Total synthesis and biological investigation of promysalin and analogues

Myristic acid serves as biosynthetic precursor of a plethora of secondary metabolites. These metabolites demonstrate a wide range of antibacterial and antivirulence activity ranging from the inhibition of biofouling and biofilm formation to the disruption of quorum sensing mechanism.1 The metabolites are active against both gram positive and negative bacteria. The rapid rise of antibiotic resistant superbugs justifies the need for identifying new compounds targeting specific pathogenic bacteria. In 2011 Wen Li and coworkers isolated the myristamide metabolite promysalin from rhizosphere of rice root associated Pseudomonas putida RW10S1.2 The natural product exhibits a submicromolar activity against Pseudomonas aeruginosa (PA) and some other gram negative bacteria. The compound also promotes swarming of the producer and its surface colonization. The most recent studies have demonstrated that promysalin disperses established biofilms and inhibits pyoverdine production. The unusual bioactivity, unknown mode of action and structural uniqueness increased the interest for the compound. Here in us report a convergent total synthesis of promysalin.3 The synthetic approach is based around a salicyldehydroproline core and a dihydroxymyristamide fragment. The key steps include a MacMillan asymmetric α-hydroxylation4 applied for the construction of the myristamide framework and one pot reduction of lactam with Superhydride and base mediated concomitant elimination of lactamol to obtain the dehydroproline fragment.5 The synthetic route can be easily adapted for the rapid generation of analogues.