Solid-phase synthesis of a library of hydroxyproline derivatives.
The synthesis of a library of N-alkylated O-arylated hydroxyproline derivatives has been achieved on solid phase. The choice of O-protection and the optimization of the Mitsunobu reaction involving a secondary alcohol were key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-O-THP-hydroxyproline was accomplished readily. Subsequent deprotection of the Fmoc and reductive amination with different aldehydes resulted in the tertiary amine intermediate. The deprotection of the THP group by p-toluenesulfonic acid was followed by a Mitsunobu reaction with a series of phenols. Finally, the products were cleaved from the resin using trifluoroacetic acid to produce a 10 200 member library.
Vergnon
Anne L
AL
3-Dimensional Pharmaceuticals, Inc., 8 Clarke Drive, Cranbury, New Jersey 08512, USA.
Pottorf
Richard S
RS
Player
Mark R
MR
D000215:Acylation; D000438:Alcohols; D000447:Aldehydes / Q000737:chemistry; D000478:Alkylation; D001557:Benzenesulfonates; D006909:Hydroxyproline / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D014269:Trifluoroacetic Acid
D000438:Alcohols; D000447:Aldehydes; D001557:Benzenesulfonates; D007202:Indicators and Reagents; D014269:Trifluoroacetic Acid; C029501:4-toluenesulfonic acid; D006909:Hydroxyproline