The synthesis of emetine and related compounds. Part IX. The use of Wittig-type reagents in the synthesis of 2,3-dehydroemetine

Abstract

The (±)-ketone (I)(3-ethyl-1,3,4,6,7,11b-hexahydro-9,10-dimethoxybenzo[a]quinolizin-2-one) is converted in one operation through the mixture of isomeric 2-ethoxycarbonylmethylene derivatives (IIb) and (IIIb) into ethyl 3-ethyl-1,4,6,7-tetrahydro-9,10-dimethoxy-11bH-benzo[a]quinolizine-2-acetate (Vb), which gives, in 75% overall yield from (I), the (±)-N-(3,4-dimethoxyphenethyl) amide (VI) required for production of racemic 2,3-dehydroemetine (IX). Similarly, the (–)-ketone (I) gives the (–)-amide (VI) corresponding to (–)-2,3-dehydroemetine (IX).

The emetine skeleton has also been synthesised by linking together the benzo[a] quinolizine and isoquinoline moieties directly. The novel 3,4-dihydro-6,7-dimethoxyisoquinolin-1-ylmethylenetriphenylphosphorane (XIV) obtained from the chloromethyldihydroisoquinoline hydrochloride (XI) condenses with the ketone (I) to form 2,3-dehydro-O-methylpsychotrine (VIII) or its isomer (X), depending on the reaction conditions. Treatment of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinolin-1-ylmethyltriphenylphosphonium bromide hydrobromide (XVI) with sodium methylsulphinylmethanide produces methylenetriphenylphosphorane as well as the 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinolin-1-ylmethylenetriphenylphosphorane (XVIII) and the latter reacts with the ketone (I) to give the 2-(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinolin-1-ylmethylene) derivative (XXI) of (I).

Fusion of 2-(2-acetamidoethyl)-4,5-dimethoxyphenacylidenetriphenylphosphorane (XXVII) with the ketone (I) leads to a variety of fragmentation products.