Organocatalytic Asymmetric Synthesis Of Chiral Alkynyl Thiazolidines Using Alkynyl Imines

Chiral thiazolidine units are widely existed in many synthetic drugs and natural products.Owing to their unique biological and pharmaceutical activities,synthetic chemists have developed many efficient methods for the construction of this scaffold.Recently,encouraged by the organocatalytic asymmetric reaction of imines,cascade asymmetric addition/cyclization reaction of imines and sulfides has become a representative strategy for the synthesis of chiral thiazolidines.Among them,asymmetric addition/cyclization reaction of stable imines is well-developed.Although the structure,synthesis method and application of in-situ generated imines are more common,the nucleophilic nucleons produced by the formation of imines are more likely to hurt the sulfur addition process.At present,only one example of in-situ generated imines to synthesize chiral thiazolidines via three-step synthesis(addition/reduction/substitution).The addition/cyclization reaction of direct in-situ imines has not been reported.Herein,a chiral phosphoric acid-catalyzed cascade asymmetric addition/cyclization reaction of alkynyl aldimines in-situ generated and 2,5-dihydroxy-1,4-dithiane was designed and developed,which could easily access to chiral 2-alkynylthiazolidines.This thesis mainly includes the following parts.In first part,the importance and catalytic methods for the synthesis of chiral thiazolidines were reviewed.In second part,a chiral phosphoric acid-catalyzed cascade asymmetric addition/cyclization reaction of alkynyl aldimines and 2,5-dihydroxy-1,4-dithiane was developed.After screening and optimizing the reaction conditions,the optimized conditions were employed anhydrous toluene as solvent,5 mol%chiral spiro-phosphoric acid as catalyst,and the reaction temperature was 40?.To further improve the stereoselectivity,the resulting mixture was directly conducted to the PDC oxidative condition.Then,the best result for the synthesis of 2-alkynylthiazolidinones was delivered with 69%yield and 90%ee.With the optimized condition in hand,a serial of N,O-acetal alkynyl imines were investigated.And 15 examples of chiral 2-alkynylthiazolidinones were afforded by this developed method with good yields and enantioselectivities.In third part,the cascade asymmetric addition/cyclization reaction of trifluoromethyl alkynyl ketimines and 2,5-dihydroxy-1,4-dithiane was described.After the preliminar investigation,under the anhydrous chloroform and 10 mol%quinine thioureas at room temperature,the reaction could yield the thiazolidine products containing with a trifluoromethyl group and quaternary carbon center in 95%yield.In summary,a chiral phosphoric acid-catalyzed cascade asymmetric addition/cyclization reaction of N,O-acetal alkynyl aldimines and 2,5-dihydroxy-1,4-dithiane was firstly developed,which could directly access to chiral thiazolidines from the in-situ generated imines.The method provides a complementary,convenient and efficient method for the synthesis of chiral thiazolidine compounds.Additionally,the cascade asymmetric addition/cyclization reaction of alkynyl ketimines containing trifluoromethyl group was also demonstrated to allow the construction of chiral thiazolidines containing with a trifluoromethyl group.