Key words asymmetric catalysis - organocatalysis - enol silanes
Silicon-mediated organic synthesis has become an important subject that is gaining
more attention in recent years.[1 ] In this context, silicon–hydrogen exchange reactions interconvert silylated (C−SiR3 or O−SiR3 ) and hydrogenated (C−H or O−H) compounds, exhibiting promising potential in asymmetric
synthesis.[2 ] Catalyzed by chiral acids, such transformations can be used to access highly valuable
enantiopure enol silanes. For example, we have recently shown that symmetric ketones
can be desymmetrized using strong and confined imidodiphosphorimidate (IDPi) catalysts
(Scheme [1a ]). Alternatively, racemic enol silanes can be formally hydrolyzed using the exact
same catalyst, enabling access to the opposite enol silane enantiomer (Scheme [1b ]). We have also been successful at expanding the scope of such hydrolytic-type kinetic
resolutions to racemic enol silanes derived from 2-substituted ketones. However, we
have never applied our approach to a deprotosilylative kinetic resolution of α-branched
ketones. We expected this reaction design to be somewhat challenging since Yamamoto
and co-workers have previously shown that Lewis acid assisted Brønsted acids, in
the absence of a stoichiometric silyl group acceptor, readily catalyze the isomerization
of the kinetic enol silane to its corresponding thermodynamic, achiral isomer.[3 ] This reactivity has also been observed by Takasu and co-workers who have used Tf2 NH as catalyst for the same isomerization.[4 ]
Scheme 1 Asymmetric catalytic silicon–hydrogen exchange reactions. Applied in (a) a desymmetrization
of achiral ketones, (b) a protodesilylative kinetic resolution of racemic enol silanes,
and (c) a deprotosilylative kinetic resolution of racemic, 2-substituted ketones (this
work).
Remarkably, we have now found that conditions can be developed that allow for a highly
enantioselective kinetic resolution to occur in deprotosilylative reactions of 2-substituted
cyclic ketones with tert -butyldimethyl(2-methylallyl)silane (Scheme [1c ]). Our method provides an alternative entry to enantioenriched enol silanes, which
are of high value in several fundamental applications.[5 ]
[6 ]
[7 ]
Our studies commenced with the identification of a proper acid catalyst for the asymmetric
silicon–hydrogen exchange reaction of 2-phenylcyclohexan-1-one (1a ) and methallylsilane 2 .[8 ] As reported in our previous work, while moderately acidic Brønsted acids, such as
chiral phosphoric acids (CPA)[9 ] imidodiphosphates (IDP),[10 ] and disulfonimides (DSI)[11 ] were ineffective, the desired enol silane products were obtained under the catalysis
of the much more acidic IDPi catalysts (see the Supporting Information, Table S1).[12 ]
[13 ] The thermodynamically favored enol silane 4a was observed to be the major product (3a :4a = 1:2) when the reaction was performed at 25 °C in toluene-d
8 using IDPi 5a (Scheme [2 ]). Replacement of the Tf substituent with a C6 F5 SO2 group gave catalyst 5b , which led to an even higher 3a :4a ratio of 1:5. We also investigated different aryl substituents at the 3,3′-positions
of the binaphthyl backbone and, to our delight, the kinetically favored product 3a could indeed be obtained as the major regioisomer when catalyst IDPi 5c , bearing a 3-Ph-C6 H4 substituent, was employed. Further endeavors focused on modifying the inner core
of the catalyst. For example, IDPi 5d possessing a C6 F5 SO2 group enabled formation of enol silane 3a with good regioselectivity and a promising enantioselectivity of 88:12. With our
newly developed catalyst 5e bearing a 2-C10 F7 inner core substituent, the e.r. of the desired enol silane 3a could be further improved to 93:7 with a conversion of roughly 50%. Ultimately, beneficial
effects on both regioselectivity and enantioselectivity were observed by decreasing
the temperature to 0 °C, furnishing 3a in 56:1 r.r. and 96:4 e.r.. Gratifyingly, ketone 1a can be recovered in 94:6 e.r. with high selectivity (s ).
Scheme 2 Reaction development. Reactions were conducted with rac -1a (0.05 mmol), methallyl-TBS agent 2 (2.0 equiv.), and catalyst 5a –5e (1.0 mol%) in toluene (0.1 M) at indicated temperature. a Conversions were determined by GC analysis, calibrating with 1,3,5-trimethoxybenzene
as internal standard. b The regioisomeric ratio (r.r. = 3a :4a ) was determined by 1 H NMR analysis. c The enantiomeric ratio (e.r.) was determined by HPLC analysis. d
s = ln[(1 − conv.)(1 – ee
1a
)] / ln[(1 − conv.)(1 + ee
1a
)]. e Reactions in toluene-d
8 monitored by 1 H NMR.
Under these optimized reaction conditions, we next explored the substrate scope of
the silicon–hydrogen exchange reaction with several racemic 2-substituted ketones.
In most cases, the reactions proceeded cleanly and the desired kinetic enol silane
regioisomers were obtained in high selectivities along with the recovered ketones.
As summarized in Scheme [3 ], product 3a can be obtained in 49.5% yield and 96:4 e.r. with ketone 1a recovered in 47.6% yield and 94:6 e.r. on a 0.1 mmol scale. Substrates with strong
electron-donating groups (Me, OMe) and a strong electron-withdrawing group (F) at
the para position of the phenyl ring were well tolerated under the reaction conditions, affording
the corresponding enol silane products 3b –3d in 49–50.5% yields with 93:7–95:5 e.r., and ketones 1b –1d in 47.5–49% yields with 92:8–95:5 e.r., respectively. It is noteworthy that the catalytic
system is very well compatible with the silicon–hydrogen exchange reaction of a 7-membered
ketone, furnishing the enol silane product 3e in 45.4% yield with 98:2 e.r. and the recovered ketone 1e in 42.3% yield with 96.5:3.5 e.r.. In this case, a remarkably high selectivity of
211 was obtained.
Scheme 3 Substrate scope of the enol silane synthesis from 2-substituted cyclic ketones 1 and methallyl-TBS agent 2 . Reactions were conducted with rac -1 (0.1 mmol), methallyl-TBS agent 2 (2.0 equiv.), and catalyst 5e (1.0 mol%) in toluene (0.1 M) at 0 °C. a Conv. = (ee
1
) / (ee
1
+ ee
3
). b All yields were determined by crude 1 H NMR analysis with CH2 Br2 as internal standard. c The regioisomeric ratio (r.r.) was determined by 1 H NMR analysis. d The enantiomeric ratio (e.r.) was determined by HPLC analysis. e
s = ln[(1 − conv.)(1 – ee
1
)] / ln[(1 − conv.)(1 + ee
1
)]. f With 5 mol% catalyst 5e .
Toward a deeper understanding of the reaction, two comparison experiments were carried
out using two enantiomerically pure substrates (Scheme [4 ]). Only 6% conversion was observed after 56 hours at 0 °C from the reaction of ketone
(S )-1a , which furnished enol silane (S )-3a and ketone (S )-1a without loss of enantiopurity but with moderate regioselectivity (3a :4a = 5.3:1) (eq. 1). In stark contrast, the reaction of ketone (R )-1a proceeded much faster, providing enol silane (R )-3a as the only regioisomer and ketone (R )-1a was recovered with 99:1 e.r. (eq. 2). Interestingly, when the reaction of rac -1a was performed at room temperature, the e.r. of enol silane 3a gradually decreased, and ketone 1a remained nearly racemic throughout the reaction (see the Supporting Information,
Figure S11). These control experiments indicate that racemization of the ketone hardly
occurs at 0 °C, but takes place at room temperature, suggesting potential for a dynamic
kinetic resolution upon identification of a suitable acid catalyst.
Scheme 4 Asymmetric catalytic silicon–hydrogen exchange reactions with enantiopure ketones
1a (0.1 mmol), methallyl-TBS agent 2 (2.0 equiv.), and catalyst 5e (1.0 mol%) in toluene (0.1 M) at 0 °C. (1) Reactivity comparison reaction of ketone
(S )-1a with 2 , and (2) the reaction of ketone (R )-1a with 2 .
We have developed access to enantiopure enol silanes from 2-substituted ketones, via
silicon–hydrogen exchange reaction using a strongly acidic and confined IDPi catalyst.
The newly established catalytic system complements our previously reported methods.
We are currently exploring this remarkably general approach to obtain a variety of
functionalized molecules and toward developing catalysts that can realize a dynamic
kinetic asymmetric silicon–hydrogen exchange reaction.
