Convergent total synthesis of khafrefungin and its inhibitory activity of fungal sphingolipid syntheses.
A convergent total synthesis of khafrefungin, a novel inhibitor of fungal sphingolipid syntheses isolated from the fermentation culture MF6020, has been developed. Alkenylboronic acid 5 and alkenyliodide 6, key fragments for the total synthesis, were prepared from the corresponding achiral aldehydes using tin(II)-catalyzed and Zr(IV)-catalyzed asymmetric aldol reactions, respectively. The Suzuki coupling reaction of these two fragments was successfully performed to give 17 in good yield. Through the total synthesis, epimerization of the C4 position having a rather highly acidic proton did not occur, indicating that khafrefungin was under strict conformational constraints to prevent the epimerization process. This characteristic stability of khafrefungin has also been discussed using semiempirical calculation and synthesis. Finally, khafrefungin derivatives have also been synthesized, and their antifungal activities have been measured to obtain information on the structure--activity relationships.
Kobayashi
S
S
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. skobayas@mol.f.u-tokyo.ac.jp
Mori
K
K
Wakabayashi
T
T
Yasuda
S
S
Hanada
K
K
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D006017:Glycolipids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D013107:Sphingolipids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D006017:Glycolipids; D013107:Sphingolipids; C109747:khafrefungin