Stereogenic: Cis -2-substituted- N -acetyl-3-hydroxy-indolines via ruthenium(ii)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation

Article abstract of DOI:10.1039/c8cc07336h

Ruthenium(ii)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation of racemic 2-substituted-N-acetyl-3-oxoindolines to cis-2-substituted-N-acetyl-3-hydroxyindolines is reported. Using the homochiral {Ru[TfDPEN](p-cymene)} catalyst with S/C = 400 in a HCO₂H/Et₃N mixture, up to >99.9% ee and >99:1 dr are obtained with high yields (79-98%). This method provides the first example of preparing enantiomerically pure indolines through asymmetric transfer hydrogenation (ATH).

Full text of DOI:10.1039/c8cc07336h

Showcasing research from Professor Lei Zhang’s laboratory,
MOE Joint International Research Laboratory of Synthetic
Biology and Medicine, School of Biology and Biological
Engineering, South China University of Technology,
Guangzhou, PR China. Image designed and illustrated
by Xin Lin.
As featured in:
Stereogenic cis-2-substituted-N-acetyl-3-hydroxy-indolines via
ruthenium(II)-catalyzed dynamic kinetic resolution-asymmetric
transfer hydrogenation
Ruthenium(II)-catalyzed dynamic kinetic resolution-asymmetric
transfer hydrogenation of rac 2-substituted-N-acetyl-3-
oxoindolines to cis-2-substituted-N-acetyl-3-hydroxyindolines
is reported. Using homochiral {Ru[TfDPEN](p-cymene)} catalyst
with S/C = 400 in HCO2H/Et3N mixture, up to >99.9% ee and
>99 : 1 dr are obtained in high yields (79–98%).
See Lei Zhang,
Zhongqing Wang et al.,
Chem. Commun., 2018, 54, 13503.
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Stereogenic cis-2-substituted-N-acetyl-3-
hydroxy-indolines via ruthenium(II)-catalyzed
dynamic kinetic resolution-asymmetric transfer
Cite this: Chem. Commun., 2018,
54, 13503
Received 10th September 2018,
Accepted 10th October 2018
hydrogenation†
bc
Zhonghua Luo,a Guodong Sun,
Zihong Zhou,b Guozhu Liu,b Baolei Luan,b
DOI: 10.1039/c8cc07336h
Yicao Lin,b Lei Zhang*a and Zhongqing Wang
*
bc
rsc.li/chemcomm
Ruthenium(II)-catalyzed dynamic kinetic resolution-asymmetric trans-
fer hydrogenation of racemic 2-substituted-N-acetyl-3-oxoindolines
to cis-2-substituted-N-acetyl-3-hydroxyindolines is reported. Using
the homochiral {Ru[TfDPEN](p-cymene)} catalyst with S/C = 400 in a
HCO2H/Et3N mixture, up to 499.9% ee and 499 : 1 dr are obtained
with high yields (79–98%). This method provides the first example of
preparing enantiomerically pure indolines through asymmetric trans-
fer hydrogenation (ATH).
As important structural motifs, chiral indolines are widely
found in bioactive compounds and pharmaceutical molecules.
For instance, oleracein A–D1 and benzastatin E2 are all natu-
rally occurring biologically active alkaloids and present a wide
and varied range of biological activities.1a,3 These structural
motifs also appear in the potent angiotensin converting enzyme
Fig. 1 Examples of bioactive chiral indolines.
inhibitors and antihypertensive agent Wy-44221,4 as well as in remain problematic due to some drawbacks, such as the need of
an intermediate used in the synthesis of perindopril (Fig. 1).5 high-pressure reactors, the use of strong acidic additives or the
Thus, the asymmetric synthesis of these scaffolds is of great choice of expensive fluorinated alcohol as a solvent.
importance and therefore has attracted considerable attention
To solve these problems, asymmetric transfer hydrogenation
in recent years.6 Among the synthetic approaches, asymmetric (ATH)9 is generally proved to be a realistic alternative, which
hydrogenation of indoles is considered to be one of the most provides several advantages over traditional hydrogenation
efficient methods to obtain chiral indolines.
methods. However, to the best of our knowledge, there is still
Since the pioneering work7a on the asymmetric hydro- no report on the synthesis of enantiomerically pure indolines
genation of N-protected indoles by Kuwano and co-workers in via asymmetric transfer hydrogenation. Only few asymmetric
2000, the methods for asymmetric hydrogenation of either transfer hydrogenation methods for related compounds such
N-protected7 or N-unprotected8 indoles with metal catalysts have as 1-indanones10 and 3-oxo-coumarans11 have been reported
been widely reported (previous work, Scheme 1). Indeed, the during the last decade.
asymmetric hydrogenation of indoles provides the most efficient
Recently, our group became interested in ruthenium(II)-
and economic synthetic method to afford chiral indoles with catalyzed dynamic kinetic resolution-asymmetric transfer hydro-
excellent enantioselectivities. However, these catalytic systems genation (DKR-ATH).12 Thus, we envisioned that 2-substituted
3-oxoindolines could be a series of idealistic substrates for the
a School of Biology and Biological Engineering, South China University of
Technology, Guangzhou 510640, P. R. China. E-mail: lzhangce@scut.edu.cn
b HEC Research and Development Center, HEC Pharm Group, Dongguan 523871,
P. R. China. E-mail: wangzhongqing@hecpharm.com
preparation of enantiomerically pure indolines via ruthenium(II)-
catalyzed asymmetric transfer hydrogenation through dynamic
kinetic resolution (this work, Scheme 1).
With the above idea in mind, we initiated our studies by
investigating various Ru catalysts (R,R-C1–C7) for DKR-ATH of
N-acetyl-2-methoxycarbonyl-3-oxo-indoline 1a, and all the reac-
tions were carried out using HCOOH/Et3N as a hydrogen donor
c State Key Laboratory of Anti-Infective Drug Development, Sunshine Lake Pharma
Co., Ltd., Dongguan 523871, P. R. China
† Electronic supplementary information (ESI) available. CCDC 1858401. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c8cc07336h
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Table 1 Ru(II) catalyst screening for the DKR-ATH of 1aa
Scheme 1 Reduction strategies to stereoenriched 2,3-disubstituted indolines.
Entry
Ru Cat.
Conv.b (%)
drc (cis : trans)
eed (%)
1
2
3
4
5
6
7
8
9
10
R,R-C1
R,R-C2
R,R-C3
R,R-C4
R,R-C5
R,R-C6
R,R-C7
R,R-C1e
R,R-C1f
R,R-C1g
100
100
100
94
94
96
499 : 1
499 : 1
499 : 1
499 : 1
499 : 1
499 : 1
499 : 1
499 : 1
499 : 1
499 : 1
499
99
499
90
91
89
and DCM as the solvent. All catalysts, with the exception of oxo-
tethered-Ru catalyst R,R-C2 and Wills catalyst R,R-C3,9e–h were
generated in situ from [RuCl2(p-cymene)]2 and ligands in DCM
at reflux. Screening of the catalysts revealed that all catalysts
provided excellent conversion and stereoselectivity (Table 1,
entries 1–7). Catalyst R,R-C1 and Wills catalyst R,R-C3 both
gave the best results (full conversion, 499% ee and 499 : 1 dr,
entries 1 and 3, Table 1), considering the cost and availability of
the catalyst R,R-C1 was preferable. The oxo-tethered Ru catalyst
R,R-C2 also showed full conversion and excellent stereo-
selectivity (99% ee and 499 : 1 dr, Table 1, entry 2), but the
enantioselectivity was slightly lower than that of R,R-C1.
92
92
499
499
89
499
499
97
a
Reaction conditions: 1a (4.29 mmol), Ru cat. (1.0 mol%), HCO2H/Et3N
b
(5 : 2) (3 equiv.), DCM (8 mL) at reflux for 12 h. Determined by HPLC.
c
d
Determined by 1H-NMR. Determined by chiral HPLC using a DAICEL
e
f
CHIRALPAK column. 0.5 mol% of R,R-C1 was used. 0.25 mol% of
R,R-C1 was used. 0.1 mol% of R,R-C1 was used.
g
Attempts to reduce the catalyst loading from 1.0 mol% to 0.5 or Different positions of the substituted group (i.e. 4-monosubstituted,
even 0.25 mol% were proved successful (Table 1, entries 8 and 9), 5-monosubstituted, 6-monosubstituted, and 5,6-disubstituted)
and the conversions were up to 99% and the stereoselectivity on the aryl moiety of substrates were all well tolerated, while the
remained outstanding. It is regrettable that the conversion 7-methoxy substrate 1f afforded the lowest enantioselectivity
shrank obviously when the catalyst loading was decreased to (94% ee, 2f, Table 2). Besides, to further investigate the sub-
0.1 mol% (Table 1, entry 10), but the stereoselectivity remained strate scope, the methoxycarbonyl group was replaced with a
excellent.
benzyl group. To our delight, both of the substrates with the
Based on our experimental studies, the scope of the Ru- benzyl group (1o and 1p, Table 2) afforded excellent conversion
catalyzed DKR-ATH for a series of 2-substituted N-acetyl-3-oxo- and stereoselectivity.
indolines 1a–1p (Table 2) was subsequently examined. A wide
Furthermore, it was found that only cis diastereomers were
variety of substitution patterns on the aryl moiety were tolerant detected in all the above cases.13 This result might confirm
to the reaction conditions. Either electron-rich or electron-poor the proposed mechanism that the absolute configuration was
N-acetylindoxyl derivatives were suitable for this transforma- controlled by the C–H/p interaction between the p-cymene of
tion, affording the desired product in good to high yields R,R-C1 and the phenyl group of the substrate (Fig. 2).14 The
(50–98%) and excellent stereoselectivities (up to 499% ee transition state adduct of the Ru-hydride catalyst (R,R)-C1 and
and 499 : 1 dr). Although the electronic effect showed no 1d with the methoxycarbonyl group away from the catalyst is
significant influence on the stereoselectivity, substrates with favoured due to the lack of steric hindrance, thereby producing
different substituents on the phenyl skeleton showed different 2d with cis-selectivity ((2R,3S)-isomer). The absolute configuration
reaction activities for DKR-ATH. For example, substrates with of 2d was determined to be 2R,3S based on single-crystal X-ray
electron-withdrawing groups (1b, 1c, 1g, 1i, and 1j; Table 2) analysis (X-ray structure15 of 2d, Fig. 3).
converted completely within 15 hours, whereas substrates with
electron donating groups (1m and 1n; Table 2) required a much for the asymmetric transfer hydrogenation of 3-oxoindoline
longer reaction time (48 h). derivatives via dynamic kinetic resolution. The reaction was
In conclusion, we have developed a highly efficient method
However, there was an exception that compound 1k bearing carried out with only 0.25 mol% Tf-DPEN-Ru catalyst (R,R-C1)
a NO2 group gave a relatively low isolated yield (50%) and this under mild conditions, and could be tolerant to a wide range of
might due to the poor solubility of 1k in the reaction system. substrates. The desired 2-substituted N-acetyl-3-hydroxy-indoline
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Table
2
Ru(II)-catalyzed DKR-ATH of 2-substituted N-acetyl-3-oxo-
derivatives were obtained as only cis diastereomers in high
yields (up to 98%) with excellent diastereoselectivity (499 : 1 dr)
and enantioselectivity (up to 499% ee). This method provides
the first example of preparing enantiomerically pure indolines
through ATH, which opens a new field of the asymmetric synthesis
of indoline-containing compounds.
indolinesa
We gratefully acknowledge financial support from the State
Key Laboratory of Anti-infective Drug Development (Sunshine
Lake Pharma Co., Ltd) (No. 2015DQ780357). We thank Zhongjian
Zhong (HEC pharm Co., Inc.) for NMR assistance and Lei Zhao
(HEC pharm Co., Inc.) for HPLC and optical rotation assistance.
Conflicts of interest
There are no conflicts to declare.
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