13.9 Hz, CaH(pro-S)-2), 2.53 (m,
1H, CaH(pro-R)-4), 2.53 (m, 1H, CaH(pro-S)-6), 2.45 (m, 1H, CaH(pro-S)-2),
2.44 (m, 1H, CaH(pro-S)-4), 1.42 (s, 9H, 3ꢄMe), 1.43 (s, 9H, Boc), 1.29 (s,
6H, 2ꢄMe), 1.28 ppm (s, 3H, Me); 13C NMR (100 MHz, CDCl3): d=
172.3, 171.6, 171.0, 170.1, 169.9, 169.8, 156.8, 111.7, 111.6, 111.5, 104.9,
104.8, 104.8, 83.9, 83.6, 83.4, 81.4, 81.2, 81.1, 80.1, 80.1, 79.8, 79.3, 57.5,
57.4, 57.3, 51.9, 47.5, 46.9, 46.2, 44.8, 44.7, 44.0, 37.9, 37.6, 35.5, 28.3 (3C),
26.7, 26.7, 26.4, 26.4, 26.2, 26.2 ppm; IR (KBr): n˜ =3384, 3080, 2985, 2935,
1715, 1664, 1535, 1439, 1375, 1251, 1216, 1165, 1119, 1079, 1022, 958, 889,
Boc-Gly-(S)-b-Caa-Gly-(S)-b-Caa-OMe (6): As described for the synthe-
sis of 1, a mixture of 15a (0.05 g, 0.28 mmol), HOBt (0.04 g, 0.34 mmol),
and EDCI (0.07 g, 0.34 mmol) in CH2Cl2 (3 mL) was stirred at 08C for
15 min and treated with 18b [prepared from 18 (0.19 g, 0.28 mmol) and
CF3COOH (0.3 mL) in CH2Cl2 (1.5 mL)] and DIPEA (0.07 mL,
0.40 mmol) under an N2 atmosphere for 8 h. Workup and purification by
column chromatography silica gel, 2.1% methanol in CHCl3) afforded 6
(0.11 g, 52%) as a solid. M.p. 101–1038C; [a]2D7 =À8.2 (c=0.1, CHCl3);
1H NMR (600 MHz, CDCl3, 278 K): d=7.47 (d, 1H, J=8.2 Hz, NH-2),
7.35 (dd, 1H, J=5.2, 6.7 Hz, NH-3), 6.84 (d, 1H, J=8.1 Hz, NH-4), 5.98
(d, 1H, J=3.8 Hz, C1H-4), 5.90 (d, 1H, J=3.8 Hz, C1H-2), 5.47 (dd, 1H,
J=5.9, 6.3 Hz, NH-1), 4.62 (d, 2H, J=3.8 Hz, C2H-2 & C2H-4), 4.51 (m,
1H, CbH-4), 4.45 (dd, 1H, J=3.1, 9.1 Hz, C4H-4), 4.44 (m, 1H, CbH-2),
4.33 (dd, 1H, J=3.1, 8.2 Hz, C4H-2), 4.06 (dd, 1H, J=6.7, 16.4 Hz,
CaH(pro-R)-3), 3.92 (d, 1H, J=3.1 Hz, C3H-2), 3.80 (dd, 1H, J=6.3,
16.4 Hz, CaH(pro-R)-1), 3.70 (dd, 1H, J=5.2, 16.4 Hz, CaH(pro-S)-3), 3.70 (s,
3H, COOMe), 3.63 (dd, 1H, J=5.9, 16.4 Hz, CaH(pro-S)-1), 3.38 (s, 3H,
OMe), 3.37 (s, 3H, OMe), 2.72 (dd, 1H, J=5.7, 16.1 Hz , CaH(pro-R)-4),
2.67 (dd, 1H, J=5.1, 14.3 Hz , CaH(pro-R)-2), 2.59 (dd, 1H, J=5.6, 16.1 Hz,
CaH(pro-S)-4), 2.39 (dd, 1H, J=5.1, 14.3 Hz, CaH(pro-S)-2), 1.48 (s, 3H, Me),
1.46 (s, 3H, Me), 1.44 (s, 9H, Boc), 1.31 ppm (s, 6H, 2ꢄMe); 13C NMR
(150 MHz, CDCl3): d=171.8, 171.1, 170.1, 169.3, 156.6, 111.8, 111.7,
104.9, 104.8, 83.9, 83.7, 81.4, 81.2, 80.1, 79.9, 79.4, 57.5, 57.5, 51.9, 47.1,
45.8, 44.6, 43.6, 37.9, 35.7, 28.3 (3C), 26.7, 26.7, 26.3, 26.2 ppm; IR (KBr):
n˜ =3379, 2985, 2935, 1723, 1665, 1541, 1375, 1252, 1166, 1079, 1023, 890,
633, 539 cmÀ1; HRMS (ESI): m/z: calcd for C32H52N4NaO15: 755.3321
[M+Na]+; found: 755.3334.
Boc-(S)-b-Caa-Gly-(S)-b-Caa-Gly-(S)-b-Caa-OMe (7): As described for
the synthesis of 1, a mixture of 18a (0.14 g, 0.22 mmol), HOBt (0.04 g,
0.26 mmol), and EDCI (0.05 g, 0.26 mmol) in CH2Cl2 (2 mL) was stirred
at 08C for 15 min and treated with 16b [prepared from 16 (0.09 g,
0.22 mmol) and CF3COOH (0.1 mL) in CH2Cl2 (0.5 mL)] and DIPEA
(0.06 mL, 0.33 mmol) under N2 atmosphere for 8 h. Workup and purifica-
tion by column chromatography (silica gel, 3.1% methanol in CHCl3) af-
forded 7 (0.15 g, 70%) as a solid. M.p. 114–1158C; [a]2D7 =À30.8 (c=0.1,
CHCl3); 1H NMR (600 MHz, CDCl3, 280 K): d=7.51 (d, 1H, J=8.6 Hz,
NH-3), 7.39 (dd, 1H, J=4.8, 7.0 Hz, NH-4), 7.16 (t, 1H, J=6.1 Hz, NH-
2), 7.08 (d, 1H, J=8.4 Hz, NH-5), 5.98 (d, 1H, J=4.0 Hz, C1H À5), 5.92
(d, 1H, J=3.9 Hz, C1H-1), 5.90 (d, 1H, J=3.9 Hz, C1H-3), 5.53 (d, 1H,
J=8.0 Hz, NH-1), 4.62 (d, 1H, J=4.0 Hz, C2H-5), 4.61 (d, 1H, J=3.9 Hz,
C2H-3), 4.59 (d, 1H, J=3.9 Hz, C2H-1), 4.50 (dd, 1H, J=3.0, 8.9 Hz,
C4H-5), 4.45 (m, 2H, CbH-3, 5), 4.35 (dd, 1H, J=2.9, 9.5 Hz, C4H-3),
4.26 (dd, 1H, J=3.1, 8.3 Hz, C4H-1), 4.21 (m, 1H, CbH-1), 4.07 (dd, 1H,
J=7.0, 16.1 Hz, CaH(pro-R)-4), 3.94 (m, 1H, CaH(pro-R)-2), 3.92 (d, 1H, J=
2.9 Hz, C3H-3), 3.75 (d, 1H, J=3.1 Hz, C3H-1), 3.70 (s, 3H, COOMe)
3.68 (m, 1H, CaH(pro-S)-4), 3.66 (m, 1H, CaH(pro-S)-2), 3.66 (d, 1H, J=
3.0 Hz, C3H-5), 3.40 (s, 3H, OMe), 3.38 (s, 6H, OMe), 2.70 (dd, 1H, J=
5.2, 16.3 Hz , CaH(pro-R)-5), 2.66 (dd, 1H, J=4.7, 13.9 Hz, CaH(pro-R)-3),
854, 638, 553 cmÀ1
; HRMS (ESI): m/z: calcd for C45H72N6NaO21:
1055.4643 [M+Na]+; found: 1055.4669.
Boc-Gly-b-hGly-OMe (19): As described for the synthesis of 1, a mixture
of 15a (0.4 g, 2.28 mmol), HOBt (0.37 g, 2.73 mmol), and EDCI (0.52 g,
2.73 mmol) in CH2Cl2 (5 mL) was stirred at 08C for 15 min and treated
with 15c (0.32 g, 2.28 mmol; prepared from b-hGly in methanolic HCl) in
CH2Cl2 (3 mL) and DIPEA (0.55 mL, 3.16 mmol) under an N2 atmos-
Chem. Asian J. 2011, 6, 84 – 97
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G. V. M. Sharma, A. V. S. Sarma et al.
FULL PAPERS
phere for 8 h. Workup and purification by column chromatography (silica
gel, 90% EtOAc in petroleum ether) afforded 19 (0.45 g, 76%) as a
syrup. [a]2D7 =+1.3 (c=0.1, CHCl3); 1H NMR (300 MHz, CDCl3, 303 K):
d=6.81 (t, 1H, J=6.6 Hz, NH-2), 5.34 (t, 1H, J=6.1 Hz, NH-1), 3.78 (d,
2H, J=6.1 Hz, CaH-1), 3.69 (s, 3H, COOMe), 3.54–3.55 (m, 2H, CbH-2),
2.56 (t, 2H, J=5.9 Hz, CaH-2), 1.45 ppm (s, 9H, Boc); 13C NMR (CDCl3,
100 MHz): d=172.8, 169.5, 155.9, 80.1, 51.7, 44.2, 34.7, 33.6, 28.1 ppm
(3C); IR (KBr): n˜ =3425, 2981, 2932, 1722, 1692, 1529, 1392, 1368, 1235,
1163, 1109, 1055, 990, 952, 742, 602 cmÀ1; HRMS (ESI): m/z: calcd for
C11H21N2O5: 261.1354 [M+H]+; found: 261.1359.
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Boc-l-Ala-(S)-b-Caa-l-Ala-b-hGly-Gly-b-hGly-OMe (9): As described
for the synthesis of 1, a mixture of 20[14] (0.1 g, 0.17 mmol), HOBt (0.03 g,
0.20 mmol), and EDCI (0.04 g, 0.20 mmol) in CH2Cl2 (2 mL) was stirred
at 08C for 15 min and treated with 19a [prepared from 19 (0.04 g,
0.17 mmol) and CF3COOH (0.1 mL) in CH2Cl2 (0.5 mL)] and DIPEA
(0.05 mL, 0.26 mmol) under an N2 atmosphere for 8 h. Workup and pu-
rification by column chromatography (silica gel, 4.6% MeOH in CHCl3)
afforded 9 (0.04 g, 31%) as a solid. M.p. 110–1138C; [a]2D7 =+160.0 (c=
0.05, CHCl3); 1H NMR (500 MHz, CDCl3, 280 K): d=7.98 (d, 1H, J=
5.8 Hz, NH-3), 7.86 (d, 1H, J=9.4 Hz, NH-2), 7.81 (dd, 1H, J=7.6,
4.3 Hz, NH-4), 7.51 (dd, 1H, J=5.1, 6.9 Hz, NH-5), 7.02 (t, 1H, J=
5.8 Hz, NH-6), 5.90 (d, 1H, J=3.7 Hz, C1H-2), 5.09 (d, 1H, J=5.9 Hz,
NH-1), 4.60 (d, 1H, J=3.7 Hz, C2H-2), 4.51 (m, 1H, CbH-2), 4.26 (m,
1H, CaH-3), 4.20 (dd, 1H, J=6.9, 16.9 Hz, CaH-5), 4.18 (d, 1H, J=3.1,
9.5 Hz, C4H-2), 4.02 (m, 1H, CaH-1), 4.00 (d, 1H, J=3.1 Hz, C3H-2), 3.77
(m, 1H, CbH-4), 3.72 (s, 3H, COOMe), 3.58 (m, 1H, CbH-6), 3.57 (dd,
1H, J=5.1, 16.9 Hz, CaH-5), 3.42 (m, 1H, Cb’H-6), 3.39 (s, 3H, OMe),
3.24 (m, 1H, Cb’H-4), 2.66 (ddd, 1H, J=4.7, 8.3, 17.1 Hz, CaH(pro-R)-6),
2.59 (m, 1H, CaH(pro-S)-2), 2.54 (m, 1H, CaH(pro-S)-6), 2.53 (m, 1H,
CaH(pro-R)-4), 2.24 (td, 1H, J=3.2, 4.2, 13.9 Hz, CaH(pro-S)-4), 2.21 (m, 1H,
CaH(pro-R)-2), 1.49 (s, 3H, Me), 1.41 (s, 9H, Boc), 1.31 ppm (s, 3H, Me);
13C NMR (100 MHz, CDCl3): d=174.9, 173.3, 172.8, 170.1, 169.6, 155.7,
111.5, 104.9, 83.3, 81.1, 80.2, 80.0, 57.4, 51.8, 51.2, 51.0, 46.8, 43.4, 38.2,
36.6, 36.2, 34.9, 33.5, 28.2 (3C), 26.7, 25.8, 17.3, 16.8 ppm; IR (KBr): n˜ =
3410, 2932, 1731, 1658, 1642, 1547, 1536, 1489, 1447, 1370, 1251, 1167,
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1079, 1023, 896, 637, 553 cmÀ1
; HRMS (ESI): m/z: calcd for
C31H52N6NaO13: 739.3490 [M+Na]+; found: 739.3478.
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96
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The Design of a/b-Peptides
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[17] Solvent titration study was carried out by addition of [D6]DMSO se-
quentially to the peptide solutions dissolved in CDCl3 to give a final
[D6]DMSO level of 33%.
Received: June 17, 2010
Published online: October 4, 2010
Chem. Asian J. 2011, 6, 84 – 97
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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97