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F. Chagnon et al. / European Journal of Medicinal Chemistry 80 (2014) 605e620
6.2.8. 3
b
-Allyloxy-N-formyltomatidine (7)
water was removed by lyophilisation to give a white solid (m.p.
In a 3 mL round bottom flask equipped with a condenser and
placed under argon atmosphere, compound 4 (30 mg, 0.068 mmol)
was dissolved in 1 mL THF. Tris(dibenzylideneacetone) dipalla-
dium(0) (3 mg, 0.003 mmol, 0.05 eq), 1,3-bis(diphenylphosphino)
propane (5 mg, 0.012 mmol, 0.18 eq) and allyl methyl carbonate
(0.2 mL,1.76 mol, 26 eq) were then added successively. The reaction
was brought to 65 ꢀC for 6 h, and monitored by TLC (50% EtOAc/
hexanes, UV/CAM, Rf: 0.20 (starting material), 0.50 (desired com-
pound)). Upon completion, the reaction was allowed to cool down
to room temperature, then the solvent was removed in vacuo. The
crude compound was purified by flash chromatography (20%
EtOAc/Hexanes) to yield 25 mg (76%) of the desired compound.
160e163 ꢀC).
1H NMR (300 MHz, CD3OD)
d (ppm) 4.60 (m, 2H), 4.37 (q, 1H,
J ¼ 9.0 Hz), 2.80 (m, 1H), 2.70 (t, 1H, J ¼ 12.0 Hz), 2.55e2.30 (m, 1H),
2.24e2.14 (m, 1H), 2.08e1.94 (m, 3H), 1.91e1.68 (m, 5H), 1.63e1.50
(m, 6H), 1.49e1.12 (m, 12H), 1.10 (s, 3H), 1.06 (d, 3H, J ¼ 7.1 Hz), 0.96
(d, 3H, J ¼ 5.5 Hz), 0.89 (s, 2H), 0.82 (s, 1H), 0.76e0.66 (m, 2H).
13C NMR (75.5 MHz, CD3OD)
d (ppm) 213.5, 100.2, 98.0, 79.2,
62.0, 55.3, 53.7, 44.0, 42.2, 41.8, 40.7, 39.7, 38.3, 35.5, 34.8, 31.9, 31.7,
28.5, 28.0, 27.4, 20.9, 18.1, 16.0, 14.3, 10.3.
HRMS calculated for C27H44O2Nþ: 414.3372, found: 414.3376
(MHþ), 436.3192 (MNaþ).
1H NMR (300 MHz, CDCl3)
d
(ppm) 8.41 (s, 1H), 5.93 (ddt, 1H,
6.2.12. N-Formyl-3-aminotomatidine (11)
J1 ¼ 17.3 Hz, J2 ¼ 10.5 Hz, J3 ¼ 5.7 Hz), 5.34 (dq, 1H, J1 ¼ 17.1 Hz,
J2 ¼ 1.4 Hz), 1.25 (dq, 1H, J1 ¼ 10.3 Hz, J2 ¼ 1.3 Hz), 4.60 (dt, 2H,
J1 ¼ 5.8 Hz, J2 ¼ 1.4 Hz), 4.53 (quint, 1H, J ¼ 5.5 Hz), 4.29 (d, 1H,
J ¼ 11.9 Hz), 4.16e4.08 (m, 1H), 2.65 (t, 1H, J ¼ 11.3 Hz), 2.54 (t, 1H,
J ¼ 7.0 Hz), 2.01e1.94 (m, 1H), 1.94e1.84 (m, 2H), 1.81e1.68 (m, 4H),
1.65 (s, 2H), 1.62e1.47 (m, 6H), 1.46e1.35 (m, 2H) 1.35e1.28 (m,
41H), 1.22e1.08 (m, 2H), 1.05 (d, 3H, J ¼ 7.0 Hz), 1.02e0.92 (m, 1H),
0.90 (d, 4H, J ¼ 5.8 Hz), 0.83 (s, 3H), 0.82 (s, 1H), 0.65 (dt, 1H,
J1 ¼ 10.7 Hz, J2 ¼ 4.3 Hz).
In a 25 mL round flask, 44 mg 4 (0.1 mmol) was dissolved in
methanol (6 mL) along with ammonium acetate (77 mg, 1.0 mmol,
10 eq). The pH was adjusted to 6 with acetic acid, sodium cyano-
borohydride (6.9 mg, 0.11 mmol, 1.1 eq) was added and the reaction
was refluxed overnight until complete as monitored by TLC (10%
MeOH/AcOEt with 0.5% NEt3, Rf: 0). Solvents were removed under
reduced pressure, and the solid was suspended in water. The pH
was adjusted to 8 with saturated aqueous NaHCO3. The mixture
was extracted with 3ꢄ EtOAc, and the combined organic fractions
were washed with brine, dried on anhydrous magnesium sulfate
and evaporated under reduced pressure. The crude compound was
purified by flash chromatography (10% MeOH/89%EtOAc/1% NEt3)
to yield 21 mg (48%) of the desired compound.
6.2.9. 3b-Allyloxytomatidine hydrochloride (8)
Following procedure D, 7 (16 mg, 0.033 mmol), was converted
into 16.2 mg (quantitative yield) of the desired compound (Rf: 0.51
in 50/50 AcOEt/Hexanes).
1H NMR (300 MHz, CDCl3)
d (ppm) 8.40 (s, 1H), 5.91 (broad s,
1H NMR (300 MHz, CD3OD)
d (ppm) 5.98e5.83 (m, 1H), 5.28 (d,
2H), 4.28 (d, 1H, J ¼ 11.5 Hz), 4.12 (m., 1H), 2.86 (quint, 1H,
J ¼ 7.1 Hz), 2.65 (t, 1H, J ¼ 11.5), 2.53 (quint, 1H, J ¼ 7.1 Hz), 2.04e
1.92 (m, 3H) 1.90e1.82 (m, 1H), 1.80e1.42 (m, 11H), 1.38e1.18 (m,
9H) 1.17e1.06 (m, 2H), 1.04 (d, 3H, J ¼ 7.1 Hz), 0.90 (d, 4H,
J ¼ 6.2 Hz), 0.81 (s, 6H), 0.69e0.57 (m, 1H).
1H, J ¼ 17.1 Hz), 5.19 (d, 1H, J ¼ 10.5 Hz), 4.53 (d, 2H, J ¼ 5.5 Hz), 4.48
(m, 1H), 4.36 (m, 1H), 3.68 (m, 1H), 3.15e3.04 (m, 1H), 2.88 (t, 1H,
J ¼ 11.87 Hz), 2.32e2.11 (m, 1H), 2.07e1.92 (m, 2H), 1.90e1.41 (m,
10H), 1.40e1.12 (m, 11H), 1.08 (d, 4H, J ¼ 6.2 Hz), 0.95 (d, 4H,
J ¼ 6.5 Hz) 0.87 (s, 3H), 0.86e0.79 (m, 4H), 0.75e0.57 (m, 2H).
13C NMR (75.5 MHz, CD3OD)
d (ppm) 154.6, 117.1, 96.1, 81.1, 77.3,
6.2.13. 3-Aminotomatidine hydrochloride (12)
Following procedure D, 21 mg (0.047 mmol) of compound 11
were converted to 23 mg (100%) of compound 12 (Rf: 0 in 10%
MeOH/AcOEt with 0.5% NEt3).
67.6, 61.7, 61.7, 55.4, 54.0, 44.4, 40.8, 40.7, 39.6, 36.3, 35.2, 34.9, 33.6,
31.9, 31.4, 28.2, 28.1, 27.0, 25.7, 25.3, 20.7, 17.2, 15.9, 13.2, 11.1.
HRMS calculated for
C
30H50O2Nþ$H2O: 474.3942, found:
1H NMR (300 MHz, CD3OD)
d
(ppm) 4.37 (q,1H, J ¼ 7.1 Hz), 3.16e
474.3590 (MHþ þ H2O).
3.00 (m, 2H), 2.88 (t, 1H, J ¼ 11.1 Hz), 2.20 (t, 1H, J ¼ 7.1 Hz), 2.09e
1.94 (m, 2H), 1.91e1.63 (m, 10H), 1.62e1.46 (m, 6H), 1.44e1.15 (m,
12H), 1.09 (d, 3H, J ¼ 7.2 Hz), 1.06e0.98 (m, 3H), 0.95 (d, 3H,
J ¼ 6.8 Hz), 0.90 (s, 3H), 0.87 (s, 5H), 0.80e0.60 (m, 3H).
6.2.10. N-Formyl-3-oxotomatidine (9)
In a 10 mL round bottom flask, N-formyltomatidine 4 (50 mg,
0.113 mmol, 1.0 eq) and DesseMartin periodinane (95 mg,
0.225 mmol, 2.0 eq) were stirred in 6.5 mL DCM. The reaction was
monitored by TLC (50% AcOEt/Hexanes, Rf: 0.24). Upon completion,
the reaction was quenched for 30 min with Na2S2O3 (0.2 M), then
extracted 3ꢄ with EtOAc. The combined organic phases were
washed with brine, dried on anhydrous magnesium sulfate then
evaporated under reduced pressure. The crude compound was
purified by flash chromatography (50% EtOAc/Hexanes) to yield
34 mg (68%) of the desired compound.
13C NMR (75.5 MHz, CD3OD)
d (ppm) 96.2, 81.1, 61.7, 55.4, 53.8,
50.3, 44.6, 40.8, 39.5, 36.2, 35.2, 34.8, 32.5, 31.7, 31.4, 29.4, 28.2,
28.0, 26.1, 25.8, 25.3, 20.6, 17.3, 15.9, 13.3, 11.1.
HRMS calculated for C27H47ONþ2 : 415.3683, found: 415.3695.
6.2.14. N-Formyl-3-(N-Boc-aminoethyl)aminotomatidine (13)
Following the procedure used for synthesis of 11, 110 mg 6
(0.25 mmol), 36 (200 mg, 1.25 mmol, 5 eq) and sodium cyanobor-
ohydride (17 mg, 0.27 mmol, 1.1 eq) were used to yield 130 mg
(85%) of compound 13 (Rf: 0.05 in 10% MeOH/AcOEt with 0.5%
NEt3). 1H NMR shows the presence of residual starting diamine,
which was removed in the next step.
1H NMR (300 MHz, CDCl3)
d (ppm) 8.46 ppm (s, 1H), 4.32 (d, 1H,
J ¼ 12.8 Hz), 4.17 (quad, 1H, J ¼ 8.9 Hz), 2.69 (t, 1H, J ¼ 12.6 Hz), 2.58
(quint, 1H, J ¼ 6.6 Hz), 2.52e2.24 (m, 3H), 2.16e2.11 (m, 1H), 2.11e
1.98 (m, 3H), 1.91 (d, 1H, J ¼ 14.0 Hz), 1.86e1.68 (m, 4H), 1.69e1.42
(m, 7H), 1.40e1.20 (m, 7H), 1.19e1.12 (m, 2H),1.09 (d, 3H. J ¼ 7.1 Hz),
1.05 (s, 2H), 0.94 (d, 4H, J ¼ 5.5 Hz), 0.88 (s, 3H), 0.77 (dt, 1H,
J1 ¼ 12.6 Hz, J2 ¼ 4.8 Hz).
1H NMR (300 MHz, CDCl3)
d (ppm) 8.39 (s, 1H), 5.02 (s large, 1H),
4.28 (d, 1H, J ¼ 11.5 Hz), 4.12 (m, 1H), 3.24e3.15 (m, 2H), 2.77e2.69
(m, 2H), 2.64 (m, 1H) 2.54 (m, 1H), 2.44 (m, 1H), 2.04e1.46 (m, 18H)
1.43 (s, 12H), 1.33e1.15 (m, 14H), 1.04 (d, 3H, J ¼ 6.9 Hz), 0.90 (d, 3H,
J ¼ 5.7 Hz), 0.87e0.82 (m, 2H), 0.81 (s, 3H), 0.78 (s, 3H), 0.69e0.57
(m, 1H).
6.2.11. 3-Oxotomatidine hydrochloride (10)
In a 25 mL round flask, 34 mg 9 (0.077 mmol) was refluxed for
2 h in 10 mL EtOH and 5 mL aqueous HCl 2.5 N (TLC: 10% MeOH/
AcOEt with 0.5% NEt3, Rf: 0.54). Upon completion, the ethanol and
HCl were removed under reduced pressure and the remaining
6.2.15. 3-(N-Aminoethyl)-aminotomatidine hydrochloride (14)
Following procedure D, 130 mg of compound 13 were depro-
tected in quantitative yield (Rf: 0 in 10% MeOH/AcOEt with 0.5%