title: Stereodivergent approaches to the synthesis of isoxazolidine analogues of alpha-amino acid nucleosides. Total synthesis of isoxazolidinyl deoxypolyoxin C and uracil polyoxin C.
abstract: The synthesis of new nucleoside analogues is currently of high interest. We report here full details of a study leading to the synthesis of novel isoxazolidinyl analogues of alpha-amino acid nucleosides. Three different synthetic approaches starting from L-serine have been evaluated for the construction of the isoxazolidine ring. These approaches consisted of Michael addition of N-benzylhydroxylamine to alpha,beta-unsaturated esters, nucleophilic addition of silyl ketene acetals to nitrones and 1, 3-dipolar cycloaddition of nitrones with vinyl acetate. Both Michael addition and nucleophilic addition of enolates could be carried out with stereocontrol at the newly formed stereogenic carbon. The stereocontrol observed in these reactions arises from the protecting group arrangement in the L-serine-derived substrates. Thus, whereas compounds having a diprotected nitrogen led to syn adducts, compounds having a monoprotected nitrogen gave rise to anti adducts. On the other hand, substrates having either a diprotected or monoprotected nitrogen atom led to anti adducts through the cycloaddition route. So, by choosing the appropriate route, isoxazolidinyl analogues having either syn or anti configuration with respect to the glycine unit can be prepared in enantiomerically pure form. The stereoselective synthesis of isoxazolidinyl analogues of deoxypolyoxin C and uracil polyoxin C in both D and L enantiomeric forms using these techniques has been achieved in good yields.
authors.affiliation: Departamento de Quimica Organica, ICMA, Facultad de Ciencias, Universidad de Zaragoza, E-50009 Zaragoza, Aragon, Spain. pmerino@posta.unizar.es
authors.forename: P
authors.initials: P
authors.lastname: Merino
authors.forename: S
authors.initials: S
authors.lastname: Franco
authors.forename: F L
authors.initials: FL
authors.lastname: Merchan
authors.forename: T
authors.initials: T
authors.lastname: Tejero
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis*; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000935:Antifungal Agents; D010080:Oxazoles; D011741:Pyrimidine Nucleosides; C414025:isoxazolidinyl deoxypolyoxin C; C414026:uracil polyoxin C; D014498:Uracil