Reliable design of artificial metalloenzymes (ArMs) that—like natural enzymes—accelerate and control reactivity, but catalyse transformations not observed in Nature, remains an unsolved and important challenge. We report that a monomeric streptavidin (mSav) Rh(III) ArM permits asymmetric synthesis of α,β-unsaturated-δ-lactams via a novel tandem C-H activation and [4+2] annulation reaction. These products are readily derivatized to enantioenriched piperidines – the most common <i>N</i>-heterocycle found in FDA approved pharmaceuticals. mSav ArM, but not the more commonly used tetrameric form (tSav), couples substituted <i>N</i>-pivaloyloxy acrylamides with diverse styrenes under mild conditions. Desired δ-lactams are achieved in yields as high as 99% and enantiomeric excess of 97%. Studies show that Rh(III) catalysis in the mSav protein scaffold can give up to a 168-fold rate acceleration relative to the isolated biotinylated Rh(III) cofactor.

Accelerated asymmetric δ-lactam synthesis with a monomeric streptavidin artificial metalloenzyme

2019 Spring National Meeting

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