CHEMISTRY OF THE ENOLATES OF 2-ACETYLTHIAZOLE - ALDOL REACTIONS WITH CHIRAL ALDEHYDES TO GIVE 3-DEOXY ALDOS-2-ULOSES AND 3-DEOXY 2-ULOSONIC ACIDS - A SHORT TOTAL SYNTHESIS OF 3-DEOXY-D-MANNO-2-OCTULOSONIC ACID (KDO)

The acetyl group of 2-acetylthiazole (2-ATT) was selectively metalated by treatment with lithium tert-butoxide (the lithium enolate was formed) or triethylamine/zinc chloride/trimethylsilyl chloride (the silyl enol ether was formed). The use of strong bases (LDA, TMP) resulted in substantial deprotonation of the thiazole ring. The lithium enolate of 2-ATT, formed under conditions of kinetic control, reacted with aliphatic and aromatic aldehydes to give the corresponding aldols (beta-hydroxyalkyl 2-thiazolyl ketones) in isolated yields of 51-65%. The reaction of the lithium enolate with chiral compounds, i.e., various alkoxy-substituted aldehydes and one amino aldehyde derivative, occurred with a high degree of anti diastereoselectivity (80-92%), an outcome that was in accord with the Felkin-Ahn model for asymmetric induction. Hemiketalization of the aldols that resulted from the reaction of the enolate with D-glyceraldehyde acetonide and 2-O-benzyl D-erythrose acetonide and subsequent liberation of the formyl group by hydrolytic cleavage of the thiazole ring afforded the corresponding aldosuloses. Oxidation converted these to ulosonic acids. The application of this three-carbon-chain elongation to D-arabinose diacetonide afforded the octulosonic acid KDO in 6.8% overall yield.