Synthesis and biological evaluation of novel isopropanolamine derivatives as non-peptide human immunodeficiency virus protease inhibitors

Article abstract of DOI:10.1248/cpb.56.1147

Novel potential human immunodeficiency virus (HIV) protease inhibitors were designed by a combination of nelfinavir and amprenavir motifs. The designed compounds were prepared by a facile synthetic route and their stereochemistry was further confirmed by

Full text of DOI:10.1248/cpb.56.1147

August 2008
Chem. Pharm. Bull. 56(8) 1147—1152 (2008)
1147
Synthesis and Biological Evaluation of Novel Isopropanolamine
Derivatives as Non-peptide Human Immunodeficiency Virus Protease
Inhibitors
Lijun ZHOU, Qingang YANG, Yong WANG, Youhong HU, Xiaomin LUO, Donglu BAI, and Shukun LI*
Shanghai Institute of Materia Medica, Chinese Academy of Sciences; Shanghai 201203, China.
Received March 28, 2008; accepted April 30, 2008; published online May 22, 2008
Novel potential human immunodeficiency virus (HIV) protease inhibitors were designed by a combination
of nelfinavir and amprenavir motifs. The designed compounds were prepared by a facile synthetic route and
their stereochemistry was further confirmed by a stereospecific synthesis from commercially available (S)-2-oxi-
ranylmethyl m-nitrobenzenesulfonate. All compounds were tested for their ability in inhibiting HIV type 1 pro-
tease activity with the published method of reference 19. Derivatives 1a—u exhibited moderate to significant
inhibitory activities in preliminary bioassay. The best compound 1a has IC50 value of 0.02 mM, comparable to that
of amprenavir. A docking study on compounds 1a—u was performed using the published X-ray crystal structure
of HIV type 1 protease, all compounds bound to the HIV type 1 protease in an extended conformation and the
scaffoldings of the binding conformations could be aligned quite well. Comparative molecular field analysis
(CoMFA) study was performed to explore the specific contributions of electrostatic and steric effects in the bind-
ing of these new compounds to HIV type 1 protease and a predictive CoMFA model was built with thirteen com-
pounds as training set. Test analysis of other five compounds as test set demonstrated that the CoMFA model has
strong predictive ability to this series of compounds. It will be very useful to further optimize the designed
inhibitors.
Key words isopropanolamine derivative; protease inhibitor; biological evaluation; docking study; predictive model
Discovery of highly active antiretroviral therapy (HAART)
represents a significant advance in the management of ac-
quired immune deficiency syndrome (AIDS).1,2) As one of
the crucial ingredients in HAART, protease inhibitors (PIs)
play an important role in preventing the replication of human
immunodeficiency virus (HIV). Although several HIV PIs
have been used in clinical practice, emergence of viral resist-
ance,3,4) adverse side effects5—10) and high costs of the pro-
duction have limited their utilization. Development of novel
HIV PIs against multi-drug resistant viral strains with unique
profiles, is still urgently required for HAART.
It is proposed that non-peptidic HIV PIs bind to the en-
zyme active sites differently compared with the conventional
Fig. 1. Design of Derivatives 1 as New HIV PIs
peptidomimetic drugs, and the speed of emergence of drug-
resistant strains would be slowed down due to the different
binding mode.11) As a bioisostere of peptide backbone, iso-
propanolamine was found to be a binding determinant by the
structural analysis of peptidomimetic drugs.12—14) Moreover,
the decahydroisoquinoline moiety in nelfinavir and saquinavir
would interact with the subsites of the enzyme and signifi-
cantly affect the antiviral and pharmacokinetic properties of
the hybrid compounds.15,16) The methyl sulfonamide moiety
of amprenavir has also been proved to be capable of effi-
ciently interacting with both S1 and S2 enzyme pockets.13)
Therefore, we designed a series of hybrid molecules as non-
peptidic HIV PIs by incorporating methyl sulfonamide moi-
ety of amprenavir into hydroxyethyl decahydroisoquinoline
backbone of nelfinavir (Fig. 1).
Chemistry
The designed compounds were synthesized using the
method as depicted in Chart 1. Reductive amination between
allylamine 2 and isobutylaldehyde followed by sulfonylation
with p-nitrobenzenesulfonyl chloride afforded the sulfon-
Reagents and conditions: a) isobutylaldehyde, anhydrous Na2SO4, CH2Cl2, NaBH4;
b) p-nitrobenzenesulfonyl chloride, TEA, CH2Cl2, 0 °C; c) m-CPBA, CH2Cl2, 50 °C; d)
5, methanol, 50—60 °C; e) H2, 10% Pd–C, methanol.
Chart 1. Synthesis of Compound 1a
∗ To whom correspondence should be addressed. e-mail: shukunli@mail.shcnc.ac.cn
© 2008 Pharmaceutical Society of Japan

1148
Vol. 56, No. 8
amide 3. Epoxidation of the terminal double bond in com- ing of epoxide 8 with isobutylamine followed by subsequent
pound 3 resulted in racemic epoxide 4. The (3S)-decahy- sulfonylation of compound 9 with p-nitro benzenesulfonyl
droisoquinoline-3-formamide 5 was prepared utilizing the chloride and final reduction of the nitro group afforded the
method of Göhring.17) Epoxide 4 was treated with amide 5 in compound 1a. The spectra data of compound 1a obtained
methanol to provide a pair of separable diastereomers, 6 and from this route were identical with that from Chart 1. More-
its S-epimer, which could be easily separated by column over, compounds 1b—u also could be synthesized stereose-
chromatography in approximately a 1 : 1 ratio. The nitro lectively using the method from epoxide 8.
group in 6 was further hydrogenated in the presence of 10%
Biological Activity The synthesized compounds were
Pd–C to afford the desired compound 1a. In addition, other assayed for inhibitory activities against the wild-type HIV
designed compounds 1b—u could be easily synthesized by type 1 protease enzyme using the published method19) and
the same method.
the results were shown in Table 1. Amprenavir and indinavir
Stereochemistry of compound 1a was further confirmed were applied as reference compounds. The IC50 value of am-
by a stereospecific synthesis from commercially available prenavir was determined as 0.01 mM in this system.20) In gen-
(S)-2-oxiranylmethyl m-nitrobenzenesulfonate 7 (Chart 2). eral, compounds 1a—u exhibited moderate to significant
First condensation with amide 5 yielded the desired epoxide inhibitory activities against HIV protease enzyme. When R
8,18) which is an important intermediate for the synthesis of group in 1 was changed from alkyl to aryl substituents,
enantiomerically isopropanolamine derivatives. Ring-open- inhibitory activities dropped accordingly. For example deriv-
atives 1a, 1f and 1j were 4—100 times more potent than 1p
and 1t. Moreover, investigation in Rꢀ group indicated that
para-amino substitution provided the best potency in each
case. Derivatives 1a, 1f, 1p and 1t were more potent than
their corresponding counterparts 1b—d, 1e, 1g, 1h, 1o, 1q,
1r, 1s and 1u respectively, probably due to formation of the
stronger hydrogen bond than that of the para-methoxy, para-
or meta-nitro and meta-amino substituents. In particular,
compound 1a (IC50ꢁ0.02 mM) was essentially comparable in
potency to amprenavir (IC50ꢁ0.01 mM).
Molecular Modeling A docking study was performed
using the published X-ray crystal structure of HIV type 1
protease complexed with nelfinavir (PDB entry code: 1ohr)21)
Reagents and conditions: a) 5, iPr2NEt, DMF, 60 °C; b) isobutylamine, methanol,
60 °C; c) p-nitrobenzenesulfonyl chloride, TEA, CH2Cl2, 0 °C; d) H2, 10% Pd–C,
methanol.
as the template structure. The initial structures of compounds
Chart 2. Stereospecific Synthesis of Compound 1a
1a—u were generated by Sybyl and subsequently optimized
Table 1. Inhibitory Activities of Compounds 1a—u to HIV-1 PR
Entry
R
Rꢀ
IC50 (mM)
Entry
R
Rꢀ
IC50 (mM)a)
1a
1b
1c
1d
1e
1f
iPr
iPr
iPr
iPr
Et
p-NH2
m-NO2
m-NH2
p-OMe
p-NO2
p-NH2
m-NH2
p-OMe
p-OMe
p-NH2
p-OMe
0.02
ꢂ200
0.38
1l
1m
1n
1o
1p
1q
1r
1s
p-NO2
m-NO2
p-OMe
p-OMe
p-NH2
m-NH2
p-OMe
p-NO2
p-NH2
m-NH2
33.16
29.85
19.73
ꢂ200
7.20
13.83
35.75
0.47
Et
10.39
42.43
37.10
1.78
1g
1h
1i
Et
49.87
14.80
3.74
Et
Cy
Bn
Ph
1t
1j
0.05
1u
89.43
1k
4.88
a) All IC50 values are measured based on serial dilutions of compound concentration, every inhibitory rate is the mean of three runs with the variation of the mean less than
20%.

August 2008
1149
Fig. 2. Interactions between HIV Protease and Compound 1a in the Docked Complex
(A) 3D representation. Enzyme is shown in cartoon style; the residues within 3 Å around 1a are shown in line style; water and 1a are shown in stick style; hydrogen bonds are
represented as dashed lines. (B) 2D representation drawn by LIGPLOT. Dashed lines represent hydrogen bonds and spiked residues form hydrophobic contacts with the inhibitors.
Table 2. Predicted Activities (PA) vs. Experimented Activities (EA,
ꢄlog IC50) and Residues (D)
using the Powell method with Tripos force field and
Gasteiger–Hückel charges. In order to identify their binding
conformations and positions, AutoDock 3.0.5 was used to
dock these compounds to the enzyme, for which the Lamar-
ckian genetic algorithm (LGA) was applied. The population
size, the maximum number of energy evaluations, and dock-
ing runs was set to 120, 12000000, and 30, respectively.
To fully explore the specific contributions of electrostatic
and steric effects in the binding of these new compounds
to HIV type 1 protease and to build predictive quantitative
structure–activity relationship (QSAR) models, comparative
molecular field analysis (CoMFA) study was performed by
using conformations and their alignment at the binding site,
which resulted from the molecular docking. Steric and elec-
trostatic interactions were calculated using a sp3 carbon atom
Compounds EA
PA
D
Compounds EA
PA
D
1a
1c
1d
1e
1f
7.72
6.42
4.86
4.45
6.33
4.30
5.43
7.28
5.32
7.81
6.30
4.88
4.52
6.33
4.52
5.37
7.25
5.20
0.09
ꢄ0.12
0.02
0.07
0.00
1l
4.48
4.52
4.71
5.14
4.98
4.37
4.43
5.75
4.05
4.39
4.49
4.78
5.11
5.13
4.44
4.01
5.54
4.02
ꢄ0.09
ꢄ0.03
0.07
ꢄ0.03
0.15
1m
1na)
1p
1qa)
1r
1g
1i
0.22
0.07
ꢄ0.06
ꢄ0.03
ꢄ0.13
1sa)
1ta)
1u
ꢄ0.42
ꢄ0.22
ꢄ0.03
1j
1ka)
a) Compounds in test set.
as steric probe and a ꢃ1 charge as electrostatic probe with the sulfonamide moiety and the carbonyl of the decahy-
Tripos force field. Regression analysis was performed using droisoquinoline formamide moiety each accept a hydrogen
partial least square (PLS) algorithm. The final model was bond from the “flap” water that stabilizing the complex by
developed with the optimum number of components equal to forming another two hydrogen bonds with the flexible flaps
that yielding the highest q2.
(Ile 50 and Ile 50ꢀ, 2.93 Å and 2.88 Å). The hydroxyl, amino
and carbonyl groups in 1a are all located in ideal positions
and orientations, which was thought to maximize the hydro-
Results and Discussion
All compounds bind to the HIV type 1 protease in an gen bond interactions with HIV protease. In comparison with
extended conformation and the scaffoldings of the binding nelfinavir, no new amino acid residues were found within a
conformations could be aligned quite well. A representative distance of forming additional hydrogen bonds which may
result is depicted in Fig. 2 using the structure of compound indicate the huge rooms to optimize the designed molecular
1a, which has the highest inhibitory activity. As the other structure for potency improvement.
compounds, 1a has carbon-rich groups arrayed along either
Thirteen compounds among the synthesized derivatives
side, interacting with hydrophobic subsites of the pocket. were used as training set to build QSAR model while five
The tert-butyl group is situated at the S2ꢀ subsite of the bind- compounds constituted the test set for validation. A 6-com-
ing pocket. The decahydroisoquinoline ring occupies the S1ꢀ ponent of CoMFA model was obtained with cross-validated
subsite. The iso-butyl moiety resides in the S3 subsite, and q2 of 0.557, conventional r2 of 0.997, F value of 471, and
the p-amino-phenyl group occupies the S2 pocket, with standard error of 0.08, respectively. To test the reliability and
amino group hydrogen bonding to ASP30 (2.69 Å). Besides predictive ability of the constructed model, the inhibitory ac-
these hydrophobic interactions, there are some typical hydro- tivities of the five compounds in test set were predicted by it.
gen bonds also observed in the majority of HIV type 1 pro- Table 2 summarizes the correlation between experimental
tease-derivatives 1a—u complexes. With a network of hydro- and predicted values of the eighteen studied compounds. The
gen bonds, the central hydroxyl group binds to the catalytic test analysis released r2 of 0.809, demonstrating again that
aspartates (Asp 25 and Asp 25ꢀ, 2.70 Å and 2.71 Å) which the CoMFA model is fairly reliable and has rather strong pre-
are crucial to the enzyme’s hydrolytic activity. The oxygen of dictive ability to the series of isopropanolamine compounds,

1150
Vol. 56, No. 8
(3S,4aS,8aS)-N-tert-Butyldecahydroisoquinoline-3-carboxamide 5 The
compound 5 was prepared according to the procedure in reference 17. 5:
and will be useful in further optimizing designed inhibitors.
yield 58%. mp 111—113 °C. [a]D20 ꢄ70 (cꢁ1.00, MeOH). H-NMR (CDCl3):
1
Conclusion
d: 6.6 (1H, s, br), 3.06—3.02 (1H, m), 2.85—2.77 (2H, m), 1.85—1.17
(13H, m), 1.33 (9H, s).
In summary, a series of novel isopropanolamine deriva-
tives were designed and synthesized as inhibitors of HIV
protease. Derivatives 1a—u displayed moderate to significant
inhibitory activities. Among them, compound 1a exhibited
the best inhibitory activity, which is essentially equipotent to
amprenavir and represents a promising platform for synthe-
sizing potent inhibitors at low cost. Docking study of com-
pounds 1a—u was carried out for exploration of preliminary
structure–activity relationship and predictive 3D-QSAR
models were built for further optimization of the designed in-
hibitors. The test analysis on the eighteen studied compounds
(3S,4aS,8aS)-N-tert-Butyl-2-[(R)-oxiran-2-ylmethyl]decahydroiso-
quinoline-3-carboxamide 8 A solution of (3S)-decahydroisoquinoline-3-
formamide 5 (2.0 g, 8.4 mmol), (S)-2-oxiranylmethyl m-nitrobenzenesul-
fonate 7 (2.4 g, 9.3 mmol) and iPr2NEt (1.6 ml, 9.2 mmol) in DMF (40 ml)
was stirred at 60 °C for 6 h under nitrogen atmosphere. The mixture was
cooled to room temperature, diluted with water (50 ml) and saturated aq.
NaHCO3 (10 ml), extracted with ethyl acetate (100 mlꢅ2). The combined
organic layer was washed with water (50 mlꢅ2) and brine (50 ml), dried
over anhydrous sodium sulfate. Concentration and purification of the residue
by column chromatography (on silica gel, petroleum ether/ethyl acetate: 4/1)
furnished 8 as a colorless solid (2.0 g, yield 79%). [a]D20 ꢄ147.2 (cꢁ1.00,
CHCl3). 1H-NMR (CDCl3) d: 6.60 (1H, s), 2.87—3.02 (3H, m), 2.72—2.75
confirmed the reliability and predictive ability of the CoMFA (1H, m), 2.63—2.66 (1H, m), 2.56—2.61 (1H, m), 2.21 (1H, dd, Jꢁ11.7,
3.3 Hz), 2.08 (1H, dd, Jꢁ14.4, 4.8 Hz), 1.16—1.80 (12H, m), 1.37 (9H, s).
model to the series of compounds.
13C-NMR (CDCl3) d: 173.8, 69.5, 59.9, 56.4, 50.5ꢅ2, 44.1, 36.1, 33.1, 30.9,
30.8, 28.6ꢅ3, 26.3, 25.6, 20.3. ESI-MS m/z: 317 (MꢃNa). HR-MS m/z:
Experimental
317.2215 (Calcd for C17H30N2O2Na: 317.2205).
General All reaction solvents were dried and distilled before use. Other
commercial reagents were used without further purification unless otherwise
(3R,4aR,8aR)-N-tert-Butyl-2-[(R)-2-hydroxy-3-(N-isobutyl-4-nitro-
phenylsulfonamido)propyl]decahydroisoquinoline-3-carboxamide 6 and
indicated. Melting points were obtained on a Thomas Hoover melting point Its S-Epimer from Expoxide 4 A mixture of 5 (1.91 g, 8.0 mmol) and
1
apparatus and are uncorrected. H- and 13C-NMR spectra were recorded on epoxide 4 (0.63 g, 1.0 mmol) in dry methanol (30 ml) was heated to 50—
Gemini-300 spectrometers (300, 75.5 MHz, respectively). Optical rotations 60 °C with stirring for 12 h. The reacting mixture was concentrated and puri-
were measured on a Perkin-Elmer 241 MC. Mass spectrometry and high-res- fied by column chromatography (on silica gel, chloroform/methanol: 99/1)
olution mass spectrometry (HR-MS) were recorded with Varian MAT-711 to furnish product 6 (31%), further elution gave its S-epimer (33%).
and MAT-95 spectrometers respectively. All compounds 1a—u were deter-
6: Yield 31%. mp 188—192 °C (dec.). [a]D20 ꢄ60.3 (cꢁ1.00, CHCl3). IR
mined to be ꢂ95% pure by HPLC analysis with two different eluent sys- (KBr) cmꢄ1: 3338, 2926, 2870, 1645, 1529, 1456, 1390, 1348, 1159, 1088,
1
tems. The HPLC analysis was performed on an Agilent 1200 series LC sys-
tem with a UV detector (l) set at 254 nm, thermostat set at 25 °C, and a Zor-
bax Eclipse XDB-C18 column (4.6ꢅ150 mm, 80 Å) was used. The mobile m), 2.74 (1H, d, Jꢁ11.5 Hz), 2.65 (1H, dd, Jꢁ11.0, 2.9 Hz), 2.34 (1H, dd,
phase of a binary gradient (50—100% B/20 min; solvent A, H2O; solvent B, Jꢁ12.7, 10.9 Hz), 2.20 (1H, dd, Jꢁ11.5, 3.4 Hz), 2.13 (1H, dd, Jꢁ12.8,
1007. H-NMR (CDCl3) d: 8.35 (2H, dt, Jꢁ8.9, 1.7 Hz), 7.99 (2H, dt, Jꢁ
8.9, 2.0 Hz), 5.97 (1H, s), 3.91—3.86 (1H, m), 3.41 (1H, s), 3.22—2.93 (4H,
MeOH for method 1 or solvent A, H2O, solvent B, CH3CN for method 2) at
a flow rate of 0.5 ml/min was used.
2.6 Hz), 2.00—1.14 (13H, m), 1.35 (9H, s), 0.87 (6H, dd, Jꢁ10.6, 6.6 Hz).
Anal. Calcd for C27H44N4O6S: C, 58.67; H, 8.02; N, 10.14. Found: C, 58.76;
H, 7.90; N, 10.19.
N-Allyl-N-isobutyl-4-nitrobenzenesulfonamide 3 Allylamine 2 (3.10
ml, 40 mmol) in dry CH2Cl2 (20 ml) was added dropwise to a stirring so-
lution of isobutylaldehyde (3.67 ml, 40 mmol) in CH2Cl2 (20 ml) at 0 °C.
S-epimer of 6: Yield 33%. mp 185—186.5 °C. [a]D20 ꢄ72.9 (cꢁ1.00,
CHCl3). IR (film) cmꢄ1: 3400, 3107, 2943, 2862, 1658, 1606, 1525, 1466,
Then anhydrous sodium sulfate (5 g) was added. The mixture was allowed to 1392, 1365 1348, 1315, 1192, 1159, 1109, 1090, 1005. 1H-NMR (CDCl3) d:
warm up to room temperature for an additional 1 h, filtered and concen-
trated. To a solution of the residue in dry methanol (20 ml) was added
sodium borohydride (1.67 g, 44 mmol) at 0 °C. The mixture was stirred for
1 h and then concentrated under reduced pressure. The residue was diluted
8.35 (2H, dt, Jꢁ8.8, 2.0 Hz), 8.01 (2H, dt, Jꢁ8.5, 1.9 Hz), 5.76 (1H, s),
3.94—3.87 (1H, m), 3.38 (1H, dd, Jꢁ15.0, 2.0 Hz), 3.29 (1H, s, br), 3.10
(1H, dd, Jꢁ15.2, 9.5 Hz), 3.05 (2H, d, Jꢁ7.5 Hz), 2.81 (1H, dd, Jꢁ11.7,
1.8 Hz), 2.54 (1H, dd, Jꢁ10.7, 3.1 Hz), 2.39 (1H, dd, Jꢁ13.1, 7.6 Hz), 2.25
with water (40 ml), extracted with ether (40 mlꢅ3). The combined organic (1H, dd, Jꢁ11.6, 3.3 Hz), 2.19 (1H, dd, Jꢁ13.1, 5.1 Hz), 1.99—1.82 (2H,
layer was washed with saturated aq. Na2CO3 (20 mlꢅ3) and brine (20 mlꢅ3) m), 1.80—1.20 (11H, m), 1.30 (9H, s), 0.90 (6H, t, Jꢁ7.1 Hz). Anal. Calcd
successively, dried over anhydrous magnesium sulfate. Filtration and con- for C27H44N4O6S: C, 58.67; H, 8.02; N, 10.14. Found: C, 58.79; H, 7.75; N,
centration gave a colorless oil. To the solution of the crude oil in dry CH2Cl2
(30 ml) was added triethylamine (6.2 ml) and p-nitrobenzenesulfonyl chlo-
10.12.
(3R,4aR,8aR)-N-tert-Butyl-2-[(R)-2-hydroxy-3-(N-isobutyl-4-nitro-
ride (8.88 g, 44 mmol) in dry CH2Cl2 (30 ml). The resulting mixture was phenylsulfonamido)propyl]decahydroisoquinoline-3-carboxamide
6
stirred for 1 h. Concentration and purification by column chromatography
from Epoxide 8 A mixture of epoxide 8 (200 mg, 0.68 mmol) and isobuty-
(on silica gel, chloroform/petroleum ether/ethyl acetate: 60/35/5) gave 3 as a lamine (0.09 ml, 0.68 mmol) in methanol (15 ml) was stirred for 3 h at 60 °C.
pale yellow solid. Recrystallization from ethyl acetate/hexane produced 3 as The mixture was concentrated and the residue was dissolved in CH2Cl2
1
pale yellow needle crystal (5.13 g, yield 43%). mp 69—70.5 °C. H-NMR (10 ml). To the solution was added dropwise p-nitrobenzenesulfonyl chloride
(CDCl3) d: 8.36 (2H, dt, Jꢁ9.0, 2.3 Hz), 8.00 (2H, dt, Jꢁ9.0, 2.2 Hz), (230 mg, 1.0 mmol) in CH2Cl2 (5 ml) and triethylamine (0.15 ml, 1.1 mmol)
5.59—5.45 (1H, m), 5.19—5.12 (2H, m), 3.86 (2H, d, Jꢁ6.5 Hz), 2.96 (2H,
at 0 °C. The mixture was allowed to warm up to room temperature for 2 h,
d, Jꢁ7.6 Hz), 1.99—1.85 (1H, m), 0.90 (6H, d, Jꢁ6.6 Hz). Anal. Calcd for then the solvent was removed. Purification of the residue by column chro-
C13H18N2O4S: C, 52.33; H, 6.08; N, 9.39. Found: C, 52.27; H, 6.00; N, 9.29.
matography (on silica gel, petroleum ether/ethyl acetate/CH2Cl2: 4/1/1) gave
6 as a white solid (53 mg, yield 13%).
(3R,4aR,8aR)-N-tert-Butyl-2-[(R)-2-hydroxy-3-(N-isobutyl-4-
aminophenylsulfonamido)propyl]decahydroisoquinoline-3-carboxamide
(ꢀ)-N-Isobutyl-4-nitro-N-(oxiran-2-ylmethyl)benzenesulfonamide 4
mixture of 3 (4.47 g, 15 mmol) and m-CPBA (7.79 g, 45 mmol) in CH2Cl2
(150 ml) was stirred at 20—30 °C for 84 h, diluted with CH2Cl2 (150 ml),
A
washed with saturated aq. NaHSO3 (30 mlꢅ3) and brine (30 mlꢅ3) succes- 1a A mixture of compound 6 (0.30 g, 0.54 mmol) and 10% Pd–C (60 mg)
sively. The organic layer was dried over anhydrous sodium sulfate, filtered in dry methanol (20 ml) was hydrogenated for 16 h under hydrogen atmo-
and concentrated. Purification of the residue by column chromatography (on sphere. Removal of the catalyst, concentration of the filtrate and purification
silica gel, petroleum ether/chloroform/ethyl acetate: 50/45/5) gave 4 as a of the residue by column chromatography (on silica gel. chloroform/ethyl
pale yellow solid. Crystallization from ethyl acetate and hexane produced a acetate: 9/1) gave 1a as a white foam solid (0.26 g, yield 90%). [a]D20 ꢄ80.3
1
white cottony crystal (4.23 g, yield 90%). mp 97—99 °C. H-NMR (CDCl3) (cꢁ1.00, CHCl3). IR (KBr) cmꢄ1: 3462, 3373, 3242, 2926, 2866, 1666,
d: 8.37 (2H, dt, Jꢁ8.6, 2.6 Hz), 8.02 (2H, dt, Jꢁ8.9, 2.5 Hz), 3.68 (1H, dd, 1597, 1518, 1504, 1456, 1392, 1365, 1315, 1228, 1148, 1092, 1001. 1H-
Jꢁ15.2, 2.9 Hz), 3.12 (1H, dd, Jꢁ13.5, 8.0 Hz), 3.06—3.01 (1H, m), 2.97 NMR (CDCl3) d: 7.57 (2H, dt, Jꢁ8.6, 2.2 Hz), 6.67 (2H, dt, Jꢁ8.7, 2.2 Hz),
(1H, dd, Jꢁ13.5, 7.2 Hz), 2.91 (1H, dd, Jꢁ15.2, 7.0 Hz), 2.79 (1H, t,
5.95 (1H, s), 4.16 (2H, s), 4.01—3.94 (1H, m), 3.47 (1H, br s), 3.14 (1H, dd,
Jꢁ4.6 Hz), 2.52 (1H, dd, Jꢁ4.5, 2.4 Hz), 2.06—1.92 (1H, m), 0.92 (6H, dd, Jꢁ14.9, 1.8 Hz), 3.02 (1H, dd, Jꢁ13.2, 8.4 Hz), 2.98—2.88 (2H, m), 2.82
Jꢁ16.5, 6.6 Hz). Anal. Calcd for C13H18N2O5S: C, 49.67; H, 5.77; N, 8.91. (1H, dd, Jꢁ13.2, 6.3 Hz), 2.52 (1H, dd, Jꢁ10.5, 3.1 Hz), 2.38 (1H, dd, Jꢁ
Found: C, 49.65; H, 5.79; N, 8.80.
12.9, 8.1 Hz), 2.23—2.17 (2H, m), 1.94—1.06 (13H, m), 1.27 (9H, s), 0.93

August 2008
1151
(6H, dd, Jꢁ18.4, 6.6 Hz). 13C-NMR (CDCl3) d: 173.5, 150.8, 129.4ꢅ2,
33.0, 30.8, 30.6, 28.6ꢅ3, 26.1, 25.5, 20.3. ESI-MS m/z: 632 (M+1). HR-MS
126.0, 114.0ꢅ2, 70.3, 68.1, 59.9, 59.3, 58.9, 55.0, 50.5, 35.6, 32.4, 30.6, m/z: 632.2751 (Calcd for C30H42N5O8S: 632.2754).
30.5, 25.6ꢅ3, 27.1, 26.2, 25.7, 20.4, 20.1, 19.8. EI-MS m/z: 521 (Mꢃꢄ1),
422. HR-MS m/z: 521.3168 (Calcd for C27H45N4O4S: 521.3161).
The compounds 1b, 1d—e, 1h—i, 1k—n, 1r, 1s were synthesized by the 8.69—8.70 (1H, m), 8.42—8.46 (1H, m), 8.12—8.20 (2H, m), 8.05—8.06
1m: Yield 31%. mp 76—78 °C. [a]D20 ꢄ76 (cꢁ1.00, CHCl3). IR (KBr)
cmꢄ1: 3385, 2928, 2860, 1660, 1533, 1352, 1163. 1H-NMR (CDCl3) d:
similar procedure as described for the preparation of compound 6.
(1H, m), 7.71—7.76 (2H, m), 7.50—7.56 (1H, m), 5.61 (1H, s), 4.63—4.83
1b: Yield 30%. [a]D20 ꢄ84 (cꢁ1.00, CHCl3). IR (KBr) cmꢄ1: 3425, 3392, (2H, m), 3.82—3.85 (1H, m), 3.48 (1H, m), 3.13—3.21 (1H, m), 2.81—2.83
2929, 2862, 1660, 1533, 1350, 1163. 1H-NMR (CDCl3) d: 8.68 (1H, s), 8.42 (1H, m), 2.62 (1H, dd, Jꢁ11.7, 2.7 Hz), 2.53 (1H, dd, Jꢁ11.4, 3.6 Hz),
(1H, d, Jꢁ8.7 Hz), 8.15 (1H, d, Jꢁ7.8 Hz), 7.73 (1H, t, Jꢁ8.1 Hz), 5.73 (1H,
2.36—2.43 (1H, m), 2.25 (1H, dd, Jꢁ11.7, 3.3 Hz), 2.14 (1H, dd, Jꢁ13.5,
s), 3.91—3.94 (1H, m), 3.39 (1H, d, Jꢁ15.0 Hz), 3.12—3.16 (1H, m), 3.07 8.4 Hz), 1.84—1.92 (1H, m), 1.60—1.76 (11H,m), 1.25 (9H, m). 13C-NMR
(2H, d, Jꢁ7.5 Hz), 2.83 (1H, d, Jꢁ10.8 Hz), 2.54 (1H, dd, Jꢁ10.5, 2.7 Hz), (CDCl3) d: 173.6, 148.4, 148.3, 142.5, 138.3, 134.5, 132.6, 130.5, 129.8,
2.38—2.45 (1H, m), 2.17—2.29 (2H, m), 1.21—1.98 (14H, m), 1.29 (9H, 127.1, 123.0ꢅ2, 122.4, 70.2, 68.0, 60.2, 59.8, 51.9, 51.7, 51.0, 35.9, 33.1,
s), 0.89—0.93 (6H, m). 13C-NMR (CDCl3) d: 173.4, 148.3, 141.8, 132.8, 30.8, 30.6, 28.6ꢅ3, 26.1, 25.6, 20.4. ESI-MS m/z: 632 (Mꢃ1). HR-MS m/z:
130.3, 126.9, 122.5, 70.3, 67.8, 59.9ꢅ2, 57.3, 53.7, 50.9, 35.9, 33.1, 30.7ꢅ 632.2781 (Calcd for C30H42N5O8S: 632.2754).
2, 28.6ꢅ3, 26.8, 26.2, 25.8, 20.4, 19.9, 19.8. EI-MS m/z: 551 (Mꢃꢄ1), 452
(100). HR-MS m/z: 552.2932 (Calcd for C27H44N4O6S (Mꢃ): 552.2982).
1n: Yield 37%. mp 111—112 °C. [a]D20 ꢄ79 (cꢁ1.00, CHCl3). IR (KBr)
cmꢄ1: 3377, 2928, 2860, 1655, 1527, 1350, 1157. 1H-NMR (CDCl3) d: 8.13
1d: Yield 17%. [a]D20 ꢄ76 (cꢁ1.00, CHCl3). IR (KBr) cmꢄ1: 3371, 2960, (1H, d, Jꢁ8.1 Hz), 8.01 (1H, s), 7.78 (2H, d, Jꢁ9.0 Hz), 7.24 (1H, d, Jꢁ
2929, 2864, 1664, 1518, 1340, 1157. 1H-NMR (CDCl3) d: 7.73 (2H, d, 8.7 Hz), 7.51 (1H, t, Jꢁ8.1 Hz), 6.99 (1H, d, Jꢁ9.0 Hz), 5.76 (1H, s), 4.59
Jꢁ7.8 Hz), 6.96 (2H, d, Jꢁ7.8 Hz), 5.93 (1H, s), 3.96—3.98 (1H, m), 3.86 (2H, d, Jꢁ4.2 Hz), 3.89 (3H, s), 3.44 (1H, dd, Jꢁ15.0, 2.4 Hz), 2.92—3.00
(3H, s), 3.19 (1H, d, Jꢁ15.0 Hz), 2.87—3.03 (4H, m), 2.51—2.54 (1H, d, (1H, m), 2.65 (1H, dd, Jꢁ12.6, 2.4 Hz), 2.49 (1H, dd, Jꢁ13.8, 3.0 Hz),
Jꢁ8.4 Hz), 2.35—2.41 (1H, m), 2.00 (2H, d, Jꢁ12.0 Hz), 1.24—1.91 (14H, 2.33—2.39 (1H, m), 2.04—2.18 (2H, m), 1.19—1.83 (15H, m), 1.25 (9H,
m), 1.27 (9H, s), 0.91 (6H, dd, Jꢁ12.6, 6.6 Hz). 13C-NMR (CDCl3) d: 173.4,
s). 13C-NMR (CDCl3) d: 173.2, 163.2, 148.3, 139.1, 134.5, 130.9, 129.6,
163.0, 130.2, 129.5ꢅ2, 114.3ꢅ2, 70.3, 68.2, 59.9, 59.4, 58.8, 55.6, 54.9, 129.3ꢅ2, 122.9, 122.7, 114.5ꢅ2, 70.2, 68.2, 60.0, 59.6, 55.7, 52.8, 52.6,
50.6, 35.7, 33.0, 30.7, 30.6, 28.6ꢅ3, 27.1, 26.2, 25.8, 20.4, 20.1, 19.8. EI- 50.8, 35.7, 33.0, 30.6, 29.7, 28.6ꢅ3, 26.0, 25.6, 20.5. EI-MS m/z: 615 (Mꢄ
MS m/z: 536 (Mꢃꢄ1), 437 (100); HR-MS m/z: 537.3266 (Calcd for
1), 516 (100); HR-MS m/z: 615.2835 (Calcd for C31H43N4O7S: 615.2853).
C28H47N3O5S: 537.3236).
1r: Yield 28%. mp 126—128 °C. [a]D20 ꢄ79.2 (cꢁ1.00, CHCl3). IR (KBr)
1e: Yield 35%. [a]D20 ꢄ74 (cꢁ1.00, CHCl3). IR (KBr) cmꢄ1: 3409, 2962, cmꢄ1: 3383, 2941, 2864, 1657, 1491, 1325, 1254, 1155, 1095, 1026, 806.
2864, 1655, 1524, 1348, 1163. 1H-NMR (CDCl3) d: 8.35 (2H, d, Jꢁ8.7 Hz),
1H-NMR (CDCl3) d: 7.78 (2H, d, Jꢁ8.4 Hz), 6.99 (2H, d, Jꢁ9.0 Hz), 6.79
8.02 (2H, d, Jꢁ8.7 Hz), 5.77 (1H, s), 3.90—3.97 (1H, m), 3.41 (1H, dd, Jꢁ (1H, s), 6.71 (2H, s), 5.94 (2H, s), 4.26—4.38 (2H, m), 3.88 (3H, s), 3.80—
15.0, 2.7 Hz), 3.20—3.26 (2H, m), 3.05—3.13 (1H, m), 2.85 (1H, dd, Jꢁ 3.82 (1H, m), 3.26—3.32 (1H, m), 3.93—3.01 (1H, m), 2.67—2.71 (1H, m),
18.0, 2.7 Hz), 2.57 (1H, dd, Jꢁ10.5, 2.7 Hz), 2.42—2.49 (1H, m), 2.20— 2.46 (1H, dd, Jꢁ9.6, 3.3 Hz), 2.29—2.36 (1H, m), 2.04—2.13 (2H, m),
2.32 (2H, m), 1.21—1.93 (15H, m), 1.32 (9H, s), 0.87 (3H, t, Jꢁ7.5 Hz).
13C-NMR (CDCl3): d 173.5, 149.9, 145.7, 128.4ꢅ2, 124.3ꢅ2, 70.2, 68.0,
59.9, 59.8, 52.9, 51.4, 50.9, 35.8, 33.1, 30.7, 29.6, 28.7ꢅ3, 26.1, 25.7, 21.6,
20.4, 11.0. EI-MS m/z: 537 (Mꢄ1), 438 (100). HR-MS m/z: 537.2737
(Calcd for C26H41N4O6S: 537.2747).
1.19—1.79 (14H, m), 1.25 (9H, s). 13C-NMR (CDCl3) d: 173.5, 163.0,
148.1, 147.4, 131.1, 130.0, 129.4ꢅ2, 121.9, 114.3ꢅ2, 108.8, 108.2, 101.1,
69.9, 67.4, 60.1, 58.8, 55.6, 53.3, 52.7, 50.5, 35.5, 33.0, 30.6, 30.4, 28.6ꢅ3,
26.1, 25.7, 20.5. EI-MS m/z: 614 (Mꢄ1), 515 (100). HR-MS m/z: 614.2912
(Calcd for C32H44N3O7S: 614.2900).
1h: Yield 34%. [a]D20 ꢄ73.2 (cꢁ1.00, CHCl3). IR (KBr) cmꢄ1: 3373,
1s: Yield 27%. mp 104—106 °C. [a]D20 ꢄ62.3 (cꢁ1.00, CHCl3). IR (KBr)
2926, 1674, 1597, 1462, 1336, 1153. 1H-NMR (CDCl3): d: 7.72 (2H, d, Jꢁ cmꢄ1: 3332, 2926, 2864, 1649, 1531, 1350, 1159. 1H-NMR (CDCl3) d: 8.34
8.7 Hz), 6.95 (2H, d, Jꢁ9.0 Hz), 5.99 (1H, s), 3.93—3.97 (1H, m), 3.85 (3H, (2H, d, Jꢁ8.7 Hz), 8.02 (2H, d, Jꢁ8.7 Hz), 6.77 (1H, s), 6.73 (2H, s), 5.94
s), 3.03—3.27 (3H, m), 2.89—2.97 (2H, m), 2.51—2.55 (1H, m), 2.37— (2H, s), 5.72 (1H, s), 4.37—4.51 (2H, m), 3.79—3.82 (1H, m), 3.40 (1H, dd,
2.44 (1H, m), 2.15—2.23 (2H, m), 1.23—1.89 (14H, m), 1.28 (9H, s), 0.85 Jꢁ14.8, 2.9 Hz), 3.11—3.19 (1H, m), 2.64 (1H, dd, Jꢁ3.9, 0.9 Hz), 2.51
(3H, t, Jꢁ7.5 Hz). 13C-NMR (CDCl3): d 173.5, 162.9, 130.6, 129.3ꢅ2, (1H, dd, Jꢁ10.2, 2.7 Hz), 2.34—2.41 (1H, m), 2.09—2.21 (2H, m), 1.33—
114.2ꢅ2, 70.1, 68.3, 59.9, 59.3, 55.6, 53.6, 52.2, 50.5, 35.7, 33.0, 30.6,
30.5, 28.6ꢅ3, 26.2, 25.7, 21.8, 20.4, 11.1. ESI-MS m/z: 546 (MꢃNa); HR- 147.6, 146.3, 129.2, 128.4ꢅ2, 124.2ꢅ2, 122.1, 108.8, 108.3, 101.2, 70.1,
MS m/z: 546.2977 (Calcd for C27H45N3O5SNa: 546.2978). 67.4, 60.0, 59.6, 52.5, 51.8, 50.9, 35.8, 33.0, 30.6ꢅ2, 28.6ꢅ3, 26.1, 25.6,
1.92 (13H, m), 1.28 (9H, s). 13C-NMR (CDCl3) d: 173.7, 149.8, 148.1,
1i: Yield 29%. mp 179—180 °C. [a]D20 ꢄ74.3 (cꢁ1.00, CHCl3). IR (KBr) 20.5. EI-MS m/z: 629 (Mꢄ1), 530 (100). HR-MS m/z: 629.2652 (Calcd for
cmꢄ1: 3361, 2922, 2850, 1662, 1518, 1338, 1155. 1H-NMR (CDCl3) d: 7.73
(2H, d, Jꢁ9.3 Hz), 6.97 (2H, d, Jꢁ9.0 Hz), 5.90 (1H, s), 3.91—3.99 (1H,
C32H44N3O7S (Mꢄ1): 629.2645).
The syntheses of compounds 1c, 1f, 1g, 1j, 1o—q, 1t—u were carried out
m), 3.87 (3H, s), 2.87—3.21 (5H, m), 2.50—2.55 (1H, m), 2.35—2.42 (1H, by the similar procedure as described for the preparation of 1a.
m), 2.18—2.24 (2H, m), 1.15—1.83 (22H, m), 1.27 (9H, s), 0.85—0.93
1c: Yield 84%. [a]D20 ꢄ83 (cꢁ1.00, CHCl3). IR (KBr) cmꢄ1: 3456, 3375,
(2H, m). 13C-NMR (CDCl3): d 173.4, 162.9, 130.3, 129.4ꢅ2, 114.2ꢅ2, 2926, 1664, 1317, 1151. 1H-NMR (CDCl3) d: 7.24—7.29 (1H, m), 7.13
77.2, 70.3, 68.0, 59.9, 59.4, 57.3, 55.6, 54.8, 50.6, 36.3, 35.7, 33.0, 30.9, (1H, d, Jꢁ7.5 Hz), 7.07 (1H, s), 6.84 (1H, d, Jꢁ8.1 Hz), 5.92 (1H, s), 3.92—
30.6ꢅ3, 28.6ꢅ3, 26.4, 26.1, 26.0, 25.7, 20.4. EI-MS m/z: 576 (Mꢄ1), 477 3.98 (3H, m), 3.21 (1H, d, Jꢁ13.6 Hz), 2.85—3.10 (4H, m), 2.53 (1H, dd,
(100). HR-MS m/z: 577.3535 (Calcd for C31H51N3O5S: 577.3549).
Jꢁ10.2, 2.7 Hz), 2.36—2.43 (1H, m), 2.17—2.13 (2H, m), 1.25—1.93
1k: Yield 15%. mp 74—76 °C. [a]D20 ꢄ60 (cꢁ1.00, CHCl3). IR (KBr)
(14H, m), 1.28 (9H, s), 0.94 (6H, dd, Jꢁ17.7, 6.6 Hz). 13C-NMR (CDCl3) d:
cmꢄ1: 3379, 2926, 2860, 1660, 1498, 1259, 1153. 1H-NMR (CDCl3) d: 7.77 173.5, 147.4, 139.1, 130.0, 118.9, 116.7, 113.0, 70.3, 68.2, 59.9, 59.4, 59.0,
(2H, d, Jꢁ9.0 Hz), 7.24—7.29 (5H, m), 6.97 (2H, d, Jꢁ9.0 Hz), 5.94 (1H,
55.1, 50.6, 35.7, 33.0, 30.7, 30.6, 28.6ꢅ3, 27.2, 26.2, 25.8, 20.4, 20.1, 19.8.
s), 4.42 (2H, dd, Jꢁ30.9, 14.7 Hz), 4.06—4.14 (1H, m), 3.86 (3H, s), 3.76— EI-MS m/z: 521 (Mꢄ1), 422 (100). HR-MS m/z: 522.3238 (Calcd for
3.79 (1H, m), 3.29 (1H, d, Jꢁ12.3 Hz), 2.92—3.00 (1H, m), 2.62 (1H, d, Jꢁ C27H46N4O4S: 522.3240).
12.0 Hz), 2.42 (1H, d, Jꢁ10.2 Hz), 2.25—2.29 (1H, m), 2.02—2.09 (4H, m),
1f: Yield 86%. [a]D20 ꢄ76.6 (cꢁ1.00, CHCl3). IR (KBr) cmꢄ1: 3469,
1.24—1.76 (10H, m), 1.21 (9H, s). 13C-NMR (CDCl3) d: 173.5, 163.0, 3358, 3246, 2926, 2866, 1668, 1597, 1317, 1149. 1H-NMR (CDCl3) d: 7.57
136.3, 131.0, 129.4ꢅ2, 128.7ꢅ2, 128.4ꢅ2, 127.9, 114.3ꢅ2, 69.9, 67.3, (2H, d, Jꢁ8.4 Hz), 6.67 (2H, d, Jꢁ8.7 Hz), 6.00 (1H, s), 4.16 (2H, s), 3.94—
60.0, 58.8, 55.6, 53.5, 52.8, 50.5, 35.5, 32.9, 30.6, 30.4, 28.6ꢅ3, 26.1, 25.6, 4.01 (1H, m), 2.89—3.22 (6H, m), 2.52—2.55 (1H, m), 2.38—2.45 (1H, m),
20.5. EI-MS m/z: 570 (Mꢄ1), 471 (100). HR-MS m/z: 570.3025 (Calcd for
2.21 (2H, dd, Jꢁ12.0, 3.9 Hz), 1.25—1.88 (14H, m), 1.29 (9H, s), 0.88 (3H,
C31H44N3O5S: 570.3002).
t, Jꢁ6.9 Hz). 13C-NMR (CDCl3) d: 173.6, 150.8, 129.3ꢅ2, 126.5, 114.0ꢅ2,
1l: Yield 30%. mp 161—162 °C. [a]D20 ꢄ80 (cꢁ1.00, CHCl3). IR (KBr) 70.3, 68.4, 59.9, 59.3, 53.9, 52.5, 50.6, 35.7, 33.0, 30.7, 30.6, 28.6ꢅ3, 26.2,
cmꢄ1: 3386, 2926, 2862, 1660, 1529, 1350, 1161. 1H-NMR (CDCl3) d: 8.37
(2H, d, Jꢁ8.7 Hz), 8.15 (1H, d, Jꢁ8.1 Hz), 8.07 (2H, d, Jꢁ9.0 Hz), 7.76
(1H, d, Jꢁ7.5 Hz), 7.51—7.56 (1H, m), 5.58 (1H, s), 4.64—4.79 (2H, m),
3.78—3.81 (1H, m), 3.48 (1H, dd, Jꢁ15.0, 1.8 Hz), 3.09—3.17 (1H, m),
2.51—2.59 (2H, m), 2.36—2.42 (1H, m), 2.25 (1H, dd, Jꢁ12.0, 3.0 Hz),
25.8, 21.9, 20.5, 11.1. EI-MS m/z: 507 (Mꢄ1), 408 (100). HR-MS m/z:
507.3002 (Calcd for C26H43N4O4S: 507.3005).
1g: Yield 56%. mp 185—187 °C. [a]D20 ꢄ70 (cꢁ1.00, CHCl3). IR (KBr)
cmꢄ1: 3456, 3369, 2925, 1649, 1531, 1315, 1151. 1H-NMR (CDCl3) d:
7.23—7.28 (1H, m), 7.13 (1H, d, Jꢁ7.2 Hz), 7.08—7.09 (1H, m), 6.82—
2.10—2.16 (1H, m), 1.83—1.91 (1H, m), 1.15—1.72 (13H, m), 1.27 (9H, 6.85 (1H, m), 5.97 (1H, s), 3.91—3.99 (2H, m), 2.90—3.29 (5H, m), 2.53—
s). 13C-NMR (CDCl3) d: 173.7, 150.0, 148.4, 146.1, 138.4, 134.5, 129.8,
2.57 (1H, m), 2.40—2.47 (1H, m), 2.19—2.27 (2H, m), 1.23—1.86 (16H,
128.4ꢅ2, 124.4ꢅ2, 123.0, 122.9, 70.2, 67.8, 60.0ꢅ2, 51.7, 51.6, 50.9, 35.9, m), 1.30 (9H, m), 0.86—0.91 (3H, m); 13C-NMR (CDCl3) d: 173.5, 147.4,

1152
Vol. 56, No. 8
139.6, 130.0, 118.8, 116.6, 112.9, 70.2, 68.4, 59.9, 59.4, 53.9, 52.5, 50.6, 101.2, 69.8, 67.4, 60.0, 58.8, 53.5, 52.8, 50.6, 35.5, 32.9, 30.5, 30.4,
35.7, 33.0, 30.6ꢅ2, 28.6ꢅ3, 26.2, 25.8, 21.9, 20.5, 11.1. EI-MS m/z: 507 28.6ꢅ3, 26.1, 25.7, 20.6. ESI-MS m/z: 623 (MꢃNa); HR-MS m/z: 623.2898
(Mꢄ1), 408 (100). HR-MS m/z: 507.3019 (Calcd for C26H43N4O4S: (Calcd for C31H44N4O6SNa: 623.2879).
507.3005).
1j: Yield 69%. mp 111—112 °C. [a]D20 ꢄ77 (cꢁ1.00, CHCl3). IR (KBr)
Acknowlegements This work was supported by the National Natural
1
cmꢄ1: 3471, 3379, 2926, 2862, 1653, 1597, 1309, 1148. H-NMR (CDCl3) Science Foundation of China (Grant Nos. 30600775). The authors gratefully
d: 7.56 (2H, d, Jꢁ8.7 Hz), 7.15—7.32 (5H, m), 6.65 (2H, d, Jꢁ8.4 Hz), 5.98
thank The National Center for Drug Screening for the contribution in bio-
(1H, s), 4.14 (1H, s), 3.91 (1H, s, br), 3.27—3.41 (4H, m), 2.87—2.99 (5H, logical evaluation. We also thank Ms. Min Zhou for the helpful discussion
m), 2.55 (1H, d, Jꢁ8.4 Hz), 2.40—2.47 (1H, m), 2.22 (1H, d, Jꢁ12.0 Hz), and revision of the manuscript.
1.25—1.87 (13H, m), 1.31 (9H, s). 13C-NMR (CDCl3) d: 150.8, 150.0,
138.4, 129.4ꢅ2, 128.8ꢅ2, 128.6ꢅ2, 126.6, 114.1ꢅ2, 112.5, 70.2, 68.3, References and Notes
59.8, 59.4, 54.2, 52.3, 50.7, 35.7, 35.5, 33.0, 30.6, 29.7, 28.7ꢅ3, 26.1, 25.9,
20.5. EI-MS m/z: 569 (Mꢄ1), 470 (100). HR-MS m/z: 570.3255 (Calcd for
C31H46N4O4S: 570.3240).
1) Palella F. J., Jr., Delaney K. M., Moorman A. C., Loveless M. O.,
Fuhrer J., Satten G. A., Aschman D. J., Holmberg S. D., N. Engl. J.
Med., 338, 853—860 (1998).
1o: Yield 81%. mp 96—102 °C. [a]D20 ꢄ69 (cꢁ1.00, CHCl3). IR (KBr)
cmꢄ1: 3448, 3375, 2926, 2860, 1664, 1597, 1498, 1259, 1153. 1H-NMR
(CDCl3) d: 1.79 (2H, d, Jꢁ8.7 Hz), 7.06 (1H, t, Jꢁ7.8 Hz), 6.99 (2H, d,
Jꢁ8.7 Hz), 6.22 (1H, s), 6.58 (2H, dd, Jꢁ7.5, 1.2 Hz), 5.99 (1H, s), 4.21—
4.37 (2H, m), 3.88 (3H, s), 3.82—3.86 (1H, m), 3.26 (1H, dd, Jꢁ15.0,
2.7 Hz), 2.92—3.01 (1H, m), 2.71 (1H, dd, Jꢁ12.0, 2.4 Hz), 2.43—2.46
(1H, m), 2.30—2.37 (1H, m), 2.02—2.08 (2H, m), 1.17—1.78 (15H, m),
1.26 (9H, s). 13C-NMR (CDCl3) d: 173.6, 163.0, 147.1, 137.3, 130.9, 129.6,
129.4ꢅ2, 118.3, 114.7ꢅ2, 114.3ꢅ2, 69.9, 67.6, 60.0, 58.8, 55.6, 53.7, 53.2,
50.5, 35.6, 33.0, 30.6, 30.4, 28.6ꢅ3, 26.1, 25.7, 20.6. ESI-MS m/z: 587.3
(Mꢃ1, 100), 486.4 (23). HR-MS m/z: 587.3285 (Calcd for C31H47N4O5S:
587.3267).
2) Mocroft A., Vella S., Benfield T. L., Chiesi A., Miller V., Gargalianos
P., d’Arminio Monforte A., Yust I., Bruun J. N., Phillips A. N., Lund-
gren J. D., Lancet, 352, 1725—1730 (1998).
3) Condra J. H., Schleif W. A., Blahy O. M., Gabryelski L. J., Graham D.
J., Quintero J. C., Rhodes A., Robbins H. L., Roth E., Shivaprakash
M., Nature (London), 374, 569—571 (1995).
4) Boden D., Markowitz M., Antimicrob. Agents Chemother., 42, 2775—
2783 (1998).
5) Walli R., Herfort O., Michl G. M., Demant T., Jäger H., Dieterle C.,
Bogner J. R., Landgraf R., Goeble F. D., AIDS, 12, F167—F173
(1998).
6) Lo J. C., Mulligan K., Tai V. W., Algren H., Schambelan M., Lancet,
351, 867—870 (1998).
7) Miller K. D., Jones E., Yanovski J. Shankar R., Feuerstein I., Falloon J.,
Lancet, 351, 871—875 (1998).
8) Carr A., Samaras K., Burton S., Law M., Freund J., Chisholm D. J.,
Cooper D. A., AIDS, 12, F51—F58 (1998).
9) Viraben R., Aquilina C., AIDS, 12, F37—F39 (1998).
1p: Yield 49%. [a]D20 ꢄ62.5 (cꢁ1.00, CHCl3). IR (KBr) cmꢄ1: 3450,
3365, 3238, 2926, 2860, 1662, 1597, 1313, 1149. 1H-NMR (CDCl3) d: 7.63
(2H, d, Jꢁ8.7 Hz), 7.06—7.12 (1H, m), 6.69 (2H, d, Jꢁ9.0 Hz), 6.49—6.56
(3H, m), 6.03 (1H, s), 4.23—4.35 (2H, m), 4.15 (2H, s), 3.81—3.84 (1H,
m), 3.24 (1H, dd, Jꢁ14.7, 3.0 Hz), 2.91—2.99 (1H, m), 2.79 (2H, s), 2.69
(1H, dd, Jꢁ12.3, 3.0 Hz), 2.41—2.45 (1H, m), 2.28—2.35 (1H, m), 2.01—
2.10 (2H, m), 1.18—1.76 (13H, m), 1.25 (9H, s). 13C-NMR (CDCl3) d: 10) Martinez E., Casamitjana R., Conget I., Gatell J. M., AIDS, 12, 2077—
173.7, 150.9, 147.1, 137.6, 129.6, 129.5ꢅ2, 126.9, 118.4, 114.7ꢅ2,
2079 (1998).
114.1ꢅ2, 69.9, 67.5, 60.0, 58.7, 53.9, 53.3, 50.5, 35.5, 32.9, 30.6, 30.4, 11) Leung D., Abbenante G., Fairlie D. P., J. Med. Chem., 43, 305—341
28.6ꢅ3, 26.1, 25.7, 20.6. ESI-MS m/z: 572 (Mꢃ1). HR-MS m/z: 572.3294
(Calcd for C30H46N5O4S: 572.3271).
(2000).
12) Kitchin J., Bethell R. C., Cammack N., Dolan S., Evans D. N., Holman
S., Holmes D. S., McMeekin P., Mo C. L., Nieland N., Orr D. C.,
Saunders J., Shenoy B. E. V., Starkey I. D., Storer R., J. Med. Chem.,
37, 3707—3716 (1994).
1q: Yield 54%. [a]D20 ꢄ71 (cꢁ1.00, CHCl3). IR (KBr) cmꢄ1: 3373, 2926,
1
2860, 1655, 1599, 1315, 1153, 773. H-NMR (CDCl3) d: 7.03—7.30 (4H,
m), 6.83—6.86 (1H, m), 6.54—6.60 (3H, m), 6.00 (1H, s), 4.23—4.40 (2H,
m), 3.98 (2H, s), 3.81—3.83 (1H, m), 3.70 (2H, s), 3.25—3.31 (1H, m), 13) Salituro F. G., Baker C. T., Court J. J., Deininger D. D., Kim E. E., Li
2.94—3.02 (1H, m), 2.69 (1H, dd, Jꢁ11.7, 2.1 Hz), 2.42—2.47 (1H, m),
B., Novak P. M., Rao B. G., Pazhanisamy S., Porter M. D., Schairer W.
2.29—2.36 (1H, m), 2.02—2.08 (2H, m), 1.23—1.82 (13H, m), 1.25 (9H,
C., Tung R. D., Bioorg. Med. Chem. Lett., 8, 3637—3642 (1998).
s). 13C-NMR (CDCl3) d: 173.5, 147.5, 147.1, 139.9, 137.4, 130.1, 129.6, 14) Spaltenstein A., Cleary D., Bock B., Kazmierski W., Furfine E.,
118.9, 118.4, 116.7, 114.8ꢅ2, 113.0, 69.9, 67.4, 60.0, 58.8, 53.9, 53.2, 50.6,
35.5, 32.9, 30.6, 30.4, 28.6ꢅ3, 26.1, 25.7, 20.6. EI-MS m/z: 570 (Mꢄ1),
408 (100). HR-MS m/z: 571.3111 (Calcd for C30H44N5O4S: 571.3114).
1t: Yield 72%. [a]D20 ꢄ79 (cꢁ1.00, CHCl3). IR (KBr) cmꢄ1: 3466, 3373,
Wright L., Hazen R., Andrews W., Almond M., Tung R., Salituro F.,
Bioorg. Med. Chem. Lett., 10, 1159—1162 (2000).
15) Roberts N. A., Martin J. A., Kinchington D., Broadhurst A. V., Craig J.
C., Duncan I. B., Galpin S. A., Handa B. K., Kay J., Krohn A., Lam-
bert R. W., Merrett J. H., Mills J. S., Parkes K. E. B., Redshaw S.,
Ritchie A. J., Taylor D. L., Thomas G. J., Machin P. J., Science, 248,
358—361 (1990).
1
3242, 2924, 2860, 1664, 1597, 1504, 1244, 1149. H-NMR (CDCl3) d 7.58
(2H, d, Jꢁ3.0 Hz), 6.78 (1H, s), 6.65—6.70 (4H, m), 6.00 (1H, s), 5.91 (2H,
s), 4.20—4.35 (2H, m), 4.30 (2H, s), 3.76—3.79 (1H, m), 3.24 (1H, dd,
Jꢁ15.0, 2.7 Hz), 2.89—2.97 (2H, m), 2.66 (1H, d, Jꢁ11.4 Hz), 2.41—2.44 16) Martin J. A., Drugs Future, 16, 210—212 (1991).
(1H, m), 2.26—2.33 (1H, m), 2.01—2.10 (2H, m), 1.17—1.76 (11H, m), 17) Göhring W., Gokhale S., Hilpert H., Chimia, 50, 532—537 (1996).
1.23 (9H, s). 13C-NMR (CDCl3): d 173.7, 148.1, 147.4ꢅ2, 130.2, 129.4ꢅ2, 18) Barton D. L., Press J. B., Hajos Z. G., Sawyers R. A., Tetrahedron:
121.9, 114,1, 112.6, 108.9, 108.2ꢅ2, 101.2, 69.9, 67.2, 60.0, 58.8, 53.5,
Asymmetry, 3, 1189—1196 (1992).
52.9, 50.5, 35.5, 32.9, 30.6, 29.7, 28.6ꢅ3, 26.1, 25.7, 20.6. EI-MS m/z: 599 19) For detailed assay protocol, see Wang Y., Wang R., Yang L., Li J., Xu
(Mꢄ1), 500 (100); HR-MS m/z: 600.3031 (Calcd for C31H44N4O6S:
600.2982).
W., Zheng Y., Virologica Sinica, 21, 126—130 (2006).
20) Amprenavir and indinavir were used as positive control in the bioassay.
And indinavir exhibited a inhibitory rate of 86.6% at 10 nM concentra-
tion.
1u: Yield 39%. mp 106—109 °C. [a]D20 ꢄ62.9 (cꢁ1.00, CHCl3). IR
(KBr) cmꢄ1: 3375, 2924, 2860, 1662, 1489, 1448, 1317, 1242, 1153, 1040.
1H-NMR (CDCl3) d 7.58 (2H, d, Jꢁ9.0 Hz), 6.78 (1H, s), 6.65—6.70 (4H, 21) Kaldor S. W., Kalish V. J., Davies J. F. Jr., Shetty B. V., Fritz J. E., Ap-
m), 6.00 (1H, s), 5.91 (2H, s), 4.20—4.35 (2H, m), 4.30 (2H, s), 3.76—3.80
(1H, m,), 3.24 (1H, dd, Jꢁ11.7, 2.7 Hz), 2.89—2.97 (2H, m), 2.66 (1H, d,
Jꢁ8.1 Hz), 2.41—2.44 (1H, m), 2.26—2.33 (1H, m), 2.01—2.10 (2H, m),
1.17—1.76 (12H, m), 1.23 (9H, s). 13C-NMR (CDCl3): d 173.6, 148.1,
147.4, 140.1, 130.1, 130.0ꢅ2, 122.0, 118.9, 116.5, 112.9, 108.9, 108.2,
pelt K., Burgess J. A., Campanale K. M., Chirgadze N. Y., Clawson D.
K., Dressman B. A., Hatch S. D., Khalil D. A., Kosa M. B., Lubbe-
husen P. P., Muesing M. A., Patick A. K., Reich S. H., Su K. S., Tat-
lock J. H., J. Med. Chem., 40, 3979—3985 (1997).