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

Abstract

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

Key words

steroids - hydrogenation - receptors - aminations - stereoselectivity

References

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• 11c

  The former describes the reduction of oxime and ester groups in 5 using NaBH₄/TiCl₄. The major hydroxytriamine product has the all-α stereochemistry. The latter describes the hydrogenation of a 3,7-dioxime, again to give mainly the all-α product.

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14

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.

15

Crystal data for 9: C₄₀H₆₉N₃O_8·0.5 CH₂Cl₂, M = 762.45, a = 14.9131 (4), b = 20.251 (1), c = 32.299 (1) Å, V = 9754.5 (6) ų, orthorhombic, C222₁ (No. 20), Z = 8, D _c = 1.038 g·cm^-3, µ(MoK_α) = 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 > 2σI) were used in refinement. R1 = 0.0930 and wR2 = 0.2161 for data I > 2σI 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.) [phone]; email: [e-mail]].

16

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 1}H 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

17

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

18

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): ν_max = 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]⁺.