Enantioselective Synthesis of (−)-Jiadifenin, a Potent Neurotrophic Modulator

Abstract

The first enantioselective synthesis of (−)-jiadifenin (1), a potent neurite outgrowth promoter isolated from Illicium species, is described. The synthetic strategy builds upon bicyclic motif 6 that represents the AB ring of the natural product and proceeds in 19 steps and 1.1% overall yield. Key to our approach is a Mn(III)-mediated oxidation reaction of A ring that, following a regio- and diastereoselective α-hydroxylation and methylation sequence, produces the desired functionalities of (−)-jiadifenin. The effect of synthetic 1 in NGF-mediated neurite outgrowth was also measured in PC-12 cells.

Synthesis of the tetracyclic core of Illicium sesquiterpenes using an organocatalyzed asymmetric Robinson annulation

“…Notably, this scalable approach rendered us several hundred milligrams of compound 9 , paving the way for a diversity-oriented synthesis. For example, a Mn(III) promoted C-2 allylic oxidation [24,101–102] would provide a C-2 oxygenated functionality. Similarly, C-10 α-substitution would provide a large diversity of neurotrophic analogues based on our recent findings [26].…”

“…2) [24–26]. A potential drawback of this strategy is the late-stage modification of the A ring motif of 7 that requires additional steps for the synthesis of the target molecules.…”

Neurotrophic Natural Products: Chemistry and Biology

“…[89] Palladium-mediated carbomethoxylation [90] followed by an oxidation/epoxide opening cascade was used to build the C/D ring system of 64 , an advanced intermediate toward 14 (Scheme 9). …”

New monoterpene phenyl ethers from Illicium micranthum

“…2,3 Phytochemical investigation showed that this genus produced monoterpenoids, 4 sesquiterpene lactones, [5][6][7][8] diterpenoids, 9 triterpenoids, 10 lignans and neolignans, [11][12][13] which showed various bioactivities, such as insecticidal activity, 14 cancer chemopreventive activity, 15 and neurotrophic activity. [16][17][18] Illicium micranthum was a poisonous shrub used as a traditional pesticide. 3 Previous studies on this plant have resulted in the isolation of eight secoprezizaane sesquiterpene lactones, 5 seven phenylpropanoids 19 and several other compounds.…”