An olefin metathesis based strategy for the construction of the JKL, OPQ, and UVW ring systems of maitotoxin

Full text of DOI:10.1021/ja962862z

J. Am. Chem. Soc. 1996, 118, 10335-10336
10335
Scheme 1. Synthesis of OPQ Ring Systems 9 and 14.a
An Olefin Metathesis Based Strategy for the
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
and 98 stereocenters, this structure presents an imposing
challenge to synthetic chemistry and provides opportunities for
invention and discovery both in chemistry and biology. Al-
though considerably larger, this structure is reminiscent to that
of brevetoxin B,3 except for the carbon-carbon bonds bridging
rings K and L, O and P, and V and W (see shaded areas, Figure
1). In this paper we wish to disclose the construction of these
intriguing regions of maitotoxin (1) through application of our
recently developed olefin metathesis4 based strategy of cyclic
ethers.5 Specifically, we report the synthesis of the OPQ (14),
UVW (23), and JKL (29) representing nine of maitotoxin’s rings
and 19 of its stereocenters (antipodal,1 see Figure 1).
Our initial explorations of the olefin metathesis approach to
these frameworks focused on the simplified OPQ ring system
9 (Scheme 1) lacking the methyl group at the PQ fusion. Thus,
coupling of fragments 26 and 36 in the presence of 2-(chlorom-
ethyl)pyridinium iodide and 4-DMAP afforded ester 47 (81%).
Exposure of 4 to excess Tebbe reagent in THF, initially at 25
°C and then at reflux, led to cyclic enol ether 5 in 50% yield.
Initial attempts to introduce the required hydroxyl group via
hydroboration led predominantly to the wrong stereoisomer 68
(epimeric at C-1 and C-2) with the desired product 9 being
formed only as a minor component (6/9 ca. 2:1, 93% combined
yield). Attention was then turned to the Sharpless dihydroxy-
a Reagents and conditions: (a) for 2 + 3 f 4; 2-(chloromethyl)py-
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
(0.5 equiv), CH2Cl2, 25 °C, 3 h, 85%; (b) for 4 f 5, Tebbe reagent
(4.0 equiv), THF, 25 °C, 0.5 h, then ∆, 4 h, 50%; for 11 f 12, same
conditions as for 4 f 5, 54%; (c) BH3 (10 equiv), THF, 0 °C, 5 h,
then 3 N NaOH (50 equiv), H2O2 (50 equiv), 93%; (d) AD mix R (2.0
equiv), MeSO2NH2 (3.0 equiv), t-BuOH-H2O (1:1), 0 °C, 36 h, 98%;
(e) Et3SiH (3.0 equiv), BF3‚Et2O (1.1 equiv), CH2Cl2, 0 °C, 2 h, 35%;
(f) for 12 f 13, BH3 (10 equiv), THF, 0 °C, 4 h, then 3 N NaOH (50
equiv), H2O2 (50 equiv), 89%; (g) H2, Pd/C (0.3 wt equiv), EtOH, 25
°C, 3 h, 91%. 4-DMAP ) 4-(dimethylamino)pyridine; DCC ) 1,3-
dicyclohexylcarbodiimide; Tebbe reagent ) Cp2TiCH2ClAlMe2; THF
) tetrahydrofuran.
lation9 of 5 as a means to control the stereochemistry of the
hydroxyl group at C-2, a reaction that led to some interesting
observations: (a) while AD mix R gave exclusively compound
7 (95% yield) as expected, AD mix â led, unexpectedly, to a
preponderance of the same isomer, 7, [98% yield, ca, 13:1 ratio
with its epimer 8 (see Scheme 2)] and (b) exposure of the minor
isomer 8 to conditions similar to those of dihydroxylation
reaction [K2CO3, tBuOH/H2O (2:1), 25 °C] caused its complete
isomerization to the desired isomer 7. These observations can
be explained by the mechanism shown in Scheme 2, by which
the undesired isomer 8 is envisioned to undergo ring opening
(to 16), enolization (to 17), and exclusive reclosure to the
thermodynamically more stable isomer 7 (with both hydroxyl
and pyran groups disposed equatorially in space, see box,
Scheme 2). Dihydroxylation of 5 without a chiral ligand
[OsO4-NMO] gave 7 as the major product (7/8 ca, 5:1).
Reductive removal of the anomeric hydroxyl group from 7
(Scheme 1) was achieved with Et3SiH in the presence of BF3‚-
Et2O, affording the desired OPQ model system 9 (40% yield).10
Having established the viability of the metathesis approach
to these systems, we then set out to assemble the three
maitotoxin fragments OPQ (14, Scheme 1), UVW (23, Scheme
3), and JKL (29, Scheme 4). Construction of 14 began with
olefinic compound 1011 and followed the sequence depicted in
Scheme 1. In this instance, the ring closure of ester 11
proceeded via metathesis to afford cyclic system 12 in 54%
yield, whereas hydroboration of the latter at -78 f 0 °C proved
both efficient and stereoselective, furnishing 13 (78%) plus its
C-1, C-2 stereoisomer (15, R ) CH3, 11%). Apparently, the
(1) Just prior to submission of this work, the absolute configuration of
maitotoxin was reassigned as that shown in Figure 1 which is opposite to
the previously adopted2 absolute stereochemistry and to that of the reported
fragments OPQ (14), UVW (23), and JKL (29): (a) Sasaki, M.; Matsumori,
N.; Maruyama, T.; Nonomura, T.; Murata, M.; Tachibana, K.; Yasumoto,
T. Angew. Chem. 1996, 108, 1782. Nonomura, T.; Sasaki, M.; Matsumori,
N.; Murata, M.; Tachibana, K.; Yasumoto, T. Angew. Chem. 1996, 108,
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
Professor Y. Kishi for a preprint of this article.
(2) (a) Murata, M.; Naoki, H.; Matsunaga, S.; Satake, M.; Yasumoto, T.
J. Am. Chem. Soc. 1994, 116, 7098. (b) Sasaki, M.; Nonomura, T.; Murata,
M.; Tachibana, K. Tetrahedron Lett. 1995, 36, 9007. (c) Sasaki, M.;
Nonomura, T.; Murata, M.; Tachibana, K.; Yasumoto, T. Tetrahedron Lett.
1995, 36, 9011. (d) Sasaki, M.; Nonomura, T.; Murata, M.; Tachibana, K.
Tetrahedron Lett. 1994, 35, 5023.
(3) Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.; Golik,
J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773. (b)
Lee, M. S.; Repeta, D. J.; Nakanishi, K.; Zagorski, M. G. J. Am. Chem.
Soc. 1986, 108, 7855.
(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,
28, 446. (c) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem.
Soc. 1996, 118, 6634.
(5) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem.
Soc. 1996, 118, 1565.
(6) Compounds 2, 3, 24, and 25 were synthesized from D-glucal as
described in the Supporting Information.
(7) All new compounds exhibited satisfactory spectral and exact mass
data. Yields refer to spectroscopically and chromatographically homoge-
neous materials. All compounds are optically pure.
(8) Stereochemical assignments were made by 2-D NMR spectroscopy
on the intermediates or the corresponding acetates.
(9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483 and references cited therein.
(10) Overreduction of lactol 7 to a triol was a major side reaction.
(11) Compounds 10, 18, and 19 were synthesized from 1,4-butanediol
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
the OPQ Ring System (8 f 7)
Scheme 4. Synthesis of JKL Ring System 29a
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
provide a possible synthetic pathway to maitotoxin (1) itself.
a Reagents and conditions: (a) DCC (1.5 equiv), 4-DMAP (0.5
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),
CH2Cl2, 0 °C, 6 h, 80%; (d) TBAF (1.5 equiv), THF, 25 °C, 2 h, 91%.
TFA ) trifluoroacetic acid; TBAF ) tetra-n-butylammonium fluoride.
Acknowledgment. We thank Drs. Dee H. Huang and Gary Siuzdak
for their NMR and mass spectroscopy assistance, respectively. Finan-
cial support provided by the National Institutes of Health (USA), the
NSERC (MHDP), The Skaggs Institute of Chemical Biology, Merck,
DuPont-Merck, Pfizer, Hoffmann La-Roche, and Amgen.
methyl group in 12 directs the stereochemical outcome of the
hydroboration reaction in favor of the desired isomer 13. Hydro-
genolysis of the benzyl ether in 13 gave, in 91% yield, the
targeted OPQ ring system 14.
Supporting Information Available: Schemes for the synthesis of
compounds 2, 3, 10, 18, 19, 24, and 25 and listing of selected data for
compounds 11-14, 20-23, and 26-29 (17 pages). See any current
masthead page for ordering and access instructions.
The synthesis of the UVW system 23 is outlined in Scheme
3. Thus, DCC-mediated esterification of 1811 with 1911 fur-
nished ester 20 (93%), which upon reaction with excess Tebbe
reagent resulted in the formation of cyclic enol ether 21 in 36%
yield. Exposure of 21 to Et3SiH in the presence of CF3COOH
gave stereoselectively the saturated system 22 (80%), desily-
lation of which afforded the desired compound 23 (91%).
A sequence along similar lines (Scheme 4) resulted in the
preparation of the JKL ring system 29. Thus, coupling of 246
with 256 led to ester 26 (88% yield), whose olefination-
metathesis (26 f 27) required the use of dimethyltitanocene12,13
(20%, unoptimized).14 Finally, stereoselective hydroboration
of 27 led almost exclusively (>20:1 ratio) to the desired isomer
JA962862Z
(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.
(14) The use of Tebbe reagent gave only unidentified decomposition
products. It was assumed that enol ether 27 was unstable to the Lewis
acidic reaction conditions.4a,5
(15) For a recent review on this topic, see: Alvarez, E.; Candenas, M.-
L.; Pe´rez, R.; Ravelo, J. L.; Mart´ın, D. D. Chem. ReV. 1995, 95, 1953.
(16) For a palladium-mediated approach to these systems, see: Nicolaou,
K. C.; Sato, M.; Miller, N. D.; Gunzner, J. L.; Renaud, J.; Untersteller, E.
Angew. Chem., Int. Ed. Engl. 1996, 35, 889.
(17) For reviews, see: (a) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl.
1996, 35, 588. (b) Nicolaou, K. C. Aldrichimica Acta 1993, 26, 62.