Asymmetric synthesis of 3-prenyl-substituted pyrrolidin-2-ones

Article abstract of DOI:10.1016/j.mencom.2016.11.003

Pharmacology-relevant compounds bearing structural fragments of racetam nootropics, wound-healing acyclic isoprenoids and neurotropic GABA analogues, were enantioselectively (up to 94% ee) synthesized from available and inexpensive precursors.

Full text of DOI:10.1016/j.mencom.2016.11.003

Mendeleev
Communications
Mendeleev Commun., 2016, 26, 471–473
Asymmetric synthesis of 3-prenyl-substituted pyrrolidin-2-ones
Anna A. Sukhanova,a Yulia V. Nelyubinab and Sergei G. Zlotin*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 5328; e-mail: zlotin@ioc.ac.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
DOI: 10.1016/j.mencom.2016.11.003
Me
Cygerol
Methaprogerol
Pharmacology-relevant compounds bearing structural frag-
ments of racetam nootropics, wound-healing acyclic iso-
prenoids and neurotropic GABA analogues, were enantio-
selectively (up to 94% ee) synthesized from available and
inexpensive precursors.
R
H
1,2
Phenibut
Rolipram
Pregabalin
O
N
H
up to 95:5 dr and 94% ee
R = Ph, 3-(c-C5H9O)-4-MeOC6H3, Bui
Pyrrolidin-2-one derivatives, cyclic analogues of important natural
neurotransmitter g-aminobutyric acid (GABA), exhibit useful
biological activities.1 Well known piracetam, 2-(2-oxopyrrolidin-
1-yl)acetamide, a remedy for treatment of memory disorders and
improvement of cognitive functions,2–4 appeared at pharma-
ceutical market in 1972 as ‘Nootropil’. Afterwards, a number
of other nootropic medicines containing the pyrrolidin-2-one
fragment (rolipram, pramiracetam, phenylpiracetam, aniracetam,
levetiracetam, etc.) have been developed,5–7 which are charac-
terized by higher activity, lower toxicity and minimal side effects.8,9
In spite of this positive background, a design of novel, even
more efficient, multi-target pyrrolidine-based pharmaceuticals, in
particular chiral ones, is still a challenge. These compounds may
contain two or more privileged pharmacophoric groups which
selectively bind with different cellular receptors (the concept of
‘twin drugs’).10,11 We decided to apply this concept to enantio-
selective synthesis of pyrrolidin-2-one derivatives bearing phar-
macophoric prenyl groups along with aromatic or branched aliphatic
units. Some of synthetic isoprenoids, in particular geranylacetic
acid derivatives cygerol12 and methaprogerol,13 are used for treat-
ment of injuries, burns and acute myocardial infarction. Further-
more, methaprogerol and its analogues turned to be promising
tracking drugs for cell therapy of various human diseases and
artificially induced damages of vital organs or tissues of the
laboratory animals with mesenchymal stem cell (MSC) and MSC-
derived cardiomyoblasts.14,15 On the other hand, antiepileptic
drug pregabalin,16 GABAB receptor agonist phenibut,17 and anti-
depressant rolipram18 contain linear or cyclic (pyrrolidin-2-one)
GABA structural units. Proper absolute configuration of stereo-
centers in these medications is very important as two enantiomers
would exhibit different pharmacological activities.19,20 To the
best of our knowledge, just racemic N-methyl-3-prenylpyrrolidin-
2-one21 has been synthesized so far. Herein, we report the first
enantioselective synthesis of hybrid22 compounds I which are
the structural analogues of three types of medications: racetam
nootropics, wound-healing acyclic isoprenoids and neurotropic
GABA-derived pharmaceuticals (Scheme 1).
Ph
O
MeO
O
O
N
N
H2N
H2N
O
O
O
N
H
Rolipram
Phenylpiracetam
Piracetam
According to retro-analysis (Scheme 2), a rational approach
towards I may include asymmetric addition of malonic ester to
corresponding a-nitro olefin (step 1), stereoselective reduction/
ring closure tandem reaction of the resulting Michael adduct (step 2)
and successive alkylation and decarboxylation reactions (step 3).
Me
Me
H2N
Me
O
R
H
HO
n
* *
Pregabalin
Ph
Me
Me
O
Cy
H
2
N
H
R
CO2Me
O
R
H
4
3
n
Step 3
Step 1
Step 2
* *
*
*
I (n = 1, 2)
R = Ph, Bui,
3-(c-C5H9O)-4-MeOC6H3
H2N
Phenibut
O
HO
O
HO
O
Cygerol
(Cy = cyclohexyl)
N
H
N
H
I (n = 1, 2)
MeO2C
CO2Me
MeO2C
CO2Me
NO2
Me
H
2
+
*
R
NO2
R
Me2N HO
O
R = Ph, 3-(c-C5H9O)-4-MeOC6H3, Bui
Methaprogerol
Scheme 1
Scheme 2
© 2016 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 471 –

Mendeleev Commun., 2016, 26, 471–473
Catalytic conjugate addition of malonic and acetoacetic deriva-
were synthesized similarly with the use of DABCO30 or DBU31
(for rac-2c) as a base.
tives to a-nitro olefins provides a simple and efficient route to
g-nitro carboxylic acids which are close precursors to valuable
analogues of GABA and naturally occurring g- and d-lactones.23–25
Among known (organo)catalysts for asymmetric versions of
these reactions, thiourea-derived tertiary amine C1, developed
by Takemoto,26,27 is one of the most useful. We applied catalyst
C1 to enantioselective synthesis of nitro esters (R)-2a,b and (S)-2c
from a-nitro olefins 1a–c and dimethyl malonate (Scheme 3).†
To attain high efficacy of the reactions, we slightly modified the
reported procedures.26–29 In particular, lowering reaction tempe-
rature (10°C vs. room temperature) and catalyst loading (5 mol%
vs. 10 mol%) improved the enantiomeric enrichment (96% vs.
86% ee) of product (R)-2a, though, at the expence of increased
reaction time (16 h vs. 9 h).26 To the best of our knowledge,
adduct (R)-2b has not been prepared in the presence of catalyst
C1 so far. Importantly, the reactions allowed one to perform a
gram-scale synthesis of nitro esters 2. Compounds rac-2a–c
Reductive cyclization of enantiomerically enriched and racemic
compounds 2a–c was effectively achieved with NaBH4 (12 equiv.)/
NiCl2·6H2O (1 equiv.) system in methanol32 to afford corre-
sponding pyrrolidin-2-one derivatives 3a–c as anti-diastereo-
mers (according to 1H NMR data and literature33–35). Compounds
(3S,4R)-3a and (3S,4R)-3b have not been reported so far, though,
their enantiomers are known.33,34
At first, we treated pyrrolidin-2-ones 3a–c with prenyl bromide
4 or geranyl chloride 4' in the presence of KOH/Et3NBnCl
phase-transfer catalytic system. However, these reactions were
accompanied by polymerization and/or hydrolysis, whatever
solvent was used (MeCN, toluene, DMSO or DMF) and these
side reactions significantly complicated isolation of products.
We succeeded to improve chemoselectivity of the alkylation
reactions by performing them with sodium metal in refluxing
toluene to furnish the corresponding compounds 5a–c or 5c' as a
mixture of isomers with respect to quaternary carbon atom C-3
in 53–59% isolated yield.
NaBH4 /
CH2(CO2Me)2
C1 (5 mol%)
MeO2C
CO2Me
NO2
NiCl2 · 6H2O
(12:1)
The basic hydrolysis36/thermal decarboxylation29 reactions of
compounds 5 furnished the synthesis of pyrrolidin-2-ones 6a–c
or 6c' in 64–75% yields over two steps. According to 1H NMR
data (two sets of signals for the CH proton of the prenyl group or
for each of two geminal CH2 protons of the pyrrolidine unit),
products 6 consist of two diastereomers in up to 95:5 ratio (see
Online Supplementary Materials). The single crystal X-ray dif-
fraction study definitely proved anti-configuration of substituents
in the pyrrolidine ring for the major isomer of rac-6b, which was
isolated from the mixture of diastereomers by column chromato-
graphy on silica gel and crystallized from hexane–diethyl ether
(Figure 1).‡ By analogy, the same anti-configuration was assigned
to major isomers of products 6a, 6c and 6c' (H–H coupling
constants for protons C3H and C4H were uninformative in this
case because of significant overlapping between corresponding
signals in the mixtures of isomers).
NO2
R
MeOH
66–71%
PhMe or CH2Cl2 (for 1c)
10 °C, 16 h–7 days
75–91%
1a–c
R
(R)-2a, 96% ee
(R)-2b, 90% ee
(S)-2c, 81% ee
Me
CO2Me
R
R
4
CO2Me
3
PreBr (4) or
GerCl (4') (for 3c)
H
n
Na/PhMe, reflux
53–59%
O
O
N
N
H
H
(3S,4R)-3a,b
(3S,4S)-3c
5a–c, 5c'
Me
S
R
(R)
(R)
H
n
Ar
i, KOH, MeOH
ii, PhMe, reflux
N
N
H
H
NMe2
64–75% (2 steps)
O
N
C1
H
We have not succeeded in obtaining suitable for the X-ray
study single crystal of enantiomerically enriched compound 6b.
However, similarity of the ee values between key intermediates
2 and major isomers of corresponding compounds 6 strongly
testified to the retention of absolute configuration of stereo-
center C4 during alkylation/hydrolysis/decarboxylation reac-
Ar = 3,5-(CF3)2C6H3
(3S,4R)-6a (dr 70:30, 94% ee)
(3S,4R)-6b (dr 60:40, 91% ee)
(3S,4S)-6c (dr 75:25, 72% ee)
(3S,4S)-6c' (dr 95:5, 69% ee)
a R = Ph
a–c n = 1
c' n = 2
b R = 3-(c-C5H9O)-4-MeOC6H3
c R = Bui
Dimethyl (S)-2-(4-methyl-1-nitropent-2-yl)malonate (S)-2c. Dimethyl
malonate (0.26 g, 1.9 mmol) and catalyst C1 (40 mg, 5 mol%) were
added to a stirred solution of nitro alkene 1c (0.25 g, 1.9 mmol) in dry
dichloromethane (2 ml). The resulting mixture was stirred at 10°C under
argon for 40 h and passed through a silica gel pad to remove the catalyst
(eluent, EtOAc). The filtrate was concentrated in vacuo and the residue was
purified by column chromatography [silica gel, n-hexane–EtOAc (10:1)]
Scheme 3
†
Dimethyl (R)-2-(2-nitro-1-phenylethyl)malonate (R)-2a and dimethyl
(R)-2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-nitroethyl]malonate
(R)-2b (general procedure). Dimethyl malonate (1.24 g, 9.4 mmol) and
catalyst C1 (100 mg, 5 mol%) were added to a stirred solution of nitro
alkene 1a or 1b (4.7 mmol) in dry toluene (10 ml). The resulting mixture
was stirred at 10°C under argon for 16 h (for 1a) or 7 days (for 1b) and
passed through a silica gel pad to remove the catalyst (eluent, EtOAc).
The filtrate was concentrated in vacuo and the residue was purified by
column chromatography (silica gel, n-hexane–EtOAc, 7:1) to afford
(R)-2a or (R)-2b.
For (R)-2a: 1.20 g (91%). Colourless solid, mp 59–60°C (lit.,30 60–61°C).
1H NMR (300 MHz, CDCl3) d: 3.58 (s, 3H), 3.78 (s, 3H), 3.88 (d, 1H,
J 8.9 Hz), 4.23–4.30 (m, 1H), 4.86–4.98 (m, 2H), 7.23–7.38 (m, 5H).
According to HPLC [AD-H, n-hexane–PriOH (7:3), 0.7 ml min–1, 220 nm;
tminor = 22.7 min; tmajor = 24.0 min], enantiomeric purity of the product
was 96% ee.
For (R)-2b: 1.62 g (87%). Colourless solid, mp 88–90°C (lit.,35 94–96°C).
1H NMR (300 MHz, CDCl3) d: 1.59–1.67 (m, 2H), 1.78–1.99 (m, 6H),
3.59 (s, 3H), 3.78 (s, 3H), 3.82 (s, 3H), 3.86 (d, 1H, J 9.5 Hz), 4.13–4.21
(m, 1H), 4.75–4.88 (m, 3H), 6.74–6.82 (m, 3H). According to HPLC
[OJ, n-hexane–PriOH (7:3), 1 ml min–1, 220 nm; tmajor = 11.4 min; tminor
= 13.4 min], enantiomeric purity of the product was 90% ee.
1
to afford 0.35 g (75%) of (S)-2c as colourless oil. H NMR (300 MHz,
CDCl3) d: 0.91–0.94 (m, 6H), 1.29–1.35 (m, 2H), 1.61–1.72 (m, 1H),
2.91–3.02 (m, 1H), 3.67 (d, 1H, J 5.5 Hz), 3.77 (s, 3H), 3.78 (s, 3H),
4.53 (dd, 1H, J 13.4 and 6.4 Hz), 4.71 (dd, 1H, J 13.4 and 5.3 Hz).31,33
According to HPLC [AD-H, n-hexane–PriOH (98:2), 0.7 ml min–1, 210 nm;
tminor = 11.0 min; tmajor = 11.6 min], enantiomeric purity of the product
was 81% ee.
Full experimental details are given in Online Supplementary Materials.
X-ray data. Crystals of rac-6b (C21H29NO3, M = 343.45) are mono-
‡
clinic, space group P21/n, at 120 K: a = 12.885(2), b = 6.5217(11) and
c = 23.341(4) Å, b = 105.094(4)°, V = 1893.7(6) Å3, Z = 4 (Z' = 1),
dcalc = 1.205 g cm–3, m(MoKa) = 0.80 cm–1, F(000) = 744. Intensities of
18823 reflections were measured with a Bruker SMART APEX2 CCD
diffractometer [l(MoKa) = 0.71072 Å, w-scans, 2q < 54°], and 4142
independent reflections (Rint = 0.0929) were used in further refinement.
CCDC 1492244 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
=
– 472 –

Mendeleev Commun., 2016, 26, 471–473
References
C(21)
O(3)
C(8)
1 A. H. Gouliaev and A. Senning, Brain Res. Rev., 1994, 19, 180.
2 C. Giurgea and M. Salama, Prog. Neuro-Psychopharmacol., 1977, 1, 235.
3 B. Winblad, CNS Drug Rev., 2005, 11, 169.
4 T. Waegemans, C. R. Wilsher, A. Danniau, S. H. Ferris, A. Kurz and
B. Winblad, Dement. Geriatr. Cogn. Disord., 2002, 13, 217.
5 A. G. Malykh and M. R. Sadaie, Drugs, 2010, 70, 287.
6 P. C. R. Wheble, E. S. Sena and M. R. Macleod, Cerebrovasc. Dis.,
2008, 25, 5.
C(14)
C(12)
C(9)
C(7)
C(5)
C(15)
C(10)
C(3)
C(13)
C(6)
O(2)
C(11)
C(4)
C(1)
C(16)
C(20)
C(19)
C(2)
7 F. Gualtieri, D. Manetti, M. N. Romanelli and C. Ghelardini, Curr. Pharm.
Des., 2002, 8, 125.
8 J. De Reuck and B. Van Vleymen, Pharmacopsychiatry, 1999, 32, 33.
9 M. Koskiniemi, B. VanVleymen, L. Hakamies, S. Lamusuo and J. Taalas,
J. Neurol. Neurosurg. Psychiatry, 1998, 64, 344.
O(1)
C(17)
C(18)
N(1)
Figure 1 General view of rac-6b major diastereomer as revealed by X-ray
diffraction; atoms are shown as thermal ellipsoids at 50% probability level.
10 H. Fujii, Top. Curr. Chem., 2011, 299, 239.
11 J.-M. Contreras and W. Sippl, in The Practice of Medicinal Chemistry,
3rd edn., ed. C. G. Wermuth,Academic Press,Amsterdam, 2008, pp. 380–414
.
tion sequence. Basing on these results, we assigned (3S,4R)
absolute configuration to major isomers of compounds 6a,b and
(3S,4S) configuration – to major isomers of compounds 6c and
6c'. Note that the configuration of stereocenter C4 in the obtained
products 6 corresponds to most active enantiomers of medications
phenibut, rolipram and pregabalin.17,19,20
A synthetic utility of the developed approach to pharmaco-
logy-oriented pyrrolidin-2-one isoprenoid derivatives was further
demonstrated by N-functionalization reactions of racemic com-
pounds 6c and 6c' to afford novel 1,3,4-trisubstituted pyrrolidones
7–11 and 7'–11' (Scheme 4).
12 (a) L. S. Bondar and R. A. Okunev, British Patent GB 1173419, 1969
(Chem. Abstr., 1970, 72, 54770f); (b) L. S. Bondar and R. A. Okunev,
German Patent DE 1801868, 1970 (Chem. Abstr., 1970, 73, 34814r);
(c) L. S. Bondar and R. A. Okunev, Avtorskoe svidetel’stvo SSSR 333162,
1972 (Chem. Abstr., 1972, 77, 100910e); (d) J. Nichols and G. F. Bulbenko,
German Patent DE 2335067, 1974 (Chem. Abstr., 1976, 80, 146380x).
13 (a) L. S. Bondar and R. A. Okunev, German Patent DE 2153832, 1973
(Chem. Abstr., 1973, 79, 42708y); (b) L. S. Bondar and R. A. Okunev, US
Patent 3991086, 1976 (Chem. Abstr., 1976, 86, 105925j); (c) L. S. Bondar,
R. A. Okunev, L. V. Polezhaev, S. P. Kolchin, L. V. Cherkasova and L. F.
Nikolaeva, US Patent 4495201, 1985 (Chem. Abstr., 1985, 102, 172652e).
14 B. B. Smirnov, G. V. Kryshtal, A. G. Konopljannikov, S. G. Zlotin and
G. M. Zhdankina, RF Patent RU 2301667, 2007 (Chem. Abstr., 2007,
147, 110262).
15 G.V. Kryshtal, G. M. Zhdankina,A. G. Konoplyannikov,V.A. Tartakovsky,
E. P. Serebryakov, B. B. Smirnov, O. A. Konoplyannikova, E. V. Agaeva
and S. G. Zlotin, Russ. Chem. Bull., Int. Ed., 2012, 61, 253 (Izv. Akad.
Nauk, Ser. Khim., 2012, 253).
16 K. Hamandi and J. W. Sander, Seizure, 2006, 15, 73.
17 I. Lapin, CNS Drug Rev., 2001, 7, 471.
O
O
O
Boc2O
DMAP/NEt3
R
R
R
MeI/NaH
NMe
8 or 8'
NBoc
7 or 7'
NH
CH2Cl2,
99%
THF
83–87%
Bui
Bui
Bui
6c or 6c'
NaH THF
18 J. Zhu, E. Mix and B. Winblad, CNS Drug Rev., 2001, 7, 387.
19 F. Ohsawa, M.Yamauchi, H. Nagaso, S. Murakami, J. Baba and A. Sawa,
Jpn. J. Pharmacol., 1998, 77, 147.
20 C. P. Taylor, M. G. Vartanian, Y. Po-Wai, C. Bigge, N. Suman-Chauhan
and D. R. Hill, Epilepsy Res., 1993, 14, 11.
21 B. Coates, D. J. Montgomery and P. J. Stevenson, Tetrahedron, 1994,
50, 4025.
22 V. P. Ananikov, E. A. Khokhlova, M. P. Egorov, A. M. Sakharov, S. G.
Zlotin, A. V. Kucherov, L. M. Kustov, M. L. Gening and N. E. Nifantiev,
Mendeleev Commun., 2015, 25, 75.
28–32% BrCH2CO2Et
55%
4'
O
62–69% BrCH2CH=CMe2
R
4
N
O
N
Bui
Me
CO2Et
R
11 or 11'
O
Bui
Me
R
10 or 10'
2 H
N
23 O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem., 2002, 12,
1877.
Me
Bui
H
Me
R =
24 (a) A. Z. Halimehjani, I. N. N. Namboothiri and S. E. Hooshmand, RSC
Adv., 2014, 4, 31261; (b) A. Z. Halimehjani, I. N. N. Namboothiri and
S. E. Hooshmand, RSC Adv., 2014, 4, 48022; (c) A. Z. Halimehjani,
I. N. N. Namboothiri and S. E. Hooshmand, RSC Adv., 2014, 4, 51794.
25 A. Yu. Sukhorukov, A. A. Sukhanova and S. G. Zlotin, Tetrahedron,
2016, 72, 6191.
n
9 or 9'
7–11 n = 1
7'–11' n = 2
Scheme 4
In conclusion, we have developed an efficient approach to
enantioselective synthesis of novel pharmacology-relevant prenyl-
substituted pyrrolidin-2-ones from available and inexpensive
starting compounds (a-nitro olefins, dimethyl malonate, prenyl
halides). A favorable combination of privileged pharmacophoric
fragments (pyrrolidin-2-one unit, aryl and/or branched alkenyl
groups) and proper configuration of key stereocenters allow one
to consider the prepared compounds as prospective candidates to
further biological studies.
26 T. Okino,Y. Hoashi, T. Furukawa, X. Xu andY. Takemoto, J. Am. Chem.
Soc., 2005, 127, 119.
27 T. Okino,Y. Hoashi andY. Takemoto, J. Am. Chem. Soc., 2003, 125, 12672.
28 M. Hestericova and R. Šebesta, Tetrahedron, 2014, 70, 901.
29 J.-M. Liu, X. Wang, Z.-M. Ge, Q. Sun, T.-M. Cheng and R.-T. Li,
Tetrahedron, 2011, 67, 636.
30 P. Jakubec, D. M. Cockfield, M. Helliwell, J. Raftery and D. J. Dixon,
Beilstein J. Org. Chem., 2012, 8, 567.
31 L. Thijs, US Patent 312560 A1, 2009.
32 F. Li, Y.-Z. Li, Z.-S. Jia, M.-H. Xu, P. Tian and G.-Q. Lin, Tetrahedron,
2011, 67, 10186.
33 H. Y. Bae and C. E. Song, ACS Catal., 2015, 5, 3613.
34 R. Perlikowska, J. Piekielna, M. Mazur, R. Koralewski, J. Olczak, J.-C.
do Rego, J. Fichna, J. Modranka, T. Janecki and A. Janecka, Bioorg.
Med. Chem., 2014, 22, 4803.
35 P. S. Hynes, P. A. Stupple and D. J. Dixon, Org. Lett., 2008, 10, 1389.
36 (a) A. Padwa and A. T. Price, J. Org. Chem., 1998, 63, 556;
(b) A. Civitavecchia, G. Martelli, M. Orena and S. Rinaldi, Amino
Acids, 2014, 46, 1097.
This research was supported by the Russian Science Founda-
tion (project no. 14-50-00126). The authors are grateful to
Dr. A. S. Kucherenko for performing the HPLC analysis of
chiral products.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2016.11.003.
Received: 28th July 2016; Com. 16/5012
– 473 –