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

Bilal A. Aleiwi, Katsuhiko Mitachi, Michio Kurosu

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

We have realized that N-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 primary amines of polyfunctional molecules, we have sought a mild and convenient formylation reaction. In our screening of N-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 a water-containing media and suppress polymerization reactions due to the competitive reactions among carboxylic acids. We found that N-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 NaHCO3 in water or a mixture of water and DMF system, yielding N-formylated α-amino acids with excellent yields. Moreover, these conditions could selectively formylate primary amines over secondary amines at a controlled temperature. A usefulness of these conditions was demonstrated by selective formylation of daptomycin antibiotic which contains three different amino groups.

Original languageEnglish (US)
Pages (from-to)2077-2081
Number of pages5
JournalTetrahedron Letters
Volume54
Issue number16
DOIs
StatePublished - Apr 17 2013

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Amines
Amino Acids
Water
Daptomycin
Molecules
Carboxylic Acids
Bioactivity
Phenylalanine
Polymerization
Screening
Acetates
Anti-Bacterial Agents
Derivatives
Peptides
Temperature
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Mild and convenient N-formylation protocol in water-containing solvents. / Aleiwi, Bilal A.; Mitachi, Katsuhiko; Kurosu, Michio.

In: Tetrahedron Letters, Vol. 54, No. 16, 17.04.2013, p. 2077-2081.

Research output: Contribution to journalArticle

Aleiwi, Bilal A. ; Mitachi, Katsuhiko ; Kurosu, Michio. / Mild and convenient N-formylation protocol in water-containing solvents. In: Tetrahedron Letters. 2013 ; Vol. 54, No. 16. pp. 2077-2081.
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