This article is dedicated to the memory of Professor Murray Goodman (1928–2004).
Improved synthesis of 5-hydroxylysine (Hyl) derivatives*
Article first published online: 24 JAN 2005
The Journal of Peptide Research
Volume 65, Issue 2, pages 272–283, February 2005
How to Cite
Cudic, M., Lauer-Fields, J.L. and Fields, G. B. (2005), Improved synthesis of 5-hydroxylysine (Hyl) derivatives. The Journal of Peptide Research, 65: 272–283. doi: 10.1111/j.1399-3011.2005.00215.x
- Issue published online: 5 DEC 2008
- Article first published online: 24 JAN 2005
- Dates: Received 8 October 2004 Revised 8 November 2004 Accepted 21 November 2004
- solid-phase synthesis;
- unusual amino acids
Abstract: The synthesis of 5-hydroxylysine (Hyl) derivatives for incorporation by solid-phase methodologies presents numerous challenges. Hyl readily undergoes intramolecular lactone formation, and protected intermediates often have poor solubilities. The goals of this work were twofold: first, develop a convenient method for the synthesis of O-protected Fmoc-Hyl; secondly, evaluate the efficiency of methods for the synthesis of O-glycosylated Fmoc-Hyl. The 5-O-tert-butyldimethylsilyl (TBDMS) fluoren-9-ylmethoxycarbonyl-Hyl (Fmoc-Hyl) derivative was conveniently prepared by the addition of tert-butyldimethylsilyl trifluoromethanesulfonate to copper-complexed Hyl[ɛ-tert-butyloxycarbonyl (Boc)]. The complex was decomposed with Na+ Chelex resin and the Fmoc group added to the α-amino group. Fmoc-Hyl(ɛ-Boc, O-TBDMS) was obtained in 67% overall yield and successfully used for the solid-phase syntheses of 3 Hyl-containing peptides. The preparation of Fmoc-Hyl[ɛ-Boc, O-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)] was compared for the thioglycoside, trichloroacetimidate and Koenigs–Knorr methods. The most efficient approach was found to be Koenigs–Knorr under inverse conditions, where Fmoc-Hyl(ɛ-Boc)-OBzl and peracetylated galactosyl bromide were added to silver trifluoromethanesulfonate in 1,2-dichloroethane, resulting in a 45% isolated yield. Side-reactions that occurred during previously described preparations of glycosylated Hyl derivatives, such as lactone formation, loss of side-chain protecting groups, orthoester formation, or production of anomeric mixtures, were avoided here. Research on the enzymology of Lys hydroxylation and subsequent glycosylation, as well as the role of glycosylated Hyl in receptor recognition, will be greatly aided by the convenient and efficient synthetic methods developed here.