Diarylprolinol silyl ether as catalyst of an exo-selective, enantioselective diels-alder reaction

Article abstract of DOI:10.1021/ol071009+

In combined use with CF₃CO₂H, 2-[bis(3,5-bis- trifluoromethylphenyl) triethylsiloxymethyl]pyrrolidine was found to be an effective organocatalyst of an exo-selective, enantioselective Diels-Alder reaction of α,βunsaturated aldehydes.

Full text of DOI:10.1021/ol071009+

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2859-2862
Diarylprolinol Silyl Ether as Catalyst of
an exo-Selective, Enantioselective
Diels−Alder Reaction
Hiroaki Gotoh and Yujiro Hayashi*
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
hayashi@ci.kagu.tus.ac.jp
Received April 30, 2007
ABSTRACT
In combined use with CF3CO2H, 2-[bis(3,5-bis-trifluoromethylphenyl) triethylsiloxymethyl]pyrrolidine was found to be an effective organocatalyst
of an exo-selective, enantioselective Diels Alder reaction of -unsaturated aldehydes.
−
r,â
Diarylprolinols are a class of small, chiral organic molecules
that have proven to be particularly useful in asymmetric
synthesis. Diphenylprolinol reacts with a boron reagent to
generate chiral oxazaborolidine, which has been widely
utilized in the Corey-Bakshi-Shibata (CBS) reduction
developed by Corey.1 His group also discovered that chiral
oxazaborolidinium ions prepared from diarylprolinols are
versatile chiral Lewis acid catalysts, promoting the Diels-
Alder reaction and the cyanation reaction of aldehydes.2
Enantioselective reactions catalyzed by organocatalyst have
received a great deal of attention in recent years,3 and silyl
4,5,6
ethers of diarylprolinols
have been found to act as
effective organocatalysts of various enantioselective trans-
formations, as independently developed by Jørgensen’s4 and
(3) (a) Berkssel, A.; Groger, H. Asymmetric Organocatalysis; Wiley-
VCH: Weinheim, Germany, 2005. (b) Dalko, P. I.; Moisan, L. Angew.
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Braunton, A.; Kjasgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005,
44, 3703. (c) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964. (d) Marigo, M.;
Schulte, T.; Franzen, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127,
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Kjasgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296. (g)
Brandau, S.; Landa, A.; Franzen, J.; Marigo, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2006, 45, 4305. (h) Brandau, S.; Maerten, E.; Jørgensen,
K. A. J. Am. Chem. Soc. 2006, 128, 14986. (i) Carlone, A.; Marigo, M.;
North, C.; Landa, A.; Jørgensen, K. A. Chem. Commun. 2006, 4928. (j)
Bertelsen, S.; Diner, P.; Johansen, R. L.; Jørgensen, K. A. J. Am. Chem.
Soc. 2007, 129, 1536. (k) Bertelsen, S.; Marigo, M.; Brandes, S.; Diner,
P.; Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 12973.
(1) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925. (c) For a review, see: Corey, E.
J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
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124, 3808. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc.
2002, 124, 9992. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125,
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10.1021/ol071009+ CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/20/2007

variety of natural products.7 The selective formation of the
exo-isomer has long proven to be difficult.8 For instance,
the Diels-Alder reactions of cyclopentadiene with acrolein,
methyl acrylate, and methyl vinyl ketone all afford predomi-
nantly the endo-isomer. This endo-selectivity is enhanced
by Lewis acid.9 Even in the recently developed Diels-Alder
reaction catalyzed by organocatalyst,10 selective formation
of the exo-isomer can be a challenging problem; MacMillan
reported the first asymmetric Diels-Alder reaction catalyzed
by organocatalyst of cyclopentadiene and R,â-unsaturated
aldehydes which proceeded with excellent enantioselectivity
in spite of low diastereoselectivity.10a On the other hand,
Maruoka and co-workers reported an elegant exo- and
enantioselective Diels-Alder reaction catalyzed by binaph-
thyl-based diamine salts.10h While excellent exo- and enan-
tioselectivities were achieved, the scope was limited to
cyclopentadiene and three R,â-unsaturated aldehydes. De-
velopment of an exo-selective and enantioselective Diels-
Alder reaction of wider generality is desirable. In this paper,
we will disclose such a reaction using the catalyst diaryl-
prolinol silyl ether.
Figure 1. The diphenylprolinol-organocatalysts examined in this
study.
our5 groups. We have found that they promote the enanti-
oselective Michael reaction of nitroalkene and aldehyde to
afford the adduct with excellent diastereo- and enantio-
selectivities.5aEnders and co-workers elegantly applied this
reaction to a triple-cascade organocatalytic reaction for the
synthesis of chiral cyclohexanecarbaldehydes.6i Recently we
reported that diphenylprolinol silyl ether catalyzes the
enantioselective ene reaction of an R,â-unsaturated aldehyde
with cyclopentadiene to afford substituted cyclopentadienes
with excellent enantioselectivity (Scheme 1).5b In the course
As a model we studied the reaction of cinnamaldehyde
and cyclopentadiene in the presence of several diarylprolinol
silyl ethers (results summarized in Table 1). As we have
reported, in the presence of p-nitrophenol the tert-butyldim-
ethylsilyl ether of diphenylprolinol (1) is an effective catalyst
of an enantioselective ene reaction, affording the cyclopen-
tadiene derivative 4 with excellent enantioselectivity (Scheme
1).5b
Scheme 1. Asymmetric Ene Reaction
However when the reaction was performed under acidic
conditions, its course changed dramatically. When cinna-
maldehyde and cyclopentadiene were treated with catalyst
1 in the presence of CF3CO2H in toluene, the cyclopentadiene
derivative 4 was not formed but rather Diels-Alder adduct
of developing this reaction further, we happened to find that
an exo- and enantioselective Diels-Alder reaction proceeds
on changing the reaction conditions. That is, in the presence
of an acid catalyst, the Diels-Alder reaction becomes the
principle pathway, affording the exo-isomer with high
diastereo- and excellent enantioselectivities.
The Diels-Alder reaction is a synthetically powerful
method for the construction of regio and stereochemically
defined cyclohexane frameworks, key components of a wide
(7) For recent reviews of enantioselective Diels-Alder reactions: (a)
Evans, D. A.; Johnson, J. S. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; Vol. 3, p 1177. (b) Oppolzer, W. In ComprehensiVe Organic Synthesis;
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H. B.; Riant, O. Chem. ReV. 1992, 92, 1007. (d) Diaz, L. C.; Braz. J. Chem.
Soc. 1997, 8, 289. (e) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650.
(f) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G.
Angew. Chem., Int. Ed. 2002, 41, 1668. (g) Hayashi, Y. Catalytic
Asymmetric Diels-Alder Reactions. In Cycloaddition Reaction in Organic
Synthesis; Kobayashi, S., Jørgensen, K.A., Eds.; Wiley-VCH: Weinheim,
Germany, 2002; pp 5-55.
(8) (a) Gouverneur, V. E.; Houk, K. N.; de Pascual-Teresa, B.; Beno,
B.; Janda, K. D.; Lerner, R. A. Science 1993, 262, 204. (b) Powers, T. S.;
Jiang, W.; Su, J.; Wulff, W. D.; Waltermire, B. E.; Rheingold, A. L. J.
Am. Chem. Soc. 1997, 119, 6438. (c) Maruoka, K.; Imoto, H.; Yamamoto,
H. J. Am. Chem. Soc. 1994, 116, 12115. (d) Kundig, E. P.; Saudan, C. M.;
Alezra, V.; Viton, F.; Bernardinelli, G. Angew. Chem., Int. Ed. 2001, 40,
4481. (e) Cavill, J. L.; Peters, J.-U.; Tomkinson, N. C. O. Chem. Commun.
2003, 728.
(9) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry, 5th
ed.; John Wiley & Sons, Inc.: New York, 2001; pp 1062-1075.
(10) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243. (b) Northup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 2458. (c) Ishihara, K.; Nakano, K. J. Am. Chem.
Soc. 2005, 127, 10504. (d) Wilson, R. M.; Jen, W. S.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2005, 127, 11616. (e) Kim, K. H.; Lee, S.; Lee, D.-
W.; Ko, D.-H.; Ha, D.-C. Tetrahedron Lett. 2005, 46, 5991. (f) Lemay,
M.; Ogilvie, W. W. Org. Lett. 2005, 7, 4141. (g) Sakakura, A.; Suzuki, K.;
Nakano, K.; Ishihara, K. Org. Lett. 2006, 8, 2229. (h) Kano, T.; Tanaka,
Y.; Maruoka, K. Org. Lett. 2006, 8, 2687. (i) Sakakura, A.; Suzuki, K.;
Ishihara, K. AdV. Synth. Catal. 2006, 348, 2457.
(6) Other group’s application of diarylprolinol ether, see; (a) Chi, Y.;
Gellman, S. H. Org. Lett. 2005, 7, 4253. (b) Sunden, H.; Ibrahem, I.;
Cordova, A. Tetrahedron Lett. 2006, 47, 99. (c) Ibrahem, I.; Cordova, A.
Chem. Commun. 2006, 1760. (d) Govender, T.; Hojabri, L.; Moghaddam,
F. M.; Arvidsson, P. I. Tetrahedron: Asymmetry 2006, 17, 1763. (e) Chi,
Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804. (f) Zu, L.; Li, H.;
Wang, J.; Yu, X.; Wang, W. Tetrahedron Lett. 2006, 47, 5131. (g) Wang,
W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128, 10354. (h) Zhao,
G.-L.; Corvoda, A. Tetrahedron Lett. 2006, 47, 7417. (h) Rios, R.; Sunden,
H.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Cordova, A. Tetrahedron Lett.
2006, 47, 8547. (i) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G.
Nature 2006, 441, 861. (j) Enders, D.; Huttl, M. R. M.; Runsink, J.; Raabe,
G.; Wendt, B. Angew. Chem., Int. Ed. 2007, 46, 467. (k) Vesely, J.; Ibrahem,
I.; Zhao, G.-L.; Rios, R.; Cordova, A. Angew. Chem., Int. Ed. 2007, 46,
778. (l) Zhao, G.-L.; Xu, Y.; Sunden, H.; Eriksson, L.; Sayah, M.; Cordova,
A. Chem. Commun. 2007, 734. (m) Ibrahem, I.; Rios, R.; Vesely, J.; Zhao,
G.-L.; Cordova, A. Chem. Commun. 2007, 849. (n) Li, H.; Wang, J.;
E-Nunu, T.; Zu, L.; Jiang, W.; Wei, S.; Wang, W. Chem. Commun. 2007,
507. (o) Li, H.; Wang, J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.; Wang,
W. Org. Lett. 2007, 9, 965. (p) Li, H.; Zu. L.; Xie, H.; Wang, J.; Jiang, W.;
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Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876.
2860
Org. Lett., Vol. 9, No. 15, 2007

Table 1. Effect of the Catalyst in the Reaction of
Cinnamaldehyde and Cyclopentadiene Catalyzed by
Organocatalystsa
Table 2. Enantioselective Diels-Alder Reaction between
Cyclopentadiene and R,â-Unsaturated Aldehydes Catalyzed by
Diarylprolinol Silyl Ether 3a
ee
(exo)
[%]d
ee
(endo)
[%]d
ee
ee
time yield
[h]
[%]b exo/endoc
yield
(exo) (endo)
[%]b exo/endoc [%]d
entry
R
entry catalyst
additive
[%]d
88
1
2
3
4
5
6f
7
8
9g
Ph
26 quant 85:15
97 (2S)e 88 (2S)e
1
2
3
4
5
6
7
8
9
1
2
2
2
2
2
2
2
3
CF3CO2H
none
CH3CO2H
10
0
0
79:21
79
2-Np
28 94
78 71
86:14
78:22
96
96
96
96
82
96
84
82
o-MeOPh
p-BrPh
p-NO2Ph
2-furyl
cyclohexyl
n-Bu
24 quant 86:14
CCl3CO2H 69
87:13
84:16
57:43
88:12
95
95
69
45
79
83
5
6
93
87:13
80:20
85:15
78:22
70:30
CF3CO2H
CSA
86
10
100 67
17 78
3
94 (2S)e 78 (2S)e
97
94
84
94
93
91
64
73
TsOH‚H2O 13
0
65
TfOH
CF3CO2H
0
80
CO2Et
17 92
85:15
97
88
10h p-NO2Ph
17 quant 86:14
a Unless otherwise shown, the reaction was conducted with 0.07 mmol
of catalyst, 0.14 mmol of additive, 0.7 mmol of cinnamaldehyde, and 2.1
mmol of cyclopentadiene at rt. b Isolated yield of a mixture of 5-exo and
5-endo. c Determined by 1H NMR. d Determined by chiral HPLC analysis.
a Unless otherwise shown, the reaction was conducted with 0.07 mmol
of catalyst 3, 0.14 mmol of CF3CO2H, 0.7 mmol of cinnamaldehyde, and
2.1 mmol of cyclopentadiene at rt in toluene. b Isolated yield of a mixture
of exo and endo isomers. c Determined by H NMR (400-MHz). d The ee
1
was determined by chiral HPLC or GC analysis. e Absolute configuration,
see reference 10a. f Catalyst 3 (20 mol %) and CF3CO2H (40 mol %) were
used. g The reaction was performed at 4 °C. h Catalyst 3 (2 mol %) and
CF3CO2H (4 mol %) were used.
5 was obtained in good optical purity in spite of the low
yield (Table 1, entry 1). Moreover, the exo-isomer was
obtained predominantly. Catalyst, solvent, and additive were
screened: 3,5-bis(trifluoromethyl)phenyl-substituted catalyst
2 was found to be a superior Diels-Alder reaction catalyst
to diphenyl analogue 1. Several acids were investigated as
additives including CH3CO2H, CCl3CO2H, CF3CO2H, cam-
phorsulfonic acid, TsOH‚H2O, and TfOH. The reaction did
not proceed in the presence of a weak acid such as CH3-
CO2H nor a strong acid such as TfOH, and of these, CF3-
CO2H was found to be most effective (entry 5). In marked
contrast, no reaction proceeded in the presence of CH3CO2H
(entry 3). Screening of the solvent indicated that toluene is
suitable. The effect of the silyl group substituent was also
investigated. Triethylsilyl derivative 3 gave higher enanti-
oselectivity than the corresponding trimethylsilyl derivative
2. Results under the best reaction conditions are as follows:
When a mixture of cinnamaldehyde and cyclopentadiene was
treated with triethylsilyl ether 3 in the presence of CF3CO2H
in toluene, the Diels-Alder product 5 was obtained in 80%
yield with high exo-selectivity (exo/endo ) 85:15) and
excellent enantioselectivity (exo 97% ee, endo 88% ee, entry
9).
lent enantioselectivity were realized (entry 3). When the
substituent is electron-deficient, such as p-bromophenyl and
p-nitrophenyl, the reaction is fast, with high diastereo- and
excellent enantioselectivities (entries 4, 5). Not only aromatic
groups, but also heteroaromatic groups such as furyl are
suitable substituents (entry 6). Alkyl group-substituted ac-
rolein also gave good results, and steric size does not
compromise the enantioselectivity (entries 7, 8). 3-Ethoxy-
carbonylpropenal is also a suitable R,â-unsaturated aldehyde,
affording high selectivity (entry 9). Though we have used
10 mol % of the catalyst in the above reactions, loading can
be reduced to 2 mol %. That is, in the presence of 2 mol %
of 3 and 4 mol % of CF3CO2H, the reaction proceeds
efficiently, affording the Diels-Alder product in 99% yield
with excellent enantioselectivity (exo 94% ee, endo 73% ee,
entry 10).
Other dienes can also be employed successfully. Acyclic
dienes such as 2,3-dimethyl-1,3-butadiene and isoprene are
suitable dienes, producing the Diels-Alder products, also
with excellent enantioselectivity as shown in Table 3. In the
reaction of isoprene, there is the possibility that regio-isomers
will be formed, but only a single isomer 7 was observed.11
The absolute configuration of 6 was determined by trans-
formation to the known (1S, 6S)-(3,4-dimethyl-(6-hydroxym-
ethyl)cyclohex-3-enyl)methanol.12
As the best conditions for the Diels-Alder reaction had
been found, the generality of the reaction was investigated
(results summarized in Table 2). Not only phenyl, but also
a 2-naphthyl-substituted acrolein derivative gave an excellent
result (entry 2). Although the reaction is slow for acrolein
derivatives possessing electron-rich aromatic substituents
such as o-methoxyphenyl, a good yield was obtained by
prolonging the reaction time, high exo-selectivity and excel-
(11) The regiochemistry was determined by 2D-1H-NMR.
(12) Bauer, T.; Chapuis, C.; Kucharska, A.; Rzepecki, P.; Jurczak, J.
HelV. Chim. Acta 1998, 81, 324.
Org. Lett., Vol. 9, No. 15, 2007
2861

known that chiral oxazaborolidinium ions prepared from
diarylprolinol are versatile enantioselective Diels-Alder
catalysts,2 it is interesting to note that after appropriate
modification the same small molecule, diarylprolinol, can
act both as part of a Lewis acid catalyst and as an
organocatalyst in the asymmetric Diels-Alder reaction.
Table 3. Enantioselective Diels-Alder Reaction between
â-Ethoxycarbonylacrolein and Dienes Catalyzed by
Diarylprolinol Silyl Ether 3a
Acknowledgment. This paper is dedicated to Prof. E. J.
Corey for his elegant contributions to the chemistry of
diphenyl prolinol. This work was partially supported by the
Toray Science Foundation and a Grand-in-Aid for Scientific
Research from The Ministry of Education, Culture, Sports,
Science, and Technology (MEXT).
a Unless otherwise shown, the reaction was conducted with 0.07 mmol
of catalyst 3, 0.14 mmol of CF3CO2H, 0.7 mmol of cinnamaldehyde, and
2.1 mmol of diene at 4 °C. b Isolated yield. c The ee was determined by
chiral HPLC analysis.
Supporting Information Available: Detailed experi-
1
mental procedures, full characterization, copies of H-, 13C
NMR and IR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
In summary, we have developed an exo-selective Diels-
Alder reaction of R,â-unsaturated aldehdyes catalyzed by
diarylprolinol silyl ether 3 under acidic conditions. As it is
OL071009+
2862
Org. Lett., Vol. 9, No. 15, 2007