An enantioselective approach to 3-substituted pyrrolidines: Asymmetric synthesis for pyrrolidine core of serotonin norepinephrine reuptake inhibitors (SNRIs)

Article abstract of DOI:10.1016/j.tetlet.2017.07.069

A novel and efficient synthetic approach to enantiopure 3-substituted pyrrolidine skeleton from readily available (S)-PMB glycidyl ether as a starting material and its application to the asymmetric synthesis of pyrrolidine core 1 of serotonin norepinephrine reuptake inhibitors (SNRIs) 2 and 3 are described. The synthesis utilizes the organocatalyzed asymmetric Michael addition reaction as key step.

Full text of DOI:10.1016/j.tetlet.2017.07.069

Accepted Manuscript
An enantioselective approach to 3-substituted pyrrolidines: asymmetric synthe-
sis for pyrrolidine core of serotonin norepinephrine reuptake inhibitors (SNRIs)
Yuvraj Garg, Pooja Sharma, Satyendra Kumar Pandey
PII:
S0040-4039(17)30931-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.069
TETL 49151
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 June 2017
19 July 2017
19 July 2017
Please cite this article as: Garg, Y., Sharma, P., Pandey, S.K., An enantioselective approach to 3-substituted
pyrrolidines: asymmetric synthesis for pyrrolidine core of serotonin norepinephrine reuptake inhibitors (SNRIs),
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.069
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Tetrahedron Letters
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An enantioselective approach to 3-substituted pyrrolidines: asymmetric synthesis for
pyrrolidine core of serotonin norepinephrine reuptake inhibitors (SNRIs)
Yuvraj Garg, Pooja Sharma and Satyendra Kumar Pandey∗
School of Chemistry and Biochemistry, Thapar University, Patiala 147001, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel and efficient synthetic approach to enantiopure 3-substituted pyrrolidine skeleton from
readily available (S)-PMB glycidyl ether as a starting material and its application to the
asymmetric synthesis of pyrrolidine core 1 of serotonin norepinephrine reuptake inhibitors
(SNRIs) 2 and 3 are described. The synthesis utilizes the organocatalyzed asymmetric Michael
addition reaction as key step.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
3-Substituted pyrrolidine
Serotonin norepinephrine reuptake inhibitors
Antidepressant drugs
PMB glycidyl ether
Michael addition
Introduction
several SNRIs marketed worldwide have proven to be effective
and safe drugs in chronic painful conditions and mood disorders
Pyrrolidines and their substituted derivatives are among the
most bioactive N-heterocyclic compounds in organic chemistry
due to prevalence of these structural motifs either as itself or as a
part of a more complex structural moiety in a large number of
biologically active molecules and natural products.1 Among
them, enantiomerically pure 3-substituted pyrrolidine 1 and their
derivatives are important subclass of compounds possessing
interesting pharmacological activities.2 Serotonin norepinephrine
reuptake inhibitors (SNRIs) are advanced novel class of
antidepressant drugs which have been suggested for the treatment
of several central nervous disorders including chronic painful
conditions such as fibromyalgia and diabetic peripheral
neuropathic pain.3 The precise mechanism of action of SNRIs has
not yet been fully elucidated, but it is believed to be mainly
caused by decreasing the levels of serotonin and norepinephrine
in the synaptic cleft, resulting erratic signalling.4 Currently,
but the search for new SNRIs has always been of greater
significance upon past drugs in regards to efficacy, tolerability
and fewer side effects. In 2013, Johansson and co-workers5
reported the discovery of novel 3-substituted pyrrolidine ether
SNRI 2, which is the first example showing improved
norepinephrine transporter activity, acceptable metabolic stability
and exhibiting minimal drug to drug interaction. Stangeland and
co-workers have also reported previously the discovery of an
another novel 3-substituted pyrrolidine ether SNRI 3 which
showed inhibition of the serotonin and/or norepinephrine
transporter, for the treatment of neuropathic pain with reduced
side effects such as nausea (Figure 1).6
The SNRIs 2 and 3 have been synthetic targets of considerable
interest for pharmaceutical industries due to their utility in
treatment of central nervous disorders with an array of
functionalities.5-7 More recently, Magnus and co-workers
reported the multistep asymmetric synthesis of the SNRIs 2 and 3
that employed dynamic kinetic resolution (DKR) with enantio-
and diastereoselective hydrogenation on β-keto-γ-lactam to
afford β-hydroxy-γ-lactam as the key step.7 As part of our
ongoing research programme towards the asymmetric syntheses
of bioactive compounds,8 we became interested in developing a
flexible approach to 3-substituted pyrrolidine skeleton offering
the diversity for derivatization. Herein, we are reporting a new
and highly efficient approach for 3-substituted pyrrolidine and its
application to the asymmetric synthesis of pyrrolidine core 1 of
R1 = i-Pr R2 = H R3 = H
R2
1
O
H
R1 = i-Pr
R3 = H
OMe
Cl
R2 =
R1
N
SNRI 2
N
R3
R1 = i-Pr
R3 = H
R2 =
(1-3)
Cl
SNRI 3
Figure 1: Structures of 3-substituted pyrrolidines 1-3.
———
∗ Corresponding author. Tel.: +91-175-239-3832; fax: +91-175-236-4498; e-mail: skpandey@thapar.edu

2
Tetrahedron
SNRIs 2 and 3 employing organocatalyzed Michael addition
reaction as key step.
nitroaldehyde adduct 15 which on spontaneous intramolecular
reductive amination with Zn/CH3COOH12 followed by N-Boc
protection under basic conditions furnished N-Boc-pyrrolidine
skeleton 17 in 81% yield.
Results and Discussion
Our synthetic approach for the stereoselective synthesis of 3-
substituted pyrrolidine skeleton 4 was envisioned via the
retrosynthetic route as shown in Scheme 1. The pyrrolidine core
unit 5 could be used as a synthetic intermediate from which 3-
substituted pyrrolidine ethers 4, SNRIs 2 and 3 could be
synthesized via base catalyzed nucleophilic aromatic substitution
reaction (SNAr) with corresponding commercially available
aromatic halides. The pyrrolidinol derivative 5 in turn could be
obtained from nitroaldehyde derivative 6 via intramolecular
reductive amination. We envisaged that the nitroaldehyde 6
would serve as a key intermediate in this approach and could be
prepared by means of (S)- or (R)-diphenylprolinol silyl ether
catalyzed asymmetric Michael addition of nitromethane to
α,β−unsaturated aldehyde derived from the reduction of olefinic
ester derivative 7. The ester derivative 7 could be assembled from
mono-protected terminal alcohol derivative 8 by oxidation
followed by Wittig olefination. Enantiomerically pure alcohol
derivative 8 could be easily accessed from the chiral glycidyl
ether 9 via suitable Grignard reagents followed by standard
organic transformations. The desired configuration of 3-
substituted pyrrolidine skeleton 4 could be obtained by simply
changing the (S)- and (R)- configuration of the readily available
glycidyl ether and/or by using L- and D-diphenylprolinol silyl
ether catalyst during Michael addition step. Thus, in principle, all
the four isomers of SNRIs 2 and 3 along with different
substitutions at three different sites R1, R2 and R3 could be
accessed by this approach.
OBn
OH
O
a
b
OPMB
OPMB
OPMB
12
10
11
OBn
OBn
e
c
d
OEt
OH
O
13
14
OBn
OBn
g
f
NO2
NO2
OH
O
16
15
h
OH
OBn
H
OH
H
H
j
i
N
H
N
Boc
N
Boc
18
17
1
Scheme 2: Reagents and conditions: (a) (CH3)2CHMgBr,
anhydrous THF, CuI, -20 oC, 6 h, 86%; (b) PhCH2Br, NaH,
DMF, 0 oC to rt, 3 h, 89%; (c) DDQ, CH2Cl2, rt, 8 h, 93%; (d) (i)
(COCl)2, DMSO, Et3N, CH2Cl2, -78 oC to -60 oC, 2 h, (ii)
PPh3=CHCOOEt, THF, rt, 24 h, 90% (over two steps); (e) (i)
DIBAL-H, CH2Cl2, -78 oC, 1 h, (ii) (R)-diphenylprolinol silyl
ether (10 mol%), CH3NO2, benzoic acid, MeOH, rt, 24 h; (f)
NaBH4, MeOH, 0 oC, 30 min, 85%; (g) (i) MsCl, NEt3, CH2Cl2, 0
oC to rt, 1 h, (ii) Zn, CH3COOH, H2O, 0 oC to rt, 3 h, (iii)
(Boc)2O, NaH, DMAP, DMF, 0 oC to rt, 10 h, 76% (over three
steps); (h) (i) Zn, CH3COOH, H2O, 0 oC to rt, 3 h, (ii) (Boc)2O,
NaH, DMAP, DMF, 0 oC to rt, 10 h, 81%; (i) H2, Pd/C, MeOH,
rt, 24 h, 87%; (j) TFA, CH2Cl2, rt, 5 h, 92%.
R2
SNAr
OH
H
OP
O
H
H
*
*
*
R1
R1
*
R1
*
*
O
N
H
NO2
N
R3
Reductive Michael
Amination Addition
To further elucidate the stereochemistry during the Michael
addition, the conjugate addition of nitromethane to
5
6
4
α,β−unsaturated aldehyde was carried out with racemic catalyst
( )-diphenylprolinol silyl ether followed by reduction with
NaBH4 furnished the syn-/anti-nitroalcohol diastereomers (dr,
1:1) with 87% combined yield.13 On the other side, the conjugate
addition in the presence of catalytic amount of (R)-
Wittig
Olefination
OP
*
OP
O
*
*
R1
OH
Grignard
Reaction
OP
R1
OEt
O
8
9
7
diphenylprolinol silyl ether furnished the syn-nitroalcohol
derivative 16 as a single diastereomer in 85% yield, which is in
accordance with the previously proven model in organocatalytic
Michael addition reaction.11,13-14 The syn-nitroalcohol derivative
16 was converted to pyrrolidine 17 via O-Ms followed by
reduction with Zn/AcOH and subsequent N-Boc protection in
76% yield. With enantiomerically pure pyrrolidine derivative 17
in hand, it was then subjected to debenzylation under 1 atm H2
pressure in the presence of a catalytic amount of Pd/C which
afforded the alcohol 18 in 87% yield. The alcohol 18 upon SNAr
reaction with commercially available 6-chloro-2-methylpyridine
and subsequent N-Boc deprotection with TFA followed by
methoxide moiety addition using the literature report5 would
furnish the SNRI 2. Finally, the N-Boc deprotection of derivative
18 with TFA furnished the pyrrolidine core unit 1 in 92% yield
[α]D25 -25.6 (c 0.5, CH3OH). On the other hand, pyrrolidine core
unit 1 on SNAr reaction with commercially available 1,3-
dichloro-4-fluorobenzene under basic conditions would furnish
the pyrrolidine ether SNRI 3 using the known procedure.7
Scheme 1: Retrosynthesis of 3-substituted pyrrolidines 4.
As displayed in Scheme 2, the synthesis of pyrrolidine core 1
of SNRIs 2 and 3 commenced with Cu(I)-catalyzed
regioselective ring-opening of (S)-PMB (p-methoxybenzyl)
glycidyl ether 109 with iso-propylmagnesium bromide at -20 oC
which furnished the PMB protected alcohol (S)-11 in 86% yield.
Treatment of alcohol (S)-11 with BnBr under the basic conditions
successfully delivered the protected diol (S)-12 in 89% yield. The
selective deprotection of O-PMB ether group of (S)-12 with
DDQ furnished the terminal alcohol derivative (S)-13 in 93%
yield. Oxidation of alcohol (S)-13 under Swern conditions10 and
subsequent treatment of aldehyde with (ethoxycarbonyl-
methylene)triphenylphosphorane in THF afforded the trans-
olefinic ester (S)-14 in 90% yield.
Our next aim was to carry out the synthesis of 3-substituted
pyrrolidine moiety. Towards this end, DIBAL-H reduction of
ester (S)-14 at -78 oC to α,β−unsaturated aldehyde and
subsequent conjugate addition11 of nitromethane in the presence
of (R)-diphenylprolinol silyl ether (10 mol%) furnished the
In conclusion, we have described a novel and efficient
enantioselective approach for the synthesis of 3-substituted

5. Dreyfus, N; Myers, J. K; Badescu, V. O; de Frutos, O; de la
Puente, M. L; Ding, C; Filla, S. A; Fynboe, K; Gernert, D. L;
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synthesis of pyrrolidine core unit 1 of SNRIs 2 and 3 from
readily available chiral epoxide as starting material employing
diphenylprolinol silyl ether mediated asymmetric Michael
addition reaction as key step. The overall yield for the pyrrolidine
core unit 1 was 42% after seven column chromatographic
purification steps. The merits of described synthesis are excellent
enantio- and diastereoselectivity with high yielding reaction
steps. The synthetic approach described has also significant
potential for variation of substituents at the 3-alkyl site, O-aryl
and N-alkyl sites to synthesize various 3-substituted pyrrolidines
with expected increase in antidepressant activities.
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Acknowledgments
S.K.P. is thankful to Department of Science and Technology;
Science and Engineering Research Board (SERB), New Delhi,
for generous funding of the project (Grant No.
EMR/2016/003649). Y.G. thanks UGC, New Delhi for a senior
research fellowship.
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spectral data.
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OTMS
δ
N
Ph
Ph
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δ
BnO
NO2
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An enantioselective approach to 3-
substituted pyrrolidines: asymmetric
synthesis for pyrrolidine core of serotonin
norepinephrine reuptake inhibitors (SNRIs)
Yuvraj Garg, Pooja Sharma and Satyendra Kumar Pandey*

1. Serotonin norepinephrine reuptake
inhibitors (SNRIs), advanced antidepressant
drugs
2. An efficient approach to enantiopure 3-
substituted pyrrolidine skeleton
3. Asymmetric synthesis of pyrrolidine core of
SNRIs
4. Organocatalytic asymmetric Michael
addition reaction key step