Enantioselective Cyanosilylation of Alkynyl Ketones Catalyzed by Combined Systems Consisting of Chiral Ruthenium(II) Complex and Lithium Phenoxide

Article abstract of DOI:10.1002/adsc.201701593

Asymmetric cyanosilylation of alkynyl ketones with the catalyst systems consisting of amino acid/2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP)/ruthenium(II) complex and lithium phenoxide (Ru?Li cat.) was studied. The reaction was conducted in tert-butyl methyl ether (TBME) at ?78 °C with a substrate-to-catalyst molar ratio (S/C) as high as 2000. A series of simple and functionalized ketones was converted into the alkynyl tertiary cyanohydrin derivatives in up to 99% ee. Appropriate selection of an amino-acid ligand of the catalyst according to the substrate structure was crucially important to achieve high enantioselectivity and a wide scope of substrates. Transformation of the chiral cyanohydrin product into a functionalized lactone was also examined. (Figure presented.).

Full text of DOI:10.1002/adsc.201701593

Title: Enantioselective Cyanosilylation of Alkynyl Ketones Catalyzed by
Combined Systems Consisting of Chiral Ruthenium(II) Complex
and Lithium Phenoxide
Authors: Takeshi Ohkuma, Nobuhito Kurono, Yusuke Sakaguchi,
Kohei Yamauchi, and Taiga Yurino
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701593
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10.1002/adsc.201701593
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201
Enantioselective Cyanosilylation of Alkynyl Ketones Catalyzed
by Combined Systems Consisting of Chiral Ruthenium(II)
Complex and Lithium Phenoxide
Takeshi Ohkuma,a,* Nobuhito Kurono,b Yusuke Sakaguchi,a Kohei Yamauchi,a and
Taiga Yurinoa
a
Division of Applied Chemistry and Frontier Chemistry Center, Faculty of Engineering, Hokkaido University, Sapporo,
Hokkaido 060-8628, Japan
Phone: (+81)-11-706-6599; Fax: (+81)-11-706-6598; e-mail: ohkuma@eng.hokudai.ac.jp
Department of Chemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
b
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Asymmetric cyanosilylation of alkynyl ketones
with the catalyst systems consisting of amino acid/2,2’-
bis(diphenylphosphino)-1,1’-binaphthyl
(BINAP)
/ruthenium(II) complex and lithium phenoxide (Ru•Li cat.)
was studied. The reaction was conducted in tert-butyl
methyl ether (TBME) at –78 °C with a substrate-to-catalyst
molar ratio (S/C) as high as 2000. A series of simple and
functionalized ketones was converted into the alkynyl
tertiary cyanohydrin derivatives in up to 99% ee.
Appropriate selection of an amino-acid ligand of the
catalyst according to the substrate structure was crucially
important to achieve high enantioselectivity and a wide
scope of substrates.
Transformation of the chiral
cyanohydrin product into a functionalized lactone was also
examined.
Keywords: alkynyl ketones; asymmetric catalysis;
bimetallic catalysts; cyanosilylation; lithium; ruthenium
Development of catalytic asymmetric reactions to
produce chiral tertiary alcohol derivatives is among
the central targets in the research area of synthetic
organic chemistry. Enantioselective cyanosilylation
of ketones is the representative method for this
purpose.[1] The chiral tertiary cyanohydrin products
are regarded as a class of functionalized tertiary
alcohol derivatives. Many chiral organometallic
catalysts and organocatalysts have been developed for
this important transformation.[1] However, only three
substrates were examined for the reaction of alkynyl
ketones as follows (Scheme 1).[2] a) A chiral peptide
ligand–Al(O-i-Pr)3 system catalyzed the reaction of 3-
decyne-2-one and (CH3)3SiCN with a substrate-to-
catalyst molar ratio (S/C) of 10 (–78 °C, 24 h) to give
the cyanated product in 66% yield and 91%
enantiomeric excess (ee).[2a] b) The reaction of 4-
phenyl-3-butyne-2-one catalyzed by a chiral lithium
phosphoryl phenoxide with an S/C of 10 (–78 °C, 7 h)
gave the product in 95% yield and 90%
Scheme 1. Previous Studies on the Asymmetric
Cyanosilylation of Alkynyl Ketones.
ee.[2c] c) An alkynyl ,-dialkoxymethyl ketone was
cyanated with a chiral cinchona alkaloid base at an
S/C of 50 (–50 °C, 19 h) to afford the cyanohydrin
derivatives in 93% yield and 96% ee.[2b] The catalytic
activity and enantioselectivity as well as the substrate
scope have room for improvement.
In recent years, a variety of alkyne transformations
have been reported, such as the Pauson–Khand
reaction, enyne cycloisomerization, chalcogenation,
heterocyclization, silaboration, etc.[3]
The large
number and range of such transformations indicates
that the alkyne moiety is a useful carbon-based
functional group.
Therefore, chiral alkynyl
cyanohydrins are expected to be useful multi-
functionalized intermediates for the synthesis of
1
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10.1002/adsc.201701593
Advanced Synthesis & Catalysis
Table 1. Asymmetric Cyanosilylation of Alkynyl Ketone (CH3)3SiCN (2.0 mmol) were reacted in the presence
1a with Ru Complex 3 and C6H5OLi.[a]
of Ru[(S)-phgly]2[(S)-binap][8] ((SA,SP)-3a: 2.0 mol;
S/C = 500) and C6H5OLi (40 mM in THF, 2.0 mol)
in t-C4H9OCH3 at –78 °C for 24 h, the tertiary-
cyanohydrin silyl ether (R)-2a in 97% ee was
obtained quantitatively (entry 1). No 1,4-addition
product was observed.[9]
The excellent
enantioselectivity is notable, because the size
difference between the alkynyl moiety and methyl is
small. The reaction using 0.5 equivalent of C6H5OLi
to 3a gave the same enantioselectivity, suggesting that
an active 1:1 3a–Li+ complex was formed in this
reaction (entry 2).[10] The high catalytic activity of
the 3a–C6H5OLi system achieved complete
conversion in the reaction at an S/C of 2000 with
maintenance of the high enantioselectivity (entry 3).
The Ru complexes with 4-AnGly and (4-ClPh)Gly
ligands,8 3b and 3d, showed similar efficiency
(entries 4 and 6). Introduction of a strongly electron-
donative (CH3)2N group on the phenyl ring of the
PhGly ligand, 3c, somewhat decreased the catalytic
activity and enantioselectivity (entry 5). Interestingly,
the catalytic behavior was drastically changed by
using the alkyl-substituted amino-acid ligands, Val
and t-Leu,[8] instead of PhGly (entries 7 and 8). The
catalytic activity and enantioselectivity were both
significantly decreased, and the sense of
enantioselection was reversed.
The 3–C6H5OLi system was applied to the
asymmetric cyanosilylation of a series of alkynyl
ketones 1 (Table 2). The silyl-ethynyl methyl ketones
1a–1c were equally cyanated to afford the 1,2-adducts
quantitatively with high enantioselectivity under the
standard conditions (entries 1–3). The aryl-ethynyl
ketones 1d–1g showed different behaviors. The
cyanation of the phenyl-ethynyl ketone 1d with the
3a–C6H5OLi catalyst gave the product 2d in 85% ee
(entry 4). The enantioselectivity was increased by
using the 4-AnGly/BINAP/Ru complex 3b (entry 5).
The ee value of 95% was obtained with a 1:0.5 3b–
C6H5OLi system at an S/C of 500 (entry 6). The
comparable result was obtained in the reaction with
an S/C of 1000 (entry 7). The 2-tolyl-ethynyl
substrate 1e showed similar reactivity and
enantioselectivity (entry 8). The reaction of the
electron-rich 4-anisyl-ethynyl ketone 1f was relatively
slow, but the cyanated product 2f was obtained in
99% yield and 94% ee after 72 h (entry 9). The
electron-deficient 4-chlorophenyl-ethynyl ketone 1g
showed slightly lower enantioselectivity (entry 10).
An alkenyl-ethynyl ketone 1h was also converted to
the 1,2-adduct 2h under the regular conditions (entry
11). The 4-AnGly complex 3b showed better
enantioselectivity for this substrate (entry 12). The
reaction of tert-butyl-ethynyl ketone 1i, an alkyl-
ethynyl substrate, using the 3a–C6H5OLi catalyst with
an S/C of 100 took 54 h for completion to yield the
product 2i in 92% ee (entry 13). Notably, the
cyanation of unsubstituted ethynyl ketone 1j
quantitatively afforded the 1,2-adduct 2j (entries 14–
16). The highest ee value of 92% was obtained when
Entry
3
1a/3/Li
Yield [%][b]
>99(97)[c]
ee [%][b]
1
2
500:1:1
500:1:0.5 >99
97
97
97
95
91
3a
3a
3a
3b
3c
3d
3e
3f
3[d]
4
2000:1:1
500:1:1
500:1:1
500:1:1
500:1:1
500:1:1
99
98
81
>99
33
18
5
6
7
8
96
–22[e]
–5[e]
[a]
Unless otherwise stated, the reactions were carried out
using 1a (1.0 mmol) and (CH3)3SiCN (2.0 mmol) in t-
C4H9OCH3 (6 mL) with (SA,SP)-3 and C6H5OLi (40 mM or
20 mM in THF) in a ratio shown in the third column at –
[b]
78 °C for 24 h. Data for (R)-2a were determined by GC
on a chiral stationary phase. The isolated yield is given
in parenthesis. Reaction using 3.0 mmol of 1a. (S)-2a
was the major isomer.
[c]
[d]
[e]
(complex) biologically important compounds.
Moreover, these chiral molecules can be connected to
the naturally occurring and artificial molecular
architectures by means of the click azide–alkyne
cycloadditions.[4]
We previously reported the asymmetric
cyanosilylation of aromatic, aliphatic, and ,-
unsaturated ketones[5] as well as aldehydes[6] with our
original catalyst systems consisting of amino
acid/BINAP/Ru(II) complexes 3 and a Li compound
(see the scheme in Table 1).[7] We utilized these
catalyst systems for the asymmetric reaction of
alkynyl ketones into silylated cyanohydrins, and to
our delight we achieved high catalytic activity
(leading to low catalyst loading), chemoselectivity,
and enantioselectivity as well as a wide scope of
substrates by appropriate selection of the amino-acid
ligand in complex 3 and the reaction conditions. Both
simple and hetero-substituted alkynyl ketones were
successfully converted to the desired products.
We selected a silyl-substituted alkynyl ketone 1a as
the standard substrate to optimize the catalyst
structure (Table 1). The catalyst performance was
evaluated with the three categories of 1) activity, 2)
1,2-selectivity
enantioselectivity.
over
1,4-selectivity,
and
3)
When 1a (1.0 mmol) and
2
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10.1002/adsc.201701593
Advanced Synthesis & Catalysis
Table 2. Asymmetric Cyanosilylation of Alkynyl Ketones Table 3. Asymmetric Cyanosilylation of Functionalized
1.[a]
Alkynyl Ketones 4.[a]
Entry
4
3
4/3/Li
Time Yield
[h]
ee
[%][b]
[%][c]
1
2
3
4
5
6
7
8
500:1:1
500:1:1
1000:1:1
500:1:1
500:1:1
500:1:1
500:1:1
500:1:1
24
24
24
24
24
24
24
62
>99
>99
74(R)
95(R)
4a
4a
4a
4b
4b
4c
4c
4d
4d
3a
3f
3f
3a
3f
3a
3f
Entry
1
3
1/3/Li
Time Yield
[h]
ee
[%][b]
[%][c]
>99(99) 96(R)
>99(93) 84
>99(94) 99
>99(99) 59
>99(99) 92
1
2
3
4
5
6
7
8
500:1:1
500:1:1
500:1:1
500:1:1
500:1:1
500:1:0.5 24
1000:1:0.5 24
500:1:0.5 24
500:1:0.5 72
500:1:0.5 24
500:1:1
100:1:1
100:1:1
500:1:1
500:1:1
24
24
24
24
24
>99(97) 97(R)
>99(99) 95
>99(98) 95
>99
>99
1a
1b
1c
1d
1d
1d
1d
1e
1f
1g
1h
1h
1i
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3a
3b
3a
3a
3b
3b
3a
3a
85(R)
94(R)
75[d]
85
86
3a
3a
>99(93) 95(R)
>99 94(R)
>99(97) 92
99(90) 94
99(93) 90
9
250:1:0.5 62
95[d]
[a]
Unless otherwise stated, the reactions were carried out
using 4 (1.0 mmol) and (CH3)3SiCN (2.0 mmol) in t-
C4H9OCH3 (6 mL) with (SA,SP)-3 and C6H5OLi (40 mM or
20 mM in THF) in a ratio shown in the fourth column at –
9
10
11
12
13
14
15
16
17
54
54
54
24
24
95
85
[b]
1
78 °C.
Determined by GC or H NMR analysis. The
99(90) 91
isolated yield is given in parenthesis. [c] Determined by GC
>99(88) 92
[d]
or HPLC on a chiral stationary phase. A partial reverse
reaction to 4d on silica gel was observed.
>99[d]
>99[d]
>99[d]
88
90
92
1j
1j
1j
1k
1l
500:1:0.5 24
500:1:1
500:1:1
24
24
>99(98) 55
The cyanation of 4a with an S/C of 1000 was
completed in 24 h (entry 3).
18
97[e]
90(R)
Even higher
[a]
Unless otherwise stated, the reactions were carried out
using 1 (1.0 mmol) and (CH3)3SiCN (2.0 mmol) in t-
C4H9OCH3 (6 mL) with (SA,SP)-3 and C6H5OLi (40 mM or
20 mM in THF) in a ratio shown in the fourth column at –
enantioselectivity of 99% was achieved in the
reaction of an ,-diethoxy alkynyl ketone 4b with
the 3f–C6H5OLi catalyst (entry 5). The 3a–C6H5OLi
system showed usable selectivity for this substrate
(entry 4). Medium enantioselectivity of 59% was
obtained in the cyanation of a ,-dimethoxy alkynyl
ketone 4c with the 3a–C6H5OLi catalyst (entry 6). A
high level of enantioselectivity was again achieved by
using the 3f–C6H5OLi catalyst to give 5c in 92% ee
(entry 7). The reaction of an alkynyl -keto ester 4d
slowly afforded the product 5d (86% ee) in 95% yield
catalyzed by the 3a–C6H5OLi system with an S/C of
250 in 62 h (entries 8 and 9).
[b]
1
78 °C.
Determined by GC or H NMR analysis. The
isolated yield is given in parenthesis. [c] Determined by GC
[d]
or HPLC on a chiral stationary phase. 2j was a volatile
compound. [e] 2l was partially decomposed on silica gel.
the reaction was catalyzed by the 1:0.5 3b–C6H5OLi
system, although the size difference between ethynyl
and methyl is quite small (entry 16). Phenyl-ethynyl
ethyl ketone 1k was a difficult substrate to cyanate
with high enantioselectivity, yielding the adduct 2k in
55% ee (entry 17). The reaction of the alkynyl
aldehyde 1l afforded the secondary-cyanohydrin silyl
ether 2l in 90% ee (entry 18).
We next examined the cyanation of functionalized
substrates (Table 3). An alkynyl ketone with an -
methoxy group 4a was cyanated in the presence of the
3a–C6H5OLi catalyst under the standard conditions to
afford the cyanohydrin derivative (R)-5a in 74% ee
quantitatively (entry 1). To our delight, the use of the
t-Leu/BINAP/Ru(II) complex 3f instead of 3a
remarkably increased the ee value of 5a to 95% (entry
2). The structural modifiability is a notable feature of
this catalyst. The bidentate-character of 4a may
change the manner of interaction with the catalyst.
The alkynyl cyanohydrin product 1d was concisely
transformed to a 4-iodo-2(3H)-furanone derivative
with a chiral quaternary carbon 8 without loss of the
enantiomeric purity as shown in Scheme 2 (see also
the Supporting Information). Thus, 1d in 94% ee was
converted to the -hydroxy carboxylic acid 7 by
using Luo’s alcoholysis conditions (6: 66% yield)
followed by saponification (78% yield).[11]
Iodolactonization of 7 reported by Larock afforded 8
in 78% yield and in 94% ee.[12]
Further
functionalization of 8 would be possible by Pd-
catalyzed coupling reactions.[12] The 2(3H)-furanone
structures containing a chiral center exist in some
biologically active molecules.[13,14]
In summary, we have reported highly reactive and
enantioselective cyanosilylation of alkynyl ketones
catalyzed by the amino acid/BINAP/Ru(II) complex–
3
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10.1002/adsc.201701593
Advanced Synthesis & Catalysis
Young Researcher Overseas Visits Program for Accelerating
Brain Circulation” (No. R2401), and the MEXT (Japan) program
"Strategic Molecular and Materials Chemistry through Innovative
Coupling Reactions" of Hokkaido University.
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Scheme 2. Synthesis of
Derivative with a Chiral Quaternary Carbon 8.
a
4-Iodo-2(3H)-furanone
C6H5OLi systems. The reaction was carried out with
an S/C up to 2000, which was about two-orders of
magnitude larger than those in previous reports. A
series of simple and functionalized substrates was
converted into the alkynyl tertiary cyanohydrin silyl
ethers in 97% ee for unfunctionalized products and in
99% ee for functionalized compounds by using the
catalysts bearing appropriate amino-acid ligands in
the best cases. The wide scope of the substrates is
notable. To our knowledge the enantioselectivity is
the highest yet reported for the cyanosilylation of
alkynyl ketones. The cyanohydrin product was
readily converted to the 4-iodo-2(3H)-furanone
derivative without loss of the enantiomeric purity.
Experimental Section
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Typical Procedure for the Enantioselective Cyano-
silylation of 1a with (SA,SP)-3a
To a solution of Ru[(S)-phgly]2[(S)-binap] ((SA,SP)-3a) (2.0
mg, 2 µmol), (CH3)3SiCN (202 mg, 2.04 mmol) and 4-
(tert-butyldimethylsilyl)but-3-yn-2-one (1a) (179 mg,
0.982 mmol) in t-C4H9OCH3 (6.0 mL) was added C6H5OLi
(2 µmol) as a THF solution (40 mM, 50 µL) at –78 ºC
under an argon atmosphere. The reaction mixture was
continuously stirred for 24 h at the same temperature, then
poured into an ice water bath to terminate the reaction. The
mixture was extracted 3 times by ethyl acetate (10 mL × 3).
The collected organic phase was washed with brine and
dried over Na2SO4. After the Na2SO4 was filtered off, the
resulting mixture was concentrated in vacuo. The crude
product was purified by silica-gel column chromatography
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(hexane/ethyl acetate
= 4:1) to afford (R)-4-(tert-
butyldimethylsilyl)-2-methyl-2-((trimethylsilyl)oxy)but-3-
ynenitrile ((R)-2a) (269 mg, 97% yield, 97% ee). The ee
value of 2a was determined by chiral GC analysis: chirasil
dex (0.32 mm × 25 m), carrier gas: helium (72 kPa),
column temp: 110 ºC for 10 min then heating to 190 ºC at a
rate of 10 ºC min–1, tR of (R)-2a: 8.8 min (98.3 %), tR 1of
25
(S)-2a: 9.3 min (1.7 %), [α] ,D 0.3 (c = 1.01, CHCl3), H
NMR (400 MHz, CDCl3): δ 1.85 (s, 3H), 0.95 (s, 9H), 0.29
(s, 9H), 0.140 (s, 3H), 0.135 (s, 3H). The procedures and
chemical properties of products in detail are described in
the Supporting Information.
Acknowledgements
This work was supported by Grants-in-Aid from the Japan Society
for the Promotion of Science (JSPS) (No. 15H03802, No.
25410031, and No. 16K17900), the JSPS program “Strategic
4
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10.1002/adsc.201701593
Advanced Synthesis & Catalysis
Oestreich, E. Hartmann, M. Mewald, Chem. Rev. 2013,
=
4-anisylglycinate.
(4-ClPh)Gly
=
(4-
113, 402–441.
chlorophenyl)glycinate. Val = valinate. t-Leu = tert-
leucinate.
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5
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10.1002/adsc.201701593
Advanced Synthesis & Catalysis
UPDATE
Enantioselective Cyanosilylation of Alkynyl
Ketones Catalyzed by Combined Systems
Consisting of Chiral Ruthenium(II) Complex and
Lithium Phenoxide
Adv. Synth. Catal. Year, Volume, Page – Page
Takeshi Ohkuma,* Nobuhito Kurono, Yusuke
Sakaguchi, Kohei Yamauchi, Taiga Yurino
6
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