An alternate synthesis of appetite suppressant (R)-2-benzylmorpholine employing Sharpless asymmetric epoxidation strategy

Article abstract of DOI:10.1016/j.tetlet.2016.01.032

An alternate synthesis of (R)-2-benzylmorpholine 1, an appetite suppressant agent has been accomplished starting from readily available trans-cinnamyl alcohol employing Sharpless asymmetric epoxidation strategy as a key step, with an overall yield of 24%.

Full text of DOI:10.1016/j.tetlet.2016.01.032

Accepted Manuscript
An alternate synthesis of appetite suppressant (R)-2-benzylmorpholine employ-
ing Sharpless asymmetric epoxidation strategy
N. Viswanadh, P. Mujumdar, M. Sasikumar, S.S. Kunte, M. Muthukrishnan
PII:
S0040-4039(16)30032-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.032
TETL 47196
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
5 November 2015
6 January 2016
9 January 2016
Please cite this article as: Viswanadh, N., Mujumdar, P., Sasikumar, M., Kunte, S.S., Muthukrishnan, M., An
alternate synthesis of appetite suppressant (R)-2-benzylmorpholine employing Sharpless asymmetric epoxidation
strategy, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.01.032
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An alternate synthesis of appetite suppressant
R)-2-benzylmorpholine employing
(
Sharpless asymmetric epoxidation strategy
N. Viswanadh, P. Mujumdar, M. Sasikumar, S. S. Kunte, M. Muthukrishnan*

1
Tetrahedron Letters
journal h omepage: www.els evier. com
An alternate synthesis of appetite suppressant (R)-2-benzylmorpholine employing
Sharpless asymmetric epoxidation strategy
N. Viswanadh, P. Mujumdar,M. Sasikumar, S. S. Kunte, M. Muthukrishnan*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411 008, India
*
Corresponding author. Tel.: +91 20 25902284; fax: +91 2025902629; E-mail: address: m.muthukrishnan@ncl.res.in (M. Muthukrishnan)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Abstract: An alternate synthesis of (R)-2-benzylmorpholine 1, an appetite suppressant agent has
been accomplished starting from readily available trans-cinnamyl alcohol employing Sharpless
asymmetric epoxidation strategy as a key step, with an overall yield 24%.
2
015 Elsevier Ltd. All rights reserved.
Available online
Keywords:
(
R)-2-benzylmorpholine
Sharpless asymmetric epoxidation
appetite suppressant
C-Substituted morpholine analogues, in particular the non-
racemic ones are important structural scaffolds present in many
pharmaceutically important compounds (Fig. 1). They are
routes to these valuable compounds especially the non-racemic
7
ones are very limited. So far, methods described in the literature
1
5
to afford (R)-2-benzyl morpholine involve optical resolution,
8
potential therapeutic agents for wide variety of medical disorders
chemoenzymatic route or enantioselective method employing
2
9
such as depression (Reboxetine, Viloxesine), anorectic
proline catalyzed α-aminooxylation strategy.
3
(
Phenmetrazine, Phendimetrazine), chemotherapy induced
As part of our ongoing programme on developing a new and
improved process for the preparation of various pharmaceutically
4
nausea & vomiting (Aprepitant) etc. In that series, (R)-2-benzyl
morpholine is a classical example of chiral 2-morpholine
analogues, known to be a potent appetite suppressant and widely
10,11
important compounds for industrial applications,
we herein
report a simple and efficient approach towards the preparation of
5
studied for its pharmacological properties. Further, its potential
(R)-2-benzylmorpholine employing Sharpless asymmetric
1
2
utility in treating diabetes mellitus and certain CNS disorders are
epoxidation (SAE) strategy.
6
also under investigation. Despite their wide utility, synthetic
A retrosynthetic analysis of 1 is outlined in scheme 1. As
shown in scheme 1, the amino alcohol 5 can be visualized as a
key intermediate for the synthesis of (R)-2-benzylmorpholine (1)
which can be elaborated to the amide derivative 6 by simple N-
acylation. Further, compound 6 might be transformed to the
target molecule 1 via cyclization followed by amide reduction.
Figure 1 Few pharmaceutically important compounds possessing
chiral C-2 substituted morpholine structure
Scheme 1 Retrosynthetic analysis of (R)-2-benzylmorpholine 1

2
Tetrahedron Letters
Scheme 2: Synthesis of (R)-2-benzylmorpholine
The amino alcohol 5 might, in turn, be prepared from readily
available trans-cinnamyl alcohol 2 by means of SAE, azidation
prior to concomitant hydrogenolysis and hydrogenation
sequences.
Accordingly, our synthesis commenced with the readily
available trans-cinnamyl alcohol 2, which was subjected to
Sharpless asymmetric epoxidation conditions ((+)-DIPT,
Conclusion
In conclusion, we have developed a new and alternative
synthesis of (R)-2-benzylmorpholine 1, an appetite suppressant
agent employing SAE as a key step. Simple procedures, ready
availability of the starting materials and high enantiopurity are
some of the salient features of this approach. Further, this simple
approach offers flexibility in making diverse lead like C-2 chiral
morpholine scaffolds for application in a range of therapeutic
areas.
i
0
4 2 2
Ti(O Pr) , TBHP, CH Cl , -20 C) to give enantiomerically pure
13
epoxide alcohol 3 in 86% yield (ee >99%). Subsequently, the
epoxyalcohol 3 was converted into the corresponding azido
epoxide 4 by carrying out O-tosylation at low temperature (-20
Acknowledgements
0
C) followed by azidation using sodium azide in dry DMF. Next,
V.N. thanks the UGC, New Delhi for a research
fellowship. The authors thank Dr. Pradeep Kumar for his support
and encouragement. Financial support from the CSIR Network
projects (CSC0130, CSC0108 and BSC0121) is gratefully
acknowledged.
the azido epoxide 4 was subjected to palladium carbon-catalyzed
concomitant hydrogenolysis of epoxide and hydrogenation of
azide moiety in a single step to provide aminoalcohol 5 in 75%
yield. It is worth noting that although the regioselective ring
opening of azido epoxide 4 with various nucleophiles have been
studied, to our knowledge, the concomitant hydrogenolysis of
epoxide and hydrogenation of azide in a single step to produce
enantiopure β-amino alcohols have not been examined.
Considering the significance of enantiopure β-amino alcohols as
important structural elements present in many natural products as
well as pharmaceuticals, this reaction represents the valuable
alternative to prepare enantiopure β-amino alcohol, utilizing SAE
strategy. Further, the aminoalcohol 5 on N-acylation with
chloroacetyl chloride under basic condition provided compound
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
References and notes
1. Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; Van Delft,
F. L.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641.
2. (a) Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.;
Brown, M. T.; Wong, E. H. F. CNS Drug Rev. 2004, 10, 23;
(b) Pinder, R. M.; Brogden, R. N.; Speight, T. M.; Avery, G.
S. Drugs 1977, 13, 401.
3. Banks, M. L.; Blough, B. E.; Fennell, T. R.; Snyder, R. W.;
Negus, S. S. Drug Alcohol Depend. 2013, 130, 158.
4. Rapoport, B. L.; Jordan, K.; Boice, J. A.; Taylor, A.; Brown,
C.; Hardwick, J. S.; Carides, A.; Webb, T.; Schmoll, H.-J.
Support Care Cancer 2010, 18, 423.
6
in 87% yield. Subsequent cyclization induced by t-BuOK in
isopropanol gave the morpholinamide derivative 7 in 69% yield.
Finally, the reduction of amide bond using Red-Al in THF
completed the synthesis of (R)-2-benzylmorpholine, in overall
2
4% yield. The structure of (R)-2-benzylmorpholine (1)
1
13
confirmed by means of IR, H NMR, C NMR and mass
spectroscopic analysis.

3
5
6
.
.
Brown, G. R.; Forster, G.; Foubister, A. J.; Stribling, D. J.
Pharm. Pharmacol. 1990, 42, 797.
129.1 (CH, 2 carbons), 128.6 (CH, 2 carbons), 126.8 (CH),
73.8 (CH), 67.6 (CH ), 46.0 (CH ), 39.2 (CH ); HRMS (ESI)
calcd for C11 N [M+H] 192.1019, found 192.1019,
N [M+Na] 214.0838, found 214.0838.
2
2
2
+
(a) Bentley, J. M.; Dawson, C. E.; Guba, W.; Hebeisen, P.;
Monck, N.; Pratt, R. M.; Richter, H.; Roever, S.; Ruston, V.
PCT Int. Appl, WO 2006/077025A2, 2006; (b) Keenan, T.
P.; Kaplan, A. P. US patent, 2014/0038945A1, 2014.
Zhou, J.; Yeung, Y.-Y. J. Org. Chem. 2014, 79, 4644.
(a) D'Arrigo, P.; Lattanzio, M.; Fantoni, G. P.; Servi, S.
Tetrahedron: Asymmetry 1998, 9, 4021; (b) Parmeggiani, F.
Chim. Oggi 2011, 29, 13.
13 2
H O
+
11 13 2
C H O
D
(R)-2-benzylmorpholine (1): colorless oil; [α]25 = +1.31 (c 5,
8a
D
-
CHCl
3
); {lit. [α]25 = +1.28 (c 5, CHCl
3 3
)}; IR (CHCl , cm
1
7
8
.
.
): νmax 3020, 2400, 1652, 1403, 1216, 1093, 925, 768, 670
): δ 2.40 (bs, 1 H), 2.51-
3 H
2.68 (m, 2 H), 2.75-2.93 (m, 4 H), 3.51-3.71 (m, 2 H), 3.83-
-1
1
cm ; H NMR (500 MHz, CDCl
13
3.89 (m, 1 H), 7.17-7.32 (m, 5 H); C NMR (100 MHz,
CDCl ): δ 137.9 (C), 129.2 (CH, 2 carbons), 128.3 (CH, 2
carbons), 126.3 (CH), 77.6 (C), 68.2 (CH ), 50.8 (CH ), 45.7
(CH ), 40.3 (CH ); HRMS (ESI) calcd for C11 15ON [M+H]
178.1226, found 178.1226.
9
.
Sawant, R. T.; Waghmode, S. B. Tetrahedron 2010, 66,
3
C
2010.
2
2
+
1
0. (a) Viswanadh, N.; Velayudham, R.; Jambu, S.; Sasikumar,
2
2
H
M.; Muthukrishnan, M. Tetrahedron Lett. 2015, 56, 5269; (b)
Mujahid, M.; Kunte, S. S.; Muthukrishnan, M. Tetrahedron
Lett., 2014, 55, 3223; (c) Reddi, A.; Mujahid, M.; Sasikumar,
M.; Muthukrishnan, M. Synthesis, 2014, 46, 1751; (d)
Mujahid, M.; Muthukrishnan, M. Chirality, 2013, 25, 965;
(
e) Mujahid, M.; Mujumdar, P.; Sasikumar, M.; Kunte, S. S.;
Muthukrishnan, M. Tetrahedron: Asymmetry, 2012, 23,
512; (f) Muthukrishnan, M.; Mujahid, M.; Sasikumar, M.;
1
Mujumdar, P. Tetrahedron: Asymmetry, 2011, 22, 1353.
1. (a) Nikalje, M. D.; Sasikumar, M.; Muthukrishnan, M.
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Nikalje, M. D.; Muthukrishnan, M. Tetrahedron: Asymmetry,
1
2009, 20, 2814; (c) Muthukrishnan, M.; Garud, D. R.; Joshi,
R. R.; Joshi, R. A. Tetrahedron, 2007, 63, 1872; (d) Joshi,
R.A.; Garud, D.R.; Muthukrishnan, M.; Joshi, R.R.; Gurjar,
M.K. Tetrahedron: Asymmetry, 2005, 16, 3802.
1
1
2. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5974; (b) Heravi, M. M.; Lashaki, T. B.; Poorahmad, N.
Tetrahedron: Asymmetry 2015, 26, 405.
3. The enantiopurity purity was assessed by chiral HPLC
analysis by reference to a racemic compound 3. Racemic
compound 3 was prepared using known procedure, see
reference, Hashimoto, N.; Kanda, A. Org. Process Res. Dev.
2
002, 6,405.
Spectral data for selected compounds:
R)-2-chloro-N-(2-hydroxy-3-phenylpropyl)acetamide
(
(6):
, cm
D
-
pale yellow oil; [α]25 = -6.3 (c 1.4, CHCl
3
); IR (CHCl
3
1
)
: νmax 3423, 3022, 2928, 2403, 1741, 1594, 1532, 1423,
1
3 H
1216, 1030, 927, 765, 672; H NMR (400 MHz, CDCl ): δ
2
1
3
.33 (bs, 1 H), 2.74 (dd, J = 13.7, 8.3 Hz, 1 H), 2.84 (dd, J =
3.6, 5.0 Hz, 1 H), 3.22-3.28 (m, 1 H), 3.60-3.66 (m, 1 H),
.98-4.04 (m, 1 H), 4.07 (s, 2 H), 6.99 (bs, 1 H), 7.21-7.23
13
(
m, 1 H), 7.26-7.36 (m, 4 H); C NMR (100 MHz, CDCl
166.7 (CO), 137.1 (C), 129.3 (CH, 2 carbons), 128.8 (CH,
carbons), 126.9 (CH), 71.6 (CH), 45.0 (CH ), 42.6 (CH ),
1.5 (CH ); HRMS (ESI) calcd for C11
28.0786, found 228.0784, C11
3
):
δ
C
2
4
2
2
2
+
2
14 2
H O NCl [M+H]
NCl [M+Na] 250.0605,
+
14
H O
2
found 250.0604.
D
(R)-6-benzylmorpholin-3-one (7): semi solid; [α]25 = -30.7 (c
-
1
1
1
.81, CHCl
455, 1427, 1341, 1215, 1114, 1027, 928, 669; H NMR (200
): δ 2.76 (dd, J = 13.9, 6.4 Hz, 1 H), 2.99 (dd, J
13.9, 6.8 Hz, 1 H), 3.16-3.37 (m, 2 H), 3.84-3.97 (m, 1 H),
.2 (dd, J = 31.5, 16.9 Hz, 2 H), 6.95 (bs, 1 H), 7.18-7.37 (m,
3 3
); IR (CHCl , cm ): νmax 3019, 2400, 1681, 1496,
1
MHz, CDCl
=
4
5
3
H
1
3
3 C
H); C NMR (50 MHz, CDCl ): δ 169.1 (CO), 136.7 (C),