A novel protecting/activating strategy for beta-hydroxy acids and its use in convergent peptide synthesis.
beta-Hydroxy acids were reacted with hexafluoroacetone and carbodiimides to give carboxy-activated six-membered lactones in good yields. On reaction with amines, the corresponding amides were obtained. We demonstrate the following applications of this protecting/activating strategy: preparation of carboxamides in solution and on solid phase (both normal and reverse mode); recovery and reuse of the excess material in solid-phase synthesis; and convergent solid-phase peptide synthesis (CSPPS) with peptide segments bearing C-terminal Ser or Thr with very low levels of epimerization (<1%, HPLC).
Spengler
Jan
J
Institute for Research in Biomedicine, Barcelona Science Park, Josep Samitier 1-5, E-08028 Barcelona, Spain. jan.spengler@irbbarcelona.com
Ruíz-Rodríguez
Javier
J
Yraola
Francesc
F
Royo
Miriam
M
Winter
Manfred
M
Burger
Klaus
K
Albericio
Fernando
F
D000096:Acetone / Q000031:analogs & derivatives / Q000737:chemistry; D000577:Amides / Q000138:chemical synthesis; D000596:Amino Acids / Q000737:chemistry; D002234:Carbodiimides / Q000737:chemistry; D005449:Fluorenes / Q000737:chemistry; D005466:Fluorocarbons / Q000737:chemistry; D006880:Hydroxy Acids / Q000737:chemistry*; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry; D008293:Malates / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis*; D006845:Hydrocarbons, Fluorinated
D000096:Acetone; D000577:Amides; D000596:Amino Acids; D002234:Carbodiimides; D005449:Fluorenes; D005466:Fluorocarbons; D006880:Hydroxy Acids; D007783:Lactones; D008293:Malates; D010455:Peptides; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; C030298:malic acid; C017366:hexafluoroacetone; D006845:Hydrocarbons, Fluorinated