Synthesis of Lamellarin G Trimethyl Ether by von Miller–Pl?chl-Type Cyclocondensation

Article abstract of DOI:10.1002/ejoc.201800611

A concise synthesis of lamellarin G trimethyl ether based on a von Miller–Pl?chl-type cyclocondensation of a deprotonated α-amino nitrile with an α,β-unsaturated ketone as the key step was developed. The general strategy does not rely on molecular symmetry and allows for the independent variation of the substitution pattern.

Full text of DOI:10.1002/ejoc.201800611

A Journal of
Accepted Article
Title: Synthesis of Lamellarin G Trimethyl Ether via von Miller-Plöchl-
type Cyclocondensation
Authors: Vanessa Carolin Colligs, Clemens Dialer, and Till Opatz
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800611
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Supported by

10.1002/ejoc.201800611
European Journal of Organic Chemistry
FULL PAPER
Synthesis of Lamellarin G Trimethyl Ether via von Miller-Plöchl-
type Cyclocondensation
Vanessa C. Colligs[a], Clemens Dialer,[a] and Till Opatz*[a]
Abstract: A concise synthesis of lamellarin G trimethyl ether based
on a von Miller-Plöchl type cyclocondensation of a deprotonated α-
amino nitrile with an α,β-unsaturated ketone as the key step was
developed. The general strategy does not rely on molecular symmetry
and allows for the independent variation of the substitution pattern.
researchers as it shows a remarkable anti-proliferative activity
with IC50 values against CEM human leukaemia cells as low as
camptothecin. Interestingly, lamellarin D is able to induce
apoptosis in CEM2 cells which express
a dysfunctional
topoisomerase I. Therefore, this enzyme cannot be the only
molecular target through which lamellarin D (1) triggers cell
death.[15] Current research suggests that lamellarin D (1)
mediates apoptosis by activation of several non-related signalling
Introduction
pathways such as; inhibition of mitochondrial respiration in tumour
16]
cells[17, 22], inhibition of topoisomerase I[15,
and Induction of
The lamellarins are a class of pyrrole alkaloids exhibiting a broad
variety of pharmacological features.[1] The first five members of
this class of alkaloids have been first isolated from the
prosobranch mollusc Lamellaria sp. in 1985.[1] Later, other
members could be isolated from serveral types of marine
ascidians[2-5] and marine sponges[6, 7]. In the past three decades,
over 50 members of this family of natural products have been
discovered and characterized.[1-9] Even though these natural
products have been the subject of intense chemical and biological
research, their in vivo biosynthesis couldn’t be observed until
today.[10] The most common theory for the biosynthesis of
lamellarins has been provided by Kang and Fencial, who
postulate a route based on DOPA.[11] Based on their structural
features, the lamellarin family can be subdivided into three
different classes: type IA, type IB and type II (Figure 1).[1]
intracellular ROS-production[23]
. Because of their attractive
properties, the synthesis and evaluation of lamellarins is still of
current interest.[21, 24-40]
Results and Discussion
building block A
R8
R8
R7
R7
R6
NH
R6
NH2
CN
R8
R7
R6
O
von Miller-Plöchl-
N
Lactonization
Cyclocondensation
R8
R8
O
6
7
R7
R9
R7
R6
R
N
8
5
R5
R4
building block B
building block C
A
B
COOMe
OH
O
23
O
9
N
C
N
O
R6
10
16
R1
R5
R4
R1
R3
PGO
OMe
D
R2
1
O
18
O
11
R5
R5
R4
17
22
OMe
R2
15
19
F
E
Suzuki coupling
12
B(OH)2
20
13
14
HO
R3
R4
21
R2
R1
R1
R3
IA
R3
IB
R2
II
R5
R4
HO
R1
R2
O
O
OMe
OMe
Figure 1. Structural classes of the lamellarins.
+
The individual structural types correlate with different sets of
pharmacological profiles and different biological targets.
Lamellarins primarily target several kinds of DNA manipulating
enzymes. Two prominent examples, from a long list of biological
effects of the lamellarin alkaloids, are anti-HIV-1-integrase
activity[12], the ability to reverse multiple drug resistance upon
cancer cells[13] and cytotoxicity against malignant cells.[1, 3, 14-21] In
R3
Scheme 1. Retrosynthetic analysis.
Lamellarins of type I differ only in their oxygenation and O-
substitution patterns. Therefore, modular synthetic strategies
which allow the independent variation of each part of the molecule
are to be preferred over methods using molecular symmetry,
unless only a defined symmetrical target structure needs to be
produced. Our retrosynthetic analysis is shown in Scheme 1. It
divides the pentacyclic lamellarin core into three units, the
connection between them should occur through a von Miller-
Plöchl-type cyclocondenstaion. Although this reaction is 120
years old and largely underused, it can provide straightforward
access to the desired pyrrolo[2,1-a]isoquinoline core in a single
step.[30, 41, 42]
particular lamellarin
D (1) has attracted the attention of
[a]
Vanessa Carolin Colligs, Clemens Dialer, Till Opatz
Institute of Organic Chemistry
University of Mainz
Duesbergweg 10-14, 55128 Mainz, Germany
E-mail: opatz@uni-mainz.de
URL: https://ak-opatz.chemie.uni-mainz.de/
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800611
European Journal of Organic Chemistry
FULL PAPER
group was performed at –78 °C with BCl3[36] under monitoring of
the reaction progress with HPLC-MS. Ultimately, the hemiacetal
product 15 of the cyclization must be oxidized to give the desired
lamellarin 2. Unfortunately, we struggled to perform this
seemingly trivial transformation in satisfactory yield since the E
ring of lactol 15 proved to be extremely sensitive towards oxidizing
agents. In most cases, the benzoquinone 16 was formed as the
main product instead (for conditions, see Table 1). The formation
of the benzoquinone 16 has been proposed to be a side-reaction
MeO
MeO
HO
MeO
MeO
O
O
O
O
N
N
MeO
MeO
HO
MeO
OMe
MeO
OH
lamellarin G trimethlyl ether 2
( )
lamellarin D 1
( )
(model compound)
of the oxidation of hemiacetals like 15[51]
.
For
a full
characterization of compound 16 proving this hypothesis, see the
Supporting Information)
Figure 2. Structures of lamellarin D (1) and lamellarin G trimethyl ether (2).
Using a combination of Pd(OAc)2/PPh3, the oxidation could finally
be performed successfully and the product was obtained in a yield
of 33% over two steps after purification by HPLC.[51] Thus,
lamellarin G trimethyl ether (2) could be prepared in seven linear
steps from homoveratrylamine (8) with an overall yield of 19%.
Since the overall efficiency of this route mainly suffered from the
unsatisfactory results of the last two steps, we settled on another
approach based on the same general retrosynthetic scheme.
Therefore, the carboxy moiety was established at an earlier stage
To evaluate the practicability of the proposed strategy, lamellarin
G trimethyl ether (2) was chosen as a test compound. Although 2
is not a natural product, it is frequently employed as a benchmark
compound to compare the efficiency of synthetic approaches to
the lamellarins[43, 44] (Figure 2).
MeO
OH iPrBr,K2CO3,
MeO
MeO
OiPr
i) NBS, THF, 78°C
ii) r.t, 22 h
DMF, 75 °C, 94 h
78%
89%
MeO
MeO
Table 1. Optimization of the oxidation of hemiacetal 15
4
3
6
−
i) tBuLi, THF, 78°C, 1 h
ii) B(OMe)3 78°C, 1 h, iii) r.t., 4 h
MeO
MeO
OiPr
OiPr
−
,
entry
1
oxidizing agent
PCC, celite
solvent
DCM
conditions
r.t., 20 h
yield
Br
MeO
B(OH)2
5
quinone
(used without purification)
16
2
3
4
5
DMP
DCM
toluene
DMSO
acetone
r.t., 5 h
r.t., 48 h
r.t.,168 h
0 °C, 24 h
r.t., 13 h
quinone
16
Scheme 2. Synthesis of building block C.
Starting point of the synthesis was building block C (see scheme
1). The arylboronic acid 6 was prepared in a three step synthesis
proceeding from commercially available 3,4-dimethoxyphenol (3)
(see scheme 2)[38, 45, 46]. It was obtained in an overall yield of 69%
and was used without further purification, due to its tendency to
undergo protodeborylation easily. Before the isopropyl ether was
chosen as the protecting group in 4, benzyl protection was also
tried but was eventually given up since the halogen/lithium
exchange resulted in deprotonation at the benzylic position under
all conditions investigated. α-Amino nitrile 7 was prepared from
homoveratrylamine (8) in three steps and 88% overall yield
according to procedure earlier described by us.[47]
Homoveratrylamine (8) was converted into the corresponding
AlMe3, p-
NO2C6H4CHO
quinone
16
Pyridine∙SO3, NEt3
quinone
16
CrO3, H2SO4
quinone
16
6
7
ADD*, t-BuMgBr
THF
33%
45%
Pd(OAc)2, PPh3
DMF
120 °C, 12.5
h
*ADD = Azodicarboxylic acid dipiperidide
through a Pinnick oxidation of aldehyde 13.[33] By oxidation of the
aldehyde group before the Suzuki coupling, we hoped to avoid
the formation of quinone 16 (see scheme 4). During the Pinnick
oxidation, the desired acid 17 started to precipitate from the
reaction mixture, the reaction progress was monitored by HPLC-
MS. This compound is poorly soluble in DCM, MeCN, CHCl3,
acetone, benzene, and THF and tends to decarboxylate
spontaneously at temperatures above 50 °C. Slow decomposition
can already be observed at room temperature as can be seen
from the 13C NMR spectra which required longer accumulation
times to obtain a satisfactory signal-to-noise ratio (see Supporting
Information).
formamide, which gave dihydroisoquinoline
9
after the
subsequent Bischler-Napieralski-reaction. Enone 10 was
obtained in 82% yield by aldol condensation of veratraldehyde
(11) with 1,1-dimethoxypropan-2-one (see scheme 3).[48] The key
step of the sequence, the modified von Miller-Plöchl reaction of
the deprotonated α-amino nitrile 7 to enone 10.[47, 49] produced
pyrrolo[2,1-a]isoquinoline 12 in 75% yield.[41] To introduce the aryl
substituent in 2-position, a bromination[28] with NBS was carried
out.
For the coupling of the brominated dihydroisoquinoline 13 and
boronic acid 6 the use of Pd(PPh3)4 in refluxing, degassed DMF
proved to be the method of choice.[50] The desired coupling
product 14 was obtained in 98% yield. Cleavage of the isopropyl
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10.1002/ejoc.201800611
European Journal of Organic Chemistry
FULL PAPER
Acid 17 was dispersed in a benzene/MeOH mixture and the
methyl ester was formed by action of TMSCHN2.[33] The reaction
was complete when the solid was entirely converted to the soluble
ester 18. The subsequent Suzuki coupling was performed under
the same conditions which proved optimal in the first route.
Interestingly, ester 18 rapidly decomposed in CHCl3 to produce a
black solid. This behaviour was already observed by us for other
pyrroles[52] and may be explained by some type of radical cascade
reaction.
cyclocondensation is the initial key step. This reaction proceeded
very cleanly and did not produce unwelcome byproducts.
The first synthetic approach yielded the title compound in 19%
yield over 7 steps while the earlier oxidation permitted the
increase of the efficiency – the second route produced 2 with an
overall yield of 42% over 8 steps which compares favorably with
most other synthetic approaches reported in the literature.[43]
MeO
MeO
2-methyl-2-butene, MeO
NaClO
NaH2PO
tBuOH, 4T,HF, H
O
2,
O
N
2O,
N
MeO
10 °C, 29 h
2Et,
i) HCO
reflux, 23 h
OH
i) KCN, HCl,
MeOH, 0 °C
ii) r.t., 16 h
, DCM,
99%
ii) PCl5
Br
Br
r.t., 30 min
MeO
MeO
MeO
MeO
99%
MeO
MeO
MeO
MeO
MeO
MeO
quant.
88%
13
17
TMSCHN2,
NH
CN
NH2
N
benzene,
MeOH, r.t., 3 h
8
9
7
i) KHMDS, THF,
OH
B
−
O
O
78 °C, 5 min.
1,1-dimethoxyacetone,
piperidine, MeOH,
reflux, 5 h
−
MeO
MeO
OH
MeO
MeO
MeO
MeO
10
,
ii)
78 °C, 30 min.
MeO
OMe
OMe
OH
MeO
MeO
O
iii) reflux, 1.5 h
N
69%
OiPr
(3 steps)
82%
75%
3
6
MeO
OMe
10
11
Br
MeO
MeO
18
OH
B
MeO
MeO
MeO
MeO
Pd(Ph
MeO
MeO
O
O
i) NBS, DCM, 0 °C
ii) r.t., 13 h
K3PO4,
3P)4,
OH
N
N
83%
DMF, 110 °C, 72 h
87%
OiPr
MeO
MeO
MeO
6
Br
MeO
MeO
MeO
MeO
13
12
O
N
DCM,
O
N
MeO
MeO
AlCl3,
r.t., 4 h
OMe
OiPr
O
Pd(Ph
MeO
MeO
90%
K3PO4,
DMF, 110 °C, 72 h
3P)4,
98%
O
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
OMe
(
MeO
19
OMe
DCM,
Pd(OAc)
lamellarin G trimethyl ether
2
)
i) BCl3,
K2CO3,
PhBr, DMF,
N
−
2,
OH
O
N
78 °C
PPh3,
ii) 6 h, r.t.
Scheme 4. Synthesis of lamellarin G trimethyl ether (2) through route 2.
120 °C, 13 h
OiPr
74%
45%
MeO
MeO
MeO
OMe
14
15
MeO
OMe
Experimental Section
MeO
MeO
1,2-Dimethoxy-4-(propan-2-yloxy)benzene (4): The title compound was
procedure of George et al.[38] 3,4-
O
O
prepared according to
a
N
O
MeO
MeO
O
O
N
MeO
MeO
undesired
byproduct of the
15
Dimethoxyphenol (3) (300.0 mg, 1.95 mmol) was dissolved in dry DMF (6
mL), K2CO3 (591.7 mg, 4.28 mmol, 2.2 eq.), 2-bromopropane (526.6 mg,
4.28 mmol, 2.2 eq.) and TBAI (58.0 mg, 0.16 mmol, 0.08 aq.) were added
to the solution. The reaction mixture was heated to 75 °C for 94 h.
Subsequently, the solution was cooled to room temperature, ethyl acetate
(6 mL) and water (6 mL) were added. The organic layer was separated
and dried over Na2SO4.The solvent was removed under reduced pressure,
the product was obtained as a brown oil (340.4 mg, 1.730 mmol, 89%). Rf
= 0.59 (silica, cyclohexane /EtOAc, 1:1). IR (ATR): � = 3019, 2977, 2936,
2835, 1510, 1222, 1198, 1026, 989, 748 cm-1.1H NMR, COSY (300 MHz,
CDCl3): δ = 6.77 (d, J = 8.7 Hz, 1H, H-6), 6.51 (d, J = 2.8 Hz, 1H, H-3),
6.41 (dd, J = 8.7, J = 2.8 Hz, 1H, H-5), 6.06 (sept, J = 6.1 Hz, 1H,
CH(CH3)2), 3.85 (s, 3H, C-2-OCH3), 3.83 (s, 3H, C-1-OCH3), 1.32 (d, J =
6.1 Hz, 6H) ppm. 13C NMR, HSQC, HMBC (75 MHz, CDCl3): δ = 152.3 (C-
4), 149.8 (C-2), 143.4 (C-1), 111.8 (C-6), 105.8 (C-5), 102.4 (C-3), 70.6 (-
CH(CH3)2), 56.4 (C-1-OCH3), 55.8 (C-2-OCH3), 22.1 (2C, -CH(CH3)2) ppm.
ESI-MS: m/z 197.0 (100%) [M + H]+. The analytical data are in accordance
with the literature.[38]
oxidation of
MeO
MeO
OMe
MeO
OMe
lamellarin G trimethyl ether
2
16
(
)
Scheme 3. Synthesis of lamellarin G trimethyl ether through route 1.
The first attempt to remove the isopropyl protecting group in 19
with BCl3 resulted in decomposition. Cleavage of the isopropyl
ether could however be effected by portion wise addition of AlCl3
under careful monitoring of the reaction progress by HPLC-MS.[50]
The reaction was complete within 4 h, and lamellarin G trimethyl
ether (2) could be obtained as colorless solid in 90% yield after
recrystallization from methanol.
1-Bromo-4,5-dimethoxy-2-(propan-2-yloxy)benzene (5): The title
compound was prepared according to a procedure of George et al.[38]1,2-
Dimethoxy-4-(propan-2-yloxy)benzene (4) (508.0 mg, 2.59 mmol) was
dissolved in 2.5 mL dry THF in a Schlenk tube under argon-atmosphere.
The solution was cooled to –78 °C and NBS (461.0 mg, 2.59 mmol, 1.0
eq.) was added. After 15 minutes, the cooling bath was removed and the
Conclusions
Lamellarin G trimethyl ether was accessed by two different
synthetic routes, for both of which the von Miller-Plöchl
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10.1002/ejoc.201800611
European Journal of Organic Chemistry
FULL PAPER
mixture was allowed to warm to room temperature. The mixture was stirred
at room temperature for 22 h before the solvent was removed under
reduced pressure. The crude brown solid was purified by automatic
chromatography (cyclohexane/EtOAc, 8–66% gradient EtOAc). The
product was obtained as a brown oil (557.1 mg, 2.025 mmol, 78%). Rf =
0.59 (silica, cyclohexane/EtOAc, 1:1). IR (ATR): � = 2975, 2932, 2841,
1502, 1383, 1257, 1210, 1200, 991, 753 cm-1. 1H NMR, COSY (300 MHz,
CDCl3): δ = 7.02 (s, 1H, H-6), 6.60 (s, 1H, H-3), 4.42 (sept, J = 6.1 Hz, 1H),
3.87 (s, 3H, C-4-OCH3), 3.85 (s, 3H, C-5-OCH3), 1.37 (d, J = 6.1 Hz, 6H)
ppm. 13C NMR, HSQC, HMBC (75 MHz, CDCl3): δ = 148.8 (C-2), 148.6
(C-4), 144.6 (C-5), 115.8 (C-6), 104.4 (C-1), 103.9 (C-3), 74.3 (-CH(CH3)2),
56.5 (C-4-OCH3), 56.2 (C-5-OCH3), 22.2 (2C, -CH(CH3)2) ppm. ESI-MS:
m/z 196.1 (100%) [M – Br + H]+, 275.0 (21%) [M + H]+. The analytical data
are in accordance with the literature.[38]
82.62 mmol, quant.). Rf = 0.44 (cyclohexane/EtOAc = 1:1). IR (ATR): � =
3002, 2937, 2835, 1515, 1321, 1277, 1264, 1238, 1116, 777, 749 cm-1. 1H
NMR, COSY (400 MHz, CDCl3): δ = 8.14 (t, J = 2.2 Hz, H-1), 6.72 (s, 1H,
H-8), 6.58 (s, 1H, H-5), 3.82 (s, 3H, -OCH3), 3.81 (s, 3H, -OCH3), 3.71–
3.56 (pseudo-t, J = 8.0 Hz, 2H, H-3), 2.66–2.46 (pseudo-t, J = 8.0 Hz, 2H,
H-4) ppm. 13C NMR (101 MHz, CDCl3): δ = 159.6 (C-1), 151.1 (C-6), 147.8
(C-7), 129.8 (C-8a), 121.5 (C-4a), 110.33 (C-5), 110.28 (C-8), 56.1 (-
OCH3), 56.0 (-OCH3), 47.4 (C-3), 24.7 (C-4) ppm. ESI-MS: m/z 192.0
(100%) [M + H]+. The analytical data are in accordance with the
literature.[49]
6,7-Dimethoxy-3,4-dihydroisoquinoline-1-carbonitrile (7): The title
compound was prepared according to a modified procedure of Werner et
al.[47] To an ice cooled solution of dihydroisoquinoline
9 (4.00 g,
20.9 mmol) in methanol (10 mL), a solution of KCN (4.90 g, 65.12mmol,
3.6 eq.) in water (22 mL) was added. At 0 °C, concentrated hydrochloric
acid (16 mL) was added dropwise with a syringe. After 1 h, the cooling
bath was removed and the solution was allowed to warm to room
temperature and stirred for another 16 h. The reaction mixture was purged
with nitrogen to remove excess HCN from the solution. Aqueous NaHCO3
was added dropwise until pH 7 was reached. The aqueous layers were
extracted with DCM (5 × 15 mL), the combined organic layers were dried
over Na2SO4, and the solvent was removed in vacuo. The product was
obtained as a yellow oil (4.73 g, 18.5 mmol, 88%). IR (ATR): � = 3214,
2973, 2941, 2920, 1518, 1262, 1227, 1105, 1014, 845, 770 cm-1. 1H NMR,
COSY (300 MHz, CDCl3): δ = 6.61 (s, 1H, H-8), 6.55 (s, 1H, H-5), 4.89 (s,
1H, H-1), 3.79 (s, 3H, -OCH3), 3.79 (s, 3H, -OCH3), 3.23–3.04 (m, 2H, H-
3), 2.85–2.71 (m, 1H, H-4), 2.60 (dt, J = 16.4, J = 3.7 Hz, 1H), 2.20 (sb,
1H, NH) ppm. 13C NMR, HSQC, HMBC (75 MHz, CDCl3): δ = 149.3 (C-6),
148.0 (C-7), 127.1 (C-4a), 121.1 (C-8a), 120.4 (CN), 112.1 (C-5), 109.5
(C-8), 56.2 (-OCH3), 56.1 (-OCH3), 48.2 (C-1), 41.0 (C-3), 28.0 (C-4) ppm.
ESI-MS: m/z 192.0 (100%) [M – CN]+. The analytical data are in
accordance with the literature.[47]
[4,5-Dimethoxy-2-(propan-2-yloxy)phenyl]boronic acid (6): The title
compound was prepared according to a modified procedure of Iwao et
al.[45] In a Schlenk tube filled with argon, 1-bromo-4,5-dimethoxy-2-
(propan-2-yloxy)benzene (5) (117.0 mg, 425.4 µmol) was dissolved in dry
THF (1.7 mL). The solution was cooled to –78 °C, at this temperature t-
BuLi (0.5 mL, 1.7 M, 2.0 eq.) was added dropwise with a syringe. After
stirring at this temperature for 1 h, B(OMe)3 (73 µL, 638 µmol, 1.5 eq.) was
added. Subsequently, the solution was stirred for another 1 h at this
temperature. The cooling bath was removed and the solution was allowed
to warm to room temperature. After stirring for 4 h at room temperature,
the mixture was quenched by addition of 3 mL aqueous NH4Cl and
extracted with DCM (3 x 12 mL). The solvent was removed under reduced
pressure. The product was obtained as a yellow oil (102.0 mg) and was
used without any further purification.
(3E)-4-(3,4-Dimethoxyphenyl)-1,1-dimethoxybut-3-en-2-one (10): The
title compound was prepared according to a modified procedure of Ito et
al.[48] To a solution of veratraldehyde (11) (4.00 g, 24.0 mmol) in methanol
(100 mL), 1,1-dimethoxyacetone (15 mL, 14 g, 120 mmol, 5.0 eq.) and
piperidine (7.15 mL, 6.15 g, 72.2 mmol, 3.0 eq.) were added. The resulting
solution was heated to reflux for 5 h. The mixture was cooled to room
temperature and the solvent was removed under reduced pressure. The
product was purified by automatic chromatography (silica,
cyclohexane/EtOAc, 2:1) to yield a yellow solid (5.23 g, 19.6 mmol, 82%).
M.p. 52.0−52.8 °C. Rf = 0.23 (silica, cyclohexane/EtOAc, 2:1). IR (ATR):
�= 2947, 2838, 1695, 1590, 1579, 1259, 1136, 1086, 1036, 790 cm-1. 1H
NMR, COSY (300 MHz, CDCl3): δ = 7.76 (d, J = 16.0 Hz, 1H, H-4), 7.18
(dd, J = 8.2, J = 2.0 Hz, 1H, H-6‘), 7.12 (d, J = 2.0 Hz, 1H, H-2‘), 6.93 (d, J
= 16.0 Hz, 1H, H-3), 6.87 (d, J = 8.2 Hz, 1H, H-5‘), 4.74 (s, 1H, H-1), 3.92
(s, 3H, Ar-OCH3), 3.92 (s, 3H, Ar-OCH3), 3.46 (s, 6H, C-1(OCH3)2) ppm.
13C NMR, HSQC, HMBC (75 MHz, CDCl3): δ = 193.7 (C-2), 151.8 (C-4‘),
149.3 (C-3‘), 145.4 (C-4), 127.6 (C-1‘), 124.0 (C-6‘), 118.5 (C-3), 111.1 (C-
5‘), 109.9 (C-2‘), 104.0 (C-1), 56.1 (2C, Ar-OCH3), 54.60 (2C, C-1(OCH3)2)
ppm. ESI-MS: m/z 207.1 (100%) [M – 2 x OMe + H]+, 289.1 (68%) [M +
Na]+. The analytical data are in accordance with the literature.[48]
1-(3,4-Dimethoxyphenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-
a]isoquinoline-3-carbaldehyde (12): The title compound was prepared
according to a modified procedure of Meyer et al.[41] A solution of α-amino
nitrile 7 (2.50 g, 11.5 mmol, 1.14 eq.) in dry THF (100 mL) was cooled to
−78 °C, a solution of KHMDS (2.74 g, 13.7 mmol, 1.4 eq.) in dry THF (25
mL) added. After 15 minutes a solution of the enone 10 (2.68 g,
10.1 mmol) in dry THF (25 mL) was added, stirring was continued for
another 30 minutes at this temperature. The solution was diluted with
methanol (23 mL), acetic acid (5 mL), and water (36 mL), the mixture was
heated to reflux for 90 minutes. The volume of the reaction mixture was
reduced to 40 mL under reduced pressure. The remaining aqueous
solution was extracted with ethyl acetate (3 × 80 mL). The combined
organic layers were washed with aqueous NaHCO3 (3 × 60 mL), brine
(1 × 60 mL) and dried over Na2SO4. The solvent was removed in vacuo
and the remaining brown oil was purified by automatic chromatography
(silica, cyclohexane/EtOAc, gradient 12–37% EtOAc). The product was
obtained as a yellow solid (2.97 g, 7.55 mmol, 75%). M.p. 122.1−123.0 °C.
Rf = 0.28 (silica, cyclohexane/EtOAc, 1:1). IR (ATR): �= 3021, 2836, 1657,
1424, 1394, 1231, 1146, 1121, 805, 744 cm-1. 1H NMR, COSY (300
MHz,CDCl3): δ = 9.53 (s, 1H, CHO), 7.00 (dd, J = 8.1, J = 1.9 Hz, 1H, H-6‘),
6.96 (d, J = 1.9 Hz, 1H, H-5‘), 6.91 (d, J = 8.1 Hz, 1H, H-2‘), 6.89 (s, 1H,
H-10), 6.74 (s, 1H, H-7), 4.64 (t, J = 6.6 Hz, 2H, H-5a,b), 3.91 (s, 3H, C-4‘-
OCH3 ), 3.89 (s, 3H, C-8-OCH3), 3.83 (s, 3H, C-3‘-OCH3), 3.43 (s, 3H, C-
9-OCH3), 3.03 (t, J = 6.6 Hz, 2H, H-6a,b) ppm. 13C NMR, HSQC, HMBC (75
MHz, CDCl3): δ = 179.2 (CHO), 149.0 (C-8), 149.0 (C-3‘), 148.3 (C-4‘),
147.5 (C-9), 134.4 (C-10b), 129.8 (C-3), 128.7 (C-1‘), 127.0 (C-6a), 125.7
(C-2), 123.2 (C-1), 121.8 (C-6‘), 120.1 (C-10a), 112.7 (C-2‘), 111.4 (C-5‘),
111.0 (C-7), 109.1 (C-10), 56.1 (-OCH3), 56.1 (-OCH3), 56.0 (-OCH3),
55.6 (-OCH3), 42.6 (C-5), 28.9 (C-6) ppm. ESI-MS: m/z 394.2 (100%) [M
+ H]+. ESI-HRMS calcd. for [C23H23NO5 + H]+ 394.1654, found: 394.1654.
6,7-Dimethoxy-3,4-dihydroisoquinoline (9): The title compound was
prepared according to a modified procedure of J.C. Rohloff et al.[49]
Homoveratrylamine (8) (14.3 mL, 15.0 g, 82.8 mmol) was dissolved in
ethyl formate (23 mL) and the mixture was heated to reflux for 23 h. Excess
ethyl formate was removed under reduced pressure. The solid residue was
dissolved in DCM (100 mL) and the resulting solution was added dropwise
to a solution of PCl5 (20.68 g, 99.3 mmol, 1.2 eq.) in DCM (50 mL). The
mixture was stirred for 30 minutes at room temperature and then poured
into an ice/hexane mixture. The organic layer was separated and extracted
with water (4 × 30 mL). To the combined aqueous layers, solid KOH was
added until pH 12, followed by extraction with DCM (3 × 60 mL). The
combined organic layers were dried over Na2SO4. The solvent was
removed under reduced pressure to obtain the product as a red oil (15.80 g,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800611
European Journal of Organic Chemistry
FULL PAPER
2-Bromo-1-(3,4-dimethoxyphenyl)-8,9-dimethoxy-5,6-
Procedure route 1
dihydropyrrolo[2,1-a]isoquinoline-3-carbaldehyde (13): The title
compound was prepared according to a modified procedure of Handy et
al.[28] To a solution of carbaldehdye 12 (953.0 mg, 2.422 mmol) in dry DCM
(68 mL), N-bromosuccinimide (474.0 mg, 2.663 mmol, 1.12 eq.) was
added in portions at a temperature of 0 °C. The solution was allowed to
warm to room temperature overnight and diluted with water (30 mL) and
DCM (10 mL). The organic layer was separated and washed with aqueous
Na2CO3 (3 × 30 mL), water (1 × 30 mL), brine (1 × 30 mL) and dried over
Na2SO4. The solvent was removed under reduced pressure. The
remaining oil was purified by automatic chromatography (silica,
cyclohexane/EtOAc, 3:1) to obtain aldehyde 13 as a yellow solid (992.9 mg,
The title compound was prepared according to a modified procedure of
Iwao et al.[19] In a Schlenk tube, compound 15 (496.9 mg, 845.5 µmol) was
dissolved under argon-atmosphere in DCM (130 mL). The solution was
cooled to –78 °C, at this temperature, BCl3 (7.61 mL, 1M in DCM,
7.61 mmol, 9.0 eq.) was added under stirring. The solution was allowed to
warm to room temperature and stirred at this temperature for 18 h. The
mixture was quenched by addition of aqueous NaHCO3 (82 mL), the
organic layer was separated. The aqueous layer was extracted with DCM
(3 x 30 mL). The combined organic layers were washed with brine (80 mL),
dried over Na2SO4 and evaporated to dryness. The product was obtained
as a yellow foam (425.0 mg, max. 92%) and used without further
purification.
2.102 mmol, 87%). M.p. 165.2−165.4 °C. Rf
=
0.40 (silica,
cyclohexane/EtOAc, 1:1). IR (ATR): � = 2937, 2838, 1653, 1462, 1425,
1256, 1337, 1220, 1179, 821 cm-1.1H NMR, COSY (300 MHz, CDCl3): δ =
9.77 (s, CHO), 6.98 (d, J = 8.2 Hz, 1H, H-5‘), 6.94 (dd, J = 8.2, J = 1.8 Hz,
1H, H-6‘), 6.89 (d, J = 1.8 Hz, 1H, H-2‘), 6.72 (s, 1H, H-7), 6.62 (s, 1H, H-
10), 4.67 (t, J = 6.7 Hz, 2H, H-5a,b), 3.92 (s, 3H, C-4‘-OCH3), 3.88 (s, 3H,
C-8-OCH3), 3.85 (s, 3H, C-3‘-OCH3), 3.35 (s, 3H, C-9-OCH3), 3.03 (t, J =
6.7 Hz, 2H, H-6a,b) ppm.13C NMR, HSQC, HMBC (75 MHz, CDCl3): δ =
179.6 (-CHO), 149.4 (C-8), 149.2 (C-3‘), 148.9 (C-4‘), 147.6 (C-9), 134.5
(C-10b), 126.9 (C-6a), 126.2 (C-1‘), 125.2 (C-2), 123.4 (C-6‘), 122.6 (C-1),
119.2 (C-10a), 114.7 (C-3), 113.9 (C-2‘), 111.4 (C-5‘), 111.0 (C-7), 109.2
(C-10), 56.2 (C-3‘-OCH3), 56.1 (C-4‘-OCH3), 56.1 (C-8-OCH3) , 55.4 (C-9-
OCH3) , 42.5 (C-5), 28.5 (C-6) ppm. ESI-MS: m/z 473.2 (100%) [M + H]+.
ESI-HRMS calcd. for [C23H22BrNO5 H]+ 472.0762, found 472.0776.
According to a modified procedure of Ruchirawat et al,[51] a solution of the
crude product (30.0 mg, max. 55.0 µmol) in dry DMF (2.38 mL) was purged
with argon for 20 minutes by passing a mild argon flow through the mixture.
Under argon atmosphere, K2CO3 (8.36 mg, 60.5 µmol, 1.1 eq.), Pd(OAc)2
(3.70 mg, 16.5 µmol, 0.3 eq.), PPh3 (8.65 mg, 33.0 µmol, 0.6 eq.), and
PhBr (11.6 µL, 66.0 µmol, 1.2 eq.) were added. The mixture was heated
to 120 °C and stirred at this temperature for 13 h. The solvent was
removed under reduced pressure. The crude green oil was purified by
HPLC (MeCN/H2O 50:50, C18-PFP). The product was obtained as a
colourless solid (13.5 mg, 24.8 µmol, 45%).
Procedure route 2
1-(3,4-Dimethoxyphenyl)-2-[4,5-dimethoxy-2-(propan-2-
yloxy)phenyl]-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]-isoquinoline-
3-carbaldehyde (14): The title compound was prepared according to a
modified procedure of Alvarez et al.[50] The boronic acid 6 (crude, 101.6
mg, max. 423.4 µmol, 2.0 equiv.) was transferred to a Schlenk tube and
five argon/vacuum-cycles were performed to exclude the presence of
oxygen. The aryl bromide 13 (100.0 mg, 211.7 µmol), aqueous K3PO4
(359.5 mg, 1.694 mmol, 4.0 eq. in 0.42 mL) and dry DMF (3.3 mL) were
added. The mixture was purged with argon over the course of 10 minutes
by passing a mild argon flow through the mixture. Subsequently,
Pd(PPh3)4 (48.9 mg, 42.3 µmol, 0.2 eq.) was added under argon-
atmosphere. The mixture was heated to 110 °C for 72 h. The solvent was
removed under reduced pressure. The resulting crude brown oil was
purified by automatic flash chromatography (silica, cyclohexane/EtOAc,
3:1). The product was obtained as yellow foam (121.8 mg, 207.3 µmol,
98%). Rf = 0.23 (silica, cyclohexane/EtOAc,1:1). IR (ATR): � = 3013, 2931,
2837, 1643, 1421, 1260, 1212, 1162, 864, 752 cm-1. 1H NMR, COSY,
NOESY (400 MHz, benzene-d6): δ = 10.07 (s, 1H, CHO), 7.07 (s, 1H, H-
10), 6.78 (s, 1H, H-2‘‘), 7.00–6.98 (m, 2H, H-2‘,H-6‘) 6.48 (d, J = 8.5 Hz,
1H, H-5‘), 6.42 (s, 1H, H-6‘‘), 6.30 (s, 1H, H-7), 4.98–4.57 (m, 2H, H-5a,b),
4.19–4.10 (sept, 1H, J = 6.06 Hz, CH-(CH3)2), 3.41 (s, 3H, C-5‘‘-OCH3),
3.35 (s, 3H, C-8-OCH3), 3.343 (s, 3H, C-3‘-OCH3), 3.337 (s, 3H,
C-4‘‘-OCH3), 3.30 (s, 3H, C-4‘-OCH3), 3.20 (s, 3H, C-9-OCH3), 2.65–2.40
(m, 2H, H-6a,b), 1.11 (d, J = 6.06 Hz, 3H, CH-(CH3)2), 1.02 (d, J = 6.06 Hz,
3H, CH-(CH3)2) ppm. 13C-NMR, HSQC, HMBC (101 MHz, benzene-d6): δ
= 180.6 (-CHO), 150.2 (C-2‘‘), 150.0 (C-5‘‘), 149.7 (C-3‘), 149.4 (C-8),
148.7 (C-4‘), 148.2 (C-9), 143.9 (C-4‘‘), 134.8 (C-1‘‘), 133.1 (C-10b), 128.3
(C-1‘), 126.9 (C-3), 126.8 (C-6a), 123.2 (C-6‘), 122.3 (C-1), 120.4 (C-10a),
117.5 (C-3‘‘), 115.2 (C-2), 115.0 (C-5‘‘), 112.0 (C-5‘), 111.5 (C-7), 109.9
(C-10), 102.0 (C-6‘‘), 71.0 (CH-(CH3)2), 55.9 (C-4‘‘-OCH3), 55.5 (C-5‘‘-
OCH3), 55.2 (C-4‘-OCH3), 55.2 (C-3‘-OCH3), 55.1 (C-8-OCH3), 54.7 (C-9-
OCH3), 42.3 (C-5), 28.5 (C-6), 21.9 (CH-(CH3)2), 21.8 (CH-(CH3)2) ppm.
ESI-MS: m/z 588.5 (100%) [M + H]+. ESI-HRMS calcd. for [C23H22BrNO5 +
H]+ 588.2597, found 588.2593.
According to a modified procedure of Alvarez et al,[50] the Suzuki coupling
product 19 (260.0 mg, 0.4210 mmol) was transferred to a Schlenk tube
and five argon/vacuum-cycles were performed to exclude oxygen. Under
argon counterflow, dry DCM (3 mL) was added. The reaction mixture was
stirred at room temperature, AlCl3 (568.9 mg, 4.267 mmol, 7.8 eq) was
added in six portions, the reaction progress was monitored by HPLC-MS.
Within 4 h, the conversion was complete and the reaction was quenched
by adding aq. NH4Cl (4 mL) and DCM (7 mL). The organic layer was
separated and washed with water and brine (10 mL each) and dried over
Na2SO4. The solvent was removed under reduced pressure and the crude
product was recrystallized from methanol to yield a pale grey solid (205.7
mg, 0.3785 mmol, 90%). M.p. 231.0–233.0 °C. (Lit.: 235 °C)[51]. Rf = 0.16
(silica, cyclohexane/EtOAc, 1:1). IR (ATR): � = 2954, 2922, 2853, 1703,
1485, 1462, 1262, 1241, 1027, 758 cm-1. 1H NMR, COSY (400 MHz,
CDCl3): δ = 7.11 (dd, J = 8.1, J = 1.8 Hz, 1H, H-12), 7.07 (d, J = 8.1 Hz,
1H, H-15), 7.05 (d, J = 1.8 Hz, H-16), 6.90 (s, 1H, H-22), 6.76 (s, 1H, H-7),
6.71 (s, 1H, H-10), 6.66 (s, 1H, H-19), 4.85–4.73 (m, 2H, H-5a,b), 3.95 (s,
3H, OCH3), 3.89 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
3.45 (s, 3H, OCH3), 3.36 (s, 3H, OCH3), 3.12 (m, 2H, H-6a,b) ppm. 13C NMR,
HSQC, HMBC (100 MHz,): δ = 155.5 (C=O), 149.7 (C-OCH3), 149.0 (C-
OCH3), 148.8 (C-OCH3), 148.8 (C-OCH3), 147.5 (C-OCH3), 146.1 (C-18),
145.5 (C-OCH3), 135.9 (C-10b), 128.2 (C-17), 128.0 (C-11), 126.6 (C-6a),
123.6 (C-16), 120.0 (C-10a), 114.7 (C-1), 114.0 (C-12), 113.7 (C-3), 111.9
(C-15), 111.0 (C-7), 110.3 (C-2), 108.7 (C-10), 104.5 (C-19), 100.5 (C-22),
56.2, 56.1, 56.0, 55.9, 55.5, 55.2, 42.4 (C-6), 28.7 (C-5) ppm. ESI-MS: m/z
544.3 (100%) [M + H]+.
14-(3,4-Dimethoxyphenyl)-2,3,11,12-tetramethoxy-8,9-dihydro-6H-
chromeno[4’,3’:4,5]pyrrolo[2,1-a] ]isoquinolin-6-ol (16): Compound 16
is a red oil which was obtained as the main product in many of the reactions
given in Table 1. Rf = 0.12 (silica, cyclohexane/EtOAc, 1:1). IR (ATR): � =
2925, 2853, 2360, 2031, 1711, 1649, 1232, 1181, 1160, 1139 cm-1. 1H
NMR, COSY, NOESY (600 MHz,CDCl3): δ = 9.43 (s, 1H, CHO), 6.88 (d,
J = 8.2 Hz, 1H, H-5’), 6.81 (dd, J = 8.2, J = 1.9 Hz, 1H, H-6’), 6.79 (d, J =
1.9 Hz, 1H, H-2’), 6.75 (s, 1H, H-7), 6.63 (m, 2H, H-10, H-2’’), 5.97 (s, 1H,
H-5’’), 4.75 (s, 2H, H-5ab), 3.91 (s, 3H, C-8-OCH3), 3.90 (s, 3H, C-4’-OCH3),
Lamellarin G trimethyl ether (2):
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800611
European Journal of Organic Chemistry
FULL PAPER
3.85 (s, 3H, C-4’’-OCH3 ), 3.78 (s, 3H, C-3’-OCH3 ), 3.36 (s, 3H, C-9-OCH3),
3.10 (t, 2H, J = 6.5 Hz) ppm.13C NMR, HSQC, HMBC (150 MHz, CDCl3):
δ = 86.1 (C-6’’), 181.4 (C-3’’), 178.5 (CHO), 158.6 (C-4’’), 149.0 (C-3’),
148.4 (C-4’), 147.4 (C-9), 141.6 (C-1”), 134.4 (C-2’’), 134.0 (C-2), 128.3
(C-10b), 127.5 (C-3), 126.8 (C-6a), 126.4 (C-1’), 123.0 (C-6’), 122.6 (C-1),
119.4 (C-10a), 113.4 (C-2’), 111.3 (C-5), 110.7 (C-7), 108.9 (C-10), 107.8
(C-5’’), 56.4 (C-4’’-OCH3), 56.0 (C-3’-OCH3), 55.9 (C-8-OCH3), 55.9 (C-4’-
OCH3), 55.3 (C-9-OCH3), 42.6 (C-5), 28.5 (C-6) ppm. ESI-MS: m/z 530.4
(100%) [M + H]+. ESI-HRMS calcd. for [C30H27NO8 + Na]+ 552.1629, found
552.1627.
(COOCH3), 43.5 (C-5), 28.8 (C-6) ppm. ESI-MS m/z 504.1 (100%) [M +
H]+. ESI-HRMS calcd. for [C24H24BrNO6 + Na]+ 524.0679, found 524.0688.
Methyl-1-(3,4-dimethoxyphenyl)-2-[4,5-dimethoxy-2-(propan-2-
yloxy)phenyl]-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a] ]isoquinoline-
3-carboxylate (19): The title compound was prepared according to a
modified procedure of Alvarez et al.[50] The boronic acid 6 (crude, 102.1
mg, max. 0.4254 mmol, 2.0 eq) was transferred to a Schlenk tube, the
absence of oxygen was ensured by five argon/vacuum-cycles. Aryl
bromide 18 (120.0 mg, 0.2127 mmol), aqueous K3PO4 (202.8 mg, 9.555
mmol, 4.0 eq. in 0.47 mL) and dry DMF (3.7 mL) were added. The mixture
was purged with argon over the course of 10 minutes,. Subsequently,
Pd(PPh3)4 (55.2 mg, 47.8 µmol, 0.2 eq.) was added under argon
atmosphere. The mixture was heated to 110 °C for 72 h. Thereafter, the
solvent was removed under reduced pressure. The crude brown oil was
purified by automatic chromatography (cyclohexane/EtOAc, 10–64%
gradient EtOAc). The title compound was obtained as colourless foam
(109.4 mg, 0.1770 mmol, 83%). M.p. 94.0–99.0 °C. Rf = 0.26 (silica,
cyclohexane/EtOAc, 1:1). IR (ATR): � = 2946, 2903, 2836, 1691, 1532,
1438, 1258, 1241, 1213, 1197 cm–1. 1H NMR, COSY (400 MHz, CD3CN):
δ = 6.86 (s, 1H, H-7), 6.85 (d, J = 8.2 Hz, 1H, H-5’), 6.73 (m, 1H, H-2’),
6.72 (m, 1H, H-6’), 6.60 (s, 1H, H-10), 6.52 (s, 1H, H-6’’), 6.51 (s, 1H, H-
3’’), 4.50 (m, 2H, H-5a,b), 4.27 (hept, J = 6.0 Hz, CH(CH3)2), 3.79 (s, 3H, C-
8-OCH3), 3.76 (s, 3H, C-5’’-OCH3), 3.75 (s, 3H, C-4’-OCH3), 3.58 (s, 3H,
C-3’-OCH3), 3.54 (s, 3H, COOCH3), 3.51 (s, 3H, C-4’’-OCH3), 3.26 (s, 3H,
C-9-OCH3), 3.01 (t, J = 6.7 Hz, 2H, H-6a,b), 1.11 (d, J = 6.0 Hz, CH(CH3)2),
1.04 (d, J = 6.0 Hz, CH(CH3)2) ppm. 13C NMR, HSQC, HMBC (100 MHz,):
δ = 163.0 (COOMe), 150.8 (C-2’’), 149.8 (C-3’), 149.3 (C-4’), 149.2 (C-8),
149.0 (C-5’’), 148.2 (C-9), 143.6 (C-4’’), 131.3 (C-10b), 129.4 (C-1’), 128.9
(C-1’’), 127.1 (C-6a), 124.2 (C-2’), 122.4 (C-1), 121.6 (C-10a), 120.2 (C-3),
119.0 (C-2), 117.1 (C-6’’), 115.7 (C-6’), 112.5 (C-5’), 109.5 (C-10), 102.8
(C-3’’), 72.3 (CH(CH3)2), 56.8 (C-4’’-OCH3), 56.4 (C-OCH3), 56.3 (C-
OCH3), 56.3 (C-OCH3), 56.2 (C-3’-OCH3), 55.4 (C-9-OCH3), 51.3
(COOCH3), 43.8 (C-5), 29.5 (C-6), 22.5 (CH(CH3)2), 22.4 (CH(CH3)2) ppm.
2-bromo-1-(3,4-dimethoxyphenyl)-8,9-dimethoxy-5,6-
dihydropyrrolo[2,1-a]isoquinoline-3-carboxylic acid (17): The title
compound was prepared according to a modified procedure of Jia et al.[33]
Carbaldehyde 13 (137.0 mg, 0.2901 mmol) was dissolved in a tBuOH/THF
mixture (1:1, 13.8 mL) and cooled to 10 °C. At this temperature, 2-methyl-
but-2-ene (0.270 mL, 163 mg, 2.33 mmol, 8 eq.) was added. A solution of
NaClO2 (78.7 mg, 0.870 mmol, 3.0 eq.) and NaH2PO4 (104.4 mg, 0.870
mmol, 3.0 eq.) in H2O (1.92 mL) was added dropwise through a syringe.
The reaction mixture was stirred at 10 °C for 29 h with the reaction
progress being monitored by HPLC-MS. The precipitation of a yellow solid
was observed. The reaction was quenched by addition of aqueous NH4Cl,
(15 mL) the solvent was removed under reduced pressure. The residue
was washed with cold THF, the product was obtained as yellow solid
(140.3 mg, 0.2873 mmol, 99%). M.p. 181.0–185.0 °C (decomp.). Rf = 0.04
(silica, cyclohexane/EtOAc, 1:1). IR (ATR): � = 3647, 2991, 2963, 2933,
.
2833, 1650, 1457, 1241, 1229, 1134, 1039, 867 cm–1 1H NMR, COSY
(400 MHz, DMSO-d6): δ = 12.89 (s, 1H, COOH), 7.07 (d, 3J = 8.3 Hz, 1H,
H-5’), 6.91 (s, 1H, H-7), 6.86 (d, 4J = 2.0 Hz, 1H, H-2’), 6.82 (dd, 3J = 8.3
Hz, 4J = 2.0 Hz, 1H, H-6’), 6.44 (s, 1H, H-10), 4.51 (t, 3J = 6.7 Hz, 2H, H-
5
a,b), 3.79 (s, 3H, C-3’-OCH3), 3.75 (s, 3H, C-8-OCH3), 3.70 (s, 3H, C-3’-
OCH3), 3.19 (s, 3H, C-9-OCH3), 2.99 (t, 3J = 6.7 Hz, 2H, H-6a,b) ppm. 13
C
NMR, HSQC, HMBC (101 MHz, DMSO-d6): δ = 161.9 (COOH), 149.3 (C-
3’), 148.8 (C-4’), 148.7 (C-8), 147.2 (C-9), 131.4 (C-10b), 127.2 (C-1’),
126.6 (C-6a), 123.6 (C-6’), 122.0 (C-1), 119.7 (C-10a), 119.2 (C-3), 114.9
(C-2’), 112.6 (C-6a), 112.0 (C-7), 108.8 (C-10), 106.9 (C-2), 56.1 (OCH3),
56.0 (OCH3), 54.9 (OCH3), 43.6 (C-4), 28.3 (C-5) ppm. ESI-MS: m/z 490.1
(100%) [M + H]+. ESI-HRMS calcd. for [C23H23BrNO6 + H]+ 488.0703,
found 488.0695.
ESI-MS: m/z 18.4 (100%) [M + H]+. ESI-HRMS calcd. for [C35H39NO9
Na]+ 640.2517, found 640.2520.
+
Acknowledgements
Methyl-2-bromo-1-(3,4-dimethoxyphenyl)-8,9-dimethoxy-5,6-
We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopy, Dr.
N. Hanold (Mainz, deceased) for HR-mass spectrometry, and the
Rhineland-Palatinate Center for Natural Products Research for
helpful discussions. We thank Dennis Imbri (Mainz) for initial
studies on the cyclization reaction. Part of this work was
supported by the German Federal Ministry of Education and
Research (grant no. 01DG17013).
dihydropyrrolo[2,1-a]-isoquinoline-3-carboxylate (18): The title
compound was prepared according to a modified procedure of Jia et al.[33]
Acid 17 (120.0 mg, 0.2457 mmol) was dispersed in a MeOH/benzene
mixture (1:3, 3.3 mL). TMSCHN2 (56.1 mg, 0.491 mmol, 2 eq.) was added
with a syringe, the suspension was stirred at room temperature, the
reaction progress was monitored by HPLC-MS. The conversion was
complete within 3 h. The endpoint of the reaction was accompanied by the
transition of the turbid suspension into a homogeneous reaction mixture.
The solvent was removed under reduced pressure and the product was
obtained as a colorless solid (122.2 mg, 0.2432 mmol, 99%). M.p. 230.0 °C
(decomp.). Rf = 0.36 (silica, cyclohexane/EtOAc, 1:1). IR (ATR): � = 2951,
2837, 1695, 1547, 1517, 1499, 1462, 1249, 1214, 1198, 1026 cm-1. 1H
NMR, COSY (600 MHz, CDCl3): δ = 6.97 (d, J = 8.2 Hz, 1H, H-5’), 6.94
(dd, J = 8.2 Hz, J = 1.9 Hz, 1H, H-6’), 6.89 (d, J = 1.9 Hz, 1H, H-2’), 6.71
(s, 1H, H-7), 6.57 (s, 1H, H-10), 4.61 (pseudo-t, J = 6.1 Hz, 2H, H-5a,b),
3.93 (s, 3H, C-4’-OCH3), 3.92 (s, 3H, COOCH3), 3.88 (s, 3H, C-8-OCH3),
3.85 (s, 3H, C-3’-OCH3), 3.34 (s, 3H, C-9-OCH3), 3.03 (t, J = 6.1 Hz, 2H,
H-6a,b) ppm. 13C NMR, HSQC, HMBC (150 MHz, CDCl3): δ = 161.4
(COOMe), 149.0 (C-3’), 148.5 (C-8), 148.4 (C-4’), 147.3 (C-9), 132.0 (C-
10b), 127.2 (C-1’), 125.8 (C-6a), 123.4 (C-6’), 122.4 (C-1), 119.9 (C-10a),
118.5 (C-3), 114.0 (C-2’), 111.2 (C-5’), 110.6 (C-7), 108.5 (C-10), 107.7
(C-2), 56.0 (2C, C-3’/4’-OCH3), 55.9 (C-8-OCH3), 55.2 (C-9-OCH3), 51.3
Keywords: Nitrogen heterocycles • pyrrole alkaloids • natural
products • von Miller-Plöchl-cyclocondensation • total synthesis
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
alkaloid synthesis*
Vanessa C. Colligs, Clemens Dialer, Till
Opatz*
R8
R7
R6
R1
PGO
Page No. – Page No.
NH2
R2
B(OH)2
Synthesis of Lamellarin G Trimethyl
Ether via von Miller-Plöchl-type
Cyclocondensation
O
Text for Table of Contents
R5
OMe
OMe
R4
R3
The von Miller-Plöchl cyclocondensation serves as the key step a high-yielding
modular synthesis of the skeleton of the type-I lamellarins alkaloids. Starting from
simple precursors, lamellarin G trimethyl ether was obtained in 42% overall yield.
*one or two words that highlight the emphasis of the paper or the field of the study
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