Organocatalytic Enantioselective Mukaiyama–Mannich Reaction of Isatin-Derived Ketimines for the Synthesis of Oxindolyl-β3, 3-Amino Acid Esters

Article abstract of DOI:10.1002/chem.201903512

Mukaiyama–Mannich reactions of ester enolate equivalents with aldimines have been elegantly used for the asymmetric synthesis of β-amino acids; nevertheless, the corresponding asymmetric reaction employing ketimines are unexplored. Herein, the first organocatalytic enantioselective Mukaiyama–Mannich reaction employing isatin-derived ketimines with unsubstituted silyl ketene acetals is disclosed towards the scalable synthesis of 2-oxoindolinyl-β^{3, 3}-amino acid esters at room temperature with excellent enantioselectivities (ee >99.5 %). Ultra-low catalyst loadings (as low as 250 ppm) could be used for the quantitative product formation with high enantiopurity. The synthetic utility of this protocol has been showcased in the short formal synthesis of pharmaceutically demanded (+)-AG-041R, a potent gastrin/CCK-B receptor antagonist.

Full text of DOI:10.1002/chem.201903512

DOI: 10.1002/chem.201903512
Full Paper
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Organocatalysis
Organocatalytic Enantioselective Mukaiyama–Mannich Reaction of
Isatin-Derived Ketimines for the Synthesis of Oxindolyl-b3,3-Amino
Acid Esters
Saumen Hajra,*[a] Sujay Laskar,[a] and Bibekananda Jana[a, b]
Dedicated to Professor Vinod K. Singh (IIT Kanpur) on the occasion of his 60th birthday
Abstract: Mukaiyama–Mannich reactions of ester enolate
equivalents with aldimines have been elegantly used for the
asymmetric synthesis of b-amino acids; nevertheless, the
corresponding asymmetric reaction employing ketimines are
unexplored. Herein, the first organocatalytic enantioselective
Mukaiyama–Mannich reaction employing isatin-derived keti-
mines with unsubstituted silyl ketene acetals is disclosed to-
wards the scalable synthesis of 2-oxoindolinyl-b3,3-amino
acid esters at room temperature with excellent enantioselec-
tivities (ee >99.5%). Ultra-low catalyst loadings (as low as
250 ppm) could be used for the quantitative product forma-
tion with high enantiopurity. The synthetic utility of this pro-
tocol has been showcased in the short formal synthesis of
pharmaceutically demanded (+)-AG-041R, a potent gastrin/
CCK-B receptor antagonist.
Introduction
b-Amino acid derivatives have emerged as an essential build-
ing block en route to the synthesis of complex natural prod-
ucts,[1] pharmaceutical targets,[2] b-lactam antibiotics,[3] and
peptidomimetics[4] with unique structural properties. Conse-
quently, tremendous efforts have been devoted toward the
catalytic asymmetric synthesis of b-amino acid motif.[5–6]
Among the available strategies, the Mukaiyama–Mannich reac-
tion of structurally distinct imines with silyl ketene acetals is es-
pecially attractive as it involves the straightforward construc-
tion of carbon–carbon bonds by employing two units of simi-
lar complexity in a catalytic asymmetric manner.[7] Recent ef-
forts have focused on the advancement of the enantioselective
Mukaiyama–Mannich reaction with unsubstituted silyl ketene
acetals, which provides a-unsubstituted-b-amino acid deriva-
tives (Scheme 1a–b).[7a,g,i] Nevertheless, the corresponding cata-
lytic asymmetric Mukaiyama–Mannich reaction with ketimines
to afford a tetrasubstituted stereogenic center has remained
elusive and a daunting unmet challenge (Scheme 1c). Derived
products of such a reaction, indolyl b3,3-amino acid derivatives,
[a] Prof. Dr. S. Hajra, Dr. S. Laskar, B. Jana
Centre of Biomedical Research
Scheme 1. Catalytic enantioselective Mannich-type reaction of unsubstituted
silyl ketene acetals with imines.
Sanjay Gandhi Post-Graduate Institute of Medical Sciences Campus
Raebareli Road, Lucknow 226014 (India)
E-mail: saumen.hajra@cbmr.res.in
belong to the core unit of several therapeutic agents
(Figure 1).
The indole-based b3,3-amino ester, bearing a C3-tetrasubsti-
tuted stereogenic center is a privileged structural motif in the
development of new drug candidates, notably (+)-AG-041R, a
clinically potent gastrin/cholecystokinin-B receptor antagonist
[b] B. Jana
Department of Chemistry
Indian Institute of Technology Kharagpur
Kharagpur 721302 (India)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201903512.
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Results and Discussion
To probe the immediate feasibility of our hypothesis, a model
reaction of N-benzyl protected isatin-derived N-Boc ketimine
1a (Table 1, entry 1) and the silyl ketene acetal 2a was con-
Table 1. Optimization of the reaction conditions.[a]
Figure 1. Representative natural products and clinical candidates containing
2-oxoindolinyl-b3,3-amino acid ester and 3-aminopyrroloindoline module.
No.
1
Catalyst
Time
3
Yield [%]
ee [%][b]
1
2
3
4[c]
5
6
7
8
9
10
11
12
13[d,e]
14[d,f]
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1c
1c
1c
rac-BNP
C1
C2
C2
C3
C4
C5
C1
C2
C1
C2
C3
C2
48 h
48 h
3 h
10 h
5.5 h
32 h
18 h
34 h
4 h
96 h
<5 min
30 h
20 min
1 h
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3c
3c
3c
3c
86
68
95
63
86
74
72
79
71
32
95
70
95
94
–
13
56
17
58
04
07
55
28
02
>99.5
82
99
99
(Figure 1).[8] Indeed, the framework is a very promising precur-
sor for the facile construction of 3-aminopyrroloindoline to-
wards the total synthesis of complex pyrroloindoline alkaloids
(Figure 1).[9] In accord with its medicinal relevancy, few fascinat-
ing indirect approaches have been well documented towards
the catalytic asymmetric synthesis of 2-oxoindolinyl-b3,3-amino
esters.[8b,9b–c,10] Surprisingly, only two direct, elegant catalytic
enantioselective approaches have been reported by Shibata
et al. and Ohshima et al., involving decarboxylative Mannich-
type addition of malonic acid half-thioesters (MAHT) to isatin-
derived ketimines, achieving enantioselectivities of up to 86%
ee.[11] Thus, finding an unprecedented reaction pathway to
render the 2-oxoindolinyl-b3,3-amino esters with excellent
enantioselectivities under sustainable reaction conditions
would be significantly rewarding.
C2
[a] Reactions were carried out with 0.1 mmol of imine and 0.3 mmol of
silyl ketene acetal in 1.0 mL of toluene at 258C. [b] Determined by HPLC
with a chiral stationary phase. [c] The reaction was carried at 08C. [d] Re-
actions were carried out with 0.25 mmol of imine 1c and 0.75 mmol of
silyl ketene acetal 2a in 2.5 mL of toluene (entry 13) and 1.25 mL of tolu-
ene (entry 14) at 258C. [e] Using 0.5 mol% of catalyst C2. [f] Using
0.25 mol% of catalyst C2.
We speculated that the direct addition of ester enolate
equivalents to the isatin-derived ketimines (Mukaiyama–Man-
nich variant) could be a robust route to deliver the medicinally
demanded 2-oxoindolinyl-b3,3-amino esters (Scheme 1c). How-
ever, the sluggish reactivity of the ketimine system with con-
comitant creation of an enantiofacial tetrasubstituted stereo-
center poses a formidable challenge. We further anticipated
that the nature of the ketimines should also influence the out-
come of the reaction. Indeed, we sought to develop scalable
approach in an organocatalytic fashion. Strikingly, chiral Brønst-
ed acids, typically chiral phosphoric acids (CPAs), have recently
blossomed as efficient catalysts for asymmetric Mannich-type
reactions, replacing transition-metal catalysts.[12] Herein, we
report the first disulfonimide-catalyzed enantioselective Mu-
kaiyama–Mannich reaction of isatin-derived ketimines with un-
substituted silyl ketene acetals, achieving the scalable synthesis
of 2-oxoindolinyl-b3,3-amino acid esters (ee >99.5%) at room
temperature.
ducted in the presence of 10 mol% rac-BINOL-derived phos-
phoric acid (BNP acid) in toluene at room temperature. Gratify-
ingly, the strategy worked efficiently, affording the desired rac-
emic 2-oxoindolinyl-b3,3-amino ester 3a (Table 1, entry 1) in
good yield (86%). Immediately, we employed a chiral surrogate
C1 to furnish enantioselectivity (Table 1, entry 2). Disappoint-
ingly, the desired b3,3-amino ester was obtained in moderate
yield with negligible asymmetric induction (68% yield, 13%
ee). Meanwhile, before commencing the routine investigation
with the toolbox of auxiliary chiral phosphoric acids (CPAs), we
attempted to recruit chiral disulfonimides (DSIs) in the model
reaction as the chiral disulfonimide conjugated silylium-based
“asymmetric counter anion-directed catalysis” (ACDC) has re-
cently been proven to be an efficient chiral pre-catalyst in Mu-
kaiyama-type reactions.[13] Pioneering progress in this particular
field has been done by the List group utilizing chiral disulfoni-
mides as stereoinducing counter anions to enable asymmetric
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transformations. To implement our assumption, the disulfoni-
mide C2 has been employed in the model reaction (Table 1,
entry 3). To our delight, the desired product 3a was obtained
in almost quantitative yield with a significant increase in enan-
tioselectivity (95% yield, 56% ee). Encouraged by this proof-of-
principle result, a systematic exploration of different reaction
conditions was conducted. The subsequent solvent screening
revealed toluene to be the optimal choice (see the Supporting
Information). The rate of the uncatalyzed racemic reaction was
also found to be moderate (ꢀ25% yield in 48 h), indicating
the influence of the background reaction in diminishing the
enantioselectivity through the catalytic pathway. To prevent
this situation, we turned our attention to decreasing the reac-
tion temperature to 08C; although the chemical yield dropped
to 63% with poor enantioselectivity (17% ee, Table 1, entry 4).
Screening of other disulfonimides (Table 1, entries 5–7) showed
that the use of C3 was encouraging as the selectivity was ele-
vated to 58%. At this juncture, two principle parameters could
be taken into account to improve the enantioselectivity:
a) steric and electronic remodulation of the catalyst and b) re-
structuring the ketimine substrate by installing other protect-
ing groups.
Under the optimized conditions, the scope of the enantiose-
lective Mukaiyama–Mannich reaction of the N-trityl-protected
isatin-derived N-Boc ketimines catalyzed by disulfonimide C2
was next investigated (Scheme 2). Ketimines possessing both
electron-rich and electron-withdrawing substituents at the 5, 6,
and 7 positions of the indolinone ring were examined in this
newly developed protocol. The effect of various alkoxy sub-
stituents on the silyl ketene acetals was also considered. Re-
markably, all the reactions proceeded smoothly and the de-
sired 2-oxoindolinyl-b3,3-amino esters 3c–3x were obtained in
excellent yields with outstanding enantiopurities. In general, all
the reactions were very clean, energy-efficient, and could
easily be followed by visual color check of the reaction mix-
ture. Notably, with a tert-butyl substituent on the silyl ketene
acetal, the reaction was not successful at all because of the
steric hindrance. It is also worth noting that the tetrasubstitut-
ed silyl ketene acetal derived from methyl iso-butyrate does
not respond to the reaction with the ketamine 1c under the
optimized conditions or even at higher temperature (up to
808C).
To further demonstrate the practicability and robustness of
the developed protocol, a gram-scale synthesis was conducted
with 2.0 g (4.124 mmol) of isatin-derived ketimine 1c and com-
mercially available silyl ketene acetal 2b in the presence of
1000 ppm (0.10 mol%) of disulfonimide catalyst C2 (Table 2,
entry 1). We are pleased to report that the reaction proceeded
smoothly and led to the final product 3l in excellent yield with
outstanding enantioselectivity (96% yield, >99% ee). It is note-
worthy that further reduction of the catalyst loading to
250 ppm (0.025 mol%) could still successfully catalyze the Mu-
kaiyama–Mannich reaction of ketimine 1c (500 mg batch,
1.031 mmol) in full conversion with good enantioselection
albeit with longer reaction time (5 days; Table 2, entries 2–3).
To the best of our knowledge, this is the lowest catalyst load-
ing achieved to date for the Mukaiyama–Mannich reaction
with excellent enantioselectivity. This chiral disulfonimide cata-
lyzed Mukaiyama acetate Mannich reaction followed the analo-
gous ACDC reaction mechanism reported in the literature.[13b]
To demonstrate the utility of the newly developed enantio-
selective Mukaiyama–Mannich protocol, we pursued the
formal synthesis of (+)-AG-041R, a potential cholecystokinin-B/
gastrin receptor antagonist (Scheme 3). Starting from the enan-
tiopure building block 3l, the single-step deprotection of both
the Boc and trityl groups by the employment of TFA in di-
We envisioned that reconstructing the ketimine system
could be the superior choice as the catalyst (C2) is readily
available in addition to its potency in ACDC catalysis. Pleasing-
ly, our speculation was in harmony with the following experi-
mental results. When ketimine 1c, containing a triphenylmeth-
yl (trityl=Tr) group, was employed as the substrate, the de-
sired product 3c was obtained in excellent yield with out-
standing enantioselectivity (95% yield, >99.5% ee) within
5 min at room temperature (Table 1, entry 11). Catalyst C2 was
deemed to be the optimal choice owing to its enhanced reac-
tivity compared with catalysts C1 and C3 (Table 1, entries 10
and 12). The disulfonimide catalyst C2 was also found to be su-
perior to catalyst C1 when applying the ketimine 1a (Table 1,
entries 2 and 3), but the catalyst C1 was suited better for the
ketamine 1b in terms of enantioselectivity although the reac-
tion was faster with catalyst C2 (Table 1, entries 8 and 9). The
concomitant steric effect of the N-trityl functionality was a
clear advantage for achieving high enantioselectivity. The re-
sults also led us to consider the possibility of additional non-
covalent interactions between the catalyst (C2) and the trityl
group of the imine substrate during the reaction.
Although organocatalysis has already been recognized as
the third pillar in modern asymmetric catalysis toward the total
synthesis of natural and pharmaceutical products, one criticism
is that organocatalytic processes commonly require a large cat-
alyst loading in comparison with the metal-catalyzed pathways
to furnish the reactions useful. It is noteworthy that very few
enantioselective organocatalytic CÀC bond-forming reactions
have been reported as using ultra-low catalyst loadings
(<0.5 mol%) or even with ppm and sub-ppm levels of load-
ing.[14] Fortunately, we were able to determine that only
0.25 mol% catalyst loading was sufficient to afford the desired
2-oxoindolinyl-b3,3-amino ester 3c in excellent yield while
maintaining the high enantioselectivity (Table 1, entries 13–14,
for details please see the Supporting Information).
chloromethane afforded the N-unprotected 2-oxoindolinyl-b3,3
-
amino ester 7. The compound 7 could be converted into
(+)-AG-041R by following the reported literature procedure,
thereby accomplishing the formal synthesis of (+)-AG-041R.[10]
The obtained 2-oxoindolinyl-b3,3-amino ester 7 could also serve
as a precursor for the synthesis of spiro-b-lactam 11, a skeleton
of the natural product chartellines. The absolute configuration
of the compound 3l was determined as the (R)-configuration
by correlating the sign of the specific rotation of 7 with the lit-
erature data (for details see the Supporting Information).[10]
The absolute configuration of the other compounds was tenta-
tively assigned by analogy.
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Scheme 2. Substrate scope and visual check of the reaction. The data in parenthesis refers to the reaction with 0.25 mol% catalyst loading. Images of the
crude reaction mixtures with thin-layer chromatography (TLC eluent: ethyl acetate/hexane=1:4) on a 2 g scale with 1000 ppm catalyst loading (left image: at
the beginning of the reaction, right image: upon full conversion after 4.5 h).
Table 2. The practicability of the developed protocol.
Entry
C2 loading [ppm]
Weight of 1c (mmol)/mmol of 2b/concentration
Time
Yield [%]
ee [%][a]
1
2
3[b]
1000
500
250
2.0 g (4.124 mmol)/10.31 mmol/1 m
1.0 g (2.062 mmol)/4.124 mmol/2 m
0.5 g (1.031 mmol)/2.062 mmol/4 m
4.5 h
16 h
5 days
96
92
88
>99
99
90 (>99.5)[c]
[a] Determined by HPLC with a chiral stationary phase. [b] The reaction was conducted at 408C. [c] After a single recrystallization.
Conclusion
available chiral disulfonimide organocatalyst. Notably, the
products directly achieved through such a reaction are medici-
nally useful indolyl-b3,3-amino acid derivatives. Ultra-low cata-
lyst loading (as low as 250 ppm), gram-scale synthesis, short
reaction times, and the creation of a tetrasubstituted stereo-
We have explored the first highly enantioselective facile Mu-
kaiyama–Mannich reaction employing isatin-derived ketimines
with unsubstituted silyl ketene acetals by using a commercially
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Experimental Section
General procedure for the catalytic asymmetric Mukaiyama–
Mannich reaction of isatin-derived ketimines with silyl
ketene acetals (3c–3x)
A septum-capped oven-dried vial (cooled in argon flow) containing
a Teflon-coated magnetic stirring bar was charged with the corre-
sponding ketimine (0.2 mmol, 1.0 equiv) and molecular sieves
(50 mg, 4 ꢁ MS). Disulfonimide catalyst C2 (0.5/0.25 mol%; from
freshly prepared catalyst stock solution in dry toluene) was loaded
into the reaction vial via a syringe and dry toluene was further
added to adjust the reaction concentration to 0.2m (with respect
to ketimine). The corresponding silyl ketene acetal (0.6 mmol,
2.0 equiv) was then added to the reaction mixture via a microliter
syringe and the resulting solution was left to stir at room tempera-
ture for 15–105 min under argon atmosphere. The progress of the
reaction course was monitored by TLC. Upon completion of the re-
action, the reaction mixture was directly applied to silica gel, and
purified by flash column chromatography using hexanes/EtOAc as
eluent. The desired products were obtained as viscous liquids or
colorless solids.
Acknowledgements
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We thank SERB, New Delhi (Grant No. EMR/2016/001161 to
S.H.) and SERB-National Postdoctoral fellowship award (Refer-
ence No. PDF/2016/002585 to S.L.) for providing financial sup-
port. B.J. thanks UGC, New Delhi for his fellowship.
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The authors declare no conflict of interest.
Keywords: asymmetric synthesis · disulfonimide catalysts ·
ketimines · low catalyst loading · Mukaiyama–Mannich reaction
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Manuscript received: August 1, 2019
Accepted manuscript online: September 3, 2019
Version of record online: && &&, 0000
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FULL PAPER
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Organocatalysis
S. Hajra,* S. Laskar, B. Jana
&& – &&
Organocatalytic Enantioselective
Mukaiyama–Mannich Reaction of
Isatin-Derived Ketimines for the
Synthesis of Oxindolyl-b3,3-Amino Acid
Esters
Low loading: Ultra-low chiral disulfoni-
mide catalyst loading (as low as 250
ppm) is used in the asymmetric Mu-
kaiyama–Mannich reaction of isatin-de-
rived ketimines with unsubstituted silyl
ketene acetals. The reaction has been
developed under sustainable reaction
condition for the synthesis of medicinal-
ly useful indolyl-b3,3-amino acid esters
with outstanding enantioselectivity (ee
>99.5%).
Chem. Eur. J. 2019, 25, 1 – 7
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ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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