Stereoselective synthesis of morphine fragments trans- and cis-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinolines

Article abstract of DOI:10.1016/j.tet.2004.10.067

A stereoselective synthesis of the ACNO partial structures of morphine has been developed. Palladium-catalyzed cyclization of carbamate 2 provided the tetracyclic (ACNO) 3-ethoxycarbonyl-9-methoxy-2,3,5,6,7,7a-hexahydro-1H- benzofuro[3,2-e]isoquinoline (14); while treatment of 5-(2-bromo-6- methoxyphenoxy)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (8) under the same reaction condition gave 8a-(2-hydroxy-3-methoxyphenyl)-1,2,3,4,6,7,8,8a- octahydroisoquinoline (11) via an unusual Claisen rearrangement. 9-Methoxy-3-methyl-2,3,5,6,7,7a-hexahydro-1H-benzofuro[3,2-e]isoquinoline (7) was successfully transformed to trans-octahydroisoquinoline 3 and cis-octahydroisoquinoline 4 via catalytical hydrogenation over PtO₂ and chemical reduction with acidic NaBH₄, respectively.

Full text of DOI:10.1016/j.tet.2004.10.067

Tetrahedron 61 (2005) 513–520
Stereoselective synthesis of morphine fragments trans- and
cis-octahydro-1H-benzo[4,5]furo[3,2-e]isoquinolines
*
Ling-Wei Hsin, Li-Te Chang, Chien-Wei Chen, Chia-Huei Hsu and Hung-Wei Chen
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road,
Room 1336, Taipei 10018, Taiwan, ROC
Received 31 May 2004; revised 17 August 2004; accepted 11 October 2004
Abstract—A stereoselective synthesis of the ACNO partial structures of morphine has been developed. Palladium-catalyzed cyclization of
carbamate 2 provided the tetracyclic (ACNO) 3-ethoxycarbonyl-9-methoxy-2,3,5,6,7,7a-hexahydro-1H-benzofuro[3,2-e]isoquinoline (14);
while treatment of 5-(2-bromo-6-methoxyphenoxy)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (8) under the same reaction condition
gave 8a-(2-hydroxy-3-methoxyphenyl)-1,2,3,4,6,7,8,8a-octahydroisoquinoline (11) via an unusual Claisen rearrangement. 9-Methoxy-3-
methyl-2,3,5,6,7,7a-hexahydro-1H-benzofuro[3,2-e]isoquinoline (7) was successfully transformed to trans-octahydroisoquinoline 3 and cis-
octahydroisoquinoline 4 via catalytical hydrogenation over PtO2 and chemical reduction with acidic NaBH4, respectively.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
these ACNO compounds have not been developed for
clinical use yet.
The rigid structure of morphine, a potent analgesic alkaloid,
consists of five rings (ABCNO, Chart 1). Although narcotic
analgesics display excellent antinociceptive activity, the
numerous adverse effects of opiate narcotics continue to
stimulate the discovery and development of better analgesics
with no abuse-liability and milder side effects.1 Approaches
based on simplification of the morphine skeleton for the
development of potent and nonaddictive analgesics have been
adopted by generations of medicinal chemists and have
resulted in the discovery of many potent analgesics, such as
meperidine, pentazocine, and levorphanol.1–3
Researches in this laboratory have been focused on the
development of novel synthetic strategies for stereoselective
construction of the ACNO ring system of morphine and
investigation of pharmacological activities of new ACNO
compounds.11–13 Previously, we reported a convergent
approach towards the construction of the ACNO fragment
of morphine via an intramolecular radical cyclization.13
Octahydro-1H-benzofuro[3,2-e]isoquinolin-9-ols, which
contain the ACNO partial structure of morphine, have
been found to retain potent analgesic activity.4,5 The N-
cyclopropylmethyl analog 1 (J-6549) displayed potent oral
analgesic and narcotic-antagonism activity and therefore, is
likely to have a low potential for addiction.5 Since the first
synthesis of the ACNO skeleton of morphine by Schultz
et al.,6 several synthetic strategies have been published for
the construction of the ACNO fragment of morphine.4,7–12
Nevertheless, either due to inefficiency in these synthesis or
inadequate structure-activity relationship (SAR) study,
Keywords: Stereoselective; Morphine; Intramolecular cyclization; Heck
reaction; Claisen rearrangement.
* Corresponding author. Tel: C886 2 2395 2310; fax: C886 2 2351 2086;
e-mail: lwh@ntumc.org
Chart 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.067

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L.-W. Hsin et al. / Tetrahedron 61 (2005) 513–520
However, the difficulty in control of stereoselectivity
prohibited further application.
Aminoalcohol 9 was prepared from 5,6,7,8-tetrahydroiso-
quinoline in five steps according to the previous pro-
cedures.13 Coupling of 9 with 2-bromo-6-methoxyphenol
and 2-iodo-6-methoxyphenol18 under Mitsunobu reaction
conditions provided aryl halides 8 and 10, respectively
(Scheme 2). Then the tetracyclic enamine 7 was supposed to
be prepared from either bromide 8 or iodide 10 using the
cyclization condition in the literature.14 However, all
attempts to convert aryl bromide 8 to enamine 7 using
different Heck reaction conditions failed and afforded only
one identifiable product 11.
Another attractive pathway towards the construction of the
ACNO partial structure of morphine was demonstrated by
Liou et al., in which a palladium-catalyzed cyclization was
adopted as the key step (Chart 2).14 However, the chirality
of C-4a has not been established yet, and the stereoisomers
may possess significantly different pharmacological pro-
files.15–17 Therefore, to further study the SAR and the
therapeutic potential of ACNO derivatives, an efficient and
stereoselective synthetic route is highly desired. As a
continued effort in this area, we have developed a novel
synthetic approach, in which the O ring and the crucial
quaternary carbon center were formed simultaneously by an
intramolecular cyclization of carbamate 2 and the trans- and
cis-C/N ring junctions were constructed via stereoselective
catalytic hydrogenation and acidic NaBH4 reduction, respec-
tively. Here, we report this concise and stereoselective
approach towards the construction of ACNO fragments of
morphine, as exemplified by the synthesis of compounds 3–6.
Initially, compound 11 was misinterpreted as the desired
compound 7 since compound 11 and the reference
compound, which was prepared and assigned as 7 in the
literature,14 showed almost identical 1H and 13C NMR
spectra as shown in Tables 1 and 2. However, to our
knowledge, the H-7a and C-7a of ACNO compounds
usually display signals in the characteristic regions in the
NMR spectra (i.e. d 4.0–4.5 and 85–95, respectively). The
disappearance of these typical signals prompted us to
reinterpret the structure of 11. The high-resolution mass
(HRMS) data suggested that compound 11 contained two
more hydrogen atoms than compound 7. 2D NMR
experiments, including COSY, NOESY, HMBC, and
HMQC, were conducted and the structure of compound
11 was determined as 8a-(2-hydroxy-3-methoxyphenyl)-
1,2,3,4,6,7,8,8a-octahydroisoquinoline. The X-ray diffrac-
tion analysis of the HCl salt of compound 11 confirmed the
assigned structure (Fig. 1). Crystallographic data (excluding
structure factors) for the structure have been deposited with
the Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 251042.
Chart 2. Intramolecular palladium-catalyzed cyclization.14
2. Results and discussion
In general, the aryl iodides are more active than the aryl
bromides in palladium-catalyzed cyclization. Therefore,
iodide 10 was subjected to the same Heck reaction
conditions as above. Again, the rearrangement product 11
was the only product isolated in a yield similar to that of
using bromide 8 as Heck reaction substrate.
Initially, palladium-catalyzed cyclization reaction was
considered as one of the key reactions in our retrosynthetic
route as shown in Scheme 1. The trans- and cis-C/N ring
junctions in compounds 3 and 4 could be established by
stereoselective reductions of enamine 7, which is prepared
from aryl bromide 8 via the Heck reaction. Compound 8 is
synthesized by coupling of compound 9 with 2-bromo-6-
methoxyphenol under Mitsunobu reaction condition as
previously described.13
A [3,3]-sigmatropic-rearrangement and a reduction reaction
were involved in this reaction. To study the mechanism of
this unusual rearrangement, the debrominated derivative 12
Scheme 1.

L.-W. Hsin et al. / Tetrahedron 61 (2005) 513–520
515
Scheme 2. Reagents and conditions: (a) 2-bromo-6-methoxyphenol or 2-iodo-6-methoxyphenol, DEAD, Bu3P, THF, rt; (b) Pd(OAc)2, PPh3, Et3N, CH3CN,
125 8C.
Table 1. The 1H NMR spectral data (d, ppm) of compounds 11, ‘7’,14 and 7
11
‘7’14
7
1.44–1.54 (m, 3H)
1.96–2.10 (m, 5H)
2.12–2.21 (m, 1H)
2.26 (s, 3H)
2.30–2.34 (m, 1H)
2.87–2.90 (m, 1H)
3.84 (s, 3H)
1.44–1.54 (m, 3H)
1.96–2.10 (m, 4H)
2.12–2.21 (m, 1H)
2.26 (s, 3H)
2.30–2.34 (m, 1H)
2.87–2.90 (m, 1H)
3.84 (s, 3H)
1.10–1.26 (m, 1H), 1.35–1.45 (m, 1H), 1.55–1.62 (m, 1H)
1.78–1.89 (m, 3H), 1.91–1.96 (m, 1H)
2.03–2.07 (m, 1H)
2.60 (s, 3H)
2.68–2.74 (m, 1H)
2.76–2.82 (m, 1H)
3.86 (s, 3H)
3.86–3.87 (m, 1H)
5.62 (s, 1H)
6.68–6.76 (m, 3H)
3.86–3.87 (m, 1H)
5.62 (s, 1H)
6.68–6.76 (m, 3H)
4.43 (dd, JZ9.2, 6.1 Hz, 1H)
5.88 (s, 1H)
6.73–6.94 (m, 3H)
was prepared by coupling of 9 with phenol under Mitsunobu
reaction condition and then subjected to the same
palladium-catalyzed reaction condition. Only starting
material was recovered after heating for 72 h as shown in
Chart 3. Furthermore, treatment of 8 under the same
reaction condition except in the absence of Pd(OAc)2 only
afforded the starting material from the resulting reaction
mixture. Thus, both the palladium and bromo-substituent
are essential for this unusual rearrangement. Shown in
Scheme 3 is the proposed mechanism for the palladiun-
induced rearrangement of compound 8. Oxidative addition
of 8 to the Pd(0) in the presence of ligands, such as PPh3 and
bromide anion, gave Pd(II) species I. Coordination of the
long electron pair of basic nitrogen atom to Pd provided
species II. Then an unusual Claisen rearrangement of II
including a [3,3]-sigmatropic-rearrangement and a rear-
omatization of the unstable intermediate III gave species
IV. Hydrolysis of IV provided product 11.
The failure of the Heck reaction and the undesired
rearrangement may be due to the basic amino group in
compounds 8 and 10. Therefore, a modified synthetic
pathway using carbamate 2 as key intermediate for the
palladium-catalyzed cyclization reaction was developed
(Scheme 4). Treatment of compound 1318 with 2-iodo-6-
methoxyphenol14 under Mitsunobu conditions provided
Table 2. The 13C NMR spectral data (d, ppm) of compounds 11, ‘7’,14 and 7
11
‘7’14
7
19.8
25.4
19.7
25.5
22.6
29.2
33.0
35.9
45.3
55.8
57.2
64.7
77.2
29.6, 33.1
35.8
45.4
55.8
57.3
29.6
37.0
42.9
45.8
46.6
55.8
90.6
64.8
—
108.4
118.2
122.4
123.6
131.0
140.0
145.1
148.5
108.5
118.2
122.5
123.7
131.0
140.0
145.0
148.5
106.6
111.3
116.7
120.5
134.2
138.1
145.1
146.0
Figure 1.

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L.-W. Hsin et al. / Tetrahedron 61 (2005) 513–520
Chart 3.
Scheme 3.
Scheme 4. Reagents and conditions: (a) 2-iodo-6-methoxyphenol, DEAD, Bu3P, THF, rt; (b) Pd(OAc)2, PPh3, K2CO3, (n-Bu)4NBr, CH3CN, 125 8C; (c) H2,
PtO2, EtOH, rt; (d) LiAlH4, ether, rt; (e) CH3SO3H, NaBH4, MeOH, rt; (f) BBr3–(CH3)2S, ClCH2CH2Cl, reflux.

L.-W. Hsin et al. / Tetrahedron 61 (2005) 513–520
517
carbamate 2. Compound 2 was subjected to Heck reaction
condition using Pd(OAc)2, PPh3, (n-Bu)4NBr, and K2CO3 in
acetonitrile at 125 8C in a sealed bottle and the tetracyclic
(ACNO) carbamate 14 was successfully afforded in 41%
yield. Furthermore, there was no rearrangement product
observed in the crude reaction mixture. This result offered
another evidence to support that the basic nitrogen atom is
essential for the rearrangement.
steps by its directing effects. Thus, optically active (K)-3
was successfully prepared starting from (C)-13 via the
same reaction sequence for the synthesis of racemic 3. The
hydrochloride salt of optically active (K)-3 was recrystal-
lized to afford optically pure (K)-3 (eeZ100%).
In summary, we have established an efficient and stereo-
selective synthesis for construction of the ACNO partial
structure of morphine. Compounds 3 and 4 with the trans
and cis-C/N ring junctions could be afforded selectively
from enamine 7 via catalytical hydrogenation over PtO2
and chemical reduction with acidic NaBH4, respectively.
Palladium-catalyzed (Heck) cyclization of carbamate 2
successfully formed the quaternary carbon center and the O
ring, and provided compound 14 containing the tetracyclic
ACNO skeleton. Treatment of amines 8 or 10 under the
same Heck reaction conditions gave compound 11 via an
unusual Claisen rearrangement. The detailed mechanism
and application of this reaction in organic synthesis are
currently under investigation.
Another task in this paper is the stereoselective establish-
ment of the chirality of C-4a. Previously, catalytic
hydrogenation was used to stereoselectively introduce H-
4a into the 7-oxygenated ACNO derivatives.11 Therefore,
compound 14 was hydrogenated over platinum oxide
(PtO2). However, a mixture of the trans-carbamate 15 and
cis-carbamate 16 in a ratio of 2:3 (the ratio was determined
1
based on the H-7a signals in the H NMR spectrum) was
afforded. Thus, the carbamate group of 14 was removed
using LiAlH4 in THF to provide enamine 7.
As mentioned above, the disappearance of the characteristic
H-7a and C-7a signals in the NMR spectra of compound 11
led us to discover the unusual rearrangement and the correct
structure of 11. Therefore, the NMR spectra of enamine 7
are compared with those of compound 11: (i) compound 7
shows a characteristic double doublet at d 4.43 for H-7a and
a tertiary carbon peak at d 90.6 for C-7a, whereas compound
11 does not show any corresponding signals; (ii) the N-
methyl proton signal of enamine 7 is significantly more
downfield than that of amine 11 (d 2.60 and 2.26,
respectively); (iii) in DEPT spectra, enamine 7 displays
five CH2 and five CH carbon signals, whereas compound 11
possesses six CH2 and four CH carbon signals.
3. Experimental
3.1. General procedures
Melting points were determined on a MEL-TEMP II
apparatus by Laboratory Devices and are uncorrected.
NMR spectra were recorded on Bruker DPX-200 and AMX-
400 FT-NMR spectrometers. Chemical shifts are expressed
in parts per million (ppm) on the d scale relative to a
tetramethylsilane (TMS) internal standard. Mass spectra
were recorded on a Jeol JMS-D300 mass spectrometer.
High-resolution mass spectroscopy (HRMS) measurements
were obtained using a Jeol-HX110 mass spectrometer.
Elemental analyses were performed with a Perkin–Elmer
2400-CHN instrument, and were within G0.4% for the
elements indicated. The enantiomeric excess (ee) values
were determined by HPLC based on the UV absorption
areas of the two enantiomers using a chiral column (Daicel
chiralcel OD, 0.46 cm!25 cm), a flow rate of 1 mL/min,
and 1w10% 2-propanol in n-hexane with 0.2% diethyl-
amine as the mobile phase. Thin-layer chromatography
(TLC) was performed on Merck (art. 5554) silica gel plates
and visualized under UV light (254 nm), upon treatment
with iodine vapor, or upon heating after treatment with 5%
phosphomolybdic acid in ethanol. Flash column chromato-
graphy was performed with Merck (art. 9385) 40–63 mm
silical gel 60. Anhydrous tetrahydrofuran was distilled from
sodium-benzophenone prior to use. No attempt was made to
optimize yields.
Catalytic hydrogenation of enamine 7 over PtO2 in ethanol
provided trans-decahydroisoquinoline 3 as the major
product (i.e. trans/cisZ8:1). Stereoselective synthesis of
cis-decahydroisoquinoline 4 was achieved by acidic NaBH4
reduction7 of 7, which provided cis-4 as the major product
(i.e. trans/cisZ1:12). O-Demethylation of compounds 3
and 4 using BBr3–(CH3)2S in 1,2-dichloroethane gave
phenols trans-5 and cis-6, respectively.
Another attractive advantage of this synthetic strategy is the
feasibility of asymmetric synthesis of chiral ACNO
derivatives. In our preliminary results, oxidation of racemic
carbamate 13 with activated MnO2 afforded ketone 17.
Asymmetric reduction of 17 with (S)-2-methyl-CBS-
oxazaborolidine19,20 gave optically active carbamate (C)-
13 in a moderate yield and in 64% ee as shown in Scheme 5.
The chirality in (C)-13 was then used to control the
chirality of other chiral centers formed in the following
Scheme 5. Reagents and conditions: (a) MnO2, CH2Cl2, reflux; (b) BH3, (S)-MeCBS, THF, rt; (c) 2-iodo-6-methoxyphenol, DEAD, Bu3P, THF, rt;
(d) Pd(OAc)2, PPh3, K2CO3, (n-Bu)4NBr, CH3CN, 125 8C; (e) LiAlH4, ether, rt; (f) H2, PtO2, EtOH, rt.

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L.-W. Hsin et al. / Tetrahedron 61 (2005) 513–520
3.1.1.
5-(2-Iodo-6-methoxyphenoxy)-2-methyl-
solvent was evaporated and the residue was chromato-
graphed (silica gel; 25% EtOAc in n-hexane) to afford 2
1,2,3,4,5,6,7,8-octahydroisoquinoline (10). To a stirred
solution of 9 (429 mg, 2.56 mmol), tributylphosphine
(1.9 mL, 5.13 mmol), and 2-iodo-6-methoxyphenol14
(1.92 g, 5.13 mmol) in dry THF (10 mL) was added diethyl
azodicarboxylate (DEAD, 5.13 mmol) dropwise at rt. After
40 min, the solvent was evaporated and the residue was
chromatographed (silica gel; NH4OH/CH3OH/CH2Cl2
0.6:5.4:94) to afford 10 (886 mg, 86%) as a pale yellow
oil; 1H NMR (200 MHz, CDCl3) d 1.39–1.62 (m, 2H), 1.89–
1.91 (m, 2H), 1.96–2.20 (m, 2H), 2.25–2.32 (m, 1H), 2.31
(s, 3H), 2.35–2.39 (m, 1H), 2.60–2.73 (m, 3H), 2.91 (d, JZ
15.7 Hz, 1H), 3.76 (s, 3H), 4.66 (s, 1H), 6.69 (t, JZ8.0 Hz,
1H), 6.82 (dd, JZ8.2, 1.5 Hz, 1H), 7.31 (dd, JZ7.8, 1.6 Hz,
1H); 13C NMR (50 MHz, CDCl3) d 18.4, 27.80, 27.84, 28.3,
45.6, 52.5, 55.3, 58.4, 77.5, 93.5, 112.4, 124.9, 126.4, 130.9,
132.6, 147.4, 152.5; HRMS (FAB) Calcd for C17H23INO2
[MCH]C 400.0774, found 400.0783.
1
(2.47 g, 66%) as a pale yellow oil; H NMR (200 MHz,
CDCl3) d 1.25 (t, JZ7.1 Hz, 3H), 1.37–1.62 (m, 2H), 1.95–
2.13 (m, 5H), 2.56–2.64 (m, 1H), 3.43–3.75 (m, 1H), 3.75–
3.90 (m, 3H), 3.80 (s, 3H), 4.13 (q, JZ7.1 Hz, 2H), 4.67 (s,
1H), 6.72 (t, JZ7.9 Hz, 1H), 6.84 (dd, JZ7.9, 1.3 Hz, 1H),
7.33 (dd, JZ7.9, 1.3 Hz, 1H); 13C NMR (50 MHz, CDCl3) d
14.8, 18.4, 26.8, 27.5, 28.3, 40.9, 46.7, 55.5, 61.1, 77.2,
93.6, 112.5, 125.2, 127.3, 131.1, 132.1, 147.3, 152.6, 155.5;
HRMS (FAB) Calcd for C19H25INO4 [MCH]C 458.0828,
found 458.0826.
3.1.5. 9-Methoxy-2,3,5,6,7,7a-hexahydro-1H-benzo[4,5]-
furo[3,2-e]isoquinoline-3-carboxylic acid ethyl ester
(14). A solution of 2 (450 mg, 0.98 mmol) and a catalytic
amount of Pb(OAc)2 (22 mg, 0.098 mmol), triphenylpho-
sphine (77 mg, 0.29 mmol), K2CO3 (813 mg, 5.88 mmol)
and (n-Bu)4NBr (630 mg, 1.96 mmol) in dry acetonitrile
(40 mL) was heated in a sealed bottle at 125 8C for 36 h. The
solvent was evaporated and the residue was treated with
EtOAc. The EtOAc solution was washed with saturated
aqueous NaHCO3, dried over MgSO4, filtered, and evapor-
ated. The crude residue was chromatographed (silica gel;
17% EtOAc in n-hexane) to afford 14 (132 mg, 41%) as a
3.1.2. 8a-(2-Hydroxy-3-methoxyphenyl)-1,2,3,4,6,7,8,8a-
octahydroisoquinoline (11). A solution of 8 (130 mg,
0.37 mmol) and a catalytic amount of Pb(OAc)2 (8.3 mg,
0.037 mmol), triphenylphosphine (29.1 mg, 0.11 mmol) and
triethylamine (0.15 mL, 1.11 mmol) in dry acetonitrile
(11 mL) was heated in a sealed bottle at 125 8C for 38 h.
The solvent was evaporated and the residue was treated with
EtOAc. The EtOAc solution was washed with saturated
aqueous NaHCO3, dried (MgSO4), filtered, and evaporated.
The crude residue was chromatographed (silica gel;
CH3OH/CH2Cl2 1:15) to afford 11 (40 mg, 40%) as a pale
yellow solid; mp 126–128 8C (HCl salt, acetone); 1H NMR
(400 MHz, CDCl3) d 1.44–1.54 (m, 3H), 1.96–2.10 (m, 5H),
2.12–2.21 (m, 1H), 2.26 (s, 3H), 2.30–2.34 (m, 1H), 2.87–
2.90 (m, 1H), 3.84 (s, 3H), 3.85–3.87 (m, 1H), 5.62 (s, 1H),
6.68–6.76 (m, 3H); 13C NMR (50 MHz, CDCl3) d 19.8,
25.4, 33.0, 35.9, 45.3, 55.8, 57.2, 64.7, 77.2, 108.4, 118.2,
122.4, 123.6, 131.0, 140.0, 145.1, 148.5; HRMS (EI) Calcd
for C17H23NO2 [M]C 273.1729, found 273.1721. Anal.
Calcd for C17H23NO2$HCl$H2O: C, 62.28; H, 7.99; N, 4.27.
Found: C, 62.20; H, 7.83; N, 4.06.
1
colorless oil; Rf 0.41 (40% EtOAc in n-hexane); H NMR
(200 MHz, CDCl3) d 1.22–1.34 (q, JZ7.3 Hz, 3H), 1.40–
1.53 (m, 1H), 1.61–1.73 (m, 2H), 1.80 (dd, JZ13.1, 4.0 Hz,
1H), 1.89–1.95 (m, 2H), 2.05 (m, 2H), 3.11–3.24 (m, 1H),
3.85 (s, 3H), 3.95–4.02 (m, 1H), 4.16–4.26 (m, 2H), 4.46
(dd, JZ9.5, 6.3 Hz, 1H), 6.66 (dd, JZ5.9, 2.5 Hz, 1H),
6.76–6.81 (m, 2H), (6.87, 6.98) (s, 1H); 13C NMR (50 MHz,
CDCl3) d 14.5, 22.0, 29.3, 29.7, 35.3, (38.3, 38.5), (46.8,
46.9), 55.9, (61.8, 61.9), 90.1, 111.8, (114.9, 115.3), 116.5,
120.9, (121.6, 122.1), 135.6, 145.4, 146.1, (153.1, 153.5);
HRMS (EI) Calcd for C19H23NO4 [M]C 329.1627, found
329.1620 (since the carbamate group in compound 14 could
adopt either a cis or trans configuration, some of the 1H and
13C signals appear as pairs).
3.1.6. 9-Methoxy-3-methyl-2,3,5,6,7,7a-hexahydro-1H-
benzo[4,5]furo[3,2-e]isoquinoline (7). To a stirred solution
of LiAlH4 in diethyl ether (0.53 M, 1.5 mL) was added a
solution of 14 (127 mg, 0.39 mmol) in diethyl ether (2 mL).
The mixture was stirred at rt for 1 h, and then a solution of
20% H2O in THF was added and stirred for 10 min. To the
solution was added 40% aqueous NaOH, and then the
resulting mixture was stirred for another 10 min, dried over
MgSO4, filtered, and evaporated. The crude residue was
chromatographed (silica gel; 30% EtOAc in n-hexane) to
afford 7 (90 mg, 85%) as a pale yellow oil; Rf 0.33 (40%
3.1.3. 2-Methyl-5-phenoxy-1,2,3,4,5,6,7,8-octahydroiso-
quinoline (12). To a stirred solution of alcohol 9 (207 mg,
1.24 mmol), tributylphosphine (0.6 mL, 2.48 mmol) and
phenol (233 mg, 2.48 mmol) in THF (6 mL) was added
dropwise DEAD (1.0 mL, 2.48 mmol) at rt. After 1 h, the
mixture was evaporated and the residue was chromato-
graphed (silica gel; 6% CH3OH in CH2Cl2) to afford 12
(187 mg, 62%) as a yellow oil; 1H NMR (200 MHz, CDCl3)
d 1.57–1.79 (m, 3H), 1.81–2.06 (m, 3H), 2.08–2.24 (m, 1H),
2.27–2.43 (m, 2H), 2.36 (s, 3H), 2.52–2.77 (m, 2H), 2.96 (d,
JZ15.8 Hz, 1H), 4.50 (s, 1H), 6.85–6.96 (m, 3H), 7.20–7.30
(m, 2H); 13C NMR (50 MHz, CDCl3) d 17.8, 27.5, 27.6,
27.7, 45.6, 52.3, 58.3, 73.2, 116.0, 120.6, 125.8, 129.4,
132.9, 158.6; HRMS (EI) Calcd for C16H21NO [M]C
243.1623, found 243.1628.
1
EtOAc in n-hexane); H NMR (400 MHz, CDCl3) d 1.10–
1.26 (m, 1H), 1.35–1.45 (m, 1H), 1.55–1.62 (m, 1H), 1.78–
1.89 (m, 3H), 1.91–1.96 (m, 1H), 2.03–2.07 (m, 1H), 2.60
(s, 3H), 2.68–2.74 (m, 1H), 2.76–2.82 (m, 1H), 3.86 (s, 3H),
4.43 (dd, JZ9.2, 6.1 Hz, 1H), 5.88 (s, 1H), 6.73–6.94 (m,
3H); 13C NMR (50 MHz, CDCl3) d 22.6, 29.2, 29.6, 37.0,
42.9, 45.8, 46.6, 55.8, 90.6, 106.6, 111.3, 116.7, 120.5,
134.2, 138.1, 145.1, 146.0; HRMS (EI) Calcd for
C17H21NO2 [M]C 271.1572, found 271.1568.
3.1.4. 5-(2-Iodo-6-methoxy-phenoxy)-3,4,5,6,7,8-hexa-
hydro-1H-isoquinoline-2-carboxylic acid ethyl ester (2).
To a stirred solution of alcohol 13 (1.85 g, 8.2 mmol), tri-
butylphosphine (6.1 mL, 24.6 mmol) and 2-iodo-6-methoxy-
phenol (6.15 g, 24.6 mmol) in dry THF (60 mL) was added
dropwise DEAD (24.6 mmol) at rt and stirred for 1 h. The
3.1.7. trans-9-Methoxy-3-methyl-2,3,4,4ab,5,6,7,7ab-
octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (3). A

L.-W. Hsin et al. / Tetrahedron 61 (2005) 513–520
519
mixture of 7 (49 mg, 0.18 mmol) and PtO2 (5 mg) in EtOH
(3 mL) was shaken in a Parr hydrogenator under 10 bar of
H2 at rt for 18 h. The catalyst was removed via filtration
through Celite and the filtrate was evaporated. The crude
residue was chromatographed (silica gel; NH4OH/CH3OH/
CH2Cl2 0.8:8:92) to afford 3 as a pale yellow solid; mp 189–
191 8C (HCl salt, 2-propanol/EtOAc); Rf 0.18 (NH4OH/
(dd, JZ5.3, 3.3 Hz, 1H); 13C NMR (50 MHz, CDCl3) d
20.3, 24.7, 28.3, 38.8, 39.1, 45.8, 48.4, 50.8, 57.1, 89.3,
115.5, 118.5, 120.1, 132.8, 142.2, 147.3; HRMS (EI) Calcd
for C16H21NO2 [M]C 259.1572, found 259.1562. Anal.
Calcd for C16H21NO2$HCl: C, 64.97; H, 7.50; N, 4.74.
Found: C, 64.84; H, 7.47; N, 4.73.
1
CH3OH/CH2Cl2 0.1:1:15); H NMR (200 MHz, CDCl3) d
3.1.10. cis-9-Hydroxy-3-methyl-2,3,4,4aa,5,6,7,7ab-octa-
hydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (6). A solu-
tion of 4 (52 mg, 0.19 mmol) and BBr3–(CH3)2S (0.9 mmol)
in ClCH2CH2Cl (18 mL) was heated to reflux for 3 h, and
then cooled to rt. The reaction mixture was treated with H2O
and basified to pHZ9 with NH4OH(conc.). The solution was
extracted with a solution of 2-propanol and CH2Cl2 (1:4,
75 mL!3). The organic layer was dried over MgSO4,
filtered, and evaporated. The crude residue was chromato-
graphed (silica gel; NH4OH/CH3OH/CH2Cl2 1.4:12.6:86)
to afford 6 (26 mg, 53%) as a colorless oil; mp 276–278 8C
(HCl salt, 2-propanol/EtOAc); 1H NMR (200 MHz, CDCl3)
d 1.49–1.82 (m, 8H), 1.98–2.06 (m, 2H), 2.33 (s, 3H), 2.40–
2.44 (m, 1H), 2.52–2.70 (m, 3H), 4.30 (s, 1H), 6.71–6.76
(m, 2H), 7.00 (t, JZ4.3 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 20.2, 26.4, 26.5, 30.6, 38.6, 44.8, 46.7, 53.4, 57.6,
87.7, 115.0, 116.2, 120.9, 138.6, 141.3, 145.6; HRMS (EI)
Calcd for C16H21NO2 [M]C 259.1572, found 259.1571.
1.10–1.24 (m, 1H), 1.32–1.60 (m, 4H), 1.76–1.83 (m, 2H),
1.93–2.09 (m, 2H), 2.30–2.44 (m, 1H), 2.40 (s, 3H), 2.54 (t,
JZ11.6 Hz, 1H), 2.65–2.77 (m, 2H), 3.87 (s, 3H), 4.48 (t,
JZ5.6 Hz, 1H), 6.78–6.81 (m, 2H), 7.12 (t, JZ4.3 Hz, 1H);
13C NMR (50 MHz, CDCl3) d 19.8, 24.5, 28.1, 39.3, 39.4,
46.1, 48.0, 50.9, 55.7, 57.3, 89.4, 111.0, 119.5, 119.6, 133.0,
145.2, 148.4; HRMS (EI) Calcd for C17H23NO2 [M]C
273.1729, found 273.1724. Anal. Calcd for C17H23NO2$HCl:
C, 65.90; H, 7.81; N, 4.52. Found: C, 65.76; H, 8.02; N,
4.26. Optically active (K)-3 was dissolved in a solution of
HCl in CH2Cl2, and then evaporated to provide (K)-3$HCl.
Recrystallization of the hydrochloride salt of (K)-3
afforded optically pure (K)-3$HCl (eeZ100.0%):
[a]DZK35.68 (cZ0.58, MeOH).
3.1.8. cis-9-Methoxy-3-methyl-2,3,4,4aa,5,6,7,7ab-octa-
hydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (4). To a
stirred solution of compound 7 (170 mg, 0.626 mmol) in
MeOH (10 mL) cooled in an ice bath was added methane-
sulfonic acid (66 mg, 0.689 mmol) and the ice bath was
removed after 5 min. Ten minutes later the mixture was
again cooled in an ice bath, and NaBH4 (284 mg,
7.51 mmol) was then added in portions over 1 min. The
reaction mixture was stirred for 13 h at rt, and then brine
(20 mL) was added to the resulting solution followed by
2 M aqueous HCl (9 mL), 3 M aqueous NaOH (20 mL), and
H2O (20 mL). The mixture was extracted with CHCl3
(50 mL!2). The combined organic layer was dried over
MgSO4, filtered, and evaporated. The crude residue was
chromatographed (silica gel; NH4OH/CH3OH/CH2Cl2
0.5:5.5:94) to afford 4 (130 mg, 76%) as a colorless oil;
mp 246 8C (HCl salt, 2-propanol/EtOAc); Rf 0.38 (NH4OH/
3.1.11. 5-Oxo-3,4,5,6,7,8-hexahydro-1H-isoquinoline-2-
carboxylic acid ethyl ester (17). To a stirred solution of
13 (4.00 g, 17.8 mmol) in CH2Cl2 (250 mL) was added
activated MnO2 (46.0 g, 450 mmol) by portions. The
mixture was stirred at rt for 48 h, filtered through Celite
and the filtrate was evaporated. The residue was chromato-
graphed (silica gel; CH3OH/CH2Cl2 1:20) to afford 17
(2.88 g, 43%) as a yellow oil; 1H NMR (200 MHz, CDCl3) d
1.18 (t, JZ7.1 Hz, 3H), 2.01–2.05 (m, 2H), 2.29–2.34 (m,
4H), 2.45 (t, JZ6.1 Hz, 2H), 3.54 (t, JZ5.7 Hz, 2H), 4.05
(s, 2H), 4.17 (q, JZ7.1 Hz, 2H); 13C NMR (50 MHz,
CDCl3) d 14.4, 21.6, 22.0, 27.7, 37.4, 40.2, 46.6, 61.2,
130.2, 152.2, 155.1, 197.4; HRMS (EI) Calcd for
C12H17NO3 [M]C 223.1208, found 223.1209.
1
CH3OH/CH2Cl2 0.1:1:15); H NMR (200 MHz, CDCl3) d
1.46–1.50 (m, 1H), 1.63–1.80 (m, 7H), 1.95–2.17 (m, 2H),
2.32 (s, 3H), 2.39–2.47 (m, 1H), 2.54–2.75 (m, 2H), 3.87 (s,
3H), 4.30 (s, 1H), 6.75–6.90 (m, 2H), 7.08–7.12 (m, 1H);
HRMS (EI) Calcd for C17H23NO2 [M]C 273.1729, found
273.1727.
Acknowledgements
We acknowledge the National Science Council of the
Republic of China (Grant No. NSC 91-2320-B-002-205) for
partial financial support of this work.
3.1.9. trans-9-Hydroxy-3-methyl-2,3,4,4ab,5,6,7,7ab-
octahydro-1H-benzo[4,5]furo[3,2-e]isoquinoline (5).4,10
A solution of 3 (51 mg, 0.19 mmol) and BBr3–(CH3)2S
(0.9 mmol) in ClCH2CH2Cl (18 mL) was brought to reflux
for 3 h, and then cooled to rt. The reaction mixture was
treated with H2O and basified to pHZ9 with saturated
aqueous Na2CO3. The solution was extracted with a solution
of 2-propanol and CH2Cl2 (1:4, 75 mL!3). The organic
layer was dried over MgSO4, filtered, and evaporated. The
crude residue was chromatographed (silica gel; NH4OH/
CH3OH/CH2Cl2 1.4:12.6:86) to afford 5 (40 mg, 83%) as a
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2004.10.
067.
1
colorless oil; mp 268 8C (HCl salt, 2-propanol/EtOAc); H
NMR (200 MHz, CDCl3) d 1.17–1.23 (m, 2H), 1.40–1.53
(m, 4H), 1.80–1.85 (m, 2H), 1.95–2.01 (m, 2H), 2.41 (s,
3H), 2.35–2.49 (m, 1H), 2.58 (t, JZ11.8 Hz, 1H), 2.77–2.83
(m, 2H), 4.43 (t, JZ5.3 Hz, 1H), 6.71–6.76 (m, 2H), 7.00
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