Highly enantioselective aldol reaction of acetaldehyde and isatins only with 4-hydroxydiarylprolinol as catalyst: concise stereoselective synthesis of (R)-convolutamydines B and E, (-)-donaxaridine and (R)-chimonamidine

Article abstract of DOI:10.1016/j.tet.2009.12.041

A highly enantioselective aldol reaction of acetaldehyde and a wide scope of isatins has been presented only using readily available 4-hydroxydiarylprolinol as catalyst, affording various desired 3-substituted 3-hydroxyindolin-2-one adducts with moderate to high yield (up to 95%) and good enantioselectivities (up to 98% ee). This method not only represents an example of concise stereoselective synthesis of enantiopure (R)-convolutamydines B and E, but also firstly exhibits expedient asymmetric synthesis optically active (-)-donaxaridine and (R)-chimonamidine.

Full text of DOI:10.1016/j.tet.2009.12.041

Tetrahedron 66 (2010) 1441–1446
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly enantioselective aldol reaction of acetaldehyde and isatins only with
4-hydroxydiarylprolinol as catalyst: concise stereoselective synthesis of (R)-
convolutamydines B and E, (ꢀ)-donaxaridine and (R)-chimonamidine
,
,
*
Wen-Bing Chen a b, Xi-Lin Du c, Lin-Feng Cun a, Xiao-Mei Zhang a, Wei-Cheng Yuan a
a Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, PR China
b Graduate School of Chinese Academy of Sciences, Beijing 100049, PR China
c Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an 710038, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 October 2009
Received in revised form 8 December 2009
Accepted 18 December 2009
Available online 24 December 2009
A highly enantioselective aldol reaction of acetaldehyde and a wide scope of isatins has been presented
only using readily available 4-hydroxydiarylprolinol as catalyst, affording various desired 3-substituted
3-hydroxyindolin-2-one adducts with moderate to high yield (up to 95%) and good enantioselectivities
(up to 98% ee). This method not only represents an example of concise stereoselective synthesis of
enantiopure (R)-convolutamydines B and E, but also firstly exhibits expedient asymmetric synthesis
optically active (ꢀ)-donaxaridine and (R)-chimonamidine.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Organocatalysis
Aldol reaction
Acetaldehyde
Asymmetric catalysis
Isatins
1. Introduction
Chimonanthus Precox Link. In this context, it should be importance
to develop efficient and practical methods for the synthesis of op-
3-Substituted-3-hydroxyindolin-2-ones are useful synthetic
intermediates for alkaloids and biologically active compounds,
such as convolutamydines A–E,1 donaxaridine,2 chimonamidine,2
30-hydroxyglucoisatisin,3 and TMC-95s4 (Fig. 1). Convolutamydines
A–E are members of a class of oxindole alkaloids having 4,6-
dibromo-3-hydroxyoxindole as a common motif and differ each
other in a side chain moiety at C-3 (Fig. 1). Notably, the interest in
their skeletal structures and the potent biological activities of
convolutamydines A and B1a,b are reflected by some methodologies
that have been developed and continue to be explored for their
synthesis.5–7 However, as for convolutamydines A–E, there are only
few reports for the synthesis of optically active convolutamydines B
and E through an enantioselective reaction so far6,7, moreover, the
potential biological effects of convolutamydine B or E have not been
sufficiently evaluated due to the scarcity of them. At the same time,
we also amazedly note that there no any catalytic asymmetric
synthetic methods reported for the synthesis of optically active
donaxaridine2c (Fig. 1), which is a very important alkaloid isolated
from Arundo donax, and chimonamidine2b (Fig. 1), which is a novel
tryptamine-related alkaloid isolated from the seeds of
tically active convolutamydines B and E, chimonamidine, and
donaxaridine.
In the last years, organocatalysis has proved to be a powerful
tool in the development of a large number of enantioselective re-
actions.8 There have been ample reports on the reaction employing
various aldehydes as nucleophiles.9 However, until recently, using
acetaldehyde as a nucleophile has been identified as a powerful,
metal-free method for the synthesis of 1,3-diols,
b-amino alde-
hydes, and -substituted-
b
g
-nitroaldehydes.7,10 In spite of this, the
aldol reaction of acetaldehyde with ketones is strongly desired
since the resulting tertiary products are valuable building blocks for
the subunits. Consequently, it is interesting that developing an
asymmetric aldol reaction between acetaldehyde with high re-
active ketones. Isatin and its derivatives are susceptible to nucleo-
philic attack at C-3 ketone carbonyl and aldol type condensations
are readily performed under a variety of conditions.11,12 Based on
this chem-information and our interest in the investigation into the
reactivity of isatins,12 we envision that the asymmetric aldol re-
action between acetaldehyde and isatins should be achievable, and
thus provide various chiral 3-substituted-3-hydroxyindolin-2-
ones. Recently, Nakamura and co-workers firstly reported the
asymmetric aldol reaction of acetaldehyde and isatin catalyzed by
N-(2-thiophenesulfonyl)prolinamide and its synthetic applications
* Corresponding author: Fax: þ86 28 85229250.
E-mail address: yuanwc@cioc.ac.cn (W.-C. Yuan).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.041

1442
W.-B. Chen et al. / Tetrahedron 66 (2010) 1441–1446
Table 1
Me
Br
Screening of various reaction conditionsa
O
HO
N
A: R = CH2COCH3
B: R = CH2CH2Cl
C: R = CH3
D: R = CH=CH2
E: R = CH2CH2OH
NHR'
* R
OH
*
O
HO
O
O
HO
N
Br
NaBH4 (5.0 equiv.)
CH3OH, 0 °C
1(x mol %)
H
O
+
O
H
R' = H, Donaxaridine
R' = Me, Chimonamidine
solvent
N
N
Convolutamydine A-E
H
H
4a
2a
3
O
HO
H
O
HO
R1
R2
R2
N
CH3
H
O
HO
NH
R2
R2
*
O
O
R3
COOH
N
O
O
N
H
H
N
H
N
_
HO
1a: R1 = H
1b: R1 = OH
HN
NH2
CH3
OSO3
OH
S
N
O
O
HO
H
1c -1g
HO
HO
OH
O
O
1c: R2 = H, R3 = H
1d: R2 = CF3, R3 = H
1e: R2 = CF3, R3 = OH
CH3
H
N
HN
Ph
Ph
N
H
3'-Hydroxygluoisatisin
O
1f: R2 = CF3, R3 = OBn
1g: R2 = CF3, R3 = TBDMSO
TMC-95A
HO
1h
Figure 1. Representative examples of biologically active 3-substituted-3-hydroxy-
indolin-2-ones.
Entry
1 (x)
Solvent
Time (h)
T (ꢁC)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1f (10)
1g (10)
1h (10)
1e (10)
1e (10)
1e (10)
1e (10)
1e (10)
1e (10)
1e (10)
1e (5)
1e (20)
1e (20)
1e (20)
1e (20)
1e (20)
1e (20)
1e (20)
1e (20)
1e (20)
DME
DME
DME
DME
DME
DME
DME
DME
THF
24
24
36
36
24
24
24
24
24
36
24
24
24
24
24
24
15
24
40
72
96
90
90
90
90
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
25
50
70
87
90
83
83
77
70
80
71
66
84
39
61
21
93
85
90
25
90
80
80
62
90
(ꢀ)15
17
to chiral convolutamydine B and E.7a However, in this method, the
gainable high enantioselectivities were only limited to halogen-
substituted isatin substrates. Shortly after this, while our this
manuscript was soon ready to submit, Hayashi and co-workers also
reported the asymmetric aldol reaction of acetaldehyde and isatin
derivatives with 4-hydroxydiarylprolinol as catalyst.7b In this re-
port, it was inevitable that using 30 mol % catalysts loading and the
same amount ClCH2CO2H as additive for completion the aldol re-
actions, which only tolerated limited N-protected isatin derivatives
generating desired adducts in moderate yields with the highest 85%
ee. Despite this, herein, we also hope to report our highly enan-
tioselective aldol reaction of acetaldehyde with a wide scope of
isatins only use 4-hydroxydiarylprolinol as catalyst for smoothly
providing desired products with good yields (up to 95%) and good
enantioselectivities (up to 98% ee), which is further used for concise
stereoselective synthesis of optically active convolutamydines B
and E, donaxaridine and chimonamidine.
(ꢀ)25
67
70
69
66
53
62
32
35
55
55
39
60
71
72
72
74
75
9
10
11
12
13
14
15
16
17
18
19
20
21d
22
23
24
25
DCM
CH3CN
Et2O
Dioxane
C2H5OH
AcOEt
DME
DME
DME
DME
DME
DME
DME
DME
DME
DME
0
ꢀ10
ꢀ20
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
80
66e
66f
70g
59h
2. Results and discussion
a
Unless otherwise noted, reactions were performed with 2a (0.5 mmol),
in the corresponding solvent (0.5 mL). c¼1.0 M.
DME¼1,2-Dimethoxyethane, DCM¼Dichloromethane.
3
(2.5 mmol), and catalysts
1
As a model reaction, we studied the reactivity of free isatin (2a)
with acetaldehyde (3) in the presence of various catalysts and un-
der different reaction conditions, and the aldol adduct was reduced
by NaBH4 in methanol at 0 ꢁC giving optically active product 4a as
aim product to facilitate the separation and detection13 (Table 1).
Initial experiments were performed with 2a, 5.0 equiv 3 and
10 mol % catalysts in 1,2-dimethoxyethane (DME) at 15 ꢁC to screen
catalysts, It was appeared from the results given in entries 1–8
(Table 1) that catalyst 1e was the most effective catalyst for the
reaction in terms of reactivity and selectivity (Table 1, entry 5). And
then, the screening of solvents showed that the model reaction
proceeded smoothly in a variety of reaction medium, significantly,
1,2-dimethoxyethane (DME) was found to be superior to other
solvents in terms of yield and ee value (Table 1, entries 5 and 9–15).
Interestingly, we found that the reaction even proceeded smoothly
only with catalyst 1e in DME, however, in Hayashi’s system,7b the
reaction must be catalyzed by catalyst 1e and with acid as additive
in DMF. Through the further investigation to catalysts loading, we
found that very low yield was observed when the reaction was
carried out with 5 mol % 1e, albeit giving almost unchanged ee
value (Table 1, entry 16). On the other hand, increasing the catalyst
loading to 20 mol %, the reaction completed in shorter reaction
time and furnished product 4a in 93% isolated yield and 72% ee
(Table 1, entry 17). Further optimization to reaction temperature, no
significant change was found in enantioselectivity when the
b
Yield of isolated product by column chromatography after the aldol adduct was
reduced.
c
The ee values were determined by chiral stationary phase HPLC.
d
The reaction was performed with 2a (0.1 mmol), 3 (0.5 mmol), and catalyst 1e
(20 mol %) in DME (1.2 mL) at ꢀ10 ꢁC for 96 h. c¼0.08 M.
e
The reaction was conducted as Table 1, entry 21 for 90 h, and using 20 mol %
PhCOOH as additive.
f
The reaction was conducted as Table 1, entry 21 for 90 h, and using 20 mol %
AcOH as additive.
g
The reaction was conducted as Table 1, entry 21 for 90 h, and using 20 mol %
Cl2CHCOOH as additive.
h
The reaction was conducted as Table 1, entry 21 for 90 h, and using 20 mol % 3,5-
dinitrobenzoic acid as additive.
reaction was run at 0 ꢁC (Table 1, entry 18), and slighter higher ee
value was observed for the reaction carried out at ꢀ10 ꢁC with
prolonged reaction time (Table 1, entry 19). However, the product
only in 25% yield was obtained with further decreasing tempera-
ture to ꢀ20 ꢁC even though prolonging reaction time to 72 h (Table
1, entry 20). Gratifying, the reaction proceeded also smoothly under
low concentration at ꢀ10 ꢁC and provided 4a in 80% ee and 90%
isolated yield with longer reaction time (Table 1, entry 21). Sub-
sequently, we tried to further improve the enantioselectivity
through adding PhCOOH, AcOH, Cl2CHCOOH, and 3,5-dini-
trobenzoic acid as additive, respectively (Table 1, entries 22–25), it
revealed that with the addition of various acid, the reactions were

W.-B. Chen et al. / Tetrahedron 66 (2010) 1441–1446
1443
slightly faster but the enantioselectivities significantly decreased
(Table 1, entries 22–25 vs entry 21).
Scheme 1, the optically (R)-convolutamydine E (4j) could be readily
transformed into (R)-convolutamydine B (5) with sequence of
tosylation and chlorination without racemization (Scheme 1).16
Having established what we believed to be the optimal reaction
conditions,14 we next examined the scope of this methodology with
a variety of isatin derivatives to establish the generality of the
process. The scope of the reaction was summarized in Table 2. It
was found that various isatin derivatives 2b–j and 2n bearing either
electro-donating or electron-withdrawing substituent on the phe-
nyl ring could be well tolerated, and the corresponding products
were obtained in good to excellent enantioselectivities (84–98% ee)
and moderate to very high yield (50–95%, Table 2, entries 2–10 and
14). It should be noted that incorporation of substituent at the C-4
position of isatins showed obvious improvement to the enantio-
selectivity of the reaction (Table 2, entries 5, 8, and 10). Importantly,
the enantiomeric excesses could be readily improved to 99% from
80% after a single recrystallization (Table 2, entry 1). The reaction
also took place well with substrates bearing methyl, allyl, and
benzyl substituents at the N-1 position with good yields and ee
values (Table 2, entries 11–13). Gratifyingly, (R)-convolutamydine E
(4j) could be easily obtained in 97% ee with this approach (Table 2,
entry 10). Furthermore, we also showed that this reaction could be
performed in scale up to 1.0 mmol giving (R)-convolutamydine E
with the same excellent enantioselectivity and good yield under
the same reaction conditions (Table 2, entries 10 vs 15).15
Br
OH
Br
Cl
HO
HO
1) TsCl (2.0 equiv.)
Pyridine, r.t.
O
O
2) LiCl, DMF,
N
N
Br
Br
H
80 °C
H
4j
5
(R)-convolutamydine E
(R)-convolutamydine B
97 % ee
50% yield (two steps)
97 % ee
Scheme 1. The synthesis of optically active (R)-convolutamydine B.
To further illustrate the synthetic potential of this methodology,
we undertook the formal synthesis of chiral (ꢀ)-donaxaridine and
(R)-chimonamidine. As shown in Scheme 2, 4a and 4k were first,
respectively, protected with 4-methylbenzene-1-sulfonyl (Ts)
group by exposure to 4-methylbenzene-1-sulfonyl chloride (TsCl)
and pyridine, to give the corresponding tosylation products (6 and
7), and then treated in the methylamine solution in alcohol to
undergo a transamidation of methylamino intermediate to suc-
cessfully generate high enantiopurity (ꢀ)-donaxaridine (8) in 99%
ee and (R)-chimonamidine (9) in 96% ee.17 To the best of our
knowledge, this is the first report on the synthesis of optically ac-
tive (ꢀ)-donaxaridine and (R)-chimonamidine through catalytic
asymmetric approach.16
On the base of the successful synthesis of (R)-convolutamydine
E, an application of this methodology was investigated with
a concise synthesis of (R)-convolutamydine B. As illustrated in
Table 2
OH
OTs
Scope of aldol reaction with isatins 2a–m and acetaldehyde 3a
HO
HO
HO
NMe
TsCl (2.0 equiv.)
MeNH2
75 °C, 10 h
OH
O
HO
O
O
NaBH4
(5.0 equiv.)
4
1e
4
7
Pyridine, r.t.
overnight
O
O
N
N
5
6
5
6
(20 mol %)
N
+
O
O
R
R
R
H
H
CH3OH, 0 °C
DME, -10 °C
N
R
N
4a R = H, 99% ee
4k R = Me, 77% ee
8 R = H, yield 86%, 99% ee
((-)-Donaxaridine)
6 R = H, yield 70%
7 R = Me, yield 61%
7
2a-n
R
9 R = Me, yield 72% 76% ee
Recrystallization 96% ee
((R)-Chimonamidine)
4a-n
3
2a: 4,5,6,7 = H, R = H
2h: 5,6,7 = H, 4 = Br, R = H
2i: 4,6 = H, 5,7 = Br, R = H
2j: 5,7 = H, 4,6 = Br, R = H
2k: 4,5,6,7 = H, R = Me
2l: 4,5,6,7 = H, R = allyl
2m: 4,5,6,7 = H, R = Bn
2n: 4,6,7 = H, 5 = MeO, R = H
2b: 4,6,7 = H, 5 = Me, R = H
2c: 4,6,7 = H, 5 = Cl, R = H
2d: 4,5,7 = H, 6 = Cl, R = H
2e: 5,6,7 = H, 4 = Cl, R = H
2f: 4,6,7 = H, 5 = Br, R = H
2g: 4,5,7 = H, 6 = Br, R = H
Scheme 2. The synthesis of optically active (ꢀ)-donaxaridine and (R)-chimonamidine.
3. Conclusions
Entry
2
Time (h)
4
Yieldb (%)
eec (%)
80(99)d
88
87
84
In conclusion, we have presented a highly enantioselective aldol
reaction of acetaldehyde with isatins catalyzed by organocatalyst.
As for this method, several advantages are worthy to be mentioned:
(1) only using readily available 4-hydroxydiarylprolinol as catalyst
and needless for any other additive;14 (2) wide scope of substrates,
not only free isatin but also various substituted isatins;7 (3) mod-
erate to high yield (up to 95%) and good enantioselectivities (up to
98% ee) for various 3-substituted 3-hydroxyindolin-2-ones; (4) an
example of concise stereoselective synthesis of enantiopure (R)-
convolutamydines B and E; (5) the first example of expedient
asymmetric synthesis of optically active (ꢀ)-donaxaridine and (R)-
chimonamidine.
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2j
96
108
96
96
96
108
120
100
96
108
96
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4j
90
87
90
80
92
93
70
74
92
73
75
73
95
50
70
95
90
83e
98
9
88e
97f
77
10
11
12
13
14
15
96
96
108
108
77
78
84
97f,g
a
Unless otherwise noted, reaction were performed with
2
(0.1 mmol), 3
4. Experimental
(0.5 mmol), and 1e (20 mol %) in DME (1.2 mL) at ꢀ10 ꢁC.
b
Yield of isolated product by column chromatography after the aldol adducts
4.1. General remarks
were reduced.
c
The ee values were determined by chiral stationary phase HPLC.
ee value in parentheses is that obtained after single recrystallization.
Reaction were performed with 2 (0.2 mmol), 3 (1.0 mmol), and 1e (20 mol %) in
d
e
Reagents were purchased from commercial sources and were
used as received unless mentioned otherwise. Reactions were
monitored by thin layer chromatography using silica gel HSGF254
plates. 1H NMR and 13C NMR (300 and 75 MHz, respectively)
spectra were recorded in CDCl3 and (CD3)2SO. 1H NMR chemical
shifts are reported in parts per million relative to tetramethylsilane
the DME (2.4 mL) at ꢀ10 ꢁC.
f
The absolute configuration of 4j was R assigned by comparison of the sign of the
optical rotation with reported data.7a The other products were assigned by analogy
by assuming a similar catalytic mechanism.
g
Reaction was performed in scale up to 1.0 mmol.

1444
W.-B. Chen et al. / Tetrahedron 66 (2010) 1441–1446
(TMS) with the solvent resonance employed as the internal stan-
dard (CDCl3 at 7.26 ppm, (CD3)2SO at 2.50 ppm). Data are reported
as follows: chemical shift, multiplicity (s¼singlet, br s¼broad sin-
glet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet), coupling
constants (Hz) and integration. 13C NMR chemical shifts are
reported in parts per million from tetramethylsilane (TMS) with the
solvent resonance as the internal standard (CDCl3 at 77.20 ppm,
(CD3)2SO at 39.51 ppm).
250.02390, found: 250.02414; HPLC Chiralpak AD-H, i-propanol/
hexane¼20/80, flow rate 1.0 mL/min,
l¼254 nm, tR (minor)-
¼8.9 min, tR (major)¼10.2 min.
4.2.5. (R)-4-Chloro-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
25
(4e). White solid, mp 182–183 ꢁC; 92% yield, 95% ee; [
a]
ꢀ2.8 (c
D
0.40, MeOH); 1H NMR (300 MHz, (CD3)2SO)
d
10.38 (br s, 1H), 7.23–
7.18 (m, 1H), 6.93 (d, J¼8.1 Hz, 1H), 6.74 (d, J¼7.5 Hz, 1H), 5.96 (br s,
1H), 4.37 (t, J¼4.8 Hz, 1H), 3.15–3.07 (m, 2H), 2.34–2.30 (m, 1H),
4.2. Typical procedure for the aldol reaction of acetaldehyde
and isatin
2.23–2.16 (m, 1H); 13C NMR (75 MHz, (CD3)2SO)
d
37.9, 56.3, 75.3,
3404, 3295,
108.5, 122.3, 127.5, 130.3, 130.6, 143.9, 178.3; IR (KBr)
n
3110, 2935, 1720, 1621, 1592 cmꢀ1; HRMS (ESI) Calculated for
C10H10ClNO3 [MþNa]þ: 250.02390, found: 250.02414; HPLC Chir-
alpak AD-H, i-propanol/hexane¼20/80, flow rate 1.0 mL/min,
Acetaldehyde (30 mL, 0.5 mmol purity 98.5%) was added to
a mixture of 1e (0.02 mmol, 11 mg) and isatin (0.1 mmol, 15 mg) in
DME (1.2 mL) at ꢀ10 ꢁC. After the reaction mixture had been stirred
for four days, methanol (2 mL) and NaBH4 (20 mg, 5.0 equiv) were
added at 0 ꢁC (NaBH4 was slowly added portions). The resulting
reaction mixture was stirred for additional 30 min at 0 ꢁC, before it
was quenched with saturated NH4Cl solution. The mixture was
extracted with ethyl acetate, and the combined organic phase was
dried over Na2SO4. Purification by flash column chromatography on
silica gel (ethyl acetate/hexane 1:2–2:1) to gave product 4a.
l¼254 nm, tR (minor)¼8.5 min, tR (major)¼10.4 min.
4.2.6. (R)-5-Bromo-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
25
(4f). White solid, mp 143–147 ꢁC; 93% yield, 90% ee; [
a]
þ4.5 (c
D
1.10, MeOH); 1H NMR (300 MHz, (CD3)2SO)
d
10.29 (br s, 1H), 7.40–
7.33 (m, 2H), 6.73 (d, J¼8.1 Hz, 1H), 5.99 (br s, 1H), 4.37 (t, J¼4.8 Hz,
1H), 3.25 (d, J¼4.8 Hz, 2H), 1.98–1.94 (m, 2H); 13C NMR (75 MHz,
(CD3)2SO)
178.7; IR (KBr)
d 40.3, 56.2, 74.5, 111.6, 113.3, 126.9, 131.6, 134.5, 141.0,
n
3311, 2919, 1719, 1622, 1474 cmꢀ1; HRMS (ESI)
4.2.1. (R)-3-Hydroxy-3-(2-hydroxyethyl)indolin-2-one (4a). White
Calculated for C10H10BrNO3 [MþNa]þ: 293.97363, found: 293.97317;
HPLC Chiralpak AD-H, i-propanol/hexane¼20/80, flow rate 1.0 mL/
25
solid, mp 139–140 ꢁC; 90% yield, 80% ee; [
a
]
þ15.6 (c 1.25, MeOH);
D
1H NMR (300 MHz, (CD3)2SO)
d
10.21 (br s, 1H), 7.27–7.22 (m, 1H),
min,
l¼254 nm, tR (minor)¼7.2 min, tR (major)¼9.3 min.
7.18 (d, J¼7.5 Hz, 1H), 6.98–6.93 (m, 1H), 6.79 (d, J¼7.5 Hz, 1H), 5.89
(br s, 1H), 4.40 (t, J¼5.1 Hz, 1H), 3.52–3.24 (m, 2H), 1.97 (dd, J¼6.0
4.2.7. (R)-6-Bromo-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
25
and 8.4 Hz, 2H); 13C NMR (75 MHz, (CD3)2SO)
d
40.6, 56.3, 74.3,
3336, 3172,
(4g). White solid, mp 134–135 ꢁC; 70% yield, 83% ee; [
0.35, MeOH); 1H NMR (300 MHz, (CD3)2SO)
10.31 (br s, 1H), 7.22–
7.12 (m, 2H), 6.93 (s, 1H), 5.94 (br s, 1H), 4.35 (br s, 1H), 3.32–3.27
(m, 2H), 2.00–1.97 (m, 2H); 13C NMR (75 MHz, (CD3)2SO)
40.3,
a
]
þ7.5 (c
D
109.5, 121.6, 124.0, 128.9, 132.0, 141.6, 179.2; IR (KBr)
n
d
2920, 1705, 1626, 1475 cmꢀ1; HRMS (ESI) Calculated for C10H11NO3
[MþNa]þ: 216.06311, found: 216.06189.;HPLC Chiralpak AD-H,
d
i-propanol/hexane¼20/80, flow rate 1.0 mL/min,
(minor)¼7.8 min, tR (major)¼9.5 min.
l¼254 nm, tR
56.1, 74.0, 112.3, 121.3, 124.0, 125.9, 131.3, 143.4, 178.9; IR (KBr) n
3523, 3346, 1919, 1731, 1678, 1614 cmꢀ1; HRMS (ESI) Calculated for
C10H10BrNO3 [MþNa]þ: 293.97363, found: 293.97317; HPLC Chir-
alpak AD-H, i-propanol/hexane¼20/80, flow rate 1.0 mL/min,
4.2.2. (R)-3-Hydroxy-3-(2-hydroxyethyl)-5-methylindolin-2-one
25
(4b). White solid, mp 120–121 ꢁC; 87% yield, 88% ee; [
a]
þ16.5 (c
l¼254 nm, tR (minor)¼8.4 min, tR (major)¼9.7 min.
D
0.34, MeOH); 1H NMR (300 MHz, (CD3)2SO)
d
10.09 (br s, 1H), 7.08
(s, 1H), 6.99 (d, J¼7.8 Hz, 1H), 6.68 (d, J¼7.8 Hz, 1H), 5.84 (br s, 1H),
4.38 (t, J¼5.1 Hz, 1H), 3.31–3.22 (m, 2H), 2.25 (s, 3H), 1.96 (t,
4.2.8. (R)-4-Bromo-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
25
(4h). White solid, mp 160–161 ꢁC; 74% yield, 98% ee; [
a
]
þ1.0 (c
D
J¼8.1 Hz, 2H); 13C NMR (75 MHz, (CD3)2SO)
d
20.7, 40.6, 56.4, 74.4,
0.36, MeOH); 1H NMR (300 MHz, (CD3)2SO)
d
10.32 (br s, 1H), 7.20–
109.3, 124.7, 129.1, 130.4, 132.1, 139.1, 179.3; IR (KBr)
n
3455, 3205,
7.15 (m, 2H), 7.02 (d, J¼1.8 Hz, 1H), 5.95 (br s, 1H), 4.37 (br s, 1H),
2923, 1699, 1625, 1492 cmꢀ1; HRMS (ESI) Calculated for C11H13NO3
3.38–3.28 (m, 2H), 2.12–2.10 (m, 2H); 13C NMR (75 MHz, (CD3)2SO)
[MþNa]þ: 230.07876, found: 230.07817; HPLC Chiralpak AD-H, i-
d 40.2, 56.2, 74.1, 112.4, 121.4, 124.1, 125.9, 131.3, 143.3, 178.9; IR
propanol/hexane¼20/80, flow rate 1.0 mL/min,
(minor)¼7.6 min, tR (major)¼9.8 min.
l
¼254 nm, tR
(KBr) n
3404, 3104, 2940, 1713, 1617, 1586 cmꢀ1; HRMS (ESI) Cal-
culated for C10H10BrNO3 [MþNa]þ: 293.97363, found: 293.97317;
HPLC Chiralpak AD-H, i-propanol/hexane¼20/80, flow rate 1.0 mL/
4.2.3. (R)-5-Chloro-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
min,
l¼254 nm, tR (minor)¼8.8 min, tR (major)¼10.8 min.
25
(4c). White solid, mp 141–143 ꢁC; 90% yield, 87% ee; [
a
]
þ8.2 (c
D
0.42, MeOH); 1H NMR (300 MHz, (CD3)2SO)
d
10.31 (br s, 1H), 7.31–
4.2.9. (R)-5,7-Dibromo-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
25
7.22 (m, 2H), 6.80 (d, J¼8.1 Hz, 1H), 6.00 (br s, 1H), 4.38 (t, J¼4.8 Hz,
(4i). White solid, mp 188–189 ꢁC; 92% yield, 88% ee; [
a
]
ꢀ0.1 (c
D
1H), 3.38–3.28 (m, 2H), 2.01–1.97 (m, 2H); 13C NMR (75 MHz,
0.69, MeOH); 1H NMR (300 MHz, (CD3)2SO)
d
10.65 (br s,1H), 7.63 (d,
(CD3)2SO)
178.9;IR (KBr)
d
40.3, 56.2, 74.5, 111.0, 124.3, 125.6, 128.7, 134.1, 140.6,
n
J¼1.8 Hz, 1H), 7.45 (d, J¼1.8 Hz, 1H), 6.14 (br s, 1H), 4.38 (t, J¼5.1 Hz,
3254, 3070, 2937,1730,1675,1624 cmꢀ1;HRMS (ESI)
1H), 3.28–3.24 (m, 2H), 2.06–1.98 (m, 2H); 13C NMR (75 MHz,
Calculated for C10H10ClNO3 [MþNa]þ: 250.02390, found: 250.02414;
HPLC Chiralpak AD-H, i-propanol/hexane¼20/80, flow rate 1.0 mL/
(CD3)2SO)
178.5;IR (KBr)
d 40.0, 56.1, 75.4, 102.7, 113.7, 126.2, 133.3, 135.7, 140.7,
n
3525, 3340, 2912,1708,1614,1581 cmꢀ1; HRMS(ESI)
min,
l¼254 nm, tR (minor)¼7.1 min, tR (major)¼8.9 min.
Calculated for C10H9Br2NO3 [MþNa]þ: 371.88414, found: 371.88359;
eewas determined with the corresponding tosylationproduct. HPLC
Chiralpak AD-H, i-propanol/hexane¼20/80, flow rate 1.0 mL/min,
4.2.4. (R)-6-Chloro-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
25
(4d). White solid, mp 129–130 ꢁC; 80% yield, 84% ee; [
a
]
D
þ5.7 (c
l¼254 nm, tR (minor)¼8.2 min, tR (major)¼10.1 min.
0.50, MeOH); 1H NMR (300 MHz, (CD3)2SO)
d
10.32 (br s, 1H), 7.26
(d, J¼7.8 Hz, 1H), 7.00 (dd, J¼1.8 and 7.8 Hz, 1H), 6.80 (d, J¼1.8 Hz,
1H), 5.94 (br s, 1H), 4.36 (t, J¼5.1 Hz, 1H), 3.30–3.24 (m, 2H), 2.02–
4.2.10. (R)-4,6-Dibromo-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
25
(4j)7a. White solid, mp 206–208 ꢁC; 71% yield, 97% ee; [
a
]
ꢀ9.3 (c
D
1.94 (m, 2H); 13C NMR (75 MHz, (CD3)2SO)
d
40.2, 56.2, 73.9, 109.5,
3372, 2955, 1732,
1.00, MeOH); 1H NMR (300 MHz, (CD3)2SO)
d
10.49 (br s, 1H), 7.31
121.1, 125.5, 130.8, 132.9, 143.2, 179.0; IR (KBr)
n
(d, J¼1.2 Hz, 1H), 6.93 (d, J¼1.2 Hz, 1H), 6.00 (br s, 1H), 4.38 (t,
J¼4.8 Hz, 1H), 3.17–3.06 (m, 2H), 2.37–2.33 (m, 1H), 2.18–2.08 (m,
1618, 1488 cmꢀ1; HRMS (ESI) Calculated for C10H10ClNO3 [MþNa]þ:

W.-B. Chen et al. / Tetrahedron 66 (2010) 1441–1446
1445
1H); 13C NMR (75 MHz, (CD3)2SO)
d
37.5, 56.2, 75.7, 111.8, 119.7,
3349, 3222, 2937, 1739,
hexane 1:4–1:2) to afford corresponding tosylation product. The
mixture of the resulting tosylationproduct (43 mg, 0.085 mmol) and
LiCl (22 mg, 0.512 mmol) in DMF (1 mL) was stirred at 80 ꢁC for 12 h.
After complete conversation, DMF was removed in low pressure and
the product was purified by flash column chromatography on silica
gel (ethyl acetate/hexane 1:4–1:2), 50% yield for two steps.
122.2, 126.9, 128.7, 145.5, 178.3; IR (KBr)
n
1611, 1577 cmꢀ1; HRMS (ESI) Calculated for C10H9Br2NO3 [MþNa]þ:
371.88414, found; 371.88359; HPLC Chiralpak AD-H, i-propanol/
hexane¼20/80, flow rate 1.0 mL/min,
¼8.8 min, tR (major)¼11.1 min.
l¼254 nm, tR (minor)-
4.2.11. (R)-3-Hydroxy-3-(2-hydroxyethyl)-1-methylindolin-2-one
4.3.1. (R)-4,6-Dibromo-3-(2-chloroethyl)-3-hydroxyindolin-2-one
25
25
(4k). White solid, mp 99–101 ꢁC; 75% yield, 78% ee; [
a
]
þ14.0 (c
((R)-convolutamdine B (5))7a. White solid, 97% ee; [
a
]
þ0.5 (c
D
D
0.28, MeOH); 1H NMR (300 MHz, (CD3)2SO)
d
7.33–7.28 (m, 2H),
þ0.35, MeOH); 1H NMR (300 MHz, DMSO-d6)
d 10.70 (br s, 1H), 7.37
7.07–7.02 (m, 1H), 6.97 (d, J¼7.8 Hz, 1H), 5.95 (br s, 1H), 4.38 (t,
J¼5.1 Hz, 1H), 3.28–3.21 (m, 2H), 3.08 (s, 3H), 2.00 (dd, J¼6.6,
(s, 1H), 7.98 (s, 1H), 6.30 (br s, 1H), 3.50–3.44 (m, 1H), 3.18–3.16 (m,
1H), 2.50–2.45 (m, 2H); 13C NMR (75 MHz, DMSO-d6)
75.8, 112.4, 119.9, 122.9, 127.5, 128.0, 145.4, 177.7; IR (KBr)
3220, 2921, 1713, 1609 cmꢀ1; HPLC Chiralpak AD-H, i-propanol/
d
37.3, 39.2,
3328,
12.6 Hz, 2H); 13C NMR (75 MHz, (CD3)2SO)
d
25.8, 40.6, 56.3, 74.1,
n
108.4, 122.3. 123.6, 129.1, 131.4, 143.2, 177.4; IR (KBr)
n 3386, 3322,
2956, 1704, 1614, 1488 cmꢀ1; HRMS (ESI) Calculated for C11H13NO3
hexane¼20/80, flow rate 1.0 mL/min,
l¼254 nm, tR (minor)-
[MþNa]þ: 230.07876, found: 230.07817; HPLC Chiralpak AD-H, i-
¼8.2 min, tR (major)¼10.2 min.
propanol/hexane¼20/80, flow rate 1.0 mL/min,
(minor)¼8.1 min, tR (major)¼8.7 min.
l
¼254 nm, 25 ꢁC: tR
4.4. Synthesis of (L)-donaxaridine (8) and (R)-
chimonamidine (9)
4.2.12. (R)-1-Allyl-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
25
(4l). White solid, mp 86–88 ꢁC; 73% yield, 77% ee; [
a]
þ28.2 (c
To a solution of 4a or 4k (0.67 mmol) in dry pyridine (4.0 mL)
was added p-toluenesulfonyl chloride (1.35 mmol) at room tem-
perature and stirred at room temperature overnight. 1 N HCl was
added to quench the reaction, which was then extracted with ethyl
acetate. The combined extract was washed with saturated Na2CO3
and brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure to give a residue that was purified by flash col-
umn chromatography on silica gel (ethyl acetate/hexane 1:3–1:2)
to afford corresponding product 6 (yield 70%) or 7 (yield 61%).
The mixture of 6 or 7 (0.25 mmol) in methylamine solution
(40 wt % in absolute ethanol) (8 mL) was stirred at 75 ꢁC. After dis-
appearance of 6 or 7 was confirmed by TLC (10 h), the reaction
mixture was concentrated under reduced pressure. The residue was
directly purified by flash column chromatography on silica gel (ethyl
acetate/hexane 1:2) to afford the corresponding product 8 (yield
86%, ee 99%) or 9 (yield 72%, ee 76%). After single recrystallization,
the ee value of product 9 was improved to 96% from 76%.
D
0.34, MeOH); 1H NMR (300 MHz, CDCl3)
d
7.38 (d, J¼7.2 Hz, 1H),
7.28–7.23 (m, 1H), 7.09–7.04 (m, 1H), 6.79 (d, J¼7.8 Hz, 1H), 5.78 (dt,
J¼5.1, 17.1 Hz, 1H), 5.28–5.17 (m, 2H), 4.98 (br s, 1H), 4.33 (dd, J¼4.8,
16.2 Hz,1H), 4.18 (dd, J¼4.8,16.2 Hz,1H), 3.87 (s, 2H), 3.50 (br s,1H),
2.23–2.02 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 39.4, 42.2, 58.2, 75.7,
109.3, 117.6, 122.9, 123.1, 129.4, 130.7, 130.9, 141.9, 178.2; IR (KBr)
n
3500, 2952, 2929, 1685, 1616, 1468 cmꢀ1; HRMS (ESI) Calculated for
C13H15NO3 [MþNa]þ: 256.09441, found: 256.09416; HPLC Chiralpak
AD-H, i-propanol/hexane¼20/80, flow rate 1.0 mL/min,
tR (minor)¼7.5 min, tR (major)¼8.9 min.
l¼254 nm,
4.2.13. (R)-1-Benzyl-3-hydroxy-3-(2-hydroxyethyl)indolin-2-one
25
(4m). Sticky liquid, 95% yield, 77% ee; [
a]
þ27.1 (c 0.52, MeOH);
D
1H NMR (300 MHz, CDCl3)
d
7.40 (d, J¼7.2 Hz,1H), 7.33–7.17 (m, 6H),
7.08–7.03 (m, 1H), 6.70 (d, J¼7.8 Hz, 1H), 4.95 (d, J¼15.6 Hz, 1H),
4.75 (d, J¼15.6 Hz, 1H), 4.60 (br s, 1H), 3.96 (t, J¼5.7 Hz, 2H), 3.15 (br
s, 1H), 2.31–2.24 (m, 1H), 2.14–2.04 (m, 1H); 13C NMR (75 MHz,
25
CDCl3)
d
39.3, 43.8, 58.5, 76.1, 109.6, 123.3, 123.9, 127.2, 127.7, 128.8,
4.4.1. (ꢀ)-Donaxaridine (8)2f. White solid, 99% ee; [
a]
ꢀ162 (c
D
129.6, 130.6, 135.3, 141.9, 178.5; IR (KBr)
n
3388, 3060, 2925, 1705,
0.40, EtOH); 1H NMR (300 MHz, CDCl3)
d 7.11–7.05 (m, 1H), 6.83 (d,
1614, 1488 cmꢀ1; HRMS (ESI) Calculated for C17H17NO3 [MþNa]þ:
J¼6.6 Hz, 1H), 6.69–6.64 (m, 1H), 4.60 (br s, 2H), 4.57 (br s, 1H),
306.11006, found: 306.10980; HPLC Chiralpak AD-H, i-propanol/
3.32–3.21 (m, 2H), 2.95 (s, 3H), 2.72 (dt, J¼5.1, 6.3 Hz,1H), 2.45–2.38
hexane¼20/80, flow rate 1.0 mL/min,
¼10.6 min, tR (major)¼11.8 min.
l
¼254 nm, tR (minor)-
(m, 1H); 13C NMR (75 MHz, (CD3)2SO)
d 30.1, 32.9, 45.6, 19.4, 117.9,
118.2, 125.1, 125.6, 129.1, 145.8, 175.1; IR (KBr)
n 3492, 3396, 3304,
1668, 1617, 1496, 1310 cmꢀ1; HPLC Chiralpak AD-H, ethanol/
4.2.14. (R)-3-Hydroxy-3-(2-hydroxyethyl)-5-methoxyindolin-2-one
hexane¼30/70, flow rate 1.0 mL/min,
¼12.8 min, tR (major)¼15.5 min.
l
¼254 nm, tR (minor)-
25
(4n). Sticky colorless oil, 50% yield, 84% ee; [
a
]
þ2.0 (c 0.27,
D
Me2CO); 1H NMR (300 MHz, (CD3)2SO)
d
10.05 (br s,1H), 6.88 (s,1H),
20
6.75–6.78 (m, 2H), 5.91 (br s, 1H), 4.42 (t, J¼4.8 Hz, 1H), 3.69 (s, 3H),
4.4.2. (R)-Chimonamidine (9)2b. White solid, 96% ee; [
a]
ꢀ153 (c
D
3.26–3.22 (m, 2H), 1.95–1.95 (m, 2H); 13C NMR (75 MHz, (CD3)2SO)
0.18, EtOH); 1H NMR (300 MHz, CDCl3)
d 7.26–7.19 (m, 1H), 6.83 (dd,
d
40.6, 55.5, 563, 74.8,110.0,110.9,113.6,133.3,134.8,154.9,179.2; IR
J¼1.2, 7.5 Hz 1H), 6.72 (d, J¼8.1 Hz 1H), 6.66–6.11 (m, 1H), 5.81 (br s,
1H), 4.31 (br s, 1H), 3.31–3.20 (m, 2H), 2.97 (s, 3H), 2.84 (s, 3H), 2.71
(dd, J¼5.1, 12.9 Hz, 1H), 2.45–2.38 (m, 1H); 13C NMR (75 MHz,
(KBr)n
3369, 2924, 2854, 1730, 1607, 1462 cmꢀ1; HRMS (ESI) Calcu-
lated for C11H13NO4 [MþNa]þ: 246.07368, found: 246.07342; ee was
determined with the corresponding tosylation product; HPLC Chir-
alpak AD-H, i-propanol/hexane¼20/80, flow rate 1.0 mL/min,
(CD3)2SO) d 30.1, 30.2, 33.1, 45.7, 79.7, 111.7, 116.6, 124.6, 125.4, 129.4,
148.3,175.2; HPLC Chiralpak AD-H, ethanol/hexane¼30/70, flow rate
l
¼254 nm, tR (minor)¼9.4 min, tR (major)¼17.0 min.
1.0 mL/min,
l¼254 nm, tR (major)¼5.4 min, tR (minor)¼6.2 min.
4.3. Synthesis of (R)-convolutamdine B (5)
Acknowledgements
To a solution of 4j (100 mg, 0.285 mmol) in dry pyridine (1.0 mL)
was added p-toluenesulfonyl chloride (110 mg, 0.576 mmol) at room
temperature. After stirring at room temperature overnight,
quenched with 1.0 M HCl and extracted with ethyl acetate, washed
with a saturated Na2CO3 and brine. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated in low pressure. A
residue that was purified by column chromatography (ethyl acetate/
We are grateful for financial support from the National Natural
Science Foundation of China (NO. 20802074).
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2009.12.041.

1446
W.-B. Chen et al. / Tetrahedron 66 (2010) 1441–1446
Chem. Commun. 2006, 819–824; (g) Guillena, G.; Na´jera, C.; Ramo´n, D. J. Tet-
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13. After the aldol reaction, the aldol adduct was reduced by NaBH4 (5.0 equiv to
isatin) in methanol to give 4a. In this reduction steps, the NaBH4 should be
added slowly in portions at 0 ꢁC.
6. Synthesis of enantiopure convolutamydines B and E using chiral auxiliary, see:
Nakamura, T.; Shirokawa, S.; Hosokawa, S.; Nakazaki, A.; Kobayashi, S. Org. Lett.
2006, 8, 677–679.
14. Comparing with Hayashi’s system,7b we use 1,2-dimethoxyethane (DME) as
solvent only with 20 mol % 4-hydroxydiarylprolinol as catalyst under ꢀ10 ꢁC,
but Hayashi applied DMF as solvent with 30 mol % 4-hydroxydiarylprolinol as
catalyst and 30 mol % ClCH2CO2H as necessary additive under 4 ꢁC.
15. The optically active (R)-convolutamydine E was obtained with 250 mg (white solid).
16. About the detailed procedure, see Experimental section.
7. Synthesis of optical convolutamydines B or E through catalytic asymmetric
methods, see: (a) Hara, N.; Nakamura, S.; Shibata, N.; Toru, T. Chem.d Eur. J. 2009,
15, 6790–6793; (b) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009,11, 3854–3857.
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3, 719–724; (e) List, B.; Yang, J.-W. Science 2006, 313, 1584–1586; (f) List, B.
17. The absolute configuration of chimonamidine (9) was R assigned by comparison
of the sign of the optical rotation with reported data in Ref. 2b.