Practical first total synthesis of the potent phytotoxic (±)-naphthotectone, isolated from tectona grandis

Article abstract of DOI:10.1002/ejoc.201300783

Naphthotectone is a quinone isolated recently from teak extracts of Tectona grandis. It has been shown to be one of the most abundant compounds and the most active compound isolated form teak. Thus, it has been proposed that naphthotectone is one of the compounds responsible for the allelophathic activity of this plant. An efficient total synthesis of (±)- naphthotectone was achieved in seven steps and 31 % overall yield. The best results were obtained by using an aqueous Wittig reaction as a key step. Other reactions used were the formation of an epoxide ring by the Corey-Chaykovsky method, and an innovative one-pot anodic electrooxidation and demethylation. An efficient total synthesis of (±)-naphthotectone was achieved in seven steps and 31 % overall yield. This natural product has been proposed as one of the compounds responsible for the allelopathic activity of Tectona grandis. The synthetic route includes an aqueous Wittig olefination, a Corey-Chaikovsky epoxidation, and an innovative one-pot anodic electrooxidation and demethylation.

Full text of DOI:10.1002/ejoc.201300783

Job/Unit: O30783
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Date: 05-08-13 10:22:51
Pages: 7
FULL PAPER
DOI: 10.1002/ejoc.201300783
Practical First Total Synthesis of the Potent Phytotoxic (؎)-Naphthotectone,
Isolated from Tectona grandis
Guillermo A. Guerrero-Vásquez,[a] Carlos Kleber Z. Andrade,[b] José M. G. Molinillo,[a] and
Francisco A. Macías*[a]
Keywords: Total synthesis / Natural products / Napthoquinones / Electrochemistry / Epoxidation / Green chemistry
Naphthotectone is a quinone isolated recently from teak ex-
tracts of Tectona grandis. It has been shown to be one of the
most abundant compounds and the most active compound
isolated form teak. Thus, it has been proposed that
naphthotectone is one of the compounds responsible for the
allelophathic activity of this plant. An efficient total synthesis
of (Ϯ)-naphthotectone was achieved in seven steps and 31%
overall yield. The best results were obtained by using an
aqueous Wittig reaction as a key step. Other reactions used
were the formation of an epoxide ring by the Corey–
Chaykovsky method, and an innovative one-pot anodic elec-
trooxidation and demethylation.
mechanisms.[5] This makes naphthotectone an important
future target in the development of drugs and ecoherbic-
ides. This gives sufficient reason to develop an efficient syn-
thetic route to this apparently simple structure.
Introduction
The allelopathic synergy of the forest species Ver-
benaceae Tectona grandis with agricultural species such as
mountain rice, cotton, tapioca, chilli, and ginger, which is
seen in teak plantations in Cuba and Venezuela with maize
or bean cultures, can be important for the success of the
agroforestal system known as taungya.[1] This system in-
volves an allelophathic interaction of crops in young teak
plantations,[1,2] and gives excellent harvests, in which fields
remain clean and free from competition from undesirable
plants.[2a,3]
Evidence of the phytotoxic effects of teak leaf extracts
on the germination of monocot species has been found.[4]
This phenomenon was recently confirmed when our group
reported[5] the isolation and characterization of naphthotec-
tone (1; Figure 1) from biologically active leaf extracts of
Cuban Tectona grandis; 1 was the major component of this
highly phytotoxic extract.[1,5] This natural product is an iso-
prenoid quinone that is structurally similar to alkannin (2)
and shikonin (3; Figure 1), both of which are natural prod-
ucts with interesting biological activities.[6] Our research
group has proposed that naphthotectone is one of the
major compounds responsible for the allelophathic activity
shown by teak, and also that it is involved in other defense
Figure 1. Structures of naphthotectone (1), alkannin (2), and
shikonin (3).
Our retrosynthetic analysis of 1 is shown in Scheme 1.
The key point of our strategy was the binding of the carbon
chain to the naphthoquinone nucleus. For this, we tested
various approaches, including Heck, Suzuki, and Sonoga-
shira reactions, but all of these were unsuccessful. A com-
plete analysis of the cause of the unexpected lack of success
using these obvious classic reactions is ongoing. Conse-
quently, a linear synthetic strategy was used in which the
diol system of 1 was accessed via epoxide 4. A 1,4,5,8-tetra-
methoxynaphthalene moiety was used as a precursor to the
naphthazarin core, and the side-chain was assembled simi-
larly to previously reported successful syntheses of 2 and
3.[7] The conjugated double bond was obtained with a high
[a] INBIO Institute of Biomolecules, Allelopathy Group,
Department of Organic Chemistry, School of Sciences,
University of Cadiz,
C/República Saharaui, s/n, 11510 Puerto Real, Spain
E-mail: famacias@uca.es
Homepage: http://fqm286.uca.es/
[b] Permanent address: Laboratório de Química Metodológica e
Orgânica Sintética (LaQMOS), Instituto de Química,
Universidade de Brasília,
C.P. 4478, Brasília, DF 70910-970, Brazil
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300783
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F. A. Macías at al.
FULL PAPER
E selectivity in a Wittig reaction between a stabilized ylide
and aldehyde 5, which was synthesized in four high-yielding
steps from 1,4-dimethoxybenzene (6) and 2,3-dichloro-
maleic anhydride (7).[8] We tried to avoid chromatographic
separations to increase the overall yield of the synthesis and
also to use Sephadex rather than silica gel where possible,
because the substrates are highly unstable on silica gel.
Scheme 2. Synthesis of key aldehyde 5.
Scheme 1. Retrosynthetic analysis of naphthotectone (1).
Results and Discussion
The synthesis started with the large-scale preparation of
2,3-dichloronaphthazarin (8) by a double Friedel–Crafts
acylation[8] between p-dimethoxybenzene (6) and 2,3-
dichloromaleic anhydride (7), followed by reduction of the
naphthoquinone core of 8 with anhydrous tin(II) chloride
in HCl (4 m) under reflux conditions[8e,8f] to give leucon-
aphthazarin (9).
Protected intermediate 1,4,5,8-tetramethoxynaphthalene
(10) was obtained by methylation[9] of moderately air-sensi-
tive diketo tautomer[8c] 9 with dimethyl sulfate. Treatment
of 10 with POCl3/DMF (Vilsmeier–Haak reaction) gave
useful 2-formyl-1,4,5,8-tetramethoxynaphthalene[8e,10] (5)
(Scheme 2). Purification by column chromatography was
Scheme 3. E-Selective synthesis of enone 12 by a Wittig reaction in
water, and non-selective synthesis of 14 in THF.
A cheap, easy, and accessible preparation of trimethyl-
not necessary in any of the steps of this large-scale synthetic sulfonium methylsulfate[14] (17) was achieved with a mixture
sequence, since the intermediates were isolated with high of dimethyl sulfide (15) and dimethyl sulfate (16) in acetone,
purities.
which gave a very hygroscopic white solid (Scheme 4). Ho-
It has been found that when water is used as a reaction mologation of the side-chain of naphthotectone was
medium, Wittig products are formed with high E selectivity achieved by the known Corey–Chaykovsky reaction[15]
when a stabilized ylide is used, and (Z)-alkene products are (Scheme 5). Intermediate epoxide 4 was obtained in a one-
obtained with non-stabilized ylides.[11] Indeed, the Wittig pot procedure by the selective addition of a methylene
reaction between aldehyde 5 and the stabilized ylide derived group to the carbonyl group of 12. A solution of dimethyl-
from acetonylidenetriphenylphosphorane (11), in water as sulfoniomethylide (18) could be generated in situ from salt
solvent at 90 °C, provided α,β-unsaturated ketone 12 with 17 and potassium hydride in dry dichloromethane under
complete E selectivity and in high yield on a large scale argon. A dichloromethane solution of ketone 12 was then
(Scheme 3). This reaction represents an example of the use added at room temperature, and this was followed by heat-
of green chemistry.[12] In contrast, under normal condi- ing at reflux for 24 h. The intermediate epoxide (i.e., 4) was
tions,[13] diene 14 was obtained as a very unstable complex not isolated, but controlled treatment with acid led to neu-
3:1 mixture of E and Z isomers, and this approach was tralization of the reaction mixture and opening of the epox-
therefore abandoned.
ide ring of 4 to furnish theand light; it reacts to give the
2
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Total Synthesis of (Ϯ)-Naphthotectone
corresponding aldehyde at position C-5Ј. This problem was
overcome by selective acetylation of the primary alcohol of
19 under basic conditions to give 20 (Scheme 6).
Scheme 4. Synthesis of trimethylsulfonium methylsulfate (17).
Scheme 7. Synthesis of 21 and 22 by using simple silica-gel-sup-
ported CAN.
Next, we investigated the formation of the quinone moi-
ety from compound 20 using a new anodic electrooxidation
method.[7a,20] This two-step approach involved a simple ex-
perimental set-up with graphite electrodes under argon by
using mixtures of LiClO4 (0.01 m) in H2O/CH3CN (1:1) as
the electrolyte (Scheme 8). The first oxidation step, carried
out at 1.7 V for 21 h, led to the complete conversion of 20
into a mixture of 21 and 22, as shown by TLC analysis. A
second oxidation step, carried out at 3 V for 7 h, led to the
clean conversion into our desired target naphthotectone in
90% yield by demethylation of intermediates 21 and 22 fol-
lowed by tautomerization of 23. Naphthotectone (1) could
be easily purified by using a Sephadex LH-20 column with
isocratic H2O/CH3CN mixtures.
Scheme 5. One-pot synthesis of diol 19 by Corey–Chaykovsky
epoxidation.
Scheme 6. Selective acetylation of diol 19.
Ceric ammonium nitrate (CAN) has gained widespread
popularity as an effective oxidizing agent, especially for the
formation of quinone structures.[16] We found that the use
of silica-gel-supported CAN[17] with an organic solution of
20 gave a clean mixture of regioisomeric dimethoxynaph-
thoquinones 21 and 22 after simple filtration of the reaction
mixture. This approach limits the production of waste water
contaminated with cerium metal[18] (Scheme 7). This high-
yielding reaction was faster (15 min) than the same reaction
carried out in a mixture of H2O/CH3CN (2 h). Despite its
greater efficiency, only a modest regioselectivity[17] was ob-
tained in favor of the desired compound (i.e., 22; the re-
gioisomers were separated by reverse-phase HPLC using a
mixture of H2O/CH3CN to provide 40% of 22 and 25% of
21). Further demethylation of 21 and 22 by treatment with
AgO and HNO3[16c,16d] in acetone[17] or dioxane[19a] or with
Scheme 8. Oxidation, demethylation, and tautomerization reaction;
one-pot synthesis of naphthotectone from 20 by anodic electro-
chemistry.
[16c,16d,17,19b,19c]
[16c,19c–19e]
AlCl3
or BBr3
did not efficiently
generate the desired target molecule.
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F. A. Macías at al.
FULL PAPER
placed in a flame-dried round-bottomed flask under argon. Meth-
ylallyl bromide (1 mL, 10 mmol) was added, and the mixture was
heated at reflux at 120 °C for 18 h. The precipitate was filtered off
under vacuum, washed with dry diethyl ether, and dried in an oven
to give 13 (3.75 g, 95%) as a white solid. M.p. 187–189 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.83–7.69 (m, 9 H, 3Ј-H, 3ЈЈ-H, 3ЈЈЈ-
H, 4Ј-H, 4ЈЈ-H, 4ЈЈЈ-H, 5Ј-H, 5ЈЈ-H, 5ЈЈЈ-H), 7.66–7.57 (m, 6 H, 2Ј-
H, 2ЈЈ-H, 2ЈЈЈ-H, 6Ј-H, 6ЈЈ-H, 6ЈЈЈ-H), 5.01–4.94 (m, 1 H, 3a-H),
4.83 (dt, J = 5.2, 1.0 Hz, 1 H, 3b-H), 4.58 (d, J = 15.3 Hz, 2 H, 1-
H), 1.52 (dd, J = 2.9, 1.3 Hz, 3 H, 4-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 135.1 (C-4ЈЈ, C-4ЈЈЈ), 135 (C-4Ј), 134 (C-2ЈЈ, C-2ЈЈЈ),
133.9 (C-2Ј), 132.6 (C-2), 132.5 (C-2), 130.3 (C-3ЈЈ, C-3ЈЈЈ), 130.2
(C-3Ј), 121.6 (C-1ЈЈ, C-1ЈЈЈ)*, 121.5 (C-1Ј)*, 117.7 (C-3), 31.9 (C-
1), 24.7 (C-4), 24.7 (C-4) ppm. 31P NMR (162 MHz, CDCl3): δ =
20.13 ppm.
Conclusions
Naphthotectone,
a
potent phytotoxic isoprenoid
naphthoquinone, was synthesized in seven steps and 31%
overall yield from readily available starting materials. This
approach avoided the need for chromatographic separations
in the first four steps. The naphthoquinone nucleus was ef-
ficiently obtained in a one-pot reaction by a new anodic
electrooxidation and demethylation method. Naphthotec-
tone was isolated as a chiral compound, and this synthetic
route will allow the preparation of new derivatives in order
to gain insights into the structural requirements for bio-
logical activity, as well as the preparation of the natural
enantiomer, and this work is ongoing.
1,4,5,8-Tetramethoxy-2-[(1E and 1Z)-3-methylbuta-1,3-dien-1-yl]-
naphthalene (14): A mixture of (2-methylprop-2-en-1-yl)triphenyl-
phosphonium bromide (13; 216 mg, 0.54 mmol) and dry THF
(1 mL) was placed in a flame-dried round-bottomed flask at 0 °C.
nBuLi (2.5 m in hexanes; 0.13 mL, 0.33 mmol, 1.2 equiv.) was
added, and the mixture was stirred for 30 min. A solution of 2-
formyl-1,4,5,8-tetramethoxynaphthalene (5; 75 mg, 0.27 mmol) in
dry THF (1 mL) was added dropwise over 5 min. The mixture was
warmed to room temp. and stirred for 3 h. The solvent was evapo-
rated, and water (10 mL) was added to the residue. The aqueous
phase was extracted with diethyl ether (3ϫ 10 mL). The combined
organic extracts were washed with brine, dried with anhydrous
Na2SO4, and concentrated under reduced pressure. The crude ma-
terial was purified by silica gel column chromatography (ethyl acet-
ate/hexanes, 40%) to give 14 [mixture of products E/Z (3:1); 85 mg,
99%; silica gel TLC: Rf = 0.63 in ethyl acetate/hexanes, 40%] as a
yellow solid. M.p. 65–71 °C.
Experimental Section
General Information: IR spectra (KBr) were recorded with Perkin–
Elmer FTIR Spectrum 1000 or Matton 5020 spectrophotometers.
NMR spectra were recorded with Agilent INOVA-400 and Varian
INOVA 500 spectrometers. Chemical shifts are given in ppm; 1H
NMR spectra were calibrated to the residual solvent signal of
CDCl3 (δ = 7.26 ppm), and 13C NMR spectra were calibrated to
the solvent signal (δ = 77.0 ppm). HRMS data were recorded with
a Waters SYNAPT G2 mass spectrometer (70 eV). HPLC was car-
ried out by using a Merck–Hitachi instrument, with RI detection,
using Merck LiChrospher columns: SI 60 (5 μm, 250ϫ4 mm).
Melting points were recorded with a Logen Scientific-LS melting
point apparatus. Commercially available reagents and solvents were
analytical grade, or were purified by standard procedures before
use. Compounds were analyzed by IR spectroscopy, NMR spec-
troscopy (1H, 13C, and 31P), and high-resolution ESI mass spec-
trometry, which gave data consistent with the proposed structures.
1
Data for E Isomer: H NMR (400 MHz, CDCl3): δ = 7.14 (d, J =
16.3 Hz, 1 H, 1Ј-H), 7.07 (s, 1 H, 3-H), 6.94 (d, J = 16.3 Hz, 1 H,
2Ј-H), 6.86–6.78 (m, 2 H, 7-H, 6-H), 5.14 (d, J = 24.4 Hz, 2 H, 4Ј-
H), 3.98 (s, 3 H, -OCH3), 3.94 (s, 3 H, -OCH3), 3.76 (s, 3 H, -
OCH3), 3.76 (s, 3 H, -OCH3), 2.05 (s, 3 H, 5Ј-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 153.3 (C-5), 151.6 (C-1), 150.9 (C-8), 148.3
(C-4), 142.8 (C-3Ј), 132.49 (C-1Ј), 127.5 (C-9), 123.5 (C-2Ј), 123.3
(C-3), 117.4 (C-4Ј), 110.2 (C-10), 108.8 (C-7)*, 108.7 (C-6)*, 108.5
(C-2), 104.9 (C-3), 62.1 (C-1a), 57.9 (C-5a), 57.4 (C-4a), 57.3 (C-
8a), 18.9 (C-5Ј) ppm. *Assignments may be interchanged.
(3E)-4-(1,4,5,8-Tetramethoxy-2-naphthyl)but-3-en-2-one (12):[11]
A
mixture of 2-formyl-1,4,5,8-tetramethoxynaphthalene (5; 0.79 g,
2.86 mmol) and acetylmethylenetriphenylphosphorane (1.63 g,
5.14 mmol, 1.8 equiv.) in water (28 mL) was heated at reflux at
90 °C for 3 h. CHCl3 (29 mL) was added to the reaction mixture.
The organic phase was separated, and the aqueous phase was ex-
tracted with CHCl3 (3ϫ 30 mL). The combined organic extracts
were dried with Na2SO4 and filtered, and the solvents were evapo-
rated. The crude material was purified by silica gel column
chromatography (ethyl acetate/hexanes, 1:1) to give recovered start-
ing material 5 (0.08 g, 9%; silica gel TLC Rf = 0.48 in ethyl acetate/
hexanes, 1:1) and product 12 (0.81 g, 90%; silica gel TLC Rf = 0.43
in ethyl acetate/hexanes, 1:1) as a yellow solid. M.p. 122–123 °C.
1
Data for Z Isomer: H NMR (400 MHz, CDCl3): δ = 7.07 (s, 1 H,
3), 6.86–6.78 (m, 2 H, 7-H, 6-H), 6.73 (d, J = 12.3 Hz, 1 H, 1Ј-H),
6.28 (d, J = 12.4 Hz, 1 H, 2Ј-H), 5.01 (d, J = 9.7 Hz, 2 H, 4Ј-H),
3.98 (s, 3 H, -OCH3), 3.93 (s, 3 H, -OCH3), 3.88 (s, 3 H, -OCH3),
3.76 (s, 3 H, -OCH3), 1.78 (s, 3 H, 5Ј-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 152.2 (C-5), 151.4 (C-1), 150.7 (C-8), 148.1 (C-4),
142.1 (C-3Ј), 133.2 (C-1Ј), 128.9 (C-9), 125.8 (C-2Ј), 120.3 (C-3),
117.3 (C-4Ј), 110.4 (C-10), 108.8 (C-7)*, 108.7 (C-6)*, 108 (C-2),
104.9 (C-3), 62.8 (C-1a), 57.8 (C-5a), 57.4 (C-4a), 57.2 (C-8a), 22.4
(C-5Ј) ppm. *Assignments may be interchanged. HRMS (ESI):
calcd. for C19H22O4 [M]+ 314.1518; found 314.1518.
IR (neat): ν = 2926 (C–H), 2850 (O–CH ), 1662 (C=O), 1598
˜
3
(C=C–C=O), 1458 (CH3–CO), 1372 (–CH3), 1262 (C–O), 1072
(–CH3) cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J =
16.6 Hz, 1 H, 1Ј-H), 6.92 (d, J = 8.7 Hz, 1 H, 7-H), 6.89 (d, J =
8.7 Hz, 1 H, 6-H), 6.72 (d, J = 16.6 Hz, 1 H, 2Ј-H), 4.04 (s, 3 H,
1a-OCH3), 3.96 (s, 3 H, 4a-OCH3)*, 3.90 (s, 3 H, 5a-OCH3)*, 3.80
(s, 3 H, 8a-OCH3)*, 2.44 (s, 3 H, 4Ј-CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 199.1 (C-3Ј), 153.6 (C-5), 151.6 (C-1), 151.2
(C-8), 151.0 (C-4), 138.5 (C-1Ј), 128.3 (C-2Ј), 124.7 (C-10), 122.9
(C-2), 122.1 (C-9), 110.8 (C-7), 108.9 (C-3), 103.6 (C-6), 63.8 (C-
1a), 58.1 (C-5a)*, 57.2 (C-8a)*, 57.1 (C-4a)*, 27.0 (C-4Ј) ppm. *As-
signments may be interchanged. HRMS (ESI): calcd. for
C18H20O5Na [M + Na]+ 339.1208; found 339.1216.
(3E)-2-Methyl-4-(1,4,5,8-tetramethoxy-2-naphthyl)but-3-ene-1,2-
diol (19):[14,15] Potassium hydride (30% dispersion in mineral oil;
0.51 mmol) was placed in a 25 mL two-necked round-bottomed re-
action vessel and washed four times with hexane (10 mL) by swirl-
ing, allowing the hydride to settle, and decanting, in order to re-
move the mineral oil. In another 25 mL two-necked round-bot-
tomed reaction vessel, dry CH2Cl2 (1 mL) was added to trimeth-
ylsulfonium methylsulfate (17; 0.51 mmol) under argon. This solu-
tion was then added to the first vessel, and the mixture was stirred
(2-Methylprop-2-en-1-yl)triphenylphosphonium Bromide (13): Tri-
phenylphosphane (2.62 g, 10 mmol) and dry toluene (20 mL) were
4
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Total Synthesis of (Ϯ)-Naphthotectone
at room temp. for 1 h to obtain dimethylsulfoniomethylide. A solu-
tion of (3E)-4-(1,4,5,8-tetramethoxy-2-naphthyl)but-3-en-2-one
(12; 53.6 mg, 0.17 mmol) in dry CH2Cl2 (1.8 mL) was added, and
the reaction mixture was heated at reflux at 60 °C for 24 h under
argon to generate the epoxide intermediate. Sulfuric acid (0.05 m
aq.; 13.5 mL) was added at 0 °C. Stirring was continued at room
temp. for 3 d. After the epoxide-opening reaction was complete,
NaHCO3 (0.11 g) was added, and the solution was stirred for
30 min. The organic phase was decanted, and the aqueous phase
was extracted with dichloromethane (3ϫ 50 mL). The combined
organic extracts were washed with brine and dried with anhydrous
Na2SO4. Evaporation of the solvent gave a residue, which was puri-
fied on Sephadex LH-20 (CH2Cl2/hexane, 95 %) to give 19
(40.5 mg, 68%; silica gel TLC Rf = 0.22 in ethyl acetate/hexanes,
mixture was filtered under reduced pressure through a sintered-
glass funnel. The solid was washed with CH2Cl2 (ca. 50 mL). The
solvent was removed under reduced pressure by using a rotary
evaporator to give a mixture of products 21 and 22 (quantitative)
as a yellow/orange oil. The mixture was purified by reverse-phase
HPLC D7000 (acetonitrile/water, 40%). Pure 21 (10.0 mg, 40%;
silica gel TLC Rf = 0.37 in acetonitrile/water, 60%) was obtained
as an orange oil, along with 22 (6.9 mg, 25%; silica gel TLC Rf =
0.25 in acetonitrile/water, 60%) as a red oil.
Data for Compound 21: IR (neat): ν = 3462 (–OH), 3014, 2940 (C–
˜
H), 2844 (O–CH3), 2362, 2344 (Ar), 1740 (O–C=O), 1654 (C=O),
1586 (C=C–C=O), 1478, 1462 (–OCH3), 1260 (C–O), 1048 (–CH3)
cm–1. 1H NMR (50 MHz, CD3OD): δ = 7.59 (s, 1 H, 3-H), 7.09
(d, J = 16.3 Hz, 1 H, 2Ј-H), 6.8 (s, 2 H, 6-H, 7-H), 6.64 (d, J =
16.3 Hz, 1 H, 1Ј-H), 4.15 (d, J = 11.1 Hz, 1 H, 5Јa-H), 4.05 (d, J
= 11.1 Hz, 1 H, 5Јb-H), 3.99 (s, 3 H, 1a-OCH3), 3.78 (s, 3 H, 4a-
OCH3), 2.07 (s, 3 H, 7Ј-H), 1.42 (s, 3 H, 4Ј-H) ppm. 13C NMR
(125 MHz, CD3OD): δ = 186.2 (C-8), 185.8 (C-5), 172.6 (C-6Ј),
157.6 (C-1), 152.5 (C-4), 141.9 (C-2), 140.9 (C-1Ј), 140.1 (C-7),
139.2 (C-6), 127 (C-9), 123.2 (C-2Ј), 120.7 (C-10), 117.5 (C-3), 73.2
(C-3Ј), 71.5 (C-5Ј), 62.4 (C-4a)*, 57 (C-1a)*, 25 (C-4Ј), 20.8 (C-7Ј)
ppm. HRMS (ESI): calcd. for C19H20O7Na [M + Na]+ 383.1107;
found 383.1123.
1:1) as a yellow oil. IR (neat): ν = 3464 (–OH), 2930 (C–H), 2838
˜
(O–CH3), 2062 (Ar), 1686 (C=O), 1602 (C=C–C–O), 1462 (CH3–
CO), 1366 (–CH3), 1260 (C–O), 1072 (–CH3) cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.2 (d, J = 16.3 Hz, 1 H, 1Ј-H), 6.94 (s, 1
H, 3-H), 6.83–6.79 (m, 2 H, 6-H, 7-H), 6.30 (dd, J = 16.3 Hz, 1 H,
2Ј-H), 3.91 (s, 6 H, 5a-OCH3, 8a-OCH3)*, 3.87 (s, 3 H, 4a-OCH3)*
3.71 (s, 3 H, 1a-OCH3)*, 3.65 (d, J = 10.8, 1 H, 5Јa-H), 3.55 (d, J
= 10.8, 1 H, 5Јb-H), 1.41 (s, 3 H, 4Ј-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 153.3 (C-5), 151.5 (C-1), 150.8 (C-8), 148 (C-4), 134.5
(C-10), 131 (C-2), 126.7 (C-2Ј), 124.2 (C-1Ј), 120.6 (C-9), 108.9 (C-
3), 108.6 (C-6), 105.2 (C-7), 73.9 (C-3Ј), 70.2 (C-5Ј), 62.7 (C-1a),
57.9 (C-5a)*, 57.4 (C-8a)*, 57.3 (C-4a)*, 24.6 (C-4Ј) ppm. *Assign-
ments may be interchanged. HRMS (ESI): calcd. for C19H24O6Na
[M + Na]+ 371.1471; found 371.1469.
Data for Compound 22: IR (neat): ν = 3482 (–OH), 2924 (C–H),
˜
2854 (O–CH3), 2366, 2342 (Ar), 1738 (O–C=O), 1656 (C=C–C=O),
1464 (–OCH3), 1246 (C–O), 1054 (–CH3) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 7.52 (s, 2 H, 6-H, 7-H), 6.83 (d, J =
0.86 Hz, 1 H, 1Ј-H), 6.82 (d, J = 0.79 Hz, 1 H, 3-H), 6.81 (dd, J =
16.3 Hz, 1 H, 1Ј-H), 6.72 (d, J = 16.3 Hz, 1 H, 2Ј-H), 4.09 (d, J =
11.03 Hz, 1 H, 5Јa-H), 4.02 (d, J = 11.03 Hz, 1 H, 5Јb-H), 3.93 (s,
3 H, 5a-OCH3)*, 3.92 (s, 3 H, 8a-OCH3)*, 2.1 (s, 3 H, 4Ј-H), 1.4
(s, 3 H, 7Ј-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 186.5 (C-
1), 185.8 (C-4), 172.6 (C-6Ј), 155.2 (C-5), 154.8 (C-8), 145.3 (C-2),
143.9 (C-2Ј), 132.4 (C-1Ј), 122.3 (C-3), 122.2 (C-9), 122.1 (C-6), 122
(C-7), 121.6 (C-10), 73.2 (C-3Ј), 71.4 (C-5Ј), 57.2 (C-5a)*, 57.1 (C-
(3E)-2-Hydroxy-2-methyl-4-(1,4,5,8-tetramethoxy-2-naphthyl)but-3-
en-1-yl Acetate (20): Acetic anhydride (34 μL, 0.31 mmol) was
added to a stirred, cooled solution of 19 (0.11 g, 0.31 mmol) in dry
pyridine (400 μL). The mixture was stirred for 6 h, and then it was
concentrated under vacuum. The residue was purified on Sephadex
LH-20 (CH2Cl2/hexane, 95%) to give 20 (0.1 g, 82%; silica gel TLC
Rf = 0.44 in ethyl acetate/hexanes, 80%) as a yellow oil. IR (neat):
ν = 3472 (–OH), 2932 (C–H), 2838 (O–CH ), 2064 (Ar), 1740
˜
3
(C=O), 1602 (C–O), 1458 (–CH3–C–O), 1370 (CH3), 1260 (C–O), 8a)*, 24.8 (C-4Ј), 20.7 (C-7Ј) ppm. *Assignments may be inter-
1
1074 (–CH3) cm–1. H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = changed. HRMS (ESI): calcd. for C19H20O7Na [M + Na]+
16.3 Hz, 1 H, 1Ј-H), 6.95 (s, 1 H, 3-H), 6.85 (d, J = 8.6 Hz, 1 H, 383.1107; found 383.1106.
7-H), 6.82 (d, J = 8.6 Hz, 1 H, 6-H), 6.3 (d, J = 16.3 Hz, 1 H, 2Ј-
(؎)-Naphthotectone (1):[20] A mixture of compound 20 (20.8 mg,
0.053 mmol) and lithium perchlorate (159.6 mg, 1.50 mmol) in
aqueous acetonitrile (50%; 15 mL) was introduced into an undi-
H), 4.23 (d, J = 11.2 Hz, 1 H, 5Јa-H), 4.10 (d, J = 11.2 Hz, 1 H,
5Јb-H), 3.95 (s, 3 H, 8a-OCH3)*, 3.93 (s, 3 H, 5a-OCH3)*, 3.89 (s,
3 H, 4a-OCH3)*, 3.73 (s, 3 H, 1a-OCH3), 2.10 (s, 3 H, 7Ј-H), 1.46
vided electrolytic cell with graphite electrodes under argon. The
solution was electrolyzed in two steps. First step, oxidation: Elec-
trolysis at 1.71 V for 21 h generated a mixture of products 21 and
22 (quantitative). Second step, demethylation and tautomerization:
Electrolysis at 3.09 V for 7 h transformed the mixture of 21 and 22
into the desired naphthotectone (1). The solvent was removed un-
der reduced pressure at 45 °C until the volume of the solution was
5 mL, and the resulting solution was extracted with chloroform
(6ϫ 10 mL). The combined organic extracts were washed with
brine and dried with anhydrous Na2SO4. The solvent was removed,
and the residue was purified on Sephadex LH-20 (acetonitrile/
water, 60%) to give pure naphthotectone (1) (16.0 mg, 90%; silica
gel TLC Rf = 0.5 in acetonitrile/water, 60%) as an amorphous red
solid. The spectroscopic data of 1 are in good agreement with those
previously reported for the natural product.[5] HRMS (ESI): calcd.
for C17H16O7Na [M + Na]+ 355.0794; found 355.0805.
(s, 3 H, 4Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.2 (C-
6Ј), 153.4 (C-5), 151.5 (C-1), 150.8 (C-8), 148.1 (C-4), 133.8 (C-2Ј),
126.6 (C-10), 124.3 (C-1Ј), 123.2 (C-2), 120.7 (C-9), 109.0 (C-7),
108.6 (C-6), 105.2 (C-3), 72.8 (C-3Ј), 71.2 (C-5Ј), 62.7 (C-1a), 57.9
(C-5a)*, 57.4 (C-4a)*, 57.3 (C-8a)*, 25.1 (C-4Ј), 21.1 (C-7Ј) ppm.
*Assignments may be interchanged. HRMS (ESI): calcd. for
C21H26O7Na [M + Na]+ 413.1576; found 413.1581.
(3E)-4-(1,4-Dimethoxy-5,8-dioxo-5,8-dihydronaphthalen-2-yl)-2-hy-
droxy-2-methylbut-3-en-1-yl Acetate (21) and (3E)-4-(5,8-Dimeth-
oxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2-hydroxy-2-methylbut-
3-en-1-yl Acetate (22):[18] A solution of CAN (0.12 g, 0.23 mmol)
in water (0.40 mL) was added dropwise with continuous stirring to
chromatography-grade silica gel (0.4 g) in a 10 mL round-bottomed
flask fitted with a rubber septum. The silica gel was stirred for
approximately 5 min after the addition was complete, and a free-
flowing yellow solid was obtained. A solution of 20 (0.030 g,
0.076 mmol) in CH2Cl2 (1.2 mL) was added to the stirred reaction
mixture. The reaction mixture changed from yellow to dark orange
immediately upon addition of the starting material. After the reac-
tion was complete (approximately 15 min according to TLC), the
Supporting Information (see footnote on the first page of this arti-
1
cle): Complete experimental procedures and copies of H and 13C
NMR spectra for known compounds 8, 9, 10, 5, and 17, and de-
tailed experimental procedures, characterization, and copies of 1H,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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/KAP1
Date: 05-08-13 10:22:51
Pages: 7
F. A. Macías at al.
FULL PAPER
13C, 31P, COSY, HSQC, and HMBC NMR spectra of new com-
pounds.
[7]
[8]
a) V. P. Papageorgiou, A. N. Assimopoulou, E. A. Coula-
douros, D. Hepworth, K. C. Nicolaou, Angew. Chem. 1999,
111, 280–311; Angew. Chem. Int. Ed. 1999, 38, 270–300; b) R.
Wang, H. Guo, J. Cui, S. Li, Tetrahedron Lett. 2012, 53, 3977–
3980.
a) R. Huot, P. Brassard, Can. J. Chem. 1974, 5, 838–842; b) L.
Huang, F. Chang, K. Lee, J. Wang, C. Teng, S. Kuo, Bioorg.
Med. Chem. 1998, 6, 2261–2269; c) D. B. Bruce, R. H. Thom-
son, J. Chem. Soc. 1955, 1089–1096; d) B. Horowska, Z. Ma-
zerska, A. Ledochowski, G. Cristalli, P. Franchetti, S. Martelli,
Eur. J. Med. Chem. 1988, 23, 91–96; e) D. Xu, P. Guan, S. Li,
J. Chem. Res. 2006, 779–780; f) J. R. Lewis, J. Paul, Z. Natur-
forsch. B 1977, 32, 1473–1475.
Acknowledgments
The authors gratefully acknowledge the Spanish Ministry of Sci-
ence and Technology, Project No. AGL2008-04716/AGR, and the
Consejería de Innovación, Ciencia e Industria (P07-FQM-03031).
We also acknowledge Coordenação de Aperfeiçoamento de Pessoal
de nivel Superior (CAPES) and the ϾSpanish Ministry of Science
and Technology for fellowships.
[9]
M. Kawasaki, F. Matsuda, S. Terashima, Tetrahedron 1988, 44,
5713–5725.
[1] K. F. Wiersum, Agroforest Syst. 1982, 11, 53–70.
[2] a) G. H. Raets, Bol. Inst. Forestal Lat. Am. 1965, 18, 29–40; b)
J. Mishra, U. N. Prasad, Indian For. 1980, 106, 675–695.
[3] B. A. Betancourt, Silvicultura Especial de Árboles Maderables
Tropicales, Editorial Científico-Técnica, Havana City, Cuba,
1983, pp. 342–345.
[4] a) M. Jayakumar, M. Eyini, A. Pannirselvam, Geobios 1987,
14, 66–69; b) A. Krishna, G. O. Manjunath, R. Rathod, K. J.
Kannur, Agric. Sci. 2003, 16, 430–433; c) V. R. Evangeline,
E. J. J. Prakash, A. S. Samuel, M. Jayakumar, Pak. J. Weed Sci.
Res. 2012, 18, 65–70.
[10]
[11]
T. Akira, T. Yasuhiro, H. Akira, S. Hiroshi, Bull. Chem. Soc.
Jpn. 1987, 205–213.
a) J. Dambacher, W. Zhao, A. El-Batta, R. Anness, C. Jiang,
M. Bergdahl, Tetrahedron Lett. 2005, 46, 4473–4477; b) A. El-
Batta, C. Jiang, W. Zhao, R. Anness, A. L. Cooksy, M.
Bergdahl, J. Org. Chem. 2007, 72, 5244–5259.
J. L. Tucker, Org. Process Res. Dev. 2006, 10, 315–319.
For Wittig reactions, see: B. E. Maryanoff, A. B. Reitz, Chem.
Rev. 1989, 89, 863–927.
[12]
[13]
[14] P. Mosset, R. Grée, Synth. Commun. 1985, 15, 749–757.
[5] R. Lacret, R. M. Varela, J. M. G. Molinillo, C. Nogueiras, [15] For Corey–Chaykovsky reactions, see: a) E. J. Corey, M. Chay-
F. A. Macías, J. Chem. Ecol. 2011, 37, 1341–1348.
kovsky, J. Am. Chem. Soc. 1965, 87, 1353–1364; b) E. J. Corey,
M. Chaykovsky, J. Am. Chem. Soc. 1962, 84, 3782–3783.
[16] a) P. Jacob, P. S. Callery, A. T. Shulgin, N. Castagnoli, Jr., J.
Org. Chem. 1976, 41, 3627–3629; b) Y. Tanoue, A. Terada, Y.
Sugyo, J. Org. Chem. 1987, 52, 1437–1439; c) Y. Tanoue, A.
Terada, T. Tsuboi, T. Hayashida, O. Tsuge, Bull. Chem. Soc.
Jpn. 1987, 60, 2927–2930; d) A. Terada, Y. Tanoue, A. Hatada,
H. Sakamoto, Bull. Chem. Soc. Jpn. 1987, 60, 205–213.
[17] Y. Tanoue, A. Terada, Bull. Chem. Soc. Jpn. 1988, 61, 2039–
2045.
[6] For isolation and antioxidative activity, see: A. N. Assimopou-
lou, D. Boskou, V. P. Papageorgiou, Food Chem. 2004, 87, 433–
438; J. Han, X. Weng, K. Bi, Food Chem. 2008, 106, 2–10.
For anti-inflammatory activity, see: S. Tanaka, M. Tajima, M.
Tsukada, M. Tabata, J. Nat. Prod. 1986, 49, 466–469; M. Hay-
ashi, Nippon Yakurigaku Zasshi 1977, 73, 193–203. For wound-
healing activity, see: V. P. Papageorgiou, A. N. Assimopoulou,
A. C. Ballis, Curr. Med. Chem. 2008, 15, 3248–3267. For anti-
fungal activity, see: G. Honda, F. Sakakibara, K. Yazaki, J.
Nat. Prod. 1988, 51, 152–154. For antitumor activity, see: B.-
Z. Ahn, K.-U. Baik, G.-R. Kweon, K. Lim, B.-D. Hwang, J.
Med. Chem. 1995, 38, 1044–1047; N. Calonghi, E. Pagnota,
C. Parolin, C. Mangano, M. L. Bolognesi, C. Melchiorre, L.
Masotti, Biochem. Biophys. Res. Commun. 2007, 354, 409–413.
For antibacterial activity, see: V. P. Papageorgiou, Planta Med.
1980, 38, 193–203. For antithrombotic properties, see: F. N.
Ko, Y. S. Lee, S. C. Kuo, Y. S. Chang, C. M. Teng, Biochim.
Biophys. Acta Mol. Cell Res. 1995, 1268, 329–334. For analge-
sic activity, see: M. Hayashi, Nippon Yakurigaku Zasshi 1977,
73, 205–214. For antipyretic activity, see: M. Hayashi, Nippon
Yakurigaku Zasshi 1977, 73, 177–191. For inmunostimulatory
activity, see: H. Wagner, B. Kreher, K. Jurcic, Arzneim.-Forsch.
1988, 38, 273–275. For cancer treatment, see: A. I. Öberg, K.
Yassin, R. I. Csikasz, N. Dehvari, I. G. Shabalina, D. S. Hutch-
inson, M. Wilcke, C.-G. Östenson, T. Bengtsson, PLoS One
2011, 6, e22510; C. Sevimli-Gur, I. H. Akgun, I. Deliloglu-Gur-
han, K. S. Korkmaz, E. Bedir, J. Nat. Prod. 2010, 73, 860–864;
Y. Hou, T. Guo, C. Wu, X. He, M. Zhao, Yakugaku Zasshi
2006, 126, 1383–1386; V. P. Papageorgiou, A. N. Assimopou-
lou, V. F. Samanidou, I. N. Papadoyannis, Curr. Org. Chem.
2006, 10, 2123–2142.
[18] M. Hashmat Ali, M. Niedbalski, G. Bohnert, D. Bryant, Synth.
Commun. 2006, 36, 1751–1759.
[19] For demethylation of naphthazarin ethers with AgO, HNO3,
and dioxane, see: a) H. Yang, Q. Li, J. X. Bao, W. Lu, H. A.
Aisa, J. C. Cai, Chin. Chem. Lett. 2002, 13, 515–518. For de-
methylation of naphthazarin ethers with AlCl3, see: b) Y.
Tanoue, A. Terada, Y. Umezu, Bull. Chem. Soc. Jpn. 1991, 64,
2557–2559. For demethylation of naphthazarin ethers with
BBr3, see: c) C. L. Chai, J. A. Elix, F. E. Moore, J. Org. Chem.
2006, 71, 992–1001; d) C. L. Chai, J. A. Elix, F. E. Moore, Tet-
rahedron Lett. 2001, 42, 8915–8917; e) D. L. J. Clive, M. Can-
tin, A. Khodabocus, X. Kong, Y. Tao, Tetrahedron 1993, 49,
7917–7930.
[20] a) D.-F. Xu, L.-M. Zhao, Z.-Q. Mao, S.-S. Li, Org. Prep. Pro-
ced. Int. 2008, 40, 93–96; b) K. C. Nicolaou, D. Hepworth,
Angew. Chem. 1998, 110, 864–866; Angew. Chem. Int. Ed. 1998,
37, 839–841; c) I. Menegazzo, G. Sandonà, S. Moro, V. Sheeba,
G. Zagotto, Tetrahedron Lett. 2000, 41, 6631–6634; d) D. A.
Frey, N. Wu, K. D. Moeller, Tetrahedron Lett. 1996, 37, 8317–
8320.
Received: May 27, 2013
Published Online: ᭿
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30783
/KAP1
Date: 05-08-13 10:22:51
Pages: 7
Total Synthesis of (Ϯ)-Naphthotectone
Natural Product Synthesis
G. A. Guerrero-Vásquez, C. K. Z. Andrade,
J. M. G. Molinillo, F. A. Macías* ..... 1–7
Practical First Total Synthesis of the Potent
Phytotoxic (Ϯ)-Naphthotectone, Isolated
from Tectona grandis
Keywords: Total synthesis / Natural prod-
ucts / Napthoquinones / Electrochemistry /
Epoxidation / Green chemistry
An efficient total synthesis of (Ϯ)-naphtho-
tectone was achieved in seven steps and
31% overall yield. This natural product has
been proposed as one of the compounds re-
sponsible for the allelopathic activity of
Tectona grandis. The synthetic route in-
cludes an aqueous Wittig olefination, a
Corey–Chaikovsky epoxidation, and an in-
novative one-pot anodic electrooxidation
and demethylation.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7