Bicuculline synthesis

Synthesis of bicuculline and nitroadlumine. Groenewoud and Robinson synthesised bicuculline by the general method devised by Hope and Robinson, the initial products in this case being 6-nitro-3 4-methylene-dioxyphthalide (IV) prepared by a new method from normeconin, and hydrastinine (V). The condensation produet, called nitro-a -bicuculline (the X indicating that the dZ-product eannot yet be allocated to the a- or )3-stereoisomeric series cf. synthesis of hydrastine, p. 167), forms minute yellow needles, sinters at 176° and decomposes at 179°. It was reduced to amino-a -bicuculline (I R = NHj), yellow prisms, m.p. 208—4°, the latter... 

Benzodiazepine derivatives are thought to exert their anticonvulsant activity by facilitating GABAer-gic transmission. Substances that inhibit the synthesis of GABA (e.g., isoniazid) or block the GABA recognition site (e.g., bicuculline) cause convulsions (Figure 65.6). 

The interesting conversion of nornarceine (181) into the rhoeadine analogues (187) and (188) has been carried out as shown in Scheme 9. Nornarceine (181), obtained from (— )-a-narcotine, was heated in base to afford the enamine (182) which readily cyclized in dilute acetic acid to the y-lactone (183). Upon standing, (183) was oxidized to the ketone (184). Lithium borohydride reduction led to the c/.s-acid (185). The derived ds-fused lactone (186) was then reduced to the hemi-acetal (187) which upon O-methylation with trimethyl orthoformate gave (188). The structure of the methiodide salt of (187) was confirmed by an X-ray analysis. The phthalideisoquinoline alkaloid (— )-bicuculline (189) was then converted into naturally occurring (+ )-rhoeadine (190) by an analogous route. Since (— )-bicuculline was obtained from (—)-)3-hydrastine, whose synthesis had been reported in 1950, this transformation represents the first total synthesis of a rhoeadine alkaloid. ... 

The synthesis of bicuculline was achieved by Groenewoud and Robinson (86) by condensing hydrastinine with 6-nitro-4,5-methylenedioxy-phthalide fXLVIII), which was readily obtained by nitrating methylenedi-oxyphthalide (XXXVI). The resulting nitro-a -bicuculline was converted... 

Bicuculline as an effective antagonist of an inhibitory neurotransmitter, y-aminobutyric acid (GABA), many procedures have been developed for its preparation. Orito and colleagues applied palladium-catalyzed alkoxycarbonylation as the key step in its total synthesis (Scheme 10.16) [88]. 

Ingvar, M., Nilsson, B., Siesjo, B. K., 1981 Local cerebral blood flow in the brain during bicuculline-induced seizures and the modulating influence of inhibition of prostaglandin synthesis. Acta Physiol. Scand. Ill, 205-212. 

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