18652-93-2Relevant articles and documents
Asymmetric catalysis, 125: Synthesis of the stereoisomers of methohexital by palladium-catalyzed allylation
Brunner, Henri,Deml, Irmgard,Dirnberger, Wolfgang,Ittner, Karl-Peter,Rei?er, Walter,Zimmermann, Markus
, p. 51 - 59 (1999)
Allylation of 1-methyl-5-(1'-methylpent-2'-ynyl)barbituric acid (MBS) with allyl acetate using in situ catalysts of palladium(II) acetylacetonate and chiral phosphane imine ligands resulted in the enantioselective formation of 5-allyl-1-methyl-5-(1'-methylpent-2'-ynyl)barbituric acid (Methohexital), an important anesthetic drug. Both, MBS and Methohexital contain two stereogenic carbon atoms. In MBS, the asymmetric centre in the barbiturate system is labile due to enolization. The asymmetric centre in the hexyne side chain is stable and racemic. The two asymmetric centres of Methohexital are stable and give rise to four stereoisomers, two diastereomeric racemates. An analysis of the isomers of MBS and Methohexital was established on the basis of 1H NMR and, in particular, GC including a base-line separation of the four stereoisomers of Methohexital. The stereoselectivity of the allylation is difficult to control, because the new quaternary asymmetric centre in the barbiturate ring of Methohexital is formed within the nucleophile, attacking the η3-allyl ligand of the catalyst from the side opposite to the palladium atom. Classical optically active ligands, such as diop or norphos, give only 2-6 % ee. Chiral phosphane imine ligands are a successful class of compounds, synthesized by Schiff base condensation of (2-formylphenyl)diphenylphosphane with optically active primary amines. The most efficient ligands have a hydroxymethyl and a bulky alkyl substituent at the asymmetric centre in the imine part, e.g. the L-iso-leucinol and the L-tert-leucinol derivatives 5 and 7. In the Pd-catalyzed allylation of MBS a kinetic resolution and the effect of the enantioselective catalyst interplay, the contributions of which are separated. For MBS the best stereoselectivity factor of the kinetic resolution s = k(R)/k(S) was 2.6 and 83 % 'ee' were achieved. The corresponding values for Methohexital were s = 3.5 and 80 % ee in the α-dl pair. For 10 mixtures of Methohexital stereoisomers the anesthetic doses for rats were determined. With 9.1 mg/kg body weight of the animal the sample obtained from the catalysis with the D-α-phenylglycinol derivative 8 gave a much lower anesthetic dose than the widely used narcotic BrevimytalNatrium, the sodium salt of the α-dl racemate of Methohexital, with 13.0 mg/kg body weight.
Highly enriched mixtures of methohexital stereoisomers by palladium-catalyzed allylation and their anaesthetic activity
Brunner, Henri,Ittner, Karl-Peter,Lunz, Dirk,Schmatloch, Stefan,Schmidt, Thomas,Zabel, Manfred
, p. 855 - 862 (2007/10/03)
The stereoselective Pd-catalyzed allylation of MBA [5-(2′-hex-3′-yny1)-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).
