We
report here an application of iron catalysis for the kilogram
scale asymmetric synthesis of a proton pump inhibitor, esomeprazole,
in 87% yield and 99.4% ee by catalytic sulfoxidation with hydrogen
peroxide using an iron salt/chiral Schiff base in combination with
a carboxylate salt. Under similar reaction conditions, other proton
pump inhibitors such as (S)-lansoprazole, (S)-rabeprazole, and (S)-pantoprazole, were
also synthesized in high yield and ee. A carboxylate additive was
crucial for the success of this reaction, and we consider that it
coordinates to the active iron species, and it also acts as a hydrogen-bond
acceptor to coordinate to the substrate through the imidazole NH.
A series of (+)-negamycin 1 analogues were synthesized, and their readthrough-promoting activity was evaluated for nonsense mutations in Duchenne muscular dystrophy (DMD). A structure-activity relationship study indicated that 11b was the most potent drug candidate. Immunohistochemical analyses suggested that treatment with 11b restored dystrophin expression in mdx mice, a DMD mouse model. Furthermore, 11b decreased serum creatine kinase (CK) levels, an indicator of muscle fiber destruction. Most importantly, 11b demonstrated lower toxicity than 1, and thus, it could be a useful candidate for long-term treatment of DMD.
Herein, we describe an efficient strategy for the total synthesis of (+)-negamycin using commercially available achiral N-Boc-2-aminoacetaldehyde as starting material with 42% overall yield for a limited number of steps.
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