Synthetic organic chemistry plays a central role in the discovery and production of molecules with biological and medical significance. The long-term goal of our laboratory is to advance synthetic methods and strategies that allow for new directions in the discovery of such entities. This proposal describes the development of a suite of synthetic methods for the preparation of nitrogen-containing small molecules (acyclic and heterocyclic). As molecules of this class have been quite successful in the development of small molecule therapeutics, methods that facilitate the construction of such architectures are important for advancing biology, medicine, and public health. The central focus of this work is the development of bimolecular carbometalation reactions of substituted olefins and alkynes with azametallacyclopropenes, enabled by stepwise encapsulation of the metal center with heterobidentate organic ligands. Overall, we describe new methods for the synthesis of ene-1,5-aminoalcohols, saturated 1,5-aminoalcohols, piperidines, pyrroles, lactams and pyrroloindolines.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Hagan, Ann A
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Scripps Florida
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Kier, Matthew J; Leon, Robert M; O'Rourke, Natasha F et al. (2017) Synthesis of Highly Oxygenated Carbocycles by Stereoselective Coupling of Alkynes to 1,3- and 1,4-Dicarbonyl Systems. J Am Chem Soc 139:12374-12377
O'Rourke, Natasha F; A, Mu; Higgs, Henry N et al. (2017) Function-Oriented Studies Targeting Pectenotoxin 2: Synthesis of the GH-Ring System and a Structurally Simplified Macrolactone. Org Lett 19:5154-5157
Micalizio, Glenn C; Mizoguchi, Haruki (2017) The Development of Alkoxide-Directed Metallacycle-Mediated Annulative Cross-Coupling Chemistry. Isr J Chem 57:228-238
O'Rourke, Natasha F; Kier, Matthew J; Micalizio, Glenn C (2016) Metallacycle-Mediated Cross-Coupling in Natural Product Synthesis. Tetrahedron 72:7093-7123
O'Rourke, Natasha F; Micalizio, Glenn C (2016) Cyclopropenes in Metallacycle-Mediated Cross-Coupling with Alkynes: Convergent Synthesis of Highly Substituted Vinylcyclopropanes. Org Lett 18:1250-3
Aquino, Claudio; Greszler, Stephen N; Micalizio, Glenn C (2016) Synthesis of the Cortistatin Pentacyclic Core by Alkoxide-Directed Metallacycle-Mediated Annulative Cross-Coupling. Org Lett 18:2624-7
Cheng, Xiayun; Micalizio, Glenn C (2016) Synthesis of Neurotrophic Seco-prezizaane Sesquiterpenes (1R,10S)-2-Oxo-3,4-dehydroneomajucin, (2S)-Hydroxy-3,4-dehydroneomajucin, and (-)-Jiadifenin. J Am Chem Soc 138:1150-3
Mizoguchi, Haruki; Micalizio, Glenn C (2016) Synthesis of Angularly Substituted trans-Fused Decalins through a Metallacycle-Mediated Annulative Cross-Coupling Cascade. Angew Chem Int Ed Engl 55:13099-13103
Cassidy, James S; Mizoguchi, Haruki; Micalizio, Glenn C (2016) Acceleration of metallacycle-mediated alkyne-alkyne cross-coupling with TMSCl. Tetrahedron Lett 57:3848-3850
Kim, Wan Shin; Aquino, Claudio; Mizoguchi, Haruki et al. (2015) LiOOt-Bu as a terminal oxidant in a titanium alkoxide-mediated [2+2+2] reaction cascade. Tetrahedron Lett 56:3357-3359

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