Novel modifications in the alkenyldiarylmethane (ADAM) series of non- nucleoside reverse transcriptase inhibitors

Article abstract of DOI:10.1021/jm990343b

In an effort to obtain more insight into the interaction between HIV-1 reverse transcriptase and the alkenyldiarylmethanes (ADAMs), a new series of compounds has been synthesized and evaluated for inhibition of HIV-1 replication. The modifications reporte

Full text of DOI:10.1021/jm990343b

J . Med. Chem. 1999, 42, 4861-4874
4861
Novel Mod ifica tion s in th e Alk en yld ia r ylm eth a n e (ADAM) Ser ies of
Non -Nu cleosid e Rever se Tr a n scr ip ta se In h ibitor s
Agustin Casimiro-Garcia,† Mark Micklatcher,† J im A. Turpin,§ Tracy L. Stup,§ Karen Watson,§
Robert W. Buckheit,§ 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, Serquest,
a Southern Research Institute Company, 431 Aviation Way, Frederick, Maryland 21701
Received J uly 6, 1999
In an effort to obtain more insight into the interaction between HIV-1 reverse transcriptase
and the alkenyldiarylmethanes (ADAMs), a new series of compounds has been synthesized
and evaluated for inhibition of HIV-1 replication. The modifications reported in this new series
include primarily changes to the alkenyl chain. The most potent compound proved to be methyl
3′,3′′-dibromo-4′,4′′-dimethoxy-5′,5′′-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (28), which
displayed an EC50 of 1.3 nM for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells.
ADAM 28 inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 µM. Mutations that
conferred greater than 10-fold resistance to ADAM 28 clustered at residues Val 106, Val 179,
Tyr 181, and Tyr 188. Results derived from this series indicate that ADAMs containing chlorines
in the aromatic rings might bind to HIV-1 reverse transcriptase in a slightly different mode
when compared with those analogues incorporating bromine in the aromatic rings.
In tr od u ction
AZT.8 In this report, we present a new series of ADAMs
which has been evaluated for prevention of the cyto-
pathic effect of HIV-1 and for inhibition of HIV-1 reverse
transcriptase (RT).
The therapeutic agents currently approved for the
treatment of HIV infections include two non-nucleoside
HIV-1 reverse transcriptase inhibitors (NNRTIs), nevi-
rapine and delavirdine.1,2 Although the therapeutic
potential of this class of drugs has been compromised
by the rapid development of resistance, its use has been
recently recommended when employed in combination
therapy.1,3 Encouraging results have been reported
when triple drug combinations that include one NNRTI
are used.4 In most of these studies, a reduction in HIV-1
RNA level, or an increase in CD4 lymphocyte count, or
both have been observed and are associated with a delay
in disease progression. However, there are certain
factors that restrict the selection of the agents for
combination therapy, including drug compatibilities,
adverse effects, and cross-resistance.1 Therefore, the
development of new NNRTIs with pharmacokinetic
characteristics and resistance mutation profiles more
compatible with other anti-HIV agents is important for
a more successful application of this class of drugs in
combination therapy.
We previously reported the alkenyldiarylmethanes
(ADAMs) as a new class of NNRTIs.5-8 Further interest
in this class of NNRTIs has been augmented by the
finding that one of our compounds, methyl 3′,3′′-dichloro-
4′,4′′-dimethoxy-5′,5′′-bis(methoxycarbonyl)-6,6-diphenyl-
5-hexenoate (ADAM II, 1), proved to be a nanomolar
inhibitor (EC50 ) 13 nM) of the cytopathic effect of HIV-
1RF in CEM-SS cells.7,8 In addition, virus strains con-
taining mutations that confer resistance to AZT showed
increased sensitivity to ADAM II, which indicated the
possible role of ADAM II in combination therapy with
Ch em istr y
During the design of ADAM II, it was proposed that
functional groups which are capable of acting as hydro-
gen bond acceptors present at the end of the alkenyl
chain could interact favorably with the Glu 138 or Lys
103 residue of HIV-1 RT. The alkenyl chain length and
the nature of the functionality present at the end of the
chain were initially investigated as described in our last
report.8 In an effort to gain more insight into the role
of this part of the molecule during the binding with
HIV-1 RT, we decided to explore additional modifica-
tions in the alkenyl chain, including: (1) its length; (2)
the functional group present at the end of it; and (3)
reduction of the double bond. Two other modifications
were planned in this new series: replacement of the
chlorine atoms present in 1 with other halogens and
modifications of the aromatic methoxycarbonyl groups.
With these considerations in mind, a new series of
ADAMs was synthesized and evaluated for inhibition
of HIV-1 RT and for prevention of the cytopathic effect
of HIV-1 in cell culture.
A set of compounds was planned in which the meth-
oxycarbonyl group of the alkenyl chain present in 1
would be maintained constant but the length of the
chain would be varied. The first analogue of this set that
incorporates a two-carbon shorter alkenyl chain was
prepared from the previously reported carboxylic acid
2.9 Reaction of 2 with diazomethane afforded analogue
3.
† Purdue University.
§ Serquest.
10.1021/jm990343b CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/21/1999

4862 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Casimiro-Garcia et al.
fashion as the methoxycarbonyl present in 1 but also
on the fact that this group might react with Lys 103 to
give a covalently bonded inhibitor. Analogue 11 would
incorporate the same chain length present in ADAM II.
This compound was obtained by Swern oxidation of
alcohol 6.17
The McMurry reaction was used for the preparation
of additional ADAM II analogues.18,19 Among the dif-
ferent titanium reagents reported for this reaction, we
have employed the commercially available titanium
tetrachloride-tetrahydrofuran complex (1:2) and zinc
dust for all our reactions. In this way, we have been
able to carry out several couplings between benzophe-
none 13 and different aldehydes, providing the corre-
sponding cross-coupled products in good yields (50-
75%). Under these conditions, benzophenone 13 was
reacted with aldehyde 1620 in THF to give ester 12. This
compound incorporates the methoxycarbonyl group at-
tached at the end of a six-atom chain, which makes it
the one-carbon-extended chain ADAM II analogue.
For the preparation of congener 18, benzophenone 13
was coupled with aldehyde 17 (obtained in three steps
from methyl 5-chloro-5-oxovalerate)21,22 under condi-
tions previously described (Scheme 1). Interestingly, the
ketal group of the alkenyl chain of 18 was not affected
under the acidic conditions of the McMurry coupling.
This compound was then used for the preparation of
several analogues. Reduction of 18 with DIBAL-H (4.3
equiv) in dichloromethane-toluene afforded diol 20 as
the main product, along with some aldehyde 21. Con-
version of diol 20 into the corresponding dialdehyde 23
was achieved by Swern oxidation.17 The direct conver-
sion of diester 18 to dialdehyde 23 was attempted using
DIBAL-H (2.2 equiv), but only mixtures of 20 and 21
were obtained. Removal of the ketal group from 18, 20,
and 23 with pyridinium p-toluenesulfonate (PPTS) in
Wittig chemistry was used to install the alkenyl linker
chain in some of the new ADAMs. Reacting ketone 1310
with the ylide derived from the commercially available
phosphonium bromide 14 and sodium bis(trimethylsi-
lyl)amide afforded dioxolane 4. In a similar fashion, the
ylide obtained from phosphonium bromide 1511 was
reacted with benzophenone 13 to provide ester 5. This
analogue incorporates the same functionality at the end
of the alkenyl chain as that present in ADAM II (1),
but the chain is shortened by one carbon.
Sch em e 1a
The incorporation of the azido group at the end of the
alkenyl chain is a modification that provided interesting
results in our previous work.8 Therefore, we planned to
prepare a series of derivatives that would incorporate
this functionality, halogens, or a carbamate group. The
latter functionality was considered because it contains
three moieties that can be involved in hydrogen bonding
with the enzyme. The new groups would be attached at
the end of a five-carbon alkenyl chain. This chain length
was chosen because it would situate the new functional-
ity in the same position as the carbonyl oxygen of the
alkenyl chain ester group of ADAM II. It is believed that
this oxygen is relevant in the binding of ADAM II with
RT. This new series of analogues was prepared from
alcohol 6.8 Bromide 7 was obtained when 6 was reacted
with carbon tetrabromide and triphenylphosphine in
acetonitrile.12,13 Reacting alcohol 6 with methanesulfo-
nyl chloride in dichloromethane gave chloride 8.14 In a
separate experiment, the crude product was reacted
with sodium azide in DMF to afford azide 9. Conversion
of alcohol 6 to the N-ethylcarbamate 10 was achieved
by reacting the alcohol with excess ethyl isocyanate and
a catalytic amount of DMAP.15,16
a
Reagents and conditions: (a) TiCl4‚2THF, Zn(0), THF, reflux,
2 h; then 13 and 17, THF, reflux, 1.5 h, 75.5%; (b) PPTS,
CH3COCH3-H2O, reflux, 2.25 h; 19: 62.5%; 22: 64.2%; 24: 64.8%;
(c) DIBAL-H, CH2Cl2-PhCH3, -78 °C, 4 h, 93.5%; (d) (i) (COCl)2,
DMSO, -78 °C; (ii) Et3N, -78 °C to rt, 60%.
Aldehyde 11 was planned based not only on the
consideration that this functionality might interact with
the enzyme through hydrogen bonding in a similar

Modifications in the ADAM Series of NNRTIs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4863
Sch em e 2a
refluxing acetone-water provided the corresponding
ketones 19, 22, and 24, respectively.23
Hydrogenation of the double bond has not been
previously studied. This is a significant change to the
conformational rigidity of this class of compounds. This
modification would provide valuable information about
the rigidity required for optimal interaction of this class
of NNRTIs with the enzyme. Hydrogenation of 1 under
atmospheric pressure in ethyl acetate, using platinum
oxide as catalyst, afforded 25.
Replacement of the chlorines of ADAM II by bromines
was then considered. In our previous series,5,8 the
interchange of these two halogens provided congeners
with similar antiviral potency. Therefore, we decided
to prepare analogue 28. The McMurry coupling between
ketone 266 and aldehyde 2724 under the conditions
discussed above gave ester 28. Compound 28 was also
prepared using Wittig chemistry. However, preparation
of 28 by the Wittig reaction was not consistently
reproducible.
a
Reagents and conditions: (a) H2SO4, MeOH, H2O, -78 to 0
°C, 1 h; then HCHO, -78 °C to ambient temp, overnight, 95%; (b)
Me2SO4, K2CO3, acetone, reflux, 20 h, 79%; (c) Ac2O, CrO3, 20 h,
81%; (d) TiCl4‚2THF, Zn(0), THF, reflux, 1 h; then 34 and hexanal,
THF, reflux, 30 min, 66%; (e) TiCl4‚2THF, Zn(0), THF, reflux, 1
h; then 34 and 27, THF, reflux, 45 min, 46%.
hydrogen-bonding or electrostatic interactions with Lys
103 led us to consider other compounds with potential
for a cation-π interaction.25 This interaction has been
shown recently to be approximately energetically equiva-
lent to a hydrogen bond.26 ADAM 30 was shown by
molecular modeling to have the alkenyl chain phenyl
ring situated for optimal cation-π interaction with Lys
103. Compound 30 was prepared by a McMurry coupling
of benzophenone 26 with hydrocinnamaldehyde (29)
under the conditions described above.
In our previous series, we reported the replacement
of the aromatic chlorines or bromines with iodines. To
complete the aromatic halogen series, difluoro ADAM
analogues 35 and 36 were planned (Scheme 2). The
synthesis of these compounds started with 3-fluorosali-
cylic acid (31).27 This compound was condensed with
formaldehyde under acidic conditions in methanol to
yield the difluorodisalicylmethane intermediate 32.
Permethylation of 32 with dimethyl sulfate in refluxing
acetone using potassium carbonate as the base provided
33. Oxidation of 33 to the benzophenone 34 was ac-
complished with chromic anhydride. McMurry coupling
of benzophenone 34 with hexanal or methyl 5-oxopen-
tanoate (27) afforded difluoro analogues 35 and 36,
respectively.
Biologica l Resu lts a n d Discu ssion
The 20 new ADAMs synthesized in this study were
evaluated for prevention 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.
These compounds were also tested for inhibition of
HIV-1 RT, and the resulting IC50 values are also
included in Table 1. Nine ADAMs prevented the cyto-
pathic effect of HIV-1RF with EC50 values ranging from
50.5 to 0.0013 µM. These analogues were also found to
inhibit HIV-1 RT with poly(rC)‚oligo(dG) as the tem-
plate primer with IC50 values ranging from 100 to 0.3
µM.
The potent activity of the ADAM analogues with
functionality in the side chain suitably situated to form

4864 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Ta ble 1. Anti-HIV-1 Activities of ADAMs
Casimiro-Garcia et al.
a >7000-fold difference in antiviral potency between 28
(EC50 ) 0.0013 µM) and 37 (EC50 ) 9.2 µM). ADAM 28
was also tested for inhibition of HIV-1 RT with poly-
(rA)‚oligo(dT) as the template primer. Only a small
difference in IC50 values is observed between 1 and 28
(1: IC50 ) 1.9 µM; 28: IC50 ) 1.0 µM). The remaining
new ADAMs were less potent than 28 as inhibitors of
HIV-1 RT with poly(rC)‚oligo(dG) as the template
primer. Interestingly, the second most potent analogue
of this series, methyl ester 12, was also the only new
ADAM that inhibited the enzyme at submicromolar
concentrations with poly(rC)‚oligo(dG) as the template
primer (IC50 ) 0.47 µM). Several congeners were found
to inhibit HIV-1 RT at low micromolar concentrations,
but they did not display antiviral activity. Most of the
results obtained in the present and previous studies
indicate there is not a strong correlation in the ADAM
series between potency for inhibition of RT in cell-free
systems with poly(rC)‚oligo(dG) as the template primer
and potency for inhibition of the cytopathic effect of HIV-
1RF in CEM-SS cells. The in vitro IC50 for compound 28
vs HIV-1 RT with poly(rC)‚oligo(dG) as the template/
primer (0.3 µM) is significantly higher than its EC50 for
inhibition of the cytopathic effect of HIV-1RF in CEM-
SS cell culture (1.3 nM). This difference is not at all
unusual for the NNRTIs.28-31 As discussed elsewhere,
the discrepancy may simply reflect the differences
between the in vitro assay, in which synthetic template/
primer has been added, and the cellular system.30 This
might imply that another template primer may be more
advantageous for evaluating the inhibitory activity of
these and other NNRTIs on HIV-1 RT and correlating
the results with antiviral potency. In certain cases,
primed ribosomal RNA (16S/23S) appears to more
accurately resemble native viral RNA than synthetic
templates in the inhibition of HIV-1 RT assay.32
RT IC50 (µM)a
XTT assay
compd
rCdG
rAdT
EC50 (µM)b
CC50 (µM)c
TId
1
3
4
5
7
0.3
2.2
3.2
7.2
11.0
70
1.3
3.2
4.9
0.47
NI
1.9
0.013
NA
6.5
4.8
2.8
50.5
7.1
NA
NA
1.5
31.6
13.3
26.0
29.4
98.7
>316
175.5
8.4
2430
>100
20.5
>100
1.9
NI
0.8
1.2
4.2
3.35
NI
20.5
6.1
35.2
6.2
8
9
24.7
10
11
12
18
19
20
21
22
24
25
28
30
35
36
9.6
152.5
19.9
24.6
16.9
5.8
14.2
1.13
21.3
13.0
31.50
13.4
68.3
101
8.8
NA
2.8
1.0
3.2
31.6
31.6
NI
NA
NA
NA
NA
NA
0.0013
NA
NA
1.9
100
0.3
1.0
10000
35.9
10
a
Inhibitory activity vs HIV-1 RT with either rCdG or rAdT as
b
the template primer. The EC50 is the 50% inhibitory concentra-
tion for cytopathicity of HIV-1RF in CEM-SS cells. c The CC50 is
d
the 50% cytotoxic concentration for mock-infected CEM cells. The
TI is the therapeutic index, which is the CC50 divided by the EC50
.
NA means there was no observed inhibition of HIV-1 cytopathicity
up to the cytotoxic concentration in uninfected cells.
Ester 28 was the most potent compound of the new
series. This compound only differs from 1 in the
halogens present on the aromatic ring, incorporating
bromines instead of chlorines. ADAM 28 displayed an
EC50 of 0.0013 µM for inhibition of the cytopathic effect
of HIV-1RF in CEM cells, which represents a 10-fold
increase in potency over ADAM II (1) (EC50 ) 0.013 µM).
The therapeutic index was also increased by a factor of
4. The other new compounds that displayed anti-HIV-1
activity are methyl esters 12 and 36, ketone 19, bromide
7, methyl ester 5, dioxolane 4, azide 9, and chloride 8.
The remaining new ADAMs did not prevent the cyto-
pathic effect of HIV-1 at concentrations up to those
resulting in cytotoxicity in uninfected cells.
To gain a better understanding of the interaction of
ADAM 28 with HIV-1 RT, we constructed a hypothetical
model for the docking of this compound in the NNRTI
binding pocket. The model was derived in the following
manner. Using Sybyl (Tripos, Inc., version 6.5, 1998),
the X-ray crystal structure of HIV-1vRT complexed with
nevirapine (1VRT)33 was clipped to include enzyme
information within a 9 Å sphere of nevirapine. Com-
pound 28 was then overlayed onto the structure of
nevirapine, and nevirapine was deleted from the com-
plex. The protein was frozen except for Lys 103 using
the aggregate option of Sybyl. The Lys 103 side chain
amino group was rotated toward the side chain methyl
ester of the ligand and then frozen in order to facilitate
minimization in the direction of the local minimum
which includes the hydrogen-bonding interaction be-
tween these two moieties. Gasteiger-Hu¨ckel charges
were calculated for compound 28, and the charges from
the Kollman united-atom force field were loaded for the
enzyme portion of the complex. The complex was
minimized using the conjugate gradient method em-
ploying the current charges option in the energy setup.
The model obtained in this manner is displayed in
Figure 1. Further support for this hypothetical binding
model was obtained by minimizing a series of enzyme-
bound conformers designated by structures 28a -d . The
“right” and “left” aromatic rings of these structures
correspond to the “right” and “left” aromatic rings of the
As predicted from our previous series,8 the increase
in antiviral potency observed for 28 vs 37 (EC50 ) 9.2
µM) and 1 (EC50 ) 0.013 µM) is not associated with an
increase in potency for inhibition of HIV-1 RT with poly-
(rC)‚oligo(dG) as the template primer, even though the
anti-HIV activity of these compounds clearly results
from inhibition of RT. ADAM II (1), ester 28, and our
initial lead compound ADAM I (37)6 have very similar
IC50 values for inhibition of HIV-1 RT (1: IC50 ) 0.3
µM; 28: IC50 ) 0.3 µM; 37: IC50 ) 0.38 µM) with poly-
(rC)‚oligo(dG) as the template primer, but still there is

Modifications in the ADAM Series of NNRTIs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4865
F igu r e 1. Hypothetical model of ADAM 28 docked in the NNRTI binding pocket of HIV-1 RT. The ligand is shown in red, while
the Leu 100, Lys 103, and Val 179 residues are shown in green. Potential hydrogen-bonding interactions between the alkenyl
chain methoxycarbonyl group of 28 and the backbone amide of Lys 101 and the side chain amino group of Lys 103 are shown as
yellow dotted lines.
Ta ble 2. Energy Calculations for Enzyme-Bound Conformers
of 28
Ch a r t 1. Alkenyl Chain Numbering
conformer
total Ea
steric E
electrostatic E
28a
28b
28c
28d
-47.456
-33.341
-25.024
-29.550
-49.691
-31.665
-25.570
-30.043
-2.235
-1.649
-0.546
0.493
a
Energy values are in kcal/mol.
ligand in the complex as designated by the structure of
the ligand-enzyme complex displayed in Figure 1. The
conformers chosen for these minimizations are near
logical local minima on the potential energy surface.
Each conformer was minimized by the procedure de-
scribed above for the generation of the hypothetical
model. After minimization, the energy of the ligand-
enzyme complex was calculated using the Dock utility
within the Sybyl platform. The data obtained in this
manner is given in Table 2. Note that rotation of either
aromatic ring relative to its orientation in the hypo-
thetical model results in an increase in the energy of
the ligand-enzyme complex. In addition, as would be
expected, rotation of both aromatic rings relative to their
orientations in the hypothetical model results in the
highest energy complex. This hypothetical model pro-
vides interesting features, including: (a) the overall
conformation of enzyme-bound ADAM 28 closely ap-
proximates the general “butterfly” structure observed
by X-ray crystallography for a variety of other NNR-
TIs;34,35 (b) the aromatic rings of 28 are in close
proximity to several residues suitable for hydrophobic
interactions; (c) the methyl group of the alkenyl chain
ester moiety is likely to be engaged in hydrophobic
contacts with Val 179, as the distance between the
methyl moiety and the Val Cγ is <3.7 Å; (d) the alkenyl
chain carbonyl oxygen is involved in bifurcated hydro-
gen bonding with the backbone amide of Lys 101 and
with the side chain amino group of Lys 103; (e) hydrogen
bonding is also possible between the ꢀ-amino group of
Lys 103 and the carboxyl oxygen of the alkenyl chain
ester group. As discussed in the following sections,
support for some of the interactions observed in the
model can be derived from the structure-activity rela-
tionships. Moreover, the resistance mutation results of
ADAMs 1 and 28 provide additional information re-
garding the mode of binding of this class of NNRTIs
with HIV-1 RT that can be correlated with the hypo-
thetical model.
Str u ctu r e-Activity Rela tion sh ip s. 1. Len gth of
th e Alk en yl Ch a in . Comparison of ADAMs 1, 3, 5, 12,
and 28 containing a methoxycarbonyl group at the end
of the chain but differing in chain length strongly
indicates that an eight-atom alkenyl chain (not counting
hydrogens; for numbering see Chart 1) provides the
most potent compounds. Shortening or extending this
chain by only one methylene unit causes a significant
drop in the antiviral potency, as observed for esters 5
and 12. Shortening the chain by one more methylene
group as in analogue 3 completely abolishes the anti-
HIV-1 activity.
2. F u n ction a lity P r esen t a t th e En d of th e Alk -
en yl Ch a in . When attached at the end of a five-atom
alkenyl chain, two functional groups have provided
compounds with anti-HIV-1 activity. A methoxycarbonyl
group is present in esters 1 and 28, which are the most
potent ADAMs prepared up to this date. The propionyl
group present in ketone 19 was tolerated, but a signifi-
cant decrease in antiviral potency was observed. The
aldehyde group present in 11, or the carboxylic acid
moiety contained in the previously reported analogue
38, did not provide compounds capable of inhibiting the

4866 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Casimiro-Garcia et al.
F igu r e 2. Value of the electrostatic potential of ADAM II (1) (a) and ketone 19 (b) is shown color encoded onto the total electron
density surface. Colors toward red indicate electron-rich regions of the molecule.
cytopathic effect of HIV-1. Functional groups tolerated
when attached at the end of a six-atom chain include
bromine, chlorine, azide, and methoxycarbonyl. These
groups are incorporated in derivatives 7-9 and 12,
respectively. However, the antiviral potency of these
compounds is only in the low micromolar range. Func-
tionality that is not tolerated at this position includes
alcohol and carbamate groups. Congener 30, which
includes a phenyl ring incorporated at the end of a four-
atom chain, did not show any anti-HIV-1 activity. As
discussed above, the alkenyl chain phenyl ring in 30 was
considered to be situated for optimal cation-π interaction
with Lys 103. The lack of antiviral activity of this
analogue suggests that the Lys 103 side chain is not
protonated and, therefore, is uncharged. Consequently,
this residue is probably capable of hydrogen bonding,
but it may not be involved in electrostatic interactions.
It is clear that there is a very strong correlation of
anti-HIV-1 potency with the length of the alkenyl chain
and the functionality attached at its end. It seems to
be important that the length of the chain should be
appropriate to position a moiety for interaction with the
side chain amino group of Lys 103 and another group
for hydrophobic contact with Val 179 (see hypothetical
model displayed in Figure 1). Hydrogen bonding is
probably the mode of interaction between the ꢀ-amino
group of Lys 103 and the moiety present in the inhibitor.
In ADAM II (1) and 28, this moiety is believed to be
the oxygen of the carbonyl group in the ester functional-
ity. Following the numbering shown in Chart 1, this
oxygen is attached to the sixth carbon atom in the chain.
Therefore, it might be expected that analogues contain-
ing moieties capable of hydrogen bonding at this position
would provide active compounds. The results obtained
with azide 9 and ketone 19 provide support for this idea.
Moreover, high electron density is probably required in
this moiety for successful interaction with the ꢀ-amino
group of Lys 103. This might explain the significant
difference in antiviral potency between ADAM II and
ketone 19. The carbonyl oxygen of the ester has higher
electron density than the carbonyl oxygen of the ketone
due to a resonance effect of the methoxy group of the
ester. This property was calculated for ADAMs 1 and
19 using MacSpartan (version 1.1, Wavefunction, Inc.,
Irvine, CA). The atomic charge for the carbonyl oxygen
of 1 is -0.56 electrostatic units, while that of ketone 19
is -0.48 electrostatic units. This difference between
ADAMs 1 and 19 is evident in the graphical representa-
tion showing the electrostatic potential combined with
the electron density surfaces of these ADAMs. The
graphics were generated using MacSpartan and are
displayed in Figure 2. In these graphics, the value of
the electrostatic potential is color encoded onto the total
electron density surface, with colors toward red indicat-
ing electron-rich regions of the molecule.
As mentioned above, the length of the chain should
also position a moiety capable of hydrophobic interaction
with Val 179. In ADAM 28, this moiety might be the
methoxy group of the ester (see model Figure 1).
Hydrophobic interactions between Val 179 and different
NNRTIs have been reported, including the contacts with
the 5-methyl group on the diazepin ring of Cl-TIBO,36
the carboxamide moiety of R-APA,33 and the methylthi-
omethylene group of the quinoxaline HBY 097.37
3. Alk en yl Ch a in Dou ble Bon d . Hydrogenation of
ADAM II provided analogue 25, which was completely
devoid of anti-HIV-1 activity. This is a very drastic
modification in this series because it provides a signifi-
cant increase in conformational freedom. According to
this result, the double bond is essential to secure the
molecular geometry required for interaction with HIV-1
RT.
4. Ha logen on th e Ar om a tic Rin gs. Taking into
consideration the results obtained with this new series
of ADAMs, there is more evidence that suggests that
analogues containing bromine are more potent than
those containing chlorine. This is observed when one
compares ADAM II (1) (EC50 ) 0.013 µM) vs ester 28
(EC50 ) 0.0013 µM). This hypothesis is also supported
with results from our initial work in this series, from
which ADAM I (37) (EC50 ) 9.2 µM) was observed to be
more potent than 39 (EC50 ) 16.0 µM). When chlorine
is replaced by fluorine as in derivative 36, a drastic
decrease in antiviral potency is observed. The significant
drop in potency is probably related to a reduction in the
van der Waals radius when going from chlorine (1.80

Modifications in the ADAM Series of NNRTIs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4867
Ta ble 3. Activity of ADAMs 1, 28, and 37 Against a Site-Directed Panel of Resistant Isolates in CEM-SS Cells
ADAM 1a ADAM 37b
ADAM 28
mutation
in RT
fold
resistance
fold
resistance
fold
resistance
EC50 (µM)
EC50 (µM)
EC50 (µM)
NL4-3c
L74V
A98G
L100I
K101E
K103N
V106A
V108I
1.78
2.23
0.84
>0.16
3.05
>50
12.7
12.0
50
>50
10.80
0.90
0.27
>50
0.06
0.019
0.22
0.26
0.07
0.42
9.51
0.67
40.2
6.13
1.73
0.07
0.33
3.5
12.3
5.47
24.1
NCd
NCd
Se
Se
3.7
Se
2
4.3
NCd
>28
7.13
6.74
28
NCd
7
>100
23.6
>100
>8
NCd
>8
158.5
10
V179D
Y181C
Y188C
670
102
28.8
NCd
5.5
>100
>100
>100
0.93
>8
>8
>8
Se
>28
6.07
NCd
Se
4X AZTf
4X AZT/L100If
4X AZT/Y181Cf
>28
58.3
a
d
Taken from ref 8. b Taken from ref 6. c Wild-type enzyme. No significant change in sensitivity. e Enhanced sensitivity. f AZT-resistant.
F igu r e 3. HIV-1 NNRTI binding site. Mutation of the yellow- and red-colored residues results in resistance to known NNRTIs.
Mutation of the yellow residues also results in resistance to ADAM 28, while mutation of the red residue results in no change in
sensitivity to ADAM 28.
Å) or bromine (1.95 Å) to fluorine (1.35 Å). We previously
correlated the lack of anti-HIV-1 activity in analogues
containing iodine to a possible size limitation for activ-
ity.8 Combined, these results indicate that only chlorine
and bromine are tolerated. Other halogens (iodine or
fluoride), or hydrogen, compromise the biological activity
significantly.
largely hydrophobic, and therefore, hydrophobic contacts
account for the majority of interactions in the enzyme-
inhibitor complex.38,39 Consequently, it can be expected
that the aromatic methoxycarbonyl groups in the AD-
AMs are involved in such interactions. Further support
for this hypothesis comes from the lack of antiviral
activity observed in the analogues incorporating a
carboxylic acid or a benzylic alcohol, which are not as
likely to be involved in hydrophobic interactions.
Resista n ce Mu ta tion s. ADAM 28 was evaluated for
inhibition of the cytopathic effect of a variety of HIV-1
strains containing defined mutations in RT, and the
results are presented in Table 3. Mutations that con-
ferred resistance to the antiviral activity of 28 were
clustered within the amino acid residues comprising the
NNRTI binding pocket.34,38,40,41 The mutations confer-
ring greater than 10-fold resistance to ADAM 28 were
located at residues Val 106, Val 179, Tyr 181, and Tyr
188.
The mutations conferring resistance to ADAM 28 are
displayed graphically in Figure 3, which was con-
structed by erasing nevirapine from the structure of the
nevirapine-RT complex.40 This shows the amino acid
residues in the p66 subunit surrounding the NNRTI
binding pocket. Mutation of the yellow-colored residues
in Figure 3 results in resistance to the antiviral activity
of 28, while mutation of the red-colored residue did not
5. Ar om a tic Meth oxyca r bon yl Gr ou p . In our
initial report of this class of NNRTIs,6 the aromatic
methoxycarbonyl groups were replaced by primary,
secondary, or tertiary amides and by carboxylic acids.
These modifications led only to inactive compounds. In
this report, the aromatic methyl esters were replaced
by benzylic alcohols or aldehydes, which provided
analogues 22 and 24, respectively. These congeners can
be compared directly with ketone 19 since this com-
pound incorporates the same functionality in the alkenyl
chain as that present in 22 and 24, but includes
methoxycarbonyl groups on the aromatic rings. The
moderate antiviral potency of ketone 19 (EC50 ) 2.8 µM)
contrasts with the lack of antiviral activity in 22 and
24 and emphasizes the importance of methoxycarbonyl
groups at these positions. Without an X-ray crystal
structure of ADAMs 1 or 28 bound with HIV-1 RT, it is
difficult to assess the role of this functionality in the
interaction of this class of NNRTIs with the enzyme.
The internal surface of the NNRTI binding pocket is

4868 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Casimiro-Garcia et al.
change the sensitivity significantly. The clustering of
the resistance mutations around the NNRTI binding
pocket of HIV-1 RT provides convincing evidence that
inhibition of RT is responsible for the antiviral activity
of 28 and the other NNRTIs in this series. Similar, but
not identical, resistance profiles were also observed
previously for NNRTIs 37 and 1.6,8 Furthermore, we
have previously shown with compound 37 that the
ADAMs are RT inhibitors by exclusion of other possible
mechanisms of action.6
toward this mutant. This situation has been noted
previously for other NNRTIs, including compounds in
the TIBO and pyridinone series, where minor alter-
ations restored activity against a mutant strain of HIV-
1.43,44 The distance of 4.14 Å calculated from one of the
γ-carbons of Leu 100 to the closer bromine atom of 28
makes possible interactions of the halogens of the ligand
and the side chain of the amino acid residue at position
100 plausible (see Figure 1).
Taking into consideration all of the results discussed
above, ADAM II (1) and its congener 28 appear to
interact slightly differently with HIV-1 RT. The aro-
matic portion of both ADAMs probably makes contacts
with the hydrophobic residues of the NNRTI binding
pocket including Val 106, Val 108, Tyr 181, and Tyr 188.
This mode of interaction correlates with the observa-
tions derived from the hypothetical model of ADAM 28
bound to RT (see Figure 1). The replacement of the
aromatic chlorines present in ADAM 1 by the bulkier
bromines present in ADAM 28 may force this analogue
to change the mode of interaction with the binding
pocket. In the case of ADAM 1, the alkenyl chain
methoxycarbonyl group might be suitably positioned for
hydrogen bonding with the side chain amino moiety of
Lys 103. Probably, this is one of the most important
interactions of the alkenyl chain ester moiety of 1. This
hypothesis is supported by the results of the resistance
mutation studies. For ADAM 28, the most significant
interaction of the alkenyl chain methyl ester group may
be through hydrophobic contacts with Val 179. The
hypothetical model of ADAM 28 bound to HIV-1 RT
offers some plausibility for interaction with this residue.
However, this model also shows 28 hydrogen bonding
with Lys 103. It is important to mention that reports of
other classes of NNRTIs have indicated that analogues
containing minor structural changes interact with RT
in similar ways, but the specific interactions with the
enzyme and the shape of the NNRTI binding pocket may
be different.45,46 This might be the case in the ADAM
series.
ADAM 28 was also evaluated against the virus
containing the 4X AZT enzyme, which has four muta-
tions in its RT and is resistant to AZT. ADAM 28
displayed similar antiviral potency against this AZT-
resistant strain as that observed for the wild-type virus
containing the NL4-3 enzyme. Moreover, the combina-
tion of the 4X AZT mutation with two typical NNRTI
mutations (L100I and Y181C) does not significantly
change the antiviral potency of 28 (4X AZT/L100I 5.5-
fold resistance vs L100I alone 4.3-fold resistance; 4X
AZT/Y181C 58.3-fold resistance vs Y181C alone 102-
fold resistance). Results from this study demonstrate
once again that this class of NNRTIs may have potential
clinical utility against AZT-resistant strains of HIV-1.
A comparison can be made between the results
obtained in this study with those obtained previously
for ADAM II (1),6,8 which are included in Table 3. There
is an apparent, close correlation between antiviral
potency and degree of resistance. Ester 28 is the most
potent compound of this class of NNRTIs, but it is also
the one causing stronger resistance for the V106A,
V179D, Y181C, and Y188C mutants. Analysis of these
mutations is providing a better understanding of the
residues involved in the binding of these compounds
with HIV-1 RT. The V179D and Y181C mutants have
been observed to provide the most significant resistance
to ADAM II (1) and 28. Both mutations have been
reported before for other NNRTIs, and in fact, the
Y181C is one of the mutations conferring the most
generalized cross-resistance.42 More interesting is the
V179D mutant because it emphasizes the important role
of this residue in the binding of 28 with the enzyme.
The V179D mutant showed a 670-fold resistance against
ADAM 28 and was by far the mutation providing the
highest level of resistance against this ADAM. This high
level of resistance was not observed for ADAM II (1)
and may provide an indication that these two inhibitors
interact slightly differently with the NNRTI binding
pocket. As discussed above, we believe that hydrophobic
contacts between Val 179 and the methoxy group of the
ester attached at the end of the alkenyl chain may be
in part responsible for the high affinity of 28 for HIV-1
RT. Possible contacts of ADAM 28 with Val 179 were
also detected in the hypothetical model displayed in
Figure 1. This interaction would be lost in the V179D
mutant.
High resistance against the K103N mutant was
observed for ADAM II (1).8 Surprisingly, this mutation
was not as significant for ADAM 28, resulting in only a
7-fold increase in the EC50 value. The role of this residue
in the binding of these two ADAMs with the enzyme
was discussed above. Again, the different degrees of
resistance might indicate that ADAMs 1 and 28 may
interact differently with RT. The change of Lys to Asn
does not eliminate the possibility of hydrogen bonding
with the amino acid residue. The fact that the K103N
mutation does not affect the activity of 37, which does
not have a hydrogen bond acceptor at the end of the
alkenyl chain, is consistent with the hypothetical hy-
drogen bond donor and acceptor roles proposed for Lys
103 and the ligand side chain ester carbonyl groups,
respectively.
Exp er im en ta l Section
Gen er a l. Melting points were determined in capillary tubes
on a Mel-Temp apparatus and are uncorrected. Spectra were
obtained as follows: CI mass spectra on a Finnegan 4000
spectrometer; FAB mass spectra and EI mass spectra on a
Kratos MS50 spectrometer; 1H NMR spectra on Varian VXR-
500S and Bruker ARX-300 spectrometers; IR spectra on a
Beckman IR-33 spectrometer or a Perkin-Elmer 1600 series
FTIR. Microanalyses were performed at the Purdue Mi-
croanalysis Laboratory, and all values were within (0.4% of
The activity against the L100I mutant also deserves
discussion. Increased sensitivity versus this mutant was
detected with ADAM II (1),8 but a 4.3-fold resistance
was observed with ADAM 28. It is interesting that the
replacement of the aromatic bromines present in 28 by
the aromatic chlorines of ADAM 1 restores the activity

Modifications in the ADAM Series of NNRTIs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4869
the calculated compositions. Silica gel used for column chro-
matography was 230-400 mesh.
it was cooled and the solvent evaporated. The residue was then
purified by flash chromatography on silica gel (∼30 g; col-
umn: 2 × 22 cm), eluting with hexanes:ethyl acetate (6:1).
Bromide 7 was obtained as a colorless solid in excellent yield
(0.107 g, 95.5%). The analytical sample was recrystallized from
acetone-ethanol: mp 99-101 °C; 1H NMR (300 MHz, CDCl3)
δ 7.47 (d, J ) 2.4 Hz, 1 H), 7.45 (d, J ) 2.2 Hz, 1 H), 7.29 (d,
J ) 2.1 Hz, 1 H), 7.27 (d, J ) 2.4 Hz, 1 H), 6.03 (t, J ) 7.5 Hz,
1 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H),
3.35 (t, J ) 6.6 Hz, 2 H), 2.10 (q, J ) 7.5 Hz, 2 H), 1.83 (m, 2
H), 1.58 (m, 2 H); IR (film) 2949, 1731, 1477, 1266, 1207, 998,
743 cm-1; FABMS m/z 559 (MH+), 528 (MH+ - 31). Anal.
(C24H25BrCl2O6) C, H.
Meth yl 3′,3′′-Dich lor o-4′,4′′-dim eth oxy-5′,5′′-bis(m eth oxy-
ca r bon yl)-4,4-d ip h en yl-3-bu ten oa te (3). Carboxylic acid 29
(0.050 g, 0.104 mmol) was dissolved in THF (2.5 mL). Excess
ethereal diazomethane solution (∼0.1 mL) was added. The pale
yellow solution was left at room temperature for 2 h. Acetic
acid (5 drops) was then added to destroy excess diazomethane.
The solvent was removed and the residue was purified by flash
chromatography on silica gel (25 g; column: 2 × 19.5 cm),
eluting with hexanes:ethyl acetate (3:1). Compound 3 was
obtained as a colorless oil in good yield (41 mg, 80%): 1H NMR
(300 MHz, CDCl3) δ 7.51 (d, J ) 2.5 Hz, 1 H), 7.47 (d, J ) 2.2
Hz, 1 H), 7.32 (dd, J ) 2.8 and J ) 2.5 Hz, 2 H), 6.23 (t, J )
7.5 Hz, 1 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 3.89 (s, 3 H), 3.88 (s,
3 H), 3.12 (s, 3 H); IR (film) 2950, 1735, 1476, 1261, 1165, 997,
846 cm-1; FABMS m/z 497 (MH+), 496 (M+), 465 (MH+ - CH3-
OH). Anal. (C23H22Cl2O8) C, H.
3′,3′′,6-Tr ich lor o-4′,4′′-d im eth oxy-5′,5′′-bis(m eth oxyca r -
bon yl)-1,1-d ip h en yl-1-h exen e (8). A solution of alcohol 6
(0.100 g, 0.201 mmol) and Et3N (0.08 mL, 0.603 mmol) in dry
dichloromethane (1.5 mL) was stirred in an ice bath under
Ar. Mesyl chloride (0.05 mL, 0.603 mmol) was added and the
reaction mixture was stirred for 7 h, while maintaining the
temperature below 10 °C. Additional mesyl chloride (0.03 mL)
was added. The reaction mixture was stirred at room temper-
ature overnight. The mixture was diluted with dichlo-
romethane (15 mL) and washed with 1.0 N HCl (2 × 20 mL),
satd NaHCO3 (1 × 15 mL), and brine (1 × 20 mL). The organic
extracts were then dried over magnesium sulfate and filtered,
and the solvent was removed. Purification by flash chroma-
tography on silica gel (30 g; column: 2 × 20 cm), eluting with
hexanes:ethyl acetate (5:1), afforded compound 8 as a white
solid in moderate yield (64 mg, 61%): mp 106-107 °C; 1H
NMR (300 MHz, CDCl3) δ 7.47 (d, J ) 2.3 Hz, 1 H), 7.45 (d, J
) 2.2 Hz, 1 H), 7.29 (d, J ) 2.2 Hz, 1 H), 7.27 (d, J ) 2.3 Hz,
1 H), 6.03 (t, J ) 7.5 Hz, 1 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 3.90
(s, 3 H), 3.89 (s, 3 H), 3.48 (t, J ) 6.4 Hz, 2 H), 2.10 (q, J ) 7.4
Hz, 2 H), 1.74 (m, 2 H), 1.58 (m, 2 H); IR (film) 2950, 1731,
1477, 1266, 1208, 999, 742 cm-1; FABMS m/z 515 (MH+), 483
(MH+ - CH3OH). Anal. (C24H25Cl3O6) C, H.
3′,3′′-Dich lor o-4′,4′′-d im eth oxy-5′,5′′-bis(m eth oxyca r bo-
n yl)-1,1-d ip h en yl-3-(1,3-d ioxola n -2-yl)-1-p r op en e (4). A
suspension of phosphonium bromide 14 (0.833 g, 1.878 mmol)
in dry THF (25 mL) was stirred at 0 °C under an argon
atmosphere. A 1.0 M solution of NaN(SiMe3)2 in THF (1.94
mL, 1.937 mmol) was added dropwise. The yellow mixture was
stirred at 0 °C for 30 min. A solution of ketone 1310 (0.500 g,
1.174 mmol) in dry THF (20 mL) was then added dropwise.
The ice bath was removed and the dark brown reaction
mixture was stirred at room temperature for 4.25 h. The
reaction mixture was quenched with satd NH4Cl solution (30
mL). The phases were separated and the aqueous one was
extracted with Et2O (3 × 35 mL). The combined organic
extracts were washed with brine (1 × 40 mL), dried over
magnesium sulfate, and filtered and the solvent was removed.
Purification was achieved by flash chromatography on silica
gel (55 g; column: 3 × 20 cm), eluting with hexane:ethyl
acetate (2:1). Compound 4 was obtained as a yellow oil in
moderate yield (0.271 g, 45.2%): 1H NMR (300 MHz, CDCl3)
δ 7.51 (d, J ) 2.2 Hz, 1 H), 7.49 (d, J ) 2.4 Hz, 1 H), 7.40 (d,
J ) 2.2 Hz, 1 H), 7.30 (d, J ) 2.4 Hz, 1 H), 6.12 (t, J ) 7.6 Hz,
1 H), 4.96 (t, J ) 4.5 Hz, 1 H), 4.00-3.86 (m, 4 H), 3.96 (s, 3
H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 2.46 (dd, J ) 4.5
6-Azido-3′,3′′-dich lor o-4′,4′′-dim eth oxy-5′,5′′-bis(m eth oxy-
ca r bon yl)-1,1-d ip h en yl-1-h exen e (9). A solution of alcohol
6 (0.100 g, 0.201 mmol) and Et3N (0.15 mL, 1.005 mmol) in
dry dichloromethane (1.5 mL) was stirred in an ice bath under
Ar. Mesyl chloride (0.08 mL, 1.005 mmol) was added and the
yellowish mixture was stirred in an ice bath for 5 h and then
at room temperature overnight. The mixture was diluted with
dichloromethane (20 mL) and washed with 2.0 N HCl (2 × 15
mL), satd NaHCO3 (15 mL), and brine (20 mL). The organic
extracts were then dried over magnesium sulfate and filtered,
and the solvent was evaporated. The yellow residue was
dissolved in dry DMF (2 mL) and sodium azide (0.065 g, 1.005
mmol) was added. The reaction mixture was stirred at 55 °C
for 20 h. The mixture was cooled, diluted with water (20 mL),
and extracted with ethyl ether (4 × 20 mL). The combined
organic extracts were washed with brine (1 × 30 mL), dried
over magnesium sulfate, and filtered and the solvent was
removed. The crude residue was purified by flash chromatog-
raphy on silica gel (∼30 g; column: 2 × 22.5 cm), eluting with
hexanes:ethyl acetate (4:1). Compound 9 was obtained as a
white solid in moderate yield (0.05 g, 52%): mp 70-72 °C; 1H
NMR (300 MHz, CDCl3) δ 7.47 (d, J ) 2.5 Hz, 1 H), 7.45 (d, J
) 2.1 Hz, 1 H), 7.29 (d, J ) 2.1 Hz, 1 H), 7.27 (d, J ) 2.5 Hz,
1 H), 6.02 (t, J ) 7.5 Hz, 1 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 3.90
(s, 3 H), 3.89 (s, 3 H), 3.23 (t, J ) 6.4 Hz, 2 H), 2.11 (q, J ) 7.2
Hz, 2 H), 1.54 (m, 4 H); IR (film) 2949, 2096, 1735, 1477, 1263,
and 7.6 Hz, 2 H); IR (film) 2915, 1731, 1477, 1257, 997 cm-1
;
FABMS m/z 511 (MH+). Anal. (C24H24Cl2O8) C, H.
Meth yl 3′,3′′-Dich lor o-4′,4′′-dim eth oxy-5′,5′′-bis(m eth oxy-
ca r bon yl)-5,5-d ip h en yl-4-p en ten oa te (5). A suspension of
(methoxycarbonylpropyl)triphenylphosphonium bromide (15)11
(0.25 g, 0.563 mmol) in dry THF (15 mL) was stirred at -78
°C under an argon atmosphere. A 1.0 M solution of NaN-
(SiMe3)2 in THF (0.53 mL, 0.528 mmol) was added dropwise.
The mixture was stirred at -78 °C for 40 min. A solution of
ketone 1310 (0.150 g, 0.352 mmol) in dry THF (6 mL) was then
added dropwise. The reaction mixture was stirred at -78 °C
for 12 h and then at 25 °C for 16 h. The reaction mixture was
quenched with satd NH4Cl solution (15 mL). The phases were
separated and the aqueous one was extracted with Et2O (3 ×
25 mL). The combined organic extracts were washed with brine
(1 × 30 mL), dried over magnesium sulfate, and filtered. The
solvent was removed and the residue was flash chromato-
graphed on silica gel (29 g; column: 2 × 25 cm), eluting with
hexane:ethyl acetate (4:1). Compound 5 was obtained in good
yield (0.13 g, 72%) as a yellowish oil: 1H NMR (300 MHz,
CDCl3) δ 7.46 (d, J ) 2.3 Hz, 1 H), 7.45 (d, J ) 2.1 Hz, 1 H),
7.32 (d, J ) 2.2 Hz, 1 H), 7.27 (d, J ) 2.4 Hz, 1 H), 6.01 (t, J
) 7.2 Hz, 1 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.89
(s, 3 H), 3.66 (s, 3 H), 2.41 (m, 4 H); IR (film) 2952, 1736, 1477,
1436, 1263, 1207, 996 cm-1; FABMS m/z 511 (MH+). Anal.
(C24H24Cl2O8) C, H.
1207, 998, 743 cm-1; FABMS m/z 522 (MH+), 490 (MH+
MeOH). Anal. (C24H25Cl2N3O6) C, H, N.
-
5′,5′′-Dich lor o-4′,4′′-d im eth oxy-5′,5′′-bis(m eth oxyca r bo-
n yl)-6,6-d ip h en yl-5-h exen -1-yl N-Eth ylca r ba m a te (10). A
solution of alcohol 6 (0.100 g, 0.202 mmol) in dry Et3N (3 mL)
was stirred at room temperature under Ar. DMAP (10 mg,
0.082 mmol) and ethyl isocyanate (0.05 mL, 0.606 mmol) were
added and the mixture stirred at room temperature for 24 h.
At this time, additional ethyl isocyanate (0.05 mL) was added
and stirring continued for 24 h. The mixture was diluted with
ethyl acetate (50 mL) and washed with 2 N HCl (3 × 30 mL)
and brine (1 × 30 mL). The organic phase was dried over
6-Br om o-3′,3′′-d ich lor o-4′,4′′-d im eth oxy-5′,5′′-bis(m eth -
oxyca r bon yl)-1,1-d ip h en yl-1-h exen e (7). A solution of al-
cohol 68 (0.100 g, 0.201 mmol) and carbon tetrabromide (0.133
g, 0.402 mmol) in dry acetonitrile (3.5 mL) was heated at reflux
under Ar. A solution of triphenylphosphine (0.158 g, 0.603
mmol) in dry acetonitrile (5.5 mL) was added over 3 min. The
reaction mixture was heated at reflux for 80 min. At this time,

4870 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Casimiro-Garcia et al.
magnesium sulfate and filtered and the solvent removed.
Purification was achieved by flash chromatography on silica
gel (∼35 g; column: 2 × 24.5 cm), eluting with hexanes:ethyl
acetate (2:1 to 1:1). Carbamate 10 was obtained in excellent
yield (0.11 g, 98%) as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 7.47 (d, J ) 2.4 Hz, 1 H), 7.45 (d, J ) 2.0 Hz, 1 H),
7.29 (d, J ) 2.1 Hz, 1 H), 7.26 (d, J ) 2.2 Hz, 1 H), 6.03 (t, J
) 7.4 Hz, 1 H), 4.63 (bs, 1 H), 4.00 (m, 2 H), 3.97 (s, 3 H), 3.90
(s, 6 H), 3.88 (s, 3 H), 3.18 (m, 2 H), 2.10 (q, J ) 7.2 Hz, 2 H),
1.58-1.48 (m, 4 H); IR (film) 3393, 2950, 1718, 1476, 1252,
temperature, and a 10% solution of K2CO3 (50 mL) was added.
The resulting mixture was stirred at room temperature
overnight. The mixture was filtered through a pad of Celite
and washed with ethyl acetate (3 × 35 mL) and water (50 mL).
The layers were separated and the aqueous one was extracted
with ethyl acetate (3 × 35 mL). The combined organic extracts
were washed 10% K2CO3 (50 mL) and brine (50 mL). The
organic extracts were dried over MgSO4 and filtered. The
residue was purified by column chromatography on silica gel
(∼170 g; column: 5 × 23.5 cm), eluting with hexanes:ethyl
acetate (3:1). Compound 18 was obtained as a white solid in
good yield (0.972 g, 75.5%): mp 74-76 °C; 1H NMR (300 MHz,
CDCl3) δ 7.47 (d, J ) 2.4 Hz, 1 H), 7.44 (d, J ) 2.2 Hz, 1 H),
7.29 (d, J ) 2.1 Hz, 1 H), 7.26 (d, J ) 2.3 Hz, 1 H), 6.03 (t, J
) 7.4 Hz, 1 H), 3.97 (s, 3 H), 3.90 (s, 4 H), 3.90 (s, 3 H), 3.89
(s, 3 H), 3.88 (s, 3 H), 2.08 (q, J ) 7.2 Hz, 2 H), 1.62-1.45 (m,
6 H), 0.87 (t, J ) 7.4 Hz, 3 H); IR (film) 2951, 2878, 1736,
1476, 1264, 1206, 999, 742 cm-1; FABMS m/z 567 (MH+), 536
(MH+ - OCH3). Anal. (C28H32Cl2O8) C, H.
3′,3′′-Dich lor o-4′,4′′-d im eth oxy-5′,5′′-bis(m eth oxyca r bo-
n yl)-1,1-d ip h en yl-6-oxo-1-octen e (19). A solution of ketal
18 (0.080 g, 0.141 mmol) and pyridinium p-toluenesulfonate
(0.012 g, 0.048 mmol) in wet acetone (2 mL containing 3 drops
of water) was heated under reflux for 2.25 h. The mixture was
allowed to cool and the solvent removed. The residue was
diluted with ethyl ether (15 mL) and washed with satd
NaHCO3 (15 mL) and brine (15 mL). After drying over MgSO4,
the solvent was removed and the residue was purified by flash
chromatography on silica gel (∼30 g; column: 2 × 17.5 cm),
eluting with hexanes:ethyl acetate (3:1). Compound 19 was
obtained in moderate yield (0.046 g, 62.5%) as a thick colorless
oil: 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J ) 2.4 Hz, 1 H),
7.44 (d, J ) 2.2 Hz, 1 H), 7.29 (d, J ) 2.2 Hz, 1 H), 7.26 (d, J
) 2.4 Hz, 1 H), 6.02 (t, J ) 7.4 Hz, 1 H), 3.97 (s, 3 H), 3.91 (s,
3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 2.38 (t, J ) 7.3 Hz, 2 H), 2.37
(q, J ) 7.3 Hz, 2 H), 2.07 (q, J ) 7.5 Hz, 2 H), 1.70 (qn, J )
7.4 Hz, 2 H), 1.00 (t, J ) 7.4 Hz, 3 H); IR (film) 2950, 1734,
1716, 1476, 1287, 1262, 998 cm-1; FABMS m/z 523 (MH+), 491
(MH+ - CH3OH). Anal. (C26H28Cl2O7) C, H.
1207, 998, 743 cm-1; FABMS m/z 568 (MH+). Anal. (C27H31
-
Cl2NO8) C, H, N.
3′,3′′-Dich lor o-4′,4′′-d im eth oxy-5′,5′′-bis(m eth oxyca r bo-
n yl)-6,6-d ip h en yl-5-h exen a l (11). A solution of oxalyl chlo-
ride (0.1 mL, 1.14 mmol) in dichloromethane (4.0 mL) was put
under argon and cooled to -78 °C. A solution of DMSO (0.16
mL, 2.279 mmol) in dichloromethane (3.5 mL) was added over
8 min. The mixture was stirred for 15 min, and then a solution
of alcohol 6 (0.514 g, 1.036 mmol) in dichloromethane (6 mL)
was added over 5 min. The reaction mixture stirred for 20 min
at -78 °C. Triethylamine (0.722 mL, 5.18 mmol) was added
and stirring was continued at -78 °C for 15 min. The bath
was removed and the mixture was allowed to warm to room
temperature. Dichloromethane (40 mL) was added followed
by water (45 mL). The phases were separated and the aqueous
layer was extracted with dichloromethane (3 × 30 mL). The
combined organic extracts were washed with brine (40 mL),
dried over MgSO4, and filtered, and the solvent was removed.
The residue was flash chromatographed on silica gel (∼65 g;
column: 3 × 26 cm), eluting with hexanes:ethyl acetate (3:1
to 2:1). Aldehyde 11 was obtained as a white solid in good yield
(0.32 g, 79%; based on recovered unreacted 6: 0.105 g): mp
102-104 °C; 1H NMR (300 MHz, CDCl3) δ 9.73 (t, J ) 1.4 Hz,
1 H), 7.47 (d, J ) 2.6 Hz, 1 H), 7.46 (d, J ) 2.9 Hz, 1 H), 7.28
(d, J ) 1.9 Hz, 1 H), 7.26 (d, J ) 2.4 Hz, 1 H), 6.01 (t, J ) 7.4
Hz, 1 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H),
2.43 (dt, J ) 7.2 Hz and J ) 1.3 Hz, 2 H), 2.12 (q, J ) 7.5 Hz,
2 H), 1.76 (qn, J ) 7.3 Hz, 2 H); IR (film) 2950, 1735, 1477,
1263, 1208, 998, 743 cm-1; FABMS m/z 495 (MH)+, 463 (MH+
- CH3OH). Anal. (C24H24Cl2O7) C, H.
3′,3′′-Dich lor o-5′,5′′-d ih yd r oxym eth yl-4′,4′′-d im eth oxy-
1,1-diph en yl-5-(2-eth yl-(1,3)-dioxolan -2-yl)-1-pen ten e (20).
A solution of ester 18 (0.171 g, 0.302 mmol) in dichloromethane
(5 mL) was cooled to -78 °C and put under Ar. A 1.0 M
solution of DIBAL-H in toluene (1.26 mL, 1.26 mmol) was
added. The mixture was stirred at -78 °C for 4 h. A
concentrated aqueous solution of Rochelle salt (potassium
sodium tartrate, 15 mL) was added and the mixture warmed
to room temperature over 3 h. The mixture was diluted with
dichloromethane (15 mL) and the phases were separated. The
aqueous layer was extracted with dichloromethane (3 × 20
mL). The combined organic extracts were washed with brine
(30 mL), dried over MgSO4, and filtered, and the solvent was
removed. The residue was purified by flash chromatography
on silica gel (∼30 g; column: 2 × 24 cm), eluting with hexanes:
ethyl acetate (1:1). Compound 20 was obtained as a colorless
oil in very good yield (0.144 g, 93.5%): 1H NMR (300 MHz,
CDCl3) δ 7.11 (d, J ) 2.2 Hz, 1 H), 7.08 (d, J ) 2.0 Hz, 1 H),
7.07 (d, J ) 2.3 Hz, 1 H), 7.03 (d, J ) 2.1 Hz, 1 H), 5.98 (t, J
) 7.5 Hz, 1 H), 4.70 (s, 2 H), 4.64 (s, 2 H), 3.93 (s, 3 H), 3.89
(s, 3 H), 3.87 (s, 4 H), 2.05 (q, J ) 7.3 Hz, 2 H), 1.61-1.43 (m,
6 H), 0.85 (t, J ) 7.5 Hz, 3 H); IR (film) 3421, 2938, 2879,
1479, 1231, 1002, 873 cm-1; FABMS m/z 512 (M+ + 2), 511
(MH+). Anal. (C26H32Cl2O8) C, H.
Meth yl 3′,3′′-Dich lor o-4′,4′′-dim eth oxy-5′,5′′-bis(m eth oxy-
car bon yl)-7,7-diph en yl-6-h epten oate (12). A slurry of TiCl4‚
2THF complex (0.705 g, 2.112 mmol) and Zn dust (0.276 g,
4.224 mmol) in THF (20 mL) was stirred and heated under
reflux for 2 h. A solution of benzophenone 1310 (0.300 g, 0.704
mmol) and methyl 6-oxohexanoate (16)20 (0.162 g, 1.124 mmol)
in THF (15 mL) was added. The black mixture was heated
under reflux for 3 h. It was then cooled to room temperature
and a 10% solution of K2CO3 (30 mL) was added. The mixture
was stirred at room temperature overnight. It was filtered
through a pad of Celite and washed with EtOAc (3 × 30 mL).
The layers were separated and the aqueous one was extracted
with EtOAc (2 × 20 mL). The combined organic extracts were
washed with brine (30 mL), dried over MgSO4, and filtered,
and the solvent was removed. The residue was flash chro-
matographed on silica gel (∼35 g; column: 2 × 27 cm) eluting
with hexanes:ethyl acetate (3:1) to provide 12 as a pale
yellowish oil in moderate yield (0.219 g, 57.8%): 1H NMR (300
MHz, CDCl3) δ 7.46 (d, J ) 2.4 Hz, 1 H), 7.44 (d, J ) 2.2 Hz,
1 H), 7.29 (d, J ) 2.2 Hz, 1 H), 7.27 (d, J ) 2.3 Hz, 1 H), 6.02
(t, J ) 7.5 Hz, 1 H), 3.97 (s, 3 H), 3.90 (s, 3 H), 3.89 (s, 3 H),
3.88 (s, 3 H), 3.64 (s, 3 H), 2.26 (t, J ) 7.3 Hz, 2 H), 2.09 (q, J
) 7.3 Hz, 2 H), 1.65-1.54 (m, 2 H), 1.50-1.40 (m, 2 H); IR
(film) 2933, 1734, 1474, 1261, 1206, 1092, 998 cm-1; FABMS
m/z 539 (MH+), 507 (MH+ - CH3OH). Anal. (C26H28Cl2O8) C,
H.
3′,3′′-Dich lor o-4′,4′′-d im et h oxy-5′-for m yl-5′′-h yd r oxy-
methyl-1,1-diphenyl-5-(2-ethyl-(1,3)-dioxolan-2-yl)-1-pentene
(21). This compound eluted in the first fractions during the
chromatographic purification of 20. Compound 21 was ob-
tained as a colorless oil in low yield (0.010 g, 6%): 1H NMR
(300 MHz, CDCl3) δ 10.35 (s, 0.5 H), 10.30 (s, 0.5 H), 7.56 (d,
J ) 2.5 Hz, 1 H), 7.39 (d, J ) 2.4 Hz, 1 H), 7.05 (m, 2 H), 6.04
(dt, J ) 7.3 and 7.2 Hz, 1 H), 4.71 (s, 1 H), 4.65 (s, 1 H), 4.04
(s, 2 H), 3.97 (s, 1 H), 3.93 (s, 1 H), 3.89 (s, 4 H), 3.87 (s, 2 H),
2.07 (m, 2 H), 1.61-1.44 (m, 6 H), 0.86 (t, J ) 7.5 Hz, 3 H); IR
5′,5′′-Dich lor o-4′,4′′-d im eth oxy-3′,3′′-bis(m eth oxyca r bo-
n yl)-1,1-d ip h en yl-5-[(2-et h yl-(1,3)-d ioxola n -2-yl)-1-p en -
ten e (18). A slurry of TiCl4‚2THF complex (2.28 g, 6.822 mmol)
and zinc dust (0.892 g, 13.644 mmol) in THF (60 mL) was put
under Ar and heated under reflux for 2 h. A solution of ketone
1310 (0.97 g, 2.274 mmol) and aldehyde 1721,22 (0.470 g, 2.729
mmol) in THF (45 mL) was added. The black mixture was
heated under reflux for 1.5 h. It was allowed to cool at room

Modifications in the ADAM Series of NNRTIs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4871
(film) 3421, 2938, 2879, 1479, 1231, 1002, 873 cm-1; FABMS
Compound 25 was obtained as a colorless oil in moderate yield
(0.038 g, 73%): 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J ) 2.2
Hz, 2 H), 7.32 (d, J ) 2.2 Hz, 2 H) 3.90 (s, 6 H), 3.88 (s, 6 H),
3.78 (t, J ) 7.8 Hz, 1 H), 3.62 (s, 3 H), 2.26 (t, J ) 7.4 Hz, 2
H), 1.97 (q, J ) 7.8 Hz, 2 H), 1.64 (qn, J ) 7.6 Hz, 2 H), 1.28-
1.18 (m, 2 H); IR (film) 2950, 2865, 1736, 1475, 1258, 1198,
999, 738 cm-1; FABMS m/z 527 (MH+), 495 (MH+ - MeOH).
Anal. (C25H28Cl2O8) C, H.
m/z 510 (M+ + 2), 508 (M+). Anal. (C26H30Cl2O8) C, H.
3′,3′′-Dich lor o-5′,5′′-d ih yd r oxym eth yl-4′,4′′-d im eth oxy-
6-oxo-1,1-d ip h en yl-1-octen e (22). A solution of ketal 20
(0.070 g, 0.137 mmol) and pyridinium p-toluenesulfonate
(0.012 g, 0.048 mmol) in wet acetone (2 mL containing 3 drops
of water) was heated under reflux for 2.5 h. The mixture was
allowed to cool and the solvent removed. The residue was
diluted with ethyl ether (25 mL) and washed with satd
NaHCO3 (15 mL) and brine (15 mL). After drying over MgSO4,
the solvent was removed and the residue was purified by flash
chromatography on silica gel (∼30 g; column: 2 × 24.5 cm),
eluting with hexanes:ethyl acetate (1:1). Compound 22 was
obtained in moderate yield (0.04 g, 64%) as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 7.16 (d, J ) 2.0 Hz, 1 H), 7.11 (d, J
) 2.2 Hz, 1 H), 7.07 (d, J ) 2.2 Hz, 1 H), 7.01 (d, J ) 2.1 Hz,
1 H), 5.94 (t, J ) 7.6 Hz, 1 H), 4.73 (s, 2 H), 4.63 (s, 2 H), 3.92
(s, 3 H), 3.85 (s, 3 H), 2.39 (t, J ) 6.8 Hz, 2 H), 2.35 (q, J ) 7.3
Hz, 2 H), 2.00 (q, J ) 7.7 Hz, 2 H), 1.69 (qn, J ) 6.9 Hz, 2 H),
0.97 (t, J ) 7.2 Hz, 3 H); IR (film) 3600-3200, 2936, 1705,
Meth yl 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 yl-5-h exen oa te (28). A slurry of TiCl4‚
2THF complex (0.315 g, 0.945 mmol) and zinc dust (0.123 g,
1.89 mmol) in THF (10 mL) was put under Ar and heated
under reflux for 2 h. A solution of ketone 266 (0.162 g, 0.315
mmol) and aldehyde 2724 (0.082 g, 0.63 mmol) in THF (10 mL)
was added. The black mixture was heated under reflux for 1.5
h. It was allowed to cool at room temperature, and 1.0 N HCl
(20 mL) was added. The resulting mixture was stirred for 2 h.
The layers were separated and the aqueous one was extracted
with ethyl acetate (3 × 20 mL). The combined organic extracts
were washed with brine (25 mL), dried over MgSO4 and
filtered, and the solvent was removed. Purification was
achieved by flash chromatography on silica gel (∼40 g;
column: 2 × 29 cm), eluting with hexane:ethyl acetate (3:1).
Compound 28 was obtained as a pale yellow oil in low yield
(0.044 g, 22.8%): 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J )
2.4 Hz, 1 H), 7.48 (d, J ) 2.2 Hz, 1 H), 7.45 (d, J ) 2.2 Hz, 1
H), 7.44 (d, J ) 2.3 Hz, 1 H), 6.00 (t, J ) 7.5 Hz, 1 H), 3.96 (s,
3 H), 3.90 (s, 3 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.61 (s, 3 H),
2.28 (t, J ) 7.4 Hz, 2 H), 2.11 (q, J ) 7.5 Hz, 2 H), 1.75 (qn, J
) 7.4 Hz, 2 H); IR (film) 2950, 1736, 1473, 1434, 1258, 1207,
996 cm-1; FABMS m/z 613 (MH+), 581 (MH+ - CH3OH). Anal.
(C25H26Br2O8) C, H.
1478, 1231, 1113, 1001, 870 cm-1; FABMS m/z 449 (MH+
H2O). Anal. (C24H28Cl2O5) C, H.
-
3′,3′′-Dich lor o-5′,5′′-difor m yl-4′,4′′-dim eth oxy-1,1-diph en -
yl-5-(2-eth yl-(1,3)-d ioxola n -2-yl)-1-p en ten e (23). A solution
of oxalyl chloride (0.1 mL, 1.147 mmol) in dry CH2Cl2 (2.0 mL)
was cooled to -78 °C and put under Ar. A solution of DMSO
(0.16 mL, 2.295 mmol) in CH2Cl2 (3.0 mL) was added over 8
min, and the mixture was then stirred for 15 min at -78 °C.
A solution of alcohol 20 (0.234 g, 0.459 mmol) in CH2Cl2 (4.0
mL) was added over 5 min. The mixture was stirred for 20
min. Et3N (0.72 mL, 5.187 mmol) was added slowly; the
mixture was stirred for 15 min at -78 °C and then allowed to
warm to room temperature. The mixture was diluted with CH2-
Cl2 (30 mL) and washed with water (30 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were washed with brine (35 mL), dried over
MgSO4, and filtered. The solvent was removed, and the residue
was purified by flash chromatography on silica gel (∼75 g;
column: 3 × 30 cm), eluting with hexanes:ethyl acetate (3:1).
Compound 23 was obtained as a yellowish oil in moderate yield
(0.14 g, 60%): 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1 H),
10.31 (s, 1 H), 7.51 (d, J ) 2.2 Hz, 1 H), 7.50 (d, J ) 2.1 Hz,
1 H), 7.39 (d, J ) 2.3 Hz, 1 H), 7.38 (d, J ) 2.2 Hz, 1 H), 6.07
(t, J ) 7.4 Hz, 1 H), 4.06 (s, 3 H), 3.98 (s, 3 H), 3.90 (s, 4 H),
2.09 (q, J ) 7.1 Hz, 2 H), 1.62-1.44 (m, 6 H), 0.87 (t, J ) 7.4
3′,3′′-Dib r om o-4′,4′′-d im et h oxy-5′,5′′-d im et h oxyca r b o-
n yl-1,1,3-tr ip h en yl-1-p r op en e (30). TiCl4‚2THF (0.970 g,
2.91 mmol) and zinc dust (0.369 g, 5.81 mmol) were mixed in
THF (11 mL). The slurry was heated at reflux for 45 min under
nitrogen. [3′,3′′-Dibromo-4′,4′′-dimethoxy-5′,5′′-di(methoxycar-
bonyl)diphenyl]methanone (26)6 (0.283 g, 0.584 mmol) and
hydrocinnamaldehyde (29) (90% technical grade; 0.130 g, 0.872
mmol) were taken up in THF (11 mL) and transferred to the
low-valent titanium slurry via cannula under nitrogen pres-
sure. The resulting reaction mixture was heated at reflux for
45 min and then poured at once onto a column of silica gel (25
g). The product was eluted from the column with EtOAc and
the solution concentrated on a rotary evaporator to give the
crude product as a yellow oil. The product was further purified
by flash column chromatography on silica gel (30 g) using a
gradient of 0-12% EtOAc in hexanes as the eluent. Concen-
tration of the fractions containing the product afforded the
pure product as a colorless oil (0.26 g, 76%): 1H NMR (300
MHz, C6D6) δ 7.67 (d, J ) 2.2 Hz, 1 H), 7.54 (d, J ) 2.2 Hz, 1
H), 7.50 (d, J ) 2.1 Hz, 1 H), 7.24 (d, J ) 2.2 Hz, 1 H), 7.13-
6.92 (m, 5 H), 5.70 (t, J ) 7.7 Hz, 1 H), 3.74 (s, 3 H), 3.71 (s,
3 H), 3.34 (s, 3 H), 3.31 (s, 3 H), 2.41 (t, J ) 6.9 Hz, 2 H), 2.12
(m, 2 H); IR (neat on NaCl) 2950, 1733, 1595, 1474, 1436, 1423,
Hz, 3 H); IR (film) 2937, 2877, 1693, 1476, 1241, 994 cm-1
;
FABMS m/z 507 (MH+). Anal. (C26H28Cl2O6) C, H.
3′,3′′-Dich lor o-5′,5′′-d ifor m yl-4′,4′′-d im eth oxy-6-oxo-1,1-
d ip h en yl-1-octen e (24). A solution of ketal 23 (0.140 g, 0.277
mmol) and pyridinium p-toluenesulfonate (0.024 g, 0.97 mmol)
in wet acetone (4 mL containing 6 drops of water) was heated
under reflux for 8 h. The mixture was allowed to cool and the
solvent removed. The residue was diluted with ethyl ether (40
mL) and washed with satd NaHCO3 (25 mL) and brine (25
mL). After drying over MgSO4, the solvent was removed and
the residue was purified by flash chromatography on silica gel
(∼28 g; column: 2 × 22 cm), eluting with hexanes:ethyl acetate
(3:1). Compound 24 was obtained in moderate yield (0.08 g,
65%) as a colorless thick oil: 1H NMR (300 MHz, CDCl3) δ
10.36 (s, 1 H), 10.31 (s, 1 H), 7.50 (d, J ) 2.4 Hz, 1 H), 7.48 (d,
J ) 2.3 Hz, 1 H), 7.38 (d, J ) 2.1 Hz, 1 H), 7.37 (d, J ) 2.0 Hz,
1 H), 6.05 (t, J ) 7.4 Hz, 1 H), 4.05 (s, 3 H), 3.98 (s, 3 H), 2.37
(t, J ) 7.2 Hz, 2 H), 2.36 (q, J ) 7.2 Hz, 2 H), 2.07 (q, J ) 7.5
Hz, 2 H), 1.70 (qn, J ) 7.4 Hz, 2 H), 1.00 (t, J ) 7.4 Hz, 3 H);
IR (film) 2936, 2873, 1694, 1592, 1476, 1242, 993 cm-1; FABMS
m/z 463 (MH+). Anal. (C24H24Cl2O5) C, H.
Meth yl 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 exa n oa te (25). Methyl ester 17,8
(0.052 g, 0.099 mmol) was dissolved in ethyl acetate (6 mL)
and hydrogenated over PtO2 (26 mg) for 1 h at room temper-
ature. The catalyst was filtered off and washed with ethyl
acetate, and the filtrate was evaporated in vacuo. The residue
was purified by flash chromatography on silica gel (∼40 g;
column: 2 × 29 cm), eluting with hexanes:ethyl acetate (4:1).
1400, 1263, 1208, 1164, 1089, 996, 892, 794, 721, 701 cm-1
Anal. (C28H26Br2O6) C, H.
.
(3,3′-Dica r boxy-5,5′-d iflu or o-4,4′-d ih yd r oxyd ip h en yl)-
m eth a n e (32). 3-Fluorosalicylic acid (31)27 (748 mg, 4.72
mmol) was taken up in methanol (3.5 mL) and water (0.6 mL).
The mixture was cooled to -78 °C and stirred vigorously while
concentrated sulfuric acid (8.3 mL) was added dropwise. The
dry ice/acetone bath was exchanged for an ice bath and stirring
was continued for 1 h at 0 °C. The reaction mixture was again
cooled to -78 °C and an aqueous 37% solution of formaldehyde
(2 mL) was added dropwise over 5 min. The mixture was
warmed to 0 °C and stirred for 5 h. The ice bath was removed
and the solution was allowed to warm to room temperature
and stir overnight. The reaction mixture was poured over
crushed ice (50 g) and the precipitate was collected by vacuum
filtration on a Buchner funnel. The solid was dried first at
room temperature overnight and then in a vacuum desiccator
to afford the product as a white solid (743 mg, 95%). An
analytical sample was obtained by recrystallization from

4872 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23
Casimiro-Garcia et al.
acetone-heptane (2:1): mp 288 °C; 1H NMR (200 MHz,
acetone-d6) δ 7.61 (m, 2 H), 7.37 (dd, J ) 11.8 and 2.2 Hz, 2
H), 3.98 (s, 2 H); IR (Kbr pellet) 3400-2500, 1665, 1622, 1485,
1448, 1274, 1187, 995, 809, 735 cm-1; FABMS m/z 325 (MH+),
324 (M+), 307 (MH+ - H2O). Anal. (C15H10F2O6) C, 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); IR (film) 2953, 2858, 1732,
1613, 1574, 1493, 1436, 1420, 1373, 1260, 1201, 1168, 1112,
1004, 884, 793, 774, 677, 650 cm-1; CIMS m/z 463 (MH+), 462
(M+), 431 (MH+ - MeOH). Anal. (C25H28F2O6) C, H.
[3,3′-Diflu or o-4,4′-d im eth oxy-5,5′-bis(m eth oxyca r bon -
yl)d ip h en yl]m eth a n e (33). A 250-mL three-necked, round-
bottomed flask was equipped with a mechanical stirrer, a 10-
mL pressure equalizing dropping funnel, and a reflux condenser
fitted with a drying tube. (3,3′-Dicarboxy-5,5′-difluoro-4,4′-
dihydroxydiphenyl)methane (32) (2.86 g, 8.77 mmol) was
added to the flask and taken up in acetone (90 mL) with
stirring. Potassium carbonate (9.68 g, 70 mmol) was added to
the stirring mixture, and the reaction mixture was heated at
reflux. The dropping funnel was charged with dimethyl sulfate
(4.60 mL, 48.5 mmol), which was added dropwise to the
vigorously stirring reaction mixture. The mixture was stirred
vigorously under reflux for 20 h. The mixture was filtered, and
the inorganic salts were washed with methylene chloride (4
× 5 mL). The solvents were removed in vacuo, water (10 mL)
was added, and the mixture was extracted with methylene
chloride (3 × 5 mL). The combined organic extracts were
washed with water, dried over sodium sulfate, and evaporated
in vacuo to yield the crude product as a yellow oil. The product
was purified by flash column chromatography on silica gel (100
g) using 25% ethyl acetate in hexanes as the eluent. The
fractions containing pure product were concentrated to yield
the product as a crystallizing oil (2.65 g, 79%). An analytical
sample was obtained by recrystallization from hexane and
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 (36). TiCl4‚2THF (1.64
g g, 4.9 mmol) and zinc dust (0.0.641 g, 9.8 mmol) were heated
at reflux in THF (16 mL) under an argon atmosphere for 1 h.
Benzophenone 34 (0.387 g, 0.98 mmol) and methyl 5-oxopen-
tanoate (27)24 (0.255 g, 2.0 mmol) were taken up in THF (16
mL) and added in one portion via cannula under argon
pressure to the refluxing mixture. TLC (50% EtOAc/hexanes)
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 trans-
ferred 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. Purification of the crude product
was accomplished 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 which crystallized on cooling in a freezer
(-10 °C) to give a slightly yellow solid (0.22 g, 46%): mp 54-
56 °C; 1H 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, 2 H); 19F NMR (282 MHz,
CDCl3, relative to TFA as external standard) δ -13.5 (d, J )
11.3 Hz, 1 F), -13.9 (d, J ) 12.2 Hz, 1 F); IR (Kbr pellet) 2956,
1734, 1708, 1492, 1438, 1347, 1307, 1267, 1199, 993, 878, 788,
773 cm-1; CIMS m/z 493 (MH+), 461 (MH+ - MeOH). Anal.
(C25H26F2O8) C, H.
1
diethyl ether: mp 48 °C; H NMR (200 MHz, CDCl3) δ 7.33
(m, 2 H), 7.00 (dd, J ) 11.6, 1.6 Hz, 2 H), 3.94 (s, 3 H), 3.93 (s,
3 H), 3.90 (s, 6 H), 3.90 (s, 2 H); IR (Kbr pellet) 2944, 2838,
1722, 1493, 1435, 1321, 1281, 1202, 1019, 799, 766 cm-1; CIMS
m/z 381 (MH+), 349 (MH+ - MeOH). Anal. (C19H18F2O6) C, H.
3,3′-Diflu or o-4,4′-d im eth oxy-5,5′-bis(m eth oxyca r bon yl-
)d ip h en yl Keton e (34). [3,3′-Difluoro-4,4′-dimethoxy-5,5′-bis-
(methoxycarbonyl)diphenyl]methane (33) (1.3 g, 3.58 mmol)
was taken up in acetic anhydride (30 mL) with stirring. The
mixture was cooled in an ice bath, and chromic anhydride (1.44
g, 14.3 mmol) was added in small portions over 10 min. The
resulting reaction mixture was warmed to room temperature
and stirred for 20 h. The inorganic salts were filtered off and
washed with methylene chloride (5 × 10 mL). The solvent was
removed in vacuo yielding the crude product as a dark green
solid. The product was purified by flash column chromatog-
raphy on silica gel (25 g) using methylene chloride as the
eluent. The fractions containing the pure product were con-
centrated on a rotary evaporator yielding the pure product as
a white solid (1.09 g, 81%): mp 90-91 °C; 1H NMR (200 MHz,
CDCl3) δ 7.92 (dd, J ) 2.2 and 1.4 Hz, 2 H), 7.68 (dd, J ) 11.6
and 2.2 Hz, 2 H), 4.10 (s, 3 H), 4.09 (s, 3 H), 3.91 (s, 6 H); IR
(Kbr pellet) 3079, 2959, 1736, 1713, 1664, 1609, 1495, 1425,
1272, 1207, 993, 835, 759 cm-1; CIMS m/z 395 (MH+), 363
(MH+ - MeOH). Anal. (C19H16F2O6) C, H.
3′,3′′-Diflu or o-4′,4′′-d im eth oxy-5′,5′′-bis(m eth oxyca r bo-
n yl)-1,1-d ip h en yl-1-h ep ten e (35). TiCl4‚2THF (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. 3,3′-
Difluro-4,4′-dimethoxy-5,5′-bis(methoxycarbonyl)diphenyl ke-
tone (34) (0.486 g, 1.23 mmol) and hexanal (0.22 mL, 1.85
mmol) were taken up in THF (20 mL) and added in one portion
via cannula under argon pressure to the refluxing mixture.
TLC (50% EtOAc/hexanes) showed the reaction to be complete
in 30 min. The reaction mixture was cooled to ambient
temperature and silica gel (20 mL) 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 concentrated in vacuo to give the crude product.
Purification of the crude product by flash column chromatog-
raphy on silica gel (10 g) using a gradient of 0-4% EtOAc in
hexanes as the eluent yielded the pure product as a slightly
yellow oil (0.373 g, 66%): 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),
In Vitr o An ti-HIV Assa y. Anti-HIV screening of test
compounds against various viral isolates and cell lines was
performed as previously described.47 This cell-based microtiter
assay quantitates the drug-induced protection from the cyto-
pathic effect of HIV-1. Data are presented as the percent
control of XTT values for the uninfected, drug-free control.
EC50 values reflect the drug concentration that provides 50%
protection from the cytopathic effect of HIV-1 in infected
cultures, while the CC50 reflects the concentration of drug that
causes 50% cell death in the uninfected cultures. XTT-based
results were confirmed by measurement of cell-free superna-
tant RT and p24 levels. All XTT cytoprotection data were
derived from triplicate tests on each plate, with two separate
sister plates. Thus, the EC50 value from each plate represents
the average of triplicates, and the two EC50 values from sister
plates were averaged. The variation from the mean averaged
less than 10%.
Scr een in g Aga in st HIV-1 Vir u ses Con ta in in g NNRTI
Resista n ce Mu ta tion s. These studies were performed as
previously described.48
Assa y for In h ibition of HIV-1 RT. The effects of the
compounds on the HIV-1 RT enzyme were performed using
purified p66/51 RT (a kind gift of S. Hughes, ABL-Basic
Research Program, NCI-FCRDC). Inhibition of reverse tran-
scription was measured by the level of incorporation of [32P]-
TTP into the poly(rA)-oligo(dT) (rAdT) or [32P]GTP into the
poly(rC)-oligo(dG) (rCdG) homopolymer template primer sys-
tem.6
Ack n ow led gm en t. This investigation was made
possible by Grant RO1-AI-43637, awarded by the Na-
tional Institutes of Health, DHHS. A.C.-G. thanks
Consejo Nacional de Ciencia y Tecnologia (Mexico) for
a scholarship and Cytel Corp. for financial support.

Modifications in the ADAM Series of NNRTIs
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 23 4873
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