Synthetic Studies Directed toward the Total Synthesis of Azaspiracid

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Synthetic Studies Directed toward the Total
Synthesis of Azaspiracid
Dave J. Weldon and Rich G. Carter Department of
Chemistry and Biochemistry University of
Mississippi
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Isolation and Biological Activity of Azaspiracid
Isolated from the mussels, Mytilus edulis, in
Killary Harbor, Ireland. MacMahon, T. Silke,
J. Harmful Algae News 1996, 14, 2.
Stereochemistry determined by extensive 2D NMR
studies.
Yasumoto, T. et. al. J. Am. Chem. Soc. 1998,
120, 9967. Two structurally similar derivatives
were later discovered in Donegal, Ireland.
Yasumoto, T. et. al. Nat. Toxins 1999, 7, 99.
Azaspiracids 1-3 possess considerable toxicity in
vitro with lethal doses in mice of 0.2, 0.11, and
0.14 mg/kg, respectively. Contains three
separate spirocyclic linkages, including a rare
azaspiro linkage. Possesses 20 stereocenters
and nine rings. No total syntheses of the
azaspiracids have been reported to date.
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Goals of the Project
Complete the first total synthesis of
azaspiracid. Efficiently address the diverse
stereochemical relationships of azaspiracid.
Determine the absolute stereochemistry. Supply
sufficient amounts of the target, as well as
analogs, for biological screening.
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Retrosynthetic Strategy of Azaspiracid
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Retrosynthetic Strategy for Northern Portion of
Azaspiracid
Carter, R. G. Weldon, D. J. Org. Lett. 2000, 2,
3913.
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Retrosynthetic Strategy for Southern Portion of
Azaspiracid
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Retrosynthetic Strategy for Fragment A
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Construction of the C6 Stereocenter
Carter, R. G. Weldon, D. J. Org. Lett. 2000, 2,
3913.
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Alternative Strategy for Incorporation of the C6
Stereocenter
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Synthesis of Fragment A
Carter, R. G. Weldon, D. J. Org. Lett. 2000, 2,
3913.
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Retrosynthetic Strategy for Fragments C and E
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Synthesis of Key Lactone
Andrus, M. B. et. al. J. Org. Chem. 1997, 62,
5542-49.
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Synthesis of Fragment C
Carter, R. G. Weldon, D. J. Org. Lett. 2000, 2,
3913.
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Progress Towards the Synthesis of Fragment E
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Conclusion
Considerable progress has been achieved towards
the total synthesis of azaspiracid. The
synthesis of the C1-C12 fragment A has been
achieved in 9 steps utilizing a key Sharpless
kinetic resolution. The construction of the
C21-C25 fragment C has been accomplished in 9
steps. Considerable progress toward the
synthesis of the C35-C47 fragment E has been made.
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Acknowledgements
T. Campbell Bourland Dr. David Graves Univers
ity of Mississippi