α,β-Unsaturated Amides as Dipolarophiles: Catalytic Asymmetric exo-Selective 1,3-Dipolar Cycloaddition with Nitrones

Article abstract of DOI:10.1002/chem.201702330

1,3-Dipolar cycloaddition is a commonly exploited method to access 5-membered chemical entities with a variety of peripheral functionalities and their stereochemical arrangements. Nitrones are isolable 1,3-dipoles that exhibit sufficient reactivity toward electron-deficient olefins in the presence of Lewis acids to deliver highly substituted isoxazolidines. Herein we document that α,β-unsaturated amides, generally regarded as barely reactive in a 1,3-dipolar reaction manifold, were effectively activated using the designed 7-azaindoline auxiliary in an In(OTf)₃/bishydroxamic acid catalytic system. The broad substrate scope and clean removal of the 7-azaindoline auxiliary from the product highlight the synthetic utility of the present catalysis.

Full text of DOI:10.1002/chem.201702330

A Journal of
Accepted Article
Title: α,βꢀ-Unsaturated Amides as Dipolarophiles: Catalytic
Asymmetric Exo-selective 1,3-Dipolar Cycloaddition with Nitrones
Authors: Ming Zhang, Naoya Kumagai, and Masakatsu Shibasaki
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To be cited as: Chem. Eur. J. 10.1002/chem.201702330
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α,β-Unsaturated Amides as Dipolarophiles: Catalytic Asymmetric
Exo-selective 1,3-Dipolar Cycloaddition with Nitrones
Ming Zhang,[a] Naoya Kumagai,*[a] and Masakatsu Shibasaki*[a]
Dedication ((optional))
Abstract: 1,3-Dipolar cycloaddition is a commonly exploited method
to access 5-membered chemical entities with a variety of peripheral
functionalities and their stereochemical arrangements. Nitrones are
isolable 1,3-dipoles that exhibit sufficient reactivity toward electron-
deficient olefins in the presence of Lewis acids to deliver highly
substituted isoxazolidines. Herein we document that α,β-unsaturated
amides, generally regarded as barely reactive in a 1,3-dipolar
reaction manifold, were effectively activated using the designed 7-
azaindoline auxiliary in an In(OTf)3/bishydroxamic acid catalytic
system. The broad substrate scope and clean removal of the 7-
azaindoline auxiliary from the product highlight the synthetic utility of
the present catalysis.
imides[13] preferentially produce exo-cycloadducts with high
enantioselectivity under Cu(II)/bisoxazoline catalysis. Alkylidene
malonates[14] and 1,3-thiazolidine-2-thiones[15] were later
revealed to exhibit exo-selectivity. Although more reactive
monodentate enals are also incorporated in the catalytic
asymmetric 1,3-DC reaction manifold with
a
variety of
organocatalytic and metal-based catalytic systems, the majority
of them are endo-selective reactions,[16] with some exceptions in
which ketonitrones are employed.[16p,16s] While organocatalytic
1,3-DC of nitroalkenes provide exo-cycloadducts,[17] the number
of examples of exo-selective 1,3-DC reactions remains limited
despite extensive research spanning more than two decades.[10,
18] [19]
Herein we document our exploration of exo-selective 1,3-
DC reactions using α,β-unsaturated 7-azaindoline amides 1.
α,β-Unsaturated amides are generally less electrophilic than
other classes of α,β-unsaturated carbonyl compounds and
nitroolefins, and thus barely act as dipolarophiles except for
aromatic amides[10] and imides.[3-5,15] α,β-Unsaturated 7-
azaindoline amides engaged in 1,3-DC reactions with both
aromatic and aliphatic nitrones 2 by the actions of a catalyst
comprising In(OTf)3 and modified Yamamoto’s bishydroxamic
acid (BHA) ligands,[20] affording exo-cycloadducts in a highly
enantioselective manner. Divergent conversion of the amide
functional group highlights the synthetic utility of the present
catalysis.
Introduction
Given the inherent nature of cycloaddition reactions to forge two
bonds in one event, they are extensively utilized to construct
molecular architectures of interest.[1] The 1,3-dipolar
cycloaddition (1,3-DC) reaction is
a cycloaddition reaction
variant that couples 1,3-dipoles and dipolarophiles to produce 5-
membered ring systems.[1c,2] Nitrones are an archetypal 1,3-
dipole commonly used in 1,3-DC reactions with dipolarophiles
having multiple bonds, allowing for expeditious access of multi-
substituted isoxazolidines. The 1,3-DC reaction was first
rendered catalytic and asymmetric by Jørgensen et al., in which
a
Ti(IV)/TADDOL complex promoted the reaction with
oxazolidinone-based electron-deficient olefin as a dipolarophile
in an exo-selective manner.[2b,3] This discovery triggered the
development of catalytic asymmetric 1,3-DC reactions of
alkenoyl oxazolidinones,[4] including highly endo-selective and
enantioselective examples.[5] Palomo et al. and Evans et al.
reported
that
different
dipolarophiles
with
chelating
characteristics, e.g., α‘-hydroxy enones[6] and 2-alkenoyl
imidazoles,[7] are potential substrates. Further exploration of
bidentate dipolarophiles revealed that α’-phosphoric enones,[8]
alkenoylpyridine N-oxides,[9] alkenoyl pyrazoles,[10] and alkenyl
2-pyridylsulfones[11] are also compatible in catalytic asymmetric
1,3-DC reactions. In contrast to the prior reports of the above-
mentioned bidentate dipolarophiles exhibiting endo-selectivity,
except for Jørgensen’s pioneering work, Sibi et al. reported that
2-alkenoyl-3-pyrazolidinones[12] and α,β-disubstituted alkenyl
Scheme 1. Exo-selective catalytic asymmetric 1,3-DC reaction of 7-
azaindoline amides 1 and nitrones 2.
Results and Discussion
In the course of our ongoing research, we reasoned that α,β-
unsaturated 7-azaindoline amides 1 are viable dipolarophiles in
catalytic asymmetric 1,3-DC reactions. The 7-azaindoline
amides are characterized by their intrinsic stability and acquired
reactivity in the presence of suitable Lewis acids, which is
ascribed to a conformational change in the amide
[a]
Dr. Ming Zhang, Dr. Naoya Kumagai, and Prof. Dr. Masakatsu
Shibasaki
Institute of Microbial Chemistry (BIKAKEN), Tokyo
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021
E-mail: nkumagai@bikaken.or.jp, mshibasa@bikaken.or.jp
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1. Optimization of catalytic asymmetric 1,3-DC reaction of α,β-unsaturated
7-azaindoline amide 1a and nitrone 2a.[a]
O
O
–O
Ph
Bn
H
+
catalyst
x mol%
N
N
N
O
+
N
RT, 24 h
N
N
Ph
3a
Bn
1a
2a
Yield[b]
[%]
ee[c]
[%]
Entry
Catalyst
x
Solvent
exo/endo[b]
1
2
Cu(OTf)2/L1
In(OTf)3/L1
10
10
10
10
10
10
10
10
10
10
10
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
toluene
THF
26
18
39
94
21
99
12
7
7/1
2/1
17
26
36
95
65
19
19
0
3
In(OTf)3/BHA-1
In(OTf)3/BHA-2
In(OTf)3/BHA-3
Cu(OTf)2/BHA-2
Ni(OTf)2/BHA-2
In(OTf)3
7/1
Figure 1. Utility of 7-azaindoline amides
1 as pronucleophiles and
electrophiles.
4
>20/1
4/1
5
6
2/1
7
10/1
—
geometry; the stable E-conformer is switched to a Z-conformer
via bidentate coordination (Figure 1). The activated Z-conformer
elicits masked reactivity to allow for catalytic enolization
8
9
In(OTf)3/BHA-2
In(OTf)3/BHA-2
In(OTf)3/BHA-2
In(OTf)3/BHA-2
In(OTf)3/BHA-2
86
12
95
60
93
>20/1
2/1
96
—
97
97
98
10
11
12
13[d]
(nucleophilic activation)[21] and also serves as
a Michael
>20/1
>20/1
>20/1
acceptor when conjugated with a double bond (electrophilic
activation).[22] Given the electrophilic activation mode of the α,β-
unsaturated!amide by Lewis acids, we began screening chirally
decorated Lewis acidic catalysts for a 1,3-DC reaction of amide
1a and nitrone 2a (Table 1). A Cu(II) and In(III) complex of tBu-
PyBox ligand L1 preferentially delivered exo-cycloadduct 3a,
albeit in low yield and with low enantioselectivity (Entries 1,2).
BHA-type ligands with In(OTf)3 exhibited generally higher
catalytic activity, and BHA-2 with 3,3-diphenylpropionic
hydroxamic acid units significantly outperformed other
structurally similar BHA ligands, e.g., BHA-1 and BHA-3 (Entries
3–5). BHA-2 was uniquely effective with In(OTf)3 and the use of
other metal salts, e.g., Cu(OTf)2 and Ni(OTf)2, gave significantly
lower stereoselectivity (Entries 4,6,7). The ligand substantially
accelerated the reaction, which barely proceeded in the absence
of the ligand (Entry 8). A brief survey of solvents identified THF
as optimal and the reaction reached completion with 5 mol% of
catalyst at a higher concentration (Entries 9–13).
THF
5
THF
[a] 1a: 0.1 mmol, 2a: 0.12 mmol, 0.2 M. 1.2 equiv of ligand was used relative to
metal salts. [b] Determined by 1H NMR analysis. [c] Determined by HPLC
analysis. [d] Run on 0.5 M with 2 equiv of 2a (0.2 mmol).
O
O
N
N
O
O
N
HO OH
N
N
tBu
tBu
L1
BHA-3
O
O
O
O
N
N
N
N
Ph
Ph
HO OH
HO OH
BHA-1
BHA-2
The electrophilic activation mode proposed in Figure 1 was
supported by NMR analysis of 1a in the absence and presence
of the In(OTf)3/BHA-2 complex (Figure 2). The α-proton (Ha) of
1a was abnormally downfielded close to 8 ppm, which is
indicative of E-conformation and intramolecular hydrogen
bonding with the pyridyl nitrogen of the azaindoline (Figure 2a).
Addition of the In(OTf)3/BHA-2 complex to 1a resulted in a
significant upfield shift of Ha (> 1 ppm), suggesting that the
hydrogen bonding was abandoned to render bidentate
coordination to the In(III) complex in a Z-conformation (Figure
2b). The observed NOE between the α-proton (Ha) and Hc on
the azaindoline provided further support for Z-conformation.[23]
The downfield shift of the β-proton (Hb) implied that electrophilic
activation was manifested for the subsequent 1,3-DC reaction
with incoming nitrones. In contrast to explicit peaks of 1a, NMR
signals derived from In(OTf)3/BHA-2 were very broad, giving
little information. This observation is assumed to indicate that
the mixture of In(OTf)3 and BHA-2 did not form a discrete
complex and gave the oligomeric species in equilibrium.[24] The
Figure 2. 1H NMR analysis of amide 1a in the absence and presence of the
In(III)/BHA-2 complex. (a) 1a in THF-d8. (b) 1a : In(OTf)3/BHA-2 = 1:1 in THF-
d8.
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Table 2. Catalytic asymmetric 1,3-DC reaction of 1a and 2a with BHA-2 and
Table 3. Substrate generality of nitrones in catalytic asymmetric 1,3-DC
reaction of α,β-unsaturated 7-azaindoline amide 1a.[a]
its derivatives.[a]
O
O
O
O
In(OTf)3 10 mol%
BHA ligands 12 mol%
–O
Ph
Bn
H
+
cat.
In(OTf)3
BHA-2
N
N
O
–O
Ar
R
H
+
N
+
N
N
N
N
O
THF, RT, 24 h
+
N
N
Ph
3a
N
Bn
THF, RT, 48 h
N
N
Ar
R
1a
2a
"N" =
1a
2
3
O
O
O
O
O
O
O
O
N
N
N
N
"N"
"N"
"N"
"N"
O
O
O
O
HO OH
MeO OH
N
N
N
N
Bn
Bn
Bn
Bn
BHA-2
95%, 97% ee
exo/endo >20/1
BHA-2A
60%, 38% ee
exo/endo 1.5/1
3a: 5 mol%
93%, 98% ee
exo/endo >20/1
3b: 5 mol%
74%, 93% ee
exo/endo >20/1
3c: 5 mol%
92%, 96% ee
exo/endo >20/1
3d: 5 mol%
88%, 92% ee
exo/endo >20/1
O
O
O
O
N
N
N
N
O
O
O
O
MeO OMe
H H
"N"
O
"N"
O
"N"
O
"N"
O
N
N
N
N
BHA-2B
69%, 0% ee
exo/endo 1.7/1
BHA-2C
63%, 0% ee
exo/endo 1/2
Bn
Bn
Bn
Bn
[a] 1a: 0.1 mmol, 2a: 0.12 mmol, 0.2 M. Yield and exo/endo ratio were
determined by 1H NMR analysis of the crude mixture. Enantioselectivity of the
major diastereomers is shown.
F3C
F
Cl
3e: 5 mol%
92%, 97% ee
exo/endo >20/1
3f: 10 mol%
88%, 98% ee
exo/endo >20/1
3g: 5 mol%
89%, 98% ee
exo/endo >20/1
3h: 5 mol%
93%, 99% ee
exo/endo >20/1
bishydroxamic acid units proved essential for both efficient
reaction progress and high stereoselectivity (Table 2). In the
identical substrate set in Table 1, the reactions with modified
ligands mono-O-methylated BHA-2A and di-O-methylated BHA-
2B gave product 3a in lower yield and substantially decreased
stereoselectivity; and the latter gave a virtually racemic product.
Together with the lack of enantiodiscrimination observed for the
bisamide analog BHA-2C, bishydroxamic acid units in a suitable
spatial arrangement were critical for the present exo-selective
1,3-DC reaction, although the three-dimensional structure of the
complex remained elusive.
O
O
O
O
"N"
O
"N"
O
Br
"N"
"N"
O
O
N
N
N
N
Bn
Bn
Bn
Bn
Br
NC
MeO
3i: 5 mol%
87%, 99% ee
exo/endo >20/1
3j: 10 mol%
67%, 94% ee
exo/endo >20/1
3k: 10 mol%
89%, 97% ee
exo/endo >20/1
3l: 5 mol%
90%, 91% ee
exo/endo >20/1
O
O
O
O
"N"
O
MeO
"N"
O
"N"
O
"N"
O
N
N
N
N
The optimized conditions using the In(OTf)3/BHA-2
catalyst could be generalized for the reactions of various
nitrones 2 derived from aromatic aldehydes and 7-azaindoline
(E)-crotonoylamide 1a (Table 3).[25] Only exo-adducts 3 were
obtained in all cases, and the reactions could be conducted at
room temperature.[26] High yield and enantioselectivity were
observed, irrespective of the substitution pattern of the non-polar
substituents (3b–e). Electron-withdrawing (3f–k) and -donating
groups (3l,m) were tolerated, but the reaction with o-Br
substituted nitrone proceeded sluggishly even with 10 mol% of
catalyst loading, likely due to steric factors (3j). Nitrones bearing
a potentially Lewis basic heteroaromatic functional group were
applicable (3n,o), albeit with lower conversion of the 2-furyl
substituted product (3o). N-Me nitrone was accommodated with
a marginal loss of enantioselectivity (3p).
Unexpectedly, nitrones bearing an aliphatic substituent
gave poor results with BHA-2, prompting us to further screen
BHA-type ligands in the exo-selective 1,3-DC reactions (Table 4).
Specifically for nitrone 2q, derived from hexanal, BHA-type
ligands in the previous screening set were re-evaluated; BHA-2,
optimal for aromatic nitrones, exhibited inferior performance
compared with BHA-3, whose hydroxamic acid units are 1
O
Bn
Bn
Bn
Me
N
3m: 5 mol%
85%, 95% ee
exo/endo >20/1
3n: 5 mol%
85%, 96% ee
exo/endo >20/1
3o: 10 mol%
75%, 95% ee
exo/endo >20/1
3p: 5 mol%
82%, 83% ee
exo/endo >20/1
[a] 1a: 0.1 mmol, 2a: 0.12 mmol, 0.2 M. 1.2 equiv of BHA-2 was used relative
to In(OTf)3. Isolated yield and ee of exo-adducts are shown.
methylene shorter. A similar tendency was observed for 3,5-xylyl
analogs BHA-4 and BHA-5. Based on BHA-2, a bulkier
mesitylene analog (BHA-6), linked analog (BHA-7), and
aliphatic analog (BHA-8) were synthesized, but none of them
afforded better stereoselectivity than BHA-2. Gratifyingly, the
rigidified analog BHA-9 afforded 3q with reasonably high
exo/endo selectivity (8/1) and enantioselectivity (75% ee for exo-
isomer). Less demanding cinnamoyl analog BHA-10 exhibited
inferior selectivity.
BHA-9 was useful for exo-selective 1,3-DC reactions of
aliphatic nitrones 2q–s and α,β-unsaturated amides 1b–e with
other β-substituents (Table 5).[27] Nitrones with an α-branched
structure afforded slightly better enantioselectivity, reaching 90%
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Table 4. Screening of BHA ligands for aliphatic nitrone 2q.[a]
[a] 1a: 0.1 mmol, 2a: 0.12 mmol, 0.2 M. Yield and exo/endo ratio were determined by 1H NMR analysis of the crude mixture. Enantioselectivity of exo-3q is
shown. [b] ent-3q was obtained as major enantiomer.
ee (3r). Amide 1b without any substituent at the β-position had
Table 5. Utility of BHA-9 in catalytic asymmetric 1,3-DC reaction of aliphatic
nitrones and differently substituted α,β-unsaturated 7-azaindoline amides 1.[a]
lower enantioselectivity, and moderate exo selectivity and
R1
O
enantioselectivity were observed even with BHA-9. Amide 1c,d
with longer alkyl chains benefited from the use of BHA-9,
delivering the desired products 3u,v in decent yield and with
moderate stereoselectivity. In the specific case of amide 1e
possessing an ether-type substituent, BHA-2 was superior to
BHA-9 and 3w was obtained with excellent stereoselectivity.
O
cat.
In(OTf)3
BHA-2 or 9
–O
R2
+
Bn
H
N
R1
N
N
O
+
N
THF, RT, 48 h
N
N
R2
Bn
"N" =
1a: R1 = Me
1b: R1 = H
1c: R1 = Et
1d: R1 = nPr
2a: R2 = Ph
3
2q: R2 = nPen
2r : R2 = cHex
Figure
3 highlights the exclusive utility of the α,β-
2s: R2 = (CH2)2Ph
1e: R1 = CH2OBn
unsaturated 7-azaindoline amide as a competent dipolarophile in
the present catalytic system. In the reaction of nitrone 2a
promoted by the In(OTf)3/BHA-2 catalyst, a series of α,β-
unsaturated amides 4–7 was tested. Structurally-related amides
4 and 5 sharing the indoline architecture failed in the reaction,
indicating that the nitrogen atom at the 7-position is crucial and
supports the the activation mode shown in Figure 2. While a
similar activation mode via bidentate coordination to the In(III)
complex is possible, amide 6 having a 2-pyridyl group showed
no reactivity in the present catalytic system. In general, α,β-
unsaturated amides and esters are poor Michael acceptors and
dipolarophiles, and simple dimethyl amide 7 and methyl ester 8
remained unchanged as expected.
It is important to note the two advantages of the 7-
azaindoline unit; it not only enabled the exo-selective catalytic
activation of 1,3-DC reactions, but also served as a handle for
divergent transformation (Scheme 2). The 7-azaindoline amide
is bench-stable and easy-to handle, but readily hydrolyzed by
treatment with 2M HCl/MeOH at 80 °C to give the corresponding
carboxylic acid 9 in quantitative yield. Upon nucleophilic addition
of a metallated carbanion or hydride, the transient tetrahedral
intermediate was fairly stable to prevent over-alkylation or over-
reduction, affording ketone 10 and aldehyde 11 in high yield.
O
O
O
"N"
"N"
"N"
O
O
O
N
N
N
Bn
Bn
Bn
[1a + 2q]
3q: 5 mol%
[1a + 2r]
[1a + 2s]
3s: 5 mol%
BHA-9
85%, 81% ee
exo/endo 5/1
3r: 5 mol%
BHA-9
83%, 90% ee
exo/endo 13/1
BHA-9
91%, 79% ee
exo/endo 8/1
O
O
O
O
O
H H
"N"
"N"
"N"
"N"
O
N
O
O
O
N
N
N
Bn
Bn
Bn
Bn
[1b + 2a]
3t: 5 mol%
BHA-9
95%, 80% ee
[1c + 2a]
3u: 10 mol%
BHA-9
[1d + 2a]
3v: 10 mol%
BHA-9
[1e + 2a]
3w: 5 mol%
BHA-2
91%, 98% ee
exo/endo >20/1
91%, 90% ee
89%, 90% ee
exo/endo 16/1 exo/endo >20/1
exo/endo 3/1
[a] 1: 0.1 mmol, 2: 0.12 mmol, 0.2 M. 1.2 equiv of BHA ligand was used
relative to In(OTf)3. Isolated yield and enantioselectivity of exo-adducts are
shown.
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10.1002/chem.201702330
Chemistry - A European Journal
COMMUNICATION
O
This work was financially supported by ACT-C (JPMJCR12YO)
from JST, and KAKENHI (25713002, 17H03025, and
JP16H01043 in Precisely Designed Catalysts with Customized
Scaffolding) from JSPS and MEXT. NK thanks The Naito
Foundation for financial support. Dr. Tomoyuki Kimura is
gratefully acknowledged for the X-ray crystallographic analysis.
We thank Dr. Ryuichi Sawa, Ms. Yumiko Kubota, and Dr. Kiyoko
Iijima for the NOE & DOSY analyses.
–O
Ph
Bn
H
+
In(OTf)3 10 mol%
BHA-2 12 mol%
O
X
N
O
+
N
X
CH2Cl2, RT, 24 h
Ph
Bn
dipolarophiles
2a
1,3-DC products
X =
N
N
N
N
N
O
N
N
Keywords: cycloaddition • asymmetric catalysis • indium •
N
1a
4
5
6
7
8
isoxazolidine • bishydroxamic acid
94%
exo/endo >20/1
ND
ND
ND
ND
ND
95% ee
[1]
a) S. Kobayashi, K. A. Jørgensen, Cycloaddition reactions in organic
synthesis, Wiley-VCH, Weinheim, Germany, 2002; b) N. Nishiwaki,
Wiley, Hoboken, New Jersey, 2014, pp. 1 online resource (xii; c) L.
Klier, F. Tur, P. H. Poulsen, K. A. Jorgensen, Chem. Soc. Rev. 2017,
46, 1080.
Figure 3. Exclusive reactivity of 7-azaindoline amide 1a in the present 1,3-DC
reaction.
[2]
a) K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998, 98, 863; b) K. V.
Gothelf, K. A. Jørgensen, Chem. Commun. 2000, 1449; c) S.
Kanemasa, Synlett 2002, 1371; d) H. Pellissier, Tetrahedron 2007, 63,
3235; e) L. M. Stanley, M. P. Sibi, Chem. Rev. 2008, 108, 2887; f) S.
Kanemasa, Heterocycles 2010, 82, 87; g) M. Kissane, A. R. Maguire,
Chem. Soc. Rev. 2010, 39, 845; h) C. Nájera, J. M. Sansano, M. Yus, J
Braz. Chem. Soc. 2010, 21, 377; i) T. Hashimoto, K. Maruoka, Chem.
Rev. 2015, 115, 5366; j) M. S. Singh, S. Chowdhury, S. Koley,
Tetrahedron 2016, 72, 1603.
O
O
Ph
MeO
O
O
N
N
Ph
Ph
Bn
Bn
9
10
O
quant.
88%
2M HCl/MeOH
80 °C, 12 h
PhCH2MgCl
N
O
THF, 0 °C, 1 h
N
LiAlH4
LiAlH(OtBu)3
[3]
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N
Ph
3a
Bn
THF, –40 °C, 3 h
THF, 0 °C to RT
12 h
91%
quant.
O
H
HO
O
N
O
N
Ph
11
Ph
Bn
Bn
12
Scheme 2. Divergent transformation of the 7-azaindoline amide moiety of 1,3-
DC adduct 3a.
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O
N
–OTf
+
N
BP-1
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Ming Zhang,[a] Naoya Kumagai,*[a] and
Masakatsu Shibasaki*[a]
Page No. – Page No.
α,β-Unsaturated Amides as
Dipolarophiles; Catalytic Asymmetric
Exo-selective 1,3-Dipolar
Cycloaddition with Nitrones
Text for Table of Contents 1,3-Dipolar cycloaddition is a commonly exploited
method to access 5-membered chemical entities with a variety of peripheral
functionalities and their stereochemical arrangements. Nitrones are isolable 1,3-
dipoles that exhibit sufficient reactivity toward electron-deficient olefins in the
presence of Lewis acids to deliver highly substituted isoxazolidines. Herein we
document that α,β-unsaturated amides, generally regarded as barely reactive in a
1,3-dipolar reaction manifold, were effectively activated using the designed 7-
azaindoline auxiliary in an In(OTf)3/bishydroxamic acid catalytic system. The broad
substrate scope and clean removal of the 7-azaindoline auxiliary from the product
highlight the synthetic utility of the present catalysis.
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