Study One The Synthesis Of Analogous SGLT2 Inhibitors And Selective Synthesis Of Pyrrole[1,2-f] Phenanthridines Via Isocyanide-Based Multicomponent Reaction

Sodium glucose co-transporter 2 (SGLT2) inhibitors are a kind of new glucose-lowering drugs. They can reduce the renal reabsorption of glucose by increasing the clearance of renal glucose and make the extra glucose exclude through urine thus can lower blood sugar. Therefore, SGLT2 inhibitors provided a new method for the treatment of diabetes. In this paper, analogous SGLT2 inhibitors--thiazole derivatives containing glycosyl were synthesized to improve the bioactivity and poor water-solubility of triazoles.Pyrrolophenanthridine derivatives displayed high antitumor and antileukemic activity. Some of them could be used as molecular scale devices. Therefore, they play an important role in nitrogen-containing heterocycles. Isocyanides with its unique functional groups could form zwitterions with some electrophiles to construst novel protocols for the synthesis of heterocycles and carbocycles. Here, we developed the reaction of the zwitterions generated in situ from isocyanides and electrophiles with phenanthridine via 1,3-dipolar cycloaddition.Firstly, the synthesis and applications of hydrazide, thiosemicarbazide, triazoles, peracetylglucopyranosyl bromide, and SGLT2 inhibitors were reviewed in brief. Then isocyanide, isocyanide-based multicomponet reactions (IMCRs) and fused heterocyclic phenanthridine were introduced.Secondly, hydrazide compound was derived from the reaction of hydroxybenzoate with hydrazine hydrate. Thiosemicarbazide derivatives were synthesized through hydrazide and phenylisothiocyanate containing different subtituents. Thiosemicarbazide derivatives cyclized at alkaline conditions and then reacted with alkyl halide to obtain 1,2,4-triazole derivatives. Under phase transfer conditions, triazole derivatives proceeded with 2,3,4,6-tetra-O-acetyl-α- D-glucopyranosyl bromide to give the peracetylated sugar derivatives which underwent hydrolysis to give analogous SGLT2 inbitors. The synthesis of 1,2,4-triazole derivatives proceeded with the common method without using solid phase synthesis to make this reaction convenient and easy to trace. Adjusting the reactant amount could avoid the protection of hydroxyl group during the alkylation reaction. Using phase transfer catalyst could increase the reaction rate and improve the yield effectively under mild conditions. Three target compounds 1b, 2b and 3b were synthesized.Finally, Novel pyrrolophenanthridine derivatives were constructed through three-component reaction of isocyanides, 2-arylidenemalononitriles with phenanthridine as well as four-component reaction of isocyanides, malononitrile, aromatic aldehyde with phenanthridine. The reaction conditions including solvent and substituents were also investigated. Using diethyl ether as the solvent resulted in higher yields and shorter reaction time at room temperature in three-component reaction. The steric hinerance of substituents of isocyanides and different electronically substituents of arylidenemalononitriles also had some influence on the yields. All the isolated products only need washing with diethyl ether twice rather than column chromatography or recrystallization. These reactions proceeded in mild conditions and are rapid to execute without using any catalyst or activation. All the target compounds owned two chiral centers but only one corresponding stereoisomers was achieved. This indicated that this transformation provided a highly regio- and stereoselective method for the preparation of pyrrolophenanthridine derivatives. Twenty-five target compounds 4a-4k, 5a-5f, 6a-6h were synthesizedStructures of all the target compounds were confirmed by IR, ¹H NMR, ¹³C NMR, and HRMS, and the possible mechanism was also proposed. The unambiguous molecular structure of 4a, 5f and 6d were determined by X-ray diffraction analysis.