layer was washed with brine, dried over Na2SO4, and evaporated
under vacuum to leave a crude solid residue that was purified
by recrystallization in EtOH.
dolinones, Horner-type reaction, deprotection, and ulti-
mate diaryl ether coupling has been applied to an
efficient construction of the aristocularine skeleton. The
advantage of this synthesis lies in the small number of
synthetic steps and the ease of elaboration of the inter-
mediates involved in the assembly of these alkaloids. The
synthetic potential of this method also has been demon-
strated by the third known total synthesis of the alkaloid
aristoyagonine.
(Z)-4-Ben zyloxy-3-(2-br om o-3,4-d im eth oxyben zylid en e)-
5-m eth oxy-2-m eth yl-2,3-dih ydr o-1H-isoin dol-1-on e (26). The
arylmethyleneisoindolinone 26 was obtained as a mixture of
unseparable Z and E isomers (0.96 g, 42%). The isomeric ratio
(Z/ E 70:30) was determined from the 1H NMR spectrum and
integration of the N-CH3 protons [δ 2.89 ppm for (Z)-26 and δ
3.39 ppm for (E)-26]. The crude mixture dissolved in hexane (100
mL) was refluxed overnight with cat. I2 to give rise exclusively
and quantitatively to the Z isomer, which was ultimately
purified by recrystallization in EtOH to afford (Z)-26 as pale
Exp er im en ta l Section
1
yellow crystals; mp 132-133 °C; H NMR (300 MHz, CDCl3) δ
Typ ica l P r oced u r e for th e Syn th esis of th e P h osp h o-
r yla ted Isoin d olin on es 14-16. A solution of KHMDS (0.5 M
in toluene, 8.8 mL, 4.4 mmol) was added dropwise to a carefully
degassed solution of the phosphorylated 2-methoxybenzamide
derivative 17-19 (4.0 mmol) and 18-crown-6 (1.16 g, 4.4 mmol)
in THF (50 mL) at -78 °C under Ar. The solution was stirred
for 15 min and then allowed to warm to room temperature over
a period of 2 h. Aqueous NH4Cl solution (10%, 10 mL) was added
and after dilution with water the mixture was extracted with
Et2O (2 × 25 mL) and CH2Cl2 (2 × 25 mL). The organic extracts
were washed with water and brine, dried over Na2SO4, and
evaporated in vacuo. Flash column chromatography on silica gel
with ethyl acetate/hexanes (9:1) as eluent followed by recrys-
tallization from hexane-toluene afforded the phosphorylated
isoindolinones 14-16.
2.89 (s, 3 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 3.96 (s, 3 H), 5.20 (s, 2
H), 6.85 (d, J ) 8.5 Hz, 1 H), 6.94 (d, J ) 8.5 Hz, 1 H), 7.04 (d,
J ) 8.3 Hz, 1 H), 7.21 (s, 1 H), 7.30-7.36 (m, 3 H), 7.51 (d, J )
7.8 Hz, 2 H), 7.60 (d, J ) 8.3 Hz, 1 H); 13C NMR (75 MHz, CDCl3)
δ 30.4, 56.1, 56.4, 60.6, 74.7, 110.6, 111.1, 113.1, 119.6, 120.1,
122.6, 126.6, 128.3, 128.5, 128.6, 129.4, 129.6, 135.5, 136.9, 143.0,
152.8, 156.4, 168.5. Anal. Calcd for C26H24BrNO5: C, 61.19; H,
4.74; N, 2.74. Found: C, 60.98; H, 4.84; N, 2.50.
Typ ica l P r oced u r e for th e Syn th esis of th e Dep r otected
3-Ar ylm eth ylen eisoin d olin on es 8-10. A solution of BCl3 (1
M in CH2Cl2, 1.06 mL, 1.06 mmol, 2 equiv, for 26 and 28) or
BBr3 (1 M in CH2Cl2, 1.06 mL, 1.06 mmol, 2 equiv, for 27) was
added by syringe to a cooled solution (-78 °C) of the protected
arylmethylene isoindolinone 26-28 (0.53 mmol) in CH2Cl2 (15
mL). The reaction mixture was stirred at -78 °C for 2 h and
MeOH (5 mL) was subsequently added three times. The organic
solvents were removed in a vacuum, the crude solid residue was
dissolved in Et2O (25 mL), and the resulting ethereal solution
was washed with brine and dried over Na2SO4. Flash column
chromatography on silica gel with ethyl acetate/hexanes (1:1)
as eluent afforded the phenolic derivatives 8-10.
4-Ben zyloxy-3-d ip h en ylp h osp h in oyl-5-m eth oxy-2-m eth -
yl-2,3-d ih yd r o-1H-isoin d ol-1-on e (14). White solid, 1.29 g
1
(67%); mp 161-162 °C; H NMR (300 MHz, CDCl3) δ 3.00 (s, 3
H), 3.85 (s, 3 H), 4.74 (s, 2 H), 4.87 (d, J HP ) 7.6 Hz, 1 H), 6.98
(d, J ) 8.1 Hz, 1 H), 7.09-7.13 (m, 2 H), 7.25-7.47 (m, 12 H),
7.61-7.68 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 30.8, 56.3, 63.6
(d, J CP ) 70 Hz), 74.4, 113.7, 119.6, 126.9 (d, J CP ) 2 Hz), 127.9
(d, J CP ) 97 Hz), 128.2, 128.21 (d, J CP ) 12 Hz), 128.25 (d, J CP
(Z)-3-(2-Br om o-3,4-d im eth oxyben zylid en e)-4-h yd r oxy-5-
m eth oxy-2-m eth yl-2,3-d ih yd r o-1H-isoin d ol-1-on e (8). Pale
1
) 12 Hz), 128.26, 128.7, 130.8 (d, J CP ) 96 Hz), 131.6 (d, J CP
)
yellow crystals from EtOH, 174 mg (78%); mp 207-208 °C; H
9 Hz), 131.7 (d, J CP ) 8 Hz), 132.2 (d, J CP ) 3 Hz), 132.4 (d, J CP
) 3 Hz), 132.8 (d, J CP ) 3 Hz), 137.0, 142.5 (d, J CP ) 3 Hz),
155.2 (d, J CP ) 2 Hz), 168.3; 31P NMR (121 MHz, CDCl3) δ 30.3.
Anal. Calcd for C29H26NO4P: C, 72.04; H, 5.42; N, 2.90. Found:
C, 72.35; H, 5.20; N, 3.09.
NMR (300 MHz, CDCl3) δ 2.92 (s, 3 H), 3.87 (s, 3 H), 3.89 (s, 3
H), 3.95 (s, 3 H), 6.53 (s, 1 H), 6.86 (d, J ) 8.5 Hz, 1 H), 6.95 (d,
J ) 8.2 Hz, 1 H), 7.02 (d, J ) 8.5 Hz, 1 H), 7.09 (s, 1 H), 7.40 (d,
J ) 8.2 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 30.2, 56.1, 56.6,
60.5, 110.6, 110.7, 110.9, 115.4, 120.1, 122.3, 122.9, 126.7, 129.6,
Typ ica l P r oced u r e for th e Syn th esis of th e 3-Ar ylm eth -
ylen eisoin d olin on es 26-28. The synthesis was initially car-
ried out as described above. After addition of the metalating
agent at -78 °C, the reaction mixture was stirred for an
additional 15 min and then treated by dropwise addition of a
solution of 2-bromobenzaldehyde derivative 11-13 (4.0 mmol)
in THF (10 mL). The mixture was stirred at -78 °C for 30 min,
warmed to 0 °C over a period of 1 h, and subsequently warmed
to room temperature for a longer period (2 h). Aqueous NH4Cl
solution (10%, 10 mL) was added followed by water and the
aqueous phase was extracted with Et2O (2 × 30 mL). The organic
135.6, 141.1, 146.4, 149.9, 152.7, 168.6. Anal. Calcd for C19H18
BrNO5: C, 54.30; H, 4.32; N, 3.33. Found: C, 54.44; H, 4.24; N,
3.52.
-
Typ ica l P r oced u r e for t h e Syn t h esis of t h e Ar ist o-
cu la r in es 2a ,c,d . A solution of compound 8-10 (0.6 mmol), Cs2-
CO3 (277 mg, 0.85 mmol), and copper(I) trifluoromethane-
sulfonate toluene complex (15.5 mg, 0.03 mmol) in pyridine (10
mL) was refluxed for 24 h. The reaction mixture was poured
into 1 M HCl (5 mL) and extracted with ethyl acetate (2 × 15
mL). The organic layer was stirred with 10% NaOH solution (20
mL) and then washed with water and brine, dried over MgSO4,
filtered, and concentrated to give a yellow solid. Aristoyagonine2
(2a ) was obtained by recrystallization from MeOH as bright
yellow crystals, 163 mg (80%).
(19) For example, a sizable nOe effect (10%) of the aromatic proton
C-6′ (δ 7.02 ppm) was observed upon irradiation of the N-methyl group
(δ 2.92) for compound 8.
Ack n ow led gm en t. This research was supported by
the Centre National de la Recherche Scientifique and
MENESR (grant to A.M.). We also acknowledge helpful
discussions and advice from Dr. T. G. C. Bird (Astra-
Zeneca Pharma).
Su p p or tin g In for m a tion Ava ila ble: General methods
and materials and characterization for all other substrates.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) (a) Xing, X.; Padmanaban, D.; Yeh, L.-A.; Cuny, G. D. Tetra-
hedron 2002, 58, 7903-7910. (b) Marcoux, J . F.; Doyen, S.; Buchwald,
S. L. J . Am. Chem. Soc. 1997, 119, 10539-10540.
J O049869G
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