Synthesis of C3 heteroatom-substituted azetidinones that display potent cholesterol absorption inhibitory activity

Article abstract of DOI:10.1021/jm970676d

The C3 phenylpropyl side chain N-phenylazetidinones related to SCH 56524 was modified by replacing the hydroxymethylene with various isoelectronic or isosteric groups. Modifications at the 3' position led to less-active compounds; however, modifications a

Full text of DOI:10.1021/jm970676d

752
J . Med. Chem. 1998, 41, 752-759
Syn th esis of C3 Heter oa tom -Su bstitu ted Azetid in on es Th a t Disp la y P oten t
Ch olester ol Absor p tion In h ibitor y Activity
Brian A. McKittrick,* Ke Ma, Keith Huie, Nathan Yumibe, Harry Davis, J r., J ohn W. Clader, and
Michael Czarniecki
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New J ersey 07033
Andrew T. McPhail
Department of Chemistry, Duke University, Durham, North Carolina 27708
Received October 6, 1997
The C3 phenylpropyl side chain of N-phenylazetidinones related to SCH 56524 was modified
by replacing the hydroxymethylene with various isoelectronic or isosteric groups. Modifications
at the 3′ position led to less-active compounds; however, modifications at the 1′ position provided
compounds with improved cholesterol absorption inhibitory activity. An enantioselective route
for the synthesis of C3 1′-sulfur-substituted azetidinones and the development of structure-
activity relationships for this series of compounds are presented.
Sch em e 1. Early SAR and Compounds Selected for
Synthesis
In tr od u ction
The reduction of serum cholesterol levels is an estab-
lished therapeutic approach for the treatment and
prevention of coronary heart disease. This has been
effectively accomplished by inhibiting cholesterol bio-
synthesis, by increasing the rate of cholesterol clearance,
or by blocking the absorption of dietary cholesterol.
SCH 48461 is a trans-azetidinone that was identified
as a potent cholesterol absorption inhibitor (CAI) in the
cholesterol-fed hamster1 and monkey models.2 Subse-
quently, SCH 48461 has been shown to reduce serum
cholesterol in human clinical trials.3 Although the
specific mechanism of action for SCH 48461 has not
been established, data suggest a unique mode of action
that is unrelated to ACAT activity or the sequestration
of bile acid.2
We recently reported that a structurally related cis-
azetidinone, SCH 56524, which contains a 1′-hydroxyl
group, had improved CAI activity relative to its des-
hydroxy analogue.4 The improved activity of SCH
56524 was thought to be a result of either (i) pre-
organization of the C3 side chain in a biologically active
conformation through the formation of an intramolecu-
lar H bond, (ii) the hydroxyl group acting as a H bond
acceptor or donor with the biological receptor, or (iii)
improved pharmacokinetics. Additionally, the 3′-hy-
droxyl derivative, SCH 56191, was identified as a
metabolite that retained good CAI activity.5 To further
develop the structure-activity relationship (SAR) in this
area and to address the role of the hydroxyl group, we
have examined the effect of incorporating isosteric or
isoelectronic replacements for the hydroxyl group at
either the 1′ or 3′ position. Accordingly, the sulfoxide,
sulfone, and phosphinic acid derivatives, 1 and 2 shown
in Scheme 1, were selected for synthesis.
wall;6 consequently, it was thought that compounds that
were more poorly absorbed into the blood stream could
exhibit improved CAI activity with an even better safety
profile, due to lower blood levels and a longer residence
in the intestine.
Ch em ica l Syn th esis a n d Biologica l Resu lts
We focused initially on preparing the trans-substi-
tuted azetidinones 1 and 2 in racemic form and planned
to prepare the scalemic material and the corresponding
cis isomers of those analogues that displayed good CAI
activity. The incorporation of sulfur and phosphorus
atoms at the 3′ position was readily accomplished from
the chloroethyl-substituted azetidinone 5 which was
The sulfoxide and phosphinic acids were attractive
targets since these polar groups could be expected to
have a pronounced effect of the bioavailability of these
molecules. Data suggested that the site of action for
azetidinones such as SCH 48461 was the intestinal
S0022-2623(97)00676-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/03/1998

C3-Substituted Azetidinones with CAI Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 753
Sch em e 2. Synthesis of 3′-Modified Azetidinones (Ar ) 4-MeOPh)
5
4
6
3
8
7
6
5
10
11
9
Sch em e 3. Synthesis of 1′-Modified Azetidinones (Ar ) 4-MeOPh)
15
13
14
12
16
17
18
19
20
obtained from the ketene imine reaction with 4-chloro-
butyryl chloride (3)7 (Scheme 2). Reaction of 5 with
thiophenol gave 6 which could be selectively oxidized
to either the sulfoxide 8 or the sulfone 7. Finkelstein
reaction with 5 gave the iodo compound 9. This was
reacted with methylphosphinic acid to give 10 followed
by deprotection to give the acid 11.
The 1′-thioether 13 and 1′-phosphinic acid 20 were
obtained as shown in Scheme 3. An ester enolate
reaction with 12 and the imine derived from p-anis-
aldehyde and aniline give a mixture of trans- and cis-
azetidinones 13 and 14. Reaction of the trans-thioether
13 with 1 equiv of mCPBA gave a 3:2 mixture of
sulfoxides 15. The sulfone 16 was cleanly obtained by
treatment of 13 with 2 equiv of mCPBA. The phos-
phinic ester 19 was obtained from reaction of the Li
enolate of the C3 unsubstituted azetidinone with methyl
phenethylphosphonoyl chloride 18. Subsequent depro-
tection with TMSBr gave the desired phosphinic acid
20.
Compounds were evaluated for in vivo activity using
a 7-day cholesterol-fed hamster model.1 Table 1 con-
tains the biological results for the racemic compounds
modified at the 1′ or 3′ position. All of the changes at
the 3′ position led to compounds that were less active
than SCH 56191 despite the wide range of functional-
ities introduced. The results for the 1′-phosphinic acid
20, phosphinic ester 19, and sulfone 16 were equally
disappointing. In contrast, the thioether 13 and the
sulfoxide 15 showed very significant CAI activity.
Since earlier studies have demonstrated that the
absolute configuration at C4 is a critical determinant
of CAI activity, an enantioselective synthesis of 13 and
15 was needed in order to more thoroughly evaluate the
CAI activity of these compounds. We focused on modi-
fying the Thiruvengadam route to SCH 48461, whereby

754 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5
McKittrick et al.
Sch em e 4. Enantioselective Synthesis of 1′-Sulfur-Substituted Azetidinones
21
Ta ble 1. Percent Reduction of Liver Cholesterol Ester Levels
after po Administration of Compounds for 7 days in
Cholesterol-Fed Hamstersa
Ta ble 2. Percent Reduction of Liver Cholesterol Ester Levels
after po Administration of Compounds for 7 days in
Cholesterol-Fed Hamstersa
compd
% reduction of CEb
compd
% reduction of CEb
thio-
ether activityb sulfoxide activityb sulfoxide activityb
SCH 48461
(2.2)
SCH 56524 (0.4)
SCH 56191
6
7
8
10
11
(0.9)
13
14
15
16
19
20
97% @25
R ) Me
trans
R ) Me
cis
R ) H
trans
R ) H
cis
24
25
33
34
89% @1
(0.13)
31% @10
26
28
35
37
58% @1
(0.90)
78% @3
27
29
36
38
82% @1
(0.21)
58% @1
(0.58)
0% @10
23% @10
21% @10
0% @25
0% @25
-31% @10
97% @ 25 (0.59)
54% @25
0% @25
0% @25
83% @1
0% @1
56% @10
40% @1
82% @1
42% @1
a
b
Dose given in mg/kg/day. % I @ dose or (ED50) in mpk/day,
n ) 4/compound.
a
b
Dose given in mg/kg/day. % I @ dose or (ED50) in mpk/day,
n ) 4/compound.
the reaction of a titanium enolate, derived from an
Evans chiral acyloxazolidinone, and an imine was used
for the diastereoselective synthesis of â-amino acid
derivatives.8 Condensation of the titanium enolate of
22 with the imine derived from p-anisaldehyde and
aniline provided 23 (Scheme 4) as a single diastereomer
in 25-30% yield (50-60% based on recovered starting
material). Despite the poor yield of this reaction, the
desired compound was readily obtained in pure form by
a single crystallization. A subsequent silylation-de-
silylation-cyclization sequence provided the trans- and
cis-azetidinones 24 and 25 in good yield as a 5:1 mixture
(97% enantiomeric purity by chiral HPLC). In control
experiments, the purified trans azetidinone 24 was
subjected to these reaction conditions and gave a similar
5:1 ratio of trans- and cis-azetidinones, suggesting that
the cis isomer resulted from TBAF-catalyzed epimer-
ization of the C3 substituent. After separation of 24
and 25, these were individually oxidized with mCPBA
to provide the sulfoxides 26 and 27, and 28 and 29,
respectively, as diastereomeric mixtures which were
separated by chromatography and crystallization.
Biological results for the enantiomerically pure series
of 1′-thioethers and sulfoxides are given in Table 2. In
the trans-azetidinone series with R ) Me, both the
thioether 24 and the sulfoxide 27 showed improved CAI
activity relative to their corresponding carbon analogues
or the analogues that contained a hydroxyl group at the
1′ position. Surprisingly, in the cis series with R ) Me,
the thioether 25 displayed only weak CAI activity and
was approximately 100-fold less active than the trans-
thioether, even though the cis-sulfoxide 29 still dis-
played very good CAI activity.

C3-Substituted Azetidinones with CAI Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 755
The encouraging biological results for compounds 24,
27, and 29 led us to further modify this series. Since
the C4 arylmethoxyl group of SCH 48461 is known to
be demethylated in vivo,6 we chose to prepare the
corresponding phenols of the most active compounds.
In addition, we replaced the N-phenyl group with a
4-fluorophenyl substituent in order to prevent metabolic
hydroxylation at this position.
experiments showed that only a small amount (<5%)
of thioether is metabolized to the sulfoxides 35 and 36.
Furthermore, treatment with sulfoxide 36 did not lead
to detectable levels of the thioether 33 (data not shown).
These results indicate that there is little in vivo inter-
conversion between the thioether and the sulfoxide and
suggest that neither compound is a prodrug for the
other.
Accordingly, the reaction sequence in Scheme 4 was
repeated using the TBDMS-protected imine prepared
from p-hydroxybenzaldehyde and 4-fluoroaniline. How-
ever, in this case, the Evans chemistry gave the desired
compound 30 in only 8-14% yield, along with 70-80%
of recovered starting material. It seemed likely that the
poor yield was due to incomplete enolate formation and/
or a facile retro-aldol reaction. Two important modifica-
tions of the reaction conditions improved the yield. The
use of i-PrOTiCl3 instead of TiCl4 improved the yield to
40%, presumably as a result of the more reversible
nature of the complexation of DIPEA and i-PrOTiCl3.9
Furthermore,, the nature of the quenching agent was
found to have a pronounced effect on the yield: quench-
ing the reaction at -78 °C with IPA (instead of AcOH)
further improved the yield to 55-60%, to give 30 as a
5:1 mixture of diastereomers. The crude reaction
mixture was readily purified by crystallization from
MeOH to give the single diastereomer 30 in 40% yield.
Compound 30 was cyclized as before to give 31 and 32.
After chromatographic separation, 31 was treated with
aqueous HF and the resultant phenol 33 oxidized using
mCPBA to give sulfoxides 35 and 36 as a 2:1 mixture.
Using (S)-camphorsulfonyloxaziridine to oxidize 33,
however, allowed us to reverse the selectivity of oxida-
tion and gave 35 and 36 as a 1:2.5 mixture. For the
large-scale preparation of 36, the sulfoxide 35 was
efficiently recycled by a reduction with NaI and TsOH
which proceeded in quantitative yield.10 To complete
the preparation of the cis-sulfoxides, compound 34 was
oxidized with mCPBA to give 37 and 38.
Discu ssion
In this report we have focused on the preparation and
evaluation of a series of azetidinones as inhibitors of
cholesterol absorption. We previously observed that a
hydroxyl group at either the 1′ or 3′ position of the C3
side chain was well-tolerated or in some cases improved
the CAI activity approximately 10-fold relative to the
compounds that lacked a hydroxyl group. In addition,
we speculated that the 1′-hydroxyl-containing com-
pound, SCH 56524, had improved CAI activity due to
either an intramolecular H bond between the hydroxyl
and the azetidinone carbonyl or the hydroxyl group
acting as an H bond donor or acceptor to the receptor.
This led us to replace the hydroxymethylene group at
the 1′ or 3′ position with various isosteric or isoelectronic
groups. Intially the targeted compounds were prepared
in racemic form. Although all of the modifications that
were made at the 3′ position gave less active compounds,
incorporating the same modifications at the 1′ position,
however, was more successful as the thioether 13 and
sulfoxides 15 showed improved CAI activity.
Earlier work in this area had demonstrated the
importance of the absolute configuration at C4 for CAI
activity. Accordingly, we developed an enantioselective
route to further evaluate the SAR in this series. This
enantioselective route allowed a complete analysis of
both the optically pure trans and cis compounds which
led to the identification of some particularly potent
compounds: the trans-azetidinone thioethers 24 and 33,
the trans-sulfoxides 27 and 36, and the cis-sulfoxide 29,
all of which are orally active inhibitors of cholesterol
absorption with approximately a 4-15-fold improve-
ment in CAI activity over SCH 48461.
The identification and elucidation of the biological
receptor for these molecules remains an area of active
research. Among other things this will enable us to
establish whether the improved biological activity of this
series of compounds is a result of increased binding
affinities or whether it is due to altered pharmaco-
kinetics. Even in the absence of an in vitro binding
assay, by pursuing a hypothesis on the potential role of
the 1′-hydroxyl group, a series of 1′-sulfur-substituted
azetidinones was discovered which had improved CAI
activity. Furthermore, this work uncovered some in-
triguing structure-activity relationships and impor-
tantly indicates that although SAR trends for the trans-
and cis-azetidinones can be quite different, potent
compounds can be obtained in both series. Additional
efforts to further modify the C3 side chain in this series
are in progress and will be reported shortly.
The relative and absolute configuration of 36 was
established by X-ray analysis to be 1′(R),3(R),4(R). The
X-ray structure of the sulfoxide 36 contained a H bond
from the OH of IPA, that cocrystallized with 36, to the
sulfoxide oxygen. This result was particularly interest-
ing, since one of our initial rationales for preparing the
sulfoxides was to introduce a group that was a potential
H bond acceptor.
The biological data for the phenolic compounds, Table
2 (R ) H), paralleled the results for the methoxyl series
(R ) Me) in that the trans-thioether 33 and one of the
diastereomeric trans-sulfoxides 36 both displayed very
potent CAI activity and were equipotent to each other.
In the cis series the thioether 34 was again much less
active than the corresponding trans isomer 33, but the
cis-sulfoxides 37 and 38 still retained CAI activity. A
possible explanation for this could be that, in both the
trans and cis series, the sulfoxide is actually the more
biologically active species and the trans-thioether is
oxidized, in vivo, to the sulfoxide more rapidly than the
more sterically crowded cis-thioether. To investigate
this possibility, the thioether 33 and sulfoxide 36 were
individually dosed 50 mpk po in the cynomolgus mon-
key. Bile concentrations of these compounds were
analyzed by HPLC 6 and 24 h postdosing. These
Exp er im en ta l Section
Gen er a l. All reagents were used as received with the
exception of mCBPA which was purified by washing with
phosphate buffer according to the procedure of Schwartz.12 All
melting points were taken on a Thomas-Hoover or Mel-Temp

756 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5
McKittrick et al.
II melting point apparatus and are uncorrected. Chromatog-
raphy was performed over Universal Scientific or Selecto
Scientific flash silica gel, 32-63 µM. 1H NMR spectra were
determined with a Varian VXR 200, Gemini 300, or Gemini
400 MHz instrument using residual solvent signal as internal
standards. J values are given in hertz (Hz). IR spectra were
obtained on a Perkin-Elmer 727B series IR spectrophotometer
or on a Nicolet 10 MX-FTIR instrument. Rotations were
determined on a Rudolph Autopol III or Perkin-Elmer 243B
polarimeter. Mass spectra were obtained on VG-ZAB-SE,
Extrel-401, HP-MS Engine, or J EOL HX-110 mass spectrom-
eters. Elemental analyses were determined by the Physical-
Analytical Department of Schering-Plough Research Institute
using either CEC 240-HA, CEC CE-440, or Fisons EA 1108
CHNS elemental analyzers and are within 0.4% of the
theoretical value unless otherwise noted.
In Vivo Meta bolism Stu d ies. A 5.7-kg adult male cyno-
molgus monkey from the Schering-Plough Research Institute
(Lafayette, NJ ) was fasted for at least 18 h prior to being
anesthetized with halothane. The gall bladder was removed,
and the bile duct was cannulated at two ends with a single
piece of Tygon Microbore tubing (Formulation S-54-HL). This
closed-loop cannula allowed for normal bile flow into the GI
tract prior to sample collection. The monkey was fitted with
a jacket to minimize damage to the exposed cannula, and after
the animal regained consciousness, blood clinical chemistry
data and urinary and fecal output were evaluated to ensure
that the animal was suitable for the study. To initiate the
experiment, the exposed cannula was cut and both ends were
placed in a 50-mL plastic centrifuge tube to collect bile. The
monkey was dosed orally by gavage with either 50 mg of 33
or 36/kg, and bile was collected for 24 h. Approximately 2 mL
of bile was hydrolyzed with Glusulase (Sigma Chemicals; 3500
units for 16 h at 37 °C) since glucuronide conjugates of several
SCH 48461 metabolites have previously been identified in
monkey bile. The biliary metabolites were initially isolated
from endogenous components using a Waters C-18 Sep-Pak
solid-phase extraction cartridge (Waters Corp.). The material
which eluted from the Sep-Pak cartridge with methanol was
concentrated in vacuo; the residue was reconstituted in the
mobile phase and analyzed using a Waters HPLC system with
on-line UV detection at 260 nm. Separation was achieved on
a J ones chromatography Hypersil C-18 column (4.6 × 250 mm)
using a water/methanol gradient system starting at 50%
methanol/50% water, held isocratic for 10 min, followed by a
5-min gradient to 70% methanol/30% water, which was then
held isocratic for 10 min, followed by a 5-min gradient to 80%
methanol/20% water. This gradient separated all available
putative metabolite standards, including the diastereoisomeric
sulfoxides 35 and 36. Metabolites were identified by compari-
son of retention times with authentic standards and by particle
beam LC/MS (Hewlett-Packard Instruments).
6.81 mmol) in THF (5 mL) was added dropwise and the
resultant mixture stirred at room temperature overnight. The
reaction mixture was diluted with EtOAc (100 mL), washed
with NaHCO3 and brine, and then dried (MgSO4) and evapo-
rated. Flash chromatography on silica gel using EtOAc/Hex
(1:6) afforded 6 (2.32 g, 50% yield): NMR δ 2.15 (m, 1H, CH2),
2.28 (m, 1H, CH2), 3.07 (m, 1H, SCH2), 3.17 (m, 1H, SCH2),
3.25 (m, 1H, C3H), 3.80 (s, 3H, OMe), 4.67 (d, J ) 2.3, 1H,
C4H), 6.9 (d, 2H, ArH), 7.03 (dd, 1H, ArH), 7.17-7.36 (m, 11H,
ArH); MS (CI) 390 (M+ H), 418 (M+ C2H5). Anal. (C24H23
NO2S) C, H, N.
-
3-[2-(P h en ylsu lfon yl)et h yl]-4-(4-m et h oxyp h en yl)-N-
p h en yl-2-a zetid in on e, 7. To a solution of 6 (0.185 g, 0.48
mmol) in DCM (20 mL) was added mCPBA (0.205 g) at room
temperature. After 3 h, a saturated solution of NaHSO3 (10
mL) and NaHCO3 (20 mL) was added, and the mixture was
extracted with EtOAc. The organic layer was purified by flash
chromatography on silica gel using EtOAc/Hex (1:4) to give 7
as a colorless solid (0.154 g, 76.4% yield): NMR δ 2.21-2.40
(m, 2H, CH2), 3.08 (m, 1H, C3H), 3.25 (ddd, 1H, SO2CH), 3.42
(m, 1H, SO2CH), 3.80 (s, 3H, OMe), 4.62 (d, J ) 2.3, 1H, C4H),
6.88 (d, 2H, ArH), 7.04 (m, 1H, ArH), 7.22-7.29 (m, 6H, ArH),
7.58 (m, 2H, ArH), 7.67 (m, 1H, ArH), 7.90 (d, 2H, ArH); MS
(FAB) 422 (M+ H). Anal. (C24H23NO4S) C, H, N.
3-[2-(P h e n ylsu lfin yl)e t h yl]-4-(4-m e t h oxyp h e n yl)-N-
p h en yl-2-a zetid in on e, 8. To a solution of 6 (0.25 g, 0.64
mmol) in DCM (20 mL) at -78 °C was added mCPBA (0.13 g,
0.64 mmol). After 2 h, a saturated solution of NaHSO3 (10
mL) was added, and the mixture was allowed to warm to room
temperature and then extracted with EtOAc. The organic
layer was purified by flash chromatography on silica gel using
EtOAc/Hex (1:1) to give 8 as a colorless solid (0.19 g, 73%
yield), as a 1:1 mixture of diastereomers by NMR: NMR δ
2.04-2.48 (m, 2H, CH2), 2.85 (m, 1H, C3H), 2.98-3.21 (m, 2H,
SOCH2), 3.80 (s, 3H, OMe), 4.62, 4.64 (d, J ) 2.4, 1H, C4H),
6.89 (d, 2H, ArH), 7.03 (m, 1H, ArH), 7.21-7.30 (m, 6H, ArH),
7.52 (m, 3H, ArH), 7.60 (m, 2H, ArH); HRMS (FAB) calcd
406.1477, found 406.1466. Anal. (C24H23NO3S) H, N; C: calcd,
71.09; found, 70.11.
3-[2-(Me t h oxyp h e n ylp h osp h in yl)e t h yl]-4-(4-m e t h -
oxyp h en yl)-N-p h en yl-2-a zetid in on e, 10. Step 1: To a
solution of 5 (1.0 g, 3.17 mmol) in acetone (30 mL) was added
NaI (0.95 g, 6.34 mmol). The mixture was heated to reflux
for 4 h, then additional NaI (0.95 g) was added, and the
reaction mixture refluxed overnight. Water was added to the
cooled mixture, and it was partitioned with Et2O, washed with
brine, dried (MgSO4), and evaporated to give compound 9
which was used without further purification.
Step 2: To a solution of methyl phenylphosphinic acid (0.109
g, 0.7 mmol) in THF (5 mL) was added NaH (17 mg, 0.7 mmol)
at 0 °C. The mixture was warmed to room temperature and
stirred for 10 min. To this was added dropwise a solution of
9 (0.19 g, 0.47 mmol) in THF (3 mL). After stirring at room
temperature overnight the mixture was concentrated in vacuo,
and the residue was purified by flash chromatography on silica
gel using EtOAc/Hex (1:4) to give a 1:1 mixture of diastereo-
mers 10 as a solid (0.11 g, 54% yield): NMR δ 1.92-2.30 (m,
4H, CH2CH2), 3.08 (bt, 1H, C3H), 3.61, 3.65 (d, 3H, POMe),
3.78, 3.80 (s, 3H, OMe), 4.58, 4.61 (d, J ) 2.4, 1H, C4H), 6.88
(dd, 2H, ArH), 7.03 (m, 1H, ArH), 7.20-7.28 (m, 6H, ArH),
7.50 (m, 2H, ArH), 7.76 (dd, 2H, ArH); MS (FAB) 436 (M+ H).
Anal. (C25H26NO4P‚0.33H2O) C, H, N.
Ch em ica l Syn th esis. (4-Meth oxyben zylid en e)a n isi-
d in e 4. A mixture of p-anisaldehyde (60 g, 0.44 mol) and
aniline (41 mL, 0.44 mol) in toluene (1 L) was evaporated to
dryness on a rotorary evaporator and dried under high vacuum
to give 4 as a solid, 93.31 g, Y ) 100%.
3-(2-Ch lor oe t h yl)-4-(4-m e t h oxyp h e n yl)-N -p h e n yl-2-
a zetid in on e, 5. A solution of 4-chlorobutyryl chloride (8.35
g, 59.25 mmol) in toluene (20 mL) was added dropwise to a
refluxing solution of 4 (12.5 g, 59.25 mmol) and DIPEA (10.3
mL, 59.2 mmol). After refluxing for 14 h the cooled reaction
was quenched with the addition of 1 N HCl (50 mL) and the
mixture partitioned with EtOAc (200 mL). The organic layer
was washed with brine, dried (MgSO4), and evaporated. Flash
chromatography on silica gel using EtOAc/Hex (1:6) afforded
5 (18.11 g, 96% yield): NMR δ 2.32 (m, 1H, CH2), 2.46 (m,
1H, CH2), 3.25 (m, 1H, C3H), 3.67-3.79 (m, 2H, CH2Cl), 3.80
(s, 3H, OMe), 4.74 (d, J ) 2.4, 1H, C4H), 6.90 (d, 2H, ArH),
7.03 (dd, 1H, ArH), 7.25-7.33 (m, 6H, ArH).
3-[2-(P h en ylp h osp h in yl)et h yl]-4-(4-m et h oxyp h en yl)-
N-p h en yl-2-a zetid in on e, 11. TMSBr (0.37 mL, 0.27 mmol)
was added at 0 °C to a solution of 10 (0.103 g, 0.24 mmol) in
DCM (10 mL). The mixture was warmed to room temperature
and stirred overnight. The mixture was concentrated in vacuo,
and the residue was treated with 95% acetone (3 mL).
Evaporation of the solvent gave 11 as a solid (0.045 g, 45%
yield): NMR δ 1.92-2.12 (m, 4H, CH2CH2), 2.96 (bt, 1H, C3H),
3.78 (s, 3H, OMe), 4.53 (d, J ) 2.4, 1H, C4H), 6.84 (d, 2H,
ArH), 7.03 (m, 1H, ArH), 7.21-7.25 (m, 6H, ArH), 7.38 (m,
2H, ArH), 7.47 (m, 1H, ArH), 7.73 (m, 2H, ArH); MS (FAB)
422 (M+ H). Anal. (C24H24NO4P)‚0.2H2O) C, H, N.
3-[2-(P h en ylth io)eth yl]-4-(4-m eth oxyp h en yl)-N-p h en -
yl-2-a zetid in on e, 6. NaH (245 mg, 10.2 mmol) was added
to a solution of thiophenol (1.05 mL, 10.2 mmol) in THF (15
mL) at 0 °C under N2. After 5 min a solution of 5 (2.15 g,

C3-Substituted Azetidinones with CAI Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 757
3-(2-P h en eth ylth io)-4-(4-m eth oxyp h en yl)-N-p h en yl-2-
a zetid in on e, 13 a n d 14. To a solution of diisopropylamine
(2.16 mL, 15.4 mmol) in THF at 0 °C was added n-BuLi in
hexane (1.6 M, 10.2 mL, 16.08 mmol). After 15 min, the
mixture was cooled to -78 °C, and a solution of 12 (3.0 g, 13.4
mmol) in THF (15 mL) was added over 5 min followed 60 min
later by the slow addition of a solution of the imine (3.15 g,
13.4 mmol) in THF. After 1 h, the mixture was warmed to
room temperature, stirred for 2 h, and then partitioned with
EtOAc and 1 N HCl. The organic layers were washed with
brine, dried (MgSO4), and evaporated. The residue was
dissolved in MeOH, and NaBH4 was added (to reduce un-
reacted imine). After 1 h, the solvent was removed under
vacuum, and the residue was purified by flash chromatography
on silica gel using EtOAc/Hex (1:9) to give 13 (0.67 g, 12%
yield) and 14 (0.15 g, 3% yield). 13: NMR δ 2.95 (m, 4H,
CH2CH2), 3.82 (s, 3H, OMe), 3.95 (d, J ) 2.2, 1H, C3H), 4.72
(d, J ) 2.2, 1H, C4H), 6.9 (m, 2H, ArH), 7.04 (m, 1H, ArH),
7.18-7.29 (m, 11H, ArH); MS (FAB) 390 (M+ H). Anal.
(C24H23NO2S) C, H, N. 14: NMR δ 2.80 (m, 4H, CH2CH2), 3.81
(s, 3H, OMe), 4.53 (d, 1H, J ) 5.6, C3H), 5.27 (d, 1H, J ) 5.72,
C4H), 6.9 (m, 2H, ArH), 7.04 (m, 1H, ArH), 7.13-7.26 (m, 11H,
ArH); HRMS (FAB) calcd 390.1528, found 390.1520.
3-(2-P h en eth ylsu lfin yl)-4-(4-m eth oxyp h en yl)-N-p h en -
yl-2-a zetid in on e, 15. To a solution of 13 (0.25 g, 0.64 mmol)
in DCM (20 mL) at -78 °C was added mCPBA (0.13 g, 0.64
mmol). After 2 h, a saturated solution of NaHSO3 (10 mL)
was added and the mixture allowed to warm to room temper-
ature, then extracted with EtOAc. The organic layer was
purified by flash chromatography on silica gel using EtOAc/
Hex (1:1) to give 15, a colorless solid (0.19 g, 72% yield), as a
3:2 mixture of diastereomers (a and b) by NMR: NMR δ 3.15
(m, 3H, CH2CH2), 3.82 (s, 3H, OMe), 3.90 (m, 1H, SOCH2),
3.94 (d, J ) 2.5, 0.6H, C3Ha), 4.11 (d, J ) 2.1, 0.4H, C3Hb),
5.32 (d, J ) 2.6, 0.6, C4Ha), 5.51 (d, J ) 2, 0.4H, C4Hb), 6.9
(m, 2H, ArH), 7.04 (m, 1H, ArH), 7.21-7.36 (m, 11H, ArH);
MS (EI) 405 (M+ ), 251 (100). Anal. (C24H23NO3S) C, H, N.
3-(2-P h en eth ylsu lfon yl)-4-(4-m eth oxyp h en yl)-N-p h en -
yl-2-a zetid in on e, 16. mCPBA (0.205 g, 1.2 mmol) was added
to a solution of 13 (0.185 g, 0.48 mmol) in DCM (20 mL). After
3 h, sodium bisulfite and sodium bicarbonate were added, the
mixture and stirred for 10 min and then was partitioned with
ethyl acetate. The organic fraction was purified by flash
chromatography on silica gel using hexane/ethyl acetate (4:1)
to give 16 as a white solid (0.15 g, 76%): MS (EI) 421 (M+);
NMR δ 3.2 (m, 2H, CH2), 3.55 (m, 2H, SO2CH2), 3.80 (s, 3H,
OMe), 4.23 (d, J ) 2.4, 1H, C4H), 5.53 (d, J ) 2.4, 1H, C3H),
6.9 (d, 2H, ArH), 7.1 (m, 1H, ArH), 7.28 (m, 11H, ArH). Anal.
(C24H23NO4S) C, H, N.
Dim eth yl P h en eth ylp h osp h on a te, 17. Dimethyl phos-
phite (2.0 g, 18.2 mmol) was added slowly to a suspension of
NaH (0.44 g, 18.2 mmol) in DMF at 0 °C. The mixture was
stirred for 15 min, and then (2-bromoethyl)benzene (3.72 mL,
27 mmol) was added slowly at 0 °C, and the mixture warmed
to room temperature for 3 h. The reaction mixture was diluted
with EtOAc (200 mL), washed with 1 N HCl (100 mL), 1 N
NaOH (3 × 50 mL), and brine, and then dried (MgSO4). After
concentration, the organic soluble fraction was purified by
flash chromatography on silica gel using DCM/EtOAc (24:1)
to give 17 as a colorless oil (2.21 g, 57%): NMR δ 2.07 (m, 2H,
CH2P), 2.91 (m, 2H, CH2Ar), 3.74 (d, 6H, P(OMe)2), 7.20 (m,
3H, ArH), 7.28 (m, 2H, ArH).
was dissolved in THF (7 mL) and added to a preformed
solution of the Li enolate of 4-(4-methoxyphenyl)-N-phenyl-2-
azetidinone at - 78 °C. [Prepared as follows: n-BuLi (3.5 mL
of 1.6 M in hexane) was added to a stirring solution of
N-isopropylcyclohexylamine (0.93 mL, 5.46 mmol) in THF (5
mL) at 0 °C. After 15 min this was cooled to -78 °C for 30
min followed by addition of a solution of N-phenyl-4-(4-
methoxyphenyl)-2-azetidinone (1.33 g, 5.25 mmol) in THF (5
mL) and stirred 30 min before the solution of 18 was added.]
After stirring at - 78 °C for a further 2 h, the reaction was
quenched with 20% KHSO4
(20 mL), the mixture was extracted
into EtOAc, and the organic layer was passed through silica
gel using DCM/EtOAc (99:1) to yield 19 (0.60 g, 52%) as a 3:1
mixture of diastereomers by NMR: NMR (diastereomer A) δ
2.21 (m, 2H, CH2P), 2.98 (m, 2H, CH2Ar), 3.42 (m, 1H, C3H),
3.80 (s, 3H, OMe), 3.84 (d, J ) 10, 3H, POMe), 5.32 (dd, J )
2.4, 8, C4H), 6.9 (m, 2H, ArH), 7.06 (m, 1H, ArH), 7.18-7.37
(m, 11H, ArH); NMR (diastereomer B) δ 2.33 (m, 2H, CH2P),
2.98 (m, 2H, CH2Ar), 3.51 (m, 1H, C3H), 3.72 (d, J ) 11, 3H,
POMe), 3.81 (s, 3H, OMe), 5.36 (dd, J ) 2.5, 8, C4H), 6.9 (m,
2H, ArH), 7.06 (m, 1H, ArH), 7.18-7.37 (m, 11H, ArH); MS
(FAB) 436 (M+). Anal. (C25H26NO4P) C, H, N.
3-(P h en eth ylph osph in yl)-4-(4-m eth oxyph en yl)-N-ph en -
yl-2-a zetid in on e, 20. TMSBr (1.1 equiv) was added to a
solution of 19 (244 mg, 0.56 mmol) in DCM (10 mL) at 0 °C.
After stirring for 14 h at room temperature, the mixture was
evaporated to dryness. The residue was dissolved in 95%
acetone (5 mL), stirred briefly, and then evaporated to dryness
and dried under vacuum to give 20 (235 mg, Y ) 99%): NMR
δ 2.28 (m, 2H, CH2P), 2.97 (m, 2H, CH2Ar), 3.45 (dd, J ) 3, 8,
1H, C3H), 3.78 (s, 3H, OMe), 5.40 (dd, J ) 2.5, 8, C4H), 6.84
(d, 2H, ArH), 7.03 (t, 1H, ArH), 7.20 (m, 4H, ArH), 7.27 (m,
5H, ArH), 7.33 (d, 2H, ArH), 7.33 (d, 2H, ArH), 8.48 (bs, 1H,
POH). MS (FAB) 444 (M+ Na). Anal. (C24H24NO4P) C, H, N.
[4-(ter t-Bu t yld im et h ylsiloxy)b en zylid en e]-4-flu or o-
a n isid in e. A mixture of 4-fluoroaniline (128 mL, 1.35 mol)
and 4-(tert-butyldimethylsiloxy) benzaldehyde (290 g, 1.23
mmol) was heated in toluene (1.2 L) to reflux under a Dean-
Stark trap. After 24 h, the solution was concentrated in vacuo,
and the residue was dissolved in warm hexane (0.2 L) and
cooled to -20 °C to collect the title compound (378 g, 94% yield)
by filtration: mp 51.4-52.2 °C; NMR δ 0.22 (s, 6H, Me2Si),
1.05 (s, 9H, t-BuSi), 6.95 (d, 2H, ArH), 7.12 (m, 2H, ArH), 7.19
(m, 2H, ArH),7.80 (d, 2H, ArH), 8.18 (s, 1H, NCH).
4-P h en yl-N-(ch lor oacetyl)-2-oxazolidin on e, 21. Meth od
A: A solution of chloroacetyl chloride (9.76 mL, 122 mmol) in
DCM (110 mL) was added dropwise to a solution of 4-phenyl-
oxazolidinone (10 g, 61 mmol), Et3N (35 mL, 244 mmol), and
DMAP (9.5 g, 4 mmol) in DCM (0.15 L). After 30 min at 0 °C
additional chloroacetyl chloride was added (0.2 equiv), and the
mixture was allowed to warm to room temperature. After 1
h, silica gel was added, and the reaction mixture was concen-
trated in vacuo and then loaded onto a silica gel flash column.
Elution with EtOAc/Hex (1:4) gave 21 (11.29 g, 77%).
Meth od B: Prepared using the general procedure described
by Pridgen12 for the synthesis of the bromoacetyl analogue
using in this case chloroacetyl chloride to yield a colorless
solid: NMR δ 4.38 (dd, 1H, J ) 3.8, 9), 4.68 (d, 1H, J ) 15.8),
4.75 (d, 1H, J ) 15.8), 4.78 (t, 1H, J ) 9), 5.45 (dd, 1H, J )
3.7, 9), 7.32-7.46 (m, 5H).
(S)-4-P h en yl-N-(2-p h en et h ylt h io)a cet yl-2-oxa zolid i-
n on e, 22. Phenethyl mercaptan(5.1 mL, 37.5 mmol) was
added to a solution of 21 (6.0 g, 25 mmol) and triethylamine
(5.2 mL, 37.5 mmol) in DCM (0.1 L). After stirring at room
temperature for 16 h, silica gel (approx 50 g) was added and
the mixture was concentrated in vacuo. The residue was
purified by flash chromatography on silica using ethyl acetate:
hexane 1:4 to give a colorless solid (7.81 g, 92%) which was
crystallized from ethyl acetate:hexane 1:4. NMR δ 2.65 (m,
2H), 2.80, (m, 2H), 3.68 (d, 1H, J ) 13.7, CHS), 3.97(d, 1H, J
) 13.7 CHS), 4.29 (dd, 1H, J ) 4, 9.5), 4.53 (dd, 1H, J ) 4,
8.8), 4.72 (t, 1H, J ) 8.8), 7.12-7.43 (m, 10H, ArH); Anal.
(C19H19NO3S) C, H, N; MS (FAB) 342.1 (M+H).
3-(Meth oxyph en eth ylph osph in yl)-4-(4-m eth oxyph en yl)-
N-p h en yl-2-a zetid in on e, 19. To a solution of 17 (2.2 g, 10.3
mmol) in THF (10 mL) was added a solution of LiOH-H2O
(0.52 g, 12 mmol) in H2O (5 mL). The mixture was stirred at
room temperature overnight and then acidified with 1 N HCl
and extracted with EtOAc. The organic layer was washed with
brine, dried (MgSO4), and evaporated to give the acid (2.03 g,
100%). A portion of this (0.525 g, 2.62 mmol) was dissolved
in DCM (40 mL) and a few drops of DMF added followed by
dropwise addition of oxalyl chloride (0.46 mL) at 0 °C. After
10 min, the solution was warmed to room temperature for 2 h
and concentrated to dryness. Without further purification, 18

758 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5
McKittrick et al.
(S)-4-P h en yl-N-[2-(2-p h en eth ylth io)-3-(p h en yla m in o)-
3-(4-m eth oxyph en yl) pr opion yl]-2-oxazolidin on e, 23. TiCl4
(1.0 mL of 1 N in DCM, 1 mmol) was added to a solution of 22
(0.34 g, 1 mmol) in DCM (5 mL) at -30 °C. The mixture was
stirred for 10 min and then DIPEA added (0.35 mL, 2 mmol).
After 1 h, the imine 4 (422 mg, 2 mmol) was added, and the
mixture was warmed to 0 °C for 3 h and then recooled to -25
°C. The reaction was quenched by the addition of AcOH (0.5
mL) in DCM (2 mL). After 10 min the mixture was poured
into 2 N H2SO4 (15 mL), partitioned with EtOAc, washed with
NaHCO3, H2O, brine, and dried over MgSO4. The solid
obtained after filtration and concentration was crystallized
from EtOAc/Hex (1:2) to yield 23 (150 mg, 27%): NMR δ 2.77
(s, 4H), 3.80 (s, 3H, OMe), 4.18 (dd, 1H, J ) 9, 3), 4.65 (t, 1H,
J ) 8), 4.76 (d, 1H, J ) 7), 5.16 (bs, 1H), 5.40 (dd, 1H, J ) 9,
3), 5.52 (d, 1H, J ) 7), 6.50 (d, 2H, J ) 8), 6.64 (dd, 1H, J )
8, 8), 6.78 (d, 2H, J ) 8), 6.93 (d, 2H, J ) 8), 7.02-7.31 (m,
7H).
(3R,4R)-3-(2-P h en et h ylt h io)-4-(4-m et h oxyp h en yl)-N-
ph en yl-2-azetidin on e, 24, an d (3S,4R)-3-(2-P h en eth ylth io)-
4-(4-m eth oxyp h en yl)-N-p h en yl-2-a zetid in on e, 25. Bis-
(trimethylsilyl)acetamide (BSA) (1.2 mL, 2.45 mmol) was
added to a solution of 23 (1.35 g, 2.45 mmol) in toluene (50
mL) at 90 °C under N2. After 2 h, the reaction mixture was
cooled to 50 °C and TBAF (90 mg, 0.28 mmol) added. After
1.5 h, the solvent was evaporated, and the residue was purified
by flash chromatography on silica gel using EtOAc/Hex (1:7)
to elute first the trans-azetidinone 24 (560 mg, y ) 59%): [θ]
232 nM ) +3.4 × 104, [θ] 248 nM ) -3.07 × 104; NMR δ 2.95
(m, 4H, CH2CH2), 3.82 (s, 3H, OMe), 3.95 (d, J ) 2.2, 1H, C3H),
4.72 (d, J ) 2.2, 1H, C4H), 6.9-7.3 (14H, ArH); MS (FAB) 390
(M + H), 252 (100). Anal. (C24H23NO2S) C, H, N, S. Contin-
ued elution gave the cis-azetidinone 25 (145 mg, 15%): NMR
δ 2.78 (m, 4H, CH2CH2), 3.8 (s, 3H, OMe), 4.53 (d, J ) 2.2,
1H, C3H), 5.27 (d, J ) 2.2, 1H, C4H), 6.9-7.3 (14H, ArH);
HRMS (FAB) calcd 390.1528, found 390.1512).
tetrachloride (75 mL of 1 N TiCl4 in methylene chloride) in
methylene chloride (200 mL) at 0 °C. After 15 min 22 (34.1
g) was added followed 5 min later by the addition of the imine
(66 g, 200 mmol) derived from 4-(tert-butyldimethylsiloxy)-
benzaldehyde and 4-fluoroaniline. The reaction mixture was
cooled to -40 °C internal temperature and stirred for 20 min,
and then diisopropylethylamine (35 mL) was added. After
stirring for 15 h at -40 °C, the reaction mixture was cooled to
-70 °C and isopropyl alcohol (250 mL) added. The reaction
mixture was slowly allowed to warm to room temperature over
6 h, then 0.1 N HCl (500 mL) was added, and the mixture
was partitioned with Et2O; the organic layers were washed
(H2O), dried (MgSO4), concentrated, and purified by crystal-
lization from MeOH to give 30 as a colorless solid (30.9 g,
46%): NMR δ 0.18 (s, 6H, SiMe2), 0.97 (s, 9H, Me3Si), 2.68
(m, 4H, CH2CH2), 4.20 (dd, J ) 3, 8.7, 1H, CHO), 4.65 (m, 2H,
CHO, CHS), 5.40 (dd, J ) 3, 8.5, 1H, ArCHN), 5.46 (d, J ) 8,
1H, CHN), 6.44 (m, 2H, ArH), 6.74 (m, 4H, ArH), 7.02 (m, 2H,
ArH), 7.1-7.3 (m, 10H, ArH); [R]20 ) -63.3° (1.3 mg/mL
D
MeOH).
(3R,4R)-3-(2-P h en eth ylth io)-4-(4-h yd r oxyp h en yl)-N-(4-
flu or op h en yl)-2-a zetid in on e, 33, a n d (3S,4R)-3-(2-P h en -
e t h ylt h io)-4-(4-h yd r oxyp h e n yl)-N -(4-flu or op h e n yl)-2-
a zetid in on e, 34. Step 1: Bis(trimethylsilyl)acetamide (7.4
mL, 30 mmol) was added to a solution of 30 (10 g, 15 mmol)
in toluene (0.5 L) at 90 °C. After 1 h, the reaction mixture
was cooled to 45 °C and tetrabutylammonium fluoride (0.47
g, 1.5 mmol) added. Periodically over the next 18 h, additional
bis(trimethylsilyl)acetamide (a total of 3 mol equiv) was added
with continued stirring at 45 °C. After a total time of 24 h,
the reaction mixture was diluted with MeOH (150 mL) and
stirred at room temperature for 1 h. The mixture was
concentrated in vacuo and purified by flash chromatography
on silica gel using hexane/ethyl acetate (10:1) to elute the trans
isomer 31 (4.80 g, Y ) 63%). Continued elution with hexane/
ethyl acetate (5:1) gave the cis isomer 32 (11.14 g, Y ) 15%).
3(R)-[2(S)-P h en eth ylsu lfin yl]-4(R)-(4-m eth oxyp h en yl)-
N-p h en yl-2-a zetid in on e, 26, a n d 3(R)-[2(R)-P h en eth yl-
su lfin yl]-4(R )-(4-m e t h oxyp h e n yl)-N -p h e n yl-2-a ze t id i-
n on e, 27. To a solution of 24 (0.36 g, 0.92 mmol) in dichloro-
methane (15 mL) at -78 °C wa added m-chloroperbenzoic acid
(0.16 g, 0.92 mmol). After 2 h, dilute sodium bisulfite was
added, and the mixture was warmed to room temperature and
partitioned with EtOAc. The organic layer was sequentially
washed with 10% sodium bicarbonate and brine, then dried
(MgSO4), and concentrated in vacuo. The residue was purified
by HPLC on silica gel using ethyl acetate/hexane (1:2) to elute
26 (0.185 g, Y ) 46%): [θ] 220 nM ) -5.36 × 104, [θ] 257 nM
) +5.46 × 104; NMR δ 3.15 (m, 3H, CH2CH2), 3.81 (s, 3H,
OMe), 3.9 (m, 1H, CH2), 3.94 (d, J ) 2.5, 1H, C4H), 5.33 (d, J
) 2.2, 1H, C3H), 6.9-7.35 (14H, ArH). Anal. (C24H23NO3S)
C, H, N. Continued elution gave 27 (0.10 g, Y ) 25%): [θ]
220 nM ) -4.8 × 103, [θ] 233 nM ) +7.4 × 104, [θ] 250 nM )
- 4.0 × 104; NMR δ 3.18 (m, 4H, CH2CH2), 3.80 (s, 3H, OMe),
4.12 (d, J ) 2, 1H, C4H), 5.5 (d, J ) 2, 1H, C3H), 6.9-7.35
(m, 14H, ArH). Anal. (C24H23NO3S) C, H, N.
Step 2A: Aqueous HF (2.5 mL of 48%) was added to a
solution of 31 (0.215 g, 0.42 mmol) in acetonitrile (21 mL) at
0 °C. The reaction mixture was warmed to room temperature
and stirred overnight. The mixture was partitioned with Et2O
and cold water. The organic layers were washed with 10%
sodium bicarbonate and water. The dried (MgSO4) and
concentrated organic layer was purified by flash chromatog-
raphy on silica gel using hexane/ethyl acetate (5:1) to collect
compound 33 as a colorless solid (0.16 g, 97%): MS (FAB) 394
(M + H), 256 (100); [R]25D ) +44.8° (1.25 mg/mL MeOH); NMR
δ 2.95 (m, 4H, CH2CH2), 3.93 (d, J ) 2.4, 1H, C3H), 4.67 (d, J
) 2.4, 1H, C4H), 5.06 (s, 1H, OH), 6.85 (d, 2H, ArH), 6.92 (dd,
2H, ArH), 7.15-7.3 (9H, ArH). Anal. (C23H20NO2SF) C, H,
N.
Step 2B: Aqueous HF (9 mL of 48%) was added to a
solution of 32 (0.85 g, 1.68 mmol) in acetonitrile (80 mL) at 0
°C as described in step 2A to give 34 (0.63 g, Y ) 95%): MS
(CI) 394 (M + H) (100); NMR δ 2.78 (m, 4H, CH2CH2), 4.52
(d, J ) 5, 1H, C4H), 5.23 (d, J ) 5, 1H, C3H), 6.82-7.3 (13H,
ArH); [R]21D ) -41.3° (1.9 mg/mL MeOH). Anal. (C23H20NO2-
SF) C, H, N, S.
3(S)-[2(S)-P h en eth ylsu lfin yl]-4(R)-(4-m eth oxyp h en yl)-
N-p h en yl-2-a zetid in on e, 28, a n d 3(S)-[2(R)-P h en eth yl-
su lfin yl]-4(R )-(4-m e t h oxyp h e n yl)-N -p h e n yl-2-a ze t id i-
n on e, 29. Treatment of 25 (60 mg, 0.15 mmol) with mCPBA
(27 mg, 0.15 mmol) according to the procedure for the prepara-
tion of 26 and 27 gave 28 (17 mg, Y ) 28%): NMR δ 2.85 (m,
1H, CH2), 2.95 (m, 1H, CH2), 3.12 (m, 1H, CH2), 3.62 (m, 1H,
CH2), 3.8 (s, 3H, OMe), 4.4 (d, J ) 5.6, 1H, C4H), 5.35 (d, J )
(3R,4R)-3-[2(S)-P h en et h ylsu lfin yl]-4-(4-h yd r oxyp h e-
n yl)-N-(4-flu or op h en yl)-2-a zetid in on e, 35, a n d (3R,4R)-
3-[2(R )-P h e n e t h ylsu lfin yl]-4-(4-h yd r oxyp h e n yl)-N -(4-
flu or op h en yl)-2-a zetid in on e, 36. A solution of 33 (2.3 g,
5.85 mmol) and (1S)-(+)-(10-camphorsulfonyl)oxaziridine (1.48
g, 6.45 mmol) in THF (40 mL) was heated to reflux. After 14
h, the reaction mixture was concentrated in vacuo and the
residue was purified by flash chromatography on silica gel
using dichloromethane/isopropyl alcohol (100:1) to elute first
the diastereomer 35 (0.6 g, 25%): [θ] 219 nM ) -5.49 × 104,
5.6, 1H, C3H), 6.9-7.35 (14H, ArH). Anal. (C24H23
-
NO3S‚0.2H2O) C, H, N. It also gave 29 (37 mg, y ) 61%):
NMR δ 3.17 (m, 3H, CH2CH2), 3.4 (m, 1H, CH2), 3.83 (s, 3H,
OMe), 4.69 (d, J ) 5.2, 1H, C4H), 5.55 (d, J ) 5.2, 1H, C3H),
[θ] 254 nM ) +5.2 × 104; [R]25 ) +214.4° (1.25 mg/mL
D
6.95-7.4 (14H, ArH); [R]25 ) -136° (2 mg/2 mL MeOH).
D
MeOH); NMR δ 3.15 (m, 3H, CH2CH2), 3.92 (m, 2H, CH2,
C4H), 5.25 (d, J ) 2.5, 1H, C3H), 6.01 (bs, 1H, OH), 6.8-6.9
(4H, ArH); 7.15-7.35 (9H, ArH) MS (CI) 410 (M + H). Anal.
(C23H20NO3SF) C, N, N. Then diastereomer 36 eluted, which
was crystallized from isopropyl alcohol to give a colorless solid
(1.48 g, 62%): [θ] 233 nM ) +5.56 × 104, [θ] 251 nM ) - 2.79
Anal. (C24H23NO3S‚0.2 H2O) C, H, N.
(S )-4-P h e n y l-N -[2-(2-p h e n e t h y lt h io )-3-[(4-flu o r o -
p h en yl)a m in o]-3-[4-(ter t-b u t yld im et h ylsiloxy)p h en yl]-
p r op ion yl]-2-oxa zolid in on e, 30. Titanium tetraisoproxide
(7.5 mL, 25 mmol) was added to a stirring solution of titanium

C3-Substituted Azetidinones with CAI Activity
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 759
× 104; [R]25D ) -16° (1.25 mg/mL MeOH); NMR δ 3.1-3.4 (m,
4H, CH2CH2), 4.2 (d, J ) 2, 1H, C4H), 5.39 (d, J ) 2, 1H, C3H),
6.7 (d, 2H, ArH), 6.95 (m, 2H, ArH), 7.15-7.35 (m, 9H, ArH);
CIMS 410 (M + H). Anal. (C23H20NO3SF) C, H, N.
(3S,4R)-3-(2-P h en eth ylsu lfin yl)-4-(4-h yd r oxyp h en yl)-
N-(4-flu or op h en yl)-2-a zet id in on e, 37, a n d (3S,4R)-3-(2-
P h e n e t h ylsu lfin yl)-4-(4-h yd r oxyp h e n yl)-N -(4-flu or o-
p h en yl)-2-a zetid in on e, 38. Treatment of 34 (0.52 g, 1.32
mmol) according to the procedure for the preparation of 35
and 36 and elution from a flash column using EtOAc/Hex (1:
1) gave 37 (0.19 g, Y ) 35%) [Anal. C23H20NO3SF) C, H, N, S]
and 38 (0.27 g, Y ) 50%) [Anal. (C23H20NO3SF) C, H, N, S].
Although the compounds described in this work were not tested
for ACAT inhibitory activity, earlier results1 had demonstrated
only weak ACAT activity for a series of structurally related
azetidinones. Therefore it is highly unlikely that the weak ACAT
activity that these compounds may have would account for the
potent CAI activity observed.
(3) Bergman, M.; Morales, H.; Mellars, L.; Kosoglou, T.; Burrier,
R.; Davis, H. R.; Sybertz, E. J .; Pollare, T. The clinical develop-
ment of a novel cholesterol absorption inhibitor. 12th Interna-
tional Symposium on Drugs Affecting Lipid Metabolism, 1995.
(4) McKittrick, B. A.; Ma, K.; Dugar, S.; Clader, J . W.; Davis, H.,
J r.; Czarniecki, M.; McPhail, A. T. Stereoselective synthesis and
biological activity of cis azetidinones as cholesterol absorption
inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 1947-1950.
(5) Rosenblum, S. B.; Huynh, T.; Davis, H.; Yumibe, N.; Clader, J .;
Afonso, A.; Burnett, D. B. International Symposium on Drugs
Affecting Lipid Metabolism, 1995.
(6) Van Heek, M.; France, C. F.; Compton, D. S.; McLeod, R. L.;
Yumibe, N. P.; Alton, K. B.; Sybertz, E. J .; Davis, H. R In vivo
metabolism-based discovery of a potent cholesterol absorption
inhibitor, SCH 58235, in the rat and Rhesus monkey through
the identification of the active metabolites of SCH 48461. J PET
1997, 283, 157-163.
(7) Dugar, S.; Yumibe, N.; Clader, J . W.; Vizziano, M.; Huie, K.;
Van Heek, M.; Compton, D. S.; Davis, H. R., J r. Metabolism and
structure activity data based drug design: Discovery of (-) SCH
53079 an analogue of the potent cholesterol absorption inhibitor
(-) SCH 48461. Bioorg. Med. Chem. Lett. 1996, 6, 2069-2073
(8) Thiruvendagam, T. K.; Tann, C. H.; McAllister, T. L. Process
for the stereospecific synthesis of azetidinones. U.S. Patent
5561227.
(9) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J . S.; Bilodeau, M.
T. New procedure for the direct generation of titanium enolates.
Diastereoselective bond constructions with representative elec-
trophiles. J . Am. Chem. Soc. 1990, 112, 8215-8216.
Ack n ow led gm en t. We extend our thanks to Drs.
D. Burnett and T. K. Thiruvengadam for helpful sug-
gestions regarding the enantioselective synthesis of 24
and to Dr. S. Dugar for an initial sample of 5. Also we
would like to thank Mr. Dan McGregor and Ms. Lizbeth
Hoos for the determination of the biological results and
the analytical chemistry group at Schering-Plough for
their support of this work.
Refer en ces
(1) Burnett, D. A.; Caplen, M. A.; Davis, H. R., J r.; Burrier, R. E.;
Clader, J . W. 2-Azetidinones as inhibitors of cholesterol absorp-
tion. J . Med. Chem. 1994, 37, 1733-1736. For related recent
work in this area, see: Clader, J . W.; Burnett, D. A.; Caplen,
M. A.; Domalski, M. S.; Dugar, S.; Vaccaro, W.; Sher, R.; Browne,
M. E.; Zhao, H.; Burrier, R. E.; Salisbury, B.; Davis, H. R., J r.
2-Azetidinone cholesterol absorption inhibitors: Structure-
activity relationships on the heterocyclic nucleus. J . Med. Chem.
1996, 39, 3684-3693. Rosenblum, S. B.; Huynh, T.; Afonso, A.;
Davis, H. R., J r.; Yumibe, N.; Clader, J . W.; Burnett, D. A.
Discovery of SCH 58235: A designed potent orally active
inhibitor of cholesterol absorption. J . Med. Chem. 1998, submit-
ted.
(2) Salisbury, B. G.; Davis, H. R.; Burrier, R.; Burnett, D. A.;
Boykow, G.; Caplen, M. A.; Clemmons, A. L.; Compton, D. S.;
Hoos, L. M.; McGregor, D. G.; Schnitzer-Polokoff, R.; Smith, A.
A.; Weig, B. C.; Zilli, D. L.; Clader, J . W.; Sybertz, E. J .
Hypercholesterolemic activity of a novel inhibitor of cholesterol
absorption, SCH 48461. Atherosclerosis 1995, 115, 45-63.
(10) Drabrowicz, J .; Dudzinski, B.; Mikolajczyk, M. Sulfonic acid-
sodium iodide system as an efficient reagent for the reduction
of sulfoxides. Synlett 1992, 252-254.
(11) Pridgen, L. N.; Abdel-Magid, A.; Lantos, I.; Shilcrat, S.; Eggles-
ton, D. Chelation control in metal-assisted aldol reactions of
R-halogenated imide enolates leading to predominately anti
stereoselectivity. An example of a stereocontrolled Darzens
reaction. J . Org. Chem. 1993, 58, 5107.
(12) Schwartz, N. N.; Blumbergs, J . H. Epoxidations with m-CPBA.
J . Org. Chem. 1964, 29, 1976-1979.
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