Catalytic asymmetric cyanosilylation of ketones by a chiral amino acid salt

Article abstract of DOI:10.1021/ja052629d

In this Communication, we describe the first highly enantioselective cyanosilylation of ketones catalyzed by simple chiral amino acid salt. A broad range of aromatic, α,β-unsaturated, heterocyclic ketones catalyzed by L-phenylglycine sodium salt gave the

Full text of DOI:10.1021/ja052629d

Published on Web 08/13/2005
Catalytic Asymmetric Cyanosilylation of Ketones by a Chiral Amino Acid Salt
Xiaohua Liu, Bo Qin, Xin Zhou, Bin He, and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry,
Sichuan UniVersity, Chengdu 610064, P. R. China
Received April 22, 2005; E-mail: xmfeng@scu.edu.cn
Table 1. Optimization Studiesa
Homochiral cyanohydrins are of synthetic interest as they may
be elaborated into a number of key multifunctional intermediates.1
There have been intense research activities in enantioselective
synthesis of cyanohydrins from aldehydes, ketones, and acetals in
2
recent years. The resultant reactions mainly employed catalysts
such as enzymes, cyclic dipeptides, and transition metal complexes.
But the asymmetric cyanation of ketones has been historically
considered as problematic. At present, the majority of chiral
catalysts used for this goal are chiral ligands attached to metals
yielde (%)
f
entry
catalyst
solvent
temp (
°
C)
ee (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2f
Et2O
Et2O
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
-45
-45
94
92
98
15
65
45
71
98
50
70
68
64
96
4
4
Et O
2
11
14
32
44
3
4
5
6
g
such as Al, Ti, and La, basic cinchona alkaloid catalysts, chiral
Et2O
7
8
Et2O
Et2O
Et2O
Et2O
THF
THF
THF
THF
THF
oxazaborolidinium ions, and thiourea catalysts. In these contexts,
a new methodology emerged from the study of interesting findings
by Shibasaki and our group in which the oxygen atom of the
phosphine oxide and N-oxide coordinated to the silicon atom of
TMSCN to activate TMSCN. Meanwhile, some important observa-
tions have been made regarding the effect of heterogeneous catalysts
on the synthesis of racemic cyanohydrins, such as solid acid and
g
7
2
54
80
82
94
94
b
10
11
12
13
2f
b,c
2f
b,c
2f
b,d
2f
9
10
base catalysts, diamino-functionalized mesoporous polymers, and
the inorganic/organic salts catalysts used in our early work.11 It
was of particular interest to us to explore this approach via the
development of a catalytic asymmetric cyanation of ketones with
readily accessible amino acid salts, in light of the abundance of
chiral amino acids.
a
Reactions were carried out on a 0.5 mmol scale with 1.2 equiv of
TMSCN in 1.0 mL of solvent, unless noted otherwise. b The catalyst was
stirred with 1.2 equiv of TMSCN in THF for 1 h at 30 °C before
acetophenone was added. c The catalyst was prepared in situ. 1.5 equiv
d
of TMSCN and 0.5 equiv of PrOH were used. Isolated yield. f Determined
i
e
by GC analysis. g The absolute configuration of the major product was S,
4
b
assigned by comparing GC with the literature, and the others were R (see
Herein, we described the first example of chiral organic salts as
catalysts for asymmetric cyanosilylation of ketones. Our initial
catalyst screening revealed that L-phenylglycine sodium salt 2f was
an effective catalyst and led to product formation in 44% ee.
L-Proline has been widely used as an organocatalyst in many
reactions,12 with its sodium salt giving a racemic product, however.
Both the primary amine moiety and the metal carboxylate moiety
of catalyst 2f were essential for the catalytic activity and asymmetric
induction. Lithium and potassium salts of L-phenylglycine were less
effective than the sodium salt in that the products were both racemic.
The crucial role of the primary amino group of 2f was evident upon
comparison of the amine substituent on the catalyst (see Supporting
Information for details).
Supporting Information for details).
ee (Table 1, entries 6 and 9). Moreover, some key features
associated with the use of L-phenylglycine sodium salt are
noteworthy. When the catalyst was stirred with TMSCN in THF
for 1 h at 30 °C before acetophenone was added, the enantiose-
lectivity was greatly improved from 54% to 80% ee at -20 °C
and up to 94% ee at -45 °C (entries 9-12). Interestingly, a small
amount of water contained in the catalyst 2f was crucial to retain
enantioselectivity, and any attempt to remove water from the catalyst
i
gave bad results. Moreover, introduction of PrOH greatly promoted
cyanosilylation rates, with complete acetophenone conversion within
2
1
4 h at -45 °C without loss of enantioselectivity (Table 1, entry
3) (see Supporting Information for details).
The scope of L-phenylglycine sodium salt 2f-catalyzed enantio-
selective cyanosilylation was explored using a variety of ketones.
Table 2 summarizes the most significant results obtained under
optimized conditions. In most cases, useful reaction rates were
obtained. Most of the aromatic, heterocyclic ketones were converted
into the corresponding cyanohydrin trimethylsilyl ethers with high
enantioselectivities (90-97% ee). When trans-cinnamophenone was
subjected to our reaction condition, only the 1,2-addition product
was afforded in 96% isolated yield and 97% ee (Table 2, entry 9).
The aliphatic and R,â-saturated ketones gave moderate ee values
(entries 11, 12). L-Phenglycine could be easily and efficiently
recovered for reuse by simple filtration and acidic treatment after
the reaction (ca. 94% recovery yield of L-phenylglycine).
Optimization of other reaction parameters led to further improve-
ments in enantioselectivity with catalyst 2f. The best result was
obtained when 30 mol % catalyst loading was used. The solvent
study indicated that THF afforded the best overall result, with 54%
12224
9
J. AM. CHEM. SOC. 2005, 127, 12224-12225
10.1021/ja052629d CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Cyanosilylation of Ketones Catalyzed
by 2fa
recyclable catalysts and employment of simple and convenient
experimental procedure. These features should render the reaction
a catalytic entry for the other asymmetric creation of quaternary
stereocenters. Further efforts will be devoted to search for effective
systems that tolerate a broad range of ketones with higher yield
and enantioselectivity.
entry
ketone 1
time (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
acetophenone 1a
24
54
54
27
40
54
36
54 (66)
96
81
75
90
83
80
77
84 (58)
96
90
94 d
92
97
92
Acknowledgment. We thank the National Natural Science
Foundation of China (Nos. 20225206, 20390055, and 20372050),
the Ministry of Education of China (No. 104209 and others), and
Sichuan University (No. 2004CF07) for financial support.
4′-methoxyacetophenone 1b
4′-methylacetophenone 1c
4′-fluoroacetophenone 1d
4′-chloroacetophenone 1e
3′-chloroacetophenone 1f
2′-fluoroacetophenone 1g
2-acetylthiophene 1h
trans-4-phenyl-3-buten-2-one 1i 27
â-acetonaphthone 1j
benzylacetone 1k
90
96
90
Supporting Information Available: Experimental procedures and
spectral and analytical data for the products (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
e
e
86 (92)e
97
1
1
1
0
1
2
27
20
20
96
81
55
97
92
3-methylbutanone 1l
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