Catalytic asymmetric hydrogenation of 3-ethoxycarbonyl quinolin-2-ones and coumarins

Article abstract of DOI:10.1021/acs.orglett.1c00993

A protocol of iridium catalyzed asymmetric hydrogenation of 4-alkyl substituted 3-ethoxycarbonyl quinolin-2-ones and coumarins has been reported, providing a wide range of chiral dihydroquinolin-2-ones and dihydrocoumarins in high yields with excellent enantioselectivities (up to 99% ee) and high turnover numbers (up to 28 000). This efficient protocol was successfully applied for the synthesis of MPR3160 and the key chiral intermediate of R-106578.

Full text of DOI:10.1021/acs.orglett.1c00993

pubs.acs.org/OrgLett
Letter
Catalytic Asymmetric Hydrogenation of 3‑Ethoxycarbonyl Quinolin-
2-ones and Coumarins
Qian-Kun Zhao, Xiong Wu, Fan Yang, Pu-Cha Yan,* Jian-Hua Xie,* and Qi-Lin Zhou
Cite This: Org. Lett. 2021, 23, 3593−3598
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A protocol of iridium catalyzed asymmetric hydro-
genation of 4-alkyl substituted 3-ethoxycarbonyl quinolin-2-ones
and coumarins has been reported, providing a wide range of chiral
dihydroquinolin-2-ones and dihydrocoumarins in high yields with
excellent enantioselectivities (up to 99% ee) and high turnover
numbers (up to 28 000). This efficient protocol was successfully
applied for the synthesis of MPR3160 and the key chiral
intermediate of R-106578.
Scheme 1. Asymmetric Hydrogenation of Quinolones and
Coumarins
hiral dihydroquinolin-2-ones and dihydrocoumarins are
C
common structural motifs in natural products and
pharmaceuticals.1 Typical and significant examples of these
chiral heterocyclic molecules are those having alkyl or aryl
substituents at the C4-position2 (Figure 1). In addition, these
Figure 1. Selected pharmaceuticals and natural products containing
chiral dihydroquinolin-2-one and dihydrocoumarin structures.
heterocyclic molecules are also important chiral building
blocks for the synthesis of pharmaceuticals and bioactive
natural products.3 As a consequence, the development of
efficient methods for the enantioselective syntheses of such
heterocyclic molecules has received much attention.4 Among
them, the asymmetric hydrogenation of coumarins catalyzed
by rhodium and ruthenium complexes of chiral diphosphine
ligands5 (Scheme 1a) and a biomimetic NAD(P)H analogue
(R)-FENAM in combination with achiral ruthenium catalyst6
(Scheme 1b) has been demonstrated to be one of the most
efficient ways of accomplishing the goal. However, the
substrates are limited to 4-aryl substituted coumarins and no
report has been published for the asymmetric hydrogenation of
Received: March 23, 2021
Published: April 19, 2021
https://doi.org/10.1021/acs.orglett.1c00993
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3593−3598
3593

Organic Letters
pubs.acs.org/OrgLett
Letter
quinolin-2-ones for the synthesis of chiral dihydroquinolin-2-
ones.7
Scheme 3. Asymmetric Hydrogenation of 3-Ethoxycarbonyl
Quinolinones 2 with Catalyst (R)-1b
a
We have recently found that chiral iridium complexes of
SpiroPAP ligands are extremely efficient catalysts for the
asymmetric hydrogenation of ketones8 and esters9 and were
also highly efficient for the asymmetric hydrogenation of
electron-deficient tetrasubstituted olefins.10 These interesting
results encouraged us to investigate the possibility of applying
chiral spiro iridium catalysts into the asymmetric hydro-
genation of quinolin-2-ones and coumarins. The results
showed that chiral spiro iridium catalysts (R)-1 could be
highly efficient for the hydrogenation of 4-substituted 3-
ethoxycarbonyl quinolin-2-ones and coumarins, providing the
corresponding chiral dihydroquinolin-2-ones and dihydrocou-
marins in high yields with excellent enantioselectivities
(Scheme 1c). Herein we report the results of asymmetric
hydrogenation of 4-substituted 3-ethoxycarbonyl quinolin-2-
ones and coumarins with Ir-SpiroPAP catalysts.
We initially selected 4-methyl 3-ethoxycarbonyl quinolin-2-
one 2a as a standard substrate to evaluate several catalysts in
the presence of tBuOK as base and toluene as a cosolvent11 in
EtOH under 50 atm of H2 at room temperature (Scheme 2).
Scheme 2. Evaluation of Chiral Catalysts for the
Asymmetric Hydrogenation of 2a
a
Reaction conditions: 1.0 mmol scale, (R)-1b/tBuOK/2 = 1:400:500,
EtOH (2.0 mL), toluene (0.5 mL), room temperature (25−30 °C),
50 atm of H2; isolated yields. The trans/cis ratio was determined from
the crude 1H NMR spectra, and the ee value was determined by chiral
b
c
d
HPLC analysis. 0.2 mol % (R)-1a. 0.4 mol % (R)-1b, 50 °C. 0.4
e
mol % (R)-1a. 0.4 mol % (R)-1a, 50 °C.
sluggish and less than 10% conversions were observed with
(R)-1b. Fortunately, by replacing (R)-1b with (R)-1a as the
catalyst and extending the reaction time to 48 h, a 53% yield
with 94% ee and 33% yield with 75% ee were observed for the
hydrogenation of 2h and 2i, respectively. Installing an electron-
withdrawing (2j) or electron-donating group (2k) has little
influence on the enantioselectivity (both 98% ee) while the
former achieved higher yields (3j−k). The substituent at the
nitrogen atom also has a noticeable effect on the reaction rate
and the enantioselectivity. When a methyl group at the
nitrogen atom of 2a (R = Me) was replaced by another alkyl
group such as ethyl (2l) and benzyl (2m), comparable results
were observed. However, when it was replaced by a phenyl
group such as 2n and 2o, very low conversions (<10%) were
observed with catalyst (R)-1b. Likewise, higher yields with
high enantioselectivities were obtained for the hydrogenation
of 2n (93% yield, 90%ee) and 2o (93% yield, 92% ee) with
(R)-1a, but a longer reaction time and higher catalyst loading
were required. The substrate 2p (R = H) with no substituent
at the nitrogen atom could also be hydrogenated with (R)-1b
at a higher reaction temperature (50 °C), providing 3p in 58%
yield with 83% ee.
We found that the hydrogenation could be completed within
24 h with (R)-1b as a catalyst, and the corresponding
hydrogenated product trans-3a was obtained in 95% yield with
99% ee in a ratio of 7:1. Comparable results were also achieved
with (R)-1a as a catalyst (90% yield and 93% ee), but with a
low yield and poor enantioselectivity (35% yield with 8% ee),
and no hydrogenation was observed with chiral ruthenium
catalyst RuCl2-(S)-Xyl-SDP/(R,R)-DPEN12 and chiral iridium
catalyst Ir-(S)-PHOX,13 respectively. It is worth noting that
the hydrogenation products were dominated by thermody-
namically preferred trans-3a and the ratio of trans- to cis-isomer
was determined by the thermodynamic stability constant
between the isomers because the new generated stereocenter at
C3 could be easily epimerized under a strong base condition.
Thus, we selected (R)-1b as the choice of catalyst and tested a
series of 3-ethoxycarbonyl quinolin-2-ones 2 under the same
reaction conditions.
As shown in Scheme 3, the 3-ethoxycarbonyl quinolin-2-
ones 2a−g with 4-alkyl substituents could be smoothly
hydrogenated to the corresponding chiral dihydroquinolin-2-
ones 3a−g in high yields (94−95%) with excellent
enantioselectivities (98−99% ee). By changing these less
hindered alkyl substituents into relatively bulky cyclopropyl
(2h) and phenyl (2i) groups, the reaction rates became very
These exciting results encouraged us to further explore the
asymmetric hydrogenation of 4-alkyl substituted 3-ethoxycar-
bonyl coumarins 4 (Scheme 4). Although high enantioselec-
tivity has been achieved by Zhou’s6 biomimetic asymmetric
reduction with NAD(P)H analogues based on chiral ferrocene
with hydrogen gas as the terminal reductant (Scheme 1b), low
3594
https://doi.org/10.1021/acs.orglett.1c00993
Org. Lett. 2021, 23, 3593−3598

Organic Letters
pubs.acs.org/OrgLett
Letter
nism15) to approach the catalyst (R)-1b.10b To minimize the
steric repulsion of the bulky group at the 3-position of the
pyridine ring and the rigid spiro backbone of the catalyst, the
substrate 4a tends to approach the catalyst in the direction of
the ester side close to the rigid spiro backbone (Figure 2).
Scheme 4. Asymmetric Hydrogenation of Chromen-2-ones
4 with Catalyst (R)-1m
a
Figure 2. Models of stereochemistry control for asymmetric
hydrogenations of 4a.
a
Reaction conditions: 1.0 mmol scale, (R)-1b/tBuOK/4 =
1:400:1000, EtOH (2.0 mL), room temperature (25−30 °C), 30
atm of H2; Isolated yield; The trans/cis ratio was determined from the
crude H NMR spectra, and the ee value was determined by chiral
HPLC analysis. 0.0033 mol % (R)-1b, 60 atm of H2 (initial). 0.2
1
Thus, TS-RR was favorable for 4a, leading to the formation of
(3R,4R)-5a. Since cis-product (3R,4R)-5a was prone to
epimerize to thermodynamically more stable trans-isomer
(3S,4R)-5a under basic conditions, a mixture of products
dominated by trans-isomer (3S,4R)-5a was finally observed.
The calculation result (98% ee) is in good agreement with the
experimental result (95% ee). Furthermore, based on these
transition state models we can also explain why low reactivity
and moderate enantioselectivity with “opposite” configuration
were observed for the hydrogenation of 4-aryl substituted
substrates such as 2i and 4o with (R)-1b. To avoid the larger
steric hindrance between the aryl group and the rigid spiro
backbone of the catalyst (R)-1b, TS-SS, instead of TS-RR,
became favorable, which led to the formation of hydrogenated
products such as 3i and 5o with (3S,4R) and (3R,4R)
configurations, respectively.
To exemplify the utility of these efficient asymmetric
hydrogenations, we performed the enantioselective synthesis
of a cholesterol acyltransferase (ACAT) inhibitor R-10657816
and a selected 5-HT1A receptor antagonist MPR316017
(Scheme 5). The asymmetric hydrogenation of 4k (6.4 g, 20
mmol) with (S)-1b (0.005 mol %, S/C = 20 000) under 60
atm of H2 at room temperature for 60 h provided (3R,4S)-5k
in 92% yield with 98% ee. The decarboxylation of (3R,4S)-5k,
followed by a hydrolytic opening of the lactone ring and a
subsequent methylation of the phenol, afforded the acid (S)-7,
a key intermediate for the synthesis of R-106578, in 68% yield
over two steps. The enantioselective synthesis of MPR3160
was initiated by the methylation of (3R,4R)-3o with methyl
iodide followed by hydrolysis in one pot to deliver an acid
(3S,4S)-8 in 91% yield. The acid (3S,4S)-8 was then converted
into MPR3160 via a Curtius rearrangement followed by the
reduction with borane. It is noteworthy that the absolute
configuration of 3o and 8 were assigned as (3R,4R) and
b
c
mol % (R)-1b.
yield and moderate enantioselectivity (69% ee) were observed
for the hydrogenation of 4-methyl 3-ethoxycarbonyl coumarin
(4a). Under the similar conditions with (R)-1b as the catalyst
(0.1 mol % (R)-1b and 30 atm of H2), we found that the
asymmetric hydrogenation of 4-alkyl substituted 3-ethoxycar-
bonyl chromen-2-ones 4a−k were completed within 2 h and
afforded the corresponding 3,4-dihydrocoumarins 5a−k in
high yields (up to 95%) and excellent enantioselectivities (up
to 98% ee). The coumarin substrates bearing a less sterically
hindered 4-alkyl group, such as methyl (4a), ethyl (4b), and n-
propyl (4c), gave a higher yield and enantioselectivity. Lower
yields and enantioselectivities were observed for the substrates
with a relatively bulkier 4-alkyl group, such as iPr (4e) and Cy
(4f). The ester (4i) and Boc-amino (4j) group in the
substrates were compatible in the reaction. The chromen-2-
ones 4l−n with a cyclopropyl group also afforded reduction
products 5l−n in high yields and excellent enantioselectivities
(96−97% ee), providing an efficient and potential approach to
chiral pharmaceuticals with a cyclopropyl substituted benzylic
stereocenter.14 The substrate with a 4-phenyl group (4o) could
also be hydrogenated by catalyst (R)-1b, but with a lower
enantioselectivity (73% ee). Furthermore, a catalyst loading
experiment showed that the hydrogenation of 4a could be
performed at a very low catalyst loading (0.0033 mol % (R)-
1b, S/C = 30 000) at 60 atm of H2 pressure, providing
(3S,4R)-5a in 92% yield (TON = 28 000) and 94% ee.
We selected coumarin 4a as a model substrate and
performed DFT calculations to understand the origins of the
stereochemistry of reaction. The substrate 4a was through a
six-membered-ring transition state (outer-sphere mecha-
3595
https://doi.org/10.1021/acs.orglett.1c00993
Org. Lett. 2021, 23, 3593−3598

Organic Letters
pubs.acs.org/OrgLett
Letter
Authors
Scheme 5. Enantioselective Synthesis of R-106578 and
MPR3160
Qian-Kun Zhao − State Key Laboratory and Institute of
Elemento-organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Xiong Wu − State Key Laboratory and Institute of Elemento-
organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Fan Yang − State Key Laboratory and Institute of Elemento-
organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Qi-Lin Zhou − State Key Laboratory and Institute of
Elemento-organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0002-4700-3765
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00993
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21871152, 92056105 and 21790332) and the “111”
project (B06005) of the Ministry of Education of China and
the Fundamental Research Funds for the Central Universities
(Nankai University, 020-63191746) for financial support.
(3S,4S), respectively, by X-ray diffraction analysis of the crystal
structure of acid 8.
In conclusion, we have developed an efficient catalytic
asymmetric hydrogenation of 3-ethoxycarbonyl quinolin-2-
ones and coumarins. With chiral spiro iridium catalyst (R)-1b,
a wide range of 4-alkyl substituted 3-ethoxycarbonyl quinolin-
2-ones and coumarins were hydrogenated to chiral dihydro-
quinolin-2-ones and dihydrocoumarins in high yields with
excellent enantioselectivities (up to 99% ee) and high turnover
numbers (up to 28 000). This protocol was successfully
applied for the enantioselective syntheses of MPR3160 and the
key chiral intermediate of R-106578.
REFERENCES
■
(1) For reviews, see: (a) Borges, F.; Roleira, F.; Milhazes, N.;
Santana, L.; Uriarte, E. Simple Coumarins and Analogues in
Medicinal Chemistry: Occurrence, Synthesis and Biological Activity.
Curr. Med. Chem. 2005, 12, 887. (b) Musa, M. A.; Cooperwood, J. S.;
Khan, M. A. F. A Review of Coumarin Derivatives in Pharmacother-
apy of Breast Cancer. Curr. Med. Chem. 2008, 15, 2664. (c) Sridharan,
V.; Suryavanshi, P. A.; Menendez, J. C. Advances in the Chemistry of
Tetrahydroquinolines. Chem. Rev. 2011, 111, 7157.
(2) (a) Seo, E. K.; Wani, M. C.; Wall, M. E.; Navarro, H.;
Mukherjee, R.; Farnsworth, N. R.; Kinghorn, A. D. New Bioactive
Aromatic Compounds from Vismia guianensis. Phytochemistry 2000,
55, 35. (b) Neugebauer, R. C.; Uchiechowska, U.; Meier, R.; Hruby,
H.; Valkov, V.; Verdin, E.; Sippl, W.; Jung, M. Structure−Activity
Studies on Splitomicin Derivatives as Sirtuin Inhibitors and
Computational Prediction of Binding Mode. J. Med. Chem. 2008,
51, 1203. (c) Ee, G. C. L.; Mah, S. H.; Teh, S. S.; Rahmani, M.; Go,
R.; Taufiq-Yap, Y. H. Soulamarin, a New Coumarin from Stem Bark
of Calophyllum soulattri. Molecules 2011, 16, 9721. (d) Cherry, J. J.;
Evans, M. C.; Ni, J.; Cuny, G. D.; Glicksman, M. A.; Androphy, E. J.
Identification of Novel Compounds That Increase SMN Protein
Levels Using an Improved SMN2 Reporter Cell Assay. J. Biomol.
Screening 2012, 17, 481. (e) Cherry, J. J.; Osman, E. Y.; Evans, M. C.;
Choi, S.; Xing, X.; Cuny, G. D.; Glicksman, M. A.; Lorson, C. L.;
Androphy, E. J. Enhancement of SMN Protein Levels in a Mouse
Model of Spinal Muscular Atrophy Using Novel Drug-like
Compounds. EMBO Mol. Med. 2013, 5, 1103. (f) Khan, P. M.; El-
Gendy, B. E.-D. M.; Kumar, N.; Garcia-Ordonez, R.; Lin, L.; Ruiz, C.
H.; Cameron, M. D.; Griffin, P. R.; Kamenecka, T. M. Small Molecule
Amides as Potent ROR-γ Selective Modulators. Bioorg. Med. Chem.
Lett. 2013, 23, 532. (g) Bregman, H.; Simard, J. R.; Andrews, K. L.;
Ayube, S.; Chen, H.; Gunaydin, H.; Guzman-Perez, A.; Hu, J.; Huang,
L.; Huang, X.; Krolikowski, P. H.; Lehto, S. G.; Lewis, R. T.;
Michelsen, K.; Pegman, P.; Plant, M. H.; Shaffer, P. L.; Teffera, Y.; Yi,
S.; Zhang, M.; Gingras, J.; DiMauro, E. F. The Discovery and Hit-to-
Lead Optimization of Tricyclic Sulfonamides as Potent and
Efficacious Potentiators of Glycine Receptors. J. Med. Chem. 2017,
60, 1105. (h) Libby, C. J.; Zhang, S.; Benavides, G. A.; Scott, S. E.; Li,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00993.
■
sı
Synthetic procedures, characterization, and additional
data (PDF)
Accession Codes
CCDC 2060089 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Jian-Hua Xie − State Key Laboratory and Institute of
Elemento-organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0003-3907-2530; Email: jhxie@nankai.edu.cn
Pu-Cha Yan − Raybow (Hangzhou) Pharmaceutical Science
& Technology CO., Ltd., Hangzhou 310018, China;
Email: pucha.yan@raybowpharma.com
3596
https://doi.org/10.1021/acs.orglett.1c00993
Org. Lett. 2021, 23, 3593−3598

Organic Letters
pubs.acs.org/OrgLett
Letter
Y.; Redmann, M.; Tran, A. N.; Otamias, A.; Darley-Usmar, V.;
Napierala, M.; Zhang, J.; Augelli-Szafran, C. E.; Zhang, W.;
Hjelmeland, A. B. Identification of Compounds That Decrease
Glioblastoma Growth and Glucose Uptake in Vitro. ACS Chem. Biol.
2018, 13, 2048.
(3) For recent reviews, see: (a) Kamat, D. P.; Tilve, S. G.; Kamat, V.
P.; Kirtany, J. K. Syntheses and Biological Activities of Chroman-2-
ones. A Review. Org. Prep. Proced. Int. 2015, 47, 1. (b) Muthukrishnan,
I.; Sridharan, V.; Menéndez, J. C. Progress in the Chemistry of
Tetrahydroquinolines. Chem. Rev. 2019, 119, 5057.
(4) For selected papers, see: (a) Chen, G.; Tokunaga, N.; Hayashi,
T. Rhodium-Catalyzed Asymmetric 1,4-Addition of Arylboronic Acids
to Coumarins: Asymmetric Synthesis of (R)-Tolterodine. Org. Lett.
2005, 7, 2285. (b) Paquin, J.-F.; Stephenson, C. R. J.; Defieber, C.;
Carreira, E. M. Catalytic Asymmetric Synthesis with Rh−Diene
Complexes: 1,4-Addition of Arylboronic Acids to Unsaturated Esters.
Org. Lett. 2005, 7, 3821. (c) Matsuda, T.; Shigeno, M.; Murakami, M.
Asymmetric Synthesis of 3,4-Dihydrocoumarins by Rhodium-
Catalyzed Reaction of 3-(2-Hydroxyphenyl)cyclobutanones. J. Am.
Chem. Soc. 2007, 129, 12086. (d) Luo, Y.; Carnell, A. J.
Chemoenzymatic Synthesis and Application of Bicyclo[2.2.2]-
octadiene Ligands: Increased Efficiency in Rhodium-Catalyzed
Asymmetric Conjugate Additions by Electronic Tuning. Angew.
Chem., Int. Ed. 2010, 49, 2750. (e) Kuang, Y.; Liu, X.; Chang, L.;
Wang, M.; Lin, L.; Feng, X. Catalytic Asymmetric Conjugate
Allylation of Coumarins. Org. Lett. 2011, 13, 3814. (f) Taylor, J.
G.; Correia, C. R. D. Stereoselective Synthesis of Unsymmetrical β,β-
Diarylacrylates by a Heck−Matsuda Reaction: Versatile Building
Blocks for Asymmetric Synthesis of β,β-Diphenylpropanoates, 3-Aryl-
indole, and 4-Aryl-3,4-dihydro-quinolin-2-one and Formal Synthesis
(6) Wang, J.; Zhu, Z.-H.; Chen, M.-W.; Chen, Q.-A.; Zhou, Y.-G.
Catalytic Biomimetic Asymmetric Reduction of Alkenes and Imines
Enabled by Chiral and Regenerable NAD(P)H Models. Angew. Chem.,
Int. Ed. 2019, 58, 1813.
(7) For selected reviews of asymmetric hydrogenation of
heteroarenes, see: (a) Zhou, Y.-G. Asymmetric Hydrogenation of
Heteroaromatic Compounds. Acc. Chem. Res. 2007, 40, 1357.
(b) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G. Asymmetric
Hydrogenation of Heteroarenes and Arenes. Chem. Rev. 2012, 112,
2557. (c) Luo, Y.-E.; He, Y.-M.; Fan, Q.-H. Asymmetric Hydro-
genation of Quinoline Derivatives Catalyzed by Cationic Transition
Metal Complexes of Chiral Diamine Ligands: Scope, Mechanism and
Catalyst Recycling. Chem. Rec. 2016, 16, 2697. (d) Seo, C. S. G.;
Morris, R. H. Catalytic Homogeneous Asymmetric Hydrogenation:
Successes and Opportunities. Organometallics 2019, 38, 47. (e) Kim,
A. N.; Stoltz, B. M. Recent Advances in Homogeneous Catalysts for
the Asymmetric Hydrogenation of Heteroarenes. ACS Catal. 2020,
10, 13834.
(8) For selected recent papers, see: (a) Xie, J.-H.; Liu, X.-Y.; Xie, J.-
B.; Wang, L.-X.; Zhou, Q.-L. An Additional Coordination Group
Leads to Extremely Efficient Chiral Iridium Catalysts for Asymmetric
Hydrogenation of Ketones. Angew. Chem., Int. Ed. 2011, 50, 7329.
(b) Xie, J.-H.; Liu, X.-Y.; Yang, X.-H.; Xie, J.-B.; Wang, L.-X.; Zhou,
Q.-L. Chiral Iridium Catalysts Bearing Spiro Pyridine-Amino-
phosphine Ligands Enable Highly Efficient Asymmetric Hydro-
genation of β-Aryl β-Ketoesters. Angew. Chem., Int. Ed. 2012, 51,
201. (c) Xie, J.-H.; Zhou, Q.-L. Magical Chiral Spiro Ligands. Acta
Chim. Sinica 2014, 72, 778.
(9) For a recent review, see: (a) Gu, X.-S.; Li, X.-G.; Xie, J.-H.;
Zhou, Q.-L. Recent Progress in Homogeneous Catalytic Hydro-
genation of Esters. Acta Chim. Sinica 2019, 77, 598. For papers, see:
(b) Yang, X.-H.; Xie, J.-H.; Liu, W.-P.; Zhou, Q.-L. Catalytic
Asymmetric Hydrogenation of δ-Ketoesters: Highly Efficient
Approach to Chiral 1,5-Diols. Angew. Chem., Int. Ed. 2013, 52,
7833. (c) Yang, X.-H.; Wang, K.; Zhu, S.-F.; Xie, J.-H.; Zhou, Q.-L. J.
Am. Chem. Soc. 2014, 136, 17426. (d) Yang, X.-H.; Yue, H.-T.; Yu,
N.; Li, Y.-P.; Xie, J.-H.; Zhou, Q.-L. Iridium-Catalyzed Asymmetric
Hydrogenation of Racemic α-Substituted Lactones to Chiral Diols.
Chem. Sci. 2017, 8, 1811. (e) Gu, X.-S.; Yu, N.; Yang, X.-H.; Zhu, A.-
T.; Xie, J.-H.; Zhou, Q.-L. Enantioselective Hydrogenation of
Racemic α-Arylamino Lactones to Chiral Amino Diols with Site-
Specifically Modified Chiral Spiro Iridium Catalysts. Org. Lett. 2019,
21, 4111. (f) Yang, X.-H.; Bin, H.-Y.; Xie, J.-H.; Zhou, Q.-L.
Asymmetric Synthesis of (−)-Indolizidine167B and (+)-Coniine.
Chin. J. Org. Chem. 2020, 40, 3963.
(10) (a) Liu, Y.-T.; Chen, J.-Q.; Li, L.-P.; Shao, X.-Y.; Xie, J.-H.;
Zhou, Q.-L. Asymmetric Hydrogenation of Tetrasubstituted Cyclic
Enones to Chiral Cycloalkanols with Three Contiguous Stereocenters.
Org. Lett. 2017, 19, 3231. (b) Zhao, Q.-K.; Wu, X.; Li, L.-P.; Yang, F.;
Xie, J.-H.; Zhou, Q.-L. Asymmetric Hydrogenation of β-Aryl
Alkylidene Malonate Esters: Installing an Ester Group Significantly
Increases the Efficiency. Org. Lett. 2021, 23, 1675.
of (−)-Indatraline. J. Org. Chem. 2011, 76, 857. (g) Blay, G.; Munoz,
̃
M. C.; Pedro, J. R.; Sanz-Marco, A. Enantioselective Synthesis of 4-
Substituted Dihydrocoumarins through a Zinc Bis(hydroxyamide)-
Catalyzed Conjugate Addition of Terminal Alkynes. Adv. Synth. Catal.
2013, 355, 1071. (h) Engl, O. D.; Fritz, S. P.; Käslin, A.; Wennemers,
H. Organocatalytic Route to Dihydrocoumarins and Dihydroquino-
linones in All Stereochemical Configurations. Org. Lett. 2014, 16,
5454. (i) Hu, H.; Liu, Y.; Guo, J.; Lin, L.; Xu, Y.; Liu, X.; Feng, X.
Enantioselective Synthesis of Dihydrocoumarin Derivatives by Chiral
Scandium (III)-complex Catalyzed Inverse-electron-demand Hetero-
Diels−Alder Reaction. Chem. Commun. 2015, 51, 3835. (j) Jin, J.-H.;
Li, X.-Y.; Luo, X.; Fossey, J. S.; Deng, W.-P. Asymmetric Synthesis of
cis-3,4-Dihydrocoumarins via [4 + 2] Cycloadditions Catalyzed by
Amidine Derivatives. J. Org. Chem. 2017, 82, 5424. (k) Lu, X.; Ge, L.;
Cheng, C.; Chen, J.; Cao, W.; Wu, X. Enantioselective Cascade
Reaction for Synthesis of Quinolinones through Synergistic Catalysis
Using Cu−Pybox and Chiral Benzotetramisole as Catalysts. Chem. -
Eur. J. 2017, 23, 7689. (l) Desyatkin, V. G.; Beletskaya, I. P.
Asymmetric Friedel−Crafts/Michael Reaction of Indoles and Pyrroles
with Coumarin-3-carbonylates. Synthesis 2017, 49, 4327. (m) Zhang,
X.-Z.; Gan, K.-J.; Liu, X.-X.; Deng, Y.-H.; Wang, F.-X.; Yu, K.-Y.;
Zhang, J.; Fan, C.-A. Enantioselective Synthesis of Functionalized 4-
Aryl Hydrocoumarins and 4-Aryl Hydroquinolin-2-ones via Intra-
molecular Vinylogous Rauhut−Currier Reaction of para-Quinone
Methides. Org. Lett. 2017, 19, 3207. (n) Zhang, H.; Luo, Y.; Li, D.;
Yao, Q.; Dong, S.; Liu, X.; Feng, X. Enantioselective Synthesis of 4-
Hydroxy-dihydrocoumarins via Catalytic Ring Opening/Cycloaddi-
tion of Cyclobutenones. Org. Lett. 2019, 21, 2388. (o) Tian, D.; Xu,
R.; Zhu, J.; Huang, J.; Dong, W.; Claverie, J.; Tang, W. Asymmetric
Hydroesterification of Diarylmethyl Carbinols. Angew. Chem., Int. Ed.
2021, 60, 6305.
(11) The solubility of 3-ethoxycarbonyl quinolin-2-one 2a is poor in
alcoholic solvents such as EtOH, and the addition of toluene as a
cosolvent can sufficiently help to improve its solubility in alcoholic
solvent.
(12) (a) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.; Duan,
H.-F.; Zhou, Q.-L. Synthesis of Spiro Diphosphines and Their
Application in Asymmetric Hydrogenation of Ketones. J. Am. Chem.
Soc. 2003, 125, 4404. (b) Xie, J.-H.; Zhou, Q.-L. Chiral Diphosphine
and Monodentate Phosphorus Ligands on a Spiro Scaffold for
Transition-Metal-Catalyzed Asymmetric Reactions. Acc. Chem. Res.
2008, 41, 581.
(13) (a) Lightfoot, A.; Schnider, P.; Pfaltz, A. Enantioselective
Hydrogenation of Olefins with Iridium−Phosphanodihydrooxazole
Catalysts. Angew. Chem., Int. Ed. 1998, 37, 2897. (b) Roseblade, S. J.;
Pfaltz, A. Iridium-Catalyzed Asymmetric Hydrogenation of Olefins.
Acc. Chem. Res. 2007, 40, 1402.
(5) (a) McGuire, M. A.; Shilcrat, S. C.; Sorenson, E. An Efficient
Asymmetric Catalytic Hydrogenation of 4-Aryl Coumarins, Prepara-
tion of a Key Intermediate in the Synthesis of a Class of Endothelin
Receptor Antagonists. Tetrahedron Lett. 1999, 40, 3293. (b) Ulgheri,
F.; Marchetti, M.; Piccolo, O. Enantioselective Synthesis of (S)- and
(R)-Tolterodine by Asymmetric Hydrogenation of a Coumarin
Derivative Obtained by a Heck Reaction. J. Org. Chem. 2007, 72,
6056.
3597
https://doi.org/10.1021/acs.orglett.1c00993
Org. Lett. 2021, 23, 3593−3598

Organic Letters
pubs.acs.org/OrgLett
Letter
(14) Brown, S. P.; Dransfield, P. J.; Vimolratana, M.; Jiao, X.; Zhu,
L.; Pattaropong, V.; Sun, Y.; Liu, J.; Luo, J.; Zhang, J.; Wong, S.;
Zhuang, R.; Guo, Q.; Li, F.; Medina, J. C.; Swaminath, G.; Lin, D. C.
H.; Houze, J. B. Discovery of AM-1638: A Potent and Orally
Bioavailable GPR40/FFA1 Full Agonist. ACS Med. Chem. Lett. 2012,
3, 726.
(15) (a) Abdur-Rashid, K.; Faatz, M.; Lough, A. J.; Morris, R. H.
Catalytic Cycle for the Asymmetric Hydrogenation of Prochiral
Ketones to Chiral Alcohols: Direct Hydride and Proton Transfer from
Chiral Catalysts trans-Ru(H)2(diphosphine)(diamine) to Ketones
and Direct Addition of Dihydrogen to the Resulting Hydridoamido
Complexes. J. Am. Chem. Soc. 2001, 123, 7473. (b) Abdur-Rashid, K.;
Clapham, S. E.; Hadzovic, A.; Harvey, J. N.; Lough, A. J.; Morris, R.
H. Mechanism of the Hydrogenation of Ketones Catalyzed by trans-
Dihydrido(diamine)ruthenium(II) Complexes. J. Am. Chem. Soc.
2002, 124, 15104. (c) Sandoval, C. A.; Ohkuma, T.; Muniz, K.;
̃
Noyori, R. Mechanism of Asymmetric Hydrogenation of Ketones
Catalyzed by BINAP/1,2-Diamine-Ruthenium(II) Complexes. J. Am.
Chem. Soc. 2003, 125, 13490.
(16) Murakami, M.; Kobayashi, K.; Hirai, K. Enantioselective
Synthesis of the Key Intermediate of the Acyl-CoA: Cholesterol
Acyltransferase (ACAT) Inhibitor (R-106578) Using 2,2′-Bis-
(diphenylphosphino)-1,1′-binaphthyl (BINAP)-Ru(OAc)2 as a Cata-
lyst. Chem. Pharm. Bull. 2000, 48, 1567.
(17) Porter, M. R.; Xiao, H.; Wang, J.; Smith, S. B.; Topczewski, J. J.
3-Amino-chromanes and Tetrahydroquinolines as Selective 5-HT2B,
5-HT7, or σ1 Receptor Ligands. ACS Med. Chem. Lett. 2019, 10, 1436.
3598
https://doi.org/10.1021/acs.orglett.1c00993
Org. Lett. 2021, 23, 3593−3598