Regio- and stereoselective synthesis of polysubstituted 5-hydroxypyrrolidin-2-ones from 3-alkoxysuccinimides

Article abstract of DOI:10.1016/j.tetlet.2019.151358

The synthesis of 4-ethoxy-5-hydroxypyrrolidin-2-ones and 6-hydroxyhexahydro-4H-furo[2,3-c]pyrrol-4-ones — through the regio- and stereoselective reduction of the corresponding 3-alkoxysuccinimides — is described. The reaction used NaBH₄ at low temperatures and short reaction times, providing products with yields of up to 77%. The stereoselectivity was highly influenced by both alkoxy and the N-moiety in the starting succinimide.

Full text of DOI:10.1016/j.tetlet.2019.151358

Tetrahedron Letters 61 (2020) 151358
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regio- and stereoselective synthesis of polysubstituted
5-hydroxypyrrolidin-2-ones from 3-alkoxysuccinimides
Fabio M. da Silva, Andreia M.P.W. da Silva, Mateus Mittersteiner, Valquiria P. Andrade,
⇑
Estefania da C. Aquino, Helio G. Bonacorso, Marcos A.P. Martins, Nilo Zanatta
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 4-ethoxy-5-hydroxypyrrolidin-2-ones and 6-hydroxyhexahydro-4H-furo[2,3-c]pyrrol-4-
ones — through the regio- and stereoselective reduction of the corresponding 3-alkoxysuccinimides — is
described. The reaction used NaBH4 at low temperatures and short reaction times, providing products
with yields of up to 77%. The stereoselectivity was highly influenced by both alkoxy and the N-moiety
in the starting succinimide.
Received 15 October 2019
Revised 30 October 2019
Accepted 2 November 2019
Available online 4 November 2019
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Succinimides
Regioselective reduction
Hydroxy-c-lactams
Hydroxypyrrolidinones
Introduction
N-acyliminium ion as reactive intermediate [13,14]. Despite these
aforementioned methods having been proven useful, some of them
The 5-hydroxypyrrolidin-2-ones — which are also known as
hydroxy- -lactams, and have a succinimide ring as their main pre-
require an inert atmosphere and rigorous anhydrous solvents and
laborious purification steps. With this in mind, in the last few years
our research group has demonstrated the synthetic versatility of
4-alkoxyvinyl trihalomethyl ketones in the synthesis of
pyrroles [15], tetrahydropyridines [16], pyrimidines [17,18], and
several other aza/oxa heterocycles [19], including structurally
related 5-hydroxy-5-(trifluoromethyl)pyrrolidine-2-ones [6] and
pyrrolidine-2,5-diones [20] (see Scheme 1).
Given the fact that we have already reported the cycloconden-
sation reaction of 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones with
NaCN, which furnished CF3-substituted 5-hydroxy-pyrrolidine-2-
ones [6] and the unexpected preparation of 4-cyanocarboxylic
acids and further cyclization to pyrrolidine-2,5-diones [21]
(Scheme 1), we now wish to report the asymmetric reduction of
these 3-alkoxysuccinimides (3-alkoxypyrrolidine-2,5-diones) with
c
cursor — are cyclic amides that have a hydroxyl substituent at the
5-position of the heterocyclic ring. This class of compounds is nota-
ble due to the large variety of biologically active compounds con-
taining the 5-hydroxypyrrolidin-2-one fragment, which has been
isolated from natural sources. The simplest example of this class
of compounds, 5-hydroxypyrrolidin-2-one, has been isolated from
the fruit extracts of Xanthium sibiricum [1] and also from young
leaves of the fern Pteridium aquilinum [2]. Similarly, compounds
with a more complex structure (e.g., the structural analogues
Fusarin C and Epolactaene — see Figure 1) have been isolated from
strains of Penicillium sp. Considering that Epolactaene was the first
active metabolite for the growth of neuronal SH-SY5Y human neu-
roblastoma cells, it became a reference compound for the synthesis
of new active drugs against several neurodegenerative diseases [3].
Among the methods found in the literature for the synthesis of
5-hydroxypyrrolidin-2-ones, we highlight here the ones involving
reactions of
a,b-unsaturated ketones with cyanide ion [4–6],
regioselective reduction reactions of succinimides using sodium
borohydride [7–11] or Grignard reagents [12], and reactions from
the expansion of the b-lactam ring involving the formation of the
⇑
Corresponding author.
E-mail address: nilo.zanatta@ufsm.br (N. Zanatta).
Figure 1. Bioactive natural products containing the fragment 5-hydroxypyrrolidin-
2-one.
https://doi.org/10.1016/j.tetlet.2019.151358
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
F.M. da Silva et al. / Tetrahedron Letters 61 (2020) 151358
Table 1
Optimization of reaction conditions for the selective reduction of 2a.
Entry
NaBH4 (equiv.)
Temp. (°C)
Time (min)
Product
Yield (%)a
b
1
2
3
4
5
6
5
5
1.2
1.2
1.0
1.2
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
25
30
15
15
30
15
15
3a + 3a’
3a + 3a’
3a
3a
3a
-
-
b
70
71
51
b
3a + 3a’
-
a
b
Reaction conditions: 2a (1 mmol), NaBH4, EtOH (3 mL).
isolated yield.
not
Scheme 1. Synthesis of 5-hydroxy-5-(trifluoromethyl)pyrrolidin-2-ones and pyrro-
determined.
lidine-2,5-diones.
mono- and di-reduced products. Feasible results were obtained
when using 1.2 equiv of NaBH4 (Table 1, entry 3), which provided
3 as a single product with an isolated yield of 70% after 15 min of
reaction. The product was purified by filtration over Al2O3, using
ethyl acetate as solvent.
Having controlled the reaction to provide only the single-
reduced product, we next explored the regioselectivity of the reac-
tion. Given that product 3a has two asymmetric centers, it would
be expected to be obtained as a mixture of stereoisomers — both
anti and syn are shown in Figure 2. The diastereoisomeric compo-
sition was determined by GC–MS, and, for compound 3a, we
observed a ratio of 4:1 anti/syn (Figure 2).
With the optimized conditions in hand, and having determined
the diastereoisomeric ratio, we next explored the reaction scope by
varying the R substituent in starting succinimide 2 (Table 2). All
products were obtained at moderate to good yields (54–77%) —
the higher diastereoisomeric ratio was obtained when R = benzyl,
providing a ratio of 4:1 anti:syn (Table 2, entry 1). Similar sub-
stituents (R = CH2Py, (CH2)2Ph) provided ratios in the range of
2:1. Surprisingly, when R = Et, only the anti diastereoisomer was
observed. Other alkyl substituents were used but provided a
diastereoisomeric ratio too low to be feasible; therefore, they are
not shown here. The compounds were obtained in their pure forms
after column chromatography — see Supporting Information for
more details. The syn-isomers could not be recovered as pure com-
pounds from the chromatographic method used. Table 2 shows the
diastereoisomeric ratio of products 3 (determined either by GC–MS
or by 1H NMR integrals) and the isolated yield of the mixture.
In order to evaluate the influence of the ethoxy substituent at
the 3 position of the succinimide ring, we subsequently changed
the substrate to a succinimide-tetrahydrofuran bicycle 5 (tetrahy-
dro-5H-furosuccinimides — see Scheme 3). Unlike the reduction
reactions of 3-ethoxysuccinimides 2, in which a mixture of
Scheme 2. Synthetic approach to the synthesis of succinimides 2, and products that
could possibly be obtained from the reduction with NaBH4.
a hydride source. Despite the fact that the addition of common
hydride sources (e.g., NaBH4, LiAlH4, and NaBH3CN) to carbonyl
compounds are not selective reactions, they are highly influenced
by the reaction conditions (temperature and solvent used) and
steric effects of the substrate, providing stereo- or enantio-enriched
products [22–29].
Scheme 2 comprises the synthesis of succinimides 2 from 1,1,1-
trichloro-4-ethoxybut-3-en-2-one 1, and the possible products
from the reduction of succinimides 2 with NaBH4, in which single
(3, 30’) or double reduction can occur (30).
Results and discussion
Initially, 1,1,1-trichloro-4-ethoxybut-3-en-2-one was prepared
from the trichloroacetylation reaction of ethyl vinyl ether, in accor-
dance with the method previously reported [30]. Preparation of the
corresponding 4-cyanocarboxylic acid, as well as posterior cyclo-
condensation with amines to furnish the succinimide derivatives,
was done in accordance with previous studies [20,21].
We considered succinimide 2a for optimization of the reaction
conditions, and ethanol as solvent, using conditions adapted from
elsewhere [22]. It is important to note that during this step we
did not observe the selective reduction of the carbonyl at the 5-
position of the starting 2a — only the mono-reduced (at the 2-posi-
tion of the starting 2a) and di-reduced forms were obtained. Table 1
shows the results obtained and, one can clearly see that the reac-
tion is quite sensitive to small changes (e.g., greater amounts of
NaBH4 furnished a mixture of 3a and 3a’). Small amounts (4, 3,
and 2 equiv) were used, but all tests furnished the mixture of
Figure 2. Schematic representation of the anti and syn stereoisomers for compound
3a.

F.M. da Silva et al. / Tetrahedron Letters 61 (2020) 151358
3
Table 2
Table 3
Reaction scope of the reduction reaction by varying the starting succinimide 2. The
Reaction scope for the reduction of succinimides 5.
isomer proportion was determined either by GC–MS or 1H NMR integrals.
Entry
Succinimide
R (Amine)
Product
Yield (%)a
4
1
2
3
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
-CH2C6H5
–CH2-2-Py
–CH2-3-Py
–CH2-4-Py
-(CH2)2C6H5
-(CH2)2NMe2
-(CH2)2NEt2
Me
Et
Pr
i-Pr
Allyl
6a
6b
6c
6d
6e
6f
6g
6h
6i
65
61
57
42
40
27b
57b
32
61
60
38b
46
9
10
11
12
5j
5k
5l
6j
6k
6l
a
b
Isolated yield. Product isolated with non-identified impurities.
Figure 3. Three-dimensional structures of compounds 3a and 6a, showing dihedral
angles and the related coupling constants.
were obtained from theoretical minimization energy from stan-
dard AM1 calculation. One can see that the dihedral angle between
the syn-hydrogens (H3 and H4) of compound 3a was 22° — the
same dihedral angle as that between the H3a and H6a of the rigid
compound 6a. The experimental coupling constants for this dihe-
dral angle were 6.8 and 6.0 Hz for compounds 3a and 6a, respec-
tively. The dihedral angle of the anti-hydrogens (H3 and H4) of
the compound 3a is 147° and for the compound 6a the anti-hydro-
gens (H6 and H6a) is 102°. The coupling constant observed for
these dihedral angles was 4.8 Hz for both compounds. Taking these
values for the dihedral angles and coupling constants as the basis
for determining the possible configuration of carbons 4 and 5 of
compound 3a, one can state that the configurations of these two
compounds are anti, because they presented comparable coupling
constants of 5.2 and 4.8 Hz. Therefore, the alkoxy and hydroxy
moieties are in anti-configuration for the main isomer of com-
pounds 3 as well as for the rigid products of compound 6.
Scheme 3. Approach towards the synthesis and posterior selective reduction of
succinimides 5a–l.
diastereoisomers was obtained (except for 2i), in this stage, only
one diastereoisomer was observed when using tetrahydro-5H-
furosuccinimides 5. There are two major reasons for the observed
selectivity: i) the cyclization reaction of 4-cyanocarboxylic acid
(obtained from the reaction of compound 4 with NaCN, Scheme 3)
with amines providing only the syn diastereoisomer — thus, the
product would be already stereoselected before the reduction with
NaBH4; [20] and ii) the replacement of the ethoxy group at posi-
tion-3 with the fused furan heterocycle provides greater selectiv-
ity, due to steric effects caused by the cyclic furan instead of the
flexible ethoxy group.
By reacting succinimides 5 with NaBH4, under the same exper-
imental conditions as described for the synthesis of products 3, we
observed low to moderate yields (27–65%) for the synthesis of 6,
depending on the starting succinimide. Given that some low-yield-
ing products were obtained, we increased the reaction time to 1 h;
however, the yield did not increase considerably. By adding more
equiv of NaBH4 (1.5, 2.0), a mixture of mono- and di-reduced prod-
ucts was observed in the 1H NMR spectra. Table 3 shows the reac-
tion scope for the selective synthesis of fused furan-pyrrolones 6.
Figure 3 shows dihedral angles and the related coupling con-
stants of representative compounds 3a and 6a. The dihedral angles
Conclusion
In summary, we presented a regio- and stereoselective reduc-
tion protocol for the synthesis of 4-ethoxy-5-hydroxypyrrolidin-
2-ones and 6-hydroxyhexahydro-4H-furo[2,3-c]pyrrol-4-ones,
which was accomplished by using NaBH4 at low temperatures
and short reaction times, providing products with yields of up to
77%. By controlling the reaction conditions, only the carbonyl
neighboring the alkoxy group was reduced. Regarding the regiose-
lectivity of the reductions, the ethoxysuccinimides furnished pre-
dominantly anti-configuration products; while for the
tetrahydro-5H-furosuccinimides, only the anti-product was
observed. It was observed that the stereoselectivity of the reduc-
tion was highly influenced by both the alkoxy and N-moiety in
the starting succinimide.

4
F.M. da Silva et al. / Tetrahedron Letters 61 (2020) 151358
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FAPERGS)
— FAPERGS/CNPq – PRONEX, grant no. 16/2551-
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151358.
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