Ad en ovo solid-phase synthesis of the cyclic lipodepsipeptide daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of at hreonine residue with ap rotected tryptophan. Subsequent late-stage on-resin ozonolysis, inspired by the biomimetic pathway,a fforded the kynurenine residue directly.S ynthetic daptomycin possessed potent antimicrobiala c-tivity (MIC 100 = 1.0 mgmL À1 )a gainst S. aureus,w hile five other daptomycin analogues containing (2R,3R)-3-methylglutamic acid, (2S,4S)-4-methylglutamic acid or canonical glutamic acid at position twelve prepared using this new methodology were all inactive, clearly establishing that the (2S,3R)-3methylglutamic acid plays ak ey role in the antimicrobial activity of daptomycin.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.

Tikitericin, a novel lanthipeptide was isolated and characterised together with its first total synthesis.

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