Tipranavir (PNU-140690): A potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class

Article abstract of DOI:10.1021/jm9802158

A broad screening program previously identified phenprocoumon (1) as a small molecule template for inhibition of HIV protease. Subsequent modification of this lead through iterative cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone ring systems (II and V) and amide-based substitution (III). Incorporation of sulfonamide substitution within the dihydropyrone template provided a series of highly potent HIV protease inhibitors, with structure-activity relationships described in this paper. Crystallographic studies provided further information on important binding interactions responsible for high enzymatic binding. These studies culminated in compound VI, which inhibits HIV protease with a K(i) value of 8 pM and shows an IC₉₀ value of 100 nM in antiviral cell culture. Clinical trials of this compound (PNU-140690, Tipranavir) for treatment of HIV infection are currently underway.

Full text of DOI:10.1021/jm9802158

J . Med. Chem. 1998, 41, 3467-3476
3467
Tip r a n a vir (P NU-140690): A P oten t, Or a lly Bioa va ila ble Non p ep tid ic HIV
P r otea se In h ibitor of th e 5,6-Dih yd r o-4-h yd r oxy-2-p yr on e Su lfon a m id e Cla ss∇
Steve R. Turner,*,† J oseph W. Strohbach,† Ruben A. Tommasi,‡ Paul A. Aristoff,| Paul D. J ohnson,|
Harvey I. Skulnick,| Lester A. Dolak,† Eric P. Seest,† Paul K. Tomich,§ Michael J . Bohanon,§ Miao-Miao Horng,§
J anet C. Lynn,§ Kong-Teck Chong, Roger R. Hinshaw, Keith D. Watenpaugh,† Musiri N. J anakiraman,† and
Suvit Thaisrivongs†
Departments of Structural, Analytical & Medicinal Chemistry, Medicinal Chemistry, Discovery Technologies, and
Infectious Diseases Research, Pharmacia & Upjohn, Inc., 301 Henrietta Street, Kalamazoo, Michigan 49001
Received April 8, 1998
A broad screening program previously identified phenprocoumon (1) as a small molecule
template for inhibition of HIV protease. Subsequent modification of this lead through iterative
cycles of structure-based design led to the activity enhancements of pyrone and dihydropyrone
ring systems (II and V) and amide-based substitution (III). Incorporation of sulfonamide
substitution within the dihydropyrone template provided a series of highly potent HIV protease
inhibitors, with structure-activity relationships described in this paper. Crystallographic
studies provided further information on important binding interactions responsible for high
enzymatic binding. These studies culminated in compound VI, which inhibits HIV protease
with a Ki value of 8 pM and shows an IC90 value of 100 nM in antiviral cell culture. Clinical
trials of this compound (PNU-140690, Tipranavir) for treatment of HIV infection are currently
underway.
The worldwide AIDS epidemic has stimulated a large
research effort directed toward identifying therapeutic
protocols effective for control of the disease and its
causative agent, HIV. One approach of intense scrutiny
over the past few years has been inhibition of the virally
encoded protease, an enzyme essential for maturation
of viral particles to their infectious stage.1,2 A number
of highly potent peptidemimetic HIV protease inhibitors
have been described in the literature,3-6 though the
therapeutic utility of this structural type is often
compromised by low oral bioavailability and rapid
excretion.7 Recent advances have led to protease in-
hibitors of reduced peptidic nature which generally
exhibit improved pharmacokinetic properties. An in-
creasing number of protease inhibitors8-21 are undergo-
ing clinical trials or have been approved for AIDS
therapy.
We have previously described20 the discovery of phen-
procoumon (I, Figure 1) as a lead nonpeptide HIV
protease inhibitor. This compound, which was identi-
fied via broad screening of the Pharmacia & Upjohn
compound library, inhibited HIV protease with a Ki of
1 µM and showed weak antiviral activity (ED50 100-
300 µM). With this compound as a starting point, we
embarked on a series of iterative cycles of structure-
based design, leading to the enhancements shown in
Figure 1.20,21 Favorable effects on enzymatic binding
were observed by replacing the 4-hydroxycoumarin ring
F igu r e 1.
introduction of carboxamide functionality at the meta
position of the phenyl side chain, as exemplified by
compound III (Ki 86 nM).22 Further improvements in
enzymatic and antiviral activity were realized via
cycloalkane and sulfonamide modifications, exemplified
by IV21 (Ki < 1 nM, antiviral IC50 1-2 µM), and in the
dihydropyrone series, exemplified by V23(Ki 15 nM, IC50
5 µM). Most recently, we reported preliminary results
of dihydropyrone inhibitors containing appended sul-
system with the corresponding 4-hydroxypyrone system,
as exemplified by compound II (Ki 38 nM),20 and by
∇ Dedicated to Prof. Robert E. Ireland on the occasion of his 70th
birthday.
† Structural, Analytical & Medicinal Chemistry.
‡ Present address: Novartis Pharmaceuticals Corp., RES-322, 556
Morris Avenue, Summit, NJ 07901.
| Medicinal Chemistry.
§ Discovery Technologies.
Infectious Diseases Research.
S0022-2623(98)00215-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/12/1998

3468 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
Turner et al.
Sch em e 1a
Sch em e 2a
a
(a) m-CbzNHC6H4CHO, AlCl3, THF; (b) t-BuMgCl or “t-
BuCu(CN)ZnI”, CuBr-Me2S, THF; (c) H2, Pd/C, MeOH; (d)
RSO2Cl, pyr, CH2Cl2.
reaction was important, as use of stronger tertiary
amine bases led exclusively to O-sulfonylation.
Preparation of C-3R unsubstituted analogues required
addition of hydrogen to benzylidene intermediate 2.
Treatment of the benzylidene compound with sodium
cyanoborohydride in methanol selectively reduced the
benzylidene double bond, and subsequent hydrogenation
of the nitro group afforded amine 6. Alternately, both
steps could be conducted simultaneously by simple
catalytic hydrogenation of 2 using palladium on carbon.
Sulfonylation of the amine using an appropriate sulfonyl
chloride in the presence of pyridine provided C-3R
methylene analogues 7.
a
(a) CH3COCH2CO2CH3, NaH, THF; (b) NaOH then H3O+; (c)
m-NO2C6H4CHO, AlCl3, THF; (d) Et3Al, CuBr-Me2S, THF; (e) H2,
Pd/C, MeOH; (f) RSO2Cl, pyr, CH2Cl2.
Although the above route proved quite general for
conversion of a variety of ketones to the correspondingly
6-substituted dihydropyrones, it was less well suited for
introduction of a wide array of substitution at C-3R, due
to the limited selection of available trialkylaluminums.
Attempted utilization of Grignard reagents for addition
of functionality to benzylidene intermediate 2 was
problematic, usually leading to numerous side reactions.
Presumably the source of this interference was electron
transfer between the Grignard reagent and the nitrated
substrate. To circumvent this difficulty, we explored
the organocopper-zinc reagents described by Knochel.25
Reaction of activated zinc dust with tert-butyl iodide in
dry THF at 45 °C using ultrasound provided the
putative organozinc species, which was subsequently
modified by treatment with copper(I) cyanide and
lithium chloride. Reaction of this reagent with the
freshly prepared benzylidene intermediate 2 at 0 °C
resulted in relatively clean conjugate addition, giving
products corresponding to 3 in ca. 60% yield.
fonamide functionality, exemplified by VI.24 Com-
pounds II, IV, and VI represent Pharmacia & Upjohn’s
first, second, and third generation clinical candidates
for potential treatment of AIDS. The purpose of this
full report is to describe structure-activity relationships
within this latest structural class.
Ch em istr y
Preparation of a representative series of sulfonamide-
containing dihydropyrones is depicted in Scheme 1.
Reaction of the dianion of methyl acetoacetate with
1-phenyl-3-hexanone, followed by hydrolysis of the
intermediate â-ketoester and spontaneous ring closure
upon acidification, provided the phenethyl propyl dihy-
dropyrone ring system 1 in 72% yield. Aluminum
chloride catalyzed condensation of the dihydropyrone
with m-nitrobenzaldehyde afforded benzylidene inter-
mediate 2, which was generally not isolated but reacted
directly with triethylaluminum in the presence of cop-
per(I) bromide-dimethyl sulfide to give the fully func-
tionalized dihydropyrone 3 in 80% yield. Reduction of
the nitro group was accomplished using catalytic hy-
drogenation to provide amine 4, which could be coupled
with a wide variety of sulfonyl chlorides in the presence
of pyridine to afford the final sulfonamides 5 in good
yield. The selection of base used in the sulfonylation
Alternatively, as shown in Scheme 2, Grignard re-
agents could be utilized as a source of C-3R functionality
if the reactive nitro group was absent from the conjugate
addition substrate. Aluminum trichloride catalyzed
condensation of dihydropyrone 8 with the benzyloxy-
carbonyl derivative of m-aminobenzaldehyde, in the
same fashion as described above, provided the analogous

Highly Potent HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3469
Ta ble 1. C-6 Variation
benzylidene intermediate 9. Conjugate addition of, for
example, tert-butylmagnesium chloride to 9 in the
presence of 50 mol % copper bromide-dimethyl sulfide
provided the product 10 in 57% yield. In practice, these
additions were nearly titrations; Grignard reagent was
added until a transient deep red coloration persisted,
after which little or no starting material remained.
Knochel organocopper-zinc reagents could also be
utilized in this addition. Removal of the CBZ protecting
group using catalytic transfer hydrogenolysis provided
amine 11 in 58% yield, and sulfonylation of the amine
with a variety of sulfonyl chlorides afforded the corre-
sponding sulfonamides 12 in good yield.
We felt it imperative in this study to examine the
effect on activity of the stereochemical configurations
at C-3R and C-6. For this purpose, we initially resorted
to preparative chiral HPLC separation of stereoisomeric
mixtures obtained as described above. In most cases,
these resolutions were found to be most efficient using
substrates containing a side chain Cbz-amino group
(e.g., compound 10). Chiral HPLC was effective at
separating both enantiomers and diastereomers; thus,
compounds containing stereocenters at both C-3R and
C-6 provided four components each, in roughly equiva-
lent amounts. A single X-ray crystal structural deter-
mination of one diastereomeric intermediate was suf-
ficient to correlate and assign all four stereoisomers, as
relative stereochemical relationships among these,
whether antipodal or diastereomeric, were unambigu-
ously evident from examination of the associated NMR
spectra. Efficient stereoselective syntheses of these
compounds were also subsequently developed.26
Resu lts a n d Discu ssion
Table 1 lists a number of dihydropyrone protease
inhibitors with varying functionality at C-6. For pur-
poses of comparison, the C-3R side chain and sulfona-
mide moieties contained in the compounds shown have
been held fixed as ethyl and 1-methylimidazole-4-yl,
respectively, groups that have been proven effective in
previous work with pyrone-based inhibitors.27 Shown
in the table are Ki values against HIV-1 protease and
IC50 and IC90 values in a cell culture assay using HIV-
1IIIB infected H9 cells.
Within this series of compounds, Ki values were found
to be relatively insensitive to the nature of the C-6
substituents. Inhibitory data obtained for analogues
containing simple alkyl substituents (13-16) or phenyl-
terminated alkyl substituents (18-20) are virtually
indistinguishable. A limit to the tolerances of the S1′-
S2′ sites is illustrated by adamantyl derivative 17, which
shows a 10-fold decrease in activity relative to acyclic
congeners. The oligoether derivative 21, prepared with
the goal of improving aqueous solubility, also displayed
reduced affinity, in accordance with the known prefer-
ence of the S1′ and S2′ subsites for lipophilic functional-
ity. Antiviral IC90 values in cell culture for the more
enzymatically potent members of this series were
generally under 3 µM, with the most active compound
(phenethyl propyl analogue 18) having both IC50 and
IC90 values in the submicromolar range.
seen with cyclopropyl. Effects on antiviral activity were
marginal. Removing the C-3R side chain entirely led
to decreased activity (24, 27), indicating benefit derived
from projection of this functionality into the protease
S1 subsite (vide infra).
Variation in the sulfonamide portion of the molecule
is shown in Table 3. Data are shown for two templates,
which differ at the C-3R substituent. Within the C-3R
ethyl series, one aliphatic sulfonamide prepared (28)
showed only weak activity, discouraging further explo-
ration of this structural type. In contrast, the simple
benzensulfonamide 29 showed a Ki value of 17 nM, with
further improvements being realized by appendage of
cyano, fluoro, or pyridyl moieties (30, 31, 33) or an
additional pyridyl ring (32). Superior enzymatic and
antiviral activities were observed with substituted py-
ridyl sulfonamides, with Ki values for compound 33
reaching into the low subnanomolar range.
Similar aromatic sulfonamides were also very effec-
tive within the C-3R tert-butyl template, as shown in
the right half of Table 3. The inhibitor containing a
cyanobenzenesulfonamide (34) showed a Ki value of 12
nM. Replacement of the benzene sulfonamide with
a pyridyl sulfonamide in this molecule led to order of
Exploration of C-3R variation is shown in Table 2.
Simple alkyl groups were uniformly effective at this
position, with slight improvements in Ki values being

3470 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
Ta ble 2. C-3R Variation
Turner et al.
enzyme subsites, and the C-3R ethyl and aromatic
groups occupied the S1 and S2 subsites, respectively,
with the sulfonamide moiety extending into the S3
subsite. Hydrogen-bonding interactions were also
present between the sulfonamide linkage and active site
residues.
The X-ray crystal structure of 39b complexed with the
triple mutant protease construct was determined. Sa-
lient hydrogen-bonding interactions are illustrated in
Figure 2, which shows the dihydropyrone ring to be
centered in the enzyme active site. The lactone oxygen
atom of the ring forms 3.1 Å hydrogen bonds with the
NH groups of the flap region isoleucine residues (Ile50/
50′), and the 4-hydroxy group is pseudosymmetrically
bonded to the catalytic aspartate residues 25/25′, at
distances of 2.8 and 2.5 Å. The contribution of the
sulfonamide functionality to overall binding is clearly
observed, with two hydrogen-bonding interactions formed
with Asp30 and an additional interaction with an
nearby bound water molecule.
Figure 3 more clearly illustrates the fit of the inhibitor
upon the active site surface. In this view, the enzyme
flaps have been peeled aside, with the observer peering
down into the active site region. The C-6 phenethyl and
propyl substituents of the inhibitor project into the S2′
and S1′ enzyme pockets, respectively. The C-3R ethyl
and phenyl groups access the S1 and S2 subsites,
respectively, with the trifluoromethylpyridyl sulfona-
mide moiety extending into the S3 subsite.
magnitude increases in both enzymatic and antiviral
activity, as exemplified by inhibitor 35. The nitrile
function in 35 could be replaced by nitro, trifluoro-
methyl, or amino (36, 37, and 38, respectively) without
loss of enzymatic or antiviral activity, although potential
toxic liabilities associated with the nitroaromatic and
anilino moieties contained in 36 and 38 discouraged
consideration of these compounds for further develop-
ment.
PNU-140690 also inhibited HIV-2 protease with high
potency (Ki < 1 nM) and was also effective against V82A
and V82F/I84V mutants (Ki 3.0 and 0.25 nM, respec-
tively). Selectivity for HIV protease was demonstrated
by high Ki values (2, 15, and 9 µM) against other
representative aspartyl proteases (human pepsin and
cathepsins D and E, respectively).30 The effect of
protein binding on antiviral activity was investigated
in HIV-1IIIB infected cells in the presence of 10% fetal
bovine serum and 75% human plasma. In this medium,
in which >99% of the inhibitor is protein bound, an IC90
value of 1.4 µM was observed. Studies with ritonavir
resistant HIV-1 laboratory isolates31 have shown them
to be highly resistant to saquinavir, indivanir, and
nelfinavir as well,32 with 47- to >125-fold increases in
IC90 values relative to the parent strains. These
isolates, however, remained highly sensitive to PNU-
140690, with only a 6-fold increase in IC90 values
relative to the wild type.32 In addition, a study of four
ritonavir resistant clinical isolates (showing 32- to 67-
fold increases in IC90 values) indicated only a 2-3-fold
decrease in sensitivity to PNU-140690,32 and evaluation
of the inhibitor against a panel of 10 AZT resistant
clinical isolates, representing a clinically relevant cross
section of viral resistance, showed IC90 values ranging
from 0.067 to 0.32 µM and averaging 0.16 µM.33
To evaluate the effect of stereochemistry on activity,
individual stereoisomers of some of the more active
compounds were isolated via chiral HPLC. In general,
the best chiral resolutions were obtained using the CBZ
derivatives of the penultimate amines (corresponding
to 4, Scheme 1). Enzymatic and antiviral assay results
for three sets of stereoisomers are shown in Table 4. In
these cases, enzymatic Ki data were derived from
inhibition assay using a tandem linked enzyme con-
struct,28 which prevents subunit dissociation at low
enzyme concentrations and allows accurate Ki determi-
nation for very potent inhibitors. It was commonly
observed that, within a stereochemical quartet, isomers
having the R configuration at C-3R were significantly
superior, enzymatically and antivirally, to those con-
taining the S configuration at this center. The influence
of the C-6 configuration was less dramatic, but in all
cases a preference for the 6R isomer was observed. On
the basis of these results, as well as pharmacokinetic
and safety evaluations, compound 39b (PNU-140690)
was selected as a clinical development candidate.
An X-ray crystal structure of compound 18 complexed
to an HIV-1 protease triple mutant (Q7K/L33I/L63I,
utilized due to its greater stability in structural stud-
ies)29 has previously been determined.24 The complex
showed nearly symmetrical hydrogen bonding between
the inhibitor 4-hydroxy group and the catalytic aspar-
tates and between the carbonyl oxygen and the flap
region isoleucine 50/50′ NH groups. The C-6 phenethyl
and propyl side chains projected into the S1′ and S2′
After 5 mg/kg IV dosing in rats, CLtot was 0.17 ( 0.10
L/h/kg, Vss was 0.51 ( 0.14 L/kg, and t1/2 was 5.4 ( 0.3
h. Following 10 mg/kg oral dosing in rats, F was 30%
(relative to 5 mg/kg IV dosing). Importantly, blood
levels of PNU-140690 exceeded 1 µM, the in vitro IC90
value in the presence of 10% FBS and 75% human
plasma, for 8-12 h. The single-dose safety, tolerance,
and pharmacokinetics of PNU-140690 in a dosage range
of 100 to 2000 mg were studied in normal healthy

Highly Potent HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3471
Ta ble 3. Sulfonamide Variation
a
Ki in tandem HIV assay.
Ta ble 4. Stereochemical Variation
F igu r e 2. PNU-140690: Active site hydrogen-bonding inter-
actions.
clinical evaluation of PNU-140690 (Tipranavir) for
treatment of HIV infection is continuing.
Con clu sion
In summary, previous work identified the 5,6-dihydro-
4-hydroxy-2-pyrone ring system as a promising template
for small molecule HIV protease inhibitors. We under-
took a systematic evaluation of the substitution patterns
at three critical regions of the template with the goal of
optimizing enzymatic binding, in vitro cell culture
antiviral activity, and pharmacokinetic parameters es-
sential for therapeutic efficacy. Structural variation
was examined at the dihydropyrone 3R- and 6-positions
a
Tandem HIV assay.
volunteers.34 Drug concentrations in excess of 1 µM,
the predicted IC90 value based on in vitro virology and
protein binding data, were observed for greater than 8
h after a single dose of 500 mg and above. Further

3472 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
Turner et al.
concentrated, and the residue crystallized from ether to afford
10.72 g (72%) of 1 as a white solid: 1H NMR (CDCl3) δ 0.96 (t,
J ) 7.3 Hz, 3H), 1.48 (m, 2H), 1.72 (m, 2H), 1.98 (m, 2H), 2.73
(m, 4H), 3.43 (s, 2H), 7.15-7.32 (m, 5H); IR 1658, 1605, 1218
cm-1. Anal. (C16H20O3) C, H.
5,6-Dih yd r o-4-h yd r oxy-3-[1-(3-n itr op h en yl)p r op yl]-6-
p h en et h yl-6-p r op yl-2H-p yr a n -2-on e (3). A solution of
anhydrous AlCl3 was prepared by cautious addition of 35 mL
of THF to 5.33 g (40 mmol) of AlCl3 at -78 °C under argon
followed by warming to room temperature, and this solution
was added via cannula to a stirred, argon-covered solution of
5.21 g (20 mmol) of 1 and 3.02 g (20 mmol) of m-nitrobenzal-
dehyde in 70 mL of THF. The solution was stirred at room
temperature under argon for 2 h, and then quenched by
addition of 11.5 g of Na2CO3‚10H2O. Celite and MgSO4 were
added and the mixture was stirred vigorously for 5 min, then
filtered through diatomaceous earth with ether rinses. Re-
moval of solvent left 8.95 g of benzylidene intermediate 2 as a
yellow oil. To this was added 1.23 g (6 mmol) of CuBr-Me2S
and 70 mL of THF, and the flask was filled with argon and
surrounded by a cold water bath during the addition of 24 mL
of Et3Al (1.0 M in hexane). After 20 min the mixture was
cooled to 0 °C and cautiously quenched with ice and then 6 N
HCl. The mixture was extracted twice with ether and the
organic extract dried (MgSO4) and concentrated. Flash chro-
matography of the residue using 35-40% EtOAc in hexane
F igu r e 3. PNU-140690: Protease active site surface view.
as well as within the side chain sulfonamide moiety. The
results of these studies led to the identification of PNU-
140690 as a potent HIV protease inhibitor exhibiting
low toxicity and acceptable drug delivery and distribu-
tion characteristics. PNU-140690 (Tipranavir) is cur-
rently undergoing clinical trials as a therapeutic agent
for treatment of AIDS.
provided 6.80 g (80%) of 3 as a foam: 1H NMR (CDCl3
+
CD3OD) δ 0.88-0.97 (m, 6H), 1.3 (m, 2H), 1.7 (m, 2H), 1.8-
2.2 (m, 3H), 2.22-2.28 (m, 1H), 2.55-2.64 (m, 4H), 4.2 (m,
1H), 7.05-7.28 (m, 5H), 7.37 (t, J ) 7.9 Hz, 1H), 7.75 (d, J )
7.8 Hz, 1H), 8.0 (m, 1H), 8.28 (s, 1H); IR 2965, 1607, 1529,
1388, 1350 cm-1; FAB-HRMS calcd for C25H29NO5 + H1
424.2124, found 424.2129. Anal. (C25H29N1O5) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-3-[1-(3-a m in op h en yl)p r op yl]-6-
p h en eth yl-6-p r op yl-2H-p yr a n -2-on e (4). A mixture of 6.80
g (16 mmol) of 3 and 350 mg of 10% Pd/C in 80 mL of methanol
was stirred vigorously under 1 atm H2 for 2 h, then filtered
through Celite. The filtrate was concentrated and the residue
flash chromatographed using 10% EtOAc in CH2Cl2 to afford
Exp er im en ta l Section
Ch em istr y. Reagents were from commercial sources and
used without further purification unless otherwise noted.
Diethyl ether was Mallinckrodt anhydrous grade. Dichlo-
romethane was stored over 4 Å molecular sieves. Tetrahy-
drofuran (THF) was distilled under argon from potassium
benzophenone ketyl immediately prior to use. Solvents for
chromatography were reagent grade. Flash chromatography
was conducted using EM silica gel 60, 230-400 mesh. Thin
layer chromatography (TLC) was conducted on precoated glass
plates (EM silica gel 60 or Analtech silica gel GF, 0.25 mm).
1H NMR spectra were obtained in the indicated solvent
using a Bruker AM-300 spectrometer operating at 300 MHz
and are reported as δ values relative to tetramethylsilane.
Spectra of dihydropyrones were generally complex due to
mixtures of tautomers, rotamers, and diastereomers. Infrared
spectra were obtained on a Biorad FTS-25 FTIR spectropho-
tometer or by the Structural, Analytical, and Medicinal
Chemistry department at Pharmacia & Upjohn. Mass spectra
and combustion analyses were obtained by the Structural,
Analytical, and Medicinal Chemistry department at PNU.
5,6-Dih ydr o-4-h ydr oxy-6-ph en eth yl-6-pr opyl-2H-pyr an -
2-on e (1). To a cooled (0 °C), stirred slurry of 2.86 g (71 mmol)
of sodium hydride dispersion (60% in oil) in 100 mL of THF
under argon was added dropwise 7.3 mL (68 mmol) of methyl
acetoacetate. The mixture was stirred for 10 min, and then
43 mL (69 mmol) of n-BuLi (1.6 M in hexanes) was added via
cannula over about 20 min. After another 10 min, 10 g (57
mmol) of 1-phenyl-3-hexanone was added neat, and the
mixture stirred at 0 °C for 1 h and then poured into saturated
aqueous NH4Cl. The aqueous phase was rendered acidic by
addition of 6 N HCl and extracted with one portion of EtOAc.
The organic phase was washed with brine, dried (MgSO4), and
concentrated under reduced pressure to an oil. This was
stirred in 100 mL of MeOH, 250 mL of water, and 58 mL of 1
N NaOH for 1 h, after which the aqueous solution was
extracted with ether to remove any remaining starting mate-
rial. The aqueous phase was cooled in ice and acidified with
6 N HCl, and the precipitate extracted with 4 portions of
CH2Cl2. The combined organic extract was dried (MgSO4) and
5.83 g (92%) of amine 4 as a tan foam: 1H NMR (CDCl3
+
CD3OD) δ 0.83-0.98 (m, 6H), 1.34 (m, 2H), 1.6-2.1 (m, 5H),
2.2 (m, 1H), 2.6 (m, 4H), 3.95 (m, 1H), 6.5 (m, 1H), 6.8 (m,
2H), 7.0-7.3 (m, 6H); IR 1606, 1385 cm-1. Anal. (C25H31N1O3)
C, H, N.
Ch ir a l HP LC Resolu tion of CBZ Der iva tive of Am in e
4. The CBZ derivative of amine 4 was resolved on a 5 × 50
cm Chiralcel OD column (Chiral Technologies, Inc.); the mobile
phase was 15% ethanol in heptane with addition of 0.025%
acetic acid v/v at 50 mL/min flow rate, monitored at 238 nm
(retention times: 17.1, 18.4, 25.4, and 30.3 min for the four
diastereomers), 2 g injection size.
3-(1-[3-Am in op h en yl]m eth yl)-5,6-d ih yd r o-4-h yd r oxy-6-
p h en eth yl-6-p r op ylp yr a n -2-on e (6). To a flame-dried flask
containing 800 mg (6.0 mmol) of AlCl3 at -78 °C, under argon,
was slowly added 7.0 mL of dry THF. The flask was warmed
to room temperature with vigorous stirring, then cannulated
into a solution of 450 mg (3.0 mmol) of m-nitrobenzaldehyde
and 780 mg (3.0 mmol) of 1 in 7 mL of THF. After 2 h the
reaction mixture was treated with 1.8 g of Na2CO3‚10H2O.
After 5 min the suspension was diluted with 15 mL of dry
diethyl ether and filtered through a pad of Celite with ether
washes. The combined filtrates were concentrated under
reduced pressure and the residue dissolved in 10 mL of dry
methanol, and this solution cooled to 0 °C for the addition of
230 mg (3.7 mmol) of sodium cyanoborohydride. After 1 h the
resulting mixture was carefully treated with water and par-
tioned against diethyl ether. The aqueous phase was extracted
with three additional portions of diethyl ether. The combined
organic phase was washed with brine, dried (Na2SO4), and
concentrated under reduced pressure. Flash chromatography
of the residue using 60 to 80% ethyl acetate in hexane provided
650 mg (1.65 mmol) of the corresponding nitro compound as
an off-white foam: TLC Rf 0.39 (75% ethyl acetate in hexane);
1H NMR (CDCl3 + CD3OD) δ 0.85 (t, 3H, J ) 7.2 Hz), 1.3 (m,

Highly Potent HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3473
2H), 1.65 (m, 2H), 1.8-2.0 (m, 2H), 2.55 (m, 2H), 2.7 (m, 2H),
3.73 (s, 2H), 7.0 (m, 2H), 7.1-7.3 (m, 4H), 7.55 (m, 1H), 7.95
(m, 1H), 8.1 (s, 1H); EI-MS m/z (rel intensity) 395 (M+, 6), 352
(17), 159 (30), 157 (24), 136 (18), 117 (23), 91 (100); EI-MS M+
) 395 found for C23H25NO5.
To a solution of 400 mg (1.0 mmol) of the above nitro
compound in 5.0 mL of methanol was added 1.0 g (16 mmol)
of ammonium formate followed by 100 mg of 10% palladium
on carbon. The mixture was stirred for 2 h, then filtered
through a pad of Celite with methanol washes. The filtrate
was concentrated under reduced pressure and triturated with
dichloromethane. The triturates were combined and concen-
trated to give 365 mg of crude 6 as a tan foam, which was
used directly without further purification: TLC Rf 0.20 (25%
ethyl acetate in dichloromethane).
5,6-Dih ydr o-4-h ydr oxy-6,6-dipr opyl-2H-pyr an -2-on e (8).
To a cooled (0 °C) stirred slurry of 2.86 g (71 mmol) of sodium
hydride (60% in mineral oil) in 100 mL of dry THF under argon
was added dropwise 7.3 mL (68 mmol) of methyl acetoacetate.
The mixture was stirred for 15 min, and then 43 mL (69 mmol)
of n-BuLi (1.6 M in hexanes) was added over about 20 min.
The solution was stirred another 15 min, and then 7.9 mL (56
mmol) of 4-heptanone was added via cannula. After 1 h at 0
°C, the reaction mixture was partitioned between EtOAc and
cold dil. HCl, and the aqueous phase extracted with one
additional portion of EtOAc. The combined organic phase was
washed with brine, dried (MgSO4), and concentrated under
reduced pressure to give the crude â-ketoester as a yellow oil.
This was stirred in a mixture of 250 mL water, 100 mL of
methanol, and 58 mL of 1 N NaOH for 1 h, then methanol
was removed under reduced pressure, and the residue washed
once with ether. The aqueous phase was cooled in ice and
acidified with 6 N HCl, and the resulting precipitate was
extracted into three portions of CH2Cl2. The organic phase
was dried (MgSO4) and concentrated under reduced pressure
to an oil. Recrystallization from 80% ether-hexane provided
9.80 g (88%) of dihydropyrone 8 as a white crystalline solid:
1H NMR (CD3OD) δ 0.92 (t, 6H), 1.3 (m, 4H), 1.7 (m, 4H), 2.48
(s, 2H); FAB-HRMS calcd for C11H18O3 + H1 199.1334, found
199.1350. Anal. (C11H18O3) C, H.
water and CH2Cl2. The organic extract was washed with
brine, dried (Na2SO4), and finally concentrated under reduced
pressure. The residue was flash chromatographed eluting
with 10% EtOAc in CH2Cl2 to afford 820 mg (2.28 mmol) of
amine 11 as an off-white foam: 1H NMR (CDCl3) δ 7.0-6.4
(m, 4H), 4.05 (s, 1H), 2.5-2.3 (m, 2H), 1.8-0.7 (m, 8H), 1.0 (s,
9H), 0.82 (t, 6H); EI-MS M+ ) 359 found for C22H33N1O3.
Rep r esen ta tive P r oced u r e for Su lfon yla tion : N-[3-{1-
(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6,6-d ip r op yl-2H -p yr a n -3-
yl)-2,2-d im eth ylp r op yl}p h en yl]-1-m eth yl-1H-im id a zole-
4-su lfon a m id e (26). To a cold (0 °C), stirred solution of 54
mg (0.15 mmol) of amine 11 and 24 µL (0.30 mmol) of pyridine
in 1 mL of CH2Cl2 was added 27 mg (0.15 mmol) of 1-meth-
ylimidazole-4-sulfonyl chloride. The solution instantly turned
bright orange-red. After 3-18 h, the reaction mixture was
flash chromatographed using 3-5% MeOH in CH2Cl2 to afford
52.8 mg (69%) of sulfonamide 26 as a white solid: 1H NMR
(CDCl3) δ 0.8-1.0 (m, 6H), 0.96 (s, 9H), 1.2-1.4 (m, 5H), 1.4-
1.8 (m, 4H), 2.5 (m, 1H), 3.6-3.8 (m, 4H), 6.9-7.5 (m, 6H);
EI-HRMS calcd for C26H37N3O5S 503.2454, found 503.2422.
N-[3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6,6-d ip r op yl-2H-
pyr an -3-yl)pr opyl]ph en yl]-1-m eth yl-1H-im idazolesu lfon a-
m id e (13): 1H NMR (CD3OD) δ 0.88 (m, 9H), 1.32 (m, 4H),
1.64 (m, 4H), 1.93 (m, 1H), 2.16 (m, 1H), 2.56 (s, 2H), 3.68 (s,
3H), 3.91 (m, 1H), 6.87 (m, 1H), 7.03 (m, 2H), 7.14 (s, 1H),
7.53 (s, 1H), 7.64 (s, 1H); HRMS calcd for C24H33N3O5S1 + H1
476.2219, found 476.2223. Anal. Calcd for C24H33N3O5S1: C,
60.61; H, 6.99; N, 8.83. Anal. Found for C24H33N3O5S1‚
0.4H2O: C, 59.64; H, 7.04; N, 8.48.
N-[3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6,6-d ip en tyl-2H-
p yr a n -3-yl)p r op yl]p h en yl]-1-m eth yl-1H-im id a zole-4-su l-
fon a m id e (14): 1H NMR (CD3OD) δ 0.87 (m, 9H), 1.25 (m,
12H), 1.55-1.68 (m, 4H), 1.92 (m, 1H), 2.13 (m, 1H), 2.57 (s,
2H), 3.66 (s, 3H), 3.93 (dd, 1H, J ) 9.7, 6.6 Hz), 6.86 (m, 1H),
7.03 (m, 2H), 7.16 (s, 1H), 7.55 (s, 1H), 7.63 (s, 1H); HRMS
calcd for C28H41N3O5S1 + H1 532.2845, found 541.3951. Anal.
Calcd for C28H41N3O5S1: C, 63.25; H, 7.77; N, 7.90. Anal. found
for C28H41N3O5S1‚0.3H2O: C, 62.58; H, 7.47; N, 7.84.
N-[3-[1-(5,6-Dih yd r o-4-h yd r oxy-6,6-d iisob u t yl-2-oxo-
2H-p yr a n -3-yl)p r op yl]p h en yl]-1-m eth yl-1H-im id a zole-4-
su lfon a m id e (15): 1H NMR (CD3OD) δ 0.82-0.94 (m, 15H),
1.52-1.83 (m, 6H), 1.86-2.03 (m, 1H), 2.06-2.22 (m, 1H), 2.60
(s, 2H), 3.68 (s, 3H), 3.92 (m, 1H), 6.87 (m, 1H), 7.03 (m, 2H),
7.16 (s, 1H), 7.56 (s, 1H), 7.65 (s, 1H); HRMS calcd for
C26H37N3O5S1+H1504.2532,found504.2531. Anal. (C26H37N3O5S1)
C, H, N.
3-[1-(3-Ben zyloxyca r bon yla m in op h en yl)-2,2-d im eth yl-
p r op yl]-5,6-d ih yd r o-4-h yd r oxy-6,6-d ip r op yl-2H-p yr a n -2-
on e (10). Into a stirred solution of 991 mg (5.0 mmol) of
dihydropyrone 8 and 1.28 g (5.0 mmol) of 3-(benzyloxycarbo-
nylamino)benzaldehyde in 20 mL of dry THF was cannulated
a
solution of 1.33 g (10 mmol) of anhydrous aluminum
N-(3-[1-(6,6-Di-(2-cyclop r op ylet h yl)-5,6-d ih yd r o-4-h y-
d r oxy-2-oxo-2H-p yr a n -3-yl)p r op yl]p h en yl)-1-m eth yl-1H-
im id a zole-4-su lfon a m id e (16): 1H NMR (CDCl3 + CD3OD)
δ 0.0 (m, 4H), 0.43 (m, 4H), 0.65 (m, 2H), 0.92 (t, 7.3 Hz, 3H),
1.1-1.4 (m, 6H), 1.7-2.1 (m, 5H), 2.1-2.2 (m, 1H), 3.71 (s,
3H), 3.95 (m, 1H), 6.8-7.0 (m, 1H), 7.1-7.2 (m, 3H), 7.3-7.4
(m, 1H), 7.4-7.6 (m, 1H); FAB-HRMS calcd for C28H38N3O5S
528.2532, found 528.2537.
trichloride in 10 mL of dry THF. After 2 h, 2.9 g of sodium
carbonate decahydrate was added, and the mixture was stirred
vigorously for 5 min. Ether, Celite, and MgSO4 were added,
and the mixture was filtered through Celite with ether rinses.
Removal of the solvent under reduced pressure provided the
crude benzylidene intermediate. To this were added 514 mg
(2.5 mmol) of CuBr-Me2S and 20 mL of dry THF, and to this
mixture under argon was added dropwise a 1 M solution of
tert-butylmagnesium chloride in THF. An ice bath was used
to moderate the temperature of the exothermic reaction. Each
drop of Grignard reagent caused a transient deep red color to
form; when the red color persisted (ca. 9 mL added), the
reaction was cautiously quenched with dilute HCl. The
mixture was extracted twice with EtOAc, and the combined
organic phase washed with brine and dried (MgSO4). Removal
of the solvent under reduced pressure, followed by flash
chromatography of the residue using 35% EtOAc in hexane
provided 1.41 g (57%) of 10 as a yellow foam: 1H NMR (CDCl3)
δ 0.7-1.9 (m), 1.11 (s), 2.2-2.8 (m), 5.17 (s), 5.2 (m), 6.9-7.5
(m); EI-MS m/z 493.
N-[3-[1-(3,6-Dih yd r o-4-h yd r oxy-6-oxosp ir o[2H-p yr a n -
2,2′-tr icyclo[3.3.1.13,7]d eca n ]-5-yl)p r op yl]p h en yl]-1-m eth -
yl-1H-im id a zole-4-su lfon a m id e (17): 1H NMR (CDCl3) δ
7.72 (d, 2H, J ) 6.7 Hz), 7.0-7.1 (m, 2H), 6.88 (t, 2H, J ) 8.0
Hz), 3.77 (m, 1H), 3.64 (s, 3H), 2.80 (d, 2H, J ) 6.0 Hz), 1.4-
2.2 (m, 16H), 0.76 (t, 3H, J ) 8.0 Hz); EI-HRMS calcd for
C
27H33N3O5S 511.2141, found, 511.2126.
N-[3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
p r op yl-2H -p yr a n -3-yl)p r op yl]p h en yl]-1-m et h yl-1H -im i-
d a zole-4-su lfon a m id e (18): 1H NMR (CDCl3) δ 0.75-0.96
(m, 6H), 1.17-1.43 (m, 2H), 1.45-2.11 (m, 6H), 2.43-2.68 (m,
2H), 3.24 (s, 2H), 3.64 (s, 3H), 3.94 (m, 1H), 6.72-7.51 (m,
13H); HRMS calcd for C29H35N3O5S1 + H1 538.2376, found
538.2383.
N-[3-{1(R)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(S)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-1-m eth yl-1H-im i-
d a zole-4-su lfon a m id e (18a ): 1H NMR (CDCl3 + CD3OD) δ
0.79-1.0 (m, 6H), 1.2-2.4 (m, 10H), 2.5-2.7 (m, 2H), 3.2-3.7
(m, 4H), 6.8-7.6 (m, 11H); EI-HRMS calcd for C29H35N3O5S
537.2297, found 537.2317.
3-[1-(3-Am in op h en yl)-2,2-d im eth ylp r op yl]-5,6-d ih yd r o-
4-h yd r oxy-6,6-d ip r op yl-2H-p yr a n -2-on e (11). To a solution
of 1.15 g (2.33 mmol) of CBZ compound 10 in 10 mL of
methanol under argon was added 1.55 g (24.6 mmol) of
ammonium formate and 150 mg of 10% palladium on carbon.
The black slurry was stirred for 2 h, then filtered through a
pad of Celite with methanol washings. The combined filtrates
were concentrated, and the residue was partioned between

3474 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
Turner et al.
N-[3-{1(R)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(R)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-1-m eth yl-1H-im i-
d a zole-4-su lfon a m id e (18b): 1H NMR (CDCl3 + CD3OD) δ
0.6-1.0 (m, 6H), 1.2-1.5 (m, 3H), 1.5-2.4 (m, 7H), 2.5-2.7
(m, 2H), 3.3-3.7 (m, 4H), 6.8-7.6 (m, 11H); EI-HRMS calcd
for C29H35N3O5S 537.2297, found 537.2275.
N-[3-{1(S)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(S)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-1-m eth yl-1H-im i-
d a zole-4-su lfon a m id e (18c): 1H NMR spectrum identical to
compound 18b and different from 18a , particularly in the δ
2.6,3.3-3.4,6.8,and 7.5 regions;EI-HRMS calcd for C29H35N3O5S
537.2297, found 537.2329.
N-[3-{1(S)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(R)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-1-m eth yl-1H-im i-
d a zole-4-su lfon a m id e (18d ): 1H NMR spectrum identical to
compound 18a ; EI-HRMS calcd for C29H35N3O5S 537.2297,
found 537.2312.
(m, 1H), 1.50-2.17 (m, 6H), 2.49-2.66 (m, 3H), 3.93 (m, 1H),
6.86-7.32 (m, 10H), 7.33-7.51 (m, 2H), 7.69-7.82 (m, 2H).
4-Cya n o-N-[3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en -
et h yl-6-p r op yl-2H -p yr a n -3-yl)p r op yl]p h en yl]b en zen e-
su lfon a m id e (30): 1H NMR (CDCl3) δ 0.6-1.1 (m, 6H), 1.2-
2.2 (m, 9H), 2.4-2.7 (m, 3H), 3.86-4.01 (m, 1H), 6.89-7.45
(m, 9H), 7.66-7.92 (m, 4H); HRMS calcd for C32H34N2O5S1 +
H1 559.2243, found 559.2267.
4-F lu or o-N-[3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en -
et h yl-6-p r op yl-2H -p yr a n -3-yl)p r op yl]p h en yl]b en zen e-
su lfon a m id e (31): 1H NMR (CD3OD) δ 0.75-0.96 (m, 6H),
1.31-1.48 (m, 2H), 1.57-2.01 (m, 5H), 2.09-2.22 (m, 1H),
2.48-2.71 (m, 4H), 3.92 (m, 1H), 6.86-7.24 (m, 11H), 7.72 (m,
2H); HRMS calcd for C31H34F1N1O5S1 + H1 552.2220, found
552.2230.
N-[3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
pr opyl-2H-pyr an -3-yl)pr opyl]ph en yl]-8-qu in olin esu lfon a-
m id e (32): 1H NMR (CDCl3) δ 0.66 (t, 3H, J ) 6.9 Hz), 0.90
(t, 3H, J ) 6.7 Hz), 1.17-1.44 (m, 3H), 1.58-2.03 (m, 6H),
2.38-2.64 (m, 3H), 3.77 (m, 1H), 6.68-7.27 (m, 9H), 7.35-
7.69 (m, 2H), 8.02 (m, 1H), 8.26 (m, 2H), 9.14 (m, 1H); HRMS
calcd for C34H36N2O5S1 + H1 585.2423, found 585.2402.
N-[3-{1-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6-(2-(4-flu or oph e-
n yl)eth yl)-6-pr opyl-2H-pyr an -3-yl)pr opyl}ph en yl]-1-m eth -
yl-1H-im id a zole-4-su lfon a m id e (19): 1H NMR (CDCl3
+
CD3OD) δ 0.8 (m, 6H), 1.3 (m, 2H), 1.6-2.2 (m, 5H), 2.5 (m,
3H), 3.56 (s, 2H), 3.61 (s, 3H), 3.9 (m, 1H), 6.8-7.4 (m, 10H);
EI-HRMS calcd for C29H34N3O5FS 555.2203, found 555.2192.
N-[3-{1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6,6-d ip h en eth yl-
2H-p yr a n -3-yl)p r op yl}p h en yl]-1-m eth yl-1H-im id a zole-4-
su lfon a m id e (20): 1H NMR (CDCl3) δ 0.88 (t, J ) 7.3 Hz,
3H), 1.9-2.2 (m, 5H), 2.6-2.7 (m, 5H), 3.6 (s, 2H), 3.8 (s, 3H),
3.97 (dd, J ) 9.3, J ) 6.9 Hz, 1H), 6.9-7.5 (m, 16H); FAB-
HRMS calcd for C34H38N3O5S 600.2532, found 600.2521.
N-[3-{1-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6,6-bis((2-(2-m eth -
oxyeth oxy)eth oxy)m eth yl)-2H-pyr an -3-yl)pr opyl}ph en yl]-
1-m eth yl-1H-im idazole-4-su lfon am ide (21): 1H NMR (CDCl3
+ CD3OD) δ 0.88 (t, J ) 7.3 Hz, 3H), 2.0 (m, 2H), 3.3-4.0 (m),
6.9 (m), 7.1 (m), 7.4 (m), 7.6 (m); FAB-HRMS calcd for
N-[3-{1(R,S)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(R,S)-ph en -
eth yl-6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-cya n op y-
r id in e-2-su lfon a m id e (33): 1H NMR (CDCl3 + CD3OD) δ
0.7-0.9, 1.2-2.7, 3.3-3.6 (m), 6.8-7.3 (m), 7.8-8.2 (m), 8.8
(m); FAB-HRMS calcd for
560.2231.
C31H34N3O5S 560.2219, found
N-[3-{1(R)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(S)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-cya n op yr id in e-
2-su lfon a m id e (33a ): 1H NMR (CDCl3 + CD3OD) δ 0.7-1.0
(m, 6H), 1.2-1.4 (m, 3H), 1.4-2.3 (m, 7H), 2.4-2.7 (m, 2H),
3.3-3.6 (m, 1H), 6.8-7.3 (m, 10H), 7.8-8.2 (m, 2H), 8.8-9.0
(m, 1H); FAB-HRMS calcd for C31H34N3O5S 560.2219, found
560.2210.
C
30H46N3O11S1 656.2853, found: 656.2845.
N-[3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
N-[3-{1(R)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(R)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-cya n op yr id in e-
pr opyl-2H-pyr an -3-yl)cyclopr opylm eth yl]ph en yl]-1-m eth -
yl-1H-im id a zole-4-su lfon a m id e (22): 1H NMR (CD3OD) δ
0.13 (m, 2H), 0.42 (m, 1H), 0.67 (m, 1H), 0.95 (m, 3H), 1.44
(m, 2H), 1.68-2.13 (m, 5H), 2.56 (m, 4H), 3.17 (m, 1H), 3.65
(2s, 3H), 6.91 (m, 1H), 7.01-7.33 (m, 8H), 7.52 (m, 1H), 7.63
(m, 1H); HRMS calcd for C30H35N3O5S1 + H1 550.2376, found
550.2370.
1
2-su lfon a m id e (33b): H NMR (CDCl3 + CD3OD) δ 0.6-1.1
(m, 6H), 1.2-2.4 (m, 10H), 2.5-2.7 (m, 2H), 3.3-3.6 (m, 1H),
6.9-7.3 (m, 10H), 7.8-8.2 (m, 2H), 8.8-9.0 (m, 1H); IR (mull)
3087, 3063, 3026, 1641, 1606, 1591, 1497, 1340, 1290, 1255,
1175, 1108, 701, 644, 632 cm-1; UV λmax 224 (20600, 95%
ethanol); FAB-HRMS calcd for C31H34N3O5S 560.2219, found
560.2215. Anal. (C31H33N3O5S1) C, H, N.
N-[3-{1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
pr opyl-2H-pyr an -3-yl)-2,2-dim eth ylpr opyl}ph en yl]-1-m eth -
N-[3-{1(S)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(S)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-cya n op yr id in e-
2-su lfon a m id e (33c): 1H NMR identical to compound 33b
and different from 33a , particularly in the δ 2.5, 3.4, and 7.0
regions; FAB-HRMS calcd for C31H34N3O5S 560.2219, found
560.2210.
N-[3-{1(S)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(R)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-cya n op yr id in e-
2-su lfon a m id e (33d ): 1H NMR identical to that of compound
yl-1H-im id a zole-4-su lfon a m id e (23): 1H NMR (CDCl3
+
CD3OD) δ 0.9-1.0 (m, 3H), 0.97 (s, 9H), 1.2-1.4 (m, 2H), 1.6-
2.1 (m, 4H), 2.4-2.7 (m, 4H), 3.6 (2s, 3H), 4.08 (s, 1H), 6.9-
7.5 (m, 11H); FAB-HRMS calcd for C31H39N3O5S + H1 566.2689,
found 566.2684. Anal. Calcd for C31H39N3O5S1: C, 65.82; H,
6.95; N, 7.43; S, 5.67. Found: C, 63.94; H, 6.78; N, 7.80.
N-(3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
p r op yl-2H-p yr a n -3-yl)m eth yl]p h en yl)-1-m eth yl-1H-im i-
d a zole-4-su lfon a m id e (24): 1H NMR (CDCl3 + CD3OD) δ
0.93 (t, 3H), 1.35 (m, 2H), 1.75 (m, 2H), 1.9 (m, 1H), 2.0 (m,
1H), 2.6 (m, 4H), 3.57 (m, 2H), 3.63 (s, 3H), 6.9-7.5 (m, 11H);
FAB-HRMS calcd for C27H32N3O5S 510.2063, found 510.2052.
N-[3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6,6-d ip r op yl-2H-
p yr a n -3-yl)cyclop r op ylm eth yl]p h en yl]-1-m eth yl-1H-im i-
d a zolesu lfon a m id e (25): 1H NMR (CD3OD) δ 0.12 (m, 2H),
0.43 (m, 1H), 0.68 (m, 1H), 0.90-0.97 (m, 6H), 1.36 (m, 4H),
1.71 (m, 4H), 2.60 (m, 2H), 3.12 (d, 1H, J ) 10.6 Hz), 3.67 (s,
3H), 6.88 (m, 1H), 7.06 (m, 2H), 7.24 (s, 1H), 7.51 (s, 1H), 7.65
(s, 1H); HRMS calcd for C25H33N3O5S1 + H1 488.2219, found
488.2225. Anal. (C25H33N3O5S1) C, H, N.
33a ; FAB-HRMS calcd for
C31H34N3O5S 560.2219, found
560.2210.
N-(3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
p r op yl-2H-p yr a n -3-yl)-2,2-d im eth ylp r op yl]p h en yl)-4-cy-
a n oben zen esu lfon a m id e (34): 1H NMR δ 0.8-1.0 (m, 4H),
1.06 (s, 9H), 1.3-2.8 (m, 8H), 4.2 (m, 1H), 6.2 (bs, 1H), 7.0-
7.3 (m, 10H), 7.68 (d, 2H, J ) 7.0 Hz), 7.83 (d, 2H, J ) 7.0
Hz); EI-HRMS calcd for C34H38N2O5S 586.2501, found 586.2516.
N-(3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
p r op yl-2H-p yr a n -3-yl)-2,2-d im eth ylp r op yl]p h en yl)-5-cy-
a n o-2-p yr id in esu lfon a m id e (35): 1H NMR (CDCl3 + CD3-
OD) δ 8.89 (s, 1H), 7.96 (m, 2H), 7.39 (s, 1H), 7.3-6.8 (m, 8H),
4.05 (s, 1H), 2.7-2.4 (m, 4H), 2.0-0.8 (m, 9H), 0.92 (s, 9H);
FAB-HRMS calcd for C33H38N3O5S 588.2532, found 588.2526.
N-(3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
p r op yl-2H-p yr a n -3-yl)-2,2-d im eth ylp r op yl]p h en yl)-5-n i-
tr o-2-p yr id in esu lfon a m id e (36): 1H NMR δ 9.41 (m, 1H),
8.49 (m, 1H), 8.0 (d, 1H), 7.40 (s, 1H), 7.3-6.8 (m, 8H), 4.04
(s, 1H), 2.6-2.4 (m, 4H), 1.9-0.8 (m, 9H), 0.91 (s, 9H); FAB-
HRMS calcd for C32H38N3O7S 608.2430, found 608.2412.
N-(3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6,6-d ip r op yl-2H-
p yr a n -3-yl)m eth yl]p h en yl)-1-m eth yl-1H-im id a zole-4-su l-
fon a m id e (27): 1H NMR (CDCl3 + CD3OD) δ 0.89 (t, 6H, J
) 7.2 Hz), 1.35 (m, 4H), 1.65 (m, 4H), 2.54 (s, 2H), 3.55 (s,
2H), 3.66 (s, 3H), 6.8-7.5 (m, 6H); EI-HRMS calcd for
C
22H29N3O5S 447.1828, found 447.1839.
N-[3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
p r op yl-2H -p yr a n -3-yl)p r op yl]p h en yl]b en zen esu lfon a -
m id e (29): 1H NMR (CDCl3) δ 0.82-0.92 (m, 6H), 1.23-1.41

Highly Potent HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3475
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N-(3-[1-(5,6-Dih yd r o-4-h yd r oxy-2-oxo-6-p h en et h yl-6-
p r op yl-2H-p yr a n -3-yl)-2,2-d im eth ylp r op yl]p h en yl)-5-tr i-
flu or om eth yl-2-p yr id in esu lfon a m id e (37): 1H NMR (CD3-
OD) δ 0.73 (m, 12H), 1.28-1.08 (m, 4H), 1.68-1.40 (m, 2H),
2.5-2.25 (m, 4H), 3.88 (s, 1H), 7.09-6.70 (m, 8H), 7.19 (m,
1H), 7.87-7.7 (m, 1H), 8.07-7.95 (m, 1H), 8.78 (m, 1H); FAB-
HRMS calcd for C33H37N2O5F3S 540.1906, found 540.1938.
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p r op yl-2H -p yr a n -3-yl)-2,2-d im e t h ylp r op yl]p h e n yl)-5-
a m in o-2-p yr id in esu lfon a m id e (38): 1H NMR δ 7.87 (m,
1H), 7.44 (d, 1H), 7.27 (s, 1H), 7.2-6.7 (m, 8H), 3.99 (s, 1H),
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N-[3-{1(R)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(S)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-tr iflu or om eth -
ylp yr id in e-2-su lfon a m id e (39a ): 1H NMR (CDCl3) δ 0.80
(t, J ) 7.2 Hz, 3H), 0.92 (t, J ) 7.1 Hz, 3H), 1.37 (m, 4H), 1.69
(m, 4H), 1.91 (m, 2H), 2.13 (m, 1H), 2.51 (m, 1H), 2.50 (d, J )
17.2 Hz, 1H), 2.69 (d, J ) 17.2 Hz, 1H), 3.95 (dd, 1H), 6.88 (d,
J ) 7.0 Hz, 1H), 6.97 (m, 1H), 7.25-7.04 (m, 5H), 8.00 (d, J )
8.2 Hz, 1H), 8.17 (d, J ) 8.2 Hz, 1H), 8.91 (s, 1H); FAB-MS
m/z (rel intensity) 603 (MH+, 99), 735 (18), 625 (12), 605 (11),
604 (34), 603 (99), 585 (28), 201 (16), 134 (14), 133 (35), 91
(38); EI-HRMS calcd for C31H33F3N2O5S1 602.2062, found
602.2053. Anal. (C31H33F3N2O5S1) C, H, N, S.
N-[3-{1(R)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(R)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-tr iflu or om eth -
ylp yr id in e-2-su lfon a m id e (39b, P NU-140690): 1H NMR
(CD3OD) δ 0.93-1.03 (m, 6H), 1.36-1.47 (m, 2H), 1.79-2.13
(m, 6H), 2.18-2.30 (m, 1H), 2.63-2.81 (m, 4H), 4.04 (m, 1H),
7.09-7.36 (m, 9H), 8.16 (d, J ) 8.1 Hz, 1H), 8.33 (m, 1H), 9.08
(m, 1H); [R]D +20° (ethanol); HRMS calcd for C31H33N2O5F3S1
+ H1 603.2140, found 603.2153. Anal. (C31H33N2O5F3S1) C,
H, N, S.
N-[3-{1(S)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(S)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-tr iflu or om eth -
ylp yr id in e-2-su lfon a m id e (39c): mp 93-95 °C; 1H NMR
(CD3OD) δ 8.94 (s, 1H), 8.20 (d, J ) 8.3 Hz, 1H), 8.01 (d, J )
8.2 Hz, 1H), 7.24-6.93 (m, 10H), 3.92 (dd, J ) 7.0, 9.3 Hz,
1H), 2.68-2.51 (m, 4H), 2.22-2.05 (m, 1H), 1.98-1.64 (m, 5H),
1.36-1.28 (m, 2H), 0.90-0.80 (m, 6H); 13C NMR (75 MHz,
CD3OD) δ 168.5, 165.5, 160.1, 146.7, 146.2, 141.4, 136.3, 135.6,
128.8, 128.4, 128.1, 127.8, 125.6, 124.7, 122.7, 121.1, 118.8,
104.7, 80.4, 42.2, 39.4, 39.1, 36.0, 31.4, 29.5, 24.4, 16.5, 13.3,
11.9; [R]D (MeOH, c 0.80) -21°; HRMS calcd for C31H33N2O5F3S1
+ H1 603.2140, found 603.2149. Anal. (C31H33N2O5SF3) C, H,
N.
N-[3-{1(S)-(5,6-Dih ydr o-4-h ydr oxy-2-oxo-6(R)-ph en eth yl-
6-p r op yl-2H-p yr a n -3-yl)p r op yl}p h en yl]-5-tr iflu or om eth -
ylp yr id in e-2-su lfon a m id e (39d ): mp 156-159 °C; 1H NMR
(CD3OD) δ 8.90 (s, 1H), 8.16 (d, J ) 8.3 Hz, 1H), 8.00 (d, J )
8.2 Hz, 1H), 7.26 (s, 1H), 7.20-6.97 (m, 7H), 6.88 (d, J ) 6.9
Hz, 2H), 3.95 (dd, J ) 6.9, 9.2 Hz, 1H), 2.69-2.40 (m, 4H),
2.20-2.10 (m, 1H), 1.96-1.82 (m, 2H), 1.79-1.61 (m, 3H),
1.40-1.28 (m, 2H), 0.94-0.80 (m, 6H); 13C NMR (75 MHz,
CD3OD) δ 168.2, 165.5, 160.1, 146.6, 146.0, 141.4, 136.3, 135.6,
128.8, 128.4, 128.1, 127.8, 125.5, 124.8, 122.8, 121.0, 118.8,
104.8, 80.4, 41.8, 39.4, 39.0, 36.0, 31.4, 29.4, 24.2, 16.5, 13.3,
11.8; [R]D (MeOH, c 1.5) -31°; HRMS calcd for C31H33N2O5F3S1
+ H1 603.2140, found 603.2154. Anal. (C31H33N2O5SF3) C, H,
N.
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Ack n ow led gm en t. We thank Tom M. J udge for
synthesis of compound 39a and J eanette K. Morris for
synthesis of compounds 39c and 39d .
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