Conformation-Enabled Total Syntheses of Ohmyungsamycins A and B and Structural Revision of Ohmyungsamycin B

Article abstract of DOI:10.1002/anie.201711286

The first total syntheses of the bioactive cyclodepsipeptides ohmyungsamycin A and B are described. Key features of our synthesis include the concise preparation of a linear cyclization precursor that consists of N-methyl amides and non-proteinogenic amino acids, and its macrolactamization from a bent conformation. The proposed structure of ohmyungsamycin B was revised based on its synthesis. The cyclic core of the ohmyungsamycins was shown to be responsible for the excellent antituberculosis activity, and ohmyungsamycin variants with truncated chains were evaluated for their biological activity.

Full text of DOI:10.1002/anie.201711286

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Conformationally-Inspired Total Syntheses of Ohmyungsamycins
A and B and Structural Revision of Ohmyungsamycin B
Authors: Joonseong Hur, Jaebong Jang, Jaehoon Sim, Woo Sung
Son, Hee-Chul Ahn, Tae Sung Kim, Yern-Hyerk Shin,
Changjin Lim, Seungbeom Lee, Hongchan An, Seok-Ho Kim,
Dong-Chan Oh, Eun-Kyeong Jo, Jichan Jang, Jeeyeon Lee,
and Young-Ger Suh
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711286
Angew. Chem. 10.1002/ange.201711286
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10.1002/anie.201711286
Angewandte Chemie International Edition
COMMUNICATION
Conformationally-Inspired Total Syntheses of Ohmyungsamycins
A and B and Structural Revision of Ohmyungsamycin B
Joonseong Hur,[a] Jaebong Jang,[a] Jaehoon Sim,[a][b] Woo Sung Son,[b] Hee-Chul Ahn,[c] Tae Sung
Kim,[d] Yern-Hyerk Shin,[e] Changjin Lim,[a][b] Seungbeom Lee,[a] Hongchan An,[a] Seok-Ho Kim,[b] Dong-
Chan Oh,[e] Eun-Kyeong Jo,[d] Jichan Jang,[f] Jeeyeon Lee,[a] and Young-Ger Suh*[a][b]
Abstract: The first total syntheses of bioactive cyclodepsipeptides
ohmyungsamycin A and B have been achieved. The key features of
our synthesis involve the concise preparation of the linear cyclization
precursor, which consists of N-methyl amides and non-proteinogenic
OMS-A (1), as shown in Figure 1. Primary screening of the
biological activities of the OMSs revealed potent cytotoxicity
against various cancer cell lines and antibacterial activities with a
narrow spectrum.[4]
amino
acids,
and
a
bent
conformationally-inspired
More recently, the Pauli group identified ecumicin (3), which
interestingly shares the same cyclic core as the OMSs.[5] The side
chain of antituberculotic (anti-TB) ecumicin[6] possesses a non-
ribosomal amino acid (NMe-L-allo-Ile11), which is extended to the
side chain of OMS-B. Recently, OMSs were reported to exhibit
strong anti-TB activity based on promotion of host cell
autophagy,[7] which is an innate immune system targeting
intracellular bacteria,[8] via an AMP-activated protein kinase
pathway activation.
macrolactamization. The revised structure of ohmyungsamycin B was
established by our synthesis. The cyclic core of the
ohmyungsamycins that is responsible for the excellent anti-TB activity
was also elucidated via our synthesis and biological evaluation of a
chain-truncated variant of the ohmyungsamycins.
Non-ribosomal cyclic peptides[1] belong to a major class of
macrocyclic molecules that possess a variety of biological
activities.[2] As structurally complex cyclopeptides have been
identified, many synthetic hurdles, such as the preparation of non-
proteinogenic amino acid, N-methyl amide formation, and
macrocyclization, have been overcome by synthetic chemists.[3]
Recently, novel cyclodepsipeptides, ohmyungsamycins (OMSs)
A (1) and B (2) have been reported from Streptomyces genus
strain.[4] Both natural products share a cyclic peptide core that
consists of ten L-amino acids including two non-proteinogenic
(4MeO-L-Trp4 and L-βHyPhe2) and four N-methylated amino acids.
Both OMSs possess the L-Val11-L-Val12 dipeptide side chain
appended to the core macrocycle, and OMS-B (2) possesses an
N,N-dimethyl valine rather than the terminal N-methyl valine of
[a]
J. Hur, Dr. J. Jang, Dr. J. Sim, Dr. C. Lim, Dr. S. Lee, Dr. H. An,
Prof. Dr. J. Lee, Prof. Dr. Y.-G. Suh
College of Pharmacy, Seoul National University
1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
E-mail: ygsuh@snu.ac.kr / ygsuh@cha.ac.kr
Dr. J. Sim, Prof. Dr. W. S. Son, Dr. C. Lim, Prof. Dr. S.-H. Kim, Prof.
Dr. Y.-G. Suh
College of Pharmacy, CHA University
120 Haeryong-ro, Pocheon, Gyeonggi-do 11160, Republic of Korea
Prof. Dr. H.-C. Ahn
Department of Pharmacy, Dongguk University
Dongguk-ro 32, Ilsandong-gu, Goyang, Geonggi-do 10326, Republic
of Korea
Dr. T. S. Kim, Prof. Dr. E.-K. Jo
Department of Microbiology
Chungnam National University School of Medicine
Munhwa-ro 266, Jungku, Daejeon 35015, Republic of Korea
Y.-H. Shin, Prof. Dr. D.-C. Oh
Natural Products Research Institute, College of Pharmacy,
Seoul National University
1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
Prof. Dr. J. Jang
Division of Applied Life Science, Research Institute of Life Science
Gyeongsang National University, Jinju 52828, Republic of Korea
Figure 1. Reported structures of ohmyungsamycins A and B and ecumicin.
[b]
[c]
[d]
[e]
[f]
Based on the unique structural features and interesting biological
activities of OMS-A and OMS-B, we have been interested in
establishing a synthetic route to these macrolactams. Herein, we
report the first total syntheses of OMS-A (1) and OMS-B (2;
proposed structure) as well as the structural revision of OMS-B.
In addition, we elucidated the core of the OMSs that is responsible
for the biological activities based on our synthesis and biological
evaluation of the side chain-truncated OMS (4; Δ10N-Ac
ohmyungsamycin).
Our retrosynthetic analysis is outlined in Figure 2. We envisioned
that OMS-B (2) could be obtained from OMS-A (1) by
chemoselective and reductive methylation of the terminal
monomethylamine. We paid special attention to the
macrocyclization site,[9] because OMSs are highly congested with
bulky amino acids including Val, Leu, 4MeO-Trp, and N-methyl
amino acids. Structures of OMSs with only L-form amino acids
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201711286
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COMMUNICATION
may also limit the key macrocyclization.[9, 10] Importantly, the solid-
state 3D structure of ecumicin (3) revealed a twisted β-sheet in
the cyclic core, which was stabilized by four interstrand hydrogen
bonds and two n→π* interactions (Figure 1).[11] Based on these
conformation-stabilizing factors, we considered the four amino
acid sequence from Val3 to Val6 as a potential turn inducer, which
may induce an overall bent conformation in the linear cyclization
precursor.[12] Based on the structural similarity between ecumicin
and the OMSs, we anticipated that the conformational character
of the cyclic core could be utilized in the syntheses of OMSs.
adopted palladium-catalyzed annulation.[14] Initially, the known
homoallylglycine methyl ester 5[14c] was converted to the bulky 2-
(trimethylsilyl)ethyl (TMSE) ester 6 (77% for two steps) to avoid
facile 2,5-diketopiperazine (DKP) formation[15] during the second
amidation. Unfortunately, the 4MeO-Trp intermediate 7 did not
undergo amidation with valine, which is most likely due to high
steric hindrance. Therefore, homoallylglycine
6 was first
converted to tripeptide 11 with the assistance of DEPBT[16] (49%
for four steps) and then sequential dihydroxylation and oxidative
cleavage of the terminal olefin of 11 followed by Pd(OAc)2
catalyzed annulation of the resulting aldehyde 12 afforded
tripeptide 9 possessing the 4MeO-indole moiety in 59% yield.
Scheme 1. Reagents and conditions: a) LiOH, THF/H2O; b) TMSEOH, EDC,
DMAP, CH2Cl2, 77% for 2 steps, c) 0.1 M OsO4 in toluene, NMO, THF/H2O; d)
NaIO4, THF/H2O; e) 2-iodo-3-methoxyaniline, Pd(OAc)2, DABCO, DMF, 100 oC
48% for 3 steps, f) TFA, CH2Cl2; g) Boc-NMe-L-Val-OH, DEPBT, DIPEA, CH2Cl2,
69% for 2 steps, h) TFA, CH2Cl2; i) Boc-L-Val-OH, DEPBT, DIPEA, CH2Cl2, 71%
for 2 steps, j) 0.1 M OsO4 in toluene, NMO, THF/H2O; k) NaIO4, THF/H2O, 90%
for 2 steps, l) 2-iodo-3-methoxyaniline, Pd(OAc)2, DABCO, DMF, 100 °C, 59%.
With the tripeptide fragment 9 in hand, we turned our attention to
the synthesis of tetrapeptide fragment 16 as shown in Scheme 2.
To avoid facile DKP formation upon sequential elongation from
the C-terminal NMe-Leu7 residue, we prepared tripeptide 15 from
Boc-NMe-L-Thr(OBn)-OH 13 (63% for three steps) under the
optimized coupling conditions. Deprotection of 15 and DEPBT
mediated coupling of the resulting free acid with H-NMe-L-Leu-
OAllyl provided tetrapeptide 16 in 83% yield for the two steps.
The syntheses of cyclopeptides 1, 2, and 4 are described in
Scheme 3. Dipeptides 17 and 19 were conveniently prepared via
Figure 2. Retrosynthetic analysis of ohmyungsamycins A and B.
Therefore, we selected the cyclization site opposite to the
potential turn inducer which may exploit the folded structure for
the macrocyclization. Esterification of Val1 and Thr10 and N-methyl
amide formation of Thr9 and Thr10 were precluded due to the low
reactivity in the macrocyclization.[9, 13a] Amidation of Val8 and Thr9
was also not considered due to potential steric hindrance caused
by inevitable protection of the Thr9 hydroxyl group during the
synthesis of the southern fragment. Therefore, we focused on
amidation of Val1 and βHyPhe2, which appeared to be the most
suitable ring-closing site. Indeed, macrocyclizations by
esterification or amidation at other sites were not successful or
provided the desired product in low yield (Scheme S1-S3). We
planned to extend the side chain during the preparation of the
southern part to avoid possible intramolecular O to N acyl shift[13]
even though direct attachment of the side chain to the macrocyclic
core would be ideal for further modifications.
a
standard peptide coupling procedure. The northern
pentapeptide 18 was easily assembled in 95% yield by
deprotection of tripeptide 9 and dipeptide 17 followed by a
1
DEPBT-mediated amidation. Interestingly, the H-NMR spectra
revealed that the rotarmeric mixture of tripeptide 9, which
consisted of contiguous N-methyl amides, became a single
isomer 18. In addition to this observation, the hydrogen-deuterium
exchange experiments[17] and molecular modeling based on the
exchange experiments and NOE study (See supporting
information) implied the turn-inducing effect of pentapeptide 18,
as shown in Scheme 3, in the solution state as previously
mentioned in the retrosynthesis.
Synthesis of the 4MeO-L-Trp containing tripeptide 9, which is the
most sterically encumbered fragment, is shown in Scheme 1. To
incorporate the methoxy substituted indole ring moiety, we
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10.1002/anie.201711286
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The free amine prepared by Boc-deproptection of 16 and the free
acid liberated from 19 by allyl-deprotection was coupled by
DEPBT-mediated amidation to afford hexapeptide 20 in 72%
overall yield from 16. Independently, the structural variation of the
southern part was carried out by introducing a new side chain on
Thr10. Amidation of the free amine prepared from 16 by Ac2O
treatment in DMF provided tetrapeptide 21 in 68% yield from 16.
Esterification of hydroxyl peptides 20 and 21 with Boc-Val-OH
smoothly proceeded under the reaction conditions (i.e., EDC,
DMAP, and HOAt in CH2Cl2) to afford 22 in 97% yield and 23 in
98% yield, respectively.
The final fragment assembly for the full-length dodecapeptide 24
suffered from rapid epimerization at the Cα position of Leu7.[9a]
Based on examination of a variety of coupling conditions, we
finally obtained 24 in 56% yield along with epi-24 by portionwise
addition of EDC into a mixture of deprotected 18 and 22, DIPEA,
and HOAt in CH2Cl2 at 0 °C. Decapeptide 25 was prepared under
the same reaction conditions as 24 in 50% yield.
Allyl deprotection of 24 and 25 with Pd(0) and PhNHMe followed
by careful Boc-deprotection with iPr3SiH in TFA/CH2Cl2 (1:10)
afforded the corresponding amino-acid TFA salts, which were
subjected to macrocyclization under high-dilution conditions (0.5
mM).[18] Dichloromethane was crucial for successful ring closure.
The cyclodimer and cyclotrimer were produced regardless of the
coupling reagent (e.g., EDC, HATU, PyBOP and DEPBT) when
DMF was used as a solvent, which was most likely due to the high
dielectric solvent preventing the formation of the hydrogen
bonding-induced bent conformation.[19]
Scheme 2. Reagents and conditions: a) H-L-Val-OAllyl, EDC, DIPEA, Oxyma,
DMF, 93%, b) TFA, CH2Cl2; c) Boc-L-Thr-OH, HATU, DIPEA, HOAt, DMF, 67%
for 2 steps, d) Pd(PPh3)4, PhNHMe, THF; e) H-NMe-L-Leu-OAllyl, DEPBT,
DIPEA, CH2Cl2, 83% for 2 steps.
After intensive optimization of the macrolactamization conditions,
the desired cyclopeptide 26 was obtained in 42% yield for three
steps via slow addition of the linear substrate into a CH2Cl2
solution containing PyBOP and DIPEA. Cyclization of 25
proceeded more smoothly to afford cyclopeptide 27 in 69% yield
for three steps. The increased yield was likely due to the reduced
steric effect of the side chain. Finally, hydrogenolytic deprotection
of 26 and 27 produced OMS-A (1) and the side chain-truncated
OMS (4) in 97% and 68% yield, respectively. For the synthesis of
OMS-B (2), a new methyl substituent was directly introduced onto
the terminal amine of 1 via reductive methylation[20] in 71% yield.
Scheme 3. Reagents and conditions: a) TFA, CH2Cl2; b) TBAF, THF; c) DEPBT, DIPEA, CH2Cl2, 95% from 9, d) Pd(PPh3)4, PhNHMe, THF; e) TFA, CH2Cl2; f)
DEPBT, DIPEA CH2Cl2, 72% from 16, g) Ac2O, DMF, 68% from 16, h) Boc-L-Val-OH, EDC, DMAP, HOAt, CH2Cl2, 97% for 22, 98% for 23, i) TFA, CH2Cl2; j)
Pd(PPh3)4, PhNHMe, THF; k) EDC, DIPEA, HOAt, CH2Cl2, 56% for 24, 50% for 25, l) Pd(PPh3)4, PhNHMe, THF; m) TFA, iPr3SiH, CH2Cl2; n) PyBOP, DIPEA,
CH2Cl2 (0.5 mM), 42% for 26, 69% for 27, o) Pd(OH)2, H2, MeOH, 97% for 1, 68% for 4, p) aq. HCHO, NaBH3CN, DMF/AcOH (10:1), 71%
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10.1002/anie.201711286
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COMMUNICATION
All spectroscopic data of synthetic OMS-A (1) were exactly
matched with the reported data. The structure of the new
cyclopeptide 4 was also confirmed by careful analysis of the
spectral data. Importantly, the JH-H coupling constants and major
through-space correlation measured by the ROESY experiment
were consistent with the reported data for 1,[4] supporting the role
of the cyclic core in maintaining a stable 3D structure regardless
of the side chain (Table S2 and Figure S3).
readily proceeded under the previously optimized conditions to
afford 28 in 6% overall yield from Boc-L-Ile as outlined in Scheme
4. To our delight, the spectral data of this synthetic OMS-B (28)
matched the reported data (Table S4 and Figure S9). We further
confirmed the absolute configuration of Ile in natural OMS-B by
the HPLC analysis of GITC[21] (2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl isothiocyanate) derivatives of Ile in natural OMS-
B and authetic L-Ile, L-allo-Ile, D-Ile, and D-allo-Ile (Figure S10).
(A)
(B)
0.3
0.15
0
-0.15
-0.3
10
5
0
-5
-10
(C)
(D)
0.3
0.15
0
-0.15
-0.3
10
5
0
-5
-10
Figure 3. Chemical structure of the proposed and revised OMS-B (top, Aa:
amino acid). Side chain chemical shift comparison between OMS-A and natural
or synthetic OMS-B (bottom). (A) Comparison of 1H NMR spectra for OMS-A (1)
and synthetic OMS-B (2); (B) Comparison of 13C NMR spectra for OMS-A (1)
and synthetic OMS-B (2); (C) Comparison of 1H NMR spectra for OMS-A (1)
and natural OMS-B; (D) Comparison of 13C NMR spectra for OMS-A (1) and
natural OMS-B. Y axis indicates Δδ (OMS-A – OMS-B, ppm)
Scheme 4. Reagents and conditions: a) AllylBr, K2CO3, DMF; b) TFA, CH2Cl2;
c) Cbz-NMe-L-Val-OH, EDC, DIPEA, HOAt, CH2Cl2, 68% for 3 steps, d)
Pd(PPh3)4, PhNHMe, THF; e) TFA, CH2Cl2; f) DEPBT, DIPEA CH2Cl2, g) Boc-
L-Val-OH, EDC, DMAP, HOAt, CH2Cl2, 66% from 16, h) TFA, CH2Cl2; i)
Pd(PPh3)4, PhNHMe, THF; j) EDC, DIPEA, HOAt, CH2Cl2, 36% from 31, k)
Pd(PPh3)4, PhNHMe, THF; l) TFA, iPr3SiH, CH2Cl2; m) PyBOP, DIPEA, CH2Cl2
(0.5 mM) 39% for three steps, n) Pd(OH)2, H2, MeOH, 90%
Unexpectedly, the spectral data of the synthetic OMS-B (2) were
After complete syntheses of OMS-A (1), Δ10N-Ac OMS (4), and
structurally revised OMS-B (28), we evaluated their anti-TB
activities, which are summarized in Table 1. As expected, the
synthetic OMS-A exhibited nearly the same potency (MIC50: 33.3
nM) compared to the previously reported one (MIC50: 57 nM).[7]
Interestingly, both the proposed (2) and revised OMS-B (28)
exhibited comparable anti-TB activities. It is important to note that
the side chain-truncated OMS-A (4) also exhibited good anti-TB
activity (MIC50: 740 nM), which is still more potent than ethambutol
(MIC50: 3.1 μM). These results support the crucial role of the cyclic
core for anti-TB activity as well as the significant beneficial effects
of the side chain.
not identical to those of natural OMS-B, except for the mass
1
spectroscopic data. In particular, the H and 13C NMR spectra
corresponding to the side chain were quite different (Table S3 and
Figure S4). As shown in Figure 3, a comparison of the spectral
data for the natural OMS-A with those to the synthetic (Figure 3A
and 3B) and natural OMS-B (Figures 3C and 3D) revealed
significantly different chemical shifts for the synthetic OMS-B.
This result was likely due to a difference in the electron donating
effect, which depends on the position of methyl substituent.
Therefore, we assumed that the additional methyl substituent
involved in isoleucine as the 11th amino acid based on intensive
analysis of the 1D and 2D NMR spectra as well as the COSY and
e-HSQC data (see Supporting Information). Among the four
possible diastereomers of isoleucine, we selected the naturally
abundant L-Ile. Synthesis of the structurally revised OMS-B
In conclusion, we have accomplished the first total syntheses of
ohmyungsamycins A (1) and B (28), the side chain-truncated
ohmyungsamycin B (2 to 28). The key macrocyclization strategy
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10.1002/anie.201711286
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COMMUNICATION
Table 1. Anti-TB activities of the ohmyungsamycins and structurally relevant
cyclopeptides
H. Koinuma, A. Kimbara, M. Izumikawa, Y. Mifune, H. He, K. Shin-ya, T.
Takahashi, T. Doi, J. Am. Chem. Soc. 2014, 136, 12011.
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Shin, D. C. Oh, J. Org. Chem. 2013, 78, 12321.
[4]
[5]
Compound
MIC50
W. Gao, J. Y. Kim, S. N. Chen, S. H. Cho, J. Choi, B. U. Jaki, Y. Y. Jin,
D. C. Lankin, J. E. Lee, S. Y. Lee, J. B. McAlpine, J. G. Napolitano, S. G.
Franzblau, J. W. Suh, G. F. Pauli, Org. Lett. 2014, 16, 6044.
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, J. B. McAlpine, S. Mulugeta, S.
Sunoqrot, Y. Wang, S. H. Yang, T. M. Yoon, A. L. Goldberg, G. F. Pauli,
J. W. Suh, S. G. Franzblau, S. Cho, Antimicrob. Agents Chemother. 2015,
59, 880.
OMS-A (1)
33.3 nM
64.9 nM
108.3 nM
740 nM
3.1 μM
OMS-B; proposed (2)
OMS-B; revised (28)
Δ10N-Ac OMS (4)
Ethambutol
[6]
[7]
T. S. Kim, Y.-H. Shin, H.-M. Lee, J. K. Kim, J. H. Choe, J.-C. Jang, S.
Um, H. S. Jin, M. Komatsu, G.-H. Cha, H.-J. Chae, D.-C. Oh, E.-K. Jo,
Sci. Rep. 2017, 7, 3431.
for the syntheses of the OMSs was inspired by the conformation
of the cyclic core. In addition, synthesis of the side chain-
truncated ohmyungsamycin A enabled the elucidation of the core
of ohmyungsamycins, which is responsible for the excellent anti-
TB activities. Our convergent syntheses of the ohmyungsamycins
can be widely utilized by synthetic and medicinal chemists.
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This work was supported by the National Research Foundation
of Korea grant funded by the Ministry of Science and ICT of
Korea (2009-0083533) and by the GRRC program of Gyeonggi
province (GRRC-CHA2017-B02).
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Keywords: cyclodepsipeptide • total synthesis • natural products
• macrolactamization • structural revision
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10.1002/anie.201711286
Angewandte Chemie International Edition
COMMUNICATION
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COMMUNICATION
The first total syntheses of bioactive
cyclodepsipeptides, ohmyungsamycins
A and the proposed ohmyungsamycin
B have been achieved. In addition, the
proposed structure of
Joonseong Hur, Jaebong Jang, Jaehoon
Sim, Woo Sung Son, Hee-Chul Ahn, Tae
Sung Kim, Yern-Hyerk Shin, Changjin
Lim, SeungBeom Lee, Hongchan An,
Seok-Ho Kim, Dong-Chan Oh, Eun-
Kyeong Jo, Jichan Jang, Jeeyeon Lee,
and Young-Ger Suh*
ohmyungsamycin B was revised.
Page No. – Page No.
Conformationally-Inspired Total
Syntheses of Ohmyungsamycins A
and B and Structural Revision of
Ohmyungsamycin B
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