Cyclic imidate salts in acyclic stereochemistry: Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides

• Published in: Tetrahedron Vol. 52; no. 9; pp. 3327 - 3338
• Main Authors: Maligres, P.E., Weissman, S.A., Upadhyay, V., Cianciosi, S.J., Reamer, R.A., Purick, R.M., Sager, J., Rossen, K., Eng, K.K., Askin, D., Volante, R.P., Reider, P.J.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 26-02-1996
• Subjects: Enamide; Epoxidation; Imidate; Indinavir; Iodohydrin; Enamide; Epoxidation; Iodohydrin; Imidate; Indinavir
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/0040-4020(95)01114-5

Reaction of 2-alkyl-4-enamides 1 with I
+ and aq. NaHCO
3 results in the diastereoselective formation of syn-iodohydrins 2, which are converted to the epoxides 3 with base. The reaction appears to proceed through a cyclic imidate type intermediate 4, followed by addition of water and ring opening.
Reaction of 2-alkyl-4-enamides with 1
+ and aqueous sodium bicarbonate results in the diastereoselective formation of the corresponding iodohydrins with essentially no iodolactone by-product. The reaction appears to proceed through a cyclic imidate type intermediate. This methodology has been successfully employed for the synthesis of the epoxide intermediate of the orally active HIV-1 protease inhibitor MK-639 (indinavir sulfate).