Michael Rasmussen

A highly diastereoselective vinylogous Mannich condensation and 1,4-conjugate addition of (Z)-propenyl cuprate in the synthesis of an influenza neuraminidase inhibitor

A practical synthesis of neuraminidase influenza inhibitor, A-322278, has been developed. Asymmetry is introduced into the synthesis by an enzyme mediated ester hydrolysis. A highly diastereoselective vinylogous Mannich condensation reaction of N-Boc-2-tert-butyldimethylsilyloxypyrrole (TBSOP) and an N-(triphenylmethylsulfenyl)imine proceeds under thermodynamic control to assemble the framework. A significant temperature dependent rate difference for the transfer of (Z)- and (E)-propenyl moieties from a cuprate reagent during a 1,4-conjugate addition was observed. A very selective addition of cyanide to an N-acyliminium intermediate was employed to control the final stereocenter.