Study On Synthesis Of Chiral γ-Aminobutyric Acid Analogues With Important Physiological Activities

Manyγ-aminobutyric acid analogues containing chiral tertiary carbon have been developed as a series of important drugs for the treatment of central nervous system disorders.Therefore,the development of efficient,concise and diversified synthesis of GABA analogs containing chiral tertiary carbons can enrich the molecular library of such compounds,and it is of great significance for the discovery of new lead compound molecules with central nervous activity.Based on previous work,it is very convenient to synthesize GABA analogs containing chiral tertiary carbon by conjugated addition-enantioselective protonation ofα,β-unsaturated amide with nitromethane.In this thesis,we studied the conjugate addition activity of four different kinds of N-substitutedα-arylα,β-unsaturated amides using a chiral squaramide catalyst Cat.VII with high catalytic activity,and determined N-（2-chlorophenyl）-2-phenylacrylamide（2-1a）was the best template substrate.Based on the above,the optimal reaction conditions are determined.Further investigation of the applicability of the substrate revealed that the reaction had good universality for different substituents,and a series ofα-arylα,β-unsaturated amide substrates were submitted to one-pot prepare chiral GABA analogues containing aα-position chiral tertiary carbon with high enantioselectivity.Subsequently,the reaction was scaled up on a gram scale,and the chiral retention and transfer was studied in detail.The synthesis of chiralγ-lactam was successfully completed.Finally,the absolute configuration of the reaction product 2-1a was determined by single crystal.A possible reaction mechanism is proposed.The main conclusions of this thesis are as follows:1.The conjugated addition-enantioselective protonation reaction of organically catalyzed nitroalkanes toα,β-unsaturated amides was achieved for the first time.By optimizing the reaction conditions,we determined the optimal reaction conditions:Cat.VII（10 mol%）,V（Me NO₂）/V（o-xylene）=1:1,1 m L,0.1 M,-10℃.2.Under optimal reaction conditions,the products,chiral GABA analogues withα-position chiral tertiary carbon,were obtained in moderate to good yields（42%to 89%）,good to excellent enantioselectivities（85%to 99%）.Through the gram-scale reaction（no significant decrease in yield and enantioselectivity）,chirality retention and delivery,synthesis of chiralγ-lactam,we have successfully demonstrated the potential of our approach in the synthesis of chiral compounds with anxiolytic and antidepressive activity.