Enantioselective Synthesis of Functionalized Diazaspirocycles from 4-Benzylideneisoxazol-5(4H)-one Derivatives and Isocyanoacetate Esters

Article abstract of DOI:10.1002/adsc.202000611

Enantioenriched spirocyclic compounds bearing three contiguous stereocenters and high functionalization were obtained through a formal [3+2] cycloaddition reaction catalyzed by a cooperative system. The spiro compounds were synthesized from 4-arylideneisoxazol-5-ones and isocyanoacetate esters using a bifunctional squaramide/Br?nsted base organocatalyst derived from a Cinchona alkaloid and silver oxide as Lewis acid. This method afforded two out of the four possible diastereomers with good yields and high enantiomeric excess for both diastereomers. (Figure presented.).

Full text of DOI:10.1002/adsc.202000611

Title: Enantioselective Synthesis of Functionalized Diazaspirocycles
from 4-Benzylideneisoxazol-5(4<i>H</i>)-one derivatives and
Isocyanoacetate Esters
Authors: Pablo Martinez Pardo, Adrián Laviós, Amparo Sanz-Marco,
Carlos Vila, José Pedro, and Gonzalo Blay
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000611
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Advanced Synthesis & Catalysis
10.1002/adsc.202000611
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Enantioselective Synthesis of Functionalized Diazaspirocycles
from 4-Benzylideneisoxazol-5(4H)-one derivatives and
Isocyanoacetate Esters
+
+
Pablo Martínez-Pardo, Adrián Laviós, Amparo Sanz-Marco, Carlos Vila, José R.
Pedro,* and Gonzalo Blay*
Departament de Química Orgànica, Universitat de València, C/ Dr. Moliner 50, E-46100-Burjassot (València), Spain.
E-mail: jose.r.pedro@uv.es; gonzalo.blay@uv.es
+These authors contributed equally. 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######.((Please
delete if not appropriate))
Abstract. Enantioenriched spirocyclic compounds
bearing three contiguous stereocenters and high
functionalization were obtained through a formal [3+2]
cycloaddition reaction catalyzed by a cooperative
system. The spiro compounds were synthesized from 4-
arylideneisoxazol-5-ones and isocyanoacetate esters
enantioselective construction of a chiral spiro
quaternary carbon results especially challenging. The
synthesis of quaternary stereocenters, in general, is
hampered by the huge steric hindrance and low steric
dissimilarity of the two carbon substituents on the
prochiral center. Furthermore, the generation of a
spiro quaternary stereocenter often requires
overcoming ring strain to install useful functionalities,
and the diastereoselectivity needs to be controlled
because the construction of spiro systems is often
accompanied by the formation of additional
stereocenters.
using
a
bifunctional squaramide/Brønsted base
organocatalyst derived from a Cinchona alkaloid and
silver oxide as Lewis acid. This method afforded two
out of the four possible diastereomers with good yields
and high enantiomeric excess for both diastereomers.
Keywords: Asymmetric catalysis; Enantioselectivity;
Heterocycles; Cycloaddition; Spiro compounds
Organic spirocycles are unique compounds that
feature two rings connected through just one shared
carbon (the spiroatom). This structural feature is
often present in natural products isolated from
[1]
different sources, from plants to marine organisms.
Examples of spirocompounds of natural origin
include horsfiline, a natural product isolated from
[
1d]
Horsfielda superba,
β-vetivone, extracted from
vetiver oil,[ or ()-gleenol isolated from the brown
alga Taonia atomaria (Figure 1).
1e]
[1f]
Spirocyclic
Figure 1. Selected examples of natural products and drugs
with spirocyclic structure.
compounds have also found some interesting
applications as privileged ligands for asymmetric
catalysis such as spinol,[ or in the production of
2]
[3]
circularly
polarized
photoluminescence.
Among the different methodologies designed to
[7]
Furthermore, the spirocyclic motif is becoming a
prevalent template in drug discovery,[4] since this
structural feature conveys both increased three-
dimensionality for potential improved activity, and
novelty for patenting purposes. An example of
achieve this goal,
cycloaddition reactions with
cyclic compounds bearing an exocyclic double bond
result especially appealing because of its simplicity
and the vast variety of reaction partners that can
participate in this kind of reactions. Five-membered
nitrogen-containing heterocycles are privileged
structures in medicinal chemistry. Among these, the
[5]
spirocyclic drugs is the marketed fenspiride, used
for the treatment of some respiratory diseases (Figure
1
).
For these reasons, the synthesis of spirocyclic
compounds has received a growing interest in the last
[8]
[9]
spiropyrroline, as well as the spiroisoxazol-5-one
scaffolds are featured in a great number of natural
products, biologically active compounds and
pharmaceuticals.
decade.[
6]
In
this
context,
the
catalytic
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000611
Isocyanoacetate esters are versatile scaffolds in
alone was able to catalyze the diastereoselective
reaction in a non-enantioselective manner (Table 1,
entry 3). To avoid this undesired background reaction,
we performed the reaction with T1 or SQ1 in the
absence of silver oxide (Table 1, entries 4 and 5).
However, although in both cases the enantiomeric
excess of the reaction product was improved under
these conditions, the reaction required longer times
and product 3aa was obtained in low yield despite
total consumption of the starting material. Also we
observed that SQ1 provided better enantioselectivity
than T1.
organic synthesis and can participate as formal 1,3-
dipoles in cycloaddition reactions leading to five-
[10]
membered nitrogen-containing heterocycles. In the
last years, this approach has been used in the
enantioselective synthesis of several spirocyclic
compounds (Scheme 1). Thus, the groups of Zhong,
Wang, Yan, Shi and He have reported the addition of
isocyanoacetate esters to different isatin derivatives
[11]
for the preparation of spirooxindoles.
Also
recently, the groups of Shao/He and Zhao have
reported the synthesis of spirocycles by the reaction
of isocyanoacetate esters with aurones or N-
itaconimides, respectively. [
12]
Table 1. Reaction of methyl isocyanoacetate (2a) and
benzylidene-3-phenylisoxazol-5-one (1a). Conditions and
On the other hand, 4-arylideneisoxazol-5-ones,
featuring an isoxazole-5-one ring with an exocyclic
double bond, are structures present in natural
products and other biologically active compounds,
and have raised increased interest as electrophiles in
Michael-type reactions, including organocatalyzed
reactions. Moreover, the isoxazole-5-one ring is a
versatile building block being used as synthetic
[13]
equivalent of alkynes or ketones among others.
Following our research on enantioselective
cycloaddition reactions with isocyanoacetate esters,
[
14]
we report here the synthesis of chiral hybrid
diazaspirocyclic compounds[ combining a pyrroline
and an isoxazol-5-one ring, via the formal [3+2]
cycloaddition reaction of 4-benzylideneisoxazol-5-
ones and isocyanoacetate esters (Scheme 1).
15]
catalyst screening.[a]
Entry cat
Ag
2
O
yield (%) dr[b]
ee (%)[c]
38/60
[
[
[
[
[
d]
d]
d]
d]
d]
1
2
3
4
5
6
7
8
9
1
T1
SQ1
-
5 mol % 54
5 mol % 44
5 mol % 70
-
-
-
5 mol % 55
5 mol % 72
5 mol % 55
5 mol % 48
5 mol % 47
5 mol % 51
5 mol % 47
5 mol % 67
5 mol % 67
5 mol % 71
5 mol % 66
5 mol % 75
91:9
89:11 39/44
95:5
81:19 57/76
-
T1
18
SQ1
SQ1
SQ1
T1
12
traces
95:5
n.d
85/n.d.
89/n.d.
Scheme 1. Synthesis of spiro compounds employing iso-
cyanoacetates as pronucleophiles.
75:25 80/98
95:5
92:8
58/n.d.
30/n.d.
SQ2
SQ3
SQ4
SQ5
SQ6
SQ7
SQ8
SQ9
SQ10
SQ9
0
74:26 75/98
79:21 -54/-93
74:26 -71-94
84:16 52/93
84:16 30/95
76:24 80/99
79:21 80/96
81:19 65/95
74:26 84/96
65:35 89/99
In the onset of our research, the reaction between
methyl isocyanoacetate (2a) and benzylidene-3-
phenylisoxazol-5-one (1a) in dichloromethane was
chosen to optimize the reaction conditions (Table 1).
We started by checking bifunctional thiourea T1 and
squaramide SQ1 catalysts in the presence of silver
oxide following conditions previously established in
our group, [ which performed in a similar way
providing the expected product 3aa with good
diastereoselectivity but low enantioselectivity (Table
11
12
13
14
15
16
17
18
19
14]
[
e]
SQ11 5 mol % 76
[
a]
Conditions: 1a (0.1 mmol), 2a (0.13 mmol), cat (0.01
[
b]
1
1, entries 1 and 2). We also observed that silver oxide
mmol), Ag
2
O, CH
2
Cl
2
(5 mL). Determined by H NMR.
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000611
[
c]
[d]
Determined by HPLC over chiral stationary phases.
2 2
out in 7.5 mL of CH Cl .
[
e]
Reaction carried out in 1 mL of CH
2
Cl
2
.
Reaction carried
Table 2. Reaction of arylidene-3-phenylisoxazol-5-ones 1 and isocyanoacetate esters 2. Reaction scope.[a]
[
a]
2 2 2
Conditions: 1 (0.25 mmol), 2 (0.33 mmol), SQ11 (0.025 mmol), Ag O (0.0125 mmol), CH Cl (19 mL); dr determined
1
by H NMR; ee determined by HPLC over chiral stationary phases.
Further investigation revealed that 1a decomposed
performed with similar diastereoselectivity as SQ1
in great extent by standing in solution at the reaction
but with silightly lower enantioselectivity (Table 1,
concentration, bringing about the low yields observed. entry 10). Squaramides SQ3 and SQ4, derived from
We also found out that decomposition rate of 1a
decreased in more diluted solution, unfortunately, the
reaction of 1a with the isocyano ester 2a also slowed
down and led to a small yield of 3aa, although with
high ee (Table 1, entry 6). At this point, addition of
silver oxide to the diluted reaction accelerated the
reaction and allowed to obtain the spirocyclic
compound in 55%, with fair diastereoselectivity
quinidine and cinchonine, respectively, delivered the
opposite enantiomer but with lower enantioselectivity
(Table 1, entries 11 and 12). Therefore, we decided to
test other squaramides derived from quinine bearing
an aniline or benzylamine derivative at the second
amide moiety (Table 1, entries 13-17). Squaramides
SQ8, SQ9 lead to similar results as SQ1, with
slightly better diastereoselectivity for SQ9 (Table 1,
entries 7, 15 and 16). At this point, further dilution of
the reaction mixture allowed to improve the
(
75:25), and high enantiomeric excess for both
diastereomers, 80% ee for the major diastereomer and
9
8% ee for the minor one (Table 1, entry 7). However, enantiomeric excess of 3aa (Table 1, entry 18),
performing the reaction under these conditions with
despite some decrease of diastereoselectivity.
Eventually, squaramide SQ11 derived from tert-
butylamine offered the best yield (76%), a slightly
decreased diastereoselecivity (65:35), but the highest
enantiomeric excess for both diastereomers (89% and
99%, respectively), under diluted conditions (Table 1,
entry 19). Further attempts to improve the results by
modifying the silver source, catalyst loading or
SQ/Ag molar ratios were not successful (see SI).
Under the reaction conditions recorded in Table 1,
entry 19, we studied the scope of the reaction (Table
thiourea T1 notably decreased the enantioselectivity
(
Table 1, entry 8).
Other solvents and temperatures were tested, but
none of these changes improved the results (see SI).
Next, we carried out a screening of squaramide
catalysts (Table 1, entries 9-17, see also SI). Catalyst
SQ2 derived from dihydroquinine improved the
diastereoselectivity, but the enantiomeric excess
suffered a dramatic decrease (Table 1, entry 9).
Squaramide SQ3, derived from cinchonidine,
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000611
2
). Methyl isocyanoacetate (2a) was reacted with a
Scheme 2. Hydrolysis and O-methylation of product 3aa.
number of 4-benzylidene-3-phenylisoxazol-5-one
derivatives 1a-l (R = Ph, R2 = aryl) bearing
differently substituted aromatic rings attached to the
exocyclic double bond. In general, the spirocyclic
products were obtained in moderate to excellent
yields, moderate diastereoselectivities and high
enantiomeric excesses in both diastereomers,
somehow depending on the position and electronic
nature of the substituent. Groups of either electron-
donating or electron-withdrawing character at the
para position of the phenyl group were tolerated.
However, in the case of p-halophenyl groups the size
and electronegativity of the halide was determinant,
the enantioselectivity of the reaction increasing
through the series Br<Cl<F (products 3da, 3ea, 3fa).
Electron-donating or electron-withdrawing groups
at the meta (1g-i) or ortho (1j-l) positions were also
compatible with the reaction. From these, compounds
1
It should be remarked that the cycloaddition
reaction between the arylidene-3-phenylisoxazol-5-
ones 1 and the isocyanoacetate esters 2 only gives
two out of the four possible diastereomers. The
relative stereochemistry of the two diastereomers
produced in the reactions was determined by a
combination of NMR experiments and synthetic
1
1
transformations. Multiple H H nuclear Overhauser
effect (NOE) spectroscopy experiments carried on
3ha showed a trans disposition between the methyl
ester group and the m-methoxyphenyl substituent, as
well as a trans disposition between the phenyl group
bonded to the isoxazol-5-one moiety and the m-
methoxymethyl group, in the major diastereomer (see
SI, Figure S1). A similar relative stereochemistry was
assumed for the major diastereomer in all the
cycloaddition reactions studied. Furthermore, when
both diastereomers of compound 3aa (3aa’) were
1
having an ortho-substituted phenyl ring gave better
yields although lower diastereomeric ratios, keeping
the high enantiomeric excess in all the cases
[16]
separated
and subjected to hydrolysis and O-
(
products 3ja, 3ka and 3la). Furthermore, the
methylation, they afforded enantiomer products 4 and
ent-4, respectively, without loss of enantiomeric
excess (Scheme 2 and also SI). This fact, indicated
that both diastereomers 3aa and 3aa’ had identical
configuration at the spiro carbon and opposite
configurations at the two other stereogenic centers.
isoxazolone derivative can have a bulky naphthyl
group (1m) providing spirocycle 3ma with similar
results to those obtained with phenyl derivatives.
Finally, compounds 1n and 1o bearing
a
heterocyclic 2-thienyl or a cyclopropyl group also
reacted with methyl isocyanoacetate to give the
expected products with good enantioselectivity. The
substituent at the
benzilideneisoxazol-5-one can also be a methyl group,
thus compound 1p (R = Ph, R = Me) reacted with
methyl isocyanoacetate providing 3pa in good yield,
fair
3
position of the 4-
1
2
diastereoselectivity
and
excellent
enantioselectivity for both diastereomers. On the
other hand, compound 1q bearing a cyclopropyl
group at this position yielded 3qa with good results.
Finally, benzyl isocyanoacetate (2b) could be used
instead of methyl isocyanoacetate to give 3ab upon
reaction with 1a with good results in terms of both
diastereo- and enantioselectivity. The reaction can
also be performed with α-substituted isocyanides
such as methyl 2-isocyano-2-phenylacetate, although
in this case the reaction product 3ac was obtained
with
low
yield
(45%)
and
moderate
diastereoselectivity and enantiomeric excess.
Compound 3ac was not stable and decomposed on
standing in the NMR tube for a few days.
Scheme 3. Synthetic modifications and determination of
the absolute stereochemical configuration of 3aa.
Scheme 3 outlines some synthetic transformations
of compound 3aa. Transformation A shows the
selective reduction of the imine group in the
pyrrolinic moiety to give the pyrrolidine spirocycle 5
with moderate yield (52%) and preservation of the
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000611
Financial support from the Agencia Estatal de Investigación-
Ministerio de Ciencia, Innovación y Universidades (Spanish
Government) and Fondo Europeo de Desarrollo Regional
enantiomeric excess, using triethylsilane and
trifluoroborane as
Transformation
a
Lewis acid catalyst.
B
exploits the transformation
(European Union) (Grant CTQ2017-84900-P) is acknowledged.
potential of the isoxazol-5-one structure and was used
to determine the absolute stereochemistry of
compound 3aa by chemical correlation with a
compound of known stereochemistry 8. Acidic
hydrolysis of the major diastereomer 3aa gave
quantitatively formamide 6, which was transformed
Access to NMR and MS facilities from the SCSIE-UV is
acknowledged. C. V., A. S.-M and A. L. thank the Spanish
Government for Ramon y Cajal (RyC-2016-20187), Juan de la
Cierva
(IJC2018-036682-I)
and
FPU
pre-doctoral
(FPU18/03038) contracts, respectively.
into the amidoketone 7 by reductive cleavage of the References
[17]
isoxazol-5-one ring with iron.
Further acidic
hydrolysis of the formamide and concomitant
cyclization of the intermediate aminoketone afforded
pyrroline 8 without loss of enantiomeric excess and
in 54% yield over the three steps. Compound 8
obtained in this way was assigned the (2R,3S)
configuration as it showed identical spectroscopical
features and opposite optical rotation sign compared
with the known compound (2S,3R)-8.[ Accordingly,
the absolute stereochemistry for compound 3aa
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(
major diastereomer) should be (5S,8R,9R) and for
compound 3aa’ (minor diastereomer) it should be
5S,8S,9S). For the remaining compounds 3, the
[
2] For an excellent review on the use of spirocyclic
(
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[
[
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diastereo- and enantioselective synthesis of novel,
highly functionalized spirocyclic compounds bearing
a spiro quaternary and two tertiary stereocenters. The
new spirocycles feature pyrroline and isoxazol-5-one
rings, which are privileged structures in medicinal
chemistry. The synthesis involved a formal [3+2]
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catalytic system that englobes bifunctional
a
squaramide/Brønsted base organocatalyst derived
from a Cinchona alkaloid and silver oxide as Lewis
acid. The transformation featured broad scope and
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Experimental Section
Experimental procedure for the enantioselective reaction.
Methyl isocyanoacetate (2a, 30 µL, 0.33 mmol) was added
to a solution of 4-arylideneisoxazol-5-one (1, 0.25 mmol),
organocatalyst SQ11 (11.9 mg, 0.025 mmol) and silver
oxide (2.9 mg, 0.0125 mmol) in dichloromethane (19 mL)
protected from light. The reaction was stirred until
complete consumption of compound 1 (TLC, ca. 12 h).
The product 3 was obtained as a two diastereomer mixture
after purification by flash chromatography eluting with
hexane:EtOAc mixtures.
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Advanced Synthesis & Catalysis
10.1002/adsc.202000611
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Advanced Synthesis & Catalysis
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Pablo Martínez-Pardo, Adrián Laviós, Amparo
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7
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