Asymmetric olefin isomerization of butenolides via proton transfer catalysis by an organic molecule

Article abstract of DOI:10.1021/ja205674x

An unprecedented enantioselective and general olefin isomerization was realized via biomimetic proton transfer catalysis with a new chiral organic catalyst. A broad range of mono- and disubstituted β,γ-unsaturated butenolides were transformed into the corresponding chiral α,β- unsaturated butenolides in high enantioselectivity and yield in the presence of as low as 0.5 mol % catalyst. Mechanistic studies have revealed the protonation as the rate-determining step.

Full text of DOI:10.1021/ja205674x

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Asymmetric Olefin Isomerization of Butenolides via Proton Transfer
Catalysis by an Organic Molecule
Yongwei Wu, Ravi P. Singh, and Li Deng*
Department of Chemistry, Brandeis University, Waltham, Massachusetts 02454-9110, United States
S Supporting Information
b
Scheme 1. Isomerization of Steroidal Ketones Catalyzed
by KSI
ABSTRACT: An unprecedented enantioselective and gen-
eral olefin isomerization was realized via biomimetic proton
transfer catalysis with a new chiral organic catalyst. A broad
range of mono- and disubstituted β,γ-unsaturated buteno-
lides were transformed into the corresponding chiral R,β-
unsaturated butenolides in high enantioselectivity and
yield in the presence of as low as 0.5 mol % catalyst. Mecha-
nistic studies have revealed the protonation as the rate-
determining step.
s exemplified by the Δ5-3-ketosteroid isomerase (KSI)-
Scheme 2. Proposed Isomerization Pathway of Butenolides
Catalyzed by Cinchona Alkaloids
A
catalyzed conversion of β,γ- to R,β-unsaturated steroidal
ketones (Scheme 1), enzyme-mediated olefin isomerization via a
proton transfer from one carbon atom to another in the same
substrate molecule constitutes a common and important class of
chemical reactions in biology.1 In contrast, only metal-mediated
hydride transfer catalysis has been employed in small molecule-
catalyzed asymmetric olefin isomerizations, which include en-
antioselective olefin isomerizations of allylic amines by a chiral
Rh+/BINAP complex2 and isomerization of allylic alcohols with a
Rh+/planar-chiral phosphaferrocene complex.3 Although sub-
strate-directed diastereoselective olefin isomerizations with
either achiral acids or bases have been applied in natural product
synthesis,4 only a single example of olefin isomerization by
enantioselective proton transfer catalysis, mediated by a bime-
tallic gadolinium complex, was reported in the literature.5 Herein,
we wish to report the realization of a general and highly enantio-
selective olefin isomerization with a chiral organic catalyst.
Although the KSI-catalyzed olefin isomerization does not
generate a stereocenter, the mechanism underlying the enzy-
matic proton transfer catalysis is illuminating (Scheme 1). It
involves the deprotonation of the C4-β-proton of steroidal
ketone by Asp38, while Tyr14 and Asp99 serve as acidic catalytic
residues by providing hydrogen bonds to the ketone group. With
the oxyanion engaging in hydrogen bonding interactions with
Tyr14 and Asp99, the γ-carbon of the dienolate intermediate
undergoes a protonation by Asp38 from the β-face. As illustrated
in Scheme 2, a 60-OH cinchona alkaloid in a gauche-open
conformation also has a syn-arrangement of acidic and basic
active sites, which is similar to how Tyr14 and Asp38 are arranged
in the active site of KSI. This observation in combination with the
ability of 60-OH cinchona alkaloids to serve as an acidꢀbase
bifunctional catalyst and as a chiral proton donor for asymmetric
protonation6ꢀ9 led us to envision the possibility of 60-OH
cinchona alkaloids as a catalyst for an enantioselective isomeriza-
tion via proton transfer catalysis (Scheme 2).10
The γ-substituted R,β-unsaturated butenolides constitute a
structural motif shared by many biologically interesting natural
and synthetic products. Furthermore, they are versatile chiral
building blocks for asymmetric synthesis. Thus, the preparation
of optically active γ-alkyl R,β-unsaturated butenolides have been
a topic of interest. Accordingly, several approaches utilizing easily
accessible intermediates from the chiral pool11 or synthetic chiral
precursors have been developed.12 Among these only two were
catalytic approaches, which involved the Os-mediated asym-
metric dihydroxylation of β,γ-unsaturated esters,12f,h and the
Cu-catalyzed heteroallylic asymmetric alkylation, respectively,
as the asymmetric induction step.12j,k Thus, an efficient and
general catalytic enantioselective isomerization of γ-substituted
β,γ-butenolides to the corresponding R,β-unsaturated buteno-
lides could provide a complementary method that may also
expand the scope of chiral butenolides accessible by catalytic
asymmetric synthesis (Scheme 2).
Guided by these considerations we investigated a series of
existing 60-OH cinchona alkaloids and other structurally distinct
Received: June 18, 2011
Published: July 18, 2011
r
2011 American Chemical Society
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Table 1. Isomerization of 8a to 9a Catalyzed by Cinchona
Alkaloidsa
entry
catalyst
T (°C)
Time
conv (%)b
ee (%)b
1
2
3
4
5
6
1a
rt
rt
rt
rt
rt
rt
4 h
4 h
4 h
4 h
4 h
4 h
80
0
47c
ꢀ
32
ꢀ
ꢀ
0
2a
2b
4
20
0
Figure 1. Structure of cinchona alkaloids and achiral acids.
5
0
2a + 5
<5
cinchona alkaloids (Figure 1) reported in the literature for their
ability to promote the enantioselective isomerization of the
commercially available γ-methyl β,γ-butenolide 8a to the corre-
sponding γ-methyl R,β-unsaturated butenolide 9a in dichloro-
methane at room temperature (Table 1). To our surprise, the
catalytic activity of these cinchona alkaloids for this olefin
isomerization was found to be critically dependent on not only
whether a hydrogen bond donor is presented but also where it is
located in the cinchona alkaloid skeleton. Specifically, while 60-
OH cinchona alkaloids 1a afforded promising activity, cinchona
alkaloid 2a, which bears no hydrogen bond donor, was found to
be inactive as a catalyst. Although hydroquinine (2b), a 9-OH
cinchona alkaloid, was active, its activity was significantly lower
than that of 1a (entry 3 vs 1, Table 1). Moreover, the 9-thiourea
cinchona alkaloid 4 failed to catalyze this reaction. Even in the
presence of both cinchona alkaloid 2a and 60-OH quinoline 5, no
isomerization occurred. These data indicated that the specific
spatial relationship between the hydrogen bond donor and
acceptor is largely responsible for the outstanding activity of 1a
toward this isomerization.
We next focused our attention toward the optimization of
enantioselectivity by screening various 60-OH cinchona alkaloids
(1 and 3) already reported in the literature (Table 2). As the
optical purity of chiral R,β-butenolide 9a was found to gradually
decrease at room temperature in the presence of catalyst 1a
(Table 1, footnote c), the enantioselectivity afforded by different
catalysts was evaluated by the ee of 9a obtained at 10 min after
the initiation of the isomerization. To our disappointment, 60-
OH cinchona alkaloids bearing 9-aryl and alkyl groups of various
bulk (1a, 1b, 3a, 3b) afforded similarly modest selectivity (entries
1ꢀ5, Table 2). Interestingly, the enantioselectivity was improved
with cupreidine 1c (entry 3, Table 2), albeit not to a synthetically
useful level. We also investigated a 60-thiourea cinchona alkaloid 6.
In contrast to the completely inactive 9-thiourea cinchona
alkaloid 4, 6 proved to be remarkably active but furnished only
a modest enantioselectivity. Following the hypothesis that a
perturbation of the acidity of the 60-OH might improve the
catalytic activity and enantioselectivity of the 60-OH cinchona
alkaloids,13 we prepared a novel cinchona alkaloid derivative Q-7
in which the quinoline ring was oxidized into the corresponding
N-oxide analogue as 6-hydroxyquinoline-N-oxide was deter-
mined to be more acidic than 6-hydroxyquinoline.14 To our
delight, it was shown to be a more active as well as selective
catalyst in comparison to 60-OH cinchona alkaloids 1 and 3
(entry 7 vs entries 1ꢀ5, Table 2). Importantly, QD-7 afforded
even higher activity and selectivity while providing the expected
opposite sense of asymmetric induction (entry 8, Table 2). By
a Unless noted, reactions were run with 0.05 mmol of 8a in 0.05 mL of
CH2Cl2 with 10 mol % catalyst. See Supporting Information for details.
b Determined by HPLC analysis. c 10 min, 20% conv, 67% ee.
Table 2. Asymmetric iIsomerization of 8a to 9a by a Cinch-
ona Alkaloid Bearing a 60 Hydrogen Bonding Donora
entry
catalyst
T (°C)
Time
conv (%)b
ee (%)b
1
2
1a
rt
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
24 h
20
16
12
5
67
60
1b
rt
3
1c
rt
74
4
3a
rt
60
5
3b
at
5
63
6
6
rt
55
33
17
36
80
64
7
Q-7
QD-7
QD-7
QD-7
rt
84
8
rt
ꢀ86
ꢀ92
ꢀ90
9
ꢀ20
ꢀ20
10
72 h
a Unless noted, reactions were run with 0.05 mmol of 8a in 0.05 mL of
CH2Cl2 with 10 mol % catalyst. See Supporting Information for details.
b Determined by HPLC analysis.
decreasing the reaction temperature to ꢀ20 °C, the QD-7-
mediated isomerization of 8a afforded 9a in 92% ee (entry 9,
Table 2). At this temperature, the racemization of 9a was found
to be minimal, if not completely suppressed (entry 10 vs 9,
Table 2).
With 7 as the catalyst we explored the scope of the asymmetric
olefin isomerization (Table 3). With either QD- or Q-7 the
isomerization of 8a produced 9a in 90% ee. The conversion of
this isomerization reached the maximum at near 80% due to a
reverse isomerization. Importantly, the separation of 8a and 9a
could be achieved via a standard chromatographic procedure,
thereby allowing the isolation of optically active 9a in moderate
yields (entry 1, Table 3). The enantioselectivity of the reactions
promoted by 7 was insensitive to the alteration of the steric bulk
of the alkyl substituent (entries 2ꢀ4). Due to minimal racemiza-
tion of 9d, the isomerization of γ-isopropyl β,γ-butenolide 8d
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Table 3. Isomerization of 8 to 9 Catalyzed by QD-7
and Q-7a,b
Scheme 3. Proposed Catalytic Cycle for the Enantioselective
Isomerization by QD-7
of 8f was complete within 1.0 h to afford 9f in 95% yield and 90%
ee at room temperature (entry 6, Table 3). The catalyst loading
could be reduced to as low as 0.5 mol % without sacrificing either
the enantioselectivity or the yield (entry 7, Table 3), though a
longer reaction time of 12 h was required. As exemplified with the
isomerization of 8f, a complete and high yielding reaction could
still be attained even with 0.1 mol % catalyst, although the enantio-
selectivity was slightly decreased from 90% to 86% ee (entry 8,
Table 3). Importantly, such catalytic efficiency could be extended
to a series of substrates bearing various R- and γ-alkyl groups
(entries 9ꢀ13, Table 3). The β,γ-disubstituted β,γ-unsaturated
butenolides (8lꢀm) turned out to be a more challenging class of
substrates. The isomerization of these butenolides proceeded with
a lower yet still useful level of enantioselectivity. In light of the lack
of an efficient approach toward optically active β,γ-disubstituted
R,β-butenolides,12f,i,15 the current isomerization represents a
valuable access toward these chiral building blocks.
To gain insights into the reaction mechanism, we carried out a
preliminary kinetic study of the QD-7-mediated isomerization of
8f. The reaction was found to show first-order dependence on the
QD-7 and 8f, respectively.16 In addition we measured the carbon
isotope effect on carbons 2ꢀ6 of 8f employing Singleton’s NMR
technique at natural abundance to discern the rate-limiting step of
the olefin isomerization.16,17 A pronounced carbon isotope effect
was observed on the γ-carbon when the 13C ratio of recovered 8f at
71% conversion was compared to that of the virgin sample
(13C(recovered)/13C(virgin) at Cγ = 1.023, average of three runs)
(eq 1). This kinetic isotope effect indicates the γ-protonation step
is the rate-limiting step of the isomerization reaction.
a Unless noted, reactions were run with 0.10 mmol of 8 in 0.10 mL of
CH2Cl2 with 10 mol % catalyst. b Results in parentheses were obtained
c
e
with Q-7. Isolated yield. d Determined by HPLC analysis. Reaction
f
was run with 20 mol % catalyst. Reaction was run with 0.5 mol %
catalyst. g Reaction was run with 0.10 mmol of 8f in 20 μL of CH2Cl2
with 0.1 mol % catalyst. h Absolute configuration was determined to be S;
see Supporting Information for details.
could be carried out at room temperature at which point the
reaction proceeded rapidly (entry 4). Moreover, the isomeriza-
tion of butenolide 8e, which bears a free hydroxyl group on the
alkyl chain, was also tolerated by QD-7 (entry 5, Table 3).
Interestingly, the isomerizations with R,γ-disubstituted β,γ-
unsaturated butenolides (8fꢀk) proceeded readily to comple-
tion in a highly enantioselective fashion without detectable
racemizations of the corresponding R,β-unsaturated butenolide
(9fꢀk) even at room temperature. Consequently, rapid asym-
metric isomerizations of high yield and enantioselectivity could
be achieved. For example, with 10 mol % QD-7 the isomerization
Based on these results from our mechanistic studies and the
drastic difference in catalytic activity between 60-OH cinchona
alkaloid 1a and the corresponding 60-OMe congener 2a (entry 1
vs 2, Table 1), we propose a catalytic cycle for this enantioselec-
tive isomerization reaction (Scheme 3). In this mechanism, the
deprotonation of β,γ-butenolide 8 occurs after the hydrogen-
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bond-based complexion of 8 with catalyst 7, which is followed by
the rate-determining γ-protonation. It should be noted that, in
the protonation step, either the protonated quinuclidine or the
60-OH could serve as the proton donor.
(8) Selected references for other organocatalyzed asymmetric pro-
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In summary, we have realized an unprecedented enantioselec-
tive olefin isomerization via biomimetic proton transfer catalysis
with a new chiral organic catalyst. This asymmetric transformation
is applicable to a broad range of β,γ-butenolides bearing one or
more substituents. With a low catalyst loading and a simple
experimental protocol, this reaction should provide a valuable
method for the asymmetric synthesis of chiral R,β-butenolides.
Mechanistic studies have revealed that the protonation step is the
rate-determining step of this organocatalytic olefin isomerization.
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characterization of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
deng@brandeis.edu
’ ACKNOWLEDGMENT
We are grateful for financial support from the National
Institute of Health (GM-61591). We thank Keith Bartelson for
his assistance with the 13C KIE study.
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