Stereoretentive cross-coupling of chiral amino acid chlorides and hydrocarbons through mechanistically controlled Ni/Ir photoredox catalysis

Published in Chemistry

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Figure 1. Proposed strategy towards chiral α-amino ketones

Chiral α-amino acids and their derivatives are among the most widely utilized compounds in organic and medicinal chemistry. In particular, α-amino ketones are privileged structures that often serve as key intermediates in synthetic transformations and as core moieties in a wide array of drugs and biologically active molecules. However, the streamlined synthesis of chiral α-amino ketones directly from naturally optically active α-amino acids remains challenging due to their high tendency to racemize even under mild reaction conditions.

The classical Liebeskind-Srogl type reaction employing thioesters alongside organometallic reagents such as organozinc or organoboron species is one of the most representative methods to access chiral α-amino ketone products. Although efficient, these protocols have significant limitations in terms of atom economy and applicability because of the necessity of using organometallic nucleophiles. Moreover, the scope of organometallic coupling partners has mainly been restricted to aromatic compounds, making structural diversification challenging. 

With these challenges in mind, we envisioned that the direct coupling of naturally occurring chiral α-amino acids and simple C(sp3)–H bonds under mild reaction conditions would be an ideal synthetic method for accessing structurally diverse chiral α-amino ketones, as it may offer enriched synthetic applicability in a practical and sustainable manner. Our investigation commenced with our previous study on the cross-coupling of N-acylsuccinimides with hydrocarbon substrates (Angew. Chem. Int. Ed. 2020, 59, 16933). We believed that this might provide an indirect platform to construct various chiral α-amino ketones with a natural chiral pool with simple coupling partners. However, the synthesis and purification of amino acid-derived N-acylsuccinimides proved exceptionally challenging due to their low solubility in organic solvents and high polarity. In addition, due to their practical insolubility in the reaction solvent, no conversion was observed when they were subjected to the standard reaction conditions.

To overcome this problem, we turned our attention to utilizing amino acid chlorides which are easily accessible. Nevertheless, the undesired reactivity of amino acid chlorides under the previously developed reaction conditions due to the formation of unstable acylnickel(II) intermediate called for a new mechanistic breakthrough. To address this challenge, a completely different reaction pathway was devised. To circumvent the problematic oxidative addition of acyl chlorides, we envisioned a single electron reduction based approach through the in situ formation of N-acyllutidinium intermediate. Reduction of this species would lead to the formation of an acylnickel(III) species, accelerating C–H activation and reductive elimination while kinetically inhibiting undesirable side reactions. Utilizing this strategy, a wide array of chiral amino ketone products could be prepared through the direct coupling of amino acid chlorides and hydrocarbons. In-depth mechanistic studies through computational and experimental means were also performed to verify our hypothesis. We believe that the present findings demonstrate successful mechanistic control to realize a challenging coupling reaction in Ni/photoredox catalysis, which can provide further insight into the development of new synthetic methods. Further details can be found here: “Stereoretentive Cross-Coupling of Chiral Amino Acid Chlorides and Hydrocarbons Through Mechanistically Controlled Ni/Ir Photoredox Catalysis” in Nature Communications,

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