Diarylprolinol in an asymmetric aldol reaction of an α-alkyl-α- oxo aldehyde as an electrophile

Article abstract of DOI:10.1039/c2cc31230a

The direct aldol reaction of an α-alkyl-α-oxo aldehyde was catalyzed by trifluoromethyl-substituted diarylprolinol 1 to afford a γ-oxo-β-hydroxy-α-substituted aldehyde in good yield with excellent anti-selectivity and excellent enantioselectivity. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc31230a

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COMMUNICATION
Diarylprolinol in an asymmetric aldol reaction of an a-alkyl-a-oxo
aldehyde as an electrophilewz
Yujiro Hayashi,* Yusuke Yasui, Masahiro Kojima, Tsuyoshi Kawamura and
Hayato Ishikaway
Received 18th February 2012, Accepted 5th March 2012
DOI: 10.1039/c2cc31230a
The direct aldol reaction of an a-alkyl-a-oxo aldehyde was
catalyzed by trifluoromethyl-substituted diarylprolinol 1 to afford
a c-oxo-b-hydroxy-a-substituted aldehyde in good yield with
excellent anti-selectivity and excellent enantioselectivity.
The aldol reaction is one of the most important carbon–
carbon bond-forming reactions in organic synthesis.1 The
Fig. 1 Organocatalysts investigated in the present study.
aldol reaction of a-oxo aldehyde as an electrophile affords
synthetically useful g-oxo-b-hydroxy carbonyl compounds.
While there are some successful aldol reactions of a-aryl-
a-oxo aldehydes, such as phenylglyoxal,2,3 the aldol reaction
of a-alkyl-a-oxo aldehydes is regarded as difficult because they
possess an acidic proton and easily isomerize to the enol form
under basic conditions. As pyruvaldehyde, an a-alkyl-a-oxo
aldehyde, is commercially available as an aqueous solution
(40%),4 it would be a synthetic advantage to use directly an
aqueous solution of pyruvaldehyde in the aldol reaction. The
asymmetric aldol reactions of pyruvaldehyde with acetone5
and oxyindole3 are reported, but there are no reports of
investigations into reactions with other ketones or amides.
The cross-aldol reaction of aqueous pyruvaldehyde with aldehyde
has not been reported.
We chose 3-phenylpropanal as a model aldehyde and as a
nucleophile, and the aldol reaction of aqueous pyruvaldehyde
was investigated. As the obtained aldol product isomerizes
readily, it was treated with (ethoxycarbonylmethylidene)-
triphenylphosphorane to convert it to an a,b-unsaturated
ester, which was isolated and characterized. First we used
trifluoromethyl-substituted diarylprolinol 1 as a catalyst
(Fig. 1). The reaction proceeded smoothly to afford the
desired product in good yield and excellent diastereo- and
Table 1 Effect of the catalyst and solvent in the aldol reaction of
aqueous pyruvaldehyde and 3-phenylpropanala
We developed siloxyproline,6 a proline-surfactant conjugated
catalyst,7 and proline amide,8 which are effective aldol catalysts
in the presence of water or in water.9 Recently we reported that
trifluoromethyl-substituted diarylprolinol 1 is an effective
organocatalyst in aldol reactions of acetaldehyde,10 polymeric
ethyl glyoxylate,11 trifluoroacetaldehyde ethyl hemiacetal,12 and
aqueous chloroacetaldehyde.13 Based on knowledge gained to
date, we investigated the asymmetric, cross-aldol reaction of
aqueous pyruvaldehyde with aldehydes, the successful realiza-
tion of which will be described in this communication.
Entry Catalyst Solvent
Time/h Yieldb [%] anti : sync eed [%]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
2
3
4
5
CH2Cl2
Toluene
MeOH
Et2O
48
48
24
48
18
o5
63
71
73
78
79
81
83
85
44
o5
>20 : 1 98
17 : 1
15 : 1
15 : 1
96
98
98
1,4-Dioxane 48
DMF
THF
THF
THF
THF
THF
48
22
15
12
5
>20 : 1 98
>20 : 1 >99
6.1 : 1
7.3 : 1
1.8 : 1
1.7 : 1
ꢀ34
9
81
10
11
12
ꢀ55
96
72
48
Department of Industrial Chemistry, Faculty of Engineering, Tokyo
University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601,
Japan. E-mail: hayashi@ci.kagu.tus.ac.jp; Fax: +81 (0)3-5261-4631;
Tel: +81 (0)3-5228-8318
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
Proline THF
a
Unless otherwise shown, the reaction was performed by employing
pyruvaldehyde (0.75 mmol, 112 mL, 40% aqueous solution), 3-phenyl-
propanal (0.5 mmol), and organocatalyst (0.05 mmol) in the indicated
solvent (0.5 mL) at room temperature for the indicated time. After
that, the aldol product was converted into a,b-unsaturated ester by the
treatment with the Wittig reagent, which was isolated. See ESI
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc31230a
b
c
y Present address: Department of Chemistry, Graduate School of
Science and Technology, Kumamoto University, Kurokami 2-39-1,
Kumamoto 860-8555, Japan.
for details. Isolated yield of a,b-unsaturated ester. Determined by
1H-NMR. Determined by HPLC analysis on a chiral phase.
d
c
4570 Chem. Commun., 2012, 48, 4570–4572
This journal is The Royal Society of Chemistry 2012

enantio-selectivities. Examination of the solvent (Table 1)
indicates that the reaction scarcely proceeds in CH2Cl2 and
toluene, but excellent stereoselectivites are obtained in most of
the other solvents, such as MeOH, Et2O, 1,4-dioxane, DMF,
and THF. Especially in THF, good yield and excellent diastereo-
and enantio-selectivities are obtained (entry 7).
Next, the effect of a catalyst was investigated. Diphenyl-
prolinol 3 is more reactive than diarylprolinol 1; it promotes
the reaction in a short time to afford the product in lower
diastereo- and enantio-selectivities (entry 9). The corres-
ponding silyl ethers 2 and 414 are not effective; they afford
the opposite enantiomer in low enantioselectivities (entries 8
and 10). Proline15 does not promote the reaction (entry 12).
Siloxyproline 5,6 which we developed for the asymmetric aldol
reaction in the presence of water, affords a product with
excellent enantioselectivity, but the yield and diastereo-
selectivity are low (entry 11).
Table 2 One-pot reaction of the aldol/Wittig reactiona
Xb
[eq.] [eq.]
Yc
Time/ Yieldd
ee
Entry Product
1
h
[%]
anti : syne [%]f
1
2
20
60
—
93
Having determined the best reaction conditions, the generality
of the reaction was investigated. Results are summarized in
Table 2. Acetaldehyde16 is a suitable nucleophilic aldehyde
for the reaction with aqueous pyruvaldehyde, to afford an
a-hydroxy ketone with excellent enantioselectivity (entry 1).
Not only 3-phenylpropanal, but also a-substituted acetaldehyde
derivatives, such as propanal, butanal, pentanal, and isovaler-
aldehyde, can be successfully used to obtain products with
excellent diastereo- and enantio-selectivities (entries 2–7).
a-Alkoxyaldehyde also reacts smoothly, to afford the mono-
protected diol with excellent enantioselectivity (entry 8).
b-Alkoxyaldehyde, which is a difficult substrate (because of
dehydration), is a suitable nucleophilic aldehyde (entry 9).
Double bonds and triple bonds in the nucleophilic aldehyde do
not interfere with the reaction, and a-hydroxy ketones are
obtained with excellent diastereo- and enantio-selectivities
(entries 10 and 11). Not only pyruvaldehyde, but also other
a-alkyl-a-oxo aldehydes, such as 2-oxobutanal, 2-cyclohexyl-
2-oxoethanal, and 2-oxooctanal, were successfully used as
electrophiles. Only the formyl moiety reacts with the nucleophilic
aldehyde, to afford the a-hydroxy ketone in excellent diastereo-
and enantio-selectivities (entries 12–17). The reaction proceeds
when the nucleophilic aldehyde and a-keto aldehyde are used in a
1 : 2 ratio and when used in a 2 : 1 ratio. Thus, when a precious
aldehyde is used as a nucleophile it is recommended that the
nucleophilic aldehyde and a-keto aldehyde are used in a 1 : 2
ratio.
2
3
1
2
2
1
15
12
84
81
10 : 1
10 : 1
99
99
4
1
2
2
1
1
1
20
43
50
22
20
82
80
96
79
78
16 : 1
99
5
1
14 : 1
99
6g
7
1.5
1.5
1.5
>20 : 1
>20 : 1
3.1 : 1
98
>99
99
8g,h
9
1.5
1.5
1
1
12
48
76
65
5.0 : 1
7.0 : 1
97
98
10i
11i
1.5
1
48
92
10 : 1
99
12j
13j
2
1
1
2
12
12
85
80
>20 : 1
>20 : 1
98
98
It should be noted that a small amount of water is essential
for this reaction. When anhydrous 2-cyclohexyl-2-oxoethanal
was used, the product was obtained in o10% yield after 12 h.
On the other hand, the reaction proceeded smoothly in the
presence of water (entries 14 and 15).
14j
15j
2
1
1
2
12
13
84
86
>20 : 1
>20 : 1
99
99
16j
17j
2
1
1
2
12
12
74
74
20 : 1
20 : 1
98
98
a
Unless otherwise shown, the reaction was performed by employing
organocatalyst 1 (0.05 mmol) in THF (0.5 mL) at room temperature for
the indicated time. As for pyruvaldehyde, aqueous solution (40%) was
employed. After that, the aldol product was converted into a,b-unsaturated
b
ester by the treatment with Ph3PQCHCO2Et. See ESI for details. Equi-
valent of a-oxo aldehyde. c Equivalent of nucleophilic aldehyde. d Isolated
yield of a,b-unsaturated ester. e Determined by 1H-NMR. f Determined by
HPLC analysis on a chiral phase. g 20 mol% of catalyst 1 was employed.
h
Bu3PQCHCO2Et was employed instead of Ph3PQCHCO2Et. i Catalyst
1 (15 mol%) was employed. j The reaction was performed in the presence
of water. As for the amount of water, see ESI.
Scheme 1
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4570–4572 4571

The absolute configuration was determined by comparison
with the optical rotation of the acetal, the preparation of
which is described in Scheme 1, and that described in the
literature.17 The aldol reaction of pyruvaldehyde and acetaldehyde
was conducted in the presence of D-diarylprolinol, derived from
D-proline, to afford the aldol product, which was transformed into
the acetal after syn-selective reduction.
used as an efficient catalyst,10–13,21 while its silyl ether is widely
used as an effective organocatalyst.14 (6) A small amount of
water is essential for the progress of the reaction. Without
water, the reaction scarcely proceeds.
Because the generated product is a synthetically important
chiral building block, this method offers an efficient route for
the preparation of chiral g-oxo-b-hydroxy aldehydes.
a-Hydroxy ketone is a synthetically important molecule; for
example, the TBDPS ether of the product of entry 1 in Table 2
is a synthetic intermediate of a hybrid macrolide of epothilone
and carbonolide.18 a-Hydroxy ketone can be converted into
Notes and references
1 Modern Aldol Reactions, ed. R. Mahrwald, Wiley-VCH, Weinheim,
2004, vol. 1, 2.
2 Y. Xiong, F. Wang, S. Dong, X. Liu and X. Feng, Synlett, 2008,
73; T. Kano, Y. Yamaguchi and K. Maruoka, Chem.–Eur. J.,
2009, 15, 6678.
19
a useful intermediate. Reduction with Zn(BH4)2 affords
1,2-anti-diol in good yield with excellent diastereoselectivity
3 K. Shen, X. Liu, K. Zheng, W. Li, X. Hu, L. Lin and X. Feng,
Chem.–Eur. J., 2010, 16, 3736.
(eqn (3)).
4 We used aqueous pyruvaldehyde (40%), which was purchased
from Acros Organics. Catalog number: 175791000.
ð3Þ
5 D. G. Alberg, T. B. Poulsen, S. Bertelsen, K. L. Christensen,
R. D. Birkler, M. Johannsen and K. A. Jørgensen, Bioorg. Med.
Chem. Lett., 2009, 19, 3888.
6 Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima and
M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 958.
7 Y. Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya and
M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 5527.
8 S. Aratake, T. Itoh, T. Okano, T. Usui, M. Shoji and Y. Hayashi,
Chem. Commun., 2007, 2524.
9 Y. Hayashi, Angew. Chem., Int. Ed., 2006, 45, 8103; N. Mase,
Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka and
C. F. Barbas III, J. Am. Chem. Soc., 2006, 128, 734. The selected
reviews on organocatalyst-mediated reaction in the presence of
water, see: J. Paradowska, M. Stodulski and J. Mlynarski, Angew.
Chem., Int. Ed., 2009, 48, 4288; M. Gruttadauria, F. Giacalone and
R. Noto, Adv. Synth. Catal., 2009, 351, 33; M. Raj and
V. K. Singh, Chem. Commun., 2009, 6687; N. Mase and
C. F. Barbas III, Org. Biomol. Chem., 2010, 8, 4043.
10 Y. Hayashi, T. Itoh, S. Aratake and H. Ishikawa, Angew. Chem.,
Int. Ed., 2008, 47, 2082; Y. Hayashi, S. Samanta, T. Itoh and
H. Ishikawa, Org. Lett., 2008, 10, 5581; T. Itoh, H. Ishikawa and
Y. Hayashi, Org. Lett., 2009, 11, 3854.
After protection of the hydroxy group with TIPS, the
reduction with Red-Al19 affords the protected 1,2-syn-diol unit
in excellent yield and with excellent diastereoselectivity
(eqn (4)). Thus, chiral 1,2-anti-diol and 1,2-syn-diol units are
stereoselectively synthesized from the same aldol product by
the suitable choice of reducing reagent. In both cases, three
continuous chiral centers are constructed with excellent
diastereo- and enantio-selectivities.
ð4Þ
Another application is a diastereoselective aldol reaction.
A borane enolate of a-siloxyketone reacts with an aldehyde
to afford a b0-hydroxy-a-siloxyketone with excellent diastereo-
selectivity, via 1,4-asymmetric induction (eqn (5)).20 The finding
that these polyfunctionalized compounds are synthesized with
excellent enantioselectivity in short steps from readily avail-
able compounds demonstrates the synthetic utility of the
present aldol reaction.
11 T. Urushima, Y. Yasui, H. Ishikawa and Y. Hayashi, Org. Lett.,
2010, 12, 2966.
12 Y. Hayashi, Y. Yasui, T. Kawamura, M. Kojima and H. Ishikawa,
Synlett, 2011, 485.
13 Y. Hayashi, Y. Yasui, T. Kawamura, M. Kojima and H. Ishikawa,
Angew. Chem., Int. Ed., 2011, 50, 2804.
14 Diarylprolinol silyl ether, see: Y. Hayashi, H. Gotoh, T. Hayashi
and M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212; M. Marigo,
T. C. Wabnitz, D. Fielenbach and K. A. Jørgensen, Angew. Chem.,
Int. Ed., 2005, 44, 794; M. Marigo, D. Fielenbach, A. Braunton,
A. Kjasgaard and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005,
44, 794. Review, see: C. Palomo and A. Mielgo, Angew. Chem., Int.
Ed., 2006, 45, 7876; A. Mielgo and C. Palomo, Chem.–Asian. J.,
2008, 3, 922; L.-W. Xu, L. Li and Z.-H. Shi, Adv. Synth. Catal.,
2010, 352, 243; K. L. Jensen, G. Dickmeiss, H. Jiang, L. Albrecht
and K. A. Jørgensen, Acc. Chem. Res., 2012, 45, 248.
15 B. List, R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc.,
2000, 122, 2395; A. B. Northrup and D. W. C. MacMillan, J. Am.
Chem. Soc., 2002, 124, 6798.
16 A. Cordova, W. Notz and C. F. Barbas III, J. Org. Chem., 2002,
67, 301; Y. Hayashi, T. Itoh, S. Aratake and H. Ishikawa, Angew.
Chem., Int. Ed., 2008, 47, 2082.
17 N. K. Kochetkov and A. I. Usov, Tetrahedron, 1963, 19, 973.
18 N. Nakajima and M. Ubukata, Heterocycles, 2004, 64, 333.
19 T. Nakata, T. Tanaka and T. Oishi, Tetrahedron Lett., 1983,
24, 2653.
ð5Þ
In conclusion, we have developed a practical synthesis of
g-oxo-b-hydroxy aldehyde via an asymmetric, direct aldol
reaction of a-alkyl-a-oxo aldehyde, catalyzed by diarylprolinol
1. There are several noteworthy features related to this reaction.
(1) Synthetically useful chiral g-oxo-b-hydroxy-a-substituted
aldehydes can be prepared with excellent anti-selectivity and
excellent enantioselectivity. (2) Commercially available aqueous
pyruvaldehyde is used directly without removal of water prior
to use. (3) Acetaldehyde can be successfully used as a nucleo-
philic aldehyde. (4) By the subsequent diastereoselective
reduction, three continuous chiral centers possessing both a
1,2-anti-diol and a 1,2-syn-diol unit are constructed. (5) This is
one of the rare reactions in which diarylprolinol is successfully
20 M. Lorenz, N. Bluhm and M. Kalesse, Synthesis, 2009, 3061.
21 A. Lattanzi, Org. Lett., 2005, 7, 2579; A. Lattanzi, Chem.
Commun., 2009, 1452; A. Russo and A. Lattanzi, Org. Biomol.
Chem., 2010, 8, 2633; C. Palumbo, G. Mazzeo, A. Mazziotta,
A. Gambacorta, M. A. Loreto, A. Migliorini, S. Superchi,
D. Tofani and T. Gasperi, Org. Lett., 2011, 13, 6248.
c
4572 Chem. Commun., 2012, 48, 4570–4572
This journal is The Royal Society of Chemistry 2012