Total Synthesis of Abyssomicin C, Atrop-abyssomicin C, and Abyssomicin D: Implications for Natural Origins of Atrop-abyssomicin C

In this article, the total syntheses of the antibiotic abyssomicin C (1) and its biologically inactive
sibling abyssomicin D (3) are described. A number of unforseen 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 (57), which in the presence of a 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 serves as a direct precursor of
abyssomicin D. Finally, to gain insight into the mechanism of antiobiotic activity, several synthetic
intermediates and designed analogues were evaluated for biological activity.