Cytotoxicity of lapachol, β-lapachone and related synthetic 1,4-naphthoquinones against oesophageal cancer cells

Article abstract of DOI:10.1016/j.ejmech.2012.12.048

Naphthoquinones have been found to have a wide range of biological activities, including cytotoxicity to cancer cells. The secondary metabolites lapachol, α- and β-lapachone and a series of 25 related synthetic 1,4-naphthoquinones were screened against the oesophageal cancer cell line (WHCO1). Most of the compounds exhibited enhanced cytotoxicity (IC₅₀ 1.6-11.7 μM) compared to the current drug of choice cisplatin (IC ₅₀ = 16.5 μM). This study also established that the two new synthetic halogenated compounds 12a and 16a (IC₅₀ = 3.0 and 7.3 μM) and the previously reported compound 11a (IC₅₀ = 3.9 μM), were non-toxic to NIH3T3 normal fibroblast cells. Cell death of oesophageal cancer cells by processes involving PARP cleavage caused by 11a was shown to be associated with elevated c-Jun levels, suggesting a role for this pathway in the mechanism of action of this cohort of naphthoquinone compounds.

Full text of DOI:10.1016/j.ejmech.2012.12.048

Accepted Manuscript
Cytotoxicity of lapachol, β-lapachone and related synthetic 1,4-naphthoquinones
against oesophageal cancer cells
Suthananda N. Sunassee, Clinton G.L. Veale, Nelusha Shunmoogam-Gounden,
Omalaja Osoniyi, Denver T. Hendricks, Mino R. Caira, Jo-Anne de la Mare, Adrienne
L. Edkins, Antônio V. Pinto, Eufrânio N. da Silva Júnior, Michael T. Davies-Coleman
PII:
S0223-5234(13)00004-4
10.1016/j.ejmech.2012.12.048
EJMECH 5919
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 9 August 2012
Revised Date: 27 November 2012
Accepted Date: 30 December 2012
Please cite this article as: S.N. Sunassee, C.G.L. Veale, N. Shunmoogam-Gounden, O. Osoniyi,
D.T. Hendricks, M.R. Caira, J.-A.d.l. Mare, A.L. Edkins, A.V. Pinto, E.N. da Silva Júnior, M.T.
Davies-Coleman, Cytotoxicity of lapachol, β-lapachone and related synthetic 1,4-naphthoquinones
against oesophageal cancer cells, European Journal of Medicinal Chemistry (2013), doi: 10.1016/
j.ejmech.2012.12.048.
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Graphical Abstract

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Cytotoxicity of lapachol, β-lapachone and related synthetic 1,4-naphthoquinones
against oesophageal cancer cells
Suthananda N. Sunassee,a* Clinton G. L. Veale,a Nelusha Shunmoogam-Gounden,b
Omalaja Osoniyi,b Denver T. Hendricks,b Mino R. Caira,c Jo-Anne de la Mare,d Adrienne
L. Edkins,d Antônio V. Pinto,e Eufrânio N. da Silva Júnior,f and Michael T. Davies-
Colemana
aDepartment of Chemistry, Rhodes University, Grahamstown 6140, South Africa; bDivision
of Medical Biochemistry, University of Cape Town, Medical School, Anzio Road,
Observatory, Cape Town 7925, South Africa; cDepartment of Chemistry, University of Cape
Town, Rondebosch, South Africa; dBiomedical Biotechnology Research Unit, Department
of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown 6140,
South Africa; eNatural Products Research Nucleus, Federal University of Rio de Janeiro,
P.O. Box 69035, 21944-971 Rio de Janeiro, RJ, Brazil; fInstitute of Exact Sciences,
Department of Chemistry, Federal University of Minas Gerais, 31270-901, Belo Horizonte,
MG, Brazil.
Corresponding author: Dr. Suthananda N. Sunassee, Present Address: Molecular Targets
Laboratory, Center for Cancer Research, Frederick National Laboratory for Cancer
Research, Frederick, MD 21702 Tel: +1-301-846-7413, Fax: +1-301-846-6851,
snsunassee@gmail.com.
Abstract: Naphthoquinones have been found to have a wide range of biological activities,
including cytotoxicity to cancer cells. The secondary metabolites lapachol, α- and β-
lapachone and a series of 22 related synthetic 1,4-naphthoquinones were screened against
the oesophageal cancer cell line (WHCO1). Most of the compounds exhibited enhanced
cytotoxicity (IC50 1.6 to 11.7 µM) compared to the current drug of choice cisplatin (IC50 =
16.5 µM). This study also established that the two new synthetic halogenated compounds
12a and 16a (IC50 = 3.0 and 7.3 µM) and the previously reported compound 11a (IC50 = 1.5
µM), were non-toxic to NIH3T3 normal fibroblast cells. Cell death of oesophageal cancer
cells by processes involving PARP cleavage caused by 11a was shown to be associated
with elevated c-Jun levels, suggesting a role for this pathway in the mechanism of action of
this cohort of naphthoquinone compounds.
Keywords: Naphthoquinones, cytotoxicity, SAR, oesophageal cancer cell line WHCO1.
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1. Introduction
Quinones, including 1,4-naphthoquinones, are ubiquitous in nature [1,2] and several well-
known anti-cancer drugs used to treat solid tumors (e.g. doxorubicin, mitomycin and
mitoxantrone) possess a quinonoid structure [3,4]. These compounds have also been
identified as privileged structures due to their biological activities and structural properties
[5] that have been linked to the stimulation of oxidative stress and alkylation of cellular
nucleophiles in cancer cells [6].
Squamous cell oesophageal cancer (SCOC) is the second most common form of cancer
reported in poor rural and peri-urban populations in South Africa, with residents of Soweto
near Johannesburg having a five-fold increased chance of developing this form of cancer
when compared with the global average for the incidence of SCOC [7]. The poor remission
rates (20-30%) in early diagnosed cases, albeit current chemotherapeutic interventions
using cisplatin and 5-fluorouracil [8], prompted an ongoing programme in South Africa
aimed at the discovery of new natural product-derived compounds exhibiting potential anti-
oesophageal cancer activity [9,10].
Recently, we have been attracted to the activity of the naturally occurring 1,4-
naphthoquinone lapachol (1, Figure 1), originally isolated from the wood of several
Brazilian tree species of the family Bignoniaceae [11]. Lapachol has a well-documented
history of cancer cell cytotoxicity [11], including activity against squamous cell carcinomas
[12]. The closely related secondary metabolite β-lapachone (2, Figure 1), has recently been
shown to exhibit exploitable activity against various cancer molecular targets [13-16] and is
currently in phase II clinical trials in the USA for the treatment of advanced solid tumors
[17]. Although compound 1 has been licensed in Brazil for general clinical practice as a
carcinostatic drug [18], and several studies pertaining to its anticancer properties have been
reported [4], there remains some dissension over the effectiveness of 1 as an anticancer
drug per se due to the reportedly high doses required to achieve therapeutic efficacy, with
some side effects observed in treated patients [11]. However, the relative chemical
structural simplicity of 1 and 2, coupled with their well-established cytotoxicity continues
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to inspire synthetic attempts to improve the cancer cell cytotoxicity and therapeutic efficacy
of these secondary metabolites [4,11,16,19-23], with a recent renewed interest in β-
lapachone [16,22,23] as a molecular template. Recently, the potential of 1 and 2 as
prototypes to obtain novel anticancer derivatives was explored and several substances were
described with potent activity against diverse cancer cell lines with IC50 values lower than
that of doxorubicin, an important drug used in the therapeutic treatment of cancer [24].
To the best of our knowledge, the secondary metabolites 1 and 2 have not previously been
screened for their cytotoxicity against oesophageal cancer cells, and we report here their
activities against the WHCO1 oesophageal cancer cell line (a cell line derived from a South
African cancer patient) [25], along with a series of 24 related synthetic 1,4-
naphthoquinones (Table 1).
Our initial foray into this broad-based structure activity relationship (SAR) study was the
synthesis of the marine natural product 2-deoxylapachol (3, Figure 1) [26], originally
isolated from the New Zealand brown alga Landsburgia quercifolia and found to be
cytotoxic (IC50 = 2.7 µM) against P-388 leukemia cells [27]. Simultaneously, we prepared a
number of simple (8-10 and 11a, Figure 1), where the effect on cytotoxicity of benzylic
hydroxylation compared to hydroxylation at C-2 on the 1,4-naphthoquinone nucleus of 1
and the absence of the hydroxyl functionality in 3 was established by the preparation of 8
[26]. The improved activity of 8 (IC50 = 5.2 ꢀM) compared to 1 and 3 (Table 1), encouraged
us to further explore the possible role of the oxygenated side chain in defining the
cytotoxicity in these compounds. In this preliminary survey [26], the synthetic compound 2-
(1-hydroxy-1-phenylmethyl)-1,4-naphthoquinone (11a), was found to be the most cytotoxic
(IC50 = 1.5 ꢀM), ca. eleven times more potent than the current drug of choice cisplatin (IC50
= 16.5 µM) against the WHCO1 cell line [10]. In this SAR study, we describe an
investigation of the effect of different variations on the phenyl moiety in 11a in an effort to
develop chemical entities with enhanced pharmacological activity against the WHCO1
oesophageal cancer cell line.
Figure 1. HEREABOUTS
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2. Results and Discussion
2.1. Chemistry
Lapachol was extracted from the heartwood of Tabebuia sp. (Tecoma) and purified by a
series of recrystallizations, generally using hexane as solvent. Initially, β-lapachone (2), α-
lapachone (7) and their derivatives 3-hydroxy-β-lapachone (4) and 3-bromo-β-lapachone (5)
were prepared from 1, by reaction with sulfuric acid, CH3COOH/HCl, m-CPBA and
bromine respectively, as previously reported [28], whilst nor-β-lapachone (6) was
synthesized in two steps by the Hooker oxidation of lapachol [29].
Our approach to the SAR study around 11a was three fold. First, the role of the phenyl ring
in defining the cytotoxicity of 11a was explored through (i) the synthesis of five variably
halogenated analogues of 11a (12a-16a); (ii) replacing the phenyl ring with naphthyl and
furanyl moieties to afford 17a and 18a respectively and (iii) extending the length of the side
chain containing the phenyl ring to yield 19a (Scheme 1). Second, the centrality of the
benzylic hydroxyl group to the cytotoxicity of 11a was initially investigated by oxidation of
this functionality to afford 11b, and further oxidation of the benzylic alcohol in 12a-19a to
yield 12b-19b respectively, along with the ultimate removal of the hydroxyl functionality to
afford 11c (Scheme 2). Third, the importance of the benzylic carbon to cytotoxicity was
investigated by direct coupling of the 1,4-naphthoquinone nucleus to a phenyl ring to give
2-phenyl-1,4-naphthoquinone (20, Figure 1).
Adapting the strategy previously used by our research group to prepare 11a [26], we
synthesized compounds 12a-16a from the same aldehyde precursor (21) using standard
Grignard methodology to yield the dimethoxynaphthalene derivatives 23a-27a, which were
then subjected to standard oxidative demethylation using cerium ammonium nitrate (CAN)
to obtain the respective naphthoquinones in high yields (80-94%, Scheme 1) . The Grignard
approach was also used to prepare 17a and 19a in moderate yields (43% and 48%
respectively after 2 steps, Scheme 1). Conversely, the furanyl naphthoquinone 18a was
accessed from 21 via an n-BuLi mediated metal-halogen exchange of 3-bromofuran
(Scheme 1) [30].
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Scheme 1. HEREABOUTS
The central role of the benzylic alcohol at position C-1` was explored through the oxidation
of the hydroxyl functionality in compounds 22a-30a to obtain the dimethoxynaphthalenes
22b-30b in generally quantitative yields (72-100%), followed by CAN deprotection to yield
the keto-naphthoquinones 11b and 12b-19b respectively (Scheme 2). A Ley oxidation [31]
was used to oxidize all benzylic alcohols, with the exception of 28a and 29a where yields
of 91% and 72% for 28b and 29b respectively were achieved when using MnO2 in CH2Cl2.
Additionally, to investigate the full effect of oxygenation of the C-1` position on the
cytotoxic effect of these naphthoquinone compounds, the C-1` benzylic alcohol
functionality was removed by refluxing a solution of the dimethoxynaphthalene precursor
22b, triethylsilane and boron trifluoride etherate for 2 h at 80-95 °C [32], followed by a
CAN oxidative demethylation to yield the desired naphthoquinone 11c (Scheme 2, 49%
yield after 2 steps) [33]. Finally, we completed our array of synthetic compounds available
for our SAR studies, by preparing the naphthoquinone 20 (Figure 1) in 80% yield via
standard palladium acetate mediated coupling of a phenyl ring to 1,4-naphthoquinone [34].
Cognizant of the importance of the biological testing of enantiomerically pure chiral
compounds, we generated both enantiomers of 11a, by initial derivatization of 22a using (-
)-(S)-camphanic chloride to yield a mixture of the (R,S) and (S,S)-diastereomers 31 and 32
respectively (Scheme 3). Separation of these two diastereomers using normal phase HPLC
(99% CH2Cl2 and 1% EtOAc) and subsequent crystallization of 31 from aqueous methanol
provided an opportunity to establish the R-configuration of C-1’ in this compound from
single crystal analysis (Scheme 3). Finally, saponification of the two diastereomers 31 and
32 using KOH in EtOH, followed by standard CAN oxidative demethylation afforded the R
and S enantiomers of naphthoquinone 11a respectively (Scheme 3).
13
All the structures of unpublished compounds were confirmed by 1H and C NMR, IR and
HRESI mass spectra. Compound 31 was obtained in crystalline form and the R-
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configuration at benzylic chiral center C-1`was assigned using x-ray crystallography, as
seen in the ORTEP-3 projection inserted in Scheme 3.
Scheme 2. HEREABOUTS
2.2. Biological Activity
Both natural and synthetic quinones are regularly utilized to explore the cellular
mechanisms underpinning cytotoxicity in cancer cells [35]. The redox properties of
quinones can often trigger cancer cell apoptosis through oxidative stress induced by the in
situ production of reactive oxygen species (ROS) [3] while further evidence suggests that
some quinones can either interchelate directly with DNA or inhibit proteins regulating DNA
replication and nucleotide biogenesis [3,4,35-37]. The MTT assay [38] was utilized to
investigate the cytotoxicity and to calculate the IC50 values of the naturally occurring
naphthoquinones 1, 2 and 7 together with the semi-synthetic and synthetic compounds 4-6,
11a-c, 12a,b-19a,b and 20 (Table 1), using doxorubicin as a positive control (IC50 = 0.5
ꢀM). Furthermore, the synthetic compounds 11a and 12a-16a were tested in a normal cell
(NIH3T3 fibroblast cell) cytotoxicity assay [39] in which only the disubstituted phenyl
derivative 13a and the two fluorinated compounds 14a and 15a were found to be cytotoxic
(IC50 = 7.4, 11.7 and 82.0 ꢀM respectively) . More importantly, the synthetic compounds
11a, 12a and 16a were found to be non-toxic in the NIH3T3 normal fibroblast cell assay.
Table 1. HEREABOUTS
In a recent study, Lee et al.[14] have shown that β-lapachone-induced apoptosis in the
human bladder carcinoma T24 cell line is associated with an increase in activity of the
intracellular cysteine protease caspase-3, which plays an intrinsic role in the final stages of
apoptosis. β-Lapachone 2 has also been shown to induce apoptosis in cancer cells through
the activation of the c-Jun signalling pathway [12] whilst the marine triprenylated
toluhydroquinone KLM 155 has also been shown by Whibley et al. [10] to specifically
activate the JNK/c-Jun pathway in WHCO1 cells to subsequently induce apoptosis. c-Jun is
both a pro- and anti-apoptotic protein, depending on the cellular environment and other
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signals, that enables cells to deal with damage caused by ROS production through the
regulation of antioxidant genes [14,40]. The relationship between caspase and JNK is still
elusive, although there is strong evidence suggesting that JNK can play an important role in
mediating apoptosis [14,41,42]. Increasing emphasis in SCOC chemotherapy has been
placed on the identification of critical survival and proliferation pathways by incorporating
transcription factors such as the c-Jun (AP1) that could serve as potential chemotherapeutic
targets [43].
The secondary metabolites tested in this study showed varying cytotoxicities against the
WHCO1 oesophageal cancer cell line (Table 1). β-Lapachone 2 was found to be the most
potent (IC50 = 1.6 ꢀM), 10 times more active than cisplatin (IC50 = 16.5 µM) [10].
However, 2-deoxylapachol 3, lapachol 1 and α-lapachone 7 were shown to be ten, fifteen
and eighteen times less cytotoxic (IC50 = 15.0, 24.1 and 28.7 ꢀM respectively) than β-
lapachone against the WHCO1 cell line (Table 1). 3-Bromo-β-lapachone (5, IC50 = 1.8 ꢀM)
and nor-β-lapachone (6, IC50 = 2.4 ꢀM) were not significantly more active than β-
lapachone, but they still represent important derivatives that are respectively seven and five
times more potent than cisplatin.
Twelve synthetic compounds (4-6, 12a-19a, 20), excluding compounds reported in our
previous study [26], exhibited ca. 2-9 fold increase in activity (IC50 = 1.8-11.7 ꢀM, Table
1) against the WHCO1 cell line compared to cisplatin, thus representing a significant
contribution to our search for pharmacologically more active chemical entities against the
WHCO1 oesophageal cancer cell line.
Halogenation of the phenyl moiety in our SAR study did not appear to improve the activity
compared to 11a, but it is however important to note that two of the halogenated derivatives
12a and 16a (IC50 = 3.0 and 7.3 ꢀM) were more active than cisplatin and were also non-
toxic to NIH3T3 normal fibroblast cells. Interestingly, the chlorinated analogues 12a and
13a were more cytotoxic (IC50 = 3.0 and 3.4 ꢀM respectively) than the fluorinated
compounds 14a and 15a (IC50 = 5.1 and 5.5 ꢀM respectively). The cytotoxicity of the
naphthyl, furanyl and phenylethyl derivatives (17a-19a) were found to be 2.4, 10.9 and 4.8
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ꢀM respectively (Table 1), indicating that substitution of the phenyl moiety of compound
11a with these particular functionalities and/or extending the benzylic side chain did not
offer any improvement on the cytotoxicity against the WHCO1 oesophageal cancer cell
line.
The IC50 values obtained for the oxidized products 11b, 12b-19b against oesophageal
cancer cell lines showed a marked increase (Table 1), indicating a significant decrease in
cytotoxicity against the WHCO1 cancer cell line, with 17b having no activity at all.
Therefore, the hydroxyl group at the benzylic position appears to be important in this class
of compounds for increased cytotoxicity against the WHCO1 cell line.
Of interest to us was a comparative study of the apoptotic mechanism of action of the
racemic mixture of 11a and the individual enantiomers R-11a and S-11a with the previously
established mechanism by Whibley et al. [10] for the marine natural product KLM 155. The
individual enantiomers were initially evaluated against the WHCO1 oesophageal cancer cell
line and were found to exhibit similar cytotoxicity (IC50 WHCO1, R-11a = 4.3 ꢀM and S-
11a = 3.8 ꢀM) to the racemate 11a (Table 1). Although the IC50 value (3.9 ꢀM) obtained for
11a is somewhat higher than the previously reported IC50 of 1.5 ꢀM [26], the relative
difference between the individual enatiomers R-11a and S-11a and the racemate suggests
that the absolute configuration at the benzylic position has no effect on the cytotoxicity of
11a.
Figure 2. HEREABOUTS
A Western blot analysis was performed in order to simultaneously determine whether 11a,
R-11a and S-11a caused PARP cleavage (indicative of apoptosis) in oesophageal cancer
cells [44] and to investigate the expression levels of c-Jun (Figure 2). The WHCO1
oesophageal cancer cells were treated with varying concentrations of each compound and
protein was extracted at the relevant time points. PARP (poly adenosine-diphosphate ribose
polymerase) is a known caspase-3 substrate and cleavage of PARP into 116 kDa and 85 kDa
fragments is indicative of apoptosis [44], as shown by WHCO1 cells treated with
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doxorubicin (dox) as a positive control (Figure 2). PARP cleavage was clearly observed in
cells treated with 11a, R-11a and S-11a at a concentration of 20 ꢀM (Figure 2), whilst only
slight PARP cleavage was observed with lower concentrations (< 20 ꢀM) at all time points
(Figure 2). A concentration-dependent increase in c-Jun levels was observed after all
treatment time points (Figure 2), with the highest expression observed after 24h followed
by a decline in expression at 48 h (Figures 2B and 2C). These results suggest the activation
of the JNK/c-Jun signalling pathway and the associated cleavage of PARP in WHCO1 cells,
in a similar manner to the marine natural product KLM 155 [10]. This is the first example
of JNK/c-Jun activation in oesophageal cancer cells by naphthoquinone compounds.
3. Conclusion
This SAR study has revealed that the previously established cytotoxicity of 11a against the
WHCO1 oesophageal cancer cells was comparable to that of the well-known cytotoxic
natural product β-Lapachone 2 and more than 10-16 fold greater than the related secondary
metabolites lapachol 1 and 2-deoxylapachol 3 respectively. Substitution around the phenyl
ring in 11a, replacement of the phenyl ring with either naphthyl or furanyl rings or
extending the length of the phenyl substituted side-chain did not appear to significantly
enhance the cytotoxicity to oesophageal cancer cells. A considerable reduction in
cytotoxicity was observed when the benzylic hydroxyl group in 11a and related synthetic
analogues 12a-19a was oxidized to yield the keto compounds 11b, 12b-19b or removed
completely to provide compounds 11c and 20. This indicates the key role that this benzylic
hydroxyl functionality plays in enhancing the cytotoxicity observed within this cohort of
compounds. Chiral resolution of the racemic mixture of 11a revealed equipotent
cytotoxicity to WHCO1 oesophageal cancer cells for both enantiomers (R-11a and S-11a )
compared to the racemate. Although variable halogenation of the phenyl ring has not
yielded more active compounds than 11a in our SAR study, we have however produced
two compounds 12a and 16a that are both significantly more cytotoxic (IC50 = 3.0 and 7.3
ꢀM respectively) than the current drug of choice cisplatin and, more importantly, are both
non-toxic to NIH3T3 normal fibroblast cells. Additionally, compound 11a was also found to
be non-toxic to NIH3T3 normal fibroblast cells and has also been shown to induce
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apoptosis in WHCO1 oesophageal cancer cells by activating the key JNK/c-Jun signalling
pathway, in a similar manner to the marine natural product KLM155. The relatively facile
synthetic accessibility of the cytotoxic compounds 11a, 12a and 16a renders this SAR study
a useful starting point in the search for new and improved pharmacologically improved
chemotherapeutic agents against oesophageal cancer.
4. Experimental Section
4.1. Chemistry
Melting points were measured using a Gallenkamp melting point apparatus without
correction. NMR spectra were acquired using standard pulse sequences on Bruker Avance
400 MHz and 600 MHz Avance II spectrometers. Chemical shifts are reported in ppm and
referenced to residual protonated solvent resonances with TMS as the internal standard.
Coupling constants are reported directly from the NMR spectra and corresponding coupling
constants have not been matched. Optical rotations were measured on a Perkin-Elmer 141
polarimeter at the sodium-D line (589 nm). Following standard protocol, the concentration
of solutions used to determine optical rotations is expressed in g/100 mL. Infrared spectra
were recorded on a Perkin-Elmer Spectrum 2000 FT-IR spectrometer and Digilab FTS 3100
Excalibur HE Series with compounds as films (neat) on NaCl discs. Low resolution mass
spectra were recorded on a Finnigan GCQ spectrometer at 70 eV. Normal phase semi-
preparative HPLC separations were performed on a Whatman Magnum 9 Partisil 10
column and normal phase analytical HPLC separations were performed on a Lux 5u
Cellulose-1 0.25 ꢀm column using a Spectra-Physics Spectra-Series P100 isocratic pump
and a Waters 410 Differential Refractometer. All reactions requiring anhydrous conditions
were conducted in either flame-dried or oven-dried apparatus under an atmosphere of dry
argon/nitrogen or using an anhydrous calcium chloride drying tube. Dry solvents were
prepared by standard procedures as described by Perrin and Armarego [45] and stored over
appropriate drying agent under an atmosphere of dry nitrogen or argon. High-resolution
mass spectrometry was performed on a Waters API Q-TOF Ultima instrument using
electron-spray ionization in the positive ion mode (ESI+).
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4.2. Synthetic Procedure
Compounds 11b [46], 11c [33, 47] and 22b [47] have been reported previously.
The syntheses of the 1,4-dimethoxynaphthalene precursors 23a and 23b, using methods A
and B respectively, followed by their subsequent CAN oxidative demethylation (Method C)
to yield the respective 1,4-naphthoquinone compounds 12a and 12b are described below as
representatives of the 2-(1`-hydroxy-phenyl-methyl) and 2-benzoyl-1,4-naphtoquinone
series of compounds respectively. The syntheses of 18a and 29a are also described below.
4.3. Method A
A solution of Grignard reagent (3-5 eq.) was added to a cooled solution (-10 °C) of the
aldehyde 21 (1 eq.) in 6 mL anhydrous THF under an Ar atmosphere. The resulting solution
was stirred for 1 h at -10 °C and gradually allowed to reach r.t. The mixture was stirred for a
further 16 h at r.t. before being quenched with sat. NH4Cl (10 mL) and extracted with
CHCl3 (3 × 3 mL). The combined organic extracts were washed with water (2 × 5 mL) and
sat. brine (1 × 5 mL), dried over MgSO4 and concentrated under vacuum. The resulting
benzylic alcohol product was purified by normal phase semi-preparative HPLC.
4.4. Method B
4.4.1. N-morpholine-N-oxide (2-3 eq.), powdered 4Å molecular sieves (60 mg) and
tetrapropylammonium perruthenate (TPAP) (0.5 eq) were added to a solution of 1,4-
dimethoxynaphthalene benzylic alcohol (1 eq.) in anhydrous CH2Cl2 under an atmosphere
of argon. After stirring for 2 h the reaction mixture was filtered through a silica/celite plug
and concentrated under vacuum to yield the product without the need for further
purification.
4.4.2. The 1,4-dimethoxynaphthalene benzylic alcohol (1 eq.) was dissolved in anhydrous
CH2Cl2 and finely powdered MnO2 (30 eq.) was added. The solution was stirred at ambient
temperature for 48 h and filtered through Celite (coarse 545) to afford the product without
any purification.
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4.5. Method C
A solution of 2-3 eq. of cerium ammonium nitrate (CAN) in water (0.3 mL) was added
dropwise to a solution of the dimethoxynaphthalene precursor (1 eq.) in MeCN (5 mL) until
a deep yellow colour persisted. The mixture was diluted with water (5 mL) and extracted
with Et2O (3 × 2 mL). The combined organic extracts were washed with water (5 mL) and
sat. brine (5 mL), dried over Na2SO4 and the solvent evaporated in vacuo. The 1,4-
naphthoquinone products were purified by normal phase semi-preparative HPLC.
4.6. Synthesis of compounds 11a and 22a.
Compounds 11a and 22a were synthesized according to the procedure previously described
1
by us and the H, 13C, IR, LRMS and HRMS data obtained for R-11a and S-11a were
congruent with the data of the racemic mixture of 11a [26].
22
22
R-11a : [α]D +29 (c 1.29, CHCl3) and S-11a : [α]D -26 (c 1.23, CHCl3).
4.7. 2-[1`-Hydroxy-1`-(5`-chlorophenyl)methyl-)-1,4-naphthoquinone (12a).
Standard CAN oxidative demethylation of 23a (119 mg, 0.36 mmol) using method C,
followed by purification using normal phase semi-preparative HPLC (33% EtOAc, 67%
hexane) of the crude product afforded 12a (86 mg, 0.28 mmol) as a yellow amorphous
solid. Yield: 80%; IR (film) νmax cm-1 3449, 1654, 1590, 1487, 1297, 1253, 1140, 1051,
944, 776, 743, 715, 600; 1H NMR (CDCl3, 600 MHz) δ 8.05 (1H, m, H-5), 8.01 (1H, m, H-
8), 7.71 (2H, m, H-6, H-7), 7.40 (2H, m, H-3`, H-7`), 7.32 (2H, m, H-4`, H-6`), 7.04 (1H, d,
J = 1.3 Hz, H-3), 5.93 (1H, d, J = 3.1 Hz, H-1`); 13C NMR (CDCl3, 150 MHz) δ 185.1 (qc,
C-4), 185.0 (qc, C-1), 150.5 (qc, C-2), 138.7 (qc, C-2`) 134.3 (qc, C-5`), 134.2 (CH, C-7),
133.6 (2 × CH, C-3, C-6), 132.0 (qc, C-8a), 131.9 (qc, C-4a), 128.9 (2 × CH, C-4`, C-6`),
128.3 (2 × CH, C-3`, C-7`), 126.6 (CH, C-8), 126.3 (CH, C-5), 70.4 (CH, C-1`); EIMS m/z
(rel. int.) 298 [M+] (98), 262 (5), 234 (5) 205 (5), 187 (18), 186 (100), 158 (18), 130 (25),
111 (10), 102 (10), 77 (5); HREIMS m/z 298.0388 (calcd for C17H11O3Cl [M+] 298.0397).
4.8. 2-[1`-Hydroxy-1`-(5`-chloro-3`-methylphenyl)methyl)-1,4-naphthoquinone (13a).
Standard CAN oxidative demethylation of 24a (71 mg, 0.21 mmol) using method C,
followed by purification using normal phase semi-preparative HPLC (20% EtOAc, 80%
12

ACCEPTED MANUSCRIPT
Hexane) of the crude afforded 13a (56.1 mg, 0.18 mmol) as a yellow amorphous solid.
Yield: 87%; IR (film) νmax cm-1 3515, 1657, 1591, 1483, 1303, 1255, 1143, 1045, 938, 877,
1
770, 747, 714, 698; H NMR (CDCl3, 600 MHz) δ 8.07 (1H, m, H-5), 8.04 (1H, m, H-8),
7.74 (2H, m, H-6, H-7), 7.31 (1H, d, J = 8.2 Hz, H-7’) 7.19 (1H, m, H-4’), 7.17 (1H, m, H-
13
6’), 6.85 (1H, d, J = 1.26 Hz, H-3), 6.13 (1H, d, J = 2.9 Hz, H-1’), 2.42 (3H, s, H-8’); C
NMR (CDCl3, 150 MHz) δ 185.3 (qc, C-4), 185.1 (qc, C-1), 150.5 (qc, C-2), 137.7 (qc, C-
3’), 136.3 (qc, C-2’), 134.2 (CH, C-7), 134.1 (CH, C-3), 134.0 (qc, C-5’), 133.9 (CH, C-6),
132.1 (qc, C-8a), 131.9 (qc, C-4a), 130.7 (CH, C-4’), 128.1 (CH, C-7’), 126.7 (CH, C-6’),
126.6 (CH, C-8), 126.4 (CH, C-5), 67.0 (CH, C-1’), 19.1 (CH3, C-8’); EIMS m/z (rel. int.)
312[M+] (75), 299 (8), 297 (20), 295 (8), 260 (8), 231 (5), 202 (7), 187 (18), 186 (100), 158
(18), 153 (7), 130 (22), 125 (9), 105 (3), 102 (9), 89 (6), 77 (4); HREIMS m/z 312.0555
(calcd for C18H13O3Cl [M+] 312.0548).
4.9. 2-[1`-Hydroxy-1`-(5`-fluorophenyl)methyl]-1,4-naphthoquinone (14a).
Standard CAN oxidative demethylation of 25a (63 mg, 0.20 mmol) using method C,
followed by purification using normal phase semi-preparative HPLC (20% EtOAc, 80%
Hexane) of the crude afforded 14a (50.8 mg, 0.18 mmol) as a yellow amorphous solid.
Yield: 90%; IR (film) νmax cm-1 3394, 1651, 1591, 1330, 1300, 1218, 1147, 1057, 1032,
916, 769, 740,719, 697; 1H NMR (CDCl3, 600 MHz) δ 8.06 (1H, m, H-5), 8.02 (1H, m, H-
8), 7.72 (2H, m, H-6, H-7), 7.44 (2H, m, H-3`, H-7`), 7.05 (1H, m, H-3), 7.04 (2H, m, H-4`,
H-6`), 5.95 (1H, d, J = 3.4 Hz, H-1`); 13C NMR (CDCl3, 150 MHz) δ 185.2 (qc, C-4), 185.0
(qc, C-1), 162.6 (qc, d, JF,C = 247.4 Hz C-5`), 150.7 (qc, C-2), 136.0 (qc, d, JF,C = 2.3 Hz, C-
2`), 134.0 (CH, C-7), 133.9 (CH, C-6), 133.5 (CH, C-3), 133.1 (qc, C-8a), 131.9 (qc, C-4a),
128.8 (2 × CH, d, JF,C = 7.9 Hz, C-3`, C-7`), 126.6 (CH, C-8), 126.3 (CH, C-5), 115.7 (2 ×
CH, d, JF,C = 21.3 Hz, C-4`, C-6`), 70.3 (CH, C-1`), EIMS m/z (rel. int.) 282 [M+] (100) 265
(3), 249 (3), 225 (3), 207 (3), 187 (10), 186 (78), 158 (17), 130 (22), 123 (10), 102 (10), 95
(10), 77 (3), 69 (2); HREIMS m/z 282.0701 (calcd for C17H11O3F [M+] 282.0692).
4.10. 2-[1`-Hydroxy-1`-(4`-fluorophenyl)methyl]-1,4-naphthoquinone (15a).
Standard CAN oxidative demethylation of 26a (53 mg, 0.17 mmol) using method C,
followed by purification using normal phase semi-preparative HPLC (20% EtOAc, 80%
13

ACCEPTED MANUSCRIPT
Hexane) of the crude afforded 15a (39.8 mg, 0.14 mmol) as a brown oil. Yield: 83%; IR
1
(film) νmax cm-1 3456, 1658, 1590, 1300, 1250, 1142, 1048, 957, 784, 757, 731, 702; H
NMR (CDCl3, 600 MHz) δ 8.06 (1H, m, H-5), 8.03 (1H, m, H-8), 7.73 (2H, m, H-6, H-7),
7.32 (1H, m, H-6’), 7.23 (1H, d, J = 7.7 Hz, H-7’), 7.18 (1H, m, H-3’), 7.02 (1H, d, J = 1.2
Hz, H-3), 6.99 (1H, m, H-5’), 5.95 (1H, d, J = 3.8 Hz H-1’); 13C NMR (CDCl3, 150 MHz) δ
185.1 (qc, C-4), 185.0 (qc, C-1), 162.9 (qc, d, JF,C = 246.0 Hz C-4’), 150.3 (qc, C-2), 142.7
(qc, d, JF,C = 6.7 Hz, C-2’), 134.2 (CH, C-7), 133.9 (CH, C-6), 133.9 (CH, C-3), 132.0 (qc,
C-8a), 131.9 (qc, C-4a), 130.3 (CH, d, JF,C = 8.5 Hz, C-6’), 126.6 (CH, C-8), 126.3 (CH, C-
5), 122.5 (CH, d, JF,C = 3.0 Hz, C-7’), 115.4 (CH, d, JF,C = 21.3 Hz, C-5’), 113.9 (CH, d,
JF,C = 22.5 Hz, C-3’), 70.4 (CH, d, JF,C = 2.2 Hz, C-1’); EIMS m/z (rel. int.) 282 [M+] (100),
263 (8), 218 (19), 187 (15), 186 (42), 158 (12), 130 (12), 123 (8), 102 (7), 95 (7), 77 (4), 69
(5); HREIMS m/z 282.0688 (calcd for C17H11O3F [M+], 282.0692).
4.11. 2-[1`-Hydroxy-1`-(4`-chlorophenyl)methyl]-1,4-naphthoquinone (16a).
Standard CAN oxidative demethylation of 27a (51 mg, 0.16 mmol) using method C,
followed by purification using normal phase semi-preparative HPLC (20% EtOAc, 80%
Hexane) of the crude afforded 16a (39.1 mg, 0.13 mmol) as a brown oil. Yield: 82%; IR
1
(film) νmax cm-1 3468, 1661, 1592, 1301, 1250, 1143, 1051, 943, 781, 741, 700; H NMR
(CDCl3, 600 MHz) δ 8.06 (1H, m, H-5), 8.03 (1H, m, H-8), 7.73 ( 2H, m, H-6, H-7), 7.45
(1H, s, H-3`), 7.35 (1H, m, H-7`), 7.29 (1H, m, H-6`), 7.27 (1H, m, H-5`), 7.04 (1H, d, J =
13
1.1 Hz, H-3), 5.93 (1H, d, J = 3.5 Hz, C-1`); C NMR (CDCl3, 150 MHz) δ 185.1 (qc, C-
4), 184.9 (qc, C-1), 150.2 (qc, C-2), 142.2 (qc, C-2`), 134.7 (qc, C-4`), 134.2 (CH, C-7),
133.9 (CH, C-6), 133.79 (CH, C-3), 131.9 (qc, C-8a), 131.8 (qc, C-4a), 130.0 (CH, C-6`),
128.6 (CH, C-5`), 127.0 (CH, C-3`), 126.6 (CH, C-8), 126.3 (CH, C-5), 125.1 (CH, C-7`),
70.4 (CH, C-1`); EIMS m/z (rel. int.) 298 [M+] (100), 282 (3), 263 (9), 205 (4), 187 (18),
186 (60), 158 (14), 130 (18), 111 (8), 102 (8), 77 (5); HREIMS m/z 299.0485 (calcd for
C17H12O3Cl [M+H]+ 299.0475).
4.12. 2-(1`-Hydroxy-1`-naphthylmethyl)-1,4-naphthoquinone (17a).
Standard CAN oxidative demethylation of 28a (48.2 mg, 0.14 mmol) using method C and
subsequent chromatography (25% EtOAc, 75% hexane) afforded 17a (23.1 mg, 0.07 mmol)
14

ACCEPTED MANUSCRIPT
as a yellow oil. Yield: 50%; IR (film) νmax cm-1 3433, 3059, 2919, 1664, 1349, 1297, 1121,
818, 758; 1H NMR (CDCl3, 600 MHz) δ 8.04 (1H, dd, J = 7.3, 1.2 Hz, H-5), 7.98 (1H, dd, J
= 7.3, 1.1 Hz, H-8), 7.93 (1H, br s, H-3`), 7.82 (1H, d, J = 8.0 Hz, H-10`), 7.82 (1H, m, H-
5`), 7.80 (1H, m, H-8`), 7.70 (1H, td, J = 7.1, 1.5 Hz, H-7), 7.67 (1H, td, J = 7.4, 1.5 Hz, H-
6), 7.53 (1H, dd, J = 8.5, 1.6 Hz, H-11`), 7.47 (1H, td, J = 6.4, 1.6 Hz, H-6`), 7.46 (1H, td,
J = 6.4, 1.7 Hz, H-7`), 7.12 (1H, br d, J = 1.2 Hz, H-3), 6.11 (1H, s, H-1`); 13C NMR
(CDCl3, 150 MHz) δ 185.3 (qc, C-4), 185.0 (qc, C-1), 150.8 (qc, C-2), 137.5 (qc, C-2`),
134.0 (CH, C-7), 133.8 (CH, C-6), 133.6 (CH, C-3), 133.2 (qc, C-4`, C9`), 132.1 (qc, C-8a),
131.9 (qc, C-4a), 128.7 (CH, C-10`), 128.1 (CH, C-5`), 127.7 (CH, C-8`), 126.5 (CH, C-8),
126.4 (CH, C-6`, C7`), 126.3 (CH, C-3`), 126.2 (CH, C-5), 124.4 (CH, C-11`), 71.0 (CH,
C-1`); EIMS m/z (rel. int.) 314 [M+] (33), 296 (100), 284 (13), 268 (21), 241 (9), 239 (21),
186 (2), 155 (13), 128 (8); HRFABMS m/z 314.0935 (calcd for C21H14O3 [M+], 314.0943).
4.13. 2-(1`-Hydroxy-1`-furanylmethyl)-1,4-naphthoquinone (18a).
Standard CAN oxidative demethylation of 29a (34 mg, 0.12 mmol) using method C and
subsequent chromatography (25% EtOAc, 75% hexane) afforded 18a (17 mg, 0.066 mmol)
as a brown solid. Yield: 55%; IR (film) νmax cm-1 3021, 2401, 1666, 1521, 1302, 1216, 929,
757, 669, 518; 1H NMR (CDCl3, 600 MHz) δ 8.05 (2H, m, H-8, H-5), 7.74 (1H, td, J = 7.2,
1.9 Hz, H-7), 7.72 (1H, td, J = 7.5, 1.9 Hz, H-6), 7.49 (1H, m, H-5`), 7.37 (1H, t, J = 1.7
Hz, H-4`), 7.04 (1H, br d, J = 1.3 Hz, H-3), 6.41 (1H, br d, J = 1.7 Hz, H-3`), 5.94 (1H, s,
H-1`); 13C NMR (CDCl3, 150 MHz) δ 185.3 (qc, C-4), 185.2 (qc, C-1), 150.2 (qc, C-2),
143.6 (CH, H-4`), 140.4 (CH, C-5`), 134.1 (CH, C-7), 133.9 (CH, C-6), 133.5 (CH, C-3),
132.1 (qc, C-8a), 131.9 (qc, C-4a), 126.6 (CH, C-5), 126.3 (CH, C-8), 125.4 (qc, C-2`),
108.8 (CH, C-3`), 64.2 (CH, C-1`); EIMS m/z (rel. int.) 254 [M+] (16), 237 (11), 226 (71),
225 (100), 199 (30), 197 (39), 181 (14), 169 (13), 152 (20), 141 (14), 130 (8), 105 (11), 78
(8), 51 (3); HRFABMS m/z 254.0585 (calcd for C15H10O4 [M+], 254.0579).
4.14. 2-(1`-Hydroxy-3`-phenylpropyl)-1,4-naphthoquinone (19a).
Standard CAN oxidative demethylation of 30a (38 mg, 0.12 mmol) according to method C
and purification of the crude mixture using semi-preparative HPLC (25% EtOAc, 75%
hexane) yielded 19a (45 mg, 0.15 mmol) as a brown oil; Yield: 80%; IR (film) νmax cm-1
15

ACCEPTED MANUSCRIPT
1
3442, 3020, 2401, 1662, 1303, 1216, 1064, 926, 756, 667; H NMR (CDCl3, 600 MHz) δ
8.04 (2H, m, H-8, H-5), 7.72 (2H, m, H-7, H-6), 7.25 (2H, t, J = 7.5 Hz, H-8`, H-6`), 7.20
(2H, d, J = 7.0 Hz, H-9`, H-5`), 7.15 (1H, t, J = 7.3 Hz, H-7`), 6.97 (1H, br s, H-3), 4.83
(1H, dd, J = 8.3, 3.3 Hz, H-1`), 2.89 (1H, m, H-3b`), 2.79 (1H, m, H-3a`), 2.14 (1H, m, H-
2b`), 2.00 (1H, m, H-2a`); 13C NMR (CDCl3, 150 MHz) δ 185.4 (qc, C-4), 185.1 (qc, C-1),
151.8 (qc, C-2), 141.0 (qc, C-4`), 134.0 (CH, C-7), 133.8 (CH, C-6), 133.5 (CH, C-3), 132.2
(qc, C-8a), 131.8 (qc, C-4a), 128.5 (2 × CH, C-8`-, C-6`), 128.5 (2 × CH, C-9`, C-5`), 126.4
(CH, C-5), 126.1 (CH, C-7`), 126.0 (CH, C-8), 68.7 (CH, C-1`), 37.8 (CH2, C-2`), 31.8
(CH2, C-3`); EIMS m/z (rel. int.) 292 [M+] (12), 274 (43), 257 (9), 228 (3), 202 (5), 188
(100), 160 (41), 133 (6), 105 (9), 79 (4); HRFABMS m/z 292.1100 (calcd for C19H16O3
[M+], 292.1099).
4.15. 2-[1`-Hydroxy-1`-(5`-chlorophenyl)methyl]-1,4-dimethoxynaphthalene (23a).
Compound 23a was synthesized according to method A using a solution of 4-
chlorophenylmagnesium bromide (1 M, 2.76 mmol, 3.0 eq) and aldehyde 21 (198 mg,
0.917 mmol). Normal phase HPLC (20% EtOAc, 80% hexane) of the crude product
afforded 23a (247 mg, 0.75 mmol) as a pink oil. Yield: 82%; IR (film) νmax cm-1 3396,
2936, 1595, 1368, 997, 769, 719; 1H NMR (CDCl3, 400 MHz) δ 8.22 (1H, d, J = 8.0 Hz, H-
5), 8.0 (1H, d J = 8.3 Hz, H-8), 7.54 (1H, td, J = 7.45, 0.95 Hz, H-7), 7.48 (1H, td, J = 7.6,
1.04 Hz, H-6), 7.39 (2H, d, J = 8.4 Hz, H-4`, 6`), 7.29 (2H, d, J = 8.5 Hz, H-3`, 7`), 6.71
(1H, s H-3), 6.32 (1H, s, 1`) 3.92 (3H, s, OMe-4), 3.82 (3H, s, OMe-1); 13C NMR (CDCl3,
100 MHz) δ 152.4 (qc, C-4), 146.6 (qc, C-1), 142.2 (qc, C-2`), 133.1 (qc, C-5`), 130.9 (qc, C-
2), 128.5 (2 × CH, C-3`, 7`), 128.4 (qc, C-8a), 127.8 (2 × CH, C-4`, 6`), 126.8 (CH, C-7),
126.4 (qc, C-4a), 125.7 (CH, C-6), 122.5 (CH, C-5), 121.9 (CH, C-8), 102.1 (CH, C-3),
70.4 (CH, C1`), 62.7 (CH3, 1-OMe), 55.7 (CH3, 4-OMe); EIMS m/z (rel. Int.) 328 [M+]
(100), 312 (15), 297 (29), 285 (40), 281 (13), 261 (12), 246 (10), 230 (8), 218 (18), 189
(21), 140 (15), 139 (48), 130 (10), 111 (8), 69 (9); HREIMS m/z 328.0877 (calcd for
C19H17O3Cl [M + H)]+, 328.0866).
16

ACCEPTED MANUSCRIPT
4.16. 2-[1`-Hydroxy-1`-(5`-chloro-3`-methylphenyl)methyl]-1,4-dimethoxynaphthalene
(24a).
Compound 24a was synthesized according to method A using a solution of 4-chloro-2-
methyl-phenylmagnesium bromide (0.5 M, 1.38 mmol, 3.0 eq) and aldehyde 21 (100 mg,
0.46 mmol). Normal phase HPLC (20% EtOAc, 80% hexane) of the crude afforded 24a
(150.5 mg, 0.44 mmol) as a yellow amorphous solid. Yield: 96%; IR (film) νmax cm-1 3389,
2937, 1594, 1367, 997, 768, 703; 1H NMR (CDCl3, 600 MHz) δ 8.21 (1H, d, J = 8.4 Hz, H-
5), 8.02 (1H, d, J = 8.3 Hz, H-8), 7.54 (1H, m, H-7), 7.50 (1H, d, J = 8.3 Hz, H-7`), 7.48
(1H, m, H-6), 7.19 (1H, dd, J = 8.3, 2.0 Hz, H-6`), 7.15 (1H, d, J = 1.9 Hz, H-4`), 6.57 (1H,
s, H-3), 6.48 (1H, d, J = 3.5 Hz, H-1`), 3.88 (3H, s, OMe-4), 3.85 (3H, s, OMe-1), 2.26 (3H,
13
s, H-8`); C NMR (CDCl3, 150 MHz) δ 152.3 (qc, C-4), 146.9 (qc, C-1), 139.7 (qc, C-2`),
137.7 (qc, C-3`), 133.0 (qc, C-5`), 130.3 (CH, C-4`), 129.9 (qc, C-2), 128.3 (qc, C-8a), 127.9
(CH, C-7`), 126.8 (CH, C-7), 126.4 (qc, C-4a), 125.9 (CH, C-6`), 125.8 (CH, C-6), 122.5
(CH, C-5), 121.9 (CH, C-8), 102.1 (CH, C-3), 68.7 (CH3, 1-OMe), 67.8 (CH, C-1`), 55.6
(CH3, 4-OMe), 19.1 (CH3, C-8`); EIMS m/z (rel. int.)342 [M+] (100), 327 (15), 311 (11),
295 (22), 279 (10), 263 (12), 244 (5), 231 (5), 218 (29), 202 (10), 189 (22), 173 (8), 155
(22), 153 (62), 131 (13), 125 (10), 69 (10); HREIMS m/z 342.1018 (calcd for C20H19O3Cl
[M+], 342.1023).
4.17. 2-[1`-Hydroxy-1`-(5`-fluorophenyl)methyl]-1,4-dimethoxynaphthalene (25a).
Compound 25a was synthesized according to method A using a solution of 4-
fluorophenylmagnesium bromide (2.0 M, 2.66 mmol, 3.0 eq) and aldehyde 21 (191 mg,
0.89 mmol). Normal phase HPLC (20% EtOAc, 80% hexane) of the crude afforded 25a
(209 mg, 0.67 mmol) as an orange oil. Yield: 75%; IR (film) νmax cm-1 3406, 2937, 1595,
1
1367, 997, 768, 710; H NMR (CDCl3, 400 MHz) δ 8.23 (1H, d, J = 8.3 Hz, H-5), 8.01
(1H, d, J = 8.4 Hz, H-8), 7.54 (1H, t, J = 7.5 Hz, H-7), 7.48 (1H, t, J =7.5 Hz H-6), 7.42
(2H, m, H-3`, H-7`), 7.01 (2H, t, J = 8.6 H-4`, H-6`), 6.7 (1H, s, H-3) 6.34 (1H, s, H-1`),
3.93 (3H, s, OMe-4), 3.81 (3H, s, OMe-1); 13C NMR (CDCl3, 100MHz) δ 162.1 (qc, d, JF,C
= 249.0 Hz, C-5`), 152.4 (qc, C-4), 146.6 ( qc, C-1), 139.5 (qc, d, JF,C = 3.0 Hz, C-2`), 131.2
(qc, C-2), 128.4 (qc, C-8a), 128.1 (2 × CH, d, JF,C = 8.1 Hz, C-3`, 7`), 126.8 (CH, C-7),
126.4 (qc, C-4a), 125.7 (CH, C-6), 122.5 (CH, C-5), 121.9 (CH, C-8), 115.2 (2 × CH, d, JF,C
17

ACCEPTED MANUSCRIPT
= 21.3 Hz, C-4`,6`), 102.1 ( CH, C-3), 70.5 ( CH, C-1`), 62.6 ( CH3, 1-OMe), 55.7 (CH3, 4-
OMe); EIMS m/z (rel. int.) 312 [M+] (100), 297 (8), 281 (12), 269 (35), 265 (12), 249 (10),
237 (10), 209 (11), 189 (12), 173 (8), 145 (5), 124 (5), 123 (40), 95 (7); HREIMS m/z
312.1159 (calcd for C19H17O3F [M+], 312.1162).
4.18. 2-[1`-Hydroxy-1`-(4`-fluorophenyl) methyl]-1,4-dimethoxynaphthalene (26a).
Compound 26a was synthesized according to method A using a solution of 3-
fluorophenylmagnesium bromide (1 M, 1.38 mmol, 3.0 eq) and aldehyde 21 (100 mg, 0.46
mmol). Normal phase HPLC (20% EtOAc, 80% hexane) of the crude afforded 26a (140.7
mg, 0.45 mmol) as an orange oil. Yield: 98%; IR (film) νmax cm-1 3396, 2937, 1590, 1366,
997, 760, 702; 1H NMR (CDCl3, 600 MHz) δ 8.23 (1H, d, J = 8.3 Hz, H-5), 8.02 (1H, d, J
= 8.4 Hz, H-8), 7.54 (1H, t, J = 8.8 Hz, H-7), 7.48 (1H, t, J = 8.8 Hz H-6), 7.27 ( 1H, m, H-
6`), 7.21 (1H, m, H-3`), 7.20 (1H, m, H-7`), 6.93 (1H, m, H-5`), 6.72 (1H, s, H-3), 6.33
13
(1H, s, H-1`), 3.92 (3H, s, OMe-4), 3.83 (3H, s, OMe-1); C NMR (CDCl3, 150 MHz) δ
162.9 (qc, d, JF,C = 246.1 Hz, C-4`), 152.4 (qc, C-4), 146.7 (qc, C-1), 146.4 (qc, d, JF,C = 6.7
Hz, C-2`), 130.9 (qc, C-2), 129.8 (CH, d, JF,C = 8.0 Hz, C-6`), 128.4 (qc, C-8a), 126.8 (CH,
C-7), 126.4 (qc, C-4a), 125.8 (CH,C-6), 122.5 (CH, C-5), 122.0 (CH, d, JF,C = 4.3 Hz, C-
7`), 121.9 (CH, C-8), 114.1 (CH, d, JF,C = 21.4 Hz, C-5`), 113.4 (CH, d, JF,C = 22.2 Hz, C-
3`), 102.1 (CH, C-3), 70.5 (CH, C-1`), 62.7 (CH3, 1-OMe), 55.7 (CH3, 4-OMe); EIMS m/z
(rel. int.) 312 [M+] (100), 296 (10), 281 (11), 269 (31), 249 (11), 220 (10), 209 (12), 189
(10), 183 (4), 159 (4), 145 (4), 124 (8), 123 (52), 95 (7); HREIMS m/z 312.1160 (calcd for
C19H17O3F [M+], 312.1162).
4.19. 2-[1`-Hydroxy-1`-(4`-chlorophenyl)methyl]-1,4-dimethoxynaphthalene (27a).
Compound 27a was synthesized according to method A using a solution of 3-
chlorophenylmagnesium bromide (0.5 M, 1.38 mmol, 3.0 eq) and aldehyde 21 (100 mg,
0.46 mmol). Normal phase HPLC (20% EtOAc, 80% hexane) of the crude afforded 27a
(146.4 mg, 0.45 mmol) as an orange oil. Yield: 97%; IR (film) νmax cm-1 3415, 2937, 1594,
1
1367, 997, 769, 701; H NMR (CDCl3, 600 MHz) δ 8.23 (1H, d, J = 8.3 Hz, H-5), 8.02
(1H, d, J = 8.4 Hz, H-8), 7.55 (1H, m, H-7), 7.49 (2H, m, H-6, 3`), 7.31 (1H, m, H-7`), 7.25
(1H, m, H-6`), 7.22 (1H, m, H-5`), 6.71 (1H, s, H-3), 6.32 (1H, s, H-1`), 3.93 (3H, s, OMe-
18

ACCEPTED MANUSCRIPT
13
4), 3.83 (3H, s, OMe-1); C NMR (CDCl3, 150 MHz) δ 152.44 (qc, C-4), 146.7 (qc, C-1),
145.8 (qc, C-2`), 134.3 (qc, C-4`), 130.8 (qc, C-2), 129.6 (CH, C-6`), 128.4 (qc, C-8a), 127.5
(CH, C-5`), 126.8 (CH, C-7), 126.5 (CH, C-3`), 126.4 (qc, C-4a), 125.8 (CH, C-6), 124.6
(CH, C-7`), 122.5 (CH, C-5), 122.0 (CH, C-8), 102.1 (CH, C-3), 70.6 (CH,C-1`), 62.8
(CH3, 1-OMe), 55.8 (CH3, 4-OMe); EIMS m/z (rel. int.) 328 [M+] (100), 312 (10), 297 (15),
285 (33), 281 (10), 265 (8), 246 (8), 218 (12), 202 (8), 189 (18), 159 (5), 141 (15), 139
(55), 111 (7); HREIMS m/z 328.0859 (calcd for C19H17O3Cl [M+], 328.0866).
4.20. 2-(1`-Hydroxy-1`-naphthylmethyl)-1,4-dimethoxynaphthalene (28a).
A solution of 2-naphthylmagnesium bromide (1.20 g, 5.8 mmol) was prepared in situ
according to the procedure by Beck et al.,3 and added dropwise via cannula to a stirred
solution of the 21 (250 mg, 1.16 mmol) in anhydrous THF (5 mL) at -10 °C. The resulting
solution was stirred for 1 h at -10 °C and then gradually allowed to reach RT. The resulting
mixture was allowed to stir overnight at RT before being quenched with sat. NH4Cl (10
mL) and extracted with Et2O (3 × 3 mL). The combined organic extracts were washed with
water (2 × 5 mL) and sat. brine (1 × 5 mL), dried over Na2SO4 and concentrated under
vacuum to yield a brown solid (858 mg). Normal phase semi-preparative HPLC of the
crude product (25% EtOAc, 75% hexane) afforded 28a (340 mg, 0.99 mmol) as a pale
yellow oil. Yield: 85%; IR (film) νmax cm-1 3407, 3009, 2938, 1508, 1459, 1369, 1092, 999,
756; 1H NMR (CDCl3, 600 MHz) δ 8.23 (1H, d, J = 8.3 Hz, H-5), 8.04 (1H, d, J = 8.4 Hz,
H-8), 7.95 (1H, s, H-3`), 7.83 (1H, m H-5`), 7.80 (1H, m, H-8`), 7.78 (1H, d, J = 8.6 Hz, H-
10`), 7.55 (1H, t, J = 7.5 Hz, H-7), 7.52 (1H, dd, J = 8.6, 1.6 Hz, H-11`), 7.49 (1H, t, J = 7.5
Hz, H-6), 7.47 (H, m, H-6`), 7.46 (1H, m, H-7`), 6.81 (1H, s, H-3), 6.53 (1H, s, H-1`), 3.90
(3H, s, OMe-4), 3.83 (3H, s, OMe-1); 13C NMR (CDCl3, 150 MHz) δ 152.3 (qc, C-4), 146.7
(qc, C-1), 141.1 (qc, C-2`), 133.2 (qc, C-4`), 132.7 (qc, C-9`), 131.3 (qc, C-2), 128.4 (qc, C-
8a), 128.1 (CH, C-10`), 128.1 (CH, C-5`), 127.6 (CH, C-8`), 126.7 (CH, C-7), 126.4 (qc, C-
4a), 126.1 (CH, C-6`), 125.8 (CH, C-7`), 125.6 (CH, C-6), 124.9 (CH, C-11`), 124.8 (CH,
C-3`), 122.5 (CH, C-5), 122.0 (CH, C-8), 102.5 (CH, C-3), 71.0 (CH, C-1`), 62.7 (CH3, 1-
OMe), 55.6 (CH3, 4-OMe); EIMS m/z (rel. int.) 344 [M+] (100), 313 (15), 301 (27), 269 (9),
241 (5), 215 (21), 201 (14), 189 (28), 173 (40), 145 (14), 133 (4); HRFABMS m/z 344.1425
(calcd for C23H20O3 [M+], 344.1412).
19

ACCEPTED MANUSCRIPT
4.21. 2-(1`-Hydroxy-1`-furanylmethyl)-1,4-dimethoxynaphthalene (29a).
A solution of n-butyllithium (1.6 M, 2.9 mL, 4.6 mmol, 10 eq) was added to a solution of 3-
bromofuran (680 mg, 4.6 mmol) in THF (5 mL) at -78 °C and the reaction mixture stirred
(30 min) before a solution of 21 (210 mg, 0.97 mmol) in dry THF (5 mL) was added
dropwise via cannula. The reaction was stirred at -78 °C (30 min) and gradually allowed to
reach RT. The reaction mixture was quenched with sat. NH4Cl (10 mL) and extracted with
EtOAc (3 × 5 mL). The combined organic phases were washed with sat. brine (10 mL),
dried over MgSO4 and concentrated in vacuo to give a brown oil (339 mg). Normal phase
HPLC (25% EtOAc, 75% hexane) of the crude mixture afforded 29a (200 mg, 0.70 mmol)
as a yellow oil. Yield: 73%; IR (film) νmax cm-1 3420, 3014, 2842, 1596, 1461, 1371, 1217,
1
1092,1000, 875, 758; H NMR (CDCl3, 600 MHz) δ 8.23 (1H, d, J = 8.3 Hz, H-5), 8.02
(1H, d, J = 8.3 Hz, H-8), 7.54 (1H, td, J = 6.8, 1.1 Hz, H-7), 7.48 (1H, td, J = 6.8, 1.1 Hz,
H-6), 7.37 (1H, t, J = 1.6 Hz, H-4`), 7.32 (1H, br s, H-5`), 6.83 (1H, s, H-3), 6.39 (1H, br d,
J = 1.1 Hz, H-3`), 6.30 (1H, s, H-1`), 3.94 (3H, s, OMe-4), 3.84 (3H, s, OMe-1); 13C NMR
(CDCl3, 150 MHz) δ 152.3 (qc, C-4), 146.3 (qc, C-1), 143.3 (CH, C-4`), 139.8 (CH, C-5`),
130.6 (qc, C-2), 128.9 (qc, C-2`), 128.3 (qc, C-8a), 126.7 (CH, C-7), 126.4 (qc, C-4a), 125.7
(CH, C-6), 122.4 (CH, C-5), 122.0 (CH, C-8), 109.5 (CH, C-3), 102.0 (CH, C-3`), 64.6
(CH, C-1`), 62.8 (CH3, 1-OMe), 55.7 (CH3, 4-OMe); EIMS m/z (rel. int.) 284 [M+] (54),
252 (100), 239 (24), 236 (10), 209 (29), 196 (15), 181 (25), 165 (15), 152 (42); HRFABMS
m/z 284.1058 (calcd for C17H16O4 [M+], 284.1049).
4.22. 2-(1`-Hydroxy-3`-phenylpropyl)-1,4-dimethoxynaphthalene (30a).
Compound 30a was synthesized according to method A using a solution of
phenylethylmagnesium bromide (1 M, 3.5 mL, 3.5 mmol) and aldehyde 21 (250 mg, 1.16
mmol). Trituration of the crude product with 1:1 hexane/EtOAc afforded 30a (222 mg, 0.70
mmol) as fine white needles. Yield: 60 %; mp 109-110 °C; IR (film) νmax cm-1 3438, 3020,
1597, 1460, 1217, 1000, 770; 1H NMR (CDCl3, 600 MHz) δ 8.25 (1H, d, J = 8.2 Hz, H-5),
8.03 (1H, d, J = 8.2 Hz, H-8), 7.53 (1H, td, J = 7.6, 1.1 Hz, H-7), 7.47 (1H, td, J = 7.6, 1.1
Hz, H-6), 7.28 (2H, t, J = 7.5 Hz, H-6`, H-8`), 7.23 (2H, d, J = 7.0 Hz, H-5`, H-9`), 7.18
(1H, t, J = 7.3 Hz, H-7`), 6.89 (1H, s, H-3), 5.29 (1H, dd, J = 8.3, 4.7 Hz, H-1`), 3.99 (3H,
s, OMe-4), 3.82 (3H, s, OMe-1), 2.90 (1H, ddd, J = 14.3, 10.0, 5.2 Hz, H-2b`), 2.74 (1H,
20

ACCEPTED MANUSCRIPT
ddd, J = 13.9, 9.6, 6.8 Hz, H-2a`), 2.23 (1H, dddd, J = 13.8, 9.4, 8.8, 5.2 Hz, H-3b`), 2.07
13
(1H, m, H-3a`); C NMR (CDCl3, 150 MHz) δ 152.4 (qc, C-4), 146.0 (qc, C-1), 141.8 (qc,
C-4`), 132.0 (qc, C-2), 128.5 (2 × CH, C-5`, C-7`), 128.4 (2 × CH, C-6`, C-8`), 128.4 (qc, C-
8a), 126.6 (CH, C-7), 126.2 (qc, C-4a), 125.8 (CH, C-7`), 125.4 (CH, C-6), 122.4 (CH, C-
5), 121.9 (CH, C-8), 101.6 (CH, C-3), 68.2 (CH, C-1`), 62.6 (CH3, 1-OMe), 55.7 (CH3, 4-
OMe), 39.9 (CH2, C-2`), 32.4 (CH2, C-3`); EIMS m/z (rel. int.) 322 [M+] (73), 304 (12),
217 (100), 202 (17), 189 (29), 174 (12), 159 (9), 105 (5), 93 (3); HRFABMS m/z 322.1569
(calcd for C21H22O3 [M+], 322.1569).
4.23. 2-(5`-Chlorobenzoyl)-1,4-naphthoquinone (12b).
Standard CAN oxidative demethylation of 23b (16 mg, 0.05 mmol) according to method C
and subsequent normal phase semi-preparative HPLC (20% EtOAc, 80% hexane) of the
crude product afforded 12b (12 mg, mmol) as a yellow amorphous solid. Yield: 81%; IR
(film) νmax cm-1 2162, 1665, 1587, 1487, 1401, 1347, 1296, 1251, 1175, 1092, 983, 780,; 1H
NMR (CDCl3, 600 MHz) δ 8.14 (1H, m, H-5), 8.10 (1H, m, H-8), 7.82 (4H, m, H-6, H-7,
H-3`, H-7`), 7.67 (2H, m, C-4`, C-6`) 13C NMR (CDCl3, 150 MHz) δ 190.8 (qc, C-1`),
184.3 (qc, C-4), 183.1 (qc, C-1), 146.7 (qc, C-2), 141.2 (qc, C-2`), 135.9 (qc, C-3), 134.6
(CH, C-6), 134.5 (CH, C-7), 133.8 (qc, C-5`), 131.8 (qc, C-8a), 131.4 (qc, C-4a), 130.91 (2 ×
CH, C-3`, C-7`), 129.91 (2 × CH, C-4`, C-6`), 126.9 (CH, C-8), 126.5 (CH, C-5); EIMS
m/z (rel. int.) 296 [M+] (20), 281 (4), 268 (6), 261 (55), 233 (9), 219 (28), 207 (8), 186 (5),
176 (7), 154 (9), 141 (35), 139 (100), 131 (23), 129 (9), 113 (18), 111 (51), 101 (21), 75
(41), 69 (46), 53 (9), 50 (13); HREIMS m/z 297.0312 (calcd for C17H10O3Cl [M+H]+
297.0313).
4.24. 2-(5`-Chloro-3`-methylbenzoyl)-1,4-naphthoquinone (13b).
Standard CAN oxidative demethylation of 24b using method C (19 mg, 0.06 mmol) and
subsequent normal phase semi-preparative HPLC (20% EtOAc, 80% Hexane) of the crude
afforded 13b (16.4 mg, 0.05 mmol) as a yellow oil. Yield: 88%; IR (film) νmax cm-1 2163,
1
1664, 1592, 1557, 1447, 1345, 1296, 1247, 1103, 1029, 976, 880, 774, 722; H NMR
(CDCl3, 600 MHz) δ 8.13 (1H, m, H-5), 8.08 (1H, m, H-8), 7.81 (2H, m, H-6, H-7), 7.45
(1H, d, J = 8.3 Hz, H-7`), 7.34 (1H, d, J = 1.6 Hz, H-4`), 7.21 (1H, dd, J = 8.3, 1.8 Hz, H-
21

ACCEPTED MANUSCRIPT
13
6`), 6.99 (1H, s, H-3), 2.63 (1H, s, H-8`), C NMR (CDCl3, 150 MHz) δ 193.0 (qc, C-1`),
184.6 (qc, C-4), 183.3 (qc, C-1), 147.5 (qc, C-2), 142. 2 (qc, C-2`), 139.2 (qc, C-3`), 135.8
(CH, C-3), 134.5 (2 × CH, C-6, C-7), 133.5 (qc, C-5`), 132.8 (CH, C-7`), 132.4 (CH, C-4`),
131.9 (qc, C-8a), 131.5 (qc, C-4a), 126.9 (CH, C-8), 126.5 (CH, C-5), 126.0 (CH, C-6`),
21.4 (CH3, C-8`); EIMS m/z (rel. int.) 310 [M+] (62), 275 (58), 276 (12), 275 (56), 265 (10),
254 (17), 247 (12), 219 (12), 202 (8), 189 (17), 186 (45), 155 (31), 153 (100), 130 (17), 127
(25), 125 (77), 105 (13), 101 (29), 89 (63), 75 (32), 63 (23); HREIMS m/z 310.0410 (calcd
for C18H11O3Cl [M+] 310.0397).
4.25. 2-(5`-Fluorobenzoyl)-1,4-naphthoquinone (14b).
Standard CAN oxidative demethylation of 25b using method C (17 mg, 0.05 mmol) and
subsequent normal phase semi-preparative HPLC (20% EtOAc, 80% Hexane) of the crude
afforded 14b (7.6 mg, 0.027 mmol) as a yellow oil. Yield: 54%; IR (film) νmax cm-1 2161,
1
1665, 1594, 1506, 1411, 1346, 1296, 1250, 1156, 160, 774, 719; H NMR (CDCl3, 600
MHz) δ 8.14 (1H, m, H-5), 8.11 (1H, m, H-8), 7.92 (1H, m, H-3`, H-7`), 7.82 (1H, m, H-6,
H-7), 7.17 (1H, m, H-4`, H-6`), 6.99 (1H, s, H-3); 13C NMR (CDCl3, 600 MHz) δ 190.3 (qc,
C-1`), 184.3 (qc, C-4), 183.2 (qc, C-1), 166.6 (qc, d, JF,C = 257.7 Hz, C-5`), 146.9 (qc, C-2),
135.7 (CH, C-3), 134.6 (2 × CH, C-6, C-7), 132.4 (2 × CH, d, JF,C = 9.8 Hz, C-3`, C-7`),
131.9 (qc, d, JF,C = 3.1 Hz, C-2`), 131.8 (qc, C-8a), 131.5 (qc, C-4a), 126.9 (CH, C-8), 126.5
(CH, C-5), 116.2 (2 × CH, d, JF,C = 22.4 Hz, C-4`, C-6`); EIMS m/z (rel. int.) 280 [M+]
(42), 252 (7), 224 (4), 219 (13), 207 (5), 186 (5), 157 (5), 130 (12), 123 (100), 104 (8), 101
(13), 95 (51), 75(31), 69 (20), 50 (8); HREIMS m/z 280.0525 (calcd for C17H9O3F [M+]
280.0536).
4.26. 2-(4`-Fluorobenzoyl)-1,4-naphthoquinone (15b).
Standard CAN oxidative demethylation of 26b using method C (21 mg, 0.07 mmol) and
subsequent normal phase semi-preparative HPLC (20% EtOAc, 80% Hexane) of the crude
afforded 15b (16.9 mg, 0.06 mmol) as a yellow oil. Yield: 86%; IR (film) νmax cm-1 3071,
1
2161, 1664, 1588, 1482, 1445, 1347, 1251, 1124, 897, 769, 675; H NMR (CDCl3, 600
MHz) δ 8.15 (1H, m, H-5), 8.11 (1H, m, H-8), 7.83 (2H, m, H-6, H-7), 7.63 (1H, m, H7`),
13
7.60 (1H, m, H-3`), 7.47 ( 1H, m, H-6`), 7.35 (1H, m, H-5`), 7.01 (1H, s, H-3); C NMR
22

ACCEPTED MANUSCRIPT
(CDCl3, 600 MHz) δ 190.8 (qc, d, JF,C = 2.4 Hz, C-1`), 184.2 (qc, C-4), 183.1 (qc, C-1),
162.8 (qc, d, JF,C = 249.8 Hz, C-4`), 146.6 (qc, C-2), 137.5 (qc, d, JF,C = 6.7 Hz, C-2`), 135.9
(CH, C-3), 134.6 (CH, C-7), 134.5 (CH, C-6), 131.8 (qc, C-8a), 131.4 (qc, C-4a), 130.6
(CH, d, JF,C = 7.7 Hz C-6`), 126.9 (CH, C-8), 126.6 (CH, C-5), 125.6 (CH, d, JF,C = 2.7 Hz,
C-7`), 121.6 (CH, d, JF,C = 21.4 Hz, C-5`), 115.9 (CH, d, JF,C = 22.5 Hz, C-3`); EIMS m/z
(rel. int.) 280 [M+] (58), 264 (4), 252 (10), 224 (9), 196 (8), 186 (4), 157 (8), 129 (9), 123
(100), 104 (12), 101 (24), 95 (61), 75 (41), 69 (15); HREIMS m/z 280.0532 (calcd for
C17H9O3F [M+] 280.0536).
4.27. 2-(4`-Chlorbenzoyl)-1,4-naphthoquinone (16b).
Standard CAN oxidative demethylation of 27b using method C (32 mg, 0.1 mmol) and
subsequent normal phase semi-preparative HPLC (20% EtOAc, 80% Hexane) of the crude
afforded 16b (23.6 mg, 0.08 mmol) as a yellow oil. Yield: 80%; IR (film) νmax cm-1 3319,
1
3066, 2159, 1659, 1589, 1426, 1345, 1295, 1238, 917, 781, 734, 591; H NMR (CDCl3,
600 MHz) δ 8.14 (1H, m, H-5), 8.11 (1H, m, H-8), 7.86 (1H, m, H-3`), 7.82 (2H, m, H-6,
H-7), 7.74 (1H, d, J = 7.8 Hz, H-5`), 7.60 (1H, d, J = 7.9 Hz, H-7`), 7.43 (1H, d, J = 7.9 Hz,
13
H-6`), 7.00 (1H, s, H-3); C NMR (CDCl3, 150 MHz) δ 190.8 (qc, C-1`), 184.2 (qc, C-4),
183.1 (qc, C-1), 146.5 (qc, C-2), 137.0 (qc, C-2`), 135.9 (CH, C-3), 135.3 (qc, C-4`), 134.6
(CH, C-7), 134.5 (CH, C-6), 134.4 (CH, C-3`), 131.8 (qc, C-8a), 131.4 (qc, C-4a), 130.2
(CH, C-6`), 129.3 (CH, C-5`), 127.7 (CH, C-7`), 126.9 (CH, C-8), 126.6 (CH, C-5); EIMS
m/z (rel. int.) 296 [M+] (45), 270 (7), 261 (38), 233 (20), 205 (8), 176 (9), 157 (8), 141 (32),
139 (100), 129 (12), 113 (22), 111 (66), 101 (38), 85 (4), 75 (62), 63 (4); HREIMS m/z
296.0252 (calcd for C17H9O3Cl [M+] 296.0240).
4.28. 2-Naphthoyl-1,4-naphthoquinone (17b).
Standard CAN oxidative demethylation of 28b (34 mg, 0.10 mmol) using method C and
subsequent purification of the crude using normal phase semi-preparative HPLC (25%
EtOAc, 75% hexane) yielded 17b (18.7 mg, 0.06 mmol) as a yellow solid. Yield: 60%; IR
1
(film) νmax cm-1 3020, 2401, 1662, 1589, 1469, 1216, 1076, 916, 757, 669; H NMR
(CDCl3, 600 MHz) δ 8.31 (1H, s, H-3`), 8.17 (1H, d, J = 7.1 Hz, H-5), 8.13(1H, d, J = 7.1
Hz, H-8), 8.02 (1H, d, J = 8.6 Hz, H-11`), 7.94 (1H, d, J = 8.6 Hz, H-10`), 7.91 (1H, d, J =
23

ACCEPTED MANUSCRIPT
8.4 Hz, H-5`), 7.89 (1H, d, J = 8.4 Hz, H-8`), 7.84 (1H, td, J = 7.8, 1.5 Hz, H-6), 7.82 (1H,
td, J = 7.8, 1.5 Hz, H-7), 7.63 (1H, t, J = 7.5 Hz, H-6`), 7.55 (1H, t, J = 7.5 Hz, H-7`), 7.06
(1H, s, H-3); 13C NMR (CDCl3, 150 MHz) δ 191.8 (qc, C-1`), 184.5 (qc, C-4), 183.3 (qc, C-
1), 147.2 (qc, C-2), 136.2 (qc, C-4`), 135.6 (CH, C-3), 134.5 (2 × CH, C-7, C-6), 132.9 (qc,
C-2`), 132.7 (CH, C-3`), 132.3 (qc, C-9`), 131.9 (qc, C-4a), 131.6 (qc, C-8a), 129.8 (CH, C-
5`), 129.4 (CH, C-6`), 129.0 (CH, C-10`), 127.9 (CH, C-8`), 127.2 (CH, C-7`), 126.9 (CH,
C-8), 126.5 (CH, C-5), 123.9 (CH, C-11`); EIMS m/z (rel. int.) 312 [M+] (100), 284 (41),
255 (12), 239 (3), 228 (5), 155 (37), 145 (13), 128 (10), 101 (2), 77 (5); HRFABMS m/z
312.0788 (calcd for C21H12O3 [M+], 312.0786).
4.29. 2-Furanoyl-1,4-naphthoquinone (18b).
Standard CAN oxidative demethylation of 29b (22 mg, 0.08 mmol) using method C and
subsequent purification of the crude using normal phase semi-preparative HPLC (25%
EtOAc, 75% hexane) yielded 18b (11 mg, 0.044 mmol) as fine yellow needles from
hexane/CH2Cl2. Yield: 56%; mp 138-141 °C; IR (film) νmax cm-1 3021, 2401, 1669, 1513,
1
1301, 1216, 1167, 928, 873, 769, 669; H NMR (CDCl3, 600 MHz) δ 8.13 (1H, m, H-8),
8.12 (1H, m, H-5), 7.93 (1H, s, H-5`), 7.81 (2H, m, H-7, H-6), 7.51 (1H, t, J = 1.6Hz, H-
13
4`), 7.02 (1H, s, H-3), 6.87 (1H, br d, J = 1.5 Hz, H-3`); C NMR (CDCl3, 150 MHz) δ
184.7 (qc, C-4), 184.7 (qc, C-1`), 182.7 (qc, C-1), 150.0 (CH, C-5`), 146.3 (qc, C-2), 144.9
(CH, C-4`), 135.2 (CH, C-3), 134.5 (CH, C-7), 134.5 (CH, C-6), 131.7 (qc, C-4a), 131.5 (qc,
C-8a), 127.1 (qc, C-2`), 126.9 (CH, C-8), 126.4 (CH, C-5), 108.8 (CH, C-3`); EIMS m/z
(rel. int.) 252 [M+] (54), 242 (4), 224 (100), 203 (3), 196 (25), 185 (3), 168 (17), 157 (6),
140 (8), 129 (5), 95 (47), 91 (2), 75 (10); HRFABMS m/z 252.0431 (calcd for C15H8O4
[M+], 252.0423).
4.30. 2-(1`-Oxo-3`-phenylpropyl)-1,4-naphthoquinone (19b).
Standard CAN oxidative demethylation of 30b (32.5 mg, 0.10 mmol) according to method
C, followed by normal phase semi-preparative HPLC (17% EtOAc, 83% hexane) yielded
19b (28.8 mg, 0.10 mmol) as a brown solid. Yield: 98%; IR (film) νmax cm-1 3020, 2410,
1670, 1579, 1463, 1218, 1104, 967, 933, 754, 669; 1H NMR (CDCl3, 600 MHz) δ 8.10 (1H,
dd, J = 7.1, 1.6 Hz, H-8), 8.07 (1H, dd, J = 7.0, 1.7 Hz, H-5), 7.80 (1H, td, J = 7.4, 1.6 Hz,
24

ACCEPTED MANUSCRIPT
H-7), 7.78 (1H, td, J = 7.3, 1.6 Hz, H-6), 7.27 (2H, t, J = 7.5 Hz, H-7`, H-6`), 7.22 (2H, d, J
= 7.4 Hz, H-9`, H-5`), 7.18 (1H, t, J = 7.3 Hz, H-5`), 7.04 (1H, s, H-3); 3.30 (2H, t, J = 7.5
Hz, H2-2`), 3.03 (2H, t, J = 7.5 Hz, H2-3`); 13C NMR (CDCl3, 150 MHz) δ 199.7 (qc, C-1`),
184.9 (qc, C-4), 183.3 (qc, C-1), 145.5 (qc, C-2), 140.4 (qc, C-4`), 137.0 (CH, C-3), 134.5
(CH, C-7), 134.4 (CH, C-6), 131.7 (qc, C-8a), 131.7 (qc, C-4a), 128.6 (2 × CH, C-8`, C-6`),
128.4 (2 × CH, C-9`, C-5`), 126.8 (CH, C-8`), 126.3 (CH, C-5`), 45.0 (CH2, C-2`), 29.6
(CH2, C-3`); EIMS m/z (rel. int.) 290 [M+] (100), 274 (12), 237 (25), 202 (33), 187 (44),
105 (22), 91 (39)69 (24); HRFABMS m/z 290.0947 (calcd for C19H14O3 [M+], 290.0943).
4.31. 2-(5`-Chlorobenzoyl)-1,4-dimethoxynaphthalene (23b).
The oxidation of 23a (29 mg, 0.08 mmol) using method B4.4.1 yield 23b as a yellow
amorphous solid (22.9 mg, 0.07 mmol). Yield: 88%; IR (film) νmax cm-1 2932, 2849, 1967,
1652, 1586, 1459, 1368, 1245, 1092, 1003, 958, 822, 770, 754, 667; 1H NMR (CDCl3, 600
MHz) δ 8.23 (1H, m, H-5), 8.13 (1H, m, H-8), 7.86 (2H, d, J = 8.5 Hz, H-3`, H-7`), 7.59 (
2H, m, H-6, H-7), 7.46 (2H, d, J = 8.5 Hz, H-4`, H-6`), 6.76 (1H, s, H-3), 3.98 (3H, s,
13
OMe-4), 3.71 (3H, s, OMe-1); C NMR (CDCl3, 150 MHz) δ 195.8 (qc, C-1`), 151.9 (qc,
C-4), 148.8 (qc, C-1), 139.6 (qc, C-2’), 136.0 (qc, C-5’), 131.4 (2 × CH, C-3`, C-7`) 128.7 (2
× CH, C-4`, C-6`), 128.5 (qc, C-8a), 128.1 (qc, C-4a), 127.3 ( CH, C-7), 127.2 (CH, C-6),
126.7 (qc, C-2), 122.7 (CH, C-8), 122.5 (CH, C-5), 102.8 (CH, C-3), 63.7 (CH3, 1-OMe),
55.0 (CH3, 4-OMe); EIMS m/z (rel. int) 326 [M+] (100), 311 (60), 309 (26), 296 (25), 276
(26), 261 (11), 248 (40), 233 (32), 205 (12), 201 (18), 189 (9), 157 (4), 141 (8), 139 (22),
129 (12), 110 (30), 101 (12), 75 (12); HREIMS m/z 326.0713 (calcd for C19H15O3Cl [M+],
326.0710).
4.32. 2-(5`-Chloro-3`-methylbenzoyl)-1,4-dimethoxynaphthalene (24b).
The oxidation of 24a (44 mg, 0.13 mmol) using method B4.4.1 yield 24b as a yellow
amorphous solid (43.8 mg, 0.13 mmol). Yield: 99%; IR (film) νmax cm-1 2933, 2849, 2160,
1
1652, 1593, 1459, 1369, 1235, 1114, 1098, 1003, 957, 881, 770, 712; H NMR (CDCl3,
600 MHz) δ 8.28 (1H, m, H-5), 8.09 (1H, m, H-8), 7.58 ( 2H, m, H-6, H-7), 7.38 (1H, d, J
= 8.3 Hz, H-7’), 7.29 (1H, d, J = 1.6 Hz, H-4’), 7.18 (1H, dd, J = 8.3, 1.9 Hz, H-6’) 6.91
(1H, s, H-3), 4.00 (3H, s, OMe-4), 3.63 (3H, s, OMe-1), 2.51 (3H, s, H-8’); 13C NMR
(CDCl3, 150 MHz) δ 197.5 (qc, C-1’), 151.9 (qc, C-4), 150.3 (qc, C-1), 139.9 (qc, C-2’),
25

ACCEPTED MANUSCRIPT
137.6 (qc, C-5’), 136.9 (qc, C-3’), 131.7 (CH, C-7’), 131.2 (CH, C-4’), 128.7 (qc, C-8a),
128.6 (qc, C-4a), 127.7 ( CH, C-2), 127.6 (CH, C-7), 127.2 (qc, C-6), 125.6 (CH, C-6’),
123.0 (CH, C-8), 122.6 (CH, C-5), 102.8 (CH, C-3), 63.8 (CH3, 1-OMe), 55.1 (CH3, 4-
OMe), 20.6 (CH3, C-8’); EIMS m/z (rel. int.) 340 [M+] (100), 325 (60), 310 (30), 290 (19),
275 (14), 262 (14), 247 (21), 215 (11), 201 (32), 189 (4), 155 (5), 153 (26), 129 (19), 125
(31), 114 (13), 101 (18), 89 (20), 63 (8); HREIMS m/z 340.0866. (calcd for C20H17O3Cl
[M+], 340.0866).
4.33. 2-(5`-Fluorobenzoyl)-1,4-dimethoxynaphthalene (25b).
The oxidation of 25a (40 mg, 0.13 mmol) using method B4.4.1 yielded 25b as a yellow
amorphous solid (38.7 mg, 0.12 mmol). Yield: 93%; IR (film) νmax cm-1 2935, 2847, 1664,
1
1594, 1505, 1460, 14098, 1369, 1235, 1152, 1094, 1004, 959, 854, 769, 713; H NMR
(CDCl3, 600 MHz) δ 8.29 (1H, m, H-5), 8.13 (1H, m, H-8), 7.93 (2H, m, H-3`, H-7`), 7.59 (
2H, m, H-6, H-7), 7.13 (2H, m, H-6`), 6.76 (1H, s, H-3), 3.98 (3H, s, OMe-4), 3.72 (3H, s,
13
OMe-1); C NMR (CDCl3, 150 MHz) δ 195.4 (qc, C-1`), 165.9 (qc, d, JF,C = 255.5 Hz, C-
5`), 151.9 (qc, C-4), 148.5 (qc, C-1), 133.9 (qc, C-2`), 132.7 (2 × CH, d, JF,C = 9.2 Hz, C-3`,
C-7`), 128.5 (qc, C-8a), 127.9 (qc, C-4a), 127.3 ( CH, C-7), 127.2 (CH, C-6), 126.9 (qc, C-
2), 122.7 (CH, C-8), 122.5 (CH, C-5), 115.5 (2 × CH, d, JF,C = 21.9 Hz, C-4`, C-6`), 102.8
(CH, C-3), 63.6 (CH3, 1-OMe), 55.1 (CH3, 4-OMe); EIMS m/z (rel. int.) 310 [M+] (100),
295 (61), 293 (22), 280 (34), 267 (21), 252 (31), 236 (20), 223 (11), 207 (21), 201 (16), 195
(4), 183 (3) 157 (4), 129 (11), 123 (31), 114 (9), 101 (13), 95 (38), 75 (14), 69 (10);
HREIMS m/z 310.0996 (calcd for C19H15O3F [M+], 310.1005).
4.34. 2-(4`-Fluorobenzoyl)-1,4-dimethoxynaphthalene (26b).
The oxidation of 26a (46 mg, 0.15 mmol) using method B4.4.1 yielded 26b as a yellow
amorphous solid (45.1 mg, 0.145 mmol). Yield: 97%; IR (film) νmax cm-1 2935, 2847, 1667,
1
1588, 1459, 1369, 1255, 1110, 1092, 966, 802, 764, 675; H NMR (CDCl3, 600 MHz) δ
8.29 (1H, m, H-5), 8.13 (1H, m, H-8), 7.74 (1H, d, J = 7.7 Hz, H-7`), 7.61 (1H, m, H-3`),
7.59 (2H, m, H-6, H-7), 7.42 (1H, m, H-6`), 7.28 (1H, m, H-5`), 6.76 (1H, s, H-3), 3.99
(3H, s, OMe-4), 3.73 (3H, s, OMe-1); 13C NMR (CDCl3, 150 MHz) δ 195.8 (qc, C-1`),
162.7 (qc, d, JF,C = 247.8 Hz, C-4`), 151.9 (qc, C-4), 148.9 (qc, C-1), 139.9 (qc, d, JF,C = 6.6
Hz, C-2`), 129.9 (CH, d, JF,C = 7.3 Hz, C-6`), 128.5 (qc, C-8a), 128.1 (qc, C-2), 127.3 (CH,
26

ACCEPTED MANUSCRIPT
C-7), 127.2 (CH, C-6), 126.6 (qc, C-4a), 125.9 (CH, d, JF,C = 2.9 Hz, C-7`), 122.8 (CH, C-
8), 122.5 (CH, C-5), 120.1 (CH, d, JF,C =21.8 Hz, C-5`), 116.3 (CH, d, JF,C = 22.3 Hz, C-
3`), 102.7 (CH, C-3), 63.8 (CH3, 1-OMe), 55.8 (CH3, 4-OMe); EIMS m/z (rel. int.) 310
[M+] (100), 295 (70), 280 (36), 267 (13), 252 (29), 236 (17), 223 (10), 207 (29), 196 (12),
157 (4), 129 (12), 123 (18), 101 (12), 95 (29), 75 (6); HREIMS m/z 310.1003 (calcd for
C19H15O3F [M+] 310.1005).
4.35. 2-(4`-Chlorobenzoyl)-1,4-dimethoxynaphthalene (27b).
The oxidation of 27a (71.6 mg, 0.22 mmol) using method B4.4.1 yielded 27b as a yellow
amorphous solid (69.5 mg, 0.21 mmol). Yield: 97%; IR (film) νmax cm-1 2934, 2844, 2159,
1
1663, 1592, 1459, 1369, 1234, 1119, 1096, 1009, 961, 818, 771, 750, 673; H NMR
(CDCl3, 600 MHz) δ 8.29 (1H, m, H-5), 8.14 (1H, m, H-8), 7.88 (1H, t, J = 1.7 Hz, H-3`),
7.74 (1H, m, H-7`), 7.60 (2H, m, H-6, H-7), 7.55 (1H, m, H-5`), 7.39 (1H, t, J = 7.9, H-6`),
6.76 (1H, s, H-3), 3.99 (3H, s, OMe-4), 3.72 (3H, s, OMe-1); 13C NMR (CDCl3, 150 MHz)
δ 195.7 (qc, C-1`), 151.9 (qc, C-4), 149.0 (qc, C-1), 139.4 (qc, C-2`), 134.6 (qc, C-4`), 133.0
(CH, C-5`), 129.6 (CH, C-3`), 128.5 (qc, C-2), 128.2 (CH, C-7`), 128.1 (qc, C-8a), 127.4
(qc, C-4a), 127.3 (CH, C-6`), 126.5 (2 × CH, C-6, C-7), 122.8 (CH, C-8), 122.6 (CH, C-5),
102.7 (CH, C-3), 63.8 (CH3, 1-OMe), 55.8 (CH3, 4-OMe); EIMS m/z (rel. int.) 326 [M+]
(100), 311 (61), 309 (22), 296 (22), 276 (37), 261 (12), 248 (33), 233 (30), 215 (8), 205
(12), 189 (8), 140 (6), 139 (18), 129 (16), 110 (23), 101 (13), 75 (9), HREIMS m/z
326.0708 (calcd for C19H15O3Cl [M+] 326.0710).
4.36. 2-Naphthoyl-1,4-dimethoxynaphthalene (28b).
Oxidation of 28a (100 mg, 0.29 mmol) using method B4.4.2 yielded 28b (90.5 mg, 0.26
mmol) as light yellow crystals from hexane. Yield: 91%; mp 106-109 °C; IR (film) νmax cm-
1
3019, 2938, 2400, 1656, 1461, 1372, 1216, 1111, 1032, 968, 770, 668; 1H NMR (CDCl3,
600 MHz) δ 8.35 (1H, s, H-3`), 8.34 (1H, m, H-5), 8.18 (1H, m, H-5), 8.07 (1H, dd, J = 8.7,
1.5 Hz, H-11`), 7.93 (1H, d, J = 8.4 Hz, H-10`), 7.88 (2H, m, H-6`, H-5`), 7.62 (2H, m, H-7,
H-6), 7.59 (1H, t, J = 7.3 Hz, H-7`), 7.51 (1H, d, J = 7.2 Hz, H-8`), 6.84 (1H, s, H-3), 3.99
(3H, s, OMe-4), 3.76 (3H, s, OMe-1); 13C NMR (CDCl3, 150 MHz) δ 197.0 (qc, C-1`),
151.7 (qc, C-4), 148.7 (qc, C-1), 135.7 (qc, C-4`), 135.0 (qc, C-2`), 132.5 (CH, C-3`), 132.5
(qc, C-9`), 129.7 (CH, C-5`), 128.6 (qc, C-8a), 128.5 (CH, C-8`), 128.2 (CH, C-10`), 127.9
27

ACCEPTED MANUSCRIPT
(qc, C-2), 127.8 (CH, C-6`), 127.3 (qc, C-4a), 127.2 (CH, C-7), 127.1 (CH, C-6), 126.6 (CH,
C-7`), 125.1 (CH, C-11`), 122.8 (CH, C-8), 122.5 (CH, C-5), 103.1 (CH, C-3), 63.6 (CH3,
1-OMe), 55.8 (CH3, 4-OMe); EIMS m/z (rel. int.) 342 [M+] (100), 327 (40), 312 (33), 294
(6), 256 (11), 200 (30), 173 (2), 155 (9), 127 (6), 77 (1); HRFABMS m/z 342.1252 (calcd
for C23H18O3 [M+], 342.1256).
4.37. 2-Furanoyl-1,4-dimethoxynaphthalene (29b).
Oxidation of 29a (30.0 mg, 0.11 mmol) according to method B4.4.2 afforded 29b (22.3 mg,
0.08 mmol) as a brown oil. Yield: 72%; IR (film) νmax cm-1 3024, 2963, 2407, 1651, 1574,
1
1219, 1096, 926, 756; H NMR (CDCl3, 600 MHz) δ 8.27 (1H, dd, J = 7.5, 1.6 Hz, H-5),
8.17 (1H, dd, J = 7.2, 1.8 Hz, H-8), 7.90 (1H, s, H-5`), 7.60 (1H, td, J = 6.9, 1.5 Hz, H-6),
7.57 (1H, td, J = 6.8, 1.5 Hz, H-7), 7.47 (1H, t, 1.6 Hz, H-4`), 6.92 (1H, br d, J = 1.5 Hz, H-
13
3`), 6.79 (1H, s, H-3), 3.98 (3H, s, OMe-4), 3.83 (3H, s, OMe-1); C NMR (CDCl3, 150
MHz) δ 189.9 (qc, C-1`), 151.7 (qc, C-4), 150.3 (CH, C-5`), 148.2 (qc, C-1), 143.9 (CH, C-
4`), 128.7 (qc, C-8a), 128.0 (qc, C-4a), 127.8 (2 × qc, C-2, C-2`), 127.2 (CH, C-6), 127.1
(CH, C-7), 122.8 (CH, C-8), 122.4 (CH, C-5), 109.4 (CH, C-3`), 102.7 (CH, C-3), 63.8
(CH3, 1-OMe), 55.8 (CH3, 4-OMe); EIMS m/z (rel. int.) 282 [M+] (100), 267 (13), 265 (21),
253 (13), 239 (68), 211 (31), 201 (26), 196 (24), 173 (11), 139 (11), 129 (16); HRFABMS
m/z 282.0897 (calcd for C17H14O4 [M]+, 282.0892).
4.38. 2-(1`-Oxo-3`-phenylpropyl)-1,4-dimethoxynaphthalene (30b).
Oxidation of 30a (50 mg, 0.16 mmol) according to method B4.4.1 afforded 30b (49.7 mg,
0.16 mmol) as yellow crystals from hexane/CH2Cl2. Yield: 100%; mp 80-82 °C; IR (film)
1
νmax cm-1 3020, 2938, 2401, 1668, 1596, 1459, 1372, 1216, 1101, 966, 929, 758, 670; H
NMR (CDCl3, 600 MHz) δ 8.25 (1H, m, H-5), 8.14 (1H, m, H-8), 7.60 (1H, m, H-6), 7.56
(1H, m, H-7), 7.29 (2H, t, J = 6.7 Hz, H-8`, H-6`), 7.28 (2H, d, J = 6.5 Hz, H-9`, H-5`), 7.19
(1H, tt, J = 6.5, 2.1 Hz, H-7`), 6.99 (1H, s, H-3), 3.99 (3H, s, OMe-4), 3.87 (3H, s, OMe-1),
3.50 (2H, t, J = 7.5 Hz, H2-2`), 3.10 (2H, t, J = 7.5 Hz, H2-3`); 13C NMR (CDCl3, 150
MHz) δ 202.1 (qc, C-1`), 151.9 (qc, C-4), 151.0 (qc, C-1), 141.5 (qc, C-4`), 128.8 (qc, C-4a),
128.7 (qc, C-8a), 128.5 (2 × CH, C-5`, C-9`), 128.4 (2 × CH, C-6`, C-8`), 127.6 (CH, C-7),
127.4 (qc, C-2), 127.1 (CH, C-6), 126.0 (CH, C-7`), 123.1 (CH, C-8), 122.5 (CH, C-5),
102.2 (CH, C-3), 63.9 (CH3, 1-OMe), 55.7 (CH3, 4-OMe), 44.7 (CH2, C-2`), 30.6 (CH2, C-
28