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

The incorporation of organocatalysts into protein scaffolds, i.e. the production of organocatalytic artificial enzymes, holds the promise of overcoming some of the limitations of this powerful catalytic approach. In particular, transformations for which good reactivity or selectivity is challenging for organocatalysts may find particular benefit from translation into a protein scaffold so that its chiral microenvironment can be utilised in catalysis. 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 C-C bond formation, but also by enantioselective protonation. Control over this process is an ongoing challenge for small-molecule catalysts for which general solutions do not exist. LmrR_pAF can selectively deliver a proton to one face of a prochiral enamine intermediate delivering product enantiomeric excesses and yields that rival the best organocatalyst for this transformation. 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. This study shows how organocatalytic artificial enzymes can provide solutions to transformations which otherwise require empirical optimisation and design of multifunctional small molecule catalysts.