The Silicon-Hydrogen Exchange Reaction: A Catalytic σ-Bond Metathesis Approach to the Enantioselective Synthesis of Enol Silanes

Article abstract of DOI:10.1021/jacs.0c06677

The use of chiral enol silanes in fundamental transformations such as Mukaiyama aldol, Michael, and Mannich reactions as well as Saegusa-Ito dehydrogenations has enabled the chemical synthesis of enantiopure natural products and valuable pharmaceuticals. However, accessing these intermediates in high enantiopurity has generally required the use of either stoichiometric chiral precursors or stoichiometric chiral reagents. We now describe a catalytic approach in which strongly acidic and confined imidodiphosphorimidates (IDPi) catalyze highly enantioselective interconversions of ketones and enol silanes. These "silicon-hydrogen exchange reactions"enable access to enantiopure enol silanes via tautomerizing σ-bond metatheses, either in a deprotosilylative desymmetrization of ketones with allyl silanes as the silicon source or in a protodesilylative kinetic resolution of racemic enol silanes with a carboxylic acid as the silyl acceptor.

Full text of DOI:10.1021/jacs.0c06677

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The Silicon−Hydrogen Exchange Reaction: A Catalytic σ‑Bond
Metathesis Approach to the Enantioselective Synthesis of Enol
Silanes
́
Hui Zhou, Han Yong Bae, Markus Leutzsch, Jennifer L. Kennemur, Diane Becart, and Benjamin List*
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ABSTRACT: The use of chiral enol silanes in fundamental transformations such as Mukaiyama aldol, Michael, and Mannich
reactions as well as Saegusa−Ito dehydrogenations has enabled the chemical synthesis of enantiopure natural products and valuable
pharmaceuticals. However, accessing these intermediates in high enantiopurity has generally required the use of either stoichiometric
chiral precursors or stoichiometric chiral reagents. We now describe a catalytic approach in which strongly acidic and confined
imidodiphosphorimidates (IDPi) catalyze highly enantioselective interconversions of ketones and enol silanes. These “silicon−
hydrogen exchange reactions” enable access to enantiopure enol silanes via tautomerizing σ-bond metatheses, either in a
deprotosilylative desymmetrization of ketones with allyl silanes as the silicon source or in a protodesilylative kinetic resolution of
racemic enol silanes with a carboxylic acid as the silyl acceptor.
been rare, and applications toward chiral enol silanes are
currently unknown.8−12 Access to enantiopure enol silanes
traditionally requires stoichiometric amounts of strong chiral
bases such as Simpkins’ lithium amides (Scheme 1B).13
Alternatively, silicon−hydrogen exchange reactions have
recently been used by Takasu et al.14 to prepare achiral and
racemic enol silanes from ketones with silylated triflimide as a
catalyst. Independently, we found that, under certain
conditions, enol silanes can also form as side products in
Mukaiyama aldol and Hosomi−Sakurai reactions via silylium
asymmetric counteranion-directed catalysis (Si-ACDC).15−17
Inspired by these observations, we became intrigued by the
opportunity to develop asymmetric silicon−hydrogen ex-
change reactions toward enantiopure enol silanes. We
envisioned a catalytic cycle in which, upon the formation of
a chiral silylium ion-equivalent (R3SiX*) and propene, via
protodesilylation of an allylsilane by the strong acid HX*, a
siloxocarbenium ion intermediate could be reversibly gen-
erated from the starting ketone (Scheme 1C). Its enantiose-
lective deprotonation by the chiral counteranion X*− would
then produce the enantioenriched enol silane and simulta-
neously regenerate the Brønsted acid precatalyst HX*.
ilicon−hydrogen exchange reactions can be described as
Sformal σ-bond metatheses, interconverting silylated (C−
SiR3 or O−SiR3) and hydrogenated (C−H or O−H)
compounds (Scheme 1A). These reactions are used to install
protecting groups,1 synthesize reagents such as trimethylsilyl
cyanide2 or enol silanes,3−6 and also increase the volatility of
compounds for analytical applications.7 Despite the value of
silicon−hydrogen exchange reactions and their potential to
generate enantiopure silylated compounds that are otherwise
challenging to obtain, their use in asymmetric catalysis has
Scheme 1. Design of a Catalytic Asymmetric Silicon−
Hydrogen Exchange Reaction
While the overall transformation is generally disfavored
thermodynamically, here it would presumably be driven by the
release of volatile propene. In contrast, the corresponding
reverse reaction, the protodesilylation of an enol silane, is
thermodynamically favored and indeed well-known.18−22 Such
Received: June 21, 2020
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© XXXX American Chemical Society
A

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reactions are readily catalyzed by acids, and an asymmetric
protodesilylation of racemic silyl enol ethers should be
attainable by applying the same catalysis concept outlined
above. Only now, instead of using an allylsilane as the silylating
reagent, the reaction would be mediated by a suitable proton
source (Scheme 1D). We speculated that, if the identical chiral
catalyst would be used in the protodesilylation and if the
mechanism of the protonation step would be the exact reverse
of or very similar to the above oxocarbenium deprotonation,
then, in line with the principle of microscopic reversibility,23
the same enantiomer that is created in the forward reaction
should be selectively protodesilylated in the reverse. As a
result, the opposite enantiomer would be obtained in a kinetic
resolution.24
Table 2. Substrate Scope of the Catalytic Asymmetric
Deprotosilylation of Ketones
a
Indeed, when we reacted 4-phenylcyclohexanone (1a) with
commercially available allyl silane 2a in the presence of IDPi
catalyst 4a, enol silane product 3a was obtained in 95% yield
with a promising e.r. of 82:18 (Table 1, entry 1). Other
Table 1. Optimization of the Catalytic Asymmetric
a
Synthesis of Enol Silane
b
c
entry catalyst
solvent
T (°C) yield (%)
e.r.
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
toluene
toluene
toluene
toluene
toluene
toluene
25
25
25
25
25
25
0
−20
95
99
99
99
80
99
99
99
82:18
85.5:14.5
88:12
80:20
80:20
75:25
94:6
a
Performed with 1 (0.2 mmol), 2a (2.0 equiv), and 4c (1 mol %) in
2.4 mL of toluene/dioxane. Isolated yields. e.r. determined by HPLC.
b
c
d
e
f
With 4d. With 4a. With 4b; With 4e. With triethyl(2-
4c
4c
toluene:dioxane (2:1)
toluene:dioxane (2:1)
methylallyl)silane (2b).
97:3
a
Reactions were performed with 1a (0.025 mmol), 2a (2.0 equiv),
b
c
and 4a−4f (1 mol %). 1H NMR yield. e.r. determined by HPLC.
alkyl substituted cyclohexanones 1p−1r were also tolerated,
giving the desired products 3p−3r with enantioselectivities in
the range of 92:8 to 97:3. 4,4-Disubstituted cyclohexanone 1s
provided product 3s, featuring a quaternary stereogenic carbon
center, in 94:6 e.r. Satisfyingly, product 3t bearing an ester
group was generated smoothly in 92% yield with an excellent
e.r. of 98:2. Additionally, we explored a bicyclic cyclo-
pentanone (1u) and a 3-substituted cyclobutanone (1v) to
probe the generality of the methodology. To our delight, the
corresponding enol silanes 3u and 3v were obtained with 95:5
e.r. (98% yield) and 89:11 e.r. (96% yield), respectively.
To illustrate the synthetic utility of the method, the reaction
between ketone 1a and allylsilane 2a was conducted on a gram
scale and furnished the product without erosion of
enantioselectivity (Scheme 2). Meanwhile, IDPi catalyst 4c
could be recovered (93%) and remained active in further
transformations, demonstrating the practicality of the process.
The produced enol silane 3a could be readily transformed into
different structural motifs via α-bromination,25 α-fluorina-
tion,26 Saegusa−Ito oxidation,27 [2 + 2] cycloaddition,28 and
α-benzylation reactions.29 All of these transformations
commonly used Brønsted acid catalysts such as phosphoric
acids, imidodiphosphates, and disulfonimides did not catalyze
the reaction under these conditions (Supporting Information,
Table S1).
With this encouraging result, we began optimizing the
reaction. IDPi catalysts with different steric environments were
designed by further modifying the sulfonamide core and the
substitution pattern of the 3,3′-arenes of the chiral 1,1′-bi-2-
naphthol (BINOL) scaffold. With the newly synthesized
catalysts 4b−4f, the e.r. was further improved (entries 2−6).
Gratifyingly, using a mixed solvent system at a lower
temperature significantly improved the enantioselectivity with
catalyst 4c, ultimately giving the product with an e.r. of 97:3 in
quantitative yield (entries 7 and 8).
Using the developed conditions, a variety of 4-aryl-
substituted enol silanes were prepared and isolated with
generally excellent enantioselectivities (up to 98:2 e.r.) and
yields (up to 99%) (Table 2, products 3a−3o). In addition, 4-
B
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temperature to −30 °C increased the s factor to a promising 12
(entry 3).31,32 We also explored different proton sources using
IDPi catalyst 4d at lower temperatures (entries 4−6). While
water and TMP proved to be unsuitable (entry 4), 2-biphenyl
carboxylic acid (BCA) 10 turned out to be an optimal reagent
(entry 6). Finally, recovered silyl enol ether 3x was obtained in
97:3 e.r. at 51% conversion, corresponding to a selectivity of
70, when the reaction was conducted at −60 °C for 24 h (entry
7). As expected, even though this protonation presumably
occurs via a slightly different mechanism than the enol silane
synthesis described above, the opposite enantiomer of product
3x was indeed obtained, confirming the possibility to produce
both enantiomers of the enol silane using the same catalyst
enantiomer.
Scheme 2. Synthetic Applications
Under the optimized reaction conditions, the kinetic
resolution of a broad range of enol silanes was realized
(Table 4). For example, enol silane 3a was recovered in 50%
yield after 11 h with an e.r. of 94:6 corresponding to an s-factor
of 122. Similarly, the enantioenriched 4-alkyl enol silanes 3x−
3z and 4-ester group substituted (S)-3t were recovered in high
yields and enantioselectivities. Moreover, 2-substituted enol
proceeded smoothly to give products 5−9, with complete
conservation of the enantiomeric purity. Importantly, our
method could successfully be applied to furnish enol silane 3w,
which is a known intermediate toward the synthesis of the
prostacyclin analogue iloprost, a commercial drug used for the
treatment of pulmonary arterial hypertension.30
Table 4. Kinetic Resolution of the Racemic Silyl Enol
a
Ethers
As proposed above, our catalytic asymmetric ketone
silylation reaction is likely driven by the irreversible
protodesilylation of the allylsilane. We therefore hypothesized
that, if a suitable proton source could be identified, a kinetic
resolution of racemic enolsilanes may also be achievable with
IDPi catalysts, in what is effectively the reverse of our enol
silane synthesis. Importantly, such a kinetic resolution would
not only be expected to be applicable to racemic enol silanes
derived from symmetric ketones, such as 4-substituted
cyclohexanones, but possibly also to enol silanes derived
from unsymmetrical ketones. To explore this possibility, we
investigated the protodesilylation of racemic enol silane 3x as a
model substrate and isopropanol as the initial proton source.
Indeed, the reaction proceeded smoothly and provided
moderate enantioselectivity at 68% conversion when we used
catalyst 4c (Table 3, entry 1). Interestingly, sulfonamide-
modified catalyst 4d gave significantly higher selectivity and
was therefore further investigated (entry 2). Lowering the
Table 3. Optimization of the Protodesilylative Kinetic
a
Resolution of rac-3x
b
c
d
entry
catalyst
proton source
conversion (%)
e.r.
s
1
2
4c
4d
4d
4d
4d
4d
4d
i-PrOH
i-PrOH
i-PrOH
H2O
TMP
BCA
68
66
55
49
62
52
51
64:36
87:13
91:9
66:34
85:15
91:9
2
5
12
3
5
18
70
e
3
e
4
e
5
e
6
f
7
BCA
97:3
a
a
Performed with 3x (0.1 mmol), proton sources (0.25−0.5 equiv),
Performed with 3 (0.2 mmol), 10 (0.5 equiv), and 4d (1 mol %) in
b
b,c
and catalyst (1 mol %) in 0.2 mL of toluene. Conversion determined
by GC analysis. e.r. determined by HPLC. s = ln[(1 − C)(1 − ee)]/
ln[(1 − C)(1 + ee)]. −30 °C. −60 °C.
0.4 mL of toluene. Conversions and yields determined by GC
analysis or isolation. e.r. determined by HPLC. s = ln[(1 − C)(1 −
ee)]/ln[(1 − C)(1 + ee)]. −60 °C.
c
d
d
e
e
f
f
C
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silanes 3aa and 3ab also underwent an efficient kinetic
resolution and were recovered in remarkably high selectivities,
with both an aryl and an alkyl substituent. However, the ketone
byproducts 1aa and 1ab did undergo partial racemization (see
the Supporting Information, Figures S7 and S8). Importantly,
3-phenyl cyclopentanone derived enol silane 3ac was also
recovered with synthetically useful selectivity.
To gain insight into the reaction mechanism, we first
compared the reactions using either triflimide (Tf2NH) or
IDPi catalyst 4c in the reaction of 4-phenylcyclohexanone 1a
with allyl silane 2a. Remarkably, when we used triflimide as the
catalyst, only homoaldol product 11 was obtained in
quantitative yield as a mixture of diastereomers.33 Even when
we lowered the temperature to −20 °C, only ∼5% of the enol
silane was observed and the homoaldol adducts remained the
major products. In contrast, IDPi 4c exclusively led to the
formation of product 3a in 99% isolated yield and 88:12 e.r.
(Scheme 3A). In light of our recent studies,34 we explain this
remarkable chemoselectivity by invoking confinement effects:
the competing self-aldolization is sterically challenged, as its
relatively larger cationic transition state cannot be accom-
modated by the confined active site of our IDPi catalyst anion.
The acidity difference may also play a role.35
We furthermore investigated the reaction progression of
cyclohexanone 1a with 2a by 1H NMR and 31P NMR
spectroscopy. When following the reaction under standard
conditions in toluene-d8:dioxane-d8 mixture, a significant
dormant period, in which adventitious water and TBSOH
were first converted to TBS2O, was observed before the enol
silane formation began (Scheme 3B). Such dormant periods
are quite characteristic for silylium−ACDC reactions and have
been described before in detail.36 A shorter dormant period
was observed with only toluene as solvent; hence, toluene-d8
was used for all further NMR experiments.
Toward a deeper understanding of the mechanism, we
analyzed the reaction by variable time normalization analysis
1
with kinetic data obtained from H NMR (Scheme 3C−E).
́
When following the procedures described by the Bures
group,37 we found that the overall reaction is first order in
catalyst and allyl silane but zeroth order in ketone.38
Alternatively, 31P NMR data acquired at the beginning of the
reaction shows the presence of catalyst 4c as a sharp singlet at
−16.9 ppm. After approximately 12 h, small amounts of
silylated catalyst 4c can be detected. The two doublets at
−11.3 and −20.8 ppm with J = 132 Hz indicate that the TBS
group is bound preferentially to one site of the activated
catalyst. After 24 h, the reaction is complete and the catalyst is
almost exclusively present in its silylated form (see the
Supporting Information, Figure S9). On the basis of the data
obtained, we propose that the initial silylation of the catalyst
with silane is the turnover-limiting step of the reaction
(Scheme 3F, right). Only if all easily exchangeable protons are
consumed, the silylated IDPi catalyst can engage in the
reversible activation of the ketone. Interestingly, it is possible
that the ketone silylation could already initiate the desymmet-
rization, by furnishing two different diastereomeric silylox-
ocarbenium−IDPi ion pairs. Ultimately, it is the final
deprotonation step at the α-position of the silyloxocarbenium
ion which establishes the enantiopurity of the produced enol
silane, while regenerating the free catalyst 4c.
Scheme 3. Mechanistic Studies
Based on previously reported asymmetric protonations of
enol silanes with phenols,22 we speculate that the proto-
desilylative kinetic resolution is initiated via protonation of the
achiral BCA reagent by the IDPi catalyst 4d to form an ion pair
[BCAH]+ X*−. In fact, the formation of this species was
supported by ESI-MS (see the Supporting Information, Figure
S10). As the enantioselectivity depends on the proton source,
we propose that it is this complex and not the free IDPi
catalyst that engages in the enantioselective protonation of the
(R)-enol silane, leaving the corresponding (S)-enantiomer
untouched. This step furnishes the same silyloxocarbenium−
IDPi ion pair intermediate that is also generated in the
corresponding forward reaction. Finally, the catalytic cycle is
completed upon desilylation of the oxocarbenium ion by the
carboxylic acid BCA, liberating ketone 1 and ester BCA−TBS,
while regenerating the IDPi catalyst (Scheme 3F, left).
We report a general asymmetric catalytic methodology for
tautomeric σ-bond metathesis reactions between ketones and
enol silanes. Our reactions are catalyzed by strong and
confined acids and enable both desymmetrizations of achiral
cyclic ketones and kinetic resolutions of racemic cyclic enol
silanes. Our findings suggest further utility in selective
reactions of carbonyl compounds and enol silanes.
D
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Communication
(6) Song, J. J.; Tan, Z.; Reeves, J. T.; Fandrick, D. R.; Yee, N. K.;
Senanayake, C. H. N-Heterocyclic Carbene-Catalyzed Silyl Enol
Ether Formation. Org. Lett. 2008, 10, 877−880.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c06677.
̂
(7) Villas-Boas, S. G.; Smart, K. F.; Sivakumaran, S.; Lane, G. A.
Alkylation or Silylation for Analysis of Amino and Non-Amino
Organic Acids by GC-MS. Metabolites 2011, 1, 3−20.
(8) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L.
Enantioselective Silyl Protection of Alcohols Catalysed by an
Amino-Acid-Based Small Molecule. Nature 2006, 443, 67−70.
(9) Hyodo, K.; Gandhi, S.; van Gemmeren, M.; List, B. Brønsted
Acid Catalyzed Asymmetric Silylation of Alcohols. Synlett 2015, 26,
1093−1095.
Experimental details and analytical data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Benjamin List − Max-Planck-Institut fu
45470 Mulheim an der Ruhr, Germany; orcid.org/0000-
0002-9804-599X; Email: list@kofo.mpg.de
̈
r Kohlenforschung, D-
(10) Park, S. Y.; Lee, J.-W.; Song, C. E. Parts-Per-Million Level
Loading Organocatalysed Enantioselective Silylation of Alcohols. Nat.
Commun. 2015, 6, 7512.
̈
(11) Yamashita, T.; Sato, D.; Kiyoto, T.; Kumar, A.; Koga, K.
Stereoselective Reactions. 29. Lithium-Hydrogen Interchange be-
tween Achiral Tridentate Lithium Amides and Chiral Bidentate
Amines. An Approach to Catalytic Enantioselective Deprotonation.
Tetrahedron 1997, 53, 16987−16998.
(12) Claraz, A.; Oudeyer, S.; Levacher, V. J. T. A. Enantioselective
Desymmetrization of Prochiral Ketones via an Organocatalytic
Deprotonation Process. Tetrahedron: Asymmetry 2013, 24, 764−768.
(13) Simpkins, N. S. Recent Advances in Asymmetric Synthesis
Using Chiral Lithium Amide Bases. Pure Appl. Chem. 1996, 68, 691−
694.
Authors
Hui Zhou − Max-Planck-Institut fu
Mulheim an der Ruhr, Germany
Han Yong Bae − Max-Planck-Institut fu
45470 Mulheim an der Ruhr, Germany; Department of
Chemistry, Sungkyunkwan University, 16419 Suwon, Korea
Markus Leutzsch − Max-Planck-Institut fur Kohlenforschung,
D-45470 Mulheim an der Ruhr, Germany; orcid.org/0000-
0001-8171-9399
Jennifer L. Kennemur − Max-Planck-Institut fu
Kohlenforschung, D-45470 Mulheim an der Ruhr, Germany
Diane Becart − Max-Planck-Institut fur Kohlenforschung, D-
45470 Mulheim an der Ruhr, Germany
̈
r Kohlenforschung, D-45470
̈
̈
r Kohlenforschung, D-
̈
̈
̈
̈
r
(14) Kurahashi, K.; Yamaoka, Y.; Takemoto, Y.; Takasu, K. Silyl
Enol Etherification by a Tf2NH/Amine Co-Catalytic System for
Minimizing Hazardous Waste Generation. React. Chem. Eng. 2018, 3,
626−630.
̈
́
̈
̈
̈
(15) Bae, H. Y.; Hofler, D.; Kaib, P. S.; Kasaplar, P.; De, C. K.;
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c06677
̈
Dohring, A.; Lee, S.; Kaupmees, K.; Leito, I.; List, B. Approaching
Sub-PPM-Level Asymmetric Organocatalysis of a Highly Challenging
and Scalable Carbon-Carbon Bond Forming Reaction. Nat. Chem.
2018, 10, 888−894.
(16) Kaib, P. S.; Schreyer, L.; Lee, S.; Properzi, R.; List, B. Extremely
Active Organocatalysts Enable a Highly Enantioselective Addition of
Allyltrimethylsilane to Aldehydes. Angew. Chem., Int. Ed. 2016, 55,
13200−13203.
(17) Schreyer, L.; Properzi, R.; List, B. IDPi Catalysis. Angew. Chem.,
Int. Ed. 2019, 58, 12761−12777.
(18) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. First
Example of a Highly Enantioselective Catalytic Protonation of Silyl
Enol Ethers Using a Novel Lewis Acid-Assisted Brønsted Acid
System. J. Am. Chem. Soc. 1996, 118, 12854−12855.
(19) Cheon, C. H.; Kanno, O.; Toste, F. D. Chiral Brønsted Acid
from a Cationic Gold (I) Complex: Catalytic Enantioselective
Protonation of Silyl Enol Ethers of Ketones. J. Am. Chem. Soc.
2011, 133, 13248−13251.
(20) Yanagisawa, A.; Touge, T.; Arai, T. Enantioselective
Protonation of Silyl Enolates Catalyzed by a Binap AgF Complex.
Angew. Chem., Int. Ed. 2005, 44, 1546−1548.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support from the Max Planck Society, the Deutsche
Forschungsgemeinschaft (DFG, German Research Founda-
tion), Leibniz Award to B.L. and under Germany’s Excellence
Strategy−EXC 2033−390677874−RESOLV, and the Euro-
pean Research Council (ERC, European Union’s Horizon
2020 research and innovation program “C−H Acids for
Organic Synthesis, CHAOS” Advanced Grant Agreement No.
694228) is gratefully acknowledged. The authors thank
Benjamin Mitschke for his help during the preparation of
this manuscript and several members of the group for crowd
reviewing. We also thank the technicians of our group and the
members of our NMR, MS, and chromatography groups for
their excellent service.
(21) Beck, E. M.; Hyde, A. M.; Jacobsen, E. N. Chiral Sulfinamide/
Achiral Sulfonic Acid Cocatalyzed Enantioselective Protonation of
Enol Silanes. Org. Lett. 2011, 13, 4260−4263.
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