3678
X. Wu et al.
PAPER
1H NMR (500 MHz, CDCl3): d = 8.56 (s, 1 H), 7.50 (d, J = 8 Hz, 1
H), 7.33 (d, J = 8 Hz, 1 H), 7.10–7.18 (m, 2 H), 7.01 (q, J = 7 Hz, 1
H), 5.23–5.26 (m, 1 H), 4.97 (dd, J = 12, 4 Hz, 1 H), 2.78–2.98 (m,
4 H), 2.52 (dt, J = 12, 4 Hz, 1 H), 1.86–1.89 (m, 1 H), 1.77 (d, J = 7
Hz, 3 H), 1.36–1.62 (m, 4 H), 0.97 (t, J = 7 Hz, 3 H).
HRMS (ESI): m/z calcd for (C21H26N2O3 + Na)+: 377.1943; found:
377.1996.
(2S,11bS,E)-3-Ethylidene-9,10-dimethoxy-2-phenyl-2,3,6,7-tet-
rahydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-one (10)
HPLC [Phenomenex Chiralpak amylose-2, hexane–i-PrOH (4:1);
13C NMR (125 MHz, CDCl3): d = 164.2, 136.5, 134.0, 133.9, 133.4,
127.0, 122.0, 119.7, 118.4, 111.1, 109.5, 50.0, 40.9, 34.8, 32.4,
31.6, 21.3, 20.7, 14.3, 13.9.
HRMS (ESI): m/z calcd for (C20H25N2O)+: 309.1961; found:
309.1973.
flow rate = 1.00 mL/min, l = 220 nm]: tR = 17.34 min (minor enan-
25
tiomer), tR = 22.23 min (major enantiomer); [a]D –19.1 (c 0.37,
CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.33–7.37 (m, 2 H), 7.24–7.30 (m,
4 H), 6.60 (s, 1 H), 6.43 (s, 1 H), 4.96 (dt, J = 11, 3 Hz, 1 H), 4.39
(dd, J = 11.5, 3 Hz, 1 H), 4.24–4.26 (m, 1 H), 3.84 (s, 3 H), 3.81 (s,
3 H), 2.78–2.93 (m, 2 H), 2.58–2.64 (m, 2 H), 2.06–2.10 (m, 1 H),
1.66 (d, J = 7 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 164.2, 147.8, 147.7, 141.8, 136.8,
130.8, 128.9, 128.9, 127.9, 127.6, 126.8, 111.6, 108.5, 56.3, 56.0,
51.8, 40.2, 38.5, 38.1, 28.9, 13.9.
(2R,12bS,E)-3-Ethylidene-2-pentyl-1,2,3,6,7,12b-hexahydroin-
dolo[2,3-a]quinolizin-4(12H)-one (5e)
HPLC [Daicel Chiralpak AS-H, hexane–i-PrOH (4:1); flow
rate = 0.70 mL/min, l = 220 nm]: tR = 8.5 min (major enantiomer),
tR = 16.1 min (minor enantiomer); [a]D25 –111.6 (c 0.45, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.86 (s, 1 H), 7.50 (d, J = 7 Hz, 1
H), 7.32 (d, J = 7 Hz, 1 H), 7.17 (t, J = 7 Hz, 1 H), 7.11 (t, J = 7 Hz,
1 H), 6.99 (q, J = 7.2 Hz, 1 H), 5.16–5.27 (m, 1 H), 4.91–4.98 (m, 1
H), 2.73–3.00 (m, 4 H), 2.43 (dt, J = 12.6, 4 Hz, 1 H), 1.87 (td,
J = 12.6, 4 Hz, 1 H), 1.78 (d, J = 7.2 Hz, 3 H), 1.32–1.62 (m, 8 H),
0.91 (t, J = 7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 164.1, 136.5, 134.0, 133.8, 133.6,
127.2, 122.2, 120.0, 118.6, 111.0, 110.1, 49.9, 40.8, 32.5, 32.0,
31.9, 29.8, 27.3, 22.8, 21.3, 20.7, 14.2, 13.9.
HRMS (ESI): m/z calcd for (C23H26NO3)+: 364.1907; found:
364.1919.
(E)-5-(Methoxymethoxy)pent-2-enal (2g)
To a stirred solution of LiAlH4 (102 mg, 3 mmol) in THF (5mL)
was added a solution of 119 (288 mg, 2 mmol) in THF (2 mL) drop-
wise at 0 °C. The reaction mixture was allowed to stir at r.t. for 6 h
and the progress of the reaction was followed by TLC (eluent: PE–
EtOAc, 1:1; Rf = 0.65). The mixture was quenched with H2O (0.1
mL) and 2.5 M aq NaOH (0.1 mL), and diluted with EtOAc (20
mL). Al(OH)3 was removed by filtration. The organic layer was
concentrated to afford the crude allylic alcohol, which was used di-
rectly in the next step. To a solution of crude allylic alcohol in
CH2Cl2 was added DIPEA (1.5 mL) and DMSO (1.5 mL) at 0 °C.
Pyridine·SO3 complex (1.6 g, 8 mmol) was added in portions. The
reaction mixture was stirred at 0 °C for 30 min, then quenched with
H2O (10 mL), and diluted with Et2O (15 mL). The organic layer was
washed with H2O (15 mL) and brine (15 mL), and dried (Na2SO4).
The crude product obtained after concentrating under reduced pres-
sure was purified by flash silica gel chromatography to provide al-
dehyde 2g as a colorless oil; yield: 240 mg (84%).
HRMS (ESI): m/z calcd for (C22H29N2O)+: 337.2274; found: 337.
2279.
(2R,12bS,E)-3-Ethylidene-2-heptyl-1,2,3,6,7,12b-hexahydroin-
dolo[2,3-a]quinolizin-4(12H)-one (5f)
HPLC [Daicel Chiralpak AS-H, hexane–i-PrOH (4:1); flow
rate = 0.70 mL/min, l = 220 nm]: tR = 8.04 min (major enanti-
25
omer), tR = 13.6 min (minor enantiomer); [a] D –112.9 (c 0.3,
CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.85 (s, 1 H), 7.50 (d, J = 8 Hz, 1
H), 7.32 (d, J = 8 Hz, 1 H), 7.17 (t, J = 8 Hz, 1 H), 7.12 (t, J = 8 Hz,
1 H), 6.99 (q, J = 7.2 Hz, 1 H), 5.17–5.27 (m, 1 H), 4.91–4.98 (m, 1
H), 2.71–3.01 (m, 4 H), 2.43 (dt, J = 12.8, 3.2 Hz, 1 H), 1.87 (td,
J = 12.4, 4 Hz, 1 H), 1.78 (d, J = 7.2 Hz, 3 H), 1.32–1.62 (m, 12 H),
0.91 (t, J = 6.8 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 9.51 (d, J = 7.8 Hz, 1 H), 6.88 (dt,
J = 15.6, 6.2 Hz, 1 H), 6.19 (dd, J = 15.6, 7.8 Hz, 1 H), 4.63 (s, 2
H), 3.70 (t, J = 12.3 Hz, 2 H), 3.36 (s, 3 H), 2.62–2.65 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 164.1, 136.5, 134.0, 133.8, 133.6,
127.2, 122.2, 120.0, 118.5, 111.0, 110.1, 49.8, 40.8, 32.6, 32.5,
32.0, 31.9, 29.8, 29.5, 27.7, 22.8, 21.3, 14.2, 13.9.
HRMS (ESI): m/z calcd for (C24H33N2O)+: 365.2587; found: 337.
2596.
13C NMR (100 MHz, CDCl3): d = 193.8, 154.9, 134.3, 96.5, 65.5,
55.3, 33.0.
HRMS (ESI): m/z calcd for (C7H12O3 + Na)+ 167.0606; found:
167.0623.
epi-Geissoschizol
(2S,12bS,E)-3-Ethylidene-2-[2-(methoxymethoxy)ethyl]-
1,2,3,6,7,12b-hexahydroindolo[2,3-a]quinolizin-4(12H)-one
(5g)
To a solution of compound 5g (180 mg, 0.51 mmol) in DME (5 mL)
was added DIBAL-H (1 M in toluene) dropwise at –70 °C and the
reaction mixture was allowed to stir at –15 °C for 4 h (TLC moni-
toring, eluent: PE–EtOAc, 2:1; Rf = 0.45). After quenching with aq
NaOH (2 M, 1 mL), the reaction mixture was diluted with CHCl3
(20 mL) and H2O (10 mL). The combined organic layers were
washed with H2O (15 mL) and brine (20 mL), dried (Na2SO4), and
concentrated in vacuo to afford crude 12. The O-MOM ether deriv-
ative 12 formed was dissolved in THF (5 mL), and aq HCl (1 M, 5
mL) was added via a syringe. The mixture was stirred at r.t. over-
night. Et3N (1 mL) was added and the mixture was diluted with
CHCl3 (25 mL). The organic layer was separated and washed se-
quentially with H2O (10 mL) and brine (15 mL). After drying
(Na2SO4), and concentration under reduced pressure, the residue
was purified by flash chromatography on silica gel eluting with 30:1
CH2Cl2–MeOH to afford 112 mg (72%) of epi-geissochizol as a
white solid; mp 151–153 °C; [a]D25 –29.4 (c 1.0, MeOH).
HPLC [Daicel Chiralpak AS-H, hexane–i-PrOH (3:1); flow
rate = 0.60 mL/min, l = 220 nm]: tR = 17.3 min (major enantio-
25
mer), tR = 47.0 min (minor enantiomer); [a]D –114.1 (c 1.0,
MeOH).
1H NMR (400 MHz, CDCl3): d = 8.48 (s, 1 H), 7.40 (d, J = 8.0 Hz
1 H), 7.21 (d, J = 8.0 Hz, 1 H), 6.99–7.00 (m, 2 H), 6.95 (q, J = 7.2
Hz, 1 H), 5.13 (d, J = 9.6 Hz, 1 H), 4.90 (d, J = 11.2 Hz, 1 H), 4.56
(s, 1 H), 3.54–3.61 (m, 1 H), 3.42–3.50 (m, 1 H), 3.31 (s, 3 H), 3.04–
3.14 (m, 1 H), 2.66–2.99 (m, 3 H), 2.47 (dt, J = 12.8, 1.6 Hz, 1 H),
1.80–1.88 (m, 2 H), 1.71 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.9, 136.4, 134.6, 133.7, 132.8,
126.9, 122.0, 119.7, 118.3, 111.0, 109.5, 96.8, 65.5, 55.5, 49.9,
40.8, 32.5, 32.3, 28.8, 21.2, 13.7.
Synthesis 2011, No. 22, 3675–3679 © Thieme Stuttgart · New York