Dynamic Kinetic Resolution of I-Substituted Cyclic β-Ketoesters via Asymmetric Hydrogenation: Constructing Chiral Cyclic β-Hydroxyesters with Three Contiguous Stereocenters

Article abstract of DOI:10.1021/acs.orglett.1c01689

An efficient asymmetric hydrogenation of racemic I-substituted cyclic β-ketoesters via dynamic kinetic resolution to provide chiral cyclic β-hydroxy esters with three contiguous stereocenters is reported. Using a chiral spiro iridium catalyst (R)-5 (Ir-SpiroSAP), a series of racemic I-Aryl/alkyl substituted cyclic β-ketoesters were hydrogenated to the corresponding chiral cyclic β-hydroxy esters in high yields (84-97%) with good to excellent enantioselectivities (69->99% ee) and cis,cis-selectivities (up to >99:1).

Full text of DOI:10.1021/acs.orglett.1c01689

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Letter
Dynamic Kinetic Resolution of γ‑Substituted Cyclic β‑Ketoesters via
Asymmetric Hydrogenation: Constructing Chiral Cyclic
β‑Hydroxyesters with Three Contiguous Stereocenters
Dan Yang, Xiong Wu, Xiao-Jie Zheng, Jian-Hua Xie,* and Qi-Lin Zhou
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ABSTRACT: An efficient asymmetric hydrogenation of racemic γ-substituted cyclic β-ketoesters via dynamic kinetic resolution to
provide chiral cyclic β-hydroxy esters with three contiguous stereocenters is reported. Using a chiral spiro iridium catalyst (R)-5 (Ir-
SpiroSAP), a series of racemic γ-aryl/alkyl substituted cyclic β-ketoesters were hydrogenated to the corresponding chiral cyclic β-
hydroxy esters in high yields (84−97%) with good to excellent enantioselectivities (69−>99% ee) and cis,cis-selectivities (up to
>99:1).
Upon initial investigation, we noticed that chiral cyclic β-
hydroxy esters with contiguous stereocenters are important
structural motifs widely found in bioactive natural products
and pharmaceuticals (Figure 1).5 Therefore, we first intended
to study the asymmetric hydrogenation of γ-substituted cyclic
β-ketoesters with chiral spiro ruthenium complex RuCl2-(S)-
Xyl-SDP/(R,R)-DPEN ((Sa,R,R)-3),6 an efficient catalyst for
the asymmetric hydrogenation of racemic α-substituted
aldehydes and ketones via DKR in the presence of strong
base such as tBuOK.7 We selected ethyl 3-phenyl-2-
oxocyclohexane-1-carboxylate (1a) as a model substrate and
performed the hydrogenation under the general conditions in
the presence of 0.2 mol % of (Sa,R,R)-3, and no hydrogenation
product was observed (Scheme 2). This result showed that
chiral spiro ruthenium catalyst (Sa,R,R)-3 is not effective for
the asymmetric hydrogenation of β-ketoesters even in the
presence of considerable amounts of tBuOK as a cocatalyst.
We then tested chiral spiro iridium catalysts Ir-(R)-SpiroPAP
((R)-4)8 and Ir-(R)-SpiroSAP ((R)-5),9 which are extremely
efficient for the asymmetric hydrogenation of β-ketoesters. The
ransition-metal catalyzed asymmetric hydrogenation
Trepresents a very useful and versatile method for the
preparation of optically active chiral compounds.1 By contrast,
the catalytic asymmetric hydrogenation of configurationally
labile α-substituted β-ketoesters via dynamic kinetic resolution
(DKR) holds the potential of providing chiral β-hydroxy esters
bearing two vicinal chiral centers with high efficiency (Scheme
1a) and has been successfully applied to the synthesis of chiral
drugs and bioactive natural products.2 The success of this
process relies upon the acidity of the α-C−H that facilitates the
racemization of α-chiral center through an achiral enolate
intermediate.3 However, the resolution of racemic α,γ-
disubstituted β-ketoesters for the construction of chiral β-
hydroxy esters with three contiguous stereocenters through
catalytic asymmetric hydrogenation remains a significant
challenge due to the less acidic γ-C−H of β-ketoesters
(Scheme 1b),1 despite its enormous potential synthetic utility.
̂
Thus, Genet and co-workers employed the asymmetric
hydrogenation of γ-amino α-methyl-β-ketoester derived from
(S)-proline with Ru-(S)-MeO-BIPHEP for the enantioselective
synthesis of iso-dolaproine4 (Scheme 1c). Herein, we report
the first highly efficient enantioselective dynamic kinetic
resolution asymmetric hydrogenation (DKR-AH) of racemic
α,γ-disubstituted β-ketoesters, allowing the direct access to
enantiomerically enriched β-hydroxy esters with three
contiguous stereocenters in excellent enantioselectivities (up
to 99% ee) and cis,cis-selectivities (up to >99:1) (Scheme 1d).
Received: May 19, 2021
Published: June 21, 2021
https://doi.org/10.1021/acs.orglett.1c01689
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5153−5157
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Scheme 1. Asymmetric Hydrogenation of α-Substituted and
α,γ-Disubstituted β-Ketoesters via DKR
Scheme 2. Evaluation of Chiral Catalysts for Asymmetric
Hydrogenation of 1a
a
a
Reaction conditions: 1a (0.5 mmol), cat./tBuOK/1a = 1:50:500,
solvent (2 mL), 50 atm of H2, room temperature (25−30 °C), 24 h,
isolated yield and the cis,cis-selectivities and ee values of cis,cis-product
were determined by 1H NMR and HPLC using chiral column,
respectively.
the hydrogenation. MeOH as the solvent gave higher yield
(94%) and higher enantioselectivity (98% ee). In contrast,
nPrOH and iPrOH as the solvent significantly lowered the
conversions (64% and 31%, respectively) with a slight decrease
in enantioselectivities. In addition to tBuOK, other bases such
as tBuONa, K2CO3, and KOH also provided comparable
results. Furthermore, when the amount of tBuOK was
increased from 5 to 10 mol % or decreased to 1 mol %,
similar results were also observed. To our delight, even though
the catalyst loading was decreased to 0.01 mol % (S/C =
10 000), the hydrogenation could still proceed smoothly and
afforded 2a in 91% yield with 97% ee and >99:1 cis,cis-
selectivity within 96 h.
Under the optimized reaction conditions, we examined a
series of racemic γ-aryl substituted cyclic β-ketoesters 1a−o. As
summarized in Scheme 3, the electronic properties of the
substituents on the phenyl ring of substrates 1a−e have no
obvious effect on the reaction rates and the enantioselectivities.
The corresponding hydrogenated products 2a−e were
obtained in 92−97% yields with 97−99% ee and 98:2−
>99:1 cis,cis-selectivities. Substrates 1f and 1g possessing
substituents on the meta-position of the phenyl ring also
gave comparable outcomes under the optimized conditions.
However, higher catalyst loading (1 mol %) and longer
reaction times (72 h) were required to complete the
hydrogenation when using ortho-substituted ketoesters 1h
and 1i, providing 2h and 2i in 93% yield with >99% ee and
91% yield with >99% ee, respectively. Substrate bearing a
heterocyclic moiety, such as 2-furanyl (1n), also underwent the
hydrogenation to afford the corresponding chiral product 2n in
high yield and enantioselectivity (84% yield, 94% ee). The
substrate 1o bearing a five-membered ring was also evaluated,
providing the product 2o in 92% yield with 92% ee and 98:2
cis,cis-selectivity. In addition, the absolute configuration of the
hydrogenated product 2c was determined as (1S,2R,3S) by a
single crystal X-ray diffraction analysis (see the Supporting
Information, CCDC 2049701).
Figure 1. Examples of natural products and pharmaceuticals
containing chiral cyclic β-hydroxy ester motifs with contiguous
stereocenters.
catalyst (R)-4 provided 2a (R = Et) in 87% yield and >99:1
cis,cis-selectivity but with a low enantioselectivity of 27% ee. In
contrast, excellent enantioselectivity (97% ee) and cis,cis-
selectivity (>99:1) were achieved by using the catalyst (R)-5,
albeit with a moderate yield of 41%. These results indicated
that the use of catalytic amounts of tBuOK as a base is efficient
to racemize the less acidic γ-C−H, leading to the formation of
cis,cis-γ-substituted cyclic β-hydroxy ester cis,cis-2a in optically
active form.
Thus, we choose (R)-5 as the catalyst of choice for further
optimization (see the Supporting Information). We found that
the reaction was completed within 48 h and provided 2a in
92% yield with 97% ee and >99:1 cis,cis-selectivity if increasing
the H2 pressure to 100 atm. Furthermore, we proved that the
solvent also has considerable influence on the reaction rate of
Several racemic γ-alkyl substituted cyclic β-ketoesters 1p−u
were also evaluated under the optimized reaction conditions
(Scheme 3). The hydrogenations proceeded smoothly to
provide the six-membered ring products 2p−t in 89−96%
yields with 96−98% ee and >99:1 cis,cis-selectivities. The
substrate 1u bearing a five-membered ring also provided the
corresponding product 2u in high yield and high cis,cis-
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Scheme 3. Asymmetric Hydrogenation of Racemic γ-Aryl/
alkyl Substituted Cyclic β-Ketoesters 1
Scheme 4. Enantioselective Synthesis of Chiral
a d
−
Intermediates to Natural Products (+)-Waihoensene,
(−)-Phaseic Acid, (−)-Podocarpic Acid, and
(+)-Anastrephin
a
Reaction conditions: substrate (0.5 mmol), (R)-5/tBuOK/substrate
= 1:50:500, MeOH (2 mL), 100 atm of H2, room temperature (25−
b
c
30 °C) for 48 h. Isolated yield. The cis,cis-selectivities of products 2
d
were determined by 1H NMR spectroscopy. The ee values were
determined by HPLC using chiral columns. The configuration of
e
product 2c was determined as the (1S,2R,3S)-configuration by single-
f
crystal X-ray analysis. 1.0 mol % of (R)-5, 72 h.
selectivity. The subsequent methylation of (1R,2S,3S)-2p with
methyl iodide in the presence of lithium diisopropylamide
(LDA) as a base delivered (1R,2S,3S)-9 in 76% yield, and the
configuration of 9 was determined by X-ray diffraction analyses
(see the Supporting Information, CCDC 2073807). Sub-
sequently, the Swern oxidation of (1R,2S,3S)-9 furnished
(1R,3S)-8 in 85% yield. The epimerization of the methylated
chiral tertiary center adjacent to the ketone group of (1R,3S)-8
in the presence of NaOMe as a base was proceeded smoothly,
affording the desired (1R,3R)-8 in 88% yield. In a word, we
completed the enantioselective synthesis of (1R,3S)-8 [[α] =
+84.2 (c 1.2, CHCl3) (lit.12b = +69.6 (c 1.19, CHCl3), 84%
selectivity but with moderate enantioselectivity (69% ee).
Overall, this represents the first highly efficient enantioselective
dynamic kinetic resolution using an asymmetric hydrogenation
of racemic α,γ-disubstituted β-ketoesters.
Encouraged by these results, we explored the enantiose-
lective asymmetric hydrogenation of racemic acyclic α,γ-
disubstituted β-ketoesters via dynamic kinetic resolution, for
example, ethyl 2-methyl-4-phenyl-3-oxopentanoate (6). The
hydrogenation was completed within 48 h, affording the
corresponding β-hydroxy ester 7 in 89% yield as a 92:8 mixture
of two isomers, and the ee value of the major one was 69% (see
the Supporting Information).
To demonstrate the synthetic utility of this method, we
decided to pursue the synthesis of chiral 1,3-dimethyl-2-
oxocyclohexane-1-carboxylates (1R,3R)-8 and (1R,3S)-8,
which are potential important chiral intermediates for the
total synthesis of bioactive natural products such as
(+)-waihoensene,10 (−)-phaseic acid,11 and (−)-podocarpic
acid12 (Scheme 4). The synthesis commenced from the
hydrogenation of racemic 1p with (S)-5 on a multigram scale.
With 0.05 mol % (S/C = 2000) of (S)-5 and under the optimal
reaction conditions for 60 h, rac-1p was hydrogenated to
(1R,2S,3S)-2p in 96% yield with 96% ee and >99:1 cis,cis-
ee)] and (1R,3R)-8 [[α] = −196.8 (c 0.8, CHCl3) (lit.12b
=
−153 (c 0.8, CHCl3), 89% ee)] from the hydrogenated
product (1R,2S,3S)-2p in 65% and 57% yield, respectively, via
two and three steps. To the best of our knowledge, our work
provides the first catalytic asymmetric synthesis of such chiral
1,3-dimethyl-2-oxocyclohexane-1-carboxylates.13
With chiral intermediate (1R,2S,3S)-9 in hand, we further
studied the enantioselective synthesis of chiral ketone (2S,6S)-
12,14 a key intermediate to an insect sex attracting pheromone
(+)-anastrephin15 (Scheme 4). The direct reduction of the
ester group of (1R,2S,3S)-9 with lithium aluminum hydride
followed by the Swern oxidation of the resulting diols
(1S,2S,6S)-10 provided aldehyde-ketone (1S,3S)-11 in a
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Notes
yield of 73% via two steps. A selective Wittig reaction of the
aldehyde group of (1S,3S)-11 with methyltriphenylphospho-
nium bromide using tBuOK as a base produced the ketone
(2S,6S)-12 in 81% yield. Therefore, an efficient approach to
(2S,6S)-12 was developed in 45% yield and four steps from the
hydrogenated product (1R,2S,3S)-2p.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21532003, 21871152, and 21790332), the “111” project
(B06005) of the Ministry of Education of China, the Frontiers
Sciences Center for New Organic Matter (Nankai University,
63181206), and the Fundamental Research Funds for the
Central Universities (Nankai University, 020-63191746) for
financial support.
In conclusion, we have achieved the highly efficient
asymmetric hydrogenaion of racemic γ-substituted cyclic β-
ketoesters via DKR for the enantioselective synthesis of
optically active chiral cyclic β-hydroxy esters with three
contiguous stereocenters. Using chiral spiro Ir-(R)-SpiroSAP
((R)-5) as the catalyst, a series of racemic γ-aryl/alkyl
substituted cyclic β-ketoesters were hydrogenated to the
corresponding optically active cyclic β-hydroxy esters in high
yields (84−97%) with good to excellent enantioselectivities
(69−>99% ee) and cis,cis-selectivities (up to >99:1). The
hydrogenation could be performed smoothly at a low catalyst
loading of 0.01 mol % (S/C = 10 000) without the erosion of
the yield and enantioselectivity. With this highly efficient
protocol, we developed efficient routes for the enantioselective
synthesis of the chiral key intermediates for the preparation of
bioactive natural products such as (+)-waihoensene, (−)-pha-
seic acid, (−)-podocarpic acid, and (+)-anastrephin.
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ASSOCIATED CONTENT
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■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01689.
Synthesis and characterization, detailed experimental
procedures, NMR spectra (PDF)
Accession Codes
CCDC 2049701 and 2073807 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033
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AUTHOR INFORMATION
Corresponding Author
■
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
Authors
Dan Yang − 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
Xiao-Jie Zheng − 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
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Complete contact information is available at:
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Both syn and anti Diastereoisomers of Boc-Dolaproine from (S)-
Proline through DKR Using Ruthenium-Catalyzed Hydrogenation: A
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