Molecular recognition of ketomalonates by asymmetric aldol reaction of aldehydes with secondary-amine organocatalysts

Article abstract of DOI:10.1039/c2cc32772d

A diastereo- and enantioselective aldol reaction between aldehydes and a synthetically useful ketomalonate 1c as a hydrated form was developed, and either anti- or syn-aldol adducts having a chiral tetrasubstituted carbon center were obtained in high enantioselectivities by use of a tetrazole analogue of l-proline (S)-2 or an axially chiral amino sulfonamide (S)-3 as catalyst. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc32772d

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COMMUNICATION
Molecular recognition of ketomalonates by asymmetric aldol reaction of
aldehydes with secondary-amine organocatalystsw
Taichi Kano, Sunhwa Song and Keiji Maruoka*
Received 19th April 2012, Accepted 24th May 2012
DOI: 10.1039/c2cc32772d
A diastereo- and enantioselective aldol reaction between aldehydes
and a synthetically useful ketomalonate 1c as a hydrated form
was developed, and either anti- or syn-aldol adducts having a
chiral tetrasubstituted carbon center were obtained in high
enantioselectivities by use of a tetrazole analogue of L-proline
(S)-2 or an axially chiral amino sulfonamide (S)-3 as catalyst.
Fig. 1 Unsymmetrical ketomalonate 1 in a hydrate form for asymmetric
cross-aldol reaction.
Asymmetric aldol reactions provide expedient access to optically
active b-hydroxy carbonyl compounds that are fundamental
chiral building blocks for a number of biologically active and
pharmaceutically important compounds.1 Among these reactions,
catalytic asymmetric aldol reactions of ketone electrophiles
afford tertiary alcohols, and a chiral tetrasubstituted carbon
center is efficiently constructed with these methods.2–4 In the
area of organocatalysis, the development of direct asymmetric
aldol reaction has been the subject of intensive research over
the last decade; however, reactive aldehydes were employed as
electrophiles in the most amine-catalyzed aldol reactions.5–7
Although a number of asymmetric aldol reactions between
ketone nucleophiles and ketone electrophiles have been developed,8
only a few examples using aldehyde nucleophiles, which tend
to be dimerized through the homo-aldol reaction, toward
ketone electrophiles have been reported so far.9 Additionally,
an efficient method for the stereoselective synthesis of both
diastereomers of such aldol adducts from the same set of reactants
by simply replacing the catalyst has been scarcely investigated.
Accordingly, we have been interested in the development of
organocatalytic asymmetric aldol reaction between aldehyde
nucleophiles and ketone electrophiles based on the molecular
recognition approach. The difficulty in developing the asymmetric
aldol reaction of ketones can be attributed to the lower
intrinsic electrophilicity of ketones over aldehydes, combined
with the smaller steric difference between the two groups on
the carbonyl moiety. To overcome the low reactivity of ketone
acceptors, we chose ketomalonate 1, which is obtained in a
hydrate form, as electronically activated ketone equivalent by
two different modifiable ester groups (Fig. 1). One ester group
of 1 consists of phenols, which are sterically demanding and
sufficiently good leaving group, to induce diastereoselectivity
as well as to discriminate two ester groups of 1. Herein, we
wish to report both anti and syn-selective synthesis of chiral
tertiary alcohols based on the molecular recognition approach
from the stereocontrolled aldol reaction of the hydrated
ketomalonate 1 having modifiable substituents with aldehydes
catalyzed by either the tetrazole analogue of L-proline (S)-210
or an axially chiral amino sulfonamide of type (S)-3.11
We first examined the effect of 2,6-substituents on the phenyl
group of hydrated ketomalonate 1 in the aldol reaction, and the
results are summarized in Table 1. In the presence of 20 mol% of
L-proline, the reaction between 3-phenylpropanal and 1a
(Ar = 2,6-Me2-C6H3) in dichloromethane at room temperature
proceeded smoothly to give the desired anti-aldol adduct anti-4a as
a major diastereomer in good yield with excellent enantioselectivity
(entry 1). Unfortunately, however, 4a was found to be readily
isomerized to a 1 : 1 mixture of the anti and syn-isomers after
isolation. Use of more hindered acceptors 1b (Ar = 2,6-iPr2-C6H3)
and 1c (Ar = 2,6-tBu2-C6H3) resulted in higher anti-selectivity,
and no isomerization was observed (entries 2 and 3). When
the reaction of 1c was carried out with 10 mol% of catalyst
(S)-2, the tetrazole derivative of L-proline, further improvement
of anti-selectivity was achieved (entry 4).
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 Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c2cc32772d
Having identified a suitable ketone acceptor, solvent screening
was then carried out. The desired anti-aldol product anti-4c was
formed as a major diastereomer in moderate to good yield
c
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Table 1 anti-Selective aldol reactions between 3-phenylpropanal and
1 catalyzed by L-prolinea
All reactions catalyzed by (S)-2 proceeded smoothly to give
anti-aldol adducts as major diastereomers in good yield with
excellent enantioselectivity (entries 1–5). Regardless of aldehyde
structure, the diastereochemical outcome of the aldol adducts
could be switched by using (S)-3 (entries 6–10).
The obtained aldol products anti-4c and syn-4c were versatile
intermediates in organic synthesis and readily converted to
important chiral building blocks such as g-lactones. Thus,
reduction of aldol product anti-4c with L-selectride at À78 1C
and the subsequent lactonization with 1 N HCl in one pot
provided a-hydroxy-g-lactone syn-5 in good yield without loss
of the diastereoselectivity (Scheme 1). In the case of syn-4c, the
corresponding a-hydroxy-g-lactone anti-5 was readily obtained
by treatment with L-selectride (Scheme 2). In both cases, the
carbonyl group of more reactive aryl ester was preferentially
incorporated into the lactone ring. A hydroxy group on anti-5
was converted to an amino group through mesylation, SN2
reaction with NaN3, and reduction under mild conditions.
Entry
Ar
Yieldb (%)
anti/sync
eed (%)
1
2
2,6-Me2-C6H3
2,6-iPr2-C6H3
2,6-tBu2-C6H3
2,6-tBu2-C6H3
83
94
99
88
1.8/1
2.2/1
2.6/1
3.0/1
96
96
95
99
3
4e
a
Unless otherwise noted, the reaction of 3-phenylpropanal (0.125 mmol)
with 1 (0.1 mmol) was performed in the presence of L-proline (0.02 mmol)
b
in CH2Cl2 (100 mL) at room temperature for 2 h. Isolated yield.
c
d
Determined by 1H-NMR. The ee of anti-4 was determined by HPLC
using a chiral column after conversion to the corresponding g-lactone.
Use of (S)-2 (0.01 mmol) instead of L-proline.
e
with excellent enantioselectivity in all solvents investigated
(see ESIw). Thus, toluene appeared to be the best solvent in
terms of diastereoselectivity (Table 2, entry 3).
We then turned our attention to the development of the
syn-selective aldol reaction of 1c catalyzed by an axially chiral
amino sulfonamide (S)-3, which can switch the minor diastereomer
in the reaction catalyzed by proline and its derivatives to the major
diastereomer.11 In the presence of 5 mol% of (S)-3, the reaction
between 3-phenylpropanal and 1c in toluene at room temperature
afforded the desired syn-aldol adduct syn-4c in good yield
with high enantioselectivity (Table 2, entry 8). Among solvents
tested, toluene was found to be a suitable solvent in terms of
yield and syn-selectivity (see ESIw).
Scheme 1 Synthesis of a-hydroxy-g-lactone syn-5.
Under the optimal reaction conditions, the diastereo- and
enantioselective aldol reaction of 1c with several other donor alde-
hydes was examined, and the results are summarized in Table 2.
Table 2 Stereocontrolled aldol reactions between various aldehydes
and 1c catalyzed by (S)-2 or (S)-3a
Scheme 2 Synthesis of a-hydroxy-g-lactone anti-5 and a-amino-
g-lactone syn-7.
Based on the observed stereochemistry, transition state
models can be proposed as shown in Fig. 2. In the case of
the reaction catalyzed by (S)-2, the activation and orientation
of the ketomalonate 1c by the acidic functionality of (S)-2 is
expected to occur by coordination to the sterically more
accessible lone pair on the carbonyl oxygen atom of 1c.
Consequently, the Re-face of ketomalonate 1c approaches the
Re-face of the dominant s-trans-enamine, and the anti-aldol adduct
was obtained as a major diastereomer (Fig. 2, TS1). On the other
hand, while both s-trans-enamine and s-cis-enamine might be
formed in the reaction catalyzed by (S)-3, only s-cis-enamine
can react with the activated ketomalonate 1c, giving the syn-aldol
adduct predominantly (Fig. 2, TS2).12
Entry
R
Catalyst
Yieldb (%)
anti/sync
eed (%)
1
Me
Et
Bn
CH2Cy
iPr
Me
Et
Bn
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
83
80
89
71
85
74
75
90
94
65
3.5/1
3.9/1
4.1/1
3.8 /1
4.3/1
1/4.0
1/5.6
1/6.2
1/4.9
1/3.5
95
97
98
96
96
97
95
95
95
95
2e
3
4
5e
6
7
8
9
CH2Cy
iPr
10f
a
The reaction of an aldehyde (0.125 mmol) with 1c (0.1 mmol) was
performed in the presence of (S)-2 (0.01 mmol) or (S)-3 (0.005 mmol)
b
In summary, we have developed a diastereoselective and
enantioselective direct aldol reaction of hydrated ketomalonate 1c
with aldehydes catalyzed by proline derivative (S)-2 and the axially
chiral amino sulfonamide (S)-3. This organocatalytic process
represents a rare example of stereocontrolled aldol reaction
in toluene (100 mL) at room temperature for 2 h. Isolated yield.
c
d
Determined by 1H-NMR. The ee of the major isomer was determined
by HPLC using a chiral column after conversion to the corresponding
e
f
g-lactone. The reaction was performed for 3 h. The reaction was
performed for 5 h.
c
7038 Chem. Commun., 2012, 48, 7037–7039
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Research from MEXT, Japan.
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c
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Chem. Commun., 2012, 48, 7037–7039 7039