A convenient enantioselective decarboxylative aldol reaction to access chiral a-hydroxy esters using β-keto acids

Article abstract of DOI:10.3762/bjoc.10.95

We show a convenient decarboxylative aldol process using a scandium catalyst and a PYBOX ligand to generate a series of highly functionalized chiral a-hydroxy esters. The protocol tolerates a broad range of β-keto acids with inactivated aromatic and aliphatic a-keto esters. The possible mechanism is rationalized.

Full text of DOI:10.3762/bjoc.10.95

A convenient enantioselective decarboxylative
aldol reaction to access chiral α-hydroxy esters
using β-keto acids
Zhiqiang Duan1, Jianlin Han1,2, Ping Qian1, Zirui Zhang1, Yi Wang*1,3
and Yi Pan1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 969–974.
1School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing, 210093, China, 2Institute for Chemistry & Biomedical
Sciences, Nanjing University, Nanjing, 210093, China and 3State of
Key Laboratory of Coordination, Nanjing University, Nanjing, 210093,
China
doi:10.3762/bjoc.10.95
Received: 08 January 2014
Accepted: 10 April 2014
Published: 29 April 2014
Email:
Associate Editor: V. M. Dong
Yi Wang* - yiwang@nju.edu.cn
© 2014 Duan et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
enantioselective synthesis; hydroxy esters; scandium
Abstract
We show a convenient decarboxylative aldol process using a scandium catalyst and a PYBOX ligand to generate a series of highly
functionalized chiral α-hydroxy esters. The protocol tolerates a broad range of β-keto acids with inactivated aromatic and aliphatic
α-keto esters. The possible mechanism is rationalized.
Introduction
The catalytic enantioselective construction of tertiary carbon Taking advantage of this rigid reactivity, several unique
centres is a major challenge in organic chemistry. The nucleo- catalytic decarboxylative aldol transformations of β-keto acids
philic attack of carbonyls appears as a common procedure, with various protic aldehydes have been developed [7-10]
affording chiral tertiary alcohols which are ubiquitous in the (Figure 1). High enantioselectivities were achieved with one
biological sciences and pharmaceutical industry [1-6]. The de- point-binding aldehydes and two-point binding β-keto acids
carboxylative aldol reaction, broadly used for the generation of under mild reaction conditions. The lack of strong Lewis acids
ester enolate equivalents by the promotion of releasing CO2, has or very basic intermediates enabled it to tolerate functionalities
become an appealing method to access chiral tertiary alcohols. that would normally be incompatible with ester enolates, for
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Beilstein J. Org. Chem. 2014, 10, 969–974.
Figure 1: Decarboxylative aldol reactions of β-keto acids with aldehydes.
instance, hydroxy groups, phenols, enolizable aldehydes and cient route to access α-hydroxy esters in an enantioseletive
carboxylic acids. fashion (Figure 3).
Other less reactive carbonyl derivatives such as isatins [11,12], Results and Discussion
ketimines [13] and sulfonylimines [14] have also been By investigating different Lewis acids with various chiral
employed with β-keto acids in the decarboxylative addition PyBox ligands 4–8 (Table 1), we discovered that Sc(OTf)3 and
processes.
tridentate PyBox ligand 6a could promote the decarboxylative
aldol reaction of β-keto acid 1a with α-keto ester 2a in excel-
α-Keto esters as surrogates of aldehydes for the generation of lent yield with high enantioselectivity in toluene (Table 1, entry
chiral alcohols by stereocontrolled nucleophilic alkylation [15- 9). Trace amount of side product acetophenone was formed
19], alkynylation [20,21], 1,2-addition [22-26] and aldol reac- through decarboxylative protonation of β-keto acid 1a, which
tion [27-32] have been developed. Various nucleophiles such as was commonly observed in the case of chiral organic base catal-
organometallics, boronic acids and unsaturated ketones can be ysed decarboxylative additions.
tolerated in this context (Figure 2).
Further optimisation of the reaction conditions showed
We presume that relatively hindered α-keto esters could also be that CHCl3 was the best solvent choice in terms of catalytic
engaged as aldehydes in the decarboxylative aldol reactions activity and asymmetric induction (Table 1, entry 12). Lowering
with β-keto acids, which would provide a practical and effi- the reaction temperature from 20 °C to 0 °C increased the ee
Figure 2: Nucleophilic reaction of α-keto esters to generate tertiary alcohols.
Figure 3: Decarboxylative aldol reactions of β-keto acids with α-keto esters.
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Beilstein J. Org. Chem. 2014, 10, 969–974.
Table 1: Evaluation of ligands and optimisation of reaction conditions.a
Entry
Ligand
Metal salt
Solvent
Yield (%)b
ee (%)c
1
4
Sc(OTf)3
Yb(OTf)3
La(OTf)3
In(OTf)3
Hf(OTf)4
Cu(OTf)2
Cu(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CHCl3
CH3CN
THF
93
90
90
88
91
85
83
91
95
94
90
93
88
89
91
95
27
19
11
5
2
4
3
4
4
4
5
4
15
5
6
7
7
8
17
33
76
45
49
79
33
27
62d
84e
8
5
9
6a
6b
6a
6a
6a
6a
6a
6a
10
11
12
13
14
15
16
CHCl3
CHCl3
aReaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), metal salt (10 mol %), ligand (12 mol %). bIsolated yield after column chromatography.
cDetermined by HPLC analysis using a chiralcel IA column. d10 mg 4 Å molecular sieves were added. eAt 0 °C for 48 h.
value from 79% to 84% (Table 1, entry 16). The addition of 4 Å β-keto acids 1a–d with aromatic and alkyl substituents afforded
molecular sieves was not able to accelerate the reaction or to chiral hydoxy esters 3j–n in high yields and good enantio-
improve the enantioselectivity (Table 1, entry 15).
selectivities (49–75%).
The reaction scope was investigated by using different aryl and We also examined different R3 groups of α-keto esters 2a–d.
alkyl substituted β-keto acids and α-keto esters. Evaluating the Under the established conditions, an ethyl group afforded the
results of products 3b–f, suggested that the α-keto esters with highest yield with the best selectivity. The enantioselectivity did
electron-withdrawing substituents were more favoured than not improve in the cases of methyl, isopropyl or benzyl esters
those with electron-donating groups (Scheme 1, 3b–e). The (Table 2, entries 2–4).
ortho substituted phenyl α-keto ester gave a lower ee (41%)
than those with para substituents (49–84% ee, 3b–e). Aliphatic The mechanism of the reaction was proposed based on the
α-keto esters provided the corresponding aldol products with kinetic studies of the malonic acid half thioester system by
moderate enantioselectivity (56–77% ee, 3g–i). Also, different Shair [33]. Essentially β-keto acids can undergo decarboxyla-
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Beilstein J. Org. Chem. 2014, 10, 969–974.
Scheme 1: Asymmetric decarboxylative aldol reaction of various β-keto acids with α-keto esters under optimised conditions. Reaction conditions:
1 (0.2 mmol), 2 (0.1 mmol), Sc(OTf)3 (10 mol %), ligand 6a (12 mol %). Isolated yield after column chromatography. Enatiomeric excess determined
by HPLC analysis using a chiralcel column. a4(S)-PyBox 6a was used.
Table 2: Effect of the ester group on the α-keto esters with β-keto acid 1a.a
Entry
R3
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
Et, 2a
48
36
48
48
95
93
91
89
84, 3a
47, 3o
71, 3p
67, 3q
Me, 2b
iPr, 2c
Bn, 2d
aReaction conditions: 1a (0.2 mmol), α-keto esters 2 (0.1 mmol), scandium (10 mol %), and ligand 6a (12 mol %). bIsolated yield after column chroma-
tography. cDetermined by HPLC analysis using chiralcel column.
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Beilstein J. Org. Chem. 2014, 10, 969–974.
tion or deprotonation to generate enolates. Though in the case
of enzymatic reactions, decarboxylation occurs first to form the
enolates, followed by condensation with esters; it is believed
that in the scandium-catalysed aldol process of β-keto acid,
similar to the case of malonic acid half thioesters, decarboxyla-
tion happens after the addition to the ester (Scheme 2). First,
deprotonation and enolisation of 9 followed by addition of
α-keto ester 2 gives intermediate 11. After decarboxylation to
afford 12, a protonation step occurs late in the reaction pathway
to form the aldol product 3 and completes the mechanistic
cycle.
Supporting Information
Supporting Information File 1
Experimental and analytical data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-95-S1.pdf]
Acknowledgements
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21102071)
and the Fundamental Research Funds for the Central Universi-
ties (No. 1107020522 and No. 1082020502). The Jiangsu 333
program (for Pan) and Changzhou Jin-Feng-Huang program
(for Han) are also acknowledged.
Conclusion
We have described a new convenient decarboxylative aldol
protocol to generate highly functionalised chiral α-hydroxy
esters employing a Sc(OTf)3 and PyBox catalytic system. A
broad range of inactivated α-keto esters were proven to be toler-
ated. The possible mechanism of the reaction was also rational-
ized. Further investigations to explore the reaction scope are
underway.
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