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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080269-07
Application #
8471117
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2007-07-02
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$286,184
Indirect Cost
$98,009
Name
California Institute of Technology
Department
Chemistry
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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
Bhat, Vikram; Welin, Eric R; Guo, Xuelei et al. (2017) Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations. Chem Rev 117:4528-4561
Werner, Bettina; Kalesse, Markus (2017) Pinacol Coupling Strategy for the Construction of the Bicyclo[6.4.1]tridecane Framework of Schiglautone A. Org Lett 19:1524-1526

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