ADDITION OF METHYL THIOGLYCOLATE AND BENZYLAMINE TO (Z)-LIGUSTILIDE, A BIOACTIVE UNSATURATED LACTONE CONSTITUENT OF SEVERAL HERBAL MEDICINES - AN IMPROVED SYNTHESIS OF (Z)-LIGUSTILIDE

(Z)-Ligustilide [1] is a dihydrophthalide purported to be the active ingredient of Ligusticum plant species widely used as herbal medicines in the Orient and in Native American and Hispanic cultures. It readily underwent 1,6-conjugate addition with methyl thioglycolate in the presence of triethylamine. The methyl thioglycolate reaction also yielded a product from addition to the C-6-C-7 double bond and a diadduct from both 1,6-addition and addition to the C-6-C-7 bond. Reaction of 1 with benzylamine did not afford a 1,6-adduct, but yielded instead an N-benzyllactam, presumably formed by rearrangement from initial 1,2-addition to the carbonyl. An improved total synthesis of 1 was developed. (Z)-Ligustilide had weak antiviral properties and weak antimicrobial activity against Gram-positive, Gram-negative, and yeast microorganisms. The broad biological activity of 1 and its electrophilic reactivity are consistent with the use of Ligusticum species in folk medicine.