Polymeric ethyl glyoxylate in an asymmetric aldol reaction catalyzed by diarylprolinol

Article abstract of DOI:10.1021/ol1009812

Diarylprolinol was found to be an effective organocatalyst of the direct, enantioselective aldol reaction of commercially available polymeric ethyl glyoxylate, affording γ-ethoxycarbonyl-β-hydroxy aldehydes, versatile synthetic intermediates, in good yiel

Full text of DOI:10.1021/ol1009812

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2966-2969
Polymeric Ethyl Glyoxylate in an
Asymmetric Aldol Reaction Catalyzed by
Diarylprolinol
Tatsuya Urushima, Yusuke Yasui, Hayato Ishikawa, 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 29, 2010
ABSTRACT
Diarylprolinol was found to be an effective organocatalyst of the direct, enantioselective aldol reaction of commercially available polymeric
ethyl glyoxylate, affording γ-ethoxycarbonyl-ꢀ-hydroxy aldehydes, versatile synthetic intermediates, in good yield with excellent enantioselectivity.
Ethyl glyoxylate is a versatile electrophile. It can be
converted into synthetically useful chiral building blocks in
several asymmetric catalytic reactions. For example, it is a
reactive ene component in the asymmetric glyoxylate-ene
reaction,1a dienophile in the asymmetric hetero-Diels-Alder
reaction,2 and an electrophilic aldehyde in the reaction with
ene-carbamates.3
pyrolysis of a polymer.5 The monomer form is so reactive
that it polymerizes easily and reacts readily with water to
generate the hydrated form. Ethyl glyoxylate is therefore
distilled just prior to use, after pyrolysis, and used under
nonaqueous conditions. It would be a great synthetic
advantage if ethyl glyoxylate could be directly used in the
form of the commercially available toluene solution of its
polymer under aqueous conditions.
To the best of our knowledge, there are three reports on
the use of polymeric ethyl glyoxylate in asymmetric reac-
tions, and in all cases Cu catalyst is used. Evans and co-
workers1d,g used it in the asymmetric ene reaction catalyzed
by a chiral Cu(II) complex, Kobayashi3a used it in the
asymmetric reaction of ene-carbamates catalyzed by a Cu(I)-
Ethyl glyoxylate is commercially available in its polymeric
form in toluene solution,4 and a monomer is generated by
(1) Selected references on asymmetric glyoxylate-ene reaction, see: (a)
Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 3949. (b)
Mikami, K.; Shimizu, M. Chem. ReV. 1992, 92, 1021. (c) Evans, D. A.;
Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay, S. W. J. Am. Chem.
Soc. 1998, 120, 5824. (d) Evans, D. A.; Tregay, S. W.; Burgey, C. S.; Paras,
N. A.; Vojkovsky, T. J. Am. Chem. Soc. 2000, 122, 7936. (e) Bolm, C.;
Simic, O. J. Am. Chem. Soc. 2001, 123, 3830. (f) Zheng, K.; Shi, J.; Liu,
X.; Feng, X. J. Am. Chem. Soc. 2008, 130, 15770. (g) Evans, D. A.; Kvarno,
L.; Dunn, T. B.; Beauchemin, A.; Raymer, B.; Mulder, J. A.; Olhava, E. J.;
Juhl, M.; Kagechika, K.; Favor, D. A. J. Am. Chem. Soc. 2008, 130, 16295.
(h) Zhao, J.-F.; Tsui, H.-Y.; Wu, P.-J.; Lu, J.; Loh, T.-P. J. Am. Chem.
Soc. 2008, 130, 16492.
(3) (a) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int.
Ed. 2004, 43, 3258. (b) Matsubara, R.; Kawai, N.; Kobayashi, S. Angew.
Chem., Int. Ed. 2006, 45, 3814. (c) Matsubara, R.; Doko, T.; Uetake, R.;
Kobayashi, S. Angew. Chem., Int. Ed. 2007, 46, 3047. (d) Terada, M.; Soga,
K.; Momiyama, N. Angew. Chem., Int. Ed. 2008, 47, 4122.
(4) We used ethyl glyoxylate polymer form (47% in toluene), which
was purchased from TCI (Tokyo Chemical Inddustry Co., LTD.), Catalog
no. G0242. Aldrich offers ethyl glyoxylate solution (∼50% in toluene),
which exists partly in the polymerized form, Catalog no. 50705.
(5) For the generation of monomer via pyrolysis, see ref 3d for
instance.
(2) Selected references on asymmetric glyoxylate-hetero-Diels-Alder
reaction, see: (a) Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem.
Soc. 1994, 116, 2812. (b) Wang, Y.; Wolf, J.; Zavalij, P.; Doyle, M. P.
Angew. Chem., Int. Ed. 2008, 47, 1439. (c) Momiyama, N.; Tabuse, H.;
Terada, M. J. Am. Chem. Soc. 2009, 131, 12882.
10.1021/ol1009812  2010 American Chemical Society
Published on Web 06/08/2010

diimine complex, and Shair6 used it in a decarboxylative
aldol reaction catalyzed by Cu(II). The aldol reaction is one
of the most useful carbon-carbon bond formation reactions
in synthetic organic chemistry, for which several asymmetric
catalysts have been developed.7 The aldol reaction of ethyl
glyoxylate as an electrophilic aldehyde is a useful synthesis
reaction because the resulting aldol product, the ꢀ-ethoxy-
carbonyl-ꢀ-hydroxy carbonyl derivative, possesses polyfunc-
tional groups. With regard to the asymmetric catalytic aldol
reactions of ethyl glyoxylate, chiral Lewis acids8 and
TADDOL9 have been used as catalysts to afford the aldol
products with excellent enantioselectivity.
source without pyrolysis and without the complete removal
of water in the aldol reaction for the preparation of products
with excellent enantioselectivity;as will now be described
in this communication.
We chose the aldol reaction of propanal and polymeric
ethyl glyoxylate as a model, and studied the catalyst (eq 1).
As polymeric ethyl glyoxylate is commercially available as
a toluene solution, our first investigations were performed
in toluene. Because the diastereomer ratio of the aldol product
is easily changed during the purification owing to the facile
epimerization of the product, the determinations of yield and
diastereo- and enantioselectivities were performed after
conversion to the corresponding R,ꢀ-unsaturated ester 7 by
the treatment of the aldol product with a Wittig reagent. The
reaction proceeded with the polymeric ethyl glyoxylate, and
the reactivity and enantioselectivity were found to be
dependent on the catalyst (see Table 1). While a nearly
Table 1. Effects of Catalyst and Solvent in the Aldol Reaction
of Propanal and Polymeric Ethyl Glyoxylatea
Figure 1. Organocatalysts investigated in the present study.
The field of organocatalysis10 has developed very rapidly
after the discovery of the proline-mediated intermolecular
aldol reaction as reported by List, Lerner, and Barbas.11
Many organocatalysts have been developed, and used in the
direct, enantioselective aldol reaction (Figure 1). The enan-
tioselective aldol reaction of ethyl glyoxylate in which
monomeric ethyl glyoxylate is used has been investigated
by several research groups.12 While we were preparing this
manuscript, a report appeared describing an example of the
use of polymeric ethyl glyoxylate, but the enantioselectivity
was moderate (65% ee).13
entry catalyst
solvent
toluene
toluene
toluene
toluene
toluene
MeOH
DMF
CHCl3
THF
H2O
CH3CN
aq CH3CNe
aq CH3CNe
yieldb/% syn:antic eed/%
1
proline
42
57
76
80
59
18
41
55
50
67
73
86
93
1.2:1
1:4.6
1.4:1
1:1.4
1:4.3
1:4.9
1:2.0
1:3.8
1:3.7
1:3.6
1:4.4
1:4.1
1:9.8
1
86
-20
-71
92
90
62
94
95
92
98
96
98
2
3
4
5
6
7
8
9
10
11
12
13f
3
4
2
1
1
1
1
1
1
1
1
1
It is a great synthetic advantage, and a challenge, to use
polymeric ethyl glyoxylate directly from the commercial
(6) Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc. 2003, 125,
2852.
a Reaction conditions: propanal (2.5 mmol), ethyl glyoxylate polymer
(47% in toluene, 0.5 mmol), catalyst (0.05 mmol), and solvent (0.5 mL) at
room temperature for 24 h. See the Supporting Information for details.
b Isolated yield of 7 (2 steps). c Determined by 1H NMR spectroscopy. d Ee
was determined by chiral HPLC analysis of 7. e CH3CN (0.5 mL) and H2O
(27 µL) were used as a solvent. f Propanal (0.75 mmol) was employed.
(7) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH, Weinheim,
Germany, 2004; Vols. 1 and 2.
(8) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem.
Soc. 1997, 119, 10859.
(9) Gondi, V. B.; Gravel, M.; Rawal, V. H. Org. Lett. 2005, 7, 5657.
(10) For selected 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,
Germany, 2005. (c) Hayashi, Y. Yuki Gosei Kagaku Kyokaishi 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) Enanti-
oselectiVe Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
Germany, 2007. (h) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. ReV. 2007, 107, 5471. (i) Barbas, C. F., III Angew. Chem., Int. Ed.
2007, 47, 42. (j) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47,
4638. (k) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem.,
Int. Ed. 2008, 47, 6138. (l) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. ReV.
2009, 38, 2178.
racemic product was obtained in the case of proline as
catalyst (entry 1), the enantioselectivity improved signifi-
cantly to 86% when diphenylprolinol 3 was used as catalyst
(entry 2). Diarylprolinol 1 with a trifluoromethyl group,
which is also a suitable catalyst in the asymmetric aldol
reaction of acetaldehdye as a nucleophile,14 was found to
be an effective catalyst and afforded the product with 92%
ee (entry 5), while the corresponding trimethylsilyl ether 2
afforded the opposite enantiomer with 71% ee.
(11) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000,
122, 2395.
(12) (a) Dodda, R.; Zhao, C.-G. Synlett 2007, 1605. (b) Kano, T.;
Yamaguchi, Y.; Tanaka, Y.; Maruoka, K. Angew. Chem., Int. Ed. 2007,
46, 1738. (c) Kano, T.; Yamaguchi, Y.; Maruoka, K. Chem.sEur. J. 2009,
15, 6678.
(14) (a) Hayashi, Y.; Itoh, T.; Aratake, S.; Ishikawa, H. Angew. Chem.,
Int. Ed. 2008, 47, 2082. (b) Hayashi, Y.; Samanta, S.; Itoh, T.; Ishikawa,
H. Org. Lett. 2008, 10, 5581. (c) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org.
Lett. 2009, 11, 3854.
(13) Markert, M.; Scheffler, U.; Mahrwald, R. J. Am. Chem. Soc. 2009,
131, 16642.
Org. Lett., Vol. 12, No. 13, 2010
2967

Having identified a suitable catalyst, solvent screening was
carried out next. After removal of toluene from the com-
mercial solution under reduced pressure, the reaction was
carried out after the addition of another solvent. The results
are summarized in entries 6-13 of Table 1. Excellent
enantioselectivity was obtained in all the solvents that were
considered, except in DMF. Among the solvents used, MeCN
was found to be suitable in terms of both the yield and
enantioselectivity (entry 11). It should be noted that the
reaction also proceeded when water was used as a reaction
medium (entry 10). The addition of 3 equiv of water to
MeCN increased the yield (entry 12). The quantity of
propanal used was also important. When it was reduced from
5 equiv to 1.5 equiv the diastereoselectivity increased from
1:4.1 to 1:9.8, and the excellent enantioselectivity was
maintained (entry 13).
Table 3. Generality of the Aldol Reaction of Polymeric Ethyl
Glyoxylatea
The quantity of the catalyst was also investigated (Table
2). The reaction proceeded in the presence of 2 and 5 mol
% of the catalyst (entries 2 and 3). Even in the presence of
only 1 mol % of the catalyst, the reaction proceeded to afford
the aldol product in 61% yield, with excellent diastereo- and
enantioselectivity (entry 4).
Table 2. Effect of the Loading of the Catalyst 1 in the Aldol
Reactiona
entry
Xb/mol %
time/h
yieldc/%
syn:antid
eee/%
1
2
3
4
10
5
2
20
30
40
48
93
1:9.8
1:7.6
1:7.3
1:11.5
98
98
99
99
quant
quant
61
a Unless otherwise shown, reaction conditions: aldehyde (0.75 mmol),
ethyl glyoxylate polymer (47% in toluene, 0.5 mmol), catalyst 1 (0.05
mmol), CH3CN (0.5 mL) and H2O (27 µL) at room temperature for 24 h.
As for the procedure of Wittig and acetal formation, see the Supporting
Information for details. b Isolated yield of the product over 2 steps.
c Determined by 1H NMR spectroscopy. d Ee was determined by chiral
HPLC analysis, see the Supporting Information for details. e Aldehyde (0.5
mmol), ethyl glyoxylate polymer (47% in toluene, 0.75 mmol), catalyst 1
(0.05 mmol), CH3CN (0.25 mL), and H2O (27 µL) at 5 °C for 38 h.
1
a The reaction was performed with propanal (0.75 mmol), ethyl
glyoxylate polymer (47% in toluene, 0.5 mmol), catalyst 1, CH3CN (0.5
mL), and H2O (27 µL) at room temperature for the indicated time. b Amount
of the catalyst 1. c Isolated yield of 7 (2 steps). Determined by H NMR
d
1
spectroscopy. e Ee was determined by chiral HPLC analysis of 7.
Having determined the best reaction conditions, the
generality of the reaction was then investigated by using 10
mol % of the catalyst. The aldol product was converted to
the R,ꢀ-unsaturated ester or dimethyl acetal, then isolated
and characterized, and the enantiomeric excess determined.
The results are summarized in Table 3. The diastereoselec-
tivity and enantioselectivity of the R,ꢀ-unsaturated ester and
dimethyl acetal were similar, indicating that there was no
isomerization in the Wittig reaction and acetal formation
reaction (entries 2 and 8). Although control of the reactivity
of acetaldehyde as a nucleophile is difficult because of its
high reactivity, both as a nucleophile and an electrophile,14,15
acetaldehyde was found to be a suitable nucleophile in the
present reaction;it afforded the product in good yield and
excellent enantioselectivity (entry 1). R-Alkyl-substituted
acetaldehydes, such as propanal, butanal, pentanal, and
isovaleraldehyde, were used as nucleophilic aldehydes
(entries 2-5). ꢀ-Alkoxy-substituted aldehydes such as 3-(p-
methoxyphenylmethoxy)propanal, in which ꢀ-elimination is
a possible side reaction, can be successfully used, which
indicates the mild reaction conditions in the present reaction.
Polyfunctional chiral intermediates can be synthesized with
excellent diastereo- and enantioselectivity when R-hetero-
(15) (a) Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List, B.
Nature 2008, 452, 453. (b) G-Garcia, P.; Ladepeche, A.; Halder, R.; List,
B. Angew. Chem., Int. Ed. 2008, 47, 4719. (c) Hayashi, Y.; Itoh, T.; Okubo,
M.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 4722. (d) Hayashi, Y.;
Okano, T.; Itoh, T.; Urushima, T.; Ishikawa, H.; Uchimaru, T. Angew.
Chem., Int. Ed. 2008, 47, 9053. (e) Kano, T.; Yamaguchi, Y.; Maruoka, K.
Angew. Chem., Int. Ed. 2009, 48, 1838.
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Org. Lett., Vol. 12, No. 13, 2010

atom-substituted acetaldehydes, such as benzyloxyacetalde-
hyde and N-(formylmethyl)phthalimide, are used. The ex-
cellent diastereoselectivity in the present reaction is one of
the noteworthy features, in contrast to the low diastereose-
lectivity achieved in reactions catalyzed by other
organocatalysts.12b,c
Whereas 1.5 equiv of aldehyde was used for the reactions
tabulated in Table 3, we considered it desirable to use an
excess of ethyl glyoxylate in the case of a precious aldehyde
as a nucleophile. Thus, a procedure with 1.5 equiv of ethyl
glyoxylate was developed. As shown in eq 4, good yield
(78%) with excellent anti-selectivity and enantioselectivity
was obtained.
Figure 2. The transition state of intermediate enamine and 5, Ar
) 3,5-bis(trifluoromethyl)phenyl.
ethyl glyoxylate is activated by coordination to the proton
of the hydroxy group via a hydrogen bond.14a This model
can explain the absolute configuration of the aldol product.
This interaction would be stronger in the case of the
trifluoromethyl-substituted catalyst 1 than the diphenylpro-
linol 3 because of the higher acidity of its hydroxy group.
Thus, the opposite enantiomer was generated when the
corresponding silyl ether catalyst 2 was used.
The absolute configuration was determined by the com-
parison of the optical rotations of 4,4-dimethoxy-2-hydroxy-
3-methylbutyl pivalate and 3,3-dimethoxy-2-methylpropanol,
which were synthesized as shown in eq 5, with those
described in the literature.16
In conclusion, we have developed an asymmetric, direct
aldol reaction of ethyl glyoxylate and an aldehyde catalyzed
by diarylprolinol to afford a synthetically useful ꢀ-ethoxy-
carbonyl-ꢀ-hydroxy aldehyde. There are several noteworthy
features of this reaction: (1) the commercially available ethyl
glyoxylate in its polymeric form was used directly without
pyrolysis or distillation prior to use; (2) the reaction was
conducted without the complete removal of water; (3) the
anti-isomer was obtained with excellent diastereoselectivity;
(4) excellent enantioselectivity was realized; and (5) this is
one of the rare reactions in which diarylprolinol is success-
fully used as an efficient catalyst,14,17 while its silyl ether is
widely used as an effective organocatalyst.18 As the generated
product possesses several functional groups, with excellent
diastereoselectivity and enantioselectivity, this method offers
an efficient route for the preparation of the chiral intermedi-
ates.
The large-scale preparation was successfully performed
in the presence of 2 mol % of the catalyst, using a 25 g
solution of ethyl glyoxylate (47%), to afford the aldol product
in its dimethyl acetal form in 73% yield (17 g) after
distillation (eq 6). It should be noted that neither isomeriza-
tion nor racemization occurred under the reaction conditions.
Supporting Information Available: Detailed experimen-
tal procedures, full characterization, copies of 1H, 13C NMR,
and IR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL1009812
The reaction is thought to proceed as follows: Enamine,
which is generated from aldehyde and diarylprolinol catalyst
1, reacts with ethyl glyoxylate as shown in Figure 2, in which
(17) (a) Lattanzi, A. Chem. Commun. 2009, 1452. (b) Gerasyuto, A. I.;
Hsung, R. P.; Sydorenko, N.; Slafer, B. J. Org. Chem. 2005, 70, 4248
.
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Int. Ed. 2005, 44, 4212. (b) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (c) Marigo, M.;
Fielenbach, D.; Braunton, A.; Kjasgaard, A.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 3703. Review, see: (d) Palomo, C.; Mielgo, A.
Angew. Chem., Int. Ed. 2006, 45, 7876. (e) Mielgo, A.; Palomo, C. Chem.
Asian J. 2008, 3, 922.
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Chem., Int. Ed. 2004, 43, 6722. (b) Evans, D. A.; Thomson, R. J. J. Am.
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