Cellular and Molecular Neurobiology
J=8.1 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 5.81 (s, 1H), 5.21
(d, J=25.5 Hz, 2H), 4.52 (s, 1H), 4.29 (s, 1H), 3.21–3.06
(m, 3H), 2.97 (s, 1H), 2.70–2.53 (m, 2H), 2.27–2.21 (m,
2H), 1.66 (d, J=33.9 Hz, 4H), 1.57–1.47 (m, 6H), 1.37–1.27
2.29 mmol, 0.05 eq.) in dry DCM (190 mL) was added and
38 °C under Ar for 16 h. The cooling to rt, the mixture was
fltered and washed with cold DCM, then water. The solid
was dissolved in a mixture of water and conc. aq. HCl (7:
1, 480 mL) at 40 °C. The aqueous layer was washed with
DCM, then it was basifed to pH ~ 9 with ammonia. The
resulting solid was fltered and dried under high vacuum to
(m, 6H), 1.16–1.10 (m, 6H), 0.89 (t, J=7.4 Hz, 12H). 13
C
NMR (151 MHz, CDCl3) δ 149.25, 143.60, 136.34, 135.07,
130.54, 129.10, 119.36, 116.80, 93.14, 70.32, 62.59, 60.57,
57.93, 49.61, 47.20, 38.77, 31.75, 29.17, 27.47, 22.82, 14.29,
13.89, 10.36. HRMS: m/z calcd for C38H53N5O4Sn [M+H]+:
764.3198; found 764.3212; purity>95% by HPLC.
1
yield 11 as a light orange solid (10.98 g; Yield: 83%). H
NMR (600 MHz, Methanol-d4) δ 6.65 (d, J=8.1 Hz, 1H),
6.62 (d, J=8.0 Hz, 1H), 4.69 (s, 1H), 3.13 (d, J=6.1 Hz,
1H), 3.10–2.98 (m, 3H), 2.80 (dd, J=13.4, 4.5 Hz, 1H), 2.57
(td, J = 13.0, 3.6 Hz, 1H), 2.50 (td, J = 12.4, 4.6 Hz, 1H),
2.26–2.18 (m, 1H), 1.88–1.77 (m, 1H), 1.62 (td, J = 14.2,
3.4 Hz, 1H), 1.39 (dd, J=12.3, 3.5 Hz, 1H).
N‑((4R,4aS,7R,7aR,12bS)‑3‑Allyl‑4a,9‑dihydroxy‑2,3,4,4a,
5,6,7,7a‑octahydro‑1H‑4,12‑methanobenzofuro[3,2‑e]
isoquinolin‑7‑yl)‑4‑azido‑3‑iodobenzamide (10)
DIPEA (11.2 µL, 0.064 mmol) and allyl amine 8 (7.0 mg,
0.021 mmol) were added to the stirred solution of azide
acid 4 (12.3 mg, 0.042 mmol) dissolved in DMF (700 µL)
at rt under an argon atmosphere. The reaction mixture was
cooled to 0 °C and HATU (16.3 mg, 0.064 mmol) was added
to the reaction mixture. After stirring the reaction mixture
for 2 h at 0 °C to rt., the reaction mixture was poured into
EtOAc (20 mL) and was washed with brine (7× 15 mL).
The EtOAc layer was dried over Na2SO4, fltered; and con-
centrated under reduced pressure. Then, the residue was
redissolved in MeOH (2 mL), and treated with NaOMe in
methanol (0.5 M, 150 µL), for one hour at rt. Finally, the
reaction mixture was concentrated under reduced pressure,
and the residue was purifed by silica gel column chroma-
tography (ISCO, 4 g) using 5–10% MeOH in DCM. The
desired product fractions were concentrated under reduced
pressure and dried under high vacuum to get desired prod-
uct 10 (8.0 mg; Yield 64%); 1H NMR (600 MHz, CDCl3)
δ=7.84 (dd, J=8.3, 2.0 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H),
7.09 (d, J = 8.3 Hz, 1H), 6.61 (dd, J = 57.6, 8.1 Hz, 2H),
5.90–5.69 (m, 1H), 5.25–5.11 (m, 2H), 4.64 (d, J=5.9 Hz,
1H), 4.06–4.03 (m, 1H), 3.18–3.07 (m, 3H), 2.97 (q, J=8.4,
7.0 Hz, 1H), 2.67–2.51 (m, 2H), 2.19 (d, J= 7.4 Hz, 2H),
1.99–1.89 (m, 1H), 1.69–1.65 (m, 1H), 1.62–1.56 (m, 1H),
1.52–1.41 (m, 2H), 1.29–1.21 (m, 1H). 13C NMR (151 MHz,
CDCl3) δ=142.82, 139.08, 132.29, 130.67, 128.61, 119.50,
117.99, 117.72, 92.68, 87.59, 70.48, 62.53, 57.92, 50.91,
47.39, 43.73, 31.59, 29.35, 23.45, 22.85, 14.35. HRMS: m/z
calcd for C26H26N5O4I [M+H]+: 600.1108; found 600.1084;
purity>97% by HPLC.
(4R,4aS,7aR,12bS)‑4a,9‑Dihy‑
droxy‑3‑(prop‑2‑yn‑1‑yl)‑2,3,4,4a,5,6‑hexa‑
hydro‑1H‑4,12‑methanobenzofuro[3,2‑e]isoquino‑
lin‑7(7aH)‑one (12)
Sodium carbonate (370.4 mg, 3.49 mmol) and propargyl
bromide (389 µL, 3.49 mmol, 80% in toluene) were added
to a stirred solution of noroxymorphone 11 (1 g, 3.48 mmol)
dissolved in anhydrous DMF (5 mL) at rt. under an argon
atmosphere. The reaction mixture was heated to 90 °C
overnight. Mass spectrometry of the crude reaction mixture
indicated the completion of the reaction. The solvent was
removed under reduced pressure and the residue was redis-
solved in EtOAc (50 mL). The EtOAc layer was washed
with brine (5 ×30 mL), dried over anhydrous Na2SO4, fl-
tered, and concentrated under reduced pressure. The crude
product was purifed by silica gel column chromatography
(ISCO-combifash) using 1–5% MeOH in DCM. The desired
product fractions were concentrated under reduced pressure
and dried under high vacuum to obtain of-white solid 12
(897 mg; yield 78%). 1H NMR (600 MHz, CDCl3 +MeOH)
δ=7.92–7.76 (m, 1H), 7.26 (dd, J=8.5, 4.4 Hz, 1H), 7.15 (t,
J=7.2 Hz, 1H), 5.25–5.06 (m, 1H), 3.95 (dd, J=8.3, 4.0 Hz,
2H), 3.80–3.65 (m, 2H), 3.65–3.49 (m, 1H), 3.25–3.10 (m,
2H), 2.99–2.78 (m, 4H), 2.54–2.39 (m, 1H), 2.20–2.12 (m,
2H).
(4R,4aS,7S,7aR,12bS)‑3‑(Prop‑2‑yn‑1‑yl)‑1,2,3,4,5,6,7,7a
‑octahydro‑4aH‑4,12‑methanobenzofuro[3,2‑e]isoquino‑
line‑4a,7,9‑triol (13)
(4R,4aS,7aR,12bS)‑4a,9‑Dihydroxy‑2,3,4,4a,5,6‑hex‑
ahydro‑1H‑4,12‑methanobenzofuro[3,2‑e]isoquino‑
lin‑7(7aH)‑one (11)
K-Selectride (5.2 mL, 5.22 mmol, 1 M in THF) was
slowly added to a stirred solution of ketone 12 (850 mg,
2.61 mmol) dissolved in anhydrous THF (20 mL) at 0 °C
under an argon atmosphere and the reaction was continued
for 30 min at the temperature. Then, the reaction mix-
ture was warmed to rt. and continued overnight. Mass
spectrometry of the crude reaction mixture indicated the
Dissolved naloxone (7, 15 g, 45.82 mmol) in dry DCM
(110 mL), then a solution of N,N-dimethyl barbituric
acid (4.29 g, 27.49 mmol, 0.6 eq.) and Pd(PPh3)4 (2.65 g,
1 3