Asymmetric organocatalytic direct aldol reactions of ketones with α-keto acids and their application to the synthesis of 2-hydroxy-γ-butyrolactones

Xiao Ying Xu, Zhuo Tang, Yanzhao Wang, Shi Wei Luo, Lin Feng Cun, Liu Zhu Gong

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74 Scopus citations

Abstract

(Chemical Equation Presented) A variety of organocatalysts for the asymmetric direct aldol reactions of ketones with α-keto acids were designed on the basis of molecular recognition and prepared from proline and aminopyridines. The organic molecule 8e, derived from proline and 6-methyl-2-amino pyridine, was the best catalyst, affording excellent enantioselectivities (up to 98% ee) for the direct aldol reactions of acetone or 2-butanone with a wide range of α-keto acids and for the reactions of various acyclic aliphatic ketones with 3-(2-nitrophenyl)-2-oxopropanoic acid. The aldol adducts could be converted to 2-hydroxy-γ-butyrolactones by reaction sequences of diastereoselective reduction and lactonization. Experimental and theoretical studies on the transition states revealed that the amide N-H and the pyridine N of the organocatalyst selectively form hydrogen bonds with the keto oxygen and the carboxylic acid hydroxy of the α-keto acid, respectively. These two hydrogen-bonding interactions are important for the reactivity and enantioselectivity of the direct asymmetric aldol condensation.

Original languageEnglish (US)
Pages (from-to)9905-9913
Number of pages9
JournalJournal of Organic Chemistry
Volume72
Issue number26
DOIs
StatePublished - Dec 21 2007

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