The main objective of our research program is the development of new synthetic methods using complex natural products to identify new challenges. Our endeavors in total synthesis and resulting access to natural products will also provide the basis for research in the area of bioorganic chemistry. The new synthetic methods will find further utility in pharmaceutical and medicinal research, serving for the benefit of public health through improved preparation of drugs and bioactive substances. The specific targets pursued in this application are marine toxins containing a spiroimine ring. This is an expanding group of complex marine natural products that presently includes pinnatoxins, pteriatoxins, spirolides, spiro-prorocentrimine, and gymnodimine. The unique spiroimine fragment has been determined to be critical for their bioactivity. Some of these natural products have been implicated in several global seafood intoxication events. The proposed synthetic strategy is general and can be applied for the synthesis of pinnatoxins, spirolides, and gymnodimine. The most challenging part of the target structures is the spiroimine fragment. We developed a method that enables stereoselective Ireland-Claisen rearrangement of alpha-branched allylic esters. Typically, poor diastereoselectivity is observed in these reactions. Employing our method, both diastereomers can be accessed with excellent diastereoselectivity. This is the central method that we use in the synthesis of the spiroimine fragments. We anticipate that our efforts in the area of chemical synthesis of complex natural products will enrich the arsenal of synthetic methods in general, facilitating research in the fields of medicinal chemistry and drug discovery. More specific to this application, the marine toxins featured herein are directly related to the public health issue of seafood intoxication. It is noted that a major problem in the development of precise methods for detection of algal toxins is the lack of pure standards. Thus, the targets of our syntheses will serve as pure standards for the development of detection probes for marine toxins.

Public Health Relevance

Developments in organic synthesis have long benefited human health by providing methods for drug discovery and pharmaceutical research. The total synthesis of complex natural products is a major branch of organic chemistry that defines the current state-of-the-art, stimulates innovation and discovery, and identifies new challenges to be addressed. The research proposed in this application will enrich synthetic methodology through total synthesis of complex natural products. In addition, we will develop sensitive immunoassays for the detection of marine toxins in the environment. This will benefit human health by prevention of certain types of seafood intoxication, which has become a global phenomenon.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM077379-05
Application #
8266483
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2008-06-10
Project End
2013-07-31
Budget Start
2012-06-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$381,676
Indirect Cost
$97,377
Name
University of California Santa Barbara
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
094878394
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106
Stivala, Craig E; Benoit, Evelyne; Aráoz, Rómulo et al. (2015) Synthesis and biology of cyclic imine toxins, an emerging class of potent, globally distributed marine toxins. Nat Prod Rep 32:411-35
Xiao, Qing; Young, Kyle; Zakarian, Armen (2013) An efficient synthesis of the fully elaborated isoindolinone unit of muironolide A. Org Lett 15:3314-7
Lu, Ping; Gu, Zhenhua; Zakarian, Armen (2013) Total synthesis of maoecrystal V: early-stage C-H functionalization and lactone assembly by radical cyclization. J Am Chem Soc 135:14552-5
Xiao, Qing; Jackson, Jeffrey J; Basak, Ashok et al. (2013) Enantioselective synthesis of tatanans A-C and reinvestigation of their glucokinase-activating properties. Nat Chem 5:410-6
Hess, Philipp; Abadie, Eric; Hervé, Fabienne et al. (2013) Pinnatoxin G is responsible for atypical toxicity in mussels (Mytilus galloprovincialis) and clams (Venerupis decussata) from Ingril, a French Mediterranean lagoon. Toxicon 75:16-26
Herrmann, Aaron T; Smith, Lindsay L; Zakarian, Armen (2012) A simple method for asymmetric trifluoromethylation of N-acyl oxazolidinones via Ru-catalyzed radical addition to zirconium enolates. J Am Chem Soc 134:6976-9
Stivala, Craig E; Gu, Zhenhua; Smith, Lindsay L et al. (2012) Studies toward the synthesis of spirolide C: exploration into the formation of the 23-membered all-carbon macrocyclic framework. Org Lett 14:804-7
Herrmann, Aaron T; Martinez, Steven R; Zakarian, Armen (2011) A concise asymmetric total synthesis of (+)-brevisamide. Org Lett 13:3636-9
Araoz, Romulo; Servent, Denis; Molgo, Jordi et al. (2011) Total synthesis of pinnatoxins A and G and revision of the mode of action of pinnatoxin A. J Am Chem Soc 133:10499-511
Gu, Zhenhua; Zakarian, Armen (2011) Studies toward the synthesis of maoecrystal V. Org Lett 13:1080-2

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