Synthesis of Chiral 3,4-Disubstituted Pyrrolidines with Antibacterial Properties

Article abstract of DOI:10.1002/ejoc.202000235

Chiral aliphatic heterocycles are important structural feature of many pharmaceutical agents. Antibiotic resistance is a serious medical problem, therefore new antibacterial compounds are urgently needed. Herein, we describe synthesis of a series of 3,4-disubstituted pyrrolidine derivatives via organocatalytic Michael addition followed by reductive cyclization. These compounds inhibited growth of standard as well as methicillin-resistant strains of Escherichia coli and Staphylococcus aureus.

Full text of DOI:10.1002/ejoc.202000235

A Journal of
Accepted Article
Title: Synthesis of chiral 3,4-disubstituted pyrrolidines with antibacterial
properties
Authors: Lenka Rodriguez, Roman Fisera, Barbora Gaálová, Kamila
Koci, Helena Bujdakova, Maria Meciarova, Renata Gorova,
Helena Jurdakova, and Radovan Sebesta
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000235
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000235
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10.1002/ejoc.202000235
European Journal of Organic Chemistry
FULL PAPER
Synthesis of chiral 3,4-disubstituted pyrrolidines with
antibacterial properties
Lenka Rodriguez,[a] Roman Fišera,[a] Barbora Gaálová,[b] Kamila Koči, [b] Helena Bujdáková,[b] Mária
Mečiarová, [c] Renáta Górová,[d] Helena Jurdáková,[d] and Radovan Šebesta*[c]
antipsychotic drugs remoxipride and asenapine also belong to the
group of pyrrolidine based pharmaceuticals.[4] Sulfonamide
derivatives of pyrrolidine are promising therapeutics for the
treatment of type 2 diabetes.[5]
Abstract: Chiral aliphatic heterocycles are important structural
A number of pyrrolidine derivatives with antimicrobial activities
feature of many pharmaceutical agents. Antibiotic resistance is a
were described in the literature.[6] Le Goffic proved that pyrrolidine
serious medical problem, therefore new antibacterial compounds are
moiety increased antibiotic activity of lincosamide antibiotics.[7]
urgently needed. Herein, we describe synthesis of a series of 3,4-
Highly substituted methoxyquinolines with pyrrolidine heterocycle
disubstituted pyrrolidine derivatives via organocatalytic Michael
exhibited potent in vitro antibacterial activity against various
addition followed by reductive cyclization. These compounds inhibited
respiratory
pathogens,
including
multidrug-resistant
growth of standard as well as methicillin-resistant strains of
Streptococcus pneumoniae and Staphylococcus aureus.[8] Poly-
hydroxypyrolidine inhibitor was effective against both
Mycobacterium tuberculosis as well as Streptomyces coelicolor.[9]
Zhang et al. tested novel benzofuroxan-based pyrrolidine
hydroxamates as matrix metalloproteinase inhibitors.[10] They
found a derivative demonstrating competitive antitumor activity in
vivo. Reddy et al. recently synthetized several pyrrolidine
chalcone derivatives with anticancer, anti-inflammatory as well as
antibacterial activities.[11] Some derivatives were efficient against
Escherichia coli and Staphylococcus aureus.
Introduction
Efficient organic synthetic methodologies are indispensable for
sustaining development of new drugs.[1] Construction and
manipulation of saturated nitrogen heterocycles has been named
as one of the challenges of the modern organic synthesis within
the framework of drug synthesis.[2] Especially, five-membered
nonaromatic nitrogen-containing heterocycles exhibit important
pharmacological activities. Pyrrolidine structure occurs in many
natural compounds, e.g. nicotine, hygrine, mesembrine,
slaframine, or kainic acid. Several marketed drugs, such as
almotriptan for treating migraines, asimadoline – k-opioid agonist,
mitiglidine – antidiabetic drug, or procyclidine – anticholinergic
drug also contain a pyrrolidine moiety.[3] Antiseizure drug
ethosuximide, muscle relaxant rocuronium, antibiotic clindamycin,
Staphylococcus
aureus,
Enterococcus
faecalis,
and
Mycobacterium tuberculosis.[12] Efficiency against M. tuberculosis
seems promising, as compounds with pyrrolidinone or pyrrolidine
cores are able to interact with the enoyl-acyl carrier protein
reductase, the essential enzyme for synthesis of the M.
tuberculosis cell wall.[13]
Antimicrobial activity against S. aureus and E. coli (Gram-positive
and Gram-negative bacteria, respectively) is very interesting as
well as representatives of both species often manifest resistance
to generally available antimicrobial agents.[14] Moreover, they are
frequently associated with biofilm infection in patients with
indwelling medical devices.[15] Methicillin resistant S. aureus
(MRSA) or E. coli possessing resistance to a wide-spectrum beta-
lactams or aminoglycosides are a serious medical problem.[16]
According to World Health Organization antibiotic resistance is
one of the biggest threats to global health, food security, and
development today. Therefore, searching for new compounds
with antimicrobial properties is an essential challenge.
[a]
[b]
L. Rodriguez, Dr. R. Fišera
SYNKOLA Ltd.
Ilkovičova 6, 84215, Bratislava, Slovakia
Dr. B. Gaálová, Dr. K. Koči, Prof. Dr. H. Bujdáková
Department of Microbiology, Faculty of Natural Sciences
Comenius University in Bratislava
Various synthetic strategies are available for stereoselective
construction pyrrolidine core such as dipolar cycloadditions of
azomethine ylides,[17] or various reductive amination strategies.[18]
In the last two decades, stereoselective organocatalysis
developed into one of the pillars of asymmetric catalysis
Mlynská dolina, Ilkovičova 6, 84215 Bratislava, Slovakia
[c]
[d]
Prof. M. Mečiarová, Prof. Dr. R. Šebesta
Department of Organic Chemistry, Faculty of Natural Sciences
Comenius University in Bratislava
Mlynská dolina, Ilkovičova 6, 84215 Bratislava, Slovakia
E-mail: radovan.sebesta@uniba.sk
comparable
Organocatalytic methodologies served well also in syntheses of
medicinally important and bioactive
compounds.[20]
with
metal-catalysis
and
biocatalysis.[19]
Homepage: www.radovansebesta.com
Dr. R. Gorová, Dr. H. Jurdáková
Organocatalyzed Michael additions are among the most robust
and reliable methodologies, which enable introduction of non-
trivial functional groups and can lead to complex molecular
architectures with desired functions.[21]
Institute of Chemistry, Faculty of Natural Sciences
Comenius University in Bratislava
Mlynská dolina, Ilkovičova 6, 84215 Bratislava, Slovakia
In this context, we decided to prepare a series of new chiral
pyrrolidines with potential antibacterial activities. As a vehicle for
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.202000235
European Journal of Organic Chemistry
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pyrrolidine construction, we have employed organocatalytic
Michael addition of aldehydes to nitroalkenes. Stereoselective
Michael additions with enolizable carbonyl compounds proceed
well via enamine activation.[22] This robust Michael addition
provides key chiral intermediates, -nitroaldehydes which are
subjected to reductive cyclization (Scheme 1).[23] In this paper, we
present synthesis of a series of chiral 3,4-disubstituted pyrrolidine
derivatives and evaluation of their antibacterial activities.
stable and usually provides consistently good results in catalysis.
We have observed epimerization of Michael adducts during
chromatographic purification. Diastereomeric ratio for adducts 3
changed in favor of anti-minor isomer during the column
chromatography. Interestingly, trituration of the crude products 3
with Et2O gave pure syn-adducts 3 without necessity of column
chromatography.
Scheme 1. Concept of this work.
Results and Discussion
Synthesis of pyrrolidines
The first step of the synthesis of chiral pyrrolidines was Michael
addition of aldehydes 2a-f to nitroalkene 1 (Scheme 2). We have
focused on the 2-phthalimido-1-nitroethene (1) as an acceptor
because phthalimido group provides convenient synthetic handle
for further transformations. Nitroalkene 1 has been used in
several organocatalytic transformations.[24] Ma and coworkers
employed nitroalkene 1 in the Michael reactions with aldehydes
during their investigations of organocatalytic synthesis of
Scheme 2. Organocatalytic Michael addition of aldehydes 2a-f to nitroalkene 1.
Absolute configuration of Michael adducts were assigned by
comparison of sign of optical rotation and chiral HPLC data for
compound 3a with those reported in the work of Ma.[24a]
Stereochemistry of Michael adducts can be rationalized via
application of Seebach-Golinski model for enamine additions to
nitroalkenes.[27] Here, (E)-anti enamine generated from an
aldehyde and catalyst C1 attack with its Re face a nitroalkene
from its Si face. Enamine and nitroalkene are positioned in
synperiplanar arrangement due to attractive electrostatic
interaction between nitrogens in enamine and nitro group. This
arrangement provides syn-adducts with (S,S)-configurations
(Scheme 3a).
We have calculated corresponding transition states for the
Michael addition of aldehyde 2a and nitroalkene 1 with catalyst
C1. Geometries were obtained using long-range corrected
hybrid density ωB97X-D functional with 6-31G* basis set.[28]
Energies were refined at ωB97X-D/6-311+G** level using C-PCM
(Et2O) solvation model.[29] These calculations show that preferred
transition state is 16.7 kJ/mol more favorable than the minor one.
This difference is probably due to steric hindrance between
approaching nitroalkene and CPh2(OTMS) moiety (Scheme 3b).
oseltamivir.[24a] The combination of diethyl ether as a solvent and
25]
Hayashi-Jørgensen catalyst C1[22a,
gave the adducts in
satisfactory yields with high diastereoselectivity and high
enantiomeric purity of syn-adducts (Table 1). Inspired by the work
of Ma, and our previous experiences,[24a, 26] we have performed
the reaction in chloroform at first. In order to simplify purification
and isolation of the Michael adduct, we tested several other
solvents such as dichloromethane, methyl(tert-butyl)ether, THF,
1,4-dioxane, 2-methyltetrahydrofurane, and diethylether. The use
of Et2O retained high enantiomeric and diastereomeric purities,
and allowed isolation of the major diastereomer of products 3 by
trituration. Low diastereoselectivity (3:1) as well as somewhat
lower enantioselectivity (85 % ee) were observed in the case of
adduct 3d (Table 1, entry 4). To increase stereoselectivity, we
performed Michael addition of aldehyde 2d under various reaction
conditions. We managed to increase the diastereoselectivity to
10:1 using the C2 catalyst, but the conversion dropped below
10 %. (S)-Proline (C3) and pyrrolidine-substituted squaramide C4
were much less active. As we focused on practicality of this work,
we did not continue with larger catalyst screening. We have
continued to use catalysts C1, which is commercially available,
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10.1002/ejoc.202000235
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4e was prepared under modified conditions (AcOH/H2O/1,4-
dioxane; ultrasonic irradiation in a cleaning bath for 1 h, then
magnetic stirring at room temperature for 22 h, because of poor
solubility of the corresponding Michael adduct 3e. During the
reductive cyclization, one carbonyl group in isoindoline-1,3-dione
moiety was also reduced.
Scheme 4. Reductive cyclization of Michael adducts 3a-f.
Owing to the next reaction steps, it was necessary to protect
secondary amino group of pyrrolidines 4a-f. We used tert-
butoxycarbonyl, mesyl and tosyl protecting groups (Scheme 5).
Boc-protected pyrrolidine 5a-f were directly used in the next
reaction step without any further purification. Pyrrolidines 5g and
5h were obtained after column chromatography with the yields of
82 and 85 %, respectively. The next reaction step was oxidation
of 3-hydroxyisoindolin-1-one moiety of compounds 5a-h with
pyridinium dichromate (PDC) to isoindoline-1,3-dione moiety
(Scheme 4). The corresponding products 6a-h were obtained in
63–89 % yields after column chromatography (average values of
several experiments). Nitroalkene 1 has solubility similar with the
Michael adducts 3a-f and their mixtures are difficult to separate
by trituration with Et2O. Fortunately, the nitroalkene 1 did not
influence the next reaction steps and it was separated later. An
important feature of this synthetic method is that only one column
chromatography is necessary for these four reaction steps
sequence. The overall procedure comprising Michael addition,
reductive cyclization, pyrrolidine protection, and oxidation of
hemiaminal corresponding products in overall yields up to 60 %.
Scheme 3. a) Stereochemical model of the Michael addition of aldehydes 2a-f
to nitroalkene 1 catalyzed with C1; b) transition states calculated at the ωB97X-
D/6-311+G** (Et2O)//ωB97X-D/6-31G* level of theory.
Table 1. Organocatalytic Michael addition of aldehydes 2a-f to nitroalkene 1
using C1.
Entry
X
Solvent
Time (h)
Yield [a]
Syn/anti[b]
ee
(syn)[c]
1
2
3
4
5
6
H
CHCl3
Et2O
Et2O
Et2O
Et2O
Et2O
18[d]
23[e]
23[e,f]
23[e]
40[e]
24[d]
41 (3a)
70 (3b)
69 (3c)
64 (3d)
84 (3e)
31 (3f)
10:1
20:1
20:1
3:1
97
4-Cl
4-F
92
99
4-CF3
3-Cl
3-CF3
85
77:1
80:1
99[g]
99
[a] Yield of major isomer gained by trituration with Et2O; [b] dr was
determined by 1H NMR of crude reaction mixture; [c] ee was determined by
HPLC on IC Chiralpak column; [d] 10 mol% of catalyst C1 were used; [e] 15
mol% of catalyst C1 were used; [f] 13 mol% of acetic acid were used; [g]
determined after derivatization with Wittig reagent Ph3PCHCO2Et.
The pyrrolidine scaffold was synthesized by reductive cyclization
of Michael adducts 3. A reduction of nitro group with freshly
activated zinc was followed by intramolecular cyclization leading
to pyrrolidine 4 (Scheme 4). The yields (62–91 %) of pyrrolidines
4a-f represent average values of several experiments. Pyrrolidine
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10.1002/ejoc.202000235
European Journal of Organic Chemistry
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Scheme 5. Protection and subsequent oxidation of pyrrolidine 4a-f.
Scheme 7. Hydrazinolysis of phthalimido group (a); preparation of sulfonamides
9a,b (b).
A series of protected pyrrolidines 6a-h has been extended to
derivatives 6i-l with substituted benzyl group on nitrogen. They
were prepared in two steps. After the Boc-group deprotection with
4M HCl, reductive amination afforded corresponding benzyl
derivatives 6i-l in high yields (81–92 %) (Scheme 6).
In order to increase their solubility in aqueous media for the needs
of biological tests hydrochlorides of pyrrolidines 4a-f, 8a-l, and
9a,b were prepared using 4 M HCl in dioxane. The hydrochlorides
were isolated after trituration with Et2O as solids in the yields over
85
% (Scheme 8). For more details see Supplementary
Information.
Scheme 6. Preparation of pyrrolidines 6i-l.
Phthalimido protection group was removed in the next step by
hydrazinolysis. The deprotection was performed at room
temperature in most cases, except for substrates 6e and 6g,
which had to be subjected to hydrazinolysis at 50 °C. The
products 8a-l were obtained in yields of 55–92 % after column
chromatography (Scheme 7a).
Sulfonamides 9a,b were prepared from amine 8a by the same
procedure as sulfonamides 5g,h. Both products were obtained in
high yields after column chromatography (Scheme 7b).
Scheme 8. Preparation of hydrochlorides 10a-l and 11a-h.
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10.1002/ejoc.202000235
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Biological evaluation
5
6
7
11f
0.164 / 0.328
2.149 / 4.298
0.425 / 3.407
0.164 / 0.128
2.149 / 4.298
0.853 / 3.407
Initially, hydroxyisoindolinone derivative 5g was screened for
antimicrobial activity on both standard strains of E. coli and S.
aureus with MIC50 and MIC100 1.25 and 2.5 mg/mL, respectively
(3.23 mmol/L, and 6.47 mmol/L).
11g
11h
Then, two representatives of phthalimido substituted pyrrolidines
6g and 6h were tested for antimicrobial activity on both bacteria;
MIC50 were 1.25 mg/mL (3.25, and 2.71 mmol/L) and MIC100 2.5
or > 2.5 mg/mL (6.50, and 5.43 mmol/L).
Hydrochlorides 10b-l were screened for antimicrobial properties
on both standard strains of E. coli and S. aureus. Results are
summarized in Table 2.
The most efficient derivatives, 10i-k and 11d-f were also tested
on resistant strains of E. coli and S. aureus (Table 4). Obtained
efficiencies on resistant strains determined in the MIC50 or MIC100
were the same or very close to those estimated for sensitive
standard strains. The derivative 10i proved to be the most efficient
with MIC50 and MIC100 17 and 37 μmol/L, respectively, for both
resistant bacteria. The same efficient concentrations suggest
similar mechanisms of action on both Gram-positive and Gram-
negative bacteria.
Table 2. Antimicrobial activity of hydrochlorides of pyrrolidines 10b-l
on bacteria of E. coli and S. aureus.
Entry
Compound
Effectiveness in MIC50 / MIC100 [mmol/L]
Table 4. Antimicrobial activity of hydrochlorides of pyrrolidines 10i-k and
11d-f
E. coli
S. aureus
on resistant bacteria of E. coli and S. aureus.
1
10b
10c
10d
10e
10f
0.180 / 1.440
0.387 / 1.511
0.164 / 0.328
0.360 / 0.720
0.656 / 1.313
> 1.719
0.180 / 0.720
0.189 / 1.511
0.164 / 0.328
0.360 / 1.440
1.313 / 1.313
> 1.719
2
3
4
5
Entry
Compound
Effectiveness in MIC50
[mmol/L]
/ MIC100
6
10g
10h
10i
E. coli R
S. aureus R
7
0.341 / 0.681
0.017 / 0.037
0.084 / 0.170
0.087 / 0.176
0.356 / 0.713
0.341 / 1.363
0.017 / 0.037
0.084 / 0.170
0.087 / 0.176
0.356 / 0.713
1
2
10i (X = 4-Cl, R = 4-CF3Bn)
0.017 / 0.027
0.017 / 0.037
8
10j (X
= 4-Cl, R = 4-
0.084 / 0.340
0.087 / 0.176
0.164 / 0.328
0.170 / 0.340
0.086 / 0.176
0.081 / 0.164
9
10j
OMeBn)
10
11
10k
10l
3
4
10k (X = 4-F, R = 4-ClBn)
11d (X = 4-CF3, R = 3-
hydroxyisoindoline-1-one)
5
6
11e (X
hydroxyisoindoline-1-one)
= 3-Cl, R = 3-
0.360 / > 1.440
0.328 / 0.656
0.360 / 1.440
0.328 / 0.656
We have evaluated antimicrobial activity also for hydroxyindoline
derivative 11a-f as well as for mesyl and tosyl derivatives 11g and
11h (Table 3).
11f (X
hydroxyisoindoline-1-one)
= 3-CF3, R =3-
Table 3. Antimicrobial activity of hydrochlorides of pyrrolidines 11b-h
on bacteria of E. coli and S. aureus.
Entry
Compound
Effectiveness in MIC50 / MIC100 [mmol/L]
Conclusions
E. coli
S. aureus
1
2
3
4
11b
11c
11d
11e
0.360 / 0.720
0.756 / 1.511
0.164 / 0.328
0.360 / 0.720
0.360 / 0.720
0.756 / 1.511
0.081 / 0.164
0.180 / 0.360
A series of chiral 3,4-disubstituted pyrrolidines was prepared via
organocatalytic Michael addition of enolizable aldehydes to
nitroalkenes. Michael adducts were formed as syn-diastereomers
with high enantiomeric purities. These adducts were then
reductively cyclized to corresponding trans-3,4-disubstituted
pyrrolidines by zinc in acetic acid. Pyrrolidines with phthalimido,
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10.1002/ejoc.202000235
European Journal of Organic Chemistry
FULL PAPER
not successfully achieved. HRMS-ESI+ (m/z): calculated for
[C19H15FN2O5+CH3OH+Na]+: 425.1119; found 425.1123.
sulphonamide or free amine group were subjected to antibacterial
tests.
Some of compounds selected for antimicrobial testing proved to
be efficient and inhibited growth of E. coli and S. aureus bacterial
strains regardless of their susceptibility/resistance pattern.
Activity against methicillin-resistant strains is of particular interest.
The compound 10i manifested excellent antimicrobial properties
and will be assumed for another study.
(2S,3S)-3-(1,3-dioxoisoindolin-2-yl)-4-nitro-2-(4-
(trifluoromethyl)benzyl)butanal (3d). White solid (64 %). M. p.: 133−137
20
°C. [α]D = -14.8 (c 0.75, CHCl3). IR (FTIR): ν 1774, 1711, 1559, 1322,
1065, 1016, 717, 625, 530, 499 cm−1. 1H NMR (600 MHz, CDCl3): δ 9.76
(s, 1H), 7.70 (s, 2H), 7.29 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 5.37
(td, J = 10.5, 3.2 Hz, 1H), 5.18 (dd, J = 13.0, 10.7 Hz, 1H), 4.85 (dd, J =
13.3, 3.1 Hz, 1H), 3.81 (dd, J = 16.2, 7.8 Hz, 1H), 3.16 (dd, J = 14.6, 6.3
Hz, 1H), 2.79 (dd, J = 14.7, 8.2 Hz, 1H). 13C NMR (151 MHz, CDCl3): δ
199.4, 167.5, 140.0, 134.6, 130.8, 129.2 (q, JC-F =32.7 Hz), 128.7, 125.5
(q, JC-F =3.8 Hz), 123.6 (q, JC-F = 273.3 Hz), 123.5, 73.5, 51.2, 48.0, 33.1.
HPLC: Chiralpak IA column, hexane/i-PrOH 80:20, 221 nm, flow rate 0.60
Experimental Section
General procedure for synthesis of chiral nitroaldehydes 3a-f
mL/min,
ee
85
%.
HRMS-ESI+
(m/z):
calculated
for
[C20H15F3N2O5+CH3OH+Na]+: 475.1087; found 475.1094.
(E)-2-(2-nitrovinyl)isoindoline-1,3-dione (1) (1.09 g, 5.0 mmol) was added
to the solution of aldehyde 2a-f (10 mmol) in solvent (14 mL containing
0.08 % water) at 0 °C. Next, the solution of catalyst C1 (167–254 mg, 0.5–
0.75 mmol) in solvent (1 mL) and acetic acid (0.05–0.10 mL, 0.65–1.5
mmol) were added in one portion. The reaction mixture was stirred at 0 °C
for 30 min and then 18−40 h at 22 °C. The reaction mixture was
concentrated under vacuum to afford crude product as a mixture of
diastereomers. The crude product was triturated with diethyl ether to give
one diastereomer. Products were obtained as white solids and directly
used to the following reaction step without purification, which was not
necessary.
(2S,3S)-2-(3-chlorobenzyl)-3-(1,3-dioxoisoindolin-2-yl)-4-nitrobutanal
(3e). White solid (84 %). M. p.: 183−186 °C. [α]D20 = -4.9 (c 0.55, CHCl3).
IR (FTIR): ν 1770, 1705, 1556, 1362, 999, 718 cm−1. 1H NMR (600 MHz,
CDCl3): δ 9.74 (s, 1H), 7.74 (dd, J = 21.8, 2.6 Hz, 4H), 7.06−7.00 (m, 2H),
6.91 (m, 2H), 5.34 (dd, J = 10.3, 7.6 Hz, 1H), 5.24−5.13 (m, 1H), 4.83 (dd,
J = 13.3, 2.9 Hz, 1H), 3.75 (dd, J = 17.0, 7.7 Hz, 1H), 3.03 (dd, J = 14.7,
7.0 Hz, 1H), 2.74 (dd, J = 14.6, 7.5 Hz, 1H). 13C NMR (151 MHz, CDCl3):
δ 199.8, 167.5, 137.9, 134.6, 134.5, 130.9, 130.0, 128.6, 127.0, 126.6,
123.7, 73.5, 51.2, 47.9, 33.0. HPLC: The product 3e was not determined
by HPLC because of poor solubility in the most of organic solvents. HRMS-
ESI+ (m/z): calculated for [C19H15ClN2O5+CH3OH+Na]+: 441.0824; found
441.0827.
Characterization data of nitroaldehydes 3a-f
(2S,3S)-2-benzyl-3-(1,3-dioxoisoindolin-2-yl)-4-nitrobutanal
(3a).
(2S,3S)-3-(1,3-dioxoisoindolin-2-yl)-4-nitro-2-(3-
20
White solid (41 %). M. p.: 129−130 °C. [α]D -36.2 (c 0.55, CHCl3). IR
(FTIR): ν 1771, 1706, 1560, 1380, 1231, 717, 480 cm−1. 1H NMR (300 MHz,
CDCl3): δ 9.72 (s, 1H), 7.81−7.67 (m, 4H), 7.16−6.97 (m, 5H), 5.35 (td, J =
10.4, 3.4 Hz, 1H), 5.18 (dd, J = 13.1, 10.4 Hz, 1H), 4.83 (dd, J = 13.1, 3.4
Hz, 1H), 3.76 (dd, J = 17.5, 7.6 Hz, 1H), 3.00 (dd, J = 14.5, 7.8 Hz, 1H),
2.80 (dd, J = 14.5, 7.8 Hz, 1H). HPLC: Chiralpak IC column, hexane/i-
PrOH 60:40, 254 nm, flow rate 0.75 mL/min, ee 97%. Spectral data are in
agreement with data published in literature.[24a]
(trifluoromethyl)benzyl)butanal (3f). White solid (31 %). M. p.: 118−120
°C. [α]D20 = -21.5 (c 1, CHCl3). IR (FTIR): ν 1770, 1707, 1559, 1324, 1126,
897, 719 cm−1. 1H NMR (600 MHz, CDCl3): δ 9.76 (s, 1H), 7.77−7.67 (m,
4H), 7.31-7.20 (m, 4H), 5.36 (td, J = 10.3, 3.5 Hz, 1H), 5.18 (dd, J = 13.3,
10.3 Hz, 1H), 4.84 (dd, J = 13.4, 3.5 Hz, 1H), 3.80 (dd, J = 17.0, 6.9 Hz,
1H), 3.13 (dd, J = 14.8, 6.9 Hz, 1H), 2.84 (dd, J = 14.8, 7.6 Hz, 1H). 13
C
NMR (151 MHz, CDCl3): δ 199.6, 167.5, 136.9, 134.5, 131.7, 131.0 (q, JC-
F = 32.4 Hz), 130.8, 129.2, 125.1 (q, JC-F = 3.7 Hz), 123.7 (q, JC-F = 3.5 Hz),
123.7, 123.6 (q, JC-F = 272.4 Hz), 73.5, 51.2, 47.9, 33.1. HPLC: Chiralpak
IC column, hexane/i-PrOH 60:40, 254 nm, flow rate 0.75 mL/min, ee 99 %.
HRMS-ESI+ (m/z): calculated for [C20H15F3N2O5+CH3OH+Na]+: 475.1087;
found 475.1092.
(2S,3S)-2-(4-chlorobenzyl)-3-(1,3-dioxoisoindolin-2-yl)-4-nitrobutanal
(3b). White solid (70 %). M. p.: 162−164 °C. [α]D20 = -11.9 (c 1, CHCl3). IR
.
(FTIR): ν 1771, 1703, 1552, 1369, 1132, 1092, 858, 719, 528 cm−1 1H
NMR (600 MHz, CDCl3): δ 9.73 (s, 1H), 7.79−7.70 (m, 4H), 7.04 (d, J = 8.3
Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 5.34 (td, J = 10.3, 3.3 Hz, 1H), 5.17 (dd,
J = 13.2, 10.5 Hz, 1H), 4.82 (dd, J = 13.3, 3.4 Hz, 1H), 3.73 (dd, J = 17.3,
7.4 Hz, 1H), 3.02 (dd, J = 14.6, 7.1 Hz, 1H), 2.74 (dd, J = 14.6, 7.6 Hz, 1H).
13C NMR (151 MHz, CDCl3): δ 199.9, 167.6, 134.6, 134.3, 132.8, 131.0,
129.8, 128.8, 123.6, 73.6, 51.2, 48.0, 32.8. HPLC: Chiralpak IC column,
hexane/i-PrOH 68:32, 221 nm, flow rate 0.65 mL/min, ee 92 %. HRMS-
ESI+ (m/z): calculated for [C19H15ClN2O5+CH3OH+Na]+: 441.0824; found
441.0826.
General procedure for reductive cyclization of nitroaldehydes 3a-f
Freshly activated zinc powder (2.35 g, 36.0 mmol) was added to the
suspension of Michael adduct 3a-f (2.4 mmol) in acetic acid/water (1:1, 40
mL) at 0 °C in three portions over the period of 10 min. The reaction
mixture was stirred at room temperature for 18−20 h. When the full
conversion was observed (TLC), the pH of reaction mixture was adjusted
to 12 with 4 M NaOH solution. The white colloid was filtered out and filtrate
was extracted with DCM (3100 mL). The combined organic layers were
washed with brine (1100 mL) and dried over anhydrous Na2SO4. The
solvent was evaporated under vacuum. The products 4a-f were obtained
as yellowish foams and directly used to the next reaction step.
(2S,3S)-3-(1,3-dioxoisoindolin-2-yl)-2-(4-fluorobenzyl)-4-nitrobutanal
(3c). White solid (69 %). M. p.: 140−141 °C. [α]D20 = -24.8 (c 1, CHCl3). IR
.
(FTIR): ν 1771, 1709, 1550, 1355, 1002, 720 cm−1 1H NMR (600 MHz,
CDCl3): δ 9.72 (s, 1H), 7.81−7.76 (m, 2H), 7.75−7.71 (m, 2H), 7.03 (dd, J
= 8.2, 5.3 Hz, 2H), 6.79 (t, J = 8.5 Hz, 2H), 5.34 (td, J = 10.3, 3.4 Hz, 1H),
5.17 (dd, J = 13.2, 10.4 Hz, 1H), 4.82 (dd, J = 13.3, 3.4 Hz, 1H), 3.72 (dd,
J = 17.2, 7.5 Hz, 1H), 2.99 (dd, J = 14.6, 7.6 Hz, 1H), 2.78 (dd, J = 14.7,
Characterization data for pyrrolidine 4a-f
2-((3S,4R)-4-benzylpyrrolidin-3-yl)-3-hydroxyisoindolin-1-one
(4a).
7.1 Hz, 1H). 13C NMR (151 MHz, CDCl3): δ 200.2, 167.6, 161.7 (d, JC-F
=
White foam (87 %). M. p.: 69−72 °C. IR (FTIR): ν 2923, 2851, 1675, 1412,
1372, 1207, 1056, 745, 696, 530, 479 cm−1. 1H NMR (600 MHz, CDCl3): δ
7.79−7.74 (m, 1H), 7.57−7.54 (m, 2H), 7.51−7.45 (m, 1.5), 7.26−7.22 (m,
246.3 Hz), 134.6, 131.5, 130.0, 123.7, 115.7, 115.5, 73.6, 51.4, 47.9, 32.6.
HPLC: Chiralpak IC column, hexane/i-PrOH 70:30, 221 nm, flow rate 0.60
mL/min, ee 99 %. Satisfactory separation of peaks of the racemate was
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000235
European Journal of Organic Chemistry
FULL PAPER
1H), 7.21−7.14 (m, 3.5), 5.97 (s, 0.5H), 5.89 (s, 0.5H), 4.92−4.88 (m, 0.5H),
4.57−4.54 (m, 0.5H), 4.17 (bs, 2H), 3.51 (d, J = 11.3 Hz, 0.5H), 3.41 (dd,
J = 10.3, 8.2 Hz, 0.5H), 3.30−3.20 (m, 1H), 3.17 (dd, J = 11.6, 7.1 Hz,
0.5H), 3.11 (dd, J = 10.5, 6.1 Hz, 0.5H), 3.02 (dd, J = 13.6, 6.0 Hz, 0.5H),
2.89 (dt, J = 13.9, 11.2 Hz, 0.5H), 2.83−2.73 (m, 1H), 2.72−2.64 (m, 1H),
2.64−2.58 (m, 1H). Spectral data are in agreement with data published in
literature.[24a]
3.50 (d, J = 11.2 Hz, 0.5H), 3.41 (dd, J = 13.6, 4.8 Hz, 1H), 3.22−3.17 (m,
0.5H), 3.15 (d, J = 10.2 Hz, 0.5H), 3.09 (dd, J = 11.2, 6.3 Hz, 0.5H), 3.04
(dd, J = 10.1, 5.7 Hz, 1H), 2.78−2.71 (m, 0.5H), 2.67−2.61 (m, 1.5H), 2.58
(dd, J = 13.6, 11.3 Hz, 0.5H), 2.51 (dd, J = 9.7, 8.2 Hz, 0.5H), 2.02−1.50
(bs, 1H). 13C NMR (151 MHz, CDCl3): δ 167.3&166.9, 143.4&143.3,
141.6&141.1, 134.3&134.1, 132.2&132.0, 131.41, 129.9&129.7,
129.5&129.4, 128.9&128.8, 127.0&126.8, 126.7&126.4, 123.3&123.1,
123.1&123.1, 81.0&79.9, 56.9&55.8, 51.9&51.7, 51.4&43.4, 49.2&47.8,
40.0&39.7. HRMS-ESI+ (m/z): calculated for [C19H19ClN2O2+H]+:
343.1208; found: 343.1211.
2-((3S,4R)-4-(4-chlorobenzyl)pyrrolidin-3-yl)-3-hydroxyisoindolin-1-
one (4b). White foam (86 %). M. p.: 79−81 °C. [α]D20 +35.0 (c 0.8, CHCl3).
IR (FTIR): ν 2925, 2855, 1674, 1407, 1056, 745, 695 cm−1. 1H NMR (600
MHz, CDCl3): δ 7.78 (dd, J = 13.0, 7.5 Hz, 1H), 7.58−7.54 (m, 2H),
7.52−7.46 (m, 1H), 7.23 (dd, J = 15.8, 8.4 Hz, 2H), 7.15−7.09 (m, 2H), 6.07
(s, 0.5H), 5.97 (s, 0.5H), 4.89 (d, J = 11.2 Hz, 0.5H), 4.54 (dd, J = 5.7, 2.2
Hz, 0.5H), 3.49 (d, J = 11.2 Hz, 0.5H), 3.43−3.35 (m, 1.5H), 3.21−3.16 (m,
0.5H), 3.13 (d, J = 10.2 Hz, 0.5H), 3.08 (dd, J = 11.3, 6.2 Hz, 0.5H),
3.05−2.99 (m, 1H), 2.77−2.69 (m, 0.5H), 2.68−2.58 (m, 2.5H), 2.53−2.46
(m, 0.5H), 2.31 (bs, 1H). 13C NMR (151 MHz, CDCl3): δ 167.4&167.0,
143.5&143.4, 138.0&137.5, 132.3&132.2, 132.0&131.9, 133.0&131.3,
130.1&130.0, 129.5&129.4, 128.7&128.5, 123.3&123.1, 123.1&123.0,
81.1&79.9, 56.8&56.3, 51.7&51.6, 51.2&43.3, 49.0&47.5, 39.4&39.2.
HRMS-ESI+ (m/z): calculated for [C19H19ClN2O2+H]+: 343.1208; found:
343.1210.
3-Hydroxy-2-((3S,4R)-4-(3-(trifluoromethyl)benzyl)pyrrolidin-3-
yl)isoindolin-1-one (4f). White foam (82 %). M. p.: 78−80 °C. [α]D20 +27.1
(c 1, CHCl3). IR (FTIR): ν 3283, 2924, 1675, 1413, 1325, 1116, 1070, 746,
1
658 cm−1. H NMR (600 MHz, CDCl3): δ 7.78 (dd, J = 15.2, 7.5 Hz, 1H),
7.59−7.54 (m, 3H), 7.53−7.35 (m, 5H), 6.08 (s, 0.5H), 5.99 (s, 0.5H), 4.90
(dd, J = 5.2 Hz, 0.5H), 4.56 (dd, J = 6.0, 2.2 Hz, 0.5H), 3.52-3.47 (m, 1H),
3.40 (dd, J = 9.5, 7.9 Hz, 0.5H), 3.21−3.13 (m, 1.5H), 3.13−3.08 (m, 0.5H),
3.06 (dd, J = 10.2, 5.4 Hz, 0.5H), 2.81−2.76 (m, 1H), 2.76−2.69 (m, 1H),
2.69−2.61 (m, 0.5H), 2.51 (dd, J = 9.7, 8.2 Hz, 0.5H), 1.60 (s, 1H). 13C
NMR (151 MHz, CDCl3): δ 167.3&166.9, 143.4&143.4, 140.6&140.1,
132.2&132.1, 132.0&131.9, 131.4&131.4, 130.9&130.7 (q, J = 32.1 Hz),
129.5&129.4, 129.1&128.7, 125.4&125.3 (q, JC-F = 3.8 Hz), 123.6&123.5
(q, JC-F = 272.4 Hz), 123.4&123.1 (q, JC-F = 3.7 Hz), 123.3&123.1,
123.1&123.0, 81.0&79.9, 57.0&55.9, 52.0&51.8, 51.4&43.4, 49.3&47.9,
40.1&39.9. HRMS-ESI+ (m/z): calculated for [C20H19F3N2O2+H]+:
377.1471; found: 377.1472.
2-((3S,4R)-4-(4-fluorobenzyl)pyrrolidin-3-yl)-3-hydroxyisoindolin-1-
one (4c). White foam (91 %). M. p.: 64−65 °C. [α]D20 +28.4 (c 1, CHCl3).
IR (FTIR): ν 3284, 2921, 2855, 1676, 1507, 1217, 745 cm−1. 1H NMR (600
MHz, CDCl3): δ 7.77 (dd, J = 12.2, 7.5 Hz, 1H), 7.56 (t, J = 7.9 Hz, 2H),
7.52−7.44 (m, 1H), 7.16−7.11 (m, 2H), 6.95 (dt, J = 15.9, 8.6 Hz, 2H), 6.02
(s, 0.5H), 5.97 (s, 0.5H), 4.88 (d, J = 5.2 Hz, 0.5H), 4.53-4.50 (m, 0.5H),
3.46 (d, J = 11.2 Hz, 0.5H), 3.42−3.37 (m, 0.5H), 3.34 (dd, J = 13.6, 4.9
Hz, 0.5H), 3.21−3.15 (m, 0.5H), 3.12 (d, J = 10.1 Hz, 0.5H), 3.07 (dd, J =
11.2, 6.3 Hz, 0.5H), 3.04−2.99 (m, 1H), 2.73 (ddd, J = 10.6, 5.1, 2.9 Hz,
0.5H), 2.68−2.55 (m, 2H), 2.50 (dd, J = 17.4, 7.9 Hz, 0.5H), 2.40−2.35 (bs,
1H), 1.67 (bs, 1H). 13C NMR (151 MHz, CDCl3): 167.3&166.9, 161.5 (d, J
= 244.6 Hz)&161.4 (d, J = 244.3 Hz), 143.6&143.5, 135.3 (d, J =3.1
Hz)&134.8 (d, J = 3.2 Hz), 132.15&132.0, 132.0&131.4, 130.2&130.1,
130.1&130.0, 129.5&129.4, 123.3&123.1, 123.0&123.0, 115.4&115.3,
115.2&115.1, 81.2&79.9, 57.0&55.8, 51.9&51.8, 51.4&43.6, 49.4&48.0,
39.4&39.2. HRMS-ESI+ (m/z): calculated for [C19H19FN2O2+H]+:
327.1503; found: 327.1503.
N-Boc protected pyrrolidines 5a-f
Triethylamine (0.28 mL, 1.95 mmol) and di-tert-butyl dicarbonate (340 mg,
1.56 mmol) were at 0 °C added to the solution of pyrrolidine 4a-f (1.30
mmol) in DCM (19.8 mL). The reaction mixture was stirred at 0 °C for 30
min (the starting material was totally, monitored by TLC). The reaction
mixture was then quenched with 10 % aqueous citric acid solution (30 mL)
and then was extracted with DCM (380 mL). The combined organic layers
were washed with brine (1150 mL) and dried over Na2SO4. The solvent
was evaporated under reduced pressure. N-Boc protected pyrrolidines 5a-
f were obtained as dark yellow foams and directly used to the next reaction
step without purification and characterization.
N-sulfonamides 5g-h
3-hydroxy-2-((3S,4R)-4-(4-(trifluoromethyl)benzyl)pyrrolidin-3-
yl)isoindolin-1-one (4d). White foam (62 %). M. p.: 68−70 °C. [α]D
20
Triethylamine (0.21 mL, 1.5 mmol) and methansulfonyl chloride or p-
toluenesulfonyl chloride (1.2 mmol) were at 0 °C added to the solution of
pyrrolidine 4a (1 mmol) in DCM (15 mL). The reaction mixture was stirred
at this temperature for 1−3 h. The reaction mixture was poured into water
(20 mL) and then extracted with DCM (350 mL). The combined organic
layers were dried over Na2SO4. Solvent was evaporated under reduced
pressure. The crude products were purified by column chromatography
using hexanes/EtOAc (2:1) as an eluent. Pyrrolidines 5g,h were obtained
as white foams.
+23.0 (c 1, CHCl3). IR (FTIR): ν 3000, 2899, 1731, 1631, 1454, 1347, 1145,
1
717 cm−1. H NMR (600 MHz, CDCl3): δ 7.78 (dd, J = 14.1, 7.5 Hz, 1H),
7.59−7.55 (m, 1.5), 7.53 (dd, J = 11.4, 8.1 Hz, 2.5), 7.48 (dd, J = 7.9, 4.0
Hz, 0.5H), 7.30 (t, J = 8.6 Hz, 2H), 6.05 (s, 0.5H), 5.97 (s, 0.5H), 4.92 (dd,
J = 5.2 Hz, 0.5H), 4.57 (dd, J = 4.0 Hz, 0.5H), 3.52 (dd, J = 11.3 Hz, 0.5H),
3.49-3.39 (m, 1.5H), 3.20 (t, J = 9.7 Hz, 1H), 3.16−3.06 (m, 2H), 2.81 (dd,
J = 3.2 Hz, 1H), 2.78−2.63 (m, 3H), 2.55−2.50 (m, 0.5H). 13C NMR (151
MHz, CDCl3): 167.4&167.0, 143.5&143.4, 143.6&143.1, 132.3&132.1,
131.9&131.3, 129.6&129.5, 129.1&128.9, 129.2&129.0, 128.8&128.5,
125.5 (q, J = 3.6 Hz)&125.3 (q, 3.7 Hz), 124.2 (q, J = 271.7 Hz)&124.1 (q,
2-((3S,4R)-4-Benzyl-1-(methylsulfonyl)pyrrolidin-3-yl)-3-
hydroxyisoindolin-1-one (5g). White foam (82 %). M. p.: 70−73 °C. [α]D
J
= 271.8 Hz), 123.3&123.0, 123.1&123.0, 81.1&79.9, 56.9&55.7,
20
51.6&51.6, 51.3&43.1, 49.0&47.4, 39.9&39.6. HRMS-ESI+ (m/z):
calculated for [C20H19F3N2O2+H]+: 377.1471; found: 377.1474.
-3.1 (c 1.05, CHCl3). IR (FTIR): ν 3352, 2924, 1670, 1322, 1147, 1039, 74,
697 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.75 (d, J = 8.1 Hz, 1H), 7.76−7.46
(m, 3H), 7.23−6.99 (m, 5H), 5.65 (d, J = 11.2 Hz, 0.5H), 5.54 (d, J = 11.4
Hz, 0.5H), 4.54 (dd, J = 17.3, 8.5 Hz, 0.5H), 4.38 (dd, J = 17.5, 8.7 Hz,
0.5H), 4.12 (dd, J = 14.3, 7.1 Hz, 0.5H), 3.82−3.57 (m, 2.5H), 3.38 (dt, J =
16.2, 8.5 Hz, 0.5H), 3.23-3.06 (m, 1.5), 3.02-2.90 (m, 0.5H), 2.87 (d, J =
3.1 Hz, 3H), 2.82−2.51 (m, 2.5H). 13C NMR (151 MHz, CDCl3): δ 167.6
(2), 143.4 (2), 138.7&138.3, 132.71, 131.2&130.9, 130.2&130.1, 128.6
2-((3S,4R)-4-(3-chlorobenzyl)pyrrolidin-3-yl)-3-hydroxyisoindolin-1-
one (4e). White foam (78 %). M. p.: 97−100 °C. [α]D20 +26.3 (c 1, CHCl3).
IR (FTIR): ν 3054, 2853, 1674, 1412, 1373, 1055, 746 cm−1. 1H NMR (600
MHz, CDCl3): δ 7.79 (dd, J = 14.4, 7.5 Hz, 1H), 7.60−7.54 (m, 2H),
7.53−7.44 (m, 1H), 7.24−7.11 (m, 3H), 7.11−7.02 (m, 1H), 6.08 (s, 0.5H),
5.99 (s, 0.5H), 4.89 (dd, J = 5.3 Hz, 0.5H), 4.55 (dd, J = 5.9, 2.2 Hz, 0.5H),
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10.1002/ejoc.202000235
European Journal of Organic Chemistry
FULL PAPER
(2), 128.6&128.5, 126.5 (2), 123.4&123.3, 123.2&123.1, 82.2&81.6,
56.5&55.8, 51.9&51.7, 49.6&48.9, 42.4&41.9, 37.8&37.6, 35.1&34.9.
HRMS-ESI+ (m/z): calculated for [C20H22N2O4S+Na]+: 409.1192; found:
409.1194.
Tert-butyl
(3R,4S)-3-(4-chlorobenzyl)-4-(1,3-dioxoisoindolin-2-yl)
pyrrolidine-1-carboxylate (6b). White solid (66 %). M. p.: 139−140 °C.
[α]D20 +4.4 (c 1, CHCl3). IR (FTIR): ν 2974, 1684, 1388, 1127, 712 cm−1
.
1H NMR (600 MHz, CDCl3): δ 7.72−7.67 (m, 4H), 6.99 (d, J = 8.1 Hz, 2H),
6.94 (t, J = 6.3 Hz, 2H), 4.52 (dd, J = 19.4, 10.1 Hz, 1H), 3.83−3.60 (m,
3H), 3.53−3.40 (m, 1H), 3.07 (dd, J = 19.5, 10.1 Hz, 1H), 2.83 (td, J = 14.3,
2-((3S,4R)-4-Benzyl-1-tosylpyrrolidin-3-yl)-3-hydroxyisoindolin-1-
one (5h). White foam (85 %). M. p.: 77−79 °C. [α]D20 +17.3 (c 0.7, CHCl3).
IR (FTIR): ν 3359, 2922, 1672, 1335, 1153, 1033, 746, 661, 546 cm−1. 1H
NMR (300 MHz, CDCl3): δ 7.69 (t, J = 8.1 Hz, 3H), 7.62−7.52 (m, 1H),
7.52−7.42 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.21−6.97 (m, 5H), 5.60 (d, J
= 10.0 Hz, 1H), 4.47−4.26 (m, 1H), 4.17−4.03 (m, 0.5H), 3.72−3.45 (m,
2.5H), 3.29−3.19 (m, 0.5H), 3.00−2.89 (m, 1.5H), 2.87−2.77 (m, 1H),
2.79−2.54 (m, 2H), 2.46 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 167.7 (2),
143.9&143.6, 143.6, 138.9&138.3, 133.1&133.0, 132.6 (2), 131.0&130.8,
129.9 (2), 129.8, 128.6&128.5, 128.4, 127.6&127.5, 126.4 (2),
123.2&123.0, 123.2 (2), 81.8&81.2, 55.9&55.3, 51.7&51.6, 49.9&49.1,
42.1&41.7, 37.8&37.7, 21.6. HRMS-ESI+ (m/z): calculated for
[C26H25N2O4S+H]+: 485.1505; found: 485.1507.
6.1 Hz, 1H), 2.54 (dd, J = 13.9, 8.8 Hz, 1H), 1.46 (d, J = 19.5 Hz, 9H). 13
C
NMR (151 MHz, CDCl3): δ 167.9, 154.2 (154.1)*, 136.8, 164.1 (164.0)*,
132.0, 131.3, 129.7, 128.3, 123.0, 79.7, 53.7 (53.2)*, 50.2 (49.7)*, 47.0
(46.6)*, 39.6 (38.9)*, 36.9 (36.8)*, 28.5 (28.4)*. (*Rotamers) HRMS-ESI+
(m/z): calculated for [C24H25ClN2O4+Na]+: 463.1395; found: 463.1400.
Tert-butyl
pyrrolidine-1-carboxylate (6c). White solid (63 %). M. p.: 147−149 °C.
[α]D20 +6.5 (c 0.8, CHCl3). IR (FTIR): ν 2697, 1690, 1686, 1125, 715 cm−1
(3S,4R)-3-(1,3-dioxoisoindolin-2-yl)-4-(4-fluorobenzyl)
.
1H NMR (600 MHz, CDCl3): δ 7.75−7.64 (m, 4H), 7.02 (dd, J = 7.6, 5.8 Hz,
2H), 6.68 (t, J = 8.3 Hz, 2H), 4.56−4.49 (m, 1H), 3.78 (dt, J = 18.4, 9.2 Hz,
1H), 3.76−3.67 (m, 1H), 3.63 (t, J = 9.3 Hz, 1H), 3.45 (ddd, J = 25.8, 17.5,
8.0 Hz, 1H), 3.07 (dd, J = 18.2, 10.3 Hz, 1H), 2.82 (dd, J = 13.6, 6.4 Hz,
1H), 2.61−2.52 (m, 1H), 1.46 (d, J = 19.1 Hz, 9H). 13C NMR (151 MHz,
CDCl3): δ 167.9, 161.2 (d, JC-F = 244.6 Hz), 154.2, 134.0 (d, J = 4.1 Hz),
134.0 (d, J = 2.9 Hz), 131.4 (d, J = 4.7 Hz), 129.8 (t, J = 7.6 Hz), 123.0,
114.9 (d, J = 21.2 Hz), 79.6, 53.8 (53.3)*, 50.2 (49.7)*, 47.0 (46.6)*, 39.7
(39.2)*, 36.7 (36.6)*, 28.5 (28.4)*. (*Rotamers) HRMS-ESI+ (m/z):
calculated for [C24H25FN2O4+Na]+: 447.1691; found: 447.1694.
Oxidation of 3-hydroxyisoindolinones 5a-h
Pyridinium dichromate (PDC) (978 mg, 2.6 mmol) was at RT added to the
solution of pyrrolidine 5a-h (1.30 mmol) in DMF (10 mL) and the reaction
mixture was stirred at room temperature for 1 h. Reaction mixture was
poured into cold water (100 mL) and extracted with EtOAc (3120 mL).
The combined organic layers were washed with brine (1150 mL) and
dried over Na2SO4. Solvent was evaporated under reduced pressure. The
crude product was purified on silica gel column (hexanes/EtOAc 4:1). Full-
protected pyrrolidines 6a-h were obtained as white solids.
Tert-butyl (3S,4R)-3-(1,3-dioxoisoindolin-2-yl)-4-(4-(trifluoromethyl)
benzyl)pyrrolidine-1-carboxylate (6d). White solid (76 %). M. p.
135−138 °C. [α]D20 +8.4 (c 1, CHCl3). IR (FTIR): ν 1690, 1688, 1387, 1317,
1119, 1063, 716 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.65 (d, J = 5.6 Hz,
4H), 7.21 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 4.54 (dd, J = 19.1,
10.2 Hz, 1H), 3.84 (dd, J = 10.7, 8.1 Hz, 1H), 3.81−3.76 (m, 1H), 3.75−3.66
(m, 1H), 3.66−3.48 (m, 1H), 3.14−3.07 (m, 1H), 3.00−2.93 (m, 1H),
2.64−2.57 (m, 1H), 1.47 (d, J = 22.3 Hz, 9H). 13C NMR (151 MHz, CDCl3):
δ 168.0, 154.4 (154.3)*, 142.7, 134.3 (d, J = 9.6 Hz), 131.3 (d, J = 4.3 Hz),
128.9 (d, J = 5.8 Hz), 128.4 (q, JC-F = 32.5 Hz), 125.2 (q, JC-F = 3.5 Hz),
124.87, 123.1, 80.0, 54.0 (53.4)*, 50.4 (49.9)*, 47.2 (46.8)*, 39.7 (39.0)*,
37.6 (37.5)*, 28.7 (28.6)*. (*Rotamers) HRMS-ESI+ (m/z): calculated for
[C25H25F3N2O4+Na]+: 497.1659; found: 497.1661.
Preparation of N-Benzyl pyrrolidine derivatives (in two steps):
The 4 M HCl in 1,4-dioxane (3.3 mmol, 0.80 mL) was added to the solution
of pyrrolidine 6b,c (0.33 mmol) in DCM/MeOH (1:1, 4 mL) at room
temperature. The reaction mixture was stirred at this temperature for 23 h.
When full conversion was achieved (TLC), the solvents were evaporated
under reduced pressure to give hydrochloride. The products 7a,b were
obtained by trituration in diethyl ether as light yellow solids (quant. yields)
and directly used to the next reaction step.
Tert-butyl
(3R,4S)-3-(3-chlorobenzyl)-4-(1,3-dioxoisoindolin-2-yl)
Triethylamine (0.99 mmol, 0.13 mL), aldehyde (0.33 mmol) and sodium
triacetoxyborohydride (0.48 mmol, 101 mg) were added at room
temperature to the suspension of hydrochloride 7a,b in THF (4.4 mL). The
reaction mixture was stirred at room temperature for 20 h. Reaction
mixture was then diluted in water (40 mL) and extracted with DCM (370
mL). The combined organic layers were dried over Na2SO4 and the solvent
was evaporated under vacuum. Crude products were purified by column
chromatography (hexanes/EtOAc 4:1−2:1).
pyrrolidine-1-carboxylate (6e). White solid (81 %). M. p.: 125−126 °C.
[α]D20 +1.2 (c 1, CHCl3). IR (FTIR): ν 2970, 1720, 1694, 1386, 1155, 1116,
882, 715, 531 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.74−7.69 (m, 2H), 7.67
(dd, J = 5.2, 2.9 Hz, 2H), 7.04 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.91 (d, J
= 7.7 Hz, 1H), 6.72 (d, J = 6.9 Hz, 1H), 4.52 (dt, J = 10.1, 8.2 Hz, 1H), 3.80
(dt, J = 10.7, 4.6 Hz, 1H), 3.77−3.67 (m, 1H), 3.63 (t, J = 9.4 Hz, 1H),
3.56−3.40 (m, 1H), 3.08 (td, J = 10.7, 4.6 Hz, 1H), 2.84 (dd, J = 13.7, 6.0
Hz, 1H), 2.58-2.52 (m, 1H), 1.46 (d, J = 20.2 Hz, 9H). 13C NMR (151 MHz,
CDCl3): δ 167.8, 154.2 (154.1)*, 140.4, 133.9, 133.9, 131.3, 129.5, 128.5,
126.6, 126.0, 123.0, 79.7, 53.8 (53.7)*, 50.1 (49.6)*, 46.9 (46.5)*, 36.64
(39.0)*, 37.2 (37.1)*, 28.5 (28.4)*. (*Rotamers) HRMS-ESI+ (m/z):
calculated for [C24H25ClN2O4+Na]+: 463.1395; found: 463.1403.
Characterization data for protected pyrrolidines 6a-l
Tert-butyl (3R,4S)-3-benzyl-4-(1,3-dioxoisoindolin-2-yl)pyrrolidine-1-
20
carboxylate (6a). White solid (66 %). M. p.: 107−109 °C. [α]D +5.0 (c
0.75, CHCl3). IR (FTIR): ν 2976, 2924, 1693, 1387, 1152, 880, 702, 650,
530 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.69 (t, J = 6.7 Hz, 4H), 7.06 (d, J
= 7.2 Hz, 2H), 6.99 (t, J = 7.5 Hz, 2H), 6.79 (t, J = 7.1 Hz, 1H), 4.54 (dd, J
= 19.9, 9.8 Hz, 1H), 3.76 (ddd, J = 14.7, 10.5, 6.3 Hz, 2H), 3.36−3.57 (m,
1H), 3.56−3.40 (m, 1H), 3.09 (t, J = 10.6 Hz, 1H), 2.84 (dd, J = 13.7, 6.6
Hz, 1H), 2.60 (dd, J = 13.7, 8.2 Hz, 1H), 1.58-1.40 (m, 9H) 13C NMR (151
MHz, CDCl3): 167.9, 154.2, 138.4, 131.7, 128.4, 128.2, 125.8, 123.0, 79.6,
53.8 (53.2)*, 50.3 (49.8)*, 47.0 (46.6)*, 39.9 (39.2)*, 37.5 (37.4)*,
Tert-butyl (3S,4R)-3-(1,3-dioxoisoindolin-2-yl)-4-(3-(trifluoromethyl)
benzyl)pyrrolidine-1-carboxylate (6f). White solid (89 %). M. p.: 46−48
°C. [α]D20 +4.4 (c 0.75, CHCl3). IR (FTIR): ν 2974, 1710, 1687, 1383, 1325,
1160, 1117, 881, 716, 529 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.69−7.63
(m, 4H), 7.32 (s, 1H), 7.12 (t, J = 7.7 Hz, 2H), 7.05-7.02 (m, 1H), 4.60−4.51
(m, 1H), 3.84−3.77 (m, 1H), 3.77−3.72 (m, 1H), 3.72−3.61 (m, 1H),
3.60−3.47 (m, 1H), 3.10 (t, J = 10.6 Hz, 1H), 2.93 (dd, J = 13.8, 6.1 Hz,
1H), 2.64 (dt, J = 13.8, 9.4 Hz, 1H), 1.46 (d, J = 20.6 Hz, 9H). 13C NMR
(151 MHz, CDCl3): δ 167.7, 154.2, 139.4, 134.0 (d), 131.8, 131.2, 130.5
(q, JC-F = 32.3 Hz), 128.7, 125.0 (q, JC-F = 3.8 Hz), 123.6 (q, JC-F = 272.4
28.4(2)*.
(*Rotamers)
HRMS-ESI+
(m/z):
calculated
for
[C24H26N2O4+Na]+: 429.1785; found: 429.1790.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000235
European Journal of Organic Chemistry
FULL PAPER
Hz), 123.1, 127.4 (d), 79.7, 53.7(53.2)*, 50.2(49.7)*, 46.9(46.5)*,
39.7(39.0)*, 37.4(37.3)*, 28.4. (*Rotamers) HRMS-ESI+ (m/z): calculated
for [C25H25F3N2O4+Na]+: 497.1659; found: 497.1662.
ESI+ (m/z): calculated for [C26H22ClFN2O2+H]+: 449.1427; found:
449.1431.
2-((3S,4R)-4-(4-fluorobenzyl)-1-(4-methoxybenzyl)pyrrolidin-3-yl)
isoindoline-1,3-dione (6l). Yellow oil (81 %). [α]D20 +15.6 (c 1, CHCl3). IR
2-((3S,4R)-4-benzyl-1-(methylsulfonyl)pyrrolidin-3-yl)isoindoline-1,3-
20
dione (6g). White solid (75 %). M. p.: 168−169 °C. [α]D +11.5 (c 1,
(FTIR): ν 2903, 2931, 2792, 1700, 1509, 1385, 1217, 1038, 715, 529 cm−1
.
CHCl3). IR (FTIR): ν 1705, 1386, 1317, 1145, 1035, 721, 642, 518 cm−1
.
1H NMR (600 MHz, CDCl3): δ 7.77−7.71 (m, 2H), 7.70−7.65 (m, 2H),
7.25−7.27 (m, 2H), 7.05 (dd, J = 8.2, 5.6 Hz, 2H), 6.85 (dd, J = 8.5 Hz, 2H),
6.77 (t, J = 8.6 Hz, 2H), 4.54 (q, J = 8.2 Hz, 1H), 3.80 (s, 3H), 3.67 (dd, J
= 12.8 Hz, 1H), 3.57 (d, J = 12.8 Hz, 1H), 3.14 (dq, J = 15.4, 7.7 Hz, 1H),
2.92 (dt, J = 15.3, 8.6 Hz, 2H), 2.86 (t, J = 8.8 Hz, 1H), 2.81 (dd, J = 13.8,
7.8 Hz, 1H), 2.70 (dd, J = 13.8, 7.9 Hz, 1H), 2.64 (dd, J = 9.2, 5.2 Hz, 1H).
13C NMR (151 MHz, CDCl3): δ 167.9, 161.2 (d, J = 243.9 Hz), 135.4 (d, J
= 3.2 Hz), 133.9, 131.7, 131.0, 130.0 (d, J = 7.7 Hz), 129.7, 128.6, 114.9,
114.8, 113.6, 59.5, 58.1, 55.9, 55.2, 54.4, 41.7, 39.2. HRMS-ESI+ (m/z):
calculated for [C27H25FN2O3+H]+: 445.1922; found: 445.1925.
1H NMR (600 MHz, CDCl3): δ 7.76−7.66 (m, 4H), 7.10−7.03 (m, 4H), 6.89
(dd, J = 7.5, 5.3 Hz, 1H), 4.65 (dd, J = 18.6, 9.3 Hz, 1H), 3.78−3.67 (m,
3H), 3.48−3.36 (m, 1H), 3.21 (t, J = 10.1 Hz, 1H), 2.93 (s, 3H), 2.82 (dd, J
= 13.9, 7.2 Hz, 1H), 2.67 (dd, J = 13.9, 7.8 Hz, 1H). 13C NMR (151 MHz,
CDCl3): δ 167.7, 137.8, 134.1, 131.4, 128.4, 128.4, 126.2, 123.2, 53.8,
51.7, 48.2, 41.0, 37.3, 35.1. HRMS-ESI+ (m/z): calculated for
[C20H20N2O4S+Na]+: 407.1036; found: 407.1037.
2-((3S,4R)-4-Benzyl-1-tosylpyrrolidin-3-yl)isoindoline-1,3-dione (6h).
20
White solid (79 %). M. p.: 179−182 °C. [α]D +6.9 (c 0.85, CHCl3). IR
(FTIR): ν 1702, 1333, 1323, 1149, 1028, 718, 667, 544 cm−1. 1H NMR (600
MHz, CDCl3): δ 7.72 (d, J = 8.2 Hz, 2H), 7.69−7.63 (m, 4H), 7.36 (d, J =
8.0 Hz, 2H), 7.03−6.96 (m, 4H), 6.85−6.79 (m, 1H), 4.41 (dd, J = 18.8, 9.6
Hz, 1H), 3.66−3.57 (m, 3H), 3.39−3.29 (m, 1H), 3.06 (t, J = 9.6 Hz, 1H),
2.75 (dd, J = 13.9, 7.0 Hz, 1H), 2.54 (dd, J = 13.9, 8.1 Hz, 1H), 2.48 (s,
3H). 13C NMR (151 MHz, CDCl3): δ 167.6, 143.7, 137.9, 134.0, 133.7,
131.3, 129.8, 128.3, 128.3, 127.5, 126.0, 123.1, 53.4, 51.6, 48.4, 40.1,
37.5, 21.6. HRMS-ESI+ (m/z): calculated for [C26H24N2O4S+Na]+:
483.1349; found: 483.1352.
Hydrazinolysis of phthalimido protection group
Hydrazine hydrate (0.18 mL, 3.75 mmol) was added at room temperature
to the solution of pyrrolidine 6a-l (0.25 mmol) in THF/EtOH (8:1, 2.7 mL).
The reaction mixture was stirred at room temperature (at 50 °C for
compounds 6g and 6e) for 20 h. The solvent was evaporated under
reduced pressure and crude products were purified on silica gel column
(DCM/MeOH 95:5). The products were obtained as yellow oils or as
yellowish solids.
2-((3S,4R)-4-(4-chlorobenzyl)-1-(4-(trifluoromethyl)benzyl)pyrrolidin-
3-yl)isoindoline-1,3-dione (6i). White solid (92 %). M. p.: 93−95 °C. [α]D
Characterization data for amines 8a-l
20
+9.4 (c 1, CHCl3). IR (FTIR): ν 2814, 1702, 1383, 1323, 1120, 1064, 880,
717, 503 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.75 (dd, J = 5.3, 3.1 Hz, 2H),
7.68 (dd, J = 5.4, 3.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 7.9 Hz,
2H), 7.04 (q, J = 8.5 Hz, 4H), 4.55 (q, J = 8.1 Hz, 1H), 3.79 (d, J = 13.6 Hz,
1H), 3.67 (d, J = 13.6 Hz, 1H), 3.17 (dq, J = 15.3, 7.7 Hz, 1H), 2.95 (d, J =
8.8 Hz, 1H), 2.92 (d, J = 8.5 Hz, 2H), 2.81 (dd, J = 13.8, 7.7 Hz, 1H), 2.71
(dd, J = 13.8, 7.9 Hz, 1H), 2.63 (dd, J = 9.2, 5.6 Hz, 1H). 13C NMR (151
MHz, CDCl3): δ 167.9, 143.1, 134.0, 131.8, 131.6, 130.0, 129.3 (q, J = 32.2
Hz), 128.6, 128.3, 126.8, 125.2 (q, J = 3.7 Hz), 124.2 (q, J = 272.0 Hz),
123.0, 59.6, 58.2, 55.9, 54.3, 41.6, 39.1. HRMS-ESI+ (m/z): calculated for
[C27H22ClF3N2O2+H]+: 499.1395; found: 499.1400.
Tert-butyl (3S,4R)-3-amino-4-benzylpyrrolidine-1-carboxylate (8a).
White solid (74 %). M. p.: 64–66 °C. [α]D20 -50.7 (c 1, CHCl3). IR (FTIR): ν
3358, 2933, 1679, 1472, 1407, 1366, 1163, 1135, 1076, 878, 743, 699,
543 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.36–7.23 (m, 3H), 7.19 (t, J = 8.9
Hz, 2H), 3.79–3.61 (m, 1H), 3.61–3.43 (m, 1H), 3.25–3.12 (m, 1H), 3.12–
2.92 (m, 3H), 2.87 (dd, J = 13.7, 5.9 Hz, 1H), 2.63–2.47 (m, 1H), 1.44 (s,
9H), 1.39 (bs, 2H). 13C NMR (100 MHz, CDCl3): δ 154.4, 139.7, 128.7,
128.5, 126.3, 79.3, 59.0 (55.2)*, 53.8 (53.3)*, 50.1 (49.9)*, 48.7 (48.2)*,
37.7 (37.6)*, 28.5. (*Rotamers) HRMS-ESI+ (m/z): calculated for
[C16H24N2O2+H]+: 277.1911; found: 277.1913.
Tert-butyl
(3S,4R)-3-amino-4-(4-chlorobenzyl)pyrrolidine-1-
2-((3S,4R)-4-(4-chlorobenzyl)-1-(4-methoxybenzyl)pyrrolidin-3-yl)
isoindoline-1,3-dione (6j). Yellow oil (87 %). [α]D05 +12.8 (c 0.6, CHCl3).
IR (FTIR): ν 2810, 1706, 1510, 1241, 1170, 881, 716, 529 cm−1. 1H (600
MHz, CDCl3): δ 7.75−7.73 (m, 2H), 7.69−7.67 (m, 2H), 7.26−7.24 (m, 1H),
7.03−7.01 (m, 5H), 6.86−6.84 (m, 2H), 4.53 (q, J = 7.8 Hz, 1H), 3.80 (s,
3H), 3.67 (d, J = 13.2 Hz, 1H), 3.57 (d, J = 12.6 Hz, 1H), 3.15 (dq, J = 7.8,
5.4 Hz, 1H), 2.93−2.85 (m, 3H), 2.81 (dd, J = 13.8, 7.2 Hz, 1H), 2.69 (dd,
J = 13.8, 7.8 Hz, 1H), 2.62 (dd, J = 9.0, 5.4 Hz, 1H). 13C NMR (150 MHz,
CDCl3): δ 167.9, 158.6, 138.2, 133.9, 131.7, 131.6, 130.9, 130.0, 129.7,
128.2, 123.0, 113.6, 59.5, 58.0, 55.8, 55.2, 54.4, 41.4, 39.2. HRMS-ESI+
(m/z): calculated for [C27H25ClN2O3+H]+: 461.1626; found: 461.1631.
carboxylate (8b). Yellow oil (86 %). [α]D20 -53.6 (c 1, CHCl3). IR (FTIR): ν
2972, 2930, 2874, 1682, 1364, 1163, 1090, 769 cm−1. 1H NMR (600 MHz,
CDCl3): δ 7.30–7.22 (m, 2H), 7.13–7.08 (m, 2H), 3.68 (ddd, J = 23.8, 18.4,
11.4 Hz, 1H), 3.50 (ddd, J = 34.4, 18.6, 10.8 Hz, 1H), 3.16 (t, J = 18.2 Hz,
1H), 3.10–2.93 (m, 2H), 2.86 (dd, J = 10.8, 5.6 Hz, 1H), 2.59–2.40 (m, 1H),
2.12–2.01 (m, 1H), 1.47 (bs, 2H), 1.44 (s, 9H). 13C NMR (150 MHz, CDCl3):
δ 154.4, 138.1 (138.0)*, 132.1, 130.0, 128.7 (128.6)*, 79.5 (79.4)*, 55.9
(55.1)*, 53.7 (53.1)*, 49.8 (49.7)*, 48.3 (47.9)*, 37.0 (36.9)*, 28.5.
(*Rotamers) HRMS-ESI+ (m/z): calculated for [C16H23ClN2O2+Na]+:
333.1340; found: 333.1342.
Tert-butyl
(3S,4R)-3-amino-4-(4-fluorobenzyl)pyrrolidine-1-
2-((3S,4R)-1-(4-chlorobenzyl)-4-(4-fluorobenzyl)pyrrolidin-3-yl)
isoindoline-1,3-dione (6k). White solid (86 %). M. p.: 112−114 °C. [α]D
+8.7 (c 1, CHCl3). IR (FTIR): ν 2905, 2841, 2808, 1773, 1698, 1510, 1386,
1039, 802, 704 cm−1 1H NMR (600 MHz, CDCl3): δ 7.76−7.73 (m, 2H),
.
7.70−7.66 (m, 2H), 7.28 (s, 4H), 7.05 (dd, J = 8.2, 5.6 Hz, 2H), 6.78 (t, J =
8.6 Hz, 2H), 4.54 (q, J = 8.1 Hz, 1H), 3.70 (dd, J = 10.7 Hz, 1H), 3.58 (d, J
= 13.3 Hz, 1H), 3.14 (dq, J = 15.2, 7.6 Hz, 1H), 2.94-2.85 (m, 3H), 2.80
(dd, J = 13.8, 7.8 Hz, 1H), 2.71 (dd, J = 13.8, 7.9 Hz, 1H), 2.62 (dd, J =
9.2, 5.4 Hz, 1H). 13C NMR (151 MHz, CDCl3): δ 167.9, 161.2 (d, J = 244.0
Hz), 137.4, 135.2 (d, J = 3.1 Hz), 133.9, 132.6, 131.6, 130.03 (d, J = 7.8
Hz), 129.8, 128.6, 128.4, 128.2, 59.4, 58.2, 55.9, 54.3, 41.8, 39.1. HRMS-
carboxylate (8c). Yellow oil (92 %). [α]D20 -49.7 (c 0.25, CHCl3). IR (FTIR):
ν 2932, 1684, 1508, 1402, 1219, 1156, 815, 770 cm−1. 1H NMR (600 MHz,
CDCl3): δ 7.14–7.09 (m, 2H), 7.01–6.93 (m, 2H), 3.76–3.63 (m, 1H), 3.58–
3.44 (m, 1H), 3.15 (d, J = 4.7 Hz, 1H), 3.11–2.93 (m, 2H), 2.86 (dd, J =
13.7, 5.1 Hz, 1H), 2.57–2.41 (m, 1H), 2.11–1.98 (m, 1H), 1.70–1.50 (m,
2H), 1.44 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 161.5 (d, J = 244.4 Hz),
154.5, 135.3, 130.03 (d, J = 7.8 Hz), 115.3 (d, J = 21.2 Hz), 79.4, 56.0
(55.2)*, 53.9 (53.4)*, 49.9 (49.7)*, 48.7 (48.3)*, 36.9 (36.8)*, 28.5.
(*Rotamers) HRMS-ESI+ (m/z): calculated for [C16H23FN2O2+Na]+:
317.1636; found: 317.1636.
20
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000235
European Journal of Organic Chemistry
FULL PAPER
Tert-butyl (3S,4R)-3-amino-4-(4-(trifluoromethyl)benzyl)pyrrolidine-1-
carboxylate (8d). Yellow oil (89 %). [α]D20 -37.1 (c 0.7, CHCl3). IR (FTIR):
ν 2975, 2933, 1682, 1406, 1321, 1065, 1017, 885, 770 cm−1. 1H NMR (600
MHz, CDCl3): δ 7.55 (dd, J = 17.5, 7.7 Hz, 2H), 7.29 (dd, J = 6.5 Hz, 2H),
3.78-3.64 (m, 1H), 3.55–3.43 (m, 1H), 3.16 (dd, J = 7.1 Hz, 1H), 3.09–2.93
(m, 3H), 2.59 (dd, J = 22.5, 9.1 Hz, 1H), 2.17–2.02 (m, 1H), 1.52 (d, J =
29.7 Hz, 2H), 1.44 (s, 9H). 13C NMR (151 MHz, CDCl3): δ 154.4, 143.7,
129.0, 128.8 (q, JC-F = 32.2 Hz), 125.5, 124.16 (q, JC-F = 272.0 Hz), 79.6
(79.5)*, 55.9 (55.1)*, 53.6 (53.0)*, 49.8 (49.6)*, 48.0 (47.7)*, 37.4 (37.3)*,
28.4. (*Rotamers) HRMS-ESI+ (m/z): calculated for [C17H23F3N2O2+H]+:
345.1784; found: 345.1783.
(d, J = 8.2 Hz, 2H), 3.69−3.63 (m, 2H), 3.40−3.36 (m, 1H), 2.98 (dd, J =
13.7, 5.9 Hz, 1H), 2.91 (t, J = 8.5 Hz, 1H), 2.80−2.75 (m, 1H), 2.75−2.72
(m, 2H), 2.59 (dd, J = 13.4, 9.9 Hz, 1H), 2.43−2.36 (m, 1H), 2.20−2.12 (m,
1H). 13C NMR (151 MHz, CDCl3): δ 142.9, 138.8, 131.9, 130.0, 129.2 (q,
JC-F = 32.2 Hz), 128.7, 128.6, 125.2 (q, JC-F = 3.7 Hz), 124.2 (q, JC-F = 271.9
Hz), 62.6, 59.6, 59.1, 56.7, 49.6, 39.1. HRMS-ESI+ (m/z): calculated for
[C19H20ClF3N2+H]+: 369.1340; found: 369.1342.
(3S,4R)-4-(4-Chlorobenzyl)-1-(4-methoxybenzyl)pyrrolidin-3-amine
20
(8j). Yellowish oil (82 %). [α]D -18.1 (c 0.2, CHCl3). IR (FTIR): ν 2920,
1510, 1244, 1032, 813, 516 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.28 (d, J
= 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 6.86 (d, J
= 8.6 Hz, 2H), 3.79 (s, 3H), 3.68 (q, J = 12.6 Hz, 2H), 3.27 (q, J = 8.3 Hz,
1H), 2.99–2.84 (m, 4H), 2.68–2.59 (m, 2H), 2.38–2.30 (m, 1H), 2.29–2.22
(m, 1H). 13C NMR (151 MHz, CDCl3): δ 159.1, 138.7, 132.1, 130.3, 129.9,
129.6, 128.8, 63.2, 61.5, 59.4, 58.7, 56.5, 55.4, 48.7, 38.8. HRMS-ESI+
(m/z): calculated for [C19H23ClN2O+H]+: 331.1572; found: 331.1575.
Tert-butyl
(3S,4R)-3-amino-4-(3-chlorobenzyl)pyrrolidine-1-
carboxylate (8e). Yellow oil (89 %). [α]D20 -33.4 (c 1, CHCl3). IR (FTIR): ν
2972, 2930, 1678, 1403, 1364, 1161, 885, 772, 683 cm−1. H NMR (600
1
MHz, CDCl3): δ 7.25–7.15 (m, 3H), 7.08–7.04 (m, 1H), 3.76 (dt, J = 17.0,
11.7 Hz, 1H), 3.59–3.47 (m, 1H), 3.34–3.18 (m, 1H), 3.11–3.00 (m, 1H),
2.99–2.88 (m, 1H), 2.73 (bs, 2H), 2.51 (dd, J = 22.0, 9.7 Hz, 1H), 2.37–
2.30 (m, 1H), 2.22–2.16 (m, 1H), 1.43 (s, 9H). 13C NMR (151 MHz, CDCl3):
δ 154.5 (154.4)*, 141.3 (141.2)*, 134.31, 129.9, 128.8, 126.9, 126.7, 79.9
(79.6)*, 55.5 (54.5)*, 52.5 (51.4)*, 49.5, 46.7 (46.5)*, 37.06, 28.4.
(*Rotamers) HRMS-ESI+ (m/z): calculated for [C16H23ClN2O2+Na]+:
333.1340; found: 333.1341.
(3S,4R)-1-(4-chlorobenzyl)-4-(4-fluorobenzyl)pyrrolidin-3-amine (8k).
20
Yellow oil (74 %). [α]D -14.9 (c 0.7, CHCl3). IR (FTIR): ν 2920, 2853,
2795, 1219, 1014, 803 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.29–7.23 (m,
4H), 7.13 (dd, J = 8.1, 5.6 Hz, 2H), 6.92 (t, J = 8.6 Hz, 2H), 4.13 (bs, 2H),
3.59 (dd, J = 13.2 Hz, 1H), 3.54 (dd, J = 13.2 Hz, 1H), 3.29 (dd, J = 9.7,
4.0 Hz, 1H), 2.91 (dt, J = 14.3, 7.1 Hz, 1H), 2.86 (t, J = 8.5 Hz, 1H), 2.78–
2.72 (m, 1H), 2.60 (dt, J = 12.1, 6.2 Hz, 2H), 2.32–2.24 (m, 1H), 2.20–2.14
(m, 1H). 13C NMR (151 MHz, CDCl3): δ 161.4 (d, JC-F = 244.0 Hz), 137.2,
136.0 (d, J = 3.2 Hz), 132.6, 130.1, 130.0, 129.9, 115.2 (d, J = 21.2 Hz),
62.4, 59.4, 59.1, 56.6, 49.6, 38.9. HRMS-ESI+ (m/z): calculated for
[C18H20ClFN2+H]+: 319.1372; found: 319.1372.
Tert-butyl (3S,4R)-3-amino-4-(3-(trifluoromethyl)benzyl)pyrrolidine-1-
carboxylate (8f). Yellow oil (55 %). [α]D20 -43.1 (c 1, CHCl3). IR (FTIR): ν
2923, 1684, 1406, 1326, 1117, 1071, 702, 661 cm−1. 1H NMR (600 MHz,
CDCl3): δ 7.51–7.45 (m, 1H), 7.45–7.38 (m, 2H), 7.38–7.33 (m, 1H), 3.78–
3.65 (m, 1H), 3.56–3.41 (m, 1H), 3.17 (s, 1H), 3.07–2.94 (m, 3H), 2.58 (dd,
J = 22.2, 8.9 Hz, 1H), 2.09 (ddd, J = 22.5, 14.2, 7.5 Hz, 1H), 1.44 (s, 9H),
1.19 (s, 2H). 13C NMR (150 MHz, CDCl3): δ 154.4, 140.6, 132.1, 130.9 (q,
J = 32.0 Hz), 129.7, 129.0, 125.3, 124.1 (q, J = 272.4 Hz), 123.3 (q, J =
3.8 Hz), 79.4, 56.0 (55.2), 53.7 (53.2), 49.7 (49.7), 48.3 (47.9), 28.4.
(*Rotamers) HRMS-ESI+ (m/z): calculated for [C17H23F3N2O2+Na]+:
367.1604; found: 367.1604.
(3S,4R)-4-(4-Fluorobenzyl)-1-(4-methoxybenzyl)pyrrolidin-3-amine
(8l). Yellow oil (64 %). [α]D20 -22.8 (c 0.2, CHCl3). IR (FTIR): ν 2910, 2786,
1507, 1242, 1217, 1032, 814 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.22 (d,
J = 8.4 Hz, 2H), 7.13 (dd, J = 8.2, 5.6 Hz, 2H), 6.95 (t, J = 8.6 Hz, 2H), 6.84
(d, J = 8.5 Hz, 2H), 3.79 (s, 3H), 3.57 (d, J = 12.8 Hz, 1H), 3.49 (d, J = 12.8
Hz, 1H), 3.13 (dd, J = 11.0, 5.0 Hz, 1H), 2.84–2.83 (m, 3H), 2.62 (dd, J =
13.7, 8.6 Hz, 1H), 2.42 (dd, J = 9.5, 4.7 Hz, 1H), 2.19 (dd, J = 17.1, 9.1 Hz,
1H), 2.07 (dq, J = 14.6, 7.3 Hz, 1H), 1.81 (bs, 2H). 13C NMR (151 MHz,
CDCl3): δ 161.3 (d, JC-F = 244.0 Hz), 158.7, 136.0 (d, JC-F = 3.2 Hz), 130.2,
130.0 (d, JC-F = 7.7 Hz), 130.0, 115.2 (d, JC-F = 21.1 Hz), 113.6, 62.1, 59.4,
58.8, 56.5, 55.2, 49.5, 38.8. HRMS-ESI+ (m/z): calculated for
[C19H23FN2O+H]+: 315.1867; found: 315.1865.
(3S,4R)-4-Benzyl-1-(methylsulfonyl)pyrrolidin-3-amine (8g). White
20
solid (90 %). M. p.: 104–105 °C. [α]D -36.7 (c 1, CHCl3). IR (FTIR): ν
3377, 861, 1314, 1141, 1016, 750, 702, 513, 460 cm−1. 1H NMR (600 MHz,
CDCl3): δ 7.30 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 7.1
Hz, 2H), 3.68 (dd, J = 10.1, 6.4 Hz, 1H), 3.49 (dd, J = 9.9, 7.3 Hz, 1H),
3.30 (q, J = 6.5 Hz, 1H), 3.12 (dd, J = 9.9, 7.2 Hz, 1H), 3.01 (dd, J = 10.1,
6.3 Hz, 1H), 2.90 (dd, J = 13.8, 6.1 Hz, 1H), 2.82 (s, 3H), 2.59 (dd, J =
13.7, 9.0 Hz, 1H), 2.22–2.14 (m, 1H), 1.43 (bs, 2H). 13C NMR (151 MHz,
CDCl3): δ 139.1, 128.7, 128.7, 126.6, 56.0, 55.2, 51.5, 49.1, 37.5, 34.9.
HRMS-ESI+ (m/z): calculated for [C12H18N2O2S+H]+: 255.1162; found:
255.1162.
Sulfonamides 9a,b were prepared from amine 8a by the same procedure
as sulfonamides 5g,h.
Characterization of sulfonamides 9a,b
(3S,4R)-4-Benzyl-1-tosylpyrrolidin-3-amine (8h). White solid (67 %). M.
p.: 54–56 °C. [α]D -36.4 (c 1, CHCl3). IR (FTIR): ν 3344, 2920, 1583,
Tert-butyl
(3R,4S)-3-benzyl-4-(methylsulfonamido)pyrrolidine-1-
20
carboxylate (9a). White solid (82 %). M. p.: 100–103 °C. [α]D20 -41.9 (c 1,
CHCl3). IR (FTIR): ν 3224, 2931, 1697, 1395, 1318, 1132, 984, 764, 742,
536, 515 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.31 (t, J = 6.9 Hz, 2H), 7.26
–7.21 (m, 1H), 7.17 (d, J = 7.2 Hz, 2H), 4.45–4.42 (m, 1H), 3.88–3.84 (m,
1H), 3.72–3.69 (d, J = 6.6 Hz, 1H), 3.53–3.48 (2, 1H), 3.24–3.15 (m, 1H),
3.13–3.06 (m, 1H), 2.97–2.89 (m, 4H), 2.64 (s, 1H), 2.37–2.27 (s, 1H), 1.44
(s, 9H). 13C NMR (151 MHz, CDCl3): δ 154.2, 138.6, 128.7, 126.6, 79.9,
57.1 (56.3*), 51.9 (51.0)*, 49.1 (48.9)*, 46.2 (45.4)*, 41.4 (41.4)*, 37.1
(37.0)*, 28.4. (*Rotamers) HRMS-ESI+ (m/z): calculated for
[C17H26N2O4S+Na]+: 377.1505; found: 377.1507.
1493, 1330, 1155, 1024, 811, 583, 460 cm−1. 1H NMR (600 MHz, CDCl3):
δ 7.68 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 7.3 Hz,
2H), 7.21 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.2 Hz, 2H), 3.59 (dd, J = 10.0,
6.7 Hz, 1H), 3.39 (dd, J = 10.1, 7.5 Hz, 1H), 3.07 (q, J = 6.8 Hz, 1H), 2.99
(dd, J = 10.1, 7.4 Hz, 1H), 2.88 (dd, J = 10.0, 6.7 Hz, 1H), 2.75 (dd, J =
13.8, 6.0 Hz, 1H), 2.44 (s, J = 4.1 Hz, 4H), 2.00 (dq, J = 14.5, 7.2 Hz, 1H),
1.31 (bs, 2H). 13C NMR (151 MHz, CDCl3): δ 143.5, 139.1, 133.6, 129.7,
128.6, 128.6, 127.5, 126.5, 56.0, 55.3, 51.6, 48.8, 37.7, 21.5. HRMS-ESI+
(m/z): calculated for [C18H22N2O2S+H]+: 331.1475; found: 331.1474.
(3S,4R)-4-(4-Chlorobenzyl)-1-(4-(trifluoromethyl)benzyl)pyrrolidin-3-
amine (8i). Yellowish oil (90 %). [α]D -29.0 (c 0.5, CHCl3). IR (FTIR): ν
2900, 1511, 1310, 1120, 970, 520 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.53
(d, J = 8.0 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 7.10
Tert-butyl
(3R,4S)-3-benzyl-4-(phenylsulfonamido)pyrrolidine-1-
20
carboxylate (9b). White solid (81 %). M. p.: 56–57 °C. [α]D25 -27.1 (c 1,
CHCl3). IR (FTIR): ν 3220, 2973, 1664, 1402, 1326, 1156, 1092, 662, 545
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10.1002/ejoc.202000235
European Journal of Organic Chemistry
FULL PAPER
cm−1. 1H NMR (600 MHz, CDCl3): δ 7.68 (d, J = 7.9 Hz, 1H), 7.29 (d, J =
7.9 Hz, 2H), 7.26–7.19 (m, 3H), 7.07–7.01 (m, 1H), 4.58 (d, J = 7.5 Hz,
1H), 3.61–3.52 (m, 1H), 3.52–3.46 (m, 1H), 3.46–3.40 (m, 1H), 3.02–2.93
(m, 2H), 2.80–2.70 (m, 1H), 2.51–2.46 (m, 1H), 2.43 (s, 3H), 2.30–2.20 (m,
1H), 1.40 (s, 9H). 13C NMR (150 MHz, CDCl3): δ 154.2, 143.7, 138.8
(138.5)*, 137.2, 129.9 (129.8)*, 128.7, 128.6, 127.1 (127.0)*, 126.4, 79.7,
56.6 (56.0)*, 51.5 (50.5)*, 49.0 (48.7)*, 46.0 (45.1)*, 36.8 (36.8)*, 28.4,
21.5. (*Rotamers) HRMS-ESI+ (m/z): calculated for [C23H30N2O4S+Na]+:
453.1818; found: 453.1823.
Development Operational Programme funded by the European
Regional Development Fund (ERDF).
Keywords: asymmetric organocatalysis • Michael addition •
reductive cyclization • pyrrolidine • antibacterial activity
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Acknowledgments
This work was supported by the Slovak Research and
Development Agency under the contract No. APVV-15-0039 and
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Entry for the Table of Contents
Layout 2:
FULL PAPER
Asymmetric organocatalysis
L. Rodriguez, R. Fišera, B. Gaálová, K.
Koči, H. Bujdáková, M. Mečiarová, R.
Górová, H. Jurdáková, R. Šebesta*
Page No. – Page No.
Organocatalytic Michael addition of aldehydes to nitroalkenes followed by reductive
cyclization afford chiral 3,4-disubstituted pyrrolidines, which are active against
methicillin-resistant strains of Escherichia coli and Staphylococcus aureus.
Synthesis of chiral 3,4-disubstituted
pyrrolidines with antibacterial
properties
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