Enantioselective synthesis of AG-041R by using N-heteroarenesulfonyl cinchona alkaloid amides as organocatalysts

Article abstract of DOI:10.1002/chem.201200367

The organocatalytic enantioselective decarboxylative addition of malonic acid half thioesters to ketimines derived from isatins by using N-heteroarenesulfonyl cinchona alkaloid amides afforded products with high enantioselectivity. The products could be c

Full text of DOI:10.1002/chem.201200367

FULL PAPER
DOI: 10.1002/chem.201200367
Enantioselective Synthesis of
N
G-041R by using N-Heteroarenesulfonyl
Noriyuki Hara, Shuichi Nakamura,* Masahide Sano, Ryota Tamura,
Yasuhiro Funahashi, and Norio Shibata*[a]
Abstract: The organocatalytic enantioselective decarboxylative addition of malonic
acid half thioesters to ketimines derived from isatins by using N-heteroarenesul-
fonyl cinchona alkaloid amides afforded products with high enantioselectivity. The
products could be converted into optically active AG-041R. X-ray crystallographic
analysis revealed that the hydrogen bonding between the sulfonimide proton and
the 8-quinolyl nitrogen atom plays an important role in exerting the enantioselec-
tivity of the reaction.
Keywords: enantioselectivity · keti-
mines · organocatalysis · reaction
mechanisms
Introduction
the formal enantioselective synthesis of AG-041R by the
enantioselective amination of oxindole.[3,4] Although re-
markable progress has been made in the synthesis of optical-
ly active AG-041R, development of an asymmetric synthesis
of AG-041R is desired for a more simple operation. One of
the simplest ways to construct the chiral 3-substituted 3-
amino-2-oxindole backbone is by the direct nucleophilic re-
action of ketimines derived from isatins. However, the enan-
tioselective reaction of ketimines is not a trivial task due to
their low reactivity and the difficulty of enantiofacial con-
trol. To the best of our knowledge, there are only a few re-
ports on the enantioselective nucleophilic addition reactions
of ketimines derived from isatins.[5] On the other hand, the
asymmetric decarboxylative addition reactions of malonic
acid half-thioesters (MAHTs), which are important candi-
dates for the generation of ester enolate equivalents under
very mild reaction conditions, to various imines have attract-
ed considerable attention.[6,7] However, there are no reports
on the enantioselective decarboxylative addition of MAHTs
to ketimines.[8] Therefore the development of an efficient
protocol for the enantioselective decarboxylative addition of
MAHTs to ketimines is highly desired. Recently, we report-
ed the enantioselective decarboxylative addition of MAHTs
to isatins in the presence of bifunctional organocatalysts.[9]
In this work we have extended this line of research to the
enantioselective decarboxylative addition of MAHTs to ke-
timines derived from isatins in the presence of bifunctional
organocatalysts and the enantioselective synthesis of AG-
041R (Figure 1).[10]
AG-041R, 2-{(R)-1-(2,2-diethoxyethyl)-2-oxo-3-[3-(p-tolyl)-
ureido]-2,3-dihydro-1H-indol-3-yl}-N-(p-tolyl)acetamide (1),
is a gastrin/cholecyctokinin-B receptor antagonist and effec-
tive reagent for the repair of particular cartilage defects.[1]
AG-041R has a tetrasubstituted stereocenter with an R con-
figuration, and the absolute configuration of this tetrasubsti-
tuted carbon center could modulate its biological activity.
Therefore, in its synthesis it is of very important to control
the chirality of AG-041R through high enantiocontrol. How-
ever, there are only a few reports on the synthesis of optical-
ly active AG-041R. The first synthesis of enantiomerically
pure AG-041R was accomplished by Chugai pharmaceuti-
cal’s group by optical resolution using l-menthol.[1a] Recent-
ly, Emura et al. reported the diastereoselective alkylation of
oxindole enolates by using l-menthyl bromoacetate as the
chiral alkylation reagent to give the optically active AG-
041R.[1h] On the other hand, there is only one report of the
catalytic enantioselective synthesis of AG-041R. In 2009,
Iwabuchi and co-workers reported the first catalytic enantio-
selective synthesis of AG-041R by intramolecular aza-spiro-
cyclization onto indoles using a chiral rhodium catalyst.[2]
Although the level of enantioinduction in the aza-spirocycli-
zation was high, the introduction of two deuterium atoms
was essential for the efficient promotion of the key spirocyc-
lization. More recently, Shibasaki and co-workers reported
[a] N. Hara, Prof. S. Nakamura, M. Sano, R. Tamura, Prof. Y. Funahashi,
Prof. N. Shibata
Department of Frontier Materials, Graduate School of Engineering
Nagoya Institute of Technology, Gokiso
Showa-ku, Nagoya 466-8555 (Japan)
Fax : (+81)52-735-5245
E-mail: snakamur@nitech.ac.jp
nozshiba@nitech.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200367.
Figure 1. Structure of AG-041R (1) and the strategy towards its synthesis.
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Results and Discussion
The control experiment without any catalyst did not
afford product 3a (run 1). The addition of cinchonine (4a)
as organocatalyst efficiently activated the decarboxylative
Mannich-type reaction to give product 3a but with moder-
ate enantioselectivity (run 2). Interestingly, the reaction with
9-amino-9-deoxy-epi-cinchonine (4b) gave product 3a in
low yield whereas the reaction with toluenesulfonylated 9-
amino-9-deoxy-epi-cinchonidine 5a[12] afforded 3a in good
yield (run 4). To improve the enantioselectivity of the reac-
tion, we optimized the structure of arenesulfonylated 9-
amino-9-deoxy-epi-cinchonidine.[13] Recently, we found that
the insertion of heteroarenesulfonyl groups into organocata-
lysts increased their catalytic activity and the enantioselec-
tivity of the products.[14] Therefore we next tried to intro-
duce heteroarenesulfonyl groups into the amino group of
the 9-amino-9-deoxy-epi-cinchonidine substrate. Although
the reaction with 2-thiophene- or 2-pyridinesulfonylated 9-
amino-9-deoxy-epi-cinchonidines 5c,d afforded product 3a
with low enantioselectivities, 8-quinolinesulfonylated cata-
lysts 5e–h gave 3a with high enantioselectivities (runs 6–
11).[15] Previously, our studies on the reactions of isatins with
MAHTs have shown that chiral squaramide catalyst 6 de-
rived from 9-amino-9-deoxy-epi-quinine is an effective pro-
moter.[9a] Therefore we also used chiral squaramide catalyst
6 in the reaction of ketimine 2a with MAHT, which gave
product 3a in 81% yield but with 11% ee (run 12). Thus, N-
(8-quinolinesulfonyl)-9-amino-9-deoxy-epi-cinchonidine 5g
proved to be the catalyst of choice.
We first examined the reactions of ketimines derived from
isatins 2a[11] with MAHTs in the presence of chiral organo-
catalysts 4–6 in cyclopentyl methyl ether (CPME). The re-
sults are shown in Table 1.
Table 1. Decarboxylative addition of MAHTs to ketimines derived from
isatins in the presence of various organocatalysts.
We next examined the reactions of 2a with various
MAHTs in the presence of catalyst 5g. The reactions of var-
ious arylthio and alkylthio esters gave products 3b–h in
good yields with good enantioselectivities (runs 13–19). The
best enantioselectivity was obtained in the reaction with the
phenylthio ester (run 10). The addition of an excess amount
(2.2 equiv) of MAHT improved the yield of the product
(run 20).
Under these optimized conditions, the reactions of
a series of ketimines derived from isatins and malonic acid
S-phenyl monoester in the presence of catalyst 5g were ex-
amined (Table 2). Products 3i–s were obtained in moderate-
to-good yields with high enantioselectivities (entries 2–
12).[16]
Run
Cat.
R1
3
Yield [%]
ee [%][a,b]
1
2
3
4
5
6
7
8
–
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3 f
3g
3h
3a
–
–
4a
4b
5a
5b
5c
5d
5e
5 f
5g
5h
6
5g
5g
5g
5g
5g
5g
5g
5g
92
13
73
69
70
52
69
65
69
58
81
78
68
70
72
90
75
79
91
44 (S)
16 (S)
25 (R)
54 (R)
30 (R)
33 (R)
75 (R)
80 (S)
83 (S)
75 (R)
11 (R)
79 (S)
78 (S)
82 (S)
81 (S)
77 (S)
70 (S)
73 (S)
83 (S)
We next tried to convert the product into chiral AG-041R
(Scheme 1). The R isomer of AG-041R can be obtained
from (R)-3o, which was prepared from the reaction of 2o
with MAHT in the presence of catalyst 5e. The reaction of
73% ee of (R)-3o with Mg/MeOH gave the methyl ester 7
in high yield. The removal of the Boc group in 7 by using
hexafluoroisopropyl alcohol (HFIP) followed by treatment
with p-tolyl isocyanate afforded urea 8. After crystallization,
(R)-8 was obtained with high enantiopurity (96% ee). Final-
ly, hydrolysis of 8 with KOH in EtOH/H2O and condensa-
tion with p-toluidine in the presence of N’-(3-dimethylami-
nopropyl)-N-ethylcarbodiimide (EDC)/HCl afforded AG-
041R (1; [a]D25 = +28.3 (c=0.37 in CHCl3); lit.:[1a] [a]2D5 = +
27.9 (c=3.05 in CHCl3)) in high yield with high enantiopuri-
ty.
9
10
11
12
13
14
15
16
17[c]
18[c]
19[c]
20[c,d]
Ph
Ph
Ph
p-MeC6H4
p-MeOC6H4
p-ClC6H4
2-naphthyl
PhCH2
tBu
cyclohexyl
Ph
[a] The ee values were determined by HPLC analysis. [b] The absolute
configuration of
(2.2 equiv) is used.
2
is provided in parentheses. [c] 48 h. [d] MAHT
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Enantioselective Synthesis of AG-041R
FULL PAPER
Table 2. Decarboxylative addition of malonic acid S-phenyl monoester to
ketimines derived from isatins in the presence of various organocatalysts.
Entry
R1
R2
3
Yield [%]
ee [%][a]
1
2
3
4
5
6
7
8
Me
Et
iPr
H
H
H
H
H
H
H
H
H
3a
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
90
64
72
72
90
87
92
71
64
58
80
81
83 (S)
82
80
81
82
83
81
80 (S)
74
75
cyclopentyl
CH3OCH2
PhCH2OCH2
CH2 =CHCH2
Figure 2. X-ray crystal structure of 5g.
G
9
PhCH2
p-CH3OC6H4CH2
5g, the mechanism for the reactions of ketimines with
MAHTs in the presence of a chiral sulfonamide catalyst 5 is
shown in Figure 3. The sulfonamide functionality could acti-
vate the MAHT through hydrogen bonding. The carboxylic
acid in MAHT may then be deprotonated and decarboxylat-
ed at a basic site of the cinchona alkaloid to give the thioest-
er enolate. Next, the ketimine coordinates to a hydrogen
atom on protonated 5. The reaction of the thioester enolate
with ketimine in the coordination sphere of the chiral sulfo-
namide gives a product with high enantioselectivity.
10
11
12
H
Me
MeO
Me
Me
80
78
3s
[a] The ee values were determined by HPLC analysis.
Scheme 1. Synthesis of optically active (+)-AG-041R (1).
Figure 3. Proposed reaction mechanism for the decarboxylative addition
of MAHTs to ketimines derived from isatins in the presence of catalyst
5.
The enantioselective reactions of 2 with MAHTs in the
presence of organocatalysts 5e–h with a heteroarenesulfonyl
group gave products with good enantioselectivities, although
the reactions with organocatalysts 5a,b did not give good re-
sults (Table 1). Therefore the heteroarenesulfonyl group
plays an important role in promoting the enantioselectivity
of the reaction. To identify the structure of the organocata-
lyst, we studied 5g by X-ray crystallographic analysis
(Figure 2).
The crystal analysis reveals that the two nitrogen atoms of
the quinoline and quinuclidine are directed towards the hy-
drogen on the sulfonimide. The distances between the sulfo-
nimide hydrogen and these two nitrogen atoms are 2.32 and
2.30 ꢁ.[17] This implies that the hydrogen on the sulfonimide
in 5g forms hydrogen bonds with the nitrogen atoms in the
quinoline and quinuclidine. On the basis of the structure of
From the above considerations and the absolute configu-
rations of the products, a transition state for the reaction of
the thioester enolate with ketimines in the presence of
chiral sulfonimide catalyst 5g is proposed in Figure 4. Be-
cause the thioester enolate approaches the Re face of the
ketimine, the S isomer is preferentially formed. Further
studies are required to fully elucidate the detailed mecha-
nism of the addition reaction.
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for clarity.
Conclusion
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We have developed a highly enantioselective decarboxyla-
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by using novel 8-quinolinesulfonylated organocatalysts. To
the best of our knowledge, this is the first example of decar-
boxylative addition of MAHTs to ketimines. The products
obtained could be converted into optically active (+)-AG-
041R. Further studies focusing on the scope of the asymmet-
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tion and will be reported in due course.
Experimental Section
Typical procedure for the synthesis of 3a in the presence of 5g: Malonic
acid half thioester (0.084 mmol, 16.4 mg) was added to a solution of keti-
mine 2a (0.038 mmol, 10.0 mg) and catalyst 5g (0.008 mmol, 3.9 mg) in
CPME (0.5 mL) and the mixture was stirred for 48 h. After removal of
the solvent, the residue was purified by silica gel column chromatography
(eluent: hexane/AcOEt, 80:20) to afford (S)-3a (14.3 mg, 91%) as
a white solid.
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Acknowledgements
This work was partly supported by an A-Step (AS232Z00124G) from the
Japan Science and Technology Agency (JST) and the Toyoaki Founda-
tion.
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Enantioselective Synthesis of AG-041R
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N. Shibata, T. Toru, Chem. Eur. J. 2009, 15, 6790–6793; c) S. Naka-
mura, N. Shibata, T. Toru, J. Synth. Org. Chem. Jpn. 2010, 68, 1017–
1027; d) N. Hara, S. Nakamura, N. Shibata, T. Toru, Adv. Synth.
Catal. 2010, 352, 1621–1624; See also, ref. [9c]; for related recent
studies from our group, see: e) S. Nakamura, H. Nakashima, H. Su-
gimoto, H. Sano, M. Hattori, N. Shibata, T. Toru, Chem. Eur. J.
2008, 14, 2145–2152; f) S. Nakamura, H. Nakashima, A. Yamamura,
N. Shibata, T. Toru, Adv. Synth. Catal. 2008, 350, 1209–1212; g) S.
Nakamura, Y. Sakurai, H. Nakashima, N. Shibata, T. Toru, Synlett
2009, 1639–1642.
[15] We also examined the reaction in CH2Cl2, toluene, Et2O, TBME,
THF, and DMF, however, the product 3a was obtained with lower
enantioselectivity than in CPME.
[16] Unfortunately, ketimines derived from nonsubstituted isatin (R1 =
H) and isatin with an electron-withdrawing group could not be ob-
tained under various reaction conditions.
[10] For reviews of organocatalysts, see: a) Asymmetric Organocatalysis,
A. Berkessel, H. Grçger, Wiley-VCH, Weinheim, 2005; b) Enantio-
selective Organocatalysis, P. I. Dalko, Ed. Wiley-VCH, Weinheim,
2007; c) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev.
2007, 107, 5471–5569.
[11] The ketimines derived from isatins were prepared by using the pro-
cedure of Maruoka for the reactions of isatins with N-Boc-N-TMS
amides, see: T. Hashimoto, K. Yamonoto, K. Maruoka, Chem. Lett.
2011, 40, 326–327.
[12] a) U. Sundermeier, C. Dçbler, G. M. Mehltretter, W. Baumann, M.
Beller, Chirality 2003, 15, 127–134; b) S. H. Oh, H. S. Rho, J. W.
Lee, J. E. Lee, S. H. Youk, J. Chin, C. E. Song, Angew. Chem. 2008,
120, 7990–7993; Angew. Chem. Int. Ed. 2008, 47, 7872–7875;
[17] We also examined the MO calculation of 5g by using Gaussian 09 at
the HF/6-311+G** level of theory. The calculation also revealed
the hydrogen bond between nitrogen in the quinoline and the hy-
drogen on the sulfonamide. The NBO analysis estimated that the
energy of interaction between the nitrogen lone pair and the s* or-
bital of the N H bond was 2.92 kcalmolÀ1. For the NBO analysis,
À
see E. D. Glendening, A. E. Reed, J. E. Carpenter, F. Weinhold,
NBO Version 3.1, See also: a) A. E. Reed, R. B. Weinstock, F. Wein-
hold, J. Chem. Phys. 1985, 83, 735–746; b) A. E. Reed, L. A. Curtiss,
F. Weinhold, Chem. Rev. 1988, 88, 899–926.
Received: February 3, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!

S. Nakamura, N. Shibata et al.
Organocatalysis
N. Hara, S. Nakamura,* M. Sano,
R. Tamura, Y. Funahashi,
N. Shibata* .................... &&&& — &&&&
Enantioselective Synthesis of ACHNTUGRNENUG G-
Enantioselective catalysis: The organo-
catalytic enantioselective decarboxyla-
tive addition of malonic acid half thio-
esters to ketimines affords products
with high enantioselectivities (see
scheme; CPME=cyclopentyl methyl
ether). The products can be converted
into optically active AG-041R. Hydro-
gen bonding plays an important role in
the enantioselectivity of the reaction.
041R by using N-Heteroarenesulfonyl
Cinchona Alkaloid Amides as Organo-
catalysts
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www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!