THE SYNTHESIS OF BETA-KETO LACTONES VIA CYCLIZATION OF BETA-KETO ESTER DIANIONS OR THE CYCLIZATION OF MELDRUM ACID-DERIVATIVES

Two new methods to synthesize macrocyclic beta-keto lactones have been developed. The first involves the synthesis of omega-halo-beta-keto esters and an intramolecular alkylation of the dianions to these compounds. The reaction is complicated by elimination in the small and medium ring systems and by difficulties in purifying the final products. However, it is possible to obtain modest yields of the desired beta-keto lactones. This procedure was used to synthesize the 25- and 27-membered ring beta-hydroxy lactones that are the constituents of termite defense compounds. The second method involves the thermolysis of acylated Meldrum's acid derivatives, which leads directly to beta-keto lactones. This process gives modest yields of macrocyclic systems and good yield of the unsubstituted 3-oxopentan-5-olide (25). The 14-membered [GRAPHICS] macrocyclic beta-keto lactone 9j has a complex H-1 NMR spectrum, which has been interpreted in terms of multiple conformations. The temperature dependence of the NMR spectrum of 9j is consistent with entropic, rather than enthalpic, control of the equilibrium. Quasiharmonic entropy calculations are consistent with this model.