Reactivity and Selectivity of Iminium Organocatalysis Improved by a Protein Host

• Published in: Angewandte Chemie International Edition Vol. 57; no. 38; pp. 12478 - 12482
• Main Authors: Nödling, Alexander R., Świderek, Katarzyna, Castillo, Raquel, Hall, Jonathan W., Angelastro, Antonio, Morrill, Louis C., Jin, Yi, Tsai, Yu‐Hsuan, Moliner, Vicent, Luk, Louis Y. P.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 17.09.2018; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: Binding Sites; Biotin; Biotin - chemistry; Biotin - metabolism; Biotinylation; Catalysis; Chemistry; Chemistry, Multidisciplinary; Communication; Communications; Computer simulation; Crystal structure; enzyme models; Gas Chromatography-Mass Spectrometry; Hydrogen Bonding; Imines - chemistry; Molecular Conformation; molecular dynamics; Molecular Dynamics Simulation; organocatalysis; Physical Sciences; Protein structure; Proteins; Pyrrolidine; Science & Technology; Stereoisomerism; Stereoselectivity; Streptavidin; Streptavidin - chemistry; Streptavidin - metabolism; supramolecular chemistry; CATALYSIS; ASYMMETRIC CONJUGATE ADDITION; ARTIFICIAL TRANSFER HYDROGENASES; METALLOENZYMES; DIPHENYLPROLINOL SILYL ETHER; molecular dynamics; BIOTIN-STREPTAVIDIN TECHNOLOGY; enzyme models; DIRECTED EVOLUTION; MICHAEL ADDITION; organocatalysis; proteins; AVIDIN TECHNOLOGY; STEREOGENIC CENTERS; supramolecular chemistry
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201806850

There has been growing interest in performing organocatalysis within a supramolecular system as a means of controlling reaction reactivity and stereoselectivity. Here, a protein is used as a host for iminium catalysis. A pyrrolidine moiety is covalently linked to biotin and introduced to the protein host streptavidin for organocatalytic activity. Whereas in traditional systems stereoselectivity is largely controlled by the substituents added to the organocatalyst, enantiomeric enrichment by the reported supramolecular system is completely controlled by the host. Also, the yield of the model reaction increases over 10‐fold when streptavidin is included. A 1.1 Å crystal structure of the protein–catalyst complex and molecular simulations of a key intermediate reveal the chiral scaffold surrounding the organocatalytic reaction site. This work illustrates that proteins can be an excellent supramolecular host for driving stereoselective secondary amine organocatalysis. The perfect host: A supramolecular system for stereoselective secondary amine organocatalysis was developed based on the streptavidin‐biotin technology. The results combined from catalyst screening, protein crystallography, and molecular simulations clearly reveal that both the reactivity and stereoselectivity are dictated by the protein host.