A xylochemically inspired synthesis of lamellarin G trimethyl ether via an enaminone intermediate

Article abstract of DOI:10.1021/acs.joc.9b01604

A concise high yielding synthesis of lamellarin G trimethyl ether has been achieved from precursors and solvents that can in principle be derived from xylochemical (woody biomass) sources. The route is comparatively green in that some reactions are performed without solvent or with relatively benign solvents. In addition, chromatographic purification of products is avoided, and only a single aqueous workup is performed. The novelty of the synthesis lies in the intermediacy of an enaminone for the construction of the central pyrrole ring. The overall yield of the product is among the highest reported to date.

Full text of DOI:10.1021/acs.joc.9b01604

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Article
A Xylochemically-Inspired Synthesis of Lamellarin
G Trimethyl Ether via an Enaminone Intermediate
Robin Klintworth, Charles B. de Koning, Till Opatz, and Joseph Philip Michael
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01604 • Publication Date (Web): 08 Aug 2019
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The Journal of Organic Chemistry
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A Xylochemically-Inspired Synthesis of Lamellarin G Trimethyl Ether via
an Enaminone Intermediate
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Robin Klintworth,a Charles B. de Koning,a Till Opatzb and Joseph P. Michael*,a
aMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Wits 2050, Johannesburg, South Africa
*Email: Joseph.michael@wits.ac.za
bInstitut für Organische Chemie, Johannes Gutenberg-University, Duesbergweg 10-14, D-55128 Mainz, Germany.
Supporting Information Placeholder
Br
MeO
MeO
O
MeO
MeO
NH2
O
OEt
Ethyl bromoacetate
N
Homoveratrylamine
O
MeO
MeO
HO2C
OMe
CO2H
MeO
OMe
MeO
Lamellarin G trimethyl ether
MeO
OMe
MeO
Homoveratric acid
Asaronic acid
ABSTRACT: A concise high-yielding synthesis of lamellarin G trimethyl ether has been achieved from precursors and solvents
that can in principle be derived from xylochemical (woody biomass) sources. The route is comparatively green in that some
reactions are performed without solvent or with relatively benign solvents. In addition, chromatographic purification of products is
avoided, and only a single aqueous workup is performed. The novelty of the synthesis lies in the intermediacy of an enaminone for
the construction of the central pyrrole ring. The overall yield of the product is among the highest reported to date.
aromatic precursors (“xylochemicals”) that can formally be
INTRODUCTION
derived from the valorization of lignin and lignocellulose.8 In
The lamellarins are an interesting and topical group of
alkaloids found in a variety of marine invertebrates, including
molluscs, sponges and tunicates.1,2 Most of these alkaloids are
characterized by a highly oxygenated fused pentacyclic
skeleton containing a central pyrrole core, and also bear a
pendent aromatic ring at C-1, as seen in lamellarins D (1) and
G (2) (Figure 1). Since many lamellarins exhibit potent
cytotoxicity,2 most notably as potential anticancer agents,3
there has been considerable interest in the development of
synthetic strategies for constructing their 1-aryl-6H-chromeno-
this article we disclose a new efficient, essentially green,
convergent route that yields 3 in an overall yield of 58%–61%
based on commercially available homoveratric acid — the
second-highest to date (cf. 69% overall yield based on 3,4-
dimethoxyphenylacetonitrile6e).
6
HO
RO
5
O
O
N
N
3
MeO
MeO
O
O
1
2
HO
MeO
RO
MeO
[4',3':4,5]pyrrolo[2,1-a]isoquinolin-6-one
framework.4,5
Lamellarin G trimethyl ether (3), although not itself a natural
product, is a popular target for synthesis,6 and provides a
touchstone for evaluating new approaches to the formation of
the fused pentacyclic lamellarin scaffold.
OH
OMe
MeO
RO
2 R = H
3 R = Me
1
Figure 1. Lamellarin D (1), lamellarin G (2) and lamellarin G
trimethyl ether (3).
In the interests of devising an environmentally responsible
route to 3, we sought a method that avoided, as far as possible,
the use of noxious precursors, tedious chromatographic
purifications and undesirable (especially chlorinated) solvents.
Furthermore, in pursuance of our current efforts to sidestep
coal- and petroleum-derived precursors for the synthesis of
natural products,7 we have chosen to begin with oxygenated
RESULTS AND DISCUSSION
Most reported syntheses of the pentacyclic lamellarins proceed
via precursors or intermediates already possessing a suitably
functionalized pyrrole core, onto which the additional rings
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The Journal of Organic Chemistry
are elaborated.9 Less commonly, the pyrrole ring is created by
Page 2 of 7
steps from vanillin,17-19 a common xylochemical derived from
lignin by hydrothermal depolymerization8a or electrolysis.20
Their condensation to form the amide 10 was accomplished in
the absence of solvent in a slight modification of a reported
procedure21 by heating equimolar quantities of the reactants at
180 °C in a closed microwave vessel at a power setting of 150
W for one hour (Scheme 2). After this time NMR
spectroscopy showed no trace of the precursors. Trituration of
the reaction mixture with ethyl acetate afforded pure amide 10
in 96% yield. Its cyclisation to the hydrochloride salt of
dihydropapaverine (6) was accomplished by Bischler–
Napieralski reaction, which was performed by heating 10 with
phosphorus oxychloride in toluene. The crude product
precipitated when the hot reaction mixture was cooled, and it
could be obtained in crystalline form after trituration with cold
toluene followed by brief heating at the boiling point of the
solvent. However, the salt was found to absorb atmospheric
moisture rapidly to give a hydrate, traces of which were
always apparent in its 1H NMR spectrum at approximately 2.3
ppm. For further reaction, the salt could be dried by heating
under vacuum at 100 °C. We also found that, although
dihydropapaverine itself could be released from the salt by
treatment with aqueous ammonia, the free base was not easy
to purify and very unstable to benzylic oxidation during
storage, as has been reported previously.22 The hydrochloride
salt was therefore used in the ensuing reactions (vide infra).
1
2
3
4
5
6
7
8
cyclization involving condensation or cycloaddition between
an isoquinoline precursor and moieties that supply either the
C-1/C-2/C-3 or the C-2/C-3 components of the targets.10 Even
rarer are approaches in which the pyrrole ring is formed by the
attachment of a building block that provides only C-3, with
most or all of the lamellarin’s carbon framework already in
place.11 The disconnection envisaged in the present approach
is of the latter type (Scheme 1). The reason for this choice of
strategy arises from our long-standing interest in the use of
enaminones as intermediates for the synthesis of alkaloids and
other nitrogen heterocycles.12,13 We visualized a pivotal role
for the enaminone 4 in a late-stage assembly of the pyrrole. By
reacting this intermediate with a bifunctional reagent such as
ethyl bromoacetate, we believed we could take advantage of
the enaminone’s nucleophilicity at nitrogen in displacing the
halide, and its electrophilicity at the carbonyl substituent by
condensation with the α-methylene site of the ester. This
process installs the required heterocycle in a formal [4 + 1]
cycloaddition, thereby forming the known intermediate 5,
9
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which has been converted into the target
3
after
hydrogenolysis of the benzyl ether.6i Such a route to the
pyrrole hub of lamellarins via an enaminone appears to be
unprecedented, although a similar but low-yielding reaction
between ethyl bromoacetate and
isoquinoline precursor containing
a
a
fully unsaturated
small amount of
enaminone tautomer was used by Iwao and co-workers in their
synthesis of lamellarin D.11b Other syntheses of pyrroles by [4
+ 1] cycloaddition between enaminones and α-halo esters are
virtually unknown.14 Enaminone 4 itself was considered to be
accessible by base-mediated C-acylation of dihydropapaverine
(6) with a functionalized benzoate such as 7 in an aza-enolate
variant of a Claisen condensation, the resulting imine then
equilibrating to the hydrogen-bonded enaminone tautomer 4.
The envisaged acylation of a lithiated azaenolate (ketimine α-
anion) on carbon rather than on nitrogen is precedented;
reactions with esters15 or other acylating agents16 have been
reported to give various enaminones (vinylogous amides and
related products) in fair to excellent isolated yields in most
cases. Although dihydropapaverine is a common synthetic
precursor for lamellarins,4 its use in this manner has not been
reported previously.
Scheme 2. Modified synthesis of dihydropapaverine
hydrochloride (6·HCl)
CO2H
MeO
µW (150 W)
180 °C, 1 h
MeO
MeO
+
NH2
MeO
MeO
96%
9
8
MeO
POCl3, PhMe
reflux, 1 h
NH
O
N·HCl
MeO
MeO
MeO
MeO
ca 100%
MeO
MeO
10
6·HCl
The protected benzoate 7 required for the C-acylation of 6 was
made in three steps from another commercially available
compound, asaronic acid (11), which can itself be prepared
from the natural product asarone by heating with potassium
permanganate in basic medium.23 Despite the presence of three
methoxy substituents in 11, selective demethylation of the
ether ortho to the carboxylic acid was accomplished in 94%
yield according to a patented procedure by stirring 11 in hot
toluene with aluminum trichloride solubilized in situ with
dimethylformamide, followed by hydrolysis of the crude
mixture with hydrochloric acid24 (Scheme 3). Alternative
procedures reported in the same patents and that employ either
sodium bromide and boron trifluoride etherate in ethyl acetate,
or titanium tetrachloride in ethyl acetate, reportedly gave
lower yields of the desired o-hydroxy acid 12. Fischer
esterification of 12 with methanol and sulfuric acid afforded
the ester 13, after which benzylation of the liberated phenol
under standard conditions completed the synthesis of the
requisite building block 7 in 92% overall yield based on
asaronic acid.
Scheme 1. Retrosynthetic analysis for lamellarin G trimethyl
ether (3)
MeO
MeO
MeO
MeO
MeO
Br
N
N
MeO
MeO
H
O
CO2Et
OBn
CO2Et
OBn
3
MeO
MeO
OMe
MeO
OMe
5
4
MeO
MeO
O
N
OBn
MeO
MeO
+
MeO
OMe
MeO
6
7
Our synthesis of lamellarin G trimethyl ether (3) began with
two commercially available precursors, homoveratrylamine
(8) and homoveratric acid (9). Both can be made in several
With both the imine hydrochloride 6·HCl and the substituted
benzoate 7 in hand, the assembly of the key enaminone 4 was
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The Journal of Organic Chemistry
tackled. As mentioned before, the hygroscopic hydrochloride
by some preliminary results with related crowded
enaminones,26 we devised a set of reaction conditions for the
heterocycle formation that entailed dissolving 3 in just enough
ethyl bromoacetate (2–3 equivalents) with anhydrous
tripotassium phosphate as base, and irradiating the mixture
under a low microwave power of only 20 W, as the inorganic
salt is a highly effective absorber of microwave energy
(Scheme 5). An internal temperature of 120 °C was reached
within a few minutes, and heating was maintained for 2.5
hours. At this stage the bright yellow color of the enaminone
had vanished, and both TLC and NMR spectroscopy indicated
complete consumption of 3. The NMR spectrum of the crude
mixture also showed that some ethyl bromoacetate was still
present along with contaminants arising from concomitant
alkylation of the phosphate anion by ethyl bromoacetate
(including triethyl 2,2',2''-[phosphoryltris(oxy)]triacetate27 and
mono- and di-alkylated analogues). The entire mixture
containing the putative intermediate 5 was transferred into a
hydrogenation flask together with a catalytic amount of
palladium on carbon (10%) under a balloon of hydrogen gas.
The mixture was left to stir for 24–36 hours until NMR
showed no trace of the benzyl protecting group or of residual
toxic ethyl bromoacetate, which was also destroyed during the
hydrogenation. To telescope the final suite of reactions even
further, the solvent was removed and the residue was
suspended in methanol containing a few drops of triethylamine
in order to neutralize any remaining acetic acid, as well as to
promote lactone formation. After overnight stirring at room
temperature, lamellarin G trimethyl ether (3) had precipitated
cleanly from the solution and could easily be filtered off,
leaving all remaining contaminants in solution. The yield of 3
from enaminone 4 by this four-step tandem process was 72%.
(This yield could be improved to 79% when triethylamine was
replaced by DBU, but this base cannot be made easily from
1
salt needed to be dried in vacuo at 100 °C before being used.
2
3
4
5
6
7
8
9
Scheme 3. Conversion of asaronic acid (11) into methyl 2-
benzyloxy-4,5-dimethoxybenzoate (7)
CO2H
OMe
CO2H
OH
1. AlCl3, DMF, PhMe, 85 °C, 1.5 h
2. Conc. HCl, H2O, 75 °C, 1 h
94%
MeO
MeO
MeO
OMe
11
OMe
12
CO2Me
CO2Me
Conc. H2SO4, MeOH
BnBr, K2CO3
OH
10
11
12
13
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OBn
reflux , 30 h
Me2CO, reflux, 48 h
ca 100%
98%
MeO
OMe
OMe
13
7
The deprotonation of the salt was then performed in
tetrahydrofuran at −78 °C with n-butyllithium (2.3
equivalents), the first equivalent of which neutralized the
protonated base (Scheme 4). Formation of 14, the putative
aza-enolate of 6, was indicated by the development of a deep
maroon-colored solution. Subsequent addition of the ester 7 and
gradual warming of the reaction mixture to room temperature
saw the color changing to yellow, which deepened overnight.
Aqueous work-up with neutralization of the excess base,
extraction with ethyl acetate and filtration of the extracts
through a short plug of silica gel followed by removal of the
solvent gave chromatographically and spectroscopically pure
enaminone 4 as a bright yellow solid in 81% yield. That
product 4 exists as the enamine, rather than the imine,
tautomer was indicated by the signal for the intramolecularly
1
hydrogen-bonded N–H substituent in the H NMR spectrum,
which was located at 13.22 ppm. This intramolecular
hydrogen bonding also implies that 4 is the (Z)-geometric
1
isomer. The distinctive signal for the carbonyl group in the 13
NMR spectrum was found at 192.2 ppm.
C
xylochemical precursors.) The H NMR spectroscopic data
obtained for lamellarin G trimethyl ether were within 0.03
ppm of those reported for the same compound in a recent
publication,6e while the 13C values were within 0.2 ppm.
Scheme 4. Formation of the key enaminone intermediate 4
MeO
MeO
Scheme 5. Telescoped final steps in the synthesis of lamellarin
G trimethyl ether (3)
n-BuLi (2.3 eq.), THF
–78 °C to –15 °C, 1 h
N·HCl
N
MeO
MeO
MeO
MeO
MeO
MeO
O
BrCH2CO2Et (2.76 eq.),
K3PO4, w (120 °C,
20 W), 2.5 h
NH
N
MeO
MeO
MeO
MeO
MeO
MeO
OEt
6·HCl
14
O
O
MeO
OBn
OBn
CO2Me
MeO
MeO
N
OBn
MeO
MeO
H
O
MeO
MeO
15
OMe
OMe
MeO
4
–78 °C to rt, 18 h
OBn
OMe
MeO
no purification or work-up
of intermediates required
72%
7 (1 eq.)
MeO
81%
OMe
4
MeO
MeO
MeO
MeO
MeO
MeO
1. H2 (1 atm), Pd/C,
AcOH-EtOH (1:1),
rt, 24-36 h
2. NEt3 (cat.), MeOH,
rt, 24 h
O
N
N
CO2Et
OBn
It was now the moment of truth for finding out whether
enaminone 4 would indeed prove to be a suitable scaffold on
which to construct the target’s pyrrole ring. Although the
ambident nucleophilicity of enaminones in general appears to
favor intermolecular reaction with alkylating agents (among
other electrophiles) at the enamine carbon site rather than
nitrogen,25 we reasoned that steric hindrance at this site in our
intermediate would deflect alkylation with ethyl bromoacetate
towards nitrogen, presumably giving the N-alkyl compound 15
en route to the pyrrole-containing intermediate 5. Encouraged
O
MeO
MeO
OMe
MeO
MeO
OMe
5
Lamellarin G trimethyl ether (3)
CONCLUSION
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The overall yields of lamellarin G trimethyl ether (3) based on
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CDCl3) δ 6.81 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 5.1 Hz, 1H),
6.70 (d, J = 6.3 H z, 2H), 6.63 (d, J = 2.0 Hz, 1H), 6.53 (dd, J
= 8.1, 2.0 Hz, 1H), 5.44 (br s, 1H), 3.89 (s, 3H), 3.87 (s, 3H),
3.84 (s, 6H), 3.49 (s, 2H), 3.48-3.40 (m, 2H), 2.69 (t, J = 6.9
Hz, 2H). The chemical shifts are within 0.01 ppm of those
reported in the literature.21
1
2
3
4
5
6
7
8
homoveratric acid (9) and asaronic acid (11), both of which
can in principle be derived from non-petrochemical sources,
are 56% and 66% respectively when triethylamine is used as
the basic catalyst in the final step (61% and 73% respectively
when non-xylochemical DBU is used as base). The most
efficient route to 3 hitherto reported results in a 69% overall
yield based on 3,4-dimethoxyphenylacetonitrile.6e Our new
route incorporates the novel use of enaminone 4 in the late-
stage construction of the central pyrrole ring, and telescopes
this step into a tandem sequence of reactions that ultimately
give the target product. The route employed is substantially
green in that it eschews chlorinated solvents as well as
chromatographic purification of intermediates, most of which
could be obtained spectroscopically pure by crystallization or
precipitation from the reaction medium. When solvents and
certain other reagents (among them ethyl bromoacetate and n-
butyllithium) are necessary for reaction or purification, they
can in principle be derived from xylochemically derived
precursors such as methanol, ethanol and butanol. The reaction
conditions include just a single aqueous workup and one
filtration through silica gel; and microwave heating in the
absence of solvent is employed in two steps.
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroiso-
quinoline
hydrochloride) (6·HCl). To
hydrochloride
(3,4-dihydropapaverine
a
suspension of N-(3,4-
dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)acetamide (10)
(1.40 g, 3.9 mmol) in toluene (80 ml) was added POCl3 (0.8
ml, ca 1.31 g, ca 8.5 mmol) dropwise at room temperature.
The mixture was heated under reflux for 1 h under an inert
atmosphere of Ar gas, then allowed to cool to room
temperature. The cooled viscous precipitate of the crude imine
HCl salt was triturated under toluene until it began to solidify
as an off-white solid. [Note: This process was quite
unpredictable, but could be promoted by the addition of a seed
crystal of the dry product, with the addition of diethyl ether, or
simply by cooling the flask overnight in a freezer.] The
solvent was re-heated to its boiling point, at which it was
maintained for some minutes until the colorless solid had
taken on a crystalline appearance. The suspension was filtered
while still hot, washed with toluene (or diethyl ether for ease
of drying), and immediately dried under vacuum to prevent
adsorption of atmospheric water (hydrate detectable at 2.3
9
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EXPERIMENTAL
Solvents were dried and purified, where necessary, by
appropriate standard procedures. All other chemicals were
purchased from commercial sources (Sigma-Aldrich, Alfa
Aesar, Carbolution Chemicals, Acros Organics) and used as
received unless mentioned otherwise. All reactions were
performed under an inert atmosphere of argon in oven-dried
glassware. Microwave heating was performed in capped vials
of appropriate size in a CEM Discover microwave reactor, and
temperature was monitored by means of an external surface
1
ppm by H NMR). Thus was obtained the almost completely
dry imine hydrochloride 6·HCl as a fluffy white solid (1.53 g,
quant.), m.p. 201-205 °C (lit., 106-115 °C;28 114–117 °C;29
186 °C30). H NMR (300 MHz, CDCl3) δ 14.20 (br s, 1H),
1
7.37 (s, 1H), 7.07 (d, J = 1.8 Hz, 1H), 6.89 (dd, J = 8.2, 1.8
Hz, 1H), 6.80 and 6.78 (superimposed s and d, J = 8.4 Hz,
2H), 4.48 (s, 2H), 3.99 (s, 3H), 3.95 (br s, 2H), 3.89 (s, 6H),
3.83 (s, 3H), 3.03 (t, J = 7.7 Hz, 2H). The chemical shifts are
in broad agreement with those reported in the literature.29
1
sensor. An oil bath was used for conventional heating. H and
13C{1H} NMR spectra were recorded on a Bruker Avance III
HD 300 spectrometer at frequencies of 300 MHz and 75 MHz
2-Hydroxy-4,5-dimethoxybenzoic acid (12). (Method
adapted from ref. 24). Anhydrous AlCl3 (6.28 g, 47.1 mmol)
was suspended in dry toluene (20 g) under an inert atmosphere
of Ar gas. DMF (20 g, 273 mmol) was added dropwise at
room temperature, which caused the evolution of heat and the
solubilization of AlCl3, presumably as a DMF chelate. 2,4,5-
Trimethoxybenzoic acid (asaronic acid, 11) (10.0 g, 47.1
mmol) was added, and the mixture was heated at 85 °C for 1.5
h. Once the mixture had cooled, concentrated HCl (35%, 5.89
g) was added dropwise, followed by water (17 ml). Heating at
75 °C for 1 h resulted in precipitation of a solid, which was
collected by filtration, washed with water and dried to provide
12 (8.76 g, 94%) as a colorless solid, m.p. 200-211 °C (lit.,31
1
respectively. Chemical shifts (δ) of H signals are reported as
parts per million (ppm) downfield from Me4Si as internal
reference, while carbon resonances are referenced to the
residual solvent signal. Deuterated solvents for NMR
measurements were obtained from Deutereo and used as
received. FT-IR spectra were recorded on a Tensor 27
spectrometer (Bruker) equipped with a diamond ATR unit.
High-resolution masses (ESI) were recorded on a Q-ToF-
Ultima 3 instrument (Waters) with a LockSprayTM interface
and a suitable external calibrant. Thin-layer chromatography
(TLC) was carried out on silica gel 60 F254 plates (Merck).
Compounds were visualized using UV light and/or by
immersion in a solution of KMnO4 (3 g), K2CO3 (20 g), 5%
aqueous NaOH (5 mL) and water (300 mL) followed by
heating.
1
210 °C decomp.). H NMR (300 MHz, DMSO-d6) δ 13.51 (v
br s, 1H), 11.31 (v br s, 1H), 7.17 (s, 1H), 6.56 (s, 1H), 3.81 (s,
3H), 3.71 (s, 3H).
Methyl
2-hydroxy-4,5-dimethoxybenzoate
(13).
A
N-(3,4-Dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-
acetamide (10). (Method adapted from ref. 21). To 3,4-
dimethoxyphenylacetic acid (homoveratric acid, 9) (1.0 g, 5.1
mmol) in a microwave vial was added 3,4-dimethoxy-
phenethylamine (homoveratrylamine, 8) (954 mg, 5.26 mmol).
The vial was capped, and the mixture was heated in a
microwave reactor (180 °C at 50 W power) for 1 h until an
NMR spectrum of a sample showed complete formation of
amide 10. The residue in the vial was suspended in EtOAc (10
ml), and the resulting precipitated solid was filtered to provide
amide 10 (1.757 g, 96%) as a white solid. 1H NMR (300 MHz,
suspension of 2-hydroxy-4,5-dimethoxybenzoic acid (12) (5.0
g, 25.2 mmol) in MeOH (120 ml) containing sulfuric acid
(95%; 5.2 g, 50.4 mmol, 2 equiv.) was heated at reflux for 30
h, after which time NMR spectroscopy of a sample showed the
reaction to be complete. Addition of an equal volume of water
(120 ml) resulted in precipitation of a colorless solid, which
was collected by filtration to provide the methyl ester 13 (5.34
1
g, quant.), m.p. 92-93 °C (lit.,32 94-94.5 °C). H NMR (300
MHz, CDCl3) δ 10.73 (s, 1H), 7.19 (s, 1H), 6.47 (s, 1H), 3.92
(s, 3H), 3.89 (s, 3H), 3.84 (s, 3H); 13C{1H} NMR (75 MHz,
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CDCl3) δ 170.3, 158.3, 155.7, 142.1, 110.3, 103.1, 100.2, 56.3,
CDCl3) δ 192.2, 158.7, 150.0, 148.7, 148.6, 148.2, 146.9,
146.0, 142.9, 138.0, 133.6, 132.1, 128.3, 127.5, 126.9, 126.1,
125.8, 121.4, 116.6, 114.1, 111.9, 110.4, 109.8, 107.1, 99.7,
71.9, 56.3, 55.9, 55.8, 55.8, 55.7, 55.1, 39.2, 28.9. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C36H38NO8 612.2592;
Found 612.2588.
56.2, 52.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
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2
3
4
5
6
7
8
C10H13O5 213.0757; Found 213.0760.
Methyl 2-benzyloxy-4,5-dimethoxybenzoate (7). Benzyl
bromide (4.70 g, 27.5 mmol, 1.1 equiv.) was added to a
suspension of methyl ester 13 (5.34 g, 25.2 mmol) and
anhydrous K2CO3 (10.6 g, 76.7 mmol) in acetone (200 ml).
The mixture was heated at reflux for 48 h, at which time the
reactions was shown to be complete by TLC and NMR
spectroscopy. The solids were removed by filtration and
washed with acetone, and the combined organic phase was
evaporated in vacuo to yield an oil. Dissolving in EtOAc
(addition of cyclohexane was found to promote crystallization
in some cases) led to the formation of 7 as white needles (7.47
g, 98%), m.p. 101-102 °C. IR (ATR, cm−1) νmax 2988 (w),
2968 (w), 2902 (w), 1721 (s), 1518 (m), 1433 (m), 1382 (m),
1346 (m), 1248 (s), 1216 (s), 1199 (s), 1158 (s), 1077 (s), 1037
Lamellarin G trimethyl ether (3). (a) Enaminone 4 (100 mg,
0.16 mmol) was dissolved in
a minimum of ethyl
bromoacetate (50 μl, ca 75 mg, ca 0.45 mmol, ca 2.76 equiv.)
in a microwave vessel, to which was added anhydrous K3PO4
(100 mg, 0.47 mmol). The vessel was capped, and the bright
yellow suspension was stirred gently while being heated to
120 °C in a microwave reactor (20 W power) for 2.5 h, at
which stage the yellow color had disappeared and an almost
colorless supernatant solution had been formed. TLC showed
the enaminone (Rf 0.4; EtOAc) had been replaced by a single
brilliant blue fluorescent spot (Rf 0.8; EtOAc), and signals for
the enaminone were also absent from the NMR spectrum of
the crude reaction mixture.
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(m), 1014 (s)813 (m), 750 (m); 699(m); H NMR (300 MHz,
CDCl3) δ 7.56–7.48 (m, 2H), 7.44 (s, 1H), 7.44–7.30 (m, 3H),
6.56 (s, 1H), 5.16 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.87 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 166.2, 154.4, 153.3,
143.2, 136.9, 128.5, 127.9, 127.2, 114.1, 111.9, 100.6, 77.5,
77.1, 76.6, 72.6, 56.3, 56.0, 51.9. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C17H19O5 303.1227; Found 303.1235.
The entire contents of the microwave vial, including solids,
were transferred to a hydrogenation flask with 50% glacial
AcOH in EtOH (50 mL). The flask was briefly flushed with
Ar gas before the addition of Pd/C (10%; 10% of the total
mass of crude material; 17.5 mg). The suspension was stirred
at room temperature under an atmosphere of H2 (balloon
pressure) until the reaction was shown to be complete by
NMR spectroscopy (24–36 h). The solution was filtered
through Celite, which was then rinsed with EtOAc (100 mL).
Solvent was removed on a rotary evaporator to yield a pale
amber oily residue. MeOH (20 mL) containing a few drops of
NEt3 was added, and the solution was left to stir at room
temperature. Within 1–2 h crystals of lamellarin G trimethyl
ether (3) had begun to develop. After 24 h the precipitated
material was collected by filtration and rinsed with MeOH.
After drying, lamellarin G trimethyl ether (3) (64 mg, 72%)
was obtained as a white solid, m.p. 246-247 °C (lit., 235-236
°C;6e 233-234 °C;6f 238-239 °C;6h 239.1-240.7 °C33). 1H NMR
(300 MHz, CDCl3) δ 7.14 (dd, J = 8.1, 1.8 Hz, 1H), 7.11–7.05
(m, 2H), 6.90 (s, 1H), 6.78 (s, 1H), 6.73 (s, 1H), 6.68 (s, 1H),
4.79 (hept, J = 6.6 Hz, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 3.89 (s,
3H), 3.88 (s, 3H), 3.48 (s, 3H), 3.38 (s, 3H), 3.13 (t, J = 6.7
Hz, 2H);. 13C{1H} NMR (75 MHz, CDCl3) δ 155.5, 149.7,
149.0, 148.83, 148.75, 147.5, 146.1, 145.6, 136.0, 128.2,
128.0, 126.6, 123.6, 120.0, 114.8, 114.0, 113.7, 111.9, 111.0,
110.3, 108.7, 104.5, 100.5, 56.2, 56.2, 56.0, 55.9, 55.5, 55.2,
42.4, 28.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C31H30NO8 544.1962; Found 544.1966.
(Z)-1-[2-(Benzyloxy)-4,5-dimethoxyphenyl]-2-(6,7-
dimethoxy-3,4-dihydroisoquinolin-1(2H)-ylidene)-2-(3,4-
dimethoxyphenyl)-ethanone (enaminone 4). The imine
hydrochloride 6·HCl (250 mg, 0.66 mmol) was heated to 100
°C under vacuum and with constant stirring for 1 h in order to
remove traces of moisture. The reaction flask was then
immediately flushed with dry Ar gas, and the solid was
suspended in freshly distilled dry THF (5 mL). The mixture
was cooled to −78 °C in an acetone/dry-ice cooling bath, after
which n-butyllithium (1.6 M in hexanes; 0.95 mL, 1.52 mmol,
2.3 equiv.) was added by syringe. The mixture became
homogeneous, and a deep maroon-red color developed. The
solution was then warmed to −15 °C in a bath made by adding
dry-ice to a saturated brine solution until water-ice had
covered the dry-ice pellets. The solution was left to stir for 1 h,
after which time the red color had ceased to deepen. The
solution was again cooled to −78 °C, and methyl 2-
(benzyloxy)-4,5-dimethoxybenzoate (7) (201 mg, 0.66 mmol,
1 equiv.) in freshly distilled dry THF (3 mL) was added
dropwise such that the internal temperature remained constant.
The solution’s red color remained throughout the addition and
began to fade slowly thereafter. Stirring was continued at −78
°C for 5 min, after which the solution was allowed to reach
room temperature. As the solution warmed, the deep red color
changed to pale yellow, which intensified to a rich yellow
color after 18 h. Residual base was neutralized with
concentrated aq. NH4Cl solution. EtOAc (50 mL) was added
to allow for a manageable volume at this small scale, and the
organic phase was separated, washed with brine, dried
(Na2SO4) and filtered through a short plug of silica gel, which
was washed with additional EtOAc until all of the yellow
eluents had been collected. After removal of the solvent,
chromatographically pure enaminone 4 (328 mg, 81%) was
(b) The above procedure was repeated with enaminone 4 (47.0
mg, 0.077 mmol), ethyl bromoacetate (50 μl, ca 75 mg, ca
0.45 mmol, ca 2.76 equiv.) and anhydrous K3PO4 (120 mg,
0.57 mmol). After hydrogenolysis of the benzyl ether and
workup as described above, the crude reaction mixture was
dissolved in toluene (20 ml), to which was added a drop of
DBU. The mixture was heated to 80 °C for 40 min. The
solvent was then removed on a rotary evaporator and the
residue was suspended in MeOH (10 ml). After a few minutes
crystals of 3 began to develop. These were collected by
filtration and rinsed with MeOH. After drying, lamellarin G
trimethyl ether (3) was obtained as a white solid (33 mg,
79%); characterization as above.
1
obtained as a yellow solid; m.p. 89-90 °C. H NMR (300
MHz, CDCl3) δ 13.22 (s, 1H), 7.42–7.25 (m, 8H), 6.65 (s, 1H),
6.58 (s, 1H), 6.54–6.47 (m, 2H), 6.43 (dd, J = 8.2, 1.9 Hz,
1H), 6.40 (s, 1H), 6.27 (s, 1H), 4.92 (s, 2H), 3.88 (s, 3H), 3.75
(s, 3H), 3.70 (s, 3H), 3.67 (s, 3H), 3.61–3.47 (m, 2H), 3.42 (s,
3H), 3.16 (s, 3H), 3.01–2.80 (m, 2H) 13C{1H} NMR (75 MHz,
ASSOCIATED CONTENT
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Page 6 of 7
Eaton, J. E.; Rieck, E. A.; Smith, K. L.; Keough, M. J.; Barelli, P. J.;
Supporting Information
Firich, L. T.; Hempel, J. E.; Smith, T. M.; Kanters, R. P. F. The
Application of Vinylogous Iminium Salt Derivatives to Efficient
Formal Syntheses of the Marine Alkaloids Lamellarin G Trimethyl
Ether and Ningalin B. Tetrahedron 2009, 65, 4283–4292. (h) Yadav,
J. S.; Gayathri, K. U.; Subba Reddy, B. V.; Prasad, A. R. Modular
Total Synthesis of Lamellarin G Trimethyl Ether. Synlett 2009, 43–
46. (i) Liermann, J. C.; Opatz, T. Synthesis of Lamellarin U and
Lamellarin G Trimethyl Ether by Alkylation of a Deprotonated α-
Aminonitrile. J. Org. Chem. 2008, 73, 4526–4531. For syntheses
prior to 2008, see reference 4.
(7) (a) Kühlborn, J.; Konhäuser, M.; Gross, J.; Wich, P. R.; Opatz,
T. Xylochemical Synthesis of Cytotoxic 2-Aminophenoxazinone-
Type Natural Products Through Oxidative Cross Coupling. ACS
Sustainable Chem. Eng. 2019, 7, 4414–4419. (b) Kühlborn, J.;
Danner, A.-K.; Frey, H.; Iyer, R.; Arduengo, III, A. J.; Opatz, T.
Examples of Xylochemistry: Colorants and Polymers. Green Chem.
2017, 19, 3780–3786. (c) Sevenich, A.; Liu, G.-Q.; Arduengo, III, A.
J.; Gupton, B. F.; Opatz, T. Asymmetric One-Pot Synthesis of
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol: A Key Component of
Current HIV Protease Inhibitors. J. Org. Chem. 2017, 82, 1218–1223.
(d) Stubba, D.; Lahm, G.; Geffe, M.; Runyon, J. W.; Arduengo, III,
A. J.; Opatz, T. Xylochemistry—Making Natural Products Entirely
from Wood. Angew. Chem., Int. Ed. 2015, 54, 14187–14189.
(8) Recent examples and reviews: (a) Abad-Fernández, N.; Pérez,
E.; Cocero, M. J.; Aromatics from Lignin Through Ultrafast
Reactions in Water. Green Chem. 2019, 21, 1351–1360. (b) Van den
Bosch, S.; Koelewijn, S. F.; Renders, T.; Van den Bossche, G.;
Vangeel, T.; Schutyser, W.; Sels, B. F. Catalytic Strategies Towards
Lignin-Derived Chemicals. Top Curr. Chem. 2018, 376, 1–40. (c)
Schutyser, W.; Renders, T.; Van den Bosch, S.; Koelewijn, S. F.;
Beckham, G. T.; Sels, B. F. Chemicals from Lignin: An Interplay of
Lignocellulose Fractionation, Depolymerisation, and Upgrading.
Chem. Soc. Rev. 2018, 47, 852–908. (d) Ma, R.; Guo, M.; Zhang, X.
Recent Advances in Oxidative Valorization of Lignin. Catal. Today
2018, 302, 50–60. (e) Cao, L.; Yu, I. K. M.; Liu, Y.; Ruan, X.; Tsang,
D. C. W.; Hunt, A. J.; Ok, Y. S.; Song, H.; Zhang, S. Lignin
Valorization for the Production of Renewable Chemicals: State-of-the
Art Review and Future Prospects. Bioresour. Technol. 2018, 269,
465–475. (f) Gillet, S.; Aguedo, M.; Petitjean, L.; Morais, A. R. C.; da
Costa Lopes, A. M.; Lukasik, R. M.; Anastas, P. T. Lignin
Transformations for High Value Applications: Towards Targeted
Modifications Using Green Chemistry. Green Chem. 2017, 19, 4200–
4233.
(9) (a) Shirley, H. J.; Koyioni, M.; Muncan, F.; Donohoe, T. J.
Synthesis of Lamellarin Alkaloids Using Orthoester-Masked α-Keto
Acids. Chem Sci. 2019, 10, 4334–4338. (b) Mei, R.; Zhang, S.-K.;
Ackermann, L. Concise Synthesis of Lamellarin Alkaloids by C–
H/N–H Activation: Evaluation of Metal Catalysts in Oxidative
Alkyne Annulation. Synlett 2017, 28, 1715–1718. (c) Lade, D. M.;
Pawar, A. B.; Mainkar, P. S.; Chandrasekhar, S. Total Synthesis of
Lamellarin D Trimethyl Ether, Lamellarin D, and Lamellarin H. J.
Org. Chem. 2017, 82, 4998–5004. (d) Fukuda, T.; Katae, T.; Harada,
I.; Iwao, M. Synthesis of Lamellarins via Regioselective Assembly of
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3
4
5
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7
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The Supporting Information is available free of charge on the
ACS Publications website.
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*Email: Joseph.michael@wits.ac.za
ORCID
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Robin Klintworth: 0000-0003-1413-917X
Charles B. de Koning: 0000-0003-4525-5130
Till Opatz: 0000-0002-3266-4050
Joseph P. Michael: 0000-0002-2307-8068
Author Contributions
The authors declare no competing financial interests. All authors
have given approval to the final version of the manuscript.
ACKNOWLEDGMENTS
The authors thank the South African National Research
Foundation (NRF; grant numbers 85964, 93447 and 105839), the
University of the Witwatersrand and the German Federal Ministry
of Education and Research (BMBF; grant number 01DG17013)
for funding the project, and for providing bursaries to RK. We are
grateful to Professor W. A. L. van Otterlo (University of
Stellenbosch) for discussions, and to Drs G. L. Morgans and S. M.
Scalzullo for preliminary investigations.
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