Total synthesis, revised structure, and biological evaluation of biyouyanagin A and analogues thereof.
Isolated from Hypericum species H. chinese L. var. salicifolium, biyouyanagin A was assigned structure 1a or 1b on the basis of NMR spectroscopic analysis. This novel natural product exhibited significant anti-HIV properties and inhibition of lipopolysaccharide-induced cytokine production. Described herein are the total syntheses of biyouyanagin A and several analogues (3-11), structural revision of biyouyanagin A to 2b, and the biological properties of all synthesized compounds. The total synthesis proceeded through cascade sequences that efficiently produced enantiomerically pure key building blocks 15b (ent-zingiberene) and 18 (hyperolactone C) and featured a novel [2 + 2] photoinduced cycloaddition reaction which occurred with complete regio- and stereoselectivity. Biological investigations with the synthesized biyouyangagins A (2-11) and hyperolactones C (12-16) revealed that the activity of biyouyanagin A most likely resides in its hyperolactone C structural domain.
Nicolaou
K C
KC
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. kcn@scripps.edu
Wu
T Robert
TR
Sarlah
David
D
Shaw
David M
DM
Rowcliffe
Eric
E
Burton
Dennis R
DR
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006678:HIV / Q000187:drug effects; D006801:Humans; D020902:Hypericum / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D012680:Sensitivity and Specificity; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013141:Spiro Compounds; D013237:Stereoisomerism
D019380:Anti-HIV Agents; D016207:Cytokines; D005663:Furans; D008070:Lipopolysaccharides; D012717:Sesquiterpenes; D013141:Spiro Compounds; C509583:biyouyanagin A; C488315:hyperolactone C