Enantioselective Michael addition catalyzed by chiral tripodal oxazoline-tBuOK complexes

Article abstract of DOI:10.1016/S0040-4039(01)00681-5

Benzene-based tripodal oxazolines are found to be novel chiral ligands for the catalytic enantioselective Michael addition via potassium enolates. Thus, methyl phenylacetate undergoes 1,4-addition to methyl acrylate using a catalytic amount of a tBuOK-oxa

Full text of DOI:10.1016/S0040-4039(01)00681-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4175–4177
Enantioselective Michael addition catalyzed by chiral tripodal
oxazoline–tBuOK complexes
Sung-Gon Kim and Kyo Han Ahn*
Department of Chemistry and Center for Integrated Molecular Systems, Division of Molecular and Life Sciences,
Pohang University of Science and Technology, San 31 Hyoja-dong, Pohang 790-784, Republic of Korea
Received 21 March 2001; revised 16 April 2001; accepted 20 April 2001
Abstract—Benzene-based tripodal oxazolines are found to be novel chiral ligands for the catalytic enantioselective Michael
addition via potassium enolates. Thus, methyl phenylacetate undergoes 1,4-addition to methyl acrylate using a catalytic amount
of a tBuOK–oxazoline complex in toluene at −78°C, and up to 82% ee is obtained. © 2001 Elsevier Science Ltd. All rights
reserved.
Conjugate addition reactions are some of the funda-
mental organic reactions, which are widely used for
carbonꢀcarbon bond forming reactions. Their asym-
metric versions have been intensively investigated in
recent years catalyzed by various organometallic spe-
cies.1,2 Among them, the conjugate additions of eno-
lates generated from carbonyl or nitro compounds,
usually called Michael addition reactions, have been
widely studied with catalysts such as alkali metal and
transition metal complexes. For the alkali metal com-
plexes, chiral ligands such as Cinchona alkaloids, alkox-
ides, phenoxides, crown ethers, and their derivatives
have been used as the ligands.2 For the title reaction,
several crown ether derivatives3,4 have been studied
since the early report of Cram.5 Herein, we wish to
report that a new class of ligands, the benzene-based
tripodal oxazoline (BTO) system, is potentially useful
chiral ligands for the potassium complexes,6 which is
demonstrated for the title reaction.
In the course of our study on the selective molecular
recognition of NH4 over K+ using BTOs as artificial
+
receptors,7 we have found that they have significant
affinities toward K+ ion. This finding led us to evaluate
the compounds as chiral ligands in the catalytic asym-
metric reactions that involve complexes of K+ such as
potassium enolates.
An initial experiment, the Michael reaction between
methyl phenylacetate and methyl acrylate, with 10
mol% of tBuOK–valinol-derived iPr-BTO 17 in toluene
at −78°C yielded the addition product in 75% yield
after 3 h and with an enantioselectivity of 35% ee.8 To
find optimal conditions with the BTO we varied the
reaction conditions including solvents and the molar
ratio of the base to the ligand, the results of which are
listed in Table 1. Toluene and dichloromethane are
found to be good solvents, but the former is favored
over the latter in terms of enantioselectivity. As
CN
O
iPr
R
N
R
N
O
(S,S,S)-BTO
N
1: R = iPr
2: R = tBu
3: R = Ph
O
N
O
N
O
iPr
(S,S)-BBO, 4
R
Keywords: Michael addition; tripodal oxazoline; asymmetric catalyst; potassium enolate.
* Corresponding author. Tel.: +82 54-279-2105; fax: +82 54-279-3399; e-mail: ahn@postech.ac.kr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00681-5

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S.-G. Kim, K. H. Ahn / Tetrahedron Letters 42 (2001) 4175–4177
Table 1. Enantioselective Michael addition catalyzed by BTO–tBuOK complexes
(S,S,S)-BTO 1-3
CO2Me
+
Ph
CO2Me
CO2Me
KOtBu
Ph
CO2Me
(R)
Entry
BTO (mol%)
KOtBu (mol%)
Conditiona
Solvent
Time
Ee (%)b
Yield (%)c
1
2
3
4
5
6
7
8
1 (10)
1 (5)
10
10
20
50
20
20
20
20
20
20
20
A
A
A
A
B
A
A
A
A
B
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
Wet toluene
THF
3 h
6 h
3 h
15 min
3 h
35
36
46
31
56
47
–
75
51
86
55
80
80
–
17
63
83
85
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
2 (10)
2 (10)
3 (10)
6 h
d
3 h
3 h
8 h
3 h
3
9
10
11
Toluene
Toluene
Toluene
64
82e
41
A
a Condition A: a mixture of tBuOK and BTO in toluene was stirred at room temperature for 1 h, then the mixture was cooled to −78°C followed
by the addition of the ester and methyl acrylate. Condition B: a mixture of tBuOK and the ester in toluene was stirred for 15 min at −78°C
followed by the addition of BTO, and the resulting mixture was further stirred for 15 min before the dropwise addition of methyl acrylate in
toluene.
b Determined from optical rotation data (Ref. 8).
c Isolated by SiO2 chromatography.
d Very slow.
e [h]2D2=−73.0 (c 1.0, EtOH).
expected, coordinating solvents such as THF or the
presence of water in toluene gave poor reactivity and
enantioselectivity. Also, the molar ratio of the base to
BTO 1 was found to affect the enantioselectivity. Thus,
when we doubled the amount of tBuOK, from 10 to 20
mol%, the enantioselectivity was raised from 35 to 46%
ee. However, further increasing the base gave worse
effects in both the yield and the enantioselectivity.
Interestingly, an apparent improvement in the enan-
tioselectivity (increment of 10% ee) was observed when
we changed the addition sequence of reactants, from A
to B. Thus, an optimized reaction condition is to use 10
mol% of the BTO and 20 mol% of tBuOK in toluene
under condition B at −78°C. It is notable that the
reaction did not proceed at all when the base was
replaced with tBuONa.
Michael reaction. This expectation was found to be the
case: A significant improvement in the enantioselectiv-
ity was achieved under the established condition using
tBu-BTO 2, and an enantioselectivity of 82% ee was
obtained, a comparable enantioselectivity to the highest
ones obtained so far (83–85% ee).3 In the case of
Ph-BTO 3, a slightly lower enantioselectivity was
observed compared to that observed with iPr-BTO 1.
The observed enantioselectivities depending on the
BTOs indicate that for better enantioselectivity more
tight molecular interactions are required between the
Michael acceptor and the potassium enolate, which is
presumably coordinated to the BTO.
In regard to the mechanism of the Michael addition, we
believe that a potassium enolate of the ester bounds to
the BTO through a tripodal coordination of the oxazo-
line nitrogens to the K+ ion. A face-selective approach
of the Michael acceptor to a p-face of the enolate
would result in the addition product enriched in one
enantiomer.‡ Thus, the geometric isomerism of the
enolate3d as well as the chiral environment around both
the enolate and the acceptor would determine the sense
and degree of the enantio-discrimination. A reliable
description is guaranteed by a further mechanistic
study. To answer an important question whether the
BTOs coordinate the K+ ion in the described tripodal
mode, not in a bidentate chelated one, we have synthe-
sized a new chiral bis(oxazoline), BBO 4,§ and evalu-
Next, applying the established reaction condition, we
evaluated two other ligands, tBu-BTO 2 and Ph-BTO
3.9 The former had to be synthesized from (2,4,6-
trimethylbenzene)-1,3,5-triacetic acid and tert-leucinol,
following the procedure used for the synthesis of the
others.† The bulky tBu groups on the oxazoline rings
are expected to provide a highly crowded environment
around the potassium ion coordinated to the oxazoline
ligands, which may increase the enantioselectivity of the
† tBu-BTO 2: overall 22% yield in a one-pot reaction; Rf=0.45 (ethyl
acetate/hexanes=3/2, by volume); mp 134–135°C; [h]2D1=−137.6 (c
1
0.50, CHCl3); H NMR (300 MHz, CDCl3): l 4.07 (dd, 3H, J=8.6,
9.9), 3.92 (dd, 3H, J=8.0, 8.6), 3.78 (dd, 3H, J=8.0, 9.9), 3.72 (s,
6H), 2.37 (s, 9H) 0.83 (s, 27H); 13C NMR (75 MHz, CDCl3): l
166.0, 136.1, 131.1, 76.0, 69.0, 34.0, 30.5, 26.3, 17.6; MS (FAB): m/z
(rel. intensity) 538 (M+1, 100), 480 (13). Elemental analysis for
‡ Possibility of enantioselective protonation of a potassium enolate as
the chiral discrimination mode is excluded by examining the optical
purity of reaction mixture at different time intervals, which gave the
same optical purity in each case.
C33H51N3O3: calcd: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.53; H,
§ To be published elsewhere.
9.56; N, 7.93.

S.-G. Kim, K. H. Ahn / Tetrahedron Letters 42 (2001) 4175–4177
4177
ated its effectiveness as the chiral ligand in the
References
Michael addition. The same experiment under other-
wise identical condition B, however, did not give any
appreciable product after a prolonged reaction time
at −78°C and at room temperature, with remaining
starting materials and the ligand. This observation
along with the unsuccessful result obtained with
tBuONa indicates that the catalytic reaction proceeds
1. Tomioka, K.; Nagaoka, Y. In Comprehensive Asymmetric
Catalysis III; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Eds. Conjugate addition of organometallic reagents.;
Spring–Verlag: Berlin, 1999; pp. 1105–1120.
2. Yamaguchi, M. In Comprehensive Asymmetric Catalysis III;
Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds. Conjugate
addition of stabilized carbanions.; Spring–Verlag: Berlin,
1999; pp. 1121–1139.
via
a tripodal complex between the BTO and
tBuOK.¶
3. For selected examples: (a) Alonso-Lo´pez, M.; Mart´ın-
Lomas, M.; Penade´s, S. Tetrahedron Lett. 1986, 27, 3551–
3554; (b) Aoki, S.; Sasaki, S.; Koga, K. Tetrahedron Lett.
1989, 30, 7229–7230; (c) Crosby, J.; Stoddart, J. F.; Sun, X.;
Venner, M. R. W. Synthesis 1993, 141–145; (d) Brunet, E.;
Poveda, A. M.; Rabasco, D.; Oreja, E.; Font, L. M.; Batra,
M. S.; Rodr´ıgues-Ubis, J. C. Tetrahedron: Asymmetry 1994,
In summary, we have demonstrated for the first time
that tripodal oxazoline compounds are a new class of
potentially useful chiral ligands for the asymmetric
reactions that involve potassium complexes such as
the Michael addition studied here. Applications of
BTOs to other catalytic asymmetric reactions are
under investigation.
5, 935–948; (e) To9 ke, L.; Fenichel, L.; Albert, M. Tetra-
hedron Lett. 1995, 36, 5951–5954.
4. For an example of chiral alkoxide catalyst for the title
reaction, see: Kumamoto, T.; Aoki, S.; Nakajima, M.;
Koga, K. Tetrahedron: Asymmetry 1994, 5, 1431–1432.
5. Cram, D. J.; Sogah, G. D. Y. J. Chem. Soc., Chem. Commun.
1981, 625–628.
6. For the catalysis and chiral recognition with tripodal
ligands, see: Moberg, C. Angew. Chem., Int. Ed. Engl. 1998,
37, 248–268.
Acknowledgements
We thank KOSEF (CIMS) for financial support of
this work.
7. Ahn, K. H.; Kim, S.-G.; Jung, J.; Kim, K.-H.; Kim, J.; Chin,
J.; Kim, K. Chem. Lett. 2000, 170–171.
8. The enantioselectivity was determined by comparison of the
optical rotation of the adduct with the literature value (The
maximum rotation of [h]2D5=+89 (c 5, EtOH) for the
(S)-(+)-product: Kawazu, K.; Fujita, T.; Mitsui, T. J. Am.
Chem. Soc. 1957, 81, 932).
¶ One referee raised a question why TBO gives high enantioselectivity
whereas BBO does not at all. We think that the bidentate BBO has a
lower binding affinity toward spherical K+, and furthermore this
property would result in poor transportation of the ion from the
aqueous phase into the organic layer where the reaction occurs.
9. Kim, S.-G.; Ahn, K. H. Chem. Eur. J. 2000, 6, 3399–3403.
.