Synthetic studies on maitotoxin. 1. Stereoselective synthesis of the C D E F -ring system having a side chain

Article abstract of DOI:10.1021/ol800267x

The stereoselective synthesis of the maitotoxin C D E F -ring system having a side chain has been accomplished through a convergent strategy. The key reactions include Horner-Wadsworth-Emmons coupling of the C D E -ring and the side chain and subsequent c

Full text of DOI:10.1021/ol800267x

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1675-1678
Synthetic Studies on Maitotoxin. 1.
Stereoselective Synthesis of the
C′D′E′F′-Ring System Having a Side
Chain
Masayuki Morita,†,# Seishi Ishiyama,‡ Hiroyuki Koshino,† and Tadashi Nakata*,‡
RIKEN (The Institute of Physical and Chemical Research), 1-2 Hirosawa, Wako-shi,
Saitama 351-0198, Japan, and Department of Chemistry, Faculty of Science, Tokyo
UniVersity of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
nakata@rs.kagu.tus.ac.jp
Received February 6, 2008
ABSTRACT
The stereoselective synthesis of the maitotoxin C′D′E′F′-ring system having a side chain has been accomplished through a convergent strategy.
The key reactions include Horner-Wadsworth-Emmons coupling of the C′D′E′-ring and the side chain and subsequent construction of the
F′-ring by silane reduction of dihydropyran.
Maitotoxin (MTX; 1, Figure 1), isolated from the dinoflagel-
late Gambierdiscus toxicus, is one of the most structurally
awe-inspiring and largest natural products (MW 3422) ever
isolated.1 It is implicated in ciguatera food poisoning, and
influences Ca2+-dependent mechanisms in a wide range of
cell types.2 The full structure of MTX, including a partial
stereochemical assignment, was reported by the Murata-
Yasumoto group between 1992-1995.3 The relative stere-
ochemistry of the remaining acyclic parts and the absolute
structure of MTX were determined independently by Ta-
chibana4 and Kishi5 and their colleagues in 1996.6 The giant
structure of MTX contains 32 fused ether rings, 28 hydroxyl
groups, 21 methyl groups, 2 sulfates, and 98 chiral centers.
The skeletal novelty, complexity, and biological activity of
MTX have attracted the attention of both chemists and
biologists. We now report the stereoselective synthesis of
the MTX C′D′E′F′-ring having a side chain through a con-
vergent strategy.7
(4) (a) Sasaki, M.; Matsumori, N.; Maruyama, T.; Nonomura, T.; Murata,
M.; Tachibana, K.; and 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.
† RIKEN (The Institute of Physical and Chemical Research).
‡ Tokyo University of Science.
# On leave from Chemicrea Inc.
(1) Yokoyama, A.; Murata, M.; Oshima, Y.; Iwashita, T.; Yasumoto,
T. J. Biochem. 1988, 104, 184.
(5) (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.
(2) Takahashi, M.; Ohizumi, Y.; Yasumoto, T. J. Biol. Chem. 1982,
257, 7287.
(3) (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.
(6) 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.
10.1021/ol800267x 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 C′D′E′F′-Ring System
ficiently accomplished by SmI2-induced cyclization.9 The
intermediate 2 was converted into the key aldehyde 5
required as a coupling partner (Scheme 2). After protection
of the alcohol 2 with TBSOTf, successive DIBALH reduction
and benzylation afforded dibenzyl ether 4, quantitatively.
Cleavage of the olefin 4 by ozonolysis thereafter provided
the desired aldehyde 5.
The synthesis of the side chain 14 having four chiral
centers began with the known alcohol 610,11 (Scheme 3).
Oxidation of 6 with SO3·py-DMSO gave aldehyde,11a which
was subjected to HWE reaction with a chiral imide 1512 to
The C′D′E′F′-ring system of MTX consists of a trans-
fused 6,6,6,6-membered tetracyclic ether core containing nine
chiral centers, three angular methyl groups, and a 1,2-syn-
dihydroxy-4,5-anti-dimethyl-oct-7-ene side chain. Our syn-
thetic strategy to obtain the C′D′E′F′-ring i having a side
chain is shown in Scheme 1. The synthesis of the target
compound i would be accomplished via coupling of the side
chain ꢀ-ketophosphonate iv and the C′D′E′-ring aldehyde v
using a Horner-Wadsworth-Emmons (HWE) reaction. The
F′-ring would be synthesized by Lewis acid-mediated silane
reduction of methyl acetal ii, which would be prepared from
hydroxy ketone iii.
(9) (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) Hori, N.; Matsuo, G.; Matsukura,
H.; Nakata, T. Tetrahedron 2002, 58, 1853.
We have already reported the stereoselective synthesis of
the C′D′E′F′-ring lactone 3 via 2,8 in which construction of
1,3-diaxial angular methyl groups of the D′-ring was ef-
(10) The alcohol 6 was synthesized starting from (R)-3-tert-butyloxy-
carbonyl-2-methylpropanoic acid (>99.6% ee) in five steps: (1) BH3, (2)
MOMCl, (3) LiAlH4, (4) NaH, BnBr, (5) conc. HCl, MeOH. We thank
(7) Kishi et al.5a reported the synthesis of an E′F′-ring model compound
with no angular methyl groups, having a side chain, for structure deter-
Mitsubishi Rayon Co., Ltd. for providing the starting carboxylic acid.
mination.
(11) (a) Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H. J. Org.
Chem. 1992, 57, 1179. (b) White, J. D.; Xu, Q.; Lee, C.-S.; Valeriote, F. A.
(8) Sakamoto, Y.; Matsuo, G.; Matsukura, H.; Nakata, T. Org. Lett. 2001,
3, 2749.
Org. Biomol. Chem. 2004, 2, 2092
.
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Org. Lett., Vol. 10, No. 9, 2008

Scheme 3
Scheme 4
give 7 in 86% yield (two steps). 1,4-Conjugate addition of
ring system 22 (Scheme 4). The HWE reaction of the
C′D′E′-ring aldehyde 5 with 14 was too slow to give the
coupling product. However, the present reaction using 10
equiv of 14 proceeded slowly, and enone 18 was obtained
in 84% yield (two steps from the olefin 4) after three days.
Hydrogenation of 18 followed by TBAF treatment af-
forded diol-ketone 19. Attempts to achieve methyl ac-
etalization of 19 under various conditions failed, giving
a complex mixture, for example, camphorsulfonic acid
(CSA) and CH(OMe)3 in CH2Cl2-MeOH. During these
reactions, dihydropyran was first formed and gradually
decomposed. Thus, we turned our efforts to the formation
of dihydropyran, which might be converted to the desired
tetrahydropyran. Several attempts to generate the dihy-
dropyran ring gave unsatisfactory results, for example,
treatment with CSA, TsOH, PPTS, etc. After many trials,
we found that treatment of 19 with Nafion-H NR5018 in
the presence of molecular sieve (MS) 4A in CH2Cl2 at rt
effectively induced dehydration to give the desired dihy-
dropyran 20 in 77% yield (three steps from 18).
Dess-Martin oxidation of 20 followed by Wittig reaction
using Ph3PdCH2 afforded olefin 21, quantitatively.
7 with MeMgBr and CuBr·Me2S13 afforded R-methyl adduct
8 in 98% yield (dr ) 98:2).14 Reduction of 8 with LiBH4,
protection with tert-butyldiphenylsilylchloride (TBDPSCl),
and removal of the benzyl group with lithium di-tert-
butylbiphenylide (LiDBB)15 afforded alcohol 10 in 71% yield
(three steps). Oxidation of 10 with Dess-Martin periodinane
followed by HWE reaction using (EtO)2P(O)CH2CO2Me and
t-BuOK afforded R,ꢀ-unsaturated ester 11 in 91% yield (two
steps). The Sharpless asymmetric dihydroxylation16 using
AD-mix-ꢀ provided R-diol 12 (dr ) 98:2) in 93% yield.17
After protection of the diol as its acetonide (93%), the
resulting ester 13 was treated with (MeO)2P(O)Me and
n-BuLi to give ꢀ-ketophosphonate 14 in 95% yield.
With the requisite coupling partners 5 and 14 in hand,
we focused our attention on the synthesis of the C′D′E′F′-
(12) We thank Chemicrea Inc. for providing (S)-4-phenyl-2-oxazolidi-
none as the starting material for preparing 15.
(13) Nicolas, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58,
766.
(14) The anti configuration of the dimethyl group in 8 was confirmed
by comparison of NMR data of the diol, prepared from 10 by TBAF
treatment, and those of authentic anti-3,4-dimethylhexane-1,6-diol reported
by Kishi et al.5
Org. Lett., Vol. 10, No. 9, 2008
1677

Here, reduction of dihydropyran to tetrahydropyran, a
crucial step, was examined using model compound 16.
Reduction of 16 with Et3SiH in the presence of TFA or
TMSOTf in CH2Cl2 at rt afforded tetrahydropyran 17 in 55%
or 50% yield, respectively. The best result (74%) was
obtained by treatment with Et3SiH in the presence of AgBF4.
Thus, that condition was applied to the reduction of 21.
Upon treatment of 21 with Et3SiH and AgBF4 in CH2Cl2 at
rt, reduction of dihydropyran took place, accompanied with
deprotection of the acetonide, to give the desired tetrahy-
dropyran 22 in 81% yield, corresponding to the MTX
C′D′E′F′-ring having a side chain. The stereostructure of 22
was unequivocally confirmed by NMR analyses (1H and 13
C
NMR, NOE, and HMBC).
1
Figure 2 shows the difference in the H (600 MHz) and
13C (150 MHz) chemical shifts between synthetic C′D′E′F′-
ring 22 and MTX (1).19 The 1H and 13C NMR chemical shifts
for both compounds are in excellent accordance, although
several values differ from those of MTX, because of the
absence of the oxepene B′-ring, etc. This synthesis provides
reconfirmation of the stereostructure of the corresponding
portion in MTX.
1
Figure 2.
Differences in the H (600 MHz) and 13C (150 MHz)
chemical shifts (∆δ/ppm) between synthetic 22 and the values
reported for MTX (1:1 C5D5N-CD3OD). The x- and y-axes represent
carbon number and ∆δ (∆δ ) δMTX - δ22 in ppm), respectively.
HWE coupling of the C′D′E′-ring and the side chain, fol-
lowed by construction of the F′-ring.
In summary, stereoselective synthesis of the MTX C′D′E′F′-
ring system having a side chain has been accomplished via
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.
(15) (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.
(16) (a) Hentges, S. G.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
4263. (b) Kolb, H. C.; Van Nievwennze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483.
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.
(17) Stereochemistry of the R-diol in 12 was assigned according to the
empirical rule for Sharpless asymmetric dihydroxylation.16
(18) Olah, G. A.; Iyer, P. S.; Prakash, G. K. S. Synthesis 1986, 513.
(19) The numbering of 22 follows that of the corresponding carbon atom
in MTX.
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Org. Lett., Vol. 10, No. 9, 2008