Construction of three stereocenters via hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones

Article abstract of DOI:10.1007/s11426-020-9873-6

A Ru-catalyzed hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones was developed for construction of three stereocenters including two coherent and discontiguous chiral centers and a chiral quaternary carbon with excellent enantio- and diastereoselectivities. Stereodivergent synthesis of four stereoisomers could be conducted with high enantios-electivities. The desymmetrization could be achieved at gram scale without loss of reactivity and optical purity, and a formal synthesis of bioactive molecule (-)-isocelorbicol was completed.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s11426-020-9873-6

SCIENCE CHINA
Chemistry
•ARTICLES•
February 2021 Vol.64 No.2: 232–237
https://doi.org/10.1007/s11426-020-9873-6
Construction of three stereocenters via hydrogenative
desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones
Yi-Xuan Ding1,2, Zhou-Hao Zhu1,2, Han Wang1, Chang-Bin Yu1* & Yong-Gui Zhou1,3*
1State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China;
2University of Chinese Academy of Sciences, Beijing 100049, China;
3State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Received August 15, 2020; accepted September 14, 2020; published online December 11, 2020
A Ru-catalyzed hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones was developed for construction
of three stereocenters including two coherent and discontiguous chiral centers and a chiral quaternary carbon with excellent
enantio- and diastereoselectivities. Stereodivergent synthesis of four stereoisomers could be conducted with high enantios-
electivities. The desymmetrization could be achieved at gram scale without loss of reactivity and optical purity, and a formal
synthesis of bioactive molecule (−)-isocelorbicol was completed.
desymmetrization, hydrogenation, 1, 3-cyclohexanediones, three stereocenters, chiral quaternary carbon
Citation:
Ding YX, Zhu ZH, Wang H, Yu CB, Zhou YG. Construction of three stereocenters via hydrogenative desymmetrization of 2,2,5-trisubstituted
cyclohexane-1,3-diones. Sci China Chem, 2021, 64: 232–237, https://doi.org/10.1007/s11426-020-9873-6
1 Introduction
tempts usually focused on the construction of two
consecutive stereo-centers with a quaternary carbon via
mono-reduction of cyclic 1,3-diketones. Enzyme [8], Corey-
Bakshi-Shibata reagent (CBS) [9] and transition metals [10]
could all help to catalyze the desymmetrization of cyclic
symmetric 1,3-diketones with two different substituents at
the prochiral carbon (Scheme 1(a)). Recently, our group [11]
reported stereoselective reduction of prochiral diketones
with Noyori catalyst [12] to build two discontiguous ste-
reocenters via remote control (Scheme 1(b)). McIntosh and
Zhang’s group [13] applied ruthenium catalysts to the hy-
drogenative desymmetrization of cyclic meso-epoxy dike-
tones independently, offering the chiral epoxy hydroxy
ketones with three contiguous stereocenters (Scheme 1(c)).
To sum up, by using the desymmetrisation methodology, the
construction of two consecutive chiral centers, two dis-
contiguous stereocenters, or three coherent stereocenters has
been successfully developed. We wondered whether all the
goals above can be achieved through substrate design.
Desymmetrization is represented as a powerful synthetic tool
for converting meso and prochiral substrates into chiral or-
ganic molecules [1], often with multiple stereocenters or a
chiral quaternary carbon. Recently, desymmetrization of
prochiral cyclic diketones, which is emerging as one of the
useful building blocks in synthetic organic chemistry, has
been diffusely applied to aldol reaction [2], Michael addition
[3], Schmidt reaction [4], Diels-Alder reaction [5], retro-
Claisen reaction [6] and so on [7]. Among these asymmetric
reactions, desymmetrization has been important to the for-
mation of multiple stereocenters or the construction of fully
substituted stereocenters.
Stereoselective reduction of one of the diketone moiety is
also a useful approach to conduct the enantioselective de-
symmetrization of cyclic diketones. Most of previous at-
*Corresponding authors (email: cbyu@dicp.ac.cn; ygzhou@dicp.ac.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020
chem.scichina.com link.springer.com

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Ding et al. Sci China Chem February (2021) Vol.64 No.2
Herein, we report the ruthenium-catalyzed hydrogenative
desymmetrization of 2,2,5-trisubstituted 1,3-cyclohexane-
diones to construct three stereocenters containing two dis-
crete stereocenters and a chiral quaternary carbon stereo-
center. Moreover, stereodivergent syntheses of four
stereoisomers could be conveniently accessed by combina-
tion of substrates and chiral ruthenium catalysts (Scheme 1
(d)).
quaternary carbon center as the model substrate [7d]. In the
presence of 2 mol% RuCl[(R,R)-Tsdpen](p-cymene) catalyst
3 and 4.0 equivalent amount of azeotrope of formic acid and
triethylamine at 40 °C in tetrahydrofuran under an argon
atmosphere, we indeed observed the desirable reductive
product 2a after 4 h in full conversion with 99.3% ee (Table
1, entry 1). Subsequently, solvent optimization demonstrated
that dimethylformamide, dichloromethane, ethyl acetate and
ethanol could afford excellent conversions and enantios-
electivities (entries 2–5). When isopropanol was used as
solvent, the conversion declined to 57% (entry 6). Con-
sidering the low toxicity and operational convenience, ethyl
acetate was chosen as the solvent for further optimization.
Moreover, the results were not affected when decreasing the
dosage of reductant to 2 equivalents (entry 7). Gratifyingly,
we found that both enantioseletivity and reactivity could
maintain at 0.2 mmol scale in 96% yield and with 99.5% ee
(entry 8), and determined entry 8 as optimal conditions.
Then, cis isomer of 2,2,5-trisubstituted cyclohexane-1,3-
dione cis-4a was also tried under the above optimal condition
(entry 9). To our delight, excellent 99% ee and 95% isolated
yield could be still obtained.
2 Experimental
Under the nitrogen atmosphere, a mixture of 2,2-di-
substituted 5-phenylcyclohexane-1,3-diones (0.2 mmol) and
RuCl[(R,R)-Tsdpen](p-cymene)
catalyst
(2.5 mg,
0.004 mmol) in an azeotrope of formic acid, triethylamine
(5:2, 67 μL, 0.8 mmol) and ethyl acetate (1.0 mL) was stirred
at 40 °C for 4 h in which carbon dioxide was released once
an hour. After the reaction completion, the volatile was re-
moved under the reduced pressure; the crude residue was
directly purified by silica gel column chromatography to
afford the desired reductive products. The optical purity was
determined by chiral HPLC analysis.
Having optimized the reaction, we proceeded to in-
vestigate the substrate scope and functional group tolerance
(Scheme 2). The reaction was found to tolerate an array of
functional groups on the aromatic ring of the 2-position
substituents, including both electron-donating and -with-
drawing substituents in all of the ortho-, meta- and para-
3 Results and discussion
At our outset, we chose trans 2-(2-bromobenzyl)-2-methyl-
5-phenylcyclohexane-1,3-dione trans-1a bearing a prochiral
Table 1 Optimization of the reaction conditions
Entrya)
Substrate
trans-1a
trans-1a
trans-1a
trans-1a
trans-1a
trans-1a
trans-1a
trans-1a
cis-4a
Solvent
THF
DMF
DCM
EA
Conv. (%)b)
>95
ee (%)c)
99.3
99.5
99.6
99.6
99.5
99.2
99.6
99.5
99.9
1
2
>95
3
>95
4
>95
5
EtOH
iPrOH
EA
>95
6
57
7d)
8e)
9e)
>95
EA
>95 (96)f)
>95 (95)f)
EA
a) Conditions: 1a (0.15 mmol), (R,R)-3 (2.0 mol%), HCO2H/Et3N
(4 equiv.), solvent (1.0 mL), 40 °C, 4 h, dr>20:1. THF: tetrahydrofuran,
DMF: N,N-dimethylformamide, DCM: dichloromethane, EA: ethyl acetate.
b) Determined by NMR. c) Determined by HPLC. d) 2 Equivalent amount
of HCO2H/Et3N was used. e) 0.20 mmol scale. f) Isolated yields.
Scheme 1 Mono-reduction of cyclic 1,3-diketones.

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Ding et al. Sci China Chem February (2021) Vol.64 No.2
Scheme 2 Substrate scope of trans- and cis-2,2,5-trisubstituted cyclohexane-1,3-diones.
positions (2a–2g). Next, we switched focus on the diverse 5-
position substituents of 1,3-cyclohexanediones. The corre-
sponding para-fluoro, para-methyl and ortho-methyl sub-
stituted on the aromatic ring at 5-position delivered the
desirable products 2h–2j in excellent yields, enantio- and
diastereoselectivities. Presumably due to steric hindrance,
substrate 2j required longer reaction time to obtain 98%
yield. Diketones with an alkyl group at 5-position were also
suitable reaction partners (2k, 2l). Functional groups such as
phenylpropargyl (2m), cinnamyl (2n) and cyanoethyl (2o)
could be tolerated without erosion of enatioselectivity and
reactivity. Notably, the excellent results could still be ac-
quired when there were two substituents virtually equal in
size at the 2-position, such as Me and Et (2p).
we were fortunate to get single crystals of the products
(−)-2a and (−)-5e. After X-ray crystallographic analysis, the
absolute configurations of (−)-2a and (−)-5e were assigned
as (2S,3R,5S)-2a and (2R,3R,5S)-5e, respectively. We dis-
covered that the configuration of the hydroxyl group was
remotely controlled by the 5-phenyl and had nothing to do
with the substituents at the 2-position. However, the reaction
rate of the cis substrate was higher than that of the trans,
possibly due to the different steric hindrance of the sub-
stituents.
We then set out to establish the availability of the stereo-
divergent access to four stereoisomers 9, 10, 11 and 12
(Scheme 3) from the same readily available starting material
6. Under the optimized condition, the reactions of cis-7 and
trans-8 proceeded smoothly, affording four stereoisomers of
9, 10, 11 and 12 in high yields with >99% ee and >20:1 dr.
The identity and configuration of diastereomers 10 and 12
were confirmed in comparison with the known data in the
literature [14]. To our delight, the synthetic utilization of 10
was demonstrated in the formal synthesis of (−)-iso-
Next, the transfer hydrogenative desymmetrization of a
series of cis isomers of diketones cis-4 (16 examples) was
achieved, giving the desirable products with excellent yields,
diastereoseletivities and enantioselectivities regardless of the
steric and electronic effect and functional groups.
To determine the absolute configuration of the products,

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Ding et al. Sci China Chem February (2021) Vol.64 No.2
Scheme 3 The stereodivergent synthesis of four stereoisomers.
celorbicol [14], which was found in many plants of the fa-
mily Celastraceae, as shown in Scheme 4. The key inter-
mediate hydroxyl ketone 10 could be obtained by transfer
hydrogenative desymmetrization of diketone 7 which was
acquired from (−)-Carvone through epoxidation, hydrolysis
and alkylation [15].
which probably underwent an isomerization. Furthermore,
the protection of 2a with TBS and Wittig olefination [10d]
afforded terminal olefin 14 in 93% yields (eq. (3)). In ad-
dition, chiral oxime ether 15 could be obtained with 93%
yield by reaction of 2p and O-benzyl-hydroxylamine [17] in
the presence of phosphoric acid (eq. (4)).
This desymmetrization reaction could be scaled up
smoothly at gram scale without any loss of enantioselectivity
and reactivity (Scheme 5, eq. (1)). Meanwhile, the utility of
hydroxyl cyclohexanone products as building blocks for
further elaboration was demonstrated in Scheme 5. We first
tried to protect the hydroxy groups in 5l with tert-
butyldimethylsilyl (TBS) and completed the conversion of
carbonyl to vinyl triflate subsequently based on a related
procedure reported by Weix et al. [16]. Fortuitously, the
more stable conjugated olefin 13 was obtained (eq. (2)),
4 Conclusions
In conclusion, we successfully realized the construction of
three stereocenters in one step, in which two discontiguous
chiral centers and a chiral quaternary carbon were presented.
This method, totally scalable and operationally simple, al-
lowed the hydrogenative desymmetrization of cis and trans
2,2,5-trisubstituted cyclohexane-1,3-diones with a diverse
Scheme 4 Formal synthesis of (−)-isocelorbicol.

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Ding et al. Sci China Chem February (2021) Vol.64 No.2
Scheme 5 Gram scale experiment and elaborations.
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Acknowledgements This work was supported by the National Natural
Science Foundation of China (21532006, 21690074) and Chinese Academy
of Sciences (XDB17020300, SSW-SLH035).
Conflict of interest The authors declare no conflict of interest.
Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains en-
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