A cost and synthetic efficient method that enables facile reagent and solvent recycling in SPPS using cross-linked polystyrene resins in greener solvents is reported.
An SPPS method for the on-resin removal of acid labile protecting groups using TFA/TIS in EtOAc/MeCN and lactamization with PyBOP/DIEA in NBP/EtOAc is reported.
Aiming at advancing protocols for safer, environmentally sensible peptide synthesis we report our findings with regards to the occurrence of hydrogen cyanide (HCN, prussic acid) in amide bond forming reactions mediated by diisopropylcarbodiimide (DIC) and ethyl (hydroxyimino)cyanoacetate (Oxyma). We have determined that HCN is always formed in amide bond forming reactions on solid support in N,N-dimethylformamide (DMF) when employing DIC/Oxyma. In an attempt to minimize the formation of prussic acid by means of preventing the linear DIC/Oxyma adduct 2 from cyclizing to oxadiazole 3 and in turn releasing HCN, we evaluated a series of greener solvents such as N-butylpyrrolidinone (NBP), NBP/ethyl acetate (EtOAc, 1:1), methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate (PolarClean, PC), and PC/EtOAc (1:1). We found that the ratio between 2 and 3 greatly depends on the solvent used and consequently, we further examined DMF, NBP, NBP/EtOAc (1:1) and NBP/EtOAc (1:4) as solvents for DIC/Oxyma mediated amidations on solid support and in solution. We found that using carboxylic acid/Oxyma/DIC in a 1:1:1 ratio the rate of HCN formation decreases in the following order
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