Aryl hydrazides as linkers for solid phase synthesis which are cleavable under mild oxidative conditions

Tetrahedron Letters

Volumn 39, Issue 39, 1998, Pages 7201-7204

  Millington, Christopher R ^a   Quarrell, Rachel ^a   Lowe, Gordon ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Linkers; Oxidative cleavage; Peptide synthesis; Solid phase synthesis

Indexed keywords

HYDRAZIDE DERIVATIVE;

ARTICLE; BIOASSAY; DRUG DEGRADATION; DRUG OXIDATION; DRUG SYNTHESIS; SOLID PHASE EXTRACTION;

EID: 0032563916     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)01543-3     Document Type: Article

References (19)

1. 1 For recent reviews see: Lowe, G., Chem. Soc. Revs. 1995, 309-317, and Terret, N.K.; Gardner, M.; Gordon, D.W.; Kobylecki, R.J.; Steele, J. Tetrahedron 1995, 53, 8135.
2. 1 For recent reviews see: Lowe, G., Chem. Soc. Revs. 1995, 309-317, and Terret, N.K.; Gardner, M.; Gordon, D.W.; Kobylecki, R.J.; Steele, J. Tetrahedron 1995, 53, 8135.
3. 2 For a review of current linkers refer to: Sucholeiki, I in Combinatorial Chemistry-Synthesis and Application ed. Wilson, S.R. and Czarnik, A.W., John Wiley and Sons, 1997, 119-133.
4. 3 Newbold, B.T. in "The Chemistry of the hydrazo, azo and azoxy group" Part 1, ed. Patai, S., John Wiley and Sons, 1975, 542.
5. 4 Fehling, H.; Ann. Chem. Pharm. 1849, 72, 106.
6. 5 Semenov, A.N.; Gordeev, K., Int. J. Pept. Prot. Res. 1995, 45, 303-304.
7. 6 Abbreviations: Boc, t-butyloxycarbonyl; Cbz, benzyloxycarbonyl; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DCCI, N,N′-dicyclohexylcarbodiimide; Fmoc, 9-fluorenylmethoxycarbonyl; HOBt, 1-hydroxybenzotriazole; PTSA, p-toluenesulphonic acid; TFA, trifluoroacetic acid; Pmc, pentamethylchromansulphonyl; Trt, trityl.
8. 7 DBU is incompatible with copper (II) acetate/methanol causing the copper to drop out of solution as an insoluble salt.
9. 8 Fmoc-HBA was synthesised in a single step from 4-hydrazino-benzoic acid (26 mmol) in dioxane (35 ml)/10% sodium bicarbonate (aq) (65 ml), with Fmoc-Cl (28 mmol) in dioxane (35 ml). The product was recrystallised from EtOH/EtOAc in 75% yield.
10. 9 NovaSyn® TG resin (Novabiochem) was used and the symmetrical anhydride formed using DCCI. Three couplings were required using a five fold excess of reagent for each coupling.
11. 10 β-alanine was initially employed but was poorly resolved in the amino acid analysis, however p-chlorophenylalanine had a very distinct retention time and was easily identified.
12. 11 King, D.S.; Fields, C.G.; Fields, G.B., Int. J. Pept. Prot. Res. 1990, 36, 255.
13. 12 For a guide to Fmoc methodology see: Atherton, E; Sheppard, R.C., Solid Phase Synthesis: A Practical Approach, IRL Press, Oxford, 1989.
14. 13 Chelex is a commercially available cation exchange resin, purchased from the Sigma Chemical Co.
15. 14 In amide work-up, excess amine should be removed prior to use of Chelex due to competitive coordination which limits copper (II) removal. When producing esters, Chelex-promoted hydrolysis should be minimised by addition of acetic acid to neutralise the base prior to removal of copper ions.
16. 15 For N-acylated peptides the solvents and excess base were evaporated off and the product extracted using DCM and 0.5 M HCl (aq).
17. tBu (Glu, Ser, Thr, Tyr) and Boc (Lys).
18. 17 Plunkett, M.J.; Ellman, J.A.; J.Org. Chem. 1995, 60, 6006-6007.
19. 18. Fmoc-hydrazinobenzoylaminomethyl-polystyrene is available from Calbiochem-Novabiochem (see letter 2/98). The linker attached to the new high-load PEG-PS resin will be available from the same company shortly.