Design And Synthesis Of Novel Sugar Amino Acids

Sugar amino acids(SAAs) are carbohydrate derivatives bearing both amino and carboxylic acid functional groups. SAAs represent an important class of multifunctional building blocks amenable to serve as glycomimetics or peptidomimetics with well-defined structures and useful properties. Because SAAs exist in nature in many forms with various biological activities, recently, many unnatural SAAs, as the demand for finding new molecules to discover new drugs and new materials, have been designed and synthesized by a number of research groups.In this paper, we have developed a convenient method for the synthesis of novel SAAs 12 a and 12 b for the first time. The structure of 12 a was similar to the natural SAA glucosaminuronic acid which was a component of many typical bacterial cell walls and could be used for the preparation of type D flu vaccine, while 12 b was similar to the natural SAA galactosaminuronic acid which was one of bacterial Vi-antigen components of Escherichia coli. Firstly, started from unexpensive and commercially available D-glucose and D-galactose, 3,4,6-tri-O-benzyl-D-glycals(3a and 3b) were achieved in 3 steps. Then, C-2-malonyl carbohydrates(5a and 5b) were synthesized by radical addition reaction and successive decarboxylation. After that, through 7 steps including debenzylation, iodination reaction, azide reaction, benzylation, reductive amination reaction, acetylation of amine and debenzylation, two novel SAAs 12 a and 12 b were achieved in the linear 12 steps with 16% yield and 8% yield, respectively. Secondly, in order to improve the reaction yield and reduce the reaction routes, we optimized the synthesis of 12 a and 12 b. Started from D-glucose and D- galactose, 3,4,6-tri-O-acetyl-D-glycals(2a and 2b) were achieved in 2 steps. Then C-2-malonyl carbohydrates(14a and 14b) were synthesized by CAN-mediated radical addition reaction and successive decarboxylation. Finally, through 4 steps including deacetylation, iodination reaction, azide reaction and one-pot reductive amination reaction, 12 a and 12 b were gained in the shortest linear 8 steps with 20% yield and 13% yield, respectively. Obviously, we successfully optimized the synthetic route with shorter steps and higher yields. Thirdly, the SAAs building blocks used for developing new biological peptidomimetics were obtained by selective orthogonally protecting amino and carboxylic acid functional groups of the two novel SAAs. Eventually, the dimer and tetramer linear oligo-(sugar amino acids) were synthesized in solution using peptide coupling methods. All the new compounds were characterized by IR, 1H NMR, 13 C NMR and HRMS data.