Synthesis of alkenyldiarylmethane (ADAM) non-nucleoside HIV-1 reverse transcriptase inhibitors with non-Identical aromatic rings

Article abstract of DOI:10.1016/S0968-0896(01)00282-6

The existing methods for the synthesis of alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors proceed from symmetrical benzophenones and therefore result in products with identical aromatic rings. New methods have therefore been de

Full text of DOI:10.1016/S0968-0896(01)00282-6

Bioorganic & Medicinal Chemistry 10 (2002) 283–290
Synthesis of Alkenyldiarylmethane (ADAM) Non-Nucleoside
HIV-1 Reverse Transcriptase Inhibitors with Non-Identical
Aromatic Rings
Guozhang Xu,a Tracy L. Hartman,b Heather Wargo,b Jim A. Turpin,b
Robert W. Buckheit, Jrb and Mark Cushmana,*
aDepartment of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University,
West Lafayette, IN 47907, USA
bInfectious Disease Research Department, Southern Research Institute, 431 Aviation Way, Frederick, MD 21701, USA
Received 14 May 2001; accepted 31 July 2001
Abstract—The existing methods for the synthesis of alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors
proceed from symmetrical benzophenones and therefore result in products with identical aromatic rings. New methods have
therefore been devised for the preparation of stereochemically defined ADAMs with non-identical aromatic rings. The new routes
rely on palladium-catalyzed reactions, including Sonogashira, Suzuki, Stille, and hydroarylation methodology. Several of the new
ADAMs inhibited the cytopathic effect of HIV-1 in cell culture and HIV-1 reverse transcriptase at submicromolar concentrations.
# 2001 Elsevier Science Ltd. All rights reserved.
The non-nucleoside reverse transcriptase inhibitors
(NNRTIs) are a structurally diverse set of compounds
that act by an allosteric mechanism.1 A number of
NNRTIs, including nevirapine, delavirdine, and efavir-
enz, are used in combination chemotherapy for the
treatment of AIDS.2À4 However, drug incompatibilities,
adverse effects, the emergence of resistant viral strains,
and cross-resistance continue to limit the clinical use-
fulness of the NNRTIs.5À9 Additional NNRTIs are
therefore needed that might have improved pharmaco-
kinetics, limited toxicities, and more favorable resis-
tance mutation profiles. The alkenyldiarylmethanes
(ADAMs) have recently been identified as a new class of
NNRTIs.10À13 Several of the ADAMs, including com-
pounds 1–3, are potent inhibitors of the cytopathic
effect of HIV-1 in cell culture, with EC50 values in the
low nanomolar range. A number of HIV-1 strains con-
taining AZT resistance mutations have shown increased
sensitivity to some of the ADAMs, indicating a possible
therapeutic role for the ADAMs in combination with
AZT.12
The existing ADAM syntheses include the attachment
of the alkenyl chain to symmetrical benzophenone deriva-
tives by Wittig,10À12,14 McMurry,13,15 or Horner–
Emmons12 reactions. These methods are not ideal for the
synthesis of ADAMs having differently substituted aro-
matic rings because they would lead to mixtures of cis
and trans isomers when employed with benzophenones
having non-identical aromatic rings. In addition, ben-
zophenones with different substituents on each aromatic
ring are not as readily available as those with identical
substituents. Since the two aromatic rings of the
ADAMs are not in identical environments when bound
in the NNRTI binding pocket of HIV-1 reverse tran-
scriptase,12,13 it is logical to conclude that ADAMs with
identical aromatic substituents are not the ideal choice
to ‘fit’ the binding site. Consequently, a need does exist
for ADAMs with non-identical aromatic rings, and we
have therefore recently investigated ADAM syntheses
that do not proceed from benzophenones, including the
use of palladium-catalyzed reactions in the solid phase
synthesis of ADAMs 4 and 5.16
The present communication details the use of the
Sonogashira, Suzuki, Stille, and hydroarylation reac-
tions in stereochemically defined, solution phase synth-
eses of new ADAMs 6–8 with differently substituted
*Corresponding author. Tel.: +1-765-494-1465; fax: +1-765-494-
1414; e-mail: cushman@pharmacy.purdue.edu
0968-0896/02/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00282-6

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G. Xu et al. / Bioorg. Med. Chem. 10 (2002) 283–290
Scheme 1. Reagents and conditions: (a) (i) TMSCHN2, MeOH, ben-
zene, 23 ꢀC(2 h); (ii) NaI, NaOH, MeOH, then NaOCl (5.25%), 0–
3 ꢀC(3 h); (b) Me 2SO4, K2CO3, acetone, reflux (24 h); (c) methyl 5-
hexynoate, Pd(OAc)2, PPh3, CuI, triethylamine, EtOAc, 23 ꢀC(12 h);
(d) Bu3SnH, Pd(PPh3)4, THF, 23 ꢀC(1 h); (e) I 2, C HCl2, 23 ꢀC(50
2
min); (f) 3,4-dimethoxyphenylboronic acid, Na2CO3, Pd(PPh3)4,
CH3CN/H2O, 90 oC(19 h).
methanol and benzene.17 The resulting methyl ester was
iodinated using sodium iodide in the presence of sodium
hypochlorite as an oxidant to afford intermediate 15
(Scheme 1).18 Treatment of the iodinated ester 15 with
dimethyl sulfate and K2CO3 produced methyl 5-iodo-3-
methyl-2-methoxybenzoate 16 in 90% overall yield.
Palladium-catalyzed Sonogashira coupling of methyl 5-
hexynoate with iodinated ester 16 afforded the alkyne
17,19,20 which underwent hydrostannation in the pre-
sence of Pd(PPh3)4 to give the regiochemically and ste-
reochemically defined vinylstannane 18 in 39% overall
yield.21 Subsequent treatment of 18 with I2 in CH2Cl2
produced vinyl iodide 19.22 The Suzuki coupling of 19
with 3,4-dimethoxyphenylboronic acid in the presence
of Pd(PPh3)4 and Na2CO3 afforded the desired ADAM
6 in 53% yield.23,24
aromatic rings. These compounds were chosen to
explore the importance of the aromatic methyl ester
groups and halogen atoms for biological activity. In
addition, the truncated compounds 10 and 11, in which
one of the aromatic rings of 3 has been eliminated, were
prepared. The corresponding reduction product 12, as
well as the oxidized compound 13, were also synthe-
sized. The investigation of the biological activities of
these compounds should be helpful in the identification
of the ADAM ‘pharmacophore’.
Palladium-catalyzed Sonogashira coupling of 2-iodo-
pyrazine (20) with methyl 5-hexynoate afforded alkyne
21 in 81% yield (Scheme 2). Subsequent hydrostanna-
tion and I2 displacement of the tributyltin group pro-
duced vinyl iodide 23 in 76% yield. Coupling of 23 with
3,4-dimethoxyphenylboronic
conditions afforded ADAM 7 in 52% yield.
acid
under
Suzuki
As shown in Scheme 3, treatment of 5-iodosalicylic acid
24 with dimethyl sulfate and K2CO3 produced 25, which
coupled with methyl 5-hexynoate under Sonogashira
reaction conditions to afford alkyne 26. Palladium-
catalyzed hydroarylation of alkyne 26 served as a key step
to construct the second aromatic ring in compound 8.25
Results and Discussion
3-Methylsalicylic acid (14) was quantitatively converted
into its methyl ester using TMSCHN2 in a mixture of

G. Xu et al. / Bioorg. Med. Chem. 10 (2002) 283–290
285
Since the addition can happen at both positions of the
carbon–carbon triple bond, two structural isomers (8
and 27) are formed in almost equal yield. Careful pre-
parative TLCisolation afforded pure ADAM 8 in 31%
yield, and well as pure 27 in 30% yield.
through complete hydrogenation of 17 or by heating 17
in refluxing formic acid.26
The new ADAMs synthesized in this study were eval-
uated for inhibition of the cytopathic effect of HIV-1RF
in CEM-SS cells, and the resulting EC50 values are listed
in Table 1. The cytotoxic concentrations in uninfected
CEM-SS cells (CC50 values) were determined as well.
These compounds were also tested for inhibition of
HIV-1 RT, and the resulting IC50 values are also inclu-
ded in Table 1. Two of the new ADAMs (6 and 8)
inhibited the cytopathic effect of HIV-1RF with EC50
values of 0.21 and 0.47 mM, respectively. These analo-
gues were also found to inhibit HIV-1 RT with
The same strategy was employed to construct ADAM 9
as outlined in Scheme 4. 2-Chlorophenol was iodinated
using sodium iodide in the presence of sodium hypo-
chlorite as an oxidant. Treatment of the iodinated phe-
nol 29 with dimethyl sulfate and K2CO3 produced 30.
Sonogashira coupling of iodo compound 30 with methyl
5-hexynoate gave alkyne 31. Palladium-catalyzed
hydroarylation of alkyne 31 gave a mixture of com-
pounds 9 and 32. Purification of both 9 and 32 was
achieved by preparative TLC.
.
poly(rC) oligo(dG) as the template primer with IC50
values of 0.074 and 0.504 mM. Compound 7, with a
heterocyclic ring, was inactive. The esters on the aro-
matic ring seem to be essential for the anti-HIV activity
(ADAM 9 was inactive, vs ADAM 2 with EC50 of 13
nM). However, the halogen atoms on the aromatic ring
The syntheses of compounds 10–13 are illustrated in
Scheme 5. Hydrogenation of 17 using Lindlar’s catalyst
gave the cis-alkene 10. Palladium-catalyzed Heck cou-
pling of methyl 5-hexenoate with 16 produced the trans-
alkene 11. Additional analogues (12–13) were also made
Scheme 2. Reagents and conditions: (a) methyl 5-hexynoate,
Pd(OAc)2, PPh3, CuI, triethylamine/EtOAc, 23 ꢀC(12 h); (b) Bu 3SnH,
Pd(PPh3)4/THF, 23 ꢀC(1 h); (c) I 2/CH2Cl2, 23 ꢀC(30 min); (d) 3,4-
Scheme 4. Reagents and conditions: (a) NaI, NaOH, NaOCl/MeOH,
23 ꢀC(2 h); (b) (CH 3)2SO4, K2CO3, acetone, reflux (14 h); (c) methyl 5-
hexynoate, Pd(OAc)2, PPh3, CuI, TEA, EtOAc, 23 ꢀC(12 h); (d)
Compound 30, Pd2(dba)3, Et2NH, HCOOH, EtOAc, reflux (12 h).
dimethoxyphenylboronic acid, Na2CO3, Pd(PPh3)4,
90 ꢀC(14 h).
C HCN/H2O,
3
Scheme 5. Reagents and conditions: (a) Methyl 5-hexenoate,
Pd(OAc)2, TEA, EtOAc, 70 ꢀC(18 h); (b) Methyl 5-hexynoate,
Pd(OAc)2, PPh3, CuI, TEA, EtOAc, 23 ꢀC(12 h); (c) H 2, Pd (5%) on
BaSO4, quinoline, 23 ꢀC(18 h); (d) H 2, Pd (5%) on activated carbon
(14 h); (e) HCOOH, reflux (2–4 h).
Scheme 3. Reagents and conditions: (a) (CH3)2SO4, K2CO3, acetone,
reflux (14 h); (b) methyl 5-hexynoate, Pd(OAc)2, PPh3, CuI, TEA,
EtOAc, 23 ꢀC(12 h); (c) Compound 25, Pd2(dba)3, Et2NH, HCOOH,
EtOAc, reflux (12 h).

286
G. Xu et al. / Bioorg. Med. Chem. 10 (2002) 283–290
significantly increase the activity (ADAM 2, EC50=13
nM; ADAM 8, EC50=470 nM). The large difference in
lipophilicity between ADAM 2 and ADAM 8 due to the
incorporation of halogen atoms on the aromatic ring
may account for the lower activity of ADAM 8. Both
cis- and trans-alkenes 10 and 11 were inactive against
HIV-1 viruses and HIV-1 RT. This suggests that both
aromatic rings are required for targeting the hydrophobic
pocket of the RT enzyme, and is also consistent with the
‘butterfly model’ proposed for the binding of NNRTIs
to HIV-1 RT.10,12,13,27
the ADAMs are in fact acting as non-nucleoside reverse
transcriptase inhibitors.10,12,13
The methyl ester groups present in the most potent
ADAMs are likely to be substrates for a variety of
esterases present in the body. Future work in the
ADAM series should therefore focus on the exchange of
these ester groups with metabolically stable
replacements that will retain the anti-HIV activity.
Experimental
It is apparent from the data in Table 1 that there is not a
perfect correlation between the anti-HIV-1 EC50 values
and the reverse transcriptase IC50 values. For example,
compound 6 is one of the most potent reverse tran-
scriptase inhibitors ever synthesized in the ADAM ser-
ies (IC50 0.074 mM), but it is about three fold less potent
as an inhibitor of the cytopathic effect of HIV-1 in cell
culture (EC50 0.21 mM). In contrast, ADAM 1 is less
potent than 6 versus RT in the cell-free assay system
(IC50 0.3 mM), but it is considerably more potent as an
antiviral agent (EC50 0.0013 mM). However, this differ-
ence is not unusual for the non-nucleoside reverse tran-
scriptase inhibitors.28-31 The reverse transcriptase
inhibition studies were performed in a cell-free system
with a synthetic template/primer, poly(rC).oligo(dG).
As discussed elsewhere, the discrepancy in EC50 values
for inhibition of the cytopathic effect of the virus and
the IC50 values for reverse transcriptase inhibition may
simply reflect the differences between the in vitro assay,
in which synthetic template/primer has been added, and
the cellular system.30 In spite of the lack of close corre-
lation of reverse transcriptase inhibitory activity with
antiviral activity in the ADAM series, prior work with
ADAM-resistant HIV-1 strains having mutations in
reverse transcriptase leaves little doubt that in general,
Melting points were obtained in capillary tubes and are
uncorrected. 1H NMR spectra were determined at
300 MHz. Chemical ionization mass spectra (CIMS)
were run using isobutane as the reagent gas. Micro-
analyses were performed at the Purdue University
Microanalysis Laboratory. Silica gel flash chromato-
graphy was accomplished using 230–400 mesh silica gel.
Unless otherwise stated, chemicals and solvents were
reagent grade and used as obtained from commercial
sources without further purification. Compounds 15
and 16 were synthesized as described elsewhere.16
Methyl 6-[4-methoxy-5-(methoxycarbonyl)-3-methylphe-
nyl]hex-5-ynoate (17). Methyl 5-hexynoate (0.593 g,
4.71 mmol), methyl 5-iodo-3-methyl-2-methoxy-
benzoate 16 (1.2 g, 3.92 mmol), Pd(OAc)2 (62.4 mg,
0.278 mmol), Ph3P (145.8 mg, 0.556 mmol), copper(I)
iodide (0.15 g, 0.788 mmol), and triethylamine (1.14 g,
11.25 mmol) were stirred in ethyl acetate (30 mL) at
room temperature overnight under argon. The mixture
was diluted with water (15 mL), and the layers were
separated. The organic layer was washed with water and
brine, dried over sodium sulfate, and concentrated to
give a black residue, which was purified by flash chro-
matography on silica gel (120 g, column: 5Â30 cm,
hexanes–EtOAc 3:1) to afford 17 as a brown liquid (488
Table 1. Anti-HIV activities of the ADAMs
1
mg, 41%): H NMR (CDCl3) d 7.67 (d, J=2.08 Hz,
Compd RT (IC50, mM)a EC50 (mM)b CC50 (mM)c
TId
1H), 7.36 (d, J=1.69 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 3H),
3.68 (s, 3H), 2.50 (t, J=6.20 Hz, 2H), 2.46 (t, J=5.65
Hz, 2H), 2.27 (s, 3H), 1.91 (m, 2H); 13C NMR (CDCl3)
d 173.51, 166.11, 157.81, 137.71, 132.82, 132.26, 124.38,
118.98, 88.64, 80.07, 61.46, 52.12, 51.49, 32.74, 23.72,
18.68, 15.78; EIMS m/z 304 (M+); HRMS calcd for
C17H20O5 304.1311, found 304.1318. Anal. calcd for
C17H20O5: C, 67.07; H, 6.58. Found: C, 66.95; H, 6.47.
113
212
333
416
516
6
7
8
9
10
11
12
13
17
32
0.3
0.3
1.0
0.0013
0.013
0.25
0.020
0.080
0.21
NAe
0.47
NA
NA
NA
NA
NA
13
31.6
6.0
1.46
2.17
1.14
19.40
2.0
ꢁ6.25
157.0
1.70
108
200
62.50
ꢁ6.25
10,000
2431
24
0.516
0.587
0.074
100
0.504
100
88.2
100
1.75
73
27
5.48
4.27
Methyl
(5E)-6-[4-methoxy-5-(methoxycarbonyl)-3-me-
thylphenyl]-6-(tributylstannyl)hex-5-enoate (18). To a
stirred solution of alkyne 17 (67 mg, 0.22 mmol) in dry
THF (20 mL) at room temperature was added
(Ph3P)4Pd (7.6 mg, 0.007 mmol) and, dropwise, Bu3SnH
(96.2 mg, 0.33 mmol). The reaction mixture was kept
stirring for 1 h under argon. The solvent was evaporated
and the brown residue was purified by flash chromato-
graphy on silica gel (30 g, hexanes–EtOAc 3:1, v/v) to
100
100
100
NA
NA
aInhibitory activity versus HIV-1 reverse transcriptase with rCdG as
the template primer.
bThe EC50 is the 50% inhibitory concentration for cytopathicity of
HIV-1RF in CEM-SS cells.
cThe CC50 is the 50% cytotoxic concentration for mock-infected
CEM-SS cells.
1
afford a colorless oil (116 mg, 94%): H NMR (CDCl3)
d 7.16 (d, J=2.25 Hz, 1H), 6.86 (d, J=2.15 Hz, 1H),
5.70 (t, J=6.92 Hz, JSnH=31.24 Hz, 1H), 3.88 (s, 3H),
3.80 (s, 3H), 3.60 (s, 3H), 2.27 (s, 3H), 2.23 (t, J=7.66
Hz, 2H), 2.01 (dt, J=7.31 and 6.90 Hz, 2H), 1.65 (m,
dThe TI is the therapeutical index, which is the CC50 divided by the
EC50
.
eNA (not active): no observed inhibition of HIV-1 cytopathicity up to
the cytotoxic concentration in uninfected cells.

G. Xu et al. / Bioorg. Med. Chem. 10 (2002) 283–290
287
2H), 1.18–1.44 (m, 18H), 0.83 (t, J=7.25 Hz, 9H);
ESIMS m/z 595 (MH+). Anal. calcd for C29H48SnO5:
C, 58.59; H, 8.08. Found: C, 58.47; H, 7.96.
was added (Ph3P)4Pd (99 mg, 0.086 mmol) and, drop-
wise, Bu3SnH (749 mg, 2.57 mmol). The reaction mix-
ture was kept stirring for 1 h under argon. The solvent
was evaporated and the brown residue was purified by
flash chromatography on silica gel (30 g, hexanes–
EtOAc 3:1, v/v) to afford a colorless oil (750 mg,
88.3%): 1H NMR (CDCl3) d 8.48 (br, 1H), 8.34 (s, 1H),
8.28 (d, J=1.90 Hz, 1H), 5.93 (t, J=7.10 Hz,
JSnH=31.56 Hz, 1H), 3.63 (s, 3H), 2.36 (t, J=7.47 Hz,
2H), 2.28 (t, J=7.34 Hz, 2H), 1.77 (m, 2H), 1.23–1.47
(m, 12H), 0.90 (t, J=7.48 Hz, 6H), 0.84 (t, J=7.27 Hz,
9H); EIMS m/z 436/438 (M+ – C4H9). Anal. calcd for
C23H40N2SnO2: C, 55.87; H, 8.10; N, 5.67. Found: C,
55.87; H, 8.17; N, 5.62.
Methyl (5E)-6-iodo-6-[4-methoxy-5-(methoxycarbonyl)-
3-methylphenyl]hex-5-enoate (19). The vinyl tributyl-
stannane 18 (80 mg, 0.13 mmol) was dissolved in dry
CH2Cl2 (5 mL). Finely divided I2 (49.3 mg, 0.19 mmol)
was added and the mixture was stirred vigorously at
room temperature for 50 min. Saturated aqueous
Na2S2O3 (5 mL) was added, the phases were separated,
and the aqueous phase was extracted with CH2Cl2
(3Â10 mL). The combined organic extracts were dried
(Na2SO4) and concentrated. The residue was purified by
flash chromatography on silica gel (30 g, hexanes–
EtOAc 3:1, v/v) to afford a colorless oil (50.5 mg, 90%):
1H NMR (CDCl3) d 7.51 (d, J=2.01 Hz, 1H), 7.24 (d,
J=2.0 Hz, 1H), 6.44 (t, J=7.41 Hz, 1H), 3.91 (s, 3H),
3.83 (s, 3H), 3.62 (s, 3H), 2.30 (s, 3H), 2.26 (t, J=7.43
Hz, 2H), 2.01 (dt, J=7.41 and 7.52 Hz, 2H), 1.70 (m,
2H); CIMS m/z 433 (MH+). Anal. calcd for C17H21IO5:
C, 47.22; H, 4.86. Found: C, 47.21; H, 4.70.
Methyl (5E)-6-iodo-6-pyrazin-2-ylhex-5-enoate (23). The
vinyl tributylstannane 22 (600 mg, 1.21 mmol) was dis-
solved in dry CH2Cl2 (10 mL). Finely divided I2 (463
mg, 1.82 mmol) was added and the mixture was stirred
vigorously at room temperature for 30 min. Saturated
aqueous Na2S2O3 (10 mL) was added, the phases were
separated, and the aqueous phase was extracted with
CH2Cl2 (3Â10 mL). The combined organic extracts
were dried (Na2SO4) and concentrated. The residue was
purified by flash chromatography on silica gel (35 g,
hexanes–EtOAc 3:1, v/v) to afford a light yellow oil (347
Methyl
(5Z)-6-(3,4-dimethoxyphenyl)-6-[4-methoxy-3-
(methoxycarbonyl)-5-methylphenyl]hex-5-enoate (6). The
vinyl iodide 19 (44.7 mg, 0.103 mmol) and 3,4-dime-
thoxyphenylboronic acid (18.8 mg, 0.103 mmol) were
added to a solution of sodium carbonate (21.8 mg, 0.21
mmol) in water (1 mL) and CH3CN (2 mL). To the
above degassed solution was added Pd(PPh3)4 (6.0 mg,
0.005 mmol). The resulting mixture was heated at 90 ꢀC
(oil bath) under argon for 14 h. The reaction mixture
was concentrated and subjected to flash column chro-
matography on silica gel (30 g, hexanes–EtOAc 3:1, v/v)
1
mg, 86.4%): H NMR (CDCl3) d 8.64 (s, 1H), 8.58 (br,
1H), 8.44 (br, 1H), 6.76 (t, J=7.82 Hz, 1H), 3.63 (s,
3H), 2.29 (t, J=7.30 Hz, 2H), 2.18 (dt, J=7.29 and 7.60
Hz, 2H), 1.77 (m, 2H); EIMS m/z 332 (M+). Anal. calcd
for C11H13N2IO2: C, 39.76; H, 3.92; N, 8.43. Found: C,
39.79; H, 4.00; N, 8.24.
Methyl
(5E)-6-(3,4-dimethoxyphenyl)-6-pyrazin-2-yl-
1
to afford a light yellow oil (24 mg, 52.7%): H NMR
hex-5-enoate (7). The vinyl iodide 23 (214 mg, 0.64
mmol) and 3,4-dimethoxyphenylboronic acid (117 mg,
0.64 mmol) were added to sodium carbonate (150 mg,
1.42 mmol) in water (1 mL) and CH3CN (2 mL). To the
above degassed solution was added Pd(PPh3)4 (52.1 mg,
0.045 mmol). The resulting mixture was heated at 90 ꢀC
(oil bath) under argon for 14 h. The reaction mixture
was concentrated and subjected to flash column chro-
matography on silica gel (80 g, hexanes–EtOAc 1:1, v/v)
(CDCl3) d 7.43 (d, J=1.60 Hz, 1H), 7.12 (d, J=1.60 Hz,
1H), 6.79 (d, J=1.60 Hz, 1H), 6.75 (d, J=6.57 Hz, 1H),
6.63 (dd, J=6.57 and 1.60 Hz, 1H), 5.94 (t, J=7.46 Hz,
1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H),
3.63 (s, 3H), 2.31 (s, 3H), 2.30 (t, J=7.30 Hz, 2H), 2.10
(dt, J=7.52 and 7.34 Hz, 2H), 1.77 (m, 2H); EIMS m/z
442 (M+). Anal. calcd for C25H30O7: C, 67.87; H, 6.79.
Found: C, 67.85; H, 6.70.
1
to afford 7 as a light yellow oil (114 mg, 51.8%): H
Methyl 6-pyrazin-2-ylhex-5-ynoate (21). Methyl 5-hexy-
noate (800 mg, 6.35 mmol), 2-iodopyrazine (872 mg,
4.23 mmol), Pd(OAc)2 (76 mg, 0.34 mmol), PPh3 (178
mg, 0.68 mmol), copper(I) iodide (161 mg, 0.85 mmol),
and triethylamine (930 mg, 9.2 mmol) were added to
ethyl acetate (40 mL). The reaction mixture was stirred
at room temperature overnight under argon and then
concentrated. The residue was purified by flash chro-
matography on silica gel (80 g, EtOAc–hexanes 2:3, v/v)
NMR (CDCl3) d 8.64 (s, 1H), 8.49 (br, 2H), 6.78 (d,
J=8.28 Hz, 1H), 6.77 (br, 1H), 6.65 (dd, J=8.28 and
1.86 Hz, 1H), 6.17 (t, J=7.25 Hz, 1H), 3.87 (s, 3H), 3.83
(s, 3H), 3.64 (s, 3H), 2.33 (t, J=7.40 Hz, 2H), 2.22 (dt,
J=7.46 and 7.45 Hz, 2H), 1.83 (m, 2H); EIMS m/z 342
(M+). Anal. calcd for C19H22N2O4: C, 66.67; H, 6.43.
Found: C, 66.91; H, 6.68.
Methyl 5-iodo-2-methoxybenzoate (25). 5-Iodosalicylic
acid (7.0 g, 26.5 mmol) was dissolved in acetone (40
mL). Anhydrous K2CO3 (5.5 g, 39.75 mmol) and dime-
thylsulfate (3.8 mL, 39.75 mmol) were added. The reac-
tion mixture was heated at reflux for 14 h, and then the
inorganic salts were filtered. The solvent was evaporated
and the residue was washed with water (3Â20 mL). The
crude residue was crystallized from acetone to afford 25
1
to afford 21 as a brown liquid (700 mg, 81.1%): H
NMR (CDCl3) d 8.61 (br, 1H), 8.50 (d, J=2.37 Hz,
1H), 8.43 (d, J=2.37 Hz, 1H), 3.68 (s, 3H), 2.56 (t,
J=6.98 Hz, 2H), 2.52 (t, J=7.35 Hz, 2H), 1.96 (m, 2H);
CIMS m/z 204 (M+). Anal. calcd for C11H12N2O2: C ,
64.71; H, 5.88. Found: C, 64.64; H, 5.81.
as white solid (7.0 g, 90.4%): mp 47–48 ꢀC; H NMR
1
Methyl (5E)-6-pyrazin-2-yl-6-(tributylstannyl)hex-5-eno-
ate (22). To a stirred solution of alkyne 21 (350 mg,
1.72 mmol) in dry THF (20 mL) at room temperature
(CDCl3) d 8.05 (d, J=2.15 Hz, 1H), 7.70 (dd, J=8.57
and 2.30 Hz, 1H), 6.73 (d, J=8.68 Hz, 1H), 3.88 (s, 6H).

288
G. Xu et al. / Bioorg. Med. Chem. 10 (2002) 283–290
Methyl 6-[4-methoxy-5-methoxycarbonyl)phenyl]hex-5-
ynoate (26). Methyl 5-hexynoate (441 mg, 3.5 mmol),
iodide 25 (984 mg, 3.5 mmol), Pd(OAc)2 (63 mg, 0.28
mmol), copper(I) iodide (133 mg, 0.70 mmol), and trie-
thylamine (990 mg, 9.8 mmol) were mixed in ethyl ace-
tate (40 mL) and the mixture was kept stirring at room
temperature overnight under argon. Then the mixture
was concentrated and the residue was purified by flash
chromatography on silica gel (80 g, solvent: EtOAc–
hexanes 1:2, v/v) to give 26 as a yellow oil (380 mg,
cooled to 0 ꢀCin an ice-water bath. Aqueous sodium
hypochlorite (119.2 g of 5% solution) was added drop-
wise. The mixture was stirred at room temperature for 2
h and the excess hypochlorite was quenched with 10%
aqueous sodium thiosulfate (30 mL). The mixture was
adjusted to pH 4 using 1 N HCl. The mixture was
extracted with ether (3Â40 mL). The ether layers were
combined and dried over Na2SO4. After the solvent was
evaporated, the crude solid was crystallized from ace-
tone–hexanes (1:1, v/v) to give 2-chloro-4-iodophenol as
a light brown solid (19.35 g, 99%): mp 54.5–55.5 ꢀC; 1H
NMR (CDCl3) d 7.62 (d, J=1.98 Hz, 1H), 7.45 (dd,
J=8.47 and 1.90 Hz, 1H), 6.78 (d, J=8.65 Hz, 1H),
1
26%): H NMR (CDCl3) d 7.81 (d, J=2.15 Hz, 1H),
7.45 (dd, J=8.57 and 2.30 Hz, 1H), 6.87 (d, J=8.68 Hz,
1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.66 (s, 3H), 2.48 (t,
J=7.40 Hz, 2H), 2.44 (t, J=6.87 Hz, 2H), 1.90 (m,
5.59 (s, 1H); 13CNMR (CDCl
136.90, 121.08, 118.17, 81.54.
3) d 151.34, 137.29,
2H); 13CNMR (CDCl
3) d 173.47, 165.80, 158.37,
136.33, 134.83, 119.91, 115.63, 111.85, 88.00, 80.01,
55.96, 51.96, 51.46, 32.76, 23.75, 18.68; CIMS m/z 291
(MH+).
2-Chloro-4-iodoanisole (30). The above phenol 29 (8.0 g,
31.45 mmol) was dissolved in acetone (50 mL), followed
by addition of anhydrous K2CO3 (6.52 g, 47.17 mmol)
and dimethylsulfate (4.46 mL, 47.17 mmol). The reac-
tion mixture was heated at reflux for 14 h, and then the
inorganic salts were filtered. The solvent was evaporated
and the residue was washed with water (3Â20 mL). The
crude residue was crystallized from acetone to afford 30
Hydroarylation of compound 26 to afford 8 and 27.
Compound 26 (374 mg, 1.29 mmol), aryl iodide 25 (414
mg, 1.42 mmol), and Pd2(dba)3 (83 mg, 0.09 mmol) were
dissolved in ethyl acetate (40 mL). Diethylamine (310
mg, 4.26 mmol) was added, followed by formic acid
(131 mg, 2.84 mmol), and the solution was heated to
reflux overnight. The reaction mixture was then cooled
to room temperature and washed with diluted HCl and
brine. The organics were dried over Na2SO4, and the
solvent was removed under reduced pressure. The pro-
ducts 8 and 27 were isolated by flash chromatography
(hexane/EtOAc 3:1, v/v; silica gel: 100 g) and
preparative TLC(hexanes/EtOAc 5:1, v/v).
as light brown needles (8.0 g, 94%): mp 83–84 ꢀC: H
1
NMR (CDCl3) d 7.65 (d, J=2.03 Hz, 1H), 7.49 (dd,
J=8.58 and 1.96 Hz, 1H), 6.69 (d, J=8.63 Hz, 1H),
3.97 (s, 3H); 13CNMR (CDCl
136.51, 123.75, 113.89, 81.81, 56.13; EIMS m/z 269
3) d 155.05, 138.15,
(MH+).
Methyl 6-(3-chloro-4-methoxyphenyl)hex-5-ynoate (31).
Methyl 5-hexynoate (504 mg, 4.0 mmol), iodide com-
pound 30 (1.07 g, 4.0 mmol), Pd(OAc)2 (71.8 mg, 0.32
mmol), copper(I) iodide (152 mg, 0.80 mmol), and tri-
ethylamine (1.17 g, 11.56 mmol) were mixed in ethyl
acetate (40 mL) and the mixture was kept stirring at
room temperature overnight under argon atmosphere.
The mixture was then concentrated and the residue was
purified by flash chromatography on silica gel (80 g,
eluent: EtOAc–hexanes 1:4, v/v) to give 31 as a brown
oil (827 mg, 78%): 1H NMR (CDCl3) d 7.41 (d, J=1.95
Hz, 1H), 7.25 (dd, J=8.57 and 2.0 Hz, 1H), 6.83 (d,
J=8.57 Hz, 1H), 3.89 (s, 3H), 3.68 (s, 3H), 2.50 (t,
J=7.42 Hz, 2H), 2.46 (t, J=7.86 Hz, 2H), 1.91 (m, 2H);
13C NMR (CDCl3) d 173.51, 154.66, 133.15, 131.08,
122.12, 116.79, 111.63, 88.28, 79.89, 56.10, 51.55, 32.82,
23.80, 18.77; CIMS m/z 267 (MH+).
Methyl 6,6-bis[4-methoxy-3-(methoxycarbonyl)phenyl]-
hex-5-enoate (8). Light yellow oil. Yield: 188 mg
1
(32%). H NMR (CDCl3) d 7.65 (d, J=2.39 Hz, 1H),
7.56 (d, J=2.22 Hz, 1H), 7.23 (dd, J=2.03 and 2.08 Hz,
1H), 7.18 (d, J=2.49 Hz, 1H), 6.98 (d, J=8.62 Hz, 1H),
6.85 (d, J=8.76 Hz, 1H), 5.96 (t, J=7.45 Hz, 1H), 3.93
(s, 3H), 3.88 (s, 3H), 3.86 (s, 6H), 3.62 (s, 3H), 2.29 (t,
J=7.50 Hz, 2H), 2.14 (dt, J=7.32 and 7.47 Hz, 2H),
1.78 (m, 2H); 13CNMR (CDCl 3) d 173.83, 166.71,
166.52, 158.14, 139.77, 134.80, 134.71, 132.88, 132.25,
131.52, 129.98, 128.54, 119.85, 111.91, 111.70, 56.05,
52.02, 51.44, 33.48, 29.11, 25.03; CIMS m/z 457 (MH+).
Anal. calcd for C25H28O8: C, 65.78; H, 6.14. Found: C,
65.13; H, 6.22.
Methyl 5,6-bis[4-methoxy-3-(methoxycarbonyl)phenyl]-
hex-5-enoate (27). Light yellow oil. Yield: 176 mg
(30%). H NMR (CDCl3) d 7.88 (d, J=2.30 Hz, 1H),
7.74 (d, J=2.22 Hz, 1H), 7.54 (dd, J=2.30 and 2.22 Hz,
1H), 7.41 (dd, J=2.30 and 2.22 Hz, 1H), 6.98 (s, 1H),
6.96 (s, 1H), 6.62 (s, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 3.89
(s, 3H), 3.59 (s, 3H), 2.68 (t, J=7.73 Hz, 2H), 2.28 (t,
J=7.32 Hz, 2H), 1.71 (m, 2H); CIMS m/z 457 (MH+).
Anal. calcd for C25H28O8: C, 65.78; H, 6.14. Found: C,
65.47; H, 6.35.
Hydroarylation of compound 31 to afford 9 and 32.
Compound 31 (508 mg, 1.90 mmol), aryl iodide 30
(563.6 mg, 2.1 mmol), and Pd2(dba)3 (122 mg, 0.133
mmol) were dissolved in ethyl acetate (45 mL). Diethyl-
amine (458 mg, 6.27 mmol) was added, followed by
formic acid (210 mg, 4.56 mmol), and the solution was
heated to reflux under argon overnight. The reaction
mixture was then cooled to room temperature and
washed with diluted HCl and brine. The organics were
dried over Na2SO4, and the solvent was removed under
reduced pressure. The products were isolated through
flash chromatography (hexane–EtOAc 3:1, v/v; silica
gel: 100 g) and preparative TLC(hexane–EtOAc 5:1,
v/v).
1
2-Chloro-4-iodophenol (29). 2-Chlorophenol (10.0 g,
77.82 mmol) was dissolved in MeOH (200 mL). Sodium
iodide (11.70 g, 77.82 mmol) and sodium hydroxide
(3.12 g, 77.82 mmol) were added, and the mixture was

G. Xu et al. / Bioorg. Med. Chem. 10 (2002) 283–290
289
Methyl 6,6-bis(3-chloro-4-methoxyphenyl)hex-5-enoate
(9). Colorless oil. Yield: 295 mg (38%). 1H NMR
(CDCl3) d 7.22 (d, J=2.26 Hz, 1H), 7.14 (d, J=1.99 Hz,
1H), 7.02 (dd, J=3.92 and 2.13 Hz, 1H), 6.98 (dd,
J=3.50 and 1.88 Hz, 1H), 6.93 (d, J=8.38 Hz, 1H),
6.81 (d, J=8.61 Hz, 1H), 5.92 (t, J=7.44 Hz, 1H), 3.93
(s, 3H), 3.90 (s, 3H), 3.63 (s, 3H), 2.29 (t, J=7.44 Hz,
2H), 2.13 (dt, J=7.33 and 7.37 Hz, 2H), 1.77 (m, 2H);
CIMS m/z 409 (MH+). Anal. calcd for C21H22Cl2O4: C ,
61.62; H, 5.42; Cl, 17.32. Found C, 61.50; H, 5.46; Cl,
17.30.
3.91 (s, 3H), 3.80 (s, 3H), 3.66 (s, 3H), 2.36 (t, J=7.42
Hz, 2H), 2.29 (s, 3H), 2.24 (dt, J=7.18 and 6.83 Hz,
2H), 1.80 (m, 2H); EIMS m/z 306 (M+); HRMS calcd
for C17H22O5 306.1467, found 306.1465. Anal. calcd for
C17H22O5: C, 66.66; H, 7.19. Found: C, 66.54; H, 7.30.
Methyl 6-[4-methoxy-5-(methoxycarbonyl)-3-methylphe-
nyl]hexanoate (12). The alkyne 17 (231 mg, 0.76 mmol)
was hydrogenated at atmospheric pressure over palla-
dium (5%) on activated carbon (40 mg) in ethyl acetate
(15 mL). After TLC(silica gel, hexanes–EtOAc 4:1, v/v)
had shown that all the starting material was consumed
(14 h), the catalyst was removed by filtration and the
solvent was removed at reduced pressure to give a
brown oil. This crude product was flash chromato-
graphed on silica gel (10 g) using hexanes–EtOAc (4:1 v/
v) as eluent. Evaporation of the solvent gave the pro-
Methyl 5,6-bis(3-chloro-4-methoxyphenyl)hex-5-enoate
(32). Colorless oil. Yield: 287 mg (37%). 1H NMR
(CDCl3) d 7.46 (d, J=2.12 Hz, 1H), 7.30 (m, 2H), 7.16
(dd, J=8.49 and 2.0 Hz, 1H), 6.93 (d, J=8.57 Hz, 2H),
6.56 (s, 1H), 3.92 (s, 6H), 3.63 (s, 3H), 2.66 (dt, J=7.11
and 2.41 Hz, 2H), 2.29 (t, J=7.27 Hz, 2H), 1.72 (m,
1
duct 12 (200 mg, 85.5%) as a light yellow oil: H NMR
2H); 13CNMR (CDCl
3) d 173.52, 154.27, 153.65,
(CDCl3) d 7.42 (d, J=2.22 Hz, 1H), 7.14 (d, J=2.11 Hz,
1H), 3.90 (s, 3H), 3.79 (s, 3H), 3.66 (s, 3H), 2.54 (t,
J=7.72 Hz, 2H), 2.30 (t, J=7.0 Hz, 2H), 2.28 (s, 3H),
1.62 (m, 4H), 1.34 (m, 2H); 13C NMR (CDCl3) d 174.11,
166.98, 156.65, 137.56, 135.10, 132.32, 128.57, 124.43,
61.34, 52.00, 51.37, 34.72, 33.84, 30.88, 28.57, 24.62,
15.91; CIMS m/z 309 (MH+); HRMS calcd for
C17H25O5 (MH+) 309.1702, found 309.1689. Anal.
calcd for C17H24O5: C, 66.23; H, 7.79. Found: C, 66.20;
H, 7.81.
140.22, 135.61, 131.20, 130.43, 128.27, 128.03, 126.80,
125.69, 122.40, 122.16, 111.88, 111.79, 56.14, 51.49,
33.45, 29.14, 23.63; CIMS m/z 409 (MH+). Anal. calcd
for C21H22Cl2O4: C, 61.62; H, 5.42; Cl, 17.32. Found C,
61.65; H, 5.62; Cl, 17.32.
Methyl (5Z)-6-[4-methoxy-5-(methoxycarbonyl)-3-me-
thylphenyl]hex-5-enoate (10). The alkyne 17 (112 mg,
0.37 mmol) was hydrogenated using 5% palladium on
barium sulfate (20 mg) and pure quinoline (20 mg) in 10
mL of MeOH. After 18 h, the catalyst was removed by
filtration and the solvent was evaporated. The resulting
residue was purified by flash chromatography on silica
gel (20 g, column: 1Â30 cm), using hexanes–EtOAc (3:1
v/v) as eluent, to give a colorless oil (100 mg, 88.5%):
1H NMR (CDCl3) d 7.51 (d, J=2.03 Hz, 1H), 7.23 (d,
J=1.58 Hz, 1H), 6.36 (d, J=11.63 Hz, 1H), 5.62 (dt,
J=11.60 and 5.84 Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H),
3.64 (s, 3H), 2.34 (t, J=5.67 Hz, 2H), 2.31 (s, 3H), 2.23
(dt, J=7.2 and 5.9 Hz), 1.78 (m, 2H); 13CNMR
(CDCl3) d 173.78, 166.77, 156.79, 135.16, 132.76,
132.31, 131.76, 129.18, 128.31, 124.08, 61.35, 52.03,
51.34, 33.28, 27.61, 24.84, 15.96; EIMS m/z 306 (M+);
HRMS calcd for C17H22O5 306.1467, found 306.1467.
Anal. calcd for C17H22O5: C, 66.66; H, 7.19. Found: C,
66.47; H, 7.28.
Methyl 6-[4-methoxy-5-(methoxycarbonyl)-3-methylphe-
nyl]-6-oxohexanoate (13). The alkyne 17 (124 mg, 0.41
mmol) and formic acid (10 mL) were placed in a 25 mL
round-bottomed flask equipped with reflux condenser
that was properly connected to a 100 mL graduate
cylinder inverted in a breaker of water in order to
monitor the evolution of carbon monoxide gas. The
reaction flask was immersed in an oil bath at 100 ꢀC. Gas
evolution ceased after 1 h, and the system was left for 1
h to reach ambient temperature. The solvent was eva-
porated to give pure ketone 13 as a yellow oil (120 mg
1
90.9%): H NMR (CDCl3) d 8.20 (d, J=2.17 Hz, 1H),
7.94 (d, J=1.47 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.66
(s, 3H), 2.96 (t, J=6.78 Hz, 2H), 2.36 (t, J=7.09 Hz,
2H), 2.34 (s, 3H), 1.73 (m, 4H); 13CNMR (CDCl 3) d
198.16, 173.77, 166.14, 162.12, 134.24, 133.22, 131.93,
129.50, 124.14, 61.51, 52.32, 51.44, 37.84, 33.75, 24.39,
23.45, 16.15; CIMS m/z 323 (MH+); HRMS calcd for
C17H23O6 (MH+) 323.1495, found 323.1489. Anal.
calcd for C17H22O6: C, 63.35; H, 6.83. Found: C, 63.20;
H, 6.79.
Methyl
(5E)-6-[4-methoxy-5-(methoxycarbonyl)-3-me-
thylphenyl]hex-5-enoate (11). A solution of methyl 5-
iodo-3-methyl-2-methoxybenzoate 16 (673 mg, 2.2
mmol), methyl 5-hexenoate (256 mg, 2.0 mmol), palla-
dium acetate (7 mg, 0.03 mmol), tri-o-tolyphosphine (37
mg, 0.12 mmol), triethylamine (7 mL), and acetonitrile
(15 mL) was heated under argon at 70 ꢀCfor 18 h. The
cooled reaction mixture was evaporated and diluted
with water (8 mL) and methylene chloride (40 mL). The
methylene chloride layer was separated, washed with
water, and dried over anhydrous sodium sulfate. Eva-
poration of the solvent then gave a brown residue,
which was further purified by flash chromatography on
silica gel (80 g, hexanes/EtOAc 4:1, v/v) to afford a yel-
In vitro anti-HIV assay. Anti-HIV screening of test
compounds against various viral isolates and cell lines
was performed as previously described.32 This cell-based
microtiter assay quantitates the drug-induced protection
from the cytopathic effect of HIV-1. Data are presented
as the percent control of MTS (CellTiter1, Promega,
Madison, WI, USA) values for the uninfected, drug-free
control. EC50 values reflect the drug concentration that
provides 50% protection from the cytopathic effect of
HIV-1 in infected cultures, while the CC50 reflects the
concentration of drug that causes 50% cell death in the
uninfected cultures. MTS-based results were confirmed
1
low oil (300 mg, 42.1%): H NMR (CDCl3) d 7.60 (d,
J=2.35 Hz, 1H), 7.32 (d, J=2.06 Hz, 1H), 6.32 (d,
J=15.83 Hz, 1H), 6.12 (dt, J=15.72 and 6.96 Hz, 1H),

290
G. Xu et al. / Bioorg. Med. Chem. 10 (2002) 283–290
by measurement of cell-free supernatant RT and p24
levels. All MTS cytoprotection data were derived from
triplicate tests on each plate with the EC50 value repre-
senting the average of the triplicates. The error of the
triplicates was less than 10% for all determinations.
13. Casimiro-Garcia, A.; Micklatcher, M.; Turpin, J. A.;
Stup, T. L.; Watson, K.; Buckheit, R. W., Jr.; Cushman, M. J.
Med. Chem. 1999, 42, 4861.
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Assay for inhibition of HIV-1 RT. The effects of the
compounds on the HIV-1 RT enzyme were performed
using purified p66/51 RT (a kind gift of S. Hughes,
ABL-Basic Research Program, NCI-FCRDC). Inhibi-
tion of reverse transcription was measured by the level
of incorporation of [32P]GTP into the poly(rC)-oli-
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Acknowledgements
This investigation was made possible by Grant RO1-AI-
43637, awarded by the National Institutes of Health,
DHHS.
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