The synthesis of β-keto lactones via cyclization of β-keto ester dianions or the cyclization of Meldrum's acid derivatives

Abstract

Two new methods to synthesize macrocyclic β-keto lactones have been developed. The first involves the synthesis of ω-halo-β-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 β-keto lactones. This procedure was used to synthesize the 25- and 27-membered ring β-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 β-keto lactones. This process gives modest yields of macrocyclic systems and good yield of the unsubstituted 3-oxopentan-5-olide (25). The 14-mem-[Formula: see text]bered macrocyclic β-keto lactone 9j has a complex 1H 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.