Synthetic studies on maitotoxin. 3. Stereoselective synthesis of the BCDE-ring system

Article abstract of DOI:10.1021/ol8002699

The stereoselective synthesis of the BCDE-ring system of maitotoxin has been accomplished through a two-directional strategy for the construction of polycyclic ether. The key reactions involve Sml₂-induced double cyclization of a ss-alkoxyacrylate and a double dihydroxylation for construction of the B- and E-rings.

Full text of DOI:10.1021/ol8002699

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1683-1685
Synthetic Studies on Maitotoxin.
3. Stereoselective Synthesis of the
BCDE-Ring System
Masanori Satoh,† Hiroyuki Koshino,‡ and Tadashi Nakata*,†
Department of Chemistry, Faculty of Science, Tokyo UniVersity of Science,
1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan, and RIKEN (The Institute of
Physical and Chemical Research), 1-2 Hirosawa, Wako-shi, Saitama 351-0198, Japan
nakata@rs.kagu.tus.ac.jp
Received February 6, 2008
ABSTRACT
The stereoselective synthesis of the BCDE-ring system of maitotoxin has been accomplished through a two-directional strategy for the
construction of polycyclic ether. The key reactions involve SmI2-induced double cyclization of a ꢀ-alkoxyacrylate and a double dihydroxylation
for construction of the B- and E-rings.
Maitotoxin (MTX, 1, Figure 1), isolated from the dinoflagel-
late Gambierdiscus toxicus, is the most toxic and largest
natural product (MW 3422) known thus far, except for
biopolymers, such as proteins or polysaccharides.1 The
complete relative and absolute structure of MTX was
determined by the MuratasYasumoto,2 Tachibana3 and
Kishi4 groups.5 MTX has 32 fused ether rings, 28 hydroxyl
groups, 21 methyl groups, 2 sulfates, and 98 chiral centers;
the complex structure presents a formidable challenge to
synthetic chemists. In the previous papers,6 we reported the
syntheses of the C′D′E′F′-ring system having a side chain
and the WXYZA′-ring system. We now report an efficient
synthesis of the BCDE-ring system of MTX (1) through a
two-directional strategy for the construction of polycyclic
ether.
The ABCDEF-ring system of MTX consists of a trans-
fused 6,7,6,6,6,6-membered hexacyclic ether core containing
17 chiral centers, two angular methyl groups, and five
hydroxyl groups. Our first issue was the construction of the
BCDE-ring system, because the A- and F-rings could be
constructed at the late stage, following coupling with
appropriate side chains. Our synthetic strategy for the BCDE-
† Tokyo University of Science.
‡ RIKEN (The Institute of Physical and Chemical Research).
(1) (a) For reviews on marine polycyclic ethers, see: 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.
(2) (a) Murata, M.; Iwashita, T.; Yokoyama, A.; Sasaki, M.; Yasumoto,
T. J. Am. Chem. Soc. 1992, 114, 6594. (b) Murata, M.; Naoki, H.; Iwashita,
T.; Matsunaga, S.; Sasaki, M.; Yokoyama, A.; Yasumoto, T. J. Am. Chem.
Soc. 1993, 115, 2060. (c) Murata, M.; Naoki, H.; Matsunaga, S.; Satake,
M.; Yasumoto, T. J. Am. Chem. Soc. 1994, 116, 7098. (d) Satake, M.; Ishida,
S.; Yasumoto, T.; Murata, M.; Utsumi, H.; Hinomoto, T. J. Am. Chem.
Soc. 1995, 117, 7019.
(3) (a) Sasaki, M.; Matsumori, N.; Maruyama, T.; Nonomura, T.; Murata,
M.; Tachibana, K.; Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1672. (b) Nonomura, T.; Sasaki, M.; Matsumori, N.; Murata, M.; Tachibana,
K.; Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1675. (c) Sasaki,
M.; Nonomura, T.; Murata, M.; Tachibana, K. Tetrahedron Lett. 1994, 35,
5023. (d) Sasaki, M.; Nonomura, T.; Murata, M.; Tachibana, K. Tetrahedron
Lett. 1995, 36, 9007. (e) Sasaki, M.; Matsumori, N.; Murata, M.; Tachibana,
K. Tetrahedron Lett. 1995, 36, 9011.
(5) The stereochemistry at the J/K ring junction was recently questioned,
but the originally assigned structure was supported through synthesis of
the GHIJK-ring system by Nicolaou et al. (a) Gallimore, A. R.; Spencer,
J. B. Angew. Chem., Int. Ed. 2006, 45, 4406. (b) Nicolaou, K. C.; Frederick,
M. O. Angew. Chem., Int. Ed. 2007, 46, 5278. (c) Nicolaou, K. C.; Cole,
K. P.; Frederick, M. O.; Aversa, R. J.; Denton, R. M. Angew. Chem., Int.
Ed. 2007, 46, 8875.
(4) (a) Zheng, W.; DeMattei, J. A.; Wu, J.-P.; Duan, J. J.-W.; Cook,
L. R.; Oinuma, H.; Kishi, Y. J. Am. Chem. Soc. 1996, 118, 7946. (b) Cook,
L. R.; Oinuma, H.; Semones, M, A.; Kishi, Y. J. Am. Chem. Soc. 1997,
119, 7928.
(6) (a) Morita, M.; Ishiyama, S.; H.; Koshino, H.; Nakata, T. Org. Lett.
2008, 10, 1675. (b) Morita, M.; Haketa, T.; Koshino, H.; Nakata, T. Org.
Lett. 2008, 10, 1679.
10.1021/ol8002699 CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society

Figure 1. Structure of maitotoxin (1).
Scheme 2
Scheme 1. Synthetic Strategy for the BCDE-Ring System
ring system i is shown in Scheme 1. We planned to apply a
two-directional strategy for efficient construction of the B-
and E-rings, because they have similar functional groups on
the rings, although the ring sizes are different. Thus, double
hydroxylation of diketone ii would provide the BCDE-ring
i. The precursor iii would be synthesized from bis(aldehyde)
iv in one step by our recently developed SmI2-induced
cyclization.7 The bis(aldehyde) iv would be efficiently
synthesized from the CD-ring v by means of several double
reactions at the left and right sides.
The synthesis of the CD-ring began with the known
tetrahydropyran 28 as the C-ring, prepared from commercially
available 2-deoxy-D-ribose (Scheme 2). The diol 2 was
converted into dibenzyl ether 3 by protective group manipu-
lation, that is, (1) benzylation, (2) removal of benzylidene,
(3) di-TBS protection, and (4) selective removal of the TBS
group. Mesylation of the alcohol 3 followed by treatment
with NaCN in DMSO afforded nitrile 4 in 96% yield (two
steps). Reduction of 4 with DIBALH, Grignard reaction using
MeMgBr, and TPAPsNMO oxidation9 gave methyl ketone
5 in 86% yield (three steps). After removal of the TBS group
in 5, hetero-Michael addition with methyl propiolate in the
presence of N-methylmorpholine (NMM) afforded ꢀ-alkoxy-
10
acrylate 6, quantitatively. Upon treatment of 6 with SmI2
in the presence of MeOH in THF, reductive cyclization
effectively took place to give the desired trans-fused CD-
ring 7 as a single product, quantitatively.7
The dibenzyl ether 7 was converted into bis(ꢀ-alkoxy-
acrylate) 13, a key intermediate for double construction of
the B- and E-rings (Scheme 3). Removal of the dibenzyl
(7) (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) Suzuki, K.; Matsukura, H.; Matsuo, G.; Koshino, H; Nakata,
T Tetrahedron Lett. 2002, 43, 8653. (e) Matsuo, G.; Kadohama, H.; Nakata,
T. Chem. Lett. 2002, 148. (f) Hori, N.; Matsuo, G.; Matsukura, H.; Na-
kata, T. Tetrahedron 2002, 58, 1853.
(9) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625. (b) Griffith, W. P.; Ley, S. V.
Aldrichimica Acta 1990, 23, 13.
(10) (a) Namy, J. L.; Girard, P.; Kagan, H. B. NouV. J. Chim. 1977, 1,
5. (b) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693. (c) Kagan, B. H. New J. Chem. 1990, 14, 453.
(8) Matsuo, G.; Matsukura, H.; Hori, N.; Nakata, T. Tetrahedron Lett.
2000, 41, 7673.
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Org. Lett., Vol. 10, No. 9, 2008

Scheme 3
group in 7, di-TBS protection, and selective removal of the
of 17 with LiHMDS and TMSCl gave bis(silylenol ether)
18, which, upon treatment with OsO4sNMO, stereoselec-
tively underwent double hydroxylation to provide di-TBS
19 in 42% yield (two steps), corresponding to the BCDE-
ring system of MTX (1). The stereoselective hydroxylation
of 18 would proceed from the less hindered R-side to give
19, bacause of the steric hindrance of angular Me groups
with ꢀ-axial configuration. The structure of 19 was un-
equivocally confirmed by extensive NMR analyses (1H and
13C NMR, NOE, and HMBC).
TBS group with CSA afforded diol 8 in 78% yield (three
steps). Oxidation of 8 with TPAPsNMO followed by Wittig
reaction using Ph3PdCHCO2Et afforded R,ꢀ-unsaturated
ester 9 in 94% yield (two steps), and this was subjected to
successive hydrogenation and TMS protection to give diester
10 in 96% yield (two steps). The diester 10 was efficiently
converted into the desired bis(aldehyde) 13 via several double
reactions at the left and right sides. Reduction of 10 with
DIBALH afforded bis(aldehyde), which was treated with 1,3-
propanedithiol and BF3·Et2O to give bis(thioacetal) 11 in 67%
yield (two steps). Treatment of 11 with methyl 3-methoxy-
acrylate and PPTS in toluene at reflux7d effected double
hetero-Michael addition to give bis(ꢀ-alkoxyacrylate) 12 in
58% yield. Removal of two thioacetals in 12 by treatment
with MeI afforded bis(aldehyde) 13 in 89% yield. Upon
treatment with SmI2 in the presence of MeOH in THF, the
desired double cyclization took place, constructing the syn-
trans-oxepane B-ring and syn-trans-tetrahydropyran E-ring
with complete stereoselection, to give esterslactone 14
(60%) and diester 15 (29%). Each product, 14 and 15, was
treated with LiAlH4 to give the same tetraol as a single
product, which was treated with TBSCl to give di-TBS ether
16 in 78% yield (two steps). Oxidation of the diol 16 with
TPAPsNMO afforded diketone 17 in 69% yield. Treatment
In summary, stereoselective synthesis of the BCDE-ring
system 19 has been accomplished through a two-directional
strategy based on several double reactions at the left and
right sides, including SmI2-induced reductive cyclization.
Acknowledgment. This work was financially supported
in part by the Uehara Memorial Foundation and a Grant-in-
Aid for Scientific Research on Priority Areas from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan.
Supporting Information Available: Detailed experimen-
tal procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL8002699
Org. Lett., Vol. 10, No. 9, 2008
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