Summary
Since the discovery of suitable Chan-Lam conditions for peptide esterification hints were given
towards non-epimerized peptide esters. To further test this hypothesis dipeptides containing very
racemization-prone phenylglycine residues were synthesized. Boc-Phe-L-Phg-OH and its
diastereoisomer Boc-Phe-D-Phg-OH were prepared in 80+ % yield and subjected to Chan-Lam
conditions using tris-(4-methylthiophenyl)boroxine as phenyl donor. In general yields were 70+ %
and no sign of epimerization of the peptide (4-methylthio)phenyl (MTP) esters was observed, under
condition that the peptide acids were recrystallized.
Subsequent oxidation of the MTP moiety to (4-methylsulfonyl)phenyl (MSO2P) with aid of Oxone
afforded active esters in quantitative yield. A decline in optical purity was not observed. Subsequent
ester aminolysis with H-Gly-OtBu or H-Val-OtBu afforded only mixtures of diastereoisomers,
demonstrating the base sensitivity of the activated phenylglycyl moiety.
An epimerization free coupling method was found in native chemical ligation (NCL). However, the
low solubility of the hydrophobic peptide esters in buffer required the use of a 1:1 ACN:Buffer
mixture. Exceptional ligation conditions were required to prevent side-chain acylated product.
Therefore the ester was added to excess cysteine to afford the tripeptides in 65-67% yield. UPLC
analysis revealed high diastereopurity of both peptides (>98%).
Furthermore electron-deficient boroxines were investigated which would obtain active esters.
Several were investigated but surprisingly 4-nitrophenyl (Np) esters could be prepared in 30-49%
yield starting from tris-(4-nitrophenyl)boroxine.