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 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 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 iridium- and palladium-catalyzed stereoselective alkylation reactions that produce densely substituted building blocks for synthesis, b) the development of palladium- catalyzed conjugate addition processes, c) the utilization of these novel methods for the synthesis of fused, spiro, and bridged ring system arrays, and d) the implementation of these new tactics in the syntheses of multiple natural and non-natural bioactive small molecules. Specifically, we outline approaches to isopalhinine A, the yuccaols A-E, and the abietane diterpenoids. 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

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 implementation of these methods in highly complex situations relevant to human medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM080269-09
Application #
9054656
Study Section
Special Emphasis Panel (ZRG1-BCMB-D (02))
Program Officer
Lees, Robert G
Project Start
2007-07-02
Project End
2019-07-31
Budget Start
2015-09-15
Budget End
2016-07-31
Support Year
9
Fiscal Year
2015
Total Cost
$315,112
Indirect Cost
$112,312
Name
California Institute of Technology
Department
Chemistry
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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
Craig 2nd, Robert A; Stoltz, Brian M (2017) Polycyclic Furanobutenolide-Derived Cembranoid and Norcembranoid Natural Products: Biosynthetic Connections and Synthetic Efforts. Chem Rev 117:7878-7909
Pritchett, Beau P; Kikuchi, Jun; Numajiri, Yoshitaka et al. (2017) A FISCHER INDOLIZATION STRATEGY TOWARD THE TOTAL SYNTHESIS OF (-)-GONIOMITINE. Heterocycles 95:1245-1253
Roizen, Jennifer L; Jones, Amanda C; Smith, Russell C et al. (2017) Model Studies To Access the [6,7,5,5]-Core of Ineleganolide Using Tandem Translactonization-Cope or Cyclopropanation-Cope Rearrangements as Key Steps. J Org Chem 82:13051-13067
Duquette, Douglas Charles; Jensen, Thomas; Stoltz, Brian Mark (2017) Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core. J Antibiot (Tokyo) :
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
Starkov, Pavel; Moore, Jared T; Duquette, Douglas C et al. (2017) Enantioselective Construction of Acyclic Quaternary Carbon Stereocenters: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Amide Enolates. J Am Chem Soc 139:9615-9620
Craig 2nd, Robert A; Roizen, Jennifer L; Smith, Russell C et al. (2017) Enantioselective, Convergent Synthesis of the Ineleganolide Core by a Tandem Annulation Cascade. Chem Sci 8:507-514
Shockley, Samantha E; Hethcox, J Caleb; Stoltz, Brian M (2017) Asymmetric Synthesis of All-Carbon Quaternary Spirocycles via a Catalytic Enantioselective Allylic Alkylation Strategy. Tetrahedron Lett 58:3341-3343
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

Showing the most recent 10 out of 95 publications