The objectives of this grant application are to continue and expand research directed towards the full characterization, total synthesis, and environmental detection of the azaspiracid natural products. The azaspiracids are marine toxins that accumulate in shellfish cultivated and collected for human consumption. Azaspiracids are likely to be produced by the dinoflagellate Protoperidinium crassipes, that has widespread geographical distribution. The toxins have a unique mode of action, are neurotoxic, necrotic, and tumor promoting in mice. They have caused numerous human poisonings via the consumption of contaminated shellfish, and their surveillance and quantitative detection is critical to minimize further human exposures. The structures of the azaspiracids are complex and only partially defined. They are amino acids of enormous proportion, having 40 contiguous carbons in their backbone and containing an unprecedented array of structural features. These include THF-fused trioxadispiroketal moiety and a polycyclic spiroaminal terminus.
The specific aims of this proposal are to develop efficient syntheses of both enantiomers of the C26-C40 spiroaminal-containing domain, develop enantioselective syntheses of the the trioxadispiroketal-containing C1-C20 domain, develop standards and haptens for the sensitive and quantitative environmental monitoring of the azaspiracids, completely define the stereochemistry of azaspiracid-1, and develop an enantioselective total laboratory synthesis of azaspiracid-1. This work will continue to contribute to understanding of the structure, occurrence, toxicology, and chemical and biological reactivity of the azaspiracids. It will provide continued impetus for fundamental developments in organic synthesis, including novel strategies and tactics for the total synthesis of complex molecular architecture. A novel immunostereochemical study is proposed to aid in the complete structural definition of the azaspiracids. This approach fuses synthetic organic, natural products, and immunochemistry to support structural elucidation and the development of an ELISA system for the universal detection of all of the azaspiracids that are currently known.
| Zhang, Zhigao; Chen, Yong; Adu-Ampratwum, Daniel et al. (2016) Synthesis of the C22-C40 Domain of the Azaspiracids. Org Lett 18:1824-7 |
| Samdal, Ingunn A; Løvberg, Kjersti E; Briggs, Lyn R et al. (2015) Development of an ELISA for the Detection of Azaspiracids. J Agric Food Chem 63:7855-61 |
| Zhang, Zhigao; Ding, Yue; Xu, Jianyan et al. (2013) Synthesis of the C1-C21 domain of azaspiracids-1 and -3. Org Lett 15:2338-41 |
| Fang, Chao; Pang, Yucheng; Forsyth, Craig J (2010) Formal total synthesis of okadaic acid via regiocontrolled gold(I)-catalyzed spiroketalizations. Org Lett 12:4528-31 |
| Trygstad, Timothy M; Pang, Yucheng; Forsyth, Craig J (2009) Versatile synthesis of the C3-C14 domain of 7-deoxyokadaic acid. J Org Chem 74:910-3 |
| Li, Yongfeng; Zhou, Feng; Forsyth, Craig J (2007) Gold(I)-catalyzed bis-spiroketalization: synthesis of the trioxadispiroketal-containing A-D rings of azaspiracid. Angew Chem Int Ed Engl 46:279-82 |
| Wang, Ce; Forsyth, Craig J (2006) Synthesis of the spirastrellolide A trioxadispiroketal. Org Lett 8:2997-3000 |
| Forsyth, Craig J; Xu, Jianyan; Nguyen, Son T et al. (2006) Antibodies with broad specificity to azaspiracids by use of synthetic haptens. J Am Chem Soc 128:15114-6 |
| Geisler, Lisa K; Nguyen, Son; Forsyth, Craig J (2004) Synthesis of the azaspiracid-1 trioxadispiroketal. Org Lett 6:4159-62 |
| Dounay, A B; Forsyth, C J (2001) Synthetic studies toward the C5-C20 domain of the azaspiracids. Org Lett 3:975-8 |
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