合成路线1

Artemisin can be synthesized by several related ways: 1) The reaction of L-menthone (I) with paraformaldehyde and dimethylamine hydrochloride gives the dimethylaminomethyl derivative (II), which is cyclized with ethyl acetoacetate by means of sodium ethoxide and methyl iodide to the octahydronaphthalenone (III) (Indian J Chem 1976, 14B: 901). Epoxidation of (III) with H2O2/NaOH in methanol/water yields the epoxide (IV), which is reduced with LiAlH4 in ether to the diol (V). Selective acetylation of (V) with acetic anhydride in pyridine affords the monoacetoxy compound (VI), which is cyclized by means of lead tetraacetate, catalyzed by irradiation with white light, yielding the furo-decaline (VII). The hydrolysis of the acetoxy group of (VII) followed by oxidation with pyridinium chlorochromate (PCC) gives the ketone (VIII), which is submitted to ring opening with acidic alumina in ethyl acetate/benzene, yielding the unsaturated hydroxy ketone (IX). Hydrogenation of (IX) with H2 over Pd/C in methanol affords the corresponding saturated ketone (X), which by a Grignard methylation with methylmagnesium iodide in ether gives the diol (XI). Selective acetylation of (XI) with acetic anhydride in pyridine gives the monoacetoxy compound (XII), which is dehydrated with POCl3/pyridine to the octahydronaphthalene (XIII). The hydrolysis of (XIII) with KOH in ethanol gives the alcohol (XIV), which is submitted to ozonolysis with O3 in dichloromethane followed by cyclization with p-toluenesulfonic acid, yielding the 2-benzopyran (XVI). The photochemical oxidation of (XVI) with O2 and methylene blue in dichloromethane irradiated with an Na lamp followed by a cyclization catalyzed by p-toluenesulfonic acid affords deoxoartemisinin (XVII), which is finally oxidized with RuCl3 and NaIO4 in acetonitrile/water. 2) The alcohol (XIV) can also be obtained from artemisinic acid (XV) by methylation to the corresponding methyl ester with diazomethane and reduction with LiAlH4-NiCl2 in methanol.