Bio-inspired Water-Driven Catalytic Enantioselective Protonation

Article abstract of DOI:10.1021/jacs.0c11815

Catalytic enantioselective protonation of a prochiral carbanion in water is a common transformation in biological systems, but has been beyond the capability of synthetic chemists since unusually rapid movement of a proton in water leads to uncontrolled racemic protonation. Herein we show a crucial role of water, which enables a highly enantioselective glyoxalase I-mimic catalytic isomerization of hemithioacetals which proceeds via enantioselective protonation of an ene-diol intermediate. The use of on-water condition turns on this otherwise extremely unreactive catalytic reaction as a result of the strengthened hydrogen bonds of water molecules near the hydrophobic reaction mixture. Furthermore, under on-water conditions, especially under biphasic microfluidic on-water conditions, access of bulk water into the enantio-determining transition state is efficiently blocked, consequently enabling the enantioselective introduction of a highly ungovernable proton to a transient enediol intermediate, which mimics the action of enzymes.

Full text of DOI:10.1021/jacs.0c11815

pubs.acs.org/JACS
Article
Bio-inspired Water-Driven Catalytic Enantioselective Protonation
Si Joon Park,† In-Soo Hwang,† Young Jun Chang,† and Choong Eui Song*
Cite This: J. Am. Chem. Soc. 2021, 143, 2552−2557
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Catalytic enantioselective protonation of a prochiral
carbanion in water is a common transformation in biological
systems, but has been beyond the capability of synthetic chemists
since unusually rapid movement of a proton in water leads to
uncontrolled racemic protonation. Herein we show a crucial role of
water, which enables a highly enantioselective glyoxalase I-mimic
catalytic isomerization of hemithioacetals which proceeds via
enantioselective protonation of an ene-diol intermediate. The use
of on-water condition turns on this otherwise extremely unreactive
catalytic reaction as a result of the strengthened hydrogen bonds of
water molecules near the hydrophobic reaction mixture.
Furthermore, under on-water conditions, especially under biphasic
microfluidic on-water conditions, access of bulk water into the enantio-determining transition state is efficiently blocked,
consequently enabling the enantioselective introduction of a highly ungovernable proton to a transient enediol intermediate, which
mimics the action of enzymes.
enantioselectivity for a broad range of substrates. However,
as noted, enantioselective introduction of a highly ungovern-
able proton to transient enediol intermediates in an aqueous
environment remains extremely challenging. We were inter-
ested therefore in addressing this challenge by developing a
biomimetic glyoxalase I-like system with which highly
enantioselective catalysis could be achieved in water.
In biological transformation processes, water plays several
roles, acting as a solvent, as a reactant molecule, or as a
reaction regulator (or reaction enforcer).7 Therefore, under-
standing the role of water is of fundamental importance for
designing catalytic reaction systems to mimic the action of
enzymes in nature as well as to achieve high reaction rates and
(stereo)selectivities. Thus, in recent years, mimicking water-
mediated enzymatic reactions has been the focus in the
chemistry community.8 In particular, “on-water”9 catalysis has
recently received considerable attention due to its effective-
ness.10 On-water catalysis enables enforced hydrophobic
interactions between catalysts and substrates as a result of
hydrophobic hydration effects,11 consequently increasing
reaction rates. According to recent spectroscopic and
theoretical studies, the origin of the hydrophobic hydration
effect is the strengthened H-bond network of water molecules
INTRODUCTION
■
Catalytic enantioselective protonation of a prochiral carbanion
such as an enolate derivative1 in water is a common
transformation in biological systems to generate molecules
with single handedness,1a,2 but its application in synthetic
chemistry has been a formidable challenge. The abnormally
high mobility of the proton in water,3 along with its relative
lightness and small size,4 renders enantioselective protonation
in water extremely difficult as unusually fast proton diffusion in
water, which occurs by stepwise hopping of a proton to a water
molecule within a time frame of roughly 1−2 ps (i.e., by the so-
called Grotthuss mechanism3), leads to uncontrolled racemic
protonation. Therefore, governing the movement of protons
within a catalytically active site in an enantioselective manner is
extremely challenging.5 To prevent the racemic protonation
pathway and thus to achieve successful enantioselective
protonation in water, it is essential to block the access of
bulk water into catalytic sites, as is done by enzymes.
Among enzymes capable of catalyzing enantioselective
protonations (e.g., decarboxylase,2a esterase,2a triose phosphate
isomerase,2b,c glyoxalase,2d−f etc.), glyoxalase I in particular
plays a critical role in the enzymatic defense against glycation
by catalyzing the enantioselective isomerization of hemi-
thioacetals, which form spontaneously between highly toxic
α-keto aldehydes (e.g., methylglyoxal) and glutathione (GSH),
to (S)-α-hydroxyacylglutathione derivatives.2d−f Inspired by
the mechanism employed by natural glyoxalase I, we recently
developed a highly efficient artificial enzyme model that
mimics natural glyoxalase I.6 In anhydrous organic solvents,
this biomimetic glyoxalase I system showed exceptional
Received: November 10, 2020
Published: January 13, 2021
https://dx.doi.org/10.1021/jacs.0c11815
J. Am. Chem. Soc. 2021, 143, 2552−2557
© 2021 American Chemical Society
2552

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
near hydrophobic solutes.12 Our recent studies have shown
that the “hydrophobic amplification”13 achieved under on-
water conditions even enabled discovery of new catalytic
reactions of otherwise completely unreactive substrates.14
Furthermore, and more interestingly, we also demonstrated
that water can function as a chirality amplifier in asymmetric
catalytic reactions.15 However, the positive effect of water on
enantioselectivity is not a general rule. Rather, in many cases,
the introduction of water as a reaction medium in asymmetric
catalysis negatively influences enantioselectivity, because of its
capacity for disrupting hydrogen bonds at catalytic sites.
Here we report that, despite the abnormally high mobility of
the proton in water, water can be an exceptionally efficient
reaction medium for catalytic enantioselective protonation
reaction. By employing “on-water” conditions, highly enantio-
selective organocatalytic glyoxalase I-mimicking isomerization
of spontaneously formed hemithioacetal adducts between
diverse α-oxoaldehydes and thiols has been achieved, affording
enantioenriched α-hydroxy thioesters. The same reactions are
almost impossible to conduct in organic solvents. Furthermore,
we also demonstrated that the on-water approach, especially
when employing a biphasic microfluidic approach, can be an
efficient tool to limit access of bulk water into transition states,
enabling successful enantioselective control of proton transfer.
Scheme 1. Glyoxalase I-Mimicking Reaction Design and
Initial Findings
a
RESULT AND DISCUSSION
■
Bio-inspired Reaction Design and Initial Findings.
The glyoxalase I catalyzed isomerization of hemithioacetals
proceeds via (i) activation of the hemithioacetals by metallic
Lewis acids (Zn or Ni), (ii) deprotonation of the α-proton by
the basic catalytic site to form an enediol intermediate, and
(iii) its enantioselective reprotonation, affording enantiopure
α-hydroxyacylglutathiones.2d−f We speculated that bifunctional
thiourea organocatalysts would mimic this enzymatic process.
The hydrogen-bond-chelating interaction between the acidic
thiourea of the organocatalyst and two oxygen atoms of the
hemithioacetals can enhance the electrophilicity of the
carbonyl carbon atom of hemithioacetals, consequently
increasing the acidity of the α-proton. The basic amine moiety
can further deprotonate the acidic α-proton of the hemi-
thioacetals, producing enediol intermediates which can then be
enantioselectively reprotonated, producing enantioenriched α-
hydroxy esters (Scheme 1A).
To test our concept, bifunctional Takemoto-type catalysts 5
as artificial glyoxalase I mimics were examined for the
isomerization of the hemithioacetal 3aa, generated in situ
from phenylglyoxal 1a and benzylthiol 2a as the GSH
surrogate, affording α-hydroxy thioester 4aa. As shown in
Scheme 1B, when reactions were performed in an organic
solvent such as cyclopentyl methyl ether (CPME), almost no
conversion was obtained even after 48 h. However,
surprisingly, the use of water as reaction medium turned on
this otherwise extremely unreactive catalytic reaction. Under
on-water conditions, the reaction rate was remarkably
accelerated presumably due to enforced hydrophobic inter-
actions between catalysts and reactants and, thus, the reaction
was completed within 9 h (using catalyst 5b) or 18 h (using
catalyst 5a) (Scheme 1B). Although water enabled this
biomimetic catalytic reaction, the ee values achieved in the
absence of a hydrophobic cosolvent (i.e., only in water) were
much lower than those obtained in CPME (Scheme 1B). It is
probable that the interfacial hydrogen bonding activation of
electrophile by bulk water molecules at the water-organic
a
(A) Plausible working hypothesis for the enantioselective isomer-
ization of hemithioacetals catalyzed by bifunctional thiourea organo-
catalysts as an artificial glyoxalase I. (B) First observation of the
hydrophobic amplification under on-water conditions. Conditions:
phenyl glyoxal 1a (0.1 mmol), benzyl thiol 2a (0.12 mmol), and
catalyst 5a or 5b (30 mol %) with 2 mL of reaction media at 20 °C.
*5 equiv of CPME was added. †20 equiv of CPME was added (Tables
‡
S1 and S2). (C) Selected condition optimization. 10 equiv of R-SH
and 10 equiv of eucalyptol were used.
2553
https://dx.doi.org/10.1021/jacs.0c11815
J. Am. Chem. Soc. 2021, 143, 2552−2557

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
phase boundary (i.e., the non-enantioselective on-water
catalytic effect) can negatively influence enantioselectivity.10e,16
Therefore, to achieve successful enantioselective catalysis in
water, it is important to suppress the hydrogen bonding
interactions of water molecules at the enantio-determining
step. The use of a hydrophobic cosolvent represents one of the
simplest means of achieving this end; the hydrophobic
cosolvent shields the transition state from contact with water.14
To our delight, the addition of CPME as a hydrophobic
cosolvent additive yielded markedly enhanced enantioselectiv-
ity. For example, using catalyst 5a, the enantioselectivity was
increased from 38% ee to 74% ee by adding 5 equiv of CPME
(Scheme 1B). With these encouraging results, a number of
hydrophobic cosolvents were further screened using 5a as
catalyst, and it was found that eucalyptol, a natural cyclic ether
and a monoterpenoid, proved optimal with respect to both
chemical yield and enantioselectivity of the desired product
(Scheme 1C and Supporting Information, Table S1). Using
eucalyptol as a hydrophobic cosolvent, we then evaluated the
effect of thiol structures on reaction rate and enantioselectivity.
Regardless of the degree of substitution, alkyl thiols were found
to serve as general GSH surrogates in terms of enantiose-
lectivity (Scheme 1C and Supporting Information, Figure S1).
Notably, the enantioselectivity of alkyl thiols increases with the
steric bulkiness of the substituent. Thus, a significant
enhancement in enantioselectivity was observed when the
substituent was changed from a primary to a tertiary alkyl
group (from 77% to 87% ee). However, when tertiary butyl
thiol was used, the reaction rate decreased dramatically due to
the steric effect (only 18% conversion after 24 h) (Scheme
1C). The problem of low conversion was easily addressed by
increasing the molar ratio of thiols. With 10 equiv of thiols, the
reaction could be completed after 4 days and, moreover,
increased ee values were obtained (for example, an ee of 4ad
from 87% to 91%) (Supporting Information, Table S2).
Condition Optimization Using Biphasic Microfluidic
Conditions. As described, the use of a hydrophobic cosolvent
was pivotal in achieving high enantioselectivity; this is ascribed
to the “spatial separation” of water from the transition state.
Nevertheless, under stirred conditions, it is difficult to perfectly
suppress the negative interfacial hydrogen bonding interaction
between the aqueous phase and organic reactants, since new
organic-water interfaces are constantly regenerated as a result
of stirring. We hypothesized that this problem could be
addressed by employing a biphasic microfluidic system, where
precisely defined micron-sized monodisperse water and
organic plugs could easily be generated in a tube reactor.15,17
Under static conditions in a tube reactor, new organic-water
interfaces cannot be recreated during the reaction and, thus,
the interfacial surface area must be incomparably smaller than
the interfacial surface area generated with stirring, con-
sequently minimizing the contact area between bulk water
molecules and the transition state. Furthermore, the diffusion
process of protons in water might be influenced by the
confinement effect.18 According to recent studies using
polarization-resolved femtosecond infrared transient absorp-
tion spectroscopy, in nanosized confined water droplets, the
diffusion rate of protons is significantly slower than that in bulk
water.18 Considering all these assumptions, catalytic isomer-
ization of the hemithioacetal 3aa, spontaneously generated
from 1a and 2a, was performed as a model reaction in a
biphasic microfluidic system (eucalyptol/brine).
This system was set using a cross-junction meeting of
controlled flows of brine and organic solutions containing the
organic reactants (1a and 2a) and catalyst 5a. The reaction
mixture was injected into the system using a syringe pump. A
series of droplets of different sizes were created in the
hydrophobic tubing (fluorinated ethylene propylene, FEP,
inner diameter (ø) = 500 μm, length = 15 m) by adjusting the
flow rate ratio (Qw/Qo) between the aqueous and organic
phases (Scheme 2A). After the tube was filled with the reaction
a
Scheme 2. Microfluidic Experiments
a
(A) Biphasic microfluidic system for isomerization of hemithioacetal
3a. Conditions: phenyl glyoxal 1a (0.1 mmol), benzyl thiol 2a (1
mmol), catalyst 5a (30 mol %), and eucalyptol (10 equiv): plugs form
at the junction between eucalyptol solution containing the reagents
(organic phase) and an aqueous phase (brine). Plugs then travel down
the FEP tubing where the reaction occurs. (B) Reaction profiles under
different conditions. (C) Effect of biphasic microfluidic conditions on
enantioselectivity. Conditions: (a) magnetic stirring (1150 rpm),
brine (2 mL), eucalyptol (10 equiv), 20 °C. (b) Microfluidic
condition (Qo:Qw = 6:120 μL/min) in ø = 500 μm FEP tubing, 20 °C.
(c) microfluidic condition (Qo:Qw = 6:120 μL/min) in ø = 500 μm
FEP tubing, 20 °C, 150 psi BPR. *The isolated yields could not be
determined since the total amount of organic reaction mixture in the
micro-tube was too small to determine the correct yield. Thus, we
determined the conversions using 1H NMR integration instead of
isolation yields.
mixture, the flows of brine and organic solutions were stopped,
and the outlet of the tube was then sealed with paraffin film.
The static biphasic plugs were then kept inside the tubing for
96 h at 20 °C, without any shaking. Gratifyingly, the reactions
proceeded smoothly even in the static droplets. The reaction
profile in the static droplets is almost the same as that observed
under the conventional stirring condition (Scheme 2B) (see
Supporting Information, Table S3, for additional experimental
2554
https://dx.doi.org/10.1021/jacs.0c11815
J. Am. Chem. Soc. 2021, 143, 2552−2557

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
results regarding the effect of droplet size on the catalytic
results). However, the same reaction proceeded extremely
sluggishly when the organic plugs were generated by injecting
argon gas instead of water into the tube reactor, further
confirming the crucial role of on-water conditions for the
observed rate acceleration (Scheme 2B). Furthermore, as per
our expectations, the microfluidic on-water conditions created
consistently higher ee values than those obtained under stirring
conditions (Scheme 2C). Notably, the pressure within the
microfluidic system which was controlled using a back pressure
regulator (BPR) (ca. 10 bar) resulted in an additional increase
in ee values (Scheme 2C). One plausible explanation for this
slight, but noticeable, increase in enantioselectivity under
pressure is increased water viscosity (i.e., decreased proton
mobility) with rising pressure.19 All the above-mentioned
results strongly indicate that the microfluidic on-water
condition perfectly limits the access of bulk water to the
transition state.
Scheme 3. Substrate Generality of Water-Induced
Hydrophobic Amplification in the Enantioselective
a
Isomerization of Hemithioacetals
Substrate Scope of Water-Driven Enantioselective
Protonation. Next, substrate generality was investigated using
both microfluidic and batch reactors. For all aromatic,
heteroaromatic, and aliphatic substrates 1a−1o tested in this
study, a dramatic increase in reaction rate was observed under
both on-water and static biphasic microfluidic conditions
compared with those obtained in a homogeneous organic
solvent. Thus, all aromatic α-oxoaldehydes 1a−1k examined in
this study smoothly underwent the reaction, producing the
corresponding (R)-α-hydroxy thioesters 4ad−4kd in high
yields with good to excellent enantioselectivities. Heteroar-
omatic glyoxal 1l was also smoothly converted into the desired
product 4ld with high enantioselectivity. Furthermore, highly
toxic methylglyoxal 1m and other alkyl glyoxals 1n−1o were
also smoothly converted into the corresponding α-hydroxy
thioesters 4md, 4nd, and 4od, respectively, albeit with
moderate enantioselectivity. For all substrate classes, as
anticipated, the microfluidic on-water system gave noticeably
higher enantioselectivities than those obtained with on-water
batch conditions (condition a vs conditions b and c in Scheme
3). Here again, in some cases (e.g., for 4ad, 4fd, 4gd, 4md,
4nd, and 4od), additional increases in enantioselectivity were
achieved by increasing pressure within the microfluidic system
(condition b vs c in Scheme 3). Considering these results in
sum, the use of biphasic microfluidic systems could provide a
solution for the intrinsic problem of the introduction of water
as a solvent in asymmetric catalysis in which water can
interfere with the catalysis.
Physical Origin of Water-Driven Catalysis. It is
reasonable to assume that, under “on-water” catalytic
conditions, water molecules around hydrophobic reactants
would form stronger hydrogen bonds than in the bulk, as
observed with a purely hydrophobic small molecule like
methane.12b This enhanced hydrogen bonding could then
pressurize the hydrophobic reactants in water cages. Thus,
chemical reactions with a negative volume of activation, ΔV⧧
(i.e., when the difference in the volume of the transition state
and the starting materials is <0), could be accelerated under
“on-water” conditions.20 However, experimental proof for
strengthened hydrogen bonds of water molecules under on-
water catalytic conditions has never been reported.
a
*The isolated yields could not be determined since the total amount
of organic reaction mixture in the micro-tube was too small to
determine the correct yield. Thus, we determined the conversions
1
using H NMR integration instead of isolation yields.
be used as a reliable and sensitive H-bond strength marker. A
downshift (red shift) of the νOH or νOD stretching mode,
relative to the reference spectrum of bulk water, should
indicate enhanced H-bond strength. Therefore, to determine
whether enhanced hydrogen bond strengths of water
molecules occur under the present on-water conditions, the
O-D stretching band spectra of isotopically diluted HDO
molecules were recorded in the absence and in the presence of
the hydrophobic reaction mixture. The spectrum of νOD of
HDO molecules perturbed by the reaction mixture was
obtained by applying the double-subtraction procedure12b,21
to remove contributions from H2O and HDO in the bulk to IR
spectra (see Supporting Information, Figure S2). As shown
from the resulting O-D spectrum that is perturbed only by the
reaction mixture (Figure 1A), a remarkable red shift of νOD
(ΔνOD) of about 60 cm−1 was observed. This result strongly
indicates that the hydrogen bonds of water molecules in the
first hydration shell of the hydrophobic reaction mixture under
on-water conditions also become significantly enhanced
relative to bulk water. To the best of our knowledge, this is
the first spectroscopic evidence for the strengthened hydrogen
bonds of water molecules near hydrophobic reactants under
on-water catalytic conditions.
IR spectroscopy is a powerful tool for determining the
relative strengths of hydrogen bonds between water molecules
near hydrophobic solutes.12a,b Frequencies of O-H or O-D
stretching mode (νOH or νOD) in vibrational spectroscopy can
2555
https://dx.doi.org/10.1021/jacs.0c11815
J. Am. Chem. Soc. 2021, 143, 2552−2557

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
movement of a highly mobile proton in water in an
enantioselective manner. Water enables highly enantioselective
glyoxalase I-mimic catalytic isomerization of hemithioacetals
generated in situ from glyoxals and thiols in the presence of
bifunctional organocatalysts, a reaction which proceeds via
enantioselective protonation of the cis-enediol intermediate.
Under on-water conditions, the reaction rate was dramatically
accelerated. By contrast, the same reactions were almost
impossible to conduct in organic solvents. A remarkable red
shift of the isotopically decoupled IR O-D stretching vibrations
under on-water conditions and a negative volume of activation
of the present reaction strongly suggest that this water-enabled
catalysis stems from the strengthened hydrogen bonds of water
molecules near the hydrophobic reaction mixture (i.e.,
hydrophobic hydration effect), which drives tight hydrophobic
interactions between catalyst and reactants in confined water
cages. Furthermore, under on-water conditions, especially
under biphasic microfluidic conditions, access of bulk water to
the enantio-determining transition state is efficiently blocked,
consequently enabling the highly enantioselective introduction
of a highly mobile proton to the transient enediol intermediate
which mimics the action of enzymes. In most cases, the α-
hydroxy thioester products were obtained with over 90%
enantiomeric excess. Thus, employing biphasic microfluidic
systems could provide a solution for addressing the intrinsic
problem of the introduction of water as a solvent in
asymmetric catalysis, in which water can negatively interfere
with the catalysis, lowering stereoselectivity. We also believe
that our results may provide a potential starting point for
designing more challenging biomimetic catalytic asymmetric
reactions in which water helps regulate reaction rates and
selectivity.
Figure 1. Mechanism study for elucidating origin of the acceleration
effect of on-water condition. (A) Spectra of the νOD of the HDO
molecules under on-water conditions (blue line, HDO solution in
H2O (20 °C, 1 bar); red line, HDO molecules perturbed by the
reaction mixture (eucalyptol (0.059 M), 1a (0.2 equiv), 2d (1 equiv),
(R)-5a (0.06 equiv), and a mixture of 1.4% (v/v) D2O in H2O (2
mL)). (B) Determination of activation volume according to the
equation ln(kP/k1 bar) = −(ΔΔV⧧/RT)(P − 1) + C (krel = 1.0 (1 bar),
krel = 2.93 (1.5 kbar), krel = 5.40 (2 kbar), krel = 9.05 (3 kbar), krel
=
11.33 (4 kbar) (Table S4).
Next, we performed kinetic measurement of the catalytic
isomerization reaction of 3aa at various pressures to determine
the activation volume (ΔV⧧) and, thus, to shed light on the
nature of the transition state of the reaction under the on-water
system. All kinetic measurements under applied pressure
(between 1 and 4 kbar) were carried out at 20 °C in CH2Cl2,
monitoring the consumption of hemithioacetal 3aa and the
formation of hydroxyl thioester 4aa by 1H NMR analysis. The
reaction was significantly accelerated by pressure, showing an
11-fold rate increase from 1 bar to 4 kbar (see Supporting
Information, Table S4). From these data, the activation volume
was determined to be −19.4 mL/mol (Figure 1B).20c,d This
study indicates that the transition state of our process is
significantly more compact than the combinations of starting
materials, confirming that the reaction must be accelerated
under on-water conditions by strengthened H-bonds of water
molecules near a hydrophobic reaction mixture (i.e., by
hydrophobic hydration effect).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11815.
Mechanistic Studies in Support of the Proposed
Reaction Pathway. Finally, to further elucidate the
mechanism of the present biomimetic catalytic reaction, we
carried out isotope experiments using 1-deuterated-phenyl-
glyoxal. The isotope experiments clearly confirmed that, in a
manner similar to natural glyoxalase I, the isomerization
reaction proceeded with deprotonation of the α-proton of
hemithioacetal to form the enediol intermediate and
subsequent enantioselective protonation.2f,6 We exclude a
direct 1,2-hydride shift reaction mechanism since no
deuterium incorporation was observed at the α-carbon position
of the thioester group in the final product (see Supporting
Information, Figure S3).22 The observed primary kinetic
isotope effect (kH/kD > 5) further indicates that the
deprotonation of the α-proton of hemithioacetals providing
the enediol is the rate-determining step (see Supporting
Information, Figure S4). Moreover, the experimentally
observed linear relationship between the catalyst ee and the
product ee confirms that the reaction involves a single catalyst
in the enantio-determining protonation step (see Supporting
Information, Table S5).
Experimental details, analytical data for all new
compounds, and mechanistic experiments (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Choong Eui Song − Department of Chemistry, Sungkyunkwan
University, Suwon 16419, Korea; orcid.org/0000-0001-
9221-6789; Email: s1673@skku.edu
Authors
Si Joon Park − Department of Chemistry, Sungkyunkwan
University, Suwon 16419, Korea
In-Soo Hwang − Department of Chemistry, Sungkyunkwan
University, Suwon 16419, Korea
Young Jun Chang − Department of Chemistry,
Sungkyunkwan University, Suwon 16419, Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11815
Author Contributions
†These authors contributed equally.
CONCLUSION
■
Notes
In summary, we provide a successful example of enantiose-
lective protonation in water revealing how to govern the
The authors declare no competing financial interest.
2556
https://dx.doi.org/10.1021/jacs.0c11815
J. Am. Chem. Soc. 2021, 143, 2552−2557

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
“on water". Chem. Rev. 2009, 109, 725−748. (d) Butler, R. N.; Coyne,
A. G. Water: nature’s reaction enforcer−comparative effects for
organic synthesis “in-water” and “on-water". Chem. Rev. 2010, 110,
6302−6337. (e) Butler, R. N.; Coyne, A. G. Organic synthesis
reactions on-water at the organic−liquid water interface. Org. Biomol.
Chem. 2016, 14, 9945−9960. (f) Kitanosono, T.; Kobayashi, S.
Reactions in water through “on-water” mechanism. Chem. - Eur. J.
2020, 26, 9408−9426.
(11) (a) Breslow, R. Hydrophobic effects on simple organic
reactions in water. Acc. Chem. Res. 1991, 24, 159−164. (b) Blokzijl,
W.; Engberts, J. B. F. N. Hydrophobic effects - opinions and facts.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1545−1579. (c) Otto, S.;
Engberts, J. B. F. N. Hydrophobic interactions and chemical reactivity.
Org. Biomol. Chem. 2003, 1, 2809−2820.
(12) (a) Merzel, F.; Avbelj, F. Why do water molecules around small
hydrophobic solutes form stronger hydrogen bonds than in the bulk?
Biochim. Biophys. Acta, Gen. Subj. 2020, 1864, 129537. (b) Grdadolnik,
J.; Merzel, F.; Avbelj, F. Origin of hydrophobicity and enhanced water
hydrogen bond strength near purely hydrophobic solutes. Proc. Natl.
Acad. Sci. U. S. A. 2017, 114, 322−327. (c) Strazdaite, S.; Versluis, J.;
Backus, E. H. G.; Bakker, H. J. Enhanced ordering of water at
hydrophobic surfaces. J. Chem. Phys. 2014, 140, 054711. (d) Davis, J.
G.; Gierszal, K. P.; Wang, P.; Ben-Amotz, D. Water structural
transformation at molecular hydrophobic interfaces. Nature 2012,
491, 582−585. (e) Raschke, T. M.; Levitt, M. Nonpolar solutes
enhance water structure within hydration shells while reducing
interactions between them. Proc. Natl. Acad. Sci. U. S. A. 2005, 102,
6777−6782.
(13) Kleiner, C. M.; Schreiner, P. R. Hydrophobic amplification of
noncovalent organocatalysis. Chem. Commun. 2006, 4315−4317.
(14) (a) Bae, H. Y.; Song, C. E. Unprecedented hydrophobic
amplification in noncovalent organocatalysis “on water”: hydrophobic
chiral squaramide catalyzed Michael addition of malonates to
nitroalkenes. ACS Catal. 2015, 5, 3613−3619. (b) Sim, J. H.; Song,
C. E. Water-enabled catalytic asymmetric Michael reactions of
unreactive nitroalkenes: one-pot synthesis of chiral GABA-analogs
with all-carbon quaternary stereogenic centers. Angew. Chem., Int. Ed.
2017, 56, 1835−1839.
(15) Song, C. E.; Park, S. J.; Hwang, I.-S.; Jung, M. J.; Shim, S. Y.;
Bae, H. Y.; Jung, J. Y. Hydrophobic chirality amplification in confined
water cages. Nat. Commun. 2019, 10, 851.
(16) Jung, Y.; Marcus, R. A. On the theory of organic catalysis “on
water”. J. Am. Chem. Soc. 2007, 129, 5492−5502.
(17) Mellouli, S.; Bousekkine, L.; Theberge, A. B.; Huck, W. T. S.
Investigation of “on water” conditions using a biphasic fluidic
platform. Angew. Chem., Int. Ed. 2012, 51, 7981−7984.
ACKNOWLEDGMENTS
■
We thank Ms. Hyun-Ju Lee for carrying out preliminary work.
The authors are also grateful to Prof. H. Y. Bae
(Sungkyunkwan University) and Prof. J.-W. Lee (University
of Kopenhagen) for helpful discussions. Financial support from
the Ministry of Science, ICT and Future Planning (NRF-
2019R1A4A2001440 and NRF-2017R1A2A1A05001214) is
gratefully acknowledged.
REFERENCES
■
(1) (a) Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Enantioselective
̀
protonation. Nat. Chem. 2009, 1, 359−369. (b) Oudeyer, S.; Briere,
J.-F.; Levacher, V. Progress in Catalytic asymmetric protonation. Eur.
J. Org. Chem. 2014, 2014, 6103−6119.
(2) (a) Ohta, H. Enzyme-mediated enantioselective protonation to
enolates in an aqueous medium. Bull. Chem. Soc. Jpn. 1997, 70, 2895−
2911. (b) Knowles, J. R. Enzyme catalysis: not different, just better.
Nature 1991, 350, 121−124. (c) Harris, T. K.; Cole, R. N.; Comer, F.
I.; Mildvan, A. S. Proton transfer in the mechanism of triosephosphate
isomerase. Biochemistry 1998, 37, 16828−16838. (d) Silva, M. S.;
Gomes, R. A.; Ferreira, A. E. N.; Freire, A. P.; Cordeiro, C. The
glyoxalase pathway: the first hundred years··· and beyond. Biochem. J.
2013, 453, 1−15. (e) Thornalley, P. J. Glyoxalase I − structure,
function and a critical role in the enzymatic defence against glycation.
Biochem. Soc. Trans. 2003, 31, 1343−1348. (f) Hall, S. S.; Doweyko,
A. M.; Jordan, F. Glyoxalase I enzyme studies: nuclear magnetic
resonance evidence for an enediol-proton transfer mechanism. J. Am.
Chem. Soc. 1976, 98, 7460−7461.
́
(3) Codorniu-Hernandez, E.; Kusalik, P. G. Probing the mechanisms
of proton transfer in liquid water. Proc. Natl. Acad. Sci. U. S. A. 2013,
110, 13697−13698.
(4) Xiong, W.; Gasparian, A.; Gao, H.; Dutta, D.; Khandaker, M.;
Liyanage, N.; Pasyuk, E.; Peng, C.; Bai, X.; Ye, L.; et al. A small proton
charge radius from an electron−proton scattering experiment. Nature
2019, 575, 147−150.
(5) (a) Kitanosono, T.; Sakai, M.; Ueno, M.; Kobayashi, S. Chiral-Sc
catalyzed asymmetric Michael addition/protonation of thiols with
enones in water. Org. Biomol. Chem. 2012, 10, 7134−7147.
́
(b) García-Fernandez, A.; Megens, R. P.; Villarino, L.; Roelfes, G.
DNA-accelerated copper catalysis of Friedel−Crafts conjugate
addition/enantioselective protonation reactions in water. J. Am.
Chem. Soc. 2016, 138, 16308−16314. (c) Kitanosono, T.; Sakai, M.;
Zhu, L.; Kobayashi, S. Enantioselective aza-Michael/protonation
reactions in water. Chem. Lett. 2019, 48, 783−786.
(6) Park, S. Y.; Hwang, I.-S.; Lee, H.-J.; Song, C. E. Biomimetic
catalytic transformation of toxic α-oxoaldehydes to high-value chiral
α-hydroxythioesters using artificial glyoxalase I. Nat. Commun. 2017,
8, 14877.
(7) Berne, B. J.; Weeks, J. D.; Zhou, R. Dewetting and hydrophobic
interaction in physical and biological systems. Annu. Rev. Phys. Chem.
2009, 60, 85−103.
(8) (a) van der Helm, M. P.; Klemm, B.; Eelkema, R. Organo-
catalysis in aqueous media. Nat. Rev. Chem. 2019, 3, 491−508.
(b) Kitanosono, T.; Masuda, K.; Xu, P.; Kobayashi, S. Catalytic
organic reactions in water toward sustainable society. Chem. Rev.
2018, 118, 679−746. (c) Science of Synthesis: Water in Organic
Synthesis; Kobayasi, S., Ed.; Thieme: Stuttgart, 2012. (d) Organic
Reactions in Water: Principles, Strategies and Applications; Lindstrom,
U. M., Ed.; Wiley-Blackwell: Hoboken, NJ, 2007. (e) Comprehensive
Organic Reactions in Aqueous Media; Li, C.-J., Chan, T.-H., Eds.;
Wiley-Interscience: Hoboken, NJ, 2007.
(9) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. “On water”: unique reactivity of organic compounds
in aqueous suspension. Angew. Chem., Int. Ed. 2005, 44, 3275−3279.
(10) (a) Klijn, J. E.; Engberts, J. B. F. N. Fast reactions ‘on water’.
(18) Sofronov, O. O.; Bakker, H. J. Slow Proton Transfer in
Nanoconfined Water. ACS Cent. Sci. 2020, 6, 1150−1158.
(19) Franck, E. U.; Hartmann, D.; Hensel, F. Proton mobility in
water at high temperatures and pressures. Discuss. Faraday Soc. 1965,
39, 200−206.
(20) (a) Pirrung, M. C.; Sarma, K. D. Aqueous medium effects on
multi-component reactions. Tetrahedron 2005, 61, 11456−11472.
(b) Pirrung, M. C. Acceleration of organic reactions through aqueous
̈
solvent effects. Chem. - Eur. J. 2006, 12, 1312−1317. (c) Klarner, F.-
G.; Diedrich, M. K.; Wigger, A. E. Effect of Pressure on Organic
Reactions. In Chemistry under Extreme or Non-classical Conditions; van
Eldik, R., Hubbard, C. D., Eds.; John Wiley: New York, 1997; pp
103−161. (d) High Pressure Organic Synthesis; Margetic, D., Ed.; De
Gruyter, 2019.
(21) Bergstrom, P. A.; Lindgren, J.; Kristiansson, O. An IR study of
−
−
2−
the hydration of ClO4 , NO3 , I−, Br−, Cl−, and SO4 anions in
aqueous-solution. J. Phys. Chem. 1991, 95, 8575−8580.
(22) (a) Wang, P.; Tao, W.-J.; Sun, X.-L.; Liao, S.; Tang, Y. A highly
efficient and enantioselective intramolecular Cannizzaro reaction
under TOX/Cu(II) catalysis. J. Am. Chem. Soc. 2013, 135, 16849−
16852. (b) Russell, A. E.; Miller, S. P.; Morken, J. P. Efficient Lewis
acid catalyzed intramolecular Cannizzaro reaction. J. Org. Chem. 2000,
65, 8381−8383.
̈
Nature 2005, 435, 746−747. (b) Lindstrom, U. M.; Andersson, F.
Hydrophobically directed organic synthesis. Angew. Chem., Int. Ed.
2006, 45, 548−551. (c) Chanda, A.; Fokin, V. V. Organic synthesis
2557
https://dx.doi.org/10.1021/jacs.0c11815
J. Am. Chem. Soc. 2021, 143, 2552−2557