Synthesis of Biologically Active Compounds by Means of an Intramolecular Polar Cycloaddition of Thionium Ions

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1. In order to establish the synthetic utility of the polar cycloaddition of thionium ions, we first examined an intermolecular version of the [4^++2] type reaction. Thus, when m-tolylthiomethyl chloride was allowed to react with various 1-methyl- and 1.2-dimethl-l-cyclopentenes in the presence of Lewis acid, the cyclopentane fused thiochromans derivatives were obtained in good yields. These products were transformed into the aromatic sesquiterpenes such as cuparene, alpha-cuparenone, beta-cuparenone, and tochuinyl acetate.2. Several sttempts have been made to synthesize podophyllotoxin derivatives by using the intramolecular version of the above [4^++2] reaction, but failed. Then, as an alternate route to podophyllotoxins, we examined the Heck reaction of (Z)-alpha-benzylidene- beta-(o-bromobenzyl)gamma-lactone, prepared from piperonal, gamma-crotonolactone, and 3, 4, 5-trimethoxybenzaldehyde via 10 steps : this gave gamma-apopicropodophyllin in good yield. Since this product has already been converted into podophyllotoxin, the whole sequence of the reactions means the formal total synthesis of podophyllotoxin.3. The intramolecular [2^++4] polar cycloaddition of the thionium ion derived from 1-methylsulfinyl-5.7-octadiene-2-one followed by base-treatment of the resultant product gave 1-methylthio-6-vinylbicyclo [3.1.0] hexane-2-one, whose transformation into prostaglandin derivatives is under intense investigation.