The objective of this research program is to discover and develop new reaction methodology en route to the synthesis of complex bioactive molecules. Our proposed studies will focus on the development of methods that enable the synthesis of core structural and stereochemical subunits prevalent in many bioactive, polycyclic natural products. The processes that we develop will find utility in the synthesis of a variety of structures for which there is currently no efficient synthetic roadmap. Importantly, the methods presented in this application will be useful outside of the contexts described herein and will arm practitioners of synthetic chemistry (in academics, government, and industry) with a new set of important tools to access crucial building blocks for synthesis. The research proposed in this grant application is focused on a) the development of new palladium- and copper-catalyzed enantio-selective alkylation and protonation reactions that produce important building blocks for synthesis, b) the utilization of these novel methods for the synthesis of fused, spiro, and bridged ring system arrays, and c) the implementation of these new tools in the syntheses of numerous natural and non-natural bioactive small molecules. Specifically, we outline approaches to variecolin, przewalskin B, the rocaglate lignans, and the communesin alkaloids. These molecules are important from a biological standpoint, but also serve as a testing ground for our new technologies. As a consequence of this approach, we will have access to a) novel, medicinally relevant structures, b) a general platform for their synthesis, and c) new synthetic methodology that will benefit a host of diverse applications.

Public Health Relevance

At the core of chemistry rests the power to manipulate the elements for the preparation of specific arrays of atoms in a predictable and reliable fashion. As synthetic chemists, our capacity to construct molecules with exquisite precision is unique in the sciences. In this proposal we outline a number of new approaches toward constructing important linkages and implementing these methods in highly complex situations of relevance to human medicine.

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)
Program Officer
Lees, Robert G
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California Institute of Technology
Schools of Engineering
United States
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Hethcox, J Caleb; Shockley, Samantha E; Stoltz, Brian M (2016) Iridium-Catalyzed Stereoselective Allylic Alkylation Reactions with Crotyl Chloride. Angew Chem Int Ed Engl 55:16092-16095
Pritchett, Beau P; Kikuchi, Jun; Numajiri, Yoshitaka et al. (2016) Enantioselective Pd-Catalyzed Allylic Alkylation Reactions of Dihydropyrido[1,2-a]indolone Substrates: Efficient Syntheses of (-)-Goniomitine, (+)-Aspidospermidine, and (-)-Quebrachamine. Angew Chem Int Ed Engl 55:13529-13532
Liu, Wen-Bo; Okamoto, Noriko; Alexy, Eric J et al. (2016) Enantioselective γ-Alkylation of α,β-Unsaturated Malonates and Ketoesters by a Sequential Ir-Catalyzed Asymmetric Allylic Alkylation/Cope Rearrangement. J Am Chem Soc 138:5234-7
Han, Seo-Jung; Doi, Ryohei; Stoltz, Brian M (2016) Nickel-Catalyzed Intramolecular C-O Bond Formation: Synthesis of Cyclic Enol Ethers. Angew Chem Int Ed Engl 55:7437-40
Liniger, Marc; VanderVelde, David G; Takase, Michael K et al. (2016) Total Synthesis and Characterization of 7-Hypoquinuclidonium Tetrafluoroborate and 7-Hypoquinuclidone BF3 Complex. J Am Chem Soc 138:969-74
Hayashi, Masaki; Bachman, Shoshana; Hashimoto, Satoshi et al. (2016) Ni-Catalyzed Enantioselective C-Acylation of α-Substituted Lactams. J Am Chem Soc 138:8997-9000
Mohr, Justin T; Moore, Jared T; Stoltz, Brian M (2016) Enantioconvergent catalysis. Beilstein J Org Chem 12:2038-2045
Han, Seo-Jung; Stoltz, Brian M (2016) A mild and efficient approach to enantioenriched α-hydroxyethyl α,β-unsaturated δ-lactams. Tetrahedron Lett 57:2233-2235
Estipona, Benzi I; Pritchett, Beau P; Craig 2nd, Robert A et al. (2016) Catalytic enantioselective total synthesis of (+)-eucomic acid. Tetrahedron 72:3707-3712
Korch, Katerina M; Eidamshaus, Christian; Behenna, Douglas C et al. (2015) Enantioselective synthesis of α-secondary and α-tertiary piperazin-2-ones and piperazines by catalytic asymmetric allylic alkylation. Angew Chem Int Ed Engl 54:179-83

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