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
Reid, Bradley T; Mailyan, Artur K; Zakarian, Armen (2018) Total Synthesis of (+)-Guadinomic Acid via Hydroxyl-Directed Guanidylation. J Org Chem 83:9492-9496
Mailyan, Artur K; Chen, Joanna L; Li, Weiwei et al. (2018) Short Total Synthesis of [15N5]-Cylindrospermopsins from 15NH4Cl Enables Precise Quantification of Freshwater Cyanobacterial Contamination. J Am Chem Soc 140:6027-6032
Lacharity, Jacob J; Fournier, Jeremy; Lu, Ping et al. (2017) Total Synthesis of Unsymmetrically Oxidized Nuphar Thioalkaloids via Copper-Catalyzed Thiolane Assembly. J Am Chem Soc 139:13272-13275
Yu, Kai; Lu, Ping; Jackson, Jeffrey J et al. (2017) Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries. J Am Chem Soc 139:527-533
Molgó, Jordi; Marchot, Pascale; Aráoz, Rómulo et al. (2017) Cyclic imine toxins from dinoflagellates: a growing family of potent antagonists of the nicotinic acetylcholine receptors. J Neurochem 142 Suppl 2:41-51
Cano, Rafael; Zakarian, Armen; McGlacken, Gerard P (2017) Direct Asymmetric Alkylation of Ketones: Still Unconquered. Angew Chem Int Ed Engl 56:9278-9290
Martinez, Juliana A; Xiao, Qing; Zakarian, Armen et al. (2017) Antidiabetic Disruptors of the Glucokinase-Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface. Biochemistry 56:3150-3157
Burns, Alexander S; Wagner, Alexander J; Fulton, Jennifer L et al. (2017) Determination of the Absolute Configuration of ?-Chiral Primary Alcohols Using the Competing Enantioselective Conversion Method. Org Lett 19:2953-2956
Ma, Yun; Mack, Kyle A; Liang, Jun et al. (2016) Mixed Aggregates of the Dilithiated Koga Tetraamine: NMR Spectroscopic and Computational Studies. Angew Chem Int Ed Engl 55:10093-7
Alvarado, Joseph; Fournier, Jeremy; Zakarian, Armen (2016) Synthesis of Functionalized Dihydrobenzofurans by Direct Aryl C-O Bond Formation under Mild Conditions. Angew Chem Int Ed Engl 55:11625-11628

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