Enantioselective access to L-Carnosine via one-pot catalytic protocol

The worldwide demand for L-Carnosine continues to rise, fuelled by its increasing use in nutritional supplements, pharmaceutical formulations, and cosmetic products. This naturally occurring dipeptide, consisting of β-alanine and L-histidine, is well known for its antioxidant properties and its role in energy metabolism, and it has shown promising therapeutic relevance in disorders including diabetes, Alzheimer’s disease, and Parkinson’s disease.[1] To address the need for a more sustainable and high-performing synthetic approach capable of delivering L-Carnosine with excellent yield and enantiomeric purity, we designed an efficient one-pot synthetic strategy (Figure 1) based on ethyl methyl (Z)-2-(2-cyanoacetamido)-3-(1H-imidazol-4-yl)acrylate, selected as a Privileged Precursor (PP) for L-Carnosine production. The methodology involves an initial asymmetric hydrogenation of the C=C double bond of the PP catalysed by [RhCOD(R,R)-Ephos]+TfO⁻, followed by reduction of the cyano group using a heterogeneous Rh/C catalyst under basic conditions.[2,3] Both transformations were conducted sequentially in a single reaction vessel without intermediate purification, enabling the direct formation of L-Carnosine with an overall yield of 68% and enantiomeric excess value reaching 73%, as determined by HPLC-MS analysis. Although this approach markedly simplifies the synthetic and downstream processing steps, ongoing optimization efforts are aimed at enhancing its suitability for industrial-scale implementation.