Bis tertiary amide inhibitors of the HIV-1 protease generated via protein structure-based iterative design

Article abstract of DOI:10.1021/jm960092w

A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protease, his tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structure of the protein- ligand complex of 9 revealed the inhibitor binds in an inverted binding mode relative to 3. Examination of the protein-ligand complex of 9 suggested several modifications in the P1 and P1' pockets. Through these modifications it was possible to improve the activity of the inhibitors another 100-fold, highlighting the utility of crystallographic feedback in inhibitor design. These compounds were found to have good antiviral activity in cell culture, were selective for the HIV protease, and were orally available in three animal models.

Full text of DOI:10.1021/jm960092w

J . Med. Chem. 1996, 39, 2795-2811
2795
Bis Ter tia r y Am id e In h ibitor s of th e HIV-1 P r otea se Gen er a ted via P r otein
Str u ctu r e-Ba sed Iter a tive Design
Michael Melnick,* Siegfried H. Reich, Kathy K. Lewis, Lennert J . Mitchell, J r., Dzuy Nguyen,
Anthony J . Trippe, Heather Dawson, J ay F. Davies II, Krzysztof Appelt, Bor-Wen Wu, Linda Musick,
Dan K. Gehlhaar, Stephanie Webber, Bhasker Shetty, Maha Kosa, Deborah Kahil, and Dominic Andrada
Agouron Pharmaceuticals Inc., 3565 General Atomics Court, San Diego, California 92121
Received J anuary 31, 1996X
A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the
structure of compound 3 bound to the HIV protease, bis tertiary amide inhibitor 9 was designed
and prepared. Compound 9 was found to be about 17 times more potent than 3, and the
structure of the protein-ligand complex of 9 revealed the inhibitor binds in an inverted binding
mode relative to 3. Examination of the protein-ligand complex of 9 suggested several
modifications in the P1 and P1′ pockets. Through these modifications it was possible to improve
the activity of the inhibitors another 100-fold, highlighting the utility of crystallographic
feedback in inhibitor design. These compounds were found to have good antiviral activity in
cell culture, were selective for the HIV protease, and were orally available in three animal
models.
In tr od u ction
fied either by rational design7 or by broad screening of
compound libraries.8 Thus, in order to avoid the inher-
ent difficulties associated with developing peptidic lead
compounds into drugs, it would appear necessary to
identify nonpeptide inhibitors of the HIV-PR early in
the drug discovery process.
The spread of acquired immunodeficiency disease
(AIDS) continues to be a health problem of global
proportions, and the search for useful therapeutics to
help combat and control the disease continues. One
encouraging approach involves inhibiting the virally
encoded protease (HIV-PR). This aspartyl protease is
responsible for the cleavage of the gag and gag-pol
polyproteins into the structural and functional proteins
of the mature virion. The HIV-PR is essential for viral
replication and when disabled via mutation or inhibition
produces immature virions which are replication in-
competent.1 Thus the HIV-PR represents an ideal
target for interruption of the viral life cycle, and several
HIV-PR inhibitors are currently being evaluated in the
clinic.2
Crystallographic studies have shown that the HIV-
PR is a C2 symmetric homodimer. Each monomer
contains one of the catalytic aspartic acid residues and
a â turn or flap region. These flap regions fold onto the
substrate or inhibitor, making several hydrogen bonding
contacts upon binding. Since its discovery, the HIV-
PR has undergone extensive structural studies and is
arguably one of the best characterized proteases to
date.3 The protease is unique in its substrate specificity,
cleaving phenylalanine (tyrosine)-proline peptide bonds.
Taken together, this increases the attractiveness of the
HIV-PR as a therapeutic target.1
Early inhibitors of the HIV-PR were substrate ana-
logs, examples of which include Ro31-8959 (Saquinivar,
1)4 and LY289612 (2).5 Unfortunately these inhibitors
were peptidic in nature and displayed poor pharmaco-
kinetic properties (short half-life, low availability) in
animal models. These shortcomings were generally
attributed to the poor solubility and high molecular
weight of these inhibitors. A great deal of work has
been spent attempting to convert peptidic lead mol-
ecules into compounds with superior properties, and in
some cases this has been successful.6 More recently,
nonpeptide inhibitors of the HIV-PR have been identi-
In a previous report, a series of novel inhibitors of
the HIV-PR based on the structural information of
LY219612 (2) bound to the HIV-PR was described.9 This
resulted in the discovery of AG1132 (3), a nonpeptide
inhibitor with good inhibitory activity (IC50 ) 20 µM).
More significantly, the structure of the complex of 3
bound to the HIV-PR was obtained, and with appropri-
ate modifications the activity of 3 was improved by 20-
fold. In this report, a new series of inhibitors based on
the structure of 3 is presented. By the use of structure-
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
S0022-2623(96)00092-1 CCC: $12.00 © 1996 American Chemical Society

2796 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Melnick et al.
Sch em e 1a
a
Reagents: (i) Me3Al, HOCH2CH2NHtBu, PhCH3, ∆; (ii) Me3Al,
H2NtBu, (ClCH2)2, ∆.
Ta ble 1. Biological Activity of HIV Protease Inhibitors
Ki (µM)b
ED50 (µM)c TC50
a
a
d
compd
R1
R4
1
2
3
6
7
Ro31-8959
LY219612
AG1132
0.0009(0.00002)e
0.002(0.0006)f
20(4.4)
34(9.6)
18(4.1)
1.1(0.12)
0.090(0.033)
0.11(0.03)
0.002e
0.020f
ndg
nd
nd
36
>10
122
nd
nd
nd
>150
>150
nd
-
-
-
-
b
-
-
a
9
F igu r e 1. Design of inhibitor 9 based on the binding mode of
3: (a) binding mode of 3; (b) proposed binding mode of 9; (c)
experimentally observed binding mode of 9.
40
40
40
40
40
40
41
42
42
42
42
42
42
43
44
45
47
49
56
58
62
3.4
3.7
a
d
a
b
a
a
a
a
b
c
c
c
c
c
-
-
-
-
-
-
-
e
b
f
g
b
b
b
b
h
d
i
b
-
-
-
-
-
-
-
1.3(0.12)
nd
2.2
7.2
7.6
4.9
4.2
0.81
0.78
0.79
1.37
1.11
0.72
0.59
0.95
1.7
0.86
0.88
0.65
0.84
nd
122
nd
nd
nd
nd
nd
103
nd
nd
nd
97
nd
nd
nd
nd
nd
nd
0.021(0.006)
0.145(0.038)
0.064(0.014)
0.15(0.034)
0.063(0.016)
0.018(0.004)
0.008(0.002)
0.0004(0.0005)
0.006(0.003)
0.035(0.006)
0.002(0.001)
0.004(0.003)
0.010(0.003)
0.051(0.011)
0.010(0.004)
0.006(0.0014)
0.002(0.001)
0.009(0.003)
based iterative ligand design, a series of bis tertiary
amides was identified which has undergone a critical
change in binding. This change in binding mode was
exploited, improving activity over 3 by greater than
1000-fold and producing inhibitors which possess both
good antiviral and pharmacological properties.10
In h ibitor Design
In our previous report, the optimization of the P1 and
P1′ groups of 3 was described; however, no effort was
made with regard to the amide groups.9 Upon inspec-
tion of the structure of 3 bound to the HIV-PR, it was
apparent that the amide NH’s were not interacting
directly with the protein, but rather were undergoing
hydrogen bonding through ordered water molecules to
the carbonyl of glycine 27/127 (Figure 1a). One modi-
fication would be to extend alkyl chains off the amide
nitrogens, producing tertiary amides. The initial idea
was to utilize hydroxyethyl groups to act as hydrogen-
bonding “extentions” which could potentially donate a
hydrogen bond to the carboxylate side chain of aspartic
acid 30/130 (Figure 1b). Thus the ligand could interact
through the hydroxyl groups directly with the protein
as well as allow the inhibitor to access the P3 and P3′
binding sites. This idea was originally explored in the
sulfide series (Figure 1b, X ) S). Both the mono and
bis hydroxyethyl tertiary amides were prepared (Scheme
1), and these compounds were modest improvements
over the parent inhibitor (data not shown), but were
similar in activity to 3 (Table 1, compounds 6 and 7). It
was known from the AG1132 series that substituting a
methylene for sulfur produced a 3-5-fold improvement
nd
a
b
See Scheme 4 for R1 and R4 groups. Standard deviation is
in parentheses. c Antiviral activity in CEM cells. Concentration
d
(µM) at which 50% of the cells were viable. e See ref 4. f See ref 5.
g
Not determined.
in activity.9 Thus the methylene version of 7 (Figure
1b, X ) CH2) was prepared (Scheme 1, 9) as a racemic
mixture and found to be a good inhibitor of the HIV-PR
(Ki ) 1.1 µM, Table 1). This represented a nearly 17-
fold improvement over 3, and the HIV-PR-ligand com-
plex of 9 was determined in order to ascertain the
binding mode.
The HIV-PR complex of 9 was solved at 2.4 Å
resolution and revealed a very interesting and unex-
pected result. The inhibitor was found to bind in an
inverted mode compared to 3 (see Figure 1c and
compare with 1a). In this manner, it appeared the
active enantiomer was the R configuration (as inferred
from the crystal structure), while for 3, it was found to
be the S enantiomer by synthesis.9,10 Several interest-

Inhibitors of the HIV-1 Protease
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2797
prepared and found to be about 11-fold more active than
9 (Ki ) 0.090 nM). Solution of the protein-ligand
complex of 40a b at 2.35 Å resolution indicated that the
compound bound as anticipated (see Figure 3B and
compare with 3A) with the necessary protein movement
to accommodate the phenyl group (proline 81/181 was
observed to move approximately 2.1 Å relative to its
position in 9). An additional point that should be made
is that this modification did not alter the new binding
mode.
Encouraged by these results, the protein-ligand
complexes of 9 and 40a b were further scrutinized for
binding pockets which were not adequately filled. It
was quickly realized that the P1 pocket could also be
filled with a dimethylbenzyl group and this modification
was successful, although the improvement in activity
was not as large (about 4-fold) as observed with the P1′
dimethylbenzyl group (40bb in Table 1). Although this
change might be expected to produce an equal or nearly
equal improvement in activity (compared to the P1′
dimethylbenzyl), it must be realized that although the
active site of the HIV-PR is symmetrical, the inhibitor
is not. Thus the second dimethylbenzyl group does not
interact with the protein in completely the same man-
ner. This phenomenon has been previously observed
in the secondary amide series.9,10 Careful inspection of
the P2′ phenyl ring revealed a small pocket which could
be filled nicely by a methyl group in the 5 position. This
resulted in a slight improvement in activity (compare
40a b with 42a b, see Table 1). Interestingly a similar
pocket exists on the P2 phenyl ring; however, this
modification resulted in an almost 2-fold loss in activity
(compare 41a b and 40a b in Table 1). It is not clear
from the structure of 40a b why there is a loss of potency
in this case. Perhaps there is some subtle communica-
tion between binding pocket residues in this case.
F igu r e 2. Crystal structure of 9 complexed to the HIV-PR
determined at 2.4 Å resolution. Carbon atoms are in green,
nitrogen atoms are in blue, and oxygen atoms are in red. A
solvent accessible surface is seen in purple.
ing features should be noted (see Figure 2). With the
reversal of the binding mode, the phenyl rings were now
located in P2 and P2′ (in 3 they were located in P1 and
P1′ pockets), while the tert-butyl groups were in P1 and
P1′ (in 3 they were found in the P2 and P2′ pockets).
Interestingly, ordered water molecules were observed
interacting with the π clouds of the aromatic rings and
accepting a hydrogen bond from the amide NH of
aspartic acid 30/130. In this inverted binding mode, the
hydroxyethyl groups were unable to hydrogen bond to
the side chain carboxylates of aspartic acid 30/130, but
instead were found to be hydrogen bonded to the same
ordered water molecule interacting with the aromatic
rings. This new binding mode resulted in improved
bond vectors for reaching deeper into P1 and P1′ which
by inspection of the protein-ligand complex were only
marginally occupied.
This last observation cannot be over emphasized. A
new structure/binding mode is only as useful as its
ability to access all binding pockets. In 3, the phenyl
rings allowed additional access to P1 and P1′, but the
bond vectors of the phenyl ring allowed for only limited
changes. As will be discussed in detail below, the tert-
butyl substituent permits access to the P1 and P1′
pockets from all three methyl groups, thus allowing a
variety of changes in these binding pockets. Also the
phenyl rings in P2 and P2′ appeared to be ideally located
for placement of additional substituents and the hy-
droxyethyl groups allowed access to P3 and P3′.
As mentioned above, the P1 and P1′ sites of the
structure of the HIV-PR complexed with 9 were only
marginally occupied by the tert-butyl groups. The first
modifications were directed at improving binding in the
P1′ pocket which by inspection had a lipophilic cavity
which could be filled by replacing a methyl group with
a larger substituent. On the basis of modeling studies
using the crystal structure of 9 (Figure 3A), it was
decided to replace a methyl of the P1′ tert-butyl group
with a phenyl ring. In order for this group to fit, the
protein residues in this vicinity (threonine 80/180-
proline 181/181-valine 82/182) would have to move
about 2 Å. Such movement has been previously ob-
served in the structure of Ro 31-8959 (1) complexed to
the HIV-PR.11 In this case, the large decahydroisoquino-
line system effected the protein movement. Thus it was
predicted that the protein could accommodate the larger
phenyl group. This compound (40a b in Table 1) was
New structural leads were also generated with a
Monte Carlo de novo ligand generation (MCDNLG)
program which was performed on both the P1 and P1′
sites to produce several new ideas.12 In P1′ two new
ideas were suggested that were synthetically viable. In
the first case, a 1,1-diethylbutyl group replaced the tert-
butyl group to produce a potent inhibitor (40a d , Table
1) being about 11-fold more potent than 9. An alterna-
tive suggestion was the use of a cis-perhydroindan
system. This idea was particularly interesting since the
saturated indan ring system would have to place one
ring into the active site parallel to the butyl connecting
chain (“doubling back on itself”), thus filling space that
has not been addressed by previous inhibitors in this
series. This modification was prepared as an insepa-
rable mixture of diasteriomers, but the mixture was
found to be quite active, about 20-fold more potent than
9 (40a g, Table 1). Structures of these compounds (40a d
and 40a g) complexed to the HIV-PR were determined
at 2.1 and 2.2 Å resolution, respectively, and can be seen
in Figure 3C,D. Both 40a d and 40a g bound essentially
as predicted. In the perhydroindan case we could not
unambiguously determine which ring was located in the
active site parallel to the butyl chain although the
cyclopentyl ring appeared to fit the data best.
On the P1 side, MCDNLG suggested a three-carbon
homologation in the form of a 1-ethylcyclopentyl group
to replace the tert-butyl group. Like the perhydroindan
system, this would require either the ethyl group or the

2798 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Melnick et al.
F igu r e 3. Modifications of 9 in P1′: (A, top left) P1′ group of 9 (tert-butyl); (B, top right) P1′ group of 40a b (dimethylbenzyl); (C,
bottom left) P1′ group of 40a d (1,1-diethylbutyl); (D, bottom right) P1′ group of 40a g (cis-perhydroindan). Atom colors are the
same as in Figure 2.
cyclopentyl ring to double back on the inhibitor, filling
space not addressed by previous inhibitors. This group
was a 7-fold improvement over the tert-butyl group in
P1 (compare 42cb with 42a b in Table 1). Thus the
combination of the cyclopentyl ethyl (in P1) with the
dimethylphenyl (in P1′) and the 5-methyl group in P2′
produced the highly potent inhibitor 42cb. This rep-
resents a greater than 2000-fold improvement over
AG1132 (3) and an over 100-fold improvement over 9.
A structure of 42cb bound to the HIV-PR was deter-
mined and revealed excellent complimentarity with the
active site.10
(Scheme 1). Thus both the ester and lactone were
reacted simultaneously with the aluminum amide de-
rived from hydroxyethyl-tert-butylamine and trimethyl-
aluminum to produce 9 in modest yield. However, this
chemistry was not ammendable to preparing compounds
with two different amide groups, so an alternate syn-
thesis was developed, which is outlined in Scheme 4.
The key step was the coupling of an o-toluoyl anion14
with the N,O-dimethylamides 34 or 35 to generate
ketones15 36-39, which were easily reduced and depro-
tected to give the final inhibitors.
In Schemes 2 and 3 the synthesis of the tertiary
amide precursers is described. The starting amines
10b-h were either literature compounds or were pre-
pared by known methods (see the Experimental Sec-
tion). In the case of amine 10i, the synthesis was
carried out according to Scheme 3. The known pyran-
4-carboxylic acid16 (28) was converted to the tertiary
carbinol 29 with methyllithium. The alcohol was treated
with KCN and H2SO4 in acetic acid to give amine 10i
after acidic hydrolysis of the formamide intermediate.
The amines 10b-i were alkylated with ethylene oxide
in the presence of LiClO4,17 and the resultant alcohol
was protected as a tert-butyldiphenylsilyl ether to
produce compounds 16b-h (Scheme 2). In addition
(Scheme 3) amine 21 was prepared by reaction of 10b
Ch em istr y
Initially, the sulfide analogs 6 and 7 were prepared
because they were synthetically more accessible. These
compounds were prepared by the chemistry in Scheme
1. Reaction of lactone ester 49 with a 6-fold excess of
the aluminum amide derived from hydroxyethyl-tert-
butylamine produced the lactone amide 5.13 This mate-
rial was reacted with aluminum amides derived from
either tert-butylamine or hydroxyethyl-tert-butylamine
to produce the final compounds 6 or 7, respectively.
The synthesis of the carbon analog 9 was accom-
plished in one step from the known intermediate9
8

Inhibitors of the HIV-1 Protease
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2799
Sch em e 2a
Sch em e 3a
a
Reagents: (i) LiClO4, THF/CH3CN; (ii) (1) TEA, CH2Cl2, (2)
t
KOH, aqueous MeOH; (iii) Bu(Ph)2SiCl, TEA, CH2Cl2; (iv) TEA,
CH2Cl2.
with 4-bromobutene. Reductive amination of 10b with
acetaldehyde followed by acylation with 12 produced
amide 27. Alkylation of 10b with the mesylate derived
from 24 produced amine 25.
a
Reagents: (i) 4-bromobutene, Hunig’s base, 110 °C; (ii) TEA,
Acylation of the amines with o-toluoyl chloride (12),
2,5-dimethylbenzoyl chloride (13) or 5-chloro-2-methyl-
benzoyl chloride (17) furnished the toluamides 18a -c,
19a ,b,d , 20b, 22, 26, and 31. In some cases, the
hydroxyethylamines 11 were acylated directly with 12
or 13 to form an ester amide which was treated with
sodium hydroxide to produce the hydroxyamides 14a ,
b, d -h or 15a (Scheme 2).
The toluoyl amide 18a -c or 19a was ortho metalated
with sec-butyllithium in THF at -78 °C, and the
resultant anion was quenched with excess ethylene
oxide yielding the homologated alcohol (Scheme 4).
Oxidation with either J ones reagent or pyridinium
dichromate (PDC) produced the carboxylic acids 32 or
33. The carboxylic acids 32a -c or 33a were coupled
with N,O-dimethylhydroxylamine using either (benzo-
triazol-1-yloxy)tris(dimethylamino)phosphonium hexa-
fluorophosphate (BOP) or diethylphosphoryl cyanide
(DEPC) to produce the amides 34a -c or 35a .
The compounds were completed by C-acylation of the
requisite toluoyl anions generated by deprotonation of
amides 14a ,b,d -h , 18b, 19b,d , 20b, 22, 26, 27, or 31
with s-BuLi followed by reaction with N,O-dimethyl-
amides 34a -c or 35a (Scheme 4). This produced
ketones 36-39, which were subsequently reduced with
NaBH4 and deprotected with tetrabutylammonium
fluoride (TBAF) to produce the final compounds 40-43
13, CH2Cl2; (iii) C(Me)2(OMe)2, p-TSA, CH2Cl2; (iv) NaCl, H2O,
DMSO, ∆; (v) LiAlH4, Et2O; (vi) MeSO2Cl, TEA, 0 °C; (vii) 10b,
Hunig’s base; (viii) acetaldehyde, NaCNBH3, MeOH/H2O; (ix) TEA,
12, CH2Cl2; (x) MeLi, THF, -78 °C; (xi) MeLi, THF, 0 °C; (xii) (1)
KCN, HOAc, H2SO4, 55 °C, (2) concentrated HCl, ∆;(xiii) LiClO4,
t
ethylene oxide, THF/CH3CN; (xiv) Bu(Ph)2SiCl, TEA, CH2Cl2.
as racemic mixtures. In most cases we found we could
take the crude ketone directly into the reduction and
deprotection step and purify the product at the end.
Compounds 44, 45, 47, and 49 were prepared in an
analogous fashion (Scheme 5). In the case of 45, the
final step involved acidic deprotection of the acetal 44
to produce the tetrol. Compound 49 was prepared by
cis hydroxylation of 48 with OsO4 to produce the tetrol.
The synthesis of phenol 56 and O-alkylated deriva-
tives 58 and 62 can be seen in Schemes 6 and 7. The
requisite amine 52 was prepared from 4-isopropylphenol
(50) by silyl protection and oxidative nucleophilic sub-
stitution with trimethylsilyl azide, followed by azide
reduction to yield the amine.18 Standard alkylation
with ethylene oxide, silyl protection, and acylation gave
the desired toluamide 54. The toluamide 54 was
C-acylated with N,O-dimethylamide 34c under our
standard conditions to produce ketone 55 which could
be reduced and deprotected in standard fashion to yield
final compound 56. Alternately, 55 could be selectively
desilated at the phenol hydroxyl with TBAF at -50 °C

2800 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Melnick et al.
Sch em e 4a
Replacing the hydrogen in the 5-position of the P2′
phenyl with a methyl group resulted also in an improve-
ment in activity. Changing to chloro improved activity
even more (compare 43cb with 42cb), presumably by
inductive effects. Substituents larger than methyl did
not result in further improvements (data not shown)
even though the crystal structure indicated that some-
what larger substitutents could be accommodated.
On the P1 side, a trend similar to P1′ was found in
that going from tert-butyl to dimethylbenzyl improved
activity but not as dramatically as in the P1′ side (about
a 4 fold improvement compare 40a b with 40bb). Better
results were obtained with the 1-ethylcyclopentyl group
which produced a larger increase (42a b versus 42cb).
Interestingly there appeared to be a pocket of the P2
side of the inhibitor which could also be filled by a
methyl group in the 5-position. Yet this modification
did not improve activity (compare 41a b with 40a b). On
the basis of the above SAR the combination of a
dimethylbenzyl in P1′, methyl in P2′ and cyclopentyl-
ethyl in P1 were found to be the optimal both from an
activity and chemistry standpoint. We utilized this
optimal framework to explore some changes in the P3′
site that could improve antiviral and pharmacological
properties.
a
Reagents: (i) s-BuLi, ethylene oxide, THF, -78 °C; (ii) PDC,
DMF; (iii) J ones reagent, acetone; (iv) BOP or DEPC, Me(Me-
O)NH-HCl, Hunigs base, CH2Cl2; (v) s-BuLi, 14a ,b,d -h , 18b,
19b,d , 20b, 31, THF -78 °C; (vi) NaBH4, MeOH; (vii) TBAF (2
equiv), THF.
It was found that the hydroxyl groups (of the hy-
droxyethyl groups) appear to be important for good
activity as the data for 47 indicated. The P3′ region
appeared to be able to accommodate a variety of
structural diols such as compounds 49 and 45. Inter-
estingly, the precursor to 45, acetal 44, was also a potent
inhibitor, although this modification was not pursued
due to the lability of the acetal group.
followed by O-alkylation with 3-(chloromethyl)pyridine
to yield ketone 57. Again reduction and deprotection
produced the final compound 58. Finally morpholine
derivative 62 (Scheme 7) was prepared from amide 54
by selective deprotection with TBAF at 0 °C followed
by O-alkylation with chloroethylmorpholine to give the
amide 60. Ortho metalation of 60 followed by reaction
with 34c produced ketone 61. The final compound 62
was obtained by reduction and deprotection in the usual
fashion.
It was also discovered from the structure of 40a b and
42cb that the 4-position of the phenyl ring in P1′ was
directed toward solvent and would be an ideal position
to attach groups to improve solubility. This was ac-
complished with a phenol, which could be selectively
alkylated with a suitable group. As the data in Table
1 indicates, the phenol 44 had activity nearly identical
to that of 42cb. Functionalizing the phenol with a
3-methylpyridine group or an ethylmorpholine group
produced the potent compounds 58 and 62, respectively.
Resu lts
The biological results for the various compounds are
summarized in Table 1. Clearly the carbon analogs
were superior to the sulfur-linked inhibitors (compare
7 and 9). As was discussed in the ligand design section,
increasing the bulk of the P1 and P1′ groups of the
inhibitor generally improved activity. In P1′, increasing
the size of the inhibitor from tert-butyl to dimethylben-
zyl to cyclopentylphenyl (compare 9 with 40a b and 42cb
with 42ch ) produced a dramatic increase in activity
versus the enzyme. Interestingly the 1,1-diethylbutyl
group appeared as effective as the dimethylbenzyl group
(compare 40a d with 40a b ), while the perhydroindan
40a g was even better, especially if one takes into
account that it is a mixture of four diastereomers. Some
P1′ modifications were not as successful, such as the
dimethylnaphthyl 40a f, which was less active than the
dimethylbenzyl. Also, the 1,1-dimethyl-2-phenethyl
group in P1′ 40a e had essentially the same activity as
a tert-butyl group in P1′ (9), indicating that the phenyl
group is probably not interacting with the protein.
Saturated rings such as a 4-pyran were also tolerated,
compare 42cb with 42ci.
The antiviral data from cell culture in CEM cells can
be seen in Table 1. One notices a good correlation of
antiviral activity with Ki for the less potent compounds,
but as the Ki improved antiviral activity only improved
marginally. For example the antiviral activity in going
from 9 to 40a b parallels the Ki data very nicely, but
when one compares the antiviral activity of 42cb with
that of 40a b the improvement is not as dramatic as one
might anticipate. One also notices that as the com-
pounds become more lipophilic in P1′ the antiviral data
begins to drop off as well. For example the compounds
40a g and 40a f are similar in activity to 40a b versus
the enzyme, but are both less potent in the anti-
viral assay. Also compare the antiviral activity of
compound 42cb with 42ch and 42cd . This phenom-
enom has been observed with other HIV PR inhibitors
and may be due to the highly lipophilic nature of the
inhibitors.19
Attempts to improve antiviral activity by altering the
properties of 42cb was attempted, and examples can
be seen in Table 1. Thus incorporation of an additional
hydroxyl as seen in 45 and 49 did not effect the Ki

Inhibitors of the HIV-1 Protease
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2801
Sch em e 5a
a
Reagents: (i) s-BuLi, 34c, THF, -78 °C; (ii) NaBH4, MeOH; (iii) TBAF, THF; (iv) p-TSA MeOH; (v) s-BuLi, 27, THF, -78 °C; (vi)
s-BuLi, 22, THF, -78 °C; (vii) OsO4, NMMNO, acetone/H2O.
Sch em e 6a
a
t
Reagents: (i) Bu(Me)2SiCl, imidazole, DMF; (ii) (1) Me3SiN3, DDQ, CHCl3, (2) Pd/BaSO4, H2, EtOH; (iii) ethylene oxide, LiClO4,
THF; (iv) 13, TEA, THF; (v) s-BuLi, 34c, THF, -78 °C; (vi) NaBH4, MeOH; (vii) TBAF, THF; (viii) TBAF, THF/hexanes, -50 °C; (ix)
3-(chloromethyl)pyridine, Cs2CO3, KI, acetone.
significantly, but no improvement in antiviral activity
was observed. Effectively the same results were ob-
served for phenol 44, 3-pyridyl compound 58, and
morpholino compound 62. The parent structural skel-
eton 42cb being highly lipophilic, it may require more
dramatic structural changes in order to significantly
alter the physical properties of these molecules. None-
theless, several compounds possessed good antiviral
activity and their pharmacological properties were
investigated in several animal models.

2802 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Melnick et al.
Sch em e 7a
a
Reagents: (i) TBAF, PhCH3, 0 °C; (ii) Cs2CO3, chloroethyl morpholine, dioxane, 80 °C; (iii) s-BuLi, 34c, THF, -78 °C; (iv) NaBH4,
MeOH; (v) TBAF, THF.
Ta ble 2. Pharmacokinetic Parameters of Selected Compounds
Ta ble 3. Pharmacokinetic Parameters of Selected Compounds
in the Rat
in the Dog and Monkey
dosea
(mg/kg)
routeb
(unfasted)
Cmax
(µg/mL)
dose
(mg/kg)
route
(unfasted)
Cmax
(µg/mL)
compd
T1/2c (h)
% Fd
compd
T1/2 (h) % F
42bb
50
50
50
50
50
50
50
50
50
50
50
50
60
50
iv
po
iv
po
iv
po
iv
po
iv
po
iv
po
iv
po
88.9
1.2
88.35
2.78
110.9
1.4
52.2
1.16
110.8
0.84
41.3
no levels
87.2
0.86
0.5
nc
1.3
nce
1.7
nc
1.0
nc
1.3
nc
-
34
-
39
-
31
-
7
-
2
-
0
Dog
po
iv
po
po
po
po
po
42bb
42cb
15
15
15
30
0.39
15.95
0.38
0.69
3.26
2.07
0.24
nc
nc
0.52
nc
nca
-
42cb
43cb
45
3
nc
33
nc
nc
30 + antacidb
43cb
45
15
15
0.59-2.25
1.17
0.34
49
Monkey
po
iv
po
po
po
42bb
42cb
25
25
25
25
25
0.86c
18.28
1.91
no levels
0.81
-
-
-
56
1.4
-
1.0
nc
1.08
1.07
-
32
-
58
-
43cb
45
5f
nc
nc
a
b
All compounds dosed in propylene glycol/water. iv ) intra-
a
b
nc ) not calculated. CaCO3 (500 mg) dosed orally 10 min
prior to and 60 min postdosing of 42cb. c No levels detected in
second monkey.
venous, po ) oral. c Half life. Fraction of compound bioavailable.
d
e Not calculated. f Dose corrected.
P h a r m a cology
were also examined in dogs and monkeys. These results
are found in Table 3. In the case of dogs, when dosed
at 15 mg/kg, quite variable results were observed among
our compounds although it appeared 43cb had the best
overall results. Because 42cb was also found to have
some acid instability, it was decided to dose it at 30 mg/
kg along with CaCO3 as an antacid. In this case much
better results were obtained. Due to compound supply,
we could not dose all of the compounds with this
alternate protocol, although 43cb was considerably
more stable than 42cb under acidic conditions, perhaps
explaining its good availability.
Finally several of our compounds were tested in
monkeys, and these results are also in Table 3. In this
case only 42cb displayed good results. Strangely, with
43cb no levels of compound could be detected when
dosed orally. On the basis of these results, it appeared
that 42cb had the best overall pharmacokinetic proper-
ties after oral administration, with oral bioavailability
of greater than 30% and plasma levels maintained at
or above the antiviral IC90 beyond 5 h when dosed in
rats at 50 mg/kg, dogs at 30 mg/kg, and monkeys at 25
mg/kg.
In order to ascertain if this series of inhibitors
possessed good pharmacological properties, it was de-
cided to dose compound 9 in mice. Using propylene
glycol/water as vehicle, 9 was dosed at 100 mg/kg both
intravenously and intraperitoneally. Compound 9 dis-
played a Cmax ) 9.7 µg/mL and an availablilty of 46%.
Likewise when 40a b was dosed in mice under the same
conditions, a Cmax of 4.6 µg/mL and an availability of
11% was observed.
With these encouraging results in hand, several of the
more potent inhibitors were dosed in rats intravenously
and orally. This data can be seen in Table 2. The rat
studies involved 42cb and derivatives of this structure.
42cb actually gave good results when dosed both
intravenously and orally in rats at 50 mg/kg. Various
other derivatives also gave encourgaing results as can
be seen in Table 2. Most notable are 42bb and 43cb,
which were both comparable to 42cb. Phenol 56
produced no detectable levels of drug when dosed orally.
This was found to be due to its very high acid sensitivity
in which it loses the phenolic residue. Other modifica-
tions (45, 49, 58) designed to improve solubility gave
marginal results.
Because selectivity is also a concern for a protease
inhibitor, 42cb was assayed against the following hu-
man proteases: renin, cathepsin D and E, and pepsin.20
Since it was not possible to distinguish between some
of our compounds in the rat model, several compounds

Inhibitors of the HIV-1 Protease
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2803
s, NH rotomers), 5.40 and 4.85 (1 H, br s, OH rotomers), 3.93
and 3.82 (1 H, m, rotomers), 3.52-2.57 (8 H, series of m), 1.49
and 1.44 (9 H, rotomers), 1.47 and 1.45 (9 H, rotomers);
HRFABMS calcd for C27H39N2O4S 487.2631, found 487.2638.
Anal. (C27H38N2O4S‚1.25H2O) C, H, N, S.
Excellent selectivity was observed in that 42cb possesed
only micromolar inhibition against these proteases.
Con clu sion s
N-ter t-Bu tyl-N-(2-h yd r oxyeth yl-2-[[2-h yd r oxy-3-[2-[(2-
h yd r oxyeth yl)-ter t-bu tylca r ba m oyl]p h en yl]p r op yl]th io]-
ben za m id e (7). A solution of trimethylaluminum (2.0 M in
hexane, 0.73 mL, 1.45 mmol) was added dropwise to a solution
of tert-butylhydroxyethylamine (170 mg, 1.45 mmol) in 5 mL
of toluene at 0 °C. The mixture was stirred for 45 min at room
temperature, a solution of lactone 5 (400 mg, 1.22 mmol) in 1
mL dichloroethane was added dropwise, and the mixture was
heated to 110 °C for 5 h. The reaction mixture was cooled
and quenched with 5 mL of dilute NH4Cl solution and
extracted with three 10 mL portions of ethyl acetate. The
organic phase was dried over MgSO4, filtered, and concen-
trated. The crude residue was purified by flash chromatog-
raphy (15 g of silica gel, 3% MeOH/CH2Cl2) to yield 18 mg
(23%) of diamide 7 as a pink solid: IR (film) 3393 (br OH),
1611 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.53-7.09 (8 H, series
of m), 3.84-3.79 (1 H, br m), 3.56-2.63 (12 H, series of br m),
1.53, 1.47, and 1.44 (18 H, tert-butyl rotomers); HRFABMS
calcd for C29H43N2O5S 531.2893, found 531.2904. Anal.
(C29H42N2O5S‚0.25H2O) C, H, N, S.
Through the use of protein structure-based iterative
ligand design, a new series of potent inhibitors of the
HIV-1 protease has been identified. Starting from our
lead structure 3, a series of bis tertiary amides was
designed which had improved activity due to an inver-
sion in binding mode. This new binding mode allowed
for improved access to all the binding pockets, and it
was possible to improve activity of 3 by over 1000-fold
with a minimum of compound preparation. These new
compounds were selective for the HIV-PR and possesed
good antiviral activity and good pharmacological prop-
erties in three animal models. This work emphasizes
the critical importance of structural feedback when
either designing new classes of inhibitors or modifying
existing ones whose binding modes may be speculative.
Exp er im en ta l Section
All melting points and boiling points are uncorrected.
Melting points were obtained on a Mel-Temp melting point
apparatus. Infrared spectra were obtained with a Midac FT
infrared spectrophotometer. 1H NMR spectra were obtained
with a QE300 spectrometer. Mass spectra were obtained from
the mass spectroscopy facilities of UC Rivereside, UC Berkeley,
and the Scripps Research Institute (La J olla, CA). Elemental
analyses were obtained from Atlantic Microlab Inc. (Norcross,
GA). Tetrahydrofuran was distilled from Na/benzophenone
ketyl. All other solvents were used as received. The following
amines were prepared according to literature methods: 1-meth-
yl-1-phenylethylamine (10b),21 1,1-diethylbutylamine (10d ),22
1-ethylcyclopentylamine (10c),23 2-methyl-3-phenyl-2-amino-
propane (10e),24 cis-octahydroinden-3a-ylamine (10g),25 1-phen-
ylcyclopentylamine (10h ).26
N-ter t-Bu tyl-N-(2-h yd r oxyeth yl)-2-[(9-oxo-6,7-d ih yd r o-
9H -8-oxa -5-t h ia b e n zocycloh e p t e n -7-yl)m e t h yl]b e n z-
a m id e (5). A solution of trimethylaluminum (2.0 M in hexane,
3.66 mL, 7.32 mmol) was added dropwise to a solution of tert-
butylhydroxyethylamine (863 mg, 7.32 mmol) in 15 mL toluene
at 0 °C. The mixture was stirred for 45 min at room
temperature, a solution of lactone 4 (400 mg, 1.22 mmol) in 5
mL of toluene was added dropwise, and the mixture was
heated to 90 °C for 18 h. The reaction mixture was cooled
and quenched with 5 mL of dilute NH4Cl solution and
extracted with three 15 mL portions of ethyl acetate. The
organic phase was washed with 10 mL of H2O, dried over
MgSO4, filtered, and concentrated. The crude residue was
purified by flash chromatography (75 g of silica gel, 5-10%
ethyl acetate/CH2Cl2) to yield 160 mg (32%) of lactone 5 as a
white solid: IR (film) 3449 (br OH), 1726, 1626 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.58-7.14 (8 H, series of m), 4.52 (1 H, br
m), 3.63-2.94 (8 H, series of m), 1.53 and 1.39 (9 H, s, tert-
butyl rotomers); HRFABMS calcd for C23H28NO4S 414.1791,
found 414.1735.
N-ter t-Bu tyl-N-(2-h yd r oxyeth yl)-2-[3-h yd r oxy-4-[2-[(2-
h y d r o x y e t h y l)-t er t -b u t y lc a r b a m o y l]p h e n y l]b u t y l]-
ben za m id e (9). A solution of 2-(N-tert-butylamino)ethanol
(0.55 g, 4.72 mmol) in toluene (5 mL) was cooled in an ice bath,
after which a solution of trimethylaluminum (2.0 M in hex-
anes, 2.4 mL, 4.72 mmol) was added over a period of 8 min.
The reaction mixture was allowed to stir at ambient temper-
ature for 45 min, after which a solution of lactone 8 (0.15 g,
0.47 mmol) in toluene (2 mL) was added. The reaction mixture
was heated for 14 h at 90 °C and at reflux for an additional 6
h. It was treated with 0.5 N NH4Cl (5 mL) and H2O (30 mL)
and extracted with EtOAc (2 × 30 mL). The combined organic
layers were dried (Na2SO4) and evaporated to leave a yellow
oily residue (0.26 g) which was purified by column chroma-
tography (EtOAc) to give the product 9 as a white foam: yield
1
0.075 g, 31%; IR (film) 3391, 1612 cm-1; H NMR (CDCl3) δ
7.10-7.30 (8 H, series of m), 1.40-3.80 (36 H, series of m);
HRFABMS calcd for C30H45N2O5 513.3328, found 513.3304.
Anal. (C30H44N2O5‚0.5H2O) C, H, N.
N-ter t-Bu t yl-[2-[(ter t-b u t yld ip h en ylsilyl)oxy]et h yl]-
a m in e (16a ). To a solution of 2-(tert-butylamino)ethanol (11a )
(11.72 g, 0.1 mol) and imidazole (8.85 g, 0.13 mol, 1.3 equiv)
in CH2Cl2 (50 mL) cooled to 0 °C was added tert -butyldiphen-
ylsilyl chloride (28 g, 0.102 g, 1.02 equiv) over a 15 min period
while the temperature was maintained between 0 and 10 °C.
The reaction mixture was allowed to stir at room temperature
for 18 h, after which it was treated with saturated NaHCO3
(100 mL), poured into H2O (600 mL), and extracted with 200
mL of Et2O. The organic layer was washed with H2O (600
mL), dried (Na2SO4), and concentrated to give the product 16a
as a clear colorless oil: yield 31.2 g, 88%.
N-ter t-Bu tyl-N-[2-(ter t-bu tyld ip h en ylsilyl)oxy]eth yl]-
2-m eth ylben za m id e (18a ). A solution of 16a (25.5 g, 71.7
mmol) and its HCl salt (5.1 g, 13 mmol) in CH2Cl2 (50 mL)
was treated with Et3N (18 mL, 130 mmol) and cooled to 0°C.
o-Toluoyl chloride (12) (13.1 g, 85 mmol) was added to the
solution over a 5 min period, after which the reaction was
stirred at room temperature for 21 h. The mixture was washed
with saturated NaHCO3 (100 mL) and H2O (2 × 500 mL), dried
over Na2SO4, and evaporated to give an orange oil (21.6 g)
which was Kugelrohr distilled (230 °C, 1.9 Torr) to give a
product still contaminated with o-tolouyl chloride. Chroma-
tography on SiO2 eluting with 10-100% EtOAc/hexane gave
N-ter t-Bu tyl-2-[[2-h yd r oxy-3-[2-[(2-h yd r oxyeth yl)-ter t-
bu tylca r ba m oyl]p h en yl]p r op yl]th io]ben za m id e (6).
A
solution of trimethylaluminum (2.0 M in hexane, 0.36 mL, 0.73
mmol) was added dropwise to a solution of tert-butylamine (53
mg, 76 µL, 0.73 mmol) in 3 mL of dichloroethane at 0 °C. The
mixture was stirred for 45 min at room temperature, a solution
of lactone 5 in 0.5 mL of dichloroethane was added, and the
mixture was heated to 60 °C for 18 h. The reaction mixture
was cooled, quenched with dilute NH4Cl solution, and ex-
tracted three times with 10 mL portions of ethyl acetate. The
solution was dried over MgSO4, filtered, and concentrated to
1
18a as a light yellow oil: yield 9.69 g, 42%; H NMR (CDCl3)
δ 7.55-7.00 (14 H, series of m), 3.60-3.20 (4 H, m), 2.20 (3 H,
s), 1.50 (9 H, s, tert-butyl), 0.90 (9 H, s, tert-butyl).
a
yellow oil. The crude material was purified by flash
3-[2-[N -t er t -Bu t yl-[2-[(t er t -b u t yld ip h e n ylsilyl)oxy]-
eth yl]ca r ba m oyl]p h en yl]p r op ion ic Acid (32a ). A solution
of 18a (9.06 g, 19.1 mmol) and diisopropylamine (0.4 mL, 2.9
mmol, 0.15 equiv) in THF (100 mL) was cooled to -78 °C and
treated with 1.2 M sec-butyllithium (19.1 mL, 23 mmol) over
chromatography (20 g of silica gel, 15-30% ethyl acetate/
CH2Cl2) to yield 45 mg (76%) of diamide 6 as a colorless solid:
IR (film) 3302 (br OH), 1638, 1613 cm-1; H NMR (300 MHz,
1
CDCl3) δ 7.51-7.08 (8 H, series of m), 6.50 and 6.25 (1 H, br

2804 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Melnick et al.
a 15 min period while the temperature was maintained at -70
°C. The resulting deep purple solution was stirred for 1.5 h,
after which ethylene oxide (2.8 mL, 57 mmol, 3 equiv) was
added in one portion and the reaction mixture allowed to warm
to room temperature for 16 h. It was then quenched with 0.5
N NH4Cl (10 mL), poured into H2O (600 mL), and extracted
with EtOAc (2 × 200 mL). The organic layers were combined,
dried (Na2SO4), and concentrated in vacuo to leave a peach-
colored viscous oil (9.98 g) which was chromatographed on SiO2
(45% EtOAc/hexanes) to give the homologated alcohol as a
white solid was filtered and washed with a 1:1 hexane/EtOAc
mixture (50 mL) to yield 3.96 g (48%) of amide 14b: mp 139-
1
141 °C; IR (film) 1609 cm-1; H NMR (DMSO-d6) 7.41-7.11
(4 H, series of m), 4.75 (1H, t, OH), 3.45-3.33 (4 H, m), 2.18
(3 H, s, CH3), 1.72 (6 H, s, CH3). Anal. (C19H23NO2) C, H, N.
N-ter t-Bu tyl-N-(2-h yd r oxyeth yl)-2-[3-h yd r oxy-4-[2-[(2-
h y d r o x y e t h y l)(1-m e t h y l-1-p h e n y le t h y l)c a r b a m o y l]-
p h en yl]bu tyl]ben za m id e (40a b). To a solution of 14b (0.12
g, 0.42 mmol) and diisopropylamine (0.009 mL, 0.063 mmol,
0.15 equiv) in THF (5 mL) cooled to -78 °C was added 1.3 M
sec-butyllithium (0.71 mL, 0.92 mmol, 2.2 equiv) over a 5 min
period. The resulting deep red solution was stirred for an
additional 50 min, after which a solution of 34a (0.25 g, 0.42
mmol) in THF (5 mL) was added. The mixture was allowed
to warm to room temperature over 17.5 h, quenched with 0.5
N NH4Cl, diluted with H2O (75 mL), and extracted with EtOAc
(2 × 25 mL). The combined organic layers were dried and
evaporated leaving the crude ketone 36a b, which was dis-
solved in EtOH (5 mL), treated with NaBH4 (0.045 g, 1.2
mmol), and stirred for 45 min. The reaction was quenched
with saturated NaHCO3 (4 mL), poured into brine (40 mL),
and extracted with EtOAc (2 × 25 mL). The combined organic
layers were dried (Na2SO4) and evaporated to give the crude
alcohol, which was dissolved in THF (5 mL), treated with a
solution of tetrabutylammonium fluoride (1.0 M in THF, 0.7
mL, 0.68 mmol), and stirred at room temperature for 18 h.
The reaction was quenched with saturated NaHCO3 (2 mL),
poured into brine (40 mL), and extracted with EtOAc (2 × 15
mL). The combined organic layers were dried (Na2SO4) and
evaporated to give an oil (0.32 g). Purification by column
chromatography (EtOAc) afforded product 40a b as a white
viscous yellow oil: yield 7.08 g, 72%; IR (film) 3420, 1622 cm-1
;
1H NMR (CDCl3) δ 7.51-6.99 (14 H, series of m), 3.50-1.70
(11 H, series of m), 1.48 (9 H, s, tert-butyl), 0.93 (9 H, s, tert-
butyl). Anal. (C32H43NO3Si) C, H, N.
A solution of the alcohol (7.0 g, 13.5 mmol) and pyridinum
dichromate (25.43 g, 67.6 mmol) in DMF (50 mL) was stirred
at room temperature for 17 h, after which it was poured into
H2O (3 L) and extracted with EtOAc (2 × 500 mL). The
combined organic layers were washed with H2O (2 L), dried
(Na2SO4), and evaporated to a viscous brown oil (4.85 g) which
was purified by column chromatography (10% MeOH/CH2Cl2)
to give 2.31 g (32%) of carboxylic acid 32a as a brown oil: 1H
NMR (CDCl3) δ 7.50-7.01 (14 H, series of m), 3.54-2.52 (8
H, series of m), 1.46 (9 H, s, tert-butyl), 0.94 (9 H, s, tert-butyl).
Anal. (C32H41NO4Si) H, N; C: calcd, 72.28; found, 71.82.
N-ter t-Bu tyl-N-[2-[(ter t-bu tyld ip h en ylsilyl)oxy]eth yl]-
2-[2-(m eth oxym eth ylca r ba m oyl)eth yl]ben za m id e (34a ).
A solution of 32a (2.31 g, 4.3 mmol), BOP (2.02 g, 4.56 mmol,
1.05 equiv), N,O-dimethylhydroxylamine hydrochloride (0.47
g, 4.78 mmol, 1.1 equiv) and diisopropylethylamine (2.1 mL,
11.9 mmol, 2.75 equiv) in CH2Cl2 (15 mL) was stirred at
ambient temperature for 2 h, after which it was washed with
H2O (200 mL), dried (Na2SO4), and evaporated to leave a
brown residue (3.52 g) which was purified by column chroma-
tography (1:1 EtOAc/hexane) to give 34a as a clear, colorless
oil: yield 1.48 g, 59%; IR (film) 1640 cm-1; 1H NMR (CDCl3) δ
7.53-7.01 (14 H, series of m), 3.58 (3 H, s, OCH3), 3.15 (3 H,
s, CH3), 3.52-2.60 (8 H, series of m), 1.45 (9 H, s, tert-butyl),
0.94 (9 H, s, tert-butyl). Anal. (C34H46N2O4Si) C, H, N.
1-Meth yl-1-p h en yleth yla m in e (10b) was prepared by the
method of Kalir;21 however, the azide was reduced with LiAlH4
instead of Raney nickel/NH2NH2. The amine was purified by
vacuum distillation (60 °C, 3.2 Torr) as a colorless liquid: yield
46.82 g, 74%.
foam: yield 111 mg, 46% from 14b; IR (film) 3383, 1613 cm-1
;
1H NMR (CDCl3) δ 7.34-7.10 (13 H, series of m), 3.69-1.51
(34 H, series of m); HRFABMS calcd for MH+ 575.3485, found
575.3481. Anal. (C35H46N2O5‚0.5H2O) C, H, N.
2-[(1,1-Dieth ylbu tyl)a m in o]eth a n ol (11d ). 1,1-Diethyl-
butylamine (910 mg, 7.05 mmol) was alkylated with ethylene
oxide in the same fashion as amine 10b to yield 630 mg (52%)
of 11d as a colorless liquid. The product was purified by
kugelrohr distillation at reduced pressure (bp 90-95 °C, 0.5
Torr): 1H NMR (CDCl3) δ 3.59 (2 H, t, J ) 5.3 Hz), 2.59 (2 H,
t, J ) 5.3 Hz), 2.01 (2 H, br s, NH, OH), 1.32 (4 H, q, J ) 7.5
Hz), 1.23 (4 H, m), 0.90 (3 H, m), 0.78 (6 H, t, J ) 7.4 Hz).
Anal. (C10H23NO‚0.25H2O) C, H, N.
2-[(1-Meth yl-1-p h en yleth yl)a m in o]eth a n ol (11b). To
THF (25 mL) cooled to -78 °C was added ethylene oxide (5.4
mL, 0.11 mol, 1.1 equiv), after which was suspended LiClO4
(10.64 g, 0.1 mol) and the mixture was warmed to 0 °C. After
stirring at 0 °C for 10 min, a solution of 10b (13.52 g, 0.1 mol)
in CH3CN (12.5 mL) was added over a 2 min period followed
by stirring at ambient temperature for 3 h. The mixture was
poured into brine (200 mL) and extracted with Et2O (2 × 50
mL). The combined organic layers were dried (Na2SO4) and
concentrated, and the oily residue was Kugelrohr distilled at
180 °C (2 Torr) to give 11b as a colorless, viscous oil: yield
N -(1,1-Die t h ylb u t yl)-N -(2-h yd r oxye t h yl)-2-m e t h yl-
ben za m id e (14d ). Amine 11d (500 mg, 2.89 mmol) was
acylated with o-toluoyl chloride (12) in the same fashion as
amine 11b to produce 90 mg (11%) of amide 14d after
chromatography: IR (film) 3402 (br), 1614 cm-1 1H NMR
;
(CDCl3) δ 7.20-7.03 (4 H, m), 3.35 and 3.12 (4 H, br m
rotomers), 2.28 (3 H, s), 2.20 and 1.90 (6 H, br m, rotomers),
1.25 (2 H, m), 0.94 (3 H, t, J ) 7.2 Hz), 0.85 (6 H, t, J ) 7.4
Hz). Anal. (C18H29NO2) C, H, N.
N-ter t-Bu tyl-N-(2-h yd r oxyeth yl)-2-[3-h yd r oxy-4-[2-[(2-
h ydr oxyeth yl)(1,1-dieth ylbu tyl)car bam oyl]ph en yl]bu tyl]-
ben za m id e (40a d ). Amide 14d (0.087 g, 0.3 mmol) was ortho
metalated with s-butyllithium and acylated with N,O-di-
methylamide 34a in the same fashion as compound 14b to
yield ketone 36a d . The crude product was reduced and
deprotected without purification in fashion identical to com-
pound 36a b. The crude product was purified by column
chromatography on SiO2 eluting with EtOAc followed by
chromaography on SiO2 eluting with 25% EtOAc/hexane to
yield 0.040 g (23% over three steps) of 40a d as a white solid:
1
10.80 g, 60%; IR (film) 3320 cm-1; H NMR (CDCl3) δ 7.44-
7.19 (5 H, m), 3.56 (2 H, t, J ) 5.2 Hz), 2.48 (2 H, t, J ) 5.2
Hz), 1.47 (6 H, s, CH3). Anal. (C11H17NO) C, H, N.
N-(2-H yd r oxyet h yl)-2-m et h yl-N-(1-m et h yl-1-p h en yl-
eth yl)ben za m id e (14b). To a solution of 11b (5.0 g, 28 mmol)
and DMAP (0.51 g, 4 mmol, 0.15 equiv) in pyridine (40 mL)
cooled to 0 °C was added o-toluoyl chloride (12) (17.2 g, 14.5
mL, 11 mmol, 4 equiv) over a 10 min period. The solution
was stirred for 15 h at 120 °C and poured into H2O (100 mL),
treated with 1 N HCl (400 mL), and extracted with Et2O (3 ×
100 mL). The combined organic layers were washed with 1 N
HCl (300 mL) followed by H2O (500 mL), dried (Na2SO4), and
evaporated to give an orange oil (16.8 g), which was treated
with a solution of 90% aqueous MeOH (175 mL) and 50%
NaOH (15 mL) and stirred at room temperature for 20 min.
The reaction mixture was poured into H2O (1500 mL) and
extracted with Et2O (2 × 100 mL) and CH2Cl2 (100 mL). The
combined organic layers were dried and evaporated to give an
orange solid (4.5 g) which was triturated with a 1:1 hexane/
EtOAc mixture (40 mL) followed by additional hexanes (75
mL). After standing in the freezer for 2 h, the resulting off-
IR (neat) 3376, 1609 cm-1 1H NMR (CDCl3) δ 7.30-7.10 (8
;
H, series of m), 3.80-0.80 (44 H, series of m); HRFABMS calcd
for C34H53N2O5 569.3954, found 569.3954. Anal. (C34H52N2O5)
C, H, N.
2-[(1-Eth ylcyclop en tyl)a m in o]eth a n ol (11c). 1-Ethyl-
cyclopentylamine (58 g, 0.51 mol) was alkylated with ethylene
oxide in the same fashion as amine 10b to yield 52 g (65%) of
11c as a colorless low-melting solid after kugelrohr distillation
(bp 75-80 °C, 0.4 Torr): 1H NMR (CDCl3) δ 3.58 (2 H, t, J )
5.1 Hz), 2.63 (2 H, t, J ) 5.2 Hz), 2.23 (2 H, br s, NH, OH),
1.69-1.41 (10 H, series of m), 0.85 (3 H, t, J ) 7.4 Hz).

Inhibitors of the HIV-1 Protease
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2805
N-[2-[(ter t-Bu t yld ip h en ylsilyl)oxy]et h yl]-N-(1-et h yl-
cyclop en t yl)-2-m et h ylben za m id e (18c). (Hydroxyethyl)-
cyclopentylamine 11c (25.0 g, 0.16 mol) was silated with
diphenyl-tert-butylsilyl chloride and acylated with o-toluoyl
chloride (12) in the same manner as amine 11b to produce 57
g (79%) of amide 18c as a white solid. The product was
isolated by crystallization from hexanes: 1H NMR (CDCl3) δ
7.51-7.00 (14 H, series of m), 3.46 and 3.27 (4 H, br m,
rotomers), 2.21 (3 H, s), 2.05 and 1.94 (6 H, br m, rotomers),
1.61 (4 H, br m), 0.95 (9 H, s), 0.88 (3 H, t, J ) 7.4 Hz). Anal.
(C33H43NO2Si) C, H, N.
N-ter t-Bu tyl-N-[2-[(ter t-bu tyld ip h en ylsilyl)oxy]eth yl]-
2-[2-(m e t h oxym e t h ylca r b a m oyl)e t h yl]-5-m e t h ylb e n z-
a m id e (35a ) was prepared from 33a (0.64 g, 1.2 mmol) in the
same manner as 34a with a reaction time of 16 h at room
temperature. The product was purified by column chroma-
tography (1:1 EtOAc/hexane) to give 318 mg (46%) of N,O-
dimethylamide 35a as a clear viscous oil: IR (neat) 1640 cm-1
;
1H NMR (CDCl3) δ 7.53-6.85 (13 H, series of m), 3.58 (3 H,
m, OCH3), 3.50-3.30 (4 H, m), 3.14 (3 H, s, CH3), 2.79 (4 H,
m), 2.15 (3 H, s, CH3), 1.47 (9 H, s, tert-butyl), 0.95 (9 H, s,
tert-butyl). Anal. (C35H48N2O4Si) C, H, N.
N-[2-(ter t-Bu tyld ip h en ylsiloxy)eth yl]-N-(1-eth ylcyclo-
p e n t y l ) -2 -[ 2 -( m e t h o x y m e t h y l c a r b a m o y l ) e t h y l ] -
ben za m id e (34c). o-Toluoyl amide 18c (47.0 g, 0.092 mol)
was ortho metalated and alkylated with ethylene oxide in the
same fashion as amide 18a to produce after chromatography
45 g (88%) of the homologated alcohol as a tan viscous oil: IR
N-ter t-Bu tyl-N-(2-h ydr oxyeth yl)-4-m eth yl-2-[3-h ydr oxy-
4-[2-[(2-h yd r oxyeth yl)(1-m eth yl-1-p h en yleth yl)ca r ba m -
oyl]p h en yl]bu tyl]ben za m id e (41a b) was prepared from
amide 15b (0.20 g, 0.7 mmol) and N,O-dimethylamide 35a (0.4
g, 0.7 mmol) in the same fashion as 40a b. The product was
purified by column chromatography (EtOAc) to afford 155 mg
(38% overall) of 41a b as a white foam: IR (film) 3387, 1614
cm-1; 1H NMR (CDCl3) δ 7.54-6.98 (12 H, series of m), 3.65-
1.58 (27 H, series of m), 0.96 (9 H, s, tert-butyl); HRFABMS
(film) 3422 (br), 1620, 1111 cm-1 1H NMR (CDCl3) δ 7.51-
;
7.01 (14 H, series of m), 3.79 (1 H, br t, J ) 6.1 Hz, OH), 3.36
(4 H, m), 2.45 (2 H, m), 2.30 (1 H, m), 2.13 (1 H, m), 1.95-
1.59 (12 H, series of m), 0.93 (9 H, s), 0.89 (3 H, t, J ) 7.5 Hz).
This material was oxidized (14.01 g, 0.025 mol) to the car-
boxylic acid with J ones reagent in the same fashion as the
alcohol derived from 32b to produce 12.6 g (88%) of the crude
carboxylic acid 32c as a tan foam which was used without
purification in the next step.
calcd for
C36H49N2O5 589.3641, found 589.3654. Anal.
(C36H48N2O5‚0.9H2O) C, H, N.
1-Meth yl-1-n a p h th -2-yleth yla m in e (10f). To a solution
of CH3MgBr (3 M in diethyl ether, 47 mL, 0.14 mol) and Et2O
(30 mL) was added a solution of 2′-acetonaphthone in Et2O
(70 mL) over a 5 min period at room temperature during which
time a white precipitate formed. The mixture was heated at
reflux for 45 min and treated with 10% aqueous H2SO4 (100
mL) and ice (50 g) followed by extraction by Et2O (2 × 100
mL). The combined organic layers were washed with a 5%
bisulfite solution (100 mL) and evaporated to give an oil which
was purified by column chromatography using a gradient of
CHCl3 to CH2Cl2 to give the alcohol (15 g) as a white solid. To
a solution of this alcohol (5 g, 26.8 mmol) in CHCl3 (30 mL)
was susupended NaN3 (3.49 g, 54 mmol, 2 equiv), and the
mixture was cooled to 0 °C followed by addition of trifluoro-
acetic acid (10.3 mL, 15.3 g, 134 mmol, 5 equiv) in CHCl3 over
a 15 min period. The mixture was stirred at room temperature
for 17 h and treated with NH4OH (150 mL) and H2O (125 mL).
The organic layer was dried (Na2SO4) and evaporated to give
the crude azide as a clear oil (5.15 g, 91%), which was dissolved
in Et2O (15 mL) and added to a suspension of LiAlH4 (15.7 g,
41 mmol, 1.7 equiv) at 0 °C over 30 min. After 30 min of
stirring at ambient temperature, the mixture was recooled in
ice and carefully quenched with 25% NaOH (100 mL), ex-
tracted with Et2O (2 × 75 mL), dried (Na2SO4), concentrated
and Kugelrohr distilled (180 °C, 2 Torr) to give the amine 10f
as a colorless liquid: yield 3.52 g, 48% overall; 1H NMR
(CDCl3) δ 7.41-6.92 (7 H, series of m), 1.68 (s, 2H, NH2), 1.58
(6 H, s, CH3). Anal. (C13H15N) C, H, N.
N,O-Dimethylamide 34c was prepared from carboxylic acid
32c (12.6 g, 0.022 mol) in similar fashion as amide 34a .
Diethylphosphonocyanide (DEPC) was utilized as the coupling
reagent (instead of BOP). The product was isolated by flash
chromatography (350 g of silica gel, 25-40% ethyl acetate/
hexanes) to yield 10.5 g (78%) of the desired diamide as a
1
colorless viscous glass: IR (film) 1667, 1640 cm-1; H NMR
(300 MHz, CDCl3) δ 7.53-7.05 (14 H, series of m), 3.62 (3 H,
s), 3.54-3.30 (4 H, br m), 3.19 (3 H, s), 2.89-2.70 (4 H, br m),
2.08-1.61 (10 H, series of br m), 0.98 (9 H, s), 0.92 (3 H, t, J
) 7.5 Hz).
N-ter t-Bu tyl-N-[2-[(ter t-bu tyld ip h en ylsilyl)oxy]eth yl]-
2,5-d im eth ylben za m id e (19a ). A suspension of 2,5-dimeth-
ylbenzoic acid (5.0 g, 33 mmol) in toluene (50 mL) was cooled
in an ice bath followed by the addition of oxalyl chloride (9.3
g, 73 mmol, 2.2 equiv) and DMF (0.8 mL, 1 mmol, 0.3 equiv).
After the addition, the reaction mixture was allowed to warm
to room temperature, during which time all solid had gone into
solution. After 40 min the solvent was evaporated and THF
was added (20 mL), and the resulting mixture added to a 0 °C
solution of 16a (11.84 g, 33 mmol) and Et3N (2.65 mL, 37
mmol, 1.1 equiv) in THF (50 mL) over a 5 min period. After
stirring overnight, the reaction mixture was poured into H2O
(1 L) followed by extraction with EtOAc (2 × 200 mL). The
combined organic layers were dried (Na2SO4) and evaporated
to give an orange-colored oil (20.7 g), which was purified by
column chromatography (15% EtOAc/hexanes) to give 19a as
a cream-colored solid: yield 3.75 g, 23%; mp 92-94 °C; 1H
NMR (CDCl3) δ 7.50-6.85 (13 H, series of m), 3.55-3.28 (4
H, s), 2.16 (6 H, s, CH3), 1.48 (9 H, s, tert-butyl), 0.95 (9 H, s,
tert-butyl). Anal. (C19H41NO2Si) C, H, N.
2-[(1-Meth yl-1-n a p h th -2-yleth yl)a m in o]eth a n ol (11f).
To a suspension of LiClO4 (1.07 g, 10.2 mmol) in THF (4 mL)
cooled to -78 °C was added ethylene oxide (0.55 mL, 11.2
mmol, 1.1 equiv) followed by 10f in CH3CN (8 mL), and the
reaction mixture was stirred at 0 °C for 1 h. After an
additional 7 h of stirring at ambient temperature, the reaction
mixture was recooled to -78 °C and treated with an additional
3 equiv of ethylene oxide. After 26 h of stirring at ambient
temperature, the reaction mixture was poured into saturated
brine (100 mL) and extracted with EtOAc (2 × 25 mL). The
combined organic layers were dried and evaporated to give the
desired product 11f as a viscous orange oil (2.51 g, 100%) of
sufficient purity to use in the next step. An analytical sample
prepared by Kugelrohr distillation had bp 250 °C, 1.8 Torr:
IR (film) 3306 cm-1; 1H NMR (CDCl3) δ 7.83-7.44 (7 H, series
of m), 1.58 (s, 6 H, CH3), 3.56 (2 H, t, J ) 5.2 Hz), 2.51 (2 H,
3-[2-[ter t-Bu tyl[2-[(ter t-bu tyld ip h en ylsilyl)oxy]eth yl]-
ca r ba m oyl]-4-m eth ylp h en yl]p r op ion ic a cid (33a ) was
prepared from 19a (3.75 g, 7.7 mmol) in two steps by the same
method used to prepare 32a . The homologated alcohol was
purified by column chromatography (1:1 EtOAc/hexanes) to
give a light green solid: yield 2.29 g, 60%; IR (film) 1624 cm-1
;
1H NMR (CDCl3) δ 7.51-6.81 (13 H, series of m), 3.62-3.28
(8 H, series of m), 2.43 (2 H, m), 2.21 (3 H, s), 1.49 (9 H, s,
tert-butyl), 0.94 (9 H, s, tert-butyl). Anal. (C33H45NO3Si) C,
H, N.
t, J ) 5.2 Hz), 1.78 (2 H, bs, NH,OH). Anal. (C15H16
NO‚0.2H2O) C, H, N.
-
This material (2.29 g, 4.3 mmol) was oxidized with PDC in
the same fashion as the material used to prepare 32a and the
product purified by column chromatography (10% MeOH/
CH2Cl2) to give 635 mg (27%) of carboxylic acid 33a as a light
orange oil: IR (film) 1719 cm-1; 1H NMR (CDCl3) δ 8.02-6.85
(13 H, series of m), 3.60-2.20 (8 H, series of m), 2.16 (3 H, s,
CH3), 1.48 (9 H, s, tert-butyl), 0.95 (9 H, s, tert-butyl);
HRFABMS calcd for C33H43NO4Si 546.3039, found 546.3046.
N-(2-Hyd r oxyeth yl)-2-m eth yl-N-(1-m eth yl-1-n a p h th -2-
yleth yl)ben za m id e (14f) was prepared from 11f (2.52 g, 8.7
mmol) in the same fashion as 14b. The product, an oil which
solidified slowly, was swirled with 1:1 EtOAc/hexanes and
filtered to give 1.1 g (37%) of amide 14f as a cream-colored
solid: mp 149-151 °C; IR (film) 3308, 1606 cm-1 1H NMR
;
(CDCl3) δ 7.83-7.13 (11 H, series of m), 1.57-1.86 (s and bs,

2806 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Melnick et al.
6 H, CH3), 3.70-3.40 (4 H, m), 2.32 (3 H, s, CH3). Anal. (C23H25
-
N-[2-[(ter t-Bu tyld ip h en ylsilyl)oxy]eth yl]-2,5-d im eth yl-
N-(1-m eth yl-1-p h en yleth yl)ben za m id e (19b). A solution
of 16b (12.87 g, 30.8 mmol) and Et3N (12.9 mL, 9.2 mmol, 3
equiv) in CH2Cl2 (70 mL) was cooled in an ice bath followed
by addition of 13 (10.0 g, 59.6 mmol) (prepared by the
procedure for the preparation of 19c) over a 2 min period
followed by stirring for 19 h at room temperature. The
reaction mixture was poured into H2O (500 mL), the organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (100 mL). The combined organic layers were washed
with H2O (500 mL), dried (MgSO4), and evaporated to leave
an orange oil (20.7 g) which was purified by column chroma-
tography (15-30% EtOAc/hexane) to give 19b as a viscous
NO2) C, H, N.
N-ter t-Bu tyl-N-(2-h yd r oxyeth yl)-2-[3-h yd r oxy-4-[2-[(2-
h ydr oxyeth yl)-(1-m eth yl-1-(n aph th -2-yleth yl)car bam oyl]-
p h en yl]bu tyl]ben za m id e (40a f) was prepared from amide
14f (0.1 g, 0.29 mmol) and N,O-dimethylamide 34a (0.17 g,
0.29 mmol) in the same fashion as 40a b. Purification by
column chromatography (10% hexane/EtOAc) afforded 84 mg
(46% overall) of 36a f as a white foam: IR (neat) 3370, 1613
cm-1; 1H NMR (CDCl3) δ 7.80-7.11 (15 H, series of m), 3.78-
1.24 (series of m, 33 H); FABMS 625.6 [M + H]+. Anal.
(C36H48N2O5‚0.5H2O) C, H, N.
[2-[(t er t -Bu t yld ip h e n ylsilyl)oxy]e t h yl](1-m e t h yl-1-
p h en yleth yl)a m in e (16b). To a solution of 11b (0.8 g, 4.5
mmol) and Et3N (0.8 mL, 5.82 mmol) in CH2Cl2 (6 mL) was
added the tert-butyldiphenylsilyl chloride (1.24 g, 4.53 mmol)
in CH2Cl2 (3 mL) and stirred at room temperature for 2.5 h,
after which the reaction mixture was poured into H2O (40 mL)
and extracted with CH2Cl2 (2 × 25 mL). The combined organic
layers were washed with saturated Na2CO3 (30 mL), dried
(Na2SO4), and evaporated to give a crude colorless oil (1.56 g)
which was Kugelrohr distilled (250 °C, 1.8 Torr) to remove
impurities, leaving behind the product as a light yellow oil:
yield 1.0 g, 54%; 1H NMR (CDCl3) δ 7.70-7.11 (15 H, series of
m), 3.74 (2 H, t, J ) 5.2 Hz), 2.47 (2 H, t, J ) 5.2 Hz), 1.46 (6
H, s, CH3), 1.06 (s, 9 H, tert-butyl). Anal (C27H35NOSi) C, H,
N.
oil: yield 11.4 g, 67%; IR (film) 3289, 1640 cm-1
.
N-(1-Met h yl-1-p h en ylet h yl)-N-(2-h yd r oxyet h yl)-2-[3-
h yd r oxy-4-[2-[(2-h yd r oxyeth yl)(1-m eth yl-1-p h en yleth yl)-
ca r ba m oyl]-4-m eth ylp h en yl]bu tyl]ben za m id e (42bb) was
prepared from amide 19b (3.94 g, 6.2 mmol) and N,O-
dimethylamide 34b (3.40 g, 6.2 mmol) in the same fashion as
40a b. The product was purified by column chromatography
(EtOAc) to give 1.99 g (49% overall) of 42bb as a white foam:
1
IR (film) 3372, 1616 cm-1; H NMR (CDCl3) δ 7.45-6.97 (17
H, series of m), 3.80-1.58 (33 H, series of m); HRFABMS calcd
for C41H51N2O5 651.3798, found 651.3825. Anal. (C41H50N2O5‚
1.2H2O) C, H, N.
2-[(Octa h ydr oin den -3a -yl)a m in o]eth a n ol (11g) was pre-
pared from cis-2-octahydroinden-3a-ylamine (10g) in the same
fashion as 11b with a reaction time of 13.5 h. The crude
product was purified by Kugelrohr distillation (200 °C, 2.3 torr)
to give 11g as a clear liquid: yield 1.94 g, 62%; 1H NMR
N-[2-[(ter t-Bu tyld ip h en ylsilyl)oxy]eth yl]-2-m eth yl-N-
(1-m eth yl-1-p h en yleth yl)ben za m id e (18b). To a solution
of 16b (13.5 g, 32.2 mmol) and Et3N (13.5 mL, 64.5 mmol) in
CH2Cl2 (65 mL) cooled to 0 °C was added o-toluoyl chloride
(8.4 mL, 64.5 mmol) over a 2 min period, and the mixture was
stirred at room temperature for 5 h, after which it was poured
into H2O (500 mL) and extracted with CH2Cl2 (100 mL). The
organic layer was dried, concentrated, and purified by column
chromatography (70% EtOAc/hexane) to give a colorless oil.
The mixed fractions were rechromatographed (15-40% EtOAc/
hexane) to give a total yield of 9.0 g (52%) of amide 18b: IR
(CDCl3) δ 3.62-1.18 (21 H, series of m). Anal. (C11H21
NO‚0.3H2O) C, H, N.
-
N-(2-H yd r oxyet h yl)-2-m et h yl-N-(oct a h yd r oin d en -3a -
yl)ben za m id e (14g) was prepared in the same manner as
14b, with a reaction time of 18 h and saponification time of 1
h. The crude oily product (0.72 g) was purified by column
chromatography (1:1 EtOAc/hexane) to give 14g as an amber
oil: yield 0.4 g, 34%; IR (film) 3383, 1612 cm-1 1H NMR
;
1
(film) 1649 cm-1; H NMR (CDCl3) δ 7.70-7.00 (19 H, series
(CDCl3) δ 7.23-7.16 (4 H, m), 3.60-1.30 (23 H, series of m).
Anal. (C19H27NO2) C, H, N.
of m), 3.70-3.40 (4 H, bs), 2.20 (3 H, s, CH3), 1.70 (6 H, bs,
CH3), 0.30 (9 H, s, tert-butyl). Anal. (C35H41NO2Si) C, H, N.
3-[2-[2-[(ter t-Bu t yld ip h en ylsilyl)oxy]et h yl](1-m et h yl-
1-p h en yleth yl)ca r ba m oyl]p h en yl]p r op ion ic Acid (32b)
was prepared in two steps in a manner similar to 32a . Amide
18b (1.8 g, 3.4 mmol) was homologated with s-BuLi and
ethylene oxide to produce 1.46 g (75%) of the alcohol as a
viscous oil after chromatography (30% hexane/EtOAc): IR
N-ter t-Bu tyl-N-(2-h yd r oxyeth yl)-2-[3-h yd r oxy-4-[2-[(2-
h yd r oxye t h yl)(cis-oct a h yd r oin d e n -3a -yl)ca r b a m oyl]-
p h en yl]bu tyl]ben za m id e (40a g) was prepared from 14g
(0.15 g, 0.5 mmol) and N,O-dimethylamide 34a (0.29 ng, 0.5
mmol) in the same manner as 40a b. The crude product was
purified by column chromatography (EtOAc) to give 99 mg
(34% overall) of 40a g as a white foam: IR (film) 3374, 1608
1
cm-1; H NMR (CDCl3) δ 7.29-7.03 (8 H, series of m), 3.70-
1
(film) 3424, 1630 cm-1; H NMR (CDCl3) δ 7.45-6.90 (19 H,
1.39 (42 H, series of m); HRFABMS calcd for C35H51N2O5
579.3798, found 579.3798. Anal. (C35H50N2O5‚0.3H2O) C, H,
N.
series of m), 3.70-1.51 (26 H, series of m). Anal. (C37H45
-
NO3Si) C, H, N. A solution of 2.67 M J ones reagent (9.62 mL,
0.26 mmol) was added to an ice-cooled solution of the alcohol
(5.96 g, 0.1 mmol) in acetone (120 mL) over a 6 min period.
The reaction mixture was warmed to ambient temperature
over 30 min. Upon recooling in an ice bath, the reaction was
quenched with isopropyl alcohol (10 mL), and the Cr salts were
filtered off and washed with acetone (2 × 30 mL). The filtrate
was concentrated to a bluish residue which was dissolved in
Et2O (150 mL) and washed with H2O (500 mL) and saturated
NaCl (300 mL). The Cr salts were dissolved in H2O (150 mL)
and extracted with Et2O (2 × 125 mL). The combined organic
layers were dried and concentrated, and the resulting residue
was taken up in C6H6 (100 mL) and concentrated to give 5.36
g (88%) of the crude carboxylic acid 32b as a nearly colorless
N -(1-E t h ylcyclop e n t yl)-N -(2-h yd r oxye t h yl)-2-[3-h y-
d r oxy-4-[2-[(2-h yd r oxyet h yl)(1-m et h yl-1-p h en ylet h yl)-
ca r ba m oyl]-4-m eth ylp h en yl]bu tyl]ben za m id e (42cb) was
prepared from amide 19b (11.38 g, 20.7 mmol) and N,O-
dimethylamide 34c in the same fashion as 40a b. The crude
product was purified by column chromatography (EtOAc) to
give the 42cb as a white foam: yield 7.7 g, 59% overall; IR
1
(film) 3372, 1611 cm-1
; H NMR (CDCl3) δ 7.40-7.00 (12 H,
m), 3.70-0.91 (40 H, series of br m); HRFABMS calcd for
H53N2O5 629.3924, found 629.3964. Anal. (C39H52N2O5) C,
C39
H, N.
2-[(1-P h en ylcyclop en tyl)a m in o]eth a n ol (11h ) was pre-
viscous oil suitable for further use: IR (film) 1711, 1626 cm-1
;
pared in the same manner as 11b, starting with 2-(1-phenyl-
cyclopentyl)amine 10h (2.76 g, 17 mmol) and a reaction time
of 1 h 45 min. The product was purified by Kugelrohr
distillation to give the starting amine 10h (1.6 g, 145 °C, 2
Torr) and 11h (0.86 g, 177 °C, 2 Torr) as a viscous oil: yield
0.86 g, 61% (based on recovered starting material); IR (film)
1H NMR (CDCl3) δ 7.80-7.00 (19 H, series of m), 3.70-1.00
(23 H, series of m).
N-[2-[(ter t-Bu t yld ip h en ylsilyl)oxy]et h yl]-2-[2-(m et h -
oxym eth ylca r ba m oyl)eth yl]-N-(1-m eth yl-2-p h en yleth yl)-
ben za m id e (34b) was prepared in the same manner as 34a ,
except that DEPC (1.5 mL, 9.9 mmol, 1.1 equiv) was used as
the coupling reagent instead of BOP. The product was purified
by column chromatography (1:1 EtOAc/hexane) to give 3.94 g
(69%) of N,O-dimethylamide 34b as a colorless oil: IR (film)
1
3318 cm-1; H NMR (CDCl3) δ 7.39-7.18 (5 H, series of m),
3.46 (2 H, m), 2.39 (2 H, m), 2.05-1.67 (10 H, series of m).
Anal. (C13H19NO) C, H, N.
N-(2-H yd r oxyet h yl)-2-m et h yl-N-(1-p h en ylcyclop en -
tyl)ben za m id e (14h ) was prepared in the same manner as
14a , starting with 11h (0.99 g, 5.0 mmol) and a reaction time
of 65 h and a 45 min saponification time. The product was
1
1645 cm-1; H NMR (CDCl3) δ 7.51-6.99 (19 H, series of m),
3.60-1.26 (20 H, series of m), 0.95 (9 H s, tert-butyl). Anal.
(C39H48N2O4Si‚0.2H2O) C, H, N.

Inhibitors of the HIV-1 Protease
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2807
purified by column chromatography (1:1 EtOAc/hexane) to give
1-[2-[N-(R,R-Dim eth ylben zyl)-N-bu t-3-en ylca r ba m oyl]-
4-m eth ylp h en yl]-4-[2-(N-(1-eth ylcyclop en tyl)-N-[2-[(ter t-
b u t yld ip h en ylsilyl)oxy]et h yl]ca r b a m oyl]p h en yl]-2-b u -
ta n ol (48). Amide 22 (300 mg, 0.93 mmol) was combined with
diisopropylamine (20 µL, 0.14 mmol) in anhydrous THF (5 mL)
and was cooled to -78 °C under argon. sec-Butyllithium (1.6
M solution in cyclohexane, 1.31 mL, 2.05 mmol) was added,
and the deep red solution was stirred for 35 min at -78 °C.
N,O-Dimethylamide 34c (574 mg, 0.93 mmol) in THF (5 mL)
was added, and the solution was gradually warmed to room
temperature. After 1 h the solution was quenched with 0.5 N
ammonium chloride and extracted with ethyl acetate (3 × 15
mL). The organic layers were combined, washed with H2O (3
× 15 mL), dried over MgSO4, and evaporated to give 687 mg
of an amber-colored residue. Purification by column chroma-
tography eluting with hexanes/ethyl acetate (95:5) gave the
ketone as a white amorphous solid: yield 387 mg (48%); IR
(film) 1717, 1643 cm-1; 1H NMR (CDCl3) δ 7.36 (22 H, m), 5.49
(1 H, m), 4.95 (2 H, m), 3.50 (4 H, br m), 2.75 (2 H, m), 2.32 (2
H, br m), 2.01 (2 H, m), 1.77 (3 H, s), 1.56 (6 H, s), 0.92 (9 H,
br m). The ketone (387 mg, 0.44 mmol) was combined with
absolute EtOH (10 mL) and treated with NaBH4 (64 mg, 1.56
mmol) at room temperature. The alcoholic mixture was
diluted with H2O (15 mL), extracted with diethyl ether (3 ×
20 mL), dried over MgSO4, and evaporated to afford 378 mg
of the alcohol 48 as a white amorphous solid: yield 99%; IR
0.98 g (59%) of amide 14h as an amber oil: IR (film) 3383,
1
1622 cm-1; H NMR (CDCl3) δ 7.40-6.99 (8 H, series of m),
3.60-1.6 (19 H, series of br m). Anal. (C22H27NO2‚0.5H20) C,
H, N.
N -(1-E t h ylcyclop e n t yl)-N -(2-h yd r oxye t h yl)-2-[3-h y-
d r oxy-4-[2-[(2-h yd r oxyeth yl)(1-cyclop en tyl-1-p h en yl)ca r -
bam oyl]-4-m eth ylph en yl]bu tyl]ben zam ide (42ch ) was pre-
pared from amide 14h (0.14 g, 0.40 mmol) and N,O-
dimethylamide 34c (0.25 g, 0.4 mmol) in the same fashion as
40a b. The crude product was purified by column chromatog-
raphy (EtOAc) to yield 0.070 g (27%) of 42ch as a white foam:
1
IR (film) 3380, 1611 cm-1; H NMR (CDCl3) δ 7.60-6.80 (12
H, series of m), 3.40-0.90 (42 H, series of m); HRFABMS calcd
for C41H55N2O5 655.4111, found 655.4115. Anal. (C41H54N2O5)
C, H, N.
N -E t h yl-2-m e t h yl-N -(1,1-d im e t h yl-1-p h e n yle t h yl)-
ben za m id e (27). A solution of amine 10b (1.0 g, 7.4 mmol)
in MeOH was cooled to 0 °C and treated with acetaldehyde
(326 mg, 7.4 mmol). The solution’s pH was adjusted to 6-7
by the addition of 0.5 N HCl and then treated with NaBH3CN
(418 mg, 6.6 mmol). The mixture was stirred at 0 °C for
several hours, gradually warmed to room temperature, and
stirred overnight. The solvent was evaporated, leaving a
slurry that was taken up in H2O (20 mL). The aqueous
mixture was made alkaline with 1 N NaOH to a pH of 11.
The basic solution was treated with saturated NaCl (5 mL)
and was extracted with Et2O (3 × 50 mL). All organic extracts
were combined, washed with H2O (3 × 50 mL), dried over
MgSO4, and concentrated to give 750 mg (63%) of the second-
ary amine as a light yellow liquid: 1H NMR (CDCl3) δ 7.43 (5
H, m), 2.39 (2 H q, J ) 7.2 Hz), 1.74 (1 H, s), 1.46 (6 H, s),
1.06 (3 H, t, J ) 7.1 Hz). The amine was acetylated with
o-toluoyl chloride in the same fashion as 16b to yield 600 mg
of an orange oil. Purification by column chromatography
eluting with 20% ethyl acetate/hexanes gave the amide 27 as
a light yellow oil: yield 325 mg (68%); 1H NMR (CDCl3) δ 7.48
(10 H, m), 3.51 (2 H, br m), 2.28 (3 H, s), 1.82 (6 H, s), 1.56 (1
H, s), 1.14 (3 H, t, J ) 7.3 Hz).
1-[2-[N-(r,r-dim eth ylben zyl)-N-eth ylcar bam oyl]ph en yl]-
4-[2-[N-(1-eth ylcyclop en tyl)-N-(2-h yd r oxyeth yl)ca r ba m -
oyl]p h en yl]-2-bu ta n ol (47). The compound was prepared
from amide 27 (87 mg, 0.31 mmol) and N,O-dimethylamide
34c (189.7 mg, 0.31 mmol) following the same procedure used
to prepare 40a b. The product was purified by column chro-
matography eluting with 20% ethyl acetate/hexanes to yield
65 mg (68%) of 47 as a white amorphous solid: IR (film) 3396
(br), 1609 cm-1; 1H NMR (CDCl3) δ 7.35 (13 H, m), 3.46 (2 H,
br m), 2.75 (1 H, br m), 2.01 (1 H, br m), 1.87 (3 H, br m), 1.80
(6 H, br m), 1.60 (6 H, s), 1.20 (3 H, m), 0.93 (3 H, t, J ) 6.9
Hz); HRFABMS calcd for C38H51N2O4 599.3849, found 599.3849.
Anal. (C38H50N2O4‚0.5H2O) C, H, N.
N-Bu t-3-en yl-1,1-d im eth ylben zyla m in e (21). A solution
of amine 10b (10.0 g, 37.0 mmol), 4-bromo-1-butene (5.0 g, 37.0
mmol), and Hunig’s base (4.77 g, 37.0 mmol) was heated to
140 °C under argon for 2.5 h. A white precipitate fell out of
solution during heating, and the solution turned yellow. The
mixture was cooled to room temperature and was diluted with
Et2O (25 mL) and stirred until the HBr salt of Hunig’s base
precipitated out. The solution was filtered and the filtrate
concentrated to a dark yellow liquid. The residual salt was
filtered and the filtrate distilled (60-70 °C, 0.5 Torr) to give
amine 21 as a clear liquid: yield 5.31 g (76%); 1H NMR (CDCl3)
δ 7.42 (5 H, m), 5.85 (1 H, m), 5.04 (2 H, t, J ) 1.2 Hz), 4.75
(1 H, s), 2.40 (2 H, t, J ) 7.0 Hz), 2.20 (2 H q, J ) 7.1 Hz),
1.49 (6 H, s).
N -Bu t -3-e n yl-2,5-d im e t h yl-N -(1,1-d im e t h ylb e n zyl)-
ben za m id e (22) was prepared from amine 21 (471 mg, 2.49
mmol) and toluoyl chloride 13 (837 mg, 4.98 mmol) by the same
method used to prepare 18b . The product was purified by
column chromatography with ethyl ether/hexanes (95:5) as
elutant to give 455 mg (59%) of amide 22 as a white solid: IR
(film) 1642 cm-1; 1H NMR (CDCl3) δ 7.41 (8 H, m), 5.49 (1 H,
m), 4.95 (2 H, t, J ) 1.2 Hz), 3.50 (2 H, br m), 2.33 (3 H, s),
2.29 (3 H, s), 1.82 (6 H, s).
(film) 3350 cm-1
.
1-[2-[N-(r,r-Dim eth ylben zyl)-N-(3,4-d ih yd r oxybu tyl)-
car bam oyl]-4-m eth ylph en yl]-4-[2-[N-(1-eth ylcyclopen tyl)-
N-(2-h yd r oxyeth yl)ca r boxa m id o]p h en yl]-2-bu ta n ol (49).
N-Methylmorpholine N-oxide (21.8 mg, 0.181 mmol) was
combined with tert-butyl alcohol (0.05 mL) in H2O (4.8 mL).
This mixture was treated with OsO4 (2% solution in tert-butyl
alcohol, 0.6 mL, 0.002 mmol) and stirred for 20 min under
argon. Alcohol 48 (150 mg, 0.174 mmol) in acetone (4 mL)
was added, and the mixture was stirred under argon overnight.
The mixture was acidified with H2SO4 to a pH of 3 and added
to a slurry of florasil in H2O (25 mg in 5 mL). The slurry
mixture was stirred for 10 min and diluted with ethyl acetate
(20 mL). The organic layer was washed with H2O (3 × 10 mL),
dried over MgSO4, and evaporated to give the diol as an amber
1
residue: yield 140 mg (89%); H NMR (CDCl3) δ 7.50 (22 H,
series of m), 3.50 (4 H, br m), 2.75 (2 H, br m), 2.32 (2 H, br
m), 2.01 (2 H, br m), 1.77 (3 H, br m), 1.56 (6 H, br m), 0.92 (9
H, br m). The diol (139 mg, 0.16 mmol) was combined with
THF (10 mL) and reacted with tetrabutylammonium fluoride
(1.0 M in THF, 0.47 mL, 0.47 mmol) at room temperature. The
solution was stirred for 2 h, diluted with H2O (5 mL), and
extracted with ethyl acetate (3 × 10 mL). All organic extracts
were combined, washed with H2O (3 × 10 mL), dried over
MgSO4, and evaporated to give 119 mg of a light brown
residue. Purification by column chromatography eluting with
hexanes and ethyl acetate (1:1) gave 65 mg of 49 as a light
brown amorphous solid: yield (68%); IR (film) 3387, 1609 cm-1
;
1H NMR (CDCl3) δ 7.49 (12 H, br m), 3.85 (2 H, br m), 3.50 (4
H, br m), 2.75 (2 H, br m), 2.25 (2 H, br m), 1.68 (6 H, br m),
1.71 (8 H, br m), 1.60 (6 H, br m), 1.21 (4 H, br m), 0.98 (8 H,
br m); HRFABMS calcd for C41H56N2O6Cs 805.3193, found
805.3199. Anal. (C41H56N2O6‚1.5H2O) C, H, N.
N-(1,1-Diet h ylb u t yl)-N-[2-ter t-b u t yld ip h en ylsiloxy)-
eth yl]a m in e (16d ) was prepared from amine 11d and tert-
butyldiphenylsilyl chloride in the same fashion as amine 16a :
1H NMR (CDCl3) δ 7.69-7.26 (10 H, series of m), 3.75 (2 H, t,
J ) 5.3 Hz), 2.53 (2 H, t, J ) 5.3 Hz), 1.55-0.74 (12 H, series
of m). Anal. (C26H41NOSi) C, H, N.
N-(1,1-Diet h ylb u t yl)-N-[2-(ter t-b u t yld ip h en ylsiloxy]-
eth yl]-2,4-d im eth ylben za m id e (19d ). Amide 19d was pre-
pared from amine 16d and 2,5-dimethylbenzoyl chloride(13)
in the same fashion as 19a : 1H NMR (CDCl3) δ 7.75-7.00 (13
H, series of m), 3.60-3.20 (4 H, series of m), 2.20-0.75 (18 H,
series of m). Anal. (C35H49NO2Si) C, H, N.
N -(1-E t h ylcyclop e n t yl)-N -(2-h yd r oxye t h yl)-2-[3-h y-
dr oxy-4-[2-[(2-h ydr oxyeth yl)(1,1-dieth ylbu tyl)car bam oyl]-
4-m eth ylp h en yl]bu tyl]ben za m id e (42cd ) was prepared
from N-(1,1-diethylbutyl)-N-[2-(tert-butyldiphenylsiloxy)ethyl]-
2,4-dimethylbenzamide 19d (0.30 g, 0.55 mmol) and N,O-di-

2808 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Melnick et al.
methylamide 34c (0.34 g, 0.55 mmol) in the same manner as
40a b. The product was purified by column chromatography
(EtOAc) to give 42cd as a white foam (0.14 g, 40% overall):
IR (film) 3368, 1609 cm-1; 1H NMR (CDCl3) δ 7.40-6.70 (7 H,
series of m), 3.80-0.90 (51 H, series of m); HRFABMS calcd
for C38H59N2O5 623.4424, found 623.4436. Anal. (C38H58N2O5)
C, H, N.
once with CH2Cl2 (100 mL), the combined organics were dried
and evaporated, and the residue was purified twice by column
chromatography (5% MeOH/CH2Cl2 followed by 25% EtOAc/
hexane) to give 31 as a clear, viscous oil: yield 534 mg, 68%;
1H NMR (CDCl3) δ 7.47-7.01 (13 H, series of m), 2.13 (3 H, s,
CH3), 4.02-1.34 (19 H, series of m), 0.93 (9 H, s, tert-butyl).
Anal. (C35H47NO3Si) C, H, N.
N -(1-E t h ylcyclop e n t yl)-N -(2-h yd r oxye t h yl)-2-[3-h y-
d r oxy-4-[2-[(2-h yd r oxye t h yl)[1-m e t h yl-1-(t e t r a h yd r o-
p yr a n -4-yl)e t h yl]ca r b a m oyl]-4-m e t h ylp h e n yl]b u t yl]-
ben za m id e (42ci) was prepared from amide 31 (0.3 g, 0.54
mmol) and N,O-dimethylamide 34c (0.3 g, 0.54 mmol) in the
same manner as 40a b. The product was purified by column
chromatography (EtOAc) to give 42ci as a white foam: yield
92 mg, 27% overall; 1H NMR (CDCl3) δ 7.30-6.80 (7 H, series
of m), 4.00-0.90 (49 H, series of m); HRFABMS calcd for
C38H57N2O6 637.4217, found 637.4220. Anal. (C38H56N2O6‚
0.5H2O) C, H, N.
2-(Tet r a h yd r op yr a n -4-yl)p r op a n -2-ol (29). To an ice-
cooled solution of tetrahydropyran-4-carboxylic acid16 (28) (15
g, 115 mmol) in THF (300 mL) was added a solution of
methyllithium (1.4 M in Et2O, 82 mL, 115 mmol) over a 25
min period during which time a white solid formed and then
gradually disappeared during addition. After stirring at 0 °C
for 2 h, the reaction was quenched with 0.5 N HCl, allowed to
stir for 10 min, and then extracted with Et2O (2 × 100 mL).
The combined organic layers were dried and azeotroped from
benzene (30 mL), and the material was again dissolved in THF
(300 mL), cooled, and treated again with methyllithium (1.4
M in Et2O, 82 mL, 115 mmol) over a 20 min period. The
mixture was allowed to warm to ambient temperature over
30 h and was followed by recooling and quenching with 0.5 N
HCl (100 mL). It was extracted with Et2O (2 × 100 mL), dried,
and evaporated, and the product 29 was Kugelrohr distilled
N -(H yd r oxye t h yl)-2-m e t h yl-3-p h e n yl-2-a m in op r o-
p a n e (11e) was prepared in the same manner as amine 11b
to yield a viscous oil (Kugelrohr, 170 °C/2 Torr, 59% yield).
1H NMR (CDCl3) δ 7.30 (3 H, m), 7.27 (1 H, d, J ) 7.6 Hz),
7.16 (1 H, d, J ) 8.0 Hz), 3.61 (2 H, t, J ) 5.2 Hz), 2.80 (2 H,
t, J ) 5.1 Hz), 2.69 (2 H, s), 2.05 (1 H, br), 1.07 (6 H, s).
[N -(H y d r o x y e t h y l)-N -(2-m e t h y l-3-p h e n y lp r o p y l)-
ben za m id e (14e) was prepared in the same manner as amide
14b to yield a viscous oil. (58% yield): 1H NMR (CDCl3) δ
7.32 (5 H, m), 7.16 (3 H, m), 7.14 (1 H, m), 3.97 (1 H, bd, J )
12.6 Hz), 3.22 (1 H, m), 2.99 (3 H, m), 2.88 (2 H, d, J ) 12.9
1
(125 °C, 4 Torr): yield 8.78 g, 53%; IR (film) 3413 cm-1; H
NMR (CDCl3) δ 4.08 (4 H, d, J ) 7.1 Hz), 3.40 (4 H, t, J )
11.5 Hz), 1.52 (1 H, m), 1.21 (6 H, s).
1-Meth yl-1-(tetr a h yd r op yr a n -4-yl)eth yla m in e (30). To
a cooled slurry of HOAc (7 mL) and NaCN (1.6 g, 33.3 mmol)
was added a solution of H2SO4 (7 mL) in HOAc (3.5 mL) over
a 10 min period, keeping the temperature below 20 °C, after
which 29 (4.0 g, 27.7 mmol) was added over 3 min followed by
stirring at 15 °C for 45 min and 2 h at 80 °C. The mixture
was then removed from heat, poured onto cracked ice (100 mL),
brought to pH 9 with Na2CO3, and extracted with Et2O (100
mL), salt was added to the aqueous layer, and the mixture
was extracted once more with Et2O (100 mL). The combined
organic layers were dried and evaporated to give the crude
formamide which was treated with concentrated HCl (2.5 mL)
and heated at reflux for 2 h 45 min. The mixture was then
treated with H2O (5 mL) and extracted with Et2O (2 × 25 mL).
The organic layer was discarded and the aqueous layer brought
to pH 13 with 50% NaOH and extracted with Et2O (25 mL).
NaCl was added to the aqueous layer and extracted once more
with Et2O (25 mL). The combined organic layers were dried,
evaporated at 30 °C, and Kugelrohr distilled (95 °C, 2.5 Torr)
to give 30 as a colorless oil: yield 0.23 g, 6%.
Hz), 2.29 (3 H, s), 1.63 (3 H, s), 1.47 (3 H, s). Anal. (C20H25
NO2) C, H, N.
-
2-[4-[2-(ter t-Bu tyl(2-h yd r oxyeth yl)ca r ba m oyl]p h en yl]-
2-h yd r oxybu tyl]-N-(1,1-d im eth yl-2-p h en yleth yl)-N-(2-h y-
d r oxyeth yl)ben za m id e (40a e) was prepared in the same
fashion as 40a b. Amide 14e was lithiated with s-BuLi and
quenched with Weinreb amide 34a to give crude ketone 36a e,
which was reduced (NaBH4) and deprotected (n-Bu4NF) to give
40a e as an amorphous solid after column chromatography on
silica (3:1 EtOAc/hexanes) (35% yield from 14e): 1H NMR
(CDCl3) δ 7.10-7.40 (13 H, m), 4.45 (2 H, m), 3.25-3.80 (5 H,
m), 2.55-2.95 (4 H, m), 1.60-2.10 (3 H, m), 1.55 (18 H, bs).
Anal. (C36H48N2O5‚0.5H2O) C, H, N.
N-(1,1-Dim eth yleth yl)-N-(2-h yd r oxyeth yl)-2,5-d im eth -
ylben za m id e (15b) was prepared in the same manner as
amide 14b from 2,5-dimethylbenzoic acid (12% yield, three
1
steps): IR (film) 3316, 2953, 1607 cm-1; H NMR (CDCl3) δ
7.30 (6 H, m), 7.01 (2 H, bs), 6.81 (1 H, bs), 3.66 (2 H, bs), 3.51
(2 H, m), 2.26 (3 H, s), 2.25 (3 H, s), 1.75 (6 H, bs).
N-[2-(ter t-Bu tyld ip h en ylsiloxy)eth yl]-2,5-d im eth yl-N-
[1-m eth yl-1-(tetr a h yd r op yr a n -4-yl)eth yl]ben za m id e (31).
To THF (2 mL) cooled to -78 °C was added a cooled solution
of ethylene oxide (0.35 mL, 7.14 mmol) followed by LiClO4 (0.69
g, 7.14 mmol) and stirring for 5 min. A solution of 30 (0.93 g,
6.49 mmol) in CH3CN (2 mL) was added over a 3 min period.
The mixture was allowed to warm to ambient temperature
over 4 h. The solvents were evaporated, and the residue was
dissolved in EtOAc (20 mL) and washed with brine (2 × 10
mL). The organic layer was dried and evaporated, and the
product was Kugelrohr distilled (170 °C, 2 Torr) to a clear
N-ter t-Bu tyl-N-(2-h yd r oxyeth yl)-2-[3-h yd r oxy-4-[2-[(2-
h yd r oxye t h yl)(1-m e t h yl-1-p h e n yle t h yl)ca r b a m oyl]-4-
m et h ylp h en yl]b u t yl]b en za m id e (42a b ) was prepared
in the same fashion as 40a b. Amide 15b was lithiated with
s-BuLi and quenched with Weinreb amide 34a to give crude
ketone 38a b which was reduced (NaBH4) and deprotected (n-
BuN4F) to give 42a b as an amorphous solid (17% yield from
15b): 1H NMR (CDCl3) δ 6.80-7.60 (13 H, m), 4.45 (2 H, m),
3.20-3.85 (5 H, m), 2.40-3.00 (4 H, m), 2.29 (3 H, m), 1.20-
2.00 (21 H, m). Anal. (C36H48N2O5‚0.5H2O) C, H, N.
1
colorless oil: yield 424 mg, 35%; H NMR (CDCl3) δ 1.02 (s,
ter t-Bu tyl(4-isop r op ylp h en oxy)d im eth ylsila n e (51). A
solution of 4-isopropylphenol (50) (20 g, 146.8 mmol) in 250
mL of DMF was treated with imidazole (15.0 g, 220 mmol)
and tert-butyldimethylsilyl chloride (24.3 g, 162 mmol) por-
tionwise at 25 °C. After 3 h the reaction mixture was poured
into 500 mL water and ether was added. The aqueous layer
was separated and extracted with ether. The combined
organic layer was washed with 0.1 N HCl and saturated
aqueous NaHCO3, dried (MgSO4), and concentrated to afford
a clear oil which was used without further purification (36.6
g, 100%): 1H NMR (CDCl3) δ 7.07 (2 H, d, J ) 8.4 Hz), 6.76 (2
H, d, J ) 8.4 Hz), 2.85 (1 H, m), 1.21 (6 H, d, J ) 7.0 Hz), 1.02
(9 H, s), 0.19 (6 H, s).
6 H, CH3), 1.60-4.00 (series of m, 15 H). Anal. (C10H21NO2‚
0.1H2O) C, H, N. To a solution of above hydroxyethylamine
(0.42 g, 2.21 mmol) and imidazole (0.33 g, 4.9 mmol) in 7 mL
of CH2Cl2 was added tert-butyldiphenylsilyl chloride (1.34 g,
4.9 mmol) in CH2Cl2 (5 mL), and the mixture was stirred for
2 h at room temperature after which the reaction mixture was
washed with H2O (50 mL) and the aqueous layer extracted
with CH2Cl2 (10 mL). The organic layers were combined,
dried, and evaporated, and the residue was purified by column
chromatography (5% MeOH/CH2Cl2) to give the product as a
viscous oil: yield 620 mg, 66%; 1H NMR (CDCl3) δ 1.00 (s,
9H, tert-butyl), 1.04 (s, 6 H, CH3), 1.60-4.00 (series of m, 14
H), 7.26-7.67 (series of m, 10 H). Anal. (C26H39NO2Si) C, H,
N. A solution of the siloxyamine (0.6 g, 1.4 mmol), 2,5-
dimethylbenzoyl chloride (13) (0.47 g, 2.8 mmol), and Et3N (0.6
mL, 4.2 mmol) in CH2Cl2 (3 mL) was stirred for 24 h at room
temperature followed by addition of CH2Cl2 (10 mL) and
washing with H2O (100 mL). The aqueous layer was washed
1-[4-[(ter t-Bu t yld im et h ylsilyl)oxy]p h en yl]-1-m et h yl-
eth yla m in e (52). The silyl ether 51 (20 g, 79.8 mmol) in 140
mL of CHCl3 was treated with azidotrimethylsilane18 (36.8 g,
319 mmol) and dichlorodicyanobenzoquinone (DDQ, 36.2 g, 160
mmol) portionwise at 25 °C. After 3 h the reaction was carefully

Inhibitors of the HIV-1 Protease
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2809
poured into a solution of saturated NaHCO3, and the aqueous
layer was extracted with ether, washed with brine, dried
(MgSO4), and concentrated to afford 33 g of a crude amber oil.
This material was filtered through a plug of silica, eluting with
7:1 hexanes/ether, yielding 12.5 g of crude azide. The azide
in 140 mL of EtOH was treated with 2 g of 5% Pd-BaSO4 and
placed under 1 atm of H2 at 25 °C. After 5 h starting azide
was still present and an additional gram of catalyst was added.
After 28 h the reaction was complete and the solution was
filtered through a pad of Celite and concentrated to afford a
light yellow oil (10.5 g, 50%): 1H NMR (CDCl3) δ 7.33 (2 H, d,
J ) 8.7 Hz), 6.78 (2 H, d, J ) 8.7 Hz), 1.64 (2 H, bs), 1.47 (6
H, s), 0.99 (9 H, s), 0.20 (6 H, s).
(2,2-Dim eth yl[1,3]d ioxa n -5-yl)m eth a n ol (24). A mixture
of diethyl bis(hydroxymethyl)malonate 23 (25 g, 113 mmol),
50 mL of dimethoxymethane, and p-toluenesulfonic acid mono-
hydrate (1.0 g, 5.2 mmol) was combined and stirred for 54 h.
The reaction mixture was diluted with ether, washed with
saturated aqueous NaHCO3 and brine, dried (MgSO4), and
concentrated to afford 28.9 g (98%) of a yellow oil. The crude
diester (15 g, ca. 57.6 mmol) in a mixture of 75 mL of DMSO
and 2 mL of H2O was treated with NaCl (3.37 g, 57.6 mmol)
and heated to reflux for 12 h. Upon cooling, the reaction was
diluted with water and extracted with ether. The ether layer
was washed with brine, dried (MgSO4), and concentrated to
afford 7.4 g (69%) of monoester as a light yellow oil: 1H NMR
(CDCl3) δ 4.19 (2 H, q, J ) 7.1 Hz), 4.05 (4 H, m), 2.80 (1 H,
m), 1.45 (3 H, s), 1.41 (3 H, s), 1.27 (3 H, t, J ) 7.1 Hz). To a
solution of LiAlH4 (1.04 g, 27.5 mmol) and 120 mL of ether
was added a solution of ester (4.7 g, 24.9 mmol) in 20 mL of
ether so as to maintain a gentle reflux. The reaction was
carefully quenched by the slow addition of 1 mL of H2O,
followed by 1 mL of 15% aqueous NaOH and then 3 mL of
additional H2O followed by vigorous stirring for 1 h. The
solution was filtered from the white precipitate that had
formed, the precipitate was washed with EtOAc, and the
combined organic layer was washed with H2O and brine, dried
(MgSO4), and concentrated to afford 3.56 g of crude oil. Flash
chromatography (SiO2, 2:1 ether/hexanes) gave 2.86 g (78%)
of alcohol 24 as a clear oil: 1H NMR (CDCl3) δ 4.03 (2 H, dd,
J ) 4.2 Hz), 3.82 (5 H, m), 1.85 (1 H, m), 1.45 (3 H, s), 1.41 (3
H, s). Anal. (C7H14O3) C, H.
[(2,2-Dim e t h yl[1,3]d ioxa n -5-yl)m e t h yl](1-m e t h yl-1-
p h en yleth yl)a m in e (25). Formation of the mesylate of
alcohol 24 as described above and displacement with 1,1-
dimethylbenzylamine afforded amine 25 in 56% yield for the
two steps: 1H NMR (CDCl3) δ 7.42 (2 H, d, J ) 6.4 Hz), 7.35
(2 H, t, J ) 6.4 Hz), 7.21 (1 H, m), 3.93 (2 H, dd, J ) 11.9, 3.5
Hz), 3.59 (2 H, dd, J ) 11.9, 8.0 Hz), 2.29 (2 H, d, J ) 7.0 Hz),
1.80 (1 H, m), 1.44 (6 H, s), 1.40 (3 H, s), 1.35 (3 H, s).
N-[(2,2-Dim eth yl[1,3]d ioxa n -5-ylm eth yl]-N-(1-m eth yl-
1-p h en yleth yl)ben za m id e (26) was prepared by the same
procedure used to prepare amide 14b, as a viscous oil (45%
yield from amine 25): 1H NMR (CDCl3) δ 7.40 (2 H, d, J ) 7.5
Hz), 7.33 (2 H, t, J ) 7.3 Hz), 7.23 (1 H, t, J ) 5.3 Hz), 7.00 (2
H, s), 6.84 (1 H, bs), 3.82 (2 H, br), 3.35-3.65 (4 H, m), 2.26 (6
H, s), 1.85 (4 H, m), 1.75 (3 H, bs), 1.35 (3 H, s), 1.16 (3 H, s).
Anal. (C25H33NO3‚0.2H2O) C, H, N.
N-(1-Eth ylcyclopen tyl)-2-[4-[2-[(2,2-dim eth yl[1,3]dioxan -
5-yl)m eth yl](1-m eth yl-1-p h en yleth yl)ca r ba m oyl]-4-m eth -
ylp h e n yl]-3-h yd r oxyb u t yl]-N -(2-h yd r oxye t h yl)b e n z-
a m id e (44) was prepared in the same manner as 40a b.
Amide 26 was lithiated with s-BuLi and quenched with
Weinreb amide 34c to give crude ketone which was reduced
(NaBH4)and deprotected (n-Bu4NF) to give 44 as an amor-
phous solid after column chromatography on silica (1:1 EtOAc/
hexanes) (48% yield from 26): 1H NMR (CDCl3) δ 7.00-7.45
(16 H, m), 4.60 (1 H, br), 3.75-3.85 (4 H, m), 3.25-3.60 (7 H,
m), 2.50-2.85 (4 H, m), 1.65-2.10 (18 H, m), 1.34 (3 H, bs),
1.08 (4 H, m), 0.96 (3 H, t, J ) 7.2 Hz); HRFABMS calculated
for C44H60N2O6‚Cs 845.3506, found 845.3491.
N -(1-E t h ylcyclop e n t yl)-N -(2-h yd r oxye t h yl)-2-[3-h y-
dr oxy-4-[2-[[3-h ydr oxy-2-(h ydr oxym eth yl)pr opyl](1-m eth -
yl-1-p h e n yle t h yl)ca r b a m oyl]-4-m e t h ylp h e n yl]b u t yl]-
ben za m id e (45). 44 was deprotected (p-TosOH-MeOH) to
give 45 as an amorphous solid after column chromatography
on silica (12:1 EtOAc/hexanes) (67% yield): 1H NMR (CDCl3)
δ 7.00-7.40 (16 H, m), 4.25 (1 H, br), 3.50-3.80 (6 H, m), 3.45
(5 H, m), 2.45-2.80 (4 H, m), 1.60-2.35 (18 H, m), 1.27 (3 H,
bs), 0.96 (3 H, m). Anal. (C41H56N2O6 ) C, H, N.
2-[[1-[4-[(ter t-Bu tyld im eth ylsilyl)oxy]p h en yl]-1-m eth -
yleth yl]a m in o]eth a n ol (53). The amine 52 (5.22 g, 19.7
mmol) was treated with ethylene oxide and LiClO4 as described
previously to afford alcohol 53 (73% yield), after chromatog-
raphy on silica (5% MeOH/CH2Cl2 with NH3): 1H NMR
(CDCl3) δ 7.30 (2 H, d, J ) 8.6 Hz), 6.82 (2 H, d, J ) 8.6 Hz),
3.67 (2 H, bt, J ) 5.0 Hz), 2.60 (2 H, bt, J ) 5.0 Hz), 2.46 (2
H, bs), 1.58 (6 H, s), 0.98 (9 H, s), 0.20 (6 H, s). Anal. (C17H31
-
NO2Si‚0.6H2O) C, H, N.
N-[2-[(ter t-Bu tyld im eth ylsilyl)oxy]eth yl]-N-[1-[4-[(ter t-
b u t yld im et h ylsilyl)oxy]p h en yl]-1-m et h ylet h yl]-2,5-d i-
m eth ylben za m id e (54). Alcohol 53 was silylated using the
procedure described for 50 to afford compound 54 as an oil
(95%). Amine was acylated with 2,5-dimethylbenzoyl chloride
as described previously to give amide 54 in 67% yield as an
oil after flash chromatography (12:1 hexanes/EtOAc): 1H NMR
(CDCl3) δ 7.36 (1 H, s), 7.24 (1 H, s), 7.00 (2 H, s), 6.89 (1 H,
bs), 6.79 (1 H, s), 6.76 (1 H, s), 3.58 (2 H, m), 3.38 (2 H, m),
2.28 (3 H, s), 2.21 (3 H, s), 1.79 (6 H, bs), 0.97 (9 H, s), 0.79 (9
H, s), 0.19 (6 H, s), -0.14 (6 H, s). Anal. (C32H53NO3Si2) C,
H, N.
N -(1-E t h y lc y c lo p e n t y l)-N -(2-h y d r o x y e t h y l)-2-[3-
h yd r oxy-4-[2-[(2-h yd r oxyet h yl)[1-(4-h yd r oxyp h en yl)-1-
m e t h yle t h yl]ca r b a m oyl]-4-m e t h ylp h e n yl]b u t yl]b e n z-
a m id e (56) was prepared in the same fashion as 40a b. Amide
54 was lithiated with s-BuLi and quenched with Weinreb
amide 34c to give purified ketone 55 (63%) which was reduced
(NaBH4) and deprotected (n-Bu4NF) to give 56 as an amor-
phous solid after column chromatography on silica (1:4 EtOAc/
hexanes) (78% yield from 54): 1H NMR (CDCl3) δ 6.60-7.35
(13 H, m), 4.45 (2 H, m), 3.10-3.80 (5 H, m), 2.40-2.80 (4 H,
m), 2.29 (2 H, bs), 2.26 (2 H, bs), 1.50-2.10 (17 H, m), 0.93 (3
H, m). Anal. (C36H48N2O5) C, H, N.
N -(1-E t h ylcyclop e n t yl)-N -(2-h yd r oxye t h yl)-2-[3-h y-
d r oxy-4-[2-[(2-h yd r oxyeth yl)[1-m eth yl-1-[4-(p yr id in -3-yl-
m eth oxy)ph en yl]eth yl]car bam oyl]-4-m eth ylph en yl]bu tyl]-
ben za m id e (58). A solution of ketone 55 (3.80 g, 3.42 mmol)
in 60 mL of THF and 65 mL of hexanes was cooled to -50 °C
and treated with n-Bu4NF (3.44 mmol, 3.44 mL of a 1 M
solution in THF). After stirring for 2.5 h the reaction was
diluted with water and EtOAc. The organic layer was dried
(Na2SO4) and concentrated to give 4.0 g of an oil. Purification
using chromatography on silica (20-30% EtOAc/hexanes)
afforded 2.8 g (83%) of phenol as an amorphous solid: 1H NMR
(CDCl3) δ 6.90-7.50 (19 H, m), 6.50 (2 H, d, J ) 8.5 Hz), 3.65
(4 H, bs), 3.42 (2 H, m), 3.20-3.35 (3 H, m), 3.07 (1 H, br),
2.35-2.62 (8 H, m), 2.31 (3 H, s), 1.50-2.20 (16 H, m), 0.91 (9
H, s), 0.83 (9 H, s), -0.06 (3 H, s), -0.08 (3 H, s). The phenol
(1.83 g, 1.83 mmol) was treated with 3-(chloromethyl)pyridine
(0.47 g, 3.66 mmol), Cs2CO3 (1.2 g, 3.66 mmol), and KI (0.04
g, 0.24 mmol) in 60 mL of dry acetone, and the mixture was
heated to 53 °C for 4 h. After the reaction mixture was allowed
to cool to 25 °C, the solution was concentrated and the residue
taken up in EtOAc, washed with saturated aqueous NaHCO3,
dried (Na2SO4), and concentrated to afford 1.42 g (71%) of
ketone 57 after chromatography on silica (1:1 hexanes/EtOAc).
Ketone 57 was reduced (NaBH4) and deprotected (nBu4NF)
to give 58 as an amorphous solid (82%) after chromatography
on silica (100% EtOAc): 1H NMR (CDCl3) δ 8.59 (2 H, m), 7.78
(1 H, br), 6.80-7.50 (12 H, m), 5.02 (2 H, m), 3.20-3.80 (8 H,
m), 2.70 (3 H, br), 2.28 (1.5 H, bs), 2.25 (1.5 H, bs), 1.50-2.10
(23 H, m), 0.92 (3 H, bt). Anal. (C45H57N3O6‚0.3H2O) C, H,
N.
N-[2-[(ter t-Bu t yld im et h ylsilyl)oxy]et h yl]-N-[1-(4-h y-
dr oxyph en yl)-1-m eth yleth yl]-2,5-dim eth ylben zam ide (59).
Silyl ether 54 (2.2 g, 3.9 mmol) in 20 mL of toluene was treated
with n-Bu4NF (3 mmol, 3 mL of 1 M solution in THF) at 0 °C,
and after 5 min water was added. The aqueous layer was
extracted with EtOAc, and the combined organic layers were
dried (Na2SO4) and concentrated to yield 3 g of a crude oil.
Chromatography (SiO2, 2% MeOH/CH2Cl2) afforded 1.08 g
(82%) of phenol 59 as a white amorphous solid: 1H NMR

2810 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Melnick et al.
(CDCl3) δ 7.20 (2 H, d, J ) 8.5 Hz), 7.02 (2 H, s), 6.89 (1 H,
bs), 6.59 (2 H, d, J ) 8.5 Hz), 6.13 (1 H, bs), 3.60 (3 H, bs),
3.40 (1 H, br), 2.29 (3 H, s), 2.21, (3 H, s), 1.78 (6 H, bs), 0.80
(9 H, s), -0.12 (6 H, s).
tions of compounds required to produce 50% inhibition of
HIV-1 induced cell death (ED50) were determined and are
listed in Table 1. The concentration of compound that
produced a 50% reduction in the number of viable cells
(uninfected with virus) as determined by metabolism of MTT
is designated the TC50 in Table 1. The details of the methods
used in the pharmacokinetic studies have been reported
previously.10
N-[2-[(ter t-Bu tyld im eth ylsilyl)oxy]eth yl]-2,5-d im eth yl-
N-[1-m eth yl-1-[4-(2-m or p h olin -4-yleth oxy)p h en yl]eth yl]-
ben za m id e (60). A mixture of phenol 59 (264 mg, 0.59 mmol),
CsCO3 (780 mg, 2.4 mmol), and 2-(chloroethyl)morpholine (free
base, prepared from the hydrochloride salt via extraction with
EtOAc-saturated NaHCO3 and MgSO4 drying; 893 mg, 6.0
mmol) in 30 mL of dry dioxane was heated to 80 °C for 1 h.
After cooling to 25 °C the reaction was filtered, concentrated,
taken up in EtOAc, washed with water and brine, dried
(MgSO4), and concentrated again. Chromatography (SiO2,
100% EtOAc) yielded 182 mg (55%) of ether 60 as a viscous
oil: 1H NMR (CDCl3) δ 7.32 (2 H, d, J ) 8.7 Hz), 7.00 (2 H, s),
6.86 (1 H, bs), 6.86 (2 H, d, J ) 8.7 Hz, overlapping bs), 4.10
(2 H, t, J ) 7.7 Hz), 3.74 (4 H, t, J ) 4.6 Hz), 3.58 (4 H, br s),
2.79 (2 H, t, J ) 5.7 Hz), 2.58 (4 H, t, J ) 4.6 Hz), 2.28 (3 H,
s), 2.21 (3 H, s), 1.79 (6 H, bs), 0.80 (9 H, s), -0.13 (6 H, s).
N -(1-E t h ylcyclop e n t yl)-N -(2-h yd r oxye t h yl)-2-[3-h y-
d r oxy-4-[2-[(2-h yd r oxyeth yl)[1-m eth yl-1-[4-(2-m or p h olin -
4-ylet h oxy)p h en yl]et h yl]ca r b a m oyl]-4-m et h ylp h en yl]-
bu tyl]ben za m id e (62) was prepared as described previously.
Amide 60 was lithiated with s-BuLi and quenched with
Weinreb amide 34c to give ketone 61 (75%) which was reduced
(NaBH4) and deprotected (n-Bu4NF) to give 62 as an amor-
phous solid after preparative thin layer chromatography on
silica (10% MeOH/CH2Cl2) (35% yield from 60): 1H NMR
(CDCl3) δ 7.00-7.40 (9 H, m), 6.86 (2 H, m), 4.60 (1 H, br),
4.10 (2 H, m), 3.74 (4 H, bt), 3.48 (10 H, br), 3.25 (1 H, br), 3.0
(1 H, br), 2.65-2.75 (4 H, m), 2.58 (6 H, br s), 2.29 (3 H, bs),
2.26 (3 H, bs), 2.00 (2 H, br), 1.60-1.85 (12 H, br), 0.95 (3 H,
br). Anal. (C45H63N3O7‚1.0H2O) C, H, N.
N-[2-[(ter t-Bu t yld ip h en ylsilyl)oxy]et h yl]-5-ch lor o-2-
m et h yl-N-(1-m et h yl-1-p h en ylet h yl)b en za m id e (20b ).
3-Chloro-5-methylbenzoic acid27 was converted to the acid
chloride as described previously ((COCl)2, catalytic DMF) and
treated with amine 16b to afford the amide 20b in 73% yield
after chromatography (SiO2, 7:1 hexanes/EtOAc).
N-[2-[(ter t-Bu t yld ip h en ylsilyl)oxy]et h yl]-2-[4-[2-[[2-
[(ter t-bu tyld ip h en ylsilyl)oxy]eth yl](1-m eth yl-1-p h en yl-
eth yl)ca r ba m oyl]-4-ch lor op h en yl]-3-oxobu tyl]-N-(1-eth -
ylcyclop en tyl]ben za m id e (39bc) was prepared as described
previously. Amide 20b was lithiated with s-BuLi and quenched
with Weinreb amide 34c to give ketone 39bc (35%) after
chromatography (SiO2, 20-33% hexanes/EtOAc): 1H NMR
(CDCl3) δ 7.00-7.70 (32 H, m), 3.73 (2 H, m), 3.65 (2 H, m),
3.48 (5 H, m), 3.25 (1 H, br), 2.70 (4 H, m), 1.75-2.00 (8 H,
m), 1.70 (8 H, bs), 1.05 (9 H, s), 0.95 (9 H, s), 0.85 (3 H, t, J )
7.2 Hz). Anal. (C70H83N2O5Si2Cl) C, H, N, Cl.
2-[4-[4-Ch lor o-2-[(2-h yd r oxyeth yl)(1-m eth yl-1-p h en yl-
eth yl)ca r ba m oyl]p h en yl]-3-h yd r oxybu tyl]-N-(1-eth ylcy-
clop en tyl)-N-(2-h yd r oxyeth yl)ben za m id e Alcoh ol (43bc).
Ketone 39bc was reduced (NaBH4) and deprotected (n-Bu4NF)
as described previously to give 43bc as an amorphous solid
after chromatography on silica (2:1 EtOAc/hexanes) (84% yield
from 39bc): 1H NMR (CDCl3) δ 7.46 (1 H, bs), 7.00-7.40 (11 H,
m), 4.95 (1 H, bs), 3.90 (1 H, bs), 3.40-3.75 (7 H, m), 3.23 (1
H, m), 2.55-2.75 (4 H, m), 2.10-2.30 (2 H, m), 1.90 (8 H, m),
1.50-1.75 (10 H, m), 0.96 (3 H, t, J ) 7.2 Hz). Anal.
(C38H49N2O5Cl‚0.4H2O) C, H, N, Cl.
Cr ysta llogr a p h y. The crystallization conditions, data
collection, and structure solution methods have been previ-
ously reported.10 The resolution limit of the diffraction data
and the final crystallographic R factors for the structures are
as follows: compound 9, 2.4 Å and R ) 0.174; compound 40a b,
2.35 Å and R ) 0.186; compound 40a d , 2.2 Å and R ) 0.213;
compound 40a g, 2.1 Å and R ) 0.211; and compound 42bc,
2.3 Å and R ) 0.189.
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Nonpeptide Potent HIV-1 Protease Inhibitors: (4-Hydroxy-6-
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(9) Previous paper: Reich, S. H.; Melnick, M.; Pino, M. J .; Fuhry,
M. A. M.; Trippe, A. J .; Appelt, K.; Davies, J . F.; Wu, B.-W.;
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Inhibitors of the HIV-1 Protease
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J M960092W