Synthesis of the WXYZA' domain of maitotoxin

Article abstract of DOI:10.1021/ja109533y

A synthesis of the WXYZA' domain (7) of the marine neurotoxin maitotoxin (1) is reported. The convergent synthetic strategy involves construction of key building blocks 11 and 12, their coupling, and the elaboration of the resulting ester (10) to the targ

Full text of DOI:10.1021/ja109533y

Published on Web 12/17/2010
Synthesis of the WXYZA′ Domain of Maitotoxin
K. C. Nicolaou,*,†,‡ Thomas M. Baker,† and Tsuyoshi Nakamura†
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States, and
Department of Chemistry and Biochemistry, UniVersity of California, San Diego, 9500 Gilman
DriVe, La Jolla, California 92093, United States
Received October 22, 2010; E-mail: kcn@scripps.edu
Abstract: A synthesis of the WXYZA′ domain (7) of the marine neurotoxin maitotoxin (1) is reported. The
convergent synthetic strategy involves construction of key building blocks 11 and 12, their coupling, and
the elaboration of the resulting ester (10) to the target molecule through a ring-closing metathesis and a
hydroxy dithioketal cyclization as the key steps. For the construction of fragment 11, the Noyori reduction/
Achmatowicz rearrangement and hydroxy epoxide opening technologies were applied (starting from furfuryl
alcohol (13)), whereas for the synthesis of fragment 12, a carbohydrate-based approach was adopted
(starting from 2-deoxy-D-ribose (14)). The synthesized WXYZA′ domain (7) of maitotoxin (1) exhibited the
expected 13C NMR chemical shifts, supporting the originally assigned structure of the corresponding region
of the natural product.
WXYZA′ domain4 7 (Figure 1) of this molecule and confirm
its original stereochemical assignment3 through 13C NMR
comparison with the natural product. With this accomplishment,
all the major domains of maitotoxin (1) have now been
synthesized, including fragments 2,5 3,6 4,7 5,8 6,1 and 7 (present
work) (Figure 1).
1. Introduction
In a preceding article,1 we described the synthesis of the
C′D′E′F′ fragment 6 (Figure 1) of maitotoxin (1, Figure 1), the
largest and most toxic secondary metabolite ever isolated and
characterized.2,3 Herein, we report the construction of the
† The Scripps Research Institute.
2. Results and Discussion
‡ University of California, San Diego.
2.1. Retrosynthetic Analysis. The synthesis of the targeted
WXYZA′ domain (7) of maitotoxin is complicated by the
presence of the seven-membered ring and the 5 methyl groups
on the periphery of its pentacyclic framework, not to mention
its 12 stereogenic centers. Driven by our desire to devise a
convergent synthetic strategy toward the targeted maitotoxin
domain 7, we disassembled the molecule retrosynthetically, as
shown in Figure 2. Thus, disconnection at the indicated
carbon-oxygen bond of 7 through a hydroxy dithioketal
cyclization/methylation process4b,8,9 unraveled hydroxy ketone
8 as a possible precursor. It was reasoned that the latter
intermediate could arise from cyclic enol ether 9 through a
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Yasumoto, T.; Nakajima, I.; Bagnis, R.; Adachi, R. Bull. Chem. Soc.
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Yasumoto, T. J. Am. Chem. Soc. 1992, 114, 6594. (b) Murata, M.;
Naoki, H.; Iwashita, T.; Matsunaga, S.; Sasaki, M.; Yokoyama, A.;
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Muruyama, T.; Nonomura, T.; Murata, M.; Tachibana, K.; Yasumoto,
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Sasaki, M.; Matsumori, N.; Murata, M.; Tachibana, K.; Yasumoto,
T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1675.
(4) Synthesis of related WXYZA′ fragments: (a) Morita, M.; Haketa, T.;
Koshino, H.; Nakata, T. Org. Lett. 2008, 10, 1679. (b) Oishi, T.;
Hasegawa, F.; Torikai, K.; Konoki, K.; Matsumori, M.; Murata, M.
Org. Lett. 2008, 10, 3599.
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R. M. Angew. Chem., Int. Ed. 2007, 46, 8875.
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Rivas, F.; Cole, K. P.; Aversa, R. J.; Gibe, R.; Umezawa, T.; Suzuki,
T. J. Am. Chem. Soc. 2008, 130, 7466.
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J. Am. Chem. Soc. 2010, 132, 9900.
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9
220 J. AM. CHEM. SOC. 2011, 133, 220–226
10.1021/ja109533y  2011 American Chemical Society

Synthesis of the WXYZA′ Domain of Maitotoxin
A R T I C L E S
Figure 1. Structures of maitotoxin (1), previously synthesized maitotoxin domains GHIJK (2), ABCDEFG (3), GHIJKLMNO (4), QRSTU (5), and C′D′E′F′
(6), and the targeted WXYZA′ domain (7).
hydroboration/oxidation protocol. The seven-membered ring of
tetracycle 9 was then disconnected through a postulated Takai
olefination/metathesis sequence, revealing tricyclic ester 10 as
its progenitor.10 This ester was then disassembled to generate
secondary alcohol 11 and carboxylic acid 12 as the required
building blocks. Finally, these building blocks were traced back
to furfuryl alcohol (13) and 2-deoxy-D-ribose (14), respectively,
whose ready availability and low cost boded well for the devised
synthetic strategy.
rangement protocol12 and a hydroxy epoxide opening (see
Scheme 1).13 Thus, furfuryl alcohol (13) was converted to A′
ring tertiary alcohol 15 in six steps and 76% overall yield, as
described previously for a related system.6,1 Following TMS
protection of 15 (TMSOTf, 94% yield), the resulting product
was regio- and stereoselectively hydroborated and converted
to the corresponding alcohol (i-amyl2BH, aq NaOH, H2O2, 58%
yield plus 16% recovered starting material). This alcohol was
sequentially silylated (TBSOTf, quant. yield) and debenzylated
(H2, 20% Pd(OH)2/C) to afford the corresponding primary
alcohol, which was oxidized ((COCl)2, DMSO, Et3N) to afford
aldehyde 16 in 69% overall yield for the last two steps. Reaction
of this aldehyde with stabilized phosphorane Ph3PdC(Me)CO2Et
gave the corresponding R,ꢀ-unsaturated ester in 90% yield.
Following protection of the tertiary alcohol as a TMS ether
(TMSOTf, 2,6-lut., 93% yield), the ester moiety of the resulting
product was reduced with DIBAL-H to the corresponding allylic
alcohol (96% yield), whose Sharpless asymmetric epoxidation14
((-)-DET, Ti(i-OPr)4, t-BuOOH, 4 Å MS) gave epoxide 17
(97% yield) as a 10:1 inseparable mixture of epoxide diaste-
reoisomers. Oxidation of this hydroxy epoxide to the corre-
sponding epoxy aldehyde employing Parikh-Doering condi-
2.2. Construction of Building Blocks 11 and 12. The desired
building block 11 was constructed in enantiopure form through
a sequence featuring a Noyori reduction11/Achmatowicz rear-
(10) Takai-Utimoto reagent: (a) Takai, K.; Kakiuchi, T.; Kataoka, Y.;
Utimoto, K. J. Org. Chem. 1994, 59, 2668. For a review summarizing
the applications of olefin metathesis in the synthesis of fused
polyethers, see: (b) Clark, J. S. Chem. Commun. 2006, 3571. For earlier
methods using ring-closing metathesis to form enol ethers, see: (c)
Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426. (d) Fu,
G. C.; Nguyn, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115,
9856. (e) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994,
59, 4029. (f) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F.
J. Am. Chem. Soc. 1996, 118, 1565. (g) Nicolaou, K. C.; Postema,
M. H. D.; Yue, E. W.; Nadin, A. J. Am. Chem. Soc. 1996, 118, 10335.
(h) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 123. (i) Clark,
J. S.; Kettle, J. G. Tetrahedron 1999, 55, 8231. For recent work using
the Takai-Utimoto reagent for the synthesis of polyethers, see: (j)
Majumder, U.; Rainier, J. D. Tetrahedron Lett. 2005, 46, 7209. (k)
Iyer, K.; Rainier, J. D. J. Am. Chem. Soc. 2007, 129, 12604.
(11) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 2521. (b) Ferrie, L.; Reymond, S.; Capdevielle,
P.; Cossy, J. Org. Lett. 2007, 9, 2461.
(12) Achmatowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165.
(13) (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) Nicoalou, K. C.; Prasad, C. V. C.; Somers, P. K.;
Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5335.
(14) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5976.
(b) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
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J. AM. CHEM. SOC. VOL. 133, NO. 2, 2011 221

A R T I C L E S
Nicolaou et al.
Scheme 1. Synthesis of A′Z Ring Fragment 11a
a Reagents and conditions: (a) TMSOTf (1.5 equiv), Et3N (2.5 equiv),
CH2Cl2, -78 °C, 1 h, 94%; (b) i-amyl2BH (0.8 M in THF, 8.0 equiv),
THF, -78 to 0 °C, 6 d; then 1 M aq NaOH, excess H2O2, 58% plus 16%
recovered starting material; (c) TBSOTf (2.0 equiv), Et3N (5.0 equiv),
CH2Cl2, 0 f 25 °C, 16 h, quant.; (d) H2, 20% Pd(OH)2/C (0.2 equiv), EtOH,
25 °C, 18 h; (e) (COCl)2 (3.0 equiv), DMSO (4.0 equiv), Et3N (8.0 equiv),
CH2Cl2, -78 f 0 °C, 2 h, 69% over the two steps; (f) Ph3PdC(Me)CO2Et
(1.3 equiv), CH2Cl2, 25 °C, 90%; (g) TMSOTf (1.3 equiv), 2,6-lut. (2.0
equiv), CH2Cl2, 0 °C, 93%; (h) DIBAL-H (1.0 M in CH2Cl2, 3.0 equiv),
CH2Cl2, -78 °C, 96%; (i) (-)-DET (0.25 equiv), Ti(Oi-Pr)4 (0.2 equiv),
t-BuOOH (5.5 M in decane, 1.5 equiv), 4 Å MS, CH2Cl2, -20 °C, 17 h,
97% (ca. 10:1 dr); (j) SO3 ·py (3.0 equiv), Et3N (5.0 equiv), DMSO, CH2Cl2,
0 f 25 °C; (k) Ph3PdC(H)CO2Me (1.5 equiv), CH2Cl2, 25 °C, 14 h, 97%
over the two steps; (l) TBAF (1.0 M in THF, 1.1 equiv), THF, 0 °C, 86%;
(m) PPTS (1.0 equiv), CH2Cl2, 40 °C, 60%; (n) PMBOC(NH)CCl3 (1.5
equiv), La(OTf)3 (0.05 equiv), PhMe, 25 °C, 6 h; (o) NiCl2 ·6H2O (0.04
equiv), NaBH4 (3.0 equiv), EtOH, 0 °C, 1 h; (p) LiAlH4 (2.0 equiv), Et2O,
25 °C, 78% over the three steps; (q) SO3 ·py (3.0 equiv), Et3N (5.0 equiv),
DMSO, CH2Cl2, 0 f 25 °C; (r) Ph3P(Et)Br (3.2 equiv), NaHMDS (0.6 M
in THF, 3.0 equiv), THF, 0 °C, 80% over the two steps; (s) DDQ (2.0
equiv), phosphate-buffered saline, CH2Cl2, 0 °C, 2 h, 90%. Abbreviations:
TMS ) trimethylsilyl, Tf ) trifluoromethane sulfonyl, TBS ) tert-
butyldimethylsilyl, DMSO ) dimethyl sulfoxide, lut. ) lutidine, DIBAL-H
) diisobutylaluminum hydride, MS ) molecular sieves, TBAF ) tetra-n-
butylammonium fluoride, PPTS ) pyridinium para-toluene sulfonate, PMB
) para-methoxybenzyl, NaHMDS ) sodium bis(trimethylsilyl)amide, DDQ
) 2,3-dichloro-5,6-dicyanobenzoquinone.
Figure 2. Retrosynthetic analysis of the WXYZA′ maitotoxin domain 7.
tions15 (SO3 ·py, DMSO, Et3N), followed by Wittig olefination
(Ph3PdCHCO2Me, 97% yield for the two steps) and selective
monodesilylation (TBAF, 86% yield), afforded olefinic hydroxy
epoxide 18, setting the stage for the fusion of the next
tetrahydropyran ring system. Indeed, substrate 18 underwent
regio- and stereoselective ring closure under the influence of
PPTS in CH2Cl2 at 40 °C to generate A′Z ring system 19 in
60% yield.16 The secondary hydroxyl group of the latter
intermediate was then protected as a PMB ether (PMBOC-
(NH)CCl3, La(OTf)3 (cat.)). Stepwise reduction of the R,ꢀ-
unsaturated moiety of the so-obtained product (NaBH4,
NiCl2 ·6H2O (cat.); LiAlH4, 78% yield over the three steps),
followed by Parikh-Doering oxidation (SO3 ·py, DMSO, Et3N)
of the resulting primary alcohol, furnished the corresponding
aldehyde, whose reaction with the ylide derived from Ph3P(Et)Br
and NaHMDS led to Z olefin 20 in 80% yield for the last two
steps.17 Finally, the PMB group was oxidatively cleaved from
(15) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
(16) Nicolaou, K. C.; Veale, C. A.; Hwang, C.-K.; Hutchinson, J.; Prasad,
C. V. C.; Ogilvie, W. W. Angew. Chem., Int. Ed. Engl. 1991, 30,
299.
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Synthesis of the WXYZA′ Domain of Maitotoxin
A R T I C L E S
Scheme 2. Synthesis of W Ring Building Block 12a
NMO-TPAP (cat.)20 to afford aldehyde 23. Wittig-type meth-
ylenation of the latter compound (Ph3PdCH2, 97% yield for
the last two steps) and exchange of protecting groups on the
secondary alcohol (TsOH ·H2O, 82% yield; TESCl, quant. yield)
led to derivative 24. This protecting group switch was dictated
by subsequent steps (see below). It should also be noted that
attempts to prepare the TES-protected derivative from the diol
obtained from benzylidene 22 through bis-TES protection/
monodesilylation proved less efficient than the sequence involv-
ing the TBS group. Finally, conversion of the terminal olefin
of 24 to the desired carboxyl moiety was accomplished through
the standard three-step sequence involving hydroboration
(Cy2BH; aq NaOH, H2O2, 89% yield) and oxidation (DMP
followed by Pinnick, quant. yield for the two steps).21,22
2.3. Coupling of Building Blocks and Completion of the
Synthesis of the WXYZA′ Maitotoxin Domain 7. The union of
fragments 11 and 12 and the elaboration of the resulting product
to the targeted WXYZA′ domain 7 of maitotoxin are sum-
marized in Scheme 3. Thus, coupling of alcohol 11 and
carboxylic acid 12 under the influence of the Shiina reagent23
(MNBA, Et3N, DMAP) afforded the corresponding ester in 84%
yield. The Takai ring-closing olefination/metathesis of the W
ring TES-protected olefinic ester 25a proved problematic as it
did earlier with the corresponding TBS-protected derivative
(25d) (which was prepared from aldehyde 23 (Scheme 2)).
Neither substrate served well under conditions expected to
induce the desired cyclization (TiCl4, TMEDA, Zn, PbCl2,
CH3CHBr2; see Table 1, entries 1-3),10,17,24 with starting
material being the only recoverable compound. Additionally,
the method previously developed by us10f,g to accomplish similar
transformations employing the Tebbe reagent25 proved unsuc-
cessful in this instance, leading only to extensive decomposition.
We reasoned that the difficulty in this reaction arose from the
bulkiness of the substituent on the W ring hydroxyl moiety.
We, therefore, opted to exchange the TES group of 25a for a
TMS group and a hydrogen. In contrast to our inability to
selectively remove the TBS group from the originally synthe-
sized TBS-protected derivative (25d), the desired cleavage of
the TES group from the TES-protected substrate (25a) pro-
ceeded smoothly in the presence of the other three silyl
protecting moieties. Indeed, this was the reason we were forced
to switch from the TBS-protected series of intermediates to their
TES-protected counterparts (23 f 24, Scheme 2; see above).
The exchange of the TES group in 25a to a TMS group in 25c
a Reagents and conditions: (a) O3, CH2Cl2/MeOH (5:1), -78 °C; then
NaBH4 (1.0 equiv), CH2Cl2/MeOH (5:1), -78 f 25 °C; (b) TBDPSCl (1.5
equiv), imidazole (3.0 equiv), CH2Cl2, 25 °C, 5 h, 93% over three steps;
(c) CSA (0.25 equiv), MeOH/CH2Cl2 (4:1), 0 °C, 2 h, 97%; (d) TBSOTf
(3.0 equiv), 2,6-lut. (4.0 equiv), CH2Cl2, 0 °C, 0.5 h, 98%; (e) CSA (0.2
equiv), MeOH, 0 °C, 1 h, 80%; (f) NMO (3.0 equiv), TPAP (0.05 equiv),
4 Å MS, CH2Cl2, 0 f 25 °C, 4 h; (g) Ph3PCH3Br (3.1 equiv), NaHMDS
(0.6 M in PhMe, 2.9 equiv), THF, 0 f 25 °C, 4 h, 97% over the two steps;
(h) TsOH·H2O (6.0 equiv), MeOH/CH2Cl2 (3:1), 25 °C, 3 h, 82%; (i)
TESCl, (2.0 equiv), imidazole (4.0 equiv), CH2Cl2, 25 °C, 1 h, quant.; (j)
Cy2BH (5.0 equiv), THF, 25 °C, 1 h; then 2 M aq NaOH, excess H2O2, 0
f 25 °C, 1 h, 89%; (k) DMP (1.5 equiv), NaHCO3 (2.0 equiv), CH2Cl2,
25 °C, 3 h; (l) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O, 25
°C, 0.5 h, quant. over the two steps. Abbreviations: Bn ) benzyl, TBAI )
tetra-n-butylammonium iodide, TBDPS ) tert-butyldiphenylsilyl, CSA )
(()-camphor-10-sulfonic acid, TPAP ) tetra-n-propylammonium perruth-
enate, NMO ) N-methylmorpholine-N-oxide, TES ) triethylsilyl, Cy )
cyclohexyl, DMP ) Dess-Martin periodinane.
20 with DDQ to afford targeted building block A′Z ring system
11 in 90% yield.
The construction of building block 12 was accomplished from
W ring system 21 (synthesized from 2-deoxy-D-ribose (14) in
12 steps and 39% overall yield as previously described),18,19 as
summarized in Scheme 2. Thus, reductive ozonolytic cleavage
of the terminal olefin (O3, NaBH4) and reaction of the resulting
primary alcohol with TBDPSCl and imidazole furnished fully
protected intermediate 22 in 93% overall yield. Methanolysis
of the benzylidene acetal of 22 under acidic conditions (CSA,
MeOH/CH2Cl2) then generated the corresponding diol (97%).
To differentiate between the two hydroxyl groups of the latter
intermediate, it was necessary to employ a two-step procedure
involving bis-silylation (TBSOTf, 2,6-lut., 98% yield) and
selective monodesilylation (CSA (cat.), MeOH, 0 °C, 80%
yield). The resulting primary alcohol was then oxidized with
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A R T I C L E S
Nicolaou et al.
Scheme 3. Coupling of Fragments 11 and 12 and Synthesis of the WXYZA′ Domain of Maitotoxin (7)a
a Reagents and conditions: (a) 12 (1.0 equiv), MNBA (1.05 equiv), Et3N (2.7 equiv), DMAP (0.1 equiv), 4 Å MS, PhMe, 25 °C, 10 min; then 11 (1.0
equiv), 13 h, 84%; (b) TsOH·H2O (2.0 equiv), MeOH/CH2Cl2 (3:1), 0 °C, 40 min, 93%; (c) TMSCl (1.2 equiv), imidazole (3.0 equiv), CH2Cl2, 25 °C, 1 h,
96%; (d) from 25c: TiCl4 (1.0 M in CH2Cl2, 87.5 equiv), TMEDA (503 equiv), Zn (189 equiv), PbCl2 (10.2 equiv), CH3CHBr2 (84.9 equiv), THF, CH2Cl2,
0 f 65 °C, 76%, 1.8:1 26c/27c; from 25b: TiCl4 (1.0 M in CH2Cl2, 50 equiv), TMEDA (285 equiv), Zn (110 equiv), PbCl2 (5.0 equiv), CH3CHBr2 (50
equiv), THF, CH2Cl2, 0 f 65 °C, 84%, 1:3.9 26b/27b; (e) TMSOTf (3.0 equiv), 2,6-lut. (4.0 equiv), CH2Cl2, 0 °C, 1 h, quant.; (f) Cy2BH (15 equiv), THF,
25 °C, 6 h; then 1 M aq NaOH, excess H2O2, 14 h, 71%; (g) DMP (3.0 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 0 f 25 °C, 3 h, 89%; (h) TsOH ·H2O (0.1
equiv), MeOH/CH2Cl2 (3:1), 0 °C, 30 min, 79%; (i) Zn(OTf)2 (5.0 equiv), CH2Cl2/EtSH (5:1), 25 °C, 16 h, 65% (2.5:1 dr); (j) m-CPBA (4.0 equiv), CH2Cl2,
-78 f -30 °C, 2.5 h; (k) AlMe3, (40 equiv), -78 f 0 °C, 1 h, quant.; (l) TBAF (1.0 M in THF, 5.0 equiv), THF, 25 f 40 °C, 13 h, 81%; (m) H2, 20%
Pd(OH)2/C (0.2 equiv), EtOH, 25 °C, 18 h, quant. Abbreviations: MNBA ) 2,6-methylnitrobenzoyl anhydride, TMEDA ) tetramethylethylenediamine,
m-CPBA ) meta-chloroperoxybenzoic acid.
Table 1. Optimization of the Utimoto-Takai Olefination/Metathesis
25a and 25d led to a mixture of bis-olefins 26c (four geometrical
isomers) and cyclic enol ether 27c (76% combined yield, ca.
1.8:1 ratio), in which, however, undesired products 26c were
predominating (Table 1, entry 4). Chromatographic separation
of the mixture led to bis-olefin products 26c (49% yield, four
geometrical isomers) and cyclic enol ether 27c (27% yield) and
allowed recycling of the bis-olefin (26c) through ozonolysis/
Wittig olefination (to afford starting material 25c, 50% overall
yield). Through further prep-TLC purification (multiple elu-
tions), the mixture of bis-olefins 26c was separated into two
pairs of isomers, each consisting of a single geometrical isomer
at the trisubstituted olefinic bond (enol ether) and a mixture at
the disubstituted olefinic bond (ca. 6:1 ratio). On the basis of
the chemical shift of the enol ether proton (δ ) 4.77 ppm, 600
MHz, C6D6), the less polar isomer (26c′) was assigned the Z
geometry and the more polar isomer (26c′′, δ ) 5.36-5.31 ppm,
600 MHz, C6D6) the E geometry. Attempts to convert the
mixture of bis-olefin 26c directly to cyclic enol ether 27c through
olefin metathesis with Grubbs’ second generation catalyst,26
Sequencea
yield (%)
entry substrate
R
solvent
time (h) tempb (°C)
27
26
25
1
2
3
4
5
6
7
8
9
25d
25d
25a
25c
25b
25b
25b
25b
25b
TBS
TBS
TES
CH2Cl2
THF
CH2Cl2
1.0
1.0
5.0
1.0
2.0
6.0
1.5
1.0
3.0
65
65
65
65
60
60
65
65
80
90
100
80
TMS CH2Cl2
27 49
24
20
67 17
62 20
20
H
H
H
H
H
CH2Cl2
CH2Cl2
THF
THF
PhMe
36
30
48
a Reactions were carried out on a 0.02 f 0.18 mmol scale. Yields
refer to chromatographically and spectroscopically homogeneous
materials. b Oil bath temperature.
was carried out through the intermediacy of the free alcohol
25b (TsOH·H2O, MeOH/CH2Cl2, 25b, 93% yield; then TMSCl,
imid., 25c, 96% yield). Pleasantly, exposure of substrate 25c
to the same Takai reaction conditions as mentioned above for
9
224 J. AM. CHEM. SOC. VOL. 133, NO. 2, 2011

Synthesis of the WXYZA′ Domain of Maitotoxin
A R T I C L E S
Table 2. C99 to C118 and C155 to C159 Chemical Shifts (δ) for
Maitotoxin (MTX, 1) and the WXYZA′ Ring System 7 and Their
Differences (∆δ, ppm)a
afforded a mixture of S,O-acetals 29a and 29b (29a/29b ca.
2.8:1, 50% combined yield), plus 36% recovered starting
material (28), which could be recycled (bringing the yield of
29ab after three iterations to 65%).16,4b Oxidation of 29a and
29b, individually or as a mixture, with excess m-CPBA (CH2Cl2,
-30 °C), followed by addition of excess AlMe3 at -78 °C in
the same pot, led to protected WXYZA′ pentacyclic system 30
in quantitative yield.9a,4b That this reaction proceeded with
stereoselective installation of the methyl group at C107 was
confirmed through NOE studies on the ultimate product (i.e.,
7; see below). Finally, deprotection of the latter intermediate
(TBAF, 25 f 40 °C, 81% yield; H2, 20% Pd(OH)2/C (cat.),
quant. yield) furnished the desired WXYZA′ maitotoxin domain
7, whose shown stereochemical assignment at C107 was con-
firmed by the indicated NOE (see structure 7, Scheme 3).
2.4. Comparison of the 13C NMR Chemical Shifts of the
WXYZA′ Ring System 7 with Those Corresponding to the
Same Region of Maitotoxin. Having obtained the WXYZA′
fragment 7 through synthesis, we took the opportunity to
compare its 13C NMR spectral data with those of the WXYZA′
domain of the natural product as a means of providing further
evidence for the correctness of the originally assigned structure
of the natural product.30,31 Table 2 lists the 13C NMR chemical
shifts (δ, ppm) for the WXYZA′ ring system 7, together with
those of the corresponding domain of natural maitotoxin (MTX
(1)) and their differences (∆δ, ppm).3d As seen from the small
deviations between these values, which are also depicted
graphically in Figure 3, there is excellent agreement between
the two sets of chemical shifts for the two structures, except
for those carbons residing at the edges of these domains due to
the drastically different structural motifs at these locations. The
average chemical shift deviation (∆δ, ppm) for C102 to C115 and
C155 to C159 is 0.36 ppm, with the largest difference being 2.2
ppm. These findings are in line with those reported by the
Nakata group for a related domain of maitotoxin4a and provide
further support for the originally assigned structure of this region
of the natural product.
carbon
δ for MTX (1) (ppm)
δ for (7) (ppm)
difference (∆δ, ppm)
118
117
116
115
159
114
113
112
111
110
158
109
108
107
106
157
105
104
156
103
102
101
100
155
99
31.5
84.7
76.6
46.7
21.7
74.1
83.8
30.3
87.7
79.6
23.5
40.4
39.1
79.6
84.6
18.3
42.8
74.6
20.2
72.6
31.0
74.7
78.8
19.5
87.8
63.0
86.2
65.9
48.9
21.8
73.8
82.5
30.3
87.6
79.1
23.2
40.4
39.1
79.6
84.5
18.4
42.6
74.8
20.3
72.7
31.8
69.3
79.3
21.0
69.3
-31.5
-1.5
10.7
-2.2
-0.1
0.3
1.3
0.0
0.1
0.5
0.3
0.0
0.0
0.0
0.1
-0.1
0.2
-0.2
-0.1
-0.1
-0.8
5.4
-0.5
-1.5
18.5
a 150 MHz, 1:1 methanol-d4/pyridine-d5.
Hoveyda-Grubbs’ second generation catalyst,27 and Schrock’s
catalyst28 failed, presumably due to steric congestion around
the reactive sites of the substrate. Gratifyingly, however,
substrate 25b, bearing a free hydroxyl group on the W ring,
was found to be a better substrate for the Takai cyclization to
generate the desired enol ether (27b). Thus, through a judicious
choice of solvent29 and reaction time (see Table 1, entries 5-9),
product 27b was successfully forged in 67% yield, together with
a small amount of the corresponding bis-olefin 26b (17% yield,
Table 1, entry 7). After installing a TMS group on the free
hydroxyl group of 27b (TMSOTf, 2,6-lut., quant.), regioselective
hydroboration of the resulting enol ether (27c) with Cy2BH and
oxidation of the so-obtained borane (aq NaOH, H2O2) afforded
the corresponding alcohol (71% yield) as a single diastereoi-
somer. The latter compound was then oxidized with DMP to
furnish ketone 28 in 89% yield. The syn stereochemical
assignment of the newly generated stereocenter was supported
by the indicated NOE (see structure 28, Scheme 3). Selective
methanolysis of the TMS group from 28 (TsOH·H2O (cat.),
MeOH/CH2Cl2) led to the corresponding hydroxy ketone (79%
yield), whose cyclization in the presence of EtSH and Zn(OTf)2
3. Conclusion
The described chemistry culminated in a convergent synthesis
of the WXYZA′ domain (7) of maitotoxin (1), allowing a 13C
NMR chemical shift comparison of its carbons with those of
the corresponding carbons of the same region of the natural
product and ultimately providing further support for the orig-
inally assigned structure of the natural product. The construction
of this target molecule was based primarily on synthetic
technologies previously developed in these laboratories and
incorporating improvements reported from other groups. Specif-
Figure 3. Graphically depicted 13C chemical shift differences (∆δ, ppm) for each carbon between C99 to C118 and C155 to C159 for maitotoxin (1) and the
WXYZA′ ring system 7.
9
J. AM. CHEM. SOC. VOL. 133, NO. 2, 2011 225

A R T I C L E S
Nicolaou et al.
ically, a Noyori reduction/Achmatowicz rearrangement-based
tetrahydropyran synthesis,5,12,32 a hydroxy epoxide opening,13
a metathesis-based ring closure,10b-h,17,24 and a hydroxy
dithioketal cyclization/methylation were employed.4b,9a,b,16,33
With this domain (7) of maitotoxin now synthesized, a set of
six large domains (i.e., 2-7, Figure 1) of this neurotoxin has
been completed.1,5–8 With appropriate modifications, the de-
veloped routes to these fragments can, in principle, deliver
suitable fragments, whose coupling and further elaboration may
lead to even larger domains of the natural product. Biological
investigations with these molecules may provide further under-
standing of the mechanism of action of maitotoxin and other
members of the polyether marine biotoxin class.34
(26) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
Acknowledgment. We thank Drs. D.-H. Huang and G. Siuzdak
for spectroscopic and mass spectrometric assistance, respectively.
Financial support for this work was provided by the National
Institutes of Health (U.S.A.), The Skaggs Institute of Chemical
Biology, and a Schering-Plough European Postdoctoral Fellowship
(T.M.B.).
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and, consequently, no olefination products were observed.
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Supporting Information Available: Experimental procedures,
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226 J. AM. CHEM. SOC. VOL. 133, NO. 2, 2011