A convenient protocol for selective cleavage of 2-hydroxy acid amides. Application to semisynthesis of the cyclic heptapeptide aza HUN-7293.
A two-step protocol for the first chemoselective cleavage of 2-hydroxy acid amides has been developed. Mesylation of the model substrate 2-(hydroxypropionylamino)-4-methylpentanoic acid methyl ester (11) followed by treatment with N-ethylthiourea (13) allows cleavage of 2-hydroxy acid amides under smooth conditions. Successful application of this methodology to the open-chain transesterification product 15 (methylester) of the cyclic heptadepsipeptide HUN-7293, a potent inhibitor of inducible cell adhesion molecule expression, delivered the corresponding hexapeptide 18 with unprotected N-terminus in 70-75% yield. This result demonstrates that the protocol developed even works in the presence of an ester and several methylated and unmethylated amide bonds. Finally, a sequence of ligation of methyl D-dehydroglutaminate (20) to the C-terminus of the saponification product 21, followed by the degradation protocol and ring closure, allowed chemical "point mutation" at the DGCN site affording the aza analogue of HUN-7293 (24) in 15% overall yield. To the best of our knowledge this is the first report on chemoselective cleavage of 2-hydroxy acid amides.
Schreiner
Erwin P
EP
Novartis Forschungsinstitut, Brunner Strasse 59, A-1235 Vienna, Austria. erwin.schreiner@pharma.novartis.com
Kern
Michael
M
Steck
Andrea
A
D000577:Amides / Q000737:chemistry*; D000595:Amino Acid Sequence; D002384:Catalysis; D002448:Cell Adhesion / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D006880:Hydroxy Acids / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000032:analysis / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D000577:Amides; C097977:HUN 7293; D006880:Hydroxy Acids; D010456:Peptides, Cyclic