Total synthesis of abyssomicin C, atrop-abyssomicin C, and abyssomicin D: Implications for natural origins of atrop-abyssomicin C.

摘要

The total synthesis of the antibiotic abyssomicin C and its biologically inactive sibling abyssomicin D is described. A number of unforeseen roadblocks in our synthetic plan encouraged innovation, which culminated in the discovery of a new Lewis acid-templated Diels-Alder reaction. En route to abyssomicin C, we prepared and characterized its stable conformational isomer atrop-abyssomicin C, which in the presence of strong acid underwent an unusual interconversion with the targeted natural product. Close inspection of the X-ray crystallographic structures of these compounds led to hypotheses on the mechanism of their interconversion. Attempted reduction of both atropisomers revealed that atrop-abyssomicin C afforded abyssomicin D much more readily, suggesting that this previously unknown atropisomer may be synthesized by the host organism and serve as a direct precursor of abyssomicin D. Finally, in order to gain insight into the mechanism of antibiotic activity, several synthetic intermediates and designed analogs were evaluated for biological activity.