Synthesis of pipecolic acid-based spiro bicyclic lactam scaffolds as beta-turn mimics.
A series of 6.5.5 spiro bicyclic lactam scaffolds were synthesized from pipecolic acid in a sequence of reactions that was initiated with the alpha-allylation of tert-butoxycarbonyl pipecolic acid. Oxidative cleavage of the olefin to give an aldehyde followed by condensation with D-cysteine methyl ester gave a mixture of pipecolyl thiazolidines. Cyclization of the pipecolyl thiazolidines with Mukaiyama's reagent yielded the spiro bicyclic lactams 4a-d. Epimerization of the 7'a bridgehead carbon under acidic conditions was observed for those spiro bicyclic lactam scaffolds with an S stereochemistry at this position. The 6.5.5 spiro bicyclic lactam scaffold with the 3'S,6'R,7'aR stereochemistry mimicked a type II beta-turn, while the scaffold with the 3'S,6'S,7'aR stereochemistry mimicked a right-handed poly-d-proline II helix.
Somu
Ravindranadh V
RV
Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
Johnson
Rodney L
RL
D000447:Aldehydes / Q000737:chemistry; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis*; D002264:Carboxylic Acids / Q000737:chemistry; D003545:Cysteine / Q000737:chemistry; D007769:Lactams / Q000138:chemical synthesis*; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry; D010875:Pipecolic Acids / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011760:Pyrrolidinones / Q000737:chemistry; D013141:Spiro Compounds / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000737:chemistry
D000447:Aldehydes; D001643:Bridged Bicyclo Compounds; D002264:Carboxylic Acids; D007769:Lactams; D010455:Peptides; D010875:Pipecolic Acids; D011760:Pyrrolidinones; D013141:Spiro Compounds; D013843:Thiazines; C011083:polyproline; C031345:pipecolic acid; D003545:Cysteine