TOTAL SYNTHESIS OF (-)-EBELACTONE-A AND (-)-EBELACTONE-B-1

The beta-lactone enzyme inhibitors (-)-ebelactone A (1) and (-)-ebelac tone B (2) have been prepared in 12 steps from diethyl ketone (4 and 3 % overall yield, respectively). The synthetic strategy adopted for the ebelactones demonstrates the use of reagent- and substrate-derived st ereocontrol and requires the minimal use of protecting groups. The ste reocenters at C-2, C-3, C-8, C-10, and C-11 were constructed using bor on aldol methodology. An asymmetric syn, aldol addition of diethyl ket one to 2-ethyl/acrolein gave adduct 8 in 86% ee, followed by a diaster eoselective syn aldol reaction to give 11. Subsequently, an Ireland-Cl aisen rearrangement was used to relay 1,2-syn into 1,5-syn relative st ereochemistry, as in 12 --> 14. In the anti aldol construction of the C-2-C-3 bond, the use of either a propionate or butyrate thioester eno late allowed for a divergent approach from aldehyde 17 to both (-)-ebe lactone A and B. Several novel analogues of ebelactone A and B were al so prepared with inverted stereochemistry at C-2, C-3, or C-12.