Expanding the structural repertoire of β/α Ant-Pro (anthranilic acid-proline) oligomers into γ/α 2-Amb-Pro (2-aminomethyl benzoic acid-proline) oligomers

Article abstract of DOI:10.1016/j.tet.2012.02.006

In this article, we report a novel class of heterogeneous synthetic oligomers featuring the conformationally constrained amino acid residues - 2-aminomethyl benzoic acid (2-Amb) and proline (Pro) in repeating sequences. Oligomers as large as hexadecamers featuring the conformationally restricted γ/α 2-Amb-Pro motif have been assembled using solution-phase Boc strategy, following multi-step synthetic sequences starting from the commercially available O-toluic acid. EDC-mediated peptide coupling has been found to be optimum for the assembly of the relatively non-polar oligomers, which could be readily purified by the standard column chromatographic purification procedures. This study offers considerable prospects of expanding the structural repertoire of β/α Ant-Pro motif, which has been described earlier to assume right-handed helical architecture displaying robust nine-membered-ring closed network of hydrogen-bonding interactions, into γ/α 2-Amb-Pro motif.

Full text of DOI:10.1016/j.tet.2012.02.006

Tetrahedron 68 (2012) 4399e4405
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Expanding the structural repertoire of
b/a Ant-Pro (anthranilic acid-proline)
oligomers into 2-Amb-Pro (2-aminomethyl benzoic acid-proline) oligomers
g/a
a
a
b
c
,
a,
*
*
€
Veera V.E. Ramesh , Gowri Priya , P.R. Rajamohanan , Hans-Jorg Hofmann , Gangadhar J. Sanjayan
a Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
b Central NMR Facility, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
c
€
€
€
€
€
Universitat Leipzig, Fakultat fur Biowissenschaften, Pharmazie und Psychologie, Institut fur Biochemie, Bruderstraße 34, D-04103 Leipzig, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
In this article, we report a novel class of heterogeneous synthetic oligomers featuring the conforma-
tionally constrained amino acid residues e 2-aminomethyl benzoic acid (2-Amb) and proline (Pro) in
Received 30 September 2011
Received in revised form 26 January 2012
Accepted 6 February 2012
repeating sequences. Oligomers as large as hexadecamers featuring the conformationally restricted
g/
a
2-Amb-Pro motif have been assembled using solution-phase Boc strategy, following multi-step syn-
Available online 10 February 2012
thetic sequences starting from the commercially available O-toluic acid. EDC-mediated peptide coupling
has been found to be optimum for the assembly of the relatively non-polar oligomers, which could be
readily purified by the standard column chromatographic purification procedures. This study offers
Dedicated to Professor Padmanabhan Ba-
laram, Indian Institute of Science, Bangalore,
India, in recognition of his exemplary con-
tribution in the area of Biomimetism
considerable prospects of expanding the structural repertoire of
b/a Ant-Pro motif, which has been
described earlier to assume right-handed helical architecture displaying robust nine-membered-ring
closed network of hydrogen-bonding interactions, into
g
/
a
2-Amb-Pro motif.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Foldamer
Peptides
Synthetic oligomers
Proline
Amino acids
1. Introduction
GCN4 e a yeast transcription factor. Owing to their structural tun-
ability and stability, foldamers can be potential candidates for diverse
applications.4 One of the promising applications of foldamers is in the
area of molecular recognition.5 The inherently weak non-covalent
interactions in foldamers facilitate molecules to become flexible
and adaptable, which would help them to act as better synthetic re-
ceptors. Through proper designing, the cavity sizes of certain fol-
damers can be tuned to act as selective receptors for hydrophilic or
hydrophobic guest molecules.6 Foldamers that can respond to ex-
ternal stimuli, such as pH and light have also attracted considerable
attention recently.7 The Huc group elegantly demonstrated recently
the utility of foldamers as building blocks in developing molecular
motors.8,9 Double helical foldamers have been shown to wind around
the rod shaped guest molecule, which can undergo screw-type
motion.9
Conformationally ordered synthetic oligomers, also called as fol-
damers, as a class of compounds have ushered into prominence and
interest in this class of compounds continues unabated primarily due
to the fact they hold considerable promise of developing oligomers of
diverse structural architectures, shapes and function e quite often
closely mimicking the conformational and functional features of na-
tive peptides.1 The scope and feasibilityof thisconcept are reflected in
the exponential growth from its foundation in the early 21st century
to the present stage.2 The recent surge of activity in this area was
fuelled by the startling structural and functional features exhibited by
some of the oligomersreported recently. For instance, intheir seminal
recent publications, Gellman’s group reported a series of a/b hetero-
geneous peptides displaying four-helix bundle quaternary structure
in the crystalline state.3 It should be emphasized that these hetero
One of the promising goals in the foldamer research area is to
mimic biopolymers, both structurally and functionally.2 Gellman’s
group has recently developed foldamers that can bind with anti-
foldamers are based on the well-studied 33-residue a-peptide GCN4-
pLI, which is an engineered derivative of the dimerization domain of
apoptotic proteins, such as Bcl-xL. A foldamer consisting of nine
a/
b
-amino acid segments and six -amino acid segments has been
a
shown to display significant binding affinity for Bcl-xL in nanomolar
* Corresponding authors. Tel./fax: þ91 020 2590 2449; e-mail address: gj.san-
range.10
jayan@ncl.res.in (G.J. Sanjayan).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.006

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V.V.E. Ramesh et al. / Tetrahedron 68 (2012) 4399e4405
Similar to homo oligomers, foldamers with heterogeneous
backbone offer wide range of structural architectures and biological
applications. In fact, the structural repertoire exhibited by hetero
foldamers is enormously large when compared to their homo
oligomer counterparts since mixing of residues in various pro-
portions and sequences can enormously augment conformational
diversity. A striking feature of the heterogeneous oligomers is their
intriguing conformational architectures, which are distinctly dif-
ferent from their classically observed homo oligomer counterparts.
The combined conformational preferences of the individual resi-
dues in a heterogeneous backbone play crucial role in dictating the
overall structural architecture of these oligomers. Although the
quest in foldamer chemistry started with the modification of nat-
ural a-peptides with their b- and g
-counterparts,11,12 diverse classes
of backbones with varying combinations of amino acid residues
have been developed and reported later.13 Heterogeneous fol-
damers featuring
a-aminoxy acid and sugar amino acids on the
backbone have been reported by the group of Sharma and Kunwar.
According to their studies, 12/10-mixed helical structures are
obtained from peptides containing C-linked carbo-
b-amino acid
[(R)- -Caa] and
b
a
-aminoxy acid [(R)-Ama] building blocks.14 Fleet’s
group also pioneered in the generation of diverse class of sugar
amino acids15 (SAAs) with intriguing preferences for secondary
structure formation. The group of Taillefumier and Alison recently
reported interesting classes linear and cyclic
a/b-alternating pep-
Fig. 1. Comparison of a four-residue ideal
residue Ant-Pro turn, C9 structure (B), expanded
ing block reported herein (C), and another possible expanded
building block (D). The contrasting hydrogen-bonding directions in Fig. A and B are
highlighted with shaded arrows, and the distance: d(C -C ) is shown in double headed
arrow. Note: C iþ2 distance range shown for the Ant-Pro reverse turn (B) is
iꢀ1eC
taken from the crystal structure, reported earlier.20 The dihedral angle
has been
shown for the aryl rings, which are constrained
-amino acids.22
b
-turn, C10 structure (A), with the two-
2-Amb-Pro dipeptide build-
2-Aap-Pro dipeptide
toids that assume ordered conformations.16,17
b-a
g-a
g-a
We have been involved for quite some time in the conforma-
tional mapping of hetero foldamers, investigating their conforma-
tional propensities and characteristics.18 Our interests have been
focused in the generation of foldamers of heterogeneous backbones
containing constrained aromatic and aliphatic amino acids. Ex-
tensive conformational mapping involving crystal structure and
NMR studies have shown that hetero foldamer strategy involving
conformationally constrained aromatic-aliphatic amino acid resi-
dues can effectively generate synthetic oligomers of unprecedented
structural architectures, distinctly different from their corre-
sponding homo oligomer counterparts.19 In an effort to understand
the influence of steric constraints in conformational bias, we had
previously undertaken the investigation of conformational pro-
a
a
a
a
q
b
involve four residues to form hydrogen-bonded network featuring
backward 1)4 amino acid interactions (Fig. 1A, B). Such an in-
triguing structural feature prompted us to further explore the
prospects of expanding structural repertoire of
into Amb-Pro (2-aminomethyl benzoic acid-proline) motif
(Fig. 1C). An alternate possibility of structural expansion also exists
as in the case of the 2-Apa-Pro (2-aminophenylacetic acid-
b/a Ant-Pro motif
g/a
pensities of the
b-
a
anthranilic acid-Proline (Ant-Pro) motif (Fig. 1).
g/a
The closer positioning, separated by an amide group, of Pro residue
preceded by an Ant residue was anticipated to have strong steric
repulsion between the Ant and Pro rings, forcing the rings to adopt
an anti-periplanar conformation. Such an orientation of the two
rings was anticipated to display a folded conformation, featuring
a nine-membered-ring hydrogen-bonding involving the amide
NeH of the Ant residue and the carbonyl (C]O) of the Pro residue,
which we called as Ant-Pro reverse turn.20 (Fig. 1B). Indeed,
structural investigations, both in solid- and solution-state, clearly
suggested that the Ant and Pro residues, which form the turn
segment, maintain a perfect anti-periplanar orientation throughout,
leaving little possibility for the formation of the otherwise possible
six-membered hydrogen-bonding (within the N-acyl anthranila-
mides) that requires a coplanar disposition of the two amino acid
residues. Oligomers containing the Ant-Pro building blocks have
been shown to feature right-handed helical architecture displaying
repeating turns of closed nine-membered-ring hydrogen-bonded
network.
proline) motif (Fig. 1D), although we haven’t investigated it at
present due to the anticipated difficulties in coupling the aryl
amines during oligomer synthesis. Gratifyingly, the segment dou-
bling of the
g/a Amb-Pro motif proceeded quite efficiently, as
expected, without serious synthetic hassles. Using iterative cou-
plings, we have been able to make oligomers as large as hex-
adecamer in the solution-state involving column chromatographic
purification procedures.
2. Results and discussion
2.1. Synthesis of oligomers
The oligomers were assembled as described in Scheme 1. O-
toluic acid methyl ester 1 was first converted into the azido acid 3
using a literature protocol.23 The azido acid 3 was then coupled
with (L) proline methyl ester using the acid chloride strategy fur-
nishing the dipeptide 4, which was subsequently hydrogenated in
presence of Boc anhydride to afford the orthogonally protected
dipeptide building block 5a. Repetitive segment doubling of the
dipeptide building block 5a successfully furnished the tetrapeptide
6a, the octapeptide 7a and the hexadecapeptide 8a, in acceptable
yields without much synthetic and purification hassles. The C-ter-
minal methyl amides (5d, 6d, 7d and 8b) were accessed readily by
direct amidation of the corresponding esters (5a, 6a, 7a and 8a),
respectively, using saturated methanolic methylamine.
Although the Ant-Pro reverse turn displayed a folded confor-
ꢀ
mation with a terminal C
expected for
a
distance [d(C
a
eC
a
)] to be 5.3 A, which is
b
-turn mimetics,21 there were substantial differences
in the hydrogen-bonding directions in the turn segment. For in-
stance, the closed hydrogen-bonded network observed in the Ant-
Pro reverse turn motif, formed in forward direction of the sequence
(1/2 amino acid interactions) involving only two amino acid
residues, is clearly in stark contrast to the native
b-turns that

V.V.E. Ramesh et al. / Tetrahedron 68 (2012) 4399e4405
4401
Scheme 1. Synthesis of oligomers. Reagents and conditions: (i) a. NBS, (BzO)2 (cat.), CCl4, reflux, 1 h; b. NaN3, MeOH, reflux, 24 h; (ii) 2 M NaOH/MeOH (1:1 v/v), rt, 30 min; (iii) a.
(COCl)2, DCM, DMF (cat.), 0 ꢁC, then rt, 3 h; b. HCl$H-(L)-Pro-OMe, Et3N, rt, 6 h; (iv) PdeC, Boc anhydride, Et3N, H2, 60 psi, EtOAc, rt, 5 h; (v) TFA/DCM (1:1), rt, 1 h; (vi) methanolic
methylamine, rt, 6 h; (vii) EDC$HCl, HOBt, amine, DCM, rt, 8 h.

4402
V.V.E. Ramesh et al. / Tetrahedron 68 (2012) 4399e4405
2.2. Conformational investigations
Extensive efforts to crystallize the oligomers to explore their
solid-state conformational features did not meet with success,
since none of them crystallized, despite best efforts. All oligomers
were readily soluble in non-polar solvents suggesting that the
backbone amide. NHs are strongly solvent shielded, preventing
aggregation in solution. Unfortunately, due to chemical shift over-
lapping, the conformational studies of the oligomers posed con-
siderable challenges, though the conformational investigations of
the dipeptide 5d could be undertaken after solvent-induced signal
shifts in toluene-d8. The C-terminal amide NH was found to be
deshielded (7.39 ppm) in comparison to the solvent exposed N-
terminal carbamate NH (6.83 ppm), suggestive of intramolecular
hydrogen bonding. The observed NOE pattern (Fig. 2) supported the
folded conformation, which is in agreement with the molecular
modelling studies (vide infra).
Fig. 3. Structural architecture of 5d at the HF/6e31G* level of ab initio MO theory
showing two conformers e one having strong H-bonding (left) and another showing
relatively week interaction (right). Hydrogens, other than the polar ones, have been
omitted for clarity.
Fig. 2. Selected NOE extracts from the 2D NOESY spectra of 5d (toluene-d8, 500 MHz).
Observed NOEs that support the folded conformation are highlighted in double headed
arrows.
In order to gain further insights into the conformational features
of these oligomers, we undertook extensive ab initio molecular
modelling studies using the 6e31G* basis set. It is noteworthy that
computational investigations employing ab initio MO theory have
considerably contributed to predict and to understand the folding
patterns of a variety of foldamer architectures.19,20
Conformational investigations using ab initio modelling studies
suggested that there are two conformers possible for 5d retaining
similar C12 H-bonding network, although they differ in their H-
bonding distances. Further difference is seen in their positioning of
the benzylic methylene, wherein the conformer with short H-
bonding distance (Fig. 3, left) has the CH2 projecting down juxta-
posed to the proline ring, though a reverse arrangement is noted for
the other conformer (Fig. 3, right). Indeed, the dipolar coupling
pattern observed in the NMR studies supported the predominance
of the former conformer, although the latter one does exist in
negligible amounts.
Fig. 4. Structural architecture of the tetrapeptide 6d (A), octapeptide 7d (B) and
hexadecapeptide 8b (C) at the HF/6e31G* level of ab initio MO theory showing right-
handed helical conformation with repeating C12 H-bonding networks. Hydrogens,
other than the polar ones, have been omitted for clarity.
perfect back-to-back hydrogen-bonding interactions, eventually
aiding the oligomer to assume a right-handed helical conformation.
Ab initio molecular modelling studies using the 6e31G* basis
set clearly revealed the right-handed helical architecture of the
3. Conclusion
large
g
/
a
2-Amb-Pro oligomers (6d, 7d and 8b), featuring repeating
In conclusion, we report a novel class of heterogeneous syn-
thetic oligomers featuring the conformationally constrained amino
acid residues e 2-aminomethyl benzoic acid (2-Amb) and proline
(Pro). Oligomers as large as hexadecamers featuring the
C12 H-bonding networks (Fig. 4AeC). The onset of helicity was
evident from the tetrameric oligomer 6d itself (Fig. 4A). Except the
N-terminus carbamate NH, all backbone amide NHs involve in

V.V.E. Ramesh et al. / Tetrahedron 68 (2012) 4399e4405
4403
conformationally restricted
g
/
a
2-Amb-Pro motif in repeating se-
Calcd for C14H16N4O3: C, 58.32; H, 5.59; N, 19.43. Found: C, 58.49; H,
5.41; N, 19.27.
quences have been efficiently assembled using solution-phase Boc
strategy, starting from the commercially available O-toluic acid. It is
noteworthy that this study offers considerable prospects of
expanding the structural repertoire of b/a Ant-Pro motif, which has
been described earlier to assume right-handed helical architecture
displaying robust nine-membered-ring closed network of
4.2.2. (S)-Methyl-1-(2-((tert-butoxycarbonylamino)methyl) benzoyl)
pyrrolidine-2-carboxylate (5a). To the solution of compound 4
(12 g, 41.6 mmol, 1 equiv) in ethyl acetate (100 mL), Boc anhydride
(10.89 g, 49.9 mmol, 1.2 equiv) and Et3N (8.49 mL, 62.4 mmol,
1.5 equiv) were added. The mixture was subjected to hydro-
genolysis using 10% PdeC (1 g) and H2 (60 psi). After completion of
reaction, the reaction mixture was filtered over Celite pad. The
filtrate on evaporation under reduced pressure yielded crude
product, which on purification by column chromatography (60:40
pet. ether/ethyl acetate, Rf: 0.5) afforded 5a as a colourless liquid
hydrogen-bonding interactions, into
mers featuring repeating segments of the conformationally re-
stricted 2-Amb-Pro have been shown to adopt right-handed
g/a 2-Amb-Pro motif. Oligo-
g/a
helical conformation, periodically displaying C12 hydrogen-
bonding network.
(14.0 g, 93%). ½a D24
ꢂ
ꢀ20 (c 1, CHCl3); IR (CHCl3)
n
(cmꢀ1): 3014, 1741,
4. Experimental section
4.1. General methods
1703, 1697, 1633, 1516, 1506, 754; 1H NMR (200 MHz, CDCl3)
d:
7.43e7.12 (m, 4H), 6.12e6.04 (m, 1H), 4.63e4.56 (m, 1H), 4.22 (d,
J¼6.32 Hz, 2H), 3.75 (s, 2.8H), 3.72conformer (s, 0.2H), 3.44e3.24 (m,
2H), 2.31e2.17 (m, 1H), 2.09e1.79 (m, 3H), 1.35conformer (s, 0.2H),
Unless otherwise stated, all the chemicals and reagents were
obtained commercially. Dry solvents were prepared by the stan-
dard procedures. Analytical Thin Layer Chromatography was done
on precoated silica gel plates (Kieselgel 60F254, Merck). Unless
otherwise stated, Column Chromatographic purifications were
done with 100e200 mesh silica gel. NMR spectra were recorded in
CDCl3 on AV 200 MHz spectrometer. All chemical shifts are repor-
1.32 (s, 8.8H); 13C (50 MHz, CDCl3)
d: 172.7, 172.4, 169.9, 169.7, 155.8,
136.6, 136.4, 135.7, 130.2, 129.7,129.4, 127.0, 125.6, 125.5,125.4, 78.6,
58.2, 52.3, 52.0, 49.1, 48.5, 42.3, 29.4, 28.2, 24.5; ESI Mass: 363.1542
(MþH)þ, 385.0594 (MþNa)þ, 401.1011 (MþK)þ; Anal. Calcd for
C19H26N2O5: C, 62.97; H, 7.23; N, 7.73. Found: C, 63.13; H, 7.05; N,
7.89.
ted in
d parts per million downfield to TMS and peak multiplicities
4.2.3. (S)-1-(2-((tert-Butoxycarbonylamino)methyl)benzoyl) pyrroli-
dine-2-carboxylic acid (5b). A general procedure for the C-terminus
ester saponification is as follows: to a solution of 5a (6 g, 16.5 mmol,
1 equiv) in methanol (40 mL), LiOH$H2O (1.38 g, 33.1 mmol,
2 equiv) dissolved in water (15 mL) was added and the reaction
mixture was stirred for 12 h. The solvent was stripped off under
reduced pressure and the product was partitioned between
dichloromethane and water, repeatedly extracted with dichloro-
methane. The combined organic layer was dried over anhydrous
Na2SO4 and evaporated under reduced pressure to get the crude
product quantitatively, which was taken for the next reaction
without further purification.
as singlet (s), doublet (d), quartet (q), broad singlet (br s) and
multiplet (m). Elemental analyses were performed on an Elmentar-
Vario-EL (Heraeus Company Ltd., Germany). IR spectra were
recorded in CHCl3 using Shimadzu FTIR-8400 spectrophotometer.
Melting points were determined on a Buchi Melting Point B-540.
Electrospray ionization (ESI) Mass Spectrometric measurements
were done with API QSTAR Pulsar mass Spectrometer. MALDI-TOF
Spectrometric measurements were done with Voyager-OR-STAR
(Applied Biosystems). The azido acid 3 was made starting from O-
toluic acid following a literature protocol.23
4.2. Synthesis of building blocks and oligomers
4.2.4. (S)-Methyl-1-(2-(aminomethyl)benzoyl)pyrrolidine-2-
carboxylate (5c). A general procedure for the N-terminus tBoc
deprotection is as follows: a solution containing the dipeptide 5a
(6 g, 16.5 mmol) in dichloromethane (20 mL) was subjected to Boc
deprotection using DCM/TFA (50%, 20 mL). After completion of the
reaction (1 h), the solvent was stripped off under reduced pressure
and the residue was partitioned between dichloromethane and
water, and repeatedly extracted with dichloromethane. The com-
bined organic layer was dried over anhydrous Na2SO4 and evapo-
rated under reduced pressure to get the crude product
quantitatively, which was taken for the next reaction without fur-
ther purification.
4.2.1. (S)-Methyl-1-(2-(azidomethyl)benzoyl)pyrrolidine-2-
carboxylate (4). To an ice-cold stirred solution of the 2-(azido-
methyl)benzoic acid 3 (12 g, 62.8 mmol, 1 equiv) in dry dichloro-
methane (120 mL) was added dry DMF (0.48 g, 6.2 mmol, 0.1 equiv)
followed by oxalyl chloride (6.03 mL, 69.1 mmol, 1.1 equiv). The
resulting mixture was stirred for 3 h at room temperature. The
solvent was evaporated under reduced pressure and dried. The
residue containing the acid chloride was dissolved in dry
dichloromethane (100 mL) and added drop wise to an ice cooled
solution of HCl$H-(L)-Pro-OMe (11.46 g, 69.1 mmol, 1.1 equiv) and
Et3N (18.81 mL, 138.2 mmol, 2.2 equiv) in dichloromethane
(120 mL). The reaction mixture was then stirred at room temper-
ature for 6 h. The reaction mixture was diluted with dichloro-
methane, and the organic layer was washed sequentially with
dilute HCl solution, water, saturated sodium bicarbonate and sat-
urated brine. The organic layer was then dried over anhydrous
Na2SO4 and evaporated under reduced pressure to get the crude
product, which on purification by column chromatography (70:30
pet. ether/ethyl acetate, Rf: 0.5) afforded 4 as a colourless liquid
4.2.5. (S)-tert-Butyl-2-(2-(methylcarbamoyl)pyrrolidine-1-carbonyl)
benzylcarbamate (5d). A general procedure for the C-terminus
amidation using methanolic methylamine is as follows: the ester 5a
(1 g, 2.7 mmol) was taken in saturated methanolic methylamine
solution (10 mL) and stirred at room temperature for 6 h. The sol-
vent was removed under reduced pressure, and the product was
purified by column chromatography (5:95 pet. ether/ethyl acetate,
(12.39 g, 68%). ½a D24
ꢂ
ꢀ56 (c 1, CHCl3); IR (CHCl3)
n
(cmꢀ1): 2955,
Rf: 0.5) furnishing 5d as a sticky colourless liquid (0.95 g, 96%); ½a D24
ꢂ
2100, 1745, 1633, 1600, 1421, 754; 1H NMR (200 MHz, CDCl3)
d:
ꢀ40 (c 0.2, CHCl3); IR (CHCl3)
n
(cmꢀ1): 2892, 1702,1674, 1619, 1503,
7.47e7.41 (m, 4H), 4.77 (q, 1H), 4.66e4.47 (m, 2H), 3.84 (s, 3H),
1424, 1215, 669; 1H NMR (200 MHz, CDCl3)
d: 7.24e6.97 (m, 5H),
3.59e3.30 (m, 2H), 2.47e1.86 (m, 4H); 13C (50 MHz, CDCl3)
d: 172.4,
6.12e6.09 (m, 1H), 4.54e4.39 (m, 1H), 4.12e3.88 (m, 2H), 3.21e2.96
172.2, 168.9, 168.6, 136.1, 135.9, 132.9, 132.7, 130.2, 129.5, 129.4,
129.0, 128.8, 128.0, 127.8, 126.1, 125.9, 125.5, 125.4, 60.8, 58.2, 58.0,
52.1, 52.0, 51.6, 49.1, 48.5, 45.9, 31.1, 30.9, 29.4, 29.33, 24.6, 24.6,
22.7, 22.5; ESI Mass: 311.1485 (MþNa)þ, 327.1411 (MþK)þ; Anal.
(m, 2H), 2.62 (d, J¼4.67 Hz, 3H), 2.11e1.56 (m, 4H), 1.17 (s, 9H); 13C
NMR (50 MHz, CDCl3) d: 172.4, 171.7, 171.1, 170.2, 156.0, 136.5, 136.1,
130.4, 129.4, 129.0, 127.2, 125.8, 125.5, 125.3, 79.9, 59.8, 59.1, 49.7,
49.2, 42.2, 29.4, 28.2, 27.8, 26.2, 26.1, 24.7, 24.6; LCeMS: 384.09

4404
V.V.E. Ramesh et al. / Tetrahedron 68 (2012) 4399e4405
(MþNa)þ; 400.06 (MþK)þ; Elemental analysis calculated for
C19H27N3O4: C19H27N3O4: C, 63.14; H, 7.53; N, 11.63. Found: C, 63.14;
H, 7.42; N, 11.75.
for C58H68N8O11: C, 66.14; H, 6.51; N,10.64. Found: C, 65.98; H, 6.70;
N, 10.55.
4.2.9. tert-Butyl-2-((S)-2-(2-((S)-2-(2-((S)-2-(2-((S)-2-(methyl-
carbamoyl)pyrrolidine-1-carbonyl)benzylcarbamoyl) pyrrolidine-1-
4.2.6. (S)-Methyl-1-(2-(((S)-1-(2-((tert-butoxycarbonylamino)
methyl)benzoyl)pyrrolidine-2-carboxamido)methyl)benzoyl) pyrroli-
dine-2-carboxylate (6a). A general procedure for the peptide cou-
pling is as follows: to an ice cooled solution of the acid 5b (5.76 g,
16.5 mmol,1 equiv) in drydichloromethane, was added the amine 5c
(4.32 g,16.5 mmol,1 equiv) followed by EDC$HCl (3.48 g,18.2 mmol,
1.1 equiv) and HOBt (0.42 g, 3.3 mmol, 0.2 equiv). The reaction
mixture was allowed to proceed for 8 h at room temperature and
then diluted with dichloromethane. The organic layer was washed
sequentially with dilute HCl solution, water, saturated sodium bi-
carbonate and saturated brine and dried over anhydrous Na2SO4.
The organic layer was then evaporated under reduced pressure to
obtain the crude product, which on purification by column chro-
matography (50:50 pet. ether/ethyl acetate, Rf: 0.3) afforded 6a as
carbonyl)benzylcarbamoyl)pyrrolidine-1-carbonyl)
benzylcarba-
moyl)pyrrolidine-1-carbonyl)benzylcarbamate (7d). The product
was purified by column chromatography (10% MeOH/AcOEt, Rf: 0.5)
furnishing 7d as a white solid (0.55 g, 92%); mp: 175e177 ꢁC; ½a D24
ꢂ
þ158 (c 1, CHCl3); IR (CHCl3)
n
(cmꢀ1): 3019, 1659, 1524, 1428, 1215,
758; 1H NMR (200 MHz, CDCl3)
d: 9.02e8.77 (m, 2H), 7.57e6.98 (m,
18H), 6.89e6.79 (m, 1H), 4.73e3.53 (m, 16H), 3.43e3.08 (m, 4H),
2.87 (d, J¼4.55 Hz, 2.7H), 2.76 (d, J¼4.80 Hz, 0.3H), 2.45e1.64 (m,
16H), 1.44conformer (s, 3H), 1.36 (s, 6H); 13C (50 MHz, CDCl3)
d: 173.6,
173.4, 172.4, 169.9, 169.7, 169.6, 136.6, 136.5, 136.3, 136.1, 135.9,
135.8,130.9,130.7,129.0,128.7,127.3,127.2,127.1,127.0,126.0, 125.9,
125.6, 125.5, 78.3, 60.0, 59.6, 59.3, 49.8, 49.5, 41.9, 41.8, 41.5, 30.5,
30.4, 30.1, 30.0, 28.4, 26.4, 25.0, 24.6; MALDI-TOF: 1075.85
(MþNa)þ, 1091.89 (MþK)þ; Anal. Calcd for C58H69N9O10: C, 66.20;
H, 6.61; N, 11.98. Found: C, 66.11; H, 6.46; N, 12.16.
a sticky colourless liquid (6.30 g, 63%). ½a D24
þ40 (c 1, CHCl3); IR
ꢂ
(CHCl3)
n
(cmꢀ1): 3352, 1747, 1681, 1631, 1514, 1504, 1427, 771; 1H
NMR (200 MHz, CDCl3) d: 7.85e7.73 (m, 1H), 7.54e7.14 (m, 8H),
7.02e6.53 (m, 1H), 4.62e4.45 (m, 3H), 4.33e3.98 (m, 3H), 3.82 (s,
2.4H), 3.80conformer (s, 0.6H), 3.77e3.56 (m, 1H), 3.48e3.11 (m, 3H),
2.48e1.71 (m, 8H), 1.40conformer (s, 1H), 1.36 (s, 8H); 13C (50 MHz,
4.2.10. (S)-Methyl-1-(2-(((S)-1-(2-(((S)-1-(2-(((S)-1-(2-(((S)-1-(2-
(((S)-1-(2-(((S)-1-(2-(((S)-1-(2-((tert-butoxycarbonylamino) methyl)
benzoyl)pyrrolidine-2-carboxamido)methyl)benzoyl) pyrrolidine-2-
carboxamido)methyl)benzoyl)pyrrolidine-2-carboxamido)methyl)
benzoyl)pyrrolidine-2-carboxamido) methyl)benzoyl)pyrrolidine-2-
CDCl3) d: 173.3, 173.1, 171.9, 171.3, 170.2, 169.8, 169.6, 155.9, 136.8,
136.3,136.2,135.8,135.7,135.6,134.0,130.4,130.4,130.1,130.1,129.4,
129.0, 128.7, 127.2, 127.1, 126.9, 125.7, 125.6, 125.5, 125.2, 78.4, 59.6,
59.2, 58.4, 58.3, 52.4, 52.3, 49.4, 49.3, 49.2, 48.9, 42.3, 41.2, 41.1, 40.8,
29.9, 29.4, 29.2, 29.1, 28.2, 24.7; ESI Mass: 593.5390 (MþH)þ,
615.4870 (MþNa)þ, 631.4747 (MþK)þ; Anal. Calcd for C32H40N4O7: C,
64.85; H, 6.80; N, 9.45. Found: C, 65.01; H, 6.71; N, 9.31.
carboxamido)methyl)benzoyl)
pyrrolidine-2-carboxamido)methyl)
benzoyl)pyrrolidine-2-carboxamido)methyl)benzoyl)pyrrolidine-2-
carboxylate (8a). The crude product was purified by column chro-
matography (35:65 pet. ether/ethyl acetate, Rf: 0.5) to afford 8a as
a white solid (0.46 g, 33%). Mp: 206e208 ꢁC; ½a D24
þ206 (c 1, CHCl3);
ꢂ
IR (CHCl3) n
(cmꢀ1): 3261, 1737, 1666,1631,1573,1566, 1450, 767; 1H
4.2.7. tert-Butyl-2-((S)-2-(2-((S)-2-(methylcarbamoyl) pyrrolidine-
1-carbonyl)benzylcarbamoyl)pyrrolidine-1-carbonyl) benzylcarba-
mate (6d). The product was purified by column chromatography
(5% MeOH/AcOEt, Rf: 0.5) furnishing 6d as a sticky colourless liquid
NMR (200 MHz, CDCl3) d: 9.24e9.19 (m, 3H), 9.01e8.88 (m, 2H),
8.40e7.98 (m, 1H), 7.47e6.99 (m, 33H), 6.92e6.80 (m, 1H),
4.65e3.87 (m, 24H), 3.78 (s, 3H), 3.70e3.41 (m, 8H), 3.34e2.98 (m,
8H), 2.48e1.52 (m, 32H), 1.34conformer (s, 2H), 1.25 (s, 7H); 13C
(0.93 g, 94%); ½a D24
ꢂ
þ50 (c 1, CHCl3); IR (CHCl3)
n
(cmꢀ1): 1693, 1651,
: 8.56e8.15 (m,
(50 MHz, CDCl3) d: 173.9, 173.5, 173.4, 173.4, 173.3, 169.7, 169.4,
1633, 1600, 1435, 769; 1H NMR (200 MHz, CDCl3)
d
169.3, 156.0, 136.9, 136.9, 136.8, 136.8, 136.5, 136.2, 136.1, 136.0,
135.8, 135.8, 130.6, 130.6, 130.5, 130.4, 130.4, 130.4, 129.1, 128.7,
128.7, 128.7, 128.6, 128.6, 128.5, 128.4, 127.3, 127.2, 127.0, 126.9,
126.9, 126.8, 126.5, 126.0, 125.9, 125.8, 125.6, 78.6, 78.2, 59.5, 59.4,
59.1, 59.1, 58.5, 58.4, 52.6, 49.3, 42.1, 42.1, 42.0, 41.9, 41.8, 30.4, 30.1,
30.0, 29.9, 29.5, 28.3, 24.9, 24.8, 24.5; MALDI-TOF: 1995.9229
(MþNa)þ, 2011.2896 (MþK)þ; Anal. Calcd for C110H124N16O19: C,
66.92; H, 6.33; N, 11.35. Found: C, 67.10; H, 6.19; N, 11.26.
1H), 7.49e7.17 (m, 8H), 6.51 (br s, 1H), 4.52e3.97 (m, 6H), 3.69e3.17
(m, 4H), 2.70e2.62 (m, 3H), 2.16e1.61 (m, 8H), 1.34conformer (s, 2H),
1.30 (s, 7H); 13C NMR (50 MHz, CDCl3)
d: 173.0, 172.9, 172.3, 171.4,
170.2, 169.8, 169.5, 169.4, 136.4, 136.1, 136.0, 135.9, 135.5, 135.5,
130.4, 129.1, 129.0, 127.1, 126.9, 125.4, 125.3, 78.5, 59.9, 59.5, 59.5,
49.7, 49.5, 42.1, 41.0, 30.0, 28.2, 26.1, 25.9, 24.7, 24.5; ESI-MS:
614.5207 (MþNa)þ; 1206.2248 (2MþNa)þ; Elemental analysis cal-
culated for C32H41N5O6: C, 64.96; H, 6.98; N, 11.84. Found: 64.83, H,
7.13, N, 11.68.
4.2.11. Hexadecamer methyl amide (8b). The product was purified
by column chromatography (15% MeOH/AcOEt Rf: 0.5) furnishing
4.2.8. (S)-Methyl-1-(2-(((S)-1-(2-(((S)-1-(2-(((S)-1-(2-((tert-butox-
ycarbonylamino)methyl)benzoyl)pyrrolidine-2-carboxamido)methyl)
benzoyl)pyrrolidine-2-carboxamido) methyl)benzoyl)pyrrolidine-2-
carboxamido)methyl)benzoyl) pyrrolidine-2-carboxylate (7a). The
product was purified by column chromatography (40:60 pet. ether/
ethyl acetate, Rf: 0.5) afforded 7a as a white solid (2.19 g, 56%). Mp:
8b as a white solid (0.27 g, 91%); mp: 228e230 ꢁC; ½a D24
þ190 (c 1,
ꢂ
CHCl3); IR (CHCl3)
n
(cmꢀ1): 3020, 1656, 1624, 1563, 1542, 1428,
1215, 756; 1H NMR (200 MHz, CDCl3)
d: 9.25e8.73 (m, 5H),
7.50e7.37 (m, 7H), 7.28e7.15 (m, 26H), 6.94e6.62 (m, 3H),
4.69e4.32 (m, 22H), 4.09e3.96 (m, 2H), 3.76e3.40 (m, 8H),
3.34e2.99 (m, 8H), 2.80e1.65 (m, 3H), 2.24e1.70 (m, 32H),
157e159 ꢁC; ½a 2D4
ꢂ
þ184 (c 1, CHCl3); IR (CHCl3)
n
(cmꢀ1): 3269, 1747,
: 9.01e8.89 (m,
1.63e1.27 (m, 9H); 13C (50 MHz, CDCl3)
d: 173.7, 173.6, 173.5, 173.4,
1660, 1626, 1427, 756; 1H NMR (200 MHz, CDCl3)
d
169.5, 169.4, 169.3, 156.2, 155.9, 136.9, 136.7, 136.2, 136.1, 136.0,
135.9, 130.9, 130.7, 130.5, 128.8, 128.8, 130.5, 128.8, 128.8, 128.5,
127.2, 127.1, 126.9, 125.9, 125.7, 78.6, 59.6, 59.2, 49.8, 49.6, 49.5, 42.1,
41.9, 30.6, 30.4, 30.2, 30.1, 28.4, 25.0; MALDI-TOF: 1998.22
(MþNa)þ, 2014.37 (MþK)þ; Anal. Calcd for C110H125N17O18: C,
66.95; H, 6.38; N, 12.07. Found: C, 67.13; H, 6.19; N, 11.95.
2H), 8.14e8.08 (m, 1H), 7.57e7.11 (m, 15H), 7.14e6.99 (m, 1H),
6.96e6.70 (m, 1H), 4.76e4.71 (m, 2H), 4.65e4.23 (m, 10H), 3.88 (s,
3H), 3.86e3.14 (m, 8H), 2.25e1.82 (m,16H),1.45conformer (s, 2H),1.37
(s, 7H); 13C (50 MHz, CDCl3)
d: 173.9, 173.8, 173.3, 173.3, 173.0, 172.3,
171.4, 169.7, 169.6, 169.5, 169.5, 169.4, 169.1, 168.9, 156.0, 136.9,
136.4, 136.3, 136.2, 136.2, 136.1, 136.0, 135.8, 135.7, 130.6, 130.5,
130.2, 129.1, 129.0, 128.8, 128.6, 127.2, 127.0, 126.9, 126.8, 125.9,
125.7, 125.5, 125.3, 78.6, 78.2, 60.2, 59.5, 59.4, 59.2, 58.5, 52.6, 49.4,
49.3, 42.3, 41.8, 41.7, 41.4, 30.4, 30.1, 29.8, 29.4, 28.3, 24.9, 24.4, 22.6;
MALDI-TOF: 1075.1877 (MþNa)þ, 1091.1556 (MþK)þ; Anal. Calcd
Acknowledgements
This work was funded partly by International Foundation for
Science (IFS), Sweden; Grant No. F/4193-1, and NCL-IGIB joint

V.V.E. Ramesh et al. / Tetrahedron 68 (2012) 4399e4405
4405
Khurram, M.; Qureshi, N.; Beck, E. M.; Smith, M. D. Chem. Commun. 2007,
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search), New Delhi, for a research fellowship.
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