Selective activation with three leaving groups

Based on the three-dimensional structure of CHS, we proposed that the initiation/elongation/cyclization cavity serves as a structural template that selectively stabilizes a particular folded conformation of the linear tetraketide, allowing the Claisen condensation to proceed from C6 to Cl of the reaction intermediate.14 In contrast, CTAL formation can occur either in solution or alternatively while sequestered in the enzyme active site. In either case, enolization of the C5 ketone followed by nucleophilic attack on the Cl ketone with either a hydroxyl group (in solution) or the cysteine thiolate (enzyme bound) as the leaving group results in CTAL. Similar lactones are commonly formed as by-products of in vitro reactions in other PKS systems.36 38... 

To test the generality of the Ritchie equation, we reacted the olefins 9-(dinitromethylene)fluorene (FDN), 9-(dicyanomethylene)fluorene (FDCN), and 9-(nitromethylene)fluorene (FN) with a series of nucleophiles (4, 5). The reaction of these three substrates resemble that of anion-cation combination reactions in the absence of leaving group departure at the transition state. Yet, in spite of the fact that these substrates are not positively charged, an excellent correlation was observed with the N+ scale. Similar results were observed for other uncharged substrates such as carbonyl functions (6) and activated aryl halides (7). However, the three systems, FDN, FDCN, and FN, are unique in that the slopes of log k versus N+ are significantly larger than 1. This necessitates the incorporation of a selectivity parameter (S+) into the Ritchie equation. 

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