Studies On Copper-Catalyzed Enantioselective Radical Desymmetrization Of Diols

Chiral oxygen-containing compounds exist widely in natural products,biologically active substances as well as pharmaceutical molecules,and thus the efficient synthesis of such structures has significant application in multiple disciplines.Among numerous synthetic methods,the enantioselective desymmetrization of diols has recently attracted increasing attention because it features many advantages,such as the easy availability of substrates and expedient access to quaternary stereocenters.However,the current reports mainly focused on the ionic process,which suffered from the limited substrate scope and narrow functional group tolerance as well as the difficulty in constructing all-carbon quaternary stereocenters.Radicals are generally highly reactive,compatible with diverse functional groups,and insensitive to steric crowding.Nevertheless,the stereoselective control of radical reactions remains one of the most challenging issues in modern organic synthesis,and catalytic enantioselective desymmetrization reactions involving radicals have not been reported to date.To address this challenge,this dissertation developed several copper catalysts to systematically investigate the enantioselective radical desymmetrization reactions of diols.These strategies allowed the expedient synthesis of chiral oxygen-containing compounds and especially those with quaternary carbon stereocenters providing new insight into the stereoselective control of radicals.The main contents are as follows:First,a Cu(I)/chiral phosphoric acid cooperative catalytic system was designed to realize the stereoselective control of highly reactive π-type alkyl radicals through the tight interaction between catalyst and in situ generated alkyl radical species.A new catalytic radical-involved enantioselective desymmetrization reaction has been achieved.The reaction was initiated by the SET reduction of perfluoroalkyl sulfonyl chlorides with the Cu(I)/chiral phosphoric acid catalyst to generate the perfluoroalkyl sulfonyl radicals and chiral Cu(II)phosphate.The radicals added to the alkene moiety of the alkenyl diols to deliver an alkyl radical,which was trapped by the substrate-sequestered Cu(II)phosphate to furnish the desired chiral tetrahydrofurans in up to 96% yield with 20:1 dr and 97% ee.Silver carbonate was used to quench the in situ generated HCl byproduct,thus inhibiting the racemic background reactions.The reaction scope was broad,covering arenes and heteroarenes with distinct electronic properties and tolerates diverse functional groups.The facile transformations gave rise to valuable spiro-heterocycle bearing two chiral tetrasubstituted carbons.This study provided a new efficient strategy for the construction of tetrahydrofuran derivatives bearing two all-carbon quaternary stereocenters.Second,a Cu(I)/chiral sulfonamide bidentate ligand catalytic system was developed and achieved the remote enantioselective control of σ-type acyl radicals through intermolecular enantioselective desymmetrization of diols.The reaction employed readily available(hetero)aryl and alkyl aldehydes as high atom-economic acyl radical precursors and was compatible with several alcohol compounds,including prochiral 1,3-diols,2-amino-1,3-diols,1,2,3-triols,and protected meso-erythritol,providing enantioenriched esters characterized by challenging acyclic all-carbon quaternary and N-,O-and Cl-bearing tetrasubstituted stereocenters in up to 89% yield with 98% ee.The translation potential of the strategy is highlighted by the expedient preparation of chiral C3 building blocks and α,α-disubstituted unnatural amino acids.Mechanistic experimental studies demonstrated that acyl radicals were involved in the enantio-control step and rule out the possible ionic reaction pathway.This reaction provided a new method for enantioselective control of high-reactive σ radicals.Third,a highly enantioselective heteroatomic S–O coupling reaction of sulfonyl radicals with diols was developed by utilizing the Cu(I)/chiral sulfonamide bidentate ligand catalytic system.The key to success was that designed a single-electron reductive elimination outer-sphere pathway for the heteroatomic cross-coupling overcoming the challenging two-electron reductive elimination process.Prochiral 1,3-diols,meso-1,2-diols,and 1,2,3-triols were smoothly transformed into synthetically challenging acyclic all-carbon quaternary and oxygen-bearing tetrasubstituted carbon stereocenters with up to 97% yield and up to 99% ee.Mechanistic studies suggested that sulfonyl radical was involved in the enantioselective determine step,and control experiments support silver carbonate and proton sponge as quenchers for the in situ generated HCl to improve reaction efficiency and enantioselectivity.In terms of practical applications,glycerol could be used directly as the starting material in a gram-scale.Highly enantioenriched chiral product was obtained from glycerol in a one-step catalytic reaction,and various high-value-added chiral C3 building blocks were obtained through further simple derivatization,realizing the high-value-added conversion of glycerol.Remarkably,the crude glycerol with 71% purity could be directly employed to give valuable compounds with good enantioselectivity(82% ee).In addition,the approach was also utilized for the synthesis of an important synthetic intermediate toward the antifungal agents and drug levodropropizine,demonstrating the potential application value of the reaction.