Chloride-Assisted Peptide Macrocyclization

Article abstract of DOI:10.1021/acs.orglett.0c00036

The role of the Cl^- anion as a templating agent for the synthesis of cyclopeptides was assessed through the preparation of three new homocyclolysines and other six cyclic peptides by head-to-tail lactamization. Isolated yields of products obtai

Full text of DOI:10.1021/acs.orglett.0c00036

pubs.acs.org/OrgLett
Letter
Chloride-Assisted Peptide Macrocyclization
§
§
́
̌
́
Nikolina Vidovic, Gordan Horvat, Davide Riva, Tamara Rinkovec, Nikola Cindro, Vladislav Tomisic,*
and Giovanna Speranza*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00036
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The role of the Cl− anion as a templating agent for the synthesis of cyclopeptides was assessed through the
preparation of three new homocyclolysines and other six cyclic peptides by head-to-tail lactamization. Isolated yields of products
obtained by chloride-templating approach were considerably higher than those gained by a cation-promoted procedure, whereby, in
some cases, only the anion-assisted synthesis yielded the desired cyclopeptides.
tarting from the isolation of the antibiotic gramicidin S, the
first biologically active cyclopeptide identified in 1944,
incorporating turn-inducing structural elements along the
polypeptide chain12 and/or by using an external template
such as metal ions.1,4 The latter approach relies on the well-
documented capacity of cyclopeptides to act as ionophores
binding metal ions in vivo and in solution.11,13−17 Several
examples of metal ion-assisted peptide macrocyclization are
known.4,18−20
Herein, we report that not only cations but also anions are
able to act as directing agents for promoting the cyclization of
linear peptides. As a part of a long-term project on
supramolecular receptors for cations and anions,21 we have
ventured into the synthesis of functionalized homocyclopep-
tides, i.e., cyclic peptides with multiple occurrences of a single
amino acid residue bearing a substituent on the side chain,
which enables the design of receptors with specific binding
properties.
S
cyclic peptides have attracted an increasing interest, because of
their unique chemical and biological properties.1−4 When the
polypeptide chain is constrained into a cyclic structure, both
reduction of the conformational flexibility and an increased
resistance to in vivo enzymatic degradation result. As a
consequence, cyclic peptides generally exhibit improved
metabolic stability and bioavailability, as well as enhanced
binding affinity and selectivity toward receptors, compared to
their more-flexible linear analogues. These features make cyclic
peptides promising lead compounds for drug discovery and
excellent tools for understanding complex biological processes
such as protein−protein and generally host−guest interac-
tions.4,5 So far, beside naturally occurring peptides comprising
a cyclic backbone, thousands of cyclic peptides have been
prepared via chemical synthesis and many of them are
endowed with potent biological activities such as antifungal,
antibacterial, antineoplastic, insecticidal, anti-inflammatory,
and melanin production inhibitory effects.2,6
However, the synthesis of cyclic peptides, especially late-
stage cyclization step, continues to represent a significant
synthetic challenge, although efforts to develop improved
methods for their preparation have grown exponentially in
recent years.1−4,7−10 Regardless of the macrocyclization
strategy, the main factor that affects the success of a ring
closure reaction is the conformational preorganization, that is
the ability of a linear precursor to bring its reactive termini in
close spatial proximity.4,11 A favorable conformation facilitating
the intramolecular cyclization process may be achieved by
To this aim, as a first approach, we prepared tetralysine,
pentalysine, and hexalysine (1−3; see Scheme 1) via the
standard solution-phase peptide synthesis, using the orthogo-
nally protected lysine derivatives (CbzHN-Lys(Boc)-COOH
and H2N-Lys(Boc)COOMe) as building blocks, and repeated
steps of condensation/deprotection as depicted in Scheme 1.
Received: January 4, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00036
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 1. Synthesis of Compounds 1−6: (a) HOBt,
EDCxHCl, TEA, DMF; (b) H2, Pd/C, EtOH; (c)
CbzLys(Boc)-OH, HOBt, EDCxHCl, TEA, DMF; and (d)
Table 1. Yields of Cyclization Reaction of the Linear
Precursors Assisted by Different Salts
a
LiOH and MeOH, Followed by H2, Pd/C, EtOH
Yield (%)
a
linear peptide
LiCl/NaCl
NaTPB
TEACl
NaClO4
b
K4 (1)
K5 (2)
K6 (3)
L5 (7)
(FLL)2 (8)
I4 (11)
I5 (12)
S5 (13)
F5 (14)
21
8
26
10
15
6
47
43
17
52
23
18
26
29
46
0
0
0
0
<5
0
c
35
c
15
c
<5
b
<5
<5
<5
c
11
0
c
21
a
a
Steps b and c were repeated two, three, and four times for tetralysine
For all linear precursors, except 13, cyclization reactions were
(1), pentalysine (2), and hexalysine (3), respectively. To prepare 4−
6, methyl ester protecting groups were not removed in step d.
performed also in the presence of TEAOAc and without the addition
of salts. The presence of cyclic products was not observed in either
case. LiCl. NaCl.
b
c
Compounds 1, 2, and 3 were submitted to cyclization under
the experimental conditions reported by Ye et al.,18,19 i.e., in
highly diluted N,N-dimethylformamide (DMF) solution (ca.
10−4 M) using 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-
4(3H)-one (DEPBT) as the coupling reagent, triethylamine
(TEA) as the base, and LiCl, NaCl, NaClO4, or sodium
tetraphenylborate (NaTPB) salts as sources of metal ions to
promote head-to-tail lactamization. The corresponding cyclic
peptides (cyclo-1, cyclo-2, and cyclo-3) were isolated in poor
to modest yields (15%−35%; see Table 1) with no
epimerization observable by nuclear magnetic resonance
(NMR) spectroscopy.
actually reacted with the linear precursors, bringing the C-
terminus and the N-terminus closer to each other. Taking into
account the recently reported chloride-templated synthesis of
pseudopeptidic macrocycles,22,23 the possible role of this anion
in promoting the amide-bond formation in the preparation of
12- to 18-membered cyclic peptides (cyclo-1−cyclo-3) can be
envisaged.
To test the hypothesis that the cyclization process is actually
promoted by the interaction of the Cl− anion with the linear
precursors, we repeated the synthesis of cyclopeptides from
compounds 1−3 and prepared six additional cyclic peptides
cyclo-7, cyclo-8, and cyclo-11−cyclo-14 (for details, see the
Supporting Information)from the corresponding linear
precursors 7 and 8 and 11−14 (Scheme 2), under the same
experimental conditions as described above, and by using
various salts (see Table 1) as the sources of the ions assisting
the ring closure.
In order to thermodynamically characterize ion-assisted
conformational preorganization, we used methyl-ester deriva-
tives 4−6 (Scheme 1) as model compounds of peptides 1−3.
Complexation affinity of linear peptide derivatives toward Li+,
Na+, and K+ cations was investigated by means of micro-
1
calorimetric and H NMR titrations in DMF.
Unexpectedly, in microcalorimetric titrations of 4−6 with
LiClO4, NaClO4, and KClO4 no significant heat effect was
observed (see Figures S7, S9−S11, and S14 in the Supporting
Information), which indicated that no binding occurred or that
the complexation reaction was isoenthalpic. Analogous results
were obtained when the same experiments were performed on
the corresponding derivatives of the linear peptides 7 and 8
(Scheme 2), i.e., the pentaleucine methyl ester (9) and Phe-
Leu-Leu-Phe-Leu-Leu methyl ester (10), both lacking
functionalized side chains (see Figures S17−S19, as well as
S22−S24 in the Supporting Information for details regarding
the synthesis of these substrates).
As reported in Table 1, the highest yields of cyclization
reactions were obtained in the presence of a strongly
coordinating anion (tetraethylammonium chloride, TEACl)
and the lowest in the presence of weakly coordinating anions
(NaTPB and NaClO4). Between these yields were those
obtained when LiCl or NaCl were used. In these cases, the
templating effect of the Cl− anion seems to be less efficient,
probably as a result of ion pairing of the anion with its
counterion.24 When cyclization experiments were conducted
using pentaphenylalanine (14) as a starting material and
TEACl, or two other chloride salts containing large inert
cationsnamely, tetrabutylammonium chloride (TBACl) and
benzyltriethylammounium chloridealmost the same yields of
the cyclic product (cyclo-14) were obtained (see Table S3 in
the Supporting Information). Finally, without added salts, or in
the presence of tetraethylammonium acetate (TEAOAc), no
formation of cyclic products was detected. Data in Table 1
indicate that, for all linear precursors, an improvement in the
cyclization yields due to the chloride-templating effect has
been observed. Such an increase is remarkable in the case of
Low binding abilities of 4−6, 9, and 10 for Na+ cations in
1
dimethylformamide (DMF) were also confirmed by H NMR
titrations. Upon the stepwise addition of sodium perchlorate to
a deuterated DMF peptide solutions, no significant change of
the chemical shifts of the ligand protons resulted (see Figures
S28 and S29 in the Supporting Information).
On the basis of these findings, the question arose as to which
species in ion-assisted cyclization by alkali metal in DMF
B
https://dx.doi.org/10.1021/acs.orglett.0c00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
thus suggesting the crucial role of the salt-induced preorgani-
zation for the successful cyclization of linear peptides.
Scheme 2. Structures of Linear Precursors 7, 8, 11−14 and
Their Methyl Esters 9, 10, and 15−18
No detectable NMR signal splitting, indicative of epimeriza-
tion, in any of recorded spectra was observed. Cyclopeptides
bearing amino acids with compact residues showed Cn
symmetry (see Figures S37−S44, S55, and S56 in the
Supporting Information), which was expected, whereas
complex proton spectra were observed for peptides having
bulky side chains such as cyclo-11−cyclo-13.28,29 These
spectra also showed significant temperature and solvent
dependences (Figure S52 and S54 in the Supporting
Information), which could be explained by slow interconver-
sion between nonsymmetrical conformers.28
The affinity of linear peptide methyl-ester derivatives 4−6, 9,
10, and 18 toward the Cl− anion was investigated by
microcalorimetric titrations in DMF using TEACl. During
calorimetric experiments, the addition of TEACl to the peptide
solution resulted in the data (see Figure 1, as well as Figures
S6, S13, S16, S21, and S26 in the Supporting Information)
from which the stability constants and complexation reaction
enthalpies and entropies were derived (see Table 2). The
the linear peptides 1 and 7 (from 8% to 47% and from 15% to
52%, going from NaTPB to TEACl, respectively), and
somewhat lower but still significant in the case of the
remaining substrates. That can be considered as particularly
important, taking into account that cyclic tetrapeptides and
pentapeptides are generally difficult to prepare and that
sequences rich in Lys(Boc) are troublesome to cyclize.12,25
The highest yield (52%) was observed for cyclo-7. This value
is far greater than that recently reported26 (3%) for a head-to-
tail macrocyclization of pentaleucine (7) in the absence of any
ion template.
Among all coupling systems tested (see Table S2 in the
Supporting Information), DEPBT, which is a reagent
frequently selected to avoid racemization,27 showed far better
results, in terms of the reaction yield. However, it is worth
noting that no cyclization occurs with DEPBT in the absence
of salt additives (Table S1 in the Supporting Information),
Figure 1. (a) Microcalorimetric titration of H2N-(LysBoc)5-OMe (5)
(c = 4.90 × 10−3 M) with TEACl (c = 0.1027 M) in DMF in the
presence of TBAClO4 (c = 0.0498 M) at θ = 25 °C; (b)
microcalorimetric titration of TBAClO4 (c = 0.0498 M) with
TEACl (c = 0.1027 M) in DMF at θ = 25 °C; and (c) dependence
of successive enthalpy change on n(Cl−)/n(H2N-(LysBoc)5-OMe
■
(5)) ratio. [Legend: ( ) measured values and () calculated values.]
C
https://dx.doi.org/10.1021/acs.orglett.0c00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Table 2. Thermodynamic Parameters for Complexation of Linear Peptides with Chloride Anions in DMF at 25 °C Determined
a
1
by Microcalorimetric and H NMR Titrations
b
peptide
log K SE
ΔrG° SE (kJ mol−1
)
ΔrH° SE (kJ mol−1
)
ΔrS° SE (J K−1 mol−1
)
1.51 0.01
1.05 0.01
1.47 0.07
1.26 0.05
1.68 0.03
1.74 0.06
−8.61 0.05
−5.99 0.06
−8.4 0.4
−7.2 0.3
−9.6 0.2
−9.9 0.3
−8.33 0.05
−12.1 0.2
−11.8 0.2
−10.8 0.1
2.50 0.09
37.3 0.2
H2N-(LysBoc)4-OMe (4)
c
4.4 0.9
2.8 0.3
6.2 0.1
1.9 0.2
2.5 0.2
43
2
H2N-(LysBoc)5-OMe (5)
H2N-(LysBoc)6-OMe (6)
H2N-(Leu)5-OMe (9)
c
c
41.7 0.4
48.7 0.3
46.0 0.1
37.6 0.2
1.459 0.008
c
2.12 0.04
2.06 0.03
1.89 0.02
H2N-(PheLeuLeu)2-OMe (10)
H2N-(Phe)5-OMe (18)
c
1.54 0.04
−8.8 0.3
a
b
c
SE = standard error of the mean (N = 3). K is given in units M−1. Obtained by H NMR titrations.
1
corresponding log K values were in the range of 1.5−2.1,
indicating that all ligands had similar affinities toward the Cl−
anion. All reactions were slightly endothermic and entropy-
driven, most probably because of the entropically favorable
anion desolvation upon its coordination by the backbone
amide groups.
The binding of the Cl− anion was also observed in 1H NMR
titrations of peptide ligands 4−6, 9, and 10 with TEACl in
DMF-d7, where significant downfield shifts of amide NH and
α-protons occurred after the addition of chloride solution (see
Figure 2, as well as Figures S30−S33 in the Supporting
Information). From the recorded 1H NMR spectra, the
stability constant of peptide-chloride complexes were deter-
mined and agreed very well with those obtained via
microcalorimetry (see Table 2).
NMR analysis clearly showed that the conformational
preorganization of linear precursors occurred upon the
addition of chloride salt. The addition of TEACl resulted in
the NOE signals of amide protons of pentaphenylalanine
methyl ester (18) showing interactions with each other and
indicating that these groups were in close proximity upon the
chloride binding (see Figure S58 in the Supporting
Information).
Note that the cyclization processes proceeded even in the
presence of bulky anions, such as tetraphenylborate (Table 1),
but with much lower yields, compared to those performed via
the addition of TEACl. That could be tentatively explained by
taking into account that interactions of linear peptide H2N−
(LysBoc)5−OMe (5) and TPB was (surprisingly) observed in
the course of the corresponding NMR titration (see Figure S34
in the Supporting Information), although the shifts of the
proton signals were much smaller than in the case of the
titration with TEACl. That indicated weak, but still existing,
interaction of tetraphenylborate with the linear peptide, which
could lead to the formation of the cyclic product.
1
Figure 2. (a) H NMR titration of H2N-(LysBoc)5-OMe (5) (c =
1.16 × 10−3 M) with TEACl (c = 0.287 M) in DMF−d7 at θ = 25 °C;
and (b) dependence of chemical shift of protons on n(Cl−)/n(H2N-
An additional indication that the Cl− ion plays a key role in
the ring closure reactions (Scheme 3) came from the study of
the corresponding macrocyclization reaction kinetics. Cycliza-
tion experiments of pentaphenylalanine (14) were performed
using an increasing concentration of TEACl (from 2 equiv to
100 equiv). Higher concentration of TEACl caused faster
macrocyclization reaction and its larger final yield, as evidenced
by both quantitative 1H NMR and TLC analysis (see Figure 3,
as well as Figures S2−S5 in the Supporting Information).
Moreover, the reaction was performed in the presence of
AgClO4 to sequester chlorides, whereby that equimolar
■
(LysBoc)5-OMe (5)) ratio. [Legend: ( ) measured values and ()
calculated values.]
amount of this salt, with respect to chlorides, was added to
the reaction mixture 4 h after mixing of the reactants. Indeed, a
substantial reduction of the reaction rate was observed, which
can be clearly seen in Figure S1 in the Supporting Information.
Moreover, the templating effect of halides other than
chloride was investigated. A significant decrease of the reaction
D
https://dx.doi.org/10.1021/acs.orglett.0c00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 3. Proposed Mechanism of the Anion-Assisted
Macrocyclization of Peptides
Figure 4. Structure of H2N-Lys(Boc)5-OMe (5)-Cl− complex
obtained by MD simulation in DMF. Carbon-bound hydrogen
atoms are omitted for the sake of clarity.
performed in the presence of different salts (LiCl, NaCl,
NaTPB, NaClO4, TEACl, TEAOAc), suggested a role of the
Cl− anion in the conformational preorganization of reactive
ends of the linear precursors. Complexation of methyl-ester
derivatives (4−6, 9, and 10) with different cations and the Cl−
anion was studied by microcalorimetric and NMR titrations,
indicating a high affinity of the compounds studied toward the
Cl− ion. These findings were strengthened by the results of
MD simulations. Although anion recognition by cyclopeptides
is well-documented30 and several examples of the use of anions
as directing agents for the synthesis of a wide range of
inorganic and organic assemblies are known,31 to the best of
our knowledge, no example of anion-templated synthesis of
cyclopeptides has been reported so far. Using this approach, in
the present work, nine cyclopeptidesthree of them being
Boc-protected homolysineswere obtained in moderate to
high yields.
Figure 3. Kinetics of cyclization of compound 14 (1.40 × 10−3 M) in
the presence of DEPBT coupling reagent (1.54 × 10−3 M) and
TEACl in DMF. The inset shows kinetic traces recorded during the
first 6 h after mixing of the reactants.
yield of cyclo-14 formation was observed going from TBACl
(74%) to TBABr (21%) and TBAI (5%) by quantitative TLC
analysis (see Table S3 in the Supporting Information). Such a
templating effect (Cl− > Br− > I−) was in agreement with the
results reported for the preparation of pseudopeptidic
macrocycles.23
Work is underway to gain more-detailed insights into the
role of cations/anions in affecting the ring closure of linear
peptides.
ASSOCIATED CONTENT
* Supporting Information
Structural characterization of chloride-peptide complexes of
ligands 4−6, 9, and 10 was also performed via molecular
dynamics (MD) simulations with explicit solvent molecules. In
these simulations, it was found that the Cl− ion was
coordinated by all backbone amide groups and N-terminal
amine group of the peptides (Table S4 in the Supporting
Information), which was experimentally corroborated by the
NOE interactions of amide protons in chloride complexes of
compound 18 (see Figure S58 in the Supporting Information).
Such binding resulted in the cyclic conformation of the linear
peptide adequate for the subsequent cyclization reaction (see
Figure 4, as well as Figures S35 and S36 in the Supporting
Information). In the course of the MD simulations of the
ligands with bound Na+ cations, complex dissociation was
observed in all cases. This indicated that the binding of the Na+
cation by the peptides was weak or nonexistent, which was in
agreement with the experimental results.
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00036.
Experimental procedures (synthesis and physicochem-
ical measurements); NMR, HRMS, and IR spectra; ITC
and 1H NMR titrations data; results of molecular
dynamics simulations (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
̀
Giovanna Speranza − Dipartimento di Chimica, Universita
degli Studi di Milano, 20133 Milano, Italy;
Email: giovanna.speranza@unimi.it
̌
́
Vladislav Tomisic − Department of Chemistry, Faculty of
Science, University of Zagreb, 10000 Zagreb, Croatia;
orcid.org/0000-0002-1191-2123; Email: vtomisic@
chem.pmf.hr
The above findings suggest that (i) Cl− ions are directly
involved in peptide folding (Scheme 3) and (ii) the
mechanism of head-to-tail cyclization suggested by Ye et al.18
should be at least partially revised.
Authors
́
̀
To conclude, head-to-tail macrocyclizations of three
homolysines (1−3) and six other peptides (7, 8, 11−14),
Nikolina Vidovic − Dipartimento di Chimica, Universita degli
Studi di Milano, 20133 Milano, Italy
E
https://dx.doi.org/10.1021/acs.orglett.0c00036
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
́
̌
́
G.; Stilinovic, V.; Kaitner, B.; Frkanec, L.; Tomisic, V. Inorg. Chem.
Gordan Horvat − Department of Chemistry, Faculty of Science,
̌
̌
́
́
2013, 52, 12702. (d) Cindro, N.; Pozar, J.; Barisic, D.; Bregovic, N.;
University of Zagreb, 10000 Zagreb, Croatia
̌
̌
̌
́
Piculjan, K.; Tomas, R.; Frkanec, L.; Tomisic, V. Org. Biomol. Chem.
2018, 16, 904. (e) Horvat, G.; Frkanec, L.; Cindro, N.; Tomisic, V.
Phys. Chem. Chem. Phys. 2017, 19, 24316.
(22) Alfonso, I.; Bolte, M.; Bru, M.; Burguete, M. I.; Luis, S. V.;
Rubio, J. J. Am. Chem. Soc. 2008, 130, 6137.
(23) Martí-Centelles, V.; Burguete, M. I.; Luis, S. V. J. Org. Chem.
2016, 81, 2143.
̀
Davide Riva − Dipartimento di Chimica, Universita degli Studi
̌
́
di Milano, 20133 Milano, Italy
Tamara Rinkovec − Department of Chemistry, Faculty of
Science, University of Zagreb, 10000 Zagreb, Croatia
Nikola Cindro − Department of Chemistry, Faculty of Science,
University of Zagreb, 10000 Zagreb, Croatia
(24) Patil, U. N.; Tembe, B. L. Mol. Simul. 2016, 42, 1193.
(25) (a) Meutermans, W. D. F.; Bourne, G. T.; Golding, S. W.;
Horton, D. A.; Campitelli, M. R.; Craik, D.; Scanlon, M.; Smythe, M.
L. Org. Lett. 2003, 5, 2711. (b) De Leon Rodriguez, L. M.; Weidkamp,
A. J.; Brimble, M. A. Org. Biomol. Chem. 2015, 13, 6906.
(26) Hill, T. A.; Lohman, R.; Hoang, H. N.; Nielsen, D. S.; Scully, C.
C. G.; Kok, W. M.; Liu, L.; Lucke, A. J.; Stoermer, M. J.; Schroeder, C.
I.; Chaousis, S.; Colless, B.; Bernhardt, P. V.; Edmonds, D. J.; Griffith,
D. A.; Rotter, C. J.; Ruggeri, R. B.; Price, D. A.; Liras, S.; Craik, D. J.;
Fairlie, D. P. ACS Med. Chem. Lett. 2014, 5, 1148.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00036
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(27) Ramu, V. G.; Bardaji, E.; Heras, M. Synthesis 2014, 46, 1481.
(28) Skropeta, D.; Jolliffe, K. A.; Turner, P. J. Org. Chem. 2004, 69,
8804.
■
This work was supported by the Croatian Science Foundation,
under Project Nos. IP-2014-09-7309 (SupraCAR) and IP-
2019-04-9560 (MacroSol), as well as by the Foundation of the
Croatian Academy of Sciences and Arts under Project
Template-assisted peptide cyclization in solution. Computa-
tional resources provided by the Isabella cluster (https://www.
srce.unizg.hr/isabella) at the Zagreb University Computing
Centre (Srce) were used for this publication.
(29) Horton, D. A.; Bourne, G. T.; Coughlan, J.; Kaiser, S. M.;
̈
Jacobs, C. M.; Jones, A.; Ruhmann, A.; Turner, J. Y.; Smythe, M. L.
Org. Biomol. Chem. 2008, 6, 1386.
(30) (a) Sharma, G. V. M.; Manohar, V.; Dutta, S. K.; Sridhar, B.;
Ramesh, V.; Srinivas, R.; Kunwar, A. C. J. Org. Chem. 2010, 75, 1087.
(b) Elmes, R. B. P.; Jolliffe, K. A. Chem. Commun. 2015, 51, 4951.
(c) Yang, D.; Qu, J.; Li, W.; Zhang, Y. H.; Ren, Y.; Wang, D. P.; Wu,
Y. D. J. Am. Chem. Soc. 2002, 124, 12410. (d) Yang, D.; Li, X.; Sha, Y.;
Wu, Y. D. Chem. - Eur. J. 2005, 11, 3005. (e) Fiehn, T.; Goddard, R.;
Seidel, R. W.; Kubik, S. Chem. - Eur. J. 2010, 16, 7241. (f) Young, P.
G.; Jolliffe, K. A. Org. Biomol. Chem. 2012, 10, 2664. (g) Butler, S. J.;
Jolliffe, K. A. Org. Biomol. Chem. 2011, 9, 3471. (h) McDonough, M.
J.; Reynolds, A. J.; Lee, W. Y. G.; Jolliffe, K. A. Chem. Commun. 2006,
2971. (i) Mungalpara, D.; Valkonen, A.; Rissanen, K.; Kubik, S. Chem.
Sci. 2017, 8, 6005. (j) Kubik, S.; Goddard, R.; Kirchner, R.; Nolting,
D.; Seidel, J. Angew. Chem., Int. Ed. 2001, 40, 2648. (k) Kubik, S.;
Goddard, R. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 5127. (l) Kubik,
S.; Goddard, R. Chem. Commun. 2000, 633. (m) Kubik, S.; Goddard,
R. J. Org. Chem. 1999, 64, 9475. (n) Kubik, S. J. Am. Chem. Soc. 1999,
121, 5846. (o) Schaly, A.; Belda, R.; García-Espana, E.; Kubik, S. Org.
Lett. 2013, 15, 6238. (p) Schnopp, M.; Ernst, S.; Haberhauer, G. Eur.
J. Org. Chem. 2009, 2009, 213. (q) Haberhauer, G.; Oeser, T.;
Rominger, F. Chem. - Eur. J. 2005, 11, 6718.
REFERENCES
■
(1) Wu, J.; Tang, J.; Chen, H.; He, Y.; Wang, H.; Yao, H.
Tetrahedron Lett. 2018, 59, 325.
(2) Zhang, R.-Y.; Thapa, P.; Espiritu, M. J.; Menon, V.; Bingham, J.-
P. Bioorg. Med. Chem. 2018, 26, 1135.
(3) Tapeinou, A.; Matsoukas, M.-T.; Simal, C.; Tselios, T.
Biopolymers 2015, 104, 453.
(4) White, C. J.; Yudin, A. K. Nat. Chem. 2011, 3, 509.
(5) Mungalpara, D.; Valkonen, A.; Rissanen, K.; Kubik, S. Chem. Sci.
2017, 8, 6005.
(6) Fagundez, C.; Sellanes, D.; Serra, G. ACS Comb. Sci. 2018, 20,
212.
(7) Lee, C.; Lam, H. Y.; Li, X. Nat. Prod. Rep. 2015, 32, 1274.
(8) De Leon Rodriguez, M.; Weidkamp, A. J.; Brimble, M. A. Org.
Biomol. Chem. 2015, 13, 6906.
(9) Davies, J. S. J. Pept. Sci. 2003, 9, 471.
(10) Lambert, J. N.; Mitchell, J. P.; Roberts, K. D. J. Chem. Soc.,
Perkin Trans. 1 2001, 0, 471.
(11) Blankenstein, J.; Zhu, J. Eur. J. Org. Chem. 2005, 2005, 1949.
(12) Thakkar, A.; Trinh, T. B.; Pei, D. ACS Comb. Sci. 2013, 15, 120.
(13) Kotynia, A.; Pap, J. S.; Brasun, J. Inorg. Chim. Acta 2018, 472, 3.
(14) Eshelman, M. R.; Aldous, A. R.; Neupane, K. P.; Kritzer, J. A.
Tetrahedron 2014, 70, 7651.
(31) (a) Vilar, R. Angew. Chem., Int. Ed. 2003, 42, 1460. (b) Young,
P. G.; Clegg, J. K.; Bhadbhade, M.; Jolliffe, K. A. Chem. Commun.
2011, 47, 463. (c) Martí-Centelles, V.; Pandey, M. D.; Burguete, M.
I.; Luis, S. V. Chem. Rev. 2015, 115, 8736.
(15) Ekman, J. V.; Kruglov, A.; Andersson, M. A.; Mikkola, R.;
Raulio, M.; Salkinoja-Salonen, M. Microbiology 2012, 158, 1106.
(16) Starck, A. M.; Sisommay, N.; Laporte, F. A.; Oros, S.; Lebrun,
C.; Delangle, P. Inorg. Chem. 2015, 54, 11557.
(17) Krzywoszynska, K.; Kozlowski, H. Dalton Trans. 2014, 43,
16207.
(18) Liu, M.; Tang, Y.-C.; Fan, K.-Q.; Jiang, X.; Lai, L.-H.; Ye, Y.-H.
J. Pept. Res. 2005, 65, 55.
(19) Ye, Y.-H.; Gao, X.-M.; Liu, M.; Tang, Y.-C.; Tian, G.-L. Lett.
Pept. Sci. 2003, 10, 571.
̈
(20) Haas, K.; Ponikwar, W.; Noth, H.; Beck, W. Angew. Chem., Int.
Ed. 1998, 37, 1086.
̌
́
́
̌
́
(21) (a) Barisic, D.; Cindro, N.; Kulcsar, M. J.; Tireli, M.; Uzarevic,
́
̌
́
K.; Bregovic, N.; Tomisic, V. Chem. - Eur. J. 2019, 25, 4695.
́
̌
̌
́
(b) Bregovic, N.; Cindro, N.; Bertosa, B.; Barisic, D.; Frkanec, L.;
Uzarevic, K.; Tomisic, V. Chem. - Eur. J. 2017, 23, 10396. (c) Horvat,
̌
́
̌
́
F
https://dx.doi.org/10.1021/acs.orglett.0c00036
Org. Lett. XXXX, XXX, XXX−XXX