Tandem Friedel‐Crafts‐Alkylation‐Enantioselective‐Protonation by Artificial Enzyme Iminium Catalysis

Abstract

The incorporation of organocatalysts into protein scaffolds holds the promise of overcoming some of the limitations of this powerful catalytic approach. Previously, we showed that incorporation of the non-canonical amino acid para-aminophenylalanine into the non-enzymatic protein scaffold LmrR forms a proficient and enantioselective artificial enzyme (LmrR_ pAF) for the Friedel-Crafts alkylation of indoles with enals. The unnatural aniline side-chain is directly involved in catalysis, operating via a well-known organocatalytic iminium-based mechanism. In this study, we show that LmrR_pAF can enantioselectively form tertiary carbon centres not only during CÀ C bond formation, but also by enantioselective protonation, delivering a proton to one face of a prochiral enamine intermediate. The importance of various side-chains in the pocket of LmrR is distinct from the Friedel-Crafts reaction without enantioselective protonation, and two particularly important residues were probed by exhaustive mutagenesis.

Review on Recent Developments in Biocatalysts for Friedel–Crafts Reactions

“…Roelfes and his group used the term "blank canvas" for the LmrR scaffold and proposed that the amino acid side chains in the LmrR scaffold's pocket could be exploited to promote a variety of catalytic processes. 48 Using ArMs, excellent enantioselectivity up to 99% (LmRr_A92E) was obtained. ArMs are a blossoming concept, and we firmly believe that their industrial potential will be shown up in the near future.…”

“…47 In one of their recent articles, the same group showed the potential of the LmrR_pAF scaffold for performing the challenging tandem F−C alkylation−enantioselective protonation (FC-EP) reaction. 48 Another noncanonical amino acid (8-hydroxyquinolin-3yl)alanine (HQAla) was also explored for catalyzing F−C reactions. Hydroxyquinoline has been used as an analytical reagent to bind transition metals through an N−O bidentate binding mode.…”

Biocatalytic Friedel‐Crafts Reactions

“…[116,[118][119][120] B. Organocatalytic artificial enzyme catalysed Friedel-Crafts alkylation [125] and (C.) tandem-enantioselective protonation reactions. [126] See references for full reaction conditions. features a designed catalytic triad based esterase active site.…”

“… A. Friedel‐Crafts alkylation catalysed by artificial enzymes based on copper(II) and MDR protein scaffolds [116,118–120] . B. Organocatalytic artificial enzyme catalysed Friedel‐Crafts alkylation [125] and (C.) tandem‐enantioselective protonation reactions [126] . See references for full reaction conditions.…”

“…Two rounds of directed evolution and one round of rational combination of individual beneficial mutations improved these metrics markedly, with the best triple mutant giving 87 % ee, and showing improved reactivity and selectivity with every tested substrate over the parent. This approach was also extended to α‐substituted α,β‐unsaturated aldehydes, where the stereo centre is formed by enantioselective protonation of an enamine intermediate (Scheme 10C) [126] . LmrR pAF affords the product with 88 % ee without the need for any further mutations.…”