1.Synthetic studies on voglibose 2.Copper-mediated cross-coupling approach for the synthesis of heteroaryl quinolones 3.Development of 7-azaindole-based PI3K-Trk dual inhibitors

Abstract

Part 1. Synthetic Studies on Voglibose Voglibose 1, one of the N-substitued valiolamine 2, exhibits potent inhibitory activity of α-glucosidase, which is enzyme for the cleavage of glycosidic bonds. As a result of its potent inhibitory activity, voglibose 1 can serve sources of orally active antidiabetic medicine. Amino unit in voglibose 1 was introduced by reduction of imine 94. For the synthesis of imine 94, ketone 84 was coupled with serine derivative 92 followed by hydrogenation. Ketone 84 which is important synthetic intermediate of voglibose 1 was obtained from selective oxidation of cyclohexenediol 81 furnished by diastereoselective dihydroxylation of cyclohexene 80. Two hydroxyl groups adjacent of chiral tertiary alcohol in voglibose 1 were introduced from each epoxidation using chiral tertiary alcohol moiety in cyclohexene 62 and diastereoselectivity arising from protection group in cyclohexene 68, respectively. Quaternary carbon center represented as a chiral tertiary alcohol in voglibose 1 was implemented by desymmetrizing monobenzoylation of easily obtained glycerol derivative 44 with high chemical yield and enantiomeric excess (ee) value. This synthetic route could allow us to synthesize of protected voglibose 96 as well as important intermediate, ketone 84. Meanwhile, formal synthesis of voglibose 1 was accomplished by completion of protected valiolamine 103 afforded by reduction of oxime 101 which is originated from ketone 84.

Part 2. Copper-Mediated Cross-Coupling Approach for the Synthesis of Heteroaryl Quinolones The family of quinolones constitutes an important class of naturally occurring compounds and privileged medicinal scaffolds. Especially, 3-heteroaryl substituted quinolones have been extensively investigated because of their promising biological activities including anti-tumor and anti-viral activities. With aim of providing a convenient access to 3-heteroaryl quinolones and related scaffolds since previous synthesis was limite...