Although there has been sustained interest in the field of C-H bond oxidation, there is still a need for new methods and strategies for the functionalization of Csp3-H bonds in complex hydrocarbon systems. Within the context of a two-phase approach to terpene synthesis (a logic derived from the biosynthetic pathway of complex terpenoids), the carbogenic framework generated in the synthetic cyclase phase would be subjected to a series of Csp3-H oxidations en route to a highly oxidized terpene target. This "oxidase phase" would use a strategic combination of known Csp3-H oxidation techniques, but it would naturally highlight gaps in current methodology, eliciting invention and discovery. Specifically, the ent-atisane and taxane families of diterpenoids were chosen due to their large arrays of oxidative diversity found in Nature, and two methods in Csp3-H functionalization are proposed herein in order to minimize the number of steps and non-strategic redox fluctuations toward their total syntheses. To this end, a hydroxyl-directed desaturation reaction (to act as a "desaturase mimic") and a hydroxyl-directed methyl group hydroxylation reaction (to act as a "hydroxylase mimic") would be developed in the course of these synthetic endeavors. The ent-atisane and taxane families exhibit biological activities in almost every conceivable therapeutic area. Because of its similarity to biosynthesis, the "oxidation level ascent" within these terpene families would naturally lead to the synthesis of related family members and closely related analogs during the pursuit of highly oxidized ent-atisane (e.g., ent-atisenol) and taxane (e.g., Taxol(R)) targets. The scalable, enantioselective synthesis of a lowly oxidized ent-atisane or taxane core similar to the ones employed in Nature, followed by a short series of sequential, site-selective Csp3-H oxidations, would allow for a divergent synthesis that could target large quantities of scarce biologically active natural products and non-natural analogs for use in the fields of cancer, Alzheimer

Public Health Relevance

The ent-atisane and taxane families exhibit biological activities in almost every conceivable therapeutic area due to its large array of structural diversity. The scalable, enantioselective synthesis of a lowly oxidized ent-atisane or taxane core similar to the ones employed in Nature, followed by sequential, site-selective Csp3-H oxidations, would allow for a divergent synthesis that could target many ent-atisanes and taxanes from common intermediates. This work aims to synthesize large quantities of scarce biologically active natural products and non-natural analogs for use in the fields of cancer, Alzheimer's and infectious disease, as well as to fill gaps in the chemical toolbox of current Csp3-H oxidation techniques.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM097444-04
Application #
8636031
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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