The biological effects of structural variation at the meta position of the aromatic rings and at the end of the alkenyl chain in the alkenyldiarylmethane series of non-nucleoside reverse transcriptase inhibitors

Article abstract of DOI:10.1021/jm010212m

In an effort to elucidate a set of structure-activity relationships in the alkenyldiarylmethane (ADAM) series of non-nucleoside reverse transcriptase inhibitors, a number of modifications were made at two locations: (1) the meta positions of the two aromatic rings and (2) the end of the alkenyl chain. Forty-two new ADAMs were synthesized and evaluated for inhibition of the cytopathic effect of HIV-1_RF in CEM-SS cell culture and for inhibition of HIV-1 reverse transcriptase. The size of the aromatic substituents was found to affect anti-HIV activity, with optimal activity appearing with Cl, CH₃, and Br substituents and with diminished activity occurring with smaller (H and F) or larger (I and CF₃) substituents. The substituents at the end of the alkenyl chain were also found to influence the antiviral activity, with maximal activity associated with methyl or ethyl ester groups and with diminished activity resulting from substitution with higher esters, amides, sulfides, sulfoxides, sulfones, thioesters, acetals, ketones, carbamates, ureas, and thioureas. Twelve of the new ADAMs displayed submicromolar EC₅₀ values for inhibition of the cytopathic effect of HIV-1_RF in CEM-SS cells. Selected ADAMs, 19 and 21, were compared to previously published ADAMs 15 and 17 for antiviral efficacy and activity against the HIV-1 reverse transcriptase enzyme. All four ADAMs were found to inhibit HIV-1 reverse transcriptase enzyme activity, to inhibit the replication of a variety of HIV-1 clinical isolates representing syncytium-inducing, nonsyncytium-inducing, and subtype representative isolates, and to inhibit HIV-1 replication in monocytes. Subsequent assessment against a panel of site-directed reverse transcriptase mutants in NL4-3 demonstrated no effect of the K103N mutation on antiviral efficacy and a slight enhancement (6- to 11-fold) in sensitivity to AZT-resistant viruses. Additionally, ADAMs 19 (44-fold) and 21 (29-fold) were more effective against the A98G mutation (found in association with nevirapine resistance in vitro), and ADAM 21 was 5-fold and 2-fold more potent against the Y181C inactivation mutation than the previously reported ADAMs 15 and 17, respectively. All four ADAMs were tested for efficacy against a multidrug-resistant virus derived from a highly experienced patient expressing resistance to the reverse transcriptase enzyme inhibitors AZT, ddI, 3TC, d4T, foscarnet, and nevirapine, as well as the protease inhibitors indinavir, saquinavir, and nelfinavir. ADAM 21 was 2-fold more potent than ADAM 15 and 6-fold more potent than ADAMs 17 and 19 at preventing virus replication. Thus, we have identified a novel series of reverse transcriptase inhibitors with a favorable profile of antiviral activity against the primary mutation involved in clinical failure of non-nucleoside reverse transcriptase inhibitors, K103N, and that retain activity against a multidrug-resistant virus.

Full text of DOI:10.1021/jm010212m

4092
J . Med. Chem. 2001, 44, 4092-4113
Th e Biologica l Effects of Str u ctu r a l Va r ia tion a t th e Meta P osition of th e
Ar om a tic Rin gs a n d a t th e En d of th e Alk en yl Ch a in in th e
Alk en yld ia r ylm eth a n e Ser ies of Non -Nu cleosid e Rever se Tr a n scr ip ta se
In h ibitor s
Guozhang Xu,† Mark Micklatcher,† Maximilian A. Silvestri,† Tracy L. Hartman,‡ J ennifer Burrier,‡
Mark C. Osterling,‡ Heather Wargo,‡ J im A. Turpin,‡ Robert W. Buckheit, J r.,‡ and Mark Cushman*,†
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences,
Purdue University, West Lafayette, Indiana 47907, and Infectious Disease Research Department,
Southern Research Institute, 431 Aviation Way, Frederick, Maryland 21701
Received May 11, 2001
In an effort to elucidate a set of structure-activity relationships in the alkenyldiarylmethane
(ADAM) series of non-nucleoside reverse transcriptase inhibitors, a number of modifications
were made at two locations: (1) the meta positions of the two aromatic rings and (2) the end
of the alkenyl chain. Forty-two new ADAMs were synthesized and evaluated for inhibition of
the cytopathic effect of HIV-1RF in CEM-SS cell culture and for inhibition of HIV-1 reverse
transcriptase. The size of the aromatic substituents was found to affect anti-HIV activity, with
optimal activity appearing with Cl, CH3, and Br substituents and with diminished activity
occurring with smaller (H and F) or larger (I and CF3) substituents. The substituents at the
end of the alkenyl chain were also found to influence the antiviral activity, with maximal activity
associated with methyl or ethyl ester groups and with diminished activity resulting from
substitution with higher esters, amides, sulfides, sulfoxides, sulfones, thioesters, acetals,
ketones, carbamates, ureas, and thioureas. Twelve of the new ADAMs displayed submicromolar
EC50 values for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells. Selected ADAMs,
19 and 21, were compared to previously published ADAMs 15 and 17 for antiviral efficacy and
activity against the HIV-1 reverse transcriptase enzyme. All four ADAMs were found to inhibit
HIV-1 reverse transcriptase enzyme activity, to inhibit the replication of a variety of HIV-1
clinical isolates representing syncytium-inducing, nonsyncytium-inducing, and subtype rep-
resentative isolates, and to inhibit HIV-1 replication in monocytes. Subsequent assessment
against a panel of site-directed reverse transcriptase mutants in NL4-3 demonstrated no effect
of the K103N mutation on antiviral efficacy and a slight enhancement (6- to 11-fold) in
sensitivity to AZT-resistant viruses. Additionally, ADAMs 19 (44-fold) and 21 (29-fold) were
more effective against the A98G mutation (found in association with nevirapine resistance in
vitro), and ADAM 21 was 5-fold and 2-fold more potent against the Y181C inactivation mutation
than the previously reported ADAMs 15 and 17, respectively. All four ADAMs were tested for
efficacy against a multidrug-resistant virus derived from a highly experienced patient expressing
resistance to the reverse transcriptase enzyme inhibitors AZT, ddI, 3TC, d4T, foscarnet, and
nevirapine, as well as the protease inhibitors indinavir, saquinavir, and nelfinavir. ADAM 21
was 2-fold more potent than ADAM 15 and 6-fold more potent than ADAMs 17 and 19 at
preventing virus replication. Thus, we have identified a novel series of reverse transcriptase
inhibitors with a favorable profile of antiviral activity against the primary mutation involved
in clinical failure of non-nucleoside reverse transcriptase inhibitors, K103N, and that retain
activity against a multidrug-resistant virus.
In tr od u ction
agents has been reported to result in decreased HIV-1
RNA levels, increased CD4 lymphocyte counts, and
delayed disease progression. However, drug incompat-
ibilities, adverse effects, and cross-resistance continue
to restrict the selection of anti-HIV agents for combina-
tion chemotherapy.5-9 Therefore, the synthesis of ad-
ditional NNRTIs, which might have novel resistance
mutation profiles and pharmacokinetic properties, re-
mains a worthwhile goal. The new compounds synthe-
sized in the present investigation were evaluated as
inhibitors of the HIV-1 reverse transcriptase and HIV-1
replication in vitro. The lead alkenyldiarylmethanes
exhibited a broad range of antiviral activity against a
variety of clinical isolates including subtype representa-
The three currently available non-nucleoside reverse
transcriptase inhibitors (NNRTIs) for the treatment of
AIDS are nevirapine, delavirdine, and efavirenz.1-3
Although the therapeutic use of the NNRTIs is compli-
cated by the rapid development of viral resistance and
drug toxicity, they have proven to be useful in combina-
tion therapy with nucleoside reverse transcriptase
inhibitors and protease inhibitors.4 The employment of
NNRTIs in combination with two additional anti-HIV
* To whom correspondence should be addressed. Phone: 765-494-
1465. Fax: 765-494-6790. E-mail: cushman@pharmacy.purdue.edu.
† Purdue University.
‡ Southern Research Institute.
10.1021/jm010212m CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/18/2001

Alkenyldiarylmethane Series of Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4093
compounds were evaluated as inhibitors of the cyto-
pathic effect of HIV-1RF in CEM-SS cell culture and as
inhibitors of HIV-1 reverse transcriptase.
Ch em istr y
tive isolates, monocyte tropic isolates, and virus derived
from a retroviral experienced patient with resistance
to the RT inhibitors AZT, ddI, 3TC, d4T, foscarnet, and
nevirapine, as well as the PR inhibitors indinavir,
saquinavir, and nelfinavir.
The alkenyldiarylmethanes 1-50 were synthesized
either directly through McMurry reactions of the ben-
zophenones 51-57 with the appropriate aldehydes or
Several recent publications from our laboratory have
documented a new class of NNRTIs, the alkenyldiaryl-
methanes (ADAMs).10-14 Interest in this class of
NNRTIs has resulted from the extremely potent anti-
HIV activities of several members of this series as
inhibitors of the cytopathic effect of HIV-1RF in CEM-
SS lymphocytes, including ADAM 17 (EC50 ) 1.3 nM).
In addition, certain HIV-1 strains containing AZT-
resistance mutations displayed increased sensitivity to
ADAM 15, indicating a possible therapeutic role for the
ADAMs in combination with AZT.13 In the present
communication, we report the synthesis of an extensive
set of ADAMs with structural alterations at the meta
positions of the aromatic rings and at the terminus of
the alkenyl chain, and we report a detailed analysis of
the biological effects of these variations. The new

4094 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ta ble 1. Anti-HIV Activities of the ADAMs
Xu et al.
Sch em e 1a
compd
RT (IC50, µM)a
EC50 (µM)b
CC50 (µM)c
TId
1e
3.2
NAf
NAf
16
14.0
13.4
>29.1
17.2
138
2g
10
3h
NTi
>1.8
2.5
15
4
1.0
6.8
5e
0.38
11
9.2
6e
NAf
NAf
1.3
>316
106
7
8
9
NTi
NTi
42.7
>200
>200
>200
>200
>200
68.3
31.6
6.0
33
6.0
258
99
>100
>100
NTi
0.3
<1.0
0.3
>200
0.233
0.181
0.359
8.3
4.7
13
8.2
1.7
13.1
1.9
>43
>15
>24
>43
>15
36
a
10
11
12
13
14g
15e
16
17g
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
Reagents and conditions: (a) K2CO3, Me2SO4, Me2CO, reflux
(20 h); (b) aqueous AcOH, CrO3, 23 °C (18 h).
Sch em e 2a
0.013
0.25
0.0013
14.3
0.01
0.03
0.007
1.29
1.29
1.14
0.84
NAf
4.33
0.38
1.51
NAf
5.37
95.4
5.31
11.7
NAf
2.42
3.95
NAf
NAf
1.22
0.21
0.20
0.71
0.67
NAf
NAf
NA
2431
24
10000
1.2
1600
297
2357
10.8
4.20
>17.5
42.9
13
17.2
16.0
8.91
16.5
13.9
5.40
>20
36.1
4.32
16.4
2.65
7.40
3.59
14.7
>200
>20
36.9
14.9
12.5
12.6
18.1
19.10
12.40
12.40
8.10
12.20
3.59
14.60
1.36
17.20
5.13
13.00
1.95
29.7
9.15
>100
60.4
70.8
0.687
5.65
>100
7.12
>100
>100
NTi
3.79
6.94
4.91
a
Reagents and conditions: (a) H2CO, MeOH, aqueous H2SO4,
-78 to 23 °C (12 h); (b) Me2SO4, K2CO3, MeOH, reflux (12 h); (c)
2.74
CrO3, Ac2O, 23 °C (12 h).
>2.10
>3.77
3.15
previously reported and are included in Table 1 for
comparison purposes. The required benzophenones 51,13
52,19 53,21 55,11 and 5613 were prepared as previously
described, and the remaining two benzophenones 54 and
57 were synthesized as outlined in Schemes 1 and 2.
Alkylation of both phenoxide anions and both carbox-
ylates derived from the substituted diphenylmethane
5822 with dimethyl sulfate, using potassium carbonate
in acetone as the base, afforded intermediate 59, which
was then oxidized to the desired benzophenone 54 with
chromium trioxide in acetic acid (Scheme 1). As shown
in Scheme 2, treatment of 3-(trifluoromethyl)salicylic
acid (60)23 with formaldehyde under acidic conditions
afforded the diphenylmethane 61, which was meth-
ylated and oxidized to yield the substituted benzo-
phenone 57.
NTi
NTi
5.15
3.20
NTi
>100
> 100
4.43
4.93
2.39
1.93
0.016
>100
>100
65.4
2.95
9.47
0.499
10.19
59.05
40.5
17.17
5.34
0.76
2.15
0.02
6.73
6.02
104.5
a
Inhibitory activity vs HIV-1 reverse transcriptase with rCdG
b
as the template primer. The EC50 is the inhibitory concentration
Aldehydes 64,24 65,25 66,26 and 6727 were synthesized
by pyridinium chlorochromate (PCC) oxidation of the
corresponding alcohols, while 63 was commercially
available. Alcoholysis or aminolysis of δ-valerolactone
for cytopathicity of HIV-1RF in CEM-SS cells. c The CC50 is the
d
50% cytotoxic concentration for mock-infected CEM-SS cells. The
TI is the therapeutic index, which is the CC50 divided by the EC50
.
e The synthesis and biological evaluation of this compound was
reported previously: Cushman, M.; Casimiro-Garcia, A.; Hejch-
man, E.; Ruell, J . A.; Huang, M.; Schaeffer, C. A.; Williamson, K.;
Rice, W. G.; Buckheit, R. W., J r. J . Med. Chem. 1998, 41, 2076-
f
2089. NA (not active): no observed inhibition of HIV-1 cytopath-
g
icity up to the cytotoxic concentration in uninfected cells. The
synthesis and biological evaluation of this compound was reported
previously: Casimiro-Garcia, A.; Micklatcher, M.; Turpin, J . A.;
Stup, T. L.; Watson, K.; Buckheit, R. W., J r.; Cushman, M. J . Med.
h
Chem. 1999, 42, 4861-4874. The synthesis and biological evalu-
ation of this compound was reported previously: Cushman, M.;
Golebiewski, W. M.; Graham, L.; Turpin, J . A.; Rice, W. G.;
Filakas-Boltz, V.; Buckheit, R. W., J r. J . Med. Chem. 1996, 39,
3217-3227. NT: not tested. All data are derived from triplicate
tests with the variation of the mean averaging 10%.
(68) afforded the corresponding primary alcohols, which
were oxidized with PCC to yield the aldehydes 69-73
(Scheme 3).
i
indirectly by McMurry reactions that afforded precur-
sors to alkenyldiarylmethanes that were then converted
into the desired products.15-18 The syntheses of 1,13 2,19
3,11 5,13 6,13 14,14 15,13 and 1719 were carried out as
The trimethylsilylated aldehyde 75 was prepared as
outlined in Scheme 4. Protection of the aldehyde group
of ethyl 5-oxopentanoate (69) was accomplished by
converting it to the dimethylacetal 74 with methanol

Alkenyldiarylmethane Series of Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4095
Sch em e 3a
Sch em e 5a
a
a
Reagents and conditions: (a) ROH, H2SO4, reflux (3-5 h), or
Reagents and condtitions: (a) (COCl)2, DMF, THF, 23 °C; (b)
amines, THF, 23 °C (48-72 h); (b) PCC, CH2Cl2, 23 °C (1.5-4.0
h).
RSNa, DMF, 0 °C (12 h) or RSH, Et3N, DMF, 23 °C (12 h); (c) H2,
Pd/BaSO4, quinoline, EtOAc, 23 °C; (d) O3, 23 °C (40 min), then
Me2S, 23 °C (2 h).
Sch em e 4a
a
Reagents and conditions: (a) 2,2-dimethoxypropane, HCl,
CHCl3, 23 °C (6 h); (b) NaOH, EtOH, 23 °C (12 h); (c) BOP-Cl,
Me3SiCH2CH2OH, Et3N, CH2Cl2, 23 °C (2 h); (d) HCl, Me2CO,
23 °C (2 h).
oxidation of these alcohols afforded the desired alde-
hydes 87, 88, and 89.
The aldehyde 92 used in the synthesis of the oxa-
zolidinone-containing ADAMs 49 and 50 were obtained
as portrayed in Scheme 7. Reaction of 4-bromo-1-butene
(90) with 2-oxazolidinone using cesium carbonate as the
base gave the alkene 91.30 Oxidation of the double bond
present in 91 with 4-methylmorpholine N-oxide and
osmium tetroxide afforded the vicinal diol, which was
cleaved with sodium periodate, yielding the aldehyde
92.
under acidic conditions. Esterification of the acid of 74
with 2-(trimethylsilyl)ethanol in the presence of BOP-
Cl, followed by deprotection of the aldehyde in the
presence of HCl in acetone, afforded 75, which was used
in the synthesis of ADAM 32.
Commercially available 4-(methylthio)-1-butanol was
oxidized to afford the aldehyde 76 using Dess-Martin
The amide 39, urea 45, and thiourea 46 derivatives
were synthesized from N-Fmoc-â-alanine (93) as shown
in Scheme 8. The conversion of 93 to its acid chloride
was accomplished with oxalyl chloride and a catalytic
amount of DMF, followed by reduction with (Ph3P)4Pd
and tri-n-butyltin hydride in THF to afford the aldehyde
periodinane. McMurry coupling of 76 with the dichloro-
benzophenone 53 afforded ADAM 33, which was con-
verted to the sulfoxide 34 with sodium periodate on
acidic alumina in ethanol.28 On the other hand, the
sulfone 35 was obtained by oxidation of 33 with oxone
(potassium peroxymonosulfate) in aqueous methanol.29
As shown in Scheme 5, 5-hexynoic acid (77) was
converted to the corresponding acid chloride with oxalyl
chloride, followed by reaction with methanethiolate or
ethanethiol, to afford the thioesters 78 and 79. The two
alkynes 78 and 79 were converted to the alkenes by
hydrogenation with Lindlar catalyst in the presence of
quinoline in ethyl acetate, and the alkenes were trans-
formed to the aldehydes 80 and 81 by ozonolysis.
The previously reported aldehyde 8219 was converted
to its dimethylacetal derivative 38 with 2,2-dimethoxy-
propane in acetonitrile in the presence of a catalytic
amount of HCl.
Sch em e 6a
The aldehydes required for the synthesis of the
ADAMs 40-44, 47, and 48 were prepared as shown in
Scheme 6. Commercially available 3-amino-1-propanol
was converted to the carbamates 84, 85, and 86 by
reaction with the required alkyl chloroformates. Swern
a
Reagents and conditions: (a) ROCOCl, aqueous K2CO3, 0 °C
(2 h); (b) (COCl)2, DMSO, Et3N, -78 °C (1 h).

4096 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Xu et al.
Sch em e 7a
38 ADAMs ranging in EC50 values from 95 to 0.0013
µM. Of the 42 compounds tested vs HIV-1 reverse
transcriptase, 11 were found to be inactive and the
remaining 31 compounds displayed IC50 values ranging
from 258 to 0.181 µM.
Ar om a tic Su bstitu tion s. Considering first the effect
of substituting different aromatic groups (R2 in the
structures displayed here), the two sets with the great-
est structural variation are the alkenes 1-7 and the
methyl esters 14-18. The effective van der Waals radii
of the groups involved, determined by rotational barri-
ers, are 1.20 Å (H), 1.47 Å (F), 1.73 Å (Cl), 1.80 Å (CH3),
1.86 Å (Br), 1.97 Å (I), and 2.2 Å (CF3).31 In the alkene
1-7 series, the ADAMs with the two smallest substit-
uents (H and F) are inactive as inhibitors of the
cytopathic effect of HIV-1, as are the two members of
the series with the largest substituents (I and CF3). Of
the three remaining substituents, the CH3 group con-
ferred the greatest activity (EC50 ) 6.8 µM), followed
closely by Br (EC50 ) 9.2 µM) and Cl (EC50 ) 16 µM).
Comparison of these values with those present in the
substantially more active methyl ester series 14-18
reveals similar trends, although in this case all of the
compounds were active. The most active compound
proved to be the dibromo compound 17 (EC50 ) 0.0013
µM), followed by the dichloro congener 15 (EC50 ) 0.013
µM), the dimethyl analogue 16 (EC50 ) 0.25 µM), the
difluoro derivative 14 (EC50 ) 1.9 µM), and the bis-
(trifluoromethyl) compound 18 (EC50 ) 14.3 µM). The
results in the two series 1-7 and 14-18 seem to
indicate that as the effective van der Waals radii of the
substituents increase from H or F to CH3 or Br, there
is an increase in activity. The activity peaks with CH3
or Br and then decreases as the size of the substituents
is increased farther. Accordingly, the aromatic substit-
uents employed in the remaining series of compounds
were restricted to Cl, CH3, and Br.
a
Reagents and conditions: (a) 2-oxazolidinone, Cs2CO3, Me2CO,
reflux (12 h); (b) 4-methylmorpholine N-oxide, OsO4, aqueous
MeOH, 23 °C (12 h), then NaIO4, aqueous Me2CO, 23 °C (4 h).
Sch em e 8a
a
Reagents and conditions: (a) (COCl)2, DMF, THF, 23 °C (2
h), then (Ph3P)4Pd, Bu3SnH, THF, 23 °C (1 h); (b) TiCl4/THF (1:
2), Zn, reflux (2 h), then 53 and 94, reflux (6 h); (c) piperidine,
THF, 23 °C (3 h); (d) MeCOCl, EtNCO, or SCNMe, Et3N, THF.
94. McMurry coupling of the aldehyde 94 with the
substituted dichlorobenzophenone 53 resulted in the
formation of the Fmoc-protected ADAM 95. The Fmoc
protecting group was then removed from intermediate
95 in the presence of piperidine in THF to provide the
amine 96. Reaction of 96 with acetyl chloride, ethyl
isocyanate, or methyl isothiocyanate afforded the amide
39, urea 45, and thiourea 46 derivatives, respectively.
In the remaining four series of compounds 19-21,
22-24, 25-27, and 40-42 in which all three substit-
uents were present (Cl, CH3, and Br), the dibromo
compound was the most active in inhibiting the cyto-
pathic effect of the virus in three series while the
dichloro compound was the most active in the remaining
one (25-27). If one compares the relative activities of
the four pairs of compounds in which only Cl and CH3
are present (28 and 29, 30 and 31, 43 and 44, and 47
and 48), the methyl groups confer greater activity in
three of the cases, and chlorine confers greater activity
in the remaining one (28 vs 29). There are also four
pairs of compounds containing Br and Cl, namely, 8 and
9, 10 and 11, 12 and 13, and 49 and 50. In two of these
four pairs, the Cl compound is more active than the Br
compound, while in the remaining two pairs, the Br
compound is more active. Overall, it seems clear that
Br (radius 1.86 Å), CH3 (radius 1.80 Å), and Cl (radius
1.73 Å) are more active than any of the other substit-
uents tried, but there is no clear decision that can be
made regarding which of the three would confer maxi-
mal activity in an unknown series. However, the three
most active compounds in the whole series (17, 21, and
50) are all brominated.
Biologica l Resu lts a n d Discu ssion
The 42 new ADAMs synthesized in this study were
evaluated for inhibition of the cytopathic effect of HIV-
1RF in CEM-SS cells and for cytotoxicity in uninfected
CEM-SS cells, and the results are listed in Table 1,
along with the results from eight previously synthesized
ADAMs that are included in the table for comparison
purposes. These compounds were also tested for inhibi-
tion of HIV-1 reverse transcriptase, and the resulting
IC50 values are also included in Table 1.
The present series of ADAMs was designed in order
to more completely define the structure-activity rela-
tionships in two specific regions of the ADAM template.
First, several new analogues incorporate a variety of
functionalities at or near the terminus of the alkenyl
side chain (see R1 in structures 1-48). Second, several
new compounds incorporate modifications in the aro-
matic region in the position that is typically occupied
by a halogen (R2 in structures 1-48). As seen from
examination of the results listed in Table 1, structural
variation at these two locations has resulted in a wide
range of biological activity. In addition to the 12
compounds that were inactive as inhibitors of the
cytopathic effect of HIV-1RF in CEM cells, there were
Alip h a tic Su bstitu tion s. Turning to the biological
effects of changing the substituent at the end of the
alkenyl chain, one would of course want to compare

Alkenyldiarylmethane Series of Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4097
F igu r e 1. Hypothetical model of ADAM 17 docked in the NNRTI binding site of HIV-1 reverse transcriptase. The ligand is
displayed in red. The figure is programmed for walleyed viewing.
compounds having identical aromatic substituents. The
most extensive set of compounds differing at the end of
the alkenyl chain, but having identical aromatic sub-
stituents, consists of the dichlorinated derivatives. This
includes 20 compounds, with 15 active compounds and
5 inactive compounds. The active compounds range in
anti-HIV potency from 0.01 to 16 µM and contain, in
order of decreasing activity, the following end groups:
CH2COOMe (15, EC50 ) 0.013 µM), CH2COOEt (19,
EC50 ) 0.01 µM), CH2CONMe2 (28, EC50 ) 0.38 µM),
NHCOOEt (43, EC50 ) 0.71 µM), CH2COOi-Pr (25,
EC50 ) 0.84 µM), NHCOOMe (40, EC50 ) 1.22 µM),
CH2COOn-Pr (22, EC50 ) 1.29 µM), CH2CtCH (8, EC50
) 1.3 µM), CH2Ph (12, EC50 ) 1.7 µM), CH2COSMe (36,
EC50 ) 2.42 µM), CH2COSEt (37, EC50 ) 3.95 µM),
strated that electron donation toward the carbonyl
group from an attached oxygen atom increased activity
relative to the corresponding ketone (CH2COOCH3 vs
CH2COCH2CH3).19 The carbonyl oxygens of thioesters
more closely resemble ketone carbonyl oxygens than
ester carbonyl oxygens and have been claimed to have
about 40% less net negative charge than ester carbonyl
oxygens.33 In the present case, the activity observed for
the thioester 36 (EC50 ) 2.42 µM) is very close to that
previously recorded for the corresponding ethyl ketone
(EC50 ) 2.8 µM), in which the sulfur of 36 is replaced
by a methylene group.19 Calculation of the Gasteiger-
Hu¨ckel charges using the Sybyl program provided
charges for the carboxyl oxygens of -0.537 esu for ester
17, -0.392 esu for the corresponding ethyl ketone, and
-0.379 esu for thioester 36.
CH2SMe (33, EC50 ) 5.31 µM), CH2SOMe (34, EC50
)
11.7 µM), CH2CHdCH2 (10, EC50 ) 13 µM), and CH2Et
(3, EC50 ) 16 µM). The inactive compounds contained
CH2-piperidyl, CH2SO2CH3, CH2CH(OCH3)2, NHCOCH3,
and CH2COOCH2CH(CH3)2 end groups. From this list
it is apparent that the most active compounds all have
carbonyl groups in the same location. These carbonyl
groups are present in ester, amide, or carbamate
functional groups, and it is proposed that they might
act as hydrogen bond acceptors from the backbone
amide of Lys101 of reverse transcriptase (Figure 1).13,19
In Figure 1, the originally proposed bifurcated hydrogen
bond involving the side chain ester carbonyl of ADAM
17 with the terminal amino group of Lys103 and the
backbone NH of Lys101 has been modified to include
bonding between the backbone NH of Lys101 and the
ester carbonyl only, which seems to be more consistent
with the present observation of resilience of ADAMs 15,
17, 19, and 21 to the K103E mutation (Table 3).13,19 As
judged from the activities displayed by 36 and 37, the
thioesters are not as active as the corresponding esters
15 and 19, amide 28, or carbamates 40 and 43. Because
sulfur is not a good electron donor toward the carbonyl
group in a thioester,32,33 the lower activity of the
thioesters is consistent with prior work that demon-
The phenyl analogues 12 and 13 were designed in
order to take advantage of a potential cation π interac-
tion between the protonated Lys103 side chain of the
protein and the phenyl groups at the end of the alkenyl
chain of the ligands (see Figure 1).34 This strategy seems
to have some merit when one compares the activity of
the dichloro compound 12 (EC50 ) 1.2 µM) vs the
alkenyl compound 3 (EC50 ) 16 µM). However, in the
dibromo series 5 (EC50 ) 9.2 µM) and 13 (EC50 ) 13.1
µM), the phenyl group at the end of the chain had
decreased activity. In any case, the activities of these
phenyl analogues indicate a tolerance for steric bulk at
the end of the alkenyl chain.
The sulfoxide 35 and sulfone 36 analogues were
designed in order to place an electron-rich, negatively
charged oxygen in the same location as the carbonyl
oxygens of the highly active esters, amides, and car-
bamates in this series. However, as judged from their
anti-HIV activities, the sulfoxide 35 (EC50 ) 11.7 µM)
and the sulfone 36 (not active) were not good mimics of
the carbonyl groups. In fact, the corresponding sulfide
34 (EC50 ) 5.31 µM) was more active than either
compound. The greater activity of the sulfide 34 in
comparison to the corresponding hydrocarbon 3 (EC50

4098 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Ta ble 2. Antiviral Range of Action
Xu et al.
a
ADAM IC50 (µM)
isolate
cell type
PBLsb
virus
15
17
19
21
TC50 (µM)
IC50 AZTa (µM)
clinical isolates
ROJ O (SI)c
WEJ O (SI)
SLKA NSI)
TEKI (NSI)
0.75
0.6
1.3
0.54
0.4
1
0.39
0.7
0.9
0.2
NDd
1.1
>190
>190
>190
>190
0.001
0.001
0.001
0.002
0.8
0.9
1.0
1.0
subtype isolates
PBLs
A
B
C
D
E
F
G
O
0.1
12.7
0.41
0.18
0.3
1.3
0.6
12
0.2
5.4
0.31
0.18
0.2
1.9
0.3
16
0.2
12.5
0.82
0.15
0.2
0.3
0.8
30
0.2
4.9
0.15
0.03
0.1
0.76
0.4
>180
>200
>200
>200
>170
>200
>170
>170
0.001
0.009
0.004
0.007
0.002
0.002
0.002
0.001
21
monocyte tropic isolate
monocyte
PBLs
Ba-L
MDR769e
5.4
3.6
8.9
4.4
6.3
>200
>172
0.002
0.025
multidrug resistant
16.9
48.8
45.2
a
Concentration required for 50% inhibition of viral replication as determined by measurement of supernatant RT activity in PBMCs
or by ELISA for p24 antigen in monocyte macrophage cell cultures. All data are derived from triplicate tests with the variation of the
b
d
mean averaging 10%. Peripheral blood lymphocytes. c SI: syncytium-inducing. NSI: non-syncytium-inducing. ND: not determined.
e Multidrug-resistant HIV-1 isolate from a highly experienced patient. In vivo engendered resistance to AZT, ddI, 3TC, d4T, foscarnet,
nevirapine, indinavir, saquinavir, and nelfinavir. Primary mutations in the reverse transcriptase gene: M41L, K65R, D67N, V75I, F116Y,
Q151M, Y181I.
) 16 µM) agrees with the general observation that
increasing electron density near the end of the chain
increases activity. The same effect seems to be operating
with the alkenes and alkynes 8-11.
lymphocytes (PBLs) or monocyte/macrophages against
clinical isolates of HIV-1. Therefore, ADAMs 15, 17, 19,
and 21 were evaluated as inhibitors of viral replication
in PBLs and monocytes, as monitored by supernatant
RT activity or p24 antigen, and the results are listed in
Table 2. The ADAMs were significantly less cytotoxic
(10- to 20-fold) to PBLs and primary monocyte/macro-
phages than CEM-SS cells (Table 2). The TC50 was
greater than 170 µM for ADAMs 15, 17, 19, and 21, thus
resulting in significantly better therapeutic indexes for
all compounds. Additionally, the ADAMs were effec-
tive against all HIV-1 isolates tested. This includes
low-passage pediatric clinical isolates with defined
syncytium-inducing (SI) or nonsyncytium-inducing (NSI)
phenotypes and HIV-1 subtype representative viruses.
The ADAMs were least effective against subtype O
viruses. The ADAMs also inhibited the replication of the
monocyte tropic virus Ba-L in primary monocyte/macro-
phages. Thus, in contrast to efficacy determinations in
CEM-SS cells, the ADAMs 15, 17, 19, and 21 are less
cytotoxic on primary lymphocytes and monocyte/mac-
rophages and display antiviral activity against a wide
range of clinically relevant virus isolates.
Activity of th e ADAMs a ga in st Vir u ses Exp r ess-
in g HIV Resista n ce Mu ta tion s. The ADAMs 15, 17,
19, and 21 were tested in CEM-SS cells using viruses
with specific reverse transcriptase resistance mutations
placed in the molecular clone NL4-3 by site mutagen-
esis. The anti-HIV-1 activities of the compounds were
determined by monitoring inhibition of the cytopathic
effect of the virus or p24 expression, depending on the
replication competency of the virus. Antiviral effects of
the ADAMs on the A98G, K103E, L74V, 4XAZT/L100I,
and 4XAZT mutants were measured with p24 levels,
while effects on the other mutants were determined by
inhibition of the cytopathic effect. The 4XAZT virus
contains the mutations D67N, K70R, T215Y, and K219Q.
The NL4-3 replication was measured by both methods
and gave IC50 values within 2-fold of each other. Thus,
for NL4-3 sensitivity calculations, an average of the p24
and cytopathic effect IC50 values were used.
Effects on Rever se Tr a n scr ip tion . With regard to
the HIV-1 reverse transcriptase inhibitory activities
reported in Table 1, it is obvious that there is not a
perfect correlation between the anti-HIV-1 EC50 values
and the reverse transcriptase IC50 values. For example,
the IC50 values observed for the more potent anti-HIV-1
agents in the series, including 15-17 and 19-21, are
significantly higher than their EC50 values. However,
this difference is not unusual for the non-nucleoside
reverse transcriptase inhibitors.35-38 The reverse tran-
scriptase inhibition studies were performed in a cell-
free system with recombinant purified enzyme and a
synthetic homopolymeric 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.37 Although,
generally speaking, the compounds with submicromolar
EC50 values also have submicromolar IC50 values, there
are obvious exceptions provided by compounds 25, 41-
43, and 48. In the case of 25, it is unlikely that
inhibition of RT is responsible for the antiviral activity.
However, the prior work with ADAM-resistant HIV-1
strains having mutations in reverse transcriptase has
established that in general the ADAMs are in fact acting
as non-nucleoside reverse transcriptase inhibitors.11,13,14
Furthermore, a number of the ADAMs have displayed
inactivity or very low activity when tested against a
number of other potential antiviral targets, including
HIV-1 integrase, protease, nucleocapsid p7 protein,
virion attachment, and syncytia formation.11,13
Ra n ge of An tivir a l Action . We selected ADAMs 15,
17, 19, and 21 for further analysis because of their
efficacy in the cytoprotection assay and against HIV RT.
Anti-HIV-1 and reverse transcriptase activity has al-
ready been reported for ADAMs 1513 and 17,39 but they
have not been assessed for activity in peripheral blood
The IC50 values for the anti-HIV-1 effects of the
compounds against the panel of mutant viruses are

Alkenyldiarylmethane Series of Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4099
Ta ble 3. Antiviral Activity [IC50 (µM) (Fold Resistance vs Wild Type)] of ADAMs 15, 17, 19, and 21 Against a Site-Directed Panel of
Resistant Isolates in CEM Cellsa
mutation
L74V
A98G
L100I
K101E
K103N
V106A
V179D
AZT
nevirapine
ADAM 15
ADAM 17
0.284
ADAM 19
ADAM 21
0.04
0.061
0.469
0.31
0.408
0.366
0.6
>20(>23)
1.3
0.885
0.352
0.008
0.222 (7.6)
0.18 (6.2)
0.005 (-5.8)b
1.44 (49.6)
1.88(65)
0.46
0.013 (-44.6)b
0.08 (-7.2)b
0.164
0.015 (-29)b
0.015 (-29)b
0.957
0.006 (-2.8)b
0.046 (2.7)b
0.007 (-2.4)b
0.014
0.084 (-4.7)b
0.594
0.35
0.27
10.3 (17.8)
2.3 (4)
19.1 (33)
4.1 (7)
0.46
9.84 (24)
1.3 (3.2)
8.3 (21)
2 (5)
7.02 (15.9)
2.5 (5.7)
4.4 (10)
1.8 (4)
0.02
0.07
Y181C
Y188C
0.08 (4.7)
0.087 (5)
0.87 (51)
0.082 (4.8)
0.017
8.27 (285)
8.3 (286)
0.207 (7.1)
0.008 (-3.6)b
0.029
>20(>23)
3.3 (3.9)
0.49
4X AZT +L100Ic
4X AZTc
NL4-3 WTd
0.32
0.37
0.37
0.075 (-11)b
0.85
0.032 (-12.5)b
0.40
0.076 (-7.6)b
0.58
0.07 (-6.3)b
0.44
a
Antiviral effects on the A98G, K103E, L74V, 4XAZT/L101I, and 4XAZT mutants were measured with p24 levels, while effects on the
other mutants were determined by inhibition of the cytopathic effect. All data are derived from triplicate tests with the variation of the
b
d
mean averaging 10%. Enhanced sensitivity. c AZT-resistant. Wild-type enzyme.
F igu r e 2. Non-nucleoside reverse transcriptase inhibitor (MMRTI) binding site. Mutation of the yellow residues results in
resistance to three or more of the ADAMs 15, 17, 19, and 21, while mutation of the red residues results in increased sensitivity
to two or more of the ADAMs 15, 17, 19, and 21. The figure is programmed for walleyed viewing.
listed in Table 3. The resistance mutations to all four
of the ADAMs include V106A, Y181C, and Y188C. Al-
though the Y181C mutation, a nevirapine, and NNRTI
resistance mutation engendered a 10-fold resistance to
ADAM 21, this resistance was significantly less than
that seen with ADAMs 15, 17, or 19, and ADAM 21 was
28-fold less resistant than nevirapine in the presence
of this mutation. The V179D mutation conferred slight
resistance to ADAMs 17, 19, and 21 but not to ADAM
15. On the other hand, increased sensitivity to the
antiviral effects of ADAMs 19 and 21, but not ADAMs
15 and 17, was seen with the A98G mutation. Similarly,
the L100I mutation conferred increased sensitivity to
the antiviral effects of ADAMs 17, 19, and 21 but not
ADAM 15. In some cases, the increase in sensitivity
seen with the A98G and L100I mutations was large.
Examples are the 45-fold increase in sensitivity seen
with ADAM 19 vs that of the A98G mutant, and the
29-fold increase in sensitivity seen with ADAM 21 vs
that of the A98G mutant. The L100I mutation caused
a 29-fold increase in sensitivity to ADAM 21. Signifi-
cantly, the AZT-resistant virus 4X AZT showed in-
creased sensitivity to all four ADAMs, suggesting their
possible use against AZT-resistant HIV-1 infections. The
ADAMs retained activity against K101E.
Table 3 also lists the effects of the resistance muta-
tions on the activity of nevirapine, a non-nucleoside
reverse transcriptase inhibitor that is presently used
in combination with other anti-HIV agents for the
treatment of AIDS.3,40 Several of the mutations confer-
ring nevirapine resistance did not affect sensitivity to
the ADAMs. Examples include the A98G mutation vs
ADAM 17, the K103N mutation vs all four ADAMs, and
the L100I mutation vs ADAM 15. The activity of the
ADAMs vs the K103N mutant is noteworthy because
K103N is the primary mutation found in vivo to be
resistant to the NNRTIs, and it confers cross-resistance
among nevirapine, delavirdine, and efaviranz.41 In the
case of the Y188C mutation, the degree of resistance vs
the ADAMs was much less than that seen with nevi-
rapine. A number of the nevirapine resistance muta-
tions conferred increased sensitivity to the ADAMs.
These included the A98G mutation vs ADAMs 19 and
21 and the L100I mutation vs ADAMs 17, 19, and 21.

4100 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Xu et al.
EtOAc. The eluent was removed in vacuo to give the crude
product. Purification of the crude product by flash column
chromatography on silica gel (20 mL), using a gradient of
0-4% EtOAc in hexanes as the eluent yielded pure 2 as a
slightly yellow oil (0.373 g, 66%): IR (neat on NaCl) 2953,
2858, 1732, 1613, 1574, 1493, 1436, 1420, 1373, 1260, 1201,
1168, 1112, 1004, 884, 793, 774, 677, 650 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.35 (m, 2 H), 7.02 (m, 2 H), 6.07 (t, J ) 7.5
Hz, 1 H), 4.03 (s, 3 H), 3.96 (s, 3 H), 3.90 (s, 6 H), 2.08 (m, 2
H), 1.43 (m, 2 H), 1.26 (m, 4 H), 0.87 (t, J ) 6.9 Hz, 3 H).
Anal. (C25H28F2O6) C, H.
These effects are significant because one of the strate-
gies for dealing with NNRTI resistance to a particular
agent is to switch to another NNRTI that remains
effective against the virus, or even has enhanced activity
resulting from the mutation.42,43 All four of the ADAMs,
as well as nevirapine and AZT, also remained active in
the presence of the L74V mutation, which confers
resistance to ddI and abacavir.44-48
Figure 2, which was obtained by erasing nevirapine
from the crystal structure of the nevirapine/RT complex,
shows the amino acid residues in the p66 subunit
surrounding the NNRTI binding pocket.49 Mutation of
the yellow residues results in resistance to three or more
of the ADAMs 15, 17, 19, or 21, while mutation of the
red residues results in increased sensitivity to two or
more of the ADAMs 15, 17, 19, or 21. Taken together,
the yellow and red residues shown in Figure 2 depict a
constellation of amino acid residues that are likely to
be involved in ADAM binding, and they surround a well-
defined cavity that constitutes the ADAM binding site.
In vivo resistance to antiviral species is often engen-
dered through a number of key mutations, along with
secondary mutations that may or may not alter com-
pound sensitivity. To verify that the ADAMs would be
effective against nevirapine- and AZT-resistant viruses,
we obtained a clinical isolate expressing resistance to
nevirapine and AZT. This isolate is multidrug-resistant,
expressing additional resistance to the reverse tran-
scriptase enzyme inhibitors ddI, 3TC, d4T, and foscar-
net, as well as the protease inhibitors indinavir,
saquinavir, and nelfinavir. Table 2 shows that all four
lead ADAMs were active against this multidrug-
resistant virus in the presence of a 12-fold reduction in
sensitivity to AZT and a >20-fold reduction in sensitiv-
ity to nevirapine (data not shown). Thus, the ADAMs
represent a new class of NNRTIs with activity against
viruses that arises from in vivo therapeutic failure.
4′,4′′-Dim et h oxy-3′,3′′-d i(m et h oxyca r b on yl)-5′,5′′-d i-
m eth yl-1,1-d ip h en yl-1-h ep ten e (4). TiCl4/THF 1:2 complex
(4.32 g, 12.9 mmol) and zinc dust (1.69 g, 25.9 mmol) were
suspended in THF (43 mL) under an argon atmosphere, and
the resulting mixture was heated under reflux for 1 h. Di(4-
methoxy-3-methoxycarbonyl-5-methylphenyl) ketone (54, 1.00
g, 2.59 mmol) and hexanal (0.47 mL, 3.91 mmol) were taken
up in THF (43 mL) and added in one portion via cannula under
argon pressure to the refluxing mixture. TLC (SiO2,EtOAc/
hexanes, 1:1) showed the reaction to be complete in 30 min.
The reaction mixture was cooled to ambient temperature, and
silica gel (15 g) was added to the reaction mixture. The slurry
was transferred to a chromatography column containing silica
gel (25 g), and the inorganic salts were filtered off by elution
of the product mixture with EtOAc. The eluent was removed
to give the crude product. Purification of the crude product by
flash column chromatography on silica gel (50 g), using a
gradient of 0-7.5% EtOAc in hexanes as the eluent yielded
pure 4 as a colorless oil (1.03 g, 87%): IR (neat on NaCl) 2953,
2930, 2857, 1731, 1600, 1577, 1481, 1437, 1379, 1365, 1298,
1259, 1227, 1195, 1173, 1143, 1122, 1040, 1011, 887, 800, 737
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.46 (d, J ) 2.0 Hz, 1 H),
7.42 (d, J ) 1.9 Hz, 1 H), 7.10 (s, 2 H), 5.99 (t, J ) 7.3 Hz, 1
H), 3.90 (s, 6 H), 3.87 (s, 3 H), 3.81 (s, 3 H), 2.31 (s, 3 H), 2.25
(s, 3 H), 2.07 (q, J ) 7.3 Hz, 2 H), 1.42 (m, 2 H), 1.27 (m, 4 H),
0.87 (t, J ) 6.8 Hz, 3 H). Anal. (C27H34O6) C, H.
3′,3′′-Bis(m eth oxyca r bon yl)-5′,5′′-bis(tr iflu or om eth yl)-
4)′,4′′-d im eth oxy-1,1-d ip h en yl-1-h ep ten e (7). TiCl4/THF 1:2
complex (0.392 g, 1.17 mmol) and Zn dust (0.153 g, 2.34 mmol)
were suspended with stirring in THF (5 mL). The mixture was
heated under reflux in an oil bath for 1 h. Di[4-methoxy-3-
methoxycarbonyl-5-(trifluoromethyl)phenyl] ketone (57, 0.116
g, 0.235 mmol) and hexanal (0.035 g, 0.35 mmol) were
dissolved in THF (5 mL) and were added in one portion to the
TiCl4/Zn mixture. The reaction mixture was heated under
reflux for 1 h, at which time TLC (SiO2, EtOAc/hexanes, 1:1)
verified that the reaction was complete. The reaction mixture
was cooled to ambient temperature, and silica gel (2.5 g) was
added to the stirring reaction mixture. The slurry was
transferred to a chromatography column containing silica gel
(10 g). The inorganic salts were filtered off by elution of the
product with EtOAc. The eluent was removed on a rotary
evaporator to give the crude product. Purification of the crude
product by flash column chromatography on silica gel (10 g),
using a gradient of 0-10% EtOAc in hexanes as the eluent
afforded the pure product as a slightly yellow oil (0.069 g,
52%): IR (neat on NaCl) 3002, 2962, 2878, 1732, 1607, 1582,
1486, 1434, 1347, 1300, 1252, 1130, 1096, 999, 918, 858, 811,
Exp er im en ta l Section
Melting points were determined in capillary tubes and are
1
uncorrected. H NMR spectra were determined at 200 or 300
MHz. 13C NMR spectra were obtained at 75 MHz. 19F NMR
spectra were recorded at 282 MHz using trifluoroacetic acid
in DMSO as the external standard. Chemical ionization mass
spectra (CIMS) were determined using isobutane as the
reagent gas. Microanalyses were performed at the Purdue
University Microanalysis Laboratory. Silica gel flash chroma-
tography was performed using 230-400 mesh silica gel. Unless
otherwise stated, chemicals and solvents were reagent grade
and were used as obtained from commercial sources without
further purification. Tetrahydrofuran was freshly distilled
from sodium/benzophenone ketyl radical prior to use. Com-
pounds 1, 3, 5, 6, 15, and 17 were synthesized as previously
described.11,13,14
1
768, 707, 677 cm-1; H NMR (300 MHz, C6D6) δ 7.94 (d, J )
2.1 Hz, 1 H), 7.91 (d, J ) 2.5 Hz, 1 H), 7.70 (d, J ) 2.4 Hz, 1
H), 7.67 (d, J ) 1.5 Hz, 1 H), 5.83 (d, J ) 7.6 Hz, 1 H), 3.64 (s,
3 H), 3.62 (s, 3 H), 3.30 (s, 3 H), 3.28 (s, 3 H), 1.88, (dt, J )
7.3, 7.7 Hz, 2 H), 1.27 (m, 6 H), 0.83 (t, J ) 6.9 Hz, 3 H); 19F
NMR (282 MHz, C6D6, rel to TFA external standard) δ 13.73
(s, 3 F), 13.67 (s, 3 F). Anal. (C27H28F6O6) C, H.
1,1-Bis[3-ch lor o-4-m eth oxy-5-(m eth oxyca r bon yl)p h en -
yl]h ep t-1-en -6-yn e (8). TiCl4/THF 1:2 complex (1.1282 g,
3.378 mmol) was added to a dry two-necked flask, under an
argon atmosphere, equipped with a condensor, magnetic stir
bar, and a rubber septum. Zinc dust (0.4130 g, 6.3179 mmol)
was then added to the flask. The solids where suspended in
dry THF (25 mL). The suspension was heated at reflux for 2
h. A solution of 3,3′-dichloro-4,4′-dimethoxy-5,5′-bis(methoxy-
3′,3′′-Diflu or o-4′,4′′-d im et h oxy-5′,5′′-b is(m et h oxyca r -
bon yl)-1,1-d ip h en yl-1-h ep ten e (2). TiCl4/THF 1:2 complex
(2.05 g, 6.15 mmol) and zinc dust (0.804 g, 12.3 mmol) were
heated at reflux in THF (20 mL) under an argon atmosphere
for 1 h. Di[3-fluoro-4-methoxy-5-(methoxycarbonyl)phenyl]
ketone (52, 0.486 g, 1.23 mmol) and hexanal (0.22 mL, 1.85
mmol) were taken up in THF (20 mL) and were added in one
portion via cannula under argon pressure to the refluxing
mixture. TLC (SiO2, EtOAc/hexanes, 1:1) showed the reaction
to be complete in 30 min. The reaction mixture was cooled to
ambient temperature, and silica gel (10 g) was added to the
reaction mixture. The slurry was transferred to a chromatog-
raphy column containing silica gel (80 mL), and the inorganic
salts were filtered off by elution of the product mixture with

Alkenyldiarylmethane Series of Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4101
carbonyl)benzophenone (53) (0.4438 g, 1.053 mmol) and 5-hexyn-
1-al (64) (0.1967 g, 2.046 mmol) in dry THF (20 mL) was
transferred via cannula under an argon atmosphere to the
titanium suspension. The resulting suspension was heated at
reflux for 1.5 h. The suspension was then cooled to ambient
temperature, and 0.5 M HCl (50 mL) was added. The reaction
solution was stirred at ambient temperature overnight. The
reaction solution was then poured into a separatory funnel,
and the aqueous and organic layers were separated. The
aqueous layer was extracted with ethyl acetate (3 × 30 mL).
The combined organic extracts were washed with brine (50
mL) and dried over anhydrous magnesium sulfate. Solvents
were removed in vacuo, yielding a yellow oil. The crude oil
was purified by flash chromatography using silica (75 g, 3 cm
× 30 cm), with a gradient eluent from 10 to 12.5% ethyl acetate
in hexanes. Like fractions were combined and solvent was
removed in vacuo to yield 8 as an amorphous solid (0.130 g,
25.0%). 3′,3′′-Dichloro-4′,4′′-dimethoxy-5′,5′′-bis(methoxycar-
bonyl)-1,1-diphenyl-1,6-heptadiene (10) was also obtained after
chromatography as a side product (0.010 g, 2%). ADAM 8: IR
(film) 3303.5, 2950.3, 1732.8, 1596.1, 1557.7, 1476.9, 1435.7,
1402.0, 1287.2, 1261.0, 1208.7, 998.6 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.48 (d, J ) 2.38 Hz, 1 H), 7.45 (d, J ) 2.19 Hz, 1 H),
7.32 (d, J ) 2.18 Hz, 1 H), 7.28 (d, J ) 2.38 Hz, 1 H), 6.04 (t,
J ) 7.54 Hz, 1 H), 3.97 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H),
3.88 (s, 3 H), 2.23-2.15 (m, 4 H), 1.90 (t, J ) 2.62 Hz, 1 H),
1.66 (dt, J ) 7.05 Hz, J ) 7.15 Hz, 2 H); CIMS m/z 490.92
(MH+), 458.88 (MH+ - MeOH). Anal. (C25H24Cl2O6) C, H.
1,1-Bis[3-br om o-4-m eth oxy-5-(m eth oxyca r bon yl)p h en -
yl]h ep t-1-en -6-yn e (9). TiCl4/THF 1:2 complex (0.9861 g,
2.953 mmol) was added to a dry two-necked flask, under an
argon atmosphere, equipped with a condensor, magnetic stir
bar, and a rubber septum. Zinc dust (0.4093 g, 6.2613 mmol)
was then added to the flask. The solids where suspended in
dry THF (20 mL). The suspension was heated at reflux for 3
h. A solution of 3,3′-dibromo-4,4′-dimethoxy-5,5′-bis(methoxy-
carbonyl)benzophenone (55) (0.2984 g, 0.5781 mmol) and
5-hexyn-1-al (64) (0.1747 g, 1.8172 mmol) in dry THF (20 mL)
was transferred via cannula under an argon atmosphere to
the titanium suspension. The resulting suspension was heated
at reflux for 2 h. The suspension was cooled to ambient
temperature, and 0.5 M HCl (50 mL) was added. The reaction
solution was stirred at ambient temperature overnight. The
reaction solution was then poured into a separatory funnel,
and the aqueous and organic layers were separated. The
aqueous layer was extracted with ethyl acetate (3 × 50 mL).
The combined organic extracts were washed with brine (50
mL) and dried over anhydrous magnesium sulfate. Solvents
were removed in vacuo, yielding a yellow oil. The crude oil
was purified by flash chromatography using silica (50 g, 3 cm
× 15 cm), with a gradient eluent from 0 to 12% ethyl acetate
in hexanes. Like fractions were combined and solvent was
removed in vacuo to yield 9 as an amorphous solid (0.0899 g,
27%). 3′,3′′-Dibromo-4′,4′′-dimethoxy-5′,5′′-bis(methoxycar-
bonyl)-1,1-diphenyl-1,6-heptadiene (11) was also obtained after
chromatography as a side product (0.0176 g, 5%). ADAM 9:
IR (film) 3299.7, 3000.0, 2949.6, 2865.1, 2117.4, 1731.7, 1714.7,
1594.2, 1548.1, 1471.6, 1434.7, 1260.5, 1208.8, 998.1 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.52-7.45 (m, 4 H), 6.03 (t, J )
7.64 Hz, 1 H), 3.96 (s, 3 H), 3.92 (s, 3 H), 3.90 (s, 3 H), 3.89 (s,
3 H), 2.28-2.16 (m, 4 H), 1.92 (t, J ) 2.28 Hz, 1 H), 1.70-1.61
(m, 2 H); ESIMS m/z 601 (MNa+). Anal. (C25H24Br2O6) C, H.
suspension was heated at reflux for 1.5 h. The suspension was
then cooled to ambient temperature, and 0.5 M HCl (20 mL)
was added. The reaction solution was stirred at ambient
temperature overnight. The reaction solution was then poured
into a separatory funnel, and the aqueous and organic layers
were separated. The aqueous layer was extracted with ethyl
acetate (3 × 30 mL). The combined organic extracts were
washed with brine (50 mL) and dried over anhydrous magne-
sium sulfate. Solvents were removed in vacuo, yielding a
yellow oil. The crude oil was purified by flash chromatography
using silica (40 g, 2 cm × 30 cm), with a 4:1 hexane/ethyl
acetate eluent. Like fractions were combined and solvent was
removed in vacuo to yield a colorless oil that crystallized upon
standing to a white solid (0.1349 g, 33.16%): mp 89-90 °C;
IR (film) 2934.6, 1735.8, 1476.8, 1436.1, 1261.1, 998.5 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.50 (d, J ) 2.41 Hz, 1 H), 7.47
(d, J ) 2.19 Hz, 1 H), 7.32 (d, J ) 2.20 Hz, 1 H), 7.30 (d, J )
2.33 Hz, 1 H), 6.07 (t, J ) 7.57 Hz, 1 H), 5.76 (ddt, J ) 6.68
Hz, 10.22 Hz, 16.90 Hz, 1 H), 5.02-4.92 (m, 2 H), 3.99 (s, 3
H), 3.93 (s, 3 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 2.15-2.02 (m, 3
H), 1.60-1.50 (m, 3 H); CIMS m/z 493 (MH+), 461 (MH+
MeOH). Anal. (C25H26Cl2O6) C, H.
-
3′,3′′-Dib r om o-4′,4′′-d im et h oxy-5′,5′′-b is(m et h oxyca r -
bon yl)-1,1-d ip h en yl-1,6-h ep ta d ien e (11). TiCl4/THF 1:2
complex (0.9953 g, 2.980 mmol) was added to a dry two-necked
flask, under an argon atmosphere, equipped with a condensor,
magnetic stir bar, and a rubber septum. Zinc dust (0.3871 g,
5.9216 mmol) was then added to the flask. The solids were
suspended in dry THF (25 mL). The suspension was heated
at reflux for 3 h. A solution of 3,3′-dibromo-4,4′-dimethoxy-
5,5′-bis(methoxycarbonyl)benzophenone (55) (0.3153 g, 0.6108
mmol) and 5-hexen-1-al (65) (0.1337 g, 1.362 mmol) in dry THF
(20 mL) was transferred via cannula under an argon atmo-
sphere to the titanium suspension. The resulting suspension
was heated at reflux for 1.5 h. The suspension was then cooled
to ambient temperature, and 0.5 M HCl (50 mL) was added.
The reaction solution was stirred at ambient temperature
overnight. The reaction solution was then poured into a
separatory funnel, and the aqueous and organic layers were
separated. The aqueous layer was extracted with ethyl acetate
(3 × 30 mL). The combined organic extracts were washed with
brine (50 mL) and dried over anhydrous magnesium sulfate.
Solvents were removed in vacuo, yielding a yellow oil. The
crude oil was purified by flash chromatography using silica
(40 g, 2 × 30 cm), with an 8:1 hexane/ethyl acetate eluent.
Like fractions were combined and solvent was removed in
vacuo to yield a colorless oil (0.1870 g, 52.5%) that crystallized
upon standing to a white solid: mp 87-88 °C; IR (film) 2949.4,
1731.8, 1639.7, 1593.9, 1546.2, 1472.1, 1435.0, 1285.5, 1258.7,
1207.2, 998.1 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J )
2.40 Hz, 1 H), 7.50 (d, J ) 3.05 Hz, 1 H), 7.47 (d, J ) 2.20 Hz,
1 H), 7.46 (d, J ) 2.40 Hz, 1 H), 6.04 (t, J ) 7.53 Hz, 1 H),
5.74 (ddt, J ) 6.73 Hz, 10.28 Hz, 16.83 Hz, 1 H), 4.99-4.91
(m, 2 H), 3.96 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H),
2.13-2.00 (m, 3 H), 1.57-1.48 (m, 3 H); CIMS m/z 580.78
(MH+), 548.84 (MH+ - MeOH). Anal. (C25H26Br2O6) C, H.
1,1-Bis[3-ch lor o-4-m eth oxy-5-(m eth oxyca r bon yl)p h en -
yl]-5-p h en yl-1-p en ten e (12). TiCl4/THF 1:2 complex (0.7064
g, 2.2771 mmol) was added to a dry two-necked flask, under
an argon atmosphere, equipped with a condensor, magnetic
stir bar, and a rubber septum. Zinc dust (0.3021 g, 4.6214
mmol) was then added to the flask. The solids where sus-
pended in dry THF (20 mL). The suspension was heated at
reflux for 2 h. A solution of 3,3′-dichloro-4,4′-dimethoxy-5,5′-
bis(methoxycarbonyl)benzophenone (53) (0.3122 g, 0.7307
mmol) and 4-phenyl-1-butanal (66) (0.2323 g, 1.5674 mmol)
in dry THF (20 mL) was transferred via cannula under an
argon atmosphere to the titanium suspension. The resulting
suspension was heated at reflux for 2 h. The suspension was
then cooled to ambient temperature, and 0.5 M HCl (50 mL)
was added. The reaction solution was stirred at ambient
temperature overnight. The reaction solution was then poured
into a separatory funnel, and the aqueous and organic layers
were separated. The aqueous layer was extracted with ethyl
3′,3′′-Dich lor o-4′,4′′-d im et h oxy-5′,5′′-b is(m et h oxyca r -
bon yl)-1,1-d ip h en yl-1,6-h ep ta d ien e (10). TiCl4/THF 1:2
complex (0.7034 g, 2.1066 mmol) was added to a dry two-
necked flask, under an argon atmosphere, equipped with a
condensor, magnetic stir bar, and a rubber septum. Zinc dust
(0.2754 g, 4.2131 mmol) was then added to the flask. The solids
were suspended in dry THF (20 mL). The suspension was
heated at reflux for 2 h. A solution of 3,3′-dichloro-4,4′-
dimethoxy-5,5′-bis(methoxycarbonyl)benzophenone (53) (0.300
g, 0.702 mmol) and 5-hexen-1-al (65) (0.1575 g, 1.6044 mmol)
in dry THF (20 mL) was transferred via cannula under an
argon atmosphere to the titanium suspension. The resulting

4102 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Xu et al.
acetate (3 × 50 mL). The combined organic extracts were
washed with brine (50 mL) and dried over anhydrous magne-
sium sulfate. Solvents were removed in vacuo, yielding a
yellow oil. The crude oil was purified by flash chromatography
using silica (50 g, 2 cm × 29 cm), with a gradient eluent from
0 to 16% ethyl acetate in hexanes. Like fractions were
combined and solvent was removed in vacuo to yield an
amorphous solid (0.2312 g, 58.22%): IR (film) 3060.9, 3026.9,
2949.5, 2856.5, 1732.1, 1596.2, 1557.4, 1477.2, 1454.0, 1435.7,
1287.5, 1260.0, 1207.9, 999.0 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.46-7.44 (m, 2 H), 7.29-7.09 (m, 7 H), 6.05 (t, J ) 7.51
Hz, 1 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H),
2.59 (t, J ) 7.43 Hz, 2 H), 2.15-2.08 (m, 2 H), 1.80-1.73 (m,
2 H); ESIMS m/z 565 (MNa+). Anal. (C29H28Cl2O6) C, H.
) 7.5 Hz, 2 H); 19F NMR (282 MHz, CDCl3, rel to TFA external
standard) δ -13.5 (d, J ) 11.3 Hz, 1 F), -13.9 (d, J ) 12.2
Hz, 1 F). Anal. (C25H26F2O8) C, H.
Met h yl 4′,4′′-Dim et h oxy-3′,3′′-d i(m et h oxyca r b on yl)-
5′,5′′-d im eth yl-6,6-d ip h en yl-5-h exen oa te (16). TiCl4/THF
1:2 complex (1.75 g, 5.25 mmol) and zinc dust (0.686 g, 10.5
mmol) were suspended in THF (17 mL) under an argon
atmosphere, and the resulting mixture was heated under
reflux for 1 h. Di(4-methoxy-3-methoxycarbonyl-5-methyl-
phenyl) ketone (54, 0.404 g, 1.05 mmol) and methyl 5-oxo-
pentanoate27 (67, 0.204 g, 1.6 mmol) were taken up in THF
(17 mL) and were added in one portion via cannula under
argon pressure to the refluxing mixture. After 45 min, the
reaction mixture was cooled to ambient temperature and silica
gel (5 g) was added. The slurry was transferred to a chroma-
tography column containing silica gel (25 g), and the inorganic
salts were filtered off by elution of the product mixture with
EtOAc. The eluent was removed in vacuo to give the crude
product. Flash column chromatography on silica gel (25 g),
using a gradient of 0-15% EtOAc in hexanes as the eluent
afforded the pure product as a thick, slightly yellow oil (0.250
g, 49%): IR (neat on NaCl) 2951, 1732, 1601, 1481, 1436, 1367,
1,1-Bis[3-br om o-4-m eth oxy-5-(m eth oxyca r bon yl)p h en -
yl]-5-p h en yl-1-p en ten e (13). TiCl4/THF 1:2 complex (0.9344
g, 2.7982 mmol) was added to a dry two-necked flask, under
an argon atmosphere, equipped with a condensor, magnetic
stir bar, and a rubber septum. Zinc dust (0.4040 g, 6.1802
mmol) was then added to the flask. The solids where sus-
pended in dry THF (20 mL). The suspension was heated at
reflux for 3 h. A solution of 3,3′-dibromo-4,4′-dimethoxy-5,5′-
bis(methoxycarbonyl)benzophenone (55) (0.3157 g, 0.6116
mmol) and 4-phenyl-1-butanal (66) (0.1874 g, 1.2645 mmol)
in dry THF (20 mL) was transferred via cannula under an
argon atmosphere to the titanium suspension. The resulting
suspension was heated at reflux for 2 h. The suspension was
cooled to ambient temperature, and 0.5 M HCl (50 mL) was
added. The reaction solution was stirred at ambient temper-
ature overnight. The reaction solution was then poured into a
separatory funnel, and the aqueous and organic layers were
separated. The aqueous layer was extracted with ethyl acetate
(3 × 50 mL). The combined organic extracts were washed with
brine (50 mL) and dried over anhydrous magnesium sulfate.
Solvents were removed in vacuo, yielding a yellow oil. The
crude oil was purified by flash column chromatography using
silica (50 g, 3 cm × 18 cm), with a gradient eluent from 0 to
10% ethyl acetate in hexanes. Like fractions were combined
and solvent was removed in vacuo to yield an amorphous solid
(0.2485 g, 64%): IR (film) 3001.9, 2947.7, 2860.3, 1733.3,
1594.6, 1542.3, 1473.6, 1435.5, 1285.4, 1258.4, 1206.1, 998.2
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.49-7.42 (m, 4 H), 7.26-
7.09 (m, 5 H), 6.04 (t, J ) 7.48 Hz, 1 H), 3.96 (s, 3 H), 3.90 (s,
3 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 2.59 (t, J ) 7.51 Hz, 2 H),
2.15-2.07 (m, 2 H), 1.81-1.73 (m, 2 H). ESIMS m/z 653
(MNa+). Anal. (C29H28Br2O6) C, H, Br.
1
1299, 1257, 1228, 1197, 1173, 1135, 1009, 883, 802 cm-1; H
NMR (200 MHz, CDCl3) δ 7.46 (d, J ) 2.5 Hz, 1 H), 7.41 (d, J
) 2.3 Hz, 1 H), 7.09 (d, J ) 2.3 Hz, 2 H), 5.96 (t, J ) 7.4 Hz,
1 H), 3.90 (s, 6 H), 3.88 (s, 3 H) 3.81 (s, 3 H), 3.63 (s, 3 H),
2.36-2.30 (m, 2 H), 2.32 (s, 3 H), 2.25 (s, 3 H), 2.13 (m, 2 H),
1.77 (m, 2 H). Anal. (C27H32O8) C, H.
Meth yl 3′,3′′-Di(m eth oxyca r bon yl)-5′,5′′-bis(tr iflu or o-
m eth yl)-4′,4′′-d im eth oxy-6,6-d ip h en yl-5-h exen oa te (18).
TiCl4/THF 1:2 complex (2.09 g, 6.25 mmol) and zinc dust (0.817
g, 12.5 mmol) were suspended with stirring in THF (30 mL)
under an atmosphere of argon. The resulting mixture was
heated under reflux in an oil bath for 1.5 h. Di[4-methoxy-3-
methoxycarbonyl-5-(trifluoromethyl)phenyl] ketone (57, 0.640
g, 1.25 mmol) and methyl 5-oxopentanoate27 (67, 0.244 g, 1.88
mmol) were taken up in THF (30 mL), and the resulting
mixture was added in one portion to the TiCl4/Zn mixture. The
reaction mixture was heated under reflux for 1 h, at which
time TLC (SiO2, EtOAc/hexanes, 1:1) verified that the reaction
was complete. The reaction mixture was cooled to ambient
temperature, and silica gel (7 g) was added to the stirring
reaction mixture. The resulting slurry was transferred to a
chromatography column containing silica gel (50 g). The
inorganic salts were filtered off by elution of the product with
EtOAc. The eluent was removed on a rotary evaporator to give
the crude product. Purification of the crude product by flash
column chromatography on silica gel (50 g), using a gradient
of 0-16% EtOAc in hexanes as the eluent afforded the pure
product as a colorless oil (0.356 g, 48%): IR (neat on NaCl)
2954, 2844, 1737, 1582, 1485, 1437, 1290, 1263, 1207, 1135,
999 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J ) 2.3 Hz, 1
H), 7.72 (d, J ) 2.3 Hz, 1 H), 7.51 (m, 2 H), 6.09 (t, J ) 7.4 Hz,
1 H), 3.97 (s, 3 H), 3.95 (s, 3 H), 3.92 (s, 3 H), 3.90 (s, 3 H),
3.62 (s, 3 H), 2.31 (t, J ) 7.4 Hz, 2 H), 2.13 (m, 2 H), 1.79 (m,
2 H); 19F NMR (282 MHz, CDCl3, rel to TFA external standard)
δ 13.38 (s, 3 F), 13.32 (s, 3 F). Anal. (C27H26F6O8) C, H.
Eth yl 3′,3′′-Dich lor o-4′,4′′-d im eth oxy-5′,5′′-bis(m eth oxy-
ca r bon yl)-6,6-d ip h en ylh exen oa te (19). A mixture of TiCl4/
THF 1:2 complex (1.0 g, 3.0 mmol) and Zn powder (0.39 g, 6.0
mmol) in dry THF (30 mL) was heated under reflux for 1.5 h
under nitrogen. A solution of benzophenone 53 (0.43 g, 1.0
mmol) and aldehyde 69 (0.20 g, 1.5 mmol) in dry THF (15 mL)
was added. The reaction mixture was stirred at room temper-
ature for 1 h and then heated under reflux for 3 h. The mixture
was allowed to cool, and 10% aqueous potassium carbonate
(25 mL) was added. The resulting mixture was stirred at room
temperature overnight, then filtered through a Celite pad, and
washed with ethyl acetate (3 × 30 mL). The organic solvents
were evaporated, and the crude residue was purified by silica
gel flash chromatography (hexanes/EtOAc 3:1, v/v) to afford a
colorless liquid (220 mg, 40.8%): 1H NMR (CDCl3) δ 7.46 (d,
J ) 2.31 Hz, 1 H), 7.43 (d, J ) 2.16 Hz, 1 H), 7.28 (d, J ) 2.23
Hz, 1 H), 7.26 (d, J ) 2.28 Hz, 1 H), 6.01 (t, J ) 7.46 Hz, 1 H),
Meth yl 3′,3′′-Diflu or o-4′,4′′-dim eth oxy-5′,5′′-bis(m eth oxy-
ca r bon yl)-6,6-d ip h en yl-5-h exen oa te (14). TiCl4/THF 1:2
complex (1.64 g, 4.9 mmol) and zinc dust (0.641 g, 9.8 mmol)
were heated under reflux in THF (16 mL) under an argon
atmosphere for 1 h. Di[3-fluoro-4-methoxy-5-(methoxycarbon-
yl)phenyl] ketone (52, 0.387 g, 0.98 mmol) and methyl 5-oxo-
pentanoate27 (67, 0.255 g, 2.0 mmol) were taken up in THF
(16 mL) and were added in one portion via cannula under
argon pressure to the refluxing mixture. TLC (SiO2, EtOAc/
hexanes, 1:1) showed the reaction to be complete in 45 min.
The reaction mixture was cooled to ambient temperature, and
silica gel (10 g) was added to the reaction mixture. The slurry
was transferred to a chromatography column containing silica
gel (40 g), and the inorganic salts were filtered off by elution
of the product mixture with EtOAc. The eluent was removed
in vacuo to give the crude product. The crude product was
purified by flash column chromatography on silica gel (10 g),
using a gradient of 0-18% EtOAc in hexanes as the eluent.
Evaporation of the eluent yielded the pure product as a slightly
yellow oil that crystallized on cooling in a freezer (-10 °C) to
give a slightly yellow solid (0.220 g, 46%): mp 54-56 °C; IR
(KBr pellet) 2956, 1734, 1708, 1492, 1438, 1347, 1307, 1267,
1
1199, 993, 878, 788, 773 cm-1; H NMR (300 MHz, CDCl3) δ
7.37 (d, J ) 2.3 Hz, 1 H), 7.31 (d, J ) 2.1 Hz, 1 H), 7.03 (dd,
J H-H ) 2.1 Hz, J H-F ) 9.7 Hz, 1 H), 6.99 (dd, J H-H ) 2.3 Hz,
J H-F ) 11.2 Hz, 1 H), 6.04 (t, J ) 7.4 Hz, 1 H), 4.15 (s, 3 H),
4.04 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.64 (s, 3 H), 2.31 (t,
J ) 7.4 Hz, 2 H), 2.14 (dt app q, J ) 7.4 Hz, 2 H), 1.78 (m, J

Alkenyldiarylmethane Series of Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4103
4.05 (q, J ) 7.16 Hz, 2 H), 3.95 (s, 3 H), 3.88 (s, 3 H), 3.87 (s,
3 H), 3.86 (s, 3 H), 2.29 (t, J ) 7.26 Hz, 2 H), 2.09 (m, 2 H),
1.76 (m, 2 H), 1.18 (t, J ) 7.13 Hz, 3 H); 13C NMR (CDCl3) δ
173.07, 165.73, 165.43, 155.03, 154.73, 138.31, 137.87, 135.20,
134.93, 132.38, 132.03, 130.94, 129.72, 129.42, 128.02, 126.81,
126.63, 61.92, 60.26, 52.44, 33.58, 29.11, 24.69, 14.11; CIMS
m/z (relative intensity) 540 (MH+, 100), 508 (M+ - OCH3, 78).
Anal. (C26H28Cl2O8) C, H.
2 H), 2.14 (dt, J ) 7.40 and 7.34 Hz, 2 H), 1.77 (m, 2 H), 1.60
(m, 2 H), 0.90 (t, J ) 7.42 Hz, 3 H); 13C NMR (CDCl3) δ 173.20,
165.72, 165.38, 154.99, 154.69, 138.27, 137.75, 135.15, 134.89,
132.37, 131.97, 130.88, 129.68, 129.38, 127.98, 126.73, 126.56,
65.92, 61.91, 52.42, 33.57, 29.09, 24.69, 21.82, 10.23; EIMS
m/z 553 (M+); HRMS calcd for C27H29Cl2O8 (M - H)+ 552.1318,
found 552.1306. Anal. (C27H30Cl2O8) C, H, Cl.
P r opyl 3′,3′′-Dim eth yl-4′,4′′-dim eth oxy-5′,5′′-bis(m eth oxy-
ca r bon yl)-6,6-d ip h en yl-5-h exen oa te (23). A mixture of
TiCl4/THF 1:2 complex (1.04 g, 3.1 mmol) and Zn dust (405
mg, 6.2 mmol) was slurried in dry THF (10 mL) under argon.
After 1 h of reflux, the black mixture was cooled and a solution
of benzophenone 54 (386 mg, 1.0 mmol) and aldehyde 70 (237
mg, 1.5 mmol) in dry THF (10 mL) was added. The mixture
was stirred for 1 h at room temperature and then heated at
reflux for 14 h. After the mixture was cooled to room temper-
ature, it was poured into 10% aqueous potassium carbonate
(20 mL). Then it was filtered through a pad of Celite. The
filtrate was concentrated and subjected to flash chromatog-
raphy on silica gel (45 g, EtOAc/hexanes 1:3, v/v) to afford a
light-yellow liquid (250 mg, 48.8%): 1H NMR (CDCl3) δ 7.45
(d, J ) 1.93 Hz, 1 H), 7.40 (d, J ) 1.93 Hz, 1 H), 7.09 (s, 2 H),
5.96 (t, J ) 7.41 Hz, 1 H), 3.98 (t, J ) 6.71 Hz, 2 H), 3.89 (s,
3 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 2.31 (s, 3 H),
2.27 (t, J ) 7.38 Hz, 2 H), 2.24 (s, 3 H), 2.13 (dt, J ) 7.38 and
7.23 Hz, 2 H), 1.78 (m, 2 H), 1.62 (m, 2 H), 0.90 (t, J ) 7.44
Hz, 3 H); 13C NMR (CDCl3) δ 173.42, 166.94, 166.67, 157.36,
157.24, 140.01, 137.77, 136.24, 134.68, 133.72, 132.65, 132.26,
130.22, 129.62, 127.43, 124.22, 65.81, 61.40, 52.09, 33.70,
29.06, 24.98, 21.83, 16.03, 10.24; CIMS m/z 513 (MH+); HRMS
calcd for C29H36O8 512.2410, found 512.2400. Anal. (C29H36O8)
C, H.
Eth yl 3′,3′′-Dim eth yl-4′,4′′-dim eth oxy-5′,5′′-bis(m eth oxy-
ca r bon yl)-6,6-d ip h en ylh exen oa te (20). A mixture of TiCl4/
THF 1:2 complex (1.45 g, 4.35 mmol) and Zn dust (0.57 g, 8.7
mmol) was slurried in dry THF (15 mL) under argon. After
1.5 h of reflux, the black mixture was cooled and a solution of
benzophenone 54 (0.56 g, 1.45 mmol) and aldehyde 69 (0.31
g, 2.18 mmol) in dry THF (10 mL) was added. The mixture
was stirred for 1 h at room temperature and then heated at
reflux for 14 h. After the mixture was cooled to room temper-
ature, it was poured into 10% aqueous potassium carbonate
(20 mL). It was then filtered through a pad of Celite. The
filtrate was concentrated, dissolved in CH2Cl2 (1 mL), and
subjected to flash chromatography (EtOAc/hexanes 1:2, v/v)
to afford a light-yellow liquid (150 mg, 20.8%): 1H NMR
(CDCl3) δ 7.43 (d, J ) 1.93 Hz, 1 H), 7.39 (d, J ) 1.93 Hz, 1
H), 7.07 (s, 2 H), 5.94 (t, J ) 7.32 Hz, 1 H), 4.06 (q, J ) 7.17
Hz, 2 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.78 (s, 3 H),
2.29 (s, 3 H), 2.24 (t, J ) 7.72 Hz, 2 H), 2.22 (s, 3 H), 2.11 (m,
2 H), 1.76 (m, 2 H), 1.18 (t, J ) 7.18 Hz, 3 H); 13C NMR (CDCl3)
δ 173.36, 166.96, 166.72, 157.40, 157.31, 140.08, 137.81,
136.28, 134.74, 133.76, 132.71, 132.30, 130.26, 129.68, 127.47,
124.29, 61.44, 60.19, 52.12, 33.73, 29.09, 24.98, 16.08, 14.12;
CIMS m/z 499 (MH+); HRMS (CI) calcd for C28H34O8 499.2332,
found 499.2316. Anal. (C28H34O8) C, H.
Eth yl 3′,3′′-Dibr om o-4′,4′′-d im eth oxy-5′,5′′-bis(m eth oxy-
ca r bon yl)-6,6-d ip h en yl-5-h exen oa te (21). A slurry of TiCl4/
THF 1:2 complex (0.95 g, 2.83 mmol) and Zn powder (0.37 g,
5.67 mmol) was heated under reflux for 1.5 h. The resulting
dark suspension was cooled to room temperature, and a
mixture of benzophenone 55 (0.45 g, 0.87 mmol) and aldehyde
69 (0.25 g, 1.74 mmol) in THF (15 mL) was added. The mixture
was heated at reflux and stirred for 20 h, cooled, and poured
into 10% aqueous potassium carbonate (20 mL). It was then
filtered through a pad of Celite. The filtrate was evaporated,
and the resulting crude residue was purified by flash chro-
matography (EtOAc/hexanes 1:3, v/v) to afford a colorless
liquid (122 mg, 22.0%): 1H NMR (CDCl3) δ 7.51 (d, J ) 2.71
Hz, 1 H), 7.50 (d, J ) 2.71 Hz, 1 H), 7.46 (d, J ) 2.37 Hz, 1 H),
7.45 (d, J ) 2.42 Hz, 1 H), 6.01 (t, J ) 7.48 Hz, 1 H), 4.07 (q,
J ) 7.12 Hz, 2 H), 3.96 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H),
3.88 (s, 3 H), 2.27 (t, J ) 7.41 Hz, 2 H), 2.12 (m, 2 H), 1.76 (m,
2 H), 1.19 (t, J ) 7.20 Hz, 3 H); 13C NMR (CDCl3) δ 173.13,
165.67, 165.39, 156.04, 155.76, 138.85, 137.98, 137.66, 135.69,
135.47, 132.21, 131.80, 128.97, 126.62, 126.47, 119.26, 119.04,
62.13, 60.32, 52.51, 33.63, 29.13, 24.73, 14.16; EIMS m/z 627
(M+); HRMS (EI) calcd for C26H28Br2O8 626.0151, found
626.0131. Anal. (C26H28Br2O8) C, H, Br.
P r opyl 3′,3′′-Dibr om o-4′,4′′-dim eth oxy-5′,5′′-bis(m eth oxy-
ca r bon yl)-6,6-d ip h en ylh exen oa te (24). A slurry of TiCl4/
THF 1:2 complex (932 mg, 2.79 mmol) and Zn powder (365
mg, 5.58 mmol) in dry THF (10 mL) was heated under reflux
for 2 h. The resulting dark suspension was cooled to room
temperature, and a mixture of benzophenone 55 (0.45 g, 0.87
mmol) and aldehyde 70 (234 mg, 1.48 mmol) in THF (10 mL)
was added. The mixture was heated at reflux and stirred for
16 h, cooled, and poured into 10% aqueous potassium carbon-
ate (20 mL). Then it was filtered through a pad of Celite. The
filtrate was evaporated, and the resulting crude residue was
purified by flash chromatography (EtOAc/hexanes 1:3, v/v) to
afford a colorless liquid (114 mg, 20.4%): 1H NMR (CDCl3) δ
7.52 (d, J ) 2.70 Hz, 1 H), 7.51 (d, J ) 2.43 Hz, 1 H), 7.48 (d,
J ) 2.06 Hz, 1 H), 7.46 (d, J ) 2.41 Hz, 1 H), 6.02 (t, J ) 7.42
Hz, 1 H), 3.99 (t, J ) 6.72 Hz, 2 H), 3.97 (s, 3 H), 3.91 (s, 3 H),
3.90 (s, 3 H), 3.88 (s, 3 H), 2.29 (t, J ) 7.36 Hz, 2 H), 2.13 (dt,
J ) 7.37 and 7.40 Hz, 2 H), 1.76 (m, 2 H), 1.61 (m, 2 H), 0.90
(t, J ) 7.38 Hz, 3 H); 13C NMR (CDCl3) δ 173.14, 165.59,
165.32, 155.97, 155.71, 138.78, 137.91, 137.60, 135.61, 135.40,
132.13, 131.72, 128.90, 126.54, 126.40, 119.19, 118.98, 65.90,
62.04, 52.43, 33.56, 29.08, 24.69, 21.83, 10.23; HRMS calcd
for C27H30Br2O8 642.0464, found 642.0441. Anal. (C27H30Br2O8‚
0.3H2O) C, H, Br.
P r opyl 3′,3′′-Dich lor o-4′,4′′-dim eth oxy-5′,5′′-bis(m eth oxy-
ca r bon yl)-6,6-d ip h en ylh exen oa te (22). A mixture of TiCl4/
THF 1:2 complex (1.0 g, 3.0 mmol) and Zn powder (0.39 g, 6.0
mmol) in dry THF (10 mL) was heated under reflux for 1.5 h
under nitrogen. A solution of benzophenone 53 (400 mg, 0.939
mmol) and aldehyde 70 (252 mg, 1.6 mmol) in dry THF (10
mL) was added. The reaction mixture was stirred at room
temperature for 1 h, then heated under reflux for 14 h. The
mixture was allowed to cool, and 10% aqueous potassium
carbonate (25 mL) was added. The resulting mixture was
stirred at room temperature overnight, then filtered through
a Celite pad, and washed with ethyl acetate (3 × 20 mL). The
organic solvents were evaporated, and the crude residue was
purified by silica gel flash chromatography (hexanes/EtOAc
7:2, v/v) to afford a colorless liquid (210 mg, 40.5%): 1H NMR
(CDCl3) δ 7.49 (d, J ) 2.49 Hz, 1 H), 7.46 (d, J ) 2.10 Hz, 1
H), 7.31 (d, J ) 2.21 Hz, 1 H), 7.29 (d, J ) 2.19 Hz, 1 H), 6.04
(t, J ) 7.44 Hz, 1 H), 4.00 (t, J ) 6.85 Hz, 2 H), 3.99 (s, 3 H),
3.92 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 2.30 (t, J ) 7.42 Hz,
Isopr opyl 3′,3′′-Dich lor o-4′,4′′-dim eth oxy-5′,5′′-bis(m eth -
oxyca r bon yl)-6,6-d ip h en yl-5-h exen oa te (25). A mixture of
TiCl4/THF 1:2 complex (953 mg, 2.85 mmol) and Zn powder
(373 mg, 5.71 mmol) in dry THF (10 mL) was heated under
reflux for 1.5 h under nitrogen. A solution of benzophenone
53 (380 mg, 0.892 mmol) and aldehyde 71 (282 mg, 1.78 mmol)
in dry THF (10 mL) was added. The reaction mixture was
stirred at room temperature for 1 h and then heated under
reflux for 14 h. The mixture was allowed to cool, and 10%
aqueous potassium carbonate (25 mL) was added. The result-
ing mixture was stirred at room temperature overnight and
then filtered through a Celite pad and washed with ethyl
acetate (3 × 20 mL). The organic solvents were evaporated
and the crude residue was purified by silica gel flash chroma-
tography (silica gel, 50 g, hexanes/EtOAc 3:1, v/v) to afford a
colorless liquid (190 mg, 38.5%): 1H NMR (CDCl3) δ 7.49 (d,
J ) 2.17 Hz, 1 H), 7.46 (d, J ) 2.10 Hz, 1 H), 7.31 (d, J ) 2.10
Hz, 1 H), 7.29 (d, J ) 2.23 Hz, 1 H), 6.04 (t, J ) 7.45 Hz, 1 H),

4104 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Xu et al.
4.98 (m, 1 H), 3.99 (s, 3 H), 3.93 (s, 3 H), 3.92 (s, 3 H), 3.91 (s,
3 H), 2.26 (t, J ) 7.43 Hz, 2 H), 2.14 (dt, J ) 7.36 and 7.34
Hz, 2 H), 1.78 (m, 2 H), 1.19 (d, J ) 6.23 Hz, 6 H); 13C NMR
(CDCl3) δ 172.58, 165.72, 165.42, 155.01, 154.71, 138.31,
137.79, 135.17, 134.89, 132.36, 132.02, 130.88, 129.67, 129.37,
127.97, 126.76, 126.61, 67.52, 61.91, 52.40, 33.96, 29.12, 24.77,
21.67; EIMS m/z 553 (M+); HRMS calcd for C27H29Cl2O8 (M -
H)+ 552.1318, found 552.1309. Anal. (C27H30Cl2O8) C, H, Cl.
3 H), 3.90 (s, 3 H), 2.95 (broad s, 6 H), 2.28 (t, J ) 7.47 Hz, 2
H), 2.14 (dt, J ) 7.61 and 7.37 Hz, 2 H), 1.80 (m, 2 H); 13C
NMR (CDCl3) δ 172.39, 165.79, 165.55, 154.98, 154.73, 138.41,
137.56, 135.37, 135.02, 132.59, 132.45, 130.98, 129.69, 129.45,
128.07, 126.82, 126.63, 61.98, 52.48, 32.51, 29.44, 24.83; HRMS
(EI) calcd for C26H29NCl2O7 537.1321, found 537.1336. Anal.
(C26H29NCl2O7) C, H, Cl.
N,N-Dim eth yl-3′,3′′-d im eth yl-4′,4′′-d im eth oxy-5′,5′′-bis-
(m eth oxyca r bon yl)-6,6-d ip h en ylh exen a m id e (29). A mix-
ture of TiCl4/THF 1:2 complex (1.24 g, 3.72 mmol) and Zn dust
(0.49, 7.44 mmol) was heated at reflux in dry THF (15 mL)
under argon. After 2 h of reflux, the black mixture was cooled
and a solution of benzophenone 54 (0.463 g, 1.2 mmol) and
aldehyde 72 (0.257 g, 1.8 mmol) in dry THF (10 mL) was
added. The mixture was stirred for 40 min at room tempera-
ture and then heated at reflux for 5 h. The mixture was cooled
to room temperature, and 10% aqueous K2CO3 (15 mL) was
added. The resulting mixture was stirred overnight, then
filtered through a Celite pad, and washed with ethyl acetate
(3 × 10 mL). The solvents were removed under reduced
pressure, and the crude residue was purified by silica gel (33
g) flash chromatography (column, 2.5 cm × 31 cm), eluting
with ethyl acetate, to afford a colorless oil (104 mg, 17.4%):
1H NMR (CDCl3) δ 7.40 (d, J ) 2.33 Hz, 1 H), 7.36 (d, J )
2.14 Hz, 1 H), 7.14 (d, J ) 2.22 Hz, 1 H), 7.09 (d, J ) 1.85 Hz,
1 H), 5.99 (t, J ) 7.34 Hz, 1 H), 3.88 (s, 3 H), 3.86 (s, 3 H),
3.85 (s, 3 H), 3.77 (s, 3 H), 3.01 (s, 3 H), 2.96 (s, 3 H), 2.46 (t,
J ) 7.89 Hz, 2 H), 2.28 (s, 3 H), 2.22 (s, 3 H), 2.14 (dt, J )
7.34 and 7.07 Hz, 2 H), 1.83 (m, 2 H); 13C NMR (CDCl3) δ
175.67, 166.98, 166.83, 157.37, 157.31, 140.09, 137.72, 136.40,
134.78, 133.85, 132.80, 132.38, 130.18, 129.60, 127.53, 124.26,
61.43, 52.15, 37.97, 36.32, 32.97, 29.35, 25.35, 16.12, 16.04;
CIMS m/z 498 (MH+); HRMS (CI) calcd for C28H36NO7 (MH+)
498.2492, found 498.2477. Anal. (C28H35NO7) C, H, N.
Isopr opyl 3′,3′′-Dim eth yl-4′,4′′-dim eth oxy-5′,5′′-bis(m eth -
oxyca r bon yl)-6,6-d ip h en ylh exen oa te (26). A mixture of
TiCl4/THF 1:2 complex (969 mg, 2.90 mmol) and Zn dust (379
mg, 5.80 mmol) was slurried in dry THF (8 mL) under argon.
After 1 h of reflux, the black mixture was cooled and a solution
of benzophenone 54 (350 mg, 0.907 mmol) and aldehyde 71
(265 mg, 1.54 mmol) in dry THF (10 mL) was added. The
mixture was stirred for 1 h at room temperature and then
heated at reflux for 14 h. After the mixture was cooled to room
temperature, it was poured into 10% aqueous potassium
carbonate (20 mL). It was then filtered through a pad of Celite.
The filtrate was concentrated and subjected to flash chroma-
tography on silica gel (60 g, EtOAc/hexanes 1:4, v/v) to afford
a light-yellow liquid (125 mg, 26.9%): 1H NMR (CDCl3) δ 7.46
(d, J ) 2.37 Hz, 1 H), 7.41 (d, J ) 2.02 Hz, 1 H), 7.09 (br, 2 H),
5.96 (t, J ) 7.39 Hz, 1 H), 4.96 (m, 1 H), 3.91 (s, 3 H), 3.90 (s,
3 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 2.31 (s, 3 H), 2.27 (t, J ) 7.38
Hz, 2 H), 2.24 (s, 3 H), 2.13 (dt, J ) 7.38 and 7.23 Hz, 2 H),
1.75 (m, 2 H), 1.17 (d, J ) 6.44 Hz, 6 H); 13C NMR (CDCl3) δ
172.82, 166.92, 166.69, 157.37, 157.24, 139.95, 137.77, 136.21,
134.68, 133.69, 132.22, 130.20, 129.68, 127.40, 124.23, 67.37,
61.38, 52.04, 34.08, 29.05, 25.03, 21.66, 16.01; CIMS m/z 513
(MH+); HRMS calcd for C29H36O8 512.2410, found 512.2400.
Anal. (C29H36O8) C, H.
Isopr opyl 3′,3′′-Dibr om o-4′,4′′-dim eth oxy-5′,5′′-bis(m eth -
oxyca r bon yl)-6,6-d ip h en yl-5-h exen oa te (27). A slurry of
TiCl4/THF 1:2 complex (870 mg, 2.61 mmol) and Zn powder
(341 mg, 5.21 mmol) in dry THF (8 mL) was heated under
reflux for 1.5 h. The resulting dark suspension was cooled to
room temperature, and a mixture of benzophenone 55 (420
mg, 0.81 mmol) and aldehyde 71 (218 mg, 1.38 mmol) in THF
(10 mL) was added. The mixture was heated at reflux and
stirred for 20 h, cooled, and poured into 10% aqueous potas-
sium carbonate (20 mL). Then it was filtered through a pad
of Celite. The filtrate was evaporated, and the resulting crude
residue was purified by flash chromatography (EtOAc/hexanes
1:3, v/v) to afford a colorless liquid (175 mg, 33.6%): 1H NMR
(CDCl3) δ 7.53 (d, J ) 2.33 Hz, 1 H), 7.52 (d, J ) 2.43 Hz, 1
H), 7.48 (d, J ) 2.11 Hz, 1 H), 7.46 (d, J ) 2.19 Hz, 1 H), 6.03
(t, J ) 7.46 Hz, 1 H), 4.97 (m, 1 H), 3.98 (s, 3 H), 3.92 (s, 3 H),
3.91 (s, 3 H), 3.90 (s, 3 H), 2.26 (t, J ) 7.44 Hz, 2 H), 2.13 (dt,
J ) 7.49 and 7.28 Hz, 2 H), 1.78 (m, 2 H), 1.19 (d, J ) 6.23
Hz, 6 H); 13C NMR (CDCl3) δ 172.63, 165.62, 165.33, 155.98,
155.75, 138.82, 137.93, 137.56, 135.64, 135.43, 132.20, 131.75,
128.92, 126.56, 126.41, 119.22, 119.01, 67.54, 62.06, 52.45,
33.96, 29.11, 24.77, 21.68; CIMS m/z 641.9 (MH)+; HRMS calcd
for C27H30Br2O8 640.0307, found 640.0306. Anal. (C27H30Br2O8)
C, H, Br.
6,6-Bis(3-ch lor o-4-m eth oxy-5-m eth oxycar bon ylph en yl)-
1-p ip er id ylh ex-5-en -1-on e (30). A mixture of TiCl4/THF 1:2
complex (1.04 g, 3.10 mmol) and Zn dust (0.41 g, 6.20 mmol)
was heated at reflux in dry THF (10 mL) under argon. After
2 h at reflux, the black mixture was cooled and a solution of
benzophenone 53 (0.426 g, 1.0 mmol) and aldehyde 73 (0.275
g, 1.5 mmol) in dry THF (15 mL) was added dropwise. The
mixture was heated at reflux for 14 h and then cooled to room
temperature, and 10% aqueous K2CO3 (15 mL) was added. The
resulting mixture was stirred overnight, then filtered through
a Celite pad, and washed with ethyl acetate (3 × 10 mL). The
solvents were removed under reduced pressure, and the crude
residue was purified by flash chromatography on silica gel (25
g, 2.5 cm × 31 cm), eluting with ethyl acetate, to afford a
colorless oil (234 mg, 40.5%): 1H NMR (CDCl3) δ 7.45 (d, J )
2.21 Hz, 1 H), 7.42 (d, J ) 2.15 Hz, 1 H), 7.27 (d, J ) 2.11 Hz,
1 H), 7.24 (d, J ) 2.45 Hz, 1 H), 6.03 (t, J ) 7.46 Hz, 1 H),
3.93 (s, 3 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.46 (t,
J ) 5.40 Hz, 2 H), 3.30 (t, J ) 5.27 Hz, 2 H), 2.23 (t, J ) 7.51
Hz, 2 H), 2.10 (dt, J ) 7.53 and 7.48 Hz, 2 H), 1.73 (m, 2 H),
1.42-1.59 (m, 6 H); 13C NMR (CDCl3) δ 170.44, 165.70, 165.46,
154.94, 154.67, 138.38, 137.47, 135.32, 134.96, 132.59, 132.39,
130.95, 129.64, 129.38, 128.04, 126.78, 126.60, 61.91, 60.25,
52.42, 46.47, 42.54, 32.55, 29.47, 26.43, 25.47, 25.08, 24.45,
N,N-Dim eth yl-3′,3′′-d ich lor o-4′,4′′-d im eth oxy-5′,5′′-bis-
(m eth oxyca r bon yl)-6,6-d ip h en yl-5-h exen a m id e (28). A
mixture of TiCl4/THF 1:2 complex (1.04 g, 3.10 mmol) and Zn
dust (0.41, 6.20 mmol) was heated at reflux in dry THF (15
mL) under argon. After 1 h at reflux, the black mixture was
cooled and a solution of benzophenone 53 (0.426 g, 1.0 mmol)
and aldehyde 72 (172 mg, 1.2 mmol) in dry THF (15 mL) was
added dropwise. The mixture was heated at reflux for 14 h
and then cooled to room temperature, and 10% aqueous K2CO3
(15 mL) was added. The resulting mixture was stirred over-
night, then filtered through a Celite pad, and washed with
ethyl acetate (3 × 10 mL). The solvents were removed under
reduced pressure, and the crude residue was purified by flash
chromatography on silica gel (25 g, 2.5 cm × 31 cm), eluting
with ethyl acetate, to afford a colorless oil (215 mg, 40%): 1H
NMR (CDCl3) δ 7.50 (d, J ) 2.45 Hz, 1 H), 7.45 (d, J ) 2.11
Hz, 1 H), 7.31 (d, J ) 2.11 Hz, 1 H), 7.28 (d, J ) 2.40 Hz, 1 H),
6.08 (t, J ) 7.49 Hz, 1 H), 3.98 (s, 3 H), 3.92 (s, 3 H), 3.91 (s,
20.91, 14.08; EIMS m/z 578 (M+); HRMS (EI) calcd for C29H33
-
NCl2O7 578.1712, found 578.1697. Anal. (C29H33NCl2O7) C, H,
N.
6,6-Bis(3-m eth yl-4-m eth oxy-5-m eth oxycar bon ylph en yl)-
1-p ip er id ylh ex-5-en -1-on e (31). TiCl4/THF 1:2 complex (1.35
g, 4.03 mmol) was added to a stirred suspension of zinc dust
(0.53 g, 8.06 mmol) in dry THF (15 mL) under argon. The
resulting dark mixture was heated under reflux for 2 h. The
suspension was cooled to room temperature, and a solution of
benzophenone 54 (501 mg, 1.3 mmol) and aldehyde 73 (357
mg, 1.95 mmol) in dry THF (15 mL) was added. The mixture
was heated at reflux for 14 h and then cooled to room
temperature. An aqueous 10% K2CO3 solution (20 mL) was
added, and the mixture was stirred for 2 h, followed by
filtration through a pad of Celite. The filtrate was evaporated,
and the brown residue was purified by flash chromatography

Alkenyldiarylmethane Series of Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4105
on silica gel (32 g, 2.5 cm × 31 cm), eluting with ethyl acetate,
to afford a pale-yellow oil (217 mg, 31%): 1H NMR (CDCl3) δ
7.43 (d, J ) 2.23 Hz, 1 H), 7.38 (d, J ) 1.94 Hz, 1 H), 7.07 (br
s, 2 H), 5.97 (t, J ) 7.42 Hz, 1 H), 3.88 (s, 3 H), 3.86 (s, 3 H),
3.84 (s, 3 H), 3.78 (s, 3 H), 3.49 (t, J ) 5.46 Hz, 2 H), 3.32 (t,
J ) 5.26 Hz, 2 H), 2.28 (s, 3 H), 2.25 (t, J ) 7.73 Hz, 2 H),
2.22 (s, 3 H), 2.13 (dt, J ) 7.43 and 7.42 Hz, 2 H), 1.73 (m, 2
H), 1.43-1.63 (m, 6 H); 13C NMR (CDCl3) δ 170.85, 166.96,
166.76, 157.37, 157.28, 139.78, 137.87, 136.36, 134.86, 133.77,
132.68, 132.29, 130.26, 130.17, 127.48, 124.26, 61.44, 52.12,
46.53, 42.54, 32.76, 29.42, 26.45, 25.47, 25.41, 24.48, 16.07;
CIMS m/z 538 (MH+); HRMS (CI) calcd for C31H40NO7 538.2805,
found 538.2828. Anal. (C31H39NO7) C, H, N.
EtOAc/hexanes, 1:1) at this time showed the reaction to be
incomplete. However, the solution was filtered to remove the
solids. The solids were washed with CH2Cl2 (10 mL). The
solvent was removed on a rotary evaporator. The crude product
was purified by column chromatography on silica gel (20 g),
using a gradient of 0-15% ethyl acetate in hexanes to elute
the starting material (0.041 g recovered) followed by a gradient
of 0-20% acetone in CH2Cl2 to elute the product. The fractions
containing the product were combined and condensed on a
rotary evaporator to yield the pure product as a glassy solid
(0.075 g, 48%): mp 120-122 °C; IR (thin film on NaCl) 2951,
1733, 1477, 1436, 1257, 1209, 1167, 1095, 1051, 998, 742 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.49 (d, J ) 2.3 Hz, 1 H), 7.45
(d, J ) 2.2 Hz, 1 H), 7.30 (d, J ) 2.2 Hz, 1 H), 7.27 (d, J ) 2.3
Hz, 1 H), 6.04 (t, J ) 7.4 Hz, 1 H), 3.99 (s, 3 H), 3.92 (s, 6 H),
3.91 (s, 3 H), 2.76-2.59 (m, 2 H), 2.57 (s, 3 H), 2.32-2.24 (m,
2 H), 1.99-1.88 (m, 2 H). Anal. (C24H26Cl2O7S) C, H, Cl.
2-(Tr im eth ylsilyl)eth yl 3′,3′′-Dim eth yl-4′,4′′-d im eth oxy-
5′,5′′-bis(m eth oxycar bon yl)-6,6-diph en yl-5-h exen oate (32).
A mixture of TiCl4/THF 1:2 complex (0.53 g, 1.58 mmol) and
Zn (0.21 g, 3.16 mmol) in dry THF (8 mL) was heated under
reflux for 2 h under argon. A solution of benzophenone 54 (0.20
g, 0.51 mmol) and aldehyde 75 (0.11 g, 0.51 mmol) in dry THF
(14 mL) was added. The mixture was stirred for 1 h at room
temperature and then heated at reflux for 14 h. After the
mixture was cooled to room temperature, it was poured into
10% aqueous potassium carbonate (5 mL). Then it was filtered
through a pad of Celite. The filtrate was concentrated, dis-
solved in chloroform (1.5 mL), and subjected to flash chroma-
tography (hexanes/EtOAc 3:1, v/v) to afford a light-yellow
liquid (80 mg, 28%): 1H NMR (CDCl3) δ 7.45 (d, J ) 2.39 Hz,
1 H), 7.40 (d, J ) 2.20 Hz, 1 H), 7.09 (d, J ) 1.92 Hz, 2 H),
5.95 (t, J ) 7.42 Hz, 1 H), 4.13 (t, J ) 8.08 Hz, 2 H), 3.83 (s,
3 H), 3.82 (s, 3 H), 3.81 (s, 3 H), 3.79 (s, 3 H), 2.30 (s, 6 H),
2.24 (t, J ) 7.70 Hz, 2 H), 2.10 (m, 2 H), 1.75 (m, 2 H), 0.94 (t,
J ) 8.08 Hz, 2 H), 0.02 (s, 9 H); 13C NMR (CDCl3) δ 173.51,
166.98, 166.74, 157.43, 157.31, 140.05, 137.84, 136.28, 134.75,
133.76, 132.68, 132.30, 130.26, 129.71, 127.50, 124.29, 62.43,
61.45, 52.13, 33.91, 29.15, 25.02, 17.23, 16.09, -1.58; CIMS
m/z 571 (MH+). Anal. (C31H42SiO8) C, H.
3′,3′′-Dich lor o-4′,4′′-d im et h oxy-5′,5′′-d i(m et h oxyca r -
bon yl)-1,1-d ip h en yl-5-(m eth ylth io)-p en t-1-en e (33). TiCl4/
THF 1:2 complex (2.92 g, 5.65 mmol) and zinc dust (0.739 g,
11.3 mmol) were suspended with stirring in THF (35 mL)
under an atmosphere of argon. The resulting suspension was
heated under reflux for 2 h. Di[3-chloro-4-methoxy-5-(meth-
oxycarbonyl)phenyl] ketone (53, 0.482 g, 1.13 mmol) and
4-(methylthio)butanal (76, 0.200 g, 1.69 mmol) were taken up
in THF (35 mL). The solution of ketone and aldehyde was
tranferred to a suspension of low-valent titanium via cannula
after the initial 2 h of heating. The resulting suspension was
heated under reflux for 1.5 h. TLC (SiO2, EtOAc/hexanes, 1:1)
at this time showed the reaction to be complete. The entire
reaction mixture was poured onto a column of silica gel (30
g), and the product was eluted from the column with ethyl
acetate. The solvent was removed from this mixture with a
rotary evaporator, yielding the crude product. The product was
further purified by flash column chromatography on silica gel
(50 g), using a gradient of 0-18% ethyl acetate in hexanes as
the eluent. Fractions containing the product were evaporated,
yielding the pure product as a slightly yellow solid (0.423 g,
73%): mp 90-93 °C; IR (KBr pellet) 2929, 2829, 1733, 1594,
1558, 1475, 1425, 1364, 1291, 1249, 1210, 1090, 995, 968, 919,
894, 833, 805, 744, 679, 619 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.48 (d, J ) 2.1 Hz, 1 H), 7.46 (d, J ) 2.2 Hz, 1 H), 7.31 (d,
J ) 2.2 Hz, 1 H), 7.27 (d, J ) 2.2 Hz, 1 H), 6.05 (t, J ) 7.2 Hz,
1 H), 3.99 (s, 3 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H),
2.47 (t, J ) 7.3, 2 H), 2.19 (q, J ) 7.6 Hz, 2 H), 2.07 (s, 3 H),
1.73 (dt, J ) 7.2, 7.4 Hz, 2 H). Anal. (C24H26Cl2O6S) C, H, Cl.
3′,3′′-Dich lor o-4′,4′′-d im e t h oxy-5′,5′′-d im e t h oxyca r -
b on yl-5,5-d ip h en yl-1-(m et h ylsu lfon yl)p en t -4-en e (35).
3′,3′′-Dichloro-4′,4′′-dimethoxy-5′,5′′-dimethoxycarbonyl-5,5-di-
phenyl-1-(methylthio)-pent-4-ene (33, 0.150 g, 0.292 mmol) was
taken up with stirring in MeOH (8 mL). The resulting solution
was cooled in an ice bath. A solution of oxone (0.270 g, 0.876
mmol KHSO5) dissolved in water (4 mL) was added in one
portion to the stirring mixture. Stirring was continued for 22
h at which time TLC analysis (SiO2, acetone/CH2Cl2, 1:9)
showed the reaction to be complete. The reaction mixture was
poured into H2O (50 mL) and extracted with CHCl3 (3 × 30
mL). The organic extracts were combined and dried over
MgSO4. The solution was filtered and condensed to yield the
crude product. The crude product was purified by column
chromatography on silica gel (30 g), using a gradient of 0-6%
acetone in CH2Cl2 to elute the product. The fractions contain-
ing the product were combined and condensed on a rotary
evaporator to yield the pure product as a slightly yellow oil
(0.121 g, 76%): IR (thin film on NaCl) 3008, 2952, 1732, 1596,
1557, 1479, 1436, 1404, 1360, 1290, 1210, 1168, 1132, 1095,
998, 963, 885, 851, 804, 741 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.50 (d, J ) 2.6 Hz, 1 H), 7.46 (d, J ) 2.2 Hz, 1 H), 7.30 (d,
J ) 2.2 Hz, 1 H), 7.28 (d, J ) 2.6 Hz, 1 H), 6.03 (t, J ) 7.4 Hz,
1 H), 4.00 (s, 3 H), 3.94 (s, 3 H), 3.93 (s, 3 H), 3.92 (s, 3 H),
3.02-2.96 (m, 2 H), 2.90 (s, 3 H), 2.29 (dt, J ) 7.4, 7.5 Hz, 2
H), 2.06-1.96 (m, 2 H). Anal. (C24H26Cl2O8S) C, H, Cl.
Meth yl 5-{1-[3-Ch lor o-4-m eth oxy-5-(m eth oxyca r bon -
yl)ph en yl]-6-m eth ylth io-6-oxoh ex-1-en yl}-3-ch lor o-2-m eth -
oxyben zoa te (36). A mixture of TiCl4/THF 1:2 complex (866
mg, 2.59 mmol) and Zn dust (339 mg, 5.18 mmol) was heated
at reflux in dry THF (25 mL) under argon. After 1 h of reflux,
a mixture of the substituted dichlorobenzophenone 53 (345 mg,
0.81 mmol) and aldehyde 80 (120 mg, 0.82 mmol) in dry THF
(15 mL) was added dropwise. The resulting mixture was
heated again at reflux for 14 h and then was cooled to room
temperature and poured into a 10% K2CO3 solution (10 mL).
The white precipitate was filtered off, and the filtrate was
partitioned between ethyl acetate and water. The organic
layers were combined and dried over Na2SO4 and then
evaporated to give a light-yellow residue. The residue was
purified by flash chromatography (silica gel 45 g, eluent
hexanes/ethyl acetate 3:1, v/v) to afford a colorless oil (131 mg,
30%): 1H NMR (CDCl3) δ 7.48 (m, 1 H), 7.46 (d, J ) 2.12 Hz,
1 H), 7.31 (m, 1 H), 7.28 (d, J ) 2.32 Hz, 1 H), 6.02 (t, J )
7.47 Hz, 1 H), 3.99 (s, 3 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 3.90 (s,
3 H), 2.55 (t, J ) 7.31 Hz, 2 H), 2.27 (s, 3 H), 2.13 (dt, J )
7.30 and 7.41 Hz, 2 H), 1.82 (m, 2 H); 13C NMR (CDCl3) δ
194.61, 161.12, 160.85, 150.47, 149.76, 133.65, 133.44, 131.67,
130.51, 130.33, 129.54, 127.80, 127.12, 126.31, 125.26, 125.12,
124.84, 123.41, 122.18, 122.03, 57.33, 47.85, 38.42, 24.34,
20.65, 6.85; CIMS m/z 541 (MH+), 509 (M - MeOH).
3′,3′′-Dich lor o-4′,4′′-d im e t h oxy-5′,5′′-d im e t h oxyca r -
bon yl-5,5-d ip h en yl-1-(m eth ylsu lfin yl)p en t-4-en e (34). A
slurry of NaIO4 supported on acidic alumina28 (0.200 g, 0.60
mmol) in ethanol (absolute, 3 mL) was stirred in a 10 mL
round-bottomed flask. 3′,3′′-Dichloro-4′,4′′-dimethoxy-5′,5′′-
dimethoxycarbonyl-5,5-diphenyl-1-(methylthio)-pent-4-ene (33,
0.150 g, 0.292 mmol) was added to the slurry in one portion.
The reaction mixture was placed under an argon atmosphere,
and stirring was continued for 22 h. TLC analysis (SiO2,
Meth yl 5-{1-[3-Ch lor o-4-m eth oxy-5-(m eth oxyca r bon -
yl)p h en yl]-6-eth ylth io-6-oxoh ex-1-en yl}-3-ch lor o-2-m eth -
oxyben zoa te (37). A mixture of TiCl4/THF 1:2 complex (0.73
g, 2.18 mmol) and Zn dust (286 mg, 4.37 mmol) was heated at
reflux in dry THF (12 mL) under argon. After 1 h of reflux, a
mixture of the substituted dichlorobenzophenone 53 (292 mg,

4106 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Xu et al.
0.68 mmol) and aldehyde 81 (112 mg, 0.70 mmol) in dry THF
(15 mL) was added dropwise. The resulting mixture was
heated again at reflux for 14 h, then was cooled to room
temperature and poured into a 10% K2CO3 solution (10 mL).
The white precipitate was filtered off, and the filtrate was
partioned between ethyl acetate and water. The organic layers
were combined and dried over Na2SO4 and then evaporated
to give a light-yellow residue. The residue was purified by flash
chromatography (silica gel 50 g, solvent hexanes/ethyl acetate
2:1, v/v) to afford a colorless oil (75 mg, 20%): 1H NMR (CDCl3)
δ 7.48 (d, J ) 2.42 Hz, 1 H), 7.46 (d, J ) 2.29 Hz, 1 H), 7.30
(d, J ) 2.19 Hz, 1 H), 7.28 (d, J ) 2.42 Hz, 1 H), 6.02 (t, J )
7.51 Hz, 1 H), 3.99 (s, 3 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 3.90 (s,
3 H), 2.85 (q, J ) 7.36 Hz, 2 H), 2.53 (t, J ) 7.32 Hz, 2 H),
2.12 (dt, J ) 7.51 and 7.30 Hz, 2 H), 1.81 (m, 2 H), 1.23 (t, J
) 7.33 Hz, 3 H); 13C NMR (CDCl3) δ 194.37, 161.15, 161.06,
160.85, 150.46, 149.77, 133.68, 133.41, 131.67, 130.50, 130.35,
129.55, 127.81, 127.18, 126.34, 125.28, 125.14, 124.84, 123.43,
122.19, 122.03, 57.30, 47.84, 38.61, 35.12, 24.34, 20.65, 18.58,
10.02; CIMS (MH+) m/z 554. Anal. (C26H28Cl2SO7) C, H, S.
H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.64 (s, 3 H), 3.28
(dt, J ) 6.35 and 6.31 Hz, 2 H), 2.30 (dt, J ) 7.08 and 6.88
Hz, 2 H); 13C NMR (CDCl3) δ 165.66, 165.39, 156.88, 155.08,
154.84, 139.32, 138.04, 134.92, 134.84, 132.43, 130.84, 129.77,
129.44, 129.08, 128.06, 126.80, 126.59, 61.89, 52.44, 52.03,
40.42, 30.59; ESI-MS m/z 526 (MH+); HRMS calcd for C24H25
-
NCl2O8 525.0957, found 525.0934. Anal. (C24H25NCl2O8) C, H,
N: C, 54.75; H, 4.75; N, 2.66; Cl, 13.50. Found: C, 55.02; H,
5.02; N, 2.51; Cl, 13.43.
4-(N-Meth yloxyca r bon yl)a m in o-3′,3′′-d im eth yl-4′,4′′-d i-
m eth oxy-5′,5′′-bis(m eth oxyca r bon yl)-1,1-d ip h en ylbu ten e
(41). TiCl4/THF 1:2 complex (965 mg, 2.89 mmol) was added
to a stirred suspension of zinc dust (378 mg, 5.78 mmol) in
dry THF (8 mL). The resulting black mixture was heated under
reflux for 1 h under argon. The suspension was cooled to room
temperature, and a solution of benzophenone 54 (328 mg, 0.85
mmol) and aldehyde 87 (167 mg, 1.27 mmol) in dry THF (15
mL) was added. The mixture was heated at reflux for 14 h
and then concentrated. The concentrated residue was passed
through a short column (silica gel 5 g, eluent ethyl acetate 30
mL) to removed the black solid. The combined fractions were
evaporated, and the brown residue was purified by flash
chromatography on silica gel (50 g, 1.5 cm × 31 cm), eluting
with hexanes/ethyl acetate (2:1, v/v), to give a colorless oil (160
mg, 38.8%): 1H NMR (CDCl3) δ 7.46 (d, J ) 2.32 Hz, 1 H),
7.41 (d, J ) 1.98 Hz, 1 H), 7.09 (m, 2 H), 5.95 (t, J ) 7.39 Hz,
1 H), 4.67 (br, 1 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.87 (s, 3 H),
3.81 (d, J ) 7.67 Hz, 2 H), 3.80 (s, 3 H), 3.65 (s, 3 H), 3.28 (td,
J ) 6.12 and 6.27 Hz, 2 H), 2.31(s, 3 H), 2.29 (dt, J ) 7.02 and
6.88 Hz, 2 H), 2.25 (s, 3 H); 13C NMR (CDCl3) δ 166.87, 166.65,
157.48, 157.42, 156.88, 141.70, 137.43, 136.12, 134.41, 133.72,
132.82, 132.34, 130.11, 127.46, 126.52, 124.29, 61.39, 52.09,
51.93, 40.70, 30.40, 16.00; ESI-MS m/z 486 (MH+); HRMS calcd
Meth yl 5-{1-[3-Ch lor o-4-m eth oxy-5-(m eth oxyca r bon -
yl)ph en yl]-6,6-dim eth oxyh ex-1-en yl}-3-ch lor o-2-m eth oxy-
ben zoa te (38). Aldehyde 8219 (22 mg, 0.047 mmol) was
dissolved in an acetonitrile solution (4 mL) containing 2,2-
dimethoxypropane (1.5 mL). To this mixture was added one
drop of concentrated HCl. The resulting solution was stirred
for 4 h and then concentrated. The residue was subjected to
flash chromatography on silica gel (15 g, hexanes/EtOAc 3:2
as eluent) to give the dimethyl acetal 38 as a colorless oil (20.9
mg, 82%): 1H NMR (CDCl3) δ 7.53 (d, J ) 2.21 Hz, 1 H), 7.51
(d, J ) 2.16 Hz, 1 H), 7.36 (d, J ) 2.11 Hz, 1 H), 7.33 (d, J )
2.20 Hz, 1 H), 6.10 (t, J ) 7.44 Hz, 1 H), 4.36 (t, J ) 5.22 Hz,
1 H), 4.04 (s, 3 H), 3.97 (s, 3 H), 3.96 (s, 3 H), 3.95 (s, 3 H),
3.34 (s, 6 H), 2.16 (dt, J ) 7.27 and 7.40 Hz, 2 H), 1.64 (m, 2
H), 1.54 (m, 2 H); 13C NMR (CDCl3) δ 171.21, 165.75, 165.45,
154.94, 154.64, 138.43, 137.35, 135.31, 134.95, 132.80, 132.38,
130.91, 129.62, 129.38, 127.99, 126.72, 126.57, 61.94, 52.64,
for C26H31NO8 (M+) 485.2050, found 485.2046. Anal. (C26H31
-
NO8‚H2O) C, H, N.
4-(N-Met h oxyca r b on yl)a m in o-3′,3′′-d ib r om o-4′,4′′-d i-
m eth oxy-5′,5′′-bis(m eth oxyca r bon yl)-1,1-d ip h en ylbu ten e
(42). A slurry of TiCl4/THF 1:2 complex (968 mg, 2.90 mmol)
and Zn dust (379 mg, 5.80 mmol) in THF (10 mL) was heated
under reflux for 1 h. A mixture of benzophenone 55 (0.44 g,
0.85 mmol) and aldehyde 87 (201 mg, 1.54 mmol) in dry THF
(15 mL) was added. The black mixture was stirred at room
temperature for 30 min and then heated under reflux for 14
h. The solvent was evaporated, and the residue was filtered
through a pad of Celite. The filtrate was concentrated and
purified by flash chromatography on silica gel (40 g, 1.5 cm ×
31 cm, eluent ethyl acetate/hexanes 1;2, v/v) to afford a
colorless oil (200 mg, 38.1%): 1H NMR (CDCl3) δ 7.53 (d, J )
2.28 Hz, 1 H), 7.51 (d, J ) 2.16 Hz, 1 H), 7.48 (d, J ) 2.16 Hz,
2 H), 6.04 (t, J ) 7.45 Hz, 1 H), 4.73 (br, 1 H), 3.97 (s, 3 H),
3.93 (s, 3 H), 3.92 (s, 3 H), 3.90 (s, 3 H), 3.66 (s, 3 H), 3.28 (td,
J ) 6.34 and 6.32 Hz, 2 H), 2.31 (td, J ) 7.07 and 6.92 Hz, 2
H); 13C NMR (CDCl3) δ 165.60, 165.33, 156.88, 156.10, 155.86,
139.15, 138.54, 137.87, 135.49, 135.41, 131.69, 129.23, 128.99,
126.62, 126.44, 119.31, 119.05, 62.08, 52.48, 52.09, 40.38,
30.60. Anal. (C24H25NBr2O8) C, H, Br.
4-(N -E t h oxyca r b on yl)a m in o-3′,3′′-d ich lor o-4′,4′′-d i-
m eth oxy-5′,5′′-bis(m eth oxyca r bon yl)-1,1-d ip h en ylbu ten e
(43). A mixture of TiCl4/THF 1:2 complex (1.07 g, 3.2 mmol)
and Zn dust (418 mg, 6.4 mmol) was heated at reflux in dry
THF (8 mL) under argon. After 1 h of reflux, a mixture of
benzophenone 53 (426 mg, 1.0 mmol) and aldehyde 88 (290
mg, 2.0 mmol) in dry THF (15 mL) was added dropwise. The
mixture was heated again at reflux for 14 h and then
concentrated. The resulting residue was filtered through a pad
of Celite and washed with ethyl acetate (30 mL). The filtrate
was evaporated, and the brown residue was further purified
by flash chromatography on silica gel (60 g, 2.5 cm × 31 cm,
eluent ethyl acetate/hexanes 3:2, v/v) to afford a colorless oil
(180 mg, 33.3%): 1H NMR (CDCl3) δ 7.49 (d, J ) 2.20 Hz, 1
H), 7.46 (d, J ) 2.24 Hz, 1 H), 7.31 (d, J ) 2.25 Hz, 1 H), 7.29
(d, J ) 2.61 Hz, 1 H), 6.04 (t, J ) 7.47 Hz, 1 H), 4.10 (q, J )
7.10 Hz, 2 H), 3.99 (s, 3 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 3.90 (s,
3 H), 3.26 (dt, J ) 6.26 and 6.10 Hz, 2 H), 2.31 (dt, J ) 7.13
52.40, 31.92, 29.41, 24.50; ESI m/z 541 (MH+). Anal. (C26H30
-
Cl2O8) C, H, Cl.
Met h yl 5-{4-(Acet yla m in o)-1-[3-ch lor o-4-m et h oxy-5-
(m eth oxyca r bon yl)p h en yl]bu t-1-en yl}-3-ch lor o-2-m eth -
oxyben zoa te (39). Amine 96 hydrochloride salt (42.0 mg,
0.083 mmol) was dissolved in dry THF (8 mL) containing
triethylamine (31.5 mg, 0.31 mmol). Acetyl chloride (9.8 mg,
0.125 mmol) was added. The mixture was stirred for 2 h at 0
°C, and then the reaction was quenched with methanol (10
mL). The solvent was removed, and the residue was purified
by flash chromatography on silica gel (silica gel 25 g, EtOAc
as eluent) to afford a light-yellow solid (30 mg, 70.8%): 1H
NMR (CDCl3) δ 7.50 (d, J ) 2.27 Hz, 1 H), 7.46 (d, J ) 2.18
Hz, 1 H), 7.31 (d, J ) 2.13 Hz, 1 H), 7.28 (d, J ) 2.35 Hz, 1 H),
6.05 (t, J ) 7.73 Hz, 1 H), 3.99 (s, 3 H), 3.92 (s, 3 H), 3.91 (s,
3 H), 3.90 (s, 3 H), 3.75 (t, J ) 7.51 Hz, 2 H), 2.35 (dt, J )
7.64 and 7.73 Hz, 2 H), 2.31 (s, 3 H); 13C NMR (CDCl3) δ
172.81, 165.60, 165.33, 155.26, 155.02, 139.71, 137.62, 134.67,
132.35, 130.63, 129.98, 129.56, 128.03, 127.64, 127.01, 126.65,
61.92, 52.48, 44.00, 29.47, 26.17; CIMS m/z 510 (MH+). Anal.
(C24H25NCl2O7) C, H, Cl.
4-(N-Met h oxyca r b on yl)a m in o-3′,3′′-d ich lor o-4′,4′′-d i-
m eth oxy-5′,5′′-bis(m eth oxyca r bon yl)-1,1-d ip h en ylbu ten e
(40). A mixture of TiCl4/THF 1:2 complex (1.01 g, 3.02 mmol)
and Zn dust (395 mg, 6.05 mmol) was heated at reflux in dry
THF (8 mL) under argon. After 1 h of reflux, a mixture of
benzophenone 53 (379 mg, 0.89 mmol) and aldehyde 87 (163
mg, 1.02 mmol) in dry THF (12 mL) was added dropwise. The
mixture was heated again at reflux for 14 h, then concentrated.
The resulting residue was filtered through a pad of Celite and
washed with ethyl acetate (30 mL). The filtrate was evapo-
rated, and the brown residue was further purified by flash
chromatography on silica gel (35 g, 1.5 cm × 31 cm, eluent
ethyl acetate/hexanes 3:2, v/v) to afford a colorless oil (150 mg,
32%): 1H NMR (CDCl3) δ 7.48 (d, J ) 2.19 Hz, 1 H), 7.45 (d,
J ) 2.10 Hz, 1 H, 7.30 (d, J ) 2.50 Hz, 1 H), 7.28 (d, J ) 2.80
Hz, 1 H), 6.03 (t, J ) 7.45 Hz, 1 H), 4.77 (br, 1 H), 3.98 (s, 3

Alkenyldiarylmethane Series of Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4107
and 6.90 Hz, 2 H), 1.70 (br, 1 H), 1.22 (t, J ) 7.17 Hz, 3 H);
13C NMR (CDCl3) δ 165.68, 165.39, 156.47, 155.11, 154.89,
139.30, 138.88, 138.06, 134.95, 134.86, 132.44, 130.82, 129.80,
129.46, 129.11, 128.06, 126.83, 126.62, 61.94, 60.77, 52.43,
40.31, 30.66, 14.49; CIMS m/z 540 (MH+); HRMS (CI) calcd
for C25H27Cl2NO8 540.1192, found 540.1180. Anal. (C25H27Cl2-
NO8‚0.15H2O) C, H, N, Cl.
(15 mL) was added. The black mixture was stirred at room
temperature for 30 min and then heated under reflux for 14
h. The solvent was evaporated, and the residue was filtered
through a pad of Celite. The filtrate was concentrated and
purified by flash chromatography on silica gel (40 g, 1.5 cm ×
31 cm, eluent ethyl acetate/hexanes 1;2, v/v) to afford a
colorless oil (240 mg, 39.8%): 1H NMR (CDCl3) δ 7.48 (d, J )
2.30 Hz, 1 H), 7.45 (d, J ) 2.14 Hz, 1 H), 7.30 (d, J ) 2.06 Hz,
1 H), 7.29 (d, J ) 2.01 Hz, 1 H), 6.04 (t, J ) 7.41 Hz, 1 H),
4.74 (br, 1 H), 3.98 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.89 (s,
3 H), 3.82 (d, J ) 6.61 Hz, 2 H), 3.28 (td, J ) 6.34 and 6.39
Hz, 2 H), 2.31 (td, J ) 6.87 and 7.16 Hz, 2 H), 1.85 (m, 1 H),
0.88 (d, J ) 6.72 Hz, 6 H); 13C NMR (CDCl3) δ 165.66, 165.39,
156.65, 155.08, 154.84, 139.21, 138.07, 134.95, 134.85, 132.44,
130.82, 129.80, 129.44, 129.19, 128.09, 126.80, 126.59, 70.97,
61.92, 52.44, 40.32, 30.70, 27.85, 18.90; CIMS m/z 568 (MH+);
HRMS calcd for C27H32Cl2NO8 (MH+) 568.1505, found 568.1487.
Anal. (C27H31Cl2NO8) C, H, Cl.
4-(N-E t h oxyca r b on yl)a m in o-3′,3′′-d im e t h yl-4′,4′′-d i-
m eth oxy-5′,5′′-bis(m eth oxyca r bon yl)-1,1-d ip h en ylbu ten e
(44). A mixture of TiCl4/THF 1:2 complex (1.45 g, 4.35 mmol)
and Zn dust (0.57 g, 8.7 mmol) was heated at reflux in dry
THF (15 mL) under argon. After 1 h of reflux, a mixture of
benzophenone 54 (0.56 g, 1.45 mmol) and aldehyde 88 (0.32
g, 2.18 mmol) in dry THF (15 mL) was added dropwise. The
mixture was heated again at reflux for 14 h and then
concentrated. The resulting residue was filtered through a pad
of Celite and washed with ethyl acetate (30 mL). The filtrate
was evaporated, and the brown residue was further purified
by flash chromatography on silica gel (75 g, 2.5 cm × 31 cm,
eluent ethyl acetate/hexanes 3:2, v/v) to afford a colorless oil
(300 mg, 41.5%): 1H NMR (CDCl3) δ 7.40 (d, J ) 2.34 Hz, 1
H), 7.37 (d, J ) 2.12 Hz, 1 H), 7.30 (d, J ) 1.87 Hz, 1 H), 7.25
(d, J ) 1.64 Hz, 1 H), 6.26 (br, 1 H), 6.10 (t, J ) 7.42 Hz, 1 H),
4.04 (q, J ) 7.10 Hz, 2 H), 3.85 (s, 6 H), 3.83 (s, 3 H), 3.79 (s,
3 H), 3.25 (m, 2 H), 2.32 (s, 3 H), 2.30 (t, J ) 6.87 Hz, 2 H),
2.25 (s, 3 H), 1.16 (t, J ) 7.05 Hz, 3 H); 13C NMR (CDCl3) δ
171.60, 171.25, 162.36, 162.26, 161.50, 145.95, 142.95, 141.09,
139.80, 138.37, 137.76, 137.32, 137.0, 134.86, 132.91, 132.26,
130.06, 65.88, 64.76, 56.50, 45.41, 35.79, 20.39, 19.25; EIMS
m/z 499 (M+); HRMS calcd for C27H33NO8 499.2206, found
499.2212. Anal. (C27H33NO8) C, H, N.
Meth yl 5-{1-[3-Ch lor o-4-m eth oxy-5-(m eth oxyca r bon -
yl)p h en yl]-4-[(eth yla m in o)ca r bon yla m in o]bu t-1-en yl}-3-
ch lor o-2-m et h oxyb en zoa t e (45). Amine 96 hydrochloride
salt (21.0 mg, 0.0416 mmol) was dissolved in dry THF (5 mL)
containing triethylamine (10.5 mg, 0.104 mmol). Ethyl iso-
cyanate (8.9 mg, 0.125 mmol) was added. The mixture was
stirred for 2 h and then quenched with methanol (10 mL). The
solvent was removed under reduced pressure, and the residue
was passed through a short column (silica gel 5 g, EtOAc as
eluent) to afford the desired urea compound 45 as white
needles in quantitative yield: mp 103-104 °C; 1H NMR
(CDCl3) δ 7.49 (d, J ) 2.20 Hz, 1 H), 7.46 (d, J ) 2.24 Hz, 1
H), 7.31 (d, J ) 2.25 Hz, 1 H), 7.29 (d, J ) 2.61 Hz, 1 H), 6.04
(t, J ) 7.45 Hz, 1 H), 4.67 (br, 1 H), 4.10 (q, J ) 7.14 Hz, 2 H),
3.99 (s, 3 H), 3.92 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.26 (m,
2 H), 2.31 (dt, J ) 7.13 and 6.90 Hz, 2 H), 1.22 (t, J ) 7.27
Hz, 3 H); HRMS calcd for C25H28N2Cl2O7 539.1352, found
539.1342. Anal. (C25H28N2Cl2O7) C, H, Cl.
Meth yl 5-(1-[3-Ch lor o-4-m eth oxy-5-(m eth oxyca r bon -
yl)p h en yl]-4-{[(m eth yla m in o)th ioxom eth yl]a m in o}bu t-
1-en yl)-3-ch lor o-2-m eth oxyben zoa te (46). Amine 96 hy-
drochloride salt (23.2 mg, 0.0046 mmol) was dissolved in dry
THF (5 mL) containing triethylamine (11.6 mg, 0.115 mmol).
Methyl isothiocyanate (10.1 mg, 0.138 mmol) was added. The
mixture was stirred for 40 min and then concentrated and
subjected to flash chromatography on silica gel (30 g, EtOAc
as eluent) to give the thiourea 46 (17.9 mg, 71.9%) as a viscous
oil: 1H NMR (CDCl3) δ 7.51 (d, J ) 2.42 Hz, 1 H), 7.46 (d, J
) 2.21 Hz, 1 H), 7.32 (d, J ) 2.31 Hz, 1 H), 7.31 (d, J ) 2.25
Hz, 1 H), 6.08 (t, J ) 7.46 Hz, 1 H), 5.80 (br, 1 H), 3.98 (s, 3
H), 3.92 (s, 6 H), 3.90 (s, 3 H), 3.63 (m, 2 H), 2.95 (d, J ) 4.60
Hz, 3 H), 2.41 (dt, J ) 7.21 and 7.14 Hz, 2 H), 1.70 (br, 1 H);
13C NMR (CDCl3) δ 182.76, 165.69, 165.59, 155.13, 154.90,
139.45, 137.79, 134.86, 132.45, 130.79, 129.92, 129.50, 128.54,
128.06, 126.89, 126.57, 61.98, 61.91, 52.54, 52.46, 43.89, 29.84,
14.04; CIMS m/z 541 (MH+); HRMS calcd for C24H26N2Cl2SO6
540.0889, found 540.0865. Anal. (C24H26N2Cl2SO6) C, H, Cl.
4-(N-Isobu tyloxycar bon yl)am in o-3′,3′′-dim eth yl-4′,4′′-di-
m eth oxy-5′,5′′-bis(m eth oxyca r bon yl)-1,1-d ip h en ylbu ten e
(48). Titanium tetrachloride/THF 1:2 complex (1.35 g, 4.03
mmol) was added to a stirred suspension of zinc dust (0.53 g,
8.03 mmol) in dry THF (15 mL). The resulting black mixture
was heated under reflux for 1 h under argon. The suspension
was cooled to room temperature, and a solution of benzo-
phenone 54 (0.50 g, 1.3 mmol) and aldehyde 89 (340 mg, 1.95
mmol) in dry THF (15 mL) was added. The mixture was heated
at reflux for 14 h and then concentrated. The concentrated
residue was passed through a short column (silica gel 5 g,
eluent ethyl acetate 30 mL) to remove the black solid. The
combined fractions were evaporated, and the brown residue
was purified by flash chromatography on silica gel (35 g, 1.5
cm × 31 cm), eluting with hexanes/ethyl acetate (2:1, v/v), to
give a colorless oil (219 mg, 32%): 1H NMR (CDCl3) δ 7.45 (d,
J ) 2.34 Hz, 1 H), 7.40 (d, J ) 2.06 Hz, 1 H), 7.09 (m, 2 H),
5.95 (t, J ) 7.41 Hz, 1 H), 4.68 (br, 1 H), 3.89 (s, 3 H), 3.88 (s,
3 H), 3.86 (s, 3 H), 3.81 (d, J ) 7.67 Hz, 2 H), 3.80 (s, 3 H),
3.27 (td, J ) 6.12 and 6.27 Hz, 2 H), 2.31 (t, J ) 7.02 Hz, 2
H), 2.30 (s, 3 H), 2.24 (s, 3 H), 1.89 (m, 1 H), 0.88 (d, J ) 6.72
Hz, 6 H); 13C NMR (CDCl3) δ 166.86, 166.62, 157.48, 157.42,
156.65, 141.60, 137.51, 136.14, 134.44, 133.72, 132.82, 132.31,
130.12, 127.48, 126.63, 124.29, 70.90, 61.40, 52.08, 40.64,
30.48, 27.86, 18.90, 16.04; CIMS m/z 527 (MH+); HRMS calcd
for C29H38NO8 (MH+) 528.2597, found 528.2588. Anal. (C29H38
NO8) C, H, N.
-
Meth yl 5-{1-[3-Ch lor o-4-m eth oxy-5-(m eth oxyca r bon -
yl)ph en yl]-4-(2-oxo(1,3-oxazolidin -3-yl))bu t-1-en yl}-3-ch lo-
r o-2-m eth oxyben zoa te (49). A mixture of TiCl4/THF 1:2
complex (1.46 g, 4.37 mmol) and Zn dust (571 mg, 8.74 mmol)
was heated at reflux in dry THF (12 mL) under argon. After
1 h of reflux, a mixture of substituted benzophenone 53 (583
mg, 1.37 mmol) and aldehyde 92 (204 mg, 1.43 mmol) in dry
THF (15 mL) was added dropwise. The resulting mixture was
heated again at reflux for 14 h and then cooled to room
temperature and poured into a 10% K2CO3 solution (15 mL).
The white precipitate was filtered off, and the filtrate was
partioned between ethyl acetate and water. The organic layer
was dried over Na2SO4 and then evaporated to give a light-
yellow residue. The residue was purified by flash chromatog-
raphy (silica gel 70 g, solvent hexanes/ethyl acetate 2:3, v/v)
to afford a colorless oil (235 mg, 32%): 1H NMR (CDCl3) δ 7.47
(d, J ) 2.13 Hz, 1 H), 7.46 (d, J ) 1.96 Hz, 1 H), 7.32 (d, J )
2.04 Hz, 2 H), 6.03 (t, J ) 7.49 Hz, 1 H), 4.28 (t, J ) 7.76 Hz,
2 H), 3.98 (s, 3 H), 3.91 (s, 6 H), 3.89 (s, 3 H), 3.38 (t, J ) 7.50
Hz, 2 H), 3.37 (t, J ) 6.90 Hz, 2 H), 2.36 (dt, J ) 7.19 and
6.88 Hz, 2 H); 13C NMR (CDCl3) δ 165.63, 165.36, 158.41,
155.10, 154.91, 139.44, 137.82, 134.92, 134.74, 132.46, 130.65,
129.85, 129.47, 128.51, 128.16, 126.92, 126.63, 61.95, 61.86,
61.52, 52.47, 52.38, 44.40, 43.68, 27.93; CIMS m/z 538 (MH)+;
Anal. (C25H25NCl2O8) C, H, N.
4-(N-Isobu tyloxycar bon yl)am in o-3′,3′′-dich lor o-4′,4′′-di-
m eth oxy-5′,5′′-bis(m eth oxyca r bon yl)-1,1-d ip h en ylbu ten e
(47). A slurry of TiCl4/THF 1:2 complex (1.09 g, 3.27 mmol)
and Zn dust (428 mg, 6.55 mmol) in THF (10 mL) was heated
under reflux for 1 h. A mixture of benzophenone 53 (0.45 g,
1.06 mmol) and aldehyde 89 (274 mg, 1.58 mmol) in dry THF
Meth yl 5-{1-[3-Br om o-4-m eth oxy-5-(m eth oxyca r bon -
yl)ph en yl]-4-(2-oxo(1,3-oxazolidin -3-yl))bu t-1-en yl}-3-br o-
m o-2-m et h oxyb en zoa t e (50). A mixture of TiCl4/THF 1:2
complex (898 mg, 2.69 mmol) and Zn dust (351 mg, 5.38 mmol)

4108 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Xu et al.
was heated at reflux in dry THF (12 mL) under argon. After
1 h of reflux, a mixture of substituted benzophenone 55 (433
mg, 0.84 mmol) and aldehyde 92 (156 mg, 1.09 mmol) in dry
THF (15 mL) was added dropwise. The resulting mixture was
heated again at reflux for 14 h, cooled to room temperature,
and poured into a 10% K2CO3 solution (15 mL). The white
precipitate was filtered off, and the filtrate was partioned
between ethyl acetate and water. The organic layers were
combined and dried over Na2SO4 and evaporated to give a
light-yellow residue. The residue was purified by flash chro-
matography (silica gel 70 g, solvent hexanes/ethyl acetate 2:3,
v/v) to afford a colorless oil (268 mg, 51%): 1H NMR (CDCl3)
δ 7.46 (dd, J ) 2.55 and 0.70 Hz, 2 H), 7.43 (dd, J ) 2.75 and
0.77 Hz, 2 H), 5.97 (t, J ) 7.55 Hz, 1 H), 4.23 (t, J ) 7.72 Hz,
2 H), 3.92 (s, 3 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 3.84 (s, 3 H),
3.34 (t, J ) 6.91 Hz, 2 H), 3.31 (t, J ) 6.82 Hz, 2 H), 2.32 (dt,
J ) 7.28 and 6.92 Hz, 2 H); 13C NMR (CDCl3) δ 165.64, 165.36,
158.38, 156.19, 156.04, 139.35, 138.39, 137.83, 135.61, 135.44,
131.57, 129.16, 128.72, 126.83, 126.56, 119.45, 119.16, 62.23,
62.10, 61.54, 52.59, 52.54, 44.50, 43.80, 28.03; CIMS m/z 626
(MH+), 594 (M - MeOH). Anal. (C25H25NBr2O8) C, H, N, Br.
the solids, and condensed on a rotary evaporator to yield the
crude product as a white solid. The product was purified by
flash column chromatography on silica gel (25 g), using a
gradient of 10-20% ethyl acetate in hexanes as the eluent.
The solvent was removed on a rotary evaporator to give the
product as a white solid (0.430 g, 73%). An analytical sample
was prepared by recrystallization from diethyl ether and
hexane, giving clear colorless crystals: mp 74-77 °C; IR (KBr
pellet) 3010, 2945, 2826, 1720, 1577, 1480, 1444, 1377, 1331,
1
1274, 1248, 1228, 1198, 1126, 1006, 867, 802 cm-1; H NMR
(300 MHz, CDCl3) δ 7.44 (d, J ) 2.2 Hz, 2 H), 7.12 (d, J ) 2.0
Hz, 2 H), 3.90 (s, 6 H), 3.84 (s, 2 H), 3.80 (s, 6 H), 2.27 (s, 6 H).
Anal. (C21H24O6) C, H.
Di[3-ca r b oxy-4-h yd r oxy-5-(t r iflu or om et h yl)p h en yl]-
m eth a n e (61). 3-(Trifluoromethyl)salicylic acid (60,23 0.254
g, 1.23 mmol) was taken up in methanol (0.90 mL) and water
(0.16 mL) with stirring. The solution was cooled to -78 °C,
and concentrated sulfuric acid (2.16 mL) was added dropwise
via an addition funnel. The reaction mixture was warmed to
0 °C, stirred for 1 h, and recooled to -78 °C. Formaldehyde
(0.52 mL, 19 mmol, 37% aqueous solution) was added dropwise
through the addition funnel. The reaction mixture was allowed
to slowly come to ambient temperature overnight. The reaction
mixture was poured over ice (20 g). When all of the ice was
melted, the precipitate was collected on a Bu¨chner funnel. The
solid was taken up in acetone, dried over MgSO4, filtered, and
condensed to afford the product as an off-white solid (0.198 g,
76%). An analytical sample was purified by column chroma-
tography on silica gel (10 g) using AcOH/EtOH/CHCl3 (1:5:
94) as the eluent: mp 306-310 °C (dec); IR (KBr pellet) 3052,
2919, 2861, 1676, 1611, 1445, 1292, 1235, 1167, 1143, 1120,
Di(4-m eth oxy-3-m eth oxycar bon yl-5-m eth ylph en yl) Ke-
ton e (54). Di(4-methoxy-3-methoxycarbonyl-5-methylphenyl)-
methane (59, 4.23 g, 11.4 mmol) was taken up in glacial acetic
acid (550 mL). A solution of chromic anhydride (3.19 g, 31.9
mmol) in glacial acetic acid (25 mL) and water (15 mL) was
prepared and added dropwise to the stirring solution of the
diaryl methane. The resulting solution was stirred for 18 h.
The reaction mixture was diluted to 3 L with water, and the
resulting solution was saturated with NaCl. Portions (500 mL)
of the resulting solution were extracted twice with ethyl
acetate (100 mL). The organic extracts were combined and
dried over anhydrous MgSO4. The solids were removed by
filtration, and the solvent was removed on a rotary evaporator.
The resulting crude yellow solid was purified by chromatog-
raphy on silica gel (200 g), using a gradient elution of 10-
15% ethyl acetate in hexane to elute the product. The eluent
was removed on a rotary evaporator to give the product as a
white solid (2.21 g, 50%). An analytical sample of the product
was prepared by recrystallization from methylene chloride and
hexane: mp 130-132 °C; IR (KBr pellet) 3000, 2959, 2856,
1731, 1664, 1597, 1577, 1474, 1429, 1413, 1382, 1336, 1290,
1254, 1218, 1172, 1136, 1120, 1013, 993, 926, 911, 880, 803,
1
1096, 946, 911, 802, 690 cm-1; H NMR (300 MHz, acetone-
d6) δ 8.08 (d, J ) 1.9 Hz, 2 H), 7.84 (d, J ) 1.8 Hz, 2 H), 4.15
(s, 2 H), 3.08 (br. s, 4 H); 19F NMR (282 MHz, acetone-d6, rel
to TFA external standard) δ 12.66 (s, 6 F). Anal. (C17H10F6O6).
Di[3-m eth oxyca r bon yl-4-m eth oxy-5-(tr iflu or om eth yl)-
p h en yl]m et h a n e (62). Di[3-carboxy-4-hydroxy-5-(trifluoro-
methyl)phenyl]methane (61, 0.950 g, 2.24 mmol) was taken
up with stirring in acetone (27 mL). Potassium carbonate (2.48
g, 17.9 mmol) and dimethyl sulfate (0.66 mL, 7.0 mmol) were
added, and the resulting mixture was heated to reflux in an
oil bath. The reaction mixture was heated at reflux overnight
and then cooled to ambient temperature. Water (25 mL) was
added, and the resulting mixture was extracted with EtOAc
(3 × 25 mL). The organic extracts were combined and dried
(MgSO4). The solution was filtered to remove the solids and
condensed on a rotary evaporator to yield the crude product.
The product was purified by chromatography on silica gel (45
g), using a gradient of 0-15% EtOAc in hexanes as the eluent.
Evaporation of the eluent yielded the pure product as a white
solid (0.314 g, 29%). An analytical sample was prepared by
recrystallization from diethyl ether and hexane: mp 96-98
°C; IR (KBr pellet) 3074, 3006, 2962, 2845, 1728, 1593, 1484,
1436, 1352, 1296, 1257, 1212, 1122, 989, 944, 890, 855, 808,
1
762, 736 cm-1; H NMR (300 MHz, CDCl3) δ 8.03 (d, J ) 2.0
Hz, 2 H), 7.80 (s, 2 H), 3.92 (s, 6 H), 3.92 (s, 6 H), 2.38 (s, 6 H).
Anal. (C21H22O7) C, H.
Di[4-m eth oxy-3-m eth oxyca r bon yl-5-(tr iflu or om eth yl)-
p h en yl] Keton e (57). Di[3-methoxycarbonyl-4-methoxy-5-
(trifluoromethyl)phenyl]methane (62, 0.377 g, 0.785 mmol) was
taken up in acetic anhydride (15 mL) with stirring. Chromic
anhydride (0.330 g, 3.30 mmol) was added in one portion, and
the reaction mixture was stirred overnight. The reaction
mixture was filtered through a plug of Celite in a sintered glass
funnel. The Celite plug was washed with ethyl acetate (50 mL).
The solvents were removed on a rotary evaporator, giving the
crude product as a dark-green paste. The product was purified
by flash column chromatography on silica gel (30 g), using a
gradient of 0-20% ethyl acetate in hexanes as the eluent. The
fractions containing the product were evaporated to dryness,
yielding the product as a colorless oil (0.349 g, 90%): IR (neat
on NaCl) 3005, 2957, 1737, 1670, 1606, 1484, 1439, 1343, 1304,
1262, 1232, 1210, 1137, 1096, 993, 928, 767, 746, 689, 659
1
777, 760, 693, 668 cm-1; H NMR (300 MHz, C6D6) δ 7.64 (d,
J ) 2.1 Hz, 2 H), 7.31 (d, J ) 2.1 Hz, 2 H), 3.60 (s, 6 H), 3.33
(s, 6 H), 3.19 (s, 2 H); 19F NMR (282 MHz, C6D6, rel to TFA
external standard) δ 13.8 (s, 6 F). Anal. (C21H18F6O6) C, H.
Eth yl 5-Oxop en ta n oa te (69). A solution of δ-valerolactone
(4.0 g, 40 mmol) and concentrated H2SO4 (4 drops) in dry
ethanol (80 mL) was heated under reflux for 5 h. The mixture
was cooled in an ice/salt bath, and NaHCO3 (0.4 g) was added.
Stirring was continued for 10 min, the solid was separated by
filtration, and the solvent was removed at 25 °C. The light-
tan residue was dissolved in dry CH2Cl2 (25 mL) and used for
the next step. PCC (13.0 g, 60.3 mmol) was suspended in dry
CH2Cl2 (50 mL). The CH2Cl2 solution of the alcohol was then
added, and the mixture was stirred under nitrogen for 2 h.
Dry ethyl ether (80 mL) was added, and the dark mixture was
allowed to stand overnight. The solid was filtered off and
washed with ethyl ether (2 × 25 mL). The combined solvents
were removed, and the residue was purified by flash chroma-
tography (hexanes/EtOAc 4:1, v/v) to afford aldehyde 69 as a
colorless oil (3.0 g, 52.1%): 1H NMR (CDCl3) δ 9.76 (s, 1 H),
1
cm-1; H NMR (300 MHz, CDCl3) δ 8.38 (d, J ) 2.3 Hz, 2 H),
8.20 (d, J ) 2.2 Hz, 2 H), 4.02 (s, 6 H), 3.97 (s, 6 H); 19F NMR
(282 MHz, CDCl3, rel to TFA external standard) δ 12.80 (s, 6
F). Anal. (C21H16F6O7).
Di(4-m et h oxy-3-m et h oxyca r b on yl-5-m et h ylp h en yl)-
m eth an e (59). Di(3-carboxy-4-hydroxy-5-methyl)methane (58,22
0.500 g, 1.58 mmol) and potassium carbonate (2.11 g) were
suspended with stirring in acetone (10 mL). The solution was
heated to reflux for 30 min. Dimethyl sulfate (1.65 mL, 17.4
mmol) was added via cannula under argon pressure. The
solution was stirred under reflux for 20 h. The reaction mixture
was then cooled to ambient temperature, filtered to remove

Alkenyldiarylmethane Series of Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4109
4.12 (q, J ) 7.09 Hz, 2 H), 2.52 (t, J ) 7.24 Hz, 2 H), 2.35 (t,
filtered off. The filtrate was evaporated, and the crude residue
was purified by flash chromatography on silica gel (120 g, 5
cm × 30 cm), eluting with EtOAc, to give pure aldehyde 73 as
a light-yellow oil (2.1 g, 29%): 1H NMR (CDCl3) δ 9.78 (t, J )
1.20 Hz, 1 H), 3.53 (t, J ) 5.45 Hz, 2 H), 3.38 (t, J ) 5.30 Hz,
2 H), 2.56 (dt, J ) 6.87 and 1.21 Hz, 2 H), 2.36 (t, J ) 7.23
Hz, 2 H), 1.96 (m, 2 H), 1.48-1.66 (m, 6 H); 13C NMR (CDCl3)
δ 202.19, 170.16, 46.45, 43.24, 42.57, 31.99, 26.42, 25.48, 24.45,
17.65. CIMS m/z 184 (MH+); HRMS (CI) calcd for C10H18NO2
184.1338, found 184.1333 (MH+).
5,5-Dim eth oxyp en ta n oic Acid (74). 2,2-Dimethoxypro-
pane (5.9 g, 56.65 mmol) and a small amount of concentrated
HCl (6 drops) were added to a chloroform solution (15 mL)
containing ethyl 5-oxopentanoate (69) (1.25 g, 8.68 mmol). The
reaction mixture was stirred at room temperature for 6 h and
then evaporated in vacuo to afford almost pure acetal (1.56 g,
95%) that was used without further purification: 1H NMR
(CDCl3) δ 4.36 (t, J ) 5.27 Hz, 1 H), 4.11 (q, J ) 7.16 Hz, 2
H), 3.30 (s, 6 H), 2.31 (t, J ) 6.92 Hz, 2 H), 1.63 (m, 4 H), 1.23
(t, J ) 7.08 Hz, 3 H); 13C NMR (CDCl3) δ 174.08, 104.92, 60.37,
52.63, 33.88, 31.75, 20.02, 14.17. The acetal compound (1.39
g, 7.34 mmol) was dissolved in a solution of 1 N NaOH (20
mL) and EtOH (10 mL). The mixture was stirred overnight
and then neutralized to pH 5.5-6.0 by addition of 0.5 N HCl.
The mixture was evaporated and extracted with CH2Cl2. The
combined CH2Cl2 extracts were evaporated to afford acid 74
as a viscous liquid (1.07 g, 90%): 1H NMR (CDCl3) δ 4.38 (t,
J ) 5.04 Hz, 1 H), 3.33 (s, 6 H), 2.39 (t, J ) 6.77 Hz, 2 H),
1.68 (m, 2 H); 13C NMR (CDCl3) δ 179.17, 104.08, 52.63, 34.13,
31.70, 19.94.
2-(Tr im eth ylsilyl)eth yl 5-Oxop en ta n oa te (75). BOP-Cl
(1.68 g, 6.60 mmol) was added to a solution of acid 74 (1.07 g,
6.60 mmol), 2-(trimethylsilyl)ethanol (0.86 g, 7.27 mmol), and
triethylamine (1.33 g, 13.20 mmol) in dry CH2Cl2 (30 mL). The
reaction mixture was stirred at room temperature under argon
for 2 h. A 5% aqueous sodium carbonate solution (40 mL) was
added, and the phases were separated. The organic phase was
diluted with ethyl acetate (2 × 20 mL) and washed with water
(30 mL). The organic solvents were evaporated, and the crude
residue was immediately hydrolyzed in 0.5 N HCl/acetone (1:
1, v/v, 40 mL) for 2 h. The solution was then concentrated,
and the crude product was purified by flash chromatography
on silica gel (100 g, 5 cm × 17.5 in.), eluting with hexanes/
EtOAc (1:1, v/v) to afford aldehyde 75 as a colorless liquid (0.60
g, 42%): 1H NMR (CDCl3) δ 9.76 (s, 1 H), 4.15 (t, J ) 8.50 Hz,
2 H), 2.51 (t, J ) 7.16 Hz, 2 H), 2.33 (t, J ) 7.24 Hz, 2 H), 1.93
(t, J ) 7.20 Hz, 2 H), 0.96 (t, J ) 8.52 Hz, 2 H), 0.02 (s, 9 H);
13C NMR (CDCl3) δ 201.47, 172.95, 62.61, 42.87, 33.23, 17.25,
1.59; CIMS m/z 217 (MH+); HRMS calcd for C10H21SiO3 (MH+)
217.1260, found 217.1261.
J ) 7.26 Hz, 2 H), 1.94 (m, 2 H), 1.24 (t, J ) 7.14 Hz, 3 H); 13
C
NMR (CDCl3) δ 197.66, 172.86, 60.40, 42.87, 33.13, 17.28,
14.15; CIMS m/z 145 (MH+).
P r op yl 5-Oxop en t a n oa t e (70). A solution of δ-valero-
lactone (4.0 g, 40 mmol) and concentrated H2SO4 (6 drops) in
dry propanol (80 mL) was heated under reflux for 3 h. The
mixture was cooled in an ice/NaCl salt bath, and NaHCO3 (0.8
g) was added. Stirring was continued for 10 min, the solid was
separated by filtration, and the solvent was removed at 25 °C.
The light-tan residue was used for the next step without
further purification. PCC (13.2 g, 61.2 mmol) was suspended
in dry CH2Cl2 (50 mL). The alcohol was then added, and the
mixture was stirred under nitrogen for 2 h. Dry ethyl ether
(100 mL) was added, and the dark mixture was allowed to
stand overnight. The solid was filtered off and washed with
ethyl ether (2 × 30 mL). The combined solvents were removed,
and the residue was purified by flash chromatography (hex-
anes/EtOAc 4:1, v/v) on silica gel (120 g) to afford aldehyde
70 as a colorless oil (3.5 g, 55%): 1H NMR (CDCl3) δ 9.78 (s,
1 H), 4.03 (t, J ) 6.74 Hz, 2 H), 2.53 (t, J ) 7.20 Hz, 2 H), 2.37
(t, J ) 7.26 Hz, 2 H), 1.95 (m, 2 H), 1.64 (m, 2 H), 0.93 (t, J )
7.42 Hz, 3 H); 13C NMR (CDCl3) δ 201.51, 172.90, 65.99, 42.83,
33.05, 21.83, 17.24, 10.24. EIMS m/z (relative intensity) 175
(74, hydrate form of aldehyde 2), 157 (100).
Isop r op yl 5-Oxop en ta n oa te (71). A solution of δ-valero-
lactone (3.5 g, 35 mmol) and concentrated H2SO4 (8 drops) in
dry 2-propanol (100 mL) was heated under reflux for 3 h. The
mixture was cooled in an ice/NaCl salt bath, and NaHCO3 (1.0
g) was added. Stirring was continued for 20 min. The solid
was separated by filtration, and the solvent was removed at
25 °C. The light-tan liquid residue was used for the next step
without further purification. PCC (11.3 g, 52.5 mmol) was
suspended in dry CH2Cl2 (50 mL). The alcohol was then added,
and the mixture was stirred under nitrogen for 1.5 h. Dry ethyl
ether (100 mL) was added, and the dark mixture was allowed
to stand overnight. The solid was filtered off and washed with
ethyl ether (2 × 30 mL). The combined solvents were removed,
and the residue was purified by flash chromatography (hex-
anes/EtOAc 4:1, v/v) on silica gel (110 g) to afford aldehyde
71 as a colorless oil (2.15 g, 38.9%): 1H NMR (CDCl3) δ 9.78
(s, 1 H), 5.00 (m, 1 H), 2.52 (t, J ) 7.22 Hz, 2 H), 2.33 (t, J )
7.26 Hz, 2 H), 1.94 (m, 2 H), 1.23 (d, J ) 6.21 Hz, 6 H); 13C
NMR (CDCl3) δ 201.43, 172.28, 67.67, 42.82, 33.40, 21.69,
17.28; EIMS m/z (relative intensity) 175 (74, hydrate form of
aldehyde 3), 157 (100).
N,N-Dim eth yl 5-Oxop en ta n a m id e (72). N,N-Dimethyl-
amine (15 mL of 2 M dimethylamine in THF) was added to a
solution of δ-valerolactone (1.5 g, 15 mmol) in THF (10 mL).
The mixture was stirred at room temperature for 72 h, and
the solvent and excess dimethylamine were removed to give a
brown liquid, which was used for the next step without further
purification. PCC (4.3 g, 20 mmol) was suspended in dry
CH2Cl2 (25 mL). The above alcohol was added, and the reaction
mixture was stirred under nitrogen for 2 h. Dry ethyl ether
(30 mL) was then added, and the dark mixture was filtered
through a pad of Celite. The solvents were removed, and the
residue was purified by flash chromatography on silica gel (45
g, 5 cm × 17.5 in.), eluting with EtOAc/MeOH (6:1, v/v), to
afford aldehyde 72 as a colorless oil (0.76 g, 35%): 1H NMR
(CDCl3) δ 9.73 (s, 1 H), 2.93 (s, 6 H), 2.52 (t, J ) 6.17 Hz, 2
H), 2.33 (t, J ) 6.78 Hz, 2 H), 1.92 (t, J ) 6.62 Hz, 2 H); 13C
NMR (CDCl3) δ 202.20, 172.17, 43.13, 33.22, 31.92, 17.41;
CIMS m/z 144 (MH+); HRMS (CI) calcd for C7H14NO2 144.1025,
found 144.1018.
1-(5-Oxop en ta n oyl)p ip er id in e (73). δ-Valerolactone (4 g,
40 mmol) was added to piperidine (10.2 g, 120 mmol). The
reaction mixture was stirred for 48 h at room temperature,
and then the excess amine was removed through rotary
evaporation. The tan residue was dissolved in CH2Cl2 (10 mL)
and used for the next step. PCC (12.93 g, 60 mmol) was
suspended in dry CH2Cl2 (40 mL). The above alcohol was
added, and the mixture was kept stirring for 4 h. Dry ethyl
ether (100 mL) was added, and the resulting dark solid was
4-(Meth ylth io)bu tan al (76). 4-(Methylthio)-1-butanol (3.09
g, 25.7 mmol) was taken up with stirring in dichloromethane
(360 mL). Dess-Martin periodinane (10.91 g, 25.7 mmol) was
added in one portion to the stirring reaction mixture. The
reaction mixture was allowed to stir at ambient temperature
for 3 h. The reaction mixture was washed with a saturated
aqueous soluton of sodium bicarbonate (2 × 100 mL). The
organic layer was separated and was washed with brine (2 ×
100 mL). The organic layer was dried over MgSO4 and filtered,
and the solvent was removed on a rotary evaporator. The crude
product was purified by distillation under reduced pressure
(25 mmHg). The fraction that was distilled between 75 and
80 °C was collected (0.601 g, 20%): IR (neat on NaCl) 2917,
1
2834, 2724, 1723, 1428, 1127, 1062, 958 cm-1; H NMR (300
MHz, C6D6) δ 9.24 (s, 1 H), 2.05 (t, J ) 7.0 Hz, 2 H), 1.83 (t,
J ) 7.1 Hz, 2 H), 1.67 (s, 3 H), 1.55-1.45 (m, 2 H). Anal.
(C5H10OS‚0.15H2O) C, H.
1-(Meth ylth io)h ex-5-yn -1-on e (78). 5-Hexynoic acid (2.24
g, 20 mmol) was dissolved in dry THF (20 mL). Oxalyl chloride
(2.10 mL, 24 mmol) was added, followed by a catalytic amount
of DMF (2 drops). The mixture was stirred under nitrogen at
room temperature for 2 h, and the solvents were removed. The
crude acid chloride residue was dissolved in dry THF (40 mL).
NaSCH3 (2.1 g, 30 mmol) in 20 mL of DMF was added at 0

4110 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24
Xu et al.
°C. The reaction mixture was stirred under nitrogen overnight.
The mixture was diluted with water (20 mL), and the organic
layer was separated. The water layer was further extracted
with ethyl acetate (2 × 30 mL). The combined extracts were
dried over Na2SO4 and then were evaporated. The crude
residue was purified by flash chromatography on silica gel (70
g, eluent hexanes/EtOAc 5:1, v/v) to afford a light-yellow liquid
(1.4 g, 50%): 1H NMR (CDCl3) δ 2.65 (t, J ) 7.36 Hz, 2 H),
2.23 (s, 3 H), 2.20 (m, 2 H), 1.93 (t, J ) 2.46 Hz, 1 H), 1.86 (m,
2 H); 13C NMR (CDCl3) δ 199.09, 82.92, 69.18, 42.24, 24.97,
17.61, 11.43; ESI m/z 142 (M+).
purified by flash chromatography (silica gel 70 g, eluent
EtOAc/hexanes 1:3, v/v) to afford aldehyde 81 as a yellow oil
(0.7 g, 44%): 1H NMR (CDCl3) δ 9.76 (s, 1 H), 2.87 (q, J )
7.40 Hz, 2 H), 2.59 (t, J ) 7.25 Hz, 2 H), 2.50 (t, J ) 7.03 Hz,
2 H), 1.98 (m, 2 H), 1.24 (t, J ) 7.39 Hz, 3 H); 13C NMR (CDCl3)
δ 201.21, 198.79, 42.55, 23.18, 20.24, 17.78, 14.58. Anal.
(C7H12SO2) C, H, S.
Gen er a l P r oced u r e for P r ep a r a tion of 3-Hyd r oxyp r o-
p ylca r ba m a tes. 3-Aminopropanol (3.0 g, 40 mmol) was
dissolved in water (10 mL). A solution of potassium carbonate
(8.85 g, 64 mmol) in water (10 mL) was added, followed by
slow addition of alkyl chloroformate (60 mmol) at 0 °C. Stirring
was continued at 0 °C for 2 h. Then the reaction mixture was
extracted with CH2Cl2. The CH2Cl2 extracts were dried
(Na2SO4) and evaporated to give almost pure 3-hydroxy-
propylcarbamate, which was oxidized without further purifica-
tion.
Meth yl 3-Hyd r oxyp r op ylca r ba m a te (84). Colorless liq-
uid (4.7 g, 90%): 1H NMR (CDCl3) δ 3.66 (t, J ) 5.70 Hz, 2
H), 3.54 (s, 3 H), 3.34 (t, J ) 6.0 Hz, 2 H), 1.68 (m, 2 H).
Eth yl 3-Hyd r oxyp r op ylca r ba m a te (85). Colorless liquid
(5.4 g, 94%): 1H NMR (CDCl3) δ 4.10 (q, J ) 7.14 Hz, 2 H),
3.66 (t, J ) 5.75 Hz, 2 H), 3.31 (t, J ) 6.26 Hz, 2 H), 1.68 (m,
2 H), 1.22 (t, J ) 7.09 Hz, 3 H); 13C NMR (CDCl3) δ 157.45,
60.93, 59.40, 37.46, 32.52, 14.46.
Isobu tyl 3-Hyd r oxyp r op ylca r ba m a te (86). Colorless
liquid (6.37 g, 99%): 1H NMR (CDCl3) δ 3.85 (d, J ) 5.51 Hz,
2 H), 3.68 (t, J ) 5.60 Hz, 2 H), 3.34 (t, J ) 6.0 Hz, 2 H), 1.88
(m, 1 H), 1.70 (m, 2 H); 13C NMR (CDCl3) δ 155.26, 71.14,
61.72, 59.29, 32.59, 27.88, 18.88.
Sw er n Oxid a tion of 3-Hyd r oxyp r op ylca r ba m a tes. Ox-
alyl chloride (3.31 g, 26.05 mmol) was dissolved in CH2Cl2 (20
mL) at -78 °C. Dimethyl sulfoxide (5.34 g, 56.84 mmol) in
CH2Cl2 (10 mL) was added. The mixture was kept stirring for
20 min, followed by addition of 3-hydroxypropylcarbamate
(23.68 mmol) in CH2Cl2 (10 mL) and triethylamine (11.96 g,
118.4 mmol). The resulting mixture was stirred for another 1
h at room temperature and washed with water (2 × 20 mL).
The CH2Cl2 extracts were dried (Na2SO4) and evaporated. The
crude residue was purified by flash chromatography on silica
gel (120 g, 5 cm × 31 cm, ethyl acetate/hexanes 1:1, v/v) to
afford the corresponding aldehyde in more than 60% yield.
Meth yl 3-Oxop r op ylca r ba m a te (87). Colorless liquid
(2.01 g, 65%): 1H NMR (CDCl3) δ 9.70 (s, 1 H), 3.54 (s, 3 H),
3.36 (td, J ) 6.04 and 5.93 Hz, 2 H), 2.64 (t, J ) 5.67 Hz, 2
H); 13C NMR (CDCl3) δ 201.37, 156.94, 51.97, 43.94, 34.32;
CIMS m/z 132 (MH)+; HRMS calcd for C5H9NO3 131.0582,
found 131.0577.
1-(Eth ylth io)h ex-5-yn -1-on e (79). 5-Hexynoic acid (1.68
g, 15 mmol) was dissolved in dry THF (20 mL). Oxalyl chloride
(1.44 mL, 16.5 mmol) was added, followed by a catalytic
amount of DMF (2 drops). The mixture was stirred under
nitrogen at room temperature for 2 h, and the solvents were
removed. The crude acid chloride residue was dissolved in dry
THF (40 mL). Triethylamine (1.82 g, 18 mmol) was added,
followed by ethanethiol (1.16 mL, 15.75 mmol). The reaction
mixture was stirred under nitrogen overnight. The mixture
was diluted with water (20 mL), and the organic layer was
separated. The water layer was extracted with ethyl acetate
(2 × 20 mL). The combined extracts were dried over Na2SO4
and then were evaporated. The crude residue was purified by
flash chromatography on silica gel (50 g, eluent hexanes/EtOAc
5:1, v/v) to afford a light-yellow liquid (1.5 g, 64%): 1H NMR
(CDCl3) δ 2.83 (q, J ) 7.40 Hz, 2 H), 2.68 (t, J ) 7.37 Hz, 2
H), 2.25 (td, J ) 6.89 and 2.59 Hz, 2 H), 1.98 (t, J ) 2.58 Hz,
1 H), 1.86 (m, 2 H), 1.25 (t, J ) 7.49 Hz, 3 H); 13C NMR (CDCl3)
δ 198.81, 82.98, 69.14, 42.44, 24.05, 23.15, 17.62, 14.61; EIMS
m/z 157 (MH+); HRMS calcd for C8H13OS (MH+) 157.0687,
found 157.0682.
5-(Meth ylth io)-5-oxop en ta n a l (80). The alkyne 78 (1.4
g, 10 mmol) was hydrogenated using 5% palladium on barium
sulfate (100 mg) and quinoline (115 mg) in ethyl acetate (30
mL) for 14 h. The catalyst was removed by filtration, and the
solvent was evaporated. The residue was passed through a
short column (silica gel 10 g, eluent hexanes/EtOAc 5:1, v/v)
to remove quinoline and to afford an almost pure alkene
intermediate: 1H NMR (CDCl3) δ 5.75 (m, 1 H), 4.97-5.05 (m,
2 H), 2.56 (t, J ) 7.31 Hz, 2 H), 2.28 (s, 3 H), 2.09 (dt, J )
6.72 and 7.08 Hz, 2 H), 1.77 (m, 2 H); 13C NMR (CDCl3) δ
195.07, 132.79, 110.85, 38.42, 28.15, 20.04, 6.84. The alkene
(1.0 g, 6.94 mmol) was dissolved in CH2Cl2 (40 mL) and then
cooled to -78 °C. Ozonized oxygen was bubbled through this
solution for 40 min. As the reaction progressed, the solution
turned blue. Nitrogen was then passed through the reaction
mixture until the blue color disappeared. Dimethyl sulfide (861
mg, 13.8 mmol) was added, and the reaction mixture was
stirred for 2 h at room temperature. The mixture was washed
with water (2 × 10 mL) and dried over Na2SO4. The solvent
and excess dimethyl sulfide were evaporated in the hood, and
the residue was purified by flash chromatography (silica gel
70 g, eluent EtOAc/hexanes 1:3, v/v) to afford aldehyde 80 as
a yellow oil (240 mg, 24%): 1H NMR (CDCl3) δ 9.76 (d, J )
1.03 Hz, 1 H), 2.61 (t, J ) 7.23 Hz, 2 H), 2.52 (dt, J ) 7.01
and 1.03 Hz, 2 H), 2.29 (s, 3 H), 1.99 (m, 2 H); 13C NMR (CDCl3)
δ 196.53, 37.96, 37.82, 13.25, 6.88; CIMS (MH+) m/z 147.
Eth yl 3-Oxop r op ylca r ba m a te (88). Colorless liquid (2.47
g, 72%): 1H NMR (CDCl3) δ 9.80 (s, 1 H), 4.04 (q, J ) 7.10
Hz, 2 H), 3.46 (td, J ) 6.04 and 5.93 Hz, 2 H), 2.73 (t, J )
5.67 Hz, 2 H), 1.16 (t, J ) 7.05 Hz, 3 H).
Isobu tyl 3-Oxop r op ylca r ba m a te (89). Colorless liquid
(3.2 g, 85%): 1H NMR (CDCl3) δ 9.80 (s, 1 H), 3.84 (d, J )
6.13 Hz, 2 H), 3.46 (td, J ) 6.04 and 5.93 Hz, 2 H), 2.73 (t, J
) 5.67 Hz, 2 H), 1.87 (m, 1 H), 0.90 (d, J ) 6.53 Hz, 6 H); 13
C
NMR (CDCl3) δ 201.22, 157.18, 71.02, 44.06, 34.24, 27.83,
18.89.
3-Bu t-3-en yl-1,3-oxa zolid in -2-on e (91). 4-Bromo-1-butene
(2.21 g, 16.4 mmol) was added to a mixture containing
2-oxazolidinone (1.10 g, 12.6 mmol) and cesium carbonate (12.3
g, 37.9 mmol) in acetone (45 mL). The mixture was heated at
60 °C for 48 h, cooled to room temperature, and filtered. The
filtrate was evaporated, and the residue was purified by flash
chromatography on silica gel (60 g), eluting with hexanes/ethyl
acetate (1:1, v/v), to afford the desired product 91 (1.39 g, 78%)
as a colorless oil: 1H NMR (CDCl3) δ 5.80 (ddt, J ) 17.07,
3.50 and 6.74 Hz, 1 H), 5.09-5.19 (m, 2 H), 4.34 (t, J ) 7.83
Hz, 2 H), 3.60 (t, J ) 6.66 Hz, 2 H), 3.38 (t, J ) 7.12 Hz, 2 H),
2.36 (dt, J ) 7.05 and 7.00 Hz, 2 H); 13C NMR (CDCl3) δ 153.82,
129.97, 112.62, 56.99, 39.89, 38.75, 24.55.
5-(Eth ylth io)-5-oxop en ta n a l (81). The alkyne 79 (1.5 g,
10 mmol) was hydrogenated using 5% palladium on barium
sulfate (100 mg) and pure quinoline (115 mg) in ethyl acetate
(30 mL). After 14 h, the catalyst was removed by filtration
and the solvent was evaporated. The residue was passed
through a short column (silica gel 10 g, eluent hexanes/EtOAc
5:1, v/v) to remove quinoline. The combined fractions were
evaporated, dissolved in CH2Cl2 (40 mL), and then cooled to
-78 °C. Ozonized oxygen was bubbled through this solution
for 40 min. As the reaction progressed, the solution turned
blue. Nitrogen was then passed through the reaction mixture
until the blue color disappeared. Dimethyl sulfide (1.24 g, 20
mmol) was added, and the reaction mixture was stirred for 2
h at room temperature. Then the mixture was washed with
water (2 × 10 mL) and dried over Na2SO4. The solvent and
excess dimethyl sulfide were evaporated, and the residue was
3-(2-Oxo-1,3-oxa zolid in -3-yl)p r op a n a l (92). 3-But-3-enyl-
1,3-oxazolidin-2-one 91 (1.0 g, 7.09 mmol) and 4-methylmor-
pholine N-oxide (1.66 g, 14.18 mmol) were dissolved in an

Alkenyldiarylmethane Series of Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4111
aqueous MeOH solution (40 mL, MeOH/H2O 3:1, v/v). Five
drops of OsO4 (1% solution in water) were added to the solution
at 0 °C. After the reaction mixture was stirred at room
temperature overnight, the TLC showed the complete dis-
appearance of the starting material. The reaction mixture was
then concentrated, and the diol compound was too hydrophilic
to be extracted with CH2Cl2. Therefore, the crude diol was used
for the next step without puification. Sodium periodate (3.03
g, 14.2 mmol) was added to the diol (redissolved in 20 mL of
acetone/H2O, 1:1) at 0 °C. The reaction mixture was stirred at
room temperature for 4 h. As the reaction progressed, a white
precipitate was formed. The the reaction mixture was filtered,
the residue was washed with acetone, and the combined
filtrates were concentrated on a rotary evaporator. The residue
was treated with water and extracted with CHCl3 (3 × 25 mL).
The combined organic extracts were dried over Na2SO4 and
concentrated on a rotary evaporator to furnish the product,
which was further purified by passing through a short column
on silica gel (60 g, EtOAc as eluent) to afford the desired
compound as a colorless oil: yield 0.64 g (63%); 1H NMR
(CDCl3) δ 7.46 (d, J ) 2.13 Hz, 1 H), 7.45 (d, J ) 1.96 Hz, 1
H), 7.32 (d, J ) 2.04 Hz, 2 H), 6.03 (t, J ) 7.54 Hz, 1 H), 4.28
(t, J ) 8.00 Hz, 2 H), 3.98 (s, 3 H), 3.91 (s, 6 H), 3.89 (s, 3 H),
3.38 (t, J ) 7.50 Hz, 4 H), 2.36 (q, J ) 7.01 Hz, 2 H); 13C NMR
(CDCl3) δ 165.63, 165.36, 158.41, 155.10, 154.91, 139.44,
137.82, 134.92, 134.74, 132.46, 130.65, 129.85, 129.47, 128.51,
128.16, 126.92, 126.63, 61.95, 61.86, 61.52, 52.47, 52.38, 44.40,
43.68, 27.93; CIMS m/z 144 (MH)+.
solvents were removed through rotatory evaporation, and the
crude residue was purified by flash chromatography on silica
gel (35 g, 2.5 cm × 31 cm), eluting with EtOAc/hexanes (1.5:1,
v/v) to afford a light-yellow oil (201 mg, 99%): 1H NMR (CDCl3)
δ 7.50 (d, J ) 2.40 Hz, 1 H), 7.47 (d, J ) 2.16 Hz, 1 H), 7.33
(d, J ) 2.23 Hz, 1 H), 7.32 (d, J ) 2.23 Hz, 1 H), 6.08 (t, J )
7.41 Hz, 1 H), 3.96 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.88 (s,
3 H), 3.39 (br, 2 H), 2.87 (t, J ) 6.70 Hz, 2 H), 2.38 (dt, J )
7.49 and 7.05 Hz, 2 H); 13C NMR (CDCl3) δ 165.84, 165.61,
155.09, 154.85, 139.27, 138.11, 135.08, 134.99, 132.50, 130.95,
129.81, 129.48, 129.24, 128.13, 126.84, 126.63, 61.98, 52.52,
41.21, 32.31; FABMS m/z 468 (MH+).
An tivir a l Eva lu a tion s. Cells a n d Vir u ses. CEM-SS cells
were obtained from the NIAID AIDS Research and Reference
Reagent Program (Bethesda, MD). The CEM-SS cells were
maintained in RPMI 1640 medium supplemented with 10%
heat-inactivated fetal bovine serum, 2 mM glutamine, penicil-
lin (100 U/mL), and streptomycin (100 µg/mL). Human im-
munodeficiency virus type 1 (HIV-1) strains subtype A (92/
UG/037), subtype B (92/BR/014), subtype C (93/MW/959),
subtype D (92/UG/001), subtype E (92/THA/037), subtype F
(93/BR/020), subtype G (G3), and subtype O (BCOF-01) Ba-L
and RF were obtained from the NIAID AIDS Research and
Reference Reagent Program. The low-passage pediatric clinical
isolates ROJ O, WEJ O, SLKA, and TEKI were derived as
previously described.50 The MDR769 virus was generously
provided by the laboratory of T. C. Merigan (Stanford Uni-
versity).
N-F lu or en ylm eth oxyca r bon yl-3-a m in op r op a n a l (94).
N-Fmoc-â-alanine (1.5 g, 4.82 mmol) was dissolved in dry THF
(10 mL). Oxalyl chloride (0.60 mL, 6.8 mmol) was added,
followed by a catalytic amount of DMF (2 drops). The mixture
was stirred for 2 h at room temperature. Excess oxalyl chloride
and THF were removed. The residue was dissolved in dry THF
(10 mL), and (Ph3P)4Pd (56 mg, 0.048 mmol) was added.
Tributyltin hydride (1.55 mL, 5.78 mmol) was added dropwise.
The mixture was stirred for another 1 h. The solvent was
removed, and the residue was washed with hexanes. The solid
was dissolved in a minimum amount of CH2Cl2 and applied
to a silica gel (55 g) column. Elution with hexanes/EtOAc (1:
2, v/v) afforded aldehyde 94 (1.1 g, 78%) as white needles: mp
109-110 °C; 1H NMR (CDCl3) δ 9.80 (s, 1 H), 7.76 (d, J )
7.30 Hz, 2 H), 7.57 (d, J ) 7.30 Hz, 2 H), 7.38 (t, J ) 7.30 Hz,
2 H), 7.30 (t, J ) 7.30 Hz, 2 H), 5.15 (s, 1 H), 4.38 (d, J ) 6.70
Hz, 2 H), 4.18 (t, J ) 6.70 Hz, 1 H), 3.47 (dd, J ) 11.10 and
5.40 Hz, 2 H), 2.73 (t, J ) 5.40 Hz, 2 H); PDMS m/z 295 (MH+).
Anal. (C18H17NO3) C, H, N.
4-(N-F lu or en ylm eth oxyca r bon yl)a m in o-3′,3′′-d ich lor o-
4′,4′′-dim eth oxy-5′,5′′-bis(m eth oxycar bon yl)-1,1-diph en yl-
1-bu ten e (95). A slurry of TiCl4/THF 1:2 complex (0.71 g, 2.2
mmol) and Zn dust (0.30 g, 4.3 mmol) in THF (25 mL) was
heated under reflux for 2 h. A mixture of substituted benzo-
phenone 53 (0.30 g, 0.70 mmol) and aldehyde 94 (0.31 g, 1.05
mmol) in dry THF (10 mL) was added. The dark mixture was
heated under reflux for 6 h. It was then cooled to room
temperature, and water (10 mL) was added. The mixture was
stirred at room temperature for 2 h. The precipitate was
filtered off and washed with EtOAc (3 × 15 mL). The filtrate
was concentrated, and the residue was chromatographed on
silica gel (45 g, 2.5 cm × 31 cm), eluting with EtOAc/hexanes
(1:2.5, v/v) to provide 95 as a white foam (0.30 g, 62.1%): mp
71-73 °C; 1H NMR (CDCl3) δ 7.75 (d, J ) 7.50 Hz, 2 H), 7.58
(d, J ) 7.50 Hz, 2 H), 7.49 (d, J ) 1.90 Hz, 2 H), 7.46 (d, J )
2.0 Hz, 2 H), 7.37 (t, J ) 7.40 Hz, 2 H), 7.27 (t, J ) 7.40 Hz,
2 H), 6.04 (t, J ) 7.20 Hz, 1 H), 4.78 (t, J ) 7.40 Hz, 1 H), 4.41
(d, J ) 7.0 Hz, 2 H), 4.20 (t, J ) 7.0 Hz, 2 H), 3.96 (s, 3 H),
3.90 (s, 3 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 3.31 (q, J ) 6.53 Hz,
2 H), 2.26 (q, J ) 6.75 Hz, 2 H); PDMS m/z 691 (MH+). Anal.
(C37H33Cl2NO8) C, H, N.
HIV Cytop r otection Assa y a n d Cr oss-Resista n ce As-
sa ys. The inhibitory activities of the compounds were evalu-
ated as previously described with the cytopathic RF strain of
HIV-1 and CEM-SS cells.51 These are microtiter assays, which
quantitate the ability of a compound to inhibit HIV-1 induced
cell killing via syncytium formation. Cytoprotection and
compound cytotoxicity are measured with the CellTiter 96
Reagent (Promega, Madison, WI) 6 days after infection. This
reagent contains the tetrazolium compound [3-(4,5-dimeth-
ylthiazol-2-yl)-5-(carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-
tetrazolium, inner salt (MTS), and the electron-coupling agent
phenazine ethosulfate in a colorless stable solution, which
upon reduction by viable cells forms a colored solution with
absorbance at 490 nm. Antiviral and toxicity data are reported
as the concentration of compound required to inhibit 50%
virus-induced cell killing (50% effective concentration [EC50])
and the concentration of compound required to reduce cell
viability by 50% (cytotoxicity). All data are derived from
triplicate tests with the variation of the mean averaging 10%.
The efficacy of the ADAMs against the molecular cloned virus
NL4-3 expressing specific reverse transcriptase resistant
mutations by site mutagenesis in the RT gene was determined
as described above in CEM-SS cells. However, for the A98G,
K103E, L74V 4X AZT (D67N, K70R, T215Y, and K219Q), and
4X AZT/L100I, virus replication was assessed by p24 ELISA
(Coulter Immunotech, Hialeah FL) rather than cytoprotection
by CellTiter 96 reagent because of low cytopathogeneicity of
the resistant virus. The effect of nevaripine and AZT on wild-
type NL4-3 replication was determined by both methods, and
the resulting IC50 values were within 2-fold of each other.
Thus, for calculation of increased or decreased sensitivity to
the ADAMs, a mean of the two IC50 values were used.
P BMC a n d Mon ocyte/Ma cr op h a ge An tivir a l Assa ys.
Human peripheral blood mononuclear cells (PBMC) and
monocytes were isolated from hepatitis and HIV sero-negative
donors by ficoll hypaque gradient centrifugation as previously
described.52 Antiviral assays were accomplished with 3-day-
old phytohemagglutinin/IL-2 stimulated PBMC or 6-day-
cultured monocyte/macrophages. All antiviral evaluations were
performed in triplicate in RPMI 1640 supplemented with 10%
fetal bovine serum, L-glutamate (2 mM), penicillin (100 U/mL),
and streptomycin (100 µg/mL). HIV replication in PBMC
cultures was determined by measurement of supernatant
reverse transcriptase activity53 and in monocyte macrophage
cultures by ELISA for p24 antigen expression 6 days post-
infection. Cell viability by formazan dye reduction was deter-
4-Amino-3′,3′′-dichloro-4′,4′′-dimethoxy-5′,5′′-bis(methoxy-
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g, 0.435 mmol) was dissolved in dry THF (20 mL). Piperidine
(5 mL) was added to the above solution, and the reaction
mixture was stirred at room temperature for 3 h. The organic

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