Total synthesis of (-)-brevenal: A concise synthetic entry to the pentacyclic polyether core

Article abstract of DOI:10.1021/ol800685c

(Chemical Equation Presented) Total synthesis of (-)-brevenal, a novel marine polycyclic ether natural product, is described. Highly efficient and scalable entries to the AB-ring exo-olefin and the DE-ring enol phosphate and a rapid construction of the C-

Full text of DOI:10.1021/ol800685c

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2275-2278
Total Synthesis of (-)-Brevenal: A
Concise Synthetic Entry to the
Pentacyclic Polyether Core
Makoto Ebine, Haruhiko Fuwa,* and Makoto Sasaki*
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences, Tohoku
UniVersity, 1-1 Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan
hfuwa@bios.tohoku.ac.jp; masasaki@bios.tohoku.ac.jp
Received March 25, 2008
ABSTRACT
Total synthesis of (-)-brevenal, a novel marine polycyclic ether natural product, is described. Highly efficient and scalable entries to the
AB-ring exo-olefin and the DE-ring enol phosphate and a rapid construction of the C-ring by means of our Suzuki-Miyaura coupling-based
strategy realized a concise synthesis of the pentacyclic skeleton of (-)-brevenal. The present synthesis is considerably more efficient than
our previous synthesis (longest linear sequence: 50 steps from 2-deoxy-D-ribose).
The structural complexity and intriguing biological activities
of marine polycyclic ether natural products continue to attract
the attention of chemists and biologists.1,2 Brevenal, a novel
member of this family of natural products, was isolated from
the Florida red tide-forming dinoflagellate Karenia breVis
by Baden and co-workers.3 Its gross structure including the
relative stereochemistry was disclosed as 1 based on
extensive 2D-NMR analysis (Figure 1). We have recently
reported the first total synthesis of (-)-brevenal, culminating
in the structure revision of the originally proposed structure
1 and determination of the absolute configuration as shown
(1) For reviews of marine polycyclic ether natural products, see: (a)
Yasumoto, T.; Murata, M. Chem. ReV 1993, 93, 1897. (b) Murata, M.;
Yasumoto, T. Nat. Prod. Rep. 2000, 293. (c) Yasumoto, T. Chem. Rec.
2001, 3, 228
.
Figure 1. The proposed structure 1 and the revised structure 2
(2) For recent reviews of the synthesis of marine polycyclic ether natural
products, see: (a) Inoue, M. Chem. ReV. 2005, 105, 4379. (b) Nakata, T.
Chem. ReV. 2005, 105, 4314. (c) Fuwa, H.; Sasaki, M. Curr. Opin. Drug
of (-)-brevenal.
DiscoVery DeV. 2007, 10, 784
.
by 2.4 The structural characteristic of this natural product is
the densely functionalized pentacyclic polyether core ar-
ranged with a heavily substituted dienal side chain, which
(3) (a) Bourdelais, A. J.; Campbell, S.; Jacocks, H.; Naar, J.; Wright,
J. L. C.; Carsi, J.; Baden, D. G. Cell. Mol. Neurobiol. 2004, 24, 553. (b)
Bourdelais, A. J.; Jacocks, H. M.; Wright, J. L. C.; Bigwarfe, P. M., Jr.;
Baden, D. G. J. Nat. Prod. 2005, 68, 2.
10.1021/ol800685c CCC: $40.75
Published on Web 04/30/2008
2008 American Chemical Society

makes it a synthetically challenging molecule. Brevenal
competitivelydisplacestritiateddihydrobrevetoxinB([3H]PbTx-
3) from voltage-sensitive sodium channels (VSSCs) derived
from rat brain synaptosomes in a dose dependent manner
and antagonizes the toxic effects of brevetoxins in ViVo. Even
more importantly, Abraham, Baden, and co-workers have
demonstrated that picomolar concentrations of brevenal
effectively improves tracheal mucus clearance activity in an
animal model of asthma.5 Thus, brevenal represents a
structurally novel source of therapeutic agents for treatment
of mucociliary dysfunction associated with cystic fibrosis and
other lung disorders. However, exploration of the structure-
acitivity relationships of this natural product as well as
elucidation of the mode of action on the molecular basis,
including determination of the precise location of the
brevenal-binding site on VSSCs, have yet to be investigated.
In this context, the development of a focused library of
structural analogues and designed multifunctional molecular
probes would be necessary and, as a consequence, a concise
and rapid access to the pentacyclic core structure of 2
becomes essential. Unfortunately, our first-generation syn-
thesis of 2 suffered from the lengthy fragment syntheses and
from the circuitous steps for assembly of these fragments,
which were the serious bottlenecks for material throughput.
Herein, we describe a total synthesis of 2 based on a concise
synthetic entry to the pentacyclic polyether core. The
synthesis features a 2-fold use of our Suzuki-Miyaura
coupling/mixed thioacetalization strategy6–8 to attain a high
degree of convergency.
Scheme 1. Synthesis Plan of (-)-Brevenal
Lithiation of 10 with t-BuLi in the presence of B-MeO-9-
BBN generated an alkylborate,9 which was coupled with enol
phosphate 7,6b corresponding to the B-ring of brevenal, to
deliver enol ether 11 in 90% yield. Stereoselective hydrobo-
ration of 11 was best achieved using thexylborane, which
was followed by oxidation10 of the resultant alcohol to give
ketone 12. The stereochemistry at C1111 was established by
an NOE experiment as shown. Removal of the MPM group
Our synthesis plan toward 2 is summarized in Scheme 1.
We envisaged that pentacyclic core 3, a key intermediate in
the previous total synthesis,4b could be rapidly accessed from
the AB-ring exo-olefin 4 and the DE-ring enol phosphate 5
by Suzuki-Miyaura coupling and subsequent construction
of the C-ring by a mixed thioacetalization/methylation
sequence. The AB-ring exo-olefin 4 was retrosynthetically
divided into alkylborate 6 and the B-ring enol phosphate 7
based on a further application of the Suzuki-Miyaura
coupling/mixed thioacetalization strategy. On the other hand,
the DE-ring enol phosphate 5 was traced back to the E-ring
8 via lactonization of the D-ring. Thus, a 2-fold use of the
Suzuki-Miyaura coupling/mixed thioacetalization strategy
would realize a highly convergent synthesis of 2.
12
and subsequent treatment with EtSH/Zn(OTf)2 afforded
mixed thioacetal 13 in good yield. Introduction of the C12
angular methyl group was achieved by one-pot oxidation/
methylation protocol,12a giving rise to bicycle 14 in 92%
yield.
After removal of the benzyl groups, selective protection
of the resultant primary alcohol as its TIPS ether led to
alcohol 15. To install the C14 hydroxy group, the C15
secondary alcohol of 15 was first regioselectively eliminated
by a one-pot procedure.13 Thus, treatment of 15 with Tf2O/
2,6-lutidine, followed by addition of DBU, afforded olefin
The synthesis of the AB-ring exo-olefin 4 started with
iodination of alcohol 9,4 which gave iodide 10 (Scheme 2).
(4) (a) Fuwa, H.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc. 2006, 128,
9648. (b) Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki, M.
J. Am. Chem. Soc. 2006, 128, 16989.
(5) Abraham, W. M.; Bourdelais, A. J.; Sabater, J. R.; Ahmed, A.; Lee,
T. A.; Serebriakov, I.; Baden, D. G. Am. J. Respir. Crit. Care Med. 2005,
171, 26.
(9) Marshall, J. A.; Bourbeau, M. P. J. Org. Chem. 2002, 67, 2751.
(10) Ley, S. V.; Normann, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(6) (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.; Ishikawa, M.; Fuwa, H.;
(11) The carbon numbering in this paper corresponds to that of the
natural product.
(12) (a) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.;
Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321. (b) Fuwa, H.; Sasaki, M.;
Tachibana, K. Tetrahedron Lett. 2000, 41, 8371. (c) Fuwa, H.; Sasaki, M.;
Tachibana, K. Tetrahedron 2001, 57, 3019.
Tachibana, K. Tetrahedron 2002, 58, 1851
.
(7) (a) Fuwa, H.; Sasaki, M.; Satake, M.; Tachibana, K. Org. Lett. 2002,
4, 2981. (b) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem.
Soc. 2002, 124, 14983. (c) Tsukano, C.; Sasaki, M. J. Am. Chem. Soc. 2003,
125, 14294. (d) Tsukano, C.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc.
(13) We previously utilized a four-step sequence [(i) TPAP, NMO; (ii)
LHMDS, TMSCl; (iii) OsO4, NMO; (iv) DIBALH] to synthesize related
diols. See ref 4 and: Sasaki, M.; Ebine, M.; Takagi, H.; Takakura, H.; Shida,
T.; Satake, M.; Oshima, Y.; Igarashi, T.; Yasumoto, T. Org. Lett. 2004, 6,
1501.
2005, 127, 4326
.
(8) For reviews, see: (a) Sasaki, M.; Fuwa, H. Synlett 2004, 1851. (b)
Sasaki, M.; Fuwa, H. Nat. Prod. Rep. 2008, 25, 401
.
2276
Org. Lett., Vol. 10, No. 11, 2008

Scheme 2
.
Synthesis of the AB-Ring exo-Olefin 4
Scheme 3. Synthesis of the DE-Ring Enol Phosphate 5
16 in 76% yield. After protective group manipulations,
stereoselective dihydroxylation of the derived olefin 17
furnished diol 18 in 82% yield as a single stereoisomer. The
stereochemical outcome of the present reaction was con-
firmed by an NOE experiment of the acetonide derivative
of 18.14 Protection of 18 (4-methoxybenzyloxymethyl chlo-
ride, i-Pr2NEt) and cleavage of the TIPS group gave an
alcohol, which was iodinated and subsequently treated with
KOt-Bu to furnish the AB-ring exo-olefin 4.
The synthesis of the DE-ring enol phosphate 5 is sum-
marized in Scheme 3. Regioselective opening of the known
epoxide 19,15 readily available from 1,5-pentanediol in five
steps, with Ti(OMPM)4 provided diol 20 in good yield.
Selective sulfonylation of the primary alcohol of 20 with
2,4,6-trimethylbenzenesulfonyl chloride/pyridine followed by
base treatment gave epoxide 21, which was then allylated
with allylmagnesium bromide in the presence of CuI to afford
alcohol 22. Benzylation followed by Wacker oxidation16
delivered methyl ketone 24. Deprotection of the MPM group
and subsequent attachment of an acrylate unit led to
ꢀ-alkoxyacrylate 25. Treatment of 25 with SmI2 in the
presence of MeOH (THF, room temperature)17 furnished
lactone 8 in 91% yield as a single stereoisomer. The
stereochemistries of newly generated stereocenters were
established by NOE experiments.14 Reduction of 8 with
DIBALH, followed by Wittig methylenation of the resultant
hemiacetal, gave alcohol 26. After conversion of 26 to 27
in four steps, direct oxidative cyclization of the 1,6-diol 27
18
using TEMPO/PhI(OAc)2 furnished lactone 28 in a re-
markably high yield. To the best of our knowledge, applica-
tion of these conditions to oxidative cyclization of 1,6-diol
to construct seven-membered lactone has not been reported.
Enolization of 28 with KHMDS in the presence of
(PhO)2P(O)Cl delivered the DE-ring enol phosphate 5.
Assembly of the AB-ring exo-olefin 4 and the DE-ring
enol phosphate 5 and subsequent construction of the C-ring
were accomplished according to our Suzuki-Miyaura coupling-
based strategy (Scheme 4). Thus, stereoselective hydrobo-
ration of 4 using 9-BBN-H generated an alkylborane, which
was reacted with 5 in the presence of aqueous Cs2CO3 as a
base and Pd(PPh3)4 as a catalyst to furnish enol ether 29 in
92% yield as a single stereoisomer. Hydroboration of 29
proceeded stereoselectively to give an alcohol, which was
oxidized to give ketone 30 as a single stereoisomer. Cleavage
of the 4-methoxybenzyloxymethyl and silyl groups,19 mixed
(17) (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron
Lett. 1999, 40, 2811. (b) Hori, N.; Matsukura, H.; Nakata, T. Org. Lett.
1999, 1, 1099. (c) Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron Lett. 1999,
40, 8859. (d) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron
2002, 58, 1853.
(14) See Supporting Information for details.
(15) Liu, J.; Yang, J.-H.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006,
47, 6121.
(18) For oxidation of 1,5-diols using TEMPO/PhI(OAc)2, see: Hansen,
T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.; Abrams, J. N.; Forsyth,
C. J. Tetrahedron Lett. 2003, 44, 57.
(16) Smith, A. B., III; Cho, Y. S.; Friestad, G. K. Tetrahedron Lett.
1998, 39, 8765.
(19) Selective cleavage of the 4-methoxybenzyloxymethyl groups using
DDQ, CAN, or Me3SiBr gave unsatisfactory results.
Org. Lett., Vol. 10, No. 11, 2008
2277

of 2.4b Thus, the present synthesis constitutes a formal total
synthesis of 2.
Scheme 4. Total Synthesis of (-)-Brevenal
In summary, we have accomplished the total synthesis of
(-)-brevenal based on a concise synthetic entry to the
pentacyclic polyether core. The remarkable features of the
present synthesis are: (1) a highly stereocontrolled, conver-
gent synthesis of the AB-ring exo-olefin 4 by means of the
Suzuki-Miyaura coupling/mixed thioacetalization strategy,
(2) an efficient synthesis of the DE-ring enol phosphate 5
employing an oxidative lactonization of the D-ring, and (3)
a rapid construction of the C-ring based on the second use
of the Suzuki-Miyaura coupling-based strategy. The densely
functionalized pentacyclic core structure 3 was successfully
built up with a longest linear sequence (LLS) of just 32 steps.
Thus, the present synthesis is considerably more efficient
than our previous synthesis (LLS: 50 steps from 2-deoxy-
D-ribose). The present synthesis should be effective for
preparing diverse structural analogues and molecular probes
for detailed investigations on the structure-activity relation-
ships and the molecular mode of action of this biologically
intriguing natural product. Further studies are currently
underway along this line and will be reported in due course.
Acknowledgment. This work was financially supported
in part by a Grant-in-Aid for Scientific Research (B) from
JSPS and by a Grant-in-Aid for Scientific Research on
Priority Areas (“Creation of Biologically Functional Mol-
ecules”) from MEXT. M.E. is a recipient of a research
fellowship from JSPS.
thioacetalization, and ensuing silylation of the resultant
unprotected hydroxy groups delivered mixed thioacetal 31.
Introduction of the C19 methyl group was achieved in a one-
pot manner (mCPBA; then AlMe3), giving rise to the
pentacyclic polyether 32 in 96% yield as a single stereoiso-
mer. The stereochemistry of 32 was confirmed by a ROESY
experiment. Finally, debenzylation of 32 using LiDBB20
afforded alcohol 3, whose spectroscopic properties are in full
accordance with those of the authentic material that had been
synthesized as an intermediate in our previous total synthesis
Supporting Information Available: Stereochemical as-
signment of 8 and 18, detailed experiemental procedures,
1
spectroscopic data, and copies of H and 13C NMR spectra
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(20) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924. (b) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854.
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