A highly efficient synthesis of the hemibrevetoxin B ring system.

Article abstract of DOI:10.1021/ol991371r

[reaction: see text] This Letter describes the synthesis of the hemibrevetoxin B tetracyclic ring system in 14 linear transformations from the Danishefsky-Kitahara diene.

Full text of DOI:10.1021/ol991371r

ORGANIC
LETTERS
2
000
Vol. 2, No. 2
31-234
A Highly Efficient Synthesis of the
Hemibrevetoxin B Ring System
2
Jon D. Rainier,* Shawn P. Allwein, and Jason M. Cox
Department of Chemistry, The UniVersity of Arizona, Tucson, Arizona 85721
rainier@u.arizona.edu
Received December 20, 1999
ABSTRACT
This Letter describes the synthesis of the hemibrevetoxin B tetracyclic ring system in 14 linear transformations from the Danishefsky−
Kitahara diene.
The marine ladder toxins comprise a family of red tide toxins
possessing mostly trans-fused polyether rings. Included in
oxidations and C-C bond-forming reactions with metathesis
or acid-mediated annulations.
1
2
3
4
this family are the brevetoxins, ciguatoxins, maitotoxins,
While pleased with the efficiency as well as the flexibility
of these approaches in model compounds, we were intent
on demonstrating their utility in the synthesis of one of the
polyether natural products. With this in mind, we elected to
target the simplest member of the marine ladder toxin family,
hemibrevetoxin B. That hemibrevetoxin B had been synthe-
sized on four separate occasions was of added benefit; our
hemibrevetoxin B synthesis would provide us with the
opportunity to gauge the effectiveness of our strategy with
5
and gambieric acids, among others. The high degree of
6
7
symmetry in these agents has led many, including us, to
believe that iterative approaches to their synthesis might be
ideal.
We have recently communicated two such approaches to
fused polyether ring systems that require between two and
7
four steps per iteration. These strategies couple enol ether
(
1) Shimizu, Y. Marine Natural Products; Academic Press: New York,
978; Vol. 1.
2) (a) For the isolation of brevetoxin B, see: Lin, Y. Y.; Risk, M.; Ray,
8
respect to these other approaches.
1
(
Our analysis of hemibrevetoxin B is outlined in Scheme
M. S.; VanEnsen, D.; Clardy, J.; Golik, J.; James, J. C.; Nakanishi, K. J.
Am. Chem. Soc. 1981, 103, 6773. (b) For the total synthesis of brevetoxin
B, see: Nicolaou, K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J.;
Sato, M.; Untersteller, E. J. Am. Chem. Soc. 1995, 117, 10252. (c) For the
isolation of brevetoxin A, see: Shimizu, Y.; Chou, H. -N.; Bando, H.;
Van Duyne, G.; Clardy, J. C. J. Am. Chem. Soc. 1986, 108, 514. (d) For
the total synthesis of brevetoxin A, see: Nicolaou, K. C.; Yang, Z.; Shi,
G.-Q.; Gunzner, J. L.; Agrios, K. A.; G a¨ rtner, P. Nature 1998, 392, 264.
1. As envisioned, the approach was to be linear, progressing
from the six-membered A-ring to the seven-membered
D-ring.
The synthesis of the hemibrevetoxin A-ring is depicted in
9
Scheme 2. From the Danishefsky-Kitahara diene 6, a
1
0
(
3) (a) Yasumoto, T.; Satake, M. J. Toxicology-Toxin ReV. 1996, 15,
1. (b) Scheuer, P. J. Tetrahedron 1994, 50, 3.
4) (a) Zheng, W.; DeMattei, J. A.; Wu, J.-P.; Duan, J. J.-W.; Cook, L.
hetero-Diels-Alder cycloaddition with 7 provided dihy-
9
(
R.; Oinuma, H.; Kishi, Y. J. Am. Chem. Soc. 1996, 118, 7946. (b)
Nonomura, T.; Sasaki, M.; Matsumori, N.; Murata, M.; Tachibana, K.;
Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1675.
(8) Hemibrevetoxin B syntheses with number of transformations. (a)
Nicolaou group: 54 synthetic steps from D-mannose. Nicolaou, K. C.;
Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X.-Y.; Hwang, C.-K. J. Am.
Chem. Soc. 1993, 115, 3558. (b) Yamamoto group: 52 steps from
D-mannose. Kadota, I.; Yamamoto, Y. J. Org. Chem. 1998, 63, 6597. (c)
Nakata group: 61 steps from geranyl acetate. Morimoto, M.; Matsukura,
H.; Nakata, T. Tetrahedron Lett. 1996, 37, 6365. (d) Mori group: 36 steps
from tri-O-acetyl-D-glucal to a Yamamoto intermediate, 43 steps overall.
Mori, Y.; Yaegassi, K.; Furukawa, H. J. Org. Chem. 1998, 63, 6200.
(9) Danishefsky, S.; Kitahara, T.; Schuda, P. F. Org. Synth. 1983, 61,
147.
(
5) Nagai, H.; Torigoe, K.; Satake, M.; Murata, M.; Yasumoto, J. J. Am.
Chem. Soc. 1992, 114, 1102.
6) For other iterative approaches to fused polyethers, see: (a) Evans,
(
P. A.; Roseman, J. D.; Garber, L. T. J. Org. Chem. 1996, 61, 4880. (b)
Bowman, J. L.; McDonald, F. E. J. Org. Chem. 1998, 63, 3680. (c) Mori,
Y. Chem. Eur. J. 1997, 3, 849. (d) Clark, J. S.; Kettle, J. G. Tetrahedron
Lett. 1997, 38, 123.
(7) (a) Rainier, J. D.; Allwein, S. P. J. Org. Chem. 1998, 63, 5310. (b)
Rainier, J. D.; Allwein, S. P. Tetrahedron Lett. 1998, 39, 9601.
(10) McDonald, F. E.; Vadapally, P. Tetrahedron Lett. 1999, 40, 2235.
1
0.1021/ol991371r CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/05/2000

14
of acyclic and cyclic enol ethers in 67% yield. Ring-closing
metathesis using the Schrock molybdenum catalyst efficiently
converted the mixture into cyclic enol ether 12 (Scheme 3).15
Scheme 1
Scheme 3
With 12 in hand, we investigated its oxidation and C-C
bond-forming chemistry (eq 1). Exposure of 12 to dimeth-
dropyrone 8 in 92% yield.11,12 Leuche reduction and hy-
droxyl-directed m-CPBA epoxidation in methanol1 provided
diol acetal 9 as a single isomer in 65% yield for the two
steps. Differentiation of the 2° hydroxyls via stannyl ketal
formation and equatorial benzyl ether generation gave 10 in
1b
8
b
8
8% yield. Acylation of the remaining hydroxyl was
yldioxirane at -60 °C followed by propenylmagnesium
chloride at 0 °C provided 13 as the only identifiable product
in 72% yield. We believe that 13 is the result of a
stereoselective epoxidation of 12 followed by the formation
of an intermediate oxonium ion and [1,2]-hydride migration.
A subsequent stereoselective addition of propenylmagnesium
chloride to the resulting ketone gives the observed product.
Since we had been able to successfully overcome problems
associated with the formation of oxonium ions in our model
substrates through careful temperature control, we investi-
gated the effect of temperature on the addition reaction.
When propenylmagnesium chloride was added to oxidized
followed by the incorporation of the anomeric allyl group
11b
using allylsilane and BF
3
‚Et
2
O
to provide the hemibre-
vetoxin A-ring as 11 in six steps (39% overall yield) from
6.
Scheme 2
1
2 at -60 °C, we isolated 14 in 35% yield along with the
hydride migration product 13 in 15% yield. To our dismay
4 had the desired hemibrevetoxin connectivity but the
1
undesired trans-syn-cis relative stereochemistry for the
B-ring.
Having successfully synthesized the A-ring, we investi-
gated ring-closing metathesis to the B-ring. Exposure of 14
to Takai’s enol ether forming conditions13 gave a mixture
Once we overcame the initial disappointment with these
results, we recognized that we had not only stereoselectively
(
11) Others have also utilized hetero-Diels-Alder chemistry to the
hemibrevetoxin A-ring. See: (a) Gleason, M. M.; McDonald, F. E. J. Org.
Chem. 1997, 62, 6432. (b) Saleh, T.; Rousseau, G. Synlett 1999, 617.
(13) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem.
1994, 59, 2668.
(
12) It is possible to generate 11 in enantiomerically enriched form using
(14) We have determined that the cyclized product in this reaction comes
from an olefin metathesis, carbonyl olefination process. Rainier, J. D.; Cox,
J. M. Unpublished results.
Keck’s binol protocol. See ref 11 and Keck, G. E.; Li, X.-Y.; Krishnamurthy,
D. J. Org. Chem. 1995, 60, 5998.
232
Org. Lett., Vol. 2, No. 2, 2000

oxidized the enol ether but we had also stereoselectively
formed the C-C bond. Thus, a potentially straightforward
solution to our C-8 stereochemical problem would come from
reversing the order of the C-C bond-forming sequence (i.e.,
adding a methyl nucleophile to the oxonium ion). We set
out to test this hypothesis. From 10, allylsilane addition gave
ments clearly demonstrate the flexibility of our approach to
these ring systems.
From 18, our single-flask acid-mediated cyclization and
7b
elimination protocol provided the hemibrevetoxin A-C ring
system as 19 in 66% yield (Scheme 5). The addition of
15 as a single isomer in 89% yield (Scheme 4). Esterification
Scheme 5
Scheme 4
propenylmagnesium chloride to the epoxide from 19 gave
20 as a single isomer in 64% yield. As determined from NOE
difference experiments, both 19 and 20 had the desired
hemibrevetoxin C-ring stereochemistry. Presumably, the C-8
angular methyl directs the facial selectivity in the epoxidation
reaction and ultimately the stereochemistry at the newly
formed C-C bond.
of the 2° alcohol with 16 followed by ring-closing metathesis
provided the A-B ring system as 17 (eight steps, 27%
overall yield from 6).
Allyl ether formation, ring-closing metathesis using the
Epoxidation of 17 using dimethyldioxirane at -60 °C was
followed by the addition of methyl nucleophiles. While both
Grubbs ruthenium catalyst, and olefin isomerization using
6
d
Wilkinson’s catalyst provided the hemibrevetoxin A-D
ring system as 21 in 48% overall yield for the three
transformations (Scheme 6). Impressively, we had been able
MeMgBr and Me
3
Al gave 18 having the requisite trans-syn-
Al proved to be the reagent of
trans stereochemistry, Me
3
choice (Table 1). Optimized conditions utilized an excess
Scheme 6
Table 1. Addition of Methyl Nucleophiles to Oxidized 17
to generate the four hemibrevetoxin rings and 8 of the 10
stereocenters in 14 steps (4.0% overall yield) from the
8
Danishefsky-Kitahara diene.
To conclude, we have demonstrated that iterative ap-
proaches to fused polyethers which employ sequential enol
ether oxidations, carbon nucleophile additions, and annula-
of Me Al at -65 °C f rt in hexanes to provide 18 in 75%
3
(
15) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
1
6
yield. Thus, by simply reversing the order of C-C bond
formation at C-8, we had been able to generate both the
trans-syn-cis and the trans-syn-trans isomers. These experi-
446.
(16) We currently believe that the effect of a noncoordinating solvent
(
hexanes) is to favor the intramolecular delivery of the methyl nucleophile
from an aluminum-ate complex.
Org. Lett., Vol. 2, No. 2, 2000
233

tions are extremely concise while maintaining a high degree
of flexibility. Undoubtedly, the efficiency of these strategies
will make fused polyethers more readily available than they
have been to date.
Chemical Society, for support of this research. We would
also like to thank Dr. Neil Jacobsen and Dr. Arpad Somagyi
for help with NMR and mass spectroscopy experiments,
respectively.
Supporting Information Available: Spectroscopic data
for compounds 12-14, 17, 19, and 21. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. The authors are grateful to the Na-
tional Institutes of Health, General Medical Sciences
GM56677), Research Corporation, and the donors of the
(
Petroleum Research Fund, administered by the American
OL991371R
234
Org. Lett., Vol. 2, No. 2, 2000