Direct asymmetric aldol reaction of acetone with α-ketoesters catalyzed by primary-tertiary diamine organocatalysts

Article abstract of DOI:10.1016/j.tetlet.2010.02.044

Novel primary-tertiary diamine organocatalysts derived from l-serine were utilized to promote enantioselective aldol reaction of acetone with α-ketoesters. The desired products were obtained in high yields and with good to excellent enantioselectivities (up to 95% ee).

Full text of DOI:10.1016/j.tetlet.2010.02.044

Tetrahedron Letters 51 (2010) 1884–1886
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Tetrahedron Letters
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Direct asymmetric aldol reaction of acetone with
by primary–tertiary diamine organocatalysts
a-ketoesters catalyzed
*
Zhaoqin Jiang, Yixin Lu
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
Medicinal Chemistry Program, Life Sciences Institute, National University of Singapore, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel primary–tertiary diamine organocatalysts derived from
selective aldol reaction of acetone with -ketoesters. The desired products were obtained in high yields
and with good to excellent enantioselectivities (up to 95% ee).
L-serine were utilized to promote enantio-
Received 8 December 2009
Revised 21 January 2010
Accepted 5 February 2010
Available online 11 February 2010
a
Ó 2010 Elsevier Ltd. All rights reserved.
The aldol reaction is an important reaction for the construction of
b-hydroxy carbonyl compounds and has drawn a great deal of atten-
tion from synthetic organic chemists.1 Asymmetric organocatalysis
and stereoselective synthetic methods based on small organic mol-
ecules are well established as practical approaches to access chiral
molecules.2 Since the seminal discovery by List, Barbas and Lerner
of proline-catalyzed intermolecular aldol reactions via enamine
intermediates in 2000,3 proline and its numerous structural ana-
logues have found wide applications in asymmetric aldol reactions.4
Chiral primary amines have emerged as powerful and versatile
organic catalysts in asymmetric synthesis.5 It is noteworthy that
chiral primary amine-promoted reactions are often complementary
to those catalyzed by secondary amines. Our group has actively
investigated primary amino acid/amine-catalyzed organocatalytic
reactions. We demonstrated for the first time that natural trypto-
phan was an effective catalyst in intermolecular aldol reactions.6
amine-catalyzed organocatalytic reactions, we became interested
in utilizing simple acyclic ketones as potential nucleophiles in
asymmetric carbon–carbon bond formation. Towards this end,
we chose to focus our efforts on the aldol reaction of acetone with
a
-ketoesters as such reactions are expected to produce chiral ter-
tiary alcohols which are important intermediates in medicinal
chemistry.10 Although there are a few reports on the use of
-keto-
a
esters/acids as electrophiles in organocatalytic reactions, the
catalysts employed in these studies are all secondary amines.11
We envisage that primary amines can be applied to activate acyclic
ketone substrates in the direct aldol reaction, which may broaden
the substrate scope for reactions activated via primary amine-in-
duced enamine intermediates.
The catalysts employed in our study are shown in Figure 1. O-
TBDPS-L-threonine 2a was one of the most effective catalysts in
our previous reports,7 and thus we also prepared its secondary
amine analogue 2b. Moreover, O-acylated threonine derivatives 1
were synthesized as well. Diamine organocatalysts, in particular,
diamine-Brønsted acid-type catalysts, have been widely used in
We also utilized L-threonine-derived organocatalysts to promote
highly enantioselective aldol and Mannich reactions of hydroxyace-
tone, as well as conjugate additions of branched aldehydes to vinyl
sulfone.7 By employing a cinchonidine-derived primary amine, we
achieved the first highly enantioselective conjugate addition of
ketones to vinyl sulfone.8 We also introduced a novel tryptophan-
based bifunctional thiourea catalyst that was effective in promoting
O
HO
R
OTBDPS
COOH
OTBDPS
O
R'
n
a
-fluoro-b-ketoesters.9 In
N
R
enantioselective Mannich reactions of
COOH
N
R'
NH2
thisLetter, we demonstrate that a novel serine-derivedprimary–ter-
tiary diamine catalyst promotes the asymmetric addition of acetone
NHR
NH2
NH2
4a
: R' = n-C3H7, R = Ph
2a
2b
: R = H
3
4b
: R' = n-C6H13, R = Ph
: R' = n-C11H23, R = Ph
1a
1b
: n = 4
: n = 10
to
a-ketoesters.
: R = CH3
4c
4d
: R' = n-C11H23, R = Me
In primary amine-catalyzed organocatalytic reactions occurring
via the enamine mechanism, cyclic ketones are the most
commonly used substrates. This is likely due to the ready forma-
tion of the key enamine intermediates from cyclic ketones and
primary amines. In an effort to expand the scope of primary
OH
Ph
HO
R
TBSO
N
R
N
Ph
n
H
NH2
NH2
5a: n = 1
5b: n = 2
5c: n = 3
6a: R = Me
6b: R = Ph
OTBS
* Corresponding author. Tel.: +65 6516 1569; fax: +65 6779 1691.
E-mail address: chmlyx@nus.edu.sg (Y. Lu).
Figure 1. Organocatalysts derived from
L-serine and
L-threonine.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.044

Z. Jiang, Y. Lu / Tetrahedron Letters 51 (2010) 1884–1886
1885
Table 1
tive, affording the desired products in very poor yields and with
very low enantioselectivity (entries 1–4). Diamine 3 derived from
O-TBDPS-threonine, together with formic acid, proved to be a good
catalytic system, affording the desired product in high yield and
with good enantioselectivity (entry 5). Diamines 4, prepared from
Catalyst screening for the direct aldol reaction of methyl phenylglyoxylate with
acetonea
O
O
O
OH
O
Catalyst (10 mol%)
+
Ph
COOMe
HCOOH (0.1 eq.), RT
O
8a
L-serine, were shown to be efficient catalysts, yielding the desired
7a
aldol products in excellent yields and with generally high enanti-
oselectivity (entries 6–12). In particular, when diamine 4c was em-
ployed as the catalyst, the aldol product was obtained in 88% ee
(entry 9). Secondary-primary diamine catalysts 5 and tertiary–pri-
mary diamine catalysts 6 were found to be less effective, yielding
the products with moderate enantioselectivities (entries 13–17).
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
1d
2d
3d
4d
5
1a
1b
2a
2b
3
4a
4b
4c
4c
4c
4d
4d
5a
5b
5c
6a
6b
48
144
18
60
13
48
12
72
48
72
15
37
24
19
48
24
96
29
—
À23f
—
52
24
91
89
93
96
96
98
86
98
92
91
91
89
66
À32f
À18f
77
6
74
74
77
88
84
87
78
41
59
46
51
64
7
Table 3
8d
9
The aldol reaction of acetone with various
a
-ketoesters catalyzed by diamine catalyst
4ca
10e
11
12e
13
14
15
16
17
O
4c
O
OR
OH
R'
(10 mol%)
O
OR
O
R'
+
HCOOH (10 mol%), RT
O
7b-j
8b-j
Entry
Product
Time (d)
2
Yieldb (%)
eec (%)
78
O
O
OEt
OH
a
The reaction was performed employing methyl phenylglyoxylate (0.25 mmol),
acetone (1.25 mmol), catalyst (0.025 mmol) and formic acid (0.025 mmol) at room
temperature.
1
2
61
b
8b
Isolated yield.
c
The ee value was determined by HPLC analysis on a chiral phase.
No additive was used.
Reaction was performed at 0 °C.
The opposite enantiomer was observed.
O
OMe
OH
O
O
d
e
3
96
73
76
95
f
8c
Br
O
OMe
OH
asymmetric organocatalysis.12 Addition of an acid to the primary–
tertiary diamine system is believed to facilitate the formation of
enamine intermediates and promote the formation of carbon–car-
bon bonds via interaction with electrophiles. Moreover, the acid
component can be easily varied, and with judicious selection,
hydrogen-bonding networks between substrates and catalysts
are expected to work cooperatively, thus offering new reactivity
and selectivity. A few diamine catalysts, 3, derived from natural
threonine, and 5 and 6 from serine were thus prepared intending
to incorporate steric factors and hydrogen-bonding elements into
our catalyst design.
3
4
1.5
8d
NO2
O
OEt
OH
O
O
1.5
97
88
80
74
8e
NO2
O
OMe
OH
5
2
The direct aldol reaction of acetone with methyl phenyglyoxy-
late 7a was chosen as a model reaction for examining the catalytic
effects of various catalysts. The results are summarized in Table 1.
O-Acylated and O-silylated threonine derivatives were not effec-
8f
NO2
O
OMe
OH
O
O
6
7
2
1
91
69
74
74
8g
CN
Table 2
The effects of various acidic additivesa
O
OMe
OH
O
4c (10 mol%), RT
O
O
OH
O
+
Ph
additive (10 mol%)
COOMe
O
8h
O
8a
OPh
OH
7a
O
O
Entry
Additive
Time (h)
Yieldb (%)
eec (%)
8
9
1.5
1
73
83
76
57
1
2
3
4
5
6
CH3COOH
CF3COOH
C6H5COOH
m-O2NC6H4COOH
p-O2NC6H4COOH
HCOOH
22
72
96
19
72
48
98
93
93
95
92
96
79
85
80
79
75
88
8i
O
OEt
OH
8j
a
a
The reaction was performed employing methyl phenylglyoxylate (0.25 mmol),
The reaction was performed employing ketoester (0.25 mmol), acetone
acetone (1.25 mmol), catalyst 4c (0.025 mmol) and additive (0.025 mmol) at room
(1.25 mmol), catalyst 4c (0.025 mmol) and formic acid (0.025 mmol) at room
temperature.
temperature.
b
b
Isolated yield.
Isolated yield.
c
c
The ee value was determined by HPLC analysis on a chiral phase.
The ee value was determined by HPLC analysis on a chiral phase.

1886
Z. Jiang, Y. Lu / Tetrahedron Letters 51 (2010) 1884–1886
Supplementary data
O
O
OH
O
O
OH
a) NaBH(OAc)3, AcOH, THF
b) 1N HCl
R
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.044.
O
H
R
CH3
8a
: R = H
9a: R = H, dr 10:1 (96%)
References and notes
8d
: R = NO2
9b: R = NO2, dr 92:8 (95%)
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Scheme 1. Preparation of chiral lactones.
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Since the acidic additive was important for the reactions, we
subsequently examined the effects of various acidic additives on
the reaction. As shown in Table 2, formic acid was the best additive
among a number of acids examined.
Having established the optimized conditions, the reaction scope
was next examined (Table 3). Various a-ketoesters were employed
and in general, the aldol products were obtained in moderate to
excellent yields and with good enantioselectivities. In addition to
aryl ketoesters, alkyl ketoesters were also employed (entries 8
and 9). Unfortunately, we could not extend the reaction to include
acyclic ketones other than acetone.
The aldol product is rich in functionality, which allows for simple
synthetic manipulations. Thus, aldol product 8a was converted into
lactone 9a in 96% yield and a 10:1 diastereomeric ratio, following a
literature procedure.11c Similarly, lactone 9b was prepared from
8d in 95% yield and with excellent diastereoselectivity (Scheme 1).
In conclusion, we have prepared a number of novel diamine
organocatalysts and investigated their effects on the asymmetric
direct aldol reaction of acetone with a-ketoesters. Tertiary-primary
diamine catalysts derived from serine, in combination with formic
acid, proved to be the most effective, affording the desired aldol
products with up to 95% ee. Investigations on the extension of
the catalysts described herein to other asymmetric carbon–carbon
bond-forming reactions are in progress in our laboratory and will
be reported in due course.
Acknowledgements
The authors thank the National University of Singapore and
Ministry of Education (MOE) of Singapore (R-143-000-362-112)
for generous financial support.