Thiourea-Catalyzed Enantioselective Malonate Addition onto 3-Sulfonyl-3′-indolyl-2-oxindoles: Formal Total Syntheses of (-)-Chimonanthine, (-)-Folicanthine, and (+)-Calycanthine

Article abstract of DOI:10.1021/acs.orglett.8b02327

A general approach to bispyrroloindolines via a key thiourea-catalyzed addition of malonates to 3-sulfonyl-3′-indolyl-2-oxindoles is reported. The enantioselelective process is found to be highly effective (up to 94% ee), where a C-C bond formation leads

Full text of DOI:10.1021/acs.orglett.8b02327

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Thiourea-Catalyzed Enantioselective Malonate Addition onto
3‑Sulfonyl-3′-indolyl-2-oxindoles: Formal Total Syntheses of
(−)-Chimonanthine, (−)-Folicanthine, and (+)-Calycanthine
K. Naresh Babu, Avishek Roy, Manvendra Singh, and Alakesh Bisai*
Department of Chemistry, IISER Bhopal, Bhopal Bypass Road, Bhauri, Bhopal 462 066, Madhya Pradesh, India
S
* Supporting Information
ABSTRACT: A general approach to bispyrroloindolines via a key thiourea-catalyzed addition of malonates to 3-sulfonyl-3′-
indolyl-2-oxindoles is reported. The enantioselelective process is found to be highly effective (up to 94% ee), where a C−C
bond formation leads to the synthesis of a number of 2-oxindoles with an all-carbon quaternary stereocenter.
imeric cyclotryptamine alkaloids (1 and 2, Figure 1)
a wide range of cyclotryptamine alkaloids. In this communica-
tion, we report thiourea-catalyzed enantioselective addition of
malonate to 3-sulfonyl-3′-indolyl-2-oxindoles for a target-
oriented synthesis of bistryptamine alkaloids.
D
sharing vicinal all-carbon quaternary stereocenters,1,2 with
Our retrosynthetic strategy to synthesize the core structure of
1a,b is shown in Scheme 1. We envisioned that Overman
Scheme 1. Retrosynthetic Analysis of 1 and Our Hypothesis
Figure 1. Selected biscyclotryptamine alkaloids 1 and 2.
a labile C3a−C3a′ σ-bond (Figure 1), remain one of the most
fascinating targets that continues to attract tremendous
synthetic interest.3 Owing to their impressive biological
activities4 in addition to intriguing architecture, a number of
elegant total syntheses have been disclosed to date.5−9 Toward
these targets, Overman’s elegant dialkylation5 and sequenatial
Heck cyclizations for the bisaldehyde 3a intermediate6 and
Movassaghi’s Co(I)-promoted reductive dimerization reac-
tions7−9 have been explored to establish the vicinal all-carbon
quaternary stereocenters.
From 2012 onward, catalytic asymmetric approaches have
been reported to address the synthesis of vicinal all-carbon
quaternary stereocenters.10−15 These include Gong’s ene-
carbamate addition onto 3-hydroxy 2-oxindole,10a Zhang’s
indole addition onto isatylidene-3-acetaldehyde,11a Kanai and
Matsunaga’s Michael reaction of bisoxindole with nitro-
ethylene,11b Pd-catalyzed decarboxylative allylations independ-
ently by Trost12 and our group,13 and a recent Cu(II)-catalyzed
malonate addition by us.14 Despite these elegant reports, there is
a strong need to develop a catalytic enantioselective method
under “transition-metal-free” conditions, which allows access to
aldehyde 3a, which is an advanced intermediate for the total
synthesis of 1a−c and 2, could be obtained from compound 4,
which in turn could be accessed from a catalytic enantioselective
malonate addition onto 3-(3′-indolyl)-3-sulfonyl-2-oxindole 5.
It was envisioned that removal of sulfinate can be triggered by
catalytic thiourea to generate indol-2-ones 6.15,16
With the above hypothesis, it was decided to use 3-indolyl-2-
oxindoles with 3′-functionalized with a leaving group such as 3-
hydroxy (7a), 3-methoxy (7b), and 3-sulfonyl (5a) groups. At
the outset, we carried out the reaction using 1 equiv of 7a and 7b
independently with dimethyl malonate 8a (3 equiv) in 1.5 mL of
toluene at 25 °C in the presence of 10 mol % of thiourea17,18 L1
with 1.2 equiv of K2CO3, however, without any success (Table 1,
entries 1 and 2). Interestingly, changing the substrate from 7a,b
Received: July 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02327
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Letter
Table 1. Optimization of Enantioselective Malonate Addition
a
b
c
entry
7a,b, 5a
8a−f
solvent
PhMe
base
time (h)
yield % (4a−f)
% ee (4a−f)
d
1
2
3
4
5
6
7
8
7a
7b
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
8a
8a
8a
8b
8c
8d
8e
8f
8d
8d
8d
8d
8d
8d
8d
8d
8d
8d
8d
8d
8d
8d
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
DBU
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
34
30
28
32
28
29
28
28
27
25
30
25
30
28
31
29
34
36
20
35
35
34
-- (4a)
-- (4a)
ND
ND
21
25
34
86
38
60
74
28
32
94
15
35
51
47
66
ND
82
84
56
ND
d
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
1,4-dioxan
CH2Cl2
(CH2Cl)2
CHCl3
PhMe
PhMe
PhMe
64 (4a)
68 (4b)
67 (4c)
72 (4d)
73 (4e)
70 (4f)
78 (4d)
83 (4d)
54 (4d)
85 (4d)
60 (4d)
69 (4d)
60 (4d)
63 (4d)
54 (4d)
23 (4d)
67 (4d)
36 (4d)
59 (4d)
15 (4d)
9
10
11
12
13
14
15
16
e
17
f
d
d
18
19g
20
21
22
PhMe
PhMe
PhMe
a
Reactions were carried out using 0.04 mmol of 5 or 7 (1 equiv) with 0.12 mmol of dialkylmalonate 8 (3 equiv) in 1.5 mL of toluene at room
b
c
temperature under argon conditions. Isolated yields after column chromatography. Enantioselectivities were determined using chiral HPLC.
d
e
f
g
Enantioselectivity not determined. At 0 °C. At −10 °C. At 40 °C.
to 5a furnished product 4a in 64% yield with 21% ee in 28 h
(entry 3).10b
Among various catalysts, it was observed that the cinchonine-
derived thiourea L2 afforded product 4d in 68% yield (22 h)
with 83% ee (Scheme 2). Cinchonidine-derived thiourea L3
afforded product 4d in 79% yield (26 h) with −82% ee, whereas
quinine-derived thiourea L4 afforded product 4d in 81% yield
(25 h) with −92% ee. Gratifyingly, we observed that 94% ee of
(+)-4d could be achieved by performing the reaction using L1
(quinidine-derived thiourea) catalyst in toluene at rt (Scheme
2). It was also found that other catalysts (L5−L10) are not
suitable for the malonate addition reaction.
Under the optimized condition [0.04 mmol of 5 (1 equiv), 10
mol % of L1 (0.004 mmol), 1.1 equiv of K3PO4 (0.044 mmol),
and 3.0 equiv of dibenzyl malonate (0.12 mmol) in toluene], we
tested the substrate scope using various N-substituted electro-
philes19 (Scheme 3) to afford 4d,g−k in good yield and
enantiomeric excess. Further, we have utilized 3-(3′-indolyl)-3-
sulfonyl-2-oxindole substrates 5 having different functional
groups on the aromatic ring of indole and 2-oxindoles. As shown
in Scheme 3, our optimized conditions could be extended to a
variety of 3-(3′-indolyl)-3-sulfonyl-2-oxindoles of type 5 with
functionalization on both scaffolds, namely, 2-oxindole as well as
Among various malonates tested (8a−d), dibenzyl malonate
afforded product 4d in 72% yield with 86% ee in 29 h (entry 6).
The high enantioselectivity arises probably through a stabilizing
π−π interaction between the aromatic ring-sharing electron-
withdrawing group of the substrate with that of dibenzyl
malonate in the transition state during the course of this
reaction. On the other hand, a drop in enantioselectivity was also
observed in the reaction of electronegative groups on the 4-
position of the phenyl ring of dibenzyl malonate, which can
weaken the π−π interaction with the substrate (entries 7 and
8).18
Among various bases (entries 8−12), potassium phosphate
was found to be superior, which afforded 4d in 85% yield (25 h)
with 94% ee (entry 12). Among various solvents screened
(entries 12−16), the reaction is efficient in toluene (entry 12) to
afford a high yield of 4d with better enantioselectivity (94% ee).
Further, decreasing the temperature of reaction affects the yields
as well as enantioselectivity (entries 17 and 18). The same
observation was made at higher temperature, as well (entry 19).
B
DOI: 10.1021/acs.orglett.8b02327
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a b
,
Scheme 2. Optimization of Malonate Addition onto 5a
Scheme 3. Substrate Scope Using Various N-Substituted
a b
,
Electrophiles
a
Reactions were carried out using 0.04 mmol of 5 (1 equiv) with 0.12
mmol of dialkylmalonate 8d (3 equiv) in 1.5 mL of toluene at room
b
temperature under argon conditions. Isolated yields after column
chromatography.
the indole part of 5. As a result, a wide range of 3-(3′-indolyl)-3-
malonyl-2-oxindoles bearing all-carbon quaternary centers at the
pseudobenzylic position are obtained in good to excellent
enantioselectivities with high yields (4m−s; Scheme 3).
Surprisingly, it was observed that reactivity and enantioselectiv-
ity decreased in case of N,N-unprotected 3-indolyl-3-sulfonyl-2-
oxindole 5g and N-methylindole substrate 5o with dibenzyl
malonate addition under standard conditions (Scheme 4, 4l and
4t).
a
Reactions were carried out using 0.04 mmol of 5 (1 equiv) with 0.12
mmol of dialkylmalonate 4d (3 equiv) in 1.5 mL of toluene at room
b
temperature under argon conditions. Isolated yields after column
chromatography.
A plausible rationale of organocatalyzed activation of 3-
sulfonyl-3′-indolyl-2-oxindole (5a) with malonate is shown in
Figure 2. Thiourea catalyst can activate 5a in the presence of
potassium phosphate base to form a planar intermediate 2-H-
indol-2-one 6 by removal of 1 equiv of p-toluenesulfinate. There
are two forms of intermediate 6, that is, 6a and 6b (6b stabilized
by electron-rich indole at the 3-position of 2-oxindole).
Malonate can be activated by thiourea catalyst via H-bonding.18a
At the same time, intermediates 6a,b will be activated through
H-bonding by a protonated quinuclidine moiety20,21 (Figure 2).
Therefore, an organized transition state will emerge from these
stabilizing interactions. At this stage, the enolate form of
dibenzyl malonate can react with intermediates 6a,b from the
above face, leading to the formation of (R)-4.
After successful synthesis of various enantioenriched
oxindoles, we proceeded to apply the method for enantiose-
lective synthesis of dimeric cyclotryptamine alkaloids sharing
vicinal all-carbon quaternary stereocenters. Thus, we began with
2-oxindole malonate adduct 4d (94% ee) and 4g (92% ee)
(Scheme 5). Toward this end, we carried out Krapcho
debenzylative decarboxylation of one of the benzyl esters’
functionality with LiCl at increased temperature to form 10a,b
in 85−90% yields, which was alkylated using methyl iodide and
benzyl bromide to 11a,b in 84−90% yields (Scheme 5). Later,
the indole functionality of 11a was converted to 2-oxindole by
reaction with DMSO (HCl) in AcOH at 50 °C to form 12a in
Scheme 4. Malonate Addition on N,N-Unprotected and
Protected 3-Indolyl-3-sulfonyl-2-oxindole
86% yield with ∼1.66:1 dr. However, a similar reaction with 11b
was unsuccessful. Therefore, compound 11b was converted to
11c by trans-esterification using ethyl bromide in DMSO in the
presence of NaH. Compounds 11a and 11c were reacted with
DMSO (HCl) in AcOH at 50 °C to form 12a,b in 79−86% yield
with ∼1.25:1 dr. At this stage, C-alkylation of 2-oxindoles of
12a,b with bromoethyl acetate afforded bisesters 13a,b in 78−
82% yields with >20:1 dr (Scheme 5).
Later, bisesters 13a,b were reduced with LiBH4 to form C2-
symmetric diols 14a,b in 79−82% yields. As the total synthesis
of 1b is known from C2-symmetric diol 14a, our effort
culminated in the formal total synthesis of (−)-folicanthine
1b.13b The absolute configuration of the stereogenic center in
compound 4d was determined to be R on the basis of optical
C
DOI: 10.1021/acs.orglett.8b02327
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Organic Letters
Letter
indolyl-2-oxindoles 5 followed by an enantioselective malonate
addition. Utilizing the aforementioned methodology, we have
shown the formal total syntheses of (−)-chimonanthine (1a),
(−)-folicanthine (1b), and (+)-calycanthine (1c). Further
investigation on synthetic applications of our method is
currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02327.
Experimental procedures, spectroscopic data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: alakesh@iiserb.ac.in.
ORCID
Figure 2. Stereochemistry rationale.
Scheme 5. Formal Total Synthesis of (−)-1a, (−)-1b, and
(+)-1c
Alakesh Bisai: 0000-0001-5295-9756
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the DST [EMR/2016/000214], CSIR
[02(0295)/17/EMR-II], and MoES [09-DS/11/2018-PC-IV],
Govt. of India, is gratefully acknowledged. K.N.B. thanks the
CSIR for SRF. A.R. and M.S. thank IISER Bhopal for research
fellowships.
DEDICATION
■
This work is dedicated to Professor Javed Iqbal, Chairman &
Founder, Cosmic Discoveries Pvt. Ltd., Hyderabad, India.
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