ISOCHROMAN-3-ONE AS A KEY BUILDING BLOCK FOR THE SYNTHESIS OF VERSATILE SPIRO, BRIDGED, AND POLYCYCLIC SCAFFOLDS

FIRST, IN COLLABORATION WITH OFIAL’S GROUP, QUANTIFICATION OF THE NUCLEOPHILICITY OF 3-ISOCHROMANONES AND 2-COUMARANONES ON THE MAYR SCALE HAS BEEN DONE. DEPROTONATION IN DMSO GENERATED ENOLATES WHOSE SECOND-ORDER RATE CONSTANTS TOWARD QUINONE METHIDES AND ARYLIDENEMALONATES WERE MEASURED BY STOPPED-FLOW UV–VIS. FITTING TO THE MAYR–PATZ EQUATION GAVE N = 25.39, Sₙ = 0.53 (ISOCHROMANONE) AND N = 19.60, Sₙ = 0.75 (COUMARANONE), SHOWING THAT THEIR BRØNSTED ACIDITY CORRELATES WITH HIGH NUCLEOPHILICITY. WE THEN APPLIED THIS REACTIVITY IN PHASE-TRANSFER-CATALYZED MICHAEL ADDITIONS OF SUBSTITUTED ISOCHROMAN-3-ONES AND COUMARANONES TO CHALCONES UNDER MILD K₂CO₃/TBAB CONDITIONS, ESTABLISHING A GENERAL, CATALYTIC C–C BOND FORMATION WITH BROAD SCOPE. THIS ENABLED A ONE-POT DOUBLE-CASCADE TO 3-SPIROPIPERIDINES: ISOCHROMANONES FIRST COUPLED WITH 2-CYANOBENZALDEHYDES OR 2-ACETYLBENZONITRILES TO GIVE BINUCLEOPHILIC ISOINDOLINONE–ISOCHROMANONE HYBRIDS, WHICH UNDERWENT [3+3] SPIROCYCLIZATION WITH ACROLEIN OR HIGHER Α,Β-UNSATURATED ALDEHYDES. ACROLEIN GAVE SINGLE DIASTEREOMERS, AND SUBSTITUTION ON THE ISOINDOLINONE 3-POSITION CONTROLLED WHETHER A MICHAEL/HEMIAMINAL OR AZA-MICHAEL/CROSS-ALDOL PATHWAY DOMINATED. PRODUCTS WERE EASILY DIVERSIFIED (OXIDATION, DEHYDRATION, DEHYDROXYLATION). NEXT, WORKING WITH 4-BROMOISOCHROMAN-3-ONE, WE UNCOVERED A TANDEM SEQUENCE: BASE-PROMOTED AUTOXIDATION TO ISOCHROMANE-3,4-DIONE FOLLOWED BY DIENOLIZATION/DEAROMATIZATION AND A DIELS–ALDER REACTION WITH ELECTRON-POOR ALKENES, PRODUCING REGIO- AND DIASTEREOSELECTIVE BRIDGED POLYCYCLIC LACTONES. USING ISOLATED 3,4-DIONES DIRECTLY IMPROVED ATOM ECONOMY AND EXPANDED THE SCOPE TO CHALCONES, ENONES, FUMARATES/MALEATES, NITRO- AND CYANO-ALKENES, OFTEN WITH STEREOSPECIFIC OUTCOMES CONSISTENT WITH A CONCERTED [4+2] PROCESS. REDUCTIVE LACTONE OPENING (LIBH₄) AFFORDED TETRAHYDRONAPHTHALENE TETROLS RELATED TO BENZOCONDURITOL MOTIFS. FINALLY, WE EXTENDED THIS DIELS–ALDER PLATFORM TOWARD ASYMMETRIC VARIANTS USING IN SITU GENERATED DIENES UNDER COOPERATIVE ORGANOCATALYSIS, AND ALSO SHOWED THAT HYDROXY-PYRONES OR ISOCHROMAN-3,4-DIONES WITH ALLENOATES OR BUTYNOATES DIRECTLY FURNISH 1,2,3-SUBSTITUTED PHENOLS AND NAPHTHOLS VIA CYCLOADDITION–DECARBOXYLATION–REAROMATIZATION. OVERALL, THE RESULTS ESTABLISH 3-ISOCHROMANONE AS A QUANTITATIVELY VALIDATED, HIGHLY NUCLEOPHILIC BENZYLIC LACTONE ENABLING METAL-FREE MICHAEL ADDITIONS, CONCISE [3+3] SPIROCYCLIZATIONS, AND TANDEM OXIDATION/DIELS–ALDER IN THE CASE OF DIONE ROUTES TO COMPLEX POLYCYCLES WITH POTENTIAL FOR ASYMMETRIC AND MEDICINAL EXTENSIONS.