Divergent Synthesis of Enantioenriched β-Functional Amines via Desymmetrization of meso-Aziridines with Isocyanides

Article abstract of DOI:10.1021/acs.orglett.9b02242

A highly enantioselective ring-opening desymmetrization of meso-aziridines with isocyanides was achieved in the presence of a chiral N,N′-dioxide/Mg(OTf)₂ complex. The in situ generated chiral 1,4-zwitterionic intermediates were successfully trapped by intramolecular oxygen- and carbon-based nucleophiles or exogenous H₂O and TMSN₃, enabling a collective synthesis of various chiral vicinal amino-oxazoles, spiroindolines, β-amino amides, and tetrazole derivative in moderate to high yields with excellent enantioselectivities.

Full text of DOI:10.1021/acs.orglett.9b02242

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Divergent Synthesis of Enantioenriched β‑Functional Amines via
Desymmetrization of meso-Aziridines with Isocyanides
Xiangqiang Li, Qian Xiong, Mingming Guan, Shunxi Dong,* Xiaohua Liu, 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 highly enantioselective ring-opening desymmetrization of
meso-aziridines with isocyanides was achieved in the presence of a chiral
N,N′-dioxide/Mg(OTf)2 complex. The in situ generated chiral 1,4-
zwitterionic intermediates were successfully trapped by intramolecular
oxygen- and carbon-based nucleophiles or exogenous H2O and TMSN3,
enabling a collective synthesis of various chiral vicinal amino-oxazoles,
spiroindolines, β-amino amides, and tetrazole derivative in moderate to
high yields with excellent enantioselectivities.
Scheme 1. Isocyanide-Based Multicomponent Reactions
enefitting from the unique reactivity profile of the
isocyanide functional group, isocyanides have attracted
B
considerable interest in the past several decades.1,2 In
particular, isocyanide-based multicomponent reactions
(IMCRs)2 represent one of the most facile and efficient
methods for diversity-oriented synthesis of highly valuable
molecules. Comparably, the development of asymmetric
versions of such IMCRs was lagging. In the past decades,
many research groups studied this area, and an array of
enantioselective reactions including the Passerini reaction,3
Ugi reaction,4 and their variants5−7 (Scheme 1a) have been
achieved in the presence of organocatalysts or chiral Lewis acid
catalysts. In this process, both simple isocyanides and
functionalized isocyanides were involved, affording diverse
products with high enantioselectivity. Despite such impressive
achievements, the electrophiles involved in the initial addition
of isocyanides are mainly limited to polar CX bonds3−6
along with several sporadic examples of polar CC or CC
bonds.4e,7
Asymmetric desymmetrization8−14 of meso-aziridines with
many nucleophiles including nitrogen,9 halogen,10 sulfur,11
phosphorus,12 carbon,13 and others14 has been extensively
studied because it furnishes useful chiral β-functional amine
derivatives with vicinal stereocenters in a single step. Recently,
the ring-opening reaction of aziridines with α-acidic
isocyanides has also been developed.15 As shown in Scheme
1b, the reaction usually proceeded via Lewis acid promoted
SN2-type ring opening of aziridines with an α-carbanion of the
isocyanides under basic conditions. These elegant works in
conjunction with our previous works on isocyanides4e,7a,b led
us to assume that ring opening of meso-aziridines with an
isocyanide functional group would be possible as well. As
depicted in Scheme 1c, in the presence of a proper chiral
catalyst, the nucleophilic ring-opening reaction of meso-
aziridines with isocyanides could provide a new type of chiral
1,4-zwitterionic intermediate, which may be trapped by a
second nucleophile. If this hypothesis works well, it will
dramatically extend the application scope of IMCRs. However,
Received: June 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02242
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to the best of our knowledge, only a single example of this type
of reaction was established, furnishing the racemic β-amino
amide compound via SN1-type ring opening.16 Herein, we
accomplished a direct asymmetric nucleophilic ring opening of
meso-aziridines with α-isocyanoacetamides or 2-isocyanoethy-
lindoles catalyzed by a chiral N,N′-dioxide/Mg(OTf)2
complex.17 The in situ generated zwitterionic intermediates
were subsequently captured by the oxygen of amide or C3
position of indole in isocyanides, affording various vicinal
amino-oxazoles and spiroindolines in moderate to good yields
and high enantioselectivities. Moreover, exogenous H2O and
TMSN3 were found to be suitable as intermolecular
nucleophilic components when simple isocyanides were
employed, and the corresponding chiral β-amino amides and
tetrazole were obtained with good results.
to 95% with a slightly decreased ee value (90% ee) by utilizing
Na2CO3 as an additive (other bases were also examined; for
details, see the SI) and fixing the ratio of meso-aziridine 1a and
isocyanide 2a to 1:1.5 (entry 7).
With the optimized reaction conditions in hand, the
substrate scope was examined. As shown in Table 2, a series
Table 2. Substrates Scope of meso-Aziridines and α-
a
Isocyanoacetamides
To assess our hypothesis, the desymmetrization of meso-
aziridine 1a with α-isocyanoacetamide 2a were selected as the
model reaction to optimize the reaction conditions (Table
19
1).18 We were pleased to find that the complex of Mg(OTf)2
a
Table 1. Optimization of the Reaction Conditions.
b
c
entry
metal salt
ligand
solvent
yield (%)
ee (%)
1
2
3
4
5
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
L-PiMe2
L-PiPr2
L-PrPr2
L-RaPr2
L-PrPr2
L-PrPr2
L-PrPr2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
23
15
40
19
59
61
95
11
38
78
67
87
92
90
d
a
6
7
Et2O
Et2O
Performed with L-PrPr2/Mg(OTf)2 (1:1, 10 mol %), 1 (0.10
de
,
mmol), 2 (0.15 mmol), and Na2CO3 (0.10 mmol) in Et2O (1.0 mL)
under N2 at 20 °C for 48 h.
a
The reactions were performed with ligand/metal salt (1:1, 10 mol
%), 1a (0.10 mmol), and 2a (0.10 mmol) in the solvent (1.0 mL)
b
c
under N2 at 35 °C for 24 h. Isolated yield. Determined by chiral
HPLC analysis on a chiral stationary phase. At 20 °C for 48 h. With
2a (0.15 mmol), Na2CO3 (0.10 mmol).
d
e
of aziridines and α-isocyanoacetamides were investigated. The
aziridine 1b bearing an unsaturated six-membered ring
afforded the corresponding product 3ba in 80% yield with
95% ee. A screening of the protecting group of aziridine
showed that both the position and electronic property of the
substituents on the N-2-picolinoyl group of aziridines only
affected the yields (3ca−3fa, 73−99% yield, 90% ee). With the
chloro group closing to the N-atom on the pyridine ring, the
yields of the corresponding products were diminished
significantly but the enantioselectivity was maintained (3fa−
3ha). Then various α-substituted isocyanides were examined.
To our delight, isocyanides 2b−2e with different alkyl or
phenyl substituents on the α-position of isocyanoacetamides
were applicable as well, giving the corresponding products
3ab−3ae in 61−81% yield and 88−90% ee. Changing the
morpholine unit of isocyanide 2a to piperidine or pyrrolidine
moiety led to decreased yield and enantiomeric excess (82%
yield and 87% ee for 3af; 49% yield and 50% ee for 3ag). The
with L-PiMe2 promoted the reaction smoothly in slightly
higher reactivity (Table 1, 23% yield, 11% ee, entry 1). The
following survey of ligands coordinating with Mg(OTf)2
showed that the backbone of ligands had a significant influence
on the enantioselectivity.20 L-Proline-derived L-PrPr2 was
superior to L-PiPr2 and L-ramipril-derived L-RaPr2 in terms of
efficiency, delivering the desired product in 40% yield and 78%
ee (Table 1, entry 3 vs entries 2 and 4). In addition, it was
found that the solvent had a considerable effect on both the
reactivity and enantioselectivity. Better results (59% yield and
87% ee) were obtained when the reaction was carried out Et2O
as the solvent (entry 5). Performing the reaction at 20 °C
resulted in a yield of 61% with higher enantioselectivity (entry
6, 92% ee vs 87% ee). Finally, the yield was further improved
B
DOI: 10.1021/acs.orglett.9b02242
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Letter
structure of adduct ( )-3aa was confirmed by X-ray single-
crystal analysis.
Interestingly, when N-Boc-protected 2-isocyanoethylindole
6a was employed as the substrate, the vicinal amino amide was
afforded instead of spiroindolines products. In this case,21
ubiquitous H2O captured the chiral 1,4-zwitterionic inter-
mediate to deliver the amino amide product 7aa, and further
optimization suggested that good results (70% yield and 92%
ee) were obtained with addition of H2O (2 μL) under slightly
modified conditions (Table 4, footnote a).22 By changing the
Encouraged by these results, we tried to apply the
desymmetrization of meso-aziridine to the synthesis of the
enantiomerically enriched polycyclic spiroindolines by using
C2-methyl-substituted 2-isocyanoethylindoles as nucleophiles.
As expected, the vicinal amino spiroindoline product could be
obtained successfully under the investigated conditions with
Mg(OTf)2/L-PrPr2 complex (Table 3, 5aa, 80% yield, 4:1 dr
Table 4. Substrates Scope of meso-Aziridines and
Isocyanides
a
Table 3. Substrates Scope of meso-Aziridines and 2-
Isocyanoethylindoles
a
a
Performed with L-PrPr2/Mg(OTf)2 (1:1, 10 mol %), 1 (0.10
mmol), 4 (0.15 mmol), and LiNTf2 (0.03 mmol) in Et2O (1.0 mL)
under N2 at 20 °C for 48 h.
a
Performed with L-RaPr2/Mg(OTf)2 (1:1, 10 mol %), 1 (0.10
and 90% ee). Along with the exploration for the protecting
group of aziridines, a range of vicinal amino spiroindolines
were obtained (5ca−5fa). The position of the chloro group on
the pyridine ring also affected the reactivities and enantiose-
lectivities (50−68% yield, 70−94% ee, 5fa−5ha). Then the
substrates with different substitutions on the indole unit were
inspected. The phenyl group at the C2 position of the indole
supplied the desired polycyclic spiroindole 5ab in high yield
and enantioselectivity (99% yield, 6:1 dr, 90% ee). Isocyanides
with electron-donating and electron-withdrawing substituents
at the C5 position of indole were suitable in the current
system, yielding the expected products with a slightly lower
yield with high ee (5ac−5ae, 59−81% yield, 90−94% ee). The
absolute configuration of the major isomer of product 5aa was
determined to be (1R,3R,4R) by X-ray single-crystal analysis.
mmol), 6 (0.15 mmol), H2O (2 μL, 0.11 mmol), and LiNTf2 (0.03
mmol) in Et2O (1.0 mL) under N2 at 20 °C for 48 h. With 1a (0.10
mmol), tert-butyl isocyanide (0.30 mmol), and TMSN3 (0.10 mmol)
in CH2Cl2 (1.0 mL) under N2 at 30 °C for 48 h.
b
N-protected group from a Boc to a tosyl group, both the yield
and ee value were increased (7ab vs 7aa). Examination of
substitutions on the indole ring with Mg(OTf)2/L-RaPr2
complex as the catalyst suggested that both electron-donating
and electron-withdrawing groups at the C5 position could be
compatible in the current system, producing the corresponding
vicinal amino amides 7ac−7af in good yields with excellent
enantioselectivities (59−71% yield, 90−92% ee, Table 4).
Substrates with a halogen atom at the C6 position also afforded
C
DOI: 10.1021/acs.orglett.9b02242
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Letter
the desired products 7ag and 7ah in good yields with slightly
decreased enantioselectivities (90% ee). To further extend the
substrates, simple isocyanides 6i−6l were applied to obtain
prospective β-amino amides. As shown in Table 4, with
diminishing steric hindrance of isocyanides, the yields and
enantioselectivities declined significantly (7ai−7al, 49−80%
yield, 80−90% ee). Lastly, aziridines with different protecting
groups were examined to provide the desired products 7cj−7fj
(32−68% yield, 80−90% ee). Except for water, it was found
that TMSN3 could serve as the second nucleophile as well.23
However, the direct ring-opening product 8 with TMSN3 was
afforded as the major product. Further optimization indicated
that increasing the amount of isocyanide (3 equiv) was
beneficial to the ring-opening pathway with isocyanide, and the
corresponding product 9 could be obtained in 50% yield and
90% ee along with 45% yield of compound 8 in 74% ee.
To show the synthetic utility of the methodology, a gram-
scale synthesis of 3aa was performed. As shown in Scheme 2a,
Scheme 3. Proposed Catalytic Cycle
Scheme 2. (a) Gram-Scale Experiment of 3aa; (b)
Transformations of Products 3aa and 5ca
In conclusion, we developed a highly efficient desymmetri-
zation of meso-aziridines by means of ring-opening with
isocyanides by using a chiral N,N′-dioxide/Mg(OTf)2 complex
catalytic system. Isocyanoacetamides, 2-isocyanoethylindoles,
and simple isocyanides were all well tolerated, enabling the
collective synthesis of the corresponding vicinal amino-
oxazoles, spiroindolines, β-amino amides, and tetrazole in
moderate to good yields and high enantioselectivities. A
plausible catalytic cycle and working mode were proposed to
elucidate the process of the reaction and the origin of chiral
control. Further development of asymmetric isocyanide-based
multicomponent reaction is ongoing in our group.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02242.
■
2.50 mmol of 1a reacted smoothly with 3.75 mmol of 2a under
the optimized reaction conditions, and the desired product 3aa
was delivered in 83% yield (1.05 g) with 90% ee value. Next,
simple derivatizations of the products were conducted. The
vicinal amino-oxazoles 3aa could be easily hydrolyzed to form
10 in 73% yield without loss of enantioselectivity. Reduction of
5ca in the presence of NaBH4 afforded the spirocyclic indoline
11 in moderate yield and enantioselectivity.
S
Experimental procedures, full spectroscopic data for all
new compounds, and copies of 1H, 13C{1H}, and
19F{1H} NMR and HPLC spectra (PDF)
Based on the structures of Mg(OTf)2/L-RaPr2 and
Mg(OTf)2/L-PrEt2,24 a possible catalytic cycle along with a
proposed working mode are provided in Scheme 3. At first,
coordination of Mg(OTf)2/L-PrPr2 complex A to meso-
aziridine 1a leads to intermediate B, in which aziridine 1a
binds to the metal center with the aromatic nitrogen and
oxygen of the carbonyl group in a bidentate manner. The
cyclohexyl ring of aziridine prefers to locate downward to
prevent the steric hindrance with the top-right amide of the
ligand, and nucleophilic attack of the isocyanide from the back
side of the aziridine ring is favored,9c,24b furnishing the
nitrilium intermediate anti-C, which the nitrilium group and
amide anion are on the opposite side of the ring. Then, anti-C
undergoes intramolecular proton transfer and is captured by
the C3 position on the indole ring from the Re face,
establishing a new stereogenic center and affording the desired
product 5aa with (1R,3R,4R) configuration as the major
isomer.
Accession Codes
CCDC 1909099, 1909103, 1921288, and 1921801 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, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dongs@scu.edu.cn.
*E-mail: xmfeng@scu.edu.cn.
ORCID
Shunxi Dong: 0000-0002-3018-3085
Xiaohua Liu: 0000-0001-9555-0555
D
DOI: 10.1021/acs.orglett.9b02242
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Xiaoming Feng: 0000-0003-4507-0478
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate financial support from the National Natural
Science Foundation of China (No. 21801175).
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E
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(18) When the corresponding ester or benzyl 2-isocyanophenylace-
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̈
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