Phase-transfer-catalyzed asymmetric Michael reaction using newly-prepared chiral quaternary ammonium salts derived from L-tartrate

Article abstract of DOI:10.1016/S0040-4039(02)02415-2

The catalytic asymmetric Michael reaction of a glycine Schiff base was demonstrated using new PTCs and moderate to good ee's were achieved (up to 77% ee).

Full text of DOI:10.1016/S0040-4039(02)02415-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9535–9537
Phase-transfer-catalyzed asymmetric Michael reaction using
newly-prepared chiral quaternary ammonium salts derived from
L-tartrate
Shigeru Arai,* Riichiro Tsuji and Atsushi Nishida*
Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 2 October 2002; revised 23 October 2002; accepted 25 October 2002
Abstract—The catalytic asymmetric Michael reaction of a glycine Schiff base was demonstrated using new PTCs and moderate
to good ee’s were achieved (up to 77% ee). © 2002 Elsevier Science Ltd. All rights reserved.
Since phase-transfer catalysis was reported in the
1960’s, its application to transformations has attracted
considerable interest because of its high cost perfor-
mance, simplicity and safety and because it is environ-
mentally benign. This methodology is still considered
one of the most potent strategies for establishing green
chemistry.1,2 Ever since Dolling3 and O’Donnell4 inde-
pendently reported their successful results in asymmet-
ric phase-transfer chemistry, many quaternary
ammonium salts derived from natural chiral amines
such as cinchonine and cinchonidine have been exam-
ined as chiral PTCs. On the other hand, Maruoka,5,6
Belokon7 and Nagasawa8 recently have reported the
synthesis of non-natural PTCs which involves a highly
efficient asymmetric chemical transformation. In this
communication, we would like to report our results
regarding a novel PTC derived from tartrate9 and its
application to the asymmetric Michael reaction10,11
under PTC conditions.12
novel PTC which has a spiro ammonium salt, as shown
in Scheme 1. The alkylation of two hydroxy groups in
PTC A produced a variety of ether derivatives. PTC A,
which is a derivative of b-aminoalcohol, was prepared
by reacting a highly nucleophilic amine, isoindoline 2,
with dibromide 1, which is readily available from
diethyl tartrate in five steps.13 Quaternalization of these
compounds was carried out under reflux conditions in
MeOH to give the desired spiro ammonium bromide
PTC A in good yield (Scheme 1).
As expected, PTC A promoted the Michael reaction of
Schiff base 3 to 4 in the presence of base (Cs2CO3, 10
equiv.) under PTC conditions tested (Et2O, 0°C),
though the enantioselectivity was quite low under all of
the conditions (Table 1, entry 1). Next, we sought out
to prepare an O-protected ammonium salt such as PTC
B. Treatment of PTC A with benzyl bromide under
PTC conditions gave PTC B in moderate yield. This
salt have enough solubility in organic solvent to pro-
ceed the reaction even at −40°C in 37% yield with low
ee under similar conditions (entry 2). On the other
We interested in the PTC of less flexibility due to high
symmetrical spiro structure. Initially, we prepared a
Scheme 1. Synthesis of PTCs A and B.
Keywords: asymmetric; catalysis; Michael reaction; phase-transfer.
* Corresponding authors. Tel.: +81-43-290-2908; fax: +81-43-290-2909; e-mail: arai@p.chiba-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02415-2

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S. Arai et al. / Tetrahedron Letters 43 (2002) 9535–9537
Table 1. Catalytic asymmetric Michael reaction using novel PTCs
Entry
Base (equiv.)
Conditions
PTC
Yield (%)
ee (%)
1
2
3
4
Cs2CO3 (10)
Cs2CO3 (10)
CsOH·H2O (0.1)
CsOH·H2O (0.1)
0°C, 21 h
A
B
A
B
94
37
2
4
−40°C, 33 h
−40°C, 33 h
−40°C, 33 h
No reaction
57
–
22
hand, cesium hydroxide monohydrate acts as quite
effective base even in the presence of 10 mol% and we
were pleased to find that the O-protected salt (PTC B)
promoted the reaction at −40°C (57% yield, 22% ee),
even though the PTC A did not give 4 at all under
similar conditons (entries 3 and 4). Encouraged by
these results, a novel spiro ammonium salt, PTC C,
which includes two tartrate moieties, was expected to
efficiently construct an asymmetric environment. This
compound could also be quite easily prepared from
Solvent-screening in the asymmetric Michael reaction
using PTC C (2.5 mol%) with CsOH·H2O (10 mol%)
revealed that the diethyl ether gave better results than
other solvents such as toluene (37%, 46% ee) and
CH2Cl2 (16%, 43% ee) at −40°C (Table 2, entry 1). In
particular, t-butyl methyl ether gave the best results
(59% ee). Moreover, the reaction proceeded smoothly
even at −60°C to give 4 with 73% ee, although the
reaction was too slow at −78°C (entries 3 and 4). On
the other hand, in the case of the analogue with a
4-CF3 benzyl group (PTC D), prepared by a similar
method, the reaction proceeded quickly to give 4 within
26 h and its ee was slightly increased (entry 5). The
absolute configuration of 4 was determined by compari-
son to the literature result to be S.10 These results are
summarized in Table 2.16
L
-tartrate, as outlined in Scheme 2. Deprotection of
known compound 514 with PPTS gave diol in good
yield and subsequent benzylation with BnBr under PTC
conditions (10 mol% of tetrahexylammonium bromide,
KOH, toluene, rt) and removal of the tosyl group with
sodium naphthalenide gave the corresponding pro-
tected amine 6. Quaternalization of 6 with dibromide
715 in acetonitrile in the presence of K2CO3 gave the
desired PTC C in 65% yield after recrystallization from
ethyl acetate.
In conclusion, we have developed new PTCs derived
from diethyl tartrate and have applied them to the
catalytic asymmetric Michael reaction. PTC C, which
Scheme 2. Synthesis of PTCs C and D.
Table 2. Asymmetric Michael reaction of 3 to 4 using PTCs C and D
Entry
PTC (mol%)
Solvent
Time (h)
Temp. (°C)
Yield (%)
ee (%)
1
2
3
4
5
C (2.5)
C (2.5)
C (10)
C (10)
D (10)
Et2O
58
48
70
38
26
−40
−40
−60
−78
−60
90
81
86
Trace
73
52
59
73
54
77
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
All reactions were carried out in the presence of 10 mol% of CsOH·H2O.

S. Arai et al. / Tetrahedron Letters 43 (2002) 9535–9537
9537
has a spiro ammonium cation, exhibits catalytic activity
and the product was obtained with moderate to good
enantioselectivity. Further studies on the application of
these compounds to other asymmetric reactions and the
modification of PTC based on the spiro structure are
underway.
12. Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998,
39, 5347.
13. Cunningham, A. F., Jr.; Kundig, E. P. J. Org. Chem.
1988, 53, 1823.
14. Axamawart, M. T. H.; Fieet, G. W.-J.; Hannah, K. A.;
Namgoong, S. K.; Sinnott, M. L. Biochem. J. 1990, 266,
245.
15. Nemoto, H.; Takamatsu, S.; Yamamoto, Y. J. Org.
Chem. 1991, 56, 1321.
References
16. Typical experimental procedure (Table 2, entry 3): To a
test tube containing CsOH monohydrate (1.6 mg, 0.01
mmol), Schiff base 3 (29 mg, 0.1 mmol) and PTC C (6.0
mg, 10 mol%) at rt was added t-butyl methylether (0.3
mL), and the mixture was stirred for 5 min at −60°C.
t-Butyl acrylate (73 mL, 0.5 mmol) was then added slowly
at −60°C. After stirring for 70 h, the reaction was
quenched with water and extracted with AcOEt (3×10
mL), and the combined organic layers were washed with
water and dried over Na2SO4. The solvents were removed
in vacuo and subsequent flash column chromatography
gave the desired product 4 (35 mg, 86%, 73% ee). The
enantiomeric excess was determined by HPLC [Daicel
Chiralcel OD, hexane:i-PrOH=97:3, flow rate: 0.5 mL/
min (254 nm), retention times: 9.1 min (minor) and 11.8
min (major)]. Spectral data for PTC C: mp 120–120.5°C
(AcOEt); 1H NMR (400 MHz, CDCl3): l 4.14 (dd,
J=12.8, 4.4 Hz, 4H), 4.22 (dd, J=12.4, 5.2 Hz, 4H), 4.29
(br s, 4H), 4.50 (s, 8H), 7.25–7.36 (m, 20H); 13C NMR
(100 MHz, CDCl3): l 69.6, 71.4, 80.4, 128.1, 128.4, 128.7,
1. Nelson, A. Angew. Chem., Int. Ed. 1999, 38, 1583.
2. Kacprzak, K.; Gawronski, J. Synthesis 2001, 961.
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Chem. Soc. 1984, 106, 446.
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1999, 121, 6519.
6. Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am.
Chem. Soc. 2000, 122, 5228.
7. Belokon, Y. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Larionov, O. V.; Harutyunyan, S. R.;
Vyskocil, S.; North, M.; Kagan, H. B. Angew. Chem., Int.
Ed. 2001, 40, 1948.
8. Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.;
Nagasawa, K. Angew. Chem., Int. Ed. 2002, 41, 2832.
9. Shibasaki and co-workers (Univ. of Tokyo) also suc-
ceeded in the synthesis of PTCs derived from
(private communication).
L-tartrate
136.3; IR (Nujol): w 1455, 1366, 1129, 1059, 731 cm−1
;
10. Ma, D.; Cheng, K. Tetrahedron: Asymmetry 1999, 10,
713.
11. Ishikawa, T.; Araki, Y.; Kumamoto, T.; Seki, H.;
Fukuda, K.; Isobe, T. Chem. Commun. 2001, 245.
LRMS (FAB): m/z 550 (M+−Br); HRMS (FAB) calcd for
C36H40NO4: 550.2957, found: 550.2957; [h]2D4=+3.8 (c
1.0, CHCl3).