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Asymmetric catalysis

Unnatural α-amino acid synthesis

Nature Synthesis (2023)Cite this article

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Direct, stereocontrolled functionalization of ubiquitous C(sp3)–H bonds represents the most efficient route towards highly valuable molecules from feedstock chemicals. Now, diverse, enantioenriched, unnatural α-amino acids are obtained from readily available carboxylic acids in one step via iron-catalysed asymmetric nitrene transfer, overcoming the reactivity and selectivity challenges of intermolecular C–H amination.

Now, writing in Nature Synthesis, Meggers, Chen and co-workers report an enantioselective intermolecular NT strategy to convert convenient carboxylic acids into unnatural α-amino acids, which are essential synthetic building blocks (Fig. 1b)12. Here, the carboxylic acid moiety serves as a directing group for the nitrene insertion event, while enantioselectivity is imparted by a chiral iron catalyst. Although directed C–H activations employing carboxylic acids are well precedented with noble metals (such as Pd, Rh and Ir) via inner-sphere cyclometalation, analogous strategies are underdeveloped for outer-sphere processes, including nitrene-mediated C–H amination. This method is also appealing for its simple catalyst design, which employs iron, one of the most earth-abundant metals, as well as a chiral and modular bis(benzimidazole)–bipyrrolidine-based ligand scaffold. In addition, the amino functionality can be installed using common N-protecting groups, most notably the tert-butyloxycarbonyl (Boc) group, highlighting the versatility of this method for post-functionalization.

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Fig. 1: Enantioselective intermolecular C–H amination via nitrene transfer.

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  1. Department of Chemistry, University of Wisconsin, Madison, WI, USA

    Tuan Anh Trinh & Jennifer M. Schomaker

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  1. Tuan Anh Trinh
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  2. Jennifer M. Schomaker
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Correspondence to Jennifer M. Schomaker.

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Trinh, T.A., Schomaker, J.M. Unnatural α-amino acid synthesis. Nat. Synth (2023). https://doi.org/10.1038/s44160-023-00278-7

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