Asymmetric Hydrogenation of Racemic 6-Aryl 1,4-Dioxaspiro[4.5]decan-7-ones to Functionalized Chiral ?a'Aryl Cyclohexanols via a Dynamic Kinetic Resolution

Article abstract of DOI:10.1021/acs.orglett.1c00044

A ruthenium-catalyzed asymmetric hydrogenation method for the synthesis of functionalized β-aryl cyclohexanols is described. With chiral spiro ruthenium catalyst (Ra,S,S)-5c, a series of racemic α-aryl cyclohexanones bearing a β-monoethylene ketal group were hydrogenated to the corresponding functionalized β-aryl cyclohexanols in high yields with enantioselectivity of up to 99% ee via a dynamic kinetic resolution. This protocol can be conducted on a decagram scale and provide potential approaches for the synthesis of optically active and densely functionalized aryl cyclohexanols.

Full text of DOI:10.1021/acs.orglett.1c00044

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Letter
Asymmetric Hydrogenation of Racemic 6‑Aryl 1,4-
Dioxaspiro[4.5]decan-7-ones to Functionalized Chiral β‑Aryl
Cyclohexanols via a Dynamic Kinetic Resolution
Dan Yang, Ai-Jiao Yang, Yong Chen, Jian-Hua Xie,* and Qi-Lin Zhou
Cite This: Org. Lett. 2021, 23, 1616−1620
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ABSTRACT: A ruthenium-catalyzed asymmetric hydrogenation method for the synthesis of functionalized β-aryl cyclohexanols is
described. With chiral spiro ruthenium catalyst (Ra,S,S)-5c, a series of racemic α-aryl cyclohexanones bearing a β-monoethylene ketal
group were hydrogenated to the corresponding functionalized β-aryl cyclohexanols in high yields with enantioselectivity of up to
99% ee via a dynamic kinetic resolution. This protocol can be conducted on a decagram scale and provide potential approaches for
the synthesis of optically active and densely functionalized aryl cyclohexanols.
hiral β-aryl-substituted cycloalkanols are ubiquitous and
Cvaluable structural motifs in numerous natural products,
bioactive molecules, and pharmaceuticals.1 Many synthetic
methods for the synthesis of optically active chiral β-aryl-
substituted cycloalkanols have been reported so far.2 One of
the most direct and facile methods is the asymmetric
hydrogenation of racemic α-aryl cycloalkanones via a dynamic
kinetic resolution (DKR) due to their operational simplicity,
high atom economy, and environmental benefit.3 Despite the
great progress that has been made in the past few decades, a
catalytic asymmetric hydrogenation of racemic α-aryl cyclo-
alkanones to optically active chiral β-aryl substituted cyclo-
alkanols via DKR is still difficult to fulfill the requirements of
synthetic applications.4
The frequent natural occurrence of highly oxygenated
carbocycles containing β-aryl cyclohexanol motifs, coupled
with their wide range of interesting biological activities, have
made these compounds of considerable interest to pharmacol-
ogists and synthetic chemists.1 Typical examples include
amaryllidaceae alkaloids, most notably (+)-pancratistatin,5
(+)-7-deoxypancratistatin,6 and (+)-lycorine7 (Figure 1).
These compounds exhibited significant bioactivities, in
particular, cytotoxicity against tumor cell lines.8 Considerable
efforts have been devoted to their syntheses, but enantiose-
lective synthesis by employing asymmetric catalysis is still
scarce due to the lack of efficient and reliable asymmetric
Figure 1. Examples of highly oxygenated natural products containing
chiral β-aryl cyclohexanol motifs.
catalytic methods to install the chiral β-aryl cyclohexanol
motifs.9
To address the challenges of an asymmetric synthesis of
chiral β-aryl cyclohexanols containing contiguous stereo-
centers, we developed a ruthenium-catalyzed asymmetric
hydrogenation of racemic α-aryl cyclohexanones modified
with a monoethylene ketal group via DKR and successfully
applied them for the enantioselective synthesis of the potent
Received: January 6, 2021
Published: February 11, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00044
© 2021 American Chemical Society
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nonselective cannabinoid receptor (−)-CP-5594010 and
natural products (−)-Δ9-THC11 and (−)-α-lycorane.12 In-
spired by the structures of pancratistatin and analogues, we
envisioned the asymmetric hydrogenation of racemic α-aryl
cyclohexanones 1 with a β-monoethylene ketal group via DKR
for the enantioselective synthesis of functionalized chiral β-aryl
cyclohexanols 2, in view of the fact that compound 2 could
serve as potential intermediates to densely substituted and
oxygenated carbocycles including amaryllidaceae alkaloids
containing aryl cyclohexane motifs with contiguous stereo-
centers (Scheme 1). In this paper, we report our results of an
dioxaspiro[4.5]decan-7-one (1a). We initially evaluated the
chiral spiro iridium catalyst Ir-(R)-SpiroPAP ((R)-3), an
extremely efficient chiral catalyst for an asymmetric hydro-
genation of simple ketones.13 Under the general conditions (2
mol % t-BuOK, EtOH, 10 atm H2), we found it gave 2a in 47%
yield and 43% ee along with a 52% yield of byproduct 6a (R =
Et) (Table 1, entry 1). Under the same conditions, no desired
product 2a was observed for the chiral spiro iridium catalyst Ir-
(R)-SpiroSAP ((R)-4)14 (entry 2). Thus, we further evaluated
the chiral spiro diphosphine-ruthenium-diamine catalyst
(Ra,S,S)-5c15 under the general conditions (5 mol % t-
BuOK, i-PrOH, 50 atm H2) for such chiral spiro ruthenium
catalysts3c and found it provided 2a in 89% yield and 96% ee
along with a small amount of 6a (R = i-Pr, 9% yield) (entry 3).
With EtOH and n-PrOH instead of i-PrOH as solvents, catalyst
(Ra,S,S)-5c also provided high enantioselectivity (88% ee and
90% ee, respectively) but with a significant amount of
byproduct 6a (entries 4 and 5). The formation of byproduct
6a is due to the cyclohexanone 1a with an β-ethylene ketal
group being very sensitive to bases.16 The poor solubility of 1a
in alcoholic solvents such as EtOH, n-PrOH, and i-PrOH slows
the reaction rate of hydrogenation. At the same time the base-
sensitive ketone 1a was converted to byproduct 6a. Although a
higher reaction rate was observed for (Ra,S,S)-5c in i-PrOH,
byproduct 6a was still isolated in a 9% yield. Accordingly, to
increase the solubility of 1a, the hydrogenation of 1a with
(Ra,S,S)-5c was further performed in a mixture of the solvents
i-PrOH and toluene (entries 6 and 7). The results showed that
the yield of 2a was increased significantly (up to 98%),
together with a slight improvement in enantioselectivity (up to
98% ee). We then tested other chiral spiro diphosphine-
ruthenium-diamine catalysts and found that the catalysts
(Ra,S,S)-5a, (Ra,S,S)-5b, and (Ra,S,S)-5d provided comparable
yields and enantioselectivities for the hydrogenation of 1a in a
Scheme 1. Asymmetric Hydrogenation of Racemic α-Aryl
Cyclohexanones to Chiral β-Aryl Cyclohexanols via DKR
asymmetric hydrogenation of racemic α-aryl cyclohexanones 1
via DKR for the enantioselective synthesis of new type of
monoethylene ketal-functionalized chiral β-aryl cyclohexanols.
The study commenced with the evaluation of the chiral
catalysts in the hydrogenation of the racemic 6-phenyl-1,4-
a
Table 1. Asymmetric Hydrogenation of 1a. Optimizing the Reaction Conditions
b
yield (%)
c
d
entry
cat
(R)-3
base (mol %)
solvent
conv (%)
2a
6a
ee (%)
1
t-BuOK (2)
t-BuOK (2)
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
t-BuOK (5)
t-BuOLi (5)
t-BuONa (5)
t-BuOK (2)
t-BuOK (2)
EtOH
EtOH
i-PrOH
EtOH
100
100
100
100
100
100
100
100
100
100
55
47
52
96
9
43
2
(R)-4
3
(Ra,S,S)-5c
(Ra,S,S)-5c
(Ra,S,S)-5c
(Ra,S,S)-5c
(Ra,S,S)-5c
(Ra,S,S)-5a
(Ra,S,S)-5b
(Ra,S,S)-5d
(Ra,S,S)-5c
(Ra,S,S)-5c
(Ra,S,S)-5c
(Ra,S,S)-5c
89
64
68
98
96
98
99
98
36
46
99
94
96
88
90
98
97
95
93
93
92
96
98
94
4
33
26
5
n-PrOH
6
i-PrOH/toluene (1:1)
i-PrOH/toluene (2:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
7
8
9
10
11
12
13
15
12
60
100
100
e
14
4
a
Reaction conditions: 1.0 mmol of 1a, 0.1 mol % of catalyst, solvent (4 mL), 10 atm H2 (for catalysts (R)-3 and 4) or 50 atm H2 (for catalysts
(Ra,S,S)-5), room temperature (25−30 °C), 12 h. The cis/trans selectivity of the product 2a for all reactions was greater than 99:1 as determined by
b
c
d
1H NMR spectroscopy. Isolated yield. Determined by 1H NMR spectroscopy. The ee value of product 2a was determined by high-performance
e
liquid chromatography using a chiral column. 0.01 mol % (Ra,S,S)-5c, 80 atm H2 (initial), 40 h.
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mixed solvent of i-PrOH and toluene (v/v = 1:1) (entries 8−
10). Other bases, such as t-BuOLi and t-BuONa, could not
promote the full conversion of 1a because of their poor
solubility in a mixed solvent (entries 11 and 12). The
reduction of the amount of base from 0.05 to 0.02 equiv gave a
slight increase in yield (entry 13). It is worth noting that, when
the catalyst loading was reduced to 0.01 mol % (S/C =
10 000), the hydrogenation can still be performed smoothly,
providing 2a in 94% yield and 94% ee (entry 14).
With the optimal reaction conditions in hand, we examined
the substrate scope of this hydrogenation by using catalyst
(Ra,S,S)-5c. As shown in Scheme 2, the electronic property and
position of the substituents on the phenyl ring of the substrates
have an obvious effect on the enantioselectivity. Generally, the
substrates with electron-donating substituents (1c, 4-MeO,
99% ee) gave a higher enantioselectivity than the substrates
with electron-withdrawing substituents (1d, 4-F, 93% ee); the
substrates with para/meta-substituents (1b, 4-Me, 98% ee; 1h,
3-Me, 97% ee) on the phenyl ring gave a significantly higher
enantioselectivity than the substrates with ortho-substituents
(1k, 2-Me, 47% ee; 1l, 2-OMe, 73% ee). When the aryl group
was replaced by an alkyl group such as methyl (1q) and benzyl
(1r) high yields with low to moderate enantioselectivities were
observed. However, the hydrogenation of the five-membered
ring substrates such as 6-methyl substituted 1,4-
dioxaspiro[4.4]nonan-7-one gave no desired product due to
its highly base-sensitive property.17 In addition, the hydro-
genation can be easily upscaled as demonstrated in the
decagram synthesis of 2c with erosions neither in the yield nor
ee (Scheme 3). Finally, the absolute configurations of the
Scheme 3. Decagram-Scale Synthesis and Functional Group
Interconversions of 2c
Scheme 2. Asymmetric Hydrogenation of Racemic α-Aryl
a b c
, ,
Cyclohexanones 1
hydrogenation products were determined as (R,R) through the
single-crystal X-ray diffraction analysis of product 2c (see the
Supporting Information).
For instance, to further demonstrate the utility and
versatility of our method to diverse oxygenated chiral β-aryl
cyclohexanes, cyclohexanol (S,S)-2c was then transformed into
a xanthate ester 7, with which a concurrent Chugaev syn-
elimination18 could regioselectively afford a cyclohexene
product 8 with no obvious erosion of enantiopurity (Scheme
3). Oxidation of cyclohexene 8 with m-chloroperbenzoic acid
(m-CPBA) diastereroselectively yielded epoxide 9 in 73%
yield. Subsequently, deketalization of 9 with 10% HClO4
provided epoxide ketone 10 in 51% yield. Alternatively,
opening the epoxide ring of 9 with sodium azide afforded azide
alcohol 11 with 73% yield. In addition, the direct
dihydroxylation of cyclohexene
8 with NMO/
19
K2OsO2(OH)4 yielded the corresponding cis-1,2-cyclohex-
anediol 12 as a single isomer with 92% yield. Impressively, a
one-pot deketalization and diol protection of 12 uniquely in
the condition of iodine and acetone cleanly provided the
dihydroxy-protected ketone 13 in 74% yield.20 The synthesized
chiral compounds, in particular, 10 and 13 can serve as useful
building blocks for the synthesis of amaryllidaceae constituents
and unnatural derivatives9b such as the analogues of
deoxypancratistatin.21
In conclusion, we have developed an efficient method for the
synthesis of chiral β-aryl cyclohexanols by a ruthenium-
catalyzed asymmetric hydrogenation of the corresponding
racemic α-aryl cyclohexanones bearing a β-monoethylene ketal
a
Reaction conditions: 1.0 mmol of 1, 0.1 mol % (Ra,S,S)-5c, 2 mol %
t-BuOK, i-PrOH/toluene (2/2 mL), 50 atm H2, at room temperature
(25−30 °C) for 12 h. The cis/trans selectivity of the product 2 for all
reactions was greater than 99:1 as determined by 1H NMR
b
c
spectroscopy. Isolated yield. The ee value was determined by
high-performance liquid chromatography using a chiral column. The
configuration of product 2c was determined as the (R,R)-
configuration by single-crystal X-ray diffraction analysis.
d
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group via DKR. A series of functionalized β-aryl cyclohexanols
bearing two contiguous stereocenters were obtained often with
high yields and excellent enantioselectivities. This protocol
could be performed at low catalyst loading (S/C = 10 000) and
on a decagram scale without significant erosions in yield and
enantioselectivity. The obtained β-aryl cyclohexanols could be
readily converted into a wide variety of oxygenated
arylcyclohexanes. Given the extensive availability of function-
alized β-aryl cyclohexanols, we believe that this protocol will
find widespread use as building blocks for the enantioselective
synthesis of densely substituted and oxygenated aryl cyclo-
hexanes.
Fundamental Research Funds for the Central Universities
(Nankai University, 020-63191746) for financial support.
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Synthesis and characterization of detailed experimental
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CCDC 2042516 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 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
Ai-Jiao Yang − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Yong Chen − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China; orcid.org/0000-0002-7029-
6201
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:
https://pubs.acs.org/10.1021/acs.orglett.1c00044
Notes
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, and the
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