Syn-selective nitro-Michael addition of furanones to β,β-disubstituted nitroalkenes catalyzed by epi-quinine derivatives

Article abstract of DOI:10.1016/j.tetlet.2016.05.093

Epi-quinine-catalyzed asymmetric nitro-Michael addition of furanones to β,β,-disubstituted nitroalkenes is described. The reaction proceeded smoothly with 1-5 mol % loadings of epi-quinine catalysts at room temperature, giving the corresponding Michael adducts in high yields (72-93%) with extremely high diastereo- and enantioselectivities (>98/2 dr, syn major; 95-99% ee). This reaction provides an effective and straightforward method for constructing all-carbon quaternary stereogenic centers adjacent to oxygen-containing quaternary stereogenic centers.

Full text of DOI:10.1016/j.tetlet.2016.05.093

Accepted Manuscript
Syn-Selective Nitro-Michael Addition of Furanones to β,β-Disubstituted Nitro-
alkenes Catalyzed by Epi-Quinine Derivatives
Tohru Sekikawa, Hayato Kitaura, Takayuki Kitaguchi, Tatsuya Minami, Yasuo
Hatanaka
PII:
S0040-4039(16)30626-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.093
TETL 47712
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 February 2016
19 May 2016
24 May 2016
Please cite this article as: Sekikawa, T., Kitaura, H., Kitaguchi, T., Minami, T., Hatanaka, Y., Syn-Selective Nitro-
Michael Addition of Furanones to β,β-Disubstituted Nitroalkenes Catalyzed by Epi-Quinine Derivatives,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.093
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Syn-Selectieve Nitro-Michael Addition of
Furanones to ,-Disubstituted Nitroalkenes
Catalyzed by Epi-Quinine Derivatives
Leave this area blank for abstract info.
Tohru Sekikawa,* Hayato Kitaura, Takayuki Kitaguchi, Tatsuya Minami, Yasuo Hatanaka*

1
Tetrahedron Letters
Syn-Selective Nitro-Michael Addition of Furanones to ,-Disubstituted Nitroalkenes
Catalyzed by Epi-Quinine Derivatives
Tohru Sekikawa*, Hayato Kitaura, Takayuki Kitaguchi, Tatsuya Minami, Yasuo Hatanaka*
Department of Applied Chemistry, Graduate School of Engineering, Osaka City University, Sumiyoshiku, Osaka 558-8585, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Epi-quinine-catalyzed asymmetric nitro-Michael addition of furanones to ,,-disubstituted
nitroalkenes is described. The reaction proceeded smoothly with 1-5 mol % loadings of epi-
quinine catalysts at room temperature, giving the corresponding Michael adducts in high yields
(72-93%) with extremely high diastereo- and enantioselectivities (>98/2 dr, syn major; 95-99%
ee). This reaction provides an effective and straightforward method for constructing all-carbon
quaternary stereogenic centers adjacent to oxygen-containing quaternary stereogenic centers.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric Michael Reaction
All-carbon quaternary stereogenic center
Furanone
,-Disubstituted nitroalkenes
Quaternary carbon stereogenic centers exist widely in natural
products and biologically active compounds.1 Catalytic
enantioselective construction of all-carbon quaternary
stereogenic center is one of the most important subjects in or-
ganic synthesis.2
Among various strategies for constructing
enantiomerically enriched quaternary carbon centers, the cata-
lytic asymmetric Michael addition of carbon nucleophiles to
,-disubstituted nitroalkenes is one of the simple and straight-
forward method. However, only a handful studies are available
dealing this reaction.3 Significant steric repulsion between in-
coming carbon nucleophiles and sterically demanding ,-
disubstituted nitroalkenes seems to be the reason for the diffi-
culty of the nitro-Michael reaction of ,-disubstituted
nitroalkenes.
We report herein the epi-quinine catalyzed asymmetric Mi-
chael addition of 5-substituted 2(3H)-furanones 1 to ,-
disubstituted nitroalkenes 2 as a highly effective method for
constructing sterically congested all-carbon quaternary
stereogenic centers adjacent to oxygen-containing quaternary
stereogenic center (Scheme 1).4 To the best of our knowledge,
catalytic asymmetric conjugate addition of trisubstituted carbon
nucleophiles to -disubstituted nitroalkenes is very rare.
With the purpose of evaluating the catalytic activity of a
series of epi-quinine derivatives, the catalytic asymmetric
Scheme 1. Michael addition of furanones to ,-disubstituted nitroalkenes.
Michael addition of angelica lactone 1a to (Z)-1-phenyl-2-
nitroacrylate 2a was examined at 10 mol % loadings of epi-
quinines at room temperature (Table 1). Solvent screening
indicated toluene to be the solvent of choice. Quinine-derived
catalysts 4 are capable of promoting the Michael addition of 1a
to 2a, affording the corresponding Michael adduct 3aa with
syn-selectivity. For example, with a 10 mol % loading of
quinine 4a, the Michael adduct 3aa was obtained in the
moderate yield (67%), whereas diastereo- and enantioselectivity
was very low (syn/anti = 76/24; 27% ee (syn)) (entry 1).
Catalyst 4b5 showed no improvement of the catalytic activity
(entry 2). To our surprise, amide catalyst 4c exhibited very low
diastereoselectivity (syn/anti = 53/47) (entry 3), although the
nitro-Michael addition of furanones to -nitrostyrene catalyzed
by 4c gave the Michael adducts with high syn-selectivity (>98/2
dr).4a
Correspomding author. Tel.: +81 6 6605 2979; fax: +81 6 6605
2980
E-mail address: sekikawa.toru@gmail.com;
hatanaka@a-chem.eng.osaka-cu.ac.jp

2
Tetrahedron
Table 1. Catalytic nitro-Michael addition of 1a to 2a.
Figure 1. X-ray structure of compound 3ad.
Table 2. Catalytic nitro-Michael addition of furanones 1
to ,-disubstituted nitroalkenes 2.
Reaction
time (h)
Yield
(%)c
Entryb
syn/antid
76/24
83/17
53/47
>98/2
>98/2
95/5
Ee [%] (syn)e
Catalyst
4a
1
2
3
4
5
6
17
24
30
17
16
17
24
67
68
65
65g
88
57
93
27
-11
24
90
91
16
98
4b
Yield
[%]d
Ee
4c
Entry
1
Furanone
1a
Ar
R2
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Nitroalkene
Product
3ab
3ac
3adf
3ae
3af
[%]e
4d
4-
2b
2c
2d
2e
2f
91
92
89
87
89
88
82
72
80
79
78
91
87
93
95
96
97
97
98
97
99
96
96
97
98
97
98
97
MePh
4e
4-
1a
2
MeOPh
4f
1a
3
4- ClPh
3-ClPh
7f
4e
>98/2
1a
4
a
Absolute configuration was assigned by analogy with compound
2-
b
1a
5
3ad (Table 2, entry 3). Reaction of 1a (0.5 mmol) with 2a (0.25
Thienyl
mmol) was conducted with a 10 mol % loading of 4 at room tem-
perature unless otherwise noted. cIsolated yield. dDiastereomer ra-
tion was determined by 1H NMR analysis of the crude material.
1b
2a
2b
2c
2d
2e
2f
3ba
3bb
3bc
3bd
3be
3bf
6
Ph
4-
1b
7
f
eObtained by chiral HPLC analysis. Reaction was conducted in the
MePh
presence of MS 4 Å (50 mg) with a 5 mol % loading of 4e. gConjugate
addition at the  carbon of 1a took place as a side reaction, leading to
moderate yield of 3aa.
4-
1b
8
MeOPh
1b
9
4-ClPh
3-ClPh
1b
10
11
12
13
14g
2-
A
significant improvement of the diastereo- and
1b
Thienyl
enantioselectivity has been attained upon the employment of
epi-quinine derivatives 4d and 4e (entries 4 and 5). A 10 mol %
loading of 4e successfully catalyzed the Michael addition of 1a
to 2a, affording the Michael adduct 3aa in a 88% yield with
high diastereo- and enantioselectivity (>98:2 dr, syn major; 91%
ee) (entry 5). In contrast, the replacement of the 6’-OH of 4e
with 6’-OMe (4f) profoundly depresses the catalytic
effectiveness (syn/anti = 95/5 ; 16% ee) (entry 6). These results
conclusively revealed that the 6’-OH of epi-quinine derivatives
4d and 4e is essential for the high asymmetric induction. To
our delight, the addition of MS 4Å to the reaction mixture
considerably reduced the catalyst loading as low as 5 mol %
without affecting high diastereo- and enantioselectivity (>98/2
dr, syn major; 98% ee) (entry 7).
i-
Pr
i-
Pr
1a
2g
2g
2a
3ag
3bg
3aa
Ph
Ph
Ph
1b
1a
Et
a1NMR analysis of the crude material indicated that the diastereomer
ration of all reactions is >2:98, syn-major. bAbsolute configuration
was assigned by analogy with compound 3ad (entry 3). c Reaction of 1
(0.5 mmol) with 2 (0.25 mmol) was conducted with a 5 mol % load-
d
ing of 4e at room temperature for 22 h unless otherwise noted.
f
Isolated yield. e Obtained by chiral HPLC analysis. Absolute configu-
g
ration of 3ad was determined by X-ray crystallographic analysis.
Large scale reaction of 1a (20 mmol) with 2a (10 mmol) was conduct-
ed with a 1 mol % loading of 4e at room temperature for 91 h.
We then turned out our attention to the substrate scope of
the syn-selective nitro-Michael reaction catalyzed by 4e (Table
2). A 5 mol % loading of catalyst 4e allowed complete
conversion of the disubstituted nitroalkenes 2 in toluene at
room temperature, giving the corresponding Michael adducts 3
in good yields (72-93%) with extremely high diastereo- and
enantioselectivities (>98/2 dr, syn major; 95-99% ee) (entries
1-14).
The absolute configurartion of the Michael adduct 3ad
(entry 3) was unambiguously determined by X-ray
crystallographic analysis to be (5R, 1’R) (Figure 1).6 The
configurations of other Michael adducts 3 were assighned by
analogy.
(Z)-1-Aryl-2-nitroacrylate 2 bearing electron-withdrawing
and electron-releasing substituents on the aromatic ring reacted

3
smoothly with angelica lactone 1a, affording 3ab (91% yield,
95% ee), 3ac (92% yield, 96% ee), 3ad (89% yield, 97% ee),
and 3ae (87% yield, 97% ee) (entries 1-4). Thus, the electronic
properties of substituents on the aromatic rings of Michael ac-
ceptors 2 have no effect on the reaction. Substitution pattern in
the aromatic rings had no deleterious effect on the diastereo-
and enantioselectivities (entries 3, 4, 9 and 10). Furthermore,
the Michael additions of sterically demanding 5-(iso-
butyl)furanone 1b to ,-disubstituted nitroalkenes 2a, 2b, 2c,
2d, and 2e successfully took place, giving the syn-adducts 3ba
(97% ee), 3bb (99% ee) , 3bc (96% ee), 3bd (96% ee) and 3be
(97% ee) in good yields (72-82%) (entries 6-10). The reaction
of Michael acceptor 2f bearing heteroaryl substituent with the
Michael donor 1a and 1b also proceeded smoothly to furnish
the corresponding adducts 3af (98% ee) and 3bf (98% ee) in
good yields (entry 5 and 11). Furthermore, the nitroalkene 2g
bearing sterically demanding COO-i-Pr substituent also effec-
tively underwent the 4e-catalyzed Michael reaction with
furanone 1a and 1b, furnishing the corresponding Michael ad-
duct 3ag and 3bg in high yields (91% and 87%, respectively)
with excellent diastereo- and enantioselectivities (97% ee and
98% ee, respectively) (entries 12 and 13). These results demon-
strated that the steric bulkiness of the Michael donor 1 and Mi-
chael acceptor 2 had no effect on the yields as well as the
diastereo- and enantioselectivities.
nitro-Michael reaction catalyzed by 4e would result from addi-
tion-elimination mechanism depicted in Scheme 3. However,
Scheme 3. Plausible reaction mechanism of the nitro-Michael reaction
catalyzed by 4e.
We examined the large scale reaction to establish practical
reaction conditions. When the reaction of 1a (20 mmol) and 2a
(10 mmol) was conducted at room temperature, it has been
found that the catalyst loading could be reduced to only 1 mol
% without affecting the high diastereo- and enantioselectivity as
well as the high yield of the Michael adduct 3aa (>98/2 dr, 97%
ee, 93% yield, TON = 93) (entry 14). Thus, the present method
is demonstrated to be highly useful for the construction of
sterically congested all-carbon quaternary stereogenic centers
adjacent to oxygen-containing quaternary stereogenic centers
with extremely high diastereo- and enantioselectivities.
It is noteworthy that the isomerization of (Z)-1-phenyl-2-
nitroacrylate (Z)-2a to (E)-2a took place in toluene at room
temperature with 10 mol % loadings of 4d and 4e, afoording a
mixture of geometrical isomers with a Z:E ratio of 74:16 after 4
h. In contrast, catalytic amounts of 4a, 4b, and 4c did not
promote the isomerization of (Z)-2a, suggesting that the 6’-OH
of 4e and 4d plays a crucial role in the activation of the
nitroalkenes (Scheme 2).
Figure 2. Simplified structure of nitronate intermediate (2R)-6 and nitro-
ammonium intermediate (2R)-7 optimized at B3LYP/6-31G(d).
the 13C NMR spectra of the mixture of 4e and (Z)-1-phenyl-2-
nitroacrylate 2a (4e : 2a = 1 : 2, C6D6) indicated that (13C) of
the C(1) atom of 2a did not shift upon the addition of 4e,
indicating the very weak interaction between the quinuclidine
N(1) of 4e and nitrostyrene 2a.
In order to reveal the role of the 6’-OH group of catalyst 4e,
we carried out theoretical calculations (Figure 2). The
simplified structures of the nitronate intermediate (2R)-6 and
the nitro-ammonium intermediate (2R)-7 were optimized at
B3LYP/6-31G(d). The results of the calculations are wholly
surprising. The optimized structure of the intermediate (2R)-6
discloses the very weak interaction between the quinuclidine
N(1) and nitroalkene as indicated by the very long N(1)-C(2)
bond length (3.47 Å), which is roughly comparable to the sum
of van der Waals radii of N and C (3.25 Å).7 Thus, an
intramolecular H-bonding between the 6’-OH and the nitronate
oxygen seems to stabilize the intermediate (2R)-6. The
theoretical calculation strongly supports a crucial role of the 6’-
OH in promoting the conjugate addition of N(1) to the re-face
of nitroalkene.
Scheme 2. Isomerization of (Z)-2a promoted by 4e and 4d.
Based on this result, we have made an assumption that the
quinuclidine nitrogen (N1) of epi-quinine catalysts 4e and 4d
would undergo the conjugate addition to the re-face of ,-
disubstituted nitroalkenes 2, giving nitronate intermediate (2R)-
6 (Scheme 3). Protonation of 6 with furanone 1 affords nitro-
ammonium intermediate (2R)-7. Subsequently, nucleophilic
attack of dienolate 8 to the intermediate (2R)-7 takes place from
the si-face of 8 to give the Michael adduct (5R, 1’R)-3. Thus,
the extremely high diastereo- and enantioselectivities of the

4
Tetrahedron
This work has been supported by a Grant-in-Aid for Scientific
The long N(1)-C(2) bond length would be ascribed to the
Research (C) (20550101) from JSPS
strong electrostatic repulsion between the nitrate moiety and
N(1), which bears a considerable negative charge (-0.391:
Mulliken). The formal positive charge on N(1) would be
neutralized by electron releas from five neighboring hydrogen
atoms in the geminal positions relative to N(1).8 The
electrostatic repulsion between N(1) and C(2) of the (2R)-6 can
be reduced when (2R)-6 is protonated by furanones (Figure 2).
The nitroammonium intermediate (2R)-7 is considered
thermodynamically stable, but the N(1)-C(2) bond length of
1.63 Å is considerably longer than a sum of covalent radii of N
and C (1.46 Å).9
A large number of the nitro-Michael addition of aldehydes
to -monosubstituted nitroalkenes catalyzed by enamine
catalysts and bifunctional hydrogen bonding catalysts have been
reported.10 The very high diastereo- and enantioselectivities of
these reactions are explained by the transition state model
proposed by Seebach, in which donor atoms and acceptor atoms
are close to each other (Scheme 4).11 It is interesting to note
that although the nitro-Michael reaction catalyzed by 4e
proceeds through the totally different mechanism, the reaction
shows an almost perfect diastereo- and enantioselectivity.
Supplementary Material
Supplementary material associated with this article can be
found, in online version, at http://
References and notes
1.
2.
Liu, Y.; Han, S. -J.; Liu,W. –B.; Stoltz, B. M. Acc. Chem. Res.
2015, 48, 740.
(a) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (b) Corey, E. J.;
Guzman-Perez, A. Angew. Chem. Int. Ed. 1998, 37, 388. (c) Bel-
la, M.; Gasperi, T. Synthesis 2009, 1583.
3.
4.
(a) Kastl, R.; Wennemers, H. Angew. Chem. Int. Ed. 2013, 52.
7228. (b) Chen, L. –A.; Xiaojuan, T.; Jianwei, X.; Weici, X.; Lei,
G.; Meggers, E. Angew. Chem. Int. Ed. 2013, 52, 14021. (c)
Weng, J. –Q.; Deng, Q. -M.; Wu, L.; Xu, K.; Wu, H.; Liu, R. -
R.; Gao, J. -R. Org. Lett. 2014, 16, 776.
Recently, we have reported the asymmetric nitro-Michael addi-
tion of furanones promoted by alkaloid catalysts. (a) Sekikawa,
T.; Kitaguchi, T.; Kitaura, H.; Minami, T.; Hatanaka, Y. Org.
Lett. 2015, 17, 3026. (b) Sekikawa, T.; Kitaura, H.; Kitaguchi,
T.; Minami, T.; Hatanaka, Y. Org. Lett. 2016, 18, 646. (c) Man-
na, M. S.; Kumar, V.; Mukherjee, S. Chem. Commun. 2012, 48,
5193. (d) Terada, M; Ando, K. Org. Lett. 2011, 13, 2026.
Wang, Y.; Li, Z.; Xiong, T.; Zhao, J.; Meng, Q. Synlett 2014,
2155.
5.
6.
Crystallographic data for 3ad have been deposited with Cam-
bridge Crystallographic Data Centre as supplementary publica-
tion CCDC 1443401. Copy of the data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
7.
8.
9.
Mantina, M.; Chamberlin, A. C.; Valero, R.; Cramer, C. J.;
Truhlar, D. G. J. Phys. Chem. A, 2009, 113, 5806.
Chandra, A.; Chen, Z.; Hatanaka, T.; Minami, T.; Hatanaka, Y.
Organometallics, 2013, 32, 3575.
Scheme 4. Nitro-Michael reaction via Seebach’s transition state model
More noteworthy is the extremely high catalytic activity of
epi-quinine derived 4e, which can promote the carbon-carbon
bond formation between the sterically congested Michael
donors such as compound 1b and sterically demanding ,-
disubstituted nitroalkenes 2, in spite of unfavorable steric
repulsion.12 The nitro-Michael reactions catalyzed by
bifunctional hydrogen bonding catalysts such as thiourea
derivatives and secondary amine catalysts proceed with a weak
non-covalent H-bonding activation of nitroalkenes.10d,h In view
of the weak activation of nitroalkenes in the reactions catalyzed
by these catalysts, it is likely that the bifunctional hydrogen
bonding catalysts as well as the secondary amine catalysts
hardly promote the nitro-Michael addition of the sterically
demanding Michael donors to ,-disubstituted nitroalkenes 2.
As for the 4e-catalyzed reaction, strong activation of
nitroalkenes by a covalent bond eanbles the carbon-carbon bond
formation containing highly sterically congested reaction
centers.12 Thus, the potential of the 4e and similar catalysts for
the other asymmetric Michael reactions containing sterically
congested reaction centers seems to be very promising.
Pyykkö, P.; Atsumi, M. Chem. Eur. J. 2009,15, 186.
10. For selected recent review of organocatalytic asymmetric nitro-
Michael reactions and the application to organic synthesis, see:
(a) Somanatham, R.; Chávez, D.; Servin, F. A.; Romero, J. A.;
Navarrete, A.; Parra-Hake, M.; Aguirre, G.; de Parrod, C. A.;
González, J. S. Curr. Org. Chem. 2012, 16, 2440. (b) Chauhan,
P.; Chimni, S. S. RSC. Adv, 2012, 2, 737. (c) Raimondi, W.;
Bonne, D.; Rodriguez, J. Angew. Chem., Int. Ed. 2012, 51, 40.
(d) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol.
Chem. 2013, 11, 7051. (e) Xi, Y.; Shii, X. Chem. Commun.
2013. 49. 8583. (f) Roux, C.; Bressy, C. In Comprehensive
Enantioselective Organocatalysis; Dalco P., Ed.; Wiley-VCH:
Weinheim, 2013, Vol. 3, pp. 1013-1042. (g) Rios, R.; Moyano,
A. In Catalytic Asymmetric Conjugate Reaction; Cordóva, A.;
Ed.; Wiley-VCH: Weinheim, 2010; pp. 191-218. (h) Tsogoeva,
S. B. Eur. J. Org. Chem. 2007, 1701.
11. (a) Seebach, D.; Goliński, J. Helv. Chim. Acta 1981, 64, 1413.
(b) Burés, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem.
Soc. 2011, 133, 8822. (c) Patora-Komisarska, K.; Benohoud,
M.; Ishikawa, H.; Seebach, D.; Hayashi, Y. Helv. Chim. Acta
2011, 94, 71. (d) Burés, J.; Armstrong, A.; Blackmond, D. G. J.
Am. Chem. Soc. 2012, 134, 6741. (e) Ling, R.; Yoshida, M.;
Mariano, P. S. J. Org. Chem. 1996, 61, 4439.
12. Compounds 3 are highly sterically congested. The 1H NMR
spectra of compounds 3ba, 3bb, 3bc, 3bd, 3be, 3bf, and 3bg
displyed that two terminal methyl groups involved in iso-butyl
groups are not chemical shift equivalent because of rotational
hindrance of iso-butyl groups in sterically-congested environ-
ment. Two methyl groups of COO-i-Pr in compound 3ag and
3bg also are not chemical shift equivalent: see supporting mate-
rial.
In summary, we have developed a highly diastereo- and
enantioselective nitro-Michael addition of furanones to ,-
disubstituted nitroalkenes catalyzed by epi-quinine catalyst 4e.
The reaction offers an effective and reliable method for con-
structing chiral all-carbon quaternary stereogenic centers adja-
cent to oxygen-containing quaternary stereogenic centers.
Acknowledgement

5
Highlights
• Michael Addition of Furanones to ,-Disubstituted Nitroalkenes proceeded smoothly.
• Unusual high catalytic activity of epi-quinine derivatives was proved.
• Method for the construction of chiral all-carbon quaternary centers was developed.
• Diastereo- and enantioselectivities are almost perfect (>98:2 dr; 95-99% ee)