H-Pro-Pro-Asp-NH2

A series of silica-supported proline-based peptides were synthesized and applied as catalysts for direct asymmetric intermolecular aldol reactions. Among these, a peptide with two L-proline units was found to be the most efficient one for the asymmetric aldol reactions between acetone and aromatic aldehydes. The reactions generated the corresponding products with satisfactory isolated yields (up to 97%) and enantiomeric excesses (up to 96%) in the presence of this catalyst (5 mol %). Furthermore, the silica-supported organocatalyst could be recovered and recycled by a simple filtration of the reaction solution and used for five consecutive trials without loss of its reactivity.

Analysis of the structural and functional requirements within the asymmetric peptidic catalyst H-D-Pro-Pro-Asp-NH(2) led to the development of the closely related peptide H-D-Pro-Pro-Glu-NH(2) as an even more efficient catalyst for asymmetric conjugate addition reactions of aldehydes to nitroolefins. In the presence of as little as 1 mol % of H-D-Pro-Pro-Glu-NH(2), a broad range of aldehydes and nitroolefins react readily with each other. The resulting gamma-nitroaldehydes were obtained in excellent yields and stereoselectivities at room temperature. Within the structure of the peptidic catalysts, the D-Pro-Pro motif is the major contributor to the high stereoselectivities. The C-terminal amide and the spacer to the carboxylic acid in the side-chain of the C-terminal amino acid are responsible for the fine-tuning of the stereoselectivity. The peptidic catalysts not only allow for highly effective asymmetric catalysis under mild conditions, but also function in the absence of additives.

Asymmetric aldol reactions catalyzed by a novel polystyrene-immobilized proline derivative occur in short reaction times with excellent diastereo- and enantioselectivity. The catalyst can be recovered by simple filtration and shows very high reusability. The high activity depicted by the supported catalyst and its chemical and mechanical stability have allowed its application in packed-bed reactors for continuous flow processing. This system can produce enantio- and diastereomerically pure aldol adducts under continuous flow conditions with a residence time of 26 min. Furthermore, the reactor allowed processing of four different aldol products in sequence without any decrease in both catalytic activity and optical purity. The effective catalyst loading could be reduced to 1.6% (six-fold reduction of catalyst loading compared to the corresponding batch process).