Sinococuline (1) is a morphinane alkaloid isolated from the plant Cocculus trilobus native to Japan. 1 shows promising antitumor activity against animal tumor models. However, contents of 1 in the plant are inconstant, and its high polar and noncrystallizable property makes isolation/purification difficult. These hampered further preclinical studies for an anticancer agent. To develop an alternative supply route for 1, we have undertaken a program to synthesize 1 from sinomenine 2. It was envisaged that 2 would provide a suitable precursor for 1 since 2 possess a morphinane skeleton with the same substituents on ring A and is readily available in quantity from the roots of Sinomenium acuturn. C-4 phenolic hydroxyl group of 2 was protected as benzyl ether 3. 3 was subjected to N-demethylation, and the resultant amine was protected by benzyloxycarbonyl (Z) group to give 7 in 98% yield from 3. 4 was reduced stereospecifically with L-Selectride in THF to give C-6β-alcohol 10 b in 91% yield. 10b was converted to C-6α-seleno derivative 11b in 96% yield. Hydrogen peroxide oxidation of 11b gave C-81α-hydroxyl derivative 12 in 89% yield. 12 was subjected to Swern oxidation to provide diosphenol 16 (89% yield), which on treatment with methyl p-toluenesulfonate and potassium carbonate to give methyl ether 17 in 97% yield. Catalytic hydrogenation of 17 using (Ph_3)_3RhCl in benzene effected selective reduction of C-5-C-6 olefin to afford enone 5 in 97% yield. Potassium enolate of 5 was treated with (-)-(2S, 8aR)-(camphorsulfonyl)oxaziridine 22 to give C-6β-alcohol 4a and 4b in 50% and 17% yields, respectively, and 23% of 5 was recovered. 4a was protected as TBDMS ether 24 and was reduced with Super-Hydride to afford C-7β-alcohol 25a stereoselectively (25:1). 13 was deprotected to give diol 26 in 70% yield from 4a. 4a was treated with Pearlman's catalyst in refluxing cyclohexene-EtOH (1:1) to give 1 in 95% yield. The product thus obtained was found to be identical in all respects with 1 isolated from the plant. This work constitutes the first synthesis of 1 since (+)-sinomenine has been converted from thebaine.
