Total Synthesis and Structural Revision of Clavilactone D

Article abstract of DOI:10.1002/chem.201700483

A structural revision of clavilactone D, a potent inhibitor of protein tyrosine kinases, was achieved by total syntheses of two newly proposed structures. The syntheses relied on ring-opening/ring-closing metathesis, which transformed a cyclobutenecarboxylate into a γ-butenolide. The syntheses confirmed that the correct structure of clavilactone D has an amino group at C-3 instead of a hydroxy group at C-2 in the originally proposed structure.

Full text of DOI:10.1002/chem.201700483

A Journal of
Accepted Article
Title: Total Synthesis and Structural Revision of Clavilactone D
Authors: Ken-ichi Takao, Ryuichi Nemoto, Kento Mori, Ayumi Namba,
Keisuke Yoshida, and Akihiro Ogura
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the VoR from the journal website shown below when it is published
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To be cited as: Chem. Eur. J. 10.1002/chem.201700483
Link to VoR: http://dx.doi.org/10.1002/chem.201700483
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Chemistry - A European Journal
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COMMUNICATION
Total Synthesis and Structural Revision of Clavilactone D
Ken-ichi Takao,* Ryuichi Nemoto, Kento Mori, Ayumi Namba, Keisuke Yoshida, and Akihiro Ogura
Abstract: A structural revision of clavilactone D, a potent inhibitor of
protein tyrosine kinases, was achieved by total syntheses of two
A)
newly proposed structures. The syntheses relied on ring-
Me
Me
Me
opening/ring-closing
metathesis,
which
transformed
a
OH
OH
O
O
OH
OH
cyclobutenecarboxylate into
a
γ-butenolide. The syntheses
R
O
confirmed that the correct structure of clavilactone D has an amino
group at C-3 instead of a hydroxy group at C-2 in the originally
proposed structure.
O
O
O
O
O
O
O
O
Clavilactone A (1)
Clavilactone B (2)
Clavilactone C (3): R = OH
Clavilactone E (5): R = OMe
[
1,2]
Clavilactone D is a potent inhibitor of protein tyrosine kinases,
Me
O
Me
Me
O
but its structure has remained unsolved. First, antifungal and
antibacterial clavilactones A–C (1–3) were discovered from
cultures of the Basidiomycetous fungus Clitocybe clavipes by
O
O
HO
2
2
[
3]
3
Arnone and co-workers in 1994 (Figure 1A). Their structures
were determined as having 10-membered carbocycle
O
HO
3
O
O
O
a
O
O
O
O
O
O
O
connected to a hydroquinone or benzoquinone and an α,β-
epoxy-γ-lactone. In 2000, Merlini and co-workers isolated related
compounds, clavilactones D and E (5), from the same fungus by
6
7
Originally proposed structure
of clavilactone D (4)
[
1]
using different culture conditions. Because the NMR spectra of
clavilactone D and 2 were similar, the structure of clavilactone D
was originally assigned as 4 substituted with a hydroxy group in
the quinone ring of 2. The position of the hydroxy group was
elucidated by the HMBC spectrum. Studies of the biological
activity of 1, 2, and clavilactone D showed inhibitory activity
B) This work
Me
O
Me
O
H N
2
H N
2
O
O
O
O
O
O
[
2]
O
O
against epidermal growth factor tyrosine kinases,
and
8
Revised structure of
clavilactone D (9)
clavilactone D was the most potent inhibitor (IC50 5.5 µM). The
unique structures of clavilactones coupled with their important
biological
activities
have
inspired
several
synthetic
Figure 1. Structures of clavilactones.
[
4,5]
investigations.
Barrett and co-workers achieved the first total
[
6]
synthesis of (+)-clavilactone B (the antipode of 2). Next, we
completed the enantioselective total synthesis of the natural
Based on the re-evaluation of the published data for
[
7]
enantiomers of 1 and 2. In collaborative research with a
biology group, we showed that synthetic analog 6, called seco-
clavilactone B, is a novel actin polymerization inhibitor and can
[1]
clavilactone D, we had doubts about the molecular weight of
clavilactone D. In its mass spectrum, the molecular ion was
+
recorded as 302 for M by chemical ionization (CI) MS using
[
8]
serve as a bioprobe for clarifying cytoskeletal dynamics. Later,
two total syntheses of clavilactones were published by the Li
4
CH and no HRMS data was described. The molecular ion in
+
CIMS is usually observed as [M + H] . Therefore, we assumed
that the correct molecular weight of clavilactone D would be 301,
one less than the proposed weight. Next, we compared the NMR
data of natural clavilactone D with those of 4 and 7 synthesized
[
9]
[10]
group and the Yoshimitsu group. Notably, Li and colleagues
reported that neither the spectroscopic data for synthesized 4
(
the originally proposed structure) nor its regioisomer 7 matched
[
9]
those of natural clavilactone D. The correct structure should be
revealed to advance both natural product chemistry and
biological research. We herein demonstrate the correct structure
of clavilactone D to be 9 (Figure 1B) by total syntheses of two
newly proposed structures.
[9]
by Li and colleagues. The signal peak of H-3 (δ 6.15) for 4 or
H-2 (δ 6.17) for
7 appeared at a lower field than the
corresponding peak (δ 5.90) of natural product. A similar
13
difference was also observed in the C NMR spectra (δ 109.2
for C-3 of 4 or δ 109.5 for C-2 of 7 vs. δ 101.7 for natural
product). These facts indicate that clavilactone D has a stronger
electron-donating group in the quinone ring than the hydroxy
group. Consequently, we considered that the revised structure
for clavilactone D should be 8 or 9, containing an amino group at
C-2 or C-3, and that the structural revision could be
unambiguously confirmed by total syntheses of 8 and 9.
[*]
Prof. Dr. K. Takao, R. Nemoto, K. Mori, A. Namba, Dr. K. Yoshida,
Dr. A. Ogura
Department of Applied Chemistry
Keio University
Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan)
E-mail: takao@applc.keio.ac.jp
In recent years, we have been interested in ring-
Supporting information for this article is given via a link at the end of
the document.
rearrangement metathesis, a conceptually new method involving
[11,12]
domino metathesis.
To achieve the total synthesis of 1 and
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Chemistry - A European Journal
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COMMUNICATION
OMe
OMe
OR
OR
2
,
we developed
a
ring-opening/ring-closing metathesis
O N
O N
Br
(
ROM/RCM) of cyclobutenecarboxylate derivatives for concise
Ref. 14
2
b
2
[
4,7]
access to γ-butenolides.
Our strategy has been successfully
[
13]
CHO
CHO
CHO
used for butenolide synthesis by other groups. Therefore, we
envisioned an approach that would exploit the ROM/RCM of
cyclobutenecarboxylate 12 or 13 to construct γ-butenolide 10 or
OMe
OMe
9: R = H
14: R = Me
17: R = Me
8: R = H
1
1
6
a
c
1
1
1, which would be transformed into 8 or 9 by a similar
OMe
OMe
sequence of reactions to our previous synthesis of 2 (Scheme 1).
The nitro group would be used as a precursor of the amino
group at C-2 or C-3. To prepare 12 or 13, penta-substituted
benzene 14 or 15 would be required as a starting material.
O N
2
Br
O N
2
Br
d
e
OMe OH
OMe O
2
0
1
2
O
OMe
OMe
1
st Grubbs cat. (20 mol %)
R1
ROM/RCM R1
R2
OMe
Br
Br
2
2 (40 mol %)
8
or 9
O2N
Br
toluene (0.01 M), 80 °C, 3 h
R2
then
OMe O
OMe O
ethylene (1 atm)
2nd Grubbs cat. (5 mol %)
80 °C, 45 min
O
OMe O
O
0: R1 = NO , R2 = H
1: R1 = H, R2 = NO2
O
1
12: R1 = NO , R = H
13: R1
2
10
2
2
1
= H, R2 = NO2
80%
O
PCy3
N
N
OMe
OMe
Cl
Cl
Cl
Mes
Mes
Ph
O
Ph
O N
2
Br
Br
Ru
Cl
Ru
or
Cl
O
O
Cl
PCy3
PCy3
nd Grubbs cat.
CHO
O N
2
CHO
21
O
1st Grubbs cat.
2
OMe
OMe
22
1
4
15
Scheme 2. Synthesis of γ-butenolide 10. Reagents and conditions: a) conc.
SO , 50 °C, 40 h, 31% (57% based on recovered starting material); b)
PyHBr , MS 4Å, Py, –30 °C, 1 h, 87%; c) MeI, K CO , DMF, RT, 14 h, 100%;
d) CH =CHMgBr, THF, –78 °C, 1 h, 73%; e) NaHMDS, 21, THF, –78 °C, 45
min, 80%. Py pyridine, MS molecular sieves, DMF N,N-
dimethylformamide, THF = tetrahydrofuran, HMDS = hexamethyldisilazide, Cy
Scheme 1. Retrosynthetic analysis of newly proposed structures 8 and 9 of
H
2
4
clavilactone D.
3
2
3
2
=
=
=
We initially aimed to obtain 8, which is substituted with an
amino group at the same position (C-2) as the hydroxy group in
originally proposed structure 4. The synthesis started with a
regioselective preparation of 14 (Scheme 2). According to the
known procedure, a nitrated benzaldehyde derivative 17 was
regioselectively prepared from 2,5-dimethoxybenzaldehyde
=
cyclohexyl, Mes = mesityl.
The next stage of the synthesis involved construction of the
10-membered carbocycle of 8 (Scheme 3). Reduction of the γ-
lactone in 10, followed by protection of the resulting diol as a
silylene acetal, provided 23. Chemo- and stereoselective
[
14]
(
16).
could not be directly obtained from 17. However, compound 18
underwent regioselective bromination. Thus, selective
demethylation of dimethyl ether 17 with concentrated sulfuric
Despite extensive efforts, corresponding bromide 14
[
19]
epoxidation of 23 was achieved by using mCPBA.
product 24 was subjected to Stille coupling with allylstannane
Major
a
[
20]
25
to afford diene 26. Ring-closing metathesis (RCM) of 26
[
15]
[16]
acid
provided monomethyl ether 18.
Treatment of 18 with
with the second-generation Grubbs catalyst proceeded, giving
pyridinium tribromide produced desired brominated product 19,
which was re-methylated to 14. The vinyl Grignard reaction of 14
10-membered carbocycle 27. The newly formed olefin had the
[
21]
desired geometry.
At this stage, the nitro group in 27 was
[
17]
provided allylic alcohol 20.
Cyclobutenecarboxylate 12 was
chemoselectively reduced to an amino group under transfer
hydrogenation conditions and the resulting product was
protected as t-butyl carbamate 28. Removal of the silylene
acetal from 28 and subsequent Ley oxidation of the diol
reconstructed the γ-lactone, furnishing 29. Treatment of 29 with
CAN, followed by deprotection of the amino group, provided the
first target molecule (8).
[
7]
obtained by acylation of 20 with anhydride 21. The ROM/RCM
reaction of 12 proceeded using the method developed by our
[
7]
group. A solution of the first-generation Grubbs catalyst and
[
18]
benzoquinone 22
was slowly added to a solution of 12 in
toluene using a syringe pump. After stirring, the mixture was
treated with ethylene and the second-generation Grubbs catalyst
to provide γ-butenolide 10 in 80% yield.
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COMMUNICATION
Nitration of 30 proceeded with complete regioselectivity to afford
OMe
OMe
OMe
[
22]
desired penta-substituted benzene 15 as a single isomer.
O N
2
Br
O N
Br
2
a, b
c
Addition of the vinyl group provided allylic alcohol 31, which was
acylated to furnish key substrate 13 for the ROM/RCM reaction.
Cyclobutenecarboxylate 13 was transformed into γ-butenolide 11
by our method. After conversion to silylene acetal 32,
epoxidation followed by Stille coupling of epoxide 33 provided
diene 34. RCM of 34 formed a 10-membered carbocycle to
afford 35, which was converted into 37 through reduction of the
nitro group, protection–deprotection, and reconstruction of the γ-
lactone. Finally, CAN oxidation followed by deprotection afforded
the second target molecule (9). The stereochemistry of 9 was
1
0
O
Si
24
OMe O
O
O
O
Si
tBu
tBu
tBu
tBu
2
3
Me
Me
OMe
OMe
O N
2
O2N
d
e
O
O
Bu Sn
3
OMe O
O
O
OMe
Me
O
1
Si
Si
confirmed by H NMR analysis including NOE experiments.
2
5
tBu
tBu
tBu
27
tBu
1
13
Pleasingly, comparison of the H and C NMR spectra of
2
6
synthetic 9 with those of natural clavilactone D showed excellent
Me
OMe
Me
OMe
[23]
agreement,
indicating that the structure of clavilactone D
BocHN
BocHN
should be revised to be 9, and that we had completed the first
f, g
h, i
1
total synthesis of (±)-clavilactone D. The original H NMR
2
spectrum showed a broad signal peak corresponding to –NH at
O
O
O
OMe O
OMe
O
O
δ 6.59 (δ 6.56 for synthetic 9), which was assigned as impurities
in the paper on the original isolation of clavilactone D. In the
original HMBC spectrum, a strong cross peak of the proton in
Si
tBu
29
tBu
2
8
2
.9%
4
the quinone ring with C-5 ( JCH) was detected, whereas a weak
Me
H
Me
3
O
O
O
cross peak with C-14 ( JCH) had been missed, leading to the
1
3
H N
2
H2N
0.3%
j, k
misassignment of the position of the substituent in the quinone
ring.
Ha
O
6
3
5
O
O
Ja,b = 0 Hz
O
Hb
In conclusion, we have synthesized two newly proposed
O
O
8
O
structures,
8 and 9, of protein tyrosine kinase inhibitor
NOE experiment of 8
clavilactone D, and we conclude that the true structure of the
natural product is 9, with an amino group at C-3. The key
features of the synthesis are regioselective bromination and
nitration for preparing penta-substituted benzene derivatives 14
Scheme 3. Synthesis of the first target molecule (8). Reagents and conditions:
a) DIBAL-H, THF, 0 °C, 2 h; b) tBu Si(OTf) , Py, CH Cl , RT, 30 min, 73% (2
steps); c) mCPBA, CH Cl , phosphate buffer, 0 °C to RT, 4 h, 54% 24, 16%
regioisomer, and 30% di-epoxide (2 cycles); d) 25, Pd(PPh , CuCl, 1,4-
2
2
2
2
2
2
3
)
4
and
15,
an
ROM/RCM
reaction
for
transforming
dioxane, reflux, 12 h, 73%; e) 2nd Grubbs cat. (40 mol %), 22 (60 mol %),
cyclobutenecarboxylates 12 and 13 into γ-butenolides 10 and 11,
and an RCM for constructing 10-membered carbocycles in 27
and 35. Our total synthesis has an important role to play in the
toluene (0.7 mM), reflux, 16 h, 74%; f) Pd/C, 1,4-cyclohexadiene, EtOH, 70 °C,
2
h; g) (Boc)
THF, RT, 16 h; i) TPAP, NMO, MS 4Å, MeCN, RT, 1 h, 74% (2 steps); j) CAN,
MeCN–H O, RT, 10 min; k) TFA, CH Cl , RT, 3.5 h, 54% (2 steps). DIBAL-H =
diisobutylaluminum hydride, Tf = trifluoromethanesulfonyl, mCPBA = meta-
chloroperbenzoic acid, Boc t-butoxycarbonyl, TPAP tetra-n-
2 3 4
O, Et N, 1,4-dioxane, 85 °C, 48 h, 86% (2 steps); h) nBu NF,
[
24]
structural elucidation of clavilactone D, and will enable further
biological studies on this class of natural products.
2
2
2
=
=
propylammonium perruthenate, NMO = N-methylmorpholine oxide, CAN =
cerium(IV) ammonium nitrate, TFA = trifluoroacetic acid, NOE = nuclear
Overhauser effect.
Acknowledgements
The NMR data for 8 did not agree with the published natural
[
1]
1
We thank Professor L. Scaglioni (Università di Milano) for
providing the original NMR spectra of clavilactone D. This work
was supported by JSPS KAKENHI Grant Number 15K05504
and the Asahi Glass Foundation.
product data. This included discrepancies in the H NMR (e.g.,
δ 6.13 for H-6 and δ 3.61 for H-13 of 8 vs. δ 5.99 and δ 3.76 for
1
3
natural product) and the C NMR (e.g., δ 144.7 for C-5 of 8 vs. δ
[
9]
1
51.3 for natural product). However, compared with 4 and 7,
the difference in the chemical shifts of H-3 (δ 5.86 for 8 vs. δ
.90 for natural product) and C-3 (δ 149.0 for 8 vs. δ 148.8 for
natural product) decreased. In addition, although 4 and 7 were
5
Keywords: medium-ring compounds • metathesis • natural
products • structure elucidation • total synthesis
[
9]
reported as yellow solids by Li and colleagues, compound 8
was obtained as a red solid similar to natural product. Therefore,
we moved on to synthesizing the regioisomer of 8, compound 9,
in which the amino group is substituted at C-3.
This synthesis used known bromide 30, which was the
[
7]
starting material in our total synthesis of 1 and 2 (Scheme 4).
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Chemistry - A European Journal
10.1002/chem.201700483
COMMUNICATION
OMe
OMe
OMe
OMe
OMe
Br
Br
a
Br
Br
Br
b
c
d
CHO
O N
2
CHO
O N
2
O N
2
O N
2
OMe
OMe
OMe OH
OMe O
OMe O
3
0
15
31
O
O
11
1
3
Me
OMe
Me
OMe
OMe
OMe
Br
Br
e, f
g
h
i
O N
2
O N
2
O
O N
2
O
O2N
O
OMe O
O
OMe
O
O
OMe
O
O
OMe
O
O
Si
Si
Si
Si
tBu
tBu
tBu
tBu
tBu
tBu
tBu
35
tBu
3
2
33
34
2
.2%
Me
OMe
Me
OMe
Me
H
Me
O
O
1
4
0
.2%
j, k
l, m
n, o
2
Ha
O
BocHN
BocHN
H N
H N
2
2
5
O
O
O
O
O
OMe O
OMe
Ja,b = 0 Hz
O
O
Hb
O
O
O
Si
O
tBu
37
O
tBu
(±)-Clavilactone D (9)
3
6
NOE experiment of 9
Scheme 4. Total synthesis of (±)-clavilactone D (9). Reagents and conditions: a) conc. HNO
7%; c) NaHMDS, 21, THF, –78 °C, 1 h, 84%; d) 1st Grubbs cat. (20 mol %), 22 (50 mol %), toluene (0.01 M), 80 °C, 3 h, then ethylene (1 atm), 2nd Grubbs cat.
6 mol %), 80 °C, 40 min, 82%; e) DIBAL-H, THF, 0 °C, 3 h; f) tBu Si(OTf) , Py, CH Cl , RT, 30 min, 65% (2 steps); g) mCPBA, CH Cl , phosphate buffer, 0 °C to
RT, 4 h, 50% 33, 18% regioisomer, and 31% di-epoxide (2 cycles); h) 25, Pd(PPh , CuCl, 1,4-dioxane, reflux, 16 h, 82%; i) 2nd Grubbs cat. (40 mol %), 22 (70
mol %), toluene (0.7 mM), reflux, 16 h, 64%; j) Pd/C, 1,4-cyclohexadiene, EtOH, 70 °C, 1.5 h; k) (Boc) O, Et N, 1,4-dioxane, 85 °C, 64 h, 99% (2 steps); l) nBu NF,
THF, RT, 20 h; m) TPAP, NMO, MS 4Å, MeCN, RT, 1 h, 87% (2 steps); n) CAN, MeCN–H O, RT, 10 min; o) TFA, CH Cl , RT 3 h, 65% (2 steps).
3 2 2 2
, CH Cl , RT, 2.5 h, 96%; b) CH =CHMgBr, THF, –78 °C, 30 min,
7
(
2
2
2
2
2
2
3 4
)
2
3
4
2
2
2
[
1]
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2]
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Blechert, Chem. Asian J. 2007, 2, 1064–1082.
[
[
[
[
3]
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[16] For determination of the structure of 18, see the Supporting
Information.
[17] When an excess amount of the Grignard reagent (3 equiv) was used,
an indole derivative was also obtained by the Bartoli indole synthesis.
[18] S. H. Hong, D. P. Sanders, C. W. Lee, R. H. Grubbs, J. Am. Chem.
Soc. 2005, 127, 17160–17161.
[
[
7]
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9]
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Tadano, Org. Lett. 2013, 15, 5582–5585.
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[19] The stereochemistry of the epoxide in 24 was confirmed by NOE
experiments of 8, which was derived from 24.
[
[
10] H. Suizu, D. Shigeoka, H. Aoyama, T. Yoshimitsu, Org. Lett. 2015, 17,
26–129.
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1
[
11] For recent reviews on the synthetic application of metathesis, see: a)
R. H. Grubbs, A. G. Wenzel, A. K. Chatterjee in Comprehensive
Organometallic Chemistry III, Vol. 11 (Eds.: R. H. Crabtree, D. M. P.
Mingos), Elsevier, Amsterdam, 2007, pp. 179–205; b) J. Mulzer, E.
Ohler, T. Gaich in Comprehensive Organometallic Chemistry III, Vol.
[21] The geometry of the trisubstituted olefin in 27 was confirmed by NOE
experiments of 8, which was derived from 27.
[22] For determination of the structure of 15, see the Supporting
Information.
1
13
[23] The H, C NMR and HMBC spectra of natural clavilactone D were
1
1 (Eds.: R. H. Crabtree, D. M. P. Mingos), Elsevier, Amsterdam,
007, pp. 207–269; c) M. Mori, T. Kitamura in Comprehensive
kindly provided by the isolation group.
2
[24] K. C. Nicolaou, S. A. Snyder, Angew. Chem. Int. Ed. 2005, 44, 1012–
1044.
Organometallic Chemistry III, Vol. 11 (Eds.: R. H. Crabtree, D. M. P.
Mingos), Elsevier, Amsterdam, 2007, pp. 271-310; d) K. C. Nicolaou,
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Chemistry - A European Journal
10.1002/chem.201700483
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Chemistry - A European Journal
10.1002/chem.201700483
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Ken-ichi Takao,* Ryuichi Nemoto, Kento
Mori, Ayumi Namba, Keisuke Yoshida,
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Total Synthesis and Structural
Revision of Clavilactone D
A structural revision of clavilactone D was achieved by total syntheses of two newly
proposed structures. The syntheses relied on ring-opening/ring-closing metathesis,
which transformed a cyclobutenecarboxylate into a γ-butenolide. The correct
structure of clavilactone D has an amino group at C-3 instead of a hydroxy group at
C-2 in the originally proposed structure.
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