Syn-Selective asymmetric cross-aldol reactions between aldehydes and glyoxylic acid derivatives catalyzed by an axially chiral amino sulfonamide

Article abstract of DOI:10.1039/c1cc14347f

syn-Selective asymmetric cross-aldol reactions of aldehydes with tert-butyl glyoxylate and glyoxamide were realized by the use of an axially chiral amino sulfonamide (S)-1. The cross-aldol products obtained are densely functionalized and readily converted to synthetically useful and important chiral building blocks such as γ-lactone and γ-lactam.

Full text of DOI:10.1039/c1cc14347f

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syn-Selective asymmetric cross-aldol reactions between aldehydes and
glyoxylic acid derivatives catalyzed by an axially chiral amino
sulfonamidewz
Taichi Kano, Akira Noishiki, Ryu Sakamoto and Keiji Maruoka*
Received 19th July 2011, Accepted 22nd August 2011
DOI: 10.1039/c1cc14347f
syn-Selective asymmetric cross-aldol reactions of aldehydes with
tert-butyl glyoxylate and glyoxamide were realized by the use of an
axially chiral amino sulfonamide (S)-1. The cross-aldol products
obtained are densely functionalized and readily converted to
synthetically useful and important chiral building blocks such as
c-lactone and c-lactam.
interested in developing the highly syn-selective asymmetric
cross-aldol reaction of glyoxylic acid derivatives.
We first examined the cross-aldol reaction of 3-phenylpropanal
with ethyl glyoxylate (Table 1). The reaction of 3-phenylpropanal
with ethyl glyoxylate (3 equiv.) in the presence of (S)-17 (5 mol%)
was carried out in various solvents; however, low syn-selectivity
was observed in all solvents examined (entries 1–8).
Asymmetric enamine catalysis is a powerful organocatalytic
strategy for the stereoselective a-functionalization of carbonyl
compounds.1,2 In this area, the direct asymmetric aldol reactions
of carbonyl compounds have been investigated by a number of
research groups,3 since the pioneering work of List, Barbas,
and co-workers in 2000.4 Among them, the cross-aldol reaction
between two different aldehydes is an attractive approach toward
the construction of synthetically useful building blocks. Most of
such cross-aldol reactions of aldehydes proceed in a highly anti-
selective fashion;5 therefore, obtaining syn-selectivity has still been
a considerable challenge.6 Recently, Hayashi and co-workers
reported the anti-selective asymmetric cross-aldol reaction
between unmodified aldehydes and ethyl glyoxylate, which gives
densely functionalized products (Scheme 1).5p,6 In our previous
report on the syn-selective asymmetric cross-aldol reaction
catalyzed by (S)-1, ethyl glyoxylate was also examined as an
acceptor aldehyde; however, exceptionally poor syn selectivity
was observed (syn/anti = 2.3/1).6a,b In this context, we have been
To our surprise, lowering the reaction temperature decreased
both syn-selectivity and enantioselectivity (entries 9 and 10).
Table
1 Cross-aldol reaction of 3-phenylpropanal with alkyl
glyoxylatea
Entry
R
Solvent
Yield (%)b
syn/antic
ee (%)d
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
t-Bu
t-Bu
t-Bu
MeOH
DMSO
DMF
EtOAc
THF
CHCl3
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
66
96
99
88
74
84
90
97
99
97
87
89
91
1.1/1
1.4/1
1.9/1
1.5/1
1.3/1
1.3/1
1.2/1
2.3/1
1.3/1
1.2/1
2.8/1
4.0/1
5.9/1
73
76
92
90
80
82
79
92
84
74
92
93
97
9e
10f
11
12g
13h
Scheme 1 anti-Selective cross-aldol reaction of ethyl glyoxylate
developed by Hayashi.
a
Unless otherwise specified, the reaction of 3-phenylpropanal
(0.25 mmol) with alkyl glyoxylate (0.75 mmol) in a solvent was carried
out in the presence of (S)-1 (0.0125 mmol) at room temperature for
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto 606-8502, Japan.
E-mail: maruoka@kuchem.kyoto-u.ac.jp; Fax: +81-75-753-4041;
Tel: +81-75-753-4041
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
4.5 h. Isolated yield. Determined by 1H-NMR. The ee of the syn-
b
c
d
isomer was determined by HPLC analysis using a chiral column.
e
f
g
Performed at 0 1C. Performed at ꢀ20 1C. Performed for 0.5 h.
Use of 3-phenylpropanal (0.75 mmol) and t-butyl glyoxylate
(0.25 mmol).
h
z Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c1cc14347f
c
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By switching the ester moiety of ethyl glyoxylate to the tert-butyl
group, the enantioselectivity was slightly improved (entry 11).
Higher syn-selectivity was achieved with shorter reaction time
(entry 12). In this type of aldol reaction, the ratio of the major
stereoisomer can be decreased by the stereoselective retro-aldol
reaction.6b,8 With expectation of suppressing such a retro-aldol
reaction, we varied the substrate ratio. Interestingly, increasing
the amount of 3-phenylpropanal and decreasing the amount of
tert-butyl glyoxylate resulted in an improvement in both syn-
selectivity and enantioselectivity (entry 13).
Under the optimized conditions, the cross aldol reactions of
various donor aldehydes were examined, and the results are
summarized in Table 2. All reactions examined proceeded
smoothly to give the cross-aldol products in moderate syn-
selectivity and excellent enantioselectivity.
Scheme 2 Proposed transition state models TS1–TS3.
Table 2 Cross-aldol reaction of various aldehydes with t-butyl
glyoxylatea
Entry
R
Time/h
Yield (%)b
syn/antic
ee (%)d
1e
2
Me
Bu
Bn
CH2OBn
i-Pr
1
1
1
1
4.5
61
77
89
78
74
5.3/1
4.7/1
5.3/1
4.5/1
4.9/1
97
96
97
99
94
3
4e
5
a
The reaction of a donor aldehyde (0.75 mmol) with t-butyl glyoxylate
(0.25 mmol) in acetonitrile was carried out in the presence of (S)-1
b
(0.005 mmol) at room temperature. Isolated yield. Determined by
c
d
1H-NMR. The ee of the syn-isomer was determined by HPLC analysis
e
using a chiral column. Isolated as 1,3-diol after reduction with NaBH4.
Based on the absolute configuration of products, transition
state models TS1–TS3 were proposed (Scheme 2). In the reaction
of 3-phenylpropanal with tert-butyl glyoxylate (Table 1,
entry 13), a substantial amount of the anti-product was formed
in an enantioselective fashion (69% ee). The observed stereo-
chemistry (2S,3R) could be explained by transition states
TS2 and TS3 in which the Si face of tert-butyl glyoxylate
approaches the Si face of the s-cis-enamine as directed by the
triflamide group of the catalyst. The additional interaction
between the ester group of tert-butyl glyoxylate and the acidic
proton of the catalyst might increase the reaction rate through
TS2 and/or TS3. Accordingly, we were interested in the
development of the highly syn-selective cross-aldol reaction
by suppression of such secondary interaction between the
catalyst and an acceptor aldehyde. We hypothesized that the
syn-selective reaction through TS4 would be favored over TS5
and TS6 by switching the ester group of the acceptor aldehyde
to an amide group (Scheme 3). The reaction through TS5 would
be disfavored due to the lack of the secondary interaction. In
the reaction through TS6, the strong coordination of the
amide group might decrease the acidity of the catalyst proton
and the reaction rate. This hypothesis was examined by the use
of glyoxamide 29 instead of tert-butyl glyoxylate.
Scheme 3 Transition state models for the reaction of a glyoxamide.
at room temperature, and the results are summarized in
Table 3. While the reaction of 2 was much slower compared
to that of tert-butyl glyoxylate and took longer to complete,
the improved syn-selectivity was observed in all cases examined,
as expected.
The obtained cross-aldol adducts were versatile intermediates
in organic synthesis and readily converted to important
chiral building blocks. The aldol adduct 3 (syn/anti = 4.7/1)
could be converted to g-lactam 4 (trans/cis = 4.0/1) by
reductive amination and heating of the resulting amine
(Scheme 4). Alternatively, g-lactam 4 (trans/cis = 16/1) was
also prepared by the aldol reaction of 2, reductive amination and
lactamization without purification of the intermediates
(Scheme 5). When the aldol adduct 5 (syn/anti = 17/1) was
treated with 4 N HCl under reflux, g-lactone 6 (trans/cis =
17/1) was obtained in good yield with complete retention of
stereochemistry (Scheme 6).
In summary, we have developed a syn-selective asymmetric
cross-aldol reaction of aldehydes with tert-butyl glyoxylate
and glyoxamide catalyzed by the axially chiral amino sulfon-
amide (S)-1. The cross-aldol products obtained are densely
functionalized and versatile intermediates and could be readily
In the presence of (S)-1, the reaction of various donor
aldehydes with glyoxamide 2 in acetonitrile was performed
c
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Table 3 Cross-aldol reaction of various aldehydes with glyoxamide
2a
the Promotion of Science for Young Scientists for Research
Fellowships.
Notes and references
1 For reviews, see: (a) P. I. Dalko and L. Moisan, Angew. Chem.,
Int. Ed., 2001, 40, 3726; (b) P. I. Dalko and L. Moisan, Angew.
Chem., Int. Ed., 2004, 43, 5138; (c) A. Berkessel and H. Groger,
Asymmetric Organocatalysis: From Biomimetic Concepts to
Applications in Asymmetric Synthesis, Wiley-VCH, Weinheim,
2005; (d) Enantioselective Organocatalysis, ed. P. I. Dalko, Wiley-
VCH, Weinheim, 2007.
2 For reviews, see: (a) M. Marigo and K. A. Jørgensen, Chem.
Commun., 2006, 2001; (b) S. Mukherjee, J. W. Yang, S. Hoffmann
and B. List, Chem. Rev., 2007, 107, 5471; (c) P. Melchiorre,
M. Marigo, A. Carlone and G. Bartoli, Angew. Chem., Int. Ed.,
2008, 47, 6138.
3 For reviews, see: G. Guillena, C. Najera and D. J. Ramon,
Tetrahedron: Asymmetry, 2007, 18, 2249.
4 (a) B. List, B. R. A. Lerner and C. F. Barbas III, J. Am. Chem. Soc.,
2000, 122, 2395; (b) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas
III, J. Am. Chem. Soc., 2001, 123, 5260.
Entry
R
Yield (%)b
syn/antic
ee (%)d
1
2
Bu
Hex
Bn
CH2OBn
i-Pr
82
81
77
64
43
17/1
12/1
16/1
6.2/1
13/1
97
94
97
97
96
3
4e
5e
a
The reaction of a donor aldehyde (0.75 mmol) with glyoxamide 2
(0.25 mmol) in acetonitrile was carried out in the presence of (S)-1
b
(0.005 mmol) at room temperature. Isolated yield. Determined by
c
1H-NMR. The ee of the syn-isomer was determined by HPLC
d
e
analysis using a chiral column. Use of (S)-1 (0.0125 mmol).
5 Representative anti-selective cross-aldol reaction of aldehydes:
(a) A. B. Northrup and D. W. C. MacMillan, J. Am. Chem. Soc.,
2002, 124, 6798; (b) N. Mase, F. Tanaka and C. F. Barbas III,
Angew. Chem., Int. Ed., 2004, 43, 2420; (c) R. I. Storer and D. W.
C. MacMillan, Tetrahedron, 2004, 60, 7705; (d) A. Cordova,
Tetrahedron Lett., 2004, 45, 3949; (e) A. B. Northrup,
I. K. Mangion, F. Hettche and D. W. C. MacMillan, Angew. Chem.,
Int. Ed., 2004, 43, 2152; (f) I. K. Mangion, A. B. Northrup and
D. W. C. MacMillan, Angew. Chem., Int. Ed., 2004, 43, 6722;
(g) R. Thayumanavan, F. Tanaka and C. F. Barbas III, Org. Lett.,
2004, 6, 3541; (h) J. Casas, M. Engqvist, I. Ibrahem, B. Kaynak and
A. Cordova, Angew. Chem., Int. Ed., 2005, 44, 1343; (i) W. Wang,
H. Li and J. Wang, Tetrahedron Lett., 2005, 46, 5077; (j) F. Zhang,
N. Su and Y. Gong, Synlett, 2006, 1703; (k) Y. Hayashi, S. Aratake,
T. Okano, J. Takahashi, T. Sumiya and M. Shoji, Angew. Chem.,
Int. Ed., 2006, 45, 5527; (l) Y. Hayashi, S. Aratake, T. Itoh,
T. Okano, T. Sumiya and M. Shoji, Chem. Commun., 2007, 957;
(m) Y. Xiong, F. Wang, S. Dong, X. Liu and X. Feng, Synlett, 2008,
73; (n) Y. Hayashi, T. Itoh, S. Aratake and H. Ishikawa, Angew.
Chem., Int. Ed., 2008, 47, 2082; (o) S. Hajra and A. K. Giri, J. Org.
Chem., 2008, 73, 3935; (p) T. Urushima, Y. Yasui, H. Ishikawa and
Y. Hayashi, Org. Lett., 2010, 12, 2966.
6 Rare examples of the syn-selective cross-aldol reaction of aldehydes:
(a) T. Kano, Y. Yamaguchi, Y. Tanaka and K. Maruoka, Angew.
Chem., Int. Ed., 2007, 46, 1738; (b) T. Kano, Y. Yamaguchi and
K. Maruoka, Chem.–Eur. J., 2009, 15, 6678; (c) M. Markert,
U. Scheffler and R. Mahrwald, J. Am. Chem. Soc., 2009,
131, 16642; (d) J. Li, N. Fu, X. Li, S. Luo and J.-P. Cheng,
J. Org. Chem., 2010, 75, 4501.
7 (a) T. Kano, Y. Yamaguchi, O. Tokuda and K. Maruoka, J. Am.
Chem. Soc., 2005, 127, 16408; (b) T. Kano and K. Maruoka, Chem.
Commun., 2008, 5465; (c) T. Kano and K. Maruoka, Bull. Chem.
Soc. Jpn., 2010, 83, 1421.
Scheme 4 Synthesis of lactam 4 from aldol adduct 3.
Scheme 5 Synthesis of lactam 4 from glyoxamide 2.
Scheme 6 Synthesis of lactone 6.
8 S. Luo, P. Zhou, J. Li and J.-P. Cheng, Chem.–Eur. J., 2010,
16, 4457.
9 (a) N. S. Nudelman and G. Garcıa Linares, J. Org. Chem., 2000,
65, 1629; (b) Q. Liu, S. Perreault and T. Rovis, J. Am. Chem. Soc.,
2008, 130, 14066.
converted to synthetically useful and important chiral building
blocks such as g-lactone and g-lactam.
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan. R.S. thanks the Japan Society for
c
10628 Chem. Commun., 2011, 47, 10626–10628
This journal is The Royal Society of Chemistry 2011