Activation of Chiral (Salen)AlCl Complex by Phosphorane for Highly Enantioselective Cyanosilylation of Ketones and Enones

Article abstract of DOI:10.1021/jacs.5b11476

Phosphoranes 2 are identified as a class of effective Lewis bases to activate chiral (salen)AlCl complex 1 to enhance its electrophilicity. Accordingly, a three-component catalyst system consisting of complex 1, phosphorane 2e, and Ph₃PO is developed as a powerful tool for asymmetric ketone cyanosilylation. In particular, an unprecedented highly enantioselective cyanosilylation of linear aliphatic ketones is achieved. A tandem Wittig-cyanosilylation sequence starting from phosphorane 2a and enals 10 is further achieved, which internally utilizes the Ph₃PO byproduct and remaining phosphorane 2a as cocatalysts for cyanosilylation of α,β,γ,δ-unsaturated enones, providing atom-efficient access to valuable chiral conjugated dienes and enynes. The high efficiency of the cyanosilylation originates from orthogonal activation of both (salen)AlCl complex 1 and cyanotrimethylsilane by the phosphorane and Ph₃PO, respectively. This mechanistic insight is supported by NMR, MS, and ReactIR analyses and DFT calculations. Furthermore, the formation of charged complexes through the activation of chiral complex 1 by phosphorane 2a is confirmed by electrical conductivity experiments.

Full text of DOI:10.1021/jacs.5b11476

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Article
Activation of Chiral (Salen)AlCl Complex by Phosphorane for
Highly Enantioselective Cyanosilylation of Ketones and Enones
Xing-Ping Zeng, Zhong-Yan Cao, Xin Wang, Long Chen,
Feng Zhou, Feng Zhu, Cui-Hong Wang, and Jian Zhou
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11476 • Publication Date (Web): 11 Dec 2015
Downloaded from http://pubs.acs.org on December 12, 2015
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Activation of Chiral (Salen)AlCl Complex by Phosphorane for Highly
Enantioselective Cyanosilylation of Ketones and Enones
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XingꢀPing Zeng,1 ZhongꢀYan Cao,1 Xin Wang,2 Long Chen,1 Feng Zhou,1 Feng Zhu,1 CuiꢀHong Wang,1 and
Jian Zhou*1,3
1Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular
Engineering, East China Normal University, Shanghai, 200062, P R China; 2College of Chemistry, Sichuan
University, Chengdu, 610064, P R China; 3State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P R China.
ABSTRACT: Phosphoranes 2 are identified as a type of effective Lewis bases to activate chiral
(salen)AlCl complex 1 to enhance its electrophilicity. Accordingly, a threeꢀcomponent catalyst
system consisting of complex 1, phosphorane 2e and Ph3PO is developed as a powerful tool for
asymmetric ketone cyanosilylation. In particular, an unprecedented highly enantioselective
cyanosilylation of linear aliphatic ketones is achieved. A tandem Wittigꢀcyanosilylation sequence
starting from phosphorane 2a and enals 10 is further achieved, which internally utilizes byꢀ
product Ph3PO and remaining phosphorane 2a as coꢀcatalysts for cyanosilylation of α,β,γ,δꢀ
unsaturated enones, providing an atomꢀefficient access to valuable chiral conjugated dienes and
enynes. The high efficiency of the cyanosilylation originates from orthogonal activation of both
(salen)AlCl complex 1 and TMSCN by phosphorane and Ph3PO, respectively. This mechanistic
insight is supported by NMR, MS, react IR analysis and DFT calculations. Furthermore, the
formation of charged complexes through the activation of chiral complex 1 by phosphorane 2a is
confirmed by electrical conductivity experiments.
■ INTRODUCTION
To enhance the Lewis acidity of the metal centre of a chiral metal complex often plays an
important role in achieving a high catalytic activity for reaction development. In this context, a
routine and powerful strategy is to introduce weakly or nonꢀcoordinating anions to secure high
electrophilicity of a chiral metal complex.1 It is also possible to use an achiral Lewis basic coꢀ
catalyst to activate a chiral metal complex, but this conceptually different strategy is much less
explored,2 possibly because such a type of ligandꢀaccelerated catalysis3 contradicts commonly
held views that the binding of a Lewis base to a chiral metal complex will lead to reduced Lewis
acidity.4 According to the Lewis base catalysis defined by Denmark,5 the activation of a chiral
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metal complex by a Lewis base may originate from a reꢀdistribution of electronꢀdensity in the
resulting Lewis adduct, which polarizes adjacent bonds to form a hypervalent species with
enhanced Lewis acidity.6 Given polarization strong enough, ionization may occur to produce
cationic species with greatly enhanced electrophilicity. Therefore, it is interesting and rewarding
to exploit powerful Lewis bases to effectively activate easily available chiral metal complexes, to
improve catalytic activity and enantioselection. In addition, two intriguing beneficial effects may
be brought about: (1) Along with the activation of chiral metal complex for better electrophilic
activation, it is still possible to use a second coꢀcatalyst to activate the nucleophile. Such an
orthogonal activation7 is promising to develop reactions unattainable by common cooperative
catalysis8 in which the chiral catalyst is not activated. (2) It offers the promise to identify new
ligand motifs, as the structural feature of a powerful coꢀcatalyst is useful to develop new chiral
ligands. Herein, we wish to report that phosphorane 2 can effectively activate chiral (salen)AlCl
complex 19, a privileged catalyst10 easy to prepare and handle, which contributes to a highly
enantioselective cyanosilylation of simple ketones and conjugated enones.
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Since its discovery by Jacobsen et al, chiral catalyst 1 has proved to be valuable in a handful
of important reactions,9,11 including Strecker reaction,9 conjugate addition,11aꢀf FriedelꢀCrafts11g
and Passeriniꢀtype reaction11hꢀj. Despite significant achievements, it is still important to enhance
the Lewis acidity of this neutral complex to expand its application. For example, it alone failed to
catalyze ketone cyanosilylation.12 With the cooperative activation of TMSCN by Ph3PO to form a
more active species Ph3P(OTMS)(N=C:),13 Kim et al used complex 1 to realize an asymmetric
ketone cyanosilylation, but the enantioselectivity had ample room to improve.12 Based on this
work, we further developed a highly enantioselective tandem Wittigꢀcyanosilylation sequence,
aiming at recycling Ph3PO to cooperate with complex 1 for cyanosilylation of enone 4 (A,
Scheme 1).14 However, subsequent studies revealed the high efficiency of cyanosilylation step
was attributed to orthogonal activation of chiral complex 1 and TMSCN by phosphorane 2a and
Ph3PO, respectively (B, Scheme 1). This not only suggests the potential of phosphoranes as a
type of ligand motifs to develop chiral metal catalysts,15 an untrodden path in the chemistry of
ylides, but paves the way to a powerful catalyst system consisting of (salen)AlCl complex 1,
phosphorane 2e and Ph3PO for asymmetric ketone cyanosilylation. It is worth mentioning that
owing to the importance of cyanohydrins as precursors to tetrasubstituted αꢀhydroxy carbonyl
derivatives, much effort has been devoted to cyanation of ketones.16 However, while several
outstanding catalyst systems have been devised for highly enantioselective cyanosilylation of
alkyl aryl ketones,17 linear aliphatic ketones still present a challenge as a substrate class, and the
newly identified catalyst system first enables the transformation of a number of linear aliphatic
ketones to the corresponding cyanohydrins in excellent enantioselectivity (≥90% ee).
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Scheme 1. Asymmetric tandem Wittig-cyanosilylation reaction
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OTMS
CN
O
O
Asymmetric
Wittig
Ph3P
+
R
Cyanosilylation
Reaction
R
H
5
2a
(1.0 equiv)
3
R = Ar, 71-97%, 68-93% ee
(R = Ar or n-Pr)
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R = n-Pr, 66%, 75% ee
Note: complex 1 and TMSCN were added after
the completion of the Wittig step.
N
N
O
Al
Cl
t-Bu
O
t-Bu
O
(R,R)-1
(5-10 mol %)
t-Bu
t-Bu
3 (1.0 equiv)
CH2Cl2, 80 o
Ph3PO
+
R
TMSCN (2.0 equiv), -30 o
C
4
C
A) Previously assumed cooperative activation
B) Asymmetric orthogonal activation (this work)
R
R
OTMS
OTMS
t-Bu
t-Bu
O
O
N
N
CN PPh3
CN PPh3
O
t-Bu
O
t-Bu
N
N
Al
Al
Cl
O
O
t-Bu
O
t-Bu
Cl
t-Bu
t-Bu
Ph3P
■ RESULTS AND DISCUSSION
Mechanistic Studies. The reaction of α,β,γ,δꢀunsaturated enone 6a and TMSCN was first
undertaken to probe the role of each component of the catalytic system (Table 1). As expected,
no reaction took place in the presence of either chiral complex 1 or Ph3PO at 25 oC (entries 1ꢀ2).
Ph3PO was used in 100 mol % to mimic the condition in tandem Wittigꢀcyanosilylation reaction.
However, it was very surprising that the merging of 10 mol % complex 1 and 100 mol % Ph3PO
was also inefficient to promote the cyanosilylation at ꢀ30 C, the previously used condition,14
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giving product 7a in less than 5% yield even after 36 h (entry 3). Considering that in the tandem
protocol, there might be some phosphorane 2a remaining from the Wittig step, 10 mol % 2a was
added, and the reaction was indeed dramatically accelerated to give product 7a in 90% yield and
92% ee (entry 4). To understand the role of phosphorane, more control experiments were
conducted. First, it was surprising that the use of 10 mol % phosphorane 2a mediated the reaction
efficiently at ꢀ30 oC to give 7a in 92% yield (entry 5). To the best of our knowledge, phosphorane
as an organic promoter to trigger a reaction is unprecedented.18 Second, without the cooperation
of Ph3PO, the merger of complex 1 and 2a (10 mol %, each) catalyzed the reaction inefficiently
at 25 oC to give 7a in 43% yield with 65% ee after 36 h, and poorly at ꢀ30 oC (entries 6ꢀ7). These
experiments implied that phosphorane 2a coordinated to complex 1 to form an enhanced chiral
aluminum catalyst (R,R)ꢀ1/2a (entry 1 vs 6); otherwise, free phosphorane would cause severe
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racemic background reaction. On the other hand, the presence of Ph3PO was also important to
secure high reactivity and enantioselectivity, as the Lewis adduct (R,R)ꢀ1/2a was impotent to
mediate the reaction efficiently by itself at ꢀ30 oC (entries 7).
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Table 1. Control experiments for asymmetric cyanosilylation of enone 6aa
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Entry
1 (X)
2a (Y)
Ph3PO (Z)
Temp. (oC)
Yield (%)b
Ee (%)c
ꢀꢀ
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10
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
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ꢀꢀ
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25
no reaction
no reaction
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ꢀꢀ
ꢀ30
ꢀ30
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25
<5
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<5
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92
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ꢀꢀ
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10
ꢀꢀ
ꢀ30
a For details, see section 2ꢀ1 of SI. bIsolated yield. cDetermined by chiral HPLC analysis.
In the following, NMR, MS and React IR analysis were conducted (for details and discussion,
see section 2ꢀ2, 2ꢀ3 and 2ꢀ4 of supporting information, SI, respectively), which cast some light on
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the possible reaction mechanism. First, H and C NMR analysis revealed that phosphorane 2a
bound to complex 1 in an Oꢀcoordination fashion, as shown in B of Scheme 1. In addition,
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variable temperature P NMR analysis revealed that the binding of 2a to complex 1 was tight,
almost undisturbed by the presence of 10 equiv of Ph3PO. Ph3PO might bind to aluminum of
adduct (R,R)ꢀ1/2a as well, but this interaction was labile enough to allow facile coordination of
enone 6a via ligand exchange. Second, MS analysis detected a characteristic signal [2a+(R,R)ꢀ
1+6aꢀCl]+ at m/z 1061.6, consistent with the complex derived from complex 1, phosphorane 2a
and enone 6a, although it was weak. Furthermore, react IR analysis of the reaction course
confirmed that the role of Ph3PO was to activate TMSCN to form a more active nucleophile
Ph3P(OTMS)(N=C:).13
Now that the binding of phosphorane 2a to chiral (salen)AlCl complex 1 was confirmed by
NMR and MS analysis, the enhanced electrophilicity of the resulting adduct (R,R)ꢀ1/2a could be
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viewed as a result of nꢀσ* type Lewis base activation of Lewis acid.5a According to Gutmann’s
rules,6 the coordination of 2a to complex 1 might induce a reꢀdistribution of electron density in
the adduct (R,R)ꢀ1/2a, leading to the polarization of the AlꢀCl bond, thereby decrease the electron
density at the Al center and increase the electron density at the chlorine atom. Such a hypervalent
state might further result in ionization of the chloride to afford a cationic aluminum complex with
enhanced Lewis acidity. Indeed, density functional theory (DFT) calculations supported that the
binding of 2a to complex 1 easily polarized the AlꢀCl bond, as the Al–Cl distance in adduct
(R,R)ꢀ1/2a was obviously longer than that in (R,R)ꢀ1 (2.538 vs 2.286 Å in solvent CH2Cl2). In
addition, the natural bond orbital (NBO) charge of Al atom in adduct (R,R)ꢀ1/2a was more
positive than that in (R,R)ꢀ1 (1.983 vs 1.926 in solvent CH2Cl2), while the chlorine atom had
more negative charge (ꢀ0.753 vs ꢀ0.671 in solvent CH2Cl2). The adduct (R,R)ꢀ1/2a could easily
undergo an ionization of the chloride to form a cationic complex [(R,R)ꢀ1/2aꢀCl]+, with a
decrement of Gibbs free energy by only 0.8 kcal/mol. Calculation revealed that the activation of
enone 6a by (R,R)ꢀ1 was less efficient than by complex [(R,R)ꢀ1/2aꢀCl]+ (model I vs II, Figure 1),
since the Al–O distance in model I was longer than that in model II (2.343 vs 2.105 Å). The
NBO analysis also showed the more positive NBO charge of Al atom in model II than that in
model I (2.080 vs 1.938). Owing to the stronger Lewis acidity of cationic complex [(R,R)ꢀ1/2aꢀ
Cl]+, along with the activation of TMSCN by phosphine oxide, the barrier of the rateꢀdetermining
C–C bond forming step of cyanosilylation of enone 6a was lowered down to 21.0 kcal/mol, with
a substantial decrease in the total activation energy by 15.3 kcal/mol from 36.3 kcal/mol
(calculation based on complex 1). On the other hand, without any catalyst the reaction proceeded
with a high reaction barrier up to 50.5 kcal/mol. These results supported that the coordination of
phosphorane 2a to complex 1 made the aluminum more electrophilic, which effectively stabilized
the transition state and decreased the activation energy. For details, see section 2ꢀ5 of SI.
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Figure 1. DFT calculation results: Two complexes of (R,R)-1/6a and [2a/(R,R)-1/6a-Cl]+, which were
optimized at the B3LYP/6ꢀ31G(d)&LANL2DZ level. The bond distances of the optimized structures are in
angstroms and the natural bond orbital (NBO) charges are in parentheses.
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In addition to DFT calculations, electrical conductivity experiments also strongly supported
the formation of a cationic aluminum complex via the ionization of chloride, although we failed
to obtain single crystals of Lewis adduct (R,R)ꢀ1/2a or its analogues. This experiment was
inspired by Berrisford’ report that the CH2Cl2 solution of allyltrichlorosilane became conducting
in the presence of Ph3PO, which was regarded as an evidence for the formation of charged
complexes in solution.19 The electrical conductivity was measured using a twoꢀprobe method (see
section 2ꢀ6 of SI). Very interestingly, as shown in Figure 2A, although the conductivity of either
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complex 1 or phosphorane 2a in CH2Cl2 was weak (1.52 and 0.68 ꢁS/cm, 0.02 mol/L, 25 C,
respectively), the addition of phosphorane 2a to a CH2Cl2 solution of complex 1 dramatically
increased the conductivity of the resulting solution, which soared by around 400 times to 598
ꢁS/cm when 1.0 equiv of 2a was added. This observation strongly supported the formation of
ionic complexes via the activation of complex (R,R)ꢀ1 by phosphorane 2a.
800
800
700
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2.0
1.5
1.0
0.5
0.0
400
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200
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0
1.5
1.0
0.5
0.0
3
400
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200
100
0
0
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0
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-100
-100
-1
0
1
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11
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Figure 2. Electrical conductivity experiments: (A) the addition of phosphorane 2a to the CH2Cl2 solution of
complex (R,R)ꢀ1; (B) the addition of Ph3PO to the CH2Cl2 solution of complex (R,R)ꢀ1.
On the other hand, the addition of Ph3PO to a CH2Cl2 solution of complex (R,R)ꢀ1 enhanced
the conductivity as well (Figure 2B), which was increased by 98 times when 1.0 equiv of Ph3PO
was added. This result indicated that Ph3PO was less effective than 2a in activating (R,R)ꢀ1 to
form ionic complex, which was in accordance with NMR analyses that the binding of 2a to
(R,R)ꢀ1 was almost undisturbed by the presence of even 10 equivs of Ph3PO (section 2ꢀ2 of SI),
and the fact that the merger of 10 mol % (R,R)ꢀ1 and 100 mol % Ph3PO was unable to mediate
o
the cyanosilylation of enone 6a at ꢀ30 C (entry 3 of Table 1). This observation intrigued us to
determine the changes in electrical conductivity of the CH2Cl2 solution of (R,R)ꢀ1 after the
addition of 1.0 equiv of typical Lewis bases, and to examine whether there was a relationship
between the thus obtained conductivity and the performance of these Lewis bases as additives in
(R,R)ꢀ1 catalyzed cyanosilylation of enone 6a.
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Table 2. Compare phosphorane 2a with other activators in the cyanosilylation of enone 6a
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Electrical Conductivity (ꢁS/cm)a
Yield
Ee
Entry
Activator
(%)b
(%)c
Activator/(R,R)ꢀ1
Activator
(0.02 M)
(1:1, 0.02 M)
1
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8
ꢀ
ꢀ
1.52
598
245
255
308
386
37
<5
90
trace
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45
ꢀ
88
92
ꢀꢀ
0.685
0.322
1.644
0.294
2.84
2a
LB1
91
90
89
LB2
LB3
LB4
AgOTf
0.469
68.3
AgSbF6
188
ꢀ
ꢀ
a The electrical conductivity experiments were conducted using 2ꢀelectrode method in anhydrous CH2Cl2 at 25 oC. b Isolated yield.
c Determined by chiral HPLC analysis.
It was a wellꢀknown strategy to add a Lewis base to improve the reaction outcome of chiral
salen complexes catalyzed reactions.20 For example, 4ꢀphenylpyridine Nꢀoxide LB1 was used in
chiral (salen)MnCl complex catalyzed epoxidation to facilitate the generation and stabilization of
reactive intermediates.20aꢀf In the cyanation of nitroolefins catalyzed by complex 1, LB1 was
proposed to serve as an axial ligand to activate complex 1, and as a Lewis base to activate
TMSCN as well.11f It was also reported that pyridines or amines might bind to complex 1 to form
(base·[Al(salen)]) complexes that showed enhanced enantioselection but diminished catalytic
activity in indole alkylation.11g Although the role of different additive bases might vary in the
cyanosilylation reaction, we compared phosphorane 2a with some typical Lewis bases such as Nꢀ
oxides LB1-2, tertiary amine LB3, pyridines LB4-5, phosphine oxides LB6-8 and tertiary phosphine
o
LB9 in both electrical conductivity experiments and cyanosilyation of enone 6a at ꢀ30 C (for
details and discussion, see section 2ꢀ6 of SI).
First, the four Lewis bases (phosphorane 2a and LB2ꢀ4), the addition of which to a CH2Cl2
solution of complex 1 in 1:1 ratio resulted in the top four highest conductivity, were also the four
o
effective activators in the cyanosilylation of enone 6a at ꢀ30 C (entries 2 and 4ꢀ6), a condition
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that the merger of 10 mol% (R,R)ꢀ1 and 100 mol% Ph3PO was impotent (entry 1). Other Lewis
bases LB5ꢀ8 also brought about obvious increase in conductivity, but all failed to accelerate the
reaction, possibly because they could not effectively activate complex 1. Second, it turned out
that phosphorane 2a was the most efficient one in increasing conductivity and accelerating the
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cyanosilylation reaction at ꢀ30 C (entry 2 vs entries 4ꢀ6), which suggested the potential of
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phosphorane as a novel type of ligand motifs. Third, only soft Lewis base Ph3P was inert in both
conductivity experiment and cyanosilylation reaction, possibly because it had no effective
interaction with hard Lewis acid Al(III). It should be noted that the role of Lewis bases LB2-4 in
accelerating the cyanosilylation was not clear at this stage, as whether or not their binding to
complex 1 was undisturbed by the presence of 10 equivs of Ph3PO was not confirmed.21
We further examined the performance of cationic aluminum complexes produced from (R,R)ꢀ
1 via halide abstraction using an appropriate silver salt in the cyanosilylation of enone 6a.22 Very
surprisingly, no reaction took place at all when using either AgOTf or AgSbF6 to activate chiral
complex 1 to form the corresponding cationic complex, no matter AgCl was filtered off or not
(entries 7ꢀ8). In addition, the conductivity of the CH2Cl2 solution of (R,R)ꢀ1 with 1.0 equiv of
AgOTf or AgSbF6 was much lower than that of (R,R)ꢀ1 with 1.0 equiv of phosphorane 2a (entry
2 vs entries 7ꢀ8). The conductivity of AgSbF6 in CH2Cl2 was much higher than that of AgOTf
was in part due to its good solubility in CH2Cl2. These results unambiguously exhibited that the
strategy of Lewis base activation of chiral metal complex had its own advantages, as compared
with the alternative strategy of generating cationic chiral catalyst by halide abstraction.
Noticeably, the use of electrical conductivity experiments to detect the formation of charged
complexes via the activation of chiral metal complexes was unprecedented. Our results suggested
it possible to use this costꢀeffective and convenient method for rapid screening of Lewis bases
that could effectively activate a chiral metal complex, although it was inappropriate to directly
correlate the conductivity with the extent to which a chiral catalyst was activated. In addition, as
the strategy of Lewis base activation of Lewis acid23 was important in the field of asymmetric
catalysis, the conductivity experiment might have more application in the mechanistic studies.
Enantioselective Cyanosilylation of Simple Ketones. The finding that phosphorane 2a
could activate complex 1 implied the possibility of varying its substituent to improve
enantioselection. This hypothesis, along with the fact no literature method could achieve more
than 90% ee in the cyanosilylation of linear aliphatic ketones,17 promoted us to tune the
substituent of phosphorane 2 in the cyanosilylation of ketone 8a to identify a highly
enantioselective catalyst system based on chiral (salen)AlCl complex 1 for ketone cyanosilylation.
As expected, (R,R)ꢀ1 failed to mediate this reaction by itself (entry 1, Table 3). The merger of 10
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mol % (R,R)ꢀ1 and 50 mol % Ph3PO catalyzed the reaction slowly, giving product 9a in 61%
yield and 87% ee after 24 h (entry 2). This result suggested that aliphatic ketone 8a was more
active than enone 6a. The addition of 10 mol% phosphorane 2a greatly accelerated the reaction to
finish within 4 h, giving product 9a in 95% yield and 91% ee (entry 3). Finally, it was revealed
that a bulkier phosphorane 2e as the coꢀcatalyst could improve the enantioselectivity to 94%
(entry 7). In addition, the merger of (R,R)ꢀ1 and 2e (10 mol%, each) could also catalyze the
reaction slowly at ꢀ30 oC (entry 8), the presence of Ph3PO obviously accelerated the reaction, and
50 mol % was enough (entries 7, 8ꢀ10). Generally, higher enantioselectivity was observed when
any of phosphoranes 2aꢀe was used as an activator (entries 3ꢀ7 vs entry 2). Possibly, the binding
of a bulky phosphorane as an axial ligand to (salen)Al complex 1 tuned the overall conformation
of salen complex,24 which contributed to a more effective enantiofacial control.
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Table 3. Condition optimization for the asymmetric cyanosilylation of 8a
Entry
Ph3PO (X)
Time (h)
Yield (%)a
Ee (%)b
2
1
2
ꢀ
ꢀ
50
50
50
50
50
50
ꢀ
24
24
4
No reaction
ꢀ
ꢀ
61
95
87
92
93
97
36
90
96
87
91
88
91
92
94
95
94
94
3
2a: R = CH3
2b: R = Ph
2c: R = OMe
2d: R = OEt
2e: R = OtꢀBu
2e
4
7
5
7
6
7
7
6
8
24
21
8
9
20
2e
10
100
2e
a Isolated yield. b Determined by chiral HPLC analysis
Based on the above screening, we examined the scope of ketone cyanosilylation catalyzed by a
combined system of (R,R)ꢀ1, phosphorane 2e and Ph3PO (Scheme 2). Very impressively, a
variety of differently substituted aliphatic ketones worked well to give the desired cyanohydrins
9aꢀi in 85ꢀ97% yield and 90ꢀ94% ee. In addition, aryl ketones were also viable substrates, as
shown by the synthesis of cyanohydrins 9jꢀm in 89ꢀ92% ee. Nonꢀmethyl ketones were also
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viable substrates. For example, cyclohexyl ethyl ketone gave the desired product 9n in 90% yield
and 95% ee. Nevertheless, cyclohexyl vinyl ketone 8o afforded product 9o in diminished 80% ee.
Scheme 2. Scope of catalytic asymmetric ketone cyanosilylation a
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The catalyst loading could be lowered down to 1.0 mol % of (R,R)ꢀ1, 1 mol % phosphorane
2e and 5 mol % of Ph3PO. For example, the cyanosilylation of ketone 8a on a 10 mmol scale
readily afforded the desired product 9a in 97% yield and 92% ee. Furthermore, the use of chiral
complex (S,S)ꢀ1 allowed the gramꢀscale synthesis of cyanohydrin (R)ꢀ9p from methyl isopropyl
ketone 8p (8.04 g, 87% yield and 90% ee), which was the key intermediate to AMG 21, an
inhibitor of 11βꢀhydroxysteroid dehydrogenase type 1.25
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Tandem Wittig-Asymmetric Cyanosilylation Sequence. Considering that there lacked a
highly enantioselective cyanosilylation of α,β,γ,δꢀunsaturated enones,16,17 we further developed a
tandem Wittigꢀcyanosilylation sequence starting from phosphorane 2a and α,βꢀunsaturated enals
10, for the atomꢀefficient synthesis of optically active cyanohydrins bearing a conjugated diene or
enyne group as a synthetically versatile handle,26 as shown in Scheme 3. The oneꢀpot procedure
was operationally simple. After the completion of initial Wittig reaction of enals 10 with ylide 2a,
carried out in a screwꢀcapped pressure tube using CH2Cl2 as the solvent at 80 oC, chiral complex
1 and TMSCN were successively added. The following asymmetric cyanosilylation was
o
conducted at ꢀ30 or ꢀ40 C till completion. It was noteworthy that high ee value of 7a could be
secured with the ratio of phosphorane 2a to chiral complex 1 ranging from 1.0:5.0 to 2.0:1.0 (see
Table S1 of SI), so 1.1 equiv of 2a was used to ensure the full conversion of aldehydes and the
presence of at least 10 mol % phosphorane 2a.
A variety of dienes 7a-o bearing a tetrasubstituted carbon stereocenter, with two, three or four
substituents on alkene functionality, were readily prepared in good yield with high to excellent
enantioselectivity. In addition, optically active conjugated trienes 7pꢀq and enynes 7rꢀt, with
either an aryl or alkyl group, could be accessed in high to excellent enantioselectivity as well,
from the corresponding α,βꢀunsaturated enals. By using DMF as solvent for cyanosilylation step,
we further realized highly enantioselective cyanosilylation of βꢀalkyl substituted enones 4
derived from aliphatic aldehydes and phosphorane 2a, which was unsuccessful under our
previous condition.14 For example, products 5aꢀf were all obtained in high yield and excellent
enantioselectivity (Scheme 3). To show the practical use of our tandem sequence, we tried a
gramꢀscale synthesis of cyanohydrin (R)ꢀ5a, which was used as the key synthon for the total
synthesis of fostriecin,27 a natural antibiotic. Starting from aldehyde 3a and slight excess of 2a,
the use of 6 mol % complex (S,S)ꢀ1 afforded the desired cyanohydrin (R)ꢀ5a in 3.245 g, 68%
yield and 90% ee. Apart from the advantages of using easily available chiral catalyst 1 and higher
ee value for (R)ꢀ5a, our protocol was free from the isolation of intermediate enone.
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Scheme 3. Substrate scope of tandem Wittig-cyanosilylation sequence a,b
6
7
8
9
O
O
OTMS
CN
Ph3P
R1
H
+
R1
Wittig
Reaction
Asymmetric
Cyanosilylation
R
3: R1 = alkyl
10: R1 = alkenyl or alkynyl
2a (R = H)
5: R1 = alkyl
10
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12
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2f (R = Me)
7: R1 = alkenyl or alkynyl
O
2 (ca. 10 mol %)
R1
4: R1 = alkyl
(R,R)-1 (10 mol %)
2 (1.1 equiv)
CH2Cl2, 80 oC, T1
+
+
TMSCN (2.0 equiv)
-30 oC, T2
6: R1 = alkenyl or alkynyl
Ph3PO (1.0 equiv)
OTMS
OTMS
CN
OTMS
CN
R
CN
Ph
R
S
7j (R = Me): 21 h/48 h, 77%, 91% ee
7k (R = Cl): 1 h/24 h, 95%, 92% eeb
7l (R = Cl): 1 h/16 h, 96%, 92% eeb
7g: 19 h/48 h, 80%, 92% ee
7a (R = H):
25 h/48 h, 70%, 91% ee
7b (R = 3-Me): 25 h/48 h, 71%, 92% ee
7c (R = 2-F): 18 h/36 h, 82%, 93% ee
7d (R = 3-F): 21 h/48 h, 81%, 90% ee
7e (R = 4-Cl): 15 h/48 h, 77%, 91% ee
7f (R = 4-Cl): 16 h/48 h, 80%, 92% ee
OTMS
Bn
CN
X
Me
OTMS
CN
Ph
7h (X = CH2): 21 h/60 h, 60%, 90% ee
7i (X = OCH2): 21 h/120 h, 42%, 90% ee
7m (R = Me): 17 h/48 h, 72%, 80% ee
Cl
OTMS
CN
OTMS
CN
OTMS
CN
OTMS
CN
2
Ph
Ph
Ph
C H
5 11
n-
2
Br Me
7o: 0.8 h/6 h, 98%, 84% eeb
7p: 21 h/60 h, 75%, 91% ee
7q: 24 h/72 h, 60%, 92% ee
7n: 12 h/14 h, 67%, 80% ee
OTMS
OTMS
CN
OTMS
CN
CN
2
BnO
Ph
Ph
7r: 0.2 h/24 h, 95%, 83% ee
7t: 4 h/26 h, 88%, 90% ee
7s: 0.3 h/24 h, 91%, 81% ee
OTMS
CN
OTMS
CN
OTMS
CN
OTMS
CN
BnO
Ph
n
n
5a: 12 h/72 h
71%, 90% ee
5b: 19 h/48 h
5c (n = 1): 23 h/48 h, 68%, 95% ee
5d (n = 4): 19 h/48 h, 56%, 93% ee
5e (n = 1): 19 h/48 h, 74%, 93% ee
5f (n = 2): 6 h/48 h, 84%, 90% ee
75%, 93% ee
Gram-scale synthesis of a key intermediate to Fostriecin
1) CH2Cl2 (1.0 M), 80 oC, 18 h
O
OTMS
ref. 27
CN
O
BnO
BnO
Ph3P
H
+
Fostriecin
2) (S,S)-1 (597 mg, 6 mol%),
TMSCN (2.0 equiv)
DMF (0.5 M), -30 oC, 3 d
2a
(5.47g, 1.05 equiv)
3a
(2.46 g, 16.4 mmol)
(R)-5a (3.245 g)
68%, 90% ee
a The results of each product are listed as T1/T2, isolated yield/ee value (for details, see section 4&5 of SI). b Cyanosilylation run at -40 oC.
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An attractive feature of the above sequence is that both coꢀcatalysts (phosphorane 2a and
Ph3PO) required for asymmetric cyanosilylation step are the remaining reagent or byꢀproduct
from the Wittig step. This represents a unique advantage of such tandem reactions, as the internal
reuse of waste alleviates the use of extra substances, helpful in reducing waste generation. It is
worth mentioning that despite progresses, tandem reactions that internally reuse waste to benefit
downstream catalytic asymmetric step are still very limited,14, 28 as it requires rational design to
put waste into use whilst avoiding the deactivation of chiral catalyst. This research outlines a
promising strategy characterized by merging the waste with a chiral catalyst to form a
multicatalyst system,29 to realize an asymmetric reaction unattainable by the chiral catalyst itself.
This is complementary to the strategy pioneered by Shibasaki et al, namely the recycling waste as
an additive to improve reactivity and stereoselectivity.28a Furthermore, the unexpected finding of
phosphorane as a powerful coꢀcatalyst capable of activating chiral (salen)AlCl complex exhibits
that the development of tandem reactions that internally reuse waste is not always the simple
combination of known knowledge, but offers the promise to discover new chemistry.
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Scheme 4. Product elaboration
Product Elaboration. While the versatility of cyanohydrins as building blocks had been well
documented,16 the elaboration of cyanohydrins 7 featuring a conjugated diene group had not been
reported. Therefore, we examined the synthetic potential of compounds 7a and found it could be
readily converted to aminoalcohol 11, aldehyde 13, enone 14, oxazoline 15 and diol 16 with a
conjugated diene moiety at the tetrasubstituted carbon stereocenter (Scheme 4). More, the
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synthesis of polysubstituted pyrrolidine 12 and tetrahydrofuran 17 from 7a was also achieved.
The absolute configuration of 11 was determined to be S by Xꢀray analysis, and that of 7a was
accordingly assigned to be S. The relative configuration of pyrrolidine 12 was assigned by Xꢀray
analysis.
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■ CONCLUSION
In conclusion, we have identified phosphoranes as a type of potent coꢀcatalysts capable of
effective activation of chiral (salen)AlCl complex 1 via mechanistic studies of tandem Wittigꢀ
asymmetric cyanosilylation reaction. A threeꢀcomponent catalyst system consisting of complex 1,
phosphorane 2 and Ph3PO is then developed for highly enantioselective cyanosilylation of a
broad scope of ketones and conjugated enones. The high efficiency of this catalyst system is
originated from orthogonal activation of (salen)AlCl complex 1 and TMSCN by phosphorane and
Ph3PO, respectively, which further exhibits that asymmetric orthogonal activation of the chiral
catalyst and both reactants is promising to develop enantioselective reactions unattainable by
monocatalysis or common cooperative catalysis. The fact that phosphorane 2a is more efficient
than some common Lewis bases in accelerating asymmetric ketone cyanosilylation suggests the
potential of phosphorane as a novel type of ligand motifs to develop chiral metal catalyst.
Considering the powerfulness of chiral (salen)AlCl 1,9,11 the development of chiral salenꢀyilde
aluminum complexes to exploit new enantioselective reactions is in progress in our laboratory.
■ ASSOCIATED CONTENT
Supporting Information. Experimental procedures, characterization data, copies of NMR spectra, and HPLC
traces for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
■ AUTHOR INFORMATION
Corresponding Author
jzhou@chem.ecnu.edu.cn
Notes
The authors declare no competing financial interests.
■ ACKNOWLEDGMENT
We thank the financial support from the 973 program (2015CB856600), NSFC (21222204, 21472049), and
Ministry of Education (PCSIRT).
■ REFERENCE
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(13) (a) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8106. The groups of Shibasaki and Nájera have
also reported the use of phosphine oxide as additives in asymmetric reactions, see ref 4ab and (b) Sawada, D.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 10521. (c) Casas, J.; Nájera, C.; Sansano, J. M.; Saá, J.
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(14) Cao, J.ꢀJ.; Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2010, 49, 4976.
(15) Ylide derived metal complexes have been used for olefin polymerization: (a) Starzewski, K. A. O.; Witte,
J. Angew. Chem., Int. Ed. Engl. 1985, 24, 599. For selected recent examples on ylideꢀmetal complexes: (b)
Spencer, E. C.; Kalyanasundari, B.; Mariyatra, M. B.; Howard, J. A. K.; Panchanatheswaran, K. Inorg. Chim.
Acta. 2006, 359, 35. (c) Sabounchei, S. J.; Nemattalab, H.; Salehzadeh, S.; Khani, S.; Bayat, M.; Khavasi, R. H.
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Comprehensive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds.; Springer, Berlin, 1999,
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V. Coord. Chem. Rev. 2008, 252, 593. (f) Wang, W.; Liu, X.; Lin, L.; Feng, X. Eur. J. Org. Chem. 2010, 4751.
(g) Ishikawa, T. In Comprehensive Chirality; Maruoka, K.; Shibasaki, M. Eds.; Elsevier, Amsterdam, 2012, 5,
194. (h) Pellissier, H. Adv. Synth. Catal. 2015, 357, 857. Also see an example of using NaCN as the cyanide
source: (i) Zhang, Z.; Wang, Z.; Zhang, R.; Ding, K. Angew. Chem., Int. Ed. 2010, 49, 6746.
(17) For selected examples: (a) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 7412.
(b) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J.
Am. Chem. Soc. 2001, 123, 9908. (c) Deng, H.; Isler, M. P.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2002, 41, 1009. (d) Tian, S.ꢀK.; Hong, R.; Deng, L. J. Am. Chem. Soc. 2003, 125, 9900. (e) Chen, F.ꢀX.;
Zhou, H.; Liu, X.; Qin, B.; Feng, X.; Zhang, G.; Jiang, Y. Chem. Eur. J. 2004, 10, 4790. (f) Fuerst, D. E.;
Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964. (g) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007,
129, 15872. (h) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384. (i) Liu, X.; Qin, B.; Zhou, X.; He,
B.; Feng, X. J. Am. Chem. Soc. 2005, 127, 12224. (j) Qin, B.; Liu, X.; Shi, H. J.; Zheng, K.; Zhao, H. T.; Feng,
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(18) The mechanism and the scope of the phosphorane mediated cyanosilylation reaction is still in investigation,
which will be reported in due course.
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(20) For selected examples using nitrogen oxides: (a) Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.;
Deng, L. J. Am. Chem. Soc. 1991, 113, 7063. (b) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T.
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K. B.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl. 1997, 36, 1720. For the use of Ph3PO: (g) Kim, S. S.; Lee,
S. H.; Kwak, J. M. Tetrahedron: Asymmetry 2006, 17, 1165. (h) Khan, N. H.; Saravanan, S.; Kureshy, R. I.;
Abdi, S. H. R.; Bajaj, H. C. Tetrahedron: Asymmetry 2010, 21, 2076. (i) Alaaeddine, A.; Roisnel, T.; Thomas,
C. M.; Carpentier, J.ꢀF. Adv. Synth. Catal. 2008, 350, 731. For the use of tertiary amine or pyridine derivatives:
(j) Wen, Y.ꢀQ.; Hertzberg, R.; Moberg, C. J. Org. Chem. 2014, 79, 6172. For a leading review on the
discussion of the role of achiral Lewis basic additives in asymmetric metal catalysis: (k) Vogl, E. M.; Gröger,
H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 1570.
(21) While these Lewis bases might serve as an axial ligand to coordinate to complex 1, they are also known to
be capable of nucleophilic activation of TMSCN, see: (a) Gawronski, J.; Wascinska, N.; Gajewy, J. Chem. Rev.
2008, 108, 5227. (b) Liu, Y.ꢀL.; Zhou, J. Synthesis 2015, 47, 1210.
(22) Evans et al have reported the use of AgSbF6 to activate an inert chiral aluminum complex to form a highly
reactive species, see: Evans, D. A.; Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew. Chem., Int. Ed. 2001,
40, 1884.
(23) For selected recent examples: (a) Denmark, S. E.; Chi, H. M. J. Am. Chem. Soc. 2014, 136, 8915. (b)
Denmark, S. E.; Jaunet, A. J. Am. Chem. Soc. 2013, 135, 6419. (c) Denmark, S. E.; Hartmann, E.; Kornfilt, D. J.
P.; Wang, H. Nat. Chem. 2014, 6, 1056.
(24) It has also been reported that in the case of Mnꢀsalen complexes, and AlꢀSchiff base systems, the presence
of an axial ligand profoundly affects the overall conformation of the salen complex, see ref 11g, and (a)
Cavallo, L.; Jacobsen, H. Angew. Chem., Int. Ed. 2000, 39, 589. (b) ElꢀBahraoui, J.; Wiest, O.; Feichtinger, D.;
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(26) For the synthesis and application of chiral conjugated dienes, for leading reviews: (a) Nicolaou, K. C.;
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Hashimoto, S.ꢀi. J. Am. Chem. Soc. 1980, 102, 1435. (d) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.;
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Angew. Chem., Int. Ed. 2005, 44, 6533. (f) Nicolaou, K. C.; Harrison, S. T. Angew. Chem., Int. Ed. 2006, 45,
3256. (g) Fürstner, A.; Nevado, C.; Waser, M.; Tremblay, M.; Chevrier, C.; Teplý, F.; Aïssa, C.; Moulin, E.;
Müller, O. J. Am. Chem. Soc. 2007, 129, 9150. (h) Nicolaou, K. C.; Harrison, S. T. J. Am. Chem. Soc. 2007,
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(28) (a) Kinoshita, T.; Okada, S.; Park, S.ꢀR.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2003, 42,
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(29) Zhou, J. Multicatalyst system in asymmetric catalysis, John Wiley & Sons, New York, 2014.
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