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This document is downloaded from DR‑NTU (https://dr.ntu.edu.sg)Nanyang Technological University, Singapore.
Phase‑Transfer and Ion‑Pairing Catalysis ofPentanidiums and Bisguanidiniums
Zong, Lili; Tan, Choon‑Hong
2017
Zong, L., & Tan, C.‑H. (2017). Phase‑Transfer and Ion‑Pairing Catalysis of Pentanidiums andBisguanidiniums. Accounts of Chemical Research, 50(4), 842‑856.
https://hdl.handle.net/10356/87360
https://doi.org/10.1021/acs.accounts.6b00604
© 2017 American Chemical Society. This is the author created version of a work that hasbeen peer reviewed and accepted for publication by Accounts of Chemical Research,American Chemical Society. It incorporates referee’s comments but changes resultingfrom the publishing process, such as copyediting, structural formatting, may not bereflected in this document. The published version is available at:[http://dx.doi.org/10.1021/acs.accounts.6b00604].
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Phase transfer and ion pairing catalysis of
pentanidiums and bisguanidiniums
Lili Zong and Choon-Hong Tan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, 21 Nanyang Link, Singapore 637371
CONSPECTUS: Catalysts accelerate biological processes and organic reactions in a controlled
and selective fashion. There are continuing efforts in asymmetric catalysis to develop efficient
catalysts with broad reaction scope and industrial practicability. Amongst the various modes of
asymmetric catalysis, phase transfer catalysis has attracted intense interest due to its ease to scale
up and low catalyst loading. Chiral quaternary ammonium and phosphonium salts are well-
studied classes of chiral phase transfer catalysts and they typically are comprised of sp3-
hybridized quaternary onium salts. In this Account, we describe our recent attempts to develop
N-sp2 hybridized guanidinium-type salts as efficient phase transfer catalysts as well as ion pair
catalysis based on N-sp2 hybridized bisguanidinium-type salts.
The sp2-quaternized ammonium salts, pentanidiums, which contain five nitrogen atoms in
conjugation, displayed remarkable phase transfer catalytic efficiency. We have shown that
pentanidium can catalyze Michael additions of tert-butyl glycinate-benzophenone Schiff base
with various ,-unsaturated acceptors, such as vinyl ketones, acrylates and chalcones in high
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2
enantioselectivities. The structurally amendable pentanidium phase transfer catalysts supply
diverse reactivity and selectivity to various other organic transformations, such as α-
hydroxylation of 3-substituted-2-oxindoles, Michael addition of 3-alkyloxindoles with vinyl
sulfone and alkylation reactions of sulfenate anions and dihydrocoumarins. Pentanidium salts are
applicable to enantioselective transformations on a preparative scale at low catalyst loading,
allowing for the synthesis of a broad range of enantiopure compounds. From computational and
experimental results, we also proposed that halogenated pentanidium catalysts participated in
halogen bonding and this contributed to the excellent stereocontrol in alkylation reactions.
Subsequently, we articulated that chiral cations can direct functional anions besides basic anions
in traditional Brønsted basic phase transfer reactions, including metal-centered anions. We
identified dicationic bisguanidinium as an excellent ion pairing catalyst, first demonstrating that
bisguanidinium formed an ion pair with permanganate and directed the anion in enantioselective
dihydroxylation and oxohydroxylation of a,β-unsaturated esters. This initial success led us to
explore chiral cationic ion pairing catalysis as a general mode of catalysis. This mode of catalysis
is at the interphase between organocatalysis, phase transfer catalysis and organometallic
catalysis. We then identified bisguanidinium diphosphatobisperoxotungstate and bisguanidinium
dinuclear oxodiperoxomolybdosulfate ion pairs as the active catalysts in enantioselective
sulfoxidations using aqueous H2O2 as oxidant. The structure of bisguanidinium dinuclear
oxodiperoxomolybdosulfate ion pair was elucidated using single crystal X-ray analysis.
Bisguanidinium-catalyzed sulfoxidations emerged as a practical methodology for the synthesis of
enantioenriched sulfoxides including armodafinil and lansoprazole, which are commercial drugs.
Finally, we are also able to show that pentanidium and bisguanidinium hypervalent silicates are
intermediates in enantioselective alkylations using silylamide as Brønsted probase.
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1. INTRODUCTION
Guanidine, the functional group on the side chain of arginine, is a strong base and is protonated
over a wide pH range. Thus, in physiological conditions, it usually exists as guanidinium. The
guanidinium motif is known to play crucial roles in substrate recognition at the active site of
enzymes through non-covalent interactions such as hydrogen bonding.1 Interactions between
guanidinium and functional groups such as phosphates, carboxylates and enolates are also of
considerable interest in bioorganic chemistry and host-guest macromolecular chemistry.2 Since
the pioneering works of Chinchilla,3
Lipton4
and Corey5
in the 1990s, numerous exciting
outcomes have been achieved by utilizing chiral guanidines as general Brønsted base catalysts.6
Our group has reported a variety of chiral guanidine-catalyzed asymmetric reactions and these
results have been summarized in several reviews.7 This Account will emphasize our recent
efforts in using guanidinium-type and bisguanidinium-type salts 1, 2 and 3 as phase transfer8 and
ion pairing catalysts (Figure 1).
Figure 1. Guanidinium-type salts as phase transfer and ion pairing catalysts.
2. PENTANIDIUM-CATALZYED ENANTIOSELECTVE PHASE
TRANSFER REACTIONS
In our attempt to enhance the basicity of the guanidine catalyst 1, structurally novel pentanidine
containing five nitrogen atoms in conjugation was designed. The hypothesis was that with
NN
N
N N
N
R1
R2
R1
R2
Ph
PhPh
Ph
Bisguanidinium
R1, R2 = benzyl
N
N
N
R1
Ph
PhN
N
R2
Ph
Ph
Pentanidium
R1, R2 = alkyl, benzyl
R1 R2
ClNH
N
NH
Bicyclic guanidinium
I ClCl1.HI 2 3
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4
increased conjugation, it might render pentanidine with increased basicity and less acidic
nucleophiles can be activated. Although the pentanidine did not exhibit enhanced basicity,
serendipitously, we found that its fully alkylated salt, pentanidium salts 2, is an excellent phase
transfer catalyst (Figure 1). We prepared the pentanidium salts 2 from commercially available
chiral diamines and tetra-methylated pentanidium 2a can be obtained in five steps with good
chemical yield. Generally, pentanidium salts 2 can be synthesized through the coupling between
imidazolinium chloride and a guanidine partner under basic conditions (Scheme 1). Single-
crystal X-ray diffraction analysis of pentanidium 2a reveals that the five nitrogen atoms are not
coplanar and the resulting two five-membered rings are in a twisted spatial arrangement (Figure
2).9
Scheme 1. Synthesis of pentanidium salts 2 through imidazolinium chloride.
2 R1, R2
2a R1 = R2 = Me
R1 =
tBu
tBu
R2 =
X = H, F, Cl, Br, IX
tBu
tBu
R1 =
tBu
tBu
R2 =
Cl
2b
2c-g
2h-k
X = Cl, Br, I, OMe
R1 = R2 =
tBu
tBu
X
Imidazolinium chloride
+MeCN reflux
Et3N
N
N
Cl
R1
Ph
Ph
R1
ClHN N
N
R2
Ph
Ph
R2
N
N
N
R1
Ph
PhN
N
R2
Ph
Ph
Pentanidium
R1, R2 = alkyl, benzyl
R1 R2
Cl 2
Guanidine
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5
Figure 2. Crystal structure of tetra-methylated pentanidium 2a.
2.1 Pentanidium-catalyzed Michael addition of tert-butylglycinate Schiff base
Scheme 2. Pentanidium 2a-catalyzed Michael addition of Schiff base.
When we investigated the propensity for pentanidium to function as phase transfer catalyst, we
found that pentanidium 2a is an excellent catalyst for the Michael addition of tert-butylglycinate-
benzophenone Schiff base 4.9 Pentanidium 2a displayed excellent reactivity; with only 2.0 mol%
of catalyst, the reaction with methyl vinyl ketone 5a was completed within 3 h, providing the
Cs2CO3 (5.0 equiv.)
mesitylene, -20 oC
NPh2C OtBu
O
+
R2
O
R1
N
CPh2
tBuO2C
HH
4
2a (2.0 mol%)
R1 R2
O
Me
O
N
CO2tBu
Ph2C Et
O
N
CO2tBu
Ph2C n-Bu
O
N
CO2tBu
Ph2C
Ph
O
N
CO2tBu
Ph2C OEt
O
N
CO2tBu
Ph2C OBn
O
N
CO2tBu
Ph2C
ON
CPh2
tBuO2C
HHO
N
CPh2
tBuO2C
HH
5a-l6a-l
6a, 86% yield, 91% ee 6b, 92% yield, 93% ee 6c, 97% yield, 93% ee
F
ON
CPh2
tBuO2C
HH
MeO
ON
CPh2
tBuO2C
HHO
N
CPh2
tBuO2C
HHO
N
CPh2
tBuO2C
HH
6d, 50% yield, 88% ee 6e, 71% yield, 97% ee 6f, 80% yield, 96% ee
6g, 98% yield, 92% ee 6h, 89% yield, 90% ee 6i, 89% yield, 85% ee
6j, 95% yield, 90% ee 6k, 92% yield, 90% ee
S
6l, 71% yield, 87% ee
O
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6
adduct 6a in 86% yield and in 91% ee (Scheme 2). The generality of the method was
successfully demonstrated using different Michael addition acceptors such as vinyl ketones,
acrylates and chalcones. It was found that loading of the catalyst could be further lowered to 0.05
mol% for a gram-scale reaction (Scheme 3). The Michael addition between Schiff base 4 and
chalcone 5m proceeded with high stereoselectivity providing the adduct 6m in 90% ee and as a
single diastereomer; it was transformed to pyrrolidine derivative 7 in simple steps.
Scheme 3. Preparative-scale reaction with low catalyst loading.
Figure 3. Pentanidium-catalyzed reactions using prochiral intermediates.
The aforementioned result indicates that chiral pentanidium cation can discriminate efficiently
between the two enantiotopic faces of prochiral ester enolate. Further investigations reveal that
amide enolate, sulfenate anion and cyclic ester enolate are also suitable prochiral nucleophiles
(Figure 3).
NPh2C OtBu
O
+Cs2CO3 (2.5 equiv.)
mesitylene, -20 oC
24 h
2a (0.05 mol%)
5m, Ar = 4-ClC6H4 6m1.16 g, 87% yield dr> 99:1, 90% ee
4 2.5 mmol
NH
Ph
Ar
CO2tBu
7
Ph
O
Ar Ph
O
Ar
N
CPh2
tBuO2C
HH
NPh2C OtBu
O
NO
R2
R1
ester enolate
amide enolate
Hydroxylation using molecular oxygen
Michael addition to vinyl sulfone
Michael addition to a,b-unsaturatedcarbonyl compounds
cyclic ester enolate
O O
R1
Alkylation using alkyl bromides
S
S
O
Alkylation to form sulfoxides
sulfenate anion
a)
c)
b)
d)
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2.2 Pentanidium-catalyzed -hydroxylation of 3-substituted-2-oxindoles
The amide enolate (Figure 3b) generated from 3-substituted 2-oxindole has been widely
employed as key intermediate for the synthesis of enantioenriched 3,3-disubstituted oxindoles.
These oxindoles are frequently observed as the core structure in natural products and extensively
investigated in drug discovery programs due to their potent antibacterial and anticancer
activities.10
Catalytic enantioselective -oxidation of 3-substituted-2-oxindole is a direct and
attractive approach to access 3-substituted-3-hydroxy-2-oxindole core structures.11
In 2008, Itoh
reported the preparation of -hydroxyoxindoles using a Cinchonidinium catalyst under phase
transfer conditions.12
The product was obtained with moderate enantioselectivity and triethyl
phosphite was required to reduce the peroxide intermediate. Encouraged by the efficiency and
excellent stereocontrol of pentanidium, we investigated the -hydroxylation of 3-substituted-2-
oxindole 7 with air as oxidant (Scheme 4a).13
Pentanidium 2b, bearing bulkier side arms was
developed for this reaction (Scheme 1). Initially, we were perplexed that no reductant such as
triethyl phosphite was required and -hydroxyoxindoles were obtained directly with high
enantioselectivities. Using isotope labelling experiments with 0.55 equivalent of 18
O2, the role of
molecular oxygen was verified (Scheme 4b). Mass spectrometry was employed to characterize
the isolated hydroxyloxindole [18
O]-8a and 84% level of 18
O incorporation was observed.
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Scheme 4. a) Pentanidium 2b-catalyzed -hydroxylation of 3-substituted-2-oxindoles, b) isotope
labelling experiment and c) effect of the amount of oxygen on chemoselectivity.
We found that the amount of molecular oxygen in the reaction affects the amount of
hydroperoxide oxindole formed (Scheme 4c). When the reaction was conducted with excess
oxidant by using an O2 balloon, hydroperoxide oxindole 9a was obtained in 85% yield with good
enantioselectivity. Hydroperoxide oxindole 9a and hydroxyloxindole 8a were found to have the
same absolute configuration (R). To gain insights into the reaction, racemic hydroperoxide
oxindole 9a was prepared and used as oxidant in the -hydroxylation of oxindole 7a in the
absence of air (Scheme 5a). With 5 mol % of pentanidium 2b and two equivalents of racemic 9a
as oxidant, the -hydroxylated product (R)-8a was achieved with 76% ee, while the remained
hydroperoxide oxindole was determined to be (S)-9a with 51% ee. On the basis of the
experimental results (Scheme 4c and Scheme 5a), we proposed a two-step reaction that includes
a kinetic resolution step (Scheme 5b). In the first step, in the presence of pentanidium 2b and
base, the enolate generated from 3-substituted-2-oxindole 7a, adds to O2 in an enantioselective
fashion to give hydroperoxide oxindole (R)-9a. This is followed by a kinetic resolution step, in
NO
PMB
2b (5 mol%)air (0.5 equiv. O2)
50% aq. KOH
toluene, -60 oC12-96 h
No reductant
R2
RN
O
PMB
R2
R
HO
NO
PMB
MeHO
80% yield, 95% ee
NO
PMB
MeHO
75% yield, 86% ee
NO
PMB
MeHO
80% yield, 98% ee
F MeO
NO
PMB
n-BuHO
72% yield, 85% ee
NO
PMB
HO
78% yield, 91% ee
NO
PMB
HO
78% yield, 94% ee
NO
PMB
2b (5.0 mol%),
0.55 equiv. O2
conditionsMe N
O
PMB
MeHO
2b (1.0 mol%),
excess O2
conditionsN
O
PMB
MeHOO
7a
8a80% yield, 95% ee
a) b)
c)
9a85% yield, 80% ee
NO
PMB
2b (5 mol%),
0.55 equiv.18O250% aq. KOH
toluene, -60 oC72 h, 87% yield
95% ee
Me
NO
PMB
MeHO
7a [18O]-8a
84%18O incorporation
7 major 8
8a 8b 8c
8d 8e 8f
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9
which hydroperoxide oxindole (R)-9a is reduced by a second enolate of 3-substituted-2-oxindole
7a, furnishing hydroxyloxindole product (R)-8a with improved enantiopurity.
Scheme 5. a) Racemic hydroperoxide 9a as oxidant and b) proposed reaction pathway involving
a kinetic resolution process.
2.3 Pentanidium-catalyzed Michael addition of 3-alkylsubstituted oxindoles
The direct Michael addition of 3-substituted oxindole to activate alkenes is an attractive
approach to prepare 3,3-disubstitued oxindoles containing a quaternary carbon stereocenter.
Recently, successful attempts using commercially available vinyl sulfones as Michael acceptors
have been reported using organocatalysis.14
However, only limited examples of highly
enantioenriched 3,3-dialkyl oxindoles have been obtained.15
We found that pentanidium 2 are
efficient phase transfer catalysts for Michael addition of 3-alkyloxindoles 7 to phenyl vinyl
sulfone 10 at low catalyst loading (Scheme 6).
NO
PMB
NO
PMB
MeHOO
7a1.0 equiv.
rac-9a2.0 equiv.
toluene, -60 oC72 h, no O2
S = 5
(S,S)-2b (5.0 mol%)50% aq. KOH
NO
PMB
MeHO
(R)-8a76% ee
NO
PMB
MeHOO
(S)-9a51% ee
+
Pentanidium 2b
NO
PMB
Me2b
Me
7a
base
+
NO
PMB
MeHOO
(R)-9a
NO
PMB
Me2b
(S)-9a + (R)-8a
kinetic resolution process
O2
a)
b)
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10
Scheme 6. Effect on enantioselectivities using halogenated pentanidiums.
Scheme 7. Pentanidium 2f-catalyzed Michael addition of 3-alkylsubstituted oxindoles.
Pentanidium 2c, with four 3,5-di-tert-butylbenzyl side-arms, was first tested and a moderate
level of enantioselectivity was obtained (Scheme 6).16
Further modification, by installing
different halogens to the two benzyl groups, led to an enhancement in enantioselectivity and a
high level of enantiocontrol was achieved with brominated-pentanidium 2f or iodinated-
NO
PMB
Me
7a
SO2Ph+
10
2c-g (0.25 mol %)
K3PO4 (10 equiv.)
CPME, -60 oCN
O
PMB
Me SO2Ph
R2 =
2c X = H 2d X = F2e X = Cl2f X = Br2g X = I
X
tBu
tBu
N
N
N
R1
Ph
PhN
N
R2
Ph
Ph
2Pentanidium
R1 R2
Cl
R1 = 3,5-(tBu)2C6H3CH2
11a
X ee (%)
7678808390
substituent variation
increasing enantioselectivity
NO
PMB
Me SO2Ph
NO
Bn
Et SO2Ph
NO
PMB
SO2Ph
NO
PMB
SO2PhPh
99% yield, 95% ee
NO
PMB
SO2Ph
NO
PMB
SO2Ph
77% yield, 94% ee
85% yield, 92% ee 78% yield, 98% ee
N
Me
O
SO2PhEtO
O
MeO
99% yield, 90% ee
NO
PG
R1
SO2Ph+
2f (0.25 mol %)
K3PO4(10 equiv.)
CPME/m-xylene(1:2)
-60 oC
R2
NO
PG
R1
R2
SO2Ph
91% yield, 95% ee
99% yield, 99% ee
N
Me
MeON
MeH
CH3
12an analogue of esermethole
11a 11b 11c
11d 11e 11f
7 10 11
11g
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11
pentanidium 2g. With 0.25 mol% of pentanidium 2f, the reaction between a series of 3-
alkylsubstituted oxindoles 7 and phenyl vinyl sulfone 10 proceeded in a highly enantioselective
manner to furnish corresponding Michael adducts 11 with high functional group tolerance
(Scheme 7). Gram quantity of oxindole 11g can be easily obtained from scale-up experiments.
The adduct 11g then underwent simple transformations to provide pyrroloindoline derivative 12,
an analogue of the natural product precursor esermethole.17
2.4 Pentanidium-catalyzed alkylation of sulfenate
Sulfenate anion18
is an unstable reaction intermediate but it can be generated in situ; it has a
nucleophilic sulfur center, which can be used for the construction of S-C bond. This intermediate
can be used to prepare sulfoxide in a complementary way to the classical Andersen method and
direct sulfoxidation method. There are a few methods to generate sulfenate anion in situ,
including the use of base, fluoride or heat (Scheme 8).19
Perrio and co-workers reported a phase
transfer alkylation of sulfonate using Cinchonidinium catalyst and it provided chiral sulfoxides
with moderate enantioselectivity.20
Using pentanidium 2c as catalyst, we investigated the
enantioselective benzylation of 2-thienyl sulfenate generated in situ from sulfinyl methyl esters
13a (Scheme 9).21
After optimization of reaction parameters, such as sulfenate anion precursors,
solvent, inorganic base and temperature, the enantioselectivities remained moderate. Several
pentanidiums with different steric or electronic patterns were prepared and it was found that
levels of enantioselectivities significantly increases with the introduction of halogen to the
pentanidiums (2h-2j). On the contrary, pentanidium 2k, containing OMe substituted side arms,
results in significant deterioration of enantioselectivity.
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12
Scheme 8. Methods for the in situ generation of sulfenate.
Scheme 9. Development of halogenated pentanidiums for sulfenate alkylation.
The generality of this reaction was systematically evaluated with a variety of sulfenate
precursor 13 and alkyl halides using halogenated pentanidiums 2i or 2j. By trapping 2-thienyl
sulfenate with various alkyl bromides, various sulfoxides 14a-i bearing benzyl, alkyl, allylic,
propargylic, 2-naphthylmethyl groups were produced in good enantioselectivities. When thienyl
or benzothienyl sulfenates were utilized, sulfoxides 14j-o were obtained in high yields and
excellent enantioselectivities (Scheme 10). It is noteworthy that the reaction between sulfenate
and m-xylene dibromide furnished bis-sulfoxide 14k in good yield (87%, dl/meso = 4.75:1) and
excellent enantioselectivity. Sulfenates functionalized with furyl, benzofuryl and benzimidazole
moieties were also smoothly converted to their corresponding heterocyclic sulfoxides 14p-s.
RS
O
EWGEWG+
a) Base-mediated retro-Michael elimination
EWG = SO2Ph, CN, COR', CO2R'
RS
O
TMS+
b) Fluoride-mediated retro-Michael elimination
RS
O
+
c) Heat-mediated elimination
RS
Obase
fluoride
heat
RS
O
RS
O
TMSF +
R =
2c X = H 2h X = Cl2i X = Br2j X = I2k X = OMe
X
tBu
tBu
N
N
N
R
Ph
PhN
N
R
Ph
Ph
2Pentanidium
R R
Cl
X ee (%)
6179889025substituent
variation
S
O
CO2Me67 wt% aq. CsOH
CPME, -60 oC
SS S
2c, 2h-2k (1.0 mol %)BnBr (1.2 equiv.)
13a 14a
O
-
13
Remarkably, benzimidazole sulfoxide 14s, reminiscence to the drug esomeprazole,22
was
obtained in excellent enantioselectivity.
Scheme 10. Halogenated pentanidium 2i or 2j-catalyzed alkylation of sulfenate anion.
Preliminary mechanistic studies on the retro-Michael/alkylation reaction found that the base-
promoted in situ generated sulfenate anion, could undergo sulfur alkylation, oxygen Michael
addition or alkaline hydrolysis, depending on reaction conditions (Figure 4a). When a less active
alkylating reagent, benzyl chloride, was used, only oxa-Michael adduct 15 was obtained even in
the presence of pentanidium 2c. On the contrary, sulfoxide 14a was produced through sulfur
alkylation using iodinated-pentanidium 2j. These experimental studies indicated that iodinated-
RS
O
CO2Me
2i or 2j (1.0 mol %), R'Br or R'I
saturated aq. CsOH, CPME/Et2O (1:3)
-70 oC or -40 oC
RS
R'
O
13 14
S
O
S SMe
O
S S
O
S S
O
S
S
O
S S
O
S S
O
S S
O
S
S
O
S
CF3
S
O
S S
O
S
Me
S
O
S S
O
S
S
O
O
Me
Cl
S
O
O
S
O
O
Cl
S
O
N
N
Me
Me
S
O
S S
O
SMe Me
Me
Me
S
O
S
Me
14a87% yield92% ee
14b65% yield77% ee
14c66% yield81% ee
14d69% yield81% ee
OMe
14e82% yield92% ee
14f77% yield82% ee
14g83% yield94% ee
14h84% yield90% ee
14l85% yield91% ee
14m93% yield95% ee
14n89% yield92% ee
14o83% yield95% ee
14p95% yield81% ee
14q73% yield81% ee
14s99% yield90% ee
Me
MeO
14r83% yield79% ee
14i84% yield92% ee
14j85% yield91% ee
14k87% yield99% ee
Me
-
14
pentanidium 2j activated and stabilized both the electrophilic alkylating reagents and the
sulfenate.
Figure 4. a) Diverse reaction pathways of sulfenate anion, b) optimized most R-TS and c)
proposed mechanistic model.
Computational studies were performed to obtain the most stable transition state (TS) structure
for the R- and S-sets of the TS at M06/BS1:UFF calculated with ONIOM method in
Gaussian09A2. It was found that the R-TS, which leads to the experimental product 14a with R
configuration, is more stable than the S-TS by 1.2 kcal mol-1
in terms of the Gibbs free energy
(Figure 4b). Theoretical study on stereoselectivity is consistent with experimental observations.
Further analysis of the non-covalent interactions between iodinated-pentanidium 2j and the
substrates revealed that Br-I halogen bonding23
between the leaving Br of benzyl bromide and
iodide on the iodinated-pentanidium 2j, plays a key role to stabilize the TS (Figure 4c).
S
O
S
sulfenate anion
BnCl or BnBr
2j
Alkaline hydrolysis
15
OCO2MeSS
base
2c
CO2MeBnCl,Oxa-Michael addition
Sulfur alkylation to 14a
SS
O
N
IX
d-d+
X= Br, Cl
Proposed Mechanistic Model
Pentanidium 2j
Halogen bond
c)
a) Diverse reaction pathways of sulfenate anion b) Optimized most stable (in terms of G) R-TS
-
15
2.5 Pentanidium-catalyzed alkylation of dihydrocoumarins
Scheme 11. a) Silylamide BSA as a probase, b) effect of halogenated pentanidiums and c)
identification of silyl ketene acetal 18 as an intermediate.
We found that halogenated pentanidiums 2h-j exhibited excellent stereocontrol in the
alkylation of dihydrocoumarins 16, using silylamide as the probase (Scheme 11).24
In this
strategy, a base with strong basicity but weak nucleophilicity would be generated in situ and
consumed immediately for the formation of an enolate (Scheme 11a).25
The potential
background and side reactions are thus suppressed when employing this transient strong base.
The approach will allow the utilization of base-sensitive substrates and reagents, consequently
expanding the scope of asymmetric phase transfer reactions. For instance, dihydrocoumarins
16a, which will undergo alkaline hydrolysis in the presence of alkali metal alkoxides or
R = 2c X = H 2h X = Cl2i X = Br2j X = I
X
tBu
tBu
N
N
N
R
Ph
PhN
N
R
Ph
Ph
2Pentanidium
R R
Cl
X ee (%)
40919793substituent
variation
O O
Ph
2c, 2h-2j (10 mol %)BnBr (2.0 equiv.)
CsF (4.0 equiv.)
BSA (5.0 equiv.)
THF, -40 oC, 24 hBn
Ph
OO
16a 17a
Si
SiN
O
Bis(trimethylsilyl)acetamide (BSA)
chiral cation catalyst
SiN
O
(CH3)3SiF
[chiral cation]
probase
strong basicity weak nucleophilicity
a)
b)
c)O O
Ph
2i (5.0 mol %), BnBrCsF (2.0 equiv.)
BSA (3.0 equiv.)
THF, -40 oC
83% yield, 95% eeBn
Ph
OO
16a 17a
O OTMS
Ph
LiHMDSTMSCl
THF, 0 oC
2i (5.0 mol %), BnBr
CsF (3.0 equiv.)
THF, -40 oC
55% yield, 91% ee
F
18
-
16
hydroxides, due to the labile lactone moiety, was smoothly converted to the alkylated product
17a in high yield and excellent enantioselectivity. Silyl ketene acetal 18 was identified as a key
intermediate via NMR analysis of the crude reaction mixture. This was further verified by the
direct benzylation of pre-prepared silyl ketene acetal 18 (Scheme 11c). This reaction is suitable
for lactones including dihydrocoumarins, 3,4-dihydro-2H-benzo[h]chromen-2-ones and 1,2-
dihydro-3H-benzo[f]chromen-3-ones (Scheme 12).
Scheme 12. Halogenated pentanidium 2i-catalyzed enantioselective alkylation of lactones.
3. BISGUANIDINIUM-CATALZYED ION PAIRING
ENANTIOSELECTIVE REACTIONS
In 2013, we found that bicyclic guanidinium salt 1·HI can operate under phase transfer
conditions for the alkylation of 3-substituted 2-oxoindoles (Scheme 13).26
Recently, we
+
O O
Bn
O O
Bn
O
R1
O O
R1
O
R2 R2
O O
Ph
16b-m 17b-m
85% yield, 90% ee
81% yield, 93% ee 78% yield, 94% ee
O O
Ph
84% yield, 90% ee
17c 17d
17f 17g
O O
Bn
85% yield, 87% ee
17b
O
OBn
80% yield, 93% ee
17k
Ph
O O O O
Bn Bn
75% yield, 95% ee 95% yield, 90% ee
17h 17i O O
Bn
85% yield, 96% ee
17jMeO
O OO
OEtBn
87% yield, 86% ee
17e
Br R3
O
O
Ph
Bn
89% yield, 95% ee
17lBr
THF, -40 oC
R3
O
O
Ph
Bn
80% yield, 96% ee
17m
MeO
2i (5.0 mol %)CsF (2.0 equiv.)BSA (3.0 equiv.)
Ph Ph
-
17
developed dicationic bisguanidinium 3, which was initially designed with the intention to work
with dianions or multiple anions. Bisguanidinium salts27
(BG) 3 features two guanidinium
moieties linked with various spacers (Scheme 14). For ease of synthesis, commercially available
cyclic secondary diamines such as piperazine were examined as spacers between the two chiral
imidazolinium salts. The dicationic bisguanidinium salts 3 were thus achieved in excellent yields
and are amenable to modification. We hope that the dicationic moiety will lead us to discover
new chemistries.
Scheme 13. Guanidinium 1HI-catalyzed phase-transfer alkylation reaction.
Scheme 14. General route to bisguanidinium salts 3 with piperazine as spacer.
In conventional cationic phase transfer catalysis, most reactions are Brønsted base reactions,
which the functional anion is usually either hydroxide or carbonate. Occasionally, other
functional anions such as cyanide (CN) and hypochlorite (ClO
) are used in phase transfer
Strecker or oxidation reactions respectively. An innovative example is the use of (hypo)iodite
NO
Me
Ph
7
Br CO2Me+
19
1.HI (10 mol %)
K2HPO4 (3.0 equiv.)
ZnI2 (0.5 equiv.)
mesitylene, 0 oC, 96 h
NO
Me
Ph CO2MeNH
N
NHI
93% yield94% ee
20a
Imidazolinium chloride
+MeCN reflux
Et3N
N
N
Cl
R2
Ph
Ph
R1
Cl
NN
N
N N
N
R1
R2
R1
R2
Ph
PhPh
Ph
3Bisguanidinium
ClCl
HN
NH
Spacer
(S,S)-3a R1, R2 = CH2Ar
(S,S)-3b R1, R2 = CH2Arp-F
(S,S)-3c R1, R2 = CH2Aro-F(S,S)-3d R1 = CH2Arp-F R2 = CH2Aro-F
tBu
tBu
tBu
tBu
tBu
tBu
F F
Ar Arp-F Aro-F
-
18
(IO), generated in situ from iodide, by Ishihara for the phase transfer oxidative
cycloetherification.28
However, these reactions are but a subset of a more general strategy of
chiral cationic ion pairing catalysis, which is defined as reactions using a catalyst compose of an
organic chiral cation and an inorganic anionic salt (Figure 5).29
In theory, all functional inorganic
anions are possible counterparts to the chiral cations including organometallic anions. This mode
of catalysis is complementary to the anion-directed catalysis using chiral phosphates.30
Motivated by the desire to exploit more cation-directed anionic inorganic reagents, we began to
systematically investigate metal-centered anions, beginning with metal oxides.
Figure 5. Chiral cationic ion pairing catalysis.
3.1 Bisguanidinium-catalyzed dihydroxylation and oxohydroxylation of -aryl acrylates
Permanganate (MnO4) oxidation of alkenes under phase transfer condition was first reported
using stoichiometric amount of a Cinchonidinium salt.31
Moderate enantioselectivities and low
yields were reported. The lack of catalytic activity of Cinchonidinium phase transfer catalyst is
ascribed to its decomposition under the oxidation conditions. In the early stage of our research,
ChiralCationicIonPairCatalysis
Inorganicbasesi.e.,hydroxide,carbonate
Otherinorganicsaltsi.e.,cyanide,iodide
Metalanionicspeciesi.e.,permanganate,tungstate,molybdate
RadicalGeneratingSalts
i.e.,CAN(futurework)
Organo-
catalysis
PhaseTransferCatalysis Organo-
metallicCatalysis
-
19
we conducted simple experiments to determine the stability of dicationic bisguanidiniums in the
presence of large excess KMnO4; we found that bisguanidiniums 3a-d (Scheme 14) were
compatible with the oxidation conditions and were recoverable after the reactions. With 2.0
mol% BG (S,S)-3d and 20 wt% aqueous potassium iodide (KI), the oxidation of the ,-
unsaturated ester 21a proceeded smoothly to afford diol 22a with excellent enantioselectivity.32
The yield is moderate as a side product 23a is formed due to C-C cleavage (Scheme 15).
Generally, substrates bearing electron-rich aryl groups results in higher enantioselectivities than
electron-deficient ones. We were surprised that thioether group is well tolerated in this
methodology. We also demonstrated that this methodology is highly selective for ,-
unsaturated esters over simple alkenes.
Scheme 15. Bisguanidinium 3d-catalyzed dihydroxylation of -aryl acrylates.
Trisubstituted enoates were also investigated for the permanganate-mediated alkene oxidation
(Scheme 16). With 2.0 mol% of BG (S,S)-3c, a mixture of Z,E-trisubstituted enoates 24a
provided two diastereoisomers, diols 25a and 25a’ in high enantioselectivities with a significant
Ar COOtBu
2.0 mol% (S,S)-3d
KMnO4 (1.5 equiv.)
20 wt% aq. KI
TBME, -60 oC or -70 oC
Ar COOtBu
OH
HO
Ar COOtBu
O
21a-k 22a-k 23a-k
+
Ph
Me
MeO
Me
Me
Et
O
O
MeS
22k60% yield92% ee
22a65% yield92% ee
22c72% yield85% ee
22e67% yield89% ee
22f64% yield90% ee
22j71% yield86% ee
22i63% yield86% ee
22h71% yield86% ee
MeO
22d65% yield96% ee
MeO
OMe
22j63% yield94% ee
Me 22b62% yield90% ee
-
20
amount of the cleavage product observed. In an attempt to improve the yield of the desired diols,
various additives were examined. When the pH of the reaction was lowered through the addition
of acetic acid, 2-hydroxy-3-oxocarboxylic ester 26a was unexpectedly obtained exclusively in
high yield and high enantioselectivity (Scheme 16). The observed high enantioselectivity
indicates that both Z- and E-trisubstituted enoates 24a were transformed to the same enantiomer
26a under these conditions. The reaction pathways to diols and C-C cleavage products were
efficiently suppressed and we named this transformation, oxohydroxylation. Substrates bearing
alkyl, thienyl, furyl, alkene moieties are well tolerated and a series of 2-hydroxy-3-oxocarboxylic
esters 26a-n with high levels of enantioselectivities were achieved. Enantioenriched -
hydroxymalonates 26o-p were prepared using methoxy-substituted enoates E-24o-p as starting
materials.
COOtBu
O
OMe
OH
COOtBu
O
OMe
OH
COOtBu
O
OMe
OH
COOtBu
O
OMe
OH
COOtBu
nC5H11 O
OMe
OH
COOtBu
O
OMe
OH
COOtBu
O
OMe
OHi-Pr
COOtBu
nC11H23 O
OMe
OH
COOtBu
O
OMe
OH
BnO
COOtBu
O
OMe
OH
COOtBu
MeO O
OH
COOtBu
MeO O
OMe
OH
COOtBu
O
OMe
OHMeO
COOtBu
O
OH
S
Ar COOtBu
2.0 mol% (S,S)-3c
KMnO4 (1.5 equiv.)
AcOH (3.5 equiv.)
TBME/H2O (20:1)
-60 oC
R
Ar COOtBu
OR
OH
2426
R = alkyl (Z, E mixtures)R = OMe (E isomer)
26a85% yield92% ee
26b92% yield93% ee
26c79% yield92% ee
26d75% yield92% ee
26e98% yield94% ee
26f93% yield91% ee
26g85% yield93% ee
26h88% yield94% ee
26i73% yield91% ee
26j77% yield91% ee
26k49% yield96% ee
26l77% yield84% ee
26o88% yield74% ee
26p87% yield97% ee
R = alkyl, OMe
COOtBu
O
OHO
O26n
81% yield94% ee
COOtBu
O
OH
O 26m47% yield87% ee
Ar COOtBu
OHR
OH
25Not detected
-
21
Scheme 16. Bisguanidinium 3c-catalyzed oxohydroxylation of trisubstituted enoates.
Scheme 17. a) Selectivity between TBA+MnO4
− and KMnO4, b) cyclic manganate diester 27 as
an intermediate and c) proposed ion pairing working model.
A control reaction was attempted using 1.5 equivalent of tetrabutylammonium permanganate,
an oxidant soluble in organic solvent (Scheme 17a). The reaction provided high level of chiral
induction, which led us to propose that rate acceleration through ion pairing rather than the phase
transfer step is crucial for asymmetric induction. Cyclic manganate diester 2733
is widely
recognized as the common intermediate in permanganate reaction and we proposed that it is
Ph COOtBu
(S,S)-3d (2.0 mol%) 1.5 equiv. oxidant
TBME/20 wt% aq. KI
-60 oC
Ph COOtBu
OH
HO
83% ee with TBA+MnO4-
92% ee with KMnO4
a)
R CHOAr COOtBu
OC-C Cleavage
ArO
MnO
COOtBu
O O
H
R
COOtBu
Ar
OH
HOCOOtBu
Ar
OH
R
OR
Dihydroxylation
H+
Oxohydroxylation
22 or 25 26
27
+
b)
21a
c)
MnO O
O O
Mn OO
O O-
COOtBu
Ar
R
Mn OO
O O-
Ar
COOtBu
R
MnO O
O O
Ar
-O
OtBuR COOtBu
Ar
R
OMn
O
O O-
BG2+
BG2+
accelerated pathway
MnO O
O O
ArO-
OtBu
R
BG2+
low energy TS I
high energy TS II
BG2+
COOtBu
Ar
R
OMn
O
O O-BG2+
KMnO4BG2+
phase transfer
Re
COOtBu
Ar
R
E, Z
Si
oxidationproducts
Ar
COOtBu
R
E, Z
22a
´
-
22
through this intermediate that different products are obtained, via diverse pathways (Scheme
17b). We found that the isolated diols 25 were not further oxidized to 26 under oxohydroxylation
conditions, indicating that the diols are not intermediates in oxohydroxylation.
The absolute configuration of the α-chiral center of oxidation products 26, derived from both
Z- and E-trisubstituted enoates 24, is identical. On the basis of Lee’s prior work34
and our
experimental results, a working model of reaction acceleration through the formation of an
intimate ion pair between bisguanidinium and enolate anion in the transition states was proposed
(Scheme 17c). The results reveal that rate acceleration is mainly attributed to transition state
stabilization through strong electrostatic interaction between dicationic BG and enolate anion.
The disclosure of this catalytic asymmetric permanganate oxidation opens up new paradigms for
chiral cation-directed catalysis. Exploration of other functional anions will undoubtedly lead to
the discovery of interesting new transformations for asymmetric synthesis.
3.2 Bisguanidinium diphosphatobisperoxotungstate-catalyzed sulfoxidation
Peroxotungstate species have been reported to serve as catalyst for oxidation reactions such as
epoxidation35
and sulfoxidation.36
Since peroxotungstate are anionic species, we hypothesized
that their reactions can be accelerated and modulated using chiral cations. We found that with 2.0
mol% of BG (S,S)-3a and 2.0 mol% of Ag2WO4, oxidation of heterocyclic sulfides 28a went
smoothly to produce sulfoxides 29a with excellent enantioselectivities (Scheme 18).37
Notably,
the amount of additive, NaH2PO4 or NH4H2PO4 is crucial to achieve high yield and high
stereoinduction. A series of enantioenriched sulfoxides 29a-q bearing benzimidazole,
benzothiazole, pyridine, thiophene moieties were obtained, which are of potential interest for
-
23
drug development. The practical utility was further illustrated in the preparation of proton-pump
inhibitor (S)-Lansoprazole 29l.
Scheme 18. Bisguanidinium diphosphatobisperoxotungstate-catalyzed sulfoxidation.
Experimentally, we found that a ratio of greater than 2 equivalent of dihydrogen phosphate
(H2PO4−) with respect to tungstate is essential for achieving high enantioselectivity. Raman
spectra of the active catalyst was obtained (Figure 6) and an experimentally peak observed at 711
cm-1
corresponds well to a peak at 713 cm-1
in the computed Raman spectra of
28 29
(S,S)-3a (2.0 mol%)
Ag2WO4 (2.0 mol% or 5.0 mol%)
NaH2PO4 or NH4H2PO4 (10 mol%)
35%wt H2O2 (1.05 equiv.)
solvent, 0 oC
N
N S
Me
29a96% yield92% ee
N
N S
MeCl
29c81% yield97% ee
N
N S
MeF
29d78%yield 89%ee
N
N S
MeNO2
29e74%yield88%ee
N
N S
Me
29f 95%yield
99%ee
N
N S
Me
29g 84%yield
92%ee
N
N S
Me
29h72%yield 95%ee
O
O
N
N S
Me
29i71%yield82%ee
N
N S CO2Et
Me
29j 92%yield 90%ee
N
N S CO2tBu
Me
29k 86%yield
80%ee
CN
ArS R
ArS R
N
S S
29m78%yield 93%ee
N
S S
29o85%yield92%ee
N
S S
29n70%yield 91%ee
S
29p76%yield 80%ee
S S
29q53%yield94%ee
N
O
N
HN S
29l81% yield 90% ee
N
O
CF3
S
29r79%yield90%ee
N
N S
Me
29b94% yield92% ee
C6F5
Me
O
OOO
O O O
OOO
O O O
OOO
O O
-
24
[{PO2(OH)2}2{WO(O2)2}]2-
. This peak is attributed to the twisting of P-O-H group in the
phosphate ligand. A more thorough analysis of the [{PO2(OH)2}2{WO(O2)2}]2-
revealed that an
intramolecular hydrogen bond interaction between the two phosphate ligands is important for
this peak; absence of such interaction will shift the vibrational frequency towards 800 cm-1
. We
thus proposed that the active anion is diphosphatobisperoxotungstate
[{PO2(OH)2}2{WO(O2)2}]2-
(Scheme 19a). Based on both computational and experimental
results, a simple working model is proposed detailing the formation of
diphosphatobisperoxotungstate and its transport from the aqueous to the organic phase (Scheme
19b).
Figure 6. Experimental Raman spectrum of [{PO2(OH)2}2{WO(O2)2}]2-
.
-
25
Scheme 19. a) Diphosphatobisperoxotungstate 30 and b) proposed working model.
3.3 Bisguanidinium dinuclear oxodiperoxomolybdosulfate-catalyzed sulfoxidation
Similar to peroxotungstates, peroxomolybdates38
are well-known catalysts for oxidation
reactions.39
However, they are typically complex mixtures and it is widely recognized as the
challenging obstacle for elaborating them into highly enantioselective catalyst. In the attempt to
prepare enantiopure sulfoxides of 2-sulfinyl esters through alkylation of sulfenate anions using
-halogenated carboxylate, an unsatisfactory outcome was observed. Thus, direct sulfoxidation
strategy was adopted to gain access to 2-sulfinyl ester sulfoxides 31a, which can be further
elaborated to a commercial drug armodafinil. We found that with 2.5 mol % Na2MoO4·2H2O and
potassium hydrogen sulfate (KHSO4), the oxidation proceeded efficiently with 1.0 mol% of BG
(S,S)-3a and H2O2 as oxidant (Scheme 20a).40
Its practical utility was successfully demonstrated
in the gram-scale synthesis of (R)-modafinil (armodafinil) using a 0.25 mol% loading of (R,R)-
3a (Scheme 20b).
BG2+
Ag2WO4
organic phase
water phase[{PO2(OH)2}2{WO(O2)2}]2-
BG2+2Cl-
W
OP(O)(OH)2
O
OP(O)(OH)2O
O
O O
2-Ar
S
R
ArS R
O
BG2+[{PO2(OH)2}2{WO(O2)2}]2-
W
OP(O)(OH)2
O
OP(O)(OH)2O
O
O
2-
H2O2
W
O
OO
O
O
(HO)2(O)PO
OP(O)(OH)2
30Diphosphatobisperoxotungstate
2-
[{PO2(OH)2}2{WO(O2)2}]2-
+ H2O2 + NaH2PO4 (aq.)
a) b)
-
26
Scheme 20. a) Catalytic molybdate-mediated sulfoxidation and b) preparative scale synthesis of
armodafinil.
The reactive catalytic species can be prepared by mimicking the reaction conditions in the
absence of sulfide substrate (Scheme 21). The active catalyst was collected as a pale-yellow
precipitate through filtration and the structure of the catalyst, (R,R)-3a-[Mo], was confirmed
using X-ray analysis (Figure 7)41 and 95Mo NMR.42 The achiral anionic molybdenum species
[(2-SO4){Mo2O2(2-O2)2(O2)2}]2-
is revealed by X-ray crystallography to be embedded within
the chiral cavity formed by two side arms of the chiral bisguanidinium dication.
Scheme 21. Identification of the active catalyst.
S CO2MePh
Ph
SPh
Ph
(R,R)-3a (0.25 mol%)Na2MoO4.2H2O (2.5 mol%)
ent-31a91% yield91% ee
35% aq. H2O2 (1.05 equiv.)
KHSO4 (0.5 equiv.)
nBu2O (0.05 M), rt, 8 h
30a5 mmol
MeOH (2 M)rt, 24 h
NH3(10.0 equiv.)
Armodafinil, 1.19 g95% yield, 91% ee
32
CO2Me
O
SPh
Ph
O
NH2
Ob)
S CO2MePh
Ph
SPh
Ph
(S,S)-3a (0.25 mol%)Na2MoO4.2H2O (2.5 mol%)
31a99% yield94% ee
35% aq. H2O2 (1.05 equiv.)
KHSO4 (0.5 equiv.)
iPr2O (0.05 M), 0 oC, 1 h
30a0.2 mmol
CO2Me
Oa)
(R,R)-3a
BG2+[2Cl]2-
(1.0 mol%)
0.04 mmol
(R,R)-3a-[Mo]
BG2+[(m2-SO4){Mo2O2(m2-O2)2(O2)2}]2-
91% yield
Na2MoO4·2H2O (2.5 mol%), 35% aq. H2O2 (1.0 equiv.)
KHSO4 (0.5 equiv.) or H2SO4 (0.25 equiv.)Et2O (2 mL), rt, 2 h
-
27
Figure 7. X-Ray crystallographic structure of [BG]2+
[(2-SO4){Mo2O2(2-O2)2(O2)2}]2-
(R,R)-
3a-[Mo](ellipsoids at 50% probability)
The catalyst (R,R)-3a-[Mo] displayed excellent catalytic activity in sulfoxidation with H2O2 as
oxidant (Scheme 22). (R,R)-3a-[Mo] was used directly as a stoichiometric oxidant and it
provided sulfoxide ent-31a in 90% yield and 80% ee. This result confirm that (R,R)-3a-[Mo] is
the actual oxidant and high level of enantiodiscrimination can be achieved. However, using just
0.25 equivalent of (R,R)-3a-[Mo] led to the formation of ent-31a in 50% yield with 31% ee;
demonstrating that two out of four peroxo moieties on (R,R)-3a-[Mo] are active oxygen donors
as two equivalents of active oxygen from (R,R)-3a-[Mo] are transferred to the sulfides. On the
basis of the experimental results, a possible mechanistic model was proposed (Scheme 23).43
It is
proposed that the second oxygen transfer is slower and less enantioselective than the first. In the
presence of H2O2, the dimeric structure of the catalyst will be maintained and it is this structure
that provides the highly effective enantiofacial discrimination.
NN
N
N N
N
R1
R2
R1
R2
Ph
PhPh
Ph
OS
O
O O
Mo
OO
Mo
O
O
O
OO
OO
O
[(m2-SO4){Mo2O2(m2-O2)2(O2)2}]2-
(R,R)-3a-[Mo]
2-
[Mo]2-
[Mo]2- =
S CO2MePh
Ph
SPh
Ph
(R,R)-3a-[Mo] (x equiv.)
35% aq. H2O2 (y equiv.)
ent-31aiPr2O, rt, 8 h30a
CO2Me
O
x = 0.01, y = 1.05 x = 1.0, y = 0 x = 0.25, y = 0
yield 95%, ee 91%yield 90%, ee 80%yield 50%, ee 31%
-
28
Scheme 22. Mechanistic studies by using [BG]2+
[(-SO4)Mo2O2(-O2)2(O2)2]2(R,R)-3a-[Mo].
Scheme 23. Proposed catalytic cycle of bisguanidinium dinuclear oxodiperoxomolybdosulfate.
3.4 Bisguanidinium-catalyzed alkylation of cyclic ketones
Previously, we used the silylamide probase strategy with pentanidium as catalyst, to achieve
the highly enantioselective alkylation of lactones24
. For cyclic and linear ketones, we found that
bisguanidiniums are more suitable. The probase can act as a silylation reagent to generate silyl
enol ether, which is a key intermediate for the alkylation. With 10 mol% of BG (S,S)-3a and 2
equivalent of probase, bis(tert-butyldimethylsilyl)acetamide (BTBSA), a variety of -benzyl-1-
indanones and -benzyl-tetralones 32a-i can be smoothly converted to alkylation product 33a-i
in high yields and enantioselectivities (Scheme 24a).24
TBS enol ether 34 was prepared from -
benzyl-1-indanone 32a and submitted to the alkylation condition (Scheme 24b). The
enantioselectivity and yield obtained were similar to the conditions using probase directly,
demonstrating that TBS enol ether is an intermediate in the reaction. For the alkylation of linear
BG2+
BG2+
H2O2
sulfide
sulfoxide
BG2+
sulfidesulfoxide
first oxygen transfer ishighly enantioselective
second oxygen is less enantioselective
[O]
[O]
(R,R)-3a-[Mo]
formation of B was inhibited in the presence of
excess H2O2
OS
O
O O
Mo
OO
Mo
O
O
O
OO
OO
O
2-
OS
O
O O
Mo
OO
Mo
O
OO
OO
O
2-
O
OS
O
O O
Mo
OO
Mo
O
OO
O
2-
O
O
BA
-
29
ketones, such as simple phenyl ethyl ketone, due to their low reactivity, the corresponding
alkylation reaction can only be achieved via the preparation of their silyl enol ethers.
Scheme 24. a) Bisguanidinium 3a-catalyzed enantioselective alkylation of cyclic ketones using
probase strategy and b) identification of silyl enol ether as an intermediate.
CsF (5.0 equiv.)
Et2O, -40 oC
O(S,S)-3a (10 mol%)BTBSA (2.0 equiv.)
32a-n 33b-un
n = 1,2
O
Ph
98% yield, 95% ee
33a
O
Ph
99% yield, 89% ee
33b
S
O
Ph
95% yield, 85% ee
33c
O
O
98% yield, 91% ee
33d
BrO
95% yield, 95% ee
33e
S
O
99% yield, 90% ee
33f
CF3
OMe
O
O
Ph
F
99% yield, 92% ee
33i
O
CF3
75% yield, 90% ee
33j
O
87% yield, 92% ee
33k
S
O
O
CF3
87% yield, 77% ee
33lOMe
Br R3
O
Ph
90% yield, 98% ee
33g
F3C
O
Ph
96% yield, 92% ee
33hCl
R2
n = 1,2
R1
OTBS
NTBS
(BTBSA)
O
n
R1R3
b)
a)
O
Ph
PhBrO
Ph
Bn
32a 33a
(S,S)-3a (10 mol%)
CsF(5.0 equiv.)
Et2O, -40 oC
(S,S)-3a (10 mol%)BTBSA (2.0 equiv.)
CsF( 5.0 equiv.)
Et2O, -40 oC yield 98%, ee 95%
PhBrKHMDSTBSCl
34 84% yield, 94% eeTHF, -78 oC
OTBS
Ph
R2
-
30
Scheme 25. Proposed working model with BG hypervalent silicates ion pair.
Based on the experimental results, a working model for enantioselective alkylation using
silylamide as probase is putatively proposed (Scheme 25). When the probase is activated with
fluoride, BG silylamide is first formed followed by BG enolate A. Silyl enol ether B is
subsequently formed via silylation with another silylamide. We found that the steric features of
the probase affects strongly the enantioselectivities and bis(tert-butyldimethylsilyl)acetamide
(BTBSA) afforded better results than bis(trimethylsilyl)acetamide (BSA). A BG hypervalent
silicates ion pair C is proposed to be the key intermediate, which is responsible for the
enantiofacial differentiation of the incoming electrophiles.
4. CONCLUSION AND PERSPECTIVES
Over the past few years, we have developed N-sp2 hybridized guanidinium-type salts as
efficient phase transfer catalysts. We have shown that these are general catalysts for a variety of
transformations and reactions can be performed at a preparative scale with low loading of
catalyst. In some cases, commercially important compounds are prepared as a demonstration of
Br R3
BG2+[2Cl]2-
probase
N
O
Si
Si
N
O
Si
BG2+
O
Bn
CsF
O
Bn
-BG2+
O
Bn
Si
BG2+[2Cl]2-
CsF
C
O
Bn
Si
F
L
LL
F
BG2+O
Bn
N
O
Si
BG2+
chiral organic base
chiral organic base
A
B
R3
32a
33a
2-
-
31
industrial applicability. We have also articulated a new mode of catalysis at the interface of
phase transfer catalysis, organocatalysis and organometallic catalysis. We describe the possibility
of activating and modulating organometallic catalysts through ionic interactions and not through
the use of ligands. Chiral cationic ion pairing catalysis is in its infancy and we hope that more
colleagues will find this approach refreshing and join us in exploring and defining its scope.
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]
Notes
The authors declare no competing financial interest.
Biographical Information
Lili Zong was born in Henan (China) in 1985. She received her B.S. in engineering from Harbin
Institute of Technology (China) in 2006. She studied organic chemistry under the supervision of
Professor Yixiang Cheng during her M.Sc. in Nanjing University (China). In 2010, she started
her graduate studies at National University of Singapore under the tutelage of Professor Choon-
Hong Tan. She is currently a postdoctoral fellow in the laboratory of Professor Stefan Matile at
University of Geneva.
Choon-Hong Tan was born in Singapore in 1971. He received his BSc(Hons) First Class from
the National University of Singapore in 1995. He obtained financial support from Trinity College
(Cambridge), the Cambridge Commonwealth Trust and Tan Kah Kee Postgraduate Scholarship
to pursue his PhD and he graduated from the University of Cambridge in 1999. Following that,
he carried out postdoctoral training at Harvard University. He was a Research Associate at
Harvard Medical School before joining the National University of Singapore in 2003 to start his
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32
independent career. He joined Nanyang Technological University (Singapore) in 2012 and was
promoted to Full Professor in 2016.
ACKNOWLEDGMENT
We are grateful to the technical and intellectual contributions of our co-workers whose names are
listed in the relevant references. Financial support for the research was provided by National
University of Singapore and Nanyang Technological University (Singapore).
REFERENCES
(1) Riordan, J. F. Arginyl residues and anion binding sites in proteins. Mol. Cell. Biochem.
1979, 26, 71-92.
(2) (a) Müller, G.; Riede, J.; Schmidtchen, F. P. Host-Guest Bonding of Oxoanions to
Guanidinium Anchor Groups. Angew. Chem., Int. Ed. 1988, 27, 1516-1518. (b) Berger, M.;
Schmidtchen, F. P. Zwitterionic Guanidinium Compounds Serve as Electroneutral Anion Hosts.
J. Am. Chem. Soc. 1999, 121, 9986-9993.
(3) Chinchilla, R.; Nájera, C.; Sánchez-Agulló, P. Enantiomerically pure guanidine-catalysed
asymmetric nitroaldol reaction. Tetrahedron: Asymmetry 1994, 5, 1393-1402.
(4) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. Asymmetric Catalysis of the
Strecker Amino Acid Synthesis by a Cyclic Dipeptide. J. Am. Chem. Soc. 1996, 118, 4910-4911.
(5) Corey, E. J.; Grogan, M. J. Enantioselective Synthesis of α-Amino Nitriles from N-
Benzhydryl Imines and HCN with a Chiral Bicyclic Guanidine as Catalyst. Org. Lett. 1999, 1,
157-160.
(6) (a) Terada, M.; Nakano, M.; Ube, H. Axially Chiral Guanidine as Highly Active and
Enantioselective Catalyst for Electrophilic Amination of Unsymmetrically Substituted 1,3-
Dicarbonyl Compounds. J. Am. Chem. Soc. 2006, 128, 16044-16045. (b) Shen, J.; Nguyen, T. T.;
Goh, Y. P.; Ye, W. P.; Fu, X.; Xu, J. Y.; Tan, C.-H. Chiral bicyclic guanidine-catalyzed
enantioselective reactions of anthrones. J. Am. Chem. Soc. 2006, 128, 13692-13693. (c) Fu, X.;
Jiang, Z.; Tan, C.-H. Bicyclic guanidine-catalyzed enantioselective phospha-Michael reaction:
synthesis of chiral beta-aminophosphine oxides and beta-aminophosphines. Chem. Commun.
2007, 5058-5060. (d) Ye, W. P.; Jiang, Z. Y.; Zhao, Y. J.; Goh, S. L. M.; Leow, D.; Soh, Y. T.;
Tan, C.-H. Chiral bicyclic guanidine as a versatile Bronsted base catalyst for the enantioselective
Michael reaction of dithomalonates and beta-keto thioesters. Adv. Synth. Catal. 2007, 349, 2454-
2458. (e) Leow, D. S.; Lin, S. S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Enantioselective
protonation catalyzed by a chiral bicyclic guanidine derivative. Angew. Chem., Int. Ed. 2008, 47,
5641-5645. (f) Jiang, Z. Y.; Pan, Y. H.; Zhao, Y. J.; Ma, T.; Lee, R.; Yang, Y. Y.; Huang, K. W.;
Wong, M. W.; Tan, C.-H. Synthesis of a Chiral Quaternary Carbon Center Bearing a Fluorine
Atom: Enantio- and Diastereoselective Guanidine-Catalyzed Addition of Fluorocarbon
Nucleophiles. Angew. Chem., Int. Ed. 2009, 48, 3627-3631. (g) Liu, H. J.; Leow, D.; Huang, K.
W.; Tan, C.-H. Enantioselective Synthesis of Chiral Allenoates by Guanidine-Catalyzed
Isomerization of 3-Alkynoates. J. Am. Chem. Soc. 2009, 131, 7212-7213. (h) Wang, J. M.; Chen,
-
33
J.; Kee, C. W.; Tan, C.-H. Enantiodivergent and gamma-Selective Asymmetric Allylic
Amination. Angew. Chem., Int. Ed. 2012, 51, 2382-2386.
(7) (a) Leow, D.; Tan, C.-H. Chiral Guanidine Catalyzed Enantioselective Reactions. Chem.
Asian J. 2009, 4, 488-507. (d) Leow, D.; Tan, C.-H. Catalytic Reactions of Chiral Guanidines
and Guanidinium Salts. Synlett 2010, 1589-1605. (e) Wang, C.; Goh, C. M. T.; Xiao, S. H.; Ye,
W. P.; Tan, C.-H. Enantioselective Protonation Catalyzed by Chiral Bronsted Bases. J. Synth.
Org. Chem. Jpn. 2013, 71, 1145-1151.
(8) (a) Shirakawa, S.; Maruoka, K. Recent Developments in Asymmetric Phase-Transfer
Reactions. Angew. Chem., Int. Ed. 2013, 52, 4312-4348. (b) Kaneko, S.; Kumatabara, Y.;
Shirakawa, S. A new generation of chiral phase-transfer catalysts. Org. Biomol. Chem. 2016, 14,
5367-5376. (c) Albanese, D. C. M.; Foschi, F.; Penso, M. Sustainable Oxidations under Phase-
Transfer Catalysis Conditions. Org. Process Res. Dev. 2016, 20, 129-139.
(9) Ma, T.; Fu, X. A.; Kee, C. W.; Zong, L. L.; Pan, Y. H.; Huang, K. W.; Tan, C.-H.
Pentanidium-Catalyzed Enantioselective Phase-Transfer Conjugate Addition Reactions. J. Am.
Chem. Soc. 2011, 133, 2828-2831.
(10) Fonseca, G. O.; Cook, J. M. Modern Methods for Total Synthesis of Important Oxindole
Alkaloids. Org. Chem. Insights 2016, 6, 1-55.
(11) Peddibhotla, S. 3-Substituted-3-hydroxy-2-oxindole, an Emerging New Scaffold for Drug
Discovery with Potential Anti-Cancer and other Biological Activities. Curr. Bioact. Compd.
2009, 5, 20-38.
(12) Sano, D.; Nagata, K.; Itoh, T. Catalytic Asymmetric Hydroxylation of Oxindoles by
Molecular Oxygen Using a Phase-Transfer Catalyst. Org. Lett. 2008, 10, 1593-1595.
(13) Yang, Y.; Moinodeen, F.; Chin, W.; Ma, T.; Jiang, Z.; Tan, C.-H. Pentanidium–Catalyzed
Enantioselective α-Hydroxylation of Oxindoles Using Molecular Oxygen. Org. Lett. 2012, 14,
4762-4765.
(14) Li, H.; Song, J.; Liu, X.; Deng, L. Catalytic Enantioselective C−C Bond Forming
Conjugate Additions with Vinyl Sulfones. J. Am. Chem. Soc. 2005, 127, 8948-8949.
(15) (a) Ohmatsu, K.; Kiyokawa, M.; Ooi, T. Chiral 1,2,3-Triazoliums as New Cationic
Organic Catalysts with Anion-Recognition Ability: Application to Asymmetric Alkylation of
Oxindoles. J. Am. Chem. Soc. 2011, 133, 1307-1309. (b) Zhu, Q.; Lu, Y. Stereocontrolled
Creation of All-Carbon Quaternary Stereocenters by Organocatalytic Conjugate Addition of
Oxindoles to Vinyl Sulfone. Angew. Chem., Int. Ed. 2010, 49, 7753-7756.
(16) Zong, L.; Du, S.; Chin, K. F.; Wang, C.; Tan, C.-H. Enantioselective Synthesis of
Quaternary Carbon Stereocenters: Addition of 3-Substituted Oxindoles to Vinyl Sulfone
Catalyzed by Pentanidiums. Angew. Chem., Int. Ed. 2015, 54, 9390-9393.
(17) Pallavicini, M.; Valoti, E.; Villa, L.; Resta, I. New asymmetric synthesis of (−)-
esermethole. Tetrahedron: Asymmetry 1994, 5, 363-370.
(18) (a) O'Donnell, J. S.; Schwan, A. L. Generation, structure and reactions of sulfenic acid
anions. J. Sulfur Chem. 2004, 25, 183-211. (b) Schwan, A. L.; Söderman, S. C. Discoveries in
Sulfenic Acid Anion Chemistry. Phosphorus, Sulfur Silicon Relat. Elem. 2013, 188, 275-286.
(19) (a) Caupène, C.; Boudou, C.; Perrio, S.; Metzner, P. Remarkably Mild and Simple
Preparation of Sulfenate Anions from β-Sulfinylesters: A New Route to Enantioenriched
Sulfoxides. J. Org. Chem. 2005, 70, 2812-2815. (b) Maitro, G.; Vogel, S.; Sadaoui, M.; Prestat,
G.; Madec, D.; Poli, G. Enantioselective Synthesis of Aryl Sulfoxides via Palladium-Catalyzed
Arylation of Sulfenate Anions. Org. Lett. 2007, 9, 5493-5496. (c) Foucoin, F.; Caupène, C.;
-
34
Lohier, J.-F.; Sopkova de Oliveira Santos, J.; Perrio, S.; Metzner, P. 2-(Trimethylsilyl)ethyl
Sulfoxides as a Convenient Source of Sulfenate Anions. Synthesis 2007, 2007, 1315-1324.
(20) Gelat, F.; Jayashankaran, J.; Lohier, J.-F.; Gaumont, A.-C.; Perrio, S. Organocatalytic
Asymmetric Synthesis of Sulfoxides from Sulfenic Acid Anions Mediated by a Cinchona-
Derived Phase-Transfer Reagent. Org. Lett. 2011, 13, 3170-3173.
(21) Zong, L.; Ban, X.; Kee, C. W.; Tan, C.-H. Catalytic Enantioselective Alkylation of
Sulfenate Anions to Chiral Heterocyclic Sulfoxides Using Halogenated Pentanidium Salts.
Angew. Chem., Int. Ed. 2014, 53, 11849-11853.
(22) Cotton, H.; Elebring, T.; Larsson, M.; Li, L.; Sörensen, H.; von Unge, S. Asymmetric
synthesis of esomeprazole. Tetrahedron: Asymmetry 2000, 11, 3819-3825.
(23) Gilday, L. C.; Lang, T.; Caballero, A.; Costa, P. J.; Félix, V.; Beer, P. D. Angew. Chem.,
Int. Ed. 2013, 52, 4356-4360.
(24) Teng, B.; Chen, W.; Dong, S.; Kee, C. W.; Gandamana, D. A.; Zong, L.; Tan, C.-H.
Pentanidium- and Bisguanidinium-Catalyzed Enantioselective Alkylations Using Silylamide as
Brønsted Probase. J. Am. Chem. Soc. 2016, 138, 9935-9940.
(25) Inamoto, K.; Okawa, H.; Taneda, H.; Sato, M.; Hirono, Y.; Yonemoto, M.; Kikkawa, S.;
Kondo, Y. Organocatalytic deprotonative functionalization of C(sp2)-H and C(sp
3)-H bonds
using in situ generated onium amide bases. Chem. Commun. 2012, 48, 9771-9773.
(26) Chen, W.; Yang, W.; Yan, L.; Tan, C.-H.; Jiang, Z. Bicyclic guanidinium-catalyzed
enantioselective phase-transfer alkylation: direct access to pyrroloindolines and furoindolines.
Chem. Commun. 2013, 49, 9854-9856.
(27) Fu, X.; Loh, W. T.; Zhang, Y.; Chen, T.; Ma, T.; Liu, H. J.; Wang, J. M.; Tan, C.-H.
Chiral Guanidinium Salt Catalyzed Enantioselective Phospha-Mannich Reactions. Angew.
Chem., Int. Ed. 2009, 48, 7387-7390.
(28) Uyanik, M.; Okamoto, H.; Yasui, T.; Ishihara, K. Quaternary Ammonium (Hypo)iodite
Catalysis for Enantioselective Oxidative Cycloetherification. Science 2010, 328, 1376-1379.
(29) Brak, K.; Jacobsen, E. N. Asymmetric Ion-Pairing Catalysis. Angew. Chem., Int. Ed.
2013, 52, 534-561.
(30) (a) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. A Powerful Chiral Counterion
Strategy for Asymmetric Transition Metal Catalysis. Science 2007, 317, 496-499. (b) Phipps, R.
J.; Hamilton, G. L.; Toste, F. D. The progression of chiral anions from concepts to applications
in asymmetric catalysis. Nat. Chem. 2012, 4, 603-614. (c) Mahlau, M.; List, B. Asymmetric
Counteranion-Directed Catalysis: Concept, Definition, and Applications. Angew. Chem., Int. Ed.
2013, 52, 518-533.
(31) Bhunnoo, R. A.; Hu, Y.; Lainé, D. I.; Brown, R. C. D. An Asymmetric Phase-Transfer
Dihydroxylation Reaction. Angew. Chem., Int. Ed. 2002, 41, 3479-3480.
(32) Wang, C.; Zong, L.; Tan, C.-H. Enantioselective Oxidation of Alkenes with Potassium
Permanganate Catalyzed by Chiral Dicationic Bisguanidinium. J. Am. Chem. Soc. 2015, 137,
10677-10682.
(33) (a) Fatiadi, A. J. The Classical Permanganate Ion: Still a Novel Oxidant in Organic
Chemistry. Synthesis 1987, 1987, 85-127. (b) Dash, S.; Patel, S.; Mishra, B. K. Oxidation by
permanganate: synthetic and mechanistic aspects. Tetrahedron 2009, 65, 707-739.
(34) Lee, D. G.; Brown, K. C. Oxidation of hydrocarbons. 11. Kinetics and mechanism of the
reaction between methyl (E)-cinnamate and quaternary ammonium permanganates. J. Am. Chem.
Soc. 1982, 104, 5076-5081.
-
35
(35) Sato, K.; Aoki, M.; Ogawa, M.; Hashimoto, T.; Noyori, R. A Practical Method for
Epoxidation of Terminal Olefins with 30% Hydrogen Peroxide under Halide-Free Conditions. J.
Org. Chem. 1996, 61, 8310-8311.
(36) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori, R. Oxidation of sulfides to
sulfoxides and sulfones with 30% hydrogen peroxide under organic solvent- and halogen-free
conditions. Tetrahedron 2001, 57, 2469-2476.
(37) Ye, X.; Moeljadi, A. M. P.; Chin, K. F.; Hirao, H.; Zong, L.; Tan, C.-H. Enantioselective
Sulfoxidation Catalyzed by a Bisguanidinium Diphosphatobisperoxotungstate Ion Pair. Angew.
Chem., Int. Ed. 2016, 55, 7101-7105.
(38) Dickman, M. H.; Pope, M. T. Peroxo and Superoxo Complexes of Chromium,
Molybdenum, and Tungsten. Chem. Rev. 1994, 94, 569-584.
(39) (a) Shi, X.; Wei, J. Preparation, characterization and catalytic oxidation properties of bis-
quaternary ammonium peroxotungstates and peroxomolybdates complexes. Appl. Organomet.
Chem. 2007, 21, 172-176. (b) Chakravarthy, R. D.; Ramkumar, V.; Chand, D. K. A molybdenum
based metallomicellar catalyst for controlled and selective sulfoxidation reactions in aqueous
medium. Green Chem. 2014, 16, 2190-2196.
(40) Zong, L.; Wang, C.; Moeljadi, A. M. P.; Ye, X.; Hirao, H.; Tan, C.-H. Bisguanidinium
dinuclear oxodiperoxomolybdosulfate ion pair-catalyzed enantioselective sulfoxidation. Nat.
Commun. 2016, 7, 13455.
(41) Salles, L.; Robert, F.; Semmer, V.; Jeannin, Y.; Bregeault, J. M. Novel di- and trinuclear
oxoperoxosulfato species in molybdenum(VI) and tungsten(VI) chemistry: The key role of pairs
of bridging peroxo groups. Bull. Soc. Chim. Fr. 1996, 133, 319-328.
(42) Nardello, V.; Marko, J.; Vermeersch, G.; Aubry, J. M. 90
Mo NMR and kinetic studies of
peroxomolybdic intermediates involved in the catalytic disproportionation of hydrogen peroxide
by molybdate ions. Inorg. Chem. 1995, 34, 4950-4957.
(43) Thompson, D. J.; Cao, Z.; Judkins, E. C.; Fanwick, P. E.; Ren, T. Peroxo-dimolybdate
catalyst for the oxygenation of organic sulfides by hydrogen peroxide. Inorg. Chim. Acta 2015,
437, 103-109.