The objective of this submission is to advance the applications of a recently developed stereochemically random allylic alcohol transposition and trapping process to the synthesis of medicinally relevant structures. Complex molecule synthesis remains a laborious effort, and is often a limiting factor in establishing structure activity relationships for biologically active molecules. The judicious use of stereochemically unfaithful processes that precede stereochemically defined bond formation reactions can reduce the length of synthetic sequences, allowing for faster and more economical lead optimization. New advances in this powerful protocol create many opportunities to enhance the scope of the method. This proposal pursues five new research directions in this area. The first objective is to develop new protocols for substrate-, reagent-, or catalyst-based stereoinduction in the synthesis of densely functionalized tetrahydropyrans for use in natural product and conformational probe synthesis. The second objective is to apply the method to the synthesis of medicinally relevant nitrogen-containing heterocycles. The third and fourth objectives will lead to new approaches to control the stereochemical outcomes protocols for polycyclization reactions that lead to natural products and rigid scaffolds. The final objective is to employ a stereochemistry-editing step following a fragment-coupling step as a means to facilitate convergent syntheses of complex molecules. Increased access to enantiomerically pure medicinal leads can provide important information regarding the binding conformation of ligands in their biological targets, and enantioselective synthesis is highly desirable for chiral drugs tobe approved for use.

Public Health Relevance

The purpose of this submission is to advance the application of a newly developed process of stereochemically random allylic alcohol transposition and trapping toward stereoselective complex molecule synthesis. Molecular synthesis is required for developing new medicinal agents but often consumes significant amounts of time and resources. The new applications of the stereochemistry-editing and ring forming-protocol that are presented herein can facilitate the design of shorter synthetic sequences that will result in faster lead optimization with less material investment.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM103886-04
Application #
9507873
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2015-09-01
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Yang, Fei; Li, Yangshan; Floreancig, Paul E et al. (2018) Copper-catalyzed oxidative cross-dehydrogenative coupling of 2H-chromenes and terminal alkynes. Org Biomol Chem 16:5144-5149
Rohrs, Tyler M; Qin, Qi; Floreancig, Paul E (2017) Re2 O7 -Mediated Dehydrative Cyclization Reactions: Total Synthesis of Herboxidiene and Its 12-Desmethyl Analogue. Angew Chem Int Ed Engl 56:10900-10904