Asymmetric Catalytic Carbon-carbon Bond-forming Reactions For The Constrution Of Alkaloid Skeletons

Chiral cyclic molecules, especially those nitrogen-containing skeletons, are core structural element commonly present in numerous nature products and biologically active molecules, as well as important buiding blocks in organic synthesis. In this dissertation, we have developed several enantioselective catalytic methods as a broadly applicable to access key chiral building blocks, and have accomplished the first enantioselective total synthesis of (+)-Folicanthine.Optically active2,3-dihydropyrroles are important unsaturated heterocyclic compounds, which can not only be transformed into multisubstituted pyrrolidines for the further synthesis of chiral building blocks, but also have been applied to the total synthesis of natural products. We have disclosed the first asymmetric catalytic cycloaddition reaction of α-substituted isocyanoesters with nitroolefins by cinchona alkaloid derivatives to yield2,3-dihydropyrroles with excellent diastereo-and enantioselectivities (up to＞20/1dr,＞99%ee). Cinchona alkaloids bearing a C6’-hydroxy, which can serve as bifunctional organocatalysts, showed much higher stereoselectivity than their parent molecules. The applications of this asymmetric cycloaddition in the synthesis of structurally diverse pyrrolidines have been demonstrated by diastereoselective reduction and Michael addition with phenylethynyl lithium.Five-membered nitrogenous heterocycles, in particular, pyrrolidines and spirooxindoles, are key structural motifs prevalent in numerous biologically significant molecules and natural alkaloids. We have developed a highly efficient, so far unique, bio-inspired diversity-oriented synthesis of pyrrolidine derivative collection, which relies on the strategic use of phosphoric acid-catalyzed biomimetic transamination of keto esters and amines, the precursors of amino acids, to in situ generate azomethine ylides, which readily participated in the highly enantioselective1,3-dipolar cycloaddition with a structurally diverse range of dipolarophiles. As a result, highly functionalized pyrrolidines and spirooxindole derivatives were obtained with excellent enantioselectivity.C-H activation-based cross-coupling reactions have emerged as robust alternatives to conventional transformations for the creation of new C-C bonds. These reactions may be limited by the absence of binding sites in carbohydrogen compounds that enable the formation of a stereochemically defined transition state for achieving high enantioselectivity. We have disclosed a unique highly enantioselective C-H activation-based oxidative coupling reaction of3-arylmethylindoles with dibenzyl malonate by using chiral Lewis acids as catalysts. The reaction proceeded probably via a conjugate addition of the chiral Lewis acid-bonded malonate ester to the vinylogous iminium cation generated from dehydrogenation of3-arylmethylindoles with DDQ. In addition, the protocol also represents a unique sp3C-H activation-based approach to access oxindole derivatives bearing quaternary stereogenic center with high optical purity.Cyclotryptamine alkaloids constitute a large family of natural products that show fascinating biological activities. we have developed a highly enantioselective nucleophilic substitution reaction of3-hydroxyoxindoles with enecarbamates catalyzed by chiral phosphoric acids (up to96%ee), providing a new entry to3,3’-disubstituted oxindoles with creation of a quaternary all-carbon stereogenic center at the C3position. This method holds great potential in asymmetric total syntheses of hexahydropyrroloindole alkaloids. By using this protocol to prepare the key chiral building block, we accomplished the first catalytic enantioselective total synthesis of (+)-folicanthine, which was synthesized in12steps from3-hydroxyoxindole in3.7%overall yield.