Chiral bifunctional bisphosphine enabled enantioselective tandem Michael addition of tryptamine-derived oxindoles to ynones

Article abstract of DOI:10.1039/c9cc04357h

A chiral phosphine-catalyzed tandem Michael addition of tryptamine-derived oxindoles to ynones has been developed, which provides facile access to a series of optically enriched spiro[pyrrolidine-3,3′-oxindole] compounds in good yields with good to excell

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Chiral Bifunctional Bisphosphine Enabled Enantioselective
Tandem Michael Addition of Tryptamine-Derived Oxindoles to
Ynones
Received 00th January 20xx,
Accepted 00th January 20xx
Tiantian Cong,a Huamin Wang,a Xiuzheng Li,c Hai-Hong Wu*a and Junliang Zhang*ab
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
chiral phosphine-catalyzed tandem Michael addition of Therefore,
various
methods6
(Mannich
reaction6g,
tryptamine-derived oxindoles to ynones has been developed, rearrangement reaction6j, Michael addition6h, etc), especially
which provide a facile access to a series of optically enriched in an asymmetric manner, have been undertaken for the
spiro[pyrrolidine-3,3’-oxindole] compounds in good yields with synthesis of this scaffold. However, among them, examples of
good to excellent enantio- (up to 97% ee) and up to 20:1 dr. asymmetric catalytic tandem Michael additions are rarely been
Mechanistic studies indicate that this tandem reaction proceeds studied7. In 2018, Liu, Feng and co-workers developed a chiral
via an intermolecular aza-Michael/intramolecular Michael guanidine-catalyzed asymmetric tandem double Michael
process.
additions of terminal alkynones and 3-substituted oxindoles7a
(Scheme 1A). Shortly after, Xie et al. presented a chiral N,N’-
dioxide Sc(OTf)3-catalyzed asymmetric formal [4+1] annula-
tion of tryptamine-derived oxindoles with alkynones to afford
the spiro[pyrrolidine-3,3’-oxindole] compounds in excellent
yield with high enantio- and diastereoselectivity7b (Scheme 1B).
Therefore, it is highly desirable to develop more efficient
double Michael additions method for directly asymmetric
synthesis of 3-spirooxindole alkaloids.
The 3-spirooxindole alkaloids have attracted particular interest
because they are frequently encountered in numerous
biologically active natural products1 and small-molecule phar-
maceuticals2. As shown in Figure 1, spirotryprostatins A and B3,
anticancer SAR4058384, APG-1155 and antimicrobial NITD6092c.
Figure 1. Spiro[pyrrolidine-3,3’-oxindole]s with biological activity
O
O
O
O
H
NH
A) chiral guanidine as the catalyst (Liu and Feng, 2018)
HN
HN
N
H
N
H
Ph
N
N
N
Ph
O
O
S
O
X
H
H
O
O
N
O
XH
HN
Ar
O
Chiral Guanidine
H
R2
MeO
MeO
H
N
R1
O
O
+
R1
R2
N
O
88-95% ee
up to > 19:1 dr
N
H
N
Spirotryprostatin A
spiro[pyrrolidine-3,3'-oxindole]
Spirotryprostatin B
Cy
H
Cy NH
X = O or NTs
Chiral Guanidine
CONH2
OH
COOH
B) chiral N,N'-dioxide/Sc(OTf)3 as the catalyst (Xie, 2018)
Cl
Cl
n
n
Cl
F
F
O
NPG
O
O
F
OMe
O
N
N
O
O
Sc(OTf)3
N,N'-dioxide ligand
NHPG
O
NH
NH
NH
NH
O
O
R2
R1
N
N
H
O
+
R2
R1
H
O
R
R
N
66-96% ee
up to 14:1 dr
Cl
NH
N
Cl
N
H
H
N,N'-dioxide ligand
N
Cl
N
O
H
O
H
N
O
C) chiral bifuntionalized monophosphine as the catalyst (Sasai, 2017)
H
SAR405838
RO8994
APG-115
NTs
O
NHTs
O
Chiral Phosphine
+
Ph
O
O
TsHN
PPh2
Ph
one example
84% ee
> 20:1 dr
N
N
chiral phosphine
Boc
Boc
D) chiral bifuntionalized bisphosphine as the catalyst (This work)
a.
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of
Chemsitry and Molecular Engineering, East China Normal University, 3663 N.
Zhongshan Road, Shanghai 200062, P. R. China. junliangzhang@fudan.edu.cn.
b. Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai
200438, P. R. China.
PG
Ph2
P
O
N
O
NHPG
O
CF3
Chiral Bisphosphine
R2
R1
N
H
PPh2
O
R2
+
R1
O
21 examples
80-97% ee
up to >20:1 dr
N
N
Boc
Boc
CF3
Chiral Biphosphine
c. School of Pharmacy, Anhui Medical University, 81 N. Meishan Road, Hefei
230032, P. R. China.
Scheme 1. The tandem Michael addition of tryptamine-derived oxindole with
ynone
†Electronic Supplementary Information (ESI) available: Experimental procedures;
spectroscopic date for substrates, and products. X-ray crystallographic data for 3y.
CCDC 1910673. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Over the past decade, asymmetric phosphine-catalyzed oxindole in 75% yield and 84% ee (Scheme 1C). InVcieownAtritniculeaOtniloinne
9
cyclization reactions8, involving ynones as diverse dipoles of our interest in asymmetric phosphiDnOeI:c1a0t.1a0l3y9s/isC9aCnCd04w35i7tHh
have been developed for preparing diverse chiral heterocycles. several efficient chiral phosphine catalysts in hand10, we
However, to the best of our knowledge, besides these ynones
wondered whether these catalysts could be applicable to this
asymmetric reaction. Herein, we report an enantioselective
double-Michael additions process between tryptamine-derived
oxindoles and ynones, for highly enantioselective synthesis of
functionalized 3-spirooxindole alkaloids, under the catalytic action
of bifunctional bisphosphine (Scheme 1D).
Figure 2. Phosphine catalysts employed in this study
Ph2P
Ph2P
Ph2P
Ph2P
O
O
S
O
S
O
S
CF3
N
H
N
t-Bu
N
H
PPh2
t-Bu
N
t-Bu
H
H
NPG O
OTBDS
O
NHPG
CF3
R2
P5
(20
P4
P1
Ph2P
P3
R1
P2
R1
R2
+
O
O
mol%)
4 Å MS
N
N
Ph2P
toluene, -65 o
C
Boc
Boc
Ph2P
O
O
O
1
2
3
CF3
CF
3 Et
CF3
N
N
H
N
H
NTs
O
H
NTs
O
NTs
O
O
Fe
Et
PPh2
CF3
O
CF3
CF3
O
P5
P6
P7
N
N
N
Me
Boc
Boc
Boc
Me
Ph2P
Ph2P
Ph2P
3a, 77% yield,
3b, 88% yield
3c, 70% yield
O
O
O
94% ee, > 20:1 dr
95% ee, > 20:1 dr
96% ee, > 20:1 dr
CF3
NHBoc
N
H
Ar
NHBoc
N
H
PPh2
N
NTs
O
NTs
O
NTs
O
H
Ph
CF3
O
O
O
Ar = 3,5-(t-Bu)2C6H3
N
N
N
Me
OMe
F
Boc
P9
Boc
Boc
P8
P10
3d
3e
3f
, 79% yield
, 60% yield
96% ee, > 20:1 dr
, 86% yield
94% ee, 3:1 dr
91% ee, > 20:1 dr
NTs
O
NTs
O
NTs
O
acting as C3 synthons when reacting with various electrophilic
coupling partners undergoing [3+2] annulations9g-h, rarely re-
ports on they employed as C1 synthons7c. In 2017, Sasai and
co-workers7c reported the first and only one example of
phosphine-triggered enantioselective domino process of
ynone with α-substituted oxindole which furnishes chiral spiro-
O
O
O
N
N
N
Br
I
CF3
Boc
Boc
3h
Boc
3g
3i
, 83% yield
88% ee, > 20:1 dr
, 79% yield
90% ee, > 20:1 dr
, 58% yield
47% ee, 4:1 dr
NTs
O
NTs
O
NTs
O
O
O
O
N
N
N
NO2
CN
Boc
Boc
3k
Boc
3j
3l
, 55% yield
29% ee, 2:1 dr
, 63% yield
34% ee, 5:1 dr
, 78% yield
96% ee, > 20:1 dr
Table 1. Optimization of reaction conditions
NTs
O
NTs
O
NTs
O
O
S
Me
NTs
O
O
O
O
O
N
N
N
NHTs
cat. (20 mol%)
additive
O
Boc
Boc
3n
Boc
3o
Ph
3m
, 80% yield
89% ee, > 20:1 dr
, 92% yield
90% ee, > 20:1 dr
, 85% yield
95% ee, 5:1 dr
+
O
Ph
solvent
N
N
Boc
Bc
-65 o
C
NTs
O
NTs
O
NTs
O
2a
(1.2 eq)
3a
1a
(0.1 mmol)
Me
Ph
Entry
1
2
3
4
5
6
7
8
Cat.
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
DCM
EA
toluene
toluene
toluene
Yield (%)a
68
ee (%)b
5
O
O
O
N
N
N
Boc
Boc
Boc
P1
P2
P3
P4
P5
P6
P7
P8
P9
P10
P5
P5
P5
P5
P5
P5
3p
3q
3r
, 85% yield
93% ee, > 20:1 dr
, 78% yield
97% ee, > 20:1 dr
, 75% yield
90% ee, 4:1 dr
70
63
75
75
72
65
80
57
72
72
66
70
trace
trace
77
-23
37
63
82
47
50
80
-17
80
69
57
51
--
NTs
O
NTs
O
NTs
O
CO2Me
Cl
Cl
Me
O
O
O
N
N
N
Boc
Boc
3t
Boc
3s
3u
, 80% yield
96% ee, > 20:1 dr
, 75% yield
90% ee, > 20:1 dr
, 75% yield
95% ee, 9:1 dr
NTs
O
NTs
O
NNs
O
Me
9
Ph
Ph
Ph
O
O
O
10
11
12
13
14d
15e
16f
N
N
N
Me
Boc
Boc
Boc
3v
3w
, 76% yield
83% ee, > 20:1 dr
3x
, 71% yield
80% ee, > 20:1 dr
, 78% yield
87% ee, 3.5:1 dr
NMs O
NSO2Ph
Ph
O
O
Ph
N
--
94
N
O
Boc
Boc
3y
, 65% yield
92% ee, > 20:1 dr
3z
, 92% yield
89% ee, > 20:1 dr
3y
aIsolated yields of major diastereomer. bDetermined by HPLC analysis using a
chiral stationary phase. cAt -30 oC. dAt 30 oC. e 4 Å MS was added.
Scheme 2. Substrate scope of catalytic asymmetric double-Michael additions.
2 | J. Name., 2012, 00, 1-3
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To begin our investigations, the tryptamine-derived oxindole delight, a variety of aliphatic alkynones can be employed as
View Article Online
DOI: 10.1039/C9CC04357H
1a and the ynone 2a were selected as model substrates for the reaction partner to provide the synthetically useful
o
this tandem Michael addition in toluene at -65 C. We initially spirooxindoles. Both linear and branched aliphatic alkynones
screened various chiral phosphine catalysts developed in our could react smoothly to furnish the desired 3o-3r in 78-85%
group10 (Figure 2). As summarized in Table 1, chiral yields with 90-97% ee. In addition, functional groups such as
sulfinamide phosphines XiaoPhos and WeiPhos (P1-P3) were phenyl, ester, and halogen were also well-tolerated, affording
ineffective and the desired annulation products were obtained in the desired products 3s-3t with very good enantioselectivity
very low enantioselectivities (Entries 1-3). The screening of other and diastereoselectivities. While the presence of 5-Cl, 5-Me, or
chiral phosphines (P4-P10) were then carried out (Entries 4-10). 6-Me in the oxindole rings led to the formation of the
Gratifyingly, bifunctional bisphosphine P5 was shown to be an annulation product 3u, 3v and 3w in 95% ee, 80% ee and 83%
effective catalyst, delivering the product in 82% ee and >20:1 dr ee, respectively. Replacing the tosyl group with nosyl,
(Entry 5). Further solvent screening and variation of temperature methanesulfonyl and benzenesulfonyl delivered 3x-3z in good
did not lead to clear improvements (Entries 11-15). The yields (65-92%) and slightly varied enantioselectivities (87% to
addition of 4 Å MS to the reaction mixture displayed a 92% ee). The absolute configuration of 3y was established by
favorable effect and delivered 94% ee (Entry 16).
With the established optimized reaction conditions in hand,
single crystal X-ray diffraction analysis (see the SI for details).
To gain mechanistic insight into this tandem reaction,
we next evaluated the substrate scope of this double-Michael several control experiments were carried out. When the Boc-
additions, and the results are summarized in Scheme 3. In protected oxindole 4 was used in this reaction, the Michael
general, aromatic moieties in the aryl ynones were well- addition at C3 of oxindole generated 5 as a mixture of Z/E
tolerated. Substituents such as methyl, methoxy and halogen isomer in 60% conversion (Z/E =1:1.4) (eq. 1). Then the
atoms, could be tolerated and gave the corresponding prod- deprotection of the Boc group of 5 delivered the product E-6
ucts 3b-3h with high to excellent enantioselectivities (Scheme and Z-6, which were subjected to standard conditions to
2, 88-96% ee) and diastereoselectivities (3:1 to >20:1 dr) in furnish product 3a' in low ee (eq. 2 and 3). The transformation
good yields (Scheme 2, 60-86%). The position of the process with aza-Michael addition product 7 occurred in the
substituent on the benzene ring had little effect on the presence of P5 and 2a, furnishing the corresponding product
stereoselectivity. However, ynones with electron-withdrawing 3a' in 70% yield with 93% ee and > 20:1 dr (eq. 4). These
substituents showed low reactivity and poor enantioselective results suggested that the [4+1] cyclization could be a step-
control, affording 3i−3k in 55-63% yield with 29-47% ee, wise
process
via
a
tandem
aza-Michael
indicating that the reactions for these substrates may undergo addition/intramolecular Michael addition reaction.
different reaction pathway. Moreover, 2-naphthyl- and
R3P*
heteroaryl derived ynone could also afford the desired
products 3l-3n in good yields with 89-96% ee as single
2
3
R1
1
R1
O
R3*P
A
R3*P
diastereoisomer. To our
O
NTs
O
A''
A''
Ph2
P
NTs
O
O
O
R1
R1
R3*P
CF3
Michael
addition
Ts
N
H
Boc
Boc
P*R3
O
A'
Ts
Ts
N
N
N
N
Boc
N
Boc
PPh2
Ph
O
Boc
B
P5
(20 mol%)
4Å MS
CF3
O
E
Ph
O

aza-Michael addition
+
+
R1
TsHN

(1)
Ph
toluene
-65 o
O
2
NTs
R1
O
O
O
C
P*R3
F3C
N
N
N
aza-Michael
addition
O
N
PPh2
Boc
Boc
Boc
O
60% conversion
TsHN
O
R1
R1
Ph2
P
N
B'
4
2a
E-5
Z-5
23% yield
[]D20 = 0.6
(c = 0.40, CHCl3)
O
Boc
O
N
A
H
O
Boc
R1
F3
C
32% yield
[]D20 = 0.8
(c = 0.32, CHCl3)
Michael
addition
O
D'
O
O
O
N
Ts
O
TsN
A"
N
Boc
C'
R1
R3P*
NBoc
O
N
TsN
Boc
Boc
Ts
Ts
R1
C
N
HN
T
S
-
Ph
Ph
A
Ts
P5
2a
(20 mol%)
(20 mol%)
4Å MS
N
O
O
N


O
O
1
D
Boc
CF3COOH
DCM
Ph
O
O
O
R1
(2)
toluene
N
N
N
-65 o
C
H
R3*P
Boc
E-5
H
O
A''
E-6
3a'
45% yield, 16% ee
Scheme 4. Proposed Mechanism.
1:1 d.r.
Ts
Ts
Boc
N
HN
Ts
N
O
Ph
Ph
P5
2a
(20 mol%)
(20 mol%)
4Å MS


Based on the above experimental results and previous
relevant studies8,7c, a possible transition state TS-1 to control
the stereoselectivity is proposed in Scheme 4. We infer that
the phosphonium enolate A generates from the addition of
O
O
O
Ph
CF3COOH
DCM
O
O
(3)
toluene
N
N
N
Boc
Z-5
H
H
-65 o
C
Z-6
3a'
36% yield, 29% ee
2.5:1 d.r.
O
TsN
O
Ts
phosphine catalyst to ynone. Phosphonium enolate
A
N
O
Ph
P5
2a
(20 mol%)
(20 mol%)
4 Å MS
Ph
deprotonates 1 to give the intermediate B, which undergoes
aza-Michael addition to give the intermediate C. Subsequently,
the phosphonium enolate A as a BrФnsted base catalyzes the
intramolecular Michael addition of intermediate D, leading to
the chiral spirooxindole products. An alternative possible
(4)
O
N
N
toluene
-65 o
H
H
C
3a'
7
70% yield
93% ee, > 20:1 dr
Scheme 3. Control experiments
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mechanism might be also reasonable (gray catalytic circle)7b.
The tandem Michael addition through intermolecular carbon-
Michael addition followed by intramolecular aza-Michael
addition would afford the desired spirooxindole. However,
control experiments observed that this tandem process would
lead to low stereoselective control. Therefore, we believed
that ynones 3i-3k with electron-drawing substituent might
undergo Michael addition/aza-Michael addition process which
may explain why the corresponding spirooxindoles were
obtained with lower ee value and dr value.
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7
8
Conclusions
We have investigated a highly enantioselective formal [4+1]
annulation reaction of terminal alkynones and 3-substituted
oxindoles via a tandem aza-Michael addition/Michael addition
sequence under the catalysis of
a chiral bifunctional
bisphosphine. A series of optically active spiro[pyrrolidine-3,3’-
oxindole] skeletons has been constructed efficiently in
moderate to high yields with high levels of enantio- and dia-
stereoselectivity (up to 97% ee and up to 20:1 dr). Further
study focusing on the asymmetric synthesis of other
heteroatom-containing ring systems catalyzed by this chiral
bisphosphine is currently pursued in our laboratory.
We are grateful to 973 Programs (2015CB856600), National
Natural Science Foundation of China (21425205, 21672067)
and Changjiang Scholars and Innovative Research Team in
University (PCSIRT) for financial supports.
9
Conflicts of interest
There are no conflicts to declare.
Notes and references
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC04357H
Insert Table of Contents artwork here
Ph2P
PG
O
N
O
NHPG
O
CF3
P5
20 mol%
N
H
PPh2
R2
R1
O
R2
+
R1
O
4 Å MS, toluene
N
-65 o
C
N
Boc
CF3
Boc
P5
26 examples
up to 92% yield, 97% ee
> 20:1 d.r.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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