Highly Enriched Mixtures of Methohexital Stereoisomers by Palladium-Catalyzed Allylation and Their Anaesthetic Activity

The stereoselective Pd‐catalyzed allylation of MBA [5‐(2′‐hex‐3′‐ynyl)‐1‐methylbarbituric acid] gives the commercial injection narcotic methohexital, which exists as four isomers: two diastereomeric pairs of enantiomers. The isomer composition produced depends on three stereochemical parameters: catalyst control, substrate control, and kinetic resolution. Judicious choice of these parameters allowed the synthesis of methohexital samples with greatly differing isomer compositions, and these samples were investigated with respect to their anaesthetic doses in rats. Some isomer compositions obtained were much more active than the commercially used drug and showed fewer side effects. As a consequence of the determination of the absolute configuration of the methohexital (SbRh) isomer, the unknown configuration of the trade product, the so‐called α‐racemate, can be established as (RbSh) and (SbRh). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)