[C+NC+CC] Coupling-Enabled Synthesis of Influenza Neuramidase Inhibitor A-315675

Abstract

An efficient synthesis of the neuramidase inhibitor A-315675 is reported. The fully functionalized pyrrolidine core of the target is assembled in one pot via an exo-selective asymmetric [C+NC+CC] coupling reaction.

Amino Acid and Peptide‐Based Antiviral Agents

“…Another total synthesis using Hanessian chiral aldehyde 155 was reported by Garner et al [83] . In their approach, [3+2] cycloaddition of a metallated azomethine ylide with an electronically activated dipolarophile was utilized (Scheme 25).…”

“…Sm(III)‐mediated methanolysis of compound 166 resulted in formation of thioester 167 , which was subsequently transformed into corresponding aldehyde 168 . A Wittig reaction with EtPPh 3 + Br − ylide resulted in derivative 169 , which after epimerization under the basic condition and subsequent hydrolysis gave inhibitor A‐315675 [83] …”

“… Total synthesis of A‐315675 neuraminidase inhibitor based on [3+2] cycloaddition reaction proposed by Garner et al [83] …”

Recent advances in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides

“…Very recently, Garner and co-workers have developed a procedure based on glycyl sultams as azomethine ylide precursors. 62 The sultam group activates the a-position of the Schiff base making possible the in situ generation of azomethine ylides derived from enolizable aldehydes. Using Cu I /DTBM-Segphos 4a as the catalyst, in the absence of any external base, a variety of 5-alkyl-pyrrolidines were efficiently prepared (Scheme 23).…”

Catalytic Asymmetric Exo-Selective [C+NC+CC] Reaction

“…Our interest in this problem, necessitated by our desire to synthesize several target molecules possessing pyrrolidine cores with aliphatic substituents, led to the development of the asymmetric [C+NC+CC] reaction. In this multicomponent cycloaddition reaction, an aldehyde (“C” component), chiral glycyl sultam (“NC” component), and dipolarophile (“CC” component) combine to form functionalized pyrrolidines (Scheme ). − Oppolzer’s chiral glycyl sultam serves both to control the developing absolute stereochemistry and activate the α-proton for rapid dipole formation. The latter point is of particular significance because it enables the in situ generation of azomethine ylides derived from enolizable aliphatic aldehydes, thus differentiating this method from existing azomethine ylide cycloadditions that require one to preform an unstable imine.…”