Synthesis of Lamellarin D Trimethyl Ether and Lamellarin H via 6π-Electrocyclization

Article abstract of DOI:10.1021/acs.joc.5b02194

An electrocyclic ring closure of a 2-azapentadienyl anion generated in situ from a chalcone and glycine ester is the key step of an efficient synthesis of the pyrrole core of the lamellarin alkaloids. A recently developed scalable one-pot procedure provides multigram quantities of a 3,5-diaryl-4-iodopyrrole-2-carboxylate intermediate which is transformed in four further high-yielding operations including a one-pot Pomeranz-Fritsch alkylation/cyclization and an Ullmann-type lactone ring closure into the pentacyclic lamellarin skeleton.

Full text of DOI:10.1021/acs.joc.5b02194

Note
pubs.acs.org/joc
Synthesis of Lamellarin D Trimethyl Ether and Lamellarin H via 6π-
Electrocyclization
Clemes Dialer,‡ Dennis Imbri,‡ Steven Peter Hansen, and Till Opatz*
Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany
S
* Supporting Information
ABSTRACT: An electrocyclic ring closure of a 2-azapentadienyl anion generated in situ from a chalcone and glycine ester is the
key step of an efficient synthesis of the pyrrole core of the lamellarin alkaloids. A recently developed scalable one-pot procedure
provides multigram quantities of a 3,5-diaryl-4-iodopyrrole-2-carboxylate intermediate which is transformed in four further high-
yielding operations including a one-pot Pomeranz−Fritsch alkylation/cyclization and an Ullmann-type lactone ring closure into
the pentacyclic lamellarin skeleton.
he lamellarins are a large group of polycyclic marine
pyrrole alkaloids highly renowned for their potent
planarity of the ABCDE-ring system which is ensured by the
5,6-double bond.2
T
Since their discovery in 1985 by Faulkner,17 more than 50
lamellarins have been isolated, mainly from prosobranch
molluscs of the genus Lamellaria.3 Their attractive structure
has made them the target of diverse synthetic approaches18−24
which were reviewed in 2014.25 Here, we report on the
application of a recently developed one-pot synthesis of 3,5-
diaryl-4-halopyrrole-2-carboxylates and its extension to a fully
modular access to the type 1b lamellarins.
cytotoxic activity against a variety of human cancer cell
lines.1−9 On the basis of their molecular skeletons, the
lamellarins are commonly subdivided into three groups. A
pentacyclic framework of the 6H-chromeno[4′,3′:4,5]pyrrolo-
[2,1-a]isoquinolin-6-one type is characteristic for the type 1a
(partially saturated) and 1b (fully unsaturated) lamellarins,
while the less abundant and structurally simpler type 2
lamellarins contain an unfused 3,4-diarylpyrrole core (Figure
1).2,3,7,10,11
Class 1b comprises the representatives with the most potent
biological activities such as lamellarin D,1,6,8,12−15 for which a
multidrug resistance reversal activity and a strong proapoptotic
effect through the inhibition of human topoisomerase I has
been reported.4,15,16 The bioactivity correlates with the
Pyrrole-2-carboxylates represent useful intermediates in the
synthesis of more complex heterocyclic systems and are the
core structure of all existing lamellarins. In 2014, we reported a
facile method for their preparation by means of a cyclo-
condensation of enones A with glycine esters via the 6π-
electrocyclization of intermediate 2-azapentadienyl anions C
followed by dehydrogenation (Scheme 1).26
If chalcones are employed as the electrophilic component,
3,5-diarylpyrrole-2-carboxylates E are obtained and the
unsubstituted 4-position in the products can be halogenated
in situ. Introduction of the third aryl moiety (ring F) to the
pyrrole core in a Suzuki coupling allows the completion of the
ring system of the type 1b lamellarins in only three additional
operations. The annellation of the B-ring can be achieved in a
Received: September 18, 2015
Figure 1. Structure of lamellarins type 1a, 1b, and 2.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02194
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
with glycine ethyl ester hydrochloride (5) in refluxing pyridine
followed by oxidation of the in situ formed Δ1-pyrroline with
stoichiometric amounts of copper(II) acetate and regioselective
iodination of the resulting pyrrole with N-iodosuccinimide.
Thus, iodopyrrole 6 could be obtained in 39% yield (gram
scale) in a one-pot, three-step reaction sequence. However,
changing the order and timing of reactant addition permitted a
significant improvement. Addition of a pyridine solution of
enone 4 to a refluxing solution of glycine ester 5 in pyridine
afforded iodopyrrole 6 in 74% yield. A low initial concentration
of the glycine ester proved beneficial as concentrated solutions
readily form self-condensation products upon heating as judged
by HPLC/MS or TLC.
Scheme 1. Three-Step Synthesis of Halopyrrole F
Introduction of the F ring moiety was accomplished by
Suzuki−Miyaura cross-coupling with commercial 3,4-
dimethoxyphenylboronic acid (7). While numerous closely
related reactions have been reported,27,32,34 none of these was
designed to tolerate a potentially competing second halide, i.e.,
the bromine required for the lactone ring closure. Solvent, base,
and catalyst screening revealed that intermediate 6 should be
reacted with only a slight excess (1.05 equiv) of boronic acid 7
in the presence of Cs2CO3 and a catalytic amount of Pd(PPh3)4
under inert atmosphere in a degassed mixture of 1,4-dioxane/
H2O at 100−110 °C for at least 12 h. Under optimized
conditions, the cross-coupling furnished intermediate 8 in high
yield (86%), which was subsequently N-alkylated with
bromoacetaldehyde dimethyl acetal in DMF at 110 °C within
16 h. For analytical characterization, the N-alkylated
intermediate was purified by column chromatography, but
otherwise, the crude product was directly transformed into
isoquinoline 9 in a TfOH-mediated38 intramolecular cyclization
in 93% yield from pyrrole 8.27 Treatment of 9 with copper(I)
thiophene-2-carboxylate (CuTC) under microwave irradiation
without prior hydrolysis of the ester failed as expected, and the
dealkoxycarbonylated pyrrole was detected by HPLC/MS
instead. For the saponification, it appeared to be important to
use a minimum amount of a THF/MeOH (1:1) mixture with
aqueous 3 M NaOH (6 equiv) in order to avoid trans-
esterification to the methyl ester. Cyclization of the crude
sodium carboxylate with CuTC (1.2 equiv) in DMF under
microwave irradiation furnished lamellarin D trimethyl ether
(10) in 92% yield from ester 9. Its complete O-demethylation
with BBr3 furnished lamellarin H (11) in 97% yield.
two-step Pomeranz−Fritsch-type cyclization sequence through
prior N-alkylation with bromoacetaldehyde dimethyl acetal and
subsequent electrophilic closure of the 6,6a-bond under acidic
conditions.27 Finally, the lactone ring D can be closed in a one-
pot operation involving the saponification of the ester to the
carboxylate salt followed by a Cu-mediated Ullmann-type ring
closure onto a preinstalled bromide (position 18, Figure 1).
The latter reaction had been successfully employed by
Ruchirawat in their synthesis of iso-28 and azalamellarins29 as
well as by us in a high-yielding lamellarin synthesis based on α-
aminonitrile chemistry.30 It requires stoichiometric amounts of
copper(I) due to the poor nucleophilicity of the carboxylate.
The retrosynthetic strategy is depicted in Scheme 2.
Scheme 2. Retrosynthetic Approach
In summary, a very high yielding and fully modular strategy
for the synthesis of the type 1b lamellarins with an early
diversification of the pyrrole core has been devised. Its key
steps are an electrocyclic ring closure of an in situ formed 2-
azapentadienyl anion and an Ullmann-like lactone formation.
Starting from commercially available 6-bromoveratraldehyde
(2), the trimethyl ether analogue of the highly bioactive
lamellarin D could be prepared in 43% yield over nine linear
steps, combined into six discrete transformations. In addition,
the alkaloid lamellarin H was obtained in 41% yield over 10
linear steps. This corresponds to an average per step efficiency
of 91% in both cases and compares nicely with the most
efficient syntheses of the class 1b lamellarins reported so far.25
To the best of our knowledge, intermediate 6 carries a
substitution pattern hitherto unexploited for lamellarin syn-
thesis.25 It allows the amalgamation of Banwell’s and Handy’s
iterative cross-coupling concept for the decoration of the
pyrrole moiety with Iwao’s intramolecular TfOH-mediated
cyclization strategy for the unsaturated B-ring and turned out to
provide high yields and operational simplicity.10,24,27,31−34
The synthesis started with commercial 6-bromoveratralde-
hyde (2), which can alternatively be obtained by bromination
of veratraldehyde (1) with elemental bromine in 92% yield
(Scheme 3).35
EXPERIMENTAL SECTION
■
General Methods. All reactions involving air- or moisture-
sensitive reagents or intermediates were performed under an inert
atmosphere of argon in glassware that was oven-dried. Reaction
temperatures refer to the temperature of the particular cooling/heating
bath. Microwave-assisted reactions were carried out in a monomode
The subsequent aldol condensation with commercial
acetoveratrone (3) was accomplished under basic conditions
(NaOH) in 78% yield.36,37 In the key step, enone 4 was reacted
B
DOI: 10.1021/acs.joc.5b02194
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 3. Synthetic Route to Lamellarin D Trimethyl Ether and Lamellarin H
microwave apparatus using the built-in external infrared sensor for
temperature monitoring. All reagents were reagent grade and were
used without further purification unless otherwise noted. Pyridine
(99+%, extra dry) and DMF (99+%, extra dry) were purchased from
commercial suppliers and were used without further purification.
Copper(I) thiophene-2-carboxylate (CuTC) was synthesized accord-
ing to the procedure of Liebeskind et al.39 Melting points were
determined in open capillary tubes using an electronic apparatus with a
resolution of 0.1 °C. NMR spectra were recorded on a 300 or 400
MHz spectrometer equipped with a 5 mm BBFO probehead with z-
gradient and ATM capability. Chemical shifts were referenced to the
deuterated solvent (for CDCl3, δ = 7.26 and 77.16 ppm, for DMSO-d6,
δ = 2.50 and 39.52 ppm, for CD3OD, δ = 3.31 and 49.00 ppm, and for
pyridine-d5 δ = 8.74 and 150.35 ppm for 1H and 13C NMR,
respectively) and reported in parts per million (ppm, δ) relative to
tetramethylsilane (TMS, δ = 0.00 ppm).40 Coupling constants (J) are
reported in hertz, and the splitting abbreviations used were as follows:
s, singlet; d, doublet; t, triplet; quartet, q; m, multiplet; br, broad.
Standard pulse sequences were used for the 2D experiments. Infrared
spectra were recorded as FT-IR spectra using a diamond ATR unit and
are reported in terms of frequency of absorption (ν, cm−1). High-
resolution masses were recorded on a QToF-Instrument with a dual
electrospray source and a suitable external calibrant. Thin-layer
chromatography (TLC) was carried out on 0.25 mm silica gel plates
(60F254) using UV light as visualizing agent, an ethanolic solution of
hydrochloric acid and 4-(dimethylamino)benzaldehyde (Ehrlich’s
reagent) or an ethanolic solution of diluted aqueous hydrochloric
acid and 2,4-dinitrophenylhydrazine (DNPH reagent), and heat as
developing agent. Chromatography was performed using flash
chromatography of the indicated solvent system on 35−70 μm silica
gel unless otherwise indicated.
The reaction mixture was quenched with a saturated aqueous solution
of Na2S2O3 (300 mL), the contained MeOH was evaporated in vacuo,
and the aqueous residue was extracted with CH2Cl2 (3 × 200 mL).
The organic layer was washed with brine (500 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude product was
recrystallized from 2-propanol to afford the title compound as
colorless needles (20.31 g, 92%): Rf = 0.51 (silica gel, cyclohexane/
ethyl acetate = 2:1); mp 148.5−149.5 °C (lit.30 mp 144−145 °C); IR
(ATR) ν (cm−1) = 3009, 1667, 1585, 1503, 1398, 1269, 1154, 1015,
1
866, 737; H NMR (300 MHz, CDCl3) δ (ppm) = 10.18 (s, 1H,
CHO), 7.41 (s, 1H, H-6), 7.05 (s, 1H, H-3), 3.96 (s, 3H, OCH3), 3.92
(s, 3H, OCH3); 13C NMR (100.6 MHz, CDCl3) δ (ppm) = 190.9
(CO), 154.6 (C4), 149.0 (C5), 126.7 (C1), 120.6 (C2), 115.6 (C3),
110.6 (C6), 56.7 (OCH3), 56.3 (OCH3); ESI-HRMS calcd for
[C9H9(79Br)O3 + H]+ 244.9813, found 244.9824. The data are in
accordance with the literature.30,35
3-(2-Bromo-4,5-dimetohxyphenyl)-1-(3,4-dimethoxyphenyl)-
propen-1-one (4). 6-Bromoveratraldehyde (2) (5.00 g, 20.40 mmol,
1.00 equiv) and acetoveratrone (3) (6.25 g, 34.68 mmol, 1.70 equiv)
were suspended in EtOH (155 mL) and heated to reflux to form a
clear solution. The addition of 3 N aqueous NaOH (7.89 mL, 23.67
mmol, 1.16 equiv) effected the formation of a yellow precipitate a few
minutes later. The reaction mixture was stirred under reflux for 1 h
followed by suction filtration and washing with EtOH (2 × 10 mL).
The residue was dissolved in DCM, dried over anhydrous Na2SO4,
filtered, and finally concentrated to dryness in vacuo to yield the title
compound as an intensely yellow amorphous solid (6.48 g, 78%): Rf =
0.27 (silica gel, cyclohexane/ethyl acetate = 2:1); mp 166.5−167.4 °C
(lit.37 166−167 °C); IR (ATR) ν (cm−1) = 3012, 2840, 1652, 1593,
1
1501, 1256, 1159, 1021, 832, 749; H NMR, COSY, NOESY (400
MHz, CDCl3) δ (ppm) = 8.03 (d, J = 15.6 Hz, 1H, H-3), 7.65 (dd, J =
8.4, 2.0 Hz, 1H, H-6′), 7.59 (d, J = 2.0 Hz, 1H, H-2′), 7.29 (d, J = 15.6
Hz, 1H, H-2), 7.18 (s, 1H, H-6″), 7.06 (s, 1H, H-3″), 6.92 (d, J = 8.4
Hz, 1H, H-5′), 3.96 (s, 3H, OCH3-4′), 3.95 (s, 3H, OCH3-3′), 3.94 (s,
3H, OCH3-5″), 3.90 (s, 3H, OCH3-4″); 13C NMR (100.6 MHz,
2-Bromo-4,5-dimethoxybenzaldehyde (2). To a solution of
veratraldehyde (15.00 g, 90.26 mmol, 1.00 equiv) in MeOH (675
mL) was added dropwise Br2 (4.86 mL, 94.78 mmol, 1.05 equiv)
during 15 min at room temperature with subsequent stirring overnight.
C
DOI: 10.1021/acs.joc.5b02194
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
CDCl3) δ (ppm) = 189.0 (C1), 153.3 (C4′), 151.5 (C4″), 149.3
(C3′), 148.7 (C5″), 142.6 (C3), 131.3 (C1′), 127.2 (C1″), 123.2
(C6′), 122.9 (C2), 117.9 (C2″), 115.8 (C3″), 111.0 (C2′), 110.0
(C5′), 109.6 (C6″), 56.4 (OCH3), 56.3 (OCH3), 56.20 (OCH3),
56.16 (OCH3); ESI-HRMS calcd for [C19H19(79Br)O5 + H]+
407.0494, found 407.0488. The data are in accordance with the
literature.26,37
(C3′), 114.7 (C6′), 113.8 (C2″), 111.3 (C5‴), 111.1 (C2‴), 110.8
(C5″), 60.4 (OCH2CH3), 56.2 (OCH3-4′), 56.1 (OCH3-4‴), 56.0
(OCH3-5′), 55.83 (OCH3-4″), 55.81 (OCH3-3‴), 55.7 (OCH3-3″),
14.3 (OCH2CH3); ESI-HRMS calcd for [C31H32(79Br)NO8 + Na]+
648.1209, found 648.1215.
Ethyl 2-(2-Bromo-4,5-dimethoxyphenyl)-1-(3,4-dimethoxyphen-
yl)-8,9-dimethoxypyrrolo[2,1-a]isoquinoline-3-carboxylate (9). Pyr-
role 8 (1.00 g, 1.60 mmol, 1.00 equiv) and Cs2CO3 (3.12 g, 9.58
mmol, 6.00 equiv) were placed in an oven-dried Schlenk vessel and
dissolved in dry DMF (17 mL). Bromoacetaldehyde dimethyl acetal
(1.13 mL, 1.62 g, 9.58 mmol, 6.00 equiv) was added to the mixture via
syringe in one portion, followed by sealing the vessel and heating the
reaction mixture to 110 °C for 16 h. Complete conversion was
confirmed by HPLC/MS or TLC before the mixture was allowed to
reach room temperature followed by dilution with H2O (20 mL) and
DCM (35 mL). The organic layer was separated, and the aqueous
layer was washed with DCM (2 × 35 mL). The organic layers were
combined, subsequently washed with an aqueous LiCl solution (5%,
50 mL, to remove DMF) and H2O (2 × 50 mL), and dried over
Na2SO4. Evaporation of the solvent in vacuo afforded the crude title
compound as a yellowish viscous oil or an orange foam which can be
used for the next step without further purification. Alternatively, the
crude product can be purified by flash column chromatography (basic
aluminum oxide, Brockmann activity grade I, cyclohexane/ethyl
acetate = 3:1). Thus, the N-alkylated pyrrole derivative of 8 was
obtained (1.12 g, 98%) as a colorless amorphous solid: Rf = 0.33 (silica
gel, cyclohexane/ethyl acetate = 1:1, 2% triethylamine); IR (ATR) ν
(cm−1) = 2936, 2836, 1691, 1437, 1415, 1256, 1128, 1092, 1027, 863;
1H NMR, COSY, NOESY (400 MHz, CD3OD) δ (ppm) = 7.13 (s,
Ethyl 3-(2-Bromo-4,5-dimethoxyphenyl)-5-(3,4-dimethoxyphen-
yl)-4-iodo-1H-pyrrole-2-carboxylate (6). Glycine ethyl ester hydro-
chloride (5) (1.18 g, 8.47 mmol, 1.15 equiv) was placed in a two-
necked round-bottom flask equipped with a reflux condenser, and
pyridine (60 mL) was added. The suspension was heated to reflux, and
a solution of enone 4 (3.00 g, 7.37 mmol, 1.00 equiv) in pyridine (90
mL) was added dropwise to the clear and colorless refluxing solution.
Stirring and reflux were maintained for at least 24 h, and then a
solution of copper(II) acetate (2.68 g, 14.73 mmol, 2.00 equiv) in
pyridine (115 mL) was added continuously within 15 min to the
refluxing brown solution. After 4 h, the temperature of the oil bath was
lowered to 70 °C and a solution of N-iodosuccinimide (2.07 g, 9.21
mmol, 1.25 equiv) in acetonitrile (75 mL) was added continuously
within 15 min. The reaction mixture was kept at 70 °C for an
additional 6 h and then concentrated in vacuo. The residual pyridine
was removed by azeotropic distillation with toluene (2 × 100 mL).
Further purification was conducted by flash column chromatography
(silica gel, cyclohexane/ethyl acetate = 3:1) to afford the title
compound as a light yellow to colorless crystalline solid (3.35 g, 74%):
Rf = 0.61 (silica gel, cyclohexane/ethyl acetate = 1:1); mp 197.3−199.6
°C; IR (ATR) ν (cm−1) = 3280, 2936, 2838, 1671, 1506, 1432, 1250,
1208, 1178, 1025, 730; 1H NMR, COSY, NOESY (400 MHz, CDCl3)
δ (ppm) = 9.56 (br s, 1H, NH), 7.32 (d, J = 2.1 Hz, 1H, H-2″), 7.25
(dd, 3J = 8.4 Hz, 4J = 2.1 Hz, 1H, H-6″), 7.13 (s, 1H, H-3′), 6.96 (d, J
= 8.4 Hz, 1H, H-5″), 6.77 (s, 1H, H-6′), 4.18−4.04 (m, 2H,
OCH2CH3), 3.96 (s, 3H, OCH3-3″), 3.933 (s, 3H, OCH3-4″), 3.925
(s, 3H, OCH3-4′), 3.87 (s, 3H, OCH3-5′), 1.07 (t, J = 7.1 Hz, 3H,
OCH2CH3); 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3) δ
(ppm) = 160.5 (CO), 149.6 (C4″), 149.1 (C4′), 149.0 (C3″), 147.9
(C5′), 136.4 (C5), 135.1 (C3), 129.2 (C1′), 124.1 (C1″), 121.0 (C2),
120.8 (C6″), 115.1 (C2′), 115.0 (C3′), 114.6 (C6′), 111.6 (C2″),
111.3 (C5″), 69.7 (C4), 60.7 (OCH2CH3), 56.3 (OCH3), 56.25
(OCH3), 56.23 (OCH3), 56.1 (OCH3), 14.1 (OCH2CH3); ESI-
HRMS calcd for [C23H23(79Br)INO6 + Na]+ 637.9651, found
637.9657.
1H, H-3′), 6.951 (d, J = 8.3 Hz, 1H, H-5‴), 6.948 (d, J = 1.9 Hz, 1H,
H-2‴), 6.89 (dd, 3J = 8.2 Hz, 4J = 1.9 Hz, 1H, H-6‴), 6.70 (s, 1H, H-
6′), 6.57 (d, J = 8.3 Hz, 1H, H-5″), 6.49 (d, J = 2.0 Hz, 1H, H-2″),
3
4
6.42 (dd, J = 8.3 Hz, J = 2.0 Hz, 1H, H-6″), 4.56−4.52 (m, 1H,
NCH2CH(OCH3)2), 4.52−4.43 (m, 2H, NCH2CH(OCH3)2) 4.04
(m, 2H, OCH2CH3), 3.83 (s, 3H, OCH3-4‴), 3.81 (s, 3H, OCH3-4′),
3.70 (s, 3H, OCH3-3‴), 3.67 (s, 3H, OCH3-4″), 3.62 (s, 3H, OCH3-
5′), 3.42 (s, 3H, OCH3-3″), 3.28 (s, 3H, NCH2CH(OCH3)2), 3.26 (s,
3H, NCH2CH(OCH3)2), 0.95 (t, J = 7.1 Hz, 3H, OCH2CH3); 13C
NMR, HSQC, HMBC (100.6 MHz, CD3OD) δ (ppm) = 161.3 (C
O), 150.6 (C4‴), 150.2 (C3‴), 150.2 (C4′), 149.4 (C3″), 149.3
(C5′), 148.4 (C4″), 139.6 (C5), 132.5 (C3), 131.8 (C1′), 128.6
(C1″), 125.8 (C6‴), 125.3 (C1‴), 125.1 (C4), 123.9 (C6″), 121.1
(C2), 117.1 (C2′), 116.69 (C6′), 116.67 (C5‴), 116.4 (C3′), 115.3
(C2″), 112.6 (C2‴), 112.1 (C5″), 106.3 (NCH2CH(OCH3)2), 60.9
(OCH2CH3), 56.8 (OCH3-4‴), 56.6 (OCH3-3‴), 56.5 (OCH3-3″),
56.4 (OCH3-4′), 56.2 (OCH3-4″), 56.1 (OCH3-5′), 56.0 (NCH2CH-
(OCH3)2), 55.8 (NCH2CH(OCH3)2), 49.1 (NCH2CH(OCH3)2),
14.1 (OCH2CH3); ESI-HRMS calcd for [C35H40(79Br)NO10 + Na]+
736.1734, found 736.1730.
Ethyl 3-(2-Bromo-4,5-dimethoxyphenyl)-4,5-bis(3,4-dimethoxy-
phenyl)-1H-pyrrole-2-carboxylate (8). Iodopyrrole 6 (1.00 g, 1.62
mmol, 1.00 equiv), 3,4-dimethoxyphenylboronic acid (7) (0.31 g, 1.70
mmol, 1.05 equiv), Cs2CO3 (1.06 g, 3.25 mmol, 2.00 equiv), and
Pd(PPh3)4 (47 mg, 2.5 mol %) were placed in an oven-dried Schlenk
tube, and the mixture was dissolved in a degassed 1,4-dioxane/water
mixture (3:1, 38 mL). Alternatively, Pd(PPh3)4 may be introduced
after addition of the solvent mixture, which is then degassed prior to
catalyst addition. After being purged with argon, the tube was sealed
and heated to 110 °C during a period of 24 h. The solvent was
removed in vacuo by azeotropic distillation with toluene (2 × 25 mL).
Purification by flash column chromatography (silica gel, cyclohexane/
ethyl acetate = 3:1) yielded the title compound (0.87 g, 86%) as
colorless crystals: Rf = 0.44 (silica gel, cyclohexane/ethyl acetate =
1:1); mp 155.2−157.0 °C; IR (ATR) ν (cm−1) = 3307, 2937, 1667,
The crude N-alkylated pyrrole (1.03 g, 1.44 mmol) was dissolved in
dry DCM (22 mL) and cooled to 0 °C. Anhydrous TfOH (0.19 mL,
0.32 g, 2.16 mmol, 1.50 equiv) was diluted with dry DCM (8 mL), and
the solution was added dropwise to the mixture within 10 min. After
complete addition, the mixture was allowed to reach room
temperature and stirred for 1 h with subsequent addition of
NaHCO3 (2 g). In order to permit better miscibility and facilate
neutralization, dry ethanol (7 mL) was carefully added. The mixture
was filtered, the filter cake was washed thoroughly with DCM, and the
combined extracts were concentrated in vacuo. The resulting oil was
diluted with DCM (35 mL), filtered from any residual salts and
washed with DCM (2 × 20 mL). Final purification by flash column
chromatography (silica gel, cyclohexane/ethyl acetate = 3:1) gave the
title compound (0.89 g, 95%) as a bright yellow crystalline solid (93%
over two steps). In NMR, the compound was found to exist as a
mixture of two rotamers (R1:R2 = 3:2): Rf = 0.40 (silica gel,
cyclohexane/ethyl acetate = 1:1); mp 106.6−108.6 °C; IR (ATR) ν
(cm−1) = 2935, 2836, 1677, 1403, 1379, 1251, 1136, 1069, 1026, 751;
1H NMR, COSY, NOESY (400 MHz, CDCl3) δ (ppm) = 9.35 (d, J =
7.5 Hz, 1H, H-5), 7.23 (R1, s, 0.6H, H-10), 7.16 (R2, s, 0.4H, H-10),
7.02 (s, 1H, H-7), 6.98 (s, 1H, H-3″), 6.97 (d, J = 7.5 Hz, 1H, H-6),
1
1507, 1432, 1251, 1026, 914, 861, 730; H NMR, COSY, NOESY
(400 MHz, CDCl3) δ (ppm) = 9.22 (br s, 1H, NH), 7.02 (s, 1H, H-
3′), 6.97 (dd, 3J = 8.4 Hz, 4J = 2.1 Hz, 1H, H-6‴), 6.83 (d, J = 8.4 Hz,
1H, H-5‴), 6.82 (d, J = 2.1 Hz, 1H, H-2‴), 6.66 (d, J = 8.9 Hz, 1H, H-
5″), 6.62 (d, J = 1.8 Hz, 1H, H-2″), 6.62 (s, 1H, H-6′), 6.62 (dd, 3J =
4
8.9 Hz, J = 1.8 Hz, 1H, H-6″), 4.25−4.09 (m, 2H, OCH2CH3), 3.88
(s, 3H, OCH3-4‴), 3.86 (s, 3H, OCH3-4′), 3.80 (s, 3H, OCH3-4″),
3.67 (s, 3H, OCH3-5′), 3.63 (s, 3H, OCH3-3‴), 3.58 (s, 3H, OCH3-
3″), 1.11 (t, J = 7.1 Hz, 3H, OCH2CH3); 13C NMR, HSQC, HMBC
(100.6 MHz, CDCl3) δ (ppm) = 161.3 (CO), 148.9 (2C, C3‴,
C4‴), 148.6 (C4″), 148.4 (C3″), 147.7 (C5′), 147.5 (C4′), 132.3
(C5), 130.5 (C3), 128.7 (C1′), 127.1 (C1″), 124.5 (C1‴), 123.6
(C4), 122.8 (C6″), 119.8 (C6‴), 119.4 (C2), 115.7 (C2′), 114.8
D
DOI: 10.1021/acs.joc.5b02194
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
6.93 (dd, 3J = 8.1 Hz, 4J = 1.9 Hz, 1H, H-6′), 6.90 (R1, d, J = 1.9 Hz,
0.6H, H-2′), 6.87 (R2, d, J = 1.9 Hz, 0.4H, H-2′), 6.84 (R1, d, J = 8.1
Hz, 0.6H, H-5′), 6.82 (R2, d, J = 8.1 Hz, 0.4H, H-5′), 6.66 (R2, s,
0.4H, H-6″), 6.60 (R1, s, 0.6H, H-6″), 4.21−4.13 (m, 1H,
OCH2CH3), 4.11−4.02 (m, 1H, OCH2CH3), 3.95 (s, 3H, OCH3-8),
3.85 (s, 3H, OCH3-4′), 3.84 (s, 3H, OCH3-4″), 3.74 (R2, s, 1.2H,
OCH3-3′), 3.72 (R1, s, 1.8H, OCH3-3′), 3.68 (R2, s, 1.2H, OCH3-5″),
3.67 (R1, s, 1.8H, OCH3-5″), 3.45 (R1, s, 1.8H, OCH3-9), 3.43 (R2, s,
1.2H, OCH3-9), 0.97 (t, J = 7.1 Hz, 3H, OCH2CH3); 13C NMR,
HSQC, HMBC (100.6 MHz, CDCl3) δ (ppm) = 161.8 (CO), 149.4
(C8), 149.0 (C9), 148.8 (R1, C3′), 148.6 (R2, C3′), 148.43 (R1,
C4″), 148.36 (R2, C4″), 148.14 (R2, C4′), 148.07 (R1, C4′), 147.5
(R1, C5″), 147.4 (R2, C5″), 134.8 (R1, C1″), 134.7 (R2, 1″), 130.3
(R2, C10b), 130.2 (R1, C10b), 129.8 (R1, C2), 129.6 (R2, C2), 128.3
(R1, C1′), 128.0 (R2, C1′), 124.0 (R2, C6′), 123.7 (C5), 123.6 (C6a),
123.5 (R1, C6′), 119.84 (R1, 10a), 119.79 (R2, 10a), 118.22 (R1, C1),
118.20 (R2, C1), 115.39 (R2, C2″), 115.36 (R1, C2″), 114.6 (R1,
C2′), 114.54 (2C, R2-C2′, R2, C6″), 114.52 (R1, C6″), 114.4 (R2,
C3″), 114.3 (R1, C3″), 112.7 (C3), 112.39 (R2, C6), 112.36 (R1,
C6), 111.3 (R2, C5′), 110.6 (R1, C5′), 107.2 (C7), 105.2 (C10), 59.7
(OCH2CH3), 56.2 (C4′), 56.1 (R1, C5″), 56.02 (R2, C5″), 56.98 (2C,
C8, C4″), 55.9 (R2, C3′), 55.8 (R1, C3′), 55.43 (R1, OCH3-9), 55.39
(R2, OCH3-9), 13.9 (OCH2CH3); ESI-HRMS calcd for
[C33H32(79Br)NO8 + Na]+ 672.1209, found 672.1198.
Lamellarin H (11). To a stirred solution of 10 (100 mg, 0.19 mmol,
1.00 equiv) in dry DCM (19 mL) under nitrogen, BBr3 (3.32 mL, 3.32
mmol, 1 M in heptane, 18.00 equiv) was added dropwise at −78 °C.
This temperature was maintained for another 15 min followed by
removal of the cooling bath. The dark-red solution was stirred for an
additional 20 h at room temperature and then quenched by addition of
MeOH (10 mL). The solvent was removed and the residue suspended
in water (20 mL) followed by extraction with ethyl acetate (3 × 20
mL). The combined organic layers were dried over anhydrous
Na2SO4, and the solvent was concentrated in vacuo. Upon treatment
of the brown residue with a mixture of DCM/MeOH (1:2), lamellarin
H (11) was obtained (82 mg, 97%) as a brownish amorphous solid: Rf
= 0.37 (silica gel, ethyl acetate/methanol = 4:1); mp >300 °C; IR
(ATR) ν (cm−1) = 3300, 1701, 1627, 1553, 1474, 1428, 1281, 1188,
1022, 979; 1H NMR, COSY, NOESY (400 MHz, DMSO-d6) δ (ppm)
= 9.99 (br s, OH), 9.76 (br s, OH), 9.42 (br s, OH), 9.20 (br s, 2OH),
8.99 (d, J = 7.3 Hz, 1H, H-5), 8.91 (br s, OH), 7.14 (d, J = 7.3 Hz, 1H,
H-6), 7.13 (s, 1H, H-7), 6.99 (d, 3J = 8.0 Hz, 1H, H-13), 6.95 (s, 1H,
4
H-10), 6.81 (s, 1H, H-19), 6.79 (d, J = 2.0 Hz, 1H, H-16), 6.71 (dd,
4
3J = 8.0 Hz, J = 2.0 Hz, 1H, H-12), 6.57 (s, 1H, H-22); 13C NMR,
HSQC, HMBC 100.6 MHz, DMSO-d6) δ (ppm) = 154.5 (C23),
147.7 (C8), 146.8 (C20), 146.6 (C9), 146.2 (C15), 145.5 (C14),
145.3 (C18), 142.1 (C21), 133.9 (C10b), 128.9 (C2), 125.4 (C11),
123.8 (C6a), 121.4 (C12), 121.2 (C5), 118.1 (C10a), 117.6 (C16),
117.0 (C13), 112.6 (C6), 111.41 (C7), 111.39 (C1), 109.62 (C10),
109.56 (C22), 108.8 (C17), 106.3 (C3), 103.3 (C19); ESI-HRMS
calcd for [C25H15NO8 + H]+ 458.0876, found 458.0887. The data are
in accordance with the literature (compounds 2 in ref 42 and 5 in ref
43).
Lamellarin D Trimethyl Ether (10). To a solution of seco-precursor
9 (142 mg, 0.22 mmol, 1.00 equiv) in THF/MeOH (1:1, 3.17 mL) in
a Schlenk tube was added 3 N aqueous NaOH (0.44 mL, 1.31 mmol,
6.00 equiv) in one portion and the mixture was heated to 64 °C
overnight. After having confirmed complete conversion to the
carboxylate by HPLC−MS, the solvent mixture was evaporated and
the residue transferred into a microwave reaction vessel (volume: 10
mL), dissolved in dry DMF (1.90 mL), and mixed with copper(I)
thiophene-2-carboxylate (CuTC, 50 mg, 0.26 mmol, 1.20 equiv). The
vial was sealed, and the reaction mixture was irradiated via microwave
(140 °C, 230 W, 40 min, p < 2 bar). The mixture was concentrated to
dryness in vacuo, and the residue was purified by silica gel filtration
(DCM/ethyl acetate = 20:1). Final recrystallization from MeOH
afforded the title compound as colorless plates (109 mg, 92%): Rf =
0.50 (silica gel, DCM/ethyl acetate, 10:1); mp 278.5−279.8 °C (lit.41
mp >250 °C); IR (ATR) ν (cm−1) = 2936, 2836, 1697, 1490, 1414,
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02194.
1H and 13C NMR spectra of all synthesized compounds
(PDF)
AUTHOR INFORMATION
1
■
1265, 1222, 1138, 1009, 727; H NMR, COSY, NOESY (400 MHz,
pyridine-d5) δ (ppm) = 9.52 (d, 3J = 7.3 Hz, 1H, H-5), 7.56 (d, J = 2.0
Hz, 1H, H-16), 7.46 (dd, 3J = 8.1 Hz, 4J = 2.0 Hz, 1H, H-12), 7.39 (s,
1H, H-10), 7.38 (s, 1H, H-7), 7.35 (d, J = 8.1 Hz, 1H, H-13), 7.26 (d, J
= 7.3 Hz, 1H, H-6), 6.90 (s, 1H, H-19), 6.73 (s, 1H, H-22), 4.00 (s,
3H, OCH3-15), 3.95 (s, 3H, OCH3-14), 3.91 (s, 3H, OCH3-8), 3.81
(s, 3H, OCH3-20), 3.47 (OCH3-21), 3.46 (OCH3-9); 13C NMR,
HSQC, HMBC (100.6 MHz, pyridine-d5) δ (ppm) = 155.9 (C23),
151.6 (C15), 151.5 (C8), 151.0 (C20), 150.6 (C14), 150.4 (C9),
147.8 (C18), 146.8 (C21), 134.9 (C10b), 130.0 (C2), 129.1 (C11),
125.7 (C6a), 125.0 (C12), 123.4 (C5), 120.0 (C10a), 116.2 (C16),
114.1 (C13), 113.4 (C6), 112.0 (C1), 110.8 (C17), 108.9 (C7), 108.7
(C3), 106.6 (C22), 106.3 (C10), 101.9 (C19), 56.9 (OCH3-15), 56.8
(OCH3-8), 56.5 (OCH3-20), 56.3 (OCH3-14), 55.8 (OCH3-9), 55.5
Corresponding Author
*E-mail: opatz@uni-mainz.de.
Author Contributions
‡C.D. and D.I. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. J. C. Liermann (Mainz) for NMR spectroscopy
and L. Heidary-Fard (Mainz) for technical assistance. Financial
support from the Carl-Zeiss foundation (project Chem-
BioMed) is gratefully acknowledged.
1
(OCH3-21); H NMR, COSY, NOESY (400 MHz, CDCl3) δ (ppm)
3
3
4
= 9.20 (d, J = 7.3 Hz, 1H, H-5), 7.23 (dd, J = 8.1 Hz, J = 1.9 Hz,
1H, H-12), 7.17 (d, J = 1.9 Hz, 1H, H-16), 7.164 (s, 1H, H-10), 7.162
(d, J = 8.1 Hz, 1H, H-13), 7.08 (s, 1H, H-7), 7.03 (d, J = 7.3 Hz, 1H,
H-6), 6.90 (s, 1H, H-19), 6.73 (s, 1H, H-22), 3.99 (s, 3H, OCH3-15),
3.98 (s, 3H, OCH3-8), 3.89 (s, 3H, OCH3-14), 3.87 (s, 3H, OCH3-
20), 3.48 (OCH3-21), 3.47 (OCH3-9); 13C NMR, HSQC, HMBC
(100.6 MHz, CDCl3) δ (ppm) = 155.6 (C23), 150.3 (C8), 150.0
(C14), 149.7 (C20), 149.3 (C9), 149.2 (C15), 146.8 (C18), 145.7
(C21), 134.5 (C10b), 129.5 (C2), 128.4 (C11), 125.0 (C6a), 124.3
(C12), 123.4 (C5), 119.2 (C10a), 114.6 (C16), 112.5 (C6), 112.1
(C13), 111.1 (C1), 110.0 (C17), 108.0 (C3), 107.5 (C7), 105.4
(C10), 105.2 (C22), 100.7 (C19), 56.4 (OCH3-15), 56.3 (OCH3-14),
56.2 (OCH3-20), 56.1 (OCH3-8), 55.6 (OCH3-9), 55.4 (OCH3-21);
ESI-HRMS calcd for [C31H27NO8 + Na]+ 564.1635, found 564.1632.
The data are in accordance with the literature (compound 126).41
REFERENCES
■
(1) Facompre,
́
M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez, C.;
Manzanares, I.; Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392−
7399.
(2) Bailly, C. Curr. Med. Chem.: Anti-Cancer Agents 2004, 4, 363−378.
(3) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108,
264−287.
(4) Gallego, M. A.; Ballot, C.; Kluza, J.; Hajji, N.; Martoriati, A.;
Castera, L.; Cuevas, C.; Formstecher, P.; Joseph, B.; Kroemer, G.;
Bailly, C.; Marchetti, P. Oncogene 2008, 27, 1981−1992.
(5) Baunbaek, D.; Trinkler, N.; Ferandin, Y.; Lozach, O.; Ploypradith,
P.; Ruchirawat, S.; Ishibashi, F.; Iwao, M.; Meijer, L. Mar. Drugs 2008,
6, 514−527.
E
DOI: 10.1021/acs.joc.5b02194
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(6) Ballot, C.; Kluza, J.; Lancel, S.; Martoriati, A.; Hassoun, S.;
Mortier, L.; Vienne, J.-C.; Briand, G.; Formstecher, P.; Bailly, C.;
(40) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997,
62, 7512−7515.
(41) Ploypradith, P.; Petchmanee, T.; Sahakitpichan, P.; Litvinas, N.
D.; Ruchirawat, S. J. Org. Chem. 2006, 71, 9440−9448.
(42) Li, Q.; Jiang, J.; Fan, A.; Cui, Y.; Jia, Y. Org. Lett. 2011, 13, 312−
315.
Nevier
(7) Pla, D.; Albericio, F.; Alvarez, M. MedChemComm 2011, 2, 689−
697.
̀
e, R.; Marchetti, P. Apoptosis 2010, 15, 769−781.
(8) Ballot, C.; Martoriati, A.; Jendoubi, M.; Buche, S.; Formstecher,
P.; Mortier, L.; Kluza, J.; Marchetti, P. Mar. Drugs 2014, 12, 779−798.
(9) Tangdenpaisal, K.; Worayuthakarn, R.; Karnkla, S.; Ploypradith,
P.; Intachote, P.; Sengsai, S.; Saimanee, B.; Ruchirawat, S.; Chittchang,
M. Chem. - Asian J. 2015, 10, 925−937.
(43) Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Org.
Chem. 1988, 53, 4570−4574.
(10) Handy, S. T.; Zhang, Y. Org. Prep. Proced. Int. 2005, 37, 411−
445.
(11) Pla, D.; Albericio, F.; Alvarez, M. Anti-Cancer Agents Med. Chem.
2008, 8, 746−760.
(12) You, Y.-C.; Hu, D.-H.; Li, D.-P.; Wang, A.-L.; Yu, X.-S. Youji
Huaxue 2008, 28, 797−803.
(13) Vanhuyse, M.; Kluza, J.; Tardy, C.; Otero, G.; Cuevas, C.; Bailly,
C.; Lansiaux, A. Cancer Lett. 2005, 221, 165−175.
(14) Kluza, J.; Gallego, M.-A.; Loyens, A.; Beauvillain, J.-C.;
Fernandez Sousa-Faro, J.-M.; Cuevas, C.; Marchetti, P.; Bailly, C.
Cancer Res. 2006, 66, 3177−3187.
(15) Khiati, S.; Seol, Y.; Agama, K.; Dalla Rosa, I.; Agrawal, S.; Fesen,
K.; Zhang, H.; Neuman, K. C.; Pommie, Y. Mol. Pharmacol. 2014, 86,
193−199.
(16) Bailly, C. Mar. Drugs 2015, 13, 1105−1123.
(17) Andersen, R. J.; Faulkner, D. J.; He, C. H.; Van Duyne, G. D.;
Clardy, J. J. Am. Chem. Soc. 1985, 107, 5492−5495.
(18) Fuerstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995,
60, 6637−6641.
(19) Heim, A.; Terpin, A.; Steglich, W. Angew. Chem., Int. Ed. Engl.
1997, 36, 155−156.
(20) Banwell, M.; Flynn, B.; Hockless, D. Chem. Commun. 1997,
2259−2260.
(21) Ploypradith, P.; Mahidol, C.; Sahakitpichan, P.; Wongbundit, S.;
Ruchirawat, S. Angew. Chem., Int. Ed. Engl. 2004, 43, 866−868.
(22) Yadav, J. S.; Gayathri, K. U.; Reddy, B. V. S.; Prasad, A. R. Synlett
2009, 2009, 43−46.
(23) Liermann, J. C.; Opatz, T. J. Org. Chem. 2008, 73, 4526−4531.
(24) Ishibashi, F.; Miyazaki, Y.; Iwao, M. Tetrahedron 1997, 53,
5951−5962.
(25) Imbri, D.; Tauber, J.; Opatz, T. Mar. Drugs 2014, 12, 6142−
6177.
(26) Imbri, D.; Netz, N.; Kucukdisli, M.; Kammer, L. M.; Jung, P.;
Kretzschmann, A.; Opatz, T. J. Org. Chem. 2014, 79, 11750−11758.
(27) Komatsubara, M.; Umeki, T.; Fukuda, T.; Iwao, M. J. Org. Chem.
2014, 79, 529−537.
(28) Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.;
Young, L.; Ruchirawat, S. J. Org. Chem. 2007, 72, 9379−9382.
(29) Boonya-Udtayan, S.; Yotapan, N.; Woo, C.; Bruns, C. J.;
Ruchirawat, S.; Thasana, N. Chem. - Asian J. 2010, 5, 2113−2123.
(30) Imbri, D.; Tauber, J.; Opatz, T. Chem. - Eur. J. 2013, 19, 15080−
15083.
(31) Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi, F.
Tetrahedron Lett. 2003, 44, 4443−4446.
(32) Handy, S. T.; Zhang, Y. N.; Bregman, H. J. Org. Chem. 2004, 69,
2362−2366.
(33) Fujikawa, N.; Ohta, T.; Yamaguchi, T.; Fukuda, T.; Ishibashi, F.;
Iwao, M. Tetrahedron 2006, 62, 594−604.
(34) Hasse, K.; Willis, A. C.; Banwell, M. G. Eur. J. Org. Chem. 2011,
2011, 88−99.
(35) Arican, D.; Bruckner, R. Org. Lett. 2013, 15, 2582−2585.
̈
(36) Bailey, A. S.; Robinson, R. J. Chem. Soc. 1950, 1375−1379.
(37) McDonald, E.; Smith, P. J. Chem. Soc., Perkin Trans. 1 1980,
837−842.
(38) The amount of TfOH is crucial for the completion of the
reaction; catalytic amounts are insufficient.
(39) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
2748−2749.
F
DOI: 10.1021/acs.joc.5b02194
J. Org. Chem. XXXX, XXX, XXX−XXX