Kinetic Resolution of Aziridines via Catalytic Asymmetric Ring-Opening Reaction with Mercaptobenzothiazoles

Article abstract of DOI:10.1021/acs.orglett.9b02058

A highly efficient kinetic resolution of racemic 2-acyl-3-aryl-N-tosylaziridines is achieved through a chiral Lewis acid promoted ring-opening reaction with 2-mercaptobenzothiazoles as the nucleophiles. The chiral N,N′-dioxide-lanthanum complex as catalyst and the 2-mercaptobenzothiazoles as active sulfur nucleophiles are the keys to the success of the reaction. A variety of enantioenriched β-amino thioethers and aziridines are obtained in good yields with good ee values.

Full text of DOI:10.1021/acs.orglett.9b02058

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Kinetic Resolution of Aziridines via Catalytic Asymmetric Ring-
Opening Reaction with Mercaptobenzothiazoles
Fengcai Zhang,† Yu Zhang,† Qingfa Tan,† Lili Lin,*,† Xiaohua Liu,† and Xiaoming Feng*,†,‡
†Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
‡Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China
S
* Supporting Information
ABSTRACT: A highly efficient kinetic resolution of racemic 2-
acyl-3-aryl-N-tosylaziridines is achieved through a chiral Lewis
acid promoted ring-opening reaction with 2-mercaptobenzo-
thiazoles as the nucleophiles. The chiral N,N′-dioxide−
lanthanum complex as catalyst and the 2-mercaptobenzothia-
zoles as active sulfur nucleophiles are the keys to the success of
the reaction. A variety of enantioenriched β-amino thioethers
and aziridines are obtained in good yields with good ee values.
he ring-opening of three-membered cyclic compounds
Twith nucleophiles occupies an important position in
organic synthesis.1 Aziridines are attractive synthons due to
their convenient construction of useful N-containing com-
pounds. The carbon-,2 oxygen-,3 and nitrogen-based4 nucleo-
philes have been well applied in the ring-opening reaction of
aziridines (Scheme 1a). Comparatively, the ring-opening
reaction with sulfur-based nucleophiles is challenging,
especially when the Lewis acid is used as the catalyst, because
sulfur nucleophiles might poison the catalyst for their strong
coordination ability to the central metal.5 However, it allows
for construction of β-amino thioethers,6 which are important
synthetic blocks and widely present in ligands as well as in
bioactive compounds,7 such as L-cysteine, β-MeLan,8 and
mersacidin.9 To the best of our knowledge, only one catalytic
asymmetric report emerged in 2009, where Antilla’s group
realized the desymmetrization of meso-aziridines with function-
alized thiols using the chiral phosphoric acid catalyst (Scheme
1b).10
Scheme 1. Asymmetric Ring-Opening Reactions of
Aziridines
The ring-opening of racemic aziridines via kinetic
resolution11 with sulfur nucleophiles could entail both
enantiomerically enriched β-amino thioethers and aziridines
at the same time. The obtained chiral aziridines are also
meaningful since this block exists in some compounds
featuring fascinating anticancer activity.12 Therefore, it is
significant to develop efficient methods for the kinetic
resolution of aziridines with sulfur nucleophiles.13
In addition, chiral N,N′-dioxide−metal complexes have been
proved to be efficient Lewis acid catalysts in series of
asymmetric reactions.14 They might be promising in
promoting the kinetic resolution of aziridines with sulfur
nucleophiles. We selected racemic trans-2-acyl-3-aryl-N-
tosylaziridines15 as the substrates to undergo the ring-opening
reaction since the carbonyl substituent and N-protection group
in aziridines could cooperate with the catalyst in a bidentate
manner, which will facilitate the enantiodiscrimination of the
reaction.16 As for the sulfur nucleophiles, cyclohexyl
mercaptan, thiophenol, and naphthol did not or very weakly
undergo the reaction. After considerable effort, 2-mercapto-
Received: June 14, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02058
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
benzothiazoles were applied as excellent nucleophiles (Scheme
1c).17
Table 2. Substrate Scope of the Benzothiazole-2-thiol
Derivatives
a
Initially, various metal salts coordinating with N,N′-dioxide
L-PiPr2 were tested (for details, see the Supporting
Information). The complex of Sc(OTf)3 could afford the
desired product in 41% yield but 0% ee value; meanwhile,
aziridine 1a decomposed under the strong Lewis acid
conditions (Table 1, entry 1). Further investigation showed
a
Table 1. Optimization of the Reaction Conditions
b
c
yield (%)
ee (%)
entry
metal salt
ligand
1a
3aa
1a
3aa
s
1
2
3
4
5
6
7
Sc(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
L-PiPr2
L-PiPr2
L-PrPr2
L-RaPr2
L-RaEt2
L-RaMe2
L-RaPh
L-RaMe2
41
44
44
49
49
49
49
49
0
67
69
72
83
90
36
90
41
47
44
37
50
49
49
60
65
69
97
90
37
92
9
a
Unless otherwise noted, all reactions were carried out with
11
13
45
58
3
La(OTf)3/L-RaMe2 (1:1.2, 5 mol %), ( )-1a (0.2 mmol) and 2a−
b
2h (0.1 mmol) in DCE (2 mL) at 35 °C for 3 h. Yield of isolated
c
product. Determined by SFC analysis. The absolute configuration of
3aa was determined by X-ray crystallographic analysis and other
products 3 were determined by comparing their CD spectra with that
of 3aa. s = ln[(1 − conv)(1 − ee1)]/ln[(1 − conv)(1 + ee1)]; conv =
ee1/(ee1 + ee3).
d
8
62
a
Unless otherwise noted, all reactions were carried out with metal
salt/ligand (1:1, 5 mol %), ( )-1a (0.10 mmol) and 2a (0.05 mmol)
b
in DCE (0.5 mL) at 35 °C for 2.5 h, DCE = CH2ClCH2Cl. Yield of
c
isolated product. Determined by SFC analysis. The absolute
might be caused by its insoluble nature. It is worth mentioning
that 4,5-dihydrothiazole-2-thiol 2h without a phenyl ring could
also undergo the kinetic resolution process smoothly, giving
good results.
configuration of 3aa was determined by X-ray crystallographic
d
analysis. Metal salt/ligand (1:1.2, 5 mol %), ( )-1a (0.20 mmol)
and 2a (0.10 mmol), 2 mL DCE. s = ln[(1 − conv)(1 − ee1)]/ln[(1
− conv)(1 + ee1)]; conv = ee1/(ee1 + ee3).
Next, a variety of racemic aziridines were assessed (Table 3).
The electronic nature and position of substituents on the
phenyl group of aryl aziridines also had little effect on the
enantiocontrol of the kinetic resolution, and the selectivity
factors varied from 28 to 55 (Table 3, entries 1−9). The
naphthyl-substituted 1k and 1l performed well to give 3 in
excellent ee values and 1a in good ee values (Table 3, entries
10 and 11). Simultaneously, racemic aziridines with methyl-
substituted benzoyl part were tested. Meta and para
compounds gave good results, but the ortho compound
resulted in a moderate outcome (Table 3, entries 12−14),
which might be caused by the larger steric resistance. The
absolute configuration of 3aa was determined to be (1S,2R) by
X-ray crystallographic analysis, and the other products 3 were
also determined to be (1S,2R) by comparing their CD spectra
with that of 3aa.
To illustrate the potential utility of the methodology, a
gram-scale synthesis was conducted. To our surprise, only 27%
ee for the product 3aa and 32% ee for the recovered 1a were
obtained under standard conditions. We surmised that
polymeric La(III) species might exist in the catalytic system,
especially in the case of amplification. This possibility was
confirmed by the investigation of the nonlinear effect of the
reaction, where a clear positive nonlinear effect was observed
when varying the ee value of the chiral ligand and then
recording the corresponding ee of 3aa and 1a. In addition, the
that the L-PiPr2/La(OTf)3 complex could give the desired
product 3aa in 44% yield, 67% ee, and recovered 1a in 41%
yield with 60% ee (s = 9). Next, the chiral backbone in ligand
was investigated. It was found that L-ramipril-derived L-RaPr2
was more competent than L-proline-derived L-PrPr2 and (S)-
pipecolic acid derived L-PiPr2 in terms of enantiocontrol
(Table 1, entries 2−4).
By reducing the steric hindrance on the amide benzene ring
(L-RaPr2 to L-RaMe2), the selectivity factor would rise from
13 to 58 (Table 1, entries 4−6). However, with no substituent
on the phenyl ring (L-RaPh) the enantioselectivity dropped
sharply (Table 1, entry 7). Finally, when the proportion of
metal salt and ligand adjusted to 1:1.2, the enantioselectivity of
recovered 1a improved slightly, and the yields as well as the ee
value of ring-opening product 3aa were maintained (Table 1,
entry 8).
With the optimized conditions in hand, the substrate scope
was then examined. At first, a series of 2-mercaptobenzothia-
zole derivatives were probed by reacting them with ( )-1a
(Table 2). Both electron-withdrawing and electron-donating
substituents on the phenyl ring had little effect on the reaction,
and the corresponding benzenesulfonamides 3aa−3ah togeth-
er with recovered 1a were obtained in excellent yields with
good ee values, except for the recovered 2d (65% ee), which
B
DOI: 10.1021/acs.orglett.9b02058
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. Substrate Scope of the Aziridines
b
c
yield (%)
ee (%)
entry
1
Ar1
Ar2
1
3
1
3
s
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-O2NC6H4
4-F3CC6H4
4-BrC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
2-naphthyl
Ph
2-MeC6H4
3-MeC6H4
4-MeC6H4
48
47
45
42
47
48
34
50
40
44
40
50
47
44
48 (3ba)
48 (3ca)
48 (3da)
43 (3ea)
49 (3fa)
49 (3ga)
48 (3ha)
49 (3ia)
44 (3ja)
49 (3ka)
49 (3la)
49 (3ma)
49 (3na)
49 (3oa)
88
93
86
90
85
84
60
79
74
96
96
62
87
94
90 (1S,2R)
87 (1S,2R)
90 (1S,2R)
85 (1S,2R)
90 (1S,2R)
80 (1S,2R)
80 (1S,2R)
89 (1S,2R)
90 (1S,2R)
88 (1S,2R)
81 (1S,2R)
65 (1S,2R)
90 (1S,2R)
85 (1S,2R)
55
49
53
38
51
24
16
41
42
61
37
9
9
10
11
12
13
14
2-naphthyl
Ph
Ph
54
43
Ph
a
Unless otherwise noted, all reactions were carried out with La(OTf)3/L-RaMe2 (1:1.2, 5 mol %), ( )-1 (0.20 mmol), and 2a (0.10 mmol) in
b
c
DCE (2 mL) at 35 °C for 3 h. Yield of isolated product. Determined by SFC analysis. The absolute configuration of 3aa was determined by X-ray
crystallographic analysis, and other products 3 were determined by comparing their CD spectra with that of 3aa. s = ln[(1 − conv)(1 − ee1)]/ln[(1
− conv)(1 + ee1)]; conv = ee1/(ee1 + ee3).
X-ray crystal structure of the catalyst showed that two
molecules of L-RaMe2 could cooperate with La(III) complex
(Scheme 2). Thus, we performed the reaction at decreased
mixture of L-RaMe2, La(OTf)3, 1a, and 2a (1.2:1:1:1) in DCE
displayed an ion at m/z 1402.2852 ([L-RaMe2 + La3+ + 2TfO−
+ 1a]+ m/z calcd 1402.2860), suggesting that the la
coordinated to the catalyst in a 1:1 molecular ratio. Meanwhile,
the characteristic signal of 2a coordinating with the catalyst
was not observed. Hence, the single coordination of the ligand
and metal was more likely the active one, and the catalyst
activated the aziridine 1a rather than the 2-mercaptobenzo-
thiazole 2a.
Scheme 2. Gram-Scale Synthesis, Nonlinear Effect, and X-
ray Crystal Structure
On the basis of the analysis above and the determination of
the absolute configuration of product 3aa, a possible catalytic
mechanism is proposed. As shown in Scheme 3, the two
polarized oxygen atoms of N-oxide and amide oxygens of L-
RaMe2 combine with La(III) in a tetradentate manner. When
Scheme 3. Proposed Catalytic Mechanism
concentration. Just as expected, 1.57 g (48% yield) of 3aa with
84% ee and 1.11 g (49% yield) of recovered aziridine 1a with
93% ee were obtained when 6 mmol of 1a and 3 mmol of 2a
reacted in a double amount of DCE (Scheme 2).
However, as shown in the single crystal of the catalyst, the
coordination sites of the metal are occupied, and it is difficult
to activate the substrates. Thus, what was the active species in
the solution? The HRMS analysis showed that in the spectra of
the mixture of L-RaMe2, La(OTf)3, and 1a in a 1.2:1:1 ratio in
DCE an ion at m/z 1025.1782 ([L-RaMe2+ La3+ + 2TfO−]+
m/z calcd 1025.1774) was displayed, indicating that the ligand
coordinated with the metal in a 1:1 ratio. The spectra in the
C
DOI: 10.1021/acs.orglett.9b02058
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
1a is added, (2R,3S)-1a coordinates to the catalyst with the
oxygen atom of the carbonyl group and one oxygen atom of
the Ts group, forming a distorted dodecahedral conformer.
There are different activation modes in different catalytic
systems.18 The π−π interactions between the two phenyl rings
of 1a and L-RaMe2 can decrease the energy of transition state,
therefore making it favored. The inner side is blocked by the
framework of ligand and 2a attacks from the outer side,
affording the (1S,2R)-3aa. Nevertheless, if the (2S,3R)-1a
isomer coordinates to the catalyst, steric hindrance between
the chiral backbone of catalyst and the phenyl ring in aziridine
appear. Therefore, it is difficult for (2S,3R)-1a to undergo the
subsequent ring-opening process, and it is recovered.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We appreciate the National Natural Science Foundation of
China (Nos. 21890723 and 21572136) for financial support.
■
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racemic trans-2-acyl-3-aryl-N-tosylaziridines derivatives. The
corresponding β-amino thioethers were obtained in high
activity together with high levels of stereocontrol (up to 92%
ee). Besides, a possible catalytic mechanism was proposed to
illustrate the stereoinduction. Further applications of the
catalysts are underway in our laboratory.
ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02058.
Experimental details; analytic data (NMR, SFC, HRMS,
CD spectra) (PDF)
Accession Codes
CCDC 1893413 and 1893450 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
Corresponding Authors
■
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*E-mail: xmfeng@scu.edu.cn.
*E-mail: lililin@scu.edu.cn.
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ORCID
Xiaohua Liu: 0000-0001-9555-0555
Xiaoming Feng: 0000-0003-4507-0478
D
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Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b02058
Org. Lett. XXXX, XXX, XXX−XXX