A Diamino Alcohol Catalyzed Enantioselective Crossed Aldol Reaction of Acetaldehyde with Isatins – A Concise Total Synthesis of Antitumor Agents

Article abstract of DOI:10.1002/ejoc.201700399

Enantioselective crossed aldol reactions of isatin derivatives and acetaldehyde have been developed with a series of simple diamino alcohol catalysts to afford 3-substituted 3-hydroxyindolin-2-ones in high chemical yields (up to 95 %) and optical purities (up to 92 % ee). The synthetic potential of the present protocol has been demonstrated by concise, enantioselective, protecting-group-free, and transition metal-free total syntheses of antitumor and antiviral agents with the tryptanthrin architecture, that is, phaitanthrin B and cephalanthrin A, along with the biologically active indolidine alkaloids chimonamidine and donaxaridine as well as the formal synthesis of CPC-1. The highly enantioselective outcome of this catalytic crossed aldol reaction was evaluated by calculating the Gibbs free energies of the possible transition states.

Full text of DOI:10.1002/ejoc.201700399

A Journal of
Accepted Article
Title: New type of di-amino alcohol-catalyzed enantioselective crossed
aldol reaction of acetaldehyde with isatins: A concise total
synthesis of antitumor agents
Authors: Hiroto Nakano
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700399
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700399
Supported by

10.1002/ejoc.201700399
European Journal of Organic Chemistry
FULL PAPER
New type of di-amino alcohol-catalyzed enantioselective crossed
aldol reaction of acetaldehyde with isatins: A concise total
synthesis of antitumor agents
Ummareddy Venkata Subba Reddy,*[a] Madhu Chennapuram,[a] Kento Seki,[a] Chigusa Seki,[a]
Bheemreddy Anusha,[b] Eunsang Kwon,* [c] Yuko Okuyama, [d] Koji Uwai,[a] Michio Tokiwa, [e] Mitsuhiro
Takeshita, [e] and Hiroto Nakano*[a]
Abstract: An enantioselective crossed aldol reaction of isatin
derivatives and acetaldehyde has been developed using a series of
simple and novel di-amino alcohol-type catalysts, affording 3-
substituted 3-hydroxyindolin-2-ones in high chemical yields (up to
95%) and optical purity (up to 92% ee). The synthetic potential of
The crossed aldol reaction between acetaldehyde as a
nucleophile and ketone as an electrophile has great significance
since it results in a chiral quaternary carbon center, which is
immensely valuable in synthetic chemistry.5 Specifically,
enantioselective crossed aldol reaction of acetaldehyde 2 with
isatin 1a is a straight forward method to acquire chiral 3-
substituted 3-hydroxyindolin-2-one 3a, which is a valuable
building block for the synthesis of broad range of biologically
important molecules (Scheme 1). Owing to its significance as a
pharmacophore, in recent years, few research groups have
developed the asymmetric crossed aldol reaction of
acetaldehyde with isatins to afford 3-substituted 3-
hydroxyindolin-2-one derivatives.6 However, most of these
reports use either proline-derived6a-d,g or cinchona alkaloid-
present protocol has been demonstrated by
a
concise,
enantioselective, protecting group-free and transition metal-free total
synthesis of tryptanthrin architecture antitumor and antiviral agents
i.e phaitanthrin B and cephalanthrin A along with biologically active
indolidine alkaloids i.e chimonamidine, donaxaridine and formal
synthesis of CPC-1. The highly enantioselective outcome of this
catalytic crossed aldol reaction was evaluated by calculating the
Gibbs free energy of possible transition states.
h
derived amines6e, as sources of chirality. In a similar work,
Cheng and co-workers used amino acid-derived vicinal primary-
tertiary diamines as chiral organocatalysts with silicon tungstic
acid as an additive.6f
Introduction
In modern organic chemistry, the asymmetric aldol reaction
catalyzed by small organic molecules is one of the important
methods for carbon-carbon bond formation.1 However, in the
last decade, there is a significant progress in development of
enantioselective, organocatalyzed aldol reaction of various
aldehydes.2 But the direct crossed aldol reaction of
acetaldehyde, which is the simplest enolizable carbonyl
compound, has been known to be a challenging task.3,4 There
are several complications in using acetaldehyde in crossed aldol
reaction such as (i) acetaldehyde could be reactive as an
electrophile resulting in self-aldol reaction (ii) ,-unsubstituted
aldehyde is reactive as both nucleophile and electrophile leading
to side reactions (iii) dehydration of resulting product is possible.
[a]
Division of Sustainable and Environmental Engineering, Graduate
School of Engineering, Muroran Institute of Technology, 27-1
Mizumoto, Muroran 050-8585, Japan
E-mail: catanaka@mmm.muroran-it.ac.jp
uvsreddy@mmm.muroran-it.ac.jp
http://www3.muroran-it.ac.jp/hnakano/
[b]
[c]
Department of Chemistry, KVR Degree College (Women), Kurnool-
518001, Andhra Pradesh, India
Research and Analytical Center for Giant Molecules, Graduate
School of Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-
ku, Sendai 980-8578, Japan
Scheme 1. Retrosynthetic analysis of crossed aldol reaction of isatin with
acetaldehyde and synthetic importance of 3-substituted 3-hydroxyindolin-2-
ones.
[d]
[e]
Tohoku Medical and Pharmaceutical University, 4-4-1
Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Tokiwakai Group, 62 Numajiri Tsuduri-chou Uchigo Iwaki 973-8053,
Japan
The tryptanthrin architecture based indoloquinazoline alkaloids
i.e phaitanthrin B 6 and cephalanthrin A 7 were isolated recently
from
Phaius
mishmensis
(Orchidaceae)7a
and
Supporting information for this article is given via a link at the end of
the document.
Cephalantheropsis gracilis7b respectively, which exhibit potential
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10.1002/ejoc.201700399
European Journal of Organic Chemistry
FULL PAPER
anticancer and antiviral activities.7,8 To the best of our knowledge, obtained via asymmetric crossed aldol reaction of isatin 1a with
there is only one report by Jiang and co-workers on the
asymmetric synthesis of phaitanthrin B 6 and cephalanthrin A 7
via nickel (II) catalyzed decarboxylative addition of malonic acid
to tryptanthrin.8 Albeit, few reports9 exist in literature on the
synthesis of biologically active molecules such as
chimonamidine 8 and donaxaridine 9, but only one method is
reported6d using enamine organocatalyzed crossed aldol
reaction of acetaldehyde with isatin.
acetaldehyde 2, followed by Pinnick oxidation sequence
(Scheme 1). We also extended this method for the total
synthesis of indolidine alkaloids such as chimonamidine 8 and
donaxaridine 9 and formal synthesis of CPC-1 10. These
indolidine alkaloids could be synthesized from diol 5a, which
could be obtained by a simple reduction of aldol product 3a
(Scheme 1).
Recently, we have been exploring simple primary amino
alcohols as new class of organocatalysts with distinctive
properties such as easy synthesis, stability on exposure to air,
potential for convenient alteration of the steric sites and ability to
be used as bi-functional (enamine activation and non-covalent
activation) catalysts.10,11 Design and synthesis of new
organocatalysts is always important and challenging task. Due
to the planarity of acetaldehyde 2, it could be very difficult to
control the enantioselectivity using it as aldol donor. We
anticipated that the multifunctional catalyst, which could be able
to coordinate with two reactants to control the approaching path
would be the best way to test this reaction. Based on this
concept and our continuing interest on amino alcohols as
catalysts, we designed and synthesized a series of new type of
di-amino alcohols with covalent and non-covalent bonding and
steric influence sites. These new types of amino alcohols could
coordinate with acetaldehyde 2 through enamine formation and
with isatin 1a through hydrogen bonding between carbonyl
oxygen of isatin and cat ionized nitrogen of pyrrolidine ring of the
ethenamine derivative. Then acetaldehyde could attack isatin
selectively from one side through transition state A (Ts-A) to
yield the 3-substituted 3-hydroxyindolin-2-ones 3 with high
enantioselectivity (Scheme 2).
Results and Discussion
Our study commenced with the examination of catalytic activity
of simple amino alcohols 11a-d, 12a-e and 13 having one
covalent and one non-covalent binding site along with one
sterically hindered site.11d Initial attempt of crossed aldol reaction
of isatin 1a with acetaldehyde 2 using catalyst 11a as chiral
inducer and benzoic acid and water as additives in THF could
result in the aldol product. As the obtained product was unstable,
it was isolated as diol 5a after reduction with NaBH4 in low
chemical yield and poor enantioselectivity (Table 1, entry 1).
Table 1. Crossed-aldol reaction of acetaldehyde with isatin using simple
amino alcohols
O
O
O
N
2
H
Isatin
1
a
b
b
b
b
b
b
b
b
b
b
Yield
(%)a
30
67
65
37
63
41
36
46
29
28
67
Ee
(%)b
7
23
24
-14
15
-21
-18
-13
-7
1
Acetaldehyde
Entry
R
Catalyst
Isatin
steric influence
crossed aldol di-amino alcohol
reaction
organocatalyst
1
2
3
4
5
6
7
8
9
H
11a
11a
11b
11c
11d
12a
12b
12c
12d
12e
13
non-covalent
hydrogen bond site
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
O
i
n
f
s
HO
t
l
e
r
ionic
hydrogen
bonding
u
e
i
c
n
c
O
N
e
N
H
N
H
H2N
OH
3
3-hydroxyindolidine-2-one
O
H
N
OH
covalent enamine
formation site
non-covalent
hydrogen bond site
O
N
H
di-amino alcohol
organocatalyst
enamine
bond
10
11
-20
14
aIsolated yields. bThe ee was determined by HPLC using
a Daicel AD-H column (n-hexane/isopropanol: 80/20). 1.0 eq.
of isatin and 20 eq. of acetaldehyde were used in all reactions
transition state A (Ts-A)
Then, we theorized that it could be possible to enhance the
enantio-induction by using N-protected isatin as aldol acceptor
following the results of Hayashi report.6c This proved to be the
case, as the reaction using benzyl protected isatin 1b as aldol
acceptor led to the aldol product 5b with much improved
chemical yield (67%), albeit modest enhancement of optical
yield (23% ee) (Table 1, entry 2). Next, we examined the
catalytic abilities of catalysts 11b-d, 12a-e and 13 for this
reaction and the results are presented (Table 1, entries 3-11).
Scheme 2. Concept of catalyst design and asymmetric induction in crossed-
aldol reaction of isatin and acetaldehyde
To illustrate the synthetic potential of this method, we also
synthesized antitumor agents such as cephalanthrin A 7 and
phaitanthrin B 6 without using any protecting groups and harsh
transitions metals. These biologically important molecules could
be synthesized from -hydroxy acid 4, that could in turn be
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10.1002/ejoc.201700399
European Journal of Organic Chemistry
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Then, to test our assumption on the ability of multifunctional
catalysts for this reaction, we introduced an additional non-
covalent bonding (tertiary amine) site into the core structure of
catalyst. Synthesis of new catalysts was started with protection
of primary amine of compound 14 with (Boc)2O followed by
masking of primary hydroxyl group with mesylchloride affording
compound 16 in good yield. Subsequently, mesyl function of 16
was replaced with various cyclic amines (pyrrolidine, piperidine,
azepane, morpholine and thiomorpholine) under neat reaction
conditions providing 17a-e in moderate to good yields. Finally,
de-protection of Boc group of 17a-e by treating with TFA
furnished the targeted new type of multifunctional
organocatalysts 18a-e in good overall yields (Scheme 3).
Among all these tested catalysts, -tert-butyl substituted amino
alcohol 11b displayed slightly better stereo induction (24% ee) to
yield the aldol product 5b in moderate yield (65%) (Table 1,
entry 3).
We anticipated that, changing the reaction conditions such as
solvent, co-catalyst, temperature and catalyst loading of best
catalyst 11b might improve the enantioselectivity of the desired
aldol product (Table 2).
A quick solvent screening was
performed using different ethereal (Table 2, entries 1-5),
aromatic (Table 2, entries 6,7), chlorinated (Table 2, entries 8,9),
and polar solvents (Table 2, entries 10-12). It is worth
mentioning that variation of the nature of solvents results the
product with different chemical and optical yields. The effect of
loading of catalyst 11b (Table 2, entries 13,14), various co-
catalyst and loading (Table 2, entries 15-20) and temperature
(Table 2, entries 21-23) were also examined. No product was
observed in the absence of co-catalyst (Table 2, entry 24).
These results revealed that toluene, benzoic acid (30 mol%) and
20 mol% of 11b were the better conditions (Table 2, entry 6,
45% yield and 48% ee), but these results were not sufficient to
evaluate this method.
Table 2. Optimized reaction conditions of crossed-aldol reaction of N-Bn isatin
1b with acetaldehyde 2 using catalyst 11b
Scheme 3. Synthesis of new di-amino alcohol catalysts.
First, catalyst 18a was examined for this reaction under the best
conditions. As expected, newly introduced non-covalent site
(tertiary amine) had a notable effect on chemical and optical
yield of the product. To our delight, the aldol product 5b was
achieved with excellent chemical yield (90%) and good
enantioselectivity (80% ee) (Table 3, entry 1). The variation in
size of the ring of newly introduced part of catalyst showed
dramatic effect on activity. For instance, piperidine ring bearing
catalyst 18b led to a reduced chemical and optical yield
compared to catalyst 18a (Table 3, entry 2). Catalyst 18c
afforded the product in moderate chemical yield but with poor
selectivity (57% yield, 18% ee) (Table 3, entry 3). Catalysts 18d
and 18e bearing morpholine and thiomorpholine rings also
afforded the product 5b in moderate chemical yields but with low
optical purity (18d: 48%, 24% ee; 18e: 55%, 28% ee) (Table 3,
entries 4,5). However, using the best catalyst 18a at lower
temperature (-10 oC) led to the aldol product 5b in excellent yield
(95%) and much improved enantioselectivity (88% ee) (Table 3,
entry 6). And, still low temperature (-30 oC) and room
temperature experiments were also performed. In both cases,
product was accomplished with lower chemical and optical
yields (Table 3, entries 7, 8). Finally, reducing the reaction time
to 24 h did not affect the enantioselectivity (86% ee), albeit
chemical yield was considerably low (Table 3, entry 9).
Catalyst
11b
(mol%)
20
20
20
20
20
20
20
Co-
catalyst
(mol%)
30
30
30
30
30
30
30
Co-
catalyst
Temp.
(oC)
Yield
(%)a
Ee
Entry
Solvent
(%)b
1c
2
3
4
5
6
7
8
9
THF
THF
Et2O
tBuOMe
iPr2O
Toluene
Benzene
DCM
CHCl3
MeOH
1,4-
dioxane
CH3CN
Toluene
Toluene
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
0
0
0
0
0
0
0
0
0
0
65
64
41
66
64
45
39
32
32
29
24
24
33
20
26
48
31
18
22
12
20
20
20
30
30
30
10
11
20
PhCO2H
30
0
24
27
12
13
14
20
10
30
PhCO2H
PhCO2H
PhCO2H
p-NO2-
PhCO2H
p-F-
30
30
30
0
0
0
44
45
34
15
36
43
15
Toluene
20
30
0
29
33
16
17
18
Toluene
Toluene
Toluene
20
20
20
30
30
30
0
0
0
32
trace
32
39
--
PhCO2H
TFA
p-NO2-
phenol
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
--
39
19
20
21
22
23
24
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
20
20
20
20
20
20
50
100
30
30
30
--
0
0
-25
-10
rt
60
65
29
25
trace
trace
40
42
47
48
--
0
--
aIsolated yields. bThe ee was determined by HPLC using a Dacel AD-H
column (n-Hexane/isopropanol: 80/20) c H2O (5 eq) used as additive. 1.0 eq.
of isatin and 20 eq. of acetaldehyde were used in all reactions
Yet again, we anticipated that, changing the reaction conditions
such as solvent, co-catalyst, reaction time and catalyst loading
of superior catalyst 18a might further improve the chemical and
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10.1002/ejoc.201700399
European Journal of Organic Chemistry
FULL PAPER
optical yield of the desired aldol product (Table 4). The solvent
screening was performed using different ethereal (Table 4,
entries 1-3), aromatic (Table 4, entries 4,5),
The optimized conditions above (Table 3, entry 6) were then
applied to a series of isatin derivatives to check the facility of this
method (Scheme 4). Consistent results were observed with
different isatin derivatives. N-Protected isatins such as N-Methyl,
N-allyl, N-MOM and N-PMB isatins 1c-f afforded the
corresponding aldol products 5c-f in good chemical and optical
yields (up to 75-95%, up to 84-90% ee). Again, simple isatin 1a
was tested using catalyst 18a, which is essential for utility of this
method effectively for natural product synthesis. Luckily, the
respective product 5a was afforded with good enantioselectivity
(76% ee), albeit in moderate yield (40%), as against the poor
results observed using catalyst 11a (Table 1, entry 1).
Table 3. Aldol reaction of 1b with 2 using new type amino alcohols.
Entry
Catalyst 18
Temp (oC)
Yield (%)a
Ee (%)b
80
47
18
24
28
88
76
38
o
o
1
2
3
4
5
6
7
8
9c
a
b
c
d
e
a
a
a
a
0
0
0
0
0
-10
-30
rt
90
82
57
48
55
95
86
50
78
Amplification of temperature from -10 C to 0 C (due to poor
o
solubility of isatin in toluene at -10 C) afforded the product 5a
with notable improvement in chemical yield (59%) and
enantioselectivity (89% ee).
-10
86
aIsolated yields. bThe ee was determined by HPLC using a Daicel AD-H
column (n-hexane/isopropanol : 80/20). cReaction time is 24 h. 1.0 eq. of isatin
and 20 eq. of acetaldehyde were used in all reactions
chlorinated (Table 4, entries 6,7), and polar solvents (Table 4,
entries 8-10). The effect of catalyst loading and various co-
catalysts were also examined (Table 4, entries 14-17).
Unfortunately, no improvement was observed regarding either
chemical yield nor optical yield than the previous bet results
(Table 3, entry 6).
Table 4. Optimized reaction conditions of crossed-aldol reaction of N-Bn isatin
1b with acetaldehyde 2 using catalyst 18a
OH
O
HO
Catalyst 18a (mol%)
NaBH4
O
O
O
N
MeOH, 0 o
C
Co-Cat (30 mol%)
Solvent, Time
N
Bn
Bn
5b
-10 o
C
1b
2
18a
(mol%)
20
20
20
20
20
20
Time
(h)
24
24
24
24
24
24
24
Yield
(%)a
32
28
19
68
41
28
63
Ee
Entry
Solvent
Co-Cat
Yields were isolated. The ee was determined by HPLC using a Daicel AD-H
and OJ-H columns.
(%)b
58
46
49
80
68
37
57
34
1
2
3
4
5
6
7
8
THF
Et2O
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
tBuOMe
Toluene
benzene
DCM
Scheme 4. Substrate scope of crossed-aldol reaction.
CHCl3
MeOH
1,4-
Dioxane
CH3CN
Et2O
20
20
Halogen-substituted isatins 1g-j, were also compatible with this
protocol and satisfactory results were obtained (up to 49-85%,
up to 79-91% ee). The effect of electron donating and electron
withdrawing groups was also examined. 5-Methyl isatin 1k
afforded the product 5k in moderate yield and selectivity (64%,
84% ee). The best results were obtained with 5-NO2 isatin 1l.
The corresponding product 5l was attained with 57% yield and
92% ee (Scheme 4).
24
26
9
20
PhCO2H
24
36
42
10
11
12
13
14
15
20
20
20
20
10
30
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
4-NO2-
PhCO2H
2-F-
PhCO2H
24
48
48
48
48
48
37
51
62
77
46
38
29
49
60
61
73
70
THF
CHCl3
Toluene
Toluene
16
Toluene
20
48
38
65
17
Toluene
20
48
36
50
From these satisfactory results in hand, we shifted our attention
towards total synthesis of natural products. We attempted for
direct synthesis of cephalanthrin A 7 from the aldol product 5a.
Condensation of diol 5a with isatoic anhydride 19 yielded the
coupled product 20 in moderate chemical yield without loss of
enantioselectivity (88% ee). Then, we anticipated that oxidation
aIsolated yields. bThe ee was determined by HPLC using a Daicel AD-H
column (n-hexane/isopropanol : 80/20). 1.0 eq. of isatin and 20 eq. of
acetaldehyde were used in all reactions
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10.1002/ejoc.201700399
European Journal of Organic Chemistry
FULL PAPER
yield without loss of enantioselectivity. CPC-1 10 could be
synthesized from 24 via reported procedure (Scheme 7).6c
of primary alcohol of 20 could result in cephalanthrin A 7.
However, Epp and Widlanski12 reaction conditions using
Scheme 5. Attempt for synthesis of Cephalanthrin A 7.
different equimolar ratios of TEMPO/BAIB in different solvent
system did not afford the desired product. Also, the use of either
Jones reagent,13 KMnO4 in strong alkali condition14 or Cornforth
reagent15 unfortunately, did not result in the desired product
(Scheme 5) (for details see supporting information).
After these failed attempts, synthetic route was changed. Pinnick
oxidation16 of aldehyde 3a (aldol product), followed by
esterification by treating with TMSCH2N2 afforded the -hydroxy
ester 21 in good yield without loss of enatioselectivity.
Condensation of 21 with isatoic anhydride 19 offered the
targeted phaitanthrin B 6 without affecting the enantioselectivity.
Afterwards, cephalanthrin A 7 was conveniently obtained from
phaitanthrin B 6 by its treatment with base. After single
recrystallization in diethyl ether the two targeted molecules
phaitanthrin B 6 and cephalanthrin A 7 were obtained in 99% ee
(Scheme 6).
Scheme 7. Total synthesis of chimonamidine, donaxaridine and formal
synthesis of CPC-1.
Based on the high enantiopurity obtained from the crossed aldol
reaction of acetaldehyde 2 with isatin 1a, we proposed the
reaction course as follows (Scheme 8). The major enantiomer
(S)-3a might be obtained via transition state Ts-I in which, the
isatin could be fixed by hydrogen bonding interaction between
carbonyl oxygen of isatin 1a and cat ionized nitrogen of
pyrrolidine ring of the ethenamine derivative.
Scheme 6. Total synthesis of phaitanthrin B 6 and cephalanthrin A 7.
We next synthesized the proposed 3-hydroxy-2-oxindole derived
natural products. Tosylated product 22 was obatained by
treatment of diol 5c with tosyl chloride. Tosylate 22 was then
converted to the desired (S)-chimonamidine 8 by treatment with
methylamine under refluxing conditions. Following the same
path, donaxaridine 9 was also obtained from 5a through
tosylation followed by treatment with methylamine. The resulted
final compounds i.e chimonamidine 8 and donaxaridine 9 were
washed with diethyl ether (two times) to increase to the sufficient
ee values (chimonamidine 8: 94% ee, donaxaridine 9: 98% ee).
Azidation of tosylate 23 using NaN3 yielded the azide 24 in good
Scheme 8. Plausible reaction course.
Then acetaldehyde from enamine site could attack the carbonyl
carbon of isatin at 3-position leading to the major enantiomer
(S)-3a. The steric repulsion between phenyl groups of catalyst
and aromatic group of isatin in transition state Ts-II could be the
reason for minor enantiomer (R)-3a (Scheme 8).
The high enantioselectivity of the catalytic crossed-aldol reaction
was evaluated by a theoretical calculation. As shown in Figure 1,
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10.1002/ejoc.201700399
European Journal of Organic Chemistry
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Gibbs free energies of possible transition states. There are
several noteworthy features in the present study.
the cationized nitrogen of pyrrolidine ring of ethenamine
derivative, which was obtained from catalyst 18a with
acetaldehyde 2, forms a hydrogen bond with the carbonyl
oxygen of isatin 1a. The hydrogen bond afforded the two initial
Experimental Section
reactants (S-reactant and R-reactant). The relative Gibbs free
energy of the transition state leading to the S configuration (STS)
of the product was 6.5 kcal/mol lower than that of the R
configuration (RTS). These results are agreement with the
experimental results.
General Methods: All glassware was used after flame drying, and
reactions were performed under argon. Reactions were monitored by thin
layer chromatography (TLC) and analysed by UV light (254 nm), iodine
vapor, ninhydrin staining and anisaldehyde staining. TLC was performed
on silica gel 60 F
254
glass plates from Merck. Purifications of reaction
‡
products were carried out by flash chromatography on silica gel 60N (40–
50 μm) from Kanto Chemical. Unless mentioned otherwise, all chemical
reagents were used without further purification. NMR spectra were
3.20 Å
1.69
Å
1
measured using a JEOL JNM- ECA500 instrument. H NMR (500 MHz)
(NH…O) 1.91 Å
(N…H) 1.88 Å
Sproduct
(H…O) 1.34 Å
(N…H) 1.20 Å
13
18a + 2
+
Sreactant
STS
and
C NMR (125 MHz) spectra were measured in CDCl or
3
[D ]DMSO or MeOD-D3 as solvent and are given in terms of ppm from
6
‡
tetramethylsilane (δ = 0.00 ppm) or the residual solvents as an internal
1.85 Å
3.40 Å
1
1a
standard ([D ]DMSO: δ = 2.50 ppm, CDCl3: δ = 7.26 ppm for H NMR;
6
13
CDCl : δ = 77.16 ppm for C NMR). Multiplicity of chemical shifts are
(NH…O) 2.77 Å
(N…H) 1.94 Å
Rproduct
3
(H…O) 1.46 Å
(N…H) 1.13 Å
reported as s = singlet, d = doublet, t = triplet, q = quadruplet, dd =
doublet of doublets, td = triplet of doublets, m = multiplet and br. = broad,
and coupling constants J are given in Hz. Infrared (IR) spectra were
measured using a JASCO FT/IR-4100 instrument. Optical rotations were
measured using a JASCO DIP- 360 instrument with EtOH as solvent.
Melting points were measured using a Yanaco micro melting point
apparatus. HRMS spectra were measured in EI mode using Hitachi
RMG-6MG and JEOL-JNM-DX303 spectrometers. Diastereomeric ratios
and enantiomeric excesses were determined by HPLC analyses using
DAICEL CHIRALPAK AD-H and CHIRALCEL OJ-H columns.
Rreactant
RTS
∆G‡ (R) = 19.25
RTS = 10.10
∆ ∆ G‡ = 6.64
18a + 2 + 1a
(0)
STS = 3.46
∆G‡ (S) = 12.77
Rreactant = -9.15
Sreactant = -9.31
General procedure for aldol reaction using catalysts 11, 12, 13. A
solution of acetaldehyde 2 (20 eq.) and respective catalyst 11, 12 or 13 in
corresponding solvent was stirred for 5 minutes at optimized temperature
and then isatin 1b (1.0 eq.) followed by co-catalyst were added
simultaneously and stirring was continued up to completion of the
reaction. After completion of the reaction indicated by TLC, the reaction
solvent was removed under reduced pressure then reaction crude was
dissolved in MeOH followed by addition of NaBH4 (1.0 eq) at 0 oC and
stirring was continued for 30 min at same temperature. The solvent was
removed under reduced pressure, excess NaBH4 was quenched with ice
cold water then organic layer was extract with ethyl acetate (3x3 ml),
solvent was removed under vacuum and residue was purified by column
chromatography.
Sproduct = -21.74
Rproduct = -23.16
Figure 1. The optimized structures and energy profile (in kcal/mol) for the
crossed-aldol reaction between acetaldehyde 2 with catalyst 18a and isatin 1a
at the B3LYP/6-31G(d) level of theory.
Conclusions
In summary, we have designed and synthesized a series of
novel multifunctional di-amino alcohols and successfully applied
them for bilateral activation (enamine and non-covalent
activation) for enantioselective crossed aldol reaction of
acetaldehyde with isatins to afford the aldol products with high
chemical yields (up to 95%) and optical yields (up to 92% ee).
(S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3,3
-diphenylpropyl
methanesulfonate 16: To a stirred solution of primary amine 14 (1.0 g,
4.1 mmol) in dry dichloromethane (20 mL) was added triethylamine
(1.03g, 10.2 mmol) and stirred for 5 min followed by addition of (Boc)2O
(1.39 g, 6.3 mmol) then stirring was continued for 3 h at room
temperature. After completion of the reaction indicated by TLC, reaction
mixture was quenched with ice cold water and extracted with DCM (3x50
ml), solvent was removed under vacuum. The crude reaction mass 15
(1.6 g, 4.6 mmol) was dissolved in dry dichloromethane (20 mL) was
added trimethylamine (1.17g, 11.6 mmol) and methanesulfonyl chloride
(0.63 g, 5.5 mmol) at 0 oC and reaction was stirring at room temperature
for 5 h. Then reaction mixture was quenched with ice cold water and
extracted with DCM (3x50 ml), solvent was removed under vacuum and
the residue was purified by silica gel chromatography (pet. ether- ethyl
acetate 9:1) to obtain the compound 16 (1.9 g, 85% yield).
The developed method offers
a rapid, enantioselective,
protecting group free and transition metal free total synthesis of
antitumor agents i.e phaitanthrin B 6 and cephalanthrin A 7
along
with
3-hydroxyidoline-2-one
derived
alkaloids
chimonamidine 8, donaxaridine 9 and formal synthesis of CPC-1
10. Additionally, we have demonstrated for the first time the
most feasible transition states and mechanistic pathway for the
crossed-aldol reaction of acetaldehyde with isatin by calculating
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700399
European Journal of Organic Chemistry
FULL PAPER
o
21
White solid. m.p. 152-154 C. [α]D = -57.14 (c = 0.7, EtOH). IR (neat):
3012, 2966, 2817, 1622, 1456, 1158, 1028 cm-1. 1H NMR (CDCl3, 500
MHz) : 7.51 – 7.44 (m, 4H), 7.35 – 7.18 (m, 6H), 5.25 (d, J = 8.5 Hz, 1H),
4.92 – 4.85 (m, 1H), 4.38 – 4.27 (m, 2H), 3.94 (bs, 1H), 2.86 (s, 3H), 1.33
(s, 9H). 13C NMR (CDCl3, 125 MHz) : 156.1, 144.4, 143.8, 128.8, 128.4,
127.6, 127.3, 125.6, 125.2, 80.4, 80.0, 69.5, 56.0, 37.3, 28.2. FAB-MS
m/z: 422 (M+H)+. HRMS (FAB) calcd for C21H28NO6S m/z: 422.1637
(M+H)+: found: 422.1634.
MHz) : 7.60 – 7.58 (m, 2H), 7.53 – 7.51 (m, 2H), 7.33 – 7.25 (m, 4H),
7.20 – 7.15 (m, 2H), 3.93 (dd, J = 3.5 Hz, 3.5 Hz, 1H), 2.76 (dd, J = 7.0
Hz, 6.0 Hz, 1H), 2.64 – 2.56 (m, 2H), 2.44 - 2.36 (m, 2H), 2.26 (dd, J =
9.5 Hz, 3.5 Hz, 1H), 1.78 – 1.68 (m, 4H). 13C NMR (CDCl3, 125 MHz) :
146.3, 145.8, 128.4, 128.2, 126.6, 126.5, 125.9, 125.6, 79.9, 57.6, 55.1,
55.0, 23.7. FAB-MS m/z: 297 (M+H)+. HRMS (FAB) calcd for C19H25N2O
m/z: 297.1967 (M+H)+, found: 297.1963.
(S)-2-amino-1,1-diphenyl-3-(piperidin-1-yl)propan-1-ol
18b:
Pale
yellow solid. 95% yield. m.p. 125-126 °C. [α]D25 = -66 (c = 1.38, EtOH). IR
1
(neat) = 3432, 2836, 2321, 1561, 1446 cm-1. H NMR (CDCl3, 500 MHz)
General procedure for synthesis compounds 17a-e: Compound 16
(1.0 mmol) was charged in 50 mL round bottomed flask and the
corresponding cyclic amine (3 mmol) was added drop-wise at room
temperature. After 5 min stirring the temperature was raised to 70° C and
allowed to stirred for 12 h. After completion of the reaction, crude
reaction mixture was purified by flash column chromatography using
hexane:EtOAc (7:3) as eluent to give the compounds 17a-e (55% - 65%)
in moderate yields.
: 7.60 (d, J = 10.0 Hz, 2H), 7.51 (d, J = 10.0 Hz, 2H), 7.36 – 7.25 (m,
4H), 7.21 – 7.15 (m, 2H), 3.97 (dd, J = 5.0 Hz, 2.5 Hz, 1H), 2.60 – 2.38
(m, 3H), 2.28 -2.16 (m, 3H), 1.62 – 1.30 (m, 6H). 13C NMR (CDCl3, 125
MHz) : 146.3, 145.6, 128.3, 128.2, 126.69, 126.61, 126.1, 125.8, 79.6,
60.3, 55.5, 53.8, 26.3, 24.1. FAB-MS m/z: 310 (M+H)+. HRMS (FAB)
calcd for C20H27N2O m/z: 311.2123 (M+H)+: found: 311.2126.
(S)-2-amino-3-(azepan-1-yl)-1,1-diphenylpropan-1-ol 18c: Pale yellow
23
crystals solid. 86% yield. m.p. 145-146 °C. [α]D = -40 (c = 2.4, EtOH ).
IR (neat) = 3504, 2933, 2326, 1615, 1452 cm-1. 1H NMR (CDCl3, 500
MHz) : 7.61 -7.59 (m, 2H), 7.52 – 7.50 (m, 2H), 7.36 – 7.24 (m, 4H),
7.21 – 7.13 (m, 2H), 3.92 (dd, J = 4.5 Hz, 2.5 Hz, 1H), 3.71 (bs, 3H), 2.69
– 2.64 (m, 2H), 2.57 -2.45 (m, 4H), 1.71 – 1.50 (m, 9H). 13C NMR (CDCl3,
125 MHz) : 146.3, 145.5, 128.3, 128.2, 126.7, 126.6, 126.0, 125.7, 79.7,
59.9, 56.8, 54.5, 27.9, 26.9. FAB-MS m/z: 325 (M+H)+. HRMS (FAB)
calcd for C21H29N2O m/z: 325.2280 (M+H)+: found: 325.2279.
(S)-tert-butyl
(1-hydroxy-1,1-diphenyl-3-(pyrrolidin-1-yl)propan-2-
yl)carbamate 17a: White solid. 65% yield. m.p. 113-115 oC. [α]D = -
53.12 (c = 0.32, EtOH). IR (neat): 3096, 2918, 2817, 2834, 1725,
1565,1456, 1165, 1018 cm-1. 1H NMR (CDCl3, 500 MHz) : 7.54 – 7.52
(m, 2H), 7.48 – 7.47 (m, 2H), 7.31 – 7.24 (m, 4H), 7.17 – 7.13 (m, 2H),
5.23 (d, J = 5.0 Hz, 1H), 4.63 (d, J = 5.0 Hz, 1H), 2.81 – 2.74 (m, 2H),
2.70 – 2.60 (m, 2H), 2.40 – 2.30 (m, 2H), 1.78 – 1.68 (m, 4H), 1.35 (s,
9H). 13C NMR (CDCl3, 125 MHz) : 155.8, 146.8, 145.2, 128.4, 128.2,
126.68, 126.65, 125.3, 125.1, 81.7, 79.4, 56.3, 55.7, 54.3, 28.4, 28.3,
23.7. EI-MS m/z: 396 (M)+. HRMS (EI) calcd for C24H32N2O3 m/z:
396.2413 (M)+: found: m/z: 396.2417 (M)+.
21
(S)-2-amino-3-morpholino-1,1-diphenylpropan-1-ol 18d: Light yellow
solid. 85% yield. m.p. 110-113 °C. [α]D23 = -66 (c = 1.0, EtOH). IR (neat)
= 3386, 3324, 2950, 1599, 1449, 1259 cm-1. 1H NMR (500 MHz, CD3OD):
δ 7.29 (d, J = 8.00 Hz, 2H), 7.18 (d, J = 8.00 Hz, 2H), 6.98 (t, J = 8.00 Hz,
2H), 3.76 (dd, J1 = 3.00, 9.00 Hz, 1H), 2.20 (s, 2H), 2.10 (q, J = 9.00,
13.00 Hz, 1H), 1.88 (s, 2H), 1.83 (dd, J = 3.00, 12.50 Hz, 1H). 13C NMR
(125 MHz, CD3OD) δ: 147.6, 146.8, 129.5, 129.3, 127.9, 127.8, 127.2,
126.8, 80.7, 68.2, 61.2, 55.4, 54.6. FAB-MS m/z: 313 (M+H)+. HRMS
(FAB) calcd for C19H25N2O2 m/z: 313.1916 (M+H)+: found: 313.1904.
(S)-tert-butyl
(1-hydroxy-1,1-diphenyl-3-(piperidin-1-yl)propan-2-
o
21
yl)carbamate 17b: White solid. 62% yield. m.p. 85-87 C. [α]D = -88.0
(c = 0.25, EtOH). IR (neat): 3086, 2910, 2856, 1721, 1623, 1555,1467,
1148, 1022 cm-1. 1H NMR (CDCl3, 500 MHz) : 7.59 – 7.51 (m, 2H), 7.50
– 7.44 (m, 2H), 7.30 – 7.20 (m, 4H), 7.18 – 7.12 (m, 2H), 5.30 – 5.22 (m,
1H), 4.70 – 4.62 (, 1H), 2.76 – 2.73 (m, 1H), 2.56 – 2.42 (m, 2H), 2.10 –
2.02 (m, 2H), 1.60 – 1.52 (m, 4H), 1.42 – 1.30 (m, 12H). 13C NMR (CDCl3,
125 MHz) : 155. 8, 147.5, 145.2, 128.4, 128.2, 126.7, 126.6, 125.3,
125.2, 81.4, 79.4, 59.1, 56.3, 54.0, 28.4, 26.3, 23.7. EI-MS m/z: 410 (M)+.
HRMS (EI) calcd for C25H34N2O3 m/z: 410.2569 (M)+: found: m/z:
410.2565 (M)+.
(S)-2-amino-1,1-diphenyl-3-thiomorpholinopropan-1-ol 18e: White
solid. 85% yield. m.p. 94-96 °C. [α]D25 = -74 (c = 1.09, EtOH). IR (neat) =
3582, 2952, 2359, 1673, 1491 cm-1. 1H NMR (500 MHz, CD3OD): δ 7.73
(s, 1H), 7.48 (d, J = 7.50 Hz, 2H), 7.39 (d, J = 7.50 Hz, 2H), 7.20-7.12 (m,
2H), 3.93 (s, 1H), 2.64 (s, 2H), 2.48 (s, 2H), 2.35 (s, 2H), 2.30-2.25 (m,
3H), 2.12 (d, J = 13.00 Hz, 1H). 13C NMR (125 MHz, CD3OD): δ 147.4,
146.8, 129.5, 129.3, 127.9, 127.8, 127.2, 126.2, 126.9, 80.7, 61.5, 57.2,
54.9, 28.9. EI-MS m/z: 328 (M)+. HRMS (EI) calcd for C19H24N2OS m/z:
328.1609 (M)+: found: 328.1608.
General procedure for aldol reaction of isatin with acetaldehyde
using catalyst 18a. A solution of acetaldehyde 2 (20 eq.) and catalyst
18a in toluene was stirred for 5 minutes at 0 oC and then isatin 1b (1.0
eq.) followed by benzoic acid were added simultaneously and stirring
was continued for 48 h at same temperature. After completion of the
reaction indicated by TLC, the solvent was removed under reduced
pressure then reaction crude was dissolved in MeOH followed by
(S)-tert-butyl
(3-(azepan-1-yl)-1-hydroxy-1,1-diphenylpropan-2-
o
21
yl)carbamate 17c: White solid. 55% yield. m.p. 67-69 C. [α]D = -80.0
(c = 0.25, EtOH). IR (neat): 3094, 2895, 2812, 1732, 1645, 1532,1428,
1156, 1019 cm-1. H NMR (CDCl3, 500 MHz) : 7.55 (d, J = 5.0 Hz, 2H),
7.48 (d, J = 10.0 Hz, 2H), 7.30 – 7.24 (m, 4H), 7.18 – 7.12 (m, 2H), 5.28
– 5.20 (m, 1H), 4.68 – 4.62 (m, 1H), 3.00 – 2.92 (m, 1H), 2.44 – 2.36 (m,
2H), 1.70 – 1.52 (m, 8H), 1.34 (s, 9H). 13C NMR (CDCl3, 125 MHz) : 155.
7, 146.9, 145.3, 128.4, 128.2, 126.7, 126.6, 125.3, 81.5, 79.4, 59.0, 58.2,
54.0, 28.4, 27.9, 26.6. EI-MS m/z: 424 (M)+. HRMS (EI) calcd for
C26H36N2O3 m/z: 424.2726 (M)+: found: m/z: 424.2728 (M)+
1
o
addition of NaBH4 (1.0 eq.) at 0 C and stirring was continued for 30 min
at same temperature. The solvent was removed under reduced pressure,
excess NaBH4 was quenched with ice cold water then organic layer was
extract with ethyl acetate (3x3 ml), solvent was removed under vacuum
and residue was purified by column chromatography.
General procedure for synthesis of catalysts 18a-e: Compound 17 (1
mmol) was dissolved in DCM (10 mL) followed by slow addition of TFA
(0.382 mL, 10 mmol) at 0 oC and stirred for 1 h at room temperature.
After completion of reaction indicated by TLC, the residue was basified
with saturated aq. NaHCO3 solution and extract in DCM (3x15 mL) and
the combined organic layers were washed with brine and dried over
Na2SO4. The solvent was evaporated under reduced pressure and
purified the residue by flash column chromatography using
hexane:EtOAc (1:1) as eluent yielded di-amine aminoalcohols 18a-e
(85% - 95%) as pure compounds.
(S)-3-hydroxy-3-(2-hydroxyethyl)-5-methylindolin-2-one 5k: Brown
solid. 64% yield. m.p. 74-76 °C. [α]D = -52 (c = 0.3, EtOH). IR (neat) =
25
3156, 2923, 1721, 1610, 1545, 1342, 1045 cm-1. The ee was determined
by HPLC [DAICEL chiralpak AD-H column, hexane/2-propanol = 80/20,
flow rate: 1.0 mL/min, tR (major) = 7.06 min, tR (minor) = 9.6 min, ee =
84%]. 1H NMR (MeOD-d3, 500 MHz) : 7.14 (bs, 1H), 7.04 (d, J = 10.0
Hz, 1H), 6.73 (d, J = 10.0 Hz, 1H), 3.51 – 3.43 (m, 2H), 2.29 (s, 3H), 2.19
– 2.06 (m, 2H). 13C NMR (MeOD-d3, 125 MHz) : 180.6, 138.8, 132.,
131.4, 129.4, 124.4, 109.6, 75.1, 57.0, 39.9, 19.7. EI-MS m/z: 207 (M)+.
HRMS (EI) calcd for C11H13NO3 m/z: 207.0895 (M)+: found: 207.0892.
(S)-2-amino-1,1-diphenyl-3-(pyrrolidin-1-yl)propan-1-ol 18a: Light
(S)-3-hydroxy-3-(2-hydroxyethyl)-5-nitroindolin-2-one 5l: Yellow solid.
57% yield. m.p. 147-149 °C. [α]D = -57.4 (c = 0.28, EtOH). IR (neat) =
24
25
yellow solid. 90% yield. m.p. 113-115 °C. [α]D = -74 (c = 1.09, EtOH ).
IR (neat) = 2933, 2803, 1556, 1448, 1355 cm-1. 1H NMR (CDCl3, 500
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700399
European Journal of Organic Chemistry
FULL PAPER
3268, 2911, 2349, 1705, 1632, 1536, 1340, 1067 cm-1. The ee was
determined by HPLC [DAICEL chiralpak AD-H column, hexane/2-
propanol = 80/20, flow rate: 1.0 mL/min, tR(major) = 6.79 min, tR(minor) =
8.4 min, ee = 92%]. 1H NMR (DMSO-d6, 500 MHz) : 10.87 (bs, 1H), 8.15
(dd, J = 6 .0Hz, 2.5 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 6.95 (d, J = 8.5 Hz,
1H), 6.17 (bs, 1H), 4.37 (t, J = 5.0 Hz, 1H), 3.28 – 3.20 (m, 2H), 2.03 (t, J
= 7.0 Hz, 1H). 13C NMR (DMSO-d6, 125 MHz) : 179.9, 148.9, 142.6,
133.4, 126.7, 120.3, 110.2, 74.6, 56.6, 40.4. EI-MS m/z: 238 (M)+. HRMS
(EI) calcd for C10H10N2O5 m/z: 238.0590 (M)+: found: 238.0591.
75.4, 52.1, 42.7. EI-MS m/z: 322 (M)+. HRMS (EI) calcd for C18H14N2O4
m/z: 322.0954 (M)+: found: 322.0959.
Cephalanthrin A 7: To the stirred solution of Phaitanthrin B 6 (20 mg,
0.06 mmol) in MeOH (2 ml) at 0 oC, was added aq. NaOH (1.2 eq.)
dropwise at same temperature and stirring was continued for 30 min.
Reaction mass was quenched with aq. HCl (1.0 N) and then organic
compound was extracted with ethylacetate (3x5 ml), dried over Na2SO4,
washed with aq. NAHCO3, solvent was removed under reduced pressure
then crude mixture was purified by flash column chromatography using
hexane:EtOAc (6:4) as eluent gave the targeted Cephalanthrin A 7 (15
mg, 80%).
(S)-6-hydroxy-6-(2-hydroxyethyl)indolo[2,1-b]quinazolin-12(6H)-one
20: To the stirred solution of compound 5a (30 mg, 0.15 mmol) and
trimethylamine (24 mg, 0.24 mmol) was added compound 19 (25 mg,
0.15 mmol) at room temperature and stirred for 6 h at 100 oC. After
completion of the reaction, excess solvent was removed under reduced
pressure then crude reaction mixture was purified by flash column
chromatography using hexane:EtOAc (7:3) as eluent gave the coupled
product 20 (25 mg, 55%).
25
Light white solid. m.p. 160-162 °C. [α]D = +21 (c = 0.21, CHCl3). IR
(neat) = 3825, 3351, 2930, 1724, 1661, 1603, 1463, 1240, 1010, 751 cm-
1. The ee was determined by HPLC [DAICEL chiralpak AD-H column,
hexane/2-propanol = 80/20, flow rate: 0.8 mL/min, tR (minor) = 10.71 min,
tR (major) = 11.34 min, ee = 99%]. 1H NMR (MeOD-d3, 500 MHz) : 8.48
(d, J = 8.0 Hz, 1H), 8.34 (dd, J = 7.0 Hz, 1 Hz, 1H), 7.86 – 7.79 (m, 2H),
7.65 (dd, J = 7.5 Hz, 1.0 Hz, 1H), 7.60 – 7.57 (m, 1H), 7.50 (td, J = 8.0
Hz, 1.0 Hz, 1H), 7.39 (td, J = 7.5 Hz, 1.0 Hz, 1H), 3.56 (d, J = 16.5 Hz,
1H), 3.38 (d, J = 16.5 Hz, 1H). 13C NMR (MeOD-d3, 125 MHz) : 171.0,
161.5, 159.8, 147.3, 139.8, 134.5, 133.0, 129.9, 127.2, 127.0, 126.6,
126.3, 123.4, 121.7, 116.5, 74.9, 42.7. EI-MS m/z: 308 (M)+. HRMS (EI)
calcd for C17H12N2O4 m/z: 308.0797 (M)+: found: 308.0804.
25
Light brown solid. m.p. 168-170 °C. [α]D = +31.2 (c = 0.16, EtOH).
IR(neat) = 3338, 2915, 1706, 1616, 1470, 1241, 1103, 749 cm-1. The ee
was determined by HPLC [DAICEL chiralpak AD-H column, hexane/2-
propanol = 80/20, flow rate: 1.0 mL/min, tR (major) = 19.78 min, tR (minor)
= 23.03 min, ee = 89%]. 1H NMR (DMSO-d6, 500 MHz) : 10.23 (bs, 1H),
7.41 (dd, J = 6.5 Hz, 1.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.18 -7.15 m,
2H), 6.93 (t, J = 7.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.5 Hz,
1H), 6.51 (bs, 1H), 6.42 (t, J = 8.0 Hz, 1H), 6.03 (bs, 1H), 4.14 – 4.10 (m,
1H), 4.01 – 3.92 (m, 1H), 2.27 – 2.16 (m, 2H). 13C NMR (DMSO-d6, 125
MHz) : 179.3, 167.7, 151.8, 142.2, 134.4, 131.9, 131.3, 129.6, 124.6,
122.2, 116.8, 115.1, 110.2, 109.1, 74.7, 60.2, 36.8. EI-MS m/z: 294 (M)+.
HRMS (EI) calcd for C17H14N2O3 m/z: 294.1004 (M)+: found: 294.1007.
(S)-2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)ethyl
4-
methylbenzenesulfonate 22: To a stirred solution of diol 5c (40 mg,
0.19 mmol) in dry pyridine (3 ml), was added tosyl chloride (73 mg, 0.38
mmol) at 0 °C and stirring was continued for 10 h at room temperature.
The reaction mixture was quenched with aq. HCl and extracted with
ethylacetate (3x5 ml). The organic layer was washed with saturated
aqueous NH4Cl and brine, dried over Na2SO4 and solvent was
evaporated. The residue was purified by column chromatography (eluted
with hexane-ethyl acetate, 7: 3) to give the pure compound 22 (55 mg,
80% yield).
(S)-methyl 2-(3-hydroxy-2-oxoindolin-3-yl)acetate 21: To the stirred
solution of aldol product 3a in t-BuOH/H2O (3:1) solvent was added
NaH2PO4, 2-methyl-2-butene and NaClO2 simultaneously at 0 oC and
stirred for 3 h, at same temperature. After completion of reaction,
reaction mixture was quenched with aq. HCl and organic compound was
extracted with ethylacetate (5x5 ml) and then solvent was removed under
reduced pressure yielded the crude acid compound 4. The crude 4 was
dissolved in dry THF, followed by addition of TMSCH2N2 and stirring was
25
White solid. m. p.135-137 °C. [α]D = +35 (c = 1.2, EtOH). IR(neat) =
3355, 2936, 1705, 1598, 1466, 1240, 1024, 780 cm-1. The ee was
determined by HPLC [DAICEL chiralpak AD-H column, hexane/2-
propanol = 85/15, flow rate: 0.8 mL/min, tR (major) = 50.27 min, tR (minor)
1
= 57 min, ee = 84%]. H NMR (CDCl3, 500 MHz) : 7.67 (d, J = 8.5 Hz,
o
2H), 7.33 (td, J = 8.0 Hz, 1.5 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.08 (td, J
= 7.0 Hz, 0.5 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.14 – 4.04 (m, 2H), 3.14
(s, 3H), 2.43 (s, 3H), 2.38 – 2.31 (m, 1H), 2.27 – 2.21 (m, 1H), 1.73 (bs,
1H). 13C NMR (CDCl3, 125 MHz) : 177.8, 144.9, 143.3, 132.7, 130.3,
129.9, 128.8, 127.9, 124.0, 123.4, 108.9, 74.6, 65.6, 37.0, 26.3, 21.7. EI-
MS m/z: 361 (M)+. HRMS (EI) calcd for C18H19NO5S m/z: 361.0984 (M)+:
found: 361.0988.
continued for 3 h at 0 C. After completion of reaction indicated by TLC,
reaction mass was dissolved in water and organic layer was extracted
with ethylacetate (3x5 ml), dried over Na2SO4, solvent was removed
under reduced pressure then crude was purified by flash column
chromatography using hexane:EtOAc (7:3) as eluent gave the ester
product 21 overall 80% yield.
25
Light brown solid. m. p. 68-70 °C. [α]D = +12.5 (c = 0.12, EtOH).
IR(neat) = 3254, 2954, 1745, 1712, 1620, 1335, cm-1. The ee was
determined by HPLC [DAICEL chiralpak AD-H column, hexane/2-
propanol = 90/10, flow rate: 1.0 mL/min, tR (major) = 34.45 min, tR (minor)
= 54.37 min, ee = 89%]. 1H NMR (MeOD-d3, 500 MHz) : 7.32 (d, J = 7.5
Hz, 1H), 7.23 (dt, J = 8.0 Hz, 1.5 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.85
Chimonamidine 8: The solution of compound 22 (20 mg, 0.05 mmol) in
methylamine solvent (2 ml) was stirred for 10 h at 65 oC, then excess
solvent was removed under reduced pressure. The resulted crude was
purified by flash column chromatography using hexane:EtOAc (6:4) as
eluent gave the targeted Chimonamidine 8 (7.5 mg, 60%). The resulted
compound 8, was further purified by washing with ether (two times) to get
the sufficient ee value (94% ee).
(d, J = 7.5 Hz, 1H), 3.44 (s, 3H), 3.04 (dd, J = 15.5 Hz, 2.15 Hz, 2H). 13
C
NMR (MeOD-d3, 125 MHz) : 179.1, 169.5, 142.2, 130.3, 129.5, 123.8,
122.1, 109.9, 73.3, 50.7, 40.9. EI-MS m/z: 221 (M)+. HRMS (EI) calcd for
C11H11NO4 m/z: 221.0688 (M)+: found: 221.0689.
25
Light white solid. m. p.161-163 °C. [α]D = +55.97 (c = 0.12, EtOH).
IR(neat) = 3376, 2924, 1683, 1582, 1464, 1043, 744 cm-1. The ee was
determined by HPLC [DAICEL chiralpak AD-H column, hexane/2-
propanol = 70/30, flow rate: 1.0 mL/min, tR (minor) = 5.52 min, tR (major)
= 6.41 min, ee = 94%]. 1H NMR (CDCl3, 500 MHz) : 7.22 (td, J = 8.0 Hz,
1.5 Hz, 1H), 6.84 – 6.82 8m, 1H), 6.73 (d, J = 7.0 Hz, 1H), 6.64 (td, J =
7.5 Hz, 2.5 Hz, 1H), 3.30 (td, J = 10.0 Hz, 1.5 Hz, 1H), 3.24 – 3.19 (m,
1H), 2.96 (s, 3H), 2.83 (s, 3H), 2.71 (qd, J = 6.5 Hz, 1.5 Hz, 1H), 2.42 –
2.36 (m, 1H), 1.70 (bs, 1H). 13C NMR (CDCl3, 125 MHz) : 175.2, 148.3,
129.5, 125.5, 124.6, 116.7, 111.8, 79.8, 45.8, 33.1, 30.3, 30.2. EI-MS
m/z: 220 (M)+. HRMS (EI) calcd for C12H16N2O2 m/z: 220.1212 (M)+:
found: 220.1209.
Phaitanthrin B 6: To the stirred solution of compound 21 (25 mg, 0.11
mmol) and trimethylamine (17 mg, 0.17 mmol) was added compound 19
(19 mg, 0.11 mmol) at room temperature and stirred for 6 h at 100 oC.
After completion of the reaction, excess solvent was removed under
reduced pressure then crude reaction mixture was purified by flash
column chromatography using hexane:EtOAc (8:2) as eluent gave the
targeted Phaitanthrin B 6 (21 mg, 60%).
25
Pale yellow solid. m. p.156-158 °C. [α]D = -19.5 (c = 0.16, CHCl3).
IR(neat) = 3372, 2947, 1740, 1662, 1602, 1462, 1353, 752 cm-1. The ee
was determined by HPLC [DAICEL chiralpak AD-H column, hexane/2-
propanol = 80/20, flow rate: 0.8 mL/min, tR (minor) = 14.96 min, tR (major)
= 15.44 min, ee = 99%]. 1H NMR (CDCl3, 500 MHz) : 8.34 (d, J = 8.0 Hz,
1H), 8.24 (d, J = 8.0 Hz, 1H), 7.76 – 7.73 (m, 2H), 7.54 (dd, J = 7.0 Hz,
0.5 Hz, 1H), 7.50 – 7.46 (m, 1H), 7.27 (td, J = 8.0 Hz, 1 Hz, 1H), 7.19 (td,
J = 7.0 Hz, 0.5 Hz, 1H), 4.90 (bs, 1H), 3.56 (s, 3H), 3.30 (dd, J = 26.0 Hz,
16.5 Hz, 2H). 13C NMR (CDCl3, 125 MHz) : 170.5, 159.7, 159.4, 147.1,
139.0, 134.5, 131.5, 130.7, 127.9, 127.5, 127.1, 123.6, 121.8, 116.9,
(S)-2-(3-hydroxy-2-oxoindolin-3-yl)ethyl 4-methylbenzenesulfonate
23: To a stirred solution of diol 5a (25 mg, 0.12 mmol) in dry pyridine (2
ml), was added tosyl chloride (49 mg, 0.25 mmol) at 0 °C and stirring was
continued for 10 h at room temperature. The reaction mixture was
quenched with aq. HCl and extracted with ethylacetate (3x5 ml). The
organic layer was washed with saturated aqueous NH4Cl and brine, dried
over Na2SO4 and solvent was evaporated. The residue was purified by
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10.1002/ejoc.201700399
European Journal of Organic Chemistry
FULL PAPER
organic synthesis (2nd edition), 2014, 2, 273–339; d) M. Jacek, B.
Sebastian, Chem. Soc. Rev. 2014, 43, 577–587; e) B. M. Trost, C. S.
Brindle, Chem. Soc. Rev. 2010, 39, 1600–1632; f) S. Mukherjee, J. W.
Yang, S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471–5569;
Asymmetric Organocatalysis, (Eds. A. Berkessel, H. Groger), Wiley-
VCH, Weinheim, 2005; g) S. Saito, H. Yamamoto, Acc. Chem. Res.
2004, 37, 570–579.
Selective examples on aldol reaction of various aldehydes: a) L.
Patricia, S. Sonia, R. E. Carles, M. A. Pericas, Green
Chemistry 2016, 18, 3507–3512; b) G. Bartosz; M. Jacek Eur. J. Org.
Chem. 2015, 5075-5078; c) K. Taichi, M. Hiroki, S. Ryu, K. Maruoka,
Chem. Commun. 2015, 51, 10062-10065; d) Y. Hayashi, H. Sekizawa,
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Soc. 2002, 124, 6798-6799.
column chromatography using with hexane-ethyl acetate, 7: 3 as eluent
to give the pure compound 23 (40 mg, 90% yield).
25
Pale yellow solid. m. p.141-143 °C. [α]D = +28.7 (c = 0.2, EtOH).
IR(neat) = 3368, 2929, 1705, 1619, 1596, 1471, 1188, 1097, 655 cm-1.
The ee was determined by HPLC [DAICEL chiralpak AD-H column,
hexane/2-propanol = 75/25, flow rate: 1.0 mL/min, tR (major) = 20.02 min,
tR (minor) = 23.18 min, ee = 89%]. 1H NMR (MeOD-d3, 500 MHz) : 7.61
(d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.22 – 7.19 (m, 2H), 6.99 –
6.96 (m, 1H), 6.81 – 6.78 (m, 1H), 4.08 – 4.04 (m, 1H), 3.92 – 3.87 (m,
1H), 242 (s, 3H), 2.32 – 2.25 (m, 1H), 2.17 – 2.12 (m, 1H). 13C NMR
(MeOD-d3, 125 MHz) : 179.8, 145.1, 141.3, 132.6, 130.3, 129.7, 129.4,
127.6, 123.8, 122.3, 110.1, 74.3, 66.0, 36.1, 20.2. EI-MS m/z: 347 (M)+.
HRMS (EI) calcd for C17H17N1O5S1 m/z: 347.0827 (M)+: found: 347.0830.
[2]
Donaxaridine 9: The solution of compound 23 (20 mg, 0.05 mmol) in
methylamine solvent (2 ml) was stirred for 10 h at 65 oC, then excess
solvent was removed under reduced pressure. The resulted crude was
purified by flash column chromatography using hexane:EtOAc (6:4) as
eluent gave the targeted Donaxaridine 9 (7.5 mg, 60%). The resulted
compound 9, was further purified by washing with ether (two times) to get
the sufficient ee value (98% ee).
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Review on organocatalytic reactions with acetaldehyde: B. Alcaide, P.
Almendros, Angew. Chem. Int. Ed. 2008, 47, 4632–4634.
Recent and selective example of aldol reaction of acetaldehyde with
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25
Light brown solid. m. p.146-148 °C. [α]D = +39.4 (c = 0.13, EtOH).
IR(neat) = 3450, 3333, 2920, 1669, 1619, 1494, 1305, 1035, 746 cm-1.
The ee was determined by HPLC [DAICEL chiralpak AD-H column,
hexane/2-propanol = 70/30, flow rate: 1.0 mL/min, tR (minor) = 7.32 min,
tR (major) = 8.29 min, ee = 98 %]. 1H NMR (CDCl3, 500 MHz) : 7.10 (td,
J = 7.5 Hz, 1.5 Hz, 1H), 6.86 (dd, J = 8.0 Hz, 1.5 Hz, 1H), 6.72 – 6.67 (m,
2H), 4.73 (bs, 1H), 3.33 (td, J = 10.0 Hz, 2.0 Hz, 1H), 3.27 – 3.22 (m, 1H),
2.96 (s, 3H), 2.74 (qd, J = 6.0 Hz, 1.5 Hz, 1H), 2.44 – 2.38 (m, 1H). 13C
NMR (CDCl3, 125 MHz) : 175. 2, 145.9, 129.3, 125.7, 125.2, 118.4,
118.1, 79.4, 45.7, 32.9, 30.3. EI-MS m/z: 206 (M)+. HRMS (EI) calcd for
C11H14N2O2 m/z: 206.1055. (M)+: found: 206. 1049.
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(S)-3-(2-azidoethyl)-3-hydroxyindolin-2-one 24: To the stirred solution
of tosylated compound 23 (20 mg, 0.05 mmol) in dry DMF, was added
NaN3 (6 mg, 0.09 mmol) at room temperature and then stirring was
Hara, S. Nakamura, N. Shibata, T. Toru, Chem. Eur. ꢀ J. 2009, 15,
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o
continued for 6 h at 60 C. After completion of reaction temperature was
cooled r.t. Reaction mixture was diluted with ice-cold water, organic
compound was extracted with ethylacetate (3x5 ml), dried over Na2SO4,
under vacuum then crude mass was purified by flash column
chromatography using hexane:EtOAc (8:2) as eluent gave azide
compound 24 (11 mg, 89%).
White solid. m. p.144-146 °C. [α]D25 = -13.2 (c = 0.28, EtOH). IR (neat) =
3316, 3177, 2925, 2465, 2328, 2092, 1696, 1616, 1470, 1100, 753 cm-1.
The ee was determined by HPLC [DAICEL chiralpak AD-H column,
hexane/2-propanol = 80/20, flow rate: 0.8 mL/min, tR (major) = 9.04 min,
tR (minor) = 11.47 min, ee = 89%]. 1H NMR (MeOD-d3, 500 MHz) : 7.32
(dd, J = 7.5 Hz, 0.5 Hz, 1H), 7.25 (td, J = 7.5 Hz, 1.5 Hz, 1H), 7.05 (td, J
= 7.5 Hz, 0.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 3.32 – 3.25 (m, 1H), 3.18
– 3.13 (m, 1H), 2.22 – 210 (m, 2H). 13C NMR (MeOD-d3, 125 MHz) :
180.1, 141.4, 130.7, 129.4, 123.8, 122.4, 110.0, 74.8, 46.2, 36.4. EI-MS
m/z: 218 (M)+. HRMS (EI) calcd for C10H10N4O2 m/z: 218.0804. (M)+:
found: 218.0807.
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Acknowledgements
[10] Our reviews on primary amino alcohols: a) U. V. Subba Reddy, M.
Chennapuram, C. Seki, Y. Okuyama, E. Kwon, H. Nakano. Eur. J. Org.
Chem. 2016, 4124–4143; b) H. Nakano, J. Kumagai, U. V. Subba
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We thank Adaptable & Seamless Technology Transfer Program
through Target-driven R&D from Japan Science and Technology
Agency (JST) (AS231Z01382G and AS221Z01186D) for partial
financial support to this research.
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V. Subba Reddy, C. Seki, Y. Okuyama, K. Uwai, M. Tokiwa, M.
Takeshita, H. Nakano, Tetrahedron: Asymmetry, 2016, 27, 1062–1068;
b) J. Kumagai, T. Otsuki, U. V. Subba Reddy, Y. Kohari, C. Seki, K.
Uwai, Y. Okuyama, E. Kwon, M. Tokiwa, M. Takeshita, H. Nakano.
Tetrahedron Asymmetry 2015, 26, 1423–1439; c) T. Otsuki, J. Kumagai,
Y. Kohari, Y. Okuyama, E. Kwon, C. Seki, K. Uwai, Y. Mawatari, N.
Kobayashi, T. Iwasa, M. Tokiwa, M. Takeshita, A. Maeda, A.
Hashimoto, K. Turuga, H. Nakano. Eur. J. Org. Chem. 2015, 7292–
7300; d) Y. Kohari, Y. Okuyama, E. Kwon, T. Furuyama, N. Kobayashi,
T. Otuki, J. Kumagai, C. Seki, K. Uwai, G. Dai, T. Iwasa, H. Nakano. J.
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Takano, M. Tokiwa, M. Takeshita, H. Nakano. Heterocycles. 2012, 86,
Keywords: di-amino alcohols • enantioselective crossed-aldol
reaction • 3-substituted 3-hydroxyindolin-2-ones • total synthesis
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European Journal of Organic Chemistry
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10.1002/ejoc.201700399
European Journal of Organic Chemistry
FULL PAPER
Layout 2:
FULL PAPER
Di- amino alcohol organo catalyst
Ummareddy Venkata Subba Reddy,*
Madhu Chennapuram, Kento Seki,
Chigusa Seki, Bheemreddy Anusha,
Eunsang Kwon,* Yuko Okuyama, Koji
Uwai, Michio Tokiwa, Mitsuhiro
Takeshita, and Hiroto Nakano*
New type di-amino alcohols are synthesized and their catalytic activity as bilateral
activation catalysts for enantioselective crossed-aldol reaction of isatin derivatives
with acetaldehyde has been evaluated. The resulted crossed-aldol products i.e 3-
alkyl-3-hydroxyindolin-2-ones have been successful utilized for total synthesis of
bioactive natural products such as phaitanthrin B, cephalanthrin A, chimonamidine,
donaxaridine and formal synthesis of CPC-1.
Page No. – Page No.
New type of di-amino alcohol-
catalyzed enantioselective crossed
aldol reaction of acetaldehyde with
isatins: A concise total synthesis of
antitumor agents
This article is protected by copyright. All rights reserved.