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Direct Catalytic Asymmetric Mannich Reactions of Malonates and β ‐Keto Esters
Author(s) -
Marigo Mauro,
Kjærsgaard Anne,
Juhl Karsten,
Gathergood Nicholas,
Jørgensen Karl Anker
Publication year - 2003
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200204679
Subject(s) - chemistry , mannich reaction , catalysis , adduct , enantioselective synthesis , substrate (aquarium) , organic chemistry , tosyl , medicinal chemistry , oceanography , geology
The first catalytic asymmetric direct Mannich reaction of malonates and β ‐keto esters has been developed. Malonates react with an activated N ‐tosyl‐ α ‐imino ester catalyzed by chiral tert ‐butyl‐bisoxazoline/Cu(OTf) 2 to give the Mannich adducts in high yields and with up to 96 % ee. These reactions create a chiral quaternary carbon center and it is demonstrated that this new direct Mannich reactions provides for example a new synthetic procedure for the formation of optically active β ‐carboxylic ester α ‐amino acid derivatives. A series of different β ‐keto esters with various ester substituents has been screened as substrates for the catalytic asymmetric direct Mannich reaction and it was found that the best results in terms of yield, diastereo‐ and enantioselectivity were obtained when tert ‐butyl esters of β ‐keto esters were used as the substrate. The reaction of different β ‐keto tert ‐butyl esters with the N ‐tosyl‐ α ‐imino ester gave the Mannich adducts in high yields, diastereo‐ and enantioselectivities (up to 95 % ee ) in the presence of chiral tert ‐butyl‐bisoxazoline/Cu(OTf) 2 as the catalyst. To expand the synthetic utility of this direct Mannich reaction a diastereoselective decarboxylation reaction was developed for the Mannich adducts leading to a new synthetic approach to attractive optically active β ‐keto α ‐amino acid derivatives. Based on the stereochemical outcome of the reactions, various approaches of the N ‐tosyl‐ α ‐imino ester to the chiral bisoxazoline/Cu II ‐substrate intermediate are discussed.