Using Catalyst-Substrate Coimmobilization for the Discovery of Catalysts for Asymmetric Aldol Reactions in Split-and-Mix Libraries

Abstract

"Catalyst -substrate coimmobilization" has been used for the discovery of highly active and selective peptidic catalysts for asymmetric aldol reactions within split-and-mix libraries. This screening method is based on the coimmobilization of one reaction partner along with each library member via a bifunctional linker on the library beads followed by mixing of this library with a labeled second reaction partner. Here we discuss the details of the combinatorial screening and demonstrate that the exchange of the bead-bound and the labeled reaction components leads to the same hits within the library.

Investigating Sequence Space: How Important is the Spatial Arrangement of Functional Groups in the Asymmetric Aldol Reaction Catalyst H‐Pro‐Pro‐Asp‐NH2?

“…H-Pro-Pro-b-Asp-NH 2 4 has an additional methylene group in the spacer to the C-terminal amide, whereas in its analogue H-Pro-Pro-b-AspScheme 1. a) Aldol reactions catalyzed by H-Pro-Pro-Asp-NH 2 1 and b) lowest energy structure of 1 as predicted by calculations using MacroModel 8.0. [10] Scheme 2. Peptides 2-7 closely related to the asymmetric catalyst 1.…”

“…[1,7,8] Using the method of "catalyst-substrate coimmobilization" which allows identification of catalysts within splitand-mix libraries, [9] we discovered the peptides HPro-Pro-Asp-NH 2 and H-Pro-d-Ala-d-Asp-NH 2 as catalysts for asymmetric aldol reactions. [10] Both peptides emerged as consensus sequences from the screening of 3375 different tripeptides for catalytic activity. Subsequent solution-phase experiments revealed that in particular H-Pro-Pro-Asp-NH 2 1, is a highly active and selective catalyst: 1 mol% of 1 suffices to catalyze aldol reactions between acetone and several aldehydes with good to excellent yields and enantioselectivities (Scheme 1 a).…”

“…In comparion, 30 mol% of proline is required to obtain the products in comparable yields and enantioselectivities, demonstrating that the higher complexity of the tripeptidic catalyst is an excellent trade-off for higher activity. [10,11] Molecular modeling combined with CD-spectroscopic analysis suggest that peptide 1 preferentially adopts a turn-conformation in which the secondary amine and carboxylic acid are in close proximity to each other (Scheme 1 b). [10] Both the secondary amine and the carboxylic acid are crucial for effective catalysis by 1; replacement of either functional group leads to a strong reduction or total loss of catalytic activity and selectivity.…”

“…[10,11] Molecular modeling combined with CD-spectroscopic analysis suggest that peptide 1 preferentially adopts a turn-conformation in which the secondary amine and carboxylic acid are in close proximity to each other (Scheme 1 b). [10] Both the secondary amine and the carboxylic acid are crucial for effective catalysis by 1; replacement of either functional group leads to a strong reduction or total loss of catalytic activity and selectivity. [12] This finding suggests that peptide 1 catalyzes asymmetric aldol reactions by a mechanism similar to that proposed for proline catalysis.…”

Tripeptide-Catalyzed Asymmetric Aldol Reaction Between α-ketoesters and Acetone Under Acidic Cocatalyst-Free Conditions

“…Following the introduction of a proline-catalyzed asymmetric aldol reaction of aldehydes reported by List et al [19], prolinamide catalysts for this reaction have been actively developed [20,21]. Synthetic peptides in prolinamide catalysts, are recognized as effective catalysts for the direct asymmetric aldol reaction using aldehydes as electrophiles [22][23][24][25][26][27][28][29][30][31][32][33]. However, peptide catalysts for the direct asymmetric aldol reaction using ketones as electrophiles are limited [29,[33][34][35][36].…”