Catalytic, Enantioselective Sulfenylation of Ketone-Derived Enoxysilanes

Article abstract of DOI:10.1021/ja506133z

A catalytic, enantioselective, Lewis base-catalyzed α-sulfenylation of silyl enol ethers has been developed. To avoid acidic hydrolysis of the silyl enol ether substrates, a sulfenylating agent that did not require additional Br?nsted acid activation, namely N-phenylthiosaccharin, was developed. Three classes of Lewis bases - tertiary amines, sulfides, and selenophosphoramides - were identified as active catalysts for the α-sulfenylation reaction. Among a wide variety of chiral Lewis bases in all three classes, only chiral selenophosphoramides afforded α-phenylthio ketones in generally high yield and with good enantioselectivity. The selectivity of the reaction does not depend on the size of the silyl group but is highly sensitive to the double bond geometry and the bulk of the substituents on the double bond. The most selective substrates are those containing a geminal bulky substituent on the enoxysilane. Computational analysis revealed that the enantioselectivity arises from an intriguing interplay among sterically guided approach, distortion energy, and orbital interactions.

Full text of DOI:10.1021/ja506133z

Article
pubs.acs.org/JACS
Open Access on 09/05/2015
Catalytic, Enantioselective Sulfenylation of Ketone-Derived
Enoxysilanes
Scott E. Denmark,* Sergio Rossi,† Matthew P. Webster,† and Hao Wang
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801, United States
S
* Supporting Information
ABSTRACT: A catalytic, enantioselective, Lewis base-catalyzed α-
sulfenylation of silyl enol ethers has been developed. To avoid
acidic hydrolysis of the silyl enol ether substrates, a sulfenylating
agent that did not require additional Brønsted acid activation,
namely N-phenylthiosaccharin, was developed. Three classes of
Lewis basestertiary amines, sulfides, and selenophosphor-
amideswere identified as active catalysts for the α-sulfenylation
reaction. Among a wide variety of chiral Lewis bases in all three classes, only chiral selenophosphoramides afforded α-phenylthio
ketones in generally high yield and with good enantioselectivity. The selectivity of the reaction does not depend on the size of the
silyl group but is highly sensitive to the double bond geometry and the bulk of the substituents on the double bond. The most
selective substrates are those containing a geminal bulky substituent on the enoxysilane. Computational analysis revealed that the
enantioselectivity arises from an intriguing interplay among sterically guided approach, distortion energy, and orbital interactions.
who reported the first catalytic, asymmetric sulfenylation of β-
keto esters using a Ti[TADDOL(ato)] complex that afforded
products with good yields and high enantioselectivities (up to
94:6 er).16
Most recently, Feng reported a catalytic, enantioselective
sulfenylation of unprotected 3-substituted oxindoles via
cooperative catalysis of a chiral bispiperidine-N,N′-dioxide−
Sc(OTf)3 complex in the presence of a Brønsted base.17 Using
the readily available N-phenylthiophthalimide as the sulfur
source, a wide range of enantiomerically enriched 3-phenylthio-
oxindoles are obtained in excellent yields (82−98%) and
excellent enantioselectivities (>99:1 er) under mild reaction
conditions.
INTRODUCTION
■
Chiral sulfides are important for the synthesis of a wide range of
biologically relevant molecules and are also versatile synthetic
intermediates for a variety of organic transformations.1 In
recent years, a number of methods have been developed for the
direct formation of stereogenic carbon centers bearing sulfur.
The most successful is the α-sulfenylation of carbonyl
coumpounds2 such as ketones,3a lactams,4 esters,5 and
amides.3b All of these methods involve the formation of a
metalloenolate or enamine precursor6 followed by reaction with
sulfur-based electrophiles (e.g., sulfenyl chlorides, sulfenyl-
amines, thiosulfonates, or disulfides) to produce α-thio-
functionalized carbonyl compounds.
The asymmetric synthesis of 3-sulfenylated N-Boc-protected
oxindoles has been demonstrated by Enders and co-workers,
who reported the use of a hydrogen-bonding squaramide-based
organocatalyst in combination with N-(sulfanyl)succinimides to
be a highly efficient method for the preparation of a wide range
of enantiomerically enriched 3-phenylthiooxindoles.18 Using a
similar and equally enantioselective approach, N-Bn-protected
oxindoles could also be thiofunctionalized with a high level of
enantioselectivity using (DHQD)2PHAL in the presence of a
wide range of N-(sulfanyl)succinimides, as reported by Jiang,19a
who also applied a closely related catalytic system to the
enantioselective sulfenylation of azlactones.19b
Among the most recent advances is the enantioselective α-
sulfenylation of aldehydes and ketones through the intermedi-
acy of in situ-generated enamines. Wang and co-workers
employed a chiral pyrrolidine trifluoromethanesulfonamide
using N-phenylthiophthalimide as the sulfur source to produce
Already in 1979, Sato reported the enantioselective
sulfenylation of 4-alkylcyclohexanones using chiral sulfon-
amides as sulfenylating reagents.7 Six years later, Paterson
reported the use of chiral O-silylated imide enolates derived
from acyl oxazolidinones in the sulfenylation of masked ketones
using phenylsulfenyl chloride.8 Unfortunately, both methods
afforded low to modest levels of enantioselection (45:55−17:83
er). Improved enantioselectivities for thiofunctionalization of
ketones were reported some years later by Mukaiyama, who
employed in situ-generated tin(II) enolates that reacted in the
presence of a chiral diamine ligand to afford 25:75−8:92 er.9
Since these early reports, a wide variety of methods have
been introduced, using a range of chiral auxiliaries for the
synthesis of α-thiofunctionalized compounds (e.g., phenylethyl-
amine,10 imidazolidinones,11 oxazolidines/oxazolines,12 pyrrol-
idines,13 and pyrazoles14). However, until recently, only a few
examples that employ chiral sulfenylating reagents have been
reported.7,15
A novel approach for the synthesis of α-thiofunctionalized β-
dicarbonyl compounds was described by Togni and co-workers,
Received: June 22, 2014
Published: September 5, 2014
© 2014 American Chemical Society
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racemic α-phenylthio ketones and α-phenylthio aldehydes.20
Shortly thereafter, Jørgensen reported the first example of
enantioselective α-sulfenylation of aldehydes using diphenyl-L-
prolinol TMS ether as the catalyst together with benzylsulfenyl-
1,2,4-triazole as the sulfenylating agent.21 The corresponding
sulfenylated products are obtained in high yields and excellent
enantioselectivities (up to >99:1 er). Finally, Zhu and co-
workers also demonstrated the direct sulfenylation of β-keto
esters,22a β-keto phosphonates,22b and α-nitroesters22c using
diaryl-L-prolinols.
with few examples, is the sulfenylation of more reactive alkenes
such as silyl enol ethers and silyl ketene acetals.
As part of our continuing program on Lewis base activation
of Lewis acids, we have reported the catalytic, enantioselective
thiofunctionalization of unactivated alkenes using oxygen,
carbon, and nitrogen nucleophiles.32 Thus, the combination
of N-phenylthiophthalimide, a chiral Lewis base catalyst, and a
Brønsted acid (MsOH) produces enantioenriched thiiranium
ions that could be captured intramolecularly by either alcohols
or electron-rich aromatic compounds (Scheme 1).
Chiral Brønsted bases such as cinchona alkaloid derivatives
can also catalyze the direct α-sulfenylation of other substrates
such as lactones, lactams, and β-dicarbonyl compounds to
afford enantiomerically enriched α-sulfenylated compounds in
moderate to high yields (up to 95%) and enantioselectivities
(up to 96:4 er).23
Scheme 1
The highly enantioselective sulfenylation of β-keto esters via
base-free asymmetric phase-transfer catalysis was reported by
Maruoka and co-workers in 2013.24 Using a novel, bifunctional
quaternary phosphonium salt, in combination with an N-
thioaryl- or N-thiobenzylphthalimide, the α-sulfenylated
products can be isolated in excellent yields and excellent
enantioselectivities (96:4−97.5:2.5 er).
α-Thiofunctionalized carbonyl compounds can also be
prepared from silyl enol ethers of ketones as first reported by
Murai, albeit to form only racemic products.25 A catalytic
version that employs TMSOTf was introduced by Saigo,26 and
the same Lewis acid was also employed by Kita27 to promote
the facile and efficient alkyl- and aryl-sulfenylation of ketones
and esters in high yields but again in racemic form.
Using this procedure, it is also possible promote the
intermolecular capture of thiiranium ions by nucleophiles.
Treatment of an olefin with N-phenylthiophthalimide at
room temperature in the presence of 1.0 equiv of MeOH and
the same chiral Lewis base/Brønsted acid combination
produces the phenylthio methyl ether in 93% yield and 92:8
er (Scheme 2).
Finally, in a method that constructs the carbon−sulfur bond
in an electronically reversed fashion compared to all those
methods highlighted above, Coltart and co-workers reported
the sulfenylation of nitrosoalkenes using a nucleophilic sulfur
source.28 In their report, in situ-derived cyclic and acyclic
nitrosoalkenes, formed from their corresponding α-chloro
oximes and base, are combined with a range of aromatic and
heteroaromatic thiols in the presence of a hydrogen-bonding
thiourea-based catalyst to give α-sulfenyl oximes, which could
be oxidized to the corresponding α-sulfenyl ketones in high
yields using 2-iodoxybenzoic acid (83:17−94:6 er).
Scheme 2
Thus, despite considerable effort, no examples of catalytic,
enantioselective α-sulfenylation of unactivated ketones are
extant.
These promising results stimulated the investigation of the
direct, catalytic thiofunctionalization of enol derivatives, e.g.,
silyl enol ethers that formally can be considered as activated
olefins.
BACKGROUND
■
The mechanism of electrophilic addition and, in particular, the
addition of arylsulfenyl chlorides to olefins, is well documented.
It was first reported in the literature in 1937,29 which was also
the first time an “onium ion” was postulated. The classical
mechanistic description of this process suggests a rate-
determining formation of an episulfonium (thiiranium) ion
that undergoes a nucleophilic, invertive opening by chloride ion
to give an overall anti addition.30 Other mechanisms have also
been proposed, such as the formation of a sulfurane, but valid
support for this hypothesis is lacking, especially when compared
with all the structural and reactivity studies on thiiranium
ions.31
RESEARCH OBJECTIVES
■
Consideration of the proposed catalytic cycle for the Lewis
base-catalyzed α-sulfenylation of silyl enol ethers reveals a
number of concerns that have not been addressed in the
previous studies (Scheme 3). Initial protonation of the
sulfenylating agent (Het-SPh) by a stoichiometric amount of
Brønsted acid, in the presence of a catalytic amount of Lewis
base, generates the activated catalytic complex I. Subsequent
reaction of sulfenyl cation I with a silyl enol ether forms
oxocarbenium ion II. It is important to highlight that this might
occur directly or via an intermediate thiiranium ion III, the
latter scenario more closely resembling our previous work on
the catalytic asymmetric sulfenylation of unactivated alkenes
(outlined above). Finally, the α-sulfenylated ketone would be
isolated upon work-up.
Many examples of sulfenofunctionalizations via thiiranium
ions have been reported. These processes can be divided into
two main types: (1) sulfenocyclizations and (2) sulfeno-
functionalizations of isolated alkenes. A third area, represented
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Scheme 3
Scheme 4
In this scenario, the role of the heteroaromatic nucleofuge,
generated after the transfer of the sulfenium ion, requires more
consideration. In the case of thiiranium ion formation (VI), the
resulting ion pair could influence the lifetime of the ion before
the rearrangement to V. However, its presence could also
promote the desilylation of V, accelerating the formation of the
final product and potentially reducing the lifetime of the
thiiranium ion, if formed.
The Z-trimethylsilyl enol ether of propiophenone ((Z)-1a)
was selected for orienting experiments. Using conditions
described by Ireland,34 the Z isomer can be generated
selectively.35
In the presence of a chiral Lewis base, the formation of
oxocarbenium ion II would be the enantiodetermining step in
the scenario not involving an intermediate thiiranium ion III.
However, if III is generated, then its formation would be
assumed enantiodetermining in the presence of a chiral Lewis
base. Previous studies in these laboratories demonstrated that
simple thiiranium ions are configurationally stable at −20
°C.31d The configurational stability of III is unknown, but its
opening to form II is expected to be rapid and irreversible
(perhaps driven by desilylation with the conjugate base of the
Brønsted acid). Moreover, the greater nucleophilicity of the
silyl enol ether compared to isolated alkenes raises the specter
of a racemic background reaction. Finally, the requirement for a
strong Brønsted acid (MsOH) is incompatible with the silyl
enol ether due to rapid protonolysis.
Thus, the successful development of this transformation will
require reevaluation of critical reaction parameters and scope:
(1) the pKa of the Brønsted acid and its effect on the activity of
the electrophile, (2) the reactivity of the sulfenylating reagent,
and (3) the ability of the Lewis base to generate adduct I, along
with (4) the usual reaction parameters (time, temperature,
solvent), (5) the identity of suitable Lewis bases that can
catalyze the process and optimize their characteristics, e.g., the
basicity, steric bulk, and type of chiral scaffold, and (6) the
scope of the reaction with substrates having different
characteristics, e.g., silyl groups, geometries (E vs Z double
bond), steric factors, and nucleophilicity. The enhanced
reactivity of silyl enol ethers raises the possibility that a
sufficiently electrophilic sulfenylating agent could be employed
that does not require activation with a Brønsted acid. This
possibility obviates the incompatibility issue but increases the
undesired intervention of a racemic background reaction.33 The
catalytic cycle for this variant is shown in Scheme 4.
RESULTS
■
1. Investigation of Sulfenylating Agents. On the basis
of previous studies,36 three different electrophiles were
examined (Figure 1). N-Phenylthiophthalimide (2) is the
least reactive toward isolated alkenes and requires the use of a
strong Brønsted acid, e.g., CH3SO3H (pKa = −2.6 in water), to
activate the leaving group and thus increase the phenyl-
sulfenium ion donor character. This feature also dictates that
only weakly Brønsted basic Lewis bases can be employed (to
avoid protonation of the Lewis base catalyst). N-1-Phenylthio-
benzotriazole (3) is more reactive than 2 and thus requires the
use of a weaker Brønsted acid, e.g., trifluoroacetic acid (TFA,
pKa = 0.23 in water), to be activated. Thus, a broader range of
Lewis bases can be employed. Finally, N-phenylthiosaccharin
(4) is the most reactive of the three and requires an even
weaker acid, trichloroacetic acid (pKa = 0.71 in water), to be
activated.
Figure 1. Sulfenylating agents.
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On the basis of these considerations, all three phenylthio
transfer agents would be tested in the presence and in the
absence of the corresponding Brønsted acid in the α-
sulfenylation of (Z)-1a. This survey was conducted at room
temperature using dichloromethane as solvent (0.2 M). The
reaction was quenched with a pH 9 buffer solution in order to
remove any acid present. The formation of 1-phenyl-2-
(phenylthio)-propan-1-one (5) was monitored by gas chroma-
tography (GC) with an internal standard after 2 and 24 h.
As shown in Table 1, when N-phenylthiophthalimide (2) was
employed, no desired product was observed in the presence or
absence of MsOH after 24 h. The absence of Brønsted acid
allowed recovery of the silyl enol ether; however, the presence
of MsOH resulted in complete hydrolysis to the corresponding
ketone. Similarly, no reaction was observed in the case of N-1-
phenylthiobenzotriazole (3) without an acid additive. In
contrast, the addition of TFA generated the sulfenylated
ketone 5 in 79.8% conversion (GC), accompanied by a small
amount of hydrolyzed starting material. No further conversion
was detected after 2 h.
Table 2. Investigation of Background Rate at Low
Temperature
b
conv, (%)
(ketone recovered)
N-
Het-
SPh
Brønsted
a
entry
temp, °C
acid
2 h
24 h
1
2
3
3
−10
−78
CF3CO2H
CF3CO2H
89.9 (9.2)
61.5 (6.4)
88.4 (11.6)
73.7 (8.4)
3
4
5
6
7
8
9
4
4
4
4
4
4
4
25
−10
−10
−20/−25
−50
−78
−
−
47.6 (12.3)
31.9 (6.1)
50.1 (27.2)
3.1 (3.6)
78.6 (21.3)
67.3 (8.7)
49.8 (28.6)
19.6 (4.5)
12.7 (2.9)
8.8 (7.2)
Cl3CCO2H
−
−
−
3.9 (2.8)
5.4 (7.5)
−78
Cl3CCO2H
41.3 (52.9)
44.8 (51.1)
Table 1. Survey of Sulfenylating Reagents
a
1.0 equiv was used and added 10 min after the addition of the silyl
b
enol ether. Monitored by GC with internal standard.
and at −10 °C. However, when the reaction was conducted in
the presence of trichloroacetic acid at −10 °C, the conversion
was increased to 50%, due to the inhibition of the hydrolysis
process (entry 5, cf. Table 1, entry 6). When the temperature
was decreased to −25 °C, the α-sulfenylation of (Z)-1a was
slow in the absence of acid (19.6% conversion after 24 h).
Finally, the reaction was investigated at −78 °C. In the
presence of trichloroacetic acid, ketone 5 was obtained with a
moderate conversion, but, interestingly, in the absence of acid,
both the α-sulfenylation process and the hydrolysis process
were significantly slowed (only 8.8% conversion after 24 h). On
the basis of these results, it was now possible to almost
completely suppress the background reaction at −78 °C, using
4 as electrophile, without a Brønsted acid. The stage was now
set to evaluate the ability of Lewis bases to turn on the catalytic
(and stereoselective) pathway.
2. Investigation of Achiral Lewis Bases. The survey of
achiral Lewis bases was performed on a 0.2 mmol scale using
dichloromethane as solvent in the presence of 10 mol % of a
Lewis base. Product formation was monitored by GC analysis
after 24 h at −78 °C. Biphenyl was used as an internal standard.
An extensive survey of a wide range of more than 50 Lewis
bases was carried out, and these results are presented in their
entirety in the Supporting Information. A qualitative schematic
of these data is presented in Figure 2 to allow for a general
comparison of the efficiency of different Lewis bases to catalyze
this process.
From this study it was clear that the most efficient Lewis
bases were those derived from tertiary amines, sulfides, and
selenophosphoramides. In particular, in the case of tertiary
amine-based nucleophiles, the steric environment around the
nitrogen atom was demonstrated to be important, with N-i-Pr-
piperidine significantly less effective than N-Me-piperidine.
During the course of these studies, a highly effective quench
procedure was developed to ensure rapid and complete
hydrolysis of any remaining trialkylsilyl enol ether before
warming the reaction, prior to work-up. An efficient quench
was required not only to obtain accurate information on
b
conv,
%
(ketone recovered)
a
entry
N-Het-SPh
Brønsted acid
2 h
24 h
1
2
2
2
−
0 (0)
0 (0)
CH3SO3H
0 (100)
0 (100)
3
4
3
3
−
TFA
0 (0)
0 (0)
c
79.8 (13.8)
80.5 (15.0)
5
6
7
4
4
4
−
47.6 (12.3)
17.0 (77.7)
33.7 (62.8)
78.6 (21.3)
17.2 (78.6)
36.1 (63.2)
d
Cl3CCO2H
c
Cl3CCO2H
a
b
1.0 equiv was used. Monitored by GC with internal standard.
Brønsted acid added 10 min after the addition of the silyl enol ether.
Brønsted acid added 10 min before the addition of the silyl enol
ether.
c
d
N-Phenylthiosaccharin (4) provided 5 in 47.6% conversion,
even without an acid activator. The detrimental effect of acid is
evident in the use of trichloroacetic acid, which causes extensive
hydrolysis of (Z)-1a. As has been observed in previous entries,
the starting material is consumed in 2 h. It should be noted that
the order of addition of the acid is consequential to the amount
of 5 produced: the addition of trichloroacetic acid to 4 gave a
slightly higher conversion to 5 (33.7%) compared to that of the
reversed sequence of addition (17.0%).
To minimize the formation of sulfenylated ketone 5 in the
absence of Lewis base catalysis, the α-sulfenylation of (Z)-1a
was investigated at low temperature (Table 2). At −10 °C, N-1-
phenylthiobenzotriazole (3), together with a stoichiometric
amount of TFA, gave the same conversion to 5 as was obtained
at room temperature. Lowering the temperature to −78 °C
gave only a small reduction in conversion (Table 2, entries 1
and 2).
Interestingly, in the absence of acid, N-phenylthiosaccharin
(4) showed the same chemical efficiency at room temperature
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Figure 2. Survey of Lewis bases for the sulfenylation of (Z)-1a.
reaction conversion but also, upon the development of an
enantioselective protocol, to prevent a racemic background
reaction which could occur upon warming and therefore lead to
an overall reduction in the enantioselectivity observed. The
optimized quench procedure involved the addition of a
precooled (−78 °C) solution of HF·pyridine in methanol
(derived from a solution of HF in pyridine, ca. 70%) into the
reaction mixture at −78 °C. Using this procedure, the extent of
the uncatalyzed, background reaction amounted to 2.4%
conversion to 5 after 24 h at −78 °C.
4. Investigation of Chiral Lewis Bases. The selection of
suitable chiral Lewis bases was guided by the results of the
initial catalyst survey. Because tertiary amines, tetrahydro-
thiophene, and selenophosphoramides showed the best
catalytic activity, the use of chiral Lewis bases derived from
these three classes was chosen for initial investigation.
4.1. Sulfur-Containing Chiral Lewis Bases. Following
previous experience,36 chiral C2-symmetric tetrahydro-
thiophenes 6 and 7 were tested first (Scheme 5). As
anticipated, the use of (2R,5R)-2,5-dimethyltetrahydro-
thiophene (6) led to the formation of 5 with quantitative
conversion after 2 h at −78 °Cunfortunately, however, in
racemic form. It is presumed that the stereocenters are too far
away from the catalytic site and that the methyl groups are too
small for a preferential selection of one of the two enantiotopic
faces of the silyl enol ether. The bulkier tetrahydrothiophene
(7) was also investigated. However, this Lewis base promoted
the α-sulfenylation of (Z)-1a to only 15% conversion after 24 h
at −78 °C again with negligible control over the stereochemical
outcome (er, 54:46). Raising the temperature to −20 °C
afforded the desired product with 80% conversion after 24 h
but with similar enantiomeric ratio (57:43).
4.2. Nitrogen-Containing Chiral Lewis Bases. A preliminary
survey of readily available tertiary amines was carried out.
Initially, (−)-sparteine and (+)-N-methylephedrine along with
a variety of monomeric and dimeric dihydrocinchonine and
cinchonidine derivatives were examined: (DHQD)2PHAL,
(DHQ)2PHAL, and (DHQ)2AQN, nicotine, (R,R)-1,2-bis-
(dimethylamino)cyclohexane, (R,R)-2,2′-bis(N-methyl)-
pyrrolidine, and (S,S)-2,5-dimethyl-N-benzylpyrrolidine. The
most encouraging results were obtained from (DHQ)2PHAL,
which afforded an 84% conversion of (Z)-1a to 5 under
standard conditions with a 61:39 er.
4.3. Selenophosphoramide Chiral Lewis Bases. The use of
chiral selenophosphoramides as catalysts for stereoselective
transformations was first reported from these laboratories for
the asymmetric thiofunctionalization of unactivated alkenes.32
Following the same synthetic route, a family of different
selenophosphoramides was prepared for subsequent evaluation
in the enantioselective α-sulfenylation of 1 (Scheme 6). (S)-
BINAM (9) was prepared from 2-naphthylamine37a and was
converted, in two steps, to the N-methylated BINAM (S)-
10.37b,38 Following a protocol developed in these laborator-
ies,37c this precursor was transformed into a variety of
selenophosphoramides that possessed various substituents on
the external nitrogen.
The catalytic efficiency and selectivity of the different
selenophosphoramides were investigated in the α-sulfenylation
of (Z)-1a (Figure 3). Conversion was measured by GC analysis
with an internal standard, and the enantiomeric ratios were
determined after chromatographic purification by CSP-HPLC.
Gratifyingly, selenophosphoramides derived from BINAM
bearing a cyclic amine, e.g., piperidine (12a), azepane (12b),
and azocane (12c), were able to promote the reaction with
good conversions and high levels of enantioselection (up to
13:87 er for 12c). It is noteworthy that the reduced rate
observed using these Lewis bases meant that 24 h was required.
Interestingly, the use of 12d, bearing a less basic amine, was
able to maintain the same level of stereoselection but with a
decreased rate. This observation confirms that the use of more-
basic, aliphatic amines is important for the chemical efficiency
Scheme 5
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from diethylamine, afforded 5 with 79% conversion in 86:14 er.
Modification or elongation of the amine chain, e.g., 12f and
12g, afforded the product with comparable efficiencies and
selectivities.
Scheme 6
The incorporation of branched amines led to an increase in
enantioselection. The use of selenophosphoramides 12h and
12i afforded 5 with ca. 77% conversion and 10:90 er. The
selectivity improved to 7:93 when the diisopropylamino-
derived catalyst 12j was employed. The use of Lewis base 13,
wherein the binaphthyl backbone was substituted with the less
bulky biphenyl system, led to decreases in catalytic efficiency
and selectivity.
5. Development of a Catalytic, Enantioselective
Sulfenylation Protocol. In view of the highly encouraging
results described above, the substrate scope in the α-
sulfenylation process was next investigated. However, at this
stage, a number of significant challenges had been identified
that would need to be addressed as part of this endeavor.
5.1. Large-Scale Preparation of Catalyst (R)-12j. Because
selenophosphoramide 12j afforded this highest enantio-
selectivity for the conversion of (Z)-1a to 5, it was chosen
for the survey of the remaining substrates. However, the general
preparation outlined in Scheme 6 was not suitable for the bulky
diisopropylamine needed in the last step. Thus, an improved
preparation was developed that installs the diisopropylamino
group as part of the diazaphosphepine ring formation (Scheme
7). The reaction is somewhat scale-dependent, but yields up to
78% have been achieved.32e
of the catalyst. On the basis of these results, other
selenophosphoramides bearing aliphatic amines were inves-
tigated. In all cases, 5 was produced with comparable
conversions. Using the selenophosphoramide 12e, derived
Figure 3. Survey of chiral selenophosphoramides in the sulfenylation of (Z)-1a.
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isolation of enol ether (Z)-17 in 35% yield (Scheme 8). The N-
t-Boc-piperidine-based silyl enol ether (Z)-19 could also be
prepared, using the lithiodisilazide base, in excellent diastereo-
selectivity (Z/E > 25:1).
Scheme 7
5.3. Purification of the Sulfenylation Product. The fate of
any unreacted enol ether, upon reaction work-up, was
hydrolysis to the parent ketone. Separation of this ketone
from the α-sulfenylation product proved to be difficult,
especially as the chiral Lewis base also showed very similar
interactions with all stationary phases during attempts to purify
using column chromatography. Silica gel, basic alumina, and
reverse-phase C-18 chromatography were all evaluated, with
silica gel showing the best resolution. Radial chromatography
was also found to be very effective. However, the increased
acidity of the silica gel required to prepare the chromatography
plates used for radial chromatography caused epimerization of
the products. The solution to this issue required (1) the
preparation of enol ethers of high purity (i.e., not contaminated
with parent ketone), (2) that the reaction be as close to
completion as possible upon work-up, and (3) careful
chromatographic purification of the product (SiO2 and
reverse-phase C-18).
5.4. Accurate Reaction Monitoring. The low temperatures
at which the reactions were conducted (typically −78 °C)
rendered accurate reaction monitoring difficult because of the
difficulties associated with removing a sample from the reaction
mixture and quenching it before it had the opportunity to warm
up (from −78 °C). Direct quench of the entire reaction mixture
at −78 °C would ensure an accurate result; however, this would
mean multiple reaction runs per substrate. The long reaction
times of 24−48 h would make this an even less efficient
approach. The solution to this issue was to sample using
precooled, narrow-bore needles (−78 °C) with precooled
quench solutions (also −78 °C). This optimized technique
could allow, after work-up of the aliquot and 1H NMR analysis,
an accurate understanding of the reaction. This approach was
validated by comparison to a direct reaction quench.
5.2. Preparation of Silyl Enol Ethers. The syntheses of a
large number of the silyl enol ethers used in this work are
known and are therefore not described here.39 However, for a
number of substrates, preparative methods had to be
developed. Importantly, they had to provide enol ethers in
high purity and high (Z)-diastereoselectivity. High purity was
required to aid final purification of the α-sulfenylated products,
and high (Z)-diastereoselectivity was found to have an impact
on the enantiomeric purity of the products. The developed
preparative methods are detailed below.39b The configuration of
all enol ethers shown below was confirmed by nuclear
Overhauser enhancement (NOE) spectroscopy.
Although trimethylsilyl enol ether (Z)-15, derived from 1-
(naphthalenyl)-1-propanone (14), is known,40 the method
reported was found to be irreproducible, and therefore
alternative conditions were developed with the combination
of TMSOTf and Et3N, giving complete conversion of 14 to
(Z)-15 as a 95:5 Z/E mixture. Trimethylsilyl enol ether (Z)-15
was isolated in a 78% yield (Scheme 8). 1H NMR spectroscopic
analysis of enol ether (Z)-15 was not in accordance with that
reported40 but was confirmed by NOE spectroscopy.
Scheme 8
6. Substrate Scope Evaluation. With a set of standard
reaction conditions and a wide range of enol ethers prepared,
we then evaluated the efficiency of the α-sulfenylation
procedure (Table 3). As detailed above, (Z)-1a was fully
converted to 5 after 24 h at −78 °C to afford a high isolated
yield (72%) with excellent er (93:7, entry 1). It should be noted
that the catalyst loading was increased to 15 mol % to ensure
full conversion of substrates to the α-sulfenylated products. As
noted earlier, if not fully converted, residual enol ether would
be hydrolyzed to the parent ketone upon work-up, complicat-
ing purification.
Enol ether (E)-1a also showed full conversion after 24 h at
−78 °C, but in racemic form (entry 2). It was therefore decided
to not explore acyclic (E)-enol ethers further.
Investigation of the effect of the R2 substituent of the silyl
enol ether was then carried out (Table 3, entries 3 and 4). With
an ethyl substituent, full conversion was observed after 24 h at
−78 °C, and product 21 was obtained in a similar yield (75%)
and enantiomeric composition (er 90:10). However, increasing
size of the R2 substituent beyond an ethyl substituent caused a
dramatic reduction in rate at −78 °C, and the reaction had to
be warmed to −50 °C to give high conversion (entry 4).
Fortunately, the high level of enantioselectivity was retained (er
91:9).
The use of lithium 1,1,3,3-tetramethyl-1,3-diphenyldisilazide
was first reported by Masamune and co-workers for the highly
(Z)-selective synthesis of silyl enol ethers derived from dialkyl
ketones bearing one small and one medium-sized substituent.41
This protocol was successfully applied to the synthesis of
tetrahydropyranyl-based silyl enol ether (Z)-17. Complete
conversion and excellent diastereoselectivity (Z/E > 25:1) were
possible, and the method was amenable to scale-up. Separation
of the enol ether from disilazane and disilazane-related
materials proved nontrivial but was possible by column
chromatography using basic alumina, activity grade III, allowing
Variation of the R1 substituent of the silyl enol ether was far
better tolerated (entries 5−7). The (Z)-enol ether derived from
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Table 3. Enantioselective Sulfenylation of Various Silyl Enol Ethers
a
b
Yield of isolated, analytically pure product. All reactions were carried out on a 1.0 mmol scale. The enantiomeric ratio was determined by CSP-
c
d
SFC analysis or CSP-HPLC analysis, as required. 10 mol % Lewis base was used in this instance. % conversion determined by GC analysis using
biphenyl as an internal standard. After one recrystallization from MeOH.
e
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pentan-3-one (entry 5) showed a rate similar to that of (Z)-1
and afforded 25 in good enantiomeric purity (er 91:9) and
isolated yield (75%). Unfortunately, epimerization was
observed during column chromatography, and the enantiomeric
composition was compromised (er 87:13). Increasing the steric
bulk of the R1 group to cyclohexyl had little effect on the rate of
the reaction, which was close to complete after 24 h (>90%)
but was allowed to proceed for an additional 12 h to ensure
complete conversion. Again, the isolated yield and enantio-
enrichment of the product were very good (entry 6, 78%, 94:6
er). Further increasing the steric bulk with a tert-butyl
substituent at the 1-position was again well tolerated (entry
7). In fact, in this case only 10 mol % of (R)-12j was required
to achieve very good isolated yield and er after 24 h at −78 °C
(74%, 98:2 er).
The next phase of the survey evaluated the effect of
electronically modulating the enol ether by varying the
substituents on the R1 aromatic substituent. A 4-methoxy-
substituted silyl enol ether was observed to give quantitative
conversion at −78 °C after 24 h with very good er (90:10, entry
9). The reduction in selectivity, relative to (Z)-1, may be a
result of increased background reaction or Lewis base catalysis
by the methoxy substituent. Attenuation in electron density of
the enol ether by the attachment of a 4-chlorophenyl
substituent led to a significant reduction in reaction rate:
after 48 h at −78 °C, the conversion was only 87% (entry 10).
A moderate isolated yield of 34 could still be obtained (66%),
with slightly reduced enantiopurity (er 88:12) relative to entry
1. Although the reason for the lower selectivity is not clear, the
electron-deficient ketone would be more easily epimerized
upon work-up. The 4-phenyl-substituted enol ether behaved
well to afford 36 in good yield and high selectivity (entry 11).
The compatibility of Lewis basic functionalities in the
substrates was then examined (entries 12 and 13). Both the
tetrahydropyranyl- and N-t-Boc-piperidinyl-substituted silyl
enol ethers were good substrates and afforded products with
yields and enantiomeric purities very similar to those observed
with the cyclohexyl-based substrate (compare entries 6, 12, and
13).42
Scheme 9
products were assigned by analogy and confirmed via circular
dichroism spectroscopy; comparison demonstrated that all
substrates displayed a negative Cotton effect.
8. Mechanistic Considerations. 8.1. Proposed Catalytic
Cycle and Structure of Intermediates. The proposed
mechanism of the reaction is detailed in Figure 4. Reaction
of the chiral, enantioenriched Lewis base with N-phenylthio-
saccharin 4 is proposed to give the Lewis base-bound sulfenyl
cation IV.32d This active sulfenylating agent then reacts with the
silyl enol ether to produce silyloxycarbenium ion V or
thiiranium ion VI. Finally, nucleophilic removal of the
trimethylsilyl group from either V or VI by the saccharin
anion affords the α-sulfenylated product and N-trimethylsilyl-
saccharin. Although detailed kinetic studies have not been
carried out with this system, in the related sulfenylation of
isolated alkenes, thiiranium ion formation is rate-determining
and intramolecular capture is rapid.44 Since this variant does
not have a capture step and the rate of reaction is not
dependent upon the size of the silyl group,45a it is safe to
assume that electrophilic attack on the silyl enol ether is rate-
and stereo-determining here as well. Furthermore, the rate of
the reaction decreases dramatically with increasing steric bulk at
the 2-position of the enol ether, further supporting the notion
that sulfenyl group transfer is rate-determining.
Cyclic enol ethers were also examined (entries 16−18).
Substrates 39 and 41 reacted in the same way previously seen
with acyclic enol ether (E)-1a; conversion was complete at 24
h, but the er was found to be very poor. Next, to investigate the
possibility of preparing of tertiary sulfides, the trimethylsilyl
enol ether of 2-methyltetralone 43 was tested. This enol ether
was targeted specifically to serve as a comparison to previous
results with 41. The rate of sulfenylation of 43 was much
reduced in comparison to that of 41, presumably a consequence
of increased hindrance; only 77% conversion was obtained after
48 h at −40 °C. Interestingly, the selectivity in this case was
higher than for silyl enol ether 41 (85:15 vs 75:25). The
enantiomeric ratio could be upgraded to >99:1 after a single
recrystallization from MeOH.
7. Determining the Absolute Configuration of the
Sulfenylation Products. The absolute configuration of the
products was established for product 36 from the sulfenylation
of (Z)-35, which gave a crystalline product (Scheme 9). After
36 h at −78 °C, complete conversion of (Z)-35 was achieved,
and product 36 was obtained in very good yield and
enantioenrichment (77%, 94:6 er). After purification, the α-
sulfenyl ketone provided crystals from MeOH suitable for
single-crystal X-ray analysis.43 The refinement demonstrated
that (R)-12j produced (S)-36. The configurations of the other
Figure 4. Proposed catalytic cycle.
To establish whether thiiranium ion VI is a reasonable
intermediate in this process, DFT calculations (B3LYP/6-
31G(d)) were performed on the two limiting reaction profiles
shown in Scheme 10. For computational simplicity, the
phenylsulfenylating agent derived from HMPA(Se) (VII) was
employed in combination with (Z)-5. Mechanism 1 posits the
formation of thiiranium ion VI as a stable intermediate that
may open to silyloxycarbenium ion V or undergo direct
collapse to the sulfenylated product. Mechanism 2 posits the
direct formation of silyloxycarbenium ion V. Computationally,
thiiranium ion VI could not be located as a stationary state
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Scheme 10
starting from a number of different geometries, whereas
silyloxycarbenium ion V was found to be a stable entity. The
transition structure for formation of V from (Z)-1a and VII was
located and (as expected) was highly unsymmetrical, with
significantly different distances between the sulfur atom and the
two carbons of the enol ether (Figure 5).45b
Figure 6. DFT-minimized structure of (S)-VIII (hydrogens removed
for clarity).
molecular mechanics and then refining the structure prior to
DFT calculations. The DFT method employed the B3LYP-D3
hybrid functional, with a LACVP(+)* basis set. Optimizations
of the geometry were performed in dichloromethane using the
PBF solvation model.
The first calculations focused on the geometry of the
phenylsulfenyl group with respect to the Lewis base.
Interestingly, the diisopropylamino group is turned such that
the phenylsulfenyl group is pointing toward the binaphthyl
moiety and perpendicular to the naphthyl ring. This structural
feature provides an important insight for the high selectivity
seen with branched dialkylamino-derived catalysts.
Using the optimized geometry of the catalytically active
species (S)-VIII, four different α-sulfenylation transition states
for the sulfenyl group transfer to (Z)-1a were located using
B3LYP/6-31G(d) at −78 °C in the gas phase, and their
structures are shown in Figure 7. All four transition states have
highly unsymmetrical structures with significantly different
distances between the sulfur atom and the two carbons of the
enol ether, consistent with the conclusions from the foregoing
analysis. The transition-state structures TS Re-1 and TS Re-2
will lead to product (R)-5, whereas TS Si-1 and TS Si-2 lead to
(S)-5. The most stable transition state leading to (R)-5 (TS Re-
1) is 0.9 kcal/mol more stable than the lowest energy transition
state leading to (S)-5 (TS Si-1), which agrees with the
Figure 5. Energy profile and transition structure for sulfenyl group
transfer.
8.2. Origin of Enantioselectivity. To provide more detailed
insight into the origin of enantioselectivity, the structures of the
catalytically active species and the transition states for the
various stereochemical pathways for the α-sulfenylation
reaction were investigated by computational analysis. Previous
studies strongly suggested that the catalytically active species (I,
Scheme 3 or IV, Scheme 4) is the sulfenylated selenophosphor-
amide (S)-VIII (Figure 6). The calculations on this species
were performed by first establishing a rough structure with
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Figure 7. Optimized structures and energies of TS Re-1, TS Re-2, TS Si-1, and TS Si-2.
Table 4. Distortion−Interaction and NBO Analysis for the Diastereomeric Transition States
a
a
b
c
ΔEdist_A
ΔEdist_B
ΔEd
ΔEi
ΔEact
ΔH
ΔG
π(CC)−σ*(S−Se)
TSRe-1
TSRe-2
TSSi-1
TSSi-2
10.8
11.2
11.1
10.2
19.6
20.4
20.5
21.1
30.4
31.6
31.6
31.3
−26.7
−26.3
−27.3
−26.4
3.7 (0.0)
5.4 (1.7)
4.3 (0.6)
4.9 (1.2)
4.5 (0.0)
6.2 (1.7)
5.3 (0.8)
5.7 (1.2)
13.2 (0.0)
14.8 (1.6)
14.1 (0.9)
14.9 (1.7)
76.7 (6.2)
70.5 (0.0)
76.8 (6.3)
71.7 (1.2)
a
b
c
A = silyl enol ether (Z)-1a. B = catalytically active species (S)-VIII. ΔEact = ΔEd + ΔEi (ΔEd = ΔEdist_A + ΔEdist_B). π(CC)−σ*(S−Se)
orbital interaction energy is calculated by NBO analysis.
experimental stereochemical outcome (91:9 calcd; 93:7
obsd).46 However, careful inspection of these competing
transition structures failed to identify any obvious interactions
that would disfavor TS Si-1 with respect to TS Re-1. The highly
unsymmetrical transition states allow for a significant distance
between the aryl residue and the catalytically active species,
obviating any severe nonbonding interactions.
To provide additional insight into the origin of enantio-
selectivity, distortion−interaction47 and NBO48 analyses were
carried out (Table 4). These results mirror those from the DFT
analysis and suggest that a more subtle effect may be operative.
As highlighted in bold type, TS Re-1 possesses the lowest
activation energy, 0.6 kcal/mol lower than that of TS Si-1.
Interestingly, even though TS Si-1 benefits from a greater
interaction energy (ΔΔEi = −0.6 kcal/mol), this advantage is
offset by a greater distortion energy (ΔΔEd = 1.2 kcal/mol).
The greater interaction energy associated with TS Re-1 was
substantiated by the NBO analysis, which provided the
stabilization energies arising from orbital overlap from the π-
bond of the silyl enol ether to the antibonding (σ*) orbital of
the sulfur−selenium bond. The stabilization energies for TS Re-
1 and TS Si-1 are nearly identical (and are the largest of the
four transition states), indicating similar levels of orbital
overlap. However, to achieve those levels of overlap requires
greater distortion of the orbitals in TS Si-2 (likely resulting
from nonideal approach of the silyl enol ether). Thus, whereas
unfavorable steric interactions are not the apparent cause of the
enantioselectivity, it is likely that the avoidance of unfavorable
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steric interactions leads to a nonideal approach of the silyl enol
ether that manifests in the greater distortion energy
contribution to that transition state.
AUTHOR INFORMATION
Corresponding Author
sdenmark@illinois.edu
■
The composite picture gleaned from empirical results reveals
the sensitivity of the catalytic species to the shape of the olefin
substrate (Figure 8). These characteristics comport well with
the trends deduced from analysis of the intramolecular
carbosulfenylation of alkenes using the same catalyst and
presumably the same catalytically active species.44 The superior
performance of (E)-alkenes in that analysis is reflected in the
higher selectivities observed with (Z)-silyl enol ethers in this
work, as the carbon-based substituents on the double bond are
effectively trans. Moreover, the observed decrease in selectivity
with decreasing size of the R1 substituent also agrees with the
poor selectivity seen with (Z)-alkenes, because with a small R1
group, the silyloxy substituent becomes the sterically dominant
substituent on that side of the double bond, leading to a net
(Z)-alkene shape.
Author Contributions
†S.R. and M.P.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Institutes of Health for
generous financial support (R01 GM85235). M.P.W. is grateful
to the EU for a Marie Curie International Outgoing Fellowship
for Career Development. The research leading to these results
has received funding from the European Union Seventh
Framework Programme (FP7/2007-2013) under grant agree-
ment no. 303214. D. J.-P. Kornfilt and L. M. Wolf are thanked
for technical assistance.
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CONCLUSIONS
■
The development of a catalytic, asymmetric, Lewis base-
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* Supporting Information
Full experimental procedures and characterization data; X-ray
coordinates and CIF file for (S)-36; copies of 1H and 13C NMR
spectra; CSP-HPLC and CSP-SFC traces; and Cartesian
coordinates and energies for (S)-VIII and TS Re-1, TS Re-2,
TS Si-1, and TS Si-2. This material is available free of charge
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