Studies On Catalytic Asymmetric Inverse-Electron-Demand Oxo-hetero Diels-Alder Reaction

Chiral six-membered oxygenated heterocycles which are one of the most common structural motifs found in natural products and biologically active compounds are usually recognized as useful building blocks in organic synthesis.Therefore,it is of great significance in the fields of natural product chemistry and drug chemistry to de-velop new methods for their catalytic asymmetric synthesis in a simple,efficient and highly enantioselective manner.This dissertation mainly focuses on the catalytic asymmetric inverse-electron-demand oxo-hetero Diels-Alder reaction and its applica-tions in the constrction of chiral six-membered oxygenated heterocycles.Four parts are included in its main contents as follows:Part I:A novel class of chiral six-membered oxygenated heterocycles incorporating several privileged structures has been constructed through(1R,2R)-cyclohexane-1,2-diamine derived chiral tertiary amine-thiourea catalyzed asymmetric inverse-electron-demand oxo-hetero-Diels-Alder reaction of chromone oxadienes and 3-vinylindoles.In general,the reaction proceeded smoothly to afford the adducts with good to high yields and enantioselectivities(up to 87%total yield,94%ee for endo major products).Although the endol exo ratios of the adducts are moderate,the two diastereoselectivities could be easily separated by flash chroma-tography in most cases,which make it still desirable in practical application.Fur-thermore,the adduct could be easily transformed to chromone derived products with-out obvious loss of enantioselectivity.The absolute configuration of major endo products was unambiguously determined by single-crystal X-ray structural analysis of the derived product and relative configuration analysis of the adduct.Part ?:Based on binaphthol-derived chiral calcium phosphate catalyst,we have re-alized the construction of chiral six-membered oxygenated hetero-cycloalka-[2,3-b]indoles for the first time through the asymmetric in-verse-electron-demand oxo-hetero-Diels-Alder reaction of N-Boc-protected 2-oxoindolin-3-ylidenes and vinyl ethers.In general,the optically active dihydro-pyran-fused indoles are obtained with high yields and excellent diastereo-and enanti-oselectivities(up to 96%yield,>99/1 endolexo,>99%ee).And we have determined the absolute configuration of major endo products by single-crystal X-ray structural analysis of the product.The operational simplicity,mild reaction conditions,low catalyst loading(2.5 mol%),especially the commercialization of catalyst source,make it a possible strategy for the industrial synthesis of these chiral compounds.Part III:We have studied the catalytic asymmetric inverse-electron-demand oxo-hetero-Diels-Alder reaction of 3-formylchromones with different vinyl ethers with the aid of binaphthol-derived chiral phosphoric acid catalyst for the first time.Results show that the catalytic asymmetric inverse-electron-demand oxo-hetero-Diels-Alder reaction could proceed smoothly under the chiral phosphoric acid to give the major product as exo configuration,which is in contrast with the re-sults on non-catalytic condition,and the best ee value obtained for exo products is 80%.Relatively speaking,the reaction of different vinyl ethers with 3-formylchromone is not ideal whether on the aspect of diastereoselectivity or enanti-oselectivity.Despite of this,we have shortened the reaction time greatly and realized the asymmethic synthesis of these compounds for the first time compared with previ-ous reports.Part V:Based on the previous study of our laboratory on in situ fomed primary amine-imine catalyst,we have broadened its application in catalytic asymmetric aldol reaction.It's proved that it's the Aldol-type not the Michael-type addition products for the reaction of ?,y-unsaturated a-keto esters and different cyclic ketones under this catalytic systhem(up to 96/4 dr,96%ee).Given the importance of chiral ?-hydroxy carbonyl compounds in the synthesis of biologically active natural products,this method provides a new alternative for the synthesis of this class compounds.Unfor-tunately,the expected enantioselectivity was not observed for non-cyclic ketones in this system.