Potent human immunodeficiency virus type 1 protease inhibitors that utilize noncoded D-amino acids as P2/P3 ligands

Article abstract of DOI:10.1021/jm950576c

Noncoded D-amino acids have been designed to replace the quinaldic amide- asparaginyl moiety (P₂/P₃ ligand) found in several potent human immunodeficiency virus (HIV) protease inhibitors such as LY289612. The substituted nitrogen, op

Full text of DOI:10.1021/jm950576c

96
J . Med. Chem. 1996, 39, 96-108
P oten t Hu m a n Im m u n od eficien cy Vir u s Typ e 1 P r otea se In h ibitor s Th a t Utilize
Non cod ed D-Am in o Acid s a s P 2/P 3 Liga n d s
Louis N. J ungheim,*,† Timothy A. Shepherd,† Angela J . Baxter,‡ J effrey Burgess,‡ Steven D. Hatch,‡
Penny Lubbehusen,‡ MaryAnn Wiskerchen,‡ and Mark A. Muesing‡
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285-1523
Received August 2, 1995X
Noncoded D-amino acids have been designed to replace the quinaldic amide-asparaginyl moiety
(P2/P3 ligand) found in several potent human immunodeficiency virus (HIV) protease inhibitors
such as LY289612. The substituted nitrogen, optimally an N-methanesulfonyl moiety, served
as a CH2CONH2 (asparagine side chain mimic), while the amino acid side chain became the
backbone and P3 ligand of these novel inhibitors. Compounds derived from S-aryl-D-cysteine
proved to be potent HIV protease inhibitors which also exhibited potent whole cell antiviral
activity. Oxidation of the cysteines to the sulfoxide or sulfone oxidation states resulted in
significant improvements in potency. For example, the compound derived from N-(methyl-
sulfonyl)-2-S-naphthylcysteine sulfone, 17c, was a 3.5 nM inhibitor of HIV protease which
inhibited the spread of virus in MT4 cells with an IC50 ) 4.3 nM. Compounds 17c,g,i were
found to be orally bioavailable in a rat model.
In tr od u ction
Human immunodeficiency virus type 1 (HIV-1) pro-
tease, an essential enzyme in the life cycle of HIV,
remains an exciting target for anti-AIDS (acquired
immune deficiency syndrome) chemotherapeutic agents.1
Considerable effort has been spent on attempts to find
potent, orally bioavailable, peptidomimetic inhibitors of
this enzyme.2 Representative examples include Ro 31-
89593 and the MK-639,2,4 both of which are in phase
III clinical trails. The Lilly group recently reported5 on
our lead compound LY289612, and much of our contin-
ued effort in this area has focused on improving the
antiviral potency and pharmacokinetic properties of this
structure type.
The factors which determine why peptidomimetic
compounds typically exhibit poor oral bioavailability
while selected compounds such as MK-639 are well
absorbed are not yet well understood.6 Both Ro 31-8959
and LY289612 exhibit relatively low oral bioavailability
in animal models.7,8 The structural similarities between
Ro 31-8959 and LY289612 are readily apparent; thus
we reasoned one potential way to improve the pharma-
cokinetic properties might be to diverge from the
quinaldic amide-asparagine moiety found in both in-
hibitors. A reduction in both the peptide-like nature of
our inhibitor as well as the structural similarity to the
While D-amino acid substitution might improve pro-
Roche inhibitor could be achieved by replacing the only
teolytic stability, our knowledge of how LY289612 binds
remaining natural amino acid, asparagine, which serves
to the HIV protease suggested that a D-asparagine
as the P2 ligand. Of course modification of the aspar-
moiety at P2 would have a negative effect on binding
agine moiety could have a negative effect on the enzyme
affinity to the enzyme’s active site. Initially we decided
inhibition and antiviral properties of any new inhibitor.
to replace the asparagine moiety with a noncoded
For example, the Roche group systematically explored
L-amino acid. For example, we prepared a series of
the structural requirements for each subsite, P3-P1′, of
carboxamides represented by 1, a potent HIV-1 protease
their HIV-1 protease inhibitor and reported “at the P2
subsite no improvement over asparaginyl was found”.3
Several avenues of investigation were considered
including either replacement of the asparagine with a
noncoded L-amino acid or substitution of the natural
L-amino acid with the corresponding D-amino acid.9
† Medicinal Chemistry.
‡ Molecular Virology.
X Abstract published in Advance ACS Abstracts, November 15, 1995.
0022-2623/96/1839-0096$12.00/0 © 1996 American Chemical Society

HIV Protease Inhibitors That Use D-Amino Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 97
F igu r e 2. Evolution of the design concept.
finding. The lack of enzyme inhibitory activity dis-
played by the corresponding L-isomer further supported
the viability of this design concept. Several analogs
were prepared (vide infra) in an attempt to optimize the
nitrogen substituent (P2 ligand) prior to turning our
attention to the amino acid side chain (P3 ligand). Early
in our studies we concentrated on readily available
D-amino acids such as aspartic acid amides, serine-based
esters or ethers, and phenylalanine. None of these early
compounds exhibited enzyme inhibitory or antiviral
activity comparable to LY289612. We also investigated
several S-alkylated cysteine analogs and found that the
compound derived from N-acetyl-S-benzyl-D-cysteine,
13a (Figure 2), was a 45 nM inhibitor of HIV protease.
With the recognition that a sulfone can potentially act
as an amide isostere,13 we envisioned a D-cysteinesulfo-
nyl moiety that would more closely mimic the quinaldic
amide-asparagine moiety found in the Lilly, Roche, and
Monsanto14 inhibitors. Analog 15b, derived from N-
acetyl-S-quinolinylcysteine sulfone, appeared to be an
attractive target for synthesis, and thus we turned our
efforts in this direction (Figure 2).
F igu r e 1. Cartoon depicting binding of LY289612 to HIV
protease and proposed “role reversal” of the D-amino acid in
the S2-S3 region.
inhibitor which also exhibits potent antiviral activity
in vitro.10 Unfortunately no significant improvement
in oral bioavailability was found within this series.
The concept we wish to introduce herein is a hybrid
of the noncoded L-amino acid and D-amino acid replace-
ment ideas. We envisioned the design of a noncoded
D-amino acid which would mimic the quinaldic amide-
asparagine moiety found in our lead inhibitor. LY289612
binds to HIV-1 protease11 with the quinaldic amide
moiety fitting in the S3 pocket of the enzyme’s active
site, while the asparagine side chain binds to the S2
pocket as depicted in Figure 1. We postulated that
inversion of the amino acid stereochemistry would
require the substituted amino group to become the P2
ligand (R group in Figure 1), while the aromatic P3
ligand (R′ group in Figure 1) would be derived from the
side chain of the D-amino acid. The ultimate success of
this approach required the design of a relatively small
nitrogen substituent which was capable of H-bonding
(CONH2 mimic). As the amino acid side chain now
serves as the peptidomimetic’s backbone, it must mimic
the relatively large size and lipophilic nature of the
quinaldic amide moiety. In a preliminary communica-
tion, we demonstrated the successful replacement of
asparagine by appropriately substituted, commercially
available, D-aspartic acid and D-cysteine analogs wherein
the nitrogen was capped by either an acetyl or meth-
anesulfonyl group.12a We now report on our efforts to
expand our understanding of these structure-activity
relationships (SAR).
Ch em istr y
In order to test the D-amino acid concept quickly, we
searched for several commercially available, optically
pure, t-BOC-protected amino acids which contain an
aromatic moiety in the side chain. For example, we
selected N-t-BOC-D-aspartic acid â-benzyl ester as our
starting point. This material was coupled to amine 115
providing amide 2 in 87% yield.12a Treatment of 2 with
TFA gave rise to the corresponding free amine 3 as
shown in Scheme 1. Amine 3 proved to be a useful
intermediate which allowed us to explore a number of
potential mimics of the CONH2 moiety which binds to
the S2 pocket of the target enzyme. Thus, treatment of
3 with acetic anhydride gave the corresponding N-acetyl
analog 4. Acylation with propionyl chloride or butryl
chloride provided propionate 5 and butyrate 6, respec-
tively. The urea analog 7 was synthesized by condensa-
tion with trimethylsilyl isocyanate. Sulfonamide 8 was
obtained by treating amine 3 with methanesulfonyl
chloride.
Con cep t E volu t ion . The first compound we syn-
thesized12a in order to test the “D-amino acid concept”
was the benzyl N-acetyl-D-aspartate analog 4 (Scheme
1). While 4 proved to be more than 50-fold less potent
(85 vs 1.5 nM) than LY289612 as an HIV protease
inhibitor, we still considered this to be a remarkable
With the observation that cysteine-derived analogs
such as 13a were also HIV protease inhibitors, a general
route to optically pure S-alkylated D-cysteine analogs

98 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
J ungheim et al.
Sch em e 1a
To complete the synthesis of the target inhibitors, the
acids 10a -j were coupled to amine 115 (DCC, HOBt)
without any detectable racemization to give amides
12a -j in good yield (Scheme 3). Trifluoroacetic acid-
catalyzed removal of the t-BOC protecting group pro-
vided the corresponding free amines which were either
acylated (AcCl, Ac2O) or treated with methanesulfonyl
chloride to give the N-acetyl analogs 13b,c or the
sulfonamides 16a -j, respectively. Sulfide 13a was
obtained in one step by coupling amine 11 with N-
acetyl-S-benzyl-D-cysteine. Sulfoxides 14b and 17c-i
were obtained by treating the corresponding sulfides
with 1 equiv of MCPBA. Both diastereomers of sulfox-
ide 17f were isolated, while sulfoxides 14b and 17c-
e,g-i were obtained as single diastereomers of unde-
fined configuration at the sulfur center. Oxidation with
excess Oxone provided sulfones 15c and 18a ,c,d ,h ,j.
Alternatively, sulfones 15b and 18b,f,g were obtained
utilizing MCPBA as the oxidant. Sulfoxide 17e was
treated with MCPBA to provide sulfone 18e.
a
(a) TFA/CH2Cl2 provided 3 (R ) H); (b) compound 3 treated
with Ac2O/pyridine/CH2Cl2 provided 4 (R ) CH3CO), with EtCOCl/
Et3N/CH2Cl2 provided 5 (R ) EtCO), with n-PrCOCl/Et3N/CH2Cl2
provided 6 (R ) n-PrCO), with (CH3)3SiNCO/THF provided 7 (R
) CONH2), or with CH3SO2Cl/Et3N/CH2Cl2 provided 8 (R )
SO2CH3).
Sch em e 2a
We also developed a slightly more convergent ap-
proach to the target sulfones. As shown in Scheme 4,
the p-chlorophenyl-substituted acid 10k was oxidized
to sulfone 20 utilizing Oxone. The standard coupling
procedure (DCC, HOBt) with amine 11 gave rise to
amide 21. Finally, acid-catalyzed removal of the
t-BOC protecting group followed by treatment with
methanesulfonyl chloride provided target structure
18k . Attempts to convert aryl sulfone-substituted D-
amino acids such as 20 into the corresponding N-SO2-
CH3 analogs and then coupling with amine 11 led to
significant racemization at some point in the pro-
cess.
Compounds 13d and 15d were prepared as outlined
in Scheme 5. D,L-N-Acetyl-S-phenylcysteine (22) was
coupled to amine 11 in the usual fashion. The isomeric
compounds 13d and 23 were readily separated by flash
chromatography. The more polar isomer was assigned
structure 13d on the basis of its enzyme inhibitory
activity, while the less polar isomer 23 was inactive
against HIV protease. In all other instances where both
the D- and L-isomers have been unambiguously synthe-
sized, the D-isomers were active against HIV protease
while the L-isomers were found to be inactive.12a Sulfide
13d was converted to the corresponding sulfone 15d
upon treatment with oxone.
was required in order to elaborate on this SAR. To this
end, we recognized that the ring-opening reaction of
Vederas’ N-t-BOC-D-serine â-lactone (9)15 with a variety
of mercaptans would provide the desired D-amino acids
in a single step (Scheme 2). In practice the requisite
cysteine analogs 10b-i were obtained by adding the so-
dium salt of the appropriate arylmercaptan to â-lactone
9. Alternatively, acids 10j,k were prepared by thiolate
displacement of the tosylate 19,16 which also proceeded
without any apparent racemization (Scheme 4). Com-
pound 10a , R ) benzyl, is commercially available.
Sch em e 3a
a
(a) DCC/HOBt/THF; (b) TFA/CH2Cl2; (c) AcCl/CH2Cl2/Et3N; (d) CH3SO2Cl/CH2Cl2/Et3N; (e) Oxone/aqueous MeOH or MCPBA/CH2Cl2.
R substituents for a -k are as defined in Schemes 2 and 4.

HIV Protease Inhibitors That Use D-Amino Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 99
Sch em e 4a
a
(a) ArSNa/DMF; (b) LiOH/H2O/THF; (c) Oxone/H2O/MeOH; (d) 11/DCC/HOBt/THF; (e) TFA/CH2Cl2; (f) CH3SO2Cl/CH2Cl2/Et3N.
Ta ble 1. Potential Carboxamide Mimics
Sch em e 5a
IC50 (nM)
antiviral activityb
no.
R
enzyme inhibitiona
CEM
MT2
2
3
4
5
6
7
8
t-BOC
H
Ac
EtCO-
n-PrCO-
H2NCO-
Ms
>1000
>1000
85
73
323
51
5.4
5200
8700
9880
24 200
11 900
1270
22 400(1)
1090(1)
a
b
All entries are for a single determination. All entries are the
average of two determinations except where noted by a super-
scripted number in parentheses, performed at the Southern
Research Institute, Birmingham, AL.
commercially available D-amino acids which contained
an aryl moiety in the side chain were investigated and
generally gave poor results. However, the S-benzyl-D-
cysteine-substituted compound 13a was a comparable
enzyme inhibitor (45 nM) to the benzyl aspartates
(Table 2). The N-methanesulfonyl analog 16a was an
even more active enzyme inhibitor (14.7 nM), and
oxidation of the sulfide to the corresponding sulfone 18a
provided an improvement in antiviral activity as well
(IC50 ) 800 nM, CEM cells).
At this juncture we recognized that the S-quinolinyl
analogs 13b and 16b and their corresponding sulfones
15b and 18b represented, perhaps, optimal mimics of
the quinaldic amide moiety found in LY289612. Both
sulfides 13b and 16b were relatively weak enzyme
inhibitors, 14.7 and 60 nM, respectively, and 16b was
only a weak antiviral agent (IC50 ) 5.4 µM). We were
delighted to find that the corresponding sulfones 15b
(0.28 nM) and 18b (2.8 nM) were more potent enzyme
inhibitors than the sulfides and that the N-acetyl analog
a
(a) DCC/HOBt/THF; (b) Oxone/aqueous MeOH.
Resu lts a n d Discu ssion
Having established that the benzyl N-acetylaspartate
analog 4 was an 85 nM inhibitor of HIV protease, we
undertook a brief study of what other nitrogen substitu-
tions might effectively mimic the carboxamide P2 ligand.
The results are summarized in Table 1. Key intermedi-
ates in the synthesis of analogs, namely, the N-t-BOC
compound 2 and the free amine 3, were not active
against HIV protease. Increasing the chain length from
acetyl to propionyl, compound 4 vs 5, had little effect
on potency, but the N-butyryl analog 6 was significantly
less active (323 nM), indicating an apparent size restric-
tion for the nitrogen substituent. We anticipated that
a simple urea, 7, might effectively mimic a carboxamide
moiety, and a slight improvement over acetyl was seen
(51 vs 85 nM). Unfortunately none of these compounds
demonstrated useful levels of whole cell antiviral activ-
ity, as all were >5 µM inhibitors of viral replication
(Table 1). A significant increase in enzyme inhibitory
activity (5.4 nM) as well as in whole cell antiviral
activity (IC50 ) 1 µM) was observed with sulfonamide
analog 8.
15b exhibited potent antiviral activity as well (IC50
)
53 nM, CEM cells). Contrary to our observations with
aspartate-based analogs (4 vs 8), the N-acetyl-S-quino-
linyl-substituted compound 15b was much more active
than the corresponding N-methanesulfonyl-substituted
compound 18b.
At this point it seemed appropriate to concentrate on
optimization of the amino acid side chain (P3 ligand) and
to utilize the N-acetyl and N-methanesulfonyl groups
as reasonably diverse choices for the P2 ligand. Other
These exciting results prompted us to further expand
the S-arylcysteine SAR. As seen in Table 2, a variety
of compounds were tested, including mono- and bicyclic
aryl analogs, in an attempt to optimize enzyme inhibi-

100 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Ta ble 2. D-Cysteine Analogs
J ungheim et al.
18f were significantly less active enzyme inhibitors than
their quinoline counterparts 16b and 18b. Likewise,
phenyl-substituted compounds were less active, both as
enzyme inhibitors and as antiviral agents, than the
corresponding naphthyl analogs; compare 13c vs 13d ,
15c vs 15d , and 18c vs 18d . However, several 4-sub-
stituted phenyl analogs, 18g,j,k , were good enzyme
inhibitors, and each of these displayed respectable
antiviral activity as well (IC50s < 100 nM).
We also evaluated a number of sulfoxide analogs (17c-
i). In each instance only a single diastereomer was
obtained except for the pyridine analogs 17f,f′ where
both sulfoxides were produced under the oxidation
conditions employed. While there is an apparent 2-fold
difference in enzyme inhibition between sulfoxide iso-
mers 17f,f′, they both exhibit comparable antiviral
activity. The sulfoxides typically were about as active
or slightly less active than the corresponding sulfones;
thus we concentrated our effort on the sulfones, in order
to avoid the ambiguity presented by the potential for
having sulfoxide diastereomers. The 1-naphthylsulfi-
nyl-substituted compound 17e was the most potent
inhibitor of viral replication (IC50 ) 0.8 nM, CEM cells)
we found within this series of P2/P3 D-amino acid-
substituted HIV protease inhibitors.
While we were excited by the fact that several of these
novel inhibitors exhibited low-nanomolar IC50s in acute
viral infection assays, IC95s are probably better indica-
tors of a compound’s potential to perform in the clinical
setting. IC95s were determined for several of our most
potent analogs: 17c, 24 nM; 17e, 21 nM; 18c, 50 nM;
18e, 100 nM; 18k , 94 nM. HIV protease inhibitors with
antiviral IC95s in the 25-100 nM range are competitive,
in terms of whole cell activity, with compounds under-
going clinical evaluation such as Ro 31-8959 and MK-
639.
Or a l Bioa va ila bility. A rapid prescreen in rats was
developed to evaluate the potential oral absorption of
the newly synthesized HIV protease inhibitors. Com-
pounds were dissolved in an appropriate vehicle and
dosed orally to Harlan Sprague-Dawley rats. Plasma
was collected at several time points and assayed for HIV
protease inhibitory activity rather than parent drug
concentration. One cannot rule out the possibility that
the antiviral activity observed in plasma was caused in
part by the presence of active metabolites; however, this
assay method was useful for quickly assessing the
behavior of these compounds in animals. The com-
pounds tested were selected on the basis of their
antiviral activity as well as structural diversity consid-
erations. While most of the compounds tested (Table
3) were poorly absorbed, three compounds showed
modest absorption, the highly potent 2-naphthylsulfinyl-
substituted 17c as well as the weakly active N-meth-
yltetrazole-substituted 17i. The best absorption was
obtained with the moderately active (p-fluorophenyl)-
sulfinyl-substituted analog 17g which gave a peak
plasma concentration in excess of 2 µg/mL.
IC50 (nM)
antiviral activityb
enzyme
no.
R
n
R′ inhibitiona CEM
MT2
3120
CEM
13a PhCH2
0 Ac
0 Ac
0 Ac
0 Ac
1 Ac
2 Ac
2 Ac
2 Ac
0 Ms
0 Ms
0 Ms
0 Ms
0 Ms
45
2910
13b 2-quinolinyl
13c 2-naphthyl
13d Ph
14b 2-quinolinyl
15b 2-quinolinyl
15c 2-naphthyl
15d Ph
14.7
42
220
0.25
0.28
0.32
20
1130
1000(1)
5400 11 300
72
180
180
53
59
11(4)
31(3)
815
820
16a PhCH2
14.7
60
1650
5400
926(1)
16b 2-quinolinyl
16c 2-naphthyl
16d Ph
16e 1-naphthyl
16f 2-pyridyl
16g p-F-C6H4
16h p-CF3-C6H4
6440
800(3)
2750
1.8
44
530(3)
4370
270
1.2(2)
760
323
0 Ms 910
0 Ms
0 Ms 170
4.4
2130
2930
6680
1800
<0.5
100
2880
5910
9260
1910
4.3
500
6
16i N-Me-tetrazole 0 Ms
17.5
16
16j p-MeO-C6H4
17c 2-naphthyl
17d Ph
0 Ms
1 Ms
1 Ms
1 Ms
1 Ms
1 Ms
1 Ms
1 Ms
3.5(2)
6.7
0.8
474
1.9(2)
0.45
7.9
19.3
0.38
2.3
17e 1-naphthyl
17f 2-pyridyl
17f′ 2-pyridyl
17g p-F-C6H4
17h p-CF3-C6H4
<0.5
330
770
165
53
900
116
17i N-Me-tetrazole 1 Ms
2.1
19.4
2.8
0.3
5.7
0.44
22
0.77
2
5010
18a PhCH2
2 Ms
2 Ms
2 Ms
2 Ms
2 Ms
2 Ms
2 Ms
2 Ms
2 Ms
2 Ms
800
2060
<0.5
72
730(1)
18b 2-quinolinyl
18c 2-naphthyl
18d Ph
3030 5780
5
176
8.8
12
83
49
18e 1-naphthyl
18f 2-pyridyl
18g p-F-C6H4
18h p-CF3-C6H4
18j p-MeO-C6H4
18k p-Cl-C6H4
<0.5
59
204
54
440
450
150
24
32
646
107
16
2.4
0.34
138
a
All entries are for a single determination except where noted
b
with a superscripted number in parentheses. All entries are the
average of two determinations except where noted by a super-
scripted number in parentheses. Antiviral activity in the first two
columns was generated at the Southern Research Institute,
Birmingham, AL. Data in the third column were generated at
the Lilly Research Laboratories.
tory and antiviral activity. Sulfide analogs 13a -d and
16a -j were uniformly less active than their sulfoxide
or sulfone counterparts. The most active sulfide, the
1-naphthyl-substituted 16e, was a potent enzyme in-
hibitor (1.2 nM); however, its antiviral activity was a
disappointing 270-760 nM.
Alternatives to the 2-quinolinesulfonyl moiety were
explored such as 2-naphthylsulfonyl. In each instance
(15b vs 15c, 18b vs 18c) the naphthyl analogs exhibited
comparable or improved enzyme inhibitory activity
relative to the quinolines, and significantly improved
antiviral activity was obtained with the naphthyl ana-
logs as well. For example, the N-methanesulfonyl-2-
naphthylsulfonyl analog 18c was among the most potent
antiviral agents within the series (IC50 ) 12 nM, CEM
cells). It is interesting to note that the activity of the
1-naphthylsulfonyl analog 18e is indistinguishable from
that of the 2-naphthyl-substituted 18c.
Con clu sion s
A number of D-amino acids were screened for their
ability to act as mimics of the quinaldic amide-
asparagine moiety found in our lead inhibitor LY289612.
A brief SAR was developed in order to optimize the
nitrogen substituent on D-aspartate analogs, and the
N-methanesulfonyl-substituted compound 8 was found
Bicyclic aryl substituents appeared to make better P3
ligands than monocyclic aryl analogs. Pyridines 16f and

HIV Protease Inhibitors That Use D-Amino Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 101
Ta ble 3. Oral Bioavailability Prescreen
this novel approach, and additional studies will be
reported in due course.
Exp er im en ta l Section
Gen er a l P r oced u r e. All reactions were run under a
positive pressure of dry nitrogen. Fast atom bombardment
mass spectra (FABMS) were obtained on a VG ZAB-3 instru-
ment; field desorption mass spectra (FDMS) were obtained on
a VG 70SE instrument. NMR spectra were obtained on a GE
QE300 spectrometer. Optical rotations were obtained in
MeOH solution. Flash chromatography was carried out on E.
Merck Kieselgel 60 (230-400 mesh). The abbreviations THF,
DMF, DCC, HOBt, Ac, Ms, TFA, and MCPBA refer to
tetrahydrofuran, dimethylformamide, dicyclohexylcarbodiim-
ide, 1-hydroxybenzotriazole hydrate, acetyl, methanesulfonyl,
trifluoroacetic acid, and m-chloroperoxybenzoic acid, respec-
tively. Anhydrous THF, 99.9%, was purchased from Aldrich
and used directly.
no.
R
n
R′
Cmax (µg/mL)a
15c
17c
17e
17f
17g
17h
17i
18c
18d
18g
18h
18j
2-naphthyl
2-naphthyl
1-naphthyl
2-pyridyl
2
1
1
1
1
1
1
2
2
2
2
2
2
Ac
<0.1
0.33
<0.25
<0.2
2.2
<0.2
0.49
<0.1
<0.3
<0.3
<0.3
<0.3
<0.3
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
p-F-C6H4
p-CF3-C6H4
N-Me-tetrazole
2-naphthyl
Ph
p-F-C6H4
p-CF3-C6H4
p-MeO-C6H4
p-Cl-C6H4
Biologica l Meth od s. Protease inhibition assays17 and
whole cell antiviral testing18 have been described previ-
ously.
18k
a
Each compound was delivered orally to rats (40 mg/kg) (n )
2). Cmax is the maximum plasma concentration of HIV protease
inhibitory activity observed based on the potency of the parent
compound.
Oral bioavailability was determined as follows. Test com-
pounds were prepared for dosing in 100 g male, Harlan
Sprague-Dawley rats as follows: Compound was micronized
using a mortar and pestle and 20 mg transferred to a tare-
weighted, silanized glass vial (2 mL capacity); 2 mL of dosing
vehicle (10% acacia, 1% Tween 80 in water) was trickled down
the side of the vial, to prevent clumping, yielding a concentra-
tion of 10 mg/mL. The vial was capped, vortexed vigorously
for 30 s, and then sonicated in an ultrasonic water bath for 9
min. Alternate vortexing and sonicating was repeated twice.
A stir bar was placed in the vial and the emulsion left to stir
overnight on a magnetic stirplate.
After surgical implantation of a canula in the right jugular
vein, rats were allowed to recover for at least 48 h prior to
dose administration. Animals were fasted for 16-18 h prior
to dosing. Compound was given by oral gavage at a dose of
40 mg/kg. Vehicle control animals received ca. 0.4 mL of the
acacia/Tween vehicle. Typically two rats were given test
compound. Blood draws (0.2 mL) were taken via canula at 0
(predose), 0.5, 1, 2, and 4 h time points. Blood was im-
mediately transferred to a microtainer (Becton Dickson) and
placed on ice. Plasma was separated from cell fraction by
centrifugation. Plasma was stored at -70 °C until needed for
assay.
to be the most active. The best D-amino acids found to
date were S-arylcysteine analogs. The Vederas â-lac-
tone ring-opening procedure allowed for the rapid
synthesis of a variety of S-arylcysteines which were
elaborated into the proposed HIV protease inhibitors.
The majority of these compounds are potent HIV pro-
tease inhibitors (IC50 < 10 nM), and several of these
compounds possess potent antiviral activity, signifi-
cantly more potent than lead structure LY289612.
There is no readily apparent correlation between the
enzyme inhibitory activity and whole cell antiviral
activity; however, several trends are apparent. Potent
antiviral activity (IC50 < 500 nM) was only obtained
with the best enzyme inhibitors (IC50 < 10 nM), as seen
in Table 2. The sulfoxide and sulfone analogs tend to
exhibit better potency both as enzyme inhibitors and
as antivirals when compared to their sulfide counter-
parts. Perhaps these oxidized analogs serve as better
mimics of the quinaldic amide bond present in LY289612
or the peptide backbone found in the natural substrates.
Compounds containing bicyclic aryl substituents which
can serve as P3 ligands, naphthalene and quinoline, are
more active than the corresponding phenyl or pyridyl
analogs. Analogs with completely carbocyclic P3 aryl
ligands are typically more active than their heterocyclic
counterparts. Within the S-arylcysteine series of com-
pounds, NSO2Me-substituted compounds tended to be
more active than the NAc analogs, except for the
quinoline-containing compounds, e.g., 15b vs 18b.
Three compounds demonstrated measurable oral bio-
availability in an animal model. These findings have
significantly influenced our decision of which D-amino
acids to couple to alternate isosteres in an attempt to
find an HIV protease inhibitor which possesses both
potent antiviral activity and good oral bioavailability.
These studies will be the subject of a future report.
In summary, noncoded D-amino acids have been
designed which effectively replace the P2/P3 ligands of
the lead HIV-1 protease inhibitor LY289612 as evi-
denced by improved enzyme inhibitory and whole cell
antiviral activity. This “D-amino acid concept” may find
application in the design of peptidomimetic inhibitors
of other proteolytic enzymes. We continue to explore
Plasma samples were analyzed via
a high-throughput
fluorescence HPLC enzymatic assay which readily quantitates
HIV protease inhibitor activity in biological fluids. HIV
protease was incubated under optimal conditions (using ap-
propriate diluents) with FITC-substrate (N-biotin-Gly-Ser-Gln-
Asn-Tyr-Pro-Ile-Val-Gly-Lys(fluorescein isothiocyanate)-OH)
and either a known amount of test compound (standard curve)
or an unknown amount in plasma (sample analysis). Hydroly-
sis was allowed to procede for 5 h at 37 °C, and then the
reaction was stopped with 0.1% TFA. An aliquot of this
incubation mixture was injected onto a reverse-phase HPLC
column. Only two fluorescent peaks are produced. By resolv-
ing and quantifying the fluorescence of the hydrolyzed and
nonhydrolyzed FITC-substrate HPLC peaks, a percent hy-
drolysis is calculated for each injection (area of the hydrolyzed
substrate peak/total area). The percent of substrate hydrolysis
is inversely proportional to the amount of inhibitor in the
incubation.
Ten concentrations of test compound prepared in 2% plasma,
10% DMSO, and MES buffer, pH 5.5 (20 mM MES, 20 mM
NaCl, 0.2 mM EDTA, 1 mM DTT), were analyzed in duplicate
along with a buffer control. Standard curves were prepared
from
a fresh weighing of the test compound. From an
independent weighing, three concentration checks were pre-
pared and assayed in triplicate along with the above standard
curves. This defined the standard curve and validated the
accuracy and precision of the compound stocks.
Plasma samples obtained from compound-dosed rats were
prepared by making a 1:49 dilution of plasma with 10% DMSO
and MES buffer and analyzed via the HPLC assay described

102 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
J ungheim et al.
above. The concentrations of compound in plasma samples
were extrapolated from the standard curve.
0.15 mmol). The mixture was stirred at room temperature
for 30 min at which time an additional 0.035 mL of the
isocyanate was added, and stirring was continued overnight.
The mixture was diluted with EtOAc, washed with dilute
aqueous NaHCO3 solution and brine, dried (Na2SO4), and
concentrated in vacuo to give 40 mg, 68% yield, of the title
compound 7. 1H-NMR (CDCl3): δ 7.10-7.39 (m, 14H), 7.05
(d, J ) 8 Hz, 1H), 6.18 (s, 1H), 6.12 (d, J ) 8 Hz, 1H), 5.93 (br
s, 1H), 5.01 (s, 2H), 4.76 (s, 2H), 4.55 (m, 1H), 4.21 (m, 1H),
3.75 (m, 1H), 2.70-3.03 (m, 5H), 2.43 (dd, J ) 6, 12 Hz, 1H),
1.43 (s, 9H). Anal. (C33H40N4O6) C, H, N.
P r epar ation of (R)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth yl)-
a m in o]ca r b on yl]p h en yl]-2-h yd r oxy-1-(p h en ylm et h yl)-
p r op yl]-2-[(m eth ylsu lfon yl)a m in o]-4-oxo-4-(ben zyloxy)-
bu ta n a m id e (8). To a 0 °C solution of amine 3 (0.75 g, 0.97
mmol, added as a bis-TFA salt) in CH2Cl2 (5 mL) were added
Et3N (0.4 mL, 2.9 mmol) and methanesulfonyl chloride (0.075
mL, 0.97 mmol). The mixture was stirred at 0 °C for 1 h and
then at room temperature for 1 h. An additional 0.02 mL of
both methanesulfonyl chloride and Et3N was added and the
mixture stirred for 1 h. The reaction mixture was poured into
cold 1 N HCl solution and extracted with additional CH2Cl2.
The organic extracts were washed with brine, dried (Na2SO4),
and concentrated in vacuo to give 0.6 g of a beige solid. Flash
chromatography (2% MeOH/CH2Cl2) gave 0.33 g, 54% yield,
of the title compound 8 as a white solid. 1H-NMR (CDCl3): δ
7.06-7.41 (m, 15H), 6.10 (s, 1H), 5.99 (d, J ) 6 Hz, 1H), 5.80
(d, J ) 8 Hz, 1H), 5.05 (s, 2H), 4.38 (m, 1H), 4.13 (m, 1H),
3.80 (m, 1H), 2.63-3.10 (m, 5H), 2.76 (s, 3H), 2.42 (dd, J ) 6,
12 Hz, 1H), 1.45 (s, 9H). Anal. (C33H41N3O7S) C,H,N.
P r epar ation of (R)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth yl)-
a m in o]ca r b on yl]p h en yl]-2-h yd r oxy-1-(p h en ylm et h yl)-
p r op yl]-2-a m in o-4-oxo-4-(ben zyloxy)bu ta n a m id e (3). To
a solution of (R)-N-(1S,2R)-[3-[2-[[(1,1-dimethylethyl)amino]-
carbonyl]phenyl]-2-hydroxy-1-(phenylmethyl)propyl]-2-[(tert-
butoxycarbonyl)amino]-4-oxo-4-(benzoyloxy)butanamide (2)12a
(0.91 g, 1.4 mmol) in CH2Cl2 (5 mL) was added TFA (3 mL).
The mixture was stirred at room temperature for 3 h at which
time TLC indicated the starting material had been consumed.
The volatiles were removed in vacuo, and the residue was
taken up in EtOAc. The EtOAc solution was washed with 5%
aqueous NH4OH solution, and the aqueous phase was then
back-extracted with additional EtOAc. The combined organic
extracts were washed with brine, dried (Na2SO4), and concen-
trated in vacuo to give 0.72 g of the amine as a white solid.
Flash chromatography (4% MeOH/CH2Cl2 and then 6% MeOH/
CH2Cl2) gave 0.56 g, 73% yield, of the title compound 3 as a
white solid. 1H-NMR (CDCl3): δ 7.57 (d, J ) 9.1 Hz, 1H),
7.40-7.15 (m, 14H), 6.01 (br s, 1H), 5.07 (d, J ) 1.2 Hz, 2H),
4.25 (m, 1H), 3.77 (m, 1H), 3.55 (dd, J ) 3.9, 3.9 Hz, 1H), 3.12-
2.75 (m, 5H), 2.58 (dd, J ) 8.1, 8.1 Hz, 1H), 1.42 (s, 9H). [R]22
+2.8°. Anal. (C32H39N3O5) C,H,N.
D
P r ep a r a tion of (R)-N-(1S,2R)-[3-[2-[[1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-(a cetoxya m in o)-4-oxo-4-(ben zyloxy)bu ta n a m -
id e (4). To a solution of amine 3 (1.35 g, 2.47 mmol) in CH2Cl2
(5 mL) were added pyridine (0.42 mL, 5.2 mmol) and acetic
anhydride (0.26 mL, 2.72 mmol). The mixture was stirred at
room temperature for 2 h and then diluted with additional
CH2Cl2, washed with cold 0.1 N HCl solution, dried (Na2SO4),
and concentrated in vacuo. Flash chromatography (step
gradient from 3% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) gave
0.6 g, 40% yield, of the title compound 4 as a white solid. 1H-
NMR (CDCl3): δ 7.10-7.40 (m, 14H), 6.90 (d, J ) 8 Hz, 1H),
6.70 (d, J ) 6 Hz, 1H), 6.10 (s, 1H), 5.08 (s, 2H), 4.68 (m, 1H),
4.26 (m, 1H), 3.75 (m, 1H), 2.74-3.10 (m, 5H), 2.33 (d, J ) 6
Hz, 1H), 1.90 (s, 3H), 1.45 (s, 9H). FABMS (M + 1): calcd,
588.3073; found, 588.3051.
P r epar ation of (R)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth yl)-
a m in o]ca r b on yl]p h en yl]-2-h yd r oxy-1-(p h en ylm et h yl)-
p r op yl]-2-[(et h ylca r b on yl)a m in o]-4-oxo-4-(b en zyloxy)-
bu ta n a m id e (5). To a solution of amine 3 (0.15 g, 0.27 mmol)
in CH2Cl2 (4 mL) were added Et3N (0.076 mL, 0.55 mmol) and
propionyl chloride (0.024 mL, 0.27 mmol). The mixture was
stirred at room temperature for 30 min and then diluted with
additional CH2Cl2, washed with cold 1 N HCl solution, dried
(Na2SO4), and concentrated in vacuo to give 0.17 g, 100% yield,
on the title compound 5 as a white solid. 1H-NMR (CDCl3): δ
7.40-7.11 (m, 14H), 6.87 (d, J ) 9.3 Hz, 1H), 6.64 (d, J ) 7.8
Hz, 1H), 6.05 (s, 1H), 5.99 (d, J ) 5.5 Hz, 1H), 5.07 (d, J ) 2.1
Hz, 2H), 4.69 (m, 1H), 4.28 (m, 1H), 3.73 (m, 1H), 3.10-2.72
(m, 5H), 2.33 (dd, J ) 6.8, 10.4 Hz, 1H), 2.15 (q, J ) 7.6 Hz,
2H), 1.47 (s, 9H), 1.06 (t, J ) 7.6 Hz, 3H). Anal. (C35H43N3O6)
C,H,N.
P r epar ation of (R)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth yl)-
a m in o]ca r b on yl]p h en yl]-2-h yd r oxy-1-(p h en ylm et h yl)-
pr opyl]-2-[(n -pr opylcar bon yl)am in o]-4-oxo-4-(ben zyloxy)-
bu ta n a m id e (6). To a solution of amine 3 (0.16 g, 0.29 mmol)
in CH2Cl2 (4 mL) were added Et3N (0.081 mL, 0.58 mmol) and
n-butyryl chloride (0.03 mL, 0.29 mmol). The mixture was
stirred at room temperature for 15 min and then diluted with
additional CH2Cl2, washed with cold 1 N HCl solution, dried
(Na2SO4), and concentrated in vacuo to give 0.18 g, 100% yield,
of the title compound 6 as a white solid. 1H-NMR (CDCl3): δ
7.40-7.12 (m, 14H), 6.88 (d, J ) 9.3 Hz, 1H), 6.65 (d, J ) 7.8
Hz, 1H), 6.11 (s, 1H), 5.99 (d, J ) 5.5 Hz, 1H), 5.07 (d, J ) 2.3
Hz, 2H), 4.69 (m, 1H), 4.25 (m, 1H), 3.75 (m, 1H), 3.10-2.72
(m, 5H), 2.33 (dd, J ) 6.8, 10.4 Hz, 1H), 2.07 (t, J ) 6.9 Hz,
2H), 1.55 (q, J ) 7.6 Hz, 2H), 1.46 (s, 9H), 0.86 (t, J ) 7.4 hz,
3H). Anal. (C36H45N3O6) C,H,N.
P r ep a r a tion of (S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
(2-qu in olin ylth io)p r op ion ic Acid (10b). Gen er a l P r oce-
d u r e for th e P r ep a r a tion of S-Ar ylcystein es. To a solu-
tion of 2-quinolinethiol (1.9 g, 11.8 mmol) in THF (15 mL) was
added NaH (0.47 g, 11.8 mmol, 60% oil dispersion), and the
resulting mixture was stirred at room temperature for 10 min.
A solution of N-t-BOC-D-serine â-lactone (9)15 (2.0 g, 10.7
mmol) in THF (15 mL) was added dropwise over 10 min; then
stirring was continued at room temperature for 2 h. The
reaction mixture was acidified by adding 10% aqueous NaH-
SO4 solution and then extracted with ethyl acetate (EtOAc, 2
× 100 mL). The organic extracts were dried (Na2SO4), filtered,
and concentrated in vacuo to give a yellow foam. Flash
chromatography eluting first with 2% MeOH/CH2Cl2 to remove
any thiol and then increasing the polarity to 10% MeOH/0.1%
AcOH/CH2Cl2 gave 2.0 g, 54% yield, of 10b as a yellow solid.
1H-NMR (CDCl3): δ 8.05 (d, J ) 8.5 Hz, 1H), 7.99 (d, J ) 7.3
Hz, 1H), 7.80-7.63 (m, 3H), 7.50 (t, J ) 7.3 Hz, 1H), 7.32 (d,
J ) 8.7 Hz, 1H), 4.60 (m, 1H), 3.85 (dd, J ) 3.1, 15.3 Hz, 1H),
3.44 (dd, J ) 5.7, 15.3 Hz, 1H), 1.42 (s, 9H). Anal. (C17H20
N2O4S) C,H,N.
-
P r ep a r a tion of (S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
(2-n a p h th ylth io)p r op ion ic Acid (10c). As above, naph-
thalenethiol (1.9 g, 11.9 mmol) in THF (15 mL) was treated
with NaH (0.47 g, 11.8 mmol, 60% oil dispersion) followed by
addition of lactone 9 (2.0 g, 10.7 mmol) in THF (15 mL) to
give after flash chromatography (2% MeOH/CH2Cl2 followed
by 5% MeOH/1% AcOH/CH2Cl2) 3.08 g, 84% yield, of 10c as a
white foam. 1H-NMR (CDCl3): δ 7.85 (s, 1H), 7.74 (m, 3H),
7.42 (m, 3H), 5.47 (d, J ) 7.0 Hz, 1H), 4.62 (m, 1H), 3.49 (m,
2H), 1.38 (s, 9H).
P r ep a r a tion of (S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
(p h en ylth io)p r op ion ic Acid (10d ). As above, thiophenol (1
mL, 9.7 mmol) in THF (15 mL) was treated with NaH (0.39 g,
10.5 mmol, 60% oil dispersion) followed by addition of lactone
9 (1.7 g, 9.2 mmol) in THF (15 mL) to give after flash
chromatography (2% MeOH/CH2Cl2 followed by 10% MeOH/
1% AcOH/CH2Cl2) 1.9 g, 61% yield, of 10d as a colorless oil.
1H-NMR (CDCl3): δ 7.39 (m, 2H), 7.20 (m, 3H), 5.48 (d, J )
7.0 Hz, 1H), 4.58 (m, 1H), 3.39 (m, 2H), 1.38 (s, 9H).
P r ep a r a tion of (S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
(1-n a p h th ylth io)p r op ion ic Acid (10e). As above, 1-naph-
thalenethiol (0.9 g, 5.6 mmol) in THF (5 mL) was treated with
NaH (0.22 g, 5.5 mmol, 60% oil dispersion) followed by addition
of lactone 9 (1 g, 5.3 mmol) in THF (5 mL) to give after flash
chromatography (2% MeOH/CH2Cl2 followed by 10% MeOH/
1% AcOH/CH2Cl2) 1.3 g, 70% yield, of 10e as a white solid.
P r epar ation of (R)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth yl)-
a m in o]ca r b on yl]p h en yl]-2-h yd r oxy-1-(p h en ylm et h yl)-
p r op yl]-2-(ca r ba m oyla m in o)-4-oxo-4-(ben zyloxy)bu ta n -
a m id e (7). To a solution of amine 3 (0.055 g, 0.1 mmol) in
THF (2 mL) was added trimethylsilyl isocyanate (0.019 mL,

HIV Protease Inhibitors That Use D-Amino Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 103
1H-NMR (CDCl3): δ 8.45 (d, J ) 8.0 Hz, 1H), 7.88-7.39 (m,
7H), 5.26 (d, J ) 2.5 Hz, 1H), 4.50 (m, 1H), 3.42 (m, 2H), 1.40
(s, 9H). Anal. (C18H21NO4S) C,H,N.
worked up as above to give (S)-2-[(tert-butoxycarbonyl)amino]-
3-[(p-chlorophenyl)thio]propionic acid (10k ). The acid 10k (7.1
mmol theoretical) was dissolved in MeOH (40 mL) and cooled
to 0 °C. A solution of Oxone (5.26 g, 17 mmol equiv) in water
(30 mL) was added, and the mixture was allowed to warm
slowly to room temperature overnight. The methanol was
removed in vacuo and the residue extracted several times
with EtOAc. The organic extracts were washed with brine,
dried (MgSO4), and concentrated in vacuo to give 2.1 g, 81%
yield, of the title compound 20 as a white foam. Material
was used directly without further purification. 1H-NMR
(CDCl3): δ 8.1 (br s, 1H), 7.85 (d, J ) 9 Hz, 2H), 7.54 (d, J )
9 Hz, 2H), 5.57 (br d, J ) 7 Hz, 1H), 4.64 (m, 1H), 3.83 (t, J )
P r ep a r a tion of (S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
(2-p yr id ylth io)p r op ion ic Acid (10f). As above, 2-pyridi-
nethiol (1 g, 9 mmol) in THF (8 mL) was treated with NaH
(0.35 g, 8.8 mmol, 60% oil dispersion) followed by addition of
lactone 9 (1.5 g, 8 mmol) in THF (8 mL) to give after flash
chromatography (2% MeOH/CH2Cl2 followed by 5% MeOH/1%
AcOH/CH2Cl2) 2.4 g, 100% yield, of 10f as a yellowish-tinted
solid. 1H-NMR (CDCl3): δ 8.42 (d, J ) 4.8 Hz, 1H), 7.66 (t, J
) 7.3 Hz, 1H), 7.36 (d, J ) 8.1 Hz, 1H), 7.18 (t, J ) 5.7 Hz,
1H), 6.62 (br s, 1H), 4.58 (br s, 1H), 3.78 (dd, J ) 3.5, 15.1 Hz,
1H), 3.34 (dd, J ) 5.4, 15.1 Hz, 1H), 1.41 (s, 9H).
5 Hz, 2H), 1.39 (s, 9H). [R]22 +8.19°. Anal. (C14H18ClNO6S)
D
C,H,N.
P r ep a r a tion of (S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
[(p-flu or op h en yl)th io]p r op ion ic Acid (10g). As above,
p-fluorothiophenol (1.2 mL, 11.2 mmol) in THF (10 mL) was
treated with NaH (0.45 g, 11.2 mmol, 60% oil dispersion)
followed by addition of lactone 9 (2 g, 10.7 mmol) in THF (10
mL) to give after flash chromatography (2% MeOH/CH2Cl2
followed by 10% MeOH/0.2% AcOH/CH2Cl2) 2.4 g, 71% yield,
of 10g as a white solid. 1H-NMR (CDCl3): δ 7.40 (m, 2H),
6.96 (m, 2H), 5.33 (d, J ) 7.0 Hz, 1H), 4.43 (m, 1H), 3.30 (m,
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(ter t-b u t oxyca r b on yl)a m in o]-3-(b en zylt h io)-
p r op a n a m id e (12a ). Gen er a l P r oced u r e for Cou p lin g
D-Am in o Acid s to Am in e Isoster e 11. N-t-BOC-S-benzyl-
D-cysteine (10a ) (0.5 g, 1.6 mmol; purchased from Bachem),
amino alcohol 115 (0.55 g, 1.6 mmol), and HOBt (0.22 g, 1.6
mmol) were dissolved in THF (5 mL) and DMF (1 mL). The
mixture was cooled to 0 °C, and solid DCC (0.33 g, 1.6 mmol)
was added. Stirring was continued at 0 °C for 2 h and then
at room temperature overnight. The precipitate which formed
was removed by filtration and the filter cake washed with
EtOAc. The filtrate was diluted with additional EtOAc,
washed with saturated aqueous NaHCO3, water, 5% aqueous
citric acid, and brine, dried (Na2SO4), and concentrated in
vacuo to give 1 g of crude coupling product as a white solid.
Flash chromatography (2% MeOH/CH2Cl2) gave 0.74 g, 73%
yield, of the title compound 12a as a white solid. 1H-NMR
(CDCl3): δ 7.40-7.13 (m, 14H), 6.79 (d, J ) 9.0 Hz, 1H), 6.24
(s, 1H), 5.35 (d, J ) 7.0 Hz, 1H), 4.30 (m, 1H), 4.18 (m, 1H),
3.75 (m, 1H), 3.62 (s, 2H), 3.03-2.32 (m, 7H), 1.44 (s, 9H), 1.41
(s, 9H). FDMS: M + 1, 634.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(ter t-bu toxyca r bon yl)a m in o]-3-(2-qu in olin yl-
th io)p r op a n a m id e (12b). Acid 10b (1.8 g, 5.2 mmol), amine
11 (1.8 g, 5.3 mmol), and HOBt (0.7 g, 5.12 mmol) in THF (15
mL) and DMF (2 mL) were treated with DCC (1.1 g, 5.3 mmol)
and then worked up as above. Flash chromatography (2%
MeOH/CH2Cl2) followed by a second flash chromatography
(35% EtOAc/toluene) gave 1.8 g, 51% yield, of the title
compound 12b as a white solid. 1H-NMR (CDCl3): δ 8.04 (d,
J ) 8 Hz, 1H), 7.90 (d, J ) 9 Hz, 1H), 7.70 (m, 2H), 7.46 (t, J
) 7 Hz, 1H), 7.10-7.38 (m, 10H), 6.85 (d, J ) 9 Hz, 1H), 6.02
(br s, 2H), 4.52 (q, J ) 5 Hz, 1H), 4.30 (m, 1H), 3.65 (m, 1H),
3.57 (d, J ) 4 Hz, 2H), 2.95 (m, 4H), 1.45 (s, 9H), 1.40 (s, 9H).
FDMS: M+, 670.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(ter t-b u t oxyca r b on yl)a m in o]-3-(2-n a p h t h yl-
th io)p r op a n a m id e (12c). Acid 10c (0.38 g, 1.1 mmol), amine
11 (0.37 g, 1.1 mmol), and HOBt (0.15 g, 1.1 mmol) in THF (5
mL) and DMF (1 mL) were treated with DCC (0.22 g, 1.1
mmol) and then worked up as above. Flash chromatography
(2.5% MeOH/CH2Cl2) gave 0.48 g, 66% yield, of the title
compound 12c as a white solid. 1H-NMR (CDCl3): δ 7.75 (m,
4H), 7.50-7.02 (m, 12H), 6.85 (d, J ) 9.3 Hz, 1H), 6.25 (s,
1H), 5.44 (d, J ) 7.6 Hz, 1H), 4.28 (m, 2H), 3.75 (m, 1H), 3.20
(m, 2H), 3.03-2.70 (m, 5H), 1.44 (s, 9H), 1.35 (s, 9H). Anal.
(C39H47N3O5S) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(ter t-bu toxyca r bon yl)a m in o]-3-(p h en ylth io)-
p r op a n a m id e (12d ). Acid 10d (1.9 g, 5.7 mmol), amine 11
(2.0 g, 5.9 mmol), and HOBt (0.8 g, 5.9 mmol) in THF (15 mL)
and DMF (2 mL) were treated with DCC (1.2 g, 5.8 mmol) and
then worked up as above. Flash chromatography (2.5%
MeOH/CH2Cl2) gave 2.5 g, 69% yield, of the title compound
12d as a white solid. 1H-NMR (CDCl3): δ 7.40-7.15 (m, 14H),
6.55 (d, J ) 9.0 Hz, 1H), 5.95 (s, 1H), 5.18 (br s, 1H), 4.30 (m,
1H), 4.15 (m, 1H), 3.73 (m, 1H), 3.10-2.70 (m, 6H), 1.44 (s,
9H), 1.40 (s, 9H). Anal. (C35H45N3O5S) C,H,N.
2H), 1.40 (s, 9H). [R]22 + 17.03°.
D
P r ep a r a tion of (S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
[[p-(tr iflu or om eth yl)p h en yl]th io]p r op ion ic Acid (10h ).
As above, [p-(trifluoromethyl)phenyl]thiophenol (1 g, 5.6 mmol)
in THF (5 mL) was treated with NaH (0.24 g, 5.9 mmol, 60%
oil dispersion) followed by addition of lactone 9 (1 g, 5.3 mmol)
in THF (5 mL) to give after flash chromatography (2% MeOH/
CH2Cl2 followed by 10% MeOH/1% AcOH/CH2Cl2) 1.9 g, 95%
yield, of 10h as a white solid. 1H-NMR (CDCl3): δ 7.50-7.10
(m, 4H), 5.40 (m, 1H), 4.58 (m, 1H), 3.42 (m, 2H), 1.39 (s, 9H).
P r ep a r a tion of (S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
[(1-N-m eth yltetr a zol-5-yl)th io]p r op ion ic Acid (10i). To
a solution of 5-mercapto-1-methyltetrazole sodium salt (0.77
g, 5.6 mmol; Aldrich) in THF (9 mL) was added a solution of
lactone 9 (1 g, 5.3 mmol) in THF (5 mL), and the mixture was
worked up as above to give after flash chromatography (10%
MeOH/0.2% AcOH/CH2Cl2) 1 g, 63% yield, of 10i as a white
solid. 1H-NMR (CDCl3): δ 6.1 (br s, 1H), 4.50 (m, 1H), 3.81
(s, 3H), overlapping 3.80 (m, 1H), 3.58 (m, 1H), 1.36 (s, 9H).
P r ep a r a tion of (S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
[(p-m eth oxyp h en yl)th io]p r op ion ic Acid (10j). To a 0 °C
slurry of NaH (0.283 g, 7.07 mmol) in DMF (7 mL) was added
p-methoxythiophenol (0.96 mL, 7.8 mmol), and the resulting
solution was stirred at 0 °C for 20 min. A solution of tosylate
1916 (2.64 g, 7.07 mmol) in DMF (13 mL) was added, and
stirring was continued at 0 °C for 2 h. The reaction mixture
was diluted with Et2O, washed with water, saturated aqueous
K2CO3 solution, and brine, and then dried (Na2SO4) and
concentrated in vacuo to give an oil. Flash chromatography
(30% EtOAc/hexanes) gave 2.17 g, 90% yield, of (S)-methyl
2-[(tert-butoxycarbonyl)amino]-3-[(p-methoxyphenyl)thio]pro-
piolate. [R]22 +20.60°. Anal. C,H,N.
D
The ester (2.17 g, 6.07 mmol) was dissolved in dioxane (15
mL), and 0.5 M aqueous LiOH (14.6 mL) was added. The
mixture was stirred at room temperature for 8 h, and then an
additional 2 mL of 0.5 M aqueous LiOH was added and stirring
continued to an additional 16 h. The dioxane was removed in
vacuo and the residue partitioned between EtOAc and 1 N
HCl. The organic phase was washed with brine, dried
(MgSO4), and concentrated in vacuo to give 1.97 g, 99% yield,
of the title acid 10j as a white powder. 1H-NMR (CDCl3): δ
7.4 (d, J ) 9 Hz, 2H), 6.83 (d, J ) 9 Hz, 2H), 5.27 (br s, 1H),
4.45 (m, 1H), 3.78 (s, 3H), 3.25 (m, 2H), 1.41 (s, 3H). [R]22
38.18°. Anal. (C15H21NO5S) C,H,N.
+
D
P r ep a r a tion of (S)-2-[(ter t-Bu toxyca r bon yl)a m in o]-3-
[(p-ch lor op h en yl)su lfon yl]p r op ion ic Acid (20). As above,
NaH (0.285 g, 7.01 mmol) in DMF (10 mL) was treated with
p-chlorothiophenol (1.08 g, 7.5 mmol) and then with a solution
of tosylate 1916 (2.65 g, 7.1 mmol) in DMF (10 mL) which gave
after workup 2.51 g, 100% yield, of (S)-methyl 2-[(tert-butoxy-
carbonyl)amino]-3-[(p-chlorophenyl)thio]propiolate as a waxy
solid which was used without purification.
The ester (7.1 mmol theoretical) in dioxane (20 mL) was
treated with 0.5 M aqueous LiOH (24 mL) for 22 h and then

104 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
J ungheim et al.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(ter t-b u t oxyca r b on yl)a m in o]-3-(1-n a p h t h yl-
th io)p r op a n a m id e (12e). Acid 10e (1.2 g, 3.5 mmol), amine
11 (1.2 g, 3.5 mmol), and HOBt (0.47 g, 3.5 mmol) in THF (10
mL) and DMF (1.5 mL) were treated with DCC (0.71 g, 3.5
mmol) and then worked up as above. Flash chromatography
(2% MeOH/CH2Cl2 and then 3% MeOH/CH2Cl2) gave 1.8 g,
78% yield, of the title compound 12e as a white solid. 1H-
NMR (CDCl3): δ 8.35 (d, J ) 8.0 Hz, 1H), 7.90-7.10 (m, 16H),
6.50 (m, 1H), 5.95 (br s, 1H), 5.18 (m, 1H), 4.32 (m, 1H), 4.18
(m, 1H), 3.72 (m, 1H), 3.20-2.75 (m, 6H), 1.45 (s, 9H), 1.39 (s,
9H). FDMS: M+, 669.
4.08 (m, 1H), 3.78 (s, 3H), 3.74 (m, 1H), 3.1-2.7 (m, 5H), 1.48
(s, 9H), 1.40 (s, 9H).
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(ter t-bu toxycar bon yl)am in o]-3-[(p-ch lor oph en -
yl)su lfon yl]p r op a n a m id e (21). Acid 20 (0.4 g, 1.1 mmol),
amine 11 (0.37 g, 1.1 mmol), and HOBt (0.15 g, 1.1 mmol) in
THF (4 mL) were treated with DCC (0.23 g, 1.1 mmol) and
then worked up as above. Flash chromatography (2.5%
MeOH/CH2Cl2) gave 0.58 g, 77% yield, of the title compound
21 as a white solid. 1H-NMR (CDCl3): δ 7.78 (d, J ) 8.0 Hz,
2H), 7.49 (d, J ) 8.0 Hz, 2H), 7.38-7.10 (m, 9H), 6.32 (br s,
1H), 5.88 (d, J ) 7.0 Hz, 1H), 5.63 (d, J ) 9.0 Hz, 1H), 4.41
(m, 1H), 4.21 (m, 1H), 3.75 (m, 1H), 3.39 (m, 2H), 3.03-2.75
(m, 4H), 1.43 (s, 9H), 1.39 (s, 9H). FDMS: M+, 686.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-(a cet oxya m in o)-3-(p h en ylt h io)p r op a n a m id e
(13d ). Acid 22 (0.2 g, 0.83 mmol; purchased from TCl), amine
11 (0.28 g, 0.83 mmol), and HOBt (0.11 g, 0.83 mmol) in THF
(5 mL) and DMF (1 mL) were treated with DCC (0.17 g, 0.83
mmol) and then worked up as above. Flash chromatography
(step gradient of 1.5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2)
gave, as the more polar isomer on TLC (5% MeOH/CH2Cl2),
0.13 g, 27% yield, of the title compound 13d as a white solid.
1H-NMR (CDCl3): δ 7.40-7.13 (m, 14H), 6.83 (d, J ) 9.2 Hz,
1H), 6.36 (d, J ) 7.5 Hz, 1H), 6.10 (s, 1H), 4.45 (m, 1H), 4.31
(m, 1H), 3.75 (m, 1H), 3.10-2.70 (m, 6H), 1.83 (s, 3H), 1.45 (s,
9H). Anal. (C32H39N3O4S) C,H,N.
The less polar isomer 23, 0.13 g, 27% yield, was also
obtained as a white solid. Anal. (C32H39N3O4S) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-(a cetoxya m in o)-3-(2-qu in olin ylth io)p r op a n a m -
id e (13b). To a solution of protected amine 12b (1.8 g, 2.7
mmol) in CH2Cl2 (6 mL) was added TFA (6 mL), and the
resulting solution was stirred at room temperature for 1 h;
then the volatiles were removed in vacuo. The residue was
taken up in EtOAc, washed with 5% aqueous NH4OH solution
and brine, dried (Na2SO4), and concentrated in vacuo to give
1.5 g of the amine as a white solid. Flash chromatography
(step gradient of 3% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) on
0.5 g of this material gave 0.43 g, 84% yield, of the free amine
as a white solid. Anal. (C33H38N4O3S) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(ter t-bu toxycar bon yl)am in o]-3-(2-pyr idylth io)-
p r op a n a m id e (12f). Acid 10f (0.88 g, 3 mmol), amine 11 (1.0
g, 3 mmol), and HOBt (0.4 g, 3 mmol) in THF (10 mL) and
DMF (1.5 mL) were treated with DCC (0.61 g, 3 mmol) and
then worked up as above. Flash chromatography (2% MeOH/
CH2Cl2 and then 3% MeOH/CH2Cl2) gave 1.4 g, 78% yield, of
the title compound 12f as a white solid. 1H-NMR (CDCl3): δ
8.50 (d, J ) 7.0 Hz, 1H), 7.40-7.10 (m, 12H), 6.40 (m, 1H),
6.10 (m, 1H), 5.90 (br s, 1H), 4.40 (m, 2H), 3.80 (m, 1H), 3.20-
2.80 (m, 6H), 1.48 (s, 9H), 1.38 (s, 9H). FDMS: M + 1, 621.
[R]22 +3.80°.
D
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(ter t-bu toxycar bon yl)am in o]-3-[(p-flu or oph en -
yl)th io]p r op a n a m id e (12g). Acid 10g (1.1 g, 3.5 mmol),
amine 11 (1.2 g, 3.5 mmol), and HOBt (0.47 g, 3.5 mmol) in
THF (10 mL) and DMF (1.5 mL) were treated with DCC (0.72
g, 3.5 mmol) and then worked up as above. Flash chroma-
tography (3% MeOH/CH2Cl2) gave 1.7 g, 77% yield, of the title
compound 12g as a white solid. 1H-NMR (CDCl3): δ 7.40-
7.13 (m, 10H), 6.96 (m, 3H), 6.60 (d, J ) 9.0 Hz, 1H), 5.95 (s,
1H), 5.19 (d, J ) 7.0 Hz, 1H), 4.28 (m, 1H), 4.07 (m, 1H), 3.72
(m, 1H), 3.10-2.70 (m, 6H), 1.44 (s, 9H), 1.40 (s, 9H). Anal.
(C35H44FN3O5S) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(ter t-bu toxyca r bon yl)a m in o]-3-[[p-(tr iflu or o-
m eth yl)p h en yl]th io]p r op a n a m id e (12h ). Acid 10h (1 g,
2.7 mmol), amine 11 (0.93 g, 2.7 mmol), and HOBt (0.37 g,
2.7 mmol) in THF (8 mL) and DMF (1 mL) were treated
with DCC (0.56 g, 2.7 mmol) and then worked up as above.
Flash chromatography (2% MeOH/CH2Cl2) gave 1.5 g, 79%
yield, of the title compound 12h as a white solid. 1H-NMR
(CDCl3): δ 7.50 (d, J ) 8.0 Hz, 2H), 7.39 (d, J ) 8.0 Hz, 2H),
7.36-7.10 (m, 9H), 6.58 (d, J ) 9.0 Hz, 1H), 5.96 (br s, 1H),
5.20 (m, 1H), 4.34 (m, 1H), 4.19 (m, 1H), 3.75 (m, 1H), 3.10-
The amine (0.36 g, 0.63 mmol) was dissolved in CH2Cl2 (4
mL), and Et3N (0.175 mL, 1.26 mmol) was added followed by
acetyl chloride (0.045 mL, 0.63 mmol) and the resulting
solution stirred at room temperature for 30 min. The mixture
was diluted with CH2Cl2, washed with cold 1 N HCl solution,
dried (Na2SO4), and concentrated in vacuo. Flash chromatog-
raphy (3% MeOH/CH2Cl2) gave 0.35 g, 90% yield, of the title
N-acetyl compound 13b as a white solid. 1H-NMR (CDCl3):
δ 8.00 (d, J ) 7.0 Hz, 1H), 7.55 (m, 2H), 7.51 (m, 1H), 7.40-
7.14 (m, 12H), 6.15 (m, 1H), 4.63 (m, 1H), 4.32 (m, 1H), 3.79
(m, 1H), 3.53 (m, 1H), 3.10-2.80 (m, 5H), 1.85 (s, 3H), 1.44 (s,
9H). FABMS (M + 1): calcd, 613.2849; found, 613.2876.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-(a cetoxya m in o)-3-(2-n a p h th ylth io)p r op a n a m -
id e (13c). To a solution of protected amine 12c (3.9 g, 5.8
mmol) in CH2Cl2 (10 mL) was added TFA (7 mL), and the
resulting solution was stirred at room temperature for 3 h;
then the volatiles were removed in vacuo. The residue was
taken up in EtOAc, washed with 5% aqueous NH4OH solution
and brine, dried, (Na2SO4), and concentrated in vacuo to give
3.4 g of the amine as a white solid. Flash chromatography
(2.5% MeOH/CH2Cl2 and then 5% MeOH/CH2Cl2) gave 1.6 g,
2.70 (m, 6H), 1.45 (s, 9H), 1.39 (s, 9H). FDMS: M+, 687. [R]22
+11.94°.
D
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(ter t-bu toxycar bon yl)am in o]-3-[(1-N-m eth yltet-
r a zol-5-yl)th io]p r op a n a m id e (12i). Acid 10i (1 g, 3.3
mmol), amine 11 (1.12 g, 3.3 mmol), and HOBt (0.45 g, 3.3
mmol) in THF (10 mL) and DMF (1.5 mL) were treated with
DCC (0.68 g, 3.3 mmol) and then worked up as above. Flash
chromatography (3% MeOH/CH2Cl2) gave 1.1 g, 52% yield, of
the title compound 12i as a white solid. 1H-NMR (CDCl3): δ
7.40-7.10 (m, 9H), 7.00 (m, 1H), 5.97 (s, 1H), 5.66 (d, J ) 7.0
Hz, 1H), 4.45 (m, 1H), 4.32 (m, 1H), 3.85 (s, 3H), 3.78 (m, 1H),
3.42 (m, 1H), 3.21-3.08 (m, 2H), 3.02-2.78 (m, 3H), 1.44 (s,
9H), 1.38 (s, 9H). Anal. (C31H43N7O5S) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(ter t-b u t oxyca r b on yl)a m in o]-3-[(p -m et h oxy-
p h en yl)th io]p r op a n a m id e (12j). Acid 10j (1 g, 3.1 mmol),
amine 11 (1.02 g, 3 mmol), and HOBt (0.43 g, 3.1 mmol) in
THF (15 mL) and DMF (3 mL) were treated with DCC (0.65
g, 3.1 mmol) and then worked up as above. Flash chroma-
tography (25-35% EtOAc/toluene) gave 1.07 g, 55% yield, of
the title compound 12j as a white solid. 1H-NMR (CDCl3): δ
7.4-7.1 (m, 11H), 6.82 (d, J ) 9 Hz, 2H), 6.55 (br d, J ) 7 Hz,
1H), 5.98 (br m, 2H), 5.16 (br d, J ) 7 Hz, 1H), 4.28 (m, 1H),
48% yield, of the free amine as a white solid. [R]22 -16.08°.
D
Anal. (C34H39N3O3S) C,H,N.
The amine (0.31 g, 0.54 mmol) was dissolved in CH2Cl2 (4
mL), Et3N (0.15 mL, 1.1 mmol) was added followed by acetyl
chloride (0.039 mL, 0.54 mmol), and the resulting solution was
stirred at room temperature for 30 min. The mixture was
diluted with CH2Cl2, washed with cold 1 N HCl solution, dried
(Na2SO4), and concentrated in vacuo. Flash chromatography
(step gradient of 2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) gave
0.32 g, 97% yield, of the title N-acetyl compound 13c as a white

HIV Protease Inhibitors That Use D-Amino Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 105
solid. 1H-NMR (CDCl3): δ 7.80-7.70 (m, 4H), 7.45-7.11 (m,
12H), 6.90 (d, J ) 9 Hz, 1H), 6.45 (d J ) 8 Hz, 1H), 6.08 (br s,
1H), 4.55 (m, 1H), 4.32 (m, 1H), 3.77 (m, 1H), 3.20-2.70 (m,
6H), 1.80 (s, 3H), 1.43 (s, 9H). Anal. (C36H41N3O4S) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-(m eth ylsu lfon yl)a m in o]-3-(ben zylth io)p r op a n -
a m id e (16a ). Gen er a l P r oced u r e for Deblock in g a n d
P r ep a r a tion of N-Meth a n esu lfon yl An a logs. To a solution
of protected amine 12a (0.72 g, 1.14 mmol) in CH2Cl2 (4 mL)
was added TFA (3 mL), and the resulting solution was stirred
at room temperature for 1 h; then the volatiles were removed
in vacuo. The residue was taken up in EtOAc, washed with
5% aqueous NH4OH solution and brine, dried (Na2SO4), and
concentrated in vacuo to give 0.55 g of the amine as a white
solid. Flash chromatography (4% MeOH/CH2Cl2 and then 6%
MeOH/CH2Cl2) gave 0.47 g, 77% yield, of the free amine as a
white solid. Anal. (C31H39N3O3S) C,H,N.
The amine (0.44 g, 0.82 mmol) was dissolved in CH2Cl2 (5
mL), Et3N (0.23 mL, 1.6 mmol) was added followed by
methanesulfonyl chloride (0.077 mL, 0.98 mmol), and the
resulting solution was stirred at room temperature for 30 min.
The mixture was diluted with CH2Cl2, washed with cold 1 N
HCl solution, dried (Na2SO4), and concentrated in vacuo.
Flash chromatography (2.5% MeOH/CH2Cl2) gave 0.47 g, 94%
yield, of the title N-methanesulfonyl compound 16a as a white
solid. 1H-NMR (CDCl3): δ 7.42-7.17 (m, 14H), 6.78 (d, J )
9.4 Hz, 1H), 5.95 (s, 1H), 5.28 (d, J ) 7.7 Hz, 1H), 4.40 (m,
1H), 3.82 (m, 2H), 3.70 (s, 2H), 3.10-2.80 (m, 4H), 2.81 (s, 3H),
2.65 (dd, J ) 6, 10 Hz, 1H), 2.43 (dd, J ) 6, 10 Hz, 1H), 1.50
(s, 9H). Anal. (C32H41N3O5S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m eth ylsu lfon yl)a m in o]-3-(2-qu in olin ylth io)-
p r op a n a m id e (16b). The free amine was generated as
described above in the preparation of compound 13b. The
amine (1 g, 1.7 mmol) in CH2Cl2 (5 mL) was treated with Et3N
(0.49 mL, 3.5 mmol) and methanesulfonyl chloride (0.16 mL,
2.1 mmol) and then worked up as above. Flash chromatog-
raphy (2% MeOH/CH2Cl2) gave impure material which was
rechromatographed (40% EtOAc/toluene) to give 0.54 g, 49%
yield, of the title compound 16b as a white solid. 1H-NMR
(CDCl3): δ 8.19 (br s, 1H), 7.98 (d, J ) 7.0 Hz, 1H), 7.77 (m,
2H), 7.51 (m, 1H), 7.38-7.12 (m, 12H), 5.96 (s, 1H), 4.38 (m,
1H), 4.25 (m, 1H), 3.78 (m, 1H), 3.53 (m, 1H), 3.40-2.83 (m,
5H), 2.78 (s, 3H), 1.42 (s, 9H). Anal. (C34H40N4O5S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m et h ylsu lfon yl)a m in o]-3-(2-n a p h t h ylt h io)-
p r op a n a m id e (16c). The free amine was generated as
described above in the preparation of compound 13c. The
amine (1.1 g, 1.93 mmol) in CH2Cl2 (15 mL) was treated with
Et3N (0.54 mL, 3.86 mmol) and methanesulfonyl chloride (0.16
mL, 2.12 mmol) and then worked up as above. Flash chro-
matography (1.8% MeOH/CH2Cl2) gave 1.1 g, 88% yield, of the
title compound 16c as a white solid. 1H-NMR (CDCl3): δ 7.78
(m, 4H), 7.50-7.10 (m, 12H), 6.96 (d, J ) 9 Hz, 1H), 5.96 (br
s, 1H), 5.63 (d, J ) 8 Hz, 1H), 4.39 (m, 1H), 3.91 (q, J ) 7 Hz,
1H), 3.80 (m, 1H), 2.75 (s, 3H), 3.10-2.72 (m, 6H), 1.43 (s, 9H).
Anal. (C35H41N3O5S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m et h ylsu lfon yl)a m in o]-3-(1-n a p h t h ylt h io)-
p r op a n a m id e (16e). Protected amine 12e (1.8 g, 2.7 mmol)
in CH2Cl2 (3 mL) was treated with TFA (3 mL) and worked
up as above. Flash chromatography (2.5% MeOH/CH2Cl2)
gave 0.8 g, 53% yield, of the free amine as a white solid. Anal.
(C34H39N3O3S) C,H,N.
The amine (0.7 g, 1.2 mmol) in CH2Cl2 (5 mL) was treated
with Et3N (0.34 mL, 2.4 mmol) and methanesulfonyl chloride
(0.1 mL, 1.3 mmol) and then worked up as above. Flash chro-
matography (1.5% MeOH/CH2Cl2 and then 3% MeOH/CH2Cl2)
gave 0.69 g, 86% yield, of the title compound 16e as a white
solid. 1H-NMR (CDCl3): δ 8.33 (d, J ) 7.5 Hz, 1H), 7.90-
7.12 (m, 15H), 6.81 (d, J ) 8.0 Hz, 1H), 6.00 (m, 1H), 5.40 (m,
1H), 4.40 (m, 1H), 3.93 (m, 1H), 3.81 (m, 1H), 3.20-2.70 (m,
6H), 2.72 (s, 3H), 1.48 (s, 9H). Anal. (C35H41N3O5S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m eth ylsu lfon yl)a m in o]-3-(2-p yr id ylth io)p r o-
p a n a m id e (16f). Protected amine 12f (1.3 g, 2.1 mmol) in
CH2Cl2 (4 mL) was treated with TFA (4 mL) and worked up
as above. Flash chromatography (step gradient of 2.5% MeOH/
CH2Cl2 to 10% MeOH/CH2Cl2) gave 0.84 g, 76% yield, of the
free amine as a white solid. [R]22 -11.21°. The amine (0.76
D
g, 1.4 mmol) in CH2Cl2 (5 mL) was treated with Et3N (0.4 mL,
2.9 mmol) and methanesulfonyl chloride (0.13 mL, 1.7 mmol)
and then worked up as above. Flash chromatography (2%
MeOH/CH2Cl2 and then 3% MeOH/CH2Cl2) gave 0.82 g, 94%
yield, of the title compound 16f as a white solid. 1H-NMR
(CDCl3): δ 8.42 (d, J ) 7.0 Hz, 1H), 7.84 (d, J ) 7.0 Hz, 1H),
7.38-7.03 (m, 11H), 6.20 (br s, 1H), 6.14 (br s, 1H), 4.35 (m,
1H), 4.05 (m, 1H), 3.75 (m, 1H), 3.40-2.70 (m, 6H), 2.80 (s,
3H), 1.44 (s, 9H). Anal. (C30H38N4O5S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-[(p-flu or oph en yl)th -
io]p r op a n a m id e (16g). Protected amine 12g (1.7 g, 2.67
mmol) in CH2Cl2 (5 mL) was treated with TFA (5 mL) and
worked up as above. Flash chromatography (2.5% MeOH/CH2-
Cl2 and then 3% MeOH/CH2Cl2) gave 0.83 g, 59% yield, of the
free amine as a white solid. [R]22 -5.1°. Anal. (C30H36
-
D
FN3O3S) C,H,N.
The amine (0.5 g, 0.93 mmol) in CH2Cl2 (5 mL) was treated
with Et3N (0.26 mL, 1.9 mmol) and methanesulfonyl chloride
(0.086 mL, 1.1 mmol) and then worked up as above. Flash
chromatography (2% MeOH/CH2Cl2) gave 0.46 g, 81% yield,
of the title compound 16g as a white solid. 1H-NMR (CDCl3):
δ 7.42-7.18 (m, 11H), 6.99 (t, J ) 8.0 Hz, 2H), 6.88 (d, J )
9.3 Hz, 1H), 5.96 (s, 1H), 5.41 (d, J ) 7.5 Hz, 1H), 4.39 (m,
1H), 3.80 (m, 2H), 3.10-2.75 (m, 6H), 2.80 (s, 3H), 1.44 (s, 9H).
Anal. (C31H38FN3O5S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-[[p-(tr iflu or om eth yl)-
p h en yl]th io]p r op a n a m id e (16h ). Protected amine 12h (1.4
g, 2 mmol) in CH2Cl2 (4 mL) was treated with TFA (4 mL)
and worked up as above. Flash chromatography (2.5% MeOH/
CH2Cl2 and then 3% MeOH/CH2Cl2) gave 1 g, 83% yield, of
the free amine as a white solid. [R]22 -13.99°. Anal.
D
(C31H36F3N3O3S) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m et h ylsu lfon yl)a m in o]-3-(p h en ylt h io)p r o-
p a n a m id e (16d ). Protected amine 12d (2.4 g, 3.8 mmol) in
CH2Cl2 (6 mL) was treated with TFA (6 mL) and worked up
as above. Flash chromatography (2.5% MeOH/CH2Cl2 and
then 3.5% MeOH/CH2Cl2) gave 1.1 g, 55% yield, of the free
amine as a white solid. Anal. (C30H37N3O3S) C,H,N.
The amine (1 g, 1.9 mmol) in CH2Cl2 (5 mL) was treated
with Et3N (0.53 mL, 3.8 mmol) and methanesulfonyl chloride
(0.18 mL, 2.3 mmol) and then worked up as above. Flash
chromatography (2% MeOH/CH2Cl2) gave 0.7 g, 64% yield, of
the title compound 16d as a white solid. 1H-NMR (CDCl3): δ
7.42-7.15 (m, 14H), 6.83 (d, J ) 9.3 Hz, 1H), 5.93 (s, 1H),
5.40 (d, J ) 7.7 Hz, 1H), 4.39 (m, 1H), 3.85 (m, 1H), 3.80 (m,
1H), 3.10-2.80 (m, 6H), 2.77 (s, 3H), 1.45 (s, 9H). Anal.
(C31H39N3O5S2‚0.5H2O) C,H,N.
The amine (0.87 g, 1.48 mmol) in CH2Cl2 (5 mL) was treated
with Et3N (0.41 mL, 3 mmol) and methanesulfonyl chloride
(0.14 mL, 1.8 mmol) and then worked up as above. Flash
chromatography (2% MeOH/CH2Cl2) gave 0.9 g, 91% yield, of
the title compound 16h as a white solid. 1H-NMR (CDCl3): δ
7.52-7.04 (m, 13H), 6.42 (d, J ) 7.0 Hz, 1H), 6.19 (br s, 1H),
6.14 (d, J ) 9.0 Hz, 1H), 4.38 (m, 1H), 3.89 (m, 2H), 3.10-
2.62 (m, 6H), 2.72 (s, 3H), 1.43 (s, 9H). FABMS (M + 1): calcd,
666.2283; found, 666.2293. Anal. (C32H38F3N3N3O5S2) H,N;
C: calcd, 57.73; found, 58.60.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-[(1-N-m eth yltetr azol-
5-yl)th io]p r op a n a m id e (16i). Protected amine 12i (1.1 g,
1.76 mmol) in CH2Cl2 (5 mL) was treated with TFA (5 mL)
and worked up as above. Flash chromatography (4% MeOH/

106 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
J ungheim et al.
CH2Cl2 and then 6% MeOH/CH2Cl2) gave 0.58 g, 63% yield, of
the free amine as a white solid. FDMS: M+, 526. The amine
(0.58 g, 1.1 mmol) in CH2Cl2 (5 mL) was treated with Et3N
(0.3 mL, 2.1 mmol) and methanesulfonyl chloride (0.1 mL, 1.3
mmol) and then worked up as above. Flash chromatography
(3% MeOH/CH2Cl2) gave 0.48 g, 73% yield, of the title
compound 16i as a white solid. 1H-NMR (CDCl3): δ 7.40-
7.13 (m, 9H), 5.94 (s, 1H), 5.90 (d, J ) 7.5 Hz, 1H), 4.42 (m,
1H), 4.21 (m, 1H), 3.90 (s, 3H), 3.82 (m, 1H), 3.31-2.80 (m,
6H), 2.85 (s, 3H), 1.41 (s, 9H). Anal. (C27H37N7O5S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-[(p-m eth oxyph en yl)-
th io]p r op a n a m id e (16j). Protected amine 12j (1 g, 1.54
mmol) in CH2Cl2 (5 mL) was treated with TFA (5 mL) and
worked up as above to give 0.8 g, 94% yield, of the free amine
as a white solid. FDMS: M+, 549. The amine (0.8 g, 1.46
mmol) in CH2Cl2 (3 mL) was treated with N-methylmorpholine
(0.32 mL, 2.9 mmol) and methanesulfonyl chloride (0.12 mL,
1.6 mmol) and then worked up as above. Flash chromatog-
raphy (2.5% MeOH/CH2Cl2) gave 0.77 g, 84% yield, of the title
compound 16j as a white solid. 1H-NMR (CDCl3): δ 7.42-
7.20 (11H), 6.85 (d, J ) 8.7 Hz, 2H), 6.78 (d, J ) 9.2 Hz, 1H),
5.92 (br s, 1H), 5.35 (d, J ) 7.4 Hz, 1H), 4.40 (m, 1H), 3.80 (m,
2H), overlapping 3.80 (s, 3H), 3.10-2.78 (m, 6H), 2.82 (s, 3H),
1.48 (s, 9H). Anal. (C32H41N3O6S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m eth ylsu lfon yl)a m in o]-3-[(p-ch lor op h en yl)-
su lfon yl]p r op a n a m id e (18k ). Protected amine 21 (0.58 g,
0.84 mmol) in CH2Cl2 (3 mL) was treated with TFA (3 mL)
and worked up as above. Flash chromatography (step gradient
of 1.5% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) gave 0.35 g, 70%
yield, of the free amine as a white solid. FDMS: M+, 586.
The amine (0.35 g, 0.59 mmol) in CH2Cl2 (3 mL) was treated
with Et3N (0.17 mL, 1.2 mmol) and methanesulfonyl chloride
(0.055 mL, 0.71 mmol) and then worked up as above. Flash
chromatography (1.5% MeOH/CH2Cl2 and then 3% MeOH/CH2-
Cl2) gave 0.23 g, 58% yield, of the title compound 18k as a
white solid. 1H-NMR (CDCl3): δ 7.82 (d, J ) 8.0 Hz, 2H), 7.58
(d, J ) 8.0 Hz, 2H), 7.42-7.08 (m, 9H), 6.02 (br s, 1H), 5.80
(d, J ) 7.0 Hz, 1H), 4.44 (m, 1H), 4.37 (m, 1H), 3.82 (m, 1H),
3.22-2.72 (m, 6H), 2.92 (s, 3H), 1.48 (s, 9H). FDMS: M+, 664.
Anal. (C31H38ClN3O7S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-(a cet oxya m in o)-3-(2-q u in olin ylsu lfin yl)p r o-
p a n a m id e (14b ). Gen er a l Met h od for t h e MCP BA-
Catalyzed Oxidation to Su lfoxide an d/or Su lfon e An alogs.
To a -78 °C solution of sulfide 13b (0.15 g, 0.24 mmol) in CH2-
Cl2 (5 mL) was added a solution of MCPBA (0.073 g, 0.23
mmol; Lancaster, 50-55% peracid) in CH2Cl2 (2 mL). The
resulting solution was stirred at -78 °C for 30 min at which
time TLC (5% MeOH/CH2Cl2) indicated the reaction was
essentially complete. The reaction mixture was partitioned
between CH2Cl2 and saturated aqueous NaHCO3 solution. The
organic phase was dried (Na2SO4) and concentrated in vacuo
to give 0.17 g of a white solid. Flash chromatography (step
gradient of 3% MeOH/CH2Cl2 to 6% MeOH/CH2Cl2) gave 0.07
g, 47% yield, of the title compound 14b as a white solid. 1H-
NMR (CDCl3): δ 8.55 (d, J ) 8.5 Hz, 1H), 8.32 (d, J ) 9.3 Hz,
1H), 8.05 (m, 3H), 7.93 (t, J ) 5.8 Hz, 1H), 7.75 (t, J ) 7.0 Hz,
1H), 7.42 (d, J ) 7.3 Hz, 1H), 7.30-7.18 (m, 4H), 7.10 (d, J )
7.5 Hz, 2H), 6.98 (d, J ) 7.3 Hz, 1H), 6.64 (t, J ) 7.6 Hz, 2H),
6.25 (t, J ) 7.3 Hz, 1H), 5.08 (m, 1H), 4.33 (m, 1H), 4.03 (m,
1H), 3.10-2.97 (m, 3H), 2.85-2.70 (m, 3H), 1.92 (s, 3H), 1.38
(s, 9H). Anal. (C35H40N4O5S) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-(a cet oxya m in o)-3-(2-q u in olin ylsu lfon yl)p r o-
p a n a m id e (15b). A 0 °C solution of sulfide 13b (0.11 g, 0.18
mmol) in CH2Cl2 (5 mL) was treated with a solution of MCPBA
(0.11 g, 0.35 mmol) in CH2Cl2 (2 mL) and after 30 min at 0 °C
worked up as described above. Flash chromatography (4%
MeOH/CH2Cl2) gave 0.08 g, 67% yield, of the title compound
15b as a white solid. 1H-NMR (CDCl3): δ 8.40 (d, J ) 8.4 Hz,
1H), 8.20 (d, J ) 8.4 Hz, 1H), 8.05 (d, J ) 8.5 Hz, 1H), 7.91 (d,
J ) 8.2 Hz, 1H), 7.85 (t, J ) 5.8 Hz, 1H), 7.72 (t, J ) 5.8 Hz,
1H), 7.33 (m, 2H), 7.20 (m, 6H), 7.00 (t, J ) 5.8 Hz, 1H), 6.79
(d, J ) 8.0 Hz, 1H), 6.40 (br s, 1H), 5.03 (m, 1H), 4.23 (m, 1H),
3.81 (m, 1H), 3.50 (m, 1H), 3.10-2.75 (m, 4H), 1.72 (s, 3H),
1.42 (s, 9H). Anal. (C35H40N4O5S) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m eth ylsu lfon yl)a m in o]-3-(2-qu in olin ylsu lfo-
n yl)p r op a n a m id e (18b). A 0 °C solution of sulfide 16b (0.17
g, 0.26 mmol) in CH2Cl2 (5 mL) was treated with a solution of
MCPBA (0.18 g, 0.52 mmol) in CH2Cl2 (2 mL) and after 30
min at 0 °C worked up as described above. Flash chromatog-
raphy (40% toluene/EtOAc) gave 0.11 g, 61% yield, of the title
compound 18b as a white solid. 1H-NMR (CDCl3): δ 8.44 (d,
J ) 8 Hz, 1H), 8.30 (d, J ) 9 Hz, 1H), 8.10 (d, J ) 9 Hz, 1H),
7.90 (m, 2H), 7.72 (t, J ) 8 Hz, 1H), 7.40-7.05 (m, 9H), 6.82
(d, J ) 7 Hz, 1H), 6.06 (br s, 1H), 4.51 (m, 1H), 4.33 (m, 1H),
3.80 (m, 2H), 3.57 (dd, J ) 3, 15 Hz, 1H), 3.12 (dd, J ) 4, 14
Hz, 1H), 2.88 (s, 3H), 3.00-2.80 (m, 3H), 1.42 (s, 9H). FABMS
(M + 1): calcd, 681.2417; found, 681.2433.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-(2-n aph th ylsu lfin yl)-
p r op a n a m id e (17c). A -10 °C solution of sulfide 16c (1.1 g,
1.7 mmol) in CH2Cl2 (10 mL) was treated with a solution of
MCPBA (0.48 g, 1.53 mmol) in CH2Cl2 (2 mL) and after 30
min at -10 °C worked up as described above. Flash chroma-
tography (step gradient of 2% MeOH/CH2Cl2 to 10% MeOH/
CH2Cl2) gave 0.88 g, 86% yield, of the title compound 17c as
a white solid. 1H-NMR (CDCl3): δ 8.24-7.93 (m, 4H), 7.80-
7.20 (m, 8H), 7.08 (d, J ) 7.5 Hz, 2H), 6.69 (t, J ) 7.6 Hz,
2H), 6.49 (t, J ) 7.3 Hz, 1H), 6.23 (br s, 1H), 5.80 (d, J ) 9.3
Hz, 1H), 4.63 (m, 1H), 4.38 (m, 1H), 3.75 (m, 1H), 3.27 (dd, J
) 3.0, 15.0 Hz, 1H), 3.02-2.80 (m, 3H), 2.98 (s, 3H), 2.60 (t, J
) 12.4 Hz, 1H), 2.27 (t, J ) 12.4 Hz, 1H), 1.43 (s, 9H). [R]22
+29.34°. FDMS: 664. Anal. (C35H41N3O6S2) C,H,N.
D
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m et h ylsu lfon yl)a m in o]-3-(p h en ylsu lfin yl)-
p r op a n a m id e (17d ). A 0 °C solution of sulfide 17d (0.1 g,
0.16 mmol) in CH2Cl2 (4 mL) was treated with a solution of
MCPBA (0.058 g, 0.16 mmol) in CH2Cl2 (2 mL) and after 30
min at 0 °C worked up as described above. Flash chromatog-
raphy (70% EtOAc/toluene and then 85% EtOAc/toluene) gave
0.025 g, 24% yield, of the title compound 17d as a white solid.
1H-NMR (CDCl3): δ 8.30 (d, J ) 10 Hz, 1H), 7.75-7.15 (m,
10H), 7.02 (d, J ) 7 Hz, 2H), 6.60 (m, 3H), 6.28 (br s, 1H),
5.70 (d, J ) 10 Hz, 1H), 4.53 (t, J ) 9 Hz, 1H), 4.30 (m, 1H),
3.67 (q, J ) 7 Hz, 1H), 3.25 (dd, J ) 4, 14 Hz, 1H), 2.91 (s,
5H), 2.83 (dd, J ) 3, 13 Hz, 1H), 2.52 (t, J ) 12 Hz, 1H), 1.98
(t, J ) 13 Hz, 1 H), 1.42 (s, 9H). Analytical HPLC on Waters
C18 µ-Bondapak column eluting with 35% CH3CN/35% MeOH/
0.5% NH4OAc/H2O gave a retention time of 4.04 min, 90.5%
purity (UV detection at 254 nM). FABMS (M + 1): calcd,
614.2359; found, 614.2387.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-(1-n aph th ylsu lfin yl)-
p r op a n a m id e (17e). A -10 °C solution of sulfide 16e (0.4 g,
0.62 mmol) in CH2Cl2 (4 mL) was treated with a solution of
MCPBA (0.17 g, 0.56 mmol) in CH2Cl2 (2 mL) and after 30
min at -10 °C worked up as described above. Flash chroma-
tography (2.5% MeOH/CH2Cl2) gave 0.32 g, 86% yield, of the
title compound 17e as a white solid. 1H-NMR (CDCl3):
δ
8.38-8.10 (m, 4H), 7.92 (t, J ) 7.5 Hz, 1H), 7.78-7.20 (m, 8H),
6.95 (d, J ) 7.5 Hz, 2H), 6.42 (t, J ) 7.5 Hz, 2H), 6.27 (br s,
1H), 5.88 (t, J ) 7.5 Hz, 1H), 5.80 (d, J ) 9.3 Hz, 1H), 4.70
(m, 1H), 4.38 (m, 1H), 3.70 (m, 1H), 3.25 (dd, J ) 3.0, 15.0 Hz,
1H), 2.99 (s, 3H), 2.99-2.78 (m, 3H), 2.49 (t, J ) 12.4 Hz, 1H),
2.27 (t, J ) 12.4 Hz, 1H), 1.41 (s, 9H). FDMS: 664. Anal.
(C35H41N3O6S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-(1-n aph th ylsu lfon yl)-
pr opan am ide (18e). A room temperature solution of sulfoxide
17e (0.1 g, 0.15 mmol) in CH2Cl2 (3 mL) was treated with a
solution of MCPBA (0.047 g, 0.15 mmol) in CH2Cl2 (1 mL)

HIV Protease Inhibitors That Use D-Amino Acids
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 107
and after 30 min at room temperature worked up as described
above to give 0.1 g, 97% yield, of the title compound 18e as a
white solid. 1H-NMR (CDCl3): δ 8.62 (d, J ) 8.5 Hz, 1H), 8.31
(d, J ) 8.5 Hz, 1H), 8.18 (d, J ) 8.5 Hz, 1H), 8.01 (d, J ) 8.5
Hz, 1H), 7.90-7.52 (m, 4H), 7.41-7.15 (m, 6H), 7.00 (t, J )
7.5 Hz, 2H), 6.88 (t, J ) 7.5 Hz, 1H), 6.13 (br s, 1H), 5.81 (d,
J ) 8.7 Hz, 1H), 4.64 (m, 1H), 4.37 (m, 1H), 4.86 (m, 1H), 3.40-
2.70 (m, 6H), 2.94 (s, 3H), 1.47 (s, 9H). Analytical HPLC on
Waters C18 µ-Bondapak column eluting with 70% CH3CN/
0.5% NH4OAc/H2O gave a retention time of 2.63 min, 83.1%
purity (UV detection at 254 nM). None of the sulfoxide 17e
was detected. FDMS: 679.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m eth ylsu lfon yl)a m in o]-3-(2-p yr id ylsu lfin yl)-
pr opan am ide (17f,f′) an d (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth -
ylet h yl)a m in o]ca r b on yl]p h en yl]-2-h yd r oxy-1-(p h en yl-
m eth yl)p r op yl]-2-[(m eth ylsu lfon yl)a m in o]-3-(2-p yr id yl-
su lfon yl)p r op a n a m id e (18f). A -10 °C solution of sulfide
16f (0.25 g, 0.42 mmol) in CH2Cl2 (4 mL) was treated with a
solution of MCPBA (0.12 g, 0.38 mmol) in CH2Cl2 (2 mL) and
after 30 min at -10 °C worked up as described above. Flash
chromatography (step gradient of 2% MeOH/CH2Cl2 to 10%
MeOH/CH2Cl2) gave 0.01 g, 4% yield, of the sulfone 18f (least
polar spot on TLC, 5% MeOH/CH2Cl2) as a white solid. 1H-
NMR (CDCl3): δ 8.78 (d, J ) 7.0 Hz, 1H), 8.10-7.98 (m, 2H),
7.60 (m, 1H), 7.40-7.18 (m, 9H), 6.23 (d, J ) 9.0 Hz, 1H), 6.08
(br s, 1H), 4.40 (m, 2H), 3.82 (m, 1H), 3.69 (dd, J ) 7.0, 7.0
Hz, 1H), 3.40 (dd, J ) 3.0, 15.0, Hz, 1H), 3.18 (dd, J ) 3.0,
15.0 Hz, 1H), 3.00-2.82 (m, 3H), 2.90 (s, 3H), 1.48 (s, 9H).
FDMS: 631.
Sulfoxide 17f′, 0.05 g, 21% yield, was the second compound
to elute (middle spot on TLC). 1H-NMR (CDCl3): δ 8.75 (d, J
) 4.4 Hz, 1H), 8.02 (m, 2H), 7.80 (d, J ) 7.5 Hz, 1H), 7.58-
7.05 (m, 7H), 6.80 (m, 3H), 6.35 (br s, 1H), 5.91 (d, J ) 7.5 Hz,
1H), 4.58 (m, 1H), 4.38 (m, 1H), 3.72 (m, 1H), 3.24 (dd, J )
3.0, 15.0 Hz, 1H), 3.00-2.53 (m, 5H), 2.92 (s, 3H), 1.42 (s, 9H).
FDMS: M + 1, 615.
Sulfoxide 17f, 0.13 g, 54% yield, was the third compound to
elute (lowest spot on TLC). 1H-NMR (CDCl3): δ 8.60 (d, J )
4.4 Hz, 1H), 8.00-7.88 (m, 2H), 7.75 (d, J ) 7.5 Hz, 1H), 7.41-
7.20 (m, 9H), 6.11 (br s, 1H), 5.62 (d, J ) 7.5 Hz, 1H), 4.40 (m,
1H), 4.31 (m, 1H), 3.80 (m, 1H), 3.25-2.80 (m, 6H), 2.69 (s,
3H), 1.45 (s, 9H). FABMS (M + 1): calcd, 615.2311; found,
615.2335.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-[[p-(tr iflu or om eth yl)-
p h en yl]su lfin yl]p r op a n a m id e (17h ). A -10 °C solution of
sulfide 16h (0.35 g, 0.53 mmol) in CH2Cl2 (4 mL) was treated
with a solution of MCPBA (0.16 g, 0.51 mmol) in CH2Cl2 (2
mL) and after 30 min at -10 °C worked up as described above.
Flash chromatography (2.5% MeOH/CH2Cl2) gave 0.2 g, 57%
yield, of the title compound 17h as a white solid. 1H-NMR
(CDCl3): δ 7.92 (d, J ) 8.2 Hz, 2H), 7.69 (d, J ) 8.2 Hz, 2H),
7.50-7.20 (m, 5H), 7.03 (d, J ) 8.0 Hz, 2H), 6.80 (t, J ) 7.0
Hz, 2H), 6.69 (t, J ) 7.0 Hz, 1H), 6.20 (br s, 1H), 5.92 (d, J )
9.5 Hz, 1H), 5.78 (d, J ) 5.3 Hz, 1H), 4.59 (m, 1H), 4.39 (m,
1H), 3.71 (m, 1H), 3.28 (dd, J ) 3.0, 15.0 Hz, 1H), 3.00-2.90
(m, 2H), 2.96 (s, 3H), 2.71 (m, 1H), 2.58 (t, J ) 12.5 Hz, 1H),
2.18 (t, J ) 12.5 Hz, 1H), 1.45 (s, 9H). FDMS: M + 1, 682.
Anal. (C32H38F3N3O6S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-[(1-N-m eth yltetr azol-
5-yl)su lfin yl]p r op a n a m id e (17i). A -78 °C solution of
sulfide 16i (0.15 g, 0.25 mmol) in CH2Cl2 (4 mL) was treated
with a solution of MCPBA (0.078 g, 0.25 mmol) in CH2Cl2 (2
mL), and after 30 min at -78 °C, the cooling bath was removed
and stirring continued for an additional 30 min; then the
mixture was worked up as described above. Flash chroma-
tography (2.5% MeOH/CH2Cl2 and then 3% MeOH/CH2Cl2)
gave 0.07 g, 47% yield, of the title compound 17i as a white
solid. 1H-NMR (CDCl3): δ 7.60 (d, J ) 9.3 Hz, 1H), 7.42-
7.02 (m, 8H), 6.79 (t, J ) 7.0 Hz, 1H), 6.08 (m, 2H), 4.38 (m,
2H), 4.21 (s, 3H), 3.86 (m, 1H), 3.22-2.70 (m, 6H), 2.88 (s, 3H),
1.44 (s, 9H). FDMS: M + 1, 620. Anal. (C27H37N7O6S2‚1.5H2O)
C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-(a cetoxya m in o)-3-(2-n a p h th ylsu lfon yl)p r op a n -
a m id e (15c). Gen er a l Meth od for th e Oxon e-Ca ta lyzed
Oxid a tion of Su lfon e An a logs. To a 0 °C solution of sulfide
13c (0.31 g, 0.51 mmol) in MeOH (6 mL) was slowly added a
solution of Oxone (0.37 g, 1.2 mmol equiv) in H2O (2 mL). The
resulting solution was stirred at 0 °C for 15 min and then at
room temperature for 4 h at which time TLC (5% MeOH/CH2-
Cl2) indicated the reaction was essentially complete. The
reaction mixture was poured into water and extracted several
times with CHCl3. The organic phase was washed with brine,
dried (Na2SO4), and concentrated in vacuo to give 0.29 g, 88%
yield, of the title compound 15c as a white solid. 1H-NMR
(CDCl3): δ 8.45 (s, 1H), 8.00 (d, J ) 9 Hz, 2H), 7.91 (d, J ) 8
Hz, 1H), 7.79 (d, J ) 7 Hz, 1H), 7.70-6.96 (m, 10H), 6.48 (d,
J ) 8 Hz, 1H), 6.13 (br s, 1H), 4.81 (m, 1H), 4.22 (m, 1H), 3.79
(m, 1H), 3.40 (m, 1H), 3.18 (m, 1H), 3.08-2.76 (m, 4H), 1.80
(s, 3H), 1.42 (s, 9H). Analytical HPLC on Waters C18
µ-Bondapak column eluting with 35% CH3CN/35% MeOH/0.5%
NH4OAc/H2O gave a retention time of 5.7 min, 99% purity (UV
detection at 254 nM). FABMS (M + 1): calcd, 644.2794; found,
644.2827. Anal. (C36H41N3O6S‚1.7H2O) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-(a cetoxya m in o)-3-(p h en ylsu lfon yl)p r op a n a m -
id e (15d ). A 0 °C solution of sulfide 13d (0.07 g, 0.12 mmol)
in MeOH (5 mL) was treated with a solution of Oxone (0.079
g, 0.26 mmol equiv) in H2O (2 mL). After stirring for 15 min
at 0 °C and then at room temperature for 4 h, the mixture
was worked up as described above to give 0.07 g, 95% yield,
of the title compound 15d as a white solid. 1H-NMR (CDCl3):
δ 7.85 (d, J ) 8 Hz, 2H), 7.60 (m, 2H), 7.38-7.00 (m, 11H),
6.62 (d, J ) 8 Hz, 1H), 6.35 (br s, 1H), 4.82 (m, 1H), 4.22 (m,
1H), 3.80 (m, 1H), 3.25 (m, 1H), 3.12-2.75 (m, 5H), 1.82 (s,
3H), 1.43 (s, 9H). FDMS: M + 1, 594. Anal. (C32H39N3O6S2)
C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m et h ylsu lfon yl)a m in o]-3-[(p -flu or op h en yl)-
su lfin yl]p r op a n a m id e (17g). A -78 °C solution of sulfide
16g (0.22 g, 0.36 mmol) in CH2Cl2 (4 mL) was treated with a
solution of MCPBA (0.11 g, 0.36 mmol) in CH2Cl2 (2 mL) and
after 30 min at -78 °C worked up as described above. Flash
chromatography (2.5% MeOH/CH2Cl2 and then 3% MeOH/CH2-
Cl2) gave 0.13 g, 57% yield, of the title compound 17g as a
white solid. 1H-NMR (CDCl3): δ 8.16 (d, J ) 9.5 Hz, 1H), 7.60
(m, 2H), 7.43-7.30 (m, 5H), 7.20 (m, 2H), 7.01 (d, J ) 7.3 Hz,
2H), 6.83-6.68 (m, 3H), 6.31 (br s, 1H), 5.95 (d, J ) 9.5 Hz,
1H), 4.55 (m, 1H), 4.31 (m, 1H), 3.68 (m, 1H), 3.22 (m, 1H),
2.91 (s, 3H), 2.72 (m, 1H), 2.55 (m, 1H), 2.07 (t, J ) 12.6 Hz,
1H), 1.41 (s, 9H). FDMS: M + 1, 632. Anal. (C31H38FN3O6S2)
C,H,N.
Sulfoxide 18g, 0.06 g, was also isolated from the reaction
mixture.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m et h ylsu lfon yl)a m in o]-3-[(p -flu or op h en yl)-
su lfon yl]p r op a n a m id e (18g). A 0 °C solution of sulfide 16g
(0.19 g, 0.31 mmol) in CH2Cl2 (3 mL) was treated with a
solution of MCPBA (0.19 g, 0.62 mmol) in CH2Cl2 (2 mL) and
after 30 min at 0 °C worked up as described above. Flash
chromatography (2.5% MeOH/CH2Cl2) gave 0.15 g, 75% yield,
of the title compound 18g as a white solid. 1H-NMR (CDCl3):
δ 7.91 (m, 2H), 7.40-7.02 (m, 11H), 6.11 (br s, 1H), 5.89 (d, J
) 8.7 Hz, 1H), 4.45 (m, 1H), 4.33 (m, 1H), 3.80 (m, 1H), 3.20-
2.70 (m, 6H), 2.91 (s, 3H), 1.43 (s, 9H). FDMS: M + 1, 648.
Anal. (C31H38FN3O7S2) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m et h ylsu lfon yl)a m in o]-3-(b en zylsu lfon yl)-
p r op a n a m id e (18a ). A 0 °C solution of sulfide 16a (0.26 g,
0.42 mmol) in MeOH (4 mL) was treated with a solution of
Oxone (0.27 g, 0.87 mmol equiv) in H2O (2 mL). After stirring
for 15 min at 0 °C and then at room temperature for 4 h, the

108 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
J ungheim et al.
mixture was worked up as described above. Flash chroma-
tography (2.5% MeOH/CH2Cl2) gave 0.1 g, 37% yield, of the
support of the Physical Chemistry Department at the
Lilly Research Laboratories for providing analytical and
spectral data.
title compound 18a as a white solid. 1H-NMR (CDCl3):
δ
7.41-7.10 (m, 15H), 6.00 (br s, 1H), 5.81 (d, J ) 9 Hz, 1H),
4.38 (m, 2H), 4.26 (q, J ) 4 Hz, 2H), 3.80 (m, 1H), 3.10 (m,
2H), 2.90 (s, 3H), 2.80 (m, 4H), 1.46 (s, 9H). FDMS: M + 1,
644. Anal. (C32H41N3O7S2) C,H,N.
Refer en ces
(1) Debouck, C. The HIV-1 protease as a therapeutic target for
AIDS. AIDS Res. Hum. Retroviruses 1992, 8, 153-164. Fairlie,
D. P.; West, M. L. Targeting HIV-1 protease: a test of drug
design methodologies. Trends Pharmacol. 1995, 16, 67-75.
(2) Dorsey, B. D.; Levin, R. B.; McDaniel, S. L.; Vacca, J . P.; Guare,
J . P.; Darke, P. L.; Zugay, J . A.; Emini, E. A.; Schleif, W. A.;
Quintero, J . C.; Lin, J . H.; Chen, I.-W.; Holloway, M. K.;
Fitzgerald, P. M. D.; Axel, M. G.; Ostovic, D.; Anderson, P. S.;
Huff, J . R. L-735,524: The design of a potent and orally
bioavailable HIV protease inhibitor. J . Med. Chem. 1994, 37,
3443-3451 and references cited therein.
(3) Roberts, N. A.; Martin, J . A.; Kinchington, D.; Broadhurst, A.
V.; Craig, J . C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay,
J .; Kro¨hn, A.; Lambert, R. W.; Merrett, J . H.; Mills, J . S.; Parkes,
K. E. B.; Redshaw, S.; Ritchie, A. J .; Taylor, D. L.; Thomas, G.
J .; Machin, P. J . Rational design of peptide-based HIV proteinase
inhibitors. Science 1990, 248, 358-361.
(4) MK-639 was previously known as L-735,524 as described in ref
2.
(5) Kaldor, S. W.; Hammond, M.; Dressman, B. A.; Fritz, J . E.;
Crowell, T. A.; Hermann, R. A. New dipeptide isosteres useful
for the inhibition of HIV-1 protease. Bioorg. Med. Chem. Lett.
1994, 4, 1385-1390.
(6) See, for example: Smith, P. L.; Wall, D. A.; Gochoco, C. H.;
Wilson, G. (D) Routes of delivery, case studies (5) Oral absorbtion
of peptides and proteins. Adv. Drug Delivery Rev. 1992, 8, 253-
290. Burton, P. S.; Conradi, R. A.; Hilgers, A. R.; Ho, N. F. H.;
Maggiora, L. L. The relationship between peptide structure and
transport across epithelial cell monolayers. J . Controlled Release
1992, 19, 87-98.
(7) Martin, J . A. Ro 31-8959/003. Drugs Future 1991, 16, 210-212.
(8) Dahlem, A. M.; Schreiner, K. M.; Burgess, J . Unpublished
observations, Lilly Research Laboratories.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-(2-n aph th ylsu lfon yl)-
p r op a n a m id e (18c). A 0 °C solution of sulfide 16c (0.34 g,
0.52 mmol) in MeOH (5 mL) was treated with a solution of
Oxone (0.39 g, 1.2 mmol equiv) in H2O (2 mL). After stirring
for 15 min at 0 °C and then at room temperature for 4 h, the
mixture was worked up as described above. Flash chroma-
tography (2% MeOH/CH2Cl2 and then 5% MeOH/CH2Cl2) gave
0.2 g, 56% yield, of the title compound 18c as a white solid.
1H-NMR (CDCl3): δ 8.50 (s, 1H), 8.00 (d, J ) 8 Hz, 12H), 7.93
(d, J ) 8 Hz, 1H), 7.83 (d, J ) 7 Hz, 1H), 7.68 (m, 2H), 7.40-
6.92 (m, 10H), 6.04 (br s, 1H), 5.73 (d, J ) 8 Hz, 1H), 4.53 (m,
1H), 4.37 (m, 1H), 3.81 (m, 1H), 2.92 (s, 3H), 3.33-2.70 (m,
6H), 1.46 (s, 9H). FDMS: M + 1, 680. Anal. (C35H41N3O7S2)
C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
p r op yl]-2-[(m et h ylsu lfon yl)a m in o]-3-(p h en ylsu lfon yl)-
p r op a n a m id e (18d ). A 0 °C solution of sulfide 16d (0.51 g,
0.85 mmol) in MeOH (6 mL) was treated with a solution of
Oxone (0.63 g, 2 mmol equiv) in H2O (2 mL). After stirring
for 10 min at 0 °C and then at room temperature for 4 h, the
mixture was worked up as described above. Flash chroma-
tography (2% MeOH/CH2Cl2) gave 0.47 g, 87% yield, of the
title compound 18d as a white solid. 1H-NMR (CDCl3): δ 7.88
(d, J ) 9.0 Hz, 2H), 7.60 (m, 2H), 7.40-7.04 (m, 9H), 5.95 (br
s, 1H), 5.72 (d, J ) 7.0 Hz, 1H), 4.39 (m, 2H), 3.81 (m, 1H),
3.31 (m, 1H), 3.15-2.80 (m, 5H), 2.95 (s, 3H), 1.43 (s, 9H).
FDMS: M + 1, 630. Anal. (C31H39N3O7S2) C,H,N.
(9) Spellmeyer, D. C.; Brown, S.; Stauber, G. B.; Geysen, H. M.;
Valerio, R. Endothelin receptor ligands. Multiple D-amino acid
replacement net approach. Bioorg. Med. Chem. Lett. 1993, 3,
1253-1256.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-[[p-(tr iflu or om eth yl)-
p h en yl]su lfon yl]p r op a n a m id e (18h ). A 0 °C solution of
sulfide 16h (0.41 g, 0.62 mmol) in MeOH (5 mL) was treated
with a solution of Oxone (0.55 g, 1.8 mmol equiv) in H2O (2
mL). After stirring for 10 min at 0 °C and then at room
temperature for 4 h, the mixture was worked up as described
above to give 0.42 g, 97% yield, of the title compound 18h as
a white solid. 1H-NMR (CDCl3): δ 8.02 (d, J ) 7.5 Hz, 2H),
7.81 (d, J ) 7.5 Hz, 2H), 7.40-7.00 (m, 9H), 6.18 (br s, 1H),
6.01 (d, J ) 9.0 Hz, 1H), 5.95 (d, J ) 7.0 Hz, 1H), 4.53 (m,
1H), 4.35 (m, 1H), 3.83 (m, 1H), 3.20-2.64 (m, 6H), 2.88 (s,
3H), 1.44 (s, 9H). FDMS: M + 1, 699. Anal. (C32H38F3N3O7S2‚
0.8H2O) C,H,N.
P r ep a r a tion of (S)-N-(1S,2R)-[3-[2-[[(1,1-Dim eth yleth -
yl)a m in o]ca r bon yl]p h en yl]-2-h yd r oxy-1-(p h en ylm eth yl)-
pr opyl]-2-[(m eth ylsu lfon yl)am in o]-3-[(p-m eth oxyph en yl)-
su lfon yl]p r op a n a m id e (18j). A 0 °C solution of sulfide 16j
(0.24 g, 0.38 mmol) in MeOH (3 mL) was treated with a
solution of Oxone (0.34 g, 1.1 mmol equiv) in H2O (2 mL). After
stirring for 10 min at 0 °C and then at room temperature for
3 h, the mixture was worked up as described above to give
0.25 g, 99% yield, of the title compound 18j as a white solid.
1H-NMR (CDCl3): δ 7.82 (d, J ) 7.5 Hz, 2H), 7.40-7.00 (m,
11H), 6.19 (br s, 1H), 5.86 (d, J ) 7.5 Hz, 1H), 5.80 (br s, 1H),
4.50 (m, 1H), 4.33 (m, 1H), 3.90 (s, 3H), 3.80 (m, 1H), 3.20-
2.70 (m, 6H), 2.93 (s, 3H), 1.45 (s, 9H). Analytical HPLC on
Waters C18 µ-Bondapak column eluting with 35% MeOH/35%
CH3CN/0.5% NH4OAc/H2O gave a retention time of 3.94 min,
98.7% purity (UV detection at 254 nM). FDMS: M + 1, 660.
Anal. (C32H41N3O8S2‚0.8H2O) C,H,N.
(10) J ungheim, L. N.; Titus, R. W.; Cho, S. Y. S. Unpublished
Observations, Lilly Research Laboratories. LY297243 vs HIV
protease exhibited IC50 ) 1.0 and 8.5 nM antiviral activity in
CEM cells.
(11) Schevitz, R. W.; Wery, J .-P.; Clawson, D. K. (Lilly Research
Laboratories); Appelt, K. (Agouron Pharmaceuticals, Inc.) Un-
published observations.
(12) (a) Shepherd, T. A.; J ungheim, L. N.; Baxter, A. J . D-Amino acids
as novel P2/P3 ligands for inhibitors of HIV-1 protease. Bioorg.
Med. Chem. Lett. 1994, 4, 1391-1396. (b) For an alternative
approach to asparagine replacement, see: Thompson, W. J .;
Ghosh, A. K.; Holloway, M. K.; Lee, H. Y.; Munson, P. M.;
Schwering, J . E.; Wai, J .; Darke, P. L.; Zugay, J .; Emini, E. A.;
Schleif, W. A.; Huff, J . R.; Anderson, P. S. 3′-Tetrahydrofura-
nylglycine as
a novel, unnatural amino acid surrogate for
asparagine in the design of inhibitors of the HIV protease. J .
Am. Chem. Soc. 1993, 115, 801-803.
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bond isosteres. Tetrahedron Lett. 1991, 32, 5263-5264.
(14) Getman, D. P.; DeCrescenzo, G. A.; Heintz, R. M.; Reed, K. L.;
Talley, J . J .; Bryant, M. L.; Clare, M.; Houseman, K. A.; Marr,
J . J .; Mueller, R. A.; Vazquez, M. L.; Shieh, H.-S.; Stallings, W.
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protease inhibitors containing the (R)-(hydroxyethyl)urea iso-
stere. J . Med. Chem. 1993, 36, 288-291.
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to stereochemically pure â-substituted R-amino acids via â-lac-
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synthesis of optically pure non protein R-amino acids in both L
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Ackn owledgm en t. The authors wish to thank There-
sa Gygi, J oe Manetta, and Dr. J oe Colacino for as-
sistance with in vitro testing. We acknowledge the
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