Construction of Distant Stereocenters by Enantioselective Desymmetrizing Carbonyl-Ene Reaction

Article abstract of DOI:10.1021/acs.orglett.7b01329

An efficient desymmetrizing carbonyl-ene reaction of 1-substituted 4-methylenecyclohexanes with glyoxal derivatives was thus executed by a chiral N,N′-dioxide/Ni^II catalyst, providing facile access to cyclohexene derivatives bearing two remote 1,6-related stereocenters. This distal stereocontrol methodology originates from the efficient interaction between the catalyst with enophiles, discrimination of the two chair conformations of olefinic components, and the intrinsic six-membered transition-state structure of ene process.

Full text of DOI:10.1021/acs.orglett.7b01329

Letter
pubs.acs.org/OrgLett
Construction of Distant Stereocenters by Enantioselective
Desymmetrizing Carbonyl−Ene Reaction
Weiwei Luo,† Lili Lin,† Yu Zhang,† Xiaohua Liu,*,† and Xiaoming Feng*,†,‡
†Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, P. R. China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: An efficient desymmetrizing carbonyl−ene
reaction of 1-substituted 4-methylenecyclohexanes with glyoxal
derivatives was thus executed by a chiral N,N′-dioxide/NiII
catalyst, providing facile access to cyclohexene derivatives
bearing two remote 1,6-related stereocenters. This distal
stereocontrol methodology originates from the efficient
interaction between the catalyst with enophiles, discrimination
of the two chair conformations of olefinic components, and the
intrinsic six-membered transition-state structure of ene process.
1b).3 However, to the best of our knowledge, a comprehensive
he controlled construction of two stereogenic centers with
Thigh levels of diastereo- and enantioselectivity is of great study on the asymmetric synthesis of 1,6-related or more distant
stereogenic centers has not been carried out, except that a single
example of a desymmetrizing glyoxylate−ene reaction was
reported with low diastereoselectivity and excellent enantiose-
lectivity using a chiral titanium complex.4 The challenges of such
cases are associated not only with their truly substantial distance
but also with a weak and unclear stereocommunication between
the substrates and catalyst.
interest to synthetic chemists. Extensive efforts have been made
in the establishment of these stereoarrays in close proximity (e.g.,
1,2- or 1,3-relationship). In contrast, direct asymmetric entries to
stereocenters at more remote sites are less common, although
compounds bearing two long-range stereocenters could be
obtained from chiral precursors under distant asymmetric
induction.1 Noteworthy in this context is the work by Jørgensen
on trienamine-mediated formal [4 + 2]-cycloadditions to afford
1,4-related stereogenic centers (Scheme 1a).2b,d Until now, only
a single example of a catalytic mode to establish 1,5-related
stereogenic centers was reported by the Rueping group, who
developed a Brønsted acid promoted desymmetrization of meso-
1,3-dicarbonyl compounds with o-quinone methides (Scheme
Enantioselective desymmetrization represents an elegant and
powerful strategy to access enantioenriched chiral molecules
with complex structures.5 One of the challenges in asymmetric
desymmetrization reactions is the controlling stereochemistry
remote from the reaction site, and usually enzymes or catalysts of
comparable dimensions are needed to differentiate these distant
enantiotopic sites.5a,b Over the past decade, remarkable progress
has been made in the desymmetrization reactions of prochiral
cyclohexanones, such as aldol reaction,6a,b Baeyer−Villiger
Scheme 1. Strategies in Asymmetric Synthesis of Remote
Stereocenters
oxidation,6c Friedlander condensation,6d,e and so on.6f−m The
̈
desymmetrization of 4-substituted cyclohexanone-derived phe-
nylhydrazones7a and α,α-dicyanoalkenes7b were also docu-
mented by the groups of List and Chen, respectively. All of
these approaches required an anchoring group (e.g., −CO,
−CN, or −CN) in the 1-position, which is believed to
provide a key interaction with the catalyst for asymmetric
induction (Figure 1). Therefore, additional catalytic methods
without an anchoring group remain in high demand.
Desymmetrization of a symmetrical diolefinic substrate by the
glyoxylate−ene reactions was demonstrated by the Mikami
group with the 1,4-relationship of two hydroxyl groups being
Received: May 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01329
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Organic Letters
Letter
diastereoselectivity (entries 1−3). Poor results were observed
by using the aniline-derived ligand L-PiPh, while increasing the
steric bulk of the amide substituents benefited the yield and
diastereoselectivity (entries 4 and 5). Moreover, decreasing the
reaction temperature from 30 to 20 °C resulted in a loss of
reactivity but a slight improvement of the diastereoselectivity
(entry 6). Further attempts to improve the efficiency were
focused on the reaction concentration and temperature.
Performing the reaction at 10 °C and increasing the reaction
concentration as well as prolonging the reaction time of 4 days
furnished the corresponding product in 80% yield with 91:9 dr
and 99% ee (entry 8).
With the optimized reaction conditions in hand (Table 1,
entry 8), the substrate scope of the reaction was next
investigated. With respect to the glyoxal derivatives, the
diastereo- and enantiocontrol of the reaction were not sensitive
to either the electronic properties or the steric hindrance of
substituents on the phenyl ring of arylglyoxal, although the yields
changed from moderate to excellent (Table 2, entries 1−16).
The less reactive substrates containing electron-withdrawing
groups or halogen substituents required 20 °C to achieve higher
conversions (entries 6, 12, 13, and 16). Moreover, fused-ring-
substituted and heteroaromatic substrates also proved applicable
in the reaction, and the corresponding adducts were obtained in
Figure 1. Desymmetrization of substituted cyclohexanone derivatives.
established.8a In 2008, Jacobsen and co-workers reported a
desymmetrization of bis(alkenyl) aldehydes and alkenyl
dialdehydes via an intramolecular ene process, providing these
stereoarrays in very close proximity.8b Employing a catalytic
desymmetrizing carbonyl−ene strategy in the synthesis of two
distant stereogenic centers with high diastereo- and enantiose-
lectivities is still a challenge, although significant progress has
been made in the carbonyl−ene reaction.9 In this paper, we
realize this transformation enabled by a chiral Ni(II)−N,N′-
dioxide complex,9i,10 which may be useful for the construction of
more challenging 1,6-related stereocenters (Scheme 1c).
Initially, we chose the phenylglyoxal (1a) and 1-tert-butyl-4-
methylenecyclohexane (2a) as the model substrates to optimize
the reaction conditions. Preliminary studies showed that
Ni(ClO4)2·6H2O was the potentially optimal metal salt (see
the Supporting Information for details). The desired product 3aa
was obtained in 45% yield and 77.5:22.5 dr with 99% ee in the
presence of Ni(ClO4)2·6H2O and L-proline-derived L-PrPr2
(Table 1, entry 1). Next, chiral ligands with various backbone
moieties and steric hindrance were evaluated (entries 2−5). As
for the chiral backbone moiety, the L-pipecolic acid derived N,N′-
dioxide L-PiPr2 was superior to L-proline-derived L-PrPr2 and L-
ramipril derived L-RaPr2 in terms of the yield and
a
Table 2. Substrate Scope for the Glyoxal Derivatives
a
b
yield
Table 1. Optimization of the Reaction Conditions
c
c
entry
R1
3
(%)
dr
ee (%)
1
2
3
4
5
C6H5
3aa
3ba
3ca
3da
3ea
3fa
80
91:9
99
>99
2-MeC6H4
3-MeC6H4
3-MeOC6H4
3-ClC6H4
94
79
81
79
89:11
90:10
91:9
>99
99
90.5:9.5
>99
d
6
3-O2NC6H4
47 (64) 90.5:9.5
(89:11)
>99 (>99)
7
8
4-MeC6H4
4-tBuC6H4
4-MeOC6H4
4-FC6H4
3ga
3ha
3ia
3ja
3ka
3la
75
76
67
81
74
91:9
98
98
90:10
d
9
90.5:9.5
90.5:9.5
90:10
97
10
11
>99
4-ClC6H4
4-BrC6H4
>99
d
12
57 (65) 91:9
(89.5:10.5)
>99 (>99)
d
13
4-NCC6H4
4-F3CC6H4
3ma
3na
3oa
41 (58) 91:9 (89:11)
>99 (>99)
>99
b
c
c
entry
ligand
T (°C) time (h) yield (%)
dr
ee (%)
14
15
84
67
<93:7
1
2
3
4
5
6
L-PrPr2
L-PiPr2
L-RaPr2
L-PiPh
L-PiPr3
L-PiPr3
L-PiPr3
L-PiPr3
30
30
30
30
30
20
20
10
24
24
24
24
24
48
72
96
45
73
68
16
82
54
95
80
77.5:22.5
80.5:19.5
80:20
99
99
99
79
99
99
98
99
3,4-
(MeO)2C6H3
90.5:9.5
97
d
16
3,4-Cl2C6H3
1-naphthyl
2-naphthyl
2-thienyl
3pa
3qa
3ra
3sa
3ta
50 (86) 90:10 (89:11)
>99 (>99)
77:23
17
18
19
20
98
70
84
50
90:10
>99
99
88:12
90.5:9.5
90:10
90.5:9.5
90:10
98
d
7
d
c-hexyl
87:13
99
8
91:9
a
Unless specified otherwise, all reactions were performed with
a
Unless specified otherwise, all reactions were performed with
Ni(ClO4)2·6H2O/L-PiPr3 (1:1, 10 mol %), 1 (0.1 mmol), 2a (0.5
b
Ni(ClO4)2·6H2O/L (1:1, 10 mol %), 1a (0.1 mmol), 2a (0.3
mmol) in 1.0 mL of CH2Cl2. Isolated yield. Determined by HPLC
analysis on a chiral stationary phase. Using 2a (0.5 mmol) in 0.5 mL
mmol) in 0.5 mL of CH2Cl2 at 10 °C for 4 days. Isolated yield,
b
c
c
average of two runs. Determined by HPLC or SFC analysis on a
d
d
chiral stationary phase. The results in parentheses were obtained at
of CH2Cl2.
20 °C for 4 days.
B
DOI: 10.1021/acs.orglett.7b01329
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Letter
high yields with good diastereoselectivities and excellent
enantioselectivities (entries 17−19). The catalyst system was
also effective when an aliphatic substrate was applied, albeit with
a moderate yield (entry 20).
Scheme 3. (a) Glyoxylate−Ene Reaction. (b) Gram-Scale
Version of the Reaction. (c) Synthetic Utility
Then various 1-substituted 4-methylenecyclohexanes were
examined (Scheme 2). The diastereoselectivity increased
Scheme 2. Substrate Scope for 1-Substituted 4-
a
Methylenecyclohexanes
crystallographic analysis of 4a.11 In the meantime, the actual
metrics for compound 4a defined a 4.7 Å distance between the
two remote stereocenters. Moreover, the ene adduct can also be
utilized for the allylcarboxaldehyde synthesis (Scheme 3c).12
Cleavage of hydroxy ketone 3qa with sodium periodate yielded
allylcarboxaldehyde bearing a remote stereocenter on the
cyclohexene ring. Then the carbonyl group in 5 underwent a
facile reduction with NaBH4 to provide homoallylic alcohol 6 in
86% yield with 82% ee. Wittig olefination of the aldehyde group
could also give the 1,4-diene in moderate yield with a good ee
value. In addition, alkynylative homologation of the aldehyde
group (70% yield), followed by a classical click reaction under
copper(I)-mediated conditions, led to 1,2,3-triazole 9 in 83%
yield with the maintained enantioselectivity.13 In the meantime,
the corresponding ketone derivative could be accessed in 90%
yield with a dramatic erosion of the chiral center (50% ee) by
gold-catalyzed alkyne hydration.14
a
The reactions were performed with Ni(ClO4)2·6H2O/L-PiPr3 (1:1,
10 mol %), 1a (0.1 mmol), 2 (0.5 mmol) in 0.5 mL of CH2Cl2 at 10
°C for 4 days. Isolated yield is the average yield of two runs. The dr
and ee values of the products were determined by HPLC or SFC
analysis on a chiral stationary phase. The results in parentheses were
b
c
d
obtained at 20 °C for 4 days.
gradually along with improvement of the steric hindrance of
the alkyl group, which suggests that the stable conformation of
the prochiral methylenecyclohexane could probably benefit the
stereocontrol (3aa−ah). Particularly noteworthy is the high
enantioselectivity of 98% ee with the modest yield and
diastereoselection (46% yield and 66:34 dr) in the silyloxy-
substituted product 3ai, probably due to the flexible
conformation of the substrate structure. Moreover, the aryl-
substituted substrates were applicable, resulting in moderate
yields (47−57%) with good diastereoselectivities (between
86:14 and 89:11 dr) and excellent enantioselectivities (up to
>99% ee). On the other hand, the 1,1-disubstituted substrate, 4-
methylene-1-phenylcyclohexane-1-carbonitrile, was totally un-
reactive.
On the basis of the experimental results and our previous
work,9i,10a,b a possible transition-state model is described in
Figure 2. The glyoxal derivative is activated through coordination
Next, the use of this catalytic system for the glyoxylate−ene
reaction was also explored. The freshly distilled 1u reacted well
with the olefinic substrates to give the corresponding adducts in
comparable yields and stereoselectivities (Scheme 3a). To show
the prospect of using this methodology in synthesis, a gram-scale
synthesis of 3qa was performed. Treatment of 3.5 mmol of 1q
under the optimal reaction conditions smoothly proceeded
without compromising the yield or stereoselectivity (Scheme 3b,
95% yield, 90:10 dr, 99% ee). Furthermore, manipulation of the
alkenyl group offers opportunities to generate epoxide with low
yield, results we attribute to the steric factors and increased
complexity with the existence of hydroxyketone moiety (full
conversion as monitored by TLC). Therefore, the absolute
configuration of 3ka was determined to be (2S,7S) by the X-ray
Figure 2. Proposed stereochemical model.
C
DOI: 10.1021/acs.orglett.7b01329
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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enophiles, discrimination of the two conformations of ene
components, and the cyclic pretransition state structure of the
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ASSOCIATED CONTENT
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(11) CCDC 1537907 (4a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01329.
Experimental procedures, full spectroscopic data for all
new compounds, and 1H and 13C NMR, HPLC, and SFC
spectra (PDF)
X-ray crystallographic data for compound 4a (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liuxh@scu.edu.cn.
*E-mail: xmfeng@scu.edu.cn.
ORCID
Xiaoming Feng: 0000-0003-4507-0478
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We appreciate the National Natural Science Foundation of
China (Nos. 21372162 and 21432006) for financial support.
■
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D
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