Application of the asymmetric [C+NC+CC] coupling reaction to synthesis
Weerasinghe, Rancothge Laksiri
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The asymmetric [C+NC+CC] coupling reaction provides stereoselective access to highly functionalized pyrrolidine rings. The hallmark of this azomethine ylide cycloaddition cascade is the ability to successfully employ enolizable and á-chiral aldehydes without undesired enamine formation or á-epimerization. So far, this powerful methodology has been successfully applied to three biologically active target molecules, cyanocycline A, A-315675 and kaitocephalin.Cyanocycline A is a unique small molecule inhibitor of cell migration which could be used to develop small moleculer anticancer drugs. The key complexity-building reaction in the synthesis of cyanocycline A uses the AgI catalyzed endo-selective [C+NC+CC] coupling reaction to provide the target's highly functionalized pyrrolidine ring. The multicomponent reaction-based strategy reduces the number of steps previously needed to assemble this complex molecule by one-third. Neuramidase inhibitor A-315675 is a novel anti-viral drug developed at Abbott Laboratories. This compound exhibits superior activity against certain influenza virus strains when compared to Oseltamivir (Tamiflu). An efficient asymmetric synthesis of A-315675 was accomplished. The fully-functionalized pyrrolidine ring was assembled via a Cu(I) catalyed exo-selective asymmetric [C+NC+CC] coupling reaction. Subsequent steps involved a Fukuyama thioester reduction and (Z)-selective Wittig olefination.Kaitocephalin is an amino acid-based natural product originally isolated from the fungus Eupenicillium shearii. This compound is the first naturally occurring glutamate receptor antagonist and displays different affinity for subtypes of ionotropic glutamic acid receptors. The highly substituted pyrrolidine ring was assembled via an endo-selective asymmetric [C+NC+CC] coupling reaction. An efficient formal total synthesis of the target molecule was completed in 13 steps starting from aspartic acid.