Multicomponent Approach to Silica‐Grafted Peptide Catalysts: A 3 D Continuous‐Flow Organocatalytic System with On‐line Monitoring of Conversion and Stereoselectivity

Abstract

The derivatization of organocatalysts with functional appendages suitable to anchor onto solid supports is usually achieved by stepwise syntheses. As an alternative to such a strategy, this work describes a one‐pot approach to silylated prolyl‐peptide catalysts by a multicomponent reaction that enables the simultaneous incorporation of the catalytic and the heterogenizable (triethoxysilane) moieties. A microreactor with high catalytic efficacy and reproducibly in the conjugate addition of aldehydes to nitroolefins was obtained by grafting onto HPLC‐grade silica (10 μm) and packing into a column with a selected catalyst. A 3 D continuous‐flow system that includes the on‐line monitoring of the reaction outcome was set up. For that, the microreactor was coupled to a chromatographic column for the separation of the remaining substrates from the Michael adduct in the second dimension, followed by a chiral polysaccharide column for the analysis of conversion and stereoselectivity. This approach represents a new instrumental setup that combines the advantages of multidimensional chromatography and flow catalysis.

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis

“…As shown in Scheme 2, Boc-L-proline and acetone were employed as acid and oxo components, respectively, in combination either with furfurylamine and cyclohexyl isocyanide or with ( S )-α-methylbenzylamine and furfuryl isocyanide. We have previously proven the feasibility of this multicomponent approach for the combinatorial synthesis and rapid screening of pseudo-peptide catalysts [7] and their silica gel-immobilized variants [8]. The choice of using acetone and the S -configured α-methylbenzylamine was made in agreement with our previous success with this class of peptide catalyst [7].…”

“…Later, our groups developed an Ugi reaction-based multicomponent approach enabling the structure diversification of prolyl pseudo-peptide catalysts [7], which also proved great efficacy in organocatalytic asymmetric Michael reactions. As extension of this concept to the field of immobilized organocatalysts, we reported the use of the multicomponent approach for the synthesis of silica-grafted peptide catalysts for applications in continuous-flow catalysis [8]. In an endeavor to develop a cheaper and renewable polymer-supported organocatalyst, herein we describe the multicomponent synthesis of furfuryl-containing prolyl pseudo-peptide catalysts and their subsequent utilization in the preparation of PFA-supported catalysts amenable for continuous-flow asymmetric enamine catalysis [9–10].…”

New Mesoporous Silica-Supported Organocatalysts Based on (2S)-(1,2,4-Triazol-3-yl)-Proline: Efficient, Reusable, and Heterogeneous Catalysts for the Asymmetric Aldol Reaction

“…The first one is called “co-condensation method” [ 75 , 76 , 77 ], which consists of the initial synthesis of the required precursors, is followed by a second step involving the coupling or incorporation on the solid support. The second methodology is denominated “post-synthetic grafting”, which focuses on the step-by-step construction of the catalyst on the silica surface [ 78 , 79 , 80 , 81 ]. As it turned out, the present development required a hybrid synthetic approach starting from commercial silica and involving both co-condensation and post-synthetic grafting starting from commercial silica, as illustrated in the preparation of compound ( S ) -5 ( Scheme 1 ).…”

Recent Advances in Continuous‐Flow Enantioselective Catalysis

“…As previously mentioned, an immobilized peptide catalyst was constructed by using Ugi‐4CR, which was shown to be an effective method for the enantioselective Michael addition of aldehydes 111 to nitroolefins 112 . The silica‐supported prolyl‐peptide catalysts also obtained a remarkable diastereoselectivity (96:4, syn / anti ) and enantioselectivity (92 % ee ) in another article by Paixão′s group . Most importantly, based on the 3D continuous‐flow system (Scheme ), on‐line monitoring of the reaction outcome can be worked conveniently.…”