Asymmetric Synthesis of Spirooxindole δ-Lactones with Vicinal Tertiary and Quaternary Stereocenters via Regio-, Diastereo-, and Enantioselective Organocatalytic Vinylogous Aldol-cyclization Cascade Reaction

Article abstract of DOI:10.1002/adsc.201701104

A highly region-, diastereo-, and enantioselective organocatalytic vinylogous aldol-cyclization cascade reaction of prochiral 3-akylidene oxindoles to isatins has been achieved by using bifuctional organocatalysts. A variety of enantioenriched spirooxindole δ-lactones with vicinal tertiary and quaternary stereocenters were generated in good to excellent yields with good to high diastereoselectivities and enantioselectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201701104

Title: Asymmetric Synthesis of Spirooxindole δ-Lactones with Vicinal
Tertiary and Quaternary Stereocenters via Regio-, Diastereo-,
and Enantioselective Organocatalytic Vinylogous Aldol−
cyclization Cascade Reaction
Authors: Jeng-Liang Han, You-Da Cai, and Chia-Hao Chang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701104
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10.1002/adsc.201701104
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Asymmetric Synthesis of Spirooxindole δ-Lactones with Vicinal
Tertiary and Quaternary Stereocenters via Regio-, Diastereo-,
and Enantioselective Organocatalytic Vinylogous Aldol−
cyclization Cascade Reaction
Jeng-Liang Han*a, You-Da Tsai,a and Chia-Hao Chang a
a
Department of Chemistry, Chung Yuan Christian University, 200 Chung Pei Road, Chung Li District, Taoyuan City,
32023, Taiwan
Fax: (+886)-3-265-8888; phone: (+886)-3-265-3330; email: jlhan@cycu.edu.tw
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
for the development of catalytic and effective
Abstract. A highly region-, diastereo-, and enantioselective
organocatalytic vinylogous aldol−cyclization cascade methods for generating of vicinal quaternary and
reaction of prochiral 3-akylidene oxindoles to isatins has
been achieved by using bifuctional organocatalysts. A
variety of enantioenriched spirooxindole δ-lactones with
vicinal tertiary and quaternary stereocenters were generated
in good to excellent yields with good to high
diastereoselectivities and enantioselectivities.
tertiary stereocenters.
3-Alkylidene oxindoles have been documented as a
vinylogous nucleophile to functionalize at the γ-
position with a variety of electrophiles[5] employing
hydrogen-bonding organocatalysts for substrate
activation and diverse synthesis of optically pure
compounds.[6] Our group recently has described an
unexpected catalytic direct asymmetric vinylogous
aldol[7]-cyclization cascade reaction of 3-alkylidene
oxindoles with isatins using quinine-derived chiral
squaramides as hydrogen-bonding organocatalysts,[8]
a protocol that let to optically pure spirooxindole δ-
lactones bearing a quaternary center.[9] The key
transformation of this cascade reaction was the 3-
alkylidene oxindoles could react with isatins via
vinylogous aldol reaction, followed by an unusual
cyclization to cleave the oxindole ring and construct
spirooxindole δ-lactones (Scheme 1a).
Keywords: Organocatalysis; 3-Akylidene oxindoles;
Spirooxindole δ-lactones; Vinylogous aldol−cyclization.
Spirooxindole δ-lactone is a key structure element
found in a variety of natural products and biologically
active molecules.[1] The catalytic asymmetric
transformations to chiral spirooxindole δ-lactone
derivatives had been less studied. Ye,[2a] Chi, [2c] and
Yao[2b,d,g] developed elegant methods to synthesized
spirooxindole δ-lactone derivatives using NHC-
catalysis. Wu[2e] reported the formation of
spirooxindole δ-lactones from vinylogous aldol-
cyclization cascade reaction of allyl pyrazoleamides
with isatins. Xu[2f] achieved an efficient hetero-Diels-
Alder reaction of olefinic azlactones with isatins to
construct spirooxindole δ-lactone derivatives. Shi[2h-k]
and coworkers utilized the enolizable homophthalic
anhydride to react with istains to synthesize
enantioenriched spirooxindole δ-lactones. The
development of other efficient methods for the chiral
spirooxindole δ-lactones is still of considerable
synthetic and biological importance.
The vicinal tertiary and quaternary stereocenters
are present in many natural products and biologically
important molecules. A number of effort have been
made towards the asymmetric synthesis of continuous
tertiary and quaternary stereocenters.[3] However, it
always required more harsh reaction conditions to
stereoselective construct the quaternary stereocenters
due to steric hindrance.[4] Hence, there is still a need
Scheme 1. Previous and current construction of
spirooxindole δ-lactones using vinylogous aldol−
cyclization cascade reaction.
1
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10.1002/adsc.201701104
Advanced Synthesis & Catalysis
Continuing on this work, we expected this organo-
catalytic vinylogous aldol-cyclization cascade
reaction might be extended to the reaction of 3-
alkylidene oxindoles bearing a prochiral site at the γ-
position, which could be proceeded smoothly to
deliver spirooxindole δ-lactones with the vicinal
quaternary and tertiary stereocenters at the γ- and δ-
positions (Scheme 1b). To the best of our knowledge,
there is no mild, catalytic and efficient method to
synthesize chiral polycyclic spirooxindole δ-lactones
with the vicinal quaternary and tertiary stereocenters
until today. We herein describe the first example of
this transformation with perfect regioselective control,
high enantioselectivities and high diastereo-
selectivities.
reaction at room temperature in toluene with 15
mol% of catalyst 1a at 0.4M substrate concentration.
By using the quinidine-derived thiourea catalyst 1e,
the opposite enantiomer ent-4a was obtained in 88%
yield, >20:1 diastereoselectivity and >99% ee (Table
1, entry 11).
Table 1. Optimization of reaction conditions.[a]
We initiated the investigation by carrying out the
cascade reaction with oxindole 2a (1.5 equiv.) and
isatin 3a (1 equiv.) by using quinie-derived thiourea
catalyst 1a (20 mol %, Scheme 2) as the catalyst in
0.5 mL toluene and at room temperature (Table 1,
entry 1).
Entry Cat. Solvent Time Yield
dr[c]
ee
[h]
[%][b]
[%][d]
1
2
3
4
5
6
7
8
toluene
42
92
56
trace
trace
97
84
54
trace
98
93
>20:1 >99
>20:1 >99
-
-
>20:1 >99
>20:1 >99
>20:1 >99
1a
1b
1c
1d
1a
1a
1a
1a
1a
1a
1e
toluene 218
toluene 218
toluene 218
CH2Cl2
THF
CH3CN
DMF
toluene 121
toluene 70
toluene 194
-
-
69
146
74
218
-
-
9[e]
10[e,f]
>20:1 >99
>20:1 >99
>20:1 >99[g]
11[e,f]
88
a)
Unless otherwise noted, the reaction was carried out by
using 0.1 mmol of 3a, 1.5 equiv of 2a, and 20 mol % of
catalyst in 0.5 mL of solvent at rt (26-28℃)for indicated
b)
c)
time.
analysis.
Isolated yields.
Determinated by crude NMR
d)
e)
Determinated by chiral HPLC analysis. 15
mol % of catalyst was used. f) 0.25 mL of toluene. ee of
g)
Scheme 2. Catalysts evaluated in this study.
ent-4a.
To our delight, the reaction proceeded smoothly
after 42h and afforded the desired product 4a in 92%
isolated yield, with exclusive γ-site- and Z-
selectivities, and with excellent diastereoselectivity
(>20:1) and enantioselectivity (>99% ee). Urea
catalyst 1b also reacted well with isatin 3a, but
resulted in lower product yield (56%) and longer
reaction time (218h) (Table 1, entry 2). Squaramide
1c and sulfonamide 1d proved unproductive and
afforded only trace amount of product 4a (Table 1,
entries 3-4). The screening of several polar and apolar
solvents such as CH2Cl2, THF, CH3CN, and DMF
showed longer reaction time or lower product yield
outcomes as compared to reactions conducted in
toluene (Table 1, entries 5-8). Lowering the amounts
of catalyst 1a resulted in slightly increasing the yield
(98% yield) and no enantioselectivity erosion
although the reaction time was also increased (Table
1, entry 9). Increasing the reaction concentration
from 0.2M to 0.4M shortened the reaction time
without any disruption of yield, diastereoselectivity,
and enantioselectivity (Table 1, entry 10). Finally, the
optimal conditions were chosen by conducting the
With the optimal conditions established, we next
explored the general substrate scope of both acyclic
3-alkylidene oxindoles 2 and isatins 3. As shown in
Table 2, all reactions genereally proceeded well to
deliver the corresponding spirooxindole δ-lactones in
good to high isolated yields, with excellent levels of
γ-site selectivities, enantioselectivities and diastereo-
selectivities. The effect of different of N-substituted
isatins was first investigated. N-methyl, N-ethyl, and
N-allyl substituted isatins all showed good tolerance
to this cascade reaction and gave the products 4b-d in
excellent yields, diastereoselectivities and enantio-
selectivities although the dr value of 4d is lower
compared to others (Table 2, entries 2-4). To our
delight, it was found the unprotected isatin 3e also
took part into the cascade reaction and deliver the
product 4e in 99% yield, >20:1 diastereoselectivity
and 83% ee (Table 2, entry 5). Basically, the position
and the electronic properties of the aromatic ring
substituent, regardless of electron-donating or
electron-withdrawing groups, did not alter the
reaction performance significantly (Table 2, entries 6-
13).
2
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10.1002/adsc.201701104
Advanced Synthesis & Catalysis
Table 2. Substrate scope examination.[a]
Entry
R1
R2
R3
2
PG
4
Time [h]
Yield [%][b] dr[c]
ee [%][d]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
H
H
H
H
Bn
Me
Et
Allyl
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
70
62
28
48
90
72
71
93
69
69
62
38
128
20
13
92
93
93
96
93
99
83
78
70
75
70
99
82
99
99
99
99
>20:1
>20:1
>20:1
9:1
>20:1
>20:1
11:1
6:1
10:1
7:1
>20:1
>20:1
10:1
>20:1
>20:1
>20:1
>99
84
92
92
82
>99
96
>99
92
97
94
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
H
5-F
7-F
5-Cl
6-Cl
5-Br
5-Me
5-OMe
5-NO2
H
9
10
11
12
13
14
15
16
99
H
>99
>99
>99
73
5-F
6-Cl
H
H
H
a) Unless otherwise noted, the reaction was carried out by using 0.1 mmol of 3a, 1.5 equiv of 2a, and 15 mol % of catalyst
b)
c)
d)
in 0.25 mL of solvent at rt (26-28℃)for indicated time. Isolated yields. Determinated by crude NMR analysis.
Determinated by chiral HPLC analysis.
However, the halogen-substituted isatins 3g-j gave
After studying the reaction with isatins and
the product 4g-j in excellent enantioselectivities, but oxindoles with acyclic substituents, we focused our
slightly reduced product yields and diastereo- attention in the use of various cyclic ring-substituted
selectivities (Table 2, entries 7-10). Variation of the oxindoles as nucleophiles in this cascade reaction.
alkylidene donors was then surveyed in reactions with This reaction could be extended to the construction of
isatin 3a (Table 2, entries 14-15).
The 5-F substituted oxindole 2b and 6-Cl substituted potential scaffolds to medicinal chemistry.[1]
oxindole 2c were found to be compatible and We initiated our studies by evaluating the cascade
polycyclic spirooxindole δ-lactones, which were
competent substrates in this cascade reaction and reaction of oxidole 2e and isatin 3a in our optimized
afforded the spirooxindole δ-lactones 4n-o in conditions. To our disappointment, the desired
excellent
yields,
diastereoselectivities
and product 5a was obtained in low enantioselectivity
enantioselectivities.
although the yield and diastereoselectivity were
We then turned our attention to the vinylogous satisfied (Table 3, entries 1). However, the
aldol-cyclization cascade reaction of 3-alkylidene enantioselectivity (69% ee) was improved drama-
oxindoles bearing a phenyl substituent at the β- tically when the reaction was conducted in
position with isatin 3a. The alkylidene derivative (E)- dichloromethane (Table 3, entries 2). Examination of
2d, prepared according the literatures,[10] could also other cinchona-alkaloid bifunctional organocatalysts
be productively engaged in this asymmetric showed the catalyst 1c gave the highest
transformation, and delivered the corresponding enantioselectivity with excellent product yield and
product 4p with good results in terms of yield and diastereoselectivity (Table 3, entries 3-5). Intriguingly,
diastereoselectivity, albeit with modest enantio- the opposite enantiomer of 5a was obtained. The
selectivity (Table 2, entries 16).
reason for the enantioselectivity switch is still not
The unprotected oxindole, in contrast, delivered no clear. After screening of catalyst loadings, various
desired product. This indicated the occurrence of solvents and reaction temperature, the final optimal
intramolecular lactonization was probably due to an conditions were chosen by perfoming the reaction at
increasing reactivity of the oxindole ring by placing room temperature in CH2Cl2 with 15 mol% of catalyst
the Boc protecting group on nitrogen atom.
1c (Table 3, entries 6).
3
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10.1002/adsc.201701104
Advanced Synthesis & Catalysis
Table 3. Reaction conditions optimization.[a]
Entry Cat. Solvent
Time
[h]
Yield dr[c] ee
[%][b] [%][d]
99
1
2
3
4
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH3CN
CHCl3
Cl(CH2)2Cl 18
CH2Cl2
CH2Cl2
31
18
18
18
18
18
18
18
72
12
18
7:1 29
>20:1 69
>20:1 31
>20:1 93[e]
1a
1a
1b
1c
1f
1c
1c
1c
1c
1c
1c
1c
1c
1c
96
98
99
99
99
84
54
93
95
90
91
93
93
5
>20:1
6
6[f]
7[g]
8[h]
9
>20:1 93[e]
>20:1 89[e]
>20:1 88[e]
>20:1 93[e]
>20:1 91[e]
>20:1 92[e]
>20:1 94[e]
>20:1 87[e]
>20:1 90[e]
10
11
12
13[i]
24
24
14[j]
a)
Unless otherwise noted, the reaction was carried out by
using 0.1 mmol of 3a, 1.5 equiv of 2a, and 20 mol % of
catalyst in 0.5 mL of solvent at rt (20-22℃)for indicated
b)
c)
time.
analysis.
Isolated yields.
Determinated by crude NMR
d)
e)
Determinated by chiral HPLC analysis.
Opposite enantiomer. f)15 mol % of catalyst g) 10 mol % of
catalyst. h) 5 mol % of catalyst. i) 0℃. j) 10℃.
We then focused our attention on establishing the
scope with respect to both the cyclic ring-substituted
oxindoles 2e-l and isatins 3 (Scheme 3). Most isatins
with different N-protecting groups, electron-donating
and electron-withdrawing groups (5a-5k) were well
tolerated, obtaining high yields, good to high
diastereoselectivities (7:1 to >20:1) and good to high
enantiomeric excesses (83% to 96% ee), except for
products 5h (77% ee)and 5k (64% ee). The oxindoles
bearing a halogen substituent gave products 5l and
5m in excellent yields and enantioselectivities.
Remarkably, the oxindoles with different ring-size,
tetrahydropyran and piperidine substituents (2h-l)
were also worked well in this cascade reaction.
However, only oxindole 2k and 2l delivered the
products 5q and 5r in excellent yields (99%),
diastereoselectivities (10:1 and >20:1) and enantio-
meric excesses (98% and 99% ee).
The relative and absolute configurations of 4j and 5i,
bearing a Br atom, were unambiguously and
respectively determined as (C15R, C16S) and (C15S,
Scheme 3. Scope of the cascade reaction of cyclic ring-
substituted oxindoles: 0.1 mmol of 3, 1.5 equiv of 2, and
15 mol % of catalyst in 0.5 mL of CH2Cl2 at rt (20-22℃)for
16-18h. Isolated yields. Diastereomer ratios were
determinated by crude NMR analysis. Enantiomeric
C16R) configuration with a syn-structure by X-ray
[11]
crystallographic analysis (Figure 1).
The
[a]
configuration of the other products in Table 2 and
Scheme 3 were assigned by analogy assuming the
reactions retained a uniform stereochemical outcome.
excesses were determinated by chiral HPLC analysis. 30
mol% of catalyst.
4
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10.1002/adsc.201701104
Advanced Synthesis & Catalysis
stereochemistry of polycyclic spirooxindoles 5 went
through the same mechanistic pathway as 4.
However, the other possible dual activation model
proposed by Pápai[13] and Zhong[14] cannot be
excluded. The nucleophile is activated by the thiourea
group of the catalyst, while the protonated
quinuclidine nitrogen generated hydrogen bonding
with the isatins 3. The detailed mechanistic study of
this chemistry using DFT calculations is currently
underway in our laboratories.
Figure 1. Relative and absolute stereochemistry of
brominated products 4j (top) and 5i (bottom) were
determinated by single crystal X-ray analysis.
Figure 2. Possible transition states for stereochemistry.
To explain the detail stereochemistry outcome of
In summary, we have developed a highly region-,
this cascade reaction, a plausible transition model diastereo-, and enantioselective organocatalytic
utilizing Cinchona catalysts-promoted activation vinylogous aldol−cyclization cascade reaction of
models was proposed. As outlined in Figure 2, the prochiral 3-akylidene oxindoles to various substituted
quinuclidine base of the catalyst deprotonated the H isatins by using cinchona alkaloid bifunctional
atom from the γ-position of oxindoles 2 and generated organocatalysts. A broad range of enantioenriched
s-cis enolate through hydrogen bonding. Meanwhile, spirooxindole δ-lactones with vicinal quaternary and
the isatins 3 also developed hydrogen bonding with tertiary stereocenters could be smoothly synthesized
the thiourea moiety of the catalyst and finally two in good to excellent yields, high enantioselectivities
substrates were synergistically activated based on the and
diastereoselectivities.
Especially,
this
activation pathway proposed by Takemoto and methodology could be extended to the construction of
coworkers.[12] The stereochemistry of products 4 was complex polycyclic spirooxindole δ-lactones. We
speculatively determined in the first vinylogous aldol expect that these novel spirooxindole products
addition step. Through the close spatial proximity, the emerging from these studies will be valuable for
oxindole nucleophile, which the methyl group at the organic synthesis and pharmaceutical chemistry
γ-position and R3 were projected in trans geometry, communities.
preferably added to Si, Si-face trajectory of isatins 3
and afforded the spirooxindoles 4 with (C15R, C16S)
configuration and syn-conformation (Figure 2a). It is
Experimental Section
likely due to the steric repulsion between methyl
group and R3, the anti-conformation products were
the minor isomers observed in this cascade reaction
(Figure 2b). The X-ray crystallographic analysis
shows the configuration of 5 (C15S, C16R) were
opposite to spirooxindoles 4 and the conformation
(syn) were the same as 4. These results indicated the
Typical Procedure for the Enantioselective
Organocatalytic Vinylogous Aldol−cyclization
Cascade Reaction
To a solution of 3-alkylidene oxindoles 2 (0.15 mmol) and
catalyst 1a or 1c (0.015 mmol) in solvent was added isatins
3 (0.10 mmol) at room temperature until 3 was consumed
(determined by TLC). The reaction solution was
5
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10.1002/adsc.201701104
Advanced Synthesis & Catalysis
concentrated in vacuum and the crude was purified by
silica gel flash chromatography (Hexane/EA 5:1 to 3:1) to
afford the pure products 4 or 5. The enantiomeric ratio was
determined by HPLC on a chiral stationary phase. The
corresponding opposite enantiomers (ent-4) were obtained
by using catalyst 1e under the same reaction conditions.
Miao, W. Zhang, C. Sheng, Org. Lett. 2016, 18, 1028–
1031.
[4] For recent reviews, see: a) C. J. Douglas, L. E.
Overman, Proc. Natl. Acad. Sci. USA 2004, 101, 5363–
5367; b) J. Christoffers, A. Baro, Adv. Synth. Catal.
2005, 347, 1473–1482; c) B. M. Trost, C. Jiang,
Synthesis 2006, 369–396; d) O. Riant, J. Hannedouche,
Org. Biomol. Chem. 2007, 5, 873–888; e) M. Bella, T.
Gasperi, Synthesis 2009, 1583–1614.
Acknowledgements
We are grateful for financial support from Ministry of Science
and Technology, Taiwan (106-2113-M-033-006-MY2). We thank
the mass center of institute of chemistry, Academia Sinica for
HRMS measurement. We also acknowledge Mr. Ting-Shen Kuo at
department of Chemistry, National Taiwan Normal University for
X-ray crystallographic analysis.
[5] For 3-alkylidene oxindoles as a nucleophile, see: a) C.
Curti, G. Rassu, V. Zambrano, L. Pinna, G. Pelosi, A.
Sartori, L. Battistini, F. Zanardi, G. Casiraghi, Angew.
Chem. 2012, 124, 6304–6308; Angew. Chem., Int. Ed.
2012, 51, 6200–6204; b) G. Rassu, V. Zambrano, L.
Pinna, C. Curti, L. Battistini, A. Sartori, G. Pelosi, F.
Zanardi, G. Casiraghi, Adv. Synth. Catal. 2013, 355,
1881–1886; c) Q. Chen, G. Q. Wang, X. X. Jiang, Z. Q.
Xu, L. Lin, R. Wang, Org. Lett. 2014, 16, 1394–1397; d)
Y. Zhong, S. X. Ma, Z. Q. Xu, M. Chang, R. Wang,
RSC Adv. 2014, 4, 49930–49933; e) X. Xiao, H. Mei, Q.
Chen, X. Zhao, L. Lin, X. Liu, X. M. Feng, Chem.
Commun. 2015, 51, 580–583; f) Y. Liu, Y. Yang, Y.
Huang, X. –H. Xu, F. –L. Qing, Synlett, 2015, 26, 67–
72; g) J. Feng, X. Li, J. –P. Cheng, Chem. Commun.
2015, 51, 14342–14345. h) J. Feng, X. Li, J. –P. Cheng,
J. Org. Chem. 2017, 82, 1412–1419; i) J. Feng, X. Li, J.
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10.1002/adsc.201701104
Advanced Synthesis & Catalysis
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10.1002/adsc.201701104
Advanced Synthesis & Catalysis
UPDATE
Asymmetric Synthesis of Spirooxindole δ-
Lactones with Vicinal Tertiary and Quaternary
Stereocenters via Regio-, Diastereo-, and
Enantioselective Organocatalytic Vinylogous
Aldol− cyclization Cascade Reaction
Adv. Synth. Catal. Year, Volume, Page – Page
Jeng-Liang Han*, You-Da Cai, and Chia-Hao
Chang
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