Project Grant R35GM154682

NEW METHODS AND STRATEGIES FOR THE SCALABLE SYNTHESIS OF COMPLEX BIOACTIVE MOLECULES - ABSTRACT TO ENABLE RELIABLE ACCESS TO MEANINGFUL QUANTITIES OF BIOACTIVE NATURAL AND UNNATURAL COMPOUNDS WITH HIGHER COMPLEXITY, IT IS VITAL TO DEVISE NEW SYNTHESIS LOGICS AND DEVELOP NEW CHEMICAL TRANSFORMATIONS. IN THIS CONTEXT, WE PROPOSE TO INVESTIGATE THE HIGHLY COVETED IS THE RAPID ASSEMBLY OF POLYCYCLIC FRAMEWORKS ADORNED WITH SEVERAL CHIRAL CENTERS. OUR EXPLORATIONS FOCUS ON THE SYNTHESIS AND STUDY OF COMPLEX NATURAL PRODUCTS AND THEIR FULLY SYNTHETIC ANALOGUES WITH POTENTIALS FOR THE TREATMENT OF CANCER, NEUROLOGICAL DISORDERS, AND INFECTIOUS DISEASES. THE TERPENES AND ALKALOIDS WE IDENTIFIED AS TARGETS ARE PROMISING LEAD COMPOUNDS FOR THE DEVELOPMENT OF NEW MEDICINES, BUT THEIR UNKNOWN OR UNCLEAR MECHANISM OF ACTIONS AND THE LACK OF A DEPENDABLE WAY TO ACCESS THEM HAS SEVERELY HINDERED THEIR THERAPEUTICAL DEVELOPMENT. WE AIM TO SOLVE THIS ISSUE WHILE ALSO EXPANDING AND INNOVATING THE TOOLBOX AVAILABLE TO MEDICINAL AND SYNTHETIC CHEMISTS. IN FACT, THESE MOLECULES ARE NOT ONLY IMPORTANT FROM A BIOLOGICAL STANDPOINT, BUT THEY ALSO REPRESENT STATE-OF-THE-ART CHALLENGES FOR COMPLEX MOLECULE SYNTHESIS. THUS, THESE TOTAL SYNTHESIS EFFORTS STIMULATE THE INVENTION OF NEW CHEMICALS METHODS AND SERVE AS A PROVING GROUND FOR OUR NEW LOGICS AND EXISTING TRANSFORMATIONS TO SOLVE CRITICAL SYNTHESIS PROBLEMS IN COMPLEX SETTINGS. THE EXPECTED OUTCOME OF THE PROPOSED RESEARCH IS A) THE DEVELOPMENT OF NEW CATALYTIC STEREOSELECTIVE METHODS THAT GENERATE DENSELY SUBSTITUTED POLYCYCLIC BUILDING BLOCKS FOR SYNTHESIS, B) THE DESIGN OF NEW SYNTHESIS LOGICS THAT WILL FACILITATE THE PREPARATION OF COMPLEX FUNCTIONAL MOLECULES FOR WHICH THERE ARE CURRENTLY NO EFFICIENT SYNTHESIS ROADMAPS, C) RELIABLE ACCESS TO THE CHOSEN TARGET MOLECULES ENABLING THEIR USE AS BIOLOGICAL PROBES OR AS LEAD COMPOUNDS FOR DRUG DISCOVERY, D) A COLLECTION OF MEDICINALLY RELEVANT SYNTHETIC ANALOGUES FOR IN-DEPTH BIOLOGICAL EVALUATIONS.