Engineering and Exploiting Immobilized Peptide Organocatalysts for Modern Synthesis

Abstract

Short- and medium-sized peptides have long been used as effective and versatile organocatalysts. In the early 80s, Inoue used diketopiperazines in the Strecker reaction, while Juliá and Colonna reported the epoxidation of chalcone catalyzed by poly-L-Ala. Since then, a variety of peptide-catalyzed reactions have been described. However, peptide synthesis typically implicates the use of toxic reagents and generates wastes; therefore, peptide recycling is expected to significantly improve the overall sustainability of the process. Easy recovery and recycling of peptide catalysts can be expediently attained by covalent binding, inclusion, or adsorption. In addition, immobilization can significantly accelerate the screening of new peptide catalysts. For these reasons, diverse supports have been tested, including natural or synthetic polymers, porous polymeric networks, inorganic porous materials, organic-inorganic hybrid materials, and finally metal-organic frame-works.

Keywords: PEG; absorption; asymmetric catalysis; green chemistry; peptide organocatalyst; polystyrene; silica; β-turn.

Figure 1

Juliá–Colonna epoxidation of chalcone catalyzed by polyLeu, and a sketch of the proposed substrate-catalyst complex.

Figure 2

Asymmetric addition of hydrogen cyanide to benzaldehyde catalyzed by DKP.

Figure 3

Sketches of the structures of (a) polystyrene (PS) cross-linked with divinylbenzene (DVB), (b) polyethylene glycol grafted on polystyrene (PEG-PS), e.g., TentaGel S-NH₂ resin, (c) silica microstructure, (d) ordered mesoporous silica (OMS), (e) an example of microporous polymer network.

Figure 4

Direct aldol reaction using a supported dipeptide. The dipeptide containing a trans-4-styrenyl-Hyp was immobilized by thiol-ene coupling with mercaptomethyl-functionalized PS resin.

Figure 5

(a) Wennemers’ tripeptide catalysts for conjugate additions supported onto PS resins; (b,c) DMAP–peptide-resin conjugates for site-selective acylation of poly-hydroxylated compounds (the artificial DMAP-amino acid 1 is colored in pink); (d) hybrid tetrahydropyrane catalyst supported on PS.

Figure 6

Proposed model for the oxidation catalyzed by flavin-peptide hybrid supported on resin.

Figure 7

Aldol reactions between acetals and acetone using a one-pot tandem procedure.

Figure 8

β-Turn-helical peptide catalyst supported on PEG-PS for stereoselective hydrogenation.

Figure 9

Tandem oxidation/aldol reaction and peptide catalyst supported on TentaGel.

Figure 10

Wennemers’ tripeptidic catalyst for aldol reaction, supported on PEG-PS.

Figure 11

Resin immobilized β-turn-helical peptide catalyst for Friedel–Crafts alkylation of indoles.

Figure 12

Supported β-turn-helical peptide catalyst for conjugate addition of nitromethane.

Figure 13

Supported β-turn-helical peptide catalyst for cyclopropanation of enals.

Figure 14

Kinetic resolution of planar-chiral enal-ferrocenes by reduction of the unsaturated bond.

Figure 15

α-Amination of aldehydes catalyzed by a supported Pro-peptide.

Figure 16

Kinetic resolution of ansa-cyclophanes by sequential aldol/retro-aldol reaction, both catalyzed by supported peptides.

Figure 17

Identification of peptide catalysts for regioselective epoxidation.

Figure 18

Reaction between dye-marked malonate and an α,β-unsaturated aldehyde in the presence of resin-supported peptide catalysts. After reaction, colored resin beads were considered indicative of peptide catalysts, which effectively promoted the reaction.

Figure 19

Peptide catalysts supported on silica for aldol reactions, (a) anchored via APTES, (b) via ICPTES.

Figure 20

Synthesis of silica-grafted peptide catalyst scaffolds by Ugi reaction and application to subsequent conjugate addition, product isolation, and stereoisomer separation.

Figure 21

IEDDA ligation between norbornene-silica and peptide-tetrazine.

Figure 22

MPN-peptide catalyst obtained by IEDDA ligation between MPN-norbornene and peptide-tetrazine.

Figure 23

Al-MIL-101 MOFs functionalized with oligopeptide as catalyst for aldol reaction.

Figure 24

Absorption of Wennemers’ aldol peptide catalyst in silica-imidazolium.

Figure 25

Addition of branched aldehydes to maleimides promoted by dipeptides included into Mg/Al-hydrotalcite layers.

Figure 26

Conjugate addition promoted by Wennemers’ peptide adsorbed on nanocrystalline hydroxyapatite.