期刊
TETRAHEDRON LETTERS
卷 54, 期 16, 页码 2077-2081出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tetlet.2013.02.013
关键词
N-formylation; Reactions in water media; Water-soluble Oxyma; Glyceroacetonide-Oxyma; Amino acids; Kanamycin; Spectinomycin; Daptomycin
资金
- National Institutes of Health (NIAID) [AI084411-02]
- The University of Tennessee
- NIH Shared Instrumentation Grant
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 alpha-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 alpha-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 alpha-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. (c) 2013 Elsevier Ltd. All rights reserved.
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