Chiral bronsted acid from a cationic gold(I) complex: Catalytic enantioselective protonation of silyl enol ethers of ketones

Article abstract of DOI:10.1021/ja204331w

A chiral Bronsted acid has been developed from a cationic gold(I) disphosphine complex in the presence of alcoholic solvent and applied to the enantioselective protonation reaction of silyl enol ethers of ketones. Various optically active cyclic ketones were obtained in excellent yields and high enantioselectivities, including cyclic ketones bearing aliphatic substrates at the α-position. Furthermore, the application of this Bronsted acid was extended to the first Bronsted acid-catalyzed enantioselective protonation reaction of silyl enol ethers of acyclic substrates, regardless of their E/Z ratio.

Full text of DOI:10.1021/ja204331w

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Chiral Brønsted Acid from a Cationic Gold(I) Complex: Catalytic
Enantioselective Protonation of Silyl Enol Ethers of Ketones
Cheol Hong Cheon, Osamu Kanno, and F. Dean Toste*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S Supporting Information
b
could be generated by complexation of alcohol with cationic
ABSTRACT: A chiral Brønsted acid has been developed
from a cationic gold(I) disphosphine complex in the pres-
ence of alcoholic solvent and applied to the enantioselective
protonation reaction of silyl enol ethers of ketones. Various
optically active cyclic ketones were obtained in excellent
yields and high enantioselectivities, including cyclic ketones
bearing aliphatic substrates at the R-position. Furthermore,
the application of this Brønsted acid was extended to the
first Brønsted acid-catalyzed enantioselective protonation
reaction of silyl enol ethers of acyclic substrates, regardless
of their E/Z ratio.
gold, significantly enhancing the acidity of the original alcohol.
Herein we describe the development of a chiral LBA derived
from a cationic gold complex and its application to the enantio-
selective protonation reaction of silyl enol ethers of ketones.8À11
We began our investigation by examining the protonation
reaction of silyl enol ether 4a catalyzed by 3 mol % (R)-DTBM-
SEGPHOS(AuCl)2 activated by 3 mol % AgBF4 in isopropyl
alcohol as the solvent. Under these conditions, the desired
protonation product 5a was obtained in quantitative yield and
87% ee (Table 1, entry 1). Encouraged by this initial result, we
examined other chiral diphosphine(bis)gold complexes as cata-
lysts for the enantioselective protonation reaction (entries 2À6).
Among the gold(I) complexes tested, the (R)-BINAP-derived
complex proved to generate the most selective catalyst for the
asymmetric protonation reaction (entry 5).
ver the past decade, gold catalysis has attracted significant
attention from the synthetic community.1 More recently,
notable progress has been made in asymmetric catalysis using
homogeneous gold(I) complexes. In general, enantioselective
reactions have relied on the ability of cationic gold(I) com-
plexes to activate π-donor ligands such as alkynes, allenes, and
alkenes toward nucleophilic attack.2À4 In contrast, similar σ com-
plexes of cationic gold complexes with σ-donor ligands have been
little explored in asymmetric catalysis, although there have been
several reports of reactivity differences in gold catalysis in the
presence of protic additives.5 Very recently, we found that an
alcoholic additive has a dramatic effect on the regio- and
enantioselectivity in gold-catalyzed hydroamination of 1,3-
dienes.6 For example, in the absence of alcohol, 1,2-addition
products were obtained as exclusive products with very poor
enantioselectivity, whereas in the presence of an alcohol additive,
1,4-addition products were obtained in good yields with high
enantioselectivity (eq 1).
With BINAP as the diphosphine ligand on gold, we next
examined the effect of the counterion on the protonation
reaction (entries 4 and 7À11). Generation of the cationic gold(I)
complex proved to be essential for the protonation reaction, as
no protonation was observed without AgBF4 (entry 12) or when
a more coordinating counterion was used (entry 7). On the other
hand, reactive catalysts were generated from noncoordinating
anions (entries 4 and 8À11), with tetrafluoroborate providing
the protonation adduct with highest enantioselectivity. Further-
more, the catalyst derived from the monocationic gold(I) com-
plex proved to be more selective than the one from the dicationic
gold complex (entries 5 and 13). We also investigated the
possibility of protonation catalyzed by a Brønsted acid derived
O
from the AgBF4 BINAP complex; however, this silver-based
3
Brønsted acid was not reactive enough to protonate silyl enol
ether 4a (entry 14).12 Finally, the enantioselectivity could be
further increased by changing the solvent from isopropyl alcohol
to ethanol (entry 15).13
With these optimized conditions, we first investigated the
scope of the gold-catalyzed enantioselective protonation reaction
of silyl enol ethers of cyclic ketones (Table 2). Various silyl enol
ethers from 2-aryl cyclic ketones could be employed in the
enantioselective protonation reaction, and the corresponding
ketones were obtained in excellent yields with high enantioselec-
tivities (entries 1À5). The cationic gold(I)-derived LBA could be
further applied to the protonation reaction of silyl enol ethers of
2-alkyl cyclic ketones (entries 6 and 7). Tetralone and indanone
analogues bearing a methyl group at the 2-position were obtained
in quantitative yield with excellent enantioselectivity. It is
We hypothesized that in the absence of alcohol, the cationic
gold(I) complex directly activates the 1,3-diene toward nucleo-
philic attack, leading to the 1,2-addition products. On the other
hand, in the presence of alcohol, cationic gold(I) forms a σ
complex with the alcohol, generating a chiral Brønsted acid
activated by complexation with gold, that is, a so-called Lewis
acid-activated Brønsted acid (LBA).7 On the basis of these
observations, we envisioned that a new chiral Brønsted acid
Received: May 11, 2011
Published: August 04, 2011
r
2011 American Chemical Society
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Table 1. Optimization of the Reaction Conditions
Table 2. Substrate Scope for Cyclic Ketones
a Isolated yields. b Determined by chiral HPLC. c The reaction was
conducted at À24 °C. d The reaction was carried out in EtOH without
CH2Cl2. e The absolute stereochemistry was established by comparison of
the optical rotations of the known compounds 4a and 4f. The absolute
stereochemistriesof the remaining compoundswereassignedbyanalogy.13
With these challenges in mind, we examined the LBA-cata-
lyzed asymmetric protonation reactions of silyl enol ethers of
acyclic substrates (Table 3). First, we attempted to synthesize the
stereochemically pure silyl enol ether of 2-phenylpropiophenone
(6a), but after several unsuccessful attempts at this,16 we decided
to apply a mixture of (E) and (Z) silyl enol ethers to the
enantioselective protonation reaction under the standard condi-
tions developed for protonation reaction of cyclic substrates. To
our surprise, the protonation product was obtained in nearly
quantitative yield with 92% ee despite a 2:1 isomeric ratio of the
silyl enol ether substrate (Table 3, entry 1).
a Conversion was determined by 1H NMR analysis. b Enantiomeric
excess (ee) was determined by HPLC using a chiral IC column. c 6
mol % AgBF4 was used. d The reaction was carried out in the absence
of gold. e EtOH was used as the solvent. f The absolute stereochemistry
was determined by comparison of optical rotation.13
With this rather unexpected result in hand, we moved our
attention to other acyclic substrates under the same reaction
conditions. Several other silyl enol ethers obtained from 2-aryl
propiophenones were prepared were prepared as mixtures of E
and Z isomers. Protonation products, however, were obtained in
excellent yields and high enantioselectivities regardless of the
E/Z ratio in the mixture of starting silyl enol ethers (entries
2À8). Electronic effects had little impact on the enantioselec-
tivity (entries 1À4), although electron-withdrawing substituents
required somewhat longer reaction times (entry 4). The reaction
tolerated cyclic ketones bearing bulky aryl groups at the
R-position, such as an ortho-substituted aryl group, albeit with
slightly lower enantioselectivities (entries 6À8). We further
examined the effect of substituents on the aromatic ring of
2-phenyl propiophenene (entries 1 and 9À11). Substituents
on the phenyl ring had little effect on the enantioselectivity
(entries 1 and 9À10), although the silyl enol ether with an
electron-withdrawing substituent reacted more slowly in the
protonation reaction (entry 11). Furthermore, alkyl-substituted
silyl enol ether 6l could also be employed in the gold-catalyzed
protonation reaction with only slightly lower enantioselectivity
(entry 12). The catalyst system was also effective for the
protonation of the silyl enol ether of 2-phenyl butyrophenone
noteworthy that the ring size of the cyclic ketone had little effect
on the reactivity, and high levels of enantioselectivity were
obtained regardless of ring size (entry 1 vs 5 and entry 6 vs 7).
Although several examples of Brønsted acid-catalyzed enan-
tioselective protonation reactions of silyl enol ethers of cyclic
ketones have been reported,9À11 to the best of our knowledge,
there have been no reports of Brønsted acid-catalyzed enantioselective
protonation reactions of silyl enol ethers of acyclic ketones.14,15
Therefore, we next examined the use of our gold(I)-based
catalytic system for the enantioselective protonation of these
more challenging substrates. The first anticipated challenge with
acyclic substrates is the stereochemistry of the starting silyl enol
ether. In contrast to cyclic ketones having only one isomer of the
silyl enol ether, acyclic ketones can generate both (E)- and (Z)-
silyl enol ethers. Since the transition states for the protonations of
these diastereomeric silyl enol ethers are different, we anticipated
that it might be important to generate the silyl enol ethers
diastereoselectively.8e Furthermore, the acyclic substrates gen-
erally have more conformational flexibility than the corre-
sponding cyclic ones, which can also lead to lower asymmetric
induction.
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Table 3. Substrate Scope for Acyclic Ketones
be selective protonation of a rapidly equilibrating mixture of silyl
enol ether isomers, in which the isomerization is catalyzed by
either protonation or the cationic gold complex.20 However, we
did not observe any isomerization between silyl enol ethers by
either LBA or the cationic gold complex, and the ratio of E and Z
isomers did not remain constant during the protonation reaction
(Figure 1). The third scenario would be that the gold-derived
LBA discriminates between the two isomers and approaches
both silyl enol ethers from the same prochiral face, which results
in very high enantioselectivity regardless of the E/Z ratio. This
scenario is consistent with the observation that the enantioselec-
tivity of the reaction remains constant, despite changes in the
ratio of olefin isomers (Figure 1). Similarly, protonation of the
silyl enol ether of 2-phenyl propiophenone with different E/Z
ratios produced ketone 7a with comparable yields and enantio-
selectivities (eq 2).
In conclusion, we have developed the first gold-catalyzed
enantioselective protonation reaction. The chiral Brønsted acids
derived from cationic gold complexes and an alcohol were
applied to the enantioselective protonation reaction of silyl enol
ethers of ketones. Various silyl enol ethers from cyclic ketones
could be applied to this catalytic system, and the desired
protonation products were obtained in excellent yields with high
enantioselectivities. Furthermore, the catalytic system could be
extended to the first enantioselective protonation reactions of
silyl enol ethers of acyclic ketones. The silyl enol ethers of acyclic
ketones afforded the corresponding ketones with high enantio-
selectivities even when mixtures of the E and Z isomers of the silyl
enol ethers were used. Mechanistic studies suggested that a gold-
derived LBA selectively protonates the silyl enol ethers from the
same prochiral face regardless of their stereochemistry.
a Isolated yields. b Determined by chiral HPLC. c Ratio of the major silyl
enol ether to the minor silyl enol ether. d The reaction was carried out in
EtOH without CH2Cl2. The reaction time was 24 h. The absolute
stereochemistry was determined by comparison of the optical rotation of
known compound 6a, and the absolute stereochemistries of the
remaining compounds were assigned by analogy.13
e
f
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
compound characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
fdtoste@berkeley.edu
Figure 1. Enantioselectivity and E/Z ratio during protonation of 6a
with the LBA.
’ ACKNOWLEDGMENT
(6m), providing the desired ketone in 91% yield with 85% ee
(entry 13). However, the silyl enol ether possessing two alkyl
groups at the R-position provided the protonation product with
poor enantioselectivity (entry 14).17
Several experiments were conducted in order to gain insight
into the reaction mechanism. First, we tested the possibility that
the reaction proceeds by protonation of a gold enolate18,19 to
generate transmetalation of the silyl enol ether; however, silyl
enol ether 6a remained intact and we could not detect any gold
enolate formation upon treatment with the cationic gold com-
plex in the absence of alcohol. A second possible scenario would
This work was supported by the NIH NIGMS (R01 GM073932).
We thank Takasago International Corporation for the generous
donation of DTBM-SEGPHOS, DM-SEGPHOS, SEGPHOS,
and BINAP ligands and Johnson Mathey for a donation of AuCl3.
O.K. gratefully acknowledges support from DAIICHI SANKYO
Co., Ltd.
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