Enantioselective epoxidation by the chiral auxiliary approach: Asymmetric total synthesis of (+)-Ambrisentan

Article abstract of DOI:10.1002/jhet.4223

Enantioselective and a highly concise total synthesis of Ambrisentan are described. The chiral auxiliary controlled enantioselective epoxidation (Azerad protocol), photochemical regioselective epoxide opening, and base mediated ester hydrolysis reactions

Full text of DOI:10.1002/jhet.4223

Received: 9 November 2020
DOI: 10.1002/jhet.4223
Revised: 24 December 2020
Accepted: 28 December 2020
A R T I C L E
Enantioselective epoxidation by the chiral auxiliary
approach: Asymmetric total synthesis of (+)-Ambrisentan
Madasu Madhu1 | Sai Reddy Doda1 | Prem Kumar Begari1
|
Krishna Rao Dasari1 | Gangadhar Thalari2 | Sudhakar Kadari2
Jhillu Singh Yadav1,3
|
1Department of Organic Synthesis and
Abstract
Process Chemistry, CSIR – Indian
Institute of Chemical Technology,
Enantioselective and a highly concise total synthesis of Ambrisentan are
described. The chiral auxiliary controlled enantioselective epoxidation (Azerad
protocol), photochemical regioselective epoxide opening, and base mediated
ester hydrolysis reactions are the key reactions.
Hyderabad, India
2Department of Chemistry, Osmania
University, Hyderabad, India
3School of Science, Indrashil University,
Kadi, Gujarat, India
K E Y W O R D S
Correspondence
Ambrisentan, auxiliary controlled epoxidation, Azerad protocol, C-C bond formation, total
synthesis
Sudhakar Kadari, Department of
Chemistry, Osmania University,
Hyderabad 500007, India.
Email: ksudhakariict@gmail.com
Jhillu Singh Yadav, Department of
Organic Synthesis and Process Chemistry,
CSIR – Indian Institute of Chemical
Technology, Hyderabad 500007, India.
Email: yadavfna@gmail.com
Funding information
DST-SERB, Grant/Award Number: CS-
138/2012
1 | INTRODUCTION
have been reported, which involve the formation of the
epoxy derivative from benzophenone and methyl
Ambrisentan is an oral medication classified as a novel
selective endothelin-1 (ETA) receptor antagonist
approved for treatment of pulmonary arterial hyperten-
sion (PAH)[1,2] in World Health Organization (WHO)
group 1 patients and by the United States Food and Drug
Administration (FDA). PAH is an advanced chronic and
progressive disease characterized by elevation of mean
pulmonary pressure and pulmonary vascular resistance,
which may lead to right ventricular failure and death.
Untreated patients with PAH have a median survival
time of 2.8 years.[3] The selective ETA receptor antago-
nist, Ambrisentan, treats PAH by blocking ETA receptor-
dependent vascular smooth muscle contraction. Several
synthetic methods[2,4] for the synthesis of Ambrisentan
chloroacetate via a Darzens reaction or chiral catalyzed
epoxidation, acid-catalyzed regioselective epoxide open-
ing, or by nucleophilic substitution and subsequent
hydrolysis of the ester functionality. The reported proce-
dures focus on chiral resolution or catalytic epoxidation
for chiral induction. Here, we rely on a chiral auxiliary-
controlled strategy for the asymmetric synthesis of the
epoxide.
The chiral auxiliary-based asymmetric synthesis
gaining much attraction and producing groundbreaking
results over the past few decades. The chiral auxiliary-
controlled reactions are still influential tools for the con-
struction of complex bioactive molecules, especially in
[5,6]
their chiral inducing stage,
although stoichiometric
942
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J Heterocyclic Chem. 2021;58:942–946.

MADHU ET AL.
943
amounts of synthons are required. In continuation of our
interest in chiral auxiliary-controlled asymmetric synthe-
sis for the total synthesis of bioactive natural products[7]
with prominent biological activity, we were drawn to the
total synthesis of Ambrisentan.
the ester functionality yielded Ambrisentan (1) in 92%
yield. The spectral (1H and 13C NMR) and analytical data
of synthesized Ambrisentan (1) are in good agreement
with the reported values.
3 | CONCLUSIONS
2 | RESULTS AND DISCUSSION
In summary, we have disclosed an efficient and
stereoselective synthesis of Ambrisentan in a six-step lin-
ear sequence, starting from the known Evans chiral aux-
iliary. The key steps involved in this synthesis are the
Crimmins modified Evans aldol reaction Azerad protocol
for epoxide formation and a photochemical epoxide ring-
opening reaction.
As shown in the Scheme 1, the target molecule
Ambrisentan could be derived from nucleophilic substi-
tution with commercially available 4,6-dimethyl-
2-(methylsulfonyl)pyrimidine (3) and alcohol 2 followed
by ester hydrolysis. The advanced fragment could be
obtained by the chiral epoxide 4, which could be traced
back from the chiral auxiliary 5.
With the retrosynthetic blueprint in mind
(Scheme 2), the total synthesis of Ambrisentan
(Scheme 1) began with commercially available (R)-
4-benzyloxazolidin-2-one 6, which was converted to its
chloro-acetyl derivative 5 by the treatment of n-BuLi and
chloroacetyl chloride in anhydrous tetrahydrofuran at
−78ꢀC to afford compound 5 in quantitative yield.[8] The
coupling of benzophenone with chiral imide 5 achieved
by employing Crimmins modified Evans aldol condi-
tions[9] furnished the 20:1 ratio of diastereomeric mix-
ture, and upon recrystallization yielded pure isomer 7 in
85% yield as a colorless solid. The requisite epoxy geome-
try was installed through a modified Azerad protocol[10]
using NaOEt in EtOH, which involved in situ trans ester-
ification followed by ring closure. This process gave the
desired trans epoxy ester 4 in 98% yield. To open the
epoxide, we screened several reagents including
BF3ÁEt2O, TsOH, and catalytic H2SO4 in MeOH, which
produced satisfactory results (Table 1). However, our aim
is to explore photochemical oxirane ring opening, thus
for this step we followed the reported photochemical pro-
cedure. [11]
4 | EXPERIMENTAL SECTION
4.1 | General remarks
All the experiments are performed under nitrogen or
Argon atmosphere. The clean apparatus perfectly flame/
oven dried and used before the reaction. The anhydrous
solvents such as DCM, MeOH, and all reagents are pur-
chased from sigma Aldrich or Fisher Scientific and used
directly without purification. The anhydrous THF was
distilled over Na and benzophenone. Measured the opti-
cal rotation on polarimeter and given in 10-1 degcm2g-1.
The column chromatography was performed using silica
gel (100–200 mesh) purchased from Merck & Co. The
mass spectral data recorded using ESI- HRMS mass spec-
trometers. The 1H and 13C was recorded using
400, 500 MHz Brucker Apex II instrument with TMS as
internal solvent. The chemical shifts are in ppm and cou-
pling constants are reported in hert (Hz) and the follow-
ing abbreviations s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet.
The precursor 4 was subjected to photoirradiation in
methanol using 253.7 nm UV light, producing α-hydroxy
ester 2 in 91% yield. The resulting α-hydroxy ester 2 was
treated with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine
(3) and NaH in THF to give ester 8 in 97% yield. Finally,
the target molecule achieved by the basic hydrolysis of
(R)-4-benzyl-3-(2-chloroacetyl)oxazolidin-2-one
(5): n-BuLi (14 mL, 1.6 M in hexane) was added dropwise
to a stirred solution of the (R)-4-benzyloxazolidin-2-one,
6 (4.0 g, 0.023 mmol) and Ph3CH (15 mg, indicator) in
THF (50 mL) at −78ꢀC. The resulting solution was stirred
at −78ꢀC and added chloroacetyl chloride (2.8 g,
SCHEME 1 Retrosynthetic analysis
of Ambrisentan

944
MADHU ET AL.
SCHEME 2 Synthesis of
Ambrisentan (1)
TABLE 1 Investigation of epoxide opening reaction
17.39 mmol) in DCM (10 mL) and the resultant reaction
mixture was slowly warmed to RT and stirred for
2 h. Upon completion of the reaction, the reaction mix-
ture was quenched with saturated NH4Cl solution
(50 mL) and extracted with ethyl acetate (3 × 100 mL).
The combined organic layer was washed with brine solu-
tion and dried over anhydrous Na2SO4. The solvent was
removed under vacuum and the crude product was puri-
fied by silica gel column chromatography using 25% ethyl
acetate in hexanes give desired product 7 (5.8 g, 85%) as a
Entry
Conditions
Yields
77%
1
2
3
4
5
BF3.Et2O, MeOH, 0ꢀC to RT, 12 h
TsOH, MeOH, 0ꢀC to RT, 12 h
CSA, MeOH, 0ꢀC to RT, 12 h
H2SO4, MeOH, 0ꢀC to RT, 24 h
LilO4, MeOH, 60ꢀC, 24 h
53%
22%
40%
15%
25
0.0248 mmol) dropwise at −78ꢀC give a yellowish solu-
tion which was further stirred for 20 min. The resulting
solution was slowly warmed up to room temperature and
stirred for 3 h at RT and quenched saturated NH4Cl solu-
tion (25 mL). The reaction mass was extracted with ethyl
acetate (100 × 3) and the combined organic layer was
washed with saturated brine solution then dried over
Na2SO4. The solvent was removed under vacuum give
compound 5 in quantitative yield (5.71 g). [α]D25 = −86.3
(c 0.7, CH2Cl2), IR ν˜max = 3033, 1784, 1364, 1225,
colorless oil. [α]D = −28.1 (c 0.8, Chloroform); IR
(neat): ν˜max = 3028, 1783, 1215, 1065, 755 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.63–7.59 (m, 2H), 7.52–7.49
(m, 2H), 7.38–7.24 (m, 8H), 7.22–7.14 (m, 3H), 4.77 (s,
1H), 4.32–4.26 (m, 1H), 4.06 (dd, J = 2.4 Hz, 1H), 3.79 (t,
J = 8.6 Hz, 1H), 3.20 (dd, J = 3.3 Hz, 1H), 2.74 (q, J = 9.6
Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 169.3, 165.9,
153.0, 152.2, 143.4, 142.3, 134.5, 134.3, 129.2, 128.8, 128.4,
128.2, 127.6, 127.3, 125.7, 125.3, 78.8, 66.9, 66.1, 60.2,
56.7, 55.2, 55.0, 43.6, 37.4, 36.8; HRMS (ESI) calcd. for
1
997, 758 cm–1; H NMR (500 MHz, CDCl3) δ 7.36–7.29
C25H22O4NClNa
458.11221.
[M + Na]+:
458.11296;
found:
(m, 3H), 7.21 (d, J = 7.0 Hz, 2H), 4.75 (s, 2H), 4.74–4.69
(m, 1H), 4.32–4.24 (m, 2H), 3.34 (dd, J = 13. 4, 3.3 Hz,
1H), 2.82 (q, J = 9.6 Hz, 1H); 13C NMR (126 MHz, CDCl3)
δ 166.0, 153.1, 134.6, 129.3, 129.0, 127.4, 66.9, 55.3,
43.7, 37.5.
(4R)-4-Benzyl-3-(2-chloro-3-hydroxy-3,3-diph-
enylpropanoyl)oxazolidin-2-one (7): TiCl4 (1.8 mL,
16.6 mmol) was added dropwise to as stirred solution of
the compound 5 (4.0 g, 15.81 mmol) in DCM (50 mL) at
0ꢀC then stirred for 15 min and added DIPEA (3.0 mL,
17.39) slowly to the mixture at 0ꢀC. The resulting mixture
was stirred for 40 min and added 1-methyl-
2-pyrrolidinone (3.0 mL, 31.62 mmol) then stirred for
10 min. To this mixture added benzophenone (3.2 g,
(S)-Ethyl 3,3-diphenyloxirane-2-carboxylate (4):
0.78 g of NaOEt (11.4 mmol) was added to a stirred solu-
tion of 7 (5.0 g, 11.49 mmol) in ethanol (100 mL) at 0ꢀC
and stirred for 2 h. After completion of the reaction, the
mixture was quenched with saturated NH4Cl solution
(50 mL) and, removed the ethanol under vacuum and
extracted with ethyl acetate (3 × 100 mL). The combined
organic layer was washed with brine solution and dried
over Na2SO4. The solvent was removed under vacuum
and the crude product was purified by silica gel column
chromatography using 10% of ethyl acetate in hexanes
obtained compound 4 (3.01 g, 98%) as a colorless oil.
25
[α]D = +27.0 (c 1.0, CHCl3), IR (neat): ν˜max = 3525,

MADHU ET AL.
945
3392, 1710, 1232, 757, 700 cm–1; 1H NMR (500 MHz,
CDCl3) δ 7.46–7.43 (m, 2H), 7.38–7.29 (m, 8H), 4.03–3.94
(m, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 166.7, 138.7, 135.3, 128.4, 127.8, 126.7, 61.9,
61.2, 13.7; HRMS (ESI) calcd for C17H16O3Na [M
+ Na]+: 291.09917; found: 291.09841.
(2 × 50 mL) to remove organic impurities. The aqueous
phase was acidified with conc HCl to pH = 1 then
extracted with ethyl acetate (3 × 100 mL). The combine
organic layer was washed with brine solution and dried
over anhydrous Na2SO4. The solvent was removed under
vacuum give crude product as a residue. The crude resi-
due was recrystallized by washing ethyl acetate gave to
give (+)-ambrisentan 1 (490 mg, 90%, 99% ee) as white
solid. M.p = 169–179ꢀC; [α]D25 = +180. 6 (c 0. 4, MeOH),
lit.[4c] +183.37 (c 0.5, MeOH); IR (neat): ν˜max = 3745,
(S)-Ethyl
2-hydroxy-3-methoxy-3,3-
diphenylpropanoate (2): The mixture of epoxy ester
(4) and methanol (0.08 M) in a quartz tube was cooled in
water bath and externally irradiated with a 15 W low-
pressure mercury vapor lamp for 5 h under nitrogen
atmosphere. After the reaction removed the solvent
under vacuum and the crude product was purified by sil-
ica column chromatography using 5% ethyl acetate in
hexanes gave desired alcohol 2 (2.0 g, 91%) as a colorless
1
3534, 2927, 1739, 1598, 762 cm–1; H NMR (500 MHz,
CDCl3) δ 7.56 (d, J = 8.0 Hz, 2H), 7.37–7.28 (m, 9H), 6.69
(s, 1H), 6.64 (s, 1H), 3.31 (s, 3H), 2.38 (s, 6H); 13C NMR
(126 MHz, CDCl3) δ 171.0, 169.5, 163.2, 140.0, 139.1,
128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 115.1, 84.2, 53.3,
23.6; HRMS (ESI) calcd for C22H22O4N2Na [M + Na]+:
401.14718; found: 401.14596.
25
oil. [α]D = + 4. 3 (c 0.71, CHCl3), ν˜max = 3512, 2982,
1732, 1277, 1091, 757, 704 cm–1; 1H NMR (500 MHz,
CDCl3) δ 7.44–7.26 (m, 10H), 5.15 (s, 1H), 4.04–4.02 (m,
2H), 3.17 (m, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR
(126 MHz, CDCl3) δ 172.2, 140.8, 140.0, 128.7, 128.5,
127.7, 127.6, 127.5, 127.4, 84.8, 73.7, 61.5, 52.4, 13.8;
HRMS (ESI) calcd for C18H20O4Na [M + Na]+:
323.12538; found: 323.1245.
ACKNOWLEDGMENT
KSR thanks the DST-SERB (Young scientist File: CS-
138/2012), New Delhi, India, for financial support.
DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are avail-
able in the supplementary material of this article
(S)-ethyl 2-((4,6-dimethylpyrimidin-2-yl)oxy)-3-
methoxy-3,3-diphenylpropanoate (8): NaH (300 mg,
60% mineral oil) was added to a stirred solution of the
ethyl ester compound 4 (1.5 g, 5.0 mmol) in THF (10 mL)
and the mixture was stirred at RT for 30 min. To this
solution added 4,6-dimethyl-2-(methylsulfonyl)pyrimi-
dine (1.3 g, 7.0 mmol) at room temperature. The resultant
reaction mixture was stirred at RT for 4 h. After the reac-
tion, the reaction mixture was quenched with ice water
(50 mL) and extracted with ethyl acetate (3 × 50 mL).
The combine organic layer was washed with brine solu-
tion and dried over anhydrous Na2SO4. The solvent was
removed under vacuum and the crude product was puri-
fied by silica column chromatography using 20% ethyl
acetate in hexanes gave desired ester 8 (1.8 g, 97%) as a
ORCID
Sudhakar Kadari https://orcid.org/0000-0001-9475-
9779
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How to cite this article: Madhu M, Doda SR,
Begari PK, et al. Enantioselective epoxidation by
the chiral auxiliary approach: Asymmetric total
synthesis of (+)-Ambrisentan. J Heterocyclic Chem.
2021;58:942–946. https://doi.org/10.1002/jhet.4223
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