Copper-Catalyzed Asymmetric Addition of Tertiary Carbon Nucleophiles to 2 H-Azirines: Access to Chiral Aziridines with Vicinal Tetrasubstituted Stereocenters

Article abstract of DOI:10.1021/acs.orglett.8b02274

A catalytic asymmetric nucleophilic addition of tertiary carbon nucleophiles to 2H-azirines was established in the presence of the chiral N,N′-dioxide/Cu^II complex. Various chiral aziridines with vicinal tetrasubstituted stereocenters were obta

Full text of DOI:10.1021/acs.orglett.8b02274

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Asymmetric Addition of Tertiary Carbon
Nucleophiles to 2H‑Azirines: Access to Chiral Aziridines with Vicinal
Tetrasubstituted Stereocenters
Haipeng Hu, Jinxiu Xu, Wen Liu, Shunxi Dong, Lili Lin,* and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu
610064, China
S
* Supporting Information
ABSTRACT: A catalytic asymmetric nucleophilic addition of tertiary carbon nucleophiles to 2H-azirines was established in the
presence of the chiral N,N′-dioxide/CuII complex. Various chiral aziridines with vicinal tetrasubstituted stereocenters were
obtained in high yields with excellent diastereoselectivities and enantioselectivities. Moreover, on the basis of the control
experiments, X-ray structures of the products, and catalyst, a possible transition state was proposed to explain the
stereoselectivity.
Scheme 1. Asymmetric Additions of Nucleophiles to 2H-
Azirines
Aziridines are useful building blocks for organic synthesis and
may exhibit various biological properties such as antitumor and
antibacterial activities, which make them attractive synthetic
targets.1 Naturally, much attention has been drawn to
introducing the aziridine structures into different molecular
scaffolds.2 Since Somfai’s pioneering work in 2002,3 the
strategy employing nucleophilic addition to the unsaturated
nitrogen-containing heterocyclic compound, 2H-azirine,4,5 has
been one of the most efficient methods to deliver aziridines.6
However, the catalytic asymmetric version of the strategy was
not developed until recently. In 2016, we reported an
asymmetric imine amidation of 2H-azirines with oxindoles by
using a chiral N,N′-dioxide/ScIII complex catalyst (Scheme
1a).7a This was the first example of N1 of oxindole
participating in a catalytic reaction instead of C3. The
phenomenon was rationalized by the fact that the high steric
repulsion of the C3 position prevented the carbon nucleophilic
addition process which could conveniently synthesize chiral
aziridines with vicinal tetrasubstituted stereocenters. Later, the
heteroatomic additions were further developed: (1) Zhang’s
group realized a highly efficient kinetic resolution of 2H-azirine
via the nucleophilic addition of pyrazole to 2H-azirine by using
chiral imidodiphosphoric acid,7b and (2) Nakamura’s group
applied phosphite and thiol as nucleophiles to react with 2H-
azirines in the presence of chiral Bis(imidazole)/ZnII complex
and 8-quinolinesulfonamide catalysis, respectively.7c,d Despite
these successful examples, the catalytic asymmetric variant of
the carbon nucleophilic addition reaction is still rare due to the
poor nucleophilicity or high steric repulsion. Recently, the
Wang group made a breakthrough in the catalytic asymmetric
reaction of carbon nucleophiles with 2H-azirines (Scheme
1b).7e The author used the classical N-heterocyclic carbene
Received: July 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02274
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Letter
(NHC) as catalyst, which reversed the inherent polarity of the
aldehyde by forming the Breslow intermediate, successfully
achieving the catalytic enantioselective aza-Benzoin reaction of
aldehydes with 2H-azirines. A wide range of chiral aziridines
with a quaternary stereocenter were assembled. To date,
however, construction of chiral aziridines with vicinal
tetrasubstituted stereocenters proposed in our previous work
through the asymmetric addition of tertiary carbon nucleo-
philes to 2H-azirines remains a challenge. Notably, vicinal
tetrasubstituted stereocenters8 are also represented in
pharmaceutically active molecules, and development of new
catalytic methods for the construction of vicinal tetrasub-
stituted stereocenters is a goal in organic chemistry. Herein, we
report the highly enantioselective tertiary carbon nucleophilic
addition9 of β-keto amides10 to 2H-azirines by applying a chiral
N,N′-dioxide/CuII complex11 catalytic system (Scheme 1c),
and the chiral aziridines with vicinal tetrasubstituted stereo-
centers were obtained in high yields and enantioselectivities.
In our preliminary screening, the addition of β-keto amide
1a to 2,3-diphenyl-2H-azirine 2a was selected as the model
reaction to optimize the reaction conditions. The β-keto amide
1a could be completely converted to the corresponding
product in the presence of chiral N,N′-dioxide/CuII complexes
in CH2Cl2 at 0 °C for 2 days. The diastereomers 3aa and 3′aa
could be separated by column chromatography. Encouraged by
the results, the structure of chiral ligands was evaluated as
shown in Table 1. For the chiral backbone, L-proline-derived
L-PrPr2 and (s)-pipecolic acid derived L-PiPr2 delivered
poorer results than L-ramipril-derived L-RaPr2 did (entry 3 vs
entries 1 and 2). Ligand L-RaPr2, which has a three-carbonic
linkage, was superior to that of two-carbonic L2-RaPr2 or four-
carbonic L4-RaPr2 (entries 3−5). Meanwhile, after the
substituents of the amide group were changed from isopropyl
to ethyl or adamantyl, a negative effect was observed (entry 3
vs entries 6 and 7). Enhancing the steric hindrance on the 4-
positions of phenyl ring improved the enantio- and
diastereoselectivity (entry 3 vs entry 8). Finally, by adjusting
the ratio of metal to ligand to 1:1.5 and lowering the reaction
temperature to −40 °C, chiral aziridine 3aa could be isolated
in 87% yield, 92% ee, and >19:1 dr through column
chromatography (entry 9).
With the optimized reaction conditions established, the
substrate scope was then investigated. First, various β-keto
amides 1 were probed by reacting with 2H-azirine 2a (Table
2). The inden-1-one-derived β-keto amides (1a−k) with
a
Table 2. Substrate Scope for the β-Keto Amides
a
Table 1. Optimization of the Reaction Conditions
b
c
d
dr
yield (%)
ee (%)
entry
ligand
(3aa:3′aa)
(3aa/3′aa)
(3aa/3′aa)
1
2
3
4
5
6
7
8
L-PrPr2
L-PiPr2
L-RaPr2
L2-RaPr2
L4-RaPr2
L-RaEt2
L-RaAd
L-RaPr3
L-RaPr3
70:30
75:25
64:36
75:25
63:37
64:36
57:43
70:30
88:12
68/28
75/20
60/34
63/23
63/35
57/34
50/40
70/22
87/−
10/10
13/13
55/25
0/3
48/9
50/33
3/47
a
Unless otherwise noted, all reactions were performed with 1 (0.05
mmol), rac-2a (2.5 equiv), and Cu(OTf)2/L-RaPr3 (1:1.5, 10 mol %)
in CH2Cl2 (0.2 mL) at −40 °C. Determined by H NMR. Isolated
yields of 3 which were based on the β-keto amides 1. Determined by
b
c
1
d
e
HPLC on a chiral stationary phase. The reaction temperature was
f
−30 °C. The reaction was performed at −40 °C for 110 h, then −30
g
°C for 10 h. The reaction temperature was −10 °C. ND = not
66/11
92/−
detected.
e
9
different substituents (both electron-donating or electron-
withdrawing groups at C4, C5, C6, or C7 positions) all reacted
quite well with 2a to form the corresponding chiral aziridines
(3aa−ka) in 65−90% yields with moderate to excellent
enantioselectivities (60−94%) (entries 1−11). The β-keto
amide 1l incorporating a naphthyl group was also tolerable,
a
All reactions were performed with 1a (0.05 mmol), rac-2a (2.5
equiv), and Cu(OTf)2/ligand (1:1, 10 mol %) in CH2Cl2 (0.2 mL) at
0 °C for 48 h. Determined by H NMR. Isolated yields of 3aa and
b
c
1
d
3′aa which were based on the β-keto amides 1a. Determined by
e
HPLC on a chiral stationary phase. The reaction was performed with
Cu(OTf)2/L-RaPr3 (1:1.5, 10 mol %) at −40 °C for 48 h.
B
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Letter
giving chiral aziridine in 73% yield with 94% ee (entry 12).
Notably, β-keto ester 1m participated in the reaction to afford
the corresponding product 3ma in 80% yield with 75% ee
(entry 13). Additionally, β-keto amides 1n and 1o derived
from cyclopentanone and cyclohexanone were also applicable
(entries 14 and 15). The absolute configuration of the product
3ca was determined to be (1S,2S,3S) by X-ray crystallographic
analysis.
respectively, were also tolerated (entries 9 and 10). Then R2
was explored (entries 11−16). It was found that electronic
properties showed little effect on the reaction. Excellent
enantioselectivities and good yields were obtained for the
desired products 3ck−co (86−92% ee, 78−85% yield) (entries
11−15). Moreover, 2H-azirine 2p, possessing a benzyl group
on the 2-position, could also be converted to the
corresponding aziridine (entry 16). The poor results for 3cp
could be explained by the fact that the flexible skeleton led to
less steric hindrance and consequently reduced chiral
recognition. Similarly, the stereocontrol of 3-phenyl-2H-azirine
(2q) was poor, and the corresponding product 3cq was
assembled in 99% yield with 45:55 dr and 35% ee/5% ee
(entry 17).
Next, various 2H-azirines were investigated by reacting them
with 5-phenyl-substituted β-keto amide (1c) (Table 3).
a
Table 3. Substrate Scope for the 2H-Azirines
Subsequently, the synthetic value of the reaction was
investigated. A gram-scale synthesis of 3ca was carried out,
and the optically active aziridine 3ca was generated in 83%
yield (0.96 g), 90% ee (Scheme 2). Meanwhile, the product
3ca could be easily reduced to β-hydroxy-functionalized
aziridine derivative 4 (90% ee, 72% yield, > 19:1 dr) in the
presence of LiAlH4.
Scheme 2. Scaled-up Version of the Reaction and
Transformation of 3ca
a
1
Dr was determined by the H NMR of the crude product.
To explain the stereoselectivity of the catalytic reaction,
control experiments were carried out. First, racemic 2H-azirine
2a (2.0 equiv) was applied to react with β-keto amide 1a under
the standard reaction conditions (Scheme 3a). The 3aa and
3′aa were obtained in 45% and 4% yields with 86% and 15%
ee. Meanwhile, the recovered (R)-2a was obtained in 50%
yield with 68% ee. The results showed that (S)-2a reacted with
higher stereoselectivity than (R)-2a and at a faster rate, leading
to a kinetic resolution. Then, optically pure 2H-azirine (S)-2a
and (R)-2a were applied to react with 1a under the standard
a
Unless otherwise noted, all reactions were performed with 1 (0.05
mmol), rac-2 (2.5 equiv), and Cu(OTf)2/L-RaPr3 (1:1.5, 10 mol %)
b
in CH2Cl2 (0.2 mL) at 0 °C for the indicated time. Determined by
Scheme 3. Control Experiments
c
1H NMR. Isolated yields of 3 which were based on the β-keto amides
1. Determined by HPLC on a chiral stationary phase. 1a was used.
20 mol % catalyst loading. The diastereomers could not be separated
by column chromatography. The dr was determined by HPLC.
d
e
f
g
h
Delightfully, the electronic nature of the substituents on the
4-position of phenyl ring (R1) had little effect on both yields
and enantioselecitivities (83−86% yield, 89−92% ee; 3cb−ce
and 3af) (entries 2−6). Substrate 2g, having a methyl group
on the 3-position, could react smoothly to generate the
corresponding chiral aziridine 3cg in 81% yield with 92% ee by
increasing the catalyst loading to 20 mol % (entry 7). The
disubstituted 2H-azirine 2h was also a suitable substrate,
offering the chiral aziridine 3ch in 80% yield with 83% ee by
prolonging the reaction time (entry 8). Meanwhile, com-
pounds 2i/2j bearing fused ring and naphthyl substituents,
C
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Figure 1. Proposed transition state.
conditions (Scheme 3b,c). The substrate 1a could be
completely transformed to the corresponding product in
both cases. The enantioselectivities of 3aa, 3′aa, and the
recovered 2a were all maintained in Scheme 3b, indicating that
no racemization process existed. The high reactivity of the (R)-
2a under the standard reaction conditions derived from the
low selectivity of the kinetic resolution.
In combination with the X-ray structures of 3ca and 3′ca
(see the Supporting Information), we could draw a conclusion
that the diastereoselectivity derived from the C−C bond-
forming event. Moreover, the X-ray structure of the catalyst
was obtained in a THF/hexane/pyridine system, which
showed that the four oxygen atoms of the chiral ligand and
two nitrogen atoms of two pyridines coordinated to the metal,
forming a rigid octahedral complex.
Based on the above information, a possible catalytic
transition-state model was proposed in Figure 1. The enolate
of the β-keto amide 3c coordinated to the Cu(II) in a
bidentate fashion through the oxygens of the dicarbonyl
groups, forming a rigid octahedral complex. In all cases, the β-
keto amide 3c specifically attacked 2H-azirine 1a from the back
side relative to the substituent on the 2-positon of 2H-azirine
because of the reduced steric bulk. The Si-face of β-keto amide
chelated with CuII/L-RaPr3 was disfavored for the steric
repulsion between the aromatic ring of chiral ligand and the
adamantyl substituent of the substrate 3c (TS-2, TS-3). The
(S)-2a reacted at a faster rate than (R)-2a for the less steric
repulsion (TS-1 vs TS-2), thus delivering the corresponding
(1S, 2S, 3S)-configured product 3ca which was in accordance
with the observed experiment result.
In summary, the first asymmetric tertiary carbon nucleo-
philic addition of β-keto amides to 2H-azirines has been
realized by using a chiral N,N’-dioxide/CuII complex. This
strategy provides a novel and highly efficient method for the
synthesis of chiral aziridines in good yields and excellent ee
values under mild conditions. A possible transition state was
proposed to explain the origin of the stereoselectivity.
Meanwhile, the chemistry of 2H-azirine in organic synthesis
was enriched. Further studies of the 2H-azirines and aziridines
are underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02274.
Experimental procedures, full spectroscopic data for all
1
new compounds, and H and 13C NMR and HPLC
spectra (PDF)
Accession Codes
CCDC 1843563, 1843566, and 1843598 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
D
DOI: 10.1021/acs.orglett.8b02274
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2005. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (c) Wang, B.;
Tu, Y. Q. Acc. Chem. Res. 2011, 44, 1207. (d) Trost, B. M.; Osipov,
M. Angew. Chem., Int. Ed. 2013, 52, 9176.
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
́
(9) (a) Cordova, A. Acc. Chem. Res. 2004, 37, 102. (b) Shi, Y. B.;
Wang, Q. L.; Gao, Sh. H. Org. Chem. Front. 2018, 5, 1049.
̈
(c) Berkessel, A.; Groger, H. Nucleophilic Addition to C N Double
AUTHOR INFORMATION
Corresponding Authors
■
Bonds. Asymmetric Organocatalysis: From Biomimetic Concepts to
Applications in Asymmetric Synthesis; Wiley-VCH Verlag: Weinheim,
2005; Chapter 5, pp 130−244.
*E-mail: xmfeng@scu.edu.cn.
*E-mail: lililin@scu.edu.cn.
ORCID
(10) Selected recent examples for the enantioselective reaction of β-
keto amides and β-keto esters in our group: (a) Lian, X. J.; Lin, L. L.;
Fu, K.; Ma, B. W.; Liu, X. H.; Feng, X. M. Chem. Sci. 2017, 8, 1238.
(b) Guo, j.; Lin, L. L.; Liu, Y. B.; Li, X. Q.; Liu, X. H.; Feng, X. M.
Org. Lett. 2016, 18, 5540.
Xiaoming Feng: 0000-0003-4507-0478
Notes
(11) For selected examples using chiral N,N′-dioxide ligands, see:
(a) Liu, X. H.; Lin, L. L.; Feng, X. M. Acc. Chem. Res. 2011, 44, 574.
(b) Feng, X. M.; Liu, X. H. In Scandium: Compounds, Productions and
Applications; Greene, V. A., Ed.; Nova Science: New York, 2011; pp
1−48. (c) Zheng, K.; Lin, L. L.; Feng, X. M. Huaxue Xuebao 2012, 70,
1785. (d) Liu, X. H.; Lin, L. L.; Feng, X. M. Org. Chem. Front. 2014, 1,
298. (e) Liu, X. H.; Zheng, H. F.; Xia, Y.; Lin, L. L.; Feng, X. M. Acc.
Chem. Res. 2017, 50, 2621. (f) Liu, X. H.; Dong, S. X.; Lin, L. L.;
Feng, X. M. Chin. J. Chem. 2018, 36, 791.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the National Natural Science Foundation of
China (Nos. 21432006 and 21572136) for financial support.
■
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