Squaramide-Catalyzed Asymmetric Cascade Reactions

Organocatalytic cascade reactions provide a convenient method for the construction of optically active molecular skeleton of natural products,complex molecules and heterocyclic compounds,which is superior to other methods.In recent years,chiral squaramides emerged as an effective chiral organocatalyst have been successfully applied to the construction of carbon carbon bond and carbon hetero atom bond.However,the reports on the asymmetric cascade reactions catalyzed by chiral squaramides are still limited.Based on the retrosynthesis of the target molecule with potential biological activity,rational reaction path was designed and the required cascade reagents were synthsized.This doctoral dissertation was designed to develop new highly efficient,highly selective asymmetric cascade reactions for the synthesis of molecules with potential biological activity using the synthesized cascade reagents with the corresponding substrate by chiral squaramides.In addition,we also study the catalytic mechanism,and explore the relationship between the structure of the catalyst with the catalytic activity and the selectivity.The main research work is as follows:?1?A bifunctional squaramide-catalyzed Michael/Michael cascade reaction for the construction of spirotetrahydrofuran bispirooxindoles was developed.The products were obtained in moderate to excellent yields with excellent diastereo-and enantioselectivities?up to>20:1 dr,>99%ee?.This straightforward process serves as a powerful method for the enantioselective construction of potential bioactive bispirooxindoles with two of four contiguous chiral centers are spiro all-carbon quaternary centers on a single tetrahydrofuran ring.Meanwhile,the synthetic practicality of this methodology was also illustrated by performing raction in a gram-scale with the same efficiency and stereoselectivity.?2?A bifunctional squaramide-catalyzed Michael/Michael cascade reaction for the construction of five-membered spirooxindoles was developed.This reaction afforded the corresponding products with five contiguous stereocenters including one quaternary center in good to excellent yields?up to 93%?with excellent stereoselectivities?up to>99:1 dr,98%ee?.Meanwhile,the practicality of this methodology was illustrated by a gram-scale synthesis,one-pot four-component reaction and synthetic transformation of the resulting adduct.?3?A novel excellent diastereoselective and enantioselective cyclopropanation through Michael/alkylationcascadereactionbetween?E?-3-arylenechroman-4-onesor?E?-2-arylideneindan-1-ones and bromonitroalkane using chiral squaramide catalyst has been developed.This reaction constitutes a facile asymmetric synthesis of spironitrocyclopropanes with three adjacent stereogenic centers,including one quaternary center in moderate to good yields?up to 90%?,and with excellent enantioselectivities?up to>99%ee?and diastereoselectivities?up to>99:1 dr?.?4?The enantioselective cascade Michael addition reaction of dimedone and related1,3-dicarbonyl compounds with?,?-unsaturated N-acylated succinimide catalyzed by chiral squaramide catalyst was investigated.This reaction provided a new approach for the synthesis of chiral enol lactones in good yields with moderate to high enantioselectivities?up to 88%ee?through the enantioselective Michael addition followed by lactonization with removal of the succinimide auxiliary.?5?A bifunctional squaramide-catalyzed asymmetric Michael addition reaction of?-alkylidene succinimides to nitrostyrenes or a nitrodiene has been developed.This organocatalytic asymmetric reaction provides an easy access to functionalized succinimides with two contiguous stereocenters with a broad substrate scope.The desired succinimide derivatives were obtained in good to excellent yields?up to 98%?with high to excellent diastereoselectivities?up to>99:1 dr?and excellent enantioselectivities?up to 99%ee?.This protocol provides a straightforward entry to functionalized chiral succinimide derivatives from simple starting materials.?6?A bifunctional squaramide-catalyzed asymmetric cascade aza-Michael/Michael reaction between tosylaminomethyl enones or enoates with 3-ylideneoxindoles that afforded complex spiro[pyrrolidin-3,3'-oxindole]s has been developed.Single-step construction of molecules with three contiguous stereocenters including one quaternary center in excellent yields with highly diastereo-and enantioselectivity are rare and should be useful in medicinal chemistry.In addition,squaramide-catalyzed aza-Michael/Michael cascade reaction between tosylaminomethyl enones or enoates and nitroalkenes has been developed.This cascade reaction provides easy access to highly functionalized chiral pyrrolidines with a broad substrate scope,furnishing the desired products in good yields?up to 99%?with good diastereoselectivities?up to 91:9 dr?and excellent enantioselectivities?up to>99%ee?under mild conditions.?7?A bifunctional squaramide catalyzed sulfa-Michael/aldol cascade reaction between benzylidenechroman-4-ones and 1,4-dithiane-2,5-diol with a low catalyst loading has been developed.This reaction constitutes a facile asymmetric synthesis of chiral spirocyclic tetrahydrothiophene chromanone derivatives with three contiguous stereocenters in high to excellent yields?up to 99%?and with high enantioselectivities?up to 92%ee?.Additionally,a remarkable temperature effect on reaction efficiency was observed and a gram-scale synthesis proceeded smoothly with the same efficiency as smaller scale reactions.?8?An efficient asymmetric sulfa-Michael/aldol cascade reaction catalyzed by a chiral squaramide catalyst has been developed.This organocatalytic cascade reaction provides easy access to highly functionalized spirothiochromans with three contiguous stereocenters,including one quaternary center in excellent yields?up to 99%?with excellent diastereoselectivities?up to>99:1 dr?and enantioselectivities?up to 98%ee?.?9?A novel highly enantioselective one-pot dithiolation through sulfa-Michael addition/thioesterification of thiols with?,?-unsaturated N-acylated succinimides catalyzed by squaramide has been developed.This organocatalyzed reaction proceeded well in high to excellent yields?up to>99%?to afford useful bioactive?-sulfurated thioester derivatives with high enantioselectivities?up to 96%ee?.?10?A bifunctional squaramide catalyzed enantioselective conjugate Michael addition reaction of various?-mercaptoketones to?,?-unsaturated N-acylated oxazolidinones under mild reaction conditions has been developed.This catalytic reaction afforded the corresponding adducts in good yields with high enantioselectivities?up to 92%ee?.This is the first example of organocatalyzed sulfa-Michaeladditionusingvarious?-mercaptoketones as the Michael donors.?11?Anovelbifunctionalsquaramide-catalyzedone-potelectrophilic trifluoromethylthiolation–sulfa-Michael/aldol cascade reaction for the construction of CF₃S-containing spiro cyclopentanone-thiochromanes was developed.The straightforward process serves as a powerful tool for the enantioselective construction of potential bioactive spiro cyclopentanone-thiochromanes with one quaternary stereocenters containing a CF₃S group and three contiguous stereocenters including one spiro all-carbon quaternary center in moderate to good yields with excellent stereoselectivities?up to 15:1 dr,>99%ee?.A mechanism of this reaction was proposed and synthetic transformations of the resulting products were also be achieved.