Regioselective Annulation of 1,5-Diketones: Access to Functionalized Hagemann’s Esters

Abstract

The synthesis of the “functionalized” Hagemann’s ester (S)-18 was investigated. The common starting material in these approaches was enamino ester (S,Z)-5, which was prepared through the condensation of keto diester 4 with (S)-1-phenylethylamine. The Michael addition reaction of 5 with methyl vinyl ketone gave the expected adduct (S)-6 with an ee ⩾ 95%. However, all attempts at annulation of 6 invariably afforded the unwanted cyclohexenone derivatives 7 or 8. The addition of 5 to Nazarov reagent 9 furnished adduct (S)-10 with an ee ⩾ 95%. The Triton B-induced annulation of 10 unexpectedly gave aldol 11. Depending on the reaction conditions, annulation of 11 afforded either the bicyclic lactone 12, or cyclohexenones 13 or 15. An efficient way of reversing the sense of the regiochemistry of the previous annulation was found, based on the use of diethyl 2-oxo-3-vinylphosphonate (16) as a Michael acceptor. Thus, the condensation of 5 with 16 gave (S)-17 with an ee ⩾ 95%, and cyclization of (S)-17 under Horner−Wadsworth−Emmons conditions gave the desired Hagemann’s ester (S)-18. The structural assignments for 18 were ascertained by chemical correlation with the known hydrindenedione (S)-21.