Asymmetric aldol reaction of isatins with acetone in the presence of terpene amino alcohols

Article abstract of DOI:10.1016/j.mencom.2020.03.005

Asymmetric aldol reactions of isatin and 4,6-dibromoisatin with acetone are efficiently catalyzed by β-amino alcohols derived from α-pinene and 3-carene. The target compounds can be isolated by crystallization from toluene, which eliminates the need for using chromatography and makes the asymmetric synthesis of (R)-convolutamydine A (up to 94% ee and yield 75%) simple and convenient.

Full text of DOI:10.1016/j.mencom.2020.03.005

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 147–149
Asymmetric aldol reaction of isatins with acetone
in the presence of terpene amino alcohols
Sergei G. Zlotin,*a Olga A. Banina,b Denis V. Sudarikov,b Albert G. Nigmatov,a
Larisa L. Frolovab and Alexander V. Kutchinb
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: zlotin@ioc.ac.ru
b Institute of Chemistry, Komi Science Center, Ural Branch of the Russian Academy of Sciences,
167000 Syktyvkar, Russian Federation. Fax: +7 8212 218 477; e-mail: olga.ferolg.banina@mail.ru
DOI: 10.1016/j.mencom.2020.03.005
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Asymmetric aldol reactions of isatin and 4,6-dibromoisatin
with acetone are efficiently catalyzed by b-amino alcohols
derived from a-pinene and 3-carene. The target compounds
can be isolated by crystallization from toluene, which
eliminates the need for using chromatography and makes the
asymmetric synthesis of (R)-convolutamydine A (up to 94% ee
and yield 75%) simple and convenient.
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Keywords: aldol reaction, b-amino alcohols, 3-carene, a-pinene, isatin, 4,6-dibromoisatin, convolutamydine A.
Asymmetric aldol reaction is a simple and convenient method for
enantioselective formation of the carbon–carbon bond in organic
compounds.1 Effective organocatalysts for this reaction are proline
and some of its derivatives,1 as well as a number of other chiral
amines of natural origin.2 The metal complex compounds with
terpene ligands are also successfully applied in reactions of this
type.3
Among the various aldol condensations, enantioselective
reactions between two ketones in which one acts as donor and
the other as acceptor are of considerable interest as a source of
compounds valuable for pharmacology.4 In particular, products
of aldol reactions of ketones with isatin-derived acceptors,5 which
contain the motif of 3-substituted 3-hydroxy-2-indole, are useful
biologically active compounds, e.g., TMC-95 (A-D), celogentin K,
dioxibrassinine.6 (R)-Convolutamydine A, a product of reaction
of 4,6-dibromoisatin and acetone,7 was isolated from the marine
bryozoa of the genus Amathia convoluta. It inhibits the diffe-
rentiation of promyelocytic leukemia cells of human line HL-60
and exhibits potent anticancer activity.8
and valinol,2(a) where the corresponding aldols are formed with
up to 95% ee. Recently we have shown9 that b-amino alcohols
1-5 derived from a-pinene and 3-carene are also capable of cata-
lyzing these reactions.
Herein, catalystsofthistypewereappliedtothestereoselective
synthesis of (R)-convolutamydine A.
At first, the model reaction of isatin 6a with acetone (Scheme 1)
was carried out at ambient temperature in the presence of amino
alcohol 1 (20 mol%), which previously9(a) exhibited promising
stereoinduction (84% ee) in dichloromethane (Table 1, entry 1).
However, in 1,2-dichloroethane and tert-butyl methyl ether a
substantial decrease in the yield and ee of aldol (S)-7a were
recorded (entries 2 and 3).
The best enantioselectivity (90% ee) was achieved in acetone
(entry 4), though at the expense of prolonged reaction time (110 h).
Interesting results were attained in toluene, where a major part of
generated aldol (S)-7a precipitated in the course of the reaction
(entry 5). After filtration, the pure product was obtained in 77%
R
O
Asymmetric aldolization of isatin derivatives with acetone are
efficiently catalyzed by chiral b-amino alcohols, viz. leucinol
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Scheme 1 Reagents and conditions: i, catalyst 1-5, solvent, H2O (2 equiv.),
room temperature, 24-180 h.
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© 2020 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2020, 30, 147–149
Table 1 Asymmetric aldol reactions of isatins 6a,b with acetone.a
Yield (%)b
ee (%)c (configuration)
Entry
Isatin
Solvent
Catalyst (loading, mol%)
t/h
Product
solution/precipitate solution/precipitate
1
2
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
CH2Cl2
Cl(CH2)2Cl
ButOMe
Me2CO
PhMe
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (10)
1 (5)
24
40
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7b
7b
95/-
76/-
87/-
93/-
11/77
21/79
31/63
14/86
6/65
84 (S)8(a)
68 (S)
3
24
67 (S)
4
110
20
90 (S)
5
29/78 (S)
10/90 (S)
73/94 (S)
52/91 (S)
58/94 (R)
59/89 (S)
-7 (S)/99 (R)
93/93 (R)
57/72 (R)
84/78 (R)
68/94 (R)
6
PhMe
24
7
PhMe
20
8
PhMe
1 (1)
2 (5)
90
9
PhMe
42
10
11
12
13
14
15
PhMe
(+)-3 (5)
(-)-3 (5)
4 (20)
5 (20)
2 (5)
72
3/69
PhMe
20
4/76
PhMe
72
30/70
66/30
20/55
11/75
PhMe
180
72
PhMe
PhMe
(-)-3 (5)
72
a Conditions: 6a (0.07 mmol) or 6b (0.09 mmol), acetone (2.1 mmol, except for entry 4), solvent (144 equiv.), H2O (2 equiv.), room temperature. b Isolated
yields. c Determined by chiral HPLC.
yield and with 78% ee. Additional crop (~ 11%) of (S)-7a isolated
fromthemotherliquorbycolumnchromatographyhadsignificantly
loweree(29%)comparedtotheprecipitatedcrystals. Enantiomeric
enrichment of product (S)-7a via spontaneous crystallization
provides an efficient tool for facile product isolation without usage
of column chromatography. Therefore, we further studied the
reaction between 6a and acetone in toluene at 1-10 mol% catalyst
loadings and succeeded in improving enantiomeric enrichment
of crystals to 94% with 5 mol% of 1 (entries 6-8).
Next, we examined 3-carene- and a-pinene-derived catalysts
(2-5) (5, 20 mol%) in the model reaction between 6a and acetone
in toluene (see Table 1, entries 9-13).† A significant portion of
product 7a was also precipitated from MePh and could be
isolated with up to 99% ee without use of chromatography.
Reactions catalyzed by amino alcohols 2 and 3 efficiently
proceeded at 5% catalyst loading (entries 9-11), whereas the
corresponding transformations catalyzed by 4 and 5 were rather
sluggish even at 20% catalyst loading (entries 12 and 13).
Remarkable inversion of configuration of product 7a isolated from
the toluene solution (-7% ee vs. 99% ee for precipitated crystals)
was observed in the reaction catalyzed by antipode (–)-3 (entry 11).
Another important finding is that although the stereocenters at
the amino group in catalysts 4 and 5 have different configurations,
the same product (R)-7a was formed in both cases; the optical
rotations were [a]D = + 21.2 (c 0.2, MeOH) and [a]D = + 20.1 (c 0.2,
MeOH), respectively; lit.5(a) [a]D = + 27.3 (c 0.5, MeOH) for
(R)-7.
entries 14 and 15) in the presence of catalysts 2 and (–)-3 (5 mol%),
which showed the best stereoinduction in the model reaction
between 6a and acetone in MePh. Here too, a major portion of
product 7b precipitated from the reaction mixture and could be
isolated in analytically pure state without chromatography. The
crystalline substance 7b obtained in the presence of catalyst 2
(5 mol%) had enantiomeric purity of 78%, whereas in the
(–)-3-catalyzed reaction it reached 94%, a value competitive to
best previously reported results2(a) (see Table 1).
In summary, b-amino alcohols derived from a-pinene and
3-carene act as efficient stereoinductors in asymmetric aldol reac-
tions of isatin and 4,6-dibromoisatin with acetone. Carrying out
these reactions in MePh significantly simplifies workup excluding
labor-consuming chromatography. The developed procedure
may be considered as the most convenient enantioselective (up
to 94% ee) synthesis of anticancer agent (R)-convolutamydineA.
This work was supported by the Russian Foundation for Basic
Research (grant nos. 15-03-09352 A and 16-33-50061) and was
performed using the equipment of the ‘Chemistry’ Center for
Collective Use at the Institute of Chemistry, Komi Scientific Center,
Ural Branch of the Russian Academy of Sciences.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2020.03.005.
To synthesize the target convolutamydine A 7b, we carried out
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