Applications Of Vinylidene Ortho-quinone Methide(VQM)in Asymmetric Synthesis

Chiral chemistry is closely related to the development of medicinal chemistry,biological sciences,agricultural chemistry,functional materials,and other disciplines.Since most biological targets are chiral entities,it is particularly essential to design precise synthetic strategies for various chiral elements to fulfill the high selectivity required by the drug-receptor interactions.However,it remains a huge challenge in the field of asymmetric synthesis due to the wide range of chiral species.VQM（vinylidene–quinone methide）is characterized by high reactivity,multiple reaction sites,and easy preparation.These advantages make VQM compatible with the construction of different types of chiral elements.In this thesis,we focus on the application of the C4 position of the VQM in the asymmetric synthesis of axially chiral sulfone-containing styrenes,axial chiral nonsymmetric biaryltriols,chiral helicenes,and chiral cyclic ethers.The reaction mechanisms were investigated and proposed through controlled experiments,dynamic NMR studies,intermediate separation,and DFT calculations.In addition,the potential applications of the synthetic methods are illustrated by product derivatization,ion detection,and continuous flow experiments.1.Catalyst organocatalytic enantioselective construction of axially chiral sulfone-containing styrenesAs a member of the axially chiral family,the enantiomers of axially chiral styrenes exist due to the restricted rotation around a single bond between a substituted alkene and an aromatic ring.The enantioselective construction of axially chiral styrenes remains a daunting challenge in modern organic synthesis,because of the low-rotation energy to racemization and the difficulty to control the enantioselectivity.In this content,we have developed an organocatalytic enantioselective synthesis of axially chiral sulfone-containing styrene derivatives by the nucleophilic addition reaction of sodium benzenesulfinate and VQM.A broad range of valuable axially chiral sulfone-containing styrenes was synthesized in good yields with excellent enantioselectivities（up to>99%and E/Z ratios>99:1）by this newly developed method.Thermodynamic experiments confirmed the structural stability of the synthesized axial chiral styrenes and that they are not easily racemized.In addition,we synthesized axial chiral styrenes containing nitrogen and phosphine atoms by simple product transformation and inferred the mechanism of the reaction based on the control results.2.Organocatalytic atroposelective construction of axial chiral nonsymmetric biaryltriols and their applications in asymmetric synthesis and heavy metal detectionBiaryldiol moieties bearing a chiral axis are present in a number of natural products and are widely exploited in asymmetric catalysis.C₂-symmetric diaryl diphenols have been synthesized with great research progress,while the synthetic methods for non-C₂-symmetric biaryltriols are still lacking.In this content,an organocatalytic methodology toward the atroposelective construction of axial chiral nonsymmetric biaryltriols has been successfully developed,through the nucleophilic addition reaction between VQM and the C₂ position of the methoxy-substituted benzene ring.We prepared 21 examples of non-C2-symmetric biaryltriols with ee values up to 99%,which have been applied as chiral ligands for the enantioselective preparation of chiral sec-alcohols or as the newly designed organocatalyst for asymmetric petasis reaction.In addition,they have demonstrated potential utility as a selective fluorescence sensor toward Ru³⁺.3.Enantioselective control of both helical and axial stereogenic elements through an organocatalytic approachHelicenes are polycyclic aromatic compounds with nonplanar screw-shaped skeletons formed by ortho-fused benzene or other aromatic rings.Due to the steric hindrance between the aromatic rings at the end of the helicene skeleton,this type of molecule exhibits a special P/M helical chirality.Chiral helicenes have large specific spins and nonlinear optical properties,and have a wide range of applications including asymmetric catalysis,chiral molecular recognition,molecular machines,and so on.Therefore,the synthesis and properties of such compounds have become one of the hotspots in organic chemistry.Herein,we report an organocatalytic strategy for the efficient one-pot synthesis of molecules containing valuable chiral helicenes and stereogenic axes through stepwise double cyclization processes with excellent enantioselectivities and diastereoselectivities（14 examples.Up to 99%ee）.In addition,To gain insight into the reaction process,we isolated intermediates for dynamic NMR experiments and theoretical calculations.Controlled experiments were also performed to further explore the origin of the diastereoselectivity of the second step and the chiral origin of the cyclization process.4.Organocatalytic cascade reactions to multi-functionalized chiral cyclic ethers through vinylidene ortho-quinone methidesIn the last decade,tremendous advances have been achieved toward stereoselective1,4-additions of a variety of nucleophiles toα,β-unsaturated carbonyl substrates based on organocatalysis.In contrast,the stereoselective addition of nucleophiles to carbonyl moieties ofα,β-unsaturated carbonyl compounds have been a longstanding challenge and was limited to active species such as organometallic nucleophiles.Herein,we report an organocatalytic approach to achieve the addition of a wide range of alcohols into carbonyl ofα,β-unsaturated ketone mediated by VQM intermediates cascade reactions.This method enabled alcohols as weak nucleophiles to undergo enantioselective addition of carbonyl part ofα,β-unsaturated ketones.In addition,this protocol showed a broad substrate scope,as a wide range of alcohols were adapted in this transformation with high stereoselectivities.