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

Abstract

An efficient method for the enantioselective synthesis of (2R, 3S)-and (2S, 3R)-4,4,4-trifluoro-NFmoc-O-tert-butyl-threonine (tfT) on multi-gram 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 eq.) was not the first amino acid to be linked to the resin (1.0 eq.), the condition is: 2.7 eq. DIC/3.0 eq. HOBt as the coupling reagent at 0 °C for 20 h; if tfT (3.0 eq.) was the first amino acid to be linked to the resin (1.0 eq.), then 1.0 eq. of CuCl 2 needs to be added to the coupling reagent.

Introduction of the 4,4,4-Trifluorobut-2-ene Chain Exploiting a Regioselective Tsuji–Trost Reaction Catalyzed by Palladium Nanoparticles

“…Indeed, a combined isolated yield of 81% was obtained because the crude mixture of diastereoisomers (58:42) could be separated by flash chromatography. Finally, asymmetric Sharpless dihydroxylation could also be performed, and diol (−)- 11 was obtained in good yield and excellent enantioselectivity (>99% ee). , …”

Separation of fluorinated amino acids and oligopeptides from their non-fluorinated counterparts using high-performance liquid chromatography

“…(2 S , 3 S )- N -Fmoc- O-tert -butyl-threonine ( 5 ) was purchased from BACHEM. (2 S , 3 R )-4,4,4-trifluoro- N -Fmoc- O-tert -butyl-threonine ( 6 ) was synthesized and purified by us as described in a previous publication [18]. Fmoc-norvaline ( 11 ) and Fmoc-norleucine ( 12 ) were purchased from Aapptec.…”

“…HOBt, no base, 0.5 eq. CuCl 2 ·2H 2 O in DMF/DCM (1/1), 0 °C, 16 h. CuCl 2 was added to reduce racemization [18]. Cyclic peptides ( 7 and 8 ) were made by crosslinking the two cysteine residues in each peptide (intra-molecular S-S bond) in 10 mM ammonium acetate aqueous solution containing 17% DMSO (pH 7.0).…”

Fluorinated dendrimers as imaging agents for 19F MRI

“…Our group started working on 19 F imaging agents around 2005. After some initial trials and errors with different types of fluorinated molecules, we settled on fluorinated bifunctional dendrimers . The fundamental reason for using dendrimers is that the spherical symmetry of the dendritic structure makes it possible to incorporate multiple chemically identical fluorine atoms into one dendrimer, greatly enhancing the 19 F signal intensity per imaging agent molecule.…”