Kinetic Resolution of Acylsilane Cyanohydrins via Organocatalytic Cycloetherification

Article abstract of DOI:10.1002/asia.201801600

An asymmetric cyanation of acylsilanes involving the in-situ formation of chiral acylsilane cyanohydrins followed by their kinetic resolution via organocatalytic cycloetherification is described. The highly enantio- and diastereoselective cycloetherificat

Full text of DOI:10.1002/asia.201801600

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Accepted Article
Title: Kinetic Resolution of Acylsilane Cyanohydrins via Organocatalytic
Cycloetherification
Authors: Akira Matsumoto, Keisuke Asano, and Seijiro Matsubara
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Kinetic Resolution of Acylsilane Cyanohydrins via Organocatalytic
Cycloetherification
Akira Matsumoto, Keisuke Asano,* and Seijiro Matsubara*
Abstract: An asymmetric cyanation of acylsilanes involving the in
situ formation of chiral acylsilane cyanohydrins followed by their
kinetic resolution via organocatalytic cycloetherification is
acylsilanes is more favorable than that of normal ketones (Scheme
1).[14,15]
According to this reaction design, the obtained chiral acylsilane
cyanohydrins could then undergo organocatalytic mutation from a
single enantiomer by virtue of the highly enantio- and
diastereoselective nature of the cycloetherification reaction.
Consequently, the mismatched enantiomer of the acylsilane
cyanohydrin, which contains a tetrasubstituted chiral carbon center
bearing silyl, cyano, and hydroxy groups, would be obtained in an
enantioenriched form. Thus, we herein present an efficient protocol for
the enantioselective cyanation of acylsilanes involving kinetic
resolution via an asymmetric cycloetherification process based on the
use of bifunctional aminothiourea catalysts.[16,17]
described.
The highly enantio- and diastereoselective
cycloetherification was crucial for achieving a high efficiency in
the kinetic resolution. Consequently, acylsilane cyanohydrins
containing a tetrasubstituted chiral carbon atom bearing silyl,
cyano, and hydroxy groups were obtained in an enantioenriched
form. This protocol therefore offers an efficient catalytic approach
to optically active acylsilane cyanohydrins, which exhibit potential
as chiral building blocks for the synthesis of pharmaceutically
relevant chiral organosilanes.
The catalytic asymmetric cyanation of ketones constitutes
a
straightforward method for the construction of tetrasubstituted chiral
carbon centers, which is of particular interest in synthetic organic
chemistry.[1,2] Indeed, due to the synthetic utility of optically active
tertiary alcohols bearing a cyano group,[3,4] various methods for their
asymmetric synthesis have been reported to date.[1,2a–c] However, the
asymmetric cyanation of acylsilanes has been limited to a few
enzymatic approaches employing only one example substrate,[5]
although several reports into the catalytic asymmetric addition of other
carbon nucleophiles to acylsilanes have recently appeared due to the
increasing interest in silicon-containing small molecules in drug design
and development.[6–8] One possible reason for the lack of such methods
is the competing Brook rearrangement,[9] which is known to easily take
place under basic conditions.[10] Thus, as an alternative synthetic
approach to optically active acylsilane cyanohydrins, we focused on
their kinetic resolution.[11] In this context, it would be efficient to
develop a kinetic resolution protocol involving the in situ formation of
chiral cyanohydrins from more easily available acylsilanes under
nearly neutral conditions, which prevent the Brook rearrangement from
taking place.
Scheme 1.
cycloetherification.
Asymmetric cyanation of acylsilanes via organocatalytic
We initially investigated the reaction using acylsilane 1a, which
contains an α,β-unsaturated ketone moiety, and acetone cyanohydrin
(2) as the cyanation reagent. In the presence of bifunctional
aminothiourea catalyst 6a, which bears a cyclohexanediamine moiety,
the desired acylsilane cyanohydrin 3a was obtained in only 5% yield,
although tetrahydropyran derivative 4a was obtained in 61% yield
(Table 1, entry 1), in addition to a significant amount of O-silylated
cyanohydrin 5a. The formation of 5a indicates that the in situ-
generated acylsilane cyanohydrin 3a rapidly underwent a Brook
rearrangement as a competing side reaction. We then investigated the
use of other catalysts and found that the quinidine-derived
aminothiourea catalyst 6b afforded 3a in a high yield and with
excellent enantioselectivity (Table 1, entry 2); it is notable that the
formation of Brook product 5a was largely suppressed under these
reaction conditions. In addition, when the reaction was carried out
using quinine-derived aminothiourea catalyst 6c, which is a pseudo-
enantiomer of 6b, the opposite enantiomer of 3a was obtained in high
enantioselectivity (Table 1, entry 3). In contrast, catalyst 6d, which
contains a significantly less basic nitrogen atom, displayed no catalytic
activity for this transformation (Table 1, entry 4). Furthermore, the
reaction using quinidine (6e) as the catalyst exclusively afforded Brook
product 5a (Table 1, entry 5). The same trend was also observed when
achiral thiourea 7 was employed in combination with quinuclidine (8)
Recently, we developed a kinetic resolution of chiral tertiary
alcohols bearing an α,β-unsaturated ketone moiety via an
organocatalytic intramolecular oxy-Michael addition procedure.[12] We
also reported
a
highly enantio- and diastereoselective
cycloetherification reaction using cyanohydrins generated in situ from
ketones as chiral tertiary alcohols;[13] this process quantitatively
afforded optically active cyclic products by dynamic kinetic resolution,
due to the reversible nature of cyanohydrin formation. We therefore
envisaged that our methods could be applied in the asymmetric
cyanation of acylsilanes via classical kinetic resolution to irreversibly
afford optically active acylsilane cyanohydrins as the cyanation of
[*]
A. Matsumoto, Prof. Dr. K Asano, Prof. Dr. Seijiro Matsubara
Department of Material Chemistry, Graduate School of Engineering
Kyoto University
Kyotodaigaku-katsura, Nishikyo, Kyoto 615-8510 (Japan)
E-mail: asano.keisuke.5w@kyoto-u.ac.jp
matsubara.seijiro.2e@kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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and THF resulted in a reduced reactivity for the cycloetherification
reaction (Table 1, entries 10 and 11) or no conversion of starting
material 1a (Table 1, entry 12).
Table 1. Optimization of reaction conditions.[a]
With the optimal conditions in hand, we moved on to explore the
substrate scope of the reaction (Scheme 2). In the presence of
aminothiourea catalyst 6b, acylsilanes 1a–1c bearing trialkylsilyl
groups were found to be suitable substrates for this reaction, and the
corresponding acylsilane cyanohydrins 3a–3c were obtained in good
yields with high enantioselectivities. In the cases of substrates bearing
benzyl- and phenyl-substituted silyl groups, the cycloetherification
reaction was faster, and the prompt formation of acylsilane
cyanohydrins by the use of larger quantities of 2 was necessary; the
corresponding acylsilane cyanohydrins 3d and 3e were obtained in
high enantioselectivities. The influence of the enone moiety was also
examined. Indeed, products 3f and 3g, containing electron-rich and
electron-deficient enone moieties, respectively, were obtained in high
yields, and the reaction of electron-rich substrate 1f resulted in a
further enhanced enantioselectivity. It is also noteworthy that
carboxylic acid derivatives could be employed as substrates, affording
the corresponding ester 3h and thioester 3i. Although phenyl ester 1h
reacted more slowly and with moderate enantioselectivity, phenyl
thioester 1i smoothly afforded the corresponding product 3i in a high
yield with good enantioselectivity. Due to the utility of carboxylic acid
derivatives as synthetic intermediates, the potential of these
compounds as building blocks is enhanced, providing approaches to
various chiral organosilanes. The absolute configuration of 3i was
determined by X-ray crystallography (see the Supporting Information
for details), and the configurations of all other materials were assigned
analogously.
Entry
Catalyst
Solvent
Yield
of 3a
(%)[b]
Ee
of 3a
(%)
Yield
of 4a
(%)[b]
Yield
of 5a
(%)[b]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
5
49
44
<1
<1
<1
52
49
>95
41
33
<1
–66
96
–97
–
61
48
52
<1
<1
5
34
2
1
2
6a
6b
4
3
6c
<1
99
77
1
4
6d
–
5
6e
–
6
7 + 8
6b
92
95
14
58
63
–
47
49
3
7
Toluene
n-hexane
EtOAc
MeCN
2
8
6b
2
9
6b
13
14
<1
2
10
11
12
6b
24
<1
6b
THF
6b
[a] Reactions were run using 1a (0.15 mmol), 2 (0.18 mmol), and the catalyst
(0.015 mmol) in the solvent (0.30 mL). [b] Determined by 1H NMR
spectroscopy using 1,1,2,2-tetrachloroethane as the internal standard.
(Table 1, entry 6). These results imply that the bifunctionality of the
catalysts containing thiourea and tertiary amino groups on the
optimized molecular skeleton is crucial for obtaining the desired
acylsilane cyanohydrin 3a in high yields.[18,19] In addition, we also
found that the solvent significantly influences the reaction outcomes
(Table 1, entries 7–12). Specifically, halogenated solvents and toluene
gave satisfactory results with respect to both reactivity and
enantioselectivity (Table 1, entries 2, 7, and 8). In contrast, the
reaction in n-hexane afforded only trace quantities of the cyclized
product 4a, and thus 3a was obtained quantitatively but with a low
enantioselectivity (Table 1, entry 9).[20] Reactions in EtOAc, MeCN,
Scheme 2. Substrate scope. Reactions were run using 1 (0.15 mmol), 2 (0.18
mmol), and 6b (0.015 mmol) in CH2Cl2 (0.30 mL). Yields represent the
material isolated after silica gel column chromatography. [a] 3.0 Equivalents
of 2 (0.45 mmol) were used.
To examine whether cyanohydrin formation via a 1,2-addition
mechanism proceeds enantioselectively in the presence of 6b, the
reaction was carried out using acylsilane 9, which does not contain a
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Michael acceptor, under the optimized conditions (Scheme 3). Indeed,
cyanohydrin 10 was obtained in a high yield, but the enantioselectivity
was significantly lower than that of the reaction of 1i (Scheme 2).
Hence, the 1,2-addition process appeared not to be the
enantiodetermining step.
racemic cyanohydrin 3a as a substrate (Figure 1b). The reaction
profiles are similar to those shown in Figure 1a, although the initial
quantity of 3a was larger in the reaction depicted in Figure 1b. These
results support our reaction design (Scheme 1), in that cyanohydrin
formation via a 1,2-addition mechanism proceeds irreversibly, and the
subsequent highly stereoselective cycloetherification is crucial for
obtaining 3 in high enantioselectivity.
Furthermore, a gram-scale synthesis of 3i was also attempted
(Scheme 4). In this case, the reaction proceeded smoothly using 2.4 g
(6.9 mmol) of 1i under the optimized conditions, and 1.1 g (2.8 mmol,
41%) of 3i was obtained in 98% ee. To demonstrate the utility of the
products, further transformations of 3i were carried out (Scheme 5).
More specifically, the Fukuyama reduction[21] of 3i afforded 11, which
bears a synthetically useful formyl group. In addition, the selective
1,4-reduction of 3i was accomplished, with its thioester moiety
remaining intact, using Pd/C and hydrogen gas to give 10 in high
enantiomeric purity; this product failed to be synthesized by the direct
cyanation method outlined in Scheme 3. Moreover, modification of
the tertiary alcohol moiety of 10 with p-toluenesulfonyl isocyanate
proceeded smoothly, and the resulting chiral carbamate 12 was further
transformed using lithium aluminum hydride into heterocyclic
compound 13 containing a tetrasubstituted chiral carbon bearing a silyl
group without any loss of enantiomeric purity.
Scheme 3. Cyanohydrin formation from acylsilane 9.
Scheme 4. Gram-scale synthesis of 3i.
Scheme 5. Transformations of 3i.
Figure 1. Reaction profiles for the asymmetric synthesis of 3a.
In conclusion, we successfully developed
a novel, highly
enantioselective method for the cyanation of acylsilanes. This route
involved the kinetic resolution of in situ-generated acylsilane
cyanohydrins, in addition to a highly enantio- and diastereoselective
organocatalytic cycloetherification reaction, which was crucial to
obtaining highly efficient transformations. To the best of our
knowledge, this is the first example of a non-enzymatic catalytic
asymmetric approach to optically active acylsilane cyanohydrins,
which are otherwise difficult to prepare. Interestingly, the obtained
The yield of 4a and the enantiomeric excess of 3a were then
monitored (Figure 1). The reaction profiles shown in Figure 1a
indicate that the enantiomeric excess of 3a increased as 4a formed,
with 96% ee being reached when the yield of 4a was approximately
50%. This trend is consistent with typical kinetic resolution reaction
profiles.[11] The same experiments were also carried out using isolated
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products contain a densely functionalized tetrasubstituted stereogenic
carbon center bearing silyl, cyano, and hydroxy groups, and can be
employed in the synthesis of pharmaceutically relevant chiral
organosilanes. This work therefore offers a new avenue for the
catalytic asymmetric construction of synthetically challenging
tetrasubstituted chiral carbons, which can serve as structural platforms
for accumulating multiple functionalities on this chiral carbon center.
Further studies into the application of this method are ongoing in our
laboratory, and the results will be reported in due course.
Acknowledgements
We thank Professor Takuya Kurahashi (Kyoto University) for X-ray
crystallographic analysis. This work was supported financially by the
Japanese Ministry of Education, Culture, Sports, Science and
Technology (15H05845, 16K13994, 17K19120, 18K14214, and
18H04258). K.A. also acknowledges the Naito Foundation, Research
Institute for Production Development, the Tokyo Biochemical
Research Foundation, the Uehara Memorial Foundation, the Kyoto
University Foundation, the Institute for Synthetic Organic Chemistry,
and Toyo Gosei Memorial Foundation. A.M. also acknowledges the
Japan Society for the Promotion of Science for Young Scientists for
the fellowship support.
[9] a) A. G. Brook, J. Am. Chem. Soc. 1958, 80, 1886; b) A. G. Brook,
Acc. Chem. Res. 1974, 7, 77.
Keywords: acylsilane • asymmetric cyanation • tetrasubstituted
chiral carbon • cycloetherification • bifunctional organocatalyst
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[18] Results of further catalyst screening are described in Table S1 in the
Supporting Information. These results imply that the appropriate
bulkiness around a basic amino group of bifunctional catalysts is
crucial for suppressing the Brook rearrangement.
[19] Reported cyanation methods were applied to our substrate 1a (refs 1j
and 1k); these methods afforded 3a in much lower
enantioselectivities than our method.
Information for details.
See the Supporting
[20] We observed that the in situ generated acylsilane cyanohydrin 3a was
insoluble to n-hexane, which seems to prevent the following
cycloetherification.
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10.1002/asia.201801600
Chemistry - An Asian Journal
COMMUNICATION
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COMMUNICATION
Akira Matsumoto, Keisuke Asano,* and
Seijiro Matsubara*
Page No. – Page No.
Kinetic Resolution of Acylsilane
Cyanohydrins via Organocatalytic
Cycloetherification
An asymmetric cyanation of acylsilanes involving the in situ formation of chiral
acylsilane cyanohydrins followed by their kinetic resolution via organocatalytic
cycloetherification is described. The highly enantio- and diastereoselective
cycloetherification was crucial for achieving a high efficiency in the kinetic
resolution. Consequently, acylsilane cyanohydrins containing a tetrasubstituted
chiral carbon atom bearing silyl, cyano, and hydroxy groups were obtained in an
enantioenriched form. This protocol therefore offers an efficient catalytic approach
to optically active acylsilane cyanohydrins, which exhibit potential as chiral building
blocks for the synthesis of pharmaceutically relevant chiral organosilanes.
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