Total Synthesis, Revised Structure, and Biological Evaluation of Biyouyanagin A and Analogues Thereof

Abstract

Isolated from Hypericum species H. chinese L. var. salicifolium, biyouyanagin A was assigned structure 1a or 1b on the basis of NMR spectroscopic anaylsis. 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 analogs (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 or enriched 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.

Design, synthesis, and biological evaluation of a biyouyanagin compound library

“…As it turned out, the total synthesis of biyouyanagin A led to its structural revision from 1′ to 1 (see Fig. 1A) (24,25). Interestingly, our total synthesis (26) of the subsequently reported biyouyanagin B (23) also led to its structural revision from the originally assigned structure 2′ to 2 (see Fig.…”

“…Further disconnection of the hyperolactone module III through a palladium-catalyzed cascade reaction revealed propargylic alcohols IV and aryl iodides V as the required fragments (plus carbon monoxide). This analysis defined a three-domain general structure for the library (i.e., I), and inspired a ready access to its members from the three relatively simple fragments II, IV, and V through a practical and robust synthetic route (24)(25)(26).…”

“…Inspired by the novel molecular architectures and important biological properties of biyouyanagin A, we initiated a program directed toward its total synthesis (24,25). As it turned out, the total synthesis of biyouyanagin A led to its structural revision from 1′ to 1 (see Fig.…”

“…The key step of the synthetic strategy employed for the total synthesis of biyouyanagins A (1) and B (2) involved a ½2 þ 2 photocycloaddition reaction as shown in Scheme 1 (24)(25)(26). Intriguingly, this process also delivered biyouyanagin C (3, a compound not discovered in nature as yet).…”

Hypervalent iodine reagents in the total synthesis of natural products

“…77,78 The oxidation of a complex substrate bearing a primary alcohol has been described by Hirama and co-workers (Scheme 5). ROMPM, 114,115,118,183 ROBn, 80,90,104,106,110,124,191,192 ROTr, 180 ROMe, 94,101,107,113,192 RONPhth, 88 RON=CMe 2 , 88 ArOAllyl, 193 ArOMe, 108,130,131,192,194,195 ArOBn, 127,131 ArOTBS, 174 R 2 NBoc, 174,[194][195][196][197] 208 This IBX analogue generates only water during the oxidation, while DMP releases acetic acid. When DMP was applied the required keto ester was obtained in only 60%, with 40% of the starting lactone recovered (Scheme 6).…”