The synthesis of 2′,2′-bis-benzylisoquinolines and their cytostatic activities

Article abstract of DOI:10.1016/j.tet.2007.08.083

The novel laudanosine dimers in which two laudanosine units are linked via a C-2′ biaryl bond have been prepared by a sequence that involves formation of the biaryl bond first and then formation of the isoquinoline rings. Two of these compounds showed higher cytostatic activity on three cancer cell lines than thalicarpine. Crown Copyright

Full text of DOI:10.1016/j.tet.2007.08.083

Tetrahedron 63 (2007) 10896–10901
The synthesis of 20,20-bis-benzylisoquinolines and their
cytostatic activities
*
Stephen R. Taylor, Alison T. Ung and Stephen G. Pyne
*
Department of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia
Received 22 May 2007; revised 8 August 2007; accepted 23 August 2007
Available online 30 August 2007
Abstract—The novel laudanosine dimers in which two laudanosine units are linked via a C-20 biaryl bond have been prepared by a sequence
that involves formation of the biaryl bond first and then formation of the isoquinoline rings. Two of these compounds showed higher cytostatic
activity on three cancer cell lines than thalicarpine.
Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved.
1. Introduction
are linked via a C-20 biaryl bond, and an examination of their
cytostatic activities on cancer cell lines. This paper describes
the successful synthesis of rac- and meso-2 and a single
diastereomer of 3 and their cytostatic activities on three
cancer cell lines.
Over 200 bis-benzylisoquinoline alkaloids are known, the
majority of these have one or two ether linkages between
the two benzylisoquinoline moieties.1 However, a number
of these alkaloids have one of the linking ether bonds
replaced by a biphenyl linkage.2 The bis-benzylisoquinoline
alkaloids show a range of interesting biological activities.1
The related Thalictrum alkaloid, thalicarpine 1,3 comprises
the benzylisoquinoline S-laudanosine, connected via an
ether linkage to an aporphine moiety. This molecule was
found to have significant biological activity against the
Walker 256 carcinoma and antiproliferative activity on
a broad range of human and animal cell lines in vitro and
in vivo.4,5 Initial clinical trails on this compound appeared
encouraging,4–9 however, phase II clinical trials stopped
after no antitumour effect was observed.7,9
2. Results and discussion
Our initial approach to the target molecules 2 and 3 is shown
in Scheme 1 and was based on an Ullmann coupling reaction
of N-trifluoroacetyl-20-iodonorlaudanosine 7, to deliver the
MeO
EDCI, HOBT, CH2Cl2,
MeO
COOH
HN
O
18 h
MeO
MeO
I
MeO
MeO
MeO
MeO
4
NH2
I
Inspired by the structure and biological activity of thali-
carpine we became interested in the synthesis of the novel
laudanosine dimers 2 and 3, in which two laudanosine units
5
86%
MeO
1. PCl5, CH2Cl2, 18 h
2. NaBH4, MeOH, 0 °C
99% over 2 steps
TFAA, pyridine,
rt, 18 h
MeO
MeO
NH
MeO
MeO
N
H
N
70%
MeO
MeO
Me MeO
MeO
R
MeO
I
6
OMe
MeO
O
MeO
OMe
OMe
OMe
MeO
R
N
H
N
Cu-bronze,
220 °C, 1.5 h
NTFA
OMe
OMe
Me
MeO
MeO
OMe
decomposition
products
2, R = H
3, R = Me
MeO
I
1
7
* Corresponding authors. E-mail: spyne@uow.edu.au
Scheme 1.
0040–4020/$ - see front matter Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.083

S. R. Taylor et al. / Tetrahedron 63 (2007) 10896–10901
10897
desired biaryl coupled product. The key compound 7 was
prepared from the known compound, 2-iodo-4,5-dimethoxy-
phenylacetic acid 410 as shown in Scheme 1, using standard
procedures. The Bischler–Napieralski cyclisation of 5 was
carried out efficiently using PCl5 in CH2Cl2 according to
the procedure of Ziolkowski and Czarnocki11 Surprisingly
the amide 5 has only been reported once and not in a readily
accessible journal.12 The iodides 6 and 7 are new com-
pounds, while the corresponding 20-bromo analogues of
these compounds are known.13 Heating compound 7, or its
corresponding 20-bromo derivative, in the presence of copper-
bronze at 220 ꢀC under solvent free conditions for 1.5 h
leads to quantitative decomposition of the material and no
recognisable products could be isolated.
cyclisation of the bis-amide 13 using PCl5 in CH2Cl2 gave
the resulting bis-1,2-dihydro-isoquinoline 14 that was
immediately reduced with sodium borohydride to give 2 as
a 2:1 mixture of diastereomers (rac-2 and meso-2, not neces-
sarily respectively) in 67% yield. The bis-imine 14 was
extremely unstable and if the Bischler–Napieralski cyclisa-
tion reaction was left for more than 2 h at rt total decompo-
sition occurred. An alternative cyclisation procedure using
triflic anhydride in the presence of DMAP was not success-
ful.18 The instability of symmetrical di-imines is not a new
phenomenon,19 however, even attempting sequential
Bischler–Napieralski cyclisation and reduction of each
amide according to the method of Czarnocki19 failed to yield
the desired compound. Whilst only a limited number of cyc-
lisation conditions were studied, the PCl5 cyclisation condi-
tions seemed to be the best for this application.
An alternative and successful synthesis of 2 and 3 is shown
in Scheme 3, which involved formation of the key biaryl
bond early in the synthesis and then construction of the iso-
quinoline rings. To this end several methods to prepare the
known biphenyl 913–15 were examined (Scheme 2). Under
traditional Ullmann coupling reaction conditions,13 heating
compound 8 in the presence of copper-bronze at 220 ꢀC
under solvent free conditions for 1.5 h gave the desired
biphenyl 9 in 69% yield. When the corresponding bromo
analogue of 8 was employed the yield of 9 was reduced to
45% due to the formation of the debromo-derivative 10.
Alternatively, the biphenyl 9 could be obtained by direct
oxidative coupling of 10 using phenyliodotrifluoroacetate
The two isomers of 2 were readily separated by column
chromatography and had NMR and ESI-MS spectral data
consistent with their proposed structures. The major diaste-
reomer of 2 was converted to 3 by reductive N-methylation
in excellent yield (Scheme 3).
Cytostaticity studies against the cancer cell lines H460
(human non-small cell lung), MCF-7 (human breast) and
SF-268 (human CNS) were performed at the Peter Mac-
Callum Cancer Institute, Melbourne using NCI protocols.
Initially the % cell growth of cells incubated with 25 mM
of the compounds, thalicarpine 1, 2 (major diastereomer),
2 (minor diastereomer) and 3. The results are presented in
Table 1. Compound 3 (Table 1, entry 4) showed the weakest
cytostatic activity on all cell lines, while both the major and
minor diastereomers of 2 (Table 1, entries 2 and 3) showed
stronger cytostatic activity than thalicarpine (entry 1). The
IC50 of the major isomer of 2 was determined to be
>40 mM on the same three cell lines, which indicated it
had only modest cytotoxicity.
(PIFA)/BF3$Et2O in MeCN16 or molybdenum(V) chloride
17
˚
(MoCl5) /4A molecular sieves (MS) in yields of 41 and
55%, respectively. The latter method also produced the
ring chlorinated product 11, which was the major product
in the absence of an HCl scavenger. For example, treatment
of 10 with MoCl5 alone has 11 in 50% yield and the desired
biphenyl 9 in <10% yield. Although the addition of inor-
ganic bases (NaHCO3, NaH2PO4 or Na2CO3) reduced the
amount of 11 formed to 20–40% the yield of the desired bi-
phenyl 9 was still relatively low (10–20%). We found that
˚
the addition of 4 A MS to the reaction mixture worked the
best and suppressed the formation of 11 to 10% yield.
3. Conclusions
The biphenyl 9 was then taken through to the bis-benzyl-
isoquinoline 2 as shown in Scheme 3 using the chemistry
described in Scheme 1. The 1H NMR resonances attributed
to the methylene protons a to the carbonyl group of the bis-
amide 13 appeared as an ABq at d 3.23 (JAB¼15.3 Hz). Pre-
sumably the presence of the adjacent biaryl axis made these
methylene protons diastereotopic. The Bischler–Napieralski
In conclusion, the novel laudanosine dimers 2 and 3, in
which two laudanosine units are linked via a C-20 biaryl
bond have been prepared by a sequence that involves forma-
tion of the biaryl bond first and then formation of the isoqui-
noline rings. The rac- and meso-forms of 2 were readily
separated by column chromatography. Compound 3 showed
the weakest cytostatic activity on three cancer cell lines,
while both the major and minor diastereomers of 2 showed
higher cytostatic activity than thalicarpine 1.
MeO
MeO
MeO
MeO
Cu-bronze
COOMe
COOMe
OMe
220 °C, 1.5 h
I
69%
4. Experimental
4.1. General
MeOOC
8
OMe
9
PIFA, BF3.Et2O
MeCN,
PS refers to the fraction of petroleum spirit with a boiling
MeO
MeO
MeO
MeO
COOMe
1
point of 40–60 ꢀC. All H NMR spectral analyses were
COOMe
41%
9
+
performed at 300 MHz and all 13C NMR (DEPT) spectral
analyses at 75 MHz in CDCl3 solution, unless otherwise
noted. All spectra were referenced to CDCl3 (1H
or
Cl
MoCl5, CH2Cl2,
10
11
0 °C, 30 min
55%
1
d 7.26 ppm and 13C NMR d 77.00 ppm). H NMR assign-
Scheme 2.
ments were achieved with the aid of gCOSY, and in some

10898
S. R. Taylor et al. / Tetrahedron 63 (2007) 10896–10901
MeO
MeO
COOMe
OMe
K2CO3, MeOH, H2O,
40 °C, 2 h
MeO
MeO
COOH
98%
MeOOC
2
OMe
12
9
EDCI, HOBT,
DMF, 12 h
90%
MeO
MeO
NH2
MeO
MeO
MeO
N
1. PCl5, CH2Cl2;
2. NaBH4, MeOH
MeO
MeO
HN
O
67%
MeO
MeO
MeO
2
2
14
13
MeO
N
MeO
MeO
Me
MeO
NaCNBH3, CH2O, MeCN
96%
N
MeO
MeO
H
OMe
MeO
OMe
OMe
MeO
Me
2
N
2
OMe
3
Scheme 3.
NH). 13C NMR: d 169.6 (C]O), 149.6 (Ar–C–OCH3-5),
149.0 (Ar–C–OCH3-30), 148.7 (Ar–C–OCH3-4), 147.6
(Ar–C–OCH3-40), 130.9 (Ar–C-1), 130.5 (Ar–C-10), 121.6
(Ar–C–H-3), 120.5 (Ar–C–H-60), 113.0 (Ar–C–H-6),
111.7 (Ar–C–H-50), 111.1 (Ar–C–H-20), 88.8 (Ar–C-2),
56.1 (Ar–OCH3), 55.9 (Ar–OCH3), 55.84 (Ar–OCH3),
55.81 (Ar–OCH3), 48.1 (Ar–CH2–CO), 40.6 (Ar–CH2–
CH2–NH), 35.8 (Ar–CH2–CH2–NH). MS (EI+): m/z 485
(M+ 3%), 164 (100%); HRMS (EI+): calcd for
C20H24INO5¼485.0699 (Mꢂ+), found 485.0696.
Table 1. Cytostatic studies on cancer cell lines
Entry
Compound
Percentage cell growth
H460
MCF-7
SF-268
1
2
3
4
1
15
63
16.4
26.1
131
54
2 (Major)
2 (Minor)
3
0.8
5.4
95
40.9
23.7
78
cases NOESY and TOCSY experiments. 13C NMR assign-
ments were based upon DEPT, gHSQC and gHMBC exper-
iments. Compounds 4,10 820 and 1021 were prepared
according to the literature.
4.1.2. (R,S)-1-[(2-Iodo-4,5-dimethoxyphenyl)methyl]-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 6. PCl5
(107 mg, 0.51 mmol) was added to a stirred solution of 5
(100 mg, 0.21 mmol) in dry CH2Cl2 (5 mL) and the resulting
mixture stirred for 18 h at rt under an N2 atmosphere. The
solution was diluted with CH2Cl2 (10 mL), washed with
satd aqueous NaHCO3 (2ꢁ20 mL), dried over MgSO4, fil-
tered and evaporated. The resulting imine was dissolved in
dry ice-cold MeOH (5 mL) and sodium borohydride
(46 mg, 1.21 mmol) was added. The ice bath was removed
and the mixture stirred at rt for 1 h. The solvent was evapo-
rated under reduced pressure and the residue dissolved in
CH2Cl2 (10 mL). The solution was washed with satd aque-
ous Na2CO3 solution (2ꢁ10 mL), dried (K2CO3), filtered
and evaporated to yield the free amine as a white film
4.1.1. N-[2-(3,4-Dimethoxyphenyl)ethyl]-2-(2-iodo-4,5-
dimethoxyphenyl)acetamide 5. Compound 410 (1.11 g,
3.45 mmol), 2-[3,4-dimethoxyphenyl]ethylamine (1.45 mL,
8.62 mmol), HOBT (512 mg, 3.79 mmol) and EDCI
(730 mg, 3.79 mmol) were dissolved in dry DMF (15 mL)
under N2 and the solution was stirred for 18 h at rt. The mix-
ture was diluted with H2O (30 mL) and extracted with
CH2Cl2 (2ꢁ20 mL). The extracts were combined, washed
with H2O (2ꢁ30 mL), dried (MgSO4), filtered and evapo-
rated. The title compound was isolated as a white solid
(1.44 g, 86%) after purification by flash silica gel chroma-
tography with CH2Cl2/EtOAc (3:1) as mobile phase. Mp
1
(95 mg, 99%) that did not require further purification. H
1
176–178 ꢀC. H NMR: d 7.19 (s, 1H, Ar–H-3), 6.77 (s,
NMR: d 7.20 (s, 1H, Ar–H-30), 6.72 (s, 1H, Ar–H-60), 6.71
(s, 1H, Ar–H-5), 6.53 (s, 1H, Ar–H-8), 4.14 (dd, 1H,
J¼9.6, 4.2 Hz, Ar–H-1), 3.79 (s, 6H, OCH3-6, 7), 3.77 (s,
3H, OCH3-50), 3.76 (s, 3H, OCH3-40), 3.19 (dd, 1H,
J¼14.1, 4.2 Hz, Ar–CHa–CH–), 2.91–2.84 (m, 3H, Ar–
CH2–CH2–NH, Ar–CHb–CH–), 2.70 (d, 2H, J¼12.9, 6.3,
1H, Ar–H-6), 6.71 (d, 1H, J¼8.1 Hz, Ar–H-50), 6.64 (d,
1H, J¼2.1 Hz, Ar–H-20), 6.58 (dd, 1H, J¼8.1, 2.1 Hz, Ar–
H-60), 5.41 (t, J¼6.9 Hz, 1H, NH), 3.87 (s, 3H, OCH3-4),
3.85 (s, 3H, OCH3-40), 3.84 (s, 3H, OCH3-30), 3.82 (s, 3H,
OCH3-5), 3.60 (s, 2H, Ar–CH2), 3.47 (q, 2H, J¼6.9 Hz,
Ar–CH2–CH2–NH), 2.71 (t, 2H, J¼6.9, Ar–CH2–CH2–
13
Ar–CH2–CH2–NH). C NMR: d 149.4 (Ar–C–OCH3-50),

S. R. Taylor et al. / Tetrahedron 63 (2007) 10896–10901
10899
148.5 (Ar–C–OCH3-40), 147.8 (Ar–C–OCH3-7), 147.3
(Ar–C–OCH3-6), 134.1 (Ar–C-8a), 129.9 (Ar–C-4a),
127.2 (Ar–C-10), 122.0 (Ar–C–H-60), 114.0 (Ar–C–H-30),
111.9 (Ar–C–H-5), 109.9 (Ar–C–H-8), 89.0 (Ar–C-20), 56.4
(Ar–OCH3-6), 56.2 (Ar–OCH3-7), 56.1 (Ar–OCH3-50), 56.0
(Ar–OCH3-40), 55.5 (C-1), 47.0 (Ar–CH–NH), 40.7 (Ar–
CH2–CO, Ar–CH2–CH2–NH), 29.4 (Ar–CH2–CH2–NH).
MS (EI+): m/z 469 (M+ 6%), 340 (100%); HRMS (CI+): calcd
for C20H25INO4¼470.0828 (M+H+), found 470.0825.
combined, washed with satd aqueous NaHCO3 (20 mL),
dried (MgSO4), filtered and evaporated. Purification by flash
silica gel chromatography using EtOAc/PS (3:7) as the
eluent yielded the title compound.
Method 3. The title compound was also prepared in 69%
yield (clear crystals, 172 mg) by heating 820 (200 mg,
0.60 mmol) with freshly activated copper-bronze22
(200 mg) in a Wheaton vial at 220 ꢀC for 1.5 h. The heat
was removed and the mixture suspended in EtOAc
(50 mL), filtered and the solvent evaporated. The title com-
pound was purified by flash silica gel chromatography using
EtOAc/PS (3:7) as the eluent.
4.1.3. (R,S)-1-[(2-Iodo-4,5-dimethoxyoxophenyl)methyl]-
2-trifluoroacetyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline 7. Compound 6 (95 mg, 0.20 mmol) was dissolved
in dry pyridine (2 mL) and trifluoroacetic anhydride
(1.5 mL) was added. The solution was stirred for 18 h at rt.
The mixture was diluted and stirred with 1 M HCl solution
(10 mL) for 30 min, then extracted with CH2Cl2
(2ꢁ20 mL). The extracts were washed with satd aqueous
NaHCO3 solution (2ꢁ20 mL), dried (MgSO4), filtered and
evaporated. Purification by flash silica gel chromatography
with EtOAc/PS (1:1) as mobile phase yielded the title com-
pound as an orange film (81 mg, 70%). 1H NMR: d 7.19 (s,
1H, Ar–H-30), 6.65 (s, 1H, Ar–H-60), 6.60 (s, 1H, Ar–H-5),
6.52 (s, 1H, Ar–H-8), 5.71 (dd, 1H, J¼8.1, 6.3 Hz, H-1),
4.05–4.01 (m, 1H, Ar–CH2–CHa–NCOCF3), 3.86 (s, 3H,
OCH3-6), 3.84 (s, 3H, OCH3-7), 3.78 (s, 3H, OCH3-50),
3.74 (s, 3H, OCH3-40), 3.70 (d, 1H, J¼5.7 Hz, Ar–CH2–
CHb–NCOCF3), 3.26 (dd, 1H, J¼14.0, 6.3 Hz, Ar–CHa–
CH), 3.25 (dd, 1H, J¼14.0, 8.1 Hz, Ar–CHb-CH), 3.02–2.91
(m, 1H, Ar–CHa–CH2–NCOCF3), 2.79 (dt, 1H, J¼15.9,
3.9 Hz, Ar–CHb–CH2–NCOCF3). 13C NMR: d (C]O not
observed) 149.4 (Ar–C–OCH3-6), 148.7 (Ar–C–OCH3-50),
148.5 (Ar–C–OCH3-7), 147.9 (Ar–C–OCH3-40), 132.3
(Ar–C-10), 126.6 (Ar–C-4a), 125.1 (Ar–C-8a), 121.7 (Ar–
C–H-30), 116.8 (q, J¼284.1 Hz, NCOCF3), 113.1 (Ar–C–
H-60), 111.2 (Ar–C–H-5), 110.4 (Ar–C–H-8), 89.8 (Ar–C-20),
56.3 (Ar–OCH3-6), 56.2 (Ar–OCH3-7), 56.1 (Ar–OCH3-
50), 56.0 (Ar–OCH3-40), 54.5 (Ar–CH–NCOCF3), 45.6
(Ar–CH2–CH2–NCOCF3), 40.4 (Ar–CH2–CH), 28.9 (Ar–
CH2–CH2–NCOCF3). MS (EI+): m/z 565 (M+ 4%), 288
(100%); HRMS (EI+): calcd for C22H23IF3NO5¼565.0573
(Mꢂ+), found 565.0576.
Mp 142–144 ꢀC (lit.20 mp 145 ꢀC). 1H NMR: d 6.84 (s, 2H,
Ar–H-6), 6.72 (s, 2H, Ar–H-3), 3.92 (s, 6H, OCH3-5), 3.83
(s, 6H, OCH3-4), 3.60 (s, 6H, CO2CH3), 3.35 (ABq, 4H,
J¼16.5 Ar–CH2). 13C NMR: d 172.4 (C]O), 148.1 (Ar–
C–OCH3-4), 147.4 (Ar–C–OCH3-5), 132.8 (Ar–C-1), 124.6
(Ar–C-2), 113.2 (Ar–C–H-3), 112.5 (Ar–C–H-6), 55.8
(Ar–OCH3), 55.7 (Ar–OCH3), 51.8 (CO2CH3), 37.9 (Ar–
CH2). MS (CI+): m/z 419 (M+H, 100%); HRMS (EI+): calcd
for C22H26O8¼418.1627 (Mꢂ+), found 418.1615.
4.1.5. 2,20-(4,40,5,50-Tetramethoxybiphenyl-2,20-diyl)-
diacetic acid 12. Compound 9 (150 mg, 0.36 mmol) was
dissolved in methanol (2 mL) and added to a 40 ꢀC stirred
solution of K2CO3 (99 mg, 0.72 mmol) in H2O (2 mL). After
2 h the reaction was removed from the heat and the methanol
evaporated. The aqueous residue was acidified with 10%
aqueous HCl solution to pH 1, extracted with CH2Cl2
(2ꢁ20 mL), dried (MgSO4), filtered and evaporated to dry-
ness to yield the title compound as a white solid (137 mg,
98%). No further purification was required. Mp 228–
230 ꢀC (lit.20 228–230 ꢀC). 1H NMR: d 9.72 (br s, 1H,
COOH), 6.77 (s, 1H, Ar–H-3), 6.60 (s, 1H, Ar–H-6), 3.89
(s, 3H, OCH3-5), 3.82 (s, 3H, OCH3-4), 3.45 (ABq, 2H,
J¼17.7 Ar–CH2–CO). 13C NMR: d 179.1 (C]O), 148.3
(Ar–C–OCH3-4), 147.7 (Ar–C–OCH3-5), 132.9 (Ar–C-1),
124.5 (Ar–C-2), 113.1 (Ar–C–H-6), 112.8 (Ar–C–H-3),
55.9 (Ar–OCH3), 55.8 (Ar–OCH3), 37.3 (Ar–CH2–
COOH). MS (ESIꢃ): m/z 389 (Mꢃ, 37%), 114 (100%);
HRMS (ESIꢃ): calcd for C20H21O8¼389.1236 (Mꢃ), found
389.1218.
4.1.4. Dimethyl 2,20-(4,40,5,50-tetramethoxybiphenyl-2,20-
diyl)diacetate 9. Method 1. To a solution of 1021 (129 mg,
0.62 mmol) and PIFA (250 mg, 0.58 mmol) in dry MeCN
(10 mL) at 0 ꢀC under N2 was added BF3$Et2O (150 mL).
After 10 min the mixture was diluted with water (20 mL)
and extracted with CH2Cl2 (2ꢁ20 mL). The extracts were
combined, washed with satd aqueous NaHCO3 (20 mL),
dried (MgSO4), filtered and evaporated. Purification by flash
silica gel chromatography using EtOAc/PS (3:7) as the
eluent yielded the title compound as clear crystals
(53 mg, 41%).
4.1.6. N,N0-Di-[2-(3,4-dimethoxyphenyl)ethyl]-2,20-
(4,40,5,50-tetramethoxybiphenyl-2,20-diyl)diacetamide
13. The diacid 12 (130 mg, 0.33), 2-[3,4-dimethoxyphenyl]-
ethylamine (0.28 mL, 1.65 mmol), HOBT (99 mg,
0.73 mmol) and EDCI (128 mg, 0.66 mmol) were dissolved
in dry DMF (6 mL) under N2 and the solution was stirred for
18 h at rt. The mixture was diluted with H2O (30 mL) and
extracted with CH2Cl2 (2ꢁ20 mL). The extracts were
combined, washed with H2O (2ꢁ30 mL), dried (MgSO4),
filtered and evaporated. The title compound was isolated
as a white solid (214 g, 90%) after purification by flash silica
gel chromatography with CH2Cl2/EtOAc (3:1) as mobile
Method 2. The title compound was also prepared in 55%
yield (clear crystals, 110 mg) by stirring 1021 (200 mg,
0.95 mmol) in dry CH2Cl2 (20 mL) with powdered mole-
1
phase. Mp 162–164 ꢀC. H NMR: d 6.81 (s, 1H, Ar–H-30),
˚
cular sieves (4 A, 500 mg) for 30 min and cooling the mix-
6.72 (d, 1H, J¼8.1 Hz, Ar–H-5), 6.63 (d, 1H, J¼2.1 Hz,
Ar–H-2), 6.58 (s, 1H, Ar–H-60), 6.55 (dd, J¼8.1, 2.1 Hz,
Ar–H-6), 5.78 (t, 1H, J¼5.4 Hz, NH), 3.87 (s, 3H, OCH3-
40), 3.85 (s, 3H, OCH3-4), 3.81 (s, 3H, OCH3-3), 3.80 (s,
3H, OCH3-50), 3.35 (dt, 2H, J¼6.9, 5.4 Hz, Ar–CH2–CH2–
ture to 0 ꢀC. MoCl5 (570 mg, 2.11 mmol) was added to the
reaction mixture and stirring was continued at 0 ꢀC for 2 h
after which the mixture was diluted with water (15 mL)
and extracted with DCM (2ꢁ20 mL). The extracts were

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S. R. Taylor et al. / Tetrahedron 63 (2007) 10896–10901
NH), 3.23 (ABq, 2H, J¼15.3 Ar–CH2–CO), 2.66 (t, 2H,
J¼6.9, Ar–CH2–CH2–NH). 13C NMR: d 171.1 (C]O),
148.9 (Ar–C–OCH3-50), 148.5 (2ꢁAr–C-OCH3-4,40),
147.6 (Ar–C–OCH3-5), 132.6 (Ar–C-20), 131.0 (Ar–C-1),
125.7 (Ar–C-10), 120.5 (Ar–C–H-6), 113.2 (Ar–C–H-60),
112.4 (Ar–C–H-30), 111.6 (Ar–C–H-2), 111.1 (Ar–C–H-5),
56.0 (Ar–OCH3), 55.9 (Ar–OCH3), 55.8 (Ar–OCH3), 55.7
(Ar–OCH3), 40.8 (Ar–CH2–CH2–NH), 40.6 (Ar–CH2–
CO), 34.9 (Ar–CH2–CH2–NH). MS (ES+): m/z 717 (M+H,
30%), 288 (100%); HRMS (ESI+): calcd for C40H49N2O10¼
717.3387 (MH+), found 717.3402.
(Ar–CH2–CH), 39.2 (Ar–CH2–CH2–NH), 29.5 (Ar–CH2–
CH2–NH). MS: m/z (ESI+) 685 (M+H, 100%); HRMS
(ESI+): calcd for C40H49N2O8¼685.3489, found 685.3480.
4.1.8. (1RS,10RS),(1R,10S),PM-2,20-[Di-{(1,2,3,4-tetrahy-
dro-6,7-dimethoxy-2-methylisoquinolin-1-yl)methyl}]-
4,40,5,50-biphenyl 3. The major isomer of 2 (8.6 mg) was
dissolved in dry MeCN (0.5 mL) to which sodium cyanoboro-
hydride (15 mg), 28% formaldehyde solution (0.2 mL) and
acetic acid (two drops) were added and the solution was
stirred for 3 h. The reaction was diluted with CH2Cl2
(10 mL), washed with satd aqueous NaHCO3 solution
(2ꢁ10 mL), dried over anhydrous K2CO3, filtered and evap-
orated. Purification by silica gel chromatography using
CH2Cl2/EtOAc/MeOH/NH3 (10:5:1:trace) as the eluent
afforded the title compound as an opaque film (9 mg,
4.1.7. (1RS,1000RS) and (1R,1000S)-2,20-[Di-{(6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinolin-1-yl)methyl}]-4,40,5,50-
biphenyl 2. PCl5 (87 mg, 0.42 mmol) was added to a stirred
solution of compound 13 (50 mg, 0.07 mmol) in dry CH2Cl2
(2 mL) and the resulting mixture stirred for 2 h at rt under an
N2 atmosphere. The solution was diluted with CH2Cl2
(10 mL), washed with satd aqueous NaHCO3 (2ꢁ20 mL),
dried (MgSO4), filtered and evaporated. The resulting imine
was dissolved in dry ice-cold MeOH (5 mL) and sodium
borohydride (8 mg, 0.2 mmol) was added. The ice bath
was removed and the mixture stirred at rt for 1 h. The solvent
was evaporated under reduced pressure and the residue dis-
solved in CH2Cl2 (10 mL). The solution was washed with
satd aqueous Na2CO3 solution (2ꢁ10 mL), dried (K2CO3),
filtered and evaporated. The crude mixture was separated
by column chromatography using CH2Cl2/EtOH/MeOH/
NH3 (10:5:1:0.1) as the eluent to yield pure samples of the
major isomer as a white solid (20 mg, 42%, Rf 0.2) and the
minor isomer as a white solid (12 mg, 25%, Rf 0.4); reflect-
ing a combined yield of 67% for both diastereomers.
1
96%). H NMR: d 6.81 (s, 1H, Ar–H-30), 6.38 (s, 1H, Ar–
H-60), 6.07 (s, 1H, Ar–H-5), 5.60 (s, 1H, Ar–H-8), 3.79 (s,
3H, OCH3-40), 3.70 (s, 3H, OCH3-50), 3.61 (s, 3H, OCH3-
7), 3.51 (s, 3H, OCH3-6), 3.38 (s, 1H, H-1), 2.97–2.80 (m,
2H, Ar–CH2–CH), 2.77–2.63 (m, 2H, Ar–CH2–CH2–
NCH3), 2.57–2.30 (m, 2H, Ar–CH2–CH2–NCH3), 2.27 (s,
13
3H, NCH3). C NMR: d 148.0 (Ar–C–OCH3-50), 147.5
(Ar–C–OCH3-40), 147.1 (Ar–C–OCH3-70), 146.6 (Ar–C–
OCH3-60), 133.7 (Ar–C-10), 130.0 (Ar–C-2), 126.0
(Ar–C-4a), 125.4 (Ar–C-8a), 113.4 (Ar–C–H-60), 113.1
(Ar–C–H-30), 111.2 (Ar–C–H-5), 110.7 (Ar–C–H-8), 64.1
(C-1), 56.2 (Ar–OCH3), 56.1 (Ar–OCH3), 56.0 (Ar–
OCH3), 55.8 (Ar–OCH3), 45.7 (Ar–CH2–CH), 42.9
(NCH3), 37.6 (Ar–CH2–CH2–NCH3), 24.2 (Ar–CH2–CH2–
NCH3). MS: m/z (ESI+) 713 (MH+, 100%); HRMS (ESI+):
calcd for C42H53N2O8¼713.3802, found 713.3812.
1
Major isomer. H NMR (the individual methoxy signals
could not be assigned unequivocally): d 6.94 (s, 1H, Ar–H-
30), 6.46 (s, 1H, Ar–H-60), 6.26 (s, 1H, Ar–H-5), 6.05 (s,
1H, Ar–H-8), 4.06–3.93 (m, 1H, H-1), 3.83 (s, 3H, OCH3),
3.75 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 3.52 (s, 3H,
OCH3), 3.26–3.16 (m, 2H, Ar–CH2–CH), 3.11–2.96 (m,
2H, Ar–CH2–CH2–NH), 2.91–2.70 (m, 2H, Ar-CH2-CH2-
Acknowledgements
We thank Johnson and Johnson Research Pty. Limited,
Sydney and the University of Wollongong for supporting
this research and Dr. Wayne Gerlach for encouragement
and support. We thank Prof. Meinhart H. Zenk for a generous
gift of thalicarpine.
13
NH). C NMR: d 148.7 (Ar–C–OCH3-50), 148.1 (Ar–C–
OCH3-40), 147.9 (Ar–C–OCH3-7), 147.4 (Ar–C–OCH3-6),
135.4 (Ar–C-10), 134.3 (Ar–C-20), 133.0 (Ar–C-4a), 123.9
(Ar–C-8a), 113.9 (Ar–C–H-30), 112.6 (Ar–C–H-60), 111.1
(Ar–C–H-8), 110.7 (Ar–C–H-5), 56.0 (Ar–OCH3), 55.8
(Ar–OCH3), 55.7 (Ar–OCH3), 55.5 (Ar–OCH3), 51.9 (C-
1), 40.1 (Ar–CH2–CH), 37.4 (Ar–CH2–CH2–NH), 25.0
(Ar–CH2–CH2–NH). MS: m/z (ES+) 685 (M+H, 100%);
HRMS (ES+): calcd for C40H49N2O8¼684.3489, found
684.3480.
References and notes
1. ROMPP Encyclopedia of Natural Products; Steglish, W.,
Fugmann, B., Lang-Fugmann, S., Eds.; Thieme: Stuttgart,
2000; pp 84–85.
2. See for example the alkaloids, guattaminone: Berthou, S.;
ꢀ
Jossang, A.; Guinaudeau, H.; Lebceuf, M.; Cave, A.
Tetrahedron 1988, 44, 2193–2201 and tiliarine: Ray, A. K.;
Mukhopadhyay, G.; Mitra, S. K.; Guha, K. P.; Mukherjee, B.;
Rahman, A.-U.; Nelofar, A. Phytochemistry 1990, 29, 1020–
1022.
Minor isomer. 1H NMR: d 6.83 (s, 1H, Ar–H-30), 6.42 (s, 1H,
Ar–H-60), 6.09 (s, 1H, Ar–H-5), 5.79 (s, 1H, Ar–H-8), 3.97–
3.87 (m, 1H, H-1), 3.80 (s, 3H, OCH3-40), 3.73 (s, 3H,
OCH3-50), 3.72 (s, 3H, OCH3-7), 3.65 (s, 3H, OCH3-6),
3.10–2.82 (m, 2H, Ar–CH2–CH), 2.74–2.67 (m, 2H, Ar–
CH2–CH2–NH), 2.65–2.58 (m, 2H, Ar–CH2–CH2–NH).
13C NMR: d 148.1 (Ar–C–OCH3-50), 147.2 (Ar–C–OCH3-
40), 147.1 (Ar–C–OCH3-7), 146.9 (Ar–C–OCH3-6), 133.4
(Ar–C-10), 133.2 (Ar–C-20), 129.4 (Ar–C-4a), 126.5 (Ar–
C-8a), 113.6 (Ar–C–H-30), 112.9 (Ar–C–H-60), 111.4 (Ar–
C–H-8), 109.3 (Ar–C–H-5), 56.1 (C-1), 55.9 (Ar–OCH3),
55.8 (Ar–OCH3), 55.7 (Ar–OCH3), 55.6 (Ar–OCH3), 39.3
3. Kupchan, S. M.; Chakravarti, K. K.; Yokoyama, N. J. Pharm.
Sci. 1963, 52, 985–988.
4. Kupchan, S. M.; Altland, H. W. J. Med. Chem.1973, 16, 913–917.
5. Seifert, F.; Todorov, D.; Hutter, K. J.; Zeller, W. J. J. Cancer
Res. Clin. Oncol. 1996, 122, 707–710.
6. Todorov, D.; Zeller, W. J. J. Cancer Res. Clin. Oncol. 1992,
118, 83–86.
7. Creaven, P. J.; Cohen, M. H.; Selawry, O. S.; Tejada, F.; Broder,
L. E. Cancer Chemother. Rep. 1975, 59, 1001–1006.
8. Todorov, D.; Zeller, W. J. Drugs Future 1988, 13, 234–238.

S. R. Taylor et al. / Tetrahedron 63 (2007) 10896–10901
10901
9. Leimert, J. T.; Corder, M. P.; Elliott, T. E.; Lovett, J. M. Cancer
Chemother. Rep. 1980, 64, 1271–1277.
10. Olivera, R.; SanMartin, R.; Churruca, F.; Dominguez, E.
J. Org. Chem. 2002, 67, 7215–7225.
11. Ziolkowski, M.; Czarnocki, Z. Tetrahedron Lett. 2000, 41,
1963–1966.
12. Trifonov, L.; Orakhovats, A. Izv. Khim. 1978, 11, 297–304
[CAN 92:164129].
2004, 1970–1974; Waldvogel, S. R.; Aits, E.; Holst, C.;
Frohlich, R. Chem. Commun. 2002, 1278–1279; Kumar, S.;
Manickam, M. Chem. Commun 1997, 1615–1616.
18. Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J.;
Hockless, D. C. R.; Holman, J. W.; Read, R. W.; Wu, A. W.
J. Chem. Soc., Chem. Commun. 1995, 2551–2553; Banwell,
M. G.; Harvey, J. E.; Hockless, D. C. R.; Wu, A. W. J. Org.
Chem. 2000, 65, 4241–4250.
13. Ahmad, I.; Gibson, M. S. Can. J. Chem. 1975, 53, 3360–3364;
Orito, K.; Miyazawa, M.; Kanbayashi, R.; Tokuda, M.;
Suginome, H. J. Org. Chem. 1999, 64, 6583–6596.
14. Forbes, E. J.; Gray, C. J. Tetrahedron 1968, 24, 2795–2800.
15. Kametani, T.; Fukumoto, K.; Shibuya, S.; Nakano, T. Chem.
Pharm. Bull. 1963, 11, 1299–1305.
19. Czarnocki, Z.; Mieczkowski, J. B.; Ziolkowski, M.
Tetrahedron: Asymmetry 1996, 7, 2711–2720; Ziolkowski,
M.; Czarnocki, Z.; Leniewski, A.; Maurin, J. K. Tetrahedron:
Asymmetry 1999, 10, 3371–3380; Arazny, Z.; Czarnocki, Z.;
Wojtasiewicz, K.; Maurin, J. K. Tetrahedron: Asymmetry
2000, 11, 1623–1629.
16. Takada, T.; Arisawa, M.; Gyoten, M.; Hamada, R.; Tohma, H.;
Kita, Y. J. Org. Chem. 1998, 63, 7698–7706; Hamamoto, H.;
Anilkumar, G.; Tohma, H.; Kita, Y. Chem.—Eur. J. 2002, 8,
5377–5383.
17. Waldvogel, S. R. Synlett 2002, 622–624; Kramer, B.; Frohlich,
R.; Bergander, K.; Waldvogel, S. R. Synthesis 2003, 1, 91–96;
Mirk, D.; Wibbeling, B.; Frohlich, R.; Waldvogel, S. R. Synlett
20. Cromartje, R. I. T.; Harley-Mason, J.; Wannigama, D. G. P.
J. Chem. Soc. 1958, 1981–1985; Weisgraber, K. H.; Weiss,
U. J. Chem. Soc., Perkin Trans. 1 1972, 83–88.
21. Gardiner, J. M.; Bryce, M. R. J. Org. Chem. 1990, 55, 1261–
1266.
22. Kelly, T. R.; Xie, R. L. J. Org. Chem. 1998, 63, 8045–
8048.