Chiral α-amino acids and their derivatives are among the many most generally utilized compounds in natural and medicinal chemistry. Specifically, α-amino ketones are privileged constructions that usually function key intermediates in artificial transformations and as core moieties in a wide selection of medication and biologically lively molecules. Nevertheless, the streamlined synthesis of chiral α-amino ketones immediately from naturally optically lively α-amino acids stays difficult as a consequence of their excessive tendency to racemize even beneath gentle response situations.
The classical Liebeskind-Srogl kind response using thioesters alongside organometallic reagents akin to organozinc or organoboron species is among the most consultant strategies to entry chiral α-amino ketone merchandise. Though environment friendly, these protocols have vital limitations when it comes to atom economic system and applicability due to the need of utilizing organometallic nucleophiles. Furthermore, the scope of organometallic coupling companions has primarily been restricted to fragrant compounds, making structural diversification difficult.
With these challenges in thoughts, we envisioned that the direct coupling of naturally occurring chiral α-amino acids and easy C(sp3)–H bonds beneath gentle response situations can be an excellent artificial technique for accessing structurally various chiral α-amino ketones, as it might provide enriched artificial applicability in a sensible and sustainable method. Our investigation commenced with our earlier research on the cross-coupling of N-acylsuccinimides with hydrocarbon substrates (Angew. Chem. Int. Ed. 2020, 59, 16933). We believed that this may present an oblique platform to assemble numerous chiral α-amino ketones with a pure chiral pool with easy coupling companions. Nevertheless, the synthesis and purification of amino acid-derived N-acylsuccinimides proved exceptionally difficult as a consequence of their low solubility in natural solvents and excessive polarity. As well as, as a consequence of their sensible insolubility within the response solvent, no conversion was noticed after they have been subjected to the usual response situations.
To beat this drawback, we turned our consideration to using amino acid chlorides that are simply accessible. Nonetheless, the undesired reactivity of amino acid chlorides beneath the beforehand developed response situations because of the formation of unstable acylnickel(II) intermediate referred to as for a brand new mechanistic breakthrough. To handle this problem, a totally totally different response pathway was devised. To avoid the problematic oxidative addition of acyl chlorides, we envisioned a single electron discount based mostly method via the in situ formation of N-acyllutidinium intermediate. Discount of this species would result in the formation of an acylnickel(III) species, accelerating C–H activation and reductive elimination whereas kinetically inhibiting undesirable aspect reactions. Using this technique, a wide selection of chiral amino ketone merchandise may very well be ready via the direct coupling of amino acid chlorides and hydrocarbons. In-depth mechanistic research via computational and experimental means have been additionally carried out to confirm our speculation. We imagine that the current findings show profitable mechanistic management to appreciate a difficult coupling response in Ni/photoredox catalysis, which might present additional perception into the event of latest artificial strategies. Additional particulars will be discovered right here: “Stereoretentive Cross-Coupling of Chiral Amino Acid Chlorides and Hydrocarbons By way of Mechanistically Managed Ni/Ir Photoredox Catalysis” in Nature Communications, https://www.nature.com/articles/s41467-022-32851-7.