REVIEW

DOI: 10.1002/adsc.201300798

Mukaiyama Aldol Reactions in Aqueous Media

Taku Kitanosonoa and Shū Kobayashia,*
a
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan
Fax: (+ 81)-(0)3-5684-0634; phone: (+ 81)-(0)3-5841-4790; e-mail: [email protected]

Received: September 3, 2013; Published online: October 31, 2013

This paper is dedicated to Professor Teruaki Mukaiyama in celebration of the 40th anniversary of the
Mukaiyama aldol reaction.

2013 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA. This is an open access article under
the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and dis-
tribution in any medium, provided the original work is properly cited, the use is non-commercial and no modi-
fications or adaptations are made.

Abstract: Mukaiyama aldol reactions in aqueous 2 Rate Enhancement by Water in the Mukaiyama
media have been surveyed. While the original Aldol Reaction
Mukaiyama aldol reactions entailed stoichiometric 3 Lewis Acid Catalysis in Aqueous or Organic Sol-
use of Lewis acids in organic solvents under strictly vents
anhydrous conditions, Mukaiyama aldol reactions in 3.1 Water-Compatible Lewis Acids
aqueous media are not only suitable for green sus- 4 Lewis-Base Catalysis in Aqueous or Organic Sol-
tainable chemistry but are found to produce singular vents
phenomena. These findings led to the discovery of 5 The Mukaiyama Aldol Reactions in 100% Water
a series of water-compatible Lewis acids such as lan- 6 Asymmetric Catalysts in Aqueous Media and
thanide triflates in 1991. Our understanding on these Water
beneficial effects in the presence of water will be 7 Conclusions and Perspective
deepened through the brilliant examples collected in
this review.
Keywords: aldol reaction; asymmetric catalysis;
1 Introduction green chemistry; Lewis acids; water

1 Introduction Since the first report on the Mukaiyama aldol reac-

tions mediated by a stoichiometric amount of TiCl4 in
The reactions of silicon enolates with aldehydes, re- 1973, many other stoichiometric Lewis acids such as
nowned as Mukaiyama aldol reactions, are among the BF3, SnCl4, AlCl3, FeCl3, and ZnCl2 have been devel-
most reliable carbon-carbon bond-forming reactions oped.[3] Furthermore, many other electrophiles such
in organic synthesis.[1] Silicon enolates are sometimes as ketones,[4] acetals,[1b,5] thioacetals,[6] imines,[7] and
called silyl enol ethers (silicon enolates derived from ketimines,[8] have also been applied to the system.
ketones) and ketene silyl acetals (silicon enolates de- Even for nucleophiles, silicon dienolates,[9] allylsi-
rived from esters). They react with aldehydes in the lanes,[10] and silyl cyanides,[11] as well as other materi-
presence of Lewis acids or fluoride anions to afford als have been exploited under acidic conditions. The
aldol adducts. Classical aldol reactions under basic amounts of Lewis acids have decreased from stoichio-
conditions suffer from generally low selectivity due to metric to catalytic levels. The aldol-type reactions of
their reversibility and many competitive side path- acetals with silicon enolates proceeded smoothly
ways such as dehydration, dimerization, polymeri- using a catalytic amount of Me3SiOTf.[12] Triphenyl-
zation and self-condensation,[2] Mukaiyama aldol re- methyl (trityl, Tr) salts were found to work as non-
actions proceed under acidic conditions and can avoid metal Lewis acids and were applied to the Mukaiya-
these competitive processes. ma aldol reaction.[13] In the presence of a catalytic
amount of TrClO4 or TrSbCl6, the aldol reactions of

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3095
REVIEW Taku Kitanosono and Shū Kobayashi

Shū Kobayashi studied at the dation Award (1994), Springer Award in Organome-
University of Tokyo, receiving tallic Chemistry (1997), IBM Science Award (2001),
his Ph.D. in 1988 working Organic Reactions Lecturer (2002), Nagoya Silver
under the direction of Profes- Medal (2002), Mitsui Chemical Catalysis Science
sor T. Mukaiyama. Following Award (2005), JSPS Prize (2005), the Arthur C.
an initial period as assistant Cope Scholar Award from the American Chemical
professor, he was promoted to Society (2006), Howard Memorial Lecturer (2006),
lecturer then associate profes- C.S. Hamilton Award (2007), Merck-Cambridge
sor at Science University of Lecturer (2007), Humboldt Research Award (2013),
Tokyo (SUT). In 1998, he and Green Chemistry Minister of Education Award
moved to the Graduate School (2013). Professor Kobayashi is a member of the Edi-
of Pharmaceutical Sciences, the torial Board of Advanced Synthesis & Catalysis.
University of Tokyo, as full professor. In 2007, he
was appointed to his current position as professor of Taku Kitanosono earned his
organic chemistry in the Department of Chemistry, B.Sc. (2010) and M.Sc. (2012)
Faculty of Science, the University of Tokyo. He has degrees from the University
held various visiting professorships, including the of Tokyo under the supervi-
Universit Louis Pasteur, Strasbourg (1993), Kyoto sion of Professor Shū Kobaya-
University (1995), Nijmegen University (1996), Phil- shi. He is now a graduate stu-
ipps-University of Marburg (1997), Paris-Sud (2010). dent of the Ph.D. course of
Professor Kobayashi has wide-ranging research in- the University of Tokyo and is
terests that include the development of new synthet- also a junior research fellow
ic methods and novel catalysts, organic reactions in of the Japan Society for the
water, solid-phase synthesis, total synthesis of bio- Promotion of Science (JSPS). He got the Student
logically interesting compounds, and organometallic Poster Award – First Prize at the 3rd Asia-Oceania
chemistry. He has held numerous named lecture- Conference on Green & Sustainable Chemistry
ships and is a recipient of many prestigious awards, (2011). His research interests include the develop-
including the Chemical Society of Japan Award for ment of new synthetic methods and novel catalyses
Young Chemists (1991), Ciba-Geigy Research Foun- in aqueous environments.

silicon enolates with aldehydes or acetals proceeded ganic synthesis but also in inorganic chemistry and
smoothly to afford the corresponding adducts in high biochemistry. In this article, the development of the
yields. Another important aspect of silicon enolates Mukaiyama aldol reaction in aqueous media is sur-
and the Mukaiyama aldol reaction in organic chemis- veyed.
try and organic synthesis is the development of chiral
Lewis acids. After the discovery of the Mukaiyama
aldol reactions and in light of the increasing demand
for asymmetric reactions, many chiral Lewis acids 2 Rate Enhancement by Water in the
have been developed for the Mukaiyama aldol reac- Mukaiyama Aldol Reaction
tion. Chiral Lewis acids act as catalysts, and thus cata-
lytic asymmetric aldol reactions have been attained. In 1986, Lubineau et al. reported that benzaldehyde
In all cases, the reactions were carried out in organ- 1 could react with silicon enolate 2 derived from cy-
ic solvents and mostly under strictly anhydrous condi- clohexanone in water without addition of any Lewis
tions. On the other hand, organic reactions in water acids or fluoride anions.[14] While the same reaction
have been of great interest because water is a safe, in- carried out in the presence of a stoichiometric
expensive, and clean solvent. However, for the Mu- amount of TiCl4 in dichloromethane (DCM) proceed-
kaiyama aldol reaction, the use of water as a solvent ed rapidly (82% yield after 2 h), the reaction in water
was believed to be impossible because (i) Lewis acids proceeded more slowly (43% yield after 5 d). The dia-
as activators or catalysts were believed to be incom- stereoselectivity of the product was reversed in com-
patible with water because of the weakness of the parison with the conventional TiCl4-catalyzed reaction
non-covalent interactions and (ii) most silicon eno- (Table 1).[15] Although the reaction proceeded rather
lates decompose in the presence of water. slowly, an obvious rate acceleration was observed in
However, efforts to develop the Mukaiyama aldol water because no reaction occurred in DCM without
reaction in aqueous media led to many fruitful scien- any Lewis acids.
tific advances not only in organic chemistry and or-

3096 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

Table 1. Water-accelerated Mukaiyama aldol reaction.

[a]
All reactions were carried out under atmospheric pressure at a concentration of 0.4 M of
the limiting component.
[b]
Determined by NMR analysis.
[c]
Vigorous magnetic stirring or violent shaking.
[d]
Isolated yield.

Interestingly, the rate acceleration and the stereo- enolates to afford the resulting silicate, which is more
chemical outcome in water bear a striking resem- nucleophilic than the original silicon enolate.
blance to the reaction performed under high pressure, Similar rate acceleration was observed in the Mu-
as shown in Table 1. A curious coincidence between kaiyama aldol reaction using ketene silyl acetals.
reactions in water and those under high pressure has Their reaction with 2-pyridinecarboxyaldehyde 4 in
been observed ever since.[16] Yamamoto et al. indicat- water was found to be approximately four times
ed that the transition state for the syn-selective path- faster than that in organic solvents (Scheme 1).[20] The
way under high pressure was more compact.[17] As is reaction exhibited anti-selectivity in water, irrespec-
often the case for reactions that possess a smaller tive of the E/Z ratio of starting enolate 7.
molar volume of a transition state, a key factor of the The scope of the catalyst-free, water-based Mu-
rate acceleration in water is the entropy-driven aggre- kaiyama aldol reaction was explored through its ap-
gation as a result of hydrophobic interactions. It is plication to the site-selective functionalization of N-
considered that these attractive outcomes arise from terminal aldehydes of peptides and proteins. Vigorous
the unique properties of water, such as its high dielec- stirring of a dipeptide aldehyde generated by period-
tric constant and high cohesive energy density (esti- ate oxidation from a polypeptide with a ketene silyl
mated 22 kbar) relative to conventional organic sol- acetal in 10 mM sodium phosphate buffer (pH 7.0)
vents.[18,19] In addition, it is noted that water can func- was also discovered to lead to the aldol product with
tion as a Lewis base (see Section 3) toward silicon high efficiency (Scheme 2).[21] The Mukaiyama aldol
reaction could be applied to various N-terminal alde-
hydes of peptides and proteins bearing a wide range

Scheme 1. Water-accelerated Mukaiyama aldol reactions of

ketene silyl acetals. Scheme 2. Mukaiyama aldol reactions of a peptide aldehyde.

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3097
REVIEW Taku Kitanosono and Shū Kobayashi

Scheme 5. YbACHTUNGRE(OTf)3-catalyzed Mukaiyama aldol reaction in

aqueous media.

tained through the Diels–Alder pathway in other

protic solvents.[18b,24]

Scheme 3. Diastereoselective vinylogous Mukaiyama aldol 3 Lewis Acid Catalysis in Aqueous or

reactions in aqueous media: pyrrole vs. furan 2-silyloxy
dienes.
Organic Solvents
Although rate enhancement was found in the Mu-
kaiyama aldol reaction in water, low yields and low
reaction rates were often observed without activation
by Lewis acids. On the other hand, traditional Lewis
acids such as AlACHTUNGRE(III), Ti(IV), and Sn(IV) significantly
accelerate the Mukaiyama aldol reaction in organic
solvents, whereas these Lewis acids decompose rapid-
ly in the presence of water. Indeed, Lewis acids were
believed to be incompatible with water for a long
time.
However, it was discovered in 1991 that lanthanide
trifluoromethanesulfonates (triflates) [LnACHTUNGRE(OTf)3] are
water-compatible Lewis acids and accelerate the Mu-
kaiyama aldol reaction significantly in aqueous media
(water/organic solvents).[25,26] For example, YbACHTUNGRE(OTf)3,
Scheme 4. Reaction of Rawals diene 12 in water. a representative lanthanide triflate, was revealed to
exhibit superior performance in the Mukaiyama aldol
reaction of various silicon enolates with aqueous
formaldehyde 13 in water-tetrahydrofuran (THF)
of functional groups under very mild conditions. As (Scheme 5).[27] The reactions also proceeded well in
shown in the case of myoglobin, the reaction could be water-ethanol-toluene cosolvent systems.[28]
carried out without disturbing either the tertiary A wide variety of aldehydes other than formalde-
structure or the enzymatic activity of the protein. hyde could also be activated successfully by lantha-
The dual role of water as a reaction medium and nide triflates to give cross-aldol adducts in high yields.
promoter was also highlighted in vinylogous Mukaiya- Even water-soluble aldehydes such as acetaldehyde,
ma aldol reactions of pyrrole and furan 2-silyloxy acrolein, chloroacetaldehyde, and aldehydes possess-
dienes in aqueous media.[22] N-Boc-2-(trimethylsilyl- ing coordinating heteroatoms such as salicylaldehyde
ACHTUNGREoxy)pyrrole reacted with benzaldehyde in aqueous and 2-pyridinecarboxyaldehyde reacted successful-
media to afford the desired product with almost com- ly.[29] The reactions carried out without water failed to
plete g-site selectivity and good diastereomeric ratio give the corresponding aldol products, thus verifying
in favor of the anti-configured isomer, while the reac- the intriguing influence of water on these catalysts.[30]
tion failed in organic solvents or under neat condi- Moreover, water-compatible Lewis acid catalysis may
tions. A remarkable switch of diastereoselectivity was offer many advantages over traditional TiCl4-promot-
observed when furan 2-siloxydiene was used ed reactions performed under strictly anhydrous con-
(Scheme 3). ditions. For example, performing the Mukaiyama
The Mukaiyama aldol reaction of electron-rich aldol reaction in aqueous media enabled the use of
Rawals diene 12 with carbonyl compounds proceed- aqueous formaldehyde as a C1 source. In general, hy-
ed without any activator in pure water (Scheme 4).[23] droxymethylation reactions using formaldehyde as
1
H NMR analyses indicated that the solvents influ- one of the most valuable C1 electrophiles have re-
enced the reaction pathway and the aldol adducts ceived immense attention in organic synthesis.[31] Al-
were obtained in water, while the cycloadduct was ob- though formaldehyde gas and paraformaldehyde in

3098 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

Scheme 6. Mukaiyama aldol reaction of 17 with acrolein 16.

organic solvents can be employed as C1 electrophiles, toluene system (1:10:4) to afford the corresponding
tedious and harmful procedures to generate the form- keto-enone 19 as a 2:1 mixture of diastereomers after
aldehyde monomer from oligomers[32] are the main subsequent oxidization with Jones reagent
disadvantage. LnACHTUNGRE(OTf)3-catalyzed hydroxymethylation (Scheme 6). This result bears an eloquent testimony
has been employed to construct complex molecules in to the overwhelming ascendancy of the aqueous
the total synthesis of natural compounds such as A- LnACHTUNGRE(OTf)3 system as a powerful catalyst for the Mu-
seco-taxane[33] and ( )-sclerophytin A.[34] Moreover, kaiyama aldol reaction.
practical attachment of a hydroxymethyl function on Another striking feature of LnACHTUNGRE(OTf)3 is the ease of
the a-carbon adjacent to the carbonyl group has been recovery from the reaction mixture. Because these
enlisted in the total synthesis of biologically active metal triflates are soluble in water, they can be recov-
compounds such as diazonamide A,[35] ( )-strych- ered quantitatively from the aqueous layer and the
nine,[36] and acutifolone A,[37] in which the initial for- product can be obtained through simple extraction
mation of silicon enolates (TMSCl, Et3N) served to from the organic layer (Scheme 7).
create latent nucleophiles that were subsequently un-
leashed upon LnACHTUNGRE(OTf)3-catalyzed reactions with aque-
ous formaldehyde. Such a two-step, one-pot proce- 3.1 Water-Compatible Lewis Acids
dure was utilized in a d-lactone synthesis protocol.[38]
Furthermore, this aqueous strategy impedes a serious- The discovery of rare earth triflates [ScACHTUNGRE(OTf)3,
ly destructive desilylation pathway. The formation of YACHTUNGRE(OTf)3, and LnACHTUNGRE(OTf)3] as water-compatible Lewis
an undesired desilylated ketone was often the sole acids was contrary to the conventional understanding
pathway when attempting the Mukaiyama aldol reac- that Lewis acids decomposed in the presence of
tion with a conventional methodology. For instance, water. A question was why LnACHTUNGRE(OTf)3 is compatible
the Mukaiyama aldolization of TMS enolate 17 with with water, unlike conventional Lewis acids. Another
acrolein 16 towards a total synthesis of taxanes has re- question is whether there are any other water-compat-
sulted in the sole formation of 18 in the presence of ible Lewis acids besides LnACHTUNGRE(OTf)3. To answer these
any catalyst.[39] Gratifyingly, the desired reaction pro- questions, extensive research has been conducted that
ceeded smoothly with GdACHTUNGRE(OTf)3 in a water-ethanol- has led to an expansion of the availability of water-
compatible Lewis acids and catalysts. The reaction of
benzaldehyde with propiophenone-derived silicon
enolate 14 was chosen as a model and group 1–15
metal chlorides, perchlorates and triflates were
screened in a water-THF cosolvent system.[40] Selected
results are shown in Table 2a. The reaction catalyzed
by other metal salts hardly provided any of the de-
sired product 21.
In addition to rare-earth metal cations, Fe(II),
Cu(II), Zn(II), Cd(II), and Pb(II) were found to func-
tion as efficient and promising Lewis acids in aqueous
media, and this necessitated the establishment of the
criteria for catalytic activity of the metal cations. Su-
Scheme 7. Recovery of the catalyst. perior catalytic activity was observed in the presence

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3099
REVIEW Taku Kitanosono and Shū Kobayashi

Table 2. (a) Evaluation of catalysis by different Lewis acids in the Mukaiyama aldol reaction. (b) Hydrolysis constants and
exchange rate constants for substitution of inner-sphere water ligands.

of the metal cations surrounded by red squares in stants (WERC)] are suitable factors for estimating
Table 2b. Given the correlation between these metal the catalytic activity of Lewis acids.[41] These active
cations and catalytic activity, hydrolysis constants (Kh) metal compounds were found to have pKh values
and exchange rate constants for the substitution of from about 4 [4.3 for ScACHTUNGRE(III)) to 10 (10.08 for Cd(II)]
inner-sphere water ligands [water exchange rate con- and WERC values greater than 3.2 106 M 1 s 1. Cat-

3100 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

An unequivocal interrelationship between the coor-

dination environment of lanthanide triflates and the
steady-state reaction rate of the Mukaiyama aldol re-
action was also proven through luminescence-decay
measurements in combination with high-performance
liquid chromatography analyses.[44] These phenomena
can be explained as follows. The predominant coordi-
nation of a THF molecule to YbACHTUNGRE(OTf)3 stabilizes the
cyclic six-membered transition state that led to the
lower activity and anti-selectivity in the reaction when
Scheme 8. Effect of Yb salts. no water or a small amount was added.[45] On the
other hand, when the equivalents of water are gradu-
ally increased, the coordination of water induces the
ions with large pKh values do not generally undergo naked active ytterbium cation with its high water-ex-
efficient hydrolysis. Cations with pKh values less than change rate constant[46] to activate aldehydes effec-
4 are readily hydrolyzed to produce protons in suffi- tively and catalyze the reaction via an acyclic transi-
cient numbers to cause rapid decomposition of the sil- tion state.[47] That is, the structural fluctuation of coor-
icon enolate. On the other hand, when the pKh value dination water molecules around lanthanide ions de-
is higher than 10, the Lewis acidities of the cations termines favorable transition states (TS) in terms of
are too low to catalyze the aldol reaction. To act as entropy, promotes hydration of the silicon enolate
an efficient catalyst in water, large WERC values may and proton transfer to the aldehyde, and activates
be necessary to allow sufficiently fast exchange be- both substrates; this was confirmed by the AFIR
tween the water molecules coordinated to the metal method.[48] Thus, the elaborate exploitation of the
and the aldehyde substrate. “Borderline” species such unique properties of water in irreversible Mukaiyama
as Mn(II), Ag(I), and InACHTUNGRE(III), with pKh and WERC aldol reactions is expected to facilitate the catalytic
values close to the criteria limits, provide the aldol ad- turnover with simultaneous desilylation as a direct
ducts in moderate yields. Whereas the precise activity access to aldol adducts, while in conventional acid- or
of Lewis acids in aqueous media cannot be quantita- base-catalyzed aldol reactions, the reaction yields of
tively predicted by pKh and WERC values, these the aldol adducts are destined to depend upon their
values have been instrumental in the identification of thermodynamic stabilities because of the reversibility
promising metal compounds as water-compatible of the reactions.
Lewis acid catalysts,[42] and have also provided mecha- The emergence of water-compatible Lewis acids
nistic insights into Lewis acid catalysis in aqueous has definitely broken down the wall of traditional
media. By taking into account the high coordination prejudice that water is a detrimental contaminant in
numbers of these effective metals, the phenomenal organic synthesis, and has also offered industrially
rate acceleration by water can be attributed to the beneficial methodologies that facilitate recovery and
predominant ionic properties of the interaction be- reuse of these catalysts. As for heterogeneous cataly-
tween the Lewis acidic metals and the counter anions. sis, polar polyoxyethylene-polyoxypropylene (POE-
Indeed, the catalysis of ytterbium salts with more nu- POP) resin, derivatized with a 4-hydroxymethylphe-
cleophilic counter anions such as Cl , OAc , NO3 noxy linker, was employed as a solid support for
and SO4 was far less than the effective catalysis of LnACHTUNGRE(OTf)3-catalyzed Mukaiyama-type solid-phase
ytterbium salts with less-coordinating counter anions aldol reactions.[49] The utilization of an aqueous
such as OTf (91% yield, syn:anti = 73:27) or ClO4 medium was crucial for the acquisition of sufficient
(88% yield, syn:anti = 76:24)[29b] (Scheme 8). reactivities and high yields were attained for an N-ter-
The best yields were obtained with 10–20% water. minal peptide aldehyde substrate 22 (Scheme 9).
Water seems to destabilize silicon enolates through A series of fluoroalkyl end-capped 2-acrylamido-2-
hydrolysis of ytterbium salts.[43] The amount of water methylpropanesulfonic acid polymer [RF-(AMPS)n-
governs the stereochemical outcome as well as the RF ; RF = fluorinated group such as CFACHTUNGRE(CF3)OC3F7]
consequent catalytic turnover in water/THF solution. hydrogels containing ScACHTUNGRE(OTf)3 was employed in the
While the reaction of benzaldehyde with cyclohexan- Mukaiyama aldol reaction in aqueous methanol.[50] A
ACHTUNGREone-derived silicon enolates proceeded with anti-pref- gelation was derived from the synergistic interaction
erence in the absence of water, the stereochemistry of between the aggregation of end-capped fluoroalkyl
the product underwent a change toward syn confor- segments and the ionic interactions of the betaine seg-
mations as the amount of water increased; however, ments in water under non-cross-linked conditions.[51]
the selectivity changed no further (up to syn/anti = 73/ Not only did the reaction proceed smoothly, but the
27) when more than 15 equivalents of water were catalyst was also recovered quantitatively and the cat-
added.[29b] alytic activity of the recovered catalyst was unaffect-

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3101
REVIEW Taku Kitanosono and Shū Kobayashi

Scheme 9. Solid-phase Mukaiyama aldol reactions of a model peptide substrate.

Scheme 10. Synthesis of C-glycosides and C-disaccharides using Mukaiyama aldol reaction in aqueous media.

ed. Evaluation of homogeneous Lewis acid catalysis preparation of C-glycosides and C-disaccharides start-
by water-soluble sodium salts or lithium salts of the ing from formyl-2,3,4,6-tetra-O-benzyl-b-d-glucopyra-
sandwich-structured Hf/Zr-containing Keggin and noside 25 (Scheme 10).[53] YbACHTUNGRE(OTf)3 in aqueous media
Dawson POMs showed high anti-preference for Mu- led to the aldol adducts in high yields with moderate
kaiyama aldol reactions in an aqueous/CH3CN diastereoselectivities for the synthesis of C-glycosides.
system.[52] Interestingly, a significant drop in reactivity as
Lewis acid-catalyzed Mukaiyama aldol reactions in a single isomer was observed when the reaction was
aqueous media could also be efficiently applied to the performed in anhydrous THF. The better diastereose-

3102 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

lectivity observed in anhydrous THF could be ration-

alized from the Cram cyclic chelated model, in which
the ytterbium atom may coordinate the carbonyl
group and the endocyclic a-oxygen atom of the sugar
moiety. In aqueous media, the attack of the electro-
phile may not be preferentially directed to one of the
p-faces of the enolate, as depicted in the non-chelat-
Scheme 11. CaCl2-catalyzed Mukaiyama aldol reaction using
ing Felkin–Anh model. In the Mukaiyama aldol reac-
aqueous formaldehyde.
tion of the sterically hindered silicon enolate 27,
a low degree of diastereoselection was observed for
the C-4 alkylation, which might be attributed to the
Table 3. Lewis base-catalyzed Mukaiyama aldol reaction in
poor steric control induced by the substituents adja- aqueous DMF.
cent to the reactive center (at the C-6 and C-2 posi-
tions).
Thermal treatment of montmorillonite K10 was
also applicable to the Mukaiyama aldol reaction in
water.[54] The catalytic activity was attributed to the
structural features of the clay and its inherent Brønst-
ed acidity.

4 Lewis-Base Catalysis in Aqueous or

Organic Solvents
Lewis-base catalysis can also apply to the Mukaiyama
aldol reaction in the presence of water, albeit with
a limited number of examples. It is known that trime-
thylsilyl enolates are not so strongly activated by non-
ionic Lewis bases such as tertiary amines, N-oxides, or
phosphine oxides.[55] While one of the major problems
was their low solubility in organic solvents such as
THF and CH3CN, the use of protic solvents led to
side reactions such as hydrolysis of the enolates.[26a,56] [a]
Determined by 1H NMR analysis.
Few of them were soluble in THF, toluene or CH3CN, [b]
2 equiv. of 5 were added.
[c]
but they provided considerable amounts of elimina- For 6.5 h.
[d]
tion products because of their strong Brønsted basici- Isolated yield.
ty.[57] Hosomi et al. disclosed that the uncatalyzed re-
action of benzaldehyde with dimethylsilyl (DMS)
enolates proceeded under thermal conditions in DMF, DMS enolate turned out to be a competent nucleo-
while trimethylsilyl enolates hardly reacted.[58] Exten- phile in the presence of CaCl2 in water or aqueous
sive examination of additives to promote the Mu- DMF. Consequently, the CaCl2-promoted system
kaiyama aldol reactions led to the discovery of calci- could be utilized for the reaction of aqueous alde-
um chloride as a catalyst, which effectively suppressed hydes such as aqueous formaldehyde, phenylglyoxal
associated side reactions. The rate-accelerating ability and chloral, and this was the first example of Lewis
of the calcium salt depends on the intrinsic nucleophi- base-catalyzed Mukaiyama aldol reactions in aqueous
licity of the counter anion: TfO < I < Br < Cl . Tet- media (Scheme 11).
rabutylammonium chloride also exhibited good cata- Following their previous studies of the aldol reac-
lytic activity for the Mukaiyama aldol reaction of tions carried out under anhydrous conditions,[60] Mu-
DMS enolates. Given the diametrically different ob- kaiyama et al. reported that 10 mol% of lithium ace-
servations on rate acceleration between TMS and tate could function as a Lewis base catalyst to cata-
DMS enolates and the chloride ions higher nucleo- lyze the reaction between benzaldehyde and ketene
philicity compared with those of bromide or iodide silyl acetal at 45 8C in DMF:H2O = 50:1 (Table 3).[61]
ions in an aprotic solvent such as DMF, and the low Several metal carboxylates, such as sodium acetate,
Lewis acidity of CaCl2,[59] chloride ion was determined lithium benzoate, and lithium acetate were found to
to function as a Lewis base to activate the DMS eno- act as catalysts. However, electron-poor benzoate suf-
late. In spite of a much lower tolerance to water, the fered a significant drop in reactivity (entry 5). They

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3103
REVIEW Taku Kitanosono and Shū Kobayashi

Table 4. Comparison of the reactivity of TMS or DMS eno-

lates with various catalysts.

Scheme 12. AcOLi-catalyzed mechanism for Mukaiyama [a]

Isolated yield.
aldol reaction in aqueous DMF.

Table 5. Effect of surfactants on Mukaiyama aldol reaction

assumed that the role of the carboxylate in the cata- in water.
lytic cycle was the formation of a lithium aldolate, via
a hexacoordinated hypervalent silicate, that under-
went rapid hydrolysis and subsequent neutralization
to regenerate the lithium acetate catalyst
(Scheme 12). The significant dependence of reactivity
on the electrophilicity of the starting aldehydes sup-
ported their hypothesis.
Scandium fluoride (ScF3) was found to be a novel
catalyst for the hydroxymethylation reaction of DMS
enolates with aqueous formaldehyde in aqueous THF
solution.[62] Comparison of the reactivity between
TMS and DMS enolates derived from propiophenone
for hydroxymethylation reactions was examined using
typical Lewis acids or bases (Table 4). The hydroxy-
methylation was sluggish without a catalyst (entry 1),
whereas both enolates reacted to afford the product
in the presence of a Lewis acid catalyst (scandium
chloride); the TMS enolate providing a higher yield
[a]
(entry 2). The products were also obtained from both Isolated yield.
enolates in the presence of KF and 18-crown-6 with
the TMS enolate demonstrating slightly better reac-
tivity (entry 3). The addition of HF resulted in lower
yields with both enolates (entry 4). Interestingly, ScF3 5 The Mukaiyama Aldol Reactions in
produced the product only from DMS enolate 100% Water
(entry 5). This unique character of ScF3 denoted that
its reactivity toward TMS and DMS enolates was dif- A fundamental challenge of performing the Mukaiya-
ferent from that of conventional Lewis acid or fluo- ma aldol reactions in water is the competition by
ride ion[63] (Lewis base)-catalyzed reactions. Some re- rapid hydrolysis of silicon enolates, which can lower
ports have shown that fluoride ions can activate sili- reactivity and narrow the substrate generality. To
con enolates effectively even in a protic solvent.[64] make the desired catalytic pathway dominant over
The detailed mechanism of the preferential activation the competitive hydrolysis, a possible approach is to
of DMS enolates by ScF3 remains unknown. enhance the hydrophobicity of the reaction environ-
ment. The addition of a catalytic amount of surfactant
was found to increase the yield in ScACHTUNGRE(OTf)3-catalyzed

3104 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

dispersion formed. These oily particles, consisting of

the organic substrates and STDS, were stabilized and
dispersed in water to promote Mukaiyama aldol reac-
tions (Scheme 14). Because ScACHTUNGRE(OTf)3 does not react
with SDS to form STDS in situ, the catalytic efficien-
cy of STDS was superior to that of the ScACHTUNGRE(OTf)3-SDS
system.[69a] Indeed, the ScACHTUNGRE(OTf)3-SDS system makes
a kind of micelle (not a dispersion).
The use of STDS to construct highly reactive mi-
croenvironments in water enlarged the substrate
scope in the Mukaiyama aldol reaction to include
quite labile silicon enolates. Indeed, the Mukaiyama
aldol reaction was found to proceed 5 103 times
faster in water than in dichloromethane.[69a] It was
also shown that multifarious LASCs were applicable
to various reactions in water.[70,71] In aqueous solution,
surfactants aggregate into micelles, where the hydro-
phobic portions of the molecules are protected from
Scheme 13. Schematic representation of scandium tris(do- water.[72] Normally, micelles in aqueous solution form
decyl sulfate) (STDS). with the surfactant molecules orienting themselves
into spherical or elliptical structures with their hydro-
phobic tails oriented toward the center and their hy-
Mukaiyama aldol reactions in 100% water. Micellar drophilic heads oriented toward the surrounding
systems containing anionic[65] or non-ionic surfac- water.
tant[66] have led to remarkable enhancements of reac- Elaborate regulation of reaction environments in
tivity, even with ketene silyl acetals (Table 5).[67] micellar catalysis has been elucidated through many
Sodium dodecyl sulfate (SDS) was the most effective. mechanistic insights. An NMR study disclosed that
Only cetyltrimethylammonium bromide (CTAB) was the micelles formed by SDS had approximately one-
found not to be an effective surfactant because of the third of their surface covered by the hydrophilic head
possibility of hydrolysis of the silicon enolate. groups while the remaining two-thirds were covered
A major disadvantage of Lewis acid catalysis aided by the hydrocarbon tails.[73] The formation of micelles
by surfactants was that semi-catalytic use of the sur- can be explained by thermodynamics: they can form
factants was required to achieve good results. There spontaneously as a result of a balance between entro-
were also problems with separation. Because of the py and enthalpy. Despite the reduction in entropy
high affinity of water-compatible Lewis acids with caused by surfactant aggregation in water, the hydro-
water, the relative concentration of the catalyst in the phobic effect is a driving force for micelle formation.
hydrophobic micelles is low. Hence, there were severe Micelles do not form unless the concentration of a sur-
substrate limitations in the Lewis acid-SDS system;
very labile silicon enolates such as cyclohexanone-de-
rived silyl enol ether decomposed rapidly. In 1998,
a Lewis acid-surfactant combined catalyst (LASC)
emerged as an innovative catalyst, in which a Lewis
acid possessed ligands with surfactant properties to
construct an efficient hydrophobic environment sur-
rounding a Lewis acidic cation (Scheme 13).[68,69]
Scandium tris(dodecyl sulfate) [STDS, Sc(DS)3
(DS = OSO3C12H25)] was shown to dissolve in water
and after the addition of organic substrates, a white

Scheme 15. Correlation between size of colloidal dispersion

Scheme 14. LASC-catalyzed Mukaiyama aldol reaction. and reactivity.

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3105
REVIEW Taku Kitanosono and Shū Kobayashi

factant is greater than the critical micelle concentra- ceeded less smoothly. Because of aggregation of hy-
tion (CMC) and there exists a critical temperature drophobic substrates, the dispersion system was stable
(Krafft temperature) above which the solubility rapid- for only a few minutes and quick aggregation took
ly increases (to become equal to CMC).[74] Theoreti- place. Because typical emulsion sizes created in water
cally, the CMC decreases as the polar head becomes are 1 mm, this low stability of the dispersion might be
smaller and as the alkyl chain length increases. the reason for the low yields observed. All the parti-
Indeed, an NMR study of SDS micelles labeled with cles formed from the mixture of Sc(OSO2C12H25)3 and
paramagnetic ions such as Co(DS)2 revealed that the benzaldehyde in water have a diameter of 1 mm and
charged surface was smooth and the chains minimized the molecular area of Sc(OSO2C12H25)3 was deter-
their radial extension.[75] The correlation between the mined to be 132 2. Based on these facts, only ap-
size of colloidal dispersions measured by dynamic proximately 0.08 mol% Sc(OSO2C12H25)3 with respect
light scattering (DLS) and their reactivity was evalu- to benzaldehyde is sufficient to form monolayers
ated for Sc-based LASCs (Scheme 15).[76] When the around the aldehyde. This means that excess LASCs
catalyst possesses a lower CMC, for instance should be stacked at the interface between the water
Sc(OSO2C14H29)3, the Mukaiyama aldol reaction pro- and the benzaldehyde phase in the presence of more
than 0.08 mol% Sc(OSO2C12H25)3. As mentioned
above, the remarkable enhancement of reactivity by
Table 6. Effect of Brønsted acids on asymmetric Mukaiyama Brønsted acids was observed in LASC-mediated Mu-
aldol reactions in water.
kaiyama aldol reactions in water (see Table 6).[77]
The reactions of cis and trans a,b-epoxy aldehydes
with ketene silyl acetals proceeded using the
ScACHTUNGRE(OTf)3-SDS system in water were studied.[78] The
use of cosolvents failed to generate the aldol adducts,
while the best results were obtained when operating
under the micellar system with high anti-diastereofa-
cial preference. The reaction of benzylated epoxy al-
dehyde 31 with ketene silyl acetal 32 derived from
ethyl pyruvate led to ulosonic ester derivatives 33
(Scheme 16).
Polymer-supported (PS) catalysts were developed
for the Mukaiyama aldol reactions in aqueous envi-
ronments. Kobayashi’s group modified their previous-
ly reported LASC system by introducing polymer
chain spacers as the hydrophobic component to the
metallosurfactant catalyst.[79] The reaction of benzal-
dehyde with 1-ethylthio-1-trimethylsiloxy-2-methyl-1-
propene proceeded almost quantitatively in the pres-
[a] ence of 3.2 mol% of the heterogeneous catalyst, and
Determined by NMR analysis.
[b] wider substrate generality was achieved by further
Determined by chiral HPLC analysis.
modification.[80] The catalytic activity of PS-Sc was de-

Scheme 16. Aqueous Mukaiyama aldol reaction of a,b-epoxy aldehydes.

3106 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

Scheme 18. Cross-linked scandium-containing dendrimers.

metric catalysis could be also realized with this heter-

ogeneous catalyst (vide infra).
Cross-linked, scandium-containing dendrimers de-
rived from polyACHTUNGRE(amino) dendrimer as heterogeneous
catalysts with Lewis acidic properties were reported
to catalyze Mukaiyama aldol reactions in water
(Scheme 18).[84] Despite the heterogeneous material
being non-porous, catalysis was achieved and the cata-
lytically active scandium centers were accessible for
the reaction to occur. A nanostructured, polymer-sup-
ported Sc catalyst utilizing a cross-linked inverted
hexagonal lyotropic liquid-crystal phase was prepared
and utilized as an efficient catalyst for the aldol-type
reaction.[85] While ScACHTUNGRE(OTf)3 or STDS exhibited no dia-
Scheme 17. (a) Silica-supported scandium with ionic liquid stereoselectivity, the nanostructured scandium catalyst
(Silica-Sc-IL). (b) Hydrophobic reaction environment con- exhibited moderate syn preference (syn:anti = 76:24).
structed by Silica-Sc-IL. As another measure for overcoming the competi-
tive hydrolysis, calix[6]arene derivatives bearing sulfo-
nate groups on the upper rim and alkyl groups on the
pendent upon the hydrophobicity in water and was lower rim were developed.[86] These macrocycles sta-
thus superior to that of STDS. bilized labile silicon enolates to promote the Mu-
A periodic mesoporous Lewis acid catalyst kaiyama aldol reactions in aqueous media with slight
[(OTf)2Sc-OSO2C6H4-PMO] exhibited catalytic activi- anti selectivities (syn:anti = 31:69 to 40:60). These
ty and selectivity in aqueous Mukaiyama aldol reac- structures could be regarded as bundles of aromatic
tions and compared favorably with a homogeneous anionic surfactants. Indeed, the combination of aro-
catalyst ScACHTUNGRE(OTf)3 or mesoporous SBA-15[81]-supported matic surfactants and aryl aldehydes was favorable
scandium triflate catalyst [(OTf)2Sc-OSO2C6H4-SBA- for the activation in the hydrophobic cavities.[87] The
15].[82] Hydrophobicity tests and substrate adsorption recyclable inclusion complex formed from cyclodex-
experiments demonstrated that its unique catalytic trin (CD) and ytterbium tris(perfluoroalkanesulfonyl)-
performance was related to the combined advantage amide was also applied to the Mukaiyama aldol reac-
of mesoporosity and a hydrophobic microenviron- tion with ketene silyl acetals in water, albeit with
ment, which effectively stabilized and concentrated slightly lower reactivity than that in DCM.[88] It was
the substances as well as decreasing the intrinsic reported that because of hydrophobic interactions,
mass-transfer resistance. The periodically arranged CD formed inclusion complexes with the fluorocar-
Lewis acids in the mesoporous silica framework inhib- bon surfactants.[89] Because the chain length of the
ited leaching of metals from the active sites, leading perfluorobutane group was nearly equal to the length
to its high catalytic recyclability in water. of cyclodextrin ring, it was assumed that the metal
A heterogeneous scandium catalyst coated with an was located just outside the hydrophobic pockets of
ionic liquid, [DBIm]SbF6, Silica-Sc-IL, also worked CD.
efficiently in the Mukaiyama aldol reaction On the other hand, FeCl3 was reported as a homo-
(Scheme 17a).[83] The reaction rate was much faster in geneous catalyst for the Mukaiyama aldol reactions
water than in organic solvents or under neat condi- and the diastereoselectivities were found to be con-
tions. It was determined that ionic liquids played trolled kinetically in water in the presence of a surfac-
a crucial role in the construction of efficient hydro- tant.[90] Better rate acceleration and higher diastereo-
phobic environments in water (Scheme 17b). Asym-

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3107
REVIEW Taku Kitanosono and Shū Kobayashi

temperatures and strictly anhydrous conditions, this

methodology enabled the aldol reaction to be per-
formed in water at ambient temperature.

6 Asymmetric Catalysts in Aqueous

Media and Water
Recent advances in Mukaiyama aldol reactions in
aqueous media led chemists to examine the possibility
of asymmetric catalysis in an aqueous environment.
Almost all successful examples of catalytic asymmet-
ric variants reported in organic solvents since 1990[92]
entailed absolutely aprotic anhydrous conditions as
well as quite low reaction temperatures (e.g., 78 8C).
Therefore the emergence of facile, convenient, and
environmentally benign methodologies without tedi-
ous operations is desirable. However, a major difficul-
ty in achieving asymmetric catalysis in aqueous media
is the weakness of non-covalent interactions between
Scheme 19. Diastereoselective Mukaiyama aldol reaction
using diphenylboronic acid in water. substrates, chiral ligands, and metal ions under com-
petitive polar conditions. Conversely, if it can be
highly controlled, the construction of asymmetric en-
selectivity were attained in water than in water-THF vironments in the presence of water is expected to in-
solutions. hibit undesired achiral side reactions and impose
Diastereoselective aldol reactions have been suc- stricter stereochemical regulation than in organic sol-
cessfully performed in water in the presence of a cata- vents through the hydrogen bond network, specific
lytic amount of a boron source (diphenylboronic solvation, and hydrophobic interactions. Despite the
acid).[91] Only a trace amount of the product was ob- formidable task of controlling stereochemistry effi-
tained in organic solvents and a much lower yield ciently in an aqueous environment, recent attempts at
than that in water was obtained under neat conditions this challenging endeavor have been successful. The
(24% yield, syn:anti = 90:10). It was found that the successful catalyst systems for asymmetric Mukaiya-
catalytic use of benzoic acid was greatly beneficial for ma aldol reactions between hydrophobic substrates
this reaction (Scheme 19). When stronger acids such are shown in Scheme 20. The underlying strategies in
as hydrochloric acid or p-toluenesulfonic acid were common are: (i) the chiral aqua complex is stable; (ii)
employed, the yield decreased because of competitive the replacement of the coordinated water molecule
hydrolysis of the silicon enolate and the diastereose- by an aldehyde is rapid and facile; and (iii) one enan-
lectivity was also lowered, presumably because of tioface of the coordinated aldehyde carbonyl is shield-
a Brønsted acid-catalyzed reaction pathway. A careful ed effectively.
tuning of the diarylboronic acid structure led to the Copper(II) aqua structures were formed with chiral
discovery that introducing a trifluoromethyl group at bis(oxazoline) templates, although these are normally
the para position brought about a significant rate ac- prepared under anhydrous conditions.[93,94] These re-
celeration compared with the unsubstituted molecule. sults seemed to allude to the latent stability of the
Introduction of an electron-donating group at the copper(II)-bis(oxazoline) complex 36 in an aqueous
para position reduced both the yield and selectivity, environment. Because of the well-known Lewis acid
whereas high selectivity was maintained with elec- activity of copper(II) and its apparent stability in
tron-withdrawing substituents. The first-order kinetics water, Kobayashi et al. examined copper(II)-bis(oxa-
with respect to the amount of silicon enolate support- zoline) complexes as catalysts for asymmetric synthe-
ed the boron-enolate mechanism rather than the sis in aqueous media.[95] The Mukaiyama aldol reac-
Lewis-acid mechanism (Scheme 15). The exchange tions of (Z)-enolate with aldehydes were catalyzed ef-
from silicon to boron was assumed to be the rate-de- ficiently by a chiral copper(II) complex in aqueous
termining step. A significant dependence of the dia- ethanol (H2O:EtOH = 1:9) to afford the desired aldol
stereoselectivity on the enolate geometry implied the adducts in moderate to good yields and enantioselec-
formation of a chair-like six-membered transition tivities (Scheme 21). It is noteworthy that much lower
state in the aldol condensation step. Although tradi- yields and selectivities were observed without water.
tional boron-mediated aldol reactions required lower

3108 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

Scheme 20. Catalytic asymmetric Mukaiyama aldol reaction between hydrophobic substrates in aqueous media.

Exploitation of multicoordination systems is anoth-

er possible solution for the instability of chiral metal
complexes in aqueous environments. The examination
of combinations of chiral crown ethers 37 with metal
triflates on the basis of ionic radii[96] and hole sizes[97]
led to the discovery of an efficient chiral lead(II) cat-
alyst for asymmetric Mukaiyama aldol reactions in
aqueous media (Scheme 22).[98,99,100] PbACHTUNGRE(OTf)2 and
chiral crown ether 37 were quantitatively recovered
by simple extraction. Furthermore, this system could
be applied to thioester-derived silicon enolates as nu-
cleophiles. A kinetic study performed for the chiral
reaction and the PbACHTUNGRE(OTf)2-catalyzed achiral reaction
Scheme 21. First example of an asymmetric Mukaiyama resulted in the observation of almost comparable re-
aldol reaction in aqueous media. action rates and the same levels of diastereoselectiv-
ity.

Scheme 22. Chiral lead(II) catalyst for enantioselective Scheme 23. Chiral praseodymium catalyst for enantioselec-
Mukaiyama aldol reactions. tive Mukaiyama aldol reactions.

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3109
REVIEW Taku Kitanosono and Shū Kobayashi

ated reaction rates, despite the strong coordination of

the Lewis base, compared with the corresponding
achiral pathway without the chiral crown ether. To ex-
plore lanthanide catalysis,[104] macrocyclic gadolinium-
containing polyaminopolycarboxylate-based contrast
agents for magnetic resonance imaging[105] were modi-
fied, and EuACHTUNGRE(III) or NdACHTUNGRE(III) complexes were applied
Scheme 24. Plausible epimerization induced by lanthanides.
to asymmetric Mukaiyama aldol reactions in aqueous
media (Scheme 25). Unfortunately these complexes
Inspired by these successes, intensive efforts have possessed quite low catalytic activities and the activi-
been devoted to stereoselective synthesis in aqueous ties were highly dependent on the substrate.[106]
environments and they have led to the emergence of The highly coordinative nature of these chiral
highly efficient catalytic asymmetric Mukaiyama aldol crown ethers appears to be a key to understanding
reactions using water-compatible Lewis acids with the catalytic behavior of lanthanides in an aqueous
chiral ligands. For example, the catalysts composed of environment. In organic solvents, the coordination of
lanthanide triflates and chiral bis-pyridino-18-crown-6 heteroatoms generally leads to the loss of Lewis acidi-
38 exhibited higher diastereo- and enantioselectivity ty of the metal, because of the behavior of the heter-
(Scheme 23).[45,101,102] A vacant site as shown in oatoms as Lewis bases. In contrast, it is known that
Scheme 23 was suggested to be crucial for catalytic subsequent coordination of water molecules generates
activity as a recipient of an aldehyde molecule. Be- a naked metal cation, which functions as a Lewis acid
cause lanthanides are known to promote the epimeri- in an aqueous environment. A catalytic system com-
zation between syn- and anti-adducts via keto-enoliza- prised of LnACHTUNGRE(OTf)3 and chiral bis-pyridino-18-crown-6
tion, presumably because of their greater Lewis acidi- 38 in aqueous tetrahydrofuran was found to be effec-
ty in aqueous media (Scheme 24),[103] multicoordina- tive for the asymmetric hydroxymethylation reaction
tion systems play a prominent role in chiral induction. (Scheme 26a).[107] A bifunctional system of (R)-
The fit between the crown ether and the metal cat- BINAP-AgOTf complex with a fluoride source was
ions is a prominent factor in attaining high selectivi- applied as a Lewis-base catalyst for the asymmetric
ties; with the larger cations such as La, Ce, Pr and Nd hydroxymethylation of trimethoxysilyl enol ethers de-
providing the aldol adduct with high diastereo- and rived from cyclohexanone (31% yield, 57% ee) or a-
enantioselectivities, while the smaller cations such as
Dy, Ho, Yb, Y and Sc resulted in lower selectivities.
Introduction of an electron-donating (MeO) group at
the 4-position of the pyridine rings led to higher selec-
tivities for the larger cations and lower for the smaller
cations. For the electron-withdrawing (Br) group, al-
though a similar tendency was observed, the effect of
ionic radii was more significant. The asymmetric reac-
tions with lanthanide complexes had slightly deceler-

Scheme 26. (a) Praseodymium- and (b) silver-catalyzed

asymmetric hydroxymethylation in aqueous media.

Scheme 25. Chiral lanthanide catalysts for enantioselective Scheme 27. Scandium-catalyzed asymmetric hydroxymethy-
Mukaiyama aldol reactions. lation in aqueous media.

3110 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

Scheme 28. Mechanistic elucidation for scandium-catalyzed asymmetric hydroxymethylation in aqueous media. L = ligand
41; M = ScACHTUNGRE(OTf)3 ; Sub = substrate 46.

tetralone (18% yield, 57% ee) in aqueous tetrahydro-

furan, albeit in low yield (Scheme 26b).[108]
In 2004, an excellent new catalytic system, based on
a chiral scandium complex, was reported, with higher
yields and enantioselectivities than previous systems
(Scheme 27).[109]
Scheme 29. Bismuth-catalyzed asymmetric hydroxymethyla-
It has been demonstrated for the first time that
tion in aqueous media.
chiral 2,2’-bipyridine 41[110] is an exceedingly effective
ligand for catalytic asymmetric reactions in an aque-
ous environment. Given its potential to chelate with the catalyst. Moreover, saturation kinetics was not ob-
many transition metal ions, the 2,2’-bipyridine back- served, which also denies the direct bond formation
bone may represent a “privileged” ligand structure between the chiral scandium catalyst and the silicon
that can selectively catalyze many unique chemical re- enolate (Scheme 28).
actions in an aqueous environment. The chiral scandi- An extensive effort dedicated to asymmetric hy-
um complex formed with 41 functioned most effec- droxymethylation in aqueous media led to the discov-
tively in an H2O/DME solution. Under optimal condi- ery of a new catalytic system composed of BiACHTUNGRE(OTf)3
tions, asymmetric quaternary carbons can be con- and chiral 2,2’-bipyridine 41 (Scheme 29).[113] Given
structed with high selectivities, and this methodology the ease of hydrolysis in the presence of water,[114] as
can be extended to various substrates such as thioest- well as the great discrepancy in the ionic diameters
er-derived silicon enolates. In some cases, competitive between bismuth (2.34 for 8-coordination) and
hydrolysis of silicon enolates occurred, but could be scandium (1.74 for 8-coordination), this unexpected
resolved by the addition of 2,6-di-tert-butylpyridine as result offered interesting insight into asymmetric cat-
a proton scavenger.[111] Judging from X-ray analysis, alysis in an aqueous environment. Indeed, only
the chiral scandium complex adopts a pentagonal bi- a trace amount of hydroxymethylated adduct was ob-
pyramidal structure where the chiral ligand is bound tained using BiACHTUNGRE(OTf)3 in the absence of 41, because of
to the central scandium in a tetradentate manner. In the rapid decomposition of the silicon enolate pro-
a kinetic study,[112] a first-order dependence on the sil- moted by TfOH, which is generated readily from
icon enolate 46 and the catalyst represents an overall BiACHTUNGRE(OTf)3 in water. The ligand acceleration effect of
rate law: 41 suggests that the stabilization of BiACHTUNGRE(OTf)3 occurs
because of the coordination of 41 in water. A chiral
Rate = k[Silicon Enolate]ACHTUNGRE[Catalyst].
bismuth catalyst consisting of 1 mol% of BiACHTUNGRE(OTf)3,
The observation of the first-order dependence on 3 mol% of 41, and 5 mol% of 2,2’-bipyridyl was
both the silicon enolate and the catalyst negates the shown to afford the desired product in high yields
possible formation of a scandium enolate as an inter- with high enantioselectivity. Fundamental elucidation
mediate and the involvement of discrete molecules of of the catalyst structure through NMR spectroscopy

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3111
REVIEW Taku Kitanosono and Shū Kobayashi

Scheme 30. Equilibrium between bismuth-2,2’-bipyridine 41

complexes.

indicated that two equivalents of BiACHTUNGRE(OTf)3 and one

equivalent of 41 formed complex A, and that complex Scheme 32. Chiral dendritic copper(II) catalyst for enantio-
B consisting of one equivalent of BiACHTUNGRE(OTf)3 and one selective Mukaiyama aldol reactions.
equivalent of 41 was generated when an excess
amount of 41 was added (Scheme 30).[114] It is noted for the asymmetric Mukaiyama aldol reactions in
that complex B is stable even in the presence of 2,2’- aqueous media (Scheme 33). Although both aliphatic
bipyridine, and that B is readily formed from and aromatic aldehydes were applicable with moder-
BiACHTUNGRE(OTf)3-2,2’-bipyridine complex and 41. ate selectivity, aldehydes bearing heteroatoms and
In 2002, GaACHTUNGRE(OTf)3 with chiral Trost-type semicrown aqueous aldehydes were apt to be unsuccessful in the
ligand 39[115] was discovered to be an efficient catalyst former catalytic system. Meanwhile, the latter catalyst
for asymmetric Mukaiyama aldol reactions in aqueous was effective for the reactions of aromatic aldehydes.
media (Scheme 31).[116] UV-vis titration and ESI-MS To overcome the instability, capriciousness, and sen-
analysis confirmed this gallium complex to be a 1:1 sitivity of chiral iron(II) and zinc(II) complexes to
complex.[117] Control experiments performed without many reaction factors, tuned and lipophilic pybox li-
the ligand suggested that it played a key role in accel- gands 51 and 52 were designed (Scheme 34).[121] Al-
erating the reaction and suppressing the hydrolysis of though the selectivity improved comparatively in the
the silicon enolates. Comparably wide substrate scope reactions of some substrates, the reactions of aliphatic
was attained with satisfactory levels of diastereo- and aldehydes still suffered from significant drops in reac-
enantioselectivities from substrates containing thioke- tivity and selectivity.
tene silyl acetals. However, the use of aliphatic alde- In spite of these vigorous explorations pursuing ef-
hydes resulted in a significant loss of enantioselectivity. ficient catalytic systems, there have still been insur-
On the other hand, the C2-symmetric bis(oxazo- mountable limitations in catalytic activity and sub-
lines) 49 disubstituted with two Frchet-type poly- strate scope. Not only did almost all catalytic systems
ether dendrimers exhibited similar reactivities and require 10–20 mol% of Lewis acids and 12–48 mol%
enantioselectivities (up to 78% yield, syn:anti = 2.2:1, of chiral ligands, but these methodologies possessed
64% ee [syn]) for the asymmetric Cu(II)-catalyzed limited scope with some substrates, such as aliphatic
aldol reaction in aqueous media in comparison with aldehydes, for which a remarkable drop in enantiose-
Kobayashis previous work (98% yield, syn:anti = lectivity was commonly observed. In 2012, a wider
2.6:1, 61% ee [syn]) (Scheme 32).[118] substrate scope with outstanding stereoselectivity was
Another promising approach focused upon the achieved in the presence of a chiral iron(II) complex
Lewis acidity of Zn(II) and Fe(II) to develop chiral comprising FeACHTUNGRE(ClO4)2 and chiral 2,2’-bipyridine ligand
catalysts formed with ZnACHTUNGRE(OTf)2 and i-Pr-pybox ligand 41 (Scheme 35).[122,123] Nevertheless, in this catalytic
40[119] or FeCl2 and hydroxymethyl-pybox ligand 50[120] system, an excess amount of chiral ligand was re-

Scheme 31. Chiral gallium catalyst for enantioselective Mukaiyama aldol reactions.

3112 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

Scheme 33. Chiral zinc(II) and iron(II) catalysts for asymmetric Mukaiyama aldol reactions.

Scheme 34. Designed chiral iron(II) and zinc(II) catalysts.

also for enantioselectivity (up to syn:anti = 2.8:1, 69%

ee [syn]). Neither a strong Brønsted acid (CSA) nor
a weaker one (phenol) could improve the yield and
the selectivity. Even with a stoichiometric amount of
the scandium salt, the Brønsted acid was also found
to accelerate the reaction. This implied that the rate-
determining step accelerated by the Brønsted acid
was not the catalyst turnover step, but the nucleophil-
ic addition step.[129,130]
Catalytic asymmetric hydroxymethylation reactions
were successfully carried out with 10 mol% of
Sc(DS)3 and 12 mol% of chiral 2,2’-bipyridine 41 in
Scheme 35. Highly efficient chiral iron(II) catalyst for enan- the presence of Triton X-705 or with 10 mol% of
tioselective Mukaiyama aldol reactions. Sc(OSO2C12H25)3 and 12 mol% of chiral N-oxide
ligand 54[131] in the presence of C12H25SO3Na to afford
quired. Crystallographic investigations revealed that the desired aldol adducts in high yields with high
the central iron(II) ion is held in an almost square- enantioselectivities (Scheme 36).[132] A wide range of
planar fashion and the axial position of the pentago- silicon enolates including thioketene silyl acetals re-
nal bipyramidal iron(II) complex is occupied by an
additional water molecule. ESI-MS measurements
corroborated the formation of a 1:1 complex in the
reaction solution.[124]
Given the dominance of Lewis acid-Lewis base in-
teractions over other interactions and the resulting
loss of their acidity upon coordination to chiral li-
gands, Lewis acid-catalyzed asymmetric reactions in
water using hydrophilic substrates are recognized as
highly challenging, even though chiral induction can
be achieved in aqueous media.[125] The first example
of Lewis acid-catalyzed asymmetric aldol reactions in
pure water was reported as an application of LASC.
As an extension of the chiral copper(II) catalyst in
the water-ethanol system, the combination of
Cu(DS)2 and chiral bis(oxazoline) 36 was em-
ployed.[126] The LASC/Brønsted acid system men-
tioned above was further extended to this asymmetric
reaction (Table 6).[127,128] Benzoic acid and lauric acid Scheme 36. Asymmetric Mukaiyama aldol reactions using
as additives were effective not only for reactivity but formaldehyde in water.

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3113
REVIEW Taku Kitanosono and Shū Kobayashi

(Scheme 37).[133] The chiral amphiphile, which has

been mainly used in enantiomer separation by capil-
ACHTUNGRElary electrochromatography,[134] formed micelles in
water and the changes in the torsion between two
naphthyl rings might result in chiral induction.
PEG- or Triton-supported chiral bis(oxazoline)
has been employed in combination with copper(II)
salts as a catalyst for the Mukaiyama aldol reactions
of ketene silyl acetal derived from methyl isobutyrate
with aldehydes in water (Scheme 38).[135]
The Silica-Sc-IL system was also rendered asym-
Scheme 37. Chiral surfactant for enantioselective Mukaiya- metric by the addition of 56 (up to 28% yield, 66%
ma aldol reactions. ee, Scheme 39).[136] The high solubility of these ligands
in water allowed a very convenient catalyst-recycling
procedure.

7 Conclusions and Perspective

Mukaiyama aldol reactions in aqueous media have
been surveyed. While the original Mukaiyama aldol
reactions were carried out using stoichiometric
amounts of Lewis acids such as TiCl4 in organic sol-
vents under strictly anhydrous conditions, the reac-
tions were also found to proceed in water. The first
discovery was just the use of water in the reactions,
which might work as a Lewis base. However, the reac-
tions proceeded slowly and the yields were moderate.
It was then discovered that Mukaiyama aldol reac-
tions proceeded smoothly in the presence of lantha-
Scheme 38. Triton-supported chiral copper(II) complex for
nide triflates in aqueous solvents. A catalytic amount
enantioselective Mukaiyama aldol reactions. of lanthanide triflates worked well and high yields
with wide substrate scope were obtained. The original
Mukaiyama aldol reactions were expanded signifi-
cantly, because the reactions proceeded under milder
conditions and strict anhydrous conditions were not
required. Moreover, water-soluble substrates, water-
containing substrates, and substrates bearing basic ni-
trogen atoms and free hydroxy groups and others can
be used in aqueous Mukaiyama aldol reactions. The
catalyst, lanthanide triflate, can be easily recovered
and reused, and the reactions are thus suitable for
green sustainable chemistry.
Another important aspect of this discovery of the
Scheme 39. Catalytic asymmetric hydroxymethylation using lanthanide-catalyzed aqueous Mukaiyama aldol reac-
Silica-Sc-IL. tions is the expansion of the concepts of Lewis acids
and organic reactions in water. Before this discovery,
acted smoothly and high enantioselectivities were at- it was believed that Lewis acids decomposed rapidly
tained. Centrifugation of the reaction mixture even in the presence of small amounts of water. How-
(3000 rpm, 20 min) led to the successful separation of ever, it was found that lanthanide triflates worked
the colloidal dispersion into three phases; the upper, well as catalysts under aqueous conditions, and this
middle, and bottom phases corresponding to the finding led to the discovery of a series of water-com-
water, surfactant, and organic layers, respectively. patible Lewis acids. Scandium triflate is now one of
Chiral disulfonated binaphthyl dialkyl ethers with the most popular and frequently used Lewis acids in
GaACHTUNGRE(OTf)3 and CuACHTUNGRE(OTf)2 catalyzed the asymmetric organic synthesis; it was discovered during this work
Mukaiyama aldol reactions more efficiently than did as a water-compatible Lewis acid. Water-compatible
ScACHTUNGRE(OTf)3 in water with moderate selectivities Lewis acids have evolved to water-compatible chiral

3114 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

Lewis acids for asymmetric Mukaiyama aldol reac- [3] T. Mukaiyama, K. Banno, K. Narasaka, J. Am. Chem.
tions. Several new concepts have been introduced to Soc. 1974, 96, 7503–7509.
stabilize chiral Lewis acids under aqueous conditions, [4] For instance, see: a) M. Oishi, S. Aratake, H. Yama-
and these have been applied to other asymmetric re- moto, J. Am. Chem. Soc. 1998, 120, 8271–8272;
b) D. A. Evans, C. S. Burgey, M. C. Kozlowski, S. W.
actions in aqueous media.
Tregay, J. Am. Chem. Soc. 1999, 121, 686–699; c) K.
On the other hand, progress has also been made
Oisaki, Y. Suto, M. Kanai, M. Shibasaki, J. Am.
with organic reactions in water. Water is a clean, non- Chem. Soc. 2003, 125, 5644–5645.
toxic, and inexpensive solvent and thus is suitable for [5] a) T. Mukaiyama, Angew. Chem. 1977, 89, 858–866;
green sustainable chemistry. In addition, many excel- Angew. Chem. Int. Ed. Engl. 1977, 16, 817–826; b) T.
lent in vivo reactions are carried out using enzymes as Mukaiyama, T. Soga, H. Takenoshita, Chem. Lett.
catalysts under aqueous conditions. Aqueous environ- 1989, 997–1000.
ments often produce singular phenomena not ob- [6] a) M. Ohshima, M. Murakami, T. Mukaiyama, Chem.
served in conventional organic solvents, including rate Lett. 1985, 1871–1874; b) I. Mori, P. A. Bartlett, C. H.
acceleration and different selectivities. These benefi- Heathcock, J. Org. Chem. 1990, 55, 5966–5977.
cial effects in the presence of water are ascribed to its [7] a) I. Ojima, S. Inaba, Tetrahedron Lett. 1980, 21, 2077–
high dielectric constant and high cohesive energy den- 2080; b) I. Ojima, S. Inaba, M. Nagai, Synthesis 1981,
545–547; c) K. Ikeda, K. Achiwa, M. Sekiya, Tetrahe-
sity. The favorable transition states are stipulated by
dron Lett. 1983, 24, 4707–4710.
entropy-driven aggregation, dipole-dipole interaction, [8] a) Y. Matsumura, J. Fujiwara, K. Maruoka, H. Yama-
rapid proton-transfer in the order of picoseconds and moto, J. Am. Chem. Soc. 1983, 105, 6312–6314; b) O.
so on.[137] Dissociation is sometimes highly accelerated Osamu, H. Oyamada, T. Furuta, S. Kobayashi, Hetero-
by the nucleophilic addition of water. cycles 2000, 52, 1143–1162.
The chemistry in this field is, however, still imma- [9] Review: G. Casiraghi, L. Battistini, C. Curti, G. Rassu,
ture because of an intimate dependence of catalyst F. Zanardi, Chem. Rev. 2011, 111, 3076–3154.
structure on substrates. Compared with the well-re- [10] a) A. Hosomi, M. Endo, H. Sakurai, Chem. Lett. 1976,
fined catalytic systems for asymmetric hydroxymethy- 941–942; b) A. Hosomi, H. Sakurai, Tetrahedron Lett.
lation in aqueous media, contemporary catalysts for 1976, 17, 1295–1298; c) I. Fleming, in: Comprehensive
reactions between hydrophobic substrates have the Organic Synthesis, Pergamon Press, Oxford, 1991, Vol.
2, pp 563–593.
fault of substrate specificity and lack broader catalytic
[11] D. A. Evans, L. K. Truesdale, G. L. Carroll, JH. Chem.
activities. The advances reported here will have an Soc. Chem. Commun. 1973, 55–56.
immense impact on organic chemistry as an expedi- [12] S. Murata, M. Suzuki, R. Noyori, J. Am. Chem. Soc.
ent, environmentally benign and highly efficient tactic 1980, 102, 3248–3249.
capable of accessing optically active aldols. Moreover, [13] a) T. Mukaiyama, S. Kobayashi, M. Murakami, Chem.
the role of water in Mukaiyama aldol reactions war- Lett. 1985, 14, 447–450; b) S. Kobayashi, M. Muraka-
rants further investigations. mi, T. Mukaiyama, Chem. Lett. 1985, 14, 1535–1538.
[14] a) A. Lubineau, J. Org. Chem. 1986, 51, 2142–2144;
b) A. Lubineau, E. Meyer, Tetrahedron 1988, 44,
6065–6070.
Acknowledgements [15] T. Mukaiyama, K. Banno, K. Narasaka, J. Am. Chem.
Soc. 1974, 96, 7503–7509.
This work was partially supported by a Grant-in-Aid for Sci- [16] A. Lubineau, J. Aug, Top. Curr. Chem. 1999, 206, 1–
ence Research from the Japan Society for the Promotion of 39.
Science (JSPS), Global COE Program, The University of [17] Y. Yamamoto, K. Maruyama, K. Matsumoto, J. Am.
Tokyo, MEXT, Japan, Japan Science Technology Agency Chem. Soc. 1983, 105, 6963–6965.
(JST). T.K. thanks the JSPS for a Research Fellowship for
[18] Review on the effect of water, see: a) M. Pirrung,
Young Scientists.
Chem. Eur. J. 2006, 12, 1312–1317; b) M. B. Gawande,
V. D. B. Bonifcio, R. Luque, P. S. Branco, R. S.
Varma, Chem. Soc. Rev. 2013, 42, 5522–5551.
References [19] Investigation on transition state geometry of the aldol
reaction in aqueous media, see: S. Denmark, W. Lee,
[1] a) S. B. J. Kan, K. K.-H. Ng, I. Paterson, Angew. R. Adams, Tetrahedron Lett. 1992, 33, 7729–7732.
Chem. 2013, 125, 9267–9275; Angew. Chem. Int. Ed. [20] T.-P. Loh, L.-C. Feng, L.-L. Wei, Tetrahedron 2000, 56,
2013, 52, 9097–9108; b) S. Kobayashi, Y. Yamashita, 7309–7312.
W.-J. Yoo, T. Kitanosono, J.-F. Soul, The Aldol Reac- [21] J. Alam, T. Keller, T. Loh, J. Am. Chem. Soc. 2010,
tion: Group IV Enolates (Mukaiyama, Enol Ethers), 132, 9546–9548.
in: Comprehensive Organic Synthesis, 2nd edn., Elosev- [22] C. Curti, L. Battistini, F. Zanardi, G. Rassu, V. Zam-
ier, London, in press. brano, L. Pinna, G. Casiraghi, J. Org. Chem. 2010, 75,
[2] M. B. Smith, Marchs Advanced Organic Chemistry: 8681–8684.
Reactions, Mechanisms and Structure, 7th edn., Wiley, [23] M. D. Rosa, A. Soriente, Tetrahedron 2011, 67, 5949–
New Jersey, 2013. 5955.

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3115
REVIEW Taku Kitanosono and Shū Kobayashi

[24] a) Y. Huang, V. H. Rawal, Org. Lett. 2000, 2, 3321– [42] Fringuelli and co-workers reported the use of AlACHTUNGRE(III),
3323; b) Y. Huang, V. H. Rawal, J. Am. Chem. Soc. Ti(IV), and Sn(IV) as Lewis acids for epoxide opening
2002, 124, 9662–9663. reactions in acidic water with its pH is adjusted by
[25] They are reported to be prepared in aqueous solution: adding H2SO4. F. Fringuelli, F. Pizzo, L. Vaccaro, J.
a) K. F. Thom, U.S. Patent 3,615,169, 1971; Chem. Org. Chem. 2001, 66, 3554–3558.
Abstr. 1972, 76, 5436a; b) J. H. Forsberg, V. T. Spazia- [43] The pHs of YbACHTUNGRE(OTf)3 solutions were measured as fol-
no, T. M. Balasubramanian, G. K. Liu, S. A. Kinsley, lows: 5.90 (1.6 10 2 M, H2O:THF = 1:4), 6.40 (8.0
C. A. Duckworth, J. J. Poteruca, P. S. Brown, J. L. 10 2 M, H2O).
Miller, J. Org. Chem. 1987, 52, 1017–1021. [44] D. J. Averill, P. Dissanayake, M. J. Allen, Molecules
[26] a) S. Kobayashi, Lanthanide Triflate-Catalyzed 2012, 17, 2073–2081.
Carbon-Carbon Bond-Forming Reactions in Organic [45] C. H. Heathcock, in: Asymmetric Synthesis, Vol. 3,
Synthesis, in Lanthanides: Chemistry and Use in Or- Part B., (Ed.: J. D. Morrison), Academic Press, New
ganic Synthesis, (Ed.: S. Kobayashi), Springer, Heidel- York, 1984, p 111.
berg, 1999, pp 63–118; b) S. Kobayashi, Synlett 1994, [46] 8 103 according to ref.[41]
689–701; c) S. Kobayashi, Eur. J. Org. Chem. 1999, 15– [47] S. Murata, M. Suzuki, R. Noyori, J. Am. Chem. Soc.
27; d) S. Kobayashi, M. Sugiura, H. Kitagawa, W. W.- 1980, 102, 3248–3249.
L. Lam, Chem. Rev. 2002, 102, 2227–2302; e) S. Ko- [48] M. Hatanaka, S. Maeda, K. Morokuma, J. Chem.
bayashi, C. Ogawa, Chem. Eur. J. 2006, 12, 5954–5960. Theory Comput. 2013, 9, 2882–2886.
[27] S. Kobayashi, Chem. Lett. 1991, 2187–2190. [49] A. Graven, M. Grøtli, M. Meldal, J. Chem. Soc.
[28] S. Kobayashi, I. Hachiya, Y. Yamanoi, Bull. Chem. Perkin Trans. 1 2000, 955–962.
Soc. Jpn. 1994, 67, 2342–2344. [50] H. Sawada, J. Kurachi, T. Maekawa, T. Kawase, K.
[29] a) S. Kobayashi, I. Hachiya, Tetrahedron Lett. 1992, Oharu, H. Nakagawa, K. Ohira, Polym. J. 2002, 34,
33, 1625–1628; b) S. Kobayashi, I. Hachiya, J. Org. 858–859.
Chem. 1994, 59, 3590–3596; c) S. Kobayashi, Synlett [51] H. Sawada, S. Katayama, Y. Ariyoshi, T. Kawase, Y.
1994, 689–699. Hayakawa, T. Tomita, M. Baba, J. Mater. Chem. 1998,
[30] The aldols were obtained only in ca. 10% yields. 8, 1517–1524.
[31] a) T. A. Geissman, Org. React. 1944, 2, 94–113; b) T. [52] K. Nomiya, K. Ohta, Y. Sakai, T. Hosoya, A. Ohtake,
Neilsen, A. T. Houlihan, Org. React. 1968, 16, 1–438. A. Takakura, S. Matsunaga, Bull. Chem. Soc. Jpn.
[32] For example, paraformaldehyde and trioxane.
2013, 86, 800–812.
[33] S. Arseniyadis, Q. Wang, D. V. Yashunsky, T. Kaoudi,
[53] J. Zeitouni, S. Norsikian, D. Merlet, A. Lubineau,
R. B. Alves, P. Potier, Tetrahedron Lett. 1995, 36,
Adv. Synth. Catal. 2006, 348, 1662–1670.
1633–1636.
[54] T.-P. Loh, X.-R. Li, Tetrahedron 1999, 55, 10789–
[34] P. Bernardelli, O. M. Moradei, D. Friedrich, J. Yang, F.
10802.
Gallou, B. P. Dyck, R. W. Doskotch, T. Lange, L. A.
[55] a) T. Mukaiyama, H. Fujisawa, T. Nakagawa, Helv.
Praquette, J. Am. Chem. Soc. 2001, 123, 9021–9032.
Chim. Acta 2002, 85, 4518–4531; b) H. Hagiwara, H.
[35] a) K. C. Nicolaou, X. Huang, N. Giuseppone, P. B.
Inoguchi, M. Fukushima, T. Hoshi, T. Suzuki, Synlett
Rao, M. Bella, M. V. Reddy, S. A. Snyder, Angew.
2005, 2388–2390; c) M. Hatano, E. Takagi, K. Ishihara,
Chem. 2001, 113, 4841–4845; Angew. Chem. Int. Ed.
Org. Lett. 2007, 9, 4527–4530.
2001, 40, 4705–4709; b) K. C. Nicolaou, J. Hao, M. V.
Reddy, P. B. Rao, G. Rassias, S. A. Synder, X. Huang, [56] H.-J. Li, J.-L. Zhao, Y.-J. Chen, L. Li, D. Wang, C.-J.
D. Y.-K. Chen, W. E. Brenzovich, N. Giuseppone, P. Li, Green Chem. 2005, 7, 61–63.
Giannakakou, A. OBrate, J. Am. Chem. Soc. 2004, [57] A. T. Nielsen, W. J. Houlihan, Organic Reactions,
126, 12897–12906. 1968, Vol. 16, pp 1–438.
[36] T. Ohshima, Y. Xu, R. Takita, S. Shimizu, D. Zhong, [58] K. Miura, H. Sato, K. Tamaki, H. Ito, A. Hosomi, Tet-
M. Shibasaki, J. Am. Chem. Soc. 2002, 124, 14546– rahedron Lett. 1998, 39, 2585–2588.
14547. [59] CaCl2 has been reported to be ineffective in the reac-
[37] J. Shiina, M. Oikawa, K. Nakamura, R. Obata, S. tion with TMS enolate.
Nishiyama, Eur. J. Org. Chem. 2007, 5190–5197. [60] a) H. Fujisawa, T. Mukaiyama, Chem. Lett. 2002, 182–
[38] a) N. Kagawa, M. Ihara, M. Toyota, Org. Lett. 2006, 8, 183; b) H. Fujisawa, T. Mukaiyama, Chem. Lett. 2002,
875–878; b) N. Kagawa, M. Ihara, M. Toyota, J. Org. 858–859; c) T. Mukaiyama, H. Fujisawa, T. Nakagawa,
Chem. 2006, 71, 6796–6805. Helv. Chim. Acta 2002, 85, 4518–4531.
[39] A. Mendoza, Y. Ishihara, P. S. Baran, Nature Chem. [61] T. Nakagawa, H. Fujisawa, Y. Nagata, T. Mukaiyama,
2012, 4, 21–25. Bull. Chem. Soc. Jpn. 2004, 77, 1555–1567.
[40] S. Kobayashi, S. Nagayama, T. Busujima, J. Am. [62] M. Kokubo, S. Kobayashi, Synlett 2008, 1562–1564.
Chem. Soc. 1998, 120, 8287–8288. [63] For fluoride ion-catalyzed reactions, see: a) R. Noyori,
[41] a) C. F. Baes Jr, R. E. Mesmer, The Hydrolysis of I. Nishida, J. Sakata, J. Am. Chem. Soc. 1983, 105,
Cations, John Wiley & Sons, New York, 1976; b) K. B. 1598–1608; b) E. Nakamura, M. Shimizu, I. Kuwajima,
Yatsimirksii, V. P. Vasil’ev, Instability Constants of J. Sakata, K. Yokoyama, R. Noyori, J. Org. Chem.
Complex Compounds, Pergamon, New York, 1960; 1983, 48, 932–945.
c) A. E. Martell, (Ed.), Coordination Chemistry, ACS [64] a) A. Yanagisawa, Y. Nakatsuka, K. Asakawa, H. Ka-
Monograph 168; American Chemical Society, Wash- gayama, H. Yamamoto, Synlett 2001, 69–72; b) A. Ya-
ington, DC, 1978, Vol. 2. nagisawa, Y. Nakatsuka, K. Asakawa, M. Wadamoto,

3116 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118
Mukaiyama Aldol Reactions in Aqueous Media

H. Kageyama, H. Yamamoto, Bull. Chem. Soc. Jpn. [86] H.-Y. Tian, Y.-J. Chen, D. Wang, C.-C. Zeng, C.-J. Li,
2001, 74, 1477–1484. Tetrahedron Lett. 2000, 41, 2529–2532.
[65] For example, sodium dodecyl sulfate (SDS). [87] H.-Y. Tian, Y.-J. Chen, D. Wang, Y.-P. Bu, C.-J. Li, Tet-
[66] For example, Triton X. rahedron Lett. 2001, 42, 1803–1805.
[67] S. Kobayashi, T. Wakabayashi, S. Nagayama, H. Oya- [88] a) J. Nishikido, M. Nanbo, A. Yoshida, H. Nakajima,
mada, Tetrahedron Lett. 1997, 38, 4559–4562. Y. Matsumoto, K. Mikami, Synlett 2002, 1613–1616;
[68] a) S. Kobayashi, T. Wakabayashi, Tetrahedron Lett. b) J. Nishikido, A. Yoshida, J. Synth. Org. Chem. Jpn.
1998, 39, 5389–5392; b) S. Kobayashi, K. Manabe, in: 2005, 63, 144–153.
Clean Solvents, ACS Symposium Series, American [89] L. D. Wilson, R. E. Verrall, J. Phys. Chem. B 1997,
Chemical Society, Washington, D.C., 2002, Vol. 819, 101, 9270–9279.
pp 151–1665; c) M. Shiri, M. Zolfigol, Tetrahedron [90] N. Aoyama, K. Manabe, S. Kobayashi, Chem. Lett.
2009, 65, 587–598. 2004, 33, 312–313.
[69] The rate acceleration by copper(II) bis(dodecyl sul- [91] a) Y. Mori, K. Manabe, S. Kobayashi, Angew. Chem.
fate) [Cu(DS)2] in Diels–Alder reactions in water was Int. Ed. 2001, 40, 2816–2818; b) Y. Mori, J. Kobayashi,
described previously, see: S. Otto, F. Bertoncin, K. Manabe, S. Kobayashi, Tetrahedron 2002, 58, 8263–
J. B. F. N. Engberts, J. Am. Chem. Soc. 1996, 118, 8268.
7702–7707. [92] a) S. Kobayashi, Y. Fujishita, T. Mukaiyama, Chem.
[70] a) K. Manabe, S. Kobayashi, Synlett 1999, 547–548; Lett. 1990, 1455–1458; b) T. Mukaiyama, S. Kobayashi,
b) S. Kobayashi, K. Manabe, Acc. Chem. Res. 2002, H. Uchiro, I. Shiina, Chem. Lett. 1990, 129–132. See
35, 209–217. also, c) M. T. Reetz, S.-H. Kyung, C. Bolm, T. Zierke,
[71] For example, Mannich-type reactions: K. Manabe, S. Chem. Ind. 1986, 824; d) M. T. Reetz, F. Kunisch, P.
Kobayashi, Org. Lett. 1999, 1, 1965–1967; Diels–Alder Heitmann, Tetrahedron Lett. 1986, 27, 4721–4724.
reactions: K. Manabe, Y. Mori, S. Kobayashi, Tetrahe- [93] a) D. A. Evans, E. J. Olhava, J. S. Johnson, J. M. Janey,
dron 1999, 55, 11203–11208; Michael reactions: Y. Angew. Chem. 1998, 110, 3553–3557; Angew. Chem.
Mori, K. Kakumoto, K. Manabe, S. Kobayashi, Tetra- Int. Ed. 1998, 37, 3372–3375; b) D. A. Evans, S. J.
hedron Lett. 2000, 41, 3107–3111. Miller, T. Lectka, P. Von Matt, J. Am. Chem. Soc.
[72] T. Dwars, E. Paetzold, G. Oehme, Angew. Chem. 1999, 121, 7559–7573.
2005, 117, 7338–7364; Angew. Chem. Int. Ed. 2005, 44, [94] As an example of other uses of aqua complexes, hy-
7174–7199.
drated nickel complex: a) S. Kanemasa, Y. Oderao-
[73] B. Cabane, J. Phys. Chem. 1977, 81, 1639–1645.
toshi, H. Yamamoto, J. Tanaka, E. Wada, D. P.
[74] The basic principles of surfactants and micellar
Curran, J. Org. Chem. 1997, 62, 6454–6455; b) S. Ka-
chemistry are reviewed, see: a) K. Goodling, K. John-
nemasa, Y. Oderaotoshi, S. Sakaguchi, H. Yamamoto,
son, L. Lefkowitz, B. W. Williams, J. Chem. Educ.
J. Tanaka, E. Wada, D. P. Curran, J. Am. Chem. Soc.
1994, 71, A8–A12; b) J. V. Stam, S. Depaemelaere,
1998, 120, 3074–3088; c) S. Kanemasa, Y. Oderaotoshi,
F. C. D. Schryver, J. Chem. Educ. 1998, 75, 93–98.
J. Tanaka, E. Wada, Tetrahedron Lett. 1998, 39, 7521–
[75] B. Cabane, J. Physique 1981, 42, 847–859.
7524.
[76] K. Manabe, Y. Mori, T. Wakabayashi, S. Nagayama, S.
[95] a) S. Kobayashi, S. Nagayama, T. Busujima, Chem.
Kobayashi, J. Am. Chem. Soc. 2000, 122, 7202–7207.
Lett. 1999, 71–72; b) S. Kobayashi, S. Nagayama, T.
[77] a) K. Manabe, S. Kobayashi, Tetrahedron Lett. 1999,
40, 3773–3776; b) K. Manabe, Y. Mori, S. Nagayama, Busujima, Tetrahedron 1999, 55, 8739–8746.
K. Odashima, S. Kobayashi, Inorg. Chim. Acta 1999, [96] a) R. D. Shannon, C. T. Prewitt, Acta Crystallogr. B:
296, 158–163. 1969, 25, 925–946; b) R. D. Shannon, Acta Crystallogr.
[78] Y. Ruland, P. Noereuil, M. Baltas, Tetrahedron 2005, A: 1976, 32, 751–767.
61, 8895–8903. [97] a) E. P. Kyba, R. C. Helheson, K. Madan, G. W.
[79] S. Nagayama, S. Kobayashi, Angew. Chem. 2000, 112, Gokel, T. L. Tarnowski, S. S. Moore, D. J. Cram, J.
578–581; Angew. Chem. Int. Ed. 2000, 39, 567–569. Am. Chem. Soc. 1977, 99, 2564–2571; b) E. P. Kyba,
[80] S. Iimura, K. Manabe, S. Kobayashi, Tetrahedron G. W. Gokel, F. de Jong, K. Koga, L. R. Sousa, M. G.
2004, 60, 7673–7678. Siegel, L. Kaplan, G. D. Y. Sogah, D. J. Cram, J. Org.
[81] The most common types of mesoporous nanoparticles. Chem. 1977, 42, 4173–4184.
[82] F. Zhang, C. Liang, M. Chen, H. Guo, H. Jiang, H. Li, [98] S. Nagayama, S. Kobayashi, J. Am. Chem. Soc. 2000,
Green Chem. 2013, advance article. 122, 11531–11532.
[83] a) Y. Gu, C. Ogawa, J. Kobayashi, Y. Mori, S. Kobaya- [99] S. Kobayashi, T. Hamada, S. Nagayama, K. Manabe, J.
shi, Angew. Chem. 2006, 118, 7375–7378; Angew. Braz. Chem. Soc. 2001, 12, 627–633.
Chem. Int. Ed. 2006, 45, 7217–7220; b) C. Ogawa, S. [100] Ionic diameter of Pb2+ (CN = 8) is 258 pm (see ref.[96])
Kobayashi, Catalytic Asymmetric Synthesis in Noncon- and the hole size of 18-crown-6 was reported to be
ventional Media/Conditions, in: Catalytic Asymmetric 260–320 pm.
Synthesis, 3rd edn., (Ed.: I. Ojima), Wiley, Chicester, [101] a) S. Kobayashi, T. Hamada, S. Nagayama, K.
2010, pp 1–36. Manabe, Org. Lett. 2001, 3, 165–167; b) T. Hamada,
[84] M. Reetz, D. Giebel, Angew. Chem. 2000, 112, 2614– K. Manabe, S. Ishikawa, S. Nagayama, M. Shiro, S.
2617; Angew. Chem. Int. Ed. 2000, 39, 2498–2501. Kobayashi, J. Am. Chem. Soc. 2003, 125, 2989–2996.
[85] W. Gu, W. Zhou, D. Gin, Chem. Mater. 2001, 13, [102] For complexation of rare-earth metals with macrocy-
1949–1951. clic ligands, see: a) D. E. Fenton, P. A. Vigato, Chem.

Adv. Synth. Catal. 2013, 355, 3095 – 3118 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3117
REVIEW Taku Kitanosono and Shū Kobayashi

Soc. Rev. 1988, 17, 69–90; b) V. Alexander, Chem. [121] a) J. Jankowska, J. Paradowska, B. Rakiel, J. Mlynar-
Rev. 1995, 95, 273–342. ski, J. Org. Chem. 2007, 72, 2228–2231; b) J. Mlynar-
[103] O. MuÇoz-MuÇiz, M. Quintanar-Audelo, E. Juaristi, J. ski, J. Paradowska, Chem. Soc. Rev. 2008, 37, 1502–
Org. Chem. 2003, 68, 1622–1625. 1511.
[104] P. W. Roesky, (Ed.), Molecular Catalysis of Rare-Earth [122] T. Ollevier, B. Plancq, Chem. Commun. 2012, 48,
Elements, Springer-Verlag: Berlin, Heidelberg, 2010. 2289–2291.
[105] P. Caravan, J. J. Ellison, T. J. McMurry, R. B. Lauffer, [123] Quite recently, extensive research was reported, see:
Chem. Rev. 1999, 99, 2293–2352. T. Kiatanosono, T. Ollevier, S. Kobayashi, Chem.
[106] a) Y. Mei, P. Dissanayake, M. J. Allen, J. Am. Chem. Asian J. 2013, DOI: 10.1002/asia.201301149.
Soc. 2010, 132, 12871–12873; b) Y. Mei, D. J. Averill, [124] B. Plancq, T. Ollevier, Chem. Commun. 2012, 48,
M. J. Allen, J. Org. Chem. 2012, 77, 5624–5632. 3806–3808.
[107] K. Manabe, S. Ishikawa, T. Hamada, S. Kobayashi, [125] S. Kobayashi, C. Ogawa, in: Asymmetric Synthesis –
Tetrahedron 2003, 59, 10439–10444. The Essentials, (Eds.: M. Christmann, S. Br se),
[108] N. Ozawa, M. Wadamoto, K. Ishihara, H. Yamamoto, Wiley-VCH, Weinheim, 2007, pp 110–115.
Synlett 2003, 2219–2221. [126] S. Kobayashi, Y. Mori, S. Nagayama, K. Manabe,
[109] S. Ishikawa, T. Hamada, K. Manabe, S. Kobayashi, J. Green Chem. 1999, 1, 175–178.
Am. Chem. Soc. 2004, 126, 12236–12237.
[127] For other examples of Brønsted acid-assisted chiral
[110] a) C. Bolm, M. Zehnder, D. Bur, Angew. Chem. 1990,
Lewis acid catalyst, see: K. Ishihara, H. Yamamoto, J.
102, 206–208; Angew. Chem. Int. Ed. Engl. 1990, 29,
Am. Chem. Soc. 1994, 116, 1561–1562; for acetic acid
205–207; b) C. Bolm, M. Ewald, M. Felder, G.
acceleration in YbACHTUNGRE(fod)3-catalyzed ene reaction of al-
Schlingloff, Chem. Ber. 1992, 125, 1169–1190.
dehydes with alkyl vinyl ethers, see: M. V. Deaton,
[111] 2,6-Di-tert-butylpyridine was added as an additive for
M. A. Ciufolini, Tetrahedron Lett. 1993, 34, 2409–2412.
Lewis acid-catalyzed Mukaiyama aldol reactions, see:
a) S. Murata, M. Suzuki, R. Noyori, Tetrahedron 1988, [128] Brønsted acids have been used as catalysts for Mu-
44, 4275–4277; b) ref.[59b] kaiyama aldol reactions in organic solvents, see: M.
[112] C. Mukherjee, T. Kitanosono, S. Kobayashi, Chem. Kawai, M. Onaka, Y. Izumi, Bull. Chem. Soc. Jpn.
Asian J. 2011, 6, 2308–2311. 1988, 61, 1237–1245.
[113] a) S. Kobayashi, T. Ogino, H. Shimizu, S. Ishikawa, T. [129] Greeves et al. reported benzoic acid (1 equiv.) acceler-
Hamada, K. Manabe, Org. Lett. 2005, 7, 4729–4731; ation in YbACHTUNGRE(OTf)3-catalyzed allylation of aldehydes in
b) S. Kobayashi, M. Ueno, T. Kitanosono, Top. Curr. acetonitrile and proposed the mechanism whereby it
Chem. 2012, 311, 1–17. accelerated the catalyst regeneration step, see: H. C.
[114] S. Rpichet, A. Zwick, L. Vendier, C. L. Roux, J. Aspinall, N. Greeves, E. G. McIver, Tetrahedron Lett.
Dubac, Tetrahedron Lett. 2002, 43, 993–995. 1998, 39, 9283–9286.
[115] Trost developed a dinuclear zinc catalyst system with [130] Evans et al. reported that the addition of TMSOTf ac-
a chiral semicrown ether, which was applied to cata- celerated the rate-limiting catalyst turnover step in
lytic asymmetric direct aldol reactions, Henry reac- their chiral Lewis acid-catalyzed Mukaiyama aldol re-
tions, Mannich-type reactions and diol desymmetriza- action under anhydrous conditions, see: D. A. Evans,
tions. For example, see: a) B. M. Trost, H. Ito, J. Am. M. C. Kozlowski, C. S. Burgey, D. W. C. MacMillan, J.
Chem. Soc. 2000, 122, 12003–12004; b) B. M. Trost, H. Am. Chem. Soc. 1997, 119, 7893–7894.
Ito, E. R. Silcoff, J. Am. Chem. Soc. 2001, 123, 3367– [131] a) D. Shang, J. Xin, Y. Liu, X. Zhou, X. Liu, X. Feng,
3368; c) B. M. Trost, V. S. C. Yeh, Angew. Chem. 2002, J. Org. Chem. 2008, 73, 630–637; b) M. Nakajima, M.
114, 889–891; Angew. Chem. Int. Ed. 2002, 41, 861– Yamaguchi, S. Hashimoto, Chem. Commun. 2001,
863; d) B. M. Trost, V. S. C. Yeh, H. Ito, N. Bremeyer, 1596–1597.
Org. Lett. 2002, 4, 2621–2623; e) B. M. Trost, V. S. C. [132] M. Kokubo, C. Ogawa, S. Kobayashi, Angew. Chem.
Yeh, Org. Lett. 2002, 4, 3513–3516; f) B. M. Trost, 2008, 120, 7015–7017; Angew. Chem. Int. Ed. 2008, 47,
L. R. Terrell, J. Am. Chem. Soc. 2003, 125, 338–339; 6909–6911.
g) B. M. Trost, T. Mino, J. Am. Chem. Soc. 2003, 125, [133] H. J. Li, H. Y. Tian, Y. J. Chen, D. Wang, C.-J. Li, J.
2410–2411; h) B. M. Trost, A. Fettes, B. T. Shireman, J. Chem. Res. (S) 2003, 153–156.
Am. Chem. Soc. 2004, 126, 2660–2661. [134] a) K. Otsuka, S. Terabbe, J. Chromatogr. A: 2000, 875,
[116] H.-J. Li, H.-Y. Tian, Y.-J. Chen, D. Wang, C.-J. Li, 163–178; b) C. Partric, Electrophoresis 1997, 18, 2322–
Chem. Commun. 2002, 2994–2995. 2330.
[117] H.-J. Li, H.-Y. Tian, Y.-C. Wu, Y.-J. Chen, L. Liu, D. [135] M. Benaglia, M. Cinquini, F. Cozzi, G. Celentano,
Wang, C.-J. Li, Adv. Synth. Catal. 2005, 347, 1247– Org. Biomol. Chem. 2004, 2, 3401–3407.
1256. [136] Y. Gu, C. Ogawa, J. Kobayashi, Y. Mori, S. Kobayashi,
[118] B.-Y. Yang, X.-M. Chen, G.-J. Deng, Y.-L. Zhang, Q.- Angew. Chem. 2006, 118, 7375–7378; Angew. Chem.
H. Fan, Tetrahedron Lett. 2003, 44, 3535–3538.
Int. Ed. 2006, 45, 7217–7220.
[119] a) J. Mlynarski, J. Jankowska, Adv. Synth. Catal. 2005,
[137] Quite recently these experimental findings were sup-
347, 521–525; b) J. Jankowska, J. Mlynarski, J. Org.
ported by Morokuma et al. from the standpoint of
Chem. 2006, 71, 1317–1321.
computational studies; M. Hatanaka, K. Morokuma,
[120] J. Jankowska, J. Paradowska, J. Mlynarski, Tetrahe-
J. Am. Chem. Soc. 2013, 135, 13972–13979.
dron Lett. 2006, 47, 5281–5284.

3118 asc.wiley-vch.de 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3095 – 3118