Catalytic Enantioselective α-Ketol Rearrangement

Article abstract of DOI:10.1002/anie.201812244

A highly enantioselective α-ketol rearrangement has been developed. In the presence of a chiral Cu-bisoxazoline complex, achiral β-hydroxy-α-dicarbonyls were isomerized to chiral α-hydroxy-β-dicarbonyls and their bicyclic derivatives in excellent yields and enantioselectivities. Enantioenriched 2-acyl-2-hydroxy cyclohexan-1-ones, dihydroxyhexahydrobenzofuranones, and dihydroxyhexahydro-cycloheptafuranones, with up to three stereocenters, were readily prepared from achiral starting materials in one operation. The reaction is applicable to the desymmetrization of meso substrates and kinetic resolution of racemic alcohols.

Full text of DOI:10.1002/anie.201812244

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Accepted Article
Title: Catalytic Enantioselective α-Ketol Rearrangement
Authors: Hua Wu, Rémi Andres, Qian Wang, and Jieping Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812244
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10.1002/anie.201812244
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Enantioselective α-Ketol Rearrangement
Hua Wu, Rémi Andres, Qian Wang, Jieping Zhu*
Abstract: A highly enantioselective a-ketol rearrangement has
been developed. In the presence of chiral Cu-bisoxazoline complex,
the achiral b-hydroxy-a-dicarbonyls were isomerized to chiral a-
hydroxy-b-dicarbonyls and their bicyclic derivatives in excellent
yields and enantioselectivities. Enantioenriched 2-acyl-2-hydroxy
compounds 1. We were aware of the fact that the reverse
reaction, i.e., the rearrangement of a-hydroxy-b-oxocarbonyl 2
to 1 is known which constitutes in fact the key step in the
biosynthesis of valine and isoleucine.[10] To overcome the
potential pitfall caused by the reversibility of the reaction,[11] we
thought about exploiting two strategies to render the process
highly enantioselective: a) kinetic resolution of the rearranged
product. The a-hydroxy-b-dicarbonyls are known to undergo
further isomerization to afford the corresponding a-ketol
esters.[12] If the minor enantiomer underwent the acyl migration
faster than its antipode (k1 > k2, k4 > k3), then an ee enhancement
cyclohexan-1-ones,
dihydroxyhexahydrobenzofuranones
and
dihydroxyhexahydro-cycloheptafuranones with up to three
stereocenters were readily prepared from achiral starting materials
in one operation. The reaction is applicable to desymmetrization of
meso substrates and kinetic resolution of racemic alcohols.
of compound
2
would be expected.[13-15] Since the
The a-ketol rearrangement is
a family of reactions
rearrangement of 2 to 3 is, depending on the reaction conditions,
also reversible,[16] reaction conditions would have to be carefully
fine-tuned to favor the forward reactions; b) a subsequent
kinetically competent hemiacetalization reaction converting 5 to
a more complex product 6. In this case, the major enantiomer
should react faster than the minor one in order to amplify the
product ee (k1 > k2, k3 > k4). We report herein the realization of
this endeavour by developing the chiral copper-bisoxazoline
complex[17] catalyzed highly enantioselective rearrangement of
b-hydroxy-a-dicarbonyls (Scheme 1C). The resulting a-hydroxy
β-dicarbonyl compounds 2[18] and their bicyclic derivatives 6 are
found in various biologically relevant molecules[19] and are
valuable intermediates in the asymmetric syntheses of complex
natural products.[20]
converting the a-hydroxy ketones to their isomeric forms via a
1,2-alkyl(aryl) shift (Scheme 1A). The reaction takes place
reversibly under acidic, basic or thermal conditions affording the
thermodynamically more stable isomer. In spite of the
reversibility of the reaction, it has been applied to the synthesis
and structural modification of natural products.[1] Since the a-
ketol rearrangement could generate a chiral a-hydroxy ketone
from its achiral isomer (Scheme 1A, if R ≠ R1), the development
of the enantioselective version is of high synthetic value in view
of the importance of the chiral a-hydroxy ketones in the
synthesis of pharmaceuticals, agrochemicals and other
bioactive ingredients. The reversibility of this process renders
nevertheless this task a daunting challenge.[2]
In a series of papers, Brunner, Kagan and coworkers
investigated in detail the enantioselective α-ketol rearrangement
of different tertiary a-hydroxy ketones.[3-5] Under optimized
conditions, 1-benzoylcyclopentan-1-ol was converted to 2-
hydroxy-2-phenylcyclohexanone with a 48% ee at best (Scheme
1B).[5] The application scope was rather limited with most of the
other substrates being converted to the rearranged α-ketols in
moderate yields with low enantioselectivities. On the other hand,
chiral Lewis acid catalyzed enantioselective rearrangements of
a-siloxy aldehydes and of a-hydroxy aldimines have been
developed by the groups of Maruoka[6] and of Wulff,[7]
respectively. In these latter cases, 1,2-alkyl(aryl) shift produced
thermodynamically more stable compounds rendering the
reaction non-reversible, hence highly enantioselective under
kinetic conditions.
A Generic presentation of α-ketol rearrangement
O
O
O
1,2-R migration
step 1
1,2-R1 migration
step 2
OH
R1
HO
R
HO
*
*
R1
R
R
R1
R
R
R
B Enantioselective α-ketol rearrangement of 1-benzoyl cyclopentan-1-ol
(Brunner and Kagan)
NiCl2 (20 mol%
Pyrox (40 mol%)
O
O
O
OH
Ph
HO
Pyrox =
Ph
*
N
N
MeOH, 65 °C
ee 48%
C This work: Enantioselective α-ketol rearrangement enabled by in situ ee
enhancement processes. For case 1: k1 > k2, k4 > k3; for case 2: k1 > k2, k3 > k4.
O
O
case 1
k1
k2
R1
k3
OH
O
OH
O
R1
(R)-2
O
R1
k4
O
O
O
O
R1
OH
3
1
(S)-2
In connection with our ongoing research interests dealing
with enantioselective rearrangements[8] and ee enhancement
processes,[9] we became interested in developing the
asymmetric a-ketol rearrangement of b-hydroxy-a-oxocarbonyl
case 2
X
O
O
OH
O
HO
XH k3
k1
k2
O
OH
OH
O
XH
(R)-5
XH
(R)-6
O
O
X
k4
4
HO
O
OH
OH
(S)-5
(S)-6
[*]
Dr. H. Wu, R. Andres, 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
Scheme 1. The a-ketol rearrangement.
Homepage: http://lspn.epfl.ch
1-(1-Hydroxycyclopentyl)-2-phenylethane-1,2-dione (1a, n =
1, R = Ph) was chosen as a test substrate. A wide range of chiral
catalysts including chiral Lewis acids, metal phosphates and
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201812244
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Brønsted acids were screened and chiral copper-bisoxazoline
complexes turned out to be the most efficient (see SI, Figure S1-
S2). In addition to the structure of bisoxazolines (SI, Table S1
and Figure S3), survey of the reaction conditions (SI, Table S1
and Figure S4) indicated that a combination of polar solvent
racemic 1t was also successfully realized to afford the
rearranged product (S)-2t and the recovered (S)-1t with high
selectivity (Scheme 3b). However, the reaction is not without
limitation as the cyclohexanol counterpart of 1 failed to undergo
the rearrangement under our standard conditions.
–
(CH3NO2)[21] and non-coordinating counteranion (SbF6 )[22] was
Cu(SbF6)2 (10 mol%)
O
O
O
O
OH
O
optimal. Using the in situ generated Cu-(S,S)-7 complex as
catalyst and CH3NO2 as solvent, the rearrangement of 1a
reached full conversion at 40 °C in 1 h affording 2a in 70%
isolated yield with 68% ee. Gratefully, extending the reaction
time increased the ee of 2a with a slight decrease of yield and
concurrent formation of racemic 2-oxocyclohexyl benzoate 3a
(SI, Figure S5). This result suggested that the chiral Cu-(S,S)-7
complex catalyzed not only the enantioselective rearrangement
of 1a but also the selective transformation of the minor
enantiomer of 2a to 3a in line with the proposal outlined in
Scheme 1C. Overall, heating a CH3NO2 solution of 1a (c 0.2 M)
in the presence of Cu(SbF6)2 (0.1 equiv), chiral bisoxazoline
(S,S)-7 (0.12 equiv) and 3Å molecular sieves (30 mg/0.1 mmol)
at 40 °C for 12 h afforded 2a in 65% yield with 87% ee. The Cu-
bisoxazoline catalyzed aza-Henry and Henry reaction have
been developed by Jørgensen[23] and Evans.[24], respectively. It
is therefore interesting to note that the a-ketol rearrangement of
1a outcompeted completely the Henry reaction between the
solvent (CH3NO2) and the highly electrophilic 1,2-dione 1a.
(S,S)-7 (12 mol%)
O
O
O
R
R
+
R
N
N
OH
O
3
Å
MS
tBu
tBu
(S,S)-7
1
CH3NO2 (c 0.2 M)
2
3
O
O
O
O
O
O
OH
OH
OH
F
Me
2c 55%, 86% ee
35 °C, 12 h
2b 63%, 80% ee
35 °C, 24 h
2a 65% yield, 87% ee
40 °C, 12 h
O
O
O
O
O
O
O
O
OH
OH
OH
OH
CO2Et
OCF3
CF3
2d 55%, 79% ee
40 °C, 12 h
2e 64%, 85% ee
40 °C, 12 h
2f 52%, 89% ee
35 °C, 7 h
2g 45%, 92% ee
RT, 16 h
O
O
O
O
O
O
O
O
F
OMe
OH
OH
OH
OH
2h 35%, 94% ee
40 °C, 18 h
2i 61%, 86% ee
40 °C, 16 h
2j 66%, 80% ee
40 °C, 12 h
2k 60%, 80% ee
35 °C, 24 h
Cl
O
O
O
O
O
O
O
O
Ph
OH
OH
OH
OH
2l 77%, 95% ee
RT, 3.5 h
2m 81%, 97% ee
RT, 40 min
2n 76%, 98% ee
RT, 40 min
2o 65%, 96% ee
RT, 40 min
O
O
tBu
O
Me
O
tBu
O
O
OTBS
Me
The substrate scope of this a-ketol rearrangement was next
O
OH
examined under the optimized conditions.
A series of
O
OH
OH
O
OH
OH
tBu
tBu
cyclopentanol derivatives 1 were successfully converted into the
corresponding 2-acyl-2-hydroxy cyclohexanones 2 in moderate
to high yields with good to excellent ees (Scheme 2). The
presence of both electron-donating and -withdrawing groups at
the different positions of the phenyl ring were tolerated. Aromatic
rings bearing substituents at the ortho position gave the
rearranged products with excellent ees, albeit with diminished
yields (2g, 2h). The absolute configuration of 2a was determined
to be (R) by single crystal X-ray diffraction analysis and that of
the others was assigned accordingly.[25,26]
2r 95%, 81% ee
-20 °C, 12 h
2p 80%, 92% ee
RT, 40 min
2q 85%, 95% ee
RT, 40 min
8 quant, d.r. > 20:1
Scheme 2. Cu-bisoxazoline complex catalyzed a-ketol rearrangement of
cyclopentanol/kinetic resolution process. The reaction was performed on a 0.2
mmol scale. Enantiomeric excess (ee) was determined by SFC or HPLC
analysis on a chiral stationary phase.
Cu(SbF6)2 (10 mol%)
O
(S,S)-7 (12 mol%)
O
OH
O
(a)
(b)
HO
CH3NO2 (c 0.2 M)
1s
O
The tertiary alkyl substituted b-hydroxy-a-oxo ketones
underwent rearrangement to afford the a-hydroxy-β-dicarbonyl
compounds 2l-2q in good yields with excellent ees. The
presence of silyl ether in the alkyl side chain was compatible with
the reaction conditions (2q). Treatment of 2q with TBAF afforded
a bicyclic hemiacetal in excellent yield and diastereoselectivity
(see SI for details). The rearrangement of sterically bulky b-
hydroxy-a-oxo ester proceeded smoothly to furnish the desired
product 2r, which was reduced (NaBH4, MeOH, -20 °C, 2 h) to
the corresponding a,b-dihydroxy ester 8 in quantitative yield with
excellent diastereoselectivity (d.r. > 20:1). Performing the
rearrangement of 1l at 1.0 mmol scale furnished 2l with similar
synthetic efficiency (78% yield, 95% ee). Although
enantioselective hydroxylation of b-keto esters such as 2-
3Å MS, RT, 40 min
2s 83%, 95% ee
O
Cu(SbF6)2 (10 mol%)
O
O
O
HO
HO
(S,S)-7 (12 mol%)
+
O
OH
CH3NO2 (c 0.2 M)
3Å MS, -10 °C, 36 h
O
(S)-1t 42%, 83% ee
2t 43%, 84% ee
1t
s = 28
Scheme 3. Desymmetrizative a-ketol rearrangement and kinetic resolution of
indanol derivative 1t. The reaction was performed on a 0.2 mmol scale.
Enantiomeric excess (ee) was determined by SFC or HPLC analysis on a
chiral stationary phase.
We next turned our attention to the a-ketol rearrangement of
substituted 1,4-dihydroxybutane-2,3-diones 4 (Scheme 4). The
rational is that the 1,2-alkyl migration would produce a hydroxy
ketone susceptible to undergo entropically favored facile
intramolecular hemiacetalization, driving therefore the forward
reaction to completion. The potential pitfall would be the
chemoselectivity of the reaction as two types of a-ketol
rearrangements are possible from diones 4. Pleasantly,
treatment of 4a (R = Ph) under standard conditions afforded the
bicyclic furanone 6a in almost quantitative yield with 90% ee.
Monitoring the reaction progress indicated that the ee of 6a
remained constant in this case. The intermediate 5a was hardly
methoxycarbonyl-1-indanone
and
2-methoxycarbonyl-1-
tetralone has been reported,[27] that of b-diketone is known to be
problematic due to the competitive rearrangement of 2 to a-ketol
ester 3 under the hydroxylation conditions.[28]
Desymmetrization of a-hydroxy ketone 1s derived from
octahydro-2H-inden-2-one afforded the rearranged product 2s
in 83% yield with 95% ee (Scheme 3a). Enantioenriched 2s
bearing three stereocenters was difficultly accessible by the
existing synthetic methodologies.[29] Finally, kinetic resolution of
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10.1002/anie.201812244
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COMMUNICATION
with excellent diastereoselectivity (d.r. > 20:1). Using (R,R)-7 as
ligand under otherwise identical conditions, 4k was transformed
to 6k in 63% yield with much reduced d.r. (1:3.5). These results
indicated that the sense of the enantioselectivitiy was
determined by the chirality of the Cu-bisoxazoline complex in
the mismatched case.
detectable suggesting that its subsequent cyclization was a fast
process. Hemiacetal 9 (R = Ph) resulting from the cyclization of
the alternative a-ketol rearrangement product was not observed.
The release of ring strain from 5- to 6-membered ring could
explain the observed high regioselectivity. The relative and
absolute configurations of 6a were determined by X-ray
crystallographic analysis. As shown in Scheme 4, the sequence
of enantioselective 1,2-alkyl shift followed by diastereoselective
cyclization was applicable to a variety of substrates affording the
bicyclic compounds in uniformly high yields and excellent
enantioselectivities. As expected, ring expansion of
cyclopentanol took place selectively in the presence of
cyclohexanol (cf 6e). Bicycle 6f was obtained in a gram scale
experiment in excellent yield and ee. Tosylamide also
participated in this domino process to afford bicyclic
pyrrolidinone 6g in 96% yield with 98% ee. We note that these
compounds would not be accessible by the existing
enantioselective hydroxylation methodology.
A series of control experiments were performed to gain
insight on the enantioselective a-ketol rearrangement of 1a.
Submitting 2a (55% ee) to the standard reaction conditions for
4 h led to a significant enantio-enrichment of 2a (78% ee)
together with the formation of a racemic product 3a in 11% yield
(Scheme 5a). The same experiment using (R,R)-7 as chiral
ligand afforded recovered 2a with much reduced ee (27%),
while with racemic ligand (±)-7, partial isomerization of 2a
occurred with its ee unchanged. Finally, treatment of (±)-2a
under standard conditions for 34 h afforded the recovered 2a in
21% yield with 83% ee (Scheme 5b). This last experiment
clearly indicated the advantage of combining asymmetric a-
ketol rearrangement with kinetic resolution for the synthesis of
enantioenriched 2a relative to the direct kinetic resolution of
racemic 2a. As it is seen from the diagram shown in Scheme 5b,
the ee of 2a increased steadily as the reaction proceeded with
the concurrent formation of side product 3a. The result of all
these control experiments suggested that the selective
rearrangement of the minor enantiomer was responsible for the
observed ee enrichment of 2a. Finally, TMS-protected hydroxy
diketone 10 failed to undergo the rearrangement indicating the
importance of the free OH group in triggering the 1,2-alkyl shift
process (Scheme 5c).
Importantly, ring expansion of cyclohexanol 4h (n = 2, R =
Ph, Scheme 4) proceeded smoothly to afford bicyclic
cycloheptanol 6h, suggesting the important role of the
acetalization reaction in driving the present a-ketol
rearrangement forward. Desymmetrization also took place
efficiently affording 6i and 6j with very good selectivity. To the
best of our knowledge, this represented the first examples of
enantioselective ring expansion of cyclohexanols by the a-ketol
rearrangement. The moderate yields of 6h-6j were due to the
low conversion of the substrates under the standard conditions.
R
R
R
XH
Cu(SbF6)2 (10 mol%)
(S,S)-7 (12 mol%)
R
O
OH
X
O
HO
Cu(SbF6)2 (10 mol%)
L* (12 mol%)
O
O
XH
R
O
O
O
O
OH
O
OH
n
O
Ph
(a)
Ph
OH
O
R
CH3NO2 (c 0.2 M)
3Å MS, 40 °C
Ph
+
n
OH
n
O
CH3NO2 (c 0.2 M)
4 n = 1, 2
6 X = O, NTs
5
3Å MS, 40 °C, 4 h
2a 55% ee
2a
3a
Bn
Ph
(S,S)-7 (12 mol%) 61%, 78% ee
(R,R)-7 (12 mol%) 53%, 27% ee
11%
Bn
Ph
O
O
O
HO
24%
17%
HO
HO
O
OH
O
OH
O
OH
(±)-7 (12 mol%)
58%, 55% ee
Cu(SbF6)2 (10 mol%)
(S,S)-7 (12 mol%)
O
O
O
O
O
6a >99%, 90% ee
6b 93%, 90% ee
6c 93%, 96% ee
40 oC, 12 h
40 oC, 12 h
40 oC, 16 h
O
Ph
Ph
OH
+
Ph
OH
(b)
O
TBSO
OTBS
CH3NO2 (c 0.2 M)
3Å MS, 40 °C, 34 h
TsN
O
HO
O
HO
O
HO
2a 21%, 83% ee
2a 0% ee
3a 48%
O
HO
O
O
OH
O
OH
OH
OH
6f 91%, 91% ee
6d 92%, 81% ee
6e 97%, 90% ee
6g 96%, 98% ee
40 oC, 12 h
40 oC, 12 h
40 oC, 12 h
40 oC, 12 hꢀꢃꢂ
Ph
HO
Ph
O
HO
R
HO
O
Ph
Ph
Ph
O
O
Ph
OH
OH
O
OH
O
OH
O
R
OH
O
9
6h 58%,ꢀꢁꢂ 82% ee
40 oC, 14 h
6j 45%,ꢀꢁꢂ 92% ee
40 oC, 60 h
6i 35%,ꢀꢁꢂ 88% ee
40 oC, 60 h
Cu(SbF6)2 (10 mol%)
(S,S)-7 (12 mol%)
O
O
TMS
O
O
(c)
O
OH
O
OH
OH
OH
Cu(SbF6)2 (10 mol%), L* (12 mol%)
CH3NO2 (c 0.2 M)
3Å MS, 40 °C, 24 h
Me
O
Me
10
2b 0%
O
CH3NO2 (c 0.2 M), 3Å MS, 40 °C, 12 h
OH
O
(S,S)-7 (12 mol%), 83% yield, d.r. > 20:1
(R,R)-7 (12 mol%), 63% yield, d.r. 1:3.5
4k
6k
Scheme 5. Control experiments. The reaction was performed on a 0.1 mmol
scale. Enantiomeric excess (ee) was determined by SFC or HPLC analysis on
a chiral stationary phase.
Scheme 4. Enantioselective α-ketol rearrangement/diastereoselective
acetalization cascade. The reaction was performed on a 0.2 mmol scale.
Enantiomeric excess (ee) was determined by SFC or HPLC analysis on a
chiral stationary phase. [a] Results of gram scale experiment; [b] The yields of
6h, 6i and 6j were 79%, 63% and 81%, respectively, based on the conversion.
The pathway leading to the observed stereochemical
outcome is illustrated using 1a as starting material (Scheme 6).
Coordination of the [Cu{(S,S)-tBu-box}]-(SbF6)2 to diketone 1a
would afford square planar Cu(II) complex 11.[17,30] Selective
migration of C-C bond to the si face of the vicinal carbonyl and
proton transfer would furnish 2a-Cu2+L* complex which, upon
Diastereoselective 1,2-alkyl shift and acetalization of 4k
derived from L-menthone afforded the bicycle 6k in 83% yield
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10.1002/anie.201812244
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COMMUNICATION
[6]
[7]
[8]
T. Ooi, K. Ohmatsu, K. Maruoka, J. Am. Chem. Soc. 2007, 129, 2410-
2411.
ligand exchange with 1a, would generate the product 2a with the
observed initial ee (68%). Prolonging the reaction time after the
consumption of starting material, the product 2a could
coordinate to Cu2+L* to regenerate the complex 2a-Cu2+L* and
to trigger the kinetic resolution process. Formation of epoxides
12/13 followed by fragmentation and protonation of the resulting
enolates would then afford the observed side product 3a. For
the same steric reason, formation of epoxide 12 from the (S)-2a-
Cu2+L* would now be kinetically much faster than the conversion
of (R)-2a-Cu2+L* to 13 leading to the selective transformation of
the minor enantiomer, hence the amplification of the product’s
ee.
X. Zhang, R. J. Staples, A. L. Rheingold, W. D. Wulff, J. Am. Chem.
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G. Crout, D. L. Rathbone, J. Chem. Soc., Chem. Commun. 1987, 290-
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O
O
O
O
O
OH
[11] M. B. Rubin, S. Inbar, J. Org. Chem. 1988, 53, 3355-3358.
[12] M. B. Rubin, S. Inbar, Tetrahedron Lett. 1979, 20, 5021-5024.
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1984, 106, 3695-3696.
Ph
Ph
OH
Ph
+
OH
O
(R)-2a
(S)-2a
1a
–
2 SbF6
2+
–
–
2 SbF6
2+
2 SbF6
2+
tBu
tBu
[14] N. Komatsu, M. Hashizume, T. Sugita, S. Uemura, J. Org. Chem. 1993,
58, 4529-4533.
tBu
OH
H
O
O
a
O
N
N
O
O
O
O
N
N
Cu
Ph
N
N
O
O
Cu
Cu
O
Ph
+
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O
O
Ph
tBu
11
tBu
OH
tBu
(R)-2a-Cu2+L*
(S)-2a-Cu2+L*
11
Cu2+L* (SbF6
slow
fast
–
)
2
+
+
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tBu
tBu
Cu
SbF6–
SbF6–
O
O
O
N
N
Ph
N
N
O
O
O
O
O
OH
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Cu
O
O
Ph
Ph
O
tBu
tBu
O
+
HSbF6
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+
HSbF6
1a
13
12
O
OCu+L*
O
–
SbF6
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O
3a
Ph
14
6 Cu2+L* 2 SbF6
–
HSbF
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Scheme 6. Stereochemical outcome of α-ketol rearrangement of 1a.
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In summary, we developed the first examples of highly
enantioselective a-ketol rearrangements. A wide range of
enantioenriched
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a-ketol rearrangement during their preparation. Therefore, we were
unable to apply the present asymmetric conditions to this substrate.
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Acknowledgements
We thank EPFL (Switzerland) and the Swiss National Science
Foundation (SNSF 20020-155973) for financial supports. We
thank Dr. F.-T. Farzaneh and Dr. Rosario Scopelliti for the X-ray
structural analysis of compounds 2a and 6a.
Keywords: asymmetric synthesis • α-ketol rearrangement • Cu-
bisoxazoline complex • kinetic resolution • desymmetrization
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10.1002/anie.201812244
Angewandte Chemie International Edition
COMMUNICATION
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10.1002/anie.201812244
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
Asymmetric Synthesis
R
O
O
OH
O
X
R
O
O
Conditions
Conditions
HO
R1
O
R1
Hua Wu, Rémi Andres, Qian Wang, and
Jieping Zhu*__________ Page – Page
N
N
OH
R1 = -C(R)2XH
OH
O
tBu
MS
tBu
(S,S)-L
Conditions: Cu(SbF6)2 (10 mol%), (S,S)-L (12 mol%), CH3NO2 (c 0.2 M), 3Å
Catalytic Enantioselective α-Ketol
Rearrangement
Driving the reversible reaction enantioselective: In the presence of a catalytic amount of Cu(SbF6)2 and
chiral bisoxazoline ligand, the achiral b-hydroxy-a-dicarbonyls were isomerized to chiral a-hydroxy-
b-dicarbonyls and their bicyclic derivatives in excellent yields and enantioselectivities.
This article is protected by copyright. All rights reserved.