Scalable Synthesis and New Bond Disconnections

PROJECT SUMMARY/ABSTRACT
Natural products have long held societal value as folk medicines, and even in this modern era,
many FDA-approved drugs are still being derived from terpenes and alkaloids found in nature.
Biomedical research has also benefited from natural products, as previously unknown
mechanisms of action have been discovered while studying the unique biochemical pathways
that these compounds undergo in the human body. Furthermore, endeavors in the total synthesis
of these architecturally diverse compounds have continuously provided chemists with challenges,
which in turn have led to the establishment of research programs in both academic and industrial
environments. Ever since its inception, our laboratory has been pursuing, and has succeeded in,
the total synthesis of iconic natural products in both the terpene and alkaloid families. These
syntheses have identified gaps in the chemical literature, which we have subsequently addressed.
The products of this research program—new synthetic strategies, unprecedented transformations
and novel reagents—have in turn enabled the synthesis of even more natural products and
pharmaceutically relevant motifs, thus completing a catalytic cycle of discovery. We seek to
replicate this success with the current proposal: the described projects will target complex natural
products to identify shortcomings in chemical methodology, while simultaneously devising
methods of widespread interest, followed by the assessment of their practicality in the synthesis
of complex molecules. For the next five years our laboratory will generate chemical knowledge
that transcends the original objective of natural product synthesis. We will focus on efficiently
synthesize complex natural products aiming for ideality. We will also develop of useful methods
for synthesis and medicinal chemistry. The resulting procedures will be utilized in the construction
of complex pharmaceutical motifs, which will serve to expand chemical space and accelerate
discovery in drug discovery. Notably, we have already established numerous collaborations to
study the biological properties of the products that will be synthesized, to validate and field-test
new methods, and to commercialize reagents for widespread adoption in both academic and
industrial settings. Lastly, we will focus on strategic applications and development of synthetic
organic electrochemical methods, wherein the development of oxidative mediators for C-H
functionalization, desaturation of carbonyls, and reductive cross-couplings are presented.

Grant Number: 3R35GM118176-10S1
NIH Institute/Center: NIH
Principal Investigator: PHIL BARAN