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Synlett 2002(12): 2003-2006
DOI: 10.1055/s-2002-35580
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Sébastien Guery, Martine Schmitt*, Jean-Jacques Bourguignon
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 CNRS/ULP, Université Louis Pasteur, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch-Graffenstaden, France
Fax: +33(3)90244310; e-Mail: schmitt@pharma.u-strasbg.fr;
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Publication History

Received 23 August 2002
Publication Date:
20 November 2002 (online)

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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.

Key words

arginine derivatives - solid phase synthesis - Ugi reaction

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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.
Rf 0.62 (EtOAc)