Synthesis of the C'D'E'F' domain of maitotoxin

Article abstract of DOI:10.1021/ja109531d

A devised biomimetic strategy toward the C'D'E'F' domain (6) of maitotoxin (1) led to hydroxy triepoxide 8 as a postulated polyepoxide precursor. However, all attempts to induce the desired cascade to form the targeted compound through a zip-type reaction

Full text of DOI:10.1021/ja109531d

Published on Web 12/17/2010
Synthesis of the C′D′E′F′ Domain of Maitotoxin
K. C. Nicolaou,* Jae Hong Seo, Tsuyoshi Nakamura, and Robert J. Aversa
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 27, 2010; E-mail: kcn@scripps.edu
Abstract: A devised biomimetic strategy toward the C′D′E′F′ domain (6) of maitotoxin (1) led to hydroxy
triepoxide 8 as a postulated polyepoxide precursor. However, all attempts to induce the desired cascade
to form the targeted compound through a zip-type reaction under neutral or acidic conditions failed, prompting
adoption of a linear stepwise approach to 6. The successful synthetic strategy for the synthesis of the
C′D′E′F′ domain of maitotoxin commenced from furfuryl alcohol (11), proceeded through F′ ring building
block 15, and involved two regio- and stereoselective intramolecular hydroxy epoxide openings and a
stereoselective SmI2-mediated ring closure to forge rings C′, E′, and D′, respectively. 13C NMR spectroscopic
analysis of the synthesized domain (6) and comparisons with previous results confirmed the original structural
assignment of this region of maitotoxin. X-ray crystallographic analysis of 6 provided unambiguous proof
of its structure.
comprising the JK ring junction of the molecule.7 The cloud of
uncertainty cast over the maitotoxin structure prompted us to
Introduction
With the impressive molecular weight of 3422 Da, maitotoxin
enjoys the status of the largest secondary metabolite to be
isolated and characterized from nature as yet.1 This remarkable
natural product also stands as the most toxic molecule ever
discovered, other than a few proteins, with an LD50 of 50 ng/
kg.2 First detected in 1971 by Yasumoto et al. in the gut of the
surgeonfish Ctenochaetus striatus,1b,c it would be a quarter of
a century before its full structural elucidation was completed.
The originally assigned structure (1, Figure 1) of maitotoxin
by the groups of Yasumoto,3 Kishi,4 and Tachibana5 was
subsequently challenged by Gallimore and Spencer,6 who
questioned the correctness of the two asymmetric centers
undertake a reinvestigation of its structure that led, so far, to
theoretical calculations8 and the construction of several frag-
ments of the molecule, including the GHIJK (2),9 GHIJKLMNO
(4),10 ABCDEFG (3),11 and QRSTU (5)12 domains (Figure 1).
These structures provided support for the originally assigned
structure (1) of maitotoxin. Herein, we report the synthesis of
the C′D′E′F′ domain (6, Figure 1) of maitotoxin and, in the
following article, that of the remaining WXYZA′ segment (7,
Figure 1).13
Results and Discussion
In addition to the nine stereogenic centers contained within
the structure of the C′D′E′F′ ring system (6), the main challenge
(1) (a) Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293. (b)
Yasumoto, T.; Bagnins, R.; Randal, J. E.; Banner, A. H. Nippon Suisan
Gakkaishi 1971, 37, 724. (c) Yasumoto, T.; Bagnins, R.; Vernoux,
J. P. Nippon Suisan Gakkaishi 1976, 42, 359. (d) Yasumoto, T.;
Nakajima, I.; Bagnis, R.; Adachi, R. Nippon Suisan Gakkaishi 1977,
43, 1021. (e) Yokoyama, A.; Murata, M.; Oshima, Y.; Iwashita, T.;
Yasumoto, T. J. Biochem. 1988, 104, 184.
(5) (a) Sasaki, M.; Nonomura, T.; Murata, M.; Tachibana, K. Tetrahedron
Lett. 1995, 36, 9007. (b) Sasaki, M.; Nomomura, T.; Murata, M.;
Tachibana, K.; Yasumoto, T. Tetrahedron Lett. 1995, 36, 9011. (c)
Sasaki, M.; Nonomura, T.; Murata, M.; Tachibana, K. Tetrahedron
Lett. 1994, 35, 5023. (d) Sasaki, M.; Matsumori, N.; Muruyama, T.;
Nonomura, T.; Murata, M.; Tachibana, K.; Yasumoto, T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1672. (e) Nonomura, T.; Sasaki, M.;
Matsumori, N.; Murata, M.; Tachibana, K.; Yasumoto, T. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1675.
(2) (a) Takahashi, M.; Ohizumi, Y.; Yasumoto, T. J. Biol. Chem. 1982,
257, 7287. (b) Gusovsky, F.; Daly, J. W. Biochem. Pharmacol. 1990,
39, 1633. (c) Ueda, H.; Tamura, S.; Fukushima, N.; Takagi, H. Eur.
J. Pharmacol. 1986, 122, 379. (d) Konoki, K.; Hashimoto, M.;
Nanomura, T.; Sasaki, M.; Murata, M.; Tachibana, K. J. Neurochem.
1998, 70, 409. (e) Murata, M.; Gusovsky, F.; Yasumoto, T.; Daly,
J. W. Eur. J. Pharmacol. 1992, 227, 43.
(6) Gallimore, A. R.; Spencer, J. B. Angew. Chem., Int. Ed. 2006, 45,
4406.
(7) For a review on wrongly assigned structures to natural products, see:
Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005, 44, 1012.
(8) Nicolaou, K. C.; Frederick, M. O. Angew. Chem., Int. Ed. 2007, 46,
5278.
(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. J. Am. Chem.
Soc. 1995, 117, 7019.
(9) Nicolaou, K. C.; Cole, K. P.; Frederick, M. O.; Aversa, R. J.; Denton,
R. M. Angew. Chem., Int. Ed. 2007, 46, 8875.
(10) Nicolaou, K. C.; Frederick, M. O.; Burtoloso, A. C. B.; Denton, R. M.;
Rivas, F.; Cole, K. P.; Aversa, R. J.; Gibe, R.; Umezawa, T.; Suzuki,
T. J. Am. Chem. Soc. 2008, 130, 7466.
(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. (c) Kishi, Y. Pure Appl. Chem. 1998, 70, 339.
(11) Nicolaou, K. C.; Aversa, R. J.; Jin, J.; Rivas, F. J. Am. Chem. Soc.
2010, 132, 6855.
(12) Nicolaou, K. C.; Gelin, C. F.; Seo, J. H.; Huang, Z.; Umezawa, T.
J. Am. Chem. Soc. 2010, 132, 9900.
9
214 J. AM. CHEM. SOC. 2011, 133, 214–219
10.1021/ja109531d  2011 American Chemical Society

Synthesis of the C′D′E′F′ Domain of Maitotoxin
A R T I C L E S
Figure 1. Structures of maitotoxin (1), previously synthesized fragments GHIJK (2), ABCDEFG (3), GHIJKLMNO (4), and QRSTU (5), and targeted
fragments C′D′E′F′ (6) and WXYZA′ (7).
posed by this target is the array of its three methyl groups
contiguously situated on the two central rings (D′ and E′), all
of which are axially disposed.
1. Polyepoxide-Based Retrosynthetic Analysis. In our desire
to attempt a biomimetic pathway to the C′D′E′F′ segment of
maitotoxin, we adopted triepoxide 8 as a possible precursor as
shown retrosynthetically in Figure 2. The polyepoxide hypoth-
esis for the biosynthesis of brevetoxin B and related polyether
neurotoxins was first proposed by Nakanishi14 and one of us15
and recently performed in a laboratory setting by Jamison and
co-workers.16 In an effort to introduce convergency into our
synthetic strategy, precursor 8 was disconnected through a
π-allyl Stille coupling17 and two Shi epoxidations,18 revealing
allylic acetate 9 and vinyl stannane 10 as potential building
blocks. The latter fragments were traced to furfuryl alcohol (11)
and 1,2-dihydrofuran (12) as depicted in Figure 2.
2. Construction of Building Blocks 9 and 10. Key building
block allylic acetate 9 was synthesized from furfuryl alcohol
(13) Related fragments of maitotoxin have been previously synthesized by
others: (a) Nakata, T.; Nomura, S.; Matsukura, H. Chem. Pharm. Bull.
1996, 44, 627. (b) Nagasawa, K.; Hori, N.; Shiba, R.; Nakata, T.
Heterocycles 1997, 44, 105. (c) Sakamoto, Y.; Matsuo, G.; Matsukura,
H.; Nakata, T. Org. Lett. 2001, 3, 2749. (d) Morita, M.; Ishiyama, S.;
Koshino, H.; Nakata, T. Org. Lett. 2008, 10, 1675. (e) Morita, M.;
Haketa, T.; Koshino, H.; Nakata, T. Org. Lett. 2008, 10, 1679. (f)
Figure 2. Cascade retrosynthetic analysis of C′D′E′F′ ring system 6.
Satoh, M.; Koshino, H.; Nakata, T. Org. Lett. 2008, 10, 1683. (g)
Oishi, T.; Hasegawa, F.; Torikai, K.; Konoki, K.; Matsumori, N.;
(11) as summarized in Scheme 1. Thus, following our previous
synthetic strategy,9-11,19 enone 13 was prepared from 11 (five
steps, 77% overall yield)11 and subjected to 1,2-addition of
MeMgBr (Et2O, -78 °C, 98% yield) and debenzylation [H2,
20% Pd(OH)2/C, 89% yield] to afford saturated diol 14. The
Murata, M. Org. Lett. 2008, 10, 3599.
(14) (a) Nakanishi, K. Toxicon. 1985, 23, 473. (b) Lee, M. S.; Qin, G.-W.;
Nakanishi, K.; Zagorski, M. G. J. Am. Chem. Soc. 1989, 111, 6243.
(15) (a) Nicolaou, K. C. NIH application GM31398-01 (submission date:
February 24, 1982). (b) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl.
1996, 35, 588.
9
J. AM. CHEM. SOC. VOL. 133, NO. 2, 2011 215

A R T I C L E S
Nicolaou et al.
Scheme 1. Furan-Based Synthesis of F′ Ring Building Block 9a
Scheme 2. Synthesis of Vinyl Stannane 10a
a Reagents and conditions: (a) DMP (1.5 equiv), CH2Cl2, 25 °C, 1.5 h;
(b) Ph3PdCHCO2Me (1.5 equiv), CH2Cl2, 25 °C, 2 h; (c) DIBAL-H (1.0
M in CH2Cl2, 5.0 equiv), CH2Cl2, -78 °C, 1.5 h, 79% over the three steps;
(d) (-)-DET (1.2 equiv), Ti(Oi-Pr)4 (1.6 equiv), t-BuOOH (5.5 M in decane,
2.9 equiv), 4 Å MS, CH2Cl2, -20 °C, 1.5 h; (e) PMBOC(NH)CCl3 (1.5
equiv), La(OTf)3 (0.1 equiv), PhMe, 25 °C, 20 min, 80% over the two steps;
(f) LiCl (3.0 equiv), (2-fur)3P (0.5 equiv), Me3SnSnMe3 (3.0 equiv),
Pd2(dba)3 (0.1 equiv), THF, 25 °C, 30 min, 65%. Abbreviations: DMP )
Dess-Martin periodinane; DET ) diethyltartrate; MS ) molecular sieves;
PMB ) para-methoxybenzyl; Tf ) trifluoromethanesulfonyl; fur ) furyl;
dba ) dibenzylidineacetone.
a Reagents and conditions: (a) MeMgBr (3.0 M in Et2O, 2.5 equiv), Et2O,
-78 °C, 1 h, 98%; (b) 20% Pd(OH)2/C (10% w/w), H2, EtOAc/EtOH (1:
2), 25 °C, 6 h, 89%; (c) PhI(OAc)2 (2.5 equiv), TEMPO (0.1 equiv), CH2Cl2,
25 °C, 18 h; then A (3.0 equiv), 25 °C, 4 h, 92%; (d) DIBAL-H (1.0 M in
CH2Cl2, 5.0 equiv), CH2Cl2, -78 f 25 °C, 1.5 h, 89% (e) AcCl (1.1 equiv),
2,6-lut. (3.0 equiv), CH2Cl2, -78 °C, 30 min, 95%. Abbreviations: TBDPS
) tert-butyldiphenylsilyl; Bn ) benzyl; TEMPO ) 2,2,6,6-tetramethyl-1-
piperidinyloxy; DIBAL-H ) diisobutylaluminum hydride; Ac ) acetyl; lut.
) lutidine.
The synthesis of vinyl stannane 10 commenced from 1,2-
dihydrofuran (12) and proceeded through known intermediate
16 (two steps, 85% overall yield)20 as shown in Scheme 2. Thus,
a three-step sequence involving (a) oxidation (DMP), (b) Wittig
olefination (Ph3PdCHCO2Me), and (c) reduction (DIBAL-H)
led to skipped diene 17 in 79% overall yield. Sharpless
asymmetric epoxidation21 of the latter compound [Ti(Oi-Pr)4,
(-)-DET, t-BuOOH, 4 Å MS] followed by PMB protection22
[PMBOC(NH)CCl3, La(OTf)3 (cat.), 80% yield over the two
steps] furnished epoxide PMB ether 18. Subsequent palladium-
catalyzed stannane installation [Me3SnSnMe3, Pd2(dba)3 (cat.),
(2-fur)3P, 65% yield] completed the synthesis of the targeted
vinyl stannane 10, setting the stage for building block assembly.
3. Building Block Coupling and Polyepoxide Opening
Cascade Attempt. The π-allyl Stille coupling of building blocks
allylic acetate 9 and vinyl stannane 10 proceeded smoothly under
standard conditions [Pd2(dba)3 (cat.), LiCl, i-Pr2NEt] to provide
skipped diene 19 in 84% yield (Scheme 3). Shi epoxidation of
this epoxy diene (B,18b,23 Oxone) led to triepoxide 20 in 91%
yield as a mixture (ca. 7:1), presumably diastereomeric at the
epoxide site nearest to the F′ ring. This assumption was made
based on the expected influence of the F′ ring on the diaste-
reoselectivity of the epoxidation at its nearest site of unsatura-
tion.24 Hoping to influence favorably the regioselectivity of the
terminating epoxide opening event, we installed a vinyl group
at the end of the chain as shown in intermediate 21.25 This
modification was accomplished from triepoxide PMB ether 20
through a three-step sequence involving (a) DDQ cleavage of
the PMB ether, (b) DMP oxidation of the resulting alcohol, and
regio- and stereoselective Grignard addition to 13 was expected
on reactivity and steric grounds. Oxidation of the primary
alcohol of 14 was accomplished with PhI(OAc)2 in the presence
of TEMPO (cat.), and the resulting hydroxy aldehyde was
reacted, in the same pot, with stabilized phosphorane A to
generate R,ꢀ-unsaturated ester 15 in 92% overall yield. Reduc-
tion of the latter compound with DIBAL-H in CH2Cl2 at -78
°C gave the corresponding allylic alcohol (89% yield), whose
selective acetylation (AcCl, 2,6-lut., -78 °C) led to the desired
building block 9 in 95% yield.
(16) (a) Vilotijevic, I.; Jamison, T. F. Science 2007, 317, 1189. (b) Morten,
C. J.; Jamison, T. F. J. Am. Chem. Soc. 2009, 131, 6678. (c) Byers,
J. A.; Jamison, T. F. J. Am. Chem. Soc. 2009, 131, 6383. (d) Van
Dyke, A. R.; Jamison, T. F. Angew. Chem., Int. Ed. 2009, 48, 4330.
(e) Morten, C. J.; Byers, J. A.; Van Dyke, A. R.; Vilotijevic, I.;
Jamison, T. F. Chem. Soc. ReV. 2009, 38, 3175.
(17) (a) Stille, J. K.; Milstein, D. J. Am. Chem. Soc. 1978, 101, 4992. (b)
Farine, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1.
(c) Del Valle, L.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1990,
55, 3019. For an elegant application of this reaction in complex-
molecule synthesis, see: (d) Vanderwal, C. D.; Vosburg, D. A.; Weiler,
S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393.
(18) (a) Tu, Y.; Want, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
(b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224.
(19) Other groups have utilized similar methods for transformation of furans
to cyclic ethers: (a) Achmatowicz, O.; Bielski, R. Carbohydr. Res.
1977, 55, 165. (b) Guo, H.; O’Doherty, G. A. Angew. Chem., Int. Ed.
2007, 46, 5206. (c) Zhou, M.; O’Doherty, G. A. J. Org. Chem. 2007,
72, 2485. (d) Guo, H.; O’Doherty, G. A. Org. Lett. 2006, 8, 1609. (e)
Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young, V. G.; O’Doherty,
G. A. Carbohydr. Res. 2000, 328, 17. (f) Li, M.; Scott, J.; O’Doherty,
G. A. Tetrahedron Lett. 2004, 45, 1005. (g) Henderson, J. A.; Jackson,
K. L.; Phillips, A. J. Org. Lett. 2007, 9, 5299. (h) Jackson, K. L.;
Henderson, J. A.; Motoyoshi, H.; Phillips, A. J. Angew. Chem., Int.
Ed. 2009, 48, 2346. (i) Krishna, U. M.; Srikanth, G. S. C.; Trivedi,
G. K. Tetrahedron Lett. 2003, 44, 8277. A Noyori reduction is used
as a means to induce asymmetry: (j) Fujii, A.; Hashiguchi, S.; Uematsu,
N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521.
(20) Radosevich, A. T.; Chen, V. S.; Shi, H.-W.; Toste, F. D. Angew. Chem.,
Int. Ed. 2008, 47, 3755.
(21) (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.
(22) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267.
(23) Tu, Y.; Frohn, M.; Wang, Z.-X.; Shi, Y. Org. Synth. 2003, 80, 1.
(24) Diastereomers at the other two epoxide sites were too minor to be
isolated.
(25) (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.
9
216 J. AM. CHEM. SOC. VOL. 133, NO. 2, 2011

Synthesis of the C′D′E′F′ Domain of Maitotoxin
A R T I C L E S
Scheme 3. Construction of Hydroxy Triepoxide 21a
Figure 3. Linear retrosynthetic analysis of C′D′E′F′ ring system 6.
the desired polycyclic product, leading instead and as expected
to mixtures of compounds derived from undesired epoxide
openings. These failures led us to devise an alternative strategy
toward the C′D′E′F′ domain of maitotoxin as described below.
4. Linear Strategy toward the C′D′E′F′ Maitotoxin Do-
main. Having tested and failed to implement the rather daring
polyepoxide opening cascade to the C′D′E′F′ domain (6) of
maitotoxin, we adopted a more conventional and linear approach
to this tetracyclic system. Figure 3 depicts, in retrosynthetic
format, the main disconnections (two hydroxy epoxide cycliza-
tions and a SmI2-induced ring closure) that led to intermediate
15 (see Scheme 1) as a starting material.
Through this strategy, which relied on previously developed
synthetic technologies by us25 and others,27 we were able to
prepare multigram quantities of fragment 6 in enantiomerically
pure form. The practical and highly efficient synthesis of F′
ring intermediate 15 (Scheme 1) based on the furan methodo-
logy9-11,19 served as the first leg of the developed route, which
is shown in Scheme 4. Thus, 15 was rapidly converted to
hydroxy allylic epoxide 23 through a sequence involving TMS
protection of the tertiary alcohol (TMSOTf, 2,6-lut., 98% yield),
reduction of the ester moiety to the corresponding allylic alcohol
(DIBAL-H, 94% yield), Sharpless asymmetric epoxidation
[Ti(Oi-Pr)4, (-)-DET, t-BuOOH, 4 Å MS, 97% yield], oxidation
to the corresponding epoxy aldehyde (SO3 ·py), Wittig olefi-
nation (Ph3PdCH2, 93% yield for the two steps), and TMS
removal (TBAF, quant. yield). Casting of the E′ ring proceeded
smoothly from 23 through a hydroxy epoxide cyclication
(CSA)25 to afford bicycle 24 in 75% yield. Protection of the
hydroxyl group (TESCl, imid., quant. yield) of the latter
compound, followed by hydroboration of the olefin with
BH3 ·THF, furnished, upon oxidative workup (aq. NaOH, H2O2,
83% yield), primary alcohol 25. A three-step sequence [NMO,
TPAP (cat.); MeMgBr; NMO, TPAP (cat.)] was employed to
convert alcohol 25 to methyl ketone 26 in 91% overall yield.
From the several attempts to forge ring D′, Nakata’s samarium
diiodide-promoted tetrahydropyran formation27 proved the most
expedient. Thus, selective desilylation of 26 [TBAF, 97% yield],
followed by conjugate addition of the resulting hydroxyl
compound to ethyl propiolate in the presence of N-methylmor-
pholine, resulted in the formation of vinyl ether 27 (exclusively
E) in 99% yield. Treatment of the latter compound with SmI2
a Reagents and conditions: (a) 9 (1.0 equiv), 10 (2.0 equiv), LiCl (3.0
equiv), i-Pr2NEt (4.0 equiv), Pd2(dba)3 (0.2 equiv), NMP, 40 °C, 3 h, 84%;
(b)
B (2.0 equiv), Oxone (4.0 equiv), n-Bu4NHSO4 (0.2 equiv),
Na2B4O2 ·7H2O (1.0 equiv), DMM/CH3CN/0.4 mM aq. Na2EDTA/0.89 M
aq. K2CO3 (2:1:4:2), 0 °C, 3 h, 91% (7:1 dr); (d) DDQ (6.0 equiv), CH2Cl2/
H2O (10:1), 0 f 25 °C, 1.5 h, 80%; (e) DMP (3.0 equiv), NaHCO3 (10.0
equiv), CH2Cl2, 25 °C, 1 h; (f) Ph3PCH2Br (2.2 equiv), NaHMDS (0.6 M
in PhMe, 2.0 equiv), THF, 0 f 25 °C, 1 h, 63% over the two steps.
Abbreviations: NMP ) N-methylpyrrolidone; DMM ) dimethoxymethane;
EDTA ) ethylenediaminetetraacetate; DDQ ) 2,3-dichloro-5,6-dicyano-
p-benzoquinone; NaHMDS ) sodium bis(trimethylsilyl)amide; THF )
tetrahydrofuran.
(c) Witting methylenation, in 50% overall yield. Disappointingly,
all attempts to effect the much anticipated cascade polyepoxide
opening to afford the targeted tetracyclic system from 21 under
the reported (i.e., H2O, 90 °C, 7 days)16d or modified conditions
proved fruitless. Similarly, PMB ether 20 did not engage in any
productive reaction toward the desired tetracycle. Attempts to
employ different conditions (e.g., microwave irradiation, organic
solvent additives, phase transfer catalysts, salt additives)
frustratingly failed to improve the situation, with starting
material being recovered and/or intractable mixtures of highly
polar compounds being formed. The latter species are presum-
ably generated through preferential H2O attack of the epoxide
moieties26 over the desired pathway, which is most likely
prohibited by the unfavorable 1,3-diaxial interactions between
the methyl groups on the D′ and E′ rings of the anticipated
product (22) and transition states leading to it. We should note
that the use of protic or Lewis acids25 also failed to produce
(27) (a) Hori, N.; Matsukura, K.; Matsui, G.; Nakata, T. Tetrahedron Lett.
1999, 40, 2811. (b) Hori, N.; Matsukura, K.; Nakata, T. Org. Lett.
1999, 1, 1099. (c) Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron Lett.
1999, 40, 8859. (d) Hori, N.; Matsukura, H.; Matsui, G.; Nakata, T.
Tetrahedron 2002, 58, 1853.
(26) Wang, Z.; Cui, Y.-T.; Xu, Z.-B.; Qu, J. J. Org. Chem. 2008, 73, 2270.
9
J. AM. CHEM. SOC. VOL. 133, NO. 2, 2011 217

A R T I C L E S
Nicolaou et al.
Scheme 4. Synthesis of C′D′E′F′ Ring System 6 through a Linear
Table 1. C119 to C135 and C160 to C162 Chemical Shifts (δ) for
Strategya
Maitotoxin (MTX, 1) and C′D′E′F′ Ring System 6 and Their
Differences (∆δ, ppm)a
δ for MTX (1)
(ppm)
δ for 6
(ppm)
difference
(∆δ, ppm)
carbon
135
134
133
132
131
162
130
129
128
127
161
126
125
160
124
123
122
121
120
119
77.7
81.6
26.5
39.4
74.8
22.0
84.2
28.9
86.9
75.6
22.2
54.0
73.5
18.3
84.1
33.4
80.3
72.1
135.9
126.8
65.7
81.1
26.7
39.1
74.8
21.9
83.9
28.7
86.7
75.4
22.2
54.0
73.7
18.6
84.3
34.6
71.5
76.1
138.4
116.7
12.0
0.5
-0.2
0.3
0.0
0.1
0.3
0.2
0.2
0.2
0.0
0.0
-0.2
-0.3
-0.2
-1.2
8.8
-4.0
-2.5
10.1
a 150 MHz, 1:1 methanol-d4/pyridine-d5.
gave, stereoselectively, the expected hydroxy ester tricyclic
system 28, in 97% yield, through ketyl generation and intramo-
lecular 1,4-addition of the incipient carbon radical into the R,ꢀ-
unsaturated ester moiety.27 Installation of a TMS group on the
tertiary alcohol of 28 (TMSOTf, 2,6-lut., 95% yield), followed
by DIBAL-H reduction of the ester group under carefully
controlled conditions, led to the corresponding aldehyde in 90%
yield. Horner-Wadsworth-Emmons olefination of this alde-
hyde [MeO2CCH2P(O)(OEt)2, NaHMDS, 96% yield] and
DIBAL-H reduction of the resulting R,ꢀ-unsaturated ester
afforded allylic alcohol 29 (93% yield). Allylic alcohol 29 was
transformed to hydroxy epoxide 30 through a standard four-
step sequence involving Sharpless epoxidation [Ti(Oi-Pr)4, (-)-
DET, t-BuOOH, 4 Å MS, 96% yield], oxidation (SO3 ·py, Et3N,
DMSO, 84% yield), Wittig methylenation (Ph3PdCH2, 90%
yield), and selective desilylation (TBAF, 78% yield). Intramo-
lecular CSA-induced hydroxy epoxide opening of substrate 30
forged the remaining (C′) ring, furnishing C′D′E′F′ ring system
22 in 90% yield. Finally, exposure of tetracyclic compound 22
to TBAF liberated the primary hydroxyl group, thus completing
the synthesis of the C′D′E′F′ domain (6) of maitotoxin. Despite
its linear and stepwise nature, this sequence is notable for its
practicality and efficiency (average 93% yield per step).
5. Comparison of 13C NMR Chemical Shifts of the
C′D′E′F′ Ring System 6 with Those Corresponding to the
Same Region of Maitotoxin. NMR spectroscopic analysis of our
synthetic C′D′E′F′ domain 6 confirmed its stereochemical
configurations and led to assignment of the 13C chemical shifts
for all its carbons.28 Assignment of these chemical shifts allowed
us to compare them to those corresponding to the same region
of maitotoxin,3d an exercise that has previously served as a
means for supporting the assigned structure of the natural
product.3-5,8-12,13d,e,g The chemical shifts (δ, ppm) for synthetic
fragment 6, those for the same carbons (C119 to C135 and C160
to C162) of maitotoxin (1),3d and their differences (∆δ, ppm)
are given in Table 1. Figure 4 provides a graphical representation
a Reagents and conditions: (a) TMSOTf (1.3 equiv), 2,6-lut. (2.0 equiv),
CH2Cl2, 0 °C, 2 h, 98%; (b) DIBAL-H (1.0 M in hexanes, 2.5 equiv), CH2Cl2,
-78 °C, 1 h; then 0 °C, 30 min, 94%; (c) (-)-DET (1.2 equiv), Ti(Oi-Pr)4
(1.0 equiv), t-BuOOH (5.0 M in decane, 3.0 equiv), 4 Å MS, CH2Cl2, -20
°C, 1 h, 97%; (d) SO3 ·py (4.0 equiv), Et3N (8.0 equiv), CH2Cl2/DMSO (5:1),
0 f 25 °C, 9 h; (e) CH3PPh3Br (2.0 equiv), NaHMDS (0.6 M in toluene, 1.9
equiv), THF, 0 °C, 30 min; then -78 °C, aldehyde (1.0 equiv), THF, -78 f
0 °C, 93% over the two steps; (f) TBAF (1.0 M in THF, 1.2 equiv), THF, 0
°C, 30 min, 100%; (g) CSA (0.2 equiv), CH2Cl2, 0 °C, 30 min, 75%; (h) TESCl
(2.0 equiv), imidazole (3.0 equiv), CH2Cl2, 0 f 25 °C, 1 h, 100%; (i) BH3 ·THF
(1.0 M in THF, 1.2 equiv), THF, 0 °C, 2 h; then H2O2 (35% aq, 3.0 equiv),
NaOH (2.0 M aq, 2.0 equiv), 25 °C, 1 h, 83%; (j) TPAP (0.1 equiv), NMO
(3.0 equiv), 4 Å MS, 0 f 25 °C, 1 h, 95%; (k) MeMgBr (3.0 M in ether, 5.0
equiv), THF, 0 °C, 1 h; (l) TPAP (0.1 equiv), NMO (3.0 equiv), 4 Å MS, 0 f
25 °C, 12 h, 96% over the two steps; (m) TBAF (1.0 M in THF, 1.1 equiv),
THF, 0 °C, 30 min, 97%; (n) ethyl propiolate (4.0 equiv), N-methylmorpholine
(8.0 equiv), CH2Cl2, 25 °C, 23 h, 99%; (o) SmI2 (0.1 M in THF, 2.5 equiv),
MeOH (2.5 equiv), THF, 0 °C, 20 min, 97%; (p) TMSOTf (1.5 equiv), 2,6-
lut. (2.5 equiv), CH2Cl2, 0 °C, 1 h, 95%; (q) DIBAL-H (1.0 M in CH2Cl2, 1.1
equiv), CH2Cl2, -78 °C, 1 h, 90%; (r) MeO2CCH2P(O)(OEt)2 (2.0 equiv),
NaHMDS (0.6 M in PhMe, 1.9 equiv), THF, 0 °C, 1 h, 96%; (s) DIBAL-H
(1.0 M in CH2Cl2, 2.5 equiv), CH2Cl2, -78 °C, 40 min, 93%; (t) (-)-DET
(1.2 equiv), Ti(Oi-Pr)4 (1.0 equiv), t-BuOOH (5.0 M in decane, 3.0 equiv), 4
Å MS, CH2Cl2, -20 °C, 1 h, 96%; (u) SO3 ·py (5.0 equiv), DMSO (14 equiv),
Et3N (5.5 equiv), CH2Cl2, 0 f 25 °C, 1 h, 84%; (v) Ph3PCH3Br (2.0 equiv),
NaHMDS (0.6 M in PhMe, 1.9 equiv), THF, -78 °C f 0 °C, 90%; (w) TBAF
(1.05 equiv), THF, 0 °C, 1 h, 78%; (x) CSA (0.1 equiv), CH2Cl2, 0 °C, 3 h,
90%; (y) TBAF (1.0 M in THF, 5.0 equiv), THF, 25 °C, 2 h, 79%.
Abbreviations: TMSOTf ) trimethylsilyl trifluoromethanesulfonate; py )
pyridine; DMSO ) dimethylsulfoxide; TBAF ) tetra-n-butylammonium
fluoride; CSA ) camphorsulfonic acid; TES ) triethylsilyl; TPAP ) tetra-n-
propylammonium perruthenate; NMO ) N-methylmorpholine oxide.
(28) The stereochemistry and 13C chemical shift assignments of 6 were
based on 1H coupling constants and COSY, ROESY, HSQC, and
HMBC NMR spectroscopic experiments.
9
218 J. AM. CHEM. SOC. VOL. 133, NO. 2, 2011

Synthesis of the C′D′E′F′ Domain of Maitotoxin
A R T I C L E S
Figure 4. Graphically depicted 13C chemical shift differences (∆δ, ppm) for each carbon between C119 to C135 and C160 to C162 for maitotoxin (1) and
C′D′E′F′ ring system 6.
6 may be significant for its contributions to the physical and
biological properties of the natural product.
Conclusion
Described herein are two approaches to the C′D′E′F′ domain
(6) of maitotoxin (1). The first, based on biosynthetic consid-
erations, started with furfuryl alcohol (11) and called upon a
zip-type cascade hydroxy triepoxide (i.e., 21) opening sequence
to forge the targeted molecule. Despite our expectation, however,
this biomimetic hypothesis could not be implemented under a
variety of conditions, underscoring the current limitations of
such schemes, elegant as they are. A second approach to the
C′D′E′F′ target molecule, also commencing from furfuryl
alcohol (11), proceeded smoothly in a linear fashion, delivering
each ring system in a stepwise fashion in excellent overall yield.
The successful sequence relied upon the Achmatowicz/Noyori
technology,9-11,19 the hydroxy epoxide opening,25 and the SmI2-
induced27 tetrahydropyran processes to cast the desired tetra-
cyclic system. This synthesis delivered multigram quantities of
the C′D′E′F′ domain, demonstrating the power of the employed
Figure 5. ORTEP representation of maitotoxin domain 6 (a: top view; b:
synthetic technologies. It also allowed 13C NMR comparisons
side view) and key distances (d) and angles (R).
that supported the previously assigned structure of this region
of the chemical shift differences between 6 and 1. As seen from
both the table and the figure, there is excellent agreement
between the two sets of chemical shifts (except for the carbons
at the edges of 6 due to the drastically different structural motifs
between the synthetic fragment and maitotoxin; see Figure 4).
Thus, the average chemical shift deviation (∆δ, ppm) for C-123
to C-134 and C-160 to C-162 is 0.26 ppm with the largest
difference being 1.2 ppm (C123). These values lend additional
support for the assigned structure of maitotoxin (1).13d
6. X-ray Crystallographic Analysis of C′D′E′F′ Maitotoxin
Domain 6. On standing in EtOAc, compound 6 crystallized in
colorless needles, mp 226-228 °C. One of these crystals yielded
to X-ray crystallographic analysis (see ORTEP representations,
Figure 5). In addition to providing unambiguous proof of the
structure of the synthesized domain, this analysis provided a
more precise picture of its conformation. Thus, structure 6
appears to assume a distorted conformation in the solid state
that leads to a significant bending of its tetracyclic ladder-like
structure in order to relieve the strain imposed by its three axial
methyl groups. The concavity of the molecule is defined by a
number of key distances (d) and angles (R) revealed by this
X-ray structure as shown in Figure 5 [d(C1-C13) ) 9.19 Å;
d(C2-C14) ) 9.49 Å; d(H1A-H13) ) 8.58 Å; d(H2A-H14) )
10.45 Å. R(C14-C8-C2) ) 146.42°; R(C13-C7-C1) ) 153.04°].
This deviation from linearity of the C′D′E′F′ maitotoxin domain
of the natural product and an X-ray crystallographic analysis
that proved its structure unambiguously, revealing at the same
time an interesting twist in its conformation, apparently due to
the three axial methyl groups. The reported chemistry may
facilitate further synthetic and biological studies in the marine
polyether neurotoxin area.29
Acknowledgment. We thank Drs. D.-H. Huang, G. Siuzdak,
and R. Chadha for spectroscopic, mass spectrometric, and X-ray
crystallographic 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 Daiichi-Sankyo Co.,
Ltd. (T.N.).
Supporting Information Available: Experimental procedures,
characterization data for all compounds, and CIF file. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA109531D
(29) For selected reviews on the synthesis of fused polyether natural
products, see: (a) Nicolaou, K. C.; Frederick, M. O.; Aversa, R. J.
Angew. Chem., Int. Ed. 2008, 47, 7182. (b) Nicolaou, K. C. Angew.
Chem., Int. Ed. Engl. 1996, 35, 588. (c) Nakata, T. Chem. ReV. 2005,
105, 4314. (d) Inoue, M. Chem. ReV. 2005, 105, 4379. (e) Sasaki, M.
Bull. Chem. Soc. Jpn. 2007, 80, 856.
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