title: Mild and convenientN-formylation protocol in water-containing solvents.
abstract: We have realized thatN-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 formylateprimaryamines of polyfunctional molecules, we have sought a mild and convenient formylation reaction. In our screening ofN-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.N-Formylations of amino acids with HCO2H require the reactions in a water-containing media and suppress polymerization reactions due to the competitive reactions among carboxylic acids. We found thatN-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 (2), EDCI, and NaHCO3in water or a mixture of water and DMF system, yieldingN-formylated α-amino acids with excellent yields. Moreover, these conditions could selectively formylateprimaryamines oversecondaryamines at a controlled temperature. A usefulness of these conditions was demonstrated by selective formylation of daptomycin antibiotic which contains three different amino groups.
authors.affiliation: Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163, USA.
authors.forename: Bilal A
authors.initials: BA
authors.lastname: Aleiwi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mitachi
authors.forename: Michio
authors.initials: M
authors.lastname: Kurosu
keywords: Amino acids; Daptomycin; Glyceroacetonide-oxyma; Kanamycin; N-formylation; Reactions in water media; Spectinomycin; Water-soluble oxyma
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