A Flexible Approach to Grandisine Alkaloids
FULL PAPER
on silica gel (MeOH/AcOEt 1:20) to afford sulfide 20 as a colorless
syrup (132 mg, 94% yield). [a]2D2 =À185 (c=0.30 in CHCl3); IR (ATR):
(8aS,1’S,6’R)-8-(6’-Methyl-2’-oxo-cyclohex-3’-enecarbonyl)-1,5,6,8a-tetra-
hydro-2H-indolizin-3-one (22): This compound (227 mg, 54% (2 steps),
colorless syrup) was obtained from 10 (254 mg, 1.54 mmol) and (R)-5-
methylcyclohexenone (ent-18)[12] (254 mg, 2.31 mmol) by using a proce-
dure similar to that for 9 from 10. [a]2D6 =À214 (c=0.33 in CHCl3); IR
n˜ =2930, 1709, 1655 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.47–7.39 (m,
;
2H), 7.37–7.28 (m, 3H), 6.85 (brd, J=5.3 Hz, 1H), 4.58–4.48 (m, 1H),
4.29 (dd, J=13.0, 6.4 Hz, 1H), 3.82–3.73 (m, 1H), 3.70 (d, J=8.3 Hz,
1H), 2.95–2.26 (m, 9H), 2.17 (dt, J=14.4, 4.8 Hz, 1H), 1.91 (ddd, J=
14.4, 9.6, 3.9 Hz, 1H), 1.53–1.37 (m, 1H), 0.96 ppm (d, J=6.8 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=205.3, 195.8, 173.5, 141.4, 139.2, 133.1,
132.9, 129.1, 127.8, 63.9, 54.6, 45.9, 43.9, 36.0, 34.9, 32.2, 31.5, 26.6, 25.4,
20.3 ppm; MS (ESI+): m/z: 384 [M+H]+; HRMS (ESI+): m/z: calcd
for C22H26NO3S: 384.1633; found: 384.1638 [M+H]+.
1
(ATR): n˜ =2904, 1665, 1656, 1625 cmÀ1; H NMR (300 MHz, CDCl3): d=
7.01 (ddd, J=10.2, 5.7, 2.4 Hz, 1H), 6.85 (brd, J=5.4 Hz, 1H), 6.02 (ddd,
J=9.9, 2.7, 1.2 Hz, 1H), 4.61–4.49 (m, 1H), 4.30 (dd, J=12.6, 6.0 Hz,
1H), 3.85 (d, J=11.1 Hz, 1H), 2.84–2.11 (m, 10H), 1.84–1.74 (m, 1H),
1.01 ppm (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d=197.9,
196.4, 173.5, 150.1, 142.8, 138.4, 129.3, 60.0, 54.7, 34.9, 33.2, 31.9, 31.4,
25.8, 25.5, 20.0 ppm; MS (ESI+): m/z: 274 [M+H]+; HRMS (ESI+): m/
z: calcd for C16H20NO3: 274.1443; found: 274.1449 [M+H]+.
(8aS,2’R,3’S,5’S)-(3-Methyl-5-phenylsulfanyl)-2-(3-thioxo-1,2,3,5,6,8a-
hexahydro-indolizine-8-carbonyl)cyclohexanone (21): A mixture of 20
(110 mg, 0.287 mmol) and Lawessonꢁs reagent (63.7 mg, 0.158 mmol) in
toluene/CH2Cl2 (2:1, 6 mL) was stirred at 658C for 15 min. After concen-
tration, the crude product was purified by column chromatography on
silica gel (hexane/AcOEt 1:1) to afford thioamide 21 as a colorless syrup
(92.6 mg, 81%). [a]2D3 =À263 (c=0.30 in CHCl3); IR (ATR): n˜ =2929,
(8aS,1’S,2’R,4’R)-8-(2’-Methyl-6’-oxo-4’-phenylsulfanyl-cyclohexanecar-
bonyl)-1,5,6,8a-tetrahydro-2H-indolizin-3-one (23): This compound
(134 mg, 96%, colorless syrup) was obtained from 22 (100 mg,
0.366 mmol) by using a procedure similar to that for 20. [a]2D6 =À60.4 (c=
0.20 in CHCl3); IR (ATR): n˜ =2929, 1708, 1660 cmÀ1
;
1H NMR
1709, 1663 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.46–7.38 (m, 2H),
;
(300 MHz, CDCl3): d=7.44–7.40 (m, 2H), 7.36–7.29 (m, 3H), 6.85 (d, J=
5.4 Hz, 1H), 4.59–4.50 (m, 1H), 4.30 (dd, J=12.9, 6.3 Hz, 1H), 3.80
(quin., J=4.5 Hz, 1H), 3.73 (d, J=9.3 Hz, 1H), 2.99–2.84 (m, 1H), 2.79–
2.60 (m, 3H), 2.57–2.42 (m, 4H), 2.38–2.26 (m, 1H), 2.17 (brdt, J=9.6,
4.5 Hz, 1H), 1.91 (ddd, J=14.1, 10.5, 3.9 Hz, 1H), 1.70 (dq, J=12.6,
9.9 Hz, 1H), 0.96 ppm (d, J=6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=205.7, 196.1, 174.9, 141.1, 138.0, 133.2, 132.9, 129.2, 127.9, 63.9, 55.7,
46.0, 44.6, 36.3, 35.7, 31.3, 31.1, 25.8, 25.2, 20.4 ppm; MS (ESI+): m/z:
384 [M+H]+; HRMS (ESI+): m/z: calcd for C22H26NO3S: 384.1633;
found: 384.1633 [M+H]+.
7.37–7.28 (m, 3H), 6.90 (brd, J=4.2 Hz, 1H), 5.07 (dd, J=12.8, 5.7 Hz,
1H), 4.81–4.71 (m, 1H), 3.83–3.74 (m, 1H), 3.69 (d, J=8.8 Hz, 1H),
3.10–2.43 (m, 9H), 2.22–2.12 (m, 1H), 1.91 (ddd, J=14.1, 9.6, 3.9 Hz,
1H), 1.54–1.42 (m, 1H), 0.95 ppm (d, J=6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=205.1, 200.0, 195.6, 140.8, 138.9, 133.1, 133.0, 129.1,
127.9, 64.2, 61.9, 45.8, 44.3, 43.9, 39.9, 36.0, 32.1, 28.3, 25.1, 20.3 ppm; MS
(ESI+): m/z: 400 [M+H]+; HRMS (ESI+): m/z: calcd for C22H26NO2S2:
400.1405; found: 400.1415 [M+H]+.
À
Grandisine D trifluoroacetic acid salt (5·TFA): Me3O+BF4 (55.5 mg,
(8aS,2’S,3’R,5’R)-(3-Methyl-5-phenylsulfanyl)-2-(3-thioxo-1,2,3,5,6,8a-
hexahydro-indolizine-8-carbonyl)cyclohexanone (24): This compound
(29.7 mg, 57%, colorless syrup) was obtained from 23 (50.0 mg,
0.130 mmol) by using a procedure similar to that for 21. [a]2D6 =À132 (c=
0.375 mmol) was added to a solution of 21 (50.0 mg, 0.125 mmol) in
CH3CN (1.2 mL) at 48C and then the mixture was stirred at room tem-
perature for 1 h. After concentration, the residue (50.0 mg, 0.125 mmol)
was dissolved in MeOH (1.2 mL), and NaBH3CN (15.7 mg, 0.250 mmol)
was added to the solution. The mixture was stirred at room temperature
for 1 h, and then was poured into saturated aqueous NaHCO3 (5 mL),
and extracted with CH2Cl2 (5 mLꢂ3), dried (Na2SO4), and concentrated
in vacuo. The residue was dissolved in CH2Cl2 (1 mL) at 48C and TFA
(12.0 mL, 0.161 mmol) was added to the solution. The resulting mixture
was allowed to warm to room temperature, and was then stirred for 1 h.
After this time, the mixture was concentrated in vacuo. The crude prod-
uct was purified by column chromatography on silica gel (AcOEt/
MeOH/28%NH3 50:10:1) to afford 5·TFA as a colorless oil (20.6 mg,
63% yield). [a]2D3 =+65.7 (c=0.09 in MeOH); IR (ATR): n˜ =2955, 2926,
0.37, CHCl3); IR (ATR): n˜ =2928, 1708, 1666, 1488 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=7.45–7.40 (m, 2H), 7.36–7.29 (m, 3H), 6.90 (d, J=
5.9 Hz, 1H), 5.08 (dd, J=13.0, 6.1 Hz, 1H), 4.82–4.72 (m, 1H), 3.81
(quin., J=4.5 Hz, 1H), 3.70 (d, J=9.5 Hz, 1H), 3.15–2.86 (m, 4H), 2.78–
2.65 (m, 2H), 2.60–2.39 (m, 3H), 2.24–2.14 (m, 1H), 1.91 (ddd, J=14.4,
10.5, 3.9 Hz, 1H), 1.72 (dq, J=12.9, 9.9 Hz, 1H), 0.97 ppm (d, J=6.6 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=205.2, 200.4, 195.9, 141.0, 137.8,
133.3, 133.0, 129.2, 128.0, 64.3, 62.2, 46.0, 44.5, 44.3, 40.1, 36.4, 31.1, 27.6,
25.1, 20.5 ppm; MS (ESI+): m/z: 400 [M+H]+; HRMS (ESI+): m/z:
calcd for C22H26NO2S2: 400.1405; found: 400.1406 [M+H]+.
2873, 2795, 1675, 1655 cmÀ1 1H NMR (300 MHz, [D6]DMSO): d=10.15
;
9-epi-ent-Grandisine D trifluoroacetic acid salt (9-epi-ent-5·TFA)
(25·TFA): This compound (15.8 mg, 56%, colorless oil) was obtained
from 24 (30.0 mg, 0.0751 mmol) by using a procedure similar to that for
5. [a]2D6 =À9.5 (c=0.11 in MeOH); IR (ATR): n˜ =2918, 1674, 1178,
(brs, 1H), 7.34 (apparentt, J=3.8 Hz, 1H), 7.19–7.11 (m, 1H), 5.96 (dd,
J=10.0, 2.1 Hz, 1H), 4.45–4.35 (m, 1H), 4.32 (d, J=11.6 Hz, 1H), 3.63–
3.47 (m, 1H), 3.40–3.27 (m, 2H), 3.19–3.03 (m, 1H), 2.67–2.56 (m, 2H),
2.53–2.35 (m, 3H), 2.27–2.12 (m, 1H), 2.09–1.92 (m, 2H), 1.72–1.55 (m,
1H), 0.85 ppm (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, [D6]DMSO): d=
198.4, 196.8, 151.8, 140.2, 137.3, 128.4, 59.3, 58.0, 53.0, 43.1, 33.0, 32.7,
28.1, 23.0, 20.3, 19.2 ppm; MS (ESI+): m/z: 260 [M+H]+; HRMS (ESI+):
m/z: calcd for C16H22NO2: 260.1651; found: 260.1652 [M+H]+.
1129 cmÀ1 1H NMR (300 MHz, [D6]DMSO): d=10.20 (brs, 1H), 7.31
;
(apparentt, J=4.0 Hz, 1H), 7.19–7.10 (m, 1H), 5.93 (dd, J=10.0, 2.1 Hz,
1H), 4.48–4.37 (m, 1H), 4.37 (d, J=11.7 Hz, 1H), 3.59–3.46 (m, 1H),
3.39–3.26 (m, 2H), 3.20–3.08 (m, 1H), 2.66–2.56 (m, 2H), 2.54–2.31 (m,
3H), 2.29–2.14 (m, 1H), 2.10–1.95 (m, 2H), 1.84–1.69 (m, 1H), 0.86 ppm
(d, J=6.2 Hz, 3H); 13C NMR (75 MHz, [D6]DMSO): d=198.4, 197.0,
151.9, 138.9, 137.3, 128.4, 59.1, 58.1, 52.7, 43.0, 32.7, 32.3, 27.9, 22.4, 20.4,
19.1 ppm; MS (ESI+): m/z: 260 [M+H]+; HRMS (ESI+): m/z: calcd
for C16H22NO2: 260.1651; found: 260.1655 [M+H]+.
Grandisine B (2): 28% NH3 (0.25 mL) was slowly added to a solution of
5·TFA (5.0 mg, 0.134 mmol) in MeOH (0.50 mL) at 48C. The reaction
mixture was stirred for 2 h at room temperature and then concentrated
in vacuo. The residue was purified by chromatography on NH silica gel
(CH2Cl2/MeOH/28% NH3 200:10:1) to give 2 as a colorless oil (2.7 mg,
78%). [a]2D2 =À159 (c=0.08 in CH2Cl2); IR (ATR): n˜ =2952, 1727,
9-epi-ent-Grandisine B (26): This compound (1.4 mg, 40%, pale-yellow
oil) was obtained from 25·TFA (5.0 mg, 0.0134 mmol) by using a proce-
dure similar to that for 2. [a]2D6 =+96.6 (c=0.13 in CH2Cl2); IR (ATR):
1
1577 cmÀ1; H NMR (600 MHz, CDCl3): d=6.40 (td, J=4.2, 1.2 Hz, 1H),
n˜ =2953, 1728, 1577 cmÀ1 1H NMR (600 MHz, CDCl3): d=6.43 (t, J=
;
4.62–4.60 (m, 1H), 3.71–3.66 (m, 1H), 3.53 (d, J=3.0 Hz, 1H), 2.91 (ddd,
J=12.6, 7.8, 4.8 Hz, 1H), 2.86 (dd, J=11.4, 5.4 Hz, 1H), 2.83–2.77 (m,
1H), 2.65 (dt, J=11.4, 6.0 Hz, 1H), 2.44–2.27 (m, 3H), 2.14 (dt, J=19.2,
3.0 Hz, 1H), 2.04 (dd, J=18.6, 1.8 Hz, 1H), 1.97–1.92 (m, 1H), 1.88–1.74
(m, 3H), 1.37–1.31 (m, 1H), 1.25 (ddd, J=12.6, 4.8, 1.8 Hz, 1H),
1.04 ppm (d, J=7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=208.9,
171.0, 138.4, 130.2, 58.9, 56.4, 55.6, 52.6, 45.2, 40.0, 32.2, 30.0, 29.2, 24.8,
22.3, 21.2 ppm; MS (ESI+): m/z: 259 [M+H]+; HRMS (ESI+): m/z:
calcd for C16H23N2O: 259.1810; found: 259.1815 [M+H]+.
3.6 Hz, 1H), 4.66–4.63 (m, 1H), 3.88–3.81 (m, 1H), 3.61 (d, J=3.0 Hz,
1H), 2.98–2.89 (m, 2H), 2.84–2.78 (m, 1H), 2.77–2.70 (m, 1H), 2.48–2.29
(m, 3H), 2.14–2.07 (m, 2H), 2.04–1.98 (m, 1H), 1.97–1.91 (m, 1H), 1.90–
1.77 (m, 2H), 1.44–1.35 (m, 1H), 1.29 (ddd, J=12.6, 4.2, 1.2 Hz, 1H),
1.06 ppm (d, J=7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3): d=209.1,
170.5, 137.5, 129.8, 58.7, 56.3, 55.8, 53.0, 44.8, 39.5, 32.9, 29.7, 29.3, 24.9,
22.3, 21.3 ppm; MS (ESI+): m/z: 259 [M+H]+; HRMS (ESI+): m/z:
calcd for C16H23N2O: 259.1810; found: 259.1804 [M+H]+.
Chem. Eur. J. 2009, 15, 12754 – 12763
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12761