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.
Nicolaou
K C
KC
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Harrison
Scott T
ST
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
D000900:Anti-Bacterial Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C509797:abyssomicin C; C512805:abyssomicin D