Energy- and carbon-efficient synthesis of functionalized small molecules in bacteria using non-decarboxylative Claisen condensation reactions

Anabolic metabolism can produce an array of small molecules, but yields and productivities are low owing to carbon and energy inefficiencies and slow kinetics(1,2). Catabolic and fermentative pathways, on the other hand, are carbon and energy efficient but support only a limited product range(3,4). We used carbon and energy-efficient non-decarboxylative Claisen condensation reactions and subsequent beta-reduction reactions, which can accept a variety of functionalized primers and functionalized extender units and operate in an iterative manner, to synthesize functionalized small molecules. Using different omega- and omega-1-functionalized primers and alpha-functionalized extender units in combination with various termination pathways, we demonstrate the synthesis of 18 products from 10 classes, including omega-phenylalkanoic, alpha,omega-dicarboxylic, omega-hydroxy, omega-1-oxo, omega-1-methyl, 2-methyl, 2-methyl-2-enolic and 2,3-dihydroxy acids, beta-hydroxy-omega-lactones, and omega-1-methyl alcohols.