ORGANIC
LETTERS
2004
Vol. 6, No. 23
4159-4162
Synthesis of the Azaspiracid-1
Trioxadispiroketal
Lisa K. Geisler, Son Nguyen, and Craig J. Forsyth*
Department of Chemistry, Institute of Technology, UniVersity of Minnesota,
207 Pleasant Street S.E., Minneapolis, Minnesota 55113
Received July 21, 2004
ABSTRACT
The de novo analysis, design, and synthesis of the azaspiracid-1 trioxadispiroketal system is described. A revised structural model was
developed on the basis of an independent analysis of the NMR spectral data of the natural product that fit all of the data and the thermodynamically
favored spiroketal paradigm. This model was then tested via synthesis using a novel trioxadispiroketalization process and supported by
spectroscopic correlation.
The azaspiracids are remarkable natural products that
combine a unique, complex structure with an acute and
perhaps chronic human health hazard.1-3 As such, these
compounds have been the focus of intense study, including
numerous synthetic reports. Among these are many that
targeted the originally assigned relative stereochemistry of
the A-D trioxadispiroketal system.4 Most recently, however,
the total synthesis and structural revision of AZA-1 (1) have
been reported and correct three errors in the original
assignment.5 These corrections include the position of the
A-ring alkene, and the relative stereochemistry of the face-
fused C and D rings with respect to both the carbinol-linked
E ring and the dispiro-fused A and B rings. Summarized
herein are the de novo analysis, design, and synthesis of the
long problematic A-D trioxadispiroketal via a new variant
of the double intramolecular hetero-Michael addition
(DIHMA).6
One of the most curious aspects of the structural assign-
ments originally made to 1 was the relative configuration of
the C13 spiroketal center, which would not benefit from
anomeric effect stabilization.1 An established paradigm in
spiroketal natural products is that the combination of
configurations and conformations generally reflects the most
thermodynamically favored array, consistent with nonenzy-
matic ketalization processes.
(1) Satake, M.; Ofuji, K.; Naoki, H.; James, K. J.; Furey, A.; McMahon,
T.; Silke, J.; Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 9967-9968.
(2) James, K. J.; Lehane, M.; Moroney, C.; Fernandez-Puente, P.; Satake,
M.; Yasumoto, T.; Furey, A. Food Addit. Contam. 2002, 19, 555-561.
(3) Ito, E.; Satake, M.; Ofuji, K.; Higashi, M.; Harigaya, K.; McMahon,
T.; Yasumoto, T. Toxicon 2002, 40, 193-203.
(4) (a) Carter, R. G.; Weldon, D. J. Org. Lett. 2000, 2, 3913-3916. (b)
Dounay, A. B.; Forsyth, C. J. Org. Lett. 2001, 3, 975-978. (c) Carter, R.
G.; Graves, D. E. Tetrahedron Lett. 2001, 42, 6035-6039. (d) Nicolaou,
K. C.; Qian, W.; Bernal, F.; Uesaka, N.; Pihko, P. M.; Hinrichs, J. Angew.
Chem., Int Ed. 2001, 40, 4068-4071. (e) Carter, R. G.; Bourland, T. C.;
Graves, D. E. Org. Lett. 2002, 4, 2177-2179. (f) Carter, R. G.; Graves, D.
E.; Gronemeyer, M. A.; Tschumper, G. S. Org. Lett. 2002, 4, 2181-2184.
(g) Carter, R. G.; Bourland, T. C.; Zhou, X.-T.; Gronemeyer, M. A.
Tetrahedron 2003, 59, 8963-8974. (h) Nicolaou, K. C.; Li, Y.; Uesaka,
N.; Koftis, T. V.; Vyskocil, S.; Ling, T.; Govindasamy, M.; Qian, W.;
Bernal, F.; Chen, D. Y.-K. Angew. Chem., Int Ed. 2003, 42, 3643-3648.
(i) Nicolaou, K. C.; Chen, D. Y.-K.; Li, Y.; Qian, W.; Ling, T.; Vyskocil,
S.; Koftis, T. V.; Govindasamy, M. Angew. Chem., Int Ed. 2003, 42, 3649-
3653. (j) Ishikawa, Y.; Nishiyama, S. Heterocycles 2004, 63, 539-565.
(k) Ishikawa, Y.; Nishiyama, S. Heterocycles 2004, 63, 885-893. (l)
Ishikawa, Y.; Nishiyama, S. Tetrahedron Lett. 2004, 45, 351-354. (m)
Nicolaou, K. C.; Vyskocil, S.; Koftis, T. V.; Yamada, Y. M. A.; Ling, T.;
Chen, D. Y.-K.; Tang, W.; Petrovic, G.; Frederick, M. O.; Li, Y.; Satake,
M. Angew. Chem., Int. Ed. 2004, 43, 4312-4318.
There seemed to be no compelling reason to believe that
the azaspiracids should violate this phylogenic profile. Thus,
our initial work in this area involved probing the thermo-
dynamic stability of the A-D ring system as it was originally
(5) Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Ling, T.;
Yamada, Y. M. A.; Tang, W.; Frederick, M. O. Angew. Chem., Int. Ed.
2004, 43, 4318-4324.
(6) (a) Forsyth, C. J.; Hao, J.; Aiguade, J. Angew. Chem., Int. Ed. 2001,
40, 3663-3667. (b) Aiguade, J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3,
979-982. (c) Hao, J.; Forsyth, C. J. Tetrahedron Lett. 2002, 43, 1-2.
10.1021/ol048581a CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/15/2004