Efficient Total Synthesis of Dipeptidic Antibiotics (+)-Negamycin and Its Derivatives

摘要

(+)-Negamycin 1 [1], a dipeptidic antibiotic containing a hydrazine peptide bond is recently thought to be a potential therapeutic agent for genetic diseases such as Duchenne muscular dystrophy (DMD) with a nonsense mutation in the dystrophin gene [2]. Negamycin has attracted a great deal of synthetic interest. Several syntheses of negamycin in both racemic and optically active forms have been accomplished over three decades after its discovery. However, an efficient shortened synthetic route of (+)-l and its derivatives appears significant to develop promising new therapeutic candidates for DMD and other diseases caused by nonsense mutations. In the previous study, we developed a new synthetic route to obtain (+)-l from (R)ethyl-4-chloro-3-hydroxybutanoate in 26% overall yield over 13 steps [3]. Here, we report another attractive synthetic route for (+)-l from commercially available achiral Boc-glycinal 2 using modern organic chemistry techniques, including asymmetric allylboration, microwave-assisted ruthenium catalyzed cross-metathesis and asymmetric Michael addition to afford (+)-l with an overall yield 41% in 8 steps [4].