Amine-catalyzed asymmetric cross-aldol reactions using heterofunctionalized acetaldehydes as nucleophiles

Article abstract of DOI:10.1021/ol4036837

Various heterofunctionalized acetaldehydes were successfully employed in an amine-catalyzed asymmetric cross-aldol reaction, affording a variety of synthetically useful 1,2-difunctionalized compounds such as 1,2-diols and 1,2-aminoalcohols. With this method, both syn- and anti-1,2-difunctionalized compounds were obtained from the same set of reactants by using the appropriate amine catalyst.

Full text of DOI:10.1021/ol4036837

Letter
pubs.acs.org/OrgLett
Amine-Catalyzed Asymmetric Cross-Aldol Reactions Using
Heterofunctionalized Acetaldehydes as Nucleophiles
Taichi Kano, Ryu Sakamoto, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S
* Supporting Information
ABSTRACT: Various heterofunctionalized acetaldehydes were
successfully employed in an amine-catalyzed asymmetric cross-aldol
reaction, affording a variety of synthetically useful 1,2-difunctionalized
compounds such as 1,2-diols and 1,2-aminoalcohols. With this
method, both syn- and anti-1,2-difunctionalized compounds were
obtained from the same set of reactants by using the appropriate
amine catalyst.
Table 1. syn-Selective Cross-Aldol Reaction between 1a and
4-Nitrobenzaldehyde Catalyzed by (S)-2
mine-catalyzed asymmetric cross-aldol reactions between
two different aldehydes provide an attractive approach
a
A
toward the construction of useful chiral building blocks.1,2 In
such cross-aldol reactions, both syn- and anti-aldol adducts have
become available from the same set of reactants by simply
switching the amine catalyst.3 In addition, heterofunctionalized
acetaldehydes are also applicable as donor aldehydes to prepare
synthetically important 1,2-difunctionalized compounds such as
1,2-diols4 and 1,2-aminoalcohols.5 Despite their synthetic
potential and diversity, however, most cross-aldol reactions of
heterofunctionalized acetaldehydes employ benzyloxyacet-
aldehyde or siloxyacetaldehydes and are limited to the
preparation of anti-1,2-diol derivatives.6−8 This prompted us
to investigate both a syn- and anti-selective asymmetric cross-
aldol reaction of various heterofunctionalized acetaldehydes 1
(Figure 1),9,10 affording various densely functionalized
compounds, and herein, we report our recent results.
b
c
d
entry
solvent
yield (%)
syn/anti
ee (%)
1
2
3
4
5
6
7
NMP
77
69
55
70
58
48
34
>20/1
>20/1
>20/1
4.6/1
5.9/1
4.8/1
2.3/1
99
98
99
94
90
82
90
DMF
DMSO
CH3CN
THF
CH2Cl2
toluene
a
The reaction of 1a (0.125 mmol) with 4-nitrobenzaldehyde (0.250
mmol) was carried out in the presence of (S)-2 (0.00625 mmol) in a
solvent (125 μL). Isolated yield. Determined by H NMR analysis.
b
c
1
d
The ee of syn-4a was determined by HPLC using a chiral column.
used, a significant decrease in yield and stereoselectivity was
observed (Table 1, entries 4−7). Consequently, NMP was
found to be among the best in terms of both yield and
stereoselectivity.
Figure 1. Heterofunctionalized acetaldehydes.
We have previously developed the axially chiral amino
sulfonamide catalyst (S)-2,11 which shows unusual syn-
selectivity in the direct asymmetric cross-aldol reaction of
aldehydes,2a in sharp contrast to the anti-selective reaction
catalyzed by proline and the related catalysts. Accordingly, we
first examined the syn-selective direct cross-aldol reaction
between N-Z-protected aminoacetaldehyde 1a9 and 4-nitro-
benzaldehyde in the presence of 5 mol % of (S)-2 in various
solvents (Table 1). The reaction in amide solvents NMP and
DMF at room temperature afforded the desired syn-1,2-
aminoalcohol 4a in good yield with virtually perfect diastereo-
and enantioselectivity (entries 1 and 2). Use of DMSO resulted
in a slight decrease in yield (Table 1, entry 3). When other
solvents, such as acetonitrile, THF, CH2Cl2, and toluene were
With the optimized reaction conditions in hand, the syn-
selective cross-aldol reactions of various heterofunctionalized
acetaldehydes 1 with other acceptor aldehydes were examined,
and the results are summarized in Scheme 1. In the presence of
Received: December 19, 2013
© XXXX American Chemical Society
A
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Organic Letters
Letter
Scheme 1. syn-Selective Cross-Aldol Reaction of
Heterofunctionalized Acetaldehyde 1 Catalyzed by (S)-2
Scheme 2. Synthesis of Dihydropyrrole 9
a
1e and 4-nitrobenzaldehyde catalyzed by (S)-2; however, the
desired product was obtained in only 19% yield, albeit with
high stereoselectivity (syn/anti = 11/1, 97% ee (syn)). Use of
the more nucleophilic catalyst (S)-3 resulted in a higher yield
with excellent stereoselectivity (4e).3,14 These results represent
the first example of utilization of the oxyacetaldehyde protected
with acyl groups instead of commonly used protecting groups
such as benzyl and silyl groups.
To further expand the scope of the cross-aldol reaction of
heterofunctionalized acetaldehydes, we also examined the
possibility of using α-thio acetaldehydes 1f and 1g as donor
aldehydes.6b,10,15 When the cross-aldol reactions of 1f and 1g
with tert-butyl glyoxylate were performed in the presence of 5
mol % of (S)-2 in NMP at −20 °C, the desired syn-aldol
adducts were obtained as major diastereomers in good
enantioselectivities (Scheme 3).16 These aldol adducts were
isolated after the conversion to the corresponding α,β-
unsaturated ester 8f and 8g by treatment with a Wittig reagent.
a
The reaction of 1 (0.125 mmol) with an acceptor aldehyde (0.250
mmol) was carried out in the presence of (S)-2 (0.00625 mmol) in
Scheme 3. syn-Selective Cross-Aldol Reaction Using α-Thio
Acetaldehydes
b
c
NMP (125 μL) at room temperature for 48 h. Isolated yield.
Determined by 1H NMR analysis. The ee of syn-product was
determined by HPLC using a chiral column. e Use of 1 (0.250 mmol)
and an acceptor aldehyde (0.125 mmol). f The reaction was performed
d
g
h
for 24 h. Use of acetonitrile (125 μL) as solvent. Isolated after
olefination with a Wittig reagent instead of reduction. Use of (S)-3
I
(0.00625 mmol).
5 mol % of (S)-2, the reaction of N-Z-protected amino-
acetaldehyde 1a with reactive acceptor aldehydes gave the
desired syn-aldol adducts in moderate to good yields with high
diastereo- and enantioselectivities (4a, 5a, 6a, and 7a).
Unfortunately, the reaction of 1a or 1d with a less reactive
acceptor aldehyde such as benzaldehyde or pivalaldehyde gave
only a trace amount of the desired product. In addition, N-Boc-
protected aminoacetaldehyde 1b and N-allyl-N-Z-aminoacetal-
dehyde (1c) were applicable to the present aldol reaction (4b
and 8c). The absolute configuration of 4b was determined by
comparing the optical rotation with the literature value.12 The
aldol adduct in the reaction using 1c was converted to the
corresponding α,β-unsaturated ester 8c by treatment with a
Wittig reagent. The following ring-closing metathesis of 8c gave
dihydropyrrole 9 without epimerization (Scheme 2).13
When benzoyloxyacetaldehyde (1d) was employed as a new
entry of oxyacetaldehydes as a donor aldehyde, the syn-1,2-diol
derivative was obtained as a major diastereomer in moderate
yield with high enantioselectivity (6d). The benzoyl moiety of
1d and 6d was found to be slightly unstable under the reaction
conditions and silica gel column chromatography. When 2,6-
dimethylbenzoyloxyacetaldehyde (1e) was employed instead of
1d, the improved yield and diastereoselectivity were obtained as
expected (6e). We then attempted the aldol reaction between
Although some examples of anti-selective cross-aldol
reactions using heterofunctionalized acetaldehydes have been
reported to date,6,8 the diversity of the reaction is still
unsatisfactory. Thus, we turned our attention to further explore
the anti-selective cross-aldol reaction using heterofunctionalized
acetaldehydes 1. After the optimization of the reaction
conditions (see Supporting Information), the proline-catalyzed
anti-selective cross-aldol reaction of 1a with several acceptor
aldehydes was examined (Table 2). The reactions of 1a with 4-
nitrobenzaldehyde and pentafluorobenzaldehyde gave the
desired anti-aldol adducts in high yield and stereoselectivity
(Table 2, entries 1 and 2). On the other hand, the proline-
catalyzed reaction with tert-butyl glyoxylate gave an unsat-
isfactory result in terms of both yield and stereoselectivity
(Table 2, entry 3). Fortunately, use of a commercially available
prolinol catalyst (S)-10 instead of proline resulted in an
improvement of yield, anti-selectivity, and enantioselectivity
(Table 2, entry 4).17
Furthermore, the anti-selective aldol reaction of oxyacet-
aldehyde 1e with tert-butyl glyoxylate was examined (Scheme
4). Use of proline as the catalyst gave only a trace amount of
the desired product. On the other hand, the catalyst (S)-10 was
found to give the highly enantiomerically enriched product 12
B
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Organic Letters
Letter
Table 2. anti-Selective Cross-Aldol Reaction between 1a and
Acceptor Aldehydes
ASSOCIATED CONTENT
■
a
S
* Supporting Information
Experimental procedure and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
b
c
d
AUTHOR INFORMATION
entry
R
yield (%)
anti/syn
ee (%)
■
1
2
3
4-NO2C6H4
C6F5
90
90
41
61
13/1
20/1
2.1/1
4.8/1
99
99
88
95
Corresponding Author
*E-mail: maruoka@kuchem.kyoto-u.ac.jp.
Notes
CO2t-Bu
CO2t-Bu
e
4
a
The reaction of 1a (0.125 mmol) with 4-nitrobenzaldehyde (0.250
mmol) was carried out in the presence of L-proline (0.0375 mmol) in
The authors declare no competing financial interest.
b
c
1
DMAc (250 μL) at 0 °C for 24. Isolated yield. Determined by H
NMR analysis. The ee of anti-product was determined by HPLC
using a chiral column. The reaction of 1a (0.250 mmol) and tert-butyl
glyoxylate (0.125 mmol) catalyzed by (S)-10 (0.0125 mmol) was
d
ACKNOWLEDGMENTS
■
e
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT, Japan. R.S. thanks the Japan Society for
the Promotion of Science for Young Scientists for Research
Fellowships.
performed in NMP (125 μL) at room temperature.
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