Diastereoselective Synthesis of Cularine Alkaloids
3-benzyloxy-4-methoxyphenethyltriphenylphosphorane (9,
R ) H) in 94% yield, mp 150-151 °C.
Syn th eses of Keten es 10 (R3 ) OCH3). Meth od A. 4-(3,4-
Dimethoxyphenylmethylidene)-2-phenyl-5(4)-oxazolone was syn-
thesized in 76% yield and 2.5 h reaction time by the procedure
of Buck and Ide42 using conventional heating.
Meth od B. Solven t-F r ee Con d iton s. Veratraldehyde
(10.67 g, 60.0 mmol), hippuric acid (12.8 g, 72.0 mmol), and
sodium acetate (5.34 g, 70.0 mmol) (same ratio as used in
method A, but in the absence of acetic anhydride) were placed
in an Erlenmeyer flask and triturated to produce a semi-
homogeneous mixture. The flask was plugged loosely with
glass wool. Irradiation in a domestic microwave oven for 5 min,
followed by washing with warm water, gave the azalactone in
quantitative yield: mp 151-152 °C.
6.93 (dd, 1H, J ) 8.3, 2.3 Hz), 4.85 (s, 1H) (OH), 3.88 (s, 3H),
3.85 (s, 3H), 3.80 (s, 3H), 3.15 (s, 2H), 2.55 (t, 2H), 2.27 (t,
2H).
Oxid a tion of 18. To 18 (60 mg, 0.18 mmol) in toluene (15
mL) at -10 °C was added NaH (4.50 mg, 0.19 mmol), and the
mixture stirred at that temperature for 30 min, at which point
C6F5I(OCOCF3)2 (8)23 (104 mg, 0.20 mmol) was added and
stirring at -10 °C was continued for 2 h. The solution was
dried (K2CO3) and evaporated to give a mixture of 16 and 17
(53.04 mg, 89% yield), which was separated by preparative
layer chromatography (SiO2 gel, CHCl3/MeOH 99:1 v/v).
16 (51.85 mg, 87%): mp 128-129 °C (petroleum ether); IR
(KBr) 1624 (CdN), 1260 cm-1 (ArOAr); NMR (CDCl3) δ 6.87
(d, 1H, J ) 8.5 Hz), 6.86 (s, 1H), 6.78 (d, 1H, J ) 8.5 Hz), 6.52
(1H), 3.89 (s, 3H), 3.78 (s, 3H), 3.10 (s, 2H), 2.55 (t, 2H), 2.40
(t, 2H); 13C NMR δ 20.8, 35.8, 43.5, 58.2, 58.6, 60.6, 113.4,
116.3, 117.2, 118.3, 128.7, 129.4, 129.9, 149.3, 149.7, 149.9,
150.8, 151.1, 158.7; MS m/z 325 (M•+, 35.9, 310 (100), 294 (69.7)
224 (5.8), 190 (5.4),159 (12.2). Anal. Calcd for C19H18NO4: C,
70.14; H, 5.89; N, 4.30. Found: C, 70.16; H, 5.85; N, 4.32.
Homoveratric acid was synthesized from the azalactone
using a literature method43 to give the acid in 83% yield: mp
97-98 °C.
3,4-Dimethoxyphenylketene (10) was prepared using the
method of Olah et al.32 (who used it to prepare alkylketenes
from alkylacetic acids), using DCC and catalytic amounts of
Et3N. 10 was obtained in 78% yield: mp 81-82 °C; IR (KBr)
17 (1.10 mg, 2%): mp 131-132 °C. Anal. Calcd for C19H19
-
NO4: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.16; H, 5.86; N
4.31.
2118 cm-1 (-CdCdO); NMR (CDCl3) δ 8.10 (d, 1Η, J
)
1.18Ηz), 7.95 (dd, 1H, J ) 8.4 and 1.8 Hz), 7.10 (s, 1H), 6.80
(dd, 1H, J ) 8.4 Hz), 3.88 (s, 3H), 3.87 (s, 1H).
Syn th esis of 16 via a Nitr en iu m Ion . Compound 12b (see
the Supporting Information) was debrominated using Ph3P or
BuLi as described for 12a (Supporting Information) to give
13 (R3 ) NO2). The latter (100 mg, 0.20 mmol) was dissolved
in EtOH (2.5 mL) to which was then added sodium thiosulfate
(350 mg, 2.20 mmol) in water (2.5 mL), and the solution was
boiled under reflux for 1 h. On cooling the solution, a
precipitate formed and was recrystallized with 40% aq pyridine
to give 13 (R3 ) NH2) (82 mg, 88%): mp 164-165 °C; IR (KBr)
3509 d (NH2), 1624 cm-1 (CdN); NMR (CDCl3) δ 7.32 (m, 5H),
6.85 (d, 1H, J ) 8.7 Hz), 6.79 (d, 1H, J ) 8.7 Hz), 6.75, (dd,
1H, J ) 8.7, 2.0 Hz), 6.71 (d, 1H, J ) 2.0 Hz), 6.69 (d, 1H, J
) 8.7 Hz), 5.03 (s, 2H), 4.80 (s, 2H) (NH2), 3.83 (s, 3H), 3.80
(s, 3H), 3.14 (s, 2H), 2.57 (t, 2H) 2.27 (t, 2H). Anal. Calcd for
Syn th esis of 5-Br om o-8-ben zyloxy-1-(3,4-d im eth oxy-
ben zyl)-7-m eth oxy-3,4-d ih yd r oisoqu in olin e (12a ) Usin g
a n Aza -Wittig Rea ction . To a solution of iminophosphorane
9 (R ) Br) (1.0 g, 1.68 mmol) in toluene at 0 °C under dry N2
was added a solution of ketene 10 (R3 ) OMe) (430 mg, 2.43
mmol) in toluene. After 2 h, the temperature was slowly raised
to 75 °C and maintained at that temperature for 14 h. The
solvent was then evaporated, and the solid residue was
recrystallized from petroleum ether to give 12a as a white
1
solid: mp 158-159 °C (76%); IR (KBr) 1627 cm-1 (CdN); H
NMR (CHCl3) δ 7.50, (m, 5H), 7.35 (s, 1H), 7.10 (d, 1H, J )
2.3 Hz), 7.04 (d, 1H, J ) 8.3 Hz), 6.92 (dd, 1H, J ) 8.3, 2.3
Hz), 5.02 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.78 (s, 3H), 3.10
(s, 2H), 2.55 (t, 2H), 2.25 (t, 2H); 13C NMR (CDCl3) δ 21.2, 37.3,
44.8, 56.6, 56.8, 57.8, 58.7, 112.2, 115.6, 117.1, 118.4, 119.2,
119.5, 120.2, 124.3, 125.4, 129.1, 133.4, 133.7, 148.9, 149.9,
150.2, 151.3,159.2. Anal. Calcd for C26H26BrNO4: C, 62.91; H,
5.28; N, 2.82. Found: C, 62.91; H, 5.26; N, 2.82.
C
25H26N2O3: C, 74.60; H, 6.51; N, 6.96. Found: C, 74.62; H,
6.52; N, 6.98.
The amine (82 mg, 0.20 mmol) was diazotized to give 13 (R
) N3) (72 mg, 83%) as a yellow solid: mp 149-150 °C; IR (KBr)
2138 (N3), 1627 cm-1 (CdN); NMR (CDCl3) δ 7.30 (m, 5H),
6.89 (d, 1H, J ) 8.7 Hz), 6.84 (d, 1H, J ) 8.7 Hz), 6.77 (dd,
1H, J ) 8.7, 2.0 Hz), 6.73 (d, 1H, J ) 2.0 Hz), 6.69 (d, 1H, J
) 8.7 Hz), 5.02 (s, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.12 (s, 2H),
2.56 (t, 2H), 2.26, t, 2H). Anal. Calcd for C25H24N4O3: C, 70.08;
H, 5.65; N, 13.08. Found: C,70.09; H, 5.66; N, 13.10.
A solution of azide 13 (R ) N3) (70 mg, 0.16 mmol) in CCl4
(10 mL) at -5 °C was treated with TFMSA (200 mg, 1.34
mmol) and stirred for 10 h at that temperature. The solution
was then extracted with water, and the organic layer was dried
(K2CO3) and evaporated to give a mixture of 22 (81%) and 23
(∼3%). The mixture was resolved using TLC (CHCl3/MeOH
99:1 v/v). 22 (41.31 mg): mp 135-136 °C (petroleum ether);
IR (KBr) 3450-3555 d (NH2), 1625 cm-1 (CdN); 1H NMR
(CDCl3) δ 6.84 (d, 1H, J ) 8.6 Hz), 6.82 (s, 1H), 6.76 (d, 1H, J
) 8.6 Hz), 6.50 (s, 1H), 4.78 (s, 2H) (NH2), 3.83 (s, 3H), 3.76
(s, 3H), 3.05 (s, 2H), 2.54 (t, 2H) 2.37 (t, 2H); 13C NMR (CDCl3)
δ 22.8, 40.2, 45.7, 58.1, 60.1, 118.1, 118.9, 119.5, 123.1, 129.8,
132.1, 132.4, 148.1, 140.8, 150.1, 151.8, 152.3, 160.3. Anal.
Calcd for C18H18N2O3: C, 69.66; H, 5.86; N, 9.03. Found: C,
69.69; H, 5.81; N, 9.04. 23 (1.44 mg): mp 138-139 °C. Anal.
Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C,
69.69; H, 5.88; N, 9.05. 22: mp 138-139 °C. Anal. Calcd for
Syn th esis of 13 (R ) CH3O). Usin g Tr ip h en ylp h os-
p h in e:44 A solution of 12a (R ) Br) (300 mg, 0.60 mmol) and
Ph3P (160 mg, 0.60 mmol) was stirred and boiled under reflux
for 10 h. The cooled solution was stirred with cold water (30
mL) for 1 h and extracted with benzene. The extract was dried
(K2CO3) and evaporated to give 13 (R ) MeO) (160 mg, 65%):
mp 142-143 °C (petroleum ether); IR (KBr) 1627 (CdN), 1183
cm-1 (CO); NMR (CDCl3) δ 7.45 (m, 5H), 7.18 (d, 1H, J ) 8.3
Hz), 7.08 (d, 1H, J ) 2.3 Hz), 7.05 (d, 1H, J ) 8.3 Hz), 6.99 (d,
1H, J ) 8.3 Hz), 6.95 (dd, 1H, J ) 8.3, 2.3 Hz), 5.01 (s, 2H),
3.84, (s, 3H), 3.81, (s, 3H), 3.77 (s, 3H), 3.10 (s, 2H), 2.53 (t,
2H), 2.24 (t, 2H). Anal. Calcd for C26H27NO4: C, 74.80, H, 6.52;
N, 3.35. Found: C, 74.81; H, 6.51; N, 3.35.
Usin g Bu Li. To a solution of 12a (R ) Br) (250 mg, 0.50
mmol) in THF (15 mL) at -10 °C was added with stirring
n-BuLi (2.0 mL, 2.4 M in hexane). After 1 h, the temperature
was raised to 5 °C and kept there for 2 h. Standard workup
gave pure 13 (R ) MeO) (92% yield).
Syn th esis of 18. A solution of 13 (R3 ) MeO) (100 mg, 0.31
mmol) and TFMSA (40 mg, 0.27 mmol) was stirred at 60 °C
for 3 h. The solution was extracted with water repeatedly,
dried (K2CO3), and evaporated to give 18 (65 mg, 83%): mp
137-138 °C (petroleum ether); IR (KBr) 3437 (OH), 1626 cm-1
(CdN); NMR (CDCl3) δ 7.16 (d, 1H, J ) 8.3 Hz), 7.05 (d, 1H,
J ) 2.3 Hz), 7.02 (d, 1H, J ) 8.3 Hz), 6.98 (d, 1H, J ) 8.3 Hz),
C
18H18N2O3: C, 69.66; H, 5.86; N, 9.03. Found: C, 69.66; H,
5.85; N, 9.03.
22 (30 mg, 0.10, 0.10 mmmol) was diazotized with aq sodium
nitrite and 30% sulfuric acid at 0 °C with stirring for 1 h.
Distilled water (10 mL) was added, and the solution was then
heated to 60 °C and kept at that temperature for 2 h. After
cooling it was extracted with ether, the solvent was evaporated,
and the residue was treated with diazomethane in ether to
(42) Buck, J . S.; Ide, W. S. Organic Syntheses; Wiley: New York,
1943; Collect. Vol. II, p 55-56.
(43) Snyder, H. R.; Buck, J . S.; Ide, W. S. Organic Syntheses;
Wiley: New York, 1943; Collect. Vol. II, pp 333-336.
J . Org. Chem, Vol. 69, No. 9, 2004 2927