Synthesis and evaluation of 9-deoxy analogues of (-)-thysanone, an inhibitor of HRV 3C protease

Article abstract of DOI:10.1016/j.ejmech.2014.09.063

9-Deoxy analogues of the HRV 3C protease inhibitor (-)-thysanone display better inhibitory properties than the natural product, inferring the C9-OH hinders binding to the enzyme.

Full text of DOI:10.1016/j.ejmech.2014.09.063

European Journal of Medicinal Chemistry 87 (2014) 220e227
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and evaluation of 9-deoxy analogues of (ꢀ)-thysanone, an
inhibitor of HRV 3C protease
,
, c, *
Joo Young Jeong a b, Jonathan Sperry a, John A. Taylor b, Margaret A. Brimble a
a School of Chemical Sciences, The University of Auckland, 23 Symonds St., Auckland 1142, New Zealand
b School of Biological Sciences, The University of Auckland, 3A Symonds St., Auckland 1010, New Zealand
c Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
9-Deoxy analogues of the HRV 3C protease inhibitor (ꢀ)-thysanone display better inhibitory properties
Received 26 August 2014
Received in revised form
15 September 2014
Accepted 18 September 2014
Available online 22 September 2014
than the natural product, inferring the C9-OH hinders binding to the enzyme.
© 2014 Elsevier Masson SAS. All rights reserved.
Keywords:
HRV 3C protease
Inhibitor
Pyranonaphthoquinone
Thysanone
CeH activation
1. Introduction
host cell. A single polyprotein is synthesised [6] which undergoes a
series of proteolytic cleavages catalysed by virally-encoded pro-
Human rhinovirus (HRV) causes upper respiratory tract in-
fections [1] and accounts for at least 70% [2] of cases of the common
cold. HRV infections can also exacerbate lower respiratory tract
diseases such as asthma [3] and chronic obstructive pulmonary
disease [4] and the resulting healthcare expenses and loss of pro-
ductivity [2,4] place a significant economic burden on society.
Despite the high incidence of HRV infections worldwide, currently
available treatment regimens only alleviate the symptoms [1,5],
underscoring an urgent need for the development of an effective
anti-viral drug. A large number of viral serotypes (>100) [5,6] has
hindered development of an effective HRV vaccine and new
chemotherapeutic agents to treat HRV infection continues to be of
major interest to the pharmaceutical sector.
teases 2A and 3C [6,9] resulting in the release of discrete functional
proteins necessary for virus replication. Inhibition of 3C protease
leads to accumulation of an unprocessed and therefore, non-
functional protein [6,9], impeding viral replication. Moreover, the
3C protease substrate binding site is highly conserved across
different serotypes of HRV [1,6], making them a promising target
for the development of anti-rhinoviral drugs effective against a
broad-spectrum of serotypes.
(ꢀ)-Thysanone (1) is a member of the pyranonaphthoquinone
family of antibiotics discovered during a screen of the fermentation
broths of the fungus Thysanophora penicilloides [10] (Fig. 1).
(ꢀ)-Thysanone (1) was found to inhibit HRV 3C protease with an
IC50 value of 47 mM [10]. To date, three total syntheses [11e14] and
HRV belongs to the family Picornaviridae [7,8]. The viral genome
one formal synthesis [15] of (ꢀ)-thysanone (1) have been reported.
Our group has a long-standing interest in determining the
structureeactivity relationship of (ꢀ)-thysanone (1) via the syn-
thesis of analogues [16e21] and biological evaluation [22]. Our
development of a simple solid phase based fluorescent substrate
assay [22] has provided an accurate and efficient means of studying
the kinetics of the inhibitor molecules and greatly facilitated the
screening process. Recent publications from our group have high-
lighted the importance of the lactol functionality [21] and the C-7
phenol [20] for inhibitory activity (Fig. 2). These studies suggest
is
a
positive-sense, single-stranded-RNA (ssRNA) molecule
approximately 7200 nucleotides in length [8]. Translation of
genomic RNA is initiated at an internal ribosome entry site (IRES)
[9] following disassembly of the viral capsid in the cytoplasm of the
* Corresponding author. School of Chemical Sciences, The University of Auckland,
23 Symonds St., Auckland 1142, New Zealand.
E-mail addresses: ja.taylor@auckland.ac.nz (J.A. Taylor), m.brimble@auckland.ac.
nz (M.A. Brimble).
http://dx.doi.org/10.1016/j.ejmech.2014.09.063
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

J. Young Jeong et al. / European Journal of Medicinal Chemistry 87 (2014) 220e227
221
Fig. 1. (ꢀ)-Thysanone (1).
that the C-7 phenol may be involved in a hydrogen bonding
interaction with the HRV 3C protease, anchoring the molecule to
the enzyme. The question arises as to whether the C-9 phenol is
also important for biological activity and we report herein the
synthesis and biological evaluation of ( )-9-deoxythysanone (2)
that has extended our knowledge of the structural components
required for the activity of this molecule.
Scheme 1. Retrosynthetic analysis of ( )-9-deoxythysanone (2).
2. Results and discussion
2.1. Chemistry
It was envisaged that ( )-9-deoxythysanone (2) would be
available via stereoselective reduction of lactone 3. Lactone 3 would
be accessed from a key bromide intermediate 4 using a carbonyl-
ation strategy [23] in combination with radical alkylation to
construct the lactone moiety. Bromide 4 would in turn be con-
structed via regioselective iridium-catalysed CeH borylation [24] of
5
followed by oxidation [25] to regioselectively install the
oxygenated substituent at C-6 (Scheme 1).
Our initial efforts were focused on achieving an efficient regio-
selective synthesis of the initial bromide 4. Iridium-catalysed arene
CeH borylation is predominantly governed by steric factors and is
regioselective for the least hindered aromatic positions [24,26]. The
resulting boronate esters serve as excellent precursors to phenols
using a straightforward oxidationehydrolysis protocol [25]. Our
group has previously demonstrated that CeH borylation is regio-
selective for the least sterically hindered sites on polyoxygenated
naphthalene systems [24]. Moreover, our recent report on a total
synthesis of ( )-thysanone (1) was also achieved using this protocol
to introduce the C-7 phenol in the presence of an oxygenated
substituent at C-9 [14]. Using these previously established condi-
tions [24,25], an initial study of the regioselectivity of CeH bor-
ylation of bromonaphthalene 6 was undertaken (Scheme 2).
Bromonaphthalene 6 was prepared from commercially available
1,4-naphthoquinone (7) by reductive dimethylation [27] followed
by selective bromination at C-2 with N-bromosuccinimide [28].
Disappointingly, CeH borylation [24] and subsequent oxida-
tionehydrolysis [25] of 6 delivered an inseparable 2:1 mixture of
regioisomeric naphthols 8 and 9 in 75% yield over two steps.
Although steric effects are the dominant factor influencing
Scheme 2. Reagents and conditions: a) TBAI, aq. Na2S2O4, aq. KOH, Me2SO4, THF/H2O
(1:5), r.t., 16 h, 90%; b) NBS, CH2Cl2, r.t., 18 h, 92%; c) i) [Ir(COD)OMe]2, dtbpy, B2pin2,
BHpin, THF, 80 ꢁC, 12 h; ii) H2O2, NaOH (1 M), THF, 0 ꢁC, 20 min, 75% over 2 steps.
regioselectivity [24,26], this outcome indicated that electronics of
the aromatic ring system played a significant role in governing the
selectivity between the two meta-positions on 6.
Disappointed by the lack of regiochemical control in the bor-
ylation of 6, an alternative strategy was sought. It was envisaged
that installation of the phenol group prior to selective bromination
would provide the most efficient route for the synthesis of desired
bromide 4 (Scheme 3). Gratifyingly, regioselective CeH borylation
[24] followed by oxidationehydrolysis [25] of dimethoxynaph-
thalene 5 afforded naphthol 10 in 88% yield over two steps. Treat-
ment of naphthol 10 with bromine in acetic acid [29] effected
Fig. 2. StructureeActivity Relationship (SAR) of (ꢀ)-thysanone (1) and target analogue ( )-9-deoxythysanone (2).

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J. Young Jeong et al. / European Journal of Medicinal Chemistry 87 (2014) 220e227
postulated that the instability of the quinone system in alkaline
conditions resulted in decomposition of the substrate.
We next attempted to change the electronics of the aromatic
ring system by executing the reductive dimethylation of 13, with
the hope of providing a more stable substrate for the carboalkox-
ylation reaction (Scheme 5). Unfortunately, attempted reductive
alkylation [27,33] of 13 resulted in decomposition of the starting
material affording none of the desired carbonylation substrate 14.
In spite of the difficulties encountered with the intramolecular
carboalkoxylation, reduction of lactone 3 was investigated (Scheme
6). Treatment of 3 with diisobutylaluminium hydride led to com-
plete recovery of the starting material, even when using an excess
reductant. Therefore, a two-step process was adopted [13]. Pleas-
ingly, treatment of 3 with boraneedimethylsulfide complex deliv-
ered pyranonaphthoquinone ( )-15 in 48% yield. It was postulated
that aerial oxidation to quinone ( )-15 was facilitated by the loss of
intramolecular hydrogen bonding resulting from complete reduc-
tion of the carbonyl in lactone 3. However, despite establishing
conditions to complete construction of the naphthopyran frame-
work, it was difficult to access lactone 3 in synthetically useful
quantities owing to the poor reproducibility and low yield afforded
in the carboalkoxylation reaction outlined in Scheme 4. Accord-
ingly, an alternative synthetic route to lactone 3 was sought.
It was envisaged that an alternative carbonylation strategy that
involved installing an ester on the naphthalene system prior to
radical alkylation would overcome the issues experienced with the
poor-yielding carboalkoxylation step. Therefore, an alternate syn-
thetic route to lactone 3 commencing from bromide intermediate 4
was considered (Scheme 7). Pleasingly, synthesis of naphthalene
ester 16 was easily accomplished by lithiation of bromide 4 fol-
lowed by addition of ethyl chloroformate (17) [34] in 75% yield.
Attention next turned to the key radical alkylation and intra-
molecular cyclisation reactions (Scheme 8). Oxidative demethyla-
tion [20] of ester 16 delivered quinone 18 in 88% yield. Interestingly,
subjecting quinone 18 to the established radical alkylation condi-
tions [17,18] delivered an inseparable 2:1 mixture of alcohol 19 and
cyclised product 20 as observed by 1H NMR analysis, with the mildly
acidic reaction conditions presumably catalysing the cyclisation of
quinone 19 to lactone 20 in situ. In support of this hypothesis,
increasing the amount of 3-hydroxybutyric acid (12) increased the
proportion of cyclised product 20. Conducting this reaction with
excess (12) led to complete cyclisation of the alkylated product,
delivering the photosensitive lactone 20 in 60% yield. The desired
dihydroquinone intermediate 3 was delivered in an excellent yield
by facile reduction of quinone 20 with aqueous sodium dithionite
[35]. This alternative synthetic strategy provided an efficient syn-
thetic route to lactone 3. Reduction of lactone 3 to pyranonaph-
thoquinone ( )-15 was achieved as outlined in Scheme 6.
Scheme 3. Reagents and conditions: a) i) [Ir(COD)OMe]2, dtbpy, B2pin2, BHpin, THF,
80 ꢁC, 12 h; ii) H2O2, NaOH (1 M), THF, 0 ꢁC, 20 min, 88% over 2 steps; b) Br2, AcOH, r.t.,
30 min, 85%; c) TBAI, K2CO3, 2-bromopropane, acetone/DMF (12:1), reflux, 16 h, 99%.
selective bromination at C-2 in 85% yield. The C-6 phenol was then
protected as its isopropyl ether [13] 4 in 99% yield.
With bromide 4 in hand, our attention turned to the construc-
tion of the naphthopyran framework (Scheme 4). Driven by the
successful radical allylation approach used to construct the carbon
scaffold in previous syntheses of thysanone analogues [17,18], it
was proposed that radical alkylation of bromoquinone 11 with 3-
hydroxybutyric acid (12) would facilitate access to bromoalcohol
13. Intramolecular carboalkoxylation [23] of 13 would then be used
to construct the lactone moiety.
Bromoquinone 11 was prepared by oxidative demethylation of
naphthalene 4 using silver(II) oxide and 6 M nitric acid in tetra-
hydrofuran [20] in 90% yield. Pleasingly, bromoquinone 11 under-
went smooth radical alkylation by silver persulfate-catalysed
oxidative decarboxylation of 3-hydroxybutyric acid (12) [17,18],
affording bromoalcohol 13 in good yield. Construction of the
lactone functionality was enabled by palladium(0)-catalysed
carbonylation [23] of bromoalcohol 13 with carbon monoxide and
N,N-diisopropylethylamine that also effected subsequent intra-
molecular alkoxylation. The quinone moiety was also reduced un-
der the conditions employed for carboalkoxylation, delivering
lactone 3. Reduction of the quinone moiety in the presence of
palladium(0) was thought to be associated with oxidation of the
palladium(0) species to palladium(II) [30e32]. Unfortunately, the
yield of this transformation was poor (<35%), and the reaction
could not be improved despite varying the order of addition of
reagents, stoichiometry, reaction temperature and time. It was
Scheme 4. Reagents and conditions: a) AgO, HNO3 (6 M), THF, r.t., 5 min, 90%; b) AgNO3,
(NH4)2S2O8, MeCN/H2O (2:1), 80 ꢁC, 25 min, 71%; c) Pd(PPh3)4, DIPEA, CO(g), DMF,
100 ꢁC, 12 h, <35%.
Scheme 5. Failed reductive dimethylation.

J. Young Jeong et al. / European Journal of Medicinal Chemistry 87 (2014) 220e227
223
Scheme 9. Reagents and conditions: a) AlCl3, CH2Cl2, 0 ꢁC to r.t., 20 min, 94%; b) Br2,
Bz2O2, 60 W lamp, CCl4, 40 ꢁC, 1 h, then THF/H2O (2:1), 1 h, 85%.
functionality reduced the inhibitory activity suggesting that the C-1
lactol is critical for 3C protease inhibitory activity. Removal of the
hydrogen-donor capability of the C-7 phenol by protection as an
isopropyl ether led to a further reduction in potency. When com-
bined with our previous observations that ( )-7-deoxythysanone is
a poor inhibitor of 3C-protease [20], the results herein strongly
suggest that the C-7 phenol plays a pivotal role in anchoring the
molecule to the active site. Moreover, these results infer that the C-
9 phenol in (ꢀ)-thysanone (1) is detrimental to the 3C protease
inhibitory activity.
Scheme 6. Reagents and conditions: a) BH3$SMe2, THF, 0 ꢁC to r.t., 16 h, 48%.
Scheme 7. Reagents and conditions: a) t-BuLi, THF, -78 ꢁC to r.t., 12 h, 75%.
3. Conclusion
Cleavage of the isopropyl group was easily achieved by treating
( )-15 with excess aluminium trichloride [13], delivering pyr-
anonaphthoquinone ( )-21 in 94% yield (Scheme 9). Finally, ster-
eoselective oxidation at C-1 of ( )-21 by benzylic bromination
followed by hydrolysis [11,12] gave ( )-9-deoxythysanone (2) in
85% yield.
The stereochemistry of ( )-9-deoxythysanone (2) was
confirmed by the magnitude of the coupling constants of the C-4
methylene protons that established a trans-diaxial relationship
between H-3 and the axial proton at C-4 [12]. The absence of an
NOE correlation between H-1 and H-3 also supported the stereo-
chemistry being the same as that reported for (ꢀ)-thysanone (1)
(Fig. 3) [12].
In conclusion, we have achieved an efficient synthesis of ( )-9-
deoxythysanone (2) using iridium-catalysed CeH borylation to
install the C-7 phenol and a radical alkylation strategy to construct
the naphthopyran framework. Subsequent screening of ( )-9-
deoxythysanone (2) and two related analogues ( )-15 and ( )-21
has revealed that not only the C-1 lactol and the C-7 phenol are
important for inhibitory activity, but more importantly the pres-
ence of the C-9 phenol reduces the potency. ( )-9-Deoxythysanone
(2) is the most potent (ꢀ)-thysanone analogue synthesised to date
and we envisage that the structureeactivity results reported herein
will provide a basis for the future design of more potent HRV 3C
protease inhibitors based on the thysanone scaffold.
2.2. Analysis of 3C protease activity
4. Experimental protocols
( )-9-Deoxythysanone (2) was screened for its inhibitory ac-
tivity against HRV 3C protease using a solid-phase fluorescent assay
[22] developed previously by ourselves (Fig. 4). Removal of the C-9
phenol of (ꢀ)-thysanone (1) significantly increased the inhibitory
4.1. General procedures
Unless otherwise noted, all reactions were performed under an
oxygen-free atmosphere of nitrogen using standard techniques.
Tetrahydrofuran (THF) and diethyl ether were freshly distilled over
sodium/benzophenone ketyl. CH2Cl2 and CH3OH were freshly
distilled from calcium hydride. All other reagents were used as
received unless otherwise noted. Yields refer to chromatographi-
cally and spectroscopically (1H NMR) homogeneous materials,
unless otherwise stated. Reactions were monitored by thin-layer
potency (IC50 ¼ 20.3
51.8
mM for ( )-9-deoxythysanone (2) compared to
mM for thysanone (1)) indicating that the presence of the C-9
phenol moiety is detrimental to inhibitory activity (Table 1).
Related analogues ( )-15 and ( )-21 were also screened to inves-
tigate the importance of the lactol functionality at C-1 and
hydrogen bonding capability at C-7. The absence of the C-1 lactol
Scheme 8. Reagents and conditions: a) AgO, HNO3 (6 M), THF, r.t., 3 min, 88%; b) AgNO3, (NH4)2S2O8, MeCN/H2O (2:1), 80 ꢁC, 5 min, 60%; c) aq. Na2S2O4, CH2Cl2/Et2O (1:3), r.t.,
30 min, 97%.

224
J. Young Jeong et al. / European Journal of Medicinal Chemistry 87 (2014) 220e227
Fig. 3. a) 1H NMR (400 MHz, CD3OD) data of C-4 methylene protons showing characteristic trans-diaxial relationship between H-3 and Hax-4; b) Nuclear Overhauser enhancement
analysis of 9-deoxythysanone (2).
chromatography (TLC) carried out on silica gel plates using UV light
as the visualising agent and an ethanolic solution of vanillin and
ammonium molybdate and heat as developing agents. Silica gel
(60, 230e400 mesh) was used for flash column chromatography.
4.1.1. General CeH borylation procedure
A flame-dried sealed tube was charged with substrate (1 mmol).
[Ir(COD)OMe]2 (6.6 mg, 10
B2pin2 (254 mg, 1 mmol) were added under a blanket of argon. THF
(0.63 mL) was added, followed by pinacolborane (15 L, 0.1 mmol).
mmol), dtbpy (7.1 mg, 20 mmol) and
Preparatory TLC was carried out on 500
m
m, 20 ꢂ 20 cm silica gel
m
thin-layer chromatography plates. NMR spectra were recorded at
room temperature in CDCl3, CD3OD, (CD3)2CO or (CD3)2SO solutions
on either a spectrometer operating at 300 MHz for 1H nuclei and
75 MHz for 13C nuclei or a spectrometer operating at 400 MHz for
1H nuclei and 100 MHz for 13C nuclei. Chemical shifts are reported
Activation of the system was indicated by a colour change of the
solution from brown to red. The mixture was stirred at 80 ꢁC for
24 h, cooled to r.t., filtered through Celite® and concentrated in
vacuo to afford crude pinacol ester which was used directly in the
next step.
in parts per million (ppm) on the
d scale, and coupling constants, J,
are in hertz (Hz). Multiplicities are reported as “s” (singlet), “br s”
(broad singlet), “d” (doublet), “dd” (doublet of doublets), “ddd”
(doublet of doublets of doublets), “dddd” (doublet of doublets of
doublets of doublets), “dt” (doublet of triplets), “t” (triplet), and “m”
(multiplet), “sep” (septet). Where distinct from those due to the
major rotamer, resonances due to minor rotamers are denoted by
an asterisk. 1H and 13C NMR resonances were assigned using a
combination of DEPT 135, COSY, HSQC, HMBC, and NOESY spectra.
Infrared (IR) spectra were recorded as thin films on a composite of
zinc selenide and diamond crystal on a FT-IR system transform
spectrometer. Melting points are uncorrected. High-resolution
mass spectra (HRMS) were obtained using a spectrometer oper-
ating at a nominal accelerating voltage of 70 eV or on a TOF-Q mass
spectrometer.
4.1.2. General boronate oxidationehydrolysis procedure
A solution of the crude pinacol ester (1 mmol) in THF (30 mL)
was cooled to 0 ꢁC. H2O2 (30% in H2O, 1 mL) and 1 M NaOH (1 mL)
were added and the reaction mixture was stirred at 0 ꢁC for 20 min.
EtOAc (100 mL) was added, and the organic layer was removed,
washed with water (50 mL) and brine (20 mL), dried over MgSO4
and concentrated in vacuo.
4.2. Synthesis of trans-9-deoxythysanone ( )-(2)
4.2.1. Synthesis of 2-bromo-7-hydroxy-1,4-dimethoxynaphthalene
8 and 2-bromo-6-hydroxy-1,4,-dimethoxynaphthalene 9
The general CeH borylation procedure and boronate oxida-
tionehydrolysis were applied to bromonaphthalene 6 (142 mg,
0.53 mmol). Purification by flash column chromatography on silica
(hexanes/EtOAc 2:1) afforded the title compounds 8 and 9 as an
inseparable mixture of regioisomers (113 mg, 0.40 mmol, 75% over
2 steps). IR nmax (film): 3346, 2981, 1822, 1583, 1419, 1197,
1107 cmꢀ1; (*denotes the minor regioisomer) 1H NMR (400 MHz,
CDCl3)
d
¼ 8.08 (d, J ¼ 9.0 Hz, 1H), *7.95 (d, J ¼ 9.0 Hz, 1H), *7.52 (d,
J ¼ 2.5 Hz, 1H), 7.43 (d, J ¼ 2.5 Hz, 1H), *7.19 (dd, J ¼ 9.0, 2.5 Hz, 1H),
7.15 (br s, OH), 7.14 (dd, J ¼ 9.0, 2.5 Hz, 1H), *6.93 (br s, OH), *6.80 (s,
1H), 6.72 (s, 1H), *3.96 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H), *3.84 (s, 3H);
13C NMR (100 MHz, CDCl3)
d
¼ 155.5, *154.0, 152.6, *151.3, *146.6,
145.0, 130.4, *127.2, 125.0, *124.0, *123.9, 120.8, *119.0, 117.5, 113.0,
*108.9, *108.5, 105.7, *105.4, 104.1, *61.6, 61.1, *55.8, 55.8; HRMS
(ESI) m/z calcd. for [C12H11BrNaO3]þ: 304.9784, found: 304.9778.
The 1H NMR and 13C NMR data for 9 were in agreement with
that reported in the literature [29].
4.2.2. Synthesis of 6-hydroxy-1,4-dimethoxynaphthalene 10
The general CeH borylation procedure and boronate oxida-
tionehydrolysis were applied to dimethoxynaphthalene 5 (100 mg,
0.53 mmol). Purification by flash column chromatography on silica
(hexanes/EtOAc 2:1) afforded the title compound 10 as a green oil
(95 mg, 0.47 mmol, 88% over 2 steps). 1H NMR (400 MHz, CDCl3)
Fig. 4. Inhibition of 3C protease activity by the compounds described. The fluorescence
intensity was converted to relative fluorescence intensity to the uninhibited control.
IC50 was determined at the half of the maximum intensity (rel. F516 ¼ 0.5). (ꢀ)-thy-
sanone (1) was run as a control.
d
¼ 8.12 (d, J ¼ 9.0 Hz, 1H) 7.50 (d, J ¼ 2.6 Hz, 1H), 7.10 (dd, J ¼ 9.0,

J. Young Jeong et al. / European Journal of Medicinal Chemistry 87 (2014) 220e227
225
mixture was heated to 80 ꢁC and water (1.6 mL) added, immedi-
ately followed by dropwise addition of (NH4)2S2O8 (910 mg,
3.2 mmol) in water (3.2 mL). The reaction was stirred at 80 ꢁC for
25 min, then cooled to r.t. The reaction mixture was extracted with
EtOAc (3 ꢂ 10 mL), the combined organic extracts dried over
MgSO4, and concentrated in vacuo. Purification by flash column
chromatography on silica (hexanes/EtOAc 3:1) afforded the title
compound 13 as an orange oil (400 mg, 1.1 mmol, 71%). IR nmax
(film): 2977, 2933, 1667, 1587, 1285, 1109 cmꢀ1; 1H NMR (400 MHz,
Table 1
Biological evaluation of ( )-9-deoxythysanone (2) and related analogues ( )-15 and
(
)-21.
CDCl3)
d
¼ 8.05 (d, J ¼ 8.7 Hz, 1H), 7.48 (d, J ¼ 2.6 Hz, 1H), 7.13 (dd,
J ¼ 8.7, 2.6 Hz, 1H), 4.73 (sep, J ¼ 6.0 Hz, 1H), 4.21e4.13 (m, 1H), 3.09
(dd, J ¼ 12.7, 8.3 Hz, 1H), 2.98 (dd, J ¼ 12.7, 4.4 Hz, 1H), 1.39 (d,
J ¼ 6.0 Hz, 6H), 1.34 (d, J ¼ 6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
Compound
R1
R2
R3
IC50 [mM]
d
¼ 183.1, 176.6, 163.1, 148.4, 141.3, 133.6, 130.3, 124.2, 121.7, 112.2,
(
(
(
)-9-deoxythysanone (2)
)-21
)-15
OH
OH
OiPr
OH
H
H
H
OH
OH
H
H
20.3 1.5
30.9 0.1
35.7 0.8
51.8 0.7
71.1, 67.5, 41.0, 24.4, 21.9; HRMS (ESI) m/z calcd. for [C16H18BrO4]þ:
353.0383, found: 353.0391.
(ꢀ)-thysanone (1)
OH
4.2.6. Synthesis of 5,10-dihydroxy-7-isopropoxy-3-methyl-3,4,5,10-
tetrahydro-1H-benzo[g]isochromen-1-one 3
2.6 Hz,1H), 6.68 (d, J ¼ 8.3 Hz,1H), 6.55 (d, J ¼ 8.3 Hz,1H), 5.29 (br s,
OH), 3.93 (s, 6H).
A stirred solution of bromoalcohol 13 (106 mg, 0.28 mmol),
Pd(PPh3)4 (160 mg, 0.14 mmol) and diisopropylethylamine (0.1 mL)
in degassed DMF (2.1 mL) was placed under carbon monoxide and
heated at 100 ꢁC for 12 h. The reaction mixture was cooled to r.t.
and brine (12 mL) added. The layers were separated and the
aqueous layer extracted with EtOAc (3 ꢂ 10 mL). The combined
organic extracts dried over MgSO4, and concentrated in vacuo.
Purification by flash column chromatography on silica (hexanes/
EtOAc 2:1) afforded the title compound 3 as a brown solid (30 mg,
0.098 mmol, 35%).
To a stirred solution of quinone 20 (100 mg, 0.33 mmol) in
CH2Cl2/Et2O (1:3, 8.3 mL) was added a freshly prepared solution of
Na2S2O4 (402 mg, 2.31 mmol) in H2O (4.5 mL). After the mixture
was stirred vigorously for 30 min, the organic layer was separated,
washed with water (10 mL) and brine (10 mL). The combined
organic extracts dried over MgSO4, and concentrated in vacuo.
Purification by flash column chromatography on silica (hexanes/
EtOAc 2:1) afforded the title compound 3 as a brown solid (97 mg,
0.32 mmol, 97%). mp 168e172 ꢁC; IR nmax (film): 3499, 2982, 2919,
2850, 1630, 1604, 1385, 1223, 1189, 1091, 1112, 1046 cmꢀ1; 1H NMR
The 1H NMR data were in agreement with that reported in the
literature [36].
4.2.3. Synthesis of 2-bromo-6-isopropoxy-1,4-
dimethoxynaphthalene 4
To a stirred solution of bromonaphthol 9 (1.2 g 4.3 mmol) in
acetone/DMF (12:1, 15 mL) was added K2CO3 (2.4 g, 17 mmol), TBAI
(160 mg, 0.43 mmol) and 2-bromopropane (4.4 mL, 47 mmol). The
reaction mixture was heated under reflux for 16 h. The reaction
mixture was cooled to r.t. and 1 M HCl (20 mL) added slowly. The
resultant mixture was extracted with CH2Cl2 (3 ꢂ 20 mL) and the
combined organic extracts dried over MgSO4, and concentrated in
vacuo. The residue was filtered through a pad of silica and Celite® to
afford the title compound 4 as a viscous yellow oil (1.4 g, 4.3 mmol,
99%). IR nmax (film): 2974, 2929, 1380, 1102, 1065, 801 cmꢀ1
NMR (400 MHz, CDCl3)
;
1H
d
¼ 7.95 (d, J ¼ 9.0 Hz, 1H), 7.49 (d,
J ¼ 2.5 Hz, 1H), 7.17 (dd, J ¼ 9.0, 2.5 Hz, 1H), 6.84 (s, 1H), 4.74 (sep,
J ¼ 6.0 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 1.40 (d, J ¼ 6.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3)
d
¼ 156.2, 151.4, 147.1, 127.2, 124.2, 123.9,
(400 MHz, (CD3)2SO)
d
¼ 12.0 (s, OH), 8.82 (s, OH), 8.14 (d, J ¼ 9.1 Hz,
121.0,108.9,108.6,103.7, 70.1, 61.6, 56.0, 22.1; HRMS (ESI) m/z calcd.
1H), 7.51 (d, J ¼ 2.5 Hz, 1H), 7.15 (dd, J ¼ 9.1, 2.5 Hz, 1H), 4.81 (sep,
J ¼ 6.0 Hz, 1H), 4.78e4.71 (m, 1H), 3.31 (dd, J ¼ 16.6, 3.3 Hz, 1H),
2.75 (dd, J ¼ 16.6, 11.0 Hz, 1H), 1.46 (d, J ¼ 6.4 Hz, 3H), 1.36 (d,
for [C15H17BrNaO3]þ: 347.0253, found: 347.0247.
J ¼ 6.0 Hz, 6H); 13C NMR (100 MHz, (CD3)2SO)
d
¼ 170.9, 158.6,
4.2.4. Synthesis of 2-bromo-6-isopropoxynaphthalene-1,4-dione 11
To a stirred solution of bromonaphthalene 4 (400 mg, 1.2 mmol)
in THF (30 mL) was added AgO (1.7 g, 14 mmol) and 6 M HNO3
(4.0 mL, 25 mmol) dropwise. The reaction mixture was stirred at r.t.
for 5 min, then filtered through Celite®. The filtrate was extracted
with CH2Cl2 (3 ꢂ 50 mL) and the combined organic extracts dried
over MgSO4, and concentrated in vacuo. Purification by flash col-
umn chromatography on silica (hexanes/EtOAc 9:1) afforded the
title compound 11 as a yellow solid (330 mg, 1.1 mmol, 90%). mp
69e71 ꢁC; IR nmax (film): 2979, 1671, 1590, 1230, 1105, 1045, 877,
154.8, 138.7, 132.4, 125.5, 118.2, 117.7, 116.1, 103.2, 99.4, 75.8, 69.6,
28.8, 21.7, 20.6; HRMS (ESI) m/z calcd. for [C17H18NaO5]þ: 325.1046,
found: 325.1046.
4.2.7. Synthesis of 7-isopropoxy-3-methyl-3,4-dihydro-1H-benzo
[g]isochromene-5,10-dione ( )-15
To a stirred solution of lactone 3 (50 mg, 0.165 mmol) in THF
(1 mL) at 0 ꢁC was added BH3$SMe2 (1.65 mmol, 160
mL). The re-
action mixture was warmed to r.t. over 16 h. Sat. aq NH4Cl (3 mL)
was added and the aqueous layer extracted with CH2Cl2
(3 ꢂ 10 mL). The combined organic extracts dried over MgSO4, and
concentrated in vacuo. Purification by flash column chromatog-
raphy on silica (hexanes/EtOAc 4:1) afforded the title compound 15
as a yellow solid (23 mg, 0.079 mmol, 48%). mp 98e101 ꢁC; IR nmax
(film): 2979, 2918, 2850, 1651, 1592, 1304, 1278, 1233, 1115,
704 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
¼ 8.08 (d, J ¼ 8.7 Hz, 1H),
7.45 (d, J ¼ 2.6 Hz, 1H), 7.45 (s, 1H), 7.14 (dd, J ¼ 8.7, 2.6 Hz, 1H), 4.75
(sep, J ¼ 6.0 Hz, 1H), 1.39 (d, J ¼ 6.0 Hz, 6H); 13C NMR (100 MHz,
CDCl3)
d
¼ 182.8, 176.9, 163.2, 141.1, 140.0, 134.0, 130.6, 123.9, 121.8,
111.6, 71.1, 21.9; HRMS (ESI) m/z calcd. for [C13H11BrNaO3]þ:
316.9784, found: 316.9785.
1079 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
¼ 7.96 (d, J ¼ 8.6 Hz, 1H),
4.2.5. Synthesis of 2-bromo-3-(2-hydroxypropyl)-6-
isoproxynaphthalene-1,4-dione 13
To a stirred solution of bromoquinone 11 (470 mg, 1.6 mmol) in
MeCN (3.2 mL) was added AgNO3 (320 mg, 1.9 mmol) and 3-
hydroxybutyric acid (12) (0.44 mL, 4.8 mmol). The reaction
7.46 (d, J ¼ 2.6 Hz,1H), 7.10 (dd, J ¼ 8.6, 2.6 Hz,1H), 4.82 (dd, J ¼ 18.8,
2.7 Hz, 1H), 4.73 (sep, J ¼ 6.0 Hz, 1H), 4.49 (dt, J ¼ 18.8, 3.6 Hz, 1H),
3.70e3.62 (m, 1H), 2.70 (dt, J ¼ 18.8, 3.6 Hz, 1H), 2.26 (dddd,
J ¼ 18.8, 10.1, 4.1, 2.7 Hz, 1H), 1.38 (d, J ¼ 6.0 Hz, 6H), 1.36 (d,
J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
¼ 184.0, 182.6, 162.7,

226
J. Young Jeong et al. / European Journal of Medicinal Chemistry 87 (2014) 220e227
142.7, 141.4, 134.1, 128.8, 125.0, 121.3, 111.5, 70.9, 69.7, 63.5, 29.6,
22.0, 21.3; HRMS (ESI) m/z calcd. for [C17H18NaO4]þ: 309.1097,
found: 309.1098.
4.2.11. Synthesis of 7-hydroxy-3-methyl-3,4-dihydro-1H-benzo[g]
isochromene-5,10-dione ( )-21
To a stirred solution of isopropyl ether 15 (10 mg, 0.035 mmol)
in CH2Cl2 (0.7 mL) at 0 ꢁC was added AlCl3 (47 mg, 0.35 mmol)
portionwise over 5 min. The reaction mixture was warmed to r.t.
and stirred for 20 min. The reaction mixture was diluted with
CH2Cl2 (5 mL), sat. aq NH4Cl (10 mL) was added and the layers
separated. The aqueous layer was extracted with CH2Cl2
(3 ꢂ 10 mL), the combined organic extracts dried over MgSO4, and
concentrated in vacuo. Purification by flash column chromatog-
raphy on silica (hexanes/EtOAc 3:2) afforded the title compound 21
as a yellow solid (8 mg, 0.033 mmol, 94%). mp 102e106 ꢁC; IR nmax
(film): 3335, 2979, 2937,1655,1578,1303,1234,1173,1075 cmꢀ1; 1H
4.2.8. Synthesis of ethyl 6-isopropoxy-1,4-dimethoxy-2-naphthoate
16
A stirred solution of bromide 4 (600 mg, 1.9 mmol) in degassed
THF (11 mL) was cooled to ꢀ78 ꢁC under argon. t-BuLi (1.6 M in
hexanes, 1.7 mL, 2.8 mmol) was added dropwise over 10 min fol-
lowed by ethyl chloroformate (17) (1.0 mL, 11 mmol) over 5 min.
The reaction mixture was warmed to r.t. over 12 h and the aqueous
layer extracted with EtOAc (3 ꢂ 50 mL). The combined organic
extracts were washed with water (30 mL) and brine (30 mL), dried
over MgSO4 and concentrated in vacuo. Purification by flash column
chromatography on silica (hexanes/EtOAc 19:1 then 9:1) afforded
the title compound 16 as a yellow oil (454 mg, 1.4 mmol, 75%). IR
nmax (film): 2979, 1967, 1923, 1620, 1354, 1202, 1081 cmꢀ1; 1H NMR
NMR (400 MHz, (CD3)2CO)
d
¼ 7.90 (d, J ¼ 8.5 Hz, 1H), 7.41 (d,
J ¼ 2.6 Hz, 1H), 7.19 (dd, J ¼ 8.5, 2.6 Hz,1H), 4.69 (dd, J ¼ 18.5, 2.6 Hz,
1H), 4.42 (ddd, J ¼ 18.5, 4.1, 3.2 Hz, 1H), 3.72e3.64 (m, 1H), 2.67 (dt,
J ¼ 18.7, 3.2 Hz, 1H), 2.16 (dddd, J ¼ 18.7, 10.1, 4.1, 2.6 Hz, 1H), 1.31 (d,
J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, (CD3)2CO)
d
¼ 184.2, 182.8,
(400 MHz, CDCl3)
d
¼ 8.11 (d, J ¼ 9.1 Hz, 1H), 7.53 (d, J ¼ 2.5 Hz, 1H),
163.3, 143.2, 141.9, 135.2, 129.4, 125.4, 121.2, 111.3, 70.1, 63.8, 30.1,
21.5; HRMS (ESI) m/z calcd. for [C14H12NaO4]þ: 267.0628, found:
267.0630.
7.18 (s, 1H), 7.17 (dd, J ¼ 9.1, 2.5 Hz, 1H), 4.77 (sep, J ¼ 6.0 Hz, 1H),
4.44 (q, J ¼ 7.1 Hz, 2H), 4.00 (s, 3H), 3.98 (s, 3H), 1.44 (t, J ¼ 7.1 Hz,
3H), 1.40 (d, J ¼ 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
¼ 166.7,
157.9, 152.6, 150.4, 130.6, 125.6, 124.2, 120.6, 116.5, 104.5, 103.0, 70.1,
63.4, 61.1, 55.8, 22.1, 14.5; HRMS (ESI) m/z calcd. for [C18H22NaO5]þ:
341.1359, found: 341.1354.
4.2.12. Synthesis of trans-9-deoxythysanone ( )-(2)
To a stirred solution of quinone 21 (6 mg, 0.023 mmol) in CCl4
(2.5 mL) was added 1 M Br2 in CCl4 (23 mL, 0.023 mmol) and Bz2O2
(1 crystal). The reaction mixture was irradiated with a 60 W lamp at
40 ꢁC for 1 h. The reaction mixture was cooled to r.t., and concen-
trated in vacuo. The resultant yellow solid was dissolved in THF
(2 mL) and H2O (1 mL) and stirred at r.t. for 1 h. The reaction
mixture was diluted with CH2Cl2 (10 mL) and the layers separated.
The aqueous layer was extracted with CH2Cl2 (3 ꢂ 10 mL) and the
combined organic extracts were washed with brine (2 mL), dried
over MgSO4, and concentrated in vacuo. Purification by column
chromatography on silica (MeOH/CH2Cl2 1:99) afforded the title
compound (2) as an orange solid (5 mg, 0.020 mmol, 85%). mp
4.2.9. Synthesis of ethyl 6-isopropoxy-1,4-dioxo-1,4-
dihydronaphthalene-2-carboxylate 18
To a stirred solution of naphthalene ester 16 (400 mg, 1.3 mmol)
in THF (38 mL) was added AgO (1.7 g, 14 mmol) and 6 M HNO3
(4.6 mL, 25 mmol) dropwise. The reaction mixture was stirred at r.t.
for 3 min then filtered through Celite®. The filtrate was extracted
with CH2Cl2 (3 ꢂ 50 mL), the combined organic extracts dried over
MgSO4, and concentrated in vacuo. Purification by flash column
chromatography on silica (hexanes/EtOAc 5:1) afforded the title
compound 18 as a red oil (319 mg, 1.1 mmol, 88%). IR nmax (film):
139e143 ꢁC; IR nmax (film): 3439, 2972, 1659, 1594, 1308, 985 cmꢀ1
;
2981, 1740, 1668, 1591, 1296, 1231, 1056 cmꢀ1
CDCl3)
;
1H NMR (300 MHz,
¼ 8.01 (d, J ¼ 8.6 Hz, 1H), 7.41 (d, J ¼ 2.6 Hz, 1H), 7.16 (dd,
1H NMR (400 MHz, CD3OD)
d
¼ 7.91 (d, J ¼ 8.5 Hz, 1H), 7.34 (d,
d
J ¼ 2.4 Hz, 1H), 7.09 (dd, J ¼ 8.5, 2.4 Hz, 1H), 5.87 (s, 1H), 4.31e4.22
(m, 1H), 2.68 (dd, J ¼ 19.3, 3.4 Hz, 1H), 2.15 (dd, J ¼ 19.3, 11.1 Hz, 1H),
J ¼ 8.6, 2.6 Hz, 1H), 7.12 (s, 1H), 4.72 (sep, J ¼ 6.0 Hz, 1H), 4.37 (q,
J ¼ 7.1 Hz, 2H), 1.37 (d, J ¼ 6.0 Hz, 6H), 1.36 (t, J ¼ 7.1 Hz, 3H); 13C
1.33 (d, J ¼ 6.3 Hz, 3H); 13C NMR (100 MHz, CD3OD)
¼ 185.9,183.2,
d
NMR (100 MHz, CDCl3)
d
¼ 185.0, 180.3, 163.7, 163.0, 140.2, 137.3,
164.3, 143.9, 141.9, 135.4, 130.0, 125.7, 121.7, 113.0, 87.5, 63.1, 30.4,
21.4; HRMS (ESI) m/z calcd. for [C14H12NaO5]þ: 283.0577, found:
283.0582.
133.7, 129.6, 124.9, 122.2, 110.8, 71.0, 62.4, 21.9, 14.2; HRMS (ESI) m/
z calcd. for [C16H17O5]þ: 289.1071, found: 289.1073.
4.2.10. Synthesis of 7-isopropoxy-3-methyl-3,4-dihydro-1H-benzo
[g]isochromene-1,5,10-trione 20
4.3. Analysis of 3C protease activity
4.3.1. HRV 3C protease assay
To a stirred solution of quinone 18 (164 mg, 0.57 mmol) in MeCN
(1.1 mL) was added AgNO3 (145 mg, 0.854 mmol) and 3-
hydroxybutyric acid (0.5 mL, 5.7 mmol) with light excluded. The
reaction mixture was heated to 80 ꢁC and water (0.6 mL) added,
immediately followed by dropwise addition of (NH4)2S2O8 (328 mg,
1.1 mmol) in water (1.1 mL). The reaction mixture was stirred at
80 ꢁC for 5 min, then cooled to r.t. The reaction mixture was
extracted with EtOAc (3 ꢂ 10 mL), the combined organic extracts
dried over MgSO4, and concentrated in vacuo. Purification by flash
column chromatography on silica (hexanes/EtOAc 3:2) afforded the
title compound 20 as an orange solid (103 mg, 0.34 mmol, 60%). mp
All protease assays were performed at r.t. for 1 h in a 100
reaction containing rHRV 3C protease (50 g/mL), substrate (52
in tris(2-carboxyethyl)-phosphine (TCEP, 5 M) in phosphate
buffered saline (PBS) pH 6.8 under continuous rotation. The reac-
tion mixture was centrifuged, 10 L of the supernatant was added
to PBS pH 6.8 (200 L) in a 96-well opti plate. The fluorescence
mL
mM)
m
m
m
m
intensity (FI) was measured with a PerkineElmer EnSpire multi-
mode plate reader with an excitation wavelength of 495 nm and an
emission wavelength of 516 nm and 100 excitation flashes. A blank
was measured with PBS at pH 6.8 containing enzyme only and an
assay with (ꢀ)-thysanone (1) was run as a control (detected IC50 for
88e92 ꢁC; IR nmax (film): 2979, 1736, 1591, 1287, 1216, 1108 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
¼ 8.01 (d, J ¼ 8.7 Hz, 1H), 7.41 (d,
1: 51.8 0.7 mM).
J ¼ 2.6 Hz, 1H), 7.18 (dd, J ¼ 8.7, 2.6 Hz,1H), 4.71 (sep, J ¼ 6.0 Hz,1H),
4.65e4.56 (m, 1H), 3.14 (dd, J ¼ 18.8 Hz, 3.1, Hz, 1H), 2.53 (dd,
J ¼ 18.8 Hz, 11.7 Hz, 1H), 1.52 (d, J ¼ 6.3 Hz, 3H), 1.37 (d, J ¼ 6.0 Hz,
Acknowledgements
6H); 13C NMR (100 MHz, CDCl3)
d
¼ 183.9, 178.7, 162.7, 160.2, 150.9,
133.2, 129.8, 128.4, 125.3, 122.6, 111.1, 73.9, 71.1, 29.0, 21.9, 20.6;
The authors thank Dr David Goldstone (University of Auckland)
for valuable discussions and a supply of rHRV 3C protease.
HRMS (ESI) m/z calcd. for [C17H17O5]þ: 301.1071, found: 301.1074.

J. Young Jeong et al. / European Journal of Medicinal Chemistry 87 (2014) 220e227
227
[18] P. Bachu, J. Sperry, M.A. Brimble, Chemoenzymatic synthesis of deoxy ana-
logues of the DNA topoisomerase II inhibitor eleutherin and the 3C-protease
inhibitor thysanone, Tetrahedron 64 (2008) 4827e4834.
[19] M. Brimble, A. Wadsworth, J. Sperry, Synthesis of the pyranonaphthoquinones
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Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.09.063.
[20] K. Schünemann, D.P. Furkert, S. Connelly, J.D. Fraser, J. Sperry, M.A. Brimble,
Synthesis and biological evaluation of 7-deoxy analogues of the human
rhinovirus 3C protease inhibitor thysanone, Eur. J. Org. Chem. 2014 (2014)
122e128.
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