A Novel Approach to the Synthesis of N-Substituted 1-C-Aminomethyl Glycofuranosides

Abstract

Reductive amination of formyl C-glycofuranosides, easily available from hexose-derived equatorial-2-OH-glycopyranosides by DAST-promoted ring contraction, afforded N-substituted 1-C-aminomethyl glycofuranosides in most cases in high yields.

1-C-aminomethyl glycofuranosides - formyl C-glycofuranosides - reductive amination - DAST-promoted ring contraction - sugar diamines

References and Notes

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12

General Procedure for the One-Pot Preparation of Compounds 7. Compound 6 (100 mg, 0.315 mmol) was dissolved in a 9:1 TFA-H₂O mixture (2.7 mL) and the solution was kept at r.t. for 1 h. The reaction mixture was poured into ice-water (100 mL) and extracted with CH₂Cl₂ (4 × 20 mL). The combined organic layers were successively washed with sat. aq NaHCO₃ and brine, then dried (Na₂SO₄), and concentrated. The residue (crude aldehyde) was dissolved in 1,2-dicloroethane (3.1 mL) and treated with the amine (0.437 mmol) and sodium triacetoxyborohydride (93.0 mg, 0.441 mmol). The reaction was stirred at r.t. for the appropriate time (Table [1] ). The mixture was then diluted with sat. aq NaHCO₃ (25 mL) and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (Na₂SO₄), and concentrated under reduced pressure to give the crude product, which was purified by column chromatography using EtOAc-hexane, Et₂O-hexane or Et₂O-acetone as eluent.
Compound 7a: R _f = 0.37 (5:1 Et₂O-acetone); [α]_D ²⁶ +19.3 (c 0.56, CH₂Cl₂). IR: ν_max = 3324 (NH), 2106 (N₃), 1746 (CO), 1231 and 1119 (CO) cm^-1. ¹H NMR (300 MHz, acetone-d ₆): δ = 7.25-7.08 (m, 5 H, Ph), 5.31 (dd, 1 H, J _4,5 = 7.8 Hz, J _3,4 = 5.1 Hz, H-4), 4.48 (dd, 1 H, J _2,3 = 3.9 Hz, H-3), 4.32 (ddd, 1 H, J _1,2 = J _{1 ′,2} = 6.6 Hz, H-2), 4.23 (dd, 1 H, J _{6,6 ′} = 10.8 Hz, J _5,6 = 2.4 Hz, H-6), 4.07-3.95 (m, 2 H, H-5 and H-6¢), 3.83 (d, 1 H, J _{H,H ′} = 13.5 Hz, CH ^a Ph), 3.78 (d, 1 H, J _{H,H ′} = 13.8 Hz, CH ^b Ph), 2.82 (d, 2 H, H-1 and H-1¢), 2.11 and 2.02 (each 2 s, 3 H, 2 COMe) ppm. ¹³C NMR (75.4 MHz, acetone-d ₆): δ = 170.8, 170.7 (2 CO), 141.8-127.5 (Ph), 80.0 (C-2), 78.1 (C-5), 75.8 (C-4), 64.6 (C-6), 64.4 (C-3), 54.4 (CH₂Ph), 49.4 (C-1), 20.7 and 20.4 (2 COMe) ppm. HRMS (CI): m/z calcd for C₁₇H₂₂N₄O₅ + H: 363.1668; found 363.1671.

13

General Procedure for Deacetylation of 7 and Preparation of Compounds 8. The corresponding reductive amination product 7 (0.070 mmol) was dissolved in: (i) (2 mL of 1:1 MeOH-CHCl₃), (ii) (2 mL of MeOH), or (iii) (2 mL of EtOH abs.), and 5 drops of 1 M MeONa-MeOH were added to the solution [for the deprotection of 7g was used EtONa-EtOH abs. (1 M)]. The reaction mixture was kept at r.t. for 2 h. Work-up was done by one of the following procedures.
Procedure 1 (8b-d,f): the reaction mixture was cooled and 600 µL TFA was added. The residue was purified by a Dowex 50 × 8 W column, using MeOH (50 mL), H₂O (50 mL) and NH₄OH (10% aq soln; 100 mL) as eluents.
Procedure 2 (8a,e,g,h): the reaction mixture was neutralized with Amberlyst 15, the resin was removed by filtration and the solvent under reduced pressure.

14

In comparison with the NMR spectra of each direct precursor, each acetylated compound 7a-h lacked any signal of aldehyde proton and carbon, but showed instead the signals corresponding to the two new diastereotopic protons at C(1). For the compounds obtained from some primary amines (7e,f-h), the amine proton gave rise to the typical broad signal in the ¹H NMR spectrum at δ = 4.41 (7e), 4.44-4.38 (7f), 5.81 (7g), and 6.00 ppm (7h), values that can be correlated with the electron-withdrawing or electron-donating character of the substituent at the para position of the aromatic group. However, the amine proton signal of 7a was not observed, probably because it is overlapped. The molecular weight found for 9 in its HRMS agreed with the aldimine structure assigned, while its NMR spectra showed the sp ^² (C)H signal at δ = 6.86 ppm and the imine carbon at δ = 134.1 ppm, thus corroborating the assignation. For the deacetylated compounds 8a-h, their respective calculated molecular weights were in agreement with those found by HRMS. Furthermore, the ¹H NMR and ¹³C NMR spectra of these compounds showed no signal corresponding to the O-acetyl groups present in the precursors 7a-h, as expected.

15 Popowycz F. Gerber-Lemarie S. Demange R. Rodriguez-García E. Asenjo ATC. Robina I. Vogel P. Bioorg. Med. Chem. Lett.  2001,  11:  2489 

16

Compound 15 was obtained from 12 (100 mg, 0.265 mmol) and diamine 14 (78 mg, 0.287 mmol) in the presence of NaBH(OAc)₃ (60.2 mg, 0.287 mmol) by a similar one-pot procedure to that described above for the preparation of compounds 7 from 6.
More relevant data of 15: R _f = 0.45 (Et₂O); [α]_D ²⁴ +14.6 (c 0.63, acetone). IR: ν_max = 3295 (NH), 1692 (CO), 1370 (NCO), 1157, 1059 (COC), and 991 (CF) cm^-1. ¹H NMR (500 MHz, DMSO-d ₆, 363 K): δ = 7.41-7.25 (m, 5 H, Ph), 5.27 (dt, 1 H, ² J _4,F = 54.9 Hz, J _3,4 = J _4,5 = 3.0 Hz, H-4), 4.79, 4.63 (2 d, 1 H each, J _{H,H ′} = 11.5 Hz, CH ₂ Ph), 4.69 (dd, 1 H, J _{4 ′,3 ′} = J _{4 ′,5 ′b} = 5.7 Hz, H-4¢), 4.62 (d, 1 H, H-3¢), 4.55 (s, 2 H, CH ₂ Ph), 4.38 (dddd, 1 H, ³J_5,F = 30.5 Hz, J _5,6a = J _5,6b = 6.0 Hz, H-5), 4.33-4.21 (m, 2 H, H-2 and H-2¢), 4.17 (dt, 1 H, ³ J _3,F = 23.5 Hz, J _2,3 = 8.5 Hz, H-3), 3.75 (dd, 1 H, J _6a,6b = 10.2 Hz, H-6a), 3.75 (d, 1 H, J _{5 ′a,5 ′b} = 14.0 Hz, H-5¢a), 3.60 (ddd, 1 H, ⁴ J _6b,F = 1.8 Hz, H-6b), 3.32 (dd, 1 H, H-5¢b), 3.20-2.91 (m, 4 H, H-1a, H-1b, H-6¢a, H-6¢b), 1.41 (s, 9 H, CMe ₃ ), 1.34 and 1.25 (each 2 s, 3 H, CMe ₂ ) ppm. ¹³C NMR (125.7 MHz, DMSO-d ₆, 363 K): δ = 152 (CO), 137.7-126.8 (Ph), 110.6 (CMe₂), 89.1 (d, ¹ J _4,F = 188.2 Hz, C-4), 81.6 (C-3¢), 80.1 (d, ² J _3,F = 16.2 Hz, C-3), 79.5 (C-4¢), 78.4 (d, ² J _5,F = 17.1 Hz, C-5), 78.3 (CMe₃), 74.7 (C-2), 72.2 and 71.2 (CH₂Ph), 67.0 (d, ³ J _6,F = 11.6 Hz, C-6), 59.8 (C-2¢), 50.4 (C-5¢), 49.0, 46.6 (C-1, C-6¢), 27.6 (CMe ₃ ), 26.3 and 26.2 (CMe ₂ ). HRMS (CI): m/z calcd for C₃₃H₄₅N₂O₇F + H: 601.3289; found: 601.3281.