Gallou, Fabrice (2019) Site selective amide reduction of cyclosporine A yields derivatives of an important cyclic peptide. organic letters, 21 (9). pp. 3451-3455.

Abstract

The development of amide reduction catalysts able to function under mild conditions has enabled the development of novel reactions on a complex structure that has been the subject of extensive synthetic studies for its diverse medical effects. While the origins of the innate site-selectivity is as of yet un-clear, the B2-Cat system targets residues not targeted in other systems. The reduction chemistry herein has doubled the num-ber of known amide reduction CsA derivatives. Reduction of secondary amide (Ala7) reveals a secondary amine prone to diversity generating reactivity. Ala7 exists at a position which may modulate both cyclophilin and calcineurin binding. Fur-thermore, the B2-Cat catalyzed amide reductions can be di-rected with secondary silanes in the described case to select for MeBmT1 reduction over other sites. We also report that the O-silyl hemiaminal intermediate (A) can be intercepted to form new C–C bonds. These studies provide a framework which can be used in combination with other reduction chemistries to gen-erate unique selectivities with applications in late-stage func-tionalization of cyclic peptides.

Item Type:	Article
Date Deposited:	02 Jul 2019 00:45
Last Modified:	02 Jul 2019 00:45
URI:	https://oak.novartis.com/id/eprint/38950