開催日: 2017/09/20 - 2017/09/22
The anti-tumor tetrahydroisoquinoline (THIQ) alkaloids, represented by saframycin A (1), jorunnamycin A (2), renieramycin M (3) and ecteinascidin 743 (4), share a common pentacyclic scaffold that is biosynthesized by non-ribosomal peptide synthetases (NRPS). We previously revealed unique biosynthetic conversions catalyzed by SfmC, a module of NRPS, to forge the pentacyclic scaffold. Two molecules of tyrosine derivative and a peptidyl aldehyde bearing a cryptic fatty acyl chain are assembled by SfmC via iterative Pictet-Spengler reactions followed by reduction of thioesters to liberate aldehyde intermediates. Herein we report the chemo-enzymatic total synthesis of 2 by merging precise chemical synthesis with in vitro engineered biotransformation. By optimizing designer substrates compatible with SfmC through chemical synthesis, we succeeded in efficient assembly of the appropriately functionalized pentacyclic skeleton by streamlining the linkage between SfmC-catalyzed multi-step enzymatic conversions and chemical manipulations of the intermediates to install amino nitrile and N-methyl groups. This approach allowed very rapid access to the elaborated pentacyclic skeleton in a single day starting from two simple synthetic substrates (7, 15) without isolation of the intermediates. Further functional group manipulations involving hydrolysis and oxidation allowed operationally simple and expeditious synthesis of jorunnamycin A (2) that could be a versatile and common precursor for the artificial production of other anti-tumor THIQ alkaloids and their variants.