Stereoisomers of cyclic urea HIV-1 protease inhibitors: Synthesis and binding affinities

Article abstract of DOI:10.1021/jm980255b

We have synthesized stereoisomers of cyclic urea HIV-1 protease inhibitors to study the effect of varying configurations on binding affinities. Four different synthetic approaches were used to prepare the desired cyclic urea stereoisomers. The original cy

Full text of DOI:10.1021/jm980255b

J . Med. Chem. 1998, 41, 5113-5117
5113
Ster eoisom er s of Cyclic Ur ea HIV-1 P r otea se In h ibitor s: Syn th esis a n d Bin d in g
Affin ities
Robert F. Kaltenbach III,* David A. Nugiel, Patrick Y. S. Lam, Ronald M. Klabe, and Steven P. Seitz
DuPont Merck Pharmaceutical Company, P.O. Box 80500, Wilmington, Delaware 19880-0500
Received April 27, 1998
We have synthesized stereoisomers of cyclic urea HIV-1 protease inhibitors to study the effect
of varying configurations on binding affinities. Four different synthetic approaches were used
to prepare the desired cyclic urea stereoisomers. The original cyclic urea synthesis using amino
acid starting materials was used to prepare three isomers. Three additional isomers were
prepared by synthetic routes utilizing L-tartaric acid and D-sorbitol as chiral starting materials.
A stereoselective hydroxyl inversion of the cyclic urea trans-diol was used to prepare three
additional isomers. In all 9 of the 10 possible cyclic urea stereoisomers were prepared, and
their binding affinities are described.
Ch a r t 1
In tr od u ction
Human immunodeficiency virus (HIV) has been shown
to be the causative agent of acquired immunodeficiency
syndrome (AIDS). There has been an intense effort to
find inhibitors of the HIV-1-encoded aspartyl protease
(HIV-Pr) which plays an essential role in the maturation
of immature virion proteins. We have described a novel
series of highly potent cyclic urea HIV-Pr inhibitors
which were designed to displace the active site struc-
tural water.1 Compounds of this class have shown
picomolar binding affinities and good oral bioavailability
in animals. Currently clinical candidate DMP 450
(Chart 1) has been shown to be a potent HIV-Pr
inhibitor with a good pharmacokinetic profile in humans
and will be entering further clinical trials.2
Although our molecular modeling predicts the cyclic
Cyclic ureas were designed to bind to HIV-Pr with
the diol oxygens symmetrically hydrogen binding to the
catalytic Asp 25/25′. The rigid cyclic urea scaffold allows
for the optimal binding interactions of the P1/P1′ and
P2/P2′ residues with their corresponding pockets in the
active site. Modeling studies have predicted the optimal
stereochemistry for substituted cyclic ureas to be
4R,5S,6S,7R. This allows a conformation where pseudo-
diaxial benzyl groups project into the S1/S1′ pockets and
pseudodiequatorial hydroxyl groups bind with the Asp
25/25′ residues. The importance of the correct absolute
stereochemistry was demonstrated by the 1000-fold
difference in potency between the P2/P2′ allyl-substi-
tuted RSSR cyclic urea and its enantiomer.1 We have
attempted to synthesize each remaining cyclic urea
isomer to study the effect of varying stereochemistry on
binding affinities.
urea RSSR stereoisomer to be the most potent, multiple
binding modes to HIV-Pr might exist. There are a
number of examples of nonspecific binding of stereo-
isomers to HIV-Pr in other protease inhibitor classes.
Nonspecific binding to the catalytic aspartate residues
has been described for the hydroxyethylamine dipeptide
isosteres4 and the C2-symmetry-based diaminodiol5
inhibitors of HIV-Pr. In both cases a conformational
shift yields an alternate binding mode allowing the
hydroxyl residues to bind to the catalytic site.6 Re-
cently, the lack of stereospecificity in binding of a
diastereomer of Ritonavir was described.7 Inversion of
the valinyl P2 side chain of Ritonavir did not change
the inhibitory potency or the pharmacokinetic proper-
ties. Comparing the diastereomer’s X-ray crystal struc-
tures bound to HIV-Pr showed a backbone conforma-
tional shift permitting the valine residues of both
inhibitors to bind to the S2 pocket. This shift preserved
other important hydrogen-bonding interactions giving
equivalent binding affinities. We desired to synthesize
all possible cyclic urea stereoisomers to determine if a
conformational shift or alternate binding mode could
yield an isomer with equal or greater binding affinity.
The relationship between binding affinity and stereo-
chemistry has recently been demonstrated for a series
of P1/P1′ phenoxymethyl-substituted cyclic urea ana-
logues.3 A series of four C2-symmetrical stereoisomers
were prepared, and their activity against HIV-Pr was
compared to the calculated binding free energies. As
predicted, the RSSR isomer was most active with a
reported Ki ) 12 nM. The SRRS, SSSS, and RRRR
isomers showed a large decrease in binding with little
or no activity at micromolar concentrations.
Ch em istr y
With 4 contiguous chiral centers, there are 10 possible
symmetrically substituted cyclic urea stereoisomers.
10.1021/jm980255b CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/13/1998

5114 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Notes
Sch em e 1a
a
Reagents: (a) VCl3‚(THF)3, Zn, THF; (b) 2,2-dimethoxypropane, (()-camphorsulfonic acid, CH2Cl2, filter; (c) Pd(OH)2/C, H2, 98%; (d)
1,1′-CDI, CH2Cl2, 81%; (e) NaH, BnBr, DMF, 79%; (f) HCl, MeOH, H2O, 95%.
Sch em e 2a
The original cyclic urea synthesis used amino acid
starting materials and was only practical for the RSSR
cyclic urea stereoisomer 1 (Chart 1) and its enantiomer
2. We used three additional synthetic approaches in
an attempt to prepare all possible stereoisomers. Al-
though there are many P2/P2′ substituents which give
subnanomolar binding affinities, we chose the benzyl
group as a constant P2/P2′ substituent for we were only
concerned with relative changes in activity.
Cyclic urea 1 and its enantiomer 2 were prepared by
the procedure of Lam et al.8 The chiral centers of 1 were
derived from a Pedersen pinacol coupling of Cbz-D-
phenylalaninal.9 This coupling was highly stereoselec-
tive yielding predominantly the protected RSSR di-
a
Reagents: (a) H2NOMe‚HCl, EtOH, H2O, 93%; (b) BH3‚THF,
aminodiol 3a ; however, minor amounts of the RRRR
(3b) and RSRR (3c) isomers were also generated
(Scheme 1). After removal of the RSSR stereoisomer
by recrystallization,8 the RRRR isomer could be isolated
from the filtrate as the isopropylidine-protected diol 4
by the procedure of Kempf et al.10 Hydrogenolysis of 4
gave the diamine 5 which was cyclized with 1,1′-
carbonyldiimidazole (1,1′-CDI) in methylene chloride to
give the cyclic urea 6. Alkylation with benzyl bromide
followed by deprotection gave the RRRR cyclic urea 8.
THF, 54%; (c) 1,1′-CDI, CH2Cl2, 83%; (d) KOt-Bu, BnBr, THF, 81%;
(e) HCl, MeOH, H2O, 92%.
Sch em e 3a
Although the Pedersen coupling methodology could
have been used to prepare the SSSS, RSRR, and SRSS
stereoisomers, the diaminodiol isomers recovered were
minor components of the pinacol reaction mixture. In
addition, tedious purification procedures were required
to isolate the RSRR and SRSS isomers, and a more
efficient synthesis was desired. Alternate synthetic
routes were also needed to prepare the four isomers with
(4S,7R)-P1/P1′ configurations. A crossed Pedersen cou-
pling of the two Cbz-phenylalaninal enantiomers would
be impractical due to the complex mixture of possible
stereoisomers.
To synthesize the two additional (5S,6S)-diol diaster-
eomers, we chose an approach starting from L-tartaric
acid. We have previously described an alternate syn-
thetic route to P1/P1′-substituted cyclic ureas where
L-tartaric acid was used as the source of the (5S,6S)-
diol stereochemistry.11 The P1/P1′ residues were intro-
duced by addition of substituted benzyl Grignard re-
agents to activated tartrate amides to give the diketone
9. Conversion to an oxime followed by a stereoselective
reduction generated the (4R,7R)-P1/P1′ chiral centers
resulting in the desired RSSR configuration. During
the course of these studies we found that by modifying
a
Reagents: (a) RaNi, H2, MeOH, NH4OH, 92%; (b) 1,1′-CDI,
tetrachloroethane, reflux, 75%; (c) NaH, BnBr, DMF, 68%; (d) HCl,
MeOH, H2O, 91%.
the reduction conditions varying amounts of the SSSS
and RSSS diaminodiol stereoisomers 11 and 14 could
be obtained. We have optimized these conditions to
synthesize the SSSS and RSSS cyclic urea isomers as
shown in Schemes 2 and 3.
The SSSS isomer 12 was synthesized as illustrated
in Scheme 2. The diketone 9 was treated with meth-
oxylamine hydrochloride in ethanol/water to give the
bis-oxime ether 10 as a mixture of oxime isomers.
Reduction with borane‚THF afforded the diamine as a
2.5:1 mixture of the SSSS and RSSS isomers which
were separated by column chromatography. The result-
ing diamine 11 was cyclized, alkylated, and deprotected

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5115
Sch em e 4a
Sch em e 5a
a
Reagents: (a) (COCl)2, DMSO, CH2Cl2, -78 °C; (b) NaBH4,
EtOH; * indicates relative stereochemistry.
Sch em e 6a
a
Reagents: (a) 2,2-dimethoxypropane, H2SO4, acetone, 80%; (b)
70% AcOH, 45 °C, 81%; (c) Ph3P, DEAD, toluene, reflux, 65%; (d)
PhLi, CuCN, THF, -78-0 °C, 90%; (e) Ph3P, DEAD, (PhO)2P(O)N3,
THF, 0-25 °C, 20%; (f) LiAlH4, THF, quant.; (g) 1,1′-CDI,
tetrachloroethane, rt-reflux, 78%; (h) KOt-Bu, BnBr, THF, 78%;
(i) 20% concd HCl, CH3CN, 75%.
as previously described11 to give the SSSS cyclic urea
12. The configuration of 12 was confirmed by compari-
son to the RRRR isomer 8. The spectral properties (1H
NMR, IR, MS) of 12 were identical to those of 8 with
the exception of an opposite optical rotation.
Although the route illustrated in Scheme 2 could have
been used to prepare the RSSS isomer, a more efficient
synthesis was realized by again modifying the reduction
conditions as shown in Scheme 3. Hydrogenation of the
bis-oxime 13 with Raney nickel gave the diamine as a
4.3:1 mixture of the RSSS and RSSR isomers. After
separation by column chromatography the RSSS di-
amine 14 was cyclized with 1,1′-CDI in refluxing 1,1,2,2-
tetrachloroethane to give cyclic urea 15. Alkylation
followed by deprotection gave the RSSS stereoisomer
16.
a
Reagents: (a) (COCl)2, DMSO, CH2Cl2, -78 °C, 90%; (b)
NaBH4, EtOH.
oxidation. Reduction with NaBH4 in ethanol was highly
selective giving an 11:1 ratio of the RSRR stereoisomer
and regenerated RSSR cyclic urea. Purification by
column chromatography gave the RSRR stereoisomer
24. Enantiomer 25 was prepared analogously from 2.
To unambiguously confirm the stereochemical assign-
ments, an X-ray analysis was desired. Because we could
not obtain a suitable crystal from the P2/P2′ benzyl-
substituted analogue, the diol inversion was repeated
with the highly crystalline cyclopropylmethyl-substi-
tuted cyclic urea 1a .8 Single-crystal X-ray analysis of
24a confirmed the stereochemical assignments as RSRR.
To synthesize the two remaining meso diastereomers,
we attempted the diol inversion on the RSSS isomer
16 in hopes of obtaining a mixture of the RSRS 28 and
RRSS 29 stereoisomers (Scheme 6). Oxidation of 16
selectively oxidized the 6-hydroxyl giving a 7:1 mixture
of ketols 26 and 27. Reduction of this mixture gave the
RSRS cyclic urea 28 along with recovered 16; no RRSS
29 was isolated. The selectivity of the oxidation can be
rationalized assuming the conformation of the RSSS
isomer to be 4ax,5eq,6eq,7eq; therefore, the 5-hydroxyl
is sterically hindered by the 4-axial benzyl group, and
the 6-hydroxyl is preferentially oxidized yielding ketol
26. Reduction of ketol 26 with sodium borohydride gave
the RSRS stereoisomer 28. Although the minor ketol
27 could have been reduced to the RRSS isomer 29, the
4-axial benzyl group may block attack from the â-face
so reduction regenerates the RSSS isomer. It is inter-
Rather than synthesizing the SRRR isomer utilizing
the tartrate-based route shown in Scheme 3, an alter-
nate approach was desired to unambiguously confirm
the configuration generated by the stereoselective re-
duction. Scheme 4 describes the preparation of the
SRRR cyclic urea isomer 22 starting from commercially
available D-sorbitol. Treatment of D-sorbitol with 2,2-
dimethoxypropane and concentrated H2SO4 in acetone
followed by partial deprotection gave the monoacetonide
17. Treatment of 17 with triphenylphosphine and
diethyl azodicarboxylate (DEAD) in toluene provided the
diepoxide 18. Subsequent treatment of this epoxide
with excess phenyl cuprate gave the desired diol 19.
Displacement of the two hydroxyl groups with an azide
source provided the diazide 20. Reduction of the diazide
using lithium aluminum hydride provided the diamine
21 which was converted to the SRRR cyclic urea 22. The
spectral properties of 22 are consistent with the SRRR
configuration being identical to the RSSS isomer 16
with the exception of an opposite optical rotation.
Our approach to the synthesis of the four cis-diol cyclic
urea isomers was through a stereoselective hydroxyl
inversion of the trans-diol (Scheme 5). The RSSR
urea 1 was oxidized to the ketol 23 via a modified Swern

5116 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25
Ta ble 1. Binding Affinity of the Cyclic Urea Diastereomers
Notes
the preparation and design of future cyclic urea-based
HIV-Pr inhibitors.
compd
configuration
Ki (nM)a
The effect of varying stereochemistry on binding was
described. As originally predicted, the RSSR isomer 1
was the most active in our binding assay. Of compa-
rable activity was the RSRR isomer 24 which differs
by one inverted hydroxyl group. The other diastereo-
mers were substantially less potent demonstrating the
importance of substituent orientation on cyclic urea-
based HIV-Pr inhibitor potency.
1
2
8
12
16
22
24
25
28
RSSR
SRRS
RRRR
SSSS
RSSS
SRRR
RSRR
SRSS
RSRS
3.6 ( 1.1
3810 ( 1580
1350 ( 310
560 ( 100
64 ( 30
6700 ( 210
6.0 ( 2.2
1710 ( 220
250 ( 55
a
Values are expressed as the mean ( SD, n ) 2-4.
Exp er im en ta l Section
esting to note that the RSRS cyclic urea displayed an
extremely broad and complex 1H NMR spectrum at
room temperature. Although 28 is symmetrical, either
conformer is ax,eq,ax,eq, and due to slow ring inversion
an averaged spectra is only obtained at high tempera-
tures. The stereochemical assignments of 28 were
confirmed by single-crystal X-ray analysis.
All reactions were carried out with continuous stirring under
an atmosphere of dry nitrogen. Unless otherwise specified,
all solvents and commercial reagents were used as received
without additional purification. Chromatography was per-
formed with solvents indicated using EM Science silica gel 60
(230-400 mesh). 1H (300-MHz) NMR spectra were recorded
with CDCl3 as solvent using tetramethylsilane as an internal
standard. Infrared spectra were recorded on a Perkin-Elmer
1600 series FTIR spectrometer, and optical rotations were
obtained on a Perkin-Elmer 241 polarimeter. Melting points
are uncorrected. Elemental analysis was performed on all
target compounds by Quantitative Technologies, Inc., Bound
Brook, NJ .
(3S,4S)-2,5-Bis(m eth oxyim in o)-1,6-d ip h en yl-3,4-O-iso-
p r op ylid en eh exa n ed iol (10). To a solution of bis-ketone 9
(1.76 g, 5.20 mmol) in ethanol (100 mL) and water (33 mL)
was added methoxylamine hydrochloride (1.06 g, 3.95 mmol).
After stirring overnight the reaction mixture was diluted with
water and extracted with EtOAc. The combined organic layers
were washed with brine and dried (MgSO4). The solvent was
removed under reduced pressure, and the residue was chro-
matographed (silica gel, 15% ethyl acetate/hexane) to give bis-
oxime 10 as a mixture of oxime isomers (1.92 g, 93%): CIMS
(NH3) m/z 397 (M + H+, 100%).
Resu lts a n d Discu ssion
The cyclic urea stereoisomers were tested for binding
affinity,12 and the results are shown in Table 1. As
predicted the RSSR cyclic urea 1 was the most potent
with a Ki ) 3.6 nM. As originally designed, the RSSR
stereochemistry allows a conformation where the ring
substituents obtain an ax,eq,eq,ax orientation. This
allows the diols to symmetrically bind to the aspartate
residues and the P1/P1′ and P2/P2′ side chains to
optimally project into their respective pockets. The
RSRR isomer 24 showed similar activity with a Ki )
6.0 nM. With one hydroxyl group inverted, this isomer
can maintain a conformation with the ring substituents
in an ax,eq,ax,ax orientation. The catalytic aspartate
residues can bind to the one remaining equatorial
hydroxyl group, and the P1/P1′ and P2/P2′ side chains
can interact with their respective binding pockets. This
is consistent with the binding of C2-symmetrical di-
aminodiol inhibitors where inversion of one hydroxyl
group was also tolerated.5 Although one cyclic urea
hydroxyl group can be inverted with little loss in
binding, the inversion of both hydroxyls is not tolerated
as shown by the RRRR isomer 8 with a Ki ) 1350 nM.
Inverting the stereochemistry of the P1/P1′ substit-
uents is undesirable as demonstrated by the RSSS
isomer 16 with a Ki ) 64 nM. Inversion to an equatorial
P1 side chain results in a 10-fold loss in activity.
Similarly the meso RSRS isomer 28 with its ax,eq,ax,eq
orientation loses almost 2 orders of magnitude in
activity with a Ki ) 250 nM. The remaining diastereo-
mers were shown to be seriously mismatched, and they
lose over 2-3 orders of magnitude in potency versus the
originally designed RSSR cyclic urea.
(4S,5S,6S,7S)-H exa h yd r o-5,6-d ih yd r oxy-1,3,4,7-t et r a -
k is(p h en ylm eth yl)-2H-1,3-d ia za p in -2-on e (12). To a solu-
tion of bis-oxime 10 (1.92 g, 4.8 mmol) in THF (35 mL) at 0 °C
was added borane-tetrahydrofuran complex (18 mL, 18 mmol,
1.0 M in THF) dropwise. The solution was allowed to warm
to room temperature and then refluxed for 2 h. The solution
was cooled to 0 °C and carefully quenched with water (9 mL)
and then 15% aqueous NaOH (9 mL). The solution was gently
refluxed for 10 min, cooled, and extracted with CH2Cl2. The
combined organic layers were washed with brine and dried
(MgSO4). The solvent was removed under reduced pressure,
and the residue was chromatographed (silica gel, 10% methanol/
CH2Cl2) to give the diamine as a 2.5:1 mixture of the SSSS
and RSSS isomers (887 mg, 54%). The mixture of isomers
could be separated by chromatography (silica gel, 10% methanol/
CH2Cl2) to give the SSSS diamine 11. The diamine was
converted to the SSSS cyclic urea 12 as described: yield 62%
1
(from 11); mp 66-68 °C; H NMR (CDCl3) δ 7.27 (m, 16 H),
7.08 (d, J ) 7.0 Hz, 4 H), 4.75 (d, J ) 14.3 Hz, 2 H), 3.56 (s,
2 H), 3.51 (d, J ) 14.3 Hz, 2 H), 3.21 (m, 2 H), 2.97 (A of ABX,
J AB ) 13.2 Hz, J AX ) 6.6 Hz, 2 H), 2.77 (B of ABX, J AB ) 13.2
Hz, J BX ) 7.2 Hz, 2 H), 1.61 (br s, 2 H); IR (KBr) ν 3590, 3566,
1630, 1210 cm-1; CIMS (NH3) m/z 507 (M + H+, 100%); [R]25
D
) +52.50° (c ) 0.600, CHCl3). Anal. (C33H34N2O3) C,H,N.
(4R,5S,6S,7S)-H exa h yd r o-5,6-d ih yd r oxy-1,3,4,7-t et r a -
k is(p h en ylm eth yl)-2H-1,3-d ia za p in -2-on e (16). To a solu-
tion of bis-oxime 13 (2.20 g, 6.0 mmol) in methanol (150 mL)
and ammonium hydroxide (20 mL, 28% in water) was added
Raney nickel (11 g, 50% slurry). The suspension was charged
with hydrogen (50 psi) for 20 h. The suspension was carefully
filtered through Celite, and the solvent was removed under
reduced pressure. Chromatography (silica gel, 10% methanol/
CH2Cl2) gave the diamine as a 4.3:1 mixture of the RSSS and
RSSR isomers (1.86 g, 92%). The mixture of isomers could be
separated by chromatography (silica gel, 10% methanol/
CH2Cl2) to give the RSSS diamine 14. The diamine was
Con clu sion
In summary, we have prepared 9 of the 10 possible
cyclic urea stereoisomers. Three alternate synthetic
routes were required in addition to the original synthe-
sis of cyclic ureas using amino acid starting materials.
Two of the synthetic routes used L-tartaric acid or
D-sorbitol as starting materials. The third general route
exploited a stereoselective hydroxyl inversion of the
cyclic urea trans-diol to the cis-diol isomers. The
alternate synthetic routes described may be useful for

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 25 5117
converted to the RSSS cyclic urea 16 as described: yield 46%
(from 14); mp 87-90 °C; H NMR (CDCl3) δ 7.27 (m, 16 H),
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2169.
7.07 (m, 4 H), 4.72 (br d, J ) 14.3 Hz, 1 H), 4.53 (br s, 2 H),
4.19 (m, 1 H), 3.76 (br d, J ) 14.3 Hz, 1 H), 3.44 (br s, 3 H),
2.98 (m, 4 H), 1.73 (d, J ) 5.1 Hz, 1 H), 1.35 (br s, 1 H); IR
(KBr) ν 3410, 1620, 1450 cm-1; CIMS (NH3) m/z 507 (M + H+,
100%); [R]25D ) +77.00° (c ) 0.600, CHCl3). Anal. (C33H34N2O3)
C,H,N.
(4R,5S,7R)-Hexa h yd r o-5-h yd r oxy-1,3,4,7-tetr a k is(p h en -
ylm eth yl)-2H-1,3-d ia za p in e-2,6-d ion e (23). To a solution
of oxalyl chloride (83 mg, 0.65 mmol) in CH2Cl2 (2.5 mL) at
-78 °C was added methyl sulfoxide (105 mg, 0.98 mmol). The
solution was stirred for 20 min, and cyclic urea 1 (250 mg,
0.49 mmol) in THF (2 mL) was added dropwise. After 20 min,
triethylamine (198 mg, 1.96 mmol) was added, and the reaction
mixture was allowed to warm to room temperature. Water
was added, and the suspension was extracted with EtOAc. The
combined organic layers were washed with dilute HCl and
brine and dried (MgSO4). The solvent was removed under
reduced pressure, and the residue was chromatographed (silica
gel, 25% ethyl acetate/hexane) to give ketol 23 as a glass (203
mg, 82%): 1H NMR (CDCl3) δ 7.30 (m, 16 H), 7.03 (m, 2 H),
6.90 (m, 2 H), 5.00 (d, J ) 14.3 Hz, 1 H), 4.75 (d, J ) 14.3 Hz,
1 H), 4.29 (dd, J ) 5.9, 4.0 Hz, 1 H), 4.11 (m, 1 H), 4.03 (d, J
) 14.3 Hz, 1 H), 3.77 (m, 1 H), 3.49 (d, J ) 4.0 Hz, 1 H), 3.10-
2.69 (m, 5 H); IR (KBr) ν 3410, 3030, 1720, 1650, cm-1; CIMS
(NH3) m/z 505 (M + H+, 100%).
(4R,5S,6R,7R)-Hexa h yd r o-5,6-d ih yd r oxy-1,3,4,7-tetr a -
k is(p h en ylm eth yl)-2H-1,3-d ia za p in -2-on e (24). To a solu-
tion of ketol 23 (140 mg, 0.28 mmol) in ethanol (10 mL) was
added sodium borohydride (26 mg, 0.69 mmol). After 45 min
dilute HCl was carefully added, and the reaction mixture was
extracted with EtOAc. The combined organic layers were
washed with brine and dried (MgSO4). The solvent was
removed under reduced pressure, and the residue was chro-
matographed (silica gel, 33% ethyl acetate/hexane) to give the
RSRR urea 24 as a white solid (112 mg, 80%): mp 138-139
1
°C; H NMR (CDCl3) δ 7.30 (m, 18 H), 6.92 (m, 2 H), 4.89 (d,
J ) 14.3 Hz, 1 H), 4.87 (d, J ) 14.3 Hz, 1 H), 3.92 (d, J ) 14.3
Hz, 1 H), 3.57 (m, 4 H), 3.15-2.75 (m, 5 H), 2.62 (d, J ) 8.1
Hz, 1 H), 1.60 (d, J ) 5.5 Hz, 1 H); IR (KBr) ν 3290, 3030,
1600, 1450 cm-1; CIMS (NH3) m/z 507 (M + H+, 100%); [R]25
) -17.50° (c ) 0.600, CHCl3). Anal. (C33H34N2O3) C,H,N.
D
(4R,5S,6R,7S)-Hexa h yd r o-5,6-d ih yd r oxy-1,3,4,7-tetr a -
k is(p h en ylm eth yl)-2H-1,3-d ia za p in -2-on e (28). Starting
with 16, following the procedure described for the synthesis
of 23 gave the ketols 26 and 27 as a 7:1 mixture of isomers
(225 mg, 90%). Reduction following the procedure of 24 and
recrystallization with ethyl acetate/hexane gave the RSRS
urea 28 as a white solid (154 mg, 71%). The stereochemistry
was confirmed as RSRS by a single-crystal X-ray analysis (see
1
Supporting Information): mp 176-177 °C; H NMR (DMSO-
d6, 140 °C) δ 7.20 (m, 20 H), 4.58 (d, J ) 15.1 Hz, 2 H), 4.40
(m, 2 H), 3.78 (br s, 2 H), 3.65 (br s, 2 H), 3.41 (br s, 2 H), 3.11
(A of ABX, J AB ) 13.9 Hz, J AX ) 6.6 Hz, 2 H), 2.89 (B of ABX,
J AB ) 13.9 Hz, J BX ) 7.6 Hz, 2 H); IR (KBr) ν 3390, 3030, 2930,
1610, 1450 cm-1; CIMS (NH3) m/z 507 (M + H+, 100%). Anal.
(C33H34N2O3) C,H,N.
(12) Erickson-Viitanen, S.; Klabe, R. M.; Cawood, P. G.; O’Neal, P.
L.; Meek, J . L. Potency and Selectivity of Inhibition of the HIV
Protease by a Small Nonpeptide Cyclic Urea, DMP 323. Anti-
microb. Agents Chemother. 1994, 38, 1628-1634.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis of compounds 8 and 22 and atomic
coordinates for the X-ray crystal structures of compounds 24a
and 28 (16 pages). Ordering information is given on any
current masthead page.
J M980255B