Streocontrolled construction of six vicinal stereogenic centers on spiropyrazolones via organocascade michael/michael/1,2-addition reactions

Article abstract of DOI:10.1021/ol501093v

A highly stereoselective one-pot procedure for the synthesis of spiropyrazolone derivatives bearing six contiguous stereogenic centers including two tetrasubstituted carbons has been developed. Under sequential catalysis by two organocatalysts, a cinchona-derived aminosquaramide and DBU, a series of diversely functionalized spiropyrazolones are obtained in good yields (47-62%) and excellent stereoselectivities (up to >25:1 dr and 98-99% ee). The opposite enantiomers of the spiropyrazolones are also accessible by employing a pseudoenantiomeric aminosquaramide catalyst.

Full text of DOI:10.1021/ol501093v

Letter
pubs.acs.org/OrgLett
Streocontrolled Construction of Six Vicinal Stereogenic Centers on
Spiropyrazolones via Organocascade Michael/Michael/1,2-Addition
Reactions
Pankaj Chauhan, Suruchi Mahajan, Charles C. J. Loh, Gerhard Raabe, and Dieter Enders*
Institute of Organic Chemistry, RWTH Aachen University Landoltweg 1, 52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: A highly stereoselective one-pot procedure for
the synthesis of spiropyrazolone derivatives bearing six
contiguous stereogenic centers including two tetrasubstituted
carbons has been developed. Under sequential catalysis by two
organocatalysts, a cinchona-derived aminosquaramide and
DBU, a series of diversely functionalized spiropyrazolones
are obtained in good yields (47−62%) and excellent
stereoselectivities (up to >25:1 dr and 98−99% ee). The
opposite enantiomers of the spiropyrazolones are also accessible by employing a pseudoenantiomeric aminosquaramide catalyst.
the asymmetric synthesis of spirocyclic oxindole derivatives
especially employing organocascade sequences.5 Despite the
many important applications of the pyrazolone moiety, the
catalytic asymmetric synthesis of spiropyrazolones is less
explored.
he synthesis of pyrazolone derivatives has attracted
Tconsiderable attention in recent years due to their wide
spectrum of applications in dye, analytical, and pharmaceutical
chemistry.1,2 Edaravone (A), a neuroprotective agent, and
metamizole (B), an effective analgesic and antipyretic agent, are two
important pharmaceutically valuable pyrazolones (Figure 1).1c−f In
The Rios group reported the asymmetric synthesis of
spiropyrazolones bearing three contagious stereogenic centers
via a secondary amine catalyzed domino reaction (Scheme 1).6
Rios and co-workers were also able to construct four
stereocenters on a spiropyrazolones in a three-component
domino reaction.7 The cinchona-derived primary amines were
found to catalyze the domino Michael/Michael reaction of the
enones with the pyrazolones8 and the unsaturated pyrazolones9
to afford the spirocyclohexanonepyrazolones with three
consecutive stereogenic centers. Recently, spiropyrazolones
bearing an N-heterocyclic ring with three adjacent stereogenic
centers were synthesized by aminothioureas10 and quinine11
catalyzed domino Michael/cyclization reactions.
Figure 1. Biologically active pyrazolone derivatives.
To the best of our knowledge, the asymmetric synthesis of
spirocyclohexanepyrazolones bearing more than four stereo-
centers are not known. We took up this challenge and
developed a one-pot protocol for the asymmetric synthesis of
the spiropyrazolones bearing as many as six stereogenic centers
including two adjacent tetrasubstituted ones. It was envisaged
that an organocascade sequence involving a stereoselective
Michael/Michael/1−2-addition reaction between β-dicarbonyl
compounds 1, nitroalkenes 2, and unsaturated pyrazolones 3
mediated by sequential organocatalysis12 using a chiral
bifunctional organocatalyst13 and an achiral base could afford
such highly functionalized spiropyrazolones (Scheme 1).
To attain our objective at the onset, we performed a one-pot
reaction that involved a quinine-derived squaramide (1 mol %)
addition to these, the pyrazolone derivatives such as C exhibit
HIV inhibition activity.1g Recently, the pyrazolones were found
to be inhibitors of the CD80 protein and also possess potent
activity in inhibiting protease-resistant prion protein accumu-
lation, cytokines, and p38 kinases.1h−k Pyrazol-3-one derivatives
have also been studied as multidrug resistance modulators.1l
On the other hand, spirocyclic frameworks frequently found
in many synthetic bioactive compounds and natural products
fascinated many researchers to develop synthetic strategies for
their construction. Because of their complex three-dimensional
structure, the stereoselective synthesis of spirocyclic molecules
from simple precursors in an atom-economic fashion is
considered as a tough challenge.3 Recently, the organocatalytic
cascade/domino reactions emerged as an efficient strategy to
provide such complex structures in an operationally simple one-
pot procedure,4 and we have witnessed tremendous growth in
Received: April 15, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501093v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Catalytic Enantioselective Strategies for the
Synthesis of Spiropyrazolone Derivatives
Table 1. Optimization of the Reaction Conditions for the
Asymmetric Synthesis of the Spiropyrazolone 4a
a
b
c
entry
base (x mol %)
solvent
yield (%)
ee (%)
1
2
3
4
TBD (20)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
toluene
THF
41
44
43
12
14
12
35
34
35
46
52
36
57
60
99
99
99
99
98
98
99
99
99
99
99
99
99
99
DBU (20)
DBN (20)
DABCO (20)
piperidine (20)
pyrrolidine (20)
DBU (20)
d
5
d
6
7
8
DBU (20)
9
DBU (20)
10
11
DBU (30)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DBU (50)
e
12
DBU (100)
DBU (30)
f
13
catalyzed Michael addition of ethyl acetoacetate (1a) to (E)-β-
nitrostyrene (2a) in dichloromethane. After 24 h, the
unsaturated pyrazolone 3a and a guanidine base TBD
(20 mol %) in dichloromethane were added sequentially. To
our delight, the desired spiropyrazolone bearing four tertiary
and two tetrasubstituted stereogenic centers was obtained in a
good yield of 41% and excellent enantio- (99% ee) and
diastereoselectivity (>25:1 dr) (Table 1, entry 1). The
screening of other achiral bases (entries 2−6) showed that
the DBU provides the best yield as well as excellent
stereoselectivity (entry 2). The screening of solvents such as
chloroform, toluene, and THF did not result in any
improvement in the product yield (entries 7−9). Further
efforts for optimizing the yield of 4a by increasing the catalyst
loading of DBU revealed that with 50 mol % DBU a better
yield was observed; however, a further increase in the amount
of DBU did not show any improvement in the product yield.
Using 2 equiv of 3 the spiropyrazolone 4 was isolated in
maximum yield of 60% with excellent stereoselectivity (entries
13 and 14).
Armed with optimized conditions, we further evaluated the
substrate scope on a 0.5 mmol scale (Table 2). Various
pyrazolone-derived olefins bearing electron-withdrawing and
electron-releasing substituents at the different aromatic position
reacted efficiently under the standard reaction conditions to
afford the desired spiropyrazolones 4b−i in good yields and
excellent enantio- and diastereoselectivities (entries 2−9). The
heteroaromatic pyrazolone derivative was also tolerated under
this one-pot organocascade procedure, thus resulting in the
desired spiropyrazolone 4j in 55% yield with excellent ee
(entry 10). The unsaturated pyrazolone bearing an o-chloro-
phenyl group gives 47% yield of product 4k with 99% ee
(entry 11).
f
14
DBU (50)
a
Reaction conditions: 0.2 mmol of 1a, 0.2 mmol of 2a, 1 mol % of I,
b
0.24 mmol of 3a, and x mol % of base (0.1 M in solvent). Yield of
isolated 4a after flash column chromatography. Enantiomeric excess
of the major diastereomer (>25:1 dr) determined by HPLC analysis
on a chiral stationary phase. The reaction was run for 96 h in the
second step. The reaction was run for 0.5 h in the second step. 0.40
mmol of 3a was used.
c
d
e
f
bearing heteroaromatic groups also provide the desired
adducts 4p and 4q in good yields and excellent stereo-
selectivities (entries 16 and 17). We also tried other
dicarbonyl compounds such as methyl acetoacetate and
acetylacetone, which efficiently reacted under this one-pot
protocol to afford the adducts 4r and 4s in 57% and 53% yield
and 99% ee (entries 18 and 19).
After generating two tetrasubstituted adjacent carbon atoms
on the spiropyrazolone, we tried to create three consecutive
tetrasubstituted carbons by employing a trisubstituted β-
ketoester. A one-pot organocatalytic sequence promoted by I
and DBU between the β-ketoester 5, (E)-β-nitrostyrene (2a),
and pyrazolone 3a provided the spiropyrazolone 6 bearing
three contiguous tertiary and three tetrasubstituted stereogenic
centers in excellent stereoselectivity (>25:1 dr and 95% ee),
albeit in a low yield of 16% (Scheme 2).
The absolute configuration of the spiropyrazolones 4a−s
could be assigned as (1R), (2S), (3S), (4S), (5S), and (6R)
based on the X-ray structure of 4c.14
We have also tested the catalytic potential of amino-
squaramide catalyst II derived from quinidine in place of
catalyst I to generate the opposite enantiomer of the
corresponding product. With catalyst II, various spiropyrazo-
lone derivatives were accessible in good yields and excellent
enantio- and diastereoselectivities (Table 3).
Different aromatic nitroalkenes bearing electron-withdrawing
as well as electron-donating substituents also allowed an
efficient access to the spiropyrazolones 4l−o in good yield and
excellent ee of 98−99% (entries 12−15). The nitroalkenes
In order to demonstrate the practical utility of this
one-pot protocol, we have performed a gram-scale cascade
B
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Organic Letters
Letter
a
Table 2. Substrate Scope of the Asymmetric Synthesis of Spiropyrazolones 4 with Catalyst I
b
c
entry
R1
R2
R3
R4
4
yield (%)
ee (%)
1
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
62
58
62
61
60
52
57
55
57
55
47
57
58
56
56
55
59
57
53
99
99
99
99
99
99
99
99
99
99
99
99
99
98
99
99
99
99
99
2
4-ClC6H4
4-BrC6H4
4-CF3C6H4
3-ClC6H4
4-MeC6H4
4-MeOC6H4
2-MeC6H4
3-MeOC6H4
2-thienyl
Ph
3
4
5
6
7
4g
4h
4i
8
9
10
11
12
13
14
15
4j
2-ClC6H4
Ph
4k
4l
4-FC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
2-furanyl
2-thienyl
Ph
Ph
Ph
Ph
4m
4n
4o
4p
4q
4r
4s
Ph
Ph
Ph
Ph
d
16
Ph
Ph
17
18
19
Ph
Ph
Ph
Ph
Ph
Ph
Ph
a
b
Reaction conditions: 0.5 mmol of 1, 0.5 mmol of 2, 1 mol % of I, 1.0 mmol of 3, and 50 mol % of DBU (0.1 M in CH2Cl2). Yield of the isolated
c
d
product after flash column chromatography. Enantiomeric excess of the major diastereomer (>25:1 dr). 12:1 dr.
Table 3. Substrate Scope of the Asymmetric Synthesis of
Spiropyrazolones ent-4 with Catalyst II
Scheme 2. Asymmetric Synthesis of Spiropyrazolone with
Three Contiguous Tetrasubstituted Stereocenters
a
Michael/Michael/1,2-addition reaction between 1a, 2a, and
3a using a lower loading (0.5 mol %) of catalyst I (Scheme 3).
The desired spiropyrazolone 4a was obtained in 59% yield
without deteriorating the stereochemical outcome of the
reaction.
b
c
yield
ee
entry
R1
R2
R3
ent-4
(%)
(%)
1
2
3
4
5
6
7
8
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
Ph
Ph
Ph
Ph
Ph
Ph
ent-4a
ent-4b
ent-4e
ent-4f
61
57
60
50
57
60
57
56
61
59
99
97
98
98
98
97
98
97
98
98
In conclusion, we have disclosed a one-pot procedure for the
synthesis of a new series of potentially biologically important
spiropyrazolone derivatives. A variety of spirocyclohexanepyrazolone
derivatives bearing six stereocenters including two vicinal
tetrasubstituted carbons were obtained in good yields and
excellent stereoselectivities via sequential organocatalytic
Michael/Michael/1,2-addition reactions facilitated by a low
loading of a cinchona-derived amino squaramide and a readily
available achiral base. This one-pot cascade sequence can be
scaled up without losing the reaction efficiency in terms of
product yield and stereoselectivity. The opposite enantiomer of
the spiropyrazolones can be also synthesized in good yield and
excellent stereoselectivity by employing a pseudoenantiomeric
catalyst.
4-ClC6H4
3-ClC6H4
4-MeC6H4
3-MeOC6H4 ent-4i
4-FC6H4
Ph
Ph
ent-4l
4-ClC6H4
ent-4m
ent-4n
ent-4q
ent-4r
4-MeC6H4 Ph
d
9
2-thienyl
Ph
Ph
Ph
10
a
Reaction conditions: 0.5 mmol of 1, 0.5 mmol of 2, 1 mol % of II, 1.0
mmol of 3, and 50 mol % of DBU (0.1 M in CH2Cl2). Yield of the
isolated product after flash column chromatography. Enantiomeric
b
c
d
excess of the major diastereomer (>25:1 dr). 10:1 dr.
C
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Organic Letters
Letter
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Spiropyrazolone 4a
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: enders@rwth-aachen.de. Tel: +49 241 809 4676. Fax:
+49 241 809 2127.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Support from the European Research Council (ERC Advanced
Grant “DOMINOCAT”) is gratefully acknowledged.
■
́
(6) (a) Companyo, X.; Zea, A.; Alba, A.-N. R.; Mazzanti, A.; Moyano,
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D
dx.doi.org/10.1021/ol501093v | Org. Lett. XXXX, XXX, XXX−XXX