A synthetic route to (±)-clavizepine through a dibenzoxepine intermediate

Article abstract of DOI:10.1021/jo960291n

A new synthesis of (±)-clavizepine (1a), based on the dibenzoxepinediol 16 as main intermediate is described. The key step is the contraction of the oxepine ring to give the xanthene-9-carboxyaldehyde 11, on which the nitrogenated ring can be readily assembled.

Full text of DOI:10.1021/jo960291n

5818
J . Org. Chem. 1996, 61, 5818-5822
A Syn th etic Rou te to (()-Cla vizep in e th r ou gh a Diben zoxep in e
In ter m ed ia te†
M. C. de la Fuente, Luis Castedo,* and Domingo Dom´ınguez*
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad de Santiago y Seccio´n de
Alcaloides del CSIC, 15706 Santiago de Compostela, Spain
Received February 13, 1996X
A new synthesis of (()-clavizepine (1a ), based on the dibenzoxepinediol 10 as main intermediate
is described. The key step is the contraction of the oxepine ring to give the xanthene-9-
carboxyaldehyde 11, on which the nitrogenated ring can be readily assembled.
Sch em e 1
In tr od u ction
(-)-Clavizepine (1a ) is the sole member of a unique
class of alkaloids known as the dibenzopyranazepines.
First described in 1986,1 it has recently been synthesized
by two independent procedures, both of which employ a
xanthene-9-carboxylate as the key intermediate.2 Here
we describe an alternative approach in which the key step
is the ring contraction of a dibenzoxepinediol derivative
to a xanthene-9-carboxaldehyde (Scheme 1).
We have previously demonstrated the versatility of
dibenzoxepinones as intermediates for the synthesis of
both cularine alkaloids3 and the dibenzopyranazepine
skeleton (O-methylclavizepine (1b) can be prepared in
21% overall yield from dibenzoxepinone 3b in just nine
steps).4
Sch em e 2
However, application of this method to the synthesis
of natural clavizepine (1a ) was hampered by difficulties
in the preparation of the required dibenzoxepinone pre-
cursor, 3c. PPA failed to achieve intramolecular acyla-
tion of 2-[2-(benzyloxy)phenoxy]-4,5-dimethoxyphenylace-
tic acid,5 and McLean’s indirect procedure6 (involving the
morpholinamide of the acid) led to only 14% yield.
Because of the above difficulties, we approached the
preparation of 2-(benzyloxy)-4,5-dimethoxydibenzoxepi-
none (3c) by an alternative method based on alkylation
of the anion of an appropriate 1,3-dithiane with the
corresponding benzylic halide (Scheme 2).7 Although this
procedure, too, failed to afford 3c (vide infra), it turned
out to provide a new route to the dibenzoxepine 9c, which
in turn proved to be a suitable intermediate for synthesis
of clavizepine.
Resu lts a n d Discu ssion
2,3-Dihydroxybenzaldehyde (4) was selectively benzy-
lated at the hydroxyl meta to the aldehyde by treatment
† Dedicated to the memory of J . M. Boente.
with 2 equiv of NaH followed by addition of benzyl chlor-
ide.8 Treatment of the aldehyde 5 with 1,3-propanedi-
thiol under Lewis acid catalysis led to the dithioketal 6.
Although in previous work7 we protected the phenolic
hydroxyl prior to alkylation we now found that alkylation
can be successfully carried out on the dianion derivative
of 6: after treatment of the phenolic dithioketal 6 with
2 equiv of n-BuLi, the resulting dianion was alkylated
with 2-bromo-4,5-dimethoxybenzyl bromide, giving the
coupled product 7 in 74% yield.
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) Boente, J . M.; Castedo, L.; Dom´ınguez, D.; Ferro. M. C. Tetra-
hedron Lett. 1986, 34, 4077.
(2) (a) Ishibashi, H.; Takagaki, K.; Imada, N.; Ikeda, M. Synlett
1994, 49. (b) Ishibashi, H.; Takagaki, K.; Imada, N.; Ikeda, M.
Tetrahedron 1994, 50, 10215. c) Va´zquez, R.; de la Fuente, M. C.;
Castedo, L.; Dom´ınguez, D. Synlett 1994, 433.
(3) (a) Lamas, C.; Castedo, L.; Dom´ınguez, D. Tetrahedron Lett.
1990, 31, 6247. b) Garc´ıa, A.; Castedo, L.; Dom´ınguez, D. Tetrahedron
Lett. 1993, 34, 1797. c) Garc´ıa, A.; Castedo, L.; Dom´ınguez, D.
Tetrahedron 1995, 51, 8585.
(4) de la Fuente, M. C.; Castedo, L.; Dom´ınguez, D. Tetrahedron
1996, 52, 4917.
(5) Kametani, T.; Fukumoto, K.; Nakano, T. Yakugaku Zasshi 1962,
82, 1307. Chem. Abstr. 1963, 58, 13913h.
(6) Noguchi, I,; McLean, D. Can. J . Chem. 1975, 53, 125.
(7) Lamas, C.; Garc´ıa, A.; Castedo, L.; Dom´ınguez, D. Tetrahedron
Lett. 1989, 30, 6927.
(8) (a) Kessar, S. V.; Gupta, Y. P.; Mohammad, T.; Goyal, M.; Sawal,
K. K. J . Chem. Commun. 1983, 400. (b) Kessar, S. V.; Gupta, Y. P.;
Balakrishnan, P.; Sawal, K. K.; Mohammad, T.; Dutt, M. J . Org. Chem.
1988, 53, 1708.
S0022-3263(96)00291-5 CCC: $12.00 © 1996 American Chemical Society

Synthetic Route to (()-Clavizepine
J . Org. Chem., Vol. 61, No. 17, 1996 5819
Sch em e 3a
Sch em e 4
a
Reagents: (f) Raney Ni, acetone, 68% of 9c and 14% of 9a
starting from 7; (g) (i) NaH, DMF; (ii) benzyl chloride, 84%; (h)
OsO4, NMMO, THF, 82%; (i) H2SO4, AcOH, 96%; (j) NaBH4,
MeOH, 98%; (k) N-tosyl AADA, Ph3P, DEAD, THF, 52%; (l) H2,
Pd/C 10%, CH2Cl2, MeOH, 87%.
mide and N-methylation of the resulting amine (16) gave
1
a product with IR, MS, H NMR and 13C NMR spectra
that were identical to those of the natural compound
(Scheme 4).
The total synthesis of (()-clavizepine (1a ) was ac-
complished from the key dibenzoxepine 9c in nine steps
and 17% overall yield.
Ullmann reaction of bromophenol 7 afforded a mixture
that TLC showed to contain two main products of very
similar Rf, which were highly fluorescent when excited
at 360 nm. Purification by column chromatography led
to a 2:1 mixture of the two fluorescent compounds, as
determined by 1H NMR. The GC/MS of this mixture
showed the molecular ion of the major compound at m/e
466 (53%), corresponding to the dibenzoxepine structure
8 which results from â-elimination of the dithioacetal
following the Ullmann reaction. The minor compound
Exp er im en ta l Section
Gen er a l P r oced u r es. Solvents were dried by distillation
from a drying agent:11 THF and benzene from Na/benzophe-
none; pyridine, Et3N and diisopropylamine from CaH2. Melt-
ing points are uncorrected. 1H and 13C NMR spectra were
recorded at 250.13 and 62.83 MHz in CDCl3. LR and HR mass
spectra were recorded at 70 eV. Plate chromatography was
performed on Merck silica gel 60 F254 and visualized with UV
light (254 and 360 nm) or iodine vapor. Flash column
chromatography was performed on Merck silica gel 60 (230-
240 mesh ASTM).
1
has very similar H and 13C NMR data and an MS peak
(24%) at 465, which suggests a disulfide structure derived
from the oxidation of 8, but this structure could not be
firmly established.
Despite previous results,7 hydrolysis of the crude
mixture from the Ullmann reaction with acetonitrile/
concd HCl in the presence of glyoxylic acid, instead of
affording 3c, produced a complex mixture of products.
However, reduction of the mixture of fluorescent com-
pounds with Raney nickel gave the alkenes 9c (in 68%
yield) and 9a (in 14% yield); see Scheme 3. Alkene 9a
was reprotected, in 84% yield, by treatment with NaH
followed by addition of benzyl chloride.
Alkene 9c was hydroxylated in 82% yield by OsO4/
NMMO in aqueous THF. Pinacol rearrangement of diol
10 in AcOH/H2SO4 afforded a 96% yield of the aldehyde
11, which was reduced with NaBH4 in methanol to give
alcohol 12 in 98% yield. Mitsunobu reaction9 of 12 with
N-tosyl aminoacetaldehyde dimethyl acetal gave dim-
ethylacetal 13c in 52% yield,10 and debenzylation of 13c
by catalytic hydrogenation gave the phenolic compound
13a in 87% yield. Treatment of a solution of 13a in acetic
acid with HCl at 75 °C afforded the cyclic compound 14
in 79% yield. Catalytic hydrogenation of 14 gave a 92%
yield of 15, which by reductive cleavage of the sulfona-
2-[3-(Ben zyloxy)-2-Hydr oxyph en yl]-1,3-dith ian e (6). To
a solution of 3-(benzyloxy)-2-hydroxybenzaldehyde8 (14.1 g,
61.7 mmol) in dry chloroform (90 mL) were added 1,3-
propanedithiol (6.5 mL, 65 mmol), anhydrous Na2SO4 (5 g),
.
and BF3 OEt2 (3.8 mL, 30 mmol). The mixture was stirred at
rt for 2 h and then filtered, and the filtrate was washed with
water, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was recrystallized twice from CH2Cl2/n-
hexane to afford compound 6 (18.4 g, 93%). Mp: 136-138 °C.
IR (NaCl) 3510 (OH), 2900, 1610, 1590, 1475, 1385, 1355, 1270,
1
1050, 910 cm-1; H NMR δ 7.47-7.35 (m, 5H), 7.20 (dd, J )
3.1 and 6.0 Hz, 1H), 6.88-6.84 (m, 2H), 6.03 (s, 1H), 5.70 (s,
1H), 5.10 (s, 2H), 3.14 (td, J ) 14.7 and 2.4 Hz, 2H), 2.98-
2.87 (m, 2H), 2.22-214 (m, 1H), 2.02-1.92 (m, 1H); 13C NMR
δ 145.83, 142.64, 136.47, 129.02 (CH × 2), 128.70 (C), 128.09
(CH × 2), 125.16, 121.15 (CH), 120.42 (CH), 112.15 (CH), 71.53
(CH2), 44.27 (CH), 32.54 (CH2 × 2), 25.58 (CH2). MS, m/z
(%): 318 (M+, 27), 227 (14), 196 (47), 153 (31), 91 (100). Anal.
Calcd for C17H18O2S2: C 64.12, H 5.70. Found: C 63.90, H
5.56.
2-[3-(Be n zyloxy)-2-h yd r oxyp h e n yl]-2-(2-b r om o-4,5-
d im eth oxyben zyl)-1,3-d ith ia n e (7). 1.6 M n-BuLi (39.25
mL, 62.8 mmol) was added to a cooled solution (-40 °C) of
compound 6 (10 g, 31.4 mmol) in dry THF (120 mL). The
(9) Garc´ıa, A.; Castedo, L.; Dom´ınguez, D. Synlett 1993, 271.
(10) The main secondary product is 5-(benzyloxy)-2,3-dimethoxy-9-
methylenexanthene, which is easily oxidized to 5-(benzyloxy)-2,3-
dimethoxyxanthone during workup.
(11) Perrin, D. D.; Aramego, W. L. F. Purification of Laboratory
Chemicals; 3rd ed.; Pergamon: Oxford, 1988.

5820 J . Org. Chem., Vol. 61, No. 17, 1996
de la Fuente et al.
solution was warmed gradually to 0 °C, and a solution of
2-bromo-4,5-dimethoxybenzyl bromide (9.73 g, 31.4 mmol) in
THF (32 mL) was added. The mixture was stirred at rt for 8
h and then neutralized by dropwise addition of 10% HCl. The
solvent was evaporated in vacuo, and the residue was dissolved
in CH2Cl2, washed with water, dried over anhydrous Na2SO4,
and concentrated in vacuo. This final residue was purified
by column chromatography (silica gel; 1:1 CH2Cl2/hexane) to
afford dithiane 7, which was recrystallized from ether (12.7
g, 74%). Mp: 135-137 °C. IR (NaCl) 3150 (OH), 1570, 1510,
1610, 1570, 1510, 1260, 1210, 1110, 1000, 860, 800, 730, 700
cm-1
.
1H NMR δ 7.53 (d, J ) 6.8 Hz, 2H), 7.41-7.32 (m, 3H),
6.94-7.03 (m, 2H), 6.83 (s, 1H), 6.77 (dd, J ) 7.3 and 1.8 Hz,
1H), 6.69 (s, 2H), 6.64 (s, 1H), 5.16 (s, 2H), 3.83 (s, 3H), 3.75
(s, 3H); 13C NMR δ 151.24, 151.12, 150.56, 146.15, 145.56,
137.42, 132.53, 130.16 (CH), 128.81 (CH × 2), 128.64 (CH),
128.24 (CH), 127.68 (CH × 2), 124.90 (CH), 122.65 (C), 121.19
(CH), 114.22 (CH), 111.01 (CH), 105.96 (CH), 71.10 (CH2),
56.50 (OMe), 56.13 (OMe). MS, m/z (%): 360 (M+, 94), 241
(21), 225 (13), 195 (22), 91 (100). Anal. Calcd for C23H20O4:
C 76.65, H 5.59. Found: C 76.29, H 5.89.
1450, 1350, 1260, 1165, 1030, 740 cm-1 1H NMR δ 8.73 (s,
;
1H), 7.49-7.40 (m, 2H), 7.38-7.31 (m, 2H), 7.27-7.24 (m, 2H),
6.96-6.94 (m, 1H), 6.94 (s, 1H), 6.73 (t, 1H, J ) 8.1), 5.94 (s,
1H), 5.16 (s, 2H), 3.80 (s, 3H), 3.59 (s, 2H), 3.36 (s, 3H), 2.94-
2.81 (m, 2H), 2.76-2.67 (m, 2H), 2.00-1.94 (m, 2H); 13C NMR
δ 147.86, 147.81, 146.57, 146.14, 136.49, 128.05 (CH × 2),
127.42 (CH), 126.86 (CH × 2), 125.36, 125.02 (CH), 123.09,
118.46 (CH), 115.61, 114.30 (CH), 114.15 (CH), 114.06 (CH),
71.66 (CH2), 59.86, 56.17 (OMe), 55.58 (OMe), 45.43 (CH2),
28.26 (CH2 × 2), 24.50 (CH2); MS (FAB), m/z (%): 549 (3), 548
(3), 547 (M + 1,11), 546 (3), 545 (9), 351 (12), 317 (11), 229
(27), 151 (100). Anal. Calcd for C26H27O4S2Br, C 57.03, H 4.97.
Found: C 57.00, H 4.87.
Ullm a n n Rea ction of Br om op h en ol 7 To Obta in Com -
p ou n d 8. Phenol 7 (1.4 g, 2.5 mmol), CuO (1 g, 12.6 mmol),
anhydrous K2CO3 (2 g, 14.4 mmol), and dry deaerated pyridine
(10 mL) were mixed and then refluxed under Ar for 1 h. After
cooling, the reaction mixture was filtered through Celite, and
the filtrate was washed with 10% HCl and water, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude
residue was column-chromatographed (silica gel, 2:1 CH2Cl2/
hexane) to afford a main fraction (1 g) consisting of a mixture
of two compounds with very similar Rf, both of which fluo-
resced under the 360 nm lamp. The 1H NMR spectrum shows
a 2:1 mixture of dibenzoxepine 8 and an unknown compound.
1H NMR: m a jor com p ou n d (8), δ 7.54-7.51 (m, 2H),
7.41-7.33 (m, 4H), 7.08-6.98 (m, 3H), 6.82 (s, 1H), 6.62 (s,
1H), 5.16 (s, 2H, OCH2Bn), 3.81 (s, 3H, OMe), 3.70 (s, 3H,
OMe), 2.84-2.73 (m, 4H), 1.99 (q, J ) 6.8 Hz, 2H); m in or
com p ou n d , δ 7.54-7.51 (m, 2H), 7.41-7.33 (m, 4H), 7.08-
6.98 (m, 3H), 6.79 (s, 1H), 6.59 (s, 1H), 5.14 (s, 2H, OCH2Bn),
3.78 (s, 3H, OMe), 3.69 (s, 3H, OMe), 2.84-2.73 (m, 4H), 1.99
(q, J ) 6.8 Hz, 2H). GC/MS, m a jor com p ou n d (8), m/z (%)
466 (M+, 54), 433 (11), 432 (16), 392 (15), 348 (20), 347 (80),
301 (12), 257 (58), 256 (48), 229 (12), 228 (21), 91 (100); m in or
com p ou n d , m/z (%) 465 (24), 464 (42), 392 (14), 301 (17), 149
(15), 91 (100).
P r ep a r a tion of Diben zoxep in es 9a a n d 9c. Compound
7 (11.8 g, 21.6 mmol), CuO (9.07 g, 114 mmol), anhydrous K2-
CO3 (18.14 g, 131 mmol), and dry deaerated pyridine (63 mL)
were mixed and then refluxed under Ar for 1 h. After cooling,
the reaction mixture was filtered through Celite, and the
filtrate was washed with 10% HCl and water, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude
residue (a 2:1 mixture of 8 and an unknown compound) was
dissolved in acetone (100 mL) under argon, treated with Raney
nickel (90 g, 50% slurry in water), and then heated at 70 °C
for 3 h. The cooled reaction mixture was filtered through
Celite and concentrated in vacuo, and the residue was dis-
solved in CH2Cl2, washed with water, dried over Na2SO4, and
concentrated in vacuo. This final residue was purified by
column chromatography (silica gel; 2:1 CH2Cl2/hexane) to
afford alkenes 9c (5.3 g, 68%) and 9a (0.8 g, 14%).
O-Ben zyla tion of 6-Hyd r oxy-2,3 d im eth oxyben zox-
ep in e (9a ). NaH (80% dispersion in mineral oil, 266 mg, 8.8
mmol) was washed twice with dry THF (3 mL), and then dry
DMF was added followed by a solution of compound 9a (0.8 g,
2.96 mmol) in DMF (7 mL). The mixture was stirred for 1 h,
and benzyl chloride (0.5 mL, 2.96 mmol) was added. After
stirring for 18 h at rt, the solution was quenched with water,
diluted with CH2Cl2, and washed with water. The organic
layer was dried over Na2SO4 and concentrated in vacuo.
Recrystallization of the residue from ether/n-hexane afforded
alkene 9c (1.07 g, 84%).
Hyd r oxyla tion of 9c. To a solution of compound 9c (5.21
g, 14 mmol) in THF (52 mL) were added N-methylmorpholine
N-oxide monohydrate (2 g, 14.3 mmol) and 26 mL of a 5.6 ×
10-3 M solution of OsO4 (0.14 mmol). The mixture was stirred
overnight at rt and then poured into an ice cooled mixture of
10% HCl and 15% sodium bisulfite (5:1, v/v). This solution
was extracted with EtOAc, and the extract was washed with
water, dried over anhydrous Na2SO4, filtered through Celite,
and concentrated in vacuo. Recrystallization of the residue
from EtOAc/n-hexane afforded diol 10 (4.69 g, 82%). Chro-
matography of the mother liquors (silica gel, CH2Cl2) gave 169
mg of 6-(benzyloxy)-2,3-dimethoxydibenzoxepine-10,11-dione
(3% yield).
6-(Ben zyloxy)-10,11-d ih yd r o-2,3-d im eth oxyd iben zox-
ep in e-10,11-d iol (10). Mp: 161-163 °C. IR (KBr) 3480
(OH), 3320 (OH), 1610, 1510, 1200, 860, 755, 730, 695 cm-1
.
1H NMR δ 7.49-7.46 (m, 2H), 7.40-7.35 (m, 3H), 7.10-7.08
(m, 2H), 6.93-6.90 (m, 2H), 6.76 (s, 1H), 5.35-5.33 (m, 1H),
5.14 (d, J ) 11.6 Hz, 1H), 5.08 (d, J ) 11.6 Hz, 1H), 4.96-
4.93 (m, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.04 (d, J ) 8.9 Hz,
1H), 2.24 (d, J ) 9.4 Hz, 1H). 13C NMR δ (DMSO-d6): 149.40,
148.27, 147.99, 145.03, 143.87, 137.43, 135.53, 128.43 (CH ×
2), 127.81 (CH), 127.31 (CH × 2), 123.93 (CH), 122.49, 120.37
(CH), 114.47 (CH), 112.50 (CH), 104.45 (CH), 71.71 (CH), 70.03
(CH), 69.97 (CH2), 55.87 (OMe), 55.36 (OMe). MS, m/z (%):
394 (M+, 24), 347 (30), 285 (96), 269 (34), 257 (53), 229 (9), 91
(100). Anal. Calcd for C23H22O6: C 70.04, H 5.62. Found: C
69.75, H 5.58.
6-(Ben zyloxy)-2,3-d im et h oxyd ib en zoxep in e-10,11-d i-
on e. Recrystallized from EtOAc/n-hexane. Mp: 173-175 °C.
1
IR (NaCl) 1690, 1660, 1600, 1510, 1450, 1410, 1270 cm-1. H
NMR δ 7.50 (d, J ) 6.8 Hz, 2H), 7.43-7.32 (m, 5H), 7.19 (s,
1H), 7.17-7.15 (m, 1H), 6.83 (s, 1H), 5.18 (s, 2H), 3.89 (s, 3H),
3.86 (s, 3H). 13C NMR δ 188.39 (CO), 183.30 (CO), 156.05,
155.10, 150.54, 147.04, 147.00, 136.60, 130.15, 128.93 (CH ×
2), 128.57 (CH), 127.60 (CH × 2), 126.27 (CH), 122.55 (CH),
118.94 (CH), 118.49, 111.16 (CH), 104.65 (CH), 71.56 (CH2),
56.68 (OMe), 56.67 (OMe). MS, m/z (%): 390 (M+, 17), 375
(7), 360 (13), 299 (13), 283 (43), 243 (22), 91 (100). Anal. Calcd
for C23H18O6: C 70.76, H 4.65. Found: C 70.88, H 4.96.
5-(Ben zyloxy)-2,3-d im et h oxyxa n t h en e-9-ca r b oxa ld e-
h yd e (11). Diol 10 (3 g, 7.6 mmol) was dissolved in glacial
acetic acid (78 mL), the solution was deaerated by bubbling
argon through it, and three drops of concd H2SO4 were added.
This mixture was stirred for 3 min at rt, diluted with water,
and extracted with CH2Cl2. The CH2Cl2 solution was washed
with 5% K2CO3 solution and then with water, dried over
anhydrous Na2SO4, and concentrated in vacuo. Aldehyde 11
(2.75 g, 96%) was obtained as a foam that would not crystallize.
IR (NaCl) 1720 (CHO), 1610, 1510, 1270, 1215, 1010, 735, 695
6-Hyd r oxy-2,3-d im eth oxyd iben zoxep in e (9a ). Recrys-
tallized from EtOAc/n-hexane, mp 148-151 °C. IR (KBr) 3460
(OH), 1610, 1520, 1460, 1350, 1240, 1210, 1170, 1100, 1000,
860, 800 cm-1
.
1H NMR δ 6.99-6.95 (m, 2H), 6.70 (s, 1H),
6.67-6.64 (m, 1H), 6.60-6.58 (m, 3H), 6.25 (s, 1H, OH), 3.83
(s, 3H), 3.81 (s, 3H); 13C NMR δ 150.46, 150.36, 147.79, 146.46,
144.34, 130.94, 129.96 (CH), 128.81 (CH), 125.50 (CH), 122.26,
120.82 (CH), 116.02 (CH), 111.81 (CH), 105.37 (CH), 56.51
(OMe), 56.38 (OMe); MS, m/z (%): 270 (M+, 100), 255 (11),
227 (8), 199 (7), 181 (9), 149 (8), 83 (8). Anal. Calcd for
C16H14O4: C 71.10, H 5.22. Found: C 70.86, H 5.33.
cm-1 1H NMR δ 9.44 (d, J ) 3.9 Hz, 1H), 7.50 (d, J ) 7.3 Hz,
.
2H), 7.44-7.33 (m, 3H), 6.98-6.92 (m, 2H), 6.80 (s, 1H), 6.77
(dd, J ) 7.1 and 2.1 Hz, 1H), 6.60 (s, 1H), 5.21 (s, 2H), 4.68 (d,
J ) 3.9 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H). 13C NMR δ 194.97
6-(Ben zyloxy)-2,3 d im eth oxyd iben zoxep in e (9c). Re-
crystallized from EtOAc/n-hexane, mp 102-104 °C. IR (NaCl)

Synthetic Route to (()-Clavizepine
J . Org. Chem., Vol. 61, No. 17, 1996 5821
(CHO), 149.59, 147.10, 145.22, 144.54, 141.02, 136.39, 128.08
(CH × 2), 127.53 (CH), 127.04 (CH × 2), 122.53 (CH), 120.98
(CH), 115.56, 113.47 (CH), 110.39 (CH), 104.74, 100.88 (CH),
70.56 (CH2), 55.65 (OMe), 55.36 (OMe), 51.25 (CH). MS,
(FAB), m/z (%): 377 (M + 1, 17), 376 (38), 375 (82), 363 (46),
347 (100).
2.85 (dd, J ) 15.5 and 5.3 Hz, 1H), 2.42 (s, 3H). 13C NMR δ
149.03, 145.70, 145.60, 144.37, 143.79, 140.07, 137.29, 129.94
(CH × 2), 127.45 (CH × 2), 123.68 (CH), 123.53, 120.40 (CH),
114.22 (CH), 113.73, 111.89 (CH), 103.88 (CH), 100.61 (CH),
57.42 (CH2), 56.61 (OMe), 56.29 (OMe), 54.93 (OMe × 2), 51.47
(CH2), 39.24 (CH), 21.78 (Me). MS (FAB), m/z (%): 530 (M +
1, 1), 529 (2), 528 (2), 498 (3), 466 (3), 272 (9), 271 (9), 257
(100). Anal. Calcd for C27H31NO8S, C 61.23, H 5.90, N 2.64.
Found: C 61.24, H 5.90, N 2.32.
N-Tosyl-2,12b-d ih yd r o-7-h yd r oxy-10,11-d im eth oxy-1H-
[1]ben zop yr a n o[4,3,2-ef][3]ben za zep in e (14). A mixture
of acetal 13a (1.219 g, 2.3 mmol), glacial acetic acid (50 mL),
and 10% HCl (15 mL) under argon was heated at 75 °C for
0.5 h. The mixture was cooled, diluted with water, and
5 -( B e n z y l o x y ) -9 -( h y d r o x y m e t h y l ) -2 ,3 -d i m e t h -
oxyxa n th en e (12). To a solution of aldehyde 11 (2.75 g, 7.3
mmol) in methanol (160 mL), NaBH4 (excess) was carefully
added in small portions until no starting material could be
detected by TLC. A 10% solution of HCl was slowly added
until the reaction mixture was neutral, and then the methanol
was removed in vacuo. The residue was extracted with CH2-
Cl2, and this solution was washed with water, dried over
anhydrous Na2SO4, and concentrated in vacuo to afford 2.70
g of alcohol 12 (98% yield), which was recrystallized from ether.
Mp: 108 °C. IR (NaCl) 3500 (OH), 1610, 1580, 1510, 1415,
extracted with CH2
Cl2. The organic extract was washed with
5% K2CO3 solution and then with water, dried over anhydrous
Na2SO4, and concentrated to a residue. This was column
chromatographed (silica gel; 1% (v/v) EtOAC/hexane) to afford
14 (845 mg, 79%), which was recrystallized from EtOAc/n-
hexane. Mp:152-153 °C. IR (NaCl) 3440 (OH), 1635, 1610,
1600, 1510, 1490, 1460, 1340, 1220, 1200, 1160, 1000, 920
1
1270, 1220, 1120, 910, 860 cm-1; H NMR δ 7.48 (d, J ) 7.2
Hz, 2H), 7.40-7.31 (m, 3H), 6.94 (dd, J ) 9.0 and 6.6 Hz, 1H),
6.85 (d, J ) 7.2 Hz, 2H), 6.77 (s, 1H), 6.72 (s, 1H), 5.17 (s,
2H), 3.97 (t, J ) 5.9 Hz, 1H), 3.88 (s, 6H), 3.69-3.65 (m, 2H),
2.02 (bs, 1H, OH); 13C NMR δ 149.09, 147.28, 146.27, 145.46,
142.75, 137.31, 128.82 (CH × 2), 128.18 (CH), 127.64 (CH ×
2), 123.15, 122.91 (CH), 121.45 (CH), 113.30 (CH), 112.50,
111.23 (CH), 101.35 (CH), 71.51 (CH2), 69.26 (CH2), 56.66
(OMe), 56.31 (OMe), 42.10 (CH). MS, m/z (%): 378 (M+, 2),
348 (25), 347 (100), 256 (46), 228 (13). Anal calcd for C23H22O5,
C 73.00, H 5.86. Found: C 72.89, H 5.86.
cm-1 1H NMR δ 7.75 (d, J ) 8.2 Hz, 2H), 7.31 (d, J ) 8.2 Hz,
.
2H), 6.83 (dd, J ) 1.5 and 10.4 Hz, 1H), 6.78 (d, J ) 1.5 Hz,
2H), 6.73 (s, 1H), 6.57 (s, 1H), 5.68 (d, J ) 10.5 Hz, 1H), 5.53
(bs, 1H, OH), 4.58 (d, J ) 13.6 Hz, 1H), 3.97 (d, J ) 7.2 Hz,
1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.30 (dd, J ) 13.6 and 7.2 Hz,
1H), 2.4 (s, 3H).
13C NMR δ 149.53, 145.98, 144.55, 143.77,
142.82, 137.30, 136.09, 130.31 (CH × 2), 127.23 (CH × 2),
126.82, 124.75 (CH), 123.23 (CH), 121.29, 114.07 (CH), 110.89
(CH), 110.54, 109.58 (CH), 100.10 (CH), 57.07 (CH2), 56.64
(OMe), 56.31 (OMe), 38.16 (CH), 21.82 (Me). MS m/z (%): 465
(M+, 17), 311 (21), 310 (100), 294 (16), 282 (8), 265 (11), 221
(4), 155 (9). Anal. Calcd for C25H23NO6S, C 64.50, H 4.98, N
3.01. Found: C 64.49, H 5.01, N 2.77.
Mitsu n obu Rea ction of Alcoh ol 12. Alcohol 12 (2.0 g,
5.28 mmol), N-tosyl aminoacetaldehyde dimethyl acetal (1.4
g, 5.4 mmol), and triphenylphosphine (1.45 g, 5.5 mmol) were
dissolved in dry THF (80 mL) under argon. Diethyl azodicar-
boxylate (0.84 mL, 5.4 mmol) was added, and the mixture was
stirred for 3 h at rt. The THF was evaporated in vacuo, and
the residue was dissolved in CH2Cl2, washed with 15% NaOH
and then with brine, and dried over anhydrous Na2SO4.
Evaporation of the solvent in vacuo afforded a residue which
was column chromatographed (silica gel; 1:2 EtOAc/n-hexane)
to give 9-methylene-2,3-dimethoxy-5-(benzyloxy)xanthene (0.62
g, 38%), 2,3-dimethoxy-5-(benzyloxy)xanthone (95 mg, 5%), and
compound 13c (1.69 g, 52%) as a foam.
N -T o s y l -2 ,3 ,4 ,1 2 b -t e t r a h y d r o -7 -h y d r o x y -1 0 ,1 1 -
d i m e t h o x y -1 H -[ 1 ] b e n z o p y r a n o [ 4 ,3 ,2 -e f ] [ 3 ] b e n -
za zep in e (15). Compound 14 (840 mg, 1.80 mmol) and 10%
Pd/C (150 mg) in CHCl3 (45 mL) were stirred under 1 atm of
H2 for 12 h. After filtration through Celite and evaporation
of the CHCl3 in vacuo, compound 15 (776 mg, 92%) was
obtained and recrystallized from EtOAc/n-hexane. Mp: 207-
208 °C. IR (NaCl) 3420 (OH), 1615, 1595, 1510, 1495, 1460,
N-(2,2-Dim eth oxyeth yl)-N-tosyl-9-(am in om eth yl)-5-(ben -
zyloxy)-2,3-d im eth oxyxa n th en e (13c). Crystallized from
ether, Mp 145-148 °C. IR (NaCl) 1610, 1575, 1510, 1340,
1250, 1225, 1155, 1090, 1005, 730 cm-1 1H NMR δ 7.63 (d, J
.
) 8.0 Hz, 2H), 7.24 (d, J ) 8.0 Hz, 2H), 6.90 (s, 1H), 6.74 (d,
J ) 8.0 Hz, 1H), 6.70 (d, J ) 8.0 Hz, 1H), 6.60 (s, 1H), 5.63 (s,
1H, OH), 4.40 (d, J ) 8.6 Hz, 1H), 4.22 (d, J ) 13.0 Hz, 1H),
4.20-4.17 (m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.21 (t, J ) 12.6
Hz, 1H), 2.82 (dd, J ) 5.7 and 15.1 Hz, 1H), 2.70 (dd, J ) 8.6
1270, 1210, 1160, 1120, 1070, 910, 730 cm-1 1H NMR δ 7.70
.
(d, J ) 8.0 Hz, 2H), 7.49 (d, J ) 7.4 Hz, 2H), 7.41-7.35 (m,
3H), 7.27 (d, J ) 8.0 Hz, 2H), 6.97-6.95 (m, 3H), 6.79 (s, 1H),
6.77 (s, 1H), 5.19 (s, 2H), 4.37 (t, J ) 7.5 Hz, 1H), 4.03 (t, J )
4.9 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.45 (dd, J ) 7.5 and
15.0 Hz, 1H), 3.33 (dd, J ) 7.5 and 15.0 Hz, 1H), 3.13 (s, 3H),
3.12 (s, 3H), 3.03 (dd, J ) 4.9 and 15.2 Hz, 1H), 2.85 (dd, J )
4.9 and 15.2 Hz, 1H), 2.39 (s, 3H). 13C NMR δ 148.81, 147.02,
145.91, 145.24, 143.35, 142.59, 137.17, 137.06, 129.56 (CH ×
2), 128.46 (CH × 2), 127.81 (CH), 127.25 (CH × 2), 127.14 (CH
× 2), 123.90, 122.74 (CH), 121.44 (CH), 113.25 (CH, C), 111.40
(CH), 103.32 (CH), 100.89 (CH), 71.28 (CH2), 57.03 (CH2), 56.22
(OMe), 55.92 (OMe), 54.23 (OMe × 2), 50.99 (CH2), 39.14 (CH),
21.28 (Me). MS (FAB) m/z (%): 620 (M + 1, 1), 619 (3), 618
(2), 588 (4), 566 (5), 363 (20), 347 (100). Anal. Calcd for
C34H37O8NS: C 65.90, H 6.02, N 2.26. Found: C 66.20, H 6.07,
N 1.96.
and 13.0 Hz, 1H), 2.42 (t, J ) 12.2 Hz, 1H), 2.37 (s, 3H).
13C
NMR δ 149.38, 145.98, 143.91, 143.80, 143.08, 137.94, 135.60,
132.05, 130.02 (CH × 2), 127.32 (CH × 2), 123.67 (CH), 122.65,
113.55 (CH), 111.32, 111.24 (CH), 100.05 (CH), 58.11 (CH2),
56.61 (OMe), 56.30 (OMe), 48.38 (CH2), 38.98 (CH), 36.56
(CH2), 21.74 (Me). MS m/z (%): 467 (M+, 4), 313 (22), 312
(100), 285 (7), 271 (11), 270 (18), 226 (13). HRMS for C25H25
NO6S, 467.14026; found, 467.14039.
-
2,3,4,12b-Tetr a h yd r o-7-h yd r oxy-10,11-d im eth oxy-1H-
[1]ben zop yr a n o[4,3,2-ef][3]ben za zep in e (16). Tosylate 15
(560 mg, 1.19 mmol), 3% Na amalgam (29 g; Na equivalent,
37.8 mmol), and anhydrous Na2HPO4 (3.36 g, 23.7 mmol) were
mixed under Ar in dry MeOH (200 mL) and then refluxed for
12 h. The cooled reaction mixture was filtered through Celite
and concentrated in vacuo, and the residue was partitioned
between CH2Cl2 and water. The aqueous phase was separated
and further extracted with CH2Cl2 (30 mL), and the combined
organic extracts were washed with brine and then dried over
anhydrous Na2SO4. The CH2Cl2 was removed in vacuo, and
the residue was column chromatographed (silica gel; 8% (v/v)
MeOH in CH2Cl2) to afford norclavizepine (16) (273 mg, 73%)
as a foam which was crystallized from EtOAc/n-hexane. Mp:
211-213 °C dec. IR (KBr) 3440, 3240, 2930, 1505, 1450, 1250,
N-(2,2-Dim et h oxyet h yl)-N-t osyl-9-(a m in om et h yl)-2,3-
d im eth oxy-5-h yd r oxyxa n th en e (13a ). Compound 13c (1.69
g, 2.73 mmol) and 10% Pd/C (150 mg) in MeOH (20 mL) and
CH2Cl2 (20 mL) were stirred under 1 atm of H2 for 1.5 h. After
filtration through Celite and evaporation of the solvent in
vacuo, sulfonamide 13a was obtained and recrystallized from
ether/n-hexane (1.25 g, 87%). Mp: 170-171 °C. IR (KBr)
3380 (OH), 1610, 1510, 1470, 1330, 1150, 1120, 1060, 1040,
1020, 960, 940, 850 cm-1 1H NMR δ 7.70 (d, J ) 8.2 Hz, 2H),
.
7.29 (d, J ) 8.2, 2H), 6.95 (t, J ) 7.9 Hz, 1H), 6.88 (dd, J ) 1.6
and 7.9 Hz, 1H), 6.82 (s, 1H), 6.79 (dd, J ) 7.9 and 1.6 Hz,
1H), 6.70 (s, 1H), 5.62 (bs, 1H, OH), 4.36 (t, J ) 8.0 Hz, 1H),
4.05 (t, J ) 5.3 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.39 (dd, J
) 8.0 and 14.6 Hz, 1H), 3.34 (dd, J ) 8.0 and 14.6 Hz, 1H),
3.16 (s, 3H), 3.14 (s, 3H), 3.06 (dd, J ) 5.3 and 15.1 Hz, 1H),
1225 cm-1 1H NMR: δ 6.70-6.78 (m, 3H), 6.61 (s, 1H), 5.51
.
(bs, 1H), 4.30 (d, J ) 9.5 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H),
3.36 (d, J ) 13.0 Hz, 1H), 3.32-3.25 (m, 1H), 3.15-3.04 (m,
1H), 2.94 (dd, J ) 13.0 and 9.5 Hz, 1H), 2.79-2.62 (m, 2H).
13C NMR δ (DMSO-d6): 148.76, 145.03, 143.77 (C × 2), 138.36,

5822 J . Org. Chem., Vol. 61, No. 17, 1996
de la Fuente et al.
132.31, 123.66, 122.94 (CH), 113.73 (CH), 112.25, 112.01 (CH),
100.24 (CH), 58.12 (CH2), 56.08 (OMe), 55.76 (OMe), 47.53
(CH2), 39.18 (CH), 37.12 (CH2). MS m/z (%): 313 (M+, 52),
284 (22), 283 (61), 271 (100), 257 (47), 239 (7), 226 (14). HRMS
for C18H19NO4, 313.13141; found, 313.13103.
138.14, 133.40, 123.53, 122.92 (CH), 113.45 (CH), 113.11,
111.70 (CH), 100.08 (CH), 68.08 (CH2), 57.52 (CH2), 56.64
(OMe), 56.24 (OMe), 47.51 (NMe), 37.49 (CH), 35.36 (CH2). MS
m/z (%): 327 (M+, 47), 312 (5), 284 (40), 283 (100), 271 (22),
270 (24), 269 (30), 226 (12). Anal. Calcd for C19H21NO4: C
69.71, H 6.46, N 4.28. Found: C 69.62, H 6.63, N 4.03.
N -M e t h y l-2,3,4,12b -t e t r a h y d r o -7-h y d r o x y -10,11-
d i m e t h o x y -1 H -[ 1 ] b e n z o p y r a n e [ 4 ,3 ,2 -e f ] [ 3 ] b e n -
za zep in e (1a ). Norclavizepine (16) (250 mg, 0.76 mmol),
formic acid (2 mL), and 37% formaldehyde (2 mL) were mixed
under argon and then heated at 80 °C for 3 h. The reaction
mixture was cooled, water (5 mL) and 5% NaHCO3 solution
(10 mL) were added, and the resulting solution was extracted
with CH2Cl2. The organic extract was washed with water,
dried over anhydrous Na2SO4, and concentrated to a residue.
Purification of this residue by column chromatography (silica
gel; 5% (v/v) MeOH in CH2Cl2) allowed isolation of 1a (235
mg, 90%), which was recrystallized from EtOAc/n-hexane.
Mp: 214-216 °C dec. (234-235 °C for (-)-clavizepine,1 218-
219 °C dec. for (()-clavizepine2a). IR (KBr) 1610, 1515, 1460,
1440, 1415, 1250, 1230, 1205, 1175, 1125, 1030, 1005, 950, 870,
Ack n ow led gm en t . Financial support from the
CICYT (SAF93-0607) is gratefully acknowledged. We
also thank the Xunta de Galicia for a fellowship
awarded to M.C.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
analytical data for 9-methylene-2,3-dimethoxy-5-(benzyloxy)-
xanthene and 2,3-dimethoxy-5-(benzyloxy)xanthone, 1H NMR
spectrum of compound 5, and 1H and 13C NMR spectra of
compounds 6, 7, 8 (as a 2:1 mixture with an unknown
compound), 9a , 9c, 10, 11, 12, 13a , 13c, 14, 15, 16, and 1a
(32 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
810 cm-1 1H NMR: δ 6.85 (s, 1H), 6.76 (d, J ) 8.1 Hz, 1H),
.
6.71 (d, J ) 8.1 Hz, 1H), 6.59 (s, 1H), 4.41 (d, J ) 9.4 Hz, 1H),
3.87 (s, 6H), 3.23-3.11 (m, 3H), 2.71 (dd, J ) 6.0 and 15.0 Hz,
1H), 2.46 (dd, J ) 9.9 and 12.2 Hz, 1H), 2.45 (s, 3H), 2.15 (t,
J ) 11.8 Hz, 1H). 13C NMR: δ 149.01, 145.72, 144.24, 142.87,
J O960291N