Project Grant F32GM167071

DEVELOPMENT OF CHROMOPHORE ACTIVATION AS A GENERAL PLATFORM FOR PHOTOCHEMISTRY - PROJECT SUMMARY MODERN DRUG DISCOVERY DEPENDS ON METHODS THAT RAPIDLY CONVERT SIMPLE CHEMICAL FEEDSTOCKS INTO COMPLEX, BIOLOGICALLY ACTIVE STRUCTURES. IN THIS REGARD, ASYMMETRIC PHOTOCHEMISTRY OFFERS POWERFUL STRATEGIES FOR CONSTRUCTING THREE-DIMENSIONAL ARCHITECTURES INACCESSIBLE TO GROUND- STATE METHODS. HOWEVER, CURRENT APPROACHES OFTEN REQUIRE SUBSTRATES WITH INNATE CHROMOPHORES OR EXPENSIVE IR- OR RU-BASED PHOTOCATALYSTS, LIMITING SCALABILITY AND BROADER ADOPTION IN MEDICINAL CHEMISTRY. THIS PROPOSAL SEEKS TO HARNESS THE POWER OF CHROMOPHORE ACTIVATION TO DIRECTLY SENSITIZE SUBSTRATES LACKING INTRINSIC LIGHT-ABSORBING GROUPS. THIS APPROACH, DEVELOPED BY THE YOON LAB, EMPLOYS A LEWIS-BASIC AUXILIARY CHROMOPHORE TO ENGAGE IN HYDROGEN BONDING WITH A CHIRAL PHOSPHORAMIDE CATALYST TO INDUCE A BATHOCHROMIC SHIFT AND SELECTIVE PHOTOEXCITATION OF THE CHROMOPHORE-TAGGED SUBSTRATE. AS SUCH, RADICAL GENERATION AND BOND FORMATION OCCUR EXCLUSIVELY WITHIN THE CHIRAL ENVIRONMENT OF THE ORGANOCATALYST, ENABLING HIGH LEVELS OF ENANTIOSELECTIVITY. THE PROPOSED RESEARCH WILL FIRST EMPLOY CHROMOPHORE ACTIVATION FOR METAL-FREE, ENANTIOSELECTIVE [3+2] PHOTOCYCLOADDITIONS TOWARDS CHIRAL CYCLOPENTANES AND PYRROLIDINES. AIM 1 SEEKS TO ESTABLISH THE GENERAL REACTION FRAMEWORK USING THE ACYL IMIDAZOLE CHROMOPHORES PREVIOUSLY EMPLOYED BY THE YOON LAB. CHROMOPHORE-TAGGED CYCLOPROPANES WILL BE USED IN ENANTIOSELECTIVE PHOTOCYCLOADDITIONS WITH ALKENE SUBSTRATES TOWARDS CHIRAL CYCLOPENTANES. A LIBRARY OF CHIRAL PHOSPHORAMIDE AND PHOSPHORIC ACID CATALYSTS WILL BE SCREENED ALONGSIDE ALKYL AND ARYL SUBSTITUTED ACYL IMIDAZOLES TO ESTABLISH OPTIMAL REACTION CONDITIONS. IN AIM 2, THE REACTION SCOPE WILL BE EXPANDED TO INCLUDE OXIME ETHERS AND HYDRAZONES TOWARDS THE SYNTHESIS OF CHIRAL PYRROLIDINES. ADDITIONALLY, THE SCOPE OF THE REACTION WILL BE EVALUATED ACROSS DENSELY FUNCTIONALIZED AND MEDICINALLY RELEVANT SUBSTRATES BEARING ALKENES, OXIME ETHERS, AND HYDRAZONES. FINALLY, AIM 3 WILL ENABLE THE RATIONAL DESIGN OF NEXT-GENERATION CHROMOPHORES. HIGH- THROUGHPUT SCREENING ACROSS SEVERAL HUNDRED COMMERCIALLY AVAILABLE CHROMOPHORES WILL PROVIDE DATA FOR COMPUTATIONAL STUDIES AND PREDICTIVE MODELING OF OPTIMAL CHROMOPHORE STRUCTURES. TOGETHER, THESE STUDIES AIM TO ESTABLISH CHROMOPHORE ACTIVATION AS A GENERALIZABLE PLATFORM FOR STEREOSELECTIVE PHOTOCHEMICAL SYNTHESIS. MORE SPECIFICALLY, WE WILL UTILIZE MY OWN BACKGROUND IN HIGH-THROUGHPUT EXPERIMENTATION ALONGSIDE THE PHOTOCHEMISTRY AND METHODOLOGY EXPERTISE WITHIN PROFESSOR YOON'S LAB TO DEVELOP POWERFUL NEW PHOTOCHEMICAL METHODS TOWARDS COMPLEX, BIOLOGICALLY ACTIVE MOLECULES.