Catalytic Asymmetric1,3-Dipolar Cycloaddition For The Synthesis Of Nitrogenous Heterocycles

Azomethine ylides are important intermediates for the construction of nitrogenous heterocycles, over the past decade, they have been widely used to synthesize a variety of multi-substituted chiral pyrrolidine derivatives via catalytic asymmetric1,3-dipolar cycloaddition, on which our group also has done thorough research. To further expand the application of azomethine ylides in the synthesis of more kinds of nitrogenous heterocycles, several efficient organometallic catalysts were explored and applied in the following research:1The first Cu(I)-catalyzed asymmetric1,3-dipolar cycloaddition of azomethine ylides with (E)-or (Z)-ethyl4,4,4-trifluorobut-2-enoate has been developed providing various endo-or exo-trifluoromethylated pyrrolidines in excellent diastereo-/enantioselectivity (96:4->98:2dr,88-99%ee). The cycloadduct obtained from (Z)-ethyl4,4,4-trifluorobut-2-enoate can be epimerized into the corresponding thermodynamically favored isomer under basic condition due to the reversal of4-ester group. In addition, further research on the construction of new exo spiro-pyrrolidines via exo-selective asymmetric1,3-dipolar cycloaddition reaction has been made.2. Various optically active fluorinated imidazolidines have been successfully synthesized via Cu(?)/(S,Rp)-PPFOMe-catalyzed enantioselective1,3-dipolar cycloaddition of azomethine ylides with fluorinated imines. Broad substrate scope, high reactivity and good diastereo-and enatioselectivity (10:1->20:1dr,89-98%ee) were achieved. A stepwise Mannich-cyclization protocol was proposed according to preliminary mechanism studies.3. We have developed the first asymmetric1,3-dipolar [3+2n] cycloaddition of azomethine ylides with cycloheptatrienes catalyzed by CuBF4/TF-BiphamPhos complex. Various medium-sized bridged nitrogenous heterocycles bearing piperidine moiety were obtained in good yields (up to88%yield) with exclusive regioselectivities (>20:1rr) and excellent stereoselectivities (>20:1dr, up to98%ee). Additionally, we found that the electron-withdrawing group determined the annulation type according to the research on the reaction type of2-ester substituted cycloheptatriene in the catalytic system. Therefore, a plausible stepwise Michael-cyclization mechanism was proposed.