Mild and convenient -formylation protocol in water-containing solvents.

We have realized that -formylations of free amines of some drug leads can improve PK/PD property of parent molecules without decreasing their biological activities. In order to selectively formylate amines of polyfunctional molecules, we have sought a mild and convenient formylation reaction. In our screening of -formylation of an α-amino acid, L-phenylalanine, none of formylation conditions reported to date yielded the desired HCO-L-Phe-OH with satisfactory yield. -Formylations of amino acids with HCOH require the reactions in a water-containing media and suppress polymerization reactions due to the competitive reactions among carboxylic acids. We found that -formylations of α-amino acids could be achieved with a water-soluble peptide coupling additive, an oxyma derivative, (2,2-dimethyl-1,3-dioxolan-4-yl)methyl-2-cyano-2-(hydroxyimino)acetate (), EDCI, and NaHCO in water or a mixture of water and DMF system, yielding -formylated α-amino acids with excellent yields. Moreover, these conditions could selectively formylate amines over amines at a controlled temperature. A usefulness of these conditions was demonstrated by selective formylation of daptomycin antibiotic which contains three different amino groups.