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

Article abstract of DOI:10.1055/s-0037-1610722

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 83percent 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.

Full text of DOI:10.1055/s-0037-1610722

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
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D. Chen et al.
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Rhodium-Catalyzed Asymmetric Addition of Arylboronic Acids to Gly-
oxylates: Access to Optically Active Substituted Mandelic Acid Esters
Diao Chena◊
Jian-Guo Liub◊
Xu Zhanga
Ph
O
S
Cl
COOMe
N
OH
O
Ph
N
H
H
OiPr
Ar
O
Ming-Hua Xu*a,b
0
0
0
0-0
0
0
2-
1
6
9
2-2
7
1
8
[Rh], ArB(OH)2
O
O
S
0.1 M KOH, 1,4-dioxane
40 °C
clopidogrel
a State Key Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences, 555 Zuchong-
zhi 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
15 examples
70–99% yield, up to 83% ee
xumh@sustech.edu.cn
◊ D.C. and J.G.L. contributed equally.
Published as part of the Cluster Organosulfur and Organoselenium Compounds in Catalysis
Received: 31.05.2019
Accepted after revision: 25.06.2019
Published online: 17.07.2019
lyzed asymmetric additions has received a great deal of
attention, with some significant successes. However, enan-
tioselective 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-dimeth-
yldinaphtho[1,2-f:2′,1′-d][1,3,2]dioxaphosphepin-4-amine)
[(R,R)-Me-BIPAM] catalyst for the synthesis of optically ac-
tive substituted mandelic acid esters with good to high en-
antioselectivity.8c
DOI: 10.1055/s-0037-1610722; Art ID: st-2019-w0296-c
Abstract A rhodium-catalyzed enantioselective addition of glyoxylates
to arylboronic acids promoted by a simple chiral sulfinamide-based ole-
fin ligand under mild reaction conditions is described. The reaction pro-
vides access to a variety of optically active substituted mandelic acid es-
ters 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
Over the past few years, we have been involved in the
design and synthesis of novel chiral olefin ligands for asym-
metric catalysis. Interestingly, chiral sulfur-based olefins
bearing simple molecular architectures showed highly
promising performance in many rhodium-catalyzed asym-
metric transformations9 and they proved to be elegant li-
gands, particularly in enantioselective additions to carbonyl
compounds10 and imines.11 In our previous work, we have
been succeeded in the asymmetric addition of arylboronic
acids to -keto esters,10a,b -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 ole-
fins might serve as effective ligands. Here, we describe our
development of a new catalytic system of this type that per-
mits the convenient preparation of optically active substi-
tuted mandelic acid esters with synthetically useful enanti-
oselectivities under mild conditions.
Optically active -hydroxy acid structural motifs are
ubiquitous in a large variety of biologically active com-
pounds, and they are often used as important intermediates
for pharmaceuticals.1 Due to their great importance in syn-
thetic and medicinal chemistry, considerable efforts have
been devoted to the asymmetric synthesis of chiral mandel-
ic acid derivatives in recent decades. Among these, the en-
zymatic2 or nonenzymatic3 asymmetric reduction of -aryl
keto esters has proven to be an efficient protocol. The
asymmetric intramolecular Cannizzaro reaction4 of -keto
aldehydes and the asymmetric resolution5 of racemic -hy-
droxy 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 reac-
tions6 or in asymmetric additions with aryl(trime-
thoxy)silanes.7 Nevertheless, nucleophilic substrates are
limited to electron-rich aromatic compounds or appropri-
ate organosilane reagents. In recent years, the use of orga-
noboron reagents, which are widely available from com-
mercial sources, as nucleophiles in transition-metal-cata-
We initially examined the rhodium-catalyzed 1,2-addi-
tion 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 pres-
ence of 1.5 mol% chlorobis(cyclooctene)rhodium dimer
{[Rh(COE)2Cl]2} (Scheme 1). To our delight, we found that
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
D. Chen et al.
Cluster
Synlett
the reaction proceeded smoothly and gave the desired
mandelic acid ester 3a in 72% yield with 70% ee. On the ba-
sis 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 en-
antiocontrol (70% ee). When branched SOLs L6 and L7 were
tested, a clear decrease in the enantioselectivity was ob-
served. To improve the enantioselectivity, we tried elabo-
rating 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 sulfinimine12 of cinnamaldehyde, a series of
chiral SOLs L8–14 with an additional carbon stereocenter
were prepared. Gratifyingly, in all cases the (S,Rs)-SOLs L8–
12 produced an obvious increase in enantioselectivity. SOLs
L11 and L12, bearing a tert-butyl or phenyl group, respec-
tively, 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 en-
antioselectivity and yield when (R,Rs)-SOLs L13 and L14
were employed.
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
2a
OH
*
O
Ph
O
S
[Rh(COE)2Cl]2/L12
OR
H
OR
Ph
N
0.1 M KOH, solvent
H
O
O
MeO
40 °C
1
L12
(50% in toluene)
Entry
R
Solvent
3
Yieldb (%)
eec (%)
1
Bn
iPr
tBu
iPr
iPr
iPr
iPr
iPr
iPr
THF
3b
3c
3d
3c
3c
3c
3c
3c
3c
95
90
84
65
73
92
89
45
20
78
80
80
60
73
81
81
80
80
2
THF
3
THF
4
toluene
CH2Cl2
5
6
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
7d
8e
9f
B(OH)2
[Rh(COE)2Cl]2/L
OH
O
H
O
O
+
*
THF, 0.1 M KOH
40 °C
O
O
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),
MeO
MeO
1a
40 °C, <5 h.
(50% in toluene)
2a
3a
b Isolated yield.
c Determined by chiral HPLC.
d At r.t.
O
O
e With 1.5 M KF at r.t.
f With 0.1 M K3PO4 at r.t.
R
S
S
N
N
R
H
H
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 vari-
ous positions of the phenyl ring were treated with isopro-
pyl glyoxylate. We were pleased to find that in most cases
the addition reactions proceeded smoothly to give the cor-
responding 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 enantioselectivi-
ty (Table 2, entries 4 and 8–10). The reaction was effective
with sterically hindered arylboronic acids, albeit with de-
creased ee values (entries 10–12). It is notable that the re-
action appeared to suffer from steric hinderance under rho-
dium catalysis in a previous study.8b The absolute configu-
ration of the newly generated carbon stereocenter of
product 3e was determined to be S by comparison of its op-
tical rotation with reported data.5a
L1 R = Ph 72% yield, 70% ee
L6 R = 1-naphthyl 70% yield, 45% ee
L7 R = 2-naphthyl 80% yield, 50% ee
L2 R = Bn 76% yield, 53% ee
L3 R = 4-F3CC6H4 81% yield, 61% ee
L4 R = 3,4-F2C6H3 90% yield, 69% ee
L5 R = 2-naphthyl 88% yield, 70% ee
R
O
S
R
O
S
(R)
(R)
Ph
N
H
Ph
N
H
(S)
(R)
L8 R = Me, 80% yield, 76% ee
L9 R = Bn, 60% yield, 77% ee
L10 R = iPr, 80% yield, 76% ee
L11 R = tBu, 80% yield, 80% ee
L12 R = Ph, 82% yield, 80% ee
L13 R = Me, 50% yield, 50% ee
L14 R = Bn, 40% yield, 57% ee
Scheme 1 Ligand screening
Next, the effect of the ester group in glyoxylate was in-
vestigated, following up on the results obtained with L12
(Table 1). The reactions of benzyl (Bn), isopropyl (iPr), or
tert-butyl (tBu) glyoxylate all proceeded smoothly in 0.1 M
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
D. Chen et al.
Cluster
Synlett
Table 2 Rh/L12-Catalyzed Asymmetric Arylation of Glyoxylates 1a
OH
Ph
O
S
O
[Rh(COE)2Cl]2 (1.5 mol%)
OiPr
L12 (3.3 mol%)
H
OiPr
Ar
Ph
N
Ph
O
S
H
ArB(OH)2
O
O
Ph
N
1,4-dioxane/KOH (0.1 M), 40 °C
H
1
L12
3
L12
Entry
Ar
4-MeOC6H4
Product
3c
Yieldb (%)
ee (%)c
1
92
99
90
71
98
81
90
70
95
77
71
89
75
96
99
81
80
81
55
70
83
78
60
72
70
60
69
72
72
75
2
Ph
3e
3f
3
4-Tol
Ph
Ph
4
4-ClC6H4
4-PhC6H4
3-MeOC6H4
3-Tol
3g
3h
3h
3i
5
NH
S
NH
S
O
O
6
O
H
Rh
O
Rh
H
O
HO
O
O
O
7
Ar
Ar
O
Ar
H
8
3-ClC6H4
3-FC6H4
3j
O
9
3k
3l
(S)-3
10
11
12
13
14
15
2-ClC6H4
1-naphthyl
2-naphthyl
3,4-(MeO)2C6H3
3,5-Me2C6H3
3,5-(MeO)2C6H3
Si-face (unfavorable)
Re-face (favorable)
3m
3n
3o
3p
3q
Figure 1 X-ray crystal structure of L12 and the proposed transition-
state model
SOL L16, giving 4a in 98% yield with 64% ee. The absolute
configuration at the stereogenic center of 4a was deter-
mined to be S by comparison of its optical rotation with
that of the known compound.15
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.
B(OH)2
HO
O
c Determined by chiral HPLC.
OEt
[Rh(COE)2Cl]2 (1.5 mol%)
OEt
+
L (3.3 mol%), KOH (0.1 M)
O
O
MeO
THF, 40 °C, 12 h
MeO
The stereochemistry of the sulfur olefin L12 was con-
4a
2a
firmed by X-ray analysis of a single crystal (Figure 1).14
A
plausible transition-state model of the reaction stereocon-
trol is proposed (Figure 1). Transmetalation of the arylbo-
ronic acid reagent leads to an arylrhodium species with a
favorable conformation in which the aryl group is posi-
tioned trans to the olefin and the tert-butyl moiety is stag-
gered. 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.
Enantioselective addition of similar ketone analogues
would be also of great interest, as the resulting -hydroxy
acid derivatives would contain a much more challenging
quaternary carbon stereocenter. We therefore conducted
the reaction of ethyl pyruvate with (4-methoxyphenyl)bo-
ronic 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
O
S
Ph
O
S
O
S
Ph
N
Ph
N
H
Ph
N
H
H
L12
54% yield 53%ee
L15
80% yield 53%ee
L16
98% yield 64%ee
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 ath-
erosclerotic vascular disease and cerebrovascular disease.
By using the (R,Ss)-SOL L12 as the ligand, the desired addi-
tion product (R)-3l was obtained with 70% ee. Transesterifi-
cation of (R)-3l with methanol, followed by formation of
the 4-nitrobenzenesulfonate of the alcohol, gave the key in-
termediate 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 accom-
plished under the known conditions.16
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
D. Chen et al.
Cluster
Synlett
15987. (c) Sun, X.; Zhou, L.; Li, W.; Zhang, X. J. Org. Chem. 2008,
73, 1143. (d) Ramachandran, P. V.; Pitre, S.; Brown, H. C. J. Org.
Chem. 2002, 67, 5315. (e) Meng, Q.; Sun, Y.; Ratovelomanana-
Vidal, V.; Genêt, J. P.; Zhang, Z. J. Org. Chem. 2008, 73, 3842.
(f) Enders, D.; Stöckel, B. A.; Rembiak, A. Chem. Commun. 2014,
50, 4489. (g) Wu, W.; Zou, S.; Lin, L.; Ji, J.; Zhang, Y.; Ma, B.; Liu,
X.; Feng, X. Chem. Commun. 2017, 53, 3232. (h) Gu, G.; Yang, T.;
Lu, J.; Wen, J.; Dang, L.; Zhang, X. Org. Chem. Front. 2018, 5,
1209.
OH
Cl
Cl
ONs
COOMe
1. tBuNH2, MeOH
reflux
COOiPr
2. NsCl, Et3N
cat. DMAP, DCM
0 °C, 1 h
5
(R)-3l
68% yield, 69% ee
96% ee after crystallization
Ns = 4-O2NC6H4SO2
70% ee
Cl
N
COOMe
(4) (a) Ishihara, K.; Yano, T.; Fushimi, M. J. Fluorine Chem. 2008, 129,
994. (b) Russell, A. E.; Miller, S. P.; Morken, J. P. J. Org. Chem.
2000, 65, 8381. (c) Schmitt, E.; Schiffers, I.; Bolm, C. Tetrahedron
Lett. 2009, 50, 3185. (d) Wang, P.; Tao, W.-J.; Sun, X.-L.; Liao, S.;
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Zhang, Y.; Ji, J.; Huang, T.; Lin, L.; Feng, X. Chem. Commun. 2015,
51, 11646.
2
S
N
acetone, 20 °C
ref. 16
S
clopidogrel
Scheme 3 Application to the asymmetric synthesis of clopidogrel
(5) (a) Zhang, Y.; Liu, X.; Zhou, L.; Wu, W.; Huang, T.; Liao, Y.; Lin,
L.; Feng, X. Chem. Eur. J. 2014, 20, 15884. (b) Tang, L.; Deng, L. J.
Am. Chem. Soc. 2002, 124, 2870. (c) Sakakura, A.; Umemura, S.;
Ishihara, K. Synlett 2009, 1647. (d) Ebbers, E. J.; Ariaans, G. J. A.;
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In summary, we have developed a novel rhodium-cata-
lyzed enantioselective addition of arylboronic acids to gly-
oxylate esters by employing simple chiral sulfinamide ole-
fins as ligands. The reaction proceeds under mild condi-
tions, affording a range of optically active substituted
mandelic acid esters with up to 83% ee.17,18 The catalyst sys-
tem is also applicable to pyruvate addition for the synthesis
of chiral quaternary carbon-containing -hydroxy esters.
Furthermore, the application of this method to the asym-
metric synthesis of antiplatelet drug clopidogrel is show-
cased.
Funding Information
(7) Aikawa, K.; Hioki, Y.; Mikami, K. Chem. Asian J. 2010, 5, 2346.
(8) (a) Marques, C. S.; Burke, A. J. Tetrahedron: Asymmetry 2013, 24,
628. (b) Marques, C. S.; Dindaroğlu, M.; Schmalz, H.-G.; Burke,
A. J. RSC Adv. 2014, 4, 6035. (c) Yamamoto, Y.; Shirai, T.;
Miyaura, N. Chem. Commun. 2012, 48, 2803.
The National Science & Technology Major Project (2018ZX09711002-
006), National Natural Science Foundation of China (81521005,
21472205, 21325209)
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(9) (a) Feng, X.; Du, H. Asian J. Org. Chem. 2012, 1, 204. (b) Li, Y.; Xu,
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73.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610722.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
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gInformati
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References and Notes
(1) (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz,
A.; Yamamoto, H., Ed.; Springer: Berlin, 1999. (b) Coppola, G.
M.; Schuster, F. H. -Hydroxy Acids in Enantioselective Syntheses;
VCH: Weinheim, 1997. (c) Juan, Y.-P.; Tsai, T.-H. J. Chromatogr. A
2005, 1088, 146. (d) Hill, J. C.; White, R. H.; Barratt, M. D.;
Mignini, E. J. Appl. Cosmetol. 1988, 6, 53. (e) Funke, A. B. H.;
Ernsting, M. J. E.; Rekker, R. F.; Nauta, W. T. Arzneim.-Forsch.
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Dünkelmann, P. Chem. Ing. Tech. 2006, 78, 249.
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E
D. Chen et al.
Cluster
Synlett
(15) Blay, G.; Fernández, I.; Marco-Aleixandre, A.; Pedro, J. R. Org.
Lett. 2006, 8, 1287.
(18) Isopropyl (2S)-(3,4-Dimethoxyphenyl)(hydroxy)acetate (3o)
White solid; yield: 38.1 mg (75%, 72% ee). 1H NMR (400 MHz,
CDCl3):  = 7.01–6.90 (m, 2 H), 6.84 (d, J = 8.2 Hz, 1 H), 5.07 (m, 2
H), 3.88 (d, J = 1.2 Hz, 6 H), 3.54 (s, 1 H), 1.28 (d, J = 6.2 Hz, 3 H),
1.13 (d, J = 6.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3):  = 173.4,
149.1, 149.0, 131.2, 119.1, 111.0, 109.4, 72.7, 70.1, 55.9, 55.9,
21.8, 21.5.
(16) Castaldi, G.; Barreca, G.; Bologna, A. WO 03093276, 2003.
(17) Isopropyl Aryl(hydroxy)acetates 3a–q; General Procedure
Under an Ar atmosphere, a solution of the appropriate glyoxyl-
ate 1 (0.2 mmol), [Rh(COE)2Cl]2 (1.5 mol%), L12 (3.3 mol%), and
arylboronic acid (0.4 mmol) in 1,4-dioxane (2 mL) was stirred at
r.t. for 30 min. 0.1 M aq KOH (0.1 mL, 0.01 mmol) was then
added and the resulting mixture was stirred 40 °C for 5 h until
the starting materials disappeared (TLC). The solvent was evap-
orated under vacuum and the residue was purified by column
chromatography (silica gel).
Isopropyl (2S)-(3,5-Dimethoxyphenyl)(hydroxy)acetate (3q)
White solid; yield: 50.3 mg (99%, 75% ee). 1H NMR (400 MHz,
CDCl3):  = 7.01–6.90 (m, 2 H), 6.84 (d, J = 8.2 Hz, 1 H), 5.07 (m, 2
H), 3.88 (s, 6 H), 3.54 (s, 1 H), 1.28 (d, J = 6.2 Hz, 3 H), 1.13 (d, J =
6.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 173.1, 160.9, 140.9,
104.4, 100.6, 73.0, 70.3, 55.4, 21.8, 21.5.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E