Highly Enantioselective Synthesis of Fused Tri- and Tetrasubstituted Aziridines: aza-Darzens Reaction of Cyclic Imines with α-Halogenated Ketones Catalyzed by Bifunctional Phosphonium Salt

Article abstract of DOI:10.1002/anie.201900613

The first enantioselective aza-Darzens reaction of cyclic imines with α-halogenated ketones was realized under mild reaction conditions by using amino-acid-derived bifunctional phosphonium salts as phase-transfer promoters. A variety of structurally dense tri- and tetrasubstituted aziridine derivatives, containing benzofused heterocycles as well as spiro-structures, were readily synthesized in high yields with excellent diastereo- and enantioselectivities (up to >20:1 d.r. and >99.9 % ee). The highly functionalized aziridine products could be easily transformed into different classes of biologically active compounds.

Full text of DOI:10.1002/anie.201900613

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Highly Enantioselective Synthesis of Fused Tri- and Tetra-
substituted Aziridines via Bifunctional Phosphonium Salt-
Catalyzed Aza-Darzens Reaction
Authors: Jianke Pan, Jia-Hong Wu, Hongkui Zhang, Xiaoyu Ren, Jian-
Ping Tan, Lixiang Zhu, Hong-Su Zhang, Chunhui Jiang, and
Tianli Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900613
Angew. Chem. 10.1002/ange.201900613
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10.1002/anie.201900613
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Highly Enantioselective Synthesis of Fused Tri- and Tetra-substituted
Aziridines via Bifunctional Phosphonium Salt-Catalyzed Aza-Darzens
Reaction **
Jianke Pan †, Jia-Hong Wu†, Hongkui Zhang, Xiaoyu Ren, Jian-Ping Tan, Lixiang Zhu, Hong-Su Zhang,
Chunhui Jiang, and Tianli Wang*
straightforward and efficient approaches for producing such ring
systems.[5] Lewis and Brønsted acid-catalyzed aza-Darzens of -
diazoacetates and imines with offering aziridines were first
disclosed by Brookhart, Templeton and co-workers, respectively.[6]
The asymmetric variants of these acid catalyzed aza-Darzens
reactions were pioneeringly reported by Wulff[7] and further
developed by Maruoka[8] and others,[9] particularly providing cis-
or/and trans-disubstituted aziridines in high yields with excellent
stereoselectivities. However, less success has been achieved in
direct construction of trisubstituted chiral aziridine scaffolds via
this process; and only two examples were reported.[10] Maruoka and
co-workers disclosed a chiral Brønsted acid-catalyzed aziridination
between N--diazoacyl oxazolidinones and N-Boc imines, thus
creating trisubstituted chiral aziridine skeletons.[10a] Quite recently,
Trost developed a Zn-ProPhenol catalyzed aza-Darzens reaction of
chlorinated aromatic ketones with N-Boc aldimines, providing a
novel method for constructing trisubstituted chiral aziridine
motifs.[10b] Although these impressive advances have been made,
highly enantioselective preparation of trisubstituted aziridine rings
is still synthetic challenge, let alone directly asymmetric synthesis
of structurally dense tetrasubstituted chiral aziridine molecules. To
the best of our knowledge, no general and straightforward catalytic
protocol to access optically pure tetrasubstituted aziridines has
been reported so far. Therefore, it is highly desirable to explore a
utilitarian strategy to fill this void.
Abstract: The first enantioselective aza-Darzens reaction of cyclic
imines with -halogenated ketones was realized under mild
reaction conditions, by using amino acid-derived bifunctional
phosphonium salts as phase-transfer promoters. A variety of
structurally dense tri- and tetra-substituted aziridine derivatives,
containing benzo-fused heterocycles as well as spiro structures,
were readily synthesized in high yields with excellent diastereo-
and enantioselectivities (up to >20:1 dr and >99.9% ee). The
highly functionalized aziridine products could be easily
transformed into different classes of biologically active compounds
with significant synthetic challenge.
Optically pure fused N-heterocycles, especially aziridine-
containing molecules, are versatile intermediates in chemical
synthesis,[1] and they are also prevalent building blocks in many
biologically active compounds, including natural alkaloids and
pharmaceutical agents (Scheme 1).[2] Accordingly, a number of
catalytic methods have been devised for the stereoselective
construction of such structural motif over the past two decades.[3-9]
In this context, the aza-Darzens reaction becomes one of the most
In this study, we attempted to develop an alternative approach
to prepare structurally dense tri- and tetra-substituted aziridines
with readily available catalysts and reagents. In the past decades,
asymmetric phase-transfer catalysis (PTC) has been recognized as
a powerful and versatile tool for the enantioselective synthesis of
chiral compounds, and numerous quaternary ammonium salts[11]
have been commonly employed in PTC. However, asymmetric
PTC involving phosphonium salts as catalysts is still under-
developed.[12, 13] The key breakthroughs in this field were recently
reported by the groups of Maruoka[14] and Ooi.[15] Later, Ma and
co-workers introduced a binol-derived P-spiro phosphonium salt
and realized its use in asymmetric amination of benzofuranones.[16]
More recently, the groups of Zhao[17] and Lu[18] derived several
phosphonium salt catalysts from amino acids and initially
demonstrated their effectiveness in asymmetric conjugate additions
and substitution reactions. Notably, such amino acid-based
phosphonium salts possess remarkably high tunability, but its
utilization in asymmetric synthesis are rare to date. As part of our
Scheme 1. Selected aziridine-containing bioactive molecules.
[] J. Pan,[†] J.-H. Wu,[†] H. Zhang, X. Ren, J.-P. Tan, L. Zhu, H.-
S. Zhang, Dr. C. Jiang, Prof. Dr. T. Wang
Key Laboratory of Green Chemistry & Technology of Ministry
of Education, College of Chemistry, Sichuan University
29 Wangjiang Road, Chengdu 610064 (P. R. China)
E-mail: wangtl@scu.edu.cn
Dr. C. Jiang
School of Environmental and Chemical Engineering, Jiangsu
University of Science and Technology, 2 Mengxi Road,
Zhenjiang 212003 (P. R. China)
[†] These authors contributed equally to this work.
Supporting information for this article can be found under:
https://doi.org/10.1002/anie.2019xxxxx.
Scheme 2. Construction of densely mutisubstituted aziridines via
bifunctional phosphonium salt-catalyzed aza-Darzens reaction.
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10.1002/anie.201900613
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COMMUNICATION
research interest in the development of asymmetric synthetic
methods catalyzed by amino-acid-based organocatalysts,[19] we
envisioned that employment of highly tunable bifunctional
phosphonium salts may result in a practical asymmetric aza-
Darzens cyclization protocol to construct densely tri- and tetra-
substituted aziridine cores (Scheme 2). Herein, we describe our
successful development of amino acid-derived bifunctional
phosphonium salt-catalyzed enantioselective aza-Darzens reaction
between cyclic imines and -halogenated ketones. It provides
facile access to structurally dense tri- and tetra-substituted chiral
aziridines under mild conditions.
Table 1: Optimization for the asymmetric aza-Darzens reaction
of cyclic ketimine 5a with -bromoacetophenone 6a.[a]
Entry Cat.
Sol.
Base
Yield [%][b] ee [%][c]
1
1a
1b
1c
2a
2b
3a
3b
4a
4b
4b
4b
4b
4b
4b
4b
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
hexane
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
63
68
57
88
96
94
93
95
93
75
74
78
92
93
21
31
16
37
16
34
38
48
59
72
70
74
68
73
78
92
2
3
For our initial investigations, the aza-Darzens reaction between
cyclic N-sulfonyl α-ketimino ester 5a and -bromoacetophenone
6a was chosen as a model reaction to evaluate catalytic effects of
the candidated bifunctional phosphonium salts (Table 1), which
were prepared in our laboratory via a P-alkylation reaction of our
previous organophosphines[19] with the appropriate alkyl halides.
Pleasingly, all the phosphonium salts examined were effective in
promoting this reaction, leading the desired aziridine products in
4
5
6
7
8
9
10
11
12
13
14[d]
15[d]
moderate
diastereoselectivities. Generally, L-Valine-derived bifunctional
phosphonium salts with sulfonamide, amide, thiourea or
to
excellent
isolated
yields
with
high
K3PO4
K3PO4·7H2O
K3PO4·7H2O
K3PO4·7H2O
a
dipeptide were found to be ineffective in asymmetric induction,
affording the cyclization products with low ee values (entries 1−5).
L-Threonine-derived dipeptide-based phosphonium salts were
discovered favorable in stereochemical controls, furnishing the
desired products with good diastereo- and enantioselectivities
hexane/toluene
(9/1, v/v)
hexane/toluene
(4/1, v/v)
hexane/toluene
(4/1, v/v)
16[d]
4b
4b
K3PO4·7H2O
K3PO4·7H2O
K3PO4·7H2O
61
93
93
99
17[d]
>99
>99
(entries
6−9).
The
O-TBDPS-L-Thr-D-tert-Leu-based
18[d,e] 4b
phosphonium salt 4b turned out to be the best, affording the
Darzens reaction product in 93% yield and with 72% ee (entry 9).
Subsequently, we further optimized the reaction condition of base
(entries 10−14). Among all the bases tested, it was found that 4.0
equivalent of K3PO4·7H2O proved to be the best, and the ee value
could be improved to 78% (entry 14). At last, a quick solvent
screening (entries 15−17)[20] identified that the mixture of
hexane/toluene (4/1, v/v) was the solvent of choice (entry 17).
Indeed, only 5 mol% catalyst was also sufficient to promote this
reaction, and the corresponding product was isolated in 93% yield
with >99% ee (entry 18).
[a] Reactions were performed with 5a (0.05 mmol), 6a (0.06 mmol), catalyst
(0.005 mmol) and the base (2.0 equiv.) in solvent (0.5 mL) at room
temperature for 12 h. All dr values were determined by 1H NMR of crude
product. [b] Isolated yield. [c] The ee value was determined by HPLC analysis
on a chiral stationary phase. [d] 4.0 equivalent of base was used. [e] The
catalyst loading was 5 mol% and the reaction time was 24 h. TBDPS = tert-
butyldiphenylsilyl, Ts = 4-toluenesulfonyl.
Having established the optimal reaction conditions, the
substrate scope for aza-Darzens cyclization between cyclic imines
and -halogenated acetophenones was investigated for preparing
tri- and di-substituted chiral aziridines (Table 2). In general,
various cyclic ketimines bearing electron-neutral, -donating, or -
withdrawing groups on the phenyl ring could be well employed,
furnishing the corresponding products 7ah in high yields
(8696%) with excellent both diastereo- and enantioselectivities
(>20:1 dr, 8399% ee). Additionally, when 1-naphthyl and 2-
naphthyl-containing substrates were used, enantiomerically
enriched products were also isolated in high yields with excellent
stereoselectivities (7g and 7h). The substrate bearing 2-Cl
substitutent on the phenyl ring slightly lowered the
enantioselectivity of the reaction (7f), mainly due to the steric
hindrance. Subsequently, we further explored the substrate scope
of -bromo acetophenones under the optimal conditions. A wide
range of -bromoacetophenones 6 with substituents in the ortho-,
meta-, or para-position of the phenyl ring proceeded very well to
furnish the desired products 7io in high yields (9298%) with
excellent ee values (8799% ee). Notably, thienyl and naphthyl
substituted -bromoketones also proved to be excellent substrates
and afforded the products 7p and 7q with exceptionally high ee
values as >99.9% and 98%, respectively. Moreover, the catalytic
reactions worked well for cyclic aldimines 5’ when employing the
-chloro acetophenones 6’ as nucleophilic reaction partners,[19]
giving the products (8af) with excellent stereoselectivities in high
isolated yields. The X-ray crystal of rac-7a was obtained[21], and
the absolute configuration of the aza-Darzens products listed in
Table 2 were assigned by comparing both the optical rotation and
HPLC analysis of product 7a’ with previously reported results.[4j,20]
Encouraged by these results, we set our goal to extend this novel
strategy to synthesize intimidating tetrasubstituted aziridine
derivatives. This seems to be a formidable challenge as rarely that
the constructed aziridines possess all-carbon quaternary
stereogenic centers which were extremely sterically hindered; and
we reasoned we may be able to tackle this task by using this highly
tunable bifunctional phosphonium salt. To our delight, the aza-
Darzens reaction between cyclic ketimines 5 and cyclic -
bromoketones 9 proceeded smoothly with affording the desirable
tetrasubstituted aziridine products in the presence of dipeptide-
based phosphonium 4b under the above optimal conditions. As
shown in Table 3, the reaction was applicable to various cyclic
ketimines bearing different aromatic rings, regardless of the
positions and electronic properties of the substituents on the
aromatic moiety, producing the expected tetrasubstituted aziridines
10al in high yields (8798%) with excellent stereoselectivities
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Table 3: Enantioselective synthesis of tetrasubstituted aziridines
through aza-Darzens reaction of cyclic ketimines 5 with cyclic -
bromoketones 9.[a]
(up to >20:1 dr, 91>99.9% ee). As well, a broad range of cyclic
-bromo benzopyrones with different substituents in the ortho-,
meta-, or para-position of the phenyl ring were found to be
variable substrates, delivering the desired products 11an in high
yields (8699%) with high ee values (91>99.9%). Furthermore,
the seven-membered (hetero)-cyclic -bromoketones also proved
to be suitable substrates (11o and 11p). The absolute
configurations of these fused spiro aziridine products were
assigned based on X-ray crystal structural analysis of 10a.[20, 21]
Table 2: Scope for aza-Darzens reaction of cyclic imines 5/5’ with -
halogenated acetophenones 6/6’.[a]
[a] Reactions were performed with 5 (0.1 mmol), 9 (0.12 mmol), 4b (0.01 mmol)
and K3PO4·7H2O (0.4 mmol) in hexane/toluene (1 mL, v/v = 4/1) at room
temperature for 24 h. The dr values were determined by 1H NMR of crude
product and the ee value was determined by HPLC analysis on a chiral
stationary phase. [b] The solvent was hexane/chlorobenzene (1 mL, v/v = 4/1).
position of the ketone moiety, affording compound 14 in high
isolated yield. Moreover, a biologically active compound 18, which
has potential activity as an HIV-1 inhibitor,[2e-h] was prepared in
high yield with good stereoselectivities by using this aza-Darzens
protocol (Scheme 4).[20]
[a] Reactions were performed with 5 or 5’ (0.1 mmol), 6 or 6’ (0.12 mmol), 4b
(0.005mmol, 5 mol%) and K3PO4·7H2O (0.4 mmol) in hexane/toluene (1.0 mL,
Based on the obtained results and our previous studies,[19c-f] the
plausible stereocontrol models are presented in Table 4. We
propose that amide and carbamate portions of the catalyst interact
with cyclic imines via hydrogen bonding interactions, which
contribute significantly to the key transition state models leading to
the formation of the observed major stereoisomer. To provide
experimental support, we prepared methylated catalysts 4b-1 and
4b-2. When methylated phosphonium salts were used as the
catalyst, respectively; the reaction became much slower, and the
enantioselectivities decreased dramatically. When the reaction was
performed in the solvent of methanol, only racemic product was
obtained. These results clearly support the importance of the
hydrogen bonding interactions in our catalytic system. Moreover,
preliminary DFT calculations were performed to gain a better
understanding of our reaction.[22] Although the (Z)-enolate
generated from 6a is more thermodynamically stable than the (E)-
enolate, TS1 shows that irrespective of the enolate configuration,
the S configuration of the new quaternary carbon at the 7b-position
in final product will be generated. This is determined by the
v/v = 4/1) at room temperature for 24 h. The dr values were determined by 1
H
NMR of crude products. The ee value was determined by HPLC analysis on a
chiral stationary phase. [b] The solvent was p-xylene. [c] The solvent was
hexane/chlorobenzene (1.0 mL, v/v = 4/1). [d] The reaction was stirred at -10
oC for 48 hours. [e] The solvent was hexane/fluorobenzene (1.0 mL, v/v = 4/1).
To evaluate the scalability and the practicality of the process,
one gram of cyclic ketimine 5a was used to perform the aza-
Darzens reaction with -bromoacetophenone 6a, and the product
7a was obtained in 88% yield with >20:1 dr and >99% ee (Scheme
3). These highly functionalized aziridine products are not only
biologically interesting,[2] but also synthetically valuable. As
illustrated in Scheme 3, product 7a could be readily converted to
cyclic N-sulfonylamine 12 in high yield via a ring-opening reaction
without any loss of enantioselectivity (99% ee). Direct reduction of
product 7a using NaBH4 furnished hydroxyl-functionalized
compound 13 in excellent yield. Alternatively, treatment of 7a with
benzoic acid under strong basic condition led to simultaneous ring-
opening of the aziridine framework and substitution of the -
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10.1002/anie.201900613
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approaching direction of the enolate, which preferentially attacks
the imine substrate from its Si face. Subsequently, rapid ring
closure by the intramolecular nucleophilic substitution of the
bromide will afford product with either 1R (from (Z)-enolate, as
shown in TS2-(R,S)) or 1S (from (E)-enolate, as shown in TS2-
(S,S) in SI)[20] configuration. Thermodynamic equilibrium will lead
to the observed 1R-epimer which is more stable than (1S,7bS)-7a
by 4.1 kcal/mol. [20]
employing dipeptide-based chiral phosphonium salt as phase-
transfer catalyst. A wide range of optically pure trisubstituted
aziridines were obtained in high yields with excellent diastereo-
and enantioselectivities under mild reaction conditions. In addition,
plenty of structurally dense and stereodefined tetrasubstituted
aziridines possessing complex spiro-fused scaffolds, which had
never been accessible directly by any kind of catalytic asymmetric
transformation, were readily synthesized in a highly stereoselective
manner according to this methodology. The practicality and the
utility of this protocol were demonstrated by the scale-up synthetic
reaction and facile elaborations. Detailed mechanistic
investigations and applications of this novel phosphonium salt
catalysis to other challenging organic synthesis are currently
ongoing in our laboratory.
In conclusion, we have disclosed a highly efficient aza-Darzens
cyclization between cyclic imines and -halogenated ketones by
Acknowledgements
Financial support was provided by the National Natural Science
Foundation of China (21702139), the “1000-Youth Talents
Program” (YJ201702), and the Fundamental Research Funds for
the Central Universities. We thank Prof. Yixin Lu (Department of
Chemistry, National University of Singapore), Prof. Xiaoming
Feng (Sichuan University), Prof. Qing-Hua Fan (Institute of
Chemistry, Chinese Academy of Sciences), and Dr. Peiyuan Yu
(Lawrence Berkeley National Laboratory) for invaluable help. We
also acknowledge the comprehensive training platform of the
Specialized Laboratory in the College of Chemistry at Sichuan
University and the Analytical & Testing Center of Sichuan
University for compound testing.
Scheme 3. Gram-scale synthesis and synthetic manipulations of 7a.
Conflict of interest
The authors declare no conflict of interest.
Scheme 4. Synthesis of a biologically active compound 18.
Table 4. Asymmetric aza-Darzens reaction promoted by different
Keywords: bifunctional phosphonium salts · aza-Darzens reaction ·
tetrasubstituted aziridines · -halogenated ketones · cyclic imines·
phosphonium salts and the proposed transition state models.[a]
[1] For recent reviews, see: a) A. K. Yudin, Aziridines and Epoxides in Organic
Synthesis, Wiley-VCH: Weinheim, 2006; b) C. Botuha, F. Chemla, F. Ferreira,
A. Pérez-Luna in Heterocycles in Natural Product Synthesis (Eds.: K. C.
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Chem. 2002, 67, 3884.
Entry
Cat.
4b
t (h)
10
24
24
1
Yield [%][b]
dr[c]
ee [%][d]
1
2
92
85
80
96
>20:1
>20:1
>20:1
>20:1
>99
3
4b-1
4b-2
4b
3
4[e]
72
0
[a] Reaction conditions: 5a (0.10 mmol), 6a (0.12 mmol), K3PO4·7H2O (0.4
mmol) and catalyst (0.01 mmol) in hexane/toluene (1.0 mL, v/v = 4/1). [b]
Isolated yield. [c] Determined by 1H NMR of crude product. [d] Determined by
HPLC analysis on a chiral stationary phase. [e] The solvent was methanol (1.0
mL).
[2] For recent reviews, see: a) C. Mitomycin, Current Status and New Developments
(Eds.: S. K. Carter, S. T. Crooke), Academic: New York, 1979, p 254; b) Y.
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Ismail, D. O. Levitsky, V. M. Dembitsky, Eur. J. Med. Chem. 2009, 44, 3373.
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Loh, Org. Lett. 2015, 17, 1050; f) J. Mao, D. C. Baker, U.S. Patent 6458962
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Patent, 6562850 B1, 2003; h) D. C. Baker, A. Mayasundari, J, Mao, S. C.
Johnson, S. Yan, International Patent, WO 00/04004, 2000.
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2007, 107, 2080; b) Y. Zhang, Z. Lu, W. D. Wulff, Synlett 2009, 2715; c) J.
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10.1002/anie.201900613
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COMMUNICATION
Org. Lett. 2016, 18, 880; d) H. Jiang, K. Lang, H. Lu, L. Wojtas, X. P. Zhang,
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[5]
[6]
For recent reviews on catalytic asymmetric (aza)-Darzens reaction, see: a) P.
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This article is protected by copyright. All rights reserved.

10.1002/anie.201900613
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Jianke Pan, † Jia-Hong Wu, † Hongkui
Zhang, Xiaoyu Ren, Jian-Ping Tan,
Lixiang Zhu, Hong-Su Zhang, Chuihui
Jiang, and Tianli Wang*
Page No. – Page No.
Highly Enantioselective Synthesis of
Fused Tri- and Tetra-substituted
Aziridines via Bifunctional
Phosphonium Salt-Catalyzed Aza-
Darzens Reaction of Cyclic Imines
with -Halogenated Ketones
A highly enantioselective aza-Darzens cyclization between cyclic imines and -
halogenated ketones catalysed by amino acid-derived bifunctional phosphonium
salts has been developed. In the presence of 510 mol% catalyst 4b, the aza-
Darzens reaction could be completed within 24 hours, and a wide range of
enantioenriched fused tri- and tetra-substituted aziridines were isolated in high yields
with excellent diastereo- and enantioselectivities (up to >20:1 dr and >99.9% ee).
Scale-up synthesis and valuable transformations were also demonstrated.
This article is protected by copyright. All rights reserved.