Access to Enantioenriched Organosilanes from Enals and β-Silyl Enones: Carbene Organocatalysis

Article abstract of DOI:10.1002/anie.201800483

Herein, an efficient route to enantioenriched organosilanes, containing two consecutive stereogenic centers, from enals and β-silyl enones under carbene organocatalysis is described. Under mild reaction conditions, this transition-metal-free strategy exhibits a broad substrate scope, and excellent diastereo- and enantioselectivity.

Full text of DOI:10.1002/anie.201800483

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Accepted Article
Title: Access to Enantioenriched Organosilanes from Enals and β-Silyl
Enones under Carbene Organocatalysis
Authors: Yuxia Zhang, Jie Huang, Yingying Guo, Lin Li, Zhenqian Fu,
and Wei Huang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201800483
Angew. Chem. 10.1002/ange.201800483
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COMMUNICATION
Access to Enantioenriched Organosilanes from Enals and β-Silyl
Enones under Carbene Organocatalysis
[
a]
[a]
[a]
[a]
[a]
[a][b]
Yuxia Zhang, Jie Huang, Yingying Guo, Lin Li, Zhenqian Fu,* and Wei Huang*
Abstract: Herein, an efficient route to enantioenriched
organosilanes containing two consecutive stereogenic centers
from enals and β-silyl enones under carbene organocatalysis is
described. Under mild conditions, this transition-metal-free
strategy exhibits a broad substrate scope, excellent diastereo-
and enantioselectivity.
shown in Figure 1) to form intermediate III. Finally, the carbene
is released from intermediate III; meanwhile enantioenriched cis-
organosilane containing two consecutive stereogenic centers is
formed. Notably, catalytic introduction of an additional chiral
center adjacent to the carbon that is bonded with the silica in
one step under mild conditions is challenging because of the
steric hindrance of the silyl group. More importantly, efficient
construction of chiral organosilanes promoted by carbene avoids
problematic heavy-metal residues, which should substantially
increase the potential uses. Herein, we present an efficient route
to entantioenriched organosilanes from enals and β-silyl enones
enabled by carbene organocatalyst under mild conditions.
Chiral organosilanes have interesting properties because of the
presence of the silicon atom that has a particularly physical and
electronic nature, and have attracted increasing attention in
recent years. In particular, chiral organosilanes are used in
[
1]
[2]
[3]
organic synthesis,
material science,
agroscience
and
[
4]
medicinal chemistry. Considerable effort has been devoted to
this field, and many elegant catalytically asymmetric approaches
for synthesis of chiral organosilanes have been successfully
developed, including asymmetric hydrosilylation of alkenes and
asymmetric silicon-hydride bond insertions,
desymmetrization of silanes, asymmetric addition to β-silyl
[
5]
[6]
alkynes,
[
7]
[
8]
unsaturated carbonyls
and asymmetric silyl conjugated
[
9]
addition. Notably, most of the aforementioned methods have to
rely on transition metals as catalysts. In contrast, an
organocatalyzed approach for synthesis of chiral organosilanes
has not been well explored. Hoveyda and co-workers in 2011
demonstrated that a chiral imidazolinium pre-catalyst could
[10]
2 2
promote silyl (from Me PhSi-B(pin) ) conjugate addition to α,β-
unsaturated carbonyl compound to form β -silyl carbonyl
compound with a single stereogenic center (Figure 1). Chiral
organosilanes can also be obtained by chiral boron-based-
[
11]
catalysts via asymmetric hydrosilylations of imines or ketones.
Undoubtedly, developing a new strategy for the construction of
chiral organosilanes based on asymmetric organocatalysis
would be highly attractive.
Over the past decade, NHC has been proven to be one of the
most powerful organocatalysts and has enabled construction of
[
12]
a series of carbo- and heterocycles. As a part of our ongoing
[13]
interest in carbene catalysis,
we envisaged that a new
synthetic strategy for chiral organosilanes might be achieved
from the reaction of enals and β-silyl enones promoted by
carbene under mild conditions. Carbene should be able to attack
[14-17]
the enal to form an enolate intermediate II
protonation,
via β-
which then adds to a β-silyl enone via endo-
Diels-Alder cycloaddition (possible stereochemical model as
[
18]
Figure 1. Organocatalyzed approaches for synthesis of chiral organosilanes.
[
[
a]
b]
Y. Zhang, J. Huang, Y. Guo, Prof. Dr. L. Li, Prof. Dr. Z. Fu, Prof. Dr.
W. Huang, Key Laboratory of Flexible Electronics & Institute of
Advanced Materials, Jiangsu National Synergetic Innovation Center
for Advanced Materials, Nanjing Tech University, 30 South Puzhu
Road, Nanjing 211816, China. E-mail: iamzqfu@njtech.edu.cn,
iamwhuang@njtech.edu.cn
Prof. Dr. W. Huang, Shaanxi Institute of Flexible Electronics (SIFE),
Northwestern Polytechnical University (NPU), 127 West Youyi
Road, Xi'an, 710072, China.
We selected the reaction of cinnamaldehyde 1a and β-TMS
enone 2a as a model reaction for optimizing the conditions. The
key results of reaction optimization are summarized in Table 1.
To our delight, the desired lactone 3a was obtained in 49% yield
with 20:1 dr when the racemic triazolium N-Mes pre-catalyst A
2 3
was used with K CO as the base in THF at room temperature
(entry 1). Gratifyingly, the desired chiral lactone 3a was obtained
in 62% yield with excellent diastereoselectivity (>20:1 dr) and
enantioselectivity (99% ee) when the more sterically hindered
Supporting information for this article is available on the WWW
under http://www.angewandte.org.
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Angewandte Chemie International Edition
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COMMUNICATION
[
16a]
aminoindanol-derived triazolium pre-catalyst B
was used.
proving to
showed a broad scope and led to similar results as for the enals.
Notably, when R is a methyl group, the desired product 3x was
2
Next, several bases were investigated, with Cs
2
CO
3
be the best choice (entries 2-8). Subsequent solvent screening
revealed that dioxane was the most effective, providing access
to the desired product 3a in up to 98% yield without any loss in
dr or ee (entries 9-12). Decreasing the NHC loading decreased
the product yield considerably (entry 13).
formed, albeit with a lower yield.
[
a]
Table 2. Scope of reaction.
[
a]
Table 1. Optimization of reaction conditions.
a
[b]
c
c
Entry
NHC
Base
Solvent
Yield[%]
dr
ee(%)
1
2
3
4
5
6
7
8
9
A
B
B
B
B
B
B
B
B
B
B
B
B
K
K
2
CO
3
3
THF
THF
49
62
86
65
50
49
90
30
75
75
60
98
75
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
-
2
CO
99
99
99
99
99
99
99
99
99
99
99
99
DBU
Et
THF
3
N
THF
NaOAc
DIPEA
THF
THF
Cs
2
CO
3
THF
t
KO Bu
THF
Cs
Cs
Cs
Cs
Cs
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
toluene
DCM
10
11
12
3
CH CN
1,4-dioxane
1,4-dioxane
[
d]
1
3
[
a] Standard condition: cinnamaldehyde 1a (2.0 equiv), β-TMS enone 2a (0.1
mmol,), NHC precursor (20 mol %), base (0.5 equiv), 4Å MS (100 mg), solvent
0.1 M), N , rt, 24 h. [b] Isolated yields after column chromatography. [c]
(
2
[
a] Reaction conditions as in Table 1, entry 12; yields (after SiO2
Determined by chiral HPLC. Absolute configuration of product was determined
chromatography purification) were based on β-silyl enone 2. [b] 3 equiv. of
enal 1 was used.
via X-ray of 5c (Scheme 2). [d] 15 mol % NHC precursor was used.
With acceptable optimized conditions in hand (Table 1, entry
To demonstrate the generality of our approach and further
potential applications of chiral organosilanes, the TMS group
1
2), we then evaluated the scope of the reaction for enal
substrates by using β-TMS enone 2a as a model substrate
Table 2). Notably, the reactions mentioned in this manuscript
could afford the corresponding chiral organosilances 3 and 5
with excellent diastereoselectivity (>20:1 dr) and
was replaced with other substituted silyls (Me
2
PhSi and
(
MePh Si), and the results are summaried in Table 3. As
2
expected, the reactions proceeded smoothly and led to
formation of the corresponding desired enantioenriched
organosilianes 5 in good to excellent yields with >20:1 dr and
enantioselectivity (96-99% ee) in most cases. Enals bearing
various substituents with diverse electronic and steric properties
on the β-aryl were well tolerated, and all the reactions
proceeded smoothly to generate the corresponding chiral
organosilances 3a-3m in good to excellent yield. Enal with β-2-
naphtyl or heteroaromatic rings (such as 2-furyl or 2-thienyl) also
worked efficiently and furnished the corresponding products in
good yields (3h-j). β-alkyl enals also gave the desired products
in acceptable yields with excellent enantioselectivity (3k-m). We
then investigated the generality of β-TMS enones under the
9
9% ee in most cases. (2E,4E)-5-phenylpenta-2,4-dienal was a
suitable substrate for this transformation to give product 5j in
7% yield with 99% ee, albeit with lower diastereoselectivity.
6
The product 5k was obtained in 89% yield with 1:1 dr due to the
rapid exchange of Z/E configuration of enone 4c.
To probe the reaction pathway, deuterium experiment was
performed as shown in Scheme 1. Deuterium cinnamaldehyde
1a-D was used with β-TMS enone 2a under standard conditions.
2
Theoretically, 3a-D should be more than 80% in the two
optimized conditions. Variation of the R group of enones also
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COMMUNICATION
products; only 36% 3a-D was obtained due to the participation of
opening of lactone 5e with methanol, followed by Fleming-
[
20]
a trace amount of H
2
O in the system. This result indicates that
Tamao oxidation reaction,
finally afforded 8 containing a
the enolate intermediate II was formed via β-protonation of
intermediate I.
hydroxyl group in 85% overall yield with >20:1 dr and 99% ee.
[
a]
Table 3. Scope of reaction.
Scheme 2. Synthetic transformations of product 5e.
In summary, we have developed carbene enabled formal [4 +
2] annulation of enals with β-silyl enones under mild conditions.
A
diverse set of enantiopure organosilanes bearing two
consecutive stereogenic centers was obtained in good yields
with excellent diastereo- and enantioselectivities. Notably, two
consecutive stereogenic centers could be constructed in only
one step. Further investigations and exploration of this catalytic
process are underway in our laboratory.
Acknowledgements
We acknowledge financial support by National Key R&D
Program of China (2017YFA0204704), National Key Basic
Research Program of China (973) (2015CB932200), National
Natural Science Foundation of China (21602105, 81672508 and
6
(
1505076), Natural Science Foundation of Jiangsu Province
BK20171460 and BK20140951), and Jilin Province Key
Laboratory of Organic Functional Molecular Design & Synthesis
130028653 and 130028746). We thank Y. Gao in this group for
(
[
a] Reaction conditions: β-silyl enone 4 (0.1 mmol, 1 equiv), enal 1 (3 equiv),
NHC precursor B (20 mol %), Cs CO (0.5 equiv), 4Å MS (100 mg), dioxane
0.1 M), under N atmosphere, rt, 30 h; yields (after SiO chromatography
reproducing the reactions of 3a, 5a, and 5e.
2
3
(
2
2
Keywords: Enantioenriched organosilanes • N-heterocyclic
carbene • Enolate intermediate • Transition-metal free • β-silyl
enones
purification) were based on β-silylated enone 4. [b] Failed to determine the ee,
because the two isomers (1:1 dr) could not be separated by chromatography.
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Angewandte Chemie International Edition
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Angewandte Chemie International Edition
10.1002/anie.201800483
COMMUNICATION
Layout 2:
COMMUNICATION
Yuxia Zhang, Jie Huang, Yingying Guo,
Lin Li, Zhenqian Fu,* and Wei Huang*
Page No. – Page No.
Access to Enantioenriched
Organosilanes from Enals and β-Silyl
Enones under Carbene
Chiral Organosilanes: A carbene enabled formal [4 + 2] annulation of enals with β-
silyl enones under mild conditions. A diverse set of enantioenriched organosilanes
bearing two continuous stereocenters was obtained by this transition-metal-free
strategy in good yields with excellent diastereo- and enantioselectivities. Notably,
two consecutive stereogenic centers could be constructed in only one step.
Organocatalysis
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