[reaction: see text] Direct asymmetric catalytic Michael reactions have been performed using chiral-amine/acid bifunctional catalysts. Performed with 0.3 equiv of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine and 0.3 equiv of trifluoroacetic acid as the catalyst, the reaction of alpha,alpha-dialkylaldehydes with (E)-beta-nitrostyrene provided the alpha,alpha-dialkyl Michael products in up to 96% yield with up to 91% ee. With respect to enantioselectivity, l-proline was a poor catalyst of this class of Michael reactions.
The unprecedented application of unmodified aldehydes as nucleophilic donors in direct catalytic asymmetric Mannich-type reactions is disclosed in a full account. Our efforts in broadening the applicability of chiral pyrrolidine-based catalysts in direct asymmetric Mannich-type reactions led to the highly diastereo- and enantioselective and concise synthesis of functionalized alpha- and beta-amino acids, beta-lactams, and amino alcohols.
We have developed a new spectroscopic system for detecting carbon-carbon bond formation by fluorescence to enhance high-throughput catalyst screening and rapid characterization of catalysts on a small scale. Fluorogenic substrates composed of a fluorophore possessing an amino group are readily prepared as amides of alpha,beta-unsaturated carbonyl compounds and generally exhibit low fluorescence, while Michael or Diels-Alder reactions of these fluorogenic substrates provide products of significantly increased fluorescence. The product's fluorescence is approximately 20- to 100-fold higher than that of the substrate. The assay system was validated by screening potential catalysts of the Michael reaction and in solvent optimization experiments. The covalent combination of fluorophores possessing an amino group with alpha,beta-unsaturated carbonyl compounds should provide a diverse range of fluorogenic substrates that may be used to rapidly screen catalysts and to optimize reaction conditions.
[reaction: see text] A simple and efficient method for the synthesis of highly enantiomerically enriched beta-hydroxy-alpha-amino acid derivatives has been developed. Direct asymmetric aldol reactions of a glycine aldehyde (aminoacetaldehyde) derivative have been performed under organocatalysis using l-proline or (S)-5-pyrrolidine-2-yl-1H-tetrazole. The reactions afforded anti-beta-hydroxy-alpha-amino aldehydes in good yield with high diastereoselectivity (dr up to >100:1) and high enantioselectivity (up to >99.5% ee), which were easily transformed into beta-hydroxy-alpha-amino acid derivatives.
Enantioselective syntheses
Enantioselective syntheses O 0031The Direct Organocatalytic Asymmetric Mannich Reaction: Unmodified Aldehydes as Nucleophiles. -For the first time unmodified aldehydes are successfully used as donors in catalytic asymmetric Mannich-type reactions. It is showed that the proline-catalyzed reaction of N-PMP-protected α-imino ethyl glyoxylate with aldehydes provides a highly enantioselective entry to functional amino acids, β-lactam antibiotics, and serine protease inhibitors. The reaction tolerates a substantial amount of water in the solvent, it affects the chemical yield but the diastereoselectivity is not compromised. A one-pot three-component protocol, which applies aliphatic aldehydes as nucleophilic donors and affords the corresponding Mannich products in a highly enantioselective manner with good syn diastereoselectivity and exceptional chemoselectivity. -(NOTZ, W.; TANAKA, F.; WATANABE, S.-I.; CHOWDARI, N. S.; TURNER, J. M.; THAYUMANAVAN, R.; BARBAS*, C. F. I.; J. Org. Chem. 68 (2003) 25, 9624-9634; Dep. Chem., Scripps Res. Inst.,
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