Asymmetric organocatalytic direct aldol reactions of ketones with alpha-keto acids and their application to the synthesis of 2-hydroxy-gamma-butyrolactones.
A variety of organocatalysts for the asymmetric direct aldol reactions of ketones with alpha-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 alpha-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-gamma-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 alpha-keto acid, respectively. These two hydrogen-bonding interactions are important for the reactivity and enantioselectivity of the direct asymmetric aldol condensation.
Xu
Xiao-Ying
XY
Hefei National Laboratory for Physical Sciences at Microscale and Department of Chemistry, University of Science and Technology of China, Hefei 230026, China.
Tang
Zhuo
Z
Wang
Yan-Zhao
YZ
Luo
Shi-Wei
SW
Cun
Lin-Feng
LF
Gong
Liu-Zhu
LZ
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D000631:Aminopyridines / Q000737:chemistry*; D002074:Butanones / Q000737:chemistry; D002384:Catalysis; D007651:Keto Acids / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011392:Proline / Q000737:chemistry*; D013237:Stereoisomerism
D000631:Aminopyridines; D002074:Butanones; D007651:Keto Acids; D007659:Ketones; C005222:methylethyl ketone; D011392:Proline; D015107:4-Butyrolactone