Asymmetric Annulation Of In Situ Generated 6-methylenecyclohexa-2,4-dienone

As a class of important synthetic intermediates with high reactivity,6-methylenecyclohexa-2,4-dienone(ortho-quinone methides,o-QMs)are widely used for the organic syntheses and pharmaceutical chemistry.The multiple cyclic skeleton are the key motif in natural products and bioactive molecular,thus the asymmetric annulation of o-QMs to construct those skeleton attracts chemists' attention and various type of reactions as well as catalytic systems have been developed.However,the bifunctional chiral Lewis base-catalyzed asymmetric annulation of o-QMs which are in situ generated under basic condition have been rarely reported.In this dissertation,bifunctional chiral Lewis base-catalyzed asymmetric annulation of o-QMs in situ generated from 2-(1-tosylalkyl)phenols have been studied and the results are showed as below.Firstly,the quinine-derived bifunctional squaramide-catalyzed asymmetric annulation of o-QMs in situ generated from 2-(1-tosylalkyl)phenols with azlactones has been realized to synthesize chiral dihydrocoumarin derivatives bearing a quaternary amino acid moiety with excellent diastereo-and enantioselectivities.The substrate scope is wide and the reaction can procced smoothly for 27 examples,obtaining the target products with up to 97% ee.In addition,the gram-scale experiment was conducted under the optimal conditions,affording the desired product without any loss of reactivity and enantioselectivity,which reveals the good synthetic utility of this methodology.Secondly,the quinine-derived bifunctional squaramide-catalyzed asymmetric Michael addition of o-QMs in situ generated from 2-(1-tosylalkyl)phenols with pyrazolones has been developed.Then,the adducts could further convert to spiropyrazolones catalyzed by bifunctional organocatalyst in the presence of N-chlorosuccinimide(NCS)and base through cascade chlorination/cyclization with up to >20:1 dr and >99% ee.This cascade reaction provide a facile and efficient access to chiral spiropyrazolones.Next,the annulation of o-QMs in situ generated from 2-(1-tosylalkyl)phenols with 3-chlorooxindoles has been developed owing to that the 3-chlorooxindoles are both nuleophilic and electropilic,leading to the spirooxindoles with up to 97% yields and >20:1 dr.Meanwhile,bifunctional squaramide-catalyzed asymmetric annulation of o-QMs with 3-chlorooxindoles was also explored,delivering the chiral spirooxindoles with up to 47% ee after a series of condition optimization.Morever,the 3-trifluoromethylthio substituted quinolines were synthesized through two different routes starting from quinolines,based on which the chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation of 3-trifluoromethylthio quinolines with Hantzsch esters has been realized,obtaining the chiral 2,3-disubstituted 1,2,3,4-tetrahydroquinoline derivatives in excellent enantioselectivities.Finally,we realized the Ag-catalyzed 1,6-addition of azomethine ylides to paraquinone methides,offering the various types of ?,?-biaryl-?-amino acid derivatives with two continuous stereocenters in up to 98% ee and >20:1 dr.In addition,the products could transform to chiral amino acids through simple hydrolysis,making big difference to the pharmaceutical chemistry.