Dioxirane epoxidation of 10-membered-ring stilbene lactams as synthetic precursors to protoberberines

Article abstract of DOI:10.1021/jo981829n

Silylated stilbene lactams 1, prepared by intramolecular addition of an aryl radical to a trimethylsilylacetylene, were converted into protoberberines by dimethyldioxirane (DMD) epoxidation and subsequent acid- catalyzed cyclization of the epoxysilane with HCl. Treatment of the nonsilylated trans- and cis-stilbene derivatives with DMD afforded 13- hydroxytetrahydroprotoberberines and 13a-hydroxy-13- ketotetrahydroprotoberberines as the main products. Tetrahydroprotoberberines were also obtained in excellent yields by the reaction of both silylated and nonsilylated lactams with hydriodic acid.

Full text of DOI:10.1021/jo981829n

J . Org. Chem. 1999, 64, 877-883
877
Dioxir a n e Ep oxid a tion of 10-Mem ber ed -Rin g Stilben e La cta m s a s
Syn th etic P r ecu r sor s to P r otober ber in es
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 and Chantu R. Saha-Mo¨ller
Institute of Organic Chemistry, University of Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received September 8, 1998
Silylated stilbene lactams 1, prepared by intramolecular addition of an aryl radical to a
trimethylsilylacetylene, were converted into protoberberines by dimethyldioxirane (DMD) epoxi-
dation and subsequent acid-catalyzed cyclization of the epoxysilane with HCl. Treatment of the
nonsilylated trans- and cis-stilbene derivatives with DMD afforded 13-hydroxytetrahydroproto-
berberines and 13a-hydroxy-13-ketotetrahydroprotoberberines as the main products. Tetrahydro-
protoberberines were also obtained in excellent yields by the reaction of both silylated and
nonsilylated lactams with hydriodic acid.
In tr od u ction
Resu lts a n d Discu ssion
As precursors of the required stilbene macrolactams
1a and 1b, the o-(trimethylsilylethynyl)benzamides 8a
and 8b were prepared from commercially available
starting materials as shown in Schemes 2 and 3. Con-
densation of phenethylamines 4 with the acid chlorides
5 in THF at room temperature in the presence of
triethylamine gave benzamides 6a and 6b in 87% and
77% yields, and bromination of 6a and iodination of 6b
afforded the dihalogenated benzamides 7a and 7b (Scheme
2).
Treatment of 7a and 7b with (trimethylsilyl)acetylene
(1.5 equiv) in the presence of CuI (0.05 equiv) and (Ph3P)2-
PdCl2 (0.05 equiv) in Et3N at room temperature under
argon afforded the o-(trimethylsilylethynyl)benzamides
8a and 8b chemoselectively in 83% and 80% yields
(Scheme 3). Radical cyclization was performed by slow
dropwise addition of a solution of tributyltin hydride (2
equiv) and AIBN (20 wt %) in benzene to a 5 mM solution
of benzamide 8a or 8b in benzene refluxing under argon.
The desired stilbene macrolactams 1a and 1b were
obtained in 75% and 70% yields as single geometrical
isomers of unknown configuration.8
Over the past few years, we have developed a new
strategy for the synthesis of isoquinoline alkaloids such
as protoberberines1 and isoindolobenzazepines.2 Prelimi-
nary studies showed that the silylated stilbene lactam
1c, obtained by 10-endo radical macrocyclization, can be
regioselectively converted by transannular cyclization
into products with either the isoindolobenzazepine or the
protoberberine skeleton.3 The protoberberine skeleton 3c
was obtained by epoxidation of 1c with m-CPBA (3 equiv
in CH2Cl2 under reflux) followed by acid-catalyzed open-
ing of the epoxysilane 2c with removal of trimethylsilanol
(Scheme 1).
To synthesize tetrahydroprotoberberines with dioxy-
genated A or D rings for subsequent pharmacological
evaluation, we pursued the new strategy3,4 of preparing
the protoberberines 3a and 3b from the stilbene macro-
lactams 1a and 1b. The radical reactions for the synthesis
of 1a and 1b took place expectedly, but epoxidation of
1a with m-CPBA led to a complex mixture of products.
As potentially more effective epoxidizing agent, we
decided to employ the recently popular dimethyldioxirane
(DMD)5,6 and its trifluoromethyl analogue TFD,7 which
combine high reactivity, neutral pH, and ease of workup.
We report herein our results on the use of the stilbene
macrolactams 1a and 1b to synthesize protoberberines
by means of their intermediary epoxides, the latter
readily available by dioxirane oxidation.
As was mentioned above, epoxidation of 1a with
m-CPBA (3 equiv) in CH2Cl2 under reflux or at 0 °C led
to a complex mixture of products (whereas with the same
procedure 70% epoxidation of the unsubstituted lactam
(5) For a review of the chemistry of dioxiranes, 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.
† Fax: + 34-981-595012. E-mail: qocsaa@usc.es, qomingos@usc.es.
(1) Bhakuni, D. S.; J ain, S. In The Alkaloids; Brossi, A., Ed.; New
York: Academic Press: 1986; Vol. 28, pp 95-181.
(2) (a) Fajardo, V.; Elango, B.; Cassels, B. K.; Shamma, M. Tetra-
hedron Lett. 1982, 23, 39-42. (b) Valencia, E.; Freyer, A. J .; Shamma,
M. Tetrahedron Lett. 1984, 25, 599-602. (c) Valencia, E.; Weiss, I.;
Firdous, S.; Freyer, A. J .; Shamma, M. Tetrahedron 1984, 40, 3957-
3962.
(6) Adam, W.; Bialas, J .; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377.
(3) Lamas, C.; Saa´, C.; Castedo, L.; Dom´ınguez, D. Tetrahedron Lett.
1992, 33, 5653-5654.
(4) Rodr´ıguez, G.; Cid, M. M.; Saa´, C.; Castedo, L.; Dom´ınguez, D.
J . Org. Chem. 1996, 61, 2780-2782.
(7) Mello, R.; Fiorentino, M.; Sciacovelli, O.; Curci, R. J . Org. Chem.
1988, 53, 3890-3891.
(8) NOE studies and molecular modeling did not allow to assign
unequivocally the geometry of the isolated stereoisomer.
10.1021/jo981829n CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/09/1999

878 J . Org. Chem., Vol. 64, No. 3, 1999
Rodr´ıguez et al.
Sch em e 1a
a
Reagents: (i) DMD, acetone, ca. 20 °C; (ii) TFD, CH2Cl2, ca. 20 °C; (iii) HCl, MeOH, ca. 20 °C.
Sch em e 2a
Sch em e 3a
a
Reagents: (i) Et3N, THF, ca. 20 °C; (ii) Br2, AcOH, ca. 20 °C,
90%; (iii) I2, AgOCOCF3, NaHCO3, CH2Cl2, ca. 20 °C, 75%.
1c had been achieved).3 We, therefore, attempted the
epoxidation of the vinylsilane moiety with the more
effective oxidant DMD. Indeed, addition of excess DMD
(8 equiv) in several doses over 9 h at room temperature9
afforded a 47% yield of the desired epoxysilane 2a by
DMD attack on the stilbene double bond. Also a 31% yield
of the epoxymuconate diester 9 was obtained by oxidation
of both the vinylsilane functionality and the electron-rich
aromatic ring (Scheme 1).10 Probably, epoxysilane 2a is
initially formed and subsequently oxidized by excess
DMD to afford the epoxymuconate 9. This is supported
by the fact that treatment of authentic 2a with 8 equiv
DMD for 96 h produced 9 in 25% yield.11
Since the total consumption of 1a required a large
excess of DMD, epoxidation with the more reactive TFD
was conducted. Treatment of a solution of 1a in CH2Cl2
with 1.8 equiv of TFD (added in two doses) for 9 h at
room temperature afforded the muconate diester 10 in
90% yield (Scheme 1). Instead of epoxidation of the
hindered stilbene double bond, oxidative cleavage of the
dimethoxylated aromatic ring took place. The cleavage
of arenes by dioxiranes is known,12 but that the olefinic
a
Reagents: (i) (trimethylsilyl)acetylene, (Ph3P)2PdCl2, CuI,
Et3N, ca. 20 °C, 80% (ii) n-Bu3SnH, AIBN, benzene, reflux, 75%.
double bond survives epoxidation by the very reactive
TFD is unusual.13 The sterically encumbered vinylsilane
functionality and the activation of the aryl ring by the
methoxy groups are responsible that for the sterically
more demanding TFD only cleavage of 1a to 10 (see
mechanism below, Scheme 4) instead of epoxidation to
2a and 9 is observed.
The cleavage of the dimethoxylated aromatic ring in
1a by DMD is to be contrasted with its oxidation of
methoxybenzenes, which readily undergo hydroxyla-
tion.14 A possible mechanism is shown in Scheme 4, in
which epoxidation of the electron-rich dimethoxylated
double bond of ring A to a benzene oxide intermediate is
(11) 75% of starting epoxysilane 2a was recovered unchanged.
(12) (a) J eyaraman, R.; Murray, R. W. J . Am. Chem. Soc. 1984, 106,
2462-2463. (b) Mello, R.; Ciminale, F.; Fiorentino, M.; Fusco, C.;
Principe, T.; Curci, R. Tetrahedron Lett. 1990, 31, 6097-6100. (c)
Altamura, A.; Fusco, C.; D’Accolti, L.; Mello, R.; Principe, T.; Curci, R.
Tetrahedron Lett. 1991, 32, 5445-5448. (d) Murray, R. W.; Singh, M.;
Rath, N. P. J . Org. Chem. 1997, 62, 8794-8799.
(13) We thank a reviewer to bring to our attention a precedent
concerning the steric shielding to dioxirane epoxidation exercised by
trimethylsilyl groups; Maynard, G. D.; Paquette, L. A. J . Org. Chem.
1991, 56, 5480-5482.
(9) Use of less DMD (1.1-4 equiv) led to incomplete consumption
of the starting material (18% to 77% conversion) in 24 h.
(10) Regardless of the amount of DMD used, both 2a and 9 appeared
in the early stages of the reaction, as was shown by TLC monitoring.
(14) Adam, W.; Shimizu, M. Synthesis 1994, 560-562.

Epoxidation of Stilbene Lactams
J . Org. Chem., Vol. 64, No. 3, 1999 879
Sch em e 4
Sch em e 6
Sch em e 5a
Sch em e 7
a
Reagents: (i) K2CO3, MeOH, ca. 20 °C, 95%; (ii) n-Bu3SnH,
AIBN, benzene, reflux, 71%.
proposed, which equilibrates to the oxepin12b-d and a
second epoxidation with subsequent ring-opening gener-
ates the muconate 10.
In contrast, the epoxidation of the stilbene macrolac-
tam 1b afforded the epoxysilane 2b almost quantitatively
when treated at room temperature for 6 d with 5 equiv
of DMD (added in several doses); no oxidative cleavage
of the dimethoxylated aromatic ring was observed (Scheme
1). Thus, presumably the amide carbonyl group deacti-
vates the dimethoxylated ring D sufficiently to prevent
its electrophilic oxidation by DMD. The slow oxidation
rate is again due to the bulky trimethylsilyl group, which
hinders the approach of the dioxirane to the stilbene
double bond. Most gratifying, addition of HCl to metha-
nolic solutions of 2a and 2b afforded the desired proto-
berberines 3a 15 and 3b in quantitative yield (Scheme 1).
To assess the influence of the trimethylsilyl substituent
and the olefin geometry on the epoxidation process, the
unsilylated cis- and trans-stilbene macrolactams 12 were
treated with DMD. Lactams 12 were prepared from
ethynylbenzamide 11, which was obtained in 95% yield
by desilylation of benzamide 8a with catalytic amounts
of K2CO3 in MeOH at room temperature (Scheme 5). The
radical macrocyclization of 11 followed the usual proce-
dure and led to a mixture of cis- and trans-stilbene
macrolactams 12 in 47% and 24% yields.16 This is to be
contrasted with the stereoselective formation of a single
geometrical isomer when the silylated acetylene 8a was
cyclized to 1a (Scheme 3) by the same procedure.
Treatment of trans-12 with 1.2 equiv of DMD for 8 h
led to the 13-hydroxytetrahydroprotoberberine 1317 in
78% yield (Scheme 6). Epoxidation of the double bond
followed by the opening of the epoxide ring due to
nucleophilic attack by the nearby amide accounts for this
transformation. When 1.5 equiv of DMD and a longer
reaction time (24 h) were employed, a mixture of 13 (40%)
and the protoberberine 3a 15 (31%) was obtained,18 and
the latter compound was distinguished from the possible
isoindolobenzazepine 14 by an HMBC NMR experiment
that showed a three-bond coupling between H-13 and
C-12 and no coupling between H-1 and C-13.
The epoxidation of the cis-12 was more sluggish since
its completion needed a larger excess of DMD (2.5 equiv)
and a longer reaction time (2 d). The finding that cis-12
is less reactive than its trans isomer is ascribable to its
different molecular geometry: The trans isomer is flatter
and has a more accessible stilbene bond than the U-
shaped cis-12 (Scheme 7), such that in the epoxidation
of the latter the epoxidant has to approach the double
bond between the two almost parallel aryl rings.19 From
the complex oxidation mixture, we only isolated the 13a-
hydroxy-13-ketotetrahydroprotoberberine 15 in 21% yield.
The presence of a small amount of the isoindolobenza-
zepine 162a was also observed (Scheme 7).20 The forma-
tion of these overoxidized products can be ascribed to the
(17) Mardsen, R.; MacLean, D. B. Can. J . Chem. 1984, 62, 1392-
1399.
(18) Compound 13 persists in acetone solution; however, in the
presence of DMD, a slow dehydration takes place to afford 3a .
(19) Geometry optimization was carried out by PM3 semiempirical
calculations by using MacSpartan Plus 1.1.6, Wave Function, Irvine,
CA, 1996.
(15) Ninomiya, I.; Naito, T.; Takasugui, H.; J . Chem. Soc., Perkin
Trans. 1 1975, 1720-1724.
(16) Attempts to desilylate macrolactam 1a under acid and basic
conditions led to [6, 6]- and [7, 5]-azabicyclic products; Rodr´ıguez, G.;
Castedo, L.; Dom´ınguez, D.; Saa´, C. Tetrahedron Lett. 1998, 39, 6551.
(20) The isomeric structures 15 and 16 were identified by
a
combination of HMQC and HMBC NMR experiments.

880 J . Org. Chem., Vol. 64, No. 3, 1999
Rodr´ıguez et al.
Sch em e 8a
were commercially available chemicals and were used as
received. Tetrahydrofuran (THF) and benzene were distilled
from a sodium metal/benzophenone mixture. Dichloromethane,
diisopropylethylamine and triethylamine were distilled from
calcium hydride. Slow additions were carried out by using a
syringe pump (Harvard 11). Melting points are uncorrected.
1H, 13C, and DEPT-NMR spectra were recorded in CDCl3,
unless specified; chemical shifts are reported as δ values in
ppm vs tetramethylsilane (TMS).
N -[2-(2-B r o m o p h e n y l)e t h y l]-3,4-d im e t h o x y b e n z-
a m id e (6b). A solution of benzoyl chloride 5b (0.55 g, 2.75
mmol) in THF (10 mL) was cannulated to a cold, stirred
solution of 2-bromophenylethylamine 4b (0.60 g, 3.02 mmol)
and triethylamine (0.58 mL, 4.12 mmol) in THF (20 mL). Once
addition was finished, stirring was continued for 2.5 h at room
temperature (ca. 20 °C). The residue obtained by removal of
volatiles under reduced pressure was dissolved in CH2Cl2 (10
mL), washed with 5% aqueous HCl (2 × 5 mL), dried over
anhydrous Na2SO4, concentrated to dryness and recrystallized
from CH2Cl2/ethyl ether to afford 6b (0.84 g, 77%) as white
plates, mp 99-101 °C. IR (KBr): ν 3246, 2923, 1629, 1513,
1232 cm-1. 1H NMR: δ 3.10 (t, J ) 6.7 Hz, 2H), 3.69-3.76 (m,
2H), 3.91 (br s, 6H), 6.16-6.36 (m, 1H), 6.84 (d, J ) 8.3 Hz,
1H), 7.07-7.21 (m, 1H), 7.22-7.27 (m, 3H), 7.40 (br s, 1H),
7.56 (d, J ) 7.8 Hz, 1H). 13C NMR: δ 35.7 (CH2), 39.9 (CH2),
55.9 (2 × CH3), 110.2 (CH), 110.5 (CH), 119.2 (CH), 124.6 (C),
127.2 (C), 127.7 (CH), 128.3 (CH), 131.1 (CH), 132.9 (CH),
138.4 (C), 148.9 (C), 151.6 (C), 167.1 (CdO). MS m/z (relative
intensity): 365 (M+, 1), 363 (M+, 1), 181 (9), 165 (100). Anal.
Calcd for C17H18BrNO3: C, 56.06; H, 4.98; N, 3.85. Found: C,
55.98; H, 4.98; N, 3.64.
a
Reagents: (i) Bu4NF, THF, ca. 20 °C.
large excess of DMD and the long reaction time. The
absence of muconate confirms that oxidative cleavage of
the dimethoxylated aromatic ring competes only if there
is no other functionality capable of suffering oxidation
in the molecule.
A comparison of epoxidation reactions between the
silylated and nonsilylated stilbene macrolactams 1a and
12 (trans and cis) clearly shows a different fate of the
initially formed epoxides, which depends on the nature
and substitution of the stilbene double bond. Thus, for
trans- or cis-12, the intermediate epoxide suffers rapid
ring-opening by nitrogen nucleophilic attack to afford the
protoberberine skeletons (Schemes 6 and 7), whereas the
epoxysilane 2a remains intact and cyclization may be
triggered at will by acid catalysis (Scheme 1).
Unexpectedly, we have also found that hydriodic acid
treatment of the silylated stilbene macrolactams 1a and
1b and the nonsilylated stilbene macrolactams 12 led
directly to the tetrahydroprotoberberines 17a , 17b, and
18a (Scheme 8). Specifically, addition of 10 equiv of HI
(57% in water) to solutions of 1a and 1b in benzene
afforded almost quantitative yields of the silylated tet-
rahydroprotoberberines 17a and 17b, and both cis- and
trans-stilbene macrolactams 12 gave under the same
conditions 18a 21 in 75% and 87% yields. In all cases only
[6,6]-transannular cyclization occurred, in which the
carbocation responsible for the intramolecular N-alky-
lation was generated regioselectively by protonation of
the olefinic carbon atom farthest from the amide carbonyl
group.16 Desilylation of 17a and 17b by addition of
tetrabutylammonium fluoride (1.5 equiv in THF) pro-
duced the tetrahydroprotoberberines 18a and 18b in 71%
and 76% yields.
To sum up, we have shown that stilbene lactams with
10-membered lactam rings are versatile intermediates
for the synthesis of protoberberine alkaloids. DMD ep-
oxidation allows their easy conversion into protober-
berines or oxyfunctionalized tetrahydroprotoberberines.
Conveniently, hydriodic acid treatment of both silylated
and nonsilylated stilbene macrolactams affords tetrahy-
droprotoberberines by regioselective [6,6]-transannular
cyclization.
N -[2-(2-Br om o-4,5-d im e t h oxyp h e n yl)e t h yl]-2-iod o-
ben za m id e (7a ). A solution of Br2 (2.35 g, 14.76 mmol) in
glacial acetic acid (13 mL) was added dropwise to a stirred
solution of 6a (4.50 g, 10.94 mmol) in glacial acetic acid (20
mL) at 0 °C. Once addition was finished, the mixture was
allowed to warm to room temperature, stirred for 6 h, poured
into CH2Cl2 (50 mL), and washed successively with aqueous
solutions of 10% Na2S2O5 (3 × 30 mL), 10% KOH (3 × 30 mL),
and saturated brine (3 × 40 mL). The organic layers were
combined, dried over anhydrous Na2SO4, and concentrated to
dryness. The residue obtained was crystallized from methanol
to give 4.80 g of 7a (90%) as white flakes, mp 158-160 °C. IR
1
(KBr): ν 3276, 2925, 1635 cm-1. H NMR: δ 3.04 (t, J ) 7.1
Hz, 2H), 3.68-3.75 (m, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 5.86 (br
s, 1H), 6.84 (s, 1H), 7.01 (s, 1H), 7.06-7.11 (m, 1H), 7.35 (m,
2H), 7.58 (d, J ) 7.8 Hz, 1H). 13C NMR: δ 35.3 (CH2), 39.9
(CH2), 56.1 (CH3), 56.2 (CH3), 92.4 (C), 113.6 (CH), 114.3 (CH),
115.7 (CH), 128.1 (CH), 128.2 (CH), 129.9 (C), 131.1 (CH),
139.9 (CH), 142.1 (C), 148.4 (C), 148.6 (C), 169.4 (CdO). MS
m/z (relative intensity): 491 (M+, 4), 489 (M+, 4), 244 (100),
242 (99), 231 (79). Anal. Calcd for C17H17BrINO3: C, 41.66;
H, 3.49; N, 2.86. Found: C, 41.45; H, 3.49; N, 2.77.
N -[2-(2-Br om op h e n yl)e t h yl]-2-iod o-4,5-d im e t h oxy-
ben za m id e (7b). A suspension of 6b (4.01 g, 11.0 mmol),
iodine (3.07 g, 12.1 mmol), AgOCOCF3 (2.67, 12.1 mmol), and
NaHCO3 (1.02, 12.1 mmol) in CH2Cl2 (110 mL) was stirred
for 12 h at room temperature and the solids removed by
filtration. The organic layer was washed with an aqueous
solution of 10% Na2S2O5 (2 × 60 mL) and saturated brine (2
× 60 mL), dried over anhydrous Na2SO4, and concentrated to
dryness. Purification of the residue by flash column chroma-
tography (1:1 EtOAc/hexane) yielded 7b (4.04 g, 75%) as white
flakes, mp 118-120 °C (EtOAc). IR (KBr): ν 3292, 2916, 1640,
1
1253, 1208, 1021 cm-1. H NMR: δ 3.13 (t, J ) 7.0 Hz, 2H),
3.70-3.77 (m, 2H), 3.84 (s, 3H), 3.86 (s, 3H), 5.97-6.11 (m,
1H), 6.91 (s, 1H), 7.07-7.18 (m, 1H), 7.20 (s, 1H), 7.22-7.38
(m, 2H), 7.55 (d, J ) 7.9 Hz, 1H). 13C NMR: δ 35.4 (CH2),
39.8 (CH2), 56.0 (CH3), 56.2 (CH3), 80.9 (C), 111.7 (CH), 122.0
(CH), 124.6 (C), 127.6 (CH), 128.3 (CH), 131.1 (CH), 132.9
(CH), 134.1 (C), 138.1 (C), 149.0 (C), 150.4 (C), 168.8 (CdO).
MS m/z (relative intensity): 491 (M+, 2), 489 (M+, 2), 291 (100).
Anal. Calcd for C17H17BrINO3: C, 41.66; H, 3.49; N, 2.86.
Found: C, 41.86; H, 3.49; N, 2.74.
Exp er im en ta l Section
Gen er a l. All nonaqueous reactions were conducted under
an inert atmosphere of argon gas, by using flame-dried
glassware. Unless specified otherwise, solvents and reagents
(21) (a) Warrener, R. N.; Liu, L.; Russell, R. A. Chem. Commun.
1997, 2173-2174. (b) Lenz, G. R. J . Org. Chem. 1974, 39, 2846-2851.

Epoxidation of Stilbene Lactams
J . Org. Chem., Vol. 64, No. 3, 1999 881
N-[2-(2-Br om o-4,5-d im eth oxyp h en yl)eth yl]-2-[(tr im e-
th ylsilyl)eth yn yl]ben za m id e (8a ). A mixture of 7a (4.00 g,
8.16 mmol), (Ph3P)2PdCl2 (0.29 g, 0.41 mmol), CuI (0.08 g, 0.41
mmol), and (trimethylsilyl)acetylene (1.8 mL, 12.74 mmol) in
120 mL of Et3N was stirred for 6 h at room temperature and
passed through a pad of Celite to remove solids. The filtrate
was concentrated and the residue dissolved in CH2Cl2 (40 mL).
The resulting solution was washed with 5% aqueous HCl (2
× 20 mL) and saturated brine (2 × 30 mL), dried over
anhydrous Na2SO4, and concentrated to dryness. Purification
of the residue by flash chromatography on silica gel (1:2
EtOAc/hexane) afforded 8a (3.10 g, 83%), which was crystal-
lized from MeOH as white plates, mp 113-115 °C (MeOH).
IR (KBr): ν 3328, 2957, 2153, 1632, 1533, 841 cm-1. 1H NMR:
δ 0.24 (s, 9H), 3.02 (t, J ) 7.4 Hz, 2H), 3.68 (m, 2H), 3.76 (s,
3H), 3.83 (s, 3H), 6.77 (s, 1H), 7.00 (s, 1H), 7.37-7.46 (m, 2H),
7.51-7.54 (m, 1H), 7.89 (br s, 1H), 8.12 (d, J ) 7.2 Hz, 1H).
13C NMR: δ -0.3 (CH3), 35.6 (CH2), 40.0 (CH2), 55.9 (CH3),
56.1 (CH3), 101.9 (C), 103.6 (C), 113.5 (CH), 114.0 (CH), 115.5
(CH), 119.3 (C), 129.1 (CH), 130.1 (CH), 130.2 (C), 130.5 (CH),
133.9 (CH), 135.1 (C), 148.2 (C), 148.4 (C), 165.8 (CdO). MS
m/z (relative intensity): 461 (M+, 3), 459 (M+, 3), 380 (20), 244
(100), 242 (98). Anal. Calcd for C22H26BrNO3Si: C, 57.39; H,
5.69; N, 3.04. Found: C, 57.10; H, 5.95; N, 3.30.
solution of 8b (0.25 g, 0.54 mmol) in dry, degassed benzene
(70 mL) kept at reflux. After complete addition, reflux was
kept up for another 4 h. The solvent was evaporated to dryness
and the residue was dissolved in CH3CN (35 mL). This solution
was washed with hexane (3 × 20 mL), then concentrated and
the obtained residue chromatographed on silica gel (1:1 EtOAc/
hexane). Macrolactam 1b (146 mg, 70%) was obtained as white
needles, mp 182-184 °C (EtOAc/ Et2O). IR (KBr): ν 3403,
1
2948, 1653, 1500, 843 cm-1. H NMR: δ -0.15 (s, 9H), 2.51-
2.57 (m, 1H), 2.98-3.15 (m, 2H), 3.94 (s, 6H), 4.24-4.34 (m,
1H), 5.54-5.57 (m, 1H), 6.75 (s, 1H), 7.03 (s, 1H), 7.10-7.24
(m, 5H). 13C NMR: δ -0.3 (CH3), 33.8 (CH2), 44.0 (CH2), 56.0
(CH3), 56.1 (CH3), 109.7 (CH), 111.1 (CH), 126.3 (CH), 126.5
(CH), 126.6 (CH), 130.9 (CH), 131.2 (C), 131.3 (C), 139.2 (C),
144.3 (CH), 146.4 (C), 148.6 (C), 150.3 (C), 153.3 (C), 170.9
(CdO). MS m/z (relative intensity): 381 (M+, 14), 309 (22),
308 (100), 292 (44), 73 (56). Anal. Calcd for C22H27NO3Si: C,
69.25; H, 7.13; N, 3.67. Found: C, 68.92; H, 6.99; N, 3.57.
Gen er a l P r oced u r e for th e Ep oxid a tion of Ma cr ola c-
ta m s 1a , 1b, a n d 12 w ith Dim eth yld ioxir a n e. Doses of a
cooled solution (-78 °C) of dimethyldioxirane (DMD) in acetone
(0.050-0.084 M),6 dried over molecular sieves, were rapidly
added at room temperature to a stirred solution of the
appropriate macrolactam in the same solvent until complete
consumption of the starting material (TLC monitoring). The
solvent was evaporated to dryness and the residue was
subjected to silica gel chromatography.
N-[2-(2-Br om op h en yl)eth yl]-4,5-d im eth oxy-2-[(tr im e-
th ylsilyl)eth yn yl]ben za m id e (8b). A mixture of 7b (3.00 g,
6.11 mmol), (Ph3P)2PdCl2 (0.22 g, 0.31 mmol), CuI (0.08 g, 0.31
mmol) and (trimethylsilyl)acetylene (1.3 mL, 9.17 mmol) in
DMF (20 mL) and Et3N (50 mL) was stirred for 12 h at room
temperature and passed through a pad of Celite to remove
solids. The filtrate was concentrated and dissolved in CH2Cl2
(40 mL). The resulting solution was washed with 5% aqueous
HCl (2 × 20 mL) and saturated brine (2 × 30 mL), dried over
anhydrous Na2SO4, and concentrated to dryness. Purification
of the residue by flash chromatography on silica gel (1:2
EtOAc/hexane) afforded 8b (2.26 g, 80%), which was crystal-
lized from MeOH as white powder, mp 51-53 °C (MeOH). IR
10,11-Dim e t h oxy-12b -t r im e t h ylsilyl-5,6,7,8,12b ,13a -
h exa h yd r od ib en zo[c,g]oxir en o[2,3-e]-5-on e (2a ) a n d
Meth yl-2-{1a-tr im eth ylsilyl-2-[(E)-1-(m eth yloxycar bon yl)-
m et h ylid en e]-7-oxo-1a ,2,3,4,5,6,7,11b -oct a h yd r ob en zo-
[c]oxir en o[2,3-e]a zecin -3-ylid en }a ceta te (9). A solution (16
mL) of 0.078 M DMD (1.25 mmol) in acetone was added to 60
mg (0.16 mmol) of 1a in acetone (1 mL) within 9 h. Removal
of the solvent (20 °C, 740 Torr), followed by preparative TLC
of the residue on silica gel (1:2 EtOAc/hexane), afforded 37
mg (47%) of 2a and 25 mg (31%) of 9, both as white plates.
Epoxysilane 2a : mp 163-165 °C (EtOAc/hexane). IR (KBr):
ν 3312, 2954, 1636, 1510, 842 cm-1. 1H NMR: δ -0.23 (s, 9H),
2.61 (dd, J ) 3.9, 14.4 Hz, 1H), 3.04 (dt, J ) 4.9, 12.4 Hz, 1H),
3.30-3.41 (m, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 4.11 (s, 1H), 4.29-
4.40 (m, 1H), 6.18-6.23 (m, 1H), 6.66 (s, 1H), 6.95 (s, 1H),
7.36-7.50 (m, 3H), 7.68 (d, J ) 7.2 Hz, 1H). 13C NMR: δ -1.7
(CH3), 39.6 (CH2), 44.3 (CH2), 55.9 (CH3), 56.0 (CH3), 62.7 (C),
69.6 (CH), 109.0 (CH), 114.6 (CH), 126.4 (CH), 128.4 (2 × CH),
129.7 (C), 130.7 (CH), 134.3 (C), 134.8 (C), 135.5 (C), 147.6
(C), 147.8 (C), 169.0 (CdO). MS m/z (relative intensity): 397
(M+, 13), 308 (44), 307 (62), 292 (100). Muconate 9: mp 150-
152 °C (EtOAc/hexane). IR (KBr): ν 3315, 2923, 1727, 1642,
1
(KBr): ν 3384, 2953, 2135, 1631, 1024, 846 cm-1. H NMR: δ
0.24 (s, 9H), 3.10 (t, J ) 7.4 Hz, 2H), 3.67-3.75 (m, 2H), 3.93
(s, 3H), 3.96 (s, 3H), 6.95 (s, 1H), 7.05-7.30 (m, 3H), 7.55 (d,
J ) 7.6 Hz, 1H), 7.76 (s, 1H), 8.16 (br s, 1H). 13C NMR: δ
-0.2 (CH3), 36.1 (CH2), 40.0 (CH2), 56.0 (CH3), 56.1 (CH3),
100.5 (C), 104.0 (C), 111.9 (C), 112.7 (CH), 115.5 (CH), 124.5
(C), 127.6 (CH), 128.2 (CH), 128.4 (C), 131.1 (CH), 132.8 (CH),
138.4 (C), 149.6 (C), 150.4 (C), 165.3 (CdO). MS m/z (relative
intensity): 461 (M+, 2), 459 (M+, 2), 262 (27), 261 (100).
10,11-Dim eth oxy-13-tr im eth ylsilyl-5,6,7,8-tetr a h yd r o-
d iben zo[c,g]a zecin -5-on e (1a ). A solution of n-Bu3SnH (175
µL, 0.69 mmol) and AIBN (40 mg, 20 wt % of 8a ) in benzene
(12 mL) was added over 5 h by means of a syringe pump to a
solution of 8a (0.20 g, 0.43 mmol) in dry, degassed benzene
(75 mL) kept at reflux. After complete addition, reflux was
kept up for another 4 h. The solvent was evaporated to dryness
and the residue was dissolved in CH3CN (30 mL). This solution
was washed with hexane (3 × 15 mL), then concentrated and
the obtained residue chromatographed on silica gel (1:2 EtOAc/
hexane). Macrolactam 1a (125 mg, 75%) was obtained as white
needles, mp 158-160 °C (EtOAc). IR (KBr): ν 3340, 2928,
1
524 cm-1. H NMR: δ -0.11 (s, 9H), 2.27-2.36 (m, 1H), 2.95
(dd, J ) 1.8, 12.4 Hz, 1H), 3.38-3.48 (m, 1H), 3.66 (s, 3H),
3.67 (s, 3H), 4.00 (s, 1H), 4.18-4.25 (m, 1H), 5.90-5.94 (m,
1H), 6.08 (s, 1H), 6.15 (s, 1H), 7.36-7.44 (m, 3H), 7.55-7.58
(m, 1H). 13C NMR: δ -0.8 (CH3), 40.7 (CH2), 42.3 (CH2), 51.3
(CH3), 51.4 (CH3), 61.6 (C), 68.1 (CH), 116.3 (CH), 123.9 (CH),
127.3 (CH), 127.5 (CH), 128.7 (CH), 130.2 (CH), 133.1 (C),
135.5 (C), 153.3 (C), 158.4 (C), 165.0 (CdO), 166.1 (CdO), 168.6
(CdO). MS m/z (relative intensity): 429 (M+, 4), 292 (41), 280
(54), 133 (49), 73 (100). HRMS calcd for C22H27NO6Si 429.16076,
found 429.16125.
1
1644, 1506, 839 cm-1. H NMR: δ 0.19 (s, 9H), 2.44 (dd, J )
4.1, 14.2 Hz, 1H), 3.03-3.06 (m, 1H), 3.09-3.14 (m, 1H), 3.87
(s, 3H), 3.90 (s, 3H), 4.21-4.25 (m, 1H), 5.62 (dd, J ) 4.3, 9.3
Hz, 1H), 6.63 (s, 1H), 6.70 (s, 1H), 7.09 (s, 1H), 7.27 (d, J )
7.5 Hz, 1H), 7.37 (t, J ) 7.5 Hz, 1H), 7.42 (dt, J ) 1.4, 7.5 Hz,
1H), 7.69 (dd, J ) 1.0, 7.5 Hz, 1H). 13C NMR: δ -0.5 (CH3),
32.8 (CH2), 43.8 (CH2), 55.8 (CH3), 55.9 (CH3), 110.1 (CH),
114.1 (CH), 127.0 (CH), 127.6 (CH), 128.3 (CH), 129.9 (CH),
131.1 (C), 137.9 (C), 138.4 (C), 138.5 (C), 145.3 (CH), 147.0 (2
× C), 151.4 (C), 170.8 (CdO). MS m/z (relative intensity): 381
(M+, 22), 353 (26), 308 (91), 292 (44), 262 (26), 73 (100). Anal.
Calcd for C22H27NO3Si: C, 69.25; H, 7.13; N, 3.67. Found: C,
69.06; H, 7.35; N, 3.59.
2,3-D im e t h o x y -12b -t r im e t h y ls ily l-5,6,7,8,12b ,13a -
h exa h yd r od iben zo[c,g]oxir en o[2,3-e]-5-on e (2b). A solu-
tion (3.5 mL) of 0.078 M DMD (0.30 mmol) in acetone was
added to 23 mg (0.060 mmol) of 1b in acetone (0.5 mL) (see
General Procedure). After 6 d, removal of the solvent (20 °C,
740 Torr), followed by preparative TLC of the residue on silica
gel (1:1 EtOAc/hexane), afforded 23 mg (96%) of 2b as a white
powder. IR (film): ν 3315, 2923, 1637, 1508, 842, 754 cm-1
.
1H NMR: δ -0.19 (s, 9H), 2.72 (dd, J ) 3.9, 14.1 Hz, 1H),
3.05 (dt, J ) 4.8, 12.2 Hz, 1H), 3.29-3.41 (m, 1H), 3.93 (s,
3H), 3.94 (s, 3H), 4.09 (s, 1H), 4.39-4.51 (m, 1H), 6.03-6.08
(m, 1H), 6.95 (s, 1H), 7.03-7.31 (m, 4H), 7.39-7.42 (m, 1H).
13C NMR: δ -1.6 (CH3), 35.6 (CH2), 44.2 (CH2), 56.0 (CH3),
56.2 (CH3), 63.3 (C), 69.0 (CH), 108.9 (CH), 111.0 (CH), 125.6
(CH), 127.2 (2 × CH), 127.8 (C), 127.9 (C), 131.4 (CH), 137.9
2,3-Dim et h oxy-13-t r im et h ylsilyl-5,6,7,8-t et r a h yd r o-
d iben zo[c,g]a zecin -5-on e (1b). A solution of n-Bu3SnH (308
µL, 1.14 mmol) and AIBN (50 mg, 20 wt % of 8b) in benzene
(15 mL) was added over 5 h by means of a syringe pump to a

882 J . Org. Chem., Vol. 64, No. 3, 1999
Rodr´ıguez et al.
(C), 142.6 (C), 148.8 (C), 150.9 (C), 169.0 (CdO). MS m/z
(relative intensity): 397 (M+, 12), 308 (77), 307 (78), 292 (100),
193 (98), 73 (100). HRMS calcd for C22H27NO6Si 397.17093,
found 397.17070.
3H), 4.01-4.33 (m, 1H), 5.68-5.72 (m, 1H), 6.46 (d, J ) 16.6
Hz, 1H), 6.71 (s, 1H), 6.97 (s, 1H), 7.29-7.43 (m, 4H), 7.68 (d,
J ) 7.2 Hz, 1H). 13C NMR: δ 31.1 (CH2), 43.7 (CH2), 56.0 (CH3),
56.1 (CH3), 108.1 (CH), 114.1 (CH), 125.8 (CH), 127.5 (CH),
128.7 (CH), 130.0 (2 × CH), 130.8 (C), 131.9 (C), 137.3 (C),
137.7 (C), 140.2 (CH), 148.3 (C), 148.4 (C), 172.0 (CdO). MS
m/z (relative intensity): 309 (M+, 100), 308 (39), 265 (20), 165
(35). HRMS calcd for C19H19NO3 309.13649, found 309.13624.
Meth yl-2-{7-tr im eth ylsilyl-5-[(Z)-1-(m eth yloxyca r bon -
yl)m et h ylid en e]-1-oxo-1,2,3,4,5,6-h exa h yd r o-2-b en za ze-
cin -6-yliden }acetate (10). A cold solution of methyl(trifluoro)-
dioxirane7 (0.51 M in trifluoro-2-propanone, 0.12 mL, 0.060
mmol) was added to a solution of 1a (20 mg, 0.050 mmol) in
CH2Cl2 (1 mL) at room temperature. After 3.5 h, another 0.06
mL of TFD (0.030 mmol) was added and TLC monitoring
showed that the starting material had been consumed after 9
h. Removal of the solvent (20 °C, 740 Torr), followed by
preparative TLC on silica gel (1:2 EtOAc/hexane), afforded 20
mg of 10 (90%) as a pale yellow powder. IR (film): ν 3306,
13-H yd r oxy-2,3-d im et h oxy-6,8,13,13a -t et r a h yd r o-5H -
isoqu in o[3,2-a ]isoqu in olin -8-on e (13) a n d 2,3-Dim eth oxy-
6,8-d ih yd r o-5H-isoqu in o[3,2-a ]isoqu in olin -8-on e (3a ). A
solution (2.0 mL) of 0.087 M DMD (0.18 mmol) in acetone was
added to 31 mg (0.12 mmol) of trans-12 in acetone (0.5 mL)
within 24 h (see General Procedure). Removal of the solvent
(20 °C, 740 Torr), followed by preparative TLC of the residue
on silica gel (1:2 EtOAc/hexane) afforded 16 mg (40%, Rf )
0.31) of 13 and 11 mg (31%, Rf ) 0.19) of 3a , which were
recrystallized from EtOAc/hexane as a creamy powder and
white plates, respectively. Hydroxyprotoberberine 13, 1H
NMR: δ 2.76-2.97 (m, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 4.65-
4.66 (broad s, 2H), 4.97-5.01 (m, 1H), 6.76 (s, 1H), 6.98 (s,
1H), 7.42-7.48 (m, 1H), 7.59 (dt, J ) 1.4, 7.5 Hz, 1H), 7.69 (d,
J ) 7.5 Hz, 1H), 8.11 (dd, J ) 1.1, 7.7 Hz, 1H). 13C NMR: δ
30.1 (CH2), 39.2 (CH2), 55.9 (CH3), 56.1 (CH3), 61.5 (CH), 71.7
(CH), 111.6 (CH), 111.8 (CH), 123.6 (CH), 124.0 (C), 127.5 (C),
128.0 (CH), 128.3 (CH), 129.0 (C), 132.3 (CH), 140.7 (C), 147.3
(C), 148.3 (C), 164.2 (CdO). MS m/z (relative intensity): 325
(M+, 13), 192 (100). Protoberberine 3a : mp 167-169 °C
(EtOAc/hexane) [lit15 191-192 °C (MeOH)]. IR (film): ν 2924,
1
2952, 1725, 1651, 1250, 844, 754 cm-1. H NMR: δ -0.09 (s,
9H), 2.25 (ddd, J ) 4.4, 12.8, 15.3 Hz, 1H), 2.63-2.66 (m, 1H),
3.22 (tt, J ) 4.2, 13.9 Hz, 1H), 3.66 (s, 3H), 3.67 (s, 3H), 3.99-
4.03 (m, 1H), 5.40-5.42 (m, 1H), 5.91 (s, 1H), 5.97 (d, J ) 1.8
Hz, 1H), 7.22 (d, J ) 7.5 Hz, 1H), 7.33 (t, J ) 7.6 Hz, 1H),
7.39 (dt, J ) 1.3, 7.5 Hz, 1H), 7.45 (s, 1H), 7.51 (dd, J ) 1.0,
7.6 Hz, 1H). 13C NMR: δ 0.4 (CH3), 33.2 (CH2), 40.8 (CH2),
51.3 (2 × CH3), 117.5 (CH), 118.4 (CH), 126.8 (CH), 127.4 (CH),
127.9 (CH), 129.9 (CH), 137.2 (C), 137.5 (C), 140.2 (C), 149.1
(CH), 155.3 (C), 157.0 (C), 166.0 (CdO), 166.1 (CdO), 170.3
(CdO). MS m/z (relative intensity): 413 (M+, 2), 354 (100).
N-[2-(2-Br om o-4,5-d im eth oxyp h en yl)eth yl]-2-(eth yn yl-
)ben za m id e (11). Potassium carbonate (15 mg, 0.11 mmol)
was added to a stirred solution of 8a (1.00 g, 2.16 mmol) in
MeOH (50 mL), and the reaction mixture was kept at room
temperature for 15 min. After removal of volatiles under
reduced pressure, the residue was dissolved in CH2Cl2 (50 mL),
and this solution was washed with 5% aqueous HCl (3 × 25
mL) and saturated brine (3 × 30 mL), dried over anhydrous
Na2SO4, and concentrated to dryness. The residue was recrys-
tallized from methanol to give 3.10 g (95%) of 11 as yellow
needles, mp 161-163 °C (MeOH). IR (KBr): ν 3283, 3238,
1
1643, 1514, 1271 cm-1. H NMR, HMQC, and HMBC: δ 2.95
(t, J ) 6.2 Hz, 2H, H-5), 3.95 (s, 3H, OMe), 4.00 (s, 3H, OMe),
4.37 (t, J ) 6.2 Hz, 2H, H-6), 6.75 (s, 1H, H-4), 6.89 (s, 1H,
H-13), 7.28 (s, 1H, H-1), 7.41-7.47 (m, 1H, H-10), 7.55-7.66
(m, 2H, H-11 and H-12), 8.43 (d, J ) 8.1 Hz, 1H, H-9). 13C
NMR and DEPT: δ 28.1 (CH2, C-5), 39.8 (CH2, C-6), 56.1
(OCH3), 56.3 (OCH3), 101.5 (CH, C-13), 108.0 (CH, C-1), 110.5
(CH, C-4), 122.4 (C, C-13b), 124.6 (C, C-8a), 125.9 (CH, C-12),
126.2 (CH, C-10), 128.0 (CH, C-9), 128.8 (C, C-4a), 132.3 (CH,
H-11), 136.7 (C, C-12a), 137.5 (C, C-13a), 148.5 (C, C-3), 150.4
(C, C-2), 162.2 (CdO, C-8). MS m/z (relative intensity): 307
(M+, 83), 293 (21), 292 (100).
1
2910, 2099, 1638 cm-1. H NMR: δ 3.01 (t, J ) 7.0 Hz, 2H),
3,28 (s, 1H), 3.69-3.76 (m, 2H), 3.79 (s, 3H), 3.83 (s, 3H), 6.78
(s, 1H), 7.00 (s, 1H), 7.24 (br s, 1H), 7.38-7.54 (m, 3H), 7.94
(d, J ) 7.2 Hz, 1H). 13C NMR: δ 35.2 (CH2), 39.9 (CH2), 56.0
(CH3), 56.1 (CH3), 82.0 (C), 83.4 (CH), 113.6 (CH), 114.2 (CH),
115.6 (CH), 118.4 (C), 129.3 (CH), 129.5 (CH), 130.2 (C), 130.4
(CH), 134.0 (CH), 136.6 (C), 148.2 (C), 148.4 (C), 166.3 (Cd
O). MS m/z (relative intensity): 389 (M+, 6), 387 (M+, 6), 244
(100), 242 (96). HRMS calcd for C19H18BrNO3 387.04700, found
387.04814.
13a -Hyd r oxy-2,3-d im eth oxy-6,8,13,13a -tetr a h yd r o-5H-
isoqu in o[3,2-a ]isoqu in olin -8,13-d ion e (15) a n d 13a -Hy-
d r oxy-10,11-d im eth oxy-7,8,13,13a -tetr a h yd r o-5H-ben zo-
[4,5]a zep in o[2,1-a ]isoin d ol-5,13-d ion e (16). A solution (4.0
mL) of 0.087 M DMD (0.34 mmol) in acetone was added to 42
mg (0.14 mmol) of cis-12 in acetone (1 mL) within 48 h (see
General Procedure). Removal of the solvent (20 °C, 740 Torr),
followed by preparative TLC of the residue on silica gel (1:1
EtOAc/hexane), afforded 10 mg (21%, Rf ) 0.20) of 15 and 3
mg (7%, Rf ) 0.27) of 16 as white powders. Oxoprotoberberine
15, IR (film): ν 3371, 2927, 1679, 1634, 1516, 1456, 1261, 758
10,11-Dim eth oxy-5,6,7,8-tetr a h yd r od iben zo[c,g]a zecin -
5-on e (12). A solution of n-Bu3SnH (364 µL, 1.35 mmol) and
AIBN (50 mg, 20 wt % of 11) in benzene (40 mL) was added
within 5 h by means of a syringe pump, to a solution of 11
(0.25 g, 0.64 mmol) in dry, degassed benzene (100 mL) kept
at reflux. Once addition was complete, reflux was kept up for
another 4 h. The solvent was evaporated to dryness and the
resulting residue was dissolved in CH3CN (30 mL). This
solution was washed with hexane (3 × 15 mL), then concen-
trated and the obtained residue chromatographed on silica gel
(1:2 EtOAc/hexane). Macrolactams cis-12 (91 mg, 47%, Rf )
0.14) and trans-12 (35 mg, 24%, Rf ) 0.57) were obtained as
white powder and white plates after recrystallization from
EtOAc/hexane and EtOAc, respectively. cis-12: mp 65-67 °C
1
cm-1. H NMR, HMQC, and HMBC: δ 2.74 (dd, J ) 3.1, 16.4
Hz, 1H, H-5), 3.09-3.16 (m, 1H, H-5), 3.65 (dt, J ) 4.2, 12.8
Hz, 1H, H-6), 3.86 (s, 3H, OMe), 3.87 (s, 3H, OMe), 4.05 (br s,
1H, OH), 4.91 (m, 1H, H-6), 6.64 (s, 1H, H-4), 7.01 (s, 1H, H-1),
7.70 (t, J ) 7.7 Hz, 1H, H-10), 7.79 (t, J ) 7.7 Hz, 1H, H-11),
8.09 (d, J ) 7.7 Hz, 1H, H-12), 8.27 (d, J ) 7.7 Hz, 1H, H-9).
13C NMR and DEPT: δ 27.6 (CH2, C-5), 37.1 (CH2, C-6), 56.0
(OCH3), 56.1 (OCH3), 84.8 (C, C-13a), 110.3 (CH, C-1), 111.8
(CH, C-4), 124.9 (C, C-13b), 126.7 (CH, C-12), 128.7 (C + CH,
C-4a and C-9), 130.2 (C, C-12a), 131.5 (C, C-8a), 133.0 (CH,
C-11), 135.3 (CH, C-10), 147.5 (C, C-2), 149.8 (C, C-3), 161.7
(CdO, C-8), 191.4 (CdO, C-13). MS m/z (relative intensity):
339 (M+, 23), 323 (65), 308 (49), 292 (87), 206 (100). Benza-
zepinone 16, 1H NMR: δ 2.70-2.77 (m, 1H), 3.01-3.15 (m,
1H), 3.41-3.50 (m, H + OH), 3.86 (s, 3H), 3.90 (s, 3H), 4.91-
4.99 (m, 1H), 6.64 (s, 1H), 7.18 (s, 1H), 7.65-7.81 (m, 2H), 8.06
(dd, J ) 1.1, 7.6 Hz, 1H), 8.28 (dd, J ) 1.1, 7.6 Hz, 1H). 13C
NMR: δ 28.1 (CH2), 38.1 (CH2), 55.9 (CH3), 56.1 (CH3), 89.2
(C), 111.3 (2 × CH), 125.1 (C), 126.6 (CH), 128.5 (CH), 129.4
(C), 129.5 (C), 131.3 (C), 132.8 (CH), 134.8 (CH), 147.5 (C),
149.8 (C), 157.1 (CdO), 181.9 (CdO). MS m/z (relative inten-
sity): 339 (M+, 31), 338 (82), 322 (100), 244 (53).
1
(EtOAc/hexane). H NMR: δ 2.67 (dd, J ) 2.8, 13.2 Hz, 1H),
2.92 (dt, J ) 4.8, 13.2 Hz, 1H), 3.27-3.34 (m, 1H), 3.52 (s,
3H), 3.86 (s, 3H), 4.02-4.19 (m, 1H), 5.97 (d, J ) 11.0 Hz,
1H), 6.20 (s, 1H), 6.74 (s, 1H), 6.78 (d, J ) 11.9 Hz, 1H), 6.89
(d, J ) 11.9 Hz, 1H), 7.21-7.29 (m, 2H), 7.36-7.42 (m, 1H),
7.55 (d, J ) 7.7 Hz, 1H). 13C NMR: δ 33.7 (CH2), 43.1 (CH2),
55.6 (CH3), 55.7 (CH3), 111.5 (CH), 112.9 (CH), 127.6 (CH),
128.8 (C), 129.7 (C), 129.8 (CH), 130.0 (CH), 130.1 (CH), 130.2
(CH), 133.7 (C), 133.8 (C), 136.5 (CH), 147.7 (C), 149.3 (C),
168.7 (CdO). MS m/z (relative intensity): 309 (M+, 100), 308
(34), 165 (30). HRMS calcd for C19H19NO3 309.13649, found
309.13616. trans-12: mp 223-225 °C (EtOAc). IR (KBr): ν
3285, 2928, 1633, 1508 cm-1
2.91-3.15 (m, 1H), 3.76-3.83 (m, 1H), 3.89 (s, 3H), 3.94 (s,
.
1H NMR δ 2.26-2.50 (m, 1H),

Epoxidation of Stilbene Lactams
J . Org. Chem., Vol. 64, No. 3, 1999 883
2,3-Dim eth oxy-6,8-d ih yd r o-5H-isoqu in o[3,2-a ]isoqu in -
olin -8-on e (3a ). A solution of 37% aqueous HCl (0.5 mL) was
added to a solution of 2a (9 mg, 0.02 mmol) in MeOH (2 mL).
After stirring for 12 h at room temperature, the solvent was
evaporated to dryness and the residue was dissolved in CH2-
Cl2 (5 mL). This solution was washed with 10% aqueous NaOH
(2 × 3 mL) and saturated brine (2 × 5 mL), dried over
anhydrous Na2SO4 and concentrated to dryness. Purification
of the residue by preparative TLC on silica gel (1:1 EtOAc/
hexane) gave 3a (7.0 mg) almost quantitatively.
10,11-Dim et h oxy-6,8-d ih yd r o-5H -isoq u in o[3,2-a ]iso-
qu in olin -8-on e (3b). A solution of 37% aqueous HCl (0.5 mL)
was added to a solution of 2b (15 mg, 0.03 mmol) in MeOH (2
mL). After stirring for 12 h at room temperature, the solvent
was evaporated to dryness and the residue was dissolved in
CH2Cl2 (6 mL). This solution was washed with 10% aqueous
NaOH (2 × 3 mL) and saturated brine (2 × 5 mL), dried over
anhydrous Na2SO4, and concentrated to dryness. Purification
of the residue by preparative TLC on silica gel (1:1 EtOAc/
hexane) gave 11.0 mg of 3b (95%) as a white powder. 1H
NMR: δ 3.01 (t, J ) 6.1 Hz, 2H), 4.01 (s, 3H), 4.02 (s, 3H),
4.38 (t, J ) 6.1 Hz, 2H), 6.94 (s, 1H), 6.97 (s, 1H), 7.28-7.36
(m, 3H), 7.51-7.54 (m, 1H), 7.81 (s, 1H). 13C NMR: δ 28.6
(CH2), 39.6 (CH2), 56.1 (CH3), 56.2 (CH3), 102.5 (CH), 106.1
(CH), 107.8 (CH), 119.0 (C), 124.6 (CH), 126.8 (CH), 127.7
(CH), 128.4 (CH), 128.9 (C), 130.4 (C), 132.0 (C), 135.1 (C),
136.1 (C), 153.5 (C), 161.3 (CdO). MS m/z (relative intensity):
307 (M+, 100), 292 (80).
Gen er a l P r oced u r e for th e Cycliza tion of th e Ma cr o-
la cta m s 1a , 1b, cis-, a n d tr a n s-12a w ith Hyd r iod ic Acid .
A sample of 57% aqueous HI (10 mmol) was added to a solution
of the macrolactam (1 mmol) in benzene (15 mL). After stirring
for 3 h at 50 °C, the reaction mixture was allowed to cool to
room temperature and the solvent was evaporated to dryness.
The residue was dissolved in CH2Cl2 (10 mL), and this solution
was washed with 10% aqueous NaOH (2 × 5 mL) and
saturated brine (2 × 10 mL), dried over anhydrous Na2SO4,
and concentrated to dryness. The residue was purified by flash
chromatography on silica gel with 1:1 or 1:2 ethyl acetate/
hexane as eluent, followed by recrystallization.
C22H27NO3Si: C, 69.25; H, 7.13; N, 3.67. Found: C, 69.37; H,
7.07; N, 3.55.
2,3-Dim eth oxy-6,8,13,13a -tetr a h yd r o-5H-isoqu in o[3,2-
a ]isoqu in olin -8-on e (18a ). A sample of 57% aqueous HI (34
µL, 0.26 mmol) was added to a solution of cis-12 (8 mg, 0.03
mmol) in 1 mL of benzene. After stirring for 13 h at 50 °C, the
reaction was worked up as usually. Purification by preparative
TLC on silica gel (1:1 EtOAc/hexane) and recrystallization from
ethyl ether/ ethyl acetate gave 6 mg (75%) of 18a as white
prisms, mp 114-116 °C (Et2O/EtOAc) [lit21b 143-145 °C
(MeOH)].
With the same amounts of starting materials and the same
purification steps, trans-12 gave 7.0 mg (87%) of 18a . IR
1
(film): ν 2925, 1645, 1515, 1258 cm-1. H NMR: δ 2.74-3.03
(m, 4H), 3.22 (dd, J ) 3.7, 15.7 Hz, 1H), 3.89 (s, 3H), 3.91 (s,
3H), 4.86 (dd, J ) 3.7, 13.3 Hz, 1H), 4.97-5.02 (m, 1H), 6.69
(s, 1H), 6.72 (s, 1H), 7.24-7.27 (m, 1H), 7.35-7.49 (m, 2H),
8.14 (dd, J ) 1.4, 7.6 Hz, 1H). 13C NMR: δ 29.2 (CH2), 38.1
(CH2), 38.7 (CH2), 55.0 (CH), 55.9 (CH3), 56.1 (CH3), 108.8
(CH), 111.4 (CH), 126.8 (CH), 127.2 (C), 127.3 (CH), 127.6 (C),
128.6 (CH), 129.1 (C), 131.8 (C), 137.3 (C), 147.9 (C), 148.0
(C), 164.6 (CdO). MS m/z (relative intensity): 309 (M+, 100),
308 (89), 294 (37), 118 (30), 90 (30).
2,3-Dim eth oxy-6,8,13,13a -tetr a h yd r o-5H-isoqu in o[3,2-
a ]isoqu in olin -8-on e (18a ). Tetrabutylammonium fluoride
(1.1 mL, 1.1 mmol, 1 M in THF) was added to a solution of
17a (0.28 g, 0.73 mmol) in THF (10 mL) and the resulting
mixture was stirred at room temperature for 15 min. After
solvent concentration, the residue was dissolved in CH2Cl2 (10
mL) and washed (3 × 10 mL), and the organic layer was dried
over anhydrous Na2SO4, concentrated to dryness, and chro-
matographed on silica gel with 1:2 EtOAc/hexane as eluent.
After recrystallization from ethyl ether/ethyl acetate, the
tetrahydroprotoberberine 18a (0.16 g, 71%) was obtained as
white prisms.21b
10,11-Dim et h oxy-6,8,13,13a -t et r a h yd r o-5H -isoq u in o-
[3,2-a ]isoqu in olin -8-on e (18b). Tetrabutylammonium fluo-
ride (0.66 mL, 0.66 mmol, 1M in THF) was added to a solution
of 17b (0.25 g, 0.66 mmol) in THF (5 mL) and the resulting
mixture was stirred at room temperature for 5 min. After
solvent concentration, the residue was dissolved in CH2Cl2 (10
mL) and washed (3 × 10 mL), and the organic layer was dried
over anhydrous Na2SO4, concentrated to dryness and chro-
matographed on silica gel with 1:1 EtOAc/hexane as eluent.
After recrystallization from ethyl ether/ethyl acetate, the
tetrahydroprotoberberine 18b (0.15 g, 76%) was obtained as
white prisms, mp 158-160 °C (Et2O). IR (film): ν 2940, 1637,
1595 cm-1. 1H NMR: δ 2.67-2.78 (m, 4H), 3.00-3.07 (m, 1H),
3.78 (s, 6H), 4.71-4.82 (m, 2H), 6.59 (s, 1H), 7.08-7.12 (m,
4H), 7.51 (s, 1H). 13C NMR: δ 29.6 (CH2), 37.2 (CH2), 38.4
(CH2), 55.3 (CH), 55.9 (CH3), 56.0 (CH3), 109.1 (CH), 110.5
(CH), 121.4 (C), 125.7 (CH), 126.5 (CH), 126.6 (CH), 128.8
(CH), 130.9 (C), 134.9 (C), 135.9 (C), 148.0 (C), 151.7 (C), 164.5
(CdO). MS m/z (relative intensity): 309 (M+, 49), 308 (13),
178 (100), 150 (92). HRMS calcd for C19H19NO3 309.13649,
found 309.13589.
13a-Tr im eth ylsilyl-2,3-dim eth oxy-6,8,13,13a-tetr ah ydr o-
5H-isoqu in o[3,2-a ]isoqu in olin -8-on e (17a ). A sample of
57% aqueous HI (1.4 mL, 10.48 mmol) was added to a solution
of 1a (0.40 g, 1.05 mmol) in benzene (15 mL), see General
Procedure. Purification by flash chromatography (1:2 EtOAc/
hexane) and recrystallization from ethyl ether/hexane gave
0.39 g (97%) of 17a as white plates, mp 108-110 °C (Et2O/
hexane). IR (film): ν 2957, 1640, 1517, 1258, 843 cm-1 1H
.
NMR δ -0.17 (s, 9H), 2.74-3.05 (m, 3H), 3.24 (d, J ) 15.4
Hz, 1H), 3.39 (d, J ) 15.4 Hz, 1H), 3.87 (s, 3H), 3.90 (s, 3H),
5.19-5.25 (m, 1H), 6.64 (s, 2H), 7.20 (d, J ) 7.3 Hz, 1H), 7.35
(t, J ) 7.5 Hz, 1H), 7.44 (dt, J ) 1.4, 7.3 Hz, 1H), 8.06 (dd, J
) 1.0, 7.5 Hz, 1H). 13C NMR: δ -0.2 (CH3), 29.0 (CH2), 37.9
(CH2), 40.5 (CH2), 55.8 (CH3), 56.1 (CH3 + C), 107.9 (CH), 111.8
(CH), 124.9 (C), 126.7 (CH), 127.4 (CH), 128.1 (CH), 130.4 (C),
131.8 (CH), 132.6 (C), 135.8 (C), 146.9 (C), 147.7 (C), 163.7
(CdO). MS m/z (relative intensity): 381 (M+, 1), 366 (18), 309
(21), 308 (100). Anal. Calcd for C22H27NO3Si: C, 69.25; H, 7.13;
N, 3.67. Found: C, 69.40; H, 7.01; N, 3.63.
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 thanks the Xunta de Galicia for
a predoctoral fellowship and for a 4 month research stay
at the University of Wu¨rzburg.
13a -Tr im eth ylsilyl-10,11-d im eth oxy-6,8,13,13a -tetr a h y-
d r o-5H-isoqu in o[3,2-a ]isoqu in olin -8-on e (17b). A sample
of 57% aqueous HI (0.35 mL, 2.62 mmol) was added to a
solution of 1b (0.10 g, 0.26 mmol) in benzene (5 mL), see
General Procedure. Purification by flash chromatography (1:1
EtOAc/hexane) and recrystallization from ethyl ether/hexane
gave 99 mg (99%) of 17b as white plates, mp 155-157 °C
(Et2O/hexane). IR (KBr): ν 2956, 1637, 1595, 1248, 838 cm-1
.
1H NMR: δ -0.14 (s, 9H), 2.84-3.13 (m, 3H), 3.23 (d, J )
15.4 Hz, 1H), 3.36 (d, J ) 15.4 Hz, 1H), 3.94 (s, 6H), 5.15-
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 (28 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
5.23 (m, 1H), 6.67 (s, 1H), 7.10-7.23 (m, 4H), 7.60 (s, 1H). 13
C
NMR: δ -0.1 (CH3), 29.5 (CH2), 37.8 (CH2), 39.9 (CH2), 56.1
(2 × CH3), 56.4 (C), 109.2 (CH), 110.5 (CH), 123.1 (C), 124.6
(CH), 125.4 (CH), 126.5 (CH), 129.4 (C), 129.5 (CH), 132.6 (C),
141.1 (C), 148.4 (C), 152.0 (C), 163.7 (CdO). MS m/z (relative
intensity): 381 (M+, 5), 309 (20), 308 (100). Anal. Calcd for
J O981829N