Total synthesis of a thromboxane receptor antagonist, terutroban

Article abstract of DOI:10.1039/c4ob02302a

A total synthesis of terutroban is achieved using the Claisen rearrangement, Friedel-Crafts acylation and Heck coupling as key reactions, avoiding the classical Diels-Alder approach used before.

Full text of DOI:10.1039/c4ob02302a

Organic &
Biomolecular Chemistry
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Total synthesis of a thromboxane receptor
antagonist, terutroban†
Cite this: Org. Biomol. Chem., 2015,
13, 2951
Wasim Ahmed,a,b Prathama S. Mainkar,a Srihari Pabbarajaa and
Srivari Chandrasekhar*a,b
Received 29th October 2014,
Accepted 6th January 2015
DOI: 10.1039/c4ob02302a
A total synthesis of terutroban is achieved using the Claisen rearrangement, Friedel–Crafts acylation and
Heck coupling as key reactions, avoiding the classical Diels–Alder approach used before.
www.rsc.org/obc
Introduction
Thromboxane A2 (1a, Fig. 1), an unstable metabolite of arachi-
donic acid, is responsible for a wide range of pulmonary,
renal, circulatory and other disorders. Thromboxane A2 causes
irreversible platelet aggregation, vasoconstriction and smooth
muscle cell proliferation. It is released from activated platelets,
monocytes and damaged vessel walls. The activity of throm-
boxane A2 is through the thromboxane-type prostanoid (TP)
receptor extensively present on platelets and vascular smooth
muscle. TP receptor agonists and thromboxane A2 synthase
inhibitors are potential antiplatelet agents. Many of these are
also TP receptor agonists and have very short half-lives.1 Thus,
there is always a requirement for a more effective, selective and
long-lasting thromboxane receptor antagonist. In one of the
studies to find a selective antagonist, it was observed that com-
pounds containing a carboxylic acid and a benzenesulfona-
mide group separated by a spacer were found to be the best
among the compounds tested. Ramatroban (1b),2 (Fig. 1) a
compound with these features, marketed as Baynas® by Bayer
and Nippon Shinyaku Co. for allergic rhinitis, is a selective TP
receptor antagonist. The pharmacophore was further explored
by Lavielle et al., which led to the identification of a tetra-
hydronaphthalene derivative, terutroban (2) (Fig. 1) as a TP
receptor antagonist. The only reported synthesis of 2 to date is
achieved using Diels–Alder as the key reaction between an
appropriate 2-pyrone and an acetylenic derivative.3 Terutroban
is being developed by the Institut de Recherches Servier
(France) and has entered Phase III clinical trials under
PERFORM (prevention of cerebrovascular events of ischemic
origin with terutroban in patients with a history of ischemic
Fig. 1 Structure of ramatroban (1) and terutroban (2).
stroke or transient ischemic attack). The study was prematurely
stopped, and the reasons and results have not been disclosed.
Nonetheless, the skeleton attracted our attention due to our
interest in molecules with important biological activities,
including the synthesis of prostanoids, beraprost (antiplatelet
drug)4 and iloprost (drug for pulmonary arterial hyperten-
sion).5 We wish to explore a non-Diels–Alder approach for the
synthesis of this molecule which can be further extended to
synthesize analogues.
Present work
In general, the tetralin units, such as that present in terutro-
ban, are built using a Diels–Alder reaction.6 The reported syn-
thesis of terutroban considered the molecule as a substituted
benzene analogue which was built by a Diels–Alder reaction,
as is the norm. We explored the synthesis of 2 as a tetrahydro-
naphthalene analogue built starting from a benzene ring. In a
retrosynthetic analysis, (Fig. 2) terutroban can be synthesized
aDivision of Natural Products Chemistry, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad, India 500 007. E-mail: srivaric@iict.res.in;
Fax: +91-40-27160152; Tel: +91-40-27193210, 27193434
bAcademy of Scientific and Innovative Research, New Delhi, India
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob02302a
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Fig. 2 Retrosynthetic analysis.
from olefin 3 in six steps involving sulphonamidation under
Mitsunobu conditions. Compound 3 can be obtained from 4
in five sequential steps using dehydration and Heck coupling
as the key reactions. The tetralone 4 in turn can be synthesized
starting from commercially available o-cresol 5 in seven steps
involving o-allylation, Claisen rearrangement, oxidative olefin
cleavage, Wittig olefination, olefin reduction, ester hydrolysis
and a Friedel–Crafts acylation reaction.
The use of an easily available and low cost starting material,
o-cresol (∼15 USD Kg−1), was considered to enable a facile,
large scale synthesis of the target molecule 2. Thus o-cresol
gave 6 following a known sequence.7 Lemieux–Johnson oxi-
dation–dihydroxylation with catalytic osmium tetraoxide fol-
lowed by carbon–carbon bond cleavage using sodium
periodate resulted in aldehyde 7 in 75% yield over two steps
(Scheme 1).
Scheme 2 Synthesis of key intermediate 3.
the required functional groups to synthesize the target mole-
cule (Scheme 2).
The next logical step was to synthesize an aziridine12 ana-
logue, which can be selectively opened to obtain the target
molecule. The reaction of sodium chloro(4-chlorophenyl)sulfo-
nyl amide and iodine at pH 7 buffer with 3 did not yield the
required product. Other different reaction conditions also did
not yield the required aziridine.
As the desired aziridine was not obtained, the next effort
was to synthesize an epoxide and open it to obtain an alcohol.
Thus, an epoxidation reaction was tried with mCPBA, H2O2-
titanium isopropoxide, H2O2 etc.12 The reaction always resulted
in an inseparable mixture of compounds.
Wittig olefination with carbethoxymethylene triphenylphos-
phorane delivered the olefin, which upon reduction with
sodium borohydride and NiCl2·6H2O gave 8 in 72% yield over
two steps. Hydrolysis of the ester using lithium hydroxide
afforded 9 (86% yield), and intramolecular Friedel–Crafts acy-
lation with PPA resulted in tetralone 4 in 79% yield. Reduction
of the ketone with sodium borohydride at 0 °C provided
alcohol 10 in 90% yield, followed by dehydration of the sec-
ondary alcohol with PPA8 at 100 °C which gave 11 in 76%
yield. Demethylation of the phenolic methyl ether using boron
trichloride9 afforded 12 in 77% yield. Conversion of the pheno-
lic hydroxyl group to a triflate followed by Heck coupling10
with methyl acrylate in presence of bis(triphenylphosphine)-
palladium(II) chloride provided unsaturated ester 13 in 60%
yield over two steps. The double bond in 13 was selectively
reduced with magnesium in methanol11 to yield the key inter-
mediate 3 in 84% yield. Compound 3 has both the rings and
A stepwise approach was then followed to synthesize 2.
Thus, key intermediate 3 was reacted with osmium tetroxide to
get diol 14 in 78% yield. Diol 14 was converted to a carbonate
derivative with triphosgene13 with 84% yield, which on
reduction with 10% Pd/C under hydrogenation conditions14
afforded alcohol 16 in 88% yield. Mitsunobu conditions15 were
employed to convert the alcohol to an azide in 83% yield.
Reduction over 10% Pd/C under hydrogenation conditions16,
followed by in situ conversion of the amine, provided the ester
17 in 78% yield. Hydrolysis of the ester with sodium hydrox-
ide3 gave terutroban 2, in 82% yield, which resembled the
reported acid in all respects (Scheme 3).
Experimental
General
1H NMR and 13C NMR spectra were recorded on a Varian
Gemini 200, Bruker Avance 300 or Varian Innova 500 at 75,
125, 300 or 500 MHz in CDCl3 or DMSO(D6) solvent at ambient
temperature. Chemical shifts δ are given in ppm, coupling con-
stants J are in Hz. The chemical shifts are reported in ppm on
a scale downfield from TMS as the internal standard, and
signal patterns are indicated as follows: s, singlet; d, doublet;
Scheme 1 Synthesis of intermediate 7.
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tered and concentrated in vacuo. The crude was purified by
flash column chromatography (9 : 1 hexanes–EtOAc) to afford 7
1
(21.6 g, 88%) as a liquid. H NMR (300 MHz, CDCl3) δ 9. 9.72
(t, J = 2.3 Hz, 1H), 7.19–7.12 (m, 1H), 7.02 (d, J = 5.3 Hz, 2H),
3.69 (s, 3H), 3.68 (dd, J = 2.3, 0.8 Hz, 2H), 2.33 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 199.6, 157.1, 131.3, 131.0, 128.9,
125.6, 124.3, 60.0, 45.3, 16.1; IR (KBr): νmax 2937, 1731, 1248,
1124, 752 cm−1; HRMS (ESI): Calcd for C10H13O2 [M + H]+:
165.0910, found: 165.0911.
Ethyl 4-(2-methoxy-3-methylphenyl)butanoate (8). To a solu-
tion of 7 (21.4 g, 130 mmol) in benzene (200 mL) was added
carbethoxymethylene triphenylphosphine (54.42 g, 156 mmol).
The reaction mixture was stirred at rt for 12 h under a nitrogen
atmosphere, after which it was concentrated in vacuo. The
crude was purified by column chromatography (19 : 1 hexanes–
EtOAc) to afford the olefinic compound (25.3 g, 83%) as a light
Scheme 3 Synthesis of terutroban 2.
1
yellow liquid. H NMR (300 MHz, CDCl3) δ 7.18–7.11 (m, 1H),
7.10–7.05 (m, 1H), 6.99–6.96 (m, 2H), 5.79 (dt, J = 15.7, 1.5 Hz,
1H), 4.16 (q, J = 7.2 Hz, 2H), 3.71 (s, 3H), 3.55 (dd, J = 6.6,
1.5 Hz, 2H), 2.30 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 166.5, 156.7, 147.5, 131.2, 130.0, 128.1,
124.1, 122.1, 119.6, 60.5, 60.1, 32.5, 16.1, 14.2; IR (KBr): νmax
2930, 1719, 1654, 1183, 1036, 770 cm−1; HRMS (ESI): Calcd for
C14H18O3Na [M + Na]+: 257.1148, found: 257.1145.
dd, doublet of doublets; dt, doublet of triplets; t, triplet; m,
multiplet; bs, broad singlet, quin., quintet. FT-IR Spectra: a
Perkin Elmer FT-IR was used to record spectra as KBr thin
films or neat; νmax are given in cm−1. ESI- and HR-ESI-MS were
recorded using a Finnigan MAT 1020B; values are given in m/z.
All the reagents and solvents were reagent grade and used
without further purification unless specified otherwise. Tech-
nical grade ethyl acetate and hexanes used for column chrom-
atography were distilled prior to use. Column chromatography
was carried out using silica gel (60–120 mesh) packed in glass
columns. All the reactions were performed under an atmosphere
of nitrogen in oven-dried glassware with magnetic stirring.
2-(2-Methoxy-3-methylphenyl)acetaldehyde (7). To a solu-
tion of 6 (28.5 g, 175 mmol) in acetone–acetonitrile–water
(1 : 1 : 1) (300 mL), were added OsO4 (44 mg, 0.18 mmol) and
NMO (41.16 g, 351 mmol). The reaction was stirred at room
temperature for 12 h, quenched with aqueous sodium sulphite
solution and stirred for an additional 30 min. The solution
was concentrated in vacuo to remove organic solvents. The
aqueous phase was extracted with ethyl acetate (3 × 150 mL).
The combined organic extracts were washed with brine
(50 mL), dried over anhydrous Na2SO4, filtered and concen-
trated in vacuo. The crude was purified by column chromato-
graphy (1 : 1 hexanes–EtOAc) to afford diol (29.3 g, 85%) as a
To a solution of olefin (25 g, 106 mmol) in methanol
(300 mL) was added NiCl2·6H2O (25.3 g, 106 mmol). The
mixture was cooled to 0 °C and NaBH4 (8 g, 213 mmol) was
added portion-wise. Upon completion of the reaction, as indi-
cated by TLC, it was filtered on celite and concentrated
in vacuo. The crude mixture was quenched with aq. saturated
NH4Cl (40 mL). The aqueous phase was extracted with ethyl
acetate (2 × 150 mL), washed with brine (30 mL), dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The
crude was purified by column chromatography (19 : 1 hexanes–
1
EtOAc) to afford 8 (21.9 g, 87%) as a colorless liquid. H NMR
(300 MHz, CDCl3) δ 7.05–7.0 (m, 2H), 6.99–6.92 (m, 1H), 4.13
(q, J = 6.8 Hz, 2H), 3.72 (s, 3H), 2.67 (t, J = 7.5 Hz, 2H), 2.35 (t,
J = 6.8, 2H), 2.29 (s, 3H), 1.95 (quin., J = 7.5 Hz, 2H), 1.26 (t, J =
6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 173.5, 156.7, 134.2,
130.9, 129.2, 127.7, 123.9, 60.3, 60.1, 33.9, 29.1, 25.9, 16.1,
14.2; IR (KBr): νmax 2945, 1734, 1245, 1017, 753 cm−1; HRMS
(ESI): Calcd for C14H20O3Na [M + Na]+: 259.1304, found
259.1295.
1
colorless thick liquid. H NMR (300 MHz, CDCl3) δ 7.11–6.95
(m, 3H), 4.17–4.03 (m, 1H), 3.95–3.86 (m, 2H), 3.76 (s, 3H),
3.60 (dd, J = 11.5, 3.2 Hz, 1H), 3.46 (q, J = 5.7 Hz, 1H),
2.92–2.78 (m, 2H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
156.7, 131.0, 130.6, 130.0, 128.9, 124.3, 72.8, 65.8, 60.3, 31.2,
16.1; IR (KBr): νmax 3382, 2942, 1246, 753 cm−1; HRMS (ESI):
Calcd for C11H16O3Na [M + Na]+: 219.0991, found: 219.0989.
To a solution of diol (29.2 g, 148 mmol) in acetone–water
(4 : 1, 400 mL) was added sodium periodate (63.6 g,
297 mmol). The reaction mixture was stirred at 0 °C for 1 h.
Upon completion of the reaction, it was filtered on celite and
the filtrate was concentrated in vacuo to remove acetone. The
aqueous phase was extracted with ethyl acetate (3 × 150 mL),
washed with brine (100 mL), dried over anhydrous Na2SO4, fil-
4-(2-Methoxy-3-methylphenyl)butanoic acid (9). To a solu-
tion of 8 (20.8 g, 87.89 mmol) in THF–H2O (1 : 1) (200 mL) was
added LiOH·H2O (18.4 g, 439 mmol). The reaction mixture was
stirred at room temperature for 12 h. The reaction mixture was
concentrated in vacuo to remove THF. Organic impurities were
extracted with ethyl acetate (1 × 100 mL). The aqueous phase
was cooled to 0 °C and the pH was adjusted to 2 by the
addition of 2N aq. HCl. The aqueous phase was extracted with
ethyl acetate (3 × 100 mL), washed with brine (50 mL), dried
over anhydrous Na2SO4, filtered and concentrated in vacuo to
afford 9 (15.8 g, 86%) as a colorless liquid. 1H NMR (300 MHz,
CDCl3) δ 7.06–7.0 (m, 2H), 6.99–6.92 (m, 1H), 3.72 (s, 3H), 2.69
(t, J = 7.5 Hz, 2H), 2.41 (t, J = 7.4 2H), 2.29 (s, 3H), 1.96 (quin.,
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J = 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 179.9, 156.8, 127.6, 121.8, 59.9, 22.8, 20.5, 16.1; IR (KBr): ν 2934, 1566, 1086,
134.0, 131.0, 129.3, 127.8, 123.9, 60.3, 33.6, 29.1, 25.5, 16.2; IR 826 cm−1; MS (ESI): m/z 197 [M + Na]+.
(KBr): νmax 2942, 2673, 1710, 1244, 1013, 753 cm−1; MS (ESI):
m/z 207 [M – H]+.
2-Methyl-7,8-dihydronaphthalen-1-ol (12). A solution of 11
(6.8 g, 39.21 mmol) in dry CH2Cl2 (30 mL) was cooled to 0 °C
5-Methoxy-6-methyl-3,4-dihydronaphthalen-1-(2H)-one (4). and BCl3 (1 M, 78.4 mL, 78.41 mmol) was added to it drop-
Compound 9 (15.7 g, 75.41 mmol) was subjected to an intra- wise. The reaction mixture was warmed to rt and heated to
molecular Friedel–Crafts acylation with PPA (50.96 g, reflux temperature. The reaction was quenched with water
150 mmol) at 90 °C for 3 min, followed by an second addition (50 mL) and the organic layer was separated. The aqueous
of hot PPA (38 g, 113 mmol), and the resultant mixture was phase was extracted with CH2Cl2 (2 × 50 mL). The combined
stirred for 30 min. Ice (100 mL) was then placed into the reac- organic extracts were washed with brine (30 mL), dried over
tion flask. The flask was allowed to cool and the mixture was anhydrous Na2SO4, filtered and concentrated in vacuo. The
extracted with ethyl acetate (3 × 100 mL). The organic layer was crude was purified by column chromatography (19 : 1 hexanes–
washed with 5% NaOH (2 × 100 mL), H2O (2 × 100 mL), 3% EtOAc) to afford 12 as a red oil (4.8 g, 77%). 1H NMR
CH3COOH (1 × 100 mL), 5% NaHCO3 (1 × 100 mL) and brine (300 MHz, CDCl3) δ 6.91 (d, J = 7.4 Hz, 1H), 6.58 (d, J = 7.5 Hz,
(1 × 100 mL). The organic layer was dried over anhydrous 1H), 6.41 (dt, J = 9.6, 1.9 Hz, 1H), 6.0–5.91 (m, 1H), 4.64
Na2SO4, filtered and concentrated. The crude was purified by (s, 1H), 2.74 (t, J = 8.3 Hz, 2H), 2.37–2.28 (m, 2H), 2.23 (s, 3H);
column chromatography (9 : 1 hexanes–EtOAc) to afford 4 13C NMR (75 MHz, CDCl3) δ 150.4, 133.2, 127.9, 127.7, 127.1,
1
(11.3 g, 79%) as an orange liquid. H NMR (300 MHz, CDCl3) 122.6, 119.9, 118.7, 22.6, 19.9, 15.9; IR (KBr): νmax 3469, 2928,
δ 7.75 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 3.75 (s, 3H), 1658, 823 cm−1; HRMS (ESI): Calcd for C11H13O [M + H]+:
2.97 (t, J = 6.0, 2H), 2.62 (t, J = 6.2 Hz, 2H), 2.34 (s, 3H), 2.11 161.0960, found: 161.0963.
(quin., J = 6.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 198.0,
(E)-Methyl 3-(2-methyl-7,8-dihydronaphthalen-1-yl)acrylate
155.7, 137.5, 137.1, 132.2, 129.0, 122.8, 59.8, 38.7, 23.4, 22.8, (13). To a solution of 12 (4.7 g, 29.4 mmol) in dry CH2Cl2
16.5; IR (KBr): νmax 2943, 1683, 1283, 1018, 767 cm−1; HRMS (50 mL) was added NEt3 (12 mL, 88.2 mmol), followed by a
(ESI): Calcd for C12H15O2 [M + H]+: 191.1066, found 191.1065.
slow addition of triflic anhydride (5.9 mL, 35.28 mmol) at
5-Methoxy-6-methyl-1,2,3,4-tetrahydronaphthalen-1-ol (10). 0 °C. The mixture was stirred at same temperature for 1 h. The
To a solution of 4 (11.12 g, 58.46 mmol) in CH3OH (100 mL) reaction was quenched with a slow addition of aq. 1 N HCl
was added NaBH4 (2.65 g, 70.16 mmol) portion-wise at 0 °C. (30 mL). The organic layer was separated, and the aqueous
The reaction was allowed to stir for 30 min at the same tem- phase was extracted with CH2Cl2 (2 × 40 mL). The combined
perature. After completion of the reaction, as indicated by TLC, organic extracts were washed with brine (20 mL), dried over
the reaction was quenched with aq. saturated NH4Cl solution anhydrous Na2SO4, filtered and concentrated in vacuo. The
(20 mL). The reaction mixture was concentrated under reduced crude was purified by column chromatography (hexanes) to
pressure and aq. saturated NH4Cl (50 mL) was added. The afford triflate (6.9 g, 81%) as a light yellow liquid. 1H NMR
aqueous phase was extracted with ethyl acetate (3 × 60 mL), (500 MHz, CDCl3) δ 7.07 (dd, J = 7.6, 0.6 Hz, 1H), 6.94 (d, J =
washed with brine (50 mL), dried over anhydrous Na2SO4, fil- 7.6, 1H), 6.45 (dt, J = 9.6, 1.8 Hz, 1H), 6.09–6.05 (m, 1H), 2.87
tered and concentrated in vacuo. The crude was purified by (t, J = 8.3 Hz, 2H), 2.36 (s, 3H), 2.33–2.28 (m, 2H); 13C NMR
column chromatography (6 : 1 hexanes–EtOAc) to afford 10 (75 MHz, CDCl3) δ 145.6, 134.6, 129.8, 129.6, 129.1, 128.5,
1
(10.2 g, 90%) as a yellow oil. H NMR (300 MHz, CDCl3) δ 7.12 126.8, 125.6, 22.2, 21.7, 17.0; IR (KBr): ν 2930, 1556, 1410,
(d, J = 8.3 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 4.77–4.72 (m, 1H), 1215, 771 cm−1; MS (ESI): m/z 293 [M + H]+.
3.71 (s, 3H), 2.86 (dt, J = 18.9, 5.3 Hz, 1H), 2.64 (dt, J = 17.4,
PdCl2(PPh3)2 (31.9 mg, 2 mol%) was added to a degassed
6.0 Hz, 1H), 2.27 (s, 3H), 1.98–1.85 (m, 2H), 1.84–1.72 (m, 2H); solution of triflate (6.8 g, 23.27 mmol), methyl acrylate
13C NMR (75 MHz, CDCl3) δ 155.9, 138.1, 130.4, 129.8, 128.7, (10.5 mL, 116 mmol) and NEt3 (9.8 mL, 69.81 mmol) in DMF
124.2, 67.9, 59.4, 31.9, 23.4, 18.3, 15.9; IR (KBr): νmax 3382, (50 mL). The reaction mixture was stirred at 120 °C under an
2937, 1453, 1015, 820 cm−1; MS (ESI): m/z 215 [M + Na]+.
8-Methoxy-7-methyl-1,2-dihydronaphthalene
argon atmosphere for 48 h. Ice water (50 mL) was then added
(11). Com- to it. The aqueous phase was extracted with ethyl acetate (3 ×
pound 10 (10.0 g, 52.18 mmol) and PPA (88 g, 260 mmol) were 50 mL). The combined organic extracts were washed with
stirred at 100 °C for 1.5 h. After cooling to room temperature, brine (50 mL), dried over anhydrous Na2SO4, filtered and con-
the mixture was diluted with water and basified with centrated in vacuo. The crude was purified by column chrom-
ammonium hydroxide (200 mL). The aqueous phase was atography (29 : 1 hexanes–EtOAc) to afford 13 as a red oil
1
extracted with chloroform (3 × 100 mL), washed with brine (3.9 g, 75%). H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 16.5 Hz,
(100 mL), dried over anhydrous Na2SO4, filtered and concen- 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.44 (dt,
trated in vacuo. The crude was purified by column chromato- J = 9.5, 1.7 Hz, 1H), 6.03–5.99 (m, 2H), 3.82 (s, 3H), 2.81 (t, J =
graphy (99 : 1 hexanes–EtOAc) to afford 11 (6.9 g, 76%) as a 8.2 Hz, 2H), 2.31 (s, 3H), 2.29–2.24 (m, 2H); 13C NMR (75 MHz,
yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.96 (d, J = 7.5 Hz, 1H), CDCl3) δ 166.9, 143.4, 135.3, 133.5, 133.0, 132.3, 127.9, 127.8,
6.73 (d, J = 7.5 1H), 6.43 (dt, J = 9.8, 1.5 Hz, 1H), 6.02–5.94 (m, 127.7, 126.3, 124.3, 51.7, 24.9, 23.1, 20.8; IR (KBr): νmax 2949,
1H), 3.70 (s, 3H), 2.83 (t, J = 8.3 Hz, 2H), 2.33–2.24 (m, 5H); 13
C
1722, 1641, 1169, 772 cm−1; HRMS (ESI): Calcd for C15H17O2
NMR (75 MHz, CDCl3) δ 155.4, 133.5, 129.9, 128.4, 127.7, 229.1223 [M + H]+, found: 229.1224.
2954 | Org. Biomol. Chem., 2015, 13, 2951–2957
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Methyl 3-(2-methyl-7,8-dihydronaphthalen-1-yl)propanoate (m, 2H), 2.47–2.27 (m, 6H), 1.98–1.85 (m, 1H); 13C NMR
(3). To a solution of 13 (3.75 g, 16.43 mmol) in CH3OH (75 MHz, CDCl3) δ 172.9, 154.7, 138.3, 136.7, 136.5, 129.2,
(40 mL) were added Mg turnings (788 mg, 32.87 mmol). The 129.1, 127.5, 76.3, 74.9, 51.8, 33.3, 27.2, 24.4, 20.0, 19.9; IR
reaction mixture was heated at reflux temperature for 12 h. (KBr): νmax 2924, 1796, 1733, 1168, 772 cm−1; HRMS (ESI):
After completion of the reaction, as indicated by TLC, the Calcd for C16H18O5Na 313.1046 [M + Na]+, found 313.1043.
solvent was removed under reduced pressure. The reaction
Methyl 3-(6-hydroxy-2-methyl-5,6,7,8-tetrahydronaphthalen-
mixture was partitioned between aq. saturated NH4Cl and 1-yl)propanoate (16). To a solution of 15 (2.1 g, 7.23 mmol) in
ethyl acetate. The aqueous phase was extracted with ethyl CH3OH (20 mL) was added Pd/C (45.65 mg, 10% w/w) in
acetate (2 × 40 mL). The combined organic extracts were sulfur-free conditions. The reaction mixture was stirred under
washed with brine (20 mL), dried over anhydrous Na2SO4, fil- a hydrogen atmosphere at rt for 3 h. After completion, the reac-
tered and concentrated in vacuo. The crude was purified by tion mixture was filtered through celite and the solvent was
column chromatography (29 : 1 hexanes–EtOAc) to afford 3 evaporated under vacuum. The crude was purified by column
1
(3.17 g, 84%) as a liquid. H NMR (500 MHz, CDCl3) δ 6.97 (d, chromatography (6 : 1 hexanes–EtOAc) to afford 16 (1.59 g,
J = 7.5 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.42 (dt, J = 9.5, 1.8 Hz, 88%) as a liquid. 1H NMR (300 MHz, CDCl3) δ 6.97 (d, J =
1H), 6.0–5.96 (m, 1H), 3.71 (s, 3H), 3.01–2.96 (m, 2H), 2.79 (t, 7.7 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 4.18–4.08 (m, 1H), 3.72 (s,
J = 8.2 Hz, 2H), 2.47–2.42 (m, 2H), 2.33–2.28 (m, 5H); 13C NMR 3H), 3.11–2.90 (m, 4H), 2.84–2.70 (m, 2H), 2.48–2.39 (m, 2H),
(75 MHz, CDCl3) δ 173.5, 135.7, 135.2, 133.4, 132.4, 128.2, 2.30 (s, 3H), 2.15–2.03 (m, 1H), 1.90–1.76 (m, 2H); 13C NMR
128.1, 127.2, 124.5, 51.7, 33.6, 24.4, 23.7, 23.3, 19.9; IR (KBr): (75 MHz, CDCl3) δ 173.5, 136.6, 133.9, 133.6, 132.3, 128.2,
νmax 2926, 1738, 1219, 772 cm−1; HRMS (ESI): Calcd for 127.8, 66.7, 51.7, 38.8, 33.0, 31.6, 24.5, 24.3, 19.4; IR (KBr):
C15H18O2Na [M + Na]+: 253.1199, found: 253.1204.
Methyl
3-(5,6-dihydroxy-2-methyl-5,6,7,8-tetrahydro C15H20O3Na 271.1304 [M + Na]+, found 271.1302.
naphthalen-1-yl)propanoate (14). To a solution of 3 (3.1 g, Methyl 3-(6-(4-chlorophenylsulfonamido)-2-methyl-5,6,7,8-
13.46 mmol) in acetone–acetonitrile–water (1 : 1 : 1, 30 mL) tetrahydronaphthalen-1-yl)propanoate 3-(6-(4-chlorophenyl
νmax 3406, 2926, 1736, 1219, 772 cm−1; HRMS (ESI): Calcd for
were added OsO4 (33.7 mg, 0.1 mmol) and NMO (3.15 g, sulfonamido)-2-methyl-5,6,7,8-tetrahydronaphthalen-1-yl) pro-
26.92 mmol). The reaction was stirred at room temperature for panoate (17). Alcohol 16 (1.42 g, 5.72 mmol) and triphenyl-
12 h. The mixture was quenched with aq. sodium sulphite phosphine (2.24 g, 8.58 mmol) were dissolved in dry THF
solution and stirred for an additional 30 min. The solution (20 mL). The mixture was cooled to −15 °C, and diisopropyl
was concentrated in vacuo to remove organic solvents and azodicarboxylate (DIAD, 2.84 mL, 14.29 mmol) was added to it.
30 mL water was added. The aqueous phase was extracted with After stirring the solution for 10 min at −15 °C, the tempera-
ethyl acetate (3 × 30 mL). The combined organic extracts were ture was raised to 0 °C and diphenylphosphoryl azide (DPPA,
washed with brine (30 mL), dried over anhydrous Na2SO4, fil- 1.79 mL, 8.58 mmol) was added. The solution was stirred for
tered and concentrated in vacuo. The crude was purified by 30 min at 0 °C and then for 12 h at room temperature. Concen-
column chromatography (1 : 1 hexanes–EtOAc) to afford 14 tration and gradient flash chromatography (99 : 1 hexanes–
1
(2.5 g, 78%) as a colorless liquid. H NMR (300 MHz, CDCl3) δ EtOAc) gave the azide (1.3 g, 83%) as a sticky yellow liquid,
7.24 (d, J = 7.5 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.67 (d, J = which was directly used for the next step.
3.8 Hz, 1H), 4.05–3.95 (m, 1H), 3.72 (s, 3H), 3.04–2.91 (m, 3H),
To a solution of azide (1.3 g, 4.76 mmol) in EtOAc (15 mL)
2.78–2.63 (m, 1H), 2.48–2.39 (m, 2H), 2.32 (s, 3H), 2.14–1.90 was added Pd/C (6.7 mg, 10% w/w) in sulfur-free conditions
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.4, 136.5, 136.3, followed by 4-chlorobenzene-1-sulfonyl chloride (1.99 g,
134.6, 134.1, 128.8, 128.2, 70.3, 69.0, 51.7, 32.9, 26.0, 24.6, 9.51 mmol). The reaction mixture was stirred under a hydro-
24.3, 19.6; IR (KBr): νmax 3394, 2933, 1735, 1291, 1198, gen atmosphere at rt for 12 h. After completion, the reaction
773 cm−1; HRMS (ESI): Calcd for C15H20O4Na: 287.1253 mixture was filtered through celite and the solvent was evapor-
[M + Na]+, found 287.1252.
ated under vacuum. The crude was purified by column chrom-
Methyl 3-(7-methyl-2-oxo-3a,4,5,9b-tetrahydronaphtho[2,1-d] atography (4 : 1 hexanes–EtOAc) to afford 17 (1.56 g, 78%) as a
[1,3]dioxol-6-yl)propanoate (15). To a solution of 14 (2.35 g, yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 8.5 Hz, 2H),
8.89 mmol) in dry CH2Cl2 (20 mL) was added NEt3 (3.7 mL, 7.48 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 7.7,
26.67 mmol). The solution was cooled to 0 °C and triphosgene 1H), 4.76 (d, J = 7.7 Hz, 1H), 3.71 (s, 3H), 3.68–3.57 (m, 1H),
(2.64 g, 8.89 mmol) was added slowly in portions. The reaction 2.97–2.53 (m, 6H), 2.43–2.35 (m, 2H), 2.29 (s, 3H), 2.03–1.91
was stirred at rt for 1 h and quenched with water (20 mL). The (m, 1H), 1.83–1.69 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 173.3,
aqueous phase was extracted with ethyl acetate (3 × 20 mL). 139.6, 139.1, 136.9, 134.5, 132.9, 131.1, 129.4, 128.5, 128.4,
The combined organic extracts were washed with brine 127.7, 51.8, 49.1, 36.8, 32.9, 29.6, 24.4, 24.0, 19.4; IR (KBr):
(20 mL), dried over anhydrous Na2SO4, filtered and concen- νmax 2923, 1735, 1162, 772 cm−1; HRMS (ESI): Calcd for
trated in vacuo. The crude was purified by column chromato- C21H25ClNO4S 422.1187 [M + H]+, found 422.1188.
graphy (6 : 1 hexanes–EtOAc) to afford 15 (2.17 g, 84%) as a
3-(6-(4-Chlorophenylsulfonamido)-2-methyl-5,6,7,8-tetrahydro-
light yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.19 (d, J = naphthalen-1-yl)propanoic acid (2). Compound 17 (1.43 g,
7.9 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 5.68 (d, J = 7.9 Hz, 1H), 3.39 mmol) was brought to reflux in methanol (15 mL), in the
5.20–5.12 (m, 1H), 3.71 (s, 3H), 3.06–2.97 (m, 2H), 2.85–2.78 presence of 2 N sodium hydroxide (404 mg, 10.17 mmol) for
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1 h. After cooling, the solvent was evaporated in vacuo, the
mixture was washed with ethyl acetate (1 mL) and the aqueous
phase was acidified with 1N HCl. The aqueous phase was
extracted with ethyl acetate (3 × 10 mL). The combined organic
extracts were dried over anhydrous Na2SO4, filtered and con-
centrated in vacuo to give terutroban (2) (1.12 g, 82%) as a
white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.91 (d, J = 6.6 Hz,
1H), 7.84 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 6.87 (d, J =
7.7 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 3.31(m, 1H), 2.83–2.65 (m,
4H), 2.63–2.54 (m, 2H), 2.30–2.21 (m, 2H), 2.19 (s, 3H),
1.86–1.74 (m, 1H), 1.63–1.50 (m, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 174.2, 140.7, 137.3, 136.9, 133.5, 133.3, 131.9,
129.5, 128.5, 127.9, 127.1, 49.0, 36.4, 32.9, 29.5, 24.3, 24.2,
19.2; IR (KBr): νmax 2924, 1709, 1219, 772 cm−1; HRMS (ESI):
Calcd for C20H23O4NClS 408.1030 [M + H]+, found 408.1040.
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1
[Reported H NMR3a (DMSO-d6) δ 12.5 (s, 1H), 7.9 (s, 1H), 7.8
(d, 2H), 7.7 (d, 2H), 6.9–6.7 (d, 2H), 3.3 (m, 1H), 3.0–2.5 (m,
6H), 2.3 (m, 2H), 2.2 (s, 3H), 2.0–1.5 (m, 2H).]
Conclusions
In conclusion, the total synthesis of terutroban is accom-
plished using
a non-Diels–Alder approach. The Claisen
rearrangement, Friedel–Crafts acylation and Heck coupling
reaction are the key reactions utilized. The utility of cost-
effective chemicals together with the flexible route allows one
to visualise the design of analogues with ease.
Acknowledgements
The authors thank CSIR, Ministry of Science and Technology
Government of India for research grants in XII Five Year
Plan ORIGIN (CSC-0108). WA thanks CSIR for a research
fellowship.
12
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