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. 2023 Jun 7;145(22):12377-12385.
doi: 10.1021/jacs.3c03587. Epub 2023 May 22.

Aspartyl β-Turn-Based Dirhodium(II) Metallopeptides for Benzylic C(sp3)-H Amination: Enantioselectivity and X-ray Structural Analysis

Naudin van den Heuvel  1 , Savannah M Mason  1 , Brandon Q Mercado  1 , Scott J Miller  1
Affiliations

Aspartyl β-Turn-Based Dirhodium(II) Metallopeptides for Benzylic C(sp3)-H Amination: Enantioselectivity and X-ray Structural Analysis

Naudin van den Heuvel et al. J Am Chem Soc. .

Abstract

Amination of C(sp3)-H bonds is a powerful tool to introduce nitrogen into complex organic frameworks in a direct manner. Despite significant advances in catalyst design, full site- and enantiocontrol in complex molecular regimes remain elusive using established catalyst systems. To address these challenges, we herein describe a new class of peptide-based dirhodium(II) complexes derived from aspartic acid-containing β-turn-forming tetramers. This highly modular system can serve as a platform for the rapid generation of new chiral dirhodium(II) catalyst libraries, as illustrated by the facile synthesis of a series of 38 catalysts. Critically, we present the first crystal structure of a dirhodium(II) tetra-aspartate complex, which unveils retention of the β-turn conformation of the peptidyl ligand; a well-defined hydrogen-bonding network is evident, along with a near-C4 symmetry that renders the rhodium centers inequivalent. The utility of this catalyst platform is illustrated by the enantioselective amination of benzylic C(sp3)-H bonds, in which state-of-the-art levels of enantioselectivity up to 95.5:4.5 er are obtained, even for substrates that present challenges with previously reported catalyst systems. Additionally, we found these complexes to be competent catalysts for the intermolecular amination of N-alkylamides via insertion into the C(sp3)-H bond α to the amide nitrogen, yielding differentially protected 1,1-diamines. Of note, this type of insertion was also observed to occur on the amide functionalities of the catalyst itself in the absence of the substrate but did not appear to be detrimental to reaction outcomes when the substrate was present.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Selected chiral rhodium complexes and their applications, compared to the current work.
Figure 2.
Figure 2.
Synthesis of the initial dirhodium(II) peptide complex, with UPLC chromatograms of the crude reaction mixture and the purified complex.
Figure 3.
Figure 3.
(a) Scope and selected limitations of the amination reaction. aobtained with C2 instead of C1. bperformed with 2.0 equiv. of substrate and 1.0 equiv. of TfesNH2. (b) 1.0 mmol scale example of the enantioselective amination reaction. (c) Deprotection of the Tfes group.
Figure 4.
Figure 4.
(a) Rhodium-mediated formation of a 1,1-diamine product in the presence of an N,N-dimethylamide. (b) Attempted asymmetric version of the N-adjacent amination.
Figure 5.
Figure 5.
Self-amination of C1 as analyzed by LCMS.
Figure 6.
Figure 6.
Crystal structure of rac-C1·(MeOAc)2 and solution state characterization of C1 by 1H NMR. The axial methyl acetate ligands are removed for clarity. (a) Space-filling model viewed along the Rh-Rh bond axis. (b) Isolated view of the dirhodium core and ligand β-turn. (c) Axial view, showing the proximity of the different tetramer ligands to one another. (d) Equatorial view of the complex showing the inequivalent rhodium sites, one flanked by four cyclohexyl rings, the other by four prolyl rings. (e) Comparison of the 1H spectrum of the free peptide ligand and the dirhodium complex.
See this image and copyright information in PMC

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