Stereoselective synthesis of the C17–C29 fragment of amphidinolide N

Article abstract of DOI:10.1016/j.tetlet.2016.10.038

An enantio- and diastereoselective synthesis of the C17–C29 fragment of amphidinolide N, an extremely potent macrocyclic cytotoxin of marine origin, has been accomplished from a known olefinic ester by a 10-step sequence that involves a ring opening of a chiral epoxide with a dithiane derivative to construct the full carbon skeleton, a highly diastereoselective reduction of a β-hydroxy ketone intermediate to install the C21 asymmetric center, and a one-pot Sharpless AD/cyclization sequence to form a trans-substituted tetrahydrofuran ring system.

Full text of DOI:10.1016/j.tetlet.2016.10.038

Accepted Manuscript
Stereoselective synthesis of the C17–C29 fragment of amphidinolide N
Yuki Fujishima, Yusuke Ogura, Ryo Towada, Masaru Enomoto, Shigefumi
Kuwahara
PII:
S0040-4039(16)31350-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.038
TETL 48208
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 September 2016
5 October 2016
12 October 2016
Please cite this article as: Fujishima, Y., Ogura, Y., Towada, R., Enomoto, M., Kuwahara, S., Stereoselective
synthesis of the C17–C29 fragment of amphidinolide N, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.10.038
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fragment of amphidinolide N
Yuki Fujishima, Yusuke Ogura, Ryo Towada, Masaru Enomoto, Shigefumi Kuwahara

1
Tetrahedron Letters
Stereoselective synthesis of the C17–C29 fragment of amphidinolide N
Yuki Fujishima, Yusuke Ogura*, Ryo Towada, Masaru Enomoto, Shigefumi Kuwahara
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-
555, Japan
8
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An enantio- and diastereoselective syntehsis of the C17–C29 fragment of amphidinolide N, an
extremely potent macrocyclic cytotoxin of marine origin, has been accomplished from a known
olefinic ester by a 10-step sequence that involves a ring opening of a chiral epoxide with a
dithiane derivative to consrtruct the full carbon skeleton, a highly diastereoselective reduction of
a -hydroxy ketone intermediate to install the C21 asymmetric center, and a one-pot Sharpless
AD/cyclization sequence to form a trans-substituted tetrahydronfran ring system.
Available online
Keywords:
Amphidinolide
Cytotoxic
2
009 Elsevier Ltd. All rights reserved.
Macrolide
Polyketide
Partial synthesis
Amphidinolide N (1) is a 26-membered macrolide isolated in
an extremely limited amount (0.0009% yield, wet weight) from
the marine dinoflagellete Amphidinium sp. (Y-5 strain) as a
remarkably potent cytotoxin against murine lymphoma L1210
and human epidermoid carcinoma KB cells with IC50 values of
1
,2
0
.05 ng/mL and 0.06 ng/mL, respectively (Figure 1). Its
structure was originally assigned in 1994 as a macrolide devoid
1
of the C21–C24 tetrahydrofuran ring unit (2), but later in 2013
revised as depicted in Figure
1 including its relative
2
stereochemistry by detailed reinvestigation of the spectral data.
It is worth mentioning that another naturally-occurring cytotoxic
macrolide, named caribenolide I (3), discovered in the extract of
the free-swimming marine dinoflagellete Amphidinium sp. S1-
3
6-5, has the same planar structure as amphidinolide N (1);
caribenolide I (3), whose stereochemistry has yet to be assigned,
was reported to exhibit in vivo cytotoxicity against murine tumor
P388 cells (T/C: 150 at a dose of 0.03 mg/kg) as well as very
strong in vitro cytotoxicity against human colon tumor HCT 116
3
and drug-resistant HCT 116/VM 46 cells (IC50 = 1 ng/mL).
Figure 1. Structures of amphidinolide N (1), its originally proposed
structure (2), caribenolide I (3), and the C17–C29 fragment (4) of
amphidinolide N.
Prompted by the outstanding cytotoxicity of 1 and 3 that
would warrant further studies as anticancer drug candidates along
with their unique structural architecture featuring a 26-membered
macrocyclic lactone ring containing 13 asymmetric centers,
several research groups have undertaken synthetic endeavors
toward these two molecules. The first report on the synthesis of
caribenolide I (3) was disclosed in 2006 by Figadère and co-
—
——

Corresponding author. Tel./fax: +81-22-717-8783; e-mail: skuwahar@biochem.tohoku.ac.jp (S.K.), ysk.ogura@m.tohoku.ac.jp (Y.O.).

2
Tetrahedron
workers, in which the preparation of an arbitrarily chosen
standard conditions to give -hydroxy ketone 7, which was then
4
stereoisomer of its C1–C6 fragment was described. They also
subjected to syn-selective reduction using NaBH in THF/MeOH
4
published two subsequent papers concerning the synthesis of the
C1–C11 and C13–C29 segments of 3. At nearly the same time,
in the presence of Et BOMe to afford 6 as a single
2
5
14
1
diastereomer, as analyzed by the H NMR spectrum of the
crude reaction product. DDQ oxidation of the dihydroxy PMB
ether 6 in CH Cl brought about the formation of a ca. 3:1
Nicolaou and co-workers reported the total synthesis of a
stereoisomer of an iso-epoxy form of 2 and a stereoisomer of a
des-epoxy form of 3, in which convergent assembly of three
building blocks was realized by using Enders’ chiral hydrazone
2
2
mixture of cyclic acetal 13a and its regioisomer 14; the formation
of 14 would probably be ascribable to the action of weekly acidic
6
chemistry. Stereoselective approaches to the C13–C29 subunit
2,3-dichloro-5,6-dicyano-1,4-hydroquione produced as
a
of the revised structure of amphidinolide N (1) were also
described by the Trost and the Sasaki groups, and, furthermore,
byproduct in the DDQ oxidation. Fortunately, the desired product
13a was readily isolated from the mixture by silica gel column
chromatograpy, providing pure 13a in an acceptable yield of
55%. The alcohol 13a was estimated to be optically pure by
7
,8
the latter group succeeded in an efficient construction of the C8–
9
.10
C29 and C1–C13 fragments of 1. Quite recently, Hayashi and
co-workers released their total synthesis of 7,10-epi-
1
analyzing the H NMR spectra of the corresponding (R)- and (S)-
1
1
amphidinolide N. We also got interested in the phenomenally
potent cytotoxicity as well as the complex structure of 1 and
embarked on its total synthesis. As part of our efforts toward the
goal, we describe herein a stereoselective approach to the C17–
C29 fragment (4) of 1.
MTPA esters 13b, and the absolute configuration at the C21
position was ascertained to be S by the modified Mosher’s
method. The free hydroxyl group of 13a was then mesylated to
give 5. Exposure of
5
to the Sharpless asymmetric
dihydroxylation conditions using AD-mix- and subsequent in-
situ treatment of the resulting diol with K CO for the formation
2
3
Scheme1 outlines our retrosynthetic analysis of 4. The target
molecule 4 would be derived by the Sharpless asymmetric
of a trans-substituted tetrahydrofuran ring afforded 15 as a single
15
diastereomer in 81% yield from 13a. The trans relationship
dihydroxylation of olefinic mesylate
5
followed by
between the two substituents on the tetrahydrofuran ring of 15
was confirmed by observing a diagnostic NOE correlation shown
in Scheme 2. After protection of the hydroxyl group of 15 as its
TBDPS ether 16, the product was exposed to DIBAL in CH Cl
tetrahydrofuran ring formation and regioselective reductive ring
opening of the p-methoxybenzylidene acetal moiety. Compound
5
would be readily obtained from p-methoxybenzyl ether 6 via
2
2
oxidative installation of the cyclic acetal unit and subsequent
mesylation of the remaining C21 hydroxy group. The syn-diol 6
should be prepared by diastereoselective reduction of aldol 7,
which in turn would be obtainable by coupling of known epoxide
for the reductive ring opening of the p-methoxybenzylidene
acetal unit, furnishing the C17–C29 fragment 4 which was
appropriately protected for further transformations.
8
and dithiane 9 followed by hydrolytic unmasking of the dithio
acetal functionality. Finally, the dithiane 9 was traced back to
known olefinic ester 10. It is worth noting that the C17 PMB
protecting group on 7 is planned to be utilized in two additional
ways: (1) for the selective protection of the C19 hydroxyl group
as the benzylidene acetal 5; and (2) for the protection of the C19
secondary hydroxyl group as the PMB ether 4, which would be
beneficial in terms of the simplification of protecting group
manipulation.
Scheme 1. Retrosynthetic analysis of 4.
According to the synthetic plan, we began our synthesis of 4
with the reduction of 10, obtained in 2 steps from pentanal via
1
2
the Johnson–Claisen rearrangement, with DIBAL to give 11.
The aldehyde 11 was then converted into the dithiane 9. The
coupling of 9 with epoxide 8, which was readily prepared from L-
1
3
aspartic acid by a known 3-step sequence, was conducted by
treatment of 9 with t-BuLi in THF/HMPA and subsequent
epoxide ring opening of 8 with the in-situ generated carbanion.
The dithiane moiety of the product 12 was hydrolyzed under
Scheme 2. Synthesis of 4. Reagents and conditions: (a) DIBAL, Et
C, 1 h, 91%; (b) HS(CH SH, BF ·OEt , CH Cl , –78 °C, 3 h, 87%: (c) t-
BuLi, THF/HMPA (10:1), –78 °C, 2 h, 78%; (d) CaCO , MeI, MeCN/MeOH
3:1), rt, 15 h, 88%; (e) Et BOMe, THF/MeOH (4:1), NaBH , –78 °C, 1.5 h,
2
O, –78
°
2
)
3
3
2
2
2
3
(
2
4

3
9
4%; (f) DDQ, 4Å MS, CH
rt, 1 h; (h) AD-mix-, MeSO
Na , K CO , 50 °C, 3 h, 81% from 13; (i) TBDPSCl, imidazole, DMF, rt,
6 h, 71%; (j) DIBAL, CH Cl , 0 °C to rt, 1.5 h, 54%.
2
Cl
2
, –20 °C, 16 h, 55%: (g) MsCl, Et
3
N, 0 °C to
Franck, X.; Seon-Meniel, B.; Hocquemiller, R.; Figadère, B.
Tetrahedron Lett. 2006, 47, 5905–5908.
2
NH , t-BuOH/H O (1:1), 0 °C, 12 h, then
2
2
2
S
2
O
3
2
3
6. (a) Nicolaou, K. C.; Brenzovich, W. E.; Bulger, P. G.; Francis, T.
M.; Org. Biomol. Chem. 2006, 4, 2119–2157; (b) Nicolaou, K. C.;
Bulger, P. G.; Brenzovich, W. E. Org. Biomol. Chem. 2006, 4,
1
2
2
2
158–2183.
7
8
.
.
Trost, B. M.; Rey, J. Org. Lett. 2012, 14, 5632–5635.
Sasaki, M.; Kawashima, Y.; Fuwa, H. Heterocycles 2015, 90,
5
In conclusion, an enantio- and diastereoselective synthesis of
the C17–C29 fragment (4) of amphidinolide N has been
accomplished from the known unsaturated ester 10 by a 10-step
sequence. The key features of the synthesis are: (1) utilization of
the L-aspartic acid-derived epoxide 8 and the Sharpless
asymmetric dihydroxylation to install the asymmetric centers at
the C19, C24, and C25 positions; (2) highly diastereoselective
reduction of the hydroxyl ketone 7 to form the 1,3-syn diol 6; and
79–599.
9. Kawashima, Y.; Toyoshima, A.; Fuwa, H.; Sasaki, M. Org. Lett.
016, 18, 2232–2235.
0. Toyoshima, A.; Sasaki, M. Tetrahedron Lett. 2016, 57, 3532–
534.
2
1
1
3
1. (a) Ochiai, K.; Kuppusamy, S.; Yasui, Y.; Okano, T.; Matsumoto,
Y.; Gupta, N. R.; Takahashi, Y.; Kubota, T.; Kobayashi, J.;
Hayashi, Y. Chem. Eur. J. 2016, 22, 3282–3286; (b) Ochiai, K.;
Kuppusamy, S.; Yasui, Y.; Harada, K.; Gupta, N. R.; Takahashi,
Y.; Kubota, T.; Kobayashi, J.; Hayashi, Y. Chem. Eur. J. 2016,
(
1
3) one-pot construction of the trans-substituted tetrahydrofuran
5.
2
2, 3287–3291.
1
1
2. Odinokov, V. N.; Vakhidov, R. R.; Shakhmaev, R. N.; Zorin, V.
V. Chem. Nat. Compd. 1998, 34, 186–188.
Acknowledgments
3. (a) Frick, J. A.; Klassen, J. B.; Bathe, A.; Abramson, J. M.;
Rapoport, H. Synthesis 1992, 621–623; (b) Wullschleger, C. W.;
Gertsch, J.; Altmann, K.-H. Org. Lett. 2010, 12, 1120–1123.
4. Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155–158.
5. An analogous transformation of an olefinic mesylate into a trans-
substituted tetrahydrofuran has previously been performed in two
pots by the Sasaki group in their synthesis of a C18–C29 fragment
of amphidinolide N. For details, see Ref. 8.
This work was financially supported by JSPS KAKENHI (No.
2
6292056) We thank Ms. Yuka Taguchi (Tohoku University) for
1
1
her help in NMR and MS measurements.
References and notes
1
2
3
.
.
.
Ishibashi, M.; Yamaguchi, N.; Sasaki, T.; Kobayashi, J. J. Chem.
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Takahashi, Y.; Kubota, T.; Imachi, M.; Wälchli, M. R.;
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Supplementary Material
Supplementary data
characterization data, and copies of NMR spectra) associated
with this article can be found, in the online version, at
(experimental
procedures,
1
084–1086.
4
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.
.
Seck, M.; Seon-Meniel, B.; Jullian, J.-C.; Franck, X.;
Hocquemiller, R.; Figadère, B. Lett. Org. Chem. 2006, 3, 390–
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(a) Seck, M.; Franck, X.; Seon-Meniel, B.; Hocquemiller, R.;
Figadère, B. Tetrahedron Lett. 2006, 47, 4175–4180; (b) Jalce, G.;

4
Tetrahedron
Highlights
The C17–C29 fragment of amphidinolide N was
synthesized highly stereoselectively.
The synthesis required only 10 steps from a simple
starting material.
A single PMB protecting group was also utilized
for two additional intermediates.