Phosphine-oxide-catalyzed Enantioselective Cross-aldol Reactions of Aldehydes with Trichlorosilane as Lewis Acid Promoter

Article abstract of DOI:10.1002/cctc.202000914

A hypervalent silicon complex between trichlorosilane and a chiral phosphine oxide acts as an effective Lewis acid mediator that successfully promotes highly enantioselective cross-aldol reactions between two aldehydes. The high yielding transformation is

Full text of DOI:10.1002/cctc.202000914

The European Society Journal for Catalysis
Supported by
Accepted Article
Title: Phosphine-oxide-catalyzed Enantioselective Cross-aldol
Reaction of Aldehydes with Trichlorosilane as Lewis Acid
Promoter
Authors: Shunsuke Kotani, Takuya Hanamure, Yoshiki Mori, and
Makoto Nakajima
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10.1002/cctc.202000914
ChemCatChem
COMMUNICATION
Phosphine-oxide-catalyzed
Enantioselective
Cross-aldol
Reactions of Aldehydes with Trichlorosilane as Lewis Acid
Promoter
Shunsuke Kotani,* Takuya Hanamure, Yoshiki Mori, and Makoto Nakajima*
Dr. S. Kotani, Mr. T. Hanamure, Mr. Y. Mori, and Dr. M. Nakajima
Graduate School of Pharmaceutical Sciences, Kumamoto University
5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, JAPAN
E-mail: S. Kotani: skotani@kumamoto-u.ac.jp, M. Nakajima: nakajima@gpo.kumamoto-u.ac.jp
Supporting information for this article is given via a link at the end of the document.
Abstract: A hypervalent silicon complex between trichlorosilane and
a chiral phosphine oxide acts as an effective Lewis acid mediator that
successfully promotes highly enantioselective cross-aldol reactions
between two aldehydes. The high yielding transformation is realized
with the assistance of triisobutylamine, which does not decompose
trichlorosilane but rather converts the aldol donor into the silyl enol
ether that undergoes the enantioselective cross-aldol reaction with a
second aldehyde in combination with the chiral phosphine oxide
catalyst.
Phosphine oxides were historically developed as precursors of
phosphines that were used as metal ligands in organic chemistry;
nowadays, their mature structural diversity has enabled the
development of many Lewis-base-catalyzed asymmetric reactions.[1,2]
Phosphine oxides are highly polar and behave as neutral coordinating
Lewis bases; they readily form hypervalent silicon complexes in situ
with chlorosilanes. These silicon complexes consist of Lewis acidic
silicon sites with adjacent nucleophilic sites that facilitate aldol,
allylation, and conjugate reduction reactions.[3] Our research group
has developed a variety of phosphine-oxide-catalyzed asymmetric
aldol reactions using these hypervalent silicon complexes.[4,5] Since,
Scheme 1. Chiral phosphine-oxide-catalyzed, SiCl4-mediated cross-
in most cases, aliphatic aldehydes are not tolerated as electrophiles
due to the in situ-formation of silylated chlorohydrins with silicon
tetrachloride in the presence of a Lewis base catalyst,[6] hypervalent
silicon complexes discriminate between aromatic and aliphatic
aldehydes to realize cross-aldol reactions. We reported the
asymmetric cross-aldol reaction between an aromatic and an aliphatic
aldehyde (1a, 2a) by combining silicon tetrachloride with (S)-BINAPO
(3), a chiral phosphine oxide catalyst; however, the enantioselectivity
for product 4aa was unsatisfactory (Scheme 1).[4b] Although numerous
examples of asymmetric cross-aldol reactions via enamine
intermediates have been described,[7-11] there are few alternative
variations beyond the enamine-type activation mode. Given our
interest in extending the potential of hypervalent silicon complexes
formed from chiral phosphine oxide catalysts for asymmetric cross-
aldol transformations, herein, we focused on a hypervalent silicon
complex formed from trichlorosilane, which behaves as a weaker silyl
reagent than silicon tetrachloride. Trichlorosilane is a commonly used
reducing reagent for the metal-free asymmetric reductions of various
substrates, including ketones, enones and imines.[12-15] The weaker
and milder Lewis acidity of trichlorosilane compared to silicon
tetrachloride was expected to promote the aldol reaction between two
aldehydes in a more stereoselective fashion (Scheme 2).
aldol reaction.
In this reaction, the phosphine oxide catalyst coordinates in a
bidentate manner to trichlorosilane to form a hexacoordinated
hypervalent silicon complex. The subsequent elimination of a chloride
ion leads to pentacoordinated and highly Lewis-acidic hypervalent
silicon complex A. We were concerned that complex A would mediate
the reductions of aldehydes to alcohols without forming trichlorosilyl
enol ethers. A second potential problem is related to the Brønsted
acidity of the trichlorosilane proton under basic conditions, to form
trichlorosilyl anion B.[16] To realize the desired trichlorosilane-
mediated cross-aldol reactions between aldehydes, both of these
issues required resolution. In this communication, we reveal the novel
Lewis acid functionality of trichlorosilane in the phosphine-oxide-
catalyzed cross-aldol reactions of aldehydes to realize highly
enantioselective transformations.
1
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Table 1. Trichlorosilane-mediated enantioselective cross-aldol reactions
between aldehydes 1a and 2a.[a]
entry
amine
solvent
temp, °C
yield, %
ee, %[b]
1
iPr2NEt
Et3N
Cy2NiBu
iBu3N
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
EtCN
25
25
69
41
99
93
93
93
18
13
97
55
6
73
75
75
76
74
61
58
30
22
86
86
85
2
25
3
25
Scheme 2. Reaction modes and properties of trichlorosilane.
4
25
5
2,6-lutidine
iBu3N
iBu3N
iBu3N
iBu3N
iBu3N
iBu3N
iBu3N
25
6
25
We began our investigation by reacting aldehydes 1a and 2a in
the presence of trichlorosilane and (S)-3 in dichloromethane at
room temperature (Table 1, entry 1, cf., Scheme 1). The cross-
aldol reaction proceeded moderately to afford the product in 25%
yield, with a gratifying enantioselectivity (73% ee). Isolation and
analysis were conducted after reduction of aldol adduct 4aa to diol
5aa with NaBH4 in methanol. Since the tertiary amine used as the
Brønsted base might affect the product yield through competitive
deprotonation of trichlorosilane, we investigated several other
amines (entries 2–5). Triethylamine, a less hindered and more
nucleophilic amine, improved both the product yield and
enantioselectivity (entry 2), whereas sterically congested N,N-
dicyclohexylisobutylamine resulted in a lower product yield (41%,
entry 3). These results indicate that the steric bulk of the amine
notably affects reactivity in the trichlorosilane-mediated cross-
aldol reaction. On the other hand, similar selectivities were
observed, indicating that the amine is only involved in the
deprotonation step and not in the enantio-determining step of the
cross-aldol reaction. The use of triisobutylamine in the reaction
gratifyingly afforded cross-aldol adduct 4aa in 99% yield with 76%
ee (entry 4). 2,6-Lutidine also gave a good result, similarly to that
of triisobutylamine (entry 5). Solvent investigations revealed that
acetonitrile and propionitrile gave 4aa in good yields, albeit with
lower selectivities (entries 6 and 7), whereas THF and toluene
were detrimental to both chemical and optical yields (entries 8 and
9). While the enantioselectivity improved to 86% ee when the
reaction was carried out at –20 °C in dichloromethane (entry 10),
further temperature reductions led to dramatic decreases in yield
without any significant increase in enantioselectivity (entries 11
and 12).[17]
7
25
8
THF
25
9
toluene
CH2Cl2
CH2Cl2
CH2Cl2
25
10
11
12
–20
–40
–60
[a] Unless otherwise noted, the reactions were carried out by adding Cl3SiH (1.5
equiv) to a solution of aldol acceptor 1a (0.5 mmol), aldol donor 2a (1.5 equiv),
an amine (5.0 equiv), and (S)-3 (10 mol %) in a solvent (5 mL). [b]Determined by
HPLC.
Aldol reactions with silicon tetrachloride require sterically
congested amines to avoid undesirable interactions with the
silylating agent.[4] In contrast, less-hindered amines tended to give
better results with trichlorosilane. Since the weaker electrophilicity
of trichlorosilane prohibits coordination by the amine, a less-
hindered amine can be used (Figure 1). Although the least
sterically hindered amine (i.e., triethylamine) can react with
trichlorosilane, thereby reducing the product yield, the greater
steric hindrance of triisobutylamine and 2,6-lutidine successfully
suppresses both the nucleophilic attack and deprotonation of
trichlorosilane, ably mediating enolization of the aldol donor.
Figure 1. Impact of steric hindrance on reaction-path selection for
triisobutylamine in the cross-aldol reaction.
With the optimal reaction conditions in hand, we examined the
cross-aldol reactions of various aldehydes (Scheme 3). p-
Anisaldehyde (1b) bearing an electron-donating group was
slightly less reactive with aldehyde 1a, requiring 24 h for complete
reaction, but product 5ba was obtained with good
enantioselectivity (86% ee). In contrast, slightly lower
enantioselectivity was observed in the reaction of p-
bromobenzaldehyde (1c) bearing an electron-withdrawing group.
2
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Sterically hindered 1- and 2-naphthaldehydes (1d and 1e,
respectively) also reacted well to give good enantioselectivities
(84% ee and 83% ee, respectively), whereas the
enantioselectivity was lower in the reaction of cinnamaldehyde
(1f), a conjugated aldol acceptor. Various aldol donors were next
investigated in reactions with 1a. -Diethylated acetaldehyde
2b gave product 5ab with the highest enantioselectivity (91% ee).
Cyclic aliphatic aldehydes 2c and 2d gave the corresponding
products 5ac and 5ad in 76% ee and 74% ee, respectively.
The authors declare no conflicts of interest.
Keywords: Aldol reaction • Enantioselectivity • Hypervalent
silicon • Lewis base • Phosphine oxide
[1]
[2]
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[a]All reactions were carried out by adding Cl3SiH (1.5 equiv) to a solution of aldol
acceptor 1x (0.5 mmol), aldol donor 2y (1.5 equiv), iBu3N (5.0 equiv), and (S)-3
(10 mol %) in CH2Cl2 (5 mL) at –20 °C.
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In summary, we demonstrated the utility of trichlorosilane as a
Lewis acid mediator in phosphine-oxide-catalyzed aldol reactions,
realizing highly enantioselective cross-aldol reactions between
aldehydes. The key to this achievement is the use of
triisobutylamine as an effective Brønsted base to afford the aldol
products in good-to-high yields and enantioselectivities. In future
work, we hope to develop an enantioselective tandem reaction
that exploits the diverse functionalities of trichlorosilane.
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Acknowledgements
This work was partially supported by the Naito Foundation, JSPS
KAKENHI (No. 19K06997) from The Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
Conflict of Interest
3
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[17] Although we screened various phosphine oxide catalysts to improve
enantioselectivity, dramatic increases were not observed. Detailed
catalyst-screening results are provided in the Supporting Information.
4
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Entry for the Table of Contents
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Phosphine oxide catalysis with trichlorosilane. A hypervalent silicon complex formed between trichlorosilane and a chiral phosphine
oxide acts as an effective Lewis acid mediator that successfully promotes the cross-aldol reaction between two aldehydes with good-
to-high enantioselectivity. The high yielding transformation is realized by the assistance of triisobutylamine, which effectively promotes
the silyl enolization of an aldol donor, resulting in the cross-aldol reaction with an aldol acceptor.
Keywords: Aldol reaction • Enantioselectivity • Hypervalent silicon • Lewis base • Phosphine oxide
5
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