Synthetic approaches toward ecteinascidins. Part 2. Preparation of the ABCDE ring system of ecteinascidins having characteristic substituents in both benzene rings

Article abstract of DOI:10.1248/cpb.51.821

A synthesis of an advanced ABCDE ring system (24c) having characteristic substituents in both benzene rings of ecteinascidin marine natural products is described based on our model studies.

Full text of DOI:10.1248/cpb.51.821

July 2003
Chem. Pharm. Bull. 51(7) 821—831 (2003)
821
Synthetic Approaches toward Ecteinascidins. Part 2.1) Preparation of the
ABCDE Ring System of Ecteinascidins Having Characteristic
Substituents in Both Benzene Rings
*
Naoki SAITO, Ryu-ichi SEKI, Noriko KAMEYAMA, Rie SUGIMOTO, and Akinori KUBO
Meiji Pharmaceutical University; 2–522–1 Noshio, Kiyose, Tokyo 204–8588, Japan.
Received February 26, 2003; accepted April 7, 2003
A synthesis of an advanced ABCDE ring system (24c) having characteristic substituents in both benzene
rings of ecteinascidin marine natural products is described based on our model studies.
Key words ecteinascidin; marine natural product; synthesis; pentacyclic framework; protected phenol
3.18,19) Encouraged by the results of our studies, we applied
these strategies for total synthesis of 1b. We describe herein
an efficient synthesis of a pentacyclic framework (24c) that
has characteristic substituents in both benzene rings.
Since the crude aqueous extract of the colonial tunicate
Ecteinascidia turbinata was reported to possess in vivo anti-
tumor activity in 1969,2) a number of research groups had at-
tempted to isolate the active constituents in the extract and
determine their chemical structures. However, the isolation
and structure determination of the active compounds was not
completed until 1990 by an Illinois University group.3—6)
Among the isolated marine natural products, ecteinascidin
743 (1a) was ultimately selected for further clinical studies
because it was available in the greatest amount from natural
sources. In contrast, we have recently succeeded in the dis-
covery of a Thai tunicate, Ecteinascidia thurstoni HERDMAN
1891, around Phuket Island, and in the extraction, separation,
and isolation of ecteinascidin 770 (1b) in its stable form by
potassium cyanide pretreatment.7) The combination of
unique structural features and a high degree of functionaliza-
tion in 1a presents a formidable challenge to the synthetic
chemist. Corey and co-workers described the first elegant
total synthesis including an improved process.8—10) Fuku-
yama and co-workers recently described an alternative route
for the practical synthesis of 1a.11,12) In addition, the 22 steps
transformation of 1a from cyanosafracin B, which is readily
available from microbial safracin B,13—16) was described by
Pharma Mar Laboratories.17) However, one of the most in-
triguing problems, which is how to maintain a consistent sup-
ply of ecteinascidins for drug development: by isolation from
marine sources or by total synthesis still remains.
In order to reduce the number of steps, we employed the
method of reducing the double bond in 4 storing the bromine
(Chart 1).20) After numerous attempts under a variety of con-
ditions,21—23) catalytic hydrogenation of 4a18) in the presence
of 5% rhodium on carbon (Rh/C) in methanol was achieved.
Catalytic hydrogenation of 4a over 5% Rh/C at 1 atm for 1 h
afforded 5a in quantitative yield. Acetylation of 5a with
acetic anhydride and 4-dimethylaminopyridine (DMAP) in
pyridine gave 6a in 77% yield. On the other hand, the readily
available phenol (7)1) was protected with a p-toluenesulfonyl
group to afford the benzaldehyde derivative (8) in 91% yield.
Condensation of 8 with 6a in the presence of potassium tert-
butoxide gave (Z)-arylidenepiperazinedione (9a) and its (E)-
isomer (10a) in 78 and 6% yields, respectively. The Z stereo-
1
chemical assignment of 10a was based on H-NMR spectral
evidence. Alkylation of 9a with benzyl chloride and sodium
hydride in dimethylformamide (DMF) gave 11a in 88%
yield. It was difficult to remove the acetyl group in 11a under
hydrazine-hydrate in DMF for generating 12a, because the
tosyl protecting group of 11a was unstable under these con-
ditions.24) Thus, the following procedure was attempted and
optimized. Deacetylation of 11a with K2CO3 in methanol
gave the deacetylated compound (12a) in 66% yield. The
piperazine ring of 12a was activated by the introduction of a
2-propyloxycarbonyl group to give the imide (13a) in 99%
yield.
In connection with the development of a short-step synthe-
sis of ecteinascidin 770 (1b), we have previously reported the
preparation of the tricyclic lactam intermediate (2)1) and
the practical synthesis of the ABC ring model compound
The transformation of 13a into the tricyclic lactam (15a),
Fig. 1
To whom correspondence should be addressed. e-mail: naoki@my-pharm.ac.jp
© 2003 Pharmaceutical Society of Japan

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Vol. 51, No. 7
Chart 1
which is the key stage in our synthetic plan, began with the pathways for the formation of 16 from 14a including the iso-
chemoselective reduction of 13a with lithium tri-tert-bu- merization are shown in Chart 2. The results indicated that
toxyaluminohydride in tetrahydrofuran (THF) to afford a di- cyclization of E–A to the desired compound 15a was rela-
astereomeric mixture of the alcohol (14a). When 14a was tively slow because of the steric hindrance by the isopropyl
treated with trifluoroacetic acid (TFA) at 0 °C for 1 h, no de- protecting group at the A ring.
sired compound 15a could be detected; instead, compound
Next, we attempted to increase the reactivity of the A ring
16 was formed in 84% yield. Assignment of indeno[1,2- such as the phenol (13c). The substrate (13b) was prepared
b]pyrazine-2-one (16) was made based on the results of in six steps from 4b25,26) using the same procedure as used
1
NMR analysis. The H-NMR spectrum of 16 displayed only for the preparation of 13a in 44% overall yield. Reduction
one singlet at d 6.46 in the aromatic region along with the and dehydration/cyclization sequence of 13b afforded the de-
characteristic AB type methylene proton peaks (d 3.29 and sired compound 15c, but the maximum yield was only 29%.
3.50). Hydrogenation of 16 in the presence of palladium on In order to improve the reactivity of the A ring, the sequence
carbon gave the corresponding debrominated compound 17 of reactions in Chart 3 was studied. The removal of the
in 75% yield. The ortho coupling (Jϭ1.7 Hz) was observed MOM group in 13b gave 13c in 94% yield, hydride reduction
1
in the H-NMR spectrum of 17. The probable mechanistic of 13c followed by cyclization afforded 15c in 86% yield.

July 2003
823
Chart 2
Chart 3
1
The E stereochemical assignment of 15c was based on H-
NMR spectral evidence. The d value observed for the me-
thine proton (d 6.58) at the C-1 position of 15c indicated that
this proton was positioned in the deshielding zone of the aro-
matic ring of the side chain at the C-2 position and the car-
bonyl group of N-COOR. Thus, we were able to obtain the
desired compound 15c in high yield.
compound 18 in only 28% yield along with the debenzylated
product (19) in 12% yield. We thought this by-product (19)
might have been produced by the evolution of hydrogen bro-
mide. In contrast, the debromination of 15c with hydrogen
over 20% Pd/C in the presence of triethylamine gave 18 in
93% yield. Protection of the phenol in 18 with a benzyl
group gave 19a in 95% yield, and hydride reduction of 19a
with aluminium hydride afforded 20a in 90% yield (Chart 4).
Reduction of the double bond of 20a through the action of
hydrogen (4 atm) on 20% Pd/C in ethanol at 80 °C for 40 h
occurred from the less hindered a-face to afford 21c in 47%
yield accompanied with 22c in 28% yield. The other route of
this transformation was carried out using the MOM protect-
ing group. Methoxymethylation of 18 gave 19b in 85% yield,
Having established the construction of the B ring, we then
studied the conversion of 15c into the secondary amine (21).
Numerous efforts to remove the N-blocking group of 15c
under acidic and basic conditions were unsuccessful, causing
decomposition of the starting material. Debromination of 15c
also proved to be troublesome. The debromination of 15c
with hydrogen over 20% Pd/C in ethanol afforded the desired

824
Vol. 51, No. 7
Chart 4
and then hydride reduction of 19b under the same conditions ABCDE ring model of ecteinascidins. The application of this
afforded 20b in 97% yield. While the conversion 20b into the strategy to the total synthesis of natural products is under in-
amine 21b was carried out under the same conditions, the tensive investigation in our laboratories.
debenzylation was relatively slow to generate 22b in 76%
Experimental
yield, and the yield of the desired product (21b) is only 3%.
This problem was solved by using 20% Pd(OH)2 on carbon
as a catalyst to give 21b in 66% yield.
All melting points were determined with a Yanagimoto micromelting
point apparatus and are uncorrected. IR spectra were obtained with a Hitachi
260-10 IR Fourier-transform spectrometer. H-NMR spectra were recorded
1
The final stage of the investigation involved the construc-
tion of the pentacyclic framework using our modified
Pictet–Spengler reaction.27) Reaction of 21c with a large ex-
cess of paraformaldehyde in the presence of K2CO3 in
ethanol at room temperature for 72 h gave the O,N-acetal
(23c), which was subsequently treated with TFA at room
temperature for 24 h to provide the pentacyclic compound
24c in 15% yield. A large amount of 21c was recovered be-
cause 21c was relatively highly polar and its solubility in or-
ganic solvents was low. In contrast, 21b was converted into
24c via 23b in 70% yield. The stereochemistry of 24c was
readily identified on the basis of the chemical shifts of H-14b
(d 2.42) and H-14a (d 2.67) along with their coupling be-
tween H-14b and H-14a (Jϭ12.0 Hz), as noted previously
for related systems.28)
at 270 MHz on a JEOL JNM-EX 270 spectrometer, at 300 MHz on a JEOL
JNM-AL300 spectrometer, and a 500 MHz on at JEOL JNM-LA-500 spec-
trometer. Peak multiplicities are denoted by s (singlet), br s (broad singlet), d
(doublet), t (triplet), q (quartet), sept (septet), m (multiplet) or by a combina-
tion of these e.g. dd (double doublet), with coupling constants (J) given in
Hz. 13C-NMR spectra were recorded at 67.5 MHz [multiplicity determined
from off-resonance decoupled or distortionless enhancement by polarization
transfer (DEPT) spectra]. NMR spectra were measured in CDCl3, and chem-
ical shifts were recorded in dH values relative to (CH3)4Si as the internal
standard. Mass spectra were recorded on a JMS-DX 302 and JMS-700 in-
struments with a direct inlet system operating at 70 eV. Elemental analyses
were conducted on Perkin-Elmer Model 240B and YANACO MT-6 CHN
CORDER elemental analyzers. All reactions were conducted under argon at-
mosphere. Dry solvents and reagents were obtained using standard proce-
dures. Removal of the solvent was done with a rotary evaporator and, finally,
under high vacuum. Column chromatography was performed with E. Merck
silica gel (70—230 mesh).
1-Acetyl-3-(2-bromo-5-isopropoxy-4-methoxy-3-methylphenylmethyl)-
In summary, we succeeded in the preparation of the 2,5-piperazinedione (5a) A solution of 4a18) (1.701 g, 4.0 mmol) in

July 2003
825
methanol (80 ml) was hydrogenated over 5% Rh/C (800 mg) at 1 atm for 1 h. 4.22. Found: C, 57.30; H, 4.25.
The catalyst was removed by filtration and washed with methanol (500 ml).
Condensation of Acetate (6a) and Aldehyde (8) A solution of potas-
The combined filtrates were evaporated in vacuo to give a solid, the recrys- sium tert-butoxide (112.5 mg, 1.0 mmol) in tert-butyl alcohol (2 ml) was
tallization of which from acetone/hexane gave 5a (1.708 g, 100%) as color- added to a stirred solution of 6a (467.3 mg, 1.0 mmol) and 8 (334.4 mg,
1
less prisms, mp 90—92 °C. H-NMR d: 1.34, 1.36 (each 3H, d, Jϭ6.1 Hz, 1.0 mmol) in DMF (4 ml) at 0 °C over 20 min. After stirring for 4 h at room
CH(CH3)2), 2.36 (3H, s, ArCH3), 2.61 (3H, s, COCH3), 3.04 (1H, dd, temperature, the reaction mixture was poured into brine (100 ml) and ex-
Jϭ14.0, 9.4 Hz, 3-CH), 3.57 (1H, dd, Jϭ14.0, 4.4 Hz, 3-CH), 3.80 (3H, s,
OCH3), 4.23, 4.35 (each 1H, d, Jϭ18.0 Hz, 6-H), 4.45 (1H, ddd, Jϭ9.4, 4.4,
tracted with ethyl acetate (100 mlϫ3). The combined extracts were washed
with water (100 ml), dried, and concentrated in vacuo to give a solid. Chro-
2.2 Hz, 3-H), 4.50 (1H, sept, Jϭ6.1 Hz, OCH), 5.92 (1H, br s, NH), 6.66 matography on a silica gel (100 g) column with hexane–ethyl acetate (5 : 2)
(1H, s, ArH). IR (KBr) cmϪ1: 3250, 1730, 1720, 1710. MS m/z (%): 428 as the eluent gave 9a (579.8 mg, 78.0%) and 10a (46.9 mg, 6.3%).
(Mϩϩ2, 9), 426 (Mϩ, 9), 274 (11), 273 (79), 271 (83), 232 (11), 231 (98),
(Z)-1-Acetyl-6-(2-bromo-5-isopropoxy-4-methoxy-3-methylphenyl-
230 (11), 229 (100), 43 (27). Anal. Calcd for C18H23BrN2O5: C, 50.60; H, methyl)-3-[3-methyl-2-(4-methylbenzenesulfoxy)-4,5-methylene-
5.43; N, 6.56. Found: C, 50.40; H, 5.47; N, 6.37. dioxyphenylidene]piperazine-2,5-dione (9a): mp 171.5—173 °C (from ethyl
1
1,4-Diacetyl-3-(2-bromo-5-isopropoxy-4-methoxy-3-methylphenyl- acetate/ether). H-NMR d: 1.28, 1.29 (each 3H, d, Jϭ6.1 Hz, CH(CH3)2),
methyl)-2,5-piperazinedione (6a) A solution of 5a (1.708 g, 4.0 mmol) 2.17, 2.23, 2.39 (each 3H, s, ArCH3), 2.60 (3H, s, COCH3), 3.28 (1H, dd,
and DMAP (97.6 mg, 0.8 mmol) in pyridine (24 ml) was cooled with ice
Jϭ14.1, 4.2 Hz, 6-CH), 3.50 (1H, dd, Jϭ14.1, 5.7 Hz, 6-CH), 3.55 (3H, s,
water, and acetic anhydride (4.8 ml, 50.5 mmol) was added dropwise over OCH3), 4.40 (1H, sept, Jϭ6.1 Hz, OCH), 5.40 (1H, dd, Jϭ5.7, 4.2 Hz, 6-H),
10 min. The reaction mixture was stirred at room temperature for 1 h. The 6.06, 6.07 (each 1H, d, Jϭ1.3 Hz, OCHO), 6.42 (1H, s, CϭCH), 6.42, 6.54
solvent was removed in vacuo, and then the residue was taken up in water (each 1H, s, ArH), 7.28 (2H, d, Jϭ8.3 Hz, ArHϫ2), 7.49 (1H, br s, NH),
(160 ml) and extracted with ethyl acetate (160 mlϫ3). The combined ex- 7.49 (2H, d, Jϭ8.3 Hz, ArHϫ2). 13C-NMR d: 10.7 (q), 17.0 (q), 21.7 (q),
tracts were washed with brine (100 ml) and concentrated in vacuo to give a 22.0 (q), 22.1 (q), 27.1 (q), 38.4 (t), 57.0 (d), 60.2 (q), 71.5 (d), 102.3 (t),
solid, the recrystallization of which from ethyl acetate/ether gave 6a 104.9 (d), 115.0 (d), 116.6 (s), 116.7 (d), 119.7 (s), 125.0 (s), 128.5 (dϫ2),
(1.439 g, 76.6%) as colorless needles, mp 139.5—140 °C. 1H-NMR d: 1.31, 129.6 (s), 129.9 (dϫ2), 132.9 (s), 133.3 (s), 141.5 (s), 145.8 (s), 148.1 (s),
1.34 (each 3H, d, Jϭ6.1 Hz, CH(CH3)2), 2.32 (3H, s, ArCH3), 2.55 (6H, s, 148.9 (s), 149.8 (s), 159.2 (s), 165.9 (s), 172.0 (s). IR (KBr) cmϪ1: 3180,
2ϫCOCH3), 3.29 (1H, dd, Jϭ14.1, 5.5 Hz, 3-CH), 3.33 (1H, d, Jϭ18.7 Hz, 2975, 1700, 1675, 1625. MS m/z (%): 744 (Mϩϩ2, 12), 742 (Mϩ, 11), 589
6-H), 3.53 (1H, dd, Jϭ14.1, 6.8 Hz, 3-CH), 3.78 (3H, s, OCH3), 4.44 (1H, (15), 587 (12), 547 (16), 545 (15), 505 (20), 503 (21), 273 (56), 271 (55),
sept, Jϭ6.1 Hz, OCH), 4.83 (1H, d, Jϭ18.7 Hz, 6-H), 5.47 (1H, dd, Jϭ6.8, 231 (67), 229 (70), 219 (36), 218 (21), 217 (23), 192 (31), 191 (30), 190
5.5 Hz, 3-H), 6.63 (1H, s, ArH). IR (KBr) cmϪ1: 1730, 1725, 1700. MS m/z
(%): 470 (Mϩϩ2, 14), 468 (Mϩ, 15), 274 (11), 273 (52), 271 (56), 232 (10),
(40), 172 (15), 155 (14), 139 (30), 123 (22), 92 (19), 91 (68), 77 (15), 65
(24), 43 (100). Anal. Calcd for C34H35BrN2O10S: C, 54.92; H, 4.74; N, 3.77.
231 (97), 230 (10), 229 (100), 43 (61). Anal. Calcd for C20H25BrN2O6: C, Found: C, 54.64; H, 4.71; N, 3.77.
51.18; H, 5.37; N, 5.97. Found: C, 51.16; H, 5.32; N, 5.75.
(E)-1-Acetyl-6-(2-bromo-5-isopropoxy-4-methoxy-3-methylphenyl-
1,4-Diacetyl-3-(2-bromo-4-methoxy-5-methoxymethoxy-3-methyl- methyl)-3-[3-methyl-2-(4-methylbenzenesulfoxy)-4,5-methylene-
phenylmethyl)-2,5-piperazinedione (6b)
A solution of 4b (4.26 g, dioxyphenylidene]piperazine-2,5-dione (10a): mp 204.5—206 °C (from
10.0 mmol) in 2-propanol (75 ml) was hydrogenated over 5% Rh/C (750 mg) ethyl acetate–ether). 1H-NMR d: 1.28, 1.31 (each 3H, d, Jϭ6.2 Hz,
at 1 atm for 19 h. The catalyst was removed by filtration and washed with CH(CH3)2), 1.98, 2.31, 2.41 (each 3H, s, ArCH3), 2.54 (3H, s, COCH3), 3.20
methanol (500 ml). The combined filtrates were evaporated in vacuo to give (1H, dd, Jϭ14.1, 4.4 Hz, 6-CH), 3.53 (3H, s, OCH3), 3.65 (1H, dd, Jϭ14.1,
5b as a colorless amorphous powder that was used in the subsequent step 5.3 Hz, 6-CH), 4.42 (1H, sept, Jϭ6.2 Hz, OCH), 5.43 (1H, dd, Jϭ5.3,
1
without further purification. H-NMR d: 2.38 (3H, s, ArCH3), 2.62 (3H, s, 4.4 Hz, 6-H), 5.76 (1H, s, CϭCH), 6.00, 6.02 (each 1H, d, Jϭ1.3 Hz,
COCH3), 3.11 (1H, dd, Jϭ14.1, 8.8 Hz, 3-CH), 3.49 (3H, s, OCH3), 3.58 OCHO), 6.24, 6.63 (each 1H, s, ArH), 7.30 (2H, d, Jϭ8.4 Hz, ArHϫ2), 7.34
(1H, dd, Jϭ14.1, 4.6 Hz, 3-CH), 3.81 (3H, s, OCH3), 4.12, 4.32 (each 1H, d,
Jϭ18.0 Hz, 6-H), 4.44 (1H, ddd, Jϭ8.8, 4.6, 2.2 Hz, 3-H), 5.16, 5.20 (each
1H, d, Jϭ6.9 Hz, OCHO), 5.95 (1H, br s, NH), 6.91 (1H, s, ArH). IR
(CHCl3) cmϪ1: 3420, 1730, 1700. MS m/z (%): 430 (Mϩϩ2, 5), 428 (Mϩ,
(1H, br s, NH), 7.74 (2H, d, Jϭ8.4 Hz, ArHϫ2). IR (KBr) cmϪ1: 3200,
2930. 1690, 1680, 1650. MS m/z (%): 744 (Mϩϩ2, 6), 742 (Mϩ, 6), 590
(16), 586 (16), 547 (11), 546 (20), 545 (12), 544 (18), 278 (14), 275 (21),
273 (25), 271 (33), 257 (21), 246 (35), 231 (35), 229 (36), 220 (14), 219
5), 275 (76), 273 (77), 45 (100), 43 (17). High-resolution MS Calcd for (345), 218 (17), 217 (56), 193 (19), 192 (20), 191 (25), 190 (37), 172 (25),
C17H2179BrN2O6: 428.0583. Found: 428.0580.
156 (13), 155 (17), 151 (21), 139 (39), 123 (38), 108 (16), 107 (17), 92 (25),
A solution of 5b (4.29 g, 10.0 mmol) and DMAP (244.0 mg, 2.0 mmol) in 91 (90), 89 (12), 79 (19), 77 (24), 65 (35), 63 (14), 45 (31), 43 (100). Anal.
pyridine (60 ml) was cooled with ice water, and acetic anhydride (12.0 ml, Calcd for C34H35BrN2O10S: C, 54.92; H, 4.74; N, 3.77. Found: C, 54.96; H,
127.2 mmol) was added dropwise over 10 min. The reaction mixture was 4.75; N, 3.67.
stirred at room temperature for 1 h. The solvent was removed in vacuo, and
Condensation of Acetate (6b) and Aldehyde (8) A solution of potas-
then the residue was taken up in water (400 ml) and extracted with ethyl ac- sium tert-butoxide (225.0 mg, 2.0 mmol) in tert-butyl alcohol (4 ml) was
etate (400 mlϫ3). The combined extracts were washed with brine (300 ml), added to a stirred solution of 6b (942.6 mg, 2.0 mmol) and 8 (668.7 mg,
and concentrated in vacuo to give a solid, the recrystallization of which from 2.0 mmol) in DMF (8 ml) at 0 °C for 20 min. After stirring for 2 h at room
ethyl acetate/ether gave 6b (4.106 g, 87.4%) as colorless needles, mp 118—
temperature, the reaction mixture was poured into brine (200 ml) and ex-
119.5 °C. 1H-NMR d: 2.36 (3H, s, ArCH3), 2.56, 2.58 (each 3H, s, COCH3), tracted with ethyl acetate (200 mlϫ3). The combined extracts were washed
3.03 (1H, d, Jϭ18.9 Hz, 6-H), 3.35 (1H, dd, Jϭ14.1, 4.8 Hz, 3-CH), 3.44 with water (200 ml), dried, and concentrated in vacuo to give a solid. Chro-
(3H, s, OCH3), 3.57 (1H, dd, Jϭ14.1, 6.2 Hz, 3-CH), 3.79 (3H, s, OCH3), matography on a silica gel (100 g) column with hexane–ethyl acetate (2 : 1)
4.73 (1H, d, Jϭ18.9 Hz, 6-H), 5.07, 5.19 (each 1H, d, Jϭ6.8 Hz, OCHO), as the eluent gave 9b (1.086 g, 72.9%) and 10b (80.2 mg, 5.4%).
5.49 (1H, dd, Jϭ6.2, 4.8 Hz, 3-H), 6.83 (1H, s, ArH). IR (KBr) cmϪ1: 1715,
(Z)-1-Acetyl-6-(2-bromo-4-methoxy-5-methoxymethoxy-3-methyl-
1700, 1670. MS m/z (%): 472 (Mϩϩ2, 8), 470 (Mϩ, 8), 275 (64), 273 (66), phenylmethyl)-3-[3-methyl-2-(4-methylbenzenesulfoxy)-4,5-methylene-
45 (100), 43 (44). Anal. Calcd for C19H23BrN2O7: C, 48.42; H, 4.92; N, 5.94.
Found: C, 48.20; H, 4.85; N, 5.76.
3-Methyl-2-(4-methylbenzenesulfoxy)-4,5-methylenedioxybenzalde-
dioxyphenylidene]piperazine-2,5-dione (9b): mp 187—188.5 °C (from ethyl
acetate). 1H-NMR d: 2.17, 2.23, 2.38 (each 3H, s, ArCH3), 2.62 (3H, s,
COCH3), 3.36 (1H, dd, Jϭ14.3, 5.7 Hz, 6-CH), 3.45 (1H, dd, Jϭ14.3,
hyde (8) p-Toluenesulfonyl chloride (2.00 g, 10.5 mmol) was added to a 4.0 Hz, 6-CH), 3.46 (3H, s, CH2OCH3), 3.56 (3H, s, ArOCH3), 5.06, 5.09
stirred solution of 71) (1.26 g, 7.0 mmol) and triethylamine (1.46 ml, (each 1H, d, Jϭ6.7 Hz, OCHOCH3), 5.40 (1H, dd, Jϭ5.7, 4.0 Hz, 6-H),
10.5 mmol) in dichloromethane (14 ml) at 0 °C for 10 min, and the mixture 6.06, 6.08 (each 1H, d, Jϭ1.3 Hz, OCHO), 6.39 (1H, s, CϭCH), 6.42, 6.73
was stirred at the room temperature for 2 h. The reaction mixture was diluted (each 1H, s, ArH), 7.26 (2H, d, Jϭ8.3 Hz, ArHϫ2), 7.29 (1H, br s, NH),
with brine (40 ml) and extracted with dichloromethane (80 mlϫ3). The com- 7.70 (2H, d, Jϭ8.3 Hz, ArHϫ2). IR (KBr) cmϪ1: 3230, 1720, 1705, 1640.
bined extracts were washed with water (50 ml), dried, and concentrated in MS m/z (%): 746 (Mϩϩ2, 1), 744 (Mϩ, 1), 204 (10), 190 (10), 139 (22), 92
vacuo to give a solid, the recrystallization of which from ethyl acetate/ (26), 91 (42), 65 (20), 45 (100), 43 (22), 39 (11). Anal. Calcd for
1
hexane gave 8 (2.135 g, 91.2%) as colorless needles, mp 127—128 °C. H- C33H33BrN2O11S·1/2H2O: C, 52.52; H, 4.54; N, 3.71. Found: C, 52.63; H,
NMR d: 2.13 (3H, s, 3-CH3), 2.49 (3H, s, Ar-CH3), 6.09 (2H, s, OCH2O), 4.41; N, 3.69.
7.15 (1H, s, 6-H), 7.39, 7.77 (each 2H, d, Jϭ8.3 Hz, ArHϫ4), 9.52 (1H, s,
(E)-1-Acetyl-6-(2-bromo-4-methoxy-5-methoxymethoxy-3-methyl-
CHO). IR (KBr) cmϪ1: 1680. MS m/z (%): 334 (Mϩ, 38), 180 (12), 179 phenylmethyl)-3-[3-methyl-2-(4-methylbenzenesulfoxy)-4,5-methylene-
(100), 155 (11), 121 (12), 91 (17). Anal. Calcd for C16H14O6S: C, 57.48; H, dioxyphenylidene]piperazine-2,5-dione (10b): mp 191—193 °C (from ethyl

826
Vol. 51, No. 7
acetate/ether). 1H-NMR d: 2.01, 2.31, 2.39 (each 3H, s, ArCH3), 2.55 (3H, s,
13C-NMR d: 10.5 (q), 16.8 (q), 21.3 (q), 21.6 (q), 21.7 (q), 22.0 (q), 22.1 (q),
COCH3), 3.21 (1H, dd, Jϭ14.1, 4.0 Hz, 6-CH), 3.48 (3H, s, CH2OCH3), 39.4 (t), 50.1 (t), 59.1 (d), 60.1 (q), 71.3 (d), 71.6 (d), 102.3 (t), 115.2 (d),
3.55 (3H, s, ArOCH3), 3.68 (1H, dd, Jϭ14.1, 5.1 Hz, 6-CH), 4.97, 5.18
116.0 (s), 116.1 (d), 118.7 (s), 120.6 (d), 121.1 (s), 127.6 (d), 127.9 (dϫ2),
(each 1H, d, Jϭ6.7 Hz, OCHOCH3), 5.42 (1H, dd, Jϭ5.1, 4.0 Hz, 6-H), 5.72 128.4 (dϫ4), 129.8 (s), 130.0 (s), 130.2 (dϫ2), 132.7 (s), 133.1 (s), 136.2
(1H, s, CϭCH), 5.99, 6.02 (each 1H, d, Jϭ1.3 Hz, OCHO), 6.14, 6.85 (each (s), 142.1 (s), 145.6 (s), 145.8 (s), 148.4 (s), 148.5 (s), 149.8 (s), 150.7 (s),
1H, s, ArH), 7.30 (2H, d, Jϭ8.3 Hz, ArHϫ2), 7.64 (1H, br s, NH), 7.74 (2H,
161.5 (s), 166.6 (s). IR (KBr) cmϪ1: 3000, 1785, 1740, 1710. FAB-MS
d, Jϭ8.3 Hz, ArHϫ2). IR (KBr) cmϪ1: 3230, 3100, 2950, 1710, 1690, 1680.
(Magic Bullet) m/z: 877 (Mϩϩ1). Anal. Calcd for C43H45BrN2O11S: C,
MS m/z (%): 746 (Mϩϩ2, 6), 744 (Mϩ, 6), 517 (15), 515 (15), 275 (22), 273 58.84; H, 5.17; N, 3.19. Found: C, 58.84; H, 5.29; N, 3.07.
(21), 257 (17), 231 (22), 230 (16), 229 (21), 219 (28), 217 (16), 204 (30),
(Z)-1-Isopropyloxycarbonyl-6-(2-bromo-4-methoxy-5-methoxy-
192 (12), 191 (24), 190 (36), 92 (13), 91 (30), 65 (12), 45 (100), 43 (31). methoxy-3-methylphenylmethyl)-3-[3-methyl-2-(4-methylbenzenesul-
Anal. Calcd for C33H33BrN2O11S: C, 53.16; H, 4.46; N, 3.76. Found: C, foxy)-4,5-methylenedioxyphenylidene]-4-phenylmethylpiperazine-2,5-
53.13; H, 4.59; N, 3.60.
dione (13b) This compound was prepared by the three-step reaction as de-
(Z)-1-Acetyl-6-(2-bromo-5-isopropoxy-4-methoxy-3-methylphenyl- scribed above from 9b (4.464 g, 6.0 mmol) in 69.2% overall yield. Analyti-
methyl)-3-[3-methyl-2-(4-methylbenzenesulfoxy)-4,5-methylene- cal samples including all of the intermediates were obtained by recrystalliza-
dioxyphenylidene]-4-phenylmethylpiperazine-2,5-dione (11a) Sodium tion from ethyl acetate/ether.
hydride (60% oil dispersion, washed with dry hexane three times, 2.9 mg,
0.12 mmol) was added to a stirred solution of 9a (74.4 mg, 0.10 mmol) in ArCH3), 2.51 (3H, s, COCH3), 3.29 (1H, dd, Jϭ14.1, 6.2 Hz, 6-CH), 3.43
DMF (1 ml) under ice cooling, and stirring was continued at 0 °C for 30 min. (1H, dd, Jϭ14.1, 6.1 Hz, 6-CH), 3.46 (3H, s, CH2OCH3), 3.54 (3H, s,
11b: mp 159.5—161 °C. 1H-NMR d: 2.11, 2.22, 2.44 (each 3H, s,
Benzyl chloride (13.8 ml, 0.12 mmol) was added over 20 min, and the reac-
tion mixture was stirred at room temperature for 24 h. The reaction mixture OCH2OCH3), 5.48 (1H, dd, Jϭ6.2, 6.1 Hz, 6-H), 6.08 (2H, s, OCH2O), 6.71,
was concentrated in vacuo, and then the residue was diluted with water 6.77 (each 1H, s, ArH), 7.00 (1H, s, CϭCH), 7.10—7.19 (2H, m, ArHϫ2),
ArOCH3), 4.23, 5.12 (each 1H, d, Jϭ14.5 Hz, NCHAr), 5.13 (2H, s,
(10 ml) and extracted with ethyl acetate (10 mlϫ3). The combined extracts 7.22—7.24 (3H, m, ArHϫ3), 7.27, 7.81 (each 2H, d, Jϭ8.4 Hz, ArHϫ2). IR
were washed with brine (10 ml), dried, and concentrated in vacuo to furnish (KBr) cmϪ1: 1735, 1725, 1710. FAB-MS (Magic Bullet) m/z: 835 (Mϩϩ1).
a solid, the recrystallization of which from ethyl acetate/ether gave 11a
Anal. Calcd for C40H39BrN2O11S·1/2H2O: C, 56.87; H, 4.77; N, 3.32.
(73.2 mg, 87.9%) as pale yellow prisms, mp 150.5—152 °C. 1H-NMR d: Found: C, 57.16; H, 5.10; N, 3.09.
1.32, 1.33 (each 3H, d, Jϭ6.1 Hz, CH(CH3)2), 2.13, 2.24, 2.44 (each 3H, s,
ArCH3), 2.47 (3H, s, COCH3), 3.28 (1H, dd, Jϭ14.0, 6.6 Hz, 6-CH), 3.33 3.09 (1H, dd, Jϭ14.1, 9.7 Hz, 6-CH), 3.48 (3H, s, CH2OCH3), 3.55 (1H, dd,
12b: mp 161—163 °C. 1H-NMR d: 2.10, 2.36, 2.41 (each 3H, s, ArCH3),
(1H, dd, Jϭ14.0, 6.6 Hz, 6-CH), 3.60 (3H, s, OCH3), 4.24 (1H, d,
Jϭ14.6 Hz, NCHAr), 4.46 (1H, sept, Jϭ6.1 Hz, OCH), 5.10 (1H, d,
Jϭ14.1, 4.2 Hz, 6-CH), 3.75 (3H, s, ArOCH3), 4.41 (1H, ddd, Jϭ9.7, 4.2,
2.0 Hz, 6-H), 4.56, 4.71 (each 1H, d, Jϭ14.9 Hz, NCHAr), 5.16, 5.19 (each
Jϭ14.6 Hz, NCHAr), 5.49 (1H, t, Jϭ6.6 Hz, 6-H), 6.08, 6.09 (each 1H, d, 1H, d, Jϭ6.6 Hz, OCHOCH3), 5.62 (1H, d, Jϭ2.0 Hz, NH), 6.05 (2H, s,
Jϭ1.2 Hz, OCHO), 6.60, 6.76 (each 1H, s, ArH), 7.10 (1H, s, CϭCH), OCH2O), 6.60 (1H, s, CϭCH), 6.93 (2H, s, ArHϫ2), 7.06—7.09 (2H, m,
7.10—7.14 (2H, m, ArHϫ2), 7.19—7.22 (3H, m, ArHϫ3), 7.29, 7.83 (each ArHϫ2), 7.17—7.24 (3H, m, ArHϫ3), 7.28, 7.81 (each 2H, d, Jϭ8.4 Hz,
2H, d, Jϭ8.4 Hz, ArHϫ2). IR (KBr) cmϪ1: 1760, 1725, 1710. FAB-MS ArHϫ2). 13C-NMR d: 10.5 (q), 16.9 (q), 21.6 (q), 39.2 (t), 49.5 (t), 55.0 (d),
(Magic Bullet) m/z: 833 (Mϩϩ1). Anal. Calcd for C41H41BrN2O10S: C,
56.3 (q), 60.5 (q), 95.1 (t), 102.2 (t), 105.8 (d), 115.5 (s), 116.9 (d), 117.7
59.06; H, 4.96; N, 3.36. Found: C, 58.86; H, 5.06; N, 3.14.
(d), 120.0 (s), 121.7 (s), 127.3 (d), 127.6 (dϫ2), 128.3 (dϫ2), 128.4 (dϫ2),
(Z)-6-(2-Bromo-5-isopropoxy-4-methoxy-3-methylphenylmethyl)-3-[3- 129.9 (dϫ2), 130.4 (s), 130.8 (s), 133.1 (s), 133.8 (s), 136.6 (s), 141.7 (s),
methyl-2-(4-methylbenzenesulfoxy)-4,5-methylenedioxyphenylidene]-4-
phenylmethylpiperazine-2,5-dione (12a) A suspended solution of 11a
145.4 (s), 145.5 (s), 147.9 (s), 148.1 (s), 149.3 (s), 164.0 (s), 167.0 (s). IR
(KBr) cmϪ1: 3200, 1700, 1625. FAB-MS (Magic Bullet) m/z: 793 (Mϩϩ1).
(367.0 mg, 0.44 mmol) and anhydrous K2CO3 (138.2 mg, 1.0 mmol) in Anal. Calcd for C38H37BrN2O10S·1/4H2O: C, 57.18; H, 4.74; N, 3.51.
methanol (40 ml) was stirred at room temperature for 2 h. The reaction mix- Found: C, 56.91; H, 4.78; N, 3.42.
ture was diluted with water (100 ml) and extracted with chloroform
13b: mp 125—127 °C. 1H-NMR d: 1.10, 1.23 (each 3H, d, Jϭ6.2 Hz,
(50 mlϫ3). The combined extracts were washed with brine (50 ml), dried, CH(CH3)2), 2.21, 2.29, 2.44 (each 3H, s, ArCH3), 3.27 (1H, dd, Jϭ14.0,
and concentrated in vacuo to give a solid, the recrystallization of which from 8.1 Hz, 6-CH), 3.40 (1H, dd, Jϭ14.0, 5.7 Hz, 6-CH), 3.45 (3H, s,
ethyl acetate/ether gave 12a (230.4 mg, 66.2%) as colorless prisms, mp CH2OCH3), 3.65 (3H, s, ArOCH3), 4.26 (1H, d, Jϭ14.7 Hz, NCHAr), 4.91
172—174 °C. 1H-NMR d: 1.32, 1.36 (each 3H, d, Jϭ6.1 Hz, CH(CH3)2), (1H, sept, Jϭ6.2 Hz, OCH), 5.01 (1H, d, Jϭ14.7 Hz, NCHAr), 5.13, 5.16
2.10, 2.36, 2.43 (each 3H, s, ArCH3), 3.06 (1H, dd, Jϭ14.0, 9.7 Hz, 6-CH), (each 1H, d, Jϭ6.6 Hz, OCHOCH3), 5.20 (1H, dd, Jϭ8.1, 5.7 Hz, 6-H),
3.57 (1H, dd, Jϭ14.0, 4.2 Hz, 6-CH), 3.76 (3H, s, OCH3), 4.42 (1H, ddd,
6.07, 6.08 (each 1H, d, Jϭ1.3 Hz, OCHO), 6.71, 6.79 (each 1H, s, ArH),
Jϭ9.7, 4.2, 2.2 Hz, 6-H), 4.51 (1H, sept, Jϭ6.1 Hz, OCH), 4.58, 4.71 (each 7.13 (1H, s, CϭCH), 7.13—7.25 (5H, m, ArHϫ5), 7.30, 7.88 (each 2H, d,
1H, d, Jϭ14.9 Hz, NCHAr), 5.59 (1H, d, Jϭ2.2 Hz, NH), 6.06 (2H, s,
OCH2O), 6.62, 6.70 (each 1H, s, ArH), 6.96 (1H, s, CϭCH), 7.05—7.08
Jϭ8.2 Hz, ArHϫ2). IR (KBr) cmϪ1: 1730, 1720, 1690. FAB-MS (Magic
Bullet) m/z: 879 (Mϩϩ1). Anal. Calcd for C42H43BrN2O12S: C, 57.34; H,
(2H, m, ArHϫ2), 7.17—7.24 (3H, m, ArHϫ3), 7.30, 7.82 (each 2H, d, 4.93; N, 3.18. Found: C, 57.43; H, 5.25; N, 2.90.
Jϭ8.3 Hz, ArHϫ2). IR (KBr) cmϪ1: 3220, 1700, 1690. FAB-MS (Magic
Bullet) m/z: 791 (Mϩϩ1). Anal. Calcd for C39H39BrN2O9S·1/2H2O: C,
58.50; H, 5.04; N, 3.50. Found: C, 58.48; H, 4.76; N, 3.43.
Attempted Conversion of 13a into 15a A stirred solution of 13a
(43.8 mg, 0.05 mmol) in dry THF (4 ml) was cooled with ice water, and
lithium tri-tert-butoxyaluminohydride (50.9 mg, 0.8 mmol) was added to it
over 5 min. After continued stirring at the same temperature for 1 h, the reac-
(Z)-1-Isopropyloxycarbonyl-6-(2-bromo-5-isopropoxy-4-methoxy-3-
methylphenylmethyl)-3-[3-methyl-2-(4-methylbenzenesulfoxy)-4,5-meth- tion mixture was quenched by the addition of water (0.5 ml) and then filtered
ylenedioxyphenylidene]-4-phenylmethylpiperazine-2,5-dione (13a) through a Celite pad, and the filtrate was concentrated in vacuo. The unsta-
A
solution of 12a (1.583 g, 2.0 mmol), triethylamine (558.0 ml, 4.0 mmol), and ble diastereomeric mixture of alcohols 14a (45.0 mg) obtained was used in
4-DMAP (489.0 mg, 4.0 mmol) in dichloromethane (40 ml) was cooled with the subsequent step without further purification. A solution of 14a in TFA
ice water, after which isopropyl chloroformate (910.0 ml, 8.0 mmol) was (1 ml) was stirred at 0 °C for 1 h. The reaction mixture was diluted with
added dropwise over 10 min, and the mixture was stirred at room tempera-
ture for 2 h. The organic layer was washed with 1 N HCl (20 ml), and then
water (10 ml) and extracted with chloroform (10 mlϫ3). The combined ex-
tracts were washed with 5% NaHCO3 (20 ml), dried, and concentrated in
water (20 ml), dried, and concentrated in vacuo to give a residue (2.336 g). vacuo to give the residue (50 mg). Chromatography on a silica gel (10 g) col-
Chromatography on a silica gel (150 g) column with hexane–ethyl acetate umn with hexane–ethyl acetate (4 : 1) as the eluent afforded 16 (36.0 mg,
(4 : 1) as the eluent gave a solid, the recrystallization of which from ethyl ac- 83.5%) as a colorless amorphous powder.
etate/ether afforded 13a (1.736 g, 98.9%) as colorless prisms, mp 186—
188 °C. 1H-NMR d: 1.07, 1.21 (each 3H, d, Jϭ6.2 Hz, CH(CH3)2), 1.31, phenyl)methyl]-4-methyl-5-(4-methylbenzenesulfoxy)-4-methyl-8-oxo-7-
1.32 (each 3H, d, Jϭ5.9 Hz, CH(CH3)2), 2.21, 2.29, 2.45 (each 3H, s, phenylmethyl-10H-1,3-dioxolo-[6,7]indeno[1,2-b]pyrazine-10-carboxylic
6,7,8,9-Tetrahydro-9-[(2-bromo-5-isopropoxy-4-methoxy-3-methyl-
ArCH3), 3.19 (1H, dd, Jϭ13.8, 8.8 Hz, 6-CH), 3.41 (1H, dd, Jϭ13.8, 5.3 Hz, acid 1-methylethyl ester (16): 1H-NMR d (at 55 °C): 1.03 (3H, d, Jϭ5.9 Hz,
6-CH), 3.67 (3H, s, OCH3), 4.26 (1H, d, Jϭ14.7 Hz, NCHAr), 4.46 (1H, OCH(CH3)2), 1.16 (3H, d, Jϭ6.3 Hz, OCH(CH3)2), 1.21 (3H, d, Jϭ5.9 Hz,
sept, Jϭ5.9 Hz, OCH), 4.88 (1H, sept, Jϭ6.2 Hz, OCH), 5.02 (1H, d, OCH(CH3)2), 1.25 (3H, d, Jϭ6.3 Hz, OCH(CH3)2), 1.88, 2.30, 2.45 (each
Jϭ14.7 Hz, NCHAr), 5.24 (1H, dd, Jϭ8.8, 5.3 Hz, 6-H), 6.07, 6.08 (each 3H, s, ArCH3), 2.83 (1H, dd, Jϭ18.8, 10.3 Hz, 9-CHAr), 3.27 (1H, dd,
1H, d, Jϭ1.3 Hz, OCHO), 6.56, 6.71 (each 1H, s, ArH), 7.13—7.23 (5H, m, Jϭ18.8, 5.3 Hz, 9-CHAr), 3.29, 3.50 (each 1H, d, Jϭ22.4 Hz, 6-H), 3.72
ArHϫ5), 7.19 (1H, s, CϭCH), 7.32, 7.89 (each 2H, d, Jϭ8.5 Hz, ArHϫ2). (3H, s, OCH3), 4.23 (1H, sept, Jϭ5.9 Hz, OCH), 4.83 (1H, sept, Jϭ6.3 Hz,

July 2003
827
colorless prisms, mp 123.5—125.5 °C (from ethyl acetate/ether).
OCH), 4.83 (2H, s, NCH2Ar), 5.42 (1H, dd, Jϭ10.3, 5.3 Hz, 9-H), 5.89 (2H,
s, OCH2O), 6.46 (1H, s, ArH), 7.23—7.31 (5H, m, ArHϫ5), 7.35, 7.82
(each 2H, d, Jϭ8.5 Hz, ArHϫ2). 13C-NMR d (at 55 °C): 9.7 (q), 16.8 (q),
21.5 (q), 21.6 (q), 21.8 (q), 21.9 (q), 22.4 (q), 32.0 (t), 37.1 (t), 46.9 (t), 58.0
(d), 60.2 (q), 70.2 (d), 71.6 (d), 101.6 (t), 109.9 (s), 117.5 (s), 118.0 (s),
119.2 (d), 120.2 (s), 124.6 (s), 127.3 (dϫ2), 127.8 (d), 128.3 (dϫ2), 128.9
(dϫ2), 129.9 (dϫ2), 130.9 (s), 131.7 (s), 132.5 (s), 134.1 (s), 136.6 (s),
137.2 (s), 138.4 (s), 145.4 (s), 147.2 (s), 148.7 (s), 149.5 (s), 153.7 (s), 166.3
(s). IR (CHCl3) cmϪ1: 1720, 1710, 1680. MS m/z (%): 862 (Mϩϩ2, 12), 860
(Mϩ, 10), 706 (13), 503 (15), 349 (22), 339 (10), 193 (47), 192 (20), 151
(49), 139 (18), 123 (17), 92 (30), 91 (100), 77 (10), 65 (21), 43 (49), 41 (16),
39 (19). High-resolution MS Calcd for C43H4579BrN2O10S: 860.1978. Found:
860.1980.
From 13c A stirred solution of 13c (83.6 mg, 0.1 mmol) in dry THF
(8 ml) was cooled with ice water, and lithium tri-tert-butoxyalumino hydride
(101.7 mg, 0.4 mmol) was added to it over 5 min. After continued stirring at
the same temperature for 1 h, the reaction mixture was quenched by the ad-
dition of water (0.5 ml) and then filtered through a Celite pad, and the filtrate
was concentrated in vacuo. The unstable diastereomeric mixture of alcohols
14c (101.0 mg) obtained was used in the subsequent steps without further
purification. A solution of 14b in TFA (2 ml) was stirred at 0 °C for 1 h. The
reaction mixture was diluted with water (10 ml) and extracted with chloro-
form (20 mlϫ3). The combined extracts were washed with 5% NaHCO3
(20 ml), dried, and concentrated in vacuo to give a solid, the recrystallization
of which from ethyl acetate/ether gave 15c (70.2 mg, 85.6%) as colorless
prisms, mp 123.5—125.5 °C (from ethyl acetate/ether). 1H-NMR d (at
55 °C): 1.29 (6H, d, Jϭ6.3 Hz, CH(CH3)2), 2.14, 2.33, 2.43 (each 3H, s,
ArCH3), 3.05 (1H, dd, Jϭ17.2, 5.6 Hz, 6-Ha), 3.30 (1H, dd, Jϭ17.2, 1.3 Hz,
6-Hb), 3.65 (3H, s, OCH3), 4.11 (1H, d, Jϭ15.8 Hz, NCHAr), 5.04 (1H,
sept, Jϭ6.3 Hz, OCH), 5.05 (1H, d, Jϭ15.8 Hz, NCHAr), 5.21 (1H, dd,
Jϭ5.6, 1.3 Hz, 5-H), 5.53 (1H, br s, OH), 5.88 (1H, s, 2a-H), 5.96, 5.99
(each 1H, d, Jϭ1.3 Hz, OCHO), 6.58 (1H, br s, 1-H), 6.95 (2H, d, Jϭ7.6 Hz,
ArHϫ2), 7.08—7.17 (3H, m, ArHϫ3), 7.13 (1H, s, ArH), 7.23, 7.72 (each
2H, d, Jϭ8.3 Hz, ArHϫ2). 13C-NMR d (at 55 °C): 10.8 (q), 16.7 (q), 21.6
(q), 22.1 (q), 22.1 (q), 34.1 (t, C-6), 45.1 (d, C-1), 46.2 (t, NCH2Ar), 53.5 (d,
C-5), 61.1 (q, OCH3), 70.2 (d, OCH), 101.7 (t, OCH2O), 101.7 (d), 107.1
(d), 114.7 (s), 117.9 (s), 120.6 (s), 124.2 (s), 126.5 (dϫ2), 126.9 (d), 127.8
(dϫ2), 128.4 (dϫ2), 128.9 (s), 129.7 (dϫ2), 131.3 (s), 134.8 (s), 136.3 (s),
136.8 (s), 142.1 (s), 144.8 (s), 145.2 (s), 145.3 (s), 145.5 (s), 145.9 (s), 153.0
(s, NCOO), 168.0 (s, C-4). IR (KBr) cmϪ1: 3530, 1695, 1680, 1645, 1635.
MS m/z (%): 820 (Mϩϩ2, 4), 818 (Mϩ, 4), 666 (10), 664 (18), 663 (21), 579
(25), 577 (25), 282 (11), 281 (16), 270 (21), 268 (23), 191 (41), 189 (13),
139 (14), 92 (27), 91 (100), 65 (22), 43 (29), 41 (10), 39 (12). FAB-MS
(Magic Bullet) m/z 819 (Mϩϩ1). High-resolution MS Calcd for
C40H3979BrN2O10S: 818.1514. Found: 818.1509. Anal. Calcd for
C40H39BrN2O10S·1/2H2O: C, 57.97; H, 4.87; N, 3.38. Found: C, 58.21; H,
5.26; N, 2.95.
6,7,8,9-Tetrahydro-9-[(5-isopropoxy-4-methoxy-3-methylphenyl)-
methyl]-4-methyl-5-(4-methylbenzenesulfoxy)-4-methyl-8-oxo-7-phenyl-
methyl-10H-1,3-dioxolo[6,7]indeno[1,2-b]pyrazine-10-carboxylic Acid 1-
Methylethyl Ester (17) A solution of 16 (49.0 mg, 0.057 mmol) in ethanol
(10 ml) was hydrogenated over 20% Pd/C (49.0 mg) at 1 atm for 1 h. The cat-
alyst was removed by filtration and washed with ethanol (20 ml). The com-
bined filtrates were evaporated to give a residue. Chromatography on a silica
gel column with hexane–ethyl acetate (6 : 1) as the eluent gave 17 (33.4 mg,
1
75.1%) as a colorless amorphous powder. H-NMR d (at 55 °C): 1.08 (3H,
d, Jϭ5.9 Hz, OCH(CH3)2), 1.17 (3H, d, Jϭ6.3 Hz, OCH(CH3)2), 1.27 (3H, d,
Jϭ5.9 Hz, OCH(CH3)2), 1.28 (3H, d, Jϭ6.3 Hz, OCH(CH3)2), 1.88, 2.03,
2.44 (each 3H, s, ArCH3), 2.76 (1H, dd, Jϭ13.6, 8.6 Hz, 9-CHAr), 2.89 (1H,
dd, Jϭ13.6, 4.3 Hz, 9-CHAr), 3.05, 3.42 (each 1H, d, Jϭ22.0 Hz, 6-H), 3.68
(3H, s, OCH3), 4.35 (1H, sept, Jϭ5.9 Hz, OCH), 4.73, 4.83 (each 1H, d,
Jϭ15.2 Hz, NCHAr), 4.85 (1H, sept, Jϭ5.9 Hz, OCH), 5.16 (1H, dd,
Jϭ10.3, 5.3 Hz, 9-H), 5.94, 5.95 (each 1H, br s, OCHO), 6.45, 6.51 (each
1H, d, Jϭ1.7 Hz, ArH), 7.21—7.32 (5H, m, ArHϫ5), 7.33, 7.80 (each 2H, d,
Jϭ8.5 Hz, ArHϫ2). 13C-NMR d (at 55 °C): 9.6 (q), 15.6 (q), 21.5 (q), 21.6
(q), 21.9 (q), 22.2 (q), 22.3 (q), 31.8 (t), 36.7 (t), 46.8 (t), 59.7 (q), 60.0 (d),
70.3 (d), 71.1 (d), 101.5 (t), 109.9 (s), 115.6 (d), 117.7 (s), 120.5 (s), 124.4
(d), 124.7 (s), 124.5 (s), 127.3 (dϫ2), 127.8 (d), 128.3 (dϫ2), 128.9 (dϫ2),
129.9 (dϫ2), 131.2 (s), 131.3 (s), 131.7 (s), 134.0 (s), 136.5 (s), 137.2 (s),
138.5 (s), 145.4 (s), 147.1 (s), 147.8 (s), 150.4 (s), 166.9 (s). MS m/z (%):
782 (Mϩ, 21), 628 (13), 503 (15), 349 (22), 339 (25), 193 (47), 192 (20),
151 (49), 139 (18), 123 (19), 106 (16), 91 (100), 77 (12), 65 (25), 43 (40).
High-resolution MS Calcd for C43H46N2O10S: 782.2813. Found: 782.2811.
(Z)-1-Isopropyloxycarbonyl-6-(2-bromo-4-methoxy-5-hydroxy-3-
methylphenylmethyl)-3-[3-methyl-2-(4-methylbenzenesulfoxy)-4,5-meth-
Hydrogenolysis of 15c. Method A A solution of 15c (70.2 mg,
0.086 mmol) in ethanol (10 ml) was hydrogenated over 20% Pd/C (70.2 mg)
at 1 atm for 2 h. The catalyst was removed by filtration and washed with
ethanol (100 ml). The combined filtrates were concentrated in vacuo to give
a residue (71.9 mg). Chromatography on a silica gel (6 g) column using
hexane–ethyl acetate (5 : 1 to 3 : 1) as the eluent gave 18 (18.0 mg, 28.4%)
and 19 (6.6 mg, 11.8%).
ylenedioxyphenylidene]-4-phenylmethylpiperazine-2,5-dione (13c)
A
(E)-1,2,3,4,5,6-Hexahydro-10-hydroxy-9-methoxy-8-methyl-2-{[7-
methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-yl]methylene}-4-
oxo-3-phenylmethyl-1,5-imino-3-benzazocine-11-carboxylic Acid 1-
Methylethyl Ester (18): Colorless amorphous powder. 1H-NMR d (at
55 °C): 1.28 (6H, d, Jϭ6.3 Hz, CH(CH3)2), 2.19, 2.33, 2.41 (each 3H, s,
ArCH3), 3.07 (1H, d, Jϭ14.9 Hz, 6-Hb), 3.15 (1H, dd, Jϭ14.9, 5.0 Hz, 6-
Ha), 3.66 (3H, s, OCH3), 4.05, 4.75 (each 1H, br d, NCHAr), 5.03 (1H, sept,
Jϭ6.3 Hz, OCH), 5.12 (1H, br d, 5-H), 5.47 (1H, br s, OH), 5.77 (1H, s, 2a-
H), 5.97, 6.00 (each 1H, d, Jϭ1.3 Hz, OCHO), 6.50 (2H, s, 1-H, 7-H),
6.83—6.86 (2H, m, ArHϫ2), 7.10—7.12 (4H, m, ArHϫ4), 7.15, 7.69 (each
2H, d, Jϭ8.3 Hz, ArHϫ2). 13C-NMR d (at 55 °C): 10.9 (q), 15.7 (q), 21.6
(q), 22.1 (q), 22.1 (q), 31.9 (t, C-6), 45.7 (t, NCH2Ar), 46.0 (d, C-1), 53.7 (d,
C-5), 60.6 (q, OCH3), 70.0 (d, OCH), 101.7 (t, OCH2O), 107.7 (d), 114.7 (s),
118.5 (s), 122.4 (d), 124.0 (s), 126.5 (s), 126.8 (dϫ2), 126.9 (d), 127.9
(dϫ2), 128.4 (dϫ2), 128.7 (s), 129.7 (dϫ2), 129.8 (d), 130.3 (s), 135.0 (s),
136.6 (s), 142.3 (s), 144.2 (s), 145.1 (s), 145.3 (s), 145.9 (s), 146.1 (s), 153.2
(s, NCOO), 168.4 (s, C-4). IR (CHCl3) cmϪ1: 3550, 1700, 1690. MS m/z
(%): 740 (Mϩ, 18), 587 (12), 586 (43), 585 (80), 584 (36), 500 (21), 499
(65), 409 (12), 282 (12), 281 (17), 234 (24), 191 (30), 190 (100), 175 (24),
91 (91), 65 (41), 43 (45), 41 (12). High-resolution MS Calcd for
C40H40N2O10S: 740.2405. Found: 740.2404.
solution of 13b (176.0 mg, 0.2 mmol) in TFA (4 ml) was stirred at room tem-
perature for 1 h. The reaction mixture was diluted with water (10 ml) and ex-
tracted with chloroform (10 mlϫ3). The combined extracts were washed
with 5% NaHCO3 (20 ml), dried, and concentrated in vacuo to give a solid,
recrystallization of which from ethyl acetate/ether gave 13c (156.9 mg,
93.9%) as colorless needles, mp 188—190 °C. 1H-NMR d: 1.11, 1.24 (each
3H, d, Jϭ6.2 Hz, CH(CH3)2), 2.24, 2.30, 2.44 (each 3H, s, ArCH3), 3.18
(1H, dd, Jϭ14.0, 8.4 Hz, 6-CH), 3.44 (1H, dd, Jϭ14.0, 5.3 Hz, 6-CH), 3.61
(3H, s, ArOCH3), 4.25 (1H, d, Jϭ14.7 Hz, NCHAr), 4.92 (1H, sept,
Jϭ6.2 Hz, OCH), 5.01 (1H, d, Jϭ14.7 Hz, NCHAr), 5.24 (1H, dd, Jϭ8.4,
5.3 Hz, 6-H), 5.46 (1H, br s, OH), 6.07, 6.08 (each 1H, d, Jϭ1.3 Hz,
OCHO), 6.66, 6.70 (each 1H, s, ArH), 7.11 (1H, s, CϭCH), 7.13—7.23
(5H, m, ArHϫ5), 7.31, 7.88 (each 2H, d, Jϭ8.2 Hz, ArHϫ2). IR
(KBr) cmϪ1: 3275, 1770, 1690, 1675. FAB-MS (Magic Bullet) m/z: 835
(Mϩϩ1). Anal. Calcd for C40H39BrN2O11S: C, 57.49; H, 4.70; N, 3.35.
Found: C, 57.35; H, 4.77; N, 3.23.
(E)-7-Bromo-1,2,3,4,5,6-hexahydro-10-hydroxy-9-methoxy-8-methyl-
2-{[7-methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-yl]methyl-
ene}-4-oxo-3-phenylmethyl-1,5-imino-3-benzazocine-11-carboxylic Acid
1-Methylethyl Ester (15c) from 13b A stirred solution of 13b (44.0 mg,
0.05 mmol) in dry THF (4 ml) was cooled with ice water, and lithium tri-
tert-butoxyaluminohydride (50.9 mg, 0.2 mmol) was added to it over 5 min.
After continued stirring at the same temperature for 1 h, the reaction mixture
was quenched by the addition of water (0.5 ml) and then filtered through a
Celite pad, and the filtrate was concentrated in vacuo. The unstable diastereo-
meric mixture of alcohols 14b (47.0 mg) obtained was used in the subsequent
steps without further purification. A solution of 14b in TFA (1 ml) was
stirred at 0 °C for 1 h. The reaction mixture was diluted with water (10 ml)
and extracted with chloroform (10 mlϫ3). The combined extracts were
washed with 5% NaHCO3 (20 ml), dried, and concentrated in vacuo to give a
residue (50 mg). Chromatography on a silica gel (10 g) column with
hexane–ethyl acetate (4 : 1) as the eluent afforded 15c (11.9 mg, 29.0%) as
(E)-1,2,3,4,5,6-Hexahydro-10-hydroxy-9-methoxy-8-methyl-2-{[7-
methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-yl]methylene}-4-
oxo-1,5-imino-3-benzazocine-11-carboxylic acid 1-methylethyl ester (19):
1
Colorless prisms, mp 225—226.5 °C. H-NMR d (at 55 °C): 1.30 (6H, d,
Jϭ6.3 Hz, CH(CH3)2), 2.27, 2.30, 2.33 (each 3H, s, ArCH3), 3.02 (1H, d,
Jϭ16.5 Hz, 6-Hb), 3.16 (1H, dd, Jϭ16.5, 6.0 Hz, 6-Ha), 3.73 (3H, s,
OCH3), 5.03 (1H, sept, Jϭ6.3 Hz, OCH), 5.03 (1H, br d, 5-H), 5.10 (1H,
br s, OH), 5.57 (1H, s, 2a-H), 6.01, 6.04 (each 1H, s, OCHO), 6.30 (1H, s,
ArH), 6.55 (2H, s, 1-H, 7-H), 6.87, 7.53 (each 2H, d, Jϭ8.3 Hz, ArHϫ2).
13C-NMR d (at 55 °C): 10.8 (q), 15.8 (q), 21.5 (q), 22.1 (q), 22.1 (q), 31.4 (t,
C-6), 44.6 (d, C-1), 52.5 (d, C-5), 60.7 (q, OCH3), 70.4 (d, OCH), 101.7 (t,

828
Vol. 51, No. 7
744.2873.
OCH2O), 105.1 (d), 114.7 (s), 118.2 (s), 122.3 (d), 127.7 (dϫ2), 128.2 (s),
129.4 (dϫ2), 130.6 (s), 134.2 (s), 135.1 (s), 143.0 (s), 144.4 (s), 145.3 (s),
145.4 (s), 145.9 (s), 146.3 (s), 153.2 (s, NCOO), 168.5 (s, C-4). IR (KBr)
cmϪ1: 3510, 1710, 1680, 1660. MS m/z (%): 650 (Mϩ, 19), 497 (12), 496
(50), 495 (100), 494 (49), 410 (21), 409 (77), 277 (16), 235 (18), 234 (22),
192 (14), 191 (38), 190 (88), 175 (24), 158 (10), 91 (15), 43 (18). High-reso-
lution MS Calcd for C33H34N2O10S: 650.1939. Found: 650.1934.
Method B A solution of 15c (818.0 mg, 1.0 mmol) and triethylamine
(0.167 ml, 1.2 mmol) in ethanol (30 ml) was hydrogenated over 20% Pd/C
(818 mg) at 1 atm for 30 min. The catalyst was removed by filtration and
washed with ethanol (400 ml). The combined filtrates were concentrated in
vacuo to give a solid (786.8 mg). Chromatography on a silica gel (25 g) col-
umn using hexane–ethyl acetate (4 : 1) as the eluent gave 18 (690.1 mg,
93.3%) as a colorless amorphous powder, which was identical in all respects
with the authentic sample described above.
(E)-10-Benzyloxy-1,2,3,4,5,6-hexahydro-9-methoxy-8-methyl-2-{[7-
methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-yl]methylene}-
4-oxo-3-phenylmethyl-1,5-imino-3-benzazocine-11-carboxylic Acid 1-
Methylethyl Ester (19a) Sodium hydride (60% oil dispersion, washed
with dry hexane three times, 7.8 mg, 0.325 mmol) was added to a stirred so-
lution of 18 (199.8 mg, 0.27 mmol) in DMF (5.4 ml) under ice-cooling, and
stirring was continued at 0 °C for 30 min. Benzyl chloride (38.5 ml,
0.325 mmol) was added over 10 min, and the reaction mixture was stirred at
room temperature for 21 h. The reaction mixture was concentrated in vacuo,
and then the residue was diluted with water (50 ml) and extracted with chlo-
roform (50 mlϫ3). The combined extracts were washed with brine (50 ml),
dried, and concentrated in vacuo to give a residue, the recrystallization of
which from ethyl acetate/ether afforded 19a (212.3 mg, 94.7%) as colorless
prisms, mp 200—202 °C. 1H-NMR d (at 55 °C): 1.29 (6H, d, Jϭ5.8 Hz,
CH(CH3)2), 2.01, 2.20, 2.43 (each 3H, s, ArCH3), 3.06 (2H, br s, 6-H2), 3.51
(3H, s, OCH3), 4.15 (1H, d, Jϭ12.5 Hz, OCHAr), 4.41 (1H, d, Jϭ15.8 Hz,
NCHAr), 4.59 (1H, d, Jϭ12.5 Hz, OCHAr), 4.74 (1H, d, Jϭ15.8 Hz,
NCHAr), 5.01 (1H, sept, Jϭ5.8 Hz, OCH), 5.07 (1H, br d, 5-H), 5.73, 5.80
(each 1H, d, Jϭ1.3 Hz, OCHO), 5.94 (1H, s, 2a-H), 6.52 (1H, br s, 1-H),
6.69, 6.74 (each 1H, s, ArH), 6.74 (2H, m, ArHϫ2), 6.95—7.13 (8H, m,
ArHϫ8), 7.19, 7.52 (each 2H, d, Jϭ7.9 Hz, ArHϫ2). 13C-NMR d (at 55 °C):
10.7 (q), 15.6 (q), 21.6 (q), 22.2 (q), 22.2 (q), 32.3 (t, C-6), 45.0 (t,
NCH2Ar), 46.6 (d, C-1), 53.5 (d, C-5), 60.3 (q, OCH3), 69.9 (d, OCH), 74.0
(t, OCH2Ar), 101.5 (t, OCH2O), 107.6 (d), 115.2 (s), 123.1 (s), 125.1 (s),
126.0 (d), 126.6 (d), 126.8 (d), 126.9 (dϫ2), 127.1 (dϫ4), 128.1 (dϫ2),
128.2 (dϫ4), 129.7 (dϫ2), 132.4 (s), 134.8 (s), 136.5 (s), 136.6 (s), 137.7
(s), 142.0 (s), 145.1 (s), 145.3 (s), 145.9 (s), 149.3 (s), 149.5 (s), 153.0 (s,
NCOO), 168.2 (s, C-4). IR (KBr) cmϪ1: 1705, 1690, 1660. MS m/z (%): 830
(Mϩ, 18), 677 (15), 676 (52), 675 (93), 590 (13), 589 (35), 585 (11), 584
(12), 499 (13), 281 (16), 280 (13), 191 (13), 190 (54), 189 (12), 92 (15), 91
(100), 65 (12), 43 (22). Anal. Calcd for C47H46N2O10S: C, 67.94; H, 5.58; N,
3.37. Found: C, 67.63; H, 5.72; N, 3.11.
Hydrogenolysis of 20a A solution of 20a (76.7 mg, 0.103 mmol) in
ethanol (10 ml) was shaken at 80 °C for 40 h under 4 atm of hydrogen in the
presence of 20% Pd/C (40 mg). The catalyst was removed by filtration and
washed with ethanol (100 ml). The combined filtrates were concentrated in
vacuo to give a residue (77.3 mg). Chromatography on a silica gel (6 g) col-
umn using dichloromethane–methanol (75 : 1 to 60 : 1) as the eluent gave
21c (27.4 mg, 47.0%) and 22c (18.6 mg, 27.5%).
1a,2a,5a-1,2,3,4,5,6-Hexahydro-10-hydroxy-9-methoxy-8,11-dimethyl-
2-{[7-methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-yl]methyl-
ene}-1,5-imino-3-benzazocine (21c): mp 198—200 °C (colorless needles
from acetone/ether). 1H-NMR d: 1.90 (3H, s, ArCH3), 2.16 (1H, dd, Jϭ15.3,
11.3 Hz, 2a-Hb), 2.31 (3H, s, 8-CH3), 2.35 (3H, s, NCH3), 2.46 (3H, s,
SO2C6H4CH3), 2.54 (1H, d, Jϭ16.8 Hz, 6-Hb), 2.86 (1H, d, Jϭ12.8 Hz, 4-
Hb), 3.03 (1H, br s, 5-H), 3.05 (1H, dd, Jϭ16.8, 7.6 Hz, 6-Ha), 3.11 (1H,
dd, Jϭ15.3, 2.7 Hz, 2a-Ha), 3.22 (1H, dd, Jϭ12.8, 2.0 Hz, 4-Ha), 3.48 (1H,
br d, Jϭ9.2 Hz, 2-H), 3.80 (3H, s, OCH3), 4.08 (1H, br s, 1-H), 5.90, 5.91
(each 1H, d, Jϭ1.2 Hz, OCHO), 6.55, 6.63 (each 1H, s, ArH), 7.33, 7.75
(each 2H, d, Jϭ7.9 Hz, ArHϫ2). 13C-NMR d: 10.6 (q), 15.8 (q), 21.7 (q),
26.4 (t, C-6), 34.0 (t, C-2a), 41.6 (q, NCH3), 52.3 (d, C-5), 53.4 (t, C-4), 57.3
(d, C-1), 60.0 (d, C-2), 60.8 (q, OCH3), 101.4 (t, OCH2O), 107.0 (d), 114.5
(s), 116.3 (s), 121.2 (d), 127.1 (s), 128.1 (dϫ2), 128.9 (s), 129.8 (dϫ2),
131.5 (s), 134.1 (s), 141.2 (s), 143.2 (s), 145.0 (s), 145.2 (s), 145.3 (s), 146.9
(s). IR (KBr) cmϪ1: 3300, 1605, 1585. MS m/z (%): 566 (Mϩ, 3), 411 (8),
248 (12), 247 (70), 219 (14), 207 (88), 205 (25), 204 (100), 190 (12), 189
(12), 91 (12). Anal. Calcd for C30H34N2O7S·1/4H2O: C, 62.59; H, 6.13; N,
4.87. Found: C, 62.90; H, 6.13; N, 4.42.
1a,2a,5a-1,2,3,4,5,6-Hexahydro-10-hydroxy-9-methoxy-8,11-dimethyl-
2-{[7-methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-yl]methyl-
ene}-3-phenylmethyl-1,5-imino-3-benzazocine (22c): Colorless amorphous
1
powder. H-NMR d: 1.96 (3H, s, ArCH3), 2.25 (3H, s, NCH3), 2.31 (1H, d,
Jϭ16.5 Hz, 6-Hb), 2.35 (3H, s, 8-CH3), 2.38 (3H, s, SO2C6H4CH3), 2.50
(1H, dd, Jϭ11.2, 2.0 Hz, 4-Hb), 2.52 (1H, dd, Jϭ15.8, 6.6 Hz, 2a-Hb), 2.54
(1H, d, Jϭ13.2 Hz, NCHAr), 2.58 (1H, br d, Jϭ11.2 Hz, 4-Ha), 2.87 (1H,
dd, Jϭ16.5, 7.3 Hz, 6-Ha), 2.89 (1H, br s, 5-H), 3.13 (1H, m, 2-H), 3.24
(1H, dd, Jϭ16.5, 3.3 Hz, 2a-Ha), 3.63 (1H, d, Jϭ13.2 Hz, NCHAr), 3.78
(3H, s, OCH3), 4.21 (1H, br s, 1-H), 5.94, 5.95 (each 1H, s, OCHO), 6.52,
6.90 (each 1H, s, ArH), 6.90—6.92 (2H, m, ArHϫ2), 7.11—7.13 (3H, m,
ArHϫ3), 7.17, 7.62 (each 2H, d, Jϭ8.3 Hz, ArHϫ2). 13C-NMR d: 10.7 (q),
15.8 (q), 21.6 (q), 26.9 (t, C-6), 31.1 (t, C-2a), 41.0 (q, NCH3), 52.9 (d, C-5),
57.0 (t, NCH2Ar), 58.2 (d, C-1), 59.8 (t, C-4), 60.6 (q, OCH3), 66.3 (d, C-2),
101.4 (t, OCH2O), 106.0 (d), 114.5 (s), 118.0 (s), 120.7(d), 126.3 (d), 127.8
(dϫ2), 128.1 (dϫ2), 128.2 (s), 128.6 (dϫ2), 129.5 (s), 129.7 (dϫ2), 132.9
(s), 133.9 (s), 140.0 (s), 140.3 (s), 142.7 (s), 144.6 (s), 144.9 (s), 145.2 (s),
146.5 (s). IR (CHCl3) cmϪ1: 3550, 2950, 1480. MS m/z (%): 656 (Mϩ, 0.1),
338 (25), 337 (100), 206 (20), 205 (20), 204 (44), 189 (11), 91 (21). High-
resolution MS Calcd for C37H40N2O7S: 656.2556. Found: 656.2560.
(E)-1,2,3,4,5,6-Hexahydro-9-methoxy-10-methoxymethoxy-8-methyl-
2-{[7-methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-yl]methyl-
ene}-4-oxo-3-phemylmethyl-1,5-imino-3-benzazocine-11-carboxylic Acid
1-Methylethyl Ester (19b) Sodium hydride (60% oil dispersion, washed
with dry hexane three times, 18.0 mg, 0.75 mmol) was added to a stirred so-
lution of 18 (370.0 mg, 0.5 mmol) in THF (10 ml) under ice cooling, and
stirring was continued at 0 °C for 30 min. Bromomethyl methyl ether
(61.2 ml, 0.75 mmol) was added over 10 min, and the reaction mixture was
stirred at room temperature for 2 h. The reaction mixture was diluted with
water (100 ml) and then extracted with chloroform (100 mlϫ3). The com-
bined extracts were washed with brine (100 ml), dried, and concentrated in
(E)-10-Benzyloxy-1,2,3,4,5,6-hexahydro-9-methoxy-8,11-dimethyl-2-
{[7-methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-yl]methyl-
ene}-3-phenylmethyl-1,5-imino-3-benzazocine (20a) A stirred solution
of the lactam 19a (41.5 mg, 0.05 mmol) in dry THF (2 ml) was cooled with
ice water. A THF solution of aluminium hydride (0.5 mol, 0.6 ml, 0.3 mmol)
was added dropwise over 10 min, and stirring was continued at 0 °C for 3 h.
After quenching by the addition of methanol (0.5 ml), the reaction mixture
was concentrated in vacuo to give a residue. Chromatography on a silica gel
(5 g) column with benzene–ethyl acetate (5 : 1) as the eluent gave 20a
(33.5 mg, 90.1%) as a colorless amorphous powder. 1H-NMR d: 2.00 (3H, s,
NCH3), 2.01 (3H, s, SO2C6H4CH3), 2.29, 2.31 (each 3H, s, ArCH3), 2.39
(1H, d, Jϭ16.5 Hz, 6-Hb), 2.63, 2.73 (each 1H, d, Jϭ9.9 Hz, 4-H), 2.92—
3.00 (2H, m, 6-Ha, 5-H), 3.04, 3.17 (each 1H, d, Jϭ13.9 Hz, NCHAr), 3.68
(3H, s, OCH3), 4.57 (1H, d, Jϭ11.9 Hz, OCHAr), 4.81 (1H, s, 1-H), 4.94
(1H, d, Jϭ11.9 Hz, OCHAr), 5.20 (1H, s, 2a-H), 5.89, 5.94 (each 1H, d,
Jϭ1.3 Hz, OCHO), 6.70, 6.75 (each 1H, s, ArH), 6.88—6.95 (6H, m,
ArHϫ6), 7.17—7.22 (6H, m, ArHϫ8), 7.69 (2H, d, Jϭ8.3 Hz, ArHϫ2).
13C-NMR d: 11.1 (q), 15.8 (q), 21.3 (q), 27.2 (t, C-6), 40.1 (q, NCH3), 53.1
(d, C-5), 53.5 (d, C-1), 54.4 (t, NCH2Ar), 56.9 (t, C-4), 59.8 (q, OCH3), 73.4
(t, OCH2Ar), 101.3 (t, OCH2O), 101.3 (d), 108.1 (d), 115.1 (s), 124.2 (d),
126.8 (d), 127.4 (d), 127.6 (s), 127.9 (dϫ2), 128.1 (dϫ2), 128.2 (dϫ4),
128.4 (dϫ2), 128.6 (dϫ2), 129.3 (dϫ2), 130.0 (s), 130.3 (s), 135.0 (s),
137.3 (s), 138.7 (s), 142.5 (s), 144.5 (s), 144.7 (s), 145.0 (s), 148.2 (s), 148.5
(s). IR (CHCl3) cmϪ1: 1635, 1620, 1590. MS m/z (%): 744 (Mϩ, 1), 590
(20), 589 (53), 588 (32), 497 (12), 296 (14), 295 (19), 294 (50), 204 (25),
203 (26), 156 (23), 139 (12), 107 (11), 92 (45), 91 (100), 65 (35), 63 (19),
39 (14). High-resolution MS Calcd for C44H44N2O7S: 744.2869. Found:
vacuo to give
a residue, the recrystallization of which from ethyl
acetate/ether afforded 19b (334.1 mg, 85.2%) as colorless prisms, mp
1
199.5—201 °C. H-NMR d (at 55 °C): 1.19, 1.36 (each 3H, br, CH(CH3)2),
2.20 (6H, s, ArCH3ϫ2), 2.42 (3H, s, ArCH3), 3.09 (3H, s, CH2OCH3), 3.12
(2H, br s, 6-H2), 3.51 (3H, s, OCH3), 4.16 (1H, d, Jϭ5.6 Hz, OCHOCH3),
4.58 (2H, br, NCH2Ar), 4.91 (1H, d, Jϭ5.6 Hz, OCHOCH3), 5.00 (1H, sept,
Jϭ6.3 Hz, OCH), 5.04 (1H, br d, 5-H), 5.82 (1H, s, 2a-H), 5.98 (2H, s,
OCH2O), 6.36 (1H, br s, 1-H), 6.68 (1H, s, ArH), 6.74 (2H, m, ArHϫ2),
6.83 (1H, s, ArH), 7.02—7.12 (3H, m, ArHϫ3), 7.17, 7.69 (each 2H, d,
Jϭ8.2 Hz, ArHϫ2). 13C-NMR d (at 55 °C): 10.8 (q), 15.6 (q), 21.6 (q), 22.1
(q), 22.1 (q), 32.0 (t, C-6), 45.0 (t, NCH2Ar), 46.7 (d, C-1), 53.3 (d, C-5),
57.3 (q, OCH3), 59.8 (q, OCH3), 70.0 (d, OCH), 97.3 (t, OCH2OCH3), 101.7
(t, OCH2O), 106.6 (d), 107.9 (d), 115.2 (s), 124.0 (s), 125.0 (s), 126.1 (d),
126.5 (dϫ2), 126.7 (d), 128.1 (dϫ2), 128.3 (dϫ2), 128.5 (s), 128.7 (s),
129.5 (dϫ2), 132.3 (s), 134.8 (s), 136.4 (s), 137.2 (s), 141.9 (s), 145.1 (s),
146.0 (s), 146.3 (s), 148.9 (s), 153.0 (s, NCOO), 168.2 (s, C-4). IR (KBr)

July 2003
829
cmϪ1: 1700, 1680, 1650. MS m/z (%): 784 (Mϩ, 24), 631 (15), 630 (55), 629
(100), 544 (23), 543 (66), 499 (12), 234 (30), 190 (34), 91 (23). Anal. Calcd
for C42H44N2O11S: C, 64.30 H, 5.65; N, 3.57. Found: C, 64.12; H, 5.69; N,
3.33.
3.09 (1H, m, 2-H), 3.44 (3H, s, OCH2OCH3), 3.63 (1H, d, Jϭ13.2 Hz,
NCHAr), 3.78 (3H, s, OCH3), 4.23 (1H, br s, 1-H), 4.95, 5.05 (each 1H, d,
Jϭ6.0 Hz, OCHOCH3), 5.93, 5.96 (each 1H, d, Jϭ1.3 Hz, OCHO), 6.75,
6.88 (each 1H, s, ArH), 6.88—6.92 (2H, m, ArHϫ2), 7.12—7.15 (3H, m,
ArHϫ3), 7.17, 7.58 (each 2H, d, Jϭ8.3 Hz, ArHϫ2) (* the signal over-
lapped with the methyl signal). 13C-NMR d: 10.7 (q), 15.9 (q), 21.6 (q), 27.0
(t, C-6), 30.9 (t, C-2a), 41.0 (q, NCH3), 52.9 (d, C-5), 56.9 (t, NCH2Ar), 57.5
(q, OCH3), 58.1 (d, C-1), 60.0 (q, OCH3), 60.1 (t, C-4), 66.5 (d, C-2), 99.0 (t,
OCH2OCH3), 101.4 (t, OCH2O), 106.0 (d), 114.5 (s), 124.8 (d), 124.8 (s),
125.0 (s), 126.4 (d), 127.9 (dϫ2), 128.2 (dϫ2), 128.7 (dϫ2), 129.5 (s),
129.7 (dϫ2), 130.1 (s), 132.2 (s), 133.9 (s), 140.1 (s), 140.2 (s), 144.7 (s),
145.2 (s), 148.0 (s), 148.5 (s). IR (KBr) cmϪ1: 2960, 1740, 1610.
MS m/z (%): 700 (Mϩ, 0.1), 382 (25), 381 (100). Anal. Calcd for
C39H44N2O8S·3/2H2O: C, 65.16; H, 6.45; N, 3.90. Found: C, 64.85; H, 6.30;
N, 3.48.
(E)-1,2,3,4,5,6-Hexahydro-9-methoxy-10-methoxymethoxy-8,11-di-
methyl-2-{[7-methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-
yl]methylene}-3-phenylmethyl-1,5-imino-3-benzazocine (20b) A stirred
solution of the lactam 19b (297.9 mg, 0.38 mmol) in dry THF (15 ml) was
cooled with ice water. A THF solution of aluminium hydride (0.5 mol,
6.1 ml, 3.05 mmol) was added dropwise over 10 min, and stirring was con-
tinued at 0 °C for 3 h. After quenching by the addition of methanol (2.0 ml),
the reaction mixture was concentrated in vacuo to give a residue. Chro-
matography on a silica gel (12 g) column with benzene–ethyl acetate (5 : 1)
as the eluent gave 20b (257.4 mg, 97.1%) as a colorless amorphous powder.
1H-NMR d: 1.99 (3H, s, SO2C6H4CH3), 2.18, 2.22 (each 3H, s, ArCH3),
2.35 (3H, s, NCH3), 2.39 (1H, d, Jϭ16.2 Hz, 6-Hb), 2.59, 2.78 (each 1H, d,
Jϭ10.6 Hz, 4-H), 2.92—3.02 (2H, m, 6-Ha, NCH), 3.02 (1H, s, 5-H), 3.26
(each 1H, d, Jϭ13.5 Hz, NCHAr), 3.52 (3H, s, OCH3), 4.34, 4.37 (each 1H,
d, Jϭ5.7 Hz, OCHOCH3), 4.88 (1H, s, 1-H), 5.10 (1H, s, 2a-H), 5.92 (2H, s,
OCH2O), 6.63, 6.71 (each 1H, s, ArH), 6.81—6.87 (2H, m, ArHϫ2), 6.89
(2H, d, Jϭ8.6 Hz, ArHϫ2), 7.13—7.18 (3H, m, ArHϫ3), 7.60 (2H, d,
Jϭ8.6 Hz, ArHϫ2). 13C-NMR d: 11.1 (q), 15.8 (q), 21.3 (q), 27.7 (t, C-6),
40.6 (q, NCH3), 53.0 (d, C-5), 53.5 (d, C-1), 54.4 (t, NCH2Ar), 56.3 (t, C-4),
57.3 (q, OCH3), 59.7 (q, OCH3), 97.9 (t, OCH2OCH3), 101.0 (d), 101.4 (t,
OCH2O), 108.6 (d), 115.0 (s), 124.5 (d), 125.8 (s), 126.8 (d), 127.6 (s),
128.0 (dϫ2), 128.1 (dϫ2), 128.2 (dϫ2), 128.7 (s), 129.3 (dϫ2), 129.8 (s),
129.9 (s), 134.9 (s), 138.6 (s), 142.4 (s), 144.7 (s), 145.1 (s), 145.5 (s), 146.9
(s), 147.9 (s). IR (CHCl3) cmϪ1: 1630, 1610, 1480. MS m/z (%): 698 (Mϩ,
1), 545 (11), 544 (39), 543 (55), 542 (72), 481 (10), 453 (17), 451 (11), 424
(13), 295 (17), 251 (15), 250 (100), 249 (23), 248 (95), 204 (34), 203 (11),
91 (13). High-resolution MS Calcd for C39H42N2O8S: 698.2662. Found:
698.2662.
(6 ,14a ,15 )-6,7,9,14,14a,15-Hexahydro-1-hydroxy-2-methoxy-
3,12,16-trimethyl-13-(4-methylbenzenesulfoxy)-10,11-methylenedioxy-
6,15-imino-5H-isoquino[3,2-b][3]benzazocine (24c). From 21c A mix-
ture of 21c (12.7 mg, 0.022 mmol) and anhydrous K2CO3 (60.8 mg,
0.44 mmol) in ethanol (2 ml) was stirred for 10 min at room temperature.
Paraformaldehyde (6.6 mg, 0.22 mmol) was added all at once, and the mix-
ture was stirred for 72 h. The inorganic materials were removed by filtration
and washed with ethanol (100 ml). The combined filtrates were concentrated
in vacuo to give a crude product of the O,N-acetal (23c: 16.6 mg), that
was used in the subsequent step without further purification. The residue
was stirred with TFA (1 ml) at room temperature for 24 h. The mixture
was diluted with water (20 ml) and extracted with chloroform (20 mlϫ3).
The combined extracts were washed with 5% NaHCO3 solution (20 ml),
dried, and concentrated in vacuo to give a residue (10.5 mg), that was
a
a
a
subjected to chromatography on
a silica gel (10 g) column with
dichloromethane–methanol (60 : 1) as the eluent to give 24c (1.9 mg, 14.9%)
as a solid. Further elution with dichloromethane–methanol (20 : 1) gave the
original 21c (4.5 mg, 35.4%) as a solid.
Hydrogenolysis of 20b. Method A A solution of 20b (103.6 mg,
0.148 mmol) in ethanol (15 ml) was shaken at 80 °C for 24 h under 4 atm of
hydrogen in the presence of 20% Pd/C (60 mg). The catalyst was removed
by filtration and washed with ethanol (100 ml). The combined filtrates were
concentrated in vacuo to give a residue (77.3 mg). Chromatography on a sil-
ica gel (6 g) column using dichloromethane–methanol (50 : 1 to 10 : 1) as the
eluent gave 21b (2.9 mg, 3.2%) and 22b (78.6 mg, 75.9%).
From 21b A mixture of 21b (18.7 mg, 0.03 mmol) and anhydrous
K2CO3 (82.9 mg, 0.6 mmol) in ethanol (4 ml) was stirred for 10 min at room
temperature. Paraformaldehyde (9.0 mg, 0.3 mmol) was added all at once,
and the mixture was stirred for 72 h. The inorganic materials were removed
by filtration and washed with ethanol (100 ml). The combined filtrates were
concentrated in vacuo to give a crude product of the O,N-acetal (23b:
36.4 mg) that was used in the subsequent step without further purification.
The residue was stirred with TFA (1 ml) at room temperature for 24 h. The
mixture was diluted with water (20 ml) and extracted with chloroform
(20 mlϫ3). The combined extracts were washed with 5% NaHCO3 solution
(20 ml), dried, and concentrated in vacuo to give a residue (20.4 mg) that
was subjected to chromatography on a silica gel (6 g) column with
dichloromethane–methanol (60 : 1) as the eluent to afford a solid, the recrys-
tallization of which from acetone gave 24c (12.1 mg, 69.8%) as colorless
Method B A solution of 20b (257.4 mg, 0.37 mmol) in ethanol (35 ml)
was shaken at 80 °C for 48 h under 4 atm of hydrogen in the presence of 20%
Pd(OH)2/C (257 mg). The catalyst was removed by filtration and washed
with ethanol (200 ml). The combined filtrates were concentrated in vacuo to
give a residue, the recrystallization of which from ethyl acetate/ether af-
forded 21b (147.3 mg, 65.5%) as colorless needles, mp 74.5—76 °C.
1a,2a,5a-1,2,3,4,5,6-Hexahydro-9-methoxy-10-methoxymethoxy-8,11-
dimethyl-2-{[7-methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-
yl]methylene}-1,5-imino-3-benzazocine (21b): mp 198—200 °C (colorless
needles from acetone/ether). 1H-NMR d: 1.80 (3H, s, ArCH3), 2.15 (1H, dd,
Jϭ14.9, 10.9 Hz, 2a-Hb), 2.28 (3H, s, 8-CH3), 2.30 (3H, s, NCH3), 2.46
(3H, s, SO2C6H4CH3), 2.48 (1H, d, Jϭ17.5 Hz, 6-Hb), 2.85 (1H, dd, Jϭ12.2,
1.7 Hz, 4-Hb), 2.91 (1H, br d, Jϭ7.6 Hz, 5-H), 2.96 (1H, dd, Jϭ17.5, 7.6 Hz,
6-Ha), 3.09 (1H, dd, Jϭ12.2, 2.6 Hz, 4-Ha), 3.20 (1H, dd, Jϭ14.9, 3.3 Hz,
2a-Ha), 3.38 (1H, ddd, Jϭ10.9, 3.3, 2.3 Hz, 2-H), 3.57, 3.78 (3H, s, OCH3),
4.13 (1H, d, Jϭ2.3 Hz, 1-H), 5.12, 5.15 (each 1H, d, Jϭ5.9 Hz, OCHOCH3),
5.90, 5.91 (each 1H, d, Jϭ1.3 Hz, OCHO), 6.64, 6.78 (each 1H, s, ArH),
7.32, 7.71 (each 2H, d, Jϭ7.9 Hz, ArHϫ2). 13C-NMR d: 10.5 (q), 15.8 (q),
21.7 (q), 26.3 (t, C-6), 34.3 (t, C-2a), 41.7 (q, NCH3), 52.1 (d, C-5), 54.1 (t,
C-4), 57.6 (d, C-1), 57.8 (q, OCH3), 60.1 (q, OCH3), 60.8 (d, C-2), 99.0 (t,
OCH2OCH3), 101.4 (t, OCH2O), 107.5 (d), 114.3 (s), 124.3 (s), 125.3 (d),
127.1 (s), 128.1 (dϫ2), 129.8 (dϫ2), 129.8 (s), 130.4 (s), 131.5 (s), 134.1
(s), 141.1 (s), 145.0 (s), 145.0 (s), 148.0 (s), 148.5 (s). IR (KBr) cmϪ1: 2960,
1610. MS m/z (%): 610 (Mϩ, 9), 455 (14), 292 (18), 291 (100), 251 (11),
250 (73), 249 (20), 248 (80), 218 (16), 205 (13), 204 (44). Anal. Calcd for
C32H38N2O8S·1/4H2O: C, 61.13; H, 6.41; N, 4.46. Found: C, 61.20; H, 6.20;
N, 4.16.
1
prisms, mp 221—223 °C. H-NMR d: 1.73 (3H, s, 12-CH3), 2.22 (3H, s, 3-
CH3), 2.33 (3H, s, NCH3), 2.42 (1H, dd, Jϭ17.1, 12.0 Hz, 14-Hb), 2.48 (3H,
s, SO2C6H4CH3), 2.65 (1H, d, Jϭ17.6 Hz, 5-Hb), 2.67 (1H, m, 14a-H), 2.72
(1H, br, 7-Hb), 2.94 (1H, dd, Jϭ17.1, 3.1 Hz, 14-Ha), 3.06 (1H, dd,
Jϭ17.6, 7.8 Hz, 5-Ha), 3.11 (1H, d, Jϭ15.6 Hz, 9-H), 3.16 (1H, br d, 6-H),
3.73 (3H, s, OCH3), 3.88 (1H, d, Jϭ15.6 Hz, 9-H), 4.07 (1H, br s, 15-H),
5.84, 5.89 (each 1H, d, Jϭ1.2 Hz, OCHO), 6.46 (1H, s, 4-H), 7.37, 7.83
(each 2H, d, Jϭ8.1 Hz, ArHϫ2). 13C-NMR d: 10.2 (q, 12-CH3), 15.9 (q, 3-
CH3), 21.8 (q, SO2C6H4CH3), 26.8 (t, C-5), 28.0 (t, C-14), 41.5 (q, NCH3),
52.3 (t, C-9), 52.8 (d, C-6), 56.4 (d, C-15), 60.8 (q, OCH3), 61.1 (d, C-14a),
63.3 (t, C-7), 101.4 (t, OCH2O), 112.2 (s), 113.8 (s), 121.3 (d), 121.8 (s),
122.8 (s), 128.0 (dϫ2), 128.7 (s), 129.6 (dϫ2), 130.9 (s), 134.3 (s), 140.3
(s), 140.6 (s), 142.8 (s), 143.6 (s), 144.8 (s), 146.7 (s). IR (KBr) cmϪ1: 3480,
2940, 1460, 1375, 1185, 1115. MS m/z (%): 578 (Mϩ, 3), 423 (20), 220
(18), 219 (25), 218 (18), 206 (22), 205 (21), 204 (100), 203 (13), 189 (17),
173 (10), 91 (17). Anal. Calcd for C31H34N2O7S·1/2H2O: C, 63.36; H, 6.00;
N, 4.77. Found: C, 63.77; H, 6.04; N, 4.46.
Hydrogenation of 4a over 10% Pd/C Followed by Acetylation A so-
lution of 4a (297.7 mg, 0.7 mmol) in ethanol (12 ml) was hydrogenated over
10% Pd/C (150 mg) at 1 atm for 1 h. The catalyst was removed by filtration
and washed with ethanol (100 ml). The combined filtrates were evaporated
in vacuo to give a solid (256 mg) that was used in the subsequent step with-
out further purification. A solution of the crude product in acetic anhydride
(12 ml) was heated at 100 °C for 3 h. The reaction mixture was poured into
water (30 ml) and extracted with ethyl acetate (30 mlϫ3). The combined ex-
tracts were washed with brine (20 ml), dried, and concentrated in vacuo to
give a solid, the recrystallization of which from benzene gave 27 (212.2 mg,
1a,2a,5a-1,2,3,4,5,6-Hexahydro-9-methoxy-10-methoxymethoxy-8,11-
dimethyl-2-{[7-methyl-6-(4-methylbenzenesulfoxy)-1,3-benzodioxio-5-
yl]methylene}-3-phenylmethyl-1,5-imino-3-benzazocine (22b): mp 72.5—
75 °C (from ethyl acetate/ether). 1H-NMR d: 1.97 (3H, s, ArCH3), 2.25 (3H,
s, NCH3), 2.31 (3H, s, 8-CH3), 2.36 (3H, s, SO2C6H4CH3), 2.36 (2H, br, 6-
Hb, 4-Hb)*, 2.52 (1H, d, Jϭ13.2 Hz, NCHAr), 2.54 (1H, dd, Jϭ16.2,
2.3 Hz, 2a-Hb), 2.57 (1H, d, Jϭ11.5 Hz, 4-Ha), 2.84 (1H, dd, Jϭ16.3,
7.6 Hz, 6-Ha), 2.87 (1H, m, 5-H), 3.08 (1H, dd, Jϭ12.2, 2.6 Hz, 2a-Ha),

830
77.6%) as colorless needles, mp 93—94.5 °C. H-NMR d: 1.29, 1.33 (each
Vol. 51, No. 7
Preparation of 4c A suspended solution of 2526) (245.1 mg, 1.0 mmol)
1
3H, d, Jϭ6.1 Hz, CH(CH3)2), 2.17 (3H, s, ArCH3), 2.55, 2.59 (each 3H, s, and anhydrous K2CO3 (276.4 mg, 2 mmol) in dry DMF (10 ml) was cooled
COCH3), 3.08 (1H, dd, Jϭ14.1, 5.3 Hz, 3-CH), 3.21 (1H, dd, Jϭ14.1, with ice water, and benzyl bromide (238 ml, 2 mmol) was added dropwise
4.2 Hz, 3-CH), 3.36 (1H, d, Jϭ18.9 Hz, 6-H), 3.78 (3H, s, OCH3), 4.41 (1H, over 10 min. Then, it was stirred for 2 h at room temperature. The reaction
sept, Jϭ6.1 Hz, OCH(CH3)2), 4.54 (1H, d, Jϭ18.9 Hz, 6-H), 5.41 (1H, dd, mixture was diluted with water (10 ml) and extracted with ether (10 mlϫ3).
Jϭ5.3, 4.2 Hz, 3-H), 6.42 (each 1H, s, ArH). IR (KBr) cmϪ1: 1722, 1684. The combined extracts were washed with brine (10 ml), dried, concentrated
MS m/z (%): 390 (Mϩ, 15), 151 (100), 43 (12). Anal. Calcd for C20H26N2O6: in vacuo to give a solid (330.0 mg, 98.4%) that was used in the subsequent
C, 61.52; H, 6.71; N, 7.18. Found: C, 61.55; H, 6.90; N, 7.10.
step without further purification.
Hydrogenation of 4c Followed by Acetylation. Using 10% Pd/C
A
5-Benzyloxy-2-bromo-4-methoxy-3-methylbenzaldehyde (26c), mp 82—
solution of 4c (236.7 mg, 0.5 mmol) in ethanol (10 ml) was hydrogenated 83 °C. 1H-NMR d: 2.41 (3H, s, ArCH3), 3.91 (each 3H, s, OCH3), 5.14 (2H,
over 10% Pd/C (100 mg) at 1 atm for 2 h. The catalyst was removed by filtra- s, OCH2Ar), 7.10—7.24 (5H, m, ArHϫ5), 7.46 (1H, s, 6-H), 10.34 (1H, s,
tion and washed with ethanol (500 ml). The combined filtrates were evapo- CHO). IR (KBr) cmϪ1: 1690. MS m/z (%): 336 (Mϩϩ2, 6), 334 (Mϩ, 6), 92
rated in vacuo to give a solid (212 mg) that was used in the subsequent step (12), 91 (100), 65 (11). Anal. Calcd for C16H15BrO3: C, 57.33; H, 4.51.
without further purification. A solution of the crude product in acetic anhy- Found: C, 57.39; H, 4.46.
dride (5 ml) was heated at 100 °C for 2 h. The reaction mixture was poured
A solution of potassium tert-butoxide (112.5 mg, 1.0 mmol) in tert-butyl
into water (20 ml) and extracted with ethyl acetate (20 mlϫ3). The combined alcohol (2 ml) was added to a stirred solution of the crude 26c and 27
extracts were washed with brine (20 ml), dried, and concentrated in vacuo to (198.2 mg, 1.0 mmol) in DMF (2 ml) over 30 min. After stirring for 3 h at
give a solid, the recrystallization of which from ethyl acetate/ether gave 28 room temperature, the reaction mixture was poured into brine (40 ml) and
1
(160.0 mg, 82.0%) as colorless needles, mp 111.5—112.5 °C. H-NMR d: extracted with ethyl acetate (40 mlϫ3). The combined extracts were washed
2.23 (3H, s, ArCH3), 2.30, 2.56, 2.59 (each 3H, s, COCH3), 2.79 (1H, d, with water (40 ml), dried, and concentrated in vacuo to give a solid, the re-
Jϭ19.1 Hz, 6-H), 3.17 (1H, dd, Jϭ14.1, 5.5 Hz, 3-CH), 3.19 (1H, dd, crystallization of which from ethyl acetate/ether gave 4c (394.0 mg, 83.3%)
1
Jϭ14.1, 4.6 Hz, 3-CH), 3.75 (3H, s, OCH3), 4.65 (1H, d, Jϭ19.1 Hz, 6-H), as colorless needles, mp 149.5—151 °C. H-NMR d: 2.39 (3H, s, ArCH3),
5.40 (1H, dd, Jϭ5.5, 4.6 Hz, 3-H), 6.64, 6.73 (each 1H, s, ArH). IR (KBr) 2.67 (3H, s, COCH3), 3.88 (3H, s, ArOCH3), 4.48 (2H, s, 6-H2), 5.10 (2H, s,
cmϪ1: 1770, 1720, 1710, 1700. MS m/z (%): 390 (Mϩ, 10), 348 (28), 193 OCH2Ar), 6.74 (1H, s, ArH), 7.15 (1H, s, 3a-H), 7.32—7.41 (5H, m,
(33), 152 (10), 151 (100), 43 (12). Anal. Calcd for C19H22N2O7·1/4H2O: C, ArHϫ5), 7.60 (1H, br s, NH). IR (KBr) cmϪ1: 3210, 1730, 1700, 1650. MS
57.79; H, 5.74; N, 7.09. Found: C, 57.65; H, 5.63; N, 6.87.
m/z (%): 474 (Mϩϩ2, 3), 472 (Mϩ, 3), 393 (33), 351 (21), 92 (13), 91 (100).
Using PtO2 A solution of 4c (236.7 mg, 0.5 mmol) in ethanol (10 ml) Anal. Calcd for C22H21BrN2O5: C, 55.83; H, 4.47; N, 5.92. Found: C, 55.82;
was hydrogenated over PtO2 (100 mg) at 1 atm for 1 h. The catalyst was re- H, 4.43; N, 5.75.
moved by filtration and washed with ethanol (500 ml). The combined fil-
Attempted Deacetylation of 12b. Method A A mixture of 12b
trates were evaporated in vacuo to give a residue (275 mg) that was used in (416.9 mg, 0.5 mmol) with hydrazine-hydrate (0.5 ml) in DMF (5 ml) was
the subsequent step without further purification. A solution of the crude stirred at room temperature for 20 h. The reaction mixture was diluted with
product in acetic anhydride (5 ml) was heated at 100 °C for 13 h. The reac- water (30 ml) and extracted with ethyl acetate (30 mlϫ3). The combined ex-
tion mixture was poured into water (20 ml) and extracted with ethyl acetate tracts were washed with brine (30 ml), dried, and concentrated in vacuo to
(20 mlϫ3). The combined extracts were washed with brine (20 ml), dried, give a residue (404 mg). Chromatography on a silica gel (25 g) column with
and concentrated in vacuo to give a residue. Chromatography on a silica gel hexane–ethyl acetate (2 : 1) as the eluent gave 30 (75.7 mg, 23.8%) as a col-
1
(25 g) column with hexane–ethyl acetate (3 : 1) as the eluent gave a solid, the orless amorphous powder. H-NMR d: 1.19, 1.29 (each 3H, d, Jϭ6.1 Hz,
recrystallization of which from ethyl acetate/ether gave 28 (45.3 mg, 19.4%) CH(CH3)2), 2.24, 2.32 (each 3H, s, ArCH3), 3.45 (1H, dd, Jϭ13.6, 7.0 Hz, 6-
as colorless needles, mp 136—138 °C. 1H-NMR d: 2.31 (3H, s, ArCH3), CH), 3.54 (1H, dd, Jϭ13.6, 5.0 Hz, 6-CH), 3.74 (3H, s, OCH3), 4.38 (1H,
2.36, 2.55, 2.56 (each 3H, s, COCH3), 3.27 (1H, dd, Jϭ14.0, 5.7 Hz, 3-CH), sept, Jϭ6.1 Hz, OCH), 4.90 (1H, d, Jϭ15.9 Hz, NCHAr), 5.02 (1H, dd,
3.37 (1H, d, Jϭ18.9 Hz, 6-H), 3.58 (1H, dd, Jϭ14.0, 6.8 Hz, 3-CH), 3.75 Jϭ7.0, 5.0 Hz, 6-H), 5.15 (1H, d, Jϭ15.9 Hz, NCHAr), 5.94, 5.95 (each 1H,
(3H, s, OCH3), 4.90 (1H, d, Jϭ18.9 Hz, 6-H), 5.49 (1H, dd, Jϭ6.8, 5.7 Hz, d, Jϭ1.3 Hz, OCHO), 6.10 (1H, br s, NH), 6.80 (1H, s, CϭCH), 7.07—7.10
3-H), 6.84 (1H, s, ArH). IR (KBr) cmϪ1: 1770, 1720, 1710, 1700. MS m/z (2H, d, Jϭ8.3 Hz, ArHϫ2), 7.16—7.33 (4H, m, ArHϫ4). IR (CHCl3) cmϪ1
:
(%): 470 (Mϩϩ2, 3), 468 (Mϩ, 3), 428 (28), 426 (28), 273 (22), 271 (22), 3450—3200, 1700, 1685. FAB-MS (Magic Bullet) m/z 637 (Mϩϩ1). High-
232 (10), 231 (98), 230 (11), 229 (100), 43 (68). Anal. Calcd for resolution MS Calcd for C32H3379BrN2O7: 636.1471. Found: 636.1475.
C19H21BrN2O7: C, 48.63; H, 4.51; N, 5.97. Found: C, 49.03; H, 4.53; N,
5.72.
Method B A mixture of 12b (416.9 mg, 0.5 mmol) with 2 N KOH
(0.5 ml) in DMF (5 ml) was stirred at room temperature for 20 h. The reac-
Preparation of 4b A suspended solution of 2526) (4.901 g, 20.0 mmol) tion mixture was diluted with water (30 ml) and extracted with ethyl acetate
and anhydrous K2CO3 (5.528 g, 40 mmol) in dry DMF (200 ml) was cooled (30 mlϫ3). The combined extracts were washed with brine (30 ml), dried,
with ice water, and chloromethyl methyl ether (3.04 ml, 40 mmol) was added and concentrated in vacuo to give a residue (301 mg). Chromatography on a
dropwise over 10 min. Then, it was stirred for 1 h at room temperature. The silica gel (20 g) column with hexane–ethyl acetate (5 : 1) as the eluent gave a
reaction mixture was diluted with water (200 ml) and extracted with ether solid, the recrystallization of which from ethyl acetate/ether afforded 31
1
(200 mlϫ3). The combined extracts were washed with brine (200 ml), dried, (66.2 mg, 21.4%) as pale red needles, mp 242—244.5 °C. H-NMR d: 1.50
concentrated in vacuo to give a solid (5.804 g, 100%) that was used in the (6H, d, Jϭ6.1 Hz, CH(CH3)2), 2.24, 2.39 (each 3H, s, ArCH3), 3.85 (3H, s,
subsequent step without further purification. 2-Bromo-3-methoxy-5- OCH3), 4.66 (1H, sept, Jϭ6.1 Hz, OCH), 4.90 (1H, d, Jϭ15.9 Hz, NCHAr),
1
methoxymethoxy-4-methylbenzaldehyde (26b), mp 41—43 °C. H-NMR d: 5.24 (2H, s, NCH2Ar), 5.97 (2H, s, OCH2O), 6.34, 6.44 (each 1H, s,
2.41 (3H, s, ArCH3), 3.51, 3.85 (each 3H, s, OCH3), 5.25 (2H, s, ArHϫ2), 7.26—7.38 (5H, m, ArHϫ5), 7.75, 8.35 (each 1H, s, CHϭC). IR
OCH2OCH3), 7.58 (1H, s, 6-H), 10.34 (1H, s, CHO). IR (KBr) cmϪ1: 1700. (KBr) cmϪ1: 1675, 1605. MS m/z (%): 618 (Mϩϩ2, 16), 616 (Mϩ, 16), 539
MS m/z (%): 290 (Mϩϩ2, 7), 288 (Mϩ, 7), 246 (7), 244 (7), 42 (100). High- (54), 537 (34), 481 (12), 447 (28), 446 (100), 389 (31), 361 (13), 91 (34), 43
resolution MS Calcd for C11H1379BrO4: 287.9997. Found: 287.9995.
(21). FAB-MS (Magic Bullet) m/z 617 (Mϩϩ1). High-resolution MS Calcd
A solution of potassium tert-butoxide (2.25 g, 20 mmol) in tert-butyl alco- for C32H2979BrN2O6: 616.1204. Found: 616.1209.
hol (40 ml) was added to a stirred solution of the crude 26b and 1,4-di-
acetylpiperazine-2,5-dione (27: 3.964 g, 20 mmol) in DMF (40 ml) over
Acknowledgments We are grateful to Professor T. Fukuyama and Dr. T.
30 min. After stirring for 1 h at room temperature, the reaction mixture was Kan (Graduate School of Pharmaceutical Sciences, The University of
poured into brine (600 ml) and extracted with ethyl acetate (400 mlϫ3). The Tokyo) for useful discussions in the course of this work. We would like to
combined extracts were washed with water (400 ml), dried, and concentrated thank to T. Suzuki, T. Kozeki, and S. Kubota of the Analytical Center of this
in vacuo to give a solid, the recrystallization of which from ethyl University for MS and NMR measurements, and elemental analysis. This re-
acetate/ether gave 4b (6.749 g, 79.0%) as colorless needles, mp 108.5— search was partially supported by a Grant-in-Aid for Scientific Research (B)
110.0 °C. 1H-NMR d: 2.40 (3H, s, ArCH3), 2.67 (3H, s, COCH3), 3.51 (3H, (No. 14370725) from the Ministry of Education, Culture, Sports, Science
s, OCH2OCH3), 3.86 (3H, s, ArOCH3), 4.50 (2H, s, 6-H2), 5.21 (2H, s, and Technology (MEXT), Japan, and the Uehara Foundation. We thank to
OCH2OCH3), 7.00 (1H, s, ArH), 7.17 (1H, s, 3a-H), 7.73 (1H, br s, NH). IR the Japan Society for the Promotion Science (JSPS) for supporting the col-
(KBr) cmϪ1: 3580, 3250, 1730, 1720, 1710. MS m/z (%): 428 (Mϩϩ2, 6), laboration between Thai and Japanese researchers in this work.
426 (Mϩ, 7), 347 (38), 305 (51), 45 (100), 43 (10). Anal. Calcd for
C17H19BrN2O6·1/5H2O: C, 47.30; H, 4.73; N, 6.49. Found: C, 47.27; H, References and Notes
4.50; N, 6.21.
1) Saito N., Tashiro K., Maru Y., Yamaguchi K., Kubo A., J. Chem. Soc.,

July 2003
Perkin Trans. 1, 1997, 53—69 (1997).
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Youngken H. W., Jr., Marine Technol. Soc., Washington DC, 1970, pp.
281—284.
831
quence of reactions including hydrogenation with debromination, se-
lective bromination, and acetylation to generate 28. When treating 4c
with hydrogen over 10% Pd/C in ethanol followed by acetylation with
acetic anhydride gave 29 in 82% overall yield. By contrast, hydrogena-
tion of 4c with hydrogen over 10% Pd/C in ethanol gave 5c, which was
unstable and easily converted into a high polar insoluble material dur-
ing purification.
3) Rinehart K. L., Holt T. G., Fregeau N. L., Stroh J. G., Keifer P. A., Sun
F., Li L. H., Martin D. G., J. Org. Chem., 55, 4512—4515 (1990).
4) Sakai R., Rinehart K. L., Guan Y., Wang A. H.-J., Proc. Natl. Acad. 22) Another approach based on the selective hydrogenation of 4c over
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K. L., J. Am. Chem. Soc., 118, 9017—9023 (1996).
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Am. Chem. Soc., 124, 6552—6554 (2002).
PtO2 as catalyst23) followed by acetylation afforded the desired com-
pound 28 with a maximum yield of only 19%.
23) Marvel C. S., Allen R. E., Overberger C. C., J. Am. Chem. Soc., 68,
1088—1901 (1946).
24) Treatment of 11a with hydrazine-hydrate in DMF at room temperature
for 1 d gave phenol (30) in 24% yield. Furthermore, treatment of 11a
with 2 N KOH and methanol at room temperature for 21 h gave 31 in
1
21% yield. The H-NMR spectrum of 31 showed a peak at d 8.35,
which was assigned to the exo olefinic proton, thus indicating that 31
has a Z-configuration.
12) Endo A., Kan T., Fukuyama T., Synlett, 1999, 1103—1105 (1999).
13) Ikeda Y., Idemoto H., Hirayama F., Yamamoto K., Iwao K., Asao T.,
Munakata T., J. Antibiot., 36, 1279—1283 (1983).
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1289 (1983).
15) Ikeda Y., Shimada Y., Honjo K., Okumoto T., Munakata T., J.
Antibiot., 36, 1290—1294 (1983).
16) Tsuji N., Japanese Patent JP 59225189 (1985).
17) Cuevas C., Perez M., Martin M. J., Chicharro J. L., Fernandez-Rivas
C., Flores M., Francesch A., Gallego P., Zarzuelo M., Calle F., Garcia
J., Polanco C., Rodriguez I., Manzanares I., Org. Lett., 2, 2545—2548
(2000).
Fig. 2
25) Compounds 4b and 4c were prepared from 25,26) which was easily pre-
pared in seven steps from commercially available 2,3-dihydroxy-
toluene, in 79% and 82% overall yields, respectively.
18) Saito N., Tachi M., Seki R., Kamayachi H., Kubo A., Chem. Pharm.
Bull., 48, 1549—1557 (2000).
19) Saito N., Kamayachi H., Tachi M., Kubo A., Heterocycles, 51, 9—12
(1999).
20) Catalytic hydrogenation of 4a over 10% palladium on carbon (Pd/C)
followed by acetylation gave the debrominated compound (27) in 82%
overall yield (see: Experimental Section).
21) We also attempted transforming 4c25) into the acetate (28) using the se-
Chart 6
26) Saito N., Tachi M., Seki R., Sugawara Y., Takeuchi E., Kubo A., Synth.
Commun., 30, 2407—2421 (2000).
27) Kubo A., Saito N., Kawakami N., Matsuyama Y., Miwa T., Synthesis,
1987, 824—827 (1987).
28) Saito N., Harada S., Yamashita M., Saito T., Yamaguchi K., Kubo A.,
Tetrahedron, 51, 8213—8230 (1995).
Chart 5