Synthesis of β-peptides with β-helices from new C-linked carbo-β-amino acids: Study on the impact of carbohydrate side chains

Article abstract of DOI:10.1002/asia.200800249

The design and synthesis of β-peptides from new C-linked carbo-βamino acids (β-Caa) presented here, provides an opportunity to understand the impact of carbohydrate side chains on the formation and stability of helical structures. The β-amino acids, Boc-(

Full text of DOI:10.1002/asia.200800249

DOI: 10.1002/asia.200800249
Synthesis of b-Peptides with b-Helices from New C-Linked Carbo-b-Amino
Acids: Study on the Impact of Carbohydrate Side Chains
Gangavaram V. M. Sharma,*[a] Kota Sudhakar Rao,[a] Rapolu Ravi,[b]
Kongari Narsimulu,[b] Pendem Nagendar,[a] Chirutha Chandramouli,[a]
Singarapu Kiran Kumar,[b] and Ajit C. Kunwar*[b]
Abstract: The design and synthesis of
b-peptides from new C-linked carbo-b-
amino acids (b-Caa) presented here,
provides an opportunity to understand
the impact of carbohydrate side chains
on the formation and stability of helical
structures. The b-amino acids, Boc-(S)-
b-Caa(g)-OMe 1 and Boc-(R)-b-Caa(g)-
OMe 2, having a d-galactopyranoside
side chain were prepared from d-galac-
tose. Similarly, the homo C-linked
carbo-b-amino acids (b-hCaa); Boc-
(S)-b-hCaa(x)-OMe 3 and Boc-(R)-b-
hCaa(x)-OMe 4, were prepared from d-
glucose. The peptides derived from the
above monomers were investigated by
NMR, CD, and MD studies. The b-pep-
tides, especially the shorter ones ob-
tained from the epimeric (at the amine
stereocenter Cb) 1 and 2 by the concept
of alternating chirality, showed a much
smaller propensity to form 10/12-heli-
ces. This substantial destabilization of
the helix could be attributed to the
bulkier d-galactopyranoside side chain.
Our efforts to prepare peptides with al-
ternating 3 and 4 were unsuccessful.
However, the b-peptides derived from
alternating geometrically heterochiral
(at Cb) 4 and Boc-(R)-b-Caa(x)-OMe 5
(d-xylose side chain) display robust
right-handed 10/12-helices, while the
mixed peptides with alternating 4 and
Boc-b-hGly-OMe
6 (b-homoglycine),
resulted in left-handed b-helices. These
observations show a distinct influence
of the side chains on helix formation as
well as their stability.
Keywords: amino acids · carbohy-
drates · chirality · helical structures ·
peptides
Introduction
from a-amino acids, besides de novo designs.[1] The hints for
the possible formation of folded structures in the homo-olig-
omers of b-and g-amino acids,[2] were realized, for the first
time, by the independently discovered novel 14-helix in b-
peptides by Gellman et al.[3a] and Seebach et al.[3b] These re-
sults subsequently prompted the identification of new fold-
ing patterns such as 12-, 10-, 8- and 10/12-helices and led to
the emergence of ꢀfoldamersꢁ,[4] with the creation of skeletal,
secondary, and tertiary structural diversity.[5] Thus, the new
designs and motifs to develop unprecedented folded pat-
terns would provide an opportunity to understand the fac-
tors that govern the protein structure and function.[6] The
theoretical studies performed on unsubstituted b-peptides
by Wu and Wang[7a,b] and Hofmann et al.[7c] revealed that the
mixed 10/12-helices are intrinsically the most stable secon-
dary structures. The mixed 10/12-helices, also referred to as
b-helices,[7] containing intertwined 10- and 12-membered
(mr) H-bond rings, unique to b-peptides, were first realized
by Seebach et al.[8] by using alternating b2/b3-amino acids.
Subsequently, Kessler et al.[9] observed similar helices, in the
peptides derived from furanoside b-amino acid (FAA) and
b-hGly. In our search for novel foldamers, we have synthe-
The protein functions are intimately related to their three-
dimensional structures. Therefore, an understanding of the
physical principles involved in the formation of their secon-
dary and tertiary structural elements is very important. The
research efforts in the last 20 years have led to the evolution
of the principles that govern the folding in peptides derived
[a] Dr. G. V. M. Sharma, K. S. Rao, P. Nagendar, C. Chandramouli
D-211, Discovery Laboratory
Organic Chemistry Division III
Indian Institute of Chemical Technology
Hyderabad 500 007 (India)
Fax : (+91)40-27160387/27193108
E-mail: esmvee@iict.res.in
[b] R. Ravi, K. Narsimulu, S. K. Kumar, Dr. A. C. Kunwar
Center for Nuclear Magnetic Resonance
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.200800249.
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181

FULL PAPERS
sized new b-amino acids, the C-linked carbo-b-amino acids
(b-Caa(x)),[10] from d-glucose, and used them in different de-
signs to obtain b-helices. Thus, in our earlier studies,[11a] the
peptides derived with ꢀalternatingꢁ epimeric (at the amine
stereocenter Cb) (S)- and (R)-b-Caa(x) generated only right-
handed 10/12-mixed helices, even though they are enantio-
meric at the amine stereocenters. Likewise, in our other
design on mixed peptides,[11b] from (S)-b-Caa(x)/b-hGly and
(R)-b-Caa(x)/b-hGly, both the left- and right-handed 10/12-
helices respectively were identified, wherein, the handedness
of the helix is governed by the
the amino acid backbone are separated by a methylene
group as a spacer. It was anticipated that the spacer group
would provide additional flexibility and facilitate a relieving
of the steric strain inherent in the b-Caa(x). Thus, the present
work encompasses the synthesis of new b-Caas: Boc-(S)-b-
Caa(g)-OMe 1 and Boc-(R)-b-Caa(g)-OMe 2, with a bulkier
galactopyranoside side chain, from d-galactose; b-hCaas:
Boc-(S)-b-hCaa(x)-OMe
3 and Boc-(R)-b-hCaa(x)-OMe 4
(Figure 1), having a d-xylose side chain with a methylene
spacer between the backbone and side chain. These b-Caas
stereocenter of the b-Caa(x)
used in the design. More re-
cently, our designs using alter-
nating a- and g-amino acids (g-
Caa(x))[12a] and b-Caa(x) and a-
aminoxy amino acid,[12b] result-
ed in new motifs to realize the
10/12-helix.
The mass spectral studies[13]
on the dipeptides derived from
alternating (S)- and (R)-b-Caa
having different carbohydrate
side chains, revealed that the
fragmentation pattern for the
peptides with (S)-b-Caa at the
Figure 1. Structures of b-amino acids 1–6.
N-terminus is different from
the dipeptide with the N-terminus (R)-b-Caa. The above dif-
ference in the behavior was attributed to the bulk of the
side chain and stereochemistry at the amine center (at Cb).
This observation has provided us with the impetus to inves-
tigate the impact of the side chains on helix formation and
stability of the secondary structures in b-peptides containing
new b-Caas. Hence, two different b-monomers were pro-
posed: a) to have a bulky pyranoside side chain and b) to in-
troduce flexibility through a methylene spacer between the
backbone and the carbohydrate side chain.
In pursuit of the new designs on b-Caa monomers, a liter-
ature survey[14] revealed that peptidyl nucleosides, amipuri-
mycins,[14,15] and miharamycins[14,16] having branched pyra-
nose sugars, C-linked to glycine, show biological activity
against rice blast disease. In view of this, new b-Caas, Boc-
(S)-b-Caa(g)-OMe 1 and Boc-(R)-b-Caa(g)-OMe 2, having a
pyranosidic side chain were designed from d-galactose.
In a further study on mixed b-peptides,[11b] it was observed
that the flexibility provided through the backbone (in b-
hGly) permitted a switch in handedness of the helices. Thus,
based on the mass spectral studies[13] and switch in handed-
ness of the helix,[11b] a new b-Caa design, with flexibility in
the side chain, was envisaged. Further, a literature[14] survey
indicated that the higher-carbon sugar nucleosides[17] C-
linked to lysine have an antifungal activity. In these systems,
the sugar and amino acid components are separated by a
methylene unit. Hence, in yet another novel design, homo
C-linked carbo-b-amino acids (b-hCaa(x)), Boc-(S)-b-hCaa(x)-
OMe 3 and Boc-(R)-b-hCaa(x)-OMe 4 were synthesized
from d-glucose, wherein, the carbohydrate side chain and
have been used to synthesize b-peptides 7–16 (Figure 2). Ex-
tensive NMR, MD, and CD studies have been carried out to
understand the impact of the side chains and to explore the
structures present in the above b-peptides.
Results and Discussion
Synthesis of Amino Acids 1 and 2
The monomers 1 and 2 (Scheme 1) were prepared from the
ester 18, synthesized from known aldehyde 17[18] by aza-Mi-
chael addition with benzylamine.[19]
Synthesis of Amino Acids 3 and 4
Accordingly, treatment of the known[20] diol 21 with Ph3P,
imidazole, and iodine in CH2Cl2 at room temperature for
2 h afforded the 5,6-olefin 22 (78%). Wacker reaction of
the olefin 22 (Scheme 2) with catalytic PdCl2 and CuCl in
the presence of O2 in THF/H2O (6:1) at room temperature
for 6 h underwent the anti-Markonikov addition to afford
the aldehyde 23 in 85% yield. Olefination of the aldehyde
23 by the Wittig reaction with (methoxycarbonylmethylene)-
triphenyl phosphorane in benzene at reflux gave 24 (70%)
as a cis–trans mixture, which on further reaction with ben-
zylamine[16] gave a separable mixture of esters 25 (35%) and
26 (30%), epimeric at the amine stereocenter (Cb). The
esters 25 and 26 were subjected to hydrogenolysis with 10%
Pd–C in MeOH under hydrogen atmosphere to give the re-
spective amines 25a and 26a (Scheme 2), which on subse-
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Synthesis of b-Peptides with b-Helices from New C-Linked Carbo-b-Amino Acids
Synthesis of Peptides 7–10
Containing (S)-b-Caa(g) 1 and
(R)-b-Caa(g) 2
In our earlier studies,[11a] the b-
peptides
were
synthesized
based on the concept of alter-
nating chirality,[7a,b] from (R)-b-
Caa(x) and (S)-b-Caa(x). Under
the influence of identical carbo-
hydrate side chains, these pep-
tides, although enantiomeric at
the amine stereocenters in the
backbone, have been identified
with right-handed 12/10-helices.
In the present study, the same
design principle is adopted for
the synthesis of b-peptides from
the new b-amino acids, to un-
derstand the impact of the side
chains.
Accordingly,
(S)-b-Caa(g)
(Boc-(S)-b-Caa(g)-OMe)
1
(Scheme 3) on reaction with
aqueous 4n NaOH gave the
corresponding acid 27 (92%).
Peptide coupling of 27, with the
salt 28 (prepared by the expo-
sure of 2 to CF3COOH) in the
presence of EDCI, HOBt, and
DIPEA in CH2Cl2 afforded the
dipeptide 29 (88%).
Hydrolysis of the ester 29
with base (4n NaOH) furnished
the acid 30, while treatment of
the ester 29 with CF3COOH in
CH2Cl2 resulted in the salt 31.
Further, the condensation of
the acid 30 and salt 31 in the
presence of EDCI, HOBt, and
DIPEA in CH2Cl2 gave the tet-
Figure 2. Structures of peptides 7–16.
quent treatment with (Boc)2O and Et3N in THF resulted in
3 (93%) and 4 (85%). The absolute stereochemistry of the
newly created amine centers in b-hCaa(x) 3 and 4, was estab-
lished by the method of Riguera et al.[21]
rapeptide 7 in 75% yield. Compound 7 on base hydrolysis
and coupling of the resultant acid 32, with the dipeptide salt
31 under standard reaction conditions (EDCI, HOBt, and
DIPEA in CH2Cl2) afforded the hexapeptide 8 (47%).
Scheme 1. Synthesis of amino acids 1 and 2. a) BnNH2, RT, 12h; b) H2, 10% Pd–C, CH3OH, RT, 12h; c) (Boc)2O, Et3N, THF, 08C–RT, 2h.
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V. M. Sharma, A. C. Kunwar et al.
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Scheme 2. Synthesis of amino acids 3 and 4. a) Ph3P, imidazole, I2, CH2Cl2, 08C–RT, 2h; b) PdCl2, CuCl, O2, THF/H2O (6:1), RT, 6h; c) Ph3P=
CHCO2Me, benzene, reflux, 6h; d) BnNH2, RT, 12h; e) H2, 10%, Pd–C, RT, 12h; f) (Boc)2, Et3N, THF, 08–RT, 2h.
alternating chirality. However,
the attempted synthesis failed
to give the expected peptides.
This may be attributed to the
larger conformational space
and steric interactions experi-
enced by the carbohydrate side
chains arising from the addi-
À
tional flexibility in the C4 C5
(methylene spacer) between the
backbone and side chain in the
amino acids 3 and 4.
In yet another design, it was
envisaged to use the new amino
acid (R)-b-hCaa(x) 4, alternating
with (R)-b-Caa(x) 5. The obser-
vations made earlier by us from
the mass spectral studies[13] as
well as the mixed peptides,[11b]
prompted us to use monomer 4,
which is geometrically homo-
Scheme 3. Synthesis of peptides 7–10 containing 1 and 2. a) 4n NaOH, CH3OH, 08C–RT; b) HOBt (1.2 equiv),
EDCI (1.2 equiv), DIPEA (1.5 equiv), dry CH2Cl2, 08C–RT; c) CF3COOH, dry CH2Cl2, 08C–RT.
chiral with (S)-b-Caa(x), in the
present design. Accordingly, re-
action of acid 40 with 41 (pre-
Likewise, Boc-(R)-b-Caa(g)-OMe 2 (Scheme 3) was sapo-
nified with aqueous 4n NaOH to give acid 33, which on
coupling with 34 (obtained by the Boc deprotection of 1
with CF3COOH), in the presence of EDCI, HOBt, and
DIPEA in CH2Cl2 afforded the dipeptide 35 (91%). Base
hydrolysis of 35 furnished the acid 36, which on reaction
with the salt 28 gave tripeptide 38 in 62% yield, while, cou-
pling of the acid 36 with salt 37 (obtained from 35 by the ex-
posure to CF3COOH) gave the tetrapeptide 9 (64%). Ester
9 on hydrolysis with base (4n NaOH) gave the correspond-
ing acid 39, which on peptide coupling with the salt 37 af-
forded the hexapeptide 10 (49%).
pared from 4 on treatment with CF3COOH in CH2Cl2) in
the presence of EDCI, HOBt, and DIPEA in CH2Cl2 af-
forded the dipeptide 42 in 76% yield (Scheme 4). Ester 42
on base hydrolysis gave the acid 43, while, on exposure to
CF3COOH, it gave the amine salt 44. Peptide coupling of 43
and 44 afforded the tetrapeptide 11 (43%). Further, 11 was
hydrolysed using 4n NaOH to give the acid 45, which on
condensation with the salt 44 furnished hexapeptide 12
(27%).
In a further study, ester 4 on hydrolysis with base gave
the acid 46, which on coupling with the salt 47 in the pres-
ence of EDCI, HOBt, and DIPEA in CH2Cl2 afforded the
dipeptide 48 in 78% yield (Scheme 4). The acid 49, obtained
by base hydrolysis of ester 48, on condensation with the salt
50 (prepared by Boc deprotection with CF3COOH in
CH2Cl2), gave tetrapeptide 13 (55%). Further, hydrolysis of
compound 13 with 4n NaOH gave the acid 51, which on
Synthesis of Peptides 11–14 with Alternating 4 and 5
In the first design, it was proposed to use the new mono-
mers (S)-b-hCaa(x) 3 and (R)-b-hCaa(x) 4 with the concept of
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Synthesis of b-Peptides with b-Helices from New C-Linked Carbo-b-Amino Acids
Base hydrolysis of 15 gave acid
56, which on further coupling
with the salt 55 afforded the
hexapeptide 16 (48%).
Conformational Analysis of
Peptides 7–16
Most of the NMR studies were
carried out in 5–10 mm solu-
tions at 303 K, while peptides
7–10 and 13–16 were studied in
CDCl3, peptides 11 and 12 were
investigated in [D5]pyridine.[22]
The resonance assignments
were made with the help of
total correlation spectroscopy
(TOCSY) and rotating frame
nuclear Overhauser effect spec-
troscopy (ROESY) experi-
ments.[23] Usually the N-termi-
nal Boc-amide proton appears
at higher field, permitting an
easy assignment for the reso-
Scheme 4. Synthesis of peptides 11–14 having alternating 4 and 5. a) 4n NaOH, CH3OH, 08C–RT; b) HOBt
(1.2 equiv), EDCI (1.2 equiv), DIPEA (1.5 equiv), dry CH2Cl2, 08C–RT; c) CF3COOH, dry CH2Cl2, 08C–RT.
coupling with the salt 50 furnished the hexapeptide 14
(28%).
nance of the first residue. For sequential assignments, strong
CaH(i)/NH(i+1) and weak CaH(i)/NH(i) NOE correlations
provided the clue. Additionally, for most of the molecules,
the first and the last residue display NH/Boc(CH3)3 and
CaH/C(O)OMe NOE correlations, respectively. Another dis-
tinguishing feature for the first and the last residue was the
presence of only one NOE correlation between the NH and
the CaH protons, unlike other residues which had two such
peaks. The conformation in b-amino acids is defined by four
dihedral angles (Figure 3). We have derived the structural
information using the coupling constants (J), the NOE, and
the H-bonding information.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Synthesis of Peptides 15 and 16 Containing 4 and 6
In our earlier studies,[11b] the (S)-b-Caa(x)/b-hGly mixed pep-
tides switched the helical handedness compared to (S)-b-
Caa(x)/(R)-b-Caa(x) and (R)-b-Caa(x)/b-hGly peptides. Since
(R)-b-hCaa(x) 4, is geometrically homochiral with (S)-b-
Caa(x), it was felt worthwhile to investigate the influence of
À
the conformational freedom around the C4 C5 in the side
chain on helical stability, by synthesizing peptides with alter-
nating 4 and 6. Accordingly, condensation of acid 46 with
the salt 52 (obtained by the deprotection of 6 on reaction
with CF3COOH) in the presence of EDCI, HOBt, and
DIPEA in CH2Cl2 afforded the dipeptide 53 in 85% yield
(Scheme 5). The dipeptide 53 on Boc deprotection with
CF3COOH gave corresponding amine salt 55, which, on
peptide coupling with the acid 54 (prepared by the base hy-
drolysis of ester 53) afforded the tetrapeptide 15 (68%).
Figure 3. Schematic representation of backbone dihedral angles in b-pep-
tides.
Scheme 5. Synthesis of peptides 15–16 with alternating 4 and 6. a) 4n NaOH, CH3OH, 08C–RT; b) HOBt (1.2 equiv), EDCI (1.2 equiv), DIPEA
(1.5 equiv), dry CH2Cl2, 08C–RT; c) CF3COOH, dry CH2Cl2, 08C–RT.
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V. M. Sharma, A. C. Kunwar et al.
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1
In the H NMR spectrum of 7 in CDCl3, NH(1)–NH(4)
1H NMR spectrum of 8, which is well dispersed (both
amide and CaH region) along with several amide proton res-
onances at d>7 ppm, suggested the presence of a stable sec-
ondary structure. A solvent titration study confirmed that
apart from NH(2), all the amide protons, with a small DdNH
(<0.13 ppm), are involved in H-bonding. The distinctive
have chemical shift (d) values of 5.65, 7.03, 6.96, and
8.16 ppm, respectively, suggesting participation of some of
them in H-bonding. In order to confirm their involvement in
H-bonding, solvent titration studies[24] were carried out, by
adding up to 33% v/v [D6]DMSO, in these solutions. Amide
protons, which are already intramolecularly H-bonded, do
not get exposed to the [D6]DMSO solution, resulting in min-
imal changes in their chemical shifts (DdNH).[25] Exposed NH
protons, which do not participate in intramolecular H-bond-
ing, show large downfield shifts in these experiments. The
observation of a small variation in the chemical shifts
(DdNH) of <0.16 ppm for all but the NH(2), confirm their in-
volvement in H-bonding. For the second and third residue,
3JNHÀCbH are 9.6 and 9.0 Hz respectively, which permits us to
infer an anti-periplanar (ap) disposition of the NH and CbH
3
3JNHÀCbH and JCaHÀCbH couplings and the characteristic NOE
correlations like: CbH(2)/NH(4), CbH(2)/CaH(proÀR)(4),
CbH(4)/NH(6), CbH(4)/CaH(proÀR)(6), NH(3)/NH(4), NH(5)/
NH(6), NH(3)/CbH(2), and NH(5)/CbH(4), along with infor-
mation collated above provide compelling evidence for a
right-handed 10/12-helix with a 10/12/10/12/10 H-bonded ar-
rangement in peptide 8 (Figure 5).
À À
À
protons, corresponding to C(O) N Cb Ca (f) ~Æ1208
3
(Figure 4). On the other hand, JNHÀCbH values of 7.6 and
Figure 5. Schematic model of peptide 8 showing the H-bonds. The num-
bers reflect the number of atoms involved in the H-bonded pseudo ring.
Figure 4. Schematic Newman projections showing the orientation of sub-
stituents in 10/12-right-handed helix for the ideal values of torsional
angles f, q and y.[5b] view along the backbone atoms in: (A) (R)-b-Caa(g)
The tripeptide 38 derived from (R)- and (S)-b-Caa(g), with
an (R)-residue at the N-terminus, unlike the tripeptide ob-
tained from alternating (R)- and (S)-b-Caa(x),[11a] has shown
no secondary structure. However, the NMR spectrum of tet-
rapeptide 9, displays the signatures of the nucleation of a
nascent helix. The participation of NH(2) and NH(3) in H-
bonding is implied by their low field shifts (d>7 ppm) as
well as the small DdNH in the solvent titration studies. Fur-
ther support for the nascent mixed 10/12-helix comes from
the diagnostic coupling constants and rather weak NOEs,
CbH(1)/NH(3) and CbH(1)/CaH(proÀR)(3).[22]
and (B) (S)-b-Caa(g)
.
8.2 Hz for the two residues at the termini, show a definite
influence of fraying and lack of robustness of the helix,
which results in the reduction of the couplings arising from
3
averaging over several conformations. Most of the JCaHÀCbH
values are either >10 Hz or <5 Hz, thus supporting the pre-
À
dominance of a single conformation around Ca Cb. Sequen-
tial NOEs, NH(2)/CaH(proÀR)(1), NH(3)/CaH(proÀS)(2), NH(4)/
For 10, a large dispersion of the amide chemical shifts
(about 2.96 ppm) and CaH chemical shifts (about 0.72 ppm)
suggested a well-defined secondary structure. The amide
3
CaH(proÀR)(3), and individual JCaHÀCbH confirm a substantial
À
À À
population of a single conformation with N Cb Ca C(O)
À
À
À
À
(q) of ~608 and Cb Ca C(O) N (y) of ~Æ1208 (Figure 4).
This information along with very weak NOE correlations,
CbH(2)/NH(4), CbH(2)/CaH(proÀR)(4) and NH(3)/CbH(2), in-
dicate the presence of a right-handed 10/12-mixed helix,
which is in variance with the finding of very robust helices
in our earlier studies on tetrapeptides, derived from alter-
nating (R)- and (S)-b-Caa(x).[11a] The destabilization of the
helical structure in peptide 7, reflects the influence of the
bulky pyranoside side chain in the new b-amino acids 1 and
2.
protons, NH(2) NH(5), resonate at 7.44, 8.82, 7.91, and
8.20 ppm respectively, indicating their participation in H-
bonding, which was further confirmed from solvent titration
studies, which display DdNH <0.14 ppm. ROESY spectrum
(Figure 6) shows medium-range NOEs, CbH(1)/NH(3),
CbH(1)/CaH(proÀR)(3),
CbH(3)/NH(5),
and
CbH(3)/
CaH(proÀR)(5), characteristic of 12-mr H-bonding involving
À
À
NH(3) COACTHNUTRGENUG(N Boc) and NH(5) CO(2). Further, NOE correla-
tions, NH(2)/NH(3), NH(4)/NH(5), NH(2)/CbH(1), NH(4)/
CbH(3), and NH(6)/CbH(5) characterize 10-mr H-bonding
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Synthesis of b-Peptides with b-Helices from New C-Linked Carbo-b-Amino Acids
3
Considering individual JCaHÀCbH
and various sequential CaH/NH
and intra-residue CaH/CbH
NOE correlations, a value of q
~608 for all residues was de-
3
rived. Similarly, JNHÀCbH ~9 Hz,
points to a preponderance of an
ap arrangement of the NH and
CbH protons. These observa-
tions along with the presence of
medium-range NOEs, CbH(1)/
NH(2), CbH(1)/NH(3), CbH(1)/
Figure 6. The characteristic NOE correlations in 10.
À
À
involving NH(2) CO(3)and NH(4) CO(5). These character-
istic NOEs in conjunction with the JNHÀCbH ~9.4 Hz and
CaH(proÀR)(3),
and
CbH(3)/
3
NH(4) confirm the 12/10 H-bonded arrangement in tetra-
3JCaHÀCbH values of >10 Hz and <5 Hz for most of the resi-
dues, clearly suggest that 10 is forming a stable 10/12-helix
with 12/10/12/10 H-bonded arrangement. These findings
very clearly bring out the fact that while the shorter pep-
tides 7 and 9, barely exhibit an incipient helix, the right-
handed 12/10-helices are more stable for larger peptides 8
and 10. Thus the impact of the larger pyranoside side chain
in destabilizing the helix is very pronounced for the shorter
peptides compared to that for the longer ones. Thus, the
peptide backbone made from epimeric (at Cb) (R)- and (S)-
b-Caa(g), although enantiomeric at the amine center, the
identical chiral carbohydrate side chains govern the handed-
ness of the secondary structure to give right-handed helices.
The tetrapeptide, 11, contains alternating 5 ((R)-b-Caa(x))
and 4 ((R)-b-hCaa(x)). Arising from the broadening of spec-
tral lines in CDCl3 solution, 1H NMR studies on 11 were car-
ried out in [D5]pyridine. Wide dispersion of all the resonan-
ces, especially in the amide and CaH region, indicates a pos-
sibility for a periodic secondary structure. The amide pro-
tons NH(1)–NH(4) resonate at 7.86, 8.81, 8.59, and
8.98 ppm, respectively. To gain insight on intramolecular hy-
drogen bonding patterns in a pyridine solution, the tempera-
ture dependence of amide proton chemical shifts is studied.
The internal hydrogen bonding is disrupted when the tem-
perature is raised, and the chemical shifts of the amides
change. However, if the amide protons participate in intra-
molecular H-bonding, upon increasing the temperature, the
propensity for breaking these bonds is small and the change
in chemical shift or temperature coefficient (Dd/DT) will be
rather small. The NH temperature coefficients were mea-
sured in the temperature range
peptide 11. The structure is stabilized by one 12-mr H-bond
À
À
[NH(3) COACTHNUGRTNEUNG(Boc)] and one 10-mr H-bond [NH(2) CO(3)].
Hexapeptide 12, displayed all the signatures of a well-de-
fined 10/12-mixed helix. All the amide protons, excluding
NH(1) and NH(6), participate in intramolecular H-bonding,
which was confirmed by the variable temperature studies.
Coupling constants (very similar to that for 11) and the dis-
tinctive NOEs (Figure 7), CbH(1)/NH(2), CbH(1)/NH(3),
CbH(1)/CaH(proÀR)(3), NH(2)/NH(3), CbH(3)/NH(4), CbH(3)/
NH(5), CbH(3)/CaH(proÀR)(5), NH(4)/NH(5), and CbH(5)/
NH(6), along with the information on H-bonding, provide
compelling evidence for the presence of a 12/10/12/10 H-
bonded arrangements for the peptide 12.[22]
For peptide 13, apart from NH(2), all other amide protons
3
participate in intramolecular H-bonding,[22] while JNHÀCbH
3
>9.6 Hz corresponds to f ~Æ1208, JCaHÀCbH >8.2 Hz and
<5 Hz support the presence of predominantly a single con-
À
formation around Ca Cb. These observations along with
medium-range NOEs, CbH(2)/NH(4), CbH(2)/CaH(proÀR)(4)
CbH(2)/NH(3), NH(1)/NH(2), and NH(3)/NH(4), confirm
the right-handed 10/12-helix with 10/12/10 H-bonded ar-
rangement. For hexapeptide 14, NMR data provide all the
evidence for a 10/12-helix with 10/12/10/12/10 H-bonded
configuration.[22]
From the 1H NMR spectrum and the solvent titration
studies of mixed tetrapeptide 15, with alternating 4 and 6
residues, despite broadening of the spectral lines, resulting
in a concomitant loss of information, NH(2) and NH(3)
were found to participate in the H-bonding. The observation
of medium-range NOE correlations, CbH(1)/NH(3) and
from 303 K to 333 K. It is ob-
served that Dd/DT are smaller
for NH(2) (15.1 ppbKÀ1) and
NH(3) (12.2 ppbKÀ1) compared
to NH(1) (21.2 ppbKÀ1) and
NH(4) (17.7 ppbKÀ1),[26] which
point to their participation in
intramolecular
H-bonding.
3JCaHÀCbH >9.4 Hz and <5 Hz
clearly demonstrate the pres-
ence of predominantly a single
À
conformation around Ca Cb. Figure 7. The characteristic NOE correlations in 12.
Chem. Asian J. 2009, 4, 181 – 193
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187

V. M. Sharma, A. C. Kunwar et al.
FULL PAPERS
CbH(1)/CaH(proÀS)(3), support the presence of a 10/12-helix
in the tetramer. Higher mixed peptide 16, with better spec-
tral resolution, was found to have a fairly robust helical
structure. The low-field amide d values and the solvent titra-
tion studies confirmed that H bonding occurs for NH(2)–
3
NH(5). The JNHÀCbH values (3JNHÀCbH ~9.0 Hz for ((R)-b-
3
hCaa(x)); JNHÀCbH ~9.0 Hz and ~2.5 Hz for b-hGly) corre-
spond to f ~Æ1208. The predominance of a single confor-
3
mer about q was deduced from the JCaHÀCbH values (~9 Hz
or ~5 Hz). The sequential NOE correlations, NH(2)/
CaH(proÀR)(1),
NH(3)/CaH(proÀS)(2),
NH(4)/CaH(proÀR)(3),
NH(5)/CaH(proÀS)(4), NH(6)/CaH(proÀR)(5), and intraresidue
correlations, NH(i)/CbH(proÀS)(i), along with well-defined
3JCaHÀCbH values imply a predominant conformation with q ~
À608, for all these residues. This unusual change of sign of q
compared to other peptides, suggests the likely presence of
a left-handed 10/12-helix. Above details, along with the
NOEs, CbH(1)/NH(3), CbH(1)/CaH(proÀS)(3), CbH(3)/NH(5),
and CbH(3)/CaH(proÀS)(5), provide ample support for the left-
handed 10/12-helix with 12/10/12/10 H-bonded pattern in 16.
Thus, monomer 4, geometrically homochiral with (S)-b-
Caa(x),[10] behaved in a similar way[11b] in mixed peptide 16
and effected a switch in handedness to result in the left-
handed 12/10-helix.
Figure 8. Newman projections showing the orientations of various sub-
À
stituents for the predominant conformers about the C C bonds, append-
ing the sugar side chains to the peptide backbone. About Cb-C5 (c’1)
(A) for (R)-b-Caa(g) and (B) for (S)-b-Caa(g); (C) About Cb-C4 (c’’1) for
(R)-b-Caa(x); (D) About Cb-C5 (c1) and C5-C4 (c2) for (R)-b-hCaa(x)
.
as weak Me(proÀR)/C4H NOE correlation further show the en-
velope conformation of the isopropylidine ring.
The CD spectra (200 mm solution in methanol) of the pep-
tides 7–10 (Figure 9) and 11–14[22] show diagnostic signatures
of a right-handed 10/12-mixed helix, with maxima at about
203 nm. On the other hand the peptides 15–16,[22] as antici-
The couplings involving the side chains in peptides 7–10
have been used to obtain the information on the structure
of the pyranose sugar ring as well as on the dihedral angle
À
À À
N Cb C5 O (c’1). Except for the second residue in 7 and 8
and the first residue in 9 and 10, for most of the b-Caa(g),
3JCbHÀC5H ~9.0 Hz, implies c’1 ~1808 for (R)-b-Caa(g), and
~608 for (S)-b-Caa(g). However as noticed for (S)-b-Caa(x)/
(R)-b-Caa(x) peptides,[11a] for the second residue in 7 and 8
and for the first residue in 9 and 10, which incidentally is
3
(R)-b-Caa(g), JCbHÀC5H has a value of ~6 Hz, corresponding
to c’1 ~608. The galactose ring like moiety observed earli-
er,[27] exists in a slightly distorted boat form as supported by
3
3
3
the couplings, JC1HÀC2H ~5.0 Hz, JC2HÀC3H ~2.5 Hz, JC3HÀC4H
3
~7.8 Hz, JC4HÀC5H ~1.7 Hz, and a C3H/C5H NOE correla-
Figure 9. CD spectra of 7–10.
tion. The lower intensity of the Me(proÀS)/C1H NOE com-
pared to Me(proÀS)/C2H and Me(proÀR)/C5H, further show the
envelope conformation of the isopropylidine ring containing
pated, gave characteristic signatures for a left-handed 10/12-
mixed helix, with a minima at ~202 nm. The small values of
molar ellipticities ([q]max <35000 degcm2 dmolÀ1) in the CD
spectra of 7 and 9 (Figure 9) clearly show that the helical
secondary structure has just begun to nucleate in these
smaller oligomers. The [q]max for the peptides 8 and 10
À
the C1 C2 bond. Similarly, envelope conformation of the iso-
À
propylidine ring at the C3 C4 bond was confirmed by the
NOEs between Me(proÀR)/C3H and Me(proÀR)/C4H.
In peptides 11–16, for monomer (R)-b-hCaa(x),
3
3
JCbHÀC5H(proÀR) ~9 Hz, JCbHÀC5H(proÀS) ~5 Hz, JC4HÀC5H(proÀS)
3
~9 Hz and JC4HÀC5H(proÀR) ~5 Hz suggest restricted rotations
about Cb C5 and C5 C4 bonds. These couplings along with
intra-residue NOE correlations, NH/C5H(proÀR) and NH/C4H,
(Figure 9)
~300000 degcm2 dmolÀ1
and
~469000 degcm2 dmolÀ1 respectively, are pronounced, indi-
cating the stability of the mixed helices. The difference in
their molar ellipticities indicate that the peptide 10, with
(R)-b-Caa(g) at the N-terminus, is more robust than 8, where
the N-terminus residue is (S)-b-Caa(g). Similarly, the [q]max
À
À
À
À À
imply preponderance of conformers with N Cb C5 C4 (cl)
À
À À
~608 and Cb C5 C4 O (c2) ~608 (Figure 8). For (R)-b-
3
Caa(x), JCbHÀC4H ~9.0 Hz and the intra-residue NOEs, NH/
C4H, C4H/CaH(proÀR) and C4H/CaH(proÀS), are consistent with
for
12
and
14
~160000 degcm2 dmolÀ1
and
3
À
À À
N Cb C4 O (c’’1) ~1808. The couplings, JC1HÀC2H ~4 Hz,
~69700 degcm2 dmolÀ1, respectively, indicate that peptide 12
has more robust helical pattern compared to 14.
3JC2HÀC3H ~0 Hz, and JC3HÀC4H ~3 Hz, for all the sugar rings
3
in both b-Caa(x) and b-hCaa(x), correspond to a sugar pucker
of T2. Strong NOEs Me(proÀS)/C1H and Me(proÀS)/C2H as well
Thus, from the above CD spectral details, it was observed
that peptides (8 and 14) with 10/12-helical pattern have
3
188
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Chem. Asian J. 2009, 4, 181 – 193

Synthesis of b-Peptides with b-Helices from New C-Linked Carbo-b-Amino Acids
lower molar ellipticities than the peptides (10 and 12) with
12/10-helices. The theoretical predictions made by Wu and
Conclusions
Wang,[7a] where the 12/10-helices, (nucleating the mixed
helix at the N-termini with a 12-mr H-bonding) are energeti-
cally more favorable over the 10/12-helices (where the 10-
mr H-bonding initiates the helix at the N-termini) by
1.5 kcal, support these findings.
For the restraint molecular dynamics (MD) studies
(Figure 10 and 11), constraints were derived from the
volume integrals obtained from the ROESY spectra using a
In conclusion, new amino acids (R)- and (S)-b-Caa(g), having
a bulky d-galactopyranoside side chain, were synthesized
from d-galactose, while the (R)- and (S)-b-hCaa(x), with a
methylene spacer between the backbone and side chain,
were prepared from d-glucose. As anticipated, there is a sig-
nificant impact of the side chains on the helix formation and
its stability in the b-peptides derived from these b-amino
acids. Unlike in our earlier studies,[11a] the tripeptide made
from alternating 1 and 2, has shown no secondary structure.
Similarly, the tetrapeptides synthesized from 1 and 2, barely
show nucleation of an incipient 10/12-mixed helix. Further,
unlike in the earlier studies with (R)- and (S)-b-Caa(x), at-
tempted synthesis of b-peptides using alternating (S)-b-
hCaa(x) 3 and (R)-b-hCaa(x) 4 failed, which again reflects a
subtle impact of the respective side chains. However, synthe-
sis using alternating geometrically heterochiral (R)-b-Caa(x)
and (R)-b-hCaa(x) 4 was successful and yielded the peptides
with robust right-handed 10/12-mixed helices. Similarly, the
mixed b-peptides from (R)-b-hCaa(x) 4 and b-hGly have
shown left-handed 10/12-helical structures. Thus, this study
with the new monomers amply demonstrates that the side
chains do have a substantial influence on the stability of the
secondary structures besides controlling the design and syn-
thesis. The addition of new b-amino acid monomers, with
their larger conformational requirements, might help in de-
signing novel secondary structures in the arena of synthetic
peptides and proteins research.
Figure 10. Stereoview of MD structures of (A) Peptide 10 and (B) Pep-
tide 12 (sugars are replaced with methyl groups, for clarity, after calcula-
tions).
Experimental
General
CH2Cl2 was distilled over CaH2 and stored over 4 ꢃ molecular sieves.
Et3N was dried on KOH and distilled from ninhydrin. Amino acids and
peptide coupling reagents were purchased from standard catalogues.
HOBT (1-Hydroxy-1H benzotriazole) and EDCI (1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride) were used for peptide syn-
thesis. All coupling and Boc deprotection reactions were carried out
under nitrogen atmosphere. TLC was performed on Silica gel 60 F254
plates and detection with UV or dipping into the solution of ninhydrin
followed by heating. Melting points were determined in open capillaries
and were not corrected.
Figure 11. Stereoview of MD structures of 16 (sugars are replaced with
methyl groups, for clarity, after calculations).
IR spectra were recorded on KBr pallets in the 400–4000 cmÀ1 range.
NMR spectra were recorded in 5–10 mm solutions in CDCl3 and
[D5]pyridine on 500 (1H: 500 MHz, 13C: 125 MHz), 400 (1H: 400 MHz,
13C: 100 MHz), 600 (1H: 600 MHz, 13C: 150 MHz) and 300 (1H: 300 MHz,
13C: 75 MHz) MHz spectrometers. The spectra were invariably obtained
at 303 K. Chemical shifts (d) are reported in ppm downfield with respect
to internal TMS (SiMe4) (d=0 ppm). CD spectra were recorded on
0.2 mm solutions in MeOH at room temperature using a 2 mm pathlength
cell and a spectral range of 260–190 nm, with a scanning speed of
50 nmminÀ1, bandwidth of 2 nm and data pitch of 0.1 nm with 2 accumu-
lations. The values are expressed in terms of [q], the total molar elliptici-
ty (deg cm2 dmolÀ1). The binomial method is used for smoothing of the
spectra.
two-spin approximation. Figure 10A and 10B show 20
lowest energy superimposed structures of hexapeptides 10
and 12, respectively. The MD structures depict the features
that have already been suggested, with the backbone and
heavy atom RMSDs of 0.78 ꢃ and 1.23 ꢃ for 10 and 0.63 ꢃ
and 1.02 ꢃ for 12, respectively. These values are significantly
larger than those observed for the corresponding peptides
studied earlier, which resulted in very robust mixed heli-
ces.[11a] Figure 11 shows the 20 lowest energy superimposed
structures for 16. The backbone and heavy atom RMSDs for
the left-handed 10/12-helix are 0.58 ꢃ and 0.79 ꢃ.
Restraint molecular dynamics (MD) studies were carried out using IN-
SIGHT-II. The constraints were derived from the volume integrals ob-
tained from the ROESY spectra using a two-spin approximation and the
reference distance of 1.8 ꢃ for the geminal protons. The upper and lower
Chem. Asian J. 2009, 4, 181 – 193
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189

V. M. Sharma, A. C. Kunwar et al.
FULL PAPERS
bound of the distance constraints have been obtained by enhancing and
reducing the derived distance by 10%.
CDCl3): d=6.52 (d, 1H, J=8.7 Hz, NH-2), 5.52 (d, 1H, J=5.0 Hz, C1H-
1), 5.48 (d, 1H, J=5.0 Hz, C1H-2), 5.14 (d, 1H, J=6.8 Hz, NH-1), 4.58
(dd, 1H, J=2.4, 8.0 Hz, C3H-2), 4.57 (dd, 1H, J=2.5, 7.9 Hz, C3H-1),
4.45 (m, 1H, CbH-2), 4.32 (dd, 1H, J=1.7, 7.9 Hz, C4H-1), 4.30 (dd, 1H,
J=1.8, 8.0 Hz, C4H-2), 4.29 (dd, 1H, J=2.5, 5.0 Hz, C2H-1), 4.27 (dd,
1H, J=2.4, 5.0 Hz, C2H-2), 4.06 (dd, 1H, J=1.8, 7.7 Hz, C5H-2), 4.02
(dd, 1H, J=1.7, 7.6 Hz, C5H-1), 4.00 (m, 1H, CbH-1), 3.66 (s, 3H,
COOMe), 2.80 (dd, 1H, J=6.1, 16.8 Hz, CaH-2), 2.70–2.56 (m, 3H, CaH-
1, Ca’H-1, Ca’H-2), 1.53 (s, 3H, Me), 1.49 (s, 3H, Me), 1.45 (s, 3H, Me),
1.44 (s, 12H, Boc, Me), 1.33 (s, 3H, Me),1.31 (s, 6H, Me), 1.30 ppm (s,
6H, Me); 13C NMR (100 MHz, CDCl3,): d=172.3, 170.2, 156.0, 109.3,
108.8, 108.7, 96.5, 71.5, 71.0, 70.9, 70.8, 70.7, 70.5, 67.3, 66.5, 51.5, 49.4,
46.5, 37.4, 34.6, 28.4, 26.0, 25.9, 25.9, 25.8, 25.0, 24.9, 24.4, 24.2 ppm;
HRMS (ESI): m/z calculated for C34H55N2O15Na [M+Na]+ 753.3421,
found 753.3413.
Synthesis
Boc-(S)-b-Caa(g)-OCH3 (1). A solution of 19 (1.10 g, 3.01 mmol) in meth-
À
anol (5.0 mL) was treated with 10% Pd C (0.10 g) and stirred for 12 h at
room temperature. The reaction mixture was filtered through celite and
the organic layer was dried (Na2SO4). Solvent was evaporated under re-
duced pressure to give 19a (1.32 g, 93%) as a pale yellow liquid.
A solution of 19a (1.32 g, 3.98 mmol) and Et3N (1.38 mL, 9.95 mmol) in
THF (13 mL) at 08C was treated with (Boc)2O (0.92 mL, 3.98 mmol) and
stirred at room temperature for 2 h. The reaction mixture was diluted
with EtOAc (2ꢄ10 mL) and washed with water (5 mL). Organic layer
was dried (Na2SO4), evaporated under reduced pressure, and the residue
was purified by column chromatography (Silica gel, 15% EtOAc in pe-
troleum ether) to give 1 (1.61 g, 93%) as a white solid: m.p. 105–1088C;
a2D7 =À136.3 (c=0.8, CHCl3); IR (KBr): n˜ =3404, 2984, 2931, 2827, 1744,
Boc-(S)-b-Caa(g)-(R)-b-Caa(g)-(S)-b-Caa(g)-(R)-b-Caa(g)-OCH3 (7). As de-
scribed for 27, a solution of 29 (0.65, 0.89 mmol), on reaction with 4n
NaOH in MeOH gave 30 (0.276 g, 94%) as a white solid, which was used
as such for further reaction.
1709, 1516, 1440, 1368, 1174, 1072, 1022 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d=5.53 (d, 1H, J=5.0 Hz, C1H), 5.07 (d, 1H, J=7.9 Hz, NH),
4.58 (dd, 1H, J=2.4, 7.9 Hz, C3H), 4.29 (dd, 1H, J=2.4, 5.0 Hz, C2H),
4.26 (dd, 1H, J=1.7, 7.9 Hz, C4H), 4.15 (m, 1H, CbH), 4.00 (dd, 1H, J=
1.7, 6.5 Hz, C5H), 3.66 (s, 3H, COOMe), 2.79 (dd, 1H, J=6.5, 16.5 Hz,
CaH), 2.73 (dd, 1H, J=5.5, 16.5 Hz, Ca’H), 1.50 (s, 3H, Me), 1.44 (s, 3H,
Me), 1.43 (s, 9H, Boc), 1.32 (s, 3H, Me), 1.31 ppm (s, 3H, Me); 13C NMR
(100 MHz, CDCl3,): d=172.0, 155.5, 109.4, 108.7, 96.5, 71.7, 71.0, 70.6,
66.8, 51.5, 48.6, 35.8, 28.3, 25.9, 25.8, 24.9, 24.3 ppm; HRMS (ESI): m/z
calculated for C20H34NO9 [M+H]+ 432.2203, found 432.2202.
As described for the synthesis of 29, a mixture of 30 (0.35 g, 0.48 mmol),
HOBt (0.079 g, 0.58 mmol), and EDCI (0.111 g, 0.58 mmol) in CH2Cl2
(3 mL) was stirred at 08C for 15 min and treated with 31 [prepared from
29 (0.357 g, 0.488 mmol), TFA (0.35 mL) in CH2Cl2 (2.0 mL), and
DIPEA (0.12 mL, 0.72 mmol)] under N2 atmosphere for 8 h. Workup and
purification by column chromatography (Silica gel, 2.0% methanol in
CHCl3) afforded 7 (0.48 g, 75%) as a white solid: m.p. 152–1558C; aD27
À101.84 (c=0.15, CHCl3); IR (KBr): n˜ =3331, 2927, 1744, 1708, 1605,
1547, 1389, 1121, 916, 802 cmÀ1 1H NMR (500 MHz, CDCl3): d=8.16 (d,
=
Boc-(R)-b-Caa(g)-OCH3 (2). A solution of 20 (0.90 g, 2.13 mmol) in meth-
anol (2.7 mL) was treated with 10% Pd-C (0.09 g) as described for 19a
to give 20a (0.652 g, 92%) as a yellow liquid.
;
1H, J=8.2 Hz, NH-4), 7.03 (d, 1H, J=9.6 Hz, NH-2), 6.96 (d, 1H, J=
9.0 Hz, NH-3), 5.65 (d, 1H, J=7.6 Hz, NH-1), 5.54 (d, 1H, J=5.1 Hz,
C1H-3), 5.53 (d, 1H, J=4.9 Hz, C1H-1), 5.52 (d, 1H, J=5.0 Hz, C1H-4),
5.41 (d, 1H, J=5.0 Hz, C1H-2), 4.76 (m, 1H, CbH-2), 4.75 (dd, 1H, J=
1.7, 7.9 Hz, C4H-3), 4.64 (dd, 1H, J=2.5, 7.8 Hz, C3H-4), 4.59 (dd, 2H,
J=2.4, 7.9 C3H-1 and 3), 4.58 (dd, 1H, J=2.3, 7.9 Hz, C3H-2), 4.46 (m,
1H, CbH-4), 4.39 (dd, 1H, J=1.6, 7.8 Hz, C4H-4), 4.38 (m, 1H, CbH-3),
4.35 (dd, 1H, J=1.7, 8.1 Hz, C4H-1), 4.33 (dd, 1H, J=1.5, 7.9 Hz, C4H-
2), 4.31 (dd, 1H, J=2.5, 5.0 Hz, C2H-4), 4.29 (dd, 1H, J=2.4, 4.9 Hz,
C2H-1), 4.27 (dd, 1H, J=2.3, 5.0 Hz, C2H-2), 4.26 (dd, 1H, J=2.4,
5.1 Hz, C2H-3), 4.23 (m, 1H, CbH-1), 3.93 (dd, 1H, J=1.7, 9.0 Hz, C5H-
3), 3.85 (dd, 1H, J=1.7, 8.7 Hz, C5H-1), 3.84 (dd, 1H, J=1.6, 8.8 Hz,
C5H-4), 3.77 (dd, 1H, J=1.5, 5.0 Hz, C5H-2), 3.63 (s, 3H, COOMe), 2.81
(dd, 1H, J=3.8, 13.8 Hz, CaH(proÀS)-4), 2.71 (dd, 1H, J=6.5, 14.8 Hz,
CaH(proÀR)-1), 2.60 (dd, 1H, J=3.1, 12.8 Hz, CaH(proÀS)-2), 2.57 (dd, 1H,
J=4.7, 14.8 Hz, CaH(proÀS)-1), 2.52 (dd, 1H, J=9.8, 13.8 Hz, CaH(proÀR)-4),
2.51 (dd, 1H, J=3.1, 13.6 Hz, CaH(proÀR)-3), 2.41 (dd, 1H, J=5.0, 13.6 Hz,
CaH(proÀS)-3), 2.35 (dd, 1H, J=11.3, 12.8 Hz, CaH(proÀR)-2), 1.55 (s, 3H,
Me), 1.50 (s, 3H, Me), 1.48 (s, 6H, Me), 1.45 (s, 3H, Me), 1.44 (s, 9H,
Boc), 1.43 (s, 3H, Me), 1.41 (s, 3H, Me), 1.38 (s, 3H, Me), 1.34 (s, 3H,
Me), 1.33 (s, 3H, Me), 1.31 (s, 3H, Me), 1.30 (s, 9H, Me), 1.29 ppm (s,
6H, Me); 13C NMR (150 MHz, CDCl3): d=173.8, 171.3, 169.8, 155.8,
109.5, 109.3, 109.0, 108.9, 108.7, 108.4, 108.2, 96.6, 96.3, 78.7, 71.4, 71.1,
70.7, 70.6, 70.4, 70.3(2), 70.1, 68.0, 67.8, 67.7, 66.2, 52.1, 50.1, 49.7, 47.7,
46.5, 39.4, 37.4, 36.7, 36.0, 29.6, 28.4, 26.1, 26.0 (2), 25.9, 25.5, 25.2, 25.0,
24.9, 24.8, 24.7, 24.4, 24.3, 24.1 ppm; HRMS (ESI): m/z calculated for C62
H96N4O27Na [M+Na]+ 1351.6128, found 1351.6116.
As described for 1, a solution of 20a (0.652 g, 1.97 mmol) and Et3N
(0.68 mL, 4.93 mmol) in THF (7 mL) was treated with (Boc)2O (0.45 g,
1.97 mmol) to give 2 (0.773 g, 91%) as a syrup after chromatographic pu-
rification (Silica gel, 14% EtOAc in petroleum ether): a2D7 =À81.13 (c=
0.46, CHCl3); IR (Neat): n˜ =3410, 3390, 2925, 1723, 1460, 1306, 1230,
1150, 980, 847 cmÀ1 1H NMR (500 MHz, CDCl3): d=5.48 (d, 1H, J=
;
5.0 Hz, C1H), 5.33 (d, 1H, J=9.3 Hz, NH), 4.58 (dd, 1H, J=2.5, 8.0 Hz,
C3H), 4.32 (dd, 1H, J=1.7, 8.0 Hz, C4H), 4.26 (dd, 1H, J=2.5, 5.0 Hz,
C2H), 4.17 (m, 1H, CbH), 3.97 (dd, 1H, J=1.7, 7.0 Hz, C5H), 3.67 (s, 3H,
COOMe), 2.78 (dd, 1H, J=6.1, 16.4 Hz, CaH), 2.72 (dd, 1H, J=5.2,
16.4 Hz, Ca’H), 1.49 (s, 3H, Me), 1.45 (s, 3H, Me), 1.43 (s, 9H, Boc), 1.33
(s, 3H, Me), 1.31 ppm (s, 3H, Me); 13C NMR (100 MHz, CDCl3): d=
166.7, 150.4, 131.4, 130.3, 128.7, 127.2, 112.6, 105.6, 85.2, 82.7, 80.3, 46.2,
29.6, 28.5, 26.9, 26.3, 20.0 ppm; HRMS (ESI): m/z calculated for
C20H34NO9 [M+H]+ 432.2204, found 432.2201.
Boc-(S)-b-Caa(g)-(R)-b-Caa(g)-OCH3 (29). A solution of ester 1 (1.1 g,
2.55 mmol) in methanol (4.4 mL) was treated with aq. 4n NaOH solution
(4.4 mL) at 08C to room temperature. After 2 h, methanol was removed
and the pH adjusted to 2–3 with aq. 1n HCl solution at 08C and extract-
ed with EtOAc (2ꢄ10 mL). The organic layer was dried (Na2SO4) and
concentrated to give 27 (0.98 g, 92%) as a white solid, which was used as
obtained for the next step.
A solution of 2 (0.853 g, 1.98 mmol) and TFA (0.8 mL) in CH2Cl2 (5 mL)
was stirred at room temperature for 1 h. Solvent was evaporated under
reduced pressure and resulting amine salt 28 was dried under high
vacuum and used as obtained for the next step.
Boc-(S)-b-Caa(g)-(R)-b-Caa(g)-(S)-b-Caa(g)-(R)-b-Caa(g)-(S)-b-Caa(g)-(R)-b-
Caa(g)-OCH3 (8). As described for 27, a solution of 7 (0.136, 0.10 mmol),
on reaction with 4n NaOH in MeOH gave 32 (0.276 g, 94%) as a white
solid, which was used as such for further reaction.
A mixture of 27 (0.825 g, 1.98 mmol), HOBt (0.320 g, 2.37 mmol), and
EDCI (0.454 g, 2.37 mmol) in CH2Cl2 was stirred at 08C for 15 min and
the reaction mixture was treated with 28, DIPEA (0.51 mL, 2.97 mmol)
and stirred at room temperature for 8 h. It was quenched at 08C with sat.
NH4Cl (5 mL) solution. After 10 min, the reaction mixture was diluted
with CHCl3 (10 mL), washed with 1n HCl (5 mL), water (5 mL), aq. sat
NaHCO3 (5 mL) solution, and brine (5 mL). The organic layer was dried
(Na2SO4) and evaporated to give the residue, which was purified by
column chromatography (Silica gel, 40% EtOAc in petroleum ether) to
give 29 (1.28 g, 88%) as a white solid: m.p. 105–1078C; a2D7 =À119.89
(c=0.9, CHCl3); IR (KBr): n˜ =3431.9, 3043.9, 2927.5, 1734.5, 1689.4,
As described for the synthesis of 29, a mixture of 32 (0.1 g, 0.076 mmol),
HOBt (0.012 g, 0.091 mmol) and EDCI (0.018 g, 0.091 mmol) in CH2Cl2
(2 mL) was stirred at 08C for 15 min and treated with 31 [prepared from
29 (0.056 g, 0.076 mmol) and TFA (0.06 mL) in CH2Cl2 (0.5 mL)] and
DIPEA (0.02 mL, 0.114 mmol) under N2 atmosphere for 8 h. Workup
and purification by column chromatography (Silica gel, 2.3% methanol
in CHCl3) afforded 8 (0.07 g, 47%) as a white solid: m.p. 183–1868C;
a2D7 =À112.4 (c=0.21, CHCl3); IR (KBr): n˜ =3314, 2950, 2908, 2335,
1508.2, 1375.8, 1170.3, 1021.6, 996.3, 872.6 cmÀ1
;
1H NMR (500 MHz,
1725, 1658, 1492, 1219, 1165, 911, 784 cmÀ1 1H NMR (500 MHz, CDCl3):
;
190
www.chemasianj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 181 – 193

Synthesis of b-Peptides with b-Helices from New C-Linked Carbo-b-Amino Acids
d=9.09 (d, 1H, J=9.5 Hz, NH-4), 8.26 (d, 1H, J=9.8 Hz, NH-6), 7.33
(d, 1H, J=10.4 Hz, NH-3), 7.11 (d, 1H, J=10.1 Hz, NH-2), 6.79 (d, 1H,
J=7.8 Hz, NH-5), 5.54 (d, 1H, J=5.1 Hz, C1H-1), 5.53 (d, 1H, J=5.0 Hz,
C1H-3), 5.49 (d, 1H, J=4.9, C1H-6), 5.48 (brs, 1H, NH-1), 5.47 (d, 1H,
J=4.9 Hz, C1H-4), 5.41 (d, 1H, J=5.1 Hz, C1H-5), 5.38 (d, 1H, J=
5.0 Hz, C1H-2), 4.91 (m, 1H, CbH-2), 4.86 (dd, 1H, J=1.8, 8.0 Hz, C4H-
5), 4.77 (dd, 1H, J=1.6, 8.4 Hz, C4H-3), 4.63 (m, 1H, CbH-6), 4.60 (dd,
1H, J=2.4, 8.0 Hz, C3H-1), 4.58 (m, 3H, C3H-2, 4 and 5), 4.57 (m, 1H,
C3H-6), 4.54 (dd, 1H, J=2.1, 8.4 Hz, C3H-3), 4.44 (dd, 1H, J=1.8, 8.0,
C4H-1), 4.39 (m, 1H, CbH-3), 4.32 (dd, 1H, J=1.7, 7.8 Hz, C4H-4), 4.30
(m, 2H, C5H-1, C4H-6), 4.29 (dd, 2H, J=2.3, 5.0 Hz, C2H-1, 6), 4.28 (m,
1H, C4H-2), 4.28 (dd, 1H, J=2.2, 5.0 Hz, C2H-4), 4.26 (dd, 1H, J=2.2,
5.1 Hz, C2H-5), 4.25 (dd, 1H, J=2.2, 5.0 Hz, C2H-2), 4.24 (dd, 1H, J=
2.1, 5.0 Hz, C2H-3), 4.23 (m, 1H, CbH-4), 4.05 (m, 1H, CbH-5), 3.96 (dd,
1H, J=1.8, 10.0 Hz, C5H-5), 3.89 (dd, 1H, J=1.6, 9.1 Hz, C5H-3), 3.85
(m, 1H, CbH-1), 3.76 (dd, 1H, J=1.7, 4.9 Hz, C5H-2), 3.67 (dd, 1H, J=
1.6, 9.6 Hz, C5H-6), 3.64 (m, 1H, C5H-4), 3.63 (s, 3H, COOMe), 2.90 (dd,
1H, J=2.6, 15.7 Hz, CaH(proÀS)-6), 2.75 (dd, 1H, J=2.6, 13.5 Hz,
CaH(proÀS)-4), 2.64 (dd, 1H, J=2.1, 11.9 Hz, CaH(proÀS)-2), 2.58 (m, 2H,
CaH-1), 2.55 (dd, 1H, J=12.2, 15.7 Hz, CaH(proÀR)-6), 2.49 (dd, 1H, J=
2.3, 11.8 Hz, CaH(proÀR)-3), 2.46 (dd, 1H, J=4.3, 13.2 Hz, CaH(proÀR)-5),
2.39 (dd, 1H, J=2.7, 13.2 Hz, CaH(proÀS)-5), 2.38 (dd, 1H, J=3.9, 11.8 Hz,
CaH(proÀS)-3), 2.22 (t, 1H, J=11.9 Hz, CaH(proÀR)-2), 2.16 (dd, 1H, J=12.5,
13.5, CaH(proÀR)-4), 1.57 (s, 15H, Me), 1.53 (s, 3H, Me), 1.50 (s, 3H, Me),
1.47 (s, 3H, Me), 1.46 (s, 3H, Me), 1.45 (s, 3H, Me), 1.44 (s, 9H, Boc),
1.41 (s, 3H, Me), 1.39 (s, 3H, Me), 1.33 (s, 9H, Me), 1.31 (s, 6H, Me),
1.29 (s, 6H, Me), 1.28 (s, 6H, Me), 1.26 ppm (s, 9H, Me); 13C NMR
(100 MHz, CDCl3): d=172.6, 172.0, 171.7, 171.0, 170.5, 169.1, 155.7,
109.5, 109.4, 109.2, 109.1, 109.0(2), 108.7, 108.6, 108.5, 108.2, 96.8, 96.6,
96.5, 96.4, 96.3, 96.1, 95.6, 78.6, 71.9, 71.3, 71.0, 70.9, 70.8, 70.7 (2), 70.6,
70.5, 70.4, 70.2, 70.0, 69.9, 69.8, 69.6, 69.4, 69.3, 67.9, 67.5, 65.9, 51.6, 51.5,
50.1, 48.4, 48.3, 47.7, 44.0, 40.2, 39.6, 38.0, 37.9, 37.6, 36.3, 29.6, 28.4, 27.4,
27.0, 26.9, 26.3, 26.2, 26.1, 26.0, 25.9, 25.6, 25.4, 25.2, 25.1, 24.9, 24.6, 24.5,
24.4(2), 24.1 ppm; HRMS (ESI): m/z calculated for C90H138N6O39Na [M+
Na]+ 1949.9049, found 1949.9056.
Boc), 1.47 (s, 3H, Me), 1.31 ppm (s, 3H, Me); 13C NMR (150 MHz,
CDCl3): d=166.0, 149.2, 105.6, 98.6, 79, 75.4, 71.9, 51.5, 45.7, 39.9, 33.3,
26.1, 22.5, 20.5, 20.3 ppm; HRMS (ESI): m/z calculated for C18H32NO8
[M+H]+ 390.2163, found 390.2275.
Boc-(R)-b-Caa(x)-(R)-b-hCaa(x)-OCH3 (42). As described for the synthesis
of 27, a solution of 5 (0.98 g, 2.61 mmol) on reaction with 4n NaOH in
MeOH gave 40 (0.9 g, 96%) as a white solid and which was used as such
for further reaction.
As described for the synthesis of 29, a solution of 40 (0.9 g, 2.8 mmol),
HOBt (0.46 g, 3.41 mmol), and EDCI (0.65 g, 3.41 mmol) in CH2Cl2
(10 mL) was stirred at 08C under N2 atmosphere for 15 min and treated
with 41 [prepared from 4 (1.07 g, 2.8 mmol) and TFA (1.0 mL) in CH2Cl2
(10 mL)] and DIPEA (0.74 mL, 4.27 mmol) and stirred for 8 h. Workup
and purification by column chromatography (Silica gel, 50% EtOAc in
petroleum ether) gave 42 (1.20 g, 76%) as a white solid: m.p. 73–758C;
a2D7 =À23.5 (c=0.40, CHCl3); IR (KBr): n˜ =3431.9, 3343.9, 2927.5,
1744.5, 1689.4, 1508.2, 1375.8, 1170.3, 1093.6, 1021.6, 996.3, 872.6 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=6.54 (d, 1H, J=8.2 Hz, NH-2), 5.70 (d,
1H, J=8.8 Hz, NH-1), 5.86 (d, 1H, J=3.7 Hz, C1H-1), 5.84 (d, 1H, J=
3.7 Hz, C1H-2), 4.57 (d, 1H, J=3.7 Hz, C2H-2), 4.53 (d, 1H, J=3.7 Hz,
C2H-1), 4.34 (m, 1H, C4H-2), 4.24 (m, 3H, C4H-1, CbH-1, CbH-2), 3.71
(d, 1H, J=3.0 Hz, C3H-1), 3.67 (s, 3H, COOMe), 3.63 (d, 1H, J=3.3 Hz,
C3H-2), 3.41 (s, 3H, OMe), 3.40 (s, 3H, OMe), 2.70 (dd, 1H, J=5.6,
15.8 Hz, CaH-2), 2.58 (dd, 1H, J=6.6, 15.8 Hz, Ca’H-2), 2.52 (dd, 1H, J=
5.7, 15.2 Hz, CaH-1), 2.47 (dd, 1H, J=4.7, 15.2 Hz, Ca’H-1), 1.96 (m, 2H,
C5H-2, C5’H-2), 1.43 (s, 9H, Boc), 1.48 (s, 3H, Me), 1.46 (s, 3H, Me), 1.31
(s, 3H, Me), 1.30 ppm (s, 3H, Me); 13C NMR (100 MHz, CDCl3): d=
171.3, 170.4, 155.4, 111.7, 111.6, 105.0, 104.8, 84.7, 84.0, 81.6, 80.2, 78.1,
60.6, 57.8, 57.7, 46.2, 45.6, 38.0, 36.5, 29.6, 28.4, 26.8, 26.7, 26.4, 26.3 ppm;
HRMS (ESI): m/z calculated for C29H48N2O13Na [M+Na]+ 655.3079,
found 655.3052.
Boc-(R)-b-Caa(x)-(R)-b-hCaa(x)-(R)-b-Caa(x)-(R)-b-hCaa(x)-OCH3 (11). As
described for 27, a solution of 42 (0.6 g, 0.94 mmol) on reaction with 4n
NaOH in MeOH gave 43 (0.55 g, 95%) as a white solid, which was used
as such for further reaction.
Boc-(R)-b-hCaa(x)-OCH3 (4). As described for the synthesis of 19a, a so-
lution of 26 (1.2 g, 3.2 mmol) in methanol (4.0 mL) was treated with 10%
Pd–C (0.12 g) for 12 h to give 26a (0.85 g, 93%) as a pale yellow liquid.
A mixture of acid 43 (0.50 g, 0.80 mmol), HOBt (0.13 g, 0.97 mmol), and
EDCI (0.18 g, 0.97 mmol) in CH2Cl2 (10 mL) was stirred at 08C under N2
atmosphere for 15 min and treated with 44 [prepared from 42 (0.51 g,
0.8 mmol) and TFA (0.5 mL) in CH2Cl2 (3.0 mL)] and DIPEA (0.20 mL,
1.21 mmol) and stirred for 8 h. Workup as described for 29 and purifica-
tion by column chromatography (Silica gel, 2% MeOH in CHCl3) gave
11 (0.4 g, 43%) as a white solid: m.p. 90–938C; a2D7 =+1.9 (c=0.30,
CHCl3); IR (KBr): 3370, 2986, 2942, 1717, 1666, 1520, 1337, 1100, 972,
As described for the synthesis of 1, a solution of 26a (0.85 g, 2.98 mmol)
and Et3N (0.829 mL, 5.96 mmol) in THF (10 mL) at 08C was treated with
(Boc)2O (0.8 mL, 3.5 mmol) and stirred at room temperature for 3 h.
Workup and purification by column chromatography (Silica gel, 15%
EtOAc in petroleum ether) gave 4 (0.98 g, 85%) as a syrup: a2D7 =À18.3
(c=0.6, CHCl3); IR (Neat): n˜ =3404, 2984, 2931, 2827, 1744, 1709, 1516,
864 cmÀ1 1H NMR (500 MHz, Pyridine-d5): d=8.98 (d, 1H, J=8.4 Hz,
;
1440, 1368, 1174, 1072, 1022 cmÀ1
;
1H NMR (500 MHz, CDCl3): d=5.85
NH-4), 8.81 (d, 1H, J=9.1 Hz, NH-2), 8.59 (d, 1H, J=9.4 Hz, NH-3),
7.86 (d, 1H, J=9.7 Hz, NH-1), 6.11 (d, 1H, J=3.9 Hz, C1H-1), 6.06 (d,
1H, J=3.9 Hz, C1H-2), 6.03 (m, 2H, C1H-3, C1H-4), 5.22 (m, 1H, CbH-
3), 5.03 (m, 1H, CbH-1), 4.97 (m, 1H, CbH-2), 4.85 (m, 1H, CbH-4), 4.73
(d, 1H, J=3.9 Hz, C2H-2), 4.72 (m, 1H, C4H-2), 4.71 (d, 1H, J=3.9 Hz,
C2H-1), 4.71 (m, 1H, C4H-3), 4.70 (m, 2H, C2H-3, C2H-4), 4.66 (m, 1H,
C4H-4), 4.62 (dd, 1H, J=3.2, 8.7 Hz, C4H-1), 4.01 (d, 1H, J=3.2 Hz,
C3H-3), 4.00 (d, 1H, J=3.2 Hz, C3H-1), 3.85 (d, 1H, J=3.2 Hz, C3H-2),
3.77 (d, 1H, J=3.2 Hz, C3H-4), 3.63 (s, 3H, COOMe), 3.43 (s, 3H,
OMe), 3.41 (s, 3H, OMe), 3.37 (s, 3H, OMe), 3.33 (s, 3H, OMe), 3.21
(dd, 1H, J=3.9, 13.2 Hz, CaH(proÀS)-1), 3.15 (dd, 1H, J=6.1, 15.5 Hz,
CaH(proÀR)-4), 3.09 (dd, 1H, J=4.5, 13.6 Hz, CaH(proÀS)-3), 2.96 (dd, 1H, J
9.4,13.6 Hz, CaH(proÀR)-3), 2.93 (dd, 1H, J=7.3, 15.5 Hz, CaH(proÀS)-4), 2.86
(dd, 1H, J=5.2, 12.9 Hz, CaH(proÀR)-2), 2.70 (dd, 1H, J=9.7, 13.2 Hz,
CaH(proÀR)-4), 2.63 (dd, 1H, J=4.5, 12.9 Hz, CaH(proÀS)-2), 2.46 (m, 2H,
(d, 1H, J=3.9 Hz, C1H), 5.22 (d, 1H, J=8.8 Hz, NH), 4.56 (d, 1H, J=
3.9 Hz, C2H), 4.24 (dt, 1H, J=3.3, 7.1 Hz, C4H), 4.08 (m, 1H, CbH), 3.67
(s, 3H, COOMe), 3.56 (d, 1H, J=3.3 Hz, C3H), 3.41 (s, 3H, OMe), 2.65
(m, 1H, J=5.9, 15.9 Hz, CaH), 2.58 (m, 1H, J=6.3, 15.9 Hz, Ca’H), 1.93
(m, 2H, C5H, C5’H), 1.43 (s, 9H, Boc), 1.49 (s, 3H, Me)1.32 ppm (s, 3H,
Me); 13C NMR (150 MHz, CDCl3): d=166, 149, 105, 98.7, 98.0, 75.6, 78.4,
71.8, 51.7, 45.0, 39.0, 33.7, 22.5, 20.7, 20.3 ppm; HRMS (ESI): m/z calcu-
lated for C18H32NO8 [M+H]+ 390.2192, found 390.2201.
Boc-(S)-b-hCaa(x)-OCH3 (3). As described for the synthesis of 19a, a so-
lution of 25 (1.0 g, 2.6 mmol) in methanol (3.0 mL) was treated with 10%
Pd–C (0.1 g) for 12 h to give 25a (0.7 g, 92%) as a pale yellow liquid.
As described for the synthesis of 1, a solution of 25a (0.7 g, 2.4 mmol)
and Et3N (0.67 mL, 4.8 mmol) in THF (8 mL) at 08C was treated with
(Boc)2O (0.67 mL, 2.94 mmol) and stirred at room temperature for 2 h.
Workup and purification by column chromatography (Silica gel, 15%
EtOAc in petroleum ether) gave 3 (0.88 g, 93%) as a white solid:
m.p. 125–1288C; a2D7 =À48.5 (c=0.54, CHCl3); IR (KBr): n˜ =3383, 2980,
C5H(proÀS)-2, C5H(proÀR)-2), 2.36 (ddd, 1H, J=4.5, 8.4, 14.1 Hz, C5H(proÀR)
-
4), 2.27 (ddd, 1H, J=5.5, 8.4, 14.1 Hz, C5H(proÀS)-4), 1.53 (s, 9H, Boc),
1.52–1.49 (s, 12H, Me), 1.33–1.31 ppm (s, 12H, Me); 13C NMR (150 MHz,
CDCl3): d=172.3, 170.6, 170.1, 16.8, 150.9, 111.6, 111.5, 111.4, 111.3, 105,
104.5, 84.8, 84.1, 83.5, 81.8, 81.4, 81.3, 80.8, 80.7, 79.4, 78.2, 77.7, 58.1,
57.7, 57.5, 51.7, 48.8, 45.8, 44.9, 45.0, 40.1,39.4, 39.3, 38.2, 31.7, 28.4, 26.7,
26.3, 26.2 ppm; HRMS (ESI): m/z calculated for C52H84N4O23Na [M+
Na]+ 1155.5446, found 1155.5421.
2935, 1721, 1705, 1499, 1308, 1160, 1071, 1011 cmÀ1 1H NMR (500 MHz,
;
CDCl3): d=5.85 (d, 1H, J=3.9 Hz, C1H), 5.14 (d, 1H, J=9.4 Hz, NH),
4.55 (d, 1H, J=3.9 Hz, C2H), 4.21 (ddd, 1H, J=3.7, 6.2, 7.9 Hz, C4H),
4.01 (m, 1H, CbH), 3.77 (d, 1H, J=3.7 Hz, C3H), 3.68 (s, 3H, COOMe),
3.43 (s, 3H, OMe), 2.57 (m, 2H, CaH, Ca’H), 1.92 (ddd, 1H, J=4.4, 7.9,
14.1 Hz, C5H), 1.87 (ddd, 1H, J=6.2, 9.7, 14.1 Hz, C5’H), 1.43 (s, 9H,
Chem. Asian J. 2009, 4, 181 – 193
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
191

V. M. Sharma, A. C. Kunwar et al.
FULL PAPERS
Boc-(R)-b-Caa(x)-(R)-b-hCaa(x)-(R)-b-Caa(x)-(R)-b-hCaa(x)-(R)-b-Caa(x)
-
41.2, 36.3, 32.4, 28.4, 26.8, 26.7, 26.2 ppm; HRMS (ESI): m/z calculated
for C21H36N2O9Na [M+Na]+ 488.2326, found 483.2309.
(R)-b-hCaa(x)-OCH3 (12). As described for 27, a solution of 11 (0.40 g,
0.34 mmol) on reaction with 4n NaOH in MeOH gave 45 (0.35 g, 89%)
as a white solid, which was used as obtained for further reaction.
Boc-(R)-b-hCaa(x)-b-hGly-(R)-b-hCaa(x)-b-hGly-OCH3 (15).
A solution
of 53 (0.21 g, 0.45 mmol), as described for 27, on reaction with 4n NaOH
in MeOH gave 54 (0.20 g, 98%) as a white solid, which was used as ob-
tained for further reaction.
A mixture of 45 (0.20 g, 0.17 mmol), HOBt (0.03 g, 0.21 mmol), and
EDCI (0.04 g, 0.21 mmol) in CH2Cl2 (3 mL) was stirred at 08C for 15 min
and treated with 44 [prepared from 42 (0.112 g, 0.178 mmol) and TFA
(0.1 mL) in CH2Cl2 (3.0 mL)] and DIPEA (0.07 mL, 0.4 mmol) under ni-
trogen atmosphere for 8 h. Workup as described for 29 and purification
by column chromatography (Silica gel, 2.5% methanol in CHCl3) afford-
ed 12 (0.08 g, 27%) as a white solid: m.p. 120–1238C; a2D7 =+27.5 (c=
0.25, CHCl3); IR (KBr): n˜ =3412, 2939, 1720, 1657, 1546, 1378, 1209,
A mixture of acid 54 (0.2 g, 0.45 mmol), HOBt (0.072 g, 0.537 mmol) and
EDCI (0.102 g, 0.537 mmol) in CH2Cl2 (5 mL) was stirred at 08C under
N2 atmosphere for 15 min and treated with the amine salt 55 [prepared
from 53 (0.206 g, 0.45 mmol) and TFA (0.2 mL) in CH2Cl2 (2.0 mL),
DIPEA (0.117 mL, 0.67 mmol)] under nitrogen and stirred for 8 h.
Workup as described for 29 and purification by column chromatography
(Silica gel, 2.1% MeOH in CHCl3) gave 15 (0.240 g, 68%) as a white
solid: m.p. 196–1988C; a2D7 =+150.9 (c=0.10, CHCl3); IR (KBr): n˜ =
1101, 1026, 966, 879 cmÀ1 1H NMR (500 MHz, Pyridine-d5): d=9.25 (d,
;
1H, J=9.1 Hz, NH-4), 9.15 (d, 1H, J=8.5 Hz, NH-6), 9.02 (d, 1H, J=
10.1 Hz, NH-3), 8.85 (d, 1H, J=9.5 Hz, NH-2), 8.82 (d, 1H, J=9.9 Hz,
NH-5), 8.17(d, 1H, J=10.1 Hz, NH-1), 6.16 (d, 1H, J=3.9 Hz, C1H-1),
6.14 (d, 1H, J=3.9 Hz, C1H-3), 6.05 (d, 1H, J=3.9 Hz, C1H-2), 6.02 (d,
1H, J=3.9 Hz, C1H-6), 5.99 (m, 2H, C1H-4, C1H-5), 5.32 (m, 1H, CbH-
3), 5.27 (m, 1H, CbH-5), 5.08 (m, 1H, CbH-1), 5.00 (m, 1H, CbH-2), 4.91
(m, 1H, CbH-4), 4.87 (m, 1H, CbH-6), 4.77 (d, 1H, J=3.9 Hz, C2H-1),
4.73 (d, 1H, J=3.9 Hz, C2H-2), 4.71 (m, 3H, C2H-4, C2H-6, C4H-4), 4.70
(d, 1H, J=3.9 Hz, C2H-3), 4.70 (m, 2H, C4H-3, C4H-6), 4.69 (m, 2H,
C4H-2, C4H-5), 4.67 (d, 1H, J=3.9 Hz, C2H-5), 4.51 (dd, 1H, J=3.2,
8.8 Hz, C4H-1), 4.03 (d, 1H, J=3.2 Hz, C3H-3), 4.02 (d, 1H, J=3.2 Hz,
C3H-5), 4.01 (d, 1H, J=3.2 Hz, C3H-1), 3.90 (d, 1H, J=3.2 Hz, C3H-4),
3.83 (d, 1H, J=3.2 Hz, C3H-2), 3.82 (d, 1H, J=3.2 Hz, C3H-6), 3.65 (s,
3H, COOMe), 3.51 (s, 3H, OMe), 3.49 (s, 3H, OMe), 3.44 (s, 3H, OMe),
3.41 (s, 3H, OMe), 3.39 (s, 3H, OMe), 3.37 (m, 1H, CaH(proÀS)-3), 3.33 (s,
3H, C3OMe-6), 3.32 (m, 1H, CaH(proÀS)-1), 3.30 (m, 1H, CaH(proÀR)-6),
3.16 (dd, 1H, J=3.3, 13.1 Hz, CaH(proÀS)-5), 3.10 (dd, 1H, J=5.2, 12.1 Hz,
CaH(proÀR)-4), 3.05 (dd, 1H, J=10.7, 13.1 Hz, CaH(proÀR)-5), 2.94 (t, 1H,
J=11.9 Hz, CaH(proÀR)-3), 2.91 (dd, 1H, J=7.8, 15.5 Hz, CaH(proÀS)-6), 2.86
(dd, 1H, J=4.9, 12.7 Hz, CaH(proÀR)-2), 2.59 (dd, 1H, J=3.6, 12.1 Hz,
CaH(proÀS)-4), 2.54 (t, 1H, J=11.9 Hz, CaH(proÀR)-1), 2.46 (dd, 1H, J=4.3,
12.7 Hz, CaH(proÀS)-2), 2.51 (m, 2H, C5H(proÀS)-4, C5H(proÀR)-4), 2.38 (m,
2H, C5H(proÀS)-2, C5H(proÀR)-2), 2.37 (m, 1H, C5H(proÀS)-6), 2.28 (ddd, J=
5.2, 8.4, 14.0, Hz 1H, C5H(proÀR)-6), 1.52 (s, 9H, Boc), 1.52–1.50 (s, 18H,
Me), 1.34–1.31 ppm (s, 18H, Me); 13C NMR (150 MHz, CDCl3): d=
174.8, 174.7, 174.2, 173.2, 171.1, 169.8, 156.4, 111.7, 111.6, 114.4, 111.0,
110.9, 105.0, 104.9, 104.8, 104.7, 104.6, 85.7, 84.4, 84.3, 84.1, 83.9, 83.8,
81.8, 81.6, 81.5, 81.2, 81.1, 80.6, 80.4, 80.1, 78.8, 78.6, 78.2, 58.1, 57.8, 57.7,
57.4, 57.3, 52.0, 51.4, 50.1, 49.1, 48.5, 45.9, 45.8, 45.7, 42.1, 41.9, 39.0, 37.8,
29.9, 28.7, 27.3, 27.1, 27.0, 26.9, 26.8, 26.7, 26.6, 26.5, 26.5 ppm; HRMS
(ESI): m/z calculated for C75H120N6O33Na [M+Na]+ 1655.6391, found
1655.6379.
3343, 2988, 2936, 1685, 1531, 1520, 1373, 1167, 1076, 888 cmÀ1 1H NMR
;
(500 MHz, CDCl3,): d=7.47 (m, 1H, NH-2), 7.44 (d, 1H, J=8.4 Hz, NH-
3), 6.68 (t, 1H, J=6.3 Hz, NH-4), 5.89 (d, 1H, J=4.3 Hz, C1H-3), 5.85 (d,
1H, J=4.3 Hz, C1H-1), 5.37 (d, 1H, J=9.5 Hz, NH-1), 4.54 (d, 1H, J=
4.3 Hz, C2H-1), 4.53 (d, 1H, J=4.3 Hz, C2H-3), 4.32 (m, 1H, CbH-3), 4.19
(m, 1H, CbH-1), 4.25 (m, 1H, C4H-3), 4.23 (m, 1H, C4H-1), 3.76 (m, 1H,
CbH(proÀR)-2), 3.70 (s, 3H, COOMe), 3.54 (d, 1H, J=3.3 Hz, C3H-1), 3.54
(d, 1H, J=3.3 Hz, C3H-3), 3.22 (m, 1H, CbH(proÀS)-2), 3.49 (m, 2H,
CbH(proÀR)-4, CbH(proÀR)-4), 3.39 (s, 3H, OMe), 3.38 (s, 3H, OMe), 2.54 (m,
2H, CaH(proÀS)-4, CaH(proÀR)-4), 2.53 (m, 1H, CaH(proÀR)-1), 2.51 (m, 2H,
CaH(proÀS)-3, CaH(proÀR)-3), 2.35 (dd, 1H, J=8.4, 13.7 Hz, CaH(proÀS)-1),
2.24 (m, 2H, CaH(proÀS)-2, CaH(proÀR)-2), 1.89 (m, 2H, C5H(proÀS)-3,
C5H(proÀR)-3), 1.87 (m, 1H, C5H(proÀS)-1), 1.82 (ddd, 1H, J=4.1, 8.5,
13.0 Hz, C5H(proÀR)-1), 1.41 (s, 9H, Boc), 1.46–1.31 ppm (s, 12H, Me);
13C NMR (150 MHz, CDCl3): d=172.9, 171.6, 171.4, 170.8, 155.8, 111.5,
111.4, 104.7, 404., 104.5, 85.4, 85.1, 81.4, 81.3, 79.3, 77.8, 77.6, 57.7, 57.5,
51.7, 47.2, 46.2, 42.2, 40.8, 36.8, 35.9, 34.9, 33.7, 33.4, 32.3, 28.4, 26.7, 26.3,
26.2 ppm; HRMS (ESI): m/z calculated for C36H60 N4 O15Na [M+Na]+
811.3952, found 811.3934.
Boc-(R)-b-hCaa(x)-b-hGly-(R)-b-hCaa(x)-b-hGly-(R)-b-hCaa(x)-b-hGly-
OCH3 (16). A solution of 15 (0.18 g, 0.23 mmol), as described for 27, on
reaction with 4n NaOH in MeOH gave 56 (0.16 g, 93%) as a white solid,
which was used as obtained for further reaction.
A mixture of 56 (0.16 g, 0.206 mmol), HOBt (0.034 g, 0.247 mmol) and
EDCI (0.047 g, 0.247 mmol) in CH2Cl2 (2 mL)was stirred at 08C for
15 min and treated with amine salt 55 [prepared from 53 (0.095 g,
0.206 mmol), TFA (0.1 mL) in CH2Cl2 (1.0 mL)] and DIPEA (0.053 mL,
0.31 mmol)] under nitrogen atmosphere for 8 h. Workup as described for
29 and purification by column chromatography (Silica gel, 2.7% metha-
nol in CHCl3) afforded 16 (0.11 g, 48%) as a white solid: m.p. 231–
2338C; a2D7 =+62.5 (c=0.05, CHCl3 IR (KBr): n˜ =3322, 2925, 2855, 1648,
1540, 1375, 1260, 1080, 1024, 884 cmÀ1 1H NMR (500 MHz, CDCl3): d=
;
Boc-(R)-b-hCaa(x)-b-hGly-OCH3 (53). As described for 27, a solution of
4 (0.55 g, 1.41 mmol) on reaction with 4n NaOH in MeOH gave 46
(0.51 g, 96%) as a white solid, which was used as obtained for further re-
action.
8.41 (dd, 1H, J=2.9, 9.9 Hz, NH-2), 8.37 (d, 1H, J=8.2 Hz, NH-5), 8.29
(dd, 1H, J=2.8, 9.6 Hz, NH-4), 8.08 (d, 1H, J=9.7 Hz, NH-3), 6.59 (m,
1H, NH-6), 5.05 (d, 1H, J=10.5 Hz, NH-1), 5.86 (d, 1H, J=3.7 Hz, C1H-
5), 5.81 (d, 1H, J=3.7 Hz, C1H-3), 5.77 (d, 1H, J=3.7 Hz, C1H-1), 4.54
(d, 1H, J=3.7 Hz, C2H-3), 4.52 (d, 1H, J=3.7 Hz, C2H-5), 4.52 (m, 1H,
CbH-3), 4.49 (d, 1H, J=3.7 Hz, C2H-1), 4.45 (m, 1H, CbH-1), 4.40 (m,
1H, CbH-5), 4.27 (m, 1H, C4H-5), 4.25 (m, 1H, C4H-1), 4.24 (m, 1H,
C4H-3), 3.56 (d, 1H, J=3.1 Hz, C3H-5), 3.54 (d, 1H, J=3.1 Hz, C3H-1),
3.44 (d, 1H, J=3.1 Hz, C3H-3), 3.99 (m, 1H, CbH(proÀR)-2), 3.91 (m, 1H,
CbH(proÀR)-4), 3.71 (s, 3H, COOMe), 3.39–3.35 (s, 9H, OMe), 3.56 (m,
1H, CbH(proÀR)-6), 3.41 (m, 1H, CbH(proÀS)-6), 3.00 (m, 1H, CbH(proÀS)-4),
2.89 (m, 1H, CbH(proÀS)-2), 2.67 (dd, 1H, J=3.0, 12.5 Hz, CaH(proÀR)-1),
2.63 (dd, 1H, J=3.2, 12.2 Hz, CaH(proÀR)-3), 2.55 (m, 2H, CaH(proÀS)-6,
CaH(proÀR)-6), 2.54 (m, 2H, CaH(proÀS)-5, CaH(proÀR)-5), 2.39 (t, 1H, J=
12.5 Hz, CaH(proÀS)-3), 2.30 (m, 1H, CaH(proÀS)-4), 2.19 (t, 1H, J=12.5 Hz,
CaH(proÀS)-1), 2.16 (m, 1H, CaH(proÀS)-2), 2.09 (m, 1H, CaH(proÀR)-2), 2.08
A solution of 46 (0.5 g, 1.33 mmol), HOBt (0.216 g, 1.6 mmol), and EDCI
(0.305 g, 1.6 mmol) in CH2Cl2 (5 mL) was stirred at 08C under N2 atmos-
phere for 15 min and treated sequentially with the amine 52 [prepared
from 6 (0.269 g, 1.33 mmol), TFA (0.3 mL) in CH2Cl2 (3.0 mL) and
DIPEA (0.344 mL, 1.99 mol)] and stirred for 8 h. Workup as described
for 29 and purification by column chromatography (Silica gel, 50%
EtOAc in petroleum ether) gave 53 (0.52 g, 85%) as a white solid: m.p.
90–948C; a2D7 =À23.5 (c=0.40, CHCl3); IR (KBr): n˜ =3385, 2920, 2836,
1744, 1695, 1542, 1379, 1162, 1090, 1016, 879.6 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d=6.67 (d, 1H, J=7.4 Hz, NH-2), 5.68 (d, 1H, J=8.2 Hz, NH-
1), 4.83 (s, 1H, C1H-1), 4.82 (s, 1H, C1H-2), 4.73 (m, 1H, CdH-2), 4.62
(m, 1H, CgH-2), 4.47 (m, 2H, C2H-1, 2), 4.39 (m, 1H, CbH-2), 4.14 (d,
1H, J=3.1, 7.4 Hz, CbH-1), 4.07 (m, 1H, CgH-1), 3.67 (s, 3H, COOMe),
3.62 (m, 1H, CdH-1), 3.30 (s, 3H, OMe), 3.29 (s, 3H, OMe), 2.72 (m, 1H,
CaH(proÀR)-1), 2.70 (m, 1H, CaH(proÀS)-1), 2.67 (dd, 1H, J=5.4, 14.0 Hz,
CaH(proÀR)-2), 2.49 (d, 1H, J=5.4, 14.0 Hz, CaH(proÀS)-2), 1.47 (s, 3H, Me),
1.43 (s, 9H, Boc), 1.42 (s, 3H, Me), 1.29 (s, 3H, Me), 1.28 ppm (s, 3H,
Me); 13C NMR (100 MHz, CDCl3): d=171.7, 170.4, 155.5, 111.7, 111.1,
104.7, 104.6, 84.6, 84.3, 81.6, 81.4, 79.2, 77.8, 57.2, 57.6, 51.8, 45.6, 45.4,
(m, 1H, CaH(proÀR)-4), 1.94 (m, 1H, C5H(proÀS)-1), 1.91 (m, 1H, C5H(proÀS)
-
3), 1.90 (m, 2H, C5H(proÀS)-5, C5H(proÀR)-5), 1.82 (m, 1H, C5H(proÀR)-3), 1.64
(ddd, 1H, J=2.9, 9.5, 15.0 Hz, C5H(proÀR)-1), 1.41 (s, 9H, Boc), 1.47 (s,
3H, Me), 1.38 (s, 3H, Me), 1.30 (s, 3H, Me), 1.29 (s, 3H, Me), 1.27 (s,
3H, Me), 1.26 ppm (s, 3H, Me); 13C NMR (150 MHz, CDCl3): d=173.3,
172.1, 171.9, 171.5, 170.6, 156.2, 111.3, 111.2, 104.6, 104.5, 104.5, 84.6,
192
www.chemasianj.org
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 181 – 193

Synthesis of b-Peptides with b-Helices from New C-Linked Carbo-b-Amino Acids
84.4, 81.4, 81.3, 79.7, 77.6, 57.6, 57.5, 51.8, 46.0, 46.0, 45.0, 43.6, 43.4, 43.1,
38.1, 36.7, 36.6, 36.2, 35.1, 34.6, 34.2, 33.3, 32.9, 31.9, 31.4, 30.2, 29.7, 28.4,
26.6, 26.5, 26.4, 26.2 ppm; HRMS (ESI): m/z calculated for
C51H84N6O21Na [M+Na]+ 1139.5599, found 1139.5592.
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Received: June 27, 2008
Revised: September 25, 2008
Published online: November 12, 2008
Chem. Asian J. 2009, 4, 181 – 193
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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