Asymmetric vinylogous mannich reaction of silyloxy furans with n - Tert -butanesulfinyl ketimines

Article abstract of DOI:10.1021/ol4037117

A highly regio- and diastereoselective TMSOTf promoted vinylogous Mannich reaction for the synthesis of chiral quaternary 3-aminooxindole butenolides from 2-silyloxy furans and chiral ketimines is described. The method is found to be very efficient and also provides a facile access to sterically challenging 3-aminooxindole butenolides bearing two quaternary centers in continuation. Further, the versatility of the method is demonstrated by the 1,4-addition of nucleophiles on the sterically congested butenolide substructure.

Full text of DOI:10.1021/ol4037117

Letter
pubs.acs.org/OrgLett
Asymmetric Vinylogous Mannich Reaction of Silyloxy Furans with N-
tert-Butanesulfinyl Ketimines
V. U. Bhaskara Rao, Amol P. Jadhav, Dnyaneshwar Garad, and Ravi P. Singh*,‡
Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, India 411008
S
* Supporting Information
ABSTRACT: A highly regio- and diastereoselective TMSOTf promoted vinylogous Mannich reaction for the synthesis of chiral
quaternary 3-aminooxindole butenolides from 2-silyloxy furans and chiral ketimines is described. The method is found to be very
efficient and also provides a facile access to sterically challenging 3-aminooxindole butenolides bearing two quaternary centers in
continuation. Further, the versatility of the method is demonstrated by the 1,4-addition of nucleophiles on the sterically
congested butenolide substructure.
unctionalized chiral oxindoles bearing a 3,3′-disubstituted
Fcarbon stereocenter are the common structural core in
natural products and pharmaceuticals.1 Such cores also offer
valuable chiral building blocks for the enantioselective synthesis
of biologically active compounds.2 Especially, the oxindoles
with the amino group at the 3-position are vital in drug
discovery and considered important for the bioactivity of these
molecules.3 For instance, the amino-indoles are found in many
promising molecules such as antimalarial drug candidate
NITD609,3a a gastrin/CCK-B receptor antagonist AG-
041R,3b in a CRTH2 antagonist,3c and in a molecule that
inhibits the protein−protein interactions of a tumor suppressor
(transcription factor p53) and its negative regulator (Hdm2)
(Figure 1).3d In fact, it has been shown that the oral
bioavailability of a CRTH2 antagonist improves because of
the presence of a heteroatom at the C3 position.
doles,6 imine addition reaction, and Mannich reaction.7
Although considerable effort has been made in developing
such methodologies, achieving the structural complexity of a
natural product has been a big challenge, due to the lack of
adequate functional groups that can be incorporated in the 3-
aminooxindoles cores. One way of achieving the complexity
would be by using functionally rich nucleophiles such as 2-
silyloxy furans.8 We hypothesized that development of an
enantioselective nucleophilic addition reaction of 2-silyloxy
furans to isatin derived ketimines can offer a more practical and
direct approach to obtain chiral 3-substituted 3-aminooxindoles
with increased functionality in the core, thus, assisting in the
synthesis of structurally complex natural products.
The Mannich reaction of ketimines and trimethylsilyloxy
furan remains less explored due to the steric challenges that the
structure imposes. To date, there are only four reports for the
vinylogous Mannich reaction of ketimines and silyloxyfurans.9
A vinylogous Mannich reaction of 2-silyloxy furans and
isoquinolines using acyl/sulfonyl chlorides as an activating
agent was recently reported by Dodd’s group.9a Later, the first
asymmetric vinylogous Mannich reaction of 2-silyloxy furans to
α-ketimine esters was realized by Snapper and Hoveyda.9b
Recently, Deng and co-workers reported a AgOAc catalyzed
diastereoselective vinylogous Mannich reaction of ketimines
derived from isatin.9c Very recently, Nakamura reported the
Cu(OAc)2/cinchona alkaloid amide catalyzed asymmetric
vinylogous Mannich reaction of ketimines and silyloxy furans.9d
However, the enatioselective vinylogous Mannich reaction of
isatin ketimines and 2-silyloxy furans for the synthesis of chiral
quaternary 3-aminooxindoles is yet to be achieved.
In the past decade, various synthetic strategies for achieving
these oxindole frameworks have been employed. The most
commonly used methods for synthesizing 3-substituted-3-
aminooxindoles are the alkylation of 3-aminooxindoles,4
intermolecular arylation,5 amination of 3-substituted oxin-
Figure 1. Some examples of biologically active quaternary 3-
aminooxindoles.
Received: October 1, 2013
Published: January 17, 2014
© 2014 American Chemical Society
648
dx.doi.org/10.1021/ol4037117 | Org. Lett. 2014, 16, 648−651

Organic Letters
Letter
Herein, we report a trimethylsilyltriflate (TMSOTf)
promoted synthesis of quaternary 3-substituted 3-amino-
oxindoles by a very practical and highly diastereoselective
vinylogous Mannich reaction of chiral N-tert-butanesulfinyl
ketimines and various 2-trimethylsilyloxy furans. We have
achieved the enantioselectivity via chiral tert-butyl sulfinamide
and demonstrated how the vinylogous Mannich adduct can be
converted into a rich structural backbone.
The chiral sulfinyl amine auxiliaries such as p-toluene-
sulfinimines and N-tert-butanesulfinimines (NTBS) have shown
great success in asymmetric induction.10 We began our
investigation by catalyst screening and reaction optimization
using a series of N-protected isatin-derived N-tert-butanesulfinyl
ketimines (1a−d), obtained under literature reported proce-
dure,11,7j and reacted them with 2-trimethyl silyloxy furan (2a)
under different conditions (Table 1). A number of Lewis acids,
a specific isomer (trans) over a mixture of isomers.13 This
specificity can lead to easy control of the stereochemistry. To
further improve the yield and selectivity, we screened various
Lewis acids and solvents for the reaction of N-tritylketimine
with 2-trimethylsilyloxy furan. Interestingly, many metal
triflates, including Sc(OTf)3, In(OTf)3, Yb(OTf)3, and BF3·
OEt2, did not provide any further improvement in stereo-
control and reactivity (Table 1, entries 8−11). We next
investigated the impact of solvents on the reaction. We were
delighted to realize that dichloromethane produced the best
yield and selectivity for the reaction compared to all other tried
solvents (Table 1, entries 7, 12−14). The optimized conditions
were then used to explore the generality of the reaction. N-
Tritylisatin ketimines with various substituents on the aromatic
ring of isatin were explored. All reactions reached completion at
−78 °C in about 2.5 h. Generally moderate yields and good
selectivities were obtained in the presence of a variety of
substituents including electron-donating groups (3d−3f),
withdrawing groups (3i−3j), and halogen substituents at
various positions (3g, 3h, and 3k) (Table 2) on the aromatic
Table 1. Vinylogous Mannich Reactions of Isatin Ketimines
a
1 with 2-Trimethylsilyloxyfuran 2a
Table 2. Diastereoselective Vinylogous Mannich Reaction of
Various Isatin Ketimines 1 and 2-Trimethylsilyloxy Furan 2a
a b c
, ,
Using TMSOTf
yield
b
ratio of
stereoisomers
c
entry
R1
Lewis Acid
solvent
(%)
1
Me
Me
Me
Me
Bn
PMB
Tr
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
Et2O
∼5
24
32
69
72
25
78
40
35
29
30
72
45
50
−
2
In(OTf)3
BF3·OEt2
TMSOTf
TMSOTf
TMSOTf
TMSOTf
Sc(OTf)3
In(OTf)3
Yb(OTf)3
BF3·Et2O
TMSOTf
TMSOTf
TMSOTf
73:12:8:7
40:23:22:14
52:30:10:8
61:19:11:8
63:25:8:4
95:3:2
3
4
5
6
7
8
Tr
92:6:1:1
86:5:5:4
90:6:4
9
Tr
10
11
12
13
14
Tr
Tr
95:3:2
Tr
94:5:1
Tr
94:6
Tr
THF
78:11:7:4
a
Unless noted otherwise, reactions were performed under argon with
0.2 mmol of 1 and 0.3 mmol of 2a in 1.0 mL of solvent with 0.2 mmol
b
c
of catalyst. Isolated combined yield based on 1. Ratios determined
by H NMR analysis of crude mixtures.
a
1
Unless noted otherwise, reactions were performed under argon with
0.2 mmol of 1d−k and 0.3 mmol of 2a in 1.0 mL of solvent with 0.2
b
mmol of catalyst. Isolated combined yield of inseparable stereo-
c
isomers of vinylogous Mannich adducts 3d−k. Ratios determined by
such as In(OTf)3, BF3·OEt2, and TMSOTf, were screened in
the model vinylogous Mannich reaction at −78 °C for 2.5 h
(Table 1, entries 2−4). In accordance with the previous reports
on NTBS aldimine activations, it was found that the TMSOTf
mediated12 transformation yielded better conversion for the
vinylogous Mannich adduct 3a with modest selectivity (Table
1, entry 4). In(OTf)3 and BF3·OEt2 both gave poor yields.
However, better selectivity was observed for In(OTf)3 (Table
1, entries 2 and 3). In the absence of a catalyst, a trace amount
of the vinylogous Mannich adduct 3a was observed at −78 °C
(Table 1, entry 1). Interestingly, isatin-ketimines bearing a
bulkier N-protecting group such as N-trityl via TMSOTf
activation in dichloromethane afforded excellent stereocontrol
at −78 °C (Table 1, entry 7). This improved stereoselectivity
due to a bulky group could be because bulky substituents on
isatin-ketimines have been shown to promote the formation of
1H NMR analysis of crude mixtures.
ring of oxindole ketimine 1. To our surprise, substitution at the
5- or 6-position of the aromatic ring of oxindole ketimines did
not significantly impede stereocontrol of the reaction. Electron-
donating groups at the 5-position of isatin ketimines showed a
marginal loss in reactivity (Table 2, 3e and 3f).
We also investigated the reaction with various substituted 2-
trimethylsilyloxy furans (2b−2g) (Table 3). Remarkably,
TMSOTf afforded very high selectivity in all the cases. The
selectivity for reactions of sterically hindered 5-substituted 2-
trimethylsilyloxy furans (2d−2g), which generate chiral adducts
bearing adjacent quaternary−quaternary centers, was very high
(up to 99:1).
649
dx.doi.org/10.1021/ol4037117 | Org. Lett. 2014, 16, 648−651

Organic Letters
Letter
face of ketimine molecule (as depicted in the favored TS1), the
only favored attacking position for the silyloxy furan on the
ketimine is via the sterically unblocked re-face. This results in
the formation of the anti (R,R)-Mannich adduct.
Table 3. Diastereoselective Vinylogous Mannich Reaction of
Various Isatin Ketimine 1 with Substituted 2-
Trimethylsilyloxy Furan 2a Using TMSOTf
a b c
, ,
To demonstrate the synthetic utility of the Mannich adduct
3a, we subjected it to hydrogenation and 1,4-allylation (Scheme
1). Treatment of 3a with H2 (1 atm)/Pd−C reduced the α,β-
Scheme 1. Transformation of Mannich Adduct 3a
a
Unless noted otherwise, reactions were performed under argon with
0.2 mmol of 1a and 0.3 mmol of 2b−g in 1.0 mL of solvent with 0.2
b
unsaturated lactone moiety and yielded the corresponding
saturated compound 5.12d Whereas, the 1,4 allylation with an
allyl cuprate yielded lactone 6.14 The sulfinyl group
deprotection of 6 followed by acryllylation of the tertiary
amine of aminooxoindole produced compound 7. Sequential
treatment of 3a with H2 (1 atm)/Pd−C for hydrogenation, 4 M
HCl for sulfinyl group deprotection, and CH3COCl for
protection of the tertiary amine gave compound 8.
In summary, a highly practical asymmetric approach for the
efficient preparation of chiral tetrasubstituted 3-aminooxindoles
has been developed, based on a simple Lewis acid mediated
diastereoselective vinylogous Mannich process. The method
provides easy access to a wide range of highly enantiomerically
enriched 3-butenolide substituted 3-aminooxindoles, which is
the essential core structural motif in natural products and
biologically active compounds.
mmol of catalyst. Isolated combined yield of inseparable stereo-
c
isomers of vinylogogous Mannich adduct based on 1a. Ratios
d
1
determined by H NMR analysis of crude mixtures. The absolute
configuration of Mannich adduct anti-4f was established by single
crystal X-ray structure analysis (see SI).
The relative and absolute configuration of the Mannich
adduct was determined by X-ray crystal structure analysis of 4f
bearing a trityl group at N1 and a tert-butyl sulfinyl group at N2
(Figure 2). The relative configuration of the major stereoisomer
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 2. Single crystal X-ray structure of 4f (hydrogen atoms are
omitted for clarity).
Experimental procedures and characterizations of the com-
pounds (1H, 13C NMR) including X-ray data (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
of Mannich adduct 4f was established to be anti (see
Supporting Information (SI)). The observed anti stereo-
chemical configuration in these vinylogous Mannich reactions
can be due to an acyclic transition state model illustrated in
Figure 3. Most likely, the 1 equiv of the Lewis acid, which is
required for high yields, forms a monocoordinated transition
state (TS) at the N-sulfinyl group.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ravi.ps@ncl.res.in; ravips@chemistry.iitd.ac.in.
Present Address
‡Department of Chemistry, Indian Institute of Technology
Delhi, Hauz Khas, New Delhi-110016, India.
Assuming that the possible conformation of the TS is syn
periplanar and the bulky tert-butyl group is positioned at the si-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the generous financial support from CSIR-
NCL (MLP026026). V.U.B.R., A.P.J., and D.G. thank CSIR-
New Delhi for the award of a Junior Research Fellowship. We
thank Prof. N. G. Ramesh (Department of Chemistry, IIT-
Delhi) for helpful discussions. We thank Dr. Rajesh Gonnade
(Center for Materials Characterization, CSIR-NCL, Pune) for
Figure 3. Plausible transition state for the stereochemical outcome.
650
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Organic Letters
Letter
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(13) The ketimine derived from N-trityl isatin gives a product most
likely derived from E-ketimine; refs 7p and 11. Whereas, ketimine
derived from N-PMB isatin gives a product derived from the E/Z
mixture; ref 7c.
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