A tripeptide-like prolinamide-thiourea as an aldol reaction catalyst

A tripeptide-like prolinamide-thiourea catalyst with (S)-proline, (1S,2S)-diphenylethylenediamine and (S)-di-tert-butyl aspartate as building blocks provides the products of the reaction between ketones and aromatic aldehydes in high to quantitative yields and high stereoselectivities (up to 99 : 1 dr and 99% ee). Both the chiral centers of the diamine unit are essential, while the thiourea hydrogen originating from the amine and the amide hydrogen play a predominant role for the catalyst efficiency

Tripeptide-Like prolinamide catalysts for the aldol reaction

Enzymes are the foundation upon which the majority of organocatalysts bearing more than one catalytic functionalities and act either by covalent or non-covalent interactions, has been developed. The proline and its derivatives containing bio-isosteric groups as replacements of the carboxylic group, constitute a good example of catalysts that bring out transformations as the aldol and Michael reaction succesfully, via bifunctional catalysis.1 Important improvement has been the development of catalysts combining a proline or proline derivative unit with additional functionalities able to act as hydrogen bond donors. Amide catalysts based on (S)-proline and (1S,2S)-1,2-diphenylethylenediamine or (1S,2S)-1,2-diphenyl-2-aminoethanol are representative examples featuring amine or hydroxyl group respectively, as the terminal donor group.2 These analogues provide the opportunity of introducing chiral substituents between donor groups and/or to the terminal heteroatom, thus enhancing the efficacy of the resulting catalyst. Furthemore, combination of additional chiral units, together with even more hydrogen bond donors, would mimic much better a “miniature active site”, providing therefore multifunctional organocatalysts. We have shown that prolinamide catalyst based on (1S,2S)- 1,2 diphenylethylenediamine and bears a double hydrogen bond donor thiourea group linked to a substituted aromatic ring, efficiently catalyze the aldol reaction between ketones and aromatic aldehydes in high to quantitative yields and with high stereoselectivities.3 Herein, we report a structure activity relationship study undertaken to identify the functional groups of the catalyst responsible for the activity resembling structure activity relationship studies to identify the pharmacophores of a lead bioactive compound. A tripeptide-like prolinamide-thiourea catalyst having as building blocks (S)-proline (1S,2S)-1,2-diphenylenediamine and (S)-di-tertbutyl aspartate provides the products of the aldol reaction in high to quantitative yields and in high stereoselectivities (up to 99:1 dr and 99% ee)

Prolinamides carrying a thiourea group as new catalysts for the asymmetric aldol reaction

At the beginning of the 21st century, organocatalysis has emerged as a new powerful methodology for the synthesis of enantiopure organic compounds. The breakthrough of proline-catalyzed asymmetric direct aldol reaction together with the pioneering work on catalytic thioureas and imidazolidinones opened new directions in asymmetric catalysis. The five-membered secondary amine structure of proline is considered as a“privileged” structure able to activate carbonyl compounds through the formation of enamine intermediates. In an attempt to develop new organocatalysts, we thought of combining a thiourea group with prolinamide or an α-amino acid amide unit. Thiourea group is a well known double hydrogen bond donor and recently we have shown that chiral thioureas based on tert-butyl esters of α- amino acids are excellent catalysts for the asymmetric Michael reaction.1 In the present work, we describe the synthesis of various α-amino acid amides based on a chiral diamine carrying a thiourea group (general structure 1). The catalytic efficiency of the new organocatalysts was evaluated in the aldol reaction between acetone and 4-nitrobenzaldehyde. Prolinamide derivative was more efficient than the valinamide and the threonine amide derivatives. The catalyst based on (S)-proline and (1S,2S)-diphenylethylenediamine proved to be an excellent catalyst providing the products between ketones and aromatic aldehydes in high to quantitative yield and high stereoselectivitie

Organocatalytic asymmetric domino Michael-Henry reaction for the synthesis of substituted bicyclo[3.2.1]octan-2-ones

The first organocatalytic asymmetric reaction between 1,4-cyclohexanedione and nitroalkenes have been studied, affording bicyclo[3.2.1]octane derivatives containing four continuous stereogenic centres. The products were obtained through a domino Michael-Henry process as a single diastereoisomer with excellent enantioselectivities

Organocatalytic asymmetric domino Michael–Henry reaction for the synthesis of substituted bicyclo[3.2.1]octan-2-ones

This paper was submitted for publication in the journal "Chemical Communications" and the definitive version can be found at: http://dx.doi.org/10.1039/c3cc39165eThe first organocatalytic asymmetric reaction between 1,4-cyclohexanedione and nitroalkenes have been studied, affording bicyclo[3.2.1]octane derivatives containing four continuous stereogenic centres. The products were obtained through a domino Michael-Henry process as a single diastereoisomer with excellent enantioselectivities

Applications of sulfur ylides in asymmetric synthesis

EThOS - Electronic Theses Online ServiceGBUnited Kingdo