Organo-Cation Catalyzed Asymmetric Homo/Heterodialkylation of Bisoxindoles: Construction of Vicinal All-Carbon Quaternary Stereocenters and Total Synthesis of (-)-Chimonanthidine

Article abstract of DOI:10.1021/jacs.8b05386

A novel chiral spirocyclic amide (SPA)-derived triazolium organocatalyst has been designed and demonstrated to effect asymmetric homo- and heterodialkylations of various bisoxindoles, enabling enantioselective construction of vicinal all-carbon quaternary stereocenters. These reactions feature excellent enantio- and diastereoselectivities (up to 99% ee and >20:1 dr) as well as good to high yields (up to 89% over two steps). As an application of this methodology, the first asymmetric total synthesis of (-)-chimonanthidine has been achieved.

Full text of DOI:10.1021/jacs.8b05386

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Communication
Organo-Cation Catalyzed Asymmetric Homo/Hetero-Dialkylation
of Bisoxindoles: Construction of Vicinal All-Carbon Quaternary
Stereocenters and Total Synthesis of (–)-Chimonanthidine
Si-Kai Chen, Wen-Qiang Ma, Zhi-Bo Yan, Fu-Min Zhang, Shao-
Hua Wang, Yong-Qiang Tu, Xiao-Ming Zhang, and Jin-Miao Tian
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05386 • Publication Date (Web): 01 Aug 2018
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Organo-Cation Catalyzed Asymmetric Homo/Hetero-Dialkylation of
Bisoxindoles: Construction of Vicinal All-Carbon Quaternary Stere-
ocenters and Total Synthesis of (–)-Chimonanthidine
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Si-Kai Chen,† Wen-Qiang Ma,† Zhi-Bo Yan,† Fu-Min Zhang,† Shao-Hua Wang,† Yong-Qiang Tu,*,†,‡
Xiao-Ming Zhang,† and Jin-Miao Tian‡
†State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou Universi-
ty, Lanzhou 730000, P. R. China.
‡School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
Supporting Information Placeholder
Scheme 1. Representative HPI alkaloids and our designed
synthetic strategies
ABSTRACT: A novel chiral spirocyclic amide (SPA)-derived
triazolium organocatalyst has been designed and demonstrated to
effect asymmetric homo and hetero dialkylations of various bisox-
indoles, enabling enantioselective construction of vicinal all-
carbon quaternary stereocenters. These reactions feature excellent
enantio- and diastereo-selectivities (up to 99% ee and >20:1 dr),
as well as good to high yields (up to 89% over two steps). As an
application of this methodology, the first asymmetric total synthe-
sis of (–)-chimonanthidine has been achieved.
A large number of natural dimeric and oligomeric hexahydro-
pyrroloindole (HPI) alkaloids (including homo- and hetero- types,
Scheme 1) exhibit important biological activities, such as antifun-
gal and cytostatic properties.1 Structurally, these molecules usual-
ly incorporate a couple of sterically hindered vicinal all-carbon
quaternary stereocenters at C3a and C3a′, which is regarded as “a
daunting challenge” from an organic synthesis perspective.2-7 In
fact, the catalytic asymmetric construction of this congested motif
is so difficult that only limited synthetic methodologies have been
documented so far, namely, the double Michael addition6c and the
double decarboxylative allylation.6f,6i Furthermore, these reported
approaches do not always give both high yield and diastereoselec-
tivity, and they are only applicable to synthesis of the homo-type
alkaloids. As a result, there is a great need for a more efficient and
versatile catalytic asymmetric dialkylation methodology (as illus-
trated in Scheme 1) to approach this motif.
dialkylation. Based on our successful SPD (spirocyclic pyrroli-
dine) catalysis11 together with a linear trazolium catalysis for
mono-alkylation of 2-oxindoles.8h,9b,9f,12 Herein, we describe a
novel type of SPA (spirocyclic amide)-triazolium cationic catalyst,
with which we have successfully carried out both homo- and het-
ero- asymmetric dialkylation of bisoxindoles and completed the
first asymmetric total synthesis of natural (–)-chimonanthidine.
Our investigation began with the design and preparation of sev-
eral novel SPA-triazolium bromide catalysts (Cat 1–6, Table 1),
and we confirmed their absolute conformations by X-ray diffrac-
tion of Cat 4.13 Bisoxindole 2a and the commercially available
benzyl bromoacetate 3a were then selected as model substrates to
investigate the organocatalytic asymmetric dialkylation. After
extensive screening of various solvents, bases and additives,13 the
anticipated homo-dialkylated product 4aa was obtained with a
good result under the catalysis of 3 mol% Cat 1 (entry 1, 74%
yield, 93% ee, 12.6:1 dr). Although other catalysts (Cat 2–6) were
also able to catalyze this reaction (entries 2–6), inferior results
were generally obtained. Notably, the N-methyl substituted Cat 6
gave the worst enantioselectivity (-6% ee, entry 6), indicating that
the presence of the N-proton of SPA- type catalysts was essential
for generation of stereoselection during this asymmetric reaction.
In past decades, tetraammonium, triazolium salts and related
organic cationic catalysts have been demonstrated to be powerful
in the mono-alkylation of 2-oxindoles.8,9 However, they have
rarely been reported to enable the dialkylation of bisoxindole. A
possible reason is due to the increased steric interaction between
C3a and C3a′ during the second alkylation.3 This interaction could
lead to unexpected side reactions, such as diastereoisomeric alkyl-
ation and cleavage of the C3a-C3a′ bond, resulting in low stereose-
lectivity or chemical yield.10 Another challenge facing this meth-
odology is accessing the hetero-type of dialkylation (Scheme 1),
which requires a good enough match of the reactivity and stereo-
controllability of two different electrophiles (R3Br and R4Br).
Therefore, design of a robust and effective catalytic system to
address these challenges is crucial for facilitating this asymmetric
After establishing the optimal Cat 1 and experimental proce-
dure, we expanded electrophiles R3Br toward the homo-
dialkylation of 2a. The results are listed in Table 2 and showed
that three groups of electrophiles I–III (Group I: benzyl bromo-
acetate esters 3a–i, Group II: alkyl bromoacetate esters 3j–l and
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Table 1. Optimization of homo-dialkylation conditionsa
ry results in most cases (entries 1–14). In Group I, all electro-
1
2
3
4
5
6
7
8
philes 3a–i (entries 1–9) could react smoothly to give high enanti-
oselectivity (88–95% ee) as well as good chemical yield (63–
89%). Notably, the electronic properties of substituents at the
benzyl moieties of these electrophiles showed certain influences
on reaction outcomes, with the 4-F-benzyl ester 3g giving the best
result (entry 7). For Group II (entries 10–12), a steric influence of
the alkyls on reaction efficiency was evident. For example, the
small methyl ester 3j could react to provide 4aj in only 2 days
with excellent stereoselectivity (entry 10), whereas a bulkier ethyl
ester 3k needed a much longer reaction time of 10 days (entry 11).
Moreover, when the much bulkier t-butyl ester 3l was applied to
this system, the desired product 4al was undetectable (entry 12).
The allylic electrophiles 3m and 3n in Group III were also viable
for this reaction, however providing the results in inconformity.
3m reacted to give high ee and yield (entry 13), while 3n generat-
ed high dr and yield (entry 14).
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entry
Cat.
ee (%)b
yield (%)c
drc
1
2
3
4
5
6
Cat 1
Cat 2
Cat 3
Cat 4
Cat 5
Cat 6
93
86
78
86
91
-6
74
61
15
21
30
26
12.6:1
6.4:1
1.5:1
1.9:1
3.0:1
0.5:1
Table 3. Investigation of bisoxindoles for homo-
dialkylationa
aReactions were conducted with 2a (0.0646 mmol, 1 equiv),
3a (4 equiv), catalyst (3 mol%), DMSO (20 μL) and K2CO3 (6
b
c
equiv) in 3 mL toluene. Determined by chiral HPLC. Deter-
mined by 1HNMR.
Table 2. Investigation of electrophiles for homo-
dialkylationa
entry
R1
R2
product ee (%)b Y (%)c
drd
1
2
3
4
5
6
7
8
9
C7a-Me
C7a-Br
C7a-Cl
C7a-F
C7a-CF3
C6a-OMe
C6a-Br
C6a-Cl
C6a-F
H
H
H
H
H
H
H
H
H
H
H
H
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
99
95
99
97
96
89
98
97
97
87
90
94
41
70
82
85
60
57
58
65
68
47
52
58
> 20:1
> 20:1
> 20:1
12.9:1
> 20:1
5.6:1
15.6:1
12.6:1
12.5:1
8.6:1
4ja
4ka
4la
10 C5a-OMe
11
12
C5a-Me
C5a-Cl
8.7:1
12.9:1
entry R3Br (3) product (4)b ee (%)c yield (%)d
dre
4ma
C5a-Me
C7a-Me
13
H
4na
96
46
16.9:1
1
2
3
4
5
6
7
8
9
10
11f
12
13h
14i
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4aj
4ak
4al
4am
4an
92
95
90
93
93
91
94
89
88
95
90
-
70
63
66
64
69
85
89
86
73
62e
81
NDg
82
12:1
12.4:1
9.5:1
11.3:1
11.5:1
12.5:1
11.9:1
12.8:1
11:1
11.9:1
8.9:1
-
2.1:1
> 20:1
14
15
16
17
C5a-Me C5a′-Cl
C7a-Me C5a′-Cl
C5a-Me C5a′-Me
C6a-Cl C6a′-Cl
4oa
4pa
4qa
4ra
92
98
95
92
92
53
68
67
85
78
> 20:1
9.6:1
> 20:1
7.1:1
18:1
18e C5a-OMe C5a′-OMe 4sa
aUnless otherwise specified, reactions were conducted with 2
(0.0646 mmol, 1 equiv), 3a (4 equiv), Cat 1 (3 mol%), K2CO3
b
c
(6 equiv) in 3 mL toluene. Determined by chiral HPLC. Iso-
lated yields. dDetermined by 1HNMR. eWith DMSO (20 μL).
Next, a wide range of bisoxindoles 2 with various mono- and
di- substituents on aromatic rings were investigated using 3a as
the electrophile. As summarized in Table 3, a wide range of sub-
strates tolerated to this reaction with high enantioselectivity and
good to high yields. For mono-substitution at C5a, C6a or C7a, the
EWGs (electron-withdrawing group) substitutions (entries 2–5,
7–9, and 12) were generally favorable and gave the excellent re-
sults (58–85% yield, 94–99% ee, 12.5:1 to > 20:1 dr) over the
EDGs (electron-withdonating group) substitutions (41–57% yield,
87–99% ee, 5.6:1 to > 20:1 dr, entries 1, 6, 10, and 11). However,
a C4a-Cl substituted substrate could not give the desired product
but only resulted in a complex mixture, probably due to its steric
shielding over the reaction sites (C3a or C3a′). In the case of disub-
90
46
89
aUnless otherwise specified, reactions were conducted with 2a
(0.0646 mmol, 1 equiv), 3 (4 equiv), Cat 1 (3 mol%), DMSO
(20 L), K2CO3 (6 equiv) in 3 mL toluene. bAbsolute configu-
c
rations were assigned by X-ray of 4aj. Determined by chiral
HPLC. dIsolated yields. eDetermined by 1HNMR. fReacted for
10 days. gNot detected. hReacted for 24 h without DMSO.
iReacted for 48 h without DMSO.
Group III: allylic bromides 3m and 3n) worked well to generate
the expected homo-dialkylation products 4aa–4an with satisfacto-
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stituted substrates (entries 13–18), both unsymmetrical (entries
Scheme 2. Rationale for stereo-control
1
2
3
4
5
6
7
8
13–15) and symmetrical (entries 16–18) disubstitutions were ef-
fective in this reaction, affording excellent enantioselectivities
(92–98% ee), good to high diastereoselectivities (7.1:1 to > 20:1
dr) as well as moderate to good yields (46–85%). Similar to the
mono-substitutions, the electronic properties of disubstitutions
also had a significant influence on the reaction outcome. For ex-
ample, the dichloride substituted substrate reacted quickly to pro-
duce the corresponding product 4ra with a high yield of 85% and
92% ee (entry 17), while the dimethoxy substituted substrate pro-
duced a poor result (33% yield, 98% ee, and > 20:1 dr) and re-
quired further improvement by the addition of DMSO as a polar
co-solvent to generate 4sa with better efficiency (78% yield, 92%
ee, 18:1 dr, entry 18). Importantly, the products 4ca and 4da with
Br and Cl at C7a were valuable for the synthesis of more complex
trimeric HPI alkaloids via C-C coupling and further transfor-
mations.1,4
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N-H moiety showed poor stereoselectivity, both a hydrogen bond-
ing and an ion-pairing interaction between Cat 1 and the enolate
might exist during each alkylation steps. Presumably due to the
steric hindrance of the adamantyl group, nucleophilic attack of the
intermediate toward the electrophile from the back face was unfa-
vorable, thus leading to the formation of the major (S, S)-
dialkylated product.
Table 4. Investigation of hetero-dialkylation of 2aa
Scheme 3. Total synthesis of (–)-chimonanthidine (1c)
aUnless otherwise specified, reactions were conducted in one-
pot: 2a (0.0646 mmol, 1 equiv), R3Br (1 equiv), Cat 1 (3
mol%), K2CO3 (2 equiv) in 1 mL toluene, then, R4Br (3
equiv), DMSO (20 μL), and K2CO3 (4 equiv), toluene (2 mL);
Isolated yields; ee determined by chiral HPLC; dr determined
by 1HNMR. b2 equiv R4Br and 1 equiv K2CO3 without DMSO
in the second step.
To verify the efficient utility of catalytic asymmetric dialkyla-
tion strategies established above, we carried out a formal synthe-
sis of (–)-folicanthine (1a)14 and the first asymmetric total synthe-
sis of (–)-chimonanthidine (1c) (Scheme 3).15 A major challenge
in the synthesis of 1c was to selectively protect only one N-H with
a methyl group at two pyrrolidine rings, which could be easily
addressed using the hetero-dialkylation product 5c (prepared in
gram-scale reaction13 and at > 99% enantio-purity after recrystal-
lization) as the key intermediate. Accordingly, the key building
block 7 was efficiently obtained from 5c in a one-column purifi-
cation with an 81% overall yield, in which a regioselective reduc-
tive amination/cyclization of oxindole moiety was achieved. The
subsequent oxidative cleavage of the C=C bond of olefin 7 fol-
lowed by reductive benzylamination yielded product 9. Another
reductive amination/cyclization of 9 formed the second pyrroli-
dine ring of 10. Selective removal of the benzyl protecting group
of 10 by Pd(OH)2/C-catalyzed hydrogenolysis completed the
asymmetric total synthesis of (–)-1c.
Having accomplished the homo-dialkylation of bisoxindoles,
we then investigated the more challenging one-pot hetero ap-
proach with two different electrophiles R3Br and R4Br (Table 4).
Initially we tested the mono-alkylation of 2a with only one equiv-
alent of 3a under the catalysis of Cat 1 (3 mol%). The chemose-
lectivity was satisfactory and the mono-alkylation product was
observed in about 85% yield with no dialkylation product detected.
In light of this observation, we then added 3g to the reaction sys-
tem after 2a disappeared. This resulted in the generation of the
desired hetero-dialkylation product 5a in 54% yield, 96% ee and
10.7:1 dr. Encouraged by this outcome, more hetero dialkylation
reactions were conducted using different electrophiles R3Br and
R4Br, all producing the expected hetero-products 5b–f with ac-
ceptable results. In particular, 5c–f could be used as key interme-
diates in the synthesis of complex hetero HPI alkaloids because of
the distinct reactivity between R3 and R4 which facilitates late-
stage transformation.1,4
In conclusion, we have successfully developed the SPA-
triazolium cation catalyzed asymmetric homo- and hetero-
dialkylation of bisoxindoles. These reactions allowed the direct
construction of the challenging vicinal all-carbon quaternary ste-
reocenters in high efficiencies (up to 82% yield, 99% ee, > 20:1
dr). To our knowledge, this transformation is so far the most effi-
cient approach for assembling this congested unit. Additionally,
Despite the well-established alkylation sequence for triazolium
catalysis, the stereo-control of this reaction process needs to be
further considered, and thus a nucleophilic attack model (Scheme
2) for both mono- and di-alkylations was suggested, according to
the observed stereochemistry.13 Since Cat 6 without the amide
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synthesis of (–)-chimonanthidine (1c). The diverse synthesis of
other HPI alkaloids is ongoing in our group.
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ASSOCIATED CONTENT
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1307. (c) Chen, W.; Yang, W.; Yan, L.; Tan, C. -H.; Jiang, Z. Chem.
Commun. 2013, 49, 9854. (d) Deng, F.; Moteki, S. A.; Maruoka, K. Asian
J. Org. Chem. 2014, 3, 395. (e) Sorrentino, E.; Connon, S. J. Org. Lett.
2016, 18, 5204. (f) Ohmatsu, K.; Furukawa, Y.; Kiyokawa, M.; Ooi, T.
Chem. Commun. 2017, 53, 13113. (g) Craig, R.; Sorrentino, E.; Connon, S.
J. Chem. Eur. J. 2018, 24, 4528.
Experimental details (PDF)
X-ray data for compound Cat 4 (CIF)
X-ray data for compound 4aj (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: tuyq@lzu.edu.cn; tuyq@sjtu.edu.cn.
ORCID
Yong-Qiang Tu: 0000-0002-9784-4052
Fu-Min Zhang: 0000-0001-5578-1148
Shao-Hua Wang: 0000-0002-4347-8245
Xiao-Ming Zhang: 0000-0002-9294-9672
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We would like to thank NSFC (No. 21290180, 21372104,
21472077, 21772076, 21772071, and 21502080), the “111” Pro-
gram of MOE, and the fundamental research funds for the central
universities (lzujbky-2017-116, lzujbky-2018-134) for their finan-
cial support. Also, we would like to thank Prof. Chun-An Fan for
his great help in the mechanism study.
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