Asymmetric Total Synthesis of (+)-Negamycin and (-)-3-Epinegamycin via Enantioselective 1,3-Dipolar Cycloaddition

Article abstract of DOI:10.1021/jo00270a037

Enantioselective total synthesis of (+)-negamycin <(+)-1> and (-)-3-epinegamycin <(-)-2> has been achieved by the introduction of asymmetry through 1,3-dipolar cycloaddition with chiral nitrones modified with carbohydrates.For the model study, the trans-isoxazolidine-3-carboxylate (+/-)-6a, obtained by 1,3-dipolar cycloaddition of the nitrone 4 with N-(benzyloxycarbonyl)allylamine (5), was converted into the hydrazide (+/-)-13 via six steps, catalytic hydrogenation of which resulted in deprotection and N-O bond cleavage at the same time, affording (+/-)-negamycin <(+/-)-1>.This sequence was next applied to the synthesis of (+)-negamycin.Thus the enantioselective 1,3-dipolar cycloaddition of nitrones modified with carbohydrates, such as D- and L-gulose, D-ribose, and D-mannose derivatives, with 5 was investigated.Among these nitrones the gulosyl series proved to produce the best results.The trans adduct D-19a with 94percent ee thus obtained by using N-D-gulosylnitrone D-18 was converted into (+)-negamycin <(+)-1> by hydrolytic removal of the chiral auxiliary followed by a similar sequence for the synthesis of (+/-)-1.Similarly, the cis adduct D-19b with 94percent ee obtained by cycloaddition with the D-gulosylnitrone D-18 was transformed into (-)-3-epinegamycin <(-)-2>.With synthetic (+)-1 and (-)-2 in hand, antibacterial activity was examined.