Iridium-Catalyzed Asymmetric Hydrogenation of ?- A nd ?-Ketoacids for Enantioselective Synthesis of ?- A nd ?-Lactones

Article abstract of DOI:10.1021/acs.orglett.9b04253

A highly efficient asymmetric hydrogenation of ?- A nd ?-ketoacids was developed by using a chiral spiro iridium catalyst (S)-1a, affording the optically active ?- A nd ?-hydroxy acids/lactones in high yields with excellent enantioselectivities (up to >99% ee) and turnover numbers (TON up to 100000). This protocol provides an efficient and practical method for enantioselective synthesis of Ezetimibe.

Full text of DOI:10.1021/acs.orglett.9b04253

pubs.acs.org/OrgLett
Letter
Iridium-Catalyzed Asymmetric Hydrogenation of γ- and δ‑Ketoacids
for Enantioselective Synthesis of γ- and δ‑Lactones
Yun-Yu Hua,§ Huai-Yu Bin,§ Tao Wei, Hou-An Cheng, Zu-Peng Lin, Xing-Feng Fu, Yuan-Qiang Li,
Jian-Hua Xie,* Pu-Cha Yan,* and Qi-Lin Zhou
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ABSTRACT: A highly efficient asymmetric hydrogenation of γ- and δ-ketoacids was developed by using a chiral spiro iridium
catalyst (S)-1a, affording the optically active γ- and δ-hydroxy acids/lactones in high yields with excellent enantioselectivities (up to
>99% ee) and turnover numbers (TON up to 100000). This protocol provides an efficient and practical method for enantioselective
synthesis of Ezetimibe.
ptically active γ- and δ-hydroxy acids, esters, and
lactones are very important chiral building blocks for
in the hundreds of gram scale preparation of the key chiral
intermediate of Ezetimibe, which is a chiral drug for the
treatment of hypercholesterolemia.8
O
the syntheses of chiral drugs, natural products, and compounds
that exhibit significant biological activities.1 Therefore, there is
a growing interest in the development of efficient methods for
their enantioselective synthesis in both academic and industrial
laboratories. The reported methods include asymmetric
hydroboration,2 hydrosilylation,3 hydrogenation, and transfer
hydrogenation4 of the corresponding γ- and δ-ketoacids and
ketoesters, asymmetric hydroacylation of 1,4- and 1,5-
ketoalcohols,5 and the asymmetric addition of metal reagents
to aldehydes.6 Among them, transition-metal-catalyzed asym-
metric hydrogenation of the corresponding ketoacids and
ketoesters is undoubtedly one of the most promising and
practical methods for the synthesis of such chiral compounds.
However, the efficiencies of the reported catalysts are far from
what is required for practical needs. Recently, Zhang et al.
reported a chiral Ru-RuPHOX catalyst, which is highly efficient
for the asymmetric hydrogenation of γ-aryl γ-ketoacids,
providing chiral γ-lactones in excellent enantioselectivity (up
to 97% ee) with high turnover numbers (TON up to 10 000).7
Herein, we report an iridium-catalyzed asymmetric hydro-
genation of δ- and γ-ketoacids, affording optically active γ- and
δ-lactones in excellent enantioselectivities (up to >99% ee)
with very high turnover numbers (TON up to 100 000).
Notably, this highly efficient method was successfully applied
Chiral iridium complexes of tridentate spiro pyridine-
aminophosphine ligands SpiroPAP have been demonstrated
to be extremely efficient catalysts for the asymmetric
hydrogenation of ketones and ketoesters,9 and they have
been successfully applied in the industrial preparation of chiral
drugs such as Rivastigmine, Crizotinib, and Montelukast
sodium, and natural products.10 In a study on the asymmetric
hydrogenation of γ- and δ-ketoesters, we found that the chiral
spiro iridium catalysts Ir-SpiroPAP can completely or partially
converted the ester group of the substrates to primary alcohols
(see Scheme 1a).11 The ester was hydrogenated via a lactone
intermediate, which is formed in situ from the keto
hydrogenation products by an intramolecular transesterifica-
tion. Thus, we envisioned if we can synthesize optically active
γ- and δ-lactones via asymmetric hydrogenation of γ- and δ-
ketoacids. Because the hydrogenation products, γ- and δ-
hydroxylacids, are difficult to form lactones under basic
Received: November 26, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04253
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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Letter
and 4). The hydrogenation reaction also can be performed in
methanol, giving a full conversion and 90% ee (Table 1, entry
5). While in isopropanol the conversion of reaction is low (see
Table 1, entry 6, 48%, 92% ee). Using NaOtBu, KOH, and
NaOH as the base gave comparable enantioselectivity, albeit
the conversion of reaction was reduced slightly (Table 1,
entries 7−9), but no hydrogenation occurred by employing
weak base K2CO3 (Table 1, entry 10). Screening of the
catalysts revealed that the catalyst (S)-1a having a 3-methyl
group on the pyridine ring gave the best results (see Table 1,
entries 3 and 11−13). The catalyst loading can be reduced to
0.02 mol % (S/C = 5000), affording a complete reaction within
3 h and high enantioselectivity (>99% ee; see Table 1, entry
14). When the catalyst loading was reduced to 0.01 mol % (S/
C = 10 000), the hydrogenation requires higher hydrogen
pressure and longer reaction time (15 atm, 12 h, entry 15).
Under the optimal reaction conditions, a wide range of δ-
aryl-δ-ketoacids 2a−2k were hydrogenated, and the results are
shown in Table 2. The electron property and the position of
the substituent at the phenyl ring of substrates 2a−2k have no
significant effect on both yield and enantioselectivity of the
reaction. The hydrogenations completed within 2 h and the
enantioselectivities were between 96% and >99.9% ee. In
addition, we also studied the hydrogenation of γ-aryl-γ-
ketoacids 2l−2p under the same reaction conditions. The
reactions were completed within 2 h and provided the
hydrogenation products 4l−4p in 90%−98% yield with 98%
ee. Note that the hydrogenation product (R)-4p is a key
intermediate for the synthesis of sertraline,1a which is a chiral
drug widely used for the treatment of depression and anxiety-
related disorders. We also tested γ/δ-alkyl substituted γ/δ-
ketoacids such as 2q and 2r with a methyl group, but low to
moderate enantioselectivities were observed (Table 2, entries
17 and 18). In addition, the asymmetric hydrogenation of γ/δ-
aryl substituted γ/δ-keto-amides, such as 5a and 5b, performed
Scheme 1. Asymmetric Hydrogenation of δ-Ketoesters and
γ- or δ-Ketoacids with Ir-SpiroPAP
reaction conditions, the hydrogenation of acid group of
substrates can be avoided. The γ- and δ-lactones were obtained
by acidifying γ- and δ-hydroxylacids (Scheme 1b).
We initially performed the hydrogenation of δ-ketoacid 2a
under the following conditions: 1 equiv KOtBu (ratio of base
to substrate, B/S = 1) and 0.1 mol % catalyst Ir-SpiroPAP
((S)-1a) in ethanol at room temperature and 10 atm of H2.
Only a trace amount of hydrogenation product 3a was
obtained after 2 h (Table 1, entry 1). An investigation on the
effect of the amount of base to the reaction showed that a
slight excess of base (B/S = 1.1) was required for complete
conversion of 2a (Table 1, entry 2). The enantiomeric excess
(ee) of the hydrogenation product 3a was analyzed after
converting to lactone 4a by treatment with trifluoroacetic acid
(94% ee). Further increasing the amount of KOtBu to B/S 1.2
and 1.4, the ee value of the product 4a was increased to >99%
ee with no effect on the rate of the reaction (Table 1, entries 3
a
Table 1. Asymmetric Hydrogenation of 5-Oxo-5-phenylpentanoic acid (2a). Optimizing the Reaction Conditions
b
c
d
entry
(S)-1
base
B/S
solvent
time (h)
conversion (%)
enantiomeric excess, ee (%)
e
1
2
3
4
5
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1a
1a
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
KOH
NaOH
K2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
1.0
1.1
1.2
1.4
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
EtOH
EtOH
EtOH
EtOH
MeOH
iPrOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
2
2
2
2
2
trace
100
100
100
100
48
ND
94
>99
>99
90
6
2
92
7
8
9
3
3
3
3
2
3
2
3
95
97
87
0
100
100
100
100
100
99
99
99
ND
98
99
97
>99
>99
e
10
11
12
13
14
15
f
g
12
a
Reaction conditions, unless otherwise noted: 1.0 mmol scale, (S)-1 (0.1 mol %, S/C = 1000), solvent (3.0 mL), room temperature (25−30 °C),
b
c
d
1
10 atm H2. B/S = base/substrate. Determined by H NMR spectroscopy. Determined by HPLC analysis on a Chiralcel AD-H column of the
corresponding lactone (R)-4a, the absolute configuration was determined by comparison the optical rotation with literature values. ND = not
determined. 0.02 mol % of (S)-1a. 0.01 mol % of (S)-1a, 15 atm H2.
e
f
g
B
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Table 2. Asymmetric Hydrogenation of γ/δ-Ketoacids 2
with (S)-1a
Scheme 3. Enantioselective Synthesis of the Key
Intermediate of Ezetimibe
a
b
yield
(%)
enantiomeric
excess, ee (%)
c
entry
2
R
n
4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
C6H5
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
93
88
90
90
90
92
93
90
94
89
83
98
96
95
90
93
87
89
>99.9 (R)
98 (+)
96 (R)
99.6 (R)
99.5 (+)
99.4 (R)
99 (R)
99 (+)
>99.9 (+)
96 (+)
98 (+)
98 (R)
98 (R)
98 (R)
98 (+)
98 (R)
56 (R)
9 (R)
4-Me-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
3-Me-C6H4
3-MeO-C6H4
3-Cl-C6H4
2-Me-C6H4
2-MeO-C6H4
2-Cl-C6H4
C6H5
4-Me-C6H4
4−Br-C6H4
2-Cl-C6H4
3,4-(Cl)2-C6H3
Me
followed by reaction with TBSCl and hydrolysis with aqueous
NaOH solution. Activation of the acid (S)-7 with pivaloyl
chloride and subsequently coupling with (S)-4-phenyloxazoli-
din-2-one ((S)-8) yielded (S,S)-9 in 75% overall yield. The
compound (S,S)-9 can be easily converted to Ezetimibe by
using a three step procedure according to the literature.13c
Thus, an efficient and practical method for the enantioselective
preparation of Ezetimibe was developed.
In conclusion, we have developed an efficient method for
enantioselective synthesis of optically active γ/δ-hydroxy
acids/lactones. By using a chiral spiro iridium catlyst (S)-1a,
a wide range of γ/δ-aryl substituted γ/δ-ketoacids were
hydrogenated to γ/δ-hydroxy acids/lactones in high TONs
(up to 100 000) and excellent enantioselectivity (up to >99.9%
ee). With this protocol, we developed an efficient and practical
route for enantioselective preparation of the chiral drug
Ezetimibe.
Me
a
Reaction conditions were the same as those listed in Table 1, entry 3.
b
c
Isolated yield. Determined by HPLC, SFC or GC analysis on a
Chiralcel column after converting to lactone 4. The absolute
configurations were determined by comparing the optical rotations
with literature values.
very well and provided the corresponding products (R)-6a and
(R)-6b in high yields with 97% ee and 99% ee, respectively
(see Scheme 2).
Scheme 2. Asymmetric Hydrogenation of γ/δ-Aryl γ/δ-
Ketoamides 5 with (S)-1a
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04253.
Synthesis and characterization of detailed experimental
procedures (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
With this highly efficient method in hand, we then tried to
apply it for the preparation of the chiral drug Ezetimibe, which
is the first lipid-lowering drug that inhibits intestinal uptake of
dietary and biliary cholesterol without affecting the absorption
of fatsoluble nutrients.12 Usually, Ezetimibe is synthesized via
construction of the azetidinone ring, followed by installation of
the chiral benzylic hydroxyl moiety. Only a few methods
constructed the chiral benzylic hydroxyl at the side chain first,
which is a more convergent enantioselective approach to
Ezetimibe.13 Our synthetic route started from the hydro-
genation of ketoacid 2c (see Scheme 3). The hydrogenation of
2c with 0.001 mol % (S/C = 100 000) of catalyst (R)-1a at a
21 kg scale in a 500 L autoclave under 25 atm of H2 at 50 °C
for 24 h afforded the hydroxy acid (S)-3c in 91% yield with
99.5% ee. After completion of the reaction, the solvent EtOH
was recycled by distillation under reduced pressure. Then,
selected protection of the hydroxyl group of (S)-3c was
achieved by esterification with EtOH in the presence of HCl,
Jian-Hua Xie − Nankai University, Tianjin, People’s
Republic of China; orcid.org/0000-0003-3907-2530;
Email: jhxie@nankai.edu.cn
Pu-Cha Yan − Zhejiang Raybow Pharmaceutical Co., Ltd.,
Taizhou City, People’s Republic of China; orcid.org/
0000-0002-6670-7629; Email: pucha.yan@
jiuzhoupharma.com
Other Authors
Yun-Yu Hua − Zhejiang Raybow Pharmaceutical Co.,
Ltd., Taizhou City, People’s Republic of China
Huai-Yu Bin − Nankai University, Tianjin, People’s
Republic of China
Tao Wei − Nankai University, Tianjin, People’s Republic
of China
C
https://dx.doi.org/10.1021/acs.orglett.9b04253
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Letter
(b) Lipshutz, B. H.; Lower, A.; Kucejko, R. J.; Noson, K. Applications
of Asymmetric Hydrosilylations Mediated by Catalytic (DTBM-
SEGPHOS)CuH. Org. Lett. 2006, 8, 2969−2972.
Hou-An Cheng − Zhejiang Raybow Pharmaceutical Co.,
Ltd., Taizhou City, People’s Republic of China
Zu-Peng Lin − Zhejiang Raybow Pharmaceutical Co.,
Ltd., Taizhou City, People’s Republic of China
Xing-Feng Fu − Zhejiang Raybow Pharmaceutical Co.,
Ltd., Taizhou City, People’s Republic of China
Yuan-Qiang Li − Zhejiang Raybow Pharmaceutical Co.,
Ltd., Taizhou City, People’s Republic of China
(4) For selected papers for asymmetric hydrogenation and transfer
hydrogenation of γ/δ-ketoacids and ketoesters, see: (a) Li, Y.; Izumi,
T. Asymmetric Synthesis of Chiral δ-Lactones Using BINAP-
ruthenium(II) Complexes Hydrogenation Catalysts. J. Chem. Res.
2002, 2002, 567−569. (b) Starodubtseva, E. V.; Turova, O. V.;
Vinogradov, M. G.; Gorshkova, L. S.; Ferapontov, V. A.; Struchkova,
M. I. A Convenient Route to Chiral γ-Lactones via Asymmetric
Hydrogenation of γ-Ketoesters Using the RuCl3−BINAP−HCl
Catalytic System. Tetrahedron 2008, 64, 11713−11717. (c) Arai,
N.; Namba, T.; Kawaguchi, K.; Matsumoto, Y.; Ohkuma, T.
Chemoselectivity Control in the Asymmetric Hydrogenation of γ-
and δ-Keto Esters into Hydroxy Esters or Diols. Angew. Chem., Int. Ed.
2018, 57, 1386−1389. (d) Li, J.; Lin, Z.; Huang, Q.; Wang, Q.; Tang,
L.; Zhu, J.; Deng, J. Asymmetric Transfer Hydrogenation of Aryl
Ketoesters with Chiral Double-chain Surfactant-type Catalyst in
Water. Green Chem. 2017, 19, 5367−5370.
Qi-Lin Zhou − Nankai University, Tianjin, People’s
Republic of China; orcid.org/0000-0002-4700-3765
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04253
Author Contributions
§These authors contributed equally to this work.
Notes
(5) Murphy, S. K.; Dong, V. M. Enantioselective Ketone
Hydroacylation Using Noyori’s Transfer Hydrogenation Catalyst. J.
Am. Chem. Soc. 2013, 135, 5553−5556.
(6) Weber, B.; Seebach, D. Ti-TADDOLate-Catalyzed, Highly
Enantioselective Addition of Alkyl- and Aryl-Titanium Derivatives to
Aldehydes. Tetrahedron 1994, 50, 7473−7484.
(7) Li, J.; Ma, Y.; Lu, Y.; Liu, Y.; Liu, D.; Zhang, W. Synthesis of
Enantiopure γ-Lactones via a RuPHOX-Ru Catalyzed Asymmetric
Hydrogenation of γ-Keto Acids. Adv. Synth. Catal. 2019, 361, 1146−
1153.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21532003,
21871152, and 21790332), and the “111” Project (No.
B06005) of the Ministry of Education of China.
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