Enantioselective synthesis of almorexant via iridium-catalysed intramolecular allylic amidation

Article abstract of DOI:10.1039/c3ob40655e

An enantioselective synthesis of almorexant, a potent antagonist of human orexin receptors, is presented. The chiral tetrahydroisoquinoline core structure was prepared via iridium-catalysed asymmetric intramolecular allylic amidation. Further key catalytic steps of the synthesis include an oxidative Heck reaction at room temperature and a hydrazine-mediated organocatalysed reduction. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40655e

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Enantioselective synthesis of almorexant via
iridium-catalysed intramolecular allylic amidation†
Cite this: DOI: 10.1039/c3ob40655e
Martín Fañanás-Mastral,* Johannes F. Teichert, José Antonio Fernández-Salas,
Dorus Heijnen and Ben L. Feringa*
Received 3rd April 2013,
Accepted 17th May 2013
An enantioselective synthesis of almorexant, a potent antagonist of human orexin receptors, is pre-
sented. The chiral tetrahydroisoquinoline core structure was prepared via iridium-catalysed asymmetric
intramolecular allylic amidation. Further key catalytic steps of the synthesis include an oxidative Heck
reaction at room temperature and a hydrazine-mediated organocatalysed reduction.
DOI: 10.1039/c3ob40655e
www.rsc.org/obc
Introduction
Almorexant (1)1 (Fig. 1) is a potent non-peptide antagonist of
human orexin receptors which plays an important role in con-
trolling the sleep–wake cycle and related hypothalamic func-
tions.2 Developed by Actelion Pharmaceuticals,3 it has been
shown to significantly decrease wakefulness in rats, dogs and
humans.4
Almorexant features a chiral C1-substituted tetrahydroiso-
quinoline core next to a chiral α-phenyl-substituted amide.
The published enantioselective route3 relies on a Bischler–
Napieralski cyclization followed by Noyori’s ruthenium-cata-
lysed asymmetric transfer hydrogenation5 of the corres-
ponding 3,4-dihydroisoquinoline. Later, this second step was
improved by a hydrogenation reaction employing an Ir/Tania-
Phos catalyst (Scheme 1a).6
Scheme 1 Key enantioselective steps for the synthesis of almorexant 1.
We recently described a new catalytic enantioselective
approach towards chiral 1-vinyltetrahydroisoquinolines and
other chiral N-heterocycles based on an iridium-catalysed
intramolecular asymmetric allylic amidation.7 We envisioned
that this protocol could be applied to the synthesis of the key
chiral tetrahydroisoquinoline core of almorexant (Scheme 1b).
Our retrosynthetic analysis is depicted in Scheme 2. Com-
pound 1 could be obtained by reduction of the double bond
present in intermediate 2, ideally without racemisation of the
benzylic stereocentres. This reduction was expected to be cum-
bersome due to the facile racemisation of this kind of struc-
Fig. 1 Almorexant.
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG
Groningen, The Netherlands. E-mail: b.l.feringa@rug.nl, m.fananas.mastral@rug.nl;
Fax: +31 50 363 4296; Tel: +31 50 363 4278
†Electronic supplementary information (ESI) available: NMR spectra of all pro-
ducts. See DOI: 10.1039/c3ob40655e
ture.8 Compound
2 could be prepared by a sequential
N-deprotection and N-alkylation with (S)-mandelate derivative
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Scheme 3 Heck vs. oxidative Heck reaction of 6.
Scheme 2 Retrosynthetic analysis of almorexant.
conditions11 afforded a 2 : 1 mixture of compound 4 and the
isomerized enamide 7 (Scheme 3). The high temperature
required for this transformation might facilitate the isomeriza-
tion possibly promoted by a palladium hydride species formed
during the reaction. This problem in regioselectivity was over-
come by the use of the milder Pd/BIAN catalysed oxidative
Heck reaction,12 developed in our laboratories,13 which takes
place at room temperature. Thus, reaction between tetrahydro-
isoquinoline 5 and (4-(trifluoromethyl)phenyl)boronic acid
under these conditions afforded compound 4 as the only
product of the reaction (E/Z 5 : 1) in 88% yield (Scheme 3).
Once the (trifluoromethyl)phenyl moiety was introduced,
3 (see Scheme 4). Key intermediate 4 could be obtained via an
oxidative Heck type coupling reaction between (4-(trifluoro-
methyl)phenyl)boronic acid and chiral tetrahydroisoquinoline
5, a key chiral intermediate which is accessible with excellent
enantioselectivity through the iridium-catalysed intramolecu-
lar asymmetric allylic amidation of 6.7
Results and discussion
The synthetic route started with commercially available 3,4-
dimethoxyphenethylamine which was converted into allyl
carbonate 6 as described recently.7 Iridium-catalysed intra- the trifluoroacetamide group was removed by treatment with
K2CO3 in MeOH–H2O7 and the resulting secondary amine was
molecular asymmetric allylic amidation afforded 1-vinyltetra-
alkylated in very good yield using enantiomerically pure
hydroisoquinoline 5 in 97% yield with 95% ee, according to
our previously reported procedure.7 We then tried to install the (S)-mandelate derivative 33 (Scheme 4).
(trifluoromethyl)phenyl moiety by cross-metathesis9 between 5
and 4-trifluoromethyl styrene. However, all attempts using
The final step to accomplish the synthesis of almorexant 1
relied on the reduction of compound 2, which carries a stereo-
different ruthenium catalysts under different conditions genic centre adjacent to the double bond. These and related
structures often show isomerization of the double bond to an
in-conjugation position with the tetrahydroisoquinoline aro-
failed. The fact that only homocoupled styrene and starting
material were found in the reaction mixture is indicative that
the reactivity of the terminal olefin moiety of 5 is relatively low. matic group and thus loss of the stereogenic centre, when they
are subjected to transition metal-catalysed hydrogenations.8
The same low reactivity was found when we attempted the
Taking this into account, we decided to use the recently
reported olefin reduction employing a riboflavin-based organo-
catalyst and hydrazine in air which precludes any isomerisa-
tion (epimerisation).14,15 Thus, reduction of 2 employing
hydroboration of 5 in order to perform a subsequent Suzuki
coupling.10
The synthesis of compound 4 could however be achieved by
employing a Heck reaction. The reaction between 5 and
1-iodo-4-(trifluoromethyl)benzene under the classical Heck 20 mol% of riboflavin 11 and an excess of hydrazine gave rise
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Experimental
General procedures
Chromatography: Merck silica gel type 9385 230–400 mesh,
TLC: Merck silica gel 60, 0.25 mm. Components were visual-
ized by UV and cerium/molybdenum staining. Progress and
conversion of the reaction were determined by GC-MS (GC,
HP6890: MS HP5973) with an HP1 or HP5 column (Agilent
Technologies, Palo Alto, CA). Mass spectra were recorded on
an AEI-MS-902 mass spectrometer (EI+) or an LTQ Orbitrap XL
(ESI+). 1H and 13C NMR were recorded on a Varian AMX400
(400 and 100.59 MHz, respectively) or a Varian VXR300 (300
and 75 MHz, respectively) using CDCl3 as a solvent. Chemical
shift values are reported in ppm with the solvent resonance as
the internal standard (CHCl3: δ 7.26 for 1H, δ 77.0 for 13C).
Data are reported as follows: chemical shifts, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, br = broad, m =
multiplet), coupling constants (Hz), and integration. Carbon
assignments are based on APT 13C NMR experiments. Optical
rotations were measured on a Schmidt+Haensch polarimeter
(Polartronic MH8) with a 10 cm cell (c given in g per 100 mL).
Solvents were used as received. [Ir(COD)Cl]2 was purchased
from Strem Chemicals, Inc. Hydrazine monohydrate, DBU,
compounds 8 and 9, and Pd(OAc)2 were purchased from
Aldrich, and used without further purification. Ligands L116
and L213 were prepared as reported in the literature.
Scheme 4 N-Deprotection–N-alkylation sequence to 2.
(E)-3-(4,5-Dimethoxy-2-(2-(2,2,2-trifluoroacetamido)ethyl)-
phenyl)allyl methyl carbonate 7 was synthesized from commer-
cially available 3,4-dimethoxyphenethylamine according to our
previously reported procedure.7
(S)-1-(6,7-Dimethoxy-1-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)-
2,2,2-trifluoroethanone (5)7
[Ir(COD)Cl]2 (2.5 mol%) and L2 (5.0 mol%) were dissolved in
dry THF (1.0 mL per 0.2 mmol) under an N2 atmosphere.
Then, DBU (1 equiv.) was added and the reaction mixture was
heated at 50 °C for 30 min. Then, it was brought to room
temperature and 6 (1 equiv.) was added. The reaction mixture
was stirred until TLC showed full conversion. All volatiles were
removed under reduced pressure to yield the crude product.
Purification by column chromatography (SiO2, pentane–EtOAc
3 : 1) afforded 5 in 97% yield with 95% ee as a colourless oil as
a mixture of two conformers in a 3.6 : 1 ratio (determined by
1H NMR at 20 °C). Major conformer: 1H NMR (400 MHz, CDCl3)
δ 6.60 (s, 1H), 6.58 (s, 1H), 6.00–5.91 (m, 2H), 5.30 (dd, J = 9.9,
0.8 Hz, 1H), 5.12 (dd, J = 15.5, 0.8 Hz, 1H), 4.03–3.98 (m, 1H),
3.84 (s, 3H), 3.83 (s, 3H), 3.53 (ddd, J = 13.8, 12.1, 3.9 Hz, 1H),
Scheme 5 Riboflavin-based organocatalysed reduction of 2.
to almorexant 1 in excellent yield as a single enantiomer
without any epimerisation (Scheme 5). Spectral data of 1 were
identical to those previously reported.3
Conclusions
In summary, we have presented a concise enantioselective syn- 3.00–2.90 (m, 1H), 2.76–2.68 (m, 1H major). 13C NMR
thesis of almorexant, a potent antagonist of human orexin (101 MHz, CDCl3) δ 155.6 (q, J = 35.8 Hz), 148.3, 147.8, 135.6,
receptors. Key steps are an iridium-catalysed intramolecular 125.3, 124.7, 118.6, 116.8 (q, J = 287.9 Hz), 111.1, 110.6, 56.0,
asymmetric allylic amidation,
a
catalytic oxidative Heck 55.9, 55.5, 40.0, 28.7. 19F NMR: (376 MHz, CDCl3) δ = −69.4.
reaction under ambient conditions and a hydrazine-mediated HR-MS (APCI+, m/z): calculated for C15H17F3NO3 [M + H+]:
riboflavin-catalysed reduction. The chiral tetrahydroisoquino- 316.1155, found: 316.1140. [α]2D0 = +168.3 (c = 0.85 in CHCl3).
line starting material of known absolute configuration was Enantiomeric excess was determined by chiral HPLC (Chiral-
readily accessible by iridium-catalysed intramolecular allylic pak OJ-H: n-heptane–2-propanol 90 : 10, 40 °C, 210 nm), reten-
amidation.
tion times: 19.7 min (S), 24.7 min (R).
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(S,E)-1-(6,7-Dimethoxy-1-(4-(trifluoromethyl)styryl)-3,4-
dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (4)
7.34–7.29 (m, 5H), 6.91 (q, J = 4.9 Hz, 1H), 6.64 (s, 1H), 6.50
(dd, J = 15.9, 7.1 Hz, 1H), 6.37 (d, J = 15.9 Hz, 1H), 6.37 (s, 1H),
4.42 (s, 1H), 4.40 (d, J = 7.1 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H),
3.07–2.98 (m, 2H), 2.91–2.85 (m, 1H), 2.88 (d, J = 4.9 Hz, 3H),
2.61–2.55 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 172.0, 148.2,
147.3, 140.1, 137.3, 132.8, 131.8, 129.5 (q, J = 32.2 Hz), 128.7
(2C), 128.5 (2C), 128.2, 126.8, 126.7 (2C), 126.5, 125.5 (q, J = 3.8
Hz, 2C), 124.1 (q, J = 271.9 Hz), 111.4, 111.2, 70.6, 61.3, 56.0,
55.9, 41.4, 26.2, 26.1. 19F NMR (376 MHz, CDCl3) δ −62.5. [α]2D0
= −16.0 (c = 0.5, CHCl3).
To a stirred solution of Pd(OAc)2 (5 mol%) and BIAN (L2)
(7 mol%) in a 9 : 1 mixture MeOH–H2O (2 mL per 1 mmol), (S)-
1-(6,7-dimethoxy-1-vinyl-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-
trifluoroethanone 5 (1 equiv.) and (4-(trifluoromethyl)phenyl)
boronic acid 9 (3 equiv.) were added at room temperature. An
oxygen balloon was fitted to the reaction vessel, and the reac-
tion mixture was stirred at room temperature overnight. After
TLC analysis showed completion of the reaction, all volatiles
were removed under reduced pressure to afford the crude
product. Purification by flash column chromatography on
silica gel afforded the pure product 4 in 88% yield as a colour-
less oil and as a mixture of two conformers in a 4.5 : 1 ratio
(R)-2-((S)-6,7-Dimethoxy-1-(4-(trifluoromethyl)phenethyl)-3,4-
dihydroisoquinolin-2(1H)-yl)-N-methyl-2-phenylacetamide
(almorexant, 1)
1
1
To a solution of 2 (0.012 mmol, 1 equiv.) in EtOH (1 mL), an
atmosphere of oxygen was applied (balloon, 1 atm). A solution
of the riboflavin catalyst 11 (0.0024 mmol, 0.2 equiv.) in EtOH
(0.2 mL) was added. Then hydrazine hydrate (2.4 mmol, 200
equiv.) was added dropwise and the mixture was stirred at
room temperature during 48 h. CH2Cl2 (5 mL) was added and
the mixture was washed with water (3 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 2 mL), and the organic layers
were combined and dried over Na2SO4. All volatiles were
removed in vacuo to yield the crude product which was purified
by column chromatography on silica gel (EtOAc–pentane 2 : 1)
to afford pure almorexant as a single stereoisomer as a colour-
(determined by H NMR at 20 °C). Major conformer: H NMR
(201 MHz, CDCl3) δ 7.48 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz,
3H), 6.58 (s, 1H), 6.56 (s, 1H), 6.44–6.25 (m, 2H), 6.06 (d, J =
5.1 Hz, 1H), 4.08–3.90 (m, 1H), 3.81 (s, 3H), 3.76 (s, 3H),
3.65–3.43 (m, 1H), 3.06–2.83 (m, 1H), 2.80–2.62 (m, 1H). 13C
NMR (101 MHz, CDCl3) δ 155.8 (q, J = 36.4 Hz) 148.6, 148.1,
139.4, 132.6, 129.9 (q, J = 32.6 Hz), 129.6, 126.9 (2C), 125.5 (q,
J = 3.7 Hz, 2C), 125.4, 124.5, 111.2, 110.6, 56.1, 55.9, 55.1, 29.7,
28.7. 19F NMR (376 MHz, CDCl3) δ −62.6, −69.3.
(S)-6,7-Dimethoxy-1-(4-(trifluoromethyl)styryl)-1,2,3,4-tetrahydro-
isoquinoline (10)
1
less oil (87% yield). H NMR (400 MHz, CDCl3) δ 7.52 (d, J =
To a solution of 4 (1 equiv.) in MeOH–H2O (7 : 1), K2CO3
(3 equiv.) was added and the reaction mixture was stirred for
16 h. Volatiles were removed under reduced pressure, and the
resulting mixture was diluted in water (10 mL) and washed
with ethyl-acetate (3 × 5 mL). The combined organic layers
were dried with Na2SO4, and concentrated under reduced
pressure, to yield the product 10 as a colourless solid (99%
yield) as a 5 : 1 mixture of E/Z isomers. Compound 10 was used
in the next step without further purification. E isomer: 1H
NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.3 Hz, 2H), 7.42 (d, J =
8.2 Hz, 2H), 6.56 (s, 1H), 6.54 (d, J = 15.8 Hz, 1H), 6.50 (s, 1H),
6.37 (dd, J = 15.8, 7.8 Hz, 1H), 4.57 (d, J = 7.8 Hz, 1H), 3.79 (s,
3H), 3.71 (s, 3H), 3.24–3.16 (m, 1H), 3.04–2.97 (m, 1H),
2.82–2.70 (m, 2H).
8.0 Hz, 3H), 7.28–7.23 (m, 5H), 7.14 (d, J = 8.0, 2H), 6.84 (q, J =
4.8 Hz, 1H), 6.58 (s, 1H), 6.04 (s, 1H), 4.25 (s, 1H), 3.85 (s, 3H),
3.70 (s, 3H), 3.40–3.30 (m, 2H), 3.16–3.04 (m, 2H), 2.98–2.85
(m, 1H), 2.88 (d, J = 4.9, 3H), 2.71–2.61 (m, 1H), 2.51–2.42 (m,
1H), 2.18–2.06 (m, 1H), 1.85–1.75 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 172.4, 147.8, 147.3, 146.3, 137.1, 129.1, 128.7, 128.6,
128.5, 128.3, 128.1 (q, J = 32.1 Hz), 125.3 (q, J = 4.0 Hz, 2C),
125.0, 124.2 (q, J = 271.2 Hz), 111.4, 110.1, 70.1, 57.1, 55.9,
55.8, 40.7, 37.7, 33.4, 26.1, 21.8. 19F NMR (376 MHz, CDCl3) δ
−62.3. HRMS (ESI+, m/z): calcd for C29H32F3N2O3 [M + H]+:
513.23595; found: 513.23539. [α]2D0 = −27.6 (c = 0.21, CHCl3).
Chiral HPLC analysis: Chiralcel OD column, n-heptane–i-PrOH
95 : 5, 40 °C, 210 nm, retention time: 22.5 min.
(R)-2-((S)-6,7-Dimethoxy-1-(4-(trifluoromethyl)styryl)-3,4-
dihydroisoquinolin-2(1H)-yl)-N-methyl-2-phenylacetamide (2)
Acknowledgements
To a solution of 10 (1 equiv.) and DIPEA (2 equiv.) in aceto-
nitrile, (S)-2-(methylamino)-2-oxo-1-phenylethyl 4-methylben-
zenesulfonate (3) (1.1 equiv.) was added. The reaction mixture
was stirred at reflux overnight. When the reaction was judged
complete using TLC analysis, the reaction mixture was concen-
trated under reduced pressure. The residue was dissolved in
ethyl acetate and washed with sodium carbonate. The organic
layer was dried using Na2SO4, and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography on silica gel (AcOEt–pentane 2 : 1) to yield 2
We thank the Netherlands Organization for Scientific Research
(NWO-CW) and the National Research School Catalysis
(NRSC-C) for financial support.
Notes and references
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CDCl3) δ 7.55 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H),
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