1001058-64-5Relevant articles and documents
Unlocking Asymmetric Michael Additions in an Archetypical Class I Aldolase by Directed Evolution
Kunzendorf, Andreas,Xu, Guangcai,van der Velde, Jesse J. H.,Rozeboom, Henri?tte J.,Thunnissen, Andy-Mark W. H.,Poelarends, Gerrit J.
, p. 13236 - 13243 (2021/11/01)
Class I aldolases catalyze asymmetric aldol addition reactions and have found extensive application in the biocatalytic synthesis of chiral β-hydroxy-carbonyl compounds. However, the usefulness of these powerful enzymes for application in other C-C bond-forming reactions remains thus far unexplored. The redesign of class I aldolases to expand their catalytic repertoire to include non-native carboligation reactions therefore continues to be a major challenge. Here, we report the successful redesign of 2-deoxy-d-ribose-5-phosphate aldolase (DERA) fromEscherichia coli, an archetypical class I aldolase, to proficiently catalyze enantioselective Michael additions of nitromethane to α,β-unsaturated aldehydes to yield various pharmaceutically relevant chiral synthons. After 11 rounds of directed evolution, the redesigned DERA enzyme (DERA-MA) carried 12 amino-acid substitutions and had an impressive 190-fold enhancement in catalytic activity compared to the wildtype enzyme. The high catalytic efficiency of DERA-MA for this abiological reaction makes it a proficient “Michaelase” with potential for biocatalytic application. Crystallographic analysis provides a structural context for the evolved activity. Whereas an aldolase acts naturally by activating the enzyme-bound substrate as a nucleophile (enamine-based mechanism), DERA-MA instead acts by activating the enzyme-bound substrate as an electrophile (iminium-based mechanism). This work demonstrates the power of directed evolution to expand the reaction scope of natural aldolases to include asymmetric Michael addition reactions and presents opportunities to explore iminium catalysis with DERA-derived catalysts inspired by developments in the organocatalysis field.
Reactivity and Selectivity of Iminium Organocatalysis Improved by a Protein Host
N?dling, Alexander R.,?widerek, Katarzyna,Castillo, Raquel,Hall, Jonathan W.,Angelastro, Antonio,Morrill, Louis C.,Jin, Yi,Tsai, Yu-Hsuan,Moliner, Vicent,Luk, Louis Y. P.
supporting information, p. 12478 - 12482 (2018/09/06)
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 ? 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.
Remote sulfonamido group enhances reactivity and selectivity for asymmetric michael addition of nitroalkanes to α,β-unsaturated aldehydes
Huang, Yu-Chao,Uang, Biing-Jiun
supporting information, p. 2444 - 2448 (2014/11/07)
The pyrrolidine-camphorsulfonamide-based catalyst 1 a catalyzes the enantioselective conjugate addition of nitroalkanes to α,β- unsaturated aldehydes in the presence of five equivalents of water in iPrOH to give the corresponding chiral Michael adducts in good yields and high enantioselectivities (up to 99 % ee) with a catalyst loading as low as 1 mol%.
