Elimination Reactions of Esters in the Biosynthesis of Polyketides and Ribosomal Peptides

摘要

Carbon-carbon double bonds feature as characteristic structural motifs in many natural products. Nature has evolved several chemical transformations that together give rise to a wealth of functionally distinct alkenes and alkene-derived functional groups. Oxidative decarboxylation of a C-terminal cysteine residue, for example, forms the rare amino-vinylcysteine (AviCys) moiety found in several lantipepti-des. The abstraction of dihydrogen from a saturated carbon-carbon bond, which is carried out by a number of dehydrogenases, is one of the key pathways for introducing the double bonds in unsaturated fatty acids. Arguably the most widespread chemical transformation leading to the generation of a carbon-carbon double bond and the subject of this Highlight, however, is the formal elimination of water from a β-hydroxycarbonyl compound to produce an enoyl moiety. β-Elimination of water is the driving force in each of the consecutive C2 elongation cycles that characterizes fatty acid biosynthesis. In this process, malonate as its monothioester is condensed with another thioester to give a ketone, which further undergoes reduction to the corresponding β-hydroxy thioester. Deprotonation at the α-carbon atom followed by elimination of a hydroxy group then produces the carbon-carbon double bond. This is normally reduced to the single bond, thereby setting up the system for another chain elongation event. Essentially the same process is also found in polyketide biosynthesis, a pathway present in many microorganisms for the synthesis of secondary metabolites. The structural diversity of the polyketides results not only from the utilization of α-mono-substituted malonates as well as malonate, but also from the partial or complete execution of the cycle through ketoreduction of the β-carbonyl group by a ketoreductase (KR), a dehydratase (DH) mediated β-elimination, and an endoreductase (ER)-mediated hydro-genation.