Organic synthesis is established as one of the most significant tools in drug discovery and biomedical research. The development of practical, environmentally friendly chemical synthesis remains an important goal in medicinal and process chemistry, as the sustainable development of new medicines is dependent on the availability of excellent synthetic methods. Catalytic methods are highly desirable as they minimize the formation of unwanted waste byproducts, offering a more efficient alternative to classical organic reactions. This proposal describes research into new chiral Brnsted acid catalysts for alkylation reactions with trichloroacetimidate electrophiles that will provide complex heterocyclic products in an efficient, expedient manner.
In Aim 1 of the proposal will investigate the reaction of trichloroacetimidate electrophiles and indoles to produce pyrroloindolines and related systems. This chemistry will then be used to facilitate an expedient synthesis of the antitumor agent neoxaline.
In Aim 2 the synthesis of pyrroloindoline trichloroacetimidates will be investigated, and their reactivity with heteroatom nucleophiles will be determined. These reactions are also catalyzed with Brnsted acids. This methodology will then be used in a synthesis of kapakahine C, a second molecule with antitumor properties.
In Aim 3 the pyrroloindoline imidates will be used as alkylating agents with carbon nucleophiles. This methodology will then be used in the synthesis of pestalazine A and asperazine, molecules with unusual structures. The new reactions developed in this proposal will allow medicinal and process chemists more facile access to complex high value-added organic compounds. These products will in turn be useful in the synthesis of new materials and medicines to further biomedical research.

Public Health Relevance

This proposal describes research in the development of new methods that will streamline the selective formation of carbon-carbon and carbon-heteroatom bonds. This new technology will expedite the synthesis of new molecules that are of interest in pharmaceutical and biomedical research.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Academic Research Enhancement Awards (AREA) (R15)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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Syracuse University
Schools of Arts and Sciences
United States
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Mahajani, Nivedita S; Chisholm, John D (2018) Synthesis of 1,1'-Diarylethanes and Related Systems by Displacement of Trichloroacetimidates with Trimethylaluminum. J Org Chem 83:4131-4139
Mahajani, Nivedita S; Chisholm, John D (2018) Promoter free allylation of trichloroacetimidates with allyltributylstannanes under thermal conditions to access the common 1,1'-diarylbutyl pharmacophore. Org Biomol Chem 16:4008-4012
Wilhelmsen, Christopher A; Dixon, Alexandre D C; Chisholm, John D et al. (2018) Synthesis of N-Substituted 3-Amino-4-halopyridines: A Sequential Boc-Removal/Reductive Amination Mediated by Brønsted and Lewis Acids. J Org Chem 83:1634-1642
McGovern-Gooch, Kayleigh R; Mahajani, Nivedita S; Garagozzo, Ariana et al. (2017) Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation. Biochemistry 56:919-931
Adhikari, Arijit A; Radal, Léa; Chisholm, John D (2017) Synthesis of 3,3'-Disubstituted Indolenines Utilizing the Lewis Acid Catalyzed Alkylation of 2,3-Disubstituted Indoles with Trichloroacetimidates. Synlett 28:2335-2339
Adhikari, Arijit A; Suzuki, Tamie; Gilbert, Reesheda T et al. (2017) Rearrangement of Benzylic Trichloroacetimidates to Benzylic Trichloroacetamides. J Org Chem 82:3982-3989
Wallach, Daniel R; Chisholm, John D (2016) Alkylation of Sulfonamides with Trichloroacetimidates under Thermal Conditions. J Org Chem 81:8035-42
Adhikari, Arijit A; Chisholm, John D (2016) Lewis Acid Catalyzed Displacement of Trichloroacetimidates in the Synthesis of Functionalized Pyrroloindolines. Org Lett 18:4100-3
Howard, Kyle T; Duffy, Brian C; Linaburg, Matthew R et al. (2016) Formation of DPM ethers using O-diphenylmethyl trichloroacetimidate under thermal conditions. Org Biomol Chem 14:1623-8
Howard, Kyle T; Chisholm, John D (2016) Preparation and Applications of 4-Methoxybenzyl Esters in Organic Synthesis. Org Prep Proced Int 48:1-36