Job/Unit: O50365
/KAP1
Date: 28-04-15 14:47:34
Pages: 9
Total Synthesis of Galanthamine
aqueous solution) and extracted with diethyl ether (3ϫ 50 mL).
The combined organic layers were dried (Na2SO4), filtered and
concentrated under reduced pressure, and the ensuing brown oil
was subjected to flash chromatography (silica gel; 7:3 v/v petroleum
ether/ethyl acetate elution) to give, after concentration of the ap-
propriate fractions (Rf = 0.4), propargyl ether 8 (9.30 g, 89%) as a
H), 3.19 (ddd, J = 13.2, 9.3 and 6.6 Hz, 1 H), 3.10 (ddd, J = 13.2,
9.3 and 5.3 Hz, 1 H), 2.74 (s, 3 H), 2.42 (s, 3 H), 2.37–2.13 (complex
m, 5 H), 2.07 (s, 3 H), 1.82 (dd, J = 12.8 and 7.8 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.3, 143.2, 135.1, 135.0, 129.7,
127.5, 124.0, 107.9, 83.3, 80.4, 75.1, 64.6, 64.5, 56.3, 52.4, 49.4,
36.5, 35.9, 35.0, 31.6, 21.6, 20.8 ppm. IR: ν
= 2958, 2928, 2879,
˜
max
clear, brown oil. 1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 1956, 1747, 1594, 1338, 1224, 1160, 1071, 1071, 1027, 947,
8.1 Hz, 2 H), 7.30 (d, J = 8.1 Hz, 2 H), 5.52 (m, 1 H), 4.31–4.25
(complex m, 1 H), 4.24 (dd, J = 16.0 and 2.4 Hz, 1 H), 4.15 (dd, J
= 16.0 and 2.4 Hz, 1 H), 4.02–3.90 (complex m, 4 H), 3.20–3.05
(complex m, 2 H), 2.75 (s, 3 H), 2.50–2.43 (complex m, 1 H), 2.42
(s, 3 H), 2.38 (t, J = 2.4 Hz, 1 H), 2.35–2.14 (complex m, 4 H),
1.82 (dd, J = 12.8 and 7.9 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 143.2, 135.1, 135.0, 129.7, 127.6, 124.0, 107.9, 80.3,
75.0, 74.6, 64.6, 64.5, 56.1, 49.5, 36.6, 35.9, 35.1, 31.6, 21.6 ppm.
730 cm–1. MS (ESI): m/z (%) = 500 (100) [M + Na]+, 350 (90).
HRMS (ESI): calcd. for C24H31NNaO7S [M + Na]+ 500.1719;
found 500.1714.
(Z)-2-{(3aS,7aS)-rel-3a-[2-(N,4-Dimethylphenylsulfonamido)ethyl]-
7,7a-dihydro-2H-spiro(benzofuran-6,2Ј-[1,3]dioxolan)-3(3aH)-
ylidene}ethyl Acetate (11): A magnetically stirred solution of prop-
argyl acetate 10 (1.06 g, 2.1 mmol) in anhydrous benzene (30 mL)
was treated with Pd(OAc)2 (71 mg, 0.32 mmol) and N,NЈ-bis(ben-
zylidene)ethylenediamine (BBEDA) (75 mg, 0.32 mmol). The re-
sulting solution was heated at reflux for 5 h and then concentrated
under reduced pressure to give a brown oil that was subjected to
flash chromatography (silica gel; 1:1 v/v petroleum ether/ethyl acet-
ate elution). Concentration of the appropriate fractions (Rf = 0.5
in 1:2 v/v petroleum ether/ethyl acetate) then gave allylic acetate 11
IR: ν
= 3271, 2956, 2928, 2884, 2115, 1598, 1456, 1337, 1160,
˜
max
1074, 1019, 948, 817, 731 cm–1. MS (ESI): m/z (%) = 428 (100)
[M + Na]+, 406 (5) [M + H]+, 351 (10). HRMS (ESI): calcd. for
C21H27NNaO5S [M + Na]+ 428.1508; found 428.1506.
N-(2-{9-[(4-Hydroxybut-2-yn-1-yl)oxy]-1,4-dioxaspiro[4.5]dec-7-
en-8-yl}ethyl)-N,4-dimethylbenzenesulfonamide (9): A magnetically
stirred solution of propargyl ether 8 (9.30 g, 22.9 mmol) in anhy-
drous THF (100 mL) was cooled to –78 °C and then treated with
nBuLi (16.7 mL of a 1.5 m solution in hexanes, 25.2 mmol). The
ensuing solution was stirred at this temperature for 1 h before being
treated with paraformaldehyde (2.06 g, 68.7 mmol). The resulting
suspension was warmed to room temperature and, after 48 h,
quenched with NH4Cl (50 mL of a saturated aqueous solution),
then extracted with diethyl ether (3ϫ 50 mL). The combined or-
ganic layers were dried (Na2SO4), filtered and concentrated under
reduced pressure, and the ensuing brown oil was subjected to flash
chromatography (silica gel; 1:2 v/v petroleum ether/ethyl acetate
elution) to give, after concentration of the appropriate fractions (Rf
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(754 mg, 71%) as a clear, yellow oil. H NMR (400 MHz, CDCl3):
δ = 7.65 (d, J = 7.9 Hz, 2 H), 7.31 (d, J = 7.9 Hz, 2 H), 5.65 (d, J
= 10.4 Hz, 1 H), 5.64 (d, J = 10.4 Hz, 1 H), 5.39 (m, 1 H), 4.58 (d,
J = 14.2 Hz, 1 H), 4.53–4.41 (complex m, 3 H), 4.15 (dd, J = 8.2
and 4.5 Hz, 1 H), 4.01–3.90 (complex m, 4 H), 3.01 (t, J = 8.2 Hz,
2 H), 2.69 (s, 3 H), 2.43 (s, 3 H), 2.06 (s, 3 H), 2.03–1.73 (complex
m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.9, 149.1,
143.5, 134.7, 133.2, 129.8, 127.7, 127.6, 115.9, 104.5, 79.8, 68.1,
65.1, 64.6, 61.7, 48.4, 46.7, 36.4, 35.3, 35.2, 21.7, 21.0 ppm. IR:
ν
= 2953, 2926, 2874, 1737, 1339, 1230, 1160, 1064, 1027,
˜
max
738 cm–1. MS (ESI): m/z (%) = 500 (100) [M + Na]+, 478 (30) [M +
H]+. HRMS (ESI): calcd. for C24H31NNaO7S [M + Na]+ 500.1719;
found 500.1719.
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= 0.3), propargyl alcohol 9 (7.28 g, 73%) as a clear, brown oil. H
NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 2 H), 7.30 (d,
J = 8.0 Hz, 2 H), 5.50 (t, J = 3.8 Hz, 1 H), 4.39–4.28 (complex m,
4 H), 4.18 (dt, J = 15.9 and 1.7 Hz, 1 H), 3.95 (m, 4 H), 3.25 (m,
1 H), 3.12 (m, 1 H), 2.73 (s, 3 H), 2.51 (m, 2 H), 2.42 (s, 3 H),
2.36–2.12 (complex m, 4 H), 1.82 (dd, J = 12.8 and 7.3 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 143.4, 135.1, 134.8, 129.8,
127.6, 124.3, 107.8, 85.5, 81.5, 73.6, 64.6, 64.5, 55.9, 51.1, 49.4,
N,4-Dimethyl-N-{2-[(3aS,7aS)-rel-3-vinyl-7,7a-dihydro-3aH-spiro-
(benzofuran-6,2Ј-[1,3]dioxolan)-3a-yl]ethyl}benzenesulfonamide (12):
A magnetically stirred solution of allylic acetate 11 (1.40 g,
2.93 mmol) in anhydrous toluene was treated with Pd(PPh3)4
(339 mg, 0.29 mmol) and the resulting solution stirred at room tem-
perature for 0.17 h before being treated with DBU (1.32 mL,
8.79 mmol) and then heated at reflux for 2 h. The cooled reaction
mixture was subjected without concentration to flash chromatog-
raphy (neutral alumina; 3:1 Ǟ 1:1 petroleum ether/ethyl acetate
gradient elution) to give, after concentration of the appropriate
fractions (Rf = 0.8 in 1:2 v/v petroleum ether/ethyl acetate), diene
12 (1.03 g, 85%) as a viscous, clear and colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.65 (d, J = 8.2 Hz, 2 H), 7.31 (d, J =
8.2 Hz, 2 H), 6.42 (s, 1 H), 6.17 (dd, J = 17.9 and 11.5 Hz, 1 H),
5.98 (d, J = 10.3 Hz, 1 H), 5.72 (d, J = 10.3 Hz, 1 H), 5.11 (d, J =
17.9 Hz, 1 H), 4.87 (d, J = 11.5 Hz, 1 H), 4.64 (dd, J = 6.6 and
5.1 Hz, 1 H), 4.05–3.95 (complex m, 4 H), 3.14 (ddd, J = 13.7, 11.6
and 5.0 Hz, 1 H), 2.96 (ddd, J = 13.7, 11.6 and 5.0 Hz, 1 H), 2.72
(s, 3 H), 2.43 (s, 3 H), 2.21 (dd, J = 14.0 and 6.6 Hz, 1 H), 2.12–
1.96 (complex m, 2 H), 1.82 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 146.3, 143.4, 134.9, 132.4, 129.8, 127.7, 127.5 (4), 127.5
(1), 119.7, 110.0, 103.5, 83.8, 65.1, 64.6, 48.6, 46.6, 35.4, 35.3, 35.0,
36.1, 35.9, 34.8, 31.8, 21.6 ppm. IR: νmax = 3468, 2926, 2883, 2250,
˜
1956, 1597, 1335, 1160, 1069, 947, 817, 730 cm–1. MS (ESI): m/z
(%) = 458 (100) [M + Na]+, 350 (85). HRMS (ESI): calcd. for
C22H29NNaO6S [M + Na]+ 458.1613; found 458.1614.
4-({8-[2-(N,4-Dimethylphenylsulfonamido)ethyl]-1,4-dioxaspiro-
[4.5]dec-8-en-7-yl}oxy)but-2-yn-1-yl Acetate (10): A magnetically
stirred solution of propargyl alcohol 9 (7.82 g, 18.0 mmol) in anhy-
drous dichloromethane (100 mL) was cooled to 0 °C and then
treated with triethylamine (3.00 mL, 21.6 mmol), DMAP (220 mg,
1.8 mmol) and acetic anhydride (2.1 mL, 21.6 mmol). The resulting
solution was stirred at 0 °C for 6 h before being quenched with
NH4Cl (50 mL of a saturated aqueous solution) and extracted with
dichloromethane (3ϫ 50 mL). The combined organic layers were
dried (Na2SO4), filtered and concentrated under reduced pressure,
and the ensuing brown oil was subjected to flash chromatography
(silica gel; 1:1 v/v petroleum ether/ethyl acetate elution) to give,
after concentration of the appropriate fractions (Rf = 0.7 in 1:2 v/
v petroleum ether/ethyl acetate), propargyl acetate 10 (7.99 g, 93%)
21.7 ppm. IR: νmax = 2958, 2921, 2883, 2848, 1732, 1633, 1437,
˜
1339, 1160, 1119, 721, 696, 542 cm–1. MS (EI): m/z (%) = 417 (5)
[M+·], 278 (53), 277 (100), 262 (90), 205 (70), 155 (22), 91 (47).
HRMS (EI): calcd. for C22H27NO5S [M+·] 417.1610; found
417.1611.
1
as a clear, yellow oil. H NMR (400 MHz, CDCl3): δ = 7.67 (d, J
= 8.01 Hz, 2 H), 7.29 (d, J = 8.1 Hz, 2 H), 5.51 (m, 1 H), 4.68 (t,
J = 1.9 Hz, 2 H), 4.27 (dt, J = 16.1 and 1.9 Hz, 1 H), 4.23 (m, 1
H), 4.19 (dt, J = 16.1 and 1.9 Hz, 1 H), 4.10–3.90 (complex m, 4
N-{2-[(4aS,9bS)-rel-6-Formyl-4,4a-dihydro-9bH-spiro(dibenzo[b,d]-
furan-3,2Ј-[1,3]dioxolane)-9b-yl]ethyl}-N,4-dimethylbenzenesulfon-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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