Catalytic asymmetric formal [3+2] cycloaddition of isatogens with azlactones to construct indolin-3-one derivatives

Article abstract of DOI:10.1039/d0cc06418a

The chiral amide-guanidine-catalyzed asymmetric formal [3+2] cycloaddition of isatogens with azlactones is presented. This strategy provided a facile and feasible route to chiral indolin-3-one derivatives bearing two contiguous tetrasubstituted stereocent

Full text of DOI:10.1039/d0cc06418a

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DOI: 10.1039/D0CC06418A
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Catalytic asymmetric formal [3+2] cycloaddition of isatogens with
azlactones to construct indolin-3-one derivatives
Lihua Xie, Yi Li, Shunxi Dong, Xiaoming Feng, and Xiaohua Liu*a
++Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Chiral amide-guanidine-catalyzed asymmetric formal [3+2] improvement in terms of catalysts, substrate scope and product
cycloaddition of isatogens with azlactones was presented. This diversity.
strategy provided a facile and feasible route to chiral indolin-3-one
derivatives bearing two contiguous tetrasubstituted stereocenters
in moderate to good yields with high diastereoselectivities and
enantioselectivities. A possible working mode was proposed to
As part of our continuous efforts in chiral bifunctional guanidine
catalysis8 and inspired by the cycloaddition reaction with azlactones,9
we envisioned that the [3+2] cycloaddition reaction of isatogens
with azlactones will deliver fused indolin-3-one derivatives
bearing two quaternary stereocenters (Scheme 1c). The
elucidate the chiral control of the process.
nitrogen oxygen in cyclic nitrone was stronger Lewis basic than
Nitrones were employed a type of useful and versatile building
that in acyclic nitrone. The use of chiral organocatalysts might
block in organic synthesis.1 Great efforts have been devoted to the
avoid overactive coordination of cyclic nitrone with the catalyst
exploration of asymmetric transformations of acyclic nitrones
of metal complex. Herein, we report the chiral bifunctional
bearing aldimine backbone.2 In comparison, there are only sporadic
amide-guanidine-accelerated formal [3+2] cycloaddition of
examples concerning on the catalytic enantioselective reactions
azlactones with isatogens (Scheme 1c), and an array of
involving cyclic nitrones,3 especially ketimine-based ones, although
enantioenriched fused indolin-3-one derivatives were readily
the related products were frequently served as the important
furnished in moderate to good yields (up to 99% yield) with high
intermediates for the synthesis of bioactive nature products and
diastereo- and enantioselectivity (up to 19:1 dr, 99% ee).
drug molecules.4 The cyclic nitrones are different from the acyclic
(a) Asymmetric Friedel-Crafts reaction of isatogens with indoles (Jia's work)
ones in terms of configuration, steric hindrance, and basicity of the
nitrogen oxide unit. As one subclass of cyclic nitrones, indolone-N-
O
O
Ar
[Au]
Ar
oxides (INODs), commonly known as isatogens, possess
antiplasmodial properties, which were widely used in medicinal and
pharmaceutical fields.5 Moreover, the transformation of isatogens
enabled the construction of indoline-3-one derivatives, which were
found to be an intriguing motifs in natural products with diverse
biological activities.6 In this regards, Jia and co-workers
demonstrated AuCl3/chiral phosphoric acid (CPA) relay catalysis
between indole and in situ generated isatogens to synthesize 2-aryl-
2-indole substituted indolin-3-ones with high enantioselectivity
(Scheme 1a).7a N-heterocyclic carbenes (NHC)-catalyzed umpolung
formal [3+3] cycloaddition of enals with isatogens was disclosed by
the groups of Lu and Du, but a trial with the use of chiral NHC led to
moderate enantioselectivity for fused indolin-3-one skeleton
(Scheme 1b).7b Nevertheless, there still leaves great room for
N
H
Ar
NH
N
N
CPA
OH
NO2
O
up to 96% yield, 96% ee
(b) Chiral NHC-promoted [3+3] annulation of isatogens with enals (Lu and Du's work)
O
Ph
Ph
O
O
chiral NHC
Ph
N
Ph
H
N
O
O
one example
O
>95:5 dr, 58% ee
(c) Chiral guanidine-catalyzed [3+2] cycloaddtion of isatogens with azlactones (This work)
O
O
R1
R
O
NHCOR2
O
O
N
chiral guanidine
R2
R
N
N
R1
O
O
up to 99% yield, 99% ee
a. Key Laboratory of Green Chemistry & Technology, Ministry of Education, College
of Chemistry, Sichuan University, Chengdu 610064, China. E-mail:
Scheme 1 The asymmetric transformation of isatogens.
liuxh@scu.edu.cn Fax: +86 28 85418249; Tel: +86 28 85418249.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1 Optimization of the reaction conditionsa
the optimized conditions entailed the use of chiralVgieuwaAnrtiicdleinOenlGine-
6 (10 mol%) as the catalyst in THF at ‒40 C, and the desired
product was afforded in 94% yield with 95% ee.
DOI: 10.1039/D0CC06418A
O
O
O
cat. (10 mol%)
O
Bn
Bn
Table 2 Substrate scope of azlactones 2a
solvent, T C
NHCOPh
N
N
N
Ph
> 19:1 dr
O
O
O
O
O
O
3aa
1a
2a
R1
R1
NHCOR2
G-6 (10 mol%)
O
N
R
O
N
N
THF, 40 C
N
N
N
G-5: R = 2,4,6-iPr3C6H2
G-6: R = CHPh2
G-1: R = Ph
> 19:1 dr
G-2: R = 2,6-Me2C6H3
G-3: R = 2,6-Et2C6H3
G-4: R = 2,6-iPr2C6H3
R2
H
O
O
O
N
1a
2a–o
3aa–ao
G-7: R = CPh3
Cy
(Cy = cyclohexyl)
Cy
entry
R1, R2
t (h)
yield
(%)b
ee
H
(%)c
94
94
93
91
91
93
95
94
90
92
92
yield
(%)b
65
56
44
36
26
53
57
63
52
46
88
92
94
ee
1
2
Bn, Ph (3aa)
24
36
36
9
92
91
95
99
84
81
86
94
83
94
96
entry
cat.
solvent
(%)c
59
76
62
63
41
70
31
83
83
93
95
94
95
phenethyl, Ph (3ab)
isobutyl, Ph (3ac)
1
2
3
4
5
G-1: R = Ph
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
THF
THF
THF
3
G-2: R = 2,6-Me2C6H3
G-3: R = 2,6-Et2C6H3
G-4: R = 2,6-iPr2C6H3
G-5: R = 2,4,6-iPr3C6H2
G-6: R = CHPh2
4
2-(methylthio)ethyl, Ph (3ad)
(1H-indol-3-yl)methyl, Ph (3ae)
cyclohexylmethyl, Ph (3af)
4-chlorobenzyl, Ph (3ag)
4-bromobenzyl, Ph (3ah)
3-methylbenzyl, Ph (3ai)
Bn, 4-FC6H4 (3aj)
5
24
9
6
6
7
9
7
G-7: R = CPh3
8
9
8
9
G-2: R = 2,6-Me2C6H3
G-6: R = CHPh2
9
9
10
11
9
10d
11d
12d,e
13d,f
G-2: R = 2,6-Me2C6H3
G-6: R = CHPh2
G-6: R = CHPh2
Bn, 4-ClC6H4 (3ak)
9
12
13d
14
Bn, 4-BrC6H4 (3al)
9
82
65
83
78
91
91
99
94
G-6: R = CHPh2
THF
Bn, 4-MeOC6H4 (3am)
Bn, 3,5-Me2C6H3 (3an)
Bn, 2-naphthyl (3ao)
36
9
a Unless otherwise noted, the reactions were carried out with guanidine (10 mol%),
1a (0.10 mmol), and 2a (0.1 mmol) in solvent (0.1 M) at 30 C under N2 for 18 h. b
Isolated yield. c Determined by SFC analysis on a chiral stationary phase. d At −40
C. e 2a (0.12 mmol) for 24 h. f 1a (0.12 mmol) for 24 h.
15e
36
a
Unless otherwise noted, the reactions were carried out G-6 (10 mol%), 1a (0.1
mmol), and 2 (1.2 equiv) in THF (0.1 M) at −40 C under N2. Dr values (>19:1) were
b
c
determined by 1H NMR. Isolated yield. Determined by SFC analysis on a chiral
At the outset, we chose 2-cyclopropyl-3-oxo-3H-indole-1-
oxide (1a) and azlactone 2a as the model substrates to optimize
stationary phase. d At −20 C. e At −10 C.
the
reaction
conditions.
A
range
acid-derived
of
chiral
amide-
With the optimized reaction conditions in hand, we then
investigated the substrate scope. First, azlactone derivatives 2
with various substituents were subjected into the reaction with
1a (Table 2). The azlactones derived from 2-amino-4-
phenylbutanoic acid (2b), leucine (2c), methionine (2d), 3-
tryptophan (2e), and 2-amino-3-cyclohexylpropanoic acid (2f),
tolerated the reaction well in the presence of 10 mol% of the
catalyst G-6 (entries 2‒6), providing the products 3ab-3af in
good yields (81‒99%) with high ee values (91‒94% ee). The
electronic properties and position of the substituents on the
aromatic rings at C4 position (R1) in azlactones 2g‒i had a
limited influence on the outcomes (entries 7‒9, 83‒94% yield,
90‒95% ee). Electron-donating substituent (OMe, 2m) on the
phenyl group at the C2 position (R2) generally resulted in a lower
yield than those of the substrates with electron-withdrawing
groups (2j‒l), but the enantioselectivity of all these products
was >90% ee (entries 10−14). It is noteworthy that azlactones
2o bearing 2-naphthyl substituent at the C2 position were
compatible in current system, providing the corresponding
product 3ao in decent yield (72% yield) and excellent
enantioselectivity (94% ee) at −10 ⁰C (entry 15).
tetrahydroisoquinoline-3-carboxylic
guanidines G-1~G-7 were tested with CH2Cl2 as the solvent at
30 C. The reactions proceeded smoothly to afford the desired
fused indoli-3-one 3aa in low to moderate yields (26‒65%) with
promising ee values (Table 1, entries 1‒7, 31‒70% ee). It was
found that the substitution of amide group had a significant
influence on the enantioselectivity of the reaction, and the use
of guanidine G-2 with 2,6-Me2C6H3 group and guanidine G-6
with benzhydryl moiety led to better yields and higher
enantioselectivities (56% yield with 76% ee, and 53% yield with
70% ee, respectively, entries 2 and 6). Further increasing the
steric bulk of the substituents led to inferior results (entries 3‒5
and 7). It should be noted that only one diastereomer was
detected in all cases. The subsequent screening of solvents
indicated that the enantiomeric excess increased when the
reaction was carried out in THF. Good ee value (83% ee) were
afforded in the presence of chiral guanidine G-2 or G-6 (entries
8 and 9). To our delight, performing the reaction at ‒40 C was
benefit to the chiral control of the reaction (entries 10 and 11),
and chiral guanidine G-6 outcompeted guanidine G-2 in terms
of reactivity and enantioselectivity (88% yield, 95% ee vs 46%
yield, 93 % ee). The yield was slightly improved with adjusting
the ratio of starting material 1a to 2a (entries 12 and 13). Thus,
2 | J. Name., 2012, 00, 1-3
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O
Scheme 2 Substrate scope of isatogens 1a
O
View Article Online
O
O
DOI: 10.1039/D0CC06418A
Bn
Bn
Pd-C (10%), H2
eq. 1
N
O
N
H
O
N
N
O
10% H2O/dioxane
rt, 12 h
R4
O
H
H
C
Bn
NHCOPh
Bn
HO2
O
G-6 (10 mol%)
R4
Br
O
Br
THF, 40 C
12-36 h
> 19:1 dr
N
R3
N
N
R3
3al, 91% ee
4al, 84% yield, 91% ee
O
O
O
Ph
1b–m
3ba–ma
2a
O
enantioselection of the reaction, a plausible working mode for
the reaction is proposed (Figure 1). Only one diastereoisomer of
the fused indolin-3-one products were detected at the
asymmetric catalytic aspect and the racemic version using TMG
as the catalyst. The high diastereoselectivity might rise from the
favorable rel-Re-Si attack of the two components, which benefit
the attack of the oxygen to the azlactone in concern. In
comparison, the rel-Re-Re interaction is disfavored due to the
steric hindrance or the far-attack of oxygen to azlactone.
The enantioselection of the reaction might step from a
bifunctional activation mode (Figure 1, below). The amide
provides a hydrogen-bond to interact the oxygen of N-O group
in isatogen 1c. The basic guanidine unit accelerates the
enolization of azlactone 2a, contacting the formed enolate
intermediate via a hydrogen bond. Due to the block from the
amide substituent and N-substituent of guanidine, the rotation
of the two H-bonded species slows down. Then, the Re-face of
enolate intermediate approaches isatogen 1c from its Si-face.
Next, two quaternary C-C-bonded intermediate undergoes a
second bond formation between the oxyanion and the acetylide
carbon to generate the five-membered N,O-heterocyclic
compound 3ca with (S,S) configuration.
O
R4
Bn
NHCOPh
Bn
NHCOPh
N
Cl
R3
N
O
O
O
O
R3 = F (3ba), 95% yield, 92% ee
R3 = F (3ba),b 87% yield, 92% ee
R3 = Cl (3ca), 73% yield, 96% ee
R3 = Br (3da), 82% yield, 93% ee
R4 = n-C4H9 (3fa),c 24 h, 88% yield, 80% ee
R4 = n-C6H13 (3ga),c 24 h, 82% yield, 80% ee
R4 = n-C10H21 (3ha), 12 h, 90% yield, 81% ee
R4 = CH2CH2CH2Cl (3ia), 12 h, 99% yield, 71% ee
R4 = CH2CH2CH2Ph (3ja), 12 h, 99% yield, 80% ee
R4 = cyclopentyl (3ka),c 24 h, 89% yield, 59% ee
O
R3 = Me (3ea), 24 h, 84% yield, 99% ee
S
O
Bn
Ph
Bn
NHCOPh
NHCOPh
N
N
O
O
3ma
Cl
O
O
3la
Cl
30 C, 35% yield, 5% ee
30 C, 42% yield, 3% ee
20 C, 18% yield, 16% ee
20 C, 52% yield, 13% ee
a
The reactions were carried out with 1 (1.5 equiv), 2a (0.10 mmol) and G-6 (10
mol%) in THF (0.1 M) at −40 °C under N2 for 36 h. Dr values (>19:1) were
determined by 1H NMR. Performed with 1b (1.5 mmol) and azlactone 2a (1.0
b
mmol). c At −20 °C.
Furthermore, the substrate scope of isatogens 1 was explored
with azlactone 2a. The halogenated isatogens 1b–1d and
methyl substituted 1e reacted well with 2a, furnishing the
corresponding products (3ab-3ae) in good yields (73–95%) and
excellent enantioselectivities (92–99% ee). Substrates 1f–1k
with other alkyl substituents (R4) generated the desired
products 3fa–3ka in good yields (65–99%) and moderate
enantioselectivities (59–81% ee). Notably, the reactions of
isatogens (1f, 1g, 1k) were sluggish at the previously optimized
reaction condition, and elevating the reaction temperature
from −40 C to −20 C led to acceptable results. In comparison,
a phenyl or 2-thienyl substitution (1l and 1m), which shows poor
solubility in current catalytic system, resulted in low yields and
enantioselectivity, which is complementary to the substrate
generality in the other related reaction of isatogens.10 To
demonstrate the practicality of the transformations, we carried
out a scale-up synthesis of the product 3ba. In the presence of
10 mol% of the chiral catalyst G-6, the reaction of 1.5 mmol 1b
and 1.0 mmol azlactone 2a reacted well to afford the desired
adduct 3ba in 87% yield (0.40 g) with 92% ee. In addition, the
absolute configuration of the product 3ca was determined to be
(S,S) by X-ray crystallographic analysis.11
high diastereoselectivity
O
O
Cl
O
Bn
O
O
Cl
Bn
N
N
N
Bn
O
O
O
N
O
O
N
O
O
N
Ph
rel-Re-Re disfavored
Ph
Ph
rel-Re-Si favored
Cl
O
N
N
H
O
O
N
Cl
Re-Si approach
N
H
H
Si
O
N
high ee
O
Bn
Re
(S,S)-3ca
N
Ph
CCDC 1972984
Figure 1 Proposed working model for the reaction.
In conclusion, the catalytic asymmetric [3+2] cycloaddition of
isatogens with azlactones has been achieved with chiral amide-
guanidine as the catalyst. Various of optical active indolin-3-one
derivatives bearing two contiguous tetrasubstituted
stereogenic centers were readily obtained in good yield with
high diastereoselectivity and enantioselectivity. The scale-up
reaction demonstrated the potential practicality of the current
transformation. Further application of this kind of catalysts to
other reactions is underway.
The cycloaddition addcut 3al was subjected to
a
chemoselective reduction of the N-O bond to amino acid-
containing indolin-3-one derivative 4al with Pd/C catalyst in
excellent yields yields and good ee value without isomerization
(eq. 1).
Based on the general catalytic performance of the guanidine-
amide,12 as well as the diastereo- and
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Y. Sun, S. L. Morris-Natschke, K-H. Lee, Y-H. WangVaienwdACrt-icLl.eLOonnlinge,
Conflicts of interest
There are no conflicts to declare.
J. Nat. Prod., 2014, 77, 2590
.
7
8
(a) R-R. Liu, S-C. Ye, C-J. Lu, G-L. ZhuDaOngI:,10J-.1R0.3G9/aDo0,CaCn0d64Y1-8XA.
Jia, Angew. Chem., Int. Ed., 2015, 54, 11205; (b) J. Y. Xu, S. H.
Hu, Y. Y. Lu, Y. Dong, W. F. Tang, T. Lu and D. Du, Adv. Synth.
Catal., 2015, 357, 923.
For reviews from our group, see: (a) W. D. Cao, X. H. Liu, X.
M. Feng, Chin. Chem. Lett., 2018, 29, 1201; (b) S. X. Dong, X.
M. Feng, X. H. Liu, Chem. Soc. Rev., 2018, 47, 8525; (c) X. H.
Liu, S. X. Dong, L. L. Lin, X. M. Feng, Chin. J. Chem., 2018, 36,
791.
For selected example on the asymmetric cycloaddition of
azlactones from our group, see: (a) S. X. Dong, X. H. Liu, X. H.
Chen, F. Mei, Y. L. Zhang, B. Gao, L. L. Lin, X. M. Feng, J. Am.
Chem. Soc., 2010, 132, 10650; (b) K. R. Yu, X. H. Liu, X. B. Lin,
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L. L. Lin, X. M. Feng, X. H. Liu, Org. Chem. Front. 2018, 5, 32;
(e) L. H. Xie, S. X. Dong, Q. Zhang, X. M. Feng and X. H. Liu,
Chem. Commun., 2019, 55, 87. For selected recent examples
from other groups on the asymmetric cycloaddition of
azlactones, see: (f) X. H. Liu, Y. J. Wang, D. X. Yang, J. L. Zhang,
D. S. Liu and W. Su, Angew. Chem., Int. Ed., 2016, 55, 8100; (g)
C. Ma, J-Y. Zhou, Y-Z. Zhang, G-J. Mei and F. Shi, Angew. Chem.,
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and S. Mukherjee, Org. Lett., 2019, 21, 3361; (j) B-B. Sun, Q-X.
Hu, J-M. Hu, J-Q. Yu, J. Jia, X-W. Wang, Tetrahedron Lett., 2019,
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Q. J. Ni, X. Y. Wang, F. F. Xu, X. Y. Chen and X. X. Song, Chem.
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Acknowledgements
We thank the National Natural Science Foundation of China (No.
21625205 and U19A2014) for financial support.
9
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DOI: 10.1039/D0CC06418A
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ChemComm
O
O
R4
R3
O
R2
G-6
(10 mol%)
O
O
R2
NH
R4
R1
R3
N
R1
N
N
O
O
O
O
CHPh2
H
27 examples
N
N
up to 99% yield
up to 99% ee
> 19:1 dr
N
Cy
Cy
N
G-6
H
A number of enantioenriched indolin-3-one derivatives were readily obtained by chiral guanidine-catalyzed [3+2]
cycloaddition of isatogens with azlactones.