Anti-Selective Asymmetric Nitro-Michael Reaction of Furanones: Diastereocontrol by Catalyst

Article abstract of DOI:10.1021/acs.orglett.5b03539

Catalyst-controlled switching of diastereoselectivity from high syn-selectivity (>98/2 dr, syn) to anti-selectivity (up to 96/4 dr, anti) of the asymmetric nitro-Michael reaction of furanones is described. Anti-diastereoselectivity of the nitro-Michael reaction is very rare. With 0.1-5 mol % loadings of an epi-quinine catalyst, the reaction of 5-substituted 2(3H)-furanones with nitroalkenes smoothly proceeded to give the anti-Michael adducts in good yields (up to 95%) with excellent diastereo- and enantioselectivities (up to 96/4 dr, anti; up to 99% ee). DFT calculations support a model that accounts the high anti-diastereoselectivity. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b03539

Letter
pubs.acs.org/OrgLett
Anti-Selective Asymmetric Nitro-Michael Reaction of Furanones:
Diastereocontrol by Catalyst
Tohru Sekikawa,* Takayuki Kitaguchi, Hayato Kitaura, Tatsuya Minami, and Yasuo Hatanaka*
Department of Applied Chemistry, Graduate School of Engineering, Osaka City University, Sumiyoshi, Osaka 558-8585, Japan
S
* Supporting Information
ABSTRACT: Catalyst-controlled switching of diastereoselec-
tivity from high syn-selectivity (>98/2 dr, syn) to anti-
selectivity (up to 96/4 dr, anti) of the asymmetric nitro-
Michael reaction of furanones is described. Anti-diastereose-
lectivity of the nitro-Michael reaction is very rare. With 0.1−5
mol % loadings of an epi-quinine catalyst, the reaction of 5-
substituted 2(3H)-furanones with nitroalkenes smoothly
proceeded to give the anti-Michael adducts in good yields (up to 95%) with excellent diastereo- and enantioselectivities (up
to 96/4 dr, anti; up to 99% ee). DFT calculations support a model that accounts the high anti-diastereoselectivity.
mong the large variety of asymmetric Michael reactions
developed so far, nitroalkenes have been one of the most
to anti-selectivity (Scheme 2). Catalyst control of the
diastereoselectivity of an organic reaction is more practical and
A
widely used Michael acceptors because of the synthetic
importance of chiral nitroalkanes, which undergo facile β-
alkylation reactions and interconversions to important organic
functional groups.1 Although a large number of nitro-Michael
reactions catalyzed by enamine catalysts and bifunctional
hydrogen-bonding catalysts have been reported, these reactions
exclusively exhibit syn-selectivity.2 The predominant syn-
selectivity of the nitro-Michael reaction is explained by the
transition-state model proposed by Seebach, in which donor
atoms and acceptor atoms are situated close to each other
(Scheme 1a).3 The first example of an anti-selective nitro-
Scheme 2. Catalyst-Controlled Switching of
Diastereoselectivity
Scheme 1. Nitro-Michael Reaction via Seebach’s Transition-
State Model
expedient than substrate control because the need to modify the
substrate to achieve high diastereoselectivity severely limits the
substrate scope. To the best of our knowledge, a successful
organocatalyst-controlled diastereoselectivity of the nitro-
Michael reaction is very rare.1 Moreover, catalyst-controlled
switching from high syn-selectivivity (>90 dr) to high anti-
selectivity (>90 dr) of an asymmetric reaction using the same
substrates seems to be seldom.4d
Recently, we reported the asymmetric nitro-Michael reaction
of 2(3H)-furanones to give chiral β-butenolides catalyzed by epi-
quinine-derived 3,5-bis(CF3)benzamide, which exclusively ex-
hibits high syn-selectivity (>98/2 dr) and excellent enantiose-
lectivity (>90% ee) (Scheme 2).6 The extremely high syn-
selectivity of this reaction affords a perfect opportunity to
investigate the catalyst-controlled switching of the diastereose-
lectivity.
Michael reaction of aldehydes promoted by an enamine catalyst
was reported by Barbas and co-workers.4 They achieved high
anti-selectivity in the nitro-Michael reaction by introducing an
alkoxy group at the β-carbon of aldehydes. The reaction of β-
alkoxyaldehydes with enamine catalysts predominantly leads to
(Z)-enamines that are stabilized by intramolecular H-bonding,
which then give the anti-Michael adduct via Seebach’s transition-
state model (Scheme 1b). Their strategy is a substrate-controlled
diastereoselectivity, which is a typical synthetic protocol.5
We report a catalyst-controlled switching from normal syn-
selectivity of the asymmetric nitro-Michael reaction of furanones
We have found that a 10 mol % loading of PPh2Me catalyzes
the nitro-Michael reaction of angelica lactone 1a with nitro-
Received: December 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03539
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Organic Letters
Letter
styrene 2a in THF at −40 °C, giving the corresponding adduct 3a
completed the polymerization within 10 min. In contrast, the
replacement of 6′-OH of 4a with 6′-H (4b) and the replacement
of 6′-OH of 4a with 6′-OMe (4c)9a profoundly depresses the
activity of epi-quinine-derived catalysts for the polymerization
reaction. Quinine-derived 4f9b bearing 6′-OH (diastereomer of
4a) failed to promote the polymerization. These results
conclusively reveal that the 6′-OH of epi-quinine derivatives is
essential for the nucleophilic activation of 2a. The 13C NMR
spectra of the mixture of 4a and 2a (4a/2a = 1:2, C6D6) indicated
that δ (13C) of the β-carbon of 2a did not shift upon the addition
of 4a, revealing a very weak interaction between the quinuclidine
N and 2a. To reveal the role of the 6′-OH group of epi-quinine-
derived catalysts 4a, 4d, and 4e, we carried out theoretical
calculations (Figure 1). Simplified structures of the Michael
(Scheme 3a). The reaction mechanism likely involves conjugate
Scheme 3. Anti-Selective Nitro-Michael Reaction
addition of PPh2Me to 2a.7 The crucial aspect of the reaction is
the moderate anti-selectivity (anti/syn = 65/35). Based on this
result, we have made an assumption that the quinuclidine
nitrogen of quinine catalysts 4 would undergo conjugate addition
to nitroalkenes, giving nitroammonium intermediate 5 (Scheme
3b).8 Analogously to the PPh2Me-catalyzed nitro-Michael
reaction, the nucleophilic substitution of 5 with dienolate 6 is
expected to afford an anti-adduct.
With the purpose of evaluating the nucleophilicity of the
quinuclidine nitrogen, we carried out the polymerization of (E)-
β-nitrostyrene 2a promoted by epi-quinines at 10 mol % loadings
of epi-quinines in THF at the room temperature (Scheme 4).
Scheme 4. Quinine Derivative-Promoted Polymerization of
Nitrostyrene
Figure 1. Simplified models of re-face and si-face adducts optimized at
B3LYP/6-31G(d). Atomic distances in angstroms.
adducts formed by the conjugate addition of quinuclidine N(1)
to the re- and si-face of nitroalkene were optimized at B3LYP/6-
31G(d). The results of the calculations are surprising. The
structure of the optimized re-face adduct 7 discloses a very weak
interaction between quinuclidine N(1) and nitroalkene, as
indicated by the very long N(1)−C(2) bond length (3.28 Å), and
an intramolecular H-bonding between 6′-OH and nitronate
oxygen effectively stabilized 7. The long N(1)−C(2) bond
length can be ascribed to the strong electrostatic repulsion
between the nitronate moiety and N(1), which bears a
considerable negative charge (−0.3868; Mulliken). The formal
positive charge on N(1) can be neutralized by electron release
from five neighboring hydrogen atoms in the geminal positions
relative to N(1).10 In contrast, the si-face adduct 8 cannot engage
in intramolecular H-bonding between 6′-OH and the nitronate
oxygen. Consequently, 8 dissociates into the catalyst and the
nitroalkene due to the electrostatic repulsion between the
negatively charged N(1) and the nitronate moiety. The N(1)−
C(2) bond length of 8 (3.20 Å) is roughly comparable to the sum
of van der Waals radii of N and C (3.25 Å).11 Electrostatic
repulsion between N(1) and C(2) of 7 is reduced when 7 is
protonated by furanone (Figure 1). The resulting nitro-
ammonium intermediate (2R)-9 is considered to be thermody-
namically stable; the N(1)−C(2) bond length of 1.56 Å is normal
The reaction furnished poly(nitrostyrene) as an insoluble
material, whose structure was determined by elemental analysis.
We observed that bifunctional epi-quinine-derived catalysts 4a,
4d, and 4e are capable of promoting the polymerization of 2a to
give a polymer in quantitative yield. The rate of polymerization
strongly depends on the structures of the catalysts. The epi-
quinine-derived 4d bearing a 6′-OH and sterically demanding 9-
OCH2[2,4,6-(i-Pr)3C6H2] substituent exhibited a reaction rate
for the polymerization of 2a lower than that for 4a and 4e, which
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DOI: 10.1021/acs.orglett.5b03539
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Letter
as a N−C covalent bond.12 DFT calculations strongly suggested
that the conjugate addition of quinuclidine N(1) to the
nitroalkene would occur predominantly at the re-face of the
nitroalkene, affording the nitroammonium intermediate (2R)-9.
As expected from the anti-selectivity of the PPh2Me-catalyzed
nitro-Michael reaction, epi-quinine derivatives are capable of
catayzing the conjugate addition of 1a to 2a with anti-selectivity
(Table 1). For example, with 10 mol % loading of 4a, the Michael
a b
,
Table 2. Nitro-Michael Addition Catalyzed by 4d
yield
ee
e
c
d
entry furanone
Ar
product
(%)
anti/syn
(%)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1a
2b: 4-ClPh
2c: 3-ClPh
2d: 2-ClPh
2e: 4-MeOPh
2f: 4-MePh
2g: 1-naph
2h: 2-naph
2i: 2-furyl
3ab
3ac
3ad
3ae
3af
74
82
82
78
84
68
62
63
95
74
60
82
70
60
60
89
94/6
90/10
96/4
96/4
97/3
95/5
97/3
94/6
90/10
92/8
95/5
90/10
92/8
90/10
88/12
96/4
97
96
98
94
98
98
97
99
94
99
84
88
94
98
99
97
Table 1. Catalytic Nitro-Michael Addition of 1a to 2a
3
4
5
6
3ag
f
7
3ah
8
3ai
3bb
3bf
3bi
3bk
3ca
3ch
3cl
9
2b: 4-ClPh
2f: 4-MePh
2i: 2-furyl
10
11
12
13
14
2k: 4-MeO2CPh
2a: Ph
2h: 2-naph
2l: 2-thienyl
2d: 2-ClPh
b
c
d
e
entry
catalyst
solvent
yield (%)
anti/syn
ee [%] (anti)
15
g
1
2
3
4
5
6
7
8
4a
4g
4h
4d
4d
4d
4d
4d
4d
THF
THF
35
51
56
66
69
74
58
75
69
93/7
69/31
70/30
78/22
88/12
81/19
79/21
88/12
94/6
93
87
71
86
94
94
38
96
97
16
3ad
a
Absolute configuration was assigned by analogy with compound 3ah
(entry 7). Reaction was conducted in the presence of 4 Å MS (50
b
THF
THF
mg) with 5 mol % loading of 4d at room temperature unless otherwise
c
d
noted. Isolated yield. Diastereomer ratio was determined by 1H
Et2O
e
f
CH2Cl2
i-PrOH
MePh
MePh
NMR analysis. Obtained by chiral HPLC analysis. Absolute
configuration of 3ah was determined by X-ray crystallographic
analysis. Large-scale reaction of 2d (7 mmol) with 1a (10.5 mmol)
was conducted with 0.1 mol % loading of 4d in the presence of 4 Å
g
f
9
MS.
a
Absolute configuration was assigned by analogy with compound 3ah
b
(Table 2, entry 7). Reaction of 0.25 mmol of furanones 1 and 0.5
mmol of nitrostyrene 2 with 10 mol % loading of catalyst 4 at room
c
d
temperature unless otherwise noted. Isolated yield. Diastereomer
ratio was determined by 1H NMR analysis of crude product.
Obtained by chiral HPLC analysis. Reaction was conducted in the
releasing substituents on the aromatic ring smoothly reacted with
5-substituted furanones 1, affording 3 in good yields (78−82%)
with high diastereo- and enantioselectivities (90/10 to 96/4 dr;
88−94% ee) (entries 4 and 12). Thus, the electronic properties
of substituents on the aromatic rings of 2 have no effect on the
reaction. Furthermore, the substitution pattern on the aromatic
rings (entries 1−3) and the sterically demanding aromatic ring of
β-(E)-arylnitroalkenes 2g and 2h also had no deleterious effect
on the diastereo- and enantioselectivity (entries 6 and 7).
Michael additions of sterically demanding 5-iso-butylfuranone 1c
to β-arylnitroalkenes 2a, 2h, and 2l proceeded smoothly, giving
anti-adducts 3ca (94% ee), 3ch (98% ee), and 3cl (99% ee) in
moderate to high yields (entries 13−15). To evaluate the
potential of catalyst 4d, the nitro-Michael addition of more
sterically demanding 5-phenylfuranone 1b (A-value of Ph = 3.0
kcal mol−1; cf. Me = 1.70 kcal mol−1)14 to β-arylnitroalkenes 2
was carried out, affording the anti-adducts with high diastereo-
and enantioselectivities (>90/10 dr; 84−99% ee) (entries 9−
12). Thus, the present method is especially useful for
constracting the sterically congested oxygen-containing quater-
nary stereogenic centers adjacent to ternary stereogenic
centers.15 When the large-scale reaction of 1a (10.5 mmol)
and 2d (7 mmol) was conducted at room temperature, we found
that the catalyst loading could be reduced to only 0.1 mol %
without affecting the high diastereo- and enantioselectivity as
well as the high yield of the Michael adduct 3ad (96/4 dr, anti
major, 97% ee, 89% yield, TON = 890) (entry 16).16
e
f
presence of 4 Å MS (50 mg) with 5 mol % loading of 4d.
adduct 3a was obtained with high diastereo- and enantiose-
lectivity (93/7 = anti/syn, 93% ee), although the yield was very
low (35%) (entry 1). Catalysts 4g and 4h showed no
improvement in the diastereoselectivity (entries 2 and 3).
Although the diastereo- and enantioselectivity dropped consid-
erably (78/22 dr, anti major; 86% ee), 4d effectively suppressed
the polymerization of 2a, increasing the yield of 3a (66%) (entry
4). This is apparently due to the inhibition of the polymerization
by the sterically demanding 9-OCH2[2,4,6-(i-Pr)3C6H2] sub-
stituent. The screening of solvents showed toluene to be the
solvent of choice (entries 4−8). To our delight, addition of 4 Å
MS into the reaction mixture considerably improved the
diastereoselectivity without affecting the high enantioselectivity
(96/4 dr, anti major; 97% ee) (entry 9). Furthermore, catalyst
loading as low as 5 mol % can be achieved.
We then turned our attention to the substrate scope of the
anti-selective nitro-Michael reaction promoted by novel catalyst
4d. Table 2 shows that 0.1−5 mol % loadings of 4d allowed
complete conversion of the substrates in toluene at room
temperature, giving the corresponding anti-Michael adducts in
good yields (60−95%) with a high level of diastereo- and
enantioselectivities (8/12 to 97/3 dr; 84−99% ee).13 β-
Arylnitroalkenes 2 bearing electron-withdrawing and electron-
C
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Figure 2. Simplified pre-transition-state assembly model optimized at
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displays the simplified pre-transition-state assembly model
optimized at B3LYP/6-31++G(d,p) level, which accounts for
the stereochemistry of the nucleophilic attack of 6. To avoid the
steric repulsion between the substituent at the 2-position of the
intermediate (2R)-9 and the 5-substituent of the dienolate 6
bound to 6′-OH via H-bonding, dienolate 6 exposes the si-face to
(2R)-9. Repulsive interaction between the sterically demanding
9-OCH2Ar substituent and quinoline moiety directs the
quinoline moiety to form a hydrogen bond between 6′-OH
and 6. The calculation adequately predicts the sense of the
asymmetric induction.
In conclusion, we have developed a highly anti-selective nitro-
Michael reaction of furanones by a catalyst-controlled switching
of diastereoselectivity. Preliminary DFT calculations suggest that
the anti-selective nitro-Michael addition of aldehydes is
promising under similar conditions.
ASSOCIATED CONTENT
* Supporting Information
■
S
(11) Mantina, M.; Chamberlin, A. C.; Valero, R.; Cramer, C. J.;
Truhlar, D. G. J. Phys. Chem. A 2009, 113, 5806.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03539.
(12) Pyykko, P.; Atsumi, M. Chem. - Eur. J. 2009, 15, 186.
̈
(13) All substrates listed in Table 2 undergo extremely high syn-
selective nitro-Michael reaction in the presence of epi-quinine-derived
3,5-bis(CF3)benzamide catalyst; see ref 6a.
X-ray data for (5R,1S)-naphthyl (CIF)
Experimental procedure and compound characterization
(PDF)
(14) (a) Eliel, E. L.; Wilson, S. H. Stereochemistry of Organic
Compounds; Wiley: New York, 1993; pp 696−697. (b) Eliel, E. L.;
Wilson, S. H.; Doyl, M. P. Basic Organic Chemistry; Wiley: New York,
2001; pp 443−444.
(15) Bella, M.; Gasperi, T. Synthesis 2009, 2009, 1583.
(16) Most of the compounds 3 listed in Table 2 are highly crystalline
materials, which can be easily recrystallized from EtOH to give the
enantiomerically pure 3.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: sekikawa.tolu@gmail.com.
*E-mail: hatanaka@a-chem.eng.osaka-cu.ac.jp.
Notes
(17) For the X-ray analysis of 3ah, see Supporting Information.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work has been supported by a Grant-in-Aid for Scientific
Research (C) (20550101) from JSPS.
■
REFERENCES
■
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