The cinchona primary amine-catalyzed asymmetric epoxidation and hydroperoxidation of α,β-unsaturated carbonyl compounds with hydrogen peroxide

Article abstract of DOI:10.1021/ja402058v

Using cinchona alkaloid-derived primary amines as catalysts and aqueous hydrogen peroxide as the oxidant, we have developed highly enantioselective Weitz-Scheffer-type epoxidation and hydroperoxidation reactions of α,β-unsaturated carbonyl compounds (up to 99.5:0.5 er). In this article, we present our full studies on this family of reactions, employing acyclic enones, 5-15-membered cyclic enones, and α-branched enals as substrates. In addition to an expanded scope, synthetic applications of the products are presented. We also report detailed mechanistic investigations of the catalytic intermediates, structure-activity relationships of the cinchona amine catalyst, and rationalization of the absolute stereoselectivity by NMR spectroscopic studies and DFT calculations.

Full text of DOI:10.1021/ja402058v

Article
pubs.acs.org/JACS
The Cinchona Primary Amine-Catalyzed Asymmetric Epoxidation
and Hydroperoxidation of α,β-Unsaturated Carbonyl Compounds
with Hydrogen Peroxide
Olga Lifchits, Manuel Mahlau, Corinna M. Reisinger, Anna Lee, Christophe Fares, Iakov Polyak,
̀
Gopinadhanpillai Gopakumar, Walter Thiel, and Benjamin List*
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1 D-45470, Mulheim an der Ruhr, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Using cinchona alkaloid-derived primary amines as catalysts and
aqueous hydrogen peroxide as the oxidant, we have developed highly
enantioselective Weitz−Scheffer-type epoxidation and hydroperoxidation reac-
tions of α,β-unsaturated carbonyl compounds (up to 99.5:0.5 er). In this article,
we present our full studies on this family of reactions, employing acyclic enones,
5−15-membered cyclic enones, and α-branched enals as substrates. In addition to
an expanded scope, synthetic applications of the products are presented. We also
report detailed mechanistic investigations of the catalytic intermediates, structure−activity relationships of the cinchona amine
catalyst, and rationalization of the absolute stereoselectivity by NMR spectroscopic studies and DFT calculations.
The resulting peroxyenamine F then undergoes epoxide ring
closure with the expulsion of water, much like in the original
Weitz−Scheffer system.
INTRODUCTION
■
Since the seminal discoveries of Sharpless in the 1980s,1
catalytic olefin epoxidation has continued to hold a prominent
place in modern asymmetric synthesis. Milestone achievements
in this field over the last thirty years, including those associated
This catalytic platform proved to be highly efficient for the
epoxidation of unencumbered α-unbranched α,β-unsaturated
aldehydes, as demonstrated by the seminal works of Jørgensen
and later MacMillan who used various chiral secondary amines
as catalysts.5 Our group has also contributed to this reaction in
2008 with the use of asymmetric counteranion-directed
catalysis (ACDC), in which an achiral secondary amine catalyst
together with the chiral Brønsted acid TRIP were used to
induce enantioselectivity.6
Despite the success of secondary amine catalysts in the
epoxidation of α-unbranched enals, their extension to more
sterically demanding substrates remained a challenge.7
Furthermore, at the outset of our studies, the enantioselective
epoxidation of simple cyclic enones, nonchalcone-type acyclic
enones, and α-branched enals presented a general problem, for
which neither metal- nor small organic molecule-based catalysis
offered highly enantioselective protocols.
Our early interest in the use of primary amine catalysts as a
tool to tackle difficult substrates prompted us to explore this
catalyst class in various transformations.8 For example, in 2006
we developed a highly enantioselective transfer hydrogenation
of enones using an α-amino acid ester/chiral phosphate salt.8a
Encouraged by this and other seminal studies,9 we sought to
apply primary amine catalysis to asymmetric epoxidation of
challenging α,β-unsaturated carbonyl compounds. As a guiding
principle, we relied on the assumption that the reduced steric
requirements of primary amines may overcome the inherent
́
with the names of Julia and Colonna, Wynberg, Jackson,
Jacobsen, Katsuki, Enders, Shi, and Shibasaki, have not only
provided reliable synthetic protocols but also identified entirely
novel catalytic platforms.2
One of the most fundamental ways to form an oxirane ring is
the reaction of basic hydrogen peroxide with electrophilic α,β-
unsaturated ketones and aldehydes, a process described already
in 1921 by Weitz and Scheffer.3 Kinetic studies of this
transformation established it to be a two-step addition−
elimination process, in which hydrogen (or alkyl) peroxide,
deprotonated under basic conditions, adds to the β-carbon of
the unsaturated carbonyl compound, forming a β-peroxyenolate
intermediate B (Scheme 1a).4 This is followed by an
intramolecular ring closure, in which the weak O−O bond is
broken and a second C−O bond is formed, expelling a
hydroxide or an alkoxide anion as the leaving group.
Protonation of the enolate B results in the common side-
product of the reaction, hydroperoxide D (typically observed in
its more stable hemiketal form as shown). Several enantiose-
lective variants of the Weitz−Scheffer epoxidation have been
developed to date, which rely on the catalytic activation of the
substrate and/or the peroxide reagent. Most recently, it has
been recognized that Weitz−Scheffer-type epoxidation is also
amenable to covalent aminocatalysis, whereby the carbonyl
substrates are activated as iminium ion intermediates E toward
conjugate addition by the oxidant (Scheme 1b).
Received: March 5, 2013
© XXXX American Chemical Society
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Scheme 1. Weitz-Scheffer Epoxidation: (a) the Original Mechanism and (b) the Amine-Catalyzed Variant
difficulties of secondary amines in generating congested
covalent iminium ion intermediates (Scheme 2).10
chalcone-type substrates were broadly suitable, with simple
enolizable aliphatic enones still posing a considerable challenge
to chemists.2b,d,g,l,14
Inspired by our earlier success with primary amine catalysis,8a
we decided to examine trifluoroacetic acid (TFA) salts of the
cinchona alkaloid-derived amine 1a in this transformation.
Using 3-decen-2-one (2a) as a model substrate and hydrogen
peroxide as an inexpensive, environmentally benign, and easily
handled oxidant, we observed complete conversion of the
starting material to two isolable products: cyclic peroxyhemi-
ketal 3a, a known intermediate and common byproduct in
Weitz−Scheffer-type epoxidations,15 and the expected epoxide
4a as the minor product in essentially enantiopure form.
Since cyclic peroxides 3 can be quantitatively transformed
into the corresponding epoxides 4 under basic conditions,16
and serve as precursors to other useful compounds, we decided
to first optimize the hydroperoxidation reaction. The ratio of
the intermediate peroxyhemiketal 3 and the terminal epoxide
product 4 was found to mainly depend on the pKa of the acid
cocatalyst, water content, and temperature of the reaction, with
weaker acids, higher water concentration, and lower reaction
temperature favoring the hydroperoxidation product and
decelerating the formation of the epoxidation product.17 With
the optimal conditions in hand, we evaluated the scope of the
reaction, employing various aliphatic enones 2 (Table 1). A
wide variety of substrates was found to be compatible with the
reaction, affording the desired cyclic peroxyhemiketals 3 as the
major products, which could be easily separated from the
epoxide side-products 4 and isolated with reasonable yields and
invariably excellent enantioselectivities. Both linear and
branched aliphatic substituents R1 were well tolerated (entries
1−4), although the degree of branching affected the hydro-
peroxide/epoxide product distribution. Functional groups
including an isolated double bond (entry 5), acid-labile
protected alcohol moieties (entries 6−7), an ester (entry 8),
a pendant ketone (entry 9), and an unprotected hydroxy group
(entry 10) were acceptable. Notably, the second ketone group
in substrate 2j gave rise to an equilibrium mixture of two cyclic
peroxyhemiketal products, containing five- and six-membered
dioxolane rings.17 Five-membered peroxyhemiketal 3j′ was
found to exist as the typical mixture of two diastereomers, while
only one diastereomer of the six-membered isomer 3j″ could
be detected, whose relative configuration was putatively
assigned.
Scheme 2. Challenging Substrate Classes Prior to our
Studies and our Proposed Catalytic Platform
Thus, we speculated that if primary amine salts are
compatible with oxidizing conditions, they could provide a
general solution for the epoxidation of sterically demanding
substrates. Indeed, both iminium and enamine catalysis
employing chiral primary amines have started to emerge as a
powerful strategy in catalytic asymmetric transformations in
recent years.2e,10,11 Initial investigations using the salts of
cinchona alkaloid-derived primary amine catalyst 1a11a−c,g,12
confirmed our expectations, and we have recently developed
and communicated highly enantioselective epoxidation and
hydroperoxidation reactions of a variety of cyclic and acyclic
enones as well as α-branched enals.8b,c,e Subsequent to our
initial report,8c Deng et al. independently published related
alkylperoxidations of acyclic enones using catalyst 1a.11e
All of the reactions employ catalyst 1a or its close analogues
and feature both generality and a remarkable consistency in the
stereochemical outcome. Herein, we present our full studies on
this family of reactions, including an expansion of the scope,
synthetic applications, and mechanistic investigations.
Various groups R2, which render substrates 2 enolizable, all
participated in the reaction smoothly (entries 13−17), although
higher steric demand of the R2 group was found to decrease
reactivity and increasingly favor the formation of the epoxide
products 4. Surprisingly, substrate 2m bearing an isobutyl
group almost exclusively afforded the epoxide product (entry
14).
RESULTS AND DISCUSSION
■
Epoxidation and Hydroperoxidation of Acyclic Eno-
nes.8b At the outset of our studies in 2008, general and highly
enantioselective strategies for the catalytic epoxidation of
simple, α,β-unsaturated ketones were scarce.2j,13 Indeed,
despite the wealth of epoxidation methodologies, only
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Table 1. Catalytic Asymmetric Hydroperoxidation of Enones
Table 2. Catalytic Asymmetric Epoxidation of Enones
a
b
1
All reactions performed on 0.5−1 mmol scale. Determined by H
c
NMR analysis of the crude reaction mixture. Determined by GC with
a chiral stationary phase after conversion to the corresponding epoxide
a
b
1
d
All reactions performed on 0.5−1 mmol scale. Determined by H
with 1 N NaOH (1 equiv) in THF. Conducted on 3 mmol scale.
c
e
f
1
NMR analysis of the crude reaction mixture. Determined by GC with
a chiral stationary phase. Using 10 mol % [1b·2TFA]. Sum of 3q
and the corresponding peroxyhemiketal 4q at 94% conversion
determined by H NMR. Reduced yield due to the volatility of the
product. NaOEt (1 equiv) was used instead of NaOH. Second step
69% conversion determined by H NMR. er of the initially formed
d
e
g
1
epoxide 4k. 96% conversion determined by H NMR.
f
1
g
h
A slight modification of the reaction conditions and an
inclusion of a basic workup of the crude reaction mixture with
1N NaOH allowed for an efficient generation of epoxide
products 4 (Table 2).
i
was omitted. Sum of 4k and the corresponding peroxyhemiketal 3k at
j
69% conversion determined by 1H NMR. Using 20 mol %
[1a·2TFA].
Gratifyingly, good to excellent yields and very good
enantioselectivities were obtained for a range of substrates of
varying steric demands. Importantly, using the pseudoenantio-
meric catalyst 1b, the opposite enantiomers of the epoxide
products could be accessed with nearly equal efficiency (entries
1−2 and 3−4). Interestingly, both substrates 2r bearing a bulky
R1 group (entry 7) and 2m bearing a bulky R2 group (entry 21)
afforded the respective epoxide products with essentially perfect
enantiocontrol (er >99.5:0.5). In addition, epoxide 4m (entry
21) was formed as the only product of the reaction, whereby no
corresponding peroxyhemiketal product could be detected. All
of the functional groups which were found to be compatible in
the hydroperoxidation procedure (Table 1) were also suitable
for epoxidation (entries 10−16). However, the hydrolyzing
conditions of aqueous NaOH workup required in the
epoxidation protocol resulted in partial saponification of
product 4i (entry 15) which bears an ethyl ester group. This
problem could be overcome by using NaOEt in ethanol instead
of aqueous NaOH in the workup. In case of the ketone-bearing
substrate 2j (entry 16) the basic workup was omitted since it
did not improve the yield of epoxide 4j, presumably due to a
competing base-catalyzed aldol reaction. Thus, epoxide 4j was
isolated from the hydroperoxide−epoxide product mixture in
40% yield and 98.5:1.5 er (entry 16). Low conversion (69%) of
9-hydroxy-3-nonen-2-on 2k containing an unprotected hydrox-
yl group, which could not be improved by an extended reaction
time, resulted in only moderate yield of the corresponding
products, although the enantioselectivity remained high (98:2
er, entry 17).18
We also investigated the influence of olefin geometry on the
enantioselectivity of the epoxidation reaction by submitting
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isomerically pure enones (E)-2b and (Z)-2b to the optimal
reaction conditions (Scheme 3). Remarkably, both substrates
Thus, both substituents R1 and R2 are limited to alkyl groups,
a phenomenon also observed by Deng and colleagues in the 1a-
catalyzed hydroperoxidation of α,β-unsaturated ketones with
tert-butyl peroxide and related oxidants.11e Similarly, literature
analysis confirmed that the aromatic R2 substituents (Scheme
4) are only very rarely tolerated in reactions catalyzed by
cinchona alkaloid-derived primary amines.22 In this respect, our
catalytic epoxidation complements conventional methods, such
Scheme 3. Stereoconvergence in the Asymmetric
Epoxidation
́
as metal-catalyzed or Julia-Colonna epoxidations.
Despite the reaction’s tolerance of remote protected hydroxy
functionalities, a benzyloxy group in the γ position proved
deleterious (substrate 5f). Neither substitution at the α-position
nor extended conjugation of the double bond is tolerated, as
illustrated by the reaction of 1-acetylcyclohexene (5g) and β-
ionone (5h), respectively. 4-Oxoenoates 5i−j also did not
undergo epoxidation, although their use in related trans-
formations via asymmetric iminium ion catalysis is well
precedented in the literature. Surprisingly, terminal enones
were unsuitable in the reaction (substrate 5k). We speculate
that in the case of more active Michael acceptors, conjugate
addition of catalyst 1a to form β-amino ketones is favored over
condensation with the ketone group, especially given that
hydrogen peroxide (presumably in its neutral form) is a weak
nucleophile to compete with. To probe this hypothesis, we
conducted the epoxidation of our model substrate 3-decen-2-
one (2a) in the presence of the terminal enone 5k (1:1 ratio),
adjusting the reaction parameters to imitate the optimal
conditions. Only epoxide 4a was generated, albeit at a
significantly lower rate. This is consistent with the assumption
that the catalyst is captured as a β-amino ketone by 5k and only
partly released from this “catalyst resting state”, keeping its
absolute concentration low.23
furnished the same enantiomer of trans-epoxide 4b with
excellent enantioselectivity and yield, indicating complete
stereoconvergence. This behavior suggests that E/Z mixtures
of enones can be conveniently employed as epoxidation
substrates.
GC-MS analysis of samples taken from the epoxidation of
pure (Z)-2b revealed the formation of (E)-2b, indicating rapid
isomerization of the (Z)-enone to the corresponding (E)-
isomer under the reaction conditions. (Z)-2b was also found to
isomerize in the presence of catalytic salt [1a·2 TFA] alone,
without any assistance of hydrogen peroxide. This suggests that
isomerization may take place via a dienamine intermediate,
which allows free rotation about the carbon−carbon single
bond. We, and others, have proposed an analogous mechanism
in earlier studies on the asymmetric transfer hydrogenation of
α,β-unsaturated aldehydes with a secondary amine catalyst,
where similar stereoconvergence was observed.19,20
Several substrate classes currently represent a limitation of
the method and are summarized in Scheme 4. Enones
Synthetic Utility of the Obtained Epoxides and
Hydroperoxides. To demonstrate the utility of our hydro-
peroxidation and epoxidation reactions, we also explored
several synthetic applications of the corresponding products 3
and 4.
Scheme 4. Current Limitations in Enone Hydroperoxidation
and Epoxidation
We recognized that a simple reduction of the O−O bond in
hydroperoxides 3 could deliver valuable β-hydroxyketones 6.
Importantly, organocatalytic aldol approaches to these
compounds are limited by the need to use unbranched
enolizable aldehydes, which are prone to self-aldolization and
typically lead to lower yields and inferior enantioselectivities. In
contrast, hydroperoxidation of enones 2 followed by reduction,
which represents a formal enantioselective hydration of the α,β-
unsaturated ketones, could furnish β-hydroxyketones 6 from
simple starting materials and draw upon the high enantiose-
lectivity of our hydroperoxidation procedure.
Based on this rationale, we developed a one-pot protocol
which consists of asymmetric hydroperoxidation, followed by
the addition of triethylphosphite24 to the crude reaction
mixture. Various aldol-like products 6 were thus obtained in
good yields and excellent enantioselectivities (Table 3).
Alternatively, the crude peroxyhemiketals can also be
reduced by catalytic hydrogenation with equal efficiency and
without any erosion of the enantiomeric excess (Table 3, entry
2).26
The existence of potent natural products which contain
optically active five-membered 1,2-dioxolanes27 and the
noticeable lack of methodologies for their asymmetric synthesis
in the chemical literature28 stimulated us to seek approaches to
this substrate class based on our methodology. We envisaged
optically active peroxyhemiketals 3 as precursors for the
conjugated with an aromatic group (5a−c, 5e) all gave the
corresponding epoxide products in <10% yield, albeit with high
enantioselectivity of 98.5:1.5−99.5:0.5 er. Considerable amount
(up to 12%) of the starting material 5a was found to
decompose to phenylacetaldehyde, presumably via a Dakin-
type reaction.21 The use of electron-poorer and thus more
activated Michael acceptors, such as 5c, suppressed this side
reaction but did not improve the yield. Other aromatic enones,
such as furfurylidenacetone (5b), 1-phenyl-2-buten-1-one (5d),
and chalcone (5e), proved to be unreactive under the reaction
conditions.
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explored using various substituted cyclohexenones (Table 4).
It is noteworthy that initial products of hydroperoxidation
could not be detected with any of the substrates 9. Simple
Table 3. One-Pot Synthesis of β-Hydroxyketones
Table 4. Catalytic Asymmetric Epoxidation of
Cyclohexenone Derivatives
a
b
Determined by GC or HPLC with a chiral stationary phase. ii = H2
c
(1 atm), Pd/C (15 wt %), MeOH. Absolute configuration (R) was
determined by comparison with literature known optical rotation
data.25
corresponding 1,2-dioxolanes 8. Toward this end, we found
that simple ketalization of 3a with methanol and catalytic
Brønsted acid followed by triethylsilane reduction in the
presence of titanium tetrachloride could afford 1,2-dioxolane 8
in 74% overall yield and a 75:25 diastereomeric ratio in favor of
the cis-isomer (Scheme 5a). Moreover, dioxolane 8 could be
Scheme 5. Synthesis of 1,2-Dioxolanes
directly obtained in good yield and only slightly lower
diastereoselectivity (67:23 dr) via reduction of peroxyhemiketal
3a with triethylsilane in the presence of stoichiometric amounts
of triflic acid, which presumably generates Lewis acidic
triethylsilyl triflate under the reaction conditions (Scheme
5b). To the best of our knowledge, this is the first report on the
direct conversion of peroxyhemiketals into the corresponding
dioxolanes, which obviates the need to preform a peroxyketal.
Adapting the conditions of Yamaguchi and colleagues,29 we
could also carry out diastereoselective ketone reduction of
epoxides 4 to form optically active epoxyalcohols.30
Epoxidation of Cyclic Enones: Cyclohexenones.8c
Simple cyclic enones have generally been omitted within the
vast majority of studies on the asymmetric epoxidation of α,β-
unsaturated ketones.2 Thus, we decided to explore these
challenging substrates, first focusing on cyclohexenone
derivatives. Preliminary investigations identified trifluoroacetic
acid salts of the cinchona alkaloid-derived amine 1a as powerful
catalysts for the epoxidation of cyclohexenone 9a with aqueous
hydrogen peroxide. As with acyclic enones, the optimal reaction
medium proved to be 1,4-dioxane at 50 °C. Using the
optimized conditions, the scope of the epoxidation was
a
Determined by GC with a chiral stationary phase. The absolute
configuration (2S,3S) of 10a was determined from its known optical
rotation.31 Performed at 50 °C. Performed using 20 mol % catalyst
b
c
d
e
salt [1a·2 TFA]. 54% conversion determined by GC. Performed at
30 °C for 24 h. Performed using catalyst 1b (10 mol %). GC-
conversion, dr = 54:46 (anti:syn). dr = 97:3 (anti:syn).
f
g
h
E
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cyclohexenone (entry 1) and substrates bearing substituents at
the 4-position (entry 2), 5-position (entry 3), and 3-position
were all equally well tolerated, giving the corresponding
epoxide products with excellent enantioselectivities and good
yields. Diketone 9e (entry 5) proved to be less reactive but
nevertheless gave the corresponding epoxide 10e in a
reasonable yield along with high enantioselectivity of 96:4 er.
We next examined the effect of substituents at the 3-position.
Substrates bearing a variety of linear and branched alkyl
substituents underwent epoxidation smoothly with good yields
and excellent enantioselectivity (entries 6−14). Using the
pseudoenantiomeric catalyst 1b, the opposite enantiomer of
product 10m could be efficiently obtained from substrate 9m
(entry 14). A diminished yield (23%) was obtained with
substrate 9k bearing an allyl substituent (entry 11). Partial
isomerization of the terminal double bond into conjugation
with the α,β-enone moiety was observed for this substrate,
giving an unreactive dienone.32
Table 5. Catalytic Asymmetric Epoxidation of Medium and
Large Ring-Sized Enones
Extended conjugation of the double bond was not tolerated
in the reaction, with phenyl, vinyl and ethinyl substituents
rendering enones 9n−p unreactive (entries 10−12). In
addition, 2-substituted cyclic enones represent a limitation of
the method.
We were also intrigued by the possibility of a (dynamic)
kinetic resolution of racemic 4-substituted or enantiopure 5-
substituted cyclohexenones via asymmetric epoxidation.
Employing 4-methyl substituted enone rac-9q, however, we
observed the formation of both diastereomeric epoxides syn-
and anti-10q with high enantioselectivities at similar rates
(entry 18). In stark contrast, the racemic synthesis with alkaline
hydrogen peroxide in methanol proceeded with a diaster-
eoselectivity of 74:26 dr in favor of the anti-epoxide 10q.33
We further wished to probe the effect of pre-existing
stereocenters embedded in the ring scaffold, which cannot be
equilibrated in the course of the reaction. To this end, we
prepared enantioenriched 5-phenyl-3-methyl-2-cyclohexenone
(S)-9r according to a method previously developed by our
group.34 Subjecting this substrate to our standard epoxidation
conditions delivered epoxide anti-10r featuring three stereo-
genic centers with excellent yield, diastereoselectivity and
enantioselectivity (entry 19).
Epoxidation of Cyclic Enones: Medium8c and Large-
Sized Rings. Having identified a robust epoxidation procedure
for cyclohexenone derivatives, we turned our attention to
medium- and large-sized cyclic enones 11 (Table 5). Gratify-
ingly, 7−15-membered cycloalkenones all underwent epox-
idation with good to excellent yields and outstanding
enantioselectivities. Moreover, the use of the pseudoenantio-
meric catalyst 1b enabled facile synthesis of enantiomeric
product ent-12f with equal efficiency (entry 9). These results
raise the intriguing possibility of effecting stereoselective,
catalyst-controlled late-stage epoxidation of macrocyclic cores
for natural product synthesis,35 especially given the stereo-
convergent nature of our method.
Whereas epoxides were the only products observed in the 1a-
catalyzed reaction of cyclohexenones 9 with hydrogen peroxide,
optically active peroxidic side products 13 could be detected
with larger ring-sized enones 11, analogously to the acyclic α,β-
unsaturated ketones 2. In contrast to products 3, which
overwhelmingly exist as cyclic peroxyhemiketals, mixtures of
monocyclic β-hydroperoxyketone and bicyclic peroxyhemiketal
forms of 13 could be detected in solution by NMR for the
seven- and eight-membered substrates. Based on this
a
b
Determined by GC with a chiral stationary phase. alternative
conditions: [1a·2 TCA] (10 mol %), H2O2 (30 wt %; 3 equiv), 1,4-
c
dioxane (0.25 M), 32 °C, 20 h. 1H NMR conversion, 12a:13a = 23:77
d
Performed at 50 °C. Crude product was treated with 1N NaOH (1
e
f
equiv) in THF. 1H NMR conversion, 12d:13d = 12:88. Using
catalyst 1b.
observation we speculate that an internal hydrogen bond can
be established in medium-sized rings, which stabilizes the β-
hydroperoxyketone form.
The hydroperoxidation/epoxidation product distribution was
found to strongly depend on the ring size of the cyclo-
alkenones. While the smallest (n < 7) and the largest (n ≥ 12)
ring sizes significantly favored epoxidation, eight-membered 2-
cyclooctenone 11d provided peroxide 13d as the major product
(yield of epoxidation product: blue, yield of peroxidation
product: red, Figure 1). Even though data for the ring sizes 9−
11 are not available, the amount of hydroperoxide product
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Table 6. Asymmetric Synthesis of Cyclic β-Hydroxyketones
Figure 1. Hydroperoxidation/epoxidation product distribution of
cyclic enones of varying ring size and ring strain/CH2 of the
corresponding cycloalkanes.36
obtained seems to correlate with the ring strain found in the
corresponding cycloalkanes (green). As with peroxyhemiketals
3, peroxidic products 13 could be transformed to the
corresponding epoxides 12 by a simple aqueous NaOH
workup.
a
Determined by GC with a chiral stationary phase.
aldolizations rather than the seven- or eight-membered cyclic
products through enolendo-aldolizations.38
Peroxides 13a and 13d, derived from 2-cycloheptenone
(11a) and 2-cyclooctenone (11d), respectively, piqued our
interest since their bicyclic peroxidic structure resembles potent
antimalarial agents and since both compounds have not been
previously described in the literature. With the goal of
optimizing the yield of the peroxidic products at the expense
of the corresponding epoxides, we evaluated various reaction
parameters. Gratifyingly, the product ratio could be shifted in
favor of the peroxidation products by simply switching the acid
cocatalyst to trichloroacetic acid and employing less concen-
trated aqueous hydrogen peroxide (Table 5, entries 2 and 6).
We presume that conformational constraints in the seven-
and eight-membered ring systems, in contrast to 2-cyclo-
hexenone, may hamper the peroxyenamine intermediate in
adopting the proper conformation for epoxide ring closure,
which requires an antiperiplanar alignment of the π-system of
the enamine with the O−O single bond. These difficulties
might be reflected in the accumulation of hydroperoxidation
product 13 over the course of the reaction. In contrast, large
rings are very flexible and show complex conformational
behavior. As a result, cyclododecenone 11e and cyclo-
pentadecenone 11f provide almost exclusively the correspond-
ing α,β-epoxyketones 12 under both sets of conditions.
As with the acyclic epoxides 4, we wished to demonstrate the
synthetic utility of cyclic epoxides 12 by reducing them to aldol-
like products 15.37 This was achieved by the previously
established method employing in situ generated phenyl selenide
(Table 6). The resulting six- to eight-membered cyclic
hydroxyketones 15a−d were obtained in good to excellent
yields and enantioselectivities. The method also proved
effective for the generation of a highly enantioenriched
quaternary oxygenated stereocenter (entry 2). It should be
noted that none of these compounds had been accessed
through a catalytic asymmetric methodology prior to our work.
The synthesis of seven- and eight-membered products 15c and
15d is particularly valuable in light of the fact that these
compounds cannot be accessed via an intramolecular aldol
disconnection, as the required keto-aldehydes preferentially
form six-membered cyclic aldol products through enolexo-
Epoxidation of Cyclic Enones: Cyclopentenones.8h
Despite the generality of our method for enone substrates with
small, medium, and large rings, the epoxidation of cyclo-
pentenones 16 proved to be a considerable challenge. Indeed,
the substantial “flatness” of these small rings, which presumably
renders them less sensitive to the steric requirements of a chiral
catalyst, makes 2-cyclopentenones a notoriously difficult
substrate class for iminium-catalyzed asymmetric conjugate
additions.39 We have recently identified a new class of
cinchona-derived primary amine catalysts bearing a C2′-
substituent on the quinoline group, which enabled us to
develop the first asymmetric catalytic Knoevenagel condensa-
tion.8g Inspired by these results, we decided to explore this
catalyst class in the asymmetric epoxidation. Quinoline C2′-
substituted cinchona amines are readily accessible via a
protecting group-free one-pot procedure consisting of addition
of an organometallic reagent followed by oxidation. Careful
optimization identified amine 1c together with Mosher’s acid
18 as a powerful catalyst salt for the enantioselective
epoxidation of cyclopentenones.40 As in the previous systems,
1,4-dioxane remained the solvent of choice, albeit the
temperature had to be lowered to room temperature to achieve
the best enantioselectivity. With the optimal conditions in
hand, the scope of the epoxidation was explored (Table 7). To
our delight, simple 2-cyclopentenone (entry 1) as well as its
derivatives bearing a variety of linear and branched substituents
in the 3-position (entries 2−4) and 4-position (entry 5) could
be converted to the corresponding epoxy cyclopentenones 17
with excellent yields and enantioselectivities.
Epoxidation of α-Branched Enals.8e Despite the
existence of several methodologies for the nonasymmetric
epoxidation of α-branched enals,2e,41 direct catalytic enantiose-
lective variants for this transformation were lacking at the
outset of our studies.42 Encouraged by the success of catalyst 1a
in the epoxidation of various enones, we reasoned that the
similar steric requirements of α-branched enals might make
them a suitable substrate class for our developed catalytic
system. Our expectations were further supported by recent
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Table 7. Catalytic Asymmetric Epoxidation of Substituted 2-
Cyclopentenones
Table 8. Catalytic Asymmetric Epoxidation of α,β-
Disubstituted Enals
a
b
Performed on 0.2 mmol scale. Determined by GC with a chiral
stationary phase.
reports, which demonstrated that α-branched enals could be
efficiently activated for asymmetric transformations by primary
amine catalysts.9a,43
Indeed, applying the conditions optimized for enones 2 to
the epoxidation of (E)-2-methylpent-2-enal 19a, we were
pleased to obtain the desired epoxide 20a with a significant
enantiomeric ratio of 93:7, albeit with a modest chemical yield.
Starting from the (E)-configured enal 19a, the epoxide 20a was
formed as a mixture of diastereomers with moderate trans-
selectivity of 75:25. As with five- and six-membered cyclic
enones, products of initial hydroperoxidation could not be
detected in the reaction.
a
b
All reactions performed on 0.25 mmol scale. Yields refer to isolated
c
yields after NaBH4 reduction. Determined by GC of the crude
reaction mixture. Determined by GC with a chiral stationary phase.
The absolute configuration (2R,3S) of 19a was assigned by comparing
d
the optical rotation of the corresponding alcohol to the literature
Optimization of the catalyst system revealed a very strong
effect of the acid cocatalyst on the enantio- and diastereose-
lectivity of the reaction, indicating a possible involvement of the
value.44 Opposite diastereoselectivity (28:72 dr) in the racemic
e
f
reaction using alkaline hydrogen peroxide. 48 h reaction time, low
yield due to incomplete conversion. Unidentified side product also
isolated.
g
iminium counteranion in enantiodiscrimination.3 Remarkably,
e
applying the chiral phosphoric acid (R)-TRIP ((R)-21a) as the
acid cocatalyst, we observed a dramatic case of “matched”
asymmetric induction, whereby the product 20a was obtained
in essentially enantiopure form (er = 99.5:0.5). Using the (S)-
enantiomer of TRIP resulted in the loss of synergism, giving a
reversed but modest enantioselectivity of 36:64.8e After further
optimization to improve the yield, we found that the phenyl-
substituted BINOL-derived phosphoric acid (R)-21b formed a
more active but equally enantioselective catalyst salt [1a·2 (R)-
21b]. Using the optimized conditions, we examined the scope
of the asymmetric epoxidation (Table 8). Excellent enantiose-
lectivity and good diastereoselectivity and yields were observed
for all substrates, regardless of the size of the α-substituent
(entries 1−3). Cyclic substrate 19d (entry 4) and enal 19f
bearing an ester group (entry 6) underwent the epoxidation
smoothly. In contrast to enones 2, enals bearing aromatic
substituents in conjugation with the double bond (entries 5 and
8) were also suitable, although a phenyl α-substituent resulted
in the erosion of diastereoselectivity (entry 8). Interestingly, the
primary amine catalytic platform proved unsuitable for the α-
unbranched enal 19i, affording the corresponding product 20i
with the opposite absolute configuration and only modest
enantioselectivity and yield (entry 9).
Substrates containing a tetrasubstituted double bond (enals
19j and 19k) proved unreactive toward epoxidation, presum-
ably due to difficulties of the amine catalyst in condensing with
the sterically hindered aldehyde moiety. Instead, decomposition
products via Baeyer−Villiger and Dakin-type reactions were
observed (Scheme 6).
We also tested the reaction for stereoconvergence by
submitting the (Z)-configured enal 19g to the epoxidation
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The catalytic system [1a·2 (R)-21a] also proved to be highly
efficient in a kinetic resolution of a β′-substituted enal rac-22e
(Scheme 7).
Scheme 6. Current Limitations in the Epoxidation of α-
Branched Enals
Scheme 7. Kinetic Resolution of rac-22e by Asymmetric
Epoxidation
conditions and found that the reaction proceeds by a
stereoconvergent mechanism.17
We next turned our attention to the epoxidation of a related
substrate class, the 2-substituted acroleins 22. Initial inves-
tigations using the TFA salt of cinchona amine 1a as the
catalyst revealed only very low asymmetric induction (59:41 er)
for this substrate, in stark contrast to the α,β-disubstituted enal
2a (93:7 er). Because conjugate addition of hydrogen peroxide
to the unsubstituted β-carbon of enals 22 does not produce a
stereogenic center, the subsequent epoxide ring closure of the
peroxyenamine intermediate must constitute the enantiodeter-
mining step of the reaction. The different mechanistic regimes,
which are likely responsible for the enantiodetermining steps in
the epoxidation of enals 19 and 22 may thus explain the drastic
difference in the enantioselectivity of their epoxidation by the
TFA salt of cinchona amine 1a.
Gratifyingly, we found that using the chiral acid cocatalyst
(R)-21b dramatically increased the enantioselectivity of the
reaction to 91:9 er, which could be further improved to 99:1 er
by using the bulkier phosphoric acid (R)-TRIP ((R)-21a).
Using the optimized conditions, we screened various acrolein
derivatives 22 and observed excellent enantioselectivity and
good yields for all tested substrates (Table 9).
Under the standard reaction conditions, the reaction
proceeded to 53% conversion, whereby (R)-22e underwent a
highly selective epoxidation, while (S)-22e was recovered with
97:3 er.
Mechanistic Aspects. We propose that all of our
epoxidation reactions proceed via the same general mechanism
of iminium ion-catalyzed oxa-Michael addition of hydrogen
peroxide followed by epoxide ring closure of the resulting
peroxy enamine (Scheme 8), analogously to the well-studied
mechanism of the Weitz−Scheffer epoxidation.4
In particular, the initial formation of the α,β-unsaturated
iminium ion A1 (derived from enones) or A2 (derived from
enals) promotes a nucleophilic attack by hydrogen peroxide,
forming the corresponding β-peroxyenamine intermediate B1/
B2. Protonation of B1 to give iminium D followed by
hydrolysis gives hydroperoxides 3/13, which can be considered
as products of “interrupted epoxidation” (Scheme 8a). As
described in the previous sections, the stability of such products
appears to be substrate specific and their isolation limited to
acyclic,8e medium ring-sized (n = 7,8) and macrocyclic (n > 12)
enones. In contrast, no hydroperoxide intermediates could be
isolated with enals, cyclopentenones, and cyclohexenones. A
combination of enamine and Brønsted acid catalysis is believed
to promote the ring closure of B1/B2 to the epoxide
intermediate C1/C2.45 Subsequent hydrolysis liberates the
epoxide product and regenerates the catalyst.
Table 9. Catalytic Asymmetric Epoxidation of 2-Substituted
Acroleins
An important difference from the Weitz−Scheffer epox-
idation concerns the reversibility of the oxa-Michael addition of
hydrogen peroxide (step A→B, Scheme 8). The basic
conditions of Weitz−Scheffer epoxidations create a hydro-
peroxide anion as the active nucleophile, whose addition to
unsaturated carbonyls has been confirmed by kinetic data to be
fast and reversible.38 38 Under our reaction conditions in the
presence of catalyst salts, which include 2 equiv of a Brønsted
acid, neutral hydrogen peroxide rather than the hydroperoxide
anion is expected to be the active nucleophile. Consequently,
the conjugate addition is most likely irreversible and constitutes
the enantiodetermining step of the catalytic cycle.46 This is
supported by the high enantiomeric excess of the isolable
hydroperoxy intermediates 3 and 13 (er >95:5), which would
be expected to be racemic under a reversible mechanistic
regime.47
d,
e
a
b
All reactions performed on 0.25 mmol scale. Isolated yields after
c
NaBH4 reduction. Determined by GC with a chiral stationary phase.
d
e
Isolated yield of the aldehyde. The decreased yield reflects the high
volatility of the product.
Diminished yield for substrate 22c (entry 3) reflects the high
volatility of the corresponding product 23c. Applying the
pseudoenantiomeric form of the amine catalyst 1b and (S)-21a
as the catalytic salt in the epoxidation of 22a provided the
corresponding (S)-product ent-23a with only 44% yield and a
modest enantioselectivity of 71:29 er. However, complemen-
tary approaches, which furnish the (S)-products with high
enantiomeric excess, were recently reported by the groups of
Hayashi7a and Luo.11d
To provide comprehensive support for the proposed
mechanism and to elucidate the origin of enantioselectivity,
we performed mechanistic studies on both enone and enal
substrates, employing various experimental and computational
approaches.
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enone 2a. After H2O2 addition (Scheme 9), iminium ion A
could no longer be detected, suggesting its rapid consumption
by hydrogen peroxide, although the signal for the free catalyst
1a remained. Already after 1 h reaction time, two new peaks
could be detected at m/z 476 and at m/z 494 which match the
masses of the iminium ion B derived from 2,3-epoxy-2-
decanone (4a) and iminium ion C derived from the
corresponding β-hydroperoxyketone, which upon hydrolysis
affords peroxyhemiketal 3a. LRMS and HRMS data obtained
for catalyst 1a and intermediates A−C are summarized in Table
10.
Scheme 8. Proposed Catalytic Cycles for the Epoxidation of
Enone and Enal Substrates with Catalysts 1
The fact that the free catalyst 1a as well as the intermediate
products of hydroperoxidation (B) and intramolecular epoxide
closure (C) could be easily detected under the reaction
conditions, while the iminium ion A remained below the
detection limit, suggests that the initial formation of the
iminium intermediate A could be the rate-limiting step of the
reaction.17
When analyzing the reaction at 50 °C, we were particularly
intrigued by the appearance of additional signals at m/z 340,
492, and 510, which presumably correspond to the oxidized
catalyst (species 1a+O) and iminium ions B+O and C+O that
incorporate this oxygenated catalyst (Scheme 9b and Table 10).
After 12 h of reaction time, these peaks gained in intensity,
while the parent peaks 1a, B and C (m/z 324, 476 and 494,
respectively) showed considerable loss of intensity, suggesting
catalyst oxidation.17 It is noteworthy that a doubly oxidized
catalyst species, i.e. a mass incorporating two oxygens (m/z
356) could not be detected.
Since all of the reactions with the amine catalyst 1a proceed
to completion and the epoxidation products are formed with
outstanding enantioselectivities, the observed in situ oxidation
of the catalyst raised interesting mechanistic questions.
Specifically, we wondered if the oxidized catalyst 1a+O is active,
and hence if the iminium ions B+O and C+O are catalytically
relevant intermediates. Their formation suggested to us that the
primary amine functionality of the catalyst 1a cannot be
involved in the oxidation to 1a+O. We therefore hypothesized
that species 1a+O most likely arises from the N-oxidation of the
most nucleophilic quinuclidine nitrogen. Toward this end, we
synthesized 9-amino(9-deoxy)epiquinine N-oxide 24 using m-
CPBA (Scheme 10) and could unambiguously confirm the site
of N-oxidation by 15N-HMBC analysis.17
With an authentic sample of 24 in hand, we next analyzed the
catalyst species, which remained at the end of the epoxidation
reaction shown in Scheme 9. Although analysis of the crude
reaction revealed a complex mixture of compounds containing
the quinine scaffold, which presumably correspond to various
catalytic intermediates, direct elution on silica gel allowed us to
isolate a single species of significantly higher polarity.
Characterization of this product confirmed it to be identical
to 24. In addition, when we submitted 1a to the standard
conditions of epoxidation in the absence of any enone
substrate, we observed a clean and quantitative formation of
the bis-trifluoroacetic acid salt of 24.
Structure−Activity Relationship of Modified Catalyst
1a. We first verified that the presence of the primary amine
moiety in 1a is indeed crucial for the observed reaction rate and
enantioselectivity, supporting a mechanism proceeding through
iminium activation and not via other activation modes, such as
general base catalysis or phase-transfer catalysis.48 This is
further corroborated by the complementarity of scope observed
in reactions catalyzed by 1a and in phase transfer catalysis.
While steric congestion around the carbonyl group (e.g., α-
substituents in the cyclohexenone series) is detrimental in our
reactions, an opposite effect is observed under phase-transfer
catalysis in comparable systems.49
ESI-MS Studies and Catalyst N-Oxidation. To provide
further support for covalent catalytic intermediates and to
follow the fate of the amine catalyst 1a, we performed
electrospray ionization mass spectroscopy (ESI-MS) studies
using the epoxidation of acyclic enone 2a as a model system
(Scheme 9). Samples of the crude reaction mixture taken at
various time points over 24 h were analyzed, and the selected
spectra are shown in Scheme 18 in the Supporting
Information.17 The ESI(+)-MS spectrum of a sample taken
prior to the addition of hydrogen peroxide (Scheme 9a)
revealed the characteristic signals corresponding to the amine
catalyst 1a at m/z 324 ([1a+H]+) as well as iminium ion A at
m/z 460, formed by the condensation of the amine 1a and
Having thus established the identity of 1a+O as the N-oxide
24, we examined its chemical reactivity. Oh and Ryu have
recently shown that tertiary amine N-oxides can act as oxygen
transfer agents to effect asymmetric epoxidation of enones at
100 °C.50 However, mixing an excess (1.5 equiv) of 24 with
enone 2a in the absence of hydrogen peroxide at 50 °C did not
give any oxidation products, ruling out the ability of 24 to act as
an oxidant under our standard reaction conditions.
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Scheme 9. ESI(+)-MS Studies on the Epoxidation and Hydroperoxidation of 2a: (a) Spectrum of the Reaction Sample Recorded
(a) Prior to H2O2 Addition and (b) at 50 °C after 1 h
Table 10. Low- and High-Resolution Mass Spectrometric Analysis of Catalytic Species in the Epoxidation of Enone 2a
a
HRMS of purified 24.
We next investigated the competence of 24 as a catalyst,
submitting it to the epoxidation reactions of enals 19a, 22a, and
enone 2a under the corresponding optimized conditions for
each substrate, along with a control reaction using amine 1a
(Table 11).
amine 24 is catalytically active. Furthermore, when using amine
24, epoxides 20a, 23a, and 4a were formed with the same sense
of stereoinduction and similar enantio- and diastereoselectivity
as with catalyst 1a. These findings suggest that the in situ N-
oxidation of catalyst 1a creates a small amount of a different,
but similarly competent catalytic species, which might catalyze
the reaction in parallel with 1a, explaining the high
After 24 h, all substrates underwent epoxidation with a
comparable conversion using either catalyst, suggesting that the
K
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conditions, we could also prepare stable solutions of iminium
salts 26 containing 0.5−2 equivalents of Brønsted acids TFA
and (R)-TRIP ((R)-21a).
Scheme 10. Synthesis of an Authentic Sample of 9-Amino(9-
deoxy)epiquinine N-Oxide 24
Scheme 11. Synthesis of Imine 25 and Iminium Salts 26
Table 11. Catalytic Activity of N-Oxide 24
amine
acid
yield
ac
b
bd
,
,
entry catalyst cocatalyst product [%]
dr
er
1
2
3
4
5
6
1a
24
1a
24
1a
24
(R)-21b
(R)-21b
(R)-21a
(R)-21a
TFA
20a
20a
23a
23a
4a
94
93:7
86:14
−
−
>99:1
99:1 (R,S)
97.5:2.5 (R,S)
99:1 (R)
99.5
97
Unfortunately, extensive attempts to crystallize 25 or its
various salts did not meet with success. However, a
combination of solution-state NMR and DFT calculations
allowed for a detailed characterization and conformational
assignment of imine 25 and its salts 26.17 Figure 2a represents
90
94:6 (R)
99
98.5:1.5 (S,R)
96.5:3.5 (S,R)
TFA
4a
83
>99:1
a
b
1
Determined by H NMR analysis. Determined by GC with a chiral
stationary phase. Refers to the GC yield of the product 20a, 23a, or
4a. Refers to the er of the epoxide product 20a (major diastereomer),
c
d
23a or 4a (after 1 N NaOH workup). See Tables 2, 8, 12 for precise
reaction conditions. TFA = trifluoroacetic acid.
enantioselectivity maintained throughout our epoxidation
reactions and complete conversion of the starting materials.
Origin of Enantioselectivity. Despite the myriad of
synthetic transformations employing catalyst 1a and its related
cinchona-based congeners reported in recent years, only a
single computational investigation has attempted to rationalize
the origin of enantioselectivity imparted by this versatile
catalytic platform.51 A number of methodological reports have
speculated on the role of the quinuclidine moiety in catalyst 1a
suggesting that it acts as a free base in the transition state (TS),
coordinating the weakly acidic hydrogen peroxide.5b,c,8e,45 Yet
our findings of the excellent catalytic performance by the N-
oxidized catalyst 24 in which the quinuclidine nitrogen is
replaced with a weakly basic N-oxide moiety52 raised intriguing
mechanistic questions. We decided to investigate the
mechanism of facial selectivity by 1a using a combination of
conformational analysis of catalytic intermediates and computa-
tional techniques.
As outlined earlier, experimental evidence suggested that the
conjugate addition of hydrogen peroxide constitutes the
enantiodetermining step of our epoxidation reactions. We
therefore chose to investigate the chiral iminium adducts A,
which are formed by the reversible condensation of catalyst 1a
with the carbonyl substrate, and act as acceptors in the first C−
O bond-forming conjugate addition (Scheme 8). Toward this
end, we found that α-branched enals 19 provide a useful model
system, undergoing smooth condensation with amine 1a in the
presence of 4 Å molecular sieves. Using enal 19e in a slight
(5%) excess to ensure complete consumption of 1a, the
corresponding imine 25 could be isolated without purification
as a bench-stable amorphous solid containing traces of the
remaining 19e (Scheme 11). Employing strictly anhydrous
Figure 2. Structure of the monoprotonated iminium 26 elucidated by
NMR techniques (a) and gas-phase density functional calculations
(B3LYP/SVP) (b).
the structural features of the monoprotonated iminium 26
obtained by NMR analysis, which was found to be in excellent
agreement with an energy-minimized structure derived by DFT
calculations (Figure 2b).
Similarly to the parent cinchona alkaloids,53 imine 25 was
found to have a strong conformational preference in solution,
which was further rigidified by protonation. Analysis of salts
26a−e revealed that the presence of different counteranions in
different stoichiometries (0.5−2 equiv) did not influence the
overall conformation of the iminium cation, although some
L
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smaller conformational adjustments are possible. Key structural
features of 26 include an s-trans conformation adopted by the
unsaturated imine moiety, with both double bonds possessing
obtained with either chiral or achiral acid cocatalyst in methanol
(entries 1−2). These findings suggest that while an acid
additive can catalyze the reaction even in a disruptive protic
solvent by protonating the imine intermediate of type 25, it has
no influence on the stereoselectivity of the reaction if the ions
are solvent separated.55
In a parallel line of investigations, we performed the
epoxidation of enal 19a in a nondisruptive aprotic solvent but
employed Brønsted acid cocatalysts whose conjugate bases
form anions of different coordinating strengths. Figure 3 shows
1
(E)-geometry. Analysis of 15N chemical shifts and JH−N
coupling constants in monoprotonated salts 26a and 26c
revealed full protonation of the quinuclidine nitrogen and
partial protonation of the imine nitrogen, consistent with an
internal hydrogen bond forming a pseudofive-membered ring
N1−C8−C9−N21−H (Figure 2). In the presence of 2 equiv of a
Brønsted acid (salts 26b and 26d), this hydrogen bond was
found to be undisturbed, with the second site of protonation
being the quinoline nitrogen.17 The effect of this internal
hydrogen bonding manifests itself in the hindrance of C9−N21
bond rotation and C8−C9 bond rotation (with H8 and H9
adopting an anti relationship). Indeed, the only dynamic moiety
was found to be the quinoline group, which undergoes rapid
conformational exchange (rotation around the C9−C4′ bond)
at room temperature in unprotonated imine 25 and a
somewhat hindered rotation in the protonated iminium species
26 as witnessed by corresponding peak broadening and
NOESY analysis.17
Although diffusion ordered spectroscopy (DOSY) indicated
a tight association of the ammonium cation and the
counteranion in salts 26 in aprotic or weakly protic media,17
heteronuclear NOE experiments failed to pinpoint the position
of the counteranion in solution. In both TFA and (R)-TRIP
salts, a large number of weak cross-peaks from the 19F or 31P
1
nucleus to H signals from all three subcomponents of 25
Figure 3. The effect of the counteranion coordination strength in
catalyst salts [1a·2HX] on the enantioselectivity of enal epoxidation.
Conditions A: THF, 50% H2O2 (5 equiv) and B: 1,4-dioxane, 50%
H2O2 (1.5 equiv).
(quinuclidine, quinoline, and aza-diene) with similar intensities
was observed, suggesting some flexibility in the ion pairing.54
Nevertheless, the strong influence of the Brønsted acid
cocatalyst on the enantioselectivity of our epoxidation reactions
suggested involvement of the counteranion in the asymmetric
induction. In order to probe this hypothesis further, we
examined the effect of ion separation by a protic solvent. To
this end, we carried out the epoxidation of enal 19a in
methanol, which was confirmed by DOSY analysis to
completely separate the ammonium cation and the counter-
anion in salt 26c without affecting the overall conformation of
the protonated imine.17
the enantiomeric excess of the major trans-diastereomer 20a
obtained with each of the counteranions X− in the catalytic salts
[1a·2HX] (see Supporting Information for conversion and dr).
Approximate relative coordinating strength of the screened
counteranions is provided along the x-axis.56 A clear trend can
be observed with respect to counteranion association in the
catalytic salt [1a·2HX] and the enantioselectivity of the
reaction. In particular, the most tightly coordinating anions
gave the highest enantiomeric excess, even without possessing
chirality themselves.
As demonstrated in Table 12, carrying out the epoxidation in
methanol resulted in complete erosion of the reaction’s
Computational Studies and the Proposed Model of
Stereoselectivity. With the structure of the ammonium cation
established by physical methods and evidence for the
involvement of the counteranion in the asymmetric induction,
we turned to computation to complete the model of
stereoselectivity. Toward this end, we analyzed the geometries
of TSs for the enantiodetermining step, i.e., hydrogen peroxide
attack on the iminium ion. We employed DFT throughout.
Geometry optimizations were performed using the BP86
functional and the def2-SVP basis set. Single-point calculations
at the BP86/def2-SVP optimized geometries were carried out
with larger basis sets (def2-TZVP) and different functionals
(B3LYP, M06, M06-2X) and with inclusion of continuum
solvation and empirical dispersion corrections to arrive at more
accurate energetics. Thermal and entropic corrections were
evaluated at the BP86/def2-SVP level to convert the calculated
energies into free energies. The Supporting Information
contains detailed information on the applied computational
methods and the numerical results as well as more detailed
discussions of the results obtained for the various pathways
considered. In the following, we focus on the two major
Table 12. The Effect of an Ion-Separating Solvent on the
Epoxidation of 31a with Catalytic Ammonium Salts of 1a
a
a
b
entry
acid
solvent
conv. [%]
dr
er (trans)
c
1
2
3
4
(R)-21a
TFA
MeOH
MeOH
THF
37
51:49
51:49
87:13
65:35
43:57
46:54
99:1
78
81
73
(R)-21a
TFA
THF
75:25
a
b
Determined by GC. Determined by GC with a chiral stationary
c
phase. The catalyst salt was poorly soluble.
diastereoselectivity and a greatly reduced and reversed
enantioselectivity (compare entries 1−2 to entries 3−4),
although the conversion remained high (the lower conversion
obtained with the salt [1a·(R)-21a] in methanol reflects poor
catalyst solubility). More importantly, very similar results were
M
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Figure 4. Energetically lowest-lying reaction pathways and TS leading to the favored enantiomer (pathway 1, left structure) and the unfavored
enantiomer (pathway 2, right structure) computed at the BP86/def2-SVP level. See Table 3, Supporting Information, for further information.
pathways. The quoted free energy differences are either taken
directly from the BP86/def2-SVP results or represent best
estimates derived from single-point B3LYP/def2-TZVP data
with all aforementioned corrections included.
Preliminary calculations revealed that the counteranion and
hydrogen peroxide generally approach the iminium ion from
the same side, allowing the anion to take up the proton
liberated during this reaction step. We chose to use the
iminium ion derived from 9-amino(9-deoxy)epicinchonidine
1d, which corresponds to 1a with an unsubstituted quinoline
group, and enal 19e, together with TFA, as our model system
(Figure 4).57
We considered four different pathways in the TS modeling:
the quinoline group can adopt two different orientations (up
and down) during the approach of the anion and hydrogen
peroxide from the (β)-si-face or (β)-re-face, giving rise to TSs
TS-1 and TS-3 (si) or TS-2 and TS-4 (re). For each of these
pathways, a series of starting geometries were screened at the
BP86/def2-SVP level to locate the lowest-energy TS for
hydrogen peroxide attack.58
For the peroxide approach from the (β)-si-face, the
orientation of the quinoline group has little influence on the
energetics, since the conformer with this group pointing toward
the anion (TS-1, Figure 4) is only slightly favored (by 0.8 kcal/
mol, BP86) over the alternative one (TS-3) due to C−H···F
hydrogen-bonding interactions with TFA (2.43−2.58 Å). The
lowest-energy TS for peroxide attack from the (β)-re-face (TS-
2) also has the quinoline group pointing toward the anion, with
the alternative orientation (TS-4) being rather strongly
disfavored (by 4.3 kcal/mol, BP86). Importantly, both TSs
for the (β)-si-face attack are lower in energy than those for (β)-
re-face attack. The relevant free energy difference between TS-1
and TS-2 amounts to 1.9 kcal/mol (BP86) or 2.4 kcal/mol
(best B3LYP-based estimate).
NMR structure of 26 (Figure 2). This coordination also implies
that the quinuclidine nitrogen is not directly involved in
directing the peroxide attack.
There are also considerable differences between TS-1 and
TS-2, which are helpful in rationalizing the observed
enantioselectivity. In TS-1 the configuration around the
newly formed C−O bond is almost perfectly staggered, the
anion being roughly oriented toward the positively charged
iminium ion. The distance between the closer TFA oxygen and
the iminium proton is 3.95 Å. On the other hand, for TS-2, in
order to avoid a steric clash with the quinoline moiety, the
TFA-peroxide adduct prefers a different orientation. Here, the
configuration around the C−O bond is close to eclipsed, and
the cation anion distance is increased to 4.13 Å. As the anion is
much better accommodated on one side of the iminium ion
and directs hydrogen peroxide to the same side, it effectively
acts as a mediator, communicating the steric information
around the catalysts stereocenter to the rather distant point of
attack.
Our model predicts that the quinoline moiety should
influence enantioselection, but a degree of conformational
flexibility is allowed, as the two most stable rotamers around the
C9−C4′ bond both favor the same enantiomer. As described
previously, such flexibility of the quinoline ring in imine salts 26
was indeed observed by NMR experiments. Furthermore,
experiments using the truncated catalyst, which lacks a
quinoline moiety, revealed that this group is indeed essential
for the stereoinduction.17
Based on our model of stereoselectivity, we propose that the
excellent catalytic efficiency of the N-oxidized amine 24 stems
from its ability to form structurally similar iminium salts 27,
which participate in the enantiodetermining C−O bond-
forming event (Figure 5). In particular, our data suggest that
the N-oxide moiety simply expands the internal hydrogen-
bonded assembly observed in salts 26 by one oxygen atom,
forming a pseudosix-membered ring and thus causing little
perturbation in the TS. A similar type of intramolecular
hydrogen bonding has been reported in chiral N,N-dioxide
amide catalysts.59
Several common features can be noted when comparing the
two lowest-lying TSs that lead to the major and minor
enantiomer, respectively (TS-1 and TS-2). In both cases, the
peroxide O−H bond is broken, and the C−O bond is formed
in a concerted way, resulting in a direct proton transfer to the
counteranion. The second O−H bond of the nonattacking
peroxide oxygen is also coordinated to the counteranion.
Another common feature is the formation of a pseudofive-
membered ring N1−C8−C9−H21−H, as already seen in the
In order to generalize our enantioselectivity model to the
epoxidation of enone substrates, and indeed any Michael
reaction of unsaturated carbonyl compounds catalyzed by 1a,
structural information about the iminium intermediate of type
N
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Journal of the American Chemical Society
Article
epoxidations. In addition to providing direct access to optically
active peroxide and epoxide products, the described methods
allow for further product functionalization to generate such
useful building blocks as β-hydroxyketones, 1,2-dioxolanes, and
epoxyalcohols without any erosion of the enantiomeric excess.
Detailed mechanistic investigations provide extensive support
for covalent aminocatalysis and shed light on an unusual
nondetrimental catalyst oxidation pathway. In addition, NMR
and computational studies allowed for the rationalization of the
origin of stereoselectivity induced by the ammonium salts of 1.
Importantly, we have elucidated the role of the counteranion
provided by the Brønsted acid cocatalyst, which translates
remote chirality of the ammonium cation to the reaction center
and functions as a base to activate the nucleophile. Given the
excellent enantioselectivity and substrate scope, we anticipate
utility of our methods in synthesis.
Figure 5. Proposed structure of monoprotonated iminium 27 derived
from the N-oxidized catalyst 24.
A (Scheme 8) is required. In particular, with all other
parameters being equal, the imine CN bond geometry is
expected to determine the absolute facial selectivity of the
Michael addition. Unfortunately, attempts to synthesize imine
intermediates from enones for conformational studies did not
meet with success. However, computational studies by Chen
and colleagues on the epoxidation of 2-cyclohexen-1-one 9a by
chiral cinchona alkaloid-derived amine salts58 and those of Zhu,
Liu, and co-workers on the epoxidation of the same substrate
by a chiral primary diamine salt60 both suggest iminium
intermediates with the Z-configured CN bond as the
catalytically relevant species leading to the epoxide product.
These results are in agreement with our stereochemical model,
which correctly predicts the experimentally observed absolute
configuration for all enone substrate classes (cyclic, acyclic, and
macrocyclic), as long as the iminium intermediates are Z-
configured (Figure 6).
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental part: procedures, compound characterization,
NMR spectra, and GC and HPLC traces for all new
compounds. Computational part: methods, detailed numerical
results for energies, optimized Cartesian coordinates, and
further discussion of the computational results. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
list@kofo.mpg.de
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study has been generously supported by the Deutsche
Forschungsgemeinsschaft (DFG), the Max-Planck-Gesellschaft
(MPG), and the Fonds der Chemischen Industrie (FCI). We
thank our GC, HPLC, mass spectrometry, and NMR
departments as well as Marianne Hannappel, Simone Marcus,
Petra Philipps, Natascha Wippich for technical assistance.
Figure 6. Stereoselectivity Mnemonic for Epoxidation Reactions of
Unsaturated Carbonyl Compounds Catalyzed by Amine 1a.
REFERENCES
(1) Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024.
■
While we do not yet have experimental proof for this
mechanism of stereoselectivity with the enone substrates, the
models depicted in Figure 6 can serve as a useful guide for
predicting enantioselectivity. Indeed, we expect this mnemonic
to be applicable to any Michael addition of protic nucleophiles
to unsaturated carbonyl compounds catalyzed by 1a and its
closely related derivatives, given the remarkable consistency in
the stereochemical outcome reported in the literature.
(2) (a) Wynberg, H.; Greijdanus, B. J. Chem. Soc. Chem. Commun.
1978, 427. (b) Juila, S.; Guixer, J.; Masana, J.; Rocas, J.; Colonna, S.;
Annuziata, R.; Molinari, H. J. Chem. Soc. Perkin Trans. 1 1982, 1317.
(c) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5976.
(d) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahedron
Lett. 1990, 31, 7345. (e) Zhang, W.; Loebach, J. L.; Wilson, S. R.;
Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801. (f) Enders, D.; Zhu,
J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 1725. (g) Yang, D.;
Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.; Cheung, K.-K. J.
Am. Chem. Soc. 1996, 118, 491. (h) Bougauchi, M.; Watanabe, S.; Arai,
T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 2329.
(i) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224. (j) Watanabe, S.; Arai, T.; Sasai, H.; Bougauchi,
M.; Shibasaki, M. J. Org. Chem. 1998, 63. (k) Corey, E. J.; Zhang, F.-Y.
Org. Lett. 1999, 1, 1287. (l) Jacques, O.; Richards, S. J.; Jackson, R. F.
W. Chem. Commun. 2001, 2712. (m) Li, C.; Pace, E. A.; Liang, M. C.;
Lobkovsky, E.; Gilmore, T. D.; Porco, J. A., Jr. J. Am. Chem. Soc. 2001,
CONCLUSIONS
■
We have demonstrated that the readily available cinchona
alkaloid-derived primary amines 1 serve as powerful catalysts in
the asymmetric epoxidation and peroxidation of various
carbonyl compounds with hydrogen peroxide. The reactions
have been shown to tolerate a wide scope of aliphatic acyclic
α,β-unsaturated ketones, small, medium and large ring-sized
cyclic α,β-unsaturated ketones, and α-branched α,β-unsaturated
aldehydes, giving rise to an enantiomeric excess of generally
above 95:5 er. Stereoconvergence with respect to the substrate
double-bond geometry and significant catalyst control over pre-
existing stereogenic centers is a feature of most of the presented
123, 11308. (n) Berkessel, A.; Guixa, M.; Schmidt, F.; Neudorfl, J. M.;
̈
Lex, J. Chem.Eur. J. 2007, 13, 4483. (o) Erkkila, A.; Pihko, P. M.;
̈
Clarke, M.-R. Adv. Synth. Catal. 2007, 349, 802. (p) Peris, G.;
Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 8710.
(q) Zhang, W.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 286. For
O
dx.doi.org/10.1021/ja402058v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
reviews, see: (r) Porter, M. J.; Skidmore, J. Chem. Commun. 2000,
(14) (a) Bentley, P. A.; Bergeron, S.; Cappi, M. W.; Hibbs, D. E.;
Hursthouse, M. B.; Nugent, T. C.; Pulido, R.; Roberts, S. M.; Wu, L. E.
Chem. Commun. 1997, 739. (b) Daikai, K.; Hayano, T.; Kino, R.;
Furuno, H.; Kagawa, T.; Inanaga, J. Chirality 2003, 15, 83. (c) Ooi, T.;
Ohara, D.; Tamura, M.; Maruoka, K. J. Am. Chem. Soc. 2004, 126,
6844.
1215. (s) Adam, W.; Saha-Moller, C. R.; Ganeshpure, P. A. Chem. Rev.
̈
2001, 101, 3499. (t) Lane, B. S.; Burgess, K. Chem. Rev. 2003, 103,
2457. (u) Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem.
Rev. 2005, 105, 1603. (v) Lattanzi, A. Curr. Org. Synth. 2008, 5, 117.
(3) Weitz, E.; Scheffer, A. Chem. Ber. 1921, 54, 2344.
(4) (a) Bunton, C. A.; Minkoff, G. J. J. Chem. Soc. 1949, 665.
(b) Christian, C. F.; Takeya, T.; Szymanski, M. J.; Singleton, D. A. J.
Org. Chem. 2007, 72, 6183. (c) House, H. O.; Ro, R. S. J. Am. Chem.
Soc. 1958, 80, 2428. (d) Kelly, D. R.; Caroff, E.; Flood, R. W.; Heal,
W.; Roberts, S. M. Chem. Commun. 2004, 2016. (e) Kelly, D. R.;
Roberts, S. M. Pept. Sci. 2006, 84, 74. (f) Meerwein, H. J. Prakt. Chem.
1926, 113, 9. (g) Weitz, E.; Scheffer, A. Chem. Ber. 1921, 54, 2344.
(h) Wright, P.; Abbot, J. Int. J. Chem. Kinet. 1993, 25, 901. It was later
shown that for metallated peroxides, the reaction sometimes proceeds
through a concerted asynchronous manner. For a discussion, see:
(i) Svenda, J.; Myers, A. G. Org. Lett. 2009, 11, 2437 However we are
not aware of any such observation for the organocatalytic variant of the
reaction.
(5) (a) Marigo, M.; Franzen, J.; Poulsen, T. B.; Zhuang, W.;
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964−6965. (b) Sunden,
H.; Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2006, 47, 99. (c) Lee, S.;
MacMillan, D. W. C. Tetrahedron 2006, 62, 11413.
(15) (a) Cativiela, C.; Figueras, F.; Fraile, J. M.; García, J. I.; Mayoral,
J. A. Tetrahedron Lett. 1995, 36, 4125. (b) Fraile, J. M.; García, J. I.;
Mayoral, J. A.; Sebti, S.; Tahirb, R. Green Chem. 2001, 3, 271.
(c) Payne, G. J. Org. Chem. 1958, 23, 310. (d) Rieche, A.; Schmitz, E.;
Grundemann, E. Chem. Ber. 1960, 93, 2443.
̈
(16) (a) Barnier, J.-P.; Morisson, V.; Blanco, L. Synth. Commun.
2001, 31, 349. (b) Kulinkovich, O. G.; Astashko, D. A.; Tyvorskii, V.
I.; Ilyina, N. A. Synthesis 2001, 10, 1453.
(17) See Supporting Information for further details.
(18) Other hydroxy-group containing substrates were also tested. For
details on these experiments, see the Supporting Information.
(19) (a) Yang, J. W.; Hechavarria Fonseca, M. T.; Vignola, N.; List,
B. Angew. Chem., Int. Ed. 2005, 44, 108. (b) Ouellet, S. G.; Tuttle, J. B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32.
(20) For further support of the suggested mechanism from substrate
isomerization and studies on β,β-disubstituted substrates, see the
Supporting Information.
̌
(6) (a) Wang, X.; List, B. Angew. Chem., Int. Ed. 2008, 47, 1119. For
reviews on ACDC, see: (b) Mahlau, M.; List, B. Angew. Chem., Int. Ed.
2013, 52, 518. (c) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat.
Chem. 2012, 4, 603. (d) Mahlau, M.; List, B. Isr. J. Chem. 2012, 52,
(21) Dakin, H. D. Am. Chem. J. 1909, 42, 477.
(22) (a) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.;
Melchiorre, P. Org. Lett. 2007, 9, 1403. (b) Xie, J.-W.; Huang, X.; Fan,
L.-P.; Xu, D.-C.; Li, X.-S.; Su, H.; Wen, Y.-H. Adv. Synth. Catal. 2009,
351, 3077.
630. (e) Ratjen, L.; Muller, S.; List, B. Nachr. Chem. 2010, 58, 640.
̈
(7) For a single example of secondary amine catalysis used in the
epoxidation of α-branched acroleins, see: (a) Bondzic, B. P.;
Urushima, T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12, 5434.
For examples using noncovalent organocatalysis for Weitz−Scheffer-
type epoxidation, see: (b) Lattanzi, A. Org. Lett. 2005, 7, 2579.
(c) Russo, A.; Galdi, G.; Croce, G.; Lattanzi, A. Chem.Eur. J. 2012,
18, 6152.
(8) (a) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368.
(b) Reisinger, C. M.; Wang, X.; List, B. Angew. Chem., Int. Ed. 2008,
47, 8112. (c) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc.
2008, 130, 6070. (d) Zhou, J.; Wakchaure, V.; Kraft, P.; List, B. Angew.
Chem., Int. Ed. 2008, 47, 7656. (e) Lifchits, O.; Reisinger, C. M.; List,
B. J. Am. Chem. Soc. 2010, 132, 10227. (f) Jiang, G.; List, B. Angew.
Chem., Int. Ed. 2011, 50, 9471. (g) Lee, A.; Michrowska, A.; Sulzer-
Mosse, S.; List, B. Angew. Chem., Int. Ed. 2011, 50, 1707. (h) Lee, A.;
List, B. Adv. Synth. Catal. 2012, 354, 1701.
(23) Fehr, C.; Galindo, J. Helv. Chim. Acta 2005, 88, 3128.
(24) For the reduction of 3-hydroxy-1,2-dioxolanes with trivalent
phosphorus compounds, see: (a) Baumstark, A. L.; Vasquez, P. C.;
Chen, Y. Heteroat. Chem. 1993, 4, 175. (b) Morisson, V.; Barnier, J.-P.;
Blanco, L. Tetrahedron Lett. 1999, 40, 4045.
(25) Carlone, A.; Bartoli, G.; Bosco, M.; Pesciaioli, F.; Ricci, P.;
Sambri, L.; Melchiorre, P. Eur. J. Org. Chem. 2007, 5492.
(26) For the synthesis of aldol-like products 6 from epoxy ketones,
see the Supporting Information.
(27) (a) Dai, P.; Trullinger, T. K.; Liu, X.; Dussault, P. H. J. Org.
Chem. 2006, 71, 2283. (b) Martyn, D. C.; Beletsky, G.; Cortese, J. F.;
Tyndall, E.; Liu, H.; Fitzgerald, M. M.; O’Shea, T. J.; Liang, B.; Clardy,
J. Bioorg. Med. Chem. Lett. 2009, 19, 5657. (c) Oh, D.-C.; Scott, J. J.;
Currie, C. R.; Clardy, J. Org. Lett. 2009, 11, 633. (d) Scott, J. J.; Oh,
D.-C.; Yuceer, M. C.; Klepzig, K. D.; Clardy, J.; Currie, C. R. Science
2008, 322, 63.
(28) For synthetic approaches to racemic 1,2-dioxolanes, see:
(a) Dussault, P. H.; Lee, I. Q.; Lee, H.-J.; Lee, R. J.; Niu, Q. J.;
Schultz, J. A.; Zope, U. R. J. Org. Chem. 2000, 65, 8407. (b) Dussault,
P. H.; Lee, R. J.; Schultz, J. A.; Suh, Y. S. Tetrahedron Lett. 2000, 41,
5457. (c) Dussault, P. H.; Liu, X. Org. Lett. 1999, 1, 1391. (d) Dussault,
P. H.; Trullinger, T. K.; Cho-Shultz, S. Tetrahedron 2000, 56, 9213.
(e) Dussault, P. H.; Zope, U. Tetrahedron Lett. 1995, 36, 3655.
(f) McCullough, K. J.; Nojimab, M. Curr. Org. Synth. 2001, 5, 601.
(g) Tokuyasu, T.; Ito, T.; Masuyama, A.; Nojima, M. Heterocycles
2000, 53, 1293.
(9) (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127, 10504.
(b) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170.
(c) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 6366−6370. (d) Kim, H.; Yen, C.; Preston, P.; Chin, J. Org.
Lett. 2006, 8, 5239. (e) Ishihara, K.; Nakano, K. J. Am. Chem. Soc.
2007, 129, 8930. (f) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.;
Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed.
2007, 46, 389.
(10) (a) Peng, F.; Shao, Z. J. Mol. Catal. A: Chem. 2008, 285, 1.
(b) Xu, L. W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807. (c) Xu, L.-
W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047.
(29) Inanaga, J.; Kawanami, Y.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
(11) (a) Chen, Y.-C. Synlett 2008, 13, 1919. (b) Jiang, L.; Chen, Y.-C.
Catal. Sci. Technol. 2011, 1, 354. (c) Yeboah, E. M. O.; Yeboah, S. O.;
Singh, G. S. Tetrahedron 2011, 67, 1725. (d) Li, J.-L.; Fu, N.; Zhang,
L.; Zhou, P.; Luo, S.; Cheng, J.-P. Eur. J. Org. Chem. 2010, 35, 6840.
(e) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem. Soc.
2008, 130, 8134. (f) Lu, Y.; Zheng, C.; Yang, Y.; Zhao, G.; Zou, G.
Adv. Synth. Catal. 2011, 353, 3129. (g) Melchiorre, P. Angew. Chem.,
Int. Ed. 2012, 51, 9748.
1986, 59, 1521.
(30) For details on this transformation, see the Supporting
Information.
(31) Wynberg, H.; Marsman, B. J. Org. Chem. 1980, 45, 158.
(32) For a discussion of this isomerization reaction, see the
Supporting Information.
(33) We also tested the more bulky t-Bu-substituted analog. For
details, see the Supporting Information.
(34) Zhou, J.; Wakchaure, V.; Kraft, P.; List, B. Angew. Chem., Int. Ed.
2008, 47, 7656.
(35) (a) Bishara, A.; Rudi, A.; Goldberg, I.; Benayahu, Y.; Kashman,
Y. Tetrahedron 2006, 62, 12092. (b) Shen, Y.-C.; Lin, J.-J.; Wu, Y.-R.;
Chang, J.-Y.; Duh, C.-Y.; Lo, K. L. Tetrahedron Lett. 2006, 47, 6651.
(12) For the original report describing preparation of 1a, see:
Brunner, H.; Bugler, J.; Nuber, B. Tetrahedron: Asym. 1995, 6, 1699.
̈
(13) Organocatalytic methodologies for the peroxidation and
epoxidation of aliphatic enones have apeared since; see refs 11e and
11f.
P
dx.doi.org/10.1021/ja402058v | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(36) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry. Part A:
Structure and Mechanisms: Structure and Mechanisms, 5 ed.; Springer:
New York, 2007.
(37) For the application of our epoxidation methodology in the
synthesis of enantiomerically pure allylic alcohols, see: Jiang, H.;
Holub, N.; Jørgensen, K. A. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
20630−20635.
(38) (a) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem.,
Int. Ed. 2003, 42, 2785. (b) Ghobril, C.; Sabot, C.; Mioskowski, C.;
Baati, R. Eur. J. Org. Chem. 2008, 4104.
(39) (a) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975.
(b) Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem. Commun.
2005, 5346. (c) Perdicchia, D.; Jørgensen, K. A. J. Org. Chem. 2007,
72, 3565. (d) Wascholowski, V.; Knudsen, K. R.; Mitchell, C. E. T.;
Ley, S. V. Chem.Eur. J. 2008, 14, 6155. (e) Li, P.; Wen, S.; Yu, F.;
Liu, Q.; Li, W.; Wang, Y.; Liang, X.; Ye, J. Org. Lett. 2009, 11, 753.
(f) Mase, N.; Fukasawa, M.; Kitagawa, N.; Shibagaki, F.; Noshiro, N.;
Takabe, K. Synlett 2010, 2340. (g) Yoshida, M.; Hirama, K.; Narita,
M.; Hara, S. Symmetry 2011, 3, 155.
(40) For details on the optimization, see ref 8h. It is interesting to
note that while Mosher’s acid proved to be the best acid additive, its
stereoinformation had almost no influence on the selectivity of the
reaction, with only 1% reduced ee in the mismatched case.
(41) (a) Payne, G. B. J. Am. Chem. Soc. 1959, 81. (b) Payne, G. B. J.
Org. Chem. 1961, 26, 205. (c) Zakavi, S.; Abasi, A.; Pourali, A. R.;
Rayati, S. Bull. Korean Chem. Soc. 2008, 29, 866.
(49) (a) Arai, S.; Tsuge, H.; Shioiri, T. Tetrahedron Lett. 1998, 39,
7563. (b) Lygo, B.; Gardiner, S. D.; McLeod, M. C.; To, D. C. M. Org.
Biomol. Chem. 2007, 5, 2283. (c) Lygo, B.; Wainwright, P. G.
Tetrahedron Lett. 1998, 39, 1599. (d) Lygo, B.; Wainwright, P. G.
Tetrahedron 1999, 55, 6289. (e) Ooi, T.; Maruoka, K. Angew. Chem.,
Int. Ed. 2007, 46, 4222.
(50) Oh, K.; Ryu, J. Tetrahedron Lett. 2008, 49, 1935.
(51) Lu, N.; Mi, S.; Chen, D.; Zhang, G. Int. J. Quantum Chem. 2011,
111, 2874.
(52) In contrast to the highly basic quinuclidine (pKa = 11.1 in
water), tertiary amine N-oxides are only weakly basic (pKa around 4.5
in water).
(53) (a) Cinchona Alkaloids in Synthesis and Catalysis; Song, C. E.,
Ed.; Wiley-VCH: Weinheim, 2009; (b) Silva, T. H. A.; Oliveira, A. B.;
Santos, H. F. D.; Almeida, W. B. D. Struc. Chem. 2001, 12, 431.
(c) Karle, J. M.; Karle, I. L.; Gerena, L.; Milhous, W. K. Antimicrob.
Agents Chemother. 1992, 36, 1538. (d) Ferri, D.; Burgi, T.; Baiker, A. J.
̈
Chem. Soc. Perkin Trans. 2 1999, 1305. (e) Dijkstra, G. D. H.; Kellogg,
R. M.; Wynberg, H.; Svendsen, J. S.; Marko, I.; Sharpless, K. B. J. Am.
Chem. Soc. 1989, 111, 8069. (f) Dijkstra, G. D. H.; Kellogg, R. M.;
Wynberg, H. Recl. Trav. Chim. Pays-Bas 1989, 108, 195. (g) Burgi, T.;
̈
Baiker, A. J. Am. Chem. Soc. 1998, 120, 12920.
(54) For an example of specific ion pairing determined by
heteronuclear NOESY techniques, see: (a) Olsen, R. A.; Borchardt,
D.; Mink, L.; Agarwal, A.; Mueller, I. J.; Zaera, F. J. Am. Chem. Soc.
2006, 128, 15594.
Hydrogen bonding interaction between the
Brønsted acid and imine 41 also cannot be excluded: (b) Fleischmann,
M.; Drettwan, D.; Sugiono, E.; Rueping, M.; Gschwind, R. M. Angew.
Chem. 2011, 123, 6488.
(55) Similar observations were made in iminium-catalyzed intra-
molecular aza-Michael reaction of enones employing catalyst 1a, where
ethanol solvent also resulted in a lower and reversed enantioselectivity
of the product compared to THF: Liu, J.-D.; Chen, Y.-C.; Zhang, G.-
B.; Li, Z.-Q.; Chen, P.; Du, J.-Y.; Tu, Y.-Q.; Fan, C.-A. Adv. Synth.
Catal. 2011, 353, 2721.
(42) Organocatalytic methodologies for the epoxidation of branched
acroleins have apeared since: see refs 6 and 11d.
(43) (a) Galzerano, P.; Pesciaioli, F.; Mazzanti, A.; Bartoli, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7892. (b) Ishihara, K.;
Nakano, K. J. Am. Chem. Soc. 2007, 129, 8930.
(44) Colvin, E. W.; Robertson, A. D.; Wakharkar, S. J. Chem. Soc.,
Chem. Commun. 1983, 312.
(45) In epoxidations of α-substituted acroleins 34, where the epoxide
ring closure constitutes the enantiodetermining step, employing an
achiral amine with a chiral Brønsted acid cocatalyst gives
enantioenriched products. See also ref 6 for similar observations
with 3,3-disubstituted enals.
(56) (a) Díaz-Torres, R.; Alvarez, S. Dalton Trans. 2011, 40, 10742.
(b) Kotlewska, A. J.; van Rantwijk, F.; Sheldon, R. A.; Arends, I. W. C.
E. Green Chem. 2011, 13, 2154.
(57) Catalyst 1d was found to give similar enantioselectivity as
catalyst 1a but has less conformational flexibility, making it ideally
suited for computational purposes. Specifically, when the epoxidation
of (E)-31a (eq 5) was carried out using 1d under otherwise identical
conditions, the results were close to identical. Epoxialdehyde 32a was
obtained in 44% conversion, 73:27 dr and 92:8 er (38% yield, 75:25 dr
and 93:7 er with 1a).
(58) All calculations were carried out using TURBOMOLE. See
Supporting Information for computational details.
(59) Liu, X.-H.; Lin, L.-L.; Feng, X.-M. Acc. Chem. Res. 2011, 44, 574.
(60) Lv, P.-L.; Zhu, R.-X.; Zhang, D.-J.; Duan, C.-G.; Liu, C.-B. J.
Phys. Chem. A 2012, 116, 1251.
(46) An exception to this is the epoxidation of β,β-substituted enones
7/10 and α-substituted acroleins 34, where the initial Michael addition
of hydrogen peroxide does not create a stereogenic center; it is the
subsequent enamine-catalyzed ring closure that consitutes the
enantiodetermining step of the reaction.
(47) We also submitted racemic peroxyhemiketal 3a to the reaction
conditions and obtained epoxide 4a with only a low enantiomeric
excess (63:37 er) resulting from from a weak kinetic resolution at 44%
conversion. These results are incompatible with a reversible
mechanistic regime, which would be expected to furnish the epoxide
4a with > 98.5:1.5 er via dynamic kinetic resolution, i.e. the er value
observed under actual reaction conditions (see Scheme 4 and Table
2).
(48) To this goal we compared 1a to a series of structurally distinct
catalysts. For details, see the Supporting Information.
Q
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