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Synthesis of 1,4-oxazepane-2,5-diones via cyclization of rotationally restricted amino acid precursors and structural reassignment of serratin

  • Ruysbergh, Ewout
  • Van Hecke, Kristof
  • Stevens, Christian
  • De Kimpe, Norbert
  • Mangelinckx, Sven
Publication Date
Jan 01, 2017
Ghent University Institutional Archive
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Several natural products containing a 1,4-oxazepane-2,5-dione-core are known. One example is serratin, isolated from Serratia marcescens. Because of the presence of a carboxylic amide, which has a preference for a trans conformation, and the presence of a labile lactone in this core, many synthetic methodologies commonly used for the cyclization toward medium-sized heterocycles cannot be applied. As N-acyl amino acids lacking a third substituent at nitrogen failed to undergo ring-closure, several N-protecting groups were evaluated. With the use of the removable PMB-group, an N-unsubstituted 1,4-oxazepane-2,5-dione was synthesized. Via the application of pseudoprolines (i.e. serine-derived oxazolidines as another type of protecting group), a compound with the presumed structure of the natural product serratin was obtained. As a result of the differences in spectral data, the incorrect structural assignment of the natural product serratin was identified. Instead of the predicted seven-membered heterocycle, a symmetrical serratamolide analogue is proposed to be the correct structure of serratin.

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