Highly enantioselective transfer hydrogenation of racemic α-substituted β-keto sulfonamides: Via dynamic kinetic resolution

Article abstract of DOI:10.1039/c8cc01643g

Highly enantioselective transfer hydrogenation of β-keto sulfonamides was developed via dynamic kinetic resolution using a chiral Ru(ii) catalyst with an azeotropic solution of HCO₂H/Et₃N as a hydrogen donor, affording α-substituted β-hydroxyl sulfonamides in good yields with excellent diastereo- and enantioselectivities. This method is featured with mild conditions, easy operation, and a broad substrate scope, which make it possible to find wide applications in the synthesis of natural products and biologically active compounds containing the α-substituted β-hydroxyl sulfonamide core.

Full text of DOI:10.1039/c8cc01643g

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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DOI: 10.1039/C8CC01643G
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Highly Enantioselective Transfer Hydrogenation of Racemic -
Substituted -keto Sulfonamides via Dynamic Kinetic Resolution
Zhichao Xionga, Chengfeng Peia, Peng Xuea, Hui Lv*a,b,d and Xumu Zhang*c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Highly enantioselective transfer hydrogenation of -keto racemic compounds has been widely investigated.6-7 Among
sulfonamides was developed via dynamic kinetic resolution using a them, asymmetric hydrogenation of racemic -substituted
chiral Ru(II) catalyst with an azeotropic solution of HCO2H/Et3N as ketones via dynamic kinetic resolution (DKR) has been
hydrogen donor, affording -substituted -hydroxyl demonstrated to be an efficient and reliable method for the
sulfonamides in good yields with excellent diastereo- and enantio- synthesis of chiral -substituted β-hydroxyl compounds with

a

selectivities. This method is featured with mild conditions, easy two contiguous stereocenters. However, most of these
operation, and a broad substrate scope which makes it possible to reactions were conducted under basic condition, making base-
find wide applications in synthesis of nature products and sensitive substrates, such as
-halo ketones, unfit for this
biologically active compounds containing -substituted -hydroxyl transformation, which greatly limited the substrate scope.8
sulfonamides core.
Compared with traditional hydrogenation, asymmetric transfer
hydrogenation(ATH)9 has better compatibility to substrates and
is more suitable for the reduction of sensitive or complicated
Sulfa drugs, important synthetic antimicrobial agents
containing sulfonamide group, have been widely used in clinical
treatment for more than 80 years.1 Thus, sulphonamides are
regarded as privileged motifs for lead compounds in drug
discovery and attracted great attention.2 Great efforts have
been devoted to the development of efficient methods for
constructing of functionalized sulfonamides and many
approaches have been developed.3 However, the asymmetric
substrates, such as
halo ketone was used in ATH via dynamic kinetic resolution, the
dehalogenation product was obtained. For example, -alkyl
keto sulfones were well tolerated in ATH via dynamic kinetic
resolution, but -bromo -keto sulfone only afforded
debromination product in the same conditions.11 Therefore, to
develop a general and efficient method for hydrogenation of
substituted -keto sulfones/sulphonamide with excellent
 -
-halo ketone.10 Even so, when racemic

-


-
access to-substituted -hydroxyl chiral sulfonamides is still

rare4 despite these compounds are widely distributed in dugs
and nature products and exhibit important biological activities
compatibility to substrate is still a challenge. Herein, we disclose
the highly enantioselective transfer hydrogenation of racemic
(Figure 1),5 thus the development of efficient methods for
-

-substituted

-keto sulfonamides with ruthenium catalyst for
-hydroxyl sulfonamides. More
substituted -hydroxyl chiral sulfonamides is highly desirable.
the synthesis of-substituted

In the past decades, dynamic kinetic resolution (DKR) as an
efficient methodology to obtain optically pure molecules from
a
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei,
430072, P. R. China. E-mail: huilv@whu.edu.cn
b Engineering Research Center of Organosilicon Compounds & Materials, Ministry of
Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan,
Hubei, 430072, P. R. China.
CDepartment of Chemistry, South University of Science and Technology of China,
Shenzhen, Guangdong, 518055, P. R. China. E-mail: zhangxm@sustc.edu.cn
d Key Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences.
Figure 1 Biologically active compounds containing chiral
-
hydroxyl sulfonamides.
‡ Electronic supplementary information (ESI) available: Experimental procedures, NMR
spectra of compounds. See DOI: 10.1039/x0xx00000x
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importantly, -halo substituted
Journal Name


-keto sulfonamides, with excellent enantioselectivity, but it have an important
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DOI: 10.1039/C8CC01643G
challenging substrates for hydrogenation, are also well- impact on the yield. When the reaction was conducted in EtOH,
tolerated in this reaction.
dioxane, toluene, only moderated yields were obtained. When
The asymmetric transfer hydrogenation of racemic 1-phenyl- MeOH, THF, CH3CN, DMF were employed as solvents, this
2-(piperidin-1-ylsulfonyl) propan-1-one (1a) was chosen as reaction proceeded very smoothly, affording target product in
model reaction to optimize the reaction conditions. Initially, a excellent yields with high diastereo- and enantioselectivities.
variety of catalysts were examined. As showned in Table1, when It’s worth noting that this reaction also proceeded very well in
half-sandwiched Ru(II)/
6-arene catalysts were used (entries 1- the mixture of HCO2H/Et3N. Due to the relatively high
2), they both showed acceptable results, but cat. B did better in diastereoselectivity, DMF was chosen as the best solvent.
yield, enantio- and diastereoselectivity. This was probably due Subsequently, the reaction temperature was evaluated, and the
to the methyl and 2-propyl group on the arene ring and thus results disclosed that decreasing temperature lead to a
increased the reactivity and steric hindrance. When Rh (III) or Ir relatively low yield (entries 9-10).
(III) complex was employed in this reaction, only moderated
yields and enantioselectivities were obtained (entry 3-4). This Table 2 Influence of the solvents on the ATH-DKR of 1a
might suggest that ruthenium (II) is more suitable for the
transfer hydrogenation of 1a. Therefore, Ru-tethered cat. E
developed by Wills group12 was investigated, the reaction
proceeded very smoothly, affording the desired product in high
yield with excellent enatio- and diastereoselectivity (entry 5).
Subsequently, alternative molar ratios of HCO2H/Et3N were
tested, and the results revealed that a molar ratio of 5:2 is the
best condition in comparison to that of 3:2 or 1:1(entries 6-7).
yield (%)b
Ee(%)c
drd
Table 1 Influence of the catalyst on the ATH-DKR of 1a
Entry
solvent
1
MeOH
EtOH
THF
>99
50
>99
>99
>99
>99
>99
>99
>99
>99
99
12:1
12:1
12:1
15:1
15:1
15:1
>20:1
15:1
20:1
20:1
2
3
>99
36
4
Dioxane
CH3CN
Toluene
DMF
5
>99
45
6
7
>99
>99
90
8e
9f
10g
-
DMF
DMF
95
98
a
Unless otherwise noted, all reactions were carried out with a substrate/catalyst ratio
of 50:1 at 60 ºC for 12 h. b Isolated yield. cDetermined by HPLC analysis using a chiral
stationary phase. dDetermined by 1H NMR spectroscopy.e 1 mL HCO2H/Et3N mixture was
used. f room temperature, 24h. g 40 ºC, 18h.
Under the optimal reaction conditions, the substrate scope
was investigated. As shown in Table 3, the electronic properties
and the position of substituent group on benzene ring has no
influence on the reaction, all
-substituted -aryl keto
sulfonamides examined here can be hydrogenated efficiently,
giving desired products with good yield, high enantioselectivity
and excellent diastereoselectivity (2a
by polycyclic aromatic group or heteroaromatic group, such as
naphthyl and thienyl, this reaction also proceeded very well (2h
2i). When piperdinyl group of sulfonamide was changed to
pyrrolyl group, morpholinyl group or dimethyl group (2j 2l),
there are no influence to this reaction. In addition, -methyl -
-2g). Replacing aryl group
Inspired by these promising results, we investigated the
solvent effects in the presence of 2 mol% cat. B by using formic
acid/triethylamine (molar ratio 5:2) as hydrogen source. As
shown in Table 2, the solvents tested here have no influence to
the enantioselectivity and all of them afford desired product
-
-

2 | J. Name., 2012, 00, 1-3
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keto sulfone was also worked very well in this reaction (2m).13
It is worthy to note that this reaction exhibited a good tolerance
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DOI: 10.1039/C8CC01643G
to various
When the substituent R changed to a sensitive halogen group,
it also gave target products with excellent results (2n 2o). To the
best of our knowledge, this work represents the first example
to construct -halo β-hydroxy compounds with two contiguous
-functional group substituted -keto sulfonamides.
-

chiral centers by reduction of
kinetic resolution.
-halo ketones via dynamic
Scheme 1 Gram scale reaction.
In summary, we have developed an efficient and practical
strategy for the synthesis of -substituted -hydroxyl
sulfonamides by a tethered Ru (II) complex catalyzed transfer
hydrogenation of racemic -Substituted -keto sulfonamides.
Table 3 ATH-DKR results of 1a
-
1oa




The reaction features wide substrate scope, high yield, excellent
diastereo- and enantioselectivity, which make it possible to find
wide applications in the synthesis of biologically active
compounds containing -hydorxy sulfonamides core. Further
investigation on asymmetric hydrogenation of
ketones is also underway in our laboratory.
-functionalized
We are grateful for financial support from the National
Natural Science Foundation of China (Grant Nos. 21402145,
21432007, and 21372179), the Youth Chen-Guang Science and
Technology Project of Wuhan City (2015071704011640), the
Natural Science Foundation of Hubei Province (2014CFB181),
the Fundamental Research Funds for Central Universities
(2042017kf0177), the Important Sci-Tech Innovative Project of
Hubei Province (2015ACA058), Open found of CAS Key
Laboratory of Molecular Recognition and Function
(2017LMRF002) and the “111” Project of the Ministry of
Education of China.
Notes and references
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This journal is © The Royal Society of Chemistry 20xx
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13 The absolute configuration of 2m was confirmed to be (1R, 2S)
by comparison specific optical rotation with Ref 11. All the
other configurations are uncertain and based on the
assumption that the configuration follows that of 2m
.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8CC01643G
An efficient enantioselective transfer hydrogenation of racemic -substituted -keto
sulfonamides via dynamic kinetic resolution have been achieved, affording -substituted -
hydroxyl sulfonamides in good yields and excellent diastereo- and enantioselectivities
.