Stereoselective total synthesis of almorexant

Article abstract of DOI:10.1016/j.tetlet.2014.03.130

A highly stereoselective synthesis of almorexant has been achieved using (R)-tert-butanesulfinamide as a chiral source. The chiral tetrahydroisoquinoline core was constructed through allylation of chiral N-sulfinyl imine followed by ring closure of the se

Full text of DOI:10.1016/j.tetlet.2014.03.130

Tetrahedron Letters 55 (2014) 3143–3145
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective total synthesis of almorexant
⇑
N. Siva Senkar Reddy, B. V. Subba Reddy
Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective synthesis of almorexant has been achieved using (R)-tert-butanesulfinamide as a
chiral source. The chiral tetrahydroisoquinoline core was constructed through allylation of chiral N-sul-
finyl imine followed by ring closure of the secondary amide with a tethered halide. The chiral a-phenyl
amide was introduced by means of SN2 substitution of (S)-methyl 2-phenyl-2-(tosyloxy)acetate with
chiral tetrahydroisoquinoline.
Received 2 November 2013
Revised 28 March 2014
Accepted 28 March 2014
Available online 5 April 2014
Ó 2014 Published by Elsevier Ltd.
Keywords:
Asymmetric synthesis
(R)-tert-Butanesulfinamide
N-Sulfinyl imine
Grignard reaction
SN2 substitution
The neuropeptides, orexin A and orexin B are produced by neu-
rons in the hypothalamus.1,2 They play a key role in the regulation
of various biological functions such as sleep/wake cycle.3,4 Conse-
quently, a variety of orexin antagonists have been developed to
regulate the physiological functions of orexin receptors.5 Among
them, almorexant is a non-peptide antagonist of human orexin
receptors,6 which plays a major role in controlling the sleep/wake
cycle and related hypothalamic functions.2
MeO
MeO
MeO
MeO
O
O
N
N
N
H
TsO
Boc
+
N
H
HO
8
10
CF3
CF3
Almorexant comprises of a chiral tetrahydroisoquinoline core and
a chiral a-phenyl amide. Indeed, the synthesis of almorexant involves
Almorexant(1)
Br
multi-step processes such as Bischler–Napieralski cyclization and
Noyori’s ruthenium-catalyzed asymmetric transfer hydrogenation7
of the corresponding 3,4-dihydroisoquinoline. Subsequently, the
second step has been improved by asymmetric hydrogenation using
chiral Ir/Tania-Phos catalyst.8 Other methods for the construction of
chiral tetrahydroisoquinoline core are based on iridium-catalyzed
asymmetric intramolecular allylic amidation9 and Ugi reaction.10
The N-tert-butanesulfinamide is a versatile chiral auxiliary for
the asymmetric induction in the preparation of chiral amines.11
Addition of an organometallic reagent to C@N bond of an enantio-
pure sulfinimine is one of the most elegant methods for the syn-
thesis of chiral amines. The electron-withdrawing sulfinyl group
is highly stereodirecting and activates the C@N bond effectively
in nucleophilic addition reactions, and can easily be removed to
provide the enantiopure amine derivatives.12 However, the use of
this useful chiral auxiliary in the total synthesis of complex natural
products is still unexplored to a great extent. Inspired by its
MeO
MeO
Cl
MeO
MeO
+
N
Boc
N
CF3
S
O
OHC
3
7
Scheme 1. Retrosynthetic approach of almorexant (1).
versatility in asymmetric synthesis, we attempted the total synthe-
sis of almorexant using N-tert-butanesulfinamide as a source of
chirality.
Following our interest on (R)-tert-butanesulfinamide chemis-
try,13 we herein report a highly efficient total synthesis of almorex-
ant (1) via the allylation of an enantiopure sulfinimine. Our
retrosynthetic approach to the synthesis of almorexant (1) is
depicted in Scheme 1. As per our synthetic strategy, almorexant
could be accessed from tetrahydroisoquinoline 8 which can be pre-
pared by Grignard reaction of the aldehyde 7 with p-trifluoro-
methyl phenylmagnesium bromide. The key intermediate 7 was
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
http://dx.doi.org/10.1016/j.tetlet.2014.03.130
0040-4039/Ó 2014 Published by Elsevier Ltd.

3144
N. S. S. Reddy, B. V. Subba Reddy / Tetrahedron Letters 55 (2014) 3143–3145
proposed to be obtained from enantiopure N-sulfinylimine 3
through the allylation and subsequent oxidation. Aldimine 3 could
be prepared by the condensation of (R)-tert-butanesulfinamide
with aryl aldehyde 2.
MeO
MeO
MeO
MeO
a
b
N
O
N
Boc
Boc
HO
The synthesis of a key intermediate 7 is outlined in Scheme 2.
Accordingly, we started the synthesis of tetrahydroisoquinoline
core 7 from the chloro substituted aryl aldehyde 2.14 Treatment of
chloro aldehyde 2 with (R)-tert-butanesulfinamide in the presence
of CuSO4 afforded the corresponding N-sulfinylimine 3a in 80%
yield.15 Grignard reaction of N-sulfinylimine 3a with allylmagne-
sium bromide at ꢀ78 °C in dichloromethane gave the homoallylic
sulfinamide 4a in 78% yield with 9:1 ratio of diastereomers16 which
can easily be separated by column chromatography. To improve the
diastereoselectivity, we performed the allylation with N-sulfinylim-
ine 3b derived from (R)-p-tolylsulfinamide and chloro aldehyde 2.
However, the corresponding allyl derivative 4b was obtained in
73% yield with 78:22 ratio of diastereomers. Therefore, we pro-
ceeded to the next step with 4a. Base catalyzed intramolecular cycli-
zation of the chloro amide 4a in the presence of NaH in DMF at room
temperature gave the cyclized product 5a in 75% yield.17 Deprotec-
tion of the sulfinyl group using ethanolic HCl afforded the tetrahy-
droisoquinoline in 80% yield.18 Protection of the free amine with
(Boc)2O in the presence of triethyl amine furnished the N-Boc deriv-
ative 6.15 Oxidative cleavage of the terminal olefin 6 using OsO4, 2,6-
lutidine, and NaIO4 gave the aldehyde 7 in 80% yield in a single step
(Scheme 2).19
7
8
CF3
MeO
MeO
MeO
MeO
c
O
N
N
Boc
N
H
9
CF3
(1)
CF3
Scheme 3. Synthesis of target molecule (1). Reagents and conditions: (a) p-
trifluoromethylphenylmagnesium bromide, THF, rt 2 h, 82%; (b) (i) mesyl chloride,
Et3N, CH2Cl2, 0 °C, (ii) LAH, THF, 0 °C, 62% over two steps; (c) (i) TMSOTf, CH2Cl2, rt,
1 h, (ii) compound 10, DIPEA, CH3CN, reflux, 68% over two steps.
using (R)-tert-butanesulfinamide as a chiral source. Our synthetic
route involves 11 steps in 9.7% overall yield, which is similar to
other reported methods. The use of easily accessible chiral tert-
butanesulfinamide makes this synthesis more simple, quite effi-
cient, and attractive.
Further treatment of aldehyde 7 with trifluoromethylphenyl
magnesium bromide in THF at room temperature gave the hydroxy
derivative 8 in 82% yield.20 Mesylation of 8 with mesyl chloride in
the presence of triethyl amine followed by reduction with LAH
afforded the deoxygenated compound 9 in 62% yield over two
steps.21 Deprotection of Boc 9 using TMSOTf followed by SN2 sub-
stitution of tosyl derivative 10 with secondary amino functionality
in the presence of diisopropylethyl amine afforded the target alm-
Acknowledgements
B.V.S. thanks CSIR, New Delhi for the financial support as a part
of XII five year plan program under title ORIGIN (CSC-0108).
orexant (1) in 68% yield over two steps (½a D25
ꢀ25.0, c = 0.2, CHCl3)
ꢁ
Supplementary data
(Scheme 3). The optical rotation and spectral data of (ꢀ)-almorex-
ant (1)22 are in agreement with the data reported in the literature.9
In summary, we have developed a highly efficient total synthe-
sis of almorexant, a potent antagonist of human orexin receptors
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.03.
130.
References and notes
MeO
MeO
Cl
MeO
MeO
Cl
b
a
1. De Lecea, L.; Kilduff, T. S.; Peyron, C.; Gao, X.; Foye, P. E.; Danielson, P. E.;
Fukuhara, C.; Battenberg, E. L.; Gautvik, V. T.; Bartlett, F. S., 2nd; Frankel, W. N.;
van den Pol, A. N.; Bloom, F. E.; Gautvik, K. M.; Sutcliffe, J. G. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 322.
2. Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R. M.; Tanaka, H.;
Williams, S. C.; Richardson, J. A.; Kozlowski, G. P.; Wilson, S.; Arch, J.;
Buckingham, R. E.; Haynes, A. C.; Carr, S. A.; Annan, R. S.; McNulty, D. E.; Liu,
W.; Terrett, J. A.; Elshourbagy, N. A.; Bergsma, D. J.; Yanagisawa, M. Cell 1998,
92, 573.
N
R
H
S
O
O
3a, R = t-butyl
2
3b
, R = p-tolyl
MeO
MeO
Cl
MeO
MeO
c
H
N
R
3. Lin, L.; Faraco, J.; Li, R.; Kadotani, H.; Rogers, W.; Lin, X.; Qiu, X.; de Jong, P. J.;
Nishino, S.; Mignot, E. Cell 1999, 98, 365.
N
R
S
S
O
4. Chemelli, R. M.; Willie, J. T.; Sinton, C. M.; Elmquist, J. K.; Scammell, T.; Lee, C.;
Richardson, J. A.; Williams, S. C.; Xiong, Y.; Kisanuki, Y.; Fitch, T. E.; Nakazato,
M.; Hammer, R. E.; Saper, C. B.; Yanagisawa, M. Cell 1999, 98, 437.
5. For recent reviews on the medicinal chemistry of orexin antagonists, see: (a)
Roecker, A. J.; Coleman, P. J. Curr. Top. Med. Chem. 2008, 8, 977; (b) Boss, C.;
Brisbare-Roch, C.; Jenck, F. J. Med. Chem. 2009, 52, 891; (c) Boss, C.; Brisbare-
Roch, C.; Jenck, F.; Aissaoui, H.; Koberstein, R.; Sifferlen, T.; Weller, T. Chimia
2008, 62, 974.
6. (a) Brisbare-Roch, C.; Dingemanse, J.; Koberstein, R.; Hoever, P.; Aissaoui, H.;
Flores, S.; Mueller, C.; Nayler, O.; van Gerven, J.; de Haas, S. L.; Hess, P.; Qiu, C.;
Buchmann, S.; Schertz, M.; Weller, T.; Fischli, W.; Clozel, M.; Jenck, F. Nat. Med.
2007, 13, 150; (b) Owen, R. T.; Castañer, R.; Bolós, J.; Estivill, C. Drugs Future
2009, 34, 5.
7. (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc.
1996, 118, 4916; (b) Weller, T.; Koberstein, R.; Aissaoui, H.; Clozel, M.; Fischli,
W. WO 2005/118548, 2005.
8. De Vries, M. A. H.; Domin, D.; Helms, M.; Imboden, C.; Koberstein, R.; Nazir, Z.;
Skranc, W.; Stanek, M.; Tschebull, W.; Verzijl, M. G. K. WO 2009/083903, 2009.
9. Fañanás-Mastral, M.; Teichert, J. F.; Fernández-Salas, J. A.; Heijnen, D.; Feringa,
B. L. Org. Biomol. Chem. 2013, 11, 4521.
O
5
4a
4b
, R = t-butyl, dr: 90:10
, R = p-tolyl, dr: 78:22
5a, R = t-butyl
MeO
d
MeO
e
N
N
Boc
MeO
MeO
Boc
6
7
O
Scheme 2. Synthesis of aldehyde 7. Reagents and conditions: (a) (R)-tert-butane-
sulfinamide, CuSO4, CH2Cl2, 25 °C, 24 h, 80%; (b) AllylMgBr, CH2Cl2, ꢀ78 °C, 1 h, 78%;
(c) NaH, DMF, 0 °C to rt, 6 h, 75%; (d) (i) EtOH/HCl, 1,4-dioxane, 5 h, 0 °C, (ii) Boc2O,
Et3N, CH2Cl2, rt, 1 h, 75% (over two steps); (e) OsO4, 2,6-lutidine, NaIO4, 1,4-dioxane,
2 h, 80%.

N. S. S. Reddy, B. V. Subba Reddy / Tetrahedron Letters 55 (2014) 3143–3145
3145
10. (a) Boss, C.; Brisbare-Roch, C.; Jenck, F. J. Med. Chem. 2009, 52, 891; (b) Aissaoui,
H.; Cappi, M.; Clozel, M.; Fischli, W.; Koberstein, R. (Actelion Pharmaceuticals
Ltd, Switz.), WO 2001/068609, 2001, p. 158.
15. (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999,
64, 1278; (b) Harried, S. S.; Croghan, M. D.; Kaller, M. R.; Lopez, P.; Zhong, W.;
Hungate, R.; Reider, P. J. J. Org. Chem. 2009, 74, 5975.
11. (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984; (b) Sun,
X. W.; Xu, M. H.; Lin, G. Q. Org. Lett. 2006, 8, 4979; (c) Lin, G. Q.; Xu, M. H.;
Zhong, Y. W.; Sun, X. W. Acc. Chem. Res. 2008, 41, 831.
12. (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600;
(b) Davis, F. A.; Yang, B.; Deng, J.; Zhang, J. ARKIVOC 2006, vii, 120; (c)
Bosque, I.; González-Gómez, J. C.; Foubelo, F.; Yus, M. J. Org. Chem. 2012, 77,
4190.
13. (a) Reddy, N. S. S.; Reddy, B. J. M.; Reddy, B. V. S. Tetrahedron Lett. 2013, 54,
4228; (b) Reddy, N. S. S.; Reddy, A. S.; Yadav, J. S.; Reddy, B. V. S. Tetrahedron
Lett. 2012, 53, 6916.
14. (a) Yamato, M.; Washigaki, K.; Qais, N.; Ishikawa, S. Tetrahedron 1990, 46, 5909;
(b) Coldham, I.; Jana, S.; Watson, L.; Martin, N. G. Org. Biomol. Chem. 2009, 7,
1674.
16. (a) Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron 2009, 65,
1608; (b) Lin, S.; Zhao, G. Eur. J. Org. Chem. 2010, 1660.
17. (a) Natsume, M.; Wada, M. Chem. Pharm. Bull. 1972, 20, 1589; (b) Reddy, L. R.;
Das, S. G.; Liu, Y.; Prashad, M. J. Org. Chem. 2010, 75, 2236.
18. (a) Liu, M.; Sun, X.; Xu, M.; Lin, G. Chem. Eur. J. 2009, 15, 10217; (b) Sun, X.; Liu,
M.; Xu, M.; Lin, G. Org. Lett. 2008, 10, 1259.
19. Chandrasekhar, S.; Mahipal, M.; Kavitha, M. J. Org. Chem. 2009, 74, 9531.
20. Miyazaki, M.; Ando, N.; Sugai, K.; Seito, Y.; Fukuoka, H.; Kanemitsu, T.; Nagata,
K.; Odanaka, Y.; Nakamura, K. T.; Itoh, T. J. Org. Chem. 2011, 76, 534.
21. (a) Feng, D. Z.; Song, Y. L.; Jiang, H. X.; Chen, L.; Long, W. Q. Org. Biomol. Chem.
2007, 5, 2690; (b) Kim, W. H.; Hong, S. K.; Lim, S. M.; Ju, M. A.; Jung, S. K.; Kim,
Y. K.; Jung, J. H.; Kwon, M. S.; Lee, E. Tetrahedron 2007, 63, 9784.
22. Supporting Information.