Total synthesis of (-)-brevisin: A concise synthesis of a new marine polycyclic ether

Article abstract of DOI:10.1021/ol102925d

The first and highly efficient total synthesis of (-)-brevisin has been achieved. The title compound was synthesized in only 29 steps (longest linear sequence) from commercially available starting materials. The synthesis provided over 70 mg of a marine p

Full text of DOI:10.1021/ol102925d

ORGANIC
LETTERS
2011
Vol. 13, No. 4
696–699
Total Synthesis of (-)-Brevisin:
A Concise Synthesis of a New Marine
Polycyclic Ether
Takefumi Kuranaga,† Naohito Ohtani,† Ryosuke Tsutsumi,† Daniel G. Baden,‡
Jeffrey L. C. Wright,‡ Masayuki Satake,*,† and Kazuo Tachibana*,†
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Center for Marine Science,
University of North Carolina;Wilmington, 5600 Marvin K. Moss Lane,
Wilmington, North Carolina 28409, United States
msatake@chem.s.u-tokyo.ac.jp; ktachi@chem.s.u-tokyo.ac.jp
Received December 2, 2010
ABSTRACT
The first and highly efficient total synthesis of (-)-brevisin has been achieved. The title compound was synthesized in only 29 steps (longest linear
sequence) from commercially available starting materials. The synthesis provided over 70 mg of a marine polycyclic ether compound.
The polycyclic ether (-)-brevisin1 (1, Figure 1) was
isolated from the red tide dinoflagellate Karenia brevis,
which produces a variety of polycyclic ethers such as the
brevetoxins,2 brevenal,3 and the monocyclic ether amide
brevisamide.4 Brevisin’s unique structure consists of two
fused tricyclic ether ring assemblies bridged by a methylene
carbon and a conjugated aldehyde side chain, which is
similar to the side chain in brevenal and bevisamide.
Interestingly, despite 1 having a unique structure, which is
divided into two tricyclic ether units by the methylene, 1
inhibits the binding of tritiated 42-dihydrobrevetoxin B
(PbTx-3) to the voltage sensitive sodium channels.1a How-
ever, as with the other marine polycyclic ethers, the
biological activities of 1 have not been fully investigated
due to the extremely small supply from natural sources.
In order to elucidate its interaction with a target protein
and test other biological activities, such as mouse
lethality and cytotoxicity, the chemical synthesis for
† The University of Tokyo.
‡ University of North Carolina;Wilmington.
(1) (a) Satake, M.; Campbell, A.; Van Wagoner, R. M.; Bourdelais,
A. J.; Jacocks, H.; Baden, D. G.; Wright, J. L. C. J. Org. Chem. 2009, 74,
989. (b) Van Wagoner, R. M.; Satake, M.; Bourdelais, A. J.; Baden,
D. G.; Wright, J. L. C. J. Nat. Prod. 2010, 73, 1177. (c) Kuranaga, T.;
Satake, M.; Baden, D. G.; Wright, J. L. C.; Tachibana, K. Tetrahedron
Lett. 2010, 51, 4673.
(2) (a) Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.;
Golik, J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773.
(b) Shimizu, Y.; Chou, H. N.; Bando, H.; Van Duyne, G.; Clardy, J.
J. Am. Chem. Soc. 1986, 108, 514. (c) Baden, D. G.; Bourdelais, A. J.;
Jacocks, H.; Michelliza, S.; Naar, J. J. Environ. Health Perspect. 2005,
113, 621.
(4) (a) Satake, M.; Bourdelais, A. J.; Van Wagoner, R. M.; Baden,
D. G.; Wright, J. L. C. Org. Lett. 2008, 10, 3465. We have successfuly
synthesized brevisamide and tested its biological activities:(b) Kuranaga,
T.; Shirai, T.; Baden, D. G.; Wright, J. L. C.; Satake, M.; Tachibana, K.
Org. Lett. 2009, 11, 217. (c) Tsutsumi, R.; Kuranaga, T.; Wright, J. L. C.;
Baden, D. G.; Ito, E.; Satake, M.; Tachibana, K. Tetrahedron 2010, 66,
6775.
(3) (a) Bourdelais, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe,
P. M., Jr; Baden, D. G. J. Nat. Prod. 2005, 68, 2. (b) The proposed
structure was revised: Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden,
D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 128, 16989.
r
10.1021/ol102925d
Published on Web 01/19/2011
2011 American Chemical Society

phosphate 7 by our Suzuki-Miyaura cross-coupling-
based strategy.7
Scheme 2. Synthesis of the ABC Ring Fragment
Figure 1. Structures of brevisin (1), brevenal, and brevisamide.
supplying materials was essential. Here we report
the first and highly efficient total synthesis of 1 using
Suzuki-Miyaura cross coupling and an aldol addition
as the key steps.
Scheme 1. Synthetic Plan of 1
The A-ring fragment 6 was connected by Suzuki-
Miyaura cross coupling to the C-ring ketene acetal phos-
phate 7, which was prepared in eight steps1c,8 from com-
mercially available 2-deoxy-D-ribose. Namely hydroboration
of 6 with 9-BBN generated a corresponding alkylborane,
which was reacted in situ with 7 in the presence of aqueous
Cs2CO3 and a catalytic amount of PdCl2(dppf) giving rise
to a cross-coupled product 8 in 86% yield. Successive
hydroboration/oxidation of 8 with BH3 SMe2 followed
3
by regioselective DIBALH reduction9 gave diol 9. The
primary alcohol of diol 9 was selectively protected with a
TIPS group, and then the secondary alcohol was oxidized
to the ketone 10 using TPAP-NMO.10 Treatment of 10
with Zn(OTf)2 in the presence of EtSH accomplished the
deprotection of the TES groups and mixed thioacetal
formation, and subsequent benzylation of the hydroxy
group at C-10 afforded mixed thioacetal 11. Mixed thioa-
cetal 11 was oxidized to the corresponding sulfone, which
was treated with AlMe3 in a one-pot manner11 to introduce
the C-15 methyl group. Then, subsequent deprotection of
Our synthetic strategy to 1 is summarized in Scheme 1.
The side chain fragment 24c,5 and iodide fragment 3 would
be connected by means of Suzuki-Miyaura cross cou-
pling. The polycyclic ether core would be synthesized from
the ABC-ring methyl ketone 4 and the EF-ring aldehyde 5
by an aldol addition and subsequent construction of the
D-ring. Tricyclic ether 4 would be synthesized from the
A-ring exocyclic enol ether 66 and the C-ring ketene acetal
(7) (a) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K. Tetrahedron
Lett. 1998, 39, 9027. (b) Sasaki, M.; Fuwa, H.; Ishikawa, M.; Tachibana,
K. Org. Lett. 1999, 1, 1075. (c) Sasaki, M.; Fuwa, H. Nat. Prod. Rep.
2008, 25, 401.
(8) Kadota, I.; Kadowaki, C.; Park, C.-H.; Takamura, H.; Sato, K.;
Chan, P. W. H.; Thorand, S.; Yamamoto, Y. Tetrahedron 2002, 58, 1799.
(9) Takano, S.; Akiyama, Y.; Sato, S.; Ogasawara, K. Chem. Lett.
1983, 12, 1593.
(10) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 7, 639.
(5) Shirai, T.; Kuranaga, T.; Wright, J. L. C.; Baden, D. G.; Satake,
M.; Tachibana, K. Tetrahedron Lett. 2010, 51, 1394.
(6) Ohtani, N.; Tsutsumi, R.; Kuranaga, T.; Shirai, T.; Wright,
J. L. C.; Baden, D. G.; Satake, M.; Tachibana, K. Heterocycles 2010,
80, 825.
Org. Lett., Vol. 13, No. 4, 2011
697

the TIPS group gave the alcohol 12. Triflation of 12
followedby cyanidation with NaCN ledtothe correspond-
ing nitrile, which was treated with MeLi to afford the
methyl ketone 4 in 68% yield from 12 (Scheme 2).
intramolecular allylation15 to give the oxepane 20. The
relative configuration of 20 was confirmed by observed
NOE correlations between H-24/H-29, H-29/H-31, and
H3-39/H-32 and by the large proton coupling constant
(8.8 Hz) between H-31 and H-32. The regioselective DI-
BALH reduction of 20 led to diol 21. The primary alcohol
of diol 21 was selectively tosylated, and then the secondary
alcohol wasprotected by a TES group to afford tosylate22.
The tosylate 22 was reduced by LiAlH4 to afford the
EF-ring compound 23. Finally, ozonolysis of 23 provided
the aldehyde 5 (Scheme 3).
Scheme 3. Synthesis of the EF Ring Fragment
Scheme 4. Synthesis of the ABC/DEF Ring Compound 26
The connection of 4 and 5 by aldol addition and
construction of the polycyclic ether core were accom-
plished as shown in Scheme 4. Treatment of the lithium
enolate derived from 4 with aldehyde 5 furnished a
separable 2.8:1 mixture of C-23 diastereomers 24a16
and 24b.17 Treatment of 24a with Et3SiH in the pre-
sence of TMSOTf18 led to deprotection of TES ether
with concomitant stereoselective reduction to cyclized
product 25 in 98% yield. The unprecedented polycyclic
ether core of 1 could be constructed in only two steps
from the key fragments 4 and 5. Removal of all benzyl
groups of 25 followed by reprotection with the TES
group afforded pentakis TES ether 26. At this stage, in
order to convert 26 to iodide 3, only primary TES ether
The synthesis of the EF-ring fragment 5 started from the
known hydroxy epoxide 13.12 A one-pot oxidation/Wittig
reaction13 of 13 followed by the deprotection of the TBS
group led to R,β-unsaturated ester14. Treatment of14with
a catalytic amount of PPTS induced 6-endo cyclization12
to afford the pyran 15, and subsequent hydrogenation of
15 led to ester 16. Methyl acetal formation of 16 with
γ-methoxyallylstannane 1714 provided mixed methyl acetal
18 as a mixture of the diastereomers. This mixture
was treated with HMDS and TMSI to afford allylstannane
19. Reduction of the ester to the corresponding aldehyde
by DIBALH and treatment with BF3 OEt2 accomplished
3
(11) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan,
M. E.; Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321.
(12) Hydroxy epoxide 13 was synthesized by five steps from commer-
cially available 2-deoxy-D-ribose: Nicolaou, K. C.; Nugiel, D. A.;
Couladouros, E.; Hwang, C.-K. Tetrahedron 1990, 46, 4517.
(13) Vatele, J.-M. Tetrahedron Lett. 2006, 47, 715.
(14) Kadota, I.; Yamamoto, Y. J. Org. Chem. 1998, 63, 6597.
(15) (a) Yamamoto, Y.; Yamada, J.; Kadota, I. Tetrahedron Lett.
1991, 32, 7069. (b) Gevorgyan, V.; Kadota, I.; Yamamoto, Y. Tetra-
hedron Lett. 1993, 34, 1313. (c) Kadota, I.; Kawada, M.; Gevorgyan, V.;
Yamamoto, Y. J. Org. Chem. 1997, 62, 7439.
(16) The stereochemistry of the newly generated hydroxy group at the
C-23 of 24a was assigned after construction of the D ring. The coupling
constant (3 Hz) between H-23 and H-24 in 25 indicated the axial
orientation of the hydroxy group at the C-23.
(17) The minor undesired C-23 diastereomer 24b could also be
converted to 25 by an additional three steps, and the details are described
in the Supporting Information.
(18) (a) Hatakeyama, S.; Mori, H.; Kitano, K.; Yamada, H.; Nishizawa,
M. Tetrahedron Lett. 1994, 35, 4367. (b) Oishi, T.; Imaizumi, T.; Murata, M.
Chem. Lett. 2010, 39, 108.
698
Org. Lett., Vol. 13, No. 4, 2011

Scheme 5. Treatment of Tris-TES Ethers with DIBALH
Scheme 7. Selective Deprotection of 26
had to be selectively removed in the presence of four
secondary TES ethers.
ring accelerated the deprotection and generated its high
selectivity (Scheme 7). The primary alcohol 31 was con-
verted to iodide 3 with I2, PPh3, and imidazole. Finally,
connection of the fragments 2 and 3 by means of a
Suzuki-Miyaura cross coupling20 followed by the depro-
tection of all silyl groups and chemoselective oxidation of
the allylic alcohol at C-1 gave rise to 1 in 75% yield for the
three steps. The optical rotation and the other spectroscopic
data of synthetic 1 were identical with those of natural 1.
In conclusion, we have accomplished the first total synth-
esis of (-)-brevisin (1). The polycyclic ether core was con-
structed by means of a Suzuki-Miyaura cross coupling
reaction and aldol addition as the key steps. It is note-
worthy that the synthesis was accomplished in only 29
longest linear steps from commercially available 2-deoxy-
D-ribose. Furthermore, based on our highly efficient syn-
thetic strategy, we could synthesize over 70 mg of 1. The
present synthesis is a successful example of practically
supplying a marine polycyclic ether compound and will
be important for the elucidation of brevisin’s biological
activity.
Recently we reported the highly selective deprotection of
mono-and bis-silylethers by DIBALH.19 Thismethod was
also applicable to the selective deprotection of a primary
TES ether in the presence of two secondary TES ethers.
Tris-TES ethers 27 and 28 were converted to the corre-
sponding primary alcohols 29 and 30 in excellent yields
(Scheme 5).
Scheme 6. Completion of the Total Synthesis
Acknowledgment. This work was supported by KA-
KENHI (No. 20611002) and the Global COE Program
forChemistry Innovation, theUniversityofTokyo. T.K. is
grateful for a SUNBOR Scholarship. The natural brevisin
was isolated from cultures maintained under Grants P01
ES 10594 (NIEHS, DHHS) and MARBIONC, Marine
Biotechnology in North Carolina.
Supporting Information Available. Detailed experi-
mental procedures, characterizations, and copies of
1H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The completion of the total synthesis of 1 is illustrated in
Scheme 6. Application of the above selective deprotection
on pentakis-TES ether 26 gave primary alcohol 31 in 88%
yield. Perhaps the neighboring ether oxygen atom of the A
(19) Kuranaga, T.; Ishihara, S.; Ohtani, N.; Satake, M.; Tachibana,
K. Tetrahedron Lett. 2010, 51, 6345.
(20) Marshall, J.; Johns, B. J. Org. Chem. 1998, 63, 7885.
Org. Lett., Vol. 13, No. 4, 2011
699