(+)-Opium alkaloids have gained increasing attention due to their biological and medicinal applications. (+)-dihydrothebaine (6,7-didehydro-4,5-epoxy-3,6-dimethoxy-17-methylmorphinan) is a key intermediate in the synthesis of these (+)-opium alkaloids. In this report, the one-pot conversion of (+)-dihydrosinomenine (4-hydroxy-6-oxo-3,7-dimethoxy-17-methylmorphinan) to (+)-dihydrothebaine has been achieved in 70% yield. The process has been successfully scaled up to 0.5 kilograms. The oxide bridge in the 4,5 position which characterizes alkaloids of opium, 6-methoxy group and a 7,8-double bond are constructed simultaneously by heating the starting material in a mixture of methanol, acetonitrile, trimethyloxoformate and methanesulfonic acid. The reaction pathway involves multiple steps of reactions, including the formation of 4-hydroxy-3,6,6,7-tetramethoxy-17-methylmorphinan, 4-hydroxy-5,6-didehydro-3,6,7-trimethoxy-17-methylmorphinan, and 4,5-ether ring via 6-methoxy-5,6,7-allylic cation. More than a dozen intermediate species have been observed and characterized.

Practical synthesis of (+)-dihydrothebaine from (+)-dihydrosinomenine

244th National Meeting (2012)

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