Dimethylsilyl ketene acetal as a nucleophile in asymmetric Michael reaction: Enhanced enantioselectivity in oxazaborolidinone-catalyzed reaction

Article abstract of DOI:10.1021/ol048071g

(Chemical Equation Presented) Dimethylsilanyl [Me₂Si(H)] ketene S,O-acetal 6b is an effective nucleophile that retards the undesirable Si ⁺-catalyzed racemic pathway in the oxazaborolidinone-catalyzed asymmetric Michael reaction. Thr

Full text of DOI:10.1021/ol048071g

ORGANIC
LETTERS
2004
Vol. 6, No. 26
4877-4879
Dimethylsilyl Ketene Acetal as a
Nucleophile in Asymmetric Michael
Reaction: Enhanced Enantioselectivity
in Oxazaborolidinone-Catalyzed Reaction
Toshiro Harada,* Shinya Adachi, and Xiaowei Wang
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
harada@chem.kit.ac.jp
Received September 22, 2004
ABSTRACT
+
Dimethylsilanyl [Me2Si(H)] ketene S,O-acetal 6b is an effective nucleophile that retards the undesirable Si -catalyzed racemic pathway in the
+
oxazaborolidinone-catalyzed asymmetric Michael reaction. Through the further suppression of the Si -catalyzed pathway by carrying out the
reaction in the presence of 2,6-diisopropylphenol and t-BuOMe as additives, enantioselectivity up to 98% ee could be achieved for a variety
of acyclic enones.
The Michael reaction is one of the fundamental methods used
for constructing 1,5-dicarbonyl skeletons in organic synthesis.
Recently, catalytic asymmetric versions of this reaction have
received extensive attention in this regard,1 and major
progress has been made in effecting asymmetric Michael
reactions using enolate anions generated in situ.2,3 A limita-
tion of this approach, however, is the fact that the process is
often limited to nucleophilic partners that readily enolize,
such as active methylene compounds and nitromethane. For
the much less acidic ketone and carboxylic acid derived
nucleophiles, alternative approaches must be used that exploit
silyl enolates as the active nucleophiles in the presence of
chiral Lewis acids. Indeed, the Mukaiyama-Michael reaction
is now of major synthetic importance.4,5
(4) (a) Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T. Chem. Lett.
1994, 97. (b) Bernardi, A.; Colombo, G.; Scolastico, C. Tetrahedron Lett.
1996, 37, 8921. (c) Bernardi, A.; Karamfilova, K.; Sanguinetti, S.;
Scolastico, C. Tetrahedron 1997, 53, 13009. (d) Kitajima, H.; Ito, K.;
Katsuki, T. Tetrahedron 1997, 53, 17015. (e) Kitajima, H.; Katsuki, T.
Synlett 1997, 568. (f) Nishikori, H.; Ito, K.; Katsuki, T. Tetrahedron:
Asymmetry 1998, 9, 1165. (g) Evans, D. A.; Rovis, T.; Kozlowski, M. C.;
Tedrow, J. S. J. Am. Chem. Soc. 1999, 121, 1994. (h) Evans, D. A.; Willis,
M. C.; Johnston, J. N. Org. Lett. 1999, 1, 865. (i) Evans, D. A.; Johnston,
J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635. (j) Evans, D. A.;
Rovis, T.; Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem.
Soc. 2000, 122, 9134. (k) Evans, D. A.; Scheidt, K. A.; Johnston, J. N.;
Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480. (l) Zhang, F.-Y.; Corey,
E. J. Org. Lett. 2001, 3, 639. (m) Desimoni, G.; Faita, G.; Filippone, S.;
Mella, M.; Zampori, M. G.; Zema, M. Tetrahedron 2001, 57, 10203.
(5) (a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 124,
4370. (b) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
1172. (c) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
7894. (d) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2003, 125, 1192.
(1) Review: (a) Tomioka, K.; Nagaoka, Y. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. 3, Chapter 31.1. (b) Kanai, M.; Shibasaki, M. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000; p
569. (c) Sibi, M.; Manyem, S. Tetrahedron 2000, 56, 8033. (d) Krause, N.;
Hoffmann-Ro¨der, A. Synthesis 2001, 171.
(2) For leading references, see: (a) Yamaguchi, M.; Shiraishi, T.; Hirama,
M. J. Org. Chem. 1996, 61, 3520. (b) Harada, S.; Kumagai, N.; Kinoshita,
T.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2582. (c)
Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394.
(3) (a) Sawamura, H.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992,
114, 8295. (b) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1176. (c) Sasai, H.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1994, 116, 1571.
10.1021/ol048071g CCC: $27.50
© 2004 American Chemical Society
Published on Web 12/02/2004

Indeed, the Si+-catalyzed racemic pathway is predominant
when the OXB-catalyzed reaction is carried out in the
absence of the phenolic and ethereal additives. Thus, the
reaction of benzalacetone (5a) and TMS ketene S,O-acetal
6a (1.5 equiv) catalyzed by OXB 1a (20 mol %) gave adduct
7a of only in 18% ee (82% yield) (eq 1). In sharp contrast
to this, the reaction using dimethylsilanyl ketene acetal 6b
as a nucleophile afforded 7a in 62% ee and 71% yield. The
observed improvement in enantioselectivity suggested that
the dimethylsilanyl group is less prone to catalyze the
racemic pathway than the conventionally used trimethylsilyl
group.
Scheme 1. Enantioselective versus Racemic Pathway in
Asymmetric Michael Reaction
Despite recent advances, application of the asymmetric
Mukaiyama-Michael reaction to simple acyclic enones has
remained a challenging issue in this field. Recently, we found
that the chiral oxazaborolidinone (OXB) catalysts 1 were
highly effective for promoting the Mukaiyama-Michael
reaction on acyclic enones.6 By using 10 mol % of these
catalysts in the presence of 2,6-diisopropylphenol and
t-BuOMe as additives, the reactions of alkenyl methyl
ketones with a trimethylsilyl (TMS) ketene S,O-acetal
afforded Michael adducts in up to 90% ee.
Herein we wish to report that the use of a dimethylsilanyl
(Me2Si(H)) ketene S,O-acetal as a nucleophile,7 in place of
the conventional TMS derivative, not only enhances the
enantioselectivity of the OXB-catalyzed asymmetric Michael
reaction but also expands the scope of the reaction with
respect to the enone structure.
As reported previously,6 the Si+-catalyzed racemic path-
way in the OXB-catalyzed asymmetric Michael reaction with
the TMS ketene acetal can be suppressed by the use of 2,6-
diisopropylphenol as an additive, which traps intermediate
2 (ML*n ) OXB) to form the Michael adduct and 2,6-
diisopropylphenyl trimethylsilyl ether with regeneration of
the catalyst. The superior result observed for Me2Si(H)
derivative 6b encouraged us to optimize the reaction condi-
tions using the phenolic additive.
An enantioselectivity of 91% ee was observed when the
reaction of 5a was carried out with Me2Si(H) derivative 6b
in the presence of 2,6-diisopropylphenol (1 equiv) (Table 1,
entry 2). In accord with our previous observations that the
effect of the phenolic additive is enhanced by using t-BuOMe
as a second additive,6b the combined use of the phenol (1
equiv) and the ether (2 equiv) improved the enantioselectivity
to 96% ee (entry 4). The advantage of Me2Si(H) derivative
is shown by lower ee observed for the TMS derivative 6a
under the similar conditions (entry 5). The use of t-BuOMe
in the absence of the phenol was not effective (entry 3).
The observed high enantioselectivity was maintained when
the catalyst load was reduced to 10 mol %, but the level of
conversion was lower (entry 6). This result suggested ketene
acetals had lower reactivity compared to that of their TMS
counterparts. According to the previously optimized protocol,6c
these reactions were best carried out by adding a mixture of
enone 5a and the phenol slowly over 6 h to a solution of the
nucleophile and the OXB and by quenching immediately
after the completion of the addition. Complete conversion
of the enone to the product was achieved without lowering
of the enantioselectivity by carrying out the reaction for an
additional 12 h after the slow addition was complete (entry
7). However, even without using the slow addition procedure,
relatively high selectivity was still obtained in the reaction
of 6b (entries 8 and 9).
Along a plausible reaction pathway for a chiral Lewis acid
catalyzed Mukaiyama-Michael reaction, the silyl group of
the intermediate 2 needs to migrate to a relatively remote
enolate oxygen atom in order to regenerate the active catalyst
(ML*n) (Scheme 1). In competition with this, the silyl group
tends to be transferred intermolecularly to the starting enone
to form intermediate 3, leading to the formation of racemic
enolsilane product through 4.8
(6) (a) Harada, T.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku,
A. Org. Lett. 2001, 3, 2101. (b) Wang, X.; Harada, T.; Iwai, H.; Oku, A.
Chirality 2003, 15, 28. (c) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, K.;
Fujita, M.; Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046.
(7) Most recently, Hosomi et al. have reported chloride ion promoted
aldol and Michael reactions of DMS enolates. (a) Miura, K.; Sato, H.;
Tamaki, K.; Ito, H.; Hosomi, A. Tetrahedron Lett. 1998, 39, 2585. (b) Miura,
K.; Tamaki, K.; Nakagawa, T.; Hosomi, A. Angew. Chem., Int. Ed. 2000,
39, 1958. (c) Miura, K.; Nakagawa, T.; Hosomi, A. Synlett 2003, 2068.
(8) (a) Carreira, E. M.; Singer, R. A. Tetrahedron Lett. 1994, 35, 4323.
(b) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116,
8837. (c) Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117, 4570.
The scope of the OXB-catalyzed asymmetric Michael
addition of various acyclic enones 5a-m with 6b was
investigated under the optimized conditions (eq 2, Table 2).
In contrast to the reaction with TMS derivative 6a, superior
4878
Org. Lett., Vol. 6, No. 26, 2004

Table 1. Asymmetric Michael Reaction of Benzalacetone with
Me2Si(H) Ketene Acetal 6b Catalyzed by OXB 1aa
Table 2. OXB-CatalyzedAsymmetric Michael Reaction of
Enones 5a-m with Me2Si(H) Ketene Acetal 6b
1a
(mol %)
diisopropyl-
phenol (equiv)
t-BuOMe
(equiv)
yield
(%)
eeb
(%)
entry
enone 5
R1
yield of 7
eeb,c
(%)
entry
R2
(%)
1
2
3
4
5c
6
7d
8e
9f
20
20
20
20
20
10
10
10
10
0
1
0
1
1
1
1
1
1
0
0
2
2
2
1
1
0
0
71
71
73
70
88
52
78
40
42
62
91
62
96
89
95
94
93
90
1d
2
3
4
5
6
7
8
9
10
11
12
13
5a
5b
5c
5d
5e
5f
5g
5h
5i
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
83
75
54
72
63
81
68
75
60
85
79
82
64
95 (89)
95 (86)
92 (85)
95 (85)
93 (90)
92 (80)
95 (89)
98 (89)
90
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-FC6H4
p-CF3C6H4
m- CF3C6H4
Me
BnOCH2
Ph,
Me
a Unless otherwise noted, reactions were carried out at -78 °C by adding
a CH2Cl2 solution of 5a (1 M) and 2,6-diisopropylphenol to a CH2Cl2
solution of OXB 1a (0.1 M), 6b (1.5 equiv), and t-BuOMe over 6 h.
b Determined by chiral phase HPLC using a Chiralpak AD column. c TMS
derivative 6a was used as a nucleophile. d Additional 12 h of stirring after
the completion of slow addition. e Slow addition for 2 h. f Slow addition
procedure was not applied. The reaction mixture was stirred for 6 h.
5j
5k
5l
84 (59)
94
88
Et
Bu
i-Pr
Ph
Ph
5m
88 (72)
a Unless otherwise noted, reactions were carried out by using enone 5
(1 mmol), OXB 1a (10 mol %), 6b (1.5 equiv), 2,6-diisopropylphenol (1
equiv), and t-BuOMe (1 equiv) in CH2Cl2 at -78 °C. b Determined by chiral
phase HPLC analysis. c ee values obtained in the reaction with TMS ketene
acetal 6a under similar conditions (ref 6c) are shown in parentheses. d The
reaction was carried out on a 10 mmol scale.
enantioselectivities (>90% ee) were obtained for a variety
of alkenyl methyl ketones 5a-j (R2 ) Me) with â-aryl
(entries 1-7), -alkyl (entry 8), and functionalized substituent
(entry 9). Of these, the high selectivity (98% ee) observed
for 5h (R1 ) Me) is particularly noteworthy. In the reaction
with TMS derivative 6a, enantioselectivity was moderate for
ethyl and isopropyl ketones 5j,m.6 As revealed in entries
10-13, the reaction with 6b was tolerant of variation in the
alkyl group R2 (primary and secondary), exhibiting high
selectivity (84-94% ee). Therefore, the use of Me2Si(H)
derivative 6b as a nucleophile significantly expands the scope
of the OXB-catalyzed asymmetric reaction. To demonstrate
the preparative utility of this process, the reaction of enone
5a with 6b was carried out on a 10 mmol scale to afford
adduct 7a (2.3 g, 83% yield) in 95% ee (entry 1).
the expansion of the scope of the reaction with respect to
the enone structure. The study suggested that the dimethyl-
silanyl group is effective in retarding the undesirable Si+-
catalyzed racemic pathway. The observation might be utilized
in other Lewis acid catalyzed asymmetric reactions.
Acknowledgment. Financial support from the Ministry
of Education, Science, Sports and Culture of the Japanese
Government [Grant-in-Aid for Scientific Research (Priority
Areas, no. 412)] is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedure and spectra data for new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
In summary, the use of Me2Si(H) ketene acetal 6b as a
nucleophile, in place of the conventional TMS ketene acetal,
is demonstrated to enhance the enantioselectivity of the
OXB-catalyzed asymmetric Michael reaction together with
OL048071G
Org. Lett., Vol. 6, No. 26, 2004
4879