An Organocatalytic Kinetic Resolution of Aziridines by Thiol Nucleophiles

Article abstract of DOI:10.1021/acs.orglett.0c04074

We report the first organocatalytic kinetic resolution of unactivated aziridines by sulfur nucleophiles with excellent enantioselectivity. A suitable chiral phosphoric acid was found to catalyze the intermolecular ring opening under mild conditions, furni

Full text of DOI:10.1021/acs.orglett.0c04074

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Letter
An Organocatalytic Kinetic Resolution of Aziridines by Thiol
Nucleophiles
Song Sun,∥ Zhaobin Wang,∥ Shijia Li, Cong Zhou, Lijuan Song, Hai Huang,* and Jianwei Sun*
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ABSTRACT: We report the first organocatalytic kinetic resolution
of unactivated aziridines by sulfur nucleophiles with excellent
enantioselectivity. A suitable chiral phosphoric acid was found to
catalyze the intermolecular ring opening under mild conditions,
furnishing a range of highly enantioenriched β-amino thioethers and
aziridines, both of which are useful synthetic building blocks.
inetic resolution represents a powerful tool in
ones, have been demonstrated as versatile reaction partners, it
is worth noting that the use of sulfur-based nucleophiles have
remained challenging and scarce. Sometimes these nucleo-
philes may deactivate metal catalysts due to their strong
coordination ability.5 However, if successful, this process
could lead to useful enantioenriched chiral sulfur molecules
with β-amino functionality, an important family of molecules
with wide applications in medicinal chemistry and asymmetric
synthesis.6 In this context, the development of an efficient
protocol to address this limitation remains in high demand.
Recently, Feng and co-workers reported the first and only
example catalyzed by the metal complex lanthanum(III)/
N,N′-dioxide (Scheme 1b).4a While this elegant reaction was
achieved with good to excellent stereocontrol, it is worth
noting that all the aziridines used in this work are activated
donor−acceptor type. Thus, kinetic resolution of regular
unactivated aziridines by sulfur nucleophiles still remains
unknown. In 2009, Antilla and co-workers reported an
organocatalytic enantioselectivie desymmetrization of azir-
idines by thiols with chiral phosphoric acid (CPA) catalysis.4b
In this context, we report herein the first organocatalytic
kinetic resolution of this type (Scheme 1c).
K
asymmetric synthesis.1 It is particularly useful when
implemented on enantioselective opening of strained rings.
For example, catalytic asymmetric ring-opening of racemic
aziridines by kinetic resolution has been demonstrated as an
important strategy to provide expedient access to chiral
amine derivatives with various vicinal functionalities (Scheme
1a).2−4 This process also leads to enantioenriched aziridines
Scheme 1. Kinetic Resolution of Aziridines with Sulfur
Nucleophilesa
In continuation of our interest in chiral Brønsted acid
catalyzed asymmetric opening of strained rings,7 we
envisioned that the use of such an organocatalytic approach
should be able to provide an alternative solution to the metal
catalyzed system. To test this hypothesis, we employed
phenyl aziridine 1a as the model substrate. 2-Mercaptoben-
zothiazole (2a) was initially used as the nucleophile in view
of its wide utility in organic synthesis and medicinal
Received: December 9, 2020
Published: December 31, 2020
that are themselves important precursors to other useful
chiral building blocks via stereospecific transformations.
Owing to these exceptional utilities, various catalytic systems,
particularly based on metal catalysts, have been developed for
this process in the past two decades.2,3 While a range of
nucleophiles, including carbon-, nitrogen-, and oxygen-based
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chemistry (Table 1).8 Various chiral phosphoric acids
(CPAs) were examined as potential catalysts.9,10 Gratifyingly,
enantiomers was consumed, the other enantiomer was
remained essentially untouched, which highlighted the
remarkable stereocontrol. Different substituted mercaptoben-
zothiazoles were also good nucleophiles (entries 2−4).
Notably, 6-ethoxy-substituted one 2d also led to excellent
selectivity (s > 200, entry 4). However, other sulfur
nucleophiles, such as thiophenol, aliphatic thiols, and thio
acids, did not react under the standard conditions (see the
Supporting Information for details). Furthermore, 1,2-
disubstituted aziridine 1m was also an excellent substrate,
which afforded the highly enantioenriched product with two
consecutive chiral centers. While indene-derived aziridine 1n
and alkyl-substituted aziridine 1o also reacted with excellent
chemical efficiency, their enantioselectivity was very low when
2a was used as nucleophile. However, 2d could result in a
selectivity factor of about 12 (entries 17 and 18). Notably, no
other regioisomer was observed in the case of 1o. Finally, the
product absolute stereochemistry was confirmed by X-ray
crystallography in the case of 1d.
a
Table 1. Condition Optimization
This protocol could be applied to a 1 mmol scale reaction
without modification (eq 1). The reaction efficiency and
stereoselectivity at a larger scale (2 mmol of 1a) were
comparable to the results obtained in a smaller scale (Table
2, entry 1).
The highly enantioenriched products and recovered
aziridines are useful building blocks in organic synthesis.11
For example, the enantiopure aziridine 1a was known as a
versatile substrate for highly stereospecific transformations to
diversely functionalized chiral amine derivatives (Scheme 2).
Moreover, the benzothiazole unit in the enantioenriched β-
amino thioether product 3aa could also be converted or
removed. In the presence of MeONa/MeOH, the reaction
a
Reaction scale: rac-1a (0.1 mmol), 2a (0.05 mmol), solvent (1.0
mL). Conversion was determined by analysis of the 1H NMR
spectrum of the crude mixture using CH2Br2 as an internal standard.
Ee was determined by HPLC with a chiral stationary phase. s = ln[(1
− conv)(1 − ee1a)]/ln[(1 − conv)(1 + ee1a)]; conv = ee1a /(ee1a
+
b
c
ee3aa). Run with 4 Å molecular sieves (20 mg). Run at 0 °C.
the reaction of racemic 1a and 2a (0.5 equiv) in DCM at
room temperature proceeded smoothly and cleanly to form
the desired β-amino thioether 3aa with complete conversion.
Among these catalysts, the BINOL- and [H8]BINOL-derived
phosphoric acids resulted in poor enantiocontrol (s = 1−4).
However, those with the spirocyclic backbone led to
improved selectivity (entries 3−5). Specifically, catalyst B3
provided the highest enantioselectivity (s = 43, entry 5).
Further solvent screening identified anhydrous chloroform to
be superior (entry 10). The use of molecular sieves as
additive could further improve the outcome (entry 11).
Furthermore, decreasing the reaction temperature to 0 °C
enhanced the selectivity factor to an excellent level (s > 200).
With this set of conditions, the product and the remained
substrate were both obtained with excellent enantiopurity
(entry 12).
Scheme 2. Product Transformations
With the optimized conditions, we examined the scope of
this kinetic resolution protocol. A range of racemic aziridines
with different substituent patterns smoothly participated in
this ring-opening reaction under mild conditions. The
corresponding β-amino thioether products and the remained
aziridines were all obtained with good to high enantiose-
lectivity. It is worth noting that excellent selectivity factors
were observed for substituted phenylazridines (entries 1−14).
These results meant that, in most cases, when one of the two
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a
Table 2. Substrate Scope
a
Reaction scale: rac-1 (0.4 mmol), 2 (0.2 mmol), (R)-B3 (5 mol %), 4 Å MS (80 mg), CHCl3 (4.0 mL), 0 °C. Isolated yield and ee are from the
same single trial. The ee values were determined by chiral HPLC. s = ln[(1 − conv)(1 − ee1)]/ln[(1 − conv)(1 + ee1)]; conv = ee1/(ee1 + ee3).
b
c
d
e
Yield and ee are referred to the recovered substrate. Yield and ee are referred to the product 3. Run at 0 °C for 48 h. Run at 0 °C for 144 h
followed by rt for 24 h.
proceeded at 40 °C to form the highly enantioenriched
methyl thioether 5 as the major product. It is believed that
this reaction initially forms the methyl aryl ether IM1 and
sulfide anion IM2 followed by a nucleophilic substitution
(SN2) reaction between these two intermediates.12 While it
was difficult to control this process to stop at the free thiol
stage, it is worth noting that the free thiol 6 could be isolated
at partial conversion.13 Notably, no obvious erosion in
product enantiopurity was observed in these transformations.
To help understand the origin of the excellent stereo-
control, we also carried out DFT calculations of the
enantiodetermining transition states. The results indicated
that the (S)-enantiomer of the aziridine substrate experiences
severe steric repulsion when the nucleophile approaches the
reactive center, resulting in much higher barrier than that of
the (R)-enantiomer (see the SI for more details).
In conclusion, we have developed the first organocatalytic
kinetic resolution of aziridines by sulfur nucleophiles. With
this new protocol, efficient kinetic resolution of unactivated
aziridines by sulfur nucleophiles has been demonstrated. The
proper choice of a suitable chiral phosphoric acid catalyst
enabled these reactions to proceed under mild conditions
with good to excellent enantiocontrol, achieving selectivity
factors among the highest in aziridine kinetic resolutions. The
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Notes
β-amino thioether products and the remained aziridines were
all obtained with good to high enantiopurity. These
molecules are important precursors to other synthetically
useful chiral building blocks.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by NSFC (91956114), Hong
Kong RGC (16302318, 16302617), Jiangsu Key Laboratory
of Advanced Catalytic Materials and Technology
(BM2012110), Changzhou Sci&Tech Program
(CJ20200082), and Jiangsu specially appointed professors
program. The Natural Science Foundation of the Jiangsu
Higher Education Institutions of China (20KJB150012).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04074.
Experimental procedures, kinetic analysis, and spectral
data; crystal data and structural refinement, atomic
coordinates and displacement parameters, and bond
lengths and angles for compound 3da; DFT calcu-
lations with energies, structures, and atomic coordi-
nates; deermination of absolute stereochemistry (PDF)
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AUTHOR INFORMATION
■
Corresponding Authors
Hai Huang − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China; Email: huanghai@cczu.edu.cn
Jianwei Sun − Department of Chemistry, the Hong Kong
University of Science and Technology, Hong Kong SAR,
China; Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China; orcid.org/0000-0002-2470-1077;
Email: sunjw@ust.hk
Authors
Song Sun − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China; orcid.org/0000-0002-9974-6456
Zhaobin Wang − Department of Chemistry, the Hong Kong
University of Science and Technology, Hong Kong SAR,
China; orcid.org/0000-0001-7934-2879
Shijia Li − Department of Chemistry, the Hong Kong
University of Science and Technology, Hong Kong SAR,
China; Shenzhen Bay Laboratory, Shenzhen 518055, China
Cong Zhou − Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology, School of Petrochemical
Engineering, Changzhou University, Changzhou 213164,
China
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https://pubs.acs.org/10.1021/acs.orglett.0c04074
Author Contributions
∥These authors contributed equally to this work.
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