Enantioselective synthesis of (2R, 3S)- and (2S, 3R)-4,4,4-trifluoro-N-Fmoc-O-tert-butyl-threonine and their racemization-free incorporation into oligopeptides via solid-phase synthesis.
An efficient method for the enantioselective synthesis of (2R, 3S)- and (2S, 3R)-4,4,4-trifluoro-N-Fmoc-O-tert-butyl-threonine on multigram scales was developed. Absolute configurations of the two stereoisomers were ascertained by X-ray crystallography. Racemization-free coupling conditions for the incorporation of tfT into oligopeptides were then explored. For solution-phase synthesis, tfT racemization was not an issue under conventional coupling conditions. For solid-phase synthesis, the following conditions were identified to achieve racemization-free synthesis: if tfT (3.0 equiv) was not the first amino acid to be linked to the resin (1.0 equiv), the condition is 2.7 equiv DIC/3.0 equiv HOBt as the coupling reagent at 0 degrees C for 20 h; if tfT (3.0 equiv) was the first amino acid to be linked to the resin (1.0 equiv), then 1.0 equiv of CuCl(2) needs to be added to the coupling reagent.
Xiao
Nu
N
Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA.
Jiang
Zhong-Xing
ZX
Yu
Y Bruce
YB
D002851:Chromatography, High Pressure Liquid / Q000379:methods; D020650:Combinatorial Chemistry Techniques; D005449:Fluorenes / Q000138:chemical synthesis* / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013912:Threonine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
C526777:4,4,4-trifluoro-N-fluorenylmethoxycarbonyl-O-tert-butylthreonine; D005449:Fluorenes; D009842:Oligopeptides; D013912:Threonine
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