An efficient synthesis of (R)- and (S)-8-ethoxy-2-(4-fluorophenyl)-3-nitro- 2H-chromene

Article abstract of DOI:10.1016/j.tetasy.2013.02.009

Racemic 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as a potent inhibitor of phosphoinositide 3-kinase (PI3K). In order to investigate the effects of its two enantiomers on tumor cell lines, we designed a novel synthesis for (R)-S14161 and (S)-S14161 using a chemical resolution and derivation strategy. The readily available 3-(tert- butyldimethylsilyloxy)-salicylaldehyde underwent a tandem oxa-Michael-Henry reaction with trans-4-fluoro-β-nitrostyrene in the presence of a catalytic amount of l-proline and triethylamine to give the 3-nitro-2H-chromene. Upon removal of the TBS protecting group, the resolution of the resulting racemic 2-(4-fluorophenyl)-8-hydroxy-3-nitro-2H-chromene was achieved via diastereomeric ester formation using (S)-(+)-α-methoxyphenylacetic acid as the derivatizing agent, followed by aminolysis. Finally, the ethyl ether formation of each enantiomer furnished (R)-S14161 and (S)-S14161 in enantiomerically pure forms. The absolute configurations of these chiral molecules were determined by a circular dichroism method. The two enantiomers showed no marked differences in inhibition of growth of human myeloma LP1 and OPM-2 cells.

Full text of DOI:10.1016/j.tetasy.2013.02.009

Tetrahedron: Asymmetry 24 (2013) 320–323
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
An efficient synthesis of (R)- and
(S)-8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene
Shu-Qiang Yin a, Can-Fei Zhang a, Xinliang Mao b, Zhao-Peng Liu a,
⇑
a Department of Organic Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012,
Shandong Province, PR China
b Cyrus Tang Hematology Center, Soochow University, Suzhou, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 January 2013
Accepted 13 February 2013
Racemic 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as a potent
inhibitor of phosphoinositide 3-kinase (PI3K). In order to investigate the effects of its two enantiomers on
tumor cell lines, we designed a novel synthesis for (R)-S14161 and (S)-S14161 using a chemical
resolution and derivation strategy. The readily available 3-(tert-butyldimethylsilyloxy)-salicylaldehyde
underwent a tandem oxa-Michael–Henry reaction with trans-4-fluoro-b-nitrostyrene in the presence
of a catalytic amount of
the TBS protecting group, the resolution of the resulting racemic 2-(4-fluorophenyl)-8-hydroxy-
3-nitro-2H-chromene was achieved via diastereomeric ester formation using (S)-(+)- -methoxyphenyl-
L-proline and triethylamine to give the 3-nitro-2H-chromene. Upon removal of
a
acetic acid as the derivatizing agent, followed by aminolysis. Finally, the ethyl ether formation of each
enantiomer furnished (R)-S14161 and (S)-S14161 in enantiomerically pure forms. The absolute configu-
rations of these chiral molecules were determined by a circular dichroism method. The two enantiomers
showed no marked differences in inhibition of growth of human myeloma LP1 and OPM-2 cells.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
properties. Stereopure drugs can often reduce the total dose of
drug given and minimize any toxicity resulting from the inactive
Aberrant signaling through the phosphatidylinositol 3-kinase
(PI3K)/AKT pathway is a prevalent phenomenon in numerous can-
cer types and has received significant attention as a drug target.1,2
Over the past two decades, a number of PI3K inhibitors have been
advanced into clinical development for cancer therapy.3–8 8-Eth-
oxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was dis-
covered as a potent PI3K inhibitor through high-throughput
screening from a library of 56,000 organic compounds (Maybridge
Chemical Company).9 S14161 inhibited the activity of phosphoino-
sitide 3-kinase in intact cells and the activity of the phosphoinosi-
tide 3-kinases in a cell-free enzymatic assay, and thus decreased
the production of PIP3 and blocked AKT translocation to the plas-
ma membrane for activation. Inhibition of the PI3K/AKT signaling
by S14161 led to multiple cancer cell death but presented less tox-
icity. For example, S14161 displayed potent pre-clinical activity
against leukemia and myeloma activity and minimal toxicity in
xenograft mice models. Therefore, S14161 serves as a new lead
for cancer therapy. However, S14161 contains a stereogenic center.
Chiral discrimination between the enantiomers is extremely
important, since both enantiomers of a chiral drug may differ in
potency, toxicity, and pharmacodynamic and pharmacokinetic
enantiomer.10 Examples of the specificity of enantiomers range
from harmless ones, such as estrone with an inactive (ꢀ) form
and active (+) form, to penicillamine, which is extremely toxic
when dosed in the L
-form.11 Therefore, during the research and
development stage of any drug candidate, there is a growing need
to investigate the properties of the enantiomers, if the drug pos-
sesses any chirality. In fact, it is becoming increasingly more of a
requirement to separate specific enantiomers in order to optimize
the potency and reduce the toxicity of certain drugs. The U.S. Food
and Drug Administration and regulatory authorities in Europe, Chi-
na, and Japan have provided guidelines indicating that preferably
only the active enantiomer of a chiral drug should be brought into
the market. Since S14161 is used as racemic mixtures in its biolog-
ical evaluations, it is necessary to develop a method for the synthe-
sis of its two enantiomers in enantiomerically pure forms for
further studies both in vitro and in vivo. Herein we report a novel
preparation of (R)-S14161 and (S)-S14161 by applying a chemical
resolution strategy.
2. Results and discussion
Chromenes, or benzopyrans, are an important class of scaffolds
found in numerous naturally occurring and synthetic molecules
possessing a broad range of biological activities.12 One of the most
⇑
Corresponding author. Tel.: +86 531 88382006; fax: +86 531 88382548.
E-mail address: liuzhaop@sdu.edu.cn (Z.-P. Liu).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.02.009

S.-Q. Yin et al. / Tetrahedron: Asymmetry 24 (2013) 320–323
321
useful synthetic methods for the preparation of 3-nitro-2-phenyl-
2H-chromenes is the domino oxa-Michael–Henry reactions of sal-
icylaldehyde with b-nitrostyrene.13 This reaction is promoted by
an organocatalyst, such as 1,4-diazabicyclo[2.2.2]octane (DABCO),
isomers matched very well with their experimental circular
dichroism (CD) data. In the 100–450 nm region, the experimental
data of (R)-S14161 showed a negative first Cotton effect at
390 nm, a positive second Cotton effect at 290 nm, a negative third
Cotton effect at 260 nm, and a positive fourth Cotton effect at
180 nm, the calculated ones showed the same pattern, but the cor-
responding wavelength shifted to 395 nm (+5 nm), 305 nm
(+15 nm), 230 nm (ꢀ30 nm), and 180 nm (+0 nm), respectively.
This phenomenon is commonly found in ECD calculations.17 In
the case of (S)-S14161, the experimental data showed an opposite
pattern, with a positive first Cotton effect at 405 nm, a negative
second Cotton effect at 295 nm, a positive third Cotton effect at
260 nm and a negative fourth Cotton effect at 210 nm, while the
calculated ones were 400 nm (ꢀ5 nm), 320 nm (+25 nm), 250 nm
(ꢀ10 nm), and 190 nm (ꢀ20 nm), respectively. In addition, the
experimental specific rotations of (R)- and (S)-S14161 showed
opposite values (ꢀ158 and +152, respectively).
2-pipecolinic acid, and L-proline, among many others. Furthermore,
a chiral pyrrolidine–thioimidazole catalyst mediated enantioselec-
tive oxa-Michael–Henry process was developed in order to give the
3-nitro-2-aryl-2H-chromenes with enhanced enantiomeric excess
(45–91% ee).14 However, it is difficult to obtain both enantiomers
in enantiomerically pure forms by an organocatalytic, enantiose-
lective approach. Therefore, we adopted a chemical resolution
and derivation strategy for the preparation of (R)- and (S)-S14161.
As shown in Scheme 1, treatment of the readily available TBS
protected salicylaldehyde derivative 115 with excess trans-4-flu-
oro-b-nitrostyrene (120 mol %) via an oxa-Michael–Henry reaction
in toluene at 90 °C in the presence of 50 mol % of L-proline as a cat-
alyst and 30 mol % of triethylamine generated the 3-nitro-2-aryl-
2H-chromene 2 in a good yield of 84% with poor enantioselectivity
(<2% ee). After removal of the TBS protecting group, the racemic
8-hydroxy analogue 3 was obtained in 89% yield. The chemical
resolution of 3 proved to be difficult. After testing a variety of deriv-
atizing agents, including (ꢀ)-menthoxyacetyl chloride, (S)-(+)-na-
In a preliminary growth inhibitory test against human myeloma
LP1 and OPM-2 cells using conventional MTT method,18 both
enantiomers did not show much difference. The GI50 values for
the (R)-S14161 were 0.55 and 2.0
for (S)-S14161 were 0.58 and 2.4
l
M, respectively, while those
l
M. Further studies are needed
proxen, Boc-
Boc- -valine and Boc-
ylacetic acid to be the optimal choice. The coupling reaction of chro-
mene with (S)-(+)- -methoxyphenylacetic acid gave two
L
-proline, Boc-
L
-leucine, Fmoc-
D
-Phe, Boc-
L-Trp-OH,
for in vivo antitumor evaluation and the determination of pharma-
codynamic and pharmacokinetic properties for both enantiomers.
L
L-alanine, we found (S)-(+)-a-methoxyphen-
3. Conclusion
3
a
diastereomers (+)-4a (more polar; >99.5% de) and (ꢀ)-4b (less
polar; >99.5% de), which were separated by silica gel column chro-
matography in 36% and 35% yields, respectively. Removal of the chi-
ral auxiliaries of (+)-4a and (ꢀ)-4b was achieved smoothly with
aqueous methylamine in CH2Cl2/Et2O solution to furnish (S)-3
(>99.5% ee) and (R)-3 (>99.5% ee) in enantiomerically pure forms. Fi-
nally, ethyl ether formation led to (R)- and (S)-S14161 with >99.6%
enantiomeric excesses.
In order to determine the absolute configuration, TD-DFT calcu-
lations of the electronic circular dichroism (ECD) spectra were
implemented in the Gaussian 03 program.14,16 As shown in
Figure 1, the theoretical ECD spectra of the (R)- and (S)-S14161
The enantiomerically pure (R)- and (S)-S14161 were prepared
via an efficient chemical resolution and derivation approach. These
two enantiomers showed no marked difference in their inhibition
of the growth of human myeloma LP1 and OPM-2 cells.
4. Experimental
4.1. General
Melting points were determined on an X-6 micro-melting point
apparatus (Beijing Tech. Co., Ltd) and are uncorrected. 1H and 13C
NO2
NO2
NO2
CHO
OH
F
HCl
O
O
THF
L-proline, Et3N, toluene
OTBS
OH
OTBS
F
F
1
2
3
, 84%
, 89%
NO2
OMe
CO2H
*
NO2
O
O
*
O
MeNH2
O
F
CH2Cl2, Et2O
OH
DCC, DMAP, CHCl3
F
MeO
(S)-3, 66%; (R)-3, 67%
(+)-4a, 36%; ( )-4b, 35%
NO2
NO2
EtI, K2CO3
DMF
O
O
OEt
(R)-S14161, 71%
Scheme 1. Synthesis of (R)- and (S)-S14161.
OEt
F
F
(S)-S14161, 74%

322
S.-Q. Yin et al. / Tetrahedron: Asymmetry 24 (2013) 320–323
Figure 1. The theoretical simulated ECD spectrum (lower) for the (R)- or (S)-configuration of S14161 by means of the TD-DFT/B3LYP/6-31+G⁄ method, compared to the
experimental CD spectrum (upper).
NMR spectra were recorded at room temperature on a Bruker-500
NMR spectrometer, and all chemical shifts are reported as d values
(ppm) relative to Me4Si (0.00 ppm) as the internal standard. Elec-
trospray-ionization mass spectrometry (ESI-MS) was performed
on an API 4000 instrument. Column chromatography was per-
formed on silica gel (200–300 mesh). Specific rotations were mea-
sured by the GYROMAT-HP digital automatic polarimeter. CD
spectra were measured by Chirascan Circular Dichroism Spectrom-
eter. Enantiomeric excess (ee) was determined by an analytical
HPLC system (CHIRALPAK IA; flow rate, 1.0 mL/min; hexane/iso-
propanol, 95:5). All reactions involving oxygen- or moisture-sensi-
tive compounds were carried out under a dry N2 atmosphere.
Unless otherwise noted, reagents were added by syringe.
(6.72 g, 84%) as a pale yellow oil. 1H NMR (600 MHz, CDCl3): d
8.09 (s, 1H), 7.39 (dd, J = 4.8, 8.4 Hz, 2H), 7.03 (t, J = 8.4 Hz, 2H),
6.99 (dd, J = 1.2, 6.2 Hz, 1H), 6.89ꢀ6.95 (m, 2H), 6.61 (s, 1H), 0.97
(s, 9H), 0.11 (s, 6H); ESI-MS (m/z): 402.5 [M+H]+.
4.3. 2-(4-Fluorophenyl)-8-hydroxy-3-nitro-2H-chromene 3
To a stirred solution of 2 (3.50 g, 8.6 mmol) in THF (15 mL) was
added concentrated hydrochloric acid (2 mL). The mixture was
stirred at room temperature for 8 h. After extraction with EtOAc
(50 mL), the organic layer was washed with water, a saturated
NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered,
and concentrated. Crystallization from hexane gave 3 as a yellow
solid (2.21 g, 89%). Mp 138ꢀ140 °C; 1H NMR (600 MHz, CDCl3): d
8.07 (s, 1H), 7.34ꢀ7.36 (m, 2H), 6.99ꢀ7.03 (m, 3H), 6.94 (d,
J = 4.8 Hz, 2H), 6.61 (s, 1H), 5.30 (s, 1H); 13C NMR (150 MHz,
4.2. 8-(tert-Butyldimethylsilyloxy)-2-(4-fluorophenyl)-3-nitro-
2H-chromene 2
CDCl3):
d 163.5 (J = 247.7 Hz), 144.8, 141.3, 139.5, 132.2
At first, trans-4-fluoro-b-nitrostyrene (4.01 g, 24 mmol),
L
-pro-
(J = 2.9 Hz), 129.3, 129.0 (J = 8.7 Hz), 123.2, 121.9, 120.5, 117.9,
line (1.15 g, 10 mmol), and triethylamine (0.56 mL, 4 mmol) were
added to a stirred solution of 3-(tert-butyldimethylsilyloxy)-sali-
cylaldehyde 1 (5.05 g, 20 mmol) in dry toluene (100 mL). The mix-
ture was heated to 90 °C and stirred at the same temperature for
24 h. The reaction mixture was diluted with water and extracted
with EtOAc. The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated. The residue was purified by silica gel
116.1 (J = 21.6 Hz), 74.2; ESI-MS (m/z): 286.2 [MꢀH]ꢀ.
4.4. (+)- and (ꢀ)-2-(4-Fluorophenyl)-3-nitro-8-[(S)-
phenylacetoxy]-2H-chromene (+)-4a and (ꢀ)-4b
a-methoxy-
To a stirred solution of 3 (2.87 g, 10 mmol) in CHCl3 (80 mL)
were added (S)-(+)- -methoxyphenylacetic acid (2.5 g, 15 mmol),
DMAP (0.5 g, 4 mmol), and DCC (3.1 g, 15 mmol). The mixture
a
column chromatography (hexane/EtOAc, 15ꢀ3:1) to give
2

S.-Q. Yin et al. / Tetrahedron: Asymmetry 24 (2013) 320–323
323
was stirred at room temperature for 24 h. After filtration, the fil-
trate was washed with brine, dried over anhydrous Na2SO4, fil-
tered, and concentrated. The residue was purified by silica gel
column chromatography (CH2Cl2/Et2O, 10:1) to give (+)-4a (1.6 g,
36%) and (ꢀ)-4b (1.52 g, 35%), respectively. (+)-4a: Pale yellow
trated. The residue was purified by silica gel column chromatogra-
phy (hexane/EtOAc, 6:1) to give (S)-14161 (325 mg, 71%) as a
yellow solid. Mp 98ꢀ100 °C (5% Et2O in CH2Cl2); ½a D20
¼ þ152 (c
ꢁ
0.63, CHCl3); 1H NMR (600 MHz, CDCl3): d 8.04 (s, 1H), 7.36ꢀ7.39
(m, 2H), 6.93ꢀ7.00 (m, 5H), 6.64 (s, 1H), 3.97ꢀ4.07 (m, 2H), 1.37
solid, mp 103ꢀ105 °C (10% AcOEt in hexane); ½a D20
ꢁ
¼ þ282 (c
(t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3)
d
164.2
0.11, CHCl3); 1H NMR (600 MHz, CDCl3): d 8.03 (s, 1H), 7.50ꢀ7.51
(m, 2H), 7.43ꢀ7.44 (m, 3H), 7.24 (d, J = 7.8 Hz, 1H), 7.07ꢀ7.11
(m, 3H), 7.01 (d, J = 7.8 Hz, 1H), 6.96ꢀ6.99 (m, 2H), 6.34 (s, 1H),
5.02 (s, 1H), 3.50 (s, 3H); 13C NMR (150 MHz, CDCl3): d 168.1,
163.3 (J = 247.8 Hz), 144.9, 141.5, 138.8, 135.5, 132.0 (J = 2.9 Hz),
129.1, 128.9 (J = 8.3 Hz), 128.7 (2C), 128.5, 128.0, 127.6, 127.3
(2C), 122.5, 119.3, 115.8 (J = 21.8 Hz), 82.2, 73.8, 57.5; ESI-MS (m/
z): 436.5 [M+H]+, 453.5 [M+NH4]+, 458.5 [M+Na]+. (ꢀ)-4b: Pale yel-
(J = 246.9 Hz), 148.0, 142.9, 141.3, 132.6 (J = 3.3 Hz), 129.6, 128.8
(J = 8.3 Hz), 122.6, 122.2, 118.9, 118.6, 115.7 (J = 21.6 Hz), 73.2,
65.0, 14.7; ESI-MS (m/z): 316.4 [M+H]+, 338.5 [M+Na]+.
4.8. (R)-8-Ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (R)-
14161
To a stirred solution of (R)-3 (450 mg, 1.55 mmol) in DMF
(10 mL) were added K2CO3 (434 mg, 3.10 mmol) and EtI (294 mg,
1.90 mmol). The mixture was then stirred at room temperature
for 16 h. The solution was diluted with water (30 mL) and
extracted with EtOAc (30 mL ꢂ 3). The organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated. The residue was purified by silica gel column chromatogra-
phy (hexane/EtOAc, 6:1) to give (R)-14161 (350 mg, 74%) as a
low solid, mp 135ꢀ137 °C (10% AcOEt in hexane); ½a D20
¼ ꢀ112:5 (c
ꢁ
0.16, CHCl3); 1H NMR (600 MHz, CDCl3): d 8.05 (s, 1H), 7.56ꢀ7.57
(m, 2H), 7.45ꢀ7.47 (m, 3H), 7.23ꢀ7.24 (d, J = 7.8 Hz, 1H), 7.07 (d,
J = 7.8 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.88ꢀ6.93 (m, 4H), 6.34 (s,
1H), 4.99 (s, 1H), 3.46 (s, 3H); 13C NMR (150 MHz, CDCl3): d
168.0, 163.2 (J = 247.5 Hz), 144.8, 141.5, 138.9, 135.7, 131.7
(J = 3.3 Hz), 129.2, 128.8 (J = 8.3 Hz), 128.74 (2C), 128.72, 128.0,
127.8 (2C), 127.5, 122.6, 119.5, 115.6 (J = 21.6 Hz), 82.3, 73.4,
57.5; ESI-MS (m/z): 436.5 [M+H]+, 453.5 [M+NH4]+, 458.5 [M+Na]+.
yellow solid, ½a D20
¼ ꢀ158 (c 0.73, CHCl3). (R)-14161 exhibited
ꢁ
the same physical and spectroscopic properties as (S)-14161 (Mp,
1H NMR, 13C NMR, MS).
4.5. (S)-2-(4-Fluorophenyl)-8-hydroxy-3-nitro-2H-chromene
(S)-3
Acknowledgment
To a stirred solution of (+)-4a (1.16 g, 2.64 mmol) in a mixture
of CH2Cl2 and Et2O (1:1, 30 mL) was added an aqueous methyl-
amine solution (5 mL). The mixture was then stirred at room tem-
perature for 1 h. The solution was adjusted to pH 6.0 with acetic
acid. After extraction with EtOAc, the organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated. The residue was purified by silica gel column chromatogra-
phy (hexane/EtOAc, 5:1) to give (S)-3 (0.51 g, 66%) as a yellow
We are very thankful to Professor Yu-Chen Ma and Dr. Hua-Bing
Yin, School of Chemistry and Chemical Engineering, Shandong Uni-
versity, for their aid in the ECD calculations.
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To a stirred solution of (ꢀ)-4b (1.22 g, 2.82 mmol) in a mixture
of CH2Cl2 and Et2O (1:1, 30 mL) was added an aqueous methyl-
amine solution (5 mL). The mixture was then stirred at room tem-
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with brine, dried over anhydrous Na2SO4, filtered, and concen-
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phy (hexane/EtOAc, 5:1) to give (R)-3 (0.54 g, 67%) as a yellow
solid. Mp 138ꢀ140 °C (15% AcOEt in hexane); ½a D20
¼ ꢀ165 (c 0.1,
ꢁ
CHCl3). The enantiomerically pure (R)-3 exhibited the same spec-
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4.7. (S)-8-Ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S)-
14161
To a stirred solution of (S)-3 (415 mg, 1.45 mmol) in DMF
(10 mL) were added K2CO3 (400 mg, 2.90 mmol) and EtI (271 mg,
1.73 mmol). The mixture was then stirred at room temperature
for 16 h. The solution was diluted with water (30 mL) and ex-
tracted with EtOAc (30 mL ꢂ 3). The organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and concen-
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