Computer-aided solvent design for suppressing HCN generation in amino acid activation

A highly toxic compound, hydrogen cyanide (HCN), was discovered to result from the reaction between Ethyl cyano (hydroxyimino) acetate (Oxyma) and diisopropylcarbodiimide (DIC), a popular reagent combination for amino acid activation. The reaction solvent has been found to influence the amount of HCN produced so that judicious solvent choice offers a route to suppressing HCN formation. Given the safety implications and the time-demanding nature of experimental solvent selection, we employ a methodology of quantum mechanical computer-aided molecular design (QM-CAMD) to design a new reaction solvent in order to minimize the amount of HCN formed. In this work, we improve on the original QM-CAMD approach with an enhanced surrogate model to predict the reaction rate constant from several solvent properties. A set of solvents is selected for model regression using model-based design of experiments (MBDoE), where the determinant of the information matrix of the design, known as D-criterion, is maximized. The use of a model-based approach is especially beneficial here as it links the large discrete space of solvent molecules to the reduced space of solvent properties. The resulting surrogate model exhibits an improved adjusted coefficient of determination and leads to more accurate predicted rate constants than the model generated without using MBDoE. The proposed DoE-QM-CAMD algorithm reaches convergence in one iteration. In the future, the main reaction of amino acid activation will be considered to design a solvent that maintains the rate of the main reaction while minimizing HCN generation.</p

Uncovering the Most Kinetically Influential Reaction Pathway Driving the Generation of HCN from Oxyma/DIC Adduct:A Theoretical Study

The combination of ethyl (hydroxyimino)cyanoacetate (Oxyma) and diisopropylcarbodiimide (DIC) has demonstrated superior performance in amino acid activation for peptide synthesis. However, it was recently reported that Oxyma and DIC could react to generate undesired hydrogen cyanide (HCN) at 20 °C, raising safety concerns for the practical use of this activation strategy. To help minimize the risks, there is a need for a comprehensive investigation of the mechanism and kinetics of the generation of HCN. Here we show the results of the first systematic computational study of the underpinning mechanism, including comparisons with experimental data. Two pathways for the decomposition of the Oxyma/DIC adduct are derived to account for the generation of HCN and its accompanying cyclic product. These two mechanisms differ in the electrophilic carbon atom attacked by the nucleophilic sp2-nitrogen in the cyclization step and in the cyclic product generated. On the basis of computed “observed” activation energies, ΔGobs⧧, the mechanism that proceeds via the attack of the sp2-nitrogen at the oxime carbon is identified as the most kinetically favorable one, a conclusion that is supported by closer agreement between predicted and experimental 13C NMR data. These results can provide a theoretical basis to develop a design strategy for suppressing HCN generation when using Oxyma/DIC for amino acid activation.</p

Continuous Platform To Generate Nitroalkanes On-Demand (in Situ) Using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor

The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with the use of peracid to prepare nitroalkane substrates and the nitroalkanes themselves. In response, a continuous and scalable chemistry platform to prepare aliphatic nitroalkanes on-demand using the oxidation of oximes with peracetic acid and direct reaction of the nitroalkane intermediate in an aza-Henry reaction is reported. A uniquely designed pipes-in-series plug-flow tube reactor addresses a range of process challenges, including stability and safe handling of peroxides and nitroalkanes. The subsequent continuous extraction generates a solution of purified nitroalkane, which can be directly used in the following enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors with high selectivity, thus completely avoiding isolation of the potentially unsafe low-molecular-weight nitroalkane intermediate. A continuous campaign (16 h) established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution