Mutanobactin D from the Human Microbiome: Total Synthesis, Configurational Assignment, and Biological Evaluation.

Mutanobactin D is a non-ribosomal, cyclic peptide isolated from Streptococcus mutans and shows activity reducing yeast-to-hyphae transition as well as biofilm formation of the pathogenic yeast Candida albicans. We report the first total synthesis of this natural product, which relies on enantioselective, zinc-mediated 1,3-dipolar cycloaddition and a sequence of cascading reactions, providing the key lipidated γ-amino acid found in mutanobactin D. The synthesis enables configurational assignment, determination of the dominant solution-state structure, and studies to assess the stability of the lipopeptide substructure found in the natural product. The information stored in the fingerprint region of the IR spectra in combination with quantum chemical calculations proved key to distinguishing between epimers of the α-substituted ß-keto amide. Synthetic mutanobactin D drives discovery and analysis of its effect on growth of other members of the human oral consortium. Our results showcase how total synthesis is central for elucidating the complex network of interspecies communications of human colonizers.

Total Synthesis of Epicolactone.

The biologically active and structurally complex secondary metabolite epicolactone is a member of the natural product pool found in cash crop endophytes of the genus Epicoccum. By exploiting inherent reactivity, a total synthesis of this highly oxygenated and polycyclic molecule met chemo- and regioselectivity challenges. The key buildup of complexity was accomplished via an intramolecular [2+2] photocycloaddition between a quinone and an electron-deficient diene followed by a cyclobutane ring expansion. The use of a dioxene as an acyl anion equivalent and an intramolecular carbonyl methenylation furnished the natural product.