The Hydroxyl Groups of Serine and Threonine

Common protectors of hydroxyls are benzyl and 2-bromobenzyl for Boc chemistry and tert-butyl for Fmoc chemistry. Trityl provides a third level of selectivity for both chemistries because it can be removed by mild acid (1% CF3C02H in CH2C12), which does not affect tert-butyl based protectors. O-Allyl is not removable by palladium-catalyzed allyl transfer, so it is not appropriate. Protection by acyl such as benzyloxycarbonyl is possible, but 0 -acyl protectors can be problematic because of their tendency to shift to adjacent amino groups (see Section 6.6) and 

H Romovacek, SR Dowd, K Kawasaki, N Nishi, K Hofmann. Studies on polypeptides. 54. The synthesis of a peptide corresponding to positions 24-104 of the peptide chain of ribonuclease I, (acyl azides) J Am Chem Soc 101, 6081, 1979. 

VM Titov, EA Meshcheryakova, TA Balashova, TM Andronova, VT Ivanov. Synthesis and immunological evaluation of the conjugates composed from muramyl peptide GMDP and tuftsin. (Z-Thr-ONSu) Int J Pept Prot Res 45, 348, 1995. 

H Mostafavi, S Austermann, W-G Forssmann, K Adermann. Synthesis of phospho-urodilatin by combination of global phosphorylation with the segment coupling approach. (Fmoc-Ser-OH + TBTU + H-Xaa-OR) Int J Pept Prot Res 48, 200, 1996. 

L Meng, H Auth, CM Crews. Eponemycin analogues synthesis and use as probes for angiogenesis. (RC02H + TBTU + H-Ser-OR) Bioorg Med Chem 6, 1209, 1998. 

---

Glycosidic Linkages to the Hydroxyl Groups of Serine and Threonine Residues... 

Direct proof for the existence of O-glycosidic linkages involving the hydroxyl groups of serine and threonine was provided simultaneously from three laboratories. Anderson et al. (39) reported partial losses of serine and threonine after treatment with 0.52V NaOH (or 0.452V KOH) at 4°C or room temperature for about 20 hours. Subsequent reduction with platinum showed formation of some alanine and < -aminobutyric acid. Harbon et al (40) treated ovine submaxillary glycoprotein at pH 12.8 for 45 minutes at 70 °C. The serine and threonine content decreased by 78 and 60%, respectively. Treatment of this product with 0.1M sulfite, (pH 9, 24 hours, room temperature) caused a conversion of the dehydroserine residues to cysteic acid, but had no action on the dehydrothreonine residues. This reaction has been further studied by Simpson et al. (41). 

Phosphoproteins. An important group that includes many major food proteins. Phosphate groups are linked to the hydroxyl groups of serine and threonine. This group includes casein of milk and the phosphoproteins of egg yolk. 

The hydroxyl group of serine and threonine should have a characteristic deformation mode, probably in the region 1350-1250 cm" in the IR (Bellamy, 1975). In j3-(Ser) , it has been assigned to a Raman band at 1399 cm" (Koenig and Sutton, 1971). Since this mode is likely to be mixed with other backbone vibrations, it is probably a poor group frequency. 

Allyl esters have been used for carboxyl group protection in Q-glycopeptide synthesis. Standard glycosylation procedures were used to substitute the hydroxyl groups of serine and threonine H-Cbz esters, and the peptide chains were extended following dealkylation using Pd(0)-catalysed allyl transfers. ... 

Peptides and amino acids may be sulfated the hydroxyl groups of serine and threonine reacted with chlorosulfonic acid in trifluoroacetic acid to give the O-sulfate esters. The free amino groups did not react since they were completely protonated in the strongly acidic media and the rates of sulfonation were determined. Peptides containing the above amino acids were also sulfated. The aromatic amino acids tyrosine and tryptophan, by treatment with chlorosulfonic acid-trifluoroacetic acid, afforded the arylsulfonic acid derivatives. In the solid phase synthesis of cholecystokinin-33, tyrosine has been sulfated to the O-sulfate with chlorosulfonic acid and this was incorporated into the peptide sequence. ... 

---