Catalytic hydrolysis, intramolecular cleavage

When the last condensation reaction has occurred, the linear precursor needs to be released from the enzyme. For this important last step, several mechanisms are known simple hydrolysis of the thioester (balhimycin, vancomycin), intramolecular cyclization leading to a lactam (tyrocidine, bacitracin) or a lactone (surfactin), or even reductive thioester cleavage (linear gramicidin). In some cases, the linear precursor is dimerized (gramicidin S) or even trimerized (bacillibactin, enterobactin) before cyclization (Fig. 2). Even though these reactions are critical for the compound s bioactivity, the catalytic domains responsible for the release are not found in all NRPS systems and will therefore be called modifying domains. 

First, cyclohexanone is alkylated by 32 giving rise to the masked triketone 33. On catalytic hydrogenation of 33, the isoxazole ring is reductively opened to give the enaminone 34, which cyclizes in situ to the enamine 35. On treatment with aqueous NaOH, 34 is converted to the 1,5-dione 36 (by enamine hydrolysis and acid cleavage of the 1,3-dicarbonyl system of the triketone intermediate), which undergoes base-induced intramolecular aldol condensation to the bicycloenone 37 (in analogy to a Robinson annulation) [317] ... 

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