Enantioselective Cyclopropanation of 4-Nitroisoxazole Derivatives

Article abstract of DOI:10.1002/adsc.202000231

The present study reports an asymmetric organocatalytic cascade reaction of 4-nitroisoxazole derivative with α,β-unsaturated aldehydes catalysed by chiral secondary amine. Using this approach, 1,2,3-trisubstituted cyclopropane products were obtained in isolated yields up to 98% with moderate diastereoselectivities, and enantiopurity up to 99% ee. Moreover, this synthetic protocol can be used for further applications, as shown by a set of additional transformations of the corresponding cyclopropanes and by the formal synthesis of GABA ligands. (Figure presented.).

Full text of DOI:10.1002/adsc.202000231

Title: Enantioselective Cyclopropanation of 4-Nitroisoxazole
Derivatives
Authors: Vojtěch Dočekal, Simona Petrželová, Ivana Císařová, and
Jan Vesely
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000231
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10.1002/adsc.202000231
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Cyclopropanation of 4-Nitroisoxazole
Derivatives
Vojtěch Dočekal,a Simona Petrželová,b Ivana Císařovác and Jan Veselýa*
a
Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 2030/8, 128 43 Prague 2,
jan.vesely@natur.cuni.cz, +420 22195 1305, http://www.orgchem.cz/vesely/
Department of Teaching and Didactics of Chemistry, Faculty of Science, Charles University, Hlavova 2030/8, 128 43
b
Prague 2
c
Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 2030/8, 128 43 Prague 2
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
ring closing (MIRC) cyclopropanation using
organocatalytic cascade reaction of 4-nitroisoxazole aminocatalysis and non-covalent catalysis.[10]
Abstract. The present study reports an asymmetric
derivative with α,β-unsaturated aldehydes catalysed by
chiral secondary amine. Using this approach, 1,2,3-
trisubstituted cyclopropane products were obtained in
Cyclopropanation based on iminium-enamine
activation involves a conjugate addition to an
electrophile producing an enamine, which then
undergoes an intramolecular ring closure.[7f] MIRC
cyclopropanation can be performed as cascade
isolated
yields
up
to
98%
with
moderate
diastereoselectivities, and enantiopurity up to 99% ee.
Moreover, this synthetic protocol can be used for further
Michael/α-alkylation
reaction
between
applications, as shown by
a
set of additional
α,β-unsaturated aldehydes activated by chiral
transformations of the corresponding cyclopropanes and by
the formal synthesis of GABA ligands.
Keywords: Asymmetric catalysis; Organocatalysis;
secondary amines and readily enolisable nucleophiles
such
as
α-halogenated
malonates,[11]
bromonitroalkanes,[12]
electron-deficient benzyl
Heterocycles; Cyclization; Domino reactions
halides[13] and sulfurylides.[14]
The smallest cycloalkanes – cyclopropanes – are a
group of compounds commonly used in modern
organic synthesis[1] to prepare not only bioactive
compounds but also natural molecules, such as
terpenes, pheromones, unusual amino and fatty acids
or their metabolites.[2] Unsurprisingly, several
cyclopropanes are available in the pharmaceutical
market, showing a wide range of biological activities,
from enzyme inhibition to antifungal, antimicrobial,
antibiotic, antibacterial, antitumor or antiviral activity
(Figure 1, A).[3] Considering the high potential of the
cyclopropane scaffold in medicinal chemistry,
considerable research has focused on the development
of efficient methods for the synthesis of
enantiomerically enriched cyclopropanes.
Since the pioneering studies by Simmons and
Smith,[4] and later by Nozaki,[5] a common strategy to
build a chiral cyclopropane motif has consisted of
[2+1] cycloaddition between olefins and carbenes or
metal-carbenoids.[6] In addition, several radical
processes have also been successfully used to prepare
chiral cyclopropanes.[8] Currently, although this
research area is dominated by transition-metal
catalysis and biocatalysis,[7] the increasing popularity
of organocatalysis has prompted organic chemists to
perform asymmetric synthesis of cyclopropanes using
Figure 1. Examples of medicinally relevant compounds
The isoxazole moiety is an important class of
five-membered heterocycles. This structural motif has
been consistently used as a versatile building block in
organic synthesis.[15] Moreover, several drugs and
natural products contain an isoxazole moiety (Figure
1, B).[16] Interestingly, the first synthesis of optically
active isoxazole derivatives using metal-free
functionalization of 4-nitro-5-styrylisoxazoles was
reported by Adamo, in 2009.[17] To date, several
enantioselective organocatalytic additions to 4-nitro-
5-styrylisoxazoles have been developed,[18] including
an organocatalytic approach.[9]
Among these
approaches, one of the most commonly applied
organocatalytic concept is based on Michael-initiated
1
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10.1002/adsc.202000231
Advanced Synthesis & Catalysis
cyclopropanation with α-halogenated malonates [19] or Table 1. Screening of catalysts and other optimization
other cyclizations using diverse soft nucleophiles.[20] studies
Recently, the nucleophilic character of 3,5-dimethyl-
4-nitroisoxazole was revealed in an enantioselective
addition to enals.[21] In addition, hard nucleophiles,
-
such as OH- or CF3 , react via addition to the
electrophilic carbon at the 5-position of the isoxazole
ring.[22] Conversely, the methyl substituent at the 5-
position reacts with soft electrophiles due to its
nucleophilic character caused by the nitro group at the
4-position.[23] Interestingly, the reactivity of readily
available 5-halomethyl-4-nitroisoxazoles has not been
studied yet.
Entry[a] Cat. Solvent Time Dr[b]
(h)
Yield[c] ee[d]
(%)
(%)
1[e]
2[f]
3[g]
4
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeCN
MeCN
Et2O
15
15
15
15
15
15
40
15
40
15
15
85
3
1.9/1/1.4 43
90/89/69
94/89/73
92/86/77
96/86/81
97/92/90
99/98/98
95/98/60
98/99/75
99/99/74
99/84/78
-1/10/23
24/-14/53
97/98/38
98/94/93
99/99/99
99/99/99
98/98/96
Figure 2. Reactivity of 3,5-dimethyl-4-nitroisoxale, 4-
nitro-5-styrylisoxazoles and 5-(chloromethyl)-3-methyl-4-
nitroisoxazole
C1
C1
C1
C1
C2
C3
C4
C5
C6
C7
C8
C9
C5
C3
C3
C3
C3
1.3/1/1.3 41
1.9/1.0/1 36
1.2/1.1/1 74
1.4/1.0/1 61
2.4/1.0/1 77
1.6/1.3/1 84
5.2/4.5/1 88
5.6/4.4/1 95
2.1/1.0/1 30
1.3/1.1/1 30
1.4/1.5/1 59
3.2/5.1/1 94
1.6/1/1.0 88
2.3/1/1.4 78
3.2/1/1.3 37
1.4/1/1.0 96
5
In sharp contrast to the well-developed MIRC
6
cyclopropanation of α,β-unsaturated aldehydes with
7
various
nucleophiles,
organocatalytic
MIRC
8
cyclopropanation between α,β-unsaturated aldehydes
and 5-(chloromethyl)-3-methyl-4-nitroisoxazole for
the preparation of 1,2,3-trisubstituted cyclopropanes
remains unpublished despite their natural occurrence
and relevant biological activity.
9
10
11
12
13
14
15
16
17[h]
We began our study by mixing readily accessible
5-(chloromethyl)-3-methyl-4-nitroisoxazole[24]
(1)
15
15
and trans-cinnamaldehyde (2a) in the presence of a
chiral Hayashi-Jørgensen catalyst (C1) and
triethylamine for trapping HCl, producing, as
expected, 3a, 4a and 5a, in a moderate combined
Toluene 15
DCM 15
[a] Reactions were conducted with 1 (0.3 mmol), 2a (0.6 mmol), NaHCO3
yield, with good enantioselectivities (entry 1, Table 1). (0.45 mmol) and 20 mol% catalyst in 1.0 ml solvent at rt. [b] Determined
by 1H-NMR analysis of the crude reaction mixture, (3a/4a/5a). [c] Isolated
combined yield. Determined by chiral HPLC analysis of methyl esters
after Wittig reaction (6a/7a/8a).
2,6-lutidine.
The enantiomeric purity of diastereomers 3a, 4a and
[d]
5a was determined by HPLC of the more stable
Using triethylamine. [f] Using
[e]
[g]
[h]
Wittig reaction adducts 6a, 7a and 8a, respectively
Using N,N-diisopropylethylamine.
Using 15 mol%
(see SI file for further information). Similar results of catalyst. TMS – trimethylsilyl, TBDMS – tetr-butyldimethylsilyl, MDPS
– methyldiphenylsilyl.
MIRC cyclopropanation between 1 and 2a were also
assessed when using other organic bases, such as 2,6-
lutidine or Hünig’s base (entries 2, 3). In turn, the
After optimizing the reaction conditions, we began
exploring the scope of this organocatalytic
cyclopropanation reaction by varying the aldehyde 2
(Table 2). We assessed the effect of the electronic
properties of the substituents at the aromatic ring on
reactivity and on stereochemical outcome. In almost
every case, corresponding cyclopropanes 3, 4 and 5
were obtained in high isolated yields (80-98%) with
enantioselectivities ranging from 80% to 99% ee and
diastereoselectivities from 1.3/1/1 to 2.5/1/1.2.
Cyclopropanes derived from aldehydes bearing
halogen or other electron-withdrawing groups in the
para position of the aromatic ring (entries 4-6 and 11,
12) were obtained in high yields (73-92%), with
enantioselectivities ranging from 83 to 99% (typically
higher than 95%) and with diastereoselectivities of up
to 1.9/1/1.1). Cyclopropanes derived from an
aldehyde with electron-donating groups in the para
model reaction conducted with NaHCO3 provided the
corresponding products with a better isolated yield
(entry 4). When using the more sterically demanding
diphenylprolinol catalysts C2 and C3 (entries 5 and
6), the enantioselectivities were increased, and the
yields were up to 77%. Other prolinol-based catalysts,
such as the O-silylated bis(3,5-trifluoromethyl)-
diphenyl prolinols C4-C6 (Jørgensen catalysts)
provided slightly higher diastereoselectivities, albeit
with a significantly reduced enantiomeric enrichment
of product 5a (entries 7-9). We also tested other
prolinol catalysts, including bifunctional catalysts
combining a proline-based secondary amine with
thiourea or with a diamine unit (C8 and C9), but the
enantiocontrol of the reaction was almost entirely lost
(entries 11, 12). For more details, see Tables S1-S4 in
the SI file.
2
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10.1002/adsc.202000231
Advanced Synthesis & Catalysis
position were prepared with similar efficiency and
selectivity.
Only
the
reaction
with
the
p-methoxycinnamic aldehyde afforded the minor
diastereomer 4h with significantly reduced
a
enantiocontrol (ee = 79%, entry 9). Conversely, the
diastereomer 4i (p-tolyl, entry 10) with the same
configuration was obtained with 95% enantiopurity.
High reactivity and stereocontrol were also reached
when using ortho- and meta-substituted aromatic
aldehydes (entries 7,8). For example, the meta-
brominated aldehyde 2f provided all cyclopropanes in
high yield (80%) and in an almost enantiopure form
for every diastereomer (99%/98%/99% ee). In
addition to aromatic aldehydes, heteroaromatic
aldehydes were explored (entries 13, 14).
Interestingly, diastereomers 5l and 4m were obtained
with slightly reduced enantioselectivities of 76% and
75% ee, respectively. Moreover, we were able to
purify the diastereomer 3l from the starting aldehyde
only by HPLC. Furthermore, we tested aliphatic
α,β-unsaturated aldehydes and ethyl (E)-4-oxobut-2-
enoate (2n). Enal 2n provided the corresponding
products with high yields and enantioselectivities,
whereas the aliphatic enals bearing γ-protons
provided a complex mixture with only traces of the
desired products (entry 16).
Subsequently, we
examined various isoxazoles 1 under optimised
reaction conditions. The reaction between
trans-cinnamaldehyde and isoxazole with a longer
aliphatic chain at the 3-position afforded the
corresponding cyclopropanes 3o, 4o, 5o in high yields
and with high enantioselectivity, albeit with reduced
diastereocontrol. Similar results were obtained when
treating trans-cinnamaldehyde with 5-(chloromethyl)-
3-phenyl-4-nitroisoxazole (entry 18). Further
variations of a key isoxazole derivative 1, such as
changing the nitro group to other electron-
withdrawing groups, such as cyano, trifluoromethyl
and ester groups, were not tested due to difficulties in
preparing the designed starting materials.
Table 2. Substrate scope of the cyclopropanation reaction
To test the developed organocatalytic system on
a large scale, 1.00 g isoxazole 1 was used to perform
the cyclopropanation reaction, obtaining the products
in 80% yield, with same enantioselectivities
(98%/99%/95% ee) and with slightly increased
diastereoselectivities (Scheme 1). The applicability of
the resulting cyclopropanes was demonstrated in the
set of transformations described in Scheme 1. The
regioselective opening of cyclopropane 3a by
NHC-catalysed redox esterification[25] afforded ester 9
3
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10.1002/adsc.202000231
Advanced Synthesis & Catalysis
in 49% yield, with 98% enantiopurity. Similarly,
when aldehyde 3a was selectively oxidized by
Pinnick oxidation and subsequently methylated using
trimetylsilyl-diazomethane,
the
yield
and
enantiopurity were 42% and 95% ee, respectively. We
were also able to transform the isoxazole ring into
carboxylic acid by treatment with KMnO4. Under
these conditions, the aldehyde moiety was also
oxidized to carboxylic acid. The resulting
dicarboxylic acid was converted into dimethyl ester
11 in 50% yield and without significantly changing
the enantiomeric purity.
Scheme 2. Formal total synthesis of (-)-dysibetaine CPa
and its desmethyl analogue
The relative configuration of all diastereomers 3,
4 and 5 prepared by MIRC cyclopropanation was
determined by 1D NOE NMR spectroscopy (for more
details, see the SI file). In addition, the absolute
configuration of diastereomers
3
and 4 was
ascertained by X-ray diffraction analysis of methyl
ester ent-6a (prepared from cyclopropyl carbaldehyde
ent-3a using Wittig olefination) and cyclopropyl
carbaldehyde 4j.[29] The configuration of ent-6a and
4j was assigned as (1S, 2R, 3S) and (1R, 2S, 3S),
respectively (Figure 3, for details, see the SI file).
Scheme 1. Gram-scale experiment and other
transformations of cyclopropane 3a
Lastly, we demonstrated the value of synthesized
1,2,3-trisubstituted cyclopropanes 3 for the synthesis
of
a
naturally
occurring
compound,
(-)-dysibetaine CPa.[26, 27] This compound and its
desmethyl analogue stand out as potential ligands for
neuronal receptors such as γ-aminobutyric acid
(GABA) receptors, as they incorporate a GABA
motif.[28] The enantioenriched key intermediate 12 can
be prepared from ethyl (E)-4-oxobut-2-enoate (2n)
using an ent-C3-catalysed cyclopropanation protocol,
followed by Pinnick oxidation, EDC-mediated
esterification and oxidation with KMnO4 (Scheme 2).
Figure 3. X-ray structures of cyclopropanes ent-6a and 4j.
Based on absolute configurations and previous
reports,[11a, 12c] a mechanism is proposed, as shown in
Scheme 3. We hypothesize that this reaction proceeds
through two aminocatalytic cycles. Initially, the
formed iminium ion I with a shielded Si-face is
stereoselectively attacked by the isoxazole
nucleophile II. This step is followed by an
intramolecular ring-closing alkylation of enamine
with a benzylic-type chloride. In the final stage of the
first catalytic cycle, the iminium ion IV is hydrolysed
to cyclopropane products 3 and 4, releasing a
secondary amine. In turn, the formation of
diastereomer 5 can proceed either by enamine V
formation via iminium IV deprotonation or via
condensation of 4 with a secondary amine catalyst.
Due
to
sterical
hindrance
of
the
diaryl((trialkylsilyl)oxy)methyl group present in the
4
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10.1002/adsc.202000231
Advanced Synthesis & Catalysis
secondary amine, enamine V is protonated from the
Re-face, thereby affording the iminium ion VI.
Subsequent hydrolysis produces the diastereomer 5.
The second catalytic cycle is also crucial for the
formation of retro-Michael products, through a
cyclopropane cleavage competing with the
protonation of V.
Acknowledgements
Vojtěch Dočekal gratefully acknowledges to Charles University
Grant Agency (1350120) for financial support. Jan Veselý
gratefully acknowledges the Czech Science Foundation (18-
20645S) for financial support. The authors also thank Dr. Carlos
V. Melo for proofreading.
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Scheme 3. Plausible reaction mechanism
In summary, we have developed an
enantioselective organocatalytic cyclopropanation of
readily available 4-nitroisoxazole derivatives with
α,β-unsaturated aldehydes. The reaction is catalysed
by a chiral secondary amine, affording chiral 1,2,3-
trisubstituted cyclopropanes in high yields and
enantioselectivities. This synthetic protocol can be
used for further applications, as shown by a set of
additional transformations of the corresponding
cyclopropanes and by the formal synthesis of GABA
ligands.
Experimental Section
The catalyst C3 (20.2 mg, 0.045 mmol, 0.15 eq.) was
added to
a
solution of the corresponding
α,β-unsaturated aldehyde 2 (0.6 mmol, 2.0 eq.) in
DCM (1.0 ml). The mixture was stirred for
10 minutes at room temperature. Then, NaHCO3 (37.8
mg, 0.45 mmol, 1.5 eq.) and compound 1 (53.1 mg,
0.3 mmol, 1.0 eq.) were added. The reaction was
stirred for the indicated time (TLC control). After
completing the reaction, the solvents were evaporated.
The crude product was purified by column
chromatography (eluting by hexane/EtOAc mixtures).
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J. Am. Chem. Soc. 2017, 139, 1049-1052; b) L. Ye,
Q.-S. Gu, Y. Tian, X. Meng, G.-C. Chen, X.-Y. Liu,
5
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10.1002/adsc.202000231
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6
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10.1002/adsc.202000231
Advanced Synthesis & Catalysis
COMMUNICATION
Enantioselective Cyclopropanation of
4-Nitroisoxazole Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Vojtěch Dočekal, Simona Petrželová, Ivana
Císařová, Jan Veselý*
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