N-spiro chiral quaternary ammonium bromide catalyzed diastereo- and enantioselective conjugate addition of nitroalkanes to cyclic α,β-unsaturated ketones under phase-transfer conditions

Article abstract of DOI:10.1021/ol0517170

(Chemical Equation Presented) Conjugate addition of various prochiral nitroalkanes to cyclic α,β-unsaturated ketones was found to be efficiently catalyzed by N-spiro C₂-symmetric chiral quaternary ammonium bromide 1b possessing a 3,5-bis(3,4,5-

Full text of DOI:10.1021/ol0517170

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5143-5146
N-Spiro Chiral Quaternary Ammonium
Bromide Catalyzed Diastereo- and
Enantioselective Conjugate Addition of
Nitroalkanes to Cyclic
Ketones under Phase-Transfer
Conditions
r,â-Unsaturated
Takashi Ooi, Saki Takada, Shingo Fujioka, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received July 20, 2005
ABSTRACT
Conjugate addition of various prochiral nitroalkanes to cyclic
symmetric chiral quaternary ammonium bromide 1b possessing a 3,5-bis(3,4,5-trifluorophenyl)phenyl substituent under solid
transfer conditions to afford the corresponding
enantiocontrol.
r
,
â
-unsaturated ketones was found to be efficiently catalyzed by N-spiro C2-
liquid phase-
γ-nitro ketones in excellent chemical yields with unprecedented levels of diastereo- and
−
The conjugate addition of appropriate stabilized carbanions
to R,â-unsaturated carbonyl compounds represents one of
the fundamental synthetic operations for the construction of
carbon-carbon bonds in organic chemistry.1 Among con-
ceivable combinations of stabilized carbanions and unsatur-
ated carbonyl substrates, the systems involving nitroalkanes
are attractive due to the diversity of the further functional
group transformations of the conjugate adducts such as
selective reduction to amino carbonyl compounds.2 There-
fore, notable efforts toward establishing the catalytic enan-
tioselective versions have been made on the basis of the
different types of strategies.2-5,7 Nevertheless, catalytic
asymmetric addition of nitroalkanes to cyclic R,â-unsaturated
ketones has only been reported for very few systems.5 In
1994, Yamaguchi and co-workers discovered the effective-
ness of rubidium prolinate as a catalyst for the addition of
nitropropane to cyclohexenone,5a,b and quite recently, Han-
(2) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001; Chapters 4 and 6. For a recent example of facile transformation
of optically active organonitro compounds, see: Czekelius, C.; Carreira,
E. M. Angew. Chem., Int. Ed. 2005, 44, 612.
(3) For review on catalytic asymmetric conjugate addition of stabilized
carbanions, see: (a) Yamaguchi, M. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. 3, Chapter 31.2. (b) Yamaguchi, M. In ComprehensiVe
Asymmetric Catalysis Supplement 1; Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds.; Springer: Berlin, 2004; p 151.
(1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992.
10.1021/ol0517170 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/14/2005

essian disclosed that the utilization of L-proline as catalyst
in the presence of trans-2,5-dimethylpiperazine significantly
improved the enantioselectivity of the addition of various
nitroalkanes to cyclic enones.5c Despite these important
contributions, however, control of both the relative and abso-
lute configuration of two adjacent stereogenic carbon centers
newly created during this bond-forming event still remains
as a challenging problem to be solved. Herein, we wish to
communicate that the conjugate addition of a series of
prochiral nitroalkanes to cyclic R,â-unsaturated ketones can
be efficiently catalyzed by N-spiro chiral quaternary ammon-
ium bromide of type 16,7 under solid-liquid phase-transfer
conditions to afford the corresponding γ-nitro ketones with
high diastereo- and enantioselectivities (Scheme 1).
Table 1. Optimization of the Conjugate Addition of
Nitropropane (3a) to Cyclohexenone (2a) under Phase-Transfer
Conditionsa
% eed
catal conc
1
T
reaction
%
entry
(M) (°C) time (h) yieldb syn/antic syn anti
1
2
3
4
5
6
7
8e
1a
1b 0.3
1c 0.3
1b 0.3
1b 0.1
1b 0.05 -20
1b 0.05 -40
1b 0.05 -40
0.3
0
0
0
0
0
0.6
0.5
15
1
1
6
99
97
95
98
99
99
91
97
87:13
93:7
78:22
94:6
94:6
96:4
98:2
98:2
76
80
21
84
86
91
92
91
30
39
4
45
47
57
37
40
Scheme 1
36
22
a Unless otherwise specified, the reaction was conducted with 5 equiv
of nitropropane (3a) in the presence of 1 equiv of Cs2CO3 and 1 mol % of
(S,S)-1 in toluene under the given reaction conditions. The relative and
absolute configurations of the conjugate addition product 4a were determined
by a single-crystal X-ray diffraction analysis after derivatization to its acetal
with (2R,3R)-butanediol. See Scheme 2. b Isolated yield. c Determined by
GLC analysis. d Enantiopurity of 4a was determined by GLC analysis using
a chiral column [Astec Chiradex Γ-TA (30 m × 0.25 mm)]. e With 3 equiv
of Cs2CO3.
concentration and at -40 °C (entry 7). It should be noted
that the use of excess Cs2CO3 led to substantial rate accel-
eration without sacrificing the stereoselectivities (entry 8).
The relative and absolute stereochemistries of syn-4a were
unequivocally determined by X-ray crystallographic analysis
after conversion to the corresponding acetal 5 with (2R,3R)-
On the basis of promising activity of chiral quaternary
ammonium bromide 1a in the conjugate addition of nitroal-
kanes to alkylidenemalonates under phase-transfer condi-
tions,7 we initially explored the possible utility of this catalyst
in the addition of nitropropane (3a) to cyclohexenone (2a).
Thus, a mixture of 2a, Cs2CO3 (1 equiv), and 1a (1 mol %)
in toluene was treated with 3a at 0 °C and then stirred at the
same temperature for 40 min, affording the corresponding
conjugate adduct 4a almost quantitatively. Here, preferential
formation of the syn isomer was observed (syn/anti ) 87:
13), and fortunately, its enantiomeric excess was determined
to be 76% ee (entry 1 in Table 1). This promising result
prompted us to further survey catalysts of this type, and we
found that 1b having the 3,5-bis(3,4,5-trifluorophenyl)phenyl
group as the 3,3′-aromatic substituent (Ar) provided the
highest levels of both diastereo- and enantiocontrols (entry
2). The importance of the m-terphenyl-derived structure of
the Ar moiety for attaining sufficient reactivity and selectivity
was evident from the diminished efficiency and stereose-
lectivities of the reaction under the influence of 1c6a,c (entry
3). Efforts were then made toward the optimization of the
reaction conditions, which revealed that decreasing the
substrate concentration at lower reaction temperature deliv-
ered a beneficial effect on the diastereo- and enantioselec-
tivities as included in Table 1. Consequently, syn-4a was
obtained predominantly (syn/anti ) 98:2) with 92% ee by
performing the conjugate addition at 0.05 M substrate
Scheme 2. Stereochemical Assignment
5144
Org. Lett., Vol. 7, No. 23, 2005

butanediol as shown in Scheme 2. Assuming the predominant
generation of the E-nitronate,8 the observed high syn
selectivity could not be fully rationalized by the nonchelate,
acyclic extended transition-state model.9 This stereochemical
preference may be accounted for by the severe steric
congestion caused by the chiral quaternary ammonium cation,
overwhelming the repulsion between the cyclohexenone
framework and the nitroalkane side chain (Et) (Figure 1, A
Table 2. Catalytic Asymmetric Conjugate Addition of
Nitroalkanes (3) to Cyclic R,â-Unsaturated Ketones (2) under
Phase-Transfer Conditionsa
Figure 1. Plausible transition-state model.
vs B). Judging from the product configuration, the chiral
ammonium cation should effectively shield the re-face of
the nitronate, and the selective approach of the cyclic enone
from the si-face should result.
Based on the above findings, we selected the catalysis of
1b at -20 °C (0.05 M substrate concentration) as optimal
conditions in terms of both asymmetric induction and reac-
tion efficiency and applied it in further experiments to probe
the substrate scope. The representative results summarized
in Table 2 clearly demonstrate the potential of this phase-trans-
fer-catalyzed conjugate addition protocol. Various prochiral
a Unless otherwise noted, the reaction was conducted with 5 equiv of 3
in the presence of 3 equiv of Cs2CO3 and 1 mol % of (S,S)-1b in toluene
at -20 °C for the given reaction time. Assignment of the relative and
absolute configurations was deduced from that of 4a. b Isolated yield. c De-
termined by 1H and 13C NMR analyses. d Enantiopurity of the major syn-4
was determined by HPLC analysis using a chiral column. For details, see
the Supporting Information. e Performed at -30 °C. f With 2 mol % of 1b.
(4) (a) Davis. A. P.; Dempsey, K. J. Tetrahedron: Asymmetry 1995, 6,
2829. (b) Keller, E.; Veldman, N.; Spek, A. L.; Feringa, B. L. Tetrahe-
dron: Asymmetry 1997, 8, 3403. (c) Funabashi, K.; Saida, Y.; Kanai, M.;
Arai, T.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 7557. (d)
Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257. (e) Kim, D. Y.; Huh,
S. C. Tetrahedron 2001, 57, 8933. (f) Bako´, T.; Bako´, P.; Szo¨llo˜sy, AÄ .;
Czugler, M.; Keglevich, G.; To˜ke, L. Tetrahedron: Asymmetry 2002, 13,
203. (g) Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002,
67, 8331. (h) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394.
(i) Allingham, M. T.; Howard-Jones, A.; Murphy, P. J.; Thomas, D. A.;
Caulkett, P. W. R. Tetrahedron Lett. 2003, 44, 8677. (j) Vakulya, B.; Varga,
S.; Csa´mpai, A.; Soo´s, T. Org. Lett. 2005, 7, 1967.
(5) (a) Yamaguchi, M.; Shiraishi, T.; Igarashi, Y.; Hirama, M. Tetra-
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S.; Shiraishi, T.; Hirama, M. Tetrahedron 1997, 53, 11223. (c) Hanessian,
S.; Pham, V. Org. Lett. 2000, 2, 2975. See also: (d) Schionato, A.; Paganelli,
S.; Botteghi, C.; Chelucci, G. J. Mol. Catal. 1989, 50, 11. (e) Tsogoeva, S.
B.; Jagtap, S. B. Synlett 2004, 2624.
(6) (a) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2000, 122, 5228. (b) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka,
K. Angew. Chem., Int. Ed. 2002, 41, 4542. (c) Ooi, T.; Kameda, M.;
Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139. (d) Ooi, T.; Kameda, M.;
Taniguchi, M.; Maruoka, K. J. Am. Chem. Soc. 2004, 126, 9685. See also:
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11790.
nitroalkanes were employed for the addition to cyclohexen-
one, and the corresponding γ-nitro ketones were obtained in
excellent chemical yields with high diastereo- and enantioselec-
tivities (entries 1-5). It should be noted that steric constraints
arising from the â- and γ-substituent of nitroalkane can be
overcome by using 2 mol % of 1b (entries 3 and 4). As an
acceptor, cycloheptenone and even cyclooctenone were found
to be a good candidate, though insufficient diastereocontrol
was observed in the case of cyclooctenone probably due to
its conformational flexibility (entries 6 and 7). Moreover,
the reaction with cyclohexenone derivative possessing addi-
tional functionilities such as 2-cyclohexen-1,4-dione monoket-
al appeared feasible with high efficiency and stereoselec-
tivities (entry 8).
In conclusion, we have demonstrated the effectiveness of
the chiral phase-transfer catalysis of N-spiro chiral quaternary
ammonium bromide 1b for the highly diastereo- and enan-
tioselective conjugate addition of nitroalkanes to cyclic R,â-
unsaturated ketones. This study certainly expands the scope
of our approach, and also implies the possibility of elaborat-
(8) Seebach, D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E. HelV.
Chim. Acta 1982, 65, 1101.
(9) (a) Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc. 1981, 103,
2016. (b) Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc. 1983, 105,
1598.
Org. Lett., Vol. 7, No. 23, 2005
5145

ing even more versatile catalyst systems for the synthetically
attractive yet relatively underdeveloped conjugate addition
chemistry of nitroalkanes.
Supporting Information Available: Representative ex-
perimental procedure, spectroscopic characterization, and 1H
and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
OL0517170
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Org. Lett., Vol. 7, No. 23, 2005