An Expeditive Method for the Synthesis of Arginine-Based Chemical Libraries

Abstract

The synthesis of a stable guanidylated aldehyde and its use in an Ugi multicomponent reaction (U-4CR) was described and used for the synthesis of a library of arginine derivatives using both solution and solid phase synthesis.

arginine derivatives - solid phase synthesis - Ugi reaction

References

1 Gicquel S. Mazarguil H. Desprat C. Allard M. Devillers JP. Simonnet G. Zajac JM. J. Med. Chem.  1994,  37:  3477 

2 Rudolf K. Eberlein W. Engel W. Wieland HA. Willim KD. Entzeroth M. Wienen W. Beck-Sickinger AG. Doods HN. Eur. J. Pharmacol.  1994,  271:  R11-13  

3 Aiglstorfer I. Hendrich I. Moser C. Bernhardt G. Dove S. Buschauer A. Bioorg. Med. Chem. Lett.  2000,  10:  1597 

4 Vincent JP. Mazella J. Kitabgi P. Trends Pharmacol. Sci.  1999,  20:  302 

5 Bourguignon JJ. Collot V. Didier B. Laulin G. Simonnet G. Proceedings of the XIVth International Symposium on Medicinal Chemistry   Elsevier Scientific; Amsterdam: 1997.  p.35-44  

6 Bonini JA. Jones KA. Adham N. Forray C. Artymyshyn R. Durkin MM. Smith KE. Tamm JA. Boteju LW. Lakhlani PP. Raddatz R. Yao WJ. Ogozalek KL. Boyle N. Kouranova EV. Quan Y. Vaysse PJ. Wetzel JM. Branchek TA. Gerald C. Borowsky B. J. Biol. Chem.  2000,  275:  39324 

7 Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 

8 Uno T. Beausoleil E. Goldsmith RA. Levine BH. Zuckermann RN. Tetrahedron Lett.  1999,  40:  1475 

9 Owens TD. Semple JE. Org. Lett.  2001,  3:  3301 

10 Guichard G. Briand JP. Friede M. Pept. Res.  1993,  6:  121 

11 Feichtinger K. Sings HL. Baker TJ. Matthews K. Goodman M. J. Org. Chem.  1998,  63:  8432 

12 Mc Dougal P. Rico JG. Young-Im O. Condon BD. J. Org. Chem.  1986,  51:  3388 

13 Read MW. Miller MW. Ray PS. Tetrahedron  1999,  55:  373 

14 Drake B. Patek M. Lebl M. Synthesis  1994,  6:  579 

15 Carretero JC. Gomez-Arrayas R. J. Org. Chem.  1998,  63:  2993 

16

Synthesis of Compound 1d:
A mixture of 4-aminobutanal diethylacetal (33 mmoles, 1 equiv) and 2,4-dimethoxybenzaldehyde (33 mmoles, 1 equiv) and benzene (90 mL) was heated at 105 °C for 3 h, using a Dean-Stark trap. The solvent was removed by evaporation under reduced pressure and the residue was dissolved in anhyd MeOH (60 mL). NaBH₄ (43.8 mmoles, 1.3 equiv) was added in portion to the stirred solution at 10 °C. The reaction was warmed to r.t., stirred for a further 1 h, and quenched with sat. NH₄Cl solution. Then, the mixture was basified with sat. K₂CO₃ solution and evaporated under reduced pressure. The residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried with sodium sulfate and evaporated to give 10.9 g of an orange oil (compound 8). Yield: 100%.
¹H NMR (300 MHz, CDCl₃): δ = 1.17-1.21 (t, 6 H, J = 7.02 Hz), 1.54-1.65 (m, 4 H), 2.57-2.62 (t, 2 H, J = 6.85 Hz), 3.43-3.53 (m, 2 H), 3.58-3.68 (m, 2 H), 3.71 (s, 2 H), 3.79 (s, 3 H), 3.80 (s, 3 H), 4.46-4.50 (t, 1 H, J = 5.29 Hz), 6.41-6.45 (m, 2 H), 7.11-7.13 (d, 1 H, J = 7.8 Hz).
A mixture of compound 8 (23.9 mmoles, 1 equiv) and pmc-1H-pyrazole-1-carboxamidine (26.3 mmoles, 1 equiv) in dry DMF (44 mL) was heated in a sealed tube for 48 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and a sat. NH₄Cl solution. The organic layer was washed with brine, dried with Na₂SO₄ and evaporated. The crude product was purified by chromatography on silica gel, eluting first with hexane/ethyl acetate (2/1) and then with hexane/ethyl acetate (1/1) to give 12.09 g of a colorless oil (compound 11). Yield: 82%.
¹H NMR (300 MHz, CDCl₃): δ = 1.13-1.18 (t, 6 H, J = 6.96 Hz), 1.30 (s, 6 H), 1.52-1.59 (m, 4 H), 1.77-1.82 (t, 2 H, J = 6.78 Hz), 2.09 (s, 3 H), 2.53-2.63 (m, 8 H), 3.32-3.44 (m, 4 H), 3.54-3.60 (m, 2 H), 3.77 (s, 6 H), 4.39-4.42 (m, 3 H), 6.34-6.44 (m, 4 H), 6.97-7.00 (d, 1 H, J = 8.67 Hz).
The compound 11 (19.5 mmoles, 1 equiv) was dissolved in HOAc/H₂O (2/1) (240 mL) and the mixture was stirred at r.t. overnight. The solution was cooled to 0 °C, alkalinised with sat. K₂CO₃ solution, and extracted with ethyl acetate. The organic layer was washed with sat. K₂CO₃ solution and then with brine, dried with Na₂SO₄ and evaporated under reduced pressure to give 10.6 g of a white foam (compound 1d).
¹H NMR (300 MHz, CDCl₃): δ = 1.31 (s, 6 H), 1.78-1.83 (m, 4 H), 2.10 (s, 3 H), 2.40-2.45 (t, 2 H, J = 6.54 Hz), 2.57-2.65 (m, 8 H), 3.30-3.36 (t, 2 H, J = 7.47 Hz), 3.80 (s, 6 H), 4.39 (s, 2 H), 6.36-6.57 (m, 4 H), 7.00-7.03 (d, 1 H, J = 8.4 Hz), 9.64 (s, 1 H).
¹³C NMR (200 MHz, CDCl₃): δ = 12.48, 17.86, 18.91, 20.19, 21.80, 27.14, 33.26, 41.01, 46.18, 46.98, 55.81, 73.93, 99.01, 104.87, 118.18, 124.17, 130.45, 134.48, 135.11, 135.78, 153.68, 156.02, 158.27, 161.19, 202.54.
R_f 0.62 (EtOAc)

17 Ugi I. Meyr R. Fetzer U. Steinbrückner C. Angew. Chem.  1959,  71:  386 

18 Szardenings AK. Burkoth TS. Lu HH. Tien DW. Campbell DA. Tetrahedron  1997,  53:  6573