Total Synthesis and Conformational Study of Callyaerin A: Anti-Tubercular Cyclic Peptide Bearing a Rare Rigidifying (Z)-2,3- Diaminoacrylamide Moiety

Article abstract of DOI:10.1002/anie.201712792

The first synthesis of the anti-TB cyclic peptide callyaerin A (1), containing a rare (Z)-2,3-diaminoacrylamide bridging motif, is reported. Fmoc-formylglycine-diethylacetal was used as a masked equivalent of formylglycine in the synthesis of the linear precursor to 1. Intramolecular cyclization between the formylglycine residue and the N-terminal amine in the linear peptide precursor afforded the macrocyclic natural product 1. Synthetic 1 possessed potent anti-TB activity (MIC₁₀₀=32 μm) while its all-amide congener was inactive. Variable-temperature NMR studies of both the natural product and its all-amide analogue revealed the extraordinary rigidity imposed by this diaminoacrylamide unit on peptide conformation. The work reported herein pinpoints the intrinsic role that the (Z)-2,3-diaminoacrylamide moiety confers on peptide bioactivity.

Full text of DOI:10.1002/anie.201712792

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Total Synthesis and Conformational Study of The Anti-tubercular
Cyclic Peptide Callyaerin A Bearing a Rare Rigidifying (Z)-2,3-
Diaminoacrylamide Moiety
Authors: Margaret Anne Brimble, Shengping Zhang, Luis De Leon
Rodriguez, Ivanhoe Leung, Greg Cook, and Paul Harris
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712792
Angew. Chem. 10.1002/ange.201712792
Link to VoR: http://dx.doi.org/10.1002/anie.201712792
http://dx.doi.org/10.1002/ange.201712792

10.1002/anie.201712792
Angewandte Chemie International Edition
COMMUNICATION
Total Synthesis and Conformational Study of The Anti-tubercular
Cyclic Peptide Callyaerin A Bearing a Rare Rigidifying (Z)-2,3-
Diaminoacrylamide Moiety
Shengping Zhang,[a] Luis M. De Leon Rodriguez,[b] Ivanhoe K. H. Leung,[a] Gregory M. Cook,[b,c] Paul
W. R. Harris[a,b] and Margaret A. Brimble*[a,b]
Dedication ((optional))
Abstract: The first synthesis of the anti-TB cyclic peptide callyaerin A
candidates given their higher target affinities and selectivity and
containing a rare (Z)-2,3-diaminoacrylamide bridging motif is reported. lower off-target effects.[4] Several naturally-occurring peptides
Fmoc-formylglycine-diethylacetal was used as a masked equivalent
of formylglycine in the synthesis of the linear precursor of callyaerin A.
Intramolecular cyclization between the formylglycine residue and the
N-terminal amine in the linear peptide precursor afforded the
macrocyclic natural product callyaerin A. Synthetic callyaerin A
possessed potent anti-TB activity (MIC100 = 32 µM) while its all-amide
congener was inactive. Variable temperature NMR studies of both the
natural product and its all amide analogue revealed the extraordinary
rigidity imposed by this diaminoacrylamide unit on peptide
conformation. The work reported herein pinpoints the intrinsic role that
the rare (Z)-2,3-diaminoacrylamide moiety confers on peptide
bioactivity.
which exhibit potent anti-TB activity have been reported, including
callyaerin A,[5] trichoderins A[6] and B,[6] lassomycin,[7] ecumicin,[8]
wollamide A[9] and teixobactin.[10] Among them, callyaerin A (1)
(Figure 1), a proline-rich cyclic peptide derived from the
Indonesian marine sponge Callyspongia aerizusa,[5] is a potent
inhibitor of M. tuberculosis (MIC100 of 6.0 µM) with no cytotoxicity
observed in human cells (IC50 > 10 μM).[5, 11] Callyaerin A (1)
features an unusual (Z)-2,3-diaminoacrylamide (DAA) unit within
the cyclic peptide, which together with the multiple Pro residues
in the sequence, influences the topology of the molecule,
potentially contributing to its remarkable bioactivity.[11] The
frequency of hydrophobic residues may also contribute to the
specificity of callyaerin A (1) against bacteria.[5] Prompted by its
unique structural features and potent anti-TB activity, we
embarked on the total synthesis of callyaerin A (1) as the first step
to explore its potential as a new anti-TB agent.
Tuberculosis (TB), a highly contagious and airborne disease
caused by Mycobacterium tuberculosis, has become one of the
leading causes of mortality worldwide. According to the WHO, in
2015 alone an estimated 10.4 million people were diagnosed with
new cases of TB infection, out of which 1.8 million people died.[1]
The situation is further aggravated by the fast-growing cases of
multi-drug-resistant (MDR) and extensively drug-resistant (XDR)
strains of M. tuberculosis, where currently-used standard
treatment with first and second line anti-TB drugs are ineffective
or require long treatment durations (>2 years) to achieve
therapeutic effect.[2] The development of novel anti-TB drugs,
however, has slowed over the past decade, with only one drug,
bedaquiline, approved for treatment of MDR-TB in the last 40
years.[3] There is a pressing need for discovery and development
of new anti-TB therapeutics.
Peptides from natural sources exhibit a wide spectrum of
bioactivities including anti-TB activity. Compared to their small
organic molecule counterparts, peptides are attractive drug
Figure 1. The structure of callyaerin A (1)
Inspired by the proposed biosynthesis[12] and previous
reports on the imino cyclization mediated synthesis of naturally
derived and synthetic peptides,[13] we envisaged that the rare DAA
moiety could be installed by reacting the aldehyde in an α-formyl
glycine (FGly) residue with an N-terminal amino group to form an
imino linkage, then followed by double-bond migration (path A,
Scheme 1). However, the synthesis of FGly-containing peptides,
such as 2, is an arduous task as highlighted in a recent review.[14]
An amenable approach is to directly oxidize the side chain
hydroxyl of Ser to an aldehyde. Unfortunately, oxidation of the Ser
residue in protected peptide 3 could not be realized (path A,
Scheme 1) possibly due to the chemical lability of FGly caused by
the acidic proton α to the carbonyl groups, similar to α-amino
[a]
S. Zhang, Ivanhoe K. H. Leung, Paul W.R. Harris, M.A. Brimble
School of Chemical Sciences, The University of Auckland,
23 Symonds St, Auckland, 1142, New Zealand
E-mail: m.brimble@auckland.ac.nz
[b]
[c]
LM De Leon Rodriguez, Gregory M. Cook, Paul W.R. Harris, M.A.
Brimble
Maurice Wilkins Centre for Molecular Biodiscovery, The University of
Auckland
Auckland, 1142, New Zealand
Gregory M. Cook
Department of Microbiology and Immunology, University of Otago,
Dunedin 9054, New Zealand
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201712792
Angewandte Chemie International Edition
COMMUNICATION
Scheme 1. Initial retrosynthesis of callyaerin A (1). R1-R8 indicate residues within the peptide ring while C1-C4 indicate residues in the peptide tail
aldehydes.[15] Alternatively, Nakazawa et al.[16] reported the
oxidation of a series of serine-containing peptides to the
corresponding peptidyl tosyl enolates that could further react with
the N-terminal amine to furnish a cyclic peptide containing a
diaminoacrylamide moiety. Use of this methodology for the
attempted oxidation/tosylation of 3 to afford the peptidyl tosyl
enolate (4) was not successful (path B, Scheme 1).
The failure of both direct and indirect oxidation protocols to
convert Ser into FGly in linear peptide 3 prompted adoption of a
new strategy. A rare building block, α-formylglycine diethylacetal
ethyl ester, has been used in the synthesis of capreomycin IB, a
naturally-occurring antibiotic encompassing an exocyclic
enediamino functionality.[17] An Nα-Fmoc protected variant of this
acetal-protected FGly (6) for solid phase peptide synthesis
(SPPS) has also been reported, highlighting the simultaneous
hydrolysis of the acetal to afford the FGly residue during peptide
cleavage.[18] We therefore decided to incorporate 6 into Fmoc-
SPPS to furnish the linear precursor of callyaerin A (2) bearing an
FGly residue after TFA-mediated peptide cleavage. Subsequent
cyclization to form the DAA moiety would then afford the natural
product directly.
containing peptide was surprisingly labile under the acidic
conditions used for peptide cleavage, resulting in a significant
amount of peptide fragment 10 (Scheme 3, found 877.6 [M+H]+,
calcd 877.6) resulting from cleavage at the FGly site. This peptide
bond scission may occur by hydrolysis of the active 4,5-
dihydrooxazole intermediate (9) generated by the nucleophilic
attack of the neighbouring carbonyl group on the formyl group of
FGly (Scheme 3). This undesirable peptide fragmentation was
minimized by reducing the cleavage reaction time (2 × 20 min),
affording the desired peptide 2 in high yield (87%) with less than
5% of by-product 10. The crude product 2 was then directly
subjected to the subsequent cyclization.
Peptide 2 was thus synthesized on Rink amide aminomethyl
polystyrene resin using Fmoc-SPPS (Scheme 2). All the amino
acids, except FGly(OEt)2-OH, were coupled using O-(7-
azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) as the coupling reagent. The
coupling of FGly(OEt)2-OH, on the other hand, was accomplished
employing
diisopropylcarbodiimide
a
mixture of
Fmoc-FGly(OEt)2-OH, N,N’-
and 6-chloro-1-
(DIC)
hydroxybenzotriazole (6-Cl-HOBt) in DMF. These base-free
coupling conditions minimized epimerization at the α position of
Fmoc-FGly(OEt)2-OH.[17]
After peptide chain assembly, the linear peptide was
released by treating the resin with 95% TFA in water (v/v).
Commonly-used silanes and thiol-based scavengers, e.g. iPr3SiH
and 1,2-ethanedithiol, are not compatible with the cleavage of
peptides containing FGly due to the reactivity of aldehydes with
nucleophiles.[18] Furthermore, we observed that the FGly-
Scheme 2. Synthetic route to callyaerin A (1). Reagents and conditions: (i) 20%
piperidine in DMF (v/v), RT, 2 × 5 min; (ii) iterative Fmoc SPPS (Fmoc-amino
acid (4 equiv.), HATU (3.9 equiv.), DIPEA (8 equiv.), DMF, RT, 40 min; 20%
piperidine in DMF (v/v), RT, 2 × 5 min); (iii) 6 (2 equiv.), DIC (2 equiv.), 6-Cl-
HOBt (2 equiv.), RT, 1 h; (iv) TFA/H2O (95:5, v/v), RT, 2× 20 min; (v) 1% formic
acid (v/v) in acetonitrile, anhydrous MgSO4(100 equiv.), RT, 10 h.
This article is protected by copyright. All rights reserved.

10.1002/anie.201712792
Angewandte Chemie International Edition
COMMUNICATION
The 1H and 13C NMR data for synthetic 1 agreed with those
reported for the natural product[5] (Table S1 in the Supporting
Information). Moreover, the successful establishment of the Z
configuration for the DAA unit was confirmed by the identical
chemical shift (7.35 ppm) and coupling constant (13.2 Hz) for the
β proton in the DAA moiety (Table S1 in the supporting
information).[5]
For comparison purposes, we also prepared a homodetic
analogue of callyaerin A (12), in which the FGly residue was
substituted with an Asp enabling formation of a lactam linkage
with the N-terminus (Scheme 4). The linear precursor of 12 (14)
was prepared using Fmoc-SPPS and a solution-phase cyclization
under high dilution (0.37 mM) then gave 12 in good yield (68%)
(Scheme 4).
Scheme 3. Proposed mechanism for fragmentation at FGly site.
Formation of the rare DAA unit in the cyclic peptide is the key
step to access callyaerin A (1). Traditionally, formation of an
enamine functionality can be achieved through acid-catalyzed
reaction of an amine with an aldehyde in water.[13c] Moreover, the
cyclization needs to be performed under high dilution in order to
prevent the intermolecular reaction. We therefore investigated
this reaction using a mixture of linear peptide and anhydrous
MgSO4 in acetonitrile at a peptide concentration of 0.75 mM with
several organic acids at different concentrations. Peptides
containing FGly were not stable in the presence of strong acid
(TFA, pKa = 0.3) or moderately strong acid (camphorsulfonic acid
(CSA, pKa = 1.2) as varying levels of peptide fragment (10) were
obtained (Figure 2). A lower concentration of acid (1% TFA vs
10% TFA) mitigated this undesirable fragmentation, but the
amount of peptide fragment (10) still increased over an extended
reaction time. Fortunately, use of weaker 1% formic acid (pKa =
3.7) showed favourable catalysis, shortening the reaction time to
10 h and effecting almost quantitative peptide cyclization with little
peptide fragmentation. Pleasingly, solution-phase peptide
cyclization performed using 1% formic acid (v/v) afforded
callyaerin A (1) in 81% yield after isolation by HPLC.
Scheme 4. Synthetic route to the homodetic analogue of callyaerin A (12).
Reagents and conditions: (i) 20% piperidine in DMF (v/v), RT, 2 × 5 min; (ii)
iterative Fmoc SPPS (Fmoc-amino acid (4 equiv.), HATU (3.9 equiv.), DIPEA (8
equiv.), DMF, RT, 40 min; 20% piperidine in DMF (v/v), RT, 2 × 5 min); (iii)
TFA/H2O/iPr3SiH (95:2.5:2.5, v/v/v), RT, 1 h; (iv) HBTU (3 equiv.), 6-Cl-HOBt (3
equiv.), DIPEA (5 equiv.), CH2Cl2/DMF (9:1) RT, 1 day.
Cyclic peptides 1 and 12 were tested in vitro for their anti-TB
activity in order to elucidate the role of the (Z)-2,3-
diaminoacrylamide on bioactivity. Callyaerin A (1) exhibited
inhibitory activity against M. tuberculosis (MIC100 = 32 μM), which
was 5-fold higher than the reported MIC100 data (6 μM).[11] The
homodetic analogue (12) did not exhibit any inhibitory activity up
to a concentration of 512 μM. This dramatic difference in
biological activity may be attributed to subtle variations in peptide
conformation, thus prompting further investigation of their
conformational properties.
Using variable temperature 1H NMR, we established a
comprehensive profile of the temperature-chemical shift
coefficients (Tcoeff) for all the amide protons in callyaerin A (1) from
which the intramolecular hydrogen-bonding pattern was deduced.
The Tcoeff index that was proposed by H. Kessler for peptides in
DMSO-d6 was used.[19] As opposed to the τ chemical shift scale
that was used in reference 19, the conventional δ chemical shift
scale was used in this study (i.e. Tcoeff = Δδ/ΔT = -Δτ/ΔT). Figure
3a shows the aligned 1H NMR spectra of callyaerin A (1) recorded
from 20 °C to 45 °C and the corresponding Tcoeff value calculated
Figure 2. Composition of peptide cyclization reaction using acids with different
pKa and concentration. Data was determined by integration of the HPLC peaks
of the corresponding reaction mixture at a wavelength of 210 nm; linear gradient
of 5%B-95%B over 30 min (ca. 3%B/min), 1 mL•min-1, using an XTerra MS C18
column (4.6 mm × 150 mm, 5 µm). A = 0.1% TFA in H2O and B = 0.1%TFA in
MeCN. Reagents and conditions: 2 (2 mg, 1.4 μmol), anhydrous MgSO4 (17.5
mg, 140.5 μmol), MeCN (1.9 mL), acids (19 or 190 μL), RT, 10 h.
This article is protected by copyright. All rights reserved.

10.1002/anie.201712792
Angewandte Chemie International Edition
COMMUNICATION
Figure 3. Variable temperature 1H NMR (500 MHz, DMSO-d6) analysis of callyaerin A (1) and its homodetic counterpart (12). (a) The 1H NMR spectra of 1 recorded
between 20 and 45 °C and the corresponding Tcoeff values calculated for all the amide protons; (b) The 1H NMR spectra of 12 recorded between 25 and 80 °C. Only
the amide region is shown.
for each amide proton. Two amide protons exhibit a Tcoeff value
that is between -2 and 0 ppb/K (DAA and C2Ile), indicating they
participate in intramolecular H-bond interactions. In addition, two
amide protons exhibit a Tcoeff value between −4 and -2 ppb/K (R4Ile
and R5Leu), thus indicating a potential tendency to participate in
H-bond interactions.[19] Interestingly, the positive Tcoeff values for
the amide protons of C3Phe and R8Leu were observed. This may
be caused by the deshielding effect of the aromatic ring of C3Phe
to the R8Leu amide proton. Thus, the amide proton of R8Leu may
be oriented above the side chain of C3Phe, forming an pseudo H-
bonding interaction with the π-electron cloud of aromatic ring.[20]
By way of contrast, the 1H NMR spectra of the lactam
analogue of callyaerin A (12) recorded at different temperatures
were more complex. The number of amide resonances exceeded
the number of amide protons present in 12, which may be
attributed to multiple exchanging rotamers. The peptide adopted
multiple conformations that were in slow transition at 298 K
(Figure 3b). As the temperature increased, the exchange rate
between the different conformers was accelerated and the peaks
became broader, indicating that the transition regime switched
from slow to slow-intermediate exchange. However, the proton
signals remained broad even when the temperature increased to
80 °C. We reasoned that a much higher temperature would be
required to force the peptide into fast exchange, which was not
available with our instrumentation.
conformational stabilizing effect may account for the large
difference in bioactivity between 1 and 12.
In summary, we have developed the first efficient route for
the synthesis of callyaerin A (1), a potent anti-tubercular cyclic
peptide featuring a rare (Z)-2,3-diaminoacrylamide moiety. Fmoc-
FGly(OEt)2-OH was incorporated into SPSS as a masked form of
an FGly residue. After careful peptide cleavage using optimized
conditions that minimized undesired peptide fragmentation, the
linear peptide was successfully cyclized using dilute acid to effect
intramolecular
acid-catalyzed
enamine formation.
The
spectroscopic data for the synthetic compound was consistent
with the reported data for the natural product. The potent anti-TB
activity of 1 contrasted with the homodetic analogue 12 which was
inactive. Finally, a variable temperature NMR study of 1 and 12
demonstrated the high conformational rigidity imposed by the (Z)-
2,3-diaminoacrylamide linkage on the peptide structure. The
significant influence that peptide conformation confers on
observed bioactivity highlights the potential use of the (Z)-2,3-
diaminoacrylamide unit as
a
novel cyclic constraint to
complement existing conformational constraining methodologies
(e.g. amide cyclization, disulfide cyclization and stapling) to
improve the properties of bioactive peptides.
Acknowledgements
Comparing the spectra of 1 and its lactam analogue 12, it is
clear that 1 was present as a single conformer in solution,
stabilized by a 2-4 intramolecular hydrogen bonds, while its
lactam counterpart 12 existed as multiple conformations in
solution probably due to the lack of appropriate structural
The authors are grateful for financial support from the Maurice
Wilkins Centre for Molecular Biodiscovery and a PhD scholarship
from the China Scholarship Council (S. Z.).
constraints.
Furthermore,
the
non-canonical
(Z)-2,3-
Keywords: peptides • diaminoacrylamide • cyclization •
formylglycine • conformational constraints
diaminoacrylamide linkage in the cyclic peptide 1 conferred
extraordinary structural rigidity to the peptide conformation that
was not evident in the homodetic analogue 12 and this unusual
This article is protected by copyright. All rights reserved.

10.1002/anie.201712792
Angewandte Chemie International Edition
COMMUNICATION
[1]
Global Tuberculosis Report 2016; World Health Organization:
Geneva, Switzerland, 2016
[2]
[3]
[4]
M. V. Nora de Souza, Fitoterapia 2009, 80, 453-460.
R. Mahajan, Int. J. Appl. Basic Med. Res. 2013, 3, 1.
D. J. Craik, D. P. Fairlie, S. Liras, D. Price, Chem. Biol. Drug Des.
2013, 81, 136-147.
[5]
[6]
[7]
[8]
S. R. M. Ibrahim, C. C. Min, F. Teuscher, R. Ebel, C. Kakoschke, W.
Lin, V. Wray, R. Edrada-Ebel, P. Proksch, Bioorg. Med. Chem. 2010,
18, 4947-4956.
P. Pruksakorn, M. Arai, N. Kotoku, C. Vilchèze, A. D. Baughn, P.
Moodley, W. R. Jacobs, M. Kobayashi, Bioorg. Med. Chem. Lett.
2010, 20, 3658-3663.
E. Gavrish, C. S. Sit, S. Cao, O. Kandror, A. Spoering, A. Peoples,
L. Ling, A. Fetterman, D. Hughes, A. Bissell, Chem. Biol. 2014, 21,
509-518.
W. Gao, J.-Y. Kim, J. R. Anderson, T. Akopian, S. Hong, Y.-Y. Jin,
O. Kandror, J.-W. Kim, I.-A. Lee, S.-Y. Lee, Antimicrob. Agents
Chemother. 2015, 59, 880-889.
[9]
Z. G. Khalil, A. A. Salim, E. Lacey, A. Blumenthal, R. J. Capon, Org.
Lett. 2014, 16, 5120-5123.
[10]
a) L. L. Ling, T. Schneider, A. J. Peoples, A. L. Spoering, I. Engels,
B. P. Conlon, A. Mueller, T. F. Schäberle, D. E. Hughes, S. Epstein,
Nature 2015, 517, 455-459; b) L. M. De Leon Rodriguez, H. Kaur,
M. A. Brimble, Org. Biomol. Chem. 2016, 14, 1177-1187.
G. Daletos, R. Kalscheuer, H. Koliwer-Brandl, R. Hartmann, N. J. de
Voogd, V. Wray, W. Lin, P. Proksch, J. Nat. Prod. 2015, 78, 1910-
1925.
[11]
[12]
[13]
D. Pappo, M. Vartanian, S. Lang, Y. Kashman, J. Am. Chem. Soc.
2005, 127, 7682-7683.
a) S. Enck, F. Kopp, M. A. Marahiel, A. Geyer, ChemBioChem 2008,
9, 2597-2601; b) S. Enck, F. Kopp, M. A. Marahiel, A. Geyer, Org.
Biomol. Chem. 2010, 8, 559-563; c) L. R. Malins, J. N. deGruyter, K.
J. Robbins, P. M. Scola, M. D. Eastgate, M. R. Ghadiri, P. S. Baran,
J. Am. Chem. Soc. 2017, 139, 5233-5241.
[14]
S. Zhang, L. M. Rodriguez, P. W. R. Harris, M. A. Brimble, Asian J.
Org. Chem. 2017, 6, 1180-1190.
[15]
[16]
J. Jurczak, A. Golebiowski, Chem. Rev. 1989, 89, 149-164.
aT. Nakazawa, T. Suzuki, M. Ishii, Tetrahedron Lett. 1997, 38, 8951-
8954; bY. Kogon, L. Goren, D. Pappo, A. Rudi, Y. Kashman, Eur. J.
Org. Chem. 2009, 2009, 1852-1854.
[17]
D. E. DeMong, R. M. Williams, J. Am. Chem. Soc. 2003, 125, 8561-
8565.
[18]
[19]
[20]
J. Rush, C. R. Bertozzi, Org. Lett. 2006, 8, 131.
H. Kessler, Angew. Chem. Int. Ed. 1982, 21, 512-523.
J. B. Mitchell, C. L. Nandi, I. K. McDonald, J. M. Thornton, S. L. Price,
J. Mol. Biol. 1994, 239, 315-331.
This article is protected by copyright. All rights reserved.

10.1002/anie.201712792
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Callyaerin A, an anti-tuberculosis
macrocyclic peptide containing a rare
Shengping Zhang, Luis M. De Leon
Rodriguez,
Ivanhoe K. H. Leung,
(Z)-2,3-diaminoacrylamide
moiety,
Gregory M. Cook, Paul W.R. Harris and
Margaret A. Brimble*
was synthesized in high yield using an
uncommon building block, Fmoc-
formylglycine-diethylacetal. Variable
temperature NMR studies revealed the
high conformational rigidity the (Z)-2,3-
diaminoacrylamide moiety confers on
peptide structure, thus highlighting its
potential as a novel conformation-
constraining structural element.
Page No. – Page No.
Total Synthesis and Conformational
Study of The Anti-tubercular Cyclic
Peptide Callyaerin A Bearing a Rare
Rigidifying (Z)-2,3-
Diaminoacrylamide Moiety
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
((Insert TOC Graphic here))
Page No. – Page No.
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.