Enantioselective organocatalytic Mukaiyama-Michael addition of silyl enol ethers to α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/ol0503337

(Chemical Equation Presented) A highly enantioselective, organocatalytic Mukaiyama-Michael addition reaction of silyl ethers and α,β- unsaturated aldehydes has been developed. The process, catalyzed by MacMillan's chiral imidazolidinone, affords δ-keto aldehydes in high yields (56-87%) and high enantioselectivities (85-97% ee). Moreover, the reaction is applicable to a wide range of silyl ethers and α,β-unsaturated aldehydes and, as such, provides access to a range of important synthetic building blocks.

Full text of DOI:10.1021/ol0503337

ORGANIC
LETTERS
2
005
Vol. 7, No. 8
637-1639
Enantioselective Organocatalytic
Mukaiyama Michael Addition of Silyl
1
−
Enol Ethers to
Aldehydes
r,â-Unsaturated
Wei Wang,* Hao Li, and Jian Wang
Department of Chemistry, UniVersity of New Mexico,
Albuquerque, New Mexico 87131-0001
wwang@unm.edu
Received February 16, 2005
ABSTRACT
A highly enantioselective, organocatalytic Mukaiyama
The process, catalyzed by MacMillan’s chiral imidazolidinone, affords
85 97% ee). Moreover, the reaction is applicable to a wide range of silyl ethers and r,â
−
Michael addition reaction of silyl ethers and
-keto aldehydes in high yields (56
-unsaturated aldehydes and, as such, provides access
r
,
â
-unsaturated aldehydes has been developed.
δ
−87%) and high enantioselectivities
(
−
to a range of important synthetic building blocks.
The Mukaiyama-Michael addition reaction is a powerful
presented.3f,4 Recent studies of organocatalysts have uncov-
ered methods to achieve 1,4- rather than 1,2-additions to
conjugated aldehydes. MacMillan reported that chiral imi-
dazolidinones serve as effective catalysts for 1,4-addition of
electron rich aromatic systems to R,â-unsaturated aldehydes.5
tool for the preparation of synthetically useful 1,5-dicarbonyl
1,2
compounds. Consequently, considerable attention has been
given to the development of a catalytic asymmetric version
of this process. Although significant progress has been made
for R,â-unsaturated ketone, ester, amide, and nitrostyrene
substrates,2 the development of a catalytic method to
promote enantioselective Michael additions to R,â-unsatur-
ated aldehydes has proven to be more challenging. One of
the main reasons for this is the greater susceptibility of R,â-
unsaturated aldehydes to 1,2-addition reactions as compared
to other unsaturated systems. Thus, it is not surprising that
only a few successful examples of these reactions have been
(3) For leading references on the catalytic asymmetric Michael reactions,
,3
see: (a) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.;
Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134. (b) Evans, D. A.; Scheidt,
K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480.
(c) Harada, T.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A. Org.
Lett. 2001, 3, 2101. (d) Heathcock, C. H.; Norman, M. H.; Uehling, D. E.
J. Am. Chem. Soc. 1985, 107, 2797. (e) Sato, T.; Wakahara, Y.; Otera, J.;
Nozaki, H.; Fukuzumi, S. J. Am. Chem. Soc. 1991, 113, 4028. (f)
Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520.
(g) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.;
Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046. (h) Ishii, T.; Fiujioka,
S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558. (i)
Halland, N.; Aburel, P. S.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2003,
42, 661. (j) Halland, N.; Hansen, T.; Jorgensen, K. A. Angew. Chem., Int.
Ed. 2003, 42, 4955. (k) Halland, N.; Aburel, P. S.; Jorgensen, K. A. Angew.
Chem., Int. Ed. 2004, 43, 1272.
(4) (a) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1176. (b) Saito, M.; Nakajima, M.; Hashimoto, S. Chem.
Commun. 2000, 1851. (c) Saito, M.; Nakajima, M.; Hashimoto, S.
Tetrahedron 2000, 56, 9589. (d) Kumaraswamy, G.; Sastry, M. N. V.; Jena,
N. Tetrahedron Lett. 2001, 42, 8515.
(
1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: Oxford, 1992.
2) For recent reviews on the catalytic asymmetric Michael reactions,
(
see: (a) Krause, N.; Hoffman-R o¨ der, A. Synthesis 2001, 171. (b) Sibi, M.;
Manyem, S. Tetrahedron 2000, 56, 8033. (c) Kanai, M.; Shibasaki, M. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York,
2
000; p 569. (d) Tomioka, K.; Nagaoka, Y. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
999; Vol. 3, Chapter 31.1.
1
1
0.1021/ol0503337 CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/17/2005

In addition, Maruoka demonstrated the utility of chiral
ammonium bifluorides as catalysts for silyl nitronate Michael
addition reactions with unsaturated aldehydes. Despite these
Table 1. Results of Exploratory Studies of Catalytic
6
Asymmetric Mukaiyama-Michael Addition Reactions of Silyl
advances, catalysts which promote the classic asymmetric
Mukaiyama-Michael addition reaction between silyl enol
ethers and R,â-unsaturated aldehydes have not yet been
developed. In this paper, we describe the first highly
enantioselective version of this process, which employs
MacMillan’s chiral imidazolidinone catalyst and provides
δ-keto aldehydes in high yields and high enantioselectivities.
Chiral pyrrolidine and pyrrolidinone derivatives have been
shown to be effective organocatalysts for asymmetric reac-
Enol Ether and trans-Cinnamaldehydea
b
c
entry
catalyst
solvent
T (°C) yield (%) ee (%)
1
2
3
4
5
6
7
8
9
I + DNBA
I + DNBA
I + DNBA
I + DNBA
I + DNBA
I + HCl
CH2Cl2
i-PrOH
i-PrOH
t-BuOH
mixture
mixture
mixture
mixture
mixture
rt
rt
0
rt
0
0
0
0
0
14
58
68
55
60
<10
d
75
40
16
d
d
76
86
87
90
d
7
tions. Consequently, in initial exploratory efforts directed
at the development of chiral amine-catalyzed asymmetric
Michael addition reactions, we screened five chiral pyrro-
lidines and pyrrolidinones (Figure 1). These substances were
e
e
e
e
e
e
e
e
I + TFA
I + DNBA
d
f
90
47
83
II + DNBA
III + DNBA mixture
IV + DNBA
V + DNBA
g
1
1
1
0
1
2
0
0
0
mixture
mixture
d
d
d
a
Unless otherwise specified, the reaction was carried out with 5 equiv
of 1a and 1 equiv of 2a in the presence of 20 mol % chiral amine and acid
b
(
20 mol %) in 0.5 mL of solvent at rt or 0 °C for 12 h. Isolated yield
c
after chromatographic purification. Determined by chiral HPLC analysis
Chiralpak AS-H, hexane/2-propanol ) 90:10). Not determined.
mixture of t-BuOH/i-PrOH (5:1 v/v) used. 30 mol % of I and 30 mol %
d
e
(
A
f
of DNBA used. g S configuration.
Figure 1. Chiral amine organocatalysts.
effect on the rate of this process (Table 1, entries 1-5).11
For example, the reactions carried out in i-PrOH and t-BuOH
gave higher yields (58% and 55%, respectively, Table 1,
entries 2 and 4). More importantly, reactions in these solvents
were highly enantioselective (87% ee in t-BuOH and 76%
ee in i-PrOH). The major enantiomer of product, 1,5-
diketoaldehyde 3a, has the R configuration. By lowering
the temperature to 0 °C for reaction in i-PrOH, both the
enantioselectivity (86% ee) and the yield (68%) were
significantly improved (Table 1, entry 3). Optimization
studies showed that a solvent system consisting of 5:1 (v/v)
mixture of t-BuOH and i-PrOH at 0 °C was ideal for this
process.
used by us and others as catalysts for the different versions
of the Michael addition reactions.5,8-10 Reaction of 1-phenyl-
1-(trimethylsilylox)ethylene 1a with trans-cinnamaldehyde
2a and 20 mol % of chiral imidazolidinone I in CH Cl at
2
2
1
2
room temperature (rt) in the presence of 2,4-dinitrobenzene-
sulfonic acid (DNBA) (20 mol %) proceeded very slowly
in low yield (14%, 12 h) (Table 1, entry 1). A survey of
solvents revealed that the reaction media had a significant
(5) For MacMillan catalyst-catalyzed reactions, see: (a) Paras, N. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 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,
An acid additive is required for this reaction in which an
5
aldiminium ion serves as a key intermediate. Evaluation of
1192. (e) Hechavarria Fonseca, M. T.; List, B. Angew. Chem., Int. Ed. 2004,
three acids revealed that strong acids, such as HCl and TFA,
caused decomposition of silyl ether 1a. In contrast, 1a
tolerated DNBA (Table 1, entries 5-7), and subsequently,
the acid was used in further studies of this process.
Studies showed that the catalytic activities of five organo-
catalysts I-V differed significantly (Table 1, entries 5 and
4
3, 3958.
(
6) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 9022.
(7) For selected reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481. (d) List, B. Acc. Chem. Res. 2004, 37, 548.
(
5
e) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37,
80.
8) Recently we have found pyrrolidine amides/sulfonamides as effective
(
9-12). Under identical reaction conditions (0 °C in t-BuOH
organocatalysts for asymmetric reactions: (a) Wang, W.; Wang, J.; Li, H.
Angew. Chem., Int. Ed. 2005, 44, 1369. (b) Wang, W.; Wang, J.; Li, H.
Org. Lett. 2004, 6, 2817. (c) Wang, W.; Mei, Y.-J.; Li, H.; Wang, J. Org.
Lett. 2005, 7, 601. (d) Wang, W.; Wang, J.; Li, H.; Liao, L.-X. Tetrahedron
Lett. 2004, 45, 7235. (e) Wang, W.; Wang, J.; Li, H. Tetrahedron Lett.
and i-PrOH (5/1, v/v) with DNBA), reaction of silylenol ether
1a with trans-cinnamaldehyde 2a catalyzed by I afforded
adduct 3a with excellent enantioselectivity (90% ee) and
2
004, 45, 7243.
9) For L-proline-catalyzed Michael reactions, see: (a) Hanessian, S.;
(
(11) More solvents were screened: THF, 16% yield; DMF, <10% yield;
DMSO, <10% yield; 1,4-dioxane, 24% yield; CH3NO2, 32% yield; CH3-
CN, 37% yield.
Pham, V. Org. Lett. 2000, 2, 2975. (b) List, B.; Pojarliev, P.; Martin, H. J.
Org. Lett. 2001, 3, 2423. (c) Ender, D.; Seki, A. Synlett 2002, 26.
(
10) For diamine-catalyzed Michael reactions, see: (a) Betancort, J. M.;
(12) The absolute (R) configuration of compound 3a was determined
by comparing the optical rotation with a known compound, which has been
reported in: Barluenga, J.; Montserrat, J. M.; Florez, J.; Garcia-Granda,
S.; Martin, E. Angew. Chem., Int. Ed. Engl. 1994, 33, 1392.
Barbas, C. F., III. Org. Lett. 2001, 3, 3737. (b) Mase, N.; Thayumanavan,
R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527. (c) Alexakis,
A.; Andrey, O. Org. Lett. 2002, 4, 3611.
1638
Org. Lett., Vol. 7, No. 8, 2005

good yield (60%, Table 1, entry 5). Moreover, increasing
the loading of I up to 30 mol % significantly improves the
yield of this reaction without sacrificing enantioselectivity
obtained with silyl ethers that possess both electron-
withdrawing (4-Br, Table 2, entry 2) and electron-donating
substituents (4-Me and 4-MeO, Table 2, entries 3 and 4). It
was noted that reactions with electron-withdrawing group
substituted aldehydes tended to give lower enantioselectivities
(e.g., 4-Br, 86% ee, entry 2), whereas those with electron-
donating group substituted substrates (4-Me and 4-MeO,
entries 3 and 4) proceeded with higher enantioselectivities
(95 and 97% ee).
Significant structural variation in the R,â-unsaturated
aldehydes was tolerated in this reaction, which occurred
efficiently, independent of the nature of substituents on the
phenyl ring (Table 2, entries 5-9, 59-71% yields, 90-95%
ee). In all cases, excellent levels (g90% ee) of enantiose-
lectivity were observed. Moreover, based on preliminary
results, it appeared that the catalytic process was applicable
to â-alkyl substituted R,â-unsaturated aldehydes (e.g., acre-
loin) and cyclic (e.g., tetralone) silylenol ethers (entries 10
and 11, 60% yield, 87% ee and 87% yield and 85% ee,
respectively). In the latter case, two stereogenic centers were
produced in the reaction with high enantioselectivity (85%
ee) and diastereoselectivity (30:1 dr) (Table 2, entry 11).13
In summary, we have developed a catalytic variant of the
asymmetric Mukaiyama-Michael addition reaction between
silyl enol ethers and R,â-unsaturated aldehydes. The reactions
are effectively catalyzed by the organocatalyst I, affording
synthetically useful 1,5-dicarbonyl compounds in high yields
and high to excellent levels of enantioselectivity. Further
investigations of the mechanistic features and scope of this
reaction are underway.
(75% yield, 90% ee, entry 8). However, the reaction
promoted by catalyst II, which has a similar structure to I,
took place with a much lower enantioselectivity (47% ee,
entry 9). Interestingly, a highly enantioselective reaction
(83% ee, entry 10) occurred when our pyrrolidine trifluoro-
methanesulfonamide catalyst III was used, but unfortunately
the rate of this process was very low. L-Proline IV and
diamine V did not serve to catalyze the formation of product
3a even after a 12 h period (entries 11 and 12).
Having established the optimal reaction conditions, we
next probed the generality of this asymmetric catalytic variant
of the Mukaiyama-Michael addition reaction with a variety
of silyl ethers 1 and R,â-unsaturated aldehydes 2 (Table 2).
Table 2. Catalytic Asymmetric Mukaiyama-Michael Addition
of Silyl Enol Ethers 1 to R,â-Unsaturated Aldehydes 2a
Acknowledgment. The research is supported by the
Department of Chemistry and the Research Relocation
Committee, University of New Mexico. We thank Professor
Patrick S. Mariano for making critical editorial comments
about the manuscript and Materia, Inc., for a generous
donation of the MacMillan catalysts.
a
See footnote in Table 1. b Isolated yield after chromatographic purifica-
tion. c Determined by chiral HPLC analysis (Chiralpak AS-H or Chialcel
OJ-H). Reaction run at -20 °C. dr determined by H NMR.
Supporting Information Available: Experimental pro-
d
e
1
1
13
cedures and H, C NMR and/or MS data for Mukaiyama-
Michael addition products. This material is available free of
charge via the Internet at http://pubs.acs.org.
The results showed that the reactions took place efficiently
56-87%), and high to excellent levels of enantioselectivity
85-97%) with all of the silyl enol ethers and unsaturated
(
(
OL0503337
aldehyde were achieved. As revealed by inspecting the results
(13) We could not determine the absolute configurations of the compound
given in Table 2, high to excellent enantioselectivities were
because of the quick racemization.
Org. Lett., Vol. 7, No. 8, 2005
1639