Chiral Silver Alkoxide Catalyzed Asymmetric Aldol Reaction of Alkenyl Esters with Isatins

Article abstract of DOI:10.1055/a-1479-4694

A catalytic enantioselective aldol reaction of alkenyl esters with isatins was achieved using a DM-BINAP·AgOTf complex as the chiral precatalyst and N, N -diisopropylethylamine as the base precatalyst in the presence of methanol or 2,2,2-trifluoroethanol.

Full text of DOI:10.1055/a-1479-4694

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–G
letter
A
en
A. Yanagisawa, A. Kawada
Letter
Synlett
Chiral Silver Alkoxide Catalyzed Asymmetric Aldol Reaction of
Alkenyl Esters with Isatins
Akira Yanagisawa*
(R)-DM-BINAP (8 mol%)
R3 R2
O
AgOTf (16 mol%)
(i-Pr)2NEt (20 mol%)
R6OH (2 equiv)
Aiko Kawada
O
HO
*
OCOCX3
R3
R1
*
Molecular Chirality Research Center, Department of Chemistry,
Graduate School of Science, Chiba University, Inage, Chiba 263-
8522, Japan
R4
O
R4
O
+
R1
THF, –40 or –20 °C
N
R5
N
R2
1.5 equiv
(X = F, Cl)
R5
up to >99% yield
anti/syn = 92:8 to <1:20
1 equiv
ayanagi@faculty.chiba-u.jp
up to 98% ee
eAMMkoialreaiClcYouaraylarnaernasCgaphigosianr@wadfliaiantcygulRAteyus.tcehhaoirbrcah-uC.ejpnter, Department of Chemistry, Graduate School of Science, Chiba University, Inage, Chiba 263-8522, Japan
Received: 26.03.2021
Accepted after revision: 10.04.2021
Published online: 12.04.2021
R3 R2
O
cat. DM-BINAP
cat. AgOTf
cat. (i-Pr)2NEt
O
HO
OCOCX3
R3
*
*
R1
R4
O
R4
O
DOI: 10.1055/a-1479-4694; Art ID: st-2021-u0113-l
+
R1
R6OH, THF
N
R5
N
R5
R2
Abstract A catalytic enantioselective aldol reaction of alkenyl esters
with isatins was achieved using a DM-BINAP·AgOTf complex as the chi-
ral precatalyst and N,N-diisopropylethylamine as the base precatalyst in
the presence of methanol or 2,2,2-trifluoroethanol. Optically active 3-
alkylated 3-hydroxy-2-oxindoles having up to 98% ee were diastereose-
lectively obtained in moderate to high yields not only from cyclic alke-
nyl esters but also from acyclic ones through the in situ generated chiral
silver enolates.
Scheme 1 Chiral silver alkoxide catalyzed asymmetric aldol reaction of
alkenyl esters with isatins
plex as the chiral precatalyst and N,N-diisopropylethyl-
amine as the base precatalyst (Scheme 1).
We have previously reported that an asymmetric aldol
reaction of aldehydes with alkenyl trihaloacetates takes
place smoothly in the presence of a catalytic amount of a
chiral silver methoxide.5 The alkenyl esters are effectively
converted into chiral silver enolates in situ and the chiral
silver catalyst is regenerated from the aldol products under
the influence of methanol. The reaction provides the corre-
sponding optically active -hydroxy carbonyl compounds
with high enantioselectivities. We envisioned that if an
isatin or its derivative could show similar reactivity to an
aldehyde, the carbonyl compound would also undergo the
aforementioned chiral silver-catalyzed asymmetric aldol
reaction to afford nonracemic -hydroxyketones having a
3-hydroxy-2-oxindole structure. Thus, we attempted to
carry out the reaction of 1-tetralone-derived alkenyl triflu-
oroacetate 1a6 with N-benzyl isatin (2d) using a chiral
phosphine, silver triflate, and N,N-diisopropylethylamine as
precatalysts with MeOH, and as a result, anticipated aldol
adduct 3ad was produced in high yield with notable asym-
metric induction. For example, when a mixture of 1a (1.5
equiv) and 2d (1 equiv) was treated with (R)-BINAP (8
mol%), AgOTf (16 mol%),7 and (i-Pr)2NEt (40 mol%) in the
presence of MeOH (5 equiv) in THF at –40 °C for 22 h, 3ad
was obtained in 92% yield with the anti/syn ratio of 45:55
(Table 1, entry 1). The anti isomer of 3ad had 67% ee. Then,
we investigated the asymmetric induction ability of chiral
Key words aldol reaction, alkenyl ester, asymmetric catalysis, isatin,
silver
Isatin and its derivatives are versatile synthetic precur-
sors for diverse biologically active molecules.1 For instance,
convolutamydine A (Figure 1) displays potent inhibitory ac-
tivity towards the differentiation of HL-60 human promy-
elocytic leukemia cells.2
Br
HO
O
O
N
Br
H
convolutamydine A
Figure 1
One of the efficient routes to obtain such an optically
active 3-alkylated 3-hydroxy-2-oxindole moiety is the cata-
lytic asymmetric aldol reaction of isatins. Although numer-
ous chiral organocatalysts3 have been developed for the en-
antioselective transformation, as far as we know, there are
few examples of the catalytic reaction that employs chiral
Lewis acid catalysts.4 We report herein an asymmetric syn-
thesis of enantiomerically enriched 3-alkylated 3-hydroxy-
2-oxindoles from isatins through an enantioselective aldol
reaction with alkenyl esters using a DM-BINAP·AgOTf com-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. Yanagisawa, A. Kawada
Letter
Synlett
phosphines other than BINAP and found that (R)-DM-
BINAP gave the best result in terms of diastereoselectivity
and enantioselectivity (entry 3). (R)-Tol-BINAP was also a
promising chiral phosphine ligand (entry 2); however, the
use of (R)-Cy-BINAP, (R)-SEGPHOS, and (R,R)-QuinoxP* led
to unsatisfactory results (entries 4–6).
Table 2 Optimization of Reaction Conditions: Alcoholsa
(R)-DM-BINAP (8 mol%)
O
AgOTf (16 mol%)
(i-Pr)2NEt (40 mol%)
OCOCF3
O
HO
*
alcohol (x equiv)
*
+
O
O
THF, –40 °C, 22 h
N
N
1a (1.5 equiv) 2d (1 equiv)
3ad
Bn
Bn
Table 1 Optimization of Reaction Conditions: Chiral Phosphinesa
Entry
Alcohol
x (equiv)
Yield (%)b
anti/sync
eed (%)
chiral phosphine (8 mol%)
AgOTf (16 mol%)
(i-Pr)2NEt (40 mol%)
1
2
3
4
5
6
7
8e
MeOH
MeOH
MeOH
MeOH
–
5
3
2
1
–
2
2
2
19
>99
82
63:37
55:45
40:60
46:54
36:64
55:45
28:72
75:25
73/9
O
OCOCF3
O
HO
81/14
95/25
94/18
19/26
82/19
49/20
98/6
*
MeOH (5 equiv)
*
+
O
O
THF, –40 °C, 22 h
N
N
>99
22
1a (1.5 equiv) 2d (1 equiv)
3ad
Bn
Bn
Entry
Chiral phosphine
Yield (%)b
anti/sync
ee (%)d
EtOH
>99
58
CF3CH2OH
MeOH
1
(R)-BINAP
92
52
19
49
<1
21
45:55
52:48
63:37
16:84
–
67/9
68/24
73/9
–25/23
–
>99
2
(R)-Tol-BINAP
(R)-DM-BINAP
(R)-Cy-BINAP
(R)-SEGPHOS
(R,R)-QuinoxP*
a Unless otherwise specified, the reaction was carried out using (R)-DM-
BINAP (8 mol%), silver triflate (16 mol%), N,N-diisopropylethylamine (40
mol%), alkenyl trifluoroacetate 1a (1.5 equiv), isatin derivative 2d (1 equiv),
and alcohol (x equiv) in THF at –40 °C for 22 h.
b Isolated yield.
3
4e
5
c Determined by 1H NMR analysis.
6
43:57
7/6
d Determined by HPLC analysis.
e The reaction was performed by using N,N-diisopropylethylamine (20
mol%) for 0.5 h.
t-Bu Me
O
(R)-BINAP (R = Ph)
N
P
PR2
PR2
O
O
PPh2
PPh2
(R)-Tol-BINAP (R = 4-MeC6H4)
(R)-DM-BINAP (R = 3,5-Me2C6H3)
N
P
(R)-Cy-BINAP (R = c-C6H11
)
O
Me t-Bu
(R,R)-QuinoxP*
With the optimum reaction conditions in hand, we ex-
amined the catalytic asymmetric aldol reaction of alkenyl
trifluoroacetate 1a with isatins 2a–f (Table 3). The protect-
ing group on the nitrogen atom of an isatin derivative is ex-
pected to have an effect on the electronic and/or steric na-
ture. First, isatin (2a) without an N-protective group was
tested in the asymmetric aldol reaction and target product
3aa was obtained with the anti/syn ratio of 40:60 in 43%
combined yield. The minor anti isomer showed 77% ee (en-
try 1). Use of N-methyl isatin (2b) resulted in raising the
isolated yield of product 3ab to >99% and anti selectivity
(entry 2). In contrast, the opposite syn selectivity as well as
a lower reactivity was observed for the reaction of isatin
derivative 2c, which has a Boc group as the N-protective
group (entry 3). N-Benzyl isatin (2d) displayed the highest
anti/syn selectivity and enantioselectivity among the N-
protected isatins 2b–f examined (compare entry 4 with en-
tries 2, 3, 5, and 6). Although N-p-methoxybenzylated de-
rivative 2e and N-tritylated derivative 2f also afforded en-
couraging results with respect to yield and/or anti/syn se-
lectivity, their enantioselectivities were somewhat
unsatisfactory (entries 5 and 6). Based on these results, we
came to the conclusion that the benzyl group is the most
suitable N-protective group for isatins. Subsequently, we
studied the catalytic asymmetric aldol reaction of alkenyl
trifluoroacetate 1a with isatin derivatives 2g–l derived
from diversely monosubstituted isatins (Table 3). High reac-
tivity and enantioselectivity were seen in the reaction of
(R)-SEGPHOS
a Unless otherwise specified, the reaction was carried out using chiral phos-
phine (8 mol%), silver triflate (16 mol%), N,N-diisopropylethylamine (40
mol%), alkenyl trifluoroacetate 1a (1.5 equiv), isatin derivative 2d (1 equiv),
and MeOH (5 equiv) in THF at –40 °C for 22 h.
b Isolated yield.
c Determined by 1H NMR analysis.
d Determined by HPLC analysis.
e MeOH (2 equiv) was used.
In order to obtain product 3ad having improved enan-
tiomeric ratio, we examined the effect of the amount of
MeOH in the aldol reaction by employing (R)-DM-BINAP as
the chiral ligand (Table 2, entries 1–4) and found that 3
equivalents of MeOH dramatically raised the isolated yield
of 3ad to >99% as well as the enantioselectivity of its anti
isomer to 81% ee (entry 2). Further decrease in the amount
of MeOH led to improvement of enantioselectivity and as a
consequence, more than 94% ee of the anti isomer of 3ad
was obtained in the case of 1 or 2 equivalents of MeOH (en-
tries 3 and 4). On the other hand, unsatisfactory yield and
stereoselectivities were observed in the absence of MeOH
(entry 5). Employment of EtOH also afforded promising re-
sults whereas CF3CH2OH reduced the yield of 3ad due to
competing protonation of alkenyl trifluoroacetate 1a with
the more acidic alcohol (entries 6 and 7). The optical purity
of the anti isomer reached 98% ee when the reaction was
carried out by using 20 mol% of (i-Pr)2NEt for 0.5 h (entry
8).
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–G

C
A. Yanagisawa, A. Kawada
Letter
Synlett
isatin derivative 2j, which has an electron-withdrawing
group at 6-position (entry 10). Isatins 2h and 2i, which
have a substituent at 5-position, furnished products 3ah
and 3ai in satisfactory isolated yields, respectively, and the
anti isomers exhibited good enantioselectivities (entries 8
and 9). However, isatins 2g and 2k gave unexpected results:
the bromo group at 4-position brought about an inverse syn
selectivity probably because of its steric effect, producing
syn isomer with 81% ee (entry 7), whereas 7-F substituted
isatin 2k significantly reduced the enantiomeric excess of
product 3ak (entry 11), although the reason for the low en-
antioselectivity is unclear at present. There were, however,
remarkable improvements in reactivity and enantioselec-
tivity when N-tritylated isatin derivative 2l was employed
instead of 2k (entry 12).
enantioselectivity of 91% ee (entry 3). The reaction of 1-in-
danone derivative 1b also furnished aldol product 3bd in
high yield, but the anti/syn ratio and the optical purity were
low (entry 1). Similar high reactivity was observed in the
cases of 6-methoxy-1-tetralone derivative 1d and 7-me-
Table 4 Enantioselective Aldol Reaction of Cyclic Alkenyl Esters 1a–h
with Isatin 2d Catalyzed by (R)-DM-BINAP·AgOTfa
(R)-DM-BINAP (8 mol%)
R3 R2
O
AgOTf (16 mol%)
(i-Pr)2NEt (20 mol%)
MeOH (2 equiv)
O
HO
OCOCX3
R3
*
*
R1
+
R1
O
O
THF, –40 °C, 0.5 h
N
N
R2
Bn
2d (1 equiv)
Bn
1a–h
3ad–hd
(X = F or Cl, 1.5
equiv)
Table 3 Enantioselective Aldol Reaction of Alkenyl Trifluoroacetate 1a
with Isatin (2a) and Isatin Derivatives 2b–l Catalyzed by (R)-DM-
BINAP·AgOTfa
Entry Alkenyl ester
OCOCF3
1b
Product Yield (%)b anti/sync ee (%)d
1
3bd
3ad
92
47:53
75:25
2/3
(R)-DM-BINAP (8 mol%)
AgOTf (16 mol%)
O
OCOCF3
O
HO
(i-Pr)2NEt (20 mol%)
*
OCOCF3
MeOH (2 equiv)
*
R1
R1
+
O
O
2
>99
98/6
THF, –40 °C, 0.5 h
N
N
R2
R2
3aa–al
1a (1.5 equiv) 2a–l (1 equiv)
1a
CF3COO
Entry Isatins 2a–l
Product Yield (%)b anti/sync eed (%)
3
3cd
>99
92:8
91/21
R1
R2
H (2a)
1c
1
2
H
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
43
>99
45
40:60
67:33
31:69
75:25
75:25
69:31
30:70
65:35
44:56
55:45
59:41
50:50
77/10
70/17
71/5
OCOCF3
H
Me (2b)
Boc (2c)
Bn (2d)
PMB (2e)
Tr (2f)
4
5
6
3dd
3ed
3fd
>99
>99
75
69:31
70:30
65:35
69/20
81/7
3
H
1d
MeO
MeO
4
H
>99
>99
78
98/6
5
H
91/4
OCOCF3
6
H
87/88
44/81
70/21
86/<1
97/3
1e
7
4-Br
5-Me
5-F
6-Cl
7-F
7-F
Bn (2g)
Bn (2h)
Bn (2i)
Bn (2j)
Bn (2k)
Tr (2l)
87
8
97
OCOCCl3
9
82
51/11
10
11
12
3aj
93
1f
3ak
3al
78
<1/12
75/12
OCOCF3
>99
7e
8f
3gd
3hd
16
96
11:89
12:88
52/36
18/1
a Unless otherwise specified, the reaction was carried out using (R)-DM-
BINAP (8 mol%), silver triflate (16 mol%), N,N-diisopropylethylamine (20
mol%), alkenyl trifluoroacetate 1a (1.5 equiv), isatin derivative (2a–l, 1
equiv), and MeOH (2 equiv) in THF at –40 °C for 0.5 h.
b Isolated yield.
1g
OCOCF3
c Determined by 1H NMR analysis.
d Determined by HPLC analysis.
1h
a Unless otherwise specified, the reaction was carried out using (R)-DM-
BINAP (8 mol%), silver triflate (16 mol%), N,N-diisopropylethylamine (20
mol%), cyclic alkenyl ester 1a–h (1.5 equiv), isatin derivative 2d (1 equiv),
and MeOH (2 equiv) in THF at –40 °C for 0.5 h.
b Isolated yield.
The above-mentioned results encouraged us to study
the utility of diverse alkenyl trifluoroacetates in the catalyt-
ic asymmetric aldol reaction of isatins. First, we focused on
cyclic alkenyl trifluoroacetates and summarize our results
in Table 4.8 1-Benzosuberone derivative 1c gave the corre-
sponding product 3cd in an almost quantitative yield with
c Determined by 1H NMR analysis.
d Determined by HPLC analysis.
e The reaction was performed for 22 h.
f The reaction was performed for 24 h.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–G

D
A. Yanagisawa, A. Kawada
Letter
Synlett
thoxy-1-tetralone derivative 1e, but with moderate diaste-
reo- and enantioselectivities (entries 4 and 5). Use of cyclo-
hexanone-derived cyclic alkenyl ester 1f9 resulted in a de-
crease in both the yield and the enantiomeric excess of
product 3fd10 (entry 6). Noteworthy is the fact that 2-meth-
yl-1-tetralone derivative 1g afforded the desired product
3gd in an unsatisfactory yield (entry 7), but 2-methyl-1-in-
danone derivative 1h had high reactivity toward isatin 2d,
regardless of the steric bulkiness at 2-position (entry 8).
Table 5 Enantioselective Aldol Reaction of Acyclic Alkenyl Esters 1i–p with Isatins 2d and 2f Catalyzed by (R)-DM-BINAP·AgOTfa
(R)-DM-BINAP (8 mol%)
R2
O
AgOTf (16 mol%)
(i-Pr)2NEt (20 mol%)
R4OH (2 equiv)
O
HO
OCOCX3
R2
*
R1
O
*
+
R1
O
THF, –40 °C, 0.5 h
N
R3
N
R3
1i–p
2d: R3 = Bn
3id–pf
(X = F or Cl,
1.5 equiv)
2f: R3 = Tr
(1 equiv)
Entry
1
Alkenyl ester
R3
R4
Product
Yield (%)b
>99
anti/sync
eed (%)
51/16
OCOCF3
Bn
Me
Me
3id
32:68
Ph
1i (E/Z < 1/20)
2
3
1i (E/Z < 1:20)
1i (E/Z < 1:20)
Tr
Tr
3if
3if
90
69
42:58
38:62
4/65
CF3CH2
22/75
OCOCF3
4
5
6
7
8
Tr
Tr
Tr
Tr
Tr
CF3CH2
CF3CH2
CF3CH2
CF3CH2
CF3CH2
3jf
68
59
86
78
88
32:68
44:56
39:61
<1:20
47:53
52/82
50/80
28/83
–/96
Ph
1j (E/Z < 1/20)
OCOCF3
3kf
3lf
Ph
1k (E/Z = 1/8)
OCOCF3
Ph
1l (E/Z = 1/10)
CF3COO
3mf
3nf
Ph
1m (E/Z < 1/20)
OCOCCl3
66/71
1n (E/Z = 1/4)
OCOCF3
9
Tr
Tr
CF3CH2
3of
3pf
75
55
40:60
43/71
Br
1o (E/Z < 1/20)
Br
OCOCF3
10
CF3CH2
<1:20
–/87
1p (E/Z = 1/2)
a Unless otherwise specified, the reaction was carried out using (R)-DM-BINAP (8 mol%), silver triflate (16 mol%), N,N-diisopropylethylamine (20 mol%), alkenyl
ester 1i–p (1.5 equiv), isatin derivative 2d or 2f (1 equiv), and MeOH or CF3CH2OH (2 equiv) in THF at –40 °C for 0.5 h.
b Isolated yield.
c Determined by 1H NMR analysis.
d Determined by HPLC analysis.
e The reaction was performed at –20 °C.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–G

E
A. Yanagisawa, A. Kawada
Letter
Synlett
In contrast to the cyclic alkenyl esters, acyclic alkenyl
esters 1i–p furnished the opposite syn selectivity, as shown
in Table 5. When propiophenone derivative 1i (E/Z <1/20)
was employed as the substrate in the catalytic asymmetric
aldol reaction under the standard reaction conditions, a
32:68 anti/syn mixture of targeted aldol adduct 3id was ob-
tained in a nearly quantitative yield but the optical purity
of the syn isomer was low (entry 1). Changing the R3 pro-
tective group into the Tr group was effective in acquiring a
higher enantiomeric excess (entry 2). Further improvement
in the enantiomeric excess of the product was attained
when CF3CH2OH was adopted as the alcohol in place of
MeOH (entry 3). Under the modified reaction conditions,
we examined various acyclic ketone-derived alkenyl trifluo-
roacetates 1j–p as the precursors of chiral silver enolates in
the asymmetric aldol reaction and found that syn adducts
were formed selectively in every case (entries 4–10). The
employment of an acyclic aromatic ketone derivative pos-
sessing a long or a bulky alkyl substituent was effective in
increasing the extent of the asymmetric induction. In fact,
the highest enantioselectivity (96% ee) was seen in the re-
action of acyclic alkenyl trifluoroacetate 1m with 2f (entry
7). 1-(2-Bromophenyl)propan-1-one derivative 1p was also
a favorable acyclic substrate for realizing a high enantio-
selectivity (entry 10).
A proposed reaction mechanism is illustrated in Scheme
2. First, (R)-DM-BINAP·AgOTf reacts with an alcohol in the
presence of N,N-diisopropylethylamine to give the corre-
sponding (R)-DM-BINAP·AgOR, which is the true catalyst in
the present asymmetric aldol reaction. Subsequently, the
thus-formed chiral silver alkoxide attacks alkenyl trihaloac-
etate 1 to give chiral silver enolate 4. The following aldol re-
action of chiral silver enolate 4 with isatin derivative 2
yields chiral silver alkoxide of aldol adduct 5. Lastly, chiral
silver alkoxide of aldol adduct 5 undergoes protonation
with an alcohol to provide optically active -hydroxy ke-
tone 3 with regeneration of the chiral silver alkoxide. The
rate of alcoholysis of silver alkoxide 5 plays a crucial role in
the catalytic cycle.11
O
R3
P
O
P
P
O
R1
R2
Ag
O
*
N
R4
Ag
R2
2
O
P
*
*
R3
O
R1
N
R4
4
5
O
R1
R2
ROCOCX3
OCOCX3
R1
ROH
R3
HO
*
P
P
*
AgOR
O
*
N
R2
3
R4
1 (X = F or Cl)
(i-Pr)2EtHN+ TfO–
P
P
PAr2
PAr2
=
ROH, (i-Pr)2NEt
*
P
AgOTf
*
(R)-DM-BINAP
(Ar = 3,5-Me2C6H3)
P
Scheme 2 Plausible catalytic cycle for the asymmetric aldol reaction
Funding Information
This work was supported by the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) and the Japan Society for the
Promotion of Science (JSPS KAKENHI, Grant Numbers 16K05766 and
19K05450). We acknowledge the generous gifts of (R)-DM-BINAP, (R)-
Cy-BINAP, and (R)-SEGPHOS from Takasago International Corporation
and (R,R)-QuinoxP* from Nippon Chemical Industrial Co., Ltd. We
gratefully acknowledge the financial support from Nippoh Chemicals
Co., Ltd.JapanSocietyforth
e
Pro
m
oti
o
n
o
f
S
cience(1
6
K
0
5
7
6
6)JapanSocietyforth
e
Pro
m
oti
o
n
o
f
S
cience(1
9
K
0
5
4
5
0)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1479-4694. Su
p
p
orti
ngInformatio
n
Su
p
p
ortingInformatio
n
References and Notes
(1) For representative examples, see: (a) Tokunaga, T.; Hume, W. E.;
Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.; Hourai, S.;
Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med.
Chem. 2001, 44, 4641. (b) Kitajima, M.; Mori, I.; Arai, K.; Kogure,
N.; Takayama, H. Tetrahedron Lett. 2006, 47, 3199.
(2) (a) Kamano, Y.; Zhang, H.-P.; Ichihara, Y.; Kizu, H.; Komiyama,
K.; Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783. (b) Zhang, H.-P.;
Kamano, Y.; Ichihara, Y.; Kizu, H.; Komiyama, K.; Itokawa, H.;
Pettit, G. R. Tetrahedron 1995, 51, 5523. (c) Takayama, H.;
Shimizu, T.; Sada, H.; Harada, Y.; Kitajima, M.; Aimi, N. Tetrahe-
dron 1999, 55, 6841. (d) Kamano, Y.; Kotake, A.; Hashima, H.;
Hayakawa, I.; Hiraide, H.; Zhang, H.-P.; Kizu, H.; Komiyama, K.;
Hayashi, M.; Pettit, G. R. Collect. Czech. Chem. Commun. 1999, 64,
1147.
(3) For reviews, see: (a) Flores, M.; Pena, J.; García-García, P.;
Garrido, N. M.; Diez, D. Curr. Org. Chem. 2013, 17, 1957.
(b) Gong, Y.; Yu, J.-S.; Hao, Y.-J.; Zhou, Y.; Zhou, J. Asian. J. Org.
Chem. 2019, 8, 610. For selected examples of asymmetric aldol
reactions of isatins using organocatalysts, see: (c) Luppi, G.;
Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.;
Tomasini, C. J. Org. Chem. 2005, 70, 7418. (d) Luppi, G.; Monari,
In summary, we have achieved a novel method for the
catalytic asymmetric synthesis of chiral isatin derivatives
through the enantioselective aldol reaction of alkenyl tri-
haloacetates with isatins. The use of in situ generated chiral
silver alkoxide12 as the chiral catalyst has permitted the
synthesis of various optically active 3-alkylated 3-hydroxy-
2-oxyindoles in a diastereoselective manner, and high en-
antioselectivities of up to 98% ee have been attained not
only from cyclic alkenyl esters but also from acyclic ones.
Further studies of related reactions catalyzed by a chiral sil-
ver alkoxide are under way.
Conflict of Interest
The authors declare no conflict of interest.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–G

F
A. Yanagisawa, A. Kawada
Letter
Synlett
M.; Corrêa, R. J.; Violante, F. A.; Pinto, A. C.; Kaptein, B.;
Broxterman, Q. B.; Garden, S. J.; Tomasini, C. Tetrahedron 2006,
62, 12017. (e) Malkov, A. V.; Kabeshov, M. A.; Bella, M.; Kysilka,
O.; Malyshev, D. A.; Pluháčková, K.; Kočovský, P. Org. Lett. 2007,
9, 5473. (f) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.;
Shibata, N.; Toru, T. Chem. Eur. J. 2008, 14. 8079. (g) Hara, N.;
Nakamura, S.; Shibata, N.; Toru, T. Chem. Eur. J. 2009, 15, 6790.
(h) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 3854.
(i) Hara, N.; Nakamura, S.; Shibata, N.; Toru, T. Adv. Synth. Catal.
2010, 352, 1621. (j) Hara, N.; Nakamura, S.; Funahashi, Y.;
Shibata, N. Adv. Synth. Catal. 2011, 353, 2976. (k) Liu, Y.-L.; Zhou,
J. Chem. Commun. 2012, 48, 1919. (l) Xue, F.; Zhang, S.; Liu, L.;
Duan, W.; Wang, W. Chem. Asian J. 2009, 4, 1664. (m) Guo, Q.;
Bhanushali, M.; Zhao, C.-G. Angew. Chem. Int. Ed. 2010, 49, 9460.
(n) Jiang, X.; Cao, Y.; Wang, Y.; Liu, L.; Shen, F.; Wang, R. J. Am.
Chem. Soc. 2010, 132, 15328. (o) Guang, J.; Guo, Q.; Zhao, C.-G.
Org. Lett. 2012, 14, 3174. (p) Liu, Y.; Gao, P.; Wang, J.; Sun, Q.;
Ge, Z.; Li, R. Synlett 2012, 23, 1031. (q) Mao, Z.; Zhu, X.; Lin, A.;
Li, W.; Shi, Y.; Mao, H.; Zhu, C.; Cheng, Y. Adv. Synth. Catal. 2013,
355, 2029. (r) Suh, C. W.; Chang, C. W.; Choi, K. W.; Lim, Y. J.;
Kim, D. Y. Tetrahedron Lett. 2013, 54, 3651. (s) Abbaraju, S.;
Zhao, J. C.-G. Adv. Synth. Catal. 2014, 356, 237. (t) Cañellas, S.;
Alonso, P.; Pericàs, M. À. Org. Lett. 2018, 20, 4806. (u) Li, Y.-L.;
Wang, X.-L.; Xiao, D.; Liu, M.-Y.; Du, Y.; Deng, J. Adv. Synth. Catal.
2018, 360, 4147. (v) Wang, J.; Deng, Z.-X.; Wang, C.-M.; Xia, P.-J.;
Xiao, J.-A.; Xiang, H.-Y.; Chen, X.-Q.; Yang, H. Org. Lett. 2018, 20,
7535. (w) Zhang, D.; Chen, Y.; Cai, H.; Yin, L.; Zhong, J.; Man, J.;
Zhang, Q.-F.; Bethi, V.; Tanaka, F. Org. Lett. 2020, 22, 6. (x) Yang,
X.; Majhi, P. K.; Chai, H.; Liu, B.; Sun, J.; Liu, T.; Liu, Y.; Zhou, L.;
Xu, J.; Liu, J.; Wang, D.; Zhao, Y.; Jin, Z.; Chi, Y. R. Angew. Chem.
Int. Ed. 2021, 60, 159.
Entry 4 in Table 3, and Entry 2 in Table 4)
A mixture of AgOTf (20.6 mg, 0.08 mmol) and (R)-DM-BINAP
(29.4 mg, 0.04 mmol) was dissolved in dry THF (6 mL) under an
argon atmosphere with direct light excluded and stirred at
room temperature for 20 min. To the resulting solution were
added MeOH (40.6 L, 1.0 mmol) and (i-Pr)2NEt (17 L, 0.10
mmol) successively at –40 °C. The mixture was stirred at that
temperature for 5 min. Then, alkenyl trifluoroacetate 1a (181.6
mg, 0.75 mmol) and isatin derivative 2d (118.6 mg, 0.5 mmol)
were successively added drop by drop to the resulting solution
at –40 °C. After stirring for 30 min at that temperature, the
mixture was treated with MeOH (3 mL). Then, the mixture was
filtered with a glass filter funnel filled with Celite® and washed
with EtOAc, and the combined filtrate and washes were concen-
trated in vacuo. The residual crude product was purified by
column chromatography on silica gel to give corresponding -
hydroxy ketone 3ad (191.7 mg, >99% yield). The anti/syn ratio
was determined to be 75:25 by 1H NMR analysis. The enantio-
meric ratio of the anti isomer was determined to be 98% ee by
HPLC analysis using a chiral column [Daicel Chiralpak AD-3,
hexane–i-PrOH (4:1), flow rate = 1.0 mL/min]: t1 = 36.0 min
(major), t2 = 47.1 min (minor). The enantiomeric ratio of the syn
isomer was determined to be 6% ee by HPLC analysis using a
chiral column [Daicel Chiralpak AD-3, hexane–i-PrOH (4:1),
flow rate = 1.0 mL/min]: t1 = 23.1 min (minor), t2 = 28.7 min
(major).
Spectral Data of the Product
anti Isomer
1H NMR (400 MHz, CDCl3):  = 8.10 (dd, J = 8.0, 1.2 Hz, 1 H), 7.49
(td, J = 7.5, 1.4 Hz, 1 H), 7.41 (dd, J = 7.3, 0.8 Hz, 1 H), 7.18–7.35
(m, 8 H), 7.06 (td, J = 7.5, 0.8 Hz, 1 H), 6.71 (d, J = 7.9 Hz, 1 H),
6.23 (s, 1 H), 4.87 (dd, J = 29.8, 15.7 Hz, 2 H), 3.21 (dd, J = 13.2,
4.7 Hz, 1 H), 2.83–2.98 (m, 2 H), 1.80–1.97 (m, 2 H). 13C NMR
(100 MHz, CDCl3):  = 199.8, 176.8, 143.9, 143.6, 135.5, 134.1,
132.5, 130.0, 128.7 (2 C), 128.6, 128.4, 127.9, 127.6, 127.3 (2 C),
127.0, 123.9, 123.2, 109.5, 78.3, 51.6, 43.8, 28.9, 24.2. IR (neat):
3300, 2959, 1681, 1614, 1496, 1467, 1433, 1389, 1358, 1321,
1264, 1221, 1183, 1156, 1073, 1015, 998, 932 cm–1. MS (ESI):
m/z calcd for [C25H21O3NNa]+ ([M + Na]+): 406.1414; found:
406.1409; []D23.8 –51.0 (c 1.0, CHCl3, 98% ee); mp 178–180 °C.
syn Isomer
(4) (a) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.;
Franz, A. K. Angew. Chem. Int. Ed. 2010, 49, 744. (b) Aikawa, K.;
Mimura, S.; Numata, Y.; Mikami, K. Eur. J. Org. Chem. 2011, 62.
(c) Yanagisawa, A.; Kushihara, N.; Sugita, T.; Yoshida, K. Synlett
2012, 23, 1783. (d) Li, J.; Li, Y.; Sun, J.; Gui, Y.; Huang, Y.; Zha, Z.;
Wang, Z. Chem. Commun. 2019, 55, 6309. For examples of
related aldol reactions: (e) Lu, Y.; Wang, M.; Zhao, X.; Liu, X.;
Lin, L.; Feng, X. Synlett 2015, 26, 1545. (f) Dai, L.; Lin, L.; Zheng,
J.; Zhang, D.; Liu, X.; Feng, X. Org. Lett. 2018, 20, 5314.
(5) Yanagisawa, A.; Miyake, R.; Yoshida, K. Eur. J. Org. Chem. 2014,
4248.
(6) (a) Gil, J.; Medio-Simon, M.; Mancha, G.; Asensio, G. Eur. J. Org.
Chem. 2005, 1561. (b) Claraz, A.; Leroy, J.; Oudeyer, S.; Levacher,
V. J. Org. Chem. 2011, 76, 6457.
(7) In our previous study on the chiral silver(I)-catalyzed asymmet-
ric allylation of aldehydes, we showed that a considerable
amount of an inert 2:1 complex of BINAP/silver(I) salt was
formed accompanied by a reactive 1:1 complex when BINAP
was added to an equimolar amount of the silver salt in MeOH. In
the reaction, a 0.6:1 mixture of BINAP/silver(I) salt was found to
produce the desired 1:1 complex without the formation of the
2:1 complex: (a) Yanagisawa, A.; Kageyama, H.; Nakatsuka, Y.;
Asakawa, K.; Matsumoto, Y.; Yamamoto, H. Angew. Chem. Int.
Ed. 1999, 38, 3701. (b) Yanagisawa, A.; Nakatsuka, Y.; Asakawa,
K.; Kageyama, H.; Yamamoto, H. Synlett 2001, 69.
(c) Yanagisawa, A.; Nakatsuka, Y.; Asakawa, K.; Wadamoto, M.;
Kageyama, H.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2001, 74,
1477.
1H NMR (400 MHz, CDCl3):  = 8.13 (dd, J = 7.9, 1.1 Hz, 1 H), 7.50
(td, J = 7.5, 1.3 Hz, 1 H), 7.27–7.37 (m, 7 H), 7.14–7.20 (m, 2 H),
6.93 (td, J = 7.6, 0.9 Hz, 1 H), 6.73 (d, J = 7.9 Hz, 1 H), 6.23 (s, 1 H),
5.00 (d, J = 15.5 Hz, 1 H), 4.86 (d, J = 15.7 Hz, 1 H), 3.45 (dd, J =
13.8, 4.4 Hz, 1 H), 3.01–3.10 (m, 1 H), 2.79 (dt, J = 16.7, 3.4 Hz, 1
H), 1.83–1.89 (m, 1 H), 1.40 (qd, J = 13.2, 4.3 Hz, 1 H). 13C NMR
(100 MHz, CDCl3):  = 201.9, 174.7, 144.3, 143.0, 135.4, 134.6,
132.2, 129.6, 129.5, 128.8 (2 C), 128.7, 127.7, 127.4, 127.3 (2 C),
126.9, 124.6, 123.3, 109.5, 78.6, 51.9, 43.9, 28.5, 24.7. IR (neat):
3399, 1685, 1615, 1492, 1456, 1371, 1226, 1172, 1073, 940 cm–1
.
MS (ESI): m/z calcd for [C25H21O3NNa]+ ([M + Na]+): 406.1414;
23.9
found: 406.1407; []D
+6.3 (c 0.99, CHCl3, 6% ee); mp 147–
148 °C.
(9) Libman, J.; Sprecher, M.; Mazur, Y. Tetrahedron 1969, 25, 1679.
(10) The anti/syn ratio of 3fd was determined by comparison with
reported 1H NMR data: (a) Zhao, H.; Meng, W.; Yang, Z.; Tian, T.;
Sheng, Z.; Li, H.; Song, X.; Zhang, Y.; Yang, S.; Li, B. Chin. J. Chem.
2014, 32, 417. See also: (b) Mao, Z.; Zhu, X.; Lin, A.; Li, W.; Shi,
Y.; Mao, H.; Zhu, C.; Cheng, Y. Adv. Synth. Catal. 2013, 355, 2029;
the anti/syn ratios of other aldol products 3 were determined by
analogy.
(8) Typical Experimental Procedure for the Asymmetric Aldol
Reaction Catalyzed by (R)-DM-BINAP·AgOTf and (i-Pr)2NEt:
Synthesis of 1-Benzyl-3-hydroxy-3-(1-oxo-1,2,3,4-tetrahy-
dronaphthalen-2-yl)indolin-2-one (3ad, Entry 8 in Table 2,
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–G

G
A. Yanagisawa, A. Kawada
Letter
Synlett
(11) Use of small amount of ROH decreases the rate of alcoholysis of
silver alkoxide 5 resulting in low yield of the desired product 3,
while excess amount of ROH accelerate the protonation of chiral
silver enolate 4 and reduces the yield of 3.
(12) Two examples of the synthesis of achiral silver alkoxides have
been reported: (a) Edworthy, I. S.; Rodden, M.; Mungur, S. A.;
Davis, K. M.; Blake, A. J.; Wilson, C.; Schröder, M.; Arnold, P. L.
J. Organomet. Chem. 2005, 690, 5710. (b) Reisinger, A.; Himmel,
D.; Krossing, I. Angew. Chem. Int. Ed. 2006, 45, 6997.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–G