Studies On The Palladium-Catalyzed Cyclization Reactions Of Functionalized Allenes

Allenes are a class of compounds with a1,2-diene functionality. Their unique reactivity is caused by the presence of the two sets of perpendicular π-orbitals and the substituent-loading capability. Efforts have already been made on the transition metal-catalyzed cyclization of functionalized allenes in our group. Based on these observations, the main theme of my dissertation is focused on palladium-catalyzed cyclization to construct macrocycles, tricycles and cyclic glucosides. This dissertation includes three parts:Part IA highly regioselective synthesis of15～20-membered macrocycles via Pd(0)-catalyzed coupling cyclization of allenes bearing a carbon or nitrogen nucleophilic functionality and organic iodides has been developed. After oxidative addition and carbopalladation, anti-n-allyl palladium intermediates were formed, which was followed by the exclusive intramolecular nucleophilic attack at the terminal carbon atom of the allene moiety to afford products with the yields ranging from44～92%and E/Z ratio up to97/3. We also made hydrogenation of those inseparable E/Z mixtures and found the solvent played an important role.Part IIWe have observed palladium-catalyzed tandem reactions of2,3-allenyl dimethyl malonate or bis(phenylsulfonyl)methane,4-methylbenzenesulfonamide, and malononitrile with yne-propargylic carbonates to afford different kinds of fused tricyclic hetero-and carbocycles. When the nucleophilic unit in allenes was dimethyl malonate or bis(phenylsulfonyl)methane, the reaction afforded fused indeno[5,6-c]furans. When the nucleophilic unit was4-methylbenzenesulfonamide, the reaction afforded fused hexahydrofuro[3,4-h]isoquinolines. When the nucleophilic unit was malononitrile, the reaction afforded fused bicyclo [2.2.2]octanes.Part III 1. We have successfully introduced two improved methods of ATA reaction developed in this group to synthesize terminal2,3-allenyl glycosides in moderate yields, which could tolerate functional groups such as ether, ester, amide and malonate unit. Allenyl β-D-glucopyranosides, β-D-galactopyranoside, thioglycosides, and disaccharides, even five allenyl β-D-glucopyranoside could be synthesized with the two methods.2. Based on the previous work on the synthesis of axially chiral allenes via EATA reaction, we observed CuBr2-mediated synthesis of axially chiral2,3-allenyl glucosides with de value up to99%for the first time. Both primary and secondary alkyl aldehydes could be introduced to this reaction. Also propargyl β-D-glucopyranosides, β-D-galactopyranoside, and thioglycosides may be applied.3. We have developed a highly regio-and stereo-selective synthesis of10-membered cyclic β-D-glucosides via Pd(0)-catalyzed coupling cyclization of allenyl β-D-glucoside and organic iodides in the yields of20～38%. We obtained cyclic β-D-glucoses with free hydroxyl groups in90～97%yields after deacetylation and tested the SGLT2inhibition activity of the11pairs of these two class of cyclic β-D-glucoses.