Nickel-Catalyzed Desymmetric Hydrogenation of Cyclohexadienones: An Efficient Approach to All-Carbon Quaternary Stereocenters

Article abstract of DOI:10.1021/jacs.9b07957

Nickel-catalyzed desymmetric hydrogenation has been achieved. With the Ni(OTf)₂/(S,S)-Ph-BPE system, a series of ?,?-disubstituted cyclohexadienones were transformed to the corresponding cyclohexenones with a chiral all-carbon quaternary center at the γposition in high yields (92-98%) and excellent enantioselectivities (92%-99% ee). This catalytic system can also tolerate the desymmetric reaction of spirocarbocyclic cyclohexadienones to produce the corresponding cyclohexenones bearing a chiral spiro quaternary carbon with high yields (94%-98%) and ee values (96%-99% ee). Furthermore, this methodology provides an efficient and concise synthetic route to the intermediate of natural products cannabispirenones A and B.

Full text of DOI:10.1021/jacs.9b07957

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Communication
Nickel-Catalyzed Desymmetric Hydrogenation of Cyclohexadienones:
An Efficient Approach to All-Carbon Quaternary Stereocenters
Cai You, Xiuxiu Li, Quan Gong, Jialin Wen, and Xumu Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07957 • Publication Date (Web): 06 Sep 2019
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Nickel-Catalyzed Desymmetric Hydrogenation of
Cyclohexadienones: An Efficient Approach to All-Carbon
Quaternary Stereocenters
Cai You, †a Xiuxiu Li, †a Quan Gong,a Jialin Wen*a,b and Xumu Zhang*a,c
aDepartment of Chemistry, Southern University of Science and Technology, 1088 Xueyuan Road, Shenzhen, 518055, China.
bAcademy of Advanced Interdisciplinary Studies, Southern University of Science and Technology, 1088 Xueyuan Road, Shenzhen,
518055, China
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cShenzhen Grubbs Institute, Southern University of Science and Technology, 1088 Xueyuan Road, Shenzhen, 518055, China
stereocenters. Using cyclohexadienones as the substrates, a series
ABSTRACT: The nickel-catalyzed desymmetric hydrogenation
compounds containing all-carbon quaternary stereocenters can be
constructed in high yields (up to 98%) with excellent
chemoselectivity and enantioselectivities (up to 99% ee).
has been achieved. With the Ni(OTf)2/(S,S)-Ph-BPE system, a
series of γ,γ-disubstituted cyclohexadienones were transformed to
the corresponding cyclohexenones with a chiral all-carbon
quaternary center at the γ position in high yields (92% to 98%) and
a)
OH
O
O
O
excellent enantioselectivities (92% to 99% ee). This catalytic
system can also tolerate the desymmetric reaction of
spirocarbocyclic cyclohexadienones to produce the corresponding
cyclohexenones bearing a chiral spiro quaternary carbon with high
yields (94% to 98%) and ee values (96% to 99% ee). Furthermore,
this methodology provides an efficient and concise synthetic route
to the intermediate of natural products cannabispirenones A and B.
Br
O
H
OMe
OH
H
Me
H
H
R
CO2H
HO
MeO
(-)-Cannabispirenone A (-)-Cannabispirenone B
R = H, Hamigeran B
R = Br, 4-Bromohamigeran B
Retigeranic acid
OH
OH
O
O
O
OH
O
H
H
H
H
MeO
MeO
NMe
All-carbon chiral quaternary stereocenters are important
structural motifs in natural products and biologically active
compounds (Figure 1a), while the construction of enantio-enriched
all-carbon quaternary centers remains a significant challenge in
chemical synthesis. In past decades, tremendous attention has been
devoted to the stereocontrolled construction of all-carbon
quaternary stereocentres using chemical catalysis, and many
distinct catalytic enantioselective approaches have been
established.1 Among these methods, catalytic enantioselective
desymmetrization of prochiral compounds or meso-compounds
provides an efficient and attractive strategy in the construction of
all-carbon quaternary stereocenters.2,3 However, the desymmetric
strategy in transition-metal (TM) catalyzed hydrogenation has far
less developed4 compared to direct enantioselective synthesis
enabled by TM-catalyzed asymmetric hydrogenation.5 Herein, we
attempted to accomplish an approach to all-carbon quaternary
stereocenters with high enantioselectivity by nickel-catalyzed
desymmetric hydrogenation (Figure 1b).
In the past decades, asymmetric hydrogenation relying on
precious metal compounds based on Rh, Ru, Ir, and Pd, etc. have
been proven as a powerful synthetic method, which can be used in
the preparation of many pharmaceuticals and biologically active
molecules.5 However, these second and third row transition metal
compounds are very expensive and their reserves in the Earth’s
crust are declining. In contrast, catalysts containing first-row
transition elements offer potential advantages in asymmetric
catalysis as they are inexpensive, environmentally friendly and
abundant. Recently, replacing the precious metals with earth-
abundant transition metals such as manganese,6 iron,7 cobalt8 and
copper9 has attracted a great deal of attention in the area of
asymmetric hydrogenation and asymmetric transfer hydrogenation.
Particularly, excellent results have been also obtained in the Ni-
catalyzed asymmetric (transfer) hydrogenation of ketones,10
alkenes11 and imines.12 However, to the best of our knowledge, the
asymmetric hydrogenation of α,β-unsaturated ketones has been
never tested in Ni-catalyzed system. Moreover, the desymmetric
strategy in the first row TM-catalyzed asymmetric hydrogenation
is still rare. Herein, for the first time, we report the nickel-catalyzed
desymmetric hydrogenation to form the chiral quaternary
H
H
H
H
H
H
O
O
O
(+)-Mesembrine
Testosterone
Progesterone
Cortisone
b)
O
X
O
O
O
Ni(OTf)2/(S,S)-Ph-BPE
Ar
H2
Ar
R
R'
R
R'
n
n
X
13 examples
up to 99% ee
up to 98% yield
12 examples
up to 99% ee
up to 98% yield
R = Aryl, Cy
R' = Me, Et
X = CH2, O, S
n = 0, 1, 2
Nickel-catalyzed
Desymmetric hydrogenation
All-carbon quaternary stereocenters
Excellent chemo- and enantio-selectivities
Figure 1. (a) Examples of natural products and biologically active
compounds containing all-carbon quaternary stereocenters. (b) Ni-
catalyzed desymmetric hydrogenation of cyclohexadienones.
We began the initial investigations with the desymmetric
hydrogenation of 1a to optimize the reaction conditions. A variety
of chiral diphosphine ligands combined with Ni(OTf)2 were
examined for the hydrogenation of 1a in methanol solution at 50
bar of H2 at 50 °C (scheme 1). The evaluation of ligands revealed
(S,S)-Ph-BPE to be superior to all others tested, although moderate
conversion with moderate enantioselectivity was obtained. The use
of (Rc,Sp)-DuanPhos as ligand afforded 16% conversion with only
37% ee. Ni catalysts based on other ligands, including Me-BPE, i-
Pr-BPE, Me-DuPhos, i-Pr-DuPhos, QunioxP*, Binapine, JosiPhos,
BINAP, SegPhos and DTBM-Segphos exhibited almost no activity
for this reaction.
With the preliminary results in hand, we sought to obtain
optimal reaction conditions, as summarized in Table 1. First, the
mixture of MeOH with a series of other solvents (v/v = 1/9) were
screened. When EtOH, iPrOH and EtOAc were used, >90%
conversions were achieved and 74% to 79% ee values were
obtained. In contrast, there was only <10% (even trace) conversion
Scheme 1. Ligand Screening for the Ni-Catalyzed Desymmetric
Hydrogenation of 1aa
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O
O
12e
13e
14e
15e
16f
NiCl2
toluene
toluene
toluene
toluene
toluene
<1
3
-
-
L
Ni(OTf)2 (1 mol%), (1.1 mol%)
1
2
3
4
5
6
7
8
Ni(OAc)2
MeOH, H2 (50 bar), 50 °C, 24 h
Ph
R
Ph
Ni(OAc)2·4H2O
Ni(BF4)2·6H2O
Ni(OTf)2
<1
34
>99
-
1a
2a
91
97
R
tBu
N
N
P
R
R
P
H
H
P
a Unless otherwise mentioned, all reactions were carried out with a
Ni(OTf)2/(S,S)-Ph-BPE/substrate ratio of 1:1.1:100, in the mixture
of MeOH (0.1 mL) with a series of other solvents (0.9 mL), at
50 °C, under hydrogen (50 bar) for 24 h. bConversions were
determined by 1H NMR spectroscopy. cEnantiomeric excesses (ee)
were determined by HPLC analysis using a chiral stationary phase.
P
P
tBu
R
P
P
P
R
RR
(S,S)-DuPhos
tBu
tBu
(S,S)-BPE
(Rc,Sp)-DuanPhos
(R,R)-QuinoxP*
R = Ph, 66% conv., 66% ee
R = Me, <1% conv.
R = Me, 2% conv.
16% conv. 37% ee
2% conv.
R = i-Pr, 4% conv.
R = i-Pr, 3% conv.
9
O
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PtBu2
dThe reaction was carried out in toluene without MeOH. The
reaction was carried out in the mixture of MeOH (0.05 mL) and
toluene (0.95 mL). 70 °C, H2 (60 bar), the over-reduced product
e
tBu
Ph2P
Fe
O
O
PAr2
PAr2
P
PPh2
PPh2
H
f
H
P
O
tBu
(4-methyl-4-phenylcyclohexan-1-one, 9%) was detected.
(S)-Binapine
JosiPhos
(S)-BINAP
(S)-SegPhos
3% conv.
<1% conv.
<1% conv.
Ar = Ph, <1% conv.
Ar = 3,5-t-Bu-4-OMe-C6H2,
<1% conv.
Scheme 2. Ni-Catalyzed Desymmetric Hydrogenation of
Cyclohexadienonesa
aAll reactions were carried out with a Ni(OTf)2/ligand/substrate
ratio of 1:1.1:100, in 1 mL of methanol, at 50 °C, under hydrogen
(50 bar) for 24 h. Conversions were determined by 1H NMR
spectroscopy. Enantiomeric excesses (ee) were determined by
HPLC analysis using a chiral stationary phase.
O
O
Ni(OTf)2 (1 mol%), (S,S)-Ph-BPE (1.1 mol%)
MeOH/toluene (1/19), H2 (50 bar), 50 °C, 24 h
R
R'
R
R'
1
2
O
O
O
O
when MeCN, THF, 1,4-dioxane and DCE were employed. Then,
two nonpolar solvents, cyclohexane and toluene, were investigated.
To our delight, full conversions with 87% ee (MeOH/cyclohexane
= 1/9) and 89% ee (MeOH/toluene = 1/9) were obtained. When the
reaction was carried out in toluene without MeOH, 93% ee was
achieved but the conversion dropped to 52%, which indicated that
the addition of MeOH can promote this transformation. Using a
mixture of MeOH/toluene in a 1/19 ratio, 93% ee was given and
complete conversion was afforded at the same time. In the
meanwhile, other nickel precursors such as NiCl2, Ni(OAc)2 and
Ni(OAc)2·4H2O were also tested. Other nickel(II) precursors than
Ni(OTf)2 resulted in eroded yield and ee value. It should be pointed
out that no over-reduced products were detected and that 2a was
the only product in this conditions (50 C, 50 bar H2). If harsher
conditions were applied, although higher ee values (97% ee) were
obtained, which is in accordance with the Horeau principle13, 9%
over-reduced product (4-methyl-4-phenylcyclohexan-1-one) was
observed (Table 1, entry 16).
MeO
2c
F3C
2d
2a
2b
96% yield
93% ee
96% yield
94% ee
94% yield
93% ee
95% yield
97% ee
O
O
O
O
MeO
F
Cl
Br
2e
2f
2g
2h
97% yield
97% ee
96% yield
95% ee
98% yield.
95% ee
94% yield
93% ee
O
O
O
O
MeO
MeO
OMe
2i
2j
2k
2l
96% yield
92% ee
96% yield
92% ee
98% yield
96% ee
95% yield
99% ee
Table 1. Optimization of Reaction Conditions in the Ni-
Catalyzed Desymmetric Hydrogenation of 1aa
O
O
O
Ni (II) source (1 mol%), (S,S)-Ph-BPE (1.1 mol%)
solvent, H2 (50 bar), 50 °C, 24 h
Ph
Ph
2a
1a
2m
92% yield
92% ee
entry
Ni (II)
solvent
conv.
(%)b
66
ee
(%)c
66
74
79
78
-
a Unless otherwise mentioned, all reactions were carried out with a
Ni(OTf)2/(S,S)-Ph-BPE/substrate ratio of 1:1.1:100, in the mixture
of MeOH (0.05 mL) and toluene (0.95 mL), at 50 °C, under
hydrogen (50 bar) for 24 h. Yield of the isolated product.
Enantiomeric excesses (ee) were determined by HPLC analysis
using a chiral stationary phase.
1
2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
MeOH
EtOH
>99
92
3
iPrOH
4
EtOAc
MeCN
THF
94
5
3
6
9
-
With the optimized conditions in hand, we investigated the
substrate scope and generality of this desymmetric transformation
(Scheme 2). Many functional groups, such as methyl (2b),
methoxyl (2c), trifluoromethyl (2d), and halides (2e-2g), at the para
position of the phenyl group are compatible with this
transformation. Substrates with meta- or ortho-substitution on the
phenyl group are also tolerated, and excellent ee values were
7
dioxane
DCE
<1
-
8
4
-
9
cyclohexane
toluene
toluene
>99
52
87
89
93
10d
11e
>99
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obtained (2h and 2i). Moreover, the product 2j with disubstituted
with a seven-membered ring, which demonstrated the strong
tolerance of this desymmetric reaction.
1
2
3
4
5
6
7
groups was obtained with high ee values as well. Reactions with 2-
naphthyl-containing substrates proceeded smoothly, and 2k was
achieved in high yield with excellent enantioselectivity. Next,
cyclohexadienones with two alkyl substituents were tested. When
the aryl substituent was changed to a cyclohexyl group, the product
2l was produced with 99% ee and 95% yield. Finally, the reaction
of 1m, with two different alkyl groups (cyclohexyl and ethyl), gave
product 2m with excellent enantioselectivity (92% ee).
Scheme 4. Transformations and Deuterium Labeling Studies
a) Gram scale desymmetric hydrogenation of 1a
O
O
Ni(OTf)2 (1 mol%), (S,S)-Ph-BPE (1.1 mol%)
MeOH/toluene (1/19), H2 (50 bar), 50 °C, 24 h
8
9
1a
6 mmol, 1.11 g
2a
1.08 g
Scheme 3. Ni-Catalyzed Desymmetric Hydrogenation of
Spirocyclic Cyclohexadienonesa
97% yield, 93% ee
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60
b) Synthesis of cannabispirenones A and B
O
O
O
HO
Ni(OTf)2 (1 mol%), (S,S)-Ph-BPE (1.1 mol%)
one step, 85%
ref. 14a
MeOH/toluene (1/19), H2 (50 bar), 50 °C, 24 h
Ar
Ar
O
n
n
O
X
X
MeO
3
4
Ni(OTf)2 (1 mol%)
(S,S)-Ph-BPE (1.1 mol%)
(-)-Cannabispirenone A
MeO
MeO
MeOH/toluene (1/19)
H2 (50 bar), 50 °C, 24 h
O
O
O
O
O
MeO
MeO
3f
4f
1.24 g
96% yield, 99% ee
MeO
5 mmol, 1.28 g
one step, 46%
Br
ref. 14b
HO
F
4b
Cl
4c
(-)-Cannabispirenone B
4a
96% yield
99% ee
95% yield
98% ee
4d
97% yield
99% ee
95% yield
99% ee
c) Deuteration experiments
O
O
O
O
O
O
0% D
H
0% D
Ni(OTf)2 (1 mol%), (S,S)-Ph-BPE (1.1 mol%)
H
MeOH/toluene (1/19), D2 (50 bar), 50 °C, 24 h
MeO
D >95%
Ph
1a
Ph
Cl
MeO
OMe
94% yield
99% ee
4e
4f
4g
4h
96% yield
99% ee
95% yield
98% ee
98% yield
98% ee
To demonstrate the synthetic utility of this desymmetric
methodology, two gram-scale transformations were conducted, as
summarized in scheme 4. First, under the standard reaction
conditions, gram-scale 1a was converted to the desired product 2a
in 97% yield with 93% ee. Then, the desymmetric reaction of 3f
was also conducted on a gram scale, and 4f was obtained in 96%
yield with undiminished enantioselectivity (99% ee). Notably, the
chiral compound 4f can be transformed to the natural products (-)-
cannabispirenones A and B in just one step according to the
reported procedure.15 The deuterium labeling experiment was also
conducted, and the results identified the role of methanol as a
proton source to complete product, which is in agreement with the
previous studies.11b,c Isotope labeling experiments supported a
hypothesis that the reactive nickel hydride complex reacts with this
conjugate enone in a 1,4-addition pathway, yielding an enolate
which deprotonates methanol to form the product ketone. This
outer-sphere manner is different from traditional inner-sphere
mechanism which involves coordination of C=C bonds.
O
O
O
O
S
S
O
4i
4j
4k
4l
95% yield
98% ee
96% yield
99% ee
96% yield
98% ee
97% yield
96% ee
a Unless otherwise mentioned, all reactions were carried out with a
Ni(OTf)2/(S,S)-Ph-BPE/substrate ratio of 1:1.1:100, in the mixture
of MeOH (0.05 mL) and toluene (0.95 mL), at 50 °C, under
hydrogen (50 bar) for 24 h. Yield of the isolated product.
Enantiomeric excesses (ee) were determined by HPLC analysis
using a chiral stationary phase.
As spiro scaffolds bearing a chiral spiro quaternary carbon are
widely present in natural products,14 which exhibit biological and
pharmacological activities, we investigated
a
series of
In conclusion, we have developed the Ni-catalyzed
cyclohexadienones incorporating a spirocarbocyclic backbone in
current desymmetric reaction as well (Scheme 3). First, we used
cyclohexadienone 3a as the substrate, to our delight, the reaction
proceeded smoothly under standard conditions and 4a was obtained
in high yield with excellent ee values (99% ee). Reactions of 3b-g,
with electrondonating or -withdrawing substituents at various
positions of the aromatic ring gave the desired products in high
yield with 98% to 99% ee. To explore the impact of the ring size of
3 on current desymmetric reaction, the transformation of 3
containing a six-membered ring was tested. The high yields (95%-
98%) and excellent ee values (98% ee) of 4g-4i illustrated these
six-membered ring-containing substrates can be tolerated very well
in current system. The spiro-fused heterocyclic compounds 3j and
3k are also accommodated, producing the desired products 4j and
4k in excellent yields and ee values. Furthermore, high
enantioselectivity (96% ee) was observed for the reaction of 3l,
desymmetric
hydrogenation
of
γ,γ-disubstituted
cyclohexadienones. This method provides an efficient and concise
route to the synthesis of compounds bearing a chiral all-carbon
quaternary stereocenters, which are important intermediates in
organic synthesis. Further investigation on the earth-abundant
transition metal-catalyzed asymmetric hydrogenation is underway
in our laboratory.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
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Yamamura, T.; Kitamura, M. Desymmetric hydrogenation of a meso-
Corresponding Author
cyclic acid anhydride toward biotin synthesis. Tetrahedron 2011, 67,
10006-10010. (d) Liu, T.-L.; Li, W.; Geng, H.; Wang, C.-J.; Zhang, X.
Catalytic Enantioselective Desymmetrization of Meso Cyclic
Anhydrides via Iridium-Catalyzed Hydrogenation. Org. Lett. 2013, 15,
1740-1743. (e) John, J. M.; Takebayashi, S.; Dabral, N.; Miskolzie, M.;
Bergens, S. H. Base-Catalyzed Bifunctional Addition to Amides and
1
2
3
4
5
6
7
8
Email: wenjl@sustech.edu.cn;
Email: zhangxm@sustech.edu.cn
Author Contributions
†Cai You and Xiuxiu Li contributed equally to this work.
Notes
Imides at Low Temperature.
A New Pathway for Carbonyl
The authors declare no competing financial interests.
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Beller, M. Manganese(I)-Catalyzed Enantioselective Hydrogenation of
Ketones Using a Defined Chiral PNP Pincer Ligand. Angew. Chem.,
Int. Ed. 2017, 56, 11237-11241. (b) Zhang, L.; Tang, Y.; Han, Z.; Ding,
K. Lutidine-Based Chiral Pincer Manganese Catalysts for
Enantioselective Hydrogenation of Ketones. Angew. Chem., Int. Ed.
2019, 58, 4973-4977. (c) Zirakzadeh, A.; de Aguiar, S. R. M. M.;
Stöger, B.; Widhalm, M.; Kirchner, K. Enantioselective Transfer
Hydrogenation of Ketones Catalyzed by a Manganese Complex
Containing an Unsymmetrical Chiral PNP’ Tridentate Ligand.
ChemCatChem 2017, 9, 1744-1748. (d) Demmans, K. Z.; Olson, M. E.;
Morris, R. H. Asymmetric Transfer Hydrogenation of Ketones with
Well-Defined Manganese(I) PNN and PNNP Complexes
Organometallics 2018, 37, 4608-4618.
(7) For reviews, see: (a) Morris, R. H. Asymmetric hydrogenation,
transfer hydrogenation and hydrosilylation of ketones catalyzed by iron
complexes. Chem. Soc. Rev. 2009, 38, 2282-2291. (b) Li, Y. Y.; Yu, S.
L.; Shen, W. Y.; Gao, J. X. Iron-, Cobalt-, and Nickel-Catalyzed
Asymmetric Transfer Hydrogenation and Asymmetric Hydrogenation
of Ketones. Acc. Chem. Res. 2015, 48, 2587-2598. (c) Morris, R. H.
Exploiting Metal-Ligand Bifunctional Reactions in the Design of Iron
Asymmetric Hydrogenation Catalysts. Acc. Chem. Res. 2015, 48,
1494-1502. (d) Chirik, P. J. Iron- and Cobalt-Catalyzed Alkene
Hydrogenation: Catalysis with Both Redox-Active and Strong Field
Ligands. Acc. Chem. Res. 2015, 48, 1687-1695. (e) Zhang, Z.; Butt, N.
A.; Zhou, M.; Liu, D.; Zhang, W. Asymmetric Transfer and Pressure
Hydrogenation with Earth-Abundant Transition Metal Catalysts. Chin.
J. Chem. 2018, 36, 443-454.
ACKNOWLEDGMENT
We are grateful to the financial support from Shenzhen Nobel Prize
Scientists Laboratory Project (C17783101)， SZDRC Discipline
Construction Program and the Shenzhen Commission of Science,
Technology and Innovation (JSGG20160608140847864).
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Isotopic Labeling Provides Insight into the Origin of Stereoselectivity
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Cannabispirone,
α-
and
β-Cannabispiranols
and
the
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TOC Graphic:
1
2
O
O
3
4
5
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up to 99% ee
up to 98% yield
R
R'
R
R'
R = Aryl, Cy
R' = Me, Et
Ni
H2
13 examples
O
O
8
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up to 99% ee
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up to 98% yield
Ar
Ar
n
X
n
X
X = CH2, O, S
n = 0, 1, 2
12 examples
Nickel-catalyzed
All-carbon quaternary stereocenters
Desymmetric hydrogenation
Excellent chemo- and enantio-selectivities
6
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