Design, synthesis, and conformational analysis of eight-membered cyclic peptidomimetics prepared using ring closing metathesis.
As part of a program to identify novel scaffolds that adopt defined secondary structure when incorporated into peptides, we have designed and prepared a library of constrained eight-membered ring lactams based upon 7-amino-8-oxo-1,2,3,6,7-pentahydroazocine-2-carboxylic acid. Ring closing metathesis (RCM) was employed as the key step, proceeding in high yields to afford the Z olefin. In this reaction sequence, the first generation benzylidene ruthenium RCM catalyst was superior to the second-generation imidazoline catalyst, which gave extensive oligomerization at higher concentrations. Conformational analysis of the 2S,7S and 2R,7S stereoisomers revealed that the 2R,7S isomer is a Type VIa beta-turn in the solid state (X-ray crystal structure) and in water (NMR analysis). The Type VIa beta-turn is relatively rare, typically bearing the cis amide bond found in proline-containing sequences. The 2S,7S diastereomer has an extended geometry of the pendent amide chains. The corresponding saturated derivatives (7-amino-8-oxoazocane-2-carboxylic acid) were also synthesized and investigated. The 2S,7S azocane bears an extended geometry and mimics the C(+) conformer of ox-[Cys-Cys], found in a variety of naturally occurring peptides. The scaffolds described here are useful for the design of constrained peptidomimics with defined secondary structure.
Creighton
Christopher J
CJ
Drug Discovery Division, PO Box 776, Welsh and McKean Rds., Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, PA 19477-0777, USA.
Leo
Gregory C
GC
Du
Yanming
Y
Reitz
Allen B
AB
D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry*; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry*; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry*
D004151:Dipeptides; D007769:Lactams; D010456:Peptides, Cyclic