Regioselective synthesis of isoquino[1,2-b][3]benzazepines (homoprotoberberines) through 11-membered-ring stilbene lactams obtained by radical macrocyclization

Article abstract of DOI:10.1021/jo9901900

Silylated 11-membered-ring stilbene lactams 3 (E and Z) were easily prepared by intramolecular addition of an aryl radical to a trimethylsilylacetylene. Oxidation of their hindered stilbene double bonds with dioxiranes gave oxidative cleavage of their electron-rich aromatic rings. However, reduction of the amide to an amine functionality in both lactams (E and Z) triggers a regioselective [7,6]-transannular cyclization to isoquino[1,2-b][3]benzazepines (homoprotoberberines).

Full text of DOI:10.1021/jo9901900

4830
J . Org. Chem. 1999, 64, 4830-4833
Regioselective Syn th esis of Isoqu in o[1,2-b][3]ben za zep in es
(Hom op r otober ber in es) th r ou gh 11-Mem ber ed -Rin g Stilben e
La cta m s Obta in ed by Ra d ica l Ma cr ocycliza tion †
Gema Rodr´ıguez, Luis Castedo, Domingo Dom´ınguez,* and Carlos Saa´*
Departamento de Quı´mica Orga´nica y Unidad Asociada al CSIC, Facultad de Qu´ımica,
Universidad de Santiago de Compostela, 15706 Santiago de Compostela, Spain
Waldemar Adam
Institute of Organic Chemistry, University of Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received February 1, 1999
Silylated 11-membered-ring stilbene lactams 3 (E and Z) were easily prepared by intramolecular
addition of an aryl radical to a trimethylsilylacetylene. Oxidation of their hindered stilbene double
bonds with dioxiranes gave oxidative cleavage of their electron-rich aromatic rings. However,
reduction of the amide to an amine functionality in both lactams (E and Z) triggers a regioselective
[7,6]-transannular cyclization to isoquino[1,2-b][3]benzazepines (homoprotoberberines).
Sch em e 1
In tr od u ction
Over the past few years, we have developed a new
strategy for the synthesis of isoquinoline alkaloids, which
is based on the use of 10-membered-ring stilbene lactams
as key intermediates. These macrolactams, obtained by
radical macrocyclization, could be regioselectively con-
verted by [6,6]- or [7,5]-transannular cyclization into
protoberberines or isoindolobenzazepines.1a-d In a con-
tinuation of our efforts to synthesize isoquinoline alka-
loids for subsequent pharmacological evaluation, we
envisioned that dioxygenated homoprotoberberines (iso-
quino[1,2-b][3]benzazepines) 1 and 2 might be interesting
candidates (Scheme 1). Homoprotoberberines, such as
puntarenine2 and saulatine,3 are isoquinoline alkaloids
obtained from Berberidaceae plants.4 Such structures are
interesting from a synthetic and pharmacological point
of view since they incorporate the [3]benzazepine moiety,
which possesses important biological activity.5 Homopro-
toberberines have been the object of various synthetic
approaches in which the key step is the formation of an
isoquinoline ring under the Bischler-Napieralski condi-
tions followed by intramolecular alkylation onto the
isoquinoline nuclei.6 We now report a regioselective
synthesis of isoquino[1,2-b][3]benzazepines 1 and 2 that
is based on the use of 11-membered-ring stilbene lactams
3 (E and Z) as key intermediates. These lactams,
obtained by an 11-endo radical macrocyclization, may be
regioselectively converted by [7,6]-transannular cycliza-
tion into homoprotoberberines 1 and 2.
* To whom correspondence should be addressed. Fax: +34-981-
595012. E-mail: qocsaa@usc.es, qomingos@usc.es.
Resu lts a n d Discu ssion
† This paper is dedicated to Prof. Ian Scott on the occasion of his
70th birthday.
The precursor to the required 11-membered-ring lac-
tams 3 is the o-(trimethylsilylethynyl)phenylacetamide
9, which was prepared by starting from homoveratryl-
amine (4) and 2-iodobenzyl chloride (6), as shown in
Scheme 2. Thus, condensation of the bromophenethyl-
amine 5 with 2-iodophenylacetyl chloride (7),7 prepared
in three steps from 6, in THF at room temperature in
the presence of triethylamine gave phenylacetamide 8
in 91% yield. Treatment of the dihalogenated amide 8
with (trimethylsilyl)acetylene (1.5 equiv) in the presence
of CuI (0.05 equiv) and PdCl2(PPh3)2 (0.05 equiv) in
triethylamine and THF as cosolvent at room temperature
gave chemoselectively the N-(2-bromophenethyl)phenyl-
acetamide 9 in 86% yield.
(1) Lamas, C.; Saa´, C.; Castedo, L.; Dom´ınguez, D. Tetrahedron Lett.
1992, 33, 5653-5654. (b) Rodr´ıguez, G.; Cid, M. M.; Saa´, C.; Castedo,
L.; Dom´ınguez, D. J . Org. Chem. 1996, 61, 2780-2782. (c) Rodr´ıguez,
G.; Castedo, L.; Dom´ınguez, D.; Saa´, C. Tetrahedron Lett. 1998, 39,
6551-6554. (d) Rodr´ıguez, G.; Castedo, L.; Dom´ınguez, D.; Saa´, C.;
Adam, W.; Saha-Mo¨ller, C. R. J . Org. Chem. 1999, 64, 877-883.
(2) Fajardo, V.; Elango, V.; Chattopadhyay, S.; J ackman, L. M.;
Shamma, M. Tetrahedron Lett. 1983, 24, 155-158.
(3) Hocquemiller, R.; Cave´, A. J . Nat. Prod. 1984, 47, 539-540.
(4) Shamma, M.; Rahimizadeh, M. J . Nat. Prod. 1986, 49, 398-405.
(5) Weinstock, J .; Hieble, J . P.; Wilson, J . W. Drugs Future 1985,
10, 645.
(6) Clemens, M.; Meise, W.; Himmel, K.; J ansen, M. Liebigs Ann.
1997, 447-457. (b) Kim, D. H. J . Heterocycl. Chem. 1992, 29, 11-16.
For the synthesis of isoquino[2]benzazepines, see: (c) Meise, W.; Arth,
D.; Zlotos, D.; J ansen, M.; Feldman, C. Liebigs Ann. 1994, 1135-1142.
(d) Meise, W.; Zlotos, D.; J ansen, M.; Zoche, N. Liebigs Ann. 1995, 567-
574.
10.1021/jo9901900 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/27/1999

Synthesis of Isoquino[1,2-b][3]benzazepines
J . Org. Chem., Vol. 64, No. 13, 1999 4831
Sch em e 2a
Sch em e 3a
a
Reagents: (i) AIBN, n-Bu3SnH, benzene, reflux, 75%; (ii) NaH,
a
Reagents: (i) Br2, AcOH, ca. 20 °C, 98%; (ii) KCN, DMSO, 70
DMF, ca. 20 °C, 36%.
°C, 70%; (iii) NaOH, EtOH/H2O, reflux, 87%; (iv) SOCl2, ca. 20
°C; (v) Et3N, THF, ca. 20 °C, 91%; (vi) (trimethylsilyl)acetylene,
PdCl2(PPh3)2, CuI, Et3N, 86%.
Sch em e 4
The radical cyclization was performed by slow, drop-
wise addition of a solution of tributyltin hydride (2 equiv)
and AIBN (20 wt %) in benzene to a 7 mM solution of
phenylacetamide 9 in benzene by refluxing under argon.
To our delight, cyclization occurred smoothly, and two
isomeric stilbene macrolactams 3a and 3b were obtained
in 50 and 25% yield.8 This result contrasts with the one
obtained in a similar cyclization to 10-membered-ring
stilbene lactams, where a single geometric isomer of
unknown stereochemistry was obtained.1 The appearance
of both E and Z stereoisomers for the 11-membered
stilbene lactams could be due to lower geometrical
constraint for the formation of the corresponding vinyl-
radical intermediates due to the larger ring size.
With the macrolactams 3 prepared, we first attempted
the transannular cyclization by following the various
conditions developed for the case of 10-membered-ring
lactams.1 Unfortunately, when the 11-membered-ring
lactams were subjected to either acidic conditions (treat-
ment with hydriodic acid)1c or basic conditions (potassium
tert-butoxide)1a,b or to tetrabutylammonium fluoride solu-
tion buffered with glacial acetic acid,1c only unidentified
complex mixtures and/or recovered starting material
were obtained. Curiously, when the E macrolactam 3a
was treated with sodium hydride (1.1 equiv) in DMF at
room temperature, desilylation occurred to the cis-
stilbene lactam 10 in low yield, thus reconfirming the
assigned E geometry of 3a (Scheme 3).9
Geometrical constraints were suspected as the reason
for the failure of [7,6]-transanular cyclization, and we
decided to epoxidize the vinylsilane moiety of lactams 3
with dioxiranes.1d,10 Accordingly, the E lactam 3a was
treated with an excess (8 equiv) of DMD11 over 30 h at
room temperature, but unfortunately, unchanged start-
ing material was completely recovered. Therefore, epoxi-
dation with the more reactive TFD12 was then tried
(Scheme 4) by treatment of a solution of the E lactam 3a
in CH2Cl2 with 1.8 equiv of TFD at room temperature
over 16 h. However, the muconate 11 was obtained in
83% yield by oxidative cleavage of the dimethoxylated
aromatic ring, but no epoxidation of the hindered double
bond was observed, analogous to the 10-membered
lactam.1d In contrast, addition of an excess (7.9 equiv) of
DMD in several doses over 5 days at room temperature
to an acetone solution of the Z lactam 3b afforded the
epoxymuconate diester 12 in moderate yield. The forma-
tion of muconate 11 suggests that steric factors play an
important role in preventing the epoxidation of the E
macrolactam 3a , since the bulky trimethylsilyl group
hinders the approach of the sterically sensitive TFD to
the double bond, and therefore, oxidation of the electron-
rich aromatic ring becomes competitive. Nonetheless, for-
mation of epoxymuconate diester 12 was due to the oxida-
tion of both the vinylsilane functionality and the electron-
rich aromatic ring. Probably, epoxidation of the more
accessible double bond of 3b, as compared to 3a , occurred
first, and the epoxysilane intermediate was subsequently
oxidized by excess DMD to the epoxymuconate 12. These
results are similar to the ones observed in the case of
the 10-membered-ring stilbene lactam homologues.1d
These interesting but inappropriate results for our
goals led us to look for another possibility to modify the
(10) For a review of dioxirane chemistry, see: (a) Adam, W.; Curci,
R.; Edwards, J . O. Acc. Chem. Res. 1989, 22, 205-211. (b) Murray, R.
W. Chem. Rev. 1989, 89, 1187-1201. (c) Curci, R.; Dinoi, A.; Rubino,
M. F. Pure Appl. Chem. 1995, 67, 811-822. (d) Adam, W.; Smerz, A.
K. Bull. Soc. Chim. Belg. 1996, 105, 581-599. (e) Adam, W.; Curci,
R.; D’Accolti, L.; Dinoi, A.; Fusco, C.; Gasparrini, F.; Kluge, R.; Paredes,
R.; Schulz, M.; Smerz, A. K.; Veloza, L. A.; Weinko¨tz, S.; Winde, R.
Chem. Eur. J . 1997, 3, 105-109. See also the references cited in ref
1d.
(7) 2-Iodophenylacetic acid was prepared by a modification of the
published procedure: Dippy, F. J .; Lewis, R. H. J . Chem. Soc. 1936,
644-649. (b) For an alternative synthetic procedure, see: Taylor, E.
C.; Kienzle, F.; Robey, R. L.; McKillop, A.; Hunt, J . D. J . Am. Chem.
Soc. 1971, 93, 4845-4850.
(8) The assignment of the geometry of the silylated stilbene lactams
is based on NOE studies.
(9) The formation of desilylated product is rationalized by invoking
the amidate and further iminosilyl ether formation due to the singular
spatial disposition of both groups. Final hydrolytic workup recovers
the amide functionality.
(11) Adam, W.; Bialas, J .; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377.
(12) Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J . Org. Chem.
1988, 53, 3890-3891.

4832 J . Org. Chem., Vol. 64, No. 13, 1999
Rodr´ıguez et al.
Sch em e 5a
N -[2-(2-Br om o-4,5-d im e t h oxy)p h e n yl]e t h yl(2-iod o-
p h en yl)a ceta m id e (8). P r ep a r a tion of 2-Iod op h en yla ce-
tic Acid . A stirred solution of 2-iodobenzyl cyanide13 (2.05 g,
8.42 mmol), prepared in 70% yield from commercial 6, and
NaOH (3.40 g, 84.2 mmol) in 75 mL of EtOH/H2O (2:1) was
refluxed for 6.5 h. The mixture was cooled to room tempera-
ture, the ethanol was removed under reduced pressure, and
the aqueous solution was acidified with 37% HCl, extracted
with CH2Cl2, washed with H2O and saturated brine, dried over
anhydrous Na2SO4, and concentrated to dryness to afford 1.93
g of 2-iodophenylacetic acid7 (87%) as colorless plates.
P r ep a r a tion of 2-Iod op h en yla cetyl Ch lor id e (7). A
solution of 2-iodophenylacetic acid (2.44 g, 9.30 mmol) and
SOCl2 (7 mL, 93 mmol) was stirred for 12 h at room temper-
ature. The excess thionyl chloride was evaporated to give crude
acyl chloride 7 (2.60 g), which was immediately used without
further purification.
P r ep a r a tion of th e Aceta m id e 8. A solution of acyl
chloride 7 (2.60 g, 9.30 mmol) in THF (20 mL) was added by
means of a cannula to a cold (0 °C), stirred solution of 51d (2.28
g, 8.78 mmol) and triethylamine (1.84 mL, 13.18 mmol) in THF
(30 mL). Once the addition was finished, the stirring was
continued for 12 h at room temperature. The residue obtained
by removal of the volatiles under reduced pressure was
dissolved in CH2Cl2, washed with 5% aqueous HCl, dried over
anhydrous Na2SO4, concentrated to dryness, and recrystallized
from MeOH/EtOAc to afford 8 (4.04 g, 91%) as colorless
needles: mp 159-161 °C (MeOH/EtOAc); IR (KBr) ν 1646
cm-1; 1H NMR δ 2.87 (t, J ) 7.0 Hz, 2H), 3.45-3.54, (m, 2H),
3.69 (s, 2H), 3.81 (s, 3H), 3.85 (s, 3H), 5.49 (br s, 1H), 6.67 (s,
1H), 6.94-7.01 (m, 1H), 6.95 (s, 1H), 7.30-7.33 (m, 2H), 7.83
(d, J ) 7.9 Hz, 1H); 13C NMR δ 34.7 (CH2), 39.2 (CH2), 47.9
(CH2), 55.7 (2 × OCH3), 110.8 (C), 112.9 (CH), 113.7 (C), 115.0
(CH), 128.3 (CH), 128.6 (CH), 129.7 (C), 130.3 (CH), 138.0 (C),
139.2 (CH), 147.7 (C), 147.9 (C) 169.4 (CdO); MS m/z (relative
intensity) 505 (M+, 3), 503 (M+, 3), 242 (100). Anal. Calcd for
a
Reagents: (i) (a) BH3‚SMe2, THF, reflux; (b) TMEDA, CH2Cl2/
Et2O, ca. 20 °C; (ii) Bu4NF, THF, ca. 20 °C.
substrates, e.g., the reduction of the amide to an amine.
Gratifyingly, our expectations were fulfilled with success
because when the macrolactams 3a and 3b were treated
with the borane-dimethyl sulfide complex both reduction
and regioselective [7,6]-transannular cyclization took
place to the desired homoprotoberberines. Thus, for
derivative 3a , the 2,3-dimethoxyisoquino[1,2-b][3]benz-
azepine (homoprotoberberine) 26a was obtained in a 29%
yield, while the diastereomer 3b gave initially the sily-
lated homoprotoberberine 13 in 22% yield, which was
easily desilylated to the desired 11,12-dimethoxyisoquino-
[1,2-b][3]benzazepine 1.6a
Most probably, the initially formed macrocyclic amines
have a geometrical disposition that favors the required
regioselectivity for the [7,6]-transannular cyclization.
Presumably, desilylation of the resulting R-trimethylsi-
lylamine intermediate is easier for the 3a diastereomer,
and consequently, the cyclization to 2 takes place directly.
For the 3b diastereomer the â-trimethylsilylamine 13 is
the primary cyclized product, which requires desilylation
to the homoprotoberberine 1.
To sum up, we have shown that stilbene lactams with
11-membered lactam rings are versatile intermediates
for the synthesis of isoquino[1,2-b][3]benzazepines (ho-
moprotoberberines). The regioselectivity of the [7,6]-
transanular cyclization is ascribed to the geometry of the
molecule imposed by the nature of the stilbene double
bond. The starting E and Z stilbene lactams were easily
obtained by intramolecular addition of an aryl radical to
a trimethylsilylacetylene.
C
18H19BrINO3: C, 42.89; H, 3.80; N, 2.78. Found: C, 42.71;
H, 4.09; N, 2.83.
N-[2-(2-Br om o-4,5-d im eth oxy)p h en yl]eth yl[2-(tr im eth -
ylsilyleth yn yl)p h en yl]a ceta m id e (9). A mixture of 8 (4.04
g, 8.01 mmol), (Ph3P)2PdCl2 (0.28 g, 0.40 mmol), CuI (76 mg,
0.40 mmol), and (trimethylsilyl)acetylene (1.7 mL, 12.02 mmol)
in 50 mL of Et3N and 30 mL of THF was stirred for 6 h at
room temperature and passed through a pad of Celite to
remove the solids. The filtrate was concentrated and the
residue dissolved in CH2Cl2. The resulting solution was washed
with 5% aqueous HCl and saturated brine, dried over
Na2SO4, and concentrated to dryness. Purification of the
residue by flash chromatography on silica gel (1:2 EtOAc/
hexane) afforded 9 (3.26 g, 86%), which was crystallized from
diethyl ether as colorless plates: mp 100-102 °C (Et2O); IR
1
(KBr) ν 2154, 1653 cm-1; H NMR δ 0.24 (s, 9H), 2.82 (t, J )
7.2 Hz, 2H), 3.41-3.49 (m, 2H), 3.73 (s, 2H), 3.78 (s, 3H), 3.84
(s, 3H), 5.79 (br s, 1H), 6.63 (s, 1H), 6.94 (s, 1H), 7.19-7.31
(m, 3H), 7.47 (d, J ) 7.3 Hz, 1H); 13C NMR δ -0.1 (CH3), 35.4
(CH2), 39.5 (CH2), 42.7 (CH2), 55.9 (OCH3), 56.0 (OCH3), 99.4
(C), 103.3 (C), 113.2 (CH), 114.0 (C), 115.4 (CH), 122.8 (C),
127.2 (CH), 129.2 (CH), 129.8 (CH), 129.9 (C), 132.6 (CH),
137.3 (C), 148.1 (C) 148.3 (C), 170.4 (CdO); MS m/z (relative
intensity) 475 (M+, 2), 473 (M+, 3), 242 (100). Anal. Calcd for
C
23H28BrNO3Si: C, 58.22; H, 5.95; N, 2.95. Found: C, 58.13;
Exp er im en ta l Section
H, 6.17; N, 3.09.
11,12-Dim eth oxy-14-tr im eth ylsilyl-6,7,8,9-tetr a h yd r o-
5H-d iben zo[d ,h ]a za cyclou n d ecin -6-on e (3). A solution of
n-Bu3SnH (0.30 mL, 1.13 mmol) and AIBN (54 mg, 20 wt % of
9) in benzene (30 mL) was added over 5 h by means of a
syringe pump to a solution of 9 (0.27 g, 0.56 mmol) in dry,
degassed benzene (80 mL) kept at reflux. After complete addi-
tion, reflux was kept up for another 4 h. The solvent was evap-
orated to dryness, and the residue was dissolved in CH3CN.
This solution was washed with hexane and then concentrated
Gen er a l Meth od s. All nonaqueous reactions were con-
ducted under an inert atmosphere of argon gas using flame-
dried glassware. Unless specified otherwise, solvents and
reagents were commercially available chemicals and were used
as received. Tetrahydrofuran (THF) and benzene were distilled
from a sodium metal/benzophenone mixture. Dichloromethane
and triethylamine were distilled from calcium hydride. Slow
additions were carried out by using a syringe pump (Harvard
1
11). Melting points are uncorrected. H, 13C, and DEPT NMR
spectra were recorded in CDCl3 unless specified; chemical
shifts are reported as δ values in ppm versus tetramethylsilane
(TMS).
(13) Curran, D. P.; Liu, H.; J osien, H.; Ko, S. B. Tetrahedron 1996,
52, 11385-11404.

Synthesis of Isoquino[1,2-b][3]benzazepines
J . Org. Chem., Vol. 64, No. 13, 1999 4833
and the residue chromatographed on silica gel (1:1 EtOAc/
hexane). Macrolactams E, 3a (0.11 g, 50%, Rf ) 0.25), and Z,
3b (56 mg, 25%, Rf ) 0.12), were obtained as colorless needles
after crystallization from EtOAc/hexane. Macrolactam E, 3a :
followed by preparative TLC of the residue on silica gel (1:2
EtOAc/hexane), afforded 15.0 mg (42%) of crude 12: 1H NMR
δ -0.15 (s, 9H), 2.24-2.36 (m, 1H), 2.84-2.95 (m, 1H), 3.24-
3.56 (m, 1H), 3.60-3.68 (m, 2H), 3.65 (s, 3H), 3.66 (s, 3H), 3.98
(s, 1H), 4.02-4.18 (m, 1H), 5.95-5.98 (m, 1H), 6.03 (s, 1H),
6.12 (s, 1H), 7.34-7.58 (m, 4H).
mp 162-164 oC (EtOAc/hexane); IR (film) ν 1672 cm-1 1H
;
NMR δ 0.12 (s, 9H), 2.34-2.39 (m, 1H), 2.46-2.57 (m, 1H),
2.72 (dt, J ) 3.1, 12.7 Hz, 1H), 3.43 (d, J ) 17.3 Hz, 1H), 3.72
(d, J ) 17.3 Hz, 1H), 3.80 (s, 3H), 3.92 (s, 3H), 4.00-4.12 (m,
1H), 5.14-5.16 (m, 1H), 6.52 (s, 1H), 6.59 (s, 1H), 7.00 (s, 1H),
7.08-7.17 (m, 3H), 7.23-7.29 (m, 1H); 13C NMR δ -1.4 (CH3),
33.4 (CH2), 41.3 (CH2), 42.7 (CH2), 55.7 (OCH3), 56.1 (OCH3),
112.8 (CH), 114.2 (CH), 127.1 (CH), 127.7 (CH), 128.9 (C),
130.5 (CH), 131.3 (CH), 132.4 (C), 133.3 (C), 138.9 (CH), 139.6
(C), 146.2 (C), 147.5 (C) 150.6 (C), 171.8 (CdO); MS m/z
(relative intensity) 395 (M+, 83), 73 (100). Anal. Calcd for
5,6,8,9,14,14a -Hexa h yd r o-2,3-d im eth oxyisoqu in o[1,2-b]-
[3]ben za zep in e (2). To a solution of 3a (0.16 g, 0.41 mmol)
in THF (7 mL) was added BH3‚SMe2 (10.0 M, 0.20 mL, 2.0
mmol). After the reaction mixture was refluxed for 12 h, the
solvent was evaporated and the residue was dissolved in a
mixture of CH2Cl2 (2 mL) and Et2O (2 mL). TMEDA (0.61 mL,
4.10 mmol) was added, and stirring was continued for 24 h at
room temperature. Removal of the solvent followed by pre-
parative TLC on silica gel (MeOH) afforded 26a (36.0 mg, 29%)
as colorless plates: 1H NMR δ 2.61-2.99 (m, 6H), 3.20-3.62
(m, 4H), 3.85-3.89 (m, 1H), 3.85 (s, 3H), 3.89 (s, 3H), 6.57 (s,
1H), 6.71 (s, 1H), 7.12-7.25 (m, 4H); 1H NMR (Py-d5) δ 2.63-
3.38 (m, 9H), 3.65-3.75 (m, 1H), 3.84 (s, 3H), 3.84-4.00 (m,
1H), 3.93 (s, 3H), 6.79 (s, 1H), 7.08 (s, 1H), 7.22-7.36 (m, 3H),
7.42-7.45 (m, 1H); 13C NMR δ 29.0 (CH2), 34.5 (CH2), 43.0
(CH2), 48.3 (CH2), 55.8 (OCH3), 56.1 (OCH3), 56.8 (CH2), 62.7
(CH), 110.3 (CH), 111.1 (CH), 126.2 (CH), 126.4 (CH), 126.9
(C), 129.0 (CH), 129.3 (CH), 131.0 (C), 141.0 (C), 142.2 (C),
147.3 (C), 147.5 (C); 13C NMR (Py-d5) δ 30.2 (CH2), 35.9 (CH2),
44.6 (CH2), 50.0 (CH2), 56.4 (CH3), 56.9 (CH3), 58.0 (CH2), 64.1
(CH), 112.7 (CH), 113.1 (CH), 127.1 (CH), 127.2 (CH), 128.6
(C), 129.8 (CH), 130.4 (CH), 132.6 (C), 142.3 (C), 143.3 (C),
148.9 (C), 149.1 (C); MS m/z (relative intensity) 309 (M+, 52),
308 (100).
5,6,8,9,14,14a-Hexah ydr o-11,12-dim eth oxyisoqu in o[1,2-
b][3]ben za zep in e (1). To a solution of 3b (44 mg, 0.11 mmol)
in THF (4 mL) was added BH3‚SMe2 (10.0 M, 56 µL, 0.56
mmol). After the reaction mixture was refluxed for 12 h, the
solvent was evaporated and the residue was dissolved in a
mixture of CH2Cl2 (2 mL) and Et2O (2 mL). TMEDA (0.20 mL,
1.34 mmol) was added to the solution, and stirring was
continued for 24 h at room temperature. Removal of the solvent
followed by preparative TLC on silica gel (48:48:4 EtOAc/
hexane/MeOH) afforded silylated homoprotoberberine 13 (9.0
mg, 22%): 1H NMR δ 0.05 (br s, 9H), 2.60-3.79 (m, 9H), 3.84
(br s, 7H), 6.51 (s, 1H), 6.61 (br s, 1H), 7.11-7.23 (m, 3H),
7.39 (br s, 1H); MS m/z (relative intensity) 381 (M+, 70), 366
(50), 308 (46), 280 (59), 223 (71), 216 (69), 192 (73), 165 (100),
73 (85).
C
23H29NO3Si: C, 69.84; H, 7.40; N, 3.54. Found: C, 69.70; H,
7.40; N, 3.67. Macrolactam Z, 3b: mp 200-202 °C (EtOAc/
hexane); IR (KBr) ν 1646 cm-1; 1H NMR δ -0.09 (s, 9H), 2.32-
2.38 (m, 1H), 2.79-2.91 (m, 1H), 3.00-3.15 (m, 1H), 3.40 (s,
2H), 3.89 (s, 3H), 3.90 (s, 3H), 4.00-4.13 (m, 1H), 5.85-5.88
(m, 1H), 6.57 (s, 1H), 6.69 (s, 1H), 7.05 (s, 1H), 7.20-7.38 (m,
3H), 7.50-7.71 (m, 1H); 13C NMR δ -0.1 (CH3), 31.4 (CH2),
42.6 (CH2), 43.6 (CH2), 55.9 (OCH3), 56.0 (OCH3), 110.3
(CH), 112.8 (CH), 126.5 (CH), 127.6 (CH), 127.7 (CH), 129.6
(C), 131.0 (CH), 135.1 (C), 138.5 (C), 139.6 (C), 144.4 (CH),
146.9 (C), 147.3 (C) 147.8 (C), 171.3 (CdO); MS m/z (rela-
tive intensity) 395 (M+, 91), 83 (100); HRMS calcd for
C
23H29NO3Si 395.19167, found 395.19157.
cis-11,12-Dim et h oxy-6,7,8,9-t et r a h yd r o-5H -d ib en zo-
[d ,h ]a za cyclou n d ecin -6-on e (10). A suspension of 3a (35.0
mg, 0.09 mmol) and NaH (2.0 mg, 0.09 mmol) in DMF (1 mL)
was stirred under argon at room temperature for 12 h. The
reaction mixture was poured into CH2Cl2, washed with water
and saturated brine, dried over Na2SO4, and concentrated to
dryness. The residue was purified by preparative TLC on silica
gel (1:2 EtOAc/hexane) to afford 10 (10.0 mg, 36%) as a yellow
oil: IR (KBr) ν 1665 cm-1; 1H NMR δ 2.43-2.48 (m, 1H), 2.51-
2.59 (m, 1H), 2.97, (dt, J ) 3.7, 12.8 Hz, 1H), 3.43 (d, J ) 17.2
Hz, 1H), 3.69 (d, J ) 17.2 Hz), 3.80 (s, 3H), 3.89 (s, 3H), 4.08-
4.19 (m, 1H), 5.16-7.19 (m, 1H), 6.54 (s, 1H), 6.80 (d, J ) 12.2
Hz, 1H), 6.83 (s, 1H), 6.91 (d, J ) 12.2 Hz, 1H), 7.08-7.24 (m,
3H), 7.40 (m, 1H); 13C NMR δ 32.4 (CH2), 41.2 (CH2), 43.1
(CH2), 55.8 (OCH3), 56.1 (OCH3), 112.3 (CH), 115.1 (CH), 126.9
(CH), 127.8 (CH), 128.7 (C), 130.4 (C), 130.7 (CH), 131.2 (CH),
131.4 (CH), 133.0 (C), 134.4 (CH), 137.6 (C), 146.3 (C) 148.5
(C), 171.6 (CdO); MS m/z (relative intensity) 323 (M+, 66), 178
(100).
Tetrabutylammonium fluoride (7.0 mg, 2.83 mmol, 1 M in
THF) was added to a solution of 13 (9.0 mg, 0.84 mmol) in
THF (1 mL), and the resulting mixture was stirred at room
temperature for 15 min. After solvent concentration, the
residue was purified by preparative TLC on silica gel (48:48:4
EtOAc/hexane/MeOH) to afford homoprotoberberine 16a (6.0
mg, 86%) as colorless plates: 1H NMR δ 2.57-3.37 (m, 10H),
3.88 (br s, 7H), 6.63 (s, 1H), 6.82 (s, 1H), 7.16-7.35 (m, 4H);
MS m/z (relative intensity) 309 (M+, 17), 165 (100).
Meth yl 2-[8-Tr im eth ylsilyl-6-[(Z)-1-(m eth yloxyca r bo-
n yl)m et h ylid en e]-2-oxo-2,3,4,5,6,7-h exa h yd r o-1H -b en z-
a za cyclou n d ecin -7-ylid en ]a ceta te (11). A cold solution of
methyl(trifluoromethyl)dioxirane1d,11 (0.51 M in 1,1,1-trifluoro-
2-propanone, 0.14 mL, 0.071 mmol) was added to a solution
of 3a (27.0 mg, 0.068 mmol) in CH2Cl2 (1 mL) at room
temperature. After 4 h, another 0.10 mL of TFD (0.051 mmol)
was added, and TLC monitoring showed that the starting
material had been consumed after 12 h. Removal of the solvent
(20 °C, 740 Torr), followed by preparative TLC on silica gel
(1:2 EtOAc/hexane), afforded 34.0 mg (83%) of 11 as a pale
Ack n ow led gm en t. We are grateful for financial
support from the Direccio´n General de Ensen˜anza
Superior (Project PB95-0824), the Xunta de Galicia
(Project XUGA 20907-B96), and the Deutsche Fors-
chungsgemeinschaft (Schwerpunktprogramm Peroxid-
chemie). G. Rodr´ıguez Longarela thanks the Xunta de
Galicia for a predoctoral fellowship and for a 4-month
research stay at the University of Wu¨rzburg. W.A.
appreciates the hospitality of the USC chemistry faculty
under the auspices of the Iberdrola Visiting Professor
Program.
solid: IR (film) ν 1727, 1681 cm-1 1H NMR δ 0.28 (s, 9H),
;
2.25-2.32 (m, 1H), 2.38-2.52 (m, 1H), 2.79-2.94 (m, 1H),
3.50-3.66 (m, 2H), 3.54 (s, 3H), 3.66 (s, 3H), 3.83-3.95 (m,
1H), 5.08-5.13 (m, 1H), 5.42 (d, J ) 2.1 Hz, 1H), 6.02 (s, 1H),
6.98 (s, 1H), 7.04-7.28 (m, 4H); 13C NMR δ 0.4 (CH3), 33.6
(CH2), 36.2 (CH2), 43.2 (CH2), 50.9 (OCH3), 51.3 (OCH3), 116.9
(CH), 122.3 (CH), 127.3 (CH), 128.4 (CH), 129.9 (CH), 130.8
(CH), 133.5 (C), 138.9 (C), 142.6 (CH), 145.0 (C), 150.7 (C),
151.9 (C), 164.6 (CdO), 165.8 (CdO), 170.8 (CdO); MS m/z
(relative intensity) 427 (M+, 4), 368 (100).
Meth yl 2-[1a -Tr im eth ylsilyl-2-[(E)-1-(m eth yloxyca r bo-
n yl)m eth ylid en e]-7-oxo -2,3,4,5,6,7,8,12b-octa h yd r o-1a H-
ben zo[d ]oxir en o[2,3-f]a za cyclou n d ecin -3- ylid en ]a ceta te
(12). A cooled (-78 °C) solution (7.2 mL) of 0.09 M DMD1d
(0.64 mmol) in acetone was added in doses at room tempera-
ture to a stirred solution of 3b (32.0 mg, 0.081 mmol) in acetone
(1 mL) over 5 d. Removal of the solvent (20 °C, 740 Torr),
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR and 13C NMR spectra of all new compounds and the
whole data list of IR and MS of compounds 8, 9, 3a ,b, 10, 11,
2, and 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O9901900