From Aspartic Acid to Dihydropyridone‐2‐carboxylates: Access to Enantiopure 6‐Substituted 4‐Oxo‐ and 4‐Hydroxypipecolic Acid Derivatives

Abstract

AbstractWe describe a method that starts from a protected (S)‐aspartic acid and employs a gold‐catalyzed cyclization to give enantiopure dihydropyridone 2‐carboxylates, which are then converted into 6‐substituted 4‐oxo‐ and 4‐hydroxypipecolic acid derivatives. Thus, the lateral chain carboxylic acid of a commercially available, protected (S)‐aspartic acid forms a Weinreb amide, which is then converted into an ynone followed by a gold‐catalyzed cyclization to furnish enantiopure enaminones in high yields. The steric hindrance from the protecting group was revealed as an efficient guide for the selectivity of the reduction reactions. Thus, classical methods that use palladium or sodium borohydride afford various enantiopure 6‐substituted 4‐oxo‐ and 4‐hydroxypipecolic acid derivatives. In these cases, the substituents have an all‐cis configuration, whereas a Luche reduction furnishes the 2,4‐trans analogues. In the case of the 6‐unsubstituted enaminone, the 1,4‐addition of a Grignard reagent furnishes the 2,6‐trans compound. All 6‐substituted 4‐hydroxy‐ and 4‐oxopipecolic derivatives were obtained in good yields. The diastereoselectivity for most of the reactions and the ease of separation of the diastereomers, in a few cases, render this method applicable for gram‐scale synthesis.