Synlett 2005(8): 1319-1321  
DOI: 10.1055/s-2005-865221
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Short Synthesis of Methyl 3α,7α,12α-Triaminocholanoate, the ‘Triaza-Analogue’ of Methyl Cholate

Vicente del Amoa, Khadga Bhattaraia, Maija Nissinenb, Kari Rissanenb, M. Nieves Pérez-Payánc, Anthony P. Davis*a
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
Fax: +44(117)9298611; e-Mail: anthony.davis@bristol.ac.uk;
b University of Jyväskylä, Department of Chemistry, P.O. Box 35, 40351 Jyväskylä, Finland
c Department of Chemistry, Trinity College, Dublin 2, Ireland
Further Information

Publication History

Received 10 November 2004
Publication Date:
14 April 2005 (online)

Abstract

Triamine 2a, a facial amphiphile and precursor for anion receptors, has been prepared in just four steps from the inexpensive steroid cholic acid.

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Two sets of conditions were used: (i) THF, NaHCO3 aq, r.t., 48 h (as described in ref.10), and (ii) MeOH, Et3N, 50 °C, 12 h. The latter method proved more convenient and effective. Details are given in ref.16 below.

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Crystal data for 9: C40H69N3O0.5 CH2Cl2, M = 762.45, a = 14.9131 (4), b = 20.251 (1), c = 32.299 (1) Å, V = 9754.5 (6) Å3, orthorhombic, C2221 (No. 20), Z = 8, D c = 1.038 g·cm-3, µ(MoKα) = 0.124 mm-1, F(000) = 3320, colourless crystal of size 0.20 × 0.20 × 0.30 mm, T = 173 ± 0.1 K. 19433 reflections collected, 8525 unique (R int = 0.074), 5049 reflections (I > I) were used in refinement. R1 = 0.0930 and wR2 = 0.2161 for data I > I and 500 parameters and R1 = 0.1607and wR2 = 0.2508 for all data. Absolute structure parameter refined -0.3 (3), Goodness of fit on F 2 = 1.109. CCDC-250336 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (internat.) +44 (1223)336033; email: deposit@ccdc.cam.ac.uk].

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Hydrogenation of Trioxime 5.
Trioxime 5 (1.4 g, 3.03 mmol), PtO2·H2O (186 mg, 0.76 mmol) and AcOH (31 mL) were stirred vigorously for 5 d under 60 atmospheres of hydrogen. The solution was filtered under reduced pressure and evaporated. The residue was dissolved in CHCl3-i-PrOH (9:1) and washed with Na2CO3 (aq sat.). The aqueous phase was extracted with 3 portions of CHCl3-i-PrOH (9:1). The combined organic layers were dried (MgSO4), filtered, and evaporated. Flash chromatography on silica gel, eluting with CHCl3-MeOH-NH3 aq (28% NH3 in H2O; 85:10:5) afforded 2a (413 mg, 32%) as an off-white solid; R f = 0.16.17 1H NMR (400 MHz, CDCl3): δ = 0.78 (s, 3 H, 18-CH3), 0.93 (s, 3 H, 19-CH3), 0.99 (d, J = 5.4 Hz, 3 H, 21-CH3), 3.05 (m, 1 H, 3β-H), 3.30 (br s, 1 H, 3β-H), 3.30 (br s, 1 H, 7β-H), 3.47 (s, 3 H, CO2CH3), 3.50 (s, 1 H, 12β-H). For characterisation as 9, triamine 2a (300 mg, 0.71 mmol) was dissolved in MeOH (7 mL), Et3N (400 µL, 290 mg, 2.9 mmol) and di-tert-butyldicarbonate (624 mg, 2.86 mmol) were added and the mixture was stirred overnight at 50 °C. Evaporation, dissolution in CH2Cl2-EtOAc (98:2) and filtration through a plug of silica gave tricarbamate 9 (480 mg, 94%) as a white solid. The product was identical (NMR, TLC) to material prepared using the method in ref.10

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The major side-products, presumably stereoisomers of 2a, possess R f ≥0.26 in this solvent system.

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Triurea 10a.
Triamine 2a (300 mg, 0.71 mmol), DMAP (88 mg, 0.72 mmol) and Et3N (396 µL, 287 mg, 2.84 mmol) were dissolved in dry THF (7 mL). Phenyl isocyanate (309 µL, 338 mg, 2.84 mmol) was added and the mixture was refluxed for 6 h under a nitrogen atmosphere. The solvent was evaporated and the residue was redissolved in CHCl3 and washed with H2O. The organic phase was dried (MgSO4), filtered, and evaporated. Flash chromatography, eluting with CH2Cl2-MeOH (97:3), and crystallisation (MeOH-CHCl3) afforded the triurea 10a (405 mg, 72%); mp 197-199 °C. IR (solid state): νmax = 3330, 2935, 2871, 1734, 1656, 1596, 1544, 1498, 1439, 1235, 1223, 751, 691 cm-1. 1H NMR (400 MHz, MeOH-d 4): δ = 0.89 (m, 3 H, 18-CH3), 0.93 (d, J = 6.4 Hz, 3 H, 21-CH3), 1.03 (s, 3 H, 19-CH3), 2.04-2.10 (m, 1 H), 2.19-2.27 (m, 1 H), 2.31-2.39 (m, 1 H), 3.27 (m, 1 H, 3β-H), 3.61 (s, 3 H, CO2CH3), 3.90 (br s, 1 H, 7β-H), 4.10 (s, 1 H, 12β-H), 6.91-7.00 (m, 3 H, ArH), 7.17-7.28 (m, 8 H, ArH), 7.35-7.39 (m, 4 H, ArH). 13C NMR (100 MHz, MeOH-d 4): δ = 14.99 (CH3), 18.68 (CH3), 24.47 (CH3), 25.23 (CH2), 28.57 (CH2), 29.10 (CH2), 30.01 (CH2), 31.06 (CH2), 32.85 (CH2), 34.45 (C), 36.88 (CH), 39.48 (CH), 44.36 (CH), 46.99 (C), 52.83 (CO2 CH3), 55.25 (CH), 121.30 (ArCH), 121.34 (ArCH), 121.36 (ArCH), 124.37 (ArCH), 124.46 (ArCH), 124.50 (ArCH), 130.62 (ArCH), 158.40 (NHCONHAr), 158.43 (2 × NHCONHAr), 177.22 (CO2CH3). MS (ES+): m/z (%) = 777 (100) [M]+.