Project Grant R35GM155273

EXPANDING ACCESS TO MOLECULAR COMPLEXITY THROUGH NATURAL PRODUCT SYNTHESIS - THE DEVELOPMENT OF MODERN MEDICINES RELIES ON THE ABILITY TO ACCESS COMPOUNDS THAT ARE POTENT, SELECTIVE, AND IDEALLY CURATIVE. TO ACHIEVE THESE GOALS, CHEMISTS HAVE SOUGHT TO PREPARE EVERMORE COMPLEX STRUCTURES IN SEARCH OF NUANCED ACTIVITY AND SELECTIVITY PROFILES, ADVANCES DEPENDENT ON THE AVAILABILITY OF TOOLS AND STRATEGIES TO SYNTHESIZE SUCH COMPOUNDS IN AN ECONOMICAL AND SCALABLE FASHION. COMPLEX NATURAL PRODUCTS HAVE TRADITIONALLY INSPIRED THE DEVELOPMENT OF SUCH TOOLS, OFTEN ACTING AS KEY MILESTONES IN THE ADVANCEMENT OF ORGANIC SYNTHESIS AND AS VITAL MEDICINES IN THEIR OWN RIGHT. HOWEVER, AT THE APEX OF COMPLEXITY, THEIR STRUCTURES CONTINUE TO TEST THE LIMITS OF CURRENT CAPABILITIES: HIGHLY INTRICATE TARGETS ARE PREPARED ONLY THROUGH ENORMOUS EFFORT IN TERMS OF MAN-YEARS AND NUMBER OF SYNTHETIC OPERATIONS, OFTEN ONLY IN A TARGET-SPECIFIC MANNER. HERE, WE PROPOSE TO UTILIZE SUCH COMPOUNDS AS VEHICLES FOR THE DISCOVERY OF COMPLEXITY-GENERATING TOOLS AND TACTICS. WE OUTLINE APPROACHES TO SEVERAL FAMILIES OF NATURAL PRODUCTS BUILT UPON TWO DISTINCT COMPLEXITY-BUILDING STRATEGIES: DEAROMATIVE TRANSFORMATIONS OF READILY AVAILABLE AROMATIC COMPOUNDS AND DESYMMETRIZATION OF SIMPLE SYMMETRICAL PRECURSORS. IN THE FORMER CASE, AROMATIC FEEDSTOCKS - AVAILABLE AS PETROLEUM BYPRODUCTS OR FROM RENEWABLE BIOMASS - REPRESENT A VERSATILE SYNTHESIS PLATFORM GIVEN WELL-ESTABLISHED, PREDICTABLE MODES FOR THEIR FUNCTIONALIZATION. WE SEEK TO DEPLOY THESE MATERIALS IN COMPLEXITY-BUILDING DEAROMATIVE REACTIONS, DISRUPTING THEIR OTHERWISE STABLE AROMATIC SYSTEMS AND TRANSFORMING THEIR FLAT SP2-SCAFFOLDS INTO SP3-RICH COMPOUNDS CONTAINING MULTIPLE STEREOGENIC CENTERS. SPECIFICALLY, WE PROPOSE TO UTILIZE THE REGIODIVERGENT OXIDATIVE COUPLING OF SIMPLE BISPHENOLIC COMPOUNDS TO ACCESS THE STRUCTURAL COMPLEXITY INHERENT TO THE QUASSINOIDS, A FAMILY OF POTENT ANTICANCER TERPENOIDS. OUR SYNTHESIS PLATFORM WILL LEVERAGE THE BUILT-IN OXIDATION OF THE AROMATIC SYSTEMS TO ENCODE FOR MUCH OF THE SP3-SKELETAL OXIDATION IN THESE HIGHLY OXIDIZED TERPENOIDS, PROVIDING A UNIQUE MEANS TO ACCESS THESE TARGETS AND ANALOGUES, AND ILLUMINATE THEIR BIOLOGICAL MODE OF ACTION. IN A SYMMETRY-BREAKING TRANSFORMATION, WE WILL DEVELOP NEW PHOTOCHEMISTRY OF PYRIDINIUM IONS TO PROVIDE CONVENIENT ACCESS TO HIGHLY FUNCTIONALIZED CYCLOPENTANE BUILDING BLOCKS, IN PARTICULAR VIA ENANTIOSELECTIVE DESYMMETRIZATION OF SYMMETRICAL ALLYLIC CATION INTERMEDIATES. WE WILL APPLY THESE INTERMEDIATES TO THE ASYMMETRIC SYNTHESIS OF PACTAMYCIN-TYPE AMINOCYCLOPENTITOLS, HIGHLY POTENT ANTIPARASITIC AGENTS. WE WILL ALSO DEVELOP A RELATED APPROACH TO TWO SUBCLASSES OF THE LYCOPODIUM ALKALOIDS, WHICH INCLUDE CENTRAL NERVOUS SYSTEM-ACTIVE COMPOUNDS, BUILT UPON TWO SEQUENTIAL PHOTOCHEMICAL DEAROMATIZATIONS OF A SIMPLE QUINOLINE. OVERALL, SUCH DISCOVERIES WILL OPEN UP NEW AREAS OF COMPLEX CHEMICAL SPACE FROM SIMPLE AROMATIC OR SYMMETRICAL PRECURSORS, PROVIDING NATURAL PRODUCTS AND DESIGNED ANALOGUES FOR INTERROGATION OF BIOLOGICAL FUNCTION. THESE STUDIES WILL LEAD TO INNOVATIONS IN DEAROMATIZATION AND DESYMMETRIZATION CHEMISTRY, AFFORD NOVEL CHEMOTYPES FOR DISEASE TREATMENT, AND PROVIDE TOOL COMPOUNDS THAT MAY LEAD TO NEW DISCOVERIES IN BIOLOGY.