Asymmetric Synthesis Of Drug-Like Skeletal Pyrano-fused Heterocycles And Their Fluorine-Containing Derivatives

Pyran-fused heterocycle widely exist in natural products,pharmaceuticals and bioactive compounds.Therefore,not surprisingly,their catalytic asymmetric synthesis has long-been a hot research topic in organic synthesis.On the other hand,due to the special physical,chemical and biological properties of fluorine atom,the selective introduction of fluorine atoms into organic compounds can often improve their metabolic stability or to enhance their biological activity.As a result,it is one of the great significance to develop highly efficient and stereoselective catalytic protocols for the construction of pyran-fused heterocycles and their fluorine-containing chiral derivatives.This thesis mainly focused on the asymmetric synthesis of four kinds of heterocyclic molecules,namely:pyran-fused-pyrrole,pyran-fusedthiazole and their fluorine-containing chiral derivatives,these research works expanded the application range of bifunctional tertiary amine-hydrogen bond catalysis.1.We have developed a highly stereoselective[4+2]cyclization reaction of dioxopyrrolidines and azlactones by using tertiary amine-squaramide catalysis.A wide range of dioxopyrrolidines and azlactones were well tolerated to give the corresponding multiply substituted pyrano[2,3-c]pyrrole containing adjacent tertiary and quaternary stereogenic centers in high yields(up to 99%)with excellent diastereo-and enantio-selectivities(up to 99%ee,all cases>20:1 dr).2.We have developed an enantioselective inverse-electron-demand Diels-Alder reaction of β,γ-unsaturated amides and 5-alkenyl thiazolones by using bifunctional quinine-derived tertiary amine-thiourea catalysis.A series of pyrano[2,3-d]thiazol containing three contiguous chiral centers were formed with moderate to excellent yields(46-99%),moderate diastereoselectivities(78:22->20:1dr)and good enantioselectivities(86 to>99%ee).3.We have developed a highly stereoselective[4+2]cyclization reaction of 2-fluoro-3oxobutanoate and dioxopyrrolidines by utilizing tertiary amine-thiourea catalysis.The corresponding pyrano[2,3-c]pyrrole derivatives with a fluorine-containing quaternary carbon were obtained in good yields with excellent diastereoselectivity and enantioselectivity(up to 99%yield,up to 99%ee and>20:1 dr).4.We have demonstrated a highly efficient[4+2]cyclization reaction of 2-fluoro-3oxobutanoate and 5-alkenyl thiazolones by employing tertiary amine-thiourea catalysis.The desired pyrano[2,3-d]thiazol products with a fluorine-containing quaternary carbon were afforded in excellent yields(up to 99%)with good stereoselectivities(up to 99%ee,up to>20:1 dr).