Betulinic acid derivatives: A new class of specific inhibitors of human immunodeficiency virus type 1 entry

Article abstract of DOI:10.1021/jm950669u

A novel series of ω-aminoalkanoic acid derivatives of betulinic acid were synthesized and evaluated for their activity against human immunodeficiency virus (HIV). The anti-HIV-1 activity of several members of this new series was found to be in the nanomolar range in CEM 4 and MT-4 cell cultures. The optimization of the ω-aminoalkanoic acid side chain is described. The presence of an amide function within the side chain was found important for optimal activity. RPR 103611 (14g), a statine derivative, was found to be inactive against HIV-1 protease, reverse transcriptase, and integrase as well as on gp120/CD4 binding. 'Time of addition' experiments suggested interaction with an early step of HIV-1 replication. As syncytium formation, but not virus-cell binding, seems to be affected, betulinic acid derivatives are assumed to interact with the postbinding virus-cell fusion process.

Full text of DOI:10.1021/jm950669u

J . Med. Chem. 1996, 39, 1069-1083
1069
Betu lin ic Acid Der iva tives: A New Cla ss of Sp ecific In h ibitor s of Hu m a n
Im m u n od eficien cy Vir u s Typ e 1 En tr y
Franc¸oise Soler, Christe`le Poujade, Michel Evers, J ean-Christophe Carry, Yvette He´nin, Anne Bousseau,
Thierry Huet, Rudi Pauwels,† Erik De Clercq,† J ean-Franc¸ois Mayaux, J ean-Bernard Le Pecq, and
Norbert Dereu*
Rhoˆne-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, De´partements de Chimie Pharmaceutique,
Biologie, et Biotechnologie, 13, quai J ules Guesde, B.P. 14, 94403 Vitry sur Seine, Cedex, France, and
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Received September 11, 1995X
A novel series of ω-aminoalkanoic acid derivatives of betulinic acid were synthesized and
evaluated for their activity against human immunodeficiency virus (HIV). The anti-HIV-1
activity of several members of this new series was found to be in the nanomolar range in CEM
4 and MT-4 cell cultures. The optimization of the ω-aminoalkanoic acid side chain is described.
The presence of an amide function within the side chain was found important for optimal
activity. RPR 103611 (14g), a statine derivative, was found to be inactive against HIV-1
protease, reverse transcriptase, and integrase as well as on gp120/CD4 binding. “Time of
addition” experiments suggested interaction with an early step of HIV-1 replication. As
syncytium formation, but not virus-cell binding, seems to be affected, betulinic acid derivatives
are assumed to interact with the postbinding virus-cell fusion process.
Several triterpenes have been described as weak
antiviral compounds. Glycyrrhetinic acids display some
limited activity against a whole range of viruses includ-
ing human immunodeficiency virus type 1 (HIV-1).1
Salaspermic acid2 and suberol3 inhibit HIV-1 in H9 cells
in the upper micromolar range. Furthermore, bile acid
derivatives were found slightly active (at 10-4 M)
against HIV-1 in MT-4 cells.4 We have previously
described new derivatives of betulinic acid as potent
inhibitors of the cytopathicity of HIV-1 in CEM 4 and
MT-4 cells without affecting HIV-1 reverse transcriptase
(RT) or protease activity.5 Even minor modifications on
the lupane backbone (ring A, isopropylidene) strongly
affect potency. In the present report we describe the
synthesis and structure-activity relationship for this
class of compounds obtained by modifying the alkanoic
acid side chain. RPR 103611 (14g), a statine derivative,
was selected for further investigations.
lowed by aqueous workup, allowed isolation of inter-
mediates 6a -g (Scheme 1).
The intermediate diesters 7a -j obtained by coupling
acids 6a -g with an ester of an ω-aminoalkanoic acid
in the presence of EDCI/HOBT gave access, after
saponification, to compounds 8a -j with yields ranging
from 23% to 100% (Scheme 2). N-[3â-Acetoxylup-20(29)-
en-28-oyl]-8-aminooctanoic acid (6g) was used as the
common precursor for the synthesis of R-amino acid
derivatives 11a -j (Scheme 3), â-amino acids 14a -f, as
well as γ-amino acids 14g-j (Scheme 4), and derivatives
of amino benzoic acids (Scheme 5).
N-[3â-Acet oxylu p-20(29)-en -28-oyl]-1,7-dia m in o-
heptane (17) is the key intermediate for the synthesis
of compounds 19a -f, containing an inverted amide
function in the lateral chain (Scheme 6). Intermediate
17 was obtained in 85% yield by reacting acid chloride
1b with an excess of 1,7-diaminoheptane. The reaction
of 17 with a variety of dicarboxylic acid monoesters in
the presence of HOBT/EDCI led to the corresponding
esters 18a -c,e,f, except in the case of the phthalic acid
derivative which led to the phthalimido compound 18d .
Alkaline hydrolysis of 18a -f gave the desired “reversed
amides” 19a -f.
Ch em istr y
Betulinic acid 1a is the common starting material for
the synthesis of the described molecules. After protec-
tion of the hydroxyl group in the 3 position as an
acetate, the carboxylic acid function in position 17 was
activated as its acid chloride. Reaction of 3â-acetoxylup-
20(29)-en-28-oyl chloride (1b) with an alkyl ester of an
ω-aminoalkanoic acid (2a -l) in the presence of triethyl-
amine afforded the resulting diesters 4a -l with yields
ranging from 39% to 91%. Saponification of diesters
4a -l with aqueous sodium hydroxide in a methanol/
THF mixture, at room temperature, resulted in the
concomitant cleavage of the terminal ester function and
the regeneration of the free hydroxyl group in position
3, yielding the corresponding ω-aminoalkanoic acid
amide of betulinic acids 5a -l (Scheme 1). Alternatively,
reacting 3â-acetoxylup-20(29)-en-28-oyl chloride (1b)
with an ω-aminoalkanoic acid trimethylsilyl ester, fol-
Resu lts a n d Discu ssion s
The structure-activity relationship for this series of
betulinic acid derivatives was investigated by evaluating
the inhibition of HIV-1 infection in CEM 4 and MT-4
cell cultures (Tables 1-3). Fifty percent cell culture
inhibitory concentrations (IC50) are defined as those
which inhibit HIV-1-induced cytopathicity by 50%.
Viral cytopathicity is assessed by the number of viable
cells, following staining with 3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyltetrazolium bromide.5d First, a system-
atic study was undertaken in order to determine the
optimal chain length (Table 1, compounds 5a -l). In-
cremental lengthening of the chain showed that signifi-
cant activity was observed for the compounds positioned
between the (betulinylamino)octanoic and (betulinyl-
† Rega Institute for Medical Research.
X Abstract published in Advance ACS Abstracts, February 1, 1996.
0022-2623/96/1839-1069$12.00/0 © 1996 American Chemical Society

1070 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Soler et al.
Sch em e 1
Sch em e 2
Sch em e 5
were found to be considerably less active than the
undecylic acid lead compound 5j. This result is not
unexpected as these compounds are in fact amides of
the poorly active or inactive molecules 5a -f. However,
compound 8g, the glycine amide of the active octanoic
acid derivative 5g, was found to be more potent than
both the lead compound and the parent compound 5g.
Replacement of the glycine by â-alanine (8h ), 3-amino-
propionic acid (8i), or 4-aminobutyric acid (8j) resulted
in very potent derivatives with an IC50 around 100 nM.
Inverting the amide moiety within the chain led to
compounds 19a -c which were found to be somewhat
more potent than the latter molecules with IC50 values
ranging between 20 and 95 nM. (Betulinylamino)-
octanoic acid amides of small R-amino acids such as the
alanine derivative 11a and derivative 11b displayed
improved activity compared to the parent glycine de-
rivative 8g (Table 2). This indicates the presence of a
small lipophilic space accommodating one or two methyl
groups. Indeed, the presence of more bulky groups such
as in compounds 11g-j leads to only poorly active
molecules. The presence of an amide (asparagine
derivative 11g) or an amine (lysine derivative 11i) is
particularly unfavorable and leads to virtually inactive
molecules.
Sch em e 3
Sch em e 4
A difference was observed between the L- and D-serine
derivatives 11c,d . Compared to 11a ,b, a 2-3-fold drop
in activity was observed for the L-serine derivative (IC50
) 250 nM), whereas a 20-fold drop was observed for the
D-serine derivative (IC50 ) 1900 nM). The sarcosine
derivative 11e and the proline derivative 11f retained
a relatively good level of activity. This result contrasts
with the complete loss of activity observed upon N-
methylation of the amide moiety at position 19 of the
triterpene.5 For the â-amino acids, small substituents
in the R or â position (compounds 14b-e) or even the
more bulky phenyl substituent in the â position (com-
pound 14a ) did not significantly influence activity. In
all these cases IC50 values around 100 nM were ob-
served, which is identical with the activity of the parent
â-alanine derivative 8h . The cyclic compound 14f was
amino)dodecanoic acids 5g-k . The most potent com-
pound was found to be the undecylic acid derivative 5j.
The successive condensation of betulinic acid with two
aminoalkanoic acids results in the introduction of an
amide moiety at different positions within the lateral
chain (compounds 8a -j, Table 1). Compounds 8a -f

Betulinic AcidssInhibitors of HIV-1 Entry
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1071
Sch em e 6
found somewhat less active (IC50 ) 185 nM) than the
latter compounds.
for 14a , the aminobenzoic acid derivatives 16b,c, and
the benzenedicarboxylic acid derivatives 19e,f. The
selectivity index for 14a , 16b,c, and 19e,f was respec-
tively 70, 37, 14, 5, and 27 on CEM 4 cells. Most of the
reported derivatives were tested against HIV-2 (ROD)
and found inactive. Surprisingly, specificity turned out
to be even higher than that for the “non nucleoside” RT
inhibitors such as TIBO or nevirapine, as much less
activity or even no activity was observed with 14g
against NDK and ELI, two HIV-1 isolates of African
origin. No inhibition was noted with 14g against RT,
integrase, or protease at concentrations well above IC50
concentrations in cellular assays (data not shown).
Compound 14g (RPR 103611) was used for further
mechanistic studies. Details are reported elsewhere.5d
Delaying the addition of compounds after the exposure
of MT-4 cells to HIV-1 (“time of addition” experiment)
for more than 1 h was sufficient to lose activity. This
suggests the interference with an early step of the virus
life cycle. Several experiments ruled out an interference
with the binding of gp120 to the CD4 molecule, as shown
either by biochemical assays (ELISA or BIAcore) or in
a cellular context (FACS analysis). Moreover, betulinic
acid derivatives were able to block efficiently syncytium
formation of CD4 cells mediated by the HIV-1 envelope
glycoproteins. This observation was made in many
systems involving different cell lines (lymphoid or
fibroblastic) either with the whole virus or by vectors
expressing only the HIV-1 envelope (gp120 and gp41)
at its surface. Thus, betulinic acid derivatives may be
postulated to interfere with the virus-cell fusion process
required for virus entry into the cells.
As observed for â-amino acids, substituents on the
γ-amino acid side chain modulated anti-HIV-1 potency
only to a slight extent. The statine derivative 14g was
found to display the best overall activity with an IC50
of 50 ( 26 nM (CEM 4) and 40 ( 19 nM (MT-4).
However, the virtually equipotent monosubstituted
derivatives 14h ,i and parent compound 8i demonstrate
the very limited influence of substituents at least on the
screening values. Nevirapine, tested under the same
conditions, displayed an IC50 value of 84 ( 21 nM (CEM
4). As exemplified by compounds 14a ,j, a good level of
activity was observed for molecules containing a sub-
stituted phenyl moiety. We therefore synthesized de-
rivatives of o-, m-, and p-aminobenzoic acids (compounds
16a -c; Table 3). The ortho aminobenzoic acid deriva-
tive 16a was found inactive, probably due to steric
hindrance as observed for the phenylalanine derivative
11j. The activities of the meta- and para-substituted
derivatives 16b,c were found in the same range as for
the best compounds 14g,l,k and 19a -c. A similar result
was obtained for the reversed amides obtained from
benzenedicarboxylic acids (compounds 19d -f).
Selectivity index (CC50) for 14g was in excess of 100.
The precise assessment of cytotoxic concentrations for
many betulinic acid derivatives was hampered by the
limited solubility of these compounds above 10 µM
(formation of gels). For the routine assessment of
activity, the highest concentration used was generally
3 µM. At this highest concentration, most of our
derivatives displayed no or marginal cytotoxicity except

1072 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Soler et al.
Ta ble 1
anti-HIV-1 activity
IC50 (nM)
no.
m
n
Y
mp, °C
anal.a
formula
CEM cells
MT-4 cells
5a
5b
5c
5d
5e
5f
5g
5h
5i
1
2
3
4
5
6
7
8
9
10
11
12
1
2
3
4
5
6
7
0
0
0
0
0
0
0
0
0
0
0
0
7
6
5
4
3
2
1
2
3
4
1
2
3
-
-
-
-
-
-
-
-
-
-
-
-
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
NHCO
NHCO
NHCO
260 dec
204
180
160
135
134
140
162
100
115
182-185
168
130
130
140-145
132
206
194
132
138
168
152
140
128
C,H,fN
C,H,N
C,bH,N
C,H,N
C,cH,N
C,H,N
C,H,N
C,H,gN
C,H,N
C,H,N
C,dH,hN
C,H,N
C,H,N
C,H,N
C,H,iN
C,H,N
C,H,jN
C,H,N
C,H,N
C,H,N
C,eH,N
C,H,N
C,H,N
C,H,N
C,H,N
C32H51NO4
na
na
na
nt
nt
nt
nt
2400
4300
465
3400
420
443
250
nt
nt
nt
nt
nt
nt
nt
156
94
129
nt
C
33H53NO4
C34H55NO4
35H57NO4
C36H59NO4
C
46%k
2300
12 000
750
420
600
230
550
35%k
30%k
20%l
5500
4500
3000
4500
150
100
44
C
C
37H61NO4
38H63NO4
C39H65NO4
C
C
40H67NO4
41H69NO4
5j
5k
5l
C42H71NO4
C
C
C
43H73NO4
40H66N2O5
40H66N2O5
8a
8b
8c
8d
8e
8f
8g
8h
8i
C40H66N2O5
40H66N2O5
C40H66N2O5
C
C
C
C
40H66N2O5
40H66N2O5
41H68N2O5
7
7
7
7
7
7
C42H70N2O5
8j
C
C
C
C
43H72N2O5
40H66N2O5
41H68N2O5
42H70N2O5
61
50
95
20
19a
19b
19c
34
53
nt
170
a
b
Elemental analyses were within 0.4% of theory unless otherwise noted. C: calcd, 75.37; found, 76.5. c C: calcd, 75.88; found, 75.4.
C: calcd, 77.13; found, 76.4. e C: calcd, 73.86; found, 73.4. f H: calcd, 10.01; found, 10.6. C: calcd, 10.71; found, 10.2. H: calcd, 10.94;
found, 11.4. H: calcd, 10.16; found, 10.7. H: calcd, 10.16; found, 10.7. Inhibition at 1 µM, does not reach IC50
does not reach IC50. na: not active. nt: not tested.
d
g
h
i
j
k
l
. Inhibition at 0.2 µM,
tography (HPLC) was performed on reverse-phase column
Bondapack C18.
In conclusion, this new class of anti-HIV-1 compounds
seems to block a postbinding event involved in the
virus-cell fusion step. Betulinic acid derivatives rep-
resent the first low molecular weight compounds to be
suggested as fusion inhibitors. To date, only very few
fusion inhibitors have been described.6 Further studies
are underway in order to determine the precise target
within the viral envelope for RPR 103611. Current
synthetic efforts are focused toward the synthesis of
derivatives with improved oral bioavailability.
Gen er a l P r oced u r e for 4a -l: Meth yl N-[3â-Acetoxylu p -
20(29)-en -28-oyl]-11-a m in ou n d eca n oa te (4j). To a solution
of methyl 11-aminoundecanoate7 (580 mg, 2.7 mmol) and 3â-
acetoxylup-20(29)-en-28-oyl chloride (1b)8 (1.03 g, 2 mmol) in
CH2Cl2 (30 mL) was added triethylamine (0.62 mL, 4.4 mmol).
After further stirring for 12 h at room temperature, the
mixture was concentrated to dryness under reduced pressure.
Column chromatography on SiO2, eluting with i-Pr2O, afforded
1.29 g (91%) of the ester 4j (Rf ) 0.31, eluent: 15% ethyl
acetate in cycloxane).
Exp er im en ta l Section
Gen er al P r ocedu r e for 5a-l: N-[3â-Hydr oxylu p-20(29)-
en -28-oyl]-11-a m in ou n d eca n oic Acid (5j). To a solution
of 4j (1.29 g, 1.8 mmol) in methanol (8 mL) and THF (13 mL)
was added 4.5 mL of aqueous NaOH (4 N). The reaction
mixture was stirred overnight at room temperature, concen-
trated to dryness under reduced pressure, diluted with distilled
water (60 mL), and then acidified to pH ) 2 with 5 N
hydrochloric acid. After further stirring for 20 min, the solid
was collected and washed with distilled water to afford 1.2 g
(95%) of 5j as a white solid: mp 115 °C; 1H NMR (CDCl3, 400
MHz) δ 0.67 (b, J ) 9 Hz, 1H, -H in 5), 0.76 (s, 3H, -CH3), 0.82
(s, 3H, -CH3), 0.93 (s, 3H, -CH3), 0.98 (s, 6H, -CH3), 1.56 (t, J
) 11.5 Hz, 1H, -CH in 18), 1.70 (s, 3H, -CH3 in 29), 2.36 (t, J
) 7.5 Hz, 2H, -CH2-COO-), 2.44 (dt, J ) 11.5, 3 Hz, 1H, -CH
in 13), 3.14 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 3.10-3.25 and
3.31 (2m, 1H each, -CONH-CH2-), 3.20 (dd, J ) 11, 5 Hz, 1H,
-CH in 3), 4.59 and 4.74 (2bs, 1H each, dCH2), 5.60 (t, J ) 5.5
Hz, 1H, -CONH-); IR (KBr, cm-1) ν 3390, 3250-2250, 3075,
2925, 2855, 1710, 1640, 1515, 1465, 1450, 1385, 1375, 1045,
1035, 88; MS (EI) 639, 624, 611, 596, 81 (base).
Melting points were recorded on a Kofler apparatus and are
uncorrected. Proton nuclear magnetic resonance spectra were
obtained on a Brucker WM (250 MHz), AC (400 MHz), or AM
(400 MHz) spectrometer, and proton chemical shifts are
relative to tetramethylsilane as an internal standard. The
following abbreviations are used to denote signal patterns: s
) singlet, d ) doublet, t ) triplet, m ) multiplet, dd ) double
doublet, dt ) double triplet, b ) broad. Mass spectra were
recorded on a Finnigan 3300 spectrometer (EI at 70 eV), a
Nermag R 10.10B instrument (DCI, using NH3 as a reactant
gas), or a Kratos MS50 instrument (FAB or LSIMS). Where
elementary analyses are reported only by symbols of the
elements in the tables, results were within 0.4% of the
theoretical values. All reactions, as well as column chroma-
tography, were monitored routinely with the aid of thin layer
chromatography with precoated silica gel 60 F256 from Merck.
Visualization was achieved with color response upon spraying
with a solution of p-anisaldehyde, sulfuric acid, and acetic acid
in ethanol (5:7:2:200, v/v). High-performance liquid chroma-

Betulinic AcidssInhibitors of HIV-1 Entry
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1073
Ta ble 2
anti-HIV-1 activity IC50 (nM)
no.
RNHR′
mp, °C
120
140
>260
252
120
142
140
120
hygrosc
116
135-140
130
formula
anal.a
CEM cells
MT-4 cells
11a
11b
11c
11d
11e
11f
11g
11h
11i
Ala
C41H68N2O5
C42H70N2O5
41H68N2O6
C,H,hN
C,H,iN
C,H,N
92
133
250
1900
250
640
18 000
950
10 000
2000
85
62
89
250
nt
333
58
nt
nt
nt
nt
47
nt
NH2C(Me)2COOH
Ser
D-Ser
sarcosine
Pro
Asp
Asn
Lys
Phe
C
C41H68N2O6
C,H,jN
C,H,N
C
C
C
C
C
C
41H68N2O6
43H70N2O5
42H68N2O7
42H69N3O6
44H75N3O5
47H72N2O5
C47H72N2O5
C42H70N2O5
C42H70N2O5
C41H67FN2O5
C42H67F3N2O5
C44H72N2O5
C,bH,N
C,cH,kN
C,dH,N
C,eH,eNe
C,H,N
11j
14a
14b
14c
14d
14e
14f
racNH2CH(C6H5)CH2COOH
racNH2CH2CH(CH3)COOH
racNH2CH(CH3)CH2COOH
racNH2CHFCH2COOH
racNH2CH(CF3)CH2COOH
C,H,N
C,H,N
130
130
95
155
134
132
140
184
C,fH,lN
C,gH,mN
C,H,N
nt
nt
nt
nt
C,H,N
185
14g
14h
14i
14j
14k
(S,S)-NH2CH(i-Bu)CHOHCH2COOH
racNH2CH2CHOHCH2COOH
(R)-NH2CH(i-Bu)CH2CH2COOH
(S,S)-NH2CH(Bz)CHOHCH2COOH
(3R,4S)-NH2CH(i-Bu)CHOHCH2COOH
158
130
116
138
130
C46H78N2O6
C42H70N2O6
C46H78N2O5
C49H76N2O6
C46H78N2O6
C,H,nN
C,H,N
C,H,N
C,H,N
C,H,N
50
200
52
130
50
40
33
85
33
44
nevirapine
84
a
b
Elemental analyses were within 0.4% of theory unless otherwise noted. C: calcd, 71.89; found, 68.8. c C: calcd, 70.75; found, 70.1.
C: calcd, 70.85; found, 61.7. e Deliquescent. f C: calcd, 73.86; found, 74.9. C: calcd, 71.68; found, 71.1. H: calcd, 10.25; found, 10.9.
H: calcd, 10.33; found, 10.8. H: calcd, 10.25; found, 11.0. H: calcd, 9.61; found, 10.3. H: calcd, 10.33; found, 11.0. H: calcd, 9.83;
found, 10.6. H: calcd, 10.41; found, 11.1. nt: not tested.
d
i
g
h
j
k
l
m
n
Ta ble 3
anti-HIV-1 activity IC50 (nM)
no.
Y
R-
mp, °C
formula
anal.
CEM cells
MT-4 cells
16a
19d
16b
19e
16c
19f
CONH
NHCO
CONH
NHCO
CONH
NHCO
o-COOHC6H4
o-COOHC6H4
m-COOHC6H4
m-COOHC6H4
p-COOHC6H4
p-COOHC6H4
116
156
160 dec
154
167
C45H68N2O5
C45H68N2O5
C45H68N2O5
C45H68N2O5
C45H68N2O5
C45H68N2O5
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
C,H,N
na
1800
80
105
70
nt
nt
nt
40
26
22
190
110
Eth yl N-[3â-Acetoxylu p-20(29)-en -28-oyl]glycin ate (4a).
Following the procedure described for 4j, 1b (2.1 g, 4 mmol)
was reacted with ethyl glycinate hydrochloride (5.60 g, 40
mmol). The crude product was purified by column chroma-
tography eluting with 18% CH2Cl2 in diisopropyl ether to yield
900 mg (38.8%) of 4a as a white powder: mp 120 °C (Rf )
0.40, eluent: 25% ethyl acetate in cyclohexane).
N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]glycin e (5a ). Fol-
lowing the procedure described for 5j, 4a (870 mg, 1.5 mmol)
led to 460 mg (59.7%) of 5a as a beige powder: mp 260 °C; 1H
NMR (CDCl3, 400 MHz) δ 0.70 (bd, J ) 9 Hz, 1H, -H in 5),
0.78 (s, 3H, -CH3), 0.84 (s, 3H, -CH3), 0.94 (s, 3H, -CH3), 0.98
(s, 3H, -CH3), 1.00 (s, 3H, -CH3), 1.61 (t, J ) 11.5 Hz, 1H, -CH
in 18), 1.70 (s, 3H, -CH3 in 29), 2.42 (dt, J ) 11.5, 3 Hz, 1H,
-CH in 13), 3.09 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 3.21 (dd,
J ) 10, 5 Hz, 1H, -CH in 3), 3.3 (b, 1H, -OH in 3), 4.07 (limit
ab, J ) 18, 5 Hz, 1H, N-CH2-COO-), 4.61 and 4.75 (2bs, 1H
each, dCH2), 6.14 (t, J ) 5 Hz, 1H, -CONH-); IR (KBr, cm-1
)
ν 3420, 3075, 2940, 2870, 1635, 1605, 1510, 1450, 1400, 1375,
1045, 1030, 880; MS (FAB) 557, 536.
Eth yl N-[3â-Acetoxylu p -20(29)-en -28-oyl]-3-a m in op r o-
p a n oa te (4b). Following the procedure described for 4j, 1b
(1 g, 2 mmol) was reacted with ethyl 3-aminopropanoate
hydrochloride (340 mg, 2.2 mmol) and triethylamine (0.62 mL,
4.4 mmol). The crude product was purified by column chro-
matography eluting with 25% ethyl acetate in cyclohexane to
yield 1 g (83%) of 4b as a white meringue (Rf ) 0.32, eluent:
30% ethyl acetate in cyclohexane).

1074 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Soler et al.
N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-3-a m in op r op a n -
oic Acid (5b). Following the procedure described for 5j, 4b
(1 g 1.6 mmol) led to 800 mg (95%) of 5b as a white powder:
mp 204 °C; IR (KBr, cm-1) ν 3430, 3200-2250, 3090, 1720,
1640, 1515, 1380, 1375, 1045, 880; MS (EI) 528, 203, 189
(base), 175, 159, 119.
3.8 mmol). The crude product was purified by preparative
HPLC eluting with CH3CN-THF-H2O (70:15:15) to yield 750
mg (79%) of 4g as a white meringue (Rf ) 0.34, eluent: 20%
ethyl acetate in cyclohexane).
N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-8-a m in ooct a n oic
Acid (5g). Following the procedure described for 5j, ester 4g
(800 mg, 1.3 mmol) led to 750 mg (100%) of 5g as a white
powder: mp 135 °C; IR (KBr, cm-1) ν 3400, 3125-2250, 3075,
2930, 2860, 1710, 1640, 1515, 1465, 1455, 1390, 1375, 1045,
1035, 885; MS (EI) 597, 569, 554, 411, 135 (base).
E t h yl
N-[3â-Acet oxylu p -20(29)-en -28-oyl]-4-a m in o-
bu tyr a te (4c). Following the procedure described for 4j, 1b
(1.38 g, 2.68 mmol) was reacted with ethyl 4-aminobutyrate
hydrochloride (520 mg, 3.1 mmol) and triethylamine (0.87 mL,
6.2 mmol). The crude product was purified by column chro-
matography eluting with diisopropyl ether to yield 1 g (61%)
of 4c as a white meringue (Rf ) 0.46, eluent: diisopropyl
ether).
E t h yl
N-[3â-Acet oxylu p -20(29)-en -28-oyl]-9-a m in o-
n on a n oa te (4h ). Following the prodecure described for 4j,
acid chloride 1b (1.03 g, 2 mmol) was reacted with ethyl
9-aminononanoate11 (442 mg, 2.2 mmol). The crude product
was purified by column chromatography eluting with 20%
ethyl acetate in cyclohexane to yield 810 mg (59%) of 4h as a
white meringue (Rf ) 0.30, eluent: 20% ethyl acetate in
cyclohexane).
N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-4-a m in ob u t yr ic
Acid (5c). Following the procedure described for 5j, 4c (1 g,
1.63 mmol) led to 870 mg (98.5%) of 5c as a white powder:
mp 180 °C (Rf ) 0.34 eluent: 10% methanol in chloroform);
IR (KBr, cm-1) ν 3425, 3200-2250, 3080, 2950, 2870, 1720,
1640, 1515, 1380, 1375, 1045, 880; MS (DCI) 542 (base); MS
(EI) 203, 189, 159, 119, 105, 81, 69 (base).
Met h yl N-[3â-Acet oxylu p -20(29)-en -28-oyl]-5-a m in o-
p en ta n oa te (4d ). Following the procedure described for 4j,
acid chloride 1b (1.71 g, 3.3 mmol) was reacted with methyl
5-aminopentanoate hydrochloride9 (650 mg, 3.8 mmol) and
triethylamine (1.07 mL, 7.6 mmol). The crude product was
purified by column chromatography eluting with diisopropyl
ether to yield 1.1 g (54%) of 4d as a white meringue (Rf ) 0.35,
eluent:diisopropyl ether).
N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-5-a m in op en t a n -
oic Acid (5d ). Following the procedure described for 5j, ester
4d (1.1 g, 1.8 mmol) led to 820 mg (82%) of 5d as a white
powder: mp 160 °C (Rf ) 0.42, eluent: 10% methanol in
chloroform); IR (KBr, cm-1) ν 3400, 3200-2250, 3090, 2940,
2870, 1710, 1640, 1515, 1380, 1375, 1045, 885; MS (EI) 555,
540, 527, 512, 411, 334, 237, 203, 189 (base), 175, 119, 95.
Met h yl N-[3â-Acet oxylu p -20(29)-en -28-oyl]-6-a m in o-
h exa n oa te (4e). Following the procedure described for 4j,
acid chloride 1b (1.03 g, 2 mmol) was reacted with methyl
6-aminohexanoate hydrochloride (380 mg, 2.1 mmol) and
triethylamine (0.53 mL, 3.8 mmol). The crude product was
purified by preparative HPLC eluting with CH3CN-THF-
H2O (75:15:10) to yield 834 mg (82%) of 4e as a white meringue
(Rf ) 0.28, eluent: 20% ethyl acetate in cyclohexane).
N -[3â-H yd r oxylu p -20(29)-e n -28-oyl]-6-a m in oh e xa n -
oic Acid (5e). Following the procedure described for 5j, ester
4e (800 mg, 1.3 mmol) led to 750 mg (100%) of 5e as a white
powder: mp 135 °C; IR (KBr, cm-1) ν 3410, 3100-2250, 3075,
2945, 2870, 1715, 1640, 1530, 1455, 1390, 1380, 1045, 1035,
885; MS (EI) 569, 541, 526, 411, 189 (base).
Met h yl N-[3â-Acet oxylu p -20(29)-en -28-oyl]-7-a m in o-
h ep ta n oa te (4f). Following the procedure described for 4j,
acid chloride 1b (1.03 g, 2.0 mmol) was reacted with methyl
7-aminoheptanoate hydrochloride10 (320 mg, 2.2 mmol) and
triethylamine (0.62 mL, 4.4 mmol). The crude product was
purified by column chromatography eluting with 20% ethyl
acetate in cyclohexane to yield 930 mg (73%) of 4f as a white
meringue (Rf ) 0.28, eluent: 20% ethyl acetate in cyclohex-
ane).
N-[3â-H yd r oylu p -20(29)-en -28-oyl]-9-a m in on on a n oic
Acid (5h ). Following the procedure described for 5j, ester 4h
(680 mg, 1 mmol) led to 290 mg (47%) of 5h as a white solid:
mp 162 °C; IR (KBr, cm-1) ν 3420, 3125-2250, 3070, 2940,
2860, 1710, 1640, 1520, 1465, 1455, 1390, 1375, 1045, 1035,
885; MS (DCI) 612 (base).
Meth yl N-[3â-Acetoxylu p -20(29)-en -28-oyl]-10-a m in o-
d eca n oa te (4i). Following the procedure described for 4j, acid
chloride 1b (570 mg, 1.1 mmol) was reacted with methyl 10-
aminodecanoate hydrochloride12 (310 mg, 1.26 mmol) and
triethylamine (0.35 mL, 2.5 mmol). The crude product was
purified by column chromatography eluting with 30% ethyl
acetate in cyclohexane to yield 600 mg (80%) of 4i as a white
meringue (Rf ) 0.74, eluent: 40% ethyl acetate in cyclohex-
ane).
N -[3 â-H y d r o x y l u p -2 0 (2 9 )-e n -2 8 -o y l ]-1 0 -a m i n o -
d eca n oa te (5i). Following the procedure described for 5j,
ester 4i (600 mg, 0.87mmol) led to 530 mg (98%) of 5i as a
white meringue: mp 100 °C; IR (KBr, cm-1) ν 3400, 3125-
2250, 3075, 2935, 2860, 1710, 1640, 1525, 1465, 1455, 1390,
1375, 1045, 1035, 885; MS (EI) 625, 610, 597, 582, 411, 69
(base).
Meth yl N-[3â-Acetoxylu p -20(29)-en -28-oyl]-12-a m in o-
d od eca n oa te (4k ). Following the procedure described for 4j,
acid chloride 1b (660 mg, 1.27 mmol) was reacted with methyl
12-aminododecanoate hydrochloride13 (374 mg, 1.4 mmol) and
triethylamine (0.40 mL, 2.8 mmol). The crude product was
purified by column chromatography eluting with 20% ethyl
acetate in cyclohexane to yield 647 mg (71%) of 4k as a white
meringue (Rf ) 0.32, eluent: 20% ethyl acetate in cyclohex-
ane).
N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-12-a m in od od ec-
a n oic Acid (5k ). Following the procedure described for 5j,
ester 4k (525 mg, 0.8 mmol) led to 466 mg (88.8%) of 5k as a
white meringue: mp 182 °C; IR (KBr, cm-1) ν 3385, 3200-
2250, 3075, 2925, 2855, 1720, 1640, 1530, 1465, 1455, 1390,
1375, 1045, 1030, 885; MS (EI) 654, 653, 626, 611, 410, 189
(base).
Meth yl N-[3â-Acetoxylu p -20(29)-en -28-oyl]-13-a m in o-
tr id eca n oa te (4l). To a solution of 13-aminotridecanoic acid14
(330 mg, 1.24 mmol) in methanol (15 mL) cooled to -20 °C,
was added thionyl chloride (0.14 mL, 1.86 mmol), and stirring
was maintained for 12 h at room temperature. The mixture
was concentrated to dryness under reduced pressure to yield
285 mg (71%) of methyl 13-aminotridecanoate as a white
powder used without purification in the next step.
Following the procedure described for 4j, acid chloride 1b
(447 mg, 0.86 mmol) was reacted with methyl 13-aminotri-
decanoate hydrochloride (265 mg, 0.95 mmol) and triethyl-
amine (0.27 mL, 1.9 mmol). The crude product was purified
by column chromatography eluting with 20% ethyl acetate in
cyclohexane to yield 567 mg (90%) of 4l as a white meringue
(Rf ) 0.35, eluent: 20% ethyl acetate in cyclohexane).
N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-12-a m in ot r id ec-
a n oic Acid (5l). Following the procedure described for 5j,
ester 4l (530 mg, 0.73 mmol) led to 470 mg (92%) of 5l as a
white meringue: mp 168 °C; IR (KBr, cm-1) ν 3450, 3375,
3070, 2925, 2850, 1640, 1525, 1465, 1455, 1390, 1375, 1045,
N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-7-a m in oh ep t a n -
oic Acid (5f). Following the procedure described for 5j, ester
4f (930 mg, 1.4 mmol) led to 740 mg (90%) of 5f as a white
powder: mp 134 °C (Rf ) 0.33, eluent: 20% ethyl acetate in
cyclohexane); IR (KBr, cm-1) ν 3400, 3200-2250, 3080, 2950,
2870, 1720, 1640, 1515, 1380, 1375, 1045, 880.
Met h yl N-[3â-Acet oxylu p -20(29)-en -28-oyl]-8-a m in o-
octa n oa te (4g). To a solution of 8-aminooctanoic acid11 (1 g,
6.2 mmol) in methanol (40 mL) cooled to -20 °C was added
thionyl chloride (0.7 mL, 9.5 mmol), and stirring was main-
tained for 12 h at room temperature. The mixture was
concentrated to dryness under reduced pressure to yield 1.29
g (100%) of methyl 8-aminooctanoate hydrochloride as a white
powder used without purification in the next step.
Following the procedure described for 4j, acid chloride 1b
(1.03 g, 2.0 mmol) was reacted with methyl 8-aminooctanoate
hydrochloride (490 mg, 2.1 mmol) and triethylamine (0.53 mL,

Betulinic AcidssInhibitors of HIV-1 Entry
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1075
1030, 885; MS (EI) 649, 639, 624, 410, 349, 189, 135, 121, 95,
81, 69, 43 (base).
-CONH-CH2-CONH-), 4.28 (b, 1H, -OH in 3), 4.53 and 4.65
(2bs, 1H each, dCH2), 7.55 (t, J ) 6 Hz, 1H, -CONH-), 7.93 (t,
J ) 6 Hz, 1H, -CONH- in 17), 12 (b, 1H, -COOH); IR (KBr,
cm-1) ν 3450, 3150-2300, 3075, 2940, 2865, 1710, 1640, 1515,
1470, 1455, 1390, 1380, 1045, 1035, 885; MS (EI) 654, 452,
410, 217, 189, 160, 113 (base), 95.
N-[3â-Acetoxylu p -20(29)-en -28-oyl]-â-a la n in e (6b). Fol-
lowing the procedure described for 6g, acid chloride 1b (1.1 g,
2.2 mmol) was reacted with â-alanine (0.23 g, 2.6 mmol). The
crude product was purified by column chromatography eluting
with 2% methanol in CH2Cl2 to yield 800 mg (64%) of 6b as a
white meringue (Rf ) 0.26, eluent: 5% methanol in CH2Cl2).
Meth yl N′-[N-[3â-Acetoxylu p-20(29)-en -28-oyl]-3-am in o-
p r op a n oyl]-7-a m in oh ep ta n oa te (7b). Following the pro-
cedure described for 7g, 6b (0.8 g, 1.4 mmol) was reacted with
methyl 7-aminoheptanoate hydrochloride (0.32 g, 1.62 mmol).
The crude product was purified by column chromatography
on silica gel eluting with 50% ethyl acetate in cyclohexane to
yield 900 mg (90%) of 7b as a white meringue (Rf ) 0.18,
eluent: cyclohexane).
N′-[N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-3-a m in op r o-
p a n oyl]-7-a m in oh ep ta n oic Acid (8b). Following the pro-
cedure described for 8g, ester 7b (0.85 g, 1.19 mmol) led to
720 mg (92%) of 8b as a white powder: mp 130 °C; IR (KBr,
cm-1) ν 3420, 3150-2250, 3075, 2940, 2870, 1715, 1640, 1520,
1465, 1455, 1390, 1375, 1045, 1030, 885; MS (DCI) 655 (base).
N-[3â-Acetoxylu p-20(29)-en -28-oyl]-4-am in obu tyr ic Acid
(6c). Following the procedure described for 6g, acid chloride
1b (2.1 g, 4.0 mmol) was reacted with 4-aminobutyric acid (470
mg, 4.4 mmol). The crude product was purified by column
chromatography eluting with 5% methanol in CH2Cl2 to yield
1.3 g (55.6%) of 6c as a white meringue (Rf ) 0.20, eluent:
5% methanol in CH2Cl2).
Gen er a l P r oced u r e: N-[3â-Acetoxylu p -20(29)-en -28-
oyl]-8-a m in ooct a n oic Acid (6g). A mixture of 8-amino-
octanoic acid (12.92 g, 81 mmol) and trimethylsilyl chloride
(14.34 g, 13.2 mmol) in CH2Cl2 (835 mL) was heated at reflux
for 4 h and cooled to room temperature. Then were added
successively a solution of acid chloride 1 (32 g, 61.9 mmol) in
CH2Cl2 (450 mL), over 15 min, and triethylamine (37.1 mL),
over 10 min. After further strirring for 12 h, the solvent was
evaporated to dryness under reduced pressure and purified
by column chromatography on silica gel eluting with 17%
CH2Cl2 and 25% ethyl acetate in cyclohexane to afford 21 g
(62%) of the acid 6g as a white meringue (Rf ) 0.30, eluent:
40% ethyl acetate in cyclohexane).
Gen er a l P r oced u r e: Met h yl N′-[N-[3â-Acet oxylu p -
20(29)-en -28-oyl]-8-a m in oocta n oyl]glycin a te (7g). A solu-
tion of 6g (1.13 g, 1.8 mmol) in CH2Cl2 (100 mL) was treated
successively with methyl glycinate hydrochloride (0.25 g, 2
mmol), 1-hydroxybenzotriazole (0.24 g, 1.8 mmol), 1-[3-(di-
methylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.69
g, 3.6 mmol), and triethylamine (0.5 mL). After further
stirring for 15 h at room temperature, distilled water (100 mL)
was added. The organic layer was separated, dried over
magnesium sulfate, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
using 30% cyclohexane in ethyl acetate as eluent to yield 1.2
g (93%) of the ester 7g as a white meringue (Rf ) 0.30,
eluent: 50% ethyl acetate in cyclohexane).
Gen er a l P r oced u r e: N′-[N-[3â-Hyd r oxylu p -20(29)-en -
28-oyl]-8-a m in oocta n oyl]glycin e (8g). A solution of 7g (1.2
g, 1.17 mmol) in methanol (17 mL) and THF (8.5 mL) was
treated with aqueous NaOH (4 N, 2.1 mL). The reaction
mixture was stirred overnight at room temperature, concen-
trated to dryness under reduced pressure, diluted with metha-
nol (10 mL) and water (40 mL), and acidified with hydrochloric
acid (5 N, 2.5 mL). After further stirring for 30 min, the solid
was collected and washed with distilled water to afford 1.03 g
(93%) of 8g as a white solid: mp 132 °C; 1H NMR (CDCl3 with
a few drops of CD3COOD-d4, 400 MHz) δ 0.63 (b, J ) 9 Hz,
1H, -H in 5), 0.70 (s, 3H, -CH3), 0.77 (s, 3H, -CH3), 0.88 (s, 3H,
-CH3), 0.91 (s, 3H, -CH3), 0.94 (s, 3H, -CH3), 1.54 (t, J ) 11.5
Hz, 1H, -CH in 18), 1.65 (s, 3H, -CH3 in 29), 2.24 (t, J ) 7.5
Hz, 2H, -CH2-CONH-), 2.36 (dt, J ) 11.5, 3 Hz, 1H, -CH in
13), 3.02 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 3.05-3.25 (m,
2H, -CONH-CH2-), 3.20 (m, 1H, -CH in 3), 4.05 (s, 2H, -CONH-
CH2-COO-), 4.53 and 4.67 (2bs, 1H each, dCH2); 1H NMR
(CDCl3, 400 MHz) δ 4.05 (d, J ) 5 Hz, 2H, -CONH-CH2-
COO-), 5.80 (t, J ) 5.5 Hz, 1H, -CONH- in 17), 6.65 (t, J ) 5
Hz, 1H, -CONH-); IR (KBr, cm-1) ν 3420, 3130-2200, 3070,
2940, 2860, 1730, 1635, 1525, 1460, 1450, 1385 and 1370, 1040
and 1030, 880; MS (EI) 654, 639, 626, 611, 410, 189, 55 (base).
N-[3â-Acetoxylu p -20(29)-en -28-oyl]glycin e (6a ). Fol-
lowing the procedure described for 6g, acid chloride 1b (5.17
g, 11.0 mmol) was reacted with glycine (0.83 g, 11.0 mmol).
The crude product was purified by column chromatography
eluting with 10% methanol in CH2Cl2 to yield 3.49 g (62.9%)
of 6a as a white solid (Rf ) 0.50, eluent: 10% methanol in
CH2Cl2).
Meth yl N′-[N-[3â-Acetoxylu p-20(29)-en -28-oyl]-4-am in o-
bu ta n oyl]-6-a m in oh exa n oa te (7c). Following the procedure
described for 7g, acid 6c (1.3 g, 2.2 mmol) was reacted with
methyl 6-aminohexanoate hydrochloride (0.44 g, 2.44 mmol).
The crude product was purified by column chromatography
on silica gel eluting with 2% ethyl acetate in CH2Cl2 followed
by 50% ethyl acetate in CH2Cl2 to yield 1.17 g (75%) of 7c as
a white meringue (Rf ) 0.61, eluent: 10% methanol in CH2Cl2).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-4-a m in o -
bu ta n oyl]-6-a m in oh exa n oic Acid (8c). Following the pro-
cedure described for 8g, ester 7c (1.1 g, 1.54 mmol) led to 1.0
g (100%) of 8c as a white solid: mp 140-145 °C; IR (KBr, cm-1
)
ν 3400, 3150-2300, 3075, 2940, 2865, 1710, 1635, 1530, 1450,
1390, 1375, 1040, 1030, 880; MS (EI) 626, 217, 200, 114 (base).
N -[3â-Ace t oxylu p -20(29)-e n -28-oyl]-5-a m in op e n t a n -
oic Acid (6d ). Following the procedure described for 6g, acid
chloride 1b (2.1 g, 4.0 mmol) was reacted with 5-aminopen-
tanoic acid (530 mg, 4.4 mmol). The crude product was
purified by column chromatography eluting with 5% methanol
in CH2Cl2 to yield 1.1 g (46%) of 6d as a white meringue (Rf )
0.24, eluent: 5% methanol in CH2Cl2).
Meth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-5-a m i-
n op en ta n oyl]-5-a m in op en ta n oa te (7d ). Following the pro-
cedure described for 7g, acid 6d (1.1 g, 1.8 mmol) was reacted
with methyl 5-aminopentanoate hydrochloride (330 mg, 2.0
mmol). The crude product was purified by column chroma-
tography on silica gel eluting with 2% ethyl acetate in CH2Cl2
followed by 50% ethyl acetate in CH2Cl2 to yield 1.0 g (86%)
of 7d as a white meringue (Rf ) 0.61, eluent: 10% methanol
in CH2Cl2).
N′-[N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-5-a m in op en -
ta n oyl]-5-a m in op en ta n oic Acid (8d ). Following the pro-
cedure described for 8g, ester 7d (1.0 g, 1.4 mmol) led to 780
mg (85%) of 8d as a white solid: mp 132 °C; IR (KBr, cm-1) ν
3400, 3150-2300, 3075, 2940, 2865, 1710, 1635, 1530, 1450,
1390, 1375, 1040, 1030, 880; MS (DCI) 655 (base).
N-[3â-Acet oxylu p -20(29)-en -28-oyl]-6-a m in oh exa n oic
Acid (6e). Following the procedure described for 6g, acid
chloride 1b (1.54 g, 3.0 mmol) was reacted with 6-aminohex-
anoic acid (440 mg, 3.3 mmol). The crude product was purified
by column chromatography eluting with 40% ethyl acetate in
cyclohexane to yield 1.1 g (61%) of 6e as a white meringue (Rf
) 0.20, eluent: 40% ethyl acetate in cyclohexane).
Meth yl N′-[N-[3â-Acetoxylu p-20(29)-en -28-oyl]-2-am in o-
a cetyl]-8-a m in oocta n oa te (7a ). Following the procedure
described for 7g, 6a (1.0 g, 1.8 mmol) was reacted with methyl
8-aminooctanoate hydrochloride (0.41 g, 2.0 mmol). The crude
product was purified by column chromatography on silica gel
eluting with 50% ethyl acetate in cyclohexane to yield 1.2 g
(93%) of 7a as a white meringue (Rf ) 0.33, eluent: 10%
methanol in CH2Cl2).
N′-[N-[3â-Hydr oxylu p-20(29)-en -28-oyl]-2-am in oacetyl]-
8-a m in oocta n oic Acid (8a ). Following the procedure de-
scribed for 8g, ester 7a (1.2 g, 1.7 mmol) led to 880 mg (79.5%)
1
of 8a as a white solid: mp 130 °C; H NMR (DMSO-d6, 300
MHz) δ 0.65 (m, 1H, -H in 5), 0.66 (s, 3H, -CH3), 0.76 (s, 3H,
-CH3), 0.83 (s, 3H, -CH3), 0.90 (s, 3H, -CH3), 0.94 (s, 3H, -CH3),
1.45 (m, 1H, -CH in 18), 1.65 (s, 3H, -CH3 in 29), 2.19 (t, J )
7.5 Hz, 2H, -CH2-COO-), 2.53 (m, 1H, -CH in 13), 2.90-3.10
(m, 4H, -CONH-CH2-, -CH in 3, -CH in 19), 3.57 (limit ab, 2H,

1076 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Soler et al.
Meth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-6-a m i-
n oh exa n oyl]-4-a m in obu tyr a te (7e). Following the proce-
dure described for 7g, acid 6e (1.1 g, 1.8 mmol) was reacted
with methyl 4-aminobutyrate hydrochloride (300 mg, 1.98
mmol). The resulting product (1.7 g, 100%) was used without
further purification in the next step (Rf ) 0.41, eluent: 40%
ethyl acetate in cyclohexane).
N′-[N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-6-a m in oh ex-
a n oyl]-4-a m in obu tyr ic Acid (8e). Following the procedure
described for 8g, ester 7e (1.7 g, 1.8 mmol) led to 1.36 g of
crude 8e which was purified by column chromatography on
silica gel eluting with 3% methanol in ethyl acetate, yielding
3.6 g (31%) of pure 8e as a white solid: mp 206 °C; IR (KBr,
cm-1) ν 3400, 3150-2250, 3075, 2940, 2865, 1715, 1640, 1450,
1390, 1375, 1045, 1035, 885; MS (DCI) 655 (base); MS (EI)
189, 95, 44 (base).
N -[3â-Ace t oxylu p -20(29)-e n -28-oyl]-7-a m in oh e p t a n -
oic Acid (6f). Following the procedure described for 6g, acid
chloride 1b (1.54 g, 3.0 mmol) was reacted with 7-aminohep-
tanoic acid (480 mg, 3.3 mmol). The crude product was
purified by column chromatography eluting with 40% ethyl
acetate in cyclohexane to yield 1.08 g (58%) of 6f as a white
meringue (Rf ) 0.26, eluent: 40% ethyl acetate in cyclohex-
ane).
Eth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-7-a m in o-
h ep ta n oyl]-3-a m in op r op ion a te (7f). Following the proce-
dure described for 7g, acid 6f (1.08 g, 1.7 mmol) was reacted
with ethyl â-alaninate hydrochloride (290 mg, 1.9 mmol). The
crude product was purified by column chromatography on
silica gel eluting with 20% ethyl acetate in CH2Cl2 to yield
470 mg (45%) of 7f as a white solid (Rf ) 0.40, eluent: 50%
ethyl acetate in CH2Cl2).
N′-[N-[3â-H yd r oxylu p -20(29)-en -28-oyl]-7-a m in oh ep -
ta n oyl]-3-a m in op r op ion ic Acid (8f). Following the proce-
dure described for 8g, ester 7f (0.47 g, 0.65 mmol) led to 150
mg (36%) of 8f as a white solid: mp 194 °C; 1H NMR (CDCl3,
400 MHz) δ 0.68 (b, J ) 9 Hz, 1H, -H in 5), 0.77 (s, 3H, -CH3),
0.83 (s, 3H, -CH3), 0.93 (s, 3H, -CH3), 0.97 (s, 6H, -CH3), 1.60
(t, J ) 12 Hz, 1H, -CH in 18), 1.68 (s, 3H, -CH3 in 29), 2.20 (t,
J ) 7.5 Hz, 2H, -CH2-CONH-), 2.40 (dt, J ) 12, 3 Hz, 1H, -CH
in 13), 2.64 (t, J ) 6 Hz, 2H, -CH2-COO-), 3.07 (dt, J ) 12, 4
Hz, 1H, -CH in 19), 3.18 (dd, J ) 11, 5 Hz, 1H, -CH in 3),
3.15-3.35 (m, 2H, -CONH-CH2- in 17), 3.53 (q, J ) 6 Hz, 2H,
-CONH-CH2-), 4.60 and 4.73 (2bs, 1H each, dCH2), 5.84 (t, J
) 6 Hz, 1H, -CONH- in 17), 6.27 (t, J ) 6 Hz: 1H, -CONH-);
IR (KBr, cm-1) ν 3400, 3150 to 2250, 3075, 2940, 2865, 1725,
1640, 1530, 1460, 1450, 1390, 1375, 1045, 1035, 885. MS(DCI)
655 (base).
Eth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-8-a m in o-
octa n oyl]-3-a m in op r op a n oa te (7h ). Following the proce-
dure described for 7g, acid 6g (900 mg, 1.4 mmol) was reacted
with ethyl â-alaninate hydrochloride (250 mg, 1.6 mmol). The
crude product was purified by column chromatography on
silica gel eluting with 2% methanol in CH2Cl2 to yield 810 mg
(78%) of 7h as a white meringue (Rf ) 0.21, eluent: 50% ethyl
acetate in cyclohexane).
described for 7g, acid 6g (500 mg, 0.78 mmol) was reacted with
methyl 4-aminobutyrate hydrochloride (140 mg, 0.93 mmol).
The resulting product (410 mg, 72%) was used without further
purification in the next step (Rf ) 0.74, eluent: ethyl acetate).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-4-a m in obu tyr ic Acid (8i). Following the proce-
dure described for 8g, ester 7i (400 mg, 0.58 mmol) led to 370
mg of crude 8i which was purified by column chromatography
on silica gel eluting with 30% cyclohexane in ethyl acetate,
yielding 90 mg (23%) of pure 8i as a white solid: mp 168 °C;
1H NMR (CDCl3, 400 MHz) δ 0.66 (bd, J ) 9 Hz, 1H, -H in 5),
0.74 (s, 3H, -CH3), 0.82 (s, 3H, -CH3), 0.92 (s, 3H, -CH3), 0.96
(s, 6H, -CH3), 1.58 (t, J ) 11.5 Hz, 1H, -CH in 18), 1.70 (s, 3H,
-CH3in 29), 2.19 (t, J ) 7.5 Hz, 2H, -CH2-CONH-), 2.39 (dt, J
) 11.5, 3 Hz, 1H, -CH in 13), 2.44 (t, J ) 7 Hz, 2H, -CH2-
COO-), 3.08 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 3.10-3.35 (m,
2H, -CONH-CH2- in 17), 3.18 (dd, J ) 10, 5 Hz, 1H, -CH in 3),
3.35 (m, 2H, -CONH-CH2-), 4.58 and 4.72 (2bs, 1H each,
dCH2), 5.72 (t, J ) 5.5 Hz, 1H, -CONH- in 17), 6.28 (b, 1H,
-CONH-); IR (KBr, cm-1) ν 3380, 3075, 2935, 2865, 2750-2250,
1715, 1635, 1535, 1450, 1390, 1375, 1040, 1030, 885; MS
(LSIMS) 683 (base).
Meth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-5-a m in op en ta n oa te (7j). Following the pro-
cedure described for 7g, acid 6g (2.0 g, 3.1 mmol) was reacted
with methyl 5-aminopentanoate hydrochloride (630 mg, 3.7
mmol). The crude product was purified by column chroma-
tography on silica gel eluting with 50% ethyl acetate in
cyclohexane to yield 500 mg (21%) of 7j as a white solid (Rf )
0.14, eluent: 50% ethyl acetate in cyclohexane).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-5-a m in op en ta n oic Acid (8j). Following the pro-
cedure described for 8g, ester 7j (480 mg, 0.64 mmol) led to
178 mg (40%) of 8j as a white solid: mp 152 °C; 1H NMR
(DMSO-d6, 400 MHz) δ 0.65 (m, 1H, -H in 5), 0.67 (s, 3H, -CH3),
0.78 (s, 3H, -CH3), 0.87 (s, 3H, -CH3), 0.90 (s, 3H, -CH3), 0.95
(s, 3H, -CH3), 1.45 (m, 1H, -CH in 18), 1.65 (s, 3H, -CH3 in
29), 2.05 (t, J ) 7.5 Hz: -CH2-CONH-), 2.22 (t, J ) 7.5 Hz:
-CH2-COO-), 2.57 (m, 1H, -CH in 13), 2.85-3.20 (m, 4H,
-CONH-CH2- in 17, -CH in 3 and -CH in 19), 3.04 (m, 2H, -CH2-
NHCO-), 4.30 (b, 1H, -OH in 3), 4.56 and 4.67 (2bs, 1H each,
dCH2), 7.55 (t, J ) 5.5 Hz, 1H, -CONH- in 17), 7.76 (t, J ) 6
Hz, 1H, -CONH-); MS (LSIMS) 677, 655 (base), 637, 611.
Ben zyl N′-[N-[3â-Acetoxylu p-20(29)-en -28-oyl]-8-am in o-
octa n oyl]-L-a la n in a te 10a . Following the procedure de-
scribed for 7g, acid 6g (500 mg, 0.78 mmol) was reacted with
benzyl L-alaninate hydrochloride (200 mg, 0.92 mmol). The
crude product was purified by column chromatography on
silica gel eluting with 30% ethyl acetate in cyclohexane
followed by 45% ethyl acetate in cyclohexane to yield 550 mg
(87%) of 10a as a white meringue (Rf ) 0.48, eluent: 50% ethyl
acetate in cyclohexane).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-L-a la n in e (11a ). Following the procedure de-
scribed for 8g, 10a (520 mg, 0.65 mmol) led to 380 mg of crude
11a which was purified by column chromatography on silica
gel eluting with 20% methanol in ethyl acetate, yielding 150
mg (34.5%) of pure 11a as a white solid: mp 120 °C; 1H NMR
(DMSO-d6, 400 MHz) δ 0.65 (m, 1H, -H in 5), 0.68 (s, 3H, -CH3),
0.79 (s, 3H, -CH3), 0.86 (s, 3H, -CH3), 0.90 (s, 3H, -CH3), 0.94
(s, 3H, -CH3), 1.25 (d, J ) 7.5 Hz, 3H, CH-CH3), 1.47 (t, J )
11.5 Hz, 1H, -CH in 13), 1.66 (s, 3H, -CH3 in 29), 2.10 (t, J )
7.5 Hz, 2H, -CH2-CONH-), 2.58 (bt, J ) 11.5 Hz, 1H, -CH in
13), 2.85-3.05 and 3.10 (2m, 1H each, -CONH-CH2-), 2.98 (m,
1H, -CH in 3), 3.03 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 4.15
(quintuplet, J ) 7.5 Hz, 1H, CH-COO-), 4.29 (b, 1H, -OH), 4.55
and 4.67 (2bs, 1H each, dCH2), 7.56 (t, J ) 5.5 Hz, 1H, -CONH-
in 17), 8.00 (d, J ) 7.5 Hz, 1H, -CONH-); IR (KBr, cm-1) ν
3410, 3120-2250, 3070, 2940 and 2870, 1730, 1640, 1525,
1455, 1390 and 1375, 1045 and 1035, 880; MS (DCI) 726, 708
(base).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-3-a m in op r op a n oic Acid (8h ). Following the
procedure described for 8g, ester 7h (810 mg, 1.1 mmol) led
to 660 mg of crude 8h which was purified by column chroma-
tography on silica gel eluting with 10% methanol in CH2Cl2,
yielding 370 mg (50.7%) of pure 8h as a white powder: mp
1
138 °C; H NMR (CDCl3, 400 MHz) δ 0.68 (bd, J ) 9 Hz, 1H,
-H in 5), 0.77 (s, 3H, -CH3), 0.83 (s, 3H, -CH3), 0.93 (s, 3H,
-CH3), 0.98 (s, 6H, -CH3), 1.59 (t, J ) 11.5 Hz, 1H, -CH in 18),
1.70 (s, 3H, -CH3 in 29), 2.19 (t, J ) 7.5 Hz, 2H, -CH2-CO-N-),
2.40 (dt, J ) 11.5, 3 Hz, 1H, -CH in 13), 2.61 (t, J ) 6 Hz, 2H,
-CH2-COO-), 3.10 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 3.10-
3.25 (m, 3H, -CONH-CH2- in 17, -CH in 3), 3.53 (m, 2H,
-CONH-CH2-), 4.60 and 4.74 (2bs, 1H each, dCH2), 5.82 (t, J
) 6 Hz, 1H, -CONH- in 17), 6.31 (t, J ) 6 Hz, 1H, -CONH-);
IR (KBr, cm-1) ν 3400, 3070, 2940, 2860, 2750-2250, 1715,
1635, 1530, 1450, 1390, 1375, 1045, 1035, 885; MS (EI) 668,
640, 410, 350, 189, 119, 95, 69 (base).
Meth yl N′-[N-[3â-Acetoxylu p-20(29)-en -28-oyl]-8-am in o-
octa n oyl]-2-a m in oisobu tyr a te (10b). Following the proce-
dure described for 7g, acid 6g (500 mg, 0.78 mmol) was reacted
with methyl 2-aminoisobutyrate hydrochloride15 (125 mg, 0.8
mmol). The crude product was purified by column chroma-
Meth yl N′-[N-[3â-Acetoxylu p-20(29)-en -28-oyl]-8-am in o-
octa n oyl]-4-a m in obu tyr a te (7i). Following the procedure

Betulinic AcidssInhibitors of HIV-1 Entry
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1077
tography on silica gel eluting with 50% ethyl acetate in
cyclohexane to yield 310 mg (54%) of 10b as a white meringue
(Rf ) 0.3, eluent: 50% ethyl acetate in cyclohexane).
510 mg (88%) of 10e as a white meringue (Rf ) 0.29, eluent:
15% ethyl acetate in CH2Cl2).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]sa r cosin e (11e). Following the procedure de-
scribed for 8g, ester 10e (490 mg, 0.66 mmol) led to 420 mg
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-2-a m in oisobu tyr ic Acid (11b). Following the
procedure described for 8g, ester 10b (300 mg, 0.4 mmol) led
to 270 mg (99%) of 11b as a white solid: mp 140 °C; 1H NMR
(CDCl3, 400 MHz) δ 0.69 (bd, J ) 9 Hz, 1H, -H in 5), 0.78 (s,
3H, -CH3), 0.84 (s, 3H, -CH3), 0.96 (s, 3H, -CH3), 0.99 (s, 6H,
-CH3), 1.59 (t, J ) 11.5 Hz, 1H, -CH in 18), 1.60 [s, 6H,
C(CH3)2], 1.70 (s, 3H, -CH3 in 29), 2.19 (t, J ) 7.5 Hz, 2H,
-CH2-CONH-), 2.43 (dt, J ) 11.5, 3.5 Hz, 1H, -CH in 13), 3.14
(dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 3.10-3.20 and 3.28 (2m,
1H each, -CONH-CH2-), 3.20 (dd, J ) 11, 5 Hz, 1H, -CH in 3),
4.60 and 4.74 (2bs, 1H each, dCH2), 5.67 (t, J ) 5.5 Hz, 1H,
-CONH- in 17), 6.17 (s, 1H, -CONH-); IR (KBr, cm-1) ν 3400,
3125-2250, 3070, 2940 and 2865, 1730, 1640, 1525, 1455, 1390
and 1375, 1045 and 1030, 885; MS (DCI) 683 (base), 665.
Meth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-L-ser in a te (10c). Following the procedure de-
scribed for 7g, acid 6g (1.5 g, 2.4 mmol) was reacted with
methyl L-serinate hydrochloride (440 mg, 2.8 mmol). The
resulting solid (1.58 g, mp 132 °C) was used without further
purification in the next step.
1
(95%) of 11e as a white solid: mp 120 °C; H NMR (DMSO-
d6, at temperature of 373 K, 400 MHz) δ 0.67 (m, 1H, -H in 5),
0.71 (s, 3H, -CH3), 0.83 (s, 3H, -CH3), 0.92 (s, 6H, -CH3), 0.95
(s, 3H, -CH3), 1.49 (t, J ) 11.5 Hz, 1H, -CH in 18), 1.67 (s, 3H,
-CH3 in 29), 2.29 (b, 2H, -CH2-CON-), 2.62 (dt, J ) 11.5, 3 Hz,
1H, -CH in 13), 2.8-3.10 (b, 3H, N-CH3), 2.85-3.10 and 3.13
(2m, 1H each, -CONH-CH2-), 2.90-3.10 (m, 2H, -CH in 3, -CH
in 19), 4.00 (s, 1H, N-CH2-COO-), 4.56 and 4.68 (2bs, 1H each,
dCH2), 7.07 (t, J ) 5.5 Hz, 1H, -CONH- in 17); IR (KBr, cm-1
)
ν 3420, 3150, 2250, 3075, 2945, 2870, 1740, 1640, 1525, 1450,
1390, 1365, 1045, 1035, 880; MS (LSIMS) 695 (base).
Meth yl N′-[N-[3â-Acetoxylu p-20(29)-en -28-oyl]-8-am in o-
octa n oyl]-L-p r olin a te (10f). Following the procedure de-
scribed for 7g, acid 6g (500 mg, 0.78 mmol) was reacted with
methyl L-prolinate hydrochloride (150 mg, 0.86 mmol). The
crude product was purified by column chromatography on
silica gel eluting with 50% ethyl acetate in cyclohexane to yield
600 mg (100%) of 10f as a white meringue (Rf ) 0.32, eluent:
50% ethyl acetate in cyclohexane).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-L-ser in e (11c). Following the procedure described
for 8g, ester 10c (1.58 g, 2.13 mmol) led to 1.2 g of crude 11c
which was purified by column chromatography on silica gel
eluting with 50% cyclohexane in ethyl acetate, yielding 210
mg (14%) of pure 11c as a white meringue: mp >260 °C (Rf )
0.10, eluent: CHCl3-MeOH-20% ammonia, 24:6:1); 1H NMR
(DMSO-d6, 400 MHz) δ 0.62 (m, 1H, -H in 5), 0.64 (s, 3H, -CH3),
0.76 (s, 3H, -CH3), 0.83 (s, 3H, -CH3), 0.87 (s, 3H, -CH3), 0.91
(s, 3H, -CH3), 1.43 (t, J ) 12.5 Hz, 1H, -CH in 18), 1.62 (s, 3H,
-CH3 in 29), 2.13 (t, J ) 7.5 Hz, 2H, -CH2-CONH-), 2.55 (bt, J
) 12.5 Hz, 1H, -CH in 13), 2.85-3.00 and 3.09 (2m, 1H each,
-CONH-CH2-), 2.96 (m, 1H, -CH in 3), 3.02 (dt, J ) 12.5, 4
Hz, 1H, -CH in 19), 3.58 and 3.67 (2dd, J ) 12, 5 Hz, 1H each,
-CH2-O-), 4.25 (dt, J ) 8, 5 Hz, 1H, -CONH-CH-), 4.52 and
4.64 (2bs, 1H each, dCH2), 7.53 (t, J ) 5.5 Hz, 1H, -CONH- in
17), 8.03 (d, J ) 8 Hz, 1H, -CONH-); IR (KBr, cm-1) ν 3415,
3125-2250, 3075, 2940, 2865, 1735, 1635, 1530, 1465, 1455,
1390, 1375, 1045, 1035, 885; MS (DCI) 685, 667, 623, 597
(base).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-L-p r olin e (11f). Following the procedure described
for 8g, ester 10f (630 mg, 0.84 mmol) led to 422 mg (72%) of
1
11f as a white solid: mp 142 °C; H NMR (CDCl3, 400 MHz)
δ 0.67 (bd, J ) 9 Hz, 1H, -H in 5), 0.76 (s, 3H, -CH3), 0.82 (s,
3H, -CH3), 0.94 (s, 3H, -CH3), 0.96 (s, 6H, -CH3), 1.56 (t, J )
11.5 Hz, 1H, -CH in 18), 1.69 (s, 3H, -CH3 in 29), 2.02 (m, 2H,
-CH2-), 2.37 (limit ab, 2H, -CH2-CON), 2.45 (dt, J ) 11.5, 3
Hz, 1H, -CH in 13), 3.14 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19),
3.15 and 3.27 (2m, 1H each, -CONH-CH2-), 3.19 (dd, J ) 11,
5 Hz, 1H, -CH in 3), 3.48 and 3.59 (2m, 1H each, N-CH2-),
4.60 (m, 1H, CH-COO-), 4.60 and 4.74 (2bs, 1H each, dCH2),
5.67 (t, J ) 5.5 Hz, 1H, -CONH-); IR (KBr, cm-1) ν 3425, 3120
to 2250, 3075, 2940, 2865, 1720, 1640, 1525, 1465, 1455, 1390,
1375, 1045, 1035, 880; MS (DCI) 685, 598 (base).
Dib en zyl
N′-[N-[3â-Acet oxylu p -20(29)-en -28-oyl]-8-
a m in oocta n oyl]-L-a sp a r ta te (10g). Following the procedure
described for 7g, acid 6g (500 mg, 0.78 mmol) was reacted with
dibenzyl L-aspartate p-toluenesulfonate (410 mg, 0.85 mmol).
The crude product was purified by column chromatography
on silica gel eluting with 10% ethyl acetate in CH2Cl2 to yield
580 mg (79%) of 10g as a colorless glaze (Rf ) 0.40, eluent:
10% ethyl acetate in CH2Cl2).
Meth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-D-ser in a te (10d ). Following the procedure
described for 7g, acid 6g (1.0 g, 1.56 mmol) was reacted with
methyl D-serinate hydrochloride (290 mg, 1.87 mmol). The
crude product was purified by column chromatography on
silica gel eluting with 50% ethyl acetate in cyclohexane to yield
760 mg (66%) of 10d as a white solid (Rf ) 0.11, eluent: 50%
ethyl acetate in cyclohexane).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-L-a sp a r tic Acid (11g). Following the procedure
described for 8g, 10g (580 mg, 0.62 mmol) led to 263 mg (60%)
1
of 11g as a white solid: mp 140 °C; H NMR (DMSO-d6 with
a few drops of CD3COOD-d4, 400 MHz) δ 0.63 (m, 1H, -H in
5), 0.66 (s, 3H, -CH3), 0.78 (s, 3H, -CH3), 0.86 (s, 3H, -CH3),
0.89 (s, 3H, -CH3), 0.94 (s, 3H, -CH3), 1.62 (s, 3H, -CH3 in 29),
2.11 (t, J ) 7.5 Hz, 2H, -CH2-CONH-), 2.55 (m, 1H, -CH in
13), 2.59 (dd, J ) 16, 7 Hz, 1H, -H of -CH2-COO-), 2.70 (dd, J
) 16, 6 Hz, 1H, the other -H of -CH2-COO-), 2.85-3.00 and
3.10 (2m, 1H each, -CONH-CH2-), 2.97 (dd, J ) 10, 7 Hz, 1H,
-CH in 3), 3.02 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 4.54 (m,
1H, -CONH-CH-), 4.52 and 4.66 (2bs, 1H each, dCH2), 7.49
(t, J ) 5.5 Hz, -CONH- in 17), 8.10 (residual d, J ) 8 Hz,
-CONH-); IR (KBr, cm-1) ν 3420, 3125-2250, 3075, 2940, 2865,
1730, 1640, 1525, 1465, 1450, 1390, 1375, 1045, 1030, 880; MS
(DCI) 713, 695 (base).
p-Nitr op h en yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-
8-a m in oocta n oyl]-L-a sp a r a gin a te (10h ). Following the
procedure described for 7g, acid 6g (500 mg, 0.78 mmol) was
reacted with p-nitrophenyl asparaginate hydrobromide (300
mg, 0.86 mmol). The crude product was triturated with
isopropyl oxide to yield 660 mg (95%) of 10h as a white solid
(Rf ) 0.20, eluent: ethyl acetate).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-D-ser in e (11d ). Following the procedure described
for 8g, ester 10d (750 mg, 1.01 mmol) led to crude 11d which
was purified by column chromatography on silica gel eluting
with 50% cyclohexane in ethyl acetate, yielding 53 mg (8%) of
1
pure 11d as a white solid: mp 252 °C; H NMR (DMSO-d6,
400 MHz) δ 0.64 (m, 1H, -H in 5), 0.66 (s, 3H, -CH3), 0.78 (s,
3H, -CH3), 0.87 (s, 3H, -CH3), 0.89 (s, 3H, -CH3), 0.94 (s, 3H,
-CH3), 1.43 (t, J ) 12 Hz, 1H, -CH in 18), 1.64 (s, 3H, -CH3 in
29), 2.14 (t, J ) 7.5 Hz, 2H, -CH2-CONH-), 2.55 (m, 1H, -CH
in 13), 2.85-3.00 and 3.10 (2m, 1H each, -CONH-CH2-), 2.85-
3.05 (m, 1H, -CH in 3), 3.03 (dt, J ) 12, 4 Hz, 1H, -CH in 19),
3.45 and 3.61 (2dd, J ) 11, 6 Hz, 1H each, -CH2-O-), 4.04 (dt,
J ) 7, 6 Hz, 1H, -CONH-CH-), 4.28 (d, J ) 5 Hz, 1H, -OH in
3), 4.55 and 4.67 (2bs, 1H each, dCH2), 7.57 (t, J ) 5.5 Hz,
1H, -CONH- in 17), 7.64 (d, J ) 7 Hz, 1H, -CONH-); IR (KBr,
cm-1) ν 3425, 3130-2250, 3075, 2940, 2870, 1735, 1640, 1525,
1465, 1455, 1390, 1375, 1045, 1035, 880; MS (DCI) 669 (base).
Eth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-8-a m in o-
octa n oyl]sa r cosin a te (10e). Following the procedure de-
scribed for 7g, acid 6g (500 mg, 0.78 mmol) was reacted with
ethyl sarcosinate hydrochloride (120 mg, 0.78 mmol). The
crude product was purified by column chromatography on
silica gel eluting with 15% ethyl acetate in CH2Cl2 to yield
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-L-a sp a r a gin e (11h ). Following the procedure
described for 8g, 10h (590 mg, 0.66 mmol) led to 170 mg (36%)
of 11h as a white solid: mp 120 °C (softening); 1H NMR
(DMSO-d6, 400 MHz) δ 0.65 (m, 1H, -H in 5), 0.67 (s, 3H, -CH3),

1078 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Soler et al.
0.79 (s, 3H, -CH3), 0.87 (s, 3H, -CH3), 0.90 (s, 3H, -CH3), 0.94
(s, 3H, -CH3), 1.48 (m, 1H, -CH in 18), 1.65 (s, 3H, -CH3 in
29), 2.10 (t, J ) 7 Hz, 2H, -CH2-CONH-), 2.42 (dd, J ) 16, 7
Hz, 1H, 1H of -CH2-CONH2), 2.58 (m, 1H, -CH in 13), 2.85-
3.20 (m, 2H, -CONH-CH2-), 2.98 (m, 1H, -CH in 3), 3.03 (dt, J
) 12, 4 Hz, 1H, -CH in 19), 4.39 (d, J ) 6 Hz, 1H, -OH in 3),
4.49 (q, J ) 7 Hz, 1H, -CONH-CH-), 4.55 and 4.67 (2bs, 1H
each, dCH2), 6.9 and 7.4 (2bs, 1H each, -CONH2), 7.57 (t, J )
5.5 Hz, 1H, -CONH- in 17), 8.09 (d, J ) 7 Hz, 1H, -CONH-);
IR (KBr, cm-1) ν 3420, 3100-2250, 3070, 2940, 2870, 1730,
1645, 1520, 1465, 1450, 1390, 1375, 1045, 1035, 885; MS (DCI)
694 (base), 597.
cm-1) ν 3400, 2750-2250, 3070, 3030, 2940, 2865, 1720, 1640,
1640, 1515, 1390, 1375, 1040, 1030, 885; 700; MS (LSIMS) 705,
683 (base), 665.
Meth yl (3R,S)-N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-
8-a m in oocta n oyl]-3-a m in oisobu tyr a te (13b). Following
the procedure described for 7g, acid 6g (1.0 g, 1.56 mmol) was
reacted with methyl (R,S)-3-aminoisobutyrate hydrochloride17
(240 mg, 1.56 mmol). The crude product was purified by
column chromatography on silica gel eluting with 40% cyclo-
hexane in ethyl acetate to yield 1.06 g (92%) of 13b as a white
meringue (Rf ) 0.5, eluent: 40% cyclohexane in ethyl acetate).
(3R,S)- N′-[N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-3-a m in o-isobu tyr ic Acid (14b). Following the
procedure described for 8g, ester 13b (1.04 g, 1.4 mmol) led to
Met h yl N′ꢀ-(Tr iflu or oa cet yl)-N′R-[N-[3â-a cet oxylu p -
20(29)-en -28-oyl]-8-a m in oocta n oyl]-L-lysin a te (10i). Fol-
lowing the procedure described for 7g, acid 6g (500 mg, 0.78
mmol) was reacted with methyl Nꢀ-(trifluoroacetyl)lysinate
hydrochloride (275 mg, 0.94 mmol). The crude product was
purified by column chromatography on silica gel eluting with
20% cyclohexane in ethyl acetate to yield 430 mg (71%) of 10i
as a white meringue (Rf ) 0.67, eluent: 20% cyclohexane in
ethyl acetate).
1
940 mg (98%) of 14b as a white solid: mp 130 °C; H NMR
(CDCl3 with a few drops of CD3COOD-d4, 400 MHz) δ 0.63
(bd, J ) 9 Hz, 1H, -H in 5), 0.71 (s, 3H, -CH3), 0.78 (s, 3H,
-CH3), 0.88 (s, 3H, -CH3), 0.90 (s, 3H, -CH3), 0.94 (s, 3H, -CH3),
1.16 (d, J ) 7 Hz, 3H, CH-CH3), 1.55 (t, J ) 11.5 Hz, 1H, -CH
in 18), 1.64 (s, 3H, -CH3 in 29), 2.18 (t, J ) 7.5 Hz, 2H, -CH2-
CONH-), 2.35 (dt, J ) 11.5, 3 Hz, 1H, -CH in 13), 2.71 (m, 1H,
CH-COO-), 3.03 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 3.05-
3.30 (m, 2H, -CONH-CH2- in 17), 3.20 (m, 1H, -CH in 3), 3.20
and 3.38 (2m, 1H each, -CONH-CH2-), 4.53 and 4.67 (2bs, 1H
each, dCH2), 5.92 (residual t, J ) 5.5 Hz: -CONH- in 17), 6.55
(residual m, -CONH-); IR (KBr, cm-1) ν 3400, 2750-2250,
3075, 2945, 2870, 1715, 1640, 1530, 1465, 1455, 1390, 1375,
1040, 1035, 885; MS (LSIMS) 705, 683 (base), 665.
Meth yl (3R,S)-N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-
8-a m in oocta n oyl]-3-a m in obu tyr a te (13c). Following the
procedure described for 7g, acid 6g (1.0 g, 1.6 mmol) was
reacted with methyl (R,S)-3-aminobutyrate hydrochloride18
(250 mg, 1.6 mmol). The crude product was purified by column
chromatography on silica gel eluting with 50% ethyl acetate
in cyclohexane to yield 660 mg (56%) of 13c as a colorless glaze
(Rf ) 0.16, eluent: 50% ethyl acetate in cyclohexane).
(3R,S)- N′-[N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-3-a m in obu tyr ic Acid (14c). Following the
procedure described for 8g, ester 13c (660 mg, 0.90 mmol) led
to 521 mg (85%) of 14c as a white solid: mp 134 °C; 1H NMR
(CDCl3 with a few drops of CD3COOD-d4, 400 MHz) δ 0.60
(bd, J ) 9 Hz, 1H, -H in 5), 0.65 (s, 3H, -CH3), 0.73 (s, 3H,
-CH3), 0.83 (s, 3H, -CH3), 0.85 (s, 3H, -CH3), 0.89 (s, 3H, -CH3),
1.16 (d, J ) 7 Hz, 3H, CH-CH3), 1.50 (t, J ) 11.5 Hz, 1H, -CH
in 18), 1.60 (s, 3H, -CH3 in 29), 2.12 (t, J ) 7 Hz, 2H, -CH2-
CONH-), 2.33 (dt, J ) 11.5, 3 Hz, 1H, -CH in 13), 2.48 (limit
ab, 2H, -CH2-COO-), 2.99 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19),
3.00-3.25 (m, 2H, -CONH-CH2-), 3.16 (dd, J ) 10, 6 Hz, 1H,
-CH in 3), 4.28 (m, 1H, -CONH-CH-), 4.49 and 4.62 (2bs, 1H
each, dCH2), 6.10 (residual t, J ) 5.5 Hz: -CONH- in 17), 6.70
(residual d, J ) 8 Hz, -CONH-); IR (KBr, cm-1) ν 3375, 3075,
2945, 2870, 2700-2250, 1715, 1635, 1535, 1455, 1390, 1375,
1045, 1035, 880; MS (LSIMS) 683 (base), 245.
Meth yl (3R,S)-N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-
8-a m in oocta n oyl]-3-a m in o-3-flu or op r op ion a te (13d ). To
a solution of (R,S)-3-amino-3-fluoropropanoic acid (300 mg, 2.1
mmol) in methanol (20 mL) cooled to -20 °C was added thionyl
chloride (0.23 mL, 3.1 mmol), and stirring was maintained for
12 h at room temperature. The mixture was concentrated to
dryness under reduced pressure to yield 360 mg (100%) of
methyl (R,S)-3-amino-3-fluoropropionate hydrochloride as a
white powder used without purification in the next step.
Following the procedure described for 7g, acid 6g (1.0 g, 1.6
mmol) was reacted with (R,S)-methyl 3-amino-3-fluoropropi-
onate hydrochloride (250 mg, 1.6 mmol). The crude product
was purified by column chromatography on silica gel eluting
with 50% ethyl acetate in cyclohexane to yield 1.08 g (91%) of
13d as a white meringue (Rf ) 0.26, eluent: 50% ethyl acetate
in cyclohexane).
(3R,S)- N′-[N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-3-a m in o-3-flu or op r op ion ic Acid (14d ). Fol-
lowing the procedure described for 8g, ester 13d (500 mg, 0.70
mmol) led to 400 mg (100%) of 14d as a white solid: mp 132
°C; 1H NMR (CDCl3 with a few drops of CD3COOD-d4, 300
MHz) δ 0.59 (bd, J ) 9 Hz, 1H, -H in 5), 0.65 (s, 3H, -CH3),
0.73 (s, 3H, -CH3), 0.83 (s, 3H, -CH3), 0.85 (s, 3H, -CH3), 0.88
N ′R-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-L-lysin e (11i). Following the procedure described
for 8g, 10i (420 mg, 0.48 mmol) led to 80 mg (23%) of 11i as
a white solid: mp 180 °C; IR (KBr, cm-1) ν 3400, 3150-2250,
3070, 2940, 2865, 1715, 1640, 1525, 1465, 1450, 1390, 1375,
1045, 1035, 885; MS (LSIMS) 726, 255 (base).
Meth yl N′-[N-[3â-a cetoxylu p -20(29)-en -28-oyl]-8-a m in o-
octa n oyl]-L-p h en yla la n in a te (10j). Following the procedure
described for 7g, acid 6g (500 mg, 0.78 mmol) was reacted with
methyl L-phenylalaninate hydrochloride (180 mg, 0.86 mmol).
The crude product was purified by column chromatography
on silica gel eluting with 35% ethyl acetate in cyclohexane to
yield 660 mg (100%) of 10j as a colorless glaze (Rf ) 0.68,
eluent: 50% ethyl acetate in cyclohexane).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-L-p h en yla la n in e (11j). Following the procedure
described for 8g, ester 10j (660 mg, 0.82 mmol) led to 400 mg
1
(65.5%) of 11j as a white solid: mp 116 °C; H NMR (CDCl3,
400 MHz) δ 0.68 (bd, J ) 9 Hz, 1H, -H in 5), 0.76 (s, 3H, -CH3),
0.82 (s, 3H, -CH3), 0.93 (s, 3H, -CH3), 0.97 (s, 6H, -CH3), 1.58
(t, J ) 11.5 Hz, 1H, -CH in 18), 1.68 (s, 3H, -CH3 in 29), 2.18
(t, J ) 7.5 Hz, 2H, -CH2-CONH-), 2.43 (dt, J ) 11.5, 3 Hz, 1H,
-CH in 13), 3.05-3.20 (m, 1H, -CH in 19), 3.05-3.20 and 3.25
(2m, 1H each, -CONH-CH2-), 3.12 and 3.22 (2dd, J ) 15, 7
Hz, 1H each, -CH2-C6H5), 3.20 (dd, J ) 10, 5 Hz, 1H, -CH in
3), 4.59 and 4.74 (2bs, 1H each, dCH2), 4.88 (q, J ) 7 Hz, 1H,
CH-COO-), 5.77 (t, J ) 5.5 Hz, 1H, -CONH- in 17), 6.20 (d, J
) 7 Hz, 1H, -CONH-), 7.10-7.35 (m, 5H, aromatics); IR (KBr,
cm-1) ν 3425, 3150-2250, 3070, 3030, 2940, 2865, 1740, 1640,
1520, 1495, 1455, 1390, 1375, 885, 740, 700; MS (LSIMS) 745
(base), 727.
Eth yl (3R,S)-N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-8-
a m in oocta n oyl]-3-a m in o-3-p h en ylp r op ion a te (13a ). Fol-
lowing the procedure described for 7g, acid 6g (960 mg, 1.5
mmol) was reacted with ethyl (R,S)-3-amino-3-phenylpropi-
onate hydrochloride16 (410 mg, 1.8 mmol). The crude product
was purified by column chromatography on silica gel eluting
with 20% ethyl acetate in CH2Cl2 to yield 1.02 g (83.6%) of
13a as a white meringue (Rf ) 0.76, eluent: 20% ethyl acetate
in CH2Cl2).
(3R ,S )-N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-
a m in oocta n oyl]-3-a m in o-3-p h en ylp r op ion ic Acid (14a ).
Following the procedure described for 8g, ester 13a (980 mg,
1.2 mmol) led to 820 mg (92%) of 14a as a white solid: mp
135 °C; 1H NMR (CDCl3, 400 MHz), mixture of diastereo-
isomers ) 50/50) δ 0.68 (bd, J ) 9 Hz, 1H, -H in 5), 0.78 (s,
3H, -CH3), 0.81 and 0.84 (2s, 3H, -CH3), 0.92 and 0.94 (2s, 3H,
-CH3), 1.00 (s, 6H, -CH3), 1.60 (t, J ) 11.5 Hz, 1H, -CH in 18),
1.69 (s, 3H, -CH3 in 29), 2.23 (m, 2H, -CH2-CONH-), 2.39 (m,
1H, -CH in 13), 2.88 and 3.03 (2dd, J ) 16, 6.5 Hz, 1H each,
-CH2-C6H5), 3.08 (dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 3.10-
3.35 (m, 2H, -CONH-CH2-), 3.18 (dd, J ) 10, 5 Hz, 1H, -CH in
3), 4.60 and 4.73 (2bs, 1H each, dCH2), 5.45 (m, 1H, -CONH-
CH), 5.79 (t, J ) 5.5 Hz, 1H, -CONH- in 17), 6.78 (d, J ) 8
Hz, 1H, -CONH-), 7.20-7.40 (m, 5H, aromatics); IR (KBr,

Betulinic AcidssInhibitors of HIV-1 Entry
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1079
(s, 3H, -CH3), 1.45 (t, J ) 12 Hz, 1H, -CH in 18), 1.58 (s, 3H,
-CH3 in 29), 2.14 (t, J ) 7.5 Hz, 2H, -CH2-CONH-), 2.30 (dt, J
) 12, 3 Hz, 1H, -CH in 13), 2.95 (dt, J ) 12, 4 Hz, 1H, -CH in
19), 3.00-3.25 (m, 2H, -CONH-CH2- in 17), 3.13 (dd, J ) 10,
6.5 Hz, 1H, -CH in 3), 3.50-3.85 (m, 2H, -CONH-CH2-), 4.48
and 4.62 (2bs, 1H each, dCH2), 4.98 (dt, J ) 48, 10 Hz, 1H,
CH-F), 5.85 (residual t, J ) 5.5 Hz, -CONH- in 17), 6.43
(residual m, -CONH-); IR (KBr, cm-1) ν 3450, 3390, 3200-
2250, 3075, 2940, 2865, 1745, 1637, 1525, 1380, 1375, 1040,
880.
3200-2250, 3075, 2940, 2860, 1730, 1637, 1525, 1385, 1375,
1040, 880; MS (LSIMS) 709 (base), 691.
Meth yl (3S,4S)-N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-
8-a m in o o c t a n o y l]-4-a m in o -3-h y d r o x y -6-m e t h y lh e p -
ta n oa te (13g). Following the procedure described for 7g, acid
6g (0.5 g, 0.78 mmol) was reacted with methyl (3S,4S)-4-
amino-3-hydroxy-6-methylheptanoate hydrochloride
20 (210 mg,
0.93 mmol). The resulting product (570 mg, 90%) was used
without further purification in the next step (Rf ) 0.2, eluent:
50% ethyl acetate in cyclohexane).
(3S,4S)-N′-[N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-4-a m in o-3-h yd r oxy-6-m eth ylh ep ta n oic Acid
(14g). Following the procedure described for 8g, 3S,4S ester
13g (550 mg, 0.68 mmol) led to 280 mg (56%) of 14g as a white
Meth yl (3R,S)-N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-
8-a m in oocta n oyl]-3-a m in o-4,4,4-tr iflu or obu tyr a te (13e).
To a solution of (R,S)-3-amino-4,4,4-trifluorobutyric acid (1.57
g, 10 mmol) in methanol (15 mL) cooled to -20 °C was added
thionyl chloride (3 mL), and stirring was maintained for 15 h
at room temperature. The mixture was concentrated to
dryness under reduced pressure to yield 2.0 g (96.6%) of methyl
(R,S)-3-amino-4,4,4-trifluorobutyrate hydrochloride as a white
powder: mp 104 °C.
To a solution of acid 6g (960 mg, 1.5 mmol) and triethyl-
amine (0.21 mL) in THF (4.5 mL) was added dropwise at -7
°C isobutyl chloroformate (0.2 mL, 1.54 mmol). After further
stirring at -7 °C for 30 min, a solution of methyl (R,S)-3-
amino-4,4,4-trifluorobutyrate hydrochloride (0.32 g, 1.54 mmol)
and triethylamine (0.22 mL) in a mixture of dioxane (4.5 mL)
and water (1.5 mL) was added. After further stirring for 15 h
at room temperature, the solvent was evaporated to dryness
under reduced pressure. The residue was diluted with CH2Cl2,
and the resulting solution was washed with distilled water,
dried over sodium sulfate, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
eluting with 15% ethyl acetate in CH2Cl2 to yield 560 mg
(46.7%) of 13e as a white meringue (Rf ) 0.36, eluent: 15%
ethyl acetate in CH2Cl2).
1
solid: mp 158 °C; H NMR (DMSO-d6, 400 MHz) δ 0.65 (m,
1H, -H in 5), 0.67 (s, 3H, -CH3), 0.78 (s, 3H, -CH3), 0.83 and
0.89 [2d, J ) 6.5 Hz, 3H each, -CH-(CH3)2], 0.87 (s, 3H, -CH3),
0.89 (s, 3H, -CH3), 0.93 (s, 3H, -CH3), 1.46 (t, J ) 11.5 Hz, 1H,
-CH in 18), 1.65 (s, 3H, -CH3 in 29), 2.10 (t, J ) 7.5 Hz, 2H,
-CH2-CONH-), 2.14 (dd, J ) 15, 9 Hz, 1H, 1H of -CH2-COO-),
2.30 (dd, J ) 15, 4.5 Hz, 1H, 1H of -CH2-COO-), 2.55 (m, 1H,
-CH in 13), 2.85-3.00 and 3.11 (2m, 1H each, -CONH-CH2-),
2.98 (dd, J ) 10, 6 Hz, 1H, -CH in 3), 3.03 (dt, J ) 11.5, 4 Hz,
1H, -CH in 19), 3.85 (m, 2H, -CONH-CH-CH-O-), 4.30 (b, 1H,
-OH in 3), 4.55 and 4.67 (2bs, 1H each, dCH2), 4.90 (b, 1H,
-OH), 7.38 (d, J ) 7.5 Hz, 1H, -CONH-), 7.55 (t, J ) 5.5 Hz,
1H, -CONH- in 17), 12.00 (b, 1H, -COOH-); IR (KBr, cm-1) ν
3605, 3450, 3425, 3375-3225, 2945, 2870, 1785, 1675, 1525,
1380, 1375, 1040, 885; MS (LSIMS) 755 (base) 737.
Meth yl (3R,S)-N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-
8-a m in oocta n oyl]-4-a m in o-3-h yd r oxybu tyr a te (13h ). To
a solution of (R,S)-4-amino-3-hydroxybutyric acid (1.19 g, 10
mmol) in methanol (25 mL) cooled to -20 °C was added thionyl
chloride (1.0 mL, 13.9 mmol), and stirring was maintained for
12 h at room temperature. The mixture was concentrated to
dryness under reduced pressure to yield 1.69 g (100%) of (R,S)
methyl 4-amino-3-hydroxybutyrate hydrochloride as a white
powder used without purification in the next step.
Following the procedure described for 7g, acid 6g (500 mg,
0.78 mmol) was reacted with methyl (R,S)-4-amino-3-hydroxy-
butyrate hydrochloride (135 mg, 0.8 mmol). The crude product
was purified by column chromatography on silica gel eluting
with ethyl acetate to yield 520 mg (88%) of 13h as a white
meringue (Rf ) 0.35, eluent: ethyl acetate).
(3R,S)- N′-[N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-4-a m in o-3-h yd r oxybu tyr ic Acid (14h ). Fol-
lowing the procedure described for 8g, ester 13h (50 g, 0.66
mmol) led to 460 mg (100%) of 14h as a white solid: mp 130
°C; 1H NMR (CDCl3 with a few drops of CD3COOD-d4, 400
MHz) δ 0.67 (bd, J ) 9 Hz, 1H, -H in 5), 0.75 (s, 3H, -CH3),
0.84 (s, 3H, -CH3), 0.95 (s, 3H, -CH3), 1.01 (s, 6H, -CH3), 1.60
(t, J ) 11.5 Hz, 1H, -CH in 18), 1.69 (s, 3H, -CH3 in 29), 2.25
(t, J ) 7.5 Hz, 2H, -CH2-CONH-), 2.40 (dt, J ) 11.5, 3 Hz, 1H,
-CH in 13), 2.54 (dd, J ) 17, 8 Hz, 1H, 1H of -CH2-COO-),
2.60 (dd, J ) 17, 5 Hz, 1H, the other H of -CH2-COO-), 3.08
(dt, J ) 11.5, 4 Hz, 1H, -CH in 19), 3.10-3.35 (m, 2H, -CONH-
CH2- in 17), 3.22 (dd, J ) 11, 6 Hz, 1H, -CH in 3), 3.29 (dd, J
) 15, 7 Hz, 2H, 1H of -CONH-CH2-), 3.52 (dd, J ) 15, 3 Hz,
2H, the other H of -CONH-CH2-), 4.17 (m, J ) 8, 7, 5, 3 Hz,
1H, CH-O-), 4.59 and 4.73 (2bs, 1H each, dCH2), 5.80 (residual
t, J ) 5.5 Hz, -CONH- in 17), 6.70 (residual t, J ) 6.5 Hz,
-CONH-); IR (KBr, cm-1) ν 3420, 3200-2250, 3075, 2945, 2870,
1717, 1637, 1537, 1380, 1375, 1040, 880; MS (LSIMS) 699
(base), 681, 598, 580.
Meth yl (4R)-N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-8-
a m in oocta n oyl]-4-a m in o-6-m eth ylh ep ta n oa te (13i). To a
solution of (4R)-4-amino-6-methylheptanoic acid21 (490 mg, 2.5
mmol) in methanol (8 mL) cooled to -70 °C was added thionyl
chloride (0.22 mL, 3.0 mmol), and stirring was maintained for
5 h at room temperature. The mixture was concentrated to
dryness under reduced pressure to yield 520 mg (99%) of
methyl (4R)-4-amino-6-methylheptanoate hydrochloride as a
white powder: mp 134 °C.
(3R,S)- N′-[N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-3-a m in o-4,4,4-tr iflu or obu tyr ic Acid (14e).
Following the procedure described for 8g, ester 13e (910 mg,
1.14 mmol) led to 734 mg (87%) of 14e as a white solid: mp
140 °C; 1H NMR (DMSO-d6, 400 MHz) δ 0.63 (m, 1H, -H in 5),
0.65 (s, 3H, -CH3), 0.77 (s, 3H, -CH3), 0.86 (s, 3H, -CH3), 0.89
(s, 3H, -CH3), 0.92 (s, 3H, -CH3), 1.474 (t, J ) 11.5 Hz, 1H,
-CH in 18), 1.63 (s, 3H, -CH3 in 29), 2.11 (t, J ) 7.5 Hz, 2H,
-CH2-CONH-), 2.52 (m, 1H, 1H of -CH2-COO-), 2.57 (m, 1H,
-CH in 13), 2.73 (dd, J ) 17, 4 Hz, 1H, the other H of -CH2-
COO-), 2.85-3.00 and 3.15 (2m, 1H each, -CONH-CH2- in 17),
2.85-3.00 (m, 1H, -CH in 3), 3.03 (dt, J ) 11.5, 4 Hz, 1H, -CH
in 19), 4.28 (b, 1H, -OH in 3), 4.53 and 4.65 (2bs, 1H each,
dCH2), 4.89 (m, 1H, -CONH-CH), 7.56 (t, J ) 5.5 Hz, 1H,
-CONH- in 17), 8.42 (d, J ) 9 Hz, 1H, -CONH-); IR (KBr, cm-1
)
ν 3440, 3200-2250, 3075, 2940, 2870, 1730, 1670, 1637, 1520,
1380, 1375, 1180, 1130, 1040, 885; MS (EI) 736, 708, 649, 418,
299, 189 (base).
Meth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]n ip ecota te (13f). Following the procedure de-
scribed for 7g, acid 6g (3.0 g, 4.69 mmol) was reacted with
methyl nipecotate hydrochloride19 (1.0 g, 5.6 mmol). The crude
product was purified by column chromatography on silica gel
eluting with 50% ethyl acetate in cyclohexane to yield 2.65 g
(76%) of 13f as a white solid: mp 108 °C.
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]n ip ecotic Acid (14f). Following the procedure
described for 8g, ester 13f (2.5 g, 3.2 mmol) led to 2.35 g of
crude 14f which was purified by column chromatography on
silica gel eluting with ethyl acetate, yielding 800 mg (78%) of
pure 14f as a white solid: mp 184 °C; 1H NMR (CDCl3, at
temperature of 333 K, 400 MHz) δ 0.72 (bd, J ) 9 Hz, 1H, -H
in 5), 0.80 (s, 3H, -CH3), 0.88 (s, 3H, -CH3), 0.98 (s, 3H, -CH3),
1.02 (s, 6H, -CH3), 1.60 (t, J ) 11.5 Hz, 1H, -CH in 18), 1.73
(s, 3H, -CH3 in 29), 1.90-2.20 (m, 2H, -CH2-CON-), 2.30-2.70
(m, 1H, CH-COO-), 2.34 and 2.54 (2m, 1H each, 1H of the
N-CH2-), 2.47 (bt, J ) 11.5 Hz, 1H, -CH in 13), 3.13 (dt, J )
11.5, 4 Hz, 1H, -CH in 19), 3.15-3.35 (m, 2H, -CONH-CH2-),
3.20 (dd, J ) 11, 6 Hz, 1H, -CH in 3), 3.65-3.95 (b, 2H, the
other H of N-CH2-), 4.38 (b, 1H, -OH), 4.60 and 4.75 (2bs, 1H
each, dCH2), 5.64 (m, 1H, -CONH-); IR (KBr, cm-1) ν 3400,
Following the procedure described for 7g, acid 6g (1.2 g, 2.0
mmol) was reacted with methyl (4R)-4-amino-6-methylhep-
tanoate hydrochloride (510 mg, 2.44 mmol). The crude product

1080 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Soler et al.
was purified by column chromatography on silica gel eluting
with 40% ethyl acetate in cyclohexane to yield 1.5 g (93%) of
13i as a white meringue (Rf ) 0.42, eluent: 50% ethyl acetate
in cyclohexane).
yield 960 mg (85%) of 13k as a white meringue (Rf ) 0.25,
eluent: 50% ethyl acetate in cyclohexane).
(3R,4S)-N′-[N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-4-a m in o-3-h yd r oxy-6-m eth ylh ep ta n oic Acid
(14k ). Following the procedure described for 8g, ester 13k
(940 mg, 1.16 mmol) led to 875 mg (91%) of 14k as a white
solid: mp 130 °C; 1H NMR (CDCl3 with a few drops of
CD3COOD-d4, 400 MHz) δ 0.65 (bd, J ) 9 Hz, 1H, -H in 5),
0.72 (s, 3H, -CH3), 0.80 (s, 3H, -CH3), 0.85 and 0.90 [2d, J ) 7
Hz, 3H each, -CH(CH3)2], 0.90 (s, 3H, -CH3), 0.93 (s, 3H, -CH3),
0.96 (s, 3H, -CH3), 1.55 (t, J ) 12 Hz, 1H, -CH in 18), 1.64 (s,
3H, -CH3 in 29), 2.20 (t, J ) 7.5 Hz, 2H, -CH2-CONH-), 2.37
(dt, J ) 12, 3 Hz, 1H, -CH in 13), 2.50 (limit ab, 2H, -CH2-
COO-), 3.04 (dt, J ) 12, 4 Hz, 1H, -CH in 19), 3.10-3.30 (m,
2H, -CONH-CH2-), 3.20 (m, 1H, -CH in 3), 4.00-4.15 (m, 2H,
-CONH-CH-CH-O-), 4.55 and 4.69 (2bs, 1H each, dCH2), 5.87
(residual t, J ) 5.5 Hz, -CONH- in 17), 6.50 (residual d, J )
9 Hz, -CONH-); IR (KBr, cm-1) ν 3375, 3200-2250, 3075, 2940
and 2870, 1720, 1637, 1530, 1380 and 1375, 1040, 880; MS
(LSIMS) 777, 755 (base), 737.
(4 R )-N ′-[N -[3 â-H y d r o x y l u p -2 0 (2 9 )-e n -2 8 -o y l ]-8 -
a m in oocta n oyl]-4-a m in o-6-m eth ylh ep ta n oic Acid (14i).
Following the procedure described for 8g, ester 13i (1.45 g,
1.8 mmol) led to 1.2 g (90%) of 14i as a white solid: mp 120
1
°C (softening); H NMR (CDCl3, 400 MHz) δ 0.67 (bd, J ) 9
Hz, 1H, -H in 5), 0.76 (s, 3H, -CH3), 0.83 (s, 3H, -CH3), 0.92 [d,
J ) 7 Hz, 6H, -CH(CH3)2], 0.96 (s, 3H, -CH3), 0.99 (s, 6H, -CH3),
1.58 (t, J ) 11.5 Hz, 1H, -CH in 18), 1.68 (s, 3H, -CH3 in 29),
2.20 (m, 2H, -CH2-CONH-), 2.40 (m, 3H, -CH in 13, -CH2-
COO-), 3.10-3.35 (m, 2H, -CONH-CH2-), 3.12 (dt, J ) 11.5, 4
Hz, 1H, -CH in 19), 3.18 (m, 1H, -CH in 3), 4.03 (m, 1H,
-CONH-CH), 4.59 and 4.73 (2bs, 1H each, dCH2), 5.70 (d, J )
9 Hz, -CONH-), 5.76 (t, J ) 5.5 Hz, -CONH- in 17); IR (KBr,
cm-1) ν 3425, 3200-2250, 3075, 2940, 2870, 1715, 1637, 1530,
1380, 1375, 1040, 880; MS (DCI) 739 (base), 721.
Meth yl (3S,4S)-N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-
8-a m in oocta n oyl]-4-a m in o-4-ben zyl-3-h yd r oxybu tyr a te
(13j). To a solution of (3S,4S)-4-[[(tert-butyloxy)carbonyl]-
amino]-4-benzyl-3-hydroxybutyric acid (0.5 g, 1.6 mmol) in
methanol (20 mL) cooled to -20 °C was added thionyl chloride
(0.19 mL, 2.4 mmol), and stirring was maintained for 12 h at
room temperature. The mixture was concentrated to dryness
under reduced pressure to yield 0.42 g (100%) of methyl
(3S,4S)-4-amino-4-benzyl-3-hydroxybutyrate hydrochloride as
a white powder used without purification in the next step.
Following the procedure described for 7g, acid 6g (500 mg,
0.78 mmol) was reacted with methyl (3S,4S)-4-amino-4-benzyl-
3-hydroxybutyrate hydrochloride (420 mg, 1.6 mmol). The
crude product was purified by column chromatography on
silica gel eluting with 50% ethyl acetate in cyclohexane to yield
600 mg (91%) of 13j as a white meringue (Rf ) 0.38, eluent:
50% ethyl acetate in cyclohexane).
Meth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-8-a m i-
n oocta n oyl]-2-a m in oben zoa te (15a ). To a solution of acid
6g (1.0 g, 1.5 mmol) in CH2Cl2 (30 mL) was added thionyl
chloride (0.150 mL, 2 mmol). After further stirring for 12 h
at room temperature, the reaction medium was concentrated
to dryness. The residue was dissolved in CH2Cl2 (30 mL) and
methyl anthranilate (0.4 mL, 3 mmol) and stirred for 12 h at
room temperature. The reaction medium was concentrated
under reduced pressure. The residue was dissolved in ethyl
acetate (30 mL), the solution was filtered, and the filtrate was
concentrated to dryness under reduced pressure. Column
chromatography on SiO2, eluting with 5% ethyl acetate in
CH2Cl2, afforded 1.15 g (65%) of the ester 15a as a white
meringue (Rf ) 0.37, eluent: 5% ethyl acetate in CH2Cl2).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-2-a m in oben zoic Acid (16a ). Following the pro-
cedure described for 5j, ester 15a (750 mg, 0.97 mmol) led to
650 mg (93.5%) of 16a as a white powder: mp 116 °C; 1H NMR
(CDCl3, 400 MHz) δ 0.68 (bd, J ) 9 Hz, 1H, -H in 5), 0.77 (s,
3H, -CH3), 0.80 (s, 3H, -CH3), 0.92 (s, 3H, -CH3), 0.97 (s, 3H,
-CH3), 0.99 (s, 3H, -CH3), 1.62 (t, J ) 11.5 Hz, 1H, -H in 18),
1.70 (s, 3H, -CH3 in 29), 2.41 (dt, J ) 11.5, 3 Hz, 1H, -H in
13), 2.47 (t, J ) 7 Hz, 2H, -CH2-CONH-), 3.10 (dt, J ) 11.5, 4
Hz, 1H, -H in 19), 3.20 (dd, J ) 11, 5 Hz, 1H, - H in 3), 3.20-
(3S,4S)-N′-[N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]-8-a m i-
n ooct a n oyl]-4-a m in o-4-b en zyl-3-h yd r oxyb u t yr ic Acid
(14j). A solution of 13j (600 mg, 0.71 mmol) in methanol (7
mL) and THF (3.5 mL) was treated with aqueous LiOH (1 N,
3.6 mL). The reaction mixture was stirred overnight at room
temperature, acidified with hydrochloric acid (5 N, 1.5 mL),
and concentrated to dryness under reduced pressure. The
residue was washed with water to afford 550 mg (100%) of
1
14j as a white solid: mp 138 °C; H NMR (CDCl3 with a few
3.40 (m, 2H, -CONH-CH2-), 4.61 and 4.77 (2bs, 1H each,
drops of CD3COOD-d4, 400 MHz) δ 0.66 (bd, J ) 9 Hz, 1H, -H
in 5), 0.74 (s, 3H, -CH3), 0.80 (s, 3H, -CH3), 0.90 (s, 3H, -CH3),
0.93 (s, 3H, -CH3), 0.97 (s, 3H, -CH3), 1.53 (t, J ) 11.5 Hz, 1H,
-CH in 18), 1.68 (s, 3H, -CH3 in 29), 2.18 (limit ab, 2H, -CH2-
CONH-), 2.39 (dt, J ) 11.5, 3 Hz, 1H, -CH in 13), 2.50 (dd, J
) 17, 4.5 Hz, 1H, 1H of -CH2-COO-), 2.54 (dd, J ) 17, 8 Hz,
1H, the other H of -CH2-COO-), 2.85 and 2.90 (2dd, J ) 14, 8
Hz, 1H each, -CH2-C6H5), 3.07 (dt, J ) 11.5, 4 Hz, 1H, -CH in
19), 3.17 and 3.24 (2m, 1H each, -CONH-CH2-), 3.22 (m, 1H,
-CH in 3), 4.08 (m, 1H, CH-O-), 4.21 (m, 1H, -CONH-CH), 4.57
and 4.71 (2bs, 1H each, dCH2), 5.93 (residual t, J ) 5.5 Hz,
-CONH- in 17), 6.70 (residual d, J ) 9 Hz, -CONH-), 7.15-
7.35 (m, 5H, aromatics); IR (KBr, cm-1) ν 3425, 3200-2250,
3070, 2940, 2870, 1720, 1637, 1525, 1380, 1375, 1040, 880, 750,
700; MS (DCI) 789, 771, 728 (base).
(3R,4S)-Meth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-
8-a m in o o c t a n o y l]-4-a m in o -3-h y d r o x y -6-m e t h y lh e p -
ta n oa te (13k ). To a solution of (3R,4S)-4-[[(tert-butyloxy)-
carbonyl]amino]-3-hydroxy-6-methylheptanoic acid (400 mg,
1.45 mmol) in methanol (8 mL) cooled to -20 °C was added
thionyl chloride (0.16 mL, 2.18 mmol), and stirring was
maintained for 12 h at room temperature. The mixture was
concentrated to dryness under reduced pressure to yield 330
mg (100%) of methyl (3R,4S)-4-amino-3-hydroxy-6-methylhep-
tanoate hydrochloride as a white powder used without puri-
fication in the next step.
dCH2), 5.79 (t, J ) 6 Hz, 1H, -CONH-), 7.11 (bt, J ) 8.5 Hz,
1H, -H aromatic in 5), 7.56 (bt, J ) 8.5 Hz, 1H, -H aromatic in
4), 8.11 (bd, J ) 8.5 Hz, 1H, -H aromatic in 3), 8.64 (bd, J )
8.5 Hz, 1H, -H aromatic in 6), 11.29 (s, 1H, -CONH-Ar); IR
(KBr, cm-1) ν 3450, 3400, 3200-2250, 3075, 2940, 2870, 1690,
1640, 1595, 1525, 1380, 1375, 1045, 880, 760; MS (EI) 716,
698, 670, 410, 380, 287, 261, 203, 189, 136 (base), 119, 93.
Eth yl N′-[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-8-a m in o-
octa n oyl]-3-a m in oben zoa te (15b). A solution of acid 6g
(640 mg, 1 mmol) in CH2Cl2 (25 mL) was treated successively
with ethyl 3-aminobenzoate (200 mg, 1.2 mmol), 1-hydroxy-
benzotriazole (150 mg, 1 mmol), 1-[3-(dimethylamino)propyl)-
3-ethylcarbodiimide hydrochloride (390 mg, 2 mmol), and
triethylamine (0.28 mL, 2 mmol). After further stirring for
19 h at room temperature, water (50 mL) was added. The
aqueous layer was extracted using CH2Cl2 (60 mL). The
combined organic layers were washed with an aqueous meth-
anesulfonic acid solution (0.1 N, 20 mL) and then with distilled
water (20 mL). The organic layer was dried over magnesium
sulfate, filtered, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel using 50%
ethyl acetate in CH2Cl2 as eluent to yield 400 mg (51%) of the
ester 15b as a white meringue (Rf ) 0.26, eluent: 5% ethyl
acetate in CH2Cl2.
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-3-a m in oben zoic Acid (16b). Following the pro-
cedure described for 5j, ester 15b (340 mg, 0.43 mmol) led to
248 mg (80.5%) of 16b as a white powder: mp 160 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 0.65 (b, J ) 9 Hz, 1H, -H in 5), 0.68 (s,
3H, -CH3), 0.81 (s, 3H, -CH3), 0.89 (s, 6H, -CH3), 0.95 (s, 3H,
-CH3), ca. 1.45 (m, 1H, -H in 18), 1.69 (s, 3H, -CH3 in 29), 2.61
Following the procedure described for 7g, acid 6g (900 mg,
1.4 mmol) was reacted with methyl (3R,4S)-4-amino-3-hy-
droxy-6-methylheptanoate hydrochloride (320 mg, 1.4 mmol).
The crude product was purified by column chromatography
on silica gel eluting with 50% ethyl acetate in cyclohexane to

Betulinic AcidssInhibitors of HIV-1 Entry
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5 1081
(bt, J ) 11.5 Hz, 1H, -H in 13), 2.34 (t, J ) 7 Hz, 2H, -CH2-
CONH-), 2.61 (bt, J ) 11.5 Hz, 1H, -H in 13), 2.90-3.10 and
3.18 (2m, 1H each, -CONH-CH2-), 3.00 (b, 1H, - H in 3), 3.08
(dt, J ) 11.5, 4 Hz, 1H, -H in 19), 4.30 (b, 1H, -OH in 3), 4.57
and 4.70 (2bs, 1H each, dCH2), 7.44 (bt, J ) 8.5 Hz, 1H, -H
aromatic in 5), 7.59 (t, J ) 5.5 Hz, 1H, -CONH-), 7.63 (bd, J )
8.5 Hz, 1H, -H aromatic in 4), 7.87 (bd, J ) 8.5 Hz, 1H, -H
aromatic in 6), 8.27 (bs, 1H, -H aromatic in 2), 11.10 (s, 1H,
-CONH-Ar), 12.50-13.40 (b, 1H, -COOH); IR (KBr, cm-1) ν
3425, 3200-2250, 3070, 2945, 2865, 1700, 1675, 1640, 1595,
1550, 1380, 1375, 1045, 880, 760; MS (DCI) 717 (base).
Meth yl N′-[N-[3â-Acetoxylu p-20(29)-en -28-oyl]-8-am in o-
octa n oyl]-4-a m in oben zoa te (15c). A solution of acid 6g (1
g, 1.6 mmol) in CH2Cl2 (100 mL) was treated successively with
methyl 4-aminobenzoate hydrochloride (330 mg, 1.76 mmol),
1-hydroxybenzotriazole (240 mg, 2.8mmol), 1-[3-(dimethyl-
amino)propyl]-3-ethylcarbodiimide hydrochloride (610 mg, 3.2
mmol), and triethylamine (0.67 mL, 4.8 mmol). After further
stirring for 12 h at room temperature, water (50 mL) was
added. The aqueous layer was extracted using ethyl acetate
(125 mL). The combined organic layers were washed with
distilled water (20 mL), dried over magnesium sulfate, filtered,
and concentrated in vacuo. The residue was purified by
column chromatography on silica gel using 5% ethyl acetate
in CH2Cl2 as eluent to yield 940 mg (76%) of the ester 15c as
a white meringue (Rf ) 0.41, eluent: 40% ethyl acetate in
cyclohexane).
N ′-[N -[3â-H y d r o x y lu p -20(29)-e n -28-o y l]-8-a m in o -
octa n oyl]-4-a m in oben zoic Acid (16c). Following the pro-
cedure described for 5j, ester 15c (940 mg, 0.1.2 mmol) led to
758 mg (87%) of 16c as a white powder: mp 167 °C; 1H NMR
(DMSO-d6, 400 MHz) δ 0.58 (m, 1H, -H in 5), 0.60 (s, 3H, -CH3),
0.73 (s, 3H, -CH3), 0.82 (s, 6H, -CH3), 0.87 (s, 3H, -CH3), ca.
1.45 (m, 1H, -H in 18), 1.59 (s, 3H, -CH3 in 29), 2.31 (t, J ) 7.5
Hz, 2H, -CH2-COO-), 2.54 (m, 1H, -H in 13), 2.80-3.00 (m,
2H, 1H of -CONH-CH2-, -H in 3), 2.99 (dt, J ) 11.5, 4 Hz, 1H,
-H in 19), 3.10 (m, 1H, the other H of -CONH-CH2-), 4.23 (d,
J ) 5 Hz, 1H, -OH in 3), 4.51 and 4.63 (2bs, 1H each, dCH2),
7.50 (t, J ) 5.5 Hz, 1H, -CONH-), 7.67 (bd, J ) 8.5 Hz, 2H, -H
aromatics in ortho of -COOH), 7.84 (bd, J ) 8.5 Hz, 2H, -H
aromatics in meta of -COOH), 10.14 (s, 1H, -CONH-Ar); IR
(KBr, cm-1) ν 3425, 3200-2250, 3075, 2940, 2870, 1690, 1640,
1595, 1525, 1385, 1375, 1040, 880, 775; MS (DCI) 717 (base),
699; MS (EI) 411, 398, 279, 223, 189, 137 (base).
(DMSO-d6, 400 MHz) δ 0.63 (m, 1H, -H in 5), 0.65 (s, 3H, -CH3),
0.75 (s, 3H, -CH3), 0.83 (s, 3H, -CH3), 0.87 (s, 3H, -CH3), 0.92
(s, 3H, -CH3), 1.42 (t, J ) 11.5 Hz, 1H, -CH in 18), 1.61 (s, 3H,
-CH3 in 29), 2.57 (m, 1H, -CH in 13), 2.85-3.15 (m, 4H,
-CONH-CH2- in 17, -CH in 3, -CH in 19), 3.04 (m, 2H, -CH2-
NHCO-), 3.09 (s, 2H, -NHCO-CH2-COO-), 4.18 (b, 1H, -OH in
3), 4.53 and 4.65 (2bs, 1H each, dCH2), 7.55 (t, J ) 5.5 Hz,
1H, -CONH- in 17), 8.05 (t, J ) 6 Hz, 1H, -CONH-); MS
(LSIMS) 677, 655 (base), 611.
Meth yl [[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-7-a m in o-
h ep tyl]ca r ba m oyl]p r op a n oa te (18b). To a solution of
succinic acid monomethyl ester (420 mg, 3 mmol), 1-hydroxy-
benzotriazole (510 mg, 3.3 mmol), and 17 (1.8 g, 2.9 mmol) in
CH2Cl2 (60 mL) was added a solution of 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (1.4g, 7.3 mmol) and
triethylamine (1.75 mL, 12 mmol) in CH2Cl2 (20 mL). After
stirring for 3 h at room temperature, distilled water (150 mL)
was added. The organic layer was separated, dried over
magnesium sulfate, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
using 1% CH3OH in CH2Cl2 as eluent to yield 1.38 g (65%) of
the ester 18b as a white meringue (Rf ) 0.38, eluent: 5%
CH3OH in CH2Cl2).
[[N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]-7-a m in oh ep tyl]-
ca r ba m oyl]p r op a n oic Acid (19b). Following the procedure
described for 5j, ester 18b (1.38 g 1.8 mmol) led to 1.10 g
(84.8%) of 19b as a white solid: mp 128 °C; 1H NMR (CDCl3,
400 MHz) δ 0.70 (bd, J ) 9 Hz, 1H, -H in 5), 0.78 (s, 3H, -CH3),
0.84 (s, 3H, -CH3), 0.95 (s, 3H, -CH3), 0.99 (s, 6H, -CH3), 1.60
(t, J ) 11.5 Hz, 1H, -CH in 18), 1.70 (s, 3H, -CH3in 29), 2.42
(dt, J ) 11.5, 3 Hz, 1H, -CH in 13), 2.54 and 2.72 (2t, J ) 6.5
Hz, 2H each, -NHCO-CH2-CH2-COO-), 3.10 (dt, J ) 11.5, 4
Hz, 1H, -CH in 19), 3.15-3.45 (m, 3H, -CONH-CH2- in 17, -CH
in 3), 3.30 (q, J ) 6 Hz, 2H, -CH2-NHCO-), 4.62 and 4.75 (2bs,
1H each, dCH2), 5.78 (t, J ) 5.5 Hz, 1H, -CONH- in 17), 6.27
(t, J ) 6 Hz, 1H, -CONH-); IR (KBr, cm-1) ν 3400, 3200-2250,
3075, 2940, 2865, 1725, 1637, 1530, 1380, 1375, 1040, 880; MS
(LSIMS) 669 (base); MS (EI) 650, 622, 553, 410, 332, 189, 121,
56 (base).
Meth yl [[N-[3â-Acetoxylu p -20(29)-en -28-oyl]-7-a m in o-
h ep tyl]ca r ba m oyl]bu ta n oa te (18c). A solution of 17 (1.81
g, 2.96 mmol) in CH2Cl2 (80 mL) was treated successively with
glutaric acid monomethyl ester22 (397 mg, 2.72 mmol), 1-hy-
droxybenzotriazole (540 mg, 3.3 mmol), 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (1.41g, 7.23 mmol),
and triethylamine (1.77 mL, 12.7 mmol). After further stirring
for 8 h at room temperature, distilled water (80 mL) was
added. The organic layer was separated, washed with distilled
water (20 mL), dried over magnesium sulfate, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel using 50% ethyl acetate in
cyclohexane as eluent to yield 1.70 g (85%) of the ester 18c as
a colorless meringue (Rf ) 0.52, eluent: CH2Cl2-MeOH-
ammoniac 24:12:1).
N-[3â-Acet oxylu p -20(29)-en -28-oyl]-1,7-d ia m in oh ep -
ta n e (17). A solution of acid chloride 1b (31 g, 60 mmol) in
CH2Cl2 (1000 mL) was added over 10 h to 1,7-diaminoheptane
(46.8 g, 36 mmol) in CH2Cl2 (120 mL). After further stirring
for 15 h at room temperature, the mixture was concentrated
to dryness under reduced pressure. Distilled water (2000 mL)
was added. The solid was filtered, washed with distilled water
(200 mL), and dissolved in ethanol (500 mL). Insoluble
material was filtered; then the solution was concentrated to
dryness under reduced pressure. The solid residue was
purified by column chromatography on SiO2, eluting with a
mixture of chloroform-methanol-ammoniac (24:6:1) to afford
28 g (85%) of 17 as a white meringue (Rf ) 0.25, eluent CHCl3-
MeOH-ammoniac, 24:6:1).
[[N-[3â-Hyd r oxylu p -20(29)-en -28-oyl]-7-a m in oh ep tyl]-
ca r ba m oyl]bu ta n oic Acid (19c). Following the procedure
described for 5j, ester 18c (1.44 g, 1.95 mmol) led to 770 mg
1
(58%) of 19c as a white solid: mp 170 °C; H NMR (CDCl3,
E t h yl [[N-[3â-Acet oxylu p -20(29)-en -28-oyl]-7-a m in o-
h ep tyl]ca r ba m oyl]a ceta te (18a ). To a solution of malonic
acid monomethyl ester (133 mg, 1 mmol), 1-hydroxybenzo-
triazole (153 mg, 1 mmol), and 17 (560 mg, 0.92 mmol) in
CH2Cl2 (25 mL) was added a solution of 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (500 mg, 2.6 mmol)
and triethylamine (0.52 mL, 3.7 mmol) in CH2Cl2 (5 mL). After
stirring for 12 h at room temperature, water (15 mL) was
added. The organic layer was separated, washed with distilled
water (30 mL), dried over magnesium sulfate, filtered, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel using 25% ethyl acetate in
cyclohexane as eluent to yield 350 mg (52%) of the ester 18a
as a white meringue (Rf ) 0.38, eluent: 5% CH3OH in CH2Cl2).
[[N-[3â-Acet oxylu p -20(29)-en -28-oyl]-7-a m in oh ep t yl]-
ca r ba m oyl]a cetic Acid (19a ). Following the procedure
described for 5j, ester 18a (350 mg, 0.48 mmol) led to 305 mg
(92.5%) of 19a as a white meringue: (mp 140 °C; 1H NMR
400 MHz) δ 0.69 (b, J ) 9 Hz, 1H, -H in 5), 0.79 (s, 3H, -CH3),
0.83 (s, 3H, -CH3), 0.94 (s, 3H, -CH3), 0.98 (s, 6H, -CH3), 1.57
(t, J ) 11.5 Hz, 1H, -H in 18), 1.69 (s, 3H, -CH3 in 29), 1.99
(m, 2H, -CH2-), 2.31 and 2.44 (2 t, J ) 7.5 Hz, 2H each, -NHCO-
CH2-CH2-CH2-COO-), 2.42 (dt, J ) 11.5, 3 Hz, 1H, -H in 13),
3.10-3.35 (m, 2H, -CONH-CH2- in 17), 3.13 (t, J ) 11.5, 4
Hz, 1H, -H in 19), 3.20 (dd, J ) 11, 5 Hz, 1H, - H in 3), 3.28
(bq, J ) 7 Hz, 2H, -CH2-NHCO-), 4.60 and 4.75 (2bs, 1H each,
dCH2), 5.72 (t, J ) 6 Hz, 1H, -CONH- in 17), 5.92 (t, J ) 7
Hz, 1H, -NH-CO-); IR (KBr, cm-1) ν 3450, 3375, 3200-2250,
3075, 2940, 2870, 1720, 1640, 1530, 1380, 1375, 1040, 880; MS
(LSIMS) 683 (base), 569.
2-[7-[[3â-Acet oxylu p -20(29)-en -28-oyl]a m in o]h ep t yl]-
p h th a lim id e (18d ). A solution of 17 (1.83 g, 3 mmol) in
CH2Cl2 (100 mL) was treated successively with isophthalic acid
monomethyl ester (540 mg, 3 mmol), 1-hydroxybenzotriazole
(560 mg, 3.3 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcar-
bodiimide hydrochloride (1.41 g, 7 mmol), and triethylamine

1082 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 5
Soler et al.
(1.85 mL, 13 mmol). After further stirring for 2 h at room
temperature, the mixture was concentrated to dryness under
reduced pressure. Ethyl acetate (100 mL) and distilled water
(100 mL) were added to the residue. The organic layer was
separated, washed with distilled water (100 mL), dried over
magnesium sulfate, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
using 40% ethyl acetate in cyclohexane as eluent to yield 2.0
g (90%) of 18d as a white meringue (Rf ) 0.57, eluent: 30%
ethyl acetate in cyclohexane).
mL), dried over magnesium sulfate, filtered, and concentrated
in vacuo. The residue was purified by column chromatography
on silica gel using 40% ethyl acetate in cyclohexane as eluent
to yield 2.06 g (89%) of the ester 18f as a colorless meringue
(Rf ) 0.39, eluent: 40% ethyl acetate in cyclohexane).
4-[[N-[3â-Hydr oxylu p-20(29)-en -28-oyl]-7-am in oh eptyl]-
ca r ba m oyl]ben zoic Acid (19f). Following the procedure
described for 5j, ester 18f (2.06 g, 2.7 mmol) led to 1.62 g (83%)
1
of 19f as a white solid: mp 190 °C; H NMR (CDCl3 with a
few drops of CD3OD-d4, 400 MHz) δ 0.52 (b, J ) 9 Hz, 1H, -H
in 5), 0.59 (s, 3H, -CH3), 0.67 (s, 3H, -CH3), 0.78 (s, 3H, -CH3),
0.80 (s, 3H, -CH3), 0.83 (s, 3H, -CH3), 1.43 (t, J ) 11.5 Hz, 1H,
-H in 18), 1.56 (s, 3H, -CH3 in 29), 2.30 (dt, J ) 11.5, 3 Hz,
1H, -H in 13), 2.90-3.05 (m, 2H, 1H of -CONH-CH2- in 17, -H
in 3), 2.96 (t, J ) 11.5, 4 Hz, 1H, -H in 19), 3.10 (m, 1H, the
other H of -CONH-CH2- in 17), 3.28 (bq, J ) 7 Hz, 2H, -CH2-
NHCO-), 4.43 and 4.57 (2bs, 1H each, dCH2), 6.21 (t, J ) 6
Hz, 1H, -CONH- in 17), 7.63 (t, J ) 7 Hz, 1H, -NH-CO-), 7.70
(bd, J ) 8.5 Hz, 2H, -H aromatics in meta of -COO-), 7.95 (bd,
2-[[N-[3â-Hydr oxylu p-20(29)-en -28-oyl]-7-am in oh eptyl]-
ca r ba m oyl]ben zoic Acid (19d ). To a solution of 18d (2.0
g, 2.7 mmol) in methanol (60 mL) and THF (60 mL) was added
10.8 mL of NaOH (5 N). The reaction mixture was stirred for
12 h at room temperature and then diluted with distilled water
(200 mL) and extracted with ethyl acetate (200 mL). The
organic layer was washed with distilled water (200 mL), dried
over sodium sulfate, and evaporated under reduced pressure
1
to afford 1.4 g of 19d (72%) as a beige solid: mp 156 °C; H
NMR (CDCl3, 300 MHz) δ 0.66 (b, J ) 9 Hz, 1H, -H in 5), 0.75
(s, 3H, -CH3), 0.79 (s, 3H, -CH3), 0.93 (s, 3H, -CH3), 0.96 (s,
6H, -CH3), 1.57 (t, J ) 11.5 Hz, 1H, -H in 18), 1.68 (s, 3H,
-CH3 in 29), 2.43 (dt, J ) 11.5, 3 Hz, 1H, -H in 13), 3.05-3.35
(m, 2H, -CONH-CH2- in 17), 3.12 (t, J ) 11.5, 4 Hz, 1H, -H in
19), 3.17 (dd, J ) 11, 5 Hz, 1H, - H in 3), 3.45 (bq, J ) 7 Hz,
2H, -CH2-NHCO-), 4.57 and 4.72 (2bs, 1H each, dCH2), 5.85
(t, J ) 5.5 Hz, 1H, -CONH- in 17), 6.90 (t, J ) 7 Hz, 1H, -NH-
CO-), 7.51 (t, J ) 8 Hz, 1H, -H aromatic in 5), 8.08 (bd, J ) 8
Hz, 1H, -H aromatic in 4), 8.18 (bd, J ) 8 Hz, 1H, -H aromatic
in 6), 8.46 (bs, 1H, -H aromatic in 6); IR (KBr, cm-1) ν 3430,
3200-2250, 3075, 2940 and 2870, 1720, 1640, 1600, 1525, 1385
and 1375, 1040, 880, 750; MS (LSIMS) 739, 717 (base), 569,
279, 261.
J ) 8.5 Hz, 2H, -H aromatics in ortho of -COO-); IR (KBr, cm-1
)
ν 3400, 3200-2250, 3075, 2940 and 2865, 1730, 1637, 1530,
1380 and 1375, 1040, 880; MS (EI) 716, 398, 279, 189, 149
(base), 119.
Biologica l Meth od s. Antiviral assays were done according
to ref 5a for CEM 4 cells and to ref 23 for MT-4 cells
Ack n ow led gm en t. We thank Marc Vuilhorgne for
assistance in obtaining analytical data. Financial sup-
port was obtained from the Agence National de Recher-
ches sur le SIDA (ANRS).
Su p p or tin g In for m a tion Ava ila ble: NMR data for com-
pounds 5b-i,k ,l, 8b-e, and 11i (5 pages). Ordering informa-
tion can be found on any current masthead page.
Meth yl 3-[[N-[3â-Acetoxylu p-20(29)-en -28-oyl]-7-am in o-
h ep tyl]ca r ba m oyl]ben zoa te (18e). A solution of 17 (1.83
g, 3 mmol) in CH2Cl2 (100 mL) was treated successively with
isophthalic acid monomethyl ester (540 mg, 3 mmol), 1-hy-
droxybenzotriazole (560 mg, 3.3 mmol), 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (1.41 g, 7 mmol),
and triethylamine (1.85 mL, 13 mmol). After further stirring
for 2 h at room temperature, ethyl acetate (100 mL) and
distilled water (100 mL) were added to the residue. The
organic layer was separated, washed with distilled water (100
mL), dried over magnesium sulfate, filtered, and concentrated
in vacuo. The residue was purified by column chromatography
on silica gel using 40% ethyl acetate in cyclohexane as eluent
to yield 1.88 g (81%) of the ester 18e as a colorless meringue
(Rf ) 0.36, eluent: 40% ethyl acetate in cyclohexane).
3-[[N-[3â-Hydr oxylu p-20(29)-en -28-oyl]-7-am in oh eptyl]-
ca r ba m oyl]ben zoic Acid (19e). Following the procedure
described for 5j, ester 18e (1.88 g, 2.4 mmol) led to 1.0 g (58%)
of 19e as a white solid: mp 154 °C; 1H NMR (CDCl3, 300 MHz)
δ 0.66 (b, J ) 9 Hz, 1H, -H in 5), 0.75 (s, 3H, -CH3), 0.79 (s,
3H, -CH3), 0.93 (s, 3H, -CH3), 0.96 (s, 6H, -CH3), 1.57 (t, J )
11.5 Hz, 1H, -H in 18), 1.68 (s, 3H, -CH3 in 29), 2.43 (dt, J )
11.5, 3 Hz, 1H, -H in 13), 3.05-3.35 (m, 2H, -CONH-CH2- in
17), 3.12 (t, J ) 11.5, 4 Hz, 1H, -H in 19), 3.17 (dd, J ) 11, 5
Hz, 1H, - H in 3), 3.45 (bq, J ) 7 Hz, 2H, -CH2-NHCO-), 4.57
and 4.72 (2bs, 1H each, dCH2), 5.85 (t, J ) 5.5 Hz, 1H, -CONH-
in 17), 6.90 (t, J ) 7 Hz, 1H, -NH-CO-), 7.51 (t, J ) 8 Hz, 1H,
-H aromatic in 5), 8.08 (bd, J ) 8 Hz, 1H, -H aromatic in 4),
8.18 (bd, J ) 8 Hz, 1H, -H aromatic in 6), 8.46 (bs, 1H, -H
aromatic in 6); IR (KBr, cm-1) ν 3430, 3200-2250, 3075, 2940,
2870, 1720, 1640, 1600, 1525, 1385, 1375, 1040, 880, 735; MS
(EI) 716, 688, 398, 305, 279, 224, 189, 166, 149 (base).
Meth yl 4-[[N-[3â-Acetoxylu p-20(29)-en -28-oyl]-7-am in o-
h ep tyl]ca r ba m oyl]ben zoa te (18f). A solution of 17 (1.83
g, 3 mmol) in CH2Cl2 (100 mL) was treated successively with
terephthalic acid monomethyl ester (540 mg, 3 mmol), 1-hy-
droxybenzotriazole (560 mg, 3.3 mmol), 1-[3-(dimethylamino)-
propyl]-3-ethylcarbodiimide hydrochloride (1.41 g, 7 mmol),
and triethylamine (1.85 mL, 13 mmol). After further stirring
for 2 h at room temperature, the mixture was concentrated to
dryness under reduced pressure. To the residue were added
ethyl acetate (100 mL) and distilled water (100 mL). The
organic layer was separated, washed with distilled water (100
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