Catalytic Enantioselective Benzilic Ester Rearrangement

Article abstract of DOI:10.1002/anie.202001258

We report the first examples of catalytic enantioselective benzilic ester rearrangement reaction. In the presence of a catalytic amount of Cu(OTf)₂ and a chiral box ligand under mild conditions, reaction of 2,3-diketoesters with alcohols afforded structurally diverse α-aryl(alkyl) substituted-α-hydroxy malonates (tartronic esters) in good to excellent yields with high enantioselectivities. Preliminary mechanistic studies indicated that hemiketalization, rather than the dynamic kinetic resolution of hemiketal, was the enantiodetermining step under our reaction conditions.

Full text of DOI:10.1002/anie.202001258

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Accepted Article
Title: Catalytic Enantioselective Benzilic Ester Rearrangement
Authors: Hua Wu, Qian Wang, and Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202001258
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10.1002/anie.202001258
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Enantioselective Benzilic Ester Rearrangement
Hua Wu, Qian Wang, and Jieping Zhu*
Abstract: We report the first examples of catalytic enantioselective
benzilic ester rearrangement reaction. In the presence of catalytic
amount of Cu(OTf)2 and a chiral box ligand under mild conditions,
reaction of 2,3-diketoesters with alcohols afforded structurally diverse
a-aryl(alkyl) substituted-a-hydroxy malonates (tartronic esters) in
good to excellent yields with high enantioselectivities. Preliminary
mechanistic studies indicated that hemiketalization, rather than the
DKR of hemiketal, was the enantiodetermining step under our
reaction conditions.
resolution (DKR) of hemiketal intermediate A in the presence of a
chiral Lewis acid complex deemed to be a viable approach and
we became particularly interested in the BER reaction of vicinal
tricarbonyl compounds[18] as this will provide 2-substituted 2-
hydroxymalonates (tartronic esters) of high synthetic value.[19] We
report herein the first examples of L*Cu(II)-catalyzed asymmetric
BER reaction of 2,3-diketoesters 1 affording 2-substituted
tartronic esters 2 in high yields and enantioselectivities (Scheme
1c). Application of the present methodology to the synthesis of
benzimidazole
oxazolidinedione
3,
a
nonsteroidal
mineralocorticoid receptor antagonist,[20] is also documented. The
preliminary experiments indicated that hemiketalization, rather
than the DKR of hemiketal, was the enantiodetermining step
under our reaction conditions.
The development of enantioselective anionotropic 1,2-
rearrangement has been a recent focus[1] and the catalytic
conditions for the semi-pinacol,[2] pinacol,[3] intramolecular
Cannizzaro reaction,[4] a-ketol (acyloin),[5] a-iminol[6] and
Meinwald[3c,7] rearrangements have been uncovered for the
synthesis of important chiral building blocks that are otherwise
difficultly accessible. Despite these notable advances, catalytic
enantioselective benzilic acid rearrangement (BAR, Scheme
1a),[8] a prototypical 1,2-anionotropic shift, remains unknown.
a) Benzilic acid (ester) rearrangement and reaction pathway
R2
R1
R2
OH
ROM
RO
O
O
M = Na, or K
O
R1
k1
k2
R2
R2
k-1
O–
OR
O
O
R1
RO
O–
R1
Reported in 1838 by von Liebig, the BAR reaction, converting
1,2-diketones to tertiary a-hydroxy acids, is the first
rearrangement reaction to be discovered. Together with the
benzilic ester rearrangement (BER),[9] they have been the
subjects of the extensive mechanistic studies[10] and have been
applied to the synthesis of complex natural products[11] as well as
the late stage structural modification of bioactive compounds.[12]
The accepted mechanism of these rearrangements is depicted in
Scheme 1a. Addition of hydroxide/alkoxide to one of the carbonyl
groups of s-trans-1,2-diketone affords the hydrate/hemiketal A.
Rotation of the central C-C bond followed by 1,2-shift affords then
the a-hydroxy acid/ester. Both kinetic studies and DFT
calculations[13] indicates that the hydration/ketalization step is
reversible and that the 1,2-migration is the rate-determining step
(k1≥k2≤k-1). The last step has also been shown to be irreversible[14]
unless it is associated with the release of ring strain.[15] Tang and
co-workers reported in 2015 an elegant diastereoselective Zn(II)-
A
R1 = R2 = arene, alkyl, ester, R = H or alkyl
established kinetics: k1 ≥ k2 ≤ k-1
b) Diastereoselective benzilic ester rearrangement developed by Tang
R1OH
OH
O
HO
Rf
R
Me
Me
Ph
Zn(OTf)2/achiral box
Rf
CO2R1
R
+
Me
Rf = CF3, CF2CF3, C6F5
O
up to 97/3 d.r.
2.0 equiv
c) This work: Catalytic enantioselective benzilic ester rearrangement
O
O
O
O
L*Cu(II)
★
⚙
ROH
R1
OR2
★
R1
+
R2O
Cl
⚙
OR
HO
O
1
2
3
Scheme 1. Benzilic acid (ester) rearrangement: Mechanism and state-of-the-
art.
catalyzed BER reaction using
2
equivalents of (-)-8-
phenylmenthol as an alcohol input (Scheme 1b).[16] Unfortunately,
all efforts aimed at developing a catalytic enantioselective version
of this rearrangement gave the product in very low
enantioselectivity (< 10% ee).[16]
By virtue of its multifunctionality, vicinal tricarbonyl
compounds have been well exploited in organic synthesis,[21] it is
therefore interesting to note that they have rarely been
investigated in asymmetric transformation.[22] We began our
studies by examining the reaction of a mixture of ethyl 2,2-
dihydroxy-3-oxo-3-phenylpropanoate 1a and its hydrate 1a’
(1a/1a’ = 1:3) with tBuOH (20.0 equiv). After initial survey of the
reaction parameters (See SI for details), the ligand structure was
fine-tuned by performing the reaction in 1,2-dichloroethane (DCE)
in the presence of Cu(OTf)2 (0.1 equiv), a chiral ligand (0.12
equiv) at room temperature under air atmosphere. As it is shown
in Table 1, the Pybox ligand L1 was inefficient in catalyzing the
transformation (entry 1), while the desired a-hydroxy a-phenyl
malonate 2a was formed in moderate yields with moderate to
good enantioselectivities (entries 2-4) when bisoxazolines (L2-L4,
Figure 1) were employed as supporting ligands. Further fine-
tuning of ligand structure was focused on those bisoxazolines
Different Lewis acids such as Al(III), Zn(II) and Cu(II) salts
have been used to catalyze/promote the BAR reaction.[17] Keeping
the above mechanistic picture in mind, a dynamic kinetic
[a]
Dr. H. Wu, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
Homepage: http://lspn.epfl.ch
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202001258
Angewandte Chemie International Edition
COMMUNICATION
conditions specified in entry 15, 2-oxo-2-phenylacetate was
isolated in 35% yield (see SI for mechanistic hypothesis) together
with the recovered starting material. Therefore, it seems that
hemiketalization of 1a/1a’ and the subsequent BER reaction is
faster than the BAR of 1a’. In accordance with this assumption,
2a was isolated in similar yield (79%) and ee (94%) when pure 1a
was used as a substrate. As vicinal tricarbonyl compounds are
easily hydrated, the fact that we can use its hydrate with only a
minimum amount of competitive BAR reaction simplified greatly
the experimental procedure. While the MS might act as a water
scavenger to promote the formation of hemiacetal intermediate,
its critical role in the enantioselectivity of the reaction (entries 16-
19) is unclear at the present stage of development. Overall, the
optimum conditions found consisted of performing the reaction of
1a/1a’ (1.0 equiv) with tBuOH (2.0 equiv) in DCE (c = 0.125 M) at
room temperature in the presence of Cu(OTf)2 (0.05 equiv), chiral
bisoxazoline L9 (0.06 equiv) and 4 Å molecular sieves (50
mg/mmol) under air atmosphere. Under these conditions, 2a was
obtained in 78% yield with 94% ee (entry 16).
Table 1. Catalytic enantioselective BER reaction of 1a/1a’ with tBuOH:
Optimization of reaction conditions[a]
O
O
O
O
Cu(OTf)2 (10 mol%)
Ligand (12 mol%)
Ph
OEt
tBuOH
+
EtO
OtBu
X
Y
HO Ph
MS, DCE, air, RT, 12 h
1a X, Y = O; 1a’ X = Y = OH
1a/1a’ = 1:3
2a
Entry
1
2
3
4
5
6
7
Ligand
L1
L2
L3
L4
L5
L6
L7
MS
yield[b]
ee[c]
–
[d]
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
4 Å
3 Å
5 Å
–
trace
56
57
51
47
64
66
61
82
57
67
65
57
61
79
78
79
50
6
42
77
78
60
89
92
83
90
94
88
96
88
84
94[e]
94[f]
92
56
-2
8
9
L8
L9
10
11
12
13
14
15
16
17
18
19
L10
L11
L12
L13
L14
L9
L9
L9
L9
L9
With the optimized conditions in hand, the scope of this
catalytic enantioselective BER reaction was examined (Scheme
2). In addition to tertiary alcohol, secondary alcohol such as
isopropanol and cyclopentanol participated in the reaction to give
the corresponding 2-substituted tartronic esters (2c, 2e, 2f) in
good yields and enantioselectivities. The Meerwein-Ponndorf-
Verley reduction of the diketoester often encountered under
classic BER conditions with secondary alcohol was not observed.
Methanol participated in the reaction to afford the BER product in
good yield with moderate ee (vide infra Scheme 3a). Reaction of
1a with (+)-menthol proceeded smoothly to provide the
corresponding product 2f in high yield with excellent
diastereoselectivity (81% yield, >20/1 d.r.). 2,3-Diketoesters
derived from phenol and primary, secondary as well as tertiary
alcohols, such as 2-(trimethylsilyl)ethyl, heptyl, benzyl, isopropyl
and tert-butyl, were all well-accepted substrates (Scheme 2).
Regarding the aryl group of 3-aryl substituted 2,3-diketoesters,
the presence of both electron-donating (Me, MeO) and electron-
withdrawing groups (F, Br, CF3, NO2) at different positions (para,
meta and ortho) of the phenyl ring were well tolerated (2m-2t) and
excellent enantioselectivity was observed with an aryl group
bearing an ortho substituent (2s, 99% ee, 2t, 96% ee). Both a-
naphthyl and b-naphthyl as well as heteroarene substituted 2,3-
diketoesters participated in this asymmetric 1,2-alkoxycarbonyl
shift process to provide the corresponding rearranged products
(2u-2x). With aliphatic 2,3-diketoesters, conditions have to be
slightly re-optimized (See SI for detail). Performing the reaction at
0 °C using bisoxazoline L12 as ligand, compounds 2y-2aa were
isolated in good yields with good to high enantiopurities. The (S)-
absolute configuration of 2a was determined by X-ray
crystallographic analysis[25] and the configuration of the other a-
hydroxy malonates were assigned by analogy. Performing the
gram scale reactions of 1a (4.0 mmol) and 1o (5.0 mmol) with
tBuOH (2.0 equiv) in the presence of only 2.5 mol% of the L9-Cu
catalyst afforded 2a and 2t, respectively, without erosion of yields
and ees.
[a] 1a (0.1 mmol), tBuOH (2.0 mmol), Cu(OTf)2 (0.01 mmol), Ligand (0.012
mmol), molecular sieves (50 mg), DCE (0.8 mL), air atmosphere, RT, 12 h. [b]
Isolated yields. [c] Determined by SFC analysis on a chiral stationary phase. [d]
Not detected. [e] 2.0 equivalents of tBuOH was used. [f] Cu(OTf)2 (5 mol%) and
L9 (6 mol%) were used. MS = molecular sieves. DCE = 1,2-dichloroethane.
Me Me
n
O
O
O
O
O
O
N
N
N
N
N
N
N
R
R
L2 R = Ph
L3 R = iPr
L4 R = tBu
L5 n = 0
L6 n = 2
L7 n = 3
L1
CF3
R =
Me
Me
R
O
R
O
CF3
Me
N
N
L8
L9
L10
L14 R = H
L11
L12
L13
Figure 1. Structure of representative chiral ligands.
derived from (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (L5-
L14)[23] and L9[24] stood out taking into consideration of both the
yield and ee of 2a (entry 9). Improved enantioselectivity was
observed when the amount of tBuOH was diminished from 20.0
to 2.0 equivalents (entry 15). Pleasingly, the catalyst loading could
be decreased to 5 mol% without impacting the reaction efficiency
(entry 16). The presence of molecular sieves (MS) is of utmost
importance, with 4 Å MS being optimum (entries 16-19). In its
absence, 1a was recovered together with a trace amount of 2a
and ethyl 2-oxo-2-phenylacetate (46% yield). The latter was also
observed as a byproduct under all the conditions examined. Its
formation could be accounted for by the benzilic acid
rearrangement of hydrate 1a’. Indeed, when ethyl 2,2-dihydroxy-
2-phenylacetate (1a’) alone was submitted to the reaction
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10.1002/anie.202001258
Angewandte Chemie International Edition
COMMUNICATION
O
O
O
O
(Scheme 3b, 3c). Finally, reaction of hemiketal 4 and isopropanol
under standard conditions provided a mixture of 2ab (70% yield,
0% ee) and 2c (7% yield, 36% ee, Scheme 3d). The results
argued against our initial assumption and indicated that, under our
conditions, hemiketallization process is an enantiodetermining
step and that 1,2-alkoxycarbonyl shift of intermediate A (cf
Scheme 1a) is a fast process (k2 > k-1).
★
Conditions[a]
⚙
R1
⚙
RO
R2OH
OR2
O
★
R1
OR
+
HO
O
1
2
O
O
O
O
O
Me
Me
EtO
HO Ph
OtBu
EtO
HO Ph
OiPr
EtO
HO Ph
O
Et
2a 78%, 94% ee
83%, 92% ee (gram scale)
2b 65%, 97% ee
2c 91%, 90% ee
Me
O
O
O
O
Conditions[a]
O
O
O
O
O
O
O
(a)
MeOH
Ph
OEt
+
EtO
HO Ph
OMe
EtO
HO Ph
O
EtO
O
EtO
HO Ph
2f 81%, >20/1 d.r.b
O
HO Ph
2ab 84% yield, 42% ee
1a
iPr
2d 76%, 91% ee
2e 84%, 90% ee
O
O
O
O
Conditions[a]
O
O
O
O
O
O
EtO
HO Ph
OMe
(b)
(c)
Ph
Ph
OEt
TMS
Me
HO OMe
O
OtBu
C7H15O
OtBu
PhO
HO Ph
OtBu
ent-2ab 66% yield, 4% ee
HO
Ph
HO Ph
2h 76%, 93% ee
Me
4
O
O
2g 50%, 93% ee
2i 80%, 91% ee
Me Me
O
O
Conditions[a]
Conditions[a]
EtO
HO Ph
OiPr
O
O
O
O
O
O
OEt
Me
Me
Me
Et
HO OiPr
BnO
HO Ph
OtBu
O
OtBu
O
O
ent-2c 76% yield, 7% ee
5
HO Ph
HO Ph
2l 51%, 88% eec
2j 71%, 92% ee
2k 77%, 91% ee
O
O
O
O
O
O
+
+
OEt
HO OMe
iPrOH
O
O
Ph
EtO
OiPr (d)
EtO
HO Ph
OMe
O
O
HO Ph
2m R= F, R' = Et, 81%, 93% ee
2n R = Br, R' = Et, 81%, 93% ee
2o R= CF3, R' = Me, 70%, 93% ee
2p R= NO2, R' = Et, 68%, 94% ee
2q R = OMe, R' = Et, 71%, 92% ee
1.0 equiv
EtO
OtBu
NO2
2r 74%, 93% ee
R'O
OtBu
2ab 70% yield, 0% ee 2c 7% yield, 36% ee
4
HO
HO
Scheme 3. Control experiments. [a] Conditions: 1a, or 4, or 5 (0.1 mmol),
Cu(OTf)2 (5 mol%), L9 (6 mol%), molecular sieves (50 mg), 1,2-
R
O
O
O
O
4 Å
O
O
dichloroethane (0.8 mL), room temperature, air. For equation (d), iPrOH (0.2
mmol, 2.0 equiv) was added.
EtO
OtBu
EtO
HO
Me
OtBu
EtO
OtBu
HO
Br
HO
2t 77%, 96% ee
75%, 95% ee (gram scale)
2s 83%, 99% ee
2u 72%, 95% ee
O
O
accessible
O
O
O
O
2 OTf
OTf
EtO
OtBu
EtO
OtBu
R
R1
R2O2C
OH
EtO
OtBu
HO
R1
RO
O
HO
HO
O
k1
+
R3
R3
R3
k2
2
O
O
O
O
Cu+
N
N
HO CO2R2
R1
CO2R
Cu
S
k–1
O
N
R3
N
R2O2C
O
O
2
OH
2v 65%, 97% ee
Me
2w 75%, 86% ee
Me
2x 76%, 91% ee
R
k2 > k–1
steric
O
O
Me
Me
O
O
O
O
B
C
Me
Bn
Me
Bn
repulsion
EtO
O
iPr
Bn
MeO
O
EtO
O
HO
HO Bn
HO Me
steric
repulsion
2y 64%, 84% eed
2z 63%, 76% eed
2aa 65%, 88% eed
R-OH
R1
2 OTf
2 OTf
R
OH
O
O
+
2
R1OC
R2O
HO CO2R2
R1
ent-2
R3
+
R3
R3
Scheme 2. Scope of catalytic enantioselective BER reaction. [a] Conditions: 1
(0.1 mmol), R2OH (0.2 mmol, 2.0 equiv), Cu(OTf)2 (5 mol%), L9 (6 mol%), 4 Å
molecular sieves (50 mg), 1,2-dichloroethane (0.8 mL), room temperature, air.
The ee was determined by supercritical fluid chromatography (SFC) or high
performance liquid chromatography (HPLC) analysis on a chiral stationary
phase. [b] The d.r. was determined by 1H NMR. [c] Cu(OTf)2 (0.1 equiv), L7
(0.12 equiv), at 40 oC. [d] Cu(OTf)2 (10 mol%), L12 (12 mol%), at 0 oC, 2 days.
O
O
2
Cu
O
O
N
N
Cu
O
N
R3
N
CO2R
R2O
O
O
R
OH
R-OH
accessible
D
E
both faces are accessible
2 OTf
O
2 OTf
+
Assuming that the 1,2-shift was the kinetically slow step as it
was widely accepted for the BAR/BER reactions, dynamic kinetic
resolution (DKR) of the hemiketal A was the working hypothesis
that guided our efforts to render the BER reaction enantioselective
(cf Scheme 1a). A series of control experiments were carried out
in order to understand the reaction course. Under standard
conditions, reaction of 1a with MeOH (2.0 equiv) afforded 2ab in
84% yield with a moderate 42% ee (Scheme 3a). However,
submitting the pure hemiketals 4 and 5 to the standard conditions
afforded 2ab (66% yield, -4% ee) and 2c (76% yield, -7% ee),
respectively, with negligible but reversed enantioselectivity
R1
R1
+
O
2
2
R3
R3
R3
R3
O
O
O
O
HO
RO
R2O
RO
HO
N
N
Cu
Cu
N
N
O
O
R2O
F
G
Scheme 4. Stereochemical model.
On the basis of aforementioned results, a plausible pathway
leading to the observed stereochemical outcome is illustrated in
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10.1002/anie.202001258
Angewandte Chemie International Edition
COMMUNICATION
Scheme 4. Coordination of L9-Cu(OTf)2 to 2,3-diketoester 1
would afford a square-planar Cu(II) complex B,[26] where the
adjacent diketo group adopts an s-cis conformation. Nucleophilic
addition of alcohol to the sterically more accessible Re face of the
central carbonyl group would afford Cu(II) species C with a
conformation preorganized for the subsequent 1,2-suprafacial
cycloetherification of 8b afforded dihydrobenzofurane 9 in non-
optimized 40% yield.
To further illustrate the synthetic potential of the present
method, synthesis of benzimidazole oxazolidinedione 3 was
undertaken. Chemoselective hydrolysis of tert-butyl ester of 2y
afforded the carboxylic acid 10 in 82% yield. Amidation of 10 with
migration of
the alkoxycarbonyl group to generate, after
4-chlorobenzene-1,2-diamine
followed
by
acid-promoted
decomplexation, the product 2 with the observed absolute
configuration. On the other hand, if bidentate coordination of the
L9-Cu(OTf)2 took place between the central and the ester
carbonyl groups as shown in the intermediate D, the preferred Si-
face attack of alcohol would afford the ent-2. In the six-membered
chelate E, the central carbonyl group lies along the C2 axis of the
box ligand and therefore, high enantioselectivity would not be
expected.[27] Overall, a stereochemical model involving the
complex B matched best with the experimental results.[22a,28] On
the other hand, when the pre-synthesized hemiketal was
submitted to the reaction conditions, the six-membered chelates
F/G might be formed[29] and the ester group in these two
diastereomeric intermediates would migrate without kinetic
preference to afford a racemic compound in accordance with the
experimental results.
cyclization of the resulting amide provided the benzimidazole 11
in 51% yield over two steps. Sodium hydroxide-promoted
cyclocondensation
of
11
with
(R)-1-fluoro-4-(1-
isocyanatoethyl)benzene gave compound 3, a nonsteroidal
mineralocorticoid receptor antagonist, in 75% isolated yield
(Scheme 8).[20] We note that two resonance structures of the
1
benzimidazole (3 and 3’) are clearly observable within H NMR
time scale.
In conclusion, we have developed the first catalytic
enantioselective benzilic ester rearrangement (BER) reaction. In
the presence of catalytic amount of Cu(OTf)2 and a chiral box
ligand under mild reaction conditions, reaction of 2,3-diketoesters
with alcohols afforded structurally diverse α-substituted-α-
hydroxy malonates in good to excellent yields with high
enantioselectivities. Although the acyclic hemiketal is in general
configurationally unstable, we believe that, under our conditions,
the hemiketalization is an enantio-determining step against the
widely accepted reaction mechanism of the BAR/BER reactions.
O
O
O
O
O
a
c
HO
OtBu
EtO
OtBu
HO
OtBu
HO Ph
HO Ar
HO Ar
6
2
2a Ar = Ph
8a Ar = Ph
2b Ar = 2-Bromophenyl
8b Ar = 2-Bromophenyl
b
8b, d
Acknowledgements
O
O
HO
COOtBu
EtO
OH
O
We thank financial support from EPFL (Switzerland) and the
Swiss National Science Foundation (SNSF 20020-155973). We
thank Dr. F.-T. Farzaneh and Dr. Rosario Scopelliti for the X-ray
structural analysis of compound 2a, L11-CuCl2 and L12-CuCl2.
HO Ph
7
O
9
Cl
Cl
HN
O
O
Me
Bn
f
e
MeOOC
HO Bn
11
MeOOC
HO Bn
10
MeOOC
N
OH
Me
HO Bn
2y
Conflict of Interest
g
+
Cl
The authors declare no conflict of interest
3
3’
Keywords: asymmetric synthesis • benzilic ester rearrangement
• 2,3-diketoester • tartronic esters • chiral copper catalyst
Scheme 5. Post-transformation and application to the synthesis of bioactive
compound. Reaction conditions: (a) 2a, NaOH, EtOH/H2O, RT, 88% yield; (b)
2a, TFA, DCM, RT, 93% yield; (c) 2a or 2b, LiBH4, EtOH/THF, 0 oC, 8a 63%
yield; 8b 61% yield; (d) 8b, CuI (0.1 equiv), tBuOLi (3.0 equiv), 1,4-dioxane,
100 °C, 40%; (e) TFA/DCM, RT, 3 h, 82% yield; (f) 4-chlorobenzene-1,2-
diamine, HATU, diisopropylethyl amine, DMF, RT, 12 h, then acetic acid, 70 oC,
3 h, 51% yield over two steps; (g) (R)-1-fluoro-4-(1-isocyanatoethyl)benzene,
NaOH, THF, 40 oC, 12 h, 75% yield (10/1 d.r.).
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Entry for the Table of Contents (Please choose one layout)
Asymmetric Synthesis
O
O
O
O
Hua Wu, Qian Wang, and Jieping
Zhu*__________ Page – Page
L*Cu(II)
R3OH
R2O
OR3
+
R1
OR2
R1
HO
Catalytic Enantioselective Benzilic
Ester Rearrangement
O
Paradigm shift hemiketal formation is the enantio-determining step against commonly
accepted mechanism of the title rearrangement
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