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 investigation and optimization of technologies 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 are currently no efficient synthetic roadmaps. Importantly, the methods presented in this application will be useful outside of the contexts described herein and will arm practitioners of synthetic chemistry (in academic, government, and industrial laboratories) with a new set of important tools to access enantioenriched and functionally diverse chemical building blocks for synthesis. The research proposed in this grant application is focused on a) the development of new palladium- and iridium-catalyzed stereoselective alkylation reactions that produce densely substituted, acyclic building blocks for synthesis, b) the development of novel nickel- and copper-catalysis for asymmetric alkylation and acylation processes, c) the development of these novel methods specifically for the preparation of all-carbon quaternary stereocenters and arrays of quaternary centers, and d) the implementation of these new tactics in the syntheses of highly complex, bioactive bis-indole alkaloids. Specifically, we outline approaches to leucophyllidine, strempeliopidine, and norpleiomutine. These molecules are not only important from a biological standpoint, they 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 impact a host of diverse applications.

Public Health Relevance

to Public Health: At the core of chemistry lies the power to manipulate the elements for the preparation of specific arrays of atoms in a predictable and reliable fashion. As synthetic chemists, our ability to construct molecules with exquisite precision is unique within the sciences. In this proposal, we outline several new approaches toward the construction of important linkages and describe the implemention of these methods in highly complex situations relevant 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)
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Brown, Patrick
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California Institute of Technology
Schools of Arts and Sciences
United States
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Alexy, Eric J; Zhang, Haiming; Stoltz, Brian M (2018) Catalytic Enantioselective Synthesis of Acyclic Quaternary Centers: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Acyclic Enol Carbonates. J Am Chem Soc 140:10109-10112
Lu, Yanhui; Goldstein, Elizabeth L; Stoltz, Brian M (2018) Palladium-Catalyzed Enantioselective Csp3-Csp3 Cross-Coupling for the Synthesis of (Poly)fluorinated Chiral Building Blocks. Org Lett 20:5657-5660
Hartrampf, Nina; Winter, Nils; Pupo, Gabriele et al. (2018) Total Synthesis of the Norhasubanan Alkaloid Stephadiamine. J Am Chem Soc 140:8675-8680
Craig 2nd, Robert A; Smith, Russell C; Roizen, Jennifer L et al. (2018) Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade. J Org Chem 83:3467-3485
Duquette, Douglas Charles; Jensen, Thomas; Stoltz, Brian Mark (2018) Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core. J Antibiot (Tokyo) 71:263-267
Krout, Michael R; Henry, Christopher E; Jensen, Thomas et al. (2018) Wolff/Cope Approach to the AB Ring of the Sesterterpenoid Variecolin. J Org Chem 83:6995-7009
Pritchett, Beau P; Stoltz, Brian M (2018) Enantioselective palladium-catalyzed allylic alkylation reactions in the synthesis of Aspidosperma and structurally related monoterpene indole alkaloids. Nat Prod Rep 35:559-574
Hethcox, J Caleb; Shockley, Samantha E; Stoltz, Brian M (2018) Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation. Angew Chem Int Ed Engl 57:8664-8667
Hethcox, J Caleb; Shockley, Samantha E; Stoltz, Brian M (2017) Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents. Org Lett 19:1527-1529
Shockley, Samantha E; Hethcox, J Caleb; Stoltz, Brian M (2017) Enantioselective Synthesis of Acyclic ?-Quaternary Carboxylic Acid Derivatives through Iridium-Catalyzed Allylic Alkylation. Angew Chem Int Ed Engl 56:11545-11548

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