Biomimetic decarboxylative condensation between malonate and acetate units attached to a glycoluril template

Compound 10 (3,4,7,8-tetramethyl-2,5-dithioglycoluril) was converted in two steps to 12a, which contains a malonate and acetate unit attached to N1 and N6, respectively. These two groups are held in proximity in a manner analogous to the loaded ketosynthase domain of polyketide and fatty acid synthases. After cleavage of the methyl ester by pig liver esterase (PLE), a polar intermediate assigned to acid 15 was separated. This material undergoes conversion to acetoacetylglycoluril 18 upon attempted isolation. The overall conversion thus resembles the decarboxylative condensation catalyzed by ketosynthase. Furthermore, isotope labeling and product studies support a mechanism in which decarboxylation of 15 precedes an intramolecular Claisen-like condensation, as it is believed to occur for the ketosynthase enzymic case. The system thus provides a functional chemical model of the key carbon-carbon bond-forming step in fatty acid and polyketide biosynthesis.