Diketoacid-genre HIV-1 integrase inhibitors containing enantiomeric arylamide functionality

Article abstract of DOI:10.1016/j.bmc.2009.05.008

Using our recently disclosed 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one and 4,5-dihydroxy-1H-isoindole-1,3(2H)-dione integrase inhibitors, we report differential effects on inhibitory potency induced by introduction of an α-chiral center into a key aryl

Full text of DOI:10.1016/j.bmc.2009.05.008

Bioorganic & Medicinal Chemistry 17 (2009) 5318–5324
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Diketoacid-genre HIV-1 integrase inhibitors containing enantiomeric
arylamide functionality
Xue Zhi Zhao a, Kasthuraiah Maddali b, Christophe Marchand b, Yves Pommier b, Terrence R. Burke Jr. a,
*
a Laboratory of Medicinal, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702, United States
b Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Using our recently disclosed 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one and 4,5-dihydroxy-1H-isoin-
dole-1,3(2H)-dione integrase inhibitors, we report differential effects on inhibitory potency induced by
introduction of an a-chiral center into a key aryl substituent. We show that introduction of the chiral cen-
ter is uniformly deleterious to binding, with the (R)-enantiomer being more deleterious than the (S)-
enantiomer. A greater enantiomeric difference in potency is shown by inhibitors that have restricted
rotation of the aryl ring, with the larger difference being due to poorer potency of the (R)-enantiomer
rather than higher potency of the (S)-enantiomer. The potency difference for enantiomers based on the
isoindoline-1,3-dione ring system is less than for those derived from the isoindol-1-one ring system.
Our findings provide useful information that should aid in understanding molecular binding interactions
of DKA-derived IN inhibitors.
Received 1 April 2009
Revised 29 April 2009
Accepted 1 May 2009
Available online 8 May 2009
Keywords:
HIV-1 integrase
Inhibit
Enantiomer
Arylamide
Diketoacid
Published by Elsevier Ltd.
1. Introduction
are thought to bind in a hydrophobic pocket(s) of the INꢀDNA com-
plex.9,10 Recent studies examining structural variation of the aryl
Integrase (IN) is a key enzyme encoded within the genome of
the human immunodeficiency virus type 1 (HIV-1) that is required
for productive infection. The recent FDA approval of the first IN
inhibitor, raltegravir (IsentressÒ), validates IN as an antiretroviral
target for the treatment of AIDS.1–3 IN catalyzes the incorporation
of viral cDNA into host DNA in a process involving two distinct
steps, termed 30-processing (30-P) and strand transfer (ST).4 These
reactions are catalyzed by three conserved acidic residues
(Asp64, Asp116 and Glu152, the ‘DDE motif’) with the assistance
of divalent metal cofactors.5 Numerous IN inhibitors that trace
their conceptual ancestry to diketoacid (DKA) progenitors6 contain
heteroatom functionality that has been hypothesized to chelate the
catalytically-essential divalent metal ions (Fig. 1).7,8 These inhibi-
tors often include aryl-containing amine or amide groups that
group highlight the importance of binding interactions originating
from this portion of the inhibitor.11–13 Previous reports have
shown that introduction of a substituent at the prochiral aryl
a-
carbon provides preferentially higher potency for the (S)-enantio-
mer relative to the (R)-enantiomer.14–17 For example, enantiomeric
potency differences of from twofold to more than 10-fold have
been observed for the
Table 1.
a-methylbenzylamides 1–3 shown in
Although these are potentially interesting observations, there
have been no systematic investigations examining enantiomeric
effects of the
a-methylbenzylamide moiety within IN inhibitors.
Our recently reported 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-
ones and 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones (4 and 5,
Fig. 1) represent structurally simple IN inhibitors that exhibit good
potency and ST selectivity in the presence of Mg2+ cofactor.13,18 In
our current report we use 4 and 5 as platforms for a detailed exam-
ination centered on enantiomeric effects of the arylamide group.
OH
O
X
HO
N
2. Results and discussion
2.1. Chemical synthesis
prochiral
center
4 X = H,H
5 X = O
Analogues 4 were prepared by reaction of the appropriately
substituted amines with methyl 2-chloromethyl-3,4-dim-
ethoxybenzoate 618–20 followed by demethylation of the resulting
lactams (7) with boron tribromide (Scheme 1).
Figure 1.
* Corresponding author. Tel.: +1 301 846 5906; fax: +1 301 846 6033.
E-mail address: tburke@helix.nih.gov (T.R. Burke).
0968-0896/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmc.2009.05.008

X. Z. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 5318–5324
5319
Table 1
Table 2
Examples of differences in HIV-1 IN inhibitory potencies for enantiomeric
methylbenzyl amides
a-
Inhibition data from an in vitro HIV-1 IN assay
OH
O
OH
O
CH3
CH3
HO
HO
(S)
(R)
N
R
N R
R =
O
No.
Structure
OH
IC50
24a
(lM)
IC50 (lM)
4
5
O
O
No.
R
IC50
(
l
M)
IC50
(l
M)
1
>300a
HO
R
N
30-P
ST
30-P
ST
O
H
H
OH
a
>333a
12.3 5.6a
72 23
0.39 0.21
HO
R
N
0.50b
5.00b
F
2
3
N
S
N
H
b
c
282 4ia
10 3a
8
3b
5
2b
OH
OH
O
N
N
61 29a
0.74 0.16a
150 36
0.72 0.25
2.05c
1.05c
N
R
O
a
b
c
Taken from Ref. 15.
Taken from Ref. 17.
Taken from Ref. 14.
d
e
f
24
4
0.8 0.2
28 10a
18
3
0.96 0.19
6.8 2.5
>333a
>333
157 28
Analogues
5 were formed by refluxing the appropriately
substituted amines with triethylamine in toluene in the presence
of 3,4-dimethoxyphthalic anhydride 8 (obtained in three steps
from 2,3-dimethoxytoluene21) followed by demethylation of the
resulting phthalimides (9) with boron tribromide (Scheme 2).
23
6
37
4
4
1
a
Data as previously reported in Ref. 18.
Data as previously reported in Ref. 13.
b
2.2. Inhibition of integrase in in vitro assays
In the current study achiral arylamides were first examined in
the context of platforms 4 and 5 by measuring 30-P and ST inhibi-
tory potencies in the presence of Mg2+ cofactor using previously re-
ported procedures (Table 2).18 With 4 as a platform, at least 10-fold
selectivity for ST inhibition was observed for all analogues tested
(4a–4f). Similar selectivity was also shown in the series 5 deriva-
tives, with the exception of the 4-F analogue 5b, which exhibited
little ST selectivity. For this latter compound the lack of selectivity
resulted from a nearly 10-fold increase in 30-P inhibitory potency
and a 10-fold decrease in ST inhibitory potency relative to the
unsubstituted benzyl analogue 5a. A very minor difference in po-
tency was observed for 4a relative to 4b. The 1-naphthylmethyl
and 2-naphthylmethyl analogues (4c and 4d, respectively) were
among the most potent inhibitors in both the series 4 and the ser-
ies 5 compounds. This indicated a moderate degree of steric toler-
ance within the IN binding pocket to allow accommodation of the
larger aryl group. For both series 4 and series 5 inhibitors the po-
tential importance of alignment of the aryl rings within the pocket
was indicated through the loss of binding affinity shown by the
phenylethyl (4e and 5e) and 2-indanyl (4f and 5f) analogues. It
can be postulated that these analogues are disadvantageous either
due to greater flexibility of the aryl substituent (for 4e and 5e) or
unfavorable conformational restriction of the aryl ring.
H3CO
H3CO
H3CO
H3CO
O
CO2CH3
Cl
H2N R, Et3N
CH3CN, reflux
N
R
6
7a – l
i) BBr3, CH2Cl2
ii) H2O
OH
O
HO
N
R
4a – l
Scheme 1.
H3CO
H3CO
H3CO
H3CO
O
O
O
H2N R, Et3N
toluene, reflux
N
R
Within the series 4 compounds the effects were next examined
of introducing a chiral center into the arylamide moiety through
O
8
9a – f, k,l
O
i) BBr3, CH2Cl2
ii) H2O
OH
O
addition of an a-methyl group (compounds 4g–4l, Table 3). Consis-
HO
tent with previous reports,14–17 the ST inhibitory potency for all
analogues tested was greater for the (S)-enantiomer than for the
respective (R)-enantiomer. The enantiomeric difference in poten-
cies ranged from approximately twofold for the benzyl analogues
4g and 4h to more than 10-fold for 1-naphthylmethyl, 1-indanyl
N
R
O
5a – f, k, l
Scheme 2.

5320
X. Z. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 5318–5324
Table 3
Table 4
Inhibition data from an in vitro HIV-1 IN assay
Inhibition data from an in vitro HIV-1 IN assay
OH
OH
O
O
HO
HO
N
R
N
R
4
O
5
No.
R
IC50
(
l
M)
IC50
(
l
M)
No.
R
IC50
(l
M)
ST
(S)-Chirality
IC50 (lM)
30-P
ST
30-P
ST
30-P
30-P
ST
(R)-Chirality
g
>333
>111
>111
>111
>333
>333
49.0 1.1
12.1 1.1
4.0 0.42
4.6 0.86
>333
100 2.5
24.4 1.5
48.3 1.2
24.0 1.3
k
l
128 11
111 13
1.8 0.3
290 18
12
81
2
2
CH3
F
h
>333
>111
>111
>333
>333
10
1
>333
CH3
CH3
i
fold to eightfold). It was of note that the previously reported
analogue 3, which also contains a second carbonyl group situated
similarly to the series 5 compounds, also exhibits a relatively low
degree of enantiomeric preference.14
j
3. Conclusion
CH3
In conclusion, understanding the molecular basis for the binding
of DKA-derived inhibitors to INꢀDNA complexes has been hampered
by the lack of X-ray crystal data leading to the development of com-
putationally derived binding models.22,23 Correlation of hypotheti-
cal inhibitor binding interactions with known patterns of
resistance IN mutants has provided an indirect means of validating
these models.24 An emerging feature in the understanding of how
DKA-derived inhibitors bind to IN is the concept that hydrophobic
interactions are critical. This has led to the postulationof a hypothet-
ical hydrophobic binding pocket(s) that accommodates specific aryl
components of the inhibitor structure.9,10 Recent studies have fo-
cused on modulating interactions with this hydrophobic pocket by
variation of aryl substituents.11–13 Previous reports have also curso-
rily indicated the existence of differential binding effects induced by
k
l
6
9
1
1
99
7
121 17
and 1-methyl(tetrahydronaphthyl) compounds (4i, 4k and 4l,
respectively). For the benzyl and naphthylmethyl derivatives, the
ST inhibitory potencies of the more potent (S)-methyl enantiomers
were approximately fourfold lower then the corresponding unsub-
stituted achiral analogues shown in Table 2. Therefore, while addi-
introduction of an
current study examines this latter phenomenon in detail. We show
that addition of an -methyl group is uniformly deleterious to bind-
a-chiral center to the key aryl substituent. Our
a
ing, with the (S)-configuration being less deleterious than the (R)-
configuration. A greaterenantiomeric difference in potencyisshown
by inhibitors that have restricted rotation of the aryl ring, with this
being due to poorer potency of the (R)-enantiomer rather than high-
er potency of the (S)-enantiomer. This potentially indicates that con-
formations of the aryl rings for the (R)-enantiomers are particularly
unfavorable. Addition of a second carbonyl group to the isoindoline-
1-one platform (series 4) to give the isoindoline-1,3-dione ring sys-
tem (series 5) reduces the potency difference by increasing the po-
tency (decreasing unfavorable binding interactions) of the (R)-
enantiomer relative to the (S)-enantiomer. Taken in total, findings
of our current study contribute to understanding the molecular
interactions of DKA-derived IN inhibitors.
tion of an
a-methyl group was uniformly deleterious to binding,
the (S)-enantiomer was less deleterious than the (R)-enantiomer.
A greater enantiomeric difference in potency (more than 10-fold)
was shown for analogues 4i, 4k and 4l. These inhibitors exhibit re-
stricted rotation of the aryl ring either through steric hindrance
(for 4i) or through ring structures (4k and 4l). In each case the lar-
ger enantiomeric difference was due to poorer potency of the (R)-
enantiomer rather than higher potency of the (S)-enantiomer. This
could indicate that conformations for the aryl rings for the (R)-
enantiomers are particularly unfavorable.
While the chiral analogues above dealt with series 4 com-
pounds, it was also of interest to examine enantiomeric effects in
series 5 compounds, which contain an additional carbonyl group
that could influence binding orientation. For this purpose the (S)-
and (R)-enantiomers of the 1-indanyl (5k) and 1-methyl(tetrahy-
dronaphthyl) (5l) compounds were prepared (Table 4). While the
corresponding series 4 analogues (4k and 4l) showed an approxi-
mate 15-fold greater ST inhibitory potency for the (S)-enantiomer
relative to the (R)-enantiomer, the preference in the series 5 com-
pounds was approximately one half as great (approximately seven-
4. Experimental
4.1. Integrase catalytic assay
Expression of the recombinant IN in Escherichia coli and
subsequent purification of the protein were performed as

X. Z. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 5318–5324
5321
previously reported25,26 with addition of 10% glycerol to all buffers.
Preparation of oligonucleotide substrates has been described.27
4.3.2. 2-(2,3-Dihydro-1H-inden-2-yl)-6,7-dimethoxyisoindolin-
1-one (7f)
Integrase reactions were performed in 10
l
L with 400 nM of re-
Prepared in 54% yield. 1H NMR (CDCl3): d 7.21–7.18 (m, 2H),
7.16–7.13 (m, 2H), 6.99 (d, 1H, J = 8.4 Hz), 6.92 (d, 1H, J = 8.4 Hz),
5.29–5.25 (m, 1H), 4.03 (s, 3H), 3.98 (s, 2H), 3.81 (s, 3H), 3.27
(dd, 2H, J = 7.6 Hz, 16.4 Hz), 2.94 (dd, 2H, J = 5.2 Hz, 16.4 Hz). 13C
NMR (CDCl3): d 166.4, 152.3, 147.1, 140.9 (2C), 134.3, 126.8 (2C),
124.9, 124.4 (2C), 117.8, 116.4, 62.5 (d, 1C, J = 1.5 Hz), 56.7 (d,
1C, J = 2.2 Hz), 51.4, 45.5, 37.7 (2C). APCI-MS m/z: 310.1 (MH+).
combinant IN, 20 nM of 50-end [32P]-labeled oligonucleotide sub-
strate and inhibitors at various concentrations. Solutions of 10%
DMSO without inhibitors were used as controls. Reactions were
incubated at 37 °C (30 min) in buffer containing at a final concen-
tration of 50 mM MOPS, pH 7.2 and 7.5 mM of divalent cations
(MgCl2 unless MnCl2 is otherwise indicated). Reactions were
stopped by addition of 20 lL of loading dye (10 mM EDTA, 98%
deionized formamide, 0.025% xylene cyanol and 0.025% bromophe-
nol blue). Reactions were heated at 95 °C (1 min) then subjected to
electrophoresis in 20% polyacrylamide–7 M urea gels. Gels were
dried and reaction products were visualized and quantitated with
a PhosphorImager (GE Healthcare, Little Chalfont, Buckingham-
shire, UK). Densitometric analyses were performed using Image-
Quant from Molecular Dynamics Inc. The concentrations at
which enzyme activity was reduced by 50% (IC50) were determined
using ‘PRISM’ software (GRAPHPAD Software, San Diego, CA) for nonlin-
ear regression to fit dose-response data to logistic curve models.
4.3.3. (S)- and (R)-6,7-Dimethoxy-2-(1-phenylethyl)isoindolin-
1-one [(S)-7g] and [(R)-7g]
(S)-7g Prepared in 47% yield; prepared in (R)-7g 45% yield. 1H
NMR (CDCl3): d 7.29–7.21 (m, 4H), 7.18–7.14 (m, 1H), 6.96 (d,
1H, J = 8.2 Hz), 6.90 (d, 1H, J = 8.2 Hz), 5.68 (dd, 1H, J = 7.2 Hz,
14.0 Hz), 4.141 (d, 1H, J = 16.8 Hz), 4.03 (s, 3H), 3.78 (d, 1H,
J = 16.8 Hz), 3.77 (s, 3H), 1.57 (d, 3H, J = 7.2 Hz). 13C NMR (CDCl3):
d 166.2, 152.2, 147.1, 140.7, 134.6, 128.5 (2C), 127.4, 127.1 (2C),
125.0, 117.8, 116.4, 62.4, 56.7, 48.9, 44.6, 17.1. APCI-MS m/z:
298.1 (MH+).
4.2. General synthetic
4.3.4. (S)- and (R)-2-(1-(4-Fluorophenyl)ethyl)-6,7-
dimethoxyisoindolin-1-one [(S)-7h] and [(R)-7h]
1H and 13C NMR data were obtained on a Varian 400 MHz spec-
trometer and are reported in ppm relative to TMS and referenced
to the solvent in which the spectra were collected. Solvent was re-
moved by rotary evaporation under reduced pressure and anhy-
drous solvents were obtained commercially and used without
further drying. Purification by silica gel chromatography was per-
formed using EtOAc–hexanes solvent systems. Preparative high
pressure liquid chromatography (HPLC) was conducted using a
Waters Prep LC4000 system having photodiode array detection
(S)-7h Prepared in 64% yield; [(R)-7h] prepared in 60% yield. 1H
NMR (CDCl3): d 7.23–7.19 (m, 2H), 6.95–6.84 (m, 4H), 5.60 (dd, 1H,
J = 7.2 Hz, 14.0 Hz), 4.11 (d, 1H, J = 16.4 Hz), 3.98 (s, 3H), 3.76 (d,
1H, J = 16.4 Hz), 3.73 (s, 3H), 1.51 (d, 3H, J = 7.2 Hz). 13C NMR
(CDCl3): d 166.2, 161.9 (d, 1C, J = 244.9 Hz), 152.2, 147.1, 136.6
(d, 1C, J = 3.0 Hz), 134.4, 128.7 (d, 2C, J = 8.4 Hz), 124.9, 117.9,
116.4, 115.2 (d, 2C, J = 20.6 Hz), 62.3, 56.6, 48.3, 44.4, 17.2. APCI-
MS m/z: 316.1 (MH+).
and Phenomenex C18 columns (250 mm ꢁ 21.2 mm 5
l
m particle
4.3.5. (S)- and (R)-6,7-Dimethoxy-2-(1-(naphthalen-1-
yl)ethyl)isoindolin-1-one [(S)-7i] and [(R)-7i]
size, 110 Å pore) at a flow rate of 10 mL/min. A binary solvent sys-
tems consisting of A = 0.1% aqueous TFA and B = 0.1% TFA in aceto-
nitrile was employed with the gradients as indicated. Products
were obtained as amorphous solids following lyophilization.
High-resolution mass spectra (HRMS) were obtained from the
UCR Mass Spectrometry Facility, University of California at River-
side and fast-atom bombardment mass spectra (FABMS) were ac-
quired with a VG Analytical 7070E mass spectrometer under the
control of a VG 2035 data system.
(S)-7i Prepared in 74% yield; (R)-7i prepared in 73% yield. 1H
NMR (CDCl3): d 8.17 (d, 1H, J = 8.4 Hz), 7.79 (d, 1H, J = 8.0 Hz),
7.59 (d, 1H, J = 7.2 Hz), 7.48–7.39 (m, 3H), 6.92 (d, 1H, J = 8.4 Hz),
6.77 (d, 1H, J = 8.0 Hz), 6.39 (dd, 1H, J = 6.4 Hz, 14.0 Hz), 4.11 (s,
3H), 4.07 (d, 1H, J = 16.8 Hz), 3.79 (s, 3H), 3.32 (d, 1H,
J = 16.8 Hz), 1.747 (d, 3H, J = 6.8 Hz). 13C NMR (CDCl3): d 165.7,
152.2, 147.2, 135.7, 134.7, 133.8, 131.6, 128.8, 128.5, 127.0,
126.0, 125.0, 124.8, 123.9, 123.6, 117.7, 116.4, 62.5, 56.8, 45.4,
44.6, 17.1. APCI-MS m/z: 348.1 (MH+).
4.3. General procedure for the synthesis of lactams (7d–7l)
4.3.6. (S)- and (R)-6,7-Dimethoxy-2-(1-(naphthalen-2-
Triethylamine (2.0 mmol) was added to a solution of methyl 2-
chloromethyl-3,4-dimethoxybenzoate (6)18–20 (1.0 mmol) and an
appropriate amine (1.0 mmol) in anhydrous acetonitrile (3.0 mL)
was added. The mixture was stirred and refluxed until the starting
material was consumed as indicated by silica gel TLC. The solvent
was evaporated and the residue was partitioned between chloro-
form and brine. The combined organic phase was dried (Na2SO4),
evaporated and the residue was purified by silica gel column chro-
matography. (Note: lactams 7a–7c and 7e have been previously
yl)ethyl)isoindolin-1-one [(S)-7j] and [(R)-7j]
(S)-7j Prepared in 56% yield; (R)-7j prepared in 65% yield. 1H
NMR (CDCl3): d 7.73–7.65 (m, 4H), 7.37–7.31 (m, 3H), 6.89 (d,
1H, J = 8.0 Hz), 6.80 (d, 1H, J = 8.0 Hz), 5.83 (dd, 1H, J = 6.8 Hz,
14.0 Hz), 4.06(s, 3H), 3.72 (s, 3H), 1.63 (d, 3H, J = 7.2 Hz). 13C
NMR (CDCl3): d 166.4, 152.2, 147.1, 138.2, 134.5, 133.2, 132.7,
128.4, 127.9, 127.5, 126.2, 126.0, 125.8, 125.3, 124.9, 117.9,
116.4, 62.4, 56.6, 48.9, 44.6, 17.0. APCI-MS m/z: 348.1 (MH+).
reported.18
)
4.3.7. (S)- and (R)-2-(2,3-Dihydro-1H-inden-1-yl)-6,7-
dimethoxyisoindolin-1-one [(S)-7k] and [(R)-7k]
(S)-7k Prepared in 55% yield, ½a D23
(CHCl3) = ꢃ98.0; (R)-7k pre-
ꢂ
pared in 57% yield, ½a D23
ꢂ
(CHCl3) = 91.5. 1H NMR (CDCl3): d 7.24–
4.3.1. 6,7-Dimethoxy-2-(naphthalen-2-ylmethyl)isoindolin-1-
one (7d)
7.19 (m, 2H), 7.13–7.10 (m, 2H), 7.02 (d, 1H, J = 8.0 Hz), 6.94 (d,
1H, J = 8.0 Hz), 6.02 (t, 1H, J = 7.6 Hz), 4.08 (s, 3H), 4.06 (d, 1H,
J = 16.8 Hz), 3.90 (d, 1H, J = 16.8 Hz), 3.84 (s, 3H), 3.07–3.00 (m,
1H), 2.96–2.88 (m, 1H), 2.54–2.45 (m, 1H), 2.06–1.97 (m, 2H). 13C
NMR (CDCl3): d 166.8, 152.3, 147.2, 143.5, 141.4, 134.6, 128.0,
126.8, 125.0, 124.9, 124.4, 117.8, 116.5, 62.5 (d, 1C, J = 3.8 Hz),
56.8 (d, 1C, J = 6.1 Hz), 56.1 (d, 1C, J = 5.4 Hz), 44.9 (t, 1C,
J = 5.0 Hz), 30.6, 30.4. APCI-MS m/z: 310.1 (MH+).
Prepared in 37% yield. 1H NMR (CDCl3): d 7.72–7.69 (m, 3H),
7.66 (s, 1H), 7.39–7.34 (m, 3H), 6.95 (d, 1H, J = 8.4 Hz), 6.87 (d,
1H, J = 8.4 Hz), 4.80 (s, 2H), 4.08 (s, 3H), 4.04 (s, 2H), 3.78 (s,
3H). 13C NMR (CDCl3):
d 166.7, 152.3, 147.2, 134.6, 134.5,
133.3, 132.8, 128.6, 127.7, 127.6, 126.9, 126.3, 126.2, 126.0,
124.7, 117.9, 116.4, 62.5, 56.7, 48.5, 46.4. APCI-MS m/z: 334.1
(MH+).

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X. Z. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 5318–5324
4.3.8. (S)- and (R)-6,7-Dimethoxy-2-(1,2,3,4-
tetrahydronaphthalen-1-yl)isoindolin-1-one [(S)-7l] and [(R)-
118.5, 115.7 (d, 2C, J = 20.5 Hz), 114.2, 48.8, 45.5, 18.3. APCI-
MS m/z: 288.1 (MH+).
7l]
(S)-7l Prepared in 51% yield, ½a D22
ꢂ
(MeOH) = ꢃ109.7; (R)-7l pre-
4.4.5. (S)- and (R)-6,7-Dihydroxy-2-(1-(naphthalen-1-
yl)ethyl)isoindolin-1-one [(S)-4i] and [(R)-4i]
pared in 56% yield, ½a D22
ꢂ
(MeOH) = 131.8. 1H NMR (CDCl3): d 7.11–
7.07 (m, 2H), 7.05–7.00 (m, 2H), 6.95–6.93 (m, 2H), 5.64 (t, 1H,
J = 7.4 Hz), 4.11 (d, 1H, J = 16.8 Hz), 4.08 (s, 3H), 3.90 (d, 1H,
J = 16.8 Hz), 3.83 (s, 3H), 2.80–2.75 (m, 2H), 2.10–2.07 (m, 1H),
1.99–1.95 (m, 1H), 1.88–1.83 (m, 2H). 13C NMR (CDCl3): d 167.2,
152.3, 147.2, 138.0, 135.1, 134.7, 129.2, 127.5, 127.0, 126.2,
124.8, 117.8, 116.5, 62.5 (d, 1C, J = 3.0 Hz), 56.8 (d, 1C, J = 4.6 Hz),
49.6, 45.3, 29.4, 28.7, 21.7.
HPLC conditions: linear gradient of 40% B to 60% B over 30 min;
retention time = 25.5 min. 1H NMR (DMSO): d 8.07–8.05 (m, 1H),
7.92–7.86 (m, 2H), 7.64 (d, 1H, J = 7.2 Hz), 7.54–7.49 (m, 1H),
7.48–7.43 (m, 2H), 6.82 (d, 1H, J = 8.0 Hz), 6.58 (d, 1H, J = 8.0 Hz),
6.11 (dd, 1H, J = 7.2 Hz, 13.6 Hz), 4.24 (d, 1H, J = 17.6 Hz), 3.29 (d,
1H, J = 17.6 Hz), 1.67 (d, 3H, J = 7.2 Hz). 13C NMR (DMSO): d
167.3, 144.8, 143.3, 136.3, 133.8, 132.5, 131.3, 129.2, 128.8,
127.1, 126.3, 125.7, 124.6, 123.2, 119.8, 118.4, 114.2, 45.3, 45.2,
17.8. APCI-MS m/z: 320.1 (MH+).
4.4. General procedure for the demethylation of methyl ethers
(conversion of 7 to 4 and 9 to 5)
4.4.6. (S)- and (R)-6,7-Dihydroxy-2-(1-(naphthalen-2-
yl)ethyl)isoindolin-1-one [(S)-4j] and [(R)-4j]
Boron tribromide (1.0 M in dichloromethane, 8.5 mmol) was
added carefully to
a
solution of appropriate methyl ether
HPLC conditions: linear gradient of 40% B to 54% B over 30 min;
retention time = 24.0 min. 1H NMR (CD3OD): d 7.83–7.76 (m, 4H),
7.45–7.38 (m, 3H), 6.91 (d, 1H, J = 8.0 Hz), 6.70 (d, 1H, J = 8.0 Hz),
5.70 (dd, 1H, J = 7.2 Hz, 14.4 Hz), 4.33 (d, 1H, J = 16.8 Hz), 3.88 (d,
1H, J = 16.8 Hz), 1.74 (d, 3H, J = 7.2 Hz). 13C NMR (CD3OD): d
169.4, 144.1, 143.0, 138.0, 133.3, 132.8, 132.5, 128.1, 127.6,
125.9, 125.7, 125.0, 124.9, 119.6, 117.6, 113.7, 49.4, 45.4, 16.4.
APCI-MS m/z: 320.1 (MH+).
(1.0 mmol in 1.0 mL anhydrous dichloromethane) and the mixture
was stirred at room temperature (overnight). The reaction was
quenched by the careful addition of ice water (1.0 mL) then the
mixture was stirred at room temperature (overnight). The resulting
suspension was filtered and the collected solid was purified by pre-
parative HPLC. (Note: Products 4a–4c and 4e have been previously
reported18 as well as 5b.13
)
4.4.1. 6,7-Dihydroxy-2-(naphthalen-2-yl)isoindolin-1-one (4d)
HPLC conditions: Linear gradient of 40% B to 60% B over 30 min;
retention time = 22.1 min. 1H NMR (DMSO): d 7.84–7.81 (m, 3H),
7.22 (s, 1H), 7.46–7.41 (m, 2H), 7.35 (dd, 1H, J = 1.6 Hz, 8.0 Hz),
6.92 (d, 1H, J = 8.0 Hz), 6.69 (d, 1H, J = 8.0 Hz), 4.76 (s, 2H), 4.17
(s, 2H). 13C NMR (DMSO): d 168.5, 144.8, 143.5, 135.6, 133.4,
132.7 (2C), 128.8, 128.0 (2C), 126.7, 126.5 (2C), 126.3, 120.0,
118.3, 114.2, 49.2, 45.7. APCI-MS m/z: 306.1 (MH+). HRMS calcd
for C19H16NO3 [MH+]: 306.1130. Found: 306.1132.
4.4.7. (S)- and (R)-2-(2,3-Dihydro-1H-inden-1-yl)-6,7-
dihydroxyisoindolin-1-one [(S)-4k] and [(R)-4k]
HPLC conditions: linear gradient of 40% B to 55% B over 30 min;
retention time = 20.2 min. 1H NMR (DMSO):
d 7.26 (d, 1H,
J = 7.6 Hz), 7.19 (t, 1H, J = 7.2 Hz), 7.15 (t, 1H, J = 7.6 Hz), 7.02 (d,
1H, J = 7.2 Hz), 6.90 (d, 1H, J = 7.6 Hz), 6.68 (d, 1H, J = 7.6 Hz),
5.73 (t, 1H, J = 8.0 Hz), 4.16 (d, 1H, J = 17.2 Hz), 3.75 (d, 1H,
J = 17.2 Hz), 3.03–2.96 (m, 1H), 2.89–2.81 (m, 1H), 2.38–2.30 (m,
1H), 2.08–1.99 (m, 1H). 13C NMR (DMSO): d 168.6, 144.7, 143.7,
143.3, 141.8, 132.5, 128.3, 127.1, 125.3, 124.3, 120.0, 118.4,
114.3, 55.9, 45.4, 30.5, 30.3. [(S)-4k] HRMS calcd for C17H15NO3Na
[MNa+]: 304.0950. Found: 304.0955. [(R)-4k] HRMS calcd for
C17H15NO3Na [MNa+]: 304.0950. Found: 304.0951.
4.4.2. 2-(2,3-Dihydro-1H-inden-2-yl)-6,7-dihydroxyisoindolin-
1-one (4f)
HPLC conditions: linear gradient of 40% B to 55% B over 30 min;
retention time = 20.6 min. 1H NMR (DMSO): d 7.21–7.19 (m, 2H),
7.14–7.11 (m, 2H), 6.90 (d, 1H, J = 7.6 Hz), 6.69 (d, 1H, J = 7.6 Hz),
4.98–4.95 (m, 1H), 4.07 (s, 2H), 3.14 (dd, 2H, J = 8.0 Hz, 16.0 Hz),
2.99 (dd, 2H, J = 8.0 Hz, 16.0 Hz). 13C NMR (DMSO): d 168.4,
144.6, 143.2 (2C), 141.3 (2C), 132.4, 127.0 (2C), 124.7 (2C), 120.0,
118.5, 114.2, 51.6, 46.2, 37.2 (2C). APCI-MS m/z: 282.0 (MH+).
4.4.8. (S)- and (R)-6,7-Dihydroxy-2-(1,2,3,4-
tetrahydronaphthalen-1-yl)isoindolin-1-one [(S)-4l] and [(R)-
4l]
HPLC conditions: linear gradient of 40% B to 50% B over 30 min;
retention time = 24.7 min. 1H NMR (DMSO): d 7.12–7.07 (m, 2H),
7.06–7.02 (m, 2H), 6.91 (d, 1H, J = 8.0 Hz), 6.80 (d, 1H, J = 7.6 Hz),
6.69 (d, 1H, J = 7.6 Hz), 5.37–5.33 (m, 1H), 4.18 (d, 1H,
J = 17.2 Hz), 3.75 (d, 1H, J = 17.2 Hz), 2.78–2.66 (m, 2H), 1.95–
1.85 (m, 3H), 1.82–1.74 (m, 1H). 13C NMR (DMSO): d 169.0,
144.8, 143.4, 138.2, 135.6, 132.5, 129.6, 127.3, 127.1, 126.6,
120.0, 118.3, 114.3, 49.4, 45.8, 29.2, 28.5, 21.9. ESI-MS m/z: 294.1
(M-H). [(S)-4l] HRMS calcd for C18H18NO3 [MH+]: 296.1281. Found:
296.1278. [(R)-4l] HRMS calcd for C18H18NO3 [MH+]: 296.1281.
Found: 296.1282.
4.4.3. (S)- and (R)-6,7-Dihydroxy-2-(1-phenylethyl)isoindolin-
1-one [(S)-4g] and [(R)-4g]
HPLC conditions: linear gradient of 40% B to 45% B over 30 min;
retention time = 20.1 min. 1H NMR (CD3OD):
d 7.31 (d, 4H,
J = 4.8 Hz), 7.24–7.21 (m, 1H), 6.92 (d, 1H, J = 8.0 Hz), 6.73–6.70
(m, 1H), 5.54 (dd, 1H, J = 6.8 Hz, 14.4 Hz), 4.31 (d, 1H,
J = 17.2 Hz), 3.88 (d, 1H, J = 17.2 Hz), 1.63 (d, 3H, J = 7.2 Hz). 13C
NMR (CD3OD): d 169.3, 144.1, 143.0, 140.6, 132.5, 128.3 (2C),
127.2, 126.5 (2C), 119.6, 117.6, 113.6, 49.4, 45.3, 16.5. APCI-MS
m/z: 270.1 (MH+).
4.5. General procedure for the synthesis of phthalimides (9a–9f,
9k, 9l)
4.4.4. (S)- and (R)-2-(1-(4-Fluorophenyl)ethyl)-6,7-
dihydroxyisoindolin-1-one [(S)-4h] and [(R)-4h]
Triethylamine (2.0 mmol) was added dropwise to a solution of
3,4-dimethoxyphthalic anhydride) (8)22 (1.0 mmol) and an appro-
priate amine (1.0 mmol) in toluene (5.0 mL) and the mixture was
stirred at reflux (overnight). The solvent was evaporated and the
residue was taken up in chloroform, dried (Na2SO4) and evapo-
rated. The product was obtained following purification by silica
gel column chromatography. (Note: Phthalimide 9b has been pre-
HPLC conditions: linear gradient of 40% B to 50% B over
30 min; retention time = 21.6 min. 1H NMR (DMSO): d 7.33–
7.29 (m, 2H), 7.14–7.09 (m, 2H), 6.90 (d, 1H, J = 8.0 Hz), 6.71
(d, 1H, J = 8.0 Hz), 5.37 (dd, 1H, J = 7.2 Hz, 14.4 Hz), 4.30 (d, 1H,
J = 17.2 Hz), 3.89 (d, 1H, J = 17.2 Hz), 1.54 (d, 3H, J = 7.2 Hz). 13C
NMR (DMSO): d 168.1, 161.7 (d, 1C, J = 242.6 Hz), 144.7, 143.3,
138.0 (d, 1C, J = 3.1 Hz), 132.5, 129.2 (d, 2C, J = 7.6 Hz), 120.0,
viously reported.13
)

X. Z. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 5318–5324
5323
4.5.1. 2-Benzyl-4,5-dimethoxyisoindoline-1,3-dione (9a)
Prepared in 16% yield. 1H NMR (CDCl3): d 7.49 (dd, 1H,
J = 1.2 Hz, 8.0 Hz), 7.39 (dd, 2H, J = 1.2 Hz, 8.0 Hz), 7.29–7.23 (m,
3H), 7.05 (d, 1H, J = 8.0 Hz), 4.76 (s, 2H), 4.10 (d, 3H, J = 1.2 Hz),
3.90 (d, 3H, J = 1.2 Hz). 13C NMR (CDCl3): d 167.3, 166.0, 157.7,
147.2, 136.5, 128.6 (4C), 127.7, 124.6, 121.9, 119.4, 115.7, 62.5,
56.6, 41.6. FAB-MS m/z: 298.2 (MH+).
124.6, 121.9, 119.3, 115.8, 62.5, 56.6 (d, 1C, J = 3.8 Hz), 49.2, 29.4,
27.9, 22.4.
4.5.8. 2-Benzyl-4,5-dihydroxyisoindoline-1,3-dione (5a)
HPLC conditions: linear gradient of 30% B to 55% B over 30 min;
retention time = 24.2 min. 1H NMR (DMSO): d 7.26–7.16 (m, 5H),
7.14 (d, 1H, J = 8.0 Hz), 6.97 (d, 1H, J = 8.0 Hz), 4.81 (s, 2H), 4.68
(s, 2H). 13C NMR (DMSO): d 168.1, 167.6, 152.3, 144.0, 137.0 (2C),
128.1 (2C), 127.5 (2C), 127.1, 122.4, 118.5, 115.9, 40.5. FAB-MS
m/z: 268.1 (MꢃH). HRMS calcd for C15H10NO4 [MꢃH]: 268.0610.
Found: 268.0613.
4.5.2. 4,5-Dimethoxy-2-(naphthalen-1-ylmethyl)isoindoline-
1,3-dione (9c)
Prepared in 18% yield. 1H NMR (CDCl3): d 8.34 (d, 1H, J = 8.8 Hz),
7.79 (dd, 2H, J = 8.0 Hz, 24.4 Hz), 7.58–7.52 (m, 1H), 7.50 (d, 1H,
J = 8.0 Hz), 7.48–7.44 (m, 2H), 7.39 (t, 1H, J = 8.0 Hz), 7.04 (d, 1H,
J = 8.0 Hz), 5.24 (s, 2H), 4.09 (s, 3H), 3.89 (s, 3H). 13C NMR (CDCl3):
d 167.5, 166.2, 157.7, 147.2, 133.7, 131.5, 131.2, 128.6, 128.5,
127.4, 126.4, 125.7, 125.3, 124.5, 123.5, 121.9, 119.5, 115.8, 62.5,
56.6, 39.5. FAB-MS m/z: 348.1 (MH+).
4.5.9. 4,5-Dihydroxy-2-(naphthalen-1-ylmethyl)isoindoline-
1,3-dione (5c)
HPLC conditions: linear gradient of 40% B to 60% B with YMC
HPLC column over 30 min; retention time = 22.3 min. 1H NMR
(DMSO): d 8.21 (d, 1H, J = 8.0 Hz), 7.91 (d, 1H, J = 8.0 Hz), 7.81 (d,
1H, J = 8.0 Hz), 7.56–7.51 (m, 3H), 7.39 (t, 1H, J = 8.0 Hz), 7.26 (d,
1H, J = 6.8 Hz), 7.17 (d, 1H, J = 7.6 Hz), 7.04 (d, 1H, J = 7.6 Hz),
5.10 (s, 2H). 13C NMR (DMSO): d 167.9, 167.0, 153.0, 144.7,
133.7, 132.5, 130.8, 129.0, 128.2, 126.9, 126.4, 125.8, 125.2,
123.5, 122.6, 119.2, 116.3, 116.1, 38.9. FAB-MS m/z: 320.1 (MH+).
HRMS calcd for C19H14NO4 [M-H]: 320.0923. Found: 320.0917.
4.5.3. 4,5-Dimethoxy-2-(naphthalen-2-ylmethyl)isoindoline-
1,3-dione (9d)
Prepared in 39% yield. 1H NMR (CDCl3): d 7.84 (s, 1H), 7.76–7.70
(m, 3H), 7.51 (dd, 1H, J = 1.6 Hz, 8.4 Hz), 7.42 (d, 1H, J = 8.4 Hz),
7.38–7.35 (m, 2H), 6.92 (d, 1H, J = 8.4 Hz), 4.90 (s, 2H), 4.08 (s,
3H), 3.79 (s, 3H). 13C NMR (CDCl3): d 167.3, 166.0, 157.6, 147.1,
134.0, 133.2, 132.8, 128.4, 127.9, 127.6, 127.5, 126.5, 126.1,
126.0, 124.5, 121.8, 119.4, 115.7, 62.5, 56.5, 41.7. APCI-MS m/z:
348.1 (MH+).
4.5.10. 4,5-Dihydroxy-2-(naphthalen-2-ylmethyl)isoindoline-
1,3-dione (5d)
HPLC conditions: linear gradient of 40% B to 60% B over 30 min;
retention time = 23.1 min. 1H NMR (DMSO): d 7.83–7.81 (m, 3H),
7.72 (s, 1H), 7.44–7.38 (m, 3H), 7.17 (d, 1H, J = 8.0 Hz), 7.04 (d,
1H, J = 8.0 Hz), 4.80 (s, 2H). 13C NMR (DMSO): d 167.8, 166.9,
152.9, 144.7, 135.2, 133.2, 132.6, 128.6, 128.0, 127.9, 126.7,
126.3, 126.1 (2C), 126.0, 122.7, 119.2, 116.2, 41.1. APCI-MS m/z:
318.1 (MꢃH). HRMS calcd for C19H12NO4 [MꢃH]: 318.0766. Found:
318.0759.
4.5.4. 4,5-dimethoxy-2-phenethylisoindoline-1,3-dione (9e)
Prepared in 61% yield. 1H NMR (CDCl3): d 7.47 (d, 1H, J = 8.0 Hz),
7.24–7.22 (m, 5H), 7.05 (d, 1H, J = 8.0 Hz), 4.08 (s, 3H), 3.90 (s, 3H),
3.84 (t, 2H, J = 7.6 Hz), 2.93 (t, 2H, J = 7.6 Hz). 13C NMR (CDCl3): d
167.4, 166.1, 157.6, 147.1, 138.1, 128.8 (2C), 128.5 (2C), 126.5,
124.6, 121.8, 119.3, 115.6, 62.5, 56.6, 39.2, 34.5. FAB-MS m/z:
312.1 (MH+).
4.5.11. 4,5-Dihydroxy-2-phenethylisoindoline-1,3-dione (5e)
HPLC conditions: linear gradient of 40% B to 50% B with YMC
HPLC column over 30 min; retention time = 18.3 min. 1H NMR
(CD3OD): d 7.22–7.11 (m, 6H), 6.96 (d, 1H, J = 7.6 Hz), 6.70 (d, 1H,
J = 8.0 Hz), 3.76 (dd, 2H, J = 7.6 Hz, 8.4 Hz), 2.89 (t, 2H, J = 7.6 Hz).
13C NMR (CD3OD): d 168.2, 167.8, 152.2, 143.8, 138.3, 128.4 (2C),
128.0 (2C), 126.1, 122.4, 118.4, 115.7, 115.5, 38.5, 34.0. FAB-MS
m/z: 284.1 (MH+). HRMS calcd for C16H14NO4 [MH+]: 284.0923.
Found: 284.0914.
4.5.5. 2-(2,3-Dihydro-1H-inden-2-yl)-4,5-dimethoxyisoind-
oline-1,3-dione (9f)
Prepared in 23% yield. 1H NMR (CDCl3): d 7.50 (d, 1H, J = 8.0 Hz),
7.19–7.13 (m, 4H), 7.07 (d, 1H, J = 8.0 Hz), 5.11–5.06 (m, 1H), 4.10
(s, 3H), 3.92 (s, 3H), 3.59 (dd, 2H, J = 9.2 Hz, 15.2 Hz), 3.12 (dd, 2H,
J = 8.8 Hz, 15.2 Hz). 13C NMR (CDCl3): d 167.7, 166.3, 157.7, 147.1,
140.9, 124.8, 126.6 (2C), 134.6, 124.3 (2C), 121.9, 119.3, 115.8,
62.5 (d, 1C, J = 3.1 Hz), 56.6 (d, 1C, J = 4.6 Hz), 49.9, 36.0 (2C).
APCI-MS m/z: 324.0 (MH+).
4.5.12. 2-(2,3-Dihydro-1H-inden-2-yl)-4,5-dihydroxyisoind-
oline-1,3-dione (5f)
4.5.6. (S)- and (R)-2-(2,3-Dihydro-1H-inden-1-yl)-4,5-
dimethoxyisoindoline-1,3-dione [(S)-9k] and [(R)-9k]
HPLC conditions: linear gradient of 30% B to 55% B over 30 min;
retention time = 29.5 min. 1H NMR (DMSO): d 7.18–7.15 (m, 2H),
7.13–7.11 (m, 2H), 7.11 (d, 1H, J = 8.0 Hz), 7.01 (d, 1H, J = 8.0 Hz),
4.91–4.87 (m, 1H), 3.36 (dd, 2H, J = 9.2 Hz, 15.6 Hz), 3.08 (dd, 2H,
J = 9.2 Hz, 15.6 Hz). 13C NMR (DMSO): d 167.9, 167.1, 152.8,
144.5, 141.4 (2C), 126.9 (2C), 124.7 (2C), 122.7, 119.1, 116.1,
115.9, 49.0, 36.1 (2C). MALDI-MS m/z: 295.54 (MH+). HRMS calcd
for C17H12NO4 [MꢃH]: 294.0766. Found: 294.0769.
(S)-9k Prepared in 14% yield, ½a D23
(CHCl3) = ꢃ127.7; (R)-9k pre-
ꢂ
pared in 15% yield, ½a D23
ꢂ
(CHCl3) = ꢃ119.4. 1H NMR (CDCl3): d 7.46
(d, 1H, J = 8.0 Hz), 7.24 (d, 1H, J = 7.6 Hz), 7.20–7.16 (m, 1H), 7.12–
7.06 (m, 2H), 7.05 (d, 1H, J = 8.0 Hz), 5.80 (dd, 1H, J = 6.8, 8.4 Hz),
4.07 (s, 3H), 3.89 (s, 3H), 3.34–3.29 (m, 1H), 2.98–2.90 (m, 1H),
2.53–2.40 (m, 2H), 13C NMR (CDCl3): d 167.3, 165.9, 157.7, 147.1,
143.8, 140.6, 127.9, 126.4, 124.8, 124.6, 123.3, 121.9, 119.3,
115.8, 62.5, 56.6, 54.7, 31.1, 29.5. APCI-MS m/z: 324.1 (MH+).
4.5.13. (S)- and (R)-2-(2,3-Dihydro-1H-inden-1-yl)-4,5-
dihydroxyisoindoline-1,3-dione [(S)-5k] and [(R)-5k]
HPLC conditions: linear gradient of 40% B to 55% B over 30 min;
4.5.7. (S)- and (R)-4,5-Dimethoxy-2-(1,2,3,4-tetrahydronaphthalen-
1-yl)isoindoline-1,3-dione [(S)-9l] and [(R)-9l]
(S)-9l Prepared in 8% yield, ½a D22
ꢂ
(MeOH) = ꢃ81.3; (R)-9l pre-
retention time = 20.8 min. 1H NMR (DMSO):
d 7.21 (d, 1H,
pared in 14% yield, ½a D22
ꢂ
(MeOH) = 78.2. 1H NMR (CDCl3): d 7.50
J = 7.6 Hz), 7.15 (t, 1H, J = 7.2 Hz), 7.11–7.04 (m, 2H), 7.02–6.99
(m, 2H), 5.61 (t, 1H, J = 8.0 Hz), 3.14–3.07 (m, 1H), 2.90–2.82 (m,
1H), 2.38–2.28 (m, 2H). 13C NMR (DMSO): d 167.5, 166.7, 152.8,
144.5, 143.7, 141.6, 127.9, 126.8, 125.0, 123.4, 122.6, 119.2,
116.1, 116.0, 54.0, 30.9, 29.6. ESI-MS m/z: 294.1 (M-H). (S)-5k
HRMS calcd for C17H12NO4 [MꢃH]: 294.0766. Found: 294.0767.
(d, 1H, J = 8.4 Hz), 7.10–7.07 (m, 3H), 7.04–7.00 (m, 1H), 6.92–
6.90 (m, 1H), 5.47 (dd, 1H, J = 6.0, 16.8 Hz), 4.09 (s, 3H), 3.92 (s,
3H), 3.02–2.94 (m, 1H), 2.80–2.76 (m, 1H), 2.42–2.33 (m, 1H),
2.11–2.03 (m, 2H), 1.86–1.75 (m, 1H). 13C NMR (CDCl3): d 167.4,
166.0, 157.7, 147.2, 137.8, 134.8, 129.2, 126.8, 126.0, 125.8,

5324
X. Z. Zhao et al. / Bioorg. Med. Chem. 17 (2009) 5318–5324
8. Bacchi, A.; Biemmi, M.; Carcelli, M.; Carta, F.; Compari, C.; Fisicaro, E.; Rogolino,
D.; Sechi, M.; Sippel, M.; Sotriffer Christoph, A.; Sanchez Tino, W.; Neamati, N. J.
Med. Chem. 2008, 51, 7253.
(R)-5k HRMS calcd for C17H12NO4 [MꢃH]: 294.0766. Found:
294.0762.
9. Jin, H.; Cai, R. Z.; Schacherer, L.; Jabri, S.; Tsiang, M.; Fardis, M.; Chen, X.; Chen, J.
M.; Kim, C. U. Bioorg. Med. Chem. Lett. 2006, 16, 3989.
4.5.14. (S)- and (R)-4,5-Dihydroxy-2-(1,2,3,4-tetrahydronaphthalen-
1-yl)isoindoline-1,3-dione [(S)-5l] and [(R)-5l]
10. Chen, X.; Tsiang, M.; Yu, F.; Hung, M.; Jones, G. S.; Zeynalzadegan, A.; Qi, X.; Jin,
H.; Kim, C. U.; Swaminathan, S.; Chen, J. M. J. Mol. Biol. 2008, 380, 504.
11. Ferro, S.; De Luca, L.; Barreca Maria, L.; Iraci, N.; De Grazia, S.; Christ, F.;
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HPLC conditions: linear gradient of 40% B to 55% B over 30 min;
retention time = 23.5 min. 1H NMR (CD3OD):
d 7.17 (d, 1H,
J = 8.0 Hz), 7.07–7.06 (m, 2H), 7.01 (d, 1H, J = 8.0 Hz), 7.01–6.98 (m,
2H), 6.85 (d, 1H, J = 7.6 Hz), 5.37 (dd, 1H, J = 6.4, 10.8 Hz), 2.96–
2.88 (m, 1H), 2.82–2.76 (m, 1H), 2.41–2.32 (m, 1H), 2.10–2.00 (m,
2H), 1.85–1.76 (m, 1H). 13C NMR (CD3OD): d 168.2, 167.7, 152.3,
137.5, 135.0, 128.7, 126.3, 125.7, 125.2, 122.4, 121.8, 118.6, 115.8,
115.5, 48.8, 29.0, 27.6, 22.3. ESI-MS m/z: 308.1 (M-H). (S)-5l HRMS
calcd for C18H14NO4 [MꢃH]: 308.0928. Found: 308.0928. (R)-5l
HRMS calcd for C18H14NO4 [MꢃH]: 308.0928. Found: 308.0921.
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Acknowledgment
This research was supported in part by the Intramural Research
Program of the NIH, Center for Cancer Research, National Cancer
Institute.
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