Project Grant R35GM152123

NEW ORGANOSULFUR-BASED STRATEGIES FOR EFFICIENT CONSTRUCTION OF CARBON-CARBON AND CARBON-HETEROATOM BONDS - ORGANOSULFUR COMPOUNDS HAVE HAD A PROFOUND EFFECT ON THE IMPROVEMENT OF HUMAN HEALTH AND WELL-BEING. THEY COMPRISE A QUARTER OF THE MOST PRESCRIBED SMALL MOLECULE DRUGS, WITH SULFUR FEATURING AS ONE OF THE THREE MOST COMMON HETEROATOMS. ORGANOSULFUR COMPOUNDS ALSO HAVE CENTRAL ROLES IN ORGANIC SYNTHESIS AND ARE USED EXTENSIVELY FOR THE CONSTRUCTION OF DRUGS, BIOLOGICAL PROBES, SYNTHETIC INTERMEDIATES, AND ADVANCED MATERIALS FOR BIOMEDICAL APPLICATIONS. DESPITE THE MEDICINAL AND SYNTHETIC IMPORTANCE OF ORGANOSULFUR COMPOUNDS, THEIR DIVERGENT PROPERTIES AND REACTIVITIES THAT ARE AMPLIFIED BY A RANGE OF OXIDATION STATES AND SUBSTITUTION PATTERNS AVAILABLE FOR THE SULFUR ATOM PRESENT SIGNIFICANT CHALLENGES TO THE DEVELOPMENT OF SELECTIVE SYNTHETIC TRANSFORMATIONS, IMPEDING PROGRESS IN MEDICINAL CHEMISTRY AND ORGANIC SYNTHESIS. OUR LONG-TERM GOAL IS TO ADVANCE ORGANIC SYNTHESIS AND MEDICINAL CHEMISTRY BY ENABLING SYNTHETIC ACCESS TO CENTRALLY IMPORTANT ORGANOSULFUR COMPOUNDS AND BY SYSTEMATICALLY DEVELOPING THEIR REGIO- AND STEREOSELECTIVE TRANSFORMATIONS TO BROAD CLASSES OF VALUABLE FUNCTIONALITIES AND STRUCTURAL MOTIFS. SULFINATES HAVE EMERGED AS CENTRALLY IMPORTANT INTERMEDIATES THAT HAVE THE POTENTIAL TO PROVIDE ACCESS TO ALL MAJOR CLASSES OF ORGANOSULFUR COMPOUNDS AND FACILITATE CONSTRUCTION OF CARBON-CARBON BONDS. HOWEVER, THE SCOPE OF SYNTHETIC TRANSFORMATIONS OF SULFINATES THAT CONVERT A VARIETY OF FUNCTIONAL GROUPS TO ORGANOSULFUR COMPOUNDS, IN PARTICULAR THE UNDERDEVELOPED BUT MEDICINALLY IMPORTANT SULFOXIDES AND SULFONIMIDO COMPOUNDS, REMAINS SMALL, AND THE REACTIVITY OF SULFINATES IN THE CONTEXT OF STEREOSELECTIVE CC BOND FORMING CROSS-COUPLING REACTIONS IS NEARLY ENTIRELY UNEXPLORED. OUR RESEARCH PROGRAM WILL ADDRESS THESE LIMITATIONS BY INNOVATING NEW SULFINATE-BASED SYNTHETIC METHODOLOGIES FOR EFFICIENT CONSTRUCTION OF CARBON-HETEROATOM AND CARBON-CARBON BONDS. IN THE FIRST PART, WE WILL DEVELOP A RADICAL- BASED PLATFORM FOR THE CONVERSION OF SYNTHETICALLY IMPORTANT FUNCTIONAL GROUPS TO SULFOXIDES IN A REACTION WITH SULFINATES AND EXTEND IT TO SULFONIMIDO COMPOUNDS. IN THE SECOND PART, WE WILL DEVELOP A BROAD-SCOPE, STEREODIVERGENT DIENYLATION REACTION FOR THE CONSTRUCTION OF CONJUGATED DIENES AND POLYENES WITH SULFOLENES AS READILY AVAILABLE DIENYLATING REAGENTS AND SULFINATES AS INTERMEDIATES. IN THE THIRD PART, THE SULFINATE-BASED METHODOLOGY WILL BE EXPANDED TO THE CONSTRUCTION OF BIS-ORTHO-SUBSTITUTED BIARYL MOTIFS THAT ARE SOME OF THE MOST WIDELY USED STRUCTURAL UNITS IN DRUG DISCOVERY AND LIGAND DESIGN. THE RESEARCH PROGRAM WILL ENABLE ACCESS TO CURRENTLY SYNTHETICALLY CHALLENGING FUNCTIONALIZED MOLECULES AND WILL CONTRIBUTE TO THE IMPROVEMENT OF HUMAN HEALTH BY FACILITATING DRUG DISCOVERY AND ACCESS TO NEW SMALL MOLECULE MEDICINES.