The synthesis of carbon-linked bisbenzylisoquinolines via ruthenium-mediated olefin-metathesis

Article abstract of DOI:10.1016/j.tet.2009.05.094

Novel laudanosine dimers in which two laudanosine units are linked at C-2′ via a two and four-carbon linker have been prepared using ruthenium-mediated olefin-metathesis. In addition, a second four-carbon linker between the two isoquinoline N-atoms was al

Full text of DOI:10.1016/j.tet.2009.05.094

Tetrahedron 65 (2009) 5990–6000
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Tetrahedron
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The synthesis of carbon-linked bisbenzylisoquinolines via ruthenium-
mediated olefin-metathesis
*
*
Uta Mbere-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 and four-carbon
linker have been prepared using ruthenium-mediated olefin-metathesis. In addition, a second four-
carbon linker between the two isoquinoline N-atoms was also present leading to a novel macrocyclic ring
system. Five of these compounds showed higher cytostatic activity on three cancer cell lines than
thalicarpine.
Article history:
Received 12 January 2009
Received in revised form 11 May 2009
Accepted 28 May 2009
Available online 6 June 2009
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
1. Introduction
(compounds of the type 3). Earlier we reported the synthesis of two
BBI derivatives (10 and 11) having a two-carbon linker using the
Over 200 bisbenzylisoquinoline (BBI) alkaloids are known, the
majority of these have one or two ether linkages between the two
benzylisoquinoline moieties.1 These alkaloids show a range of in-
teresting biological activities.1 An example of these alkaloids is the
related Thalictrum alkaloid, thalicarpine 1 (Fig. 1),2 which com-
prises the benzylisoquinoline, S-laudanosine, connected via an
ether linkage to an aporphine moiety. At the initial clinical trials,
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,3–8
however, phase II clinical trials stopped after no antitumour effect
was observed.6,8 There is also a small group of alkaloids that have
one of the linking ether bonds replaced by a biphenyl linkage.9 For
example, (þ)-tiliarine 2 (Fig. 1) contains a biphenyl linkage and
behaves as a selective in vitro inhibitor of human melanoma cell
growth.10
Inspired by the structure and biological activity of these bis-
benzylisoquinolines, we became interested in the synthesis of the
novel laudanosine dimers of the type 3 (Fig. 1), in which two lau-
danosine units are linked at C-20 through a two- to four-carbon
linker. It is noted that none of the BBI alkaloids isolated has more
than one direct C–C linkage, therefore in the example 4, a second
four-carbon linker between the two isoquinoline N-atoms was also
synthesised leading to a novel macrocyclic ring system.
Heck–Mizoroki coupling reaction, however, the preparation of four-
carbon-linked BBI compounds (for example) 4, 17, 19 and 20 would
be much more difficult using this coupling methodology.22 The
ruthenium-catalysed ring-closing metathesis (RCM) reaction11–21
for the synthesis of the conformationally restricted macrocyclic BBI
derivative 4 is also described. Grubbs’ first and second generation
catalysts, 5 and 6, respectively, were employed in this study (Fig. 2).
2. Discussion
2.1. Synthesis of C20 carbon-linked BBI derivatives
Our approach to the target molecules 3 (alkene linker, m¼n¼1)
was based on a cross-metathesis reaction of racemic N-tri-
fluoroacetyl-20-allylnorlaudanosine 7 (Scheme 1).23 Racemic com-
pounds were used in this study because of their ready availability in
our laboratory. Utilising the ability of a type I olefin like compound
7 to homocouple rapidly,11 the racemic 20-allyllaudanosine de-
rivative rac-7 was treated with 10 mol % of the Grubbs’ I catalyst 5
and the reaction mixture was heated at reflux in freshly distilled
dichloromethane for 24 h under a nitrogen atmosphere. The
homocoupled product 8 was readily obtained in 72% yield after
purification by column chromatography. The 1H NMR spectrum of 8
showed a broad overlapping signal for the olefinic and the H1 and
H10 protons at ca.
d 5.4. Because of the symmetry, the olefinic
In this paper, we report the results of an examination of
the ruthenium-mediated cross-metathesis (CM) reaction11–21 as
a method to synthesise novel mono-tethered BBI derivatives
protons are equivalent, therefore it was not possible to measure the
coupling constant or determine the (E)- or (Z)-olefin geometry for
these compounds (Fig. 3).
1H NMR analysis showed signals for two major isomers in
a ratio of 55:45, which were assumed to be the meso and the
racemic forms of 8. These were indicated by the doubling up of
* Corresponding authors.
E-mail address: spyne@uow.edu.au (S.G. Pyne).
0040-4020/$ – see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.094

U. Mbere-Nguyen et al. / Tetrahedron 65 (2009) 5990–6000
5991
CH3O
CH3O
OCH3
Grubbs I catalyst 5
CH2Cl2, N2, reflux, 24 h
NCH3
CH3O
H
NTFA
CH3O
CH3N
H
CH3O
CH3O
OCH3
OCH3
CH3O
72%
CH3O
O
1
rac-7
Thalicarpine
(R)
OCH3
N
CH3O
CH3O
TFA
O
O
1
H
NH
H
CH3N
H
2''
1'
4''
OCH3
CH3O
1''
3''
1`
CH3O
(+)-Tiliarine
OH
OCH3
OCH3
H
TFA
2
N
(S)
OCH3
4
CH3O
meso-8
single or double bond
1 N
CH3O
CH3O
R
1'
2'
CH3O
()n
OCH3
(S)
N
CH3O
()m
CH3O
CH3O
TFA
H
OCH3
OCH3
2''
4''
R
OCH3
N
CH3O
1''
3''
OCH3
OCH3
OCH3
H
3; m = n = 0;
TFA
N
(S)
m = 1, n = 0
m = n = 1
OCH3
R = H or CH3
rac-8
CH3O
Scheme 1. Cross-metathesis reaction of the 20-allyllaudanosine derivative 7 [only the
(S,S) enantiomer is shown for rac-8].
N
CH3O
CH3O
N
CH3O
OCH3
OCH3
2 x a, b
OCH3
4
OCH3
CH=CH, H1/H1`
Figure 1.
a, b
Overlapping
signals of the
a, b
olefinic and
N
N
H1/ H1`
protons
PCy3
Cl
Cl
Ph
H
Ru
PCy3
Ru
Cl
Cl
Ph
PCy3
c, d
Grubbs' I 5
Grubbs' II 6
c, d
c, d
Figure 2. Grubbs’ first and second generation catalysts.
the major aromatic proton signals a and b in the 1H NMR spec-
trum (Fig. 3). Based on the previous studies on the CM reactions
of type I olefins,24 the (E)-olefin geometry was expected for these
major isomers. A pair of minor signals (c and d) was also ob-
served in the 1H NMR spectrum of 8 representing either amide
rotamers or a different alkene geometry (Z) to that of the major
products. These signals comprised ca. 20% of the product mixture
(Fig. 3).
6
5
a, b = major isomers (meso and
racemate)
c, d = minor (Z) isomers or rotamers
(meso and racemate)
Figure 3. 1H NMR spectrum (300 MHz, CDCl3) of the aromatic region of 8 showing
pairs of aromatic signals.
The 20-vinyllaudanosine derivative 923 was subjected to the
same CM conditions as in Scheme 1 using 10 mol % of Grubbs’ I
catalyst 5 over a period of 24–72 h. Under these conditions, no
homocoupled product 10 was observed (Scheme 2). The result
obtained was not surprising since the styrene 9 is hindered due to
the closeness of the ortho isoquinoline moiety, which would be
classified as a type II olefin, resulting in a slow homocoupling
reaction rate with catalyst 5.11
The literature indicated that Grubbs’ II catalyst 6 would increase
the reactivity of a non-bulky styrene to a level of a type I olefin,

5992
U. Mbere-Nguyen et al. / Tetrahedron 65 (2009) 5990–6000
CH3O
Grubbs' I catalyst 5
CH2Cl2, N2
7
Grubbs' I 5, dry
CH2Cl2, reflux, N2,
24-72 h
(1.8 mol equiv.)
N
1
reflux, 48 h
CH3O
CH3O
TFA
+
9
No Reaction
(1 mol equiv.)
CH3O
CH3O
9
Grubbs' II 6, dry
CH2Cl2, reflux, N2,
48 h
N
CH3O
CH3O
TFA
OCH3
OCH3
OCH3
OCH3
9
54%
rac and meso- 8
2''
CH3O
CH3O
1''
3''
N
1
CH3O
CH3O
TFA
H
N
TFA
rac and meso- 11
CH3O
OCH3
d.r. = 55:45
OCH3
OCH3
11:8 = 1:1 ratio
H
TFA
N
1`
Scheme 3. CM between type I olefin 7 and type II olefin 9 [only (S,S)-11 was shown for
rac-11].
OCH3
meso-10
along with significant amounts of unreacted 7 and 9. The reaction
mixture was heated at reflux for an additional 24 h, however, the TLC
analysis showed no significant change. The crude reaction mixture
was purified by column chromatography to recover approximately
50% of a mixture of the starting materials 7 and 9. A more polar
fraction was obtained in approximately 15% yield. However, 1H NMR
analysis of this fraction indicated the presence of the desired CM
product 11 (dr¼55:45) and the homocoupled product 8 in a 1:1 ratio.
To investigate if steric factors were responsible for the low
conversion rate in the formation of compound 11, the CM reaction
of the 20-vinyllaudanosine derivative 9 with a less hindered alkene
13 was investigated.
+
CH3O
N
H
1
CH3O
CH3O
TFA
H
N
CH3O
OCH3
OCH3
OCH3
TFA
1`
The amide 13 was subjected to the CM reaction conditions with
the 20-vinyllaudanosine derivative 9 using Grubbs’ I catalyst 5. This
reaction gave the corresponding CM product 14 in 30% yield along
with the recovered styrene 9 in 54% yield. The reaction was repeated
for an additional 48 h, however, no significant change was observed
in conversion to the product 14, rather there was more de-
composition material obtained. 1H NMR analysis of 14 showed the
OCH3
rac-10
meso:rac - 55:45
Scheme 2. Cross-metathesis of the 20-vinyllaudanosine derivative 9 [only (S,S)-10 was
shown for rac-10].
expected (E)-alkene signals at
d
6.76 (d, 1H, J 15.5 Hz, H100) and 5.98
while a bulky styrene would still react as a type II olefin.11 There-
fore, Grubbs’ II catalyst 6 was used in an attempt to increase the
reactivity of the styrene 9 to the level of a type I olefin and allow for
its rapid homocoupling reaction. In the event, a solution of the
styrene 9 and Grubbs’ II catalyst 6 (10 mol %) was heated at reflux
for 48 h and the homocoupled product 10 was obtained in 54%
yield. The product had the same NMR as that reported in the lit-
erature.22 The starting styrene 9 was also recovered in 17% yield.
The reaction yield might have been improved if a longer reaction
time was permitted or if fresh catalyst was added after 48 h,
however, these variations were not examined. The geometry of the
double bond in 10 was anticipated to be 100% (E) although this
could not be readily determined by NMR due to the symmetry of 10.
Chang and co-worker have reported 100% (E)-stilbenes being
obtained from CM reactions of different styrene systems, which
supported our proposed (E)-olefin geometry for 10.25
Thecross-metathesisreactionbetweentheolefin7(1.8 mol equiv)
and olefin 9 (1 mol equiv) was carried out in dichloromethane solu-
tion at reflux temperature (Scheme 3). The less reactive Grubbs’ I
catalyst 5 was chosen for this study since it was shown above that
Grubbs’ II catalyst 5 enhanced the reactivity of the styrene 9 to the
type I level and this may have resulted in a non-selective CM reaction.
After a 24 h period, TLC analysis indicated the formation of a small
amount of a more polar compound consistent with the derivative 11
CH3O
N
TFA
CH3O
CH3O
H
N
TFA
CH3O
13
9
(1.4 mol equiv.)
(1.0 mol equiv.)
Grubbs' I
catalyst 5,
CH2Cl2,
N2, 24 h
CH3O
H
N
TFA
N
CH3O
CH3O
TFA
9
N
H
TFA
2''
H
N
CH3O
TFA
1''
3''
14
15
30%
54%
minor
Scheme 4. The CM reaction between type II olefin 9 and type I olefin 13.

U. Mbere-Nguyen et al. / Tetrahedron 65 (2009) 5990–6000
5993
CH3O
yield (85%). 1H NMR analysis of 16 showed an 80:20 mixture of two
isomers. Since the N-TFA groups had been removed, these isomers
could not be rotamers. We therefore concluded that 16 was an
80:20 mixture of the (E)- and (Z)-isomer and that when the N-TFA
group was removed, the meso and racemate forms have identical
NMR spectra. The olefinic proton signals of 16, which were ob-
scured by the H1 and H10 proton signals, were now clearly visible at
N
*
CH3O
CH3O
R
1
2''
4''
OCH3
CH3O
1''
3''
OCH3
OCH3
1`
*
d
5.44 (br s, 2H, CH]CH) for the major (E)-isomer and d 5.61 (br s,
R
N
2H, CH]CH) for the minor (Z)-isomer. Because of the signal over-
lap, the olefinic coupling constants could not be determined.
The amine 16 was subjected to reductive N-methylation to give
the corresponding N-methylated compound 17 in moderate yield.
The N-methylated products 17, however, clearly showed the meso
and racemic forms of (E)-17 in a 55:45 ratio by 1H NMR analysis.
The characteristic N-methyl signals of 17 were observed in the 1H
OCH3
meso- and rac-8; R = TFA
d.r. = 55:45 (E) and (Z) = 80:20
28 % NH3,
CH3OH
rt, 18 h
meso- and rac-16; R = H [85%]
38 %
formaldehyde
NaCNBH3,
HOAc, rt,
18 h
NMR spectrum at
d
2.51 (s, 6H, 2ꢀNCH3) for the meso and the ra-
cemic forms. 1H NMR analysis also showed 20% of a minor pair of
isomers that were thought to be the meso and racemate forms of
(Z)-17 (Scheme 5).
meso- and rac-17; R = CH3 [49%]
The synthesis of the unsaturated BBI derivative 18 was carried out
under hydrogenation conditions using palladium on activated car-
bon in methanol or ethyl acetate. Ethyl acetate proved to be the best
solvent and afforded the desired product 18 in higher purity and in
a yield of 87%. The 1H NMR spectrum of 18 showed only four aromatic
proton signals. This suggested that due to the more flexible and
d.r. = 55:45
(E) and (Z) = 80:20
meso- and rac-8; R = TFA
10 % Pd/C,solvent
48 h, H2, rt
solvent:
O
O
O
CH3O
CH3OH = 64 %
EtOAc = 87 %
Et3N, dry CH2Cl2
N2, 18 h, rt
K2CO3, CH3OH/H2O,
rt, 18 h
NH
CH3O
CH3O
rac-7
79%
90%
CH3O
CH3O
N
*
CH3O
CH3O
R
1
rac-21
2''
4''
1`
CH3O
rac-21
OCH3
O
CH3O
3''
1''
HOBt/EDCI
DMF, rt, N2, 3 d
N
O
CH3O
CH3O
OH
OCH3
OCH3
62%
R
N
*
CH3O
CH3O
OCH3
rac-22
meso- and rac-18; R = TFA
K2CO3,
CH3OH/ H2O,
rt, 2 d
O
d.r. = 55:45
Grubbs' I,
dry CH2Cl2,
reflux, 24 h
N
*
CH3O
CH3O
N
*
3''
O
meso- and rac-19; R = H [83%]
2''
38 %
formaldehyde
NaCNBH3,
HOAc, rt,
18 h
35%
2''
1''
CH3O
OCH3
OCH3
OCH3
OCH3
1''
3''
meso- and rac-20; R = CH3 [74%]
Scheme 5. Synthesis of BBI derivatives 16–20.
meso-23 and rac-23
(dt, 1H, J 15.5, 5.5 Hz, H200). The amide proton signal was also ob-
d.r. = 55:45
served at
d 7.62 (br s, 1H, NH) confirming the structure of 14. MS
CH3O
analysis of 14 also confirmed its molecular formula. In one of the
minor column chromatography fractions, traces of the starting ma-
terial 9 and the homocoupled product 15 were observed. From the
above results, it was evident that poor yields of the desired cross-
coupled products arose from the CM reactions of 9 with both hin-
dered (7, Scheme 3) and unhindered (13, Scheme 4) allyl systems.
O
N
*
CH3O
CH3O
N
*
H
H
O
2''
4''
CH3O
OCH3
OCH3
OCH3
OCH3
1''
3''
2.2. Synthesis of the tethered bisbenzylisoquinoline
derivative 16–20
meso-24 and rac-24
d.r. = 55:45
The N-TFA deprotection of 8 was carried out using 28% NH3 in
methanol at rt and afforded the corresponding amine 16 in good
Scheme 6. Synthesis of BBI derivative 24 via ring-closing metathesis.

5994
U. Mbere-Nguyen et al. / Tetrahedron 65 (2009) 5990–6000
5
CH3O
3
O
3`
1
N
CH3O
8
N
1`
6'
CH3O
O
5`
2''
4''
6``
8`
CH3O
3'
OCH3
OCH3
3''
1''
3``
OCH3
OCH3
diastereomeric mixture
7
6
5
major diastereomer 24-a
H1,1` H2'',3''
7
6
5
minor isomer of H1,H1`, H2'', H3''
H1,H1`
minor diastereomer 24-b
H2'',3''
5
H3, H3`
7
6
Figure 4. The 1H NMR spectra (300 MHz, CDCl3) of the aromatic region of the diastereomeric mixture of 24 (top), the major diastereomer 24-a (middle) and minor diastereomer 24-b
(traces of the 24-a) (bottom).
extended nature of the saturated tether, the 1H NMR analysis was not
able to distinguish between the meso and the racemate forms of 18. A
minor amide rotamer was also detected (ca. 5%) (Scheme 5).
The N-TFA deprotection of 18 was carried out using K2CO3 in
aqueous methanol over 2 days at rt to afford 19 in good yield of 83%.
As observed in the starting material 16, the meso and racemic forms
of 19 could not be distinguished as only four aromatic singlet res-
onances were observed in the 1H NMR spectrum. The deprotected
product 19 was subsequently N-methylated to afford the corre-
sponding product 20 in 74% yield. Similar to 19, the meso and ra-
cemate forms of 20 could not be distinguished in the 1H NMR
spectrum (Scheme 5).
in dry dichloromethane to Grubbs’ I catalyst at reflux for 24 h. This
reaction afforded the ring closed derivative 24 in 35% yield (Scheme 6).
1H NMR analysis of 24 showed a mixture of diastereomers in
a 55:45 ratio. The major and minor diastereomers of 24 were ex-
tremely difficult to completely separate by PTLC. The major dia-
stereomer 24-a could be obtained in ca. 95% purity by PTLC while
24-b was more difficult to purify. The 1H NMR spectra of these
isomers are shown in Figure 4. The major diastereomer 24-
a appeared as one isomer in the 1H NMR spectrum and showed
only four aromatic singlet resonances. Interestingly, the minor
diastereomer 24-b showed 1H NMR resonances for two isomers in
a 55:45 ratio. These two isomers could arise from either amide
rotamers, or from (E)- and (Z)-isomers. Further experiments in-
dicated that these two isomers were rotamers (Scheme 7).
The heats of formations of the (E)-isomer and (Z)-isomer of
meso-24 and rac-24 were calculated using Spartan Pro and the AM1
forcefield (Fig. 5). Based on these calculations, it was predicted that
the (Z)-isomer of rac-24 and meso-24 had the larger (more nega-
tive) heat of formation and therefore were expected to be ther-
modynamically more stable than the corresponding (E)-isomers.
Therefore it was speculated that 24-a was (Z)-rac-24 and 24-b was
(Z)-meso-24. However, due to the symmetry of 24, it was not pos-
sible to exactly identify the (Z)- or (E)-geometry of these isomers
based on 1H NMR analysis.
2.3. Synthesis of the macrocyclic BBI derivative 4
The racemic amine 21 was synthesised in high yield by base-
catalysed N-TFA deprotection of rac-7. A subsequent nucleophilic
ring-opening reaction of succinic anhydride with the amine 21
afforded the carboxylic acid 22 in 79% yield. The four-carbon tether
between the isoquinoline nitrogens was formed by an amide cou-
pling reaction between 21 and 22 (1:1 molar ratio) using EDCI/
HOBT to afford the tethered amide 23 in 62% yield (Scheme 6). The
reaction occurred slowly over 3 days, possibly due to the sterically
hindered nature of the secondary amine component 21.
1H NMR analysis of 23 showed the presence of the meso and
racemic forms of 23 in a ratio (not necessarily, respectively) of
55:45. In addition, the 1H NMR analysis showed two amide rotamer
forms of these isomers were also detected and accounted for 30% of
the mixture. RCM of 23 was used to construct the tether between
the C20 positions of the benzyl groups by subjecting a solution of 23
The major and minor diastereomers 24-a and 24-b, respectively,
were individually subjected to carbonyl reduction reactions using
LiAlH4 (Scheme 7). After 24 h, only the diastereomer 24-b had un-
dergone carbonyl reduction and gave the corresponding bisamine
4-b in 78% yield. The successful formation of compound 4-b was ev-
ident from the replacement of the eight aromatic proton signals of 4-

U. Mbere-Nguyen et al. / Tetrahedron 65 (2009) 5990–6000
5995
CH3O
LiAlH4, dry THF
0 °C--> rt, 24 h
CH3O
O
O
2'''
4'''
N
2'''
N
1'
1'''
O
4'''
N
1
*
CH3O
CH3O
~ 10%
3'''
CH3O
CH3O
N
1`
1'''
O
conversion
3'''
1`
*
2''
2''
CH3O
OCH3
OCH3
3''
CH3O
OCH3
OCH3
OCH3
OCH3
3''
OCH3
OCH3
24-b
meso (S, R) or
racemate (S, S- R, R)
meso- or rac-24-a
CH3O
2'''
4'''
N
1
*
CH3O
CH3O
N
*
1'''
3''
3'''
1`
2''
CH3O
OCH3
OCH3
OCH3
OCH3
meso- or rac-4-a
7
6
5
CH3O
O
CH3O
2'''
LiAlH4, dry THF
0 °C--> rt, 24 h
78%
4'''
N
N
1'
*
4'''
2'''
3'''
CH3O
CH3O
1'''
O
1`
N
3'''
1`
CH3O
CH3O
N
1'''
3''
1'
*
2''
2''
CH3O
OCH3
OCH3
3''
CH3O
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
4-b
meso (S, R) or
meso- or rac-24-b
racemate (S, S- R, R)
CH3O
4'''
2'''
3'''
1`
*
N
CH3O
CH3O
N
*
1'''
3''
1'
2''
H2'',H3''
CH3O
OCH3
OCH3
OCH3
OCH3
meso- or rac-4
7
6
5
Scheme 7. Carbonyl reduction of the major diastereomer 24-a and the minor di-
astereomer 24-b by LiAlH4.
Figure 6. 1H NMR spectrum (300 Hz, CDCl3) of the aromatic regions of the minor
diastereomer 24-b (top) and its reduced form 4-b (bottom).
b with four newly formed aromatic proton signals of 4-b in the 1H
NMR spectrum (Fig. 6) due to the lack of amide rotamers resulting
from the reduction of the carbonyl groups in 24-b.
The major diastereomer 24-a, however, showed only ca. 10%
conversion to its bisamine after 24 h. The different rates of carbonyl
reduction between the major diastereomer 24-a and the minor
diastereomer 24-b could be explained using molecular models
generated by Spartan Pro. The (Z)-rac-24 shown in Figure 7 has
a more open conformation than (Z)-meso-24, which is more folded.
Therefore carbonyl reduction could occur more rapidly in the case
of (Z)-rac-24 compared to (Z)-meso-24.
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 MacCallum Cancer Institute,
Melbourne using NCI protocols. Initially the % cell growth of cells
Heats of formations calculated by Spartan Pro
(AM1 forcefield).
incubated with 20
examined. Thalicarpine 1 was tested at 25
sented in Table 1. Compound 16 (Table 1, entry 2) showed the highest
cyctostatic activity on all three cell lines, and all compounds (Table 1,
entries 2–6) showed stronger cytostatic activity than thalicarpine 1
(Table 1, entry 1). The IC50 of the most active compounds, 16, 19 and
m
M of the compounds, 4, 11, 16, 19 and 20, were
256
254
252
250
mM. The results are pre-
meso
racemic
248
246
20, were determined to be 7–26 mM (Table 1, entries 1–3) on the same
three cell lines, which indicated they had moderate cytotoxicity.
In conclusion, five of the initially targeted compounds (4 and
17–20) were successfully synthesised using CM and RCM reactions.
The attempted synthesis of the BBI derivatives 10 and 11 having
a two-carbon linker using CM reactions proved less efficient than
the Heck–Mizoroki coupling methodology described in our pre-
vious work.22 However, the successfully prepared and novel four-
244
242
(E)-
(Z)-
Isomers
Figure 5. Heat of formation calculations for the ring closed derivative 24 (Spartan Pro,
AM1 forcefield).

5996
U. Mbere-Nguyen et al. / Tetrahedron 65 (2009) 5990–6000
otherwise noted. All spectra were referenced to CDCl3 (1H,
7.26 ppm and 13C NMR,
77.00 ppm).
1H NMR assignments were achieved with the aid of gCOSY, and
d
d
in some cases NOESY and TOCSY experiments. 13C NMR assign-
ments were based upon DEPT, gHSQC and gHMBC experiments. All
compounds were homogeneous by TLC analysis and judged to be of
>95% purity based upon 1H NMR analysis. Compound numbering
of isoquinoline derivatives is based on that of compounds 8 and 10
as shown below. The numbering used for compounds 4 and 24 in
the NMR analysis is shown below in black, systematic numbering is
shown in red.
5
4
4a
CH3O
6
3
2
7
N
CF3
4''
1
8a
1'
CH3O
CH3O
8
6'
7'
O
5'
2''
3``
2'
4'
2``
OCH
4``
3
CH3O
1''
3'
3''
5``
1``
7``
O
OCH3
6``
8`
2`
8a`
OCH
7`
3
1`
N
CF3
6`
OCH3
3`
4a`
4`
5`
8
5
4
1
4a
CH3O
6
3
2
7
N
CF3
3``
8a
8
CH3O
CH3O
6'
1'
O
7'
5'
4'
2''
2'
2``
4``
OCH3
CH3O
1''
3'
5``
OCH3
1``
O
7``
6``
8`
Figure 7. Spartan generated (AM1 forcefield) structures of (Z)-rac-24 (top) and (Z)-
meso-24 (bottom) showing the more open conformation of (Z)-rac-24 compared to the
more folded one for (Z)-meso-24.
8a`
7` OCH3
F3C
N
1`
2`
3`
6`
OCH3
4a`
4`
5`
10
Table 1
Cytostatic studies on cancer cell lines
Entry
Compound
Percentage cell
5
4
2
10
7'
4a
CH3O
6
3
growth at 20
mM (IC50, mM)
O
2'''
7
3`
4'''
11
N
2`
1
H460
15a
0.3 (7)
5 (9)
3 (10)
3
MCF-7
63a
SF-268
54a
8a
1'
14
4`
4a`
CH3O
CH3O
1'''
N
8
3'''
1
6'
1
2
3
4
5
6
1
1`
8a`
6``
O
5'
4'
meso and rac-16
meso and rac-19
meso and rac-20
meso or rac-4
meso and rac-11
2 (ND)b
26 (10)
21 (16)
25
1 (ND)b
24 (25)
5 (26)
57
5`
6`
OCH3
7``
8
2''
6
4''
2'
5
3''
1``
2``
8`
CH3O
3
3'
1''
7`
5``
OCH3
OCH3
3``
4``
24
15
66
34
OCH3
a
Percentage cell growth at 25 mM.
Not determined.
b
5
4
4a
8a
CH3O
6
3
carbon-linked BBI compounds, 4, 17, 19 and 20, would be much
more difficult to prepare using our previously described coupling
methodology.22 This study therefore demonstrates the strengths
and limitations of the CM and RCM reactions to prepare linked BBI
derivatives. Compound 16 showed the highest cyctostatic activity
on three cancer cell lines, while compounds 4, 11, 19 and 20 all
showed higher cytostatic activity than thalicarpine 1.
4'''
2
2'''
7
3`
2`
N
1
4`
4a`
CH3O
CH3O
10
N
8
1'''
3'''
3
1
6'
7'
1`
1'
8
5'
4'
5`
6`
7``
8a`
6``
2''
6
2'
4''
1``
2``
8`
CH3O
OCH3
OCH3
3''
5
3'
1''
7`
5``
3``
OCH3
4``
4
OCH3
3. Experimental
3.1. General
3.2. (1RS,10RS) and (R,S) (E and Z) 20,200-(100,400-But-200-enediyl)-
bis-[2-trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
(40,50-dimethoxyphenyl)methyl]isoquinoline (8)
Petrol refers to the fraction of petroleum spirit with a boiling
point of 40–60 ꢁC. All 1H NMR spectra were performed at 300 MHz
and all 13C NMR (DEPT) spectra at 75 MHz in CDCl3 solution, unless
A mixture of the 20-allyllaudanosine derivative 722 (400 mg,
0.854 mmol) and Grubbs’ I catalyst 5 (70 mg, 0.085 mmol) was

U. Mbere-Nguyen et al. / Tetrahedron 65 (2009) 5990–6000
5997
dissolved in dry CH2Cl2 (2 mL) under a N2 atmosphere and the so-
lution was heated at reflux for 24 h. The solvent was evaporated and
the crude product was purified by column chromatography (EtOAc/
petrol (1:1)) to afford pure 8 (284 mg, 72%) as a mixture of (E)- and
(Z)-isomer (80:20) in both meso and racemate forms (55:45). Rf 0.19
Grubbs’Icatalyst5 (15 mg, 0.019 mmol)wasaddeddryCH2Cl2 (2 mL)
undera N2 atmosphere andthesolutionwas heated at reflux for 48 h.
The solvent was evaporated and the crude product was purified by
column chromatography (EtOAc/petrol (1:1)) to give the desired
product 14 (34 mg, 30%) as a yellow oil. The starting material 9
(48 mg, 54%) was also recovered. Rf 0.38 (EtOAc/petrol (1:1)). 1H
(EtOAc/petrol (1:1)).1H NMR of the major (E)-diastereomer:
d 6.58 (s,
4H, H30, H300, H5, H50), 6.46 (s, 2H, H8, H80), 5.95 (s, 2H, H60, H600),
5.46–5.40 (m, 4H, H1, H10and CH]CH), 3.87 (dt, 2H, J 9.0, 3.6 Hz, H3,
H30), 3.83 (s, 6H, OCH3-40, OCH3-400), 3.78 (s, 6H, OCH3-6, OCH3-60),
3.71 (s, 6H, OCH3-7, OCH3-70), 3.66–3.58 (m, 2H, H3, H30), 3.49 (s, 6H,
OCH3-50, OCH3-500), 3.10–3.06 (m, 4H, H100, H400), 3.04–2.94 (m, 4H,
H70, H700), 2.89–2.83 (m, 2H, H4, H40), 2.76–2.67 (m, 2H, H4, H40). 1H
NMR of the minor (E)-diastereomer (in part): 6.44 (s, 4H, H8, H80),
5.93 (s, 4H, H60, H600), 3.47 (s, 6H, OCH3-50, OCH3-500). 1H NMR of the
NMR: d
7.62 (br s,1H, NH), 6.94 (s,1H, H30), 6.76 (d,1H, J 15.5 Hz, H100),
6.60 (s,1H, H5), 6.26 (s,1H, H60), 5.98 (dt,1H, J 15.5, 5.5 Hz, H200), 5.69
(s, 1H, H8), 5.35 (dd, 1H, J 10.0, 3.5 Hz, H1), 4.19 (dt, 1H, J 15.5, 5.5 Hz,
H300), 4.09 (dt, 1H, J 15.5, 5.5 Hz, H300), 3.95–3.91 (m, 1H, H3), 3.87 (s,
3H, OCH3-50), 3.82 (s, 3H, OCH3-7), 3.73–3.68 (m,1H, H3), 3.66 (s, 3H,
OCH3-40), 3.44 (s, 3H, OCH3-6), 3.23 (dd,1H, J 13.0, 3.5 Hz, H70), 2.94–
2.92 (m, 1H, H4), 2.91 (dd, 1H, J 13.0, 10.0 Hz, H70), 2.83–2.78 (m, 1H,
H4). 13C NMR:
d 157.4 (q, J 36.6 Hz, COCF3),156.1 (q, J 36.7 Hz, COCF3),
major (Z)-isomer (in part):
H600), 3.73(s, 6H,OCH3-7, OCH3-70), 3.44(s, 6H,OCH3-50, OCH3-500).13C
NMR of the major (E)-diastereomer: 156.0 (q, J 35.6 Hz, COCF3),
d
6.01 (s, 4H, H8, H80), 5.98 (s, 4H, H60,
148.4 (C40, C50),148.2 (C7),146.9 (C6),129.6 (CH-100),128.7 (C10),127.0
(C20), 125.9 (C4a), 124.5 (C8a), 123.9 (CH-200), 118.3 (q, J 286.1 Hz,
COCF3), 116.5 (q, J 286.0 Hz, COCF3), 114.8 (CH-60), 111.3 (CH-8), 111.0
(CH-5), 109.1 (CH-30), 56.0 (OCH3-50, OCH3-7), 55.9 (OCH3-40), 55.5
(OCH3-6), 55.3 (CH-1), 41.3 (CH2-300), 40.9 (CH-3), 39.6 (CH2-70), 28.4
(CH2-4). MS (EIþ): m/z 590 (Mþ, 30%). HRMS (ESIþ): calcd for
C27H29N2O6F6 591.1930 (MHþ), found 591.1959.
d
148.4 (C40, C400), 147.4 (C6, C60), 146.2 (C7, C70), 142.2 (C50, C500), 131.8
(C20, C200), 130.4 (CH]CH), 127.3 (C4a, C4a0), 126.5 (C8a, C8a0), 125.1
(C10, C100),116.8 (q, J 286.3 Hz, COCF3),114.3 (CH-60, CH-600),113.1 (CH-
8, CH-80), 111.1 (CH-30, CH-300), 111.9 (CH-5, CH-50), 56.1 (6ꢀOCH3),
55.8 (OCH3-50, OCH3-500), 55.5 (CH-1, CH-10), 40.8 (CH2-100, CH2-400),
38.2 (CH2-70, CH2-700), 35.5 (CH2-3, CH2-30), 28.7 (CH2-4, CH2-40). 13C
3.6. (1RS,10RS) and (R,S) (E and Z) 20,200-(100,400-But-200-enediyl)-
bis-[1,2,3,4-tetrahydro-6,7-dimethoxy-1-(40,50-
dimethoxyphenyl)methyl]isoquinoline (16)
NMR of the minor (E)-diastereomer (in part): d
27.4 (CH2-4, CH2-40).
MS (ESIþ): m/z 931 (MHþ, 10 %), 953.2 (MþNaþ, 15 %). HRMS (ESIþ):
calcd for C48H53N2O10F6 931.3604 (MHþ), found 931.3592.
To
a solution of the N-TFA protected amine 8 (243 mg,
3.3. (1RS,10RS) and (R,S) (E) 20,200-(100,200-Ethenediyl)-bis-
[2-trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
(40,50-dimethoxyphenyl)methyl]isoquinoline (10)
0.262 mmol) in CH3OH(2 mL)was addeddropwise 28%aqueous NH3
(2 mL). Thereactionmixturewasstirredatrtfor18 h. Thesolventwas
evaporated and the residue was purified by column chromatography
(CH3OH/EtOAc (1:4)) to give 16 (189 mg, 85% yield) as a yellow solid.
Compound 16 was obtained as an 80:20 mixture of (E)- and (Z)-iso-
mer, respectively. Rf 0.13 (CH3OH/EtOAc (1:4)), mp 158–160 ꢁC. 1H
A mixture of the 20-vinyllaudanosine derivative 922 (113 mg,
0.243 mmol) and Grubbs’ II catalyst 6 (31 mg, 0.036 mmol) was dis-
solved in dry CH2Cl2 (2 mL) under a N2 atmosphere and the solution
was heated at reflux for 48 h. The solvent was evaporated and the
crude product waspurified bycolumn chromatography (EtOAc/petrol
(1:1)) to afford pure 10 (55 mg, 54%). Compound 10 was isolated as
a 55:45mixture of meso-10 and rac-10. Thestartingmaterial9(19 mg,
17%) was also recovered. The spectral data of 10 obtained from this
reaction were identical to that reported from previous work.22
NMRof(E)-16:d
6.68(s, 2H, H30, H300), 6.65 (s, 2H, H5, H50), 6.57 (s, 2H,
H8, H80), 6.46 (s, 2H, H60, H600), 5.44 (br s, 2H, CH]CH), 4.06 (br s, 2H, J
9.0, 4.8 Hz, H1, H10), 3.84 (s, 6H, OCH3-40, OCH3-400), 3.81 (s, 6H, OCH3-
6, OCH3-60), 3.79 (s, 6H, OCH3-7, OCH3-70), 3.71 (s, 6H, OCH3-50, OCH3-
500), 3.31 (d, 4H, J 3.3 Hz, H100, H400), 3.21–3.18 (m, 2H, H3, H30), 3.15
(dd, 2H, J 12.9, 6.0 Hz, H70, H700), 2.90–2.81 (m, 4H, H70, H700, H3, H30),
2.72 (dt, 4H, J 9.2, 6.2 Hz, H4, H40).1H NMRof (Z)-16 (inpart):
2H, H30, H300), 6.64(s, 2H, H5, H50), 6.47 (s, 2H, H60, H600), 5.61 (br s, 2H,
CH]CH), 4.15–4.06 (m, 1H, H1). 13C NMR of (E)-16: 147.7 (C40, C400,
d 6.71 (s,
3.4. (1RS,10RS) and (1RS,10SR) (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 (66) and (RS) (E) 1-
(20-cinnamyl-40,50-dimethoxyphenyl)methyl-2-trifluoroacetyl-
1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (11)
d
C6, C60), 146.7 (C7, C70), 147.1 (C50, C500), 131.4 (C20, C200), 130.7 (C4a,
C4a0),130.1 (CH]CH),129.3 (C8a, C8a0),127.6 (C10, C100),114.0 (CH-60,
CH-600),113.4 (CH-8, CH-80),112.1 (CH-30, CH-300),101.8 (CH-5, CH-50),
56.6 (CH-1, CH-10), 56.2 (OCH3-40, OCH3-400), 56.1 (OCH3-6, OCH3-60,
OCH3-7, OCH3-70), 56.2 (OCH3-50, OCH3-500), 41.0 (CH2-3, CH2-30), 39.5
(CH2-70, CH2-700), 35.8 (CH2-100, CH2-400), 29.7 (CH2-4, CH2-40). MS
(ESIþ): m/z 739 (MHþ, 10%). HRMS (ESIþ): calcd for C44H55N2O8
739.3958 (MHþ), found 739.3950.
To a mixture of the 20-vinyllaudanosine derivative 922 (63 mg,
0.134 mmol), the 20-allyllaudanosine22 derivative
7 (114 mg,
0.244 mmol) and Grubbs’ I catalyst 5 (11 mg, 0.013 mmol) was added
dry CH2Cl2 (2 mL) under a N2 atmosphere and the solution was
heated at reflux for 48 h. The solvent was evaporated and the crude
product was purified by column chromatography (EtOAc/petrol
(1:1)) to give a mixture (18 mg) of the desired product 11 and the
homocoupled product 8, which has the same Rf and could not be
separated. The starting materials 9 (16 mg, 26%) and 7 (26 mg, 27%)
were also recovered. The NMR of the mixture consisting of com-
pounds 11 and 18 (1:1 ratio) corresponded to the NMR of each in-
dividual compound,11 and8, thathadbeenpreviouslysynthesised.22
3.7. (1RS,10RS) and (R,S) (E and Z) 20,200-(100,400-But-200-enediyl)-
bis-[1,2,3,4-tetrahydro-6,7-dimethoxy-1-(40,50-dimethoxy-
phenyl)methyl-2-methyl]isoquinoline (17)
To a solution of the amine 16 (37 mg, 0.501 mmol) in CH3CN
(1 mL) was added 38% formaldehyde (2 mL). NaCNBH3 (18 mg,
0.260 mmol) was subsequently added and the reaction mixture was
stirred at rt for 20 min. The pH was then adjusted to 6–7 using glacial
acetic acid and the reaction mixture was stirred at rt for 18 h. The
solvent was evaporated and the residue was dissolved in EtOAc. The
solution was washed with satd K2CO3 (2ꢀ), then dried (MgSO4) and
concentrated in vacuo to give an oil, which was purified by column
chromatography (CH2Cl2/EtOAc/CH3OH/NH3 (10:5:1:0.1)) to afford
17 (19 mg, 49% yield) as a yellow oil. Compound 17 was an 80:20
mixture of(E)-and(Z)-isomer, respectively, forbothmeso-17 andrac-
3.5. (RS) (E) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-6,7-
dimethoxy-1-[40,50-dimethoxy-20-(300-trifluoroacetyl-100-
propenyl)phenyl]methylisoquinoline (14)
To a mixture of the 20-vinyllaudanosine derivative 922 (88 mg,
0.189 mmol), N-TFA allylamine 1326 (40 mg, 0.261 mmol) and

5998
U. Mbere-Nguyen et al. / Tetrahedron 65 (2009) 5990–6000
17 (dr¼55:45). Rf 0.39 (DCM/EtOAc/CH3OH/NH3 (10:5:1:0.1)). 1H
(s, 4H, H30, H300, H60, H600), 6.56 (s, 2H, H5, H50), 6.46 (s, 2H, H8, H80),
4.10 (dd, 2H, J 4.4, 2.4 Hz, H1, H10), 3.82 (s, 12H, OCH3-40, OCH3-400,
OCH3-50, OCH3-500), 3.78 (s, 6H, OCH3-6, OCH3-60), 3.70 (s, 6H, OCH3-
7, OCH3-70), 3.21–3.07 (m, 4H, H3, H30 and H70, H700), 2.92–2.76 (m,
4H, H3, H30 and H70, H700), 2.71–2.69 (m, 4H, H4, H40), 2.60–2.56 (m,
4H, H100, H400), 2.32 (br s, 2H, 2ꢀNH),1.61–1.59 (m, 4H, H200, H300). 13C
NMRof(E)-17, majordiastereomer:d
6.54(s, 2H, H30, H300), 6.53(s, 2H,
H5, H50), 6.50 (s, 2H, H8, H80), 5.68 (s, 2H, H60, H600), 5.71 (br s, 2H,
CH]CH), 3.80 (s, 6H, OCH3-40, OCH3-400), 3.76 (s, 6H, OCH3-6, OCH3-
60), 3.74 (s, 6H, OCH3-7, OCH3-70), 3.62 (dd, 2H, J 8.4, 4.2 Hz, H1, H10),
3.39 (s, 6H, OCH3-50, OCH3-500), 3.24–3.14 (m, 2H, H3, H30), 3.07 (dd,
2H, J 13.5, 4.2 Hz, H70, H700), 2.91 (t, 4H, J 4.5 Hz, H100, H400), 2.87 (dd,
2H, J 13.5, 8.4 Hz, H70, H700), 2.85–2.76 (m, 4H, H3, H30, H4, H40), 2.65–
2.54 (m, 2H, H4, H40), 2.51 (s, 6H, 2ꢀNCH3). 1H NMR of (E)-17, minor
NMR:
d
147.8 (C40, C400), 147.7 (C50, C500), 147.2 (C6, C60), 147.1 (C7,
C70), 133.7 (C20, C200), 133.7 (C10, C100), 128.7 (C4a, C4a0), 127.4 (C8a,
C8a0), 114.0 (CH-30, CH-300), 112.9 (CH-60, CH-600), 112.0 (CH-5, CH-
50), 110.0 (CH-8, CH-80), 56.7 (CH-1, CH-10), 56.2 (OCH3-40, OCH3-400,
OCH3-50, OCH3-500), 56.1 (OCH3-6, OCH3-60, OCH3-7, OCH3-70), 40.9
(CH2-3, CH2-30), 39.2 (CH2-70, CH2-700), 32.8 (CH2-4, CH2-40), 32.0
(CH2-100, CH2-400), 29.9 (CH2-200, CH2-300). MS (ESIþ): m/z 741.5 (MHþ,
30 %). HRMS (ESIþ): calcd for C44H57N2O8 741.4150 (MHþ), found
741.4121.
diastereomer (in part):
3.41 (s, 6H, OCH3-50, OCH3-500). 1H NMR of (Z)-17 (in part):
2H, H30, H300), 6.56 (s, 2H, H5, H50), 5.71 (s, 2H, H60, H600). 13C NMR of
(E)-17, major diastereomer:
148.5 (C40, C400), 148.0 (C6, C60), 147.5
d
6.49 (s, 2H, H8, H80), 5.67 (s, 2H, H60, H600),
6.57 (s,
d
d
(C7, C70),146.7 (C50, C500),132.0 (C20, C200),130.3 (CH]CH),130.1 (C4a,
C4a0), 128.5 (C8a, C8a0), 125.9 (C10, C100), 114.6 (CH-60, CH-600), 113.1
(CH-8, CH-80), 111.5 (CH-30, CH-300), 111.4 (CH-5, CH-50), 64.5 (CH-1,
CH-10), 56.3 (OCH3-40, OCH3-400), 56.2 (OCH3-6, OCH3-60), 56.1 (OCH3-
7, OCH3-70), 55.6 (OCH3-50, OCH3-500), 45.1 (CH2-3, CH2-30), 41.0
(2ꢀNCH3), 37.2 (CH2-70, CH2-700), 35.6 (CH2-100, CH2-400), 23.4 (CH2-4,
3.10. (1RS,10RS) and (R,S) 20,200-(100,400-Butyldiyl)-bis-[1,2,3,4-
tetrahydro-6,7-dimethoxy-1-(40,50-dimethoxyphenyl)methyl-
2-methyl]isoquinoline (20)
CH2-40).13C NMRof (E)-17, minordiastereomer (inpart):
d 64.7 (CH-1,
CH-10), 40.7 (2ꢀNCH3), 35.6 (CH2-100, CH2-400), 22.9 (CH2-4, CH2-40).
MS (ESIþ): m/z 767.5 (MHþ, 10%). HRMS (ESIþ): calcd for C46H59N2O8
767.4271 (MHþ), found 767.4234.
The amine 19 (73 mg, 0.099 mmol) was treated as described
above in the synthesis of 18 using CH3CN (2 mL), 38% formalde-
hyde (4 mL) and NaCNBH3 (36 mg, 0.514 mmol) to give an oil,
which was purified by column chromatography (CH2Cl2/EtOAc/
CH3OH/NH3 (10:5:1:0.1)) to give 20 (56 mg, 74%) as a yellow oil. Rf
3.8. (1RS,10RS) and (R,S) 20,200-(100,400-Butanediyl)-bis-
[2-trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
(40,50-dimethoxyphenyl)methyl]isoquinoline (18)
0.37 (CH2Cl2/EtOAc/CH3OH/NH3 (10:5:1:0.1)). 1H NMR:
d 6.58 (s,
2H, H30, H300), 6.55 (s, 2H, H5, H50), 6.52 (s, 2H, H8, H80), 5.74 (s,
2H, H6, H60), 3.82 (s, 6H, OCH3-40, OCH3-400), 3.81 (s, 6H, OCH3-6,
OCH3-60), 3.76 (s, 6H, OCH3-7, OCH3-70), 3.66 (dd, 2H, J 9.3, 4.5 Hz,
H1, H10), 3.43 (s, 6H, OCH3-50, OCH3-500), 3.23 (ddd, 2H, J 13.2, 8.1,
3.6 Hz, H3, H30), 3.10 (dd, 2H, J 13.5, 4.5 Hz, H70, H700), 2.94–2.87
(m, 2H, H3, H30), 2.83–2.78 (m, 2H, H4, H40), 2.72 (dd, 2H, J 13.5,
9.3 Hz, H70, H700), 2.64–2.56 (m, 2H, H4, H40), 2.54 (s, 6H, 2ꢀNCH3),
2.26–2.24 (m, 4H, H100, H400), 1.48–1.40 (m, 4H, H200, H300). 13C
To a solution of the alkene8 (284 mg, 0.308 mmol) in EtOAc (5 mL)
was added 10% Pd/C (21 mg) in a round bottom flask sealed with
a suba seal. The flask was purged with nitrogen and then a hydrogen
filledballoonwassecuredontopoftheflask, allowingthehydrogento
circulate inside the flask. The reaction mixture was stirred at rt for
48 h under a H2 atmosphere. Nitrogen was then bubbled into the
solution for 2 min before the Pd/C was filtered. The filtrate was con-
centrated invacuoto give pure 18 (248 mg, 87%)asayellowoil. Rf 0.85
NMR:
d
147.9 (C40, C400), 147.6 (C6, C60), 147.0 (C7, C70), 146.4 (C50,
C500), 133.9 (C20, C200), 128.7 (C4a, C4a0), 127.5 (C8a, C8a0), 124.9
(C10, C100), 114.4 (CH-30, CH-300), 112.8 (CH-5, CH-50), 111.6 (CH-8,
CH-80), 111.4 (CH-60, CH-600), 64.6 (CH-1, CH-10), 56.2 (OCH3-40,
OCH3-400 and OCH3-6, OCH3-60), 56.0 (OCH3-7, OCH3-70), 55.6
(OCH3-50, OCH3-500), 31.6 (CH2-100, CH2-400), 24.7 (CH2-200, CH2-300).
MS (ESIþ): m/z 769.4 (MHþ, 30%). HRMS (ESIþ): calcd for
C46H61N2O8 769.4428 (MHþ), found 769.4396.
(EtOAc/petrol (1:1)). 1H NMR: 6.62 (s, 2H, H30, H300), 6.58 (s, 2H, H5,
d
H50), 6.45 (s, 2H, H8, H80), 6.00 (s, 2H, H60, H600), 5.45 (dd, 2H, J 8.1,
5.7 Hz,H1, H10), 3.89(dt, 2H, J12.0,5.0 Hz, H3,H30),3.83(s,12H, OCH3-
40, OCH3-400, OCH3-7, OCH3-70), 3.68 (s, 6H, OCH3-6, OCH3-60), 3.65–
3.61(m, 2H, H3,H30), 3.50(s, 6H, OCH3-50, OCH3-500),3.08–3.03(m, 2H,
H40, H400), 2.98–2.88 (m, 4H, H70, H700), 2.77–2.71 (m, 2H, H4, H40),
2.42–2.38 (m, 4H, H100, H400), 1.51–1.47 (m, 4H, H200, H300). 13C NMR:
d
155.1 (q, J 35.5 Hz, COCF3),148.4 (C40, C400),148.0 (C6, C60), 147.3 (C7,
C70), 147.0 (C50, C500), 134.0 (C20, C200), 126.8 (C4a, C4a0), 126.5 (C8a,
C8a0),125.2(C10, C100),114.3(CH-60, CH-600),113.8(q, J286.9 Hz,COCF3),
112.6 (CH-8, CH-80), 111.1 (CH-30, CH-300), 111.0 (CH-5, CH-50), 56.1
(OCH3-40, OCH3-400, OCH3-6, OCH3-60), 56.0 (OCH3-7, OCH3-70), 55.8
(OCH3-50, OCH3-500), 55.6 (CH-1, CH-10), 40.8 (CH2-3, CH2-30), 32.2
(CH2-70, CH2-700), 38.2 (CH2-4, CH2-40), 31.7 (CH2-100, CH2-400), 28.7
(CH2-200, CH2-300). MS (ESIþ): m/z 933.3 (MHþ, 70%). HRMS (ESIþ):
calcd for C48H55N2O10F6 933.3761 (MHþ), found 933.3800.
3.11. (RS) 1,2,3,4-Tetrahydro-6,7-dimethoxy-1-(40,50-
dimethoxy-20-(200-propenyl)-phenyl) methylisoquinoline (21)
N-TFA protected amine 7 (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 21 (50 mg, 90%) as a yel-
low oil. Rf 0.21 (CH3OH/EtOAc (1:5)). 1H NMR:
d
6.73 (s, 1H, H30),
3.9. (1RS,10RS) and (R,S) 20,200-(100,400-Butyldiyl)-bis-
[1,2,3,4-tetrahydro-6,7-dimethoxy-1-(40,50-
dimethoxyphenyl)methyl]isoquinoline] (19)
6.71 (s, 1H, H60), 6.58 (s, 1H, H5), 6.44 (s, 1H, H8), 5.98–5.85 (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, 8.7 Hz,
To a solution of the N-TFA protected amine 18 (247 mg,
0.267 mmol) in a mixture of CH3OH (20 mL) and H2O (2 mL) was
added K2CO3 (184 mg, 1.34 mmol). The resulting solution was stir-
red at rt for 2 days. CH3OH was evaporated and the residue was
dissolved in EtOAc. The solution was washed with H2O (3ꢀ), brine
and then dried (MgSO4). The EtOAc was evaporated and the residue
was purified by column chromatography (CH3OH/EtOAc/NH3
(1:5:0.1)) to afford the amine 19 (164 mg, 83%) as a yellow solid. Rf
H70), 2.77–2.69 (m, 2H, H4). 13C NMR:
d
147.9 (C40, C50), 147.5 (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.
0.09 (CH3OH/EtOAc/NH3 (1:5:0.1)), mp 130–134 ꢁC. 1H NMR:
d 6.64

U. Mbere-Nguyen et al. / Tetrahedron 65 (2009) 5990–6000
5999
3.12. (RS) 1,2,3,4-Tetrahydro-6,7-dimethoxy-1(40,50-
dimethoxy-20-(200-propenyl)-phenyl) methylisoquinoline
2-(4-oxo)butanoic acid (22)
2H, H5, H50), 6.53 (s, 2H, H60, H600), 5.88 (s, 2H, H8, H80), 5.84–5.80
(m, 2H, 2ꢀH200), 5.48 (dd, 2H, J 8.7, 4.2 Hz, H1, H10), 5.04–4.98 (m,
4H, H3, H3), 3.71 (s, 6H, OCH3-7, OCH3-70), 3.45 (s, 6H, OCH3-6,
OCH3-60), 3.46 (s, 6H, OCH3-40, OCH3-400), 3.11–3.07 (m, 2H, H70,
H700), 3.02 (d, 4H, J 5.7 Hz, 2ꢀH100). 1H NMR minor rotamer of both
diastereomers (in part), note: * indicates the minor diastereomer:
To a solution of the amine 21 (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 solution was
concentrated and the residue was redissolved in EtOAc. The solu-
tion was washed with 1 M KHSO4 (2ꢀ) and then brine. The solution
was dried (MgSO4) and concentrated, and the crude mixture was
purified by column chromatography (CH3OH/EtOAc (1:5)) to give
22 (334 mg, 79%) as a white solid. The product 22 was a 70:30
mixture of rotamers by 1H NMR analysis. Rf 0.71 (CH3OH/EtOAc
d
6.64 (s, 2H, H30, H300), 6.50 (s, 2H, H5, H50), 6.47 (s, 2H, H5*, H50*),
6.36 (s, 2H, H60, H600), 6.34 (s, 2H, H60*, H600*), 5.93 (s, 2H, H8, H80),
5.84 (s, 2H, H8*, H80*), 5.40 (dd, 2H, J 9.9, 5.1 Hz, H1, H10), 5.39 (dd,
2H, J 9.9, 5.1 Hz, H1*, H10*), 4.72–4.68 (m, 2H, 2ꢀH300), 4.60–4.55
(m, 2H, 2ꢀH300*). 13C NMR of the major diastereomer:
d 171.1 (CO),
148.0 (C50, C500),147.7 (C7, C70, C6, C60),147.3 (C40, C400),137.2 (2ꢀCH-
200), 131.2 (C8a, C8a0), 128.7 (C4a, C4a0), 128.4 (C10, C100), 126.1 (C20,
C200), 115.7 (2ꢀCH2-300), 114.0 (CH-30, CH-300), 112.5 (CH-60, CH-600),
111.0 (CH-8, CH-80), 110.8 (CH-5, CH50), 55.8 (8ꢀOCH3), 54.5 (CH-1,
CH-10), 41.1 (CH2-3, CH2-30), 38.1 (CH2-70, CH2-700), 36.3 (2ꢀCH2-100),
28.9 (CH2-4, CH2-40), 28.4 (CH2-2%, CH2-3%). 13C NMR of the minor
(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), 5.76 (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), 2.79–2.73 (m, 4H, H2%,
diastereomer (in part):
d
171.1 (CO), 148.3 (C50, C500), 147.7 (C7, C70,
C6, C60), 146.7 (C40, C400), 137.1 (2ꢀCH-200), 132.0 (C8a, C8a0), 115.3
(2ꢀCH2-300), 57.2 (CH-1, CH-10), 41.1 (CH2-3, CH2-30), 38.7 (CH2-70,
CH2-700), 36.9 (2ꢀCH2-100), 29.0 (CH2-4, CH2-40), 27.9 (CH2-2%, CH2-
3%). MS (ESIþ): m/z 849.5 (MHþ, 20%). HRMS (ESIþ): calcd for
C50H61N2O10 849.4326 (MHþ), found 849.4376.
H3%). 1H NMR of the minor rotamer (in part):
d
6.69 (s, 1H, H30),
6.6030 (s, 1H, H60), 6.49 (s, 1H, H5), 6.44 (s, 1H, H8), 5.99–5.88 (m, 1H,
H2 ), 5.11 (d, 1H, J 10.2, 1.8 Hz, H300(Z)), 5.00 (d, 1H, J 15.0, 1.8 Hz,
H300(E)), 4.88–4.84 (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), 3.27–3.17 (m, 1H, H4), 3.12–3.08 (m, 1H,
H70), 2.91–2.89 (m, 1H, H4), 2.87–2.85 (m, 1H, H70), 1.90–1.84 (m,
3.14. (1RS,10RS) and (R,S) 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)-tetradeca-5-phene (24)
A solution of 23 (44 mg, 0.056 mmol) and Grubbs’ I catalyst 5
(5 mg, 0.006 mmol) in dry CH2Cl2 (25 mL) was heated at reflux for
24 h under a N2 atmosphere. The solvent was evaporated and the
crude oil was purified by column chromatography (CH3OH/EtOAc
(2:8)) to give 24 (16 mg, 35 %) as a clear oil. Compound 24 was
a 55:45 mixture of diastereomers, which were separated by PTLC
(CH3OH/EtOAc (2:8)).
4H, H2%, H3%). 13C NMR of the major rotamer:
d 175.5 (COOH),
169.8 (NCO), 146.9 (C50), 146.5 (C40), 146.1 (C6), 145.9 (C7), 136.4
(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
(CH2-3%). 13C NMR of the minor rotamer (in part):
d
175.3 (COOH),
Compound 24-a. Rf 0.69 (CH3OH/EtOAc (2:8)). 1H NMR:
d 6.71 (s,
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.
2H, H30, H300), 6.57 (s, 2H, H5, H50), 6.40 (s, 2H, H60, H600), 5.73 (s, 2H,
H8, H80), 5.53 (dd, 2H, J 6.0, 2.4 Hz, H1, H10), 5.19 (t, 2H, J 4.8 Hz, H200,
H300), 3.84 (s, 12H, OCH3-50, OCH3-500, OCH3-7, OCH3-70), 3.87–3.77
(m, 2H, H3, H30), 3.73 (s, 6H, OCH3-6, OCH3-60), 3.64–3.57 (m, 4H,
H100, H400), 3.49 (dd, 2H, J 12.6, 5.4 Hz, H3, H30), 3.37 (s, 6H, OCH3-40,
OCH3-400), 3.36–3.32 (m, 2H, H2%, H3%), 3.30 (dd, 2H, J 13.3, 6.0 Hz,
H70, H700), 2.99 (dd, 2H, J 13.3, 2.4 Hz, H70, H700), 2.67–2.57 (m, 2H,
H4, H40), 2.37–2.32 (m, 2H, H4, H40), 2.18 (dt, 2H, J 14.1, 4.8 Hz, H2%,
3.13. (1RS,10RS) and (R,S) 2,20-(1%,4%-Dioxo-1%,4%-
butanediyl)-20,200-(100,400-prop-2-enediyl)-bis-[1,2,3,4-
tetrahydro-6,7-dimethoxy-1-(40,50-dimethoxy-
phenyl)methyl]isoquinoline (23)
H3%). 13C NMR:
d
171.5 (CO), 147.8 (C50, C500), 147.4 (C7, C70), 147.3
(C6, C60), 145.9 (C40, C400), 133.3 (C8a, C8a0), 129.4 (CH-200, CH-300),
128.3 (C4a, C4a0), 127.6 (C10, C100), 127.3 (C20, C200), 114.4 (CH-8, CH-
80), 112.9 (CH-30, CH-300), 111.3 (CH-60, CH-600), 110.8 (CH-5, CH50),
56.0 (OCH3-50, OCH3-500, OCH3-7, OCH3-70), 55.8 (OCH3-6, OCH3-60),
55.3 (OCH3-40, OCH3-400), 55.0 (CH-1, CH-10), 41.7 (CH2-3, CH2-30),
37.9 (CH2-70, CH2-700), 31.5 (CH2-100, CH2-400), 28.3 (CH2-2%, CH2-3%),
28.1 (CH2-4, CH2-40).
To a mixture of the acid 22 (64 mg, 0.131 mmol), amine 21
(50 mg, 0.131 mmol), HOBT (20 mg, 0.144 mmol) and EDCI (25 mg,
0.131 mmol) was added dry DMF (3 mL) under a N2 atmosphere.
The mixture was stirred at rt for 3 days. EtOAc was added and the
solution was washed with H2O (3ꢀ), then dried (MgSO4) and
concentrated to give a solid, which was purified by column chro-
matography (CH3OH/EtOAc (1:5)) to give 23 (69 mg, 62%) as a white
solid. Compound 23 was a 55:45 mixture of diastereomers. A minor
rotamer of 23 (30%) was also observed. Rf 0.88 (CH3OH/EtOAc
Compound 24-b. Rf: 0.66 (CH3OH/EtOAc (2:8)). 1H NMR of the
major rotamer: d
6.81 (s, 2H, H30, H300), 6.69 (s, 2H, H5, H50), 6.59 (s,
2H, H60, H600), 5.88 (s, 2H, H8, H80), 5.43 (dd, 2H, J 9.0, 3.6 Hz, H1,
H10), 5.29 (t, 2H, J 8.4 Hz, H200, H300), 4.22–4.17 (m, 2H, H3, H30), 3.85
(s, 6H, OCH3-50, OCH3-500), 3.83 (s, 6H, OCH3-7, OCH3-70), 3.80–3.76
(m, 2H, H3, H30), 3.60 (s, 6H, OCH3-6, OCH3-60), 3.59 (s, 6H, OCH3-40,
OCH3-400), 3.59–3.51 (m, 2H, H100, H400), 3.12–3.04 (m, 2H, H100, H400),
2.94–2.86 (m, 4H, H70, H700), 2.75–2.65 (m, 2H, H4, H40), 2.52–2.47
(m, 2H, H4, H40), 2.35–2.26 (m, 4H, H2%, H3%). 1H NMR of the minor
(1:5)), mp 142–144 ꢁC. 1H NMR of the major diastereomer:
d 6.56 (s,
6H, H30, H300, H5, H50, H60, H600), 5.89 (s, 2H, H8, H80), 5.79–5.68 (m,
2H, 2ꢀH200), 5.50 (dd, 2H, J 8.7, 4.2 Hz, H1, H10), 5.08–4.80 (m, 4H,
2ꢀH300), 3.81 (s, 6H, OCH3-50, OCH3-500), 3.82–3.78 (m, 2H, H3, H30),
3.79 (s, 6H, OCH3-7, OCH3-70), 3.72 (s, 6H, OCH3-6, OCH3-60), 3.66–
3.54 (m, 2H, H3, H30), 3.46 (s, 6H, OCH3-40, OCH3-400), 3.00 (d, 4H, J
5.7 Hz, 2ꢀH100), 3.01–2.95 (m, 2H, H70, H700), 2.90–2.84 (m, 2H, H70,
H700), 2.83–2.79 (m, 4H, H4, H40), 2.77 (br s, 4H, H2%, H3%). 1H NMR
rotamer (in part): d
6.77 (s, 2H, H30, H300), 6.63 (s, 2H, H5, H50), 6.18
(s, 2H, H60, H600), 6.11 (s, 2H, H8, H80), 5.60–5.58 (m, 4H, H1, H10, H200,
H300), 4.60–4.57 (m, 2H, H3, H30), 4.22–4.17 (m, 2H, H3, H30), 3.90 (s,
6H, OCH3-50, OCH3-500), 3.87 (s, 6H, OCH3-7, OCH3-70), 3.78 (s, 6H,
OCH3-6, OCH3-60), 3.48 (s, 6H, OCH3-40, OCH3-4), 2.80–2.76 (m, 4H,
of the minor diastereomer (in part): d
6.59 (s, 2H, H30, H300), 6.57 (s,

6000
U. Mbere-Nguyen et al. / Tetrahedron 65 (2009) 5990–6000
H70, H700), 2.64–2.62 (m, 2H, H4, H40), 2.39–2.62 (m, 2H, H4, H40). 13C
NMR of the major rotamer:
171.7 (CO), 148.5 (C50, C500), 146.8 (C7,
23.7 (CH2-4, CH2-40). MS (ESIþ): m/z 793.5 (MHþ, 100%). HRMS (ESIþ):
d
calcd for C48H61N2O8 793.4428 (MHþ), found 793.4393.
C70), 147.0 (C6, C60), 147.8 (C40, C400), 132.2 (C8a, C8a0), 128.6 (CH-200,
CH-300),128.3 (C4a, C4a0),128.1 (C10, C100),128.0 (C20, C200),115.5 (CH-
8, CH-80), 112.2 (CH-30, CH-300), 110.6 (CH-60, CH-600), 110.0 (CH-5,
CH50), 56.0 (OCH3-50, OCH3-500, OCH3-7, OCH3-70), 55.8 (OCH3-6,
OCH3-60), 55.3 (OCH3-40, OCH3-400), 54.8 (CH-1, CH-10), 41.5 (CH2-3,
CH2-30), 39.7 (CH2-70, CH2-700), 31.8 (CH2-100, CH2-400), 29.8 (CH2-2%,
CH2-3%), 27.0 (CH2-4, CH2-40). 13C NMR of the minor rotamer (in
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.
part):
d
132.4 (C8a, C8a0), 128.7 (CH-200, CH-300), 128.2 (C4a, C4a0),
111.8 (CH-30, CH-300), 36.1 (CH2-3, CH2-30), 35.0 (CH2-70, CH2-700),
26.2 (CH2-4, CH2-40). MS (ESIþ): m/z 821.5 (MHþ, 20%). HRMS
(ESIþ): calcd for C46H57N2O10 821.4013 (MHþ), found 821.4033.
References and notes
1. ROMPP Encyclopedia of Natural Products; Steglish, W., Fugmann, B., Lang-Fug-
mann, S., Eds.; Thieme: Stuttgart, 2000; pp 84–85.
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3.15. (1RS,10RS) and (R,S) (Z) or (E) 1,10-(1,2)-Di-(1,2,3,4-
tetrahydro-6,7-dimethoxyisoquinolina)-3,8-(1,2)-di-(3,4-
dimethoxy)benzenacyclotetradeca-5-phene (4-b)
To a slurry of LiAlH4 (13 mg, 0.348 mmol) in THF (1 mL) at 0 ꢁC
under a N2 atmosphere was added a solution of the amide 24-b
(24 mg, 0.029 mmol) in dry THF (1 mL). The resulting mixture was
brought to rt and was stirred for 24 h. The solution was treated sub-
sequently with H2O (0.14 mL), 1 M NaOH (0.14 mL) and H2O (0.46 mL).
The mixture was left to stir for 1 h. The solids were filtered and washed
with EtOAc. The solution was dried (MgSO4) and then concentrated in
vacuo to give 4-b (18 mg, 78%) as a white oil of >95% purity from NMR
and TLC analysis. Rf 0.06 (CH3OH/EtOAc (2:8)). 1H NMR:
d 6.82 (s, 2H,
H30,H300), 6.56 (s, 2H, H5, H50), 6.13 (s, 2H, H60,H600), 5.83 (s, 2H, H8, H80),
5.68 (t, 2H, J 4.2 Hz, H200, H300), 3.85 (s, 6H, OCH3-50, OCH3-500), 3.82 (s,
6H, OCH3-7, OCH3-70), 3.71–3.66 (m, 6H, H100, H400 and H1, H10), 3.60 (s,
6H, OCH3-6, OCH3-60), 3.51 (s, 6H, OCH3-40, OCH3-400), 3.30–3.24 (m, 4H,
H3, H30, H70, H700), 2.84 (dd, 2H, J 10.8, 4.2 Hz, H3, H30), 2.75 (dd, 2H, J
13.2, 9.0 Hz, H70, H700), 2.60–2.56 (m, 4H, H1%, H4%), 2.46–2.38 (m, 4H,
H4, H40),1.58–1.54 (m, 4H, H2%, H3&).13C NMR: 147.5 (C50, C500),147.3
d
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(C7, C70),146.3 (C6, C60),145.2 (C40, C400),131.4 (C10, C100),130.1 (C20, C200,
CH-200,CH-300),129.0 (C4a, C4a0),126.1 (C8a, C8a0),115.46 (CH-60,CH-600),
112.5 (CH-30,CH-300),112.0 (CH-8, CH-80),111.4 (CH-5, CH-50), 62.1 (CH-1,
CH-10), 56.1 (OCH3-50, OCH3-500), 55.8 (OCH3-7, OCH3-70, OCH3-6, OCH3-
60), 55.5 (OCH3-40, OCH3-400), 52.7 (CH2-1%, CH2-4%), 43.1 (CH2-3, CH2-
30), 40.8 (CH2-70, CH2-700), 30.6 (CH2-100, CH2-400), 25.4 (CH2-2%, CH2-3%),
22. Batenburg-Nguyen, U.; Ung, A. T.; Pyne, S. G. Tetrahedron 2009, 65, 318–327.
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