Download PDF
Synlett 2019; 30(14): 1693-1697
DOI: 10.1055/s-0037-1610722
cluster
© Georg Thieme Verlag Stuttgart · New York

Rhodium-Catalyzed Asymmetric Addition of Arylboronic Acids to Glyoxylates: Access to Optically Active Substituted Mandelic Acid Esters

Diao Chen
a   State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. of China
,
Jian-Guo Liu
b   Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, 1088 Xueyuan Blvd., Shenzhen 518055, P. R. of China   Email: xumh@sustech.edu.cn
,
Xu Zhang
a   State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. of China
,
Ming-Hua Xu  ∗
a   State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. of China
b   Shenzhen Grubbs Institute and Department of Chemistry, Southern University of Science and Technology, 1088 Xueyuan Blvd., Shenzhen 518055, P. R. of China   Email: xumh@sustech.edu.cn
› Author Affiliations

The National Science & Technology Major Project (2018ZX09711002-006), National Natural Science Foundation of China (81521005, 21472205, 21325209)
Further Information

Publication History

Received: 31 May 2019

Accepted after revision: 25 June 2019

Publication Date:
17 July 2019 (online)

 
 PDF Download Permissions and Reprints All articles of this category


◊ D.C. and J.G.L. contributed equally.Published as part of the Cluster Organosulfur and Organoselenium Compounds in Catalysis

Abstract

A rhodium-catalyzed enantioselective addition of glyoxylates to arylboronic acids promoted by a simple chiral sulfinamide-based olefin ligand under mild reaction conditions is described. The reaction provides access to a variety of optically active substituted mandelic acid esters in good yields with up to 83% ee. The catalytic system is also applicable to pyruvate addition. The synthetic utility of this method is highlighted by a formal synthesis of the antiplatelet drug clopidogrel.


#

Key words

asymmetric catalysis - rhodium catalysis - ligands - mandelic acid esters - glyoxylate - arylboronic acids

Optically active α-hydroxy acid structural motifs are ubiquitous in a large variety of biologically active compounds, and they are often used as important intermediates for pharmaceuticals.[1] Due to their great importance in synthetic and medicinal chemistry, considerable efforts have been devoted to the asymmetric synthesis of chiral mandelic acid derivatives in recent decades. Among these, the enzymatic[2] or nonenzymatic[3] asymmetric reduction of α-aryl keto esters has proven to be an efficient protocol. The asymmetric intramolecular Cannizzaro reaction[4] of α-keto aldehydes and the asymmetric resolution[5] of racemic α-hydroxy acids also afford chiral mandelic acids with medium to good enantioselectivities. In addition, the asymmetric addition of carbon nucleophiles to glyoxylates represents another efficient protocol. Excellent enantioselectivities can be achieved in some asymmetric Friedel–Crafts reactions[6] or in asymmetric additions with aryl(trimethoxy)silanes.[7] Nevertheless, nucleophilic substrates are limited to electron-rich aromatic compounds or appropriate organosilane reagents. In recent years, the use of organoboron reagents, which are widely available from commercial sources, as nucleophiles in transition-metal-catalyzed asymmetric additions has received a great deal of attention, with some significant successes. However, enantioselective addition of glyoxylate to organoboron reagents still remains a challenging task, and there have been only three reports of this in the literature.[8] Notably, Yamamoto et al. reported a ruthenium-catalyzed asymmetric addition of arylboronic acids to tert-butyl glyoxylate by using a RuCl2(PPh3)3/(R,R)-2,2′-[oxydi(methylene)]bis(N,N-dimethyldinaphtho[1,2-f:2′,1′-d][1,3,2]dioxaphosphepin-4-amine) [(R,R)-Me-BIPAM] catalyst for the synthesis of optically active substituted mandelic acid esters with good to high enantioselectivity.[8c]

Over the past few years, we have been involved in the design and synthesis of novel chiral olefin ligands for asymmetric catalysis. Interestingly, chiral sulfur-based olefins bearing simple molecular architectures showed highly promising performance in many rhodium-catalyzed asymmetric transformations[9] and they proved to be elegant ligands, particularly in enantioselective additions to carbonyl compounds[10] and imines.[11] In our previous work, we have been succeeded in the asymmetric addition of arylboronic acids to α-keto esters,[10a] [b] α-diketones,[10c,e] and nonactivated ketones.[10d] Encouraged by these successes, and to address the difficulties in enantiocontrol of glyoxylate addition, we surmised that this newly emerging class of chiral sulfur olefins might serve as effective ligands. Here, we describe our development of a new catalytic system of this type that permits the convenient preparation of optically active substituted mandelic acid esters with synthetically useful enantioselectivities under mild conditions.

We initially examined the rhodium-catalyzed 1,2-addition of ethyl glyoxylate to (4-methoxyphenyl)boronic acid (2a) by using our previously developed linear sulfur olefin ligand (SOL) L1 in a 0.1 M aq KOH–THF at 40 °C in the presence of 1.5 mol% chlorobis(cyclooctene)rhodium dimer {[Rh(COE)2Cl]2} (Scheme [1]). To our delight, we found that the reaction proceeded smoothly and gave the desired mandelic acid ester 3a in 72% yield with 70% ee. On the basis of this promising result, we investigated a number of chiral SOLs L2–5 bearing various substituent groups (R) on the double bond. However, screening of these ligands gave no better results. Interestingly, the structurally simplest chiral N-(sulfinyl)cinnamylamine L1 exhibited the best enantiocontrol (70% ee). When branched SOLs L6 and L7 were tested, a clear decrease in the enantioselectivity was observed. To improve the enantioselectivity, we tried elaborating the structure of linear ligand L1 by introducing an additional substituent on the allylic site adjacent to the sulfinyl amide nitrogen. By taking advantage of Grignard addition to the sulfinimine[12] of cinnamaldehyde, a series of chiral SOLs L8–14 with an additional carbon stereocenter were prepared. Gratifyingly, in all cases the (S,R s)-SOLs L8–12 produced an obvious increase in enantioselectivity. SOLs L11 and L12, bearing a tert-butyl or phenyl group, respectively, showed markedly improved enantioselectivities (80% ee) and catalytic activity (82% yield). Notably, unlike the Rh(I)-catalyzed asymmetric 1,4-addition reactions,[13] the carbon stereochemistry of ligand significantly affected the activity and enantioselectivity, leading to a much lower enantioselectivity and yield when (R,R s)-SOLs L13 and L14 were employed.

Zoom Image
Scheme 1 Ligand screening

Next, the effect of the ester group in glyoxylate was investigated, following up on the results obtained with L12 (Table [1]). The reactions of benzyl (Bn), isopropyl ( i Pr), or tert-butyl ( t Bu) glyoxylate all proceeded smoothly in 0.1 M aq KOH–THF at 40 °C to give the corresponding products with nearly the same levels of enantioselectivity (~80% ee) (Table [1], entries 1–3). Solvent assessment using isopropyl glyoxylate as the substrate revealed that 1,4-dioxane gave a slightly higher yield and enantioselectivity (entries 4–6). Performing the reaction at room temperature did not give a better result (entry 7). Further exploration of additives such as KF and K3PO4 led to much lower yields (entries 8 and 9).

Table 1 Conditions Optimizationa

Entry

R

Solvent

3

Yieldb (%)

eec (%)

1

Bn

THF

3b

95

78

2

i Pr

THF

3c

90

80

3

t Bu

THF

3d

84

80

4

i Pr

toluene

3c

65

60

5

i Pr

CH2Cl2

3c

73

73

6

i Pr

1,4-dioxane

3c

92

81

7d

i Pr

1,4-dioxane

3c

89

81

8e

i Pr

1,4-dioxane

3c

45

80

9f

i Pr

1,4-dioxane

3c

20

80

a Reaction conditions: 1 (0.25 mmol), 2a (0.5 mmol), [Rh(COE)2Cl]2 (1.5 mol%), L12 (3.3 mol%), 0.1 M KOH (0.1 mL, 0.01 mmol) in solvent (2 mL), 40 °C, <5 h.

b Isolated yield.

c Determined by chiral HPLC.

d At r.t.

e With 1.5 M KF at r.t.

f With 0.1 M K3PO4 at r.t.

Having determined the optimal conditions, we turned our attention to an investigation of the scope of the reaction (Table [2]). A broad range of arylboronic acids bearing various electron-donating or electron-withdrawing groups at various positions of the phenyl ring were treated with isopropyl glyoxylate. We were pleased to find that in most cases the addition reactions proceeded smoothly to give the corresponding products in good to high yields with moderate to good enantioselectivities (55–83% ee). It appeared that electron-withdrawing substituents on the phenyl ring have a detrimental effect on both the yield and enantioselectivity (Table [2], entries 4 and 8–10). The reaction was effective with sterically hindered arylboronic acids, albeit with decreased ee values (entries 10–12). It is notable that the reaction appeared to suffer from steric hinderance under rhodium catalysis in a previous study.[8b] The absolute configuration of the newly generated carbon stereocenter of product 3e was determined to be S by comparison of its optical rotation with reported data.[5a]

Table 2 Rh/L12-Catalyzed Asymmetric Arylation of Glyoxylates 1 a

Entry

Ar

Product

Yieldb (%)

ee (%)c

1

4-MeOC6H4

3c

92

81

2

Ph

3e

99

80

3

4-Tol

3f

90

81

4

4-ClC6H4

3g

71

55

5

4-PhC6H4

3h

98

70

6

3-MeOC6H4

3h

81

83

7

3-Tol

3i

90

78

8

3-ClC6H4

3j

70

60

9

3-FC6H4

3k

95

72

10

2-ClC6H4

3l

77

70

11

1-naphthyl

3m

71

60

12

2-naphthyl

3n

89

69

13

3,4-(MeO)2C6H3

3o

75

72

14

3,5-Me2C6H3

3p

96

72

15

3,5-(MeO)2C6H3

3q

99

75

a Reaction conditions: glyoxylate 1 (0.2 mmol), arylboronic acid (0.4 mmol), 0.1 M KOH (0.1 mL, 0.01 mmol), [Rh(COE)2Cl]2 (1.5 mol%), L12 (3.3 mol%) in 1,4-dioxane (2 mL), stirring, 40 °C, 5–6 h.

b Isolated yield.

c Determined by chiral HPLC.

The stereochemistry of the sulfur olefin L12 was confirmed by X-ray analysis of a single crystal (Figure [1]).[14] A plausible transition-state model of the reaction stereocontrol is proposed (Figure [1]). Transmetalation of the arylboronic acid reagent leads to an arylrhodium species with a favorable conformation in which the aryl group is positioned trans to the olefin and the tert-butyl moiety is staggered. The phenyl substituent on the allylic chiral carbon has the same effect as the tert-butyl group of the sulfinyl moiety in blocking the rear side. The formyl moiety of the substrate coordinates to the rhodium in such a way that the ester is oriented away from the phenyl group attached to the double bond; thus, arylation of the glyoxylate ester takes place from the Re-face of the formyl group to give the S-product.

Zoom Image
Figure 1 X-ray crystal structure of L12 and the proposed transition-state model

Enantioselective addition of similar ketone analogues would be also of great interest, as the resulting α-hydroxy acid derivatives would contain a much more challenging quaternary carbon stereocenter. We therefore conducted the reaction of ethyl pyruvate with (4-methoxyphenyl)boronic acid under our standard conditions. In the presence of L12, the desired addition product 4a was obtained in 54% yield with 53% ee (Scheme [2]). Interestingly, the best result was obtained by using the 2-biphenyl-substituted chiral SOL L16, giving 4a in 98% yield with 64% ee. The absolute configuration at the stereogenic center of 4a was determined to be S by comparison of its optical rotation with that of the known compound.[15]

Zoom Image
Scheme 2 Asymmetric arylation of ethyl pyruvate

To demonstrate the synthetic utility of our method, we explored the synthesis of clopidogrel, an antiplatelet drug developed by Bristol-Myers Squibb for the treatment of atherosclerotic vascular disease and cerebrovascular disease. By using the (R,S s)-SOL L12 as the ligand, the desired addition product (R)-3l was obtained with 70% ee. Transesterification of (R)-3l with methanol, followed by formation of the 4-nitrobenzenesulfonate of the alcohol, gave the key intermediate 5 in 68% yield with 69% ee (Scheme [3]). Notably, the optical purity of 5 could be readily improved to 96% ee after one recrystallization from petroleum ether–EtOAc. Asymmetric synthesis of clopidogrel could then be accomplished under the known conditions.[16]

Zoom Image
Scheme 3 Application to the asymmetric synthesis of clopidogrel

In summary, we have developed a novel rhodium-catalyzed enantioselective addition of arylboronic acids to glyoxylate esters by employing simple chiral sulfinamide olefins as ligands. The reaction proceeds under mild conditions, affording a range of optically active substituted mandelic acid esters with up to 83% ee.[17] [18] The catalyst system is also applicable to pyruvate addition for the synthesis of chiral quaternary carbon-containing α-hydroxy esters. Furthermore, the application of this method to the asymmetric synthesis of antiplatelet drug clopidogrel is showcased.


#

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0037-1610722.
  • Supporting Information


   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 Ligand screening
Zoom Image
Figure 1 X-ray crystal structure of L12 and the proposed transition-state model
Zoom Image
Scheme 2 Asymmetric arylation of ethyl pyruvate
Zoom Image
Scheme 3 Application to the asymmetric synthesis of clopidogrel