Anti-AIDS agents 86. Synthesis and anti-HIV evaluation of 2′,3′-seco-3′-nor DCP and DCK analogues

Article abstract of DOI:10.1016/j.ejmech.2011.07.051

In a continuing study of novel anti-HIV agents with drug-like structures and properties, 30 1′-O-, 1′-S-, 4′-O- and 4′-substituted-2′,3′-seco-3′-nor DCP and DCK analogues (8-37) were designed and synthesized. All newly synthesized seco-compounds were screened against HIV-1_NL4-3 and a multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR) strain in the TZM-bl cell line, using seco-DCK (7) and 2-ethyl-DCP (4) as controls. Several compounds (14, 18, 19, 22-24, and 32) exhibited potent anti-HIV activity with EC₅₀ values ranging from 0.93 to 1.93 μM and therapeutic index (TI) values ranging from 20 to 39. 1′-O-Isopropoxy-2′,3′-seco-3′-nor-DCP (12) showed the greatest potency among the newly synthesized compounds with EC₅₀ values of 0.47 and 0.88 μM, and TI of 96 and 51, respectively, against HIV-1_NL4-3 and RTMDR strains. The seco-compounds exhibited better chemical stability in acidic conditions compared with DCP and DCK compounds. Overall, the results suggested that seco-DCP analogues with simplified structures may be more favorable for development as novel anti-HIV candidates.

Full text of DOI:10.1016/j.ejmech.2011.07.051

European Journal of Medicinal Chemistry 46 (2011) 4924e4936
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Anti-AIDS agents 86. Synthesis and anti-HIV evaluation of 20,30-seco-30-nor DCP
and DCK analogues
,
b
b
b
Ying Chen a, Ming Cheng a, Fa-Qiang Liu a, Peng Xia a , Keduo Qian , Donglei Yu , Yi Xia ,
**
*
Zheng-Yu Yang b, Chin-Ho Chen c, Susan L. Morris-Natschke b, Kuo-Hsiung Lee b
,d,
a Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
b Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA
c Duke University Medical Center, Durham, NC 27710, USA
d Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan
a r t i c l e i n f o
a b s t r a c t
In a continuing study of novel anti-HIV agents with drug-like structures and properties, 30 10-O-, 10-S-, 40-
O- and 40-substituted-20,30-seco-30-nor DCP and DCK analogues (8-37) were designed and synthesized.
All newly synthesized seco-compounds were screened against HIV-1NL4-3 and a multiple reverse tran-
scriptase (RT) inhibitor-resistant (RTMDR) strain in the TZM-bl cell line, using seco-DCK (7) and 2-ethyl-
DCP (4) as controls. Several compounds (14, 18, 19, 22e24, and 32) exhibited potent anti-HIV activity
Article history:
Received 13 June 2011
Received in revised form
27 July 2011
Accepted 28 July 2011
Available online 4 August 2011
with EC50 values ranging from 0.93 to 1.93
10-O-Isopropoxy-20,30-seco-30-nor-DCP (12) showed the greatest potency among the newly synthesized
compounds with EC50 values of 0.47 and 0.88 M, and TI of 96 and 51, respectively, against HIV-1NL4-3
mM and therapeutic index (TI) values ranging from 20 to 39.
Keywords:
20,30-Seco-30-nor-DCPs
Anti-HIV activity
m
and RTMDR strains. The seco-compounds exhibited better chemical stability in acidic conditions
compared with DCP and DCK compounds. Overall, the results suggested that seco-DCP analogues with
simplified structures may be more favorable for development as novel anti-HIV candidates.
Ó 2011 Elsevier Masson SAS. All rights reserved.
Structureeactivity relationship (SAR)
1. Introduction
new compounds showed promising in vitro inhibitory activity in
anti-HIV replication assays, and a preliminary structure-activity
Acquired immunodeficiency syndrome (AIDS), one of the most
devastating diseases currently affecting mankind, is caused by
infection with the human immunodeficiency virus (HIV). Although
there are over 30 clinically used drugs [1], the fast emergence of
drug resistance and toxicity problems due to long-term use and
drugedrug interactions have limited their long-term drug effec-
tiveness. Therefore, studies aimed at the discovery of new anti-viral
agents with novel structures or targets are still needed.
relationship (SAR) was established. However, the problems of
poor water solubility, low bioavailability and reduced potency
against multiple reverse transcriptase (RT) inhibitor-resistant
(RTMDR) strains have obstructed the further development of
DCKs. Subsequently, 4H-chromone-4-one (DCP, 3) derivatives,
which are positional isomers of DCK, were designed and synthe-
sized [11,12]. Among them, 2-ethyl DCP (4), 5-methyl-2-ethyl DCP
(5), and 2,5-dimethyl DCP (6) not only exhibited high activity
against wild-type HIV isolates, but also retained potency against
RTMDR-1 (Fig. 1).
These favorable results led us to investigate whether the
integrity of the tricyclic system (ring-A, -B and -C) was essential for
the anti-HIV activity. While ring-A opened DCK analogues did not
exhibit antiviral activity, ring-C opened DCK analogues (seco-DCKs)
were active. In fact, compared with 2, seco-DCK analogue 7 showed
better anti-HIV activity and increased sensitivity against RTMDR in
anti-HIV replication assays using HIV-1IIIB in MT-2 cell lines, as well
as HIV-1NL4-3 and RTMDR in MT-4 lymphocytes [13]. The seco-DCKs
have a simplified skeleton, fewer hydrogen-bond acceptors and
lower log P values, resulting in increased water solubility and better
pharmacokinetic properties compared with DCKs. Our success with
In our prior research, 30R,40R-di-O-(ꢀ)-camphanoyl-(þ)-cis-
khellactone (DCK, 1) and 4-methyl-DCK (2) exhibited high potency
against HIV-1 replication in H9 lymphocytes (Fig. 1) [2,3]. Subse-
quently, diverse DCK analogues were designed and synthesized by
modifications of DCK, particularly different coumarin substituents,
ring isomers, and bioisosteric replacements [4e10]. Most of the
* Corresponding author. Tel.: þ86 21 51980116.
** Corresponding author. Natural Products Research Laboratories, UNC Eshelman
School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA.
Tel.: þ1 919 962 0066; fax: þ1 919 966 3893.
E-mail addresses: pxia@fudan.edu.cn (P. Xia), khlee@unc.edu (K.-H. Lee).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.07.051

Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
4925
Fig. 1. DCK & DCP analogues and seco-DCK.
seco-DCKs prompted us to make corresponding modifications on
DCP analogues in our search for new desirable anti-HIV inhibitors
with better drug-like properties and inhibitory activity against
RTMDR. Herein, we report the design, synthesis, biological evalu-
ation and chemical stability of novel 20,30-seco-30-nor DCP (8-31,
33-37) and DCK (32) analogues (Figs. 2e4).
the aim of slowing down possible metabolism at this position.
Accordingly, three 40-camphanol ethers of 20,30-seco-30-nor-2-
ethyl-DCPs (29e31) were generated. Prior research on bio-
isosteric replacement showed that some 1-thia and/or 10-thia DCKs
exhibited comparable or better activity against HIV replication
compared with 1-oxa and/or 10-oxa DCKs. Consequently, we
synthesized 10-thia-20,30-seco-30-nor-4-methyl-DCK (32) and 10-
thia-20,30-seco-30-nor-2-ethyl-DCP (33) to verify if seco-series
showed a similar trend. Finally, we replaced the 40-O-camphanoyl
ester with piperidinyl oxalamide moieties, and synthesized four
40e(N0-substituted piperidin-1-yl)-20,30-seco-30-nor DCP analogues
(34e37). All new compounds were evaluated in an antiviral repli-
cation assay against wild-type virus, and 15 compounds were also
assayed against RTMDR virus.
2. Design
Previous research suggested that a 40-camphanoyl moiety is
preferred for anti-HIV activity of DCK/DCP analogues. Therefore, in
our current study, we first retained the 40-camphanoyl ester
substitution, while focusing on diverse substituents at the 10-O
position of the new ring-C opened seco-DCP products. Eight 20,30-
seco-30-nor-2-ethyl DCP analogues (8e15) with different aliphatic
groups, such as methyl, ethyl, isopropyl, isobutyl, and 2-
a-bro-
3. Chemistry
moethyl, at the 10-O position were synthesized. Aromatic and
heterocyclic moieties, which were not introduced at the 10-O
position in our prior seco-DCK study, were also incorporated to
examine the effects of 10-O-aryl rings with electron-donating or
-withdrawing groups and 10-O-heterocyclic substituents on the
antiviral replication activity of new compounds (16e28). In addi-
tion, because an ether bond usually has better chemical stability
than an ester bond, the 40-camphanoyl ester [eO(C]O)e linkage]
was replaced with a 40-camphanol ether [-OeCH2e linkage] with
Scheme 1 shows the synthesis of 10-O-alkyl-20,30-seco-30-nor
DCPs (8e15). Commerciallyavailable 2,4-dihydroxy-3-methylaceto-
phenone (38) was selectively protected as the 4-methoxymethyl
(MOM) ether (39), followed by condensation with ethyl propio-
nate to afford 40, which was further reacted with concentrated
hydrochloric acid in EtOH to provide bicyclic compound 41. Four 7-
alkoxy ethers (42aed) were synthesized by alkylation of 41 with
corresponding bromides, and subsequent treatment with N-
Fig. 2. Newly designed 10-O-substituted 20,30-seco-30-nor-DCP analogues (8e31).

4926
Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
reflux-dehydration conditions. Subsequently, the 7-hydroxy
compounds (53 and 66) were converted to the 7-mercapto
compounds (56 and 69) in three steps, acylation with dimethylth-
iocarbamoyl chloride (54 and 67), Newman-Kwart rearrangement
(55 and 68), and basic hydrolysis. The alkylation of 56 and 69 with
isopropyl bromide yielded 57 and 70. Finally, target compounds 32
and 33 were prepared from 57 and 70 by the following reaction
sequence, deprotection of the 8-acetal in 1N HCl, reduction of 58
and 71 with NaBH4 in MeOH, and esterification of 60 and 72 with
camphanoyl chloride.
Fig. 3. Newly designed 10-thia-20,30-seco-30-nor-DCK (32) and -DCP (33) analogues.
4. Results and discussion
bromosuccinimide provided 8-bromomethylmonobromides (43ae
d) and 2-a-bromoethyl-8-bromomethyldibromides (44eeh). A
mixture of the mono- and di-bromides was first heated at reflux in
a solution of NaOAc/Ac2O and then hydrolyzed with 2N HCl in EtOH
All 30 newly synthesized seco-DCK and DCP analogues (8e37)
were evaluated for in vitro suppression of HIV-1NL4-3 replication in
a single cycle infection assay using the TZM-bl cell line with both 2-
ethyl-DCP (4) and seco-DCK (7) as positive controls. Moreover,
compounds 8e15, 29e31, and 34e37 were also screened for anti-
viral activity against HIV-1 RTMDR. The data are summarized in
Tables 1 and 2.
to produce 8-hydroxymethyl compounds (45aed) and 2-a-bro-
moethyl-8-hydroxymethyl compounds (46eeh), respectively.
Subsequently, the desired esters 8e15 were prepared by esterifica-
tion of 45aed and 46eeh with camphanoyl chloride in DMAP and
CH2Cl2 at room temperature.
As shown in Table 1, compounds 8e15 exhibited varying degrees
of potency against wild-type HIV-1NL4-3. Based on the size of the
alkyl group at the 10-O position, the rank order of antiviral activity
The synthesis of 10-O-aryl or -heterocyclic substituted 20,30-
seco-30-nor-2-ethyl-DCPs (16e28) is depicted in Scheme 2. To avoid
the reaction of the 7eOH group of 41 with NBS, the MOM ether 47
was prepared and subsequently brominated with NBS to yield the
8-bromomethyl compound 48, which was then treated as
described above to afford 49. Thirteen 7-aromatic and -heterocyclic
substituted ethers (50aem) were prepared by alkylation of 49 with
corresponding bromides in DMF in the presence of K2CO3 at room
temperature. Compounds 50aem were then converted into the
target compounds (16e28) by acylation with camphanoyl chloride.
As shown in Scheme 3, etherification of 7-alkyloxy-8-
bromomethyl-2-ethyl-4H-chromen-4-ones (43aec) with campha-
nol in toluene in presence of NaH afforded the three respective 40-
camphanol ether 20,30-seco-30-nor-2-ethyl-DCPs (29e31). Four
40e(N0-substituted piperidin-1-yl)-20,30-seco-30-nor DCP analogues
(34e37) were obtained from the amidation of 43b with the corre-
sponding N0-substituted piperidine in THF in presence of DMAP at
room temperature.
was methyl
substituted 12 showed the best antiviral activity against both HIV-
1NL4-3 and RTMDR with EC50 values of 0.47 and 0.88 M, and TI of
< ethyl < isobutyl <
isopropyl. 10-O-Isopropyl
m
96 and 51, respectively, which were generally comparable or better,
particularly against RTMDR, than those of prior hits 7 (EC50 0.5 and
1.89
0.20
m
m
M; TI 34.54 and 9.13, respectively) and 4 (EC50 0.12 and
M, TI 118.75 and 71.25, respectively). Compounds 12 and
14 (10-O-isobutyl-20,30-seco-30-nor-2-ethyl-DCP) had comparable
anti-RTMDR potencies (EC50 0.88 and 0.94 mM, respectively), which
were two-fold better than that of 7. Compounds with a bromine on
the 2-ethyl group (9, 11, 13, and 15) exhibited much lower anti-HIV
activity compared with the corresponding non-brominated
compounds (8, 10, 12, and 14). This finding suggested that a 2-a-
bromoethyl group was unfavorable. Overall, the results suggested
that the size of an isopropyl group at the 10-O position was more
suitable to fit within the binding pocket of wild-type virus, while
both isopropyl and isobutyl may fit into the slightly changed
binding pocket of the RTMDR strain, due to possible mutations near
the interaction site.
The syntheses of 10-thia-20,30-seco-30-nor-4-methyl-DCK (32)
and 10-thia-20,30- seco-30-nor-2-ethyl-DCP (33) are depicted in
Schemes 4 and 5, respectively. For 33, the mono-acetylation of
commercially available resorcinol (60) in an HOAc solution con-
taining zinc chloride gave 61. 2-Ethyl-7-hydroxy-4H-chromen-4-
one (64) was then obtained from 61 via three steps, 4eOH
protection with MOMCl (62), condensation with ethyl propionate
(63), and ring-A closure. Compounds 52 (Scheme 4) and 65
(Scheme 5) were obtained by Duff formylation of 51 and 64,
respectively, with hexamethylenamine in acetic acid solution.
Because hydrogen bonding between the 7-hydroxy and 8-formyl
groups could possibly interfere with the conversion of the 7eOH
to 7eSH, the 8-formyl moiety in 52 and 65 was first protected as
a cyclic acetal in intermediates 53 and 66 by reaction with ethylene
glycol in the presence of p-toluenesulfonic acid in benzene under
The three novel 40-camphanol ether seco-DCP analogues (29-
31) exhibited better inhibition activity against drug-resistant
RTMDR than wild-type HIV-1NL4-3. 10-O-Isopropyl-40-camphanol
ether 31 exhibited the best potency against RTMDR (EC50 1.49 mM,
TI 31.45). However, the 40-camphanol ether compounds (29-31)
were less potent than their corresponding 40-camphanoyl ester
analogues (8, 10, 12, respectively). The four compounds (34-37)
with a piperidinyl group rather than a camphanoyl ester or cam-
phanol ether at the 40-position showed decreased or completely
abolished inhibitory activity against HIV, further confirming our
prior finding that a 40-camphanoyl group is very important for
enhanced anti-HIV activity in the DCK/DCP series.
The anti-HIV-1NL4-3 results for 10-O-aryl and -heterocyclic 20,30-
seco-30-nor-2-ethyl- DCPs (16e28) and 10-thia compounds (32 and
33) are shown in Table 2. Among these analogues, 10-O-3-
methoxycarbonylbenzyl-20,30-seco-30-nor-2-ethyl-DCP (23) (EC50
0.93 mM, TI 39.20) and the positive control (7) (EC50 0.5 mM, TI
34.54) exhibited comparable potency. 10-O-Pyrid-3-yl-methyl,
-pyrid-4-yl-methyl, 10-O-3-cyanobenzyl, 10-O-3-methoxybenzyl,
and 10-O-3-methylbenzyl analogues (18, 19, 21, 22, and 24,
respectively) also showed moderate anti-HIV inhibitory activity
Fig. 4. Newly designed 40-(N0-substituted piperidin-1-yl)-20,30-seco-30-nor-DCP
analogues (34e37).
with EC50 values ranging from 1.26 to 2.41
mM. The significantly
reduced potency of 17, which contains a 10-O-pyrid-2-yl-methyl

Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
4927
Scheme 1. The synthetic routes to 10-O-alkyl-20,30-seco-30-nor-DCPs (8e15). Reagents and conditions: (i). chloromethyl methyl ether/K2CO3/acetone/rt; (ii). ethyl propionate/NaH/
THF/reflux; (iii). conc. HCl/EtOH/refux; (iv). variable bromides/K2CO3/DMF; (v). 1.2 equiv. NBS/CCl4/reflux; (vi). a. NaOAc/Ac2O/reflux; b. 2N HCl/EtOH/reflux; (vii). camphanoyl
chloride/DMAP/CH2Cl2/rt.
substituent, compared with 18 and 19 suggested that a nitrogen
atom at the 2-position of the aromatic ring is detrimental to the
antiviral activity. Compounds 25 and 26 with 10-O-3,5-
dimethoxybenzyl and 10-O-3-trifluoromethoxybenzyl substituents
exhibited very weak anti-HIV activity, while compounds 16, 20, 27,
Chemically, the seco-DCK/DCP analogues have lower molecular
weights and should have reduced spatial strain, because they
contain only one rather than two adjacent, extremely bulky cis-
30,40-camphanoyl esters as found in the DCK and DCP series.
Hypothetically, these changes could improve the chemical stability
of the molecules and their drug-like properties. Consequently, the
chemical stability of 4-Me-DCK (2), seco-DCK (7), 10-thia-seco-DCK
(32), 2-ethyl-DCP (4), and seco-DCP (12) were tested under acidic
conditions with HPLC monitoring. The preliminary results are listed
in Table 3. The results showed that, after 30 min, only 64% of
compound 2 was detectable, while 77% of 7 and 96% of 32 were
intact. Compound 12, which exhibited the greatest antiviral activity
among the newly synthesized seco-DCK/DCP analogues, also
showed the best chemical stability in this study (100% intact after
30 min). Overall, the seco-series of compounds showed good
stability in acidic conditions, indicating that they should remain
stable in the stomach via oral administration.
and 28 with 10-O- -butyrolactone, 10-O-3-trifluoromethylbenzyl,
g
10-O-2-bromo-5-methoxybenzyl, and 10-O-2-nitro-4,5-dimethoxy-
benzyl substituents lost all activity. These results indicated that
the 10-O-substituents have a significant impact on the analogues’
antiviral activity. The 10-O position in the seco-compounds, which
corresponds to the 20-postion of DCK and DCP analogues, should be
interacting with the viral binding target, as consistent with our
previous study in the DCK series. Finally, compound 32 (10-thia-
seco-DCK) showed moderate antiviral activity (EC50 1.53
m
M, TI
21.32), while 33 (10-thia-seco-DCP) was more active (EC50 0.56
m
M,
TI 11.25). Comparing the sulfur compounds with their oxygen
counterparts, 32 was less potent than 12, while 33 was equipotent
with 7.
Scheme 2. The synthesis of 10-O-aryl or heterocyclic substituted 20,30-seco-30-nor-2-ethyl-DCPs (16e28). Reaction Conditions: (i). chloromethyl methyl ether/K2CO3/DMF/rt; (ii). 1.2
equiv. NBS/CCl4/reflux; (iii). a. NaOAc/Ac2O/reflux; b. 2N HCl/EtOH/reflux; (iv). variable bromides/K2CO3/DMF/rt; (v). camphanoyl chloride/DMAP/CH2Cl2/rt.

4928
Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
resonance (1H NMR) spectra were measured on a Bruker-DPX
400 MHz spectrometer and 300 MHz Varian Gemini 2000 spec-
trometer using TMS as internal standard. The solvent used was CDCl3
unless indicated. Mass spectra were measured with HP5973N
analytical mass spectrometers. High resolution mass spectra (HRMS)
were measured on a Shimadzu LCMSIT-TOF with ESI interface. HPLC
purity determinations were conducted using a Shimadzu LCMS-2010
withaGraceAlltima2.1ꢁ150 mm HP C18 3
mMcolumnandShimadzu
SPD-M20A detector at 254 nm wavelength. HPLC purity analyses
were determined by using two different solvent conditions. The first
was70%MeCNassolvent A and 30% H2O assolvent B with0.2 mL/min
flow rate; the second was 70% MeOH as solvent A and 30% H2O as
solvent B with 0.1 mL/min flow rate. The HPLC model was an isocratic
system. All target compounds had purity greater than 95%.
Commercially available silica gel H was used for column chromatog-
raphy. Thin-layer chromatography (TLC) was performed on PLC silica
gel 60 F254 plates.
Scheme 3. The synthetic routes to 40-camphanol ethers of 20,30-seco-30-nor-2-ethyl-
DCPs (29e31) and 40e(N0-substituted piperidin-1-yl)-20,30-seco-30-nor
¼
DCP
analogues (36e39). Reaction Conditions: (i). camphanol/NaH/toluene/rt; (ii). variable
6.1. Synthesis of 10-alkoxy-seco-DCPs (8e15)
N0-substituted piperidines/DMAP/THF/rt.
5. Conclusions
6.1.1. 1-(2-Hydroxy-4-(methoxymethoxy)-3-methylphenyl)
ethanone (39)
In conclusion, most of the new 20,30-seco-30-nor-2-ethyl-DCP
analogues showed potent to moderate anti-HIV activity, and
compounds 12 and 14 also showed promising activity against
RTMDR. In addition, the chemical stability of seco-DCKs and seco-
DCPs was improved in comparison with DCK and DCP analogues.
Preliminary SAR conclusions were as follows, a) integrity of the
ring-C is not essential for DCK and DCP analogues, and aliphatic
alkyl substituents at 10-O-position are better than aryl or hetero-
cyclic groups, with isopropyl substitution being the most favorable
for anti-HIV potency; b) converting the 40-camphanoyl ester into
Chloromethyl methyl ether (9.14 mL, 120 mmol) was added
dropwise into a mixture of 38 (10.0 g, 60.2 mmol) and potassium
carbonate (20.8 g, 150 mmol) in anhydrous acetone (60 mL) in an
ice-bath. The reaction mixture was then allowed to warm to room
temperature and stirred for 1.5 h. The mixture was then filtered,
and the filtrate was dissolved in brine and extracted with EtOAc
(35 mL). The organic layer was dried in vacuo to provide 39 (13.9 g)
as brown oil: 91% yield. 1H NMR
d: 2.14 (3H, s, 3eCH3), 2.56 (3H, s,
1eCOCH3), 3.50 (3H, s, 4eOCH2OCH3), 5.27 (2H, s, 4eOCH2OCH3),
6.65 (1H, d, J ¼ 8.7 Hz, 6eH), 7.57 (1H, d, J ¼ 8.7 Hz, 5eH), 12.80 (1H,
s, 2eOH). ESI-MS m/z 209 (Mþ ꢀ 1).
a
camphanol ether resulted in some potency decrease, but
compounds remained more selective against RTMDR; c) 40-cam-
phanoyl is the most preferred moiety for anti-HIV activity of DCK
and DCP analogues; and d) sulfur rather than oxygen at the
10-position led to similar or slightly reduced anti-HIV activity.
6.1.2. 2-Ethyl-7-hydroxy-8-methyl-4H-chromen-4-one (41)
Sodium hydride (60% in mineral oil, 9.52 g/15.9 g, 397 mmol)
was added slowly to a mixture of 39 (13.9 mg, 66.1 mmol) and ethyl
propionate (19.0 mL, 165 mmol) in absolute THF under nitrogen.
Then, the mixture was warmed to reflux temperature for 2 h,
cooled and neutralized to pH 8 with 37% HCl (25 mL). Water
(60 mL) was added and the mixture was extracted with EtOAc
(4 ꢁ 30 mL). The organic layer was collected and evaporated in
6. Experimental
Melting points were measured with a Fisher Johns melting
apparatus without correction. The proton nuclear magnetic
Scheme 4. The synthetic route to 10-thia-20,30-seco-30-nor-4-methyl-DCK (32). Reaction Conditions: (i). hexamethylenamine/HOAc; (ii). HOCH2CH2OH/p-TSA/benzene/reflux; (iii).
dimethylthiocarbamoyl chloride/DMF/K2CO3; (iv). heat at 195e205 ꢂC; (v). KOH/MeOH; (vi). isopropyl bromide/KOH/DMF; (vii). 1N HCl; (viii). NaBH4/MeOH; (ix). camphanoyl
chloride/DMAP/CH2Cl2.

Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
4929
Scheme 5. The synthesis of 10-thia-20,30-seco-30-nor-2-ethyl-DCP (33). Reaction Conditions: (i). HOAc/ZnCl2/reflux; (ii). chloromethyl methyl ether/K2CO3/acetone/ice-water bath;
(iii). ethyl propionate/NaH/THF/reflux; (iv). conc. HCl/EtOH/reflux; (v). a. urotropin/HOAc/reflux; b. HCl/reflux; (vi). ethylene glycol/benzene/p-TSA-H2O/reflux; (vii). dimethylth-
iocarbamoyl chloride/K2CO3/MeOH; (viii). N2/220 ꢂC; (ix). K2CO3/MeOH/reflux; (x). 2-bromopropane; (xi). 1N HCl; (xii). NaBH4/MeOH; (xiii). camphanoyl chloride/DMAP/CH2Cl2.
vacuo to yield 40 as dark oil. This crude product and 37% HCl (3 mL)
were dissolved in EtOH (60 mL) and refluxed for 45 min to give 41,
which was used in the next reaction without further purification.
(eluent: hexane/EtOAc 95:5) to afford the desired compounds
(42aed) as white solids in 73e82% yields.
mp 223e224 ꢂC 1H NMR (DMSO,
d): 1.23 (3H, t, J ¼ 7.2 Hz,
6.1.3.1. 2-Ethyl-7-methoxy-8-methyl-4H-chromen-4-one (42a). 75%
2eCH2CH3), 2.20 (3H, s, 8eCH3), 2.65 (2H, q, J ¼ 7.2 Hz, 2eCH2CH3),
6.06 (1H, s, 3eH), 6.98 (1H, d, J ¼ 8.7 Hz, 6eH), 7.68 (1H, d,
J ¼ 8.7 Hz, 5eH). ESI-MS m/z 203 (Mþ ꢀ 1).
yield, mp 104e106 ꢂC 1H NMR
d
: 1.32 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3),
2.30 (3H, s, 8eCH3), 2.68 (2H, q, J ¼ 7.5 Hz, 2eCH2CH3), 3.95 (3H, s,
7eOCH3), 6.11 (1H, s, 3eH), 6.96 (1H, d, J ¼ 9.0 Hz, 6eH), 8.10 (1H, d,
J ¼ 9.0 Hz, 5eH). ESI-MS m/z 219 (Mþþ1).
6.1.3. Synthesis of 2-ethyl-7-alkoxychromones (42aed)
A mixture of 41 (1 equiv), K2CO3 (3 equiv), and halogenated
compounds (2 equiv) in DMF (5 mL) was stirred for 45 min at room
temperature. After filtering the mixture and removing the solvent
in vacuo, the residue was purified by column chromatography
6.1.3.2. 7-Ethoxy-2-ethyl-8-methyl-4H-chromen-4-one (42b). 73%
yield, mp 85e87 ꢂC 1H NMR
d: 1.33 (3H, t, J ¼ 7.5 Hz, 2-CH2CH3),
1.48 (3H, t, J ¼ 7.2 Hz, 7eOCH2CH3), 2.31 (3H, s, 8eCH3), 2.68 (2H, q,
J ¼ 7.5 Hz, 2eCH2CH3), 4.17 (2H, q, J ¼ 7.2 Hz, 7eOCH2CH3), 6.11 (1H,
Table 2
Table 1
Anti-HIV-1 NL4-3 data of seco-DCP and -DCK analogues (16e28, 32, and 33) in TZM-bl
Anti-HIV-1 NL4-3 and HIV-1 RTMDR results of seco-DCP analogues (8e15, 29e31, and
cells.a
34e37) in TZM-bl cells.a
Compd
CC50
(
m
M)
HIV-1NL4-3
Compd
CC50
(
m
M)
HIV-1NL4-3
EC50 M)
27.45
30.69
3.69
16.67
0.47
2.24
1.11
31.28
>50
18.36
2.5
RTMDR
EC50
(m
M)
TI
(
m
TI
EC50
7.91
9.70
2.26
5.18
0.88
1.52
0.94
(
m
M)
TI
8
9
>48.29
>40.64
>46.68
23.14
>45.23
16.94
37.08
>37.35
>50
>1.76
>1.32
>12.6
1.39
>95.95
7.55
33.0
>1.33
NS
>6.11
>4.19
>20.5
4.47
>51.37
11.12
39.5
>1.44
>2.14
3.96
>31.45
1.30
>1.37
>1.36
NS
71.25
9.13
16
17
18
19
20
21
22
23
24
25
26
27
28
32
33
4
e
e
NS
3.70
>40.69
>40.69
>40.69
11.00
1.26
1.93
10
11
12
13
14
15
29
30
31
34
35
36
37
4
32.29
21.08
NS
>16.09
23.57
39.20
20.65
1.64
1.87
NS
NS
21.32
11.25
118.75
34.54
>38.79
>38.42
>36.46
>39.64
>36.32
>34.81
e
2.41
1.63
0.93
1.92
22.18
18.45
e
25.90
23.3
9.28
36.72
>47
2
>18.75
NS
>1.33
>1.14
NS
1.49
>22.00
>22.30
>21.62
>20.51
14.25
>22.00
16.72
19.03
>20.51
0.12
16.94
16.28
16.0
>20.51
0.20
e
e
32.62
6.3
14.25
17.27
1.53
0.56
0.12
0.5
118.75
34.54
7
17.27
0.5
1.89
7
a
NS: no suppression at the highest tested concentration (20
m
M).
All data presented in this table were averaged from at least three independent
a
All data presented in this table were averaged from at least three independent
experiments. Cytotoxicity was determined using a Promega CytoTox-GloÔ assay kit.
experiments. Cytotoxicity was determined using a Promega CytoTox-GloÔ assay kit.
NS: no suppression at the highest tested concentration (20 mM).

4930
Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
Table 3
4.93 (2H, s, 8eCH2Br), 6.28 (1H, s, 3eH), 7.09 (1H, d, J ¼ 9.0 Hz, 6eH),
8.27 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 339 (Mþ þ 1).
Chemical stability of 4-Me-DCK (2), seco-DCK (7), 10-thia-seco-DCK (32), 2-ethyl-
DCP (4), and seco-DCP (12) in acidic conditions.a
Purity (area %)
6.1.4.5. 2-(1-Bromoethyl)-8-(bromomethyl)-7-methoxy-4H-chromen-
4-one (44e). 14% yield (starting with 300 mg of 42a): mp
Reaction Time ¼ 1 min
Reaction Time ¼ 30 min
64%
77%
96%
91%
153e156 ꢂC 1H NMR
d: 2.09 (3H, d, J ¼ 7.2 Hz, 2eCHBrCH3), 4.04 (3H,
2
7
32
4
12
100%
100%
100%
100%
100%
s, 7eOCH3), 4.81 (2H, s, 8eCH2Br), 4.94 (1H, q, J ¼ 7.2 Hz,
2eCHBrCH3), 6.33 (1H, s, 3eH), 7.02 (1H, d, J ¼ 9.0 Hz, 6eH), 8.16
(1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 377 (100).
100%
a
Condition: 1% HCl/MeOH/rt; Compound purity: peak area percentage by HPLC
6.1.4.6. 2-(1-Bromoethyl)-8-(bromomethyl)-7-ethoxy-4H-chromen-
determination.
4-one (44f). 15% yield (starting with 880 mg of 42b): mp
138e140 ꢂC 1H NMR
d
: 1.53 (3H, t, J ¼ 6.9 Hz, 7eOCH2CH3), 2.09
s, 3eH), 6.93 (1H, d, J ¼ 9.0 Hz, 6eH), 8.01 (1H, d, J ¼ 9.0 Hz, 5eH).
ESI-MS m/z 233 (Mþ þ 1).
(3H, d, J ¼ 7.2 Hz, 2eCHBrCH3), 4.26 (2H, q, J ¼ 6.9 Hz, 7eOCH2CH3),
4.82 (2H, s, 8eCH2Br), 4.95 (1H, q, J ¼ 7.2 Hz, 2eCHBrCH3), 6.33 (1H,
s, 3eH), 6.99 (1H, d, J ¼ 9.0 Hz, 6eH), 8.12 (1H, d, J ¼ 9.0 Hz, 5eH).
ESI-MS m/z 384 (100).
6.1.3.3. 2-Ethyl-7-isopropoxy-8-methyl-4H-chromen-4-one (42c). 79%
yield, mp 99e101 ꢂC 1H NMR
d: 1.33 (3H, t, J ¼ 6.9 Hz, 2eCH2CH3),
1.38 (6H, d, J ¼ 6.0 Hz, 7eOCH(CH3)2), 2.29 (3H, s, 8eCH3), 2.68 (2H,
J ¼ 6.9 Hz, 2eCH2CH3), 4.70 (1H, m, J ¼ 6.0 Hz, 7eOCH(CH3)2), 6.11
(1H, s, 3eH), 6.95 (1H, d, J ¼ 9.0 Hz, 6eH), 8.01 (1H, d, J ¼ 9.0 Hz,
5eH). ESI-MS m/z 247 (Mþþ1).
6.1.4.7. 2-(1-Bromoethyl)-8-(bromomethyl)-7-isopropoxy-4H-chro-
men-4-one (44g). 15% yield (starting with 1.2 g of 42c): mp
95e97 ꢂC 1H NMR
d
: 1.45 (6H, d, J ¼ 6.0 Hz, 7eOCH(CH3)2), 2.85 (3H,
d, J ¼ 6.9 Hz, 2eCHBrCH3), 4.80 (3H, m, J ¼ 6.0 Hz, 7eOCH(CH3)2 &
8eCH2Br), 4.94 (1H, q, J ¼ 6.9 Hz, 2eCHBrCH3), 6.32 (1H, s, 3eH),
7.00 (1H, d, J ¼ 9.0 Hz, 6eH), 8.12 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/
z 405 (100).
6.1.3.4. 2-Ethyl-7-isobutoxy-8-methyl-4H-chromen-4-one (42d). 82%
yield, mp 61e62 ꢂC 1H NMR
d:
1.07 (6H, d,
J
¼
6.6 Hz,
7eOCH2CH(CH3)2), 1.33 (3H, t, J ¼ 7.2 Hz, 2-CH2CH3), 2.16 (1H, m,
J ¼ 6.6 Hz, 7eOCH2CH(CH3)2), 2.32 (3H, s, 8eCH3), 2.68 (2H,
J ¼ 7.2 Hz, 2-CH2CH3), 3.86 (2H, d, J ¼ 6.6 Hz, 7eOCH2CH(CH3)2), 6.11
(1H, s, 3eH), 6.93(1H, d, J ¼ 9.0 Hz, 6eH), 8.01 (1H, d, J ¼ 9.0 Hz,
5eH). ESI-MS m/z 261 (Mþ þ 1).
6.1.4.8. 2-(1-Bromoethyl)-8-(bromomethyl)-7-isobutoxy-4H-chro-
men-4-one (44h). 11% yield (starting with 200 mg of 42d): mp
108e109 ꢂC 1H NMR
d
: 1.11 (6H, d, J ¼ 6.6 Hz, 7eOCH2CH(CH3)2),
2.09 (3H, d, J ¼ 6.9 Hz, 2-CHBrCH3), 2.22 (1H, m, J ¼ 6.6 Hz,
7eOCH2CH(CH3)2), 3.95 (2H, d, J ¼ 6.6 Hz, 7eOCH2CH(CH3)2), 4.83
(2H, s, 8eCH2Br), 4.94 (1H, J ¼ 6.9 Hz, 2eCHBrCH3), 6.33 (1H, s,
3eH), 7.0 (1H, d, J ¼ 9.0 Hz, 6eH), 8.12 (1H, d, J ¼ 9.0 Hz, 5eH).
ESI-MS m/z 412 (100).
6.1.4. Synthesis of bromides (43aed and 44eeh)
A mixture of 42aed (1 equiv) and NBS (1.2 equiv) in CCl4 was
refluxed for 16 h. After filtration and removal of the solvent, the
residue was purified by column chromatography with a gradient
eluent of CH2Cl2/MeOH 40:1 to 30:1 to afford pure 43aed and
44eeh in yields of 40e78% and 11e15%, respectively.
6.1.5. Synthesis of 8-hydroxymethyl compounds (45aed and
46eeh)
A mixture of the above bromides [43aed or 44eeh (1 equiv)] and
NaOAc (10 equiv) in acetic anhydride (5 mL) was refluxed for 2 h and
progress was monitored by TLC (CH2Cl2/MeOH 20:1). After removal
of solvent in vacuo, EtOH (5 mL) and 2N HCl (2 mL) were added, and
the mixture refluxed for 2 h. After the solvent was removed in vacuo,
the crude product was purified by column chromatography (eluent:
CH2Cl2/MeOH 99:1) to give 45aed and 46eeh.
6.1.4.1. 8-(Bromomethyl)-2-ethyl-7-methoxy-4H-chromen-4-one
(43a). 40% yield (starting with 300 mg of 42a): mp 162e164 ꢂC 1H
NMR
d
: 1.36 (3H, t, J ¼ 7.5 Hz, 2-CH2CH3), 2.72 (2H, q, J ¼ 7.5 Hz,
2eCH2CH3), 4.03 (3H, s, 7eOCH3), 4.78 (2H, s, 8eCH2Br), 6.15 (1H,
s, 3eH), 6.99 (1H, d, J ¼ 9.0 Hz, 6eH), 8.16 (1H, d, J ¼ 9.0 Hz, 5eH).
ESI-MS m/z 297 (Mþ þ 1).
6.1.4.2. 8-(Bromomethyl)-7-ethoxy-2-ethyl-4H-chromen-4-one (43b).
6.1.5.1. 2-EthyYl-8-(hydroxymethyl)-7-methoxy-4H-chromen-4-one
58% yield (starting with 880 mg of 42b): mp 114e116 ꢂC 1H NMR
d
:
(45a). 87% yield (starting with 300 mg of 43a): mp 139e140 ꢂC 1H
1.36 (3H, t, J ¼ 7.8 Hz, 2-CH2CH3),1.52 (3H, t, J ¼ 6.9 Hz, 7eOCH2CH3),
2.72 (2H, q, J ¼ 7.8 Hz, 2eCH2CH3), 4.25 (2H, q, J ¼ 6.9 Hz,
7eOCH2CH3), 4.79 (2H, s, 8eCH2Br), 6.14 (1H, s, 3eH), 6.96 (1H, d,
J ¼ 9.0 Hz, 6eH), 8.13 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 311 (Mþþ1).
NMR
d
: 1.32 (3H, t, J ¼ 7.5 Hz, 2-CH2CH3), 2.34 (1H, s, 8eCH2OH),
2.69 (2H, q, J ¼ 7.5 Hz, 2eCH2CH3), 4.01 (3H, s, 7eOCH3), 4.97 (2H, s,
8eCH2OH), 6.13 (1H, s, 3eH), 7.02 (1H, d, J ¼ 9.0 Hz, 6eH), 8.17 (1H,
d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 235 (Mþ þ 1).
6.1.4.3. 8-(Bromomethyl)-2-ethyl-7-isopropoxy-4H-chromen-4-one
6.1.5.2. 7-Ethoxy-2-ethyl-8-(hydroxymethyl)-4H-chromen-4-one(45b).
(43c). 45% yield (starting with 1.2 g of 42c): mp 66e68 ꢂC 1H NMR
d
:
42% yield (starting with 140 mg of 43b): mp 100e102 ꢂC H NMR
d
:
1
1.36 (3H, t, J ¼ 7.8 Hz, 2-CH2CH3), 1.44 (6H, d, J ¼ 6.0 Hz,
7eOCH(CH3)2), 2.71 (2H, q, J ¼ 7.8 Hz, 2-CH2CH3), 4.72e4.81 (3H, m,
J ¼ 6.0 Hz, 7eOCH(CH3)2 & 8eCH2Br), 6.14 (1H, s, 3eH), 6.96 (1H, d,
J ¼ 9.0 Hz, 6eH), 8.12 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 325
(Mþ þ 1).
1.32 (3H, t, J ¼ 7.2 Hz, 2eCH2CH3), 1.51 (3H, t, J ¼ 6.9 Hz, 7eOCH2CH3),
2.44 (1H, s, 8eCH2OH), 2.68 (2H, q, J ¼ 7.2 Hz, 2eCH2CH3), 4.24 (2H, q,
J ¼ 6.9 Hz, 7eOCH2CH3), 4.98 (2H, s, 8eCH2OH), 6.12 (1H, s, 3eH), 7.0
(1H, d, J ¼ 9.0 Hz, 6eH), 8.13 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 249
(Mþ þ 1).
6.1.4.4. 8-(Bromomethyl)-2-ethyl-7-isobutoxy-4H-chromen-4-one
6.1.5.3. 2-Ethyl-8-(hydroxymethyl)-7-isopropoxy-4H-chromen-4-
(43d). 78% yield (starting with 200 mg of 42d): mp 91e93 ꢂC 1H
one (45c). 35% yield (starting with 120 mg of 43c): mp 114e116 ꢂC
NMR
d
: 1.25 (6H, d, J ¼ 6.6 Hz, 7eOCH2CH(CH3)2), 1.50 (3H, t,
1H NMR
d
: 1.32 (3H,t, J ¼ 6.9 Hz, 2eCH2CH3), 1.43 (6H, d, J ¼ 6.0 Hz,
J ¼ 7.5 Hz, 2-CH2CH3), 2.35 (1H, m, J ¼ 6.6 Hz, 7eOCH2CH(CH3)2), 2.85
7eOCH(CH3)2), 2.48 (1H, t, J ¼ 6.4 Hz, 8eCH2OH), 2.68 (2H, q,
(2H, J ¼ 7.5 Hz, 2eCH2CH3), 4.07 (2H, d, J ¼ 6.6 Hz, 7eOCH2CH(CH3)2),
J ¼ 6.9 Hz, 2eCH2CH3), 4.78 (1H, m, J ¼ 6.0 Hz, 7eOCH(CH3)2), 4.96

Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
4931
(2H, d, J ¼ 6.4 Hz, 8eCH2OH), 6.12 (1H, s, 3eH), 7.0 (1H, d, J ¼ 9.3 Hz,
6eH), 8.12 (1H, d, J ¼ 9.3 Hz, 5eH). ESI-MS m/z 263 (Mþ þ 1).
1.62e2.43 (4H, m, camphanoyleCH2 ꢁ 2), 1.88 (3H, d, J ¼ 6.9 Hz, 2-
CHBrCH3), 3.99 (3H, s, 7eOCH3), 4.84 (1H, q, J ¼ 6.9 Hz, 2e
CHBrCH3), 5.57 (2H, m, 40eCH2Oe), 6.36 (1H, s, 3eH), 7.05 (1H, d,
J ¼ 9.0 Hz, 6eH), 8.23 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 493
(Mþ þ 1).
6.1.5.4. 2-Ethyl-8-(hydroxymethyl)-7-isobutoxy-4H-chromen-4-one
(45d). 58% yield (starting with 200 mg of 43d): mp 120e122 ꢂC 1H
NMR
d
: 1.08 (6H, d, J ¼ 6.6 Hz, 7eOCH2CH(CH3)2), 1.32 (3H, t,
J ¼ 7.2 Hz, 2-CH2CH3), 2.19 (1H, m, J ¼ 6.6 Hz, 7eOCH2CH(CH3)2),
2.35 (1H, s, 8-CH2OH), 2.68 (2H, J ¼ 7.2 Hz, 2eCH2CH3), 3.93 (2H, d,
J ¼ 6.6 Hz, 7eOCH2CH(CH3)2), 4.98 (2H, s, 8eCH2OH), 6.13 (1H, s,
3eH), 6.99 (1H, d, J ¼ 9.0 Hz, 6eH), 8.13 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-
MS m/z 277 (Mþþ1).
6.1.6.3. 40-((ꢀ)-Camphanoyloxymethyl)-7-ethoxy-2-ethyl-4H-chro-
men-4-one (10). 77% yield (starting with 24 mg of 45b): mp
117e118 ꢂC 1H NMR
d
0.93, 1.01, 1.10 (9H, s, camphanoyleCH3 ꢁ 3),
1.31 (3H, t, J ¼ 7.5 Hz, 2-CH2CH3),1.46 (3H, t, J ¼ 6.9 Hz, 7eOCH2CH3),
1.64e2.46 (4H, m, camphanoyleCH2 ꢁ 2), 2.66 (2H, q, J ¼ 7.5 Hz,
2eCH2CH3), 4.21 (2H, q, J ¼ 6.9 Hz, 7eOCH2CH3), 5.54 (2H, t,
J ¼ 11.4 Hz, 40eCH2O-), 6.14 (1H, s, 3eH), 6.99 (1H, d, J ¼ 9.0 Hz, 6eH),
8.20 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 429 (Mþ þ 1).
6.1.5.5. 2-(1-Bromoethyl)-8-(hydroxymethyl)-7-methoxy-4H-chro-
men-4-one (46e). 38% yield (starting with 100 mg of 44e): colorless
oil. 1H NMR
d
: 1.97 (3H, d, J ¼ 6.9 Hz, 2eCHBrCH3), 2.37 (1H, s, 8-
CH2OH), 4.01 (3H, s, 7eOCH3), 4.90 (1H, q, J ¼ 6.9 Hz, 2eCHBrCH3),
5.01 (2H, s, 8eCH2OH), 6.33 (1H, s, 3eH), 7.05 (1H, d, J ¼ 9.0 Hz, 6eH),
8.16 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 313 (Mþ þ 1).
6.1.6.4. 2-(1-Bromoethyl)-40-((ꢀ)-camphanoyloxymethyl)-7-ethoxy-
4H-chromen-4-one (11). 58% yield (starting with 19 mg of 46f): mp
151e152 ꢂC 1H NMR
1.47 (3H, t,
camphanoyleCH2 ꢁ 2 and 2eCHBrCH3), 4.23 (2H, q, J ¼ 6.9 Hz,
7eOCH2CH3), 4.88 (1H, q, 2eCHBrCH3), 5.58 (2H, m, 40eCH2O-),
6.35 (1H, d, J ¼ 8.4 Hz, 3eH), 7.02 (1H, d, J ¼ 9.0 Hz, 6eH), 8.20 (1H,
d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 507 (Mþ þ 1).
d
0.93, 1.02, 1.09 (9H, s, camphanoyleCH3 ꢁ 3),
J
¼
6.9 Hz, 7eOCH2CH3), 1.62e2.43 (7H, m,
6.1.5.6. 2-(1-Bromoethyl)-7-ethoxy-8-(hydroxymethyl)-4H-chro-
men-4-one (46f). 34% yield (starting with 90 mg of 44f): colorless
oil. 1H NMR
d
: 1.50 (3H, t, J ¼ 7.2 Hz, 7eOCH2CH3), 1.97 (3H, d,
J ¼ 6.9 Hz, 2eCHBrCH3), 2.27 (1H, s, 8eCH2OH), 4.25 (2H, q,
J ¼ 7.2 Hz, 7eOCH2CH3), 4.95 (1H, q, J ¼ 6.9 Hz, 2eCHBrCH3), 5.01
(2H, s, 8eCH2OH), 6.33 (1H, s, 3eH), 7.02 (1H, d, J ¼ 8.7 Hz, 6eH),
8.14 (1H, d, J ¼ 8.7 Hz, 5eH). ESI-MS m/z 327 (Mþ þ 1).
6.1.6.5. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-isopropoxy-4H-
chromen-4-one (12). 70% yield (starting with 38 mg of 45c): mp
168e169 ꢂC 1H NMR
d
0.94, 1.01, 1.10 (9H, s, camphanoyleCH3 ꢁ 3),
6.1.5.7. 2-(1-Bromoethyl)-8-(hydroxymethyl)-7-isopropoxy-4H-chro-
1.30 (3H, t, J ¼ 7.2 Hz, 2eCH2CH3), 1.39 (6H, d, J ¼ 6.0 Hz,
7eOCH(CH3)2), 1.63e2.45 (4H, m, camphanoyleCH2 ꢁ 2), 2.66 (2H,
q, J ¼ 7.2 Hz, 2eCH2CH3), 4.76 (2H, m, J ¼ 6.0 Hz, 7eOCH(CH3)2), 5.53
(2H, t, J ¼ 11.4 Hz, 40eCH2Oe), 6.14 (1H, s, 3eH), 7.0 (1H, d, J ¼ 9.0 Hz,
6eH), 8.20 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 443 (Mþ þ 1).
men-4-one (46g). 24% yield (starting with 120 mg of 44g): mp
63e65 ꢂC 1H NMR
d
: 1.39 (6H, d, J ¼ 6.0 Hz, 7eOCH(CH3)2), 1.97 (3H,
d, J ¼ 6.9 Hz, 2eCHBrCH3), 2.47 (1H, s, 8eCH2OH), 4.80 (1H, m,
J ¼ 6.0 Hz, 7eOCH(CH3)2), 4.91(1H, q, J ¼ 6.9 Hz, 2eCHBrCH3), 4.99
(2H, s, 8eCH2OH), 6.33 (1H, s, 3eH), 7.02 (1H, d, J ¼ 9.3 Hz, 6eH),
8.12 (1H, d, J ¼ 9.3 Hz, 5eH). ESI-MS m/z 341 (Mþ þ 1).
6.1.6.6. 2-(1-Bromoethyl)-40-((ꢀ)-camphanoyloxymethyl)-7-isopro-
poxy-4H-chromen-4-one (13). 92% yield (starting with 40 mg of
6.1.5.8. 2-(1-Bromoethyl)-8-(hydroxymethyl)-7-isobutoxy-4H-chro-
46g): mp 50e52 ꢂC 1H NMR
d 0.94, 1.01, 1.09 (9H, s,
men-4-one (46h). 14% yield (starting with 200 mg of 44h): mp
camphanoyleCH3 ꢁ 3), 1.40 (6H, d, J ¼ 6.0 Hz,7eOCH(CH3)2),
1.62e2.43 (7H, m, camphanoyl-CH2 ꢁ 2 and 2eCHBrCH3), 4.78 (1H,
m, J ¼ 6.0 Hz, 7eOCH(CH3)2), 4.88 (1H, m, 2eCHBrCH3), 5.55 (2H, m,
40eCH2Oe), 6.33 (1H, d, J ¼ 7.5 Hz, 3eH), 7.02 (1H, d, J ¼ 9.0 Hz,
6eH), 8.20 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 521 (Mþþ1).
116e118 ꢂC 1H NMR
d:1.07 (6H, d, J ¼ 6.6 Hz, 7eOCH2CH(CH3)2),
1.58 (3H, d, J ¼ 6.6 Hz, 2eCHBrCH3), 2.18 (1H, m, J ¼ 6.6 Hz,
7eOCH2CH(CH3)2), 3.10 (1H, s, 8eCH2OH), 3.93 (2H, d, J ¼ 6.6 Hz,
7eOCH2CH(CH3)2), 4.70 (1H, q, J ¼ 6.6 Hz, 2eCHBrCH3), 5.49 (2H, s,
J ¼ 15.3 Hz, 8eCH2OH), 6.34 (1H,s, 3eH), 7.0 (1H, d, J ¼ 9.0 Hz, 6eH),
8.17 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 355 (Mþ þ 1).
6.1.6.7. 40-((ꢀ)-Camphanoyoxymethyl)-2-ethyl-7-isobutoxy-4H-chro-
men-4-one (14). 85% yield (starting with 30 mg of 45d): mp
6.1.6. Synthesis of 10-alkoxy-seco-DCPs (8e15)
161e162 ꢂC 1H NMR
d
0.92, 0.99, 1.04 (9H, s, camphanoyleCH3 ꢁ 3),
1.07 (6H, d, J ¼ 6.9 Hz, 7eOCH2CH(CH3)2), 1.31 (3H, t, J ¼ 7.5 Hz,
2eCH2CH3), 1.60e2.45 (5H, m, camphanoyleCH2
The substituted 8-hydroxymethylchromone (45aed or 46eeh, 1
equiv), S-(ꢀ)-camphanic chloride (2.5 equiv), and DMAP (6 equiv)
were stirred in CH2Cl2 (3 mL) for 1 h at room temperature, moni-
tored by TLC (CH2Cl2/MeOH 20:1). At completion, the mixture was
concentrated and the residue was purified by column chromatog-
raphy with an eluent of hexane/EtOAc 3:1 to afford eight target
compounds (8e15).
ꢁ
2
&
7eOCH2CH(CH3)2), 2.67 (2H, q, J ¼ 7.5 Hz, 2-CH2CH3), 3.89 (2H, d,
J ¼ 6.9 Hz, 7eOCH2CH(CH3)2), 5.56 (2H, t, J ¼ 17.4 Hz, 40eCH2Oe),
6.14 (1H, s, 3eH), 7.0 (1H, d, J ¼ 9.0 Hz, 6eH), 8.20 (1H, d, J ¼ 9.0 Hz,
5eH). ESI-MS m/z 457 (Mþ þ 1).
6.1.6.8. 2-(1-Bromoethyl)-40-((ꢀ)-camphanoyloxymethyl)-7-isobuto-
xy-4H-chromen-4-one (15). 92% yield (starting with 23 mg of 46h):
6.1.6.1. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-methoxy-4H-chro-
men-4-one (8). 78% yield (starting with 32 mg of 45a): mp
colorless oil. 1H NMR
d
0.98, 1.05, 1.08 (9H, s, camphanoyleCH3 ꢁ 3),
1.12 (6H, d, J ¼ 6.9 Hz, 7eOCH2CH(CH3)2), 1.68 (3H, d, J ¼ 6.9 Hz,
2eCHBrCH3), 1.93e2.48 (5H, m, camphanoyleCH2
164e165 ꢂC 1H NMR
1.31 (3H, t,
camphanoyleCH2 ꢁ 2), 2.66 (2H, q, J ¼ 7.8 Hz, 2eCH2CH3), 3.97 (3H, s,
7eOCH3), 5.54 (2H, t, J ¼ 11.4 Hz, 40eCH2O-), 6.14 (1H, s, 3eH), 7.02
(1H, d, J ¼ 9.0 Hz, 6eH), 8.22 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 415
(Mþ þ 1).
d
0.92, 1.00, 1.10 (9H, s, camphanoyl-CH3 ꢁ 3),
J
¼
7.8 Hz, 2eCH2CH3), 1.61e2.46 (4H, m,
ꢁ
2 &
7eOCH2CH(CH3)2), 3.91 (2H, d, J ¼ 6.6 Hz, 7eOCH2CH(CH3)2), 5.40
(2H, s, 40eCH2Oe), 5.86 (1H, q, J ¼ 6.9 Hz, 2eCHBrCH3), 6.33 (1H, s,
3eH), 7.02 (1H, d, J ¼ 9.3 Hz, 6eH), 8.18 (1H, d, J ¼ 9.3 Hz, 5eH). ESI-
MS m/z 535 (Mþþ1).
6.1.6.2. 2-(1-Bromoethyl)-40-((ꢀ)-camphanoyloxymethyl)-7-metho-
xy-4H-chromen-4-one (9). 77%yield(starting with33mgof46e):mp
6.2. Synthesis of 10-aryloxy-seco-DCPs (16e28)
6.2.1. 2-Ethyl-7-(methoxymethoxy)-8-methyl-4H-chromen-4-one
(47). The procedure was the same as that used for the preparation
211e213 ꢂC 1H NMR
d
0.92, 1.01, 1.09 (9H, s, camphanoyl-CH3 ꢁ 3),

4932
Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
of 39. 60% yield [starting from 3.0 g of 41, but using DMF (20 mL)
instead of acetone (60 mL)]: mp 93e94 ꢂC 1H NMR
1.33 (3H, d,
J ¼ 7.2 Hz, 2eCH2CH3), 2.34 (3H, s, 8eCH3), 2.68 (2H, q, J ¼ 7.2 Hz,
2eCH2CH3), 3.51 (3H, s, 7eOCH2OCH3), 5.31 (2H, s, 7eOCH2OCH3),
6.13 (1H, s, 3eH), 7.15 (1H, d, J ¼ 9.0 Hz, 6eH), 8.01 (1H, d, J ¼ 9.0 Hz,
5eH). ESI-MS m/z 203 (Mþ ꢀ 45).
171e172 ꢂC 1H NMR
d
1.32 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 2.32 (1H, br
d
s, 8eCH2OH), 2.69 (2H, q, J ¼ 7.5 Hz, 2eCH2CH3), 5.02 (2H, s,
8eCH2OH), 5.30 (2H, s, 7eOCH2e), 6.13 (1H, s, 3eH), 7.04 (1H, d,
J ¼ 9.0 Hz, 6eH), 7.53e7.71 (4H, m, aromatic H), 8.14 (1H, d,
J ¼ 9.0 Hz, 5eH). ESI-MS m/z 377 (Mþ ꢀ H).
6.2.4.6. 3-((2-Ethyl-8-(hydroxymethyl)-4-oxo-4H-chromen-7-yloxy)
6.2.2. 8-(Bromomethyl)-2-ethyl-7-(methoxymethoxy)-4H-chromen-
4-one (48). The procedure was the same as that used for the
preparation of 43. 39% yield (starting from 1.5 g of 47): mp 61e64 ꢂC
methyl)benzonitrile (50f). 44% yield (starting from 24 mg of 49): mp
201e202 ꢂC 1H NMR
d
1.35 (3H, t, J ¼ 7.8 Hz, 2eCH2CH3), 2.74 (2H, q,
J ¼ 7.8 Hz, 2eCH2CH3), 5.00 (2H, s, 8eCH2OH), 5.31 (2H, s,
7eOCH2e), 6.17 (1H, s, 3eH), 7.06 (1H, d, J ¼ 9.0 Hz, 6eH), 7.56 (1H,
t, J ¼ 7.8 Hz, aromatic H), 7.68 (1H, d, J ¼ 7.8 Hz, aromatic H), 7.74
(1H, d, J ¼ 7.8 Hz, aromatic H), 7.81 (1H, s, aromatic H), 8.12 (1H, d,
J ¼ 9.0 Hz, 5eH). ESI-MS m/z 334 (Mþ ꢀ H).
1H NMR
d
1.36 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 2.72 (2H, q, J ¼ 7.5 Hz,
2eCH2CH3), 3.55 (3H, s, 7eOCH2OCH3), 4.80 (2H, s, 8eCH2Br), 5.39
(2H, s, 7eOCH2OCH3), 6.16 (1H, s, 3eH), 7.18 (1H, d, J ¼ 9.0 Hz, 6eH),
8.13 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 327 (Mþ þ 1).
6.2.3. 2-Ethyl-7-hydroxy-8-(hydroxymethyl)-4H-chromen-4-one
(49). The procedure was the same as that used for the preparation of
45. 50% yield (starting from 100 mg of 48): mp 147e148 ꢂC 1H NMR
6.2.4.7. 2-Ethyl-8-(hydroxymethyl)-7-(3-methoxybenzyloxy)-4H-chr-
omen-4-one (50g). 34% yield (starting from 30 mg of 49): mp
108e110 ꢂC 1H NMR
d
1.33 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 2.38 (1H, br
d
1.57 (3H, t, J ¼ 7.8 Hz, 2eCH2CH3), 2.98(2H, q, J ¼ 7.8Hz, 2eCH2CH3),
s, 8eCH2OH), 2.68 (2H, q, J ¼ 7.5 Hz, 2eCH2CH3), 3.83 (3H, s, phenyl
OCH3), 5.01 (2H, s, 8eCH2OH), 5.23 (2H, s, 7eOCH2e), 6.13 (1H,s,
3eH), 6.89e7.00 (3H, m, aromatic H), 7.05 (1H, d, J ¼ 9.0 Hz, 6eH),
7.33 (1H, t, J ¼ 8.1 Hz, aromatic H), 8.12 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-
MS m/z 339 (Mþ ꢀ H).
4.86 (2H, s, 8eCH2OH), 6.38 (1H, s, 3eH), 7.18 (1H, d, J ¼ 9.0 Hz, 6eH),
8.14 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 243 (Mþ þ Na).
6.2.4. Synthesis of 7-aryloxy-subsituted-8-(hydroxymethyl)-4H-
chromen-4-one (50aem)
The procedure was identical to that used in the preparation of
42aeb.
6.2.4.8. Methyl-3-(2-ethyl-8-(hydroxymethyl)-4-oxo-4H-chromen-7-
yloxy)benzoate (50h). 40% yield (starting from 30 mg of 49): mp
153e155 ꢂC 1H NMR
d
1.32 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 2.33(1H, br s,
6.2.4.1. 2-Ethyl-8-(hydroxymethyl)-7-(2-oxo-tetrahydrofuran-3-ylo-
xy)-4H-chromen-4-one (50a). 70% yield (starting from 30 mg of 49):
8eCH2OH), 2.69 (2H, q, J ¼ 7.5 Hz, 2eCH2CH3), 3.94 (3H, s, phenyl
OCH3), 5.03 (2H, s, 8-CH2OH), 5.30 (2H, s, 7eOCH2e), 6.13 (1H, s,
3eH), 7.05 (1H, d, J ¼ 9.0 Hz, 6eH), 7.51 (1H, t, J ¼ 7.8 Hz, aromatic H),
7.65 (1H, d, J ¼ 7.8 Hz, aromatic H), 8.05 (1H, d, J ¼ 7.8 Hz, aromatic H),
8.12 (1H, s, aromatic H), 8.14 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 367
(Mþ ꢀ H).
mp 210e212 ꢂC 1H NMR (CDCl3 þ CD3OD)
d
1.33 (3H, t, J ¼ 7.8 Hz,
2eCH2CH3), 2.54 (2H, m, J ¼ 9.0 Hz, furanone 3eH2), 2.72 (2H, q,
J ¼ 7.8 Hz, 2eCH2CH3), 2.92 (1H, br s, 8eOCH2OH), 4.45, 4.62 (2H, m,
J1 ¼ 9.0 Hz, furanone 4eH2), 4.94 (1H, s, 8eCH2OH), 5.24 (1H, t,
J ¼ 9.0 Hz, furanone 2eH), 6.19 (1H, s, 3eH), 7.17 (1H, d, J ¼ 9.0 Hz,
6eH), 8.14 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 327 (Mþ þ Na).
6.2.4.9. 2-Ethyl-8-(hydroxymethyl)-7-(3-methylbenzyloxy)-4H-chr-
omene4-one (50i). 48% yield (starting from 30 mg of 49): mp
6.2.4.2. 2-Ethyl-8-(hydroxymethyl)-7-(pyridin-2-ylmethoxy)-4H-chr-
omen-4-one (50b). 30% yield (starting from 38 mg of 49): colorless
147e149 ꢂC 1H NMR
d
1.32 (3H, t, J ¼ 7.8 Hz, 2-CH2CH3), 2.36 (1H, br
s, 8eCH2OH), 2.39 (3H, s, phenyl CH3), 2.68 (2H, q, J ¼ 7.8 Hz, 2-
CH2CH3), 5.00 (2H, br s, 8eCH2OH), 5.22 (2H, s, 7eOCH2e), 6.13 (1H,
s, 3eH), 7.07 (1H, d, J ¼ 9.0 Hz, 6eH), 7.12e7.34 (4H, m, aromatic H),
8.14 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 323 (Mþ ꢀ H).
oil. 1H NMR
d
1.36 (3H, t, J ¼ 7.8 Hz, 2-CH2CH3), 2.20 (1H, br s,
8eCH2OH), 2.75 (2H, q, J ¼ 7.8 Hz, 2eCH2CH3), 5.02 (2H, d, J ¼ 6.9 Hz,
8eCH2OH), 5.39 (2H, s, 7eOCH2e), 6.17 (1H, s, 3eH), 7.10 (1H, d,
J ¼ 9.0 Hz, 6eH), 7.37 (1H, m, J ¼ 7.2 Hz, pyridine H), 7.55, 7.84 (2H, d,
J ¼ 7.8 Hz, pyridine H), 8.10 (1H, d, J ¼ 9.0 Hz, 5eH), 8.60 (1H, m,
J ¼ 7.8 Hz, pyridine H). ESI-MS m/z 334 (Mþ þ Na).
6.2.4.10. 7-(3,5-Dimethoxybenzyloxy)-2-ethyl-8-(hydroxymethyl)-4H-
chromen-4-one (50j). 44% yield (starting from 30 mg of 49): mp
154e155 ꢂC 1H NMR
d
1.32 (3H, t, J ¼ 7.8 Hz, 2eCH2CH3), 2.37 (1H, t,
6.2.4.3. 2-Ethyl-8-(hydroxymethyl)-7-(pyridin-3-ylmethoxy)-4H-chro-
men-4-one (50c). 38% yield (starting from 30 mg of 49): mp
J ¼ 6.9 Hz, 8-CH2OH), 2.68 (2H, q, J ¼ 7.8 Hz, 2eCH2CH3), 3.81 (6H, s,
2 ꢁ OCH3), 5.01 (2H, d, J ¼ 6.9 Hz, 8eCH2OH), 5.20 (2H, s, 7eOCH2-),
6.13 (1H, s, 3eH), 6.44 (1H, t, J ¼ 2.4 Hz, aromatic H), 6.57 (2H, d,
J ¼ 2.4 Hz, aromatic H), 7.04 (1H, d, J ¼ 9.0 Hz, 6eH), 8.13 (1H, d,
J ¼ 9.0 Hz, 5eH). ESI-MS m/z 369 (Mþ ꢀ H).
115e116 ꢂC 1H NMR
d
1.33 (3H, t, J ¼ 7.8 Hz, 2eCH2CH3), 2.40 (1H, br s,
8eCH2OH), 2.70 (2H, q, J ¼ 7.8 Hz, 2eCH2CH3), 5.00 (2H, s, 8eCH2OH),
5.27 (2H, s, 7eOCH2e), 6.14 (1H, s, 3eH), 7.07 (1H, d, J ¼ 9.0 Hz, 6eH),
7.37 (1H, q, J ¼ 7.2 Hz, pyridine H), 7.81 (1H, d, J ¼ 7.8 Hz, pyridine H),
8.15 (1H, d, J ¼ 9.0 Hz, 5eH), 8.62 (1H, d, J ¼ 7.8 Hz, pyridine H), 8.72
(1H, s, pyridine H). ESI-MS m/z 334 (Mþ þ Na).
6.2.4.11. 2-Ethyl-8-(hydroxymethyl)-7-((3-trifluoromethoxy)benzy-
loxy)-4H-chromen-4-one (50k). 73% yield (starting from 30 mg of
49): mp 109e110 ꢂC 1H NMR
d
1.33 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3),
6.2.4.4. 2-Ethyl-8-(hydroxymethyl)-7-(pyridin-4-ylmethoxy)-4H-
chromen-4-one (50d). 33% yield (starting from 30 mg of 49): mp
2.29 (1H, t, J ¼ 6.6 Hz, 8eCH2OH), 2.69 (2H, q, J ¼ 7.5 Hz, 2eCH2CH3),
5.02 (2H, d, J ¼ 6.6 Hz, 8eCH2OH), 5.27 (2H, s, 7eOCH2e), 6.14 (1H,
s, 3eH), 7.03 (1H, d, J ¼ 9.0 Hz, 6eH), 7.23 (1H, d, J ¼ 7.8 Hz, aromatic
H), 7.31 (1H, s, aromatic H), 7.38 (1H, d, J ¼ 7.8 Hz, aromatic H), 7.46
(1H, t, J ¼ 7.8 Hz, aromatic H), 8.15 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS
m/z 393 (Mþ ꢀ H).
171e172 ꢂC 1H NMR
d
1.33 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 2.47 (1H, br
s, 8eCH2OH), 2.70 (2H, q, J ¼ 7.5 Hz, 2eCH2CH3), 5.06 (2H, d,
J ¼ 6.3 Hz, 8eCH2OH), 5.28 (2H, s, 7eOCH2e), 6.14 (1H, s, 3eH), 6.99
(1H, d, J ¼ 9.0 Hz, 6eH), 7.37 (2H, d, J ¼ 5.4 Hz, pyridine H), 8.14 (1H,
d, J ¼ 9.0 Hz, 5eH), 8.64 (2H, d, J ¼ 4.8 Hz, pyridine H). ESI-MS m/z
312 (Mþ þ H).
6.2.4.12. 7-(2-Bromo-5-methoxybenzyloxy)-2-ethyl-8-(hydroxymet-
hyl)-4H-chromen-4-one (50l). 39% yield (starting from 30 mg of
6.2.4.5. 2-Ethyl-8-(hydroxymethyl)-7-(3-(trifluoromethyl)benzyloxy)-
4H-chromen-4-one (50e). 29% yield (starting from 22 mg of 49): mp
49): mp 132e134 ꢂC 1H NMR
1.83 (1H, br s, 8eCH2OH), 2.69 (2H, q, J ¼ 7.8 Hz, 2eCH2CH3), 3.81
d
1.32 (3H, t, J ¼ 7.8 Hz, 2eCH2CH3),

Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
4933
(3H, s, OCH3), 5.02 (2H, s, 8eCH2OH), 5.26 (2H, s, 7eOCH2e), 6.13
(1H, s, 3eH), 6.80 (1H, dd, J1 ¼ 9.0 Hz, J2 ¼ 3.3 Hz, aromatic H), 7.04
(1H, s, aromatic H), 7.07 (1H, d, J ¼ 9.0 Hz, aromatic H), 7.51 (1H, d,
J ¼ 8.7 Hz, 6eH), 8.14 (1H, d, J ¼ 8.7 Hz, 5eH). ESI-MS m/z 441
(Mþ þ Na).
1.98, 2.35 (4H, m, camphanoyleCH2 ꢁ 2), 2.70 (2H, q, J ¼ 7.8 Hz,
2eCH2CH3), 5.29 (2H, s, 7eOCH2e), 5.60 (2H, q, J ¼ 11.4 Hz, 40eCH2e),
6.16 (1H, s, 3eH), 7.05 (1H, d, J ¼ 9.0 Hz, 6eH), 7.54e7.69 (4H, m,
aromatic H), 8.22 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 559 (Mþ þ H).
6.2.5.6. 40-((ꢀ)-Camphanoyloxymethyl)-7-(3-cyanobenzyloxy)-2-
ethyl-4H-chromen-4-one (21). 65% yield, white solid (starting from
6.2.4.13. 7-(4,5-Dimethoxy-2-nitrobenzyloxy)-2-ethyl-8-(hydroxyme-
thyl)-4H-chromen-4-one (50m). 76% yield (starting from 30 mg of
16 mg of 50f): mp 175e176 ꢂC 1H NMR
d 0.84, 0.98, 1.08 (9H, s,
49): mp 222e224 ꢂC 1H NMR
d
1.34 (3H, t, J ¼ 7.8 Hz, 2eCH2CH3),
camphanoyleCH3 ꢁ 3), 1.32 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 1.67, 1.90,
1.99, 2.40 (4H, m, camphanoyleCH2 ꢁ 2), 2.70 (2H, q, J ¼ 7.5 Hz, 2-
CH2CH3), 5.28 (2H, s, 7eOCH2e), 5.61 (2H, q, J ¼ 11.4 Hz, 40eCH2e),
6.16 (1H,s, 3eH), 7.02 (1H, d, J ¼ 9.0 Hz, 6eH), 7.54e7.75 (4H, m,
aromatic H), 8.22 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 516 (Mþ þ H).
2.18 (1H, t, J ¼ 6.0 Hz, 8-CH2OH), 2.70 (2H, q, J ¼ 7.8 Hz, 2-CH2CH3),
3.99 (6H, s, 2 ꢁ OCH3), 5.07 (2H, d, J ¼ 6.0 Hz, 8eCH2OH), 5.68 (2H, s,
7eOCH2e), 6.15 (1H, s, 3eH), 7.07 (1H, d, J ¼ 8.7 Hz, 6eH), 7.37 (1H,
s, aromatic H), 7.80 (1H, s, aromatic H), 8.16 (1H, d, J ¼ 8.7 Hz, 5eH).
ESI-MS m/z 438 (Mþ þ Na).
6.2.5.7. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-(3-methoxybenzy-
loxy)-4H-chromen-4-one (22). 57% yield, white solid (starting from
6.2.5. Synthesis of 10-aryloxy-subsituted-seco-DCPs (16e28). the
procedure was the same as that used for the preparation of 8e15
6.2.5.1. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-(2-oxo-tetrahy-
drofuran-3-yloxy)-4H-chromen-4-one (16). 37% yield, white solid
16 mg of 50g): mp 126e127 ꢂC 1H NMR
d 0.83, 0.94, 1.07 (9H, s,
camphanoyleCH3 ꢁ 3), 1.32 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 1.67, 1.87,
1.98, 2.37 (4H, m, camphanoyl-CH2 ꢁ 2), 2.69 (2H, q, J ¼ 7.5 Hz,
2eCH2CH3), 5.23 (2H, s, 7eOCH2-), 3.82 (3H, s, OCH3), 5.60 (2H, q,
J ¼ 11.4 Hz, 40eCH2-), 6.14 (1H, s, 3eH), 6.87, 6.97 (2H, dd, J1 ¼8.1 Hz,
J2 ¼ 2.1 Hz, aromatic H), 7.00 (1H, s, aromatic H), 7.05 (1H, d, J ¼ 9.0 Hz,
6eH), 7.31 (1H, t, J ¼ 8.1 Hz, aromatic H), 8.18 (1H, d, J ¼ 9.0 Hz, 5eH).
ESI-MS m/z 543 (Mþ þ Na).
(starting from29mgof50a):mp211e212 ꢂC 1HNMR
d0.88, 0.99,1.07
(9H, s, camphanoyleCH3 ꢁ 3),1.32 (3H, t, J ¼ 7.8 Hz, 2eCH2CH3),1.68,
1.90, 2.00, 2.39 (4H, m, camphanoyleCH2 ꢁ 2), 2.68 (2H, q, J ¼ 7.8 Hz,
2eCH2CH3), 2.83 (2H, m, furanone 3eH2); 4.42, 4.58 (2H, m,
J1 ¼6.6Hz, J2 ¼1.5 Hz, furanone 4eH2), 5.19 (1H, t, J ¼ 7.8Hz, furanone
2eH), 5.58 (2H, m, J ¼ 7.5Hz, 40eCH2-), 6.16 (1H, s, 3eH), 7.21 (1H, dd,
J1 ¼9.0 Hz, J2 ¼ 3.3 Hz, 6eH), 8.22 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z
507 (Mþ þ Na).
6.2.5.8. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-(3-methoxycarb-
onyl)benzyloxy)-4H-chromen-4-one (23). 97% yield, white solid
(starting from 20 mg of 50h): mp 190e191 ꢂC 1H NMR
d 0.82, 0.94,
6.2.5.2. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-(pyridin-2-ylmeth-
oxy)-4H-chromen-4-one (17). 44% yield, white solid (starting from
1.07 (9H, s, camphanoyleCH3 ꢁ 3), 1.31 (3H, t, J ¼ 7.8 Hz,
2eCH2CH3),1.66,1.87,1.99, 2.37 (4H, m, camphanoyleCH2 ꢁ 2), 2.67
(2H, q, J ¼ 7.8 Hz, 2eCH2CH3), 3.94 (3H, s, -OCOCH3), 5.29 (2H, s,
7eOCH2-), 5.60 (2H, q, J ¼ 11.7 Hz, 40eCH2Oe), 6.15 (1H, s, 3eH),
7.05 (1H, d, J ¼ 9.0 Hz, 6eH), 7.51,7.67, 8.03 (3H, d, J ¼ 7.8 Hz,
aromatic H), 8.09 (1H, s, aromatic H), 8.21 (1H, d, J ¼ 9.0 Hz, 5eH).
ESI-MS m/z 571 (Mþ þ Na).
16 mg of 50b): mp 169e170 ꢂC 1H NMR
d 0.86, 0.97, 1.08 (9H, s,
camphanoyleCH3 ꢁ 3), 1.32 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 1.66, 1.87,
2.01, 2.34 (4H, m, camphanoyleCH2 ꢁ 2), 2.68 (2H, q, J ¼ 7.5 Hz,
2eCH2CH3), 5.39 (2H, s, 7eOCH2e), 5.66 (2H, s, 40eCH2-), 6.15 (1H, s,
3eH), 7.05 (1H, d, J ¼ 9.0 Hz, 6eH), 7.26, 7.55 (2H, m, J ¼ 7.8 Hz,
pyridine H), 7.78 (1H, m, J1 ¼7.8 Hz, J2 ¼ 1.8 Hz, pyridine H), 8.18 (1H,
d, J ¼ 9.0 Hz, 5eH), 8.61 (1H, m, J ¼ 7.8 Hz, pyridine H). ESI-MS m/z
514 (Mþ þ Na).
6.2.5.9. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-(3-methylbenzy-
loxy)-4H-chromen-4-one (24). 64% yield, white solid (starting from
21 mg of 50i): mp 172e173 ꢂC 1H NMR
d 0.83, 0.94, 1.07 (9H, s,
6.2.5.3. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-(pyridin-3-ylme-
thoxy)-4H-chromen-4-one (18). 83% yield, white solid (starting
camphanoyl-CH3 ꢁ 3), 1.31 (3H, t, J ¼ 7.8 Hz, 2eCH2CH3), 1.66, 1.87,
1.98, 2.37 (4H, m, camphanoyl-CH2 ꢁ 2), 2.37 (3H, s, CH3 on phenyl),
2.67 (2H,q, J ¼ 7.8 Hz, 2eCH2CH3), 5.22 (2H, s, 7eOCH2e), 5.59 (2H,
q, J ¼ 11.1 Hz, 40eCH2Oe), 6.14 (1H, s, 3eH), 7.06 (1H, d, J ¼ 9.0 Hz,
6eH), 7.14e7.31 (4H, m, aromatic H), 8.19 (1H, d, J ¼ 9.0 Hz, 5eH).
ESI-MS m/z 527 (Mþ þ Na).
from 16 mg of 50c): mp 166e167 ꢂC 1H NMR
d 0.81, 0.95, 1.08 (9H, s,
camphanoyleCH3 ꢁ 3), 1.32 (3H, t, J ¼ 7.5 Hz, 2-CH2CH3), 1.66, 1.87,
2.01, 2.34 (4H, m, camphanoyleCH2 ꢁ 2), 2.67 (2H, q, J ¼ 7.5 Hz,
2eCH2CH3), 5.27 (2H, s, 7eOCH2e), 5.57 (2H, q, J ¼ 11.4 Hz,
40eCH2e), 6.16 (1H, s, 3eH), 7.08 (1H, d, J ¼ 8.7 Hz, 6eH), 7.39 (1H,
dd, J1 ¼ 7.8 Hz, J2 ¼ 4.8 Hz, pyridine H), 7.84 (1H, d, J ¼ 7.8 Hz,
pyridine H), 8.23 (1H, d, J ¼ 8.7 Hz, 5eH), 7.78 (1H, dd, J1 ¼ 6.3 Hz,
J2 ¼ 1.8 Hz, pyridine H), 8.69 (1H, d, J ¼ 1.2 Hz, pyridine H). ESI-MS
m/z 492 (Mþ þ H).
6.2.5.10. 40-((ꢀ)-Camphanoyloxymethyl)-7-(3,5-dimethoxybenzylo-
xy)-2-ethyl-4H-chromen-4-one (25). 65% yield, white solid (starting
from 30 mg of 50j): mp 159e160 ꢂC 1H NMR
d 0.84, 0.95, 1.07 (9H, s,
camphanoyl-CH3 ꢁ 3), 1.31 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 1.66, 1.87,
1.99, 2.37 (4H, m, camphanoyleCH2 ꢁ 2), 2.67 (2H, q, J ¼ 7.5 Hz,
2eCH2CH3), 3.80 (6H, s, 2 ꢁ CH3 on phenyl), 5.19 (2H, s, 7eOCH2e),
5.60 (2H, q, J ¼ 11.4 Hz, 40eCH2O-), 6.15 (1H, s, 3eH), 6.42 (1H, d,
J ¼ 2.4 Hz, aromatic H), 6.56 (2H, d, J ¼ 8.4 Hz, aromatic H), 7.04 (1H,
d, J ¼ 9.0 Hz, 6eH), 8.18 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 573
(Mþ þ Na).
6.2.5.4. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-(pyridin-4-ylme-
thoxy)-4H-chromen-4-one (19). 90% yield, white solid (starting
from 14 mg of 50d): mp 162e163 ꢂC 1H NMR
d 0.84, 0.97, 1.08 (9H, s,
camphanoyl-CH3 ꢁ 3), 1.33 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 1.66, 1.87,
2.01, 2.39 (4H, m, camphanoyleCH2 ꢁ 2), 2.68 (2H, q, J ¼ 7.5 Hz,
2eCH2CH3), 5.28 (2H, s, 7eOCH2e), 5.64 (2H, q, J ¼ 11.4 Hz,
40eCH2e), 6.16 (1H, s, 3eH), 7.00 (1H, d, J ¼ 9.0 Hz, 6eH), 7.38 (2H,
d, J ¼ 6.0 Hz, pyridine H), 8.21 (1H, d, J ¼ 9.0 Hz, 5eH), 8.65 (2H, d,
J ¼ 6.0 Hz, pyridine H). ESI-MS m/z 492 (Mþ þ H).
6.2.5.11. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-(3-trifluorometh-
oxybenzyloxy)-4H-chromen-4-one (26). 79% yield, white solid
(starting from 39 mg of 50k): mp 133e134 ꢂC 1H NMR
d 0.82, 0.95,
1.07 (9H, s, camphanoyleCH3 ꢁ 3), 1.32 (3H, t, J ¼ 7.5 Hz,
2eCH2CH3), 1.66, 1.87, 1.99, 2.37 (4H, m, camphanoyl-CH2 ꢁ 2), 2.67
(2H, q, J ¼ 7.5 Hz, 2eCH2CH3), 5.26 (2H, s, 7eOCH2e), 5.60 (2H, q,
J ¼ 11.1 Hz, 40eCH2Oe), 6.15 (1H, s, 3eH), 7.04 (1H, d, J ¼ 9.0 Hz,
6eH), 7.22, 7.39 (2H, d, J ¼ 7.8 Hz, aromatic H), 7.29 (1H, s, aromatic
6.2.5.5. 40-((ꢀ)-Camphanoyloxymethyl)-2-ethyl-7-(3-(trifluoromethyl)
benzyloxy)-4H-chromen-4-one (20). 74% yield, white solid (starting
from 11 mg of 50e): mp 156e157 ꢂC 1H NMR
d
0.81, 0.94, 1.07 (9H, s,
camphanoyl-CH3 ꢁ 3), 1.32 (3H, t, J ¼ 7.8 Hz, 2eCH2CH3), 1.66, 1.86,

4934
Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
H), 7.46 (1H, t, J ¼ 7.8 Hz, aromatic H), 8.21 (1H, d, J ¼ 9.0 Hz, 5eH).
ESI-MS m/z 597 (Mþ þ Na).
6.4. Synthesis of 40-piperidinyl oxalamide-seco-DCPs (34e37)
A mixture of 43b (1 equiv), piperidinyl oxalamide (1.2 equiv),
and DMAP (2.5 equiv) in THF (5 mL) was stirred for 24 h at room
temperature and monitored by TLC (CH2Cl2/MeOH 20:1). After
removal of solvent in vacuo, the residue was purified by column
chromatography (eluent: CH2Cl2/MeOH 99:1) to give 34e37.
6.2.5.12. 7-(2-Bromo-5-methoxybenzyloxy)-40-((ꢀ)-camphanoylox-
ymethyl)-2-ethyl-4H-chromen-4-one (27). 54% yield, white solid
(starting from 22 mg of 50l): mp 158e159 ꢂC 1H NMR
d 0.85, 0.95,
1.07 (9H, s, camphanoyleCH3 ꢁ 3),1.32 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3),
1.66, 1.87, 1.99, 2.37 (4H, m, camphanoyleCH2 ꢁ 2), 2.67 (2H, q,
J ¼ 7.5 Hz, 2eCH2CH3), 3.80 (3H, s, CH3 on phenyl), 5.25 (2H, s,
7eOCH2e), 5.63 (2H, q, J ¼ 11.7 Hz, 40eCH2O-), 6.16 (1H, s, 3eH), 6.77
(1H, dd, J1 ¼ 8.7 Hz, J2 ¼ 3.0 Hz, aromatic H), 7.05 (1H, d, J ¼ 9.0 Hz,
6eH), 7.08 (1H, d, J ¼ 3.0 Hz, aromatic H), 7.48 (1H, d, J ¼ 8.7 Hz,
aromatic H), 8.22 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 623 (Mþ þ Na).
6.4.1. 7-Ethoxy-2-ethyl-8-((4-(2-oxo-2-(2-thienyl)acetyl)piperazin-
1-yl)methyl)-4H-chromen-4-one (34). 27% yield, white solid (start-
ing from 50 mg of 43b): mp 62e64 ꢂC 1H NMR
d 1.31 (3H, t,
J ¼ 7.5 Hz, 2-CH2CH3), 1.46 (3H, t, J ¼ 6.9 Hz, 7eOCH2CH3), 2.58 (2H,
t, J ¼ 5.1 Hz, piperazine H2), 2.66 (4H, m, 2-CH2CH3 & piperazine H2),
3.44, 3.72 (4H, t, J ¼ 5.1 Hz, piperazine H2 ꢁ 2), 3.87 (2H, s, 8eCH2e),
4.17 (2H, q, J ¼ 6.9 Hz, 7eOCH2CH3), 6.12 (1H, s, 3eH), 6.98 (1H, d,
J ¼ 9.0 Hz, 6eH), 7.18, 7.80 (3H, d, J ¼ 3.9 Hz, thiophene H), 8.12
(1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 455 (Mþ þ 1).
6.2.5.13. 40-((ꢀ)-Camphanoyloxymethyl)-7-(4,5-dimethoxy-2-nitro-
benzyloxy)-2-ethyl-4H-chromen-4-one (28). 79% yield, light yellow
solid (starting from 43 mg of 50m): mp 211e212 ꢂC 1H NMR
d 0.81,
0.94, 1.06 (9H, s, camphanoyleCH3 ꢁ 3), 1.34 (3H, t, J ¼ 7.5 Hz,
2eCH2CH3),1.66,1.87,1.96, 2.37 (4H, m, camphanoyleCH2 ꢁ 2), 2.69
(2H, q, J ¼ 7.5 Hz, 2eCH2CH3), 4.00 (6H, s, 2 ꢁ OCH3), 5.66 (4H, s,
7eOCH2- & 40eCH2Oe), 6.17 (1H, s, 3eH), 7.09 (1H, d, J ¼ 9.0 Hz,
6eH), 7.37 (1H, s, aromatic H), 7.81 (1H, s, aromatic H), 8.24 (1H, d,
J ¼ 9.0 Hz, 5eH). ESI-MS m/z 618 (Mþ þ Na).
6.4.2. 7-Ethoxy-2-ethyl-8-((4-(2-oxo-2-phenylacetyl)piperazin-1-yl)
methyl)-4H-chromen-4-one (35). 11% yield, white solid (starting
from 50 mg of 43b): mp 61e62 ꢂC 1H NMR
d
1.31 (3H, t, J ¼ 7.5 Hz,
2eCH2CH3),1.45 (3H, t, J ¼ 7.2 Hz, 7eOCH2CH3), 2.53 (2H, t, J ¼ 5.1 Hz,
piperazine H2), 2.64 (2H, q, J ¼ 7.5 Hz, 2eCH2CH3), 2.68, 3.33, 3.75
(6H, t, J ¼ 5.1 Hz, piperazine H2 ꢁ 3), 3.87 (2H, s, 8eCH2e), 4.17 (2H, q,
J ¼ 7.2 Hz, 7-OCH2CH3), 6.12 (1H, s, 3eH), 6.98 (1H, d, J ¼ 9.0 Hz, 6eH),
7.51 (2H, t, J ¼ 7.8 Hz, aromatic H), 7.65 (1H, t, J ¼ 6.6 Hz, aromatic H),
7.94 (1H, d, J ¼ 7.4 Hz, aromatic H), 8.13 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-
MS m/z 449 (Mþ þ 1).
6.3. Synthesis of 40-camphanol-seco-DCPs (29e31)
A mixture of 43aec (1 equiv), camphanol (1.2 equiv), and NaH (6
equiv) in toluene (6 mL) was stirred for 4 h at room temperature
and monitored by TLC (CH2Cl2/MeOH 20:1). Ice-water (10 mL) was
then added to stop the reaction. Following extraction with EtOAc
(10 mL ꢁ 3), the organic layer was dried over Na2SO4. After removal
of solvent in vacuo, the residue was purified by PTLC (eluent:
CH2Cl2/MeOH 40:1 and 20:1) to give 29e31.
6.4.3. 7-Ethoxy-2-ethyl-8-((4-(2-oxo-3-phenylpropanoyl)piperazin-
1-yl)methyl)-4H-chromen-4-one (36). 10% yield, white solid (start-
ing from 50 mg of 43b): mp 54e56 ꢂC 1H NMR
d 1.30 (3H, t,
J ¼ 7.2 Hz, 2eCH2CH3), 1.45 (3H, t, J ¼ 6.9 Hz, 7eOCH2CH3), 2.06,
2.44, 3.08, 3.52 (8H, t, J ¼ 5.1 Hz, piperazine H2 ꢁ 4), 2.63 (2H, q,
J ¼ 7.2 Hz, 2eCH2CH3), 3.78 (2H, s, 8eCH2e), 4.02 (2H, s,
eCH2eC6H5), 4.16 (2H, q, J ¼ 6.9 Hz, 7eOCH2CH3), 6.13 (1H, s, 3eH),
6.97 (1H, d, J ¼ 9.0 Hz, 6eH), 7.17e7.27 (1H ꢁ 5, m, J1 ¼ 7.2 Hz,
J2 ¼ 6.6 Hz, aromatic H), 8.13 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z
463 (Mþ þ H).
6.3.1. 2-Ethyl-7-methoxy-8-(((4,7,7-trimethyl-3-oxo-2-oxabicyclo
[2.2.1]heptan-1-yl)methoxy)methyl)-4H-chromen-4-one (29). 12%
yield, white solid (starting from 50 mg of 43a): mp 127e128 ꢂC 1H
NMR
d
0.87 (6H, s, camphanoleCH3 ꢁ 2), 1.07 (3H, s, camphanol-
CH3), 1.32 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 1.58e2.10 (4H, m,
camphanoleCH2 ꢁ 2), 2.68 (2H, q, J ¼ 7.5 Hz, 2eCH2CH3), 3.84 ( 2H,
q, J ¼ 11.4 Hz, camphanoleCH2), 3.97 (3H, s, 7eOCH3), 4.86 (2H, q,
J1 ¼ 11.4 Hz, J2 ¼ 13.8 Hz, 40eCH2O-), 6.14 (1H, s, 3eH), 7.02 (1H, d,
J ¼ 9.0 Hz, 6eH), 8.18 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 423
(Mþ þ Na).
6.4.4. 40-((4-(2-(1H-Indol-3-yl)-2-oxoacetyl)piperazin-1-yl)methyl)-
2-ethyl-7-ethoxy-4H-chromen-4-one (37). 29% yield, white solid
(starting from 50 mg of 43b): mp 122e124 ꢂC 1H NMR
d 1.30 (3H, t,
J ¼ 7.5 Hz, 2eCH2CH3), 1.44 (3H, t, J ¼ 6.9 Hz, 7eOCH2CH3), 2.53,
2.66, 3.48, 3.73 (8H, t, J ¼ 5.1 Hz, piperazine H2 ꢁ 4), 2.64 (2H, q,
J ¼ 7.5 Hz, 2eCH2CH3), 3.90 (2H, s, 8eCH2e), 4.15 (2H, q, J ¼ 6.9 Hz,
7eOCH2CH3), 6.12 (1H, s, 3eH), 6.97 (1H, d, J ¼ 9.0 Hz, 6eH),
7.24e7.41 (3H, m, aromatic H), 7.85 (1H, br s, aromatic H), 8.13 (1H,
d, J ¼ 9.0 Hz, 5eH), 8.31 (1H, br s, pyrrole H), 10.09 (1H, br s, pyrrole
NH). ESI-MS m/z 488 (Mþ þ H).
6.3.2. 2-Ethyl-7-ethoxy-8-(((4,7,7-trimethyl-3-oxo-2-oxabicyclo
[2.2.1]heptan-1-yl)methoxy)methyl)-4H-chromen-4-one
yield, white solid (starting from 100 mg of 43b): mp 60e62 ꢂC 1H
NMR
(30). 9%
d
0.87 (6H, s, camphanoleCH3 ꢁ 2), 1.07 (3H, s, campha-
noleCH3), 1.32 (3H, t, J ¼ 7.5 Hz, 2eCH2CH3), 1.48 (3H, t, J ¼ 6.9 Hz,
7eOCH2CH3), 1.61e2.04 (4H, m, camphanoleCH2 ꢁ 2), 2.67 (2H, q,
J ¼ 7.5 Hz, 2eCH2CH3), 3.80 ( 2H, q, J ¼ 13.8 Hz, camphanoleCH2),
4.20 (2H, q, J ¼ 6.9 Hz, 7eOCH2CH3), 4.87 (2H, q, J1 ¼ 10.5 Hz,
J2 ¼ 24Hz, 40eCH2Oe), 6.13 (1H, s, 3eH), 6.99 (1H, d, J ¼ 9.0 Hz, 6eH),
8.16 (1H, d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 437 (Mþ þ Na).
6.5. Synthesis of 10-thia -seco-DCK (32)
6.5.1. 7-Hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde
(52). A reaction mixture of 51 (20.0 g, 114 mmol) and hexameth-
ylenetetramine (40.0 g, 285 mmol) in HOAc (150 mL) was stirred for
5.5 h at 80e90 ꢂC. Aq. HCl (300 mL, conc. HCl/H2O 84:100, v/v) was
then added, and the reaction mixture was stirred for 0.5 h at 70 ꢂC.
After cooling, the reaction mixture was poured into ice-water (1.5 L)
and extracted with EtOAc (500 mL ꢁ 3). The combined organic
fraction was dried over Na2SO4, and the solvent was removed in
vacuo. The residue was recrystallized from EtOAc to provide 52 as
a light yellow solid (2.4 g, 11% yield): mp 120e122 ꢂC.
6.3.3. 2-Ethyl-7-isopropoxy-8-(((4,7,7-trimethyl-3-oxo-2-oxabicyclo
[2.2.1]heptan-1-yl)methoxy)methyl)-4H-chromen-4-one
(31). 5%
0.87 (6H,
yield, colorless oil (starting from 200 mg of 43c). 1H NMR
d
s, camphanoleCH3 ꢁ 2), 1.06 (3H, s, camphanoleCH3), 1.32 (3H, t,
J ¼ 7.2 Hz, 2eCH2CH3), 1.40 (6H, d, J ¼ 6.0 Hz, 7eOCH(CH3)2),
1.57e2.03 (4H, m, camphanoleCH2 ꢁ 2), 2.67 (2H, q, J ¼ 7.2 Hz,
2eCH2CH3), 3.78 (2H, q, J ¼ 14.4 Hz, camphanol-CH2), 4.74 (1H, m,
J ¼ 6.0 Hz, 7eOCH(CH3)2), 4.84 (2H, q, J1 ¼ 11.4 Hz, J2 ¼ 10.8 Hz,
40eCH2Oe), 6.13 (1H, s, 3eH), 7.0 (1H, d, J ¼ 9.0 Hz, 6eH), 8.13 (1H,
d, J ¼ 9.0 Hz, 5eH). ESI-MS m/z 429 (Mþ þ 1).
6.5.2. 8-(1,3-Dioxolan-2-yl)-7-hydroxy-4-methyl-2H-chromene-2-
one (53). A mixture of 52 (2.13 g, 10.4 mmol), ethane-1,2-diol
(3.0 mL) and p-toluenesulfonic acid (120 mg) in toluene (25 mL)

Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
4935
was refluxed for 2 h with removal of water by a water separator.
After removing solvent in vacuo, the residue was dissolved in
CH2Cl2 and filtered. The filtrate was washed with saturated
NaHCO3, and the organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure to afford 53 as a yellow
6.6.2. 2-Ethyl-7-hydroxy-4-oxo-4H-chromen-8-carbaldehyde
(65). The procedure was the same as that used for the preparation
of 52. 44% yield, white crystals (starting from 650 mg of 64): mp
179e181 ꢂC.
solid (1.96 g, 76% yield): mp 215e217 ꢂC 1H NMR
d
2.39 (3H, s,
6.6.3. O-(8-(1,3-dioxolan-2-yl)-2-ethyl-4-oxo-4H-chromen-7-yl)-
N,N-dimethylcarbamothioate (67). Compound 66 was prepared by
the sameprocedure asused for thepreparationof52. However, due to
its instability, 66 was not purified, but was reacted directly with
dimethylthiocarbamoyl chloride (1.0 g, 8.09mmol)to give compound
67 following the same method used for the synthesis of 54. 31% yield,
white solid (starting from 600 mg of 66): mp 132e134 ꢂC 1H NMR
4eCH3), 4.11e4.61 (4H, m, 2 ꢁ CH2 of 1,3edioxolane), 6.12 (1H, s,
3eH), 6.39 (1H, s, 8eCHe), 6.84 (1H, d, J ¼ 9.1 Hz, 6eH), 7.50 (1H, d,
J ¼ 9.1 Hz, 5eH).
6.5.3. O-(8-(1,3-dioxolan-2-yl)-4-methyl-2-oxo-2H-chromen-7-yl)-
N,N-dimethylcarbamothioate (54). Compound 53 (1.50 g,
6.05 mmol) and KOH (2.0 g, 36 mmol) were dissolved in MeOH
(30 mL) and reacted with dimethylthiocarbamoyl chloride (2.5 g,
20 mmol) for 3 h at rt. The mixture was poured into saturated
NH4Cl (150 mL) and filtered to afford crude product, which was
purified by column chromatography (eluent: petroleum ether/
EtOAc 4:1) to give 54 as a white solid (667 mg, 33% yield): mp
d
1.31 (3H, t, J ¼ 7.43 Hz, 2eCH2CH3), 2.66 (2H, q, J ¼ 7.43 Hz,
2eCH2CH3), 3.43 (6H, s, eN(CH3)2), 4.08, 4.24 (4H, m, 2 ꢁ CH2 of
1,3edioxolane), 6.19 (1H, s, 3eH), 6.35 (1H, s, 8eCHe), 7.06 (2H, d,
J ¼ 8.6 Hz, 6eH), 8.22 (2H, d, J ¼ 8.6 Hz, 5eH). ESI-MS m/z 350 (M þ H)
6.6.4. S-(8-(1,3-dioxolan-2-yl)-2-ethyl-4-oxo-4H-chromen-7-yl)-
N,N-dimethylcarbamothioate (68). The procedure was the same as
that used for the preparation of 55. 34% yield, light yellow solid
190e192 ꢂC 1H NMR
d 2.36 (3H, s, 4eCH3), 3.38, 3.47 (6H, s,
eN(CH3)2), 4.05e4.40 (4H, m, 2 ꢁ CH2 of 1,3-dioxolane), 6.27 (2H, s,
3eH & 8eCHe), 7.02 (1H, d, J ¼ 8.6 Hz, 6eH), 7.62 (1H, d, J ¼ 8.6 Hz,
5eH). ESI-MS m/z 336 (M þ H).
(starting from 450 mg of 67): mp 132e135 ꢂC 1H NMR
d 1.32 (3H, t,
J ¼ 7.4 Hz, 2eCH2CH3), 2.66 (2H, q, J ¼ 7.4 Hz, 2eCH2CH3), 3.13 (6H, s,
eN(CH3)2), 4.08, 4.27 (4H, m, 2 ꢁ CH2 of 1,3-dioxolane), 6.21 (1H, s,
3eH), 6.59 (1H, s, 8eCHe), 7.52 (1H, d, J ¼ 8.6 Hz, 6eH), 8.20 (2H, d,
J ¼ 8.6 Hz, 5eH). ESI-MS m/z 350 (M þ H).
6.5.4. S-(8-(1,3-dioxolan-2-yl)-4-methyl-2-oxo-2H-chromen-7-yl)-
N,N-dimethylcarbamothioate (55). Compound 54 (1.50 g,
5.70 mmol) was heated to 200 ꢂC with stirring for 1 h. The crude
product was purified by column chromatography (eluent: petro-
leum ether/EtOAc 4:1) to give 55 as light yellow crystals (235 mg,
6.6.5. 2-Ethyl-7-(isopropylthio)-4-oxo-4H-chromene-8-
carbaldehyde (71). The procedure was the same as that used for the
preparation of 58. 52% yield, light yellow solid (starting from 70 mg
47% yield): mp 138e140 ꢂC 1H NMR
d 2.42 (3H, s, 4eCH3), 3.08 (6H,
s, eN(CH3)2), 4.05e4.48 (4H, m, 2 ꢁ CH2 of 1,3-dioxolane), 6.36 (1H,
s, 3eH), 6.65 (1H, s, 8eCHe), 7.46 (1H, d, J ¼ 8.29 Hz, 6eH), 7.59
(1H, d, J ¼ 8.29 Hz, 5eH). ESI-MS m/z 336 (M þ H).
of 68): mp 152e154 ꢂC 1H NMR
d
1.32 (3H, t, J ¼ 7.3 Hz, 2-CH2CH3),
1.45 (6H, d, J ¼ 6.7 Hz, 7eSCH(CH3)2), 2.72 (2H, q, J ¼ 7.3 Hz, 2-
CH2CH3), 3.67 (1H, m, J ¼ 6.7 Hz, 7eSCH(CH3)2), 6.23 (1H, s, 3eCH),
7.40 (1H, d, J ¼ 9.0 Hz, 6eH), 8.24 (1H, d, J ¼ 9.0 Hz, 5eH), 10.81 (1H,
s, 8eCHO). ESI-MS m/z 277 (M þ H).
6.5.5. 7-(Isopropylthio)-4-methyl-2-oxo-2H-chromene-8-
carbaldehyde (58). Under nitrogen and in the dark, compound 55
(200 mg, 0.6 mmol) was hydrolyzed in the presence of KOH
(500 mg) in MeOH (20 mL) for 2 h at reflux temperature. At
completion, 2-bromopropane (2.0 mL) was added, and the reaction
continued for another 30 min. The reaction solution was then
poured into cool 1N HCl (100 mL) and filtered to give 58 as a light
6.6.6. 40-((ꢀ)-Camphanoyloxymethyl)-7-(isopropylthio)-2-ethyl-4H-
chromene-2-one (33). The procedure was the same as that used for
the preparation of 32. 48% yield, white solid (starting from 27 mg of
71): mp 92e94 ꢂC 1H NMR
d
0.95, 1.05, 1.00, 1.09 (9H, s,
camphanoyleCH3 ꢁ 3), 1.31 (3H, t, J ¼ 7.3 Hz, 2eCH2CH3), 1.35 (6H,
d, 6.7 Hz, 7eSCH(CH3)2), 1.89e2.40 (4H, m,
yellow solid (12 mg, 8% yield): mp 159e162 ꢂC.1H NMR
d
1.44 (6H,
J
¼
d, J ¼ 6.7 Hz, 7eSCH(CH3)2), 2.45 (3H, s, 4eCH3), 3.62 (1H, m,
J ¼ 6.7 Hz, 7-SCH(CH3)2), 6.15 (1H, s, 3eH), 7.30 (1H, d, J ¼ 9.0 Hz,
6eH), 7.67 (1H, d, J ¼ 9.0 Hz, 5eH), 10.84 (1H, s, 8eCHO). ESI-MS m/
z 263 (M þ H).
camphanoyleCH2 ꢁ 2), 2.67 (2H, q, J ¼ 7.3 Hz, 2eCH2CH3), 3.62 (1H,
m, J ¼ 6.7 Hz, 7eSCH(CH3)2), 5.66 (2H, s, 40eCH2Oe), 6.18 (1H, s,
3eH), 7.42 (1H, d, J ¼ 8.6 Hz, 6eH), 8.14 (1H, d, J ¼ 8.6 Hz, 5eH). ESI-
MS m/z 459 (M þ H).
6.5.6. 40-((ꢀ)-Camphanoyloxymethyl)-7-(isopropylthio)-4-methyl-
2H-chromen-2-one (32). A mixture of 58 (9 mg, 0.034 mmol) and
NaBH4 (3 mg) in MeOH (2 mL) was stirred for 1 h at room
temperature, then acidified to pH 3e4 with 1 N HCl and extracted
with CH2Cl2 (10 mL ꢁ 3). The organic layer was dried over anhy-
drous Na2SO4, and most of the solvent was removed under reduced
pressure to give crude 59. Then, 32 was synthesized following the
same synthetic procedure as for 16e28, but starting from 59. 52%
6.7. HIV-1 infectivity assay
Anti-HIV-1 activity was measured as reductions in Luc reporter
gene expression after a single round of virus infection of TZM-bl
cells. HIV-1 at 200 TCID50 and various dilutions of test samples
(eight dilutions, fourfold stepwise) were mixed in a total volume of
100
Costar). After 48-h incubation, culture medium was removed from
each well and 100 L of Bright Glo luciferase reagent was added to
mL growth medium in 96-well black solid plates (Corning-
m
yield, White solid: mp 146e147 ꢂC 1H NMR
d
1.00, 1.05, 1.09 (9H, s,
each culture well. The luciferase activity in the assay wells was
measured using a Victor 2 luminometer. The 50% inhibitory dose
(EC50) was defined as the sample concentration that caused a 50%
reduction in Relative Luminescence Units (RLU) compared to virus
control wells after subtraction of background RLU.
camphanoyl-CH3 ꢁ 3), 1.34 (6H, d, J ¼ 6.7 Hz, 7eSCH(CH3)2),
1.67e2.46 (4H, m, camphanoyleCH2 ꢁ 2), 2.47 (3H, s, 4eCH3), 3.57
(1H, m, J ¼ 6.7 Hz, 7eSCH(CH3)2), 5.65 (2H, s, 40eCH2Oe), 6.27 (1H,
s, 3eH), 7.36 (1H, d, J ¼ 8.4 Hz, 6eH), 7.57 (1H, d, J ¼ 8.4 Hz, 5eH).
ESI-MS m/z 445 (M þ H).
6.8. Cytotoxicity assay
6.6. Synthesis of 10-thia-seco-DCP (33)
6.6.1. 2-Ethyl-7-hydroxy-4H-chromen-4-one (64). The procedure
was the same as that used for the preparation of 41. 52% yield, white
crystals (starting from 10 g of 60): mp 188e189 ꢂC.
Compounds were tested for cytotoxicityagainst TZM-bl cells. The
cells at 1 ꢁ105 cells/mL were added to each well in a 96-well plate in
the presence of various concentrations of the tested compounds for
an indicated period parallel to the anti-viral assays. Cell viability was

4936
Y. Chen et al. / European Journal of Medicinal Chemistry 46 (2011) 4924e4936
determined by using a Promega cytotoxicity assay kit, CellTiter-GloÒ
Luminescent Cell Viability Assay, following the manufacturer’s
instruction. The drug concentration that resulted in a 50% decrease
in viable cells was defined as the IC50 of the compound.
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This research was supported by the grants from the National
Natural Science Foundation of China awarded to P.X. (No.
20272010) and Y.C. (No. 30200348 and 30873164, respectively),
and Grant AI-33066 from the National Institute of Allergies and
Infectious Diseases awarded to K H L. Thanks are also due to the
National Drug Innovative Program (Grant No. 2009ZX09301-011)
for partial support.