Synthesis and conformational analysis of bicyclic extended dipeptide surrogates.
Regio- and diastereoselective reactions of a homoproline enolate enable the synthesis of novel extended dipeptide surrogates. Bicyclic carbamate 9 and fused beta-lactam scaffold 11 were prepared from L-pyroglutamic acid via substrate-controlled electrophilic azidation. Synthesis of orthogonally protected hexahydropyrrolizine, hexahydropyrrolizinone, and hexahydropyrroloazepinone dipeptide surrogates relied on allylation of proline derivative 5, followed by Curtius rearrangement to introduce the N-terminal carbamate group. A total of six azabicycloalkane derivatives were evaluated for conformational mimicry of extended dipeptides by a combination of X-ray diffraction and molecular modeling. Analysis of putative backbone dihedral angles and N- to C-terminal dipeptide distances indicate that compounds (alpha'S)-14b and 21 approximate the conformation of dipeptides found in beta-sheets, while tripeptide mimic 28 is also highly extended in the solid state. Structural data suggest that ring size and relative stereochemistry have a profound effect on the ability of these scaffolds to act as beta-strand mimetics and should inform the design of related conformational probes.
Ranatunga
Sujeewa
S
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico 88003, USA.
Liyanage
Wathsala
W
Del Valle
Juan R
JR
D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D021241:Spectrometry, Mass, Electrospray Ionization
D001643:Bridged Bicyclo Compounds; D004151:Dipeptides