Three-residue turn in β-peptides nucleated by a 12/10 helix

Article abstract of DOI:10.1002/asia.201402465

A new three-residue turn in β peptides nucleated by a 12/10-mixed helix is presented. In this design, β peptides were derived from the 1:1 alternation of C-linked carbo-β-amino acid ester [BocNH-(R)-β-Caa_(r)-OMe] (Boc = tert-butyloxycarbonyl), which consisted of a D-ribo furanoside side chain, and β-hGly residues. The hexapeptide with (R)-β-Caa_(r) at the N terminus showed the 'turn' stabilized by a 14-membered NH(4)...CO(6) hydrogen bond at the C terminus nucleated by a robust 12/10-mixed helix, thus providing a 'helix-turn' (HT) motif. The turn and the helix were additionally stabilized by intraresidue electrostatic interaction between the furan oxygen in the carbohydrate side chain and NH in the backbone. However, the hexapeptide with a β-hGly residue at the N terminus demonstrated the presence of a 10/12 helix through its entire length, which again showed the intraresidue interaction between NH and furan oxygen. The intraresidue NH...O-Me electrostatic interactions observed in the monomer, however, were absent in the peptides.

Full text of DOI:10.1002/asia.201402465

FULL PAPER
DOI: 10.1002/asia.201402465
Three-Residue Turn in b-Peptides Nucleated by a 12/10 Helix
Gangavaram V. M. Sharma,*[a] Thota Anupama Yadav,[a] Kanakaraju Marumudi,[b]
Prashanth Thodupunuri,[a] Pothula Purushotham Reddy,[b] and Ajit C. Kunwar*[b]
Abstract: A new three-residue turn in
b peptides nucleated by a 12/10-mixed
helix is presented. In this design, b pep-
tides were derived from the 1:1 alterna-
tion of C-linked carbo-b-amino acid
gen bond at the C terminus nucleated
by a robust 12/10-mixed helix, thus
providing a ꢀhelix-turnꢁ (HT) motif.
The turn and the helix were additional-
ly stabilized by intraresidue electrostat-
ic interaction between the furan
oxygen in the carbohydrate side chain
and NH in the backbone. However, the
hexapeptide with a b-hGly residue at
the N terminus demonstrated the pres-
ence of a 10/12 helix through its entire
length, which again showed the intrare-
sidue interaction between NH and
ester
[BocNH-(R)-b-Caa(r)-OMe]
which
(Boc=tert-butyloxycarbonyl),
furan
oxygen.
The
intraresidue
ꢀ
consisted of a d-ribo furanoside side
chain, and b-hGly residues. The hexa-
peptide with (R)-b-Caa(r) at the N ter-
minus showed the ꢀturnꢁ stabilized by
a 14-membered NH(4)···CO(6) hydro-
NH···O Me electrostatic interactions
observed in the monomer, however,
were absent in the peptides.
Keywords: electrostatic
tions · foldamers · helical structures ·
hydrogen bonds · peptides
interac-
Introduction
peating classical a turns (Figure 1A) with dihedral angles of
f=ꢀ588 and y=ꢀ478.[7] However, a turns in proteins do
not follow these norms and fall into nine distinct classes
with varying intervening dihedral angles.[6a,8] Although the
design principles of such turns for naturally occurring amino
acids are not adequately elucidated, the designs based on
the classical a turns (Figure 1A) led to the realization of di-
verse mimics.[9] The first attempt to design a turns, reported
by Balaram et al.,[10] utilized a ꢀd-Pro-l-Pro-d-Alaꢁ three-
residue turn (Figure 1B) with two unnatural d-amino acids
Secondary structures such as turns, helices, and sheets play
an important role in biomolecular mimicry.[1] Turns, which
are generally located at the surface of proteins, often partici-
pate in interactions with other biomolecules and thereby
regulate their functions.[2] In addition, the turns, also re-
ferred to as reverse turns,[3] facilitate the change in the di-
rection of the propagation of secondary structures and thus
assist the proteins in forming compact tertiary globular
structures.[4]
Most common turns are from the family of b turns, which
are termed as ꢀtwo-residue turnsꢁ,[2,5] and involve four amino
acids. The design of super-secondary structures with such
turns has engaged researchers for almost two decades, and
the underlying principles are thoroughly understood. The
next most frequently occurring turns are the ꢀthree-residue
turnsꢁ or the a turns,[6] which have a 13-member NH(i)···CO-
to generate
a
hairpin supported by 13-membered
(iꢀ1)···CO(iꢀ3) hy-
NH(i)···CO
N
N
ACHTUNGTRENNUNG
drogen bonding. However, it was observed that this loop
could not be sustained in an isolated model molecule, there-
by suggesting that its nucleation required a hairpin. Further-
more, Balaram et al.[11] expanded the scope of the two-resi-
due turns by incorporating a d-amino acid, a dipeptide iso-
stere wherein the turn was stabilized by a 13-membered hy-
drogen bond, thereby resembling a three-residue turn. More
recently, Fairlie et al.[12] designed two small cyclic peptides
by linking the side chains of constituent amino acids, which
represented two nonclassical a turns.
(iꢀ4) hydrogen-bonded pseudoring. These turns are typical-
ly exemplified by the ideal a helix, which consists of such re-
[a] Dr. G. V. M. Sharma, T. A. Yadav, P. Thodupunuri
Organic and Biomolecular Chemistry Division
CSIR-Indian Institute of Chemical Technology
Hyderabad 500 007 (India)
Fax : (+91)40-27160387/27193108
E-mail: esmvee@iict.res.in
[b] K. Marumudi, P. P. Reddy, Dr. A. C. Kunwar
Centre for NMR and Structural Chemistry
CSIR-Indian Institute of Chemical Technology
Hyderabad 500 007 (India)
E-mail: kunwar@iict.res.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402465.
Figure 1. Stick model structures of the turns: A) classical a turn,[7] B) ꢀd-
Pro-l-Pro-d-Alaꢁ turn,[10] and C) ꢀb-a-bꢁ turn.[15a]
1
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Gangavaram V. M. Sharma, Ajit C. Kunwar et al.
In a/b peptides,[13] which are an important class of ꢀfol-
damersꢁ[14] with heterogeneous backbones, we have reported
13-member hydrogen-bonded turns[15a] that mimic the a turn
at the C terminus. These turns also were nucleated by a sec-
ondary structure, a helical 11/9-template, at the N terminus,
thereby generating a helix-turn (HT) motif. These ꢀb-a-bꢁ
turns (Figure 1C) derived from C-linked-carbo-b-amino acid
(b-Caa with a d-xylo furanoside side chain) and l-Ala were
stabilized by 13-member and 7-member hydrogen bonds,
hGly at the N terminus, respectively) were synthesized by
a conventional procedure and their structures were investi-
gated in detail.
NH
N
U
i being the last residue at the C terminus. These turns in-
volve only three residues, unlike the five in a turns; in addi-
tion, the hydrogen-bond directionality is also reversed. The
HT motifs were further utilized to generate a ꢀhelix-turn-
helixꢁ (HTH) super-secondary structure by tethering another
11/9 helix at the C terminus. Interestingly, though, the as-
sembly led to the destabilization of the original ꢀb-a-bꢁ turn
with a concomitant nucleation of a new ꢀa-b-bꢁ turn, which
was stabilized by three-center bifurcated hydrogen bonding
by 11-member (NH
((NH(i)···CO
(iꢀ4)) pseudorings. The turn was additionally
supported by a 9-member NH (furanose) hydro-
(iꢀ1)···O(i)
A
E
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
gen bond. Interestingly, this turn was akin to the a turn that
involved five residues and hydrogen bonds that have the
same directionality. Later studies[15b] by our group have
shown that the turn in HT motifs initiated by a a/b helix
can accommodate a wide variety of turns, such as ꢀb-a-aꢁ,
ꢀb-a-gꢁ, and ꢀb-a-dꢁ, in which a, b, g, and d refer to a-, b-, g-,
and d-amino acids, respectively. These turns were stabilized
by 12-, 14-, and 15-member hydrogen bonds (NH-
ACHTUNGTRENNUNG
A
vely.[15b] Further studies on peptides with a ꢀb-a-bꢁ C-termi-
nal sequence that have Gly as the a residue instead of l-Ala
showed that the turn was stabilized only by a 13-member
hydrogen-bonded pseudoring,[15b] whereas the 7-member hy-
drogen bond was conspicuously absent. In yet another study,
we observed the nucleation of a 12-member ꢀa-b-aꢁ turn at
the C terminus by a 9/11 helix.[15c]
In view of the above observations on the capability of
these helices in a/b peptides to nucleate these turns, it was
proposed to explore the possibility of the nucleation of such
novel turns at the C terminus in b peptides[16] by a 12/10
helix,[17] yet another family of mixed helices. Recently we re-
ported[18] peptides from a new Boc-(R)-b-Caa(r)-OMe (Boc=
tert-butyloxycarbonyl), [(R)-b-Caa(r)] 5, which contained
a side chain with d-ribo furanoside configuration. Monomer
5 displayed an additional backbone–side-chain interaction
between the oxygen of the C-3 OMe and the NH, whereas
the a/b peptides prepared from 5 and l-Ala alternately gen-
erated a 14/15 helix in short oligomers stabilized by this ad-
ditional interaction.[18] Herein, we discuss the exploration of
the possibility to nucleate an HT motif with a likely 12/10
helix at the N terminus in regular 1:1 hybrid b peptides[19]
from (R)-b-Caa(r) 5 and b-hGly 6, in addition to understand-
ing the role of additional electrostatic interaction in their
folding propensities. Peptides 1–4 (1/2 with 5 and 3/4 with b-
Results and Discussion
Peptides 1 and 2 were prepared from (R)-b-Caa(r) 5 and 8.
Accordingly, acid 7[18] on coupling[20] with salt 8 prepared
from 6 in the presence of 1-ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide (EDCI), hydroxybenzotriazole (HOBt),
and N,N-diisopropylethylamine (DIPEA) in CH2Cl2 afford-
ed dipeptide 9 in 65% yield (Scheme 1). Treatment of pep-
tide 9 with CF3COOH in CH2Cl2 gave salt 9a, whereas 9 on
base hydrolysis with LiOH afforded acid 9b. Coupling
(EDCI, HOBt, and DIPEA) of acid 9b with salt 9a in
CH2Cl2 furnished tetrapeptide 1 in 52% yield. Ester 1 on
base hydrolysis with LiOH afforded acid 10, which on fur-
ther coupling with salt 9a gave hexapeptide 2 in 44% yield.
Likewise, coupling of acid 11 with salt 7a[18] in the pres-
ence of EDCI, HOBt, and DIPEA in CH2Cl2 afforded di-
peptide 12 in 67% yield (Scheme 2). Reaction of 12 with
CF3COOH in CH2Cl2 gave 12a, whereas 12 on base hydrol-
ysis with LiOH gave acid 12b. Coupling (EDCI, HOBt, and
DIPEA) of acid 12b with salt 12a in CH2Cl2 furnished tet-
rapeptide 3 in 52% yield. Base hydrolysis of 3 with LiOH
gave acid 13, which on further coupling with salt 12a fur-
nished hexapeptide 4 in 55% yield.
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Gangavaram V. M. Sharma, Ajit C. Kunwar et al.
close proximity, as has been re-
ported.[18] Tetramer 1 gave an
indication of a nascent underly-
ing structure and showed a simi-
lar structure for both the b-
Caa(r).[21] Chemical shifts d>
7 ppm and a nominally small
change in their values (Dd) for
some of the amide protons[21]
during solvent titration stud-
ies[23] imply their involvement
in hydrogen bonding. In addi-
Scheme 1. Reagents and conditions: a) HOBt, EDCI, DIPEA, dry CH2Cl2, 08C–RT, 5 h; b) CF3COOH, dry
CH2Cl2, 08C–RT, 2 h; and c) LiOH, THF/MeOH/H2O (3:1:1), 08C–RT, 1 h.
tion, 3J
ACTHNUTRGNEUNG(NH,CbH) values for
both the b-Caa(r) residues are
greater than 9.2 Hz, which sug-
gests the predominance of
f(CO-N-Cb-Ca)ꢁꢀ1208. How-
3
ever, other couplings such as J-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Scheme 2. Reagents and conditions: a) HOBt, EDCI, DIPEA, dry CH2Cl2, 08C–RT, 5 h; b) CF3COOH, dry
CH2Cl2, 08C–RT, 2 h; and c) LiOH, THF/MeOH/H2O (3:1:1), 08C–RT, 1 h.
dues showed distinct signatures
of conformational averaging.[21]
The presence of moderate in-
tensity
NOE
correlations,
Structural Studies
CbH(1)/NH(3), CbH(1)/CaH(pro-R)(3), and NH(2)/NH(3),
AHCTUNGTRENNUNG
NMR spectroscopic studies[21] on peptides 1–4 were under-
taken in 6–10 mm solution at 298 K in CDCl3. Exchange
peaks in the ROESY spectra implied the presence of two
isomers in most of the oligomers. However, the population
of the minor isomer was small enough to be detected in the
one-dimensional 1H NMR spectrum, and hence only the
major isomer could be studied.
suggested that some population of the molecule folds as
a mixed 12/10 helix.
For the larger hexapeptide 2, four of the amide protons in
the middle display d>7.9 ppm, which suggests their likely
participation in hydrogen bonding. The small Dd<0.24 ppm
(Figure 3) in the solvent titration studies[23] further con-
firmed the involvement of NH(2), NH(3), NH(4), and
NH(5) in hydrogen bonding, thereby implying the propensi-
The b-Caa(r) residue in dipeptide 9 and tetrapeptide 1 dis-
played all the NMR spectroscopic signatures such as 3J-
ty towards a definite structure. A detailed analysis of the H
1
A
3J
E
and
3J-
spectrum indicated an interesting fact that the b-Caa(r) resi-
dues in 2 differ structurally from those in the monomer,
dimer, and the tetramer by displaying the absence of intra-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ꢀ
ꢀ
that were observed in the Boc/COOMe-protected monomer
(Figure 2).[10,22] This justifies a high propensity of structures
with dihedral angle N-Cb-C4-O (furan) (c1)ꢁ1808, which
brings NH and OMe at the C3 carbon in the sugar ring in
residue interactions between NH and OMe, as shown in
Figure 2.
Figure 2. A) Structure of (R)-b-Caa(r) in 9 and 1. B) Structure of (R)-b-
Caa(r) in 2.
Figure 3. Variation of the NH chemical shifts on adding [D6]DMSO to so-
lution of 2 in CDCl3.
3
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Gangavaram V. M. Sharma, Ajit C. Kunwar et al.
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Unlike in the case of 9 and 1, which have J
N
3
8.0 Hz, for 2 the J
N
first, third, and fifth b-Caa(r) residues, respectively, were no-
ticed to be much smaller. This appeared to suggest that for
these residues, the dihedral angle c1 [N-Cb-C4-O (furan)]
differs in 2 with a likely preponderance of a value of ap-
proximately ꢂ608 for the first two b-Caa(r) residues, whereas
for the last one, owing to fraying, averaging over several
conformers is indicated. The result was the modification of
some characteristic NOEs in the ROESY spectrum, espe-
cially for the first two b-Caa(r) residues. Thus, C3H/CaH-
A
ACHTUNGTRNE(NUNG pro-S) were strong, whereas C4H/
ACHTUNGTRENNUNG
support the propensity of structures with c1 ꢁ608. However,
the NOE correlations between NH with C3H (medium in-
tensity) and with both the CaH (medium intensity) suggest
small populations of other rotamers with c1 ꢁꢀ608. Interest-
ingly, c1 ꢁ ꢂ608 brings the NH close to the O (furan ring) in
the b-Caa(r) residues as shown in Figure 2, thereby changing
the character of the additional electrostatic interaction.
3
All the b-Caa(r) residues had J
N
supports an anti-periplanar arrangement of the amide and
the CbH protons and the predominance of fꢁꢀ1208. It was
3
also noted that J
N
or less than 4 Hz, which in turn suggests that the dihedral
angle q (N-Cb-Ca-CO) is constrained around 60 or 1808.
The distinction between these options was achieved by in-
specting the NOE correlations, CaH
N
ACHTUNGERTN(NUNG b-
hGly)(i+1) and NH-b-hGly(i+1)/NH-b-Caa
G
R
G
Figure 4. A) Expansions of the ROESY spectrum of 2 in CDCl3 at 298 K;
B) The NOE correlations are also marked in the chemical structure as
double-headed arrows with numbering (as shown in A); hydrogen bond-
ing is shown as double-headed dotted lines. The numbers associated with
the dotted lines represent the size of the hydrogen-bonded pseudorings.
and 5) (Figure 4), thereby enabling us to fix qꢁ608. It was
also found that the CaH of the b-Caa(r) residue with the
3
smaller J
ACHTUNGTRENNUNG
the NH of the following b-hGly and was fixed as CaH
ACHTUNGTRENNUNG
3
S) relative to the CaH with a larger J
ACHTUNGTRENNUNG
was assigned as CaH(pro-R).
G
tional averaging, which arise owing to fraying in the termi-
ni). In b-hGly, owing to the absence of any side chains, the
above couplings satisfy fꢁ ꢂ1208. To make the stereospe-
cific assignments of the two Cb protons of b-hGly, we
needed to explore medium-range NOE correlations between
the CbH protons of the b-Caa(r) residues with the amide and
the CaH protons of the following b-Caa(r) residues (medium
range i/i+2 interaction), which have been the distinctive sig-
natures of a 12/10 helix. These characteristic NOE values
These findings were additionally supported by the NOE
correlations between the backbone and the side-chain pro-
tons.[21] As already discussed, the 3J
ACTHNUTRGNE(NUG CbH,C4H)=4.0 and
5.7 Hz for the first and third b-Caa(r) residues, respectively,
support a CbH-Cb-C4-C4H dihedral angle of about ꢂ608.
Moreover, strong intraresidue C3H/CaHACTHNUGRTENUNG(pro-S) and C4H/
CaHACHTUNGTRENNUNG(pro-S) and weak C4H/CaHACHTUNTGREN(NUNG pro-R) NOE correlations
enabled us to fix this angle to approximately 608 (which ac-
tually corresponds to c1 ꢁ608). Thus, the proximity (ꢁ3 ꢃ)
of the amide proton to the furan oxygen noticed from the
above deductions suggests a weak intraresidue electrostatic
interaction between NH and the furan ring ꢀOꢁ (of the car-
bohydrate side chain) in the hexamer 2, which differs from
arise only if fꢁ1208 for b-hGly, which permits us to assign
3
the CbH with smaller J
G
E
one with larger 3J
ACHUTGTNREN(NUG NH,CbH) as CbHACHTNUGTRENNUNG
found that, except for the last b-hGly, 3J
either greater than 10 Hz or less than 5 Hz, which is consis-
tent with constrained value of dihedral angle q around 60 or
1808. The distinction between these two possibilities was
made as follows. The rationale used for the stereospecific as-
signments of the CaH protons of b-Caa(r), using their NOE
values with amide protons of the following residue, was also
applicable in b-hGly residue as well. In fact, the NOE corre-
ꢀ
the NH and OMe interaction in the case of 9 and 1. In ad-
dition, the presence of the NOE cross-peak between the
amide proton of b-hGly with the CbH and the CaHACTHNUTRGNEUG(N pro-S)
of the preceding b-Caa(r) residue further suggests a constrain-
ed value of approximately 1008 for y (Cb-Ca-CO-N).
For b-hGly residues (except the one at the C terminus),
3J
N
lations, NH-b-hGly(i)/NH-b-Caa
(Figure 4), are possible only with qꢁ608. This allowed us to
assign the CaH with large 3J
(CaH,CbH) as CaH(pro-R)
(r)ACHTUNGTRENUN(NG i+1) (i=1 and 3)
strained values of f (for the last residue, these couplings are
approximately 6.0 Hz, thereby reflecting possible conforma-
A
ACHTUNGTRENNUNG
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Gangavaram V. M. Sharma, Ajit C. Kunwar et al.
3
and the one with both J
G
(pro-S).
differs from that of y). The 12/10 helix is sustained by three
hydrogen bonds at the N terminus. The average length of
(N)H···O(C) (r(N)H···O(C)) in the 12-member hydrogen bonds,
Owing to averaging of couplings in the last b-hGly, these
stereospecific assignments could not be made.
For the structure in 2, apart from the couplings, medium-
range NOEs were very distinctive. As discussed in the con-
text of 12/10 helix, CbH(1)/NH(3) and CbH(1)/CaHACTHUNTGRNEUNG(pro-
NH(3)···COACTHNGUTERNNU(G Boc) and NH(5)···CO(2), in these structures is
(2.12ꢂ0.11) and (2.29ꢂ0.06) ꢃ, respectively (Figure 5B),
whereas for the 10-member hydrogen bond, NH(2)···CO(3),
R)(3) along with NH(2)/NH(3) (Figure 4) support a 12/10-
r(N)H···O(C) is (2.29ꢂ0.05) ꢃ. The average (N)H···O
ACHTUNGTRENUN(NG furan) dis-
mixed helix at the N terminus.[17c] The observed CbH(3)/
tance of (2.72ꢂ0.23), (2.79ꢂ0.07), and (3.04ꢂ0.07) ꢃ, re-
NH(5) and CbH(3)/CaHACHTUNRGTNE(NUG pro-R)(5) correlations at the C ter-
spectively, for the first, third, and the fifth b-Caa(r) residues
minus along with NH(4)/NH(6), NH(5)/NH(6), and NH(4)/
OCH3(6) (Figure 4) are reminiscent of the presence of such
NOE correlations in a/b peptides that display a HT super-
secondary structure.[15a,b,c] The circular dichroism (CD) spec-
trum of 2 in methanol supports the above findings.[21]
clearly demonstrates the proximity of NH and OACHTUNGTRENNUNG(furan)
(Figure 5B). The average values of the NH···O angle in the
10- 12-, and 14-member hydrogen bonds are (151ꢂ5),
(150ꢂ13), and (162ꢂ10)8, respectively.
A comparison of the 14-member of the ꢀb-b-bꢁ turn (Fig-
ure 6A) of the present study with that of the 14-member of
Molecular dynamics (MD) calculations[21] were carried
out using the distance and angle constraints. Figure 5A
Figure 6. Structures of the turns: A) ꢀb-b-bꢁ turn in peptide 2, B) 14-
member turn in the ꢀb-a-gꢁ turn,[15b] and C) overlay of 14-member turns
of A and B (dark: ꢀb-b-bꢁ turn; light: ꢀb-a-gꢁ turn).
Figure 5. A) Stereoview of superimposition of ten best structures for pep-
tide 2 (the sugar moieties were replaced by methyl groups after the calcu-
lations for clarity). B) One of the structures of 2 showing average hydro-
gen-bond lengths [ꢃ] involving the amide proton and the carbonyl
oxygen (in green). The amide proton and the furan oxygen distances are
shown in red. The sugar rings have been removed for clarity (not re-
placed with methyl).
the ꢀb-a-gꢁ turn (Figure 6B) in hybrid peptides[15b] showed
a significant resemblance to each other with an RMSD of
1.5 ꢃ for the 14 intervening atoms (Figure 6C). In fact, in
these 14-member turns, the dihedral angles of the first b resi-
dues are very similar to each other. In addition, they also re-
sembled the dihedral angles (Table 1) of the first b residues
in the 13-member ꢀb-a-bꢁ and 12-member ꢀb-a-aꢁ turns.[15b]
Furthermore, the results in this study appear to suggest
that for the peptides devoid of a well-defined structure, the
c1 angle in the b-Caa(r) is predominantly approximately 1808,
shows a superimposed stereoview of the ten best structures
of peptide 2. The heavy atom and the backbone root-mean-
square deviation (RMSD) are (0.78ꢂ0.38) and (0.77ꢂ
0.29) ꢃ, with the largest viola-
tions of 0.17 ꢃ in the distance
constraints and 58 in the angle
constraints. These structures
clearly bring out an HT motif
in 2. The structure, unlike in
our earlier studies, has now
been generated in a b peptide
with a 12/10 helix, which con-
sists of a new ꢀb-b-bꢁ turn motif
at the N terminus. The dihedral
angles in the turn are f(4)=
Table 1. Dihedral angles (f, q, y) [8] in various families of turns observed in hybrid peptides.
ꢀb-a-bꢁ[15a]
ꢀb-a-aꢁ[15b]
ꢀb-a-gꢁ[15b]
ꢀa-b-aꢁ[15b]
ꢀa-b-bꢁ[15c]
ꢀb-b-bꢁ[a]
Residue (iꢀ2)[b]
f
q
79
57
76
62
89
68
ꢀ133
–
ꢀ76
–
96
63
ꢀ89
y
ꢀ103
ꢀ106
ꢀ90
Residue (iꢀ1)
58
120
f
q
ꢀ90
–
71
ꢀ98
–
66
ꢀ102
92
ꢀ59
ꢀ87
83
72
ꢀ70
ꢀ125
61
46
–
y
68
Residue (i)
(96ꢂ2)8,
y(4)=ꢀ(89ꢂ2)8,
(125ꢂ3)8,
y(5)=(46ꢂ4)8,
q(4)=(63ꢂ1)8,
f
86
68
–
157
–
–
125
ꢀ70
167
94
ꢀ88
–
–
113
102
–
ꢀ61
97
ꢀ82
–
ꢀ170
ACHTUNGTRENNUNG
f(5)=
q/q1
q2
y*[c]
ꢀG
q(5)=(61ꢂ2)8,
f(6)=(97ꢂ
149
130
126
6)8, q(6)=(82ꢂ3)8, y*(6)=
[a] From the present study. [b] The last residue in the turn is denoted as the residue (i). [c] The y* dihedral
angle is actually Cb-Ca-CO-O (for all the turns except ꢀa-b-bꢁ turns in the helix-turn-helix motifs, in which it
ꢀG(170ꢂ30)8 (y* is the Cb-Ca-
CO-O dihedral angle, which is a y (Cb-Ca-CO-N).
5
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Gangavaram V. M. Sharma, Ajit C. Kunwar et al.
whereas for the oligomer with a distinct structure, there is
a preponderance of c1 ꢁ608. It is thus meaningful to investi-
gate the general validity of such an observation in the pep-
tides 12, 3, and 4 with b-hGly-b-Caa(r) dipeptide repeats.
It was observed that in peptides 3 and 12 the b-Caa(r) resi-
due has a structure similar to that in smaller peptides (1 and
9) discussed above, exemplified by c1 ꢁ1808.[21] Like tetra-
peptide 1, yet again 3 displayed conformational averaging
and weaker signatures of a 10/12-mixed helix.[17c]
1
The H spectrum of hexapeptide 4 showed d>7.4 ppm for
the last four amide protons. Except for the second residue,
all the amide protons displayed Dd<0.36 ppm,[23] thereby
confirming their participation in hydrogen bonding
(Figure 7). In addition, 3J
ACHTNUTRGNE(UNG NH,CbH)>9.2 Hz for b-Caa(r)
Figure 8. A) Expansions of the ROESY spectrum of 4 in CDCl3 at 298 K.
B) The NOE correlations are also marked in the chemical structure as
double-headed arrows with numbering (as shown in A); hydrogen bond-
ing is shown as double-headed dotted lines. The numbers associated with
the dotted lines represent the size of the hydrogen-bonded pseudorings.
Figure 7. Variation in the NH chemical shifts on the addition of
[D6]DMSO to solution of 4 in CDCl3.
residues and >9.2 or <4.1 Hz for b-hGly residues (except
the first residue) appear to support fꢁ ꢂ1208 for the last
3
five residues. All the J
N
obtained owing to spectral overlap. However, the ones de-
duced were either greater than 10 Hz or less than 5 Hz
3
(except for those in the second b-hGly residue, which has J-
A
ACHTUNGTRENNUNG(pro-S),CbHACHTUNGTRENNUNG(pro-S))=6.6 Hz). The above couplings
AHCTUNGTRENNUNG
Figure 9. Stereoview of ten superimposed best structures for peptide 4
(the sugar moieties were replaced by methyl groups after the calculations
for clarity).
ACHTUNGTRENNUNG
(Figure 8), emphatically support a mixed helical structure in
4. The participation of all amide protons except NH(2) in
hydrogen bonding and the above deductions suggest a 10/
3
12/10/12/10-mixed helix.[21] In 4 all J
(CbH,C4H) values are
spectively, whereas for the 10-member hydrogen bonds,
NH(1)···CO(2), NH(3)···CO(4), and NH(5)···CO(6), it is
(2.23ꢂ0.01), (2.20ꢂ0.03), and (2.40ꢂ0.01 ꢃ), respectively.
The average values of the NH···O angle in the 10- and 12-
member hydrogen bonds are (160ꢂ12) and (153ꢂ5)8, re-
spectively. As observed for 2, the close proximity of NH and
less than 5 Hz and they along with NOE data justify a c1
ꢁ608, which suggests the proximity of NH and furan oxygen
ꢀ
and the absence of NH and OMe interaction. The CD
spectrum in methanol gave evidence for the presence of the
above structural information.[21]
Figure 9 displays a superposition of the ten best structures
of 4 from MD calculations with a backbone and heavy atom
RMSD of (0.26ꢂ0.31) and (0.55ꢂ0.23) ꢃ with no violation
in the distance or angle constraints. The average lengths of
r(N)H···O(C) in the 12-member hydrogen bonds, NH(4)···CO(1)
and NH(6)···CO(3), are (2.34ꢂ0.01) and (2.06ꢂ0.01) ꢃ, re-
OACTHUNGTERNNU(G furan) is yet again noted, with an average (N)H···O-
A
0.01) ꢃ for the second, fourth, and the sixth b-Caa(r) residue,
respectively.
In all the b peptides of the above study, the sugar ring
pucker and structure of the isopropylidene ring conforma-
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Gangavaram V. M. Sharma, Ajit C. Kunwar et al.
The CD spectra for peptides 2 and 4 were obtained in rectangular fused
quartz cells of a 0.2 cm path length at room temperature with a scan
range of 190–260 nm and a scanning speed of 50 nmminꢀ1 using peptide
concentrations of 0.2 mm in MeOH. The binomial method was used for
smoothing the spectra. The values are expressed in terms of [q], the total
molar ellipticity (8cm2 dmolꢀ1).[21]
tion in b-Caa(r) were identical since the intrasugar ring cou-
plings and the NOEs were very similar to those observed in
the b-Caa(r) monomer.[18] The couplings, 3J
ACHTUNGTRENNUNG
ꢁ4 Hz, 3J
N
ACHTUNGTRENNUNG
U
ACHTUNGTRENNUNG
C2H, and weak Me
consistent with a T2 pucker of the sugar ring and an enve-
lope conformation for the isopropylidene ring.
G
The Insight-II (97.0)/Discover program[26] was used for construction of
molecular models and for structural analysis of different obtained confor-
mations including molecular modeling calculations and energy minimiza-
tion. The consistent-valence force field (CVFF) with default parameters
was used throughout the calculations with the aid of a distance-depen-
dent dielectric constant with a dielectric constant (e) value of 4.8. The ini-
tial energy minimizations were done with steepest descent followed by
conjugate gradient methods for a maximum of 5000 iterations each or an
RMS deviation of 0.001 kcalmolꢀ1, whichever came first. In the simulated
annealing protocol run for 2 ns, the molecules were initially equilibrated
for 1 ps at 300 K. They were then heated to 1500 K in four steps of 300 K
by increasing the temperature and simulating for 2.5 ps at each step, and
then subsequently cooling back to 300 K in four steps of 300 K and again
simulating for 2.5 ps at each step. After this, a structure was saved and
the above process was repeated 100 times. The 100 structures generated
in this manner were energy-minimized with the above protocol, and ten
of the best possible structures were superimposed for display.
3
Conclusion
In conclusion, the present study reports the design and syn-
thesis of a new class of b peptides from (R)-b-Caa(r) and b-
hGly in 1:1 alternation to generate a new three-residue turn
and an HT motif in a short peptide. This study demonstrates
for the first time that the HT structure can also be nucleated
by a 12/10 helix at the N terminus. The three-residue turn
that consists of a ꢀb-b-bꢁ motif is stabilized by a 14-member
NH(4)···CO(6) hydrogen bond. However, the hexapeptide
with b-hGly at the N terminus showed the presence of a 10/
12 helix. The peptides with a definitive structure have
shown the proximity of NH and the furan oxygen of the
sugar ring of b-Caa(r), whereas the intraresidue interaction
The high-resolution mass spectrometry (HRMS) data were obtained
using a Q-TOF mass spectrometer.
Boc-(R)-b-Caa(r)-b-hGly-OMe (9)
A cooled (08C) solution of 5 (0.55 g, 0.15 mmol) in THF/MeOH/H2O
(3:1:1; 1 mL) was treated with LiOH (0.005 g, 0.21 mmol) and stirred at
room temperature. After 1 h, the pH was adjusted to 2–3 with 1n HCl
solution at 08C, and the solution was extracted with ethyl acetate (2ꢄ
50 mL). The organic layer was dried (Na2SO4) and evaporated to give 7
(0.5 g, 95%) as a white solid, which was used as such for further reaction.
ꢀ
between NH and OMe observed in the monomer was
ꢀ
absent. However, such an interaction (NH and OMe) was
still present in the smaller peptides that do not take on
a well-defined structure. The HT motif disclosed is an im-
portant finding in the domain of foldamers and might find
use in the design of super-secondary structures of functional
utility. Advantageously, the presence of b-hGly, with its in-
trinsic conformational freedom, in the design of peptides
makes them more attractive for the generation of diverse
structures.
A solution of acid 7 (0.53 g, 1.46 mmol), HOBt (0.29 g, 2.19 mmol), and
EDCI (0.42 g, 2.19 mmol) in CH2Cl2 (5 mL) was stirred at 08C under an
N2 atmosphere for 15 min, treated with amine 8 (prepared from 6 (0.4 g,
4.4 mmol) on reaction with dry HCl gas in MeOH at room temperature)
and DIPEA (0.37 mL, 4.38 mmol), and stirred at room temperature for
5 h. The reaction mixture was quenched with aqueous NH4Cl (10 mL) at
08C and diluted with CHCl3 (10 mL). It was subsequently washed with
1n HCl (10 mL), water (10 mL), and brine (10 mL). The organic layers
were dried (Na2SO4) and evaporated. Purification of the residue by
column chromatography (60–120 mesh silica gel, 60% ethyl acetate in
petroleum ether) afforded 9 (0.47 g, 65%) as a white solid. M.p. 1578C;
½aꢃ2D0 = +154.16 (c=0.12, CHCl3); 1H NMR (700 MHz, CDCl3, 298 K):
d=6.41 (brs, 1H; NH2), 5.71 (d, J=3.6 Hz, 1H; C1H1), 5.65 (d, J=
9.6 Hz, 1H; NH1), 4.68 (t, J=3.7 Hz, 1H; C2H1), 3.97 (m, 1H; CbH1),
Experimental Section
NMR spectra (1D and 2D experiments) for peptides 1-4 were obtained
at 300, 500, 600, and 700 MHz (1H), and at 75, 125, and 150 MHz (13C).
Chemical shifts (d) are reported with respect to an internal TMS refer-
ence. Information on hydrogen bonding in CDCl3 was obtained from sol-
vent titration studies by sequentially adding up to 33% (v/v) [D6]DMSO
to solutions of the peptides in CDCl3. States TPPI procedure was used to
run various NMR spectroscopic experiments in the phase-sensitive
mode[24] using standard programs in the library provided by the instru-
ment manufacturer. The ROESY experiments were performed with
mixing times of 200/300 ms using a continuous spin-locking field of about
2.5 kHz. The TOCSY experiments were performed with the spin-locking
field of about 10 kHz and a mixing time of 80 ms. The 2D data were pro-
cessed with Gaussian apodization in both dimensions.
ꢀ
3.84 (t, J=8.4 Hz, 1H; C4H1), 3.70 (s, 3H; COOMe), 3.67 (dd, J=
4.0,8.4, 1H; C3H1), 3.51 (m, 1H; CbH2), 3.47 (m, 1H; CbH2), 3.42 (s,
3H; OMe), 2.53 (m, 2H; CaH2), 2.47 (m, 2H; CaH1), 1.53, 1.35 (2 s,
6H; 2CH3), 1.43 ppm (s, 9H; Boc); 13C NMR (125 MHz, CDCl3, 298 K):
d=172.7, 170.7, 155.6, 113, 103.7, 83, 79.2 (2C), 78.5, 58.1, 51.7, 50.1, 38,
34.7, 33.7, 28.3 (2C), 26.7, 26.5 ppm; IR (CHCl3): n˜ =3267, 3082, 2983,
2931, 2854, 1736, 1698, 1646, 1551, 1370, 1238, 1167, 1097, 1025, 752 cmꢀ1
;
HRMS (ESI+): m/z calcd for C20H34N2O9 [M++Na]: 469.2156; found:
469.2131.
Boc-(R)-b-Caa(r)-b-hGly-(R)-b-Caa(r)-b-hGly-OMe (1)
A cooled (08C) solution of 9 (0.16 g, 0.36 mmol) in THF/MeOH/H2O
(3:1:1; 1 mL) was treated with LiOH (0.013 g, 0.55 mmol) and stirred at
room temperature. Workup as described for 7 gave 9b (0.5 g, 95%) as
a white solid, which was used as such for further reaction.
The MD calculations were carried out using the simulated annealing pro-
tocol. Isolated two-spin approximation and a reference distance of 1.8 ꢃ
for the Ca geminal protons were used to obtain the distance constraints
from the volume integrals of the cross-peaks in the ROESY spectra.[25]
The upper and lower limits of the constraints were deduced by adding or
subtracting 10% to the thus found internuclear distances. Whenever the
Amine salt 9a (prepared from 9 (0.18 g, 0.4 mmol) and CF3COOH
(0.4 mL) in CH2Cl2 (1 mL)) was added to a solution of 9b (0.15 g,
0.34 mmol), HOBt (0.07 g, 0.52 mmol), and EDCI (0.1 g, 0.52 mmol) in
dry CH2Cl2 (5 mL) and stirred at room temperature for 5 h. Workup as
described for 9 and purification of the residue by column chromatogra-
phy (60–120 mesh silica gel, 2.6% CH3OH in CHCl3) afforded 1 (0.14 g,
ꢀ
geminal proton resonances overlapped, the C1H C2H distance of 2.4 ꢃ
in the sugar ring was used as a reference. The backbone dihedral angle
constraints were used with a tolerance of ꢂ308 to the values deduced
from the couplings.
7
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Gangavaram V. M. Sharma, Ajit C. Kunwar et al.
52%) as a white solid. M.p. 2148C; ½aꢃ2D0 =ꢀ37.5 (c=0.08, CHCl3);
1H NMR (600 MHz, CDCl3, 298 K): d=7.35 (t, J=6.3 Hz, 1H; NH2),
7.20 (d, J=9.2 Hz, 1H; NH3), 6.39 (t, J=6.2 Hz, 1H; NH4), 5.73 (d, J=
3.8 Hz, 1H; C1H1), 5.72 (d, J=3.6 Hz, 1H; C1H3), 5.58 (d, J=9.9 Hz,
1H; NH1), 4.67 (d, J=3.8 Hz, 1H; C2H3), 4.67 (dd, J=3.8,8.2 Hz, 1H;
C2H1), 4.40 (qd, J=3.3, 8.7 Hz, 1H; CbH3), 4.19 (m, 1H; CbH1), 3.88
(dd, J=8.0, 8.2 Hz, 1H; C4H1), 3.84 (t, J=8.0, 8.3 Hz, 1H; C4H3), 3.7
layers were mixed, acidified with aqueous saturated KHSO4 (pH 2), and
extracted with ethyl acetate (2ꢄ5 mL). The organic layer was dried
(Na2SO4) and evaporated to give 11 (0.3 g, 94%) as a white solid, which
was used for the next reactions.
A solution of acid 11 (0.30 g, 1.93 mmol), HOBt (0.324 g, 2.34 mmol),
and EDCI (0.46 g, 2.34 mmol) in CH2Cl2 (5 mL) was stirred at 08C under
an N2 atmosphere for 15 min. Amine salt 7a (prepared from 5 (0.6 g,
0.16 mmol) and CF3COOH (0.2 mL) in CH2Cl2 (2 mL)) was added and
stirred at room temperature for 5 h. Workup as described for 9 and pu-
rification of the residue by column chromatography (60–120 mesh silica
gel, 55% ethyl acetate in petroleum ether) afforded 12 (0.56 g, 67%) as
ꢀ
(s, 3H; COOMe), 3.67 (dd, J=3.8, 8.3 Hz, 1H; C3H3), 3.67 (m, 1H;
CbH2), 3.58 (dd, J=3.8, 8.2 Hz, 1H; C3H1), 3.55 (m, 1H; CbH4), 3.40
(s, 3H; OMe), 3.43 (m, 1H; CbH4), 2.55 (dd, J=9.5, 12.4 Hz, 1H;
CaH3), 2.54 (dd, J=2.5, 14.0 Hz, 1H; CaH1), 2.56 (m, 1H; CaH’4), 2.51
(m, 1H; CaH4), 2.49 (dd, J=6.7, 12.4 Hz, 1H; CaH’3), 2.38 (dd, J=8.4,
14.0 Hz, 1H; CaH’1), 2.21 (m, 1H; CaH2), 2.24 (m, 1H; CaH’2), 1.61 (s,
a
white solid. M.p. 938C; ½aꢃ2D0 = +200 (c=0.08, CHCl3); 1H NMR
(600 MHz, CDCl3, 298 K): d=6.3 (d, J=9.5 Hz, 1H; NH2), 5.72 (d, J=
3.6 Hz, 1H; C1H2), 5.3 (t, J=5.6 Hz, 1H; NH1), 4.69 (t, J=3.6, 4.3 Hz,
1H; C2H2), 4.44 (m, 1H; CbH2), 3.96 (t, 1H; J=8.4 Hz, C4H2), 3.68 (s,
3H; -COOMe), 3.61 (dd, J=4.3, 8.4 Hz, 1H; C3H2), 3.42 (s, 3H; OMe),
3.4 (m, 2H; CbH1), 2.65 (m, 2H; CaH2, CaH’2), 2.37 (m, 2H; CaH1,
ꢀ
ꢀ
ꢀ
3H; CH3), 1.55 (s, 3H; CH3), 1.53 (s, 3H; CH3), 1.43 ppm (s, 9H;
Boc); 13C NMR (125 MHz, CDCl3, 298 K): d=173, 171.7, 171.1, 170.5,
155.8, 113 (2C), 103.8, 103.6, 83.3, 82.5, 79.4, 78.3, 58.1, 57.8, 51.8, 49.5,
38.5, 37.9, 37.3, 35.8, 34.9, 33.5, 28.3, 26.7, 26.6, 26.4 ppm; IR (CHCl3):
n˜ =3267, 3081, 2922, 2851, 1737, 1700, 1649, 1552, 1255, 1168, 1099, 1029,
ꢀ
ꢀ
CaH’1), 1.55 (s, 3H; CH3), 1.42 (s, 9H; Boc), 1.35 ppm (s, 3H; CH3);
13C NMR (125 MHz, CDCl3, 298 K): d=172.1, 168.7, 153.5, 113.2, 103.6,
83, 79.4, 79.1, 78.4, 77.3, 61.3, 58.1, 50, 35.1, 28.3, 26.8, 26.6, 21.8, 16.1,
14.1 ppm; IR (CHCl3): n˜ =3323, 2979, 2925, 2852, 1710, 1658, 1525, 1244,
1214, 1167, 1022, 751 cmꢀ1; HRMS (ESI+): m/z calcd for C20H34N2O9
[M++Na]: 469.2156; found: 469.2137.
772 cmꢀ1
;
HRMS (ESI+): m/z calcd for C34H56N4O15 [M++Na]:
783.3634; found: 783.3618.
Boc-(R)-b-Caa(r)-b-hGly-(R)-b-Caa(r)-b-hGly-(R)-b-Caa(r)-b-hGly-OMe
(2)
A cooled (08C) solution of 1 (0.54 g, 0.07 mmol) in THF/MeOH/H2O
(3:1:1) (1 mL) was treated with LiOH (0.002 g, 0.1 mmol) and stirred at
room temperature. Workup as described for 7 gave 10 (0.05 g, 92%) as
a white solid, which was used as such for further reaction.
Boc-b-hGly-(R)-b-Caa(r)-b-hGly-(R)-b-Caa(r)-OMe (3)
A cooled (08C) solution of 12 (0.16 g, 0.34 mmol) in THF/MeOH/H2O
(3:1:1; 1 mL) was treated with LiOH (0.01 g, 0.52 mmol) and stirred at
room temperature. Workup as described for 7 gave 12b (0.14 g, 90%) as
a white solid, which was used as such for further reaction.
Amine salt 9a (prepared from 9 (0.04 g, 0.07 mmol) and CF3COOH
(0.1 mL) in CH2Cl2 (0.5 mL)) was added to a solution of 10 (0.05 g,
0.06 mmol), HOBt (0.01 g, 0.09 mmol), and EDCI (0.02 g, 0.09 mmol) in
dry CH2Cl2 (5 mL) and stirred at room temperature for 5 h. Workup as
described for 9 and purification of the residue by column chromatogra-
phy (60–120 mesh silica gel, 2.8% CH3OH in CHCl3) furnished 2 (0.04 g,
44%) as a white solid. M.p. 2308C; ½aꢃ2D0 = +59.09 (c=0.22, CHCl3);
1H NMR (600 MHz, CDCl3, 298 K): d=8.14 (dd, J=3.6, 9.2 Hz, 1H;
NH2), 8.02 (d, J=9.6 Hz, 1H; NH5), 7.93 (dd, J=4.0, 8.9 Hz, 1H; NH4),
7.91 (d, J=10.5 Hz, 1H; NH3), 6.5 (t, J=6.2 Hz, 1H; NH6), 5.74 (d, J=
3.7 Hz, 1H; C1H2), 5.70 (d, J=3.7 Hz, 1H; C1H3), 5.73 (d, J=3.7 Hz,
1H; C1H1), 5.31 (d, J=10.5 Hz, 1H; NH1), 4.66 (dd, J=4.2, 3.9 Hz, 1H;
C2H5), 4.61 (dd, J=3.7, 4.5 Hz, 1H; C2H3), 4.55 (qd, J=2.5, 9.7, 6.5 Hz,
1H; CbH5), 4.44 (m, 1H; CbH1), 3.97 (m, J=4.0, 9.0 Hz, 1H; C4H1),
3.97 (m, 1H; CbH2), 3.94 (dd, J=5.7, 8.8 Hz, 1H; C4H3), 3.89 (dd, J=
6.6, 8.8 Hz, 1H; C4H5), 3.87 (m, 1H; CbH4), 3.73 (dd, J=4.2, 8.6 Hz,
A solution of 12b (0.14 g, 0.38 mmol), HOBt (0.06 g, 0.48 mmol), and
EDCI (0.09 g, 0.485 mmol) in CH2Cl2 (5 mL) was stirred at 08C under an
N2 atmosphere for 15 min, treated sequentially with 12a (prepared from
12 (0.18 g, 0.38 mmol) and CF3COOH (0.4 mL) in dry CH2Cl2 (1.2 mL)
at 08C) and DIPEA (0.16 mL, 0.93 mmol) and stirred for 8 h. Workup as
described for 9 and purification of the residue by column chromatogra-
phy (60–120 mesh silica gel, 2.2% CH3OH in CHCl3) afforded 3 (0.14 g,
52%) as a white solid. M.p. 160–1638C; ½aꢃ2D0 =ꢀ175 (c=0.06, CHCl3);
1H NMR (600 MHz, CDCl3, 298 K): d=7.20 (t, J=6.5 Hz, 1H; NH3),
6.95 (d, J=9.3 Hz, 1H; NH2), 6.83 (d, J=9.0 Hz, 1H; NH4), 5.74 (d, J=
3.2 Hz, 1H; C1H4), 5.76 (d, J=3.2 Hz, 1H; C1H2), 5.54 (t, J=5.6 Hz,
1H; NH1), 4.72 (m, J=3.7 Hz, 1H; C2H2), 4.72 (m, J=3.2 Hz, 1H;
C2H4), 4.6 (m, 1H; CbH4), 4.42 (m, 1H; CbH2), 3.83 (m, 1H; C4H2),
ꢀ
3.82 (m, J=8.4 Hz, 1H; C4H4), 3.7 (s, 3H; COOMe), 3.68 (m, 1H;
ꢀ
1H; C3H5), 3.72 (s, 3H; COOMe), 3.67 (dd, J=4.5, 8.8 Hz, 1H;
C3H4), 3.63 (dd, J=4.0, 8.4 Hz, 1H; C3H2), 3.65 (m, 1H; CbH3), 3.41
(m, 1H; CbH’3), 3.4 (s, 3H; OMe), 3.4 (m, 1H; CbH1), 3.37 (s, 3H;
OMe), 2.82 (dd, J=3.2, 14.8 Hz, 1H; CaH4), 2.61 (dd, J=9.6, 14.8 Hz,
1H; CaH’4), 2.46 (dd, J=2.5, 13.7 Hz, 1H; CaH2), 2.46 (dd, J=7.8,
13.7 Hz, 1H; CaH’2), 2.39 (m, 2H; CaH1, CaH1), 2.32 (m, 1H; CaH3),
2.31 (m, 1H; CaH’3), 2.08 (m, 1H; CaH’3), 1.61 (s, 6H; 2CH3), 1.55 (s,
C3H3), 3.58 (m, 1H; CbH6), 3.55 (m, 1H; CbH4), 3.52 (dd, J=4.3,
9.0 Hz, 1H; C3H1), 3.39 (m, 1H; CbH’6), 3.39 (s, 3H; OMe), 3.36 (s,
3H; OMe), 3.35 (s, 3H; OMe), 3.10 (m, 1H; CbH’4), 2.99 (m, 1H;
CbH’2), 2.65 (dd, J=2.6, 13.0 Hz, 1H; CaH’3), 2.61 (dd, J=3.7, 12.3 Hz,
1H; CaH1), 2.58 (dddd, J=4.5, 7.6, 17.1 Hz, 1H; CaH’6), 2.53 (dd, J=
3.0, 14.4 Hz, 1H; CaH5), 2.51 (m, 1H; CaH6), 2.48 (dd, J=10.3,
14.4 Hz, 1H; CaH’5), 2.39 (dd, J=12.2, 13.0 Hz, 1H; CaH’3), 2.28 (dd,
J=11.5, 12.3 Hz, 1H; CaH’1), 2.25 (ddd, J=3.4, 12.4, 13.5 Hz, 1H;
CaH4), 2.23 (dt, J=3.3, 10.5, 12.2 Hz, 1H; CaH2), 2.16 (m, 1H; CaH’4),
2.15 (m, 1H; CaH’2), 1.56 (s, 6H; 2CH3), 1.43 (s, 9H; Boc), 1.35 (s, 6H;
2CH3), 1.34 ppm (s, 6H; 2CH3); 13C NMR (125 MHz, CDCl3, 298 K): d=
173.2, 172.7, 172.3, 172.1, 171.4, 170.6, 156, 113, 104.2, 104, 103.8, 82.1,
81.6, 81.4, 80.9, 79.8, 79.1, 78.9, 547.9, 57.7, 57.5, 51.9, 49.9, 49.8, 48.9,
39.1, 38.5, 37.5, 37.4, 36.5, 36.2, 34.9, 33.4, 29.6, 28.3, 26.8, 26.7, 26.6,
26.5 ppm; IR (CHCl3): n˜ =3267, 3083, 2983, 2925, 2853, 1738, 1699, 1647,
3H; CH3), 1.53 (s, 3H; CH3), 1.43 ppm (s, 9H; Boc); 13C NMR
(125 MHz, CDCl3, 298 K): d=172.3, 170.7, 168.8, 168.5, 156.1, 111.8,
111.7, 104.9, 104.8, 83.9, 83.4, 81.4, 81.1, 81.0, 80.3, 80.0, 79.9, 79.8, 61.4,
58.1, 57.8, 47.2, 45.7, 36.4, 35.6, 29.7, 29.4, 28.3, 26.6, 26.1, 16.3, 15.7,
14.1 ppm; IR (CHCl3): n˜ =3303, 2922, 2852, 2309, 1720, 1710, 1649, 1536,
ꢀ
ꢀ
1456, 1370, 1168, 1023, 770 cmꢀ1
; HRMS (ESI+): m/z calcd for
C34H56N4O15Na [M++Na]: 783.3634; found: 783.3598.
Boc-b-hGly-(R)-b-Caa(r)-b-hGly-(R)-b-Caa(r)-b-hGly-(R)-b-Caa(r)-OMe
(4)
1553, 1215, 1133, 1097, 754 cmꢀ1
; HRMS (ESI+): m/z calcd for
A cooled (08C) solution of 3 (0.52 g, 0.06 mmol) in THF/MeOH/H2O
(3:1:1; 1 mL) was treated with LiOH (0.003 g, 0.1 mmol) and stirred at
room temperature. Workup as described for 7 gave 13 (0.05 g, 95%) as
a white solid, which was used as such for further reaction.
C48H78N6O21 [M++Na]: 1097.5112; found: 1097.5085.
Boc-b-hGly-(R)-b-Caa(r)-OMe (12)
A
A solution of 13 (0.05 g, 0.06 mmol), HOBt (0.01 g, 0.09 mmol), and
EDCI (0.02 g, 0.09 mmol) in CH2Cl2 (5 mL) was stirred at 08C under an
N2 atmosphere for 15 min, treated sequentially with 20a (prepared from
3 (0.33 g, 0.07 mmol) and CF3COOH (0.1 mL) in dry CH2Cl2 (1 mL) at
08C) and DIPEA (0.016 mL, 0.096 mmol), and stirred for 8 h. Workup as
(0.31 g, 3.5 mmol) in 4n NaOH (1 mL) for 2 h and stirred at room tem-
perature for 18 h. The reaction mixture was washed with petroleum ether
(3ꢄ2 mL) and the organic layer washed with aqueous saturated NaHCO3
(1ꢄ5 mL). Combined aqueous NaOH and aqueous saturated NaHCO3
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Gangavaram V. M. Sharma, Ajit C. Kunwar et al.
described for 9 and purification of the residue by column chromatogra-
phy (60–120 mesh silica gel, 4.4% CH3OH in CHCl3) afforded 4 (0.03 g,
55%) as a white solid. M.p. 166–1688C; ½aꢃ2D0 = +187.5 (c=0.3, CHCl3);
1H NMR (600 MHz, CDCl3, 298 K): d=8.23 (dd, J=3.6, 9.2 Hz, 1H;
NH3), 8.10 (d, J=9.2 Hz, 1H; NH6), 8.04 (d, J=10.1 Hz, 1H; NH4),
7.43 (dd, J=4.1, 9.2 Hz, 1H; NH5), 6.37 (d, J=10.2 Hz, 1H; NH2), 6.0
(t, J=5.3 Hz, 1H; NH1), 5.76 (d, J=3.7 Hz, 1H; C1H2), 5.73 (d, J=
3.7 Hz, 1H; C1H4), 5.71 (d, J=3.6 Hz, 1H; C1H6), 4.79 (tt, J=3.0,
11.0 Hz, 1H; CbH2), 4.66 (m, 1H; C2H4), 4.67 (m, 1H; CbH4), 4.66 (m,
1H; J=4.0, 3.7 Hz, C2H4), 4.66 (m, 1H; CbH4), 4.66 (m, J=4.0 Hz, 1H;
C2H2), 3.95 (m, J=4.0, 8.8 Hz, 1H; C4H6), 3.95 (m, 1H; C4H2), 3.95
(m, 1H; C4H4), 3.95 (m, 1H; CbH3), 3.87 (m, 1H; CbH5), 3.74 (dd, J=
[9] a) E. Cabezas, A. C. Satterthwait, J. Am. Chem. Soc. 1999, 121,
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ꢀ
4.4, 9.0 Hz, 1H; C3H6), 3.68 (s, 3H; COOMe), 3.68 (m, 1H; J=4.4,
[12] H. N. Hoang, R. W. Driver, R. L. Beyer, A. K. Malde, G. T. Le, G.
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9.0 Hz, C3H4), 3.53 (dd, J=4.4, 9.0 Hz, 1H; C3H2), 3.4 (s, 6H; OMe),
3.40 (m, 1H; CbH1), 3.40 (m, 1H; CbH’1), 3.35 (s, 3H; OMe), 3.14 (m,
1H; CbH’5), 3.0 (m, 1H; CbH’3), 2.77 (dd, J=2.8, 14.3 Hz, 1H; CaH6),
2.65 (dd, J=3.3, 13.0 Hz, 1H; CaH’2), 2.57 (dd, J=2.8, 12.4 Hz, 1H;
CaH4), 2.56 (dd, J=10.5, 14.3 Hz, 1H; CaH’6), 2.44 (t, J=12.4 Hz, 1H;
CaH’4), 2.39 (m, 1H; CaH1), 2.39 (m, 1H; CaH’1), 2.28 (t, J=11.0,
13.0 Hz, 1H; CaH’2), 2.27 (m, 1H; CaH’5), 2.25 (m, 1H; CaH3), 2.14
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ꢀ
(m, 1H; CaH’5), 2.11 (m, 1H; CaH’3), 1.56 (s, 3H; CH3), 1.55 (s, 3H;
ꢀ
ꢀ
ꢀ
CH3), 1.52 (s, 3H; CH3), 1.36 (s, 3H; CH3), 1.35 (s, 6H; 2CH3),
1.43 ppm (s, 9H; Boc); 13C NMR (125 MHz, CDCl3, 298 K): d=173.5,
172.7, 172.1, 171.8, 170.9, 156.1, 113.1, 113, 112.9, 104.2, 103.8 (2C), 81.9,
81.3, 81.2, 80.1, 78.9, 78.8, 78.7, 57.8, 57.7, 57.5, 52.1, 49.3, 48.2, 48.1, 39.1,
37.2, 36.9, 36.8, 36.6, 36.2, 35.8, 29.6, 28.4 (3C), 28.3, 26.7 (2C), 26.5
(2C), 26.4 ppm; IR (CHCl3): n˜ =3271, 3018, 2922, 2852, 1740, 1720, 1647,
1551, 1453, 1376, 1214, 1134, 991, 749 cmꢀ1; HRMS (ESI+): m/z calcd for
C48H78N6O21 [M++Na]: 1097.5112; found: 1097.5079.
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Acknowledgements
T.A.Y. and P.P.R. thank CSIR, New Delhi; and K.K. and T.P. thank
UGC, New Delhi, for the financial support in the form of fellowship. All
the authors thank CSIR, New Delhi, for financial support as a research
grant (CSC-0114).
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These are not the final page numbers! ÞÞ

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Gangavaram V. M. Sharma, Ajit C. Kunwar et al.
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[21] See the Supporting Information.
[22] Owing to identical chemical shifts for the CaH protons, stereospecif-
ic assignments could not be made. These assignments could, howev-
er, be made for both b-Caa(r) of tetrapeptide 1,[21] which showed that
C4H had a strong NOE correlation with CaH
one with CaH(pro-S).
ACHTUNGTREN(NGNU pro-R) and a weak
AHCTUNGTRENNUNG
[23] 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).
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Received: May 1, 2014
Published online: && &&, 0000
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FULL PAPER
Beta testers: We report the design and
synthesis of b peptides from the 1:1
alternation of b-Caa(r) (C-linked carbo-
b-amino acid with a d-ribo furanoside
side chain) and b-hGly with a novel ꢀb-
b-bꢁ three-residue turn and 14-member
hydrogen bonding at the C terminus.
The turn is nucleated by a 12/10 helix
at the N terminus to form a ꢀhelix-
turnꢁ motif stabilized by an intraresi-
due electrostatic interaction between
the amide NH and furan oxygen (see
figure).
Foldamers
Gangavaram V. M. Sharma,* Thota
Anupama Yadav,
Kanakaraju Marumudi,
Prashanth Thodupunuri, Pothula
Purushotham Reddy,
Ajit C. Kunwar*
&&&& — &&&&
Three-Residue Turn in b-Peptides
Nucleated by a 12/10 Helix
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These are not the final page numbers! ÞÞ