Regio- and stereoselective C10β-H functionalization of sinomenine: an access to more potent immunomodulating derivatives

Regio- and stereoselective C10β-H functionalization of sinomenine, an economically available natural immunomodulating alkaloid, has been studied, developed and successfully applied to the synthesis of new immunosuppressive sinomenine derivatives in a protecting-free fashion. Regioselective oxidation of sinomenine with (diacetoxyiodo)benzene (DIB) in water provided a single stable benzoquinone derivative 4, and subsequent 1,6-conjugated addition of 4 with alcohols, amines, and thiols afforded a new series of C10β-H functionalized sinomenine derivatives stereoselectively. Some derivatives with a newly introduced 10β-bezenesulfanyl substituent exhibited much higher TNF-α inhibitory potency than their natural parent sinomenine. This work opens a convenient access to novel sinomenine derivatives with medicinal interests.