Diphenylprolinol silyl ether catalysis in an asymmetric formal carbo [3 + 3] cycloaddition reaction via a domino michael/knoevenagel condensation

Article abstract of DOI:10.1021/ol802330h

Diphenylprolinol silyl ether was found to catalyze the formal carbo [3 + 3] cycloaddition reaction through the domino reaction via the Michael reaction, followed by Knoevenagel condensation of the α, β-unsaturated aldehyde and dimethyl 3-oxopentanedioate,

Full text of DOI:10.1021/ol802330h

ORGANIC
LETTERS
2009
Vol. 11, No. 1
45-48
Diphenylprolinol Silyl Ether Catalysis in
an Asymmetric Formal Carbo [3 + 3]
Cycloaddition Reaction via a Domino
Michael/Knoevenagel Condensation
Yujiro Hayashi,* Maya Toyoshima, Hiroaki Gotoh, and Hayato Ishikawa
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 October 7, 2008
ABSTRACT
Diphenylprolinol silyl ether was found to catalyze the formal carbo [3 + 3] cycloaddition reaction through the domino reaction via the Michael
reaction, followed by Knoevenagel condensation of the r,ꢀ-unsaturated aldehyde and dimethyl 3-oxopentanedioate, affording substituted
cyclohexenone derivatives with excellent enantioselectivity.
The cyclohexane ring system is one of the most common
structures in natural products and biologically significant
molecules. The Diels-Alder reaction ([4 + 2] cycloaddition)
is one of the most widely employed methods for the
construction of this ring system with control of the relative
and absolute configuration, and there are several asymmetric
catalytic Diels-Alder reactions promoted by chiral Lewis
acids.1 Recently, organocatalysts have been successfully
applied to this enantioselective reaction.2 The carbo [3 + 3]
cycloaddition is another useful method for the synthesis of
the cyclohexane ring (eq 1). As for the aza [3 + 3]
cycloaddition reaction, we have recently reported the first
asymmetric formal aza [3 + 3] cycloaddition for the
formation of the piperidine ring system.3-5 Carbo [3 + 3]
cycloaddition, however, is very rare, and there are only two
enantioselective, catalytic versions6 to the best of our
knowledge.
(1) For recent reviews of enantioselective Diels-Alder reactions, see:
(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) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650. (c)
Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G.
Angew. Chem., Int. Ed. 2002, 41, 1668. (d) Hayashi, Y. Catalytic
Asymmetric Diels-Alder Reactions. In Cycloaddition Reaction in Organic
Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim,
2002; pp 5-55.
(2) (a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243. (b) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005,
127, 10504. (c) Lemay, M.; Ogilvie, W. W. Org. Lett. 2005, 7, 4141. (d)
Kano, T.; Tanaka, Y.; Maruoka, K. Org. Lett. 2006, 8, 2687. (e) Gotoh,
H.; Hayashi, Y. Org. Lett. 2007, 9, 2859. (f) Hayashi, Y.; Samanta, S.;
Gotoh, H.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 6634.
Recently, the field of organocatalysis has been developing
rapidly, and many kinds of new organocatalysts have been
(3) Hayashi, Y.; Gotoh, H.; Masui, R.; Ishikawa, H. Angew. Chem., Int.
Ed. 2008, 47, 4012
(4) Zu, L.; Xie, H.; Li, H.; Wang, J.; Yu, X.; Wang, W. Chem.sEur. J.
2008, 14, 6333
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.
(5) Reviews, see; (a) Harrity, J. P. A.; Provoost, O. Org. Biomol. Chem.
2005, 3, 1349. (b) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N. Eur. J.
Org. Chem. 2005, 23
.
10.1021/ol802330h CCC: $40.75
Published on Web 12/02/2008
2009 American Chemical Society

reported.7 Diarylprolinol silyl ethers,8 which have been
developed independently by our group9 and Jørgensen’s
group,10 have been successfully utilized by several research
groups (Figure 1). We have reported the [4 + 2] cycload-
dition reaction using diarylprolinol silyl ethers as
organocatalysts.2e,f We have applied diphenylprolinol silyl
ether to the reaction of R,ꢀ-unsaturated aldehydes with
dimethyl 3-oxopentanedioate to find that a formal carbo [3
+ 3] cycloaddition reaction proceeds in a highly enantiose-
lective manner, which will be described in this paper.
unsaturated aldehyde and 3-oxopentanedioate via the domino
reaction of the Michael reaction and hydration of the resulting
enamine followed by a Knoevenagel condensation reaction.
Our scenario is as follows (Scheme 1). An amine catalyst
and R,ꢀ-unsaturated aldehyde 5 could generate an iminium
ion, which would react with dimethyl 3-oxopentanedioate 6
to generate enamine 8 by an enantioselective Michael
reaction. Hydration occurs to afford aldehyde 9, and an
intramolecular Knoevenagel condensation reaction would
proceed to provide the functionalized cyclohexenone deriva-
tive 10. It should be noted that Jørgensen and co-workers
reported the synthesis of a chiral cyclohexenone derivative
from tert-butyl 3-oxobutyrate and an R,ꢀ-unsaturated alde-
hyde in the presence of diarylprolinol silyl ether, followed
by treatment with TsOH under reflux conditions.13 During
the preparation of this manuscript, Jørgensen and co-workers
reported the domino reaction using the same starting materi-
als 5 and 6, affording the 2:1 addition product 12 with
excellent enantioselectivity without formation of the 1:1
addition product.14
Figure 1. Organocatalysts examined in the present study.
Scheme 1. Enantioselective Domino Reaction of 5 and 6
The domino reaction is a powerful method for the
construction of complex molecules in a single process,11 and
there are several successful organocatalysis-mediated domino
reactions.12 We expected that the formal carbo [3 + 3]
cycloaddition reaction would proceed between an R,ꢀ-
(6) (a) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett.
2006, 8, 2217. (b) Cao, C.-L.; Sun, X.-L.; Kang, Y.-B.; Tang, Y. Org. Lett.
2007, 9, 4151.
(7) For reviews on organocatalysis, see: (a) Asymmetric Organocatalysis;
Berkessel, A., Groger, H., Eds.; Wiley-VCH: Weinheim, 2005. (b) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Hayashi, Y. J.
Syn. Org. Chem. Jpn. 2005, 63, 464. (d) List, B. Chem. Commun. 2006,
819. (e) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001. (f)
Gaunt, M. J.; Johnsson, C. C. C.; McNally, A.; Vo, N. T. Drug DiscoVery
Today 2007, 12, 8. (g) EnantioselectiVe Organocatalysis; Dalko, P. I., Ed.;
Wiley-VCH: Weinheim, 2007. (h) Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 4638. (i) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli,
G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(8) For a review, see: (a) Palomo, C.; Mielgo, A. Angew. Chem., Int.
Ed. 2006, 45, 7876. (b) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3,
922.
(9) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int.
Ed. 2005, 44, 4212.
The reaction of cinnamaldehyde and dimethyl 3-oxopen-
tanedioate 6 was selected as a model, and the reaction was
investigated in detail. We soon found that the molar ratio of
the reagents is very important: when 1.5 equiv of tricarbonyl
compound 6 was used, the desired product was not formed;
instead, the bicylo[3.3.1]nonene derivative 12 was generated
as a single isomer in 51% yield, which is the main product
obtained by Jørgensen and co-workers.14 When 0.5 equiv
of 6 was employed, diene derivative 13 was isolated in 55%
yield, which would be generated by the overreaction of the
Michael product 9 with another cinnamaldehyde via Kno-
evenagel condensation. This result indicates that the inter-
molecular Knoevenagel condensation is faster than hydration
of the enamine 8.
(10) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. (b) Marigo, M.; Fielenbach, D.;
Braunton, A.; Kjærsgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 3703.
(11) (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006. For reviews, see: (b)
Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46,
1570. (c) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037.
(12) For selected examples of organocatalytic asymmetric domino
reactions, see: (a) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III
Angew. Chem., Int. Ed. 2003, 42, 4233. (b) Yang, J. W.; Fonseca, M. T. H.;
List, B. J. Am. Chem. Soc. 2005, 127, 15036. (c) Huang, Y.; Walji, A. M.;
Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051.
(d) Marigo, M.; Schulte, T.; Franzen, J.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 15710. (e) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe,
G. Nature 2006, 441, 861. (f) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am.
Chem. Soc. 2006, 128, 10354. (g) Carlone, A.; Cabrera, S.; Marigo, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1101. (h) Li, H.; Wang,
J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.; Wang, W. Org. Lett. 2007,
9, 965. (i) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem.,
Int. Ed. 2007, 46, 4922. (j) Reyes, E.; Jiang, H.; Milelli, A.; Elsner, P.;
Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 9202. (k)
Hazelard, D.; Ishikawa, H.; Hashizume, D.; Koshino, H.; Hayashi, Y. Org.
Lett. 2008, 10, 1445.
(13) Carlone, A.; Marigo, M.; North, C.; Landa, A.; Jørgensen, K. A.
Chem. Commun. 2006, 4928.
(14) Bertelsen, S.; Johansen, R. L.; Jørgensen, K. A. Chem. Commun.
2008, 3016.
46
Org. Lett., Vol. 11, No. 1, 2009

Despite these unsuccessful results, the desired product was
formed when an equimolar amount of reagents 5 and 6 was
employed. That is, when 5 and 6 were treated with diphe-
nylprolinol trimethylsilyl ether 1 in toluene, the desired
cyclohexenone 10 was formed, which was isolated as the
corresponding alcohol 11 as a single isomer in 35% yield
over two steps after reduction with NaBH4 (Table 1, entry
1). Studies of the effect of the solvent showed that CH2Cl2
was suitable. It was found that a small excess of tricarbonyl
compound 6 (1.1 equiv) increased the yield to 58% with
excellent enantioselectivity (92% ee, entry 2). Next, the
influence of catalyst choice was investigated, and the results
are summarized in Table 1.
Table 2. Catalytic Asymmetric Formal Carbo [3 + 3]
Cycloaddition Reaction of Dimethyl 3-Oxopentanedioate and
R,ꢀ-Unsaturated Aldehydesa
entry
R
time (h)
yieldb (%)
eec (%)
1
phenyl
phenyl
2-naphthyl
p-nitrophenyl
p-bromophenyl
p-chlorophenyl
p-methoxyphenyl
2-furyl
1
14
1.5
0.5
1
1
2
1
75
68
70
74
77
71
65
63
95
95
>99
99
99
96
2d
3
Table 1. Optimization of the Reaction Conditionsa
4
5
6
7
94
97
8
a Unless otherwise noted, the reaction was performed by employing
R,ꢀ-unsaturated aldehyde (0.5 mmol), dimethyl 3-oxopentanedioate (0.55
mmol), organocatalyst 2 (0.05 mmol), and benzoic acid (0.1 mmol) in
dichloromethane (1.0 mL) at room temperature for the indicated time. The
reaction mixture was treated with NaBH4 at 0 °C. b Isolated yield of alcohol
(two steps). c Determined by HPLC analysis on a chiral phase. d Organocatalyst
2 (2 mol %) and PhCO2H (4 mol %) were employed.
entry catalyst
additive
time (h) yieldb (%) eec (%)
1d
2
3
4
5
6
7
8
1
1
2
3
4
2
2
2
4
1
22
48
52
3
35
58
58
52
17
34
75
0
nde
92
94
92
-50
94
derivative gave an excellent result (entry 3). When the
substituent is electron deficient, such as p-nitro-, p-bromo-,
or p-chlorophenyl, the reaction also proceeds efficiently,
generating the [3 + 3] cycloadducts with excellent enanti-
oselectivities (entries 4-6). Although the reaction is a little
slower for acrolein derivatives possessing electron-rich
aromatic substituents such as p-methoxyphenyl, a good yield
was obtained with excellent enantioselectivity (entry 7). Not
only aromatic groups but also heteroaromatic groups such
as furyl are suitable substituents (entry 8). Although we used
10 mol % of the catalyst, the catalyst loading can be reduced
to 2 mol %. That is, in the presence of 2 mol % of 2 and 4
mol % of benzoic acid, the reaction of cinnamaldehyde
proceeded efficiently, affording the [3 + 3] cycloaddition
product in 68% yield without compromising the enantiose-
lectivity (95% ee) (entry 2). As for the aliphatic enals, we
could not get a good result.
The formal [3 + 3] cycloaddition product 10 is syntheti-
cally useful, because it possesses several functional groups,
including a double bond activated with two electron-
withdrawing groups such as keto and ester moieties. Further
one-pot transformations were investigated, and the following
three examples are successful transformations of this key
intermediate 10 to the more functionalized cyclohexanone
derivatives in the same pot without isolation of the inter-
mediate.
CH3CO2H
PhCO2H
CF3CO2H
1
2
95
nde
a Unless otherwise shown, the reaction was performed by employing
cinnamaldehyde (0.5 mmol), dimethyl 3-oxopentanedioate (0.55 mmol), and
organocatalyst (0.05 mmol) in CH2Cl2 (1.0 mL) at room temperature for
the indicated time. The reaction mixture was treated with NaBH4 at 0 °C,
and the product was isolated as an alcohol 11. b Isolated yield of 11.
c Determined by HPLC analysis on a chiral phase. d Dimethyl 3-oxopen-
tanedioate (0.50 mmol) was employed in toluene. e nd ) not determined.
The reaction was slow, and the opposite enantiomer was
generated in low yield with moderate enantioselectivity in
the presence of diphenylprolinol 4, which does not contain
a siloxy group (entry 5). Although trifluoromethyl-substituted
diarylprolinol silyl ether 3 gave excellent enantioselectivity,
the reaction was slow (48 h, entry 4). Among the catalysts
examined, the tert-butyldimethylsilyl ether of diphenylpro-
linol 2 was the choice (94% ee, entry 3). Further optimization
was performed with an additive to increase the yield, which
showed that benzoic acid is effective, providing the desired
alcohol 11 as a single isomer in a short time (1 h) and good
yield with excellent enantioselectivity (75%, 95% ee, entry
7).
After the reaction conditions were optimized, the generality
of the reaction was investigated, and the results are sum-
marized in Table 2. The reaction has broad applicability. Not
only phenyl but also a 2-naphthyl-substituted acrolein
A THF solution of Me2CuLi was added to the reaction
mixture of cinnamaldehyde 5, dimethyl 3-oxopentanedioate
6, a catalytic amount of catalyst 2, and benzoic acid. The
Michael reaction proceeded in a diastereoselective manner
Org. Lett., Vol. 11, No. 1, 2009
47

to generate the methyl addition product with a mixture of
amount of Pd/C were added, and the reaction was performed
under H2 atmosphere using the same reaction pot (eq 5).
Cyclohexanone 19 was obtained, which was treated with
KOH and then with acid to afford 3-substituted cyclohex-
anone 20 in 57% yield over three steps. This is one of the
most facile syntheses of chiral 3-substituted cyclohex-
anones,13,16 and it also indicates the absolute configuration
of 20 by comparison of the optical rotation with that of the
literature.17
keto and enol forms, 14. Reduction with NaBH4 in the
15
presence of CeCl3 afforded the highly substituted cyclo-
hexanol 15, the relative configuration of which was deter-
mined by the analysis of its NOESY spectra. The newly
generated stereochemistry of the methyl group was obtained
as a single isomer, as shown in eq 4.
Another transformation is the one-pot formation of epoxide
16. Addition of m-CPBA and K2CO3 to the reaction pot of
the formal [3 + 3] cycloadduct produced epoxycyclohex-
anone 16 in 76% yield as a single isomer. The epoxide 16
was further converted into the more functionalized cyclo-
hexanol 18 as shown in Scheme 2, in which the relative
stereochemistry was determined by the coupling constant and
NOE analysis. This transformation indicates that the formal
carbo [3 + 3] cycloaddition reaction is a powerful method
for the synthesis of a highly substituted cyclohexane frame-
work.
In summary, we have developed a highly enantioselective
formal carbo [3 + 3] cycloaddition reaction of R,ꢀ-
unsaturated aldehydes and dimethyl 3-oxopentanedioate
catalyzed by diphenylprolinol silyl ether as an organocatalyst
via the domino reaction of the Michael reaction/Knoevenagel
condensation. The cyclohexenone derivatives that are gener-
ated are useful synthetic intermediates with several functional
groups, and excellent enantioselectivities are obtained in most
of the reactions. This is one of the rare successful enanti-
oselective, catalytic formal carbo [3 + 3] cycloaddition
reactions for formation of the cyclohexene structure. It should
also be noted that the reaction is high yielding and clean
and that further one-pot reactions with other reagents can
be performed, which can construct complex cyclohexanones
via formation of several bonds in a single pot.
Scheme 2. Synthesis of Functionalized Cyclohexane Derivatives
Based on the Formal [3 + 3] Cycloaddition Reaction
Acknowledgment. This work was partially supported by
the Toray Science Foundation and a Grant-in-Aid for
Scientific Research from The Ministry of Education, Culture,
Sports, Science, and Technology (MEXT).
Supporting Information Available: Detailed experimen-
tal procedures, full characterization, and copies of 1H NMR,
13C NMR, and IR spectra of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802330H
After the [3 + 3] cycloaddition reaction, the solvent was
removed under reduced pressure, MeOH and a catalytic
(16) Bolze, P.; Dickmeiss, G.; Jørgensen, K. A. Org. Lett. 2008, 10,
3753
.
(17) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
(15) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
J. Am. Chem. Soc. 1998, 120, 5579.
48
Org. Lett., Vol. 11, No. 1, 2009