Convenient preparation of 4-formyl-3,5-dimethoxyphenol and its incorporation into linkers and resins for solid-phase synthesis

Journal of Combinatorial Chemistry

Volumn 3, Issue 1, 2001, Pages 97-101

  Jin, Jian ^a   Graybill, Todd L ^a   Wang, Michelle A ^a   Davis, Larry D ^a   Moore, Michael L ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0002326232     PISSN: 15204766     EISSN: None     Source Type: Journal    
DOI: 10.1021/cc000077j     Document Type: Article

References (23)

1. Albericio, F.; Kneib-Cordonier, N.; Biancalana, S.; Gera, L.; Masada, R. I.; Hudson, D.; Barany, G. Preparation and Application of the 5-(4-(9-Fluorenylmethyloxycarbonyl)-aminomethyl-3,5-dimethoxyphenoxy)valeric Acid (PAL) Handle for the Solid-Phase Synthesis of C-Terminal Peptide Amides under Mild Conditions. J. Org. Chem. 1990, 55, 3730-3743 and references therein.
2. Jensen, K. J.; Alsina, J.; Songster, M. F.; Vagner, J.; Albericio, F.; Barany, G. Backbone Amide Linker (BAL) Strategy for Solid-Phase Synthesis of C-Terminal-Modified and Cyclic Peptides. J. Am. Chem. Soc. 1998, 120, 5441-5452.
3. α-9-fluorenylmethoxycarbonyl (Fmoc) Solid-Phase Synthesis of Unprotected Peptide p-Nitroanilides and Thioesters. J. Org. Chem. 1999, 64, 8761-8769.
4. For example, see: (a) Yamashita, D. S.; Dong, X.; Oh, H -J.; Brook, C. S.; Tomaszek, T. A.; Szewczuk, L.; Tew, D. G.; Veber, D. F. Solid-Phase Synthesis of a Combinatorial Array of 1,3-Bis(acylamino)-2-butanones, Inhibitors of the Cysteine Proteases Cathepsins K and L. J. Comb. Chem. 1999, 1, 207-215.
5. (b) Gordeev, M. F.; Luehr, G. W.; Patel, D. V.; Ni, Z. J.; Gordon, E. Preparation of Oxazolidinones as Bactericides. WO 9937630, 1999.
6. (c) Hansen, T. K.; Peschke, B.; Lau, J.; Lundt, B. F.; Ankersen, M.; Watson, B.; Madsen, K. Compounds with Growth Hormone Releasing Properties. WO 9723508, 1997.
7. (d) Graybill, T. L.; Jin, J.; Wang, M. A.; Moore, M. L. Unpublished results.
8. Ngu, K.; Patel, D. V. A New and Efficient Solid-Phase Synthesis of Hydroxamic Acids. J. Org. Chem. 1997, 62, 7088-7089.
9. (a) Boojamra, C. G.; Burow, K. M.; Ellman, J. A. An Expedient and High-Yielding Method for the Solid-Phase Synthesis of Diverse 1,4-Benzodiazepine-2,5-diones. J. Org. Chem. 1995, 60, 5742-5743.
10. (b) Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. Solid-Phase Synthesis of 1,4-Benzodiazepine-2,5-diones. Library Preparation and Demonstration of Synthesis Generality. J. Org. Chem. 1997, 62, 1240-1256.
11. (c) Gray, N. S.; Kwon, S.; Schultz, P. G. Combinatorial Synthesis of 2,9-Substituted Purines. Tetrahedron Lett. 1997, 38, 1161-1164.
12. (d) del Fresno, M. D.; Alsina, J.; Royo, M.; Barany, G.; Albericio, F. Solid-Phase Synthesis of Diketopiperazines, Useful Scaffolds for Combinatorial Chemistry. Tetrahedron Lett. 1998, 39, 2639-2642.
13. These linkers are available from a number of commercial sources (e.g., 4-formyl-3,5-dimethoxyphenol (1) is available from Aldrich Chemical Co.). However, cost considerations, small lot size, supply variability, and regioisomer issues prompted our efforts reported herein.
14. Landi, J. J., Jr.; Ramig, K. Regioselective Preparation of 4-Formyl-3,5-dimethoxyphenol, An Intermediate in the Synthesis of the PAL Solid-Phase Peptide Synthesis Handle. Synth. Commun. 1991, 21, 167-171. The authors reported difficulty isolating pure 1 from the Vilsmeier product mixture. In this paper they describe an alternative regiospecific three-step synthesis of 4-formyl-3,5-dimethoxyphenol (1) via ortho-directed metalation/formylation of 1-trisisopropylsiloxy-3,5-dimethoxybenzene. While this three-step synthesis provides regiopure 1 in quantities sufficient to prepare small combinatorial libraries (see Ellman et al. ref 6a,b), it was deemed less attractive for larger-scale work.
15. Barany et al. have demonstrated that mixtures of 4-formyl and 2-formyl-3,5-dimethoxyphenol can be used to prepare linkers 2 and 3 (note: Figure 1 shows only the structure derived from 4-formyl-3,5-dimethoxyphenol) without significantly compromising yield and purity of peptidyl C-terminal-carboxamide products when cleaved under optimized conditions (reagent A or R, see ref 1). We are unaware of any subsequent comparative studies that confirm these observations when regioisomeric BAL linkers are employed for preparation of structurally diverse non-peptide libraries (particularly those obtained using less "optimal" cleavage conditions).
16. Hansen et al. (see ref 4c) have since reported scaled up preparations of Barany's original synthesis of 4-formyl-3,5-dimethoxyphenol (1) and linker 3. However, the preparations described herein offer improved yields at 10-fold larger scale.
17. A total of 40% of the starting Merrifield resin was not converted to resin 4 based on the chlorine content (2.5%) of the dried product resin.
18. (a) Rink, H. Solid-phase Synthesis of Protected Peptide Fragments Using a Trialkoxy-diphenyl-methylester Resin. Tetrahedron Lett. 1987, 28, 3787-3790.
19. (b) Hodges, J. C. Covalent Scavengers for Primary and Secondary Amines. Synlett. 2000, 1, 152-158.
20. (c) Cichy-Knight, M. A.; Ali, F. E.; Moore, M. L.; Veber, D. F. Unpublished results.
21. Bui, C. T.; Rasoul, F. A.; Ercole, F.; Pham, Y.; Maeji, N. J. Efficiencies of Reductive Amination Reactions on Different Solid Supports. Tetrahedron Lett. 1998, 39, 9279-9282.
22. Unintended release of this electron-rich anchoring point is occasionally observed when functionalized supports such as resin 4 are treated with solutions of TFA during cleavage (acid lability of benzylic ether C-O bond).
23. While compounds 9 and 2 are mentioned in the literature, no analytical data has been reported for these compounds.