Asymmetric Michael addition of silyl nitronates to cyclic α,β-unsaturated ketones catalyzed by chiral quaternary ammonium bifluorides: Isolation and selective functionalization of enol silyl ethers of optically active γ-nitro ketones

Article abstract of DOI:10.1016/j.tetlet.2005.10.154

Highly enantioselective Michael addition of silyl nitronates to cyclic α,β-unsaturated ketones has been accomplished by the utilization of N-spiro C₂-symmetric chiral quaternary ammonium bifluoride 1 as an efficient catalyst, offering a new rou

Full text of DOI:10.1016/j.tetlet.2005.10.154

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 145–148
Asymmetric Michael addition of silyl nitronates to cyclic
a,b-unsaturated ketones catalyzed by chiral quaternary ammonium
bifluorides: isolation and selective functionalization of enol
silyl ethers of optically active c-nitro ketones
Takashi Ooi, Kanae Doda, Saki Takada and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University Sakyo, Kyoto 606-8502, Japan
Received 21 October 2005; accepted 31 October 2005
Available online 22 November 2005
Abstract—Highly enantioselective Michael addition of silyl nitronates to cyclic a,b-unsaturated ketones has been accomplished by
the utilization of N-spiro C2-symmetric chiral quaternary ammonium bifluoride 1 as an efficient catalyst, offering a new route to the
enol silyl ethers of optically active c-nitro ketones. The synthetic utility of this transformation has been demonstrated by the dia-
stereoselective derivatizations of the optically active enol silyl ethers to the corresponding a-substituted cyclic ketones having three
consecutive stereochemically defined stereocenters.
ꢀ 2005 Elsevier Ltd. All rights reserved.
We recently communicated that N-spiro chiral quater-
nary ammonium bifluoride 1a catalyzes the Michael
addition of silyl nitronates to a,b-unsaturated aldehydes
with high diastereo- and enantioselectivities, providing a
direct access to both optically active c-nitro aldehydes
and their enol silyl ethers.1,2 This achievement prompted
us to further examine the scope of the efficient catalysis
of the chiral ammonium bifluoride, particularly with
respect to the Michael acceptors. Herein, we report that
the unique Michael addition protocol can be success-
fully extended to cyclic a,b-unsaturated ketones,
which allows the isolation of enol silyl ethers of the
corresponding c-nitro ketones with excellent stereoselec-
tivities (Scheme 1). In addition, synthetic advantage of
the present approach over the precedent strategies3–5
has been clearly demonstrated by the facile one-pot
functionalization of the optically active enol silyl ethers.
ence of (R,R)-1a1 (2 mol %) in toluene. The reaction was
found to proceed smoothly at ꢀ40 ꢁC to give a diaste-
reomeric mixture of the desired enol silyl ether 3a
(n = 1) in 90% isolated yield with anti/syn ratio of
98:2. The enantiomeric excess of the major anti isomer
was determined to be 87% ee after quantitative conver-
sion to the corresponding c-nitro ketone 4a (n = 1) by
treatment with 1 N HCl in THF (entry 1 in Table 1).
Encouraged by this promising result, we thoroughly
evaluated the effect of the catalyst structure mainly on
the enantioselectivity, which revealed that chiral ammo-
nium bifluoride 1b6,7 possessing 3,5-bis[3,5-bis(trifluoro-
methyl)phenyl]phenyl group exhibited a superior level
of asymmetric induction to afford anti-3a (n = 1) almost
exclusively in 91% yield (anti/syn = 99:1) with 96% ee
(entry 2).
The results of experiments to probe the scope of this
optimized asymmetric Michael addition system are also
summarized in Table 1. Cyclopentenone and cyclohepte-
none were employable as a useful acceptor, though
moderate stereoselectivity was observed in the case of
the former (entries 3 and 4). As a Michael donor, a series
of different silyl nitronates 2b–f were examined with
cyclohexenone as a representative electrophilic partner.
High levels of catalytic efficiency and stereocontrol were
available in the additions of 2b and 2c regardless of the
length of carbon chain in the silyl nitronates (entries 5
Initially, we attempted the addition of silyl nitronate 2a
derived from nitropropane to cyclohexenone in the pres-
Keywords: Chiral quaternary ammonium bifluorides; Cyclic enones;
Enol silyl ethers; Michael addition; c-Nitro ketones; Silyl nitronates.
*
Corresponding author. Tel./fax: +81 75 753 4041; e-mail: maruoka@
kuchem.kyoto-u.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.154

146
T. Ooi et al. / Tetrahedron Letters 47 (2006) 145–148
(R,R)-1
(2 mol%)
OSiMe3
N
n
n
1N HCl
R
R
n
+
O
OSiMe3
O
toluene
–78~–40˚C
THF
0 ˚C~r.t.
O
R
NO2
NO2
CF3
2
3
4
Ar
Ar
F3C
HF2
But
N
Ar =
CF3
But
(R,R)-1
1b
1a
CF3
Scheme 1.
Table 1. Asymmetric Michael addition of silyl nitronates 2 to cyclic a,b-unsaturated ketones catalyzed by chiral quaternary ammonium bifluoride 1:
Isolation of optically active enol silyl ethers 3a
OSiMe3
n
OSiMe3
(R,R)-1 (2 mol%)
N
n
R 1'
+
O
3
toluene
–78 ~ –40 ˚C
O
R
2a–f
NO2
3a–f
Entry
Silyl nitronate (R)
Enone (n = 0, 1, and 2)
n = 1
Catalyst (R,R)-1
Yieldb (%) (anti/syn)c
eed (%) (config)e
Product
1
2
3
4
5
6
7f
8f
9f
Et (2a)
1a
1b
90 (98:2)
91 (99:1)
81 (71:29)
70 (95:5)
74 (97:3)
81 (99:1)
90 (99:1)
75 (92:8)
75 (94:6)
87 (3R,10S)
96 (3R,10S)
3a (n = 1)
3a (n = 1)
3a (n = 0)
3a (n = 2)
3b
3c
3d
3e
3f
n = 0
n = 2
n = 1
70
90
Me (2b)
CH2CH2CH@CH2 (2c)
i-Pr (2d)
CH2OCH3 (2e)
CH2CH2CO2CH3 (2f)
96 (3R,10S)
94
88
97
92
a Unless otherwise noted, the reaction was conducted with 1.2 equiv of 2 and cyclic a,b-unsaturated ketone in the presence of 2 mol % of (R,R)-1 in
toluene (0.1 M substrate concentration) at ꢀ78 ꢁC for 0.5 h and at ꢀ40 ꢁC for 2 h.
b Isolated yield.
c Determined by 1H NMR analysis.
d Enantiomeric excess of the major anti-3 was determined by GLC analysis using a chiral column [Astec Chiradex C-TA (30 m · 0.25 mm)] after
conversion to the corresponding ketone 4. Optical purity of the minor syn-3 was generally lower (13–63% ee).
e The absolute configuration of 3a (n = 1) was confirmed, after hydrolysis to 4a (n = 1), by comparison of the GLC retention time with the reported
value.5 The absolute configuration of 3b was assigned, after conversion to the acetal of the corresponding a-brominated ketone with (2R,3R)-(ꢀ)-
2,3-butanediol, by X-ray crystallographic analysis.8
f The reaction was performed at ꢀ78 ꢁC for 0.5 h and then at ꢀ20 ꢁC for 2 h.
and 6). Although the use of b-branched 2d caused rate
retardation, it was overcome by raising the reaction tem-
perature to ꢀ20 ꢁC (entry 7). Silyl nitronates bearing an
additional oxygen-containing functional group such as
2e and 2f were also tolerated, and the corresponding
Michael adducts 3e and 3f were obtained with excellent
diastereo- and enantioselectivities (entries 8 and 9).
c-nitro ketones having three consecutive stereocenters
as illustrated in Scheme 2.
The generation of anti-3a (n = 1) by the chiral quater-
nary ammonium bifluoride 1b-catalyzed Michael addi-
tion of 2a to cyclohexenone at ꢀ40 ꢁC, followed by
the addition of N,N-dimethylformamide as a polar
co-solvent and N-bromosuccinimide and continuous
stirring at 0 ꢁC for 0.5 h resulted in the production of
a-brominated product 5 in 97% yield. Here, 5a with
cis-disposition of a-bromo and b-nitroalkyl substituents
was formed preferentially to another trans isomer 5b.9
The one-pot a-phenylation was also achieved with
The versatility of the optically active enol silyl ethers 3 in
synthetic chemistry serves as a stimulus for exploration
of the potential application of this methodology.
Accordingly, we established one-pot, stereoselective
transformation of 3 to the corresponding a-substituted

T. Ooi et al. / Tetrahedron Letters 47 (2006) 145–148
147
OSiMe3
N
+
O
O
Et
2a
NBS (2 equiv)
(R,R)-1b (2 mol%)
Et
Et
+
O
O
toluene
–78 ˚C, 0.5 h
toluene–DMF (1:1)
–40~0 ˚C, 0.5 h
NO2 Br 5a
NO2 Br 5b
–40 ˚C, 2 h
97% (5a/5b = 85:15)
Ph4BiF (1.1 equiv)
Et
Et
OSiMe3
O
toluene–THF (1:1)
–40 ˚C~r.t., 0.5 h
NO2
NO2 Ph
6 62%
anti-3a (n = 1, 96% ee)
single diastereomer
(HCHO)n (2 equiv)
Me2AlCl (2.4 equiv)
1N HCl
Et
*
O
CH2Cl2
NO2
–40 ˚C~r.t., 0.5 h
OH 7 52%
single diastereomer
Scheme 2.
fluorotetraphenylbismuth (Ph4BiF)10 to afford 6 in 62%
yield with complete diastereocontrol.11 Furthermore,
dimethylaluminum chloride-mediated reaction with
paraformaldehyde appeared feasible, giving rise to a-
hydroxymethylcyclohexanone derivative 7 as a single
diastereomer (52%).12
CH2), 1.87–1.72 (3H, m, CH2), 1.64–1.54 (1H, m,
CH2), 1.28–1.19 (1H, m, CH2), 0.95 (3H, t, J = 7.4 Hz,
CH3), 0.17 (9H, s, SiCH3); 13C NMR (100 MHz,
CDCl3): d 153.03, 102.34, 95.00, 38.48, 29.40, 24.78,
23.86, 21.01, 10.23, 0.00; IR (liquid film) 2941, 2866,
1665, 1549, 1458, 1373, 1254, 1211, 1196, 930, 899,
870, 847, 808, 756 cmꢀ1. To a stirred solution of 3a
(n = 1) (70.1 mg, 0.272 mmol) in THF (3 mL) was added
1 N HCl (1 mL) at 0 ꢁC. After vigorous stirring at room
temperature for 0.5 h, the whole mixture was extracted
with ether. The combined organic extracts were washed
with brine and dried over Na2SO4. Evaporation of sol-
vents and purification of the residue by column chroma-
tography on silica gel (ether/hexane = 1:1 as eluant)
afforded c-nitro ketone 4a (n = 1)5 quantitatively. The
enantiomeric excess of 4a (n = 1) was determined to be
96% ee by GLC analysis; conditions: Astec Chiradex
C-TA (30 m · 0.25 mm) column (120 ꢁC isotherm),
retention time; syn isomer: 55.8 min (3S*,10S*) and
58.1 min (3R*,10R*), anti isomer: 62.3 min (3S,10R)
and 91.5 min (3R,10S).
In summary, we have developed highly diastereo- and
enantioselective Michael addition of various prochiral
silyl nitronates to cyclic a,b-unsaturated ketones under
mild conditions by the use of N-spiro C2-symmetric chi-
ral quaternary ammonium bifluoride 1b as an efficient
catalyst; this allows the isolation of enol silyl ethers
of optically active c-nitro ketones. The synthetic utility
of this new asymmetric transformation has been high-
lighted by the diastereoselective functionalizations of
the optically active enol silyl ethers to the corre-
sponding a-substituted c-nitro ketones bearing three
consecutive stereochemically defined stereogenic carbon
centers.
Typical experimental procedure is as follows (Table 1,
entry 2): To a solution of chiral quaternary ammonium
bifluoride (R,R)-1b (9.6 mg, 0.006 mmol) in toluene
(3 mL) was added cyclohexenone (29.0 lL, 0.3 mmol)
at room temperature and the mixture was cooled to
ꢀ78 ꢁC with methanol-dry ice bath under argon atmo-
sphere. Then, silyl nitronate 2a (58.1 mg, 0.36 mmol)
was introduced. Then, this mixture was stirred for
0.5 h at that temperature followed by additional stirring
at ꢀ40 ꢁC for 2 h. The resulting mixture was directly
purified by column chromatography on silica gel 60
silanized (ether/hexane = 1:2 as eluant) to afford the
corresponding enol silyl ether 3a (n = 1) (70.1 mg,
0.272 mmol, 91% yield, anti/syn = 99:1); 1H NMR
(400 MHz, CDCl3): d 4.60 (1H, br s, CH@COSi), 4.19
(1H, ddd, J = 3.2, 7.9, 11.1 Hz, CHNO2), 2.77–2.70
(1H, m, CHCNO2), 2.04–1.92 (3H, m, CH2COSi,
Acknowledgements
This work was partially supported by the Sumitomo
Foundation and a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. K.D. is grateful to the
Japan Society, for the Promotion of Science for Young
Scientists for a Research Fellowship.
References and notes
1. Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003,
125, 9022.
2. For an account of our contributions to this area, see: Ooi,
T.; Maruoka, K. Acc. Chem. Res. 2004, 37, 526.

148
T. Ooi et al. / Tetrahedron Letters 47 (2006) 145–148
3. (a) Yamaguchi, M.; Shiraishi, T.; Igarashi, Y.; Hirama,
M. Tetrahedron Lett. 1994, 35, 8233; (b) Yamaguchi, M.;
Igarashi, Y.; Reddy, R. 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; For a recent excellent review on conjugate
addition of nitroalkanes to electron deficient olefins, see:
(f) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini,
M. Chem. Rev. 2005, 105, 933.
4. For reviews on catalytic asymmetric conjugate addition of
stabilized carbanions, see: (a) Yamaguchi, M. In Compre-
hensive 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.
5. For our recent contribution, see: Ooi, T.; Takada, S.;
Fujioka, S.; Maruoka, K. Org. Lett. 2005, 7, 5143.
6. Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003,
125, 2054.
7. For the use of this type of ammonium bromide as chiral
phase-transfer catalyst, see: (a) Ooi, T.; Taniguchi, M.;
Kameda, M.; Maruoka, K. Angew. Chem., Int. Ed. 2002,
41, 4542; (b) Ooi, T.; Kameda, M.; Taniguchi, M.;
Maruoka, K. J. Am. Chem. Soc. 2004, 126, 9685; (c)
Ooi, T.; Fujioka, S.; Maruoka, K. J. Am. Chem. Soc. 2004,
126, 11790.
9. The relative configuration was assigned by 1H NMR
analysis, which was also supported by the crystal structure
of acetal 8. See Ref. 8.
10. Ooi, T.; Goto, R.; Maruoka, K. J. Am. Chem. Soc. 2003,
125, 10494.
11. The coupling constant between Ha and Hb of the
a-phenylation product 6 was 13.0 Hz, indicating their
1,2-diaxial alignments.
O
Hb
8. The acetal 8 was recrystallized from ether/hexane. Crystal
structure data for 8 collected at 123 K: C12H20BrO4N,
Mw = 322.20, monoclinic, space group P21 (#4),
Ph
O2N
H
Ha
˚
˚
˚
a = 10.097(14) A, b = 6.784(11) A, c = 10.104(14) A,
Et
6
3
˚
b = 80.31(13) ꢁ, V = 682.2(17) A , Z = 2, Dcalcd
=
1.568 g/cm3, R1 = 0.0595, Rw = 0.1280.
12. The relative stereochemistry was not determined.