Synthesis of Siphonazole B Through Domino Cycloisomerization-Oxazolonium Ion Rearrangements

Filip Paulsen; Sebastian Clementson; Henrik von Wachenfeldt; Michał Antoszczak; Simon Fridolf; Daniel Strand

doi:10.1002/chem.202501394

Synthesis of Siphonazole B Through Domino Cycloisomerization-Oxazolonium Ion Rearrangements

Chemistry. 2025 Jun 19:e202501394. doi: 10.1002/chem.202501394. Online ahead of print.

Authors

Filip Paulsen^{1

2}, Sebastian Clementson¹, Henrik von Wachenfeldt^{1

2}, Michał Antoszczak³, Simon Fridolf¹, Daniel Strand¹

Affiliations

¹ Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, Lund, SE-221 00, Sweden.
² RG Discovery, Medicon Village, Lund, SE-223 81, Sweden.
³ Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, Poznań, 61‒614, Poland.

PMID: 40536015
DOI: 10.1002/chem.202501394

Abstract

4-Alkenyl- and 4-acyloxazoles represent important substructures across a diverse array of bioactive molecules. Practical methods to synthesize these motifs are, therefore, of considerable interest. Here, we develop a novel domino process wherein a cycloisomerization is followed by a 1,2-rearrangement via an oxazolonium ion to yield 4-alkenyloxazoles from an abundant β-chloro-N-benzyl propargylamine and acyl chlorides. The synthetic utility of the method is highlighted by its application to both oxazole units of siphonazole B, leading to a concise convergent total synthesis of this natural product.

Keywords: domino reactions; natural product synthesis; oxidative amidation; rearrangements.

Abstract

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