Enantiopure sulfoximines-catalyzed 1, 4-additions to 2-en-ketone

Article abstract of DOI:10.1016/j.mcat.2018.06.011

An efficient chiral catalyst procedure for the preparation of β-chiral ketone via the 1, 4-additions reaction of 2-en-ketone has been developed using enantiopure sulfoximines modified with functional groups as ligands. The carefully design and synthesized

Full text of DOI:10.1016/j.mcat.2018.06.011

MolecularCatalysis455(2018)210–213
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Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Enantiopure sulfoximines-catalyzed 1, 4-additions to 2-en-ketone
Hongwei Zhaoa,⁎, Hui Hanb, Hengquan Yanga, Li wangb,⁎
a
School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan, 030006, China
Institute of Environmental Science, Shanxi University, Taiyuan, 030006, China
b
A R T I C L E I N F O
A B S T R A C T
Keywords:
An efficient chiral catalyst procedure for the preparation of β-chiral ketone via the 1, 4-additions reaction of 2-
en-ketone has been developed using enantiopure sulfoximines modified with functional groups as ligands. The
carefully design and synthesized functional enantiopure sulfoximines could be used as linker. In this system the
formation of new chiral centers occurs with the regioselective addition of the ethyl moiety at the terminal carbon
of the 2-en-ketone. In addition, aromatic substituents in the substrate promote the addition reaction.
Enantiopure sulfoximines
Chiral catalysis
1,4-Addition
Sulfoxides
Resolution
Introduction
pleased to note that this complex showed high activity and delivered
enantioselectivities up to 70% ee.
Sulfoximines, which can be considered as aza analogues of sulfones,
were first reported by Whitehead and Bentley in 1950 [1]. The high
synthetic versatility of sulfoximine group derives from its ability to
function as chiral carbanion stabilizing nucleofuge [2]. Chiral sulfox-
imines have a stereogenic center at the sulfur atom, and have been
recognized as an interesting new class of chiral ligands, which can be
applied in various asymmetric catalytic reactions [3–13]. The first ap-
plication of enantiopure sulfoximine as a ligand was reported by
Johnson in 1979 [11]. Later works were focused on the design and
preparation of novel ligands. In which bi-dentated β-hydro-
xysulfoximines were the most successful sulfoximine ligands in asym-
metric catalysis of a variety of reactions, such as diethylzinc addition to
aldehydes [8], titanium catalysed asymmetric homoaldol reaction [9]
and titanium promoted addition of TMSCN to aldehyde [12]. For ex-
ample, Bolm and coworker reported using readily available β-hydro-
xysulfoximine ligands in catalytic asymmetric phenyl transfer reactions,
gaving arylphenylmethanols with moderate to high enantioselectivities
[13].
However, relatively little attention has been devoted to the use of
optically-active sulfoximines as ligands in the 1, 4-addition reactions
and the results were not satisfy. For example, copper complex catalyzed
1, 4-additions to 2-cyclohexenone giving lower ee (7–36%) [14].
As part of our continuing program on the exploration of sulfoxide
and sulfoximine chemistry [15], we designed and synthesized novel
enantiopure β-hydroxysulfoximines modified by functional groups. The
functional enantiopure sulfoximines with the linkers could be grafted to
solid support for recycle and reuse. Hydroxysulfoximine’s nickel com-
plex used as ligand on the 1,4-addition reactions were examined. It was
Results and discussion
Several methods are known for the conversion of sulfoxides into
sulfoximines [14,16]. The oldest method for the oxidative imination of
sulfoxides involves hydrazoic acid generated in situ from NaN3 and
98% sulfuric acid [17] (Scheme 1). However, the direct preparation of
enantiopure sulfoximines cannot be accomplished by this way since the
racemization of the sulfoxide is faster than the formation of the sul-
foximines.
In general, imination reactions between a nitrene or nitrene ana-
logue and the sulfoxide proceed with retention of configuration at the
sulphur [18–21], providing that the reaction conditions do not promote
racemization of sulfoxide. The most frequently used imination reagents
that allow retention of configuration at sulfoxide are o-mesitylsulfo-
nylhydroxylamine (MSH) [20,21],N-tosylimino-phenyliodinane,18 and
N-aminophthal-imide [19]. The most flexible approach to en-
antiomerically pure “free” sulfoximines appears to be via the MSH-
method. Therefore, we decided to convert enantiopure sulfoxides (from
the biotransformation reactions [15]) into sulfoximines.
The imination of optically pure sulfoxides with mesitylsulfonylhy-
droxylamine(MSH) yielded the corresponding sulfoximines with the
complete retention of configuration [21]. The reactive MSH had to be
prepared prior to imination; once prepared, it was reasonably stable
and could be kept in a freezer for up to one week (see SI). Treatment of
(+)-(R)-methyl phenyl sulfoxide 3a (99% ee) with MSH gave (-)-(R)-
methyl phenyl sulfoximine 4a in 65% yield. The resolution on chiral
phase GC showed as 99% enantiopure (Scheme 2).
⁎
Corresponding authors.
E-mail addresses: hwzhao@sxu.edu.cn (H. Zhao), wangli@sxu.edu.cn (L. wang).
https://doi.org/10.1016/j.mcat.2018.06.011
Received 7 March 2018; Received in revised form 3 June 2018; Accepted 8 June 2018
2468-8231/©2018ElsevierB.V.Allrightsreserved.

H. Zhao et al.
MolecularCatalysis455(2018)210–213
Scheme 1. Conversion of sulfoxides into sulfoximines.
N-protected sulfoximine was obtained by treating methyl phenyl
sulfoximine 4a with trimethylsilyl diethylamine and the product 5a was
purified by distillation. Since the by-product was a volatile diethyla-
mine, this procedure is perfectly suitable for the product N-protected
sulfoximine. In the following step, condensation with benzophenone
gave TM(S)-protected β-hydroxysulfoximine; reflux of the crude pro-
duct in methanol for 3–4 h gave desilylated sulfoximine 6a. The overall
yield after 3 steps was 47%. Borane reduction of a prochiral ketone was
used to test the efficiency of catalytic activity of 6a in homogeneous
reaction, and 6a (10 mol %) catalyzed the asymmetric reduction of
ketone into alcohol with good selectivity (78% ee) and in high yield.
The chiral ligand was recovered without loss of chirality, as described
in Scheme 3.
In view of the successful performance of ligand 6a, we proceeded
with the syntheses of sulfoximines 4a, 4b, and 4c with the different
functional groups on the aromatic rings that could be grafted to the
solid support. To develop efficient protocols for imination, initial
syntheses were carried out with racemic materials. Thus, sulfoximines
were prepared by treating the corresponding sulfoxides with a 40%
excess of o-mesitylsulfonylhydroxylamine in methylene chloride
(25 mL) at room temperature [22]. Because of the relatively high
acidity of free sulfoximines (pKa = 24.3) [23] the protection of the
amine is necessary before further modification. Two types of protective
groups were investigated: silyl and alkyl groups. It has been reported
that these groups have only a minor influence on the enantioselectivity
[24]. Silylation of compounds 4a and 4b was achieved by heating the
free sulfoximine with Et2NSiMe3 [25]. The allyl-substituted compound
4c which cannot tolerate these reaction conditions was alkylated using
triethyloxonium fluoroborate [26] under milder conditions to give the
ethyl N-protected 5c (Scheme 4).
Scheme 3. Borane reduction of ketone.
of N-(+)-10 camphorsulfonyl-sulfoximine diastereomers followed by
the removal of the resolving group by acid hydrolysis was developed by
Gais and co-workers (Scheme 6) [27]. The enantiomer (R)-4a can be
obtained similarly by using (-)-CSA.
The N-methylation of (S)-4a occurred with retention of the con-
figuration at sulfur center. The following condensation gave a diaster-
eomeric cis/trans mixture of 6d in good yield. The cis- and trans- mix-
ture was separated by column chromatography to give enantiopure cis
6-d and trans 6-d (> 99% ee). The structure of cis-(S)-6d was un-
ambiguously established by X-ray crystallography. The crystal data and
the crystallographic details were shown in the experimental section.
The absolute configuration of the compound was confirmed by the low
Flack parameter and lower R factors. The cis geometry of the product
was verified by the X-ray data. The crystal structure showed the pre-
sence of two independent molecules in the unit cell. These two mole-
cules have different conformations of COOEt group, which was clearly
displayed on the right-hand side of two drawings in Fig. 1.
The cyclohexane ring has the expected chair conformation with
torsion angles between 52 and 59° (+and – alternating). The C]O
bond (avg. 1.209(3) Å) is shorter than the C–O bond (avg. 1.333(2) Å)
of the ester group, while the CeO of the hydroxyl group is much longer
(avg. 1.429(2) Å). The environment around the S atom is tetrahedral,
with the angle OeSeN the largest (avg. 121.5(1) o). The avg. S]O
distance is 1.451(1) Å, while the avg. SeN bond is 1.522(2) Å. The SeC
bond distances vary between 1.7762(17) and 1.7955(17) Å.
We conducted asymmetric 1, 4 addition reaction to 2-en-ketones
achieved by reaction of diethyl zinc in the presence of nickel acet-
ylacetonate [Ni(acac)2] and chiral β-hydroxysulfoximines as chiral li-
gands. Several influence factors have been evaluated, such as the con-
centration of the catalyst and the solvent on the conjugate addition. All
reactions were carried out in propionnitrile at −30 °C as these proved
to be optimal conditions. In toluene, THF, products with lower yields
were obtained. All reactions were carried with a ligand: Ni ratio of 20:1.
Control experiments were processed. Several conclusions were
achieved: Ni was necessary to promote the reaction. Sulfoximines li-
gand did not catalyzed the conjugate addition of ZnEt2 to 2-en-ketones
in the absence of Ni(acac)2.
Unfortunately, numerous attempts at converting 5b and 5c to the
target ligands 6b and 6c gave multiple products with very low yields.
After the systematic investigation on the difficulties for the above
syntheses, an alternative ligand was designed as show in Scheme 5,
indeed, it was successful.
Biotansformation only could provide small quantity of enantiopure
sulfoxides.
A large quantity of enantiopure (S)-4a was prepared
through the resolution of racemic sulfoximine 4a with (+)-10-cam-
phorsulfonic acid ((+)-CSA) giving (S)-4a in 41% yield and 99% ee.
Large-scale preparation of enantiopure sulfoximines by the separation
Scheme 2. Synthesis of chiral sulfoximine ligands.
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H. Zhao et al.
MolecularCatalysis455(2018)210–213
Scheme 4. Preparation of N-protected sulfoximines.
Scheme 5. Synthesis of chiral β-hydroxysulfoximine ligands.
Scheme 6. Preparation of chiral sulfoximines by resolution with CSA.
Fig. 1. Labelled diagrams of the two independent molecules in the crystal of compound cis-(S)-6d. Ellipsoids correspond to 30% probability.
Under the optimized conditions, pure cis-(S)-6d and pure trans-(S)-
6d were tested as the ligands with increased amount of sulfoximine
from 20 mol% to 30 mol%, but without any improvement on either the
yield or enantioselectivity. The maximum enantiomeric excess of pro-
duct (R)-1,3-diphenylpentan-1-one 8a (75% yield, 70% ee) was
achieved by using cis : trans = 5 : 1 mixture of (S)-6d as a ligand. The
reactions catalyzed by the pure cis- and pure trans-6d were less selective
giving 61%ee and 29%ee respectively (Scheme 7).
from the reaction mixture in greater than 80% yield. The addition of
several other conjugate ketones was completed under the optimized
conditions with cis-(S)-6d as a catalyst. Interestingly, conjugate addi-
tion to methoxy-chalcone 7b and 7c afforded 8b and 8c with an en-
antiomeric excess of 58% and 54% respectively in good yields. The
presence of an arylketone moiety seems to be important to reach high
ee, as in the case of the methyl-substituted derivative 7d; the product
was obtained in low yield 20% but was essentially racemic. Alkylation
of 7d and 7e gave essentially racemic products in low yields (Scheme
The catalyst (S)-6d could be easily recovered without any change
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MolecularCatalysis455(2018)210–213
Scheme 7. 7. 1, 4 addition to 2-en-ketones.
7), which indicated that the presence of aryl groups is necessary to
achieve reasonable enantioselectivity.
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The authors gratefully acknowledge the financial support for this
work from the 131 Leading Talents Program and 100 Talents Program
of Shanxi Province (Grant no.205544901006 and 205107001). Funding
for Oversea Returnees (Grant no. 205586801011). Thanks to Scientific
Instrument Center, Shanxi University. Thanks to Prof. Margaret Kayser
for valuable discussions and Francine Bélanger-Gariépy for the crys-
tallographic work.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.mcat.2018.06.011.
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