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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080266-05
Application #
7771722
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Hagan, Ann A
Project Start
2007-03-12
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2010
Total Cost
$365,855
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
O'Rourke, Natasha F; Kier, Matthew J; Micalizio, Glenn C (2016) Metallacycle-Mediated Cross-Coupling in Natural Product Synthesis. Tetrahedron 72:7093-7123
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
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
Cassidy, James S; Mizoguchi, Haruki; Micalizio, Glenn C (2016) Acceleration of metallacycle-mediated alkyne-alkyne cross-coupling with TMSCl. Tetrahedron Lett 57:3848-3850
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
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
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
Micalizio, Glenn C; Hale, Sarah B (2015) Reaction design, discovery, and development as a foundation to function-oriented synthesis. Acc Chem Res 48:663-73
Mizoguchi, Haruki; Micalizio, Glenn C (2015) Synthesis of Highly Functionalized Decalins via Metallacycle-Mediated Cross-Coupling. J Am Chem Soc 137:6624-8
Cheng, Xiayun; Micalizio, Glenn C (2014) An annulation reaction for the synthesis of cross-conjugated triene-containing hydroindanes from acyclic precursors. Org Lett 16:5144-7

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