Sidearm effect: Improvement of the enantiomeric excess in the asymmetric Michael addition of indoles to alkylidene malonates

Article abstract of DOI:10.1021/ja026936k

A pseudo-C₃-trisoxazoline was designed and synthesized. The improvement of the traditional bisoxazoline into a novel trisoxazoline by a sidearm approach resulted in highly catalytic enantioselective Michael addition of indoles to alkylidene mal

Full text of DOI:10.1021/ja026936k

Published on Web 07/16/2002
Sidearm Effect: Improvement of the Enantiomeric Excess in the Asymmetric
Michael Addition‡ of Indoles to Alkylidene Malonates
Jian Zhou and Yong Tang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 200032 Shanghai, China
Received May 17, 2002
Table 1. Effect of Temperature and Additive on the Reaction
between Indole 5a and Benzylidene Malonate 6a
C2-symmetric chiral bisoxazoline-metal complexes enjoy high
prestige in asymmetric catalysis.1 For example, bisoxazoline 1
derived Cu(II) complexes2 have been well established as versatile
catalysts for asymmetric C-C bond formations such as aldol,3
cycloaddition,4 ene,5 Michael,6 amination,7 Friedel-Crafts,8 Henry,9
and Mannich10 reactions. In most cases, excellent enantioselectivity
could be achieved only when tert-leucinol-derived bisoxazoline 1b
was used. In sharp contrast to the great success of bisoxazolines,
the development and application of trisoxazolines are rather
limited.11 In our efforts to develop superior catalysts which are
cheap, easy to access, air-stable, and water-tolerant, we considered
a sidearm approach, focusing on the improvement of bisoxazoline
into pseudo-C3-symmetric trisoxazoline 2, for the following rea-
sons: (1) compared with C2-symmetric bisoxazolines 1, coordina-
tion of three nitrogen atoms of trisoxazoline 2 to the metallic center
induces a more tunable pseudo-C3-symmetric chiral space, to shield
distant reactive sites; (2) tridentate ligand 2 is expected to increase
the stability of active intermediates with respect to ordinary
bidentate bisoxazolines.12 Thus, the metal complex may be tolerable
to moisture, and it is possible to improve the catalytic activity. In
this communication, we report our preliminary results on this
subject.
entry
catalyst loading (%)
additive
temp (°C)
yielda (%)
eeb,c (%)
1
2
10
10
10
1
10
10
None
None
HFIP
HFIP
HFIP
HFIP
15
0
0
0
-20
-25
88
50
99
90
84
56
82
85
85
78
89
93
3
4d
5
6
a Isolated yield and performed on 0.25 mmol scale unless otherwise noted.
b Determined by chiral HPLC. c Absolute configuration was assigned by
chemical transformation. d Performed on 4 mmol scale. e All reactions were
run in acetone-ether (1:3, v/v).
acid. We are pleased to find that the catalytic activity was
comparable to that of 1b/Cu(OTf)2 and the enantioselectivity of
the reaction of indole with benzylidene malonate was enhanced
greatly (entry 1, Table 1).
The alkylation of indole 5a with malonate 6a proceeded quite
slowly at 0 °C, and the yield was only 50%; even the reaction time
was prolonged to 72 h (entry 2 in Table 1) in the absence of
hexafluoro-i-PrOH (HFIP). To our delight, we found that the
addition of 2 equiv of HFIP16 can greatly improve the reactivity
without loss of ee (entry 3). The reaction was proved to be
temperature-dependent. When the reaction temperature decreased
from 0 to -25 °C, the ee value of compound 7a increased from 85
to 93% (entries 3, 5, and 6 in Table 1).
The high yield and excellent enantioselectivity encouraged us
to study the generality of this reaction by investigating a variety of
structurally different indole derivatives and alkylidene malonates
(Table 2). Arylidene malonates with indole worked well to afford
the desired products in excellent yields with high ee. Unlike the ee
that were different between dimethyl and diethyl malonates in the
case of 1b/Cu(OTf)2, both methyl ester and ethyl ester maintained
excellent face selectivity when trisoxazoline was used (entries 1-4).
Enantiomeric excesses ranging from 90 to 92% were obtained in
high yields for various substituted arylidene malonates (entry 4-8).
Diethyl ethylidene malonate could also react with indole smoothly,
but it was less enantioselective (entry 9). The reaction of ben-
zylidene malonate with 4-methoxyindole, 5-methoxyindole, and
5-methylindole resulted in the alkylation products in high-to-
excellent yields with excellent ee value (entries 10, 11, 12),
indicating that the substituents on indole ring had almost no effect
on the enantioselectivity.
The trisoxazoline 2 can be easily synthesized from 3 and L-valinol
by two steps. Compound 3 reacted with L-valinol without solvent13
at 70 °C to afford white hydroscopic solid 4 in 61% yield. Treatment
of compound 4 with PPh3/CCl4 14 afforded desired trisoxazoline 2
as colorless oil in 75% yield.
Very recently, Jørgensen et al. pioneered asymmetric Michael
addition of indoles to alkylidene malonates.8c They found that chiral
Lewis acid 1b/Cu(OTf)2 could promote this reaction in moderate-
to-good ee value (up to 69% ee). To examine if our design is
operative, we tried the above reaction using the newly designed
trisoxazoline 2/Cu(ClO4)2‚6H2O12b,15 complex as the chiral Lewis
It is noteworthy that trisoxazoline 2/Cu(ClO4)2‚6H2O complex
is an air- and water-stable compound. It maintained the same
* To whom correspondence should be addressed. E-mail: tangy@pub.sioc.ac.cn.
‡ This reaction is also regarded as Friedel-Crafts reaction in ref 8c.
9
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J. AM. CHEM. SOC. 2002, 124, 9030-9031
10.1021/ja026936k CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric alkylation of indoles 5 with various
alkylidene malonates 6
useful. In particular, our ligand design strategy may also provide a
basis for further optimization of the sidearmed bisoxazoline to
enhance both enantioselectivity and catalytic efficiency.
Acknowledgment. We are grateful for the financial support
from the National Natural Sciences Foundation of China.
Supporting Information Available: Characterization data for all
compounds, absolute configuration, and experimental procedures (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
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catalytic reactiVity almost without loss of enantioselectiVity eVen
when the reaction was carried out under air atmosphere (entry 13
in Table 2).
Optical purity of the products could be enhanced by recrystal-
lization. For example, 99.6% ee was obtained in 71% yield after
compound 7a (86% ee) was recrystallized from a mixed solvent of
petroleum ether, CH2Cl2, and acetone. These indole derivatives
prepared by the current method are potentially synthetically useful
because they can undergo many chemical transformations, in
particular for the preparation of â-substituted tryptophans17 and
some bioactive indole derivatives.18
The high ee values obtained with L-valinol-derived trisoxazoline
2 are rather intriguing. The proposed transition-state model shown
below supports all the experimental observation and is consistent
with the absolute configuration of some selected products. The
indoles could only approach the re face of the alkylidene malonates
due to steric hindrance.
In conclusion, we have demonstrated that pseudo-C3-symmetric
trisoxazoline 2 has the encouraging ability to achieve high face
selectivity in asymmetric Michael reaction of indoles to alkylidene
malonates. The cheap and easy synthesis of trisoxazoline-Cu (II)
complexes, the high selectivity, and the mild reaction conditions
including water- and air-tolerance make our method potentially
JA026936K
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J. AM. CHEM. SOC. VOL. 124, NO. 31, 2002 9031