Solid-Phase Synthesis of Surfactin, a Powerful Biosurfactant Produced by Bacillus subtilis, and of Four Analogues

Using the Fmoc methodology, we report the chemical synthesis of surfactin and of four of its analogues, by stepwise solid-phase peptide synthesis (SPPS) on Sasrin resin. Formation of depsipeptide bond was performed with EDC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. In developing our strategy, surfactin was used as a model and we synthesized both its racemic mixture and its R isoform. (R) 3-hydroxy fatty acid was obtained using Candida antarctica lipase from the racemic fatty acid, allowing a further identification of both R and S isoforms in the racemic mixture. Analogues were synthesized as racemic linear lipopeptides. Then, both enantiomers were separated and purified by adsorption chromatography on silicic acid, following cleavage from the resin. Linear R lipoheptapeptides were identified by TLC. They exhibit, in all cases, higher Rf values than those of the corresponding S isoforms. Cyclization was then performed independently for each enantiomer, using a HATU/DIEA coupling in solution. The yields were highly dependent on the position and on the nature of the modified amino acids.