On the synthesis of protopine alkaloids

Article abstract of DOI:10.1021/jo071038y

(Chemical Equation Presented) For the synthesis of protopine alkaloids, we studied a reaction sequence based on a ring enlargement of indeno[2,1-a][3] benzazepines by a singlet oxygen oxygenation, followed by conversion of an amide carbonyl group of the resultant 10-membered keto-lactam to a methylene group, which is the last step for completion of the synthesis. The key substances, indeno[2,1-a][3]benzazepines, were prepared by Bischler-Napieralski cyclization of alkoxy-substituted 1-(2-bromobenzyl)-3-benzazepin-2-ones. Steric effects of the substituents in this synthesis were examined.

Full text of DOI:10.1021/jo071038y

On the Synthesis of Protopine Alkaloids
Yasuhiro Wada, Harumi Kaga,† Shiho Uchiito, Eri Kumazawa, Miho Tomiki, Yu Onozaki,
Nobuhito Kurono,‡ Masao Tokuda, Takeshi Ohkuma,‡ and Kazuhiko Orito*
Laboratory of Organic Synthesis, DiVision of Molecular Chemistry, School of Engineering, Hokkaido
UniVersity, Sapporo 060-8628, Japan, and National Institute of AdVanced Industrial Science and
Technology (AIST), Sapporo 062-8517, Japan
orito@org-mc.eng.hokudai.ac
ReceiVed May 24, 2007
For the synthesis of protopine alkaloids, we studied a reaction sequence based on a ring enlargement of
indeno[2,1-a][3]benzazepines by a singlet oxygen oxygenation, followed by conversion of an amide
carbonyl group of the resultant 10-membered keto-lactam to a methylene group, which is the last step
for completion of the synthesis. The key substances, indeno[2,1-a][3]benzazepines, were prepared by
Bischler-Napieralski cyclization of alkoxy-substituted 1-(2-bromobenzyl)-3-benzazepin-2-ones. Steric
effects of the substituents in this synthesis were examined.
Introduction
antihistaminic,8 anti-thrombotic,6b,9 anti-inflammatory,9 and
anti-hemeostatic activities,6b as well as activities against hepa-
totoxicity induced by actoaminophen and CCl4,10 have been
found.
Protopine and related alkaloids, which have the unique
structural feature of a nitrogen-containing 10-membered cyclic
ketone (dibenzazocine ring), are widely distributed in the
families Berberidaceae, Fumariaceae, Papaveraceae, Ranuncu-
laceae, and Rutaceae1 and have been reviewed as a group of
isoquinoline alkaloids.2 The major protopine alkaloids (1) have
four alkoxyl groups at the 2, 3, 9, and 10 positions. The 1-,
11-, or 12-alkoxyl group has been found in the minor
components.1d It was shown in 1978-1981 that allocryptopine
and protopine exhibited an antiarrhythmic effect3 and that
protopine has antibacterial4 and antianalgesic5 activities. More
recently, other notable pharmacological properties of the
alkaloids, including activities for inhibition of rabbit blood
platelet aggregation6 and calcium influx through both voltage-
and receptor-operated calcium channels,7 anti-cholinergic,8
Synthesis of protopine alkaloids has been achieved by the
transformation of protoberberine alkaloids based on a ring-
† AIST.
‡ Present address: Division of Chemical Process Engineering, Graduate School
of Engineering, Hokkaido University, Sapporo 060-8628, Japan.
(1) (a) Kametani, T. The Chemistry of the Isoquinoline Alkaloids;
Hirokawa: Tokyo, and Elsevier: Amsterdam, 1968. (b) Kametani, T. The
Chemistry of the Isoquinoline Alkaloids Vol. 2; The Sendai Institute of
Heterocyclic Chemistry: Japan, 1974. A recent report for the minor
alkaloids, see: (c) Chang, Y. C. Planta Med. 2003, 69, 148-152.
(2) (a) Shamma, M. The Isoquinoline Alkaloids; Academic Press, Inc.:
New York, 1972; pp 344-358. (b) Onda, M.; Takahashi, H. The Alkaloids;
Brossi, A., Ed.; Academic Press, Inc.: San Diego, 1988; Vol. 2, pp 181-
209.
(3) (a) Akbarov, Z. S.; Aliev, K. U.; Sultanov, M. B. Farmakol. Prir.
VeschestV 1978, 11-29. (b) Burtsev, V. N.; Dormidontov, E. N.; Salyaev,
V. N. Kardiologiiya 1978, 18, 76-79. (c) Burtsev, V. N.; Dormidontov,
E. N.; Saliaev, V. N. Kardiologiia 1978, 18, 76-79. (d) Lu, Z. A.; Wan,
D. C.; Chen, Z. H.; Wang, X. H. Chin. Pharm. J. 1992, 30, 81-84. (e)
Zipes, D. P. Heart Disease, 5th ed.; W. B. Saunders: Philadelphia, 1997;
pp 593-639. (f) Song, L.-S.; Ren, G.-J.; Chen, Z.-L.: Chen, Z.-H.; Zhou,
Z.-N.; Chen, H. Br. J. Pharmacol. 2000, 129, 893-900.
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109.
10.1021/jo071038y CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/17/2007
J. Org. Chem. 2007, 72, 7301-7306
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Wada et al.
SCHEME 1. Ring Enlargement Based on O2 Oxygenation
1
opening reaction by Hofmann degradation of their N-meth-
ochlorides (Perkin’s method)11 leading to the formation of
muramine (1a), allocryptopine (1c), and protopine (1d), K2CrO4
oxidation of the N-oxide (Bentley’s method)12 to 1a,b,c,
photooxidation of tetrahydroberberine methiodide (Hanaoka’s
method)13 to 1c, or von Brown reaction to 1a (Ro¨nsch’s
method).14 Brossi reported another transformation of phthali-
deisoquinoline alkaloids, â-hydrastine and R-narcotine, via
Perkin-type Hofmann degradation of the derived isoindolo[1,2-
b][3]benzazepine methiodides to 1c.15 13-Oxoprotopine or 13-
oxoallocryptopine has been prepared by oxidative methods with
air or Hg(OAc)2.16-18 Pseudoallocryptopine and pseudoprotopine
have also been prepared from the corresponding tetrahydropro-
toberberine N-metho salts.11d,g Biotransformation of N-metho
salts of tetrahydroprotoberberine alkaloids to protopine, 13-
oxoallocryptopine, or 13-methylallocryptopine by Corydarlis
species callus cultures has been achieved by Tani19 and Takao.20
We developed a ring-enlargement reaction based on 1O2
oxygenation of indeno[2,1-a][3]benzazepines 2 followed by
further elaboration of the resultant 10-membered keto-lactams,
which successfully produced pseudo-type protopines 3 (Scheme
1).21 We herein describe an application of the method to the
synthesis of the above-mentioned representative protopine
alkaloids muramine (1a) and protopine (1d).
Results and Discussion
The method requires an indeno[2,1-a][3]benzazepine with
alkoxyl groups at its 2-, 3-, 8-, and 9-positions, such as 4. First,
radical cyclization of 1-(2-bromobenzyl)-4,5-dihydrobenza-
zepine 8 to 4d was tested under the reaction conditions used
for a 5-endo cyclization of 1-(2-bromobenzyl)-3,4-dihydroiso-
quinolines to dibenz[b,d]indolizidines.22
As shown in Scheme 2, 3-benzazepin-2-one 5b23 was treated
with benzyl chloride 624 (1.1 equiv) in the presence of NaH (2
equiv) in a boiling 10:1 THF-DMF mixture for 5 h to give
2-benzyl-3-benzazepine 7 in 64% yield. This was converted by
DIBALH reduction to 8 (53%), which was subjected to radical
cyclization with AIBN and Bu3SnH in boiling benzene, toluene,
or o-xylene. However, none of the desired 4d was obtained,
but 9 was formed at 160 °C in 50% isolated yield. The structure
of 9 was determined by the fact that a radical coupling of 7
followed by DIBALH reduction of the product 10 also gave 9
and the fact that irradiation of the N-Me group of 9 resulted in
significant NOE on C-7 hydrogen, as depicted in Scheme 2.
Attempts to obtain 4d through Heck cyclization of 8 were
unsuccessful.
It has been reported that 3-(2-bromophenyl)propanoic acid
11 was cyclized in PPA to an indanone 12 in 72-75% yield
(Scheme 3).25 The corresponding propanoic acid derivative 15
was prepared by a modification of the method reported by
us21c,26 that involves condensation of the corresponding ben-
zonitrile with benzaldehyde followed by reduction of a double
bond of 13 with NaBH4-pyridine27 and hydrolysis of the CN
group of 14, and it was subjected to cyclization using PPA at
80 °C for 1 h to afford 1-indanone 16 in 12% yield. Its
transformation to 11-bromoindeno[2,1-a][3]benzazepine 17a,
which is equivalent to 4a, by hydrolysis under basic conditions24
as well as acidic conditions,28 failed. In addition, treatment of
propionitrile 14 with BuLi did not produce any indanones. Thus,
the attempt to establish a route via 1-indanone21c was abandoned.
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Janbaz, K. H. Gen. Pharmacol. 1995, 26, 309-315, 619-623. (c) Gilani,
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Synthesis of Protopine Alkaloids
SCHEME 2. Attempt To Prepare 4d
SCHEME 3. Attempt To Prepare 17a
We have reported that a standard Bischler-Napieralski
cyclization proceeded well to give indeno[2,1-a][3]benzazepines
2 in good yields.24 Similar treatment of 19a,d, which were
prepared from 3-benzazepin-2-ones and benzyl chlorides (5a
and 18a, or 5b and 18b), with POCl3 or P2O5 in boiling toluene,
did not induce their cyclization. Banwell’s modification using
J. Org. Chem, Vol. 72, No. 19, 2007 7303

Wada et al.
SCHEME 4. Synthesis of Protopine (1d) and Muramine (1a)
Tf2O together with 4-DMAP28 did not work. Wang’s modifica-
tion (P2O5 in boiling POCl3)29 consumed 19a,d after 2 h to give
the desired 17a,d together with the respective debromo isomers
2a,d21b in a 2:3 ratio. Separation by column chromatography
on alumina gave pure 17a,d, but only in 27% and 26% yields
(Scheme 4).
methylation of a phenolic OH of 23 with Me2SO4-KOH or
Na2CO3.
Thus, it was found that protopine (1d) was readily synthesized
in a reaction sequence involving a ring-enlargement of bromide
17d (an equivalent for indeno[2,1-a][3]benzazepine 4d) by a
singlet oxygen oxygenation, but a more efficient method is
necessary for reduction of a sterically hindered amide group
with a 7,8-dimethoxy group to a methylene group. A 7,8-
methylenedioxyindeno[2,1-a][3]benzazepine, bulgaramine (4b),
was recently found in nature,33 and its short-step synthesis via
cyclopentannulation of Fisher aminocarbene complexes was
reported by Moser’s group.34 This will be a solution to a
practical method for preparation of indeno[2,1-a][3]benzazepines.
Nevertheless, the photo-oxygenation (1O2 with Rose Bengal
in MeOH-CH2Cl2) of the formed indenoazepines 17a,d was
tested and found to proceed smoothly to give 12-bromo-8-
oxomuramine, 20a, and 12-bromo-8-oxoprotopine, 20d, both
quantitatively. The latter, methylenedioxy-substituted lactam,
was quantitatively converted by treatment with LiAlH4 (10 mol
equiv) in boiling THF for 15 h to dihydroprotopine30 (21d),
PCC oxidation of which afforded protopine31 (1d) in 78% yield.
In contrast, treatment of the former, 9,10-dimethoxy-substituted
lactam (20a), with LiAlH4 (10 mol equiv) in boiling THF
for 4 h gave no muraminol (21a), but gave 8-oxomuraminol
(22) in 60% yield. Longer treatment in boiling DME (20 h)
afforded muraminol14 (21a) together with 9-hydroxymuraminol
(23). These results may be accounted for by the steric hindrance
caused with N-Me and vicinal dimethoxy groups rather than
electronic reasons.32 PCC oxidation of 21a produced mura-
mine14 (1a) in a good yield similar to that of protopine (1d),
although a larger amount of muraminol was not obtained by
either reduction of 8-oxomuraminol (22) with BH3‚THF or
Experimental Section
1-[2-Bromo-4,5-(methylenedioxy)benzyl]-7,8-(methylenedioxy)-
3-methyl-1,2,4,5-tetrahydro-3H-3-benzazepin-2-one (19d). To a
stirred suspension of 5b, mp 170-171 °C (EtOH) (lit.23 mp 167-
168 °C) (3.29 g, 15.0 mmol), and NaH (0.72 g, 30.0 mmol) in dry
DMF and THF (1:10 volume %, 80 mL) under N2 was added
2-bromo-4,5-methylenedioxybenzyl chloride [18b, 4.12 g, 16.5
mmol, freshly prepared from the corresponding 2-bromobenzyl
alcohol with SOCl2, mp 62-63 °C (petroleum ether) (lit.35 mp 64-
65 °C)]. The mixture was heated at 80 °C in an oil bath for 5 h,
poured into water (300 mL), and extracted with CH2Cl2 (3 × 100
mL). The combined extracts were washed with water (5 × 100
(29) Wang, X. M.; Tan, J.; Grozinger, K. Tetrahedron Lett. 1998, 39,
6609-6612.
(30) Valpuesta, M.; Diaz, A.; Torres, G.; Suau, R. Tetrahedron 2002,
58, 5053-5059.
(33) Yakimov, G.; Mollov, N.; Left, J. E.; Guinaudeau, H.; Freyer, A.
J.; Shamma, M. J. Nat. Prod. 1984, 47, 1048-1049. For the synthesis by
transformation of a spirobenzylisoquinoline alkaloid, fumaricine, see:
Blasco´, G. Acta Chim. Hung. 1991, 128, 819-822.
(34) Giese, M. W.; Moser, W. H. J. Org. Chem. 2005, 70, 6222-6229.
(35) Naik, R. G.; Wheeler, T. S. J. Chem. Soc. 1938, 1780-1783.
(31) Kametani, T.; Ihara, M.; Honda, T. J. Chem. Soc. C 1970, 1060-
1064.
(32) Sha, C.-K.; young, J.-J.; Yeh, C.-P.; Chang, S.-C.; Wang, S.-L. J.
Org. Chem. 1991, 56, 2694-2696.
7304 J. Org. Chem., Vol. 72, No. 19, 2007

Synthesis of Protopine Alkaloids
mL), dried (Na2SO4), and concentrated. The residue was crystallized
mg, 99%), whose spectral data were identical with those previously
reported.30
from CH2Cl2-EtOH to give 19d, mp 218-219 °C (CH2Cl2-
EtOH), as colorless crystals (4.94 g, 76%): IR (Nujol) 1627 cm-1
;
Protopine 1d. A mixture of dihydroprotopine (21d) (71 mg, 0.2
mmol), PCC (89 mg, 0.4 mmol), and NaOAc (8 mg, 0.1 mmol) in
CH2Cl2 (10 mL) was stirred at rt for 2 h. A 1 N HCl solution (3
mL) and EtOH (1 mL) were added dropwise, and the mixture was
stirred at rt for 15 min, basified by addition of a diluted NH4OH
solution, and extracted with CH2Cl2 (3 × 10 mL) after addition of
Rochelle salt (2 g). The organic layers were washed with water (3
× 10 mL), dried (Na2SO4), and concentrated. The residue was
purified by preparative TLC with alumina developed with 1%
MeOH-CH2Cl2. A main band with Rf 0.4-0.8 gave protopine (1d),
mp 205-206 °C (MeOH) [lit.31 mp 207-208 °C], as colorless
crystals (55 mg, 78%), whose spectral data were identical with those
previously reported.31
1H NMR δ 2.90 (s, 3H), 2.93-3.04 (m, 1H), 3.16 (dd, J ) 4.3,
13.5 Hz, 1H), 3.21-3.41 (m, 2H), 3.53 (dd, J ) 9.6, 13.5 Hz, 1H),
3.84-3.94 (m, 1H), 4.43 (dd, J ) 4.3, 9.6 Hz, 1H) 5.91, 5.92 (each
s, each 1H), 5.93 (s, 2H), 6.62, 6.74, 6.97, 6.99 (each s, each 1H);
EI-MS m/z (relative intensity) 433 (M+, 0.40), 431 (M+, 0.34), 352
[(M - Br)+, 100], 215 (17), 213 (18), 190 (71). Anal. Calcd for
C20H18BrO5N: C, 55.57; H, 4.20; Br, 18.48; N, 3.24. Found: C,
55.37; H, 4.31; Br, 18.72; N, 3.28.
11-Bromo-2,3,8,9-bis(methylenedioxy)-5,6,7,12-tetrahydroin-
deno[2,1-a][3]benzazepine (17d). To a stirred solution of 3-ben-
zazepin-2-one 19d (2.17 g, 5.0 mmol) in POCl3 (7.5 mL) was added
P2O5 (1.70 g, 12 mmol). The mixture was refluxed for 2 h, cooled,
basified with a 2 N NaOH solution (100 mL) containing ice (15
g), and extracted with CH2Cl2 (3 × 50 mL). The combined extracts
were washed with a 2 N NaOH solution (50 mL) and water (50
mL) and dried (Na2SO4). The solvent was evaporated to give a 3:2
mixture of 17d and 2d (1.83 g), which was subjected to column
chromatography with Al2O3 using 20% hexane-CH2Cl2 as eluent
to give 17d, mp 255-257 °C (CH2Cl2-EtOH), as pale yellow
crystals [560 mg, 27%, Rf 0.85 (5% MeOH-CH2Cl2)]: IR (Nujol)
1-(2-Bromo-4,5-dimethoxybenzyl)-7,8-dimethoxy-3-methyl-
1,2,4,5-tetrahydro-3H-3-benzazepin-2-one (19a). Similarly, 5a,
mp 138-140 °C (EtOH) (lit.23 137-138 °C) (2.36 g, 10.0 mmol),
NaH (0.48 g, 20.0 mmol), and 2-bromo-4,5-dimethoxybenzyl
chloride [18a, 2.79 g, 10.5 mmol], mp 63-65 °C (Et2O-hexane)
(lit.36 mp 60-61 °C), gave a residue (5.02 g), which was crystallized
from CH2Cl2-EtOH to give 19a, mp 183-185 °C (CH2Cl2-EtOH),
as colorless crystals (3.40 g, 73%): IR (Nujol) 1639 cm-1; 1H NMR
δ 2.95 (s, 3H), 3.01-3.58 (m, 5H), 3.79, 3.84, 3.84, 3.85 (each s,
each 3H), 3.79-3.95 (m, 1H), 4.44 (dd, J ) 3.6, 5.6 Hz, 1H), 6.59,
6.61, 6.97, 7.00 (each s, each 1H); EI-MS m/z (relative intensity)
465 (M+, 0.9), 463 (M+, 1.0), 384 [(MH - Br)+, 94], 229 (32),
206 (100). Anal. Calcd for C22H26BrNO5: C, 56.90; H, 5.64; Br,
17.21; N, 3.02. Found: C, 57.03; H, 5.63; Br, 17.06; N, 3.05.
11-Bromo-2,3,8,9-tetramethoxy-5,6,7,12-tetrahydroindeno-
[2,1-a][3]benzazepine (17a). 3-Benzazepin-2-one (19a, 0.93 g, 2.0
mmol) was treated with P2O5 (0.60 g, 4.2 mmol) in boiling POCl3
(3 mL) for 2 h. The crude product (0.82 g, a 3:2 mixture of 17a
and 2a) was subjected to column chromatography with alumina
using 30% hexane-CH2Cl2 as eluent to give 17a, mp 169.5-
171.5 °C (EtOH), as pale yellow crystals [230 mg, 26%, Rf 0.85
1
1623, 1558 cm-1; H NMR δ 2.89 (s, 3H), 2.95 (distorted t, J )
4.3 Hz, 2H), 3.20 (distorted t, J ) 4.3 Hz, 2H), 3.69 (s, 2H), 5.96,
6.05 (each s, each 2H), 6.69, 6.87, 7.08 (each s, each 1H); EI-MS
m/z (relative intensity) 415 (M+, 99), 413 (M+, 100), 400 (41),
398 (42), 372 (17), 370 (18), 334 (20), 261 (25). Anal. Calcd for
C20H16BrNO4: C, 57.99; H, 3.89; Br, 19.29; N, 3.38. Found: C,
58.03; H, 3.96; Br, 19.12; N, 3.36. A less mobile fraction with Rf
0.7 gave 2d, mp 150-151 °C (95% EtOH) (lit.21b 150-151 °C),
as colorless crystals (200 mg, 12%).
12-Bromo-5,6,7,8,13,14-hexahydro-7-methyl-2,3,9,10-bis(meth-
ylenedioxy)dibenz[c,g]azecine-8,14-dione (20d). A solution of 17d
(560 mg, 1.35 mmol) and Rose Bengal (11 mg) in MeOH (150
mL) and CH2Cl2 (90 mL), contained in a Pyrex test tube (diameter;
40 mm × length; 360 mm) equipped with a sintered glass bubbler,
was cooled with a stream of cold water from the side of the test
tube. O2 gas was introduced through the bubbler, and the mixture
was irradiated with a 500 W tungsten lamp at 18 °C for 20 min.
The solvents were evaporated, and the residue was dissolved in
CH2Cl2 (30 mL), washed with water (5 × 30 mL), and dried over
Na2SO4. The solvent was evaporated to give a residue (796 mg),
which was purified by preparative TLC with silica gel developed
with 3% MeOH-CH2Cl2. A main band with Rf 0.5 gave 20d, mp
>200 °C dec (EtOAc), as colorless crystals (596 mg, 99%): IR
(5% MeOH-CH2Cl2)]: IR (Nujol) 1601, 1583, 1572, 1552 cm-1
;
1H NMR δ 3.04 (s, 3H), 3.02 (distorted t, J ) 4.3 Hz, 2 H), 3.18
(distorted t, J ) 4.3 Hz, 2 H), 3.69 (s, 2H), 3.86, 3.89, 3.91, 3.97
(each s, each 3H), 6.73, 6.92, 7.09 (each s, each 1H); EI-MS m/z
(relative intensity) 447 (M+, 99.9), 445 (M+, 100), 432 [(M -
CH3)+, 47.0], 430 [(M - CH3)+, 47.2], 389 (10.0), 387 (11.0). Anal.
Calcd for C22H24BrNO4: C, 59.20; H, 5.42; Br, 17.90; N, 3.14.
Found: C, 59.14; H, 5.27; Br, 17.86; N, 3.16. A less mobile fraction
with Rf 0.65 gave 2a, mp 182-183 °C (EtOH) (lit.21b mp 182-
183 °C), as colorless crystals (110 mg, 15%).
12-Bromo-7-methyl-2,3,9,10-tetramethoxy-5,6,7,8,13,14-hexa-
hydrodibenz[c,g]azecine-8,14-dione (20a). A mixture of 17a (280
mg, 0.63 mmol) and Rose Bengal (6 mg) in MeOH (70 mL) and
CH2Cl2 (10 mL) was oxygenated at 18 °C for 15 min. The residue
(327 mg) was subjected to column chromatography on silica gel
(3% MeOH-CH2Cl3) to afford 20a [297 mg, 99%, Rf 0.2-0.4 (3%
MeOH-CH2Cl2)], as a mixture of two rotamers (5:1): IR (Nujol)
1
(Nujol) 1683, 1644, 1627, 1616 cm-1; H NMR two rotamers (1:
2.4) δ 2.63-2.79 (m, 1H), 2.71, 2.97 (two s, 3H, 1:2.4), 3.37-
3.44 (m, 3H), 4.00, 4.32 (two d, J ) 15.8 Hz, 1H, 2.4:1), 4.46,
4.55 (two d, J ) 15.8 Hz, 1H, 1:2.4), 5.92-6.05 (m, 4H), 6.50,
6.70 (two s, 1H, 2.4:1), 6.96 (s, 1H), 7.05, 7.07 (two s, 1H, 2.4:1);
EI-MS m/z (relative intensity) 447 (M+, 11), 445 (M+, 12), 404
[(M - Ac)+, 10], 402 [(M - Ac)+, 13], 242 (98), 240 (100), 214
(44), 212 (45). Anal. Calcd for C20H16BrNO6: C, 53.83; H, 3.61;
Br, 17.91; N, 3.14. Found: C, 53.87; H, 3.60; Br, 17.83; N, 3.13.
Dihydroprotopine (21d). To a stirred mixture of LiAlH4 (200
mg, 5.27 mmol) in dry THF (10 mL) at rt was added dropwise a
solution of 22d (224 m0, 0.5 mmol) in dry THF (15 mL). After
the mixture was refluxed for 15 h, water (1 mL), a 2 N NaOH
solution (2 mL), and water (3 mL) were added dropwise to quench
LiAlH4. The resulting mixture was filtered, and the filtrate was
evaporated. The residue was dissolved in CH2Cl2 (30 mL), washed
with water (30 mL) containing Rochelle salt (3 g), water (30 mL),
and brine (30 mL) and dried (Na2SO4). The CH2Cl2 layer was
concentrated to give a residue (223 mg) which was purified by
preparative TLC with silica gel developed with 5% MeOH-CH2-
Cl2. A main band with Rf 0.4-0.8) gave 21d, mp 149-151 °C
(Et2O-hexane) (lit.30 mp 147-148 °C), as colorless crystals (177
1
1687, 1630 cm-1; H NMR δ 2.43-2.46, 2.79-2.93 (two m, 1H,
5:1), 2.63, 3.02 (two s, 3H, 1:5), 3.31-3.47 (m, 3H), 3.76, 3.80,
3.81, 3.88, 3.91, 3.93, 3.97 (seven s, 12H, 5:5:6:1:1:1:5), 3.97, 4.34
(two d, J ) 15.8 Hz, 1H, 5:1), 4.48, 4.58 (two d, J ) 15.8 Hz, 1H,
5:1), 6.43, 6.70 (two s, 1H, 5:1), 6.96 (s, 1H), 7.06, 7.13 (two s,
1H, 5:1); EI-MS m/z (relative intensity) 479 (M+, 6.1), 477 (M+,
6.1), 436 [(M - Ac)+, 9.3], 434 [(M - Ac)+, 9.5], 258 (98.5), 256
(100). Anal. Calcd for C22H24BrNO6: C, 55.24; H, 5.06; Br, 16.70;
N, 2.93. Found: C, 55.11; H, 5.07; Br, 16.51; N, 2.76. Recrystal-
lization from EtOAc-hexane gave a main rotamer, mp 175-
176 °C (EtOAc-hexane), as colorless crystals (234 mg, 78%).
7-Methyl-2,3,9,10-tetramethoxy-5,6,7,8,13,14-hexahydrodi-
benz[c,g]azecin-8-on-14-ol (22). To a stirred mixture of LiAlH4
(36) Olivera, R.; SanMartin, R.; Dominguez, E.; Solans, X.; Urtiaga,
M. K.; Arriortua, M. I. J. Org. Chem. 2000, 65, 6398-6411.
J. Org. Chem, Vol. 72, No. 19, 2007 7305

Wada et al.
(36 mg, 0.92 mmol) in dry THF (2.7 mL) at rt was added dropwise
a solution of 20a (44 mg, 0.09 mmol) in dry THF (2 mL). After
the mixture was refluxed for 4 h, water (4 mL) was added to quench
LiAlH4. The resulting mixture was filtered, and the filtrate was
concentrated. The residue was dissolved in CH2Cl2 (20 mL), washed
with water (20 mL) containing Rochelle salt (2 g), water (20 mL),
and brine (20 mL), and dried (Na2SO4). Evaporation of the solvent
and purification of the residue (42 mg) by preparative TLC with
silica gel developed with 7% MeOH-CH2Cl2 afforded 22, mp
203-205 °C (EtOAc-hexane), as colorless crystals (21.8 mg, 60%,
MeOH-CH2Cl2. A band with Rf 0.5-0.7 afforded muraminol (21a),
mp 178-179 °C (THF-Et2O) (lit.14 mp 175-176 °C), as colorless
crystals (29 mg, 17%), whose spectral data were identical with those
previously reported by Ro¨nsch.14 A band with Rf 0.3-0.5 gave 23,
mp 145-148 °C (CHCl3), as colorless crystals (30 mg, 18%): IR
(CHCl3) 3514 cm-1; 1H NMR δ 2.33 (s, 3H), 2.56-2.59 (m, 2H),
2.93-3.01 (m, 2H), 3.14 (m, 2H), 3.73, 4.00 (AB type, J ) 14.2
Hz, each 1H), 3.82 (s, 3H), 3.82 (s, 3H), 3.91 (s, 3H), 5.60 (br,
1H), 6.45 (s, 1H), 6.56 (d, J ) 8.2 Hz, 1H), 6.61 (d, J ) 8.2 Hz,
1H), 7.03 (s, 1H); EI-MS m/z (relative intensity) 373 (M+, 35),
224 (23), 206 (44), 194 (100), 179 (37), 151 (66). Anal. Calcd for
C21H27NO5: C, 67.54; H, 7.29; N, 3.75. Found: C, 67.46; H, 7.08;
N, 3.58.
1
Rf 0.4-0.5): IR (Nujol) 3448, 1624 cm-1; H NMR δ 2.01 (d, J
) 2.6 Hz, 1H), 2.51 (dd, J ) 7.9 Hz), 2.75 (dd, J ) 10.6 Hz), 3.00
(dd, J ) 7.9 Hz, 1H), 3.17-3.26 (m, 1H), 3.23 (s, 3H), 3.41 (dd,
J ) 7.9 Hz, 1H), 3.68-3.76 (m, 1H), 3.73, 3.75, 3.76, 3.92 (each
s, each 3H), 5.13-5.19 (m, 1H), 6.26 (s, 1H), 6.45, 6.51 (AB type,
J ) 8.3 Hz, each 1H), 6.99 (s, 1H); EI-MS m/z (relative intensity)
401 (M+, 17), 209 (30), 192 (30), 179 (100). Anal. Calcd for C,
65.82; H, 6.78; N, 3.49. Found: C, 65.68; H, 6.81; N, 3.36.
Muraminol (21a) and 7-Methyl-9,14-dihydroxy-2,3,10-tri-
methoxy-5,6,7,8,13,14-hexahydrodibenz[c,g]azecine (23). To a
stirred mixture of LiAlH4 (188 mg, 4.95 mmol) in dry THF (14
mL) at rt was added dropwise a solution of dibenz[c,g]azecine-8,-
14-dione 20a (215 mg, 0.45 mmol) in dry THF (9 mL). After the
mixture was refluxed for 20 h, water (20 mL) was added dropwise
to quench LiAlH4. The resulting mixture was extracted with CH2-
Cl2 (3 × 20 mL), washed with water (20 mL) containing Rochelle
salt (2 g) and water (2 × 20 mL), and dried (Na2SO4). The CH2Cl2
layer was concentrated to give a residue (129 mg) which was
purified by preparative TLC with alumina developed with 0.5%
Muramine (1a). According to Ro¨nsch’s method,14 muraminol
(21a, 25 mg, 0.064 mmol) was treated with PCC (28 mg, 0.13
mmol) and AcONa (2.8 mg, 0.03 mmol) in CH2Cl2 (3.2 mL) at rt
for 2 h and purified by preparative TLC with alumina developed
with 1% MeOH-CH2Cl2 to afford muramine (1a), mp 177-
178 °C (acetone) (lit.14 mp 176-177 °C), as colorless crystals (17.4
mg, 71%, Rf 0.4), whose spectral data were identical with those
previously reported by Ro¨nsch.14
Supporting Information Available: Experimental procedures
and characterization data for compounds 7-10 and 13-16, as well
1
as H NMR spectra for compounds 1a,d, 7-10, 13-17a,d, and
19a,d-23. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO071038Y
7306 J. Org. Chem., Vol. 72, No. 19, 2007