Enantioselective Oxidation of Alkenes with Potassium Permanganate Catalyzed by Chiral Dicationic Bisguanidinium

Article abstract of DOI:10.1021/jacs.5b05792

Chiral anion-controlled ion-pairing catalysis was demonstrated to be a wide-ranging strategy that can utilize a variety of cationic metal species. In a similar manner, we envision a complementary strategy using chiral cation in partnership with inorganic anionic metal salts. Herein, we report a chiral dicationic bisguanidinium-catalyzed asymmetric oxidation reaction of alkenes with potassium permanganate. Chiral induction is attributed to ion-pairing interaction between chiral cation and enolate anion. The success of the current permanganate oxidation reaction together with mechanistic insights should provide inspiration for expansion to other anionic metal salts and would open up new paradigms for asymmetric transition metal catalysis, phase-transfer catalysis, and ion-pairing catalysis.

Full text of DOI:10.1021/jacs.5b05792

Subscriber access provided by UNIV OF OTTAWA
Article
Enantioselective Oxidation of Alkenes with Potassium
Permanganate Catalyzed by Chiral Dicationic Bisguanidinium
Chao Wang, Lili Zong, and Choon-Hong Tan
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 03 Aug 2015
Downloaded from http://pubs.acs.org on August 3, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Enantioselective Oxidation of Alkenes with Potassium Per-
manganate Catalyzed by Chiral Dicationic Bisguanidinium
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Chao Wang*, Lili Zong, Choon-Hong Tan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, 21 Nanyang Link, Singapore 637371
ABSTRACT: Chiral anion-controlled ion-pairing catalysis was demonstrated to be a wide-ranging strategy that can utilize a varie-
ty of cationic metal species. In a similar manner, we envision a complementary strategy using chiral cation in partnership with inor-
ganic anionic metal salts. Herein, we report, a chiral dicationic bisguanidinium-catalyzed asymmetric oxidation reaction of alkenes
with potassium permanganate. Chiral induction is attributed to ion-pairing interaction between chiral cation and enolate anion. The
success of the current permanganate oxidation reaction together with mechanistic insights should provide inspiration for expansion
to other anionic metal salts and would open up new paradigms for asymmetric transition metal catalysis, phase-transfer catalysis
and ion-pairing catalysis.
allylation, wherein cationic metal intermediate is involved20-21
;
INTRODUCTION
this strategy is dependent on the ammonium salt and metal
catalyst to function fairly independent of each other. Concep-
tually on the other extreme, ion-pairing catalysis using chiral
cation and anionic metal species is dependent on the synergis-
tic interaction between them. It also represents a different ap-
proach to exploit asymmetric organocatalysis to induce chi-
Asymmetric catalysis is one of the most efficient strategies
to generate enantiomerically pure small molecules that are
commercially important in the chemical and pharmaceutical
industries1. Asymmetric phase-transfer catalysis is of particu-
lar interest because of its operational simplicity, ease of scala-
bility and environmental benignity2-4. Most asymmetric phase-
transfer reactions are Brønsted base reactions; inorganic hy-
droxide bases are shuttled from the aqueous phase to generate
an onium carbanion intermediate, which is subsequently
trapped by electrophilic substrates2. Other inorganic salts were
also used in phase-transfer reactions; however, they met with
relatively less success in asymmetric versions3. High level of
stereocontrol was restricted to only few transformations, such
as asymmetric Strecker reaction using cyanide salt5 and epoxi-
dation with hypochlorite salt6. Asymmetric phase-transfer
reactions are but a sub-set of a more general strategy of ion-
pairing catalysis using chiral cation and a functional anion. A
remarkable example of this approach is reported by Ishihara,
in which, the anionic (hypo)iodite reagent was utilized in cata-
lytic amount and regenerated through in situ oxidation with
co-oxidant7. Highly enantioselective cycloetherification can be
accomplished together with the Maruoka catalyst, yielding
enantio-enriched 2-acyl-2,3-dihydrobenzofurans. More recent-
ly, this (hypo)iodite catalysis was extended to an efficient,
high turn-over protocol for the synthesis of tocopherols8.
rality with metals22-25
.
a
LAu+, LPd+, LMn+, LCu+, etc;
demonstrated
metal
cation
R
O
O
O
O
chiral
anion
P
R
Chiral phosphate anion
b
MnO4-; this work
RuO4-, Co(CO)4- , etc;
future work
chiral
cation
R
R
Ph
Ph
Ph
Ph
N
N
N
N
N
N
R
metal
anion
R
Chiral bisguanidinium (BG)
Figure 1. Two distinct modes of chiral ion-pairing catalysis. a,
Cationic metal species and chiral phosphate anion. b, Anionic
metal species and chiral bisguanidinium cation.
On the other hand, chiral anion-controlled ion-pairing catal-
ysis has experienced tremendous progress recently owing
mainly to the advances made in binaphthyl-derived chiral
phosphate anion9-12 and chiral thiourea anion-binding chemis-
tries13-14. Along this line, the advent of chiral anion phase-
transfer catalysis is particularly interesting10, demonstrating
the versatility of ion-pairing catalysis. More significantly, the
strategy of using cationic metal species controlled by chiral
anions, thus forge a new direction for asymmetric metal cata-
lyzed reactions (Fig. 1a)11,12,15-19. Inspired by these advance-
ments, we envision a complementary strategy to control anion-
ic metal species with chiral cations (Fig. 1b). Chiral ammoni-
um salts have been used in palladium catalyzed asymmetric
RESULTS AND DISCUSSIONS
Metal-centered anionic reagents using achiral quaternary
ammonium salts have had precedence in the literature. Car-
-
bonylation reaction using cobalt tetracarbonyl anion [Co(CO)4
-
]
26 and oxidation reactions with perruthenate anion [RuO4 ]27
are such examples. The use of phase-transfer conditions for
-
permanganate [MnO4 ] oxidations is also known; stoichio-
metric amount of chiral Cinchonidinium salt was used to effect
asymmetric dihydroxylation of alkenes but these reactions
suffered from moderate enantioselectivities and low yields28.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
Inspired by these works, we embark to demonstrate this ion- Interestingly, we found that using different aqueous salts as
1
2
3
4
5
6
7
8
pairing strategy using permanganate oxidation as a platform.
additives has an impact on the reactivity and stereoselectivity
of the reaction. Further structure modification of the bisguani-
dinium catalysts, in particular, introduction of fluoro-
substitution on the side arms, led to increased levels of enanti-
oselectivity (entries 5-8). Catalyst BG-IV together with 20
wt% aqueous potassium iodide (KI) provided the most ideal
conditions (92% ee) (see Table S1 for more details).
It was observed that chiral Cinchonidinium salt decomposed
under permanganate dihydroxylation condition. We realized
that identification of a chiral cation that is compatible with
permanganate anion is prerequisite to achieve catalytic per-
manganate dihydroxylation. Our group has been interested in
developing N-sp2 hybridized pentanidinium salts as chiral
phase-transfer catalysts29-30 and a novel dicationic bisguani-
dinium (BG) evolved from this work serendipitously (Fig. 1b).
It is easily accessed in three synthetic steps from commercially
available chiral diamine (Fig. S1). We anticipated that the
dicationic moiety, with its highly positive charge localized in
small volume, would facilitate interactions with anionic rea-
gents or intermediates. These interactions will enhance the
ability of the catalyst to achieve high stereocontrol. We were
thrilled to find out that these chiral bisguanidiniums are stable
under permanganate oxidation condition and promoted the
dihydroxylation of α,β-unsaturated ketones catalytically in
high conversion. We are aware of the significance of this reac-
tion, as it is potentially a complementary approach to the re-
Scheme 1. Substrate Scope of α-Aryl Acrylates for Asym-
metric Permanganate Dihydroxylationa
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2 mol% BG-IV
1.5 equiv. KMnO4
HO
O
OH
+
Ar
COOtBu
TBME/20 wt% aq. KI
Ar
COOtBu
Ar
COOtBu
-60 o
C
2
1
3
Me
62% yield
90% ee
72% yield
85% ee
65% yield
92% ee
Me
2c
2a
2b
2e
67% yield
89% ee
64% yield
90% ee
71% yield
86% ee
Et
MeO
Ph
MeO
Me
2d
2fb
2i
nowned Sharpless Asymmetric Dihydroxylation (AD)31-33
.
65% yield
84% ee
63% yield
86% ee
65% yield
96% ee
MeS
Me
Table 1. Optimization of Asymmetric Permanganate Di-
hydroxylation Conditionsa
2gc
2hb
O
MeO
63% yield
94% ee
60% yield
92% ee
O
2 mol% BG
1.5 equiv. KMnO4
HO
2j
2k
O
OMe
OH
+
COOtBu
Ph
COOtBu solvent/additive
Ph
Ph
COOtBu
o
aReactions were carried out on 0.2 mmol scale at -60 C for 12
-60 o
C
2a
1a
3a
R1
N
hours unless otherwise noted; yield values refer to isolated yields
R1
N
BG-I, R1, R2 = CH2Ar
BG-II, R1, R2 = CH2Arp-F
BG-III, R1, R2 = CH2Aro-F
b
Ph
Ph
Ph
after purification and ee was determined by chiral HPLC. Reac-
N
tion for 2f and 2h were carried out at -70oC for 36 hours. For
N
c
N
R2
N
Ph
2Cl-
BG-IV, R1 = CH2Arp-F
2 = CH2Aro-F
,
absolute configuration determination, see Fig. S4.
R2
R
Bisguanidinium (BG)
With the optimized condition in hand, tert-butyl acrylates
with different α-aryl groups were investigated (Scheme 1).
Generally, the substrates with electron-neutral or electron-rich
arenes showed high reactivity, provided diols 2a-2k in high
enantioselectivities with moderate yields. The remaining
yields are manifested as the C-C cleavage byproduct. Elec-
tron-rich arenes resulted in higher enantioselectivities in con-
trast with electron-deficient ones (Fig. S2). Interestingly, me-
thylthio ether group in diol 2h was well tolerated under the
current dihydroxylation condition; although it was reported to
t-Bu
t-Bu
F
t-Bu
F
t-Bu
t-Bu
t-Bu
Ar
Arp-F
Aro-F
entry
catalyst
solvent
DCM
additive
H2O
ee of 2a (%)b
1
2
3
4
5
6
7
8
26
45
9
BG-I
PhCH3
THF
H2O
BG-I
H2O
BG-I
be oxidized by permanganate under certain conditions34,35
.
TBME
TBME
TBME
TBME
TBME
H2O
71
75
88
85
92
BG-I
Acrylates with an α-alkyl group underwent reaction smoothly
albeit with moderate enantioselectivities (Fig. S2).
aq. KIc
aq. KIc
aq. KIc
aq. KIc
BG-I
In the next stage, trisubstituted enoates were investigated
and subjected to the permanganate oxidation condition (Table
2). We found that when a mixture of Z, E-trisubstituted eno-
ates 4a were oxidized, both diastereomers 5a and 5a’ were
obtained in high enantioselectivities together with significant
amount of C-C cleavage product 3g. Catalyst BG-III showed
the highest catalytic activity and provided products with high-
est enantioselectivities (entry 1-2). When we were trying to
improve the yields of the desired diols, we were pleasantly
surprised that under acidic conditions, an unexpected 2-
hydroxy-3-oxocarboxylic ester 6a was detected. The yield of
6a was influenced by the concentration of hydrochloric acid
(entries 3-4). When acetic acid was used, 6a was obtained in
both high yield and high enantioselectivity; both diols and C-C
cleavage product formation were efficiently suppressed (entry
5) (see Table S2 for more details). As far as we are aware,
BG-II
BG-III
BG-IV
aReactions were conducted on 0.025 mmol scale in 0.5 ml sol-
vent and 0.05 ml aqueous additive. bEnantiomeric excess (ee) was
determined by chiral HPLC. c20 wt% aqueous KI was used.
After an extensive study, we decided to use α,β-unsaturated
esters as model substrates for our investigation and were en-
couraged by the preliminary results (Table 1). Using 2 mol%
of dicationic bisguanidinium salt BG-I, tert-butyl 2-
phenylacrylate 1a was fully consumed, yielding dihydroxyla-
tion product 2a in satisfactory yield and promising enantiose-
lectivity, together with C-C cleavage product 3a as the only
detectable byproduct. A survey of solvents revealed that tert-
butyl methyl ether (TBME) is the best choice (entries 1-4).
there are only a few reports describing this transformation36,37
.
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
We named this transformation oxohydroxylation as it is analo-
Scheme 2. Scope of Trisubstituted Enoates for Asymmetric
Oxohydroxylationa
1
2
3
4
5
6
gous to dihydroxylation. The high enantioselectivity observed
indicate that both Z- and E-trisubstituted enoates 4a were
transformed to the same enantiomer 6a under oxohydroxyla-
tion condition.
R
2 mol% BG-III
R
O
AcOH, 1.5 equiv. KMnO4
OH
Ar
COOtBu
Ar
COOtBu
TBME/H2O
4b
6
-60 o
C
Table 2. Optimization of Reaction Conditions for Trisub-
stituted Enoatesa
R = alkyl (Z, E mixtures)
O
O
O
O
7
8
9
OH
OH
OH
OH
OH
OH
COOtBu
COOtBu
COOtBu
COOtBu
OH
OH
79% yield
92% ee
OMe
75% yield
92% ee
92% yield
93% ee
85% yield
92% ee
2 mol% BG
1.5 equiv. KMnO4
Ar
Ar
COOtBu Ar
COOtBu
OMe
OMe
OMe
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5a'
5a
Ar
COOtBu
6a
6b
6c
6d
+
TBME/additive
O
O
E : Z = 1.3 : 1
4a Ar = 3-MeO-C6H4
O
O
n-C11H23
O
-60 o
C
O
i-Pr
OH
OH
OH
OH
OH
COOtBu
COOtBu Ar
COOtBu
COOtBu
COOtBu
COOtBu
6a
3g
98% yield
94% ee
88% yield
94% ee
93% yield
91% ee
85% yield
93% ee
OMe
6e
BnO
OMe
OMe
6g
6f
6h
ee of
ee of
6a
O
ratio of
O
O
entry catalyst additive
5a/5a’
4a:(5a+5a’):6a:3gb
OH
OH
OH
(%)c
(%)c
O
O
COOtBu
COOtBu
COOtBu
81% yield
94% ee
73% yield
91% ee
77% yield
91% ee
1
2
3
4
5
H2O
17:33:0:50
8:38:0:54
84/89
91/94
85/93
88/92
--
--
BG-IV
BG-III
BG-III
BG-III
BG-III
OMe
OMe
OMe
6k
H2O
--
6i
6j
O
O
O
1N aq. HCl
11:32:41:16
92
--
OH
OH
OH
MeO
COOtBu
COOtBu
COOtBu
0.1N aq. HCl 14:26:5:55
H2O/AcOH
90%d
49% yield
96% ee
O
S
77% yield
84% ee
47% yield
87% ee
6n
92
6l
6m
aThe reaction was conducted on 0.05 mmol scale in 1 ml
MeO
O
MeO
O
MeO
O
MeO
Ar
TBME and 0.05 ml aqueous additive; For substrate and products
OH
OH
OH
configuration determination, see Fig. S3 and S4. bRatios were
MeO
COOtBu
COOtBu
COOtBu
1
c
COOtBu
E-4-OMec
determined by H NMR analysis. ee was determined by chiral
88% yield
74% ee
81% yield
99% ee
87% yield
97% ee
HPLC. dIsolated yield of 6a.
OMe
OMe
6o
6p
6q
A series of trisubstituted enoates was then investigated un-
der the oxohydroxylation condition (Scheme 2). Substrates
with different alkyl groups, including long alkyl chain and
secondary isopropyl group, uniformly gave high levels of en-
antioselectivity in good to excellent yields (6a-6j). Notably,
isolated terminal double bond is well tolerated (6j). Different
α-aryl groups were also investigated; as anticipated, electron-
rich aryl groups showed higher reactivity and selectivity (6k-
6n). Interestingly, trisubstituted enoates with α-heteroarene
substituents including furyl and thienyl underwent oxohydrox-
ylation in high enantioselectivity. As a further extension to this
methodology, we found that methoxy-substituted enoates E-4-
OMe were transformed to α-hydroxymalonates in high enan-
tioselectivities (6o-6q). This transformation demonstrated that
asymmetric oxohydroxylation could be used to prepare chiral
α-hydroxy carbonyl compounds from hetero-substituted al-
kenes. In order to demonstrate the practicality of this new
methodology, a four-mmol reaction using 1 mol% BG-III was
conducted, yielding 6a in 81% yield and 92% ee.
o
aReactions were carried out on 0.2 mmol scale at -60 C with
isolated yields reported and ee determined by chiral HPLC. A
four-mmol scale reaction of 4a (1 gram) was conducted using 1
mol% of BG-III, yielding 6a in 81% yield and 92% ee. bFor alkyl
substituted enoates, Z, E-mixtures were used as substrates; for
configuration determination, see Fig. S3; for Z/E ratio, see Fig.
S7; cE-methoxy substituted enoates E-4-OMe were used.
When ketone 6a was subjected to reduction with sodium bo-
rohydride, both diol 5a and 5a’ were obtained in high optical
purity (Scheme 3b). Moreover, reduction with NaBH4/ZnCl2
yielded diol 5a in excellent selectivity of 10:1 ratio and in
excellent yield. On the other hand, when a Z/E-mixture of 4a
was subjected to standard Sharpless AD condition, it furnished
diol 5a in 65% ee and ent-5a’ in 96% ee (Scheme 3c). This
comparison indicated that asymmetric permanganate oxohy-
droxylation/reduction sequence provides a formal asymmetric
dihydroxylation that is complementary to Sharpless AD and
would be useful for some challenging substrates.
Mechanistically, it is widely recognized that a cyclic man-
ganate diester 7 is the common intermediate that generates
different products through diverse pathways34,35,38 (Scheme 4).
This is consistent with the experimental result that absolute
configuration of the α-chiral center of oxidation products from
both dihydroxylation and oxohydroxylation is the same. Alt-
hough the mechanism for oxohydroxylation from cyclic man-
ganate diester is currently unclear, the possibility of in situ
oxidation of dihydroxylation product to generate oxohydrox-
ylation product can be ruled out. When the dihydroxylated
alkenes were isolated and re-introduced to the reaction condi-
The difference between asymmetric permanganate dihy-
droxylation and Sharpless AD was then investigated. When an
equal amount of two alkenes, acrylate 1a and α-methyl styrene
1l, was subjected to the permanganate dihydroxylation condi-
tion, only diol 2a was obtained and α-methyl styrene was re-
covered intact. In contrast, under standard Sharpless AD con-
dition32, α-methyl styrene was dihydroxylated preferentially,
giving diol ent-2a and 2l in a ratio of 1:2.9 (Scheme 3a). This
newly developed permanganate dihydroxylation, thus provides
complementary selectivity to Sharpless AD.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
tion, they are not further oxidized to the oxohydroxylated
products (Fig. S5).
Scheme 5. Working Model
1
2+BG*
2
3
4
5
6
7
8
9
Scheme 3. Comparison between Asymmetric Permanga-
nate Oxidation and Sharpless ADa
Ar
R
O-
R
O
O
COOtBu
Ar
O
Ar
R
COOtBu
O
OtBu
Mn O
O-
O
O
Re
Mn
O
Mn
HO
O
2 mol% BG-IV
a
O- 2+BG*
O
OH
1.5 equiv. KMnO4
high energy TS II
+
+
Ar
Ph
Ph
COOtBu
COOtBu
Ph
R
Ph
Ph
Ph
COOtBu
20 wt% aq. KI
1a
1a
1l
2a
TBME, -60 o
C
COOtBu
E, Z
HO
HO
Ph
O
O
O
KMnO4
AD-mix-α
2+BG*
COOtBu
Mn
2+BG*
+
phase transfer
+
O
tBuOH:H2O (1:1) Ph
OH
ent-2a
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2lb
OH
OH
0 o
C
1l
1 : 2.9
oxidation
products
COOtBu
R
OH
b
0.6 equiv. NaBH4
EtOH, 0 o
Ar
OH
E, Z
+
2+BG*
-O
C
Ar
Ar
COOtBu
O
Ar
COOtBu
COOtBu
5a
R
OtBu
Ar
O
5a'
R
R
O
O
COOtBu
Ar
O
OH
5a / 5a' = 1 : 1.07
93% yield
94% ee / 88% ee
Ar
Ar
COOtBu
accelerated
pathway
O
O
Mn
Si
6a Ar = 3-MeO-C6H4
Mn
O-
O
Mn
O
O
O
92% ee
O- 2+BG*
1.2 equiv. NaBH4,
ZnCl2
OH
OH
low energy TS I
+
OH
OH
THF, 0 o
C
COOtBu
Ar
COOtBu
Lee and co-workers reported a mechanistic study of the re-
5a
5a'
action between methyl cinnamate and quaternary ammonium
permanganate40. The authors found that the rate of reaction is
fastest for those ions, which permit interionic distance in the
quaternary ammonium ion pair to be minimized. Stabilization
of the enolate transition state through ion pair formation was
proposed for the rate enhancement. Based on this prior work,
we propose that in the current catalytic system, the chiral cata-
lyst accelerate oxidation reaction through the formation of an
intimate ion pair with enolate anion in transition state (TS-I
and TS-II) and chiral information is imparted through this
interaction (Scheme 5). After shuttling to the organic phase,
the permanganate anion dynamically coordinates to double
bond from both prochiral faces of the substrate. The cationic
centers of bisguanidinium are deeply buried in a chiral pocket
and as a result, only the matched transition state TS-I (Si face
approach) allows the formation of intimate ion pair and reac-
tion through this pathway is accelerated selectively. In mis-
matched TS-II (Re face approach), the interionic distance
between enolate anion and cationic centers is much larger,
which results in a higher energy transition state. This working
model is in accordance with the experimental results that abso-
lute configuration of α-chiral center of oxidation products
from both Z- and E-enoates is identical.
5a / 5a' = 10 : 1
92% yield
94% ee / 91% ee
c
OH
OH
AD-mix-α
+
OH
COOtBu
OH
Ar
E : Z = 1.3 : 1
4a Ar = 3-MeO-C6H4
COOtBu
tBuOH:H2O (1:1)
Ar
COOtBu Ar
0 o
C
5a
ent-5a'
5a / ent-5a' = 1.3 : 1
95% yield
65% ee / 96% ee
aAll the ratios were determined with crude product by 1H NMR
b
analysis. Absolute configuration of 2l was determined according
to reference32.
Scheme 4. Transformation of Cyclic Manganate Diester
Intermediate 7 under Diverse Pathways
O
O
O
Mn
Dihydroxylation
Oxohydroxylation
O
H
Ar
COOtBu
R
H+
7
C-C Cleavage
O
OH
Ar
COOtBu
2 or 5
R
OH
Ar
COOtBu
+
R
CHO
O
R
Ar
COOtBu
HO
6
Scheme 6. Comparison of Selectivity Using TBA+MnO4
-
and KMnO4 as Oxidant
We then attempted to understand the origin of stereoinduc-
tion of this asymmetric permanganate oxidation. In Sharpless
AD, chiral complex is formed through a covalent bond be-
tween chiral tertiary amine and osmium tetroxide33. However,
it is unlikely for the bisguanidinium cation to form similar
covalent type of chiral entity with the permanganate anion. On
the other hand, most asymmetric phase-transfer catalyzed re-
HO
2 mol% BG-IV
1.5 equiv. oxidant
OH
Ph
COOtBu
Ph
COOtBu
TBME/20 wt% aq. KI
-60 o
C
83% ee with TBA+MnO4
92% ee with KMnO4
-
actions are enantioselective nucleophilic addition reactions2-4
.
Based on the working model, we speculated that rate accel-
eration through ion-pairing formation rather than phase sepa-
ration is crucial for reaction to go through the asymmetric
pathway selectively. We envisaged that high level of asym-
metric induction might be still applicable with an organic
phase soluble permanganate source. In order to test this hy-
pothesis, a control reaction using tetrabutylammonium per-
manganate as oxidant was conducted. With only 2 mol% chi-
ral catalyst and 1.5 equivalent of tetrabutylammonium per-
manganate, the reaction provided high level of chiral induction
(83% ee vs 92% ee) (Scheme 6). This demonstrates that the
Previously, Jew and Park demonstrated a dimeric Cinchona-
catalyzed epoxidation reaction and the authors proposed a
transition state in which the two cationic centers of the catalyst
interact with the anionic nucleophile and neutral electrophile
simultaneously39. It seems also not likely for the bisguanidini-
um dication to form such transition complex, as it is oblivious
to the configuration of trisubstituted alkenes as well as the size
of alkyl substituents. Notably, we also did not observed E/Z
isomerization under the permanganate oxidation conditions
(Fig. S6).
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
(6) Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K. J. Am. Chem. Soc.
2004, 126, 6844-6845.
(7) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010,
328, 1376-1379.
(8) Uyanik, M.; Hayashi, H.; Ishihara, K. Science 2014, 345, 291-
294.
chiral bisguanidinium dication is much better in stabilizing the
1
2
3
4
active anionic intermediates than tetrabutylammonium cation.
This might be partially ascribed to its dicationic character,
which forms stronger electrostatic interaction with enolate
anion in the transition states.
5
6
7
8
(9) Mayer, S.; List, B. Angew. Chem. Int. Ed. 2006, 45, 4193-4195.
(10) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D.
Science 2011, 334, 1681-1684.
(11) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012,
4, 603-614.
(12) Mahlau, M.; List, B. Angew. Chem. Int. Ed. 2013, 52, 518-533.
(13) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N.
Science 2010, 327, 986-990.
(14) Brak, K.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2013, 52,
534-561.
(15) Llewellyn, D. B.; Adamson, D.; Arndtsen, B. A. Org. Lett.
2000, 2, 4165-4168.
(16) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336-
11337.
(17) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science
2007, 317, 496-499.
(18) Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew.
Chem. Int. Ed. 2010, 49, 3823-3826.
(19) Ohmatsu, K.; Ito, M.; Kunieda, T.; Ooi, T. Nat. Chem. 2012, 4,
473-477.
(20) Chen, G.; Deng, Y.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi,
M. C. K.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 1567-
1571.
(21) Nakoji, M.; Kanayama, T.; Okino, T.; Takemoto, Y. Org. Lett.
2001, 3, 3329-3331.
(22) Han, Z.-Y.; Wang, C.; Gong, L.-Z. In Science of Synthesis:
Asymmetric Organocatalysis; Maruoka,K., Ed.; Georg Thieme Verlag:
Stuttgart, 2012; Vol. 2, p 697-740.
(23) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745-2755.
(24) Zhong, C.; Shi, X. Eur. J. Org. Chem. 2010, 2999-3025.
(25) Rueping, M.; Koenigs, R. M.; Atodiresei, I. Chem. Eur. J.
2010, 16, 9350-9365.
(26) Alper, H.; Eisenstat, A.; Satyanarayana, N. J. Am. Chem. Soc.
1990, 112, 7060-7061.
(27) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J.
Chem. Soc., Chem. Commun. 1987, 1625-1627.
(28) Bhunnoo, R. A.; Hu, Y.; Lainé, D. I.; Brown, R. C. D. Angew.
Chem. Int. Ed. 2002, 41, 3479-3480.
(29) Ma, T.; Fu, X.; Kee, C. W.; Zong, L.; Pan, Y.; Huang, K.-W.;
Tan, C.-H. J. Am. Chem. Soc. 2011, 133, 2828-2831.
(30) Zong, L.; Ban, X.; Kee, C. W.; Tan, C.-H. Angew. Chem. Int.
Ed. 2014, 53, 11849-11853.
CONCLUSIONS
It is generally explained that phase-transfer catalysts accel-
erate reactions by enhancing organic solubility and nucleo-
philicity of the anionic reagents2. In this newly developed
methodology, strong evidence suggests that rate acceleration is
mainly attributed to transition state stabilization through at-
tractive cation-anion interaction. This stereoselective rate ac-
celeration makes the desired asymmetric pathway much fa-
vored. Charge-acceleration effect has been previously pro-
posed in quaternary Cinchonidinium-catalyzed epoxidation
reaction41. More recently, Jacobsen demonstrated that transi-
tion state charge stabilization strategy through multiple non-
covalent interactions could be utilized in chiral anion-bonding
catalysis to induce stereoselectivity42. Although the type of
non-covalent interactions involved in this methodology re-
mains to be elucidated, the enzyme-like mode of bisguanidini-
um, with active center deeply buried in a chiral pocket, should
provide implications for catalyst design. A similar approach
has already been utilized by List with imidodiphosphoric acid,
which contains anionic sites buried within hydrophobic
groups43.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In addition, the disclosure of asymmetric permanganate oxi-
dation reaction together with mechanistic insights should pro-
vide inspiration for expansion to other anionic metal salts.
Given the frequent occurrence of transition metal-centered
anions in coordination complexes, the current chiral cation
ion-pairing strategy would open up new paradigms for asym-
metric transition metal catalysis.
ASSOCIATED CONTENT
Supporting Information.
Experimental details and characterization data. The Supporting
Information is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(31) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968-1970.
(32) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.
J. Org. Chem. 1992, 57, 2768-2771.
(33) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483-2547.
(34) Fatiadi, A. J. Synthesis 1987, 85-127.
*choonhong@ntu.edu.sg
*Wang_Chao@ntu.edu.sg
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge Nanyang Technological University
(M4080946.110, M4011372.110) for financial support.
(35) Dash, S.; Patel, S.; Mishra, B. K. Tetrahedron 2009, 65, 707-
739.
(36) Srinivasan, N. S.; Lee, D. G. Synthesis 1979, 520-521.
(37) Crout, D. H. G.; Rathbone, D. L. Synthesis 1989, 40-42.
(38) Lee, D. G. In PATAI'S Chemistry of Functional Groups;
Rapport, Z. Ed.; John Wiley & Sons, Ltd: 2009; p 419-488.
(39) Jew, S.-s.; Lee, J.-H.; Jeong, B.-S.; Yoo, M.-S.; Kim, M.-J.;
Lee, Y.-J.; Lee, J.; Choi, S.-h.; Lee, K.; Lah, M. S.; Park, H.-g. Angew.
Chem. Int. Ed. 2005, 44, 1383-1385.
(40) Lee, D. G.; Brown, K. C. J. Am. Chem. Soc. 1982, 104, 5076-
5081.
(41) Corey, E. J.; Zhang, F.-Y. Org. Lett. 1999, 1, 1287-1290.
(42) Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. U. S. A.
2010, 107, 20678-20685.
REFERENCES
(1) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric
Catalysis; University Science Books, 2009.
(2) Maruoka, K. Asymmetric Phase Transfer Catalysis; Wiley,
2008.
(3) Ooi, T.; Maruoka, K. Angew. Chem. Int. Ed. 2007, 46, 4222-
4266.
(4) Shirakawa, S.; Maruoka, K. Angew. Chem. Int. Ed. 2013, 52,
4312-4348.
(5) Ooi, T.; Uematsu, Y.; Maruoka, K. J. Am. Chem. Soc. 2006,
128, 2548-2549.
(43) Coric, I.; List, B. Nature 2012, 483, 315-319.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment