J. Liu, L. Li, X. Li et al.
European Journal of Medicinal Chemistry xxx (xxxx) xxx
3.84 (s, 3H), 2.90 (dd, J ¼ 18.6, 2.5 Hz, 1H), 2.52 (d, J ¼ 10.5 Hz, 1H),
2.01 (d, J ¼ 18.7 Hz, 1H), 1.94e1.85 (m, 1H), 1.78e1.67 (m, 2H),
1.65e1.46 (m, 6H), 1.45e1.36 (m, 1H), 1.31 (dd, J ¼ 11.5, 2.9 Hz, 1H),
flask was flushed with nitrogen and cooled to ꢀ78 ꢁC. Triethyl-
amine (118
mL, 0.85 mmol) and MsCl (27 mL, 0.34 mmol) were
added. After 30 min, TLC analysis indicated that the starting ma-
terial was consumed and then the mixture was quenched with
saturated NaHCO3, extracted with dichloromethane. The combined
organic extracts were washed with brine, dried over MgSO4,
filtered and the solvent was removed under reduced pressure to
give the mesylate ester 33, which was then carried on without
further purification. Then to another 10 mL round-bottomed flask
containing mesylate ester 33 in MeOH (2.5 mL) and toluene
1.14 (s, 3H), 0.97 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 188.4, 167.3,
158.7, 145.1, 125.8, 117.5, 60.6, 55.2, 50.2, 47.2, 43.0, 40.2, 40.1, 38.4,
37.8, 37.0, 21.1, 20.6, 20.1, 15.2. ESI-HRMS (m/z): calcd for C20H28NO2
[M þ H]þ, 314.2115; found, 314.2120.
4.1.26. (4aS,6aR,9S,11aR,11bS,E)-8-(Butoxyimino)-9,11b-dimethyl-
4-methylene-4a,5,6,7,8,9,10,11,11a,11b-decahydro-6a,9-
methanocyclohepta[a]naphthalen-3(4H)-one (31)
(0.5 mL) was added concentrated HCl (56 mL, 0.68 mmol). The
Oxime 29 (10 mg, 0.033 mmol) was dissolved in anhydrous DMF
(1 mL). Sodium hydride (60% in mineral oil, 2.6 mg, 0.06 mmol) was
then added under nitrogen atmosphere at 0 ꢁC and the reaction
mixture was stirred at room temperature for 30 min. After this
mixture was then heated to 60 ꢁC and stirred for 90 min. Then the
mixture was cooled to room temperature and 20 mL of dichloro-
methane was added to the mixture, which was washed with brine,
dried over MgSO4, filtered and concentrated under reduced pres-
sure to give the crude product. The crude product was purified by
flash chromatography to give the product 34 (32.5 mg, 65%) as a
time, 1-bromobutane (5.4 mL, 0.05 mmol) was added to the reaction
mixture and the stirring was continued for a further 2 h at room
temperature. Then the mixture was quenched with water and
extracted with dichloromethane. The combined organic extracts
were washed with brine, dried over MgSO4 and concentrated under
reduced pressure to give the crude product, which was purified by
flash chromatography to give the compound 31 (10 mg, 85%). 1H
colorless oil. 1H NMR (400 MHz, CDCl3)
d
7.21 (d, J ¼ 10.1 Hz, 1H),
6.10 (dd, J ¼ 1.8, 1.2 Hz, 1H), 6.07 (s, 1H), 5.95 (d, J ¼ 10.1 Hz, 1H),
5.22 (s, 1H), 2.88 (dd, J ¼ 18.5, 2.1 Hz, 1H), 2.55 (dd, J ¼ 11.4, 2.3 Hz,
1H), 2.03 (d, J ¼ 18.5 Hz, 1H), 1.89e1.84 (m, 1H), 1.77e1.67 (m, 2H),
1.66e1.60 (m, 2H), 1.59e1.54 (m, 1H), 1.53e1.49 (m, 1H), 1.48e1.44
(m, 1H), 1.43e1.40 (m, 1H), 1.32e1.27 (m, 2H), 1.23 (s, 3H), 1.02 (s,
NMR (600 MHz, CDCl3)
d
7.13 (d, J ¼ 10.1 Hz, 1H), 6.09 (dd, J ¼ 1.9,
1.4 Hz, 1H), 5.95 (d, J ¼ 10.1 Hz, 1H), 5.21 (s, 1H), 4.09e3.98 (m, 2H),
2.92 (dd, J ¼ 18.6, 3.3 Hz, 1H), 2.52 (dd, J ¼ 11.1, 2.3 Hz, 1H), 2.01 (d,
J ¼ 18.6 Hz, 1H), 1.93e1.85 (m, 1H), 1.77e1.73 (m, 1H), 1.72e1.68 (m,
1H), 1.65e1.56 (m, 5H), 1.53 (dd, J ¼ 11.4, 2.8 Hz, 1H), 1.50e1.46 (m,
2H), 1.45e1.40 (m, 1H), 1.40e1.35 (m, 2H), 1.31 (dd, J ¼ 11.4, 3.3 Hz,
1H), 1.14 (s, 3H), 0.98 (s, 3H), 0.93 (t, J ¼ 7.4 Hz, 3H). 13C NMR
3H). 13C NMR (101 MHz, CDCl3)
d 189.2, 173.0, 159.7, 145.6, 126.8,
118.6, 52.1, 51.8, 50.1, 49.2, 42.1, 41.0, 40.5, 39.9, 36.1, 28.9, 20.0, 19.6,
17.3. ESI-HRMS (m/z): calcd for C19H26NO2 [M þ H]þ, 300.1958;
found, 300.1961.
4.1.29. (3S,6aR,8aS,12aS,12bR)-3,4,12a-Trimethyl-9-methylene-
1,2,3,4,7,8,8a,9,12a,12b-decahydro-10H-3,6a-methanonaphtho [2,1-
d]azocine-5,10(6H)-dione (35)
To a 10 mL flame-dried round-bottomed flask of lactam 34
(50 mg, 0.17 mmol) in anhydrous DMF (3 mL) under nitrogen
protection was added sodium hydride (60% in mineral oil, 34 mg,
0.85 mmol) and the mixture was stirred for 30 min at room tem-
(151 MHz, CDCl3)
d 189.3, 167.8, 159.6, 146.0, 126.7, 118.3, 73.4, 56.1,
51.1, 48.1, 43.9, 41.1, 41.0, 39.3, 38.7, 38.0, 31.3, 22.1, 21.6, 21.0, 19.3,
16.0, 14.0. ESI-HRMS (m/z): calcd for C23H34NO2 [M þ H]þ,
356.2584; found, 356.2580.
4.1.27. (4aS,6aR,9S,11aR,11bS,E)-9,11b-Dimethyl-4-methylene-8-
((prop-2-yn-1-yloxy)imino)-4a,5,6,7,8,9,10,11,11a,11b-decahydro-
6a,9-methanocyclohepta[a]naphthalen-3(4H)-one (32)
To a stirred solution of compound 29 (50 mg, 0.17 mmol) in dry
DMF (2 mL) was added sodium hydride (60% in mineral oil, 13.6 mg,
0.34 mmol) at ice bath, and the mixture was stirred for 30 min at
perature. Then iodomethane (105
mL, 1.70 mmol) was added
dropwise and the mixture was raised to 90 ꢁC for 5 h. After this
time, TLC analysis indicated the consumption of starting material
and the reaction was carefully quenched with water. The resulting
mixture was extracted with dichloromethane and the extracts were
washed with brine, dried over MgSO4, filtered and the solvent was
removed under reduced pressure to give the crude compound,
which was purified by flash chromatography to give the product 35
(49 mg, 93%) as a white solid, mp 128e130 ꢁC. 1H NMR (400 MHz,
room temperature. Then, 3-bromopropyne (22 mL, 0.25 mmol) was
added to the reaction mixture and the stirring was continued for a
further 2 h at room temperature. Silica gel TLC analysis indicated
the consumption of the starting material. The reaction was
quenched with water, and extracted with dichloromethane. The
extracts were washed with brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography to afford the pure compound 32 (42 mg,
CDCl3)
d
7.21 (d, J ¼ 10.1 Hz,1H), 6.10 (s,1H), 5.95 (d, J ¼ 10.1 Hz,1H),
5.22 (s, 1H), 2.96 (dd, J ¼ 18.4, 2.7 Hz, 1H), 2.88 (s, 3H), 2.54 (dd,
J ¼ 11.6, 2.3 Hz, 1H), 2.15 (d, J ¼ 18.4 Hz, 1H), 2.05e1.96 (m, 1H),
1.85e1.79 (m, 1H), 1.73 (dd, J ¼ 13.1, 2.7 Hz, 1H), 1.70e1.64 (m, 1H),
1.63e1.56 (m, 2H), 1.43 (dd, J ¼ 13.1, 2.9 Hz, 1H), 1.40e1.34 (m, 2H),
1.30 (s, 3H), 1.26e1.23 (m, 2H), 1.00 (s, 3H). 13C NMR (101 MHz,
75%). 1H NMR (600 MHz, CDCl3)
d
7.13 (d, J ¼ 10.1 Hz, 1H), 6.10 (s,
1H), 5.96 (d, J ¼ 10.1 Hz, 1H), 5.21 (s, 1H), 4.64 (d, J ¼ 2.3 Hz, 2H),
2.95 (dd, J ¼ 18.7, 3.3 Hz, 1H), 2.53 (dd, J ¼ 11.3, 2.2 Hz, 1H), 2.44 (t,
J ¼ 2.3 Hz, 1H), 2.07 (d, J ¼ 18.7 Hz, 1H), 1.93e1.86 (m, 1H), 1.76 (dd,
J ¼ 12.6, 3.0 Hz, 1H), 1.74e1.69 (m, 1H), 1.68e1.64 (m, 1H), 1.62 (dd,
J ¼ 12.8, 3.5 Hz,1H),1.55 (dd, J ¼ 11.6, 2.6 Hz, 2H),1.52e1.46 (m, 2H),
1.44e1.39 (m, 1H), 1.32 (dd, J ¼ 11.5, 3.3 Hz, 1H), 1.15 (s, 3H), 0.98 (s,
CDCl3)
d 189.3, 171.3, 159.8, 145.6, 126.8, 118.6, 55.7, 51.8, 50.8, 50.2,
42.2, 41.2, 41.1, 35.9, 34.8, 27.5, 27.1, 19.9, 19.5, 17.3. ESI-HRMS (m/z):
calcd for C20H28NO2 [M þ H]þ, 314.2115; found, 314.2120.
4.1.30. (3S,6aR,8aS,12aS,12bR)-4-Benzyl-3,12a-dimethyl-9-
methylene-1,2,3,4,7,8,8a,9,12a,12b-decahydro-10H-3,6a-
3H). 13C NMR (151 MHz, CDCl3)
d 189.3, 169.9, 159.5, 145.9, 126.7,
118.4, 80.1, 74.0, 61.1, 56.0, 51.1, 48.1, 44.2, 41.1, 41.1, 39.2, 38.6, 38.1,
22.0, 21.5, 21.0, 16.1. ESI-HRMS (m/z): calcd for C22H28NO2 [M þ H]þ,
338.2115; found, 338.2116.
methanonaphtho [2,1-d]azocine-5,10(6H)-dione (36)
To a 10 mL flame-dried round-bottomed flask of lactam 34
(20 mg, 0.07 mmol) in anhydrous DMF (2 mL) under nitrogen at-
mosphere was added sodium hydride (60% in mineral oil, 14 mg,
0.35 mmol) and the mixture was stirred for 30 min at room tem-
4.1.28. (3S,6aR,8aS,12aS,12bR)-3,12a-Dimethyl-9-methylene-
1,2,3,4,7,8,8a,9,12a,12b-decahydro-10H-3,6a-methanonaphtho [2,1-
d]azocine-5,10(6H)-dione (34)
To a flame dried 10 mL round bottomed flask was added oxime
29 (50 mg, 0.17 mmol) and anhydrous dichloromethane (2 mL). The
perature. Then benzyl bromide (84 mL, 0.70 mmol) and tetrabuty-
lammonium iodide (5.2 mg, 0.014 mmol) were added to the
reaction mixture and the reaction mixture was heated to 90 ꢁC for
5 h. After TLC analysis had indicated the consumption of starting
16