The copper-catalyzed asymmetric construction of a dispiropyrrolidine skeleton via 1,3-dipolar cycloaddition of azomethine ylides to α-alkylidene succinimides

Article abstract of DOI:10.1039/c5cc02362a

A highly efficient asymmetric 1,3-dipolar cycloaddition of azomethine ylides to α-alkylidene succinimides catalyzed by a novel chiral N,O-ligand/Cu(OAc)₂ system is reported, affording dispiropyrrolidine derivatives with spiro quaternary stereog

Full text of DOI:10.1039/c5cc02362a

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DOI: 10.1039/C5CC02362A
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Copperꢀcatalyzed
dispiropyrrolidine
asymmetric
skeleton
construction
via 1,3ꢀdipolar
of
Cite this: DOI: 10.1039/x0xx00000x
cycloaddition of azomethine ylides with αꢀalkylidene
succinimides
Received 00th January 2012,
Accepted 00th January 2012
WuꢀLin Yang, a YangꢀZi Liu, a Shuai Luo, a Xingxin Yu,*a John S. Fosseyb and Weiꢀ
Ping Deng*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
mainly focused on intramolecular cyclization of aminoesters,6
A highly efficient asymmetric 1,3ꢀdipolar cycloaddition of
azomethine ylides to αꢀalkylidene succinimides catalyzed by a
intramolecular hydroamination of olefins7 and intermolecular
1,3ꢀdipolar cycloaddition.8 Among them, catalytic asymmetric
1,3ꢀdipolar cycloaddition9,10 of azomethine ylides to a variety
of electronꢀdeficient alkene dipolarophiles has arguably been
one of the most ideal synthetic strategies for the construction of
spirocyclic pyrrolidines with spiro quaternary stereogenic
centers.11,12 While dipolarophiles employed in these reactions
are mainly 2ꢀoxoindolinꢀ3ꢀylidenes,11aꢀe cyclopropylidene
acetates,12a 2ꢀalkylideneꢀcycloketones,12b,12c and αꢀmethyleneꢀγꢀ
butyrolactones,12d αꢀalkylidene succinimides that could be used
to directly construct dispiropyrrolidine skeletons have rarely
been explored (Scheme 1).8
novel chiral
N,
Oꢀligand/Cu(OAc)2 system is reported,
affording
dispiropyrrolidine derivatives with spiro
quaternary stereogenic centers in good to excellent yields (up
to 90%), excellent levels of diastereoselectivities (>20:1 dr)
and enantioselectivities (up to 97% ee).
As a privileged scaffold for pharmaceutical activity in drug
discovery, the pyrrolidinylꢀspirooxindole skeleton1 with
multiple contiguous stereogenic centers is the core structure of
numerous natural products and pharmaceuticals exhibiting a
broad spectrum of biological activities2 (Fig. 1). For instance,
Spirotryprostatin A,3 isolated from the fermentation broth of
Aspergillus fumigatus, arrests the cell cycle at the G2/M phase
and is an inhibitor of tubulin polymerization. In the past decade,
synthetic advances stemming from the vibrant field of natural
products chemistry and their corresponding analogues has
encouraged the development of more potent and selective
bioactive new molecular entities (NMEs).4 Notably, a synthetic
pyrrolidinylꢀspirooxindole, MIꢀ219,5 was found to inhibit the
cell cycle with excellent potency and represents a novel nonꢀ
peptidic, orally active, inhibitor of the p53ꢀMDM2 proteinꢀ
protein interaction.5b Nevertheless, it is noteworthy that the
dispiropyrrolidine skeleton, which is a structurally more
simpler motif, has the potential to deliver biological activities
and better drugꢀlike properties due to lower molecular weight
and offers more opportunities for structural diversity.
Scheme 1. Asymmetric construction of dispiropyrrolidines via 1,3ꢀdipolar
cycloaddition of azomethine ylides.
We have recently reported a series of newly designed 1,3ꢀ
dihydroimidazolpyridineꢀbased
N,Oꢀligands with applications
in catalytic asymmetric reactions.13 Among them, chiral N,O-
ligand/Cu(OAc)2 systems displayed excellent catalytic activity
and stereoselectivity in asymmetric 1,3ꢀdipolar cycloaddition of
azomethine ylides with alkylidene malonates.13b Given the fact
that 1,3ꢀdipolar cycloaddition of azomethine ylides to αꢀ
alkylidene succinimides would provide a straightforward
method to construct structurally novel and potentially
biologically important dispiropyrrolidines, we were eager to
Fig. 1. A selection of natural products and biologically active molecules with
dispiropyrrolidine skeletons.
Many efforts have been made developing synthetic methods
for the construction of dispiropyrrolidine scaffolds, which have
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DOI: 10.1039/C5CC02362A
determine if our newly developed
N,Oꢀligand/Cu(OAc)2 chiral N,Oꢀligands 4, 5 in this reaction. To compare the effect of
systems could be applied to this new reaction. Herein, we substitution on the imidazole ring, ligands 4a and 4b (with and
demonstrate the first catalytic asymmetric 1,3ꢀdipolar without a methyl group adjacently cis to the tertiary alcohol
cycloaddition of azomethine ylides to αꢀalkylidene respectively) were contrasted. The yield and enantioselectivity were
succinimides catalysed by chiral
N,Oꢀligand/Cu(OAc)2 sharply decreased when N,Oꢀligand 4b, which lacks the steric
systems, affording dispiropyrrolidine derivatives in good to pressure of the methyl group of 4a, was used (Table 1, entry 4). A
excellent yields, and excellent levels of diastereoselectivity (> buttressing effect of substitution adjacent to the alcohol had been
20:1) and enantioselectivities (up to 97% ee). This catalytic demonstrated in other copper catalyzed reactions reported by us, the
system was further successfully extended to a 1,3ꢀdipolar present observation is consistent with those previous finding
cycloaddition of azomethine ylides to 2ꢀoxoindolinꢀ3ꢀylidenes, suggesting mechanistic overlap between our previous reports and
providing
a
series of MIꢀ219 analogues in excellent this work. This “buttressing effect” was also found in other chiral
diastereoselectivities (> 99:1) and enantioselectivities (up to N,Oꢀligands 4cꢀf and 5 (Table 1, entries 5ꢀ10). Electronic effects of
95% ee).
substituents on ligand backꢀbone for methyl appended N,Oꢀligands
(4a, 4c, 4e, 5a) was studied. It transpired that ligands with either
electronꢀwithdrawing or ꢀdonating groups gave comparable
enantioselectivities, and the originally tested ligand 4a was optimal
in terms of achievable yield. Screening of other copper salts as metal
sources showed that both Cu(CH3CN)4BF4 and Cu(CH3CN)4ClO4
gave excellent enantioselectivities, however with a slightly lower
yield than for the latter (Table 1, entries 11ꢀ12).
Table 1. Catalyst screening for the asymmetric 1,3ꢀdipolar cycloaddition of
azomethine ylide 1a to αꢀalkylidene succinimides 2
Table 2. Substrate scope in the 1,3ꢀdipolar cycloaddition of azomethine
ylides 1 to αꢀalkylidene succinimides 2
Entry a Metal
Ligand R4
Yield (%)b
N.R.
ee (%)c
ꢀ
Entrya
1
R1/R2
R3
Yield (%)b
85 (3ab)
72 (3bb)
83 (3cb)
81 (3db)
80 (3eb)
77 (3fb)
72 (3gb)
82 (3hb)
71 (3ib)
77 (3jb)
74 (3kb)
74 (3lb)
90 (3mb)
40 (3nb)
77 (3ad)
68 (3ae)
88 (3af)
85 (3ag)
60 (3ah)
50 (3ai)
30 (3aj)
ee (%)c
95
92
96
94
97
95
95
95
93
95
95
95
91
88
95
91
96
95
90
94
87
1
Cu(OAc)2⋅H2O
4a
4a
4a
4b
4c
4d
4e
4f
H (2a)
pꢀClC6H4/Me (1a)
pꢀClC6H4/Et (1b)
Ph/Me (1c)
Ph (2b)
2
CO2Me (2b)
Cbz (2c)
85 (3ab)
80 (3ac)
40 (3ab)
64 (3ab)
trace
93
93
31
93
ꢀ
Cu(OAc)2⋅H2O
Cu(OAc)2⋅H2O
Cu(OAc)2⋅H2O
Cu(OAc)2⋅H2O
Cu(OAc)2⋅H2O
Cu(OAc)2⋅H2O
Cu(OAc)2⋅H2O
Cu(OAc)2⋅H2O
Cu(OAc)2⋅H2O
Cu(CH3CN)4BF4
2
Ph (2b)
3
3
Ph (2b)
4
CO2Me (2b)
CO2Me (2b)
CO2Me (2b)
CO2Me (2b)
CO2Me (2b)
CO2Me (2b)
CO2Me (2b)
CO2Me (2b)
CO2Me (2b)
4
oꢀClC6H4/Me (1d)
mꢀClC6H4/Me (1e)
pꢀBrC6H4/Me (1f)
pꢀFC6H4/Me (1g)
pꢀCF3C6H4/Me (1h)
oꢀMeC6H4/Me (1i)
pꢀMeC6H4/Me (1j)
pꢀMeOC6H4/Me (1k)
2ꢀnaphthyl/Me (1l)
2ꢀfuryl/Me (1m)
Cy/Me (1n)
Ph (2b)
5
5
Ph (2b)
6
6
Ph (2b)
7
68 (3ab)
59 (3ab)
72 (3ab)
50 (3ab)
85 (3ab)
70 (3ab)
93
38
92
35
93
93
7
Ph (2b)
8
8
Ph (2b)
9
5a
5b
4a
9
Ph (2b)
10
11
12
10
11
12
13
14
15
16
17
18
19
20
21
Ph (2b)
Ph (2b)
Cu(CH3CN)4ClO4 4a
Ph (2b)
a All reactions were carried out with 0.2 mmol of 1a and 0.1 mmol of 2 in 1 mL of
THF at room temperature. b Isolated yield. N.R. = no reaction. c Determined by chiral
HPLC analysis, and >20:1 dr was determined by 1H NMR of crude product.
Ph (2b)
Ph (2b)
pꢀClC6H4/Me (1a)
pꢀClC6H4/Me (1a)
pꢀClC6H4/Me (1a)
pꢀClC6H4/Me (1a)
pꢀClC6H4/Me (1a)
pꢀClC6H4/Me (1a)
pꢀClC6H4/Me (1a)
pꢀMeOC6H4 (2d)
pꢀCF3C6H4 (2e)
pꢀBrC6H4 (2f)
mꢀBrC6H4 (2g)
2ꢀfuryl (2h)
nꢀPr (2i)
We initially chose unprotected αꢀalkylidene succinimide 2a as
dipolarophile to test the feasibility of 1,3ꢀdipolar cycloaddition with
glycine methyl ester 1a in the presence of chiral N,Oꢀligand
4a/Cu(OAc)2·H2O as the catalyst and K2CO3 as base in THF at room
temperature (Table 1, entry1). Unfortunately, no reaction was
observed, perhaps due to the relatively low reactivity of αꢀalkylidene
succinimide. On the other hand, changing the R4 substituent on the
nitrogen of the αꢀalkylidene succinimide 2 such that it becomes a
methyl carbamate, 2b, gave a substrate that reacted smoothly with
glycine methyl ester 1a under the same conditions to afford endoꢀ
dispiropyrrolidines 3ab as the major diastereomer (dr > 20:1) in
good yield with excellent level of enantioselectivity, the carbamate
group may enhance the polarisability of the dipolarophiles and
contributes to the high reactivity. Changing the nitrogen substituent
to a Cbzꢀprotecting group, 2c, gave a similar result in terms of both
yield and stereoselectivity. Compound 2b (the CO2Meꢀappended αꢀ
alkylidene succinimide) was selected as the dipolarophile and
glycine methyl ester 1a as the dipolar to screen a number of our
CH=CHPh (2j)
a All reactions were carried out with 0.4 mmol of 1 and 0.2 mmol of 2 in 2 mL of
MeTHF at room temperature. b Isolated yield. c Determined by chiral HPLC analysis,
and >20:1 dr was determined by 1H NMR of crude product.
The choice of base and solvent was optimized in the presence
of 10 mol% of Cu(OAc)2·H2O and 11 mol% of chiral
N,Oꢀ
ligand 4a (see the Supporting Information, Table S1), K2CO3 as
base and MeTHF14 as solvent were found to be optimal in terms
of both yield and enantioselectivity (85% yield, 95% ee).
Additionally, the higher reactivity in MeTHF permitted lower
catalyst loading (5 mol%) in the presence of two equivalents of
2 | J. Name., 2012, 00, 1-3
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DOI: 1C0.O10M39M/CU5CNCI0C2A36T2IOA N
K2CO3,
dispiropyrrolidine 3ab in comparable results (85% yield, 95% cycloaddition of azomethine ylide 1f to αꢀalkylidene
ee). succinimide 2b demonstrated that chiral ꢀligand
The above optimization identified optimal conditions as: 5 4a/Cu(OAc)2 system was suitable for generating 2.0 g of endo
mol% of Cu(OAc)2·H2O, 5.5 mol% of chiral ꢀligand 4a 3fb in 81% yield, 95% ee, and >20:1 dr (see the Supporting
two equivalents of K2CO3, and addition of 4 Å MS (50 Information, Scheme S1) in one batch. The product endo 3fb
mg/mL), MeTHF as solvent and room temperature. The can be easily transformed into ꢀmethyl endo
generality and substrate scope were then probed using a series dispiropyrrolidine in excellent yield, a subsequent LiAlH4
of azomethine ylides and αꢀalkylidene succinimides , as reduction afforded endo in 65% yield, without loss of
shown in Table 2. Similar diastereoꢀ and enantioselectivities stereochemical integrity (Scheme 3, 95% ee). The relative and
were observed when the methyl ester of azomethine ylide 1a absolute configuration of the major diastereoisomer of was
was replaced by an ethyl ester (Table 2, entries 1ꢀ2). assigned as endoꢀ(1 ,3 ,4 ,5 ) according to single crystal Xꢀ
Azomethine ylides bearing electronꢀrich (Table 2, entries 9ꢀ ray diffraction analysis of endo (see the Supporting
11), electronicallyꢀneutral (Table 2, entries 3 and 12), and Information for details).
which
provide
the
corresponding
endo
ꢀ
base, in DCM at ꢀ20 °C. A scaled up asymmetric 1,3ꢀdipolar
N,O
ꢀ
N,
O
,
ꢀ
N
ꢀ
7
1
2
ꢀ8
6
R
R R R
1
ꢀ6
electronꢀdeficient groups (Table 2, entries 1, 2, 4ꢀ8) on the aryl
ring all reacted with αꢀalkylidene succinimide 2b smoothly
affording the corresponding products exclusively in good yields
(71ꢀ85%), excellent diastereoselectivities (>20:1 dr), and
excellent enantioselectivities (92ꢀ97% ee). It is noteworthy that
comparable results were achieved for the sterically hindered
orthoꢀchloro and orthoꢀmethylꢀsubstituted azomethine ylides
1d and 1i (Table 2, entries 4 and 9 respectively). The heteroaryl
substituted azomethine ylide 1m derived from 2ꢀfurylaldehyde
worked well in this transformation leading to desired product
formation in 90% yield and 91% ee (Table 2, entry 13).
Additionally, less reactive alkyl substituted azomethine ylide
Furthermore, the chiral N,Oꢀligand 4a/Cu(OAc)2 system was
also applicable to the asymmetric 1,3ꢀdipolar cycloaddition of
azomethine ylides 1 to 2ꢀoxoindolinꢀ3ꢀylidenes 9. After optimization
of the reaction conditions, it was found that the reaction proceeded
efficiently in the presence of Cu(OAc)2·H2O (10 mol%), chiral N,Oꢀ
ligand 4a (11 mol%), DIPEA (20 mol%), and 4 Å MS (50 mg/mL)
in CPME as solvent at room temperature (Table 3). As expected, all
reactions proceeded smoothly to afford the desired product exoꢀ10 in
good to excellent yields (88ꢀ99%), excellent diastereoselectivities
(99:1 dr) and high enantioselectivities (92ꢀ95% ee), comparable to
those obtained in previous reports.11
1n is also tolerated in this transformation affording endoꢀ3na,
albeit in a slightly lower yield and enantioselectivity (entry 14,
40% yield and 88% ee). We next turned our attention to various
Table 3. Asymmetric 1,3ꢀdipolar cycloaddition of azomethine ylides 1 to 2ꢀ
oxoindolinꢀ3ꢀylidenes 9
substituted
αꢀalkylidene
succinimides.
αꢀAlkylidene
succinimides
2 with both electronꢀdonating (Table 2, entry 15)
and electronꢀwithdrawing substituents (Table 2, entries 16ꢀ18)
at different positions on the aromatic ring were tolerated,
resulting in formation of the corresponding endoꢀ3 products in
excellent diastereoselectivities (>20:1 dr) and high
enantioselectivities (91ꢀ96% ee) (Table 2, entries 15ꢀ18).
Entrya
R1
R5
Yield (%)b
95 (10aa)
95 (10ca)
93 (10fa)
99 (10ga)
95 (10ab)
88 (10ac)
ee (%)c
95
1
2
3
4
5
6
pꢀClC6H4 (1a)
Ph (1c)
Ph (9a)
Ph (9a)
94
Remarkably, αꢀalkylidene succinimides
2 with a 2ꢀfuryl
substituent (Table 2, entry 19) and alkyl substituents (Table 2,
entries 20 and 21) were also able to undergo the asymmetric
1,3ꢀdipolar cycloadditions providing the desired endoꢀ3ahꢀ3aj
in excellent enantiomeric excesses (up to 94% ee), however
only moderate yields were attained.
pꢀBrC6H4 (1f)
pꢀFC6H4 (1g)
pꢀClC6H4 (1a)
pꢀClC6H4 (1a)
Ph (9a)
93
Ph (9a)
94
pꢀClC6H4 (9b)
94
pꢀMeC6H4 (9c)
92
a All reactions were carried out with 0.2 mmol of 1 and 0.1 mmol of 9 in 1 mL of
CPME at room temperature. b Isolated yield. c Determined by chiral HPLC analysis,
and 99:1 dr was determined by 1H NMR of crude product.
In conclusion, a highly efficient asymmetric 1,3ꢀdipolar
cycloaddition of azomethine ylides
succinimides catalyzed by
ligand/Cu(OAc)2·H2O system was developed, affording endo
dispiropyrrolidine derivatives
1
to αꢀalkylidene
2
a
novel chiral
N
,
O
ꢀ
ꢀ
Scheme 2. Asymmetric 1,3ꢀdipolar cycloaddition of azomethine ylide 1a to
αꢀalkylidene succinimide 2k.
3
in good to excellent yields (up
to 90%), excellent level of diastereoselectivities (>20:1 dr) and
enantioselectivities (up to 97% ee). This highly efficient chiral
N,
O
ꢀligand/Cu(OAc)2 catalytic system was also applicable to
the asymmetric 1,3ꢀdipolar cycloaddition of azomethine ylides
to 2ꢀoxoindolinꢀ3ꢀylidenes , affording the corresponding
1
9
exoꢀdispiropyrrolidines 10 in good to excellent yields (up to
99%), excellent diastereoselectivities (99:1 dr), and high
enantioselectivities (up to 95% ee). The highly stereoselective
Scheme 3. Transformation of cycloadduct 3fb into spirocyclic bispyrrolidine
endoꢀ8.
construction
of
dispiropyrrolidine
and
pyrrolidinylꢀ
The asymmetric 1,3ꢀdipolar cycloaddition of azomethine
ylide 1a to more reactive terminal alkene substrate 2k was also
spirooxindole skeletons with excellent diastereoꢀ and
enantioselectivities suggests a highly efficient protocol of
potential importance tomedicinal chemistry, agrochemicals and
diversityꢀorientedsynthesis. Further investigations in the area of
investigated (Scheme 2). Thus, endo
yield, 94% ee, and >20:1 dr when chiral
ꢀ
3ak was generated in 90%
ꢀligand
N,O
4a/Cu(CH3CN)4BF4 complex was used as catalyst with Et3N as
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5CC02362A
spirocyclic pyrrolidine synthesis and applications are ongoing
in our laboratories.
Chem., 2014, 771, 78; (c) R. Narayan, M. Potowski, Z.ꢀJ. Jia, A. P.
Antonchick and H. Waldmann, Acc. Chem. Res. 2014, 47, 1296; (d)
This work is supported by The Fundamental Research Funds
for the Central Universities, the National Natural Science
Foundation of China (No. 21172068 and No. 21402049),
Shanghai Pujiang Program (No. 14PJD013), and Shanghai
Yangfan Program (No. 14YF1404600). JSF thanks ECUST for
a guest professorship. The Catalysis and Sensing for our
Environment (CASE) consortium are thanked for networking
opportunities.
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a
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Eꢀmail: xxyu@ecust.edu.cn; weiping_deng@ecust.edu.cn
b
School of Chemistry, University of Birmingham, Edgbaston,
Birmingham, West Midlands, B15 2TT, UK.
† Electronic Supplementary Information (ESI) available: experimental
procedures, spectral data, and crystallographic data. See
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