Synthesis of novel, potent, diol-based HIV-1 protease inhibitors via intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal

Article abstract of DOI:10.1021/jm0011171

The synthesis of novel, potent, diol-based HIV-1 protease inhibitors, having phenethyl groups (-CH₂CH₂Ph) in P1/P1′ position is described. An intermolecular pinacol homocoupling of (2S)-2-benzyloxymethyl-4-phenylbutanal 16 was the ke

Full text of DOI:10.1021/jm0011171

J . Med. Chem. 2001, 44, 3407-3416
3407
Syn th esis of Novel, P oten t, Diol-Ba sed HIV-1 P r otea se In h ibitor s via
In ter m olecu la r P in a col Hom ocou p lin g of
(2S)-2-Ben zyloxym eth yl-4-p h en ylbu ta n a l
Anna Mu¨hlman,† J immy Lindberg,‡ Bjo¨rn Classon,†,§ Torsten Unge,‡ Anders Hallberg,|| and
Bertil Samuelsson*,†,§
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden;
Department of Cell and Molecular Biology, BMC, Uppsala University, Box 596, SE-751 24 Uppsala, Sweden;
Department of Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden
Received November 20, 2000
The synthesis of novel, potent, diol-based HIV-1 protease inhibitors, having phenethyl groups
(-CH2CH2Ph) in P1/P1′ position is described. An intermolecular pinacol homocoupling of (2S)-
2-benzyloxymethyl-4-phenylbutanal 16 was the key step in the synthesis. From this reaction
sequence four carba analogues, compounds 8a , 8b, 9a , and 9b, were prepared, having the
inverted configuration of one or both of the stereogenic centers carrying the diol hydroxyls as
compared to the parent series represented by inhibitors 6 and 7. Inhibitor 8b was found to be
a potent inhibitor of HIV-1 protease (PR), showing excellent antiviral activity in the cell-based
assay and in the presence of 40% human serum. The absolute stereochemistry of the central
diol of the potent inhibitor (8b) was determined from the X-ray crystallographic structure of
its complex with HIV-1 PR.
In tr od u ction
The human immunodeficiency virus (HIV) is the
causative agent of acquired immunodeficiency syndrome
(AIDS).1-5 The human immunodeficiency virus type 1
(HIV-1) encodes for an aspartic protease, which is
essential for the formation of mature, infectious virus.6-8
The intense efforts to discover inhibitors of this protease
have resulted in numerous reports,9-15 and efficacious
drugs are on the market.16 At present, five protease
inhibitors are approved by the US Food and Drug
Administration (FDA): saquinavir (1),17 nelfinavir (2),18
ritonavir (3),19 indinavir (4),20,21 and amprenavir (5)22
(Figure 1). These inhibitors are all nonsymmetric,
although early elegant efforts were made to take
advantage of the C2-symmetry of the HIV-1 protease.23
We have more recently discovered that L-mannaric
acid is a promising scaffold for the design and synthesis
of potent C2-symmetric HIV-1 protease inhibitors.24
Among these, compounds 6 and 7 in particular (Figure
2) have been shown to be potent HIV-1 protease inhibi-
tors in vitro. The impact of the stereochemistry of the
stereogenic centers carrying the central diol on the
activity of inhibitor 7 has also been thoroughly inves-
tigated.25 An unusual feature of these inhibitors is that
they are readily available in just three chemical steps
starting from commercially available materials.
Four of the HIV-1 PR inhibitors in clinic comprise a
P1/P1′ benzyl substituent, while a benzyloxy group is
* To whom correspondence should be addressed. Phone: +46 8
6083100. Fax: +46 8 6083199. E-mail: bertil.samuelsson@medivir.se.
F igu r e 1. FDA-approved HIV-1 protease inhibitors.
† Department of Organic Chemistry, Arrhenius Laboratory.
‡ Department of Cell and Molecular Biology, BMC, Uppsala Uni-
present in the carbohydrate-based inhibitors. This dif-
ference raises the question as to the influence of the P1/
P1′ oxygen atom on the anti-HIV activity for the latter
class of inhibitors.
versity.
§ Additional address: Medivir AB, Lunastigen 7, SE-141 44
Huddinge, Sweden.
|| Department of Organic Pharmaceutical Chemistry, BMC, Uppsala
University.
10.1021/jm0011171 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/11/2001

3408 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21
Mu¨hlman et al.
Sch em e 1
F igu r e 2.
synthesized in 95% yield from (1R,2S)-1-amino-2-
indanol by treatment with triphosgene and NEt3 in
CH2Cl2,27,28 was coupled with the acid chloride in the
presence of NaH in DMF to give 12 in 74% yield.29,30
Hydroxymethylation of 12, utilizing 1,3,5-trioxane in the
presence of TiCl4 and N-ethyldiisopropylamine (DIEA)
in CH2Cl2 afforded 74% yield of diastereomerically pure
(as determined by NMR) 13.31 It was observed that
during acidic workup conditions, dimerization of 13, via
acetal formation, occurred to some extent. However,
neutralization and immediate purification by silica gel
column chromatography eliminated this side reaction.
Benzylation of 13 with benzyl-2,2,2-trichloroacetimidate
in dioxane with a catalytic amount of TMS-OTf pro-
duced 14 in 89% yield.32,33 The subsequent reduction of
14 with LAH in THF gave 83% yield of enantiomerically
pure (Mosher’s ester methodology34) alcohol 15, which
was oxidized to (2S)-2-benzyloxymethyl-4-phenylbuta-
nal 16 (82% yield) by a Swern oxidation.35
The diols 17a -c were synthesized via a vanadium(II)-
promoted pinacol homocoupling of aldehyde 16 (Scheme
2), using the vanadium(III) chloride-tetrahydrofuran
complex (VCl3(THF)3), which was reduced by zinc dust
in CH2Cl2, to form a dimeric vanadium(II) structure.36
According to the literature, to achieve a high yield and
stereoselectivity in cross-coupling reactions of this type,
it is required of at least one of the aldehyde reactants
to be activated, i.e., contain a carbonyl group, prefer-
entially an amide or ester carbonyl, in the γ-position to
allow for a vanadium chelation-accelerated process or,
alternatively, that one of the aldehydes is present in
excess.37-39 The carbonyl group is proposed to form a
seven-membered chelate ring with the vanadium(II)
complex, thereby enhancing the rate of the reaction and
improve stereoselectivity.
F igu r e 3.
From examination of the X-ray crystallographic struc-
ture of the HIV-1 protease complex of 6 and the
isoleucine analogue of 7, it is evident that the hydroxyl
groups of the central diol do not bind symmetrically to
the active site Asp 25/125 residues. One of the hydroxyl
groups forms hydrogen bonds with both carboxyl groups,
while the other hydroxyl group points away from the
active site but still maintains one hydrogen bond to one
of the Asp residues. It could thus be anticipated that
the structural modification of atoms engaged in the
anchoring of the P1/P1′ substituents to the backbone
would have effects on the preferred chirality of the
stereogenic centers carrying the central diol in this
series. Thus, it seemed important to prepare the carba
analogues to elucidate the SAR of the promising C2-
symmetric HIV-1 PR inhibitors.
We herein describe the synthesis of two out of three
possible stereoisomers of the diol for the carba analogues
of 6 and 7. The pinacol homocoupling synthetic strategy
provided an entry into the carba analogues 8a , 8b and
9a , 9b (Figure 3) that were synthesized and evaluated
for anti-HIV activity. Compound 8b was unexpectedly
revealed to be a very potent inhibitor, even better than
the parent inhibitor 6.
Resu lts a n d Discu ssion
Ch em istr y. 4-Phenylbutyric acid 10 was converted
to the corresponding acid chloride in 98% yield using
SOCl2-pyridine (Scheme 1).26 The chiral auxiliary,
(4R,5S)-indano[1,2-d]oxazolidin-2-one (11), which was
The aldehyde 16 lacks a carbonyl group in γ-position,
and there is no preference for formation of this type of
related complex in the present case. On the other hand,
the ether oxygen oxygen atom in aldehyde 16 might

Novel, Potent, Diol-Based HIV-1 Protease Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21 3409
Sch em e 2
provide a substitute for the carbonyl group and a
chelation, depicted in Figure 4, can be anticipated.36
However, the pinacol homocoupling of aldehyde 16
provides equal amounts of 17a and an inseparable
mixture of compounds 17b/c, suggesting that no che-
lation contributing to stereochemical induction is oper-
ating.
Several different experimental procedures for achiev-
ing this coupling have been described involving varia-
tions in (a) the relative amounts of reagents employed,
(b) the temperature, (c) the procedure for workup, and
(d) the presence or absence of external complexing
agents.40-42
of the complexing agent 1,3-dimethyl-2-imidazolidinone
(DMI) and 1 equiv of aldehyde 16, at room temperature
for 4 h followed by workup under acidic conditions.
Under these conditions, all possible isomers were formed,
albeit in a low crude yield (38%). No improvement was
encountered after a longer reaction time. The carboxylic
acid derived from oxidation of aldehyde 16 constituted
the main byproduct.
Reaction with an excess amount of zinc dust present
(2 equiv instead of 1.4 equiv) and reaction in a larger
scale (2-4 g instead of 50-100 mg of 16) resulted in
significant improvements. Thus, this alteration changed
the total crude yield to 81% and the carboxylic acid was
not formed. Instead, a minor amount of alcohol 15 could
be isolated (5%). The presence of excess zinc has
previously been reported to enhance the rate and yield
of sluggish reactions between nonchelating aldehydes
and paraformaldehyde.43 Regeneration of vanadium(II)
ions from vanadium(III) products accounts for this
observation. Our results indicate that employment of
excess amounts of zinc is advantageous also for homo-
coupling of nonchelating aldehydes.
At first, we attempted 1.2 equiv of VCl3(THF)3 and
1.4 equiv of zinc dust in CH2Cl2 in the presence of excess
Diols 17a were easily separated by silica gel column
chromatography from the mixture of the two C2-sym-
metric diastereomers 17b and 17c, which were used as
such in the subsequent steps. The diols 17a and the
F igu r e 4.

3410 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21
Mu¨hlman et al.
Ta ble 1. HIV-1 Protease Inhibitory Activities
mixture of 17b/c were protected as isopropylidene ketals
by treatment with 2,2-dimethoxypropane and 2-meth-
oxypropene in acetone containing (()-camphor-10-sul-
fonic acid (CSA). Subsequent, debenzylation of 18a -c
using H2, Pd/C in EtOAc in the presence of NaHCO3
and a small quantity of water gave compounds 19a -c
in an overall yield of 64% for the three steps. Oxidation
of compounds 19a -c was accomplished with RuCl3 and
NaIO4 in CH3CN-CH2Cl2-H2O 2:2:3.44 The corre-
sponding dicarboxylic acids were immediately converted
to the active esters by treatment with N,N-disuccin-
imidyl carbonate (DSC) and pyridine in CH3CN.45 Di-
ester 20a was isolated in 22% overall yield for the two
steps and 20b/c in 43% yield. Compounds 20b and 20c
were now easily separated by silica gel column chro-
matography, to give a 1:4 ratio of 20b to 20c. The abso-
lute stereochemistry of compound 20b was deducted
from the X-ray crystallographic structure of the complex
between compound 8b and HIV-1 protease (see below).
compd
Ki (nM)
ED50 (µM)
ED50+hsb(µM)
6a
0.60
0.80
28
1.1
112
0.096
1.3
1.5
34
15
7a
8a
8b
9a
9b
>10
0.093
>10
0.39
>10
1.4
0.40
1.9
The preferred amines used in the subsequent cou-
plings, (1S,2R)-1-amino-2-indanol and H-Val-NHMe,
were selected on the basis of our previous work.24 Each
of compounds 20a -c were thus coupled with (1S,2R)-
1-amino-2-indanol in 1,2-dichloroethane (DCE) at 60 °C
to give compounds 21a -c.
a
b
See Figure 2. hs ) 50% human serum for 6 and 7 and 40%
human serum for 8a , 8b and 9a , 9b.
rying the central diols compared to inhibitor 6 and 7
(Ki ) 0.60 and 0.80 nM, respectively).
These results can be compared to earlier findings,25
where the diol epimer of inhibitor 7 was shown to be
100 times less active than inhibitor 7 itself. Kempf et
al. have, on the other hand, reported that small differ-
ences in potencies can be observed between various
diastereomeric diols, within certain series of inhibi-
tors.47,48
The final deprotection of the isopropylidene groups
proved to be a challenge. Hydrolysis using FeCl3‚6H2O
46
in CH2Cl2 was initially attempted, for which good
results have been obtained previously. Compound 21a
was successfully deprotected using this reagent to give
47% overall yield for the two steps of the unsymmetric
target molecule 8a . Deprotection of compound 21b,
using the same procedure with the modification that the
solvent was coevaporated several times in order to
remove the acetone formed in the reaction, yielded the
C2-symmetric target molecule 8b in 58% overall yield
for the two steps.
Compound 8b showed good antiviral activity (ED50
) 0.093 µM) in the cell-based assay and even more
promising was the relatively small drop (3 times) in
antiviral activity in the presence of 40% human serum
(ED50+40% hs ) 0. 39 µM), whereas compound 9b was
found to be less active (ED50 ) 1.9 µM) when tested in
cell culture and also in the presence of 40% human
serum (ED50+40% hs ) 1.4 µM).
To analyze the mode of binding to the HIV-1 protease
(PR) for the most potent inhibitor 8b and to confirm the
absolute stereochemistry, 8b was cocrystallized with
HIV-1 PR and the structure solved by X-ray crystal-
lography (Figure 5).
An overall similarity in binding conformation was
observed with the recently published structure of the
parent inhibitor 6.24 The inversion of configuration of
the stereogenic centers carrying the central diol of
inhibitor 8b in comparison to inhibitor 6 was confirmed
in the electron density map. Superimposition of the
structures of 8b and 6 clearly show this difference in
configuration (Figure 6). The hydrogen-bond pattern of
the central diol to the catalytic aspartate residues
described previously was not affected with the change
of configuration in 8b.24 As a consequence of the change
in configuration, the P2′ substituent of 8b does not reach
as deep into the S2′/S3′ subsites as inhibitor 6 (Figure
7). The difference in positioning of the P2′ substituent
(0.8 Å) influences the interactions to the S2′/S3′ subsites.
The distances between the P2′ indanol hydroxyl group
of inhibitor 8b and the hydrogen-bond-accepting/-donat-
ing groups of Asp 129 (backbone nitrogen and Oδ2)
increased by 0.4 Å, thereby exceeding optimal hydrogen-
bond distances (3.14 and 3.24 Å, respectively). In
However, in the case of compound 21c, which was
isolated in 29% yield after the coupling reaction, the
isopropylidene group could not be removed despite
examining a wide series of deprotection procedures.
FeCl3‚6H2O in CH2Cl2 failed to react, whereas N-
bromosuccinimide in CH2Cl2-H2O 9:1 or 50% TFA in
CH2Cl2 resulted in the formation of several unidentified
byproducts with complete disapperance of 21c. The
acidic procedure used previously, i.e., 4% HCl/MeOH in
CH2Cl2, initially appeared promising, but the only
product that was isolated was the dilactone, formed by
hydrolysis of both the isopropylidene group and the
amide linkages followed by intramolecular lactonization.
Coupling of 20a and 20b with H-Val-NHMe in DCE at
60 °C gave 23a and 23b, whereas the coupling of 20c
could not be achieved in this manner. Several side
products were formed instead. Deprotection of com-
pound 23a and 23b was accomplished employing the
same procedure as for 8b, which gave the unsymmetric
compound 9a in 7% overall yield for the two steps and
the C2-symmetric compound 9b in 22% yield.
An ti-HIV-1 Activity a n d 3-D Str u ctu r e. The target
molecules 8a , 8b and 9a , 9b were tested for anti-HIV
activity (Table 1). Surprisingly, compounds 8b and 9b
were found to be very potent inhibitors (Ki ) 1.1 and
0.40 nM, respectively) considering that they have the
opposite configurations of the stereogenic centers car-

Novel, Potent, Diol-Based HIV-1 Protease Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21 3411
F igu r e 7. Conformational comparison of inhibitors 6 (dark)
and 8b (light) when bound to the HIV-1 PR active site. The
difference in configuration of stereogenic centers carrying the
central diol affects the positioning of the P1′ and P2′ substit-
uents into respective subsites. Consequently, when comparing
the positioning of the P1′/P2′ substituents of 8b and 6, P1′ of
8a and P2′ of 6 reach deeper into respective subsites (0.3 and
0.8 Å, respectively). The image has been compiled using the
protein modeling software O49 and the web-based imaging
program MOLRAY.50
F igu r e 5. Schematic drawing of inhibitor 8b complexed with
HIV-1 PR. Interatomic distances for possible hydrogen bonds
are shown in Å.
to the P2′ substituent, the P1′ substituent is positioned
0.3 Å deeper in the S1′ subsite compared to the P1′
substituent of 6 (Figure 7). As a consequence of close-
packing interactions to the P2/P2′ substituent and S1/
S1′ subsites, the phenyl rings are held coplanar for both
inhibitors. In conclusion, the exchange of the ether
oxygen for a methylene group in the P1/P1′ substituents
induces minor orientational and positional shifts with
negligible effects on binding efficacy to the S1/S1′
subsites. The configuration of the central diol in inhibi-
tor 8b is confirmed to be (R,R), consequently compound
21c is the (S,S)-diol and inhibitor 9b is the (R,R)-diol.
Con clu sion
The present carba analogues of inhibitor 6 show a
novel SAR pattern relating to the diol stereochemistry.
This highlights the importance of validating optimal diol
stereochemistry, by synthesis and screening, while C2-
symmetric inhibitors are optimized. A very promising
feature of the potent inhibitor 8b is that although it is
more lipophilic and less potent than inhibitor 6, it shows
better antiviral activity in the presence of 40% human
serum (ED50+40% hs ) 0.39 µM, cf. ED50+50% hs )
1.5 µM for inhibitor 6), a screening parameter important
for clinical efficacy. The preparation of the correspond-
ing (S,S)-diol is currently being investigated by an
alternative synthetic route.
F igu r e 6. Fo - Fc inhibitor-omit electron density map for 8b
contoured at 1σ, showing the superimposition of the central
diol of 8b (light) and 6 (dark). The inversion of configuration
of inhibitor 8b in contrast to inhibitor 6 was confirmed in the
electron density map. The image has been compiled using the
protein modeling software O49 and the web-based imaging
program MOLRAY.50
contrast, optimal distances were observed for inhibitor
6 (2.73 and 2.78 Å, respectively). Replacing the O-
benzylated P1/P1′ substituents of inhibitor 6 with
phenethyl (-CH2CH2Ph) P1/P1′ substituents as in
inhibitor 8b adds different angular restraints between
the atoms. This is observed in the structure as an
orientation change of the P1/P1′ substituents of 8b
compared to 6 (Figure 7). The ether oxygen of inhibitor
6 can in theory act as a hydrogen-bond acceptor.
However, its closest neighbor, WAT307, is not in range
for hydrogen-bond formation (4.8 Å). Hence, a methyl-
ene group in that position does not reduce binding as a
consequence of fewer interactions. More likely the
hydrophobic contribution of the methylene group has
positive effects on binding to the highly lipophilic S1/
S1′ subsites. The positioning of the P1′ substituent of
8b is also affected by the configuration change of the
stereogenic centers carrying the central diol. As opposed
Exp er im en ta l Section
Cr ysta llogr a p h y. The details of the crystallization and
structure determination will be published elsewhere. Briefly,
the complex of HIV-1 PR and 8b was crystallized in space
group P21212 and determined to 2.0 Å resolution with an
R-value of 0.21 (Rfree 0.24).
HIV-1 P r otea se In h ibition (Ta ble 1, Colu m n 2). HIV-1
protease was cloned and heterologously expressed in Escheri-
chia coli,51 and Ki values were determined using a fluorometric
assay.52
In Vitr o An ti-HIV Activity (Ta ble 1, Colu m n 3). The
anti-HIV activity was measured in a HIV cytopathic assay in
MT-4 cells, where the effect was quantified using vital dye
XTT.53 The 50% inhibitory concentrations (ED50) were calcu-
lated from the percent cytoprotection for individual com-
pounds.
Gen er a l. All glassware was dried over an open flame before
use in connection with an inert atmosphere. Concentrations
were performed under reduced pressure at <40 °C (bath

3412 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21
Mu¨hlman et al.
temperature). Thin-layer chromatography was performed us-
ing silica gel 60 F-254 plates with detection by UV and
charring with 8% sulfuric acid and/or treatment with nin-
hydrin in ethanol. Silica gel (0.040-0.063 mm) was used for
column chromatography. Me4Si (0.0 ppm) was used as an
equiv) were added, and stirring was continued until TLC (Rf
0.15, toluene-EtOAc 10:1) showed complete reaction (3 h).
During this time the color of the reaction changed from dark
red to light brown. Neutralization (pH ) 7) of the cold reaction
was performed by adding saturated aqueous NaHCO3 (500
mL). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (4×). The combined organic layers were
dried (Na2SO4) and concentrated. The crude product was
immediately purified using column chromatography (toluene;
toluene-EtOAc 10:1) to give alcohol 13 (8.1 g, 23.0 mmol, 74%)
1
internal standard in H NMR, and Me4Si or CDCl3 (77.0 ppm)
was used in 13C NMR. Melting points are uncorrected. Unless
stated otherwise, all materials were obtained from commercial
suppliers and used without further purification. Yields are not
optimized.
as a colorless syrup, which solidified upon standing: [R]20
D
(4R,5S)-In d a n o[1,2-d ]oxa zolid in -2-on e (11). (1R,2S)-1-
Amino-2-indanol (18.4 g, 0.125 mol) was dissolved in CH2Cl2
(1350 mL) under a nitrogen atmosphere. The temperature was
lowered to 0 °C before addition of triphosgene (14.8 g, 49.9
mmol, 0.4 equiv) and NEt3 (35.0 mL, 0.251 mol, 2.0 equiv).
Stirring was continued at 0 °C for 1.5 h, when TLC (Rf 0.39,
CHCl3-MeOH 15:1) showed completion of the reaction. The
mixture was concentrated to 675 mL and washed with NH4Cl
(1×) and H2O (2×) and the combined aqueous layers were
extracted with EtOAc (2×). The organic layers were combined
with the mixture from above, dried (MgSO4), and concentrated
1
-174 (c 1.19, CHCl3); H NMR (300 MHz, CDCl3) δ 1.58 (s, 1
H), 1.90-2.02 (m, 1 H), 2.15-2.24 (m, 1 H), 2.63-2.84 (m, 2
H), 3.36 (d, 2 H, J ) 3.52 Hz), 3.84 (m, 2 H), 3.94-4.02 (m, 1
H), 5.14-5.19 (m, 1 H), 5.72 (d, 1 H, J ) 7.03 Hz), 7.18-7.36
(m, 8 H), and 7.58 (d, 1 H, J ) 7.47 Hz); 13C NMR (67 MHz,
CDCl3) δ 29.9, 33.8, 37.7, 45.2, 63.2, 63.8, 78.2, 125.1, 126.0,
127.1, 128.2, 128.3, 128.6, 129.8, 138.9, 139.3, 141.2, 152.9,
and 175.9. Anal. (C21H21NO4) C, H, N.
N-[(2S)-2-(Ben zyloxym eth yl)-4-p h en ylbu tyr yl]-(4R,5S)-
in d a n o[1,2-d ]oxa zolid in -2-on e (14). To a stirred solution of
alcohol 13 (18.2 g, 51.7 mmol) and benzyl 2,2,2-trichloro-
acetimidate (11.6 mL, 62.4 mmol, 1.2 equiv) in 1,4-dioxane (900
mL) was added TMS-OTf (0.9 mL, 4.96 mmol, 0.1 equiv)
dropwise under argon. Within 1 h the color changed to brown-
yellow and TLC (Rf 0.47, toluene-EtOAc 10:1) showed comple-
tion of the reaction. The reaction mixture was filtered through
to give 11 (20.9 g, 0.119 mol, 95%) as white crystals: [R]20
D
+71 (c 0.65, EtOAc); mp 200-201 °C; 1H NMR (300 MHz,
CDCl3 and CD3OD) δ 3.32 (dd, 1 H, J ) 1.76, 18.0 Hz), 3.43
(dd, 1 H, J ) 6.15, 18.0 Hz), 3.74 (s, 1 H), 5.18 (d, 1 H, J )
7.47 Hz), and 5.42 (ddd, 1 H, J ) 1.76, 6.15, 7.47 Hz); 13C NMR
(67 MHz, CDCl3 and CD3OD) δ 38.5, 61.0, 80.5, 124.6, 125.3,
127.6, 129.1, 139.5, 140.1, and 159.9. Anal. (C10H9NO2) C, H,
N.
a
pad of SiO2/NaHCO3/SiO2 in a glass filter-funnel and
concentrated. Purification by column chromatography (toluene-
EtOAc 40:1) gave the benzylated compound 14 (20.2 g, 45.8
N-(4-P h en ylbu tyr yl)-(4R,5S)-in d a n o[1,2-d ]oxa zolid in -
2-on e (12). To a stirred solution of 4-phenylbutyric acid 10
(35.0 g, 0.214 mol) and SOCl2 (98 mL, 1.34 mol, 6.3 equiv) was
added pyridine (0.64 mL, 7.9 mmol, 0.04 equiv). The solution
was stirred at room temperature for 30 min and at 40 °C for
an additional 1 h before it was concentrated to give 4-phenyl-
butanoyl chloride (38.3 g, 0.210 mol, 98%) as a yellow oil, which
was used in the next step without further purification: 1H
NMR (300 MHz, CDCl3) δ 2.03 (dt, 2 H, J ) 7.6, 7.3 Hz), 2.67
(t, 2 H, J ) 7.6 Hz), 2.88 (t, 2 H, J ) 7.3 Hz), and 7.15-7.32
(m, 5 H); 13C NMR (67 MHz, CDCl3) δ 26.4, 34.0, 46.1, 126.2,
128.3, 128.4, 140.2, and 173.4.
mmol, 89%) as a colorless syrup: [R]20 -117 (c 1.16, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 1.87-1.98 (m, 1H), 2.15-2.27
(m, 1 H), 2.61-2.78 (m, 2 H), 3.35 (d, 2 H, J ) 3.08 Hz), 3.64
(dd, 1 H, J ) 5.27, 9.22 Hz), 3.78 (dd, 1 H, J ) 7.03, 9.22 Hz)
4.23 (m, 1 H), 4.41 (s, 2 H), 5.13-5.17 (m, 1 H), 5.78 (d, 1 H,
J ) 7.03 Hz), 7.11-7.47 (m, 14 H), and 7.55 (d, 1 H, J ) 7.91
Hz); 13C NMR (67 MHz, CDCl3) δ 30.3, 33.7, 37.8, 43.2, 63.0,
71.2, 72.9, 77.8, 125.0, 126.0, 127.2, 127.3, 128.0, 128.2, 128.3,
128.6, 129.7, 138.1, 139.1, 139.3, 141.4, 152.6, and 174.8. Anal.
(C28H27NO4) C, H, N.
(2R)-2-(Ben zyloxym eth yl)-4-p h en yl-1-bu ta n ol (15). The
benzylated compound 14 (3.85 g, 8.72 mmol) was dissolved in
THF (90 mL) under an argon atmosphere, the temperature
was lowered to -60 °C, and LAH (3.38 g, 89.0 mmol, 10 equiv)
was added. Stirring was continued at -60 °C for 30 min and
at 0 °C for 1 h (Rf 0.2, toluene-EtOAc 9:1). The reaction
mixture was acidified by the addition of cold 0.6 M HCl. The
suspension was extracted with Et2O (5×), and the combined
organic layers were dried (MgSO4) and concentrated. Purifica-
tion by column chromatography (toluene-EtOAc 3:1) gave
NaH (1.61 g, 67.1 mmol, 1.1 equiv) was suspended in DMF
(150 mL) under an argon atmosphere and the temperature was
lowered to 0 °C. A dropping funnel was charged with the chiral
auxiliary 11 (10.7 g, 61.2 mmol) in DMF (90 mL), a second
dropping funnel was charged with 4-phenylbutanoyl chloride
(13.4 g, 73.4 mmol, 1.2 equiv) in DMF (90 mL), and the two
solutions were then added simultaneously to the stirred NaH
suspension during 30 min. Stirring was continued at 0 °C for
an additional 3 h (Rf 0.56, toluene-EtOAc 10:1), before slow
addition of MeOH and H2O. The layers were separated after
dilution with toluene and H2O. The organic layer was washed
with H2O (2x), followed by extraction of the combined aqueous
layers with toluene (1×). Finally, the combined organic layers
were dried (Na2SO4) and concentrated. Purification by column
chromatography (toluene; toluene-EtOAc 40:1) gave 12 (14.3
alcohol 15 (1.96 g, 7.25 mmol, 83%) as a colorless oil: [R]20
D
1
+14 (c 0.90, CHCl3); H NMR (400 MHz, CDCl3) δ 1.57-1.71
(m, 2 H), 1.86-1.93 (m, 1 H), 2.49 (s, 1 H), 2.57-2.67 (m, 2
H), 3.50-3.53 (m, 1 H), 3.62-3.69 (m, 2 H), 3.74-3.78 (m, 1
H), 4.51 (q, 2 H, J ) 12.1 and 17.6 Hz), and 7.15-7.36 (m, 10
H); 13C NMR (67 MHz, CDCl3) δ 29.8, 33.3, 40.1, 65.5, 73.4,
125.8, 127.6, 127.7, 128.3, 128.4, 138.0, and 142.1. Anal.
(C18H22O2) C, H.
(2S)-2-[(Ben zyloxym eth yl)-4-p h en ylbu tyl] (2R)-3,3,3-
Tr iflu or o-2-m eth oxy-2-p h en ylp r op a n oa te. The Mosher’s
ester of alcohol 15 was prepared according to the method
described by Wipf and Fritch,34 using 26 mg (0.096 mmol) of
15 in 1.4 mL of CH2Cl2 together with 580 µL of pyridine and
210 µL of (S)-(+)-R-methoxy-R-(trifluoromethyl)phenylacetic
acid chloride with stirring during 40 min. Purification by
column chromatography (toluene-EtOAc 40:1) gave the ester
(38 mg, 0.078 mmol, 81%) as an oil: 13C NMR (75 MHz, CDCl3)
δ 29.9, 33.1, 37.8, 55.4, 66.4, 69.6, 73.2, 121.3, 125.2, 125.8,
127.2, 127.4, 127.5, 128.2, 128.3, 129.5, 132.2, 138.1, 141.5,
and 166.4.
g, 44.5 mmol, 73%) as a colorless syrup: [R]20 -209 (c 0.948,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.98-2.08 (m, 2 H), 2.70
(t, 2 H, J ) 7.69 Hz), 3.00 (ddd, 2 H, J ) 1.76, 7.47, 9.23 Hz),
3.37 (d, 2 H, J ) 3.52 Hz), 5.26 (ddd, 1 H, J ) 3.08, 4.40, 7.47
Hz), 5.91 (d, 1 H, J ) 7.03 Hz), 7.16-7.37 (m, 8 H), and 7.62
(d, 1 H, J ) 7.03 Hz); 13C NMR (67 MHz, CDCl3) δ 26.0, 34.8,
35.2, 38.0, 63.0, 78.0, 125.2, 126.0, 127.2, 128.2, 128.4, 128.5,
129.8, 139.2, 139.5, 141.6, 153.0, and 173.4. Anal. (C20H19NO3)
C, H, N.
N-[(2S)-2-(Hyd r oxym eth yl)-4-p h en ylbu tyr yl]-(4R,5S)-
in d a n o[1,2-d ]oxa zolid in -2-on e (13). TiCl4 (3.6 mL, 32.8
mmol, 1.05 equiv) was added to a stirred solution of compound
12 (10.0 g, 31.1 mmol) in CH2Cl2 (525 mL), under an argon
atmosphere, with the temperature kept at 0 °C. A yellow
precipitate was formed within 30 min, DIEA (5.5 mL, 31.9
mmol, 1.0 equiv) was added (the color changed from yellow to
red), and stirring was continued at 0 °C for 1 h. Trioxane (2.08
g, 23.1 mmol, 0.74 equiv) and TiCl4 (4.5 mL, 40.9 mmol, 1.3
2-[(Ben zyloxym et h yl)-4-p h en ylb u t yl] (2R)-3,3,3-Tr i-
flu or o-2-m eth oxy-2-p h en ylp r op a n oa te. The racemic alco-
hol 15 was prepared by monobenzylation of 2-phenethyl-
propane-1,3-diol54 (1.0 equiv) using NaH (1.02 equiv) and BnBr

Novel, Potent, Diol-Based HIV-1 Protease Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21 3413
(1.02 equiv) in DMF under an atmosphere of nitrogen (0 °C to
room temperature, 2 h), which after column chromatography
produced a 62% yield of racemic alcohol 15 as a transparent
syrup. The Mosher’s ester of racemic 15 was prepared as
described above using 20 mg (0.074 mmol) of racemic 15, which
gave the racemic ester (28 mg, 0.058 mmol, 78%) as an oil:
13C NMR (75 MHz, CDCl3) δ 29.8, 29.9, 33.0, 37.8 (2 C), 55.4,
66.2, 66.4, 69.6, 69.7, 73.2, 121.4, 125.2, 125.8, 127.2, 127.4 (2
C), 127.5, 128.2, 128.3, 129.5, 138.1, and 141.5.
127.8, 128.1, 128.2 (2 C), 128.3 (2 C), 137.4, 137.7, 142.2, and
142.4.
(17b and 17c): 13C NMR (75 MHz, CDCl3) δ 28.5, 31.1, 33.5,
33.8, 40.7 (2 C), 70.3, 70.4, 72.6, 73.4, 73.7, 73.9, 125.7 (2 C),
127.5, 127.6 (2 C), 127.7, 128.2 (2 C), 128.3 (2 C), 137.7, 142.2,
and 142.1.
St ep II. Isop r op ylid en e P r ot ect ion . 2,2-Dimethoxy-
propane (2.5 equiv) and CSA (0.8 equiv) were added to a
solution of 17a -c (1.0 equiv) in acetone (5.3 mL/mmol) under
nitrogen. After stirring for 30 min, when TLC (Rf 18a 0.63
and Rf 18b,18 c 0.72, toluene-EtOAc 9:1) showed completion
of the reaction, the reaction mixture was poured into saturated
aqueous NaHCO3 and extracted with EtOAc (3×). Activated
charcoal and Na2SO4 were added to the organic layer, which
was stirred for 10 min before filtration through a pad of Celite
and Na2SO4 and concentration. Column chromatography
(toluene; toluene-EtOAc 20:1 and 9:1) gave the crude product,
which was used in the next step without further purification.
18a . The isopropylidene-protected compound was prepared
according to step II, using 2.29 g of 17a , and isolated as a white
solid (2.29 g): 13C NMR (75 MHz, CDCl3) δ 25.1, 26.2, 29.6,
31.0, 33.0, 33.3, 38.0, 38.2, 69.6, 71.1, 73.0, 73.1, 77.1, 77.5,
106.9, 125.6 (2 C), 127.3 (2 C), 127.4, 128.1, 128.2 (3 C), 128.3,
128.4, 138.5, 138.8, 142.3, and 142.4.
18b and 18c. The isopropylidene-protected compounds was
prepared according to step II, using 2.16 g of the mixture 17b
and 17c, and isolated a transparent syrup (1.95 g). After
column chromatography a small amount of alcohol 15 (265 mg,
0.980 mmol) was isolated as well. 13C NMR (75 MHz, CDCl3)
δ 27.4, 28.6, 31.5, 33.4, 33.8, 40.2, 40.7, 69.4, 70.7, 72.9, 73.0,
79.1, 79.3, 107.5, 107.8, 125.6, 125.7, 127.3 (2 C), 127.5, 128.1,
128.2 (2 C), 128.3, 138.4 (2 C), 142.2, and 142.3.
(2S)-2-(Ben zyloxym eth yl)-4-p h en ylbu ta n a l (16). DMSO
(4.03 mL, 56.7 mmol, 2.2 equiv) in CH2Cl2 (11.3 mL) was added
to a solution of oxalyl chloride (2.43 mL, 28.3 mmol, 1.1 equiv)
in CH2Cl2 (64 mL) at -70 °C under argon. After stirring for 5
min, alcohol 15 (6.97 g, 25.8 mmol) dissolved in CH2Cl2 (26
mL) was added dropwise (20 min). Stirring was continued for
an additional 20 min. NEt3 (7.18 mL, 54.0 mmol, 2.1 equiv)
was added, and the reaction mixture was stirred during 5 min
at -70 °C and subsequently during 1 h while the reaction
mixture slowly was allowed to attain room temperature (Rf
0.35, pentane-EtOAc 15:1 and Rf 0.57, toluene-EtOAc 9:1).
Dilution with H2O, extraction of the aqueous layer with CH2Cl2
(3×), drying (MgSO4), and concentration gave the crude
aldehyde 16. Purification by column chromatography (pen-
tane-EtOAc 25:1; 15:1 and 10:1) gave 16 (5.64 g, 21.0 mmol,
82%) as a transparent oil, which was used immediately in the
next step: [R]20 +17 (c 1.1, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 1.72-1.86 (m, 1 H), 1.97-2.12 (m, 1 H), 2.48-2.58
(m, 1 H), 2.62 (t, 2 H, J ) 7.97 Hz), 3.67 (d, 2 H, J ) 5.50 Hz),
4.47 (d, 2 H, J ) 1.65 Hz), 7.12-7.40 (m, 10 H), and 9.68 (s, 1
H); 13C NMR (75 MHz, CDCl3) δ 27.3, 32.9, 51.3, 68.3, 73.1,
125.8, 127.4, 127.5, 128.1, 128.2 (2 C), 137.6, 140.9, and 203.1.
Anal. (C18H20O2‚1/2H2O) C, H.
Step III. Deben zyla tion . Compounds 18a -c (1.0 equiv)
were dissolved in EtOAc (23 mL/mmol) and NaHCO3 (3.0
equiv), a minor amount of H2O and Pd/C (0.8 g) was added.
The suspension was stirred at room temperature under a
hydrogen atmosphere. After 19, 39, and 47 h, the suspension
was filtered through a pad of Celite and Na2SO4, fresh reagents
were added, and stirring under hydrogen was continued. When
TLC showed completion of the reaction (Rf 19a 0.33, Rf 19b,
19c 0.31, toluene-EtOAc 1:1) after 63 h, filtration and
concentration followed by column chromatography (toluene-
EtOAc 2:1) gave compounds 19a -c.
Red u ction of Ald eh yd e 16 w ith Bor a n e-Dim eth yl
Su lfid e Com p lex (BMS). Aldehyde 16 was reduced with
BMS according to the method described by Brown et al.,55
using 64 mg (0.238 mmol) of 16 in 2.0 mL of Et2O together
with 60 µL of BMS with stirring at 0 °C during 30 min,
followed by stirring at room temperature during 2.5 h.
Purification by column chromatography (toluene-EtOAc 3:1)
gave alcohol 15 (50 mg, 0.185 mmol, 78%) as an oil. Alcohol
15 (20 mg, 0.074 mmol) was converted to the Mosher’s ester
(28 mg, 0.058 mmol, 78%) according to the method described
above. 13C NMR spectral data were in agreement with those
reported above for (2S)-2-[(benzyloxymethyl)-4-phenylbutyl]
(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate.
19a . The title compound was prepared according to step III,
using 2.47 g of 18a , and isolated as a transparent syrup (1.27
1
g, 3.19 mmol): [R]20 +91 (c 1.4, CHCl3); H NMR (300 MHz,
D
(2S)-2-{(4R,5S)-5-[(1S)-1-(H yd r oxym et h yl)-3-p h en yl-
p r op yl]-2,2-d im et h yl-1,3-d ioxola n -4-yl}-4-p h en yl-1-b u -
ta n ol (19a ), (2S)-2-{(4R,5R)-5-[(1S)-1-(Hyd r oxym eth yl)-3-
p h en ylp r op yl]-2,2-d im eth yl-1,3-d ioxola n -4-yl}-4-p h en yl-
1-bu ta n ol (19b), a n d (2S)-2-{(4R,5R)-5-[(1S)-1-(Hyd r oxy-
m eth yl)-3-ph en ylpr opyl]-2,2-dim eth yl-1,3-dioxolan -4-yl}-4-
p h en yl-1-bu ta n ol (19c). Zinc dust (prewashed with 1 M HCl,
EtOH, acetone, and CH2Cl2) (2.72 g, 41.6 mg-atom, 2.0 equiv)
was added to a solution of VCl3 (THF)3 in CH2Cl2 (50 mL, 0.5
M, 25 mmol, 1.2 equiv), under an argon atmosphere, changing
the color of the solution from deep-red to violet. The mixture
was stirred at room temperature during 80 min, while the color
slowly changed from violet to black-green. DMI (16.0 mL, 146
mmol, 7.0 equiv) was added, and stirring was continued during
15 min, before dropwise addition (40 min) of aldehyde 16 (5.59
g, 20.8 mmol) dissolved in CH2Cl2 (56 mL), which gave a brown
reaction mixture. The reaction was quenched after 20 h (Rf
17a 0.32 and Rf 17b, 17c 0.21, toluene-EtOAc 9:1), by the
addition of 1 M HCl (127 mL). Stirring of the two-phase
mixture during 30 min gave a turquoise aqueous layer and a
brown organic layer, which were separated. Additional extrac-
tion of the aqueous layer with CH2Cl2 (3×), drying (MgSO4),
concentration, and subsequent separation by column chroma-
tography (toluene; toluene-EtOAc 25:1 and 15:1) gave 17a
(2.29 g) and a mixture of 17b and 17c (2.16 g), all of which
were used in the next step without further purification.
CDCl3) δ 1.26 (s, 3 H), 1.37 (s, 3 H), 1.59-1.71 (m, 4 H), 1.90
(s, 1 H), 1.97 (s, 1H), 2.12-2.28 (m, 3 H), 2.49-2.67 (m, 3 H),
3.57-3.77 (m, 4 H), 4.03-4.08 (m, 1 H), 4.29-4.32 (dd, 1 H, J
) 2.64, 6.59 Hz), and 7.03-7.25 (m, 10 H); 13C NMR (75 MHz,
CDCl3) δ 25.0, 26.1, 27.3, 30.4, 32.8, 33.1, 38.6, 39.5, 64.0, 64.2,
79.2, 81.0, 108.1, 125.8, 126.0, 128.3 (2 C), 128.4, 128.5, 141.4,
and 141.9. Anal. (C25H34O4‚1/4H2O) C, H.
19b and 19c. The mixture of the title compounds was
prepared according to step III, using 1.77 g of the mixture of
18b and 18c, and isolated as a transparent syrup (1.03 g, 2.58
mmol): 13C NMR (75 MHz, CDCl3) δ 26.9, 27.1, 27.3, 30.6, 33.3,
33.5, 40.6, 41.1, 62.2, 63.4, 79.9, 81.9, 108.8, 108.3, 125.8 (2
C), 128.2 (2 C), 128.3, 141.5, and 141.8. Anal. (C25H34O4‚1/3H2O)
C, H.
Diol 19a and the mixture of diols 19b and 19c were isolated
with a total yield of 64% over three steps (2.30 g 5.77 mmol).
A small amount of alcohol 15 (265 mg, 0.980 mmol) was also
isolated.
Gen er a l Meth od for th e P r ep a r a tion of Com p ou n d s
20a -c. Meth od I. The diols 19a -c (1.0 equiv) were dissolved
in a stirred mixture of CH3CN (4 mL/mmol), CH2Cl2 (4 mL/
mmol), and H2O (6 mL/mmol). RuCl3‚xH2O (0.05 equiv) and
NaIO4 (9.0 equiv) were added. TLC (toluene-EtOAc 1:3)
showed completion of the reaction after vigorous stirring for
105 min. The reaction mixture was diluted with CH2Cl2 (1 vol)
and stirred for an additional 10 min. Water was added (1 vol)
and the aqueous layer was extracted with EtOAc (4×). The
combined organic layers were dried (MgSO4) and concentrated
(17a ): 13C NMR (75 MHz, CDCl3) δ 26.6, 31.3, 33.8, 34.0,
38.4, 39.8, 70.2, 72.9, 73.5, 73.6 (2 C), 75.9, 125.6, 127.5, 127.7,

3414 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21
Mu¨hlman et al.
to provide the corresponding carboxylic acid, which was
immediately activated without further purification.
4.17 (d, 2 H, J ) 5.86 Hz), 4.61-4.64 (m, 2 H), 5.42 (d, 2 H, J
) 5.08 Hz), and 7.15-7.35 (m, 18 H); 13C NMR (75 MHz, CDCl3
and CD3OD) δ 26.9, 31.5, 33.1, 39.6, 50.6, 57.2, 72.5, 79.7,
108.9, 124.0, 124.9, 125.7, 126.5, 127.7, 128.0, 128.1, 139.9,
140.4, 140.7, and 173.2. Anal. (C43H48N2O6‚H2O) C, H, N.
A mixture of the carboxylic acid, DSC (5.0 equiv), and
pyridine (6.9 equiv) in CH3CN (16 mL/mmol) was stirred under
an argon atmosphere. When TLC showed completion of the
reaction after 23 h (Rf 20a 0.63, Rf 20b 0.47 and Rf 20c 0.58,
toluene-EtOAc 1:1), toluene (0.5 vol) was added and the
reaction mixture was concentrated. The residue was dissolved
in EtOAc and extracted with water (5×), and the combined
aqueous layers were washed with EtOAc (3×). The combined
organic layers were dried (Na2SO4), concentrated, and purifi-
cated by column chromatography (toluene-EtOAc 4:1) to
provide the disuccinimidyl esters 20a -c.
N1,N6-Bis[(2R)-h yd r oxy-(1S)-in d a n yl]-(2R,3R,4S,5R)-
3,4-d ih yd r oxy-2,5-bis(2-p h en yleth yl)h exa n ed ia m id e (8a ).
The title compound was prepared according to method II, using
195 mg (0.314 mmol) of the disuccinimidyl ester 20a , and
isolated as a white solid in 47% yield (96 mg, 0.148 mmol):
[R]20 +20 (c 0.94, CHCl3-MeOH 1:1); 1H NMR (400 MHz,
D
CDCl3 and CD3OD) δ 1.97-2.23 (m, 4 H), 2.61-2.85 (m, 6 H),
2.92-2.99 (m, 2 H), 3.12-3.19 (m, 2 H), 3.69 (bs, 1 H), 3.91-
3.94 (m, 1 H), 4.48 (s, 6 H), 4.54-4.61 (m, 2 H), 5.38-5.41 (m,
2 H), and 7.13-7.30 (m, 18 H); 13C NMR (75 MHz, CDCl3 and
CD3OD) δ 33.3 (2 C), 39.3, 47.0, 56.8, 56.9, 72.3, 72.4, 72.7,
73.4, 123.6, 123.8, 124.7, 125.3, 125.4, 126.5, 127.5, 127.8 (3
C), 139.7, 139.8, 140.2, 141.1, 141.5, and 175.9. Anal.
(C40H44N2O6‚11/2H2O) C, H, N.
Su ccin im id yl (2R)-2-[(4R,5S)-5-(3-P h en ylp r op yl-(1R)-
1-su ccin im id yloxyca r b on yl)-2,2-d im et h yl-1,3-d ioxola n -
4-yl]-4-p h en ylbu ta n oa te (20a ). The title compound was
prepared according to method I, using 1.14 g (2.87 mmol) of
diol 19a , and isolated as a white foam in 22% yield (393 mg,
0.633 mmol): [R]20 +19 (c 0.35, CDCl3); 13C NMR (75 MHz,
D
N1,N6-Bis[(2R)-h yd r oxy-(1S)-in d a n yl]-(2R,3R,4R,5R)-
3,4-d ih yd r oxy-2,5-bis(2-p h en yleth yl)h exa n ed ia m id e (8b).
The title compound was prepared according to method II, using
67 mg (0.108 mmol) of the disuccinimidyl ester 20c, and
isolated as a white solid in 58% yield (41 mg, 0.063 mmol):
CDCl3) δ 25.1, 25.7, 26.8, 31.8, 32.0, 32.5, 32.6, 42.2, 43.5, 76.0,
77.8, 108.9, 125.2, 125.9 (2 C), 128.1, 128.2, 128.3, 128.5, 128.7,
128.9, 140.9, 141.1, 168.2, 168.5, 168.6, and 168.8. Anal.
(C33H36N2O10) C, H, N.
Su ccin im id yl (2R)-2-[(4R,5R)-5-(3-P h en ylp r op yl-(1R)-
1-su ccin im id yloxyca r b on yl)-2,2-d im et h yl-1,3-d ioxola n -
[R]20 +30 (c 0.77, CHCl3-MeOH 1:1); 1H NMR (400 MHz,
D
4-yl]-4-p h en ylbu ta n oa te
(20b)
a n d
Su ccin im id yl
CDCl3 and CD3OD) δ 1.99-2.03 (m, 2 H), 2.05-2.15 (m, 2 H),
2.60-2.69 (m, 4 H), 2.76-2.84 (m, 2 H), 2.95 (dd, 2 H, J )
2.20, 16.48 Hz), 3.15 (dd, 2 H, J ) 5.13, 16.48 Hz), 3.81 (d, 2
H, J ) 8.79 Hz), 4.24 (s, 6 H), 4.60-4.63 (m, 2 H), 5.41 (d, 2
H, J ) 5.13 Hz), and 7.16-7.33 (m, 18 H); 13C NMR (100 MHz,
CDCl3 and CD3OD) δ 30.8, 33.4, 39.4, 50.8, 57.1, 71.6, 72.6,
124.0, 124.7, 125.5, 126.6, 127.6, 127.9, 139.8, 140.0, 141.2,
and 174.6. Anal. (C40H44N2O6‚H2O) C, H, N.
(2R)-2- [(4S,5S)-5-(3-p h en ylp r op yl-(1R)-1-su ccin im id yl-
oxyca r b on yl)-2,2-d im et h yl-1,3-d ioxola n -4-yl]-4-p h en yl-
bu ta n oa te (20c). The title compounds, separated by column
chromatography, were prepared according to method I, using
965 mg (2.42 mmol) of the mixture of diols 19b and 19c, and
isolated as white foams in 43% total yield (20b, 126 mg, 0.203
mmol; 20c, 527 mg, 0.849 mmol).
(20b): [R]20D +86 (c 0.40, CDCl3); 13C NMR (75 MHz, CDCl3)
δ 25.7, 27.4, 29.8, 32.7, 45.6, 78.8, 110.4, 126.0, 128.1, 128.3,
128.6, 128.9, 140.8, 168.3, and 168.5. Anal. (C33H36N2O10‚1/
4H2O) C, H, N.
Gen er a l Meth od for th e P r ep a r a tion of Com p ou n d s
9a a n d 9b. Meth od III. The disuccinimidyl esters 20 a -c
(1.0 equiv) and H-Val-NHMe (6.3 equiv) were dissolved in
DCE (30 mL/mmol) under a nitrogen atmosphere. The re-
action was stirred at 50 °C until TLC (Rf 23a 0.34, Rf
23b 0.41, CHCl3-MeOH 9:1) showed completion of the reac-
tion (22 h). Concentration followed by column chromatography
(CHCl3-MeOH 20:1) gave the amides 23a and 23b.
(20c): [R]20D -5.3 (c 0.75, CDCl3); 13C NMR (75 MHz, CDCl3)
δ 25.7, 27.6, 27.9, 31.4, 31.7, 32.6, 33.0, 45.0, 78.5, 80.2, 110.3,
125.2, 125.9, 126.1, 128.1, 128.3, 128.4, 128.6, 128.9, 140.4,
167.5, and 168.6. Anal. (C33H36N2O10) C, H, N.
A mixture of FeCl3‚6H2O (3.5 equiv) and the amides 23a
and 23b (1.0 equiv) was dissolved in warm CH2Cl2 (17.5 mL/
mmol) and stirred at room temperature. The reaction was
followed with TLC (Rf 9a 0.23, Rf 9b 0.40, CHCl3-MeOH 9:1),
and every other hour the reaction was concentrated and new
CH2Cl2 was added. When TLC showed completion of the
reaction (9a , 4 h and 9b, 8 h) saturated aqueous NaHCO3 (1
vol) was added and the aqueous layer was extracted with
CH2Cl2 (3×) and EtOAc (3×). Drying (MgSO4), concen-
tration, and purification by column chromatography (CHCl3;
CHCl3-MeOH 30:1 and 20:1), followed by trituration from
EtOAc, gave the target compounds 9a and 9b.
23a : 13C NMR (75 MHz, CDCl3 and CD3OD) δ 19.0, 24.3,
25.6, 25.7, 25.8, 30.8, 31.0, 31.6, 32.0, 32.3, 33.0, 46.1, 46.5,
58.5, 59.0, 76.4, 77.9, 107.7, 125.8, 128.0, 128.2, 140.9, 141.6,
172.1, 172.2, 173.0, and 174.0.
23b: 13C NMR (75 MHz, CDCl3) δ 18.6, 19.5, 26.2, 27.2, 29.7,
30.6, 33.6, 49.1, 58.8, 79.1, 109.1, 125.9, 128.3, 141.2, 171.6,
and 172.6.
Gen er a l Meth od for th e P r ep a r a tion of Com p ou n d s
8a a n d 8b. Meth od II. The disuccinimidyl esters 20a -c (1.0
equiv) and (1S,2R)-1-amino-2-indanol (6.3 equiv) were dis-
solved in DCE (30 mL/mmol) under a nitrogen atmosphere.
The reaction was stirred at 60 °C until TLC (Rf 21a 0.31, Rf
21b 0.43 and Rf 21c 0.19, toluene-EtOAc 1:1) showed comple-
tion of the reaction (16-20 h). Concentration followed by
column chromatography (toluene-EtOAc 3:1 and 1:1) gave the
amides 21a -c.
A mixture of FeCl3‚6H2O (3.5 equiv) and the amides 21a
and 21b (1.0 equiv) were dissolved in warm CH2Cl2 (15 mL/
mmol) and stirred at room temperature for 1 and 8 h,
respectively; for compound 21b, the reaction was concentrated
and new CH2Cl2 was added every other hour (Rf 8a 0.18, Rf
8b 0.21, CHCl3-MeOH 20:1). Saturated aqueous NaHCO3 (1
vol) was added and the aqueous layer was extracted with
CH2Cl2 (3×) and EtOAc (3×). Drying (MgSO4), concen-
tration, and purification by column chromatography (CHCl3;
CHCl3-MeOH 40:1 and 30:1), followed by trituration from
EtOAc, gave the target compounds 8a and 8b.
N1,N6-Bis[(1S)-2-m eth yl-1-(m eth ylca r ba m oyl)p r op yl]-
(2R,3R,4S,5R)-3,4-d ih yd r oxy-2,5-b is(2-p h en ylet h yl)h ex-
a n ed ia m id e (9a ). The title compound was prepared according
to method III, using 153 mg (0.247 mmol) of the disuccinimidyl
ester 20b, and isolated as a white solid in 7% yield (10 mg,
21a : 13C NMR (75 MHz, CDCl3) δ 23.3, 25.4, 32.7, 32.9, 33.4,
34.0, 39.2, 39.7, 46.1, 46.7, 58.0, 58.2, 73.4, 73.6, 77.4, 77.7,
107.5, 123.6, 125.0, 125.3, 125.4, 125.9, 126.0, 126.8, 127.1,
128.1, 128.3 (2 C), 128.4, 128.6, 139.8, 140.1, 140.4, 141.1,
141.5, 173.2, and 174.7.
0.017 mmol) together with recovered 23a (26 mg, 0.040
21b: 13C NMR (75 MHz, CDCl3) δ 27.3, 29.6, 33.4, 39.5, 49.8,
57.7, 73.5, 79.6, 108.9, 124.7, 125.2, 126.0, 127.2, 128.3, 128.5,
140.0, 140.2, 141.0, and 172.9.
1
mmol): [R]20 -27 (c 0.32, CHCl3-MeOH 1:1); H NMR (400
D
MHz, CDCl3 and CD3OD) δ 0.92 (d, 3 H, J ) 6.64 Hz), 0.97 (d,
9 H, J ) 6.64 Hz), 1.85-2.19 (m, 6 H), 2.54-2.72 (m, 6 H),
2.76 (s, 3 H), 2.77 (s, 3 H), 3.60-3.62 (m, 1 H), 3.70-3.73 (m,
1 H), 4.12-4.18 (m, 2 H), 4.56 (s, 6 H), and 7.16-7.55 (m, 10
H); 13C NMR (100 MHz, CDCl3 and CD3OD) δ 17.8, 18.7, 18.8,
25.2, 28.4, 30.1, 30.3, 32.5, 33.2, 46.5, 58.3, 58.5, 72.5, 73.5,
125.2, 125.3, 127.6, 127.7, 127.8, 141.0, 141.3, 171.8, 171.9,
21c: 29% yield (73 mg, 0.106 mmol); [R]20 +15 (c 0.48,
D
CHCl3-MeOH 1:1); 1H NMR (400 MHz, CDCl3 and CD3OD) δ
1.40 (s, 6H), 1.77-1.84 (m, 2 H), 2.00-2.10 (m, 2 H), 2.60-
2.68 (m, 4 H), 2.74-2.82 (m, 2 H), 2.96 (d, 2 H, J ) 16.41 Hz),
3.17 (dd, 2 H, J ) 4.69, 16.02 Hz), 3.67 (d, 2 H, J ) 3.12 Hz),

Novel, Potent, Diol-Based HIV-1 Protease Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21 3415
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175.2, and 175.4. HRMS calcd for C34H50O6N4 [M + Na]
633.3628, found [M + Na] 633.3604.
N1,N6-Bis[(1S)-2-m eth yl-1-(m eth ylca r ba m oyl)p r op yl]-
(2R,3R,4R,5R)-3,4-d ih yd r oxy-2,5-bis(2-p h en yleth yl)h ex-
a n ed ia m id e (9b). The title compound was prepared according
to method III, using 52 mg (0.084 mmol) of the disuccinimidyl
ester 20b, and isolated as a white solid in 22% yield (11 mg,
0.018 mmol) together with recovered 23b (16 mg, 0.025
1
mmol): [R]20 -23 (c 0.75, CHCl3-MeOH 1:1); H NMR (400
D
MHz, CDCl3 and CD3OD) δ 0.60-0.64 (m, 12 H), 1.61-1.74
(m, 6 H), 2.18-2.26 (m, 6 H), 2.42 (s, 6 H), 3.34 (d, 2 H, J )
8.59 Hz), 3.76-3.78 (m, 2 H), 4.32 (s, 6 H), and 6.81-7.27 (m,
10 H); 13C NMR (100 MHz, CDCl3 and CD3OD) δ 17.8, 18.5,
25.1, 29.9, 30.8, 33.0, 50.4, 58.7, 71.1, 125.1, 127.5, 141.0, 171.9,
and 174.1. HRMS calcd for C34H50O6N4 [M + Na] 633.3628,
found [M + Na] 633.3638.
Ack n ow led gm en t. We gratefully acknowledge the
Swedish National Board for Technical Development
(NUTEK) and the Swedish Foundation for Strategic
Research (SSF) for financial support, Medivir AB,
Huddinge, Sweden for financial support and biological
testings, and Seved Lo¨wgren, Department of Cell and
Molecular Biology, BMC, Uppsala University, Sweden
for preparation of the HIV-1 protease and the protease/
inhibitor crystals.
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