Synthetic studies on maitotoxin. 2. Stereoselective synthesis of the WXYZA -ring system

Article abstract of DOI:10.1021/ol800268c

The stereoselective synthesis of the WXYZA -ring system of maitotoxin has been accomplished via a linear synthetic approach, in which key reactions were Sml₂-induced cyclization of ss-alkoxyacrylate for the construction of the A -, Y-, and X-rings and 6-endo cyclization of hydroxy vinylepoxide for that of the Z- and W-rings.

Full text of DOI:10.1021/ol800268c

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1679-1682
Synthetic Studies on Maitotoxin. 2.
Stereoselective Synthesis of the
WXYZA′-Ring System
Masayuki Morita,†,# Tasuku Haketa,‡ 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 WXYZA′-ring system of maitotoxin has been accomplished via a linear synthetic approach, in which key
reactions were SmI2-induced cyclization of ꢀ-alkoxyacrylate for the construction of the A′-, Y-, and X-rings and 6-endo cyclization of hydroxy
vinylepoxide for that of the Z- and W-rings.
The polyether marine natural product, maitotoxin (MTX, 1,
Figure 1), is currently one of the most toxic and complex
natural products (MW 3422) known.1 It possesses 32 fused
ether rings, 28 hydroxyl groups, 21 methyl groups, 2 sulfates,
and 98 chiral centers, and its structure was collectively
deduced by three different groups.2–5 The synthetically
challenging complex structure and potent biological activity
have attracted the attention of synthetic chemists and
biochemists. In the preceding paper,6 we reported a synthesis
of the C′D′E′F′-ring system with an appropriate side chain.
We now report the stereoselective synthesis of the WXYZA′-
ring of MTX (1) through a linear strategy for the construction
of polycyclic ether.
† RIKEN (The Institute of Physical and Chemical Research).
# On leave from Chemicrea Inc.
‡ Tokyo University of Science.
(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.
The WXYZA′-ring system of MTX consists of a trans-
fused 6,6,7,6,6-pentacyclic ether core containing twelve chiral
centers, one hydroxyl and five methyl groups. Our synthetic
strategy to obtain the WXYZA′-ring i is shown in Scheme
1. Our synthesis features a linear synthetic route using
efficient general methods for the construction of trans-fused
polycyclic ethers, that is, SmI2-induced reductive cyclization
(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.
(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.
Ed. 2007, 46, 8875
(6) Morita, M.; Ishiyama, S.; Koshino, H.; Nakata, T. Org. Lett. 2008,
10, 1675.
.
10.1021/ol800268c 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 WXYZA′-Ring System
of a ꢀ-alkoxyacrylate (e.g., vfiv),7 and 6-endo cyclization
of a hydroxy vinylepoxide (e.g., iiifii).8 The tetrahydropyran
A′- and X-rings, and oxepane Y-ring, having 2,3-trans-3-
hydroxy-3-methyl groups, would be constructed by SmI2-
induced cyclization,7 and the tetrahydropyran W- and
Z-rings, having 2,3-trans-3-hydroxy-2,6-dimethyl groups,
would be synthesized by 6-endo cyclization.8
First, the A′-ring was synthesized as shown in Scheme 2.
After thioacetalization of 2-deoxy-D-ribose (2) and protection
as the benzylidene acetal,9 TBS protection gave thioacetal
3. Successive deprotection of the thioacetal, Grignard reaction
using MeMgBr, and oxidation with SO3·py-DMSO afforded
methyl ketone 5 in 46% yield (three steps). The methyl
ketone 5 was alternatively synthesized via olefin 4. After
the Wittig reaction of 2 with Ph3PdCH2 (75%),10 protection
as the benzylidene acetal (83%) followed by TBS protection
afforded olefin 4 in 99% yield. Wacker oxidation of 4
provided methyl ketone 5 in 77% yield. After removal of
the TBS group, hetero-Michael addition of 6 with ethyl
propiolate in the presence of N-methylmorpholine (NMM)
afforded ꢀ-alkoxyacrylate 7, quantitatively. Treatment of 7
(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.; Nakata,
T. Tetrahedron 2002, 58, 1853.
11
with SmI2 in the presence of MeOH in THF at 0 °C
(8) (a) Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K.; Somers, P. K.
J. Chem. Soc., Chem. Commun. 1985, 1359. (b) Nicolaou, K. C.; Prasad,
C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5330.
(c) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am.
Chem. Soc. 1989, 111, 5335.
(10) Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka,
M.; Brazidec, J.-Y. L.; Hirama, M. Tetrahedron 2002, 58, 6493.
(11) (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.
(9) Matsuo, G.; Kawamura, K.; Hori, N.; Matsukura, H.; Nakata, T.
J. Am. Chem. Soc. 2004, 126, 14374.
1680
Org. Lett., Vol. 10, No. 9, 2008

Scheme 3
Scheme 4
effected reductive cyclization to give the syn-trans-A′-ring
8 in 94% yield with complete stereoselection.
P(O)CH2COMe in the presence of LiCl and DBU gave R,ꢀ-
unsaturated methyl ketone, which was treated with TBAF
to give alcohol 11 in 86% yield (three steps). Upon treatment
of 11 with camphorsulfonic acid (CSA) in toluene at 0 °C,
6-endo cyclization regioselectively took place to give the
syn-trans-tetrahydropyran Z-ring 12 in 72% yield. Hydro-
genation of the R,ꢀ-unsaturated ketone 12 on Pd/C gave
saturated methyl ketone, which was subjected to hetero-
Michael addition with ethyl propiolate to give ꢀ-alkoxy-
acrylate 13 in 85% yield (two steps). Treatment of 13 with
SmI2 in the presence of MeOH at rt constructed the syn-
The Z and Y rings were synthesized by 6-endo cyclization
of hydroxy vinylepoxide8 and SmI2-induced cyclization,7
respectively (Scheme 3). The alcohol 8 was converted into
R,ꢀ-unsaturated ester 9 in 89% yield by TMS-protection,
DIBALH reduction, and Wittig reaction. After reduction of
9 with DIBALH, treatment of the resulting allylic alcohol
with m-CPBA predominantly afforded R-epoxide 10 in 91%
yield (two steps).12,13 Oxidation of the alcohol 10 with
SO3·py-DMSO followed by HWE reaction using (MeO)2-
(12) The epoxidation would proceed stereoselectively from the opposite
side of the silyloxy group through a fixed conformation (see the Supporting
(13) (a) Sakamoto, Y.; Matsuo, G.; Matsukura, H.; Nakata, T. Org. Lett.
2001, 3, 2749. (b) Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang,
C.-K. Tetrahedron 1990, 46, 4517.
Information)
.
Org. Lett., Vol. 10, No. 9, 2008
1681

trans-oxepane ring with complete stereoselection to give a
mixture of esters 14a,b and lactone 15. The mixture was
reduced with LiAlH4 to give diol 16 as a single product in
94% yield (two steps). The stereostructure of 16 was
confirmed by extensive NMR analyses (1H and 13C NMR,
NOE, and HMBC).
Oxidation of 16 with SO3·pysDMSO afforded aldehyde
(89%), which was treated with MeMgBr and then TBSOTf
to give di-TBS ether 17 in 80% yield (two steps) (Scheme
4). The benzylidene acetal 17 was converted to dibenzyl ether
18 in 94% yield by protective group manipulation, that is,
(1) hydrogenolysis, (2) dibenzylation, and (3) desilylation.
After acetylation of the secondary alcohol, hetero-Michael
addition to the tertiary alcohol of 18 using ethyl propiolate
in the presence of NMM was unsuccessful. However, this
problem was overcome by treatment with methyl 3-meth-
oxyacrylate and PPTS in toluene at reflux to give 19 in 67%
yield (two steps).7d Alkaline methanolysis of the acetate 19
followed by DesssMartin oxidation afforded methyl ketone
20 in 86% yield (two steps). Treatment of 20 with SmI2
produced a syn-trans-tetrahydropyran and gave the XYZA′-
ring as a single product; this was treated with TMSOTf to
give TMS ether 21 in 72% yield (two steps). Reduction of
21 with DIBALH followed by DesssMartin oxidation
afforded aldehyde, which was subjected to Wittig reaction
to give R,ꢀ-unsaturated ester 22 in 90% yield (three steps).
After DIBALH reduction (92%), epoxidation of 22 with
m-CPBA predominantly afforded ꢀ-epoxide 23 in 89%
yield.12,13 The epoxy alcohol 23 was converted into vinyle-
poxide 24 (96%, two steps) by oxidation and Wittig reaction.
After removal of the TMS group, treatment of 24 with CSA
effected 6-endo cyclization to give the syn-trans-tetrahydro-
pyran W-ring 25 in 80% yield (two steps), corresponding to
the WXYZA′-ring of MTX (1). The stereostructure of 25
was unequivocally confirmed by extensive NMR analyses
(1H and 13C NMR, NOE, and HMBC).
1
Figure 2.
Differences in the H (600 MHz) and 13C (150 MHz)
chemical shifts (∆δ/ppm) between synthetic 25 and the values
reported for MTX (1:1 C5D5NsCD3OD). The x- and y-axes
represent carbon number and ∆δ (∆δ ) δMTX s δ25 in ppm),
respectively.
In summary, stereoselective synthesis of the WXYZA′-
ring system of MTX (1) has been accomplished via a linear
synthetic route based on SmI2-induced cyclization of ꢀ-alkoxy-
acrylate and methyl ketone, and 6-endo cyclization of
hydroxy vinylepoxide.
1
Figure 2 shows the difference in the H (600 MHz) and
13C (150 MHz) chemical shifts between synthetic WXYZA′-
ring 25 and MTX (1).14 The 1H and 13C NMR chemical shifts
for both compounds are in excellent accordance, although
several values are different from those of MTX, because of
the absence of the tetrahydropyran V-ring and oxepene B′-
ring, etc. This synthesis provides reconfirmation of the
stereostructure of the corresponding portion in MTX.
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.
(14) The numbering of 25 follows that the corresponding carbon atoms
in MTX.
OL800268C
1682
Org. Lett., Vol. 10, No. 9, 2008