Heterogeneous Dipeptide‐Catalyzed α‐Amination of Aldehydes in a Continuous‐Flow Reactor: Effect of Residence Time on Enantioselectivity

Abstract

As olid-supported dipeptide-catalyzed continuous-flow process was developed for the direct enantioselective a-amination of aldehydes with dibenzyl azodicarboxylate as the electrophilic nitrogen source.W ith residencet ime control as an efficient toolf or the fine-tuning of the enantioselectivity,s ynthetically useful a-hydrazino alcohols were achieved with excellent ees. Thep acked-bed system provedt ob eh ighly robust:n od ecrease in catalyst activity or selectivity was detected throughout 20 ho fc ontinuous-flow operation. UPDATESScheme 2. Solid-supported peptide-catalyzed a-amination of propanal with DBAD as electrophilic nitrogen source, and reduction of the resulting a-hydrazino aldehyde to the correspondingalcohol. 3672 asc.wiley-vch.de

Harnessing the Versatility of Continuous-Flow Processes: Selective and Efficient Reactions

“…We envisioned that simply changing the catalyst bed for an immobilized organocatalyst in CF organocatalytic reactions would be beneficial. It emerged that peptidic catalysts could be immobilized in a straightforward manner by using the toolbox of solid‐phase peptide synthesis (SPPS) 44. Importantly, catalyst synthesis and immobilization can readily be combined into one process, without the need for reimmobilization or for laborious peptide workup and purification steps.…”

“…By using resin‐supported peptidic organocatalysts, we developed a CF methodology for the asymmetric 1,4‐addition of aldehydes to nitroolefins 44a. Tripeptides with the general formula H‐ d ‐Pro‐Pro‐Xaa‐NH 2 , in which Xaa is aspartic (Asp) or glutamic acid (Glu), were reported to be effective organocatalysts for conjugate additions of aldehydes 45.…”

“…We later extended the scope of the CF organocatalytic concept to asymmetric aldol reactions between aromatic aldehydes and acetone (Scheme ) 44b. The heterogeneous tripeptide H‐ l ‐Pro‐Pro‐Asp‐NH‐resin immobilized on a TentaGel resin was chosen as catalyst 47.…”

“…Heterogeneous prolyl peptides were investigated as chiral catalysts for asymmetric α‐amination reactions 44c. Tripeptides of H‐ l / d ‐Pro‐Pro‐Xaa‐NH‐TentaGel from previous studies offered only low or moderate enantioselectivities; [44a, b] however, after omission of the central Pro residue, the resulting novel dipeptides (H‐ l / d ‐Pro‐Xaa‐NH‐TentaGel) exhibited improved enantioselectivities.…”

High-performance monoliths in heterogeneous catalysis with single-phase liquid flow

“…It enables the systematic optimization of reaction times and thus helps to avoid side and consecutive reactions, a major goal, e.g., in the preparation of pharmaceuticals and fine chemicals or platform molecules from biomass. [21][22][23] Until now, high-resolution reaction time control is only implemented for open-tubular microreactors, where reactions proceeding via non-catalytic or homogeneously catalyzed pathways usually start by mixing two reaction components and are quenched thermally or chemically. 1,[24][25][26] Inefficient heating, cooling, and mixing may bias the processed data.…”