Highly enantioselective chlorination of β-keto esters and subsequent SN2 displacement of tertiary chlorides: A flexible method for the construction of quaternary stereogenic centers

Article abstract of DOI:10.1021/ja304806j

Highly enantioselective chlorination of β-oxo esters and subsequent stereospecific substitution of tertiary chlorides are described. Enantioselective chlorination of β-keto esters and malonates was performed using a chiral Lewis acid catalyst prepared from Cu(OTf)₂ and the newly developed spirooxazoline ligand 2 to yield the desired α-chlorinated products with high enantioselectivity (up to 98% ee). Nucleophilic substitution of the resulting chlorides proceeded smoothly to afford a variety of chiral molecules such as α-amino, α-alkylthio, and α-fluoro esters, without loss of enantiopurity. The results of X-ray crystallographic analysis proved that Walden inversion occurs at the chlorinated tertiary carbon center. These results supported the fact that the substitution proceeds via an S _N2 mechanism.

Full text of DOI:10.1021/ja304806j

Communication
pubs.acs.org/JACS
Highly Enantioselective Chlorination of β-Keto Esters and
Subsequent SN2 Displacement of Tertiary Chlorides: A Flexible
Method for the Construction of Quaternary Stereogenic Centers
Kazutaka Shibatomi,* Yoshinori Soga, Akira Narayama, Ikuhide Fujisawa, and Seiji Iwasa
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi
441-8580, Japan
S
* Supporting Information
Scheme 1
ABSTRACT: Highly enantioselective chlorination of β-
oxo esters and subsequent stereospecific substitution of
tertiary chlorides are described. Enantioselective chlorina-
tion of β-keto esters and malonates was performed using a
chiral Lewis acid catalyst prepared from Cu(OTf)2 and the
newly developed spirooxazoline ligand 2 to yield the
desired α-chlorinated products with high enantioselectivity
(up to 98% ee). Nucleophilic substitution of the resulting
chlorides proceeded smoothly to afford a variety of chiral
We first applied SPYMOX to the asymmetric chlorination of β-
keto esters using N-chlorosuccinimide (NCS) as the chlorina-
tion reagent. Chlorination of 3a in the presence of the
molecules such as α-amino, α-alkylthio, and α-fluoro
SPYMOX/Cu(OTf)2 complex afforded the desired product 4a
esters, without loss of enantiopurity. The results of X-ray
in high yield but with moderate enantioselectivity (78% ee;
crystallographic analysis proved that Walden inversion
Table 1, entry 1). To enhance the enantioselectivity in this
occurs at the chlorinated tertiary carbon center. These
results supported the fact that the substitution proceeds via
an SN2 mechanism.
a
Table 1. Optimization of the Reaction Conditions
he SN2 reaction, one of the most fundamental reactions in
organic transformation, can be used for the construction
T
of enantioenriched chiral carbon centers because the
substitution proceeds with complete inversion of stereo-
chemistry. Optically active tertiary chlorides could be useful
intermediates for the preparation of a variety of chiral
molecules having a quaternary stereogenic center if SN2
substitution were to occur at the chlorinated tertiary carbon.
However, this process has not been successful to date except in
a rare instance1 because of two major underlying problems:
First, as described in organic chemistry textbooks, tertiary
halides (particularly tertiary chlorides) rarely undergo SN2
substitution.2 Second, there are relatively few catalytic methods
that afford highly enantioenriched tertiary chlorides, and the
development of such a reaction with broad substrate scope
remains a challenge.3−5 We describe herein the highly
enantioselective chlorination of a wide range of β-keto esters
in the presence of a newly synthesized chiral spirooxazoline
ligand and subsequent unimpeded SN2 substitution at the
chlorinated tertiary carbon. The present method yields a variety
of chiral molecules having a quaternary stereogenic center
(Scheme 1).
b
c
entry
ligand
solvent
time (h)
% yield
% ee
1
2
3
4
5
6
1
benzene
benzene
benzene
toluene
CH2Cl2
THF
1
1
1
1
1
2
93
97
96
96
93
91
78
95
95
94
93
71
2a
2b
2a
2a
2a
a
All of the reactions were carried out using 1.5 equiv of NCS in the
presence of a Lewis acid catalyst prepared from 12 mol % chiral ligand
b
c
and 10 mol % Cu(OTf)2. Isolated yields. Determined by chiral GC
analysis.
chlorination, we designed new chiral spirooxazoline ligands 2
with a quinoline backbone. Specifically, we expected the steric
repulsion between the substrate and the additional benzene
We began by focusing on the development of an efficient
catalyst for the enantioselective chlorination. Our recent
research revealed that the chiral pyridyl spirooxazoline ligand
1, which we call SPYMOX, shows high asymmetric induction
ability in the palladium-catalyzed allylic alkylation6a and
copper(II)-catalyzed asymmetric fluorination of β-keto esters.6b
Received: January 26, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja304806j | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
ring in 2 to push the reaction center closer to the chiral
binaphthyl backbone. As expected, the enantioselectivity of the
reaction dramatically increased to 95% ee when 2 was used
under the same reaction conditions (entries 2 and 3). Screening
of various solvents showed that benzene afforded the best
enantioselectivity and reactivity.
Table 2. Enantioselective Chlorination of Active Methine
Compounds
a
With the optimized reaction conditions, we attempted to
expand the substrate scope of the asymmetric chlorination. As
summarized in Table 2, various cyclic and acyclic β-keto esters,
including both aliphatic and aromatic keto esters, were
successfully chlorinated with high enantiopurity. It was found
that a bulky ester substituent is essential for obtaining high
selectivity (entry 6 vs entry 7). Chlorination of α-
alkylmalonates also proceeded with good-to-high enantioselec-
tivity (entries 19−22).7 On the other hand, chlorination of α-
cyanoacetate and β-ketophosphonates gave poor enantioselec-
tivity (entries 23−25). In the chlorination process, certain
functional groups such as carbamate, alkene, nitrile, and an
additional ketone were well-tolerated (entries 4, 5, 13−15, 21,
and 22). The sense of stereoselection in the chlorination was
controlled by the chiral ligand even when α-chloro-β-keto
esters 4i and 4j, which have a menthyl ester as a chiral auxiliary,
were used in the reaction (entries 9 and 10). The absolute
configuration of the chlorinated chiral carbon in 4j was
determined to be S by X-ray structural analysis (see the
Supporting Information).
Encouraged by the high asymmetric induction ability of the
new chiral ligands, we next focused on the SN2 substitution of
α-chloro-β-oxo esters.8 First, we attempted to use sodium azide
as the nucleophile. The resulting azide could be converted into
a primary amine by subsequent palladium-catalyzed hydro-
genolysis. For all of the substrates used, the reaction proceeded
smoothly to yield the corresponding α-azido esters 5 and α-
amino esters 6 in high yield (Table 3). Notably, when the
palladium loading was increased to 20 mol % in the
hydrogenation of 5f and 5h, reduction of the ketone carbonyl
proceeded simultaneously with the hydrogenolysis to yield β-
hydroxy-α-amino esters 7f and 7h in a highly diastereoselective
manner (96−99% de; entries 5 and 6).9 Most importantly, the
enantiopurity of 5 was exactly the same as that of the starting
compound 4 in all cases. Furthermore, single-crystal X-ray
crystallographic analysis revealed that the nucleophilic sub-
stitution of 4 to give 5 involved a Walden inversion (see the
Supporting Information for details). These results strongly
suggested that this nucleophilic substitution proceeds via a
rigorous SN2 mechanism. The electron-withdrawing nature of
the two carbonyl groups next to the chlorinated tertiary carbon
probably enables the unusual SN2 substitution of the tertiary
chloride.2b Thus, this method will be useful for the preparation
of highly substituted α-amino acid derivatives.
We next used alkylthiols as nucleophiles. As shown in Table
4, nucleophilic substitution of α-chloro-β-keto esters proceeded
smoothly in the presence of triethylamine to yield the
corresponding α-alkylthio-β-keto esters 8,10 and the enantio-
purity was maintained in all cases (entries 1−7). On the other
hand, the reaction of α-chloromalonate 4t with benzylthiol did
not afford the desired product at all. Finally, we attempted to
carry out a much more challenging reaction, nucleophilic
substitution with fluorides for the construction of fluorinated
stereogenic centers. After screening several fluorides such as
NaF, KF, and tetrabutylammonium fluoride, we found that a
combination of CsF and 18-crown-6 efficiently promotes the
nucleophilic fluorination of 4f to afford the desired α-fluoro-β-
a
All of the reactions were carried out using 1.5 equiv of NCS in the
presence of a Lewis acid catalyst prepared from 12 mol % 2a and 10
b
mol % Cu(OTf)2, unless otherwise noted. Isolated yields.
c
d
Determined by chiral HPLC or GC analysis. Ligand 2b was used
e
f
instead of 2a. Diastereomeric excess. Absolute configuration of the
chlorinated carbon. The reaction was carried out for 48−60 h. 36
mol % 2 and 30 mol % Cu(OTf)2 were used. The reaction was carried
out under reflux conditions for 24 h with 12 mol % 2b and 10 mol %
Cu(OTf)2. The reaction was carried out under reflux conditions.
g
h
i
j
keto ester 9f in high yield with complete Walden inversion
(entry 8). The reaction of 4h also gave the desired product 9h
without loss of enantiopurity, but the yield was disappointingly
low (35%), and tert-butyl 1-hydroxy-2-naphthoate, which was
probably generated by the elimination of hydrogen chloride
and subsequent aromatization,11 was obtained as a byproduct in
B
dx.doi.org/10.1021/ja304806j | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. SN2 Substitution with Sodium Azide and
Table 4. SN2 Reaction with Alkylthiols and Cesium
a
Subsequent Hydrogenolysis To Give α-Amino Acid
Fluoride
a
Derivatives
a
b
All of the reactions were carried out using 3 equiv of NaN3. Isolated
yields of amine 6 or 7 for two steps. Yields in parentheses are the
c
isolated yields of azide 5. Enantiomeric excess of 5 determined by
d
chiral HPLC or GC analysis. Azidation was carried out at 25 °C for
6−20 h with 20 mol % Pd catalyst. 96% de. 99% de.
e
f
a
Sulfenylation was carried out using 3 equiv of alkylthiol and 6 equiv
of Et3N in CH2Cl2. Fluorination was carried out using 3 equiv of CsF
and 1 equiv of 18-crown-6 in acetonitrile, unless otherwise noted.
45% yield (entry 9). Surprisingly, fluorination of 4k (95% ee)
yielded the corresponding product 9k with decreased
enantiopurity (84% ee; entry 10),12 probably because of the
competitive SN1 pathway. Furthermore, the enantiopurity of
the starting chloride decreased during the course of the reaction
(7% of 4k was recovered, with 84% ee). This partial
racemization, which may be due to the nucleophilic substitution
(SN2 and/or SN1) of 4k by CsCl generated in situ, was also the
reason for the isolation of 9k with lower enantiopurity.
Unfortunately, fluorination of other substrates (4a, 4b, 4p, 4r,
and 4t) afforded only trace amounts of the desired product
under similar reaction conditions, and significant amounts of
byproduct were formed. Nevertheless, an important feature of
this fluorination method is that a highly enantioenriched
fluorinated stereogenic center can be constructed by using the
combination of an inexpensive oxidant (NCS) and a
nucleophilic fluorination reagent (CsF) instead of a commonly
used electrophilic fluorinating reagent13 such as N-fluoroben-
zenesulfonimide.
In conclusion, we have successfully carried out the highly
enantioselective α-chlorination of β-keto esters and malonates
with a chiral spirooxazoline ligand. Substitution of the resulting
chlorides with some nucleophiles successfully afforded the
corresponding α-heteroatom-substituted β-oxo esters without
loss of enantiopurity. The results of X-ray crystallographic
analysis proved that the nucleophilic substitution with sodium
azide involved a Walden inversion. These results strongly
b
c
d
Isolated yields. Determined by chiral HPLC analysis. The reaction
e
was carried out at 0 °C. The reaction was carried out at 80 °C for 24
f
h. Reaction was carried out at 0 °C for 168 h with 6 equiv of CsF and
g
1 equiv of 18-crown-6. The yield in parentheses was determined by
1H NMR analysis using 2,2,2-trifluoroethanol as an internal standard.
The isolated yield was low because of the volatility of the product.
suggest that the substitution proceeds via the SN2 mechanism,
although the reaction occurred at a tertiary carbon. An
advantage of our method is that it allows for the formation
of multiple optically active compounds with a quaternary
stereogenic center from a single intermediate.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data, HPLC and GC
enantiomer analyses, and NMR spectra (1H, 13C, and 19F) for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
shiba@ens.tut.ac.jp
■
Notes
The authors declare no competing financial interest.
C
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Journal of the American Chemical Society
Communication
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ACKNOWLEDGMENTS
■
This study was supported by the Asahi Glass Foundation and a
Grant-in-Aid for Young Scientists (B) (23750111) from
MEXT. We thank the Instrument Center of the Institute for
Molecular Science for permission and advice on the usage of
their X-ray diffractometer. We also thank the Nippon Synthetic
Chemical Industry Co., Ltd. for supplying ethyl isocyanoacetate
used in the synthesis of chiral ligands.
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D
dx.doi.org/10.1021/ja304806j | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX