Syn-selective and enantioselective direct cross-aldol reactions between aldehydes catalyzed by an axially chiral amino sulfonamide

Article abstract of DOI:10.1002/anie.200604640

(Chemical Equation Presented) Complementary to proline: An axially chiral amino sulfonamide (S)-1 was successfully applied as the catalyst to the direct cross-aldol reaction between two different aldehydes (see scheme; NMP = N-methylpyrrolidone). This cat

Full text of DOI:10.1002/anie.200604640

Communications
DOI: 10.1002/anie.200604640
Organocatalysis
syn-Selective and Enantioselective Direct Cross-Aldol Reactions
between Aldehydes Catalyzed by an Axially Chiral Amino
Sulfonamide**
Taichi Kano, Yukako Yamaguchi, Youhei Tanaka, and Keiji Maruoka*
The aldol reaction has long been recognized as one of the
most fundamental tools for the construction of new carbon–
carbon bonds.[1] In this area, the cross-aldol reaction between
two different aldehydes is known to be often problematic
because of undesired side reactions, including dehydration of
the product, self-aldol reaction, and multiple addition of the
enolate to the aldol product. To date, however, several cross-
aldol reactions using aldehyde-derived metal enolates, includ-
ing silyl enol ethers as nucleophile and/or non- or slowly
enolizable aldehydes as electrophile, have been reported,[2–9]
and some rare examples of the catalytic asymmetric version of
this reaction have recently been developed.[10–16] For example,
the diastereo- and enantioselective cross-aldol reaction
between aldehydes and silyl enol ethers was first accom-
plished by Denmark et al. with chiral Lewis base catalysts,[10]
and very recently Kobayashi and co-workers demonstrated
the chiral Lewis acid catalyzed diastereo- and enantioselec-
tive reaction using aldehyde-derived enecarbamates as an
activated aldehyde nucleophile.[11] With these methods, both
the syn and anti diastereomers, respectively, were formed in a
highly enantioselective fashion. On the other hand, to the best
of our knowledge, most organocatalytic direct enantioselec-
tive cross-aldol reactions of aldehydes, first reported by
MacMillan and co-workers, provide predominantly anti aldol
adducts,[12–17] albeit with only a few exceptions giving syn
adducts.[12d] In this context, we have been interested in the
possibility of developing a syn-selective direct cross-aldol
reaction between two different alde-
Our strategy is based on the recent observation that a
direct asymmetric Mannich reaction is catalyzed by the
axially chiral amino sulfonamide (S)-1 to give the anti product
predominantly, which is a minor diastereomer in the proline-
catalyzed reaction.[18] Since it would be difficult for anti
enamine A, which is generated from a donor aldehyde and
(S)-1, to react with an acceptor aldehyde that is activated by
the distal acidic proton of the triflamide of (S)-1, the cross-
aldol reaction catalyzed by (S)-1 would be expected to
proceed through syn enamine intermediate B, thus giving the
desired unusual syn product as shown in Scheme 1.
Scheme 1. Possible transition states for the enantioselective direct
cross-aldol reaction catalyzed by (S)-1.
hydes by using a chiral organocata-
lyst. Herein we wish to report such a
syn-selective and enantioselective
direct cross-aldol reaction catalyzed
by an axially chiral amino sulfona-
mide of type (S)-1.
We first examined the reaction between 4-nitrobenzalde-
hyde and hexanal in the presence of 5 mol% (S)-1 in various
solvents at room temperature, and the results are summarized
in Table 1. Unfortunately, the reaction in less polar solvents
such as dioxane, toluene, and CH2Cl2 gave the cross-aldol
product 2 in poor yield with low stereoselectivities (Table 1,
entries 1–3). In the case of acetonitrile, only a trace amount of
2 was observed, although syn-2 was slightly dominant over
anti-2 (Table 1, entry 4). While the use of DMSO, which is a
common solvent for aldol reactions catalyzed by proline or
related organocatalysts,[13a,15] led to the formation of the
desired syn-2 in a highly diastereo- and enantioselective
manner, the yield was still low (Table 1, entry 5). When the
amide solvents N,N-dimethylformamide (DMF) and N-meth-
ylpyrrolidone (NMP) were used, the desired syn-2 was
obtained in moderate yield with excellent diastereo- and
enantioselectivity (Table 1, entries 6 and 7). Accordingly,
[*] Dr. T. Kano, Y. Yamaguchi, Y. Tanaka, Prof. K. Maruoka
Department of Chemistry
Graduate School of Science
Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas “Advanced Molecular Transformation of
Carbon Resources” from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angew. Chem. Int. Ed. 2007, 46, 1738 –1740

Angewandte
Chemie
Table 1: syn-Selective aldol reaction of 4-nitrobenzaldehyde with hexanal
catalyzed by (S)-1.[a]
Table 2: syn-Selective aldol reaction between various aldehydes catalyzed
by (S)-1.[a]
Entry R1
R2
t [h] Yield [%][b] syn/anti[c] ee [%][d]
Entry Solvent Conc [m][b] t [h] Yield [%][c] syn/anti[d] ee [%][e]
1
2
3
4
5
Me
36
73
77
80
79
61
12:1
>20:1
>20:1
>20:1
>20:1
98
99
98
98
96
nBu 36
Bn 36
allyl 36
iPr 40
1
2
3
4
5
6
7
8
9
10
dioxane 0.1
toluene 0.1
36
36
36
36
36
36
36
72
36
36
22
26
31
<5
25
60
62
74
73
77
1:3.4
1:1.5
1:1.6
1.2:1
13:1
17:1
>20:1
13:1
>20:1
>20:1
8
6
25
–
96
98
99
97
99
99
CH2Cl2
0.1
CH3CN 0.1
DMSO
DMF
NMP
NMP
NMP
NMP
0.1
0.1
0.1
0.1
0.25
1.0
6
7
8
nBu 36
nBu 78
nBu 69
22
73
71
6.3:1
>20:1
6.4:1
92
99
94
[a] The reaction of 4-nitrobenzaldehyde (0.25 mmol)with hexanal
(0.5 mmol)was carried out in the presence of ( S)-1 (0.0125 mmol)at
room temperature. [b] Concentration of 4-nitrobenzaldehyde. [c] Yield of
isolated product after acetalization with 2,2-dimethyl-1,3-propanediol.
9[e]
nBu
4.5 99[g]
91[g]
2.3:1
95
96
1
[d] Determined by H NMR spectroscopy. [e] The ee value of syn-2 was
10[f]
nBu 20
>20:1
determined by HPLC by using a chiral column (Chiralpak AD-H, Daicel
Chemical Industries); details are given in the Supporting Information.
[a] Unless otherwise specified, the reaction of an acceptor aldehyde
(0.25 mmol)with a donor aldehyde (0.5 mmol)in NMP (250 mL)was
carried out in the presence of (S)-1 (0.0125 mmol)at room temperature.
[b] Yield of isolated product after acetalization or reduction, except in
entries 9 and 10; details are given in the Supporting Information.
[c] Determined by 1H NMR spectroscopy. [d] The ee value of the syn
product was determined by HPLC by using a chiral column (Chiralpak
AS-H, AD-H, Chiralcel OD-H or OJ-H, Daicel Chemical Industries);
details are given in the Supporting Information. [e] Use of 3 equiv of ethyl
glyoxylate (0.75 mmol)and 1 equiv of hexanal (0.25 mmol). [f] Phenyl-
glyoxal was used in the monohydrate form. [g] Yield of isolated product.
further optimization of the reaction conditions was inves-
tigated by using NMP as the solvent of choice. A longer
reaction time resulted in a slight decrease of both diastereo-
and enantioselectivity, albeit in higher yield (Table 1, entry 8).
On the other hand, the reactions conducted at a higher
concentration were found to give syn-2 in improved yields
without loss of stereoselectivities (Table 1, entries 9 and 10).
The absolute configuration of syn-2 in entry 10 was deter-
mined to be (2R,3R) as predicted on the basis of the transition
model in Scheme 1. It should also be noted that more than
95% of (S)-1 was recovered unchanged after column
chromatography.
With the optimal reaction conditions, the syn-selective
and enantioselective direct cross-aldol reaction of several
other reactive acceptor aldehydes with donor aliphatic
aldehydes was examined (Table 2). The reaction of 4-nitro-
benzaldehyde with various aliphatic aldehydes gave the
corresponding syn aldol adduct in moderate to good yield
with excellent diastereo- and enantioselectivity (Table 2,
entries 1–5). Although the reaction of a simple acceptor
aldehyde such as benzaldehyde with hexanal proceeded
slowly in low yield, good stereoselectivity was observed
(Table 2, entry 6). On the other hand, reactive aldehydes such
as fluorinated aromatic and heteroaromatic aldehydes as well
as ethyl glyoxylate were found to be suitable electrophiles
(Table 2, entries 7–9). The reaction catalyzed by (S)-1 was
also applicable to phenylglyoxal as its monohydrate (Table 2,
entry 10). In all cases, the (S)-1-catalyzed method was
complementary to the proline-catalyzed reactions in terms
of the syn/anti selectivity. In addition, it is important to note
that only trace amounts of byproducts arising from dimeriza-
tion of donor aldehydes were observed.
different aldehydes catalyzed by the axially chiral amino
sulfonamide (S)-1. This organocatalytic process represents a
rare example of syn-selective direct cross-aldol reaction via an
enamine intermediate. Further investigations to expand the
scope of this and related reactions are currently underway.
Received: November 15, 2006
Published online: January 23, 2007
Keywords: aldol reaction · asymmetric catalysis ·
.
diastereoselectivity · enantioselectivity · synthetic methods
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Communications
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