Asymmetric, catalytic, and direct self-aldol reaction of acetaldehyde catalyzed by diarylprolinol

Article abstract of DOI:10.1021/ol802438u

(Chemical Equation Presented) An asymmetric, catalytic, and direct self-aldol reaction of acetaldehyde was catalyzed by diarylprolinol in NMP, affording the trimer acetal, which was generated by the reaction of the self-aldol product with another acetaldehyde molecule in a moderate yield with good enantioselectivity. Acetal is the synthetic equivalent of the self-aldol product, which can be converted into other synthetically useful compounds in one pot without compromising the enantioselectivity.

Full text of DOI:10.1021/ol802438u

ORGANIC
LETTERS
2008
Vol. 10, No. 24
5581-5583
Asymmetric, Catalytic, and Direct
Self-Aldol Reaction of Acetaldehyde
Catalyzed by Diarylprolinol
Yujiro Hayashi,*,†,‡ Sampak Samanta,† Takahiko Itoh,† and Hayato Ishikawa†
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 October 22, 2008
ABSTRACT
An asymmetric, catalytic, and direct self-aldol reaction of acetaldehyde was catalyzed by diarylprolinol in NMP, affording the trimer acetal,
which was generated by the reaction of the self-aldol product with another acetaldehyde molecule in a moderate yield with good enantioselectivity.
Acetal is the synthetic equivalent of the self-aldol product, which can be converted into other synthetically useful compounds in one pot
without compromising the enantioselectivity.
The aldol reaction is one of the most important synthetic
transformations in organic synthesis, and several asymmetric
and catalytic versions have been developed.1 The direct aldol
reaction of acetaldehyde, which affords synthetically useful
R,R-unsubstituted ꢀ-hydroxy aldehyde, is regarded as a
difficult transformation because the generated aldehyde acts
both as a reactive electrophile and as a nucleophile, causing
overreactions. Indirect methods reported include the chiral
Lewis base-mediated aldol reaction of trimethyl siloxyethene,
a synthetic equivalent of acetaldehyde, by Denmark,2 while
Yamamoto has recently developed an acetaldehyde super
silyl enol ether which reacts in racemic fashion.3 Recently,
the control of the reactivity and enantioselectivity of acetal-
dehyde has been reported by our group4 and also by List
and co-workers,5 independently. Our group developed a
diarylprolinol-mediated direct asymmetric cross-aldol reac-
tion of acetaldehyde,4a while List’s group reported on a
proline-mediated Mannich reaction of acetaldehyde.5a Both
groups reported on the Michael reaction of acetaldehyde
catalyzed by diarylprolinol silyl ether.4b,5b Just recently, we
also observed the Mannich reaction of acetaldehyde catalyzed
by diarylprolinol silyl ether.4c
3-Hydroxy(or alkoxy)butanal is a synthetically useful
chiral building block. Although the self-aldol reaction of
acetaldehyde is a straightforward method for the preparation
(3) (a) Boxer, M. B.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 48.
(b) Boxer, M. B.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 2762.
(4) (a) Hayashi, Y.; Itoh, T.; Aratake, S.; Ishikawa, H. Angew. Chem.,
Int. Ed. 2008, 47, 2082. (b) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa,
H. Angew. Chem., Int. Ed. 2008, 47, 4722. (c) Hayashi, Y.; Okano, T.;
Itoh, T.; Urushima, T.; Ishikawa, H.; Uchimaru, T. Angew. Chem., Int. Ed.
2008, 47, 9053.
† Department of Industrial Chemistry, Faculty of Engineering.
‡ Research Institute for Science and Technology.
(1) (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, 2004; Vols. 1 and 2. (b) Carreira, E. M. Mukaiyama Aldol
Reaction. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. III, Chapter 29.1. (c)
Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1352.
(d) Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed. 2003, 42, 858.
(2) Denmark, S. E.; Bui, T. J. Org. Chem. 2005, 70, 10190.
(5) (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.
10.1021/ol802438u CCC: $40.75
Published on Web 11/19/2008
2008 American Chemical Society

of this important molecule, as far as we are aware, there has
been no successful, direct, asymmetric self-aldol reaction.
Wong and co-workers obtained a cyclized trimer overreaction
product of the aldol product via a double-aldol reaction when
acetaldehyde was treated with 2-deoxyribose-5-phosphate
aldolase.6 Barbas and co-workers reported that (S,E)-5-
hydroxy-2-hexenal, which was generated by the double-aldol
reaction followed by a dehydration reaction, was obtained
in a low yield with good enantioselectivity in the reaction
of acetaldehyde catalyzed by proline.7 Thus, it is difficult to
obtain the self-aldol product because of these overreactions
of the generated aldol product. Moreover, control of the
enantioselectivity is also difficult. Arylaldehydes were
employed as electrophiles in our previous cross-aldol reaction
of acetaldehyde, in which the discrimination of a large aryl
group and a small H atom was realized to generate excellent
enantioselectivity. When acetaldehyde is used as an elec-
trophile, both methyl group and H atom must be discrimi-
nated, and their sizes are similar, making this enantioselective
reaction very difficult. In this paper, we describe the first
successful realization of the direct, asymmetric self-aldol
reaction of acetaldehyde.
Table 1. Effects of Catalyst and Solvent in the Self-Aldol
Reaction of Acetaldehydea
entry
catalyst
solvent
time/day
yield (%)
eeb (%)
1
2
3
4
5
6
7
8
9
proline
neat
neat
1
4
4
4
4
4
5
5
5
5
<5c,d
61c
nd
64
65
60
65
51
76
82
70
nd
1
1
1
1
1
1
1
2
3
hexane
CH3CN
THF
CH2Cl2
DMF
NMP
NMP
NMP
68c
63c
59c
58c
55e
56e
46e
10
<5e,f
a The reaction was performed using acetaldehyde (3 mmol), catalyst
(0.2 mmol), and solvent (0.3 mL) at 4 °C for the indicated period of time,
and MeOH and NaBH4 were added to the reaction mixture at same
temperature. nd ) not determined. b The enantiomeric excess was deter-
mined by chiral HPLC analyses of bis-benzoate product. c Yield of the
isolated product 5 after column chromatography. d Crotonaldehyde was
formed in 85% yield. e Yield of the bis-benzoate (three steps) after the
treatment of diol 5 with benzoyl chloride and Et3N. f Crotonaldehyde was
formed in 20% yield.
proceeded in most solvents, such as hexane, CH3CN, THF,
CH2Cl2, DMF, and NMP, and the yields were similar, as
summarized in Table 1. However, the enantioselectivity was
different. The best results were obtained when NMP was
employed to afford the bis-benzoate in a 56% yield with
good enantioselectivity (82% ee, entry 8).
Figure 1. Organocatalysts examined in this study.
Next, different catalysts were investigated. When diphenyl-
prolinol 2 was employed, the reaction proceeded to afford the
product in a 46% yield with lower enantioselectivity (70% ee,
entry 9). The hydroxy group is essential, and the product was
obtained in less than a 5% yield with the formation of
crotonaldehyde in a 20% yield when diarylprolinol silyl ether
38 was employed, which is an effective catalyst in the Mannich
and Michael reactions of acetaldehyde (entry 10).4b,c
First, the self-aldol reaction of acetaldehyde was examined
using proline as a catalyst. Although the aldol reaction
proceeded, the successive dehydration reaction was fast,
generating crotonaldehyde as the major product in an 85%
yield (Table 1, entry 1). Trifluoromethyl-substituted diaryl-
prolinol, which gave an excellent result in the cross-aldol
reaction of acetaldehyde,4a was employed as a catalyst. The
aldol reaction was found to proceed, and the crude NMR of
the reaction mixture suggested that acetal 4 was the main
product (Table 1, eq 1); it was generated by the reaction of
the generated aldol product 8 with another acetaldehyde
molecule (Scheme 2). Acetal 4 is regarded as a synthetic
equivalent of the self-aldol product 8. We were able to isolate
acetal 4, and as acetal 4 is labile to acid, it was found to
decompose on silica gel. The aldol product 8 was isolated
as the corresponding diol 5 in a 61% yield after reduction
of the aldol product 8 after treatment with NaBH4 in MeOH.
The enantiomeric excess was determined to be 64% from
the chiral HPLC analysis of the bis-benzoate product (Table
1, entry 2). The reaction conditions were examined in detail
in order to increase the enantioselectivity. The reaction
(8) Diarylprolinol silyl ether was developed by our group and Jørgensen’s
group, independently. For our contribution of diphenylrpolinol silyl ether,
see: (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.; Hayashi, Y. Org. Lett. 2007, 9, 2859. (e) Hayashi, Y.; Gotoh, H.; Masui,
R.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47, 4012. (f) Hayashi, Y.;
Samanta, S.; Gotoh, H.; Ishikawa, H. Angew. Chem., Int. Ed. 2008, 47,
6634. For the contribution of Jørgensen’s group, see: (g) Marigo, M.;
Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 794. (h) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjasgaard,
A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703. For a recent
report of Jørgensen’s group, see: (i) Franke, P. T.; Johansen, R. L.; Bertelsen,
S.; Jørgensen, K. A. Chem. Asian. J. 2008, 3, 216. For selected examples
of other groups’ application of diarylprolinol ether, see: (j) Enders, D.; Huttl,
M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861. (k) Vesely, J.;
Ibrahem, I.; Zhao, G.-L.; Rios, R.; Cordova, A. Angew. Chem., Int. Ed.
2007, 46, 778. (l) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem.
Soc. 2007, 129, 10886. (m) Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt,
M. J. J. Am. Chem. Soc. 2008, 130, 404. For a review, see: (n) Palomo, C.;
Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876. (o) Mielgo, A.; Palomo,
C. Chem. Asian J. 2008, 3, 922.
(6) Gijsen, H. J. M.; Wong, C.-H. J. Am. Chem. Soc. 1994, 116, 8422.
(7) Cordova, A.; Notz, W., III J. Org. Chem. 2002, 67, 301.
5582
Org. Lett., Vol. 10, No. 24, 2008

As the intermediate of the reaction is acetal 4, the synthetic
transformation of acetal 4 into other synthetically useful
chiral building blocks in the same pot without compromising
the enantioselectivity was investigated.
After a period of 5 d of stirring the reaction mixture
composed of acetaldehyde and a catalytic amount of catalyst
1, the excess acetaldehyde was removed under reduced
pressure. Methanol and Amberlyst 15 were added to the
residue, which generated 4,4-dimethoxy-2-butanol 6 in a 48%
yield with an 80% ee (Scheme 1, eq 2).
Whereas the generated aldol product 8 is expected to react
as either a reactive nucleophile or electrophile to afford
overreaction products, the aldol product 8 reacted im-
mediately with another acetaldehyde molecule to generate
acetal 4, which suppressed the expected overreaction. As the
reaction proceeded under neutral conditions, side reactions,
such as dehydration reactions to afford 2-butenal, were not
observed.
Another transformation is the one-pot formation of the R,ꢀ-
unsaturated ester. Addition of triphenylcarbethoxymethyl-
enephosphorane to the reaction mixture of the acetal 4
produced ethyl 5-hydroxy-2-hexenoate 7 in a 51% yield with
an 81% ee (Scheme 1, eq 3).
Scheme 2
.
Reaction Mechanism of the Self-Aldol Reaction
Catalyzed by 1
The optically active compounds 6 and 7 are synthetically
useful as chiral building blocks and have been used in the
synthesis of several natural products.9
Scheme 1
In summary, we have found the first, highly efficient,
direct, asymmetric self-aldol reaction of acetaldehyde using
diarylprolinol 1 as a catalyst to afford the protected 3-hy-
droxybutanal 4 in moderate yield with good enantioselec-
tivity. Acetal 4 is the synthetic equivalent of the self-aldol
product 8, which can be converted into other synthetically
useful compounds, such as 4,4-dimethoxy-2-butanol 6 and
ethyl 5-hydroxy-2-hexenoate 7 by treatment with Amberlyst
in MeOH and a Wittig reagent, respectively, in one pot
without compromising the enantioselectivity.
The reaction is thought to proceed via an enamine
mechanism (Scheme 2). First, anti-enamine 9 is formed,
thereby avoiding any steric interaction with the bulky
diarylhydroxymethyl substituent. Second, the electrophilic
acetaldehyde approaches from the crowded face of the
enamine via a hydrogen-bond interaction, as shown in 10.
The aldol product 8 was obtained after hydrolysis, which
reacted further with a third acetaldehyde molecule to produce
acetal 4, the generation of which was observed using NMR.
(9) Application of the compound 6 in natural product synthesis, see:
(a) Ghiringhelli, D. Tetrahedron Lett. 1983, 24, 287. (b) Keck, G. E.; Murry,
J. A. J. Org. Chem. 1991, 56, 6606. (c) Besse, P.; Ciblat, S.; Canet, J.-L.;
Troin, Y.; Veschambre, H. Tetrahedron: Asymmetry 1999, 10, 2213. (d)
Matsuda, M.; Yamazaki, T.; Fuhshuku, K.-I.; Sugai, T. Tetrahedron 2007,
63, 8752. (e) Garcia, A. B.; Lessmann, T.; Umarye, J. D.; Mamane, V.;
Sommer, S.; Waldmann, H. Chem. Commun. 2006, 3868. For application
of the compound 7 in natural product synthesis, see: (f) Schnurrenberger,
P.; Hungerbuhler, E.; Seebach, D. Tetrahedron Lett. 1984, 25, 2209. (g)
Hills, L. R.; Ronald, R. C. J. Org. Chem. 1985, 50, 470. (h) Shimizu, I.;
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S. F. J. Org. Chem. 1994, 59, 3113. (j) Hayes, J. C.; Heathcock, C. H. J.
Org. Chem. 1997, 62, 2678. (k) Hunter, T. J.; O’Doherty, G. A. Org. Lett.
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Chem. 2002, 67, 2682. (m) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2002,
4, 4447. (n) Smith, C. M.; O’Doherty, G. A. Org. Lett. 2003, 5, 1959. (o)
Ahmed, M. M.; Berry, B. P.; Hunter, T. J.; Tomcik, D.; O’Doherty, G. A.
Org. Lett. 2005, 7, 745.
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). S.S. is grateful
to the Japan Society for the promotion of Science (JSPS)
for a postocdoctoral fellowship.
Supporting Information Available: Detailed experimen-
1
tal procedures, full characterization, and copies of H and
13C NMR and IR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL802438U
Org. Lett., Vol. 10, No. 24, 2008
5583