Enantioselective Total Synthesis of Cotylenin A

Article abstract of DOI:10.1021/jacs.0c01774

A convergent enantioselective total synthesis of cotylenin A is described. The A-ring fragment, prepared via the catalytic asymmetric intramolecular cyclopropanation developed in our laboratory, and the C-ring fragment, prepared from a known chiral compound via a modified acyl radical cyclization, were successfully assembled by the Utimoto coupling reaction. The formidable carbocyclic eight-membered ring of cotylenin A was efficiently constructed by a palladium-mediated cyclization. All the hydroxy groups in the scaffold were stereoselectively introduced, and a modified reducing reagent, Me₄NBH(O₂CⁱPr)₃, has been developed. The sugar moiety fragment was prepared via three consecutive carbon-oxygen bond-forming reactions, and the glycosylation was accomplished using Wan's protocol.

Full text of DOI:10.1021/jacs.0c01774

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Communication
Enantioselective Total Synthesis of Cotylenin A
masahiro uwamori, Ryunosuke Osada, Ryoji Sugiyama, Kotaro Nagatani, and Masahisa Nakada
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c01774 • Publication Date (Web): 12 Mar 2020
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Enantioselective Total Synthesis of Cotylenin A
Masahiro Uwamori, Ryunosuke Osada, Ryoji Sugiyama, Kotaro Nagatani, and Masahisa Nakada*
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Department of Chemistry and Biochemistry, Graduate School of Advanced Science and Engineering, Waseda University, 3-
4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
ABSTRACT: A convergent enantioselective total synthesis of cotylenin A is described. The A-ring fragment, prepared via the
catalytic asymmetric intramolecular cyclopropanation developed in our laboratory, and the C-ring fragment, prepared from a known
chiral compound via a modified acyl radical cyclization, were successfully assembled by the Utimoto coupling reaction. The
formidable carbocyclic eight-membered ring of cotylenin A was efficiently constructed by a palladium-mediated cyclization. All
the hydroxy groups in the scaffold were stereoselectively introduced and a modified reducing reagent, Me4NBH(O2CiPr)3, has been
developed. The sugar moiety fragment was prepared via three consecutive carbon-oxygen bond-forming reactions, and the
glycosylation was accomplished using Wan’s protocol.
O
Cotylenin A (Figure 1) was initially isolated as a plant
growth regulator;1 however, biological studies later revealed
that it induces the differentiation of murine and human
myeloid leukemia cells and the apoptosis of a wide range of
human cancer cell lines by combined treatment with
interferon-.2 The crystal structure of cotylenin A in a
complex with 14-3-3 protein and a phosphopeptide of H+-
ATPase (QSYpTV-COOH) has been reported3 to confirm that
cotylenin A binds to inhibitory 14-3-3 interaction sites of C-
RAF, pSer233, and pSer259 but not the activating interaction
site, pSer621. Moreover, the combined treatment of cotylenin
A with an anti-epidermal growth factor receptor antibody is
reported to synergistically suppress tumor growth in vitro and
in vivo, which provides a novel pharmacologic strategy for
treatment of RAS mutant cancers.4
OAc
H
O
O
OH
O
HO
O
OMe
HO
O
O
O
O
HO
HO
OAc
H
H
OH
OMe
H
OMe
HO
cotylenin A
fusicoccin A
OR
HO
O
O
8
9
14
7
OH
10
O
OMe
HO
13
H
B
C
11
X
O
6
R =
5
12
A
2
3
1
Because of the promising bioactivity as an anti-cancer agent
and the unique mechanism of action, cotylenin A has attracted
considerable attention from the scientific community in the
past decades. However, Cladosporium sp. 501-7W, the
producer of cotylenin A, has lost its ability to proliferate
during preservation on a slant,5 thus hampering further
biological studies. Hence, a steady supply of cotylenin A is
desired.
4
OMe
cotylenol (R = H)
HO
cotylenin B (X = Cl)
cotylenin D (X = OH)
Figure 1. Structures of cotylenin A, B, and D, cotylenol,
and fusicoccin A.
The intriguing biological activity and mechanism of action,
dearth of supply, and unique structural features make
cotylenin A an attractive synthetic target. Hence, the total
synthesis of cotylenin A was initiated, and the successful
results are reported herein.
Total synthesis is a potential method for providing cotylenin
A and for the discovery of biologically important derivatives
that are difficult to prepare from natural resources. However,
despite the elucidation of its absolute structure by X-ray
crystallographic analysis in 1998, the total synthesis of
cotylenin A has not yet been reported,6,7 and only one total
synthesis of its aglycone, cotylenol, has been reported by Kato
and co-workers thus far.8
Scheme 1 shows our retrosynthetic analysis of cotylenin A.
Cotylenin A could be synthesized via the glycosylation of
cotylenol derivative 1 and sugar moiety fragment 2. The C8-
C9 trans-1,2-diol of 1 could be formed by the stereoselective
C9 hydroxy-directed reduction of the -hydroxyketone, which
could be prepared by stereoselective C9 hydroxylation of 3.
The palladium-catalyzed alkenylation of methyl ketone 4 was
selected to construct the formidable eight-membered
carbocyclic B-ring because we previously reported that the
palladium-catalyzed intramolecular alkenylation of a methyl
ketone successfully formed the eight-membered carbocyclic
ring of taxol in 97% yield.9
The fused 5-8-5 carbocyclic ring system of cotylenin A
includes a formidable all-carbon quaternary stereogenic center,
an acid-sensitive chiral allylic tertiary alcohol, a stereotetrad
including a trans-1,2-diol, and a four-substituted alkene with
an isopropyl group. Moreover, cotylenin A bears a structurally
unique glucose-fused trioxabicyclo[2.2.1]heptane with methyl
and epoxyethyl groups, so that these structural features make
cotylenin A a distinguished member among the fusicoccan
diterpenoids.
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Scheme 1. Retrosynthetic Analysis of Cotylenin A Scheme 2. CAIMCP of 9 and Preparation of 13
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2
3
4
5
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7
8
RO OH
1) MeSO2Mes
Bn Bn
n-BuLi, 97%
O
O
glycosylation
8
9
B
OEt
H
SO2Mes
N
N
C
N2
2) TsN3, Et3N
98%
cotylenin A
O
O
12
9
A
Ligand A
CN
OMe
TMSO
Ligand A
(4.5 mol %)
CuPF6(CH3CN)4
(3.0 mol %)
O
1
9
H
H
+
NaCN, DMSO
80 ºC, 77%
H
9
O
SO2Mes
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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60
O
SO2Mes
toluene, 60 ºC
86%, 86% ee
O
O
O
BnO
Z
O
OMe
O
8
3
OMe
TMSO
99% ee (recryst)
2
intramolecular
alkenylation
Scheme 3. Preparation of 7 via Acyl Radical Cyclization
O
1) tert-C12H25SH, TBHP
CN
CuCl, 2,2'-bipyridyl
TBME, 50 ºC
H
H
A
TfO
R1
O
OTf
OTf
C
2) PhNTf2, LDA, THF
0 ºC to rt, 54% (2 steps)
TMSO
MeO
O
TBSO
(R1 = CH2OTBS)
(R1 = CHO)
14
11
1) 3HF•Et3N, 88%
2) DMP, 89%
4
5
7
CN
H
Scheme 4. Preparation of 16
H
O
CAIMCP
CN
CN
CN
SmI2
THF, 0 ºC;
NBS
THF / H2O
H
O
H
X
H
SO2Mes
SO2Mes
N2
O
O
6
8
9
A-ring fragment
ClP(O)(OEt)2
quant
0 ºC, 82%
Br
16
SO2Mes
5
OP(O)(OEt)2
O
Acyl
13
15
Radical
Cyclization
TfO
O
O
It has been reported that the Utimoto coupling reaction15,16
proceeds even when the reacting aldehyde is sterically
hindered. Hence, to examine assembly of the A- and C-ring
fragments by the Utimoto coupling reaction, 13 was converted
to -bromo ketone 16 (Scheme 4). The enolate generated from
13 using SmI2 or lithium naphthalenide was again unsuitable
for the preparation of 16, but reacted with acetic anhydride17 to
afford the corresponding enol acetate in 20-30% yield. This
result encouraged us to use chloro diethylphosphate as a
trapping reagent to improve the yield of enol phosphate 15
(quant), which was converted to 16 (82%).
O
TBSO
TBSO
7
10
11
C-ring fragment
Compound 4 could be derived from 5, which would be
prepared by assembling the A-ring fragment 6 and the C-ring
fragment 7. A-ring fragment 6 was planned to prepare via the
stereoselective reaction of sodium cyanide with cyclopropane
8, which would be formed by the catalytic asymmetric
intramolecular cyclopropanation (CAIMCP)10 of 9 developed
by us. The C-ring fragment 7 could be prepared from ketone
10 via the acyl radical cyclization11 of a known chiral aldehyde
11.12
The Utimoto coupling reaction of 16 and 7 successfully
afforded 17 as the sole product in 92% yield (Scheme 5). The
dehydration of 17 with the Burgess reagent stereoselectively
afforded enone 5, but the following Wittig methylenation
resulted in recovery of the starting material owing to the
formation of the enolate of 5. However, Takai reaction18 of 5
gratifyingly afforded the desired exo-methylene compound,
which was subjected to dihydroxylation to stereoselectively
afford the desired 18 in 46% yield (2 steps). The yield was
further improved to 71% (2 steps) when the methylenation
was carried out using ZrCl4.19 The primary hydroxy group of
18 was selectively methylated with the Meerwein reagent, and
the acid-labile tertiary hydroxyl group was protected as a TMS
ether by a one-flask operation. Subsequent conversion to
methyl ketone 4 using organometallic reagents such as methyl
lithium and methyl magnesium bromide induced reaction with
the enol triflate in the C-ring moiety. Hence, the nitrile was
converted to 20 by DIBAL-H reduction, and subsequent
methylation and oxidation afforded 4.
In the forward synthesis of the A-ring fragment (Scheme 2),
compound 9, which was prepared from compound 12, was
subjected to the CAIMCP to afford cyclopropane 8 in 86%
yield with 86% ee. The reaction of 8 with sodium cyanide
afforded -keto sulfone 13, the absolute structure of which
was confirmed by X-ray crystallographic analysis.13
The C-ring fragment 7 was synthesized from aldehyde 11
(Scheme 3). Thus, 11 was subjected to acyl radical cyclization
under the modified conditions,14 and subsequent formation of
enol triflate 14, removal of the TBS group, and Dess-Martin
oxidation furnished 7.
Having prepared 13 and 7, their coupling reaction was
attempted. Interestingly, although the desulfonation of 13 with
SmI2 proceeded, the subsequent aldol reaction with 7 did not
take place. Extensive survey of the reaction conditions,
including the use of additives and other reagents such as
lithium naphthalenide and LiDBB, did not change the results.
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Scheme 5. Enantioselective Total Synthesis of Cotylenol
1
2
3
4
5
6
CN
CN
CN
1) CH2I2, Zn, ZrCl4
PbCl2, THF, 0 ºC
N
H
H
H
Et3NO2S
CO2Me
BEt3, Ph3SnH
benzene, rt
OTf
OTf
TfO
16
+
7
2) K2OsO4•2H2O
NMO, THF/H2O
d.r. = 7 : 1
benzene, rt
HO
HO
3
84% (2 steps)
O
O
HO
17
5
18
71% (2 steps)
7
8
9
1) Me3OBF4, 2,6-tBu2-4-MePy
CH2Cl2, 0 ºC; then, TMSCl,
pyridine, 0 ºC, 71%
O
O
R
PdCl2(PCy3)2 (2.0 equiv)
PhOK (16 equiv)
1) MeMgBr
THF, –78 ºC
H
H
OTf
H
OTf
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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57
58
59
60
toluene, 50 °C
95%
2) DMP, NaHCO3
CH2Cl2, rt
91% (2 steps)
2) DIBAL, CH2Cl2
TMSO
MeO
TMSO
MeO
–78 °C, 96%
OMe
TMSO
OH
4
(R = COCH3)
19
3
HO
O
OH
HO
OH
LHMDS, LiCl
MoOPH
THF, –50 °C
Me4NBH(O2CiPr)3
8
9
9
TBAF, THF, rt
93%
H
CH3CN, rt
H
H
20
80%
52% (
19% (C9 epimer of
)
20
single diastereomer
)
OMe
HO
OMe
20
OMe
21
TMSO
TMSO
cotylenol
We have reported that the palladium-catalyzed
intramolecular alkenylation of methyl ketones effectively
affords carbocyclic eight-membered rings.9,20 Therefore, we
carried out the reaction of 4 under the same reaction
conditions as those used in the total synthesis of taxol
(Pd(PPh3)4 (30 mol %), PhOK (3.0 equiv), toluene, 100 °C).9
However, interestingly, no reaction occurred. The reaction was
attempted under several conditions that were effective for the
alkenylation in the previous studies,9,20 but the desired product
was not formed. The difference between 4 and previous
substrates is that 4 is an enol triflate and not an alkenyl halide.
Hence, electron-rich tricyclohexylphosphine was used to
enhance the oxidative addition of palladium to enol triflate 4.
The reaction with 50 mol % of PdCl2(PCy3)2 at 100 °C
dramatically afforded the product 3; however, epimerization of
the C7 position took place.21 Reduction of the temperature to
50 °C prevented the epimerization, but two equivalents of
PdCl2(PCy3)2 were required to access 95% yield of 3. It should
be noted that the enol triflate group was able to survive
through 10 steps (from 14 to 4) though it is hindered by the
adjacent all-carbon quaternary center and isopropyl group.
22 and 23 seemingly afforded 24, but reactive 22 easily
dimerized prior to the reaction with 23 under the given
conditions, and desired product 24 was not formed. The
reaction of dimethyl acetal 22’ with 23 did not afford the
desired product either, too. Hence, the rational design of an
alternative fragment instead of 22 was required to construct
the bis-acetal moiety in the trioxabicyclo[2.2.1]heptane
scaffold.
After several attempts, finally, epoxy aldehyde 2528 was
designed as the alternative fragment for 22 because it was
envisioned that the reaction of 23 and 25 under acidic
conditions would afford hemiacetal 26, and the generated
hydroxy group of the hemiacetal could successively react with
the ketone in the glucose unit to form new hemi-acetals 27a
and 27b. And finally, the resultant hydroxy group could react
with the epoxide to form compound 28. The reaction of 23 and
25 should form two diastereomers 27a and 27b, and 27a could
afford hemi-acetal 28, while another diastereomer 27b could
isomerize to the reacting diastereomer 27a via 26 under
equilibrium conditions.
As hoped, the envisioned consecutive transformations were
realized. The reaction of 23 and 25 afforded 28 in the presence
of CSA in acetonitrile at room temperature. The concentration
of the starting material (2 M) was found to be important for
the effective formation of 27a and 27b. Hemi-acetals 27a and
27b were unstable to isolate and easily decomposed to give a
mixture of 23 and 25. Indeed, 27a and 27b could not be
detected by TLC analysis, but their formation as a mixture of
We next explored the C9 hydroxylation using a variety of
reagents and found that the use of MoOPH/LHMDS in the
presence of LiCl22 as an additive improved the yield and
diastereoselectivity. The subsequent stereoselective reduction
of -hydroxy ketone 20 to trans-1,2-diol 21 was first
conducted using NaBH(OAc)3 or Me4NBH(OAc)3.23 However,
low reproducibility in the yield and stereoselectivity was
problem.24 After several attempts, the reaction with
Me4NBH(O2CiPr)3,25 which was newly developed in this
synthesis, was found to afford 21 as the single isomer. Finally,
treatment of 21 with TBAF afforded cotylenol. All the
spectroscopic data of the synthesized product were identical to
those reported for naturally occurring cotylenol.26
1
diastereomers (1:1) was confirmed by H-NMR. The reaction
of 23 and 25 to 27a and 27b reached equilibrium after 30 min
and interestingly, after the formation of 27a and 27b in the 2
M solution, dilution of the reaction mixture to 0.1 M with
acetonitrile shifted the equilibrium to the starting materials 23
and 25, resulting in the disappearance of 27a and 27b.
We next addressed the preparation of the sugar moiety
fragment of cotylenin A (Scheme 6).The sugar moiety features
the trioxabicyclo[2.2.1]heptane scaffold, which consists of -
hydroxy aldehyde bearing an epoxyethyl group 22 and
glucose-derived -hydroxy ketone 23.27 Hence, the reaction of
The intramolecular reaction of the hydroxy group in 27a
with the epoxide proceeded slowly, and compound 28 was
formed after 24 h after the initiation of the reaction. Hemi-
acetal 27b, which did not afford the bis-acetal owing to the
stereochemical restriction, remained intact because the
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reaction after 48 h did not change the yield. These results
could be attributed to the slow interconversion between 27a
and 27b.
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Scheme 6. Preparation of 24 via Acetalizations and Epoxide-Opening Cascade
intermolecular
acetalization
O
O
O
O
O
H
HO
OTs
intramolecular
acetalization
OTs
OH
OH
CSA (1.0 equiv)
CH3CN (2M), rt
O
O
O
25
H
O
BnO
PhS
BnO
PhS
+
OH
BnO
PhS
OH
OMe
OH
O
O
OTs
O
OTs
30 min
BnO
O
OMe
OMe
OMe
O
CH3CN (0.1M)
PhS
23
26
27a
27b
(desired)
(undesired)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
intramolecular
epoxide opening
O
MeO
O
OH
OTs
O
NaH, THF, rt
O
O
O
BnO
PhS
O
OH
MeO
O
OMe
BnO
PhS
HO
22
O
O
O
24 h
23%
(2 steps)
OMe
22'
24
28
In conclusion, a convergent enantioselective total synthesis
Scheme 7. Enantioselective Total Synthesis of Cotylenin
A
of cotylenin A was successfully achieved by 25 longest linear
steps from geraniol. The A-ring fragment, prepared via the
catalytic asymmetric intramolecular cyclopropanation
developed in our laboratory, and the C-ring fragment, prepared
from a known chiral compound via a modified acyl radical
cyclization, were effectively assembled by the Utimoto
coupling reaction. A palladium-mediated cyclization was
crucial for the efficient construction of the carbocyclic eight-
membered ring of cotylenin A. All the hydroxy groups in the
scaffold were stereoselectively introduced and a modified
reducing reagent, Me4NBH(O2CiPr)3, has been developed. The
sugar moiety fragment was successfully prepared via three
consecutive carbon-oxygen bond-forming reactions. The
glycosylation was accomplished using Wan’s protocol.
Studies are underway to optimize the reaction conditions of
the low-yielding steps to supply an adequate amount of
cotylenin A for biological studies.
OH
AcO
24
(1.2 equiv)
methyl 2-(4-chlorophenyl)
-2-diazoacetate (3.0 equiv)
Ac2O
Py, rt
8
9
H
21
Rh2(oct)4 (0.5 mol %)
TfOH•DTBMP (10.0 mol %)
MS 3Å, CH2Cl2, 0 °C
59%
(77% brsm)
OMe
29
TMSO
O
O
O
O
BnO
O
OMe
O
AcO
1) MeLi, Et2O, –78 °C
2) TBAF, THF, rt
8
9
cotylenin A
H
3) H2, Pd black, 45 °C
6% (7% brsm)
(4 steps)
ASSOCIATED CONTENT
Supporting Information.
OMe
30
TMSO
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/XX.XXXX/jacs.XXXXXX.
Compound 28 was not fully purified by silica-gel column
chromatography, and contained a small amount of inseparable
impurities. Hence, it was treated as is with sodium hydride to
afford epoxide 24 in 23% yield (from 23 and 25). The yield of
24 could be improved by further optimization of the reaction
conditions.
Experimental details, characterization of new compounds, HPLC
DATA, and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
Having succeeded in the preparation of the sugar moiety
fragment 24, compound 29, prepared in 59% yield (77% brsm)
by the reaction of 21 and Ac2O, was subjected to the
glycosylation with 24 (Scheme 7). Glycosylations using
common reagents such as Tf2O or MeOTf for the activation of
thioglycoside resulted in decomposition of 24, and Crich’s
conditions29 afforded 30 but unfortunately, the yield was low.
Masahisa Nakada – Department of Chemistry and Biochemistry,
Graduate School of Advanced Science and Engineering, Waseda
University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
orcid.org/0000-0001-6081-5269; Email: mnakada@waseda.jp
Authors
After several attempts, we finally found that rhodium-
catalyzed sulfonium ylide formation and subsequent Brønsted-
acid catalyzed glycosylation, recently reported by Wan’s
group,30 afforded 30 in moderate yield.31 The C8 acetate of 30
resisted hydrolysis but was successfully removed by the
reaction with methyllithium at low temperature and finally,
removal of the TMS and benzyl groups afforded cotylenin A.
The spectroscopic data of the synthesized product were
identical to those of naturally occurring cotylenin A,1,32
indicating that the enantioselective total synthesis of cotylenin
A has been accomplished.
Masahiro Uwamori
–
Department of Chemistry and
Biochemistry, Graduate School of Advanced Science and
Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku,
Tokyo 169-8555, Japan
Ryunosuke Osada – Department of Chemistry and Biochemistry,
Graduate School of Advanced Science and Engineering, Waseda
University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Ryoji Sugiyama – Department of Chemistry and Biochemistry,
Graduate School of Advanced Science and Engineering, Waseda
University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
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(7) For selected synthetic studies and total syntheses on
Kotaro Nagatani – Department of Chemistry and Biochemistry,
Graduate School of Advanced Science and Engineering, Waseda
University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
fusicoccane diterpenoids, see: (a) Kato, N.; Tanaka, S.; Takeshita, H.
Total synthesis of cycloaraneosene, a fundamental hydrocarbon of
epi-fusicoccane diterpenoids, and the structure revision of its
congener, hydroxycycloaraneosene. Chem. Lett. 1986, 1989–1892. (b)
Kato, N.; Tanaka, S.; Takeshita, H. Synthetic photochemistry.
XLII. Total synthesis of cycloaraneosene, a fundamental hydrocarbon
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contact
information
is
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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This paper is dedicated to Prof. Masaji Ohno on the occasion of
his 90th birthday. We acknowledge supports of the Materials
Characterization Central Laboratory, Waseda University, for
characterization of new compounds. This work was financially
supported by JSPS KAKENHI (Grant No. JP15H05841 in Middle
Molecular Strategy), the Naito Foundation, and a Waseda
University Grant for Special Research Projects.
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(13) CCDC 1983382 (13) contains the supplementary
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of impurities, which were finally removed at the last step of this
synthesis, subsequent three steps were carried out using materials
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(32) To the best of our knowledge, specific rotation of cotylenin A
has not been reported thus far.
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its C9 epimer in the reduced yield and stereoselectivity.8
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(25) Me4NBH(O2CiPr)3 is easily prepared by commercially
i
available Me4NBH4 and PrCO2H. The high stereoselectivity and
reproducibility which were realized using Me4NBH(O2CiPr)3 would
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favorably in the transition state and also improve solubility of the
reagent.
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(29)
Crish,
D.;
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Anhydride:
1-Benzenesulfinyl
Potent
Piperidine/Trifluoromethanesulfonic
A
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