4-hydroxy-5,6-dihydropyrones. 2. Potent non-peptide inhibitors of HIV protease

Article abstract of DOI:10.1021/jm970615f

The 4-hydroxy-5,6-dihydropyrone template was utilized as a flexible scaffolding from which to build potent active site inhibitors of HIV protease. Dihydropyrone 1c (5,6-dihydro-4-hydroxy-6-phenyl-3-[(2- phenylethyl)thio]-2H-pyran-2-one) was modeled in the active site of HIV protease utilizing a similar binding mode found for the previously reported 4-hydroxybenzopyran-2-ones. Our model led us to pursue the synthesis of 6,6- disubstituted dihydropyrones with the aim of filling S₁ and S₂ and thereby increasing the potency of the parent dihydropyrone 1c which did not fill S₂. Toward this end we attached various hydrophobic and hydrophilic side chains at the 6-position of the dihydropyrone to mimic the natural and unnatural amino acids known to be effective substrates at P₂ and P₂'. Parent dihydropyrone 1c (IC₅₀ = 2100 nM) was elaborated into compounds with greater than a 100-fold increase in potency [18c, IC₅₀ = 5 nM, 5-(3,6- dihydro-4-hydroxy-6-oxo-2-phenyl-5-[2-phenylethyl)thio]-2H-pyran-2- yl)pentanoic acid and 12c, IC₅₀ = 51 nM, 5,6-dihydro-4-hydroxy-6-phenyl-6- (2-phenylethyl)-3-[(2-phenyl-ethyl)thio]-2H-pyran-2-one]. Optimization of the 3-position fragment to fill S₁' and S₂' afforded potent HIV protease inhibitor 49 [IC₅₀ = 10 nM, 3-[(2-tert-butyl-5-methylphenyl)sulfanyl]-5,6- dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one]. The resulting low molecular weight compounds (<475) have one or no chiral centers and are readily synthesized.

Full text of DOI:10.1021/jm970615f

J . Med. Chem. 1997, 40, 3781-3792
3781
4-Hyd r oxy-5,6-d ih yd r op yr on es. 2. P oten t Non -P ep tid e In h ibitor s of HIV
P r otea se
Bradley D. Tait,*,† Susan Hagen,*,† J ohn Domagala,† Edmund L. Ellsworth,† Christopher Gajda,†
Harriet W. Hamilton,† J . V. N. Vara Prasad,† Donna Ferguson,‡ Neil Graham,‡ Donald Hupe,‡ Carolyn Nouhan,‡
Peter J . Tummino,‡ Christine Humblet,§ Elizabeth A. Lunney,§ Alexander Pavlovsky,§ J ohn Rubin,§
Stephen J . Gracheck, Eric T. Baldwin,| T. N. Bhat,| J ohn W. Erickson,| Sergei V. Gulnik,| and Beishan Liu|
Departments of Chemistry and Biochemistry and Biomolecular Structure and Drug Design, Parke-Davis Pharmaceutical
Research Division of the Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, and Structural
Biochemistry Program, NCI-Frederick Cancer Research and Development Center, PRI/ DynCorp, Frederick, Maryland 21702
Received February 12, 1997X
The 4-hydroxy-5,6-dihydropyrone template was utilized as a flexible scaffolding from which to
build potent active site inhibitors of HIV protease. Dihydropyrone 1c (5,6-dihydro-4-hydroxy-
6-phenyl-3-[(2-phenylethyl)thio]-2H-pyran-2-one) was modeled in the active site of HIV protease
utilizing a similar binding mode found for the previously reported 4-hydroxybenzopyran-2-
ones. Our model led us to pursue the synthesis of 6,6-disubstituted dihydropyrones with the
aim of filling S1 and S2 and thereby increasing the potency of the parent dihydropyrone 1c
which did not fill S2. Toward this end we attached various hydrophobic and hydrophilic side
chains at the 6-position of the dihydropyrone to mimic the natural and unnatural amino acids
known to be effective substrates at P2 and P2′. Parent dihydropyrone 1c (IC50 ) 2100 nM)
was elaborated into compounds with greater than a 100-fold increase in potency [18c, IC50
)
5 nM, 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-5-[2-phenylethyl)thio]-2H-pyran-2-yl)pentanoic
acid and 12c, IC50 ) 51 nM, 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-3-[(2-phenyl-
ethyl)thio]-2H-pyran-2-one]. Optimization of the 3-position fragment to fill S1′ and S2′ afforded
potent HIV protease inhibitor 49 [IC50 ) 10 nM, 3-[(2-tert-butyl-5-methylphenyl)sulfanyl]-5,6-
dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one]. The resulting low molecular
weight compounds (<475) have one or no chiral centers and are readily synthesized.
In tr od u ction
Acquired immunodeficiency syndrome (AIDS) was
first defined in 1982 as the clinical manifestations of
immunodeficiency. The etiological agent of AIDS was
later determined to be a retrovirus, human immunode-
ficiency virus (HIV), of the lentivirus subfamily.1 Char-
acterization of HIV has provided numerous potential
antiviral approaches, one of which is inhibition of a viral
encoded aspartyl protease.2
HIV protease is responsible for posttranslational
processing of the precursor polyproteins Gag and Gag/
Pol3 and is essential for maturation of the virus. The
proteolytic activity of HIV protease cannot be provided
by host cellular enzymes. It has been shown that HIV
which lacks this protease or contains a mutant defective
protease is noninfectious.4 The sum of these observa-
tions makes inhibition of HIV protease an attractive
target for antiviral therapy.
F igu r e 1. 4-Hydroxypyrones: P1-P1′(or P2′).
clinical emergence of resistant strains will necessitate
an ever increasing armament of drugs.8 Therefore, the
need exists for small nonpeptide HIV protease inhibitors
which are easy to synthesize, exhibit good bioavailabil-
ity, and preferably have a unique pattern of resistance
development.
The majority of the HIV protease inhibitors reported
are peptidic or peptidomimetic in nature.5 Peptidic
compounds are known to possess pharmacological prob-
lems such as biliary excretion and low bioavailability.
Additional issues with the four approved compounds
include significant side effects and the requirement of
substantial doses and, therefore, large quantities of
drug.6 Adequate supplies of these agents have been
limited by the synthetic difficulties associated with large
compounds containing multiple chiral centers.7 The
Previous reports from our laboratory described modi-
fication of the pyrone template (Figure 1) into a number
of ring systems including the tetronic acids and 5,6-
dihydropyrones.9 From our initial evaluation of these
ring systems, we chose to focus our efforts on the
4-hydroxy-5,6-dihydropyrone template (Figure 2).10 More
recently Pharmacia Upjohn has also disclosed their
efforts in this area.11 This paper will focus on efforts
to optimize the substitution on the dihydropyrone
template with modifications designed to fill the internal
four pockets (S2, S1, S1′, S2′) of HIV protease.
† Department of Chemistry, Parke-Davis.
‡ Department of Biochemistry, Parke-Davis.
Molecu la r Mod elin g
§ Biomolecular Structure and Drug Design, Parke-Davis.
Department of Infectious Diseases, Parke-Davis.
| Structural Biochemistry Program, NCI.
Molecular modeling was carried out using the Sybyl
software program12 and a preliminary X-ray structure
X Abstract published in Advance ACS Abstracts, October 15, 1997.
S0022-2623(97)00615-8 CCC: $14.00 © 1997 American Chemical Society

3782 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Tait et al.
tion and extended to S2. The inhibitor was modeled in
the cleft region, which included residues 8 Å from the
bound coumarin inhibitor in the X-ray structure. The
inner oxygen of the catalytic Asp 25 was protonated.
Ch em istr y
The synthetic pathway for the 4-hydroxy-5,6-dihy-
dropyrone HIV protease inhibitors is shown in Scheme
1 and follows the method of Groutas et al.14 Methyl
acetoacetate was converted into its dianion by treatment
with sodium hydride and then with n-butyllithium. To
the dianion was added the appropriate aldehyde or
ketone. The resulting aldol product could be isolated
by quenching with ammonium chloride. The aldol
product was cyclized by treatment with dilute NaOH
(in the presence or absence of THF) to give the dihy-
dropyrone ring system. Alternatively, the aldol product
could be taken directly to the dihydropyrone without
isolation by addition of water or dilute NaOH to the
reaction mixture. The 3-position sulfur side chain (n
) 0-3, Scheme 1) was attached to the 3-position by
reaction with the appropriate thiotosylate reagent15 and
triethylamine to give the target compounds. The thioto-
sylates (30) were prepared as shown in Scheme 2 and
Table 1, beginning with the derivatization of the cor-
responding phenol 27 with dimethylthiocarbamoyl chlo-
ride and subsequent thermal rearrangement to 28.16
Reduction to the thiol 29 was carried out with lithium
aluminum hydride, and the resulting thiol converted to
the desired thiotosylate 30 as described by Fuchs.17 An
alternative method for the synthesis of the dihydropy-
rone targets involved preparation of the 3-bromodihy-
dropyrone derivative with NBS and then displacement
of the bromide by the appropriately substituted thiophe-
nol; this route was used to prepare 11a , 11b, 33-38,
44, 45, 46, and 47.
F igu r e 2. 4-Hydroxy-5,6-dihydropyrones: P1-P1′(or P2′).
Sch em e 1. Synthesis of 4-Hydroxy-5,6-dihydropyrones
of HIV protease from a coumarin complex.13 The
dihydropyrone ring was docked in the protease active
site according to the binding mode observed for the
coumarin inhibitor. Specifically, the 4-hydroxyl group
was positioned between the two carboxylates at the
catalytic site, and the lactone was positioned to interact
directly with Ile50/150 in the flap region. The lactone
group would thus displace H2O-301 normally observed
with the peptidic inhibitors. Inhibitor 7b was modeled
with the S geometry and a ring puckering such that the
phenyl ring was in the equatorial position and bound
in S1 and the isopentyl group was in the axial orienta-
Resu lts a n d Discu ssion
The coumarin and pyrone ring systems (Figure 3) are
rigid and planar which limit the flexibility of the
substituents to adjust upon binding. Due to this rigid-
ity, groups attached to the ring system are locked into
position relative to each other and relative to the core
binding interactions. We hypothesized that the dihy-
dropyrones would offer a more flexible template which
would allow the substituents to make modest confor-
mational adjustments without interfering with the core
binding.
Sch em e 2. Preparation of Thiophenols and Tosyl Thiolates

4-Hydroxy-5,6-dihydropyrones. 2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3783
Ta ble 1. Preparation of Aromatic Thiols and Thiotosylates
compda
R
R′
source of 29b
yield of 30c
29a
29b
29c
30d
30e
30f
29g
29h
30i
Me
H
H
H
H
H
H
comm
comm
comm
expt
CHMe2
CHMeEt
cyclopentyl
cyclohexyl
CMe3
CHMe2
CHMe2
CMe3
53
62
42
F igu r e 4. Overlay of a model of 7b (red) docked in the HIV
protease active site with the X-ray structure of A-74704 (white)
bound to HIV protease. H2O-301, from the A-74704 structure,
is shown in green.
expt
comm
ref 31
expt
expt
prep
Me
CHMe2
Me
72
55
1). It was apparent from analysis of a coumarin X-ray13
and the subsequent dihydropyrone model that S2 could
be reached from the sp3 carbon atom at the six position
of the dihydropyrone by appending an appropriate
substituent (R in Figure 2).
Figure 4 shows a model of 7b overlaid with the Abbott
HIV protease inhibitor (A-74704).18 The Abbott struc-
ture assists in the visualization of the approximate
position of P1 and P2 but does not define the surface
area of the pockets. Our model indicated that from the
6-position we needed a two-atom spacer followed by the
substituent to fill S2. The model also predicted that a
phenyl at the 6-position was a reasonable substituent
to fill S1. Therefore, we held the phenyl constant and
varied the R group to reach for S2.
30j
CMe3
CHMe2
a
29 designates the benzenthiol which is used crude in general
method 7; 30 designates the thiotosylate used in general method
b
5. Comm: thiol is commercially available. Expt: corresponding
phenol is commercially available and is elaborated into the desired
thiol in the Experimental Section. Ref: thiol is prepared in the
reference indicated. Prep: synthesis of the corresponding phenol
is found in the Experimental Section. c Total yield from thiol.
Our focus at S2 was to fill the pocket with functional
groups which would mimic the substrates amino acids
known to fill both S2 and S2′ due to the symmetry of
the enzyme. Amino acids found at P2 and P2′ in the
native substrates include valine, isoleucine, leucine,
asparagine, glutamine, and glutamic acid. Unnatural
amino acids, such as phenylglycine, were also considered
when they had been shown from literature precedent
to be effective substituents at P2.17
Our initial analysis consisted of preparing straight
chain alkyl groups (2b,c-5b,c Table 2). Due to their
flexibility, the straight chain alkyl groups could readily
adjust to the surface of the enzyme to maximize
hydrophobic interactions, albeit with an entropic price.
In any event, the potency increased as the chain was
lengthened from hydrogen (IC50 ) 2100 nM, 1c) to
n-pentyl (IC50 ) 84 nM, 4c).
Branched alkyl groups designed to mimic the P2 and
P2′ hydrophobic amino acids, valine and leucine (6b,c-
8b,c Table 2) were then investigated. Modeling pre-
dicted that isopentyl (7a ,b,c) and isohexyl (8b,c) sub-
stituents would most closely mimic valine and leucine,
respectively. Analogues with branched alkyl groups
showed an increase in potency over the unsubstituted
parent (IC50 ) 2100 nM, 1c) with the most potent
compound being the isopentyl substituent (IC50 ) 96
nM, 7c), the valine mimic. The trends in activity were
in excellent agreement with our modeling predictions.
Workers at Merck19 have reported that phenylglycine
is an effective P2′ replacement for valine in peptidic HIV
protease inhibitors. In a logical extension of their work,
we prepared the phenethyl derivatives (12a -c) as
phenylglycine mimics. Compound 12c showed excellent
activity versus the enzyme with an IC50 of 51 nM.
Indeed, phenethyl proved to be the most active of the
hydrophobic P2 substituents.
F igu r e 3. Potential coumarin and pyrone core interactions.
The X-ray cocrystal structure of HIV-1 protease with
the 4-hydroxybenzopyran-2-one PD 099560 was infor-
mative in evaluating the potential binding modes of the
dihydropyrones (Figure 3).13 The key active site inter-
actions of the pyrone template involve the 4-hydroxyl
group which binds to the catalytic aspartic acids (Asp
25/125, Figure 3) and the lactone that is hydrogen
bonded to NH’s in the flap (Ile 50/150, Figure 3). The
lactone carbonyl effectively displaces H2O-301, which
is normally found in X-ray structures of HIV protease
bound with the peptide inhibitors. Due to the structural
similarities among the 4-hydroxybenzopyran-2-one, the
pyrone, and the dihydropyrone templates, we believed
that a similar core binding mode would occur in all the
templates. This was indeed substantiated by molecular
modeling and later by X-ray cocrystal structures.
We believed that the thiobenzyl and thiophenethyl
side chains at the three position (Figure 2) were flexible
enough to have no substantial influence on the binding
at the 6-position. Modeling indicated that the thiol
chains could fill either S1′ or S2′. Therefore, to ensure
the 6-position SAR would be consistent with various
3-position side chains, both the thiobenzyl and thiophen-
ethyl side chains at the 3-position were prepared. The
better variations at the 6-position were then synthesized
in combination with the thiophenyl side chain.
With the core binding and a flexible 3-position sub-
stituent set, we turned our attention to exploring ways
of filling the S2 and S1 pockets. Our model of the
6-phenylpyrones such as PD 150280 and PD 107067
indicated that the 6-position substituent filled S1 (Figure

3784 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Tait et al.
Ta ble 2. Hydrophobic Groups Designed To Fill S2:
P2P1-P1′(or P2′)
IC50 (nM)
compda
R
a (n ) 0)
b (n ) 1)
c (n ) 2)
1b,c
2b,c
3b,c
4b,c
5b,c
6b,c
7a ,b,c
8b,c
9b,c
10b
11a ,b,c
12a ,b,c
13bb
14b,cb
15bc
H
8900
290
270
124
180
440
98
183
88
137
262
60
2100
5100
400
84
112
1200
96
(CH2)2Me
(CH2)3Me
(CH2)4Me
(CH2)5Me
CH2CHMe2
(CH2)2CHMe2
(CH2)3CHMe2
CH2-c-pentyl
CH2-c-hexyl
Ph
F igu r e 5. Superposition of the difference electron density
with two binding modes of racemic 4c. The R configuration is
shown in magenta and the S configuration is shown in red.
1400
155
510
Ta ble 3. Polar Groups Designed To Fill S2: P2P1-P1′(or P2′)
110
130
152
51
(CH2)2Ph
-(CH2)2-
-(CH2)3-
(CH2)4Me
11800
2300
327
1300
a
b
Where a is n ) 0, b is n ) 1, and c is n ) 2. Spirocyclic: The
linker is connected to the ortho position of the 6-phenyl ring.
c Symmetrical compound: 6,6-di-n-pentyl. All compounds are
racemic or achiral. All IC50’s are averages of at least two runs.
compda
n
R
IC50(nM)
16c
17c
18c
19c
20c
21c
22c
23b
24b
2
2
2
2
2
2
2
1
1
(CH2)2CO2H
(CH2)3CO2H
(CH2)4CO2H
(CH2)3CONH2
(CH2)4CONH2
4-pyridyl
CH2N(Me)Ph
CH2OPh
(CH2)4OH
1200
270
5
1300
338
790
2280
172
1260
Our model indicated, and the activity confirmed, that
the isobutyl group (6b,c) was not reaching far enough
to fill S2. To more effectively fill the S2 pocket, the two
methyls of the isobutyl group were expanded and
cyclized into a 5-membered ring (9b,c) and a 6-mem-
bered ring (10b). In fact, compounds 9b and 10b were
better than compound 6b by more than 3-fold, thus
suggesting enhanced interactions with the enzyme.
We were also interested in what effect restricting the
rotation and therefore the orientation of the phenyl at
P1 might have on inhibitory activity. The spirocyclic
derivatives 13b and 14b,c were found to be much less
potent than the corresponding acyclic compounds. This
is probably due to the inability of the three-carbon linker
to fill a pocket effectively and/or the restriction of the
phenyl ring into a conformation less compatible with
the binding cleft.
An X-ray cocrystal structure of racemic 4c bound into
HIV-1 protease was obtained (Figure 5). The difference
electron density map indicated that the general core
interactions with Asp 25/125 and Ile 50/150 were
consistent with those found in the coumarin X-ray and
the dihydropyrone model. The presence of electron
density in both S1′ and S2′ indicated a mixed population
for the thiophenethyl group between the two pockets
(Figure 5). It was hoped that only the more potent
enantiomer would be bound in the active site, but the
X-ray indicated that both enantiomers of 4c were
present. An accurate determination of the preference
for the phenyl and n-pentyl groups to reside in S1 or S2
could not be obtained from the electron density. What
was clear was that the substituents (phenyl and n-
pentyl) fill both S2 and S1, thus increasing the potency
of these compounds in the enzyme inhibition assay. The
lack of apparent preference by the enzyme pockets for
the phenyl or the n-pentyl group suggested the prepara-
tion of the achiral 6,6-diphenyl and 6,6-di-n-pentyl
analogues. In fact, the symmetrical derivatives showed
a
Where a is n ) 0, b is n ) 1 and c is n ) 2. All compounds are
racemic. All IC50’s are averages of at least two runs.
good potency with IC50’s in the 110-327 nM range
(11a -c and 15b) although they were not as potent as
the racemic 6-phenyl-6-n-pentyl parent (4b,c).
We next turned our attention to filling S2 with side
chains which mimic the more polar amino acids, aspar-
agine, glutamine, and glutamic acid (Table 3). Aspar-
agine has been used at S2 in peptidic inhibitors such as
Ro-31,8959 with excellent success. Analysis of the Ro-
31,8959 interactions with HIV-1 protease indicated that
the asparagine carbonyl is within hydrogen-bonding
distance of Asp 29 (NH) and Asp 30 (NH) in the
protein.20 To mimic the polar amino acids such as
asparagine, glutamine, and glutamic acid, modeling
suggested that the optimal side chains should be
-(CH2)3CONH2, -(CH2)4CONH2, and -(CH2)4COOH, re-
spectively. The enzyme activity followed the modeling
predictions relatively well with the maximal activity
coming from carboxylic acid 18c (IC50 ) 5 nM).21 The
potency decreased by almost 2 orders of magnitude
when the carboxylic acid (18c) was replaced with a
primary amide (20c). Replacing the acid in 17c with a
CH2OH isostere 24b reduced the in vitro activity by
approximately 5-fold.
Additional derivatives with heteroatoms were pre-
pared to evaluate the effect of polarity on the inhibitory
activity (21c, 22c, 23b). The phenethyl linker in
compound 12b and 12c was modified by replacing the
distal methylene with the polar groups NMe (22c) and

4-Hydroxy-5,6-dihydropyrones. 2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3785
Ta ble 4. Optimization of P1′P2′ Substituent: P2P1-P1′P2′
Assuming that the ortho substituent effectively satis-
fied S1′, attention turned to more optimally filling the
S2′ pocket from the appropriate position of the phenyl
ring (44-50). To determine that optimal substitution,
a series of analogues were synthesized in which the
ortho substituent was held constant as an isopropyl or
tert-butyl group while varying the position para to the
alkyl moiety. The methyl isomers display either the
same activity (where R ) Ph, 44) or an enhancement
in potency (where R ) phenethyl, 45). The size of the
methyl group appeared to be nearly optimal, since the
corresponding isopropyl compounds (46, 47, 50) all
displayed a loss in activity versus the methyl derivatives
(44, 45, 49).
IC50 (nM)
compda
R′
R′′
R ) Ph
R ) (CH2)2Ph
11a , 12a
33, 34
35, 36
37, 38
39
40, 41
42, 43
44, 45
46, 47
48, 49
50
H
Me
H
H
H
H
H
H
H
110
388
23
17
14
127
49
38
119
12
130
73
14
CHMe2
CHMeEt
c-pentyl
c-hexyl
CMe3
CHMe2
CHMe2
CMe3
10
32
3
7
14
10
47
6
In general, the inhibitory activity data indicated that
a 2-tert-butyl/2-isopropyl group and 5-methyl moiety on
the phenyl ring effectively fill the S1′ and S2′ pockets,
respectively. To verify this model, an X-ray crystal-
lographic study of racemic 45 with the protein was
undertaken; unfortunately, from the electron density it
was not possible to determine either the preferred
enantiomer for binding or whether both enantiomers
were bound. To overcome this problem, the R- and
S-enantiomers were prepared25 and tested (51, 52); the
S-enantiomer (51) proved to be 20-fold more potent than
the corresponding R-enantiomer (52).
X-ray crystallographic structures26 of both the S-
enantiomer 51 and the R-enantiomer 52 complexed with
the protease enzyme were obtained (Figures 6 and 7).
As expected, in each case, the dihydropyrone ring
displaced H2O-301 while the lactone interacted directly
with the flap region (Ile-50). The 4-hydroxyl group
binds at the catalytic dyad (Asp-25 and Asp-125). Also
as predicted, the 3-position substituent occupies the S1′
site via the isopropyl group and the S2′ site via the
5-methyl substituent. The S-enantiomer binds the
phenyl group in the S1 site and orients the phenethyl
chain in the S2 pocket. Not surprisingly, the opposite
binding at the 6-position is observed for the R-enanti-
omer: that is, the phenyl ring is bound in the S2 pocket
and the phenethyl group binds in S1/S3, extending out
to solvent. The S-enantiomer, predicted to be the more
potent inhibitor, displays a binding affinity of 6 nM,
whereas the R-enantiomer has an IC50 ) 130 nM. This
is in contrast to recent reports by Upjohn where the
6-phenethyl occupies S1/S3 and a 6-n-propyl occupies
S2.11 Although the Pharmacia Upjohn and Parke-Davis
groups are both working on the dihydropyrone template,
the preferred chirality of the substituents at the 6-posi-
tion is apparently reversed.27
Me
CHMe2
Me
CHMe2
Me
Me
CMe3
CHMe2
CHMe2
51 (S)
52 (R)
130
a
All compounds are racemic or achiral except 51 (S) and 52
(R). All IC50’s are averages of at least two runs.
oxygen (23b), respectively. These compounds were
found to be less active than their respective carbon
parents by at least 3-fold. Replacement of one phenyl
in 11c with a pyridyl (21c) also resulted in a reduction
in activity.
The thiobenzyl (n ) 1) and thiophenethyl side chains
(n ) 2) at C-3 showed relatively consistent SAR trends
(Table 2). Selection of the 6-phenyl-6-phenethyl (12a -
c) as a standard for optimizing the 3-position was based
on this consistency of activity as well the potency. The
6,6-diphenyl (11a -c) variation was chosen as a stan-
dard mainly due to its lack of a chiral center.
A series of 3-(benzylthio)-5,6-dihydropyran-2-ones
with a variety of ortho substituents on the benzylthio
ring were prepared. In most cases, the potency de-
creased or remained constant when compared with the
parent compounds.22 Observed increases in efficacy
were no more than 2-fold and were therefore judged
insignificant. These results were dramatically different
than those obtained in the pyrone series of inhibitors.23
Work in the pyrone series delineated the beneficial
effect of substituting ortho to the sulfur linkage on the
phenylthio with an isopropyl moiety.24 Modeling of the
o-isopropyl functional group with the 5,6-dihyropyrone
template indicated that it probably filled the S1′ pocket.
This observation led to modifications of the initial
dihydropyrone lead, resulting in agents with improved
enzyme potency (Table 4).
To address the question of steric requirements of S1′
(Table 4), a number of derivatives containing o-alkyl
groups were prepared. Reducing the isopropyl group
to a methyl decreased the activity by 5-10-fold (33, 34);
increasing the size to sec-butyl (37, 38) or cyclopentyl
(39) instead of isopropyl (35, 36) provided equally potent
compounds. Relative to isopropyl, an o-tert-butyl moiety
engendered a 2-fold loss in activity when R′ ) Ph (42)
yet a 4-5-fold increase in activity when R′ ) 2-phen-
ethyl (IC50 of 3 nM, 43). This observation suggested
that slightly different orientations of the inhibitors in
the active site of the enzyme arise from differences in
substitution at the 6-position of the dihydropyrone ring
system.
Unfortunately, the best compounds (18c, 43, and 49)
did not show a significant therapeutic index (TD50/EC50
>10-fold) in cellular assays and did not warrant claims
of antiviral activity. This result is not surprising for
compound 18c, which would be subject to ionization of
the carboxylic acid under the conditions of the cellular
assay. The lack of cellular activity necessitated a close
examination of possible explanations. One area of
concern was the pKa of the 4-hydroxyl group (pKa ) 4.5-
6.5), which is more acidic than a normal alcohol. We
believe the protonated form of the dihydropyrone is the
bound form of the inhibitor in the active site. Thus we
were interested to see what effect raising the pH of the
assay would have on inhibitory activity. We therefore
took the best compounds and ran the assay at pH 6.2.

3786 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Tait et al.
F igu r e 6. Overlay of the X-ray cocrystal structure of 51 (blue) and the X-ray cocrystal structure of A-74704 (yellow) bound to
HIV protease. H2O-301, from the A-74704 structure, is shown in red.
F igu r e 7. Overlay of the X-ray cocrystal structures of 51 (S) in yellow and 52 (R) in white shown with the HIV-1 protease active
site.
Ta ble 5. Effect of Assay pH on IC50’sa
53-56
36, 43, 45, 49
R′
R′′
compdb
pH ) 4.7
pH ) 6.2
compd
pH ) 4.7
pH ) 6.2
CHMe2
CHMe2
CMe3
H
Me
H
53
54
55
56
37
17
17
28
700
36
45
43
49
14
7
3
97
79
104
35
CMe3
Me
282
10
a
b
All compounds are racemic or achiral. All IC50’s (nM) are averages of at least two runs. Reference 24.
Not unexpectedly, the dihydropyrones did lose potency
at the higher pH (Table 5). Although all the compounds
decreased in activity, the 2-tert-butyl-5-methyl com-
pound (49) retained more of its inhibitory efficacy than
did the other dihyropyrone derivatives. In addition, the
dihydropyrones as a class were less affected by the
increase in pH than the pyrones (Table 5).
carbonyl acts as a hydrogen bond acceptor with the flap
isoleucine 50/150 NH’s. The lactone carbonyl effectively
displaces the H2O-301 found in the X-ray cocrystal
structures of peptide inhibitors with HIV protease.
Substitution at the 6-position of the dihydropyrone ring
system to mimic substituents reported at S2 increased
the inhibitory activity by almost 400-fold from an IC50
of 2100 nM (1c) to an IC50 of 51 nM (12c) and IC50 of 5
nM (18c). Filling the four internal pockets of HIV
protease afforded compounds which were potent inhibi-
tors of HIV protease (43, IC50 ) 3 nM). Compound 49
(IC50 of 10 nM) was used as a base structure from which
further modifications afforded cellularly active com-
pounds.28
Con clu sion s
As predicted, the 4-hydroxy-5,6-dihydropyrone het-
erocycle binds to the active site of HIV-1 protease in a
manner similar to the coumarins and pyrones: the
4-hydroxyl group is hydrogen bonded to one or both of
the catalytic aspartic acids Asp25/125 and the lactone

4-Hydroxy-5,6-dihydropyrones. 2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3787
give 23% of 8: mp 124-125 °C; MS (CI + 1% NH3 in CH4)
275 (M + 1). Anal. (C17H22O3) C, H, N.
Exp er im en ta l Section
The compounds were assayed against HIV-1 protease using
the method described by Tummino et al.29 The reported IC50’s
are an averaged value from two runs.
6-(Cyclop en tylm eth yl)-5,6-d ih yd r o-4-h yd r oxy-6-p h en -
yl-2H-p yr a n -2-on e (9). 2-Cyclopentyl-1-phenylethanone was
prepared by reacting the appropriate acid chloride with AlCl3
in benzene as described by Vogel. Upon concentration of the
reaction mixture, a solid precipitated out which was recrystal-
lized from EtOAc to afford 9 in 41% yield: mp 158-160 °C;
MS (CI + 1% NH3 in CH4) 273 (M + 1). Anal. (C17H20O3) C,
H, N.
6-(Cycloh exylm eth yl)-5,6-d ih yd r o-4-h yd r oxy-6-p h en yl-
2H-p yr a n -2-on e (10). 2-Cyclohexyl-1-phenylethanone was
prepared by reacting the appropriate acid chloride with AlCl3
in benzene as described by Vogel. Upon concentration of the
reaction, a solid precipitated out which was triturated from
Et2O to afford 10 in 6.5% yield: mp 128-130 °C; MS (CI +
1% NH3 in CH4) 287 (M + 1). Anal. (C18H22O3‚0.26H20) C,
H, N.
All melting points were recorded on a Thomas-Hoover
capillary melting point apparatus and are uncorrected. Proton
NMR data were obtained on a Varian Unity 400 MHz NMR
using TMS as an internal standard. CHN data were obtained
from Parke-Davis analytical department and the sulfur analy-
sis from Robertson Microlabs. Mass spectral data were
obtained on a VG Analytical 7070 E/HF mass spectrometer.
Infrared spectra were collected on a Mattison Cygnus 100
FTIR. Flash column chromatography was performed on silica
gel 60, 230-400 mesh, purchased from Mallinckrodt. All
starting materials were obtained from commercial sources
unless otherwise specified in the experimental.
Gen er a l Meth od 1. P r ep a r a tion of 4-Hyd r oxy-5,6-
d ih yd r op yr on es (1-24). Methyl acetoacetate (1 equiv) was
added dropwise to a slurry of hexane-washed sodium hydride
(1-1.2 equiv) in anhydrous THF at 0 °C and the reaction
stirred at 0 °C for 15 min to 1 h. n-Butyllithium (1.1 equiv)
was then added at 0 °C and the reaction stirred at 0 °C for 15
min to 1 h. The aldehyde or ketone (0.9-1.1 equiv), in THF,
was added to the dianion, and the reaction was stirred at 0
°C (15 min to 24 h) and then allowed to warm to room
temperature (15 min to 24 h). To the reaction mixture was
added water or 0.1 N NaOH and the mixture allowed to stir
for 15 min to overnight. After extracting with Et2O, the
aqueous layer was cooled to 0 °C and acidified with acid (2-6
N HCl) to pH 1-2. The aqueous layer was extracted with
EtOAc or CH2Cl2. The organic extracts were combined, dried
over MgSO4, and concentrated. Compounds 1-18, and 21-
23 were prepared according to this method.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-2H-p yr a n -2-on e (1).
Concentration produced a solid which was filtered off to give
1 in 62% yield: mp 145-146 °C; 1H NMR (CDCl3) δ 2.86-
3.00 (m, 2H), 3.49 (d, J ) 19.0 Hz, 1H), 3.67 (d, J ) 19.0 Hz,
1H), 5.71 (dd, J ) 10.0 Hz, J ) 3.7 Hz, 1H), 7.26-7.52 (m,
5H); MS (EI+) 190 (M + 1). Anal. (C11H10O3) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-6-p r op yl-2H-p yr a n -2-
on e (2). The product was triturated from Et2O to afford 2 in
60% yield: mp 131.5-132 °C; MS (EI+) 233 (M + 1). Anal.
(C14H16O3) C, H, N.
6-Bu t yl-5,6-d ih yd r o-4-h yd r oxy-6-p h en yl-2H -p yr a n -2-
on e (3). The product was triturated from Et2O to afford 3 as
a solid in 58% yield: mp 124-126 °C; MS (EI+) 247 (M + 1).
Anal. (C15H18O3) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-p en tyl-6-p h en yl-2H-p yr a n -2-
on e (4). Upon concentration of the reaction, a solid precipi-
tated out which was triturated, washed with Et2O, and filtered
to give 4 as a solid in 41% yield: mp 123-124 °C; MS (CI +
1% NH3 in CH4) 261 (M + 1). Anal. (C16H20O3) C, H, N.
5,6-Dih yd r o-6,6-d ip h en yl-4-h yd r oxy-2H -p yr a n -2-on e
(11). Upon concentrating the reaction a solid precipitated out
which was triturated with Et2O and filtered to give 79% of
1
11: mp 170.5-173 °C; H NMR (CDCl3) δ 3.18 (s, 2H), 3.39
(s, 2H), 7.26-7.39 (m, 10H); MS (EI+) 266. Anal. (C17H14O3)
C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-6-(2-p h en yleth yl)-2H-
p yr a n -2-on e (12). Upon concentrating, a solid precipitated
out which was triturated with Et2O and filtered to give 63%
of 12: mp 130-130.5 °C; 1H NMR (CDCl3) δ 2.24-2.32 (m,
2H), 2.46-2.53 (m, 1H), 2.69-2.77 (m, 1H), 2.95 (d, J ) 17.4
Hz, 1H), 2.97 (d, J ) 20.4 Hz, 1H), 3.29 (d, J ) 20.4 Hz, 1H),
3.38 (d, J ) 17.3 Hz, 1H), 7.07-7.45 (m, 10H); MS (CI + 1%
NH3 in CH4) 295 (M + 1). Anal. (C19H18O3) C, H, N.
2,3-Dih ydr o-4′-h ydr oxyspir o[1H-in den e-1,2′-[2H]pyr an ]-
6′(3H′)-on e (13). The product was recrystallized from EtOAc/
Et2O to afford a 22% yield of 13: mp 119-120 °C; MS (CI +
1% NH3 in CH4) 217 (M + 1). Anal. (C13H12O3‚0.07H2O) C,
H, N.
3,4-Dih ydr o-4′-h ydr oxyspir o[n aph th alen e-1(2H),2′-[2H]-
p yr a n ]-6′(3′H)-on e (14). The product was recrystallized from
EtOAc/Et2O to afford a 47% yield of 14: mp 117-119 °C; MS
(CI + 1% NH3 in CH4) 231 (M + 1). Anal. (C14H14O3) C, H,
N.
4-Hyd r oxy-6,6-d ip en tyl-5,6-d ih yd r op yr a n -2-on e (15).
The product was obtained as an oil in 82% yield which was
carried on without further purification: 1H NMR (DMSO-d6)
δ 0.87 (t, J ) 6.5 Hz, 6H), 1.17-1.31 (m, 12H), 1.57-1.62 (m,
4H), 2.49 (q, J ) 2 Hz, 2H), 4.93 (s, 1H); MS (CI + 1% NH3 in
CH4) 255 (M + 1).
3-(3,6-Dih yd r o-4-h yd r oxy-6-oxo-2-p h en yl-2H-p yr a n -2-
yl)p r op a n oic Acid (16). The title compound was prepared
as described in general method 1 using 25 mmol of methyl
acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25
mmol of 1.6 M n-butyllithium in hexane in 50 mL of THF,
and 25 mmol of 3-benzoylpropionic acid sodium salt in 60 mL
of THF. 3-Benzoylpropionic acid sodium salt was prepared
by reacting the acid (25 mmol) with hexane-washed NaH
(26.25 mmol) in THF at 0 °C for 30 min. The crude product
was flash chromatographed using CH2Cl2/MeOH/CH3CO2H
(90/10/0.2) as eluent to give a 23% yield of 16 as a viscous
gum: 1H NMR (CDCl3) δ 2.18-2.57 (m, 4 H), 2.93 (d, J ) 17.2
Hz, 1 H), 2.97 (d, J ) 20.5 Hz, 1 H), 3.30 (d, J ) 20.5 Hz, 1 H),
3.36 (d, J ) 17.2 Hz, 1 H), 7.27-7.45 (m, 5 H).
4-(3,6-Dih yd r o-4-h yd r oxy-6-oxo-2-p h en yl-2H-p yr a n -2-
yl)bu tyr ic a cid (17). The title compound was prepared as
described for compound 16. The crude product was flash
chromatographed using CH2Cl2/MeOH/CH3CO2H (99/1/0.1 to
97.5/2.5/0.1) to give a solid which was recrystallized from
EtOAc to give 19% of 17: mp 134-137 °C; MS (CI + 1% NH3
in CH4) 277 (M + 1). Anal. (C15H16O5) C,H.
5,6-Dih yd r o-6-h exyl-4-h yd r oxy-6-p h en yl-2H -p yr a n -2-
on e (5). Upon concentration of the mixture, a solid precipi-
tated out which was triturated with Et2O and filtered to afford
5 as a solid in 27% yield: mp 119-120.5 °C; MS (CI + 1%
NH3 in CH4) 275 (M + 1). Anal. (C17H22O3) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-(2-m et h ylp r op yl)-6-p h en yl-
2H-p yr a n -2-on e (6). The crude reaction was flash chromato-
graphed using hexane/EtOAc 60/40 to 40/60 as eluent. The
solid was triturated from Et2O to afford 6 as a solid in 21%
yield: mp 123.5-125 °C; MS (CI + 1% NH3 in CH4) 247 (M +
1). Anal. (C15H18O3‚0.09H2O) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-(3-m eth ylbu tyl)-6-p h en yl-2H-
p yr a n -2-on e (7). Upon concentration of the reaction mixture,
a solid precipitated out which was triturated with Et2O and
filtered to give 4 in 44% yield: mp 134-136 °C; MS (CI + 1%
NH3 in CH4) 261 (M + 1). Anal. (C16H20O3) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-(4-m et h ylp en t yl)-6-p h en yl-
2H -p yr a n -2-on e (8). Isoheptanophenone was prepared by
reacting the appropriate acid chloride with AlCl3 in benzene
as described by Vogel in Practical Organic Chemistry (1978,
pp 770-775). Upon concentration of the reaction mixture, a
solid precipitated out which was recrystallized from EtOAc to
5-(3,6-Dih yd r o-4-h yd r oxy-6-oxo-2-p h en yl-2H-p yr a n -2-
yl)p en ta n oic Acid (18). The title compound was prepared
as described for compound 16. The crude solid was recrystal-
lized from EtOAc to give a 28% yield of 18: mp 136-140 °C;
MS (CI + 1% NH3 in CH4) 291 (M + 1). Anal. (C16H18O5) C,
H, N.

3788 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Tait et al.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-6-p yr id in -4-yl-2H-p y-
r a n -2-on e (21). The reaction mixture was acidified with CH3-
CO2H and the crude solid was filtered off and then washed
with ice water to give 21: mp 148-150 °C. Anal. (C16H13N1O3‚
0.09H2O) C, H, N.
5,6-Dih ydr o-4-h ydr oxy-6-[(m eth ylph en ylam in o)m eth yl]-
6-p h en yl-2H-p yr a n -2-on e (22). The appropriate ketone,
2-(methylphenylamino)-1-phenylethanone, was prepared by
reacting N-methylaniline (50 mmol), R-bromoacetophenone (50
mmol), and Et3N (55 mmol) in Et2O at room temperature
overnight. The Et2O was evaporated and replaced with
p-dioxane, and the mixture refluxed for 15 h. The solid Et3N-
HCl was filtered. The filtrate was concentrated, and the solids
were recrystallized from EtOAc to afford 17.5% of 2-(meth-
ylphenylamino)-1-phenylethanone as a solid: mp 118-120 °C;
MS (CI + 1% NH3 in CH4) 226 (M + 1). Anal. (C15H15N1O1‚
0.09H2O) C, H, N.
Compound 22 was prepared as described in general method
1. The product was flash chromatographed using CH2Cl2/
MeOH (99/1) to give a solid: mp 152-153 °C; MS (CI + 1%
NH3 in CH4) 310 (M + 1). Anal. (C19H19N1O3‚0.28H2O) C, H,
N.
5,6-Dih yd r o-4-h yd r oxy-6-(p h en oxym et h yl)-6-p h en yl-
2H-p yr a n -2-on e (23). The crude product was triturated from
Et2O to afford 23 as a solid: mp 133-135 °C; MS (CI + 1%
NH3 in CH4) 296. Anal. (C18H16O4) C, H.
2-ter t-Bu tyl-5-isop r op ylp h en ol. A solution of 13.6 g (100
mmol) of 3-isopropylphenol, 15.0 g (200 mmol) of dry t-BuOH,
and 3.0 mL of concentrated H2SO4 was heated at 70 °C for 4
h. The solution was cooled to room temperature, diluted with
H2O, and extracted with EtOAc. The extract was washed with
H2O, dried over MgSO4, and concentrated. The product was
chromatographed, eluting with hexanes/EtOAc (5/1), to give
11.2 g (58% yield) of the title compound. Another 2.3 g of 2,4-
di-tert-butyl-5-isopropylphenol was also obtained: 1H NMR
(CDCl3) δ 1.19 (d, J ) 6.8 Hz, 6H), 1.36 (s, 9H), 2.78 (m, 1H),
4.64 (s, 1H), 6.50 (d, J ) 1.8 Hz, 1H), 6.71 (dd, J ) 1.8 Hz, 7.9
Hz, 1H), 7.15 (d, J ) 8 Hz, 1H).
Gen er a l Meth od 4. P r ep a r a tion of Ar yl Th iotosyla tes.
A solution of tosyl bromide (1.05 equiv), NEt3 (1.05 equiv), and
CCl4 was treated with a solution of the benzenethiol (1.0 equiv)
in CCl4 in a slow, dropwise fashion. When addition was
complete, the solution was washed with 3 N HCl, saturated
NaHCO3, and brine and was dried over MgSO4. Concentration
gave an oil which was purified by chromatography, as noted
in Table 1. Compounds 30d , 30e, 30f, 30i, and 30j were
prepared in this manner.
2-Cyclop en tylp h en yl p-Tolu en esu lfon a te (30d ). The
product was obtained as a solid in 53% yield from the
corresponding benzenethiol: 1H NMR (CDCl3) δ 1.6-2.0 (m,
8H), 2.52 (s, 3H), 2.95 (m, 1H), 7.22 (m, 2H), 7.48 (m, 4H),
7.90 (m, 2H).
2-Cycloh exylp h en yl p-Tolu en esu lfon a te (30e). The
product was obtained as a solid in 62% yield from the
corresponding benzenethiol: 1H NMR (CDCl3) δ 1.25 (m, 7H),
1.69 (m, 3H), 2.49 (s, 3H), 2.60 (m, 1H), 7.18 (m, 2H), 7.45 (m,
4H), 7.88 (m, 2H).
2-ter t-Bu tylp h en yl p-Tolu en esu lfon a te (30f). The prod-
uct was obtained as a solid in a 42% yield from the corre-
sponding benzenethiol: 1H NMR (CDCl3) δ 1.21 (s, 9H), 2.40
(s, 3H), 7.22 (m, 3H), 7.43 (m, 4H), 7.44 (d, 1H).
2-ter t-Bu tyl-5-m eth ylp h en yl p-Tolu en esu lfon a te (30i).
The product was obtained as a solid: 1H NMR (CDCl3) δ 1.19
(s, 9H), 2.21 (s, 3H), 2.38 (s, 3H), 7.18 (m, 2H), 7.26 (m, 2H),
7.44 (d, 2H).
4-H yd r oxy-6-p h en yl-6-[4-(t et r a h yd r op yr a n -2-yloxy)-
bu tyl]-5,6-d ih yd r op yr a n -2-on e (24). The appropriate keto
alcohol was prepared and then protected as a THP ether to
afford 1-phenyl-5-(tetrahydropyran-2-yloxy)pentan-1-one.30 The
THP-protected alcohol was then reacted as described in
general method 1. The produce was flash chromatographed
using CH2Cl2/MeOH (99/1) to afford a 46% yield of 24 as an
unknown mixture of diastereomers: mp 72.5-80.0 °C; MS (CI
+ 1% NH3 in CH4) 263 (M + 1). Anal. (C16H22O3) C, H.
Gen er a l Meth od 2. P r ep a r a tion of Alk yl Th iotosyl-
a tes. The thiotosylate reagents were prepared by reacting
equal molar quantities of alkyl halide and potassium thioto-
sylate in absolute EtOH, refluxing for 24 h in DMF, and
stirring at room temperature for 12-72 h. The solvent was
stripped off, and the residue was taken up in EtOAc and
washed with H2O. Alternatively, H2O was added, and the
aqueous layer was extracted with Et2O or EtOAc. The organic
extracts were dried over MgSO4 and concentrated in vacuo.
Compounds 25 and 26 were prepared according to this method.
Ben zyl p-tolu en eth iosu lfon a te (25). The residue was
recrystallized from hexane to yield 10.8 g (77%) of 25: mp 52-
56.5 °C.
P h en eth yl p-Tolu en eth iosu lfon a te (26). The clear liq-
uid obtained was used without purification: 1H NMR (CDCl3)
δ 2.47 (s, 3H), 2.92 (t, 2H), 3.24 (t, 2H), 7.1-7.4 (m, 7H), 7.84
(d, 2H).
Gen er a l Meth od 3. P r ep a r a tion of Ben zen eth iols (29).
The appropriate phenol (1 equiv) was dissolved in DMF and
added dropwise to a suspension of NaH (1.2 equiv) in DMF.
After 1 h, the mixture was treated with N,N-dimethylthiocar-
bamoyl chloride all at once. The suspension was stirred at 60
°C for 18 h, poured into H2O, and extracted with EtOAc. The
organic layer was washed with 1 N NaOH, 1 N HCl, and brine
and was dried over MgSO4. The residue was chromatographed
using hexane/EtOAc (6/1) to give an oily solid.
The intermediate prepared above was heated neat to 290-
310 °C for 2-3 h and then cooled to room temperature. The
rearranged product could be purified via chromatography or
via crystallization from ether/hexane. This material (1 equiv)
was dissolved in dry ether and added dropwise to a suspension
of LAH (1.8 equiv) in ether at 0 °C. The cold bath was removed
and the mixture was stirred at room temperature for 2-24 h.
The suspension was treated cautiously with EtOAc, H2O, and
1 N HCl/5% citric acid; the organic layer was separated,
washed with brine, and dried over MgSO4. Concentration gave
an oil which was used without purification in the next step.
Compounds 29d , 29e, 29h , and 29i were prepared in the same
manner from the commercially available phenol. Compound
29j was prepared from 2-tert-butyl-5-isopropylphenol, whose
synthesis is included below.
2-ter t-Bu tyl-5-isopr opylph en yl p-Tolu en esu lfon ate (30j).
The product was obtained as a solid in 55% yield: 1H NMR
(CDCl3) δ 1.16 (d, J ) 6.8 Hz, 6H), 1.20 (s, 9H), 2.37 (s, 3H),
2.77 (m, 1H), 7.17 (m, 2H), 7.35 (m, 4H), 7.44 (d, 2H).
Gen er a l Meth od 5. P r ep a r a tion of Ta r get Dih yd r o-
p yr on es. The desired compounds were prepared by adding
the 5,6-dihydro-2H-pyrone-2-one, absolute EtOH, the p-tolu-
enethiosulfonate reagent, and Et3N to a reaction vessel. The
solution was stirred at room temperature to reflux for 4 h to
one week. The solvent was stripped off and the residue
partitioned between 1 N HCl and CH2Cl2 or EtOAc. The layers
were separated, and the aqueous layer was extracted with CH2-
Cl2 or EtOAc. The organic layers were combined and dried
over MgSO4. Compounds 1b,c; 2b,c; 3b,c; 4b,c; 5b,c; 6b,c;
7b,c; 8b,c; 9b,c; 10b; 11b,c; 12b,c; 13b; 14b,c; 15b; 16c; 17c;
18c; 19c; 20c; 21c; 22c; 23b; 24b; 39; 40; 41;42; 43; 48; 49;
and 50 were prepared according to this method.
Gen er a l Meth od 6. P r ep a r a tion of 3-Br om od ih yd r o-
p yr on es. The 3-bromo-5,6-dihydro-4-hydroxy-2H-pyran-2-one
intermediates were prepared by reacting equimolar amounts
of the appropriate dihydropyrone (7, 10, 11) with N-bromo-
succinimide (NBS) in dry t-BuOH in the dark. The solvent
was evaporated, and the residue was partitioned between
CHCl3 and water. The organic layer was washed with brine,
dried (MgSO4), and concentrated. This method was used to
prepare compound 27 (3-bromo-5,6-dihydro-4-hydroxy-6,6-
diphenyl-2H-pyran-2-one), 28 (3-bromo-5,6-dihydro-4-hydroxy-
6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one), and 29 (3-bromo-
5,6-dihydro-4-hydroxy-(3-methylbutyl)-6-phenyl-2H-pyran-2-
one) which were all used without further purification.
Gen er a l Meth od 7. Alter n a te P r ep a r a tion of Ta r get
Dih yd r op yr on es. The desired compounds were prepared by
adding piperidine (1.05 equiv) to a cold (ice bath) solution of
the 3-bromo-5,6-dihydro-4-hydroxy-2H-pyran-2-ones (1.0 equiv,
prepared in General Method 6), the requisite thiol (29, 1.05
equiv), and CH2Cl2 (20 mL). The mixture was stirred at room
temperature for 8-48 h. Water was added, and the organic

4-Hydroxy-5,6-dihydropyrones. 2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3789
phase was separated, dried over MgSO4, and concentrated.
This method was used to prepare 7a , 11a , 12a , 33, 34, 35, 36,
37, 38, 44, 45, 46, and 47.
154-155 °C): MS (CI + 1% NH3 in CH4) 369 (M + 1). Anal.
(C22H24O3S‚0.60H2O) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-(3-m et h ylb u t yl)-6-p h en yl-3-
[(p h en ylm eth yl)th io]-2H-p yr a n -2-on e (7b). The product
was flash chromatographed (hexane/EtOAc, 80/20) to afford a
44% yield of 7b as a viscous gum: MS (CI + 1% NH3 in CH4)
383 (M + 1). Anal. (C23H26O3S‚0.17H2O) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-(3-m et h ylb u t yl)-6-p h en yl-3-
[(2-p h en yleth yl)th io]-2H-p yr a n -2-on e (7c). The product
was flash chromatographed (hexane/EtOAc, 80/20) to afford a
74% yield of 7c as a viscous gum: MS (CI + 1% NH3 in CH4)
397 (M + 1). Anal. (C24H28O3S‚0.17H2O) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-(4-m eth ylp en tyl)-6-p h en yl-3-
[(p h en ylm eth yl)th io]-2H-p yr a n -2-on e (8b). The product
was flash chromatographed using CH2Cl2/MeOH (100/0 to 99/
1) to afford a 28% yield of 8b as a viscous gum: MS (CI + 1%
NH3 in CH4) 397 (M + 1). Anal. (C24H28O3S) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-(4-m eth ylp en tyl)-6-p h en yl-3-
[(2-p h en yleth yl)th io]-2H-p yr a n -2-on e (8c). The product
was flash chromatographed using hexane/EtOAc (80/20) to
afford a 67% yield of 8c as a viscous gum: MS (CI + 1% NH3
in CH4) 411 (M + 1). Anal. (C25H30O3S‚0.05H2O) C, H, N,
H2O.
6-(Cyclop en tylm eth yl)-5,6-d ih yd r o-4-h yd r oxy-6-p h en -
yl-3-[(p h en ylm eth yl)th io]-2H-p yr a n -2-on e (9b). The prod-
uct was flash chromatographed using hexane/EtOAc (75/25)
and then CH2Cl2/MeOH (99.5/0.5) to afford a 66% yield of 9b
as a viscous gum: MS (CI + 1% NH3 in CH4) 395 (M + 1).
Anal. (C24H26O3S) C, H, N.
6-(Cyclop en tylm eth yl)-5,6-d ih yd r o-4-h yd r oxy-6-p h en -
yl-3-[(2-p h en yleth yl)th io]-2H-p yr a n -2-on e (9c). The prod-
uct was flash chromatographed using hexane/EtOAc (75/25 to
60/40) to afford a 89% yield of 9c as a viscous gum: MS (CI +
1% NH3 in CH4) 409 (M + 1). Anal. (C25H28O3S‚0.23H2O) C,
H, N.
6-(Cycloh exylm eth yl)-5,6-d ih yd r o-4-h yd r oxy-6-p h en yl-
3-[(p h en ylm eth yl)th io]-2H-p yr a n -2-on e (10b). The prod-
uct was flash chromatographed using CH2Cl2/MeOH (100/0 to
99/1) to afford a 49% yield of 10b as a viscous gum: MS (CI +
1% NH3 in CH4) 395 (M + 1). Anal. (C25H28O3S‚0.70H20) C,
H, N.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-3-[(p h en ylm et h yl)-
th io]-2H-p yr a n -2-on e (1b). Concentration in vacuo gave a
solid which was broken up and made into a slurry in Et2O
and EtOAc. The solid was filtered off, and the mother liquors
were concentrated and flash chromatographed on silica gel
using CH2Cl2/MeOH (99/1 to 97/3) as eluants. The combined
1
crops gave 55% of 1b as a solid: mp 150-151.5 °C; H NMR
(CDCl3) δ 2.65 (dd, J ) 17.6 Hz, J ) 4.0 Hz, 1H), 2.78 (dd, J
) 17.6 Hz, J ) 11.8 Hz, 1H), 3.85 (d, J ) 12.6 Hz, 1H), 3.94
(d, J ) 12.6 Hz, 1H), 5.28 (dd, J ) 11.8 Hz, J ) 4.0 Hz, 1H),
7.19-7.43 (m, 11H); MS (FAB + thioglycerol) 313 (M + 1).
Anal. (C18H16O3S) C, H, N, S.
5,6-Dih ydr o-4-h ydr oxy-6-ph en yl-3-[(2-ph en yleth yl)th io]-
2H-p yr a n -2-on e (1c). The product was purified by flash
chromatography using CH2Cl2/MeOH (99/1 to 97/3) as eluants.
The viscous paste was triturated from Et2O to yield 1c as a
solid in 64% yield: mp 98-99 °C; MS (CI + 1% NH3 in CH4)
327 (M + 1). Anal. (C19H18O3S), C, H, N, S.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-3-[(p h en ylm et h yl)-
th io]-6-p r op yl-2H-p yr a n -2-on e (2b). The product was flash
chromatographed (hexane/EtOAc, 75/25) to afford a 69% yield
of 2b as a viscous gum. MS (CI + 1% NH3 in CH4) 355 (M +
1). Anal. (C21H22O3S‚0.28H2O), C, H, N.
5,6-Dih ydr o-4-h ydr oxy-6-ph en yl-3-[(2-ph en yleth yl)th io]-
6-p r op yl-2H-p yr a n -2-on e (2c). The product was flash chro-
matographed (hexane/EtOAc, 60/40) to afford a 66% yield of
2c as a viscous gum. MS (CI + 1% NH3 in CH4) 369 (M + 1).
Anal. (C22H24O3S), C, H, S.
6-Bu t yl-5,6-d ih yd r o-4-h yd r oxy-6-p h en yl-3-[(p h en yl-
m eth yl)th io]-2H-p yr a n -2-on e (3b). The product was puri-
fied by flash chromatography using CH2Cl2/MeOH (100/0 to
95/5) as eluent gave a 35% yield of 3b as a viscous oil: MS
(EI+) 368. Anal. (C22H24O3S) C, H, N.
6-Bu tyl-5,6-d ih yd r o-4-h yd r oxy-6-p h en yl-3-[(2-p h en yl-
eth yl)th io]-2H-p yr a n -2-on e (3c). The product was purified
by flash chromatography using CH2Cl2/MeOH (99/1) as eluent
gave a 77% yield of 3c as a viscous oil: MS (CI + 1% NH3 in
CH4) 383 (M + 1). Anal. (C23H26O3S‚0.32H2O) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-p en t yl-6-p h en yl-3-[(p h en yl-
m eth yl)th io]-2H-p yr a n -2-on e (4b). The product was flash
chromatographed (hexane/EtOAc, 75/25) to afford a 58% yield
of 4b as a viscous gum: MS (CI + 1% NH3 in CH4) 383 (M +
1). Anal. (C23H26O3S‚0.46H2O) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-p en tyl-6-p h en yl-3-[(2-p h en yl-
eth yl)th io]-2H-p yr a n -2-on e (4c). The product was flash
chromatographed (hexane/EtOAc, 70/30) to afford a 58% yield
of 4c as a viscous gum: MS (CI + 1% NH3 in CH4) 397 (M +
1). Anal. (C24H28O3S) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6,6-d ip h en yl-3-(p h en ylt h io)-
2H-p yr a n -2-on e (11a ). The product was triturated with
hexane/Et2O (1/1) to afford 11a in 78% yield as a solid: mp
78-80 °C; 1H NMR (DMSO-d6) δ 3.37 (bs, 2 H), 6.35 (m, 2 H),
6.93 (m, 3 H), 7.29-7.49 (m, 10 H); MS (CI + 1% NH3 in CH4)
375 (M + 1). Anal. (C23H18O3S‚0.60 H2O) C, H, N, S.
5,6-Dih ydr o-4-h ydr oxy-6,6-diph en yl-3-[(ph en ylm eth yl)-
th io]-2H-p yr a n -2-on e (11b). The product was flash chro-
matographed (CH2Cl2/MeOH 100/0 to 98/2) to afford 11b in
53% yield as a solid: mp 44-47.5 °C; MS (CI + 1% NH3 in
CH4) 389 (M + 1). Anal. (C24H20O3S‚0.36H2O) C, H, N.
5,6-Dih ydr o-4-h ydr oxy-6,6-diph en yl-3-[(2-ph en yleth yl)-
th io]-2H-p yr a n -2-on e (11c). The solid product was tritu-
rated from Et2O to afford a 70% yield of 11c as a solid: mp
153-154.5 °C; MS (CI + 1% NH3 in CH4) 403 (M + 1). Anal.
(C25H22O3S) C, H, N.
5,6-Dih yd r o-6-h exyl-4-h yd r oxy-6-p h en yl-3-[(p h en yl-
m eth yl)th io]-2H-p yr a n -2-on e (5b). The product was flash
chromatographed using CH2Cl2/MeOH (99.5/0.5) to afford a
63% yield of 5b as a viscous gum: MS (CI + 1% NH3 in CH4)
397 (M + 1). Anal. (C24H28O3S‚0.29H2O) C, H, N.
5,6-Dih yd r o-6-h exyl-4-h yd r oxy-6-p h en yl-3-[(2-p h en yl-
eth yl)th io]-2H-p yr a n -2-on e (5c). The product was flash
chromatographed using CH2Cl2/MeOH (99.75/0.25 to 99/1) to
afford a 63% yield of 5c as a viscous gum: MS (CI + 1% NH3
in CH4) 411 (M + 1). Anal. (C25H30O3S‚0.21H2O) C, H, N, S.
5,6-Dih yd r o-4-h yd r oxy-6-(2-m eth ylp r op yl)-6-p h en yl-3-
[(p h en ylm eth yl)th io]-2H-p yr a n -2-on e (6b). The product
was flash chromatographed (CH2Cl2/MeOH, 99.5/0.5) to afford
a 60% yield of 6b as a viscous gum: MS (CI + 1% NH3 in
CH4) 369 (M + 1). Anal. (C22H24O3S‚0.24H2O) C, H, N, S.
5,6-Dih yd r o-4-h yd r oxy-6-(2-m eth ylp r op yl)-6-p h en yl-3-
[(2-p h en yleth yl)th io]-2H-p yr a n -2-on e (6c). The product
was flash chromatographed (CH2Cl2/MeOH, 99.5/0.5) to afford
a 55% yield of 6c as a viscous gum: MS (EI+) 382. Anal.
(C23H26O3S‚0.30H2O) C, H, N, S.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-6-(2-p h en ylet h yl)-3-
(p h en ylth io)-2H-p yr a n -2-on e (12a ). The product was tritu-
rated with hexane/Et2O (1/1) to afford a solid. The crude
product was chromatographed on silica gel, eluting first with
CHCl3 and then with 5% MeOH in CHCl3, to give 12a in 57%
yield as a solid: mp 58-60 °C; MS (CI + 1% NH3 in CH4) 402
(M + 1). Anal. (C25H22O3S‚0.60H2O) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-6-(2-p h en ylet h yl)-3-
[(p h en ylm eth yl)th io]-2H-p yr a n -2-on e (12b). The product
was flash chromatographed (hexane/EtOAc, 80/20) to afford a
59% yield of 12b as a viscous gum: 1H NMR (CDCl3) δ 2.13-
2.39 (m, 3H), 2.72-2.79 (m, 1H), 2.97 (d, J ) 17.5 Hz, 1H),
3.03 (d, J ) 17.5 Hz, 1H), 3.53 (d, J ) 13.0 Hz, 1H), 3.76 (d,
J ) 13.0 Hz, 1H), 6.85 (d, J ) 6.7 Hz, 2H), 7.06-7.45 (m, 14H);
MS (CI + 1% NH3 in CH4) 417 (M + 1). Anal. (C26H24O3S‚
5,6-Dih yd r o-4-h yd r oxy-6-(3-m et h ylb u t yl)-6-p h en yl-3-
(p h en ylth io)-2H-p yr a n -2-on e (7a ). The crude product was
chromatographed on silica gel, eluting first with CHCl3 and
then with 5% MeOH in CHCl3, to give 7a in 22% yield: (mp
0.24H2O) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-6-(2-p h en ylet h yl)-3-
[(2-p h en ylet h yl)t h io]-2H-p yr a n -2-on e (12c). The solid
product was triturated from Et2O to afford a 16% yield of 12c

3790 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23
Tait et al.
as a solid: mp 56-58 °C; MS (EI+) 430. Anal. (C27H26O3S‚
0.26H2O) C, H, N, S.
The title compound was prepared as described in general
method 3. The product was flash chromatographed using CH2-
Cl2/MeOH (90/10) and then triturated from Et2O to afford a
47% yield of 20c as a solid (softened 100-105 °C, melted
completely at 120 °C). MS (CI + 1% NH3 in CH4) 408 (M -
16). Anal. (C24H27N1O4S‚0.27H2O) C, H, N.
5,6-Dih ydr o-4-h ydr oxy-6-ph en yl-3-[(2-ph en yleth yl)th io]-
6-p yr id in -4-yl-2H-p yr a n -2-on e (21c). The solid product was
triturated from EtOAc: mp 203-205 °C; MS (CI + 1% NH3
in CH4) 404 (M + 1). Anal. (C24H21N1O3S‚0.43H2O) C, H, N.
5,6-Dih ydr o-4-h ydr oxy-6-[(m eth ylph en ylam in o)m eth yl]-
6-p h en yl-3-[(2-p h en yleth yl)th io]-2H-p yr a n -2-on e (22c).
The solid product was flash chromatographed using CH2Cl2/
MeOH (99/1) to afford 22c as a solid: mp 48-57 °C; MS (CI +
1% NH3 in CH4) 446 (M + 1). Anal. (C27H27N1O3S) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-6-p h en oxym et h yl-6-p h en yl-3-
[(p h en ylm eth yl)th io]-2H-p yr a n -2-on e (23b). Purification
by flash chromatography using CH2Cl2/MeOH (100/0 to 95/5)
as eluent gave a solid: mp 161-163 °C; MS (CI + 1% NH3 in
CH4) 461 (M + 1). Anal. (C28H28O4S) C, H.
3-(Ben zylsu lfan yl)-5,6-dih ydr o-4-h ydr oxy-6-(4-h ydr oxy-
bu tyl)-6-ph en yl-2H-pyr an -2-on e (24b). Purification by flash
chromatography using CH2Cl2/MeOH (99/1 to 98/2) as eluent
gave a solid: mp 43-49 °C; MS (CI + 1% NH3 in CH4) 385 (M
+ 1). Anal. (C22H24O4S‚0.39H2O) C, H.
5,6-Dih yd r o-4-h yd r oxy-3-[(2-m et h ylp h en yl)su lfa n yl]-
6,6-d ip h en yl-2H-p yr a n -2-on e (33). Purification by flash
chromatography using hexane/EtOAc (4/1 to 3/2) as eluent
gave a solid: mp 149-151 °C; MS (CI + 1% NH3 in CH4) 389
(M + 1). Anal. (C24H20O3S‚0.9H2O) C, H.
2,3-Dih yd r o-4′-h yd r oxy-5′-[(p h en ylm eth yl)th io]-sp ir o-
[1H-in d en e-1,2′-[2H]p yr a n ]-6′(3H′)-on e (13b). The product
was flash chromatographed using CH2Cl2/MeOH (99/1) to
afford a 86% yield of 13b as a solid: mp 42-46 °C; MS (CI +
1% NH3 in CH4) 339 (M + 1). Anal. (C20H18O3S‚0.24H2O) C,
H, N.
3,4-Dih yd r o-4′-h yd r oxy-5′-[(p h en ylm eth yl)th io]sp ir o-
[n a p h th a len e-1(2H),2′-[2H]p yr a n ]-6′(3′H)-on e (14b). The
product was flash chromatographed using hexane/EtOAc (90/
10 to 60/40) and then triturated from Et2O to afford a 37%
yield of 14b as a solid: mp 143-145 °C; MS (CI + 1% NH3 in
CH4) 353 (M + 1). Anal. (C21H20O3S‚0.12H2O) C, H, N.
3,4-Dih yd r o-4′-h yd r oxy-5′-[(2-p h en yleth yl)th io]-sp ir o-
[n a p h th a len e-1(2H),2′-[2H]p yr a n ]-6′(3′H)-on e (14c). The
product was flash chromatographed using CH2Cl2/MeOH
(100/0 to 98/2) to afford a solid which was recrystallized from
CH2Cl2/Et2O to afford 14c in 48% yield as a solid: mp 125-
126.5 °C; MS (CI + 1% NH3 in CH4) 367 (M + 1). Anal.
(C22H22O3S) C, H, N.
3-(Ben zylsu lfa n yl)-4-h yd r oxy-6,6-d ip en tyl-5,6-d ih yd r o-
p yr a n -2-on e (15b). The resulting oil was flash chromato-
graphed twice using hexanes/EtOAc as elutant (5:1/1:1) af-
fording the product as a syrup: 1H NMR (DMSO-d6) δ 0.85 (t,
J ) 7 Hz, 6H), 1.11-1.27 (m, 12H), 1.37-1.50 (m, 4H), 2.50
(q, J ) 2 Hz, 2H), 3.84 (s, 2H), 7.19-7.26 (m, 5H), 11.26 (bs,
1H); MS (CI + 1%NH3 in CH4) 377 (M + 1). Anal. C22H32O3S‚
0.50H2O.
3-(3,6-Dih yd r o-4-h yd r oxy-6-oxo-2-p h en yl-5-[(2-p h en yl-
eth yl)th io]-2H-pyr an -2-yl)pr opan oic Acid (16c). The prod-
uct was flash chromatographed using CH2Cl2/MeOH/MeCO2H
(95/5/0.05) and then recrystallized from EtOAc to afford 23%
yield of 16c as a solid: mp 150.5-152 °C; MS (CI + 1% NH3
in CH4) 399 (M + 1). Anal. (C22H22O5S) C, H, N.
5,6-Dih yd r o-4-h yd r oxy-3-[(2-m et h ylp h en yl)su lfa n yl]-
6-p h en yl-6-(2-p h en yleth yl)-2H-p yr a n -2-on e (34). Purifica-
tion by flash chromatography using hexane/EtOAc (4/1 to 3/2)
as eluent gave a solid: mp 80-82 °C; MS (CI + 1% NH3 in
CH4) 417 (M + 1). Anal. (C26H24O3S‚0.3H2O) C, H.
5,6-Dih ydr o-4-h ydr oxy-3-[(2-isopr opylph en yl)su lfan yl]-
6,6-d ip h en yl-2H-p yr a n -2-on e (35). Purification by tritura-
tion from ether gave a solid: mp 216-217 °C; MS (CI + 1%
NH3 in CH4) 417 (M + 1). Anal. (C26H24O3S‚0.6H2O) C, H.
5,6-Dih ydr o-4-h ydr oxy-3-[(2-isopr opylph en yl)su lfan yl]-
6-p h en yl-6-(2-p h en yleth yl)-2H-p yr a n -2-on e (36). Purifica-
tion by flash chromatography using CH2Cl2/MeOH (100/0 to
98/2) as eluent gave a solid: mp 109-111 °C; MS (CI + 1%
NH3 in CH4) 445 (M + 1). Anal. (C27H26O3S‚0.4H2O) C, H.
3-[(2-sec-Bu tylp h en yl)su lfa n yl]-5,6-d ih yd r o-4-h yd r oxy-
6,6-d ip h en yl-2H-p yr a n -2-on e (37). Purification by flash
chromatography using CH2Cl2/MeOH (100/0 to 98/2) as eluent
gave a solid: mp 161-162 °C; MS (CI + 1% NH3 in CH4) 431
(M + 1). Anal. (C27H26O3S) C, H.
3-[(2-sec-Bu tylp h en yl)su lfa n yl]-5,6-d ih yd r o-4-h yd r oxy-
6-p h en yl-6-(2-p h en yleth yl)-2H-p yr a n -2-on e (38). Purifica-
tion by flash chromatography using CH2Cl2/MeOH (100/0 to
98/2) as eluent gave a solid: mp 67-68 °C; MS (CI + 1% NH3
in CH4) 459 (M + 1). Anal. (C29H30O3S‚0.3H2O) C, H.
3-[(2-Cyclop en t ylp h en yl)su lfa n yl]-5,6-d ih yd r o-4-h y-
d r oxy-6,6-d ip h en yl-2H-p yr a n -2-on e (39). Purification by
flash chromatography using hexane/EtOAc (4/1 to 3/2) as
eluent gave a solid: mp 168-170 °C; MS (CI + 1% NH3 in
CH4) 443 (M + 1). Anal. (C28H26O3S‚0.2H2O) C, H.
4-(3,6-Dih yd r o-4-h yd r oxy-6-oxo-2-p h en yl-5-[(2-p h en yl-
eth yl)th io]-2H-p yr a n -2-yl)bu tyr ic Acid (17c). The product
was flash chromatographed using CH2Cl2/MeOH/MeCO2H (95/
5/0.05) to afford 17c in 28% yield as an amorphous solid: MS
(APCI + MeOH/CH3CN (20/80) + 0.1% NH4OH) 412. Anal.
(C23H24O5S‚0.60H2O) C, H, N.
5-(3,6-Dih yd r o-4-h yd r oxy-6-oxo-2-p h en yl-5-[(2-p h en yl-
eth yl)th io]-2H-pyr an -2-yl)pen tan oic Acid (18c). The prod-
uct was flash chromatographed using CH2Cl2/MeOH/MeCO2H
(99/1/0.05) to afford 18c in 31% yield as a solid: mp 113-119.5
°C; MS (CI + 1% NH3 in CH4) 427 (M + 1). Anal. (C24H26O5S‚
0.35H2O) C, H, N.
4-(3,6-Dih yd r o-4-h yd r oxy-6-oxo-2-p h en yl-5-[(p h en yl-
eth yl)th io]-2H-p yr a n -2-yl)bu tyr a m id e (19c). To a 50 mL
reaction flask were added 0.75 mmol of 17, 1.5 mmol of
4-methylmorpholine, and 7.5 mL of CH2Cl2. The reaction
mixture was cooled to 0 °C, and 1.5 mmol of methyl chloro-
formate in 3.5 mL of CH2Cl2 was added. The reaction mixture
was stirred at 0 °C for 2 h. Ammonia was bubbled into the
vessel for 10-15 min and the reaction mixture allowed to stir
for 30 min at 0 °C and then for 1.5 h at room temperature.
The reaction was poured into EtOAc and 1 N HCl, and the
aqueous layer was extracted with 2 × EtOAc, dried over
MgSO4, and concentrated. The crude reaction mixture was
flash chromatographed using CH2Cl2/MeOH/MeCO2H (98/2/
0.05) to afford 4-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-
pyran-2-yl)butyramide as a solid (mp 51-54 °C).
The title compound was prepared as described in general
method 3. The product was flash chromatographed using CH2-
Cl2/MeOH (90/10) and then triturated from Et2O to afford 19b
as a solid: mp 119-124 °C; MS (APCI + MeOH/CH3CN (20/
80) + 0.1% NH4OH) 412 (M + 1). Anal. (C23H25N1O4S‚0.29H2O)
C, H, N.
5-(3,6-Dih yd r o-4-h yd r oxy-6-oxo-2-p h en yl-5-[(2-p h en yl-
eth yl)th io]-2H-p yr a n -2-yl)p en ta n oic Acid Am id e (20c).
The desired amide was prepared as described in 19c using
18c as the acid starting material. The crude solid was
triturated from CH2Cl2 to afford 5-(3,6-dihydro-4-hydroxy-6-
oxo-2-phenyl-2H-pyran-2-yl)pentanoic acid amide as a solid
(mp 173-174 °C).
3-[(2-Cycloh e xylp h e n yl)su lfa n yl]-5,6-d ih yd r o-4-h y-
d r oxy-6,6-d ip h en yl-2H-p yr a n -2-on e (40). Purification by
flash chromatography using hexane/EtOAc (4/1 to 3/2) as
eluent gave a solid: mp 185-186 °C; MS (CI + 1% NH3 in
CH4) 457 (M + 1). Anal. (C29H28O3S‚0.4H2O) C, H.
3-[(2-Cycloh e xylp h e n yl)su lfa n yl)-5,6-d ih yd r o-4-h y-
d r oxy-6-p h en yl-6-(2-p h en yleth yl)-2H-p yr a n -2-on e (41).
Purification by flash chromatography using hexane/EtOAc (4/1
to 3/2) as eluent gave a solid: mp 198-200 °C; MS (CI + 1%
NH3 in CH4) 485 (M + 1). Anal. (C31H32O3S‚0.4H2O) C, H.
3-[(2-ter t-Bu tylph en yl)su lfan yl]-5,6-dih ydr o-4-h ydr oxy-
6,6-d ip h en yl-2H-p yr a n -2-on e (42). Purification by flash
chromatography using CH2Cl2/MeOH (100/0 to 98/2) as eluent
gave a solid: mp 191-192 °C; MS (CI + 1% NH3 in CH4) 431
(M + 1). Anal. (C27H26O3S‚0.5H2O) C, H.
3-[(2-ter t-Bu tylph en yl)su lfan yl]-5,6-dih ydr o-4-h ydr oxy-
6-p h en yl-6-(2-p h en yleth yl)-2H-p yr a n -2-on e (43). Purifica-

4-Hydroxy-5,6-dihydropyrones. 2
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 23 3791
(10) (a) Tummino, P. J .; Vara Prasad, J . V. N.; Ferguson, D.; Nouhan,
C.; Graham, N.; Domagala, J . M.; Ellsworth, E.; Gajda, C.;
Hagen, S. E.; Lunney, E. A.; Para, K. S.; Tait, B. D.; Pavlovsky,
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Discovery and Optimization of Nonpeptide HIV-1 Protease
Inhibitors. Bioorg. Med. Chem. 1996, 4, 1401-1410. (b) Hamil-
ton, H.; Tait, B. D.; Gajda, C.; Hagen, S.; Ferguson, D.; Lunney,
E.; Pavlovsky, A.; Tummino, P. 6-Phenyl-6-alkylamido-5,6-di-
hydropyrone-2H-pyran-2-ones: Novel HIV Protease Inhibitors.
Bioorg. Med. Chem. Lett. 1996, 6, 719-724.
tion by flash chromatography using hexane/EtOAc (4/1 to 3/2)
as eluent gave a solid: mp 81-83 °C; MS (CI + 1% NH3 in
CH4) 459 (M + 1). Anal. (C29H30O3S‚0.2H2O) C, H.
5,6-Dih yd r o-4-h yd r oxy-6,6-d ip h en yl-3-[(2-isop r op yl-5-
m eth ylp h en yl)su lfa n yl]-2H-p yr a n -2-on e (44). Purification
by flash chromatography using CH2Cl2/MeOH (100/0 to 98/2)
as eluent gave a solid: mp 183-184 °C; MS (CI + 1% NH3 in
CH4) 431 (M + 1). Anal. (C27H26O3S‚0.3H2O) C, H.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-6-(2-p h en ylet h yl)-3-
[(2-isop r op yl-5-m e t h ylp h e n yl)su lfa n yl]-2H -p yr a n -2-
on e (45). Purification by flash chromatography using CH2Cl2/
MeOH (100/0 to 98/2) as eluent gave a solid: mp 66-67 °C;
MS (CI + 1% NH3 in CH4) 459 (M + 1). Anal. (C29H30O3S‚
0.2H2O) C, H.
5,6-Dih yd r o-4-h yd r oxy-6,6-d ip h en yl-3-[(2,5-d iisop r o-
p ylp h en yl)su lfa n yl]-2H-p yr a n -2-on e (46). Purification by
flash chromatography using hexane/EtOAc (4/1 to 3/2) as
eluent gave a solid: mp 66-67 °C; MS (CI + 1% NH3 in CH4)
459 (M + 1). Anal. (C29H30O3S) C, H.
5,6-Dih yd r o-4-h yd r oxy-6-p h en yl-6-(2-p h en ylet h yl)-3-
[(2,5-d iisop r op ylp h en yl)su lfa n yl]-2H-p yr a n -2-on e (47).
Purification by flash chromatography using CH2Cl2/MeOH
(100/0 to 98/2) as eluent gave a solid: mp 95-96 °C; MS (CI
+ 1% NH3 in CH4) 487 (M + 1). Anal. (C31H34O3S‚0.4H2O)
C, H.
3-[(2-ter t-Bu tyl-5-m eth ylp h en yl)su lfa n yl]-5,6-d ih yd r o-
4-h yd r oxy-6,6-d ip h en yl-2H-p yr a n -2-on e (48). Purification
by flash chromatography using hexane/EtOAc (4/1 to 3/2) as
eluent gave a solid: mp 125-127 °C; MS (CI + 1% NH3 in
CH4) 445 (M + 1). Anal. (C28H28O3S‚0.6H2O) C, H.
3-[(2-ter t-Bu tyl-5-m eth ylp h en yl)su lfa n yl]-5,6-d ih yd r o-
4-h ydr oxy-6-ph en yl-6-(2-ph en yleth yl)-2H-pyr an -2-on e (49).
Purification by flash chromatography using hexane/EtOAc (4/1
to 3/2) as eluent gave a solid: mp 71-72 °C; MS (CI + 1%
NH3 in CH4) 473 (M + 1). Anal. (C30H32O3S‚0.15H2O) C, H.
3-[(2-ter t-Bu tyl-5-isop r op ylp h en yl)su lfa n yl)-5,6-d ih y-
d r o-4-h yd r oxy-6-p h en yl-6-(2-p h en ylet h yl)-2H -p yr a n -2-
on e (50). Purification by flash chromatography using hexane/
EtOAc (4/1 to 3/2) as eluent gave a solid: mp 62-64 °C; MS
(CI + 1% NH3 in CH4) 501 (M + 1). Anal. (C32H36O3S‚0.4H2O)
C, H.
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