Organocatalytic Synthesis Of Chiral Spirooxindoles And Acyclic Purine Bases

Two projects were investigated in my dissertation. The first part was on asymmetric organocatalytic construction of chiral3,3’-spirocyclic oxindoles, and the second part was about organocatalytic enantioselective aza-Michael addition of purine bases to α, β-unsaturated ketones.Nowadays enantioselective organocatalysis has been worldwidely recognized as the third pillar of asymmetric synthesis together with metal complexes-and enzyme-mediated catalysis. This new branch of organic synthesis, which employs small metal-free organic compounds as catalysts, experienced a fast-growing period when numerous of novel organocatalysts and tandem, cascade or multicomponent reactions have been studied giving to the chemical community new tools for the generation of different natural alkaloids and pharmaceuticals with structure complexity.In the current work,3,2’-pyrrolidinyl bispirooxindole derivatives containing three stereocenters including two spiro quaternary centers were synthesized in a high-yielding, atypically rapid and stereocontrolled cascade Michael/Cyclization reaction sequence. Under mild reaction condition, all the reactions catalysed by multi-functional cinchona alkaloids finished within less than1min, providing bispirooxindoles containing three contiguous chiral centers, including two spiro quaternary stereocenters in almost quantitative yields and excellent stereocontrols (90-99%yield,8:1->20:1d.r.,81-99%ee). Significantly, catalyst reconfiguration offered access to the opposite enantiomer. The power of this straightforward process is highlighted by its extremely high efficiency in synthesizing the bispirooxindole skeletons in such a short time in one single operation, even in the experiment on a gram scale. We believe that these novel compounds based on bispirocyclic oxindole skeletons prepared here will provide novel therapeutic agents and useful biological tools.Next, we have developed an efficient organocatalytic one-pot domino Michael/intramolecular Povarov reaction to provide the enantiomerically enriched spirooctahydroacridine-3,3’-oxindole derivatives containing five stereogenic centers in good to high yields with excellent diastereo and enantioselectivities (30-89%yield,5:1->20:1d.r.,84-99%ee). Under optimal conditions, this protocol displays a great tolerance towards a variety of different substrates. This strategy not only adds to the limited repertory of examples of asymmetric synthesis of chiral spirocyclohexaneoxindoles and octahydroacridines, but also demonstrates a one-pot consecutive synthesis with an ecological and economical protocol. This one-pot tactics and the benign reaction media at ambient temperature further manifest the merit of this strategy. We believe that these novel compounds based on spirooctahydroacridine-3,3’-oxindole skeletons prepared here might possess some biological activities.During our continuous studies on the asymmetric organocatalytic synthesis of chiral spirooxindole derivatives, we have developed a highly efficient organocatalytic cascade iminium-enamine strategy for the direct construction of the biologically important spirocyclopentaneoxindole derivatives in excellent stereoselectivities (48-86%yield,78:22-99:1d.r.,95->99%ee). Remarkably, the power of the straightforward process is fueled by its high efficiency of the production of two new C-C bonds, four consecutive stereogenic centers, including a spiro quaternary center in one single operation, which otherwise is difficult to achieve by traditional strategies.The unprecedented asymmetric organocatalytic aza-Michael addition of purine bases to α, β-unsaturated ketones has been developed, affording Michael adducts in moderate to high yields and high to excellent enantioselectivities (46-96%yield,80->99%ee). A wide range of α,β-unsaturated enones ranging from aliphatic to aromatic enones were both tolerated to this process, generally demonstrating good reactivity, regioselectivity and enantioselectivity. The aromatic α, β-unsaturated ketones including aromatic P-substituted enones were first successfully employed as Michael acceptors in this aza-Michael process. This methodology offers several advantages, such as mild reaction condition, no need to use toxic and expensive organometallic complexes and easily accessible catalyst system. Meanwhile, this first successful protocol for highly enantioselective synthesis of chiral acyclonucleosides analogues from achiral α, β-unsaturated ketones provides a new access to optical active non-natural nucleosides.