Preparation of Enantiopure β-Amino Acids by Homologation of α-Amino Acids

α-Arylamino Diazoketones: Diazomethane-Loading Controlled Synthesis, Spectroscopic Investigations, and Structural X-ray Analysis

“…α-Diazoketones represent a versatile class of organic compounds given the plethora of transformations that the reactive diazo moiety can undergo . In particular, it could act as precursor of β-lactams, β-amino acid derivatives, and, in general, β-peptides via the Wolff rearrangement or as a placeholder for transition-metal-catalyzed reactions (e.g., carbenoid chemistry, cyclopropanation, ylide-mediated processes) . Effectively, the contemporaneous presence of an amino group renders the corresponding α-amino diazoketones very interesting from a synthetic medicinal chemistry perspective (Figure ).…”

“…So far, the most common access to α-amino diazoketones is constituted by the Arndt–Eistert-type diazotization , of an activated carboxylic functionality ( VII , Scheme ) such as a chloride or a (mixed) anhydride with diazomethane (CH 2 N 2 ). , However, a series of widely known drawbacks limits the applicability of these procedures: (a) the approach is evidently nonattractive from a synthetic perspective because the activation and the diazotization steps need to be repeated in parallel for the full series of amino acids; (b) as a consequence of the hazardous and safety issues of using an explosive (bp −23 °C) and a carcinogenic and skin irritant as diazomethane is, it does not represent an ideal process for suitable industrial applications; (c) the success of the method strongly depends on the nature of the substituents on the aminic nitrogen which could lead to substantial decomposition of the products; (d) from a chemoselective perspective the resulting α-amino diazoketones are contaminated by variable amounts of the corresponding methyl esters or α-halomethyl ketones (Nierenstein process) generated through side reactions dependent on the conditions employed for the activation; (e) the direct diazotization of an optically active acid chloride leads to considerable racemization and thus, the employment of synthetically noneconomical activation as mixed anhydride still remains the preferred method to overcome this issue. , For example, Siciliano and Liguori reported an effective one-pot preparation of N- Fmoc protected diazoketones highlighting the dual role of Fmoc-Cl as both protecting group source and carboxylic moiety activator agent for the diazotization . Notwithstanding, the innate potential of C 1 homologations realized with diazomethane still continues to attract interest within the synthetic community, , and the advent of microfluidic techniques allowed the design of safe reliable processes for methyl ester production, synthesis of pyrazoles or β-amino acids, , as well as Pd-catalyzed cyclopropanations, inter alia .…”