One-Pot Synthesis of (−)-Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction

The one‐pot sequential synthesis of (−)‐oseltamivir has been achieved without evaporation or solvent exchange in 36 % yield over seven reactions. The key step was the asymmetric Michael reaction of pentan‐3‐yloxyacetaldehyde with (Z)‐N‐2‐nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O‐silyl‐substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO2H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo‐ and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E–Z isomerization of the enamines derived from pentan‐3‐yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)‐N‐2‐nitroethenylacetamide. The transition‐state model for the Michael reaction of pentan‐3‐yloxyacetaldehyde with (Z)‐N‐2‐nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan‐3‐yloxyacetaldehyde with phenylmaleimide and naphthoquinone. (−)‐Oseltamivir, a neuraminidase inhibitor, was synthesized in a one‐pot operation (see scheme). A mechanistic study of the key Michael reaction revealed that both E and Z enamines are generated, acid accelerates E–Z enamine isomerization, and reactivity depends on the geometry of both Michael acceptor and enamine.