Tandem Synthesis Of Chiral 1,2-dihydropyridines And ?-trifluoromethyl Tertiary Alcohols With Silicon Reagents

Chiral 1,2-dihydropyridines and?-trifluoromethyl tertiary alcohols are privileged scaffolds in drugs and pharmaceutically active compounds.The development of highly efficient asymmetric catalytic reactions to synthesize such compounds with structural diversity is of great value,but still remains a challenge.This dissertation has developed two silicon reagent-involving tandem reactions to facilitate the diverse synthesis such chiral synthons,as introduced in the following.1)A SiCl₄-involving asymmetric Mannich/Wittig/cycloisomerization sequence was developed to access chiral 1,2-dihydropyridines from simple N-Boc aldimines,aldehydes,and phosphoranes,using chiral amine catalysts such as L-proline.In the key step,cycloisomerization of chiral N-Bocd-amino?,?-unsaturated ketones,the hydrolysis of hidden Br?nsted acid SiCl₄ by the trace H₂O in the reaction system produced HCl as true catalyst to initiate the reaction.And the subsequent reaction generated H₂O was internally used to hydrolyze SiCl₄ for gradual generation of HCl,which can adjust the HCl to an appropriate concentration to effectively suppressed side reactions.Furthermore,the mechanism studies showed that byproduct Ph₃PO from Wittig reaction could modulate the acidity of HCl via their acid–base interaction to improve the yield.The gradual reuse of byproduct to generate the true catalyst in situ at a low concentration to suppress side reactions,is unknown.This approach not only allows access to chiral 2-substituted,2,3-or 2,6-cis-disubstituted,and 2,3,6-cis-trisubstituted piperidines with highly diastereoselectivity,but also was applied in the synthesis of chiral bridged rings.2)A new bifunctional trifluoromethylation reagent Me₂(CH₂Cl)SiCF₃ has been developed and used to mediate an asymmetric trifluoromethylation/Finkelstein/radical cyclization tandem sequence for the synthesis of?-CF₃ tertiary alcohol derivatives with vicinal stereocenters.The excellent enantioselectivity achieved by using Me₂(CH₂Cl)SiCF₃ represents the highest ee reported to date for ketone trifluoromethylation.And the protocol has been successfully applied to the synthesis of chiral CF₃-substituted oxetane or?-lactone,and used for the first enantioselective gram-scale synthesis of nonsteroidal antiandrogen.