Regioselective annulation of 1,5-diketones: Access to functionalized Hagemann's esters

The synthesis of the "functionalized" Hagemann's ester (S)-18 was investiga ted. 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 greater than or equal to 9 5%. However, all attempts at annulation of 6 invariably afforded the unwant ed cyclohexenone derivatives 7 or 8. The addition of 5 to Nazarov reagent 9 furnished adduct (S)-10 with an ee greater than or equal to 95%. The Trito n B-induced annulation of 10 unexpectedly gave aldol 11. Depending on the r eaction conditions, annulation of 11 afforded either the bicyclic lactone 1 2, or cyclohexenones 13 or 15. An efficient way of reversing the sense of t he regiochemistry of the previous annulation was found, based on the use of diethyl 2-oxo-3-vinylphosphonate (16) as a Michael acceptor. Thus, the con densation of 5 with 16 gave (S)-17 with an ee greater than or equal to 95%, and cyclization of (S)-17 under Homer-Wadsworth-Emmons conditions gave the desired Hagemann's ester (S)-18. The structural assignments for 18 were as certained by chemical correlation with the known hydrindenedione (S)-21.