C O M M U N I C A T I O N S
Various combinations of 5H-oxazol-4-ones 2 and aldehydes 3 were
applied to the aldol reaction using catalyst 1c or 1e (Table 2). For
linear (non-R-branched) aldehydes, 1e was used (entries 1-6), whereas
1c was used for R-branched aldehydes and benzaldehyde (entries
7-14). As a result, product 5 was obtained with uniformly high
enantioselectivity, and moderate (entries 1-6) to excellent (entries
7-14) syn/anti selectivities were observed. Even in the case of non-
R-branched aldehydes, relatively high syn/anti selectivities were
observed in the reaction of a bulky donor substrate 2c (entries 5 and
6). Several functionalities in 2 or 3 were tolerated during the reaction
(entries 10, 11, and 13), and benzaldehyde (3i) was also applicable
(entry 14). Although the isolated yield of bulky 5k was relatively low,
the stereoselectivities were similarly high (entry 9).
stereoselectivities using new chiral guanidines 1 bearing a hydroxy
group at the appropriate position. This reaction is the first direct
catalytic asymmetric aldol reaction of R-oxygen atom-substituted
carboxylate analogues with aldehydes involving quaternary R-car-
bon atom construction.
Acknowledgment. We gratefully acknowledge Dr. Hiroki
Akutsu for the X-ray crystallographic analysis.
Supporting Information Available: Representative experimental
procedures; spectral data for chiral guanidine catalysts 1, pronucleophile
2e, aldol products 5, and derivatized products 6 and 7; and crystal-
lographic data (CIF). This material is available free of charge via the
Table 2. Direct Aldol Reaction of Various 5H-Oxazol-4-ones 2 and
Aldehydes 3 Catalyzed by 1c or 1ea
References
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Tetrahedron 1984, 40, 1313. (b) Battaglia, A.; Baldelli, E.; Barbaro, G.;
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(4) Tandem Wittig rearrangement/aldol reaction: Giampietro, N. C.; Kampf,
J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2009, 131, 12556.
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J. D. Chem. Commun. 1996, 1619. (b) Claudel, S.; Olszewski, T. K.;
Mutzenardt, P.; Aroulanda, C.; Coutrot, P.; Grison, C. Tetrahedron 2006,
62, 1787.
(6) Direct aldol reactions of carboxylate analogues: (a) Ito, Y.; Sawamura, M.;
Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405. (b) Evans, D. A.; Downey,
C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706. (c) Ooi, T.;
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Alonso, D. A.; Kitagaki, S.; Utsumi, N.; Barbas, C. F., III. Angew. Chem.,
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M. J. Am. Chem. Soc. 2009, 131, 10842. (i) Iwata, M.; Yazaki, R.; Suzuki,
Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 18244.
(7) Examples of glycolate aldol reactions without the quaternary R-carbon atom
construction: Mukaiyama-type: (a) Kobayashi, S.; Horibe, M. Chem.sEur.
J. 1997, 3, 1472. (b) Denmark, S. E.; Chung, W.-j. J. Org. Chem. 2008,
73, 4582. Direct aldol: (c) Trost, B. M.; Amans, D.; Seganish, W. M.;
Chung, C. K. J. Am. Chem. Soc. 2009, 131, 17087. A related aldol reaction
of R-hydroxy ketones: (d) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem.
Soc. 2001, 123, 3367. For a review of enamine catalysis, including
R-hydroxy ketone aldol reactions, see: (e) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471.
substrates
entry catalyst 1
2
3
time (h) product 5 yield (%)b syn:anti ratioc syn ee (%)d
1
2
3
4
5
6
7
8
1e
1e
1e
1e
1e
1e
1c
1c
1c
1c
1c
1c
1c
1c
2a 3c
2a 3d
2a 3e
2b 3a
12
4
5c
5d
5e
5f
71
67
72
65
83
81
92
66
43
79
72
74
68
84
67:33
75:25
77:23
76:24
80:20
83:17
98:2
94
93
95
92
92
95
97
96
96
95
95
96
97
96
6
4.5
2c 3a 11.5
5g
5h
5i
5j
5k
5l
5m
5n
5o
2c 3d
2a 3f
2b 3f
2c 3f
2d 3f
2e 3f
2a 3g
2a 3h
2a 3i
24
3.5
6.5
24
8.5
13.5
30
e
98:2
>98:2
97:3
9
10
11
12
13
14
98:2
>98:2
95:5
72
28
f
g
97:3
5p
a-dSee corresponding footnote in Table 1. e The absolute
configuration of 5i was determined by X-ray analysis of the
corresponding compound having a bromo substituent at the 4-position of
the phenyl group.15 f Reactions were carried out at -40 °C. g The
absolute configuration of 5p was determined by conversion into the
known R,ꢀ-dihydroxyester.15,16
Scheme 1. Derivatization of Aldol Product syn-5c to Methyl Ester
7a
(8) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.; Sakamoto,
S.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 2169.
(9) Direct aldol reactions of carboxylates involving chiral quaternary R-carbon
atom construction: (a) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem.
Soc. 2009, 131, 3430. (b) Yoshino, T.; Morimoto, H.; Lu, G.; Matsunaga,
S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 17082.
(10) Trost, B. M.; Dogra, K.; Franzini, M. J. Am. Chem. Soc. 2004, 126, 1944.
(11) Recent examples: (a) Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am. Chem. Soc.
2008, 130, 14088. (b) Hayashi, Y.; Obi, K.; Ohta, Y.; Okamura, D.;
Ishikawa, H. Chem.sAsian J. 2009, 4, 246. Also see ref 9a.
(12) Chiral guanidine catalysis: (a) Ishikawa, T. In Superbases for Organic
Synthesis; Ishikawa, T., Ed.; Wiley: Chippenham, U.K., 2009; pp 93-
143. For a review, see: (b) Leow, D.; Tan, C.-H. Chem.sAsian J. 2009, 4,
488, and references therein.
(13) Examples of bicyclic chiral guanidine catalysis: (a) Davis, A. P.; Dempsey,
K. J. Tetrahedron: Asymmetry 1995, 6, 2829. (b) Corey, E. J.; Grogan,
M. J. Org. Lett. 1999, 1, 157. (c) Kitani, Y.; Kumamoto, T.; Isobe, T.;
Fukuda, K.; Ishikawa, T. AdV. Synth. Catal. 2005, 347, 1653. (d) Jiang,
Z.; Pan, Y.; Zhao, Y.; Ma, T.; Lee, R.; Yang, Y.; Huang, K.-W.; Wong,
M. W.; Tan, C.-H. Angew. Chem., Int. Ed. 2009, 48, 3627.
a Conditions: (a) 2.5 M NaOH(aq), EtOH, 0 °C, 3 h (84%); (b) conc.
HCl, 80 °C, 3 h, then cat. H2SO4, MeOH, reflux, 6 h (84%). Optical rotation
value of 7: [R]2D0 ) -30.6 (c 1.0, CHCl3) {lit.:3b [R]2D0 ) -25.0 (c 1.0,
CHCl3) (2R,3S)}.
The aldol products 5 can easily be converted into R,ꢀ-dihy-
droxycarboxylic amides or esters without loss of enantiopurity. As
shown in Scheme 1, hydrolysis through treatment of diastereo-
merically pure syn-5c (93% ee) with aqueous NaOH in EtOH
readily afforded the corresponding amide 6, which was converted
to methyl ester 7 by simple acidic hydrolysis and subsequent H2SO4-
catalyzed esterification. The absolute configuration of 7 was
assigned as (2R,3S)15 after comparison of the optical rotation value
of the obtained 7 with the reported value.3b The enantiopurity of 7
was also confirmed as 93% ee by HPLC analysis of the corre-
sponding monobenzoate of 7.
(14) For a similar design of the catalyst, see: Takada, K.; Takemura, N.; Cho,
K.; Sohtome, Y.; Nagasawa, K. Tetrahedron Lett. 2008, 49, 1623.
(15) The absolute configurations of syn-5i and -5p were assigned as (5R,1′S),
and anti-5c was assigned as (5R,1′R). See the Supporting Information.
(16) Green, J. E.; Bender, D. M.; Jackson, S.; O’Donnell, M. J.; McCarthy,
J. R. Org. Lett. 2009, 11, 807.
In conclusion, we have developed a direct catalytic aldol reaction
of 5H-oxazol-4-ones 2 with aldehydes 3 and achieved high
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