Abstract
A novel approach is reported for the enantioselective flow synthesis of rolipram comprising a telescoped asymmetric conjugate addition–oxidative aldehyde esterification sequence followed by trichlorosilane-mediated nitro group reduction and concomitant lactamization. The telescoped process takes advantage of a polystyrene-supported chiral organocatalyst along with in situ-generated persulfuric acid as a robust and scalable oxidant for direct aldehyde esterification. This approach demonstrates significantly improved productivity compared with earlier methodologies while ensuring environmentally benign metal-free conditions.
Highlights
Due to their varied biological activities as well as structural diversity, chirally branched pyrrolidones are of outstanding importance among pharmaceutically relevant heterocycles.[1]
The best characterized biological activity of rolipram is the selective inhibition of the cyclic adenosine monophosphate-specific phosphodiesterase family known as Type IV (PDE4).[3]
Enantioselective synthetic approaches have been suggested to facilitate a more direct and atom economic access to the enantiopure substance. These typically harness chiral-coordination-complex-catalyzed asymmetric hydrogenations or conjugate additions to introduce asymmetry,[10] but metal-free organocatalysis has proven useful in the enantioselective synthesis of rolipram.[11]
Summary
Due to their varied biological activities as well as structural diversity, chirally branched pyrrolidones are of outstanding importance among pharmaceutically relevant heterocycles.[1].
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