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

  1. 1 ,
  2. 1,2 ,
  3. 1 ,
  4. 1 ,
  5. 1,3 and
  6. 1,3
1School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China
2Institute for Chemistry & Biomedical Sciences, Nanjing University, Nanjing, 210093, China
3State of Key Laboratory of Coordination, Nanjing University, Nanjing, 210093, China
  1. Corresponding author email
Associate Editor: V. M. Dong
Beilstein J. Org. Chem. 2014, 10, 969–974. https://doi.org/10.3762/bjoc.10.95
Received 08 Jan 2014, Accepted 10 Apr 2014, Published 29 Apr 2014
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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.

Keywords: enantioselective synthesis; hydroxy esters; scandium

Introduction

The catalytic enantioselective construction of tertiary carbon centres is a major challenge in organic chemistry. The nucleophilic attack of carbonyls appears as a common procedure, affording chiral tertiary alcohols which are ubiquitous in the biological sciences and pharmaceutical industry [1-6]. The decarboxylative aldol reaction, broadly used for the generation of ester enolate equivalents by the promotion of releasing CO2, has become an appealing method to access chiral tertiary alcohols. Taking advantage of this rigid reactivity, several unique catalytic decarboxylative aldol transformations of β-keto acids with various protic aldehydes have been developed [7-10] (Figure 1). High enantioselectivities were achieved with one point-binding aldehydes and two-point binding β-keto acids under mild reaction conditions. The lack of strong Lewis acids or very basic intermediates enabled it to tolerate functionalities that would normally be incompatible with ester enolates, for instance, hydroxy groups, phenols, enolizable aldehydes and carboxylic acids.

[1860-5397-10-95-1]

Figure 1: Decarboxylative aldol reactions of β-keto acids with aldehydes.

Other less reactive carbonyl derivatives such as isatins [11,12], ketimines [13] and sulfonylimines [14] have also been employed with β-keto acids in the decarboxylative addition processes.

α-Keto esters as surrogates of aldehydes for the generation of chiral alcohols by stereocontrolled nucleophilic alkylation [15-19], alkynylation [20,21], 1,2-addition [22-26] and aldol reaction [27-32] have been developed. Various nucleophiles such as organometallics, boronic acids and unsaturated ketones can be tolerated in this context (Figure 2).

[1860-5397-10-95-2]

Figure 2: Nucleophilic reaction of α-keto esters to generate tertiary alcohols.

We presume that relatively hindered α-keto esters could also be engaged as aldehydes in the decarboxylative aldol reactions with β-keto acids, which would provide a practical and efficient route to access α-hydroxy esters in an enantioseletive fashion (Figure 3).

[1860-5397-10-95-3]

Figure 3: Decarboxylative aldol reactions of β-keto acids with α-keto esters.

Results and Discussion

By investigating different Lewis acids with various chiral PyBox ligands 4–8 (Table 1), we discovered that Sc(OTf)3 and tridentate PyBox ligand 6a could promote the decarboxylative aldol reaction of β-keto acid 1a with α-keto ester 2a in excellent yield with high enantioselectivity in toluene (Table 1, entry 9). Trace amount of side product acetophenone was formed through decarboxylative protonation of β-keto acid 1a, which was commonly observed in the case of chiral organic base catalysed decarboxylative additions.

Table 1: Evaluation of ligands and optimisation of reaction conditions.a

[Graphic 1]
Entry Ligand Metal salt Solvent Yield (%)b ee (%)c
1 4 Sc(OTf)3 toluene 93 27
2 4 Yb(OTf)3 toluene 90 19
3 4 La(OTf)3 toluene 90 11
4 4 In(OTf)3 toluene 88 5
5 4 Hf(OTf)4 toluene 91 15
6 7 Cu(OTf)2 toluene 85 5
7 8 Cu(OTf)2 toluene 83 17
8 5 Sc(OTf)3 toluene 91 33
9 6a Sc(OTf)3 toluene 95 76
10 6b Sc(OTf)3 toluene 94 45
11 6a Sc(OTf)3 CH2Cl2 90 49
12 6a Sc(OTf)3 CHCl3 93 79
13 6a Sc(OTf)3 CH3CN 88 33
14 6a Sc(OTf)3 THF 89 27
15 6a Sc(OTf)3 CHCl3 91 62d
16 6a Sc(OTf)3 CHCl3 95 84e

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.

Further optimisation of the reaction conditions showed that CHCl3 was the best solvent choice in terms of catalytic activity and asymmetric induction (Table 1, entry 12). Lowering the reaction temperature from 20 °C to 0 °C increased the ee value from 79% to 84% (Table 1, entry 16). The addition of 4 Å molecular sieves was not able to accelerate the reaction or to improve the enantioselectivity (Table 1, entry 15).

The reaction scope was investigated by using different aryl and alkyl substituted β-keto acids and α-keto esters. Evaluating the results of products 3b–f, suggested that the α-keto esters with electron-withdrawing substituents were more favoured than those with electron-donating groups (Scheme 1, 3b–e). The ortho substituted phenyl α-keto ester gave a lower ee (41%) than those with para substituents (49–84% ee, 3b–e). Aliphatic α-keto esters provided the corresponding aldol products with moderate enantioselectivity (56–77% ee, 3g–i). Also, different β-keto acids 1a–d with aromatic and alkyl substituents afforded chiral hydoxy esters 3j–n in high yields and good enantioselectivities (49–75%).

[1860-5397-10-95-i1]

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.

We also examined different R3 groups of α-keto esters 2a–d. Under the established conditions, an ethyl group afforded the highest yield with the best selectivity. The enantioselectivity did not improve in the cases of methyl, isopropyl or benzyl esters (Table 2, entries 2–4).

Table 2: Effect of the ester group on the α-keto esters with β-keto acid 1a.a

[Graphic 2]
Entry R3 Time (h) Yield (%)b ee (%)c
1 Et, 2a 48 95 84, 3a
2 Me, 2b 36 93 47, 3o
3 iPr, 2c 48 91 71, 3p
4 Bn, 2d 48 89 67, 3q

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 chromatography. cDetermined by HPLC analysis using chiralcel column.

The mechanism of the reaction was proposed based on the kinetic studies of the malonic acid half thioester system by Shair [33]. Essentially β-keto acids can undergo decarboxylation 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, decarboxylation 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.

[1860-5397-10-95-i2]

Scheme 2: Proposed mechanism of decarboxylative aldol reaction.

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 tolerated. The possible mechanism of the reaction was also rationalized. Further investigations to explore the reaction scope are underway.

Supporting Information

Supporting Information File 1: Experimental and analytical data.
Format: PDF Size: 2.8 MB Download

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 Universities (No. 1107020522 and No. 1082020502). The Jiangsu 333 program (for Pan) and Changzhou Jin-Feng-Huang program (for Han) are also acknowledged.

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