P-57 Total Syntheses and Stereochemical Assignments of Neoantimycin-class Antibiotics

JBIR-04 (1) was isolated from Streptomyces violaceoniger 4541-SVS3 by Shinya and co-workers in 2007. It showed inhibitory activity against the GRP78 expression induced by the stimulation of 2-deoxyglucose in HT1080 cells. Analyses of spectroscopic data revealed that the planar structure of 1 is a 15-membered tetralactone of neoantimycin-class antibiotics. The recent discovery of prunustatin A as a selective GRP78 molecular chaperone down-regulator highlights the potential of this family as research probes. This discovery may lead to the development of new approaches for fighting cancer. Nevertheless, the absolute stereostructure of 1 has not been determined yet. In 2016, Hale reported spectroscopic comparisons between JBIR-04 natural and its synthetic compound with a 2R configuration, which is the same as that observed for prunustatin A and SW-163A, another member of the neoantimycin family. Significant differences were observed between the chemical shifts and coupling constants of H2 and H12, which confirms that the absolute stereochemistry of JBIR-04 is different than that of prunustatin A, i.e., it has a 2S configuration. Herein, we report our studies on the synthesis and stereochemical elucidation of JBIR-04 (1) and two neoantimycin-class antibiotics, namely unantimycin A (2) and JBIR-05 (3). Our synthetic strategy involves using intramolecular transesterification for the construction of a 15-membered tetralactone core, followed by the introduction of a gem-dimethyl group. Cyclization precursor 4 was derived from L-phenylalanine, L-isoleucine, L-threonine, and L-lactic acid. The key 15-membered tetralactone 6 was successfully obtained in moderate yield. Finally, amidation of 26 with benzoic acid and 3-hydroxylbenzoic acid afforded JBIR-04 (1) and unantimucin A (2), respectively. Synthetic 1 and 2 and the natural samples of 1 and 2 were identical in all aspects. However, compound 29, which was derived from D-phenylalanine, was not identical to the natural sample of 3. Further studies are now being pursued to elucidate the absolute stereostructure of JBIR-05 (3) and will be reported together.