Construction of Multiple-Substituted Chiral Cyclohexanes through Hydrogenative Desymmetrization of 2,2,5-Trisubstituted 1,3-Cyclohexanediones

Article abstract of DOI:10.1021/acs.orglett.9b03622

The construction of chiral multiple-substituted cyclohexanes motifs is a challenging topic in organic synthesis. By the combination of desymmetrization and remote stereocontrol, a ruthenium-catalyzed transfer hydrogenative desymmetrization of 2,2,5-trisubstituted 1,3-cyclohexanediones has been successfully developed for the construction of chiral multiple-substituted cyclohexanes with high enantioselectivity and diastereoselectivity. When an ester group was introduced to the two-position, a hydrogenative desymmetrization/transesterification cascade occurred, affording the bicyclic lactones bearing three stereocenters, including two discrete stereocenters and one quaternary stereogenic center, with high enantioselectivity. The products are the multiple-substituted chiral cyclohexanes bearing the hydroxyl and carbonyl functional groups, which provide a new opportunity for further precise elaboration.

Full text of DOI:10.1021/acs.orglett.9b03622

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Construction of Multiple-Substituted Chiral Cyclohexanes through
Hydrogenative Desymmetrization of 2,2,5-Trisubstituted 1,3-
Cyclohexanediones
Chang-Bin Yu,†,§ Bo Song,†,§ Mu-Wang Chen,† Hong-Qiang Shen,† and Yong-Gui Zhou*,†,‡
†State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road,
Dalian 116023, P. R. China
‡Collaborative Innovation Centre of Chemical Science and Engineering, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: The construction of chiral multiple-substituted cyclohexanes motifs is a challenging topic in organic synthesis. By
the combination of desymmetrization and remote stereocontrol, a ruthenium-catalyzed transfer hydrogenative
desymmetrization of 2,2,5-trisubstituted 1,3-cyclohexanediones has been successfully developed for the construction of chiral
multiple-substituted cyclohexanes with high enantioselectivity and diastereoselectivity. When an ester group was introduced to
the two-position, a hydrogenative desymmetrization/transesterification cascade occurred, affording the bicyclic lactones bearing
three stereocenters, including two discrete stereocenters and one quaternary stereogenic center, with high enantioselectivity.
The products are the multiple-substituted chiral cyclohexanes bearing the hydroxyl and carbonyl functional groups, which
provide a new opportunity for further precise elaboration.
ultiple-substituted chiral cyclohexanes are highly
valuable structural motifs in natural products and
concerted pericyclic reactions6 provide another solution due
to the cyclic transition state and the concerted reaction
pathway. Aminocatalysis7 also achieved the stereochemical
control by either steric shielding or the hydrogen-bond-
directing principle. Despite this remarkable progress, it
remains indispensable to find new effective approaches to
prepare structurally diverse chiral multiple-substituted cyclo-
hexane derivatives.
M
biologically active molecules (Figure 1).1 For example,
The asymmetric (transfer) hydrogenation of α-substituted
ketones has been established as one of the most direct
approaches to chiral secondary alcohols with two8 or three9
continuous stereocenters through dynamic kinetic resolution.
Despite the potential for the generation of useful function-
alized cyclic building blocks, to our knowledge, the
construction of chiral multiple-substituted cyclohexanes with
discrete stereogenic centers through hydrogenation has not
been reported. In view of the precedent work on the
desymmetrization of 1,3-diketones,10 we considered the
combined hydrogenation desymmetrization and remote
Figure 1. Bioactive molecules containing chiral cyclohexane motifs.
oseltamivir phosphate is an anti-influenza drug with potency
for the H5N1 avian flu virus.2 Abscisic acid demonstrated a
hierarchical order of toxicity that was able to suppress the
most coleoptile elongation.3 Garcinielliptone O has potential
anti-inflammatory effects.4 Considering the importance of
multifunctionalized chiral six-membered ring moieties, the
development of efficient catalytic methods to access these
motifs in a stereoselective fashion has thus been the focus of
substantial studies. In addition to enzymatic reactions,5 the
Received: October 14, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03622
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
control of five-substituted 1,3-cyclohexanediones to build
polysubstituted cyclohexane skeletons.11 Some challenges
remained, namely, the over-reduction12 and the control of
the enantioselectivity and the diastereoselectivity13 in one
step. Herein we report the construction of multiple-
substituted chiral cyclohexane skeletons through a ruthe-
nium-catalyzed hydrogenative desymmetrization of 2,2,5-
trisubstituted 1,3-cyclohexanediones by the mono-reduction
of 1,3-diketones and the control of the remote chirality
simultaneously, affording the chiral five-substituted 3-hydrox-
ycyclohexanones bearing two discrete stereogenic centers
(Scheme 1). When an ester group was introduced to the two-
Table 1. Optimization of the Reaction Conditions
b
c
entry
solvent
conv. (%)
ee (%)
1
2
3
4
5
6
7
58
80
93
75
97
27
13
>95(94)
99.6
99.6
>99.9
99.5
99.6
98.5
98.8
>99.9
THF
DMF
Scheme 1. Construction of Multiple-Substituted Chiral
Cyclohexanes through Hydrogenative Desymmetrization
DCM
EtOAc
EtOH
i-PrOH
EtOAc
d
8
a
Conditions: 1a (0.2 mmol), (R,R)-3 (1.0 mol %), HCO2H/Et3N
b
(0.5 mL), solvent (1.0 mL), 25 °C, 24 h, dr >20:1. Determined by
c
d
1H NMR. Determined by HPLC. 2.0 mol % (R,R)-3 was used.
e
Isolated yields.
Scheme 2. Tandem Transfer Hydrogenative
Desymmetrization/Transesterification
position, a hydrogenative desymmetrization/transesterification
cascade occurred, affording the chiral bicyclic lactones
bearing three stereogenic centers including two discrete
stereocenters and one quaternary stereocenter with high
enantio- and diastereoselectivities. The products are the chiral
multiple-substituted cyclohexanes bearing the hydroxyl and
carbonyl functional groups, which provide a new opportunity
for further precise elaboration.
To begin the studies, substrate 1a bearing two esters on
the two-position was chosen as the model substrate
considering the easy intramolecular transesterification of the
desymmetrization product. This substrate would allow us to
address the challenge of the construction of quaternary
carbon centers with a densely substituted bicyclo[m,n,0]
frame. First, the reaction was conducted with ruthenium
catalyst (R,R)-3 and an azeotrope of formic acid and
triethylamine. 58% conversion and excellent enantio- and
diastereoselectivity were obtained. The moderate conversion
may be rationalized as a result of the poor solubility of 1a
(Table 1, entry 1). Hence, the solvent effect was investigated;
aprotic solvents gave high ee values with 75−97% conversion
(entries 2−5). Poor yield was obtained with the protic
solvent (entries 6 and 7). A full conversion was obtained
when the catalyst loading was increased to 2 mol % (entry
8). So, the optimal conditions were established as (R,R)-3
(2.0 mol %), HCO2H/Et3N (0.50 mL), EtOAc (1.0 mL), 25
°C, and 24 h.
With the optimized reaction conditions in hand, a number
of 2,2,5-trisubstituted 1,3-cyclohexanediones bearing diverse
five-position substituents (Scheme 2) were tested. In general,
alkyl- or aryl-substituted 1,3-cyclohexanediones smoothly
underwent the hydrogenative desymmetrization/transesterifi-
cation cascade, giving the chiral bicyclic lactones products in
98 → 99.9% ee. In all cases, an over-reduction product was
not observed. The reaction was relatively insensitive to the
electronic or steric properties of the aryl substituents: The
presence of ortho, meta, and para substituents has negligible
influence on the reactivity and enantioselectivity (2a−g). The
variation of alkyl substituents was investigated and proved to
have a marginal effect on the yield and enantioselectivity (2h,
2i). Intriguingly, 1,3-cyclohexanediones (1j−l) containing an
ethyl ester functional group were also suitable substrates with
high reactivity and enantioselectivity.
Switching the substituent at the two-position to methyl
(Scheme 3), the scope of this desymmetrization reaction was
further examined. Both electron-donating and -withdrawing
B
DOI: 10.1021/acs.orglett.9b03622
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Organic Letters
Letter
Scheme 3. Substrate Scope: 2,2-Dimethyl-5-Substituted
1,3-Cyclohexanediones
Scheme 5. Substrate Scope: 2,2-Dicinnamyl-5-Substituted
1,3-Cyclohexanediones
Scheme 6. Experiment on a Gram Scale and Elaborations
substituents on the phenyl ring were successfully employed,
giving excellent enantioselectivity and diastereoselectivity.
Once more, the steric effect was also evaluated; 2-substituents
on the phenyl ring did not hinder the efficient transfer
hydrogenation (5b, 5e). In other cases, the halogen
substituents are also well tolerated (5g−i).
It is of note that the functional groups at the two-position
including the carbon−carbon double bond (6a, 6b) and the
carbon−carbon triple bond (6c) were conserved under
hydrogenation conditions (Scheme 4), providing the
potential reactive point for the further application.
Scheme 4. Substrate Scope: 5-Phenyl-2-Substituted 1,3-
Cyclohexanediones
be synthesized through TBS protection and reduction with
sodium borohydride. Notably, for the above transformations,
no loss of optical purity was observed.
In summary, by a combination of desymmetrization and
remote stereocontrol, a ruthenium-catalyzed hydrogenative
desymmetrization of 2,2,5-trisubstituted 1,3-cyclohexanedi-
ones has been successfully developed for the construction
of multiple-substituted chiral cyclohexanes. When an ester
group was introduced to the two-position, a hydrogenative
desymmetrization/transesterification cascade occurred, afford-
ing the chiral bicyclic lactones bearing three stereocenters,
including two discrete stereocenters and one quaternary
stereocenter, with high enantio- and diastereoselectivities and
a broad substrate scope and a wide tolerance of functional
groups. The above methodology provides facile and efficient
access to the chiral multiple-substituted cyclohexane
skeletons.
Next, we turned our attention to 2,2-dicinnamyl-1,3-cyclo-
hexanediones bearing diverse five-position substituents 8a−f
(Scheme 5). In general, 5-alkyl- or aryl-substituted 1,3-cyclo-
hexanediones underwent desymmetrization to deliver the
desirable chiral products with 94−99.9% ee.
To demonstrate the synthetic utility of this method, the
reaction on the gram scale was performed (Scheme 6), and
the yield and enantioselectivity were maintained. Meanwhile,
the remaining carbonyl is an attractive functional group for
further transformations. For example, oxime ether 10 was
obtained through the condensation with O-benzylhydroxyl-
amine. After the hydroxyl protection with TBSOTf,
nucleophilic addition with methyl lithium and the removal
of TBS gave the chiral diol 12 with high diastereoselectivity.
Monoprotected diol 13 with three stereogenic centers could
C
DOI: 10.1021/acs.orglett.9b03622
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03622.
■
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Accession Codes
CCDC 1552745, 1819215, 1840025, and 1855654 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
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ygzhou@dicp.ac.cn.
ORCID
Mu-Wang Chen: 0000-0001-6493-1363
Yong-Gui Zhou: 0000-0002-3321-5521
Author Contributions
§C.-B.Y. and B.S. contributed equally.
Notes
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810. (c) Hong, Y.; Chen, J.; Zhang, Z.; Liu, Y.; Zhang, W. Org. Lett.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21871255, 21532006) and Chinese
Academy of Sciences (XDB17020300, SSW-SLH035) is
acknowledged.
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DOI: 10.1021/acs.orglett.9b03622
Org. Lett. XXXX, XXX, XXX−XXX