Stereospecific synthesis, structure-activity relationship, and oral bioavailability of tetrahydropyrimidin-2-one HIV protease inhibitors

Article abstract of DOI:10.1021/jm9803626

The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of K(i) to IC₉₀ for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure- activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2- ones series.

Full text of DOI:10.1021/jm9803626

J . Med. Chem. 1999, 42, 135-152
135
Ster eosp ecific Syn th esis, Str u ctu r e-Activity Rela tion sh ip , a n d Or a l
Bioa va ila bility of Tetr a h yd r op yr im id in -2-on e HIV P r otea se In h ibitor s
George V. De Lucca,* J ing Liang, and Indawati De Lucca
DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0500
Received J une 11, 1998
The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors
has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more
unsymmetrical (different P1/P1′), less crystalline, more soluble, and more lipophilic (mono-ol
vs diol). They show a better translation of Ki to IC90 for the more polar P2 groups that in general
give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the
tetrahydropyrimidinones showed that the phenylethyl P1′ substituent, the hydroxyl group,
and the urea carbonyl are all critical for good activity. However, there was significant flexibility
in the possible P2/P2′ substituents that could be used. Many analogues that contained identical
or different P2/P2′ substituents, or only one P2 substituent, were found to have excellent enzyme
potency and several had excellent antiviral potency. Several of these compounds were examined
for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of
the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-
diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein
binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not
offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.
In tr od u ction
The human immunodeficiency virus (HIV) encodes an
aspartyl protease which is responsible for the processing
of the gag and gag-pol gene products. This processing
is required for the production of mature, infectious
virions and has been a prime target for intervention.1,2
At Dupont Merck we have previously described the
design and discovery of a novel class of cyclic urea based
HIVPR inhibitors.3 The C2 symmetric hexahydro-1,3-
diazepin-2-ones are complementary to the C2 symmetric
aspartic protease of HIV and are very potent inhibitors.
This work resulted in the identification of two clinical
candidates in this series, DMP 3234 and DMP 4505
(Figure 1).
As an extension of this work we recently disclosed the
design and synthesis of tetrahydropyrimidinones, such
as I (Figure 1), and showed by an X-ray crystallographic
study that these bind to the active site of HIVPR in a
fashion very similar to the hexahydro-1,3-diazepin-2-
ones.6 The carbonyl of I displaces the structural water
molecule usually seen in structures of complexes with
linear inhibitors and hydrogen bonds directly with the
flap residues Leu 50/150. The hydroxyl group of I has
hydrogen-bonding interactions with the catalytic aspar-
tic acid residues Asp 25/125. The nitrogen substituents
(P2, P2′) make good lipophilic contacts with the S2, S2′
specificity pockets of the enzyme and the C6 and C4 side
chain substituents (P1, P1′) of I make good contact with
the S1, S1′ specificity pockets of HIVPR. All these
interactions are nearly identical to those seen with the
hexahydro-1,3-diazepin-2-ones4 and thus account for the
near equipotency of these two classes of inhibitors.6
The C2 symmetric cyclic ureas, such as DMP 450 and
F igu r e 1. Structure of cyclic urea based clinical candidates
DMP 323 and DMP 450 and the general structure of tetra-
hydropyrimidin-2-ones discussed in text.
DMP 323, are rigid, extremely complementary to the
enzyme, and offer significant synthetic and cost advan-
tages. However, they also have significant limitations
due to their inherent crystallinity and low solubility.
On the other hand, nonsymmetric ureas are more
soluble and offer greater flexibility for adjusting the
physical and chemical properties and designing favor-
able enzyme interactions.4,7
Tetrahydropyrimidinones, as an alternate scaffold for
HIVPR inhibitors, have the advantage of being more
unsymmetrical (not C2 symmetric with different P1/P1′)
* To whom correspondence should be addressed. E-mail:
George.V.DeLucca@dupontpharma.com.
10.1021/jm9803626 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/10/1998

136 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
De Lucca et al.
Sch em e 1a
Sch em e 2a
a
Reagents and conditions: (a) acetoxyisobutyryl bromide/
CH2Cl2; (b) Zn dust/acetic acid; (c) NaOH/MeOH.
and more lipophilic (mono-ol vs diol) than the hexahy-
dro-1,3-diazepin-2-ones. This makes the tetrahydro-
pyrimidinones less crystalline (as measured by their
lower melting points) and consequently more soluble in
typical organic solvents (CH2Cl2, CHCl3). They also
show a better translation of enzyme inhibition (Ki) to
intracellular antiviral activity (IC90) for analogues with
the more polar P2 groups8 that in general improve the
potency of the enzyme inhibitors. Thus, the use of
tetrahydropyrimidinones offered a way to better address
the often conflicting issues of solubility, potency, and
oral bioavailability. In this paper we wish to describe
in detail our studies on the structure-activity relation-
ship (SAR) and oral bioavailability of tetrahydropyri-
midinones.
a
Reagents and conditions: (a) DHP/CHCl3/TsOH; (b) KO-t-Bu/
THF; (c) HCl/MeOH reflux.
from the corresponding hexahydro-1,3-diazepin-2-ones,
it had some practical limitations. If the two N,N′-
substituents of the diazepin-2-one were not the same,
then a mixture of the two possible regioisomeric tet-
rahydropyrimidinones products were obtained, and their
separation required tedious chromatography. In addi-
tion, the N,N′-substituents of the hexahydro-1,3-diaz-
epin-2-one had to be stable to the reaction conditions,
namely stability toward acid bromides, reduction, and
basic hydrolysis.
Thus, in some cases it was desirable to use the parent
N,N′-unsubstituted tetrahydropyrimidinone 9 as the
starting material. The hydroxyl group of 9 was protected
as the THP ether 10 in quantitative yield (Scheme 2).
The urea nitrogens were substituted using a variety of
alkylating agents under our standard conditions.4 For
example, treatment of 10 with 5-(bromomethyl)-1-SEM-
indazole8,11 and 1 M solution of KOt-Bu (in THF) gave
the dialkylated tetrahydropyrimidinone 11. The protect-
ing groups were removed under acidic conditions (HCl/
MeOH) to give the indazole-substituted tetrahydro-
pyrimidinone 12 in good yield.
We previously reported the stereospecific de novo
synthesis of 9 from D-phenylalanine.6 However, since
the synthesis was long and the overall yield was not
satisfactory, an alternate synthesis that used the parent
N,N′-unsubstituted hexahydro-1,3-diazepin-2-one as the
starting material was desirable. This became possible
when we discovered10 an unusual reaction of hexahydro-
1,3-diazepin-2-ones with the fluorinating agent dieth-
ylamino sulfur trifluoride (DAST).
Ch em istr y
The stereospecific synthesis of symmetrically N,N′-
disubstituted tetrahydropyrimidinones was accom-
plished using one of the two methods outlined in
Schemes 1 and 2. The first method involved the rear-
rangement of the symmetrical hexahydro-1,3-diazepin-
2-one analogues using 2-acetoxyisobutyryl bromide9 as
previously described.6,10 The enantiomerically pure
hexahydro-1,3-diazepin-2-one starting materials were
readily prepared by the methods previously reported.4
For example, when the diol 14 was treated with 2-ac-
etoxyisobutyryl bromide a nearly quantitative yield of
the tetrahydropyrimidinone bromo acetate 2 was ob-
tained. X-ray crystallographic analysis of 2 confirmed
not only the assigned structure but also the absolute
configuration of the phenethyl bromide substituent.6
The phenethyl bromide side chain of 2 was most
conveniently reduced using Zn (dust) in acetic acid to
give the phenethyl analogue 3 in nearly quantitative
yield. Finally, the hydrolysis of the acetate 3 gave the
desired alcohol 4 in excellent yield. Thus, the overall
transformation of the diol 1 to the tetrahydropyrimidi-
none 4 was achieved efficiently with an overall yield of
about 90%. This reaction sequence is quite general and
was used to synthesize many tetrahydropyrimidinone
6,10
analogues.
While this three-step procedure (Scheme 1) was a very
efficient method to synthesize tetrahydropyrimidinones

Tetrahydropyrimidin-2-one HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 137
Sch em e 3a
Sch em e 4a
a
Reagents and conditions: (a) 1 N NaOH/MeOH; (b) KOH(s)/
MeOH; (c) H2/10% Pd/C.
byproducts by chromatography. The free hydroxyl of 24
was treated under Mitsunobu conditions (Ph3P, DEAD,
chloroacetic acid) to give the rearranged chloroacetate
25. The ester 25 was hydrolyzed to give a new mono-
MEM ether alcohol 26 which was deprotected to give
the non-C2-symmetric diol 27. A 2D COSY NMR of 27
shows that it is the rearranged tetrahydropyrimidinone
analogue with one set of benzyl protons coupled to the
proton R to a hydroxyl group and not coupled to the
proton R to the nitrogen.
a
Reagents and conditions: (a) DAST/CH2Cl2; (b) HBr(g)/diox-
ane; (c) NaOH/MeOH; (d) Zn dust/acetic acid; (e) H2 10% Pd/C.
Treatment of the N,N′-unsubstituted monoacetate 13
with DAST did not give the expected fluoro analogue;
instead, it provided the aziridine 14 in good yield
(Scheme 3). Treatment of the aziridine 14 with HBr(g)
gave a nearly quantitative yield of the phenethyl
bromide 15. The bromide 15 was reduced with zinc dust
in acetic acid to give the phenethyl analogue 16 in
excellent yield. Hydrolysis of 16 gave the unsubstituted
tetrahydropyrimidinone 9 in excellent overall yield from
the monoacetate 22. Alternatively, the bromo acetate
15 was treated with excess NaOH or KOH to give the
olefinic alcohol 17 in nearly quantitative yield. Hydro-
genation of 17 gave the desired N,N′-unsubstituted
tetrahydropyrimidinone 9, again in excellent yield.
To explore the SAR of the P1′ group several substi-
tuted-phenethyl analogues were synthesized. For ex-
ample, the intermediates bromo acetates 2 or 6 were
hydrolyzed to give the bromo alcohols 18 or 20 using
mildly basic conditions (0.01 M NaOH/MeOH) as shown
in Scheme 4. Under more concentrated conditions (2 M
NaOH or KOH in MeOH), the olefinic alcohols 19 and
21 were obtained in excellent yields. Hydrogenation of
19 or 21 gave the corresponding tetrahydropyrimidino-
nes analogues 4 or 8 previously described in Scheme 1.
The rearrangement tendency of the hexahydro-1,3-
diazepin-2-ones is a very general one and can be used
to incorporate other substituents into the phenethyl side
chain.10 By using a variety of reactions it is possible to
introduce a wide diversity of substituents (fluoro, bromo,
oxygen, or nitrogen) as shown in the examples below.
Treating the diol 224 with 1 equiv of DAST gave the
rearranged 1-fluoro-2-phenethyl alcohol 23 as the major
product. The structure of 23 was confirmed by the use
of 2D COSY NMR experiments. The diol 22 was mono-
protected with MEM-Cl to give the mono-MEM ether
alcohol 24, which was separated from diol and di-MEM
The reaction of 54 (having a large 2-naphthyl P2
substituent) with 1 equiv of DAST gave the correspond-
ing tetrahydropyrimidinone analogue 28 in good yield
(Scheme 6). The diol 5 was converted to the mono-
mesylate 29. Reaction of the mesylate 29 with nucleo-
philes gave rearranged products. For example, the
reaction of 29 with NaN3 gave the azido analogue 30.
Treatment of 29 with NaI gave the trans olefin 21,
presumably via the phenethyl iodide which eliminates
HI under the reaction conditions to give the observed
olefin. The structure of the olefin 21 was further
confirmed by hydrogenation to the phenethyl analogue
8, both of which were prepared independently as shown
in Scheme 4.
The aziridine 14 can be considered a protected form
of the desired tetrahydropyrimidinone final product and
was used to synthesize unsymmetrically substituted
N,N′-analogues as summarized in Scheme 7. Alkylation
of aziridine 14 with benzyl bromide gave the N-benzyl
aziridine 31. The acetate of 31 was removed under basic
conditions to give the free alcohol 33, whose structure
was also confirmed by X-ray crystallography (Figure 2).
The aziridine 31 was sequentially treated with HBr,
zinc dust in acetic acid, and NaOH to give the mono-
N-alkylated tetrahydropyrimidinone 36.
The aziridine ring was opened by other acids in
addition to HBr. For example, treatment of 31 with
trifluoroacetic acid gave the corresponding trifluoroac-
etate (Scheme 7). Hydrolysis of the intermediate trif-
luoroacetate with NaOH gave the corresponding diol 34.
The aziridine 39, containing the N-(3-benzyloxy)benzyl
group, was hydrogenated, for a prolonged period of time,
to remove the O-benzyl protecting groups and reduce

138 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
De Lucca et al.
Sch em e 5a
regio-chemistry as shown in Scheme 8. For example, the
alcohol of 38 was protected as the MEM ether 41.
Alkylation of the urea nitrogen with cyclopropylmethyl
bromide under the usual conditions gave the dialkylated
product 42. The MEM group was removed under acidic
(HCl/dioxane) conditions to give the free alcohol, and
the cyano group was converted to the amidoxime with
hydroxylamine to give the desired unsymmetrical N,N′-
dialkylated tetrahydropyrimidinone 43.
While one mono-N-alkylated tetrahydropyrimidinone
isomer with defined regio-chemistry (such as 36 or 38)
was easily obtained from the aziridine 14, the other
regio-isomeric mono-N-alkylated product could not be
preferentially synthesized. To obtain the other regio-
isomer the sequence outlined in Scheme 9 was used. For
example, the THP-protected tetrahydropyrimidinone 10
was alkylated with 3-nitrobenzyl bromide to give a
mixture of mono-N-alkylated tetrahydropyrimidinones
44 and 45 which were separated by chromatography.
The nitro group was reduced (H2, 10% Pd/C), and the
protecting group was removed (HCl/MeOH) to give
corresponding mono-N-alkylated anilines 47 or 46. The
structure of 47 was determined by the independent
synthesis starting with the aziridine 14 as shown in
Scheme 9. Furthermore, the THP ether 49 was alky-
lated a second time to prepare the unsymmetrical N,N′-
dialkylated tetrahydropyrimidinones 93-98 (Table 4).
a
Reagents and conditions: (a) 1 equiv DAST/CH2Cl2; (b) MEM-
Cl/Et3N; (c) DEAD/Ph3P/chloroacetic acid; (d) NaOH/MeOH; (e)
HCl/MeOH.
Resu lts a n d Discu ssion
the aziridine ring and to give the tetrahydropyrimidi-
none phenol 40.
Suitably protected alcohols (such as 36 or 38) were
N-alkylated a second time to obtain unsymmetrical
N,N′-dialkylated tetrahydropyrimidinones with defined
Id en tica l P 2/P 2′ Su bstitu en ts. We initially exam-
ined a variety of symmetrically N,N′-disubstituted P2
analogues keeping the P1/P1′ substituents constant
(benzyl/phenethyl). The results are summarized in Table
1. Use of lipophilic P2 groups, such as the benzyl
Sch em e 6a
a
Reagents and conditions: (a) 1 equiv DAST/CH2Cl2; (b) Ms-Cl/Et3N; (c) NaN3/DMF; (d) NaI/DMF; (e) 50 psi H2/10% Pd/C.

Tetrahydropyrimidin-2-one HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 139
Sch em e 7a
a
Reagents and conditions: (a) NaH/DMF/Bn-Br; (b) CF3COOH; (c) HBr(g)/dioxane; (d) Zn dust/acetic acid; (e) NaOH/MeOH; (f) H2,
10% Pd/C.
Sch em e 8a
F igu r e 2. Small-molecule X-ray structure of aziridine 33,
which was used as the starting point for modeling studies
shown in Figure 4.
analogue 50, gave good enzyme potency (Ki ) 11 nM).
Introduction of hydrogen-bonding groups at the meta
position of the N-benzyl substituents gave further
improvements in potency.6 The ketone 53, the benzyl
alcohol 54, and the acid 55 all are subnanomolar
inhibitors of HIVPR. Groups capable of forming multiple
hydrogen bonds to the Asp 29, Asp 30, or Gly 48
residues, located near the edge of the S2 pockets,
showed even greater potency.6 For example the amide
56 (Ki ) 0.09 nM) and the amidoxime 60 (Ki ) 0.018
nM) are both extremely potent inhibitors of the enzyme.
The X-ray crystal structure of 60 was previously dis-
closed6 and showed an extensive network of hydrogen
bonds with HIVPR, accounting for its potency. The
antiviral potency of these analogues with hydrogen-
bonding substituents are also very good with IC90 in the
30 to 50 nM range and in general are better than the
corresponding hexahydro-1,3-diazepin-2-ones analogues.7
a
Reagents and conditions: (a) MEM-Cl/Et3N/CH2Cl2; (b) NaH/
DMF/cyclopropylmethyl bromide; (c) HCl/dioxane; (d) NH2OH‚HCl/
Et3N/EtOH/reflux.
The better translation of Ki to IC90 for the tetrahydro-
pyrimidinones is probably due to their increased lipo-
philicity.
To further improve the translation of some of the more
polar analogues we introduced fluoro substituents in

140 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
De Lucca et al.
Sch em e 9a
a
Reagents and conditions: (a) 3-NO2-benzyl bromide/KO-t-Bu/THF; (b) 50 psi H2/10% Pd/C; (c) HCl/MeOH; (d) HBr(g)/dioxane; (e)
KOH/MeOH; (f) DHP/CHCl3/TsOH.
order to increase the lipophilicity of these analogues.
Fluoro substituents were incorporated into the P2/P2′
phenyl groups ortho to the polar substituent (59, 63,
65, 66), as well as into the P1/P1′ phenyl groups (57,
58, 61, 62). The results were mixed; while the 4-fluoro
aniline analogue 65 showed improved potency (Ki and
IC90) compared to the aniline analogue 64, the 4-fluoro
carboxamide analogue 59 showed a loss in potency
compared to 56. In the other cases there was little effect
on potency or translation.
Some heterocycle containing substituents have been
found to have the correct balance of hydrogen-binding
ability and lipophilicity to produce excellent HIVPR
inhibitors in the 1,3-diazepin-2-one series.8,12,14 Intro-
duction of these substituents into the tetrahydropyri-
midinones also produced excellent results. For example,
the pyrazole analogue 68 has an IC90 of 23 nM. The
5-indazole analogue 12 was the best with an IC90 of 6
nM. The heterocyclic amides, such as 73 and 74, also
exhibited good enzyme and antiviral potency. However,
introduction of a polar amino group,13 as in the 3-amino-
5-indazole analogue 71, decreased the antiviral potency
to 383 nM.
tuted phenethyl P1′ group was the best. Any modifica-
tion resulted in a significant loss in enzyme potency.
For example the 1-fluoro-2-phenylethyl analogue 23 is
20-fold less potent than the corresponding phenethyl
analogue 75. Similar losses are seen with use of bromo,
hydroxyl, or azido substituents. The incorporation of
unsaturation into the side chain, as in the trans-styrene
analogues 19 and 21, also gave similar decreases in
enzyme activity. We previously reported6,15 that the
benzyl-containing P1′ analogue 1036 (Figure 3) is 100-
fold less potent than the phenethyl P1′ analogue 77, and
that the analogue lacking a P1′ substituent, 10415
(Figure 3), is over 100-fold less potent than the corre-
sponding phenethyl analogue 4. These results empha-
size the critical importance of having a good lipophilic
interaction between the P1 substituent of the inhibitor
with the S1 specificity pocket of the enzyme.
The X-ray structure of tetrahydropyrimidinone 606
complexed with HIVPR revealed that in order for the
phenethyl side chain of the tetrahydropyrimidinone to
interact optimally with the enzyme it has to be in a
conformation in which there is an eclipsing interaction
that is nearly anticlinal and thus is not the lowest
energy conformer.6 Any substituent on the phenethyl
side chain would make this eclipsing conformation even
more energetically unfavorable and thus lower the
binding affinity for the enzyme.
To make more unsymmetrical inhibitors and to
further explore the SAR of the P1′ substituent, several
substituted-phenethyl analogues were examined. The
results summarized in Table 3 show that an unsubsti-

Tetrahydropyrimidin-2-one HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 141
Ta ble 2. Oral Bioavailability of Tetrahydropyrimidinones
Ta ble 1. P2/P2′ SAR of Tetrahydropyrimidinone HIV Protease
Inhibitors
b
Kia
IC90
Rat poc
b
Kia
IC90
compd
P2/P2′
(nM)
(nM) Cmax (µM)
compd
P2/P2′
(nM) (nM)
53
3-acetylbenzyl
0.09
0.06
0.49
0.14
0.30
0.12
9
0.18
3-acetylbenzyld
39 0.50
109 0.24
38 0.83
115 0.12
54 0.81
2100 0.25
365 1.0
130 2.25
9
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
12
69
70
71
72
73
74
H
970
11.00 1600
14.00 1560
54
77
3-hydroxymethylbenzyl
3-hydroxymethylbenzyle
3-hydroxybenzyl
3-cyanobenzyl
3-cyanobenzylc
3-cyano-4-fluorobenzyl
230
0.91
3-hydroxybenzyle
3-hydroxybenzylf
3-aminobenzyl
3-acetylbenzyl
49
78
64
12
3-hydroxymethylbenzyl
3-carboxybenzyl
0.49 109
0.87
1.70
0.28
0.02
0.014
0.10
0.027
3-aminobenzyle
3-(carboxamido)benzyl
0.09
0.31
0.15
1.4
0.02
0.02
35
35
90
490
49
49
3-(carboxamido)benzylc
12
68
indazol-5-yl-methyl
indazol-5-yl-methylg
3-(pyrazol-3-yl)benzyl
3-(pyrazol-3-yl)benzyld
6
7
0.25 (dog)
1.0 (dog)
3-(carboxamido)benzyld
22 0.16
20 0.07
3-(carboxamido)-4-fluorobenzyl
3-(carboxamido oxime)benzyl
3-(carboxamido oxime)benzylc
3-(carboxamido oxime)benzyld
3-(carboxamido oxime)-4-fluorobenzyl
3-aminobenzyl
a
Values were measured by cleavage of a fluorescent substrate
0.01 117
0.06 51
1.70 365
0.25 36
8.00 539
4.90 328
using HPLC as described previously.4,18 Values were measured
b
by a sensitive viral RNA-based detection system described previ-
ously.4,19 Only compounds which displayed an antiviral IC90
concentration which was at least 3-fold less than the TC50
concentration are listed in the table. c Bioavailability was deter-
mined in groups of rats, unless otherwise indicated, dosed with
compound in formulations containing propylene glycol, poly(eth-
ylene glycol) 400, and water at 10 mg/kg as previously reported.4,20
The maximum plasma concentration (Cmax) is the observed peak
3-amino-4-fluorobenzyl
4-amino-3-fluorobenzyl
3-(N-methyl-amino)benzyl
3-(pyrazol-3-yl)benzyl
0.10
0.02
0.06
0.10
22
6
32
18
indazol-5-yl-methyle
indazol-6-yl-methyl
(3-methylindazol-5-yl)-methyl
3-aminoindazol-5-yl-methyl
3-aminobenzisoxazol-5-yl-methyl
3-(5-methyl-2-pyridylcarboxamido)-benzyl
3-(N-2-thiazolylcarboxamido)-benzyl
d
plasma concentration after an oral dose. Data for the correspond-
0.03 383
0.41 132
ing 1,3-diazepin-2-one analogue (ref 12). e Data for the correspond-
ing 1,3-diazepin-2-one analogue (ref 4). f Data for the analogue
0.08
0.03
26
31
g
having 1-fluoro-2-phenylethyl as the P1′ substituent. Data for
the corresponding 1,3-diazepin-2-one analogue (ref 8).
a
Values were measured by cleavage of a fluorescent substrate
using HPLC as described previously.4.18 Values were measured
b
However, they were too polar and did not translate their
good enzyme potency into good antiviral potency.
An interesting observation with the monoalkylated
tetrahydropyrimidinones was that there was a differ-
ence in enzyme activity depending on the regioisomer.
Having a P2 substituent (benzyl side) is 30- to 40-fold
better than having a P2′ substituent (phenethyl side).
For example, compare isomer 47 with 46, or isomer 86
with 87. This difference is probably due to changes in
the conformation of the tetrahydropyrimidinone ring
when the nitrogen on the phenethyl side is alkylated.
It is also interesting to note that the lack of a P2′ group
(as in 36; Ki ) 66 nM) does not cause as large a loss in
the enzyme potency of the tetrahydropyrimidinones as
the lack of a P1′ group (as in 104;15 Ki ) 2,500 nM,
Figure 3).
When both nitrogens are alkylated, there was very
little difference in enzyme potency between the two
regioisomers as one would expect for the interaction
with a C2 symmetric enzyme. Thus, the pairs of regio-
isomers that were prepared, 88/89, 90/91, and 92/93,
show nearly identical enzyme and antiviral potency.
Many of the unsymmetrical P2/P2′ analogues also
showed very good antiviral potency. In particular, the
indazole (92, 93) and the amidoxime (98) analogues all
had antiviral potency less than 20 nM.
by a sensitive viral RNA-based detection system described previ-
ously.4,19 Only compounds which displayed an antiviral IC90
concentration which was at least 3-fold less than the TC50
concentration are listed in the table. c The P1/P1′ phenyl groups
d
contain a 4-fluoro substituent. The P1/P1′ phenyl groups contain
a 3,4-difluoro substituent. e See Scheme 2.
Since the tetrahydropyrimidinones were less crystal-
line and more soluble it was hoped that these physical
characteristics would provide better pharmacokinetics.
Several of these analogues were examined for oral
bioavailability in the rat or dog at a dose of 10 mg/kg.
The results of these studies, along with the correspond-
ing hexahydro-1,3-diazepin-2-one analogues for com-
parison, are summarized in Table 2. As the data in
Table 2 indicates, despite their favorable physical
characteristics, the tetrahydropyrimidinones were less
orally bioavailable than the corresponding hexahydro-
1,3-diazepin-2-ones. In addition to the compounds listed
in Table 2, the amidoximes 60, 61, and 63 were also
examined for oral bioavailability in the rat, but no
measurable blood levels were detected.
Differ en t P 2/P 2′ Su bstitu en ts. We next turned our
attention to analogues having dissimilar P2/P2′ sub-
stituents in an effort to further decrease the symmetry
and improve the potency and oral bioavailability of the
tetrahydropyrimidinones. The results are summarized
in Table 4. Having only one nitrogen substituent was
not sufficient in most cases to make these monoalky-
lated analogues potent enough to be of interest. The
exceptions were the amidoxime 83 and the aminoinda-
zole 85 which did have subnanomolar enzyme activity.
Since we were interested in potent inhibitors which
could provide sufficient free drug at trough to inhibit
both wild type and mutant variants of HIV with BID
or TID dosing, we examined the effect of plasma protein
binding on the antiviral potency of these analogues and
we also examined them against a panel of mutant

142 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
De Lucca et al.
Ta ble 3. P1′ SAR of Tetrahydropyrimidinone Inhibitors of HIV
Protease
1,3-Dia za bicyclo[4.1.0]h ep ta n -2-on es. The mono-
alkylated tetrahydropyrimidinones showed that it was
possible to obtain subnamolar enzyme potency with
inhibitors that contain just three interacting substitu-
ents (P1, P1′, P2) as in the amidoxime 83 and the
aminoindazole 85. If the tetrahydro-pyrimidinone scaf-
fold could be modified to be less polar while maintaining
the relative positions of the P1, P1′, and P2 substituents,
then the translation of enzyme potency to antiviral
potency could be improved. The aziridine 14 seemed like
a potential candidate since it has one less N-H group
than the tetrahydropyrimidinones which would decrease
its polarity and enhance its cell penetration charater-
istics.
b
Kia
IC90
compd
P2/P2′
X
(nM)
(nM)
75
23
27
36
34
4
cyclopropylmethyl
cyclopropylmethyl
cyclopropylmethyl
benzyl (P2′ ) H)
benzyl (P2′ ) H)
benzyl
H
F
OH
H
OH
H
9.8
201
410
66
320
15
5200
2800
The small-molecule crystal structure10 of the aziridine
33 (Figure 2) showed that its conformation was such
that the P1/P2 benzyl groups as well as the hydroxyl
group could be superimposed over that of the tetrahy-
dropyrimidinone analogue. While the P1′ benzyl group
of 33, as found in its crystal structure, was not super-
imposable with the P1′ phenethyl group of the tetra-
hydropyrimidinone, rotation about the single bond
achieves a good overlap. Computer models suggested
that the energy difference in conformations would not
preclude the adoption of this conformation. A computer
model of 33 superimposed over the tetrahydropyrimi-
dinone 606 (in its HIV bound conformation) is shown in
Figure 4. On the basis of this analysis, it was surprising
to find that the aziridine 33 was a significantly less
potent inhibitor (Ki ) 3800 nM) of HIVPR than the
corresponding tetrahydropyrimidinone 36 (Ki ) 66 nM).
18
19
8
benzyl
benzyl
Br
c
H
N3
F
Br
c
H
Br
H
F
H
185
460
23
330
541
100
280
4.90
23
0.30
12
0.49
11
2-naphthylmethyl
2-naphthylmethyl
2-naphthylmethyl
2-naphthylmethyl
2-naphthylmethyl
3-(N-methyl-amino)benzyl
3-(N-methyl-amino)benzyl
3-hydroxybenzyl
3-hydroxybenzyl
3-hydroxymethylbenzyl
3-hydroxymethylbenzyl
30
28
20
21
67
76
77
78
54
79
328
115
2100
109
Br
2100
a
Values were measured by cleavage of a fluorescent substrate
using HPLC as described previously.4,18 Values were measured
b
by a sensitive viral RNA-based detection system described previ-
ously.4,19 Only compounds which displayed an antiviral IC90
concentration which was at least 3-fold less than the TC50
concentration are listed in the table. c The P1′ group contains a
trans-styrene substituent as shown in Scheme 4.
Other aziridine analogues were prepared, and the
results are summarized in Table 5 along with the
corresponding tetrahydropyrimidinone analogues for
comparison. The results showed that the SAR of the
aziridine series is nearly identical to the tetrahydro-
pyrimidinone series. In both series the potency increases
about 10-fold in going from the benzyl (33, 36) to the
carboxamide (81, 101). It increases another 10-fold from
the carboxamide to the amidoxime analogues (83, 102).
This suggests that both series are interacting with the
enzyme in a similar binding mode. A possible explana-
tion for this 100-fold difference in potency between
aziridine and tetrahydropyrimidinone analogues may
be due to the difference in the interaction of the urea
carbonyl with the flap residues of HIVPR. As shown in
Figure 4, while it is possible to overlap the P1/P1′/P2
and hydroxyl groups of the aziridine with the corre-
sponding tetrahydropyrimidinone, the carbonyl of the
two series cannot be overlapped properly. This differ-
ence in the placement of the carbonyl relative to the
other recognition elements of the inhibitor, although
small, may account for the loss in binding affinity. This
suggests that the hydrogen-bonding interactions of the
urea carbonyl with the flap residues is a very critical
element in the recognition of tetrahydropyrimidinone
inhibitors to HIVPR. The flap interaction may be nearly
equal in importance to the hydrogen-bonding interaction
of the hydroxyl group with the catalytic aspartic acids.
For example, we previously reported that the deoxy
analogue 10517 (Ki ) 99 nM; Figure 3) showed a 200-
fold loss in potency compared to the corresponding
hydroxy analogue 54 (Ki ) 0.49 nM). A similar loss in
activity is also seen with the ketone analogue 106 (Ki
F igu r e 3. Structure of several tetrahydropyrimidin-2-ones
discussed in the text.
viruses as previously described.5,7,16 Unfortunately, none
of the tetrahydropyrimidinones showed any advantage
over the analogous hexahydro-1,3-diazepin-2-ones, nei-
ther in terms of protein binding nor resistance profiles.
In most cases the tetrahydropyrimidinones showed a
greater loss of antiviral potency in the presence of
plasma proteins (45 mg/mL serum albumin plus 1 mg/
mL R-1-acid glycoprotein) than the hexahydro-1,3-
diazepin-2-ones, probably due to their greater lipophi-
licity. The lack of any advantage precluded the further
study, including pharmacokinetic evaluation, of these
analogues.

Tetrahydropyrimidin-2-one HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 143
Ta ble 4. Unsymmetrical P2/P2′ SAR of Tetrahydropyrimidinone HIVPR Inhibitors
b
compd
P2
P2′
Kia (nM)
IC90 (nM)
9
36
38
80
40
47
81
82
83
84
85
86
87
46
88
89
43
90
91
92
93
94
95
96
97
98
H
H
H
H
H
H
H
H
H
H
H
H
H
970
66
15
benzyl
3-cyanobenzyl
3-cyano-4-fluorobenzyl
3-hydroxybenzyl
3-aminobenzyl
3-(carboxamido)benzyl
3-(carboxamido)-4-fluorobenzyl
3-(carboxamido oxime)benzyl
3-(carboxamido oxime)-4-fluorobenzyl
3-aminoindazol-5-yl-methyl
indazol-5-yl-methyl
H
110
2.60
6.20
5.60
14.0
0.24
1.40
0.38
1.20
44
4800
4330
370
3780
549
590
indazol-5-yl-methyl
3-aminobenzyl
3-cyano-4-fluorobenzyl
benzyl
cyclopropylmethyl
3-aminoindazol-5-yl-methyl
benzyl
H
157
33
benzyl
3-cyano-4-fluorobenzyl
3-(carboxamido-oxime)benzylc
benzyl
3-aminoindazol-5-yl-methyl
indazol-5-yl-methyl
3-aminobenzyl
3-aminobenzyl
3-aminobenzyl
3-aminobenzyl
3-aminobenzyl
40.0
0.48
0.65
0.28
0.08
0.10
0.13
1.6
36
71
126
13
16
32
565
53
24
3-aminobenzyl
indazol-5-yl-methyl
3-methylindazol-5-yl-methyl
3-cyanobenzyl
3-aminoindazol-5-yl-methyl
3-(carboxamido)benzyl
3-(carboxamido oxime)benzyl
0.10
0.06
0.02
3-aminobenzyl
17
a
b
Values were measured by cleavage of a fluorescent substrate using HPLC as described previously.4,18 Values were measured by a
sensitive viral RNA-based detection system described previously.4,19 Only compounds which displayed an antiviral IC90 concentration
which was at least 3-fold less than the TC50 concentration are listed in the table. c As shown in Scheme 8.
F igu r e 4. Computer model of a minimized conformation of aziridine 33 (color by atom) superimposed on tetrahydropyrimidin-
2-one 60 (in green) as found in its bound conformation with HIV protease (as reported in ref 6). The P2′ substituent of 60 is
omitted for clarity. View on the left highlights the good overlap found for the corresponding P1, P1′, and P2 groups of 33 with
those of 60. The view on the right highlights the difference in urea carbonyl trajectory between 33 and 60.
) 1500 nM; Figure 3) compared to the corresponding
hydroxy analogue 4 (Ki ) 15 nM).
are all critical for good activity. However, there was
significant flexibility in the possible P2/P2′ substituents
that could be used. Many analogues that contained
identical or different P2/P2′ substituents, or only one
P2 substituent, were found to have excellent enzyme
potency and several had excellent antiviral potency.
A fair number of these compounds were examined for
oral bioavailability in the rat or the dog at 10 mg/kg.
However, despite the favorable physical charateristics
listed above, the oral bioavailability of the tetrahydro-
pyrimidinones were, in general, lower than the corre-
sponding hexahydro-1,3-diazepin-2-ones. The reason for
the lower oral bioavailability of the tetrahydropyrimi-
dinones is not known, and further studies to establish
a possible cause were not carried out.
Con clu sion
In this paper we reported our efforts to further explore
the use of tetrahydropyrimidinones as an alternate
scaffold for designing HIVPR inhibitors in order to try
to exploit some of its advantages. Since the tetrahydro-
pyrimidinones are more unsymmetrical (different P1/
P1′) less crystalline, more soluble, and more lipophilic
(mono-ol vs diol) than the corresponding hexahydro-1,3-
diazepin-2-ones,3 we hoped that the use of tetrahydro-
pyrimidinones could better address the conflicting issues
of solubility, potency, and oral bioavailability.
The SAR studies of the tetrahydropyrimidinones
reported in this paper showed that the phenylethyl P1′
substituent, the hydroxyl group, and the urea carbonyl,
Unfortunately, when all properties are considered,
including potency, protein binding, solubility, bioavail-

144 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
De Lucca et al.
Ta ble 5. SAR of Diazabicyclo[4.1.0]heptan-2-ones HIVPR
Inhibitors
33, the energy was calculated as 370.8 kcal/mol using the
Tripos force field. The structure of 33 was allowed to relax by
energy minimization to convergence using the MAXIMIN
standard options [force field, Tripos; method, Powell; charge:
Gasteiger-Huckel; dielectric constant, 1.0; termination, gradi-
ent 0.05 kcal/mol] to yield the relaxed X-ray structure of 33
with a calculated energy of 143.4 kcal/mol. Using the X-ray
structure of amidoxime 60 (complexed with HIVPR as previ-
ously reported6) as a template, the relaxed structure 33 was
manually docked to give the best overlap. An iterative process
of manually adjusting the rotatable bonds in 33 to give the
best overlap with the corresponding P1/P2/P1′ phenyl groups
of tetrahydropyrimidinone 60 followed by energy minimization
of 33 using MAXIMIN was used until the difference in
conformation and energy was as small as possible. The final
overlap is shown in Figure 4. The calculated energy of this
final conformer of 33 was 143.9 kcal/mol, an energy value
similar to that of the starting conformation (the relaxed X-ray
structure of 33).
compd
P2
Kia(nM)
99
33
H
3000
3800
66
2400
15
320
5.60
12
benzyl
benzyl
3-cyanobenzyl
36b
100
38b
101
81b
102
83b
3-cyanobenzyl
3-(carboxamido)benzyl
3-(carboxamido)benzyl
3-(carboxamido oxime)benzyl
3-(carboxamido oxime)benzyl
0.24
a
Values were measured by cleavage of a fluorescent substrate
using HPLC as described previously.4,18 b Data for the correspond-
ing tetrahydropyrimidinone analogue.
(4R,5R,6R)-Tet r a h yd r o-5-h yd r oxy-1,3,6-t r is-[p h en yl-
m eth yl]-4-(2-p h en yleth yl)-2(1H)-p yr im id in on e (4). To a
solution of (4R,5S,6S,7R)-hexahydro-5,6-dihydroxy-1,3,4,7-tet-
rakis-(phenylmethyl)-2H-1,3-diazepin-2-one 14 (1.3 g, 2.6 mmol)
in CH2Cl2 (40 mL) at room temperature was added 2-acetoxy-
isobutyryl bromide (1.7 g, 8.1 mmol), and the solution was
stirred at room temperature for 15 min at which time TLC
showed complete conversion. The solution was quenched with
saturated NaHCO3, and the organic layer was separated,
washed with water and brine, dried, and concentrated to the
corresponding bromo acetate. The crude bromo acetate was
chromatographed (MPLC, silica gel, 30% EtOAc/hexane) to
give 1.4 g of 2. A fraction of the eluent from this chromatog-
raphy was allowed to evaporate slowly to give crystals of the
bromo acetate 2 that were of sufficient quality for single-crystal
ability, and resistance profile, the tetrahydropyrimidi-
nones did not offer any advantage over the hexahydro-
1,3-diazepin-2-ones series and were not developed further.
Exp er im en ta l Section
Biologica l Meth od s. Inhibition of HIVPR (Ki) was mea-
sured by the assay of the cleavage of a fluorescent substrate
using HPLC as described previously.4,18 The antiviral activity
potency of compounds was assessed by measuring their effect
on the accumulation of viral RNA transcripts 3 days after
infection of MT-2 cells with HIV-1 RF as described previ-
ously.4,19 The concentration of test compound which reduced
the concentration of HIV viral RNA by 90% from the level
measured in an untreated infected culture was designated IC90.
The cellular toxicity of compounds was assessed by measuring
the extent of MTT dye reduction in uninfected MT-2 cell
cultures grown for 3 days in the presence of various concentra-
tions of test compound as previously described.18,19 The com-
pound concentration which decreased the level of MTT dye
reduction by 50% was designated the TC50. Only compounds
which displayed an antiviral IC90 concentration which was at
least 3-fold less than the TC50 concentration were considered
to have a specific antiviral effect. Oral bioavailability of
compounds was determined as previously reported.4,20
Gen er a l. All reactions were carried out under an atmo-
sphere of dry nitrogen. Commercial reagents were used
without further purification. 1H NMR (300 MHz) spectra were
recorded using tetramethylsilane as an internal standard. TLC
was performed on E. Merck 15710 silica gel plates. Medium-
pressure liquid chromatography (MPLC) was carried out using
EM Science silica gel 60 (230-400 mesh). HPLC chromatog-
raphy was carried out using J asco PV-987 pumps, J asco UV-
975 detectors, and Dupont Zorbax Sil or Zorbax NH2 1-in.
preparative columns. All final targets were obtained as
noncrystalline amorphous solids unless specified otherwise.
Mass spectra were measured with a HP5988A mass spectrom-
eter with particle beam interface using NH3 for chemical
ionization or Finnigan MAT 8230 mass spectrometer with
NH3-DCI or VG TRIO 2000 for ESI. High-resolution mass
spectra were measured on a VG 70-VSE instrument with NH3
chemical ionization. Elemental analysis was performed by
Quantitative Technologies, Inc., Bound Brook, NJ . For com-
pounds where analysis was not obtained, HPLC analysis was
used, and purity was determined to be >98% unless specified
otherwise. The synthesis of compounds 4, 9, 50, 54, 56, 59,
60, 64, 65, 66, 67, 75, and 77 were previously reported in ref
6.
1
X-ray analysis.6 For 2: mp 178-180 °C; H NMR (CDCl3) δ
7.42-7.16 (m, 16 H), 6.89-6.79 (m, 4 H), 5.50 (d, J ) 15 Hz,
1 H), 5.43 (d, J ) 15 Hz, 1 H), 4.71 (t, J ) 4 Hz, 1 H), 4.10 (d,
J ) 15 Hz, 1 H), 4.02 (m, 1 H), 3.87 (d, J ) 15 Hz, 1 H), 3.71
(dd, J ) 4 Hz, J ) 7 Hz, 1 H), 3.58 (m, 1 H), 3.10 (dd, J ) 6
Hz, J ) 13 Hz, 1 H), 2.95 (dd, J ) 3 Hz, J ) 15 Hz, 1 H), 2.77
(dd, J ) 10 Hz, J ) 15 Hz), 2.65 (dd, J ) 10 Hz, J ) 13 Hz, 1
H), 1.61 (s, 3 H). Anal. (C35H35N2O3Br‚0.2(C6H14)) C, H, N.
The bromo acetate 2 (1.0 g) was dissolved in 50 mL of acetic
acid and treated with Zn dust (7 g) and vigorously stirred at
room temperature until TLC analysis showed complete con-
version. The mixture was filtered and the solid washed
thoroughly with EtOAc. The filtrate was washed with water,
saturated NaHCO3, and brine, dried, and evaporated to give
the acetate. The crude acetate was chromatographed (MPLC
silica gel 65% EtOAc/hexane) to give 820 mg of the acetate 3
as a white foam. The acetate 3 (400 mg, 0.68 mol) was
dissolved in MeOH and treated with 1 N NaOH (5 mL), and
the mixture was stirred at room temperature. The mixture
was concentrated, and the residue was partitioned between 1
N HCl and EtOAc. The organic extract was washed with water
and brine, dried, and concentrated, and the resulting residue
was chromatographed (MPLC, silica gel, 65% EtOAc/hexane)
to give 300 mg of 4 as a foam: 1H NMR (CDCl3) δ 7.37-7.15
(m, 16 H), 6.97 (m, 4 H), 5.46 (d, J ) 15 Hz, 1 H), 5.42 (d, J )
14 Hz, 1 H), 3.89 (d, J ) 14 Hz, 1 H), 3.82 (d, J ) 15 Hz, 1 H),
3.41 (m, 1 H), 3.33 (m, 1 H), 3.17 (m, 1 H), 2.95 (m, 2 H), 2.85
(m, 2 H), 2.40 (t, J ) 8 Hz, 2 H), 1.9 (m, 1 H), 1.61 (m, 2 H);
CIMS (NH3) m/z 491 (M + H+, 100). Anal. (C33H34N2O2) C, H,
N.
(4R,5R,6R)-Tet r a h yd r o-1,3-b is-[2-n a p h t h ylm et h yl]-5-
h yd r oxy-4-(2-p h en yleth yl)-6-(p h en ylm eth yl)-2(1H)-p yr i-
m id in on e (8). Meth od 1. To a solution of (4R,5S,6S,7R)-
hexahydro-5,6-dihydroxy-1,3-bis-[2-naphthylmethyl]-4,7-bis-
[phenylmethyl]-2H-1,3-diazepin-2-one 54 (2.0 g, 3.3 mmol) in
CH2Cl2 (40 mL) at room temperature was added 2-acetoxy-
isobutyryl bromide (2.0 g, 10 mmol) and the solution was
stirred at room temperature for 10 min at which time TLC
showed complete conversion. The solution was quenched with
saturated NaHCO3, and the organic layer was separated and
Molecu la r Mod elin g. Molecular modeling studies were
performed using SYBYL version 6.0, commercially available
from Tripos Associates, Inc., and viewed on a Silicon Graphics
Indigo2 workstation. Using the X-ray structure coordinates of

Tetrahydropyrimidin-2-one HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 145
washed with water and brine. The organic layer was dried and
concentrated. The residue was chromatographed (MPLC, silica
gel, 30% EtOAc/hexane) to give 1.3 g of the 1-bromo-2-
phenylethyl acetate tetrahydropyrimidinone 6: 1H NMR
(CDCl3) δ 7.89-7.78 (m, 6 H), 7.74 (m, 2 H), 7.60 (m, 1 H),
7.56-7.46 (m, 5 H), 7.19-7.13 (m, 4 H), 7.04 (m, 2 H), 6.47-
6.74 (m, 2 H), 6.67 (d, J ) 8 Hz, 2 H), 5.72 (d, J ) 15 Hz, 1 H),
5.66 (d, J ) 15 Hz, 1 H), 4.67 (m, 1 H), 4.28 (d, J ) 15 Hz, 1
H), 4.13 (d, J ) 15 Hz, 1 H), 4.06 (m, 1 H), 3.77 (dd, J ) 4 Hz,
J ) 8 Hz, 1 H), 3.59 (m, 1 H), 3.20 (dd, J ) 5 Hz, J ) 13 Hz,
1 H), 2.85 (abx m, 2 H), 2.68 (dd, J ) 5 Hz, J ) 13 Hz, 1 H),
1.26 (s, 3 H); CIMS (NH3) m/z 713 (M + H+, 100) 711 (M +
H+, 95). Anal. (C43H39N2O3Br) C, H, N.
The 1-bromo-2-phenylethyl acetate 6 (0.4 g, 0.6 mmol) was
dissolved in 50 mL of acetic acid and treated with Zn dust (1
g) and vigorously stirred at room temperature until TLC
analysis showed complete conversion. The mixture was filtered
and the solid washed thoroughly with EtOAc. The filtrate was
washed with water, saturated NaHCO3, and brine. The solu-
tion was dried and evaporated to give the phenethyl acetate
7. The crude phenethyl acetate was dissolved in MeOH and
treated with 1 N NaOH (5 mL) and the mixture stirred at room
temperature. The mixture was concentrated, and the residue
was partitioned between 1 N HCl and EtOAc. The organic
extract was washed with water and brine, dried, and concen-
trated. The resulting residue was chromatographed (MPLC,
silica gel, 50% EtOAc/hexane) to give 170 mg of 8 as a white
foam.
Meth od 2. A solution of 21 (30 mg) in dioxane was treated
with 10% Pd/C (30 mg) and hydrogenated at 50 psi for 3 h.
The solution was filtered and concentrated, and the residue
was chromatographed (HPLC, Zorbax Sil, 70% EtOAc/hexane)
to give 10 mg of 8 as a white foam identical to that obtained
using method 1 above. For 8: 1H NMR (CDCl3) δ 7.87-7.77
(m, 6 H), 7.67 (s, 1 H), 7.61 (s, 1 H), 7.54-7.40 (m, 6 H), 7.26-
7.16 (m, 6 H), 7.03-6.93 (m, 4 H), 5.66 (d, J ) 15 Hz, 1 H),
5.63 (d, J ) 15 Hz, 1 H), 4.06 (d, J ) 15 Hz, 1 H), 4.01 (d, J )
15 Hz, 1 H), 3.41-3.34 (m, 2 H), 3.20 (m, 1 H), 3.08-2.81 (abx
m, 2 H), 2.42 (m, 2 H), 1.90 (m, 1 H), 1.65 (m, 1 H), 1.60 (bs,
1 H); DCI MS (NH3) m/z 591.5 (M + H+, 100). Anal.
(C41H38N2O2) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-5-h yd r oxy-4-(2-p h en yleth yl)-6-
(p h en ylm eth yl)-2(1H)-p yr im id in on e (9). Meth od 1. A
solution of 17 (7.0 g, 23 mmol) in THF/MeOH was treated with
3 g of 10% Pd/C and hydrogenated in a Parr bottle at 50 psi
for 3 h at room temperature. The solution was filtered through
Celite and the filtrate concentrated to give 6.3 g of 9. The
product was identical to that previously described.6
H), 3.97-3.42 (m, 5 H), 3.09-2.57 (m, 4 H), 1.92-1.51 (m, 8
H); CIMS (NH3) m/z 395.3 (M + H+, 100). Anal. (C24H30N2O3)
C, H, N.
[4R,5R, 6R)-Tetr a h yd r o-5-h yd r oxy-1,3-bis(1H-in d a zol-
5-ylm et h yl)-4-(2-p h en ylet h yl)-6-(p h en ylm et h yl)-2(1H )-
p yr im id in on e (12). A solution of 10 (2.47 g, 6.3 mmol) and
5-(bromomethyl)-1-SEM-indazole8,11 (4.70 g,13.8 mmol) in THF
was treated dropwise with a 1 M solution of KO-t-Bu (in THF)
via syringe. The resulting solution was stirred at room
temperature for 30 min at which time analysis by TLC showed
no starting material remained. The solution was concentrated
to dryness and the residue chromatographed (MPLC, silica gel,
25% EtOAc/hexane) to give 4.3 g of 11 (75% yield). A solution
of 11 (4.3 g, 4.6 mmol) in MeOH (150 mL) was treated with
50 mL of concentrated HCl and heated at reflux for 2 h. The
solution was concentrated to half its volume on a rotary
evaporator and made basic with 1 N NaOH. The solid
precipitate was extracted into ethyl acetate, washed with
water and brine, and dried over MgSO4. The solution was
filtered and concentrated and the residue chromatographed
(MPLC, silica gel, 1.5% MeOH/EtOAc) to give 2.3 g (88% yield)
of 12: mp 130-134 °C; 1H NMR (CDCl3) δ 10.95 (bs, 1H), 10.87
(bs, 1 H), 7.84 (s, 1 H), 7.72 (s, 1 H), 7.50 (s, 1 H), 7.47 (s, 1 H),
7.35-7.15 (m, 10 H), 7.07 (2 overlapping d, J ) 7 Hz, 2 H),
6.95 (2 overlapping d, J ) 7 Hz, 2 H), 5.51 (d, J ) 15 Hz, 1 H),
5.48 (d, J ) 15 Hz, 1 H), 4.10 (d, J ) 15 Hz, 1 H), 3.94 (d, J )
15 Hz, 1 H), 3.53 (m, 1 H), 3.42 (m, 1 H), 3.32 (m, 1 H), 2.94
(m, 2 H), 2.42 (m, 2 H), 1.90 (m, 1 H), 1.76 (m, 1 H), 1.62 (bs,
H); CIMS (NH3) m/z 571 (M + H+, 100). Anal. (C35H34N6O2)
C, H, N.
(4R,5S,6R,7R)-1,3-d ia za -4,7-bis-(p h en ylm eth yl)-5-(a cet-
yloxy)-bicyclo[4.1.0]h ep ta n -2-on e (14). A solution of mono-
acetate 134 (2.0 g, 5.0 mmol) in CH2Cl2 (30 mL) was cooled to
0 °C in an ice bath and treated with DAST (0.8 mL, 6.0 mmol)
via syringe. The solution was stirred at 0 °C for 30 min at
which time TLC analysis showed complete consumption of 13.
The solution was diluted with saturated sodium bicarbonate,
and the organic layer was separated and washed with water
and brine, dried, and concentrated to give 1.9 g of 14 as a white
solid. The solid was recrystallized from ethyl acetate: mp 222
°C; 1H NMR (CDCl3) δ 7.38-7.00 (m, 10 H), 5.54 (d, J ) 6 Hz,
1 Η), 4.97 (dd, J ) 5 Hz, J ) 7 Hz, 1 H), 3.81 (m, 1 H), 3.26
(dd, J ) 4 Hz, J ) 15 Hz, 1 H), 3.16 (dd, J ) 4 Hz, J ) 14 Hz,
1 H), 3.00-2.84 (m, 3 H), 2.65 (dd, J ) 8 Hz, J ) 15 Hz, 1 H),
2.10 (s, 3 H); DCI MS (NH3) m/z 351 (M + H+, 100). Anal.
(C21H22N2O3) C, H, N.
(4S,5S,6R)-Tetrahydro-5-(acetyloxy)-4-(1S-bromo-2-phen-
yleth yl)-6-(p h en ylm eth yl)-2(1H)-p yr im id in on e (15). A so-
lution of aziridine 14 (1.0 g, 2.9 mmol) in dioxane was cooled
in an ice bath while HBr(g) was bubbled into the solution for
10 min. Ice bath was removed and the solution stirred at room
temperature for 20 min. The solvent was removed under
vacuum, and the residue was chromatographed (MPLC, silica
gel, EtOAc) to give 900 mg of 15 as a white solid: 1H NMR
(CDCl3) δ 7.36-7.11 (m, 10 H), 5.85 (bs, 1 H), 5.07 (bs, 1 H),
5.05 (m, 1 H), 4.23 (m, 1 H), 3.95 (m, 1 H), 3.61 (m, 1 H), 3.23
(d, J ) 7 Hz, 2 H), 2.70 (abx m, 2 H), 2.12 (s, 3 H); CIMS (NH3)
m/z 433, 431 (M + H+, 35).
(4R,5R,6R)-Tetr ah ydr o-5-(acetyloxy)-4-(2-ph en yleth yl)-
6-(p h en ylm eth yl)-2(1H)-p yr im id in on e (16). A solution of
bromo acetate 15 (900 mg, 2.1 mmol) in acetic acid was treated
with 10 g of Zn dust and stirred overnight at room tempera-
ture. The solution is diluted with ethyl acetate and filtered
through a fritted funnel, and the solids were washed with ethyl
acetate. The filtrate was concentrated under vacuum, and the
residue was chromatographed (MPLC, silica gel, EtOAc - 10%
MeOH/EtOAc) to give 600 mg of 16 as a white solid: 1H NMR
(CDCl3) δ 7.35-7.10 (m, 10 H), 6.08 (bs, 1 H), 5.28 (bs, 1 H),
4.80 (m, 1 H), 3.80 (m, 1 H), 3.42 (m, 1 H), 2.83 (abx m, 2 H),
2.77 (m, 1 H), 2,62 (m, 1 H), 2.12 (s, 3 H), 1.74 (m, 2 H); 13C
NMR (CDCl3) δ 170.2, 156.3, 140.26, 135.40, 129.0, 128.9,
128.5, 128.3, 127.3, 126.2, 67.1, 53.5, 51.2, 36.9, 31.4, 20.9;
CIMS (NH3) m/z 353 (M + H+, 100).
Meth od 2. A solution of 16 (0.5 g, 1.4 mmol) in methanol
was treated with 5 mL of 1 N NaOH solution and stirred at
room temperature for 8 h. The solution was concentrated to
dryness and the residue acidified with 1 N HCl and extracted
into ethyl acetate. The organic extract was washed with water
and brine and then dried over MgSO4. The solution was filtered
and concentrated to give 0.3 g of 9. Product was identical to
that previously described:6 mp 162-163 °C; 1H NMR (CDCl3)
δ 7.38-7.19 (m, 10 H), 6.69 (bs, 1 H), 5.00 (bs, 1 H), 4.61 (d, J
) 8 Hz, 1 H), 3.60 (t, J ) 7 Hz, 1 H), 3.49 (bm, 1 H), 3.38 (bm,
1 H), 3.30 (dd, J ) 7 Hz, 14 Hz, 1 H, abx), 2.82 (dd, J ) 7 Hz,
14 Hz, 1 H, abx), 2.78 (m, 1 H, abx) 2.57 (m, 1 H, abx), 1.62
(m, 2 H); 13C NMR (CDCl3) δ 157.1, 141.7, 137.2, 129.7, 129.2,
128.8, 128.8, 127.3, 126.4, 65.9, 57.1, 53.5, 38.4, 37.7, 32.4;
CIMS (NH3) m/z 311 (M + H+, 100). Anal. (C19H22N2O2) C, H,
N.
(4R,5R,6R)-Tetr a h yd r o-5-(tetr a h yd r op yr a n -2-yl-oxy)-
4-(2-p h en ylet h yl)-6-(p h en ylm et h yl)-2(1H )-p yr im id in o-
n e (10). A solution of alcohol 9 (6.2 g, 20 mmol) in chloroform
was treated with dihydropyran (12.0 g, 140 mmol) and TsOH‚
H2O (0.4 g, 2 mmol) and stirred overnight at room tempera-
ture. The mixture was then washed with aqueous sodium
bicarbonate and brine and then dried over MgSO4. The solution
was filtered and concentrated to give 7.8 g of 10 as white
1
solid: mp 182-184 °C; H NMR (CDCl3) δ 7.38-7.19 (m, 10
H), 4.83 (bs, 0.5 H), 4.78 (bs, 0.5 H), 4.69 (bs, 1 H), 4.45 (bs, 1
(4S,5S,6R)-Tetrahydro-5-(hydroxy)-4-(â-styrene)-6-(phen-

146 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
De Lucca et al.
ylm eth yl)-2(1H)-p yr im id in on e (17). A solution of aziridine
14 (8.77 g, 25 mmol) in dioxane was cooled in an ice bath while
HBr(g) was bubbled into the solution for 10 min. The ice bath
was removed and solution stirred at room temperature for 20
min. The solvent was removed under vacuum, and the crude
bromo acetate 15 was dissolved in MeOH and treated with 10
g of KOH. The solution was stirred at room temperature
overnight. The solution was concentrated under vacuum and
the residue acidified with 1 N HCl. The solid was extracted
into chloroform (with a small amount of methanol to help
dissolve it). The extract was dried over MgSO4, filtered, and
concentrated to give 7.0 g of 17 as a white solid: mp 231-233
°C; 1H NMR (CDCl3/CD3OD) δ 7.36-7.21 (m, 10 H), 6.56 (d, J
) 16 Hz, 1 H), 6.06 (dd, J ) 5 Hz, J ) 16 Hz, 1 H), 5.74 (bs,
1 H, exchanges), 4.95 (bs, 1 H, exchanges), 4.18 (m, 1 H), 3.75
(m, 1 H), 3.58 (m, 1 H), 3.01 (abx dd, J ) 6 Hz, J ) 14 Hz, 1
H), 2.81 (abx dd, J ) 6 Hz, J ) 14 Hz, 1 H); CIMS (NH3) m/z
309 (M + H+, 100). Anal. (C19H20N2O2‚0.2H2O) C, H, N.
(4S,5S,6R)-Tet r a h yd r o-1,3-b is-[p h en ylm et h yl]-5-h y-
d r oxy-4-(1S -b r om o-2-p h e n yle t h yl)-6-(p h e n ylm e t h yl)-
2(1H)-p yr im id in on e (18): mp 135.0-137.0 °C; 1H NMR
(CDCl3) δ 7.18-7.17 (m, 16 H), 7.06-7.03 (m, 2 H), 6.88-6.85
(m, 2 H), 5.40 (d, J ) 14 Hz, 1 H), 5.36 (d, J ) 14 Hz, 1 H),
4.23 (d, J ) 15 Hz, 1 H), 4.20-4.16 (m, 1 H), 3.81-3.75 (m, 1
H), 3.64-3.60 (m, 1 H), 3.48 (d, J ) 15 Hz, 1 H), 3.38-3.31
(m, 1 H), 2.98-2.91 (m, 3 H), 2.74-2.65 (m, 1 H), 2.11-2.08
(m, 1 H); CIMS (M + NH4+) 588. HRMS calcd for C33H34N2O2-
Br (M + H+), 569.1804; found, 569.1784. Anal. (C33H33N2O2-
Br‚0.2H2O) C, H, N.
filtered and concentrated to give 50 mg of 21 as a white solid
identical to that obtained using method 1 above:
1H NMR
(CDCl3) δ 7.93-7.65 (m, 6 H), 7.59 (m, 1 H), 7.55-7.40 (m, 6
H), 7.40-7.20 (m, 9 H), 7.12 (d, J ) 8 Hz, 2 H), 6.55 (d, J ) 16
Hz, 1 H), 5.91 (dd, J ) 8 Hz, 16 Hz, 1 H), 5.70 (d, J ) 15 Hz,
1 H), 5.55 (d, J ) 15 Hz, 1 H), 4.14 (d, J ) 15 Hz, 1 H), 3.80
(m, 1 H), 3.53 (d, J ) 15 Hz, 1 H), 3.53 (m, 2 H), 2.98-2.70
(abx m, 2 H), 1.85 (d, J ) 5 Hz, 1 H); DCI MS (NH3) m/z 589
(M + H+, 100). Anal. (C41H36N2O2‚0.5H2O) C, H, N.
(4S,5S,6R)-Tetr a h yd r o-1,3-bis-[cyclop r op ylm eth yl]-5-
h yd r oxy-4-(1S-flu or o-2-p h en ylet h yl)-6-(p h en ylm et h yl)-
2(1H )-p yr im id in on e (23). A solution of (4R,5S,6S,7R)-
hexahydro-5,6-dihydroxy-1,3-bis-[cyclopropylmethyl]-4,7-bis-
[phenylmethyl]-2H-1,3-diazepin-2-one 224 (0.112 g, 0.26 mmol)
in CH2Cl2 (20 mL) was cooled to 0 °C in an ice bath and treated
with DAST (0.034 mL, 0.26 mmol) via syringe. The solution
was stirred at 0 °C for 30 min at which time TLC showed
complete conversion. The solution was diluted with water and
the organic layer was separated, washed with water and brine,
dried and concentrated. The residue was chromatographed
(HPLC, Zorbax Sil, 65% EtOAc/hexane) to give 45 mg of 23 as
a foam: 1H NMR (CDCl3) δ 7.36-7.21 (m, 8 H), 7.08-7.06 (m,
2 H), 4.83 (m, 0.5 H), 4.73 (m, 0.5 H), 4.05 (dd, J ) 7 Hz, J )
15 Hz, 1 H), 3.86 (dd, J ) 7 Hz, J ) 15 Hz, 1 H), 3.81 (m, 1 H),
3.70 (m, 1 H), 3.61 (m, 1 H), 3.30 (abx m, 2 H), 2.91-2.61 (m,
4 H), 2.49 (d, J ) 7 Hz, 1 H), 1.06 (m, 1 H), 0.96 (m, 1 H),
0.60-0.06 (m, 8 H); CIMS (NH3) m/z 437.2 (M + H+, 100).
HRMS calcd for C27H34N2O2F (M + H+), 437.2604; found,
437.2593.
(4S,5S,6R)-Tet r a h yd r o-1,3-b is-[p h en ylm et h yl]-5-h y-
d r oxy-4-(â-styr en e)-6-(p h en ylm eth yl)-2(1H)-p yr im id in o-
n e (19): mp 186.0-188.0 °C; 1H NMR (CDCl3) δ 7.37-7.18
(m, 16 H), 7.10-7.05 (m, 4 H), 6.52 (d, J ) 16 Hz, 1 H), 5.08-
5.80 (dd, J ) 7 Hz, 16 Hz, 2 H), 5.40 (d, J ) 15 Hz, 1 H), 5.33
(d, J ) 15 Hz, 1 H), 4.01 (d, J ) 15 Hz, 1 H), 3.82-3.77 (m, 1
H), 3.57-3.53 (m, 1 H), 3.46-3.40 (m, 1 H), 3.35 (d, J ) 15
Hz, 1 H), 2.97-2.91 (dd, J ) 6 Hz, 13 Hz, 1 H), 2.68-2.61 (dd,
J ) 8 Hz, 13 Hz, 1 H), 2.02 (s, 1 H); CIMS (M + H+) 489.
HRMS calcd for C33H32N2O2 (M + H+), 489.2542; found,
489.2555. Anal. (C33H32N2O2‚0.8H2O) C, H, N.
(4R,5S,6S,7R)-Hexah ydr o-5-(2-m eth oxyeth oxym eth oxy)-
6-h yd r oxy-1,3-b is-[cyclop r op ylm et h yl]-4,7-b is-[p h en yl-
m eth yl]-2H-1,3-d ia zep in -2-on e (24). A solution of diol 224
(2.06 g, 4.7 mmol) in CH2Cl2 (20 mL) was treated with MEM-
Cl (0.71 g, 5.69 mmol) and diisopropylethylamine (1.53 g, 11.8
mmol), and the mixture was heated at reflux for 8 h. The
mixture was washed with water, saturated sodium carbonate,
and brine and then dried over MgSO4. The mixture was
filtered, concentrated, and the residue was chromatographed
(HPLC, Zorbax Sil, 5% MeOH/CHCl3) to give 1.3 g of 24 as an
oil: 1H NMR (CDCl3) δ 7.30-7.11 (m, 10 H), 4.95 (s, 2 H), 4.10
(m, 1 H), 3.89 (m, 3 H), 3.75-3.46 (m, 6 H), 3.41 (s, 3 H), 3.39-
2.97 (m, 5 H), 1.98 (m, 2 H), 0.90 (m, 2 H), 0.40 (m, 4 H), 0.03
(m, 4 H); CIMS (NH3) m/z 523 (M + H+, 100).
(4R,5S,6R)-Tetr a h yd r o-1,3-bis-[cyclop r op ylm eth yl]-5-
h ydr oxy-4-(1S-h ydr oxy-2-ph en yleth yl)-6-(ph en ylm eth yl)-
2(1H)-p yr im id in on e (27). To a solution of 24 (1.0 g, 1.9
mmol) in THF were added triphenyl phosphine (1.0 g, 3.8
mmol), DEAD (0.7 g, 4.o mmol), and chloroacetic acid (0.40 g,
4.2 mmol), and the mixture was stirred for 20 h at room
temperature. The mixture was evaporated, and the residue
was chromatographed (MPLC, silica gel, 50% EtOAc/hexane)
to give 0.9 g of chloroacetate 25 as an oil: 1H NMR (CDCl3) δ
7.27-7.21 (m, 10 H), 5.39 (m, 1 H), 4.95 (d, J ) 13 Hz, 1 H),
4.80 (d, J ) 13 Hz, 1 H), 4.70 (s, 1 H), 4.27 (m, 1 H), 4.19 (m,
2 H), 4.00-3.70 (m, 5 H), 3.93 (s, 2 H), 3.48 (dd, J ) 7 Hz, J
) 15 Hz, 1 H), 3.37, (s, 3 H), 3.02-2.90 (m, 5 H), 1.90 (dd, J
) 7 Hz, J ) 15 Hz, 1 H), 1.22 (m, 2 H), 0.76 (m, 1 H), 0.57 (m,
2 H), 0.40-0.20 (m, 4 H), 0.0 (m, 1 H); CIMS (NH3) m/z 599
(M + H+, 100).
A solution of the chloroacetate 25 (0.9 g, 1.5 mmol) in
methanol (15 mL) was treated with 4 mL of a 1 N NaOH
solution and stirred at room temperature for 1 h. The solution
was concentrated to dryness and the was residue extracted
into ethyl acetate, washed with water and brine, and then
dried over MgSO4. The mixture was filtered and concentrated,
and the residue was chromatographed (HPLC, Zorbax Sil, 85%
EtOAc/hexane) to give 0.4 g of alcohol 26 as a viscous oil which
slowly solidified over a few days: 1H NMR (CDCl3) δ 7.33-
7.13 (m, 10 H), 4.92 (d, J ) 7 Hz, 1 H), 4.84 (d, J ) 7 Hz, 1 H),
4.28 (m, 1H), 4.20 (m, 1 H), 3.91-3.79 (m, 5 H), 3.60 (m, 2 H),
3.50 (dd, J ) 7 Hz, J ) 15 Hz, 1 H), 3.38 (s, 3 H), 3.06 (d, J )
7 Hz, 2 H), 2.94 (dd, J ) 7 Hz, J ) 15 Hz, 1 H), 2.82-2.62 (m,
2 H), 2.44 (d, J ) 7 Hz, 1 H), 1.91 (dd, J ) 7 Hz, J ) 15 Hz,
(4S,5S,6R)-Tet r a h yd r o-1,3-b is-[2-n a p h t h ylm et h yl]-5-
h yd r oxy-4-(1S-br om o-2-p h en yleth yl)-6-(p h en ylm eth yl)-
2(1H)-p yr im id in on e (20). The 1-bromo-2-phenylethyl acetate
6 (100 mg, 0.14 mmol) was dissolved in MeOH (5 mL) and
treated with 1 N NaOH (1 mL, 1.0 mmol) at room temperature
for 1 h. The mixture was concentrated, and the residue was
partitioned between 1 N HCl and EtOAc. The organic extract
was washed with water and brine and dried over MgSO4. The
solution was filtered and concentrated to give 80 mg of 18 as
1
a white solid: mp 85 °C (dec); H NMR (CDCl3) δ 7.89-7.78
(m, 7 H), 7.64 (m, 2 H), 7.50 (m, 4 H), 7.40-7.00 (m, 9 H),
6.67 (d, J ) 8 Hz, 2 H), 5.60 (d, J ) 15 Hz, 1 H), 5.56 (d, J )
15 Hz, 1 H), 4.21 (d, J ) 15 Hz, 1 H), 3.76 (m, 1 H), 3.62 (d, J
) 15 Hz, 1 H), 3.36 (m, 1 H), 3.01-2.90 (m, 3 H), 2.68 (dd, J
) 5 Hz, J ) 13 Hz, 1 H), 2.00 (d, J ) 7 Hz, 1 H); CIMS (NH3)
m/z 669.2 (M + H+, 67), 671.2 (M + H+, 72), 589.2 ((M - HBr
+ H+, 100). Anal. (C41H37N2O2Br‚0.2H2O) C, H, N.
(4S,5S,6R)-Tetr a h yd r o-1,3-bis-[2-n a ph th a len ylm eth yl]-
5-h yd r oxy-4-(â-styr en e)-6-(p h en ylm eth yl)-2(1H)-p yr im i-
d in on e (21). Meth od 1. A solution of mesylate 29 (100 mg,
0.15 mmol) in DMF was treated with NaI (100 mg, 1.5 mmol)
and heated at 80 °C for 2 h and then at 40 °C overnight. The
solution was diluted with water and the solid extracted into
ethyl acetate. The extracts were washed with water and brine
and dried over MgSO4. The solution was filtered and concen-
trated, and the solid residue was chromatographed (HPLC,
Zorbax Sil, 50% EtOAc/hexane) to give 50 mg of 21 as a white
solid.
Meth od 2. The 1-bromo-2-phenylethyl acetate 6 (100 mg,
0.14 mmol) was dissolved in MeOH (10 mL) and treated with
solid KOH (1.0 g, 17.8 mmol) at room temperature for 1 h.
The mixture was concentrated and the residue was partitioned
between 1 N HCl and EtOAc. The organic extract was washed
with water and brine, and dried over MgSO4. The solution was

Tetrahydropyrimidin-2-one HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 147
1 H), 1.21 (m, 1 H), 0.81 (m, 1 H), 0.58 (m, 2 H), 0.45-0.25
(m, 4 H), 0.02 (m, 2 H); CIMS (NH3) m/z 523 (M + H+, 100).
(a cetyloxy)-bicyclo[4.1.0]h ep ta n -2-on e (31). A solution of
14 (0.20 g, 0.57 mmol) in DMF was cooled in an ice bath and
treated with NaH (30 mg, 0.7 mmol, 60% oil dispersion) and
stirred for 30 min. Then benzyl bromide (0.12 g, 0.69 mmol)
was added, and the solution was allowed to warm to room
temperature for 1 h. The solution was diluted with water and
extracted into ethyl acetate. The organic extract was washed
with water and brine and then dried over MgSO4. The solution
was filtered and concentrated, and the residue was chromato-
graphed (HPLC, Zorbax Sil, 50% EtOAc/hexane) to give 80 mg
of 31 as a white solid. An additional 30 mg of the 5-benzyl
ether compound was also obtained. For 31: 1H NMR (CDCl3)
δ 7.40-7.20 (m, 13 H), 7.08 (m, 2 H), 5.05 (d, J ) 15 Hz, 1 Η),
4.53 (dd, J ) 5 Hz, J ) 7 Hz, 1 H), 3.77 (m, 1 H), 3.28 (dd, J
) 4 Hz, J ) 15 Hz, 1 H), 3.22 (abx m, 1 H), 3.05 (abx m, 1 H),
2.94 (m, 1 H), 2.83 (m, 1 H), 2.83 (d J ) 15 Hz, 1 H), 2.55 (dd,
J ) 8 Hz, J ) 15 Hz, 1 H), 1.95 (s, 3 H); DCI MS (NH3) m/z
441 (M + H+, 100).
A solution of 26 (70 mg, 0.13 mmol) in methanol was cooled
in an ice bath while HCl gas was bubbled in for 20 min. The
solution was allowed to warm to room temperature and stirred
for 1 h. The solution was evaporated to dryness under vacuum,
and the residue was chromatographed (HPLC, Zorbax Sil, 80%
EtOAc/hexane) to give 48 mg of 27 as a white foam: 1H NMR
(CDCl3) δ 7.36-7.17 (m, 10 H), 4.24 (m, 2 H), 3.98 (dd, J ) 8
Hz, J ) 15 Hz, 1 H), 3.80 (m, 1 H), 3.72 (m, 1 H), 3.68 (dd, J
) 8 Hz, J ) 15 Hz, 1 H), 3.41 (d, J ) 3 Hz, 1 H), 3.15-2.96
(m, 2 H, abx), 2. 85 (dd, J ) 7 Hz, J ) 15 Hz, 1 H), 2.79-2.51
(m, 2 H, abx), 2.19 (m, 1 H), 2.10 (dd, J ) 7 Hz, J ) 16 Hz, 1
H), 1.09 (m, 1 H), 0.82 (m, 1 H), 0.58-0.25 (m, 6 H), 0.05 (m,
2 H); CIMS (NH3) m/z 435 (M + H+, 100). HRMS calcd for
C
27H35N2O3 (M + H+), 435.2648; found, 435.2638.
(4S,5S,6R)-Tet r a h yd r o-1,3-b is-[2-n a p h t h ylm et h yl]-5-
h yd r oxy-4-(1S-flu or o-2-p h en ylet h yl)-6-(p h en ylm et h yl)-
2(1H )-p yr im id in on e (28). A solution of (4R,5S,6S,7R)-
hexahydro-5,6-dihydroxy-1,3-bis-[2-naphthylmethyl]-4,7-bis-
[phenylmethyl]-2H-1,3-diazepin-2-one 54 (0.10 g, 0.16 mmol)
in CH2Cl2 (20 mL) was cooled to 0 °C in an ice bath and treated
with DAST (0.026 mL, 0.16 mmol) via syringe. The solution
was stirred at 0 °C for 30 min at which time TLC showed
complete conversion. The solution was diluted with water, and
the organic layer was separated and washed with water and
brine. The solution was dried, filtered, and concentrated, and
the residue was chromatographed (HPLC, Zorbax Sil, 50%
EtOAc/hexane) to give 35 mg of 28 as a foam: 1H NMR (CDCl3)
δ 8.00-7.80 (m, 8 H), 7.68-7.54 (m, 6 H), 7.34-7.19 (m, 6 H),
7.06 (m, 2 H), 6.88 (d, J ) 7 Hz, 2 H), 5.83 (d, J ) 15 Hz, 1 H),
5.81 (d, J ) 15 Hz, 1 H), 4.80 (m, 0.5 H), 4.63 (m, 0.5 H), 4.24
(d, J ) 15 Hz, 1 H), 4.18 (d, J ) 15 Hz, 1 H), 3.57 (m, 2 H),
3.31 (m, 1 H), 3.20 (m, 1 H, abx), 2.98 (m, 1 H, abx), 2.80-
2.55 (m, 2 H), 1.95 (d, J ) 8 Hz, 1 H); CIMS (NH3) m/z 609 (M
+ H+, 100). HRMS calcd for C41H38N2O2F (M + H+), 609.2917;
found, 609.2911. Anal. (C41H37N2O2F‚0.2(H2O)) C, H, N.
(4R,5S,6S,7R)-Hexa h yd r o-5-(m esyloxy)-6-h yd r oxy-1,3-
bis-[2-n a p h th ylm eth yl]-4,7-bis-[p h en ylm eth yl]-2H-1,3-d i-
a zep in -2-on e (29). A solution of (4R,5S,6S,7R)-hexahydro-
5,6-dihydroxy-1,3-bis-[2-naphthylmethyl]-4,7-bis-[phenylmethyl]-
2H-1,3-diazepin-2-one 54 (0.60 g, 1.0 mmol) in pyridine was
treated with methanesulfonyl chloride (0.17 g, 1.5 mmol) and
stirred at room temperature for 3 h. The mixture was diluted
with 0.5 N HCl and extracted into ethyl acetate. The extracts
were washed with water and brine and dried over MgSO4. The
solution was filtered and concentrated, and the solid residue
was chromatographed (MPLC, silica gel, 40% EtOAc/hexane)
to give 420 mg of 29 as a white solid: 1H NMR (CDCl3) δ 7.84-
7.76 (m, 6 H), 7.58-7.40 (m, 6 H), 7.40-7.21 (m, 8 H), 7.09
(m, 4 H), 5.05 (d, J ) 14 Hz, 1 H), 5.03 (d, J ) 14 Hz, 1 H),
4.45 (dd, J ) 4.5 HZ, 10 Hz, 1 H), 3.91 (m, 1 H), 3.78 (m, 1 H),
3.66 (m, 1 H), 3.44 (d, J ) 14 Hz, 1 H), 3.22-2.85 (m, 5 H),
2.50 (s, 3 H), 2.26 (d, J ) 4 Hz, 1 H); CIMS (NH3) m/z 685 (M
+ H+, 100).
(4R,5S,6R)-Tet r a h yd r o-1,3-b is-[2-n a p h t h ylm et h yl]-5-
h yd r oxy-4-(1S-a zid o-2-p h en ylet h yl)-6-(p h en ylm et h yl)-
2(1H)-p yr im id in on e (30). A solution of 29 (100 mg, 0.15
mmol) in DMF was treated with NaN3 (100 mg, 1.5 mmol) and
heated at 80 °C for 2 h and then at 40 °C overnight. The
solution was diluted with water and the solid extracted into
ethyl acetate. The extracts were washed with water and brine
and dried over MgSO4. The solution was filtered and concen-
trated, and the solid residue was chromatographed (HPLC,
Zorbax Sil, 50% EtOAc/hexane) to give 80 mg of 30 as a white
solid: IR 2114; 1H NMR (CDCl3) δ 7.93-7.78 (m, 7 H), 7.63-
7.39 (m, 8 H), 7.25-7.05 (m, 7 H), 6.73 (d, J ) 7 Hz, 2 H), 5.76
(d, J ) 7 Hz, 1 H), 5.68 (d, J ) 7 Hz, 1 H), 4.10 (d, J ) 7 Hz,
1 H), 3.78 (d, J ) 7 Hz, 1 H), 3.62 (m, 1 H), 3.52 (m, 1 H), 3.29
(m, 2 H), 3.07-2.85 (abx m, 2 H), 2.56-2.31 (abx m, 2 H), 1.97
(d, J ) 7 Hz, 1 H); DCI MS (NH3) m/z 632 (M + H+, 100).
HRMS calcd for C41H38N5O2 (M + H+), 632.3026; found,
632.3023. Anal. (C41H37N5O2‚0.4(EtOAc)‚0.4(hexane)) C, H, N.
(4R,5S,6R,7R)-1,3-Dia za -1,4,7-t r is-(p h en ylm et h yl)-5-
(h yd r oxy)-bicyclo[4.1.0]h ep ta n -2-on e (33). A solution of 31
(20 mg) in methanol was treated with 5 mL of 1 N NaOH and
stirred at room temperature for 1 h. The solution was
concentrated to dryness, and the residue was acidified with 1
N HCl and extracted into ethyl acetate. The organic extract
was washed with water and brine and then dried over MgSO4.
The solution was filtered and concentrated, and the residue
was chromatographed (HPLC, Zorbax Sil, 70% EtOAc/hexane)
to give 15 mg of 33 as a white solid. The solid was recrystal-
lized from ethyl acetate to give crystals suitable for X-ray
analysis: 1H NMR (CDCl3) δ 7.41-7.21 (m, 13 H), 6.96 (m, 2
H), 5.08 (d, J ) 15 Hz, 1 Η), 3.63 (m, 1 Η), 3.58-3.34 (m, 3
H), 3.04 (m, 1 H), 2.95 (m, 1 H), 2.81 (m, 1 H), 2.56 (d, J ) 15
Hz, 1 H), 2.38 (dd, J ) 10 Hz, J ) 15 Hz, 1 H), 2.25 (bs, 1 H);
DCI MS (NH3) m/z 399 (M + H+, 100).
(4R,5S,6R)-Tet r a h yd r o-1,6-b is-(p h en ylm et h yl)-5-h y-
d r oxy-4-(1S-h yd r oxy-2-p h en ylet h yl)-2(1H )-p yr im id in o-
n e (34). The aziridine 31 (30 mg, 0.07 mmol) was dissolved in
1 mL of trifluoroacetic acid for 1 h. The solution was evapo-
rated under vacuum and the residue made basic with satu-
rated sodium bicarbonate and extracted into ethyl acetate. The
extract was washed with water and brine and concentrated
to dryness. The trifluoroacetate obtained was redissolved in
methanol (5 mL) and treated with 1 N NaOH (1 mL) and
stirred at room temperature for 2 h. The solution was acidified
with 1 N HCl and extracted into methylene chloride. The
extract was washed with water and brine and then dried over
MgSO4. The solution was filtered and concentrated to give 15
1
mg of 34 as a white solid: mp 193-194 °C; H NMR (CDCl3)
δ 7.41-7.15 (m, 13 H), 6.95 (m, 2 H), 5.89 (bs, 1 H), 5.05 (d, J
) 15 Hz, 1 H), 4.90 (m, 2 H), 3.41 (m, 2 H), 3.18-2.65 (m, 7
H); DCI MS (NH3) m/z 417 (M + H+, 100). Anal. (C26H28N2O3‚
0.66(CH3OH)) C, H, N.
(4R,5R,6R)-Tet r a h yd r o-1,6-b is-(p h en ylm et h yl)-5-h y-
d r oxy-4-(2-p h en yleth yl)-2(1H)-p yr im id in on e (36). Using
the same procedure detail above for the sequence 15/16/9, the
aziridine 31 was converted to 36: mp 180 °C; 1H NMR (CDCl3)
δ 7.36-7.15 (m, 13 H), 7.03 (m, 2 H), 5.16 (d, J ) 15 Hz, 1 H),
4.98 (s, 1 H), 3.49 (m, 1 H), 3.36 (m, 2 H), 3.17 (d, J ) 15 Hz,
1 H), 3.08 (dd, J ) 5 Hz, J ) 13 Hz, 1 H), 2.83 (dd, J ) 9 Hz,
J ) 13 Hz, 1 H), 2.77 (m, 1 H), 2.62 (m, 1 H), 2.09 (d, J ) 7
Hz, 1 H), 1.96 (m, 1 H), 1.73 (m, 1 H); DCI MS (NH3) m/z 401
(M + H+, 100). Anal. (C26H28N2O2) C, H, N.
(4R,5R,6R)-Tetrahydro-1-(3-cyanophenylmethyl)-6-phen-
ylm eth yl-5-h ydr oxy-4-(2-ph en yleth yl)-2(1H)-pyr im idin on e
(38). Using the same procedure detail above for the synthesis
of 36, the aziridine 32 was converted to 38: 1H NMR (CDCl3)
δ 7.48 (d, J ) 7 Hz, 1 H), 7.35-7.10 (m, 13 H), 5.35 (s, 1 H),
5.00 (d, J ) 15 Hz, 1 H), 3.53 (m, 1 H), 3.38 (m, 2 H), 3.20 (d,
J ) 15 Hz, 1 H), 3.12 (dd, J ) 5 Hz, J ) 13 Hz, 1 H), 2.87-
2.58 (m, 3 H), 2.29 (bs, 1 H), 2.05 (m, 1 H), 1.77 (m, 1 H); DCI
MS (NH3) m/z 426 (M + H+, 100). HRMS calcd for C27H28N3O2
(M + H+), 426.2181; found, 426.2159.
(4R,5R,6R)-Tetr a h yd r o-1-[3-h yd r oxyp h en ylm eth yl]-5-
h yd r oxy-4-(2-p h en yleth yl)-6-(p h en ylm eth yl)-2(1H)-p yr i-
(4R,5S,6R,7R)-1,3-Dia za -1,4,7-t r is-(p h en ylm et h yl)-5-

148 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
De Lucca et al.
m id in on e (40). A solution of 14 (1.4 g, 4.1 mmol) in DMF
was cooled in an ice bath and treated with NaH (250 mg, 6.2
mmol, 60% oil dispersion) and stirred for 30 min. Then
3-benzyloxybenzyl bromide (1.4 g, 6.2 mmol) was added and
solution was allowed to warm to room temperature for 1 h.
The solution was diluted with water and extracted into ethyl
acetate. The organic extract was washed with water and brine,
and then dried over MgSO4. The solution was filtered and
concentrated and the residue was chromatographed (MPLC,
silica gel, 50% EtOAc/hexane) to give 1 g of 39 (mixture of R
) OAc and R ) 3-benzyloxybenzyl) as a white solid. An
additional 0.5 g of pure 39 (R ) OH) was also obtained. For
39 (R ) OH): mp 184-185 °C. Anal. (C33H32N2O3) C, H, N.
A solution of 39 (mixture of R ) OAc and R ) 3-benzyloxy-
benzyl) (1 g) in methanol was treated with 1 N NaOH and
stirred at room temperature for 1 h. The solution was
concentrated to dryness and the residue acidified with 1 N HCl
and extracted into ethyl acetate. The organic extract was
washed with water and brine and then dried over MgSO4. The
solution was filtered and concentrated, and the residue was
chromatographed (MPLC, silica gel, 50% EtOAc/hexane) to
give 800 mg of 39 (mixture of R ) OH and R ) 3-benzyloxy-
benzyl) as a white solid. A solution of 39 (mixture of R ) OH
and R ) 3-benzyloxybenzyl) (800 mg) in ethanol was treated
with 10% Pd/C (800 mg) and hydrogenated at 50 psi for 2 days.
The solution was filtered through Celite and the filtrate
concentrated. The residue was chromatographed (HPLC, Zor-
bax Sil, 3% MeOH/CHCl3) to give 230 mg of 40 as a white solid.
The 2D COSY was consistent with assigned structure: 1H
NMR (CDCl3) δ 9.13 (s, 1H), 7.35-7.12 (m, 9 H), 6.83-6.80
(m, 4 H), 6.39 (d, J ) 7 Hz, 1 H), 5.19 (bs, 1 H), 5.00 (d, J )
15 Hz, 1 H), 3.36 (m, 1 H), 3.16 (m, 2 H), 3.02 (abx m, 1 H),
2.98 (d, J ) 15 Hz, 1 H), 2.70 (abx m, 1 H), 2.45 (m, 2 H), 1.86
(m, 1 H), 1.74 (d, J ) 5 Hz, 1 H), 1.30 (m, 1 H); DCI MS (NH3)
m/z 417 (M + H+, 100). HRMS calcd for C26H29N2O3 (M + H+),
417.2178; found, 417.2163.
(4R,5R,6R)-Tet r a h yd r o-1-(3-(N-h yd r oxyca r b oxim id a -
m id e)p h en ylm eth yl)-3-cyclop r op ylm eth yl-6-p h en ylm e-
th yl-5-h ydr oxy-4-(2-ph en yleth yl)-2(1H)-pyr im idin on e (43).
The alcohol 38 (0.5 g, 1.2 mmol) in methylene chloride was
treated with MEM-Cl (0.29 g, 2.4 mmol) and DIEA (0.3 g, 2.4
mmol), and the solution was heated at reflux overnight. The
solution was evaporated to dryness under vacuum and the
residue chromatographed (MPLC, silica gel, EtOAc) to give
400 mg of the MEM ether 41 as an oil: DCI MS (NH3) m/z
514.2 (M + H+, 100).
A solution of the MEM ether 41 (0.25 g, 0.5 mmol) in DMF
was treated with NaH (0.11 g, 3.0 mmol, 60% disp) and stirred
at room temperature for 30 min. Cyclopropylmethyl bromide
(0.39 g, 3.0 mmol) was added and the mixture heated at 70 °C
for 1 h. The reaction mixture was diluted with 1 N HCl and
extracted into ethyl acetate. The extract was washed with
water and brine and then dried over MgSO4. The solution was
filtered and concentrated and the residue chromatographed
(HPLC, Zorbax Sil, EtOAc) to give 42: 1H NMR (CDCl3) δ 7.50
(m, 1 H), 7.37-7.10 (m, 13 H), 4.84 (d, J ) 15 Hz, 1 H), 4.69
(dd, J ) 7 Hz, J ) 22 Hz, 2 H), 3.90 (dd, J ) 7 Hz, J ) 15 Hz,
1 H), 3.80-3.60 (m, 5 H), 3.52 (m, 2 H), 3.36 (s, 3 H), 3.20 (d,
J ) 15 Hz, 1 H), 3.20 (d, J ) 15 Hz, 1 H), 3.06-2.88 (m, 3 H),
2.52 (m, 2 H), 2.05 (m, 2 H), 1.07 (m, 1 H), 0.54 (m, 2 H), 0.32
(m, 2 H).
(m, 1H), 3.43 (m, 1 H), 3.38 (m, 1 H), 3.52 (m, 2 H), 2.96 (m,
3 H), 2.78 (dd, J ) 7 Hz, J ) 15 Hz, 1 H), 2.42 (m, 2 H), 1.87
(m, 1 H), 1.64 (m, 1 H), 1.07 (m, 1 H), 0.54 (m, 2 H), 0.32 (m,
2 H); ESI MS (NH3) m/z 513.3 (M + H+, 100). Anal.
(C31H36N4O3) C, H, N.
(4R,5R,6R)-Tetrahydro-3-(3-aminophenylmethyl)-6-phen-
ylm eth yl-5-h ydr oxy-4-(2-ph en yleth yl)-2(1H)-pyr im idin on e
(46). A solution of 10 (1.0 g, 2.5 mmol) in THF was alkylated
(K-O-t-Bu/THF) with 1 equiv of 3-nitrobenzyl chloride (0.44
g, 2.5 mmol) to give a mixture of dialkylated products, 44 and
45, and recovered starting material 10. The mixture was
chromatographed on silica gel (MPLC, 30% - 50%-100%
EtoAc in hexane step gradient) to give 100 mg of 45 as the
second monoalkylated product from the column (100% EtOAc).
The nitro group was reduced (H2; 10% Pd/C) and the THP
protecting group removed with HCl/MeOH. The crude product
was purified by chromatography (HPLC, Zorbax Sil, 10%
MeOH/EtoAc) to give 46 as a white solid: mp 148-152 °C; 1H
NMR (CDCl3) δ 7.33-7.00 (m, 11 H), 6.58-6.45 (m, 3 H), 5.14
(d, J ) 15 Hz, 1 H), 4.54 (s, 1 H), 3.75-3.44 (m, 5 H), 3.23 (m,
1 H), 2.90 (abx dd, J ) 7 Hz, J ) 13 HZ), 2.76 (abx dd, J ) 8
Hz, J ) 13 HZ), 2.97 (m, 2 H), 2.10 (bs, 1 H), 1.98 (m, 1 H),
1.65 (m, 1 H); ESI MS (NH3) m/z 416 (M + H+, 100). HRMS
calcd for C26H30N3O2 (M + H+), 416.2338; found, 416.2328.
(4R,5R,6R)-Tetrahydro-1-(3-aminophenylmethyl)-6-phen-
ylm eth yl-5-h ydr oxy-4-(2-ph en yleth yl)-2(1H)-pyr im idin on e
(47). Meth od 1. A solution of 10 (1.0 g, 2.5 mmol) in THF
was alkylated (K-Ot-Bu/THF) with 1 equiv of 3-nitrobenzyl
chloride (0.44 g, 2.5 mmol) to give a mixture of dialkylated
product, 44 and 45, and recovered starting material 10. The
mixture was chromatographed on silica gel (MPLC, 30% -
50%-100% EtoAc in hexane step gradient) to give 200 mg of
44 as the first monoalkylated product from the column (50%
EtOAc). The nitro group was reduced (H2; THF, 10% Pd/C)
and the THP protecting group removed with HCl/MeOH. The
crude product was purified by chromatography (HPLC, Zorbax
Sil, 10% MeOH/EtoAc) to give 47 as white solid.
Meth od 2. A solution of 49 in THF was hydrogenated (50
psi H2; THF, 10% Pd/C) and the THP group was removed with
HCl/MeOH. The product was purified by chromatography
(HPLC, Zorbax Sil, 10% MeOH/EtoAc) to give 47 as a white
solid identical in every respect as that obtained using method
1: mp 76-70 °C; 1H NMR (CDCl3) δ 7.33-7.10 (m, 10 H), 7.03
(t, J ) 7 Hz, 1 H), 6.52 (d, J ) 7 Hz, 1 H), 4.40 (d, J ) 7 Hz,
1 H), 6.34 (s, 1 H), 5.08 (d, J ) 15 Hz, 1 H), 5.03 (bs, 1 H),
3.59 (bs, 2 H), 3.49 (m, 1 H), 3.33 (m, 2 H),3.07 (d, J ) 15 Hz,
1 H), 3.05 (abx m, 1 H), 2.81 (abx m, 1 H), 2.79 (m, 1 H), 2.63
(m, 1 H), 2.24 (bs, 1 H), 1.95 (m, 1 H), 1.69 (m, 1 H); ESI MS
(NH3) m/z 416 (M + H+, 100). HRMS calcd for C26H30N3O2 (M
+ H+), 416.2338; found, 416.2351.
(4S,5S,6R)-Tetr ah ydr o-1-(3-n itr oph en ylm eth yl)-6-ph en -
ylm eth yl-5-h ydr oxy-4-(â-styr en e)-2(1H)-pyr im idin on e (48).
A solution of 14 (1.0 g, 2.9 mmol) in THF was alkylated (K-
Ot-Bu/THF) with 3-nitrobenzyl chloride (0.55 g, 3.3 mmol).
Using the procedure describe for 17 above the alkylation
product was treated with HBr and then KOH to give 0.5 g of
nitro olefin 48: 1H NMR (DMSO-d6) δ 8.07 (d, J ) 8 Hz, 1 H),
7.83 (s, 1 H), 7.60-7.18 (m, 11 H), 6.78 (s, 1 H), 6.55 (d, J )
16 Hz, 1 H), 6.20 (dd, J ) 7 Hz, J ) 16 Hz, 1 H), 5.55 (s, 1 H),
4.86 (d, J ) 15 Hz, 1 H), 3.89 (m, 1 H), 3.55 (m, 1 H), 3.44 (m,
2 H), 3.25 (s, 1 H), 3.07 (abx dd, J ) 5 Hz, J ) 13 Hz, 1 H),
2.73 (abx dd, J ) 8 Hz, J ) 13 Hz, 1 H); ESI MS (NH3) m/z
444 (M + H+, 100).
The MEM group was removed by dissolving 42 in 4 N HCl/
dioxane and stirring at room temperature for 3 h. The solution
was evaporated to dryness to give the crude alcohol. A solution
of the crude alcohol (40 mg) in ethanol was converted to the
amidoxime by treating with NH2OH‚HCl (60 mg) and Et3N
(80 mg) and heating at reflux for 2 h. The mixture was
evaporated to dryness and the residue partitioned between
EtOAc and water. The organic layer was washed with water
and then concentrated. The residue was chromatographed
(HPLC, Zorbax NH2, 15% MeOH/CH2Cl2) to give 43 as a
(4S,5S,6R)-Tetr ah ydr o-1-(3-n itr oph en ylm eth yl)-6-ph en -
ylm eth yl-5-(tetr ah ydr opyr an -2-yl-oxy)-4-(â-styr en e)-2(1H)-
p yr im id in on e (49). The alcohol of 48 was protected as the
THP ether (using the procedure described for 10) to give 49.
NMR shows mixture of diastereomers: 1H NMR (CDCl3) δ 8.07
(m, 1 H), 7.80 (m, 1 H), 7.43-7.10 (m, 12 H), 6.70 (overlapping
d, J ) 16 Hz, 1 H), 6.10 (m, 1 H), 5.02-4.80 (m, 2 H), 4.62 (bs,
0.5 H), 4.49 (bs, 0.5 H), 4.25-4.02 (m, 1 H), 3.81-3.25 (m, 3
H), 3.40-3.20 (m, 2 H), 3.16-2.75 (m, 2 H), 1.80-1.31 (m, 6
H).
1
foam: mp 130-134 °C; H NMR (CDCl3) δ 7.50-6. 95 (m, 14
H), 5.15 (d, J ) 15 Hz, 1 H), 4.84 (bs, 2 H), 3.90 (dd, J ) 7 Hz,
J ) 15 Hz, 1 H), 3.90 (bs, 1 H), 3.76 (d, J ) 15 Hz, 1 H), 3.57
(4R,5R,6R)-Tetr ah ydr o-1,3-bis-[(3-cyan oph en yl)m eth yl]-

Tetrahydropyrimidin-2-one HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 149
5-h yd r oxy-4-(2-(4-flu or op h en yl)eth yl)-6-(4-flu or op h en yl-
m eth yl)-2(1H)-p yr im id in on e (51): mp 63 °C; 1H NMR
(CDCl3) δ 7.62-7.31 (m, 8 H), 7.02-6.80 (m, 8 H), 5.23 (d, J )
15 Hz, 1 H), 5.13 (d, J ) 16 Hz, 1 H), 4.25 (d, J ) 16 Hz, 1 H),
3.95 (d, J ) 16 Hz, 1 H), 3.91 (m, 1 H), 3.46 (m, 2 H), 3.14 (m,
1 H), 2.88 (m, 2 H), 2.40 (m, 2 H), 1.90 (m, 1 H), 1.62 (m, 1 H);
CI MS (NH3) m/z 577 (M + H+, 100). HRMS calcd for
H), 2.39 (m, 2 H), 1.90 (m, 1 H), 1.65 (m, 2 H); ESI MS (NH3)
m/z 679 (M + H+, 100). Anal. (C35H34N2O4F4‚0.2CH2Cl2) C, H,
N.
(4R,5R,6R)-Tetr a h yd r o-1,3-bis-[(3-(N-h yd r oxyca r box-
im idam ide)-4-flu or o-ph en yl)m eth yl]-5-h ydr oxy-4-(2-ph en -
yleth yl)-6-(p h en ylm eth yl)-2(1H)-p yr im id in on e (63): mp
125-128 °C; 1H NMR (DMSO-d6) δ 9.63 (s, 1 H), 9.61 (s, 1 H),
7.56 (m, 1 H), 7.42 (m, 1 H), 7.36-7.00 (m, 14 H), 5.80 (bs, 4
H), 5.45 (bs, 1 H), 5.01 (d, J ) 15 Hz, 1 H), 4.90 (d, J ) 15 Hz,
1 H), 4.10 (d, J ) 15 Hz, 1 H), 3.52 (m,1 H), 3.21 (m, 1 H),
3.11 (m, 1 H), 2.82 (m abx, 1 H), 2.52(m abx, 1 H), 2.39 (m, 2
H), 1.88 (m, 2 H); ESI MS (NH3) m/z 643 (M + H+, 100). Anal.
(C35H36N6O4F2‚0.75H2O) C, H, N.
(4R,5R,6R)-Tetr ah ydr o-1,3-bis-[(3-(pyr azol-3-yl)ph en yl)-
m eth yl]-5-h yd r oxy-4-(2-p h en yleth yl)-6-(p h en ylm eth yl)-
2(1H)-p yr im id in on e (68): mp 121-125 °C; 1H NMR (CDCl3)
δ 10.95 (bs, 1H), 8.00 (bs, 1 H), 7.84 (s, 1 H), 7.58-7.42 (m, 4
H), 7.35-6.95 (m, 12 H), 6.85 (m, 2 H), 6.53 (m, 2 H), 5.31 (d,
J ) 15 Hz, 1 H), 5.08 (bs, 1 H), 4.30 (bs, 1 H), 3.98 (d, J ) 15
Hz, 1 H), 4.10 (d, J ) 16 Hz, 1 H), 3.94 (d, J ) 15 Hz, 1 H), 3.5
(bs, 1 H), 3.43 (m, 2 H), 3.22 (m, 1 H), 2.84 (m, 2 H), 2.34 (m,
2 H), 1.90 (m, 1 H), 1.59 (m, 1 H); ESI MS (NH3) m/z 623 (M
+ H+, 100); HRMS calcd for C39H39N6O2 (M + H+) 623.3135;
found, 623.3123. Anal. (C39H38N6O2) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-5-h yd r oxy-1,3-bis[(1H-in d a zol-
6-yl)m et h yl]-4-(2-p h en ylet h yl)-6-(p h en ylm et h yl)-2(1H )-
p yr im id in on e (69): mp 130-133 °C; 1H NMR (CDCl3/
CD3OD) δ 7.94 (s, 1 H), 7.82 (s, 1 H), 7.63-7.43 (m, 4 H), 7.20-
7.05 (m, 6 H), 7.07-6.93 (m, 4 H), 6.85 (m, 2 H), 5.32 (d, J )
15 Hz, 1 H), 5.27 (d, J ) 15 Hz, 1 H), 4.40 (d, J ) 16 Hz, 1 H),
4.00 (d, J ) 15 Hz, 1 H), 3.53 (m, 1 H), 3.45 (m, 1 H), 3.30 (m,
1 H), 2.90 (m, 2 H), 2.30 (m, 2 H), 1.82 (m, 1 H), 1.50 (m, 1 H);
CIMS (NH3) m/z 571 (M + H+, 100). Anal. (C35H34N6O2‚
0.75H2O) C, H, N.
C
35H31N4O2F2 (M + H+), 577.2415; found, 577.2429. Anal.
(C35H30N4O2F2‚0.25H2O) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-1,3-bis-[(3-cya n o-4-flu or op h en -
yl)m eth yl]-5-h yd r oxy-4-(2-p h en yleth yl)-6-(p h en ylm eth -
yl)-2(1H)-pyr im idin on e (52): mp 70-74 °C; 1H NMR (CDCl3)
δ 7.60-6.90 (m, 16 H), 5.14 (d, J ) 15 Hz, 1 H), 4.98 (d, J )
16 Hz, 1 H), 4.30 (d, J ) 16 Hz, 1 H), 3.84 (d, J ) 16 Hz, 1 H),
3.56 (m, 2 H), 3.11 (m, 1 H), 2.87 (m, 2 H), 2.50-2.34 (m, 2
H), 1.90 (m, 1 H), 1.90 (bs, 1 H), 1.62 (m, 1 H); CI MS (NH3)
m/z 577 (M + H+, 100). HRMS calcd for C35H31N4O2F2 (M +
H+), 577.2415; found, 577.2408. Anal. (C35H30N4O2F2) C, H,
N.
(4R,5R,6R)-Tetr ah ydr o-1,3-bis-[(3-acetylph en yl)m eth yl]-
5-h yd r oxy-4-(2-p h e n yle t h yl)-6-(p h e n ylm e t h yl)-2(1H )-
p yr im id in on e (53): mp 65-70 °C; 1H NMR (CDCl3) δ 7.89-
7.82 (m, 4 H), 7.62-7.31 (m, 4 H), 7.25-7.15 (m, 6 H), 7.02-
6.90 (m, 4 H), 5.34 (d, J ) 15 Hz, 1 H), 5.30 (d, J ) 16 Hz, 1
H), 4.05 (d, J ) 16 Hz, 1 H), 4.00 (d, J ) 16 Hz, 1 H), 3.51 (m,
1 H), 3.46 (m, 2 H), 3.18 (m, 1 H), 2.88 (m, 2 H), 2.58 (s, 3 H),
2.56 (s, 3 H), 2.40 (m, 2 H), 1.90 (m, 1 H), 1.90 (bs, 1 H), 1.62
(m, 1 H); CI MS (NH3) m/z 575 (M + H+, 100). Anal.
(C37H38N2O4‚0.25CDCl3) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-1,3-bis-[(3-ca r boxyp h en yl)m e-
th yl]-5-h ydr oxy-4-(2-ph en yleth yl)-6-(ph en ylm eth yl)-2(1H)-
p yr im id in on e (55): mp 112-116 °C; 1H NMR (CDCl3/DMSO-
d6) δ 8.05-7.91 (m, 4 H), 7.60-7.00 (m, 16 H), 5.41 (d, J ) 16
Hz, 1 H), 5.23 (d, J ) 16 Hz, 1 H), 4.02 (d, J ) 16 Hz, 1 H),
3.59 (d, J ) 16 Hz, 1 H), 3.60 (m, 1 H), 3.40 (m, 1 H), 3.20 (m,
1 H), 2.90 (abx m, 1 H), 2.70 (abx m, 1 H), 2.42 (m, 2 H), 1.94
(m, 1 H), 1.77 (m, 1 H); CI MS (NH3) m/z 579 (M + H+, 100).
Anal. (C35H34N2O6‚0.1CDCl3) C, H, N.
(4R,5R,6R)-Tetr ah ydr o-1,3-bis-[(3-car boxam idoph en yl)-
m eth yl]-5-h yd r oxy-4-(2-(4-flu or op h en yl)eth yl)-6-(4-flu o-
r op h en ylm eth yl)-2(1H)-p yr im id in on e (57): mp 113-115
°C; 1H NMR (CDCl3) δ 7.87 (bs, 1 H), 7.45-7.25 (m, 3 H), 7.20-
7.05 (m,4 H), 7.00-6.67 (m, 8 H), 5.20 (d, J ) 16 Hz, 1 H),
4.80 (d, J ) 16 Hz, 1 H), 4.58 (d, J ) 16 Hz, 1 H), 3.96 (d, J )
16 Hz, 1 H), 3.60 (m, 2 H), 2.82 (m, 2 H), 2.32 (m, 2 H), 1.94
(m, 1 H), 1.90 (bs, 1 H), 1.57 (m, 1 H); ESI MS (NH3) m/z 613
(M + H+, 100). Anal. (C35H34N4O4F2‚0.75H2O) C, H, N.
(4R,5R,6R)-Tetr ah ydr o-1,3-bis-[(3-car boxam idoph en yl)-
m eth yl]-5-h yd r oxy-4-(2-(3,4-d iflu or op h en yl)eth yl)-6-(3,4-
diflu or oph en ylm eth yl)-2(1H)-pyr im idin on e (58): 1H NMR
(CDCl3) δ 7.87 (bs, 1 H), 7.45-7.25 (m, 4 H), 7.10-6.67 (m, 6
H), 5.17 (d, J ) 16 Hz, 1 H), 4.90 (d, J ) 16 Hz, 1 H), 4.08 (d,
J ) 16 Hz, 1 H), 4.07 (d, J ) 16 Hz, 1 H), 3.46 (m, 2 H), 2.83
(abx m, 1 H), 2.60 (abx m, 1 H), 2.39 (m, 2 H), 1.87 (m, 1 H),
1.68 (bs, 1 H); ESI MS (NH3) m/z 649 (M + H+, 100). Anal.
(C35H32N4O4F4‚0.1CH3OH‚0.2CH2Cl2) C, H, N.
(4R,5R,6R)-Tet r a h yd r o-5-h yd r oxy-1,3-b is[(3-m et h yl-
1H-in d a zol-5-yl)m eth yl]-4-(2-p h en yleth yl)-6-(p h en ylm e-
1
th yl)-2(1H)-p yr im id in on e (70): mp 143-146 °C; H NMR
(CDCl3) 7.52 (s, 1 H), 7.39-6.95 (m, 17 H), 5.32 (d, J ) 15 Hz,
1 H), 5.47 (d, J ) 15 Hz, 1 H), 4.14 (d, J ) 16 Hz, 1 H), 3.65
(d, J ) 15 Hz, 1 H), 3.53 (m, 1 H), 3.40-3.20 (m, 3 H), 2.82
(m, 2 H), 2.48 (s, 3 H), 2.45 (s, 3 H), 2.46 (m, 2 H), 1.91 (m, 1
H), 1.79 (m, 1 H); CIMS (NH3) m/z 599 (M + H+, 100). Anal.
(C37H38N6O2‚H2O) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-5-h yd r oxy-1,3-bis[(3-a m in o-1H-
in d a zol-5-yl)m eth yl]-4-(2-p h en yleth yl)-6-(p h en ylm eth yl)-
2(1H)-p yr im id in on e (71): mp 150-154 °C; 1H NMR (CDCl3/
CD3OD) δ 7.46 (s, 1 H), 7.36 (s, 1 H), 7.28-6.93 (m, 14 H),
5.35 (d, J ) 15 Hz, 2 H), 3.97 (d, J ) 16 Hz, 1 H), 3.93 (d, J )
15 Hz, 1 H), 3.48-3.35 (m, 2 H), 3.23 (m, 1 H), 2.83 (m, 2 H),
2.39 (m, 2 H), 1.82 (m, 1 H), 1.62 (m, 1 H); CIMS (NH3) m/z
601 (M + H+, 100). Anal. (C35H36N8O2‚0.25H2O) C, H, N.
(4R,5R,6R)-Tetr ah ydr o-5-h ydr oxy-1,3-bis[(3-am in o-ben -
zisoxazol-5-yl)m eth yl]-4-(2-ph en yleth yl)-6-(ph en ylm eth yl)-
2(1H)-p yr im id in on e (72): mp 143-146 °C; 1H NMR (CDCl3)
δ 7.46 (s, 1 H), 7.40-7. 10 (m, 11 H), 7.05-6.93 (m, 4 H), 5.35
(d, J ) 15 Hz, 1 H), 5.30 (d, J ) 15 Hz, 1 H), 4.57 (bs, 2 H),
4.42 (bs, 2 H), 4.16 (d, J ) 16 Hz, 1 H), 3.91 (d, J ) 15 Hz, 1
H), 3.48-3.35 (m, 2 H), 3.23 (m, 1 H), 2.83 (m, 2 H), 2.69 (bs,
1 H), 2.40 (m, 2 H), 1.82 (m, 1 H), 1.60 (m, 1 H); CIMS (NH3)
m/z 603 (M + H+, 100). HRMS calcd for C35H35N6O4 (M + H+),
603.2720; found, 603.2696.
(4R,5R,6R)-Tetr a h yd r o-1,3-bis-[(3-(N-h yd r oxyca r box-
im idam ide)-ph en yl)m eth yl]-5-h ydr oxy-4-(2-(4-flu or oph en -
yl)eth yl)-6-(4-flu or op h en ylm eth yl)-2(1H)-p yr im id in on e
1
(61): mp 120-122 °C; H NMR (CDCl3/CD3OD) δ 7.67 (bs, 1
(4R,5R,6R)-Tetr a h yd r o-5-h yd r oxy-1,3-bis[(3-(5-m eth yl-
pyr id-2-yl)car boxam idoph en yl)m eth yl]-4-(2-ph en yleth yl)-
6-(p h en ylm eth yl)-2(1H)-p yr im id in on e (73): mp 118-120
H), 7.47 (m, 3 H), 7.40-7.15 (m, 4 H), 7.02-6.82 (m, 8 H), 5.22
(d, J ) 15 Hz, 1 H), 4.93 (d, J ) 15 Hz, 1 H), 4.01 (m, 1 H),
3.97 (d, J ) 15 Hz, 1 H), 3.51 (m, 2 H), 3.20 (m, 1 H), 2.78 (m,
2 H, abx), 2.36 (m, 2 H), 1.90 (m, 1 H), 1.65 (m, 2 H); ESI MS
(NH3) m/z 643 (M + H+, 100). Anal. (C35H36N6O4F2) C, H, N.
1
°C; H NMR (CDCl3) δ 9.18 (s, 1 H), 8.91 (s, 1 H), 8.25 (m, 2
H), 8.10-7.90 (m, 3 H), 7.81-7.63 (m, 4 H), 7.40-6.88 (m, 15
H), 5.39 (d, J ) 15 Hz, 1 H), 5.24 (d, J ) 15 Hz, 1 H), 4.41 (bs,
1 H), 4.16 (d, J ) 16 Hz, 1 H), 3.96 (d, J ) 15 Hz, 1 H), 3.48-
3.35 (m, 2 H), 3.23 (m, 1 H), 2.83 (m, 2 H), 2.40 (m, 2 H), 2.36
(s, 3 H), 2.28 (s, 3 H), 1.82 (m, 1 H), 1.60 (m, 1 H); CIMS (NH3)
m/z 759 (M + H+, 100). Anal. (C47H46N6O4‚2H2O) C, H, N.
(4R,5R,6R)-Tet r a h yd r o-5-h yd r oxy-1,3-b is[(3-(t h ia zol-
2-yl)carboxamidophenyl)methyl]-4-(2-phenylethyl)-6-(phen-
ylm eth yl)-2(1H)-p yr im id in on e (74): mp 143-146 °C; 1H
(4R,5R,6R)-Tetr a h yd r o-1,3-bis-[(3-(N-h yd r oxyca r box-
im id a m id e)-p h en yl)m et h yl]-5-h yd r oxy-4-(2-(3,4-d iflu o-
r op h en yl)et h yl)-6-(3,4-d iflu or op h en yl)-2(1H )-p yr im id i-
n on e (62): 1H NMR (CDCl3/CD3OD) δ 7.63 (bs, 1 H), 7.47 (m,
3 H), 7.40-7.15 (m, 4 H), 7.02-6.62 (m, 6 H), 5.22 (d, J ) 15
Hz, 1 H), 4.90 (d, J ) 15 Hz, 1 H), 3.95 (d, J ) 15 Hz, 1 H),
3.51 (m, 2 H), 3.20 (m, 1 H), 2.82 (m abx, 1 H), 2.58 (m abx, 1

150 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
De Lucca et al.
NMR (CDCl3) δ 8.18 (s, 1 H), 7.96 (s, 1 H), 7.85 (m, 2 H), 7.50-
6.88 (m, 20 H), 5.21 (d, J ) 15 Hz, 2 H), 4.41 (bs, 1 H), 4.16 (d,
J ) 16 Hz, 1 H), 4.06 (d, J ) 15 Hz, 1 H), 3.60-3.23 (m, 4 H),
2.83 (m, 2 H), 2.30 (m, 2 H), 1.82 (m, 1 H), 1.60 (m, 1 H); CIMS
(NH3) m/z 743 (M + H+, 100). Anal. (C41H38N6O4S2‚0.33H2O)
C, H, N.
°C; 1H NMR (CDCl3) δ 7.34 (m, 1 H), 7.25-6.85 (m, 14 H),
5.45 (s, 1 H), 5.10 (bs, 2 H), 4.96 (d, J ) 15 Hz, 1 H), 3.45 (m,
1 H), 3.38 (m, 1 H), 3.30 (m, 1 H), 3.11 (d, J ) 15 Hz, 1 H),
3.05 (dd, J ) 4 Hz, J ) 13 Hz, 1 H), 2.79-2.40 (m, 3 H), 2.24
(bs, 1 H), 1.85 (m, 1 H), 1.65 (m, 1 H); ESI MS (NH3) m/z 477
(M + H+, 100). Anal. (C27H29N4O3F‚0.25H2O) C, H, N.
(4R,5R,6R)-Tet r a h yd r o-5-h yd r oxy-1-[(3-a m in o-1H -in -
d a zol-5-yl)m et h yl]-4-(2-p h en ylet h yl)-6-(p h en ylm et h yl)-
2(1H)-p yr im id in on e (85): mp 122-126 °C; 1H NMR (CDCl3/
CD3OD) δ 7.35-6.90 (m, 13 H), 5.22 (s, 1 H), 5.07 (d, J ) 15
Hz, 1 H), 3.53 (m, 3 H), 3.10 (d, J ) 15 Hz, 1 H), 3.10 (m, 1 H),
2.80-2.50 (m, 3 H), 2.00 (m, 1 H), 1.62 (m, 1 H); ESI MS (NH3)
m/z 456 (M + H+, 100). Anal. (C27H29N5O2) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-5-h yd r oxy-1-[(1H-in d a zol-5-yl)-
m eth yl]-4-(2-p h en yleth yl)-6-(p h en ylm eth yl)-2(1H)-p yr i-
m id in on e (86): mp 102-104 °C; 1H NMR (CDCl3) δ 10.50
(bs, 1 H), 7.78 (s, 1 H), 7.35-7.00 (m, 13 H), 5.19 (bs, 1 H),
5.19 (d, J ) 15 Hz, 1 H), 3.50-3.30 (m, 3 H), 3.28 (d, J ) 15
Hz, 1 H), 3.10 (abx m, 1 H), 2.86-2.57 (m, 3 H), 1.98 (m, 1 H),
1.63 (m, 1 H); ESI MS (NH3) m/z 441 (M + H+, 100). HRMS
calcd for C27H29N4O2 (M + H+), 441.2291; found, 441.2313.
Anal. (C27H28N4O2‚0.25H2O) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-5-h yd r oxy-3-[(1H-in d a zol-5-yl)-
m eth yl]-4-(2-p h en yleth yl)-6-(p h en ylm eth yl)-2(1H)-p yr i-
m id in on e (87): mp 237-238 °C; 1H NMR (DMSO-d6) δ 13.10
(bs, 1 H), 7.98 (s, 1 H), 7.55-7.10 (m, 11 H), 6.99 (d, J ) 6 Hz,
2 H), 5.00 (bs, 1 H), 4.83 (d, J ) 15 Hz, 1 H), 4.13 (d, J ) 15
Hz, 1 H), 3.61 (m, 1 H), 3.20 (bs, 1 H), 3.37 (bs, 1 H), 3.07 (bs,
1 H), 2.91-2.71 (abx m, 2 H), 2.27 (m, 2 H), 1.78 (m, 1 H),
1.50 (m, 1 H); ESI MS (NH3) m/z 441 (M + H+, 100). HRMS
calcd for C27H29N4O2 (M + H+), 441.2291; found, 441.2284.
Anal. (C27H28N4O2‚0.1CDCl3‚CD3OD) C, H, N.
(4S,5S,6R)-Tet r a h yd r o-1,3-b is-[3-(N-m et h yl)p h en yl-
m eth yl]-5-h yd r oxy-4-(1S-br om o-2-p h en yleth yl)-6-(p h en -
ylm eth yl)-2(1H)-p yr im id in on e (76): mp 188-189 °C; 1H
NMR (CDCl3) δ 7.26-7.00 (m, 12 H), 6.86-6.36 (m, 8 H), 5.39
(d, J ) 15 Hz, 2 H), 4.18 (m, 1 H), 4.10 (d, J ) 15 Hz, 1 H),
3.70 (m, 2 H), 3.60 (m, 1 H), 3.43 (d, J ) 14 Hz, 1 H), 3.31 (m,
1 H), 3.10-2.6 (m abx, 4 H), 2.83 (s, 3 H), 2.70 (s, 3 H); CIMS
(NH3) m/z 628 (M + H+, 100). Anal. (C35H39N4O2Br) C, H, N.
(4S,5S,6R)-Tetr a h yd r o-1,3-bis-[3-h yd r oxyp h en ylm eth -
yl]-5-h yd r oxy-4-(1S-flu or o-2-p h en yleth yl)-6-(p h en ylm e-
th yl)-2(1H)-p yr im id in on e (78): 1H NMR (CDCl3) δ 7.26-
7.06 (m, 7 H), 7.00-6.65 (m, 11 H), 5.37 (d, J ) 15 Hz, 2 H),
5.10 (d, J ) 15 Hz, 1 H), 4.60 (m, 0.5 H), 4.45 (m, 0.5 H), 3.70
(m, 2 H), 4.14 (d, J ) 14 Hz, 1 H), 3.90 (d, J ) 14 Hz, 1 H),
3.41 (m, 2 H), 3.32 m, 1 H), 3.00-2.60 (m abx, 4 H), 1.85 (bs,
3 H); CIMS (NH3) m/z 541 (M + H+, 100). Anal. (C33H33N2O4F‚
0.8H2O) C, H, N.
(4S,5S,6R)-Tetr ah ydr o-1,3-bis-[3-(h ydr oxym eth yl)ph en -
ylm eth yl]-5-h ydr oxy-4-(1S-flu or o-2-ph en yleth yl)-6-(ph en -
ylm eth yl)-2(1H)-p yr im id in on e (79): 1H NMR (CDCl3) δ 7.49
(s, 1 H), 7.41-7.00 (m, 15 H), 6.80 (m, 2 H), 5.27 (d, J ) 15
Hz, 1 H), 5.25 (d, J ) 15 Hz, 1 H), 4.67 (d, J ) 6 Hz, 2 H), 4.54
(d, J ) 6 Hz, 2 H), 4.18 (m, 1 H), 4.25 (d, J ) 15 Hz, 1 H), 4.09
(m, 1 H), 3.76 (m, 1 H), 3.60 (d, J ) 15 Hz, 1 H), 3.60 (m, 1 H),
3.33 (m, 1 H),91 (m, 3 H), 2.63 (abx m, 1 H), 2.25 (bs, 3 H);
CIMS (NH3) m/z 541 (M + H+, 100). HRMS calcd for
C
35H38N2O4Br (M + H+), 629.2015; found 629.2032.
(4R,5R,6R)-Tetr a h yd r o-1,6-bis-(p h en ylm eth yl)-3-(3-cy-
a n o-4-flu or op h en ylm eth yl)-5-h yd r oxy-4-(2-p h en yleth yl)-
2(1H)-p yr im id in on e (88): mp 65-68 °C; 1H NMR (CDCl3) δ
7.55-7.10 (m, 14 H), 7.00-6.90 (m, 4 H), 5.45 (d, J ) 15 Hz,
1 H), 5.17 (d, J ) 15 Hz, 1 H), 4.01 (d, J ) 15 Hz, 1 H), 3.82
(d, J ) 15 Hz, 1 H), 3.42 (m, 2 H), 3.18-3.00 (m, 2 H), 2.81
(abx m, 1 H), 2.38 (m, 2 H), 1.80 (m, 1 H), 1.57 (m, 1 H), 1.80
(bs, 1 H); ESI MS (NH3) m/z 534 (M + H+, 100). HRMS calcd
for C27H29N4O2 (M + H+), 534.2557; found, 534.2541.
(4R,5R,6R)-Tetr a h yd r o-3,6-bis-(p h en ylm eth yl)-1-(3-cy-
a n o-4-flu or op h en ylm eth yl)-5-h yd r oxy-4-(2-p h en yleth yl)-
2(1H)-p yr im id in on e (89): mp 68-70 °C; 1H NMR (CDCl3) δ
7.45 (m, 2 H), 7.40-7.10 (m, 12 H), 7.10-6.90 (m, 4 H), 5.38
(d, J ) 15 Hz, 1 H), 4.97 (d, J ) 15 Hz, 1 H), 4.10 (d, J ) 15
Hz, 1 H), 3.91 (d, J ) 15 Hz, 1 H), 3.42 (m, 2 H), 3.18 (m, 1 H),
2.80 (abx m, 2 H), 2.42 (m, 2 H), 1.90 (m, 1 H), 1.61 (m, 1 H),
1.58 (bs, 1 H); ESI MS (NH3) m/z 534 (M + H+, 100). HRMS
calcd for C27H29N4O2 (M + H+), 534.2557; found, 534.2552.
(4R,5R,6R)-Tet r a h yd r o-1,6-b is-(p h en ylm et h yl)-3-[(3-
a m in o-1H -in d a zol-5-yl)m et h yl]-5-h yd r oxy-4-(2-p h en yl-
eth yl)-2(1H)-p yr im id in on e (90): mp 109-113 °C; δ 9.20 (bs,
1 H), 7.40-7.10 (m, 14 H), 7.00-6.90 (m, 4 H), 5.65 (d, J ) 15
Hz, 1 H), 5.21 (d, J ) 15 Hz, 1 H), 4.10 (bs, 2 H), 3.96 (d, J )
15 Hz, 1 H), 3.85 (d, J ) 15 Hz, 1 H), 3.42 (m, 3 H), 3.08-2.81
(abx m, 2 H), 2.42 (m, 2 H), 1.80 (m, 1 H), 1.57 (m, 1 H); ESI
MS (NH3) m/z 546 (M + H+, 100). Anal. (C34H35N5O2‚0.85H2O)
C, H, N.
(4R,5R,6R)-Tet r a h yd r o-3,6-b is-(p h en ylm et h yl)-1-[(3-
a m in o-1H -in d a zol-5-yl)m et h yl]-5-h yd r oxy-4-(2-p h en yl-
eth yl)-2(1H)-p yr im id in on e (91): mp 104-108 °C; 1H NMR
(CDCl3) δ 9.20 (bs, 1 H), 7.40-7.05 (m, 14 H), 7.00-6.90 (m,
4 H), 5.46 (d, J ) 15 Hz, 1 H), 5.41 (d, J ) 15 Hz, 1 H), 4.10
(bs, 2 H), 3.91 (d, J ) 15 Hz, 1 H), 3.86 (d, J ) 15 Hz, 1 H),
3.42 (m, 1 H), 3.35 (m, 1 H), 3.18 (m, 1 H), 2.98-2.80 (abx m,
2 H), 2.40 (m, 2 H), 1.82 (m, 1 H), 1.60 (m, 1 H), 1.3 (bs, 1 H);
ESI MS (NH3) m/z 546 (M + H+, 100). Anal. (C34H35N5O2‚
0.66H2O) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-1-[1H-in d a zol-5-ylm eth yl]-3-(3-
aminophenyl-methyl)-4-(2-phenylethyl)-5-hydroxy-6-(phen-
ylm eth yl)-2(1H)-p yr im id in on e (92): mp 96-101 °C; 1H
NMR (CDCl3) δ 10.50 (bs, 1 H), 7.90 (s, 1 H), 7.51 (s, 1 H),
7.40-6.90 (m, 13 H), 6.70-6.50 (m, 3 H), 5.45 (d, J ) 15 Hz,
(4R,5R,6R)-Tetr a h yd r o-1-(3-cya n o-4-flu or op h en ylm e-
th yl)-6-p h en ylm eth yl-5-h yd r oxy-4-(2-p h en yleth yl)-2(1H)-
p yr im id in on e (80): mp 62-66 °C; 1H NMR (CDCl3) δ 7.40-
7.00 (m, 13 H), 5.57 (s, 1 H),4.89 (d, J ) 15 Hz, 1 H), 3.56 (m,
1 H), 3.38 (m, 2 H), 3.20 (d, J ) 15 Hz, 1 H), 3.15 (dd, J ) 5
Hz, J ) 13 Hz, 1 H), 2.87-2.58 (m, 3 H), 2.39 (bs, 1 H), 2.05
(m, 1 H), 1.77 (m, 1 H); DCI MS (NH3) m/z 443 (M + H+, 100).
Anal. (C27H26N3O2F) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-1-(3-ca r boxa m id op h en ylm eth -
yl)-6-p h en ylm et h yl-5-h yd r oxy-4-(2-p h en ylet h yl)-2(1H )-
1
p yr im id in on e (81): H NMR (CDCl3) δ 7.62 (d, J ) 7 Hz, 1
H), 7.55 (s, 1 H), 7.35-7.10 (m, 11 H), 6.70 (bs, 1 H), 6.43 (bs,
1 H), 5.40 (s, 1 H), 4.95 (d, J ) 15 Hz, 1 H), 3.43 (m, 1 H),
3.38-3.20 (m, 2 H), 3.20 (d, J ) 15 Hz, 1 H), 3.12 (dd, J ) 4
Hz, J ) 13 Hz, 1 H), 2.80-2.43 (m, 3 H), 190 (bs, 1 H), 1.91
(m, 1 H), 1.59 (m, 1 H); DCI MS (NH3) m/z 443 (M + H+, 100).
HRMS calcd for C27H30N3O3 (M + H+), 444.2287, found,
444.2281. Anal. (C27H29N3O3‚0.25EtOAc) C, H, N.
(4R,5R,6R)-Tetr ah ydr o-1-(3-car boxam ido-4-flu or oph en -
ylm eth yl)-6-p h en ylm eth yl-5-h yd r oxy-4-(2-p h en yleth yl)-
1
2(1H)-p yr im id in on e (82): mp 92-94 °C; H NMR (CDCl3)
δ 7.71 (m, 1 H), 7.35-7.10 (m, 12 H), 7.00 (m, 1 H), 6.67 (bs,
1 H), 6.00 (bs, 1 H), 5.00 (s, 1 H),4.97 (d, J ) 15 Hz, 1 H), 3.59
(m, 1 H), 3.45 (m, 1 H), 3.38 (m, 1 H), 3.20 (d, J ) 15 Hz, 1 H),
3.07 (abx dd, J ) 5 Hz, J ) 13 Hz, 1 H), 2.83-2.58 (m, 3 H),
2.54 (d, J ) 6 Hz, 1 H), 2.00 (m, 1 H), 1.75 (m, 1 H); DCI MS
(NH3) m/z 462 (M + H+, 100). HRMS calcd for C27H29N3O3F
(M + H+), 462.2193; found, 462.2175. Anal. (C27H28N3O3F‚
0.5H2O) C, H, N.
(4R,5R,6R)-Tet r a h yd r o-1-(3-(N-h yd r oxyca r b oxim id a -
m ide)ph en ylm eth yl)-6-ph en ylm eth yl-5-h ydr oxy-4-(2-ph en -
yleth yl)-2(1H)-p yr im id in on e (83): mp 106-109 °C; 1H
NMR (CDCl3) δ 7.38 (d, J ) 7 Hz, 1 H), 7.35-6.86 (m, 14 H),
5.59 (s, 1 H), 4.96 (d, J ) 15 Hz, 1 H), 4.91 (bs, 2 H), 3.45 (m,
1 H), 3.38 (m, 1 H), 3.25 (m, 1 H), 3.05 (d, J ) 15 Hz, 1 H),
3.12 (dd, J ) 4 Hz, J ) 13 Hz, 1 H), 2.77-2.40 (m, 3 H), 2.29
(bs, 1 H), 1.85 (m, 1 H), 1.57 (m, 1 H); ESI MS (NH3) m/z 459
(M + H+, 100). Anal. (C27H30N4O3) C, H, N.
(4R,5R,6R)-Tet r a h yd r o-1-(3-(N-h yd r oxyca r b oxim id a -
m ide)-4-flu or oph en ylm eth yl)-6-ph en ylm eth yl-5-h ydr oxy-
4-(2-p h en yleth yl)-2(1H)-p yr im id in on e (84): mp 200-202

Tetrahydropyrimidin-2-one HIV Protease Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 151
1 H), 5.35 (d, J ) 15 Hz, 1 H), 3.95 (d, J ) 15 Hz, 1 H), 3.75
(d, J ) 15 Hz, 1 H), 3.60 (bs, 2 H), 3.50-3.16 (m, 3 H), 2.90
(abx m, 2 H), 2.40 (abx m, 2 H), 1.85 (m, 1 H), 1.60 (m, 1 H),
1.20 (bs, 1 H); ESI MS (NH3) m/z 546 (M + H+, 100). HRMS
calcd for C27H29N4O2 (M + H+), 545.2869; found, 546.2879.
(4R,5R,6R)-Tet r a h yd r o-1-(3-a m in op h en yl-m et h yl)-3-
[1H-in d a zol-5-ylm et h yl]-4-(2-p h en ylet h yl)-5-h yd r oxy-6-
(p h en ylm eth yl)-2(1H)-p yr im id in on e (93): mp 100-105 °C;
1H NMR (CDCl3) δ 10.50 (bs, 1 H), 7.82 (s, 1 H), 7.45 (s, 1 H),
7.40-6.98 (m, 13 H), 6.65-6.55 (m, 3 H), 5.47 (d, J ) 15 Hz,
1 H), 5.41 (d, J ) 15 Hz, 1 H), 3.90 (d, J ) 15 Hz, 1 H), 3.81
(d, J ) 15 Hz, 1 H), 3.65 (bs, 2 H), 3.50-3.23 (m, 3 H), 2.93
(abx m, 2 H), 2.42 (abx m, 2 H), 1.90 (m, 1 H), 1.62 (m, 1 H),
1.20 (bs, 1 H); ESI MS (NH3) m/z 546 (M + H+, 100). HRMS
calcd for C27H29N4O2 (M + H+), 545.2869; found, 546.2873.
(4R,5R,6R)-Tetr a h yd r o-1-(3-a m in op h en yl-m eth yl)-3-[3-
m et h yl-1H -in d a zol-5-ylm et h yl]-4-(2-p h en ylet h yl)-5-h y-
dr oxy-6-(ph en ylm eth yl)-2(1H)-pyr im idin on e (94): mp 116-
tion of acetate 14 (100 mg, 0.29 mmol) in methanol (5 mL)
was treated with 1 N NaOH (10 drops from 2 mL disposable
pipet) and stirred at room temperature for 30 min. The solution
was diluted with water and the precipitate extracted into
methylene chloride. The extracts were washed with water and
dried over MgSO4. The mixture was filtered and concentrated
to give 30 mg of 99 as a white solid: 1H NMR (CDCl3/CD3OD)
δ 7.38-7.16 (m, 10 H), 3.97 (dd, J ) 5 Hz, J ) 7 Hz, 1 H),
3.52 (m, 1 H), 3.40-3.20 (m, 2 H), 3.00-2.74 (m, 3 H), 2.51
(dd, J ) 10 Hz, J ) 15 Hz, 1 H); DCI MS (NH3) m/z 309 (M +
H+, 100). Anal. (C21H22N2O3‚0.25(CH3OH)) C, H, N.
Meth od 2. A solution of acetate 14 (350 mg, 1.0 mmol) in
THF was cooled in an ice bath and treated with LAH (76 mg,
2.0 mmol) and stirred while allowing the solution to warm to
room temperature for 3 h. The solution was diluted with water
and extracted into ethyl acetate. The extracts were washed
with water and brine and dried over MgSO4. The mixture was
filtered and concentrated to give 300 mg of 99 as a white solid.
Recrystallized from EtOAc/hexane: mp 170-176 °C (dec): 1H
NMR (CDCl3/CD3OD) δ 7.38-7.16 (m, 10 H), 3.97 (dd, J ) 5
Hz, J ) 7 Hz, 1 H), 3.52 (m, 1 H), 3.40-3.20 (m, 2 H), 3.00-
2.74 (m, 3 H), 2.51 (dd, J ) 10 Hz, J ) 15 Hz, 1 H); DCI MS
(NH3) m/z 309 (M + H+, 100). Anal. (C21H22N2O3‚0.2(EtOAc)‚
0.2(hexane)) C, H, N.
(4R,5S,6R,7R)-1,3-d ia za -1-[(3-cya n op h en yl)m eth yl]-4,7-
b is-(p h en ylm et h yl)-5-(h yd r oxy)-bicyclo[4.1.0]h ep t a n -2-
on e (100): 1H NMR (CDCl3) δ 7.51-7.16 (m, 14 H), 4.96 (d, J
) 15 Hz, 1 Η), 3.65 (m, 1 Η), 3.51-3.30 (m, 3 H), 3.00 (m, 1
H), 2.98 (m, 1 H), 2.82 (m, 1 H), 2.64 (d, J ) 15 Hz, 1 H), 2.31
(dd, J ) 10 Hz, J ) 15 Hz, 1 H), 1.6 (bs, 1 H); DCI MS (NH3)
m/z 424 (M + H+, 100). Anal. (C27H25N3O2) C, H, N.
(4R,5S,6R,7R)-1,3-d ia za -1-[3-ca r b oxa m id op h en ylm e-
t h yl]-4,7-b is-(p h en ylm et h yl)-5-(h yd r oxy)-bicyclo[4.1.0]-
h ep ta n -2-on e (101): 1H NMR (CDCl3) δ 7.51 (d, J ) 7 Hz, 1
H), 7.41-7.11 (m, 13 H), 6.40 (bs, 1 H), 6.05 (bs, 1 H), 4.91 (d,
J ) 15 Hz, 1 Η), 4.20 (bs, 1 Η), 3.63 (m, 1 Η), 3.58-3.20 (m,
3 H), 3.01-2.72 (m, 3 H), 2.60 (d, J ) 15 Hz, 1 H), 2.32 (dd, J
) 10 Hz, J ) 15 Hz, 1 H); DCI MS (NH3) m/z 442 (M + H+,
100). Anal. (C27H27N3O3‚0.15DMSO) C, H, N.
(4R,5S,6R,7R)-1,3-d ia za -1-[(N-h yd r oxyca r b oxim id a -
m id e)p h en ylm eth yl]-4,7-bis-(p h en ylm eth yl)-5-(h yd r oxy)-
bicyclo[4.1.0]h ep ta n -2-on e (102): 1H NMR (CDCl3/CD3OD)
δ 7.46-7.01 (m, 14 H), 5.01 (d, J ) 15 Hz, 1 Η), 3.60-3.20 (m,
4 H), 3.04-2.71 (m, 3 H), 2.56 (d, J ) 15 Hz, 1 H), 2.37 (dd, J
) 10 Hz, J ) 15 Hz, 1 H); ESI MS (NH3) m/z 457 (M + H+,
100). Anal. (C27H28N4O3‚0.85EtOAc) C, H, N.
(4R,5R,6R)-Tetr ah ydr o-1,3,6-tr is-[ph en ylm eth yl]-5-oxo-
4-(2-p h en ylet h yl)-2(1H )-p yr im id in on e (106): 1H NMR
(CDCl3) δ 7.46-7.00 (m, 20 H), 5.36 (d, J ) 15 Hz, 1 H), 4.92
(d, J ) 14 Hz, 1 H), 3.96 (d, J ) 14 Hz, 1 H), 3.95 (m, 1 H),
3.72 (d, J ) 15 Hz, 1 H), 3.55 (m, 1 H), 3.09 (d, J ) 7 Hz, 1 H),
2.60 (abx m, 1 H), 2.41 (abx m, 1 H), 1.99 (m, 2 H); 13C NMR
(CDCl3) 204.0, 156.8, 140.2, 136.8, 136.7, 135.7, 129.5, 128.8,
128.7, 128.6, 128.5, 128.4, 128.3, 127.8, 127.6, 127.2, 126.1,
64.2, 62.0, 49.3, 49.1, 36.8, 32.1, 30.8; CIMS (NH3) m/z 506
(M + NH4+, 100).
1
120 °C; H NMR (CDCl3) δ 10.40 (bs, 1 H), 7.40-6.98 (m, 14
H), 6.66-6.49 (m, 3 H), 5.51 (d, J ) 15 Hz, 1 H), 5.36 (d, J )
15 Hz, 1 H), 3.93 (d, J ) 15 Hz, 1 H), 3.76 (d, J ) 15 Hz, 1 H),
3.65 (bs, 2 H), 3.60-3.23 (m, 3 H), 2.96 (m, 2 H), 2.45 (m, 2
H), 2.45 (s, 3 H), 2.40 (bs, 1 H), 1.90 (m, 1 H), 1.65 (m, 1 H);
ESI MS (NH3) m/z 280.9 (M + 2H+2, 100). Anal. (C35H37N5O2‚
0.5H2O) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-1-(3-a m in op h en yl-m eth yl)-3-[3-
cyn a n op h en yl-m et h yl]-4-(2-p h en ylet h yl)-5-h yd r oxy-6-
(p h en ylm eth yl)-2(1H)-p yr im id in on e (95): mp 102.0-104.0
°C; 1H NMR (CD3OD) δ 7.68 (bs, 1 H), 7.62-7.58 (m, 2 H),
7.53-7.45 (m, 2 H), 7.39-7.12 (m, 11 H), 7.03-6.97 (m, 2 H),
5.00 (d, J ) 15 Hz, 1 H), 4.26 (d, J ) 16 Hz, 1 H), 4.19 (d, J )
16 Hz, 1 H), 3.94-3.86 (m, 1 H), 3.73-3.68 (m, 1 H), 3.61 (m,
1 H), 3.29 (bs, 2 H), 3.18-3.17 (m, 1 H), 2.96-2.89 (m, 1 H),
2.81-2.75 (m, 1 H), 2.36-2.31 (m, 2 H); 2.03-1.90 (m, 1 H),
1.71-1.65 (m, 1 H); CI MS 548 (M + NH4+, 100). HRMS calcd
for C34H35N4O2 (M + H+), 531.2760; found, 531.2753. Anal.
(C34H34N4O2‚0.33(i-C3H7OH)‚CD3OD) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-1-(3-a m in op h en yl-m eth yl)-3-[3-
a m in o-1H -in d a zol-5-ylm et h yl]-4-(2-p h en ylet h yl)-5-h y-
d r oxy-6-(p h en ylm et h yl)-2(1H )-p yr im id in on e (96): mp
1
129.0-132.0 °C; H NMR (CDCl3) δ 7.36 (bs, 1 H), 7.25-6.91
(m, 13 H), 6.63-6.55 (m, 3 H), 5.48 (d, J ) 16 Hz, 1 H), 5.27
(d, J ) 15 Hz, 1 H), 3.90 (d, J ) 14 Hz, 1 H), 3.87 (d, J ) 15
Hz, 1 H), 3.54-3.43 (m, 2 H), 3.40-3.30 (m, 1 H), 3.00-2.83
(m, 2 H), 2.43-2.37 (m, 2 H), 1.96-1.82 (m, 1 H), 1.65-1.52
(m, 1 H); ESI MS 281.4 (M + 2H+2, 100). HRMS calcd for
C
34H37N6O2 (M + H+), 561.2978; found, 561.2968. Anal.
(C34H36N6O2) C, H, N.
(4R,5R,6R)-Tetr a h yd r o-1-(3-a m in op h en yl-m eth yl)-3-[3-
car boxam idoph en yl-m eth yl]-4-(2-ph en yleth yl)-5-h ydr oxy-
6-(p h en ylm eth yl)-2(1H)-p yr im id in on e (97): mp 197.0-
1
109.0 °C; H NMR (CD3OD) δ 7.92 (bs, 1 H), 7.79-7.76 (m, 1
H), 7.55-7.52 (m, 1 H), 7.45-7.40 (m, 1 H), 7.29-6.99 (m, 11
H), 6.63-6.59 (m, 1 H), 6.50 (bs, 1 H), 6.45-6.43 (m, 1 H),
5.13 (d, J ) 15 Hz, 1 H), 5.11 (d, J ) 15 Hz, 1 H), 4.25 (d, J )
15 Hz, 1 H), 3.60-3.57 (m, 1 H); 3.44-3.42 (m, 1 H), 3.32-
3.24 (m, 2 H), 3.20-3.16 (m, 1 H), 2.88-2.86 (m, 1 H), 2.69-
2.63 (m, 1 H), 2.40-2.34 (m, 2 H), 1.87-1.81 (m, 2 H); ESI
MS 549.5 (M + H+, 100). HRMS calcd for C34H37N4O3 (M +
H+), 549.2866; found, 549.2866. Anal. (C34H36N4O3‚0.15DMSO)
C, H, N.
Ack n ow led gm en t. We thank R. M. Klabe for the
Ki data, M. M. Rayner and B. Cordova for the IC90 data,
Drs. J . Calabrese and N. J ones (Dupont CR&D) for
X-ray structure of 33, and the ADME group for bio-
availability data. We also thank all the members of the
HIVPR working group for their valuable contributions
to the program. Finally, we thank Drs. Thomas R.
Sharpe, Alex J ohnson, C. Nicholas Hodge, Soo S. Ko,
George L. Trainor, and Paul S. Anderson for their
support.
(4R,5R,6R)-Tet r a h yd r o-1-(3-a m in op h en yl-m et h yl)-3-
[(3-(N-h yd r oxyca r b oxim id a m id e)p h en yl-m et h yl]-4-(2-
p h en yleth yl)-5-h yd r oxy-6-(p h en ylm eth yl)-2(1H)-p yr im -
id in on e (98): mp 115.0-117.0 °C; 1H NMR (CDCl3) δ 7.69
(bs, 1 H), 7.29-6.90 (m, 13 H);, 6.56-6.50 (m, 3 H), 5.21 (d, J
) 15 Hz, 1 H), 5.19 (d, J ) 15 Hz, 1 H), 5.05 (bs, 1 H), 3.97 (d,
J ) 15 Hz, 1 H), 3.83 (d, J ) 15 Hz, 1 H), 3.42-3.38 (m, 2 H),
3.16-3.15 (m, 1 H), 2.88-2.75 (m, 2 H);, 2.23-2.24 (m, 2 H),
1.89-1.81 (m, 1 H), 1.55-1.46 (m, 1 H); ESI MS 282.9 (M +
2H+2, 100). HRMS calcd for C34H38N5O3 (M + H+), 564.2975;
found, 564.2999. Anal. (C34H37N5O3‚0.3C4H8O2) C, H, N.
(4R,5S,6R,7R)-1,3-d ia za -4,7-b is-(p h en ylm et h yl)-5-(h y-
d r oxy)-bicyclo[4.1.0]h ep ta n -2-on e (99). Meth od 1. A solu-
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