Novel and potent anti-malarial agents

Article abstract of DOI:10.1016/S0968-0896(02)00207-9

Readily accessible, novel, and potent anti-malarial compounds have been developed. Optimization of the initial lead structure resulted in derivatives with IC₅₀ values from 7 to 35 nM against chloroquine-sensitive and 70-350 nM against chloroquine-resistant strains of Plasmodium falciparum.

Full text of DOI:10.1016/S0968-0896(02)00207-9

Bioorganic & Medicinal Chemistry 10 (2002) 3649–3661
Novel and Potent Anti-malarial Agents
Kristin M. Brinner,a Jin Mi Kim,a,y Hiromu Habashita,a Ilya Y. Gluzman,b
Daniel E. Goldbergb and Jonathan A. Ellmana,*
aCenter for New Directions in Organic Synthesis, Chemistry Department, University of California, Berkeley, CA 94720, USA
bDepartments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Received 21 December 2001; accepted 22 April 2002
Abstract—Readily accessible, novel, and potent anti-malarial compounds have been developed. Optimization of the initial lead
structure resulted in derivatives with IC50 values from 7 to 35 nM against chloroquine-sensitive and 70–350 nM against chlor-
oquine-resistant strains of Plasmodium falciparum.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
ing upon an alternative target, many of the quinoline-
based anti-malarial drugs, such as chloroquine, show
similar effects.8
Malaria continues to be a major health crisis, infecting
approximately 400 million people and resulting in 1–3
million deaths every year.1 The rapid spread of resis-
tance to the currently used therapeutics presents an even
more serious threat.2 Unfortunately, new, effective, and
inexpensive drugs are not being aggresively developed
because the disease is prevalent in areas of the world
that lack substantial economic resources.3
Recently, using a combination of structure-based
design, mechanism-based design and combinatorial
chemistry, we identified single digit nanomolar, low
molecular weight inhibitors of the plasmodial aspartyl
proteases plasmepsins I and II.4 These enzymes are new
potential therapeutic targets that degrade hemoglobin in
the parasite food vacuole providing essential nutrients
for parasite survival.5
These drugs are hypothesized to exhibit heightened
activity in cell culture (IC50 for chloroquine=6 nM,
3D7) despite having poor activity in in vitro enzyme
inhibition assays (IC50 for chloroquine ꢀ100 mM for
heme polymerization) because of their accumulation in
the digestive vacuole. Like quinoline antimalarials,
compound 1 contains basic amines. This functional
group is thought to be important for the uptake and
concentration of chloroquine in the acidic digestive
vacuole. To confirm that this compound is not acting
as a plasmepsin inhibitor, compound 2 was prepared
since it is devoid of the secondary hydroxyl and P1 side
chain that are obligate functional groups of mechan-
ism-based aspartyl protease inhibitors.9 As expected,
compound 2 showed extremely poor inhibitory activity
against the plasmepsins (IC50 for plm IIꢁ250 mM). In
contrast, in cell culture compound 2 is only 2-fold less
potent (IC50=150 nM) than compound 1, arguing
strongly that compound 2 targets an alternative path-
way. The unknown mechanism of action, high activity,
and simple yet novel structure of 2 warrants further
investigation.
During the screening of plasmepsin inhibitor libraries,
compound 1 was identified to have potent activity in cell
culture. This compound shows high levels of inhibition
of parasite growth in cultured chloroquine sensitive
(3D7) parasite-infected human erythrocytes (IC50=70
nM),6 whereas its activity is approximately 300-fold
lower (IC50=20 mM) in in vitro plasmepsin assays.4,7
Although these results suggest that compound 1 is act-
*Corresponding author. Tel.: +1-510-642-4488; fax: +1-510-642-
8369; e-mail: jellman@uclink.berkeley.edu
yCurrent address: Boehringer-Ingelheim Pharmaceuticals, Inc., Ridge-
field, CT 06877, USA.
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00207-9

3650
J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
as shown for compounds 18, 19, and 20, the presence of
a basic amine provides a significant increase in potency.
The SARin Table 2 corroborates the SARin Table 1
where the 3- and 5- methoxy groups may be replaced
with hydrogens without significantly effecting activity
(see compounds 21 and 22).
Herein, we report structure–activity relationships that
define the key structural determinants required for
activity of this new class of antimalarial compounds.
We further report potent compounds with activity
superior to that of compound 2, which are active
against both drug sensitive and resistant parasite strains
in cell culture.
As shown in Table 3, substitutions at the R2 position
are not accommodated. Introduction of an alkyl sub-
stituent whether small, such as a methyl group in com-
pound 29, or large, such as isobutyl and benzyl groups
in compounds 31 and 32 respectively, results in a sig-
nificant drop in potency. Interestingly, acylation of the
amine to provide compound 30 completely abolishes
activity.
Results and Discussion
A number of substituents were next explored at R3 as
illustrated in Table 4. In particular, large hydrophobic
groups at this position are critical for achieving good
Structure–activity relationships (SAR)
We first chose to define the key structural determinants
for activity by variation of individual substituents in
lead structure 2. The SARprovided in Table 1 indicates
that extended aromatic functionality at R1 is essential
for good activity. However, critical binding determi-
nants beyond the extended aromatic functionality are
not apparent. Note also that the cyclohexylmethyl
group provides greater potency than the benzyl group at
R3 as illustrated by comparison of compounds 2 and 10.
Table 2. SARin the linker region
3
More detailed SARat the R position is provided in
Compd
X
Linker
R3
IC50 (nM)
3D7
Table 4. Finally, note that the 3- and 5-methoxy groups
in the most potent compound, 10, can be removed to
provide compound 11 with only a very modest reduc-
tion in activity.
2
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
OMe
H
H
CONH(CH2)3
CONH(CH2)2
CONH(CH2)4
CH2NH(CH2)2
CH2NH(CH2)3
CH2NH(CH2)4
CH2O(CH2)3
CH2C6H5
CH2C6H5
CH2C6H5
CH3C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H11
CH2C6H11
CH2C6H11
CH2C6H11
CH2C6H11
CH2C6H11
200
150
300
40
30
35
500
500
75
70
35
16
17
18
19
20
21
22
23
24
10
11
25
26
27
28
A number of analogues were prepared with modifi-
cation of the linker region to establish the key determi-
nants for activity in the central portion of the
compound (Table 2). First, as shown for the compound
series 2, 16, and 17, and for the compound series 18, 19,
and 20, change in linker length does not greatly impact
potency. In contrast, substitution of heteroatoms in the
linker has a significant effect on activity. In particular,
CH2O(CH2)3
NHCO(CH2)2
NHCO(CH2)3
CONH(CH2)3
CONH(CH2)3
CH2NH(CH2)2CO
CH2NH(CH2)3CO
SO2NH(CH2)3
CON[C2H5](CH2)3
50
>300
>200
90
H
H
H
Table 1. SARdata at the R 1 site
130
Table 3. SARin the R 2 site
Compd
R1
R3
IC50 (nM)
3D7
2
3
4
5
6
7
8
9
10
11
12
13
14
15
[4-(OBn)-3,5-(OMe)2]C6H2CO
C6H5CH2C6H4CO
[1-Naphthyl}OCH2CO
C6H5OCH2CO
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H11
CH2C6H11
CH2C6H11
CH2C6C11
CH2C6H11
CH2C6H11
150
250
350
>5000
>5000
>5000
>5000
>5000
35
50
40
100
150
3-Pyridyl-CO
MeSO2C6H4CO
Compd
R2
R3
IC50 (nM)
3D7
C6H5CO
H
[4-(OBn)-3,5-(OMe)2]C6H2CO
[4-(OBn)]C6H4CO
C6H5-E-CHCHC6H4CO
C6H5CH2CH2C6H4CO
[4-(OC6H5)]C6H4CO
C6H5CH2C6H4CO
2
H
Me
COMe
H
Isobutyl
Benzyl
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H11
CH2C6H11
CH2C6H11
150
600
>5000
30
75
29
30
10
31
32
600
100

J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
3651
activity. Notably, as shown for compound 10, the sub-
stituent at R3 does not have to be aromatic. Finally, in
preliminary data shown for compound 44 as compared
to compound 10, acyl groups provide reduced activity
relative to alkyl groups at this position.
chloroquine against the drug-resistant strain W2
(IC50=190 nM).
Chemistry
The aforementioned compounds were prepared according
to the synthetic sequences illustrated in Schemes 1–8 .
Based upon the SARprovided in Tables 1–4, com-
pounds containing the optimal substitutions at each site
were then tested both against the chloroquine sensitive
strain, 3D7, and the chloroquine resistant strain, W2
(Table 5). Compounds 45 to 47, which combine a basic
amine within the linker and the cyclohexylmethyl or 2,2-
phenylethyl groups at R3, show the highest potency of
any derivatives based upon lead 2. The compounds
remain quite active against the chloroquine resistant
strain W2, although a 5- to 10-fold reduction in activity
is observed. Notably, compounds 45–47 are of compar-
able potency to chloroquine against the drug-sensitive
strain 3D7 (IC50=6 nM), and are more potent than
To introduce diversity at the R1 site, amines 49a and
49b were alkylated with 3-chloropropyl bromide and the
resulting secondary amine products were reacted with
tert-butyl pyrocarbonate to provide intermediates 50a
and 50b, respectively. The chloride substituents in 50a
and 50b were then displaced with sodium azide, which
was subsequently reduced to provide the primary
amines 51a and 51b.10 Diversity at the R1 site was then
introduced by treating the amines 51a and 51b with a
variety of acids in a parallel format (Scheme 1). Solid
supported EDC (P-EDC) was used for amide bond
formation. Removal of the Boc group and purification
of the products were achieved simultaneously by addi-
tion of a strongly acidic ion exchange resin (P-SO3H)
Table 4. SARin the R 3 site
Compd
X
R3
IC50 (nM)
3D7
10
33
34
35
36
37
38
39
40
41
42
11
43
44
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
CH2C6H11
CH2CH(C6H5)2
CH2CH2C6H5
35
30
35
35
40
50
75
75
CH2(1-Me-3-indole)
CH2(2-naphthyl)
CH2C6H4C6H5
CH2C6H3-3,4-(methylenedioxy)
CH2-3-Me-C6H4
CH2CH2OCH2C6H5
CH2(3-pyrazoyl)
CH3
75
Scheme 1. Reagents: (a) Cl(CH2)3Br, CH3CN; (b) Boc2O, THF; (c)
NaN3, NaI, DMF; (d) PhSH, SnCl2, Et3N, THF; (e) (1) R1CO2H, P-
EDC, CHCl3, (2) P-SO3H, CHCl3, (3) NH3/MeOH.
200
2000
50
25
500
CH2C6H11
CH2CH(C6H5)2
COC6H11
H
H
Table 5. IC50 values for select compounds against W2
Scheme 2. Reagents: (a) 50a, NaH, DMF; (b) 4 N HCl/dioxane.
Compd
X
Linker
R3
IC50 (nM)
3D7
W2
33
43
10
20
45
46
47
48
OMe
H
OMe
CONH(CH2)3
CONH(CH2)3
CONH(CH2)3
CH2CH(C6H5)2
CH2CH(C6H5)2
CH2C6H11
CH2C6H5
CH2C6H11
30
25
35
30
15
12
7
200
160
350
150
180
100
70
OMe CH2NH(CH2)3
OMe CH2NH(CH2)3
OMe CH2NH(CH2)3 CH2CH(C6H5)2
H
H
CH2NH(CH2)3 CH2CH(C6H5)2
NHCO(CH2)2 CH2CH(C6H5)2
Scheme 3. Reagents: (a) BocNH(CH2)nCO2H, TBTU, iPr2EtN, DMF;
(b) 4 N HCl/dioxane; (c) N-R3-piperidone, NaBH(OAc)3, DCE.
18
130

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J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
followed by rinsing with CH2Cl2 and methanol.11 The
free amine was then isolated by elution from the sul-
fonic acid resin with NH3/MeOH.
were prepared by acylating 49b with N-Boc-b-alanine
and N-Boc-4-aminobutyric acid to provide 55a and 55b,
respectively. Removal of the Boc groups followed by
reductive alkylation with 4-benzyloxybenzaldehyde
provided 25 and 26, respectively (Scheme 4).
Compounds 16 and 17 were prepared in a similar man-
ner to 2–15 as shown in Scheme 1, except that 1-bromo-
2-chloropropane was replaced with 1-bromo-2-chlor-
oethane and 1-bromo-4-chlorobutane, respectively.
Reduction of the amides 2, 16, and 17 with LiAlH4 in
THF then provided the corresponding amines 18–20.
Sulfonamide analogue 27 was prepared through treat-
ment of sulfonyl chloride 56 with 51b followed by
deprotection of the Boc group (Scheme 5). Tertiary
amide 28 was prepared by treating alkyl chloride 50b
with ethylamine, followed by acylation with 4-benzyl-
oxybenzoic acid and subsequent Boc deprotection
(Scheme 6).
The ether functionality was incorporated in the linker by
treating the alcohols 52a and 52b with NaH followed by
addition of alkyl chloride 50a followed by Boc removal
to afford compounds 21 and 22, respectively (Scheme 2).
The compounds incorporating substituents at R2 (Table
3) were prepared by straightforward modification of the
procedures to prepare the previous compounds. The
N-methylated derivative 29 was prepared according to
the sequence illustrated in Scheme 1 with the exception
that 4-methylamino-1-benzylpiperidine was used in
place of 4-amino-1-benzylpiperidine. The acetyl group
in compound 30 was introduced by treating 2 with ace-
tyl chloride in CH2Cl2. Compounds 31 and 32 were
prepared by reductive alkylation of 10 with sodium
cyanoborohydrde and isobutyraldehyde or benzaldehyde,
respectively.
The reversed amides 23, 24, and 48 were prepared by
coupling 4-benzyloxyaniline 53 with N-Boc-b-alanine
and N-Boc-4-aminobutyric acid followed by Boc
deprotection to provide 54a and 54b, respectively
(Scheme 3). Reductive alkylation with the appropriately
N-substituted piperidone then provided 23, 24, and 48.
Compounds 25 and 26, where the relative positions of
the amide and amine displayed in 2 have been reversed,
As shown in Scheme 7, diversity at the R3 site was
introduced in a parallel format by treating the amine
precursor 59 with aldehydes under reductive conditions
(NaBH3CN, AcOH, MeOH). When the amine 59 was
consumed, the reaction mixture was diluted with
CH2Cl2. Removal of the Boc-group and purification
was accomplished simultaneously by addition of sul-
fonic acid ion exchange resin. The desired free amines
were then obtained by elution from the sulfonic acid
resin with ammonia in methanol.
Scheme 4. Reagents: (a) BocNH(CH2)nCO2H, DCC, N-hydroxy-
succinimide, iPr2EtN; (b) 4 N HCl/dioxane; (c) p-benzyloxy-
benzaldehyde, AcOH, NaBH(OAc)3, THF.
Alternatively, an amide was introduced at the R3 site by
debenzylation of 50a followed by acylation with cyclo-
Scheme 5. Reagents: (a) 51b, Et3N, 1:1:1H2O/THF/dioxane; (b) 4 N
HCl/dioxane.
Scheme 7. Reagents: (a) H2, Pd/C, AcOH, EtOAc; (b) Alloc-Cl,
iPr2EtN, CH2Cl2; (c) NaI, NaN3, DMF; (d) SnCl2, PhSH, Et3N, THF;
(e) 4-benzyloxy-3,5-dimethoxybenzoic acid, HATU, iPr2EtN, DMF;
(f) TBAF xH2O, TMSN3, Pd(PPh3)4, CH2Cl2; (g) (1) R3CHO,
NaBH3CN, AcOH, MeOH, (2) P-SO3H, CH2Cl2, (3) NH3/MeOH.
Scheme 6. Reagents: (a) EtNH2, H2O, NaI, DMF, 60ꢂC; (b)
4-benzyloxybenzoic acid, HATU, iPrEt2N, DMF; (c) 4 N HCl/dioxane.

J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
3653
hexanecarboxylic acid to provide 60 (Scheme 8). Con-
version of 60 to amine 61 was followed by reductive
alkylation with 4-benzyloxy-1-benzaldehyde and sub-
sequent Boc deprotection to provide 44.
Plasmodium falciparum-infected erythrocyte assay.
Assays of inhibitory activity in cultured parasite-infec-
ted human erythrocytes were performed as previously
described.6
Compound 50a. To a solution of 1-bromo-3-chloro-
propane (1.0 g, 6.35 mmol) in CH3CN (5 mL) was
added 4-amino-1-benzylpiperidine (3.6 g, 19.5 mmol).
The reaction mixture was stirred at room temperature
for 16 h. As the reaction proceeded, formation of a
white precipitate was observed. The reaction mixture
was brought to pH 9 with saturated NaHCO3 (15 mL),
then extracted with EtOAc (3ꢃ30 mL). The combined
organic phase was dried over Na2SO4 and concentrated
to afford a yellow oil. Silica gel column chromatography
using 19:1 CH2Cl2/MeOH afforded 1.64 g the amine as
a pale yellow solid (97%).
This compound (1.55 g, 5.82 mmol) was then dissolved
in THF (5 mL) and di-t-butyl dicarbonate (1.52 g, 6.98
mmol) was added. The reaction mixture was stirred at
room temperature for 2 h and concentrated. Silica gel
column chromatography using 99:1 CH2Cl2/MeOH
Scheme 8. Reagents: (a) H2, Pd/C, AcOH, EtOAc; (b) RCO2H,
HATU, iPr2EtN, DMF; (c) NaI, NaN3, DMF; (d) SnCl2, PhSH,
Et3N, THF; (e) 4-benzoyl-1-benzaldehyde, NaBH(OAc)3, AcOH,
DCE; (f) 4N HCl/dioxane.
1
yielded 2.0 g of 50a as a yellow solid. (94%) H NMR
(CDCl3) d 1.47 (s, 9H), 1.62–1.68 (m, 2H), 1.69–1.80 (m,
2H), 1.94–2.10 (m, 4H), 2.94 (d, 2H), 3.20–3.30 (m, 2H),
3.50 (s, 2H), 3.53 (t, J=6.4 Hz, 2H), 4.00 (bs, 1H), 7.25–
7.28 (m, 1H), 7.31–7.35 (m, 4H).
Conclusions
The compounds derived from lead compound 2 show
excellent activities in cell culture against both chlor-
oquine sensitive and resistant strains of parasitic cell
lines. In particular, compounds 45–47 are as potent as
chloroquine against the drug-sensitive strain 3D7, and
more potent than chloroquine against the drug-resistant
strain W2. Further issues still to be addressed include
establishing the mechanism of action of the most potent
compounds, although recent studies suggest that these
novel compounds may act as heme polymerization
inhibitors.12 In addition, further structure optimization
and evaluation of the most promising compounds in
animal models is underway.
Compound 50b. 2.98 g (7.99 mmol, 97.0%) of 50b was
prepared as a yellow oil according to the procedure
described for 50a. IR(cm ꢄ1) 2922, 2849, 1691, 1449. 1H
NMR(400 MHz, CDCl ) d 0.87 (m, 2H), 1.22 (m, 3H),
3
1.47 (s, 9H), 1.46 (m, 1H), 1.71 (m, 10H), 1.98 (m, 4H),
2.09 (d, 2H, J=6.8), 2.91 (d, br, 2H, J=10.4), 3.24 (m,
br, 2H), 3.53 (t, 2H, J=6.4); 13C NMR(125 MHz,
CDCl3) d 26.1, 26.7, 27.3, 28.4, 31.0, 31.9, 35.3, 43.0,
52.1, 53.8, 65.5, 79.9, 85.1, 155.4. Anal. calcd for
C20H37ClN2O2: C, 64.41; H, 10.00; N, 7.51. Found: C,
64.11; H, 9.92; N, 7.36.
Compound 51a. To a solution of 50a (1.92 g, 5.24 mmol)
in DMF (5 mL) were added NaN3 (3.41 g, 52.4 mmol)
and NaI (0.79 g, 5.24 mmol) and the reaction mixture
was stirred at 75–80 ꢂC for 15 h. The solvent was
removed in vacuo and the resultant residue was dis-
solved in CHCl3 (20 mL). The organic phase was
washed with water (2ꢃ20 mL), dried over Na2SO4, and
then concentrated. Silica gel column chromatography
using 49:1 CH2Cl2/MeOH afforded 1.84 g of the azide
derivative as a colorless oil (94%).
Experimental
General
Materials were obtained from commercial suppliers and
employed without further purification unless otherwise
stated. Ion exchange resin (AG MP-50, Cat. No. 143–
0841) was purchased from Bio-Rad (Hercules, CA,
USA). Anhydrous N,N-dimethyformamide (DMF) was
purchased from Aldrich (Milwaukee, WI, USA).
Chloroform (CHCl3) was passed through basic alumina
prior to use. Flash column chromatography was carried
To a solution of SnCl2 (76 mg, 0.40 mmol) in THF (3
mL) were added PhSH (0.18 g, 1.61 mmol) and Et3N
(0.20 g, 2.01 mmol). The mixture was added to a solu-
tion of the azide described above (0.10 g, 0.027 mmol) in
THF (2 mL) and the reaction mixture was stirred at
room temperature for 30 min. The solvent was evapo-
rated and the residue was diluted with CH2Cl2 (5 mL)
and then 2 N NaOH (5 mL) was added to the solution.
The aqueous phase was separated and extracted with
CH2Cl2 (2ꢃ10 mL). The combined organic phase was
dried over Na2SO4 and concentrated to provide 87 mg
out with Merck 60 230–400 mesh silica gel. H and 13C
1
NMRspectra were recorded using UCB Bruker AMX-
300, AM-400, and DRX-500 spectrometers. All spectra
were obtained in CDCl3 or CD3OD, and chemical shifts
are recorded in parts per million relative to the internal
solvent peak. Coupling constants are reported in hertz
(Hz). Elemental analyses were performed by M-H-W
Laboratories (Phoenix, AZ, USA).

3654
J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
of 51a as a colorless oil (93%) 1H NMR(CDCl ) d 1.43
sample vial and the resin was resubjected to NH3/
MeOH (2 mL) for an additional 30 min. The combined
filtrate was concentrated to afford an oily residue, which
was treated with 2 N HCl in ether to afford the HCl salt.
3
(s, 9H), 1.54–1.80 (m, 4H), 1.91–2.04 (m, 2H), 2.10–2.18
(bs, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.92 (d, J=11.6 Hz,
2H), 3.05–3.28 (m, 2H), 3.47 (s, 2H), 7.20–7.26 (m, 1H),
7.28–7.31 (m, 4H).
1
Compound 3. 2.5 mg, 95% yield. H NMR(CDCl ) d
3
Compound 51b. 1.85 g (4.85 mmol, 86.7%) of 51b was
prepared as a yellow oil according to the procedure
described for 51a. IR(cm ꢄ1) 3385, 2919, 1681. 1H NMR
(300 MHz, MeOD) d 0.83 (m, 2H), 1.22 (m, 3H), 1.45 (s,
9H), 1.68 (m, 10H), 1.90 (m, 2H), 2.07 (d, 2H, J=7.2),
2.51 (s, br, 3H), 2.72 (s, br, 2H), 2.90 (d, br, 2H,
J=15.2), 3.16 (s, br, 2H); 13C NMR(125 MHz, MeOD)
d 25.8, 26.4, 27.4, 27.5, 29.3, 31.7, 35.2, 38.5, 40.0, 53.6,
55.0, 65.3, 79.7, 155.7. Anal. calcd for C20H39N3O2: C,
67.94; H, 11.12; N, 11.89; found, C, 67.54; H, 10.84; N,
11.63.
1.38 (dd, J=3.6, 11.6 Hz, 2H), 1.43 (dd, J=3.6, 11.6
Hz, 2H), 1.52 (bs, 1H), 1.66 (d, J=12.0 Hz, 2H), 1.68
(quintet, J=6.4 Hz, 2H), 1.89 (dt, J=2.4 Hz, J=11.6
Hz, 2H), 2.28 (tt, J=4.0, 10.4 Hz, 1H), 2.65 (t, J=6.4
Hz, 2H), 2.73 (d, J=12.0 Hz, 2H), 3.44 (s, 2H), 3.48 (q,
J=6.0 Hz, 2H), 4.70 (s, 2H), 6.80 (d, J=7.2 Hz, 1H),
7.26–7.38 (m, 5H), 7.49–7.52 (m, 4H), 7.81–7.84 (m,
1H), 8.23–8.26 (m, 1H); MALDI calcd for
C29H35N3O=441.61, obsd=440.26. Anal. calcd for
C29H35N3O2HCl C, 67.60; H, 7.25; N, 8.17. Found C,
67.55; H, 7.37; N, 8.12.
1
Compound 2. A pre-mixed solution of 4-benzyloxy-3,5-
dimethoxybenzoic acid (93 mg, 0.32 mmol), PyBOP
(170 mg, 0.32 mmol), HOAt (44 mg, 0.32 mmol) and
diisopropylethylamine (0.12 mL, 0.67 mmol) in DMF (3
mL) was added to a solution of 51a (94 mg, 0.27 mmol)
in DMF (1 mL). The reaction mixture was stirred at
room temperature for 16 h under nitrogen, and the
DMF was removed in vacuo. The residue was diluted
with CHCl3 (10 mL) and the solution was washed with
saturated NaHCO3 (2ꢃ5 mL), then water (1ꢃ5 mL).
The organic phase was dried over Na2SO4 and con-
centrated. Silica gel column chromatography using 97:3
CH2Cl2/MeOH afforded 0.15 g (88%) of the Boc-pro-
tected product as a colorless oil. This precursor (0.78 g,
1.26 mmol) was treated with 20% TFA in CH2Cl2 (10
mL) and stirred for 2 h at 0 ꢂC, and then an additional 2
h at room temperature. The reaction mixture was con-
centrated and the residual TFA was removed by adding
toluene. Silica gel column chromatograph using 45:5:1
CH2Cl2/MeOH/NH4OH provided 0.70 g of 2 as a col-
orless oil (94%). The compound was dissolved in
MeOH (2 mL) and the solution was acidified by adding
Compound 4. 1.9 mg, 92% yield. H NMR(CDCl ) d
3
1.22 (dd, J=3.6, 11.6 Hz, 2H), 1.26 (dd, J=3.6, 11.6
Hz, 2H), 1.52 (bs, 1H), 1.66 (d, J=12.0 Hz, 2H), 1.68
(quintet, J=6.4 Hz, 2H), 1.89 (dt, J=2.4, 11.6 Hz, 2H),
2.28 (tt, J=4.0, 10.4 Hz, 1H), 2.65 (t, J=6.4 Hz, 2H),
2.73 (d, J=12.0 Hz, 2H), 3.44 (s, 2H), 3.48 (q, J=6..0
Hz, 2H), 4.70 (s, 2H), 6.80 (d, J=7.2 Hz, 1H), 7.26–7.38
(m, 5H), 7.49–7.52 (m, 4H), 7.81–7.84 (m, 1H), 8.23–8.26
(m., 1H); MALDI calcd for C27H33N3O2=431.57,
obsd=429.74. Anal. calcd for C27H33N3O22HCl C,
64.28; H, 6.99; N, 8.33. Found C, 64.31; H, 6.78; N, 8.18.
1
Compound 5. 2.1 mg, 96% yield. H NMR(CDCl ) d
3
1.36, (dd, J=3.6, 11.6 Hz, 2H), 1.40 (dd, J=3.6, 11.6
Hz, 2H), 1.70 (quintet, J=6.4 Hz, 2H), 1.83 (d, J=12.4
Hz, 2H), 1.99 (dt, J=2.0, 11.6 Hz, 2H), 2.42 (tt, J=4.0,
10.8 Hz, 1H), 2.71 (t, J=6.4 Hz, 2H), 2.84 (d, J=12.0
Hz, 2H), 3.45 (q, J=6.4 Hz, 2H), 3.54 (s, 2H), 4.49 (s,
2H), 6.93 (d, J=8.8 Hz, 2H), 7.02 (t, J=7.2 Hz, 1H),
7.23–7.27 (m, 1H), 7.29–7.36 (m, 6H), 7.60 (bs, 1H);
MALDI calcd for C23H31N3O=381.51, obsd=381.69.
Anal. calcd for C23H31N3O 2HCl: C, 60.79; H, 7.32; N,
9.25. Found: C, 60.60; H 7.49; N 9.12.
1 M HCl/ether. The solution was concentrated to afford
1
pure 2 as the HCl salt. H NMR(CD OD) d 1.82–1.93
3
1
(m, 2H), 1.94–2.05 (m, 2H), 2.39 (d, J=13.6 Hz, 2H),
3.10–3.20 (m, 4H), 3.47 (t, J=6.4 Hz, 2H), 3.48–3.52
(m, 1H), 3.65 (d, J=13.2 Hz, 2H), 3.80 (s, 6H), 5.04 (s,
2H), 7.04 (s, 2H), 7.34–7.40 (m, 5H), 7.45–7.58 (m, 5H);
MALDI calcd for C31H39N3O4=517.66, obsd=516.44.
Compound 6. 2.1 mg, 53% yield. H NMR(CDCl ) d
3
1.43 (dd, J=3.6, 11.6 Hz, 2H), 1.47 (dd, J=3.6, 11.6
Hz, 2H), 1.81 (quintet, J=5.6 Hz, 2H), 1.91 (d, J=12.0
Hz, 2H), 2.01 (t, J=11.6 Hz, 2H), 2.42 (bs, 1H), 2.53 (tt,
J=4.0, 10.8 Hz, 1H), 2.86 (d, J=11.6 Hz, 2H), 2.91 (t,
J=5.6 Hz, 2H), 3.48 (s, 2H), 3.60 (q, J=5.2 Hz, 2H),
7.23–7.28 (m, 1H), 7.29–7.34 (m, 4H), 7.37 (dd, J=8.0,
4.8 Hz, 1H), 8.16 (td, J=2.0, 8.0 Hz, 1H), 8.70 (dd,
J=1.6, 4.8 Hz, 1H), 8.80 (bs, 1H), 9.01 (d, J=2.0 Hz,
1H); MALDI calcd for C21H28N4O=352.47,
obsd=350.84.
General procedure for the synthesis of compounds 3–15
Polymer-bound EDC (0.71 mmol/g, 0.30 g) was added
to the solution of a carboxylic acid (86 mmol) in CHCl3
(2 mL) in a screw cap vial and stirred for 5 min. A
solution of amine 51a or 51b (29 mmol) in CHCl3 (1 mL)
was then added to the suspension of the resin and the
mixture was shaken for 6 h at room temperature. The
mixture was filtered and the resin was washed with
CHCl3 (3ꢃ1 mL). Approximately 300 mg of an ion
exchange resin was added to the filtrate and the mixture
was shaken for an additional 5 h. The resin was washed
with CH2Cl2 (2ꢃ2 mL) and MeOH (2ꢃ2 mL). The resin
was then treated with 2 M NH3 in MeOH (5 mL) and
shaken for 30 min. The solution was drained into a
1
Compound 7. 2.1 mg, 59% yield. H NMR(CDCl ) d
3
1.36 (dd, J=3.6, 11.6 Hz, 2H), 1.40 (dd, J=4.0, 12.0
Hz, 2H), 1.63 (bs, 1H), 1.77 (quintet, J=5.6 Hz, 2H),
1.88 (d, J=12.0 Hz, 2H), 2.01 (dt, J=2.0, 9.6 Hz, 2H),
2.47 (tt, J=4.0, 10.8 Hz, 1H), 2.86 (d, J=12.0 Hz, 2H),
2.89 (t, J=5.6 Hz, 2H), 3.07 (s, 3H), 3.49 (s, 2H), 3.59
(q, J=6.0 Hz, 2H), 7.23–7.35 (m, 5H), 7.99 (s, 4H), 8.98
(bs, 1H); MALDI calcd for C23H31N3O3S=429.58,
obsd=428.32.

J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
3655
1
Compound 8. 2.8 mg, 88% yield. H NMR(CDCl ) d
Compound 14. 39 mg, 80% yield. IR(cm ꢄ1) 3292, 2921,
2845, 1639. H NMR(400 MHz, MeOH) d 0.90 (dq,
3
1
1.37 (dd, J=3.6, 11.6 Hz, 2H), 1.42 (dd, J=3.6, 11.6
Hz, 2H), 1.58 (bs, 1H), 1.75 (quintet, J=6.0 Hz,
2H), 1.88 (d, J=12.0 Hz, 2H), 2.01 (dt, J=2.4,
12.0 Hz, 2H), 2.47 (tt, J=4.4, 10.8 Hz, 1H), 2.84
(t, J=5.6 Hz, 2H), 2.84 (d, J=12.0 Hz, 2H), 3.48 (s,
2H), 3.57 (q, J=5.2 Hz, 2H), 7.22–7.28 (m, 1H), 7.29–
7.34 (m, 4H), 7.39–7.48 (m, 3H), 7.81 (dd, J=1.6,
8.4 Hz, 2H), 8.35 (bs, 1H); HRMS-FAB (m/z)
[M+H]+ calcd for C22H30N3O1, 352.2389; found,
352.2389.
2H, J=12.5, 3), 1.25 (m, 3H), 1.43 (dq, 2H, J=12, 3.5),
1.46 (m, 1H), 1.73 (m, 8H), 1.88 (d, br, 2H), 1.94 (m, br,
2H), 2.13 (d, 2H, J=6.5), 2.49 (m, 1H), 2.69 (t, 2H,
J=7), 2.88 (m, 2H), 3.45 (t, 2H, J=6.5), 7.00 (m, 2H),
7.05 (m, 2H), 7.19 (m, 1H), 7.40 (m, 2H), 7.81 (m, 2H);
13C NMR(125 MHz, MeOD) d 25.4, 25.8, 26.3, 28.8,
31.7, 35.0, 37.3, 43.3, 52.6, 54.7, 65.4, 117.1, 119.5,
124.0, 128.8, 129.7, 147.7, 155.9, 160.6, 168.1. ESI-MS
(LR) (m/z) [M+H]+ calcd for C28H39N3O2 450; found
450.
1
Compound 9. Quantitative yield. H NMR(CD OD) d
3
2.06–2.12 (m, 4H), 2.41 (d, J=11.6 Hz, 2H), 3.07 (t,
J=6.8 Hz, 2H), 3.19–3.28 (m, 4H), 3.54–3.58 (m, 1H),
3.59 (d, J=12.4 Hz, 2H), 4.36 (s, 2H), 7.43–7.49 (m,
3H), 7.52–7.58 (m, 2H); HRMS-FAB (m/z) [M+H]+
calcd for C15H26N3, 248.2132; found, 248.2128.
Compound 15. 48 mg, 82% yield. IR(cm ꢄ1) 3288, 2921,
2848, 1639. 1H NMR(400 MHz, MeOH) d 0.87 (m,
2H), 1.21 (m, 3H), 1.42 (dq, 3H, J=12, 3.2), 1.65–1.96
(m, 11H), 2.11 (d, 2H, J=6.8), 2.47 (m, 1H), 2.68 (t, 2H,
J=7.2), 2.86 (d, br, 2H, J=12), 3.42 (t, 2H, J=6.8),
4.00 (s, 2H), 7.17 (m, 3H), 7.26 (m, 4H), 7.73 (m, 2H);
13C NMR(125 MHz, MeOD) d 27.2, 27.7, 30.2, 32.3,
33.2, 36.5, 38.8, 42.5, 44.7, 54.1, 56.2, 66.8, 127.3, 128.4,
129.6, 129.9, 130.0, 133.4, 141.9, 146.8, 170.2. ESI-MS
(LR) (m/z) [M+H]+ calcd for C28H41N3O, 448; found,
448.
Compound 10. 0.43 g (0.82 mmol, 48.2%) as a white
solid. Mp 151–152 ꢂC. IR(cm ꢄ1) 3292, 2917, 2848,
1633, 1236. 1H NMR(400 MHz, CDCl 3) d 0.81 (m, 2H),
1.15 (m, 3H), 1.37 (m, 3H), 1.73 (m, 12H), 2.03 (d, 2H,
J=7.2), 2.40 (m, 1H), 2.75 (m, 4H), 3.46 (q, br, 2H,
J=5.6), 3.81 (s, 6H), 5.00 (s, 2H), 7.04 (s, 2H), 7.27 (m,
3H), 7.43 (m, 2H), 8.14 (t, br, 1H, J=5.2); 13C NMR
(125 MHz, CDCl3) d 26.5, 27.5, 30.1, 32.2, 32.8, 36.1,
38.7, 44.5, 53.8, 55.9, 56.5, 66.5, 75.6, 105.6, 128.7,
128.9, 129.2, 130.7, 138.7, 140.5, 154.4, 168.9. Anal.
calcd for C31H45N3O4: C, 71.10; H, 8.66; N, 8.02.
Found: C, 70.98; H, 8.42; N, 7.69.
Compound 16. 85% yield. 1H NMR(CDCl ) d 1.64 (dd,
3
J=3.6, 11.6 Hz, 2H), 1.68 (dd, J=3.6, 11.2 Hz, 2H),
1.96 (d, J=13. 6 Hz, 2H), 2.01 (t, J=11. 6 Hz, 2H), 2.83
(tt, J=4.0, 10.0 Hz, 1H), 2.90 (d, J=12.0 Hz, 2H), 3.10
(t, J=5.2 Hz, 2H), 3.49 (s, 2H), 3.66 (q, J=4 Hz, 2H),
3.83 (s, 6H), 5.05 (s, 2H), 7.11 (s, 2H), 7.24–7.36 (m,
8H), 7.47 (d, J=8.0 Hz, 2H), 8.07 (bs, 1H); MALDI
calcd for C30H37N3O4=503.63, obsd=502.25.
Compound 11. 248 mg (0.54 mmol, 81%) 1H NMR
(400 MHz, CDCl3) d 0.89 (m, 2H), 1.24 (m, 3H), 1.45
(m, 3H), 1.64 (m, 7H), 1.78 (m, 4H), 1.94 (m, 2H), 2.48
(m, 1H), 22.71 (m, 1H), 2.84 (m, 4H), 3.53 (q, 2H,
J=5.6), 4.75 (bs, 1H), 5.11 (s, 2H), 6.98 (m, 2H), 7.39–
7.44 (m, 4H), 7.78 (m, 2H), 8.12 (m, 1H).
1
Compound 17. 93% yield. H NMR(CDCl ) d 1.61–
3
1.72 (m, 6H), 1.95 (d, J=10.4 Hz, 2H), 1.96 (t, J=12.4
Hz, 2H), 2.79 (tt, J=4.0, 10.1 Hz, 2H), 2.86 (t, J=7.6
Hz, 2H), 2.89 (d, J=12.4 Hz, 2H), 3.36 (q, J=6.0 Hz,
2H), 3.47 (s, 2H), 3.81 (s, 6H), 5.04 (s, 2H), 7.07 (s, 2H),
7.23–7.35 (m, 8H), 7.45 (d, J=8.4 Hz, 2H); HRMS-
FAB (m/z) [M+H]+ calcd for C32H42N3O4 532.3163;
found 532.3175.
Compound 12. 27 mg, 78% yield. IR(cm ꢄ1) 3338, 2921,
2846, 1629. 1H NMR(400 MHz, MeOH) d 0.91 (m,
2H), 1.23 (m, 4H), 1.46 (m, 3H), 1.74 (m, 5H), 1.83 (t,
2H, J=7), 1.89 (d, br, 2H, J=14), 1.97 (t, br, 2H,
J=12) 2.14 (d, 2H, J=6.5), 2.53 (m, 1H), 2.73 (t, 2H,
J=7), 2.90 (d, br, 2H, J=12.5), 3.46 (t, 2H, J=6.5),
7.21–7.38 (m, 5H), 7.58 (d, 2H, J=7.5), 7.65 (d, 2H,
J=8.5), 7.81 (d, 2H, J=8); 13C NMR(125 MHz,
MeOD) d 26.3, 26.7, 27.0, 27.8, 31.7, 34.0, 37.2,
43.7, 52.4, 53.5, 68.0, 127.4, 127.7, 128.2, 128.8,
129.0, 129.7, 132.0, 133.2, 139.2, 142.3, 170.6. ESI-
MS (LR) (m/z) [M+H]+ calcd for C30H41N3O 460;
found 460.
Procedure for synthesis of compounds 18–20
Compound 19. Compound 2 (0.10 g, 0.17 mmol) was
dissolved in THF (5 mL) and the solution was cooled to
0 ꢂC. LiAlH4 (20 mg, 0.51 mmol) was added and the
reaction mixture was heated at reflux for 8 h. The reac-
tion mixture was then cooled to 0 ꢂC and saturated
aqueous Na2SO4 was added dropwise with stirring. The
mixture was dried over MgSO4 and filtered. The filtrate
was concentrated and the resultant residue was purified
using silica gel column chromatography using 45:5:1
CH2Cl2/MeOH/NH4OH to afford 55 mg of 19 as a col-
orless oil (64%). The amine product was converted into
the HCl salt by treatment with 1 M HCl/ether: 1H NMR
(CD3OD) d 2.06–2.08 (m, 2H), 2.46 (d, J=13.3 Hz,
2H), 3.17 (t, J=14.0 Hz, 2H), 3.48–3.52 (m, 3H), 3.64
(d, J=18.0 Hz, 2H), 3,88 (s, 6H), 4.25 (s, 2H), 4.37 (s,
2H), 4.98 (s, 2H), 6.93 (s, 2H), 7.25–7.38 (m, 3H), 7.42–
7.48 (m, 2H), 7.50–7.61 (m, 5H); MALDI calcd for
C30H39N3O3=489.65, obsd=486.55.
Compound 13. 26 mg, 69% yield. IR(cm ꢄ1) 3289, 2921,
2848, 1639. 1H NMR(400 MHz, MeOH) d 0.91 (m,
2H), 1.22 (m, 3H), 1.45 (m, 3H), 1.70–1.98 (m, 12H),
2.13 (d, 2H, J=6.8), 2.49 (m, 1H), 2.70 (t, 2H, J=10.8),
2.93 (m, 6H), 3.43 (t, 2H, J=6.4), 7.13 (m, 3H), 7.23 (m,
4H), 7.69 (m, 2H); 13C NMR(125 MHz, MeOD) d 27.2,
27.8, 30.2, 32.3, 33.2, 36.5, 38.6, 38.8, 38.8, 44.7, 54.1,
56.2, 66.8, 127.0, 128.3, 129.3, 129.6, 129.8, 133.2, 142.6,
147.2, 170.3. ESI-MS (LR) (m/z) [M+H]+ calcd for
C30H43N3O 462; found 462.

3656
J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
Compound 18. Reduction of 16 as described for the
1
and concentrated. The crude product was purified by
silica gel column chromatography using 45:5:1 CH2Cl2/
MeOH/NH4OH to afford products in 77–85% yield.
synthesis of compound 19 afforded 18 in 30% yield. H
NMR(CDCl ) d 1.35 (dd, J=3.6, 12.2 Hz, 2H), 1.39
3
((2dd, J=3.6, 12.2 Hz, 2H), 1.63 (bs, 1H), 1.70 (quintet,
J=6.8 Hz, 2H), 1.84 (d, J=12.4 Hz, 2H), 2.00 (dt,
J=2.0, 11.6 Hz, 2H), 2.43 (tt, J=4.0, 10.0 Hz, 1H), 2.71
(t, J=6.8 Hz, 2H), 2.84 (d, J=12.9 Hz, 2H), 3.48 (s,
2H), 3.71 (s, 2H), 3.82 (s, 6H), 4.98 (s, 2H), 6.54 (s, 2H),
7.22–7.36 (m, 8H), 7.49 (d, J=4.9 Hz, 2H); MALDI
calcd for C31H41N3O3=503.68, obsd=502.12.
.
Compound 23. To a solution of 4-benzyloxyaniline HCl
(53) (1.83 g, 7.74 mmol) in DMF (3 mL) was added to a
pre-mixed solution of N-Boc-4-aminobutyric acid (1.31
g, 6.45 mmol), TBTU (2.48 g, 7.74 mmol) and diiso-
propylethylamine (2.08 g, 16.1 mmol) in DMF (7 mL).
The reaction mixture was stirred at room temperature
for 18 h under nitrogen atmosphere. The mixture was
concentrated in vacuo and the residue was diluted with
CH2Cl2 (20 mL). The solution was washed with aq 1 N
HCl (15 mL), saturated NaHCO3 (15 mL) and then
water (10 mL). The organic phase was dried over
Na2SO4 and concentrated. Silica gel column chromato-
graphy of the crude product using 49:1 CH2Cl2/MeOH
afforded 2.2 g of Boc-protected amine as a light brown
solid (90%). The Boc-group was then removed accord-
ing to the procedure for the synthesis of 3–15 (20%
TFA, CH2Cl2) to afford 54a. Reductive amination of
54a following the general procedure afforded 23. 1H
Compound 20. Reduction of 17 as described for the
1
synthesis of compound 19. H NMR(CDCl ) d 1.36
3
(dd, J=3.6, 12.0 Hz, 2H), 1.40 (2dd, J=3.6, 12.0 Hz,
2H), 1.52–1.60 (m, 3H), 1.84 (d, J=12.4 Hz, 2H), 2.01
(t, J=11.6 Hz, 2H), 2.46 (tt, J=4.0, 10.4 Hz. 2H), 2.63–
2.70 (m, 4H), 2.85 (d, J=12.9 Hz, 2H), 3.50 (s, 2H),
3.73 (s, 2H), 3.83 (s, 6H), 5.94 (s, 2H), 6.56 (s, 2H),
7.23–7.36 (m, 8H), 7.50 (d, J=7.2 Hz, 2H); MALDI
calcd for C32H43N3O3=517.70, obsd=516.47.
Compound 21. 4-Benzyloxy-3,5-dimethoxybenzyl alco-
hol (52a) (0.12 mg, 0.44 mmol) was added to a suspen-
sion of 60% NaH (20 mg, 0.48 mmol) in DMF (2 mL)
under nitrogen. The mixture was stirred at room tem-
perature for 4 h and 50a (80 mg, 0.22 mmol) in DMF (1
mL) was added. The reaction mixture was stirred at
room temperature for 48 h and concentrated in vacuo.
Silica gel column chromatography of the residue using
19:1 CH2Cl2/EtOAc afforded 89 mg of Boc-protected
precursor as a colorless oil (68%). The Boc-group was
then removed following the general procedure described
for the synthesis of compounds 3–15 to yield 21 (73%):
NMR(CDCl ) d 1.48 (dd, J=3.6, 11.6 Hz, 2H), 1.52
3
(dd, J=3.6, 11.2 Hz, 2H), 1.95 (d, J=12.4 Hz, 2H), 2.06
(t, J=11.2 Hz, 2H), 2.33 (bs, 1H), 2.52 (t, J=6.0 Hz,
2H), 2.57 (tt, J=4.9, 10.8 Hz, 1H), 2,90 (d, J=12.0 Hz,
2H), 3.00 (t, J=6.0 Hz, 2H), 3.53 (s, 2H), 5.04 (s, 2H),
6.92 (d, J=6.8 Hz, 2H), 7.22–7.47 (m, 12H); HRMS-
FAB (m/z) [M+H]+ calcd for C28H34N3O2 444.2640;
found 444.2651.
Compound 24. 54b was synthesized as described for the
synthesis of 54a. 54b was reductively alkylated following
the general procedure to afford 24 in 77% yield; 1H
1H NMR(CDCl ) d 1.82–1.92 (m, 2H), 1.93–2.05 (m,
3
2H), 2.06–2.15 (m, 2H), 2.18–2.28 (m, 2H), 2.88–3.92
(m, 3H), 3.94–3.13 (m, 2H), 3.44–3.52 (m, 2H), 3.83 (s,
6H), 4.41 (s, 2H), 4.99 (s, 2H), 6.55 (s, 2H), 7.21–7.40
(m, 8H), 7.49 (d, J=6.8 Hz, 2H); HRMS-FAB (m/z)
[M+H]+ calcd for C31H41N2O4 505.3062; found
505.3066.
NMR(CDCl ) d 1.38 (dd, J=3.2, 11.8 Hz, 2H), 1.42
3
(dd, J=3.2, 11.8 Hz, 2H), 1.75 (bs, 1H), 1.78–1.98 (m,
4H), 2.01 (dt, J=2.0, 11.6 Hz, 2H), 2.46 (t, J=6.8 Hz,
2H), 2.45–2.51 (m, 1H), 2.75 (t, J=6.4 Hz, 2H), 2.86 (d,
J=12.0 Hz, 2H), 3.51 (s, 2H), 5.04 (s, 2H), 6.92 (d,
J=8.8 Hz, 2H), 7.24–7.45 (m, 10H), 7.44 (d, J=8.8 Hz,
2H), 8.90 (s, 1H); HRMS-FAB (m/z) [M+H]+ calcd
for C29H36N3O2 458.2797; found 458.2808.
Compound 22. Synthesized from 52b and 50a as descri-
bed for 21 to afford 22 in 78% yield. 1H NMR
(CD3OD) d 1.52 (dd, J=3.6, 11.6 Hz, 2H), 1.56 (dd,
J=3.6, 12.0 Hz, 2H), 1.80–1.98 (m, 4H), 2.07 (t, J=12.0
Hz, 2H), 2.92–3.02 (m, 3H), 3.06 (t, J=7.2 Hz, 2H),
3.54 (s, 2H), 3.60 (t, J=5.6 Hz, 2H), 4.44 (s, 2H), 5.08
(s, 2H), 6.98 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz,
2H), 7.28–7.37 (m, 8H), 7.38–7.43 (m, 2H); HRMS-
FAB (m/z) [M+H]+ calcd for C29H37N2O2 445.2865;
found 445.2855.
Compound 48. 54a was reductively alkylated following
the general procedure to afford 48. 1H NMR(CDCl ) d
3
1.36 (dd, J=3.6, 12.0 Hz, 2H), 1.40 (dd, J=3.6, 12.0
Hz, 2H), 1.88 (d, J=11.2 Hz, 2H), 2.05 (bs, 1H), 2.10 (t,
J=11.2 Hz, 2H), 2.50 (t, J=6.0 Hz, 2H), 2.53 (tt,
J=4.0, 10.0 Hz, 1H), 2.91 (d, J=12.0 Hz, 2H), 2.97 (t,
J=5.6 Hz, 2H), 3.00 (d, J=7.2 Hz, 2H), 4.22 (t, J=7.6
Hz, 1H), 5.05 (s, 2H), 6.92 (d, J=9.2 Hz, 2H), 7.18–7.23
(m, 2H), 7.24–7.33 (m, 9H), 7.36–7.46 (m, 6H); MALDI
calcd for C35H39N3O2=533.70, obsd=532.07.
General procedure for reductive amination to prepare 23,
24, and 48
Compound 55a. To a solution of 95 mg (0.50 mmol) of
Boc-b-alanine-OH in 1 mL of CH2Cl2 was added 124
mg (0.601 mmol, 1.2 equiv) of dicyclohexylcarbodiimde
and 70 mg (0.60 mmol, 1.2 equiv) of N-hydro-
xysuccinimide. The reaction mixture was stirred at room
temperature for 15 min. The mixture was filtered and
added to a solution of 161 mg (0.599 mmol, 1.2 equiv)
of 49b and 0.45 mL (1.3 mmol, 2.6 equiv) of iPr2EtN in
1 mL of DMF. The reaction mixture was then stirred at
A mixture of amine 54a or 54b (1 equiv) and ketone (1
equiv) in DCE (0.2 M) was treated with NaBH(OAc)3
(1.5 equiv). The pH of the reaction mixture was adjus-
ted to ꢀ6 by adding AcOH. The mixture was stirred at
room temperature for 12 h and then treated with satu-
rated NaHCO3. The aqueous phase was separated from
the organic phase and re-extracted with CH2Cl2 (2ꢃ).
The combined organic phase was dried over Na2SO4

J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
3657
room temperature for 4 h. The solvent was removed in
vacuo (ca. 1 mm Hg, 30 ꢂC) and the resultant residue
brought up in 10 mL of saturated NaHCO3(aq) and
extracted with CH2Cl2 (2ꢃ20 mL). The combined
organic layers were washed with water (4ꢃ15 mL),
dried, concentrated in vacuo, and purified by column
chromatography, eluting with 20:1 CH2Cl2/MeOH to
afford 72 mg (0.19 mmol, 38%) 55a as a clear oil. IR
(cmꢄ1) 3314, 2920, 2845, 1702, 1640. 1H NMR
(400 MHz CDCl3) 0.84 (m, 2H), 1.14 (m, 3H), 1.41 (s,
9H), 1.44 (m, 3H), 1.71 (m, 5H), 1.85 (d, br, 2H,
J=10.8), 1.99 (t, br, 2H, J=8, 10), 2.07 (d, 2H, J=7.2),
2.36 (t, 2H, J=6), 2.75 (d, br, 2H, J=12), 3.36 (dd, 2H,
J=6, 6.4), 3.72 (m, 1H), 5.28 (d, br, 1H, J=5.2), 5.86 (s,
br, 1H); 13C NMR(125 MHz, CDCl 3) d 26.0, 26.6, 28.4,
29.8, 31.9, 35.1, 36.4, 36.7, 46.5, 52.7, 65.4, 79.2, 156.1,
170.6. ESI-MS (LR) [M+H]+ calcd for C20H37N3O3,
368; found 368.
To a solution of 26 mg (0.096 mmol) of the compound
described above in 1 mL of THF was added 26 mg (0.12
mmol, 1.2 equiv) of p-benzyloxybenzaldehyde, AcOH
diluted in THF was added dropwise to bring the pH to
approximately 6, and 26 mg (0.12 mmol, 1.2 equiv) of
NaBH(OAc)3 was added. The reaction mixture was
stirred at room temperature for 22 h. The solvent was
removed in vacuo, the resultant solids brought up in
saturated NaHCO3(aq) (20 mL), and extracted with
CH2Cl2 (3ꢃ20 mL). The combined organic layers were
dried and purified by column chromatography, eluting
with a gradient of 10:1 CH2Cl2/MeOH to 90:10:2
CH2Cl2MeOH/NH4OH to afford 22 mg (0.048 mmol,
48%) of 25 as a white solid. IR(cm ꢄ1) 3500, 2925, 2859,
1
1658. H NMR(400 MHz, CDCl ) d 0.88 (m, 2H), 1.17
3
(m, 4H), 1.46 (m, 3H), 1.7 (m, 6H), 1.87 (m, 2H), 2.06 (t,
br, 2H, J=11.2), 2.10 (d, 2H, J=7.2), 2.36 (t, 2H,
J=6), 2.73 (d, br, 1H), 2.88 (t, 2H J=6), 3.73 (s, 2H),
3.76 (m, 1H), 5.07 (s, 2H), 6.95 (m, 2H), 7.21 (m, 2H),
7.40 (m, 5H), 7.60 (m, 1H); 13C NMR(125 MHz,
CDCl3) d 26.1, 26.7, 32.0, 32.1, 35.3, 35.6, 45.1, 52.6,
52.7, 53.0, 65.7, 70.1, 114.9, 127.4, 127.9, 128.5, 129.4,
131.7, 136.9, 158.0, 171.8. HRMS-FAB (m/z) [M+H]+
calcd for C29H41N3O2 464.3277; found 464.3285.
Compound 55b. To 1.00 g (9.70 mmol) of 4-aminobu-
tyric acid in 3 mL of water was added 0.78 g (19 mmol,
2 equiv) of NaOH. To this solution was added 2.11 g
(9.70 mmol, 1 equiv) of di-tert-butyl dicarbonate in 15
mL of CH2Cl2. The reaction mixture was stirred at
room temperature for 32 h, monitoring progress of the
reaction by NMR. Upon disappearance of 4-aminobu-
tyric acid, the reaction mixture was brought to pH 5
with 1 M HCl(aq), and extracted with CH2Cl2 (2ꢃ20
mL). The combined organic layers were dried and con-
centrated in vacuo to afford 1.48 g (7.28 mmol, 75.1%)
4-N-Boc-aminobutyric acid as a clear oil. Spectra is in
agreement with literature data. 1H NMR(400 MHz,
CDCl3) d 1.44 (s, 9H), 1.83 (p, 2H, J=6.8, 7.2), 2.40 (t,
2H, J=7.2), 3.19 (m, br, 2H) 4.70 (s, br, 1H); 13C NMR
(500 MHz, CDCl3) d 24.9, 27.4, 30.7, 39.3, 78.5, 157.1,
175.6.
Compound 26. Boc cleavage from 55b was performed as
described for synthesis of 25 to afford 38 mg (0.14
1
mmol, 97%) of deprotected 55b as a white solid. H
NMR(400 MHz, CDCl ) d 0.85 (q, b, 2H), 1.19 (m,
3
4H), 1.44 (m, 3H), 1.71 (m, 6H), 1.82 (m, 4H), 2.00 (t,
br, 2H), 2.08 (d, 2H, J=7.2), 2.26 (t, 2H, J=7.6), 2.78
(s, b, 1H), 3.40 (m, 2H), 3.73 (m, 1H), 6.32 (d, 1H); 13C
NMR(125 MHz, CDCl ) d 25.8, 26.3, 27.1, 30.9, 31.7,
3
32.9, 35.0, 40.1, 46.6, 52.7, 65.5, 173.2.
Reductive amination of the compound described above
was performed as described for the synthesis of 25 to
afford 28 mg (0.058 mmol, 41%) of 26 as a white pow-
der. IR(cm ꢄ1) 3285, 2921, 2849, 1641. 1H NMR
(400 MHz, CDCl3) d 0.84 (m, 2H), 1.19 (m, 4H), 1.43
(m, 4H), 1.73 (m, 6H), 1.83 (m, 4H), 2.00 (t, br, 2H,
J=9.2), 2.09 (d, 2H, J=5.6), 2.43 (t, 2H, J=5.6), 2.67
(t, 2H, J=5.6), 2.75 (d, br, 1H, J=8.8), 3.71 (s, 2H),
2.75 (br, 1H), 5.10 (s, 2H), 5.85 (s, br, 1H), 6.94 (d, 2H
J=7.2), 7.32 (m, 1H), 7.39, (m, 2H), 7.44 (m, 2H); 13C
NMR(125 MHz, MeOD) d 24.6, 25.8, 26.3, 30.9, 31.7,
33.3, 35.0, 46.6, 47.3, 51.9, 52.6, 65.5, 69.5, 114.5, 127.1,
127.4, 128.0, 129.6, 130.1, 137.2, 158.3, 173.3. HRMS-
FAB (m/z) [M+H]+ calcd for C30H43N3O2 478.3434;
found 478.3421.
55b was prepared as described for 55a to afford 121 mg
(0.318 mmol, 63.6%) as a white solid. IR(cm ꢄ1) 3302,
1
2292, 2850, 1692, 1642. H NMR(400 MHz, CDCl ) d
3
0.85 (m, 2H), 1.20 (m, 4H), 1.44 (s, 9H), 1.47 (m, 3H),
1.79 (m, 6H), 1.80 (p, 2H, J=6.8), 1.90 (m, br, 2H), 2.07
(t, br, 2H), 2.13 (d, 2H, J=6.8), 2.18 (t, 2H, J=7.2),
2.81 (d, br, 1H), 3.16 (m, br, 2H) 3.79 (m, 1H), 5.30 (m,
1H); 13C NMR(125 MHz, CDCl ) d 26.1, 26.5, 26.6,
3
28.3, 28.4, 31.9, 33.8, 35.2, 39.6, 46.4, 52.7, 65.5, 79.2,
156.5, 171.9. Anal. calcd for C21H39N3O3: C, 66.10; H,
10.30; N, 11.01. Found C, 66.12; H, 10.10; N, 10.70.
Compound 25. To a solution of 5 mL of 4 M HCl in
dioxane was added 37 mg (0.1 mmol) of 55a. The reac-
tion mixture was stirred at room temperature for 15
min, and the solvent was removed in vacuo. The resul-
tant product was purified by column chromatography,
eluting with a gradient of 10:1 CH2Cl2/MeOH to
90:10:2 CH2Cl2/MeOH/NH4OH to afford 26 mg (0.096
Compound 47. Alkylation and Boc protection of 49c
was performed as described for 50a and 50b to afford
50c in 80% yield. NaN3 displacement and reduction to
the amine were performed as described for 51a and 51b
to afford 51c. Reductive amination of 51c with 4-ben-
zyloxybenzaldehyde as described for 25 and 26, fol-
lowed by Boc deprotection with 4 M HCl afforded 47 in
60% yield. 1H NMR(400 MHz, MeOD) d 1.25 (m, 2H),
1.66 (p, 2H), 1.75 (m, 2H), 2.04 (t, 2H), 2.38 (m, 1H),
2.66 (t, 4H), 2.86 (m, 2H), 2.95 (d, 2H), 3.70 (s, 2H),
4.19 (t, 1H), 5.04 (s, 2H), 6.91 (d, 2H), 7.16–7.43 (m,
17H).
1
mmol, 96%) of deprotected 55a as a white solid. H
NMR(400 MHz, CDCl ) d 0.83 (q, br, 2H), 1.17 (m,
3
4H), 1.44 (m, 3H), 1.67 (m, 6H), 1.87 (m, 2H), 2.03 (t,
br, 2H), 2.08 (d, 2H J=6.8), 2.29 (t, 2H, J=6), 2.74 (d,
br, 1H), 2.99 (s, br, 2H), 3.79 (m, 1H); 13C NMR
(125 MHz, MeOD) d 25.7, 26.3, 30.9, 31.7, 35.0, 36.9,
37.4, 43.8, 52.7, 65.5, 172.4.

3658
J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
Compound 56. To a solution of 2.00 g (8.60 mmol) p-
hydroxybenzenesulfonic acid in 80 mL of 15% 0.5 M
NaOH(aq) in EtOH was added 2.21 g (12.9 mmol, 1.5
equiv) of benzyl bromide. The reaction mixture was
refluxed for 20 h. After cooling to room temperature,
white crystals formed, which were collected and washed
with ice cold CH2Cl2. The filtrate was concentrated in
vacuo, and the resultant white powder recrystallized
from H2O to afford, in combination with the first crystal
crop, 765 mg (2.67 mmol, 31%) of p-benzyloxybenzene-
(m, 1H), 1.72 (m, 12H), 2.09 (d, 2H, J=6.9), 2.34 (m,
1H), 2.54 (t, 2H, J=7.2), 2.85 (m, 4H), 5.15 (s, 2H), 7.12
(m, 2H), 7.34 (m, 5H), 7.77 (m, 2H); 13C NMR
(125 MHz, MeOD) d 25.7, 26.2, 28.9, 31.0, 31.7, 35.0,
40.8, 43.2, 52.7, 54.6, 65.4, 69.8, 114.7, 127.1, 127.7,
128.1, 128.6, 120.1, 132.2, 136.4.
Compound 57. To a solution of 295 mg (0.791 mmol) of
50b in 1 mL of 1:1 CH3CN/DMF was added 650 mg
(4.33 mmol, 5 equiv) of NaI and 0.50 mL (6.2 mmol, 13
equiv) of 70 wt% ethylamine in water. The reaction
mixture was stirred at 40 ꢂC for 24 h. The solvent was
then removed in vacuo (ca. 1 mm Hg, 30 ꢂC), and the
resultant oil was brought up in 10 mL of saturated
NaHCO3(aq), followed by extraction with CH2Cl2 (3ꢃ10
mL). The combined organic layers were dried, con-
centrated, and purified by column chromatography,
eluting with a gradient of 30:1 CH2Cl2/MeOH to
sulfonic acid as white crystals. IR(cm ꢄ1) 3067, 1237, 23,
1
1010, 842. H NMR(400 MHz, (CD ) SO) d 5.09 (s,
3 2
2H), 6.92 (d, 2H, J=8.5) 7.31 (m, 1H), 7.37 (t, 2H,
J=7.6), 7.42 (m, 2H), 7.49 (d, br, 2H, J=8.8); 13C
NMR(125 MHz, (CD ) SO) d 69.6, 114.1, 127.5, 128.1,
3 2
128.2, 128.8, 137.4, 141.4, 158.7. ESI-MS (LR) [M-
Na+]ꢄ calcd for C13H11O4SNa 263; found 263.
To 250 mg (0.776 mmol) of the sulfonic acid described
above in 10 mL of CH2Cl2 was added 244 mg (1.17
mmol, 1.5 equiv) of PCl5. The reaction mixture was
stirred at 40 ꢂC for 24 h, brought to room temperature
and the resultant solid collected to afford 265 mg (0.937
mmol) of 56 as a pink solid in quantitative yield, which
was used without further purification. IR(cm ꢄ1) 2920,
2857, 1368, 1263, 1167. 1H NMR(500 MHz, (CD 3)2SO)
d 5.09 (s, 2H), 6.92 (dt, 2H, J=9, 2.5), 7.31 (t, 1H, J=7),
7.37 (t, 2H, J=7), 7.42 (m, 2H), 7.49 (dt, 2H, J=9, 2).
ESI-MS (LR) [M+H]+ calcd for C13H11ClO3S, 282,
found 282.
90:10:2 CH2Cl2/MeOH/NH4OH to afford 115 mg
ꢄ1
(0.302 mmol, 38.2%) of 57 as a yellow oil. IR(cm
3323, 2922, 2858, 2477, 1697. 1H NMR(500 MHz,
)
MeOD) d 0.867 (m, 2H), 1.13 (t, 3H, J=9.6), 1.24 (m,
3H), 1.54 (s, 9H), 1.55 (m, 1H), 1.70 (m, 12H), 1.94 (m,
2H), 2.12 (d, 2H, J=9.2), 2.63 (m, 4H), 2.95 (d, br, 2H,
J=4.8), 3.17 (s, br, 2H); 13C NMR(125 MHz, MeOD) d
11.3, 26.1, 26.7, 28.4, 28.5, 31.7, 31.9, 35.6, 51.0, 51.2,
53.5, 53.6, 65.4, 65.4, 79.2, 155.0. ESI-MS (LR)
[M+H]+ calcd for C22H43N3O2 382; found 382.
Compound 28. To a solution of 115 mg (0.303 mmol) of
57 in 3 mL of DMF was added 138 mg (0.363 mg, 1.2
equiv) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-
uronium hexafluorophosphate, 59 mg (0.46 mmol, 1.5
equiv) of iPr2EtN, and 173 mg (0.758 mmol, 2.5 equiv)
of p-benzyloxy-benzoic acid. The reaction mixture was
stirred at room temperature for 18 h. The solvent was
removed in vacuo (ca. 1 mm Hg, 30 C), and the residue
was dissolved in 10 mL of saturated NaHCO3(aq), fol-
lowed by extraction with CH2Cl2 (2ꢃ15 mL). The sol-
vent was removed in vacuo, and the resultant oil
purified by column chromatography, eluting with 30:1
CH2Cl2 to afford 44 mg (0.074 mmol, 24%) of the cou-
pled product as a colorless oil. IR(cm ꢄ1) 2921, 2849,
1625, 1609. 1H NMR(400 MHz, MeOD) d 0.81 (m,
2H), 1.17 (m, 6H), 1.43 (s, br, 11H), 1.66 (m, br, 13H),
2.07 (d, br, 2H, J=6.8), 2.78 (m, 2H), 3.13 (m, br, 6H),
5.06 (s, 2H), 6.94 (d, 2H, J=8.8), 7.37 (m, 7H). ESI-
MS (LR) [M+H]+ calcd for C36H53N3O4 592; found
592.
Compound 27. To a solution of 281 mg (0.738 mmol) of
51b in 9 mL of 1:1:1H2O/THF/dioxane was added 0.16
mL (1.1 mmol, 1.5 equiv) of NEt3 and 220 mg (0.810
mmol, 1.1 equiv) of 56. The reaction mixture was stirred
at room temperature for 20 h. The solvent was removed
in vacuo, the resultant oil brought up in 15 mL of
CH2Cl2, extracted with saturated NaHCO3(aq) (2ꢃ20
mL), the organic layer dried, and the solvent removed in
vacuo. The resultant oil was purified by column chro-
matography, eluting with 30:1 CH2Cl2/MeOH, to afford
260 mg (0.433 mmol, 58.7%) of the coupled sulfona-
mide product as a clear oil. IR(cm ꢄ1) 3257, 2922, 2850,
1
1686, 1365, 1157. H NMR(400 MHz, CDCl ) d 0.81
3
(m, 2H), 1.16 (m, 3H), 1.38 (s, 9H), 1.41 (m, 2H), 1.63
(m, 11H), 1.86 (s, br, 2H), 2.06 (d, br, 2H, J=6.8), 2.86
(s, br, 4H), 3.18 (br, 2H), 5.06 (s, 2H), 6.99 (d, 2H,
J=8.8), 7.35 (m, 5H), 7.77 (d, 2H, J=8.8); 13C NMR
(125 MHz, CDCl3) d 25.7, 26.3, 27.4, 29.1, 29.2, 31.6,
35.0, 40.5, 40.6, 44.7, 53.4, 65.1, 69.9, 79.7, 114.8, 127.2,
127.7, 128.2, 128.8, 132.1, 136.3, 155.6, 161.8. Anal.
calcd for C33H49N3O5S: C, 66.08; H 8.23; N, 7.01;
found C, 66.44; H, 8.07; N, 6.62.
To a solution of 2 mL of 4.0 M HCl in dioxane was
added 44 mg (0.074 mmol) of the product described
above. The reaction mixture was stirred at room tem-
perature for 2 h, the solvent was removed in vacuo, and
the resultant product was purified by column chroma-
tography, eluting with a gradient of 10:1 CH2Cl2/
MeOH to 90/10/2 CH2Cl2/MeOH/NH4OH to afford 17
mg (0.035 mmol, 47%) of 28 as a colorless oil. 1H NMR
(300 MHz, 1:1 MeOD:CD2Cl2) d 1.17 (m, br, 9H), 1.78
(m, br, 6H), 2.09 (m, br, 6H), 2.92 (d, 2H, J=6.3), 3.09
(m, 4H), 3.49 (m, 7H), 5.11 (s, 2H), 7.03 (d, 2H,
J=11.6), 7.36 (m, 7H). HRMS-FAB (m/z) [M+H]+
calcd for C31H45N3O2 492.3590; found 429.3582.
To a solution of 4.0 M HCl in dioxane was added 130
mg (0.217 mmol) of the sulfonamide described above.
The reaction mixture was stirred for 2 h at room tem-
perature, and the solvent was removed in vacuo to
afford a yellow oil which was purified by column chro-
matography, eluting with a gradient of 10:1 CH2Cl2/
MeOH to 90:10:2 CH2Cl2/MeOH/NH4OH to afford 61
mg (0.12 mmol, 55%) 27 as a clear oil. 1H NMR
(500 MHz, MeOD) d 0.88 (m, 2H), 1.28 (m, 6H), 1.48

J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
3659
Compound 29. Prepared according to general procedure
outlined for compounds 3–15 to afford 29 in 80% yield.
1H NMR(CDCl 3) d 1.59 (dd, J=3.6, 12.2 Hz, 2H), 1.63
(dd, J=3.6, 12.2 Hz, 2H), 1.70 (d, J=10.3 Hz, 2H), 1.79
(quintet, J=5.6 Hz, 2H), 1.92 (dt, J=2.0, 11.6 Hz, 2H),
2.35 (s, 3H), 2.47 (tt, J=4.0, 11.6 Hz, 1H), 2.71 (t,
J=5.6 Hz, 2H), 2.92 (d, J=12.0 Hz, 2H), 3.46 (s, 2H),
3.54 (dd, J=5.2, 11.2 Hz, 2H), 3.84 (s, 6H), 5.04 (s, 2H),
7.02 (s, 2H), 7.22–7.34 (m, 8H), 7.46 (d, J=8.4 Hz, 2H),
8.52 (t, J=4.9 Hz, 1H); HRMS-FAB (m/z) [M+H]+
calcd for C32H42N3O4, 532.3168; found, 532.3175.
Compound 58. N-Debenzylation. Compound 50a (5.42 g,
14.8 mmol) was dissolved in EtOAc (20 mL) and to the
solution was added Pd/C (1.0 g) followed by AcOH
(0.9 g, 14.8 mmol). The reaction vessel was flushed
with H2 and stirred at room temperature for 36 h.
The reaction mixture was then filtered through a Celite
pad and rinsed with MeOH. The filtrate was con-
centrated and purified by silica gel column chromato-
graphy using 45:5:1 CH2Cl2/MeOH/NH4OH to afford
3.5 g of N-debenzylated product as an off-white solid
(85%).
Compound 30. Treatment of 2 with acetyl chloride in
1
CH2Cl2 afforded 30 in 88% yield. H NMR(CDCl ) d
N-Alloc protection. To a solution of the amine (0.30 g,
1.08 mmol) obtained above and Et3N (0.16 g, 1.62
mmol) in CH2Cl2 (10 mL) was added dropwise a solu-
tion of allyl chloroformate (0.16 g, 1.30 mmol) in
CH2Cl2 (5 mL) at 0 ꢂC. The reaction mixture was stirred
at 0 ꢂC for 15 min. The reaction solution was washed
with 1 N HCl (10 mL) and then saturated NaHCO3 (10
mL). The organic layer was dried over Na2SO4 and
concentrated. Silica gel column chromatography using
97:3 CH2Cl2/MeOH yielded 0.33 g of product as an off-
white solid (85%).
3
1.68 (d, J=10.4 Hz, 2H), 1.76 (quintet, J=6.0 Hz, 2H),
1.84 (dd, J=3.6, 12.2 Hz, 2H), 1.88 (2dd, J=3.6, 12.2
Hz, 2H), 2.04 (t, J=12.0 Hz, 2H), 2.15 (s, 3H), 3.00 (d,
J=12.0 Hz, 2H), 3.36–3.39 (m, 2H), 3.44 (t, J=6.4 Hz,
2H), 3.52 (s, 2H), 3.50–3.54 (m, 1H), 3,89 (s, 6H), 5.05 (s,
2H), 7.25 (s, 2H), 7.27–7.35 (m, 8H), 7.45–7.48 (m, 2H),
8.17 (t, J=5.1 Hz, 1H); HRMS-FAB (m/z) [M+H]+
calcd for C33H42N3O5 560.3141; found 560.3124.
Compound 31. To 100 mg (0.20 mmol) of 10 in 1 mL of
THF was added 0.55 mL (0.60 mmol, 3 equiv) of dis-
tilled isobutyraldehyde. AcOH was added dropwise
until the pH was approximately equal to 7. To this
solution was added 85 mg (0.40 mmol, 2 equiv) of
NaBH(OAc)3. The reaction mixture was stirred at room
temperature for 12 h. The solvent was removed in vacuo
and the resultant product brought up in saturated
NaHCO3(aq) (30 mL) and extracted with CH2Cl2 (3ꢃ30
mL). The combined organic layers were washed with
water (1ꢃ30 mL), dried, concentrated in vacuo and
purified by column chromatography, eluting with 30:1
CH2Cl2/MeOH to afford 30 mg (0.052 mmol, 26%) of
31 as a colorless oil. IR(cm ꢄ1) 3305, 2921, 2849, 1632.
Azide 58 was prepared according to the procedure
1
described previously for compounds 51a and 51b: H
NMR(CDCl ) d 1.43 (s, 9H), 1.52–1.67 (m, 4H), 1.76
3
(quintet, J=6.8 Hz, 2H), 2.77 (bs, 2H), 3.11 (bs, 2H),
3.29 (t, J=6.4 Hz, 2H), 4.24 (bs, 2H), 4.57 (d, J=5.2
Hz, 2H), 5.20 (dd, J=1.2, 12.0 Hz, 1H), 5.28 (dd,
J=1.6, 17.2 Hz, 1H), 5.93 (ddd, J=1.2, 12.0, 17.2 Hz,
1H).
Compound 59. Amide 59 was prepared by reduction of
azide 58 (as for 51a and 51b) and acylated to afford 59
1
in 90% overall yield: H NMR(CDCl ) d 1.48 (s, 9H),
3
1H NMR(500 MHz, CDCl ) d 0.818 (m, 2H), 0.86 (d,
1.62–1.80 (m, 6H), 2.63 (t, J=9.6 Hz, 2H), 3.15 (d,
J=12.4 Hz, 2H), 3.44 (t, J=6.0 Hz, 2H), 3.41–3.48 (m,
2H), 3.71 (bs, 1H), 3.89 (s, 6H), 5.06 (s, 2H), 7.22 (s,
2H), 7.29–7.36 (m, 3H), 7.48 (d, J=6.8 Hz, 2H), 8.20
(bs, 1H).
3
6H, J=6.5), 1.20 (m, 4H), 1.41 (m, 1H), 1.54 (m, 3H),
1.65 (m, 11H), 2.04 (d, 2H, J=7), 2.17 (d, 2H, J=7),
2.46 (m, 1H), 2.60 (t, 2H, J=5.5), 2.87 (d, br, 1H,
J=12), 3.54 (q, 2H, J=6), 3.84 (s, 6H), 5.04 (s, 2H),
6.96 (s, 2H), 7.32 (m, 3H), 7.37 (m, br, 1H), 7.45 (m,
2H). 13C NMR(125 MHz, CDCl ) d 21.1, 26.1, 26.7,
3
General procedure of the synthesis of compounds 33–43
27.2, 27.2, 32.0, 35.3, 40.3, 50.3, 54.1, 54.6, 56.2, 57.8,
59.3, 65.7, 74.9, 104.3, 127.9, 128.1, 128.5, 130.9, 137.4,
139.2, 153.3, 167.4. HRMS-FAB (m/z) [M+H]+ calcd
for C35H53N3O4 580.4114; found 580.4118.
In a parallel format, a solution of the amine 59 (50 mg,
0.095 mmol) in MeOH (1 mL) was placed in a sample
vial. To this solution was added aldehyde (0.47 mmol)
in MeOH (1 mL) followed by NaBH3CN (930 mg, 0.47
mmol). The pH of the reaction was adjusted to ꢀ6 by
adding AcOH (50 mL). The reaction mixture was stir-
red at room temperature for 48 h and then diluted
with CH2Cl2 (3 mL). A strongly acidic ion exchange
resin (1 mL resin bed) was added to the solution and
stirred for 20 h. The resin was filtered and rinsed with
MeOH (2ꢃ3 mL). The resin was then eluted with 2 M
NH3 in MeOH (2ꢃ3 mL) and the filtrate was con-
centrated. Chromatograpy of the product on a short
plug of using 45:5:1 CH2Cl2/MeOH/NH4OH yielded
pure compounds 33–43 (34–94% yield). Each com-
pound was stored as the HCl salt which was obtained by
treating the oily residue with 1 M HCl/ether followed by
concentration.
Compound 32. Prepared as described for 31 using ben-
zaldehyde to afford 50 mg (0.082 mmol, 41%) of 32 as a
colorless oil. IR(cm ꢄ1) 3306, 2921, 2848, 1651. 1H
NMR(400 MHz, CDCl ) 0.84 (m, 2H), 1.19 (m, 3H),
3
1.45 (m, 1H), 1.68 (m, 13H), 2.09 (d, br, 2H, J=6.5),
2.56 (m, 1H), 2.70 (t, 2H, J=5.50), 2.94 (d, br, 2H,
J=10), 3.49 (q, 2H, J=5.5), 3.61 (s, 2H), 3.71 (s, 6H),
5.05 (s, 2H), 6.88 (s, 2H), 7.15–7.35 (m, 8H), 7.46 (m,
2H); 13C NMR(125 MHz, CDCl ) d 26.1, 26.3, 26.7,
3
27.2, 32.0, 35.3, 40.1, 48.9, 54.0, 54.7, 56.1, 57.0, 65.5,
75.9, 104.5, 127.1, 127.9, 128.1, 128.3, 128.5, 129.0,
130.4, 136.6, 137.5, 139.3, 153.2, 167.0. HRMS-FAB
(m/z) [M+H]+ calcd for C38H51N3O4 614.3958; found
614.3951.

3660
J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
1
Compound 33. H NMR(CDCl ) d 1.27 (dd, J=3.6,
2H), 3.56 (q, J=4.0 Hz, 2H), 3.87 (s, 6H), 5.06 (s, 2H),
5.93 (s, 2H), 6.70 (dd, J=1.2, 8.0 Hz, 1H), 6.74 (d,
J=7.6 Hz, 1H), 6.82 (d, J=1.2 Hz, 1H), 7.02 (s, 2H),
7.28–7.36 (m, 3H), 7.47 (d, J=7.2 Hz, 2H), 8.10 (bs,
1H); MALDI calcd for C32H39N3O6=561.67,
obsd=560.20. Anal. calcd for C39N3O62HCl: C, 60.57;
H, 6.51; N, 6.62; Found: C, 60.46; H, 6.73; N, 6.65.
3
12.2 Hz, 2H), 1.31 (dd, J=3.6, 12.2 Hz, 2H), 1.64 (bs,
1H), 1.75 (quintet, J=6.0 Hz, 2H), 1.82 (d, J=12.8 Hz,
2H), 2.02 (t, J=10.0 Hz, 2H), 2.40 (tt, J=4.0, 10.0 Hz,
1H), 2.83 (t, J=5.2 Hz, 2H), 2.90 (d, J=12.0 Hz, 2H), 2.95
(d, J=5.2 Hz, 2H), 3.55 (q, J=5.6 Hz, 2H), 3.78 (s, 6H),
4.18 (t, J=7.6 Hz, 1H), 5.05 (s, 2H), 7.00 (s, 2H), 7.16–7.37
(m, 13H), 7.48 (d, J=6.8 Hz, 2H), 8.11 (bs, 1H); MALDI
calcd for C38H45N3O4=607.78, obsd=605.57.
1
Compound 39. H NMR(CDCl ) d 1.36 (dd, J=3.6,
3
12.2 Hz, 2H), 1.41 (dd, J=3.6, 12.2 Hz, 2H), 1.76
(quintet, J=5.6 Hz, 2H), 1.87 (d, J=11.6 Hz, 2H), 1.98
(t, J=11.6 Hz, 2H), 2.35 (s, 3H), 2.46 (tt, J=4.0, 10.0
Hz, 1H), 2.84 (t, J=6.0 Hz, 2H), 2.85 (d, J=11.6 Hz,
2H), 3.43 (s, 2H), 3.55 (q, J=6.0 Hz, 2H), 3.86 (s, 6H),
5.06 (s, 2H), 7.03 (s, 2H), 7.08 (t, J=7.2 Hz, 2H), 7.11
(s, 1H), 7.20 (t, J=7.2 Hz, 1H), 7.27–7.39 (m, 3H), 7.47
(d, J=6.8 Hz, 2H), 8.12 (bs, 1H); HRMS-FAB (m/z)
[M+H]+ calcd for C32H42N3O4 532.3163; found
532.3175.
1
Compound 34. H NMR(CDCl ) d 1.39 (dd, J=3.6,
3
12.2 Hz, 2H), 1.43 (dd, J=3.6, 12.2 Hz, 2H), 1.79
(quintet, J=6.0 Hz, 2H), 1.81 (bs, 1H), 1.93 (d, J=12.0
Hz, 2H), 2.04 (t, J=12.0 Hz, 2H), 2.45 (tt, J=4.0, 10.0
Hz, 1H), 2.57 (dd, J=6.0, 10.8 Hz, 2H), 2.79 (dd,
J=6.0, 10.8 Hz, 2H), 2.85 (t, J=6.0 Hz, 2H), 2.96 (d,
J=11.6 Hz, 2H), 3.56 (q, J=5.6 Hz, 2H), 3.86 (s, 6H),
5.05 (s, 2H), 7.02 (s, 2H), 7.19 (d, J=5.6 Hz, 2H), 7.27–
7.36 (m, 3H), 7.47 (d, J=6.8 Hz, 2H), 7.98 (bs, 1H);
HRMS-FAB (m/z) [M+H]+ calcd for C32H42N3O4
532.3176; found 532.3174.
1
Compound 40. H NMR(CDCl ) d 1.36 (dd, J=3.6,
3
12.2 Hz, 2H), 1.41 (dd, J=3.6, 12.2 Hz, 2H), 1.76
(quintet, J=6.0 Hz, 2H), 1.87 (d, J=12.4 Hz, 2H), 2.02
(t, J=12.0 Hz, 2H), 2.44 (tt, J=4.0, 10.0 Hz, 1H), 2.58
(t, J=6.0 Hz, 2H), 2.83 (t, J=6.4 Hz, 2H), 2.90 (d,
J=12.0 Hz, 2H), 3.55 (t, J=6.0 Hz, 2H), 3.56 (t, J=6.0
Hz, 2H), 3.86 (s, 6H), 4.53 (s, 2H), 5.05 (s, 2H), 7.01 (s,
2H), 7.28–7.36 (m, 8H), 7.47 (d, J=6.8 Hz, 2H), 7.99
(bs, 1H); HRMS-FAB (m/z) [M+H]+ calcd for
C33H44N3O5, 562.3272; found, 562.3281.
1
Compound 35. H NMR(CDCl ) d 1.35 (dd, J=3.6,
3
12.2 Hz, 2H), 1.39 (dd, J=3.6, 12.2 Hz, 2H), 1.75
(quintet, J=5.6 Hz, 2H), 1.86 (d, J=12.4 Hz, 2H), 2.03
(t, J=11.6 Hz, 2H), 2.43 (tt, i=4.0, 10.0 Hz, 1H), 2.82
(t, J=5.6 Hz, 2H), 2.94 (d, J=11.6 Hz, 2H), 3.55 (q,
J=5.6 Hz, 2H), 3.68 (s, 2H), 3.76 (s, 3H), 3.81 (s, 6H),
5.05 (s, 2H), 6.99 (s, 1H), 7.01 (s, 2H), 7.12 (dt, J=1.2,
6.8 Hz, 1H), 7.23 (dt, J=1.2, 6.8 Hz, 1H), 7.29–7.36 (m,
4H), 7.47 (d, J=8.4 Hz, 2H), 7.68 (d, J=7.6 Hz, 1H),
8.05 (bs, 1H); HRMS-FAB (m/z) [M+H]+ calcd for
C34H43N4O4 571.3295; found 571.3284.
1
Compound 41. H NMR(CDCl ) d 1.32 (dd, J=3.6,
3
12.2 Hz, 2H), 1.36 (dd, J=3.6, 12.2 Hz, 2H), 1.76
(quintet, J=6.0 Hz, 2H), 1.87 (d, J=12.0 Hz, 2H), 1.97
(t, J=11.6 Hz, 2H), 2.00 (bs, 1H), 2.46 (tt, J=4.0, 10.0 Hz,
1H), 2.79 (d, J=11.6 Hz, 2H), 2.82 (t, J=6.0 Hz, 2H), 3.45
(s, 1H), 3.48 (s, 2H), 3.55 (q, J=5.6 Hz, 2H), 3.86 (s, 6H),
5.06 (s, 2H), 6.00 (dd, J=2.8, 5.6 Hz, 1H), 6.11 (dd, J=2.8,
5.6 Hz, 1H), 6.74 (dd, J=2.8, 4.2 Hz, 1H), 7.02 (s, 2H),
7.29–7.36 (m, 3H), 7.47 (d, J=8.4 Hz, 2H), 7.93 (bs, 1H);
MALDI calcd for C29H38N4O4=506.64, obsd=504.45.
1
Compound 36. H NMR(CDCl ) d 1.39 (dd, J=3.6,
3
12.2 Hz, 2H), 1.43 (dd, J=3.6, 12.2 Hz, 2H), 1.75
(quintet, J=6.0 Hz, 2H), 1.87 (d, J=11.2 Hz, 2H), 2.04
(t, J=11.6 Hz, 2H), 2.45 (tt, J=4.0, 10.0 Hz, 1H), 2.84
(t, J=5.6 Hz, 2H), 2.88 (d, J=11.6 Hz, 2H), 3.56 (q,
J=6.4 Hz, 2H), 3.63 (s, 2H), 3.87 (s, 6H), 5.06 (s, 2H),
7.03 (s, 2H), 7.28–7.36 (m, 3H), 7.45–7.49 (m, 5H), 7.71
(s, 1H), 7.79–7.84 (m, 3H), 8.14 (bs, 1H); MALDI calcd
for C35H41N3O4=567.72, obsd=565.43. Anal. calcd for
C35H41N3O42HCl: C, 65,62; H, 6.76; N, 6.56; Found: C,
65.48; H, 6.60; N, 6.52.
1
Compound 42. H NMR(CDCl ) d 1.33 (dd, J=3.6,
3
12.2 Hz, 2H), 1.38 (dd, J=3.6, 12.4 Hz, 2H), 1.73
(quintet, J=6.0 Hz, 2H), 1.86 (d, J=12.4 Hz, 2H), 1.93
(t, J=11.6 Hz, 2H), 2.22 (s, 3H), 2.41 (tt, J=4.0, 10.4
Hz, 1H), 2.76 (d, J=12. 0 Hz, 2H), 2.80 (t, J=6.0 Hz,
2H), 3.52 (q, J=6.4 Hz, 2H), 3.83 (s, 6H), 5.03 (s, 2H),
7.00 (s, 2H), 7.25–7.36 (m, 3H), 7.45 (d, J=8.0 Hz, 2H),
7.97 (t, J=4.8 Hz, 1H); HRMS-FAB (m/z) [M+H]+
calcd for C25H36N3O4 442.2706; found 442.2728.
1
Compound 37. H NMR(CDCl ) d 1.38 (dd, J=3.0,
3
12.0 Hz, 2H), 1.42 (dd, J=3.0, 12.0 Hz, 2H), 1.71 (bs,
1H), 1.76 (t, J=5.6 Hz, 2H), 1.89 (d, J=10.4 Hz, 2H),
2.05 (t, J=11.2 Hz, 2H), 2.46 (tt, J=4.0, 10.0 Hz, 1H),
2.86 (t, J=5.6 Hz, 2H), 2.89 (d, J=11.6 Hz, 2H), 3.51
(s, 2H), 3.57 (q, J=6.0 Hz, 2H), 3.88 (s, 6H), 5.06 (s,
2H), 7.03 (s, 2H), 7.27–7.38 (m, 6H), 7.44–7.48 (m, 4H),
7.54–7.61 (m, 4H), 8.12 (bs, 1H); MALDI calcd for
C37H43N3O4=593.76, obsd=591.36. Anal. calcd for
C37H43N3O42HCl: C, 66.80; H, 6.80; N, 6.30; Found: C,
66.80; H, 7.00; N, 6.42.
1
Compound 43. H NMR(CDCl ) d 1.35 (dd, J=3.6,
3
12.0 Hz, 2H), 1.39 (dd, J=3.6, 12.0 Hz, 2H), 1.79
(quintet, J=5.6 Hz, 2H), 1.89 (d, J=12.0 Hz, 2H), 2.06
(t, J=11.6 Hz, 2H), 2.49 (tt, J=4.0, 10.8 Hz, 1H), 2.82
(t, J=6.0 Hz, 2H), 2.89 (d, J=11.6 Hz, 2H), 2.97 (d,
J=7.2 Hz, 2H), 3.54 (q, J=6.0 Hz, 2H), 4.20 (t, J=7.6
Hz, 1H), 5.09 (s, 2H), 6.97 (d, J=8.8 Hz, 2H), 7.16–7.20
(m, 2H), 7.24–7.30 (m, 8H), 7.35–7.46 (m, 5H), 7.80 (d,
J=8.8 Hz, 2H), 8.28 (t, J=4.8 Hz, 1H); HRMS-FAB
(m/z) [M+H]+ calcd for C36H42N3O2 548.3269; found
548.3277.
1
Compound 38. H NMR(CDCl ) d 1.35 (dd, J=3.6,
3
12.2 Hz, 2H), 1.39 (dd, J=3.6, 12.2 Hz, 2H), 1.77
(quintet, J=6.0 Hz, 2H), 1.87 (d, J=12.0 Hz, 2H), 1.95
(t, J=12.0 Hz, 2H), 2.46 (tt, J=4.0, 10.0 Hz, 1H), 2.81
(d, J=12.0 Hz, 2H), 2.85 (t, J=5.6 Hz, 2H), 3.37 (s,

J. M. Kim et al. / Bioorg. Med. Chem. 10 (2002) 3649–3661
3661
Compound 60. Debenzylation of 50a according to the
procedure for the synthesis of 58 followed by acylation
with cyclohexane carboxylic acid using HATU provided
J=11.6 Hz, 2H), 2.96 (d, J=7.6 Hz, 2H), 3.72 (s, 2H),
3.81 (s, 6H), 4.19 (t, J=8.0 Hz, 1H), 4.99 (s, 2H), 6.54
(s, H), 7.19–7.20 (m, 2H), 7.23–7.31 (m, 9H), 7.33–7.37
(m, 2H), 7.51 (d, J=8.0 Hz, 2H); MALDI calcd for
C38H47N3O3=593.80, obsd=590.09.
1
compound 60. H NMR(CDCl ) d 1.14–1.30 (m, 4H),
3
1.50 (s, 9H), 1.51–1.60 (m, 3H), 1.61–1.80 (m, 8H), 1.90
(quintet, J=6.8 Hz, 2H), 2.40–2.45 (m, 2H), 2.91–3.05
(m, 1H), 3.09–3.21 (m, 2H), 3.48 (t, J=6.4 Hz, 2H), 3.93
(d, J=12.4 Hz, 1H), 4.70 (d, J=12.0 Hz, 1H).
Acknowledgements
Compound 44. Conversion of the chloro group in 60 to
an amino group as described for the synthesis of com-
pounds 51a and 51b afforded 61. Reductive amination
We gratefully acknowledge the support of the Medicines
for Malaria Venture and the Burroughs Wellcome
Foundation. The Center for New Directions in Organic
Synthesis is supported by Bristol-Myers Squibb as
Sponsoring Member.
with 4-benzyloxybenzaldehyde as described for 23, 24,
1
and 48, afforded 44. H NMR(CDCl ) d 1.20–1.40 (m,
3
5H), 1.43–1.58 (m, 2H), 1.65–1.73 (m, 3H), 1.85–1.95
(m, 6H), 2.46 (tt, J=3.2, 8.4 Hz, 1H), 2.64 (t, J=11.6
Hz, 1H), 2.74 (tt, J=3.6, 10.8 Hz, 1H), 2.79–2.90 (m,
4H), 3.03 (t, J=12.8 Hz, 1H), 3.81 (d, J=4.0 Hz, 2H),
3.88 (d, J=14.4 Hz, 1H), 4.52 (d, J=13.2 Hz, 1H), 5.06
(s, 2H), 6.95 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz,
2H), 7.31–7.44 (m, 5H); HRMS-FAB (m/z) [M+H]+
calcd for C29H40N3O3 478.3062; found 478.3070.
References and Notes
1. Woster, P. M. Annu. Rep. Med. Chem. 2001, 36, 99.
2. Murray, M. C.; Perkins, M. E. Annu. Rep. Med. Chem.
1996, 31, 141.
3. Wirth, D. F. Ann. Rep. Med. Chem. 1999, 34, 349.
4. Haque, T. S.; Skillman, G. A.; Lee, C. E.; Habashita, H.;
Gluzman, I. Y.; Ewing, T. J. A.; Goldberg, D. E.; Kuntz, I. D.;
Ellman, J. A. J. Med. Chem. 1999, 42, 1428.
Compound 45. LAH reduction of 10 afforded 45 in 79%
1
yield. H NMR(CDCl ) d 0.83, 0.87 (2d, J=12.2 Hz,
3
5. Francis, S. E.; Sullivan, D. J. Jr.; Goldberg, D. E. Annu.
Rep. Med. Chem. 1997, 51, 97.
2H), 1.13–1.26 (m, 3H), 1.34 (dd, J=3.6, 12.4 Hz, 2H),
1.38 (2dd, J=3.6, 12.4 Hz, 2H), 1.42–1.50 (m, 1H),
1.64–1.80 (m, 9H), 1.81–1.92 (m, 4H), 2.08 (d, J=7.2
Hz, 2H), 2.41 (tt, J=3.2, 8.4 Hz, 1H), 2.72 (dt, J=1.6,
6.8 Hz, 2H), 2.81 (d, J=12.0 Hz, 2H), 3.72 (s, 2H), 3.83
(s, 6H), 4.99 (s, 2H), 6.5 (s, 2H), 7.28–7.49 (m, 3H), 7.50
(d, J=8.4 Hz, 2H); HRMS-FAB (m/z) [M+H]+ calcd
for C35H40N3O2, 534.3118; found, 532.3121.
6. Gluzman, I. Y.; Francis, S. E.; Oksman, A.; Smith, C. E.;
Duffin, K. L.; Goldberg, D. E. J. Clin. Invest. 1994, 93, 1602.
7. Matayoshi, E. D.; Wang, G. T.; Krafft, G. A.; Erickson, J.
Science 1990, 241, 70. Krafft, G. A.; Wang, G. T. Methods
Enzymol. 1994, 241, 70.
8. Sullivan, D. J.; Gluzman, I. Y.; Russel, D. G.; Goldberg,
D. E. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 11865.
9. Thompson, L. A.; Tebben, A. J. Annu. Rep. Med. Chem.
2001, 36, 247.
Compound 46. LAH reduction of compound 33 afforded
1
10. Bartra, M.; Urpi, F.; Vilarraso, J. Tetrahedron Lett. 1987,
28, 5941.
46 in 44% yield. H NMR(CDCl ) d 1.24 (dd, J=3.6,
3
12.2 Hz, 2H), 1.29 (2dd, J=3.6, 12.2 Hz, 2H), 1.72
(quintet, J=6.8 Hz, 2H), 1.79 (d, J=11.6 Hz, 2H), 1.96
(bs, 1H), 2.05 (dt, J=2.0, 9.6 Hz, 2H), 2.41 (tt, J=3.2,
8.4 Hz, 1H), 2.71 (dt, J=2.0, 6.8 Hz, 2H), 2.87 (d,
11. Liu, Y.; Zhao, C.; Bergbreiter, D.; Romo, D. J. Org.
Chem. 1998, 63, 3471.
12. Choi, C., Kim, J. M., Gluzman, I. Y., Goldberg, D. E.,
Ellman, J. A., Marletta, M. A. Chem. Biol. In press.