ABSTRACT
Using an electrochemical C(sp3)-H fluorination reaction, a series of α-fluorinated tropane compounds were synthesized and their druglikeness parameters were assessed to compare with the parent compounds. Improvements were observed in membrane permeability, P-gp liability, and inhibitory effects on hERG and Nav1.5 channels, accompanied with a trend of decreased aqueous solubility and microsomal stability. It was also revealed that α-fluorination reduced the basicity of tropane nitrogen atom for about 1000-fold.
Subject(s)
Halogenation , Solubility , Tropanes , Humans , Tropanes/chemistry , Tropanes/chemical synthesis , Tropanes/pharmacology , Structure-Activity Relationship , Ether-A-Go-Go Potassium Channels/metabolism , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Cell Membrane Permeability/drug effects , Animals , Molecular Structure , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitorsABSTRACT
A grand opening: N-Boc-N-alkylsulfamides are effective substrates for the title transformation. Oxidative cyclization is highly chemoselective as well as being both stereospecific and diastereoselective. With the advent of new protocols that facilitate ring opening of the six-membered-ring heterocyclic products, access to differentially protected 1,3-diamines has been made possible (see scheme).
Subject(s)
Diamines/chemical synthesis , Rhodium/chemistry , Carbon/chemistry , Catalysis , Diamines/chemistry , Hydrogen/chemistry , StereoisomerismABSTRACT
The total synthesis of (+)-duocarmycin A and SA through a common indoline intermediate is described. The key reactions include selective lithiation of a 2,6-dibromoiodobenzene derivative and diastereoselective addition to a chiral nitroalkene, copper-mediated aryl amination, and addition of aryllithium to azlactones.
