Ruthenium-Catalyzed Highly Enantioselective Synthesis of cis-3-Quinuclidinols via DKR Asymmetric Transfer Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.0c01361

A method for the enantioselective synthesis of cis-3-quinuclidinols by Ru-catalyzed asymmetric transfer hydrogenation via dynamic kinetic resolution is described. The reaction proceeded under mild conditions using ammonium formate as the hydrogen donor, affording the products in high yields (up to 99%) with excellent diastereoselectivity (up to 99:1 dr) and enantioselectivity (95-99% ee). This protocol was applicable to gram-scale preparation with perfect enantioselectivity through simple recrystallization.

Full text of DOI:10.1021/acs.orglett.0c01361

pubs.acs.org/OrgLett
Letter
Ruthenium-Catalyzed Highly Enantioselective Synthesis of cis-3-
Quinuclidinols via DKR Asymmetric Transfer Hydrogenation
Zhonghua Luo,⊥ Zhongqing Wang,*,⊥ Guodong Sun, Weilin Jian, Fengkai Jiang, Baolei Luan, Ridong Li,
and Lei Zhang*
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ABSTRACT: A method for the enantioselective synthesis of cis-3-quinuclidinols by Ru-catalyzed asymmetric transfer
hydrogenation via dynamic kinetic resolution is described. The reaction proceeded under mild conditions using ammonium
formate as the hydrogen donor, affording the products in high yields (up to 99%) with excellent diastereoselectivity (up to 99:1 dr)
and enantioselectivity (95−99% ee). This protocol was applicable to gram-scale preparation with perfect enantioselectivity through
simple recrystallization.
hiral quinuclidines are important structural motifs
prevalently found in biologically active compounds and
methodologies toward (R)-3-quinuclidinol, limited reports are
available regarding the enantioselective synthesis of 2-
substituted quinuclidinols having two stereogenic centers.
Furthermore, asymmetric hydrogenation of bicyclic ketones is
challenging due to (1) the sterically congested and rigid [2.2.2]
cyclooctane skeleton and (2) the precise discrimination
between alkyl groups,7a which is consistent with the fact that
only a few successful examples have been reported.7 In 2010,
Ohkuma and co-workers reported the efficient asymmetric
hydrogenation (AH) of 3-quinuclidinones using a combined
catalyst system of RuCl2[(S)-binap][(R)-iphan] and t-BuOK,
which exhibited good diastereo- and enantioselectivity for 2-
diphenylmethyl-3-quinuclidinone, but only one example was
disclosed (Scheme 1a).7a Another report from a patent
described the enantioselective synthesis of 2-arylmethyl-3-
quinuclidinols with moderate enantioselectivities (85−93%
ee).7b Therefore, the development of a modular asymmetric
catalytic methodology for the preparation of a wide range of cis
quinuclidinols bearing different substituents at the 2-position is
still highly desirable.
C
natural products.1 In particular, optically active 3-quinuclidi-
nols constitute one of the common pharmacophoric elements
in drug discovery (Figure 1).2 Representative examples include
Figure 1. Selected biologically active compounds containing chiral
quinuclidine moieties.
Asymmetric transfer hydrogenation of ketones via DKR has
proved to be one of the most direct and reliable methods to
antimuscarinic agents, solifenacin2c and revatropate,2d which
were developed as potential treatments of chronic obstructive
pulmonary disease (COPD). Moreover, chiral 2-substituted-3-
quinuclidinols are also the key synthetic intermediates of a
variety of bioactive compounds.3
Received: April 20, 2020
Great efforts have been devoted to the pursuit of an efficient
synthetic route toward chiral quinuclidinols. These approaches
including asymmetric hydrogenation,4 enzymatic resolution,5
and biocatalytic reduction.6 Compared to the well-established
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A

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R)-C4,11 were screened with HCO2H/Et3N as hydrogen
donor (entries 1−4). Although quantitative conversions were
achieved in almost all cases, most of them afforded only low-
to-moderate enantioselectivities. An exception to this trans-
formation was (R,R)-C1, which provided good enantiocontrol;
however, low diastereoselectivity was also observed (entry 1).
It was shown that hydrogen donors played an important role in
the selectivity of transfer hydrogenation (entries 1 and 5). This
observation intrigued us to evaluate other hydrogen donors in
combination with different catalysts. Gratifyingly, a good
enantio- and diastereoselectivity was achieved using ammo-
nium formate as the hydrogen donor in the presence of (R,R)-
C3 (>20:1 dr, 94% ee entry 7). It should be noted that (R,R)-
C6 provided a good enantioselectivity, while the diastereose-
lectivity was poor (8:1 dr, 94% ee, entry 10).
Scheme 1. Asymmetric Catalytic Synthesis of 3-
Quinuclidinols
produce optically active alcohols.8,9 An ongoing interest in our
laboratory is the use of chiral diamine−Ru complexes as
catalysts for the construction of chiral compounds typically
found in pharmaceuticals.10 In light of this previous work, we
envisioned that the two contiguous stereogenic centers in
quinuclidinol could be established in one operation via DKR-
ATH. We herein report the successful efficient synthesis of cis-
3-quinuclidinols bearing diverse functionalized substituents at
the 2-position (Scheme 1b).
Subsequently, further condition optimization, including
solvent effect and catalyst loading, is summarized in Table 2.
a
Table 2. Further Optimization of Reaction Conditions
We set out to examine ATH of quinuclidinones using 1a as
the model substrate (Table 1). Initially, several commonly
used Ru−diamine complexes such as tethered Ru catalyst (R,
b
c
c
entry
S/C
solvent
DCM
EA
MeCN
IPA
MeOH/DCM
IPA/DCM
IPA/DCE
IPA/DCM
IPA/DCM
IPA/DCM
conv (%)
dr
ee (%)
1
2
3
4
5
6
7
8
50
50
50
50
50
50
50
100
200
500
trace
trace
87
>99
>99
>99
>99
>99
97
ND
ND
99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
ND
ND
95
Table 1. Screening of Catalysts and H-Source for ATH of 3-
a
Quinuclidinone 1a
98
97
>99
97
>99
98
d
9
d
10
95
96
a
Conditions: the reaction was performed with 1a (0.2 mmol),
HCO2NH4 (5.0 equiv), and catalyst (R, R)-C3 in 2.0 mL of solvent at
b
c
50 °C for 72 h. Determined by HPLC. Determined by chiral HPLC
d
using a CHIRALPAK IA column. The reaction was carried out on 70
°C. ND = not detected.
Extensive screening of solvents revealed their significant effect
on enantiocontrol. Isopropyl alcohol (IPA) provided a full
conversion and excellent enantioselectivity (98% ee, entry 4),
while aprotic solvents such as dichloromethane (DCM) and
ethyl acetate (EA) led to poor results (entries 1 and 2). The
best result was obtained using the mixture solvents of IPA/
DCM (v/v = 1:1) (>20:1, >99% ee, entry 8). Moreover,
lowering the catalyst loading of (R,R)-C3 resulted in slightly
decrease in enantioselectivities and conversions at 70 °C but
did not deteriorate the diastereomeric ratios (entries 9 and
10). In addition, equivalents of HCO2NH4 and reaction
temperature were also evaluated (see Tables S2 and S3 for
details). Therefore, the best result was generally obtained when
the reaction was catalyzed by (R,R)-C3 (1.0 mol %) using
HCO2NH4 as the hydrogen donor and IPA/DCM (v/v = 1:1)
as the solvent at 50 °C for 72 h.
b
c
c
entry
catalyst
H donor
conv (%)
dr
ee (%)
d
1
2
3
4
5
6
(R, R)-C1
(R, R)-C2
(R, R)-C3
(R, R)-C4
(R, R)-C1
(R, R)-C2
(R, R)-C3
(R, R)-C4
(R, R)-C5
(R, R)-C6
HCO2H/Et3N
HCO2H/Et3N
HCO2H/Et3N
HCO2H/Et3N
HCO2NH4
HCO2NH4
HCO2NH4
HCO2NH4
HCO2NH4
98
>99
>99
>99
>99
>99
>99
>99
>99
85
14:1
98:2
99:1
91
63
66
75
88
91
94
90
31
94
d
d
d
99:1
e
>99:1
>99:1
>99:1
>99:1
16:1
e
e
7
e
8
9
e
f
10
IPA/t-BuOK
8:1
a
General conditions: 1a (0.5 mmol), catalyst (2.0 mol %), and H-
donor in the solvent (20 mL) at 50 °C for 72 h. Determined by
HPLC. Determined by chiral HPLC using a Daicel Chiralpak IE
column. HCO2NH4 (5.0 equiv), MeOH used as a solvent.
HCO2H/Et3N (5:2, 1.6 mmol); DCM used as a solvent. H2 (5
MPa), t-BuOK in IPA (1 M, 0.1 equiv).
b
Under the optimal conditions, the scope of 2-arylmethyl-3-
quinuclidinones was examined (Scheme 2). In general, all of
the substrates (1a−s) could be successfully hydrogenated to
afford the desired products 2a−s in quantitative conversions
and with excellent diastereo- and enantioselectivities (up to
c
d
e
f
B
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Letter
a
Scheme 2. DKR-ATH of 3-Quinuclidinone 1a−s Catalyzed by (R, R)-C3
a
Reaction conditions: 1 (1.2 mmol), HCO2NH4 (6.0 mmol), (R, R)-C3 (1.0 mol %), IPA/DCM (20 mL, 1:1), at 50 °C for 72 h. Isolated yields ee
values and dr ratios were determined by chiral HPLC analysis of the crude reaction mixture.
99:1 dr and 99% ee). Neither the position nor electronic
properties of the substituents at the phenyl ring of the
substrates had an apparent effect on the reactivity and
selectivity. Notably, substrates with electron-withdrawing
substituents including the F, CF3 groups displayed relatively
lower enantioselectivity compared with those bearing electron-
donating substituents. For instance, the fluoro- or difluoro-
substituted substrates (1g, 1h, 1l) were hydrogenated with
96−97% ee, while the substrates bearing electron-donating
substituents Me, MeO (1b−d) provided >99% ee. Remark-
ably, heteroaromatic substrates, such as 1r and 1s, were also
compatible for this transformation to afford the products 2r
and 2s with 97% and >99% ee, respectively. Furthermore, 2-
diarylmethyl-3-quinuclidinones were also evaluated in the
optimized protocol. As shown in Scheme 3, all of the examined
substrates (1t−w) were reduced in almost full conversion with
excellent levels of diastereoselectivity (>99:1 dr) and
enantioselectivity (98−99% ee).
Scheme 3. DKR-ATH of 3-Quinuclidinone 1t−w Catalyzed
a
by (R, R)-C3
a
Reaction conditions: 1 (1.2 mmol), HCO2NH4 (6.0 mmol), (R,R)-
C3 (1.0 mol %), IPA/DCM (20 mL, 1:1), at 50 °C for 72 h. Isolated
yields ee values and dr ratios were determined by chiral HPLC
analysis of the crude reaction mixture.
Scheme 4. Gram-Scale Synthesis of 2a
With the general scope of the transformation established, we
sought to demonstrate the synthetic utility of this method-
ology. A gram-scale synthesis of 2a was performed with a
decreased catalyst loading (Scheme 4). The reaction
proceeded smoothly with quantitative conversion at 50 °C
over 72 h, affording the desired product 2a with >99% ee and
>99:1 dr without any decrease of enantioselectivity. The
C
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optically pure 2a could be further recrystallized from IPA/
hexane in 86% isolated yield.
https://pubs.acs.org/10.1021/acs.orglett.0c01361
In conclusion, we have developed a highly efficient method
for enantioselective synthesis of cis-3-quinuclidinols via Ru-
catalyzed DKR asymmetric transfer hydrogenation. The
products are efficiently accessed in good yields and excellent
diastereo- and enantioselectivities (up to 99:1 dr, 95−99% ee)
catalyzed by in-house developed Ru−diamine complexes using
ammonium formate as the hydrogen donor. This mild and
operationally simple method provides an alternative route to
cis 2-substituted-3-quinuclidinols and expands the scope for
asymmetric transfer hydrogenation of bicyclic ketones.
Furthermore, the practical utility of this method was
demonstrated by the efficient gram-scale asymmetric transfer
hydrogenation of 1a with perfect enantioselectivity through
simple recrystallization.
Author Contributions
⊥Z.L. and Z.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the State
Key Laboratory of Anti-Infective Drug Development (Sun-
shine Lake Pharma Co., Ltd), (N0. 2015DQ780357). We
thank Jiangzhong Zhong (HEC Pharm Co., Inc.) for NMR
assistance and Yanling Liu (HEC Pharm Co., Inc.) for HPLC
and optical rotation assistance.
REFERENCES
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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■
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AUTHOR INFORMATION
Corresponding Authors
■
Zhongqing Wang − State Key Laboratory of Anti-Infective Drug
Development, Sunshine Lake Pharma Co., Ltd., Dongguan
523871, P.R. China; Hunan Provincial Key Laboratory of
Xiangnan Rare-Precious Metals Compounds Research and
Application, Xiangnan University, Chenzhou 423000, China;
orcid.org/0000-0001-5194-4157;
Email: wangzhongqing@hec.cn
Lei Zhang − School of Biology and biological Engineering, South
China University of Technology, Guangzhou 510640, P.R.
China; orcid.org/0000-0002-0837-730X;
Hubner, H.; Gmeiner, P.; Heinrich, M. R. Regiospecific introduction
̈
Email: lzhangce@scut.edu.cn
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Authors
Zhonghua Luo − School of Biology and biological Engineering,
South China University of Technology, Guangzhou 510640,
P.R. China; State Key Laboratory of Anti-Infective Drug
Development, Sunshine Lake Pharma Co., Ltd., Dongguan
523871, P.R. China
Guodong Sun − State Key Laboratory of Anti-Infective Drug
Development, Sunshine Lake Pharma Co., Ltd., Dongguan
523871, P.R. China; orcid.org/0000-0003-3785-7641
Weilin Jian − State Key Laboratory of Anti-Infective Drug
Development, Sunshine Lake Pharma Co., Ltd., Dongguan
523871, P.R. China
Fengkai Jiang − State Key Laboratory of Anti-Infective Drug
Development, Sunshine Lake Pharma Co., Ltd., Dongguan
523871, P.R. China
Baolei Luan − State Key Laboratory of Anti-Infective Drug
Development, Sunshine Lake Pharma Co., Ltd., Dongguan
523871, P.R. China; orcid.org/0000-0003-1968-0942
Ridong Li − Institute of Systems Biomedicine, School of Basic
Medical Sciences, Peking University Health Science Center,
Beijing 100191, PR China
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