Highly enantioselective carbene insertion into N–H bonds of aliphatic amines

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Science  22 Nov 2019:
Vol. 366, Issue 6468, pp. 990-994
DOI: 10.1126/science.aaw9939

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A tag team approach to forming C–N bonds

Many pharmaceutical compounds contain carbon-nitrogen (C–N) bonds in just one of two mirror-image orientations. Forging these bonds with electron-rich nitrogen reactants is challenging because the nitrogen groups can coordinate with, and thus interfere with, the catalyst. Li et al. report a cooperative approach to overcoming this obstacle (see the Perspective by Ovian and Jacobsen). They used a copper catalyst to activate the carbon reactant and then a hydrogen-bonding thiourea catalyst to set the product geometry with high selectivity. The reaction is compatible with a broad range of diazo ester and amine coupling partners.

Science, this issue p. 990; see also p. 948


Aliphatic amines strongly coordinate, and therefore easily inhibit, the activity of transition-metal catalysts, posing a marked challenge to nitrogen-hydrogen (N–H) insertion reactions. Here, we report highly enantioselective carbene insertion into N–H bonds of aliphatic amines using two catalysts in tandem: an achiral copper complex and chiral amino-thiourea. Coordination by a homoscorpionate ligand protects the copper center that activates the carbene precursor. The chiral amino-thiourea catalyst then promotes enantioselective proton transfer to generate the stereocenter of the insertion product. This reaction couples a wide variety of diazo esters and amines to produce chiral α-alkyl α–amino acid derivatives.

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