The synthesis of carbon linked bis-benzylisoquinolines using Mizoroki-Heck and Sonagashira coupling reactions

Article abstract of DOI:10.1016/j.tet.2008.10.052

Novel laudanosine dimers in which two laudanosine units are linked at C-2′ via a two or three-carbon linker (alkane, alkene or alkyne) have been prepared using palladium-catalysed cross-coupling reactions (Mizoroki-Heck and Sonagashira reactions). In one

Full text of DOI:10.1016/j.tet.2008.10.052

Tetrahedron 65 (2009) 318–327
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Tetrahedron
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The synthesis of carbon linked bis-benzylisoquinolines using Mizoroki–Heck
and Sonagashira coupling reactions
*
*
Uta Batenburg-Nguyen, Alison T. Ung , Stephen G. Pyne
School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
a r t i c l e i n f o
a b s t r a c t
Novel laudanosine dimers in which two laudanosine units are linked at C-20 via a two or three-carbon
linker (alkane, alkene or alkyne) have been prepared using palladium-catalysed cross-coupling reactions
(Mizoroki–Heck and Sonagashira reactions). In one example, a second three-carbon linker between the
two isoquinoline N-atoms was also present leading to a novel macrocyclic ring system.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Article history:
Received 4 August 2008
Received in revised form 1 October 2008
Accepted 16 October 2008
Available online 1 November 2008
1. Introduction
Over 200 bisbenzylisoquinoline alkaloids are known, the ma-
jority 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 bisbenzylisoquinoline alkaloids show a range of interesting
biological activities.1 The related Thalictrum alkaloid, thalicarpine 1
(Fig. 1),3 comprises the benzylisoquinoline, S-laudanosine, con-
nected 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
Inspired by the structure and biological activities of thalicarpine,
we became interested in the synthesis of the novel laudanosine
dimers of the type 2 and 3 (Fig. 1), in which two laudanosine units
are linked at C-20 through a two or three-carbon linker (alkane,
alkene or alkyne). In the example 3, a second three-carbon linker
between the two isoquinoline N-atoms was also present leading to
a macrocyclic ring system. This paper describes the successful
synthesis of the racemic and meso forms of these target com-
pounds, and in one case the pure (S,S)-enantiomer.
CH3O
NH
H
CH3O
CH3O
CH3O
O
OCH3
H
OCH3
OCH3
HN
1
CH3O
NH
CH3O
CH3O
OCH3
OCH3
OCH3
OCH3
CH3O
CH3O
()n
single, double
or triple bond
HN
O
2, n = 0, 1
2. Discussion
N
CH3O
CH3O
N
O
Our approach to the target molecules 2 (alkene linker) was based
on a Mizoroki–Heck coupling reaction of racemic N-trifluoroacetyl-
20-iodonorlaudanosine 410 and the racemic alkenes rac-5 and rac-6.
CH3O
OCH3
OCH3
OCH3
OCH3
3
* Corresponding authors.
Figure 1.
E-mail address: spyne@uow.edu.au (S.G. Pyne).
0040-4020/$ – see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.052

U. Batenburg-Nguyen et al. / Tetrahedron 65 (2009) 318–327
319
Table 1
Pd(OAc)2
or PdCl2
CH3O
CH3O
Mizoroki–Heck coupling reactions of 4 and 5 with Pd(OAc)2 at 130 ꢀ
C
PPh3, DMF
100 °C, 36 h
NTFA
Ratio of 7/8b
Yield (%)
NTFA
Entry
Additive
Base
Solvent
CH3O
CH3O
CH3O
CH3O
of 7þ8c
1
2
3
4
5
Ph3Pa
Ph3P
NMG
d
Et3N
MeCN
NMP
NMP
NMP
NMP
50:50
60:40
80:20
40:60
90:10
29
50
66
54
24
SnBu3
NaOAc
NaOAc
NaOAc
NaOAc/
Ag3PO4
CH3O
I
CH3O
79-87 %
rac-4
rac-5
NMG
Pd(OAc)2
or PdCl2
PPh3, DMF
100 °C, 36 h
CH3O
a
Reaction temperature 110 ꢀC.
From 1H NMR analysis.
Combined yield of 7 and 8 after column chromatography.
NTFA
b
c
CH3O
CH3O
rac-4
SnBu3
60:40). The formation of regioisomers in Mizoroki–Heck reactions
on related substrates is well documented and has been shown to be
dependent upon the steric and electronic natures of the substrates
and the nature of the ligand, solvent, base and catalyst.11–20 The
ratio of 7 and 8 formed in these reactions was also dependent upon
the reaction solvent, the ligand and the nature of the base (Table 1).
The combination of N,N-dimethylglycine (DMG), sodium acetate
and N-methylpyrrolidinone (NMP) at 130 ꢀC for 18 h resulted in the
best yields (combined yield of 66%) and regioselectivities for 7 over
8 (80:20, respectively) (Table 1, entry 3). These conditions repre-
sented a significant improvement over the more traditional Heck
conditions shown in Table 1, entry 1. The use of silver salts in-
creased the regioselectivity (90:10), but decreased the yield of 7
and 8 significantly (Table 1, entry 5). The regioisomers 7 and 8 could
not be easily separated by column chromatography. On a pre-
parative scale, using the conditions in Table 1, entry 3, the major
regioisomer 7 could be isolated pure (as a mixture of racemate and
meso forms) by simply adding methanol to the reaction flask at the
end of the reaction (Scheme 3). Pure rac/meso-7 precipitated out as
a white solid in 54% yield. A small amount of meso-7 could be
isolated by trituration of this white solid with dichloromethane in
which meso-7 was much more soluble than rac-7. This synthetic
sequence was repeated using (S)-421 and (S)-5,21 which allowed the
unequivocal assignment of the (S,S), rac and meso forms of 7 (Fig. 2).
Column chromatography of the initial mother liquors from which
rac-7 precipitated then gave pure regioisomer 8 (as a mixture of
racemate and meso forms) in 12% yield (Scheme 3).
CH3O
82-89 %
rac-6
Scheme 1.
The alkenes rac-5 and rac-6 were efficiently prepared from rac-4
using Stille coupling reactions (Scheme 1). Palladium acetate gave
slightly better yields of rac-5 and rac-6 (87% and 89%, respectively)
than palladium chloride (79% and 82%, respectively).
The Mizoroki–Heck coupling reaction of rac-4 and rac-5 using
palladium acetate as the catalyst gave mixtures of the regioisomeric
products rac-7 and rac-8 (Scheme 2). These were difficult to sepa-
rate by column chromatography. These regioisomers were both
isolated as mixtures of the racemic and meso forms (ca. 55:45 to
Pd(OAc)2, base,
additive, solvent.
110-130 °C, 18 h
4
5
CH3O
NR
CH3O
CH3O
CH3O
OCH3
OCH3
OCH3
Base hydrolysis of rac/meso-7 and rac/meso-8 then gave rac/meso-9
and rac/meso-10, respectively(Scheme 2). A mixture of rac/meso-10could
NR
OCH3
K2CO3
MeOH, H2O
80 °C, 3 d
41%
rac/meso-7
7, R = TFA
9, R = H
Pd/C
H2
acetone
CH3O
NR
CH3O
CH3O
CH3O
CH3O
meso-7
NR
[30%]
CH3O
OCH3
OCH3
OCH3
R
N
OCH3
OCH3
RN
OCH3
OCH3
OCH3
CH3O
K2CO3
MeOH
H2O
rac-11; R = TFA
OCH3
[35%]
K2CO3
rac-12; R = H
8, R = TFA
10, R = H
rt, 24 h
MeOH, H2O
80 °C, 5 h
45%
[95%]
[only the (S,S)-isomer shown)]
Scheme 3.
Scheme 2.

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U. Batenburg-Nguyen et al. / Tetrahedron 65 (2009) 318–327
5
CH3O
N
1
TFA
3``
CH3O
CH3O
8
6'
CH3O
3'
OCH3
OCH3
OCH3
6``
8`
TFA
1`
N
OCH3
5`
rac/meso-7
Figure 2. The 1H NMR spectra (300 MHz, CDCl3) of the mixture of meso-7 and rac-7 (top), (S,S)-7 (middle) and meso-7 (bottom).
be separated by preparative TLC. The stereochemistry of the individual
isomers (whether rac or meso), however, could not be determined.
Compound rac/meso-7 was found to be insoluble in most solvents
commonly employed for hydrogenation reactions (e.g., MeOH, EtOH
and EtOAc) but was found to be partially soluble in acetone. Hydro-
genation of rac/meso-7 in acetone resulted in the selective hydro-
genation of the more soluble rac-7. After filtration of the catalyst,
addition of methanol to the solution resulted in the precipitation of

U. Batenburg-Nguyen et al. / Tetrahedron 65 (2009) 318–327
321
Pd(OAc)2, NaOAc, DMG
NMP, 130 °C, 18 h
mixture of the racemic and meso forms (not necessarily, re-
spectively) (Scheme 4). This mixture was then converted to an in-
separable mixture of rac/meso-14 upon base hydrolysis (Scheme 4).
A Sonagashira coupling reaction between rac-4 and trime-
thylsilylacetylene (3 equiv) gave a mixture of the desired product
rac-15 (45%) and the undesired ene–yne rac-16 (52%) (Scheme 5).
The structure of the ene–yne rac-16 was based upon the downfield
rac-4 + rac-6
48 %
CH3O
NR
CH3O
CH3O
OCH3
OCH3
OCH3
1H NMR chemical shift of its alkene proton at
alternative regioisomeric product would be expected to have an
alkene chemical shift at ca.
7.0.22–24 When 1.5 equiv of trime-
d
8.15 (s, 1H).22–24 The
OCH3
CH3O
d
thylsilylacetylene was employed the yield of rac-15 was 92%
(Scheme 5). Compound -15 was converted to the primary alkyne
rac-17, which underwent a Sonagashira coupling reaction with rac-
4 to give rac/meso-18 in 49% yield. The 1H and 13C NMR spectra of
this compound indicated a single stereoisomer had formed (no
doubling up of resonances was observed). This suggested that ei-
ther the meso or the rac form of 18 had failed to form in this reaction
or that either meso- or rac-18 was unstable to the reaction condi-
tions and decomposed. A more likely explanation is that, because of
the rigid alkyne tether, the two stereogenic centres in the iso-
quinoline ring are too remote to interact and thus the rac and meso
forms of 18 have the same NMR chemical shifts. Base hydrolysis of
rac/meso-18 gave rac/meso-19 in 79% yield. The NMR spectra of 19
also did not show the doubling up of resonances.
RN
K2CO3
MeOH
H2O
rac/meso-13; R = TFA
rac/meso-14; R = H
rt, 24 h
[58%]
Scheme 4.
pure meso-7 in 30% yield while further purification of the mother
liquors by column chromatography gave rac-11 in 35% yield (Scheme
3). Base hydrolysis of rac-11 then gave rac-12 in 95% yield (Scheme 3).
Under similar Mizoroki–Heck coupling reaction conditions to
those described in Scheme 2, rac-4 and rac-6 underwent a Mizo-
roki–Heck coupling reaction to give 13 in 48% yield as ca. 60:40
Base hydrolysis of rac-6 gave the secondary amine rac-20 in 90%
yield (Scheme 6), which was condensed with succinic anhydride to
rac-4
O
O
O
CH3O
K2CO3,
N
H
TMS
Et3N, dry DCM
N2, 18 h, rt
CH3OH/H2O CH3O
H
rt, 18 h
90 %
CH3O
PdCl2, PPh3, CuI,
Et3N, THF, rt, 4 d
rac-6
79 %
CH3O
rac-20
CH3O
CH3O
CH3O
O
NTFA
NTFA
H
HOBt/EDCI
DMF, rt, N2, 3 d
CH3O
CH3O
CH3O
CH3O
N
OH
CH3O
CH3O
O
CH3O
1''
2''
CH3O
CH3O
CH3O
NH
R
CH3O
CH3O
TMS
15; R = TMS
rac-21
KF, H2O
CH3OH
rt, 18 h
TMS
[92%]
16
17; R = H
[54%]
CH3O
Br
rac-22
82 %
CH3O
O
N
PdCl2, PPh3, CuI,
Et3N, THF, rt, 24 h
rac-4
Pd(OAc)2
Ph3P
Et3N, MeCN
110 °C
OCH3
N
CH3O
CH3O
+
rac-17
O
Br
CH3O
CH3O
NR
15%
OCH3
CH3O
CH3O
OCH3
OCH3
rac/meso-23
CH3O
OCH3
CH3O
OCH3
OCH3
O
N
CH3O
CH3O
RN
N
O
OCH3
CH3O
OCH3
OCH3
OCH3
OCH3
rac/meso-18; R = TFA
K2CO3
MeOH, H2O
rt, 24 h
[49%]
rac/meso-19; R = H
meso- or rac-3
Scheme 6.
[79%]
Scheme 5.

322
U. Batenburg-Nguyen et al. / Tetrahedron 65 (2009) 318–327
give the amido acid rac-21 in 79% yield. An amide coupling reaction
between the acid rac-21 and the 20-bromobenzylisoquinoline de-
rivative rac-2225 gave the bisamide 23 as a mixture of the racemic
and meso forms (Scheme 6). Attempts to convert rac/meso-23 to the
target macrocyclic compound 3 using the Mizoroki–Heck reaction
conditions developed in Schemes 2 and 4 were unsuccessful and
resulted in a complex mixture of products. However, under the more
traditional Heck reaction conditions (Pd(OAc)2, Ph3P and Et3N) the
desired compound 3 was obtained in 15% yield. NMR analysis of 3
indicated that a single isomer was obtained, with only one set of
separate resonances observed for each different isoquinoline moi-
ety. We made no attempts to determine whether this was the ra-
cemic or meso form of 3. The NMRevidence suggested thateither the
meso or the rac form of 3 had failed to form in this reaction or that
either meso or rac forms of 23 or 3 were unstable to the reaction
conditions and decomposed. 1H NMR analysis of 3 clearly indicated
3.2. General method for Stille coupling reactions
To a thick walled tube (sealed tube) containing a solution of 20-
iodolaudanosine 4, PdCl2 and PPh3 in dry DMF under N2 was added
allyltributylstannane or tributylvinylstannane. The tube was sealed
under a N2 atmosphere and the mixture was stirred and heated at
110 ꢀC for 36 h. The solution was cooled, diluted with CH2Cl2 and
washed with H2O (4ꢁ) and then with brine. The CH2Cl2 layer was
evaporated and the residue was redissolved in CH3CN and extracted
with hexane. The CH3CN layer was evaporated and the residue was
purified by column chromatography (EtOAc/petrol (1:1)) (unless
indicated otherwise) to afford the pure products.
3.2.1. (RS)-1-(20-Ethenyl-40,50-dimethoxyphenyl)methyl-2-
trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (5)
The 20-iodolaudanosine derivative 4 (492 mg, 0.870 mmol),
Pd(OAc)2 (16 mg, 0.071 mmol), PPh3 (43 mg, 0.174 mmol) and
tributylvinylstannane (333 mg, 1.04 mmol, 0.29 mL) in dry DMF
(10 mL) under N2 were treated as described above using the general
Stille coupling reaction conditions to afford a residue, which was
purified by column chromatography to afford 5 (352 mg, 87%) as
a yellow solid. The yellow solid was recrystallised from EtOAc/
petrol (1:1) and was a 95:5 mixture of rotamers. Rf 0.48 (EtOAc/
petrol (1:1)). Mp 132–134 ꢀC. 1H NMR of the major rotamer
that the (E)-isomer of 3 was obtained (d 6.93 (d, 1H, J 15.3 Hz)).
In summary, several novel laudanosine dimers in which two
laudanosine units are linked at C-20 via a two or three-carbon linker
(alkane, alkene or alkyne) have been prepared using palladium-cat-
alysed cross-coupling reactions. In one example, a second three-
carbon linker between the two isoquinoline N-atoms was also
present leading tothe novel macrocyclic ring system 3. The biological
activities of the N-deprotected bisisoquinoline compounds and the
macrocyclic compound 3 will be reported in a separate publication.
(500 MHz): d
6.97 (s, 1H, H30), 6.81 (dd, 1H, J 17.0, 11.0 Hz, H100), 6.56
(s,1H, H8), 6.39 (s, 1H, H5), 6.08 (s, 1H, H60), 5.50 (t, 1H, J 7.0 Hz, H1),
5.46 (d, 1H, J 17.0 Hz, H200(E)), 5.13 (d, 1H, J 11.0 Hz, H200(Z)), 3.87 (dt,
1H, J 9.0, 4.0 Hz, H3), 3.87 (s, 3H, OCH3-40), 3.82 (s, 3H, OCH3-6), 3.70
(s, 3H, OCH3-7), 3.63–3.61 (m, 1H, H3), 3.57 (s, 3H, OCH3-50), 3.16 (d,
2H, J 7.0 Hz, H70), 2.92–2.83 (m,1H, H4), 2.71 (m, 1H, H4). 1H NMR of
3. Experimental
3.1. General procedures
Petrolreferstothefractionofpetroleumspiritwitha boilingpoint
of40–60 ꢀC. All1HNMRspectrawererecordedat300 MHzandall13C
NMR (DEPT) spectra at 75 MHz in CDCl3 solution, unless otherwise
the minor rotamer (in part): d 6.57 (s, 1H, H8), 6.41 (s, 1H, H5), 5.84
(s, 1H, H60), 3.84 (s, 3H, OCH3-40), 3.84 (s, 3H, OCH3-6), 3.78 (s, 3H,
OCH3-7), 3.51 (s, 3H, OCH3-50). 13C NMR of the major rotamer
(125 MHz): (signals for COCF3 and COCF3 were not observed)
noted. All spectra were referenced to CDCl3 (1H
d C
7.26 ppm and 13
NMR
d
77.00 ppm). 1H NMR assignments were achieved with the aid
d
148.8 (C40), 148.5 (C6), 148.3 (C7), 147.6 (C50), 133.9 (CH-100), 130.4
of gCOSY, and in some cases NOESYand TOCSYexperiments.13C NMR
assignments were based upon DEPT, gHSQC and gHMBC experi-
ments. All compounds were homogeneous by TLC analysis and
judged to be of >95% purity based upon 1H NMR analysis.
(C20), 127.3 (C4a), 126.4 (C8a), 125.4 (C10), 114.5 (CH2-200), 114.1 (CH-
30), 111.2 (CH-5), 111.0 (CH-8), 108.5 (CH-60), 56.2 (OCH3-40), 56.2
(OCH3-6), 56.1 (OCH3-7), 56.0 (OCH3-50), 55.6 (CH-1), 41.0 (CH2-3),
38.2 (CH2-70), 28.7 (CH2-4). MS (ESIþ) m/z 466.1 (MHþ, 50%). HRMS
(EIþ): calcd for C24H26NO5F3 465.1763 (Mþ), found 465.1762.
Compound numbering of isoquinoline derivatives is based on that of
compound 7 as shown below. The numbering used for 3 in the NMR
analysis in shown below in black, systematic numbering is shown in red.
3.2.2. (RS)-2-Trifluoroacetyl-1,2,3,4-tetrahydro-1-(40,50-dimethoxy-
20-(200-propenyl)phenyl)methyl-6,7-dimethoxyisoquinoline (6)
The 20-iodolaudanosine derivative
4 (711 mg, 1.26 mmol),
5
4
1
4a
Pd(OAc)2 (23 mg, 0.102 mmol), PPh3 (61 mg, 0.232 mmol), allyl-
tributylstannane (499 mg, 1.51 mmol, 0.46 mL) and dry DMF (5 mL)
under N2 were treated as described above using the general Stille
coupling reaction conditions to afford an oil, which was purified by
column chromatography to give 6 (536 mg, 89%) as a white solid.
Compound 6 was recrystallised from diethyl ether and was a 95:5
mixture of rotamers. Rf 0.63 (EtOAc/petrol (1:1)). Mp 140–144 ꢀC.
6
CH3O
CH3O
3
2
7
N
CF3
3``
8a
1'
8
6'
O
7'
CH3O 5'
2''
2'
1''
4'
2``
4``
OCH3
CH3O
3'
5``
1``
OCH3
OCH3
O
7``
6``
8`
1H NMR of the major rotamer:
d
6.62 (s, 1H, H30), 6.58 (s, 1H, H5),
7`
6`
8a`
N
6.53 (s, 1H, H60), 6.00 (s, 1H, H8), 5.91–5.78 (m, 1H, H200), 5.49 (dd, J
8.1, 6.0 Hz, 1H, H1), 5.02 (dd, 1H, J 10.2, 0.9 Hz, H300(Z)), 4.94 (dd, 1H,
J 17.2, 0.9 Hz, H300(E)), 3.85 (s, 3H, OCH3-40), 3.84 (s, 3H, OCH3-6),
3.98–3.92 (m, 1H, H3), 3.76 (s, 3H, OCH3-7), 3.74–3.64 (m, 1H, H3),
3.56 (s, 3H, OCH3-50), 3.12 (dd, 2H, J 4.8, 1.5 Hz, H100), 3.04 (d, 1H, J
6.0 Hz, H70), 3.03 (d, 1H, J 8.1 Hz, H70), 2.96–2.88 (m, 1H, H4), 2.83–
F3C
1`
2`
3`
4a`
OCH3
4`
5`
7
5
4
4a
6
CH3O
3
O
2.75 (m, 1H, H4). 1H NMR of the minor rotamer (in part):
d 6.55 (s,
2
10
7'
2'''
7
3`
4'''
11
N
1
2`
14
1H, H8), 3.80 (s, 3H, OCH3-6), 3.49 (s, 3H, OCH3-50). 13C NMR of the
major rotamer: (signals for COCF3 and COCF3 were not observed):
CH3O
CH3O
8a
1'
4`
4a`
1'''
N
8
3'''
1
6'
1`
O
5'
4'
5`
6`
7``
2''
6
d
148.4 (C40), 148.1 (C6), 147.4 (C7), 147.4 (C50), 137.5 (CH-200), 131.2
8a`
6``
8
2'
4''
5
1``
3
2``
(C20), 127.4 (C4a), 126.6 (C8a), 125.1 (C10), 115.9 (CH2-300), 114.2 (CH-
30), 113.1 (CH-5), 111.2 (CH-8), 110.9 (CH-60), 56.2 (OCH3-40), 56.1
(OCH3-6), 55.8 (OCH3-7, OCH3-50), 55.6 (CH-1), 40.8 (CH2-3), 39.1
(CH2-100), 36.7 (CH2-70), 28.7 (CH2-4). 13C NMR of the minor rotamer
8`
CH3O
OCH3
OCH3
3''
3'
1''
7`
5``
OCH3
3``
4``
3
OCH3

U. Batenburg-Nguyen et al. / Tetrahedron 65 (2009) 318–327
323
(in part):
d
114.9 (CH-30), 113.8 (CH-5), 111.5 (CH-8), 111.4 (CH-60),
400, OCH3-6, OCH3-60, OCH3-7, OCH3-70), 55.8 (OCH3-50, OCH3-500),
27.4 (CH2-4). MS (CIþ): m/z 480 (MHþ, 100%). HRMS (CIþ): calcd for
55.5 (CH-1, CH-10), 41.4 (CH2-3, CH-30), 38.9 (CH2-70, CH2-700), 28.6
C25H29NO5F3 480.1998 (MHþ), found 480.2000.
(CH2-4, CH2-40). 1H NMR of the minor diastereomer, rac-7:
d 7.56 (s,
2H, CH]CH), 7.51 (s, 2H, H30,0H300), 6.54 (s, 2H, H5, H50), 6.09 (s, 2H,
H60, H600), 5.80 (s, 2H, H8, H8 ), 5.43 (dd, 2H, J 10.5, 3.3 Hz, H1, H10),
3.99 (s, 6H, OCH3-50, OCH3-500), 3.80 (m, 2H, H3, H30), 3.76 (s, 6H,
OCH3-40, OCH3-400), 3.60 (s, OCH3-6, OCH3-60), 3.49 (m, 2H, H30, H30),
3.42 (s, OCH3-7, OCH3-70), 3.38 (m, 2H, H70, H700), 2.93 (dd, 2H, J 13.2,
10.5 Hz, H70, H700), 2.91 (m, 2H, H4, H40), 2.86 (m, 2H, H4, H40). 13C
3.3. General method for Mizoroki–Heck coupling reactions
A mixture of palladium acetate, N,N-dimethylglycine (DMG),
sodium acetate and both coupling partners was placed in a thick
walled tube (sealed tube) under N2. Dry N-methylpyrolidinone
(NMP) was added and the reaction mixture was bubbled with argon
prior to sealing the tube. The reaction mixture was heated at 130 ꢀC
for 18 h. The reaction mixture was cooled and then diluted with
CH2Cl2 and the solution was washed with H2O (3ꢁ) and brine and
dried (MgSO4). The solution was evaporated to give a dark oil that
was purified by column chromatography (EtOAc/petrol (1:1)) (un-
less otherwise stated) to give the desired product.
NMR of the minor diastereomer, rac-7: d 156.1 (q, J 35.5 Hz, COCF3),
148.9 (C50, C500), 148.3 (C40, C400), 148.2 (C6, C60), 147.1 (C7, C70),130.0
(C10, C100), 127.1 (C20, C200), 126.1 (C4a, C4a0), 125.5 (C8a, C8a0), 125.0
(CH]CH), 115.2 (CH-60, CH-600), 113.5 (q, J 270.1 Hz, COCF3), 111.9
(CH-8, CH-80), 111.1 (CH-5, CH-50), 108.5 (CH-30, CH-300), 56.1 (OCH3-
40, OCH3-400, OCH3-6, OCH3-60, OCH3-7, OCH3-70), 55.8 (OCH3-50,
OCH3-500), 55.5 (CH-1, CH-10), 41.4 (CH2-3, CH-30), 38.9 (CH2-70, CH2-
700), 28.6 (CH2-4, CH2-40). MS (ESIþ): m/z 925.1 (MþNaþ, 100%).
HRMS (ESIþ): calculated for C46H49N2O10F6 903.3291 (MHþ), found
903.3251.
3.3.1. (1RS,10RS)- and (RS)-(E)-20,200-(100,200-Ethenediyl)-bis-[2-
trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-(40,50-
dimethoxyphenyl)methyl]isoquinoline (7) and (1RS,10RS)-(E)-20,200-
(100,100-ethenediyl)-bis-[2-trifluoroacetyl-1,2,3,4-tetrahydro-6,7-
dimethoxy-1-(40,50-dimethoxyphenyl)methyl]isoquinoline (8)
The 20-iodolaudanosine derivative 4 (203 mg, 0.354 mmol), the
20-vinyllaudanosine derivative 5 (166 mg, 0.354 mmol), Pd(OAc)2
(8 mg, 0.035 mmol), DMG (73 mg, 0.708 mmol), NaOAc (56 mg,
0.708 mmol) and dry NMP (5 mL) under N2 were treated as de-
scribed above in the general Mizoroki–Heck coupling reaction
procedure to give a crude mixture. To the mixture was added
methanol (5 mL) and the product 7 precipitated out as a white solid
(164 mg, 54%). The regioisomer 8 remained in the solution and was
purified by column chromatography (CH2Cl2/EtOAc/petrol (3:2:3))
to give 8 (36 mg, 12%) as a yellow oil. Compound 7 was a 55:45
mixture of diastereomers. Compound 8 was a 60:40 mixture of
diastereomers. A minor rotamer (w5%) was also observed in the 1H
NMR spectra of both 7 and 8.
Compound 8: Rf 0.25 (CH2Cl2/EtOAc/petrol (3:2:3)). 1H NMR of
the major diastereomer, rac-8:
d
6.61 (s, 2H, H30, H300), 6.52 (s, 4H,
H5, H50, H60, H600), 5.94 (s, 2H, H8, H80), 5.39 (t, 2H, J 7.5 Hz, H1, H10),
4.95 (s, 2H, C]CH2), 3.84 (s, 6H, OCH3-50, OCH3-500), 3.82 (s, 6H,
OCH3-40, OCH3-400), 3.74 (s, 6H, OCH3-6, OCH3-60), 3.76–3.70 (m, 2H,
H3, H30), 3.56 (s, 6H, OCH3-7, OCH3-70), 3.33–3.10 (m 2H, H3, H30),
2.95–2.76 (m, 4H, H70, H700, H4, H40), 2.70–2.53 (m, 4H, H70, H700, H4,
H40). 1H NMR of the minor diastereomer, meso-8 (in part):
d 6.65 (s,
2H, H30, H300), 6.56 (s, 2H, H5, H50), 5.92 (s, 2H, H8, H80), 5.49 (s, 2H,
H1, H10), 4.78 (s, 2H, C]CH2), 3.79 (s, 6H, OCH3-50, OCH3-500), 3.78
(s, 6H, OCH3-40, OCH3-400), 3.76 (s, 6H, OCH3-6, OCH3-60), 3.51 (s, 6H,
OCH3-7, OCH3-70). 13C NMR of the major diastereomer, rac-8:
d 155.9
(q, J 35.0 Hz, COCF3), 148.6 (C40, C400),148.5 (C6, C60),147.9 (C50, C500),
147.8 (C7, C70), 135.7 (C]CH2), 127.4 (C10, C100, C20, C200), 126.9 (C4a,
C4a0), 125.0 (C8a, C8a0), 120.8 (C]CH2), 114.1 (CH-30, CH-300), 113.8
(CH-5, CH-50), 112.5 (q, J 224.8 Hz, COCF3), 111.2 (CH-6, CH-60), 110.4
(CH-8, CH-80), 56.2 (OCH3-40, OCH3-400), 56.2 (OCH3-6, OCH3-60),
56.1 (OCH3-50, OCH3-500), 55.7 (OCH3-7, OCH3-70), 55.4 (CH-1, CH-
10), 41.4 (CH2-3, CH2-30), 38.1 (CH2-70, CH2-700), 28.8 (CH2-4, CH2-40).
Compounds 7 and 8 were also prepared according to the con-
ditions outlined in Table 1 under, essentially, the same conditions
using the quantities of catalyst, base and additives shown in the
Table.
13C NMR of the minor diastereomer, meso-8 (in part):
d 135.8
A small amount of (S,S)-7 (13 mg, 15%) was obtained under the
same Mizoroki–Heck coupling reaction conditions using a mixture
of (S)-5 (60 mg, 0.105 mmol) and (S)-4 (80 mg, 0.171 mmol),
Pd(OAc)2 (3 mg, 0.013 mmol), DMG (27 mg, 0.258 mmol), NaOAc
(21 mg, 0.258 mmol) and NMP (2 mL). A mixture of (S)-5 and (S)-4
(67 mg) was also recovered. Compound (S,S)-8 was also observed in
the reaction, however, not in significant quantity or purity to
characterise.
(C]CH2), 127.3 (C10, C100, C20, C200), 124.8 (C8a, C8a0), 120.5 (C]CH2),
38.0 (CH2-70, CH2-700). MS (ESIþ): m/z 925.0 (MþNaþ, 20%). HRMS
(ESIþ): calculated for C46H49N2O10F6 903.3291 (MHþ), found
903.3315.
3.3.2. (1RS,10RS)- and (RS)-(E)-20,200-(100,300-Prop-200-enediyl)-bis-
[2-trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-(40,50-
dimethoxyphenyl)methyl]isoquinoline (13)
Compound 7: Rf 0.31 (CH2Cl2/EtOAc/petrol (3:2:3)). Compound
The 20-iodolaudanosine derivative 4 (255 mg, 0.462 mmol), the
20-allyllaudanosine derivative 6 (232 mg, 0.462 mmol), Pd(OAc)2
(12 mg, 0.046 mmol), DMG (95 mg, 0.927 mmol), NaOAc (73 mg,
0.927 mmol) and dry NMP (5 mL) were treated as described above
using the general Heck coupling reaction procedure to give a dark
oil. The oil was purified by column chromatography to give the
desired product 13 (199 mg, 48%) as a yellow solid. Product 13 was
a 60:40 mixture of diastereomers and a minor rotamer (w5%) was
also observed in the 1H NMR spectrum. Rf 0.19 (EtOAc/petrol (1:1)).
25
(S,S)-7: [
a]
þ29 (c 0.84, CHCl3). Mp (meso-7 and rac-7) 226–
D
228 ꢀC. 1H NMR of the major diastereomer, meso-7:
d 7.58 (s, 4H,
CH]CH, H30, H300), 6.58 (s, 2H, H5, H50), 6.05 (s, 2H, H60, H600), 5.91
(s, 2H, H8, H80), 5.47 (dd, 2H, J 9.5, 5.4 Hz, H1, H10), 4.05 (s, 6H,
OCH3-50, OCH3-500), 3.85 (dd, 2H, J 8.1, 3.9 Hz, H3, H30), 3.81 (s,
6H, OCH3-40, OCH3-400), 3.71–3.65 (m, 2H, H3, H30), 3.57 (s, 6H,
OCH3-6, OCH3-60), 3.53 (t, 2H, J 13.2, 5.4 Hz, H70, H700), 3.47 (s, 6H,
OCH3-7, OCH3-70), 2.99 (dd, 2H, J 13.2, 9.5 Hz, H70, H700), 2.92–2.86
(m, 2H, H4, H40), 2.81–2.76 (m, 2H, H4, H40). 1H NMR of the minor
Mp 102–104 ꢀC. 1H NMR of the major diastereomer:
d 6.86 (s, 1H,
rotamer of meso-7 (in part):
d
7.45 (s, 2H, H30, H300), 7.53 (s, 2H,
H300) 6.68 (s, 1H, H30), 6.56 (s, 1H, H5), 6.53 (s, 1H, H500), 6.48 (s, 1H,
H60), 6.42 (d, 1H, J 14.1 Hz, H300), 6.37 (s, 1H, H600), 5.97 (s, 2H, H8,
H80), 5.97–5.92 (m, 1H, H200), 5.47 (dd, 2H, J 8.7, 5.7 Hz, H1, H10),
3.91–3.83 (m, 2H, H3, H30), 3.79 (s, 12H, OCH3-6, OCH3-60, OCH3-40,
OCH3-400), 3.55–3.50 (m, 2H, H3, H30), 3.70 (s, 6H, OCH3-7, OCH3-70),
3.48 (s, 6H, OCH3-50, OCH3-500), 3.32–3.18 (m, 2H, H100), 3.12–2.99
(m, 4H, H70, H700), 2.87–2.77 (m, 2H, H4, H40), 2.73–2.65 (m, 2H, H4,
CH]CH), 5.79 (s, 2H, H8, H80), 6.48 (s, 2H, H5, H50), 3.76 (s, 6H,
OCH3-50, OCH3-500), 3.71 (s, 6H, OCH3-40, OCH3-400), 3.60 (s, 6H,
OCH3-6, OCH3-60), 3.42 (s, 6H, OCH3-7, OCH3-70). 13C NMR of the
major diastereomer, meso-7: d
156.1 (q, J 35.5 Hz, COCF3), 148.9 (C50,
C500), 148.3 (C40, C400), 148.2 (C6, C60), 147.1 (C7, C70), 130.0 (C10, C100),
127.1 (C20, C200), 126.1 (C4a, C4a0), 125.5 (C8a, C8a0), 125.0 (CH]CH),
115.2 (CH-60, CH-600), 113.5 (q, J 270.1 Hz, COCF3), 111.9 (CH-8, CH-
80), 111.1 (CH-5, CH-50), 108.5 (CH-30, CH-300), 56.1 (OCH3-40, OCH3-
H40). 1H NMR of the minor diastereomer (in part):
H300), 6.67 (s, 1H, H30), 6.56 (s, 1H, H5), 6.53 (s, 1H, H500), 6.47 (s, 1H,
d 6.85 (s, 1H,

324
U. Batenburg-Nguyen et al. / Tetrahedron 65 (2009) 318–327
H60), 6.42 (d, 1H, J 14.1 Hz, H300), 6.36 (s, 1H, H600), 6.00 (s, 1H, H8),
5.92 (s, 1H, H80), 5.43 (dd, 2H, J 8.7, 5.7 Hz, H1, H10), 3.74 (s, 12H,
OCH3-6, OCH3-60, OCH3-40, OCH3-400), 3.66 (s, 6H, OCH3-7, OCH3-70),
3.46 (s, 6H, OCH3-50, OCH3-500). 13C NMR of the major diastereomer:
0.11 mL). The solution was stirred for 5 min before trimethylsilyl-
acetylene (78 mg, 0.795 mmol, 0.11 mL) was added. The reaction
mixture was stirred at rt for 4 day. Compound 15 was a 95:5 mix-
ture of rotamers. Rf 0.77 (CH2Cl2/EtOAc/petrol (3:1: 3)). Mp 114–
d
155.9 (q, J 36.1 Hz, COCF3), 148.2 (C6, C60), 148.1 (C40, C400), 147.3
118 ꢀC. 1H NMR of the major rotamer: 6.85 (s, 1H, H30), 6.65 (s, 1H,
d
(C50, C500), 147.1 (C7, C70), 131.5 (C100), 129.8 (C10), 129.5 (CH-300),
127.5 (CH-200), 127.1 (C200), 126.5 (C20), 126.2 (C4a0), 126.0 (C4a),
125.1 (C8a0), 125.0 (C8a), 114.1 (q, J 286.5 Hz, COCF3), 114.0 (CH-60),
133.8 (CH-600), 113.0 (CH-30), 110.9 (CH-5, CH-50), 110.6 (CH-8, CH-
80), 108.5 (CH-300), 55.8 (8ꢁOCH3), 55.3 (CH-1, CH-10), 40.6 (CH2-3,
CH2-30), 38.0 (CH2-70, CH2-700), 36.0 (CH2-100), 28.4 (CH2-4, CH2-40).
H60), 6.56 (s, 1H, H5), 6.33 (s, 1H, H8), 5.66 (t, 1H, J 7.2, 6.9 Hz, H1),
3.93 (dt, 1H, J 12.0, 4.5 Hz, H3), 3.82 (s, 6H, OCH3-40 and OCH3-50),
3.78 (s, 3H, OCH3-6), 3.69 (s, 3H, OCH3-7), 3.63 (dt, 1H, J 11.7, 4.5 Hz,
H3), 3.42 (dd,1H, J 13.5, 6.9 Hz, H70), 3.13 (dd,1H, J 13.5, 7.2 Hz, H70),
2.95–2.85 (m, 1H, H4), 2.74–2.66 (m, 1H, H4), 0.16 (s, 9H, Si(CH3)3).
13C NMR of the major rotamer:
d 155.4 (q, J 34.3 Hz, COCF3), 149.4
13C NMR of the minor diastereomer (in part):
d
148.1 (C6, C60), 147.9
(C40), 148.3 (C50), 147.6 (C6), 147.5 (C7), 132.5 (C20), 126.8 (C10), 124.9
(C4a), 115.7 (C8a), 114.6 (CH-30), 114.5 (q, J 204.9 Hz, COCF3), 112.3
(CH-60), 111.1 (CH-5), 110.4 (CH-8), 103.7 (ArC^CSi(CH3)3), 95.9
(CSi(CH3)3), 56.0 (OCH3-40), 55.9 (OCH3-50, OCH3-6 and OCH3-7),
54.7 (CH-1), 40.3 (CH2-3), 39.5 (CH2-70), 28.7 (CH2-4), 0.1 (Si(CH3)3).
(C40, C400), 147.1 (C50, C500), 147.0 (C7, C70), 131.5 (C100), 129.8 (C10),
129.7 (CH-300), 127.6 (CH-200), 127.2 (C200), 126.5 (C20), 126.3 (C4a0),
126.0 (C4a), 125.1 (C8a0), 125.0 (C8a), 114.0 (CH-60), 133.7 (CH-600),
113.1 (CH-30), 110.8 (CH-5, CH-50), 110.7 (CH-8, CH-80), 108.4 (CH-
300), 40.6 (CH2-3, CH2-30), 37.9 (CH2-70, CH2-700), 36.1 (CH2-100), 28.5
(CH2-4, CH2-40). MS (ESIþ) m/z 916.72 (MHþ, 10%), m/z 954.74
(MþKþ, 100%). HRMS (ESIþ) calcd for C47H51N2O10F6 917.3448
(MHþ), found 917.3451.
13C NMR of the minor rotamer (in part):þ
for C27H32NO5F3Si 535.2002 (Mþ), found 535.1984.
d 40.7 (CH2-3), 37.9 (CH2-
70), 27.3 (CH2-4). MS (CIþ): m/z 536 (MH , 10%). HRMS (EIþ): calcd
3.5.2. (RS)-2-Trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
(40,50-dimethoxy-20-(200-trimethylsilyl-200-(trimethylsilyl-
3.4. General method for hydrogenation reactions
ethynyl)ethenyl)phenyl)methylisoquinoline (16)
3.4.1. (1RS,10RS)- and (RS)-20,200-(100,200-Ethanediyl)-bis-[2-
Compound 4 (300 mg, 0.530 mmol), PdCl2 (4.5 mg, 0.027 mmol),
PPh3 (13.6 mg, 0.053 mmol) and CuI (10 mg, 0.053 mmol) were
added to a dry flask under a N2 atmosphere. Dry THF (45 mL) was
added to the mixture followed by the addition of Et3N (161 mg,
1.59 mmol, 0.11 mL). The solution was stirred for 5 min before tri-
methylsilylacetylene (158 mg, 1.59 mmol, 0.22 mL) was added. The
reaction mixture was stirred at rt for 4 days. The solvent was evap-
orated and the crude mixture was purified by column chromato-
graphy (CH2Cl2/EtOAc/petrol (3:1:3)) to give 16 (175 mg, 52%) as
a brown oil and 15 (130 mg, 45%) as a brown solid.
trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-(40,50-
dimethoxyphenyl)methyl]isoquinoline (11)
To a solution of alkene 7 (73 mg, 0.083 mmol) in acetone
(80 mL) was added 10% Pd/C (10 mg) in a round bottom flask sealed
with a suba seal. The flask was purged with nitrogen and then
a hydrogen filled balloon was secured on top of the flask, allowing
the hydrogen to circulate inside the flask. The reaction mixture was
stirred at rt for 3 days under a H2 atmosphere. Nitrogen was then
bubbled into the solution for 2 min and CH2Cl2 (1 mL) was added
until the solution became completely homogeneous. Pd/C was fil-
tered and the solvent was evaporated to give a crude mixture of
meso-7 and rac-11. The crude mixture was dissolved in CH2Cl2
(1 mL) and methanol (4 mL) was added slowly resulting in the
precipitation of meso-7. The pure meso-7 (22 mg, 30%) was filtered
as a white solid. The filtrate was evaporated and then purification
by column chromatography (CH2Cl2/EtOAc/petrol (3:2:3)) gave
pure rac-11 (26 mg, 35%) a yellow oil.
Compound 16: Rf 0.74 (CH2Cl2/EtOAc/petrol (3:1: 1)). 1H NMR:
d
8.15 (s, 1H, H100), 6.66 (s, 1H, H30), 6.56 (s, 2H, H60, H5), 5.97 (s,
1H, H8), 5.45 (dd, 1H, J 8.4, 5.4 Hz, H1), 3.88 (s, 3H, OCH3-40), 3.84–
3.80 (m, 1H, H3), 3.82 (s, 3H, OCH3-50), 3.77 (s, 3H, OCH3-6), 3.70–
3.59 (m, 1H, H3), 3.52 (s, 3H, OCH3-7), 3.18 (dd, 1H, J 13.5, 8.4 Hz,
H70), 3.12 (dd, 1H, J 13.5, 5.4 Hz, H70), 2.95–2.85 (m, 1H, H4), 2.78–
2.70 (m, 1H, H4), 0.16 (s, 9H, Si(CH3)3), 0.13 (s, 9H, Si(CH3)3). 13C
NMR (signals for COCF3 and COCF3 were not observed):
d 149.1
Compound 11: Rf 0.39 (CH2Cl2/EtOAc/petrol (3:2:3)). 1H NMR:
(C40), 148.5 (C50, C6), 147.5 (C7), 141.3 (CH-100), 129.9 (C20), 128.7
(C10), 126.1 (C4a), 125.1 (C8a), 123.2 (C200), 113.6 (CH-30), 111.4 (CH-
60), 111.1 (CH-5, CH-8), 110.7 (C^CSi(CH3)3), 106.4 (C^CSi(CH3)3),
56.0 (4ꢁOCH3, CH-1), 41.1 (CH2-3), 37.9 (CH2-70), 28.6 (CH2-4),
0.35 (Si(CH3)3), 0.10 (Si(CH3)3). MS (ESIþ): m/z 634 (MHþ, 100%).
HRMS (ESIþ): calcd for C24H24NO5F3 634.2653 (MHþ), found
634.2610.
d
6.62 (s, 2H, H30, H300), 6.57 (s, 2H, H5, H50), 6.30 (s, 2H, H60, H600),
5.90 (s, 2H, H8, H80), 5.40 (dd, 2H, J 8.4, 5.1 Hz, H1, H10), 3.93–3.85
(m, 2H, H3, H30), 3.82 (s, 6H, OCH3-40, OCH3-400), 3.79 (s, 2H, OCH3-
50, OCH3-500), 3.66 (s, 2H, OCH3-6, OCH3-60), 3.64–3.55 (m, 2H, H3,
H30), 3.48 (s, 6H, OCH3-7, OCH3-70), 2.94 (dd, 2H, J 13.5, 5.1 Hz, H70,
H700), 2.82 (s, 4H, H100, H200), 2.81 (dd, 2H, J 13.5, 8.4 Hz, H70, H700),
2.78–2.62 (m, 4H, H4, H40). 13C NMR (signals for COCF3 and COCF3
were not observed):
d
148.1 (C40, C400), 147.8 (C6, C60), 147.0 (C50,
3.5.3. (RS)-2-Trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
(40,50-dimethoxy-20-ethynylphenyl)methylisoquinoline (17)
C500), 146.8 (C7, C70), 132.7 (C20, C200), 126.8 (C10, C100), 126.1 (C4a,
C4a0), 124.9 (C8a, C8a0), 114.2 (CH-60, CH-600), 112.9 (CH-30, CH-300),
110.9 (CH-5, CH-50), 110.8 (CH-8, CH-80), 55.8 (8ꢁOCH3), 55.5 (C1,
C10), 40.7 (CH2-3, CH2-30), 38.0 (CH2-70, CH2-700), 33.5 (CH2-100, CH2-
200), 29.0 (CH2-4, CH2-40). MS (ESIþ): m/z 905.1 (MHþ, 20%). HRMS
(ESIþ): calcd for C46H51N2O10F6 905.3448 (MHþ), found 905.3411.
To a mixture of 15 (130 mg, 0.240 mmol) in CH3OH (2 mL) and
H2O (0.5 mL) was added KF (150 mg, 2.59 mmol). The suspension
was stirred at rt for 18 h. The solvent was evaporated and the res-
idue was redissolved in EtOAc. The reaction mixture was washed
with 0.1 M HCl and then with brine and dried (MgSO4). The solvent
was evaporated to give an oil, which was purified by column
chromatography (CH2Cl2/EtOAc/petrol (3:1: 4)) to give 17 (60 mg,
54% yield) as a brown oil. Compound 17 was a 95:5 mixture of
rotamers. Rf 0.38 (CH2Cl2/EtOAc/petrol (3:1:4)). 1H NMR of the
3.5. General method for Sonagashira coupling reactions
3.5.1. (RS)-2-Trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
(40,50-dimethoxy-20-(trimethylsilylethynyl)-phenyl)-
major rotamer: d
6.95 (s, 1H, H30), 6.59 (s, 1H, H60), 6.56 (s, 1H, H5),
methylisoquinoline (15)
6.55 (s, 1H, H8), 5.76 (dd, J 7.8, 5.7 Hz, H1), 3.98 (dd, 1H, J 13.5,
4.8 Hz, H3), 3.86 (s, 6H, OCH3-40 and OCH3-50), 3.75 (s, 6H, OCH3-6
and OCH3-7), 3.68–3.58 (m,1H, H3), 3.47 (dd,1H, J 13.8, 5.7 Hz, H70),
3.17 (dd, 1H, J 13.8, 7.8 Hz, H70), 3.16 (s, 1H, ArC^CH), 2.96–2.87 (m,
1H, H4), 2.73–2.65 (m, 1H, H4). 1H NMR of the minor rotamer (in
Compound 4 (300 mg, 0.530 mmol), PdCl2 (5 mg, 0.027 mmol),
PPh3 (14 mg, 0.053 mmol) and CuI (10 mg, 0.053 mmol) were
added to a dry flask under a N2 atmosphere. Dry THF (45 mL) was
added followed by the addition of Et3N (80 mg, 0.795 mmol,

U. Batenburg-Nguyen et al. / Tetrahedron 65 (2009) 318–327
325
part):
d
6.97 (s,1H, H30), 6.61 (s,1H, H60), 6.43 (s,1H, H5), 6.36 (s,1H,
155.8 (q, J 34.3 Hz, COCF3),
500), 3.83 (s, 6H, OCH3-6, OCH3-60), 3.71 (s, 6H, OCH3-7, OCH3-70),
3.31 (dd, 2H, J 13.8, 4.5 Hz, H70, H700), 3.20 (dt, 2H, J 12.0, 4.6 Hz, H3,
H30), 2.98 (dd, 2H, J 13.8, 9.0 Hz, H70, H700), 2.89 (dt, 2H, J 12.0,
5.4 Hz, H3, H30), 2.72 (t, 4H, J 5.4 Hz, H4, H40). 1H NMR of rac-9 (in
H8). 13C NMR of the major rotamer:
d
149.7 (C40), 148.4 (C50), 147.9 (C6), 147.8 (C7), 133.2 (C20), 127.1 (C10),
125.3 (C4a), 115.0 (CH-30), 114.5 (C8a), 114.0 (q, J 225.1 Hz, COCF3),
112.7 (CH-60), 111.2 (CH-5), 110.4 (CH-8), 82.6 (ArC^CH), 79.6
(ArC^CH), 56.1 (3ꢁOCH3), 56.0 (OCH3-7), 54.8 (CH-1), 40.4 (CH2-
3), 39.8 (CH2-70), 28.9 (CH2-4). MS (CIþ): m/z 464.1 (MHþ, 100%).
HRMS (EIþ): calcd for C24H24NO5F3 463.1607 (Mþ), found
463.1606.
part):
d
7.16 (s, 2H, CH]CH), 6.74 (s, 2H, H30, H300), 6.71 (s, 2H, H60,
H600), 6.59 (s, 2H, H5, H50), 6.57 (s, 2H, H8, H80), 4.14 (dd, 2H, J 11.1,
3.9 Hz, H1, H10), 3.90 (s, 6H, OCH3-40, OCH3-400), 3.86 (s, 6H, OCH3-50,
OCH3-500), 3.71 (s, 6H, OCH3-6, OCH3-60), 3.50 (s, 6H, OCH3-7, OCH3-
70). 13C NMR of meso-9: 148.9 (C50, C500), 148.3 (C40, C400), 147.8 (C6,
d
C60), 147.2 (C7, C70), 130.7 (C10, C100), 130.1 (C20, C200), 130.0 (C4a,
C4a0), 127.6 (C8a, C8a0), 126.8 (CH]CH), 113.9 (CH-60, CH-600), 112.1
(CH-30, CH-300), 110.0 (CH-5, CH-50), 109.4 (CH-8, CH-80), 57.0 (CH-1,
CH-10), 56.3 (OCH3-50, OCH3-500), 56.2 (OCH3-40, OCH3-400, OCH3-6,
OCH3-60), 56.1 (OCH3-7, OCH3-70), 40.9 (CH2-3, CH2-30), 40.1 (CH2-70,
3.5.4. (1RS,10RS)- and (RS)-20,200-(100,200-Ethynediyl)-bis-[2-
trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-(40,50-
dimethoxyphenyl)methyl]isoquinoline (18)
To a mixture of 20-iodolaudanosine 4 (144 mg, 0.255 mmol), 17
(118 mg, 0.255 mmol), PdCl2 (2 mg, 0.0127 mmol), PPh3 (7 mg,
0.026 mmol) and CuI (5 mg, 0.026 mmol) under a N2 atmosphere
was added distilled THF (10 mL). Et3N (39 mg, 0.383 mmol,
0.051 mL) was subsequently added and the mixture was stirred at
rt for 24 h. The solvent was evaporated and the residue was pu-
rified by column chromatography (CH2Cl2/CH3OH/petrol (3:1:4))
to give 18 (113 mg, 49%) as a white solid. Compound 18 was a 95:5
mixture of rotamers. Rf 0.26 (CH2Cl2/CH3OH/petrol (3:1:4)). Mp
CH2-700), 29.8 (CH2-4, CH2-40). 13C NMR of rac-9 (in part):
d 148.3
(C40, C400), 147.4 (C7, C70), 130.8 (C10, C100), 130.3 (C20, C200), 129.2
(C4a, C4a0), 128.3 (CH]CH), 113.5 (CH-60, CH-600), 109.9 (CH-5, CH-
50), 56.6 (CH-1, CH-10), 55.9 (OCH3-7, OCH3-70), 41.1 (CH2-3, OCH3-
30), 40.0 (CH2-70, CH2-700), 28.6 (CH2-4, CH2-40). MS (ESIþ): m/z
710.92 (MHþ, 20%). HRMS (ESIþ): calcd for C42H51N2O8 711.3645
(MHþ), found 711.3662.
168–172 ꢀC. 1H NMR of the major rotamer:
d
7.17 (s, 2H, H30, H300),
3.6.2. (1RS,10RS)- and (RS)-20,200-(1,1-Ethenediyl)-bis-[1,2,3,4-
tetrahydro-6,7-dimethoxy-1-(40,50-dimethoxyphenyl)-
methyl]isoquinoline (10)
6.63 (s, 2H, H60, H600), 6.58 (s, 2H, H5, H50), 6.51 (s, 2H, H8, H80),
5.69 (dd, 2H, J 8.0, 6.0 Hz, H1, H10), 4.02 (br d, 2H, J 13.5 Hz, H3,
H30), 3.84 (s, 6H, OCH3-40, OCH3-400), 3.82 (s, 2H, OCH3-50, OCH3-
500), 3.76 (s, 2H, OCH3-6, OCH3-60), 3.73 (s, 6H, OCH3-7, OCH3-70),
3.72–3.66 (m, 2H, H3, H30), 3.26 (dd, 2H, J 14.1, 6.0 Hz, H70, H700),
3.13 (dd, 2H, J 14.1, 8.0 Hz, H70, H700), 2.99–2.89 (m, 2H, H4, H40),
2.81–2.73 (m, 2H, H4, H40). 1H NMR of the minor rotamer (in part):
Compound 8 (38 mg, 0.044 mmol), CH3OH (3 mL), H2O (0.6 mL)
and K2CO3 (30 mg, 0.218 mmol) were treated as described above
using the general N-TFA deprotection reaction procedure except
that the reaction mixture was heated at 80 ꢀC for 5 h to give an oil.
The oil was purified by column chromatography (CH3OH/EtOAc
(4:6)) to give 10 (14 mg, 45%) as a yellow oil. Product 10 was
obtained as a diastereomeric mixture, which was separated by
PTLC (CH2Cl2/EtOAc/CH3OH/NH3 (10:5:1:0.1)) into the major di-
astereomer (11 mg) and minor diastereomer (3 mg). Rf (major di-
astereomer): 0.30 (DCM/EtOAc/CH3OH/NH3 (10:5:1:0.1)). Rf (minor
diastereomer): 0.24 (DCM/EtOAc/CH3OH/NH3 (10:5:1:0.1)). 1H
d
6.66 (s, 2H, H60, H600), 6.59 (s, 2H, H5, H50), 6.50 (s, 2H, H8, H80),
5.05 (s, 2H, H1, H10). 13C NMR of the major rotamer:
155.5 (q, J
d
38.4 Hz, COCF3), 150.3 (C40, C400), 148.5 (C50, C500), 148.1 (C6, C60),
147.9 (C7, C70), 134.5 (C20, C200), 127.1 (C10, C100), 125.2 (C4a, C4a0),
118.6 (q, J 254.2 Hz, COCF3), 115.0 (CH-30, CH-300), 114.1 (C8a, C8a0),
112.6 (CH-60, CH-600), 111.3 (CH-5, CH-50), 110.2 (CH-8, CH-80), 81.1
(ArC^CAr), 56.2 (OCH3-40, OCH3-400, OCH3-50, OCH3-500), 56.1
(OCH3-6, OCH3-60, OCH3-7, OCH3-70), 55.0 (CH-1, CH-10), 40.2 (CH2-
3, CH2-30), 40.1 (CH2-70, CH2-700), 29.0 (CH2-4, CH2-40). MS (ESIþ):
m/z 901.3 (MHþ, 50%). HRMS (ESIþ): calcd for C46H47N2O10F6
901.3135 (MHþ), found 901.3066.
NMR of the major diastereomer: d
7.01 (s, 2H, H30, H300), 6.72 (s, 2H,
H60, H600), 6.53 (s, 2H, H5, H50), 5.99 (s, 2H, H8, H80), 4.10 (dd, 2H, J
10.2, 4.5 Hz, H1, H10), 3.86 (s, 6H, OCH3-40, OCH3-400), 3.82 (s, 6H,
OCH3-50, OCH3-500), 3.77 (s, 6H, OCH3-6, OCH3-60), 3.65 (s, 6H, OCH3-
7, OCH3-70), 3.06 (dt, 2H, J 11.8, 5.1 Hz, H3, H30), 2.92 (dd, 2H, J 13.8,
4.5 Hz, H70, H700), 2.80 (ddd, 2H, J 11.8, 6.6, 4.8 Hz, H3, H30), 2.73–
7.65 (m, 4H, H4, H40), 2.40 (dd, 2H, J 13.8, 10.2 Hz, H70, H700). 1H NMR
3.6. General method for N-TFA deprotection
of the minor diastereomer: d
6.96 (s, 2H, H30, H300), 6.66 (s, 2H, H60,
To a solution of the N-TFA protected amine in a mixture of
CH3OH and H2O was added solid K2CO3. The reaction mixture
was stirred at rt for 18 h. CH3OH was evaporated and the res-
idue was dissolved in EtOAc. The solution was washed with
H2O (3ꢁ) and then with brine and evaporated to give a yellow
oil. The oil was purified by column chromatography (CH3OH/
EtOAc/NH3 (4:6:0.1)) (unless stated otherwise) to give the free
amine.
H600), 6.53 (s, 2H, H5, H50), 6.06 (s, 2H, H8, H80), 4.06 (dd, 2H, J 8.4,
6.6 Hz, H1, H10), 3.80 (s, 18H, OCH3-40, OCH3-400, OCH3-50, OCH3-500,
OCH3-6, OCH3-60), 3.62 (s, 6H, OCH3-7, OCH3-70), 3.10 (dt, 2H, J 12.0,
5.7 Hz, H3, H30), 2.90 (dd, 2H, J 13.8, 6.0 Hz, H70, H700), 2.84 (dd, 2H, J
11.7, 5.4 Hz, H3, H30), 2.68 (t, 4H, J 5.7 Hz, H4, H40), 2.53 (dd, 2H, J
13.8, 8.4 Hz, H70, H700). 13C NMR of the major diastereomer:
d 150.9
(C40, C400), 148.5 (C50, C500), 147.5 (C6, C60), 147.2 (C7, C70), 133.6 (C20,
C200 and C]CH2), 130.8 (C10, C100), 129.2 (C4a, C4a0), 129.2 (C8a,
C8a0), 120.2 (ArC]CH2), 115.2 (CH-30, CH-300), 114.6 (CH-60, CH-600),
111.9 (CH-5, CH-50), 108.7 (CH-8, CH-80), 56.2 (OCH3-40, OCH3-400),
56.0 (OCH3-50, OCH3-500, OCH3-6, OCH3-60), 55.6 (OCH3-7, OCH3-70),
54.9 (CH-1, CH-10), 41.4 (CH2-3, CH-30), 40.4 (CH2-70, CH2-700), 29.7
3.6.1. (1RS and 10RS)- and (RS)-20,200-(100,200-Eth-(E)-enediyl)-bis-
[1,2,3,4-tetrahydro-6,7-dimethoxy-1-(40,50-dimethoxy-
phenyl)methyl]isoquinoline (9)
The N-TFA protected stilbene 7 (108 mg, 0.123 mmol), CH3OH
(5 mL), H2O (0.6 mL) and K2CO3 (89 mg, 0.641 mmol) were treated
as described above using the general N-TFA deprotection reaction
procedure except that the mixture was heated at 80 ꢀC for 3 days to
give a yellow oil. The oil was purified by column chromatography to
give 9 (36 mg, 41%) as a yellow oil. Product 9 was a 55:45 mixture of
meso-9 and rac-9. Rf 0.07 (CH3OH/EtOAc (4:6)). 1H NMR of meso-9:
(CH2-4, CH2-40). 13C NMR of the minor diastereomer: 150.7 (C40,
d
C400), 148.6 (C50, C500), 147.6 (C6, C60), 147.0 (C7, C70), 134.6 (C20, C200,
C]CH2), 131.0 (C10, C100), 129.4 (C4a, C4a0), 127.1 (C8a, C8a0), 119.9
(C]CH2), 114.7 (CH-30, CH-300), 114.3 (CH-60, CH-600), 112.0 (CH-5,
CH-50), 109.7 (CH-8, CH-80), 56.2 (OCH3-40, OCH3-400, OCH3-50,
OCH3-500), 56.0 (OCH3-6, OCH3-60), 55.9 (OCH3-7, OCH3-70), 55.4
(CH-1, CH-10), 41.0 (CH2-3, CH-30), 40.5 (CH2-70, CH2-700), 29.6 (CH2-
4, CH2-40). MS (ESIþ): m/z 711.2 (MHþ, 100%), 733.2 (MþNaþ, 80%).
HRMS (ESIþ): calcd for C42H51N2O8 711.3645 (MHþ), found
711.3660.
d
7.07 (s, 2H, CH]CH), 6.72 (s, 2H, H30, H300), 6.64 (s, 2H, H60, H600),
6.57 (s, 2H, H5, H50), 6.55 (s, 2H, H8, H80), 4.17 (dd, 2H, J 9.0, 4.5 Hz,
H1, H10), 3.87 (s, 6H, OCH3-40, OCH3-400), 3.84 (s, 6H, OCH3-50, OCH3-

326
U. Batenburg-Nguyen et al. / Tetrahedron 65 (2009) 318–327
3.6.3. (1RS,10RS)- and (RS)-20,200-(100,200-Ethanediyl)-bis-[1,2,3,4-
tetrahydro-6,7-dimethoxy-1-(40,50-dimethoxy-
phenyl)methyl]isoquinoline (12)
70), 3.51 (td, 2H, J 12.0, 4.5 Hz, H3, H30), 3.36 (d, 4H, J 7.5 Hz, H70,
H700), 3.25–3.18 (m, 2H, H4, H40), 3.13 (td, 2H, J 12.0, 4.5 Hz, H3, H30),
3.00–2.92 (m, 2H, H4, H40). 13C NMR: 149.9 (C40, C400), 149.5 (C50,
d
Compound rac-11 (4 mg, 0.003 mmol), CH3OH (1 mL), H2O
(0.5 mL) and K2CO3 (12 mg, 0.085 mmol) were treated as described
above using the general N-TFA deprotection reaction procedure to
afford rac-12 (3 mg, 95% yield) as a yellow oil without the need for
further purification. Rf 0.14 (DCM/EOAc/CH3OH/NH3 (10:5:1:0.1)).
C500), 149.3 (C6, C60), 148.0 (C7, C70), 131.1 (C20, C200), 124.9 (C10, C100,
C4a, C4a0), 124.3 (C8a, C8a0), 122.0 (CH-30, CH-300), 115.0 (CH-60, CH-
600), 110.9 (CH-5, CH-50), 110.2 (CH-8, CH-80), 89.9 (ArC^CAr), 57.2
(OCH3-40, OCH3-400, OCH3-50, OCH3-500), 56.5 (OCH3-6, OCH3-60,
OCH3-7, OCH3-70), 55.3 (CH-1, CH-10), 45.7 (CH2-3, CH2-30), 40.2
(CH2-70, CH2-700), 26.3 (CH2-4, CH2-40). MS (ESIþ): m/z 709.1 (MHþ,
5%). HRMS (ESIþ): calcd for C42H49N2O8 709.3489 (MHþ), found
709.3474.
1H NMR:
d
6.67 (s, 2H, H30, H300), 6.57 (s, 2H, H5, H50), 6.55 (s, 2H,
H60, H600), 6.43 (s, 2H, H8, H80), 4.05 (dd, 2H, J 9.3, 5.1 Hz, H1, H10),
3.82 (s, 6H, OCH3-40, OCH3-400), 3.80 (s, 6H, OCH3-50, OCH3-500), 3.75
(s, 6H, OCH3-6, OCH3-60), 3.67 (s, 6H, OCH3-7, OCH3-70), 3.14 (dd, 2H,
J 12.3, 6.3 Hz, H3, H30), 3.06 (dd, 2H, J 13.8, 5.1 Hz, H70, H700), 2.84
(dd, 2H, J 12.3, 6.6 Hz, H3, H30), 2.82 (s, 4H, H100, H200), 2.75 (dd, 2H, J
3.7. Synthesis of macrocycle 3 (Scheme 6)
13.8, 9.3 Hz, H70, H700), 2.66 (m, 4H, H4, H40). 13C NMR:
d
147.5 (C50,
3.7.1. (RS)-1,2,3,4-Tetrahydro-6,7-dimethoxy-1-(40,50-dimethoxy-
20-(200-propenyl)phenyl)methylisoquinoline (20)
C500), 147.4 (C40, C400), 147.2 (C6, C60), 146.8 (C7, C70), 132.5 (C10, C100),
132.0 (C20, C200),131.9 (C4a, C4a0),127.0 (C8a, C8a0),113.4 (CH-60, CH-
600), 112.9 (CH-30, CH-300), 111.7 (CH-5, CH-50), 109.6 (CH-8, CH-80),
56.4 (CH-1, CH-10), 55.8 (8ꢁOCH3), 40.7 (CH2-3, CH2-30), 38.9 (CH2-
70, CH2-700), 34.1 (CH2-100, CH2-200), 29.3 (CH2-4, CH2-40). MS (ESIþ):
m/z 713.3 (MHþ, 100%). HRMS (ESIþ): calcd for C42H53N2O8
713.3802 (MHþ), found 713.3781.
N-TFA protected amine 6 (70 mg, 0.146 mmol), K2CO3 (100 mg,
0.730 mmol), CH3OH (7 mL) and H2O (1 mL) were treated as de-
scribed above using the general N-TFA deprotection procedure to
give a yellow oil. The oil was purified by column chromatography
(CH3OH/EtOAc (1:5)) to afford the amine 20 (50 mg, 90 %) as
a yellow oil. Rf 0.21 (CH3OH/EtOAc (1:5)). 1H NMR:
d 6.73 (s, 2H,
H30), 6.71 (s,1H, H60), 6.58 (s,1H, H5), 6.44 (s,1H, H8), 5.98–3.85 (m,
1H, H200), 5.06 (dd, 1H, J 9.6, 1.8 Hz, H300(Z)), 5.01 (dd, 1H, J 17.1,
1.8 Hz, H300(E)), 4.17 (dd, 1H, J 8.7, 5.7 Hz, H1), 3.85 (s, 6H, OCH3-40,
OCH3-50), 3.82 (s, 3H, OCH3-6), 3.73 (s, 3H, OCH3-7), 3.32 (d, 2H, J
6.0 Hz, H100), 3.27 (dd, 1H, J 12.0, 6.3 Hz, H3), 3.22 (dd, 1H, J 13.8,
5.7 Hz, H70), 2.97 (dd, 1H, J 12.0, 5.7 Hz, H3), 2.89 (dd, 1H, J 13.8,
3.6.4. (1RS,10RS)- and (1RS,10SR)-20,200-(100,300-Prop-2(E)-enediyl)-
bis-[1,2,3,4-tetrahydro-6,7-dimethoxy-1-(40,50-dimethoxy-
phenyl)methyl]isoquinoline (14)
Compound 13 (152 mg, 0.170 mmol), CH3OH (8 mL), H2O (2 mL)
and K2CO3 (118 mg, 0.850 mmol) were treated as described above
using the general N-TFA deprotection procedure to give an oil. The
oil was purified by column chromatography to give 60 (72 mg, 58%)
as a yellow oil. Product 14 was a 60:40 mixture of diastereomers. Rf
0.1 (CH3OH/EtOAc/NH3 (1:4:0.1)). 1H NMR of the major di-
8.7 Hz, H70), 2.77–2.69 (m, 2H, H4). 13C NMR: 147.9 (C40, C50), 147.5
d
(C6), 147.2 (C7), 137.6 (CH-200), 130.8 (C20), 129.9 (C10), 129.0 (C4a),
127.0 (C8a), 115.9 (CH2-300), 114.0 (CH-30), 113.4 (CH-60), 112.0 (CH-
5), 109.8 (CH-8), 56.4 (OCH3-40), 56.3 (OCH3-50), 56.2 (OCH3-6), 56.1
(OCH3-7, CH-1), 40.8 (CH2-100), 38.2 (CH2-70), 37.0 (CH2-3), 29.2
(CH2-4). MS (CIþ): m/z 384 (MHþ, 60 %). HRMS (CIþ): calcd for
C23H30NO4 384.2175 (MHþ), found 384.2178.
astereomer:
d
6.96 (s, 1H, H300), 6.73 (s, 2H, H30, H500), 6.64 (d, 1H, J
15.0 Hz, H300), 6.63 (s, 1H, H50), 6.58 (s, 2H, H60, H600), 6.49 (s, 1H,
H80), 6.48 (s, 1H, H8), 6.10 (m, 1H, H200), 4.11 (dd, 1H, J 8.4,
5.4 Hz, H10), 4.03 (m, 1H, H1), 3.82 (s, 24H, 8ꢁOCH3), 3.51 (d, 2H, J
6.3 Hz, H100), 3.17 (dd, 2H, J 13.2, 5.4 Hz, H70, H70), 3.12 (dd, 2H, J 12.0,
6.9 Hz, H3, H30), 2.87 (dd, 2H, J 13.2, 8.4 Hz, H70, H700), 2.81 (dd, 2H, J
12.0, 5.1 Hz, H3, H30), 2.70 (m, 4H, H4, H40). 1H NMR of the minor
3.7.2. (RS)-1,2,3,4-Tetrahydro-6,7-dimethoxy-1-(40,50-dimethoxy-
20-(200-propenyl)phenyl)methylisoquinoline 2-(4-oxo)butanoic
acid (21)
diastereomer (in part):
d
6.72 (s, 2H, H30, H500), 6.62 (s, 1H, H50), 6.53
To a solution of the amine 20 (332 mg, 0.867 mmol) in dry
CH2Cl2 (8 mL) was added triethylamine (0.14 mL), followed by
succinic anhydride (174 mg, 1.73 mmol) under a N2 atmosphere.
The reaction mixture was stirred at rt for 18 h. The organic layer
was evaporated and the residue was redissolved in EtOAc. The so-
lution was washed with 1 M KHSO4 (2ꢁ) and then with brine. The
solution was dried (MgSO4) and evaporated and the crude mixture
was purified by column chromatography (CH3OH/EtOAc (1:5)) to
give 21 (334 mg, 79%) as a white solid. Product 21 was a 70:30
mixture of rotamers by 1H NMR analysis. Rf 0.71 (CH3OH/EtOAc
(s, 2H, H60, H600), 6.46 (s, 1H, H80), 6.42 (s, 1H, H8), 6.07 (m, 1H, H200),
4.14 (m, 1H, H10), 4.05 (m, 1H, H1), 3.70 (s, 24H, 8ꢁOCH3). 13C NMR
of the major diastereomer:
d
148.3 (C6, C60), 148.0 (C40, C400), 147.8
(C50, C500),147.1 (C7, C70),131.1 (C10),131.0 (C100),129.8 (CH-300),129.5
(C20, C200), 128.9 (C4a, C4a0), 128.3 (C8a, C8a0), 127.5 (CH-200), 114.0
(CH-30), 113.5 (CH-300), 112.1 (CH-60, CH-600, CH-5, CH-50), 109.8 (CH-
8), 109.3 (CH-80), 56.2 (8ꢁOCH3, CH-1), 41.2 (CH2-3, CH2-30), 39.4
(CH2-70, CH2-700), 36.6 (CH2-100), 29.6 (CH2-4, CH2-40). 13C NMR of the
minor diastereomer (in part):
d
131.0 (C100), 129.7 (CH-300), 129.5
(C20, C200), 128.5 (C8a, C8a0), 127.4 (CH-200), 113.9 (CH-30), 36.7 (CH2-
100), 29.7 (CH2-4, CH2-40). MS (ESIþ): m/z 724.88 (MHþ, 100 %).
HRMS (ESIþ): calcd for C43H53N2O8 725.3802 (MHþ), found
725.3783.
(1:5)). Mp 138–140 ꢀC. 1H NMR of the major rotamer:
d 6.63 (s, 1H,
H5), 6.59 (s,1H, H30), 6.56 (s,1H, H60), 5.93 (s,1H, H8), 5.83–5.70 (m,
1H, H200), 5.51 (dd, 1H, J 9.0, 5.1 Hz, H1), 4.95 (dd, 2H, J 10.2, 1.8 Hz,
H300(Z)), 5.01 (dd, 1H, J 17.1, 1.8 Hz, H300(E)), 3.85 (s, 3H, OCH3-50),
3.83 (s, 3H, OCH3-6), 3.75 (s, 3H, OCH3-7), 3.70–3.65 (m, 2H, H3),
3.50 (s, 3H, OCH3-40), 3.11 (dd, 1H, J 12.5, 5.1 Hz, H4), 3.02 (dd, 1H, J
13.5, 5.1 Hz, H70), 3.00 (d, 2H, J 6.3 Hz, H100), 2.89 (dd, 1H, J 13.5,
9.0 Hz, H70), 2.82 (dd, 1H, J 12.5, 6.3 Hz, H4), 2.79–2.74 (m, 4H, H2%,
3.6.5. (1RS,10RS)- and (RS)-20,200-(100,200-Ethynediyl)-bis-[1,2,3,4-
tetrahydro-6,7-dimethoxy-1-(40,50-dimethoxyphenyl)-
methyl]isoquinoline (19)
Compound 18 (56 mg, 0.062 mmol), CH3OH (20 mL), H2O (2 mL)
and K2CO3 (44 mg, 0.311 mmol) were treated as described above
using the general N-TFA deprotection reaction procedure to afford
an oil. The oil was purified by column chromatography (CH3OH/
EtOAc (1:5)) to give 19 (34 mg, 79 % yield) as a brown solid. Rf 0.06
H3%). 1H NMR of the minor rotamer (in part): 6.69 (s, 1H, H30),
d
6.63 (s, 1H, H60), 6.49 (s, 1H, H5), 6.44 (s, 1H, H8), 5.99–5.88 (m, 1H,
H200), 5.11 (d, 1H, J 10.2, 1.8 Hz, H300(Z)), 5.00 (d, 1H, J 15.0, 1.8 Hz,
H300(E)), 4.86–4.84 (m, 1H, H1), 4.73 (ddd, 1H, J 8.4, 5.7, 2.4 Hz, H3),
3.87 (s, 3H, OCH3-50), 3.81 (s, 3H, OCH3-7), 3.79 (s, 3H, OCH3-40),
3.32 (d, 2H, J 6.3 Hz, H100), 3.23–3.18 (m, 1H, H4), 3.12–3.08 (m, 1H,
H70), 2.92–2.89 (m, 1H, H4), 2.87–2.84 (m, 1H, H70), 1.93–1.84 (m,
(EtOAc). Mp 208–210 ꢀC. 1H NMR:
d
7.20 (s, 2H, H30, H300), 7.00 (s,
2H, H60, H600), 6.59 (s, 2H, H5, H50), 6.35 (s, 2H, H8, H80), 4.73 (t, 2H, J
7.5 Hz, H1, H10), 3.84 (s, 6H, OCH3-40, OCH3-400), 3.82 (s, 6H, OCH3-50,
OCH3-500), 3.81 (s, 6H, OCH3-6, OCH3-60), 3.65 (s, 6H, OCH3-7, OCH3-
4H, H2%, H3%). 13C NMR of the major rotamer:
169.8 (NCO), 146.9 (C50), 146.5 (C40), 146.1 (C6), 145.9 (C7), 136.4
d 175.5 (COOH),

U. Batenburg-Nguyen et al. / Tetrahedron 65 (2009) 318–327
327
(CH-200), 130.0 (C10), 127.2 (C20), 126.7 (C4a), 124.6 (C8a), 114.4 (CH2-
300), 113.1 (CH-60), 111.6 (CH-30), 110.1 (CH-5), 109.8 (CH-8), 54.9
(OCH3-40, OCH3-50), 54.9 (OCH3-6), 54.6 (OCH3-7), 53.0 (CH-1), 40.5
(CH2-3), 37.0 (CH2-70), 35.3 (CH2-100, CH2-4), 27.7 (CH2-2%), 27.2
with brine. The CH2Cl2 layer was evaporated to give an oil, which
was purified by column chromatography (CH3OH/EtOAc (1:9)) to
give 3 (12 mg, 15 %) as a yellow oil. Rf 0.61 (CH3OH/EtOAc (1:9)). 1H
NMR: d
6.93 (d, 1H, J 15.3 Hz, H300), 6.86 (s, 1H, H50), 6.81 (s, 1H, H5),
(CH2-3%). 13C NMR of the minor rotamer (in part):
d
175.3 (COOH),
6.64 (s, 1H, H300), 6.59 (s, 1H, H30), 6.49 (s, 1H, H600), 6.02 (s, 1H, H60),
5.95–5.88 (m, 1H, H200), 5.90 (s, 1H, H80), 5.88 (s, 1H, H8), 5.66 (dd,
1H, J 9.0, 3.0 Hz, H10), 5.55 (dd, 1H, J 9.0, 3.0 Hz, H1), 4.40 (dd, 1H, J
13.5, 9.6 Hz, H30), 4.00–3.85 (m, 1H, H3), 3.88 (s, 3H, OCH3-500), 3.85
(s, 6H, OCH3-50, OCH3-7), 3.83 (s, 3H, OCH3-70), 3.73 (s, 3H, OCH3-6),
3.57 (s, 3H, OCH3-60), 3.49 (s, 6H, OCH3-40, OCH3-400), 3.70–3.64 (m,
1H, H3), 3.45–3.40 (m,1H, H30), 3.41–3.36 (m, 2H, H3%), 3.34 (d, 2H,
J 7.5 Hz, H100), 3.23–3.18 (m, 2H, H700, H700), 3.04 (dd, 1H, J 13.2,
3.0 Hz, H70), 2.99 (d, 1H, J 13.2, 9.0 Hz, H70), 2.84–2.67 (m, 2H, H4,
H40), 2.43–2.38 (m, 1H, H2%), 2.26–2.22 (m, 1H, H2%). 13C NMR:
170.2 (NCO),147.3 (C50),147.2 (C30),146.6 (C6),146.4 (C7),136.1 (CH-
200), 129.3 (C10), 126.8 (C20), 126.4 (C4a), 125.5 (C8a), 115.0 (CH2-300),
113.0 (CH-60), 112.3 (CH-30), 110.5 (CH-5), 108.9 (CH-8), 56.7 (CH-1),
37.8 (CH2-70), 36.0 (CH2-100), 35.0 (CH2-3), 26.9 (CH2-2%), 26.2 (CH2-
3%). MS (ESIþ): m/z 484 (MHþ, 70%). HRMS (ESIþ): calcd for
C27H34NO7 484.2335 (MHþ), found 484.2329.
3.7.3. (1RS,10RS)- and (RS)-20-(200-Propenyl)-200-bromo-2,20-
(1%,4%-dioxo-1%,4%-butanediyl)-bis-[1,2,3,4-tetrahydro-6,7-
dimethoxy-1-(40,50-dimethoxyphenyl)methyl]isoquinoline (23)
To a suspension of the amine 22 (148 mg, 0.349 mmol), the acid
21 (142 mg, 0.290 mmol), HOBT (44 mg, 0.319 mmol) and EDCI
(61 mg, 0.319 mmol) was added dry DMF (6 mL) under a N2 at-
mosphere. The reaction mixture was stirred at rt for 3 days. The
crude mixture was diluted with CH2Cl2 and washed with H2O (4ꢁ)
and then with brine. The CH2Cl2 was evaporated to give an oil,
which was purified by column chromatography (CH3OH/EtOAc
(1:5)) to give 23 (212 mg, 82%) as a yellow solid. Product 23 was
obtained as a 60:40 mixture of diastereomers, which were each
a 70:30 mixture of rotamers. Rf 0.74 (CH3OH/EtOAc (1:5)). Mp 145–
d
172.1 (CO), 171.2 (CO), 147.9 (C60), 147.7 (C6), 147.5 (C40, C400), 147.3
(C500), 147.0 (C50), 146.6 (C70), 146.2 (C7), 132.1 (CH-300), 132.4 (C100),
130.1 (C10),129.1 (C200),128.8 (C20),128.7 (CH-200),128.1 (C4a0),126.0
(C4a), 126.5 (C8a, C8a0), 115.7 (CH-600), 113.7 (CH-60), 113.1 (CH-300),
111.9 (CH-30), 111.1 (CH-50), 110.9 (CH-5), 110.8 (CH-80), 109.5 (CH-8),
51.7 (8ꢁOCH3), 54.8 (CH-10), 54.3 (CH-1), 41.7 (CH2-30), 41.1 (CH2-3),
40.2 (CH2-700), 39.0 (CH2-70), 36.6 (CH2-100), 29.7 (CH2-3%), 28.6
(CH2-2%), 28.3 (CH2-40), 28.0 (CH2-4). MS (ESIþ): m/z 807.09 (MHþ,
5%), m/z 844.86 (MþKþ, 20%). HRMS (ESIþ): calcd for C47H55N2O10
807.3857 (MHþ), found 807.3842.
148 ꢀC. 1H NMR of the major diastereomer:
d
6.96 (s, 1H, H300), 6.57
Acknowledgements
(s, 5H, H30, H5, H50, H60, H80), 6.34 (s, 1H, H600), 5.89 (s, 1H, H8),
5.72–5.67 (m,1H, H200), 5.47 (dd,1H, J 9.0, 4.8 Hz, H10), 5.18 (dd,1H, J
9.0, 4.8 Hz, H1), 4.96–4.86 (m, 2H, H300), 3.84 (s, 18H, 6ꢁOCH3),
3.84–3.76 (m, 4H, H3, H30), 3.72 (s, 6H, OCH3-40, OCH3-400), 3.27–
3.20 (m, 1H, H40), 3.09–3.05 (m, 1H, H4), 3.03–2.98 (m, 2H, H100),
2.82–2.76 (m, 4H, H70, H700), 2.68–2.60 (m, 6H, H40, H4, H2%, H3%).
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.
References and notes
1H NMR of the minor diastereomer (in part): 7.03 (s, 1H, H300), 6.59
d
(s, 5H, H30, H5, H50, H60, H80), 6.20 (s, 1H, H600), 5.84 (s, 1H, H8),
5.66–5.60 (m,1H, H200), 5.42 (dd,1H, J 9.9, 4.2 Hz, H10), 5.13 (dd,1H, J
9.9, 4.2 Hz, H1), 5.05–5.02 (m, 2H, H300), 2.30–2.26 (m, 4H, H2%,
H3%). 1H NMR of the minor rotamer of both diastereomers (in part)
1. ROMPP Encyclopedia of Natural Products; Steglish, W., Fugmann, B., Lang-Fug-
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tiliarine: Ray, A. K.; Mukhopadhyay, G.; Mitra, S. K.; Guha, K. P.; Mukherjee, B.;
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11. Cabri, W.; Candiani, I.; Bedeschi, A. J. Org. Chem. 1992, 57, 3558–3563.
12. Jeffery, T.; Ferber, B. Tetrahedron Lett. 2003, 44, 193–197.
13. Deeth, R. J.; Smith, A.; Brown, J. M. J. Am. Chem. Soc. 2004, 126, 7144–7151.
14. Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320–2322.
15. Ludwig, M.; Stromberg, S.; Svensson, M.; Akermark, B. Organometallics 1999, 18,
970–975.
16. Fristrup, P.; Quement, S. L.; Tanner, D.; Norrby, P. O. Organometallics 2004, 23,
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(note:
(s, 1H, H300), 6.95 (s, 1H, H300
6.52 (s, 5H, H30, H5, H50, H60, H80
4.76–4.68 (m, 2H, H3, H30), 2.58–2.54 (m, 2H, H3%), 2.32–2.28 (m,
2H, H2%). 13C NMR of the major diastereomer:
*
represents the rotamer of the minor diastereomer):
), 6.54 (s, 5H, H30, H5, H50, H60, H80),
), 5.88 (s, 1H, H8), 5.86 (s, 1H, H8 ),
d 7.02
*
*
*
d
171.1 (2ꢁNCO),
148.3 (C50, C500, C40, C400), 148.1 (C6, C60), 147.5 (C7, C70), 137.7 (CH-
200), 132.3 (C10, C100), 132.2 (C20, C200), 128.8 (C4a, C4a0), 128.6 (C8a,
C8a0), 115.7 (CH-60, CH600), 115.3 (CH2-300), 111.6 (CH-30, CH-300), 111.1
(CH-5, CH-50), 110.8 (CH-8, CH-80), 56.1 (8ꢁOCH3), 53.5 (CH-1, CH-
100), 42.6 (CH2-30), 41.0 (CH2-700), 38.4 (CH2-3), 36.6 (CH2-70), 36.0
(CH2-100), 29.1 (CH2-3%, CH2-2%), 28.7 (CH2-40), 28.1 (CH2-4). 13C
NMR of the minor diastereomer (in part):
d
131.2 (C10, C10), 129.8
(C20, C20), 128.3 (C4a, C4a0), 126.8 (C8a, C8a0), 111.3 (CH-30, CH-300),
111.0 (CH-5, CH50), 110.3 (CH-8, CH80), 35.7 (CH2-100). MS (ESIþ): m/z
886.79 (MHþ, 10 %). HRMS (ESIþ): calcd for C47H56N2O10Br 887.3118
(MHþ), found 887.3137.
3.7.4. (1RS,10RS)- and (RS)-(E)-1,10-(1,2)-Di-(1,2,3,4-tetrahydro-
6,7-dimethoxyisoquinolina)-3,8-(1,2)-di-(3,4-dimethoxy)-
benzenacyclo-(11,14-dioxo)-propadeca-4-phene (3)
To a mixture of 23 (71 mg, 0.080 mmol), Pd(OAc)2 (2 mg,
0.008 mmol) and PPh3 (4 mg, 0.016 mmol) in a thick walled tube
was added dry CH3CN (2 mL) under a N2 atmosphere. Triethyl-
amine (25 mg, 0.240 mmol, 0.04 mL) was added and the reaction
mixture was bubbled with argon for 5 min prior to sealing the tube.
The solution mixture was stirred and heated at 110 ꢀC for 24 h. The
solution was diluted with CH2Cl2, and washed with H2O and then
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21. These compounds were a gift from the Johnson and Johnson Research Lab at
the University of Wollongong. They were prepared using the literature pro-
cedure10 and the procedure in Scheme 1 starting from (S)-4 that was obtained
from (S)-norlaudanosine.
22. Suzenet, F.; Parrain, J. L.; Quintard, J. P. Eur. J. Org. Chem. 1999, 2957–2963.
23. Stara, I. G.; Stary, I.; Kollarovic, A.; Teply, F.; Saman, D.; Fiedler, P. Tetrahedron
1998, 54, 11209–11234.
24. Yonehara, F.; Kido, Y.; Yamaguchi, M. Chem. Commun. 2000, 1189–1190.
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