J. Am. Chem. Soc.

1996, 118, 10335-10336 10335

An Olefin Metathesis Based Strategy for the Scheme 1. Synthesis of OPQ Ring Systems 9 and 14.a
Construction of the JKL, OPQ, and UVW Ring
Systems of Maitotoxin
K. C. Nicolaou,* M. H. D. Postema, E. W. Yue, and
A. Nadin
Department of Chemistry
and The Skaggs Institute of Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
Department of Chemistry and Biochemistry
UniVersity of California San Diego
9500 Gilman DriVe, La Jolla, California 92093
ReceiVed August 15, 1996
The structure of the most potent nonpeptidic substance known
to man, the marine neurotoxin maitotoxin (1, Figure 1), has
recently been elucidated.1,2 Containing no less than 32 rings
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and 98 stereocenters, this structure presents an imposing

challenge to synthetic chemistry and provides opportunities for
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invention and discovery both in chemistry and biology. Al-

a Reagents and conditions: (a) for 2 + 3 f 4; 2-(chloromethyl)py-
though considerably larger, this structure is reminiscent to that
of brevetoxin B,3 except for the carbon-carbon bonds bridging ridinium iodide (1.5 equiv), Et3N (3.0 equiv), 4-DMAP (0.2 equiv),
CH2Cl2, 25 °C, 3 h, 81%; for 10 + 3 f 11, DCC (1.5 equiv), 4-DMAP
rings K and L, O and P, and V and W (see shaded areas, Figure (0.5 equiv), CH2Cl2, 25 °C, 3 h, 85%; (b) for 4 f 5, Tebbe reagent
1). In this paper we wish to disclose the construction of these (4.0 equiv), THF, 25 °C, 0.5 h, then ∆, 4 h, 50%; for 11 f 12, same
intriguing regions of maitotoxin (1) through application of our conditions as for 4 f 5, 54%; (c) BH3 (10 equiv), THF, 0 °C, 5 h,
recently developed olefin metathesis4 based strategy of cyclic then 3 N NaOH (50 equiv), H2O2 (50 equiv), 93%; (d) AD mix R (2.0
ethers.5 Specifically, we report the synthesis of the OPQ (14), equiv), MeSO2NH2 (3.0 equiv), t-BuOH-H2O (1:1), 0 °C, 36 h, 98%;
UVW (23), and JKL (29) representing nine of maitotoxin’s rings (e) Et3SiH (3.0 equiv), BF3‚Et2O (1.1 equiv), CH2Cl2, 0 °C, 2 h, 35%;
and 19 of its stereocenters (antipodal,1 see Figure 1). (f) for 12 f 13, BH3 (10 equiv), THF, 0 °C, 4 h, then 3 N NaOH (50
Our initial explorations of the olefin metathesis approach to equiv), H2O2 (50 equiv), 89%; (g) H2, Pd/C (0.3 wt equiv), EtOH, 25
these frameworks focused on the simplified OPQ ring system °C, 3 h, 91%. 4-DMAP ) 4-(dimethylamino)pyridine; DCC ) 1,3-
dicyclohexylcarbodiimide; Tebbe reagent ) Cp2TiCH2ClAlMe2; THF
9 (Scheme 1) lacking the methyl group at the PQ fusion. Thus,
) tetrahydrofuran.
coupling of fragments 26 and 36 in the presence of 2-(chlorom-
ethyl)pyridinium iodide and 4-DMAP afforded ester 47 (81%). lation9 of 5 as a means to control the stereochemistry of the
Exposure of 4 to excess Tebbe reagent in THF, initially at 25 hydroxyl group at C-2, a reaction that led to some interesting
°C and then at reflux, led to cyclic enol ether 5 in 50% yield. observations: (a) while AD mix R gave exclusively compound
Initial attempts to introduce the required hydroxyl group via 7 (95% yield) as expected, AD mix â led, unexpectedly, to a
hydroboration led predominantly to the wrong stereoisomer 68 preponderance of the same isomer, 7, [98% yield, ca, 13:1 ratio
(epimeric at C-1 and C-2) with the desired product 9 being with its epimer 8 (see Scheme 2)] and (b) exposure of the minor
formed only as a minor component (6/9 ca. 2:1, 93% combined isomer 8 to conditions similar to those of dihydroxylation
yield). Attention was then turned to the Sharpless dihydroxy- reaction [K2CO3, tBuOH/H2O (2:1), 25 °C] caused its complete
(1) Just prior to submission of this work, the absolute configuration of isomerization to the desired isomer 7. These observations can
maitotoxin was reassigned as that shown in Figure 1 which is opposite to be explained by the mechanism shown in Scheme 2, by which
the previously adopted2 absolute stereochemistry and to that of the reported the undesired isomer 8 is envisioned to undergo ring opening
fragments OPQ (14), UVW (23), and JKL (29): (a) Sasaki, M.; Matsumori,
N.; Maruyama, T.; Nonomura, T.; Murata, M.; Tachibana, K.; Yasumoto, (to 16), enolization (to 17), and exclusive reclosure to the
T. Angew. Chem. 1996, 108, 1782. Nonomura, T.; Sasaki, M.; Matsumori, thermodynamically more stable isomer 7 (with both hydroxyl
N.; Murata, M.; Tachibana, K.; Yasumoto, T. Angew. Chem. 1996, 108, and pyran groups disposed equatorially in space, see box,
1786. (b) 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. We thank Scheme 2). Dihydroxylation of 5 without a chiral ligand
Professor Y. Kishi for a preprint of this article. [OsO4-NMO] gave 7 as the major product (7/8 ca, 5:1).
(2) (a) Murata, M.; Naoki, H.; Matsunaga, S.; Satake, M.; Yasumoto, T. Reductive removal of the anomeric hydroxyl group from 7
J. Am. Chem. Soc. 1994, 116, 7098. (b) Sasaki, M.; Nonomura, T.; Murata,
M.; Tachibana, K. Tetrahedron Lett. 1995, 36, 9007. (c) Sasaki, M.; (Scheme 1) was achieved with Et3SiH in the presence of BF3‚-
Nonomura, T.; Murata, M.; Tachibana, K.; Yasumoto, T. Tetrahedron Lett. Et2O, affording the desired OPQ model system 9 (40% yield).10
1995, 36, 9011. (d) Sasaki, M.; Nonomura, T.; Murata, M.; Tachibana, K. Having established the viability of the metathesis approach
Tetrahedron Lett. 1994, 35, 5023.
(3) Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.; Golik, to these systems, we then set out to assemble the three
J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773. (b) maitotoxin fragments OPQ (14, Scheme 1), UVW (23, Scheme
Lee, M. S.; Repeta, D. J.; Nakanishi, K.; Zagorski, M. G. J. Am. Chem. 3), and JKL (29, Scheme 4). Construction of 14 began with
Soc. 1986, 108, 7855. olefinic compound 1011 and followed the sequence depicted in
(4) (a) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59,
4029. (b) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, Scheme 1. In this instance, the ring closure of ester 11
28, 446. (c) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. proceeded via metathesis to afford cyclic system 12 in 54%
Soc. 1996, 118, 6634. yield, whereas hydroboration of the latter at -78 f 0 °C proved
(5) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem.
Soc. 1996, 118, 1565. both efficient and stereoselective, furnishing 13 (78%) plus its
(6) Compounds 2, 3, 24, and 25 were synthesized from D-glucal as C-1, C-2 stereoisomer (15, R ) CH3, 11%). Apparently, the
described in the Supporting Information.
(7) All new compounds exhibited satisfactory spectral and exact mass (9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
data. Yields refer to spectroscopically and chromatographically homoge- 1994, 94, 2483 and references cited therein.
neous materials. All compounds are optically pure. (10) Overreduction of lactol 7 to a triol was a major side reaction.
(8) Stereochemical assignments were made by 2-D NMR spectroscopy (11) Compounds 10, 18, and 19 were synthesized from 1,4-butanediol
on the intermediates or the corresponding acetates. as described in the Supporting Information.

S0002-7863(96)02862-4 CCC: $12.00 © 1996 American Chemical Society

10336 J. Am. Chem. Soc., Vol. 118, No. 42, 1996 Communications to the Editor

Figure 1. Structure of maitotoxin (1).

Scheme 2. Proposed Mechanism for the Isomerization of Scheme 4. Synthesis of JKL Ring System 29a
the OPQ Ring System (8 f 7)

Scheme 3. Synthesis of UVW Ring System 23a a

Reagents and conditions: (a) DCC (1.5 equiv), 4-DMAP (0.2
equiv), CH2Cl2, 25 °C, 3 h, 88%; (b) Cp2TiMe2 (10 equiv), THF, ∆,
12 h, 20%; (c) BH3 (10 equiv), THF, 0 °C, 2 h, then 3 N NaOH (50
equiv), H2O2 (50 equiv), 77% (4% of C-1, C-2 isomer); (d) H2, Pd/C
(0.4 wt equiv), EtOH, 25 °C, 6 h, 98%.
28 (77%), deprotection of which was achieved via hydrogenoly-
sis, furnishing the targeted JKL ring framework 29 (98%).
Through this chemistry, the ester-olefin metathesis reaction
has proven itself as a powerful strategy for rapid constru-
ction of complex cyclic polyether frameworks.15 Specifically,
this methodology appears to offer a potential solution16 to the
assembly of maitotoxin’s JKL, OPQ, and UVW regions and,
together with our previous work17 on brevetoxin B, may even
a Reagents and conditions: (a) DCC (1.5 equiv), 4-DMAP (0.5
provide a possible synthetic pathway to maitotoxin (1) itself.
equiv), CH2Cl2, 25 °C, 3 h, 93%; (b) Tebbe reagent (4.0 equiv), THF,
25 °C, 0.5 h, then ∆, 4 h, 36%; (c) TFA (1.5 equiv), Et3SiH (3.0 equiv), Acknowledgment. We thank Drs. Dee H. Huang and Gary Siuzdak
CH2Cl2, 0 °C, 6 h, 80%; (d) TBAF (1.5 equiv), THF, 25 °C, 2 h, 91%. for their NMR and mass spectroscopy assistance, respectively. Finan-
TFA ) trifluoroacetic acid; TBAF ) tetra-n-butylammonium fluoride. cial support provided by the National Institutes of Health (USA), the
NSERC (MHDP), The Skaggs Institute of Chemical Biology, Merck,
methyl group in 12 directs the stereochemical outcome of the DuPont-Merck, Pfizer, Hoffmann La-Roche, and Amgen.
hydroboration reaction in favor of the desired isomer 13. Hydro-
genolysis of the benzyl ether in 13 gave, in 91% yield, the Supporting Information Available: Schemes for the synthesis of
targeted OPQ ring system 14. compounds 2, 3, 10, 18, 19, 24, and 25 and listing of selected data for
The synthesis of the UVW system 23 is outlined in Scheme compounds 11-14, 20-23, and 26-29 (17 pages). See any current
3. Thus, DCC-mediated esterification of 1811 with 1911 fur- masthead page for ordering and access instructions.
nished ester 20 (93%), which upon reaction with excess Tebbe JA962862Z
reagent resulted in the formation of cyclic enol ether 21 in 36%
yield. Exposure of 21 to Et3SiH in the presence of CF3COOH (12) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(13) Klauss, K.; Bestian, H. Justus Liebigs Ann. Chem. 1962, 654, 8.
gave stereoselectively the saturated system 22 (80%), desily- (14) The use of Tebbe reagent gave only unidentified decomposition
lation of which afforded the desired compound 23 (91%). products. It was assumed that enol ether 27 was unstable to the Lewis
A sequence along similar lines (Scheme 4) resulted in the acidic reaction conditions.4a,5
(15) For a recent review on this topic, see: Alvarez, E.; Candenas, M.-
preparation of the JKL ring system 29. Thus, coupling of 246 L.; Pérez, R.; Ravelo, J. L.; Martı́n, D. D. Chem. ReV. 1995, 95, 1953.
with 256 led to ester 26 (88% yield), whose olefination- (16) For a palladium-mediated approach to these systems, see: Nicolaou,
metathesis (26 f 27) required the use of dimethyltitanocene12,13 K. C.; Sato, M.; Miller, N. D.; Gunzner, J. L.; Renaud, J.; Untersteller, E.
Angew. Chem., Int. Ed. Engl. 1996, 35, 889.
(20%, unoptimized).14 Finally, stereoselective hydroboration (17) For reviews, see: (a) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl.
of 27 led almost exclusively (>20:1 ratio) to the desired isomer 1996, 35, 588. (b) Nicolaou, K. C. Aldrichimica Acta 1993, 26, 62.