Diphenylprolinol silyl ether as a catalyst in an asymmetric, catalytic, and direct michael reaction of nitroethanol with α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/ol901483x

Diphenylprollnol silyl ether was found to be an effective organocatalyst in the enantioselective and direct Michael reaction of nitroethanol and α,β-unsaturated aldehydes, affording the 1-hydroxy-trans-3,4- disubstituted tetrahydropyrans after isomerizatl

Full text of DOI:10.1021/ol901483x

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4056-4059
Diphenylprolinol Silyl Ether as a
Catalyst in an Asymmetric, Catalytic,
and Direct Michael Reaction of
Nitroethanol with r,ꢀ-Unsaturated
Aldehydes
Hiroaki Gotoh,† Daichi Okamura,† Hayato Ishikawa,† and Yujiro Hayashi*,†,‡
Department of Industrial Chemistry, Faculty of Engineering, and Research Institute for
Science and Technology, Tokyo UniVersity of Science, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
hayashi@ci.kagu.tus.ac.jp
Received June 30, 2009
ABSTRACT
Diphenylprolinol silyl ether was found to be an effective organocatalyst in the enantioselective and direct Michael reaction of nitroethanol and
r,ꢀ-unsaturated aldehydes, affording the 1-hydroxy-trans-3,4-disubstituted tetrahydropyrans after isomerization. The generated Michael addition
products are useful synthetic intermediates, which can be converted into chiral tetrahydropyran with a quaternary stereocenter, 3-substituted
cis- and trans-prolines, and r-amino acid derivatives.
Enantiomerically pure R-amino acids are extremely important
organic substances because they are found in many biologi-
cally active compounds. Accordingly, several methods have
been developed for the synthesis of the enantiomerically pure
R-monosubstituted R-amino acids.1 The Michael reaction of
glycine equivalents and an electron-deficient alkene is one
such method.2
moieties by reduction and oxidation, respectively. Thus,
nitroethanol is regarded as a synthetic equivalent of the
R-amino acid, glycine.3
In the past few years, organocatalysis has been intensively
studied.4 Many types of organocatalysts with unique proper-
(2) (a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39,
5347. (b) Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.; Yamaguchi,
K. Chem. Commun. 2003, 1734. See the review: Ooi, T.; Maruoka, K.
Angew. Chem., Int. Ed. 2007, 46, 4222.
Nitroethanol possesses nitro and hydroxy functionalities,
which are easily transformed into amine and carboxylic acid
(3) (a) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.;
Shibasaki, M. J. Org. Chem. 1995, 60, 7388. (b) Sohtome, Y.; Kato, Y.;
Handa, S.; Aoyama, N.; Nagawa, K.; Matsunaga, S.; Shibasaki, M. Org.
Lett. 2008, 10, 2231.
† Department of Industrial Chemistry, Faculty of Engineering.
‡ Research Institute for Science and Technology.
(1) Najera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584.
10.1021/ol901483x CCC: $40.75
Published on Web 08/26/2009
 2009 American Chemical Society

ties have been reported. Our group5 and Jørgensen and co-
workers6 independently developed diarylprolinol silyl ether
as an effective organocatalyst that has subsequently been
widely used by many research groups.7 Just recently, we5e
and Jørgensen’s group6c reported the asymmetric Michael
reaction of 4-substituted-2-oxazolinone and R,ꢀ-unsaturated
aldehydes catalyzed by diphenylprolinol silyl ether, which
affords R,R-disubstituted R-amino acid equivalents with
excellent enantioselectivity. As we previously reported, the
asymmetric Michael reaction of nitroalkane and R,ꢀ-unsatur-
ated aldehydes catalyzed by diphenylprolinol silyl ether5d,8
and nitroethanol was expected to react with R,ꢀ-unsaturated
aldehydes, generating R-monosubstituted R-amino acid equiva-
lents, the successful realization of which will be described
in this communication.
and cis-3a isomers were partially separated by column
chromatography and the enantiomeric excess of 2ar and 2aꢀ,
and those of 3ar and 3aꢀ were found to be the same and
excellent values (eq 2, Scheme 2). By the use of the partially
Scheme 2
Our scenario is as follows: nitroethanol should react with
R,ꢀ-unsaturated aldehyde to generate the Michael adduct,
γ-nitroaldehyde, which would cyclize to afford substituted
tetrahydropyrans 2 and 3. Although diastereoselectivity of
2 and 3 is expected to be low in view of the previous results
for nitroethane in which low diastereoselectivity is
obtained,5d isomerization would convert cis-isomer 3 into
the more thermodynamically stable trans-isomer 2 (eq 1,
Scheme 1). Tetrahydropyran 2 would be a useful synthetic
separated isomers 2a and 3a, the isomerization of 2a and
3a was investigated under several basic conditions. When a
mixture of 2a and 3a (2a:3a ) 22:78) was treated with
inorganic bases such as K2CO3, CaCO3, KHCO3, NaHCO3,
and Cs2CO3 in MeOH, NaHCO3 was found to be effective
in affording the mixture, in which the trans-isomer is formed
predominantly (2a:3a ) 89:11) with good conversion yield.
When pure trans-isomer 2a was treated under the same
conditions, a mixture of trans- and cis-isomers was obtained
with the same ratio (2a:3a ) 89:11, eq 3). These results
indicate that there is equilibrium between trans- and cis-
isomers and that its ratio is 89:11 in MeOH. Michael and
isomerization reacions can be performed in a single-pot
operation. That is, after the treatment of cinnamaldehyde and
nitroethanol with 1 and PhCO2H at room temperature for
20 h, addition of NaHCO3 to the reaction mixture and further
stirring for 48 h afforded tetrahydropyran derivatives 2a and
3a in good yield with high diastereoselectivity and excellent
enantioselectivity (Table 1, entry 1).
Scheme 1
intermediate with several functional groups for the synthesis
of nitrogen-containing molecules.
To realize this scenario, the reaction of cinnamaldehyde
and nitroethanol was selected as a model, and the Michael
reaction was examined using diphenylprolinol trimethylsilyl
ether 1 as a catalyst in the presence of benzoic acid in
MeOH.5d
Four diastereomers of tetrahydropyran derivatives 2ar,
2aꢀ, 3ar, and 3aꢀ were obtained quantitatively. Trans-2a
After the reaction conditions were optimized, the generality
of the reaction was investigated, and the results are sum-
marized in Table 1. The reaction has broad applicability. Not
only phenyl but also the 2-naphthyl-substituted acrolein
(6) (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.; Kjasgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005,
44, 3703. (c) Cabrera, S.; Reyes, E.; Aleman, J.; Milelli, A.; Kobbelgaard,
S.; Jørgensen, K. A. J. Am. Chem. Soc. 2008, 130, 12031. For recent reports,
see: (d) Jiang, H.; Falcicchio, A.; Jensen, K. L.; Paixao, M. W.; Bertelsen,
S.; Jørgensen, K. A. J. Am. Chem. Soc. 2009, 131, 7153.
(4) For reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Asymmetric Organocatalysis;
Berkessel, A., Groger, H., Eds.; Wiley-VCH: Weinheim, 2005. (c) Hayashi,
Y. J. Synth. 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.; Johansson, 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) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471. (i) Dondoni, A.; Massi,
A. Angew. Chem., Int. Ed. 2008, 47, 4638. (j) Melchiorre, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(5) (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212. (b) Gotoh, H.; Masui, R.; Ogino, H.; Shoji, M.;
Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 6853. (c) Hayashi, Y.; Okano,
T.; Aratake, S.; Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922. (d)
Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307. (e) Hayashi,
Y.; Obi, K.; Ohta, Y.; Okamura, D.; Ishikawa, H. Chem. Asian J. 2009, 4,
246, and the references cited therein.
(7) For selected examples of other group’s application of diarylprolinol
ether, see: (a) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature
2006, 441, 861. (b) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Cordova,
A. Angew. Chem., Int. Ed. 2007, 46, 778. (c) Xie, H.; Zu, L.; Li, H.; Wang,
J.; Wang, W. J. Am. Chem. Soc. 2007, 129, 10886. (d) Enders, D.; Narine,
A. A.; Benninghaus, T. R.; Raabe, G. Synlett 2007, 1667. (e) Vo, N. T.;
Pace, R. D. M.; O’Hara, F.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130,
404. For a review, see: (f) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed.
2006, 45, 7876. (g) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3, 922.
(8) Other group’s Michael reaction, see: (a) Zu, L.; Xie, H.; Li, H.;
Wang, J.; Wang, W. AdV. Synth. Catal. 2007, 349, 2660. (b) Wang, Y.; Li,
P.; Liang, X.; Zhang, T. Y.; Ye, J. Chem. Commun. 2008, 1232.
Org. Lett., Vol. 11, No. 18, 2009
4057

BF3·OEt2 to afford the trans-3,4-disubstituted tetrahydropyran
5 in 93% yield (eq 5, Scheme 3). When hydroxypyran 2
Table 1. One-Pot Michael and Isomerization Reaction of
R,ꢀ-Unsaturated Aldehyde and Nitroethanola
Scheme 3
X
Y
time
yield ee
entry
R
(mol %) (mol %) (h)b 2:3c (%)d (%)e
1
2
3
4
5
6
7
8
Ph
Ph
10
2
20
4
20 89:11 86
46 84:16 87
28 87:13 92
15 86:14 80
15 86:14 85
26 84:16 95
21 85:15 94
26 80:20 80
21 90:10 82
27 76:24 76
79 76:24 55
71 78:22 72
95
96
94
99
93
93
94
91
94
92
96
92
2-naphthyl
p-NO2C6H4-
p-BrC6H4-
p-MeOC6H4-
o-MeOC6H4-
furyl
10
10
10
10
10
10
10
10
20
20
20
20
20
20
20
20
20
0
9
thienyl
10
11
12
PhCH2CH2
cyclohexyl
isobutyl
0
0
a The reaction conditions: R,ꢀ-unsaturated aldehyde (0.60 mmol),
nitroethanol (0.90 mmol), catalyst 1 (0.060 mmol), PhCO2H (0.12 mmol),
and NaHCO3 (3.0 mmol) in MeOH (1.2 mL) were employed. See the
Supporting Information in detail. b The reaction time for the first Michael
reaction. c Diastereomeric ratio was determined by 1H NMR or 13C NMR.
d Yield of isolated products 2 and 3. e Enantiomeric excess of 2, which
was determined by chiral HPLC analysis after conversion to the corre-
sponding acetyl ester.
derivative gave an excellent result (entry 3). When the
substituent is electron deficient, such as p-nitro or p-
bromophenyl, the reaction also proceeds efficiently, generat-
ing the substituted tetrahydropyrans with good diastereose-
lectivities and excellent enantioselectivities (entries 4 and
5). Acrolein derivatives possessing electron-rich aromatic
substituents such as p- and o-methoxyphenyl are also good
substrates, generating excellent results (entries 6 and 7). Not
only aromatic groups but also heteroaromatic groups such
as furyl and thienyl are suitable substituents (entries 8 and
9). Alkyl-substituted acroleins were employed successfully,
in which better results were obtained without the addition
of PhCO2H. That is, the reaction of acroleins possessing
2-phenylethyl, cyclohexyl, and isobutyl moieties proceeds
in the presence of catalyst 1, affording the tetrahydropyran
derivatives with excellent enantioselectivity (entries 10-12).
Although we used 10 mol % of the catalyst, the catalyst
loading can be reduced to 2 mol %. Namely, in the presence
of 2 mol % of 1 and 4 mol % of benzoic acid, the reaction
of cinnamaldehyde proceeded efficiently, affording the
desired product in 87% yield without compromising the
enantioselectivity (96% ee, entry 2).
was treated with H2 in the presence of Pd(OH)2, reduction
of the nitro group and a successive intramolecular reductive
amination occurred to provide the pyrrolidine derivative,
which was isolated as the N-Boc-protected 2,3-cis-disubsti-
tuted pyrrolidine 6 in 80% yield over two steps. Oxidation
with o-iodoxybenzoic acid (IBX)9 gave cis-aldehyde 7, which
was further oxidized under Kraus conditions10 to provide
cis-3-phenylproline derivative 8 (eq 6). On the other hand,
trans-aldehyde 9 was obtained by the isomerization of cis-
isomer 7 with DBU, followed by oxidation to afford trans-
3-phenylproline derivative 10 (eq 7). By these methods,
The substituted tetrahydropyran 2 is a useful synthetic
intermediate because it possesses several functional groups,
the transformations of which were investigated next. Tet-
rahydropyran 2 was converted into acetoxytetrahydropyran
4, which was reduced with Et3SiH in the presence of
(9) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org.
Chem. 1995, 60, 7272.
(10) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825.
4058
Org. Lett., Vol. 11, No. 18, 2009

cis- and trans-3-substituted prolines can be synthesized
stereoselectively from the same starting material. The
absolute configuration of the methyl ester of 8 was
determined by a comparison of its optical rotation with
that of the literature.11
When acetoxytetrahydropyran 4 was treated with methyl
acrylate in the presence of Cs2CO3, the Michael reaction
proceeded smoothly to generate the product 11 as a single
isomer. It should be noted that the reaction proceeds with
excellent diastereoselectivity with the generation of a qua-
ternary stereocenter (eq 8).
and direct Michael reaction of nitroethanol and R,ꢀ-unsatur-
ated aldehydes catalyzed by diphenylprolinol silyl ether as
an organocatalyst, followed by isomerization. Good diaste-
reoselectivity and excellent enantioselectivity have been
obtained for a broad range of R,ꢀ-unsaturated aldehydes. We
have also demonstrated that the products are useful synthetic
intermediates with functional groups, which were success-
fully converted into chiral tetrahydropyran with a quaternary
stereocenter, 3-substituted cis- and trans-prolines, and R-ami-
no acid derivatives.
When acetoxytetrahydropyran 4 was reduced with H2 in
the presence of Pd(OH)2, the amine was generated, which
was treated with ZCl and i-Pr2EtN to afford 12 in 83% yield
over two steps. Hydrolysis of the ester, followed by the
Wittig reaction, afforded amino alcohol 13. By oxidation of
the alcohol to the carboxylic acid and conversion of the
carboxylic acid to the ester, R-amino ester derivative 14 was
synthesized stereoselectively (eq 9).
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from The Ministry
of Education, Culture, Sports, Science, and Technology
(MEXT).
Supporting Information Available: Detailed experimen-
1
tal procedures, full characterization, copies of H and 13C
In summary, we report that 1-hydroxy-trans-3,4-disubsti-
tuted tetrahydropyrans can be synthesized by the asymmetric
NMR and IR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(11) Flamant-Robin, C.; Wang, Q.; Chiaroni, A.; Sasaki, N. A. Tetra-
hedron 2002, 58, 10475.
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