Efficient synthesis of (?)-(R)- and (+)-(S)-rolipram

Article abstract of DOI:10.1016/j.tetlet.2017.09.080

A novel, efficient and protecting group free enantioselective synthetic approach of (?)-(R)-1 and (+)-(S)-rolipram 2 is described employing the organocatalyzed asymmetric Michael addition, Henry condensation, Wittig olefination and reductive lactamization

Full text of DOI:10.1016/j.tetlet.2017.09.080

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Efficient synthesis of (-)-(R)- and (+)-(S)-rolipram
Ramandeep Kaur, Satyendra Kumar Pandey
PII:
S0040-4039(17)31244-3
https://doi.org/10.1016/j.tetlet.2017.09.080
TETL 49350
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Reference:
Tetrahedron Letters
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24 September 2017
27 September 2017
Please cite this article as: Kaur, R., Pandey, S.K., Efficient synthesis of (-)-(R)- and (+)-(S)-rolipram, Tetrahedron
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Tetrahedron Letters
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Efficient synthesis of (-)-(R)- and (+)-(S)-rolipram
Ramandeep Kaur and Satyendra Kumar Pandey*
a School of Chemistry and Biochemistry, Thapar University, Patiala 147001, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel, efficient and protecting group free enantioselective synthetic approach of (-)-(R)-1 and
(+)-(S)-rolipram 2 is described employing the organocatalyzed asymmetric Michael addition,
Henry condensation, Wittig olefination and reductive lactamization reactions as key steps.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Rolipram
Michael addition
Henry condensation
γ-Aminobutyric acid
Antidepressant
Introduction
mainly effective for the PDE4B and subtype of PDE4.6
Additionally, (R)-rolipram 1 has also been proposed as a
antiinflammatory,7 immunosupressant,7 putative antiparkinson-
ian,8 neuroprotective,9 antipsychotic10 and has been suggested for
the treatment of multiple sclerosis.10 The (R)-1 and (S)-rolipram 2
have been synthetic target of considerable interest for academia
and pharmaceutical industries due to its high antidepressant
activity combined with attractive structural features. Various
elegant studies and syntheses of (R)-1 and (S)-rolipram 2 have
been documented in the literature.11 In 2008, Dixon and co-
workers11f reported an enantioselective total synthesis of (R)-
rolipram in six steps employed the bifunctional catalyst mediated
asymmetric Michael addition of malonate nucleophiles as key
step. Recently, Kobayashi and co-workers11a described the
continuous flow asymmetric synthesis of (R)- and (S)-rolipram
employed the chiral heterogeneous catalysts as key step. As part
of our ongoing research programme directed towards the
asymmetric synthesis of biologically active compounds,12 we
became interested in developing a short and efficient route to (R)-
1 and (S)-rolipram 2 with two different strategies employing the
organocatalyzed asymmetric Michael addition, Henry
condensation, Wittig olefination and reductive lactamization
reactions as the key steps.
Chirally branched pyrrolidones are among the most bioactive
heterocyclic compounds in organic chemistry due to their
ubiquitous structural motifs in natural and unnatural products
with varied biological activity.1 Among them, γ-aminobutyric
acid (GABA) and its analogues rolipram (1-2), brivaracetam 3
and (S)-pregabalin 4 are useful division of compounds possessing
interesting pharmacological activities (Fig. 1).2 The rolipram (1-
2) are simple cyclo-GABA derivative possessing a catechol type
ring at chiral carbon (C-3).3 The ( )-rolipram was discovered and
developed by Schering AG pharmaceutical company at Berlin,
Germany in early 19904 and it acts as
a selective
phosphodiesterase-4 inhibitor and potential antidepressant drug.
O
O
NH
NH
O
O
O
O
2
1
O
O
N
HO
H2N
Results and Discussion
NH2
Et
O
Our synthetic approach for the enantioselective synthesis of
pyrrolidone skeleton 5 was envisioned via the retrosynthetic
route as depicted in Scheme 1. The ester derivative 6 was
visualized as a synthetic intermediate from which pyrrolidone 5,
and rolipram (1-2) could be easily synthesized via intramolecular
cyclization under hydrogenation conditions. The ester derivative
6 in turn could be synthesized from olefin 7 or 8 by means of (R)-
and (S)-diphenylprolinolsilyl ether mediated asymmetric Michael
addition reactions followed by standard organic transformations.
4
3
Fig. 1. Some structures of GABA derivatives (1-4).
The most active enantiomer (R)-rolipram 1 is an advanced
novel class of effective antidepressant drug with additional
possible emetic,5 which act as selective inhibitor for cardiac
cyclic AMP phosphodiesterase, present in brain tissue and

2
Tetrahedron Letters
The nitro olefin derivative
7
could be derived from
12 in 87% yield (Scheme 3).11f Asymmetric Michael addition of
acetaldehyde to nitro olefin 12 in the presence of catalyst (R)-
diphenylprolinol silyl ether15 (10 mol%) in a sealed tube afforded
the nitroaldehyde adduct,16 which on spontaneous oxidation with
oxone17 and subsequent esterification using TMSCl/EtOH18
successfully furnished the ester derivative 13 in 85% yield. Our
next endeavour was to carry out the intramolecular reductive
lactamization at the nitro group site. Towards this end, nitroester
13 underwent hydrogenation in the presence of catalytic amount
of Pd/C in EtOAc/Et3N to deliver the target compound (R)-
commercially available isovanillin 9 through base catalyzed O-
alkylation and Henry condensation reaction, whereas olefinic
ester 8 could be easily synthesized from isovanillin 9 via O-
alkylation and 2C-Wittig olefination. Thus, in principle, both the
enantiomers of rolipram (1-2) along with different substitutions
at O-site could be accessed by two different approaches.
O
O
OR2
NO2
NH
R1O
O
R1O
O
∗
∗
rolipram 1 in 93% yield and >99% ee19 {[α]D −31.1 (c 1.05,
25
CH3OH), [lit.11f [α]D −31 (c 1.05, CH3OH)]}. The spectral and
25
physical data of (R)-rolipram 1 was found to be in consonance
with those reported in the literature.11c-f,i-j
5
6
R1 = cyclopentyl
R2 = Me, Et
HO
O
O
O
NO2
O
R1O
O
R3
b
a
HO
O
O
9
12
R3 = NO2,
COOEt,
9
7
O
O
8
OEt
Scheme 1. Retrosynthesis of pyrrolidone skeleton 5.
NH
O
O
NO2
O
O
c
The synthesis of (R)-rolipram 1 started with commercially
available isovanillin 9 which on treatment with
cyclopentylbromide under basic conditions followed by 2C-
Wittig olefination with (ethoxycarbonylmethylene)triphenylphos-
phorane in THF afforded the trans-olefinic ester 10 in 92% yield
13
1
Scheme 3. Reagents and conditions: (a) (i) cyclopentylbromide,
o
K2CO3, DMF, 100 C, 30 h; (ii) CH3NO2, NH4OAc, 130 C, 24 h,
o
o
(Scheme 2). The DIBAL-H reduction of ester 10 at −78 C to
87% (over two steps); (b) (i) acetaldehyde, (R)-diphenylprolinolsilyl
o
ether, 1,4-dioxane, 4 C to rt, 18 h; (ii) oxone, DMF, rt, 12 h; (iii)
α,β-unsaturated aldehyde and subsequent asymmetric Michael
oxidative esterification13 with nitromethane in the presence of
catalytic amount of (R)-diphenylprolinol silyl ether (10 mol%)
furnished the nitro aldehyde adduct which on in situ treatment
with NBS/MeOH furnished the γ-nitroester 11 in 78% yield.
O
TMSCl, EtOH, rt, 12 h, 85% (over three steps); (c) H2, Pd/C, Et3N,
EtOAc, rt, 12 h, 93%.
25
The (S)-rolipram 2 was also synthesized in >99% ee20 {[α]D
+31.8 (c 0.6, CH3OH) [lit.11j [α]D +31 (c 0.6, CH3OH)]}
rt
HO
O
a
b
OEt
following an analogous series of reactions as shown in Scheme 3
using the (S)-diphenylprolinol ether catalyst during the
asymmetric Michael addition step. The spectral and physical data
of (S)-rolipram 2 was found to be in accordance with the
literature data.11c-d,j
O
O
O
10
9
O
O
In conclusion, we have disclosed a novel, short and protecting
group free enantioselective syntheses of (R)-1 and (S)-rolipram 2
from commercially available isovanillin as a starting material
employing the (R)- and (S)-diphenylprolinol silyl ether mediated
asymmetric Michael addition reaction as key step. The overall
yields for the (R)-rolipram 1 were 66% (Scheme 2) and 69%
(Scheme 3) with two different strategies after three column
chromatographic purification steps. The merits of our synthesis
are high enantioselectivity (i.e. >99% ee) and high yielding
reaction steps. The synthetic approach also has significant
potential for the variation at O-alkyl site to synthesize various γ-
pyrrolidone derivatives with expected increase in biological
activities.
OMe
NO2
NH
O
O
O
O
c
11
1
Scheme 2. Reagents and conditions: (a) (i) cyclopentylbromide,
K2CO3, DMF, 100 oC, 30 h; (ii) PPh3CHCOOEt, THF, rt, 12 h, 92%
o
(over two steps); (b) (i) DIBAL-H, CH2Cl2, −78 C, 1 h; (ii) (R)-
diphenylprolinol silyl ether, CH3NO2, benzoic acid, MeOH, 16 h, rt;
o
(iii) NBS, 16 h, 4 C, 78% (over three steps); (c) H2, Pd/C (10%),
Et3N, EtOAc, rt, 12 h, 92%.
With enantiomerically pure ester 11 in hand, it was then
subjected to intramolecular reductive lactamization under 1 atm
H2 pressure in presence of catalytic amount of Pd/C in
EtOAc/Et3N to furnish the (R)-rolipram 1 in 92% yield and
>99% ee14 {[α]D −31.1 (c 1.05, CH3OH), [lit.11f [α]D −31 (c
1.05, CH3OH)]}. The spectroscopical and physical data of (R)-
rolipram 1 were found to be in full agreement with the literature
data.11c-f,i-j
Acknowledgments
25
25
R.K. thanks UGC, New Delhi for a MANF-Junior Research
Fellowship. S.K.P. is thankful to Department of Science and
Technology (DST-SERB), New Delhi, for generous funding of
the project (Grant No. EMR/2016/003649).
In another approach, the synthesis of (R)-rolipram 1
commenced with treatment of the isovanillin 9 with
References and notes
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4
Tetrahedron Letters
Highlights
•
•
•
•
Rolipram, an antidepressant drug and suggested
for the treatment of multiple sclerosis.
Protecting group free enantioselective synthesis
of rolipram.
TMS-prolinol mediated asymmetric Michael
addition reaction as key step.
Henry condensation and Wittig olefination
reactions.

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Efficient synthesis of (-)-(R)- and (+)-(S)-
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Ramandeep Kaur and Satyendra Kumar Pandey*