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Practical Synthesis of Iboxamycin, a Potent Antibiotic Candidate, in Amounts Suitable for Studies in Animal Infection Models

preprint
submitted on 29.03.2021, 13:38 and posted on 01.04.2021, 04:31 by Jeremy Mason, Daniel W. Terwilliger, Aditya R. Pote, Andrew G. Myers
A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation–oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp3–sp2 Negishi coupling, and a one-pot transacetalization–reduction reaction to form the target compound’s oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its in vivo profiling in murine models of infection.

Funding

LEO Foundation (grant LF18006)

History

Email Address of Submitting Author

jeremy.d.mason2@gmail.com

Institution

Harvard University

Country

United States

ORCID For Submitting Author

0000-0002-1039-0773

Declaration of Conflict of Interest

A.G.M. has filed international patent applications WO/2019/032936 and WO/2019/032956 ‘Lincosamide An-tibiotics and Uses Thereof’

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