The enantioselective synthesis of new phenanthridinone and carbazole analogs with quaternary and tertiary carbons using the Birch-Heck sequence - Project Summary/Abstract
Over the last several decades, many highly promising drug candidates have failed to
successfully navigate the complex human physiology during clinical trials. Drug candidates that
do succeed in clinical trials have a higher proportion of chiral centers and sp3 carbons than
those that don’t succeed. Unfortunately, the current limited selection of efficient synthetic
chemistry tools fosters the generation of flat aromatic and sp2 carbon structures; a large
proportion of drug candidates advanced into the clinic reflect that fact.
Phenanthridinone and carbazole are two examples of flat aromatic structures that are commonly
found in bioactive molecules and drug candidates. In fact, the phenanthridinone core is found in
3,200 bioactive compounds according to PubChem, while carbazole has been found in an
astonishing 258,000. Clearly these structures interact with many biological macromolecules. It
is likely that their structural profile contributes to their significant and indiscriminate bioactivity.
However, their extensive bioactivity creates problems in complex human physiology where
successful drug candidates are groomed for selective interactions to reduce side effects and
toxicity.
The current proposal presents a new synthetic chemistry tool that will allow the generation of
phenanthridinone and carbazole analogs with chiral centers and sp3 carbons. Creating an
efficient and enantioselective tool for this purpose will allow researchers to generate analogs
that will hopefully retain the bioactivity of phenanthridinone and carbazole, but be more selective
and potent in interactions with biological targets for therapeutic purposes.
The new synthetic chemistry tool involves a short sequence of reactions to rapidly generate
fused tricyclic ring systems with a chiral quaternary or tertiary center. The process involves
desymmetrizing cyclohexadiene structures generated in the versatile Birch reduction-alkylation
reaction. The use of palladium catalysts with chiral ligands in a desymmetrizing Mizoroki-Heck
reaction will afford enantioselective control in the key step. The versatility of the Mizoroki-Heck
reaction will allow the creation of a broad range of structures, including medium-size and
heterocyclic rings. In the process, the substrate scope of the enantioselective intramolecular
Mirzoroki-Heck reaction will be expanded. The phenanthridinone and carbazole analogs
generated through this work will be screened with our biological collaborators at Lankenau
Institute of Medical Research for anti-cancer activity.
As an R15 proposal, one additional important benefit will be the science education experiences
created for students at Bryn Mawr College. Both Bryn Mawr and the PI have a substantial
record of accomplishment in training scientists and physicians. An award will allow these critical
activities to continue.
