Asymmetric Alkylation of tert-Butyl Glycinate Schiff Base with Chiral Quaternary Ammonium Salt under Micellar Conditions

Article abstract of DOI:10.1021/ol015829c

matrix presented The asymmetric alkylation of the tert-butyl glycinate-benzophenone Schiff base 1 with various arylmethyl bromides catalyzed by O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide (2) proceeded smoothly under micellar conditions (5 equiv

Full text of DOI:10.1021/ol015829c

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1515-1517
Asymmetric Alkylation of tert-Butyl
Glycinate Schiff Base with Chiral
Quaternary Ammonium Salt under
Micellar Conditions
Tomotaka Okino and Yoshiji Takemoto*
Department of Chemistry, Graduate School of Pharmaceutical Sciences,
Kyoto UniVersity, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received March 12, 2001
ABSTRACT
The asymmetric alkylation of the tert-butyl glycinate−benzophenone Schiff base 1 with various arylmethyl bromides catalyzed by O-allyl-N-
(9-anthracenylmethyl)cinchonidinium bromide (2) proceeded smoothly under micellar conditions (5 equiv of 1 M KOH and 0.4 equiv of Triton
X-100) to give the alkylated products in good yields and with good enantioselectivity (72−85% ee), depending on the electrophiles.
The development of environmentally friendly catalysts for
organic transformation is becoming an area of growing
importance.1 From economical and environmental points of
view, catalytic use of nonmetallic catalysts such as a chiral
phase transfer catalyst (PTC) is very promising.2 Until
recently, there have been no successful applications of PTC
reaction to catalytic asymmetric synthesis.3 However, quite
recently, the highly enantioselective alkylation of the tert-
butyl glycinate-benzophenone Schiff base 1 has been
achieved under PTC conditions using N-alkylated cin-
chonidinium salts4,5 and C2-symmetric ammonium salts6
derived from chiral binaphthol. These excellent results
provided an efficient tool for the preparation of both natural
and unnatural amino acids.7 To further improve the asym-
metric alkylation with these new chiral PTC’s, several
problems must be solved. Since these catalysts, in particular
cinchonidium salts, are reported to be unstable under basic
conditions, the asymmetric alkylation usually demands the
addition of more than 10 mol % of the chiral catalyst to
attain high enantioselectivity. In addition, all of the chiral
PTC reactions reported so far have been carried out in
organic solvents such as toluene and methylene chloride or
a water/toluene two-phase system. It is desirable to develop
the PTC-catalyzed asymmetric reaction without the use of
(1) Grenn Chemistry: Frontiers in Benign Chemical Syntheses and
Processes; Anastas, P. T., Williamson, T. C., Eds.; Oxford University
Press: New York, 1998. Li, C.-J.; Chan, T.-H. Organic Reactions in
Aqueous Media; Wiley: New York, 1997. Organic Synthesis in Water;
Grieco, P. A., Ed.; Kluwer Academic Publishers: Dordrecht, 1997.
(2) For reviews of chiral PTC, see: Nelson, A. Angew. Chem., Int. Ed.
1999, 38, 1583-1585. Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer
Catalysis; VCH: Weinheim, 1993. Phase-Transfer Catalysis, Mechanism
and Synthesis; Halpern, M. E., Ed.; American Chemical Society: Wash-
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Tetrahedron: Asymmetry 1997, 8, 3163. O′Donnell, M. J. In Catalytic
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1997, 119, 12414-12415.
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10.1021/ol015829c CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/07/2001

any organic solvents, because of the inherent advantages of
using water as the only solvent. For developing an ideal PTC
which satisfies these conditions (active, stable, cheap, and
recoverable), extensive efforts are being continued.8 In this
Letter, we wish to describe a novel strategy, which has not
been reported, for overcoming these problems concurrently,
i.e., the asymmetric alkylation of 1 with O-allyl-N-(9-anthra-
cenylmethyl)cinchonidinium bromide (2) in a micellar
medium (a mixture of water and a neutral surfactant). Using
this method we successfully carried out a highly efficient
PTC-catalyzed enantioselective alkylation in water; we also
found that the amount of the chiral PTC can be reduced up
to 0.1 mol % without a serious decrease in the enantiomeric
excess.
a few attempts of application of surfactants to asymmetric
synthesis have been successful and only in a limited area.11,12
However, a serious problem that may be incurred is that the
addition of a surfactant may promote a racemic reaction
because surfactants are known as PTC catalysts.13 In fact,
treatment of 1 with BnBr and 50% KOH in the presence of
the chiral PTC 2 and Triton X-100 gave the nearly racemic
product 3 in 24% yield (entry 2). Then, with the expectation
of improving the enantioselectivity, several reaction condi-
tions, including the base and surfactant, were investigated
(entries 3-5). Consequently, use of a 1.0 M KOH solution
as a base dramatically improved the ee of 3. Among the
examined surfactants, neutral surfactants such as Triton
X-100 were revealed to efficiently promote the alkylation,
giving the desired product 3 in good yield and with good
enantioselectivity. On the other hand, neither an anionic nor
a cationic surfactant was effective in terms of the chemical
yield and enantioselectivity. In addition, it was revealed that
the addition of 2.4 equiv of BnBr to the reaction mixture
improved both the chemical yield and enantiomeric excess
(entry 6). To our surprise, the reduction of the amount of 2
from 10 to 1 mol % did not affect the asymmetric alkylation,
giving the same result (entry 7). It should be emphasized
that the alkylation can be carried out with only 0.1 mol %
of 2 without a serious decrease of the chemical yield and ee
(entry 8). The same reactions with various neutral surfactants
bearing different PEG lengths such as Triton X-114, Targitol
NP-40, and Triton X-40514 showed that these surfactants
affected only the chemical yield of 3 but not their enantio-
selectivities [Triton X-114 (76%, 84% ee), Targitol NP-40
(63%, 85% ee), and Triton X-405 (57%, 84% ee)].
We first examined the standard asymmetric alkylation of
1 with benzyl bromide without an organic solvent. The
benzylation of 1 proceeded very reluctantly without the
organic solvent, giving the desired product 3 in low yield
but with good enantioselectivity (Table 1, entry 1). Recently,
Table 1. Catalytic Enantioselective Alkylation of 1 with BnBr
in the Presence of 2a under Micellar Conditionsa
entry
surfactant
BnBr (equiv) 2a (mol %) % yieldb % eec
1
2
3
4
5
6
7
8
d
1.2
1.2
1.2
1.2
1.2
2.4
2.4
2.4
10
10
10
10
10
10
1
33
24
59
30
34
91
92
81
78
<5
78
63
39
84
85
80
Since the optimal reaction conditions could be found for
the asymmetric benzylation, we next examined the influence
of various chiral PTC’s other than 2a on the enantioselec-
tivity of 3 (Table 2). The alkylation of 1 using other
N-alkylated cinchonidium salts 2b-d4,5 bearing a different
alkyl group afforded the same product (S)-3 with similar
enantioselectivity (entries 1-3). Therefore, the alkyl groups
of 2 have only a marginal effect in terms of the chemical
yield and enantiomeric excess. Furthermore, the C2-sym-
metric ammonium salt 4,6 recently developed by Maruoka,
Triton X-100d
Triton X-100e
SDSf
CTABg
Triton X-100
Triton X-100
Triton X-100
0.1
a The reaction was carried out with BnBr (1.2-2.4 equiv), 2a (0.1-10
mol %), and 1.0 M aqueous KOH (5 equiv) in the presence of several
surfactants (0.4 equiv) at room temperature. b Isolated yield. c Enantiomeric
excess of 3 was determined by HPLC analysis of the alkylated imine using
a chiral column (DAICEL Chiralcel OD) with hexane/2-propanol as solvent.
d The reaction was performed with 50% KOH. e Me3CCH2C(Me)2C6H4-
(OCH2CH2)nOH (n ) 10). f Sodium dodecyl sulfate. g Cetyltrimethyl-
ammonium bromide.
(10) Manabe, K.; Mori, Y.; Wakabayashi, T.; Nagayama, S.; Kobayashi,
S. J. Am. Chem. Soc. 2000, 122, 7202-7207. Manabe, K.; Mori, Y.;
Kobayashi, S. Synlett 1999, 1401-1402. Akiyama, T.; Takaya, J.; Ka-
goshima, H. Tetrahedron Lett. 1999, 40, 7831-7834. Akiyama, T.; Takaya,
J.; Kagoshima, H. Synlett 1999, 1426-1428. Otto, S.; Engberts, J. B. F.
N.; Kwak, J. C. T. J. Am. Chem. Soc. 1998, 120, 9517-9525.
(11) Rabeyrin, C.; Nguefack, C.; Sinou, D. Tetrahedron Lett. 2000, 41,
7461-7464. Yonehara, K.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64,
9381-9385. Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.; Uemura, S.
J. Org. Chem. 1999, 64, 5593-5598. Grassert, I.; Schmidt, U.; Ziegler, S.;
Fischer, C.; Oehme, G. Tetrahedron: Asymmetry 1998, 9, 4193-4202.
Dwars, T.; Schmidt, U.; Fischer, C.; Grassert, I.; Kempe, R.; Fro¨hlich, R.;
Drauz, K.; Oehme, G. Angew. Chem., Int. Ed. 1998, 37, 2851-2853. Selke,
R.; Holz, J.; Riepe, A.; Bo¨rner, A. Chem. Eur. J. 1998, 4, 769-771.
(12) Studies on the asymmetric synthesis using amphiphilic resin-
supported ligand: Uozumi, Y.; Watanabe, T. J. Org. Chem. 1999, 64, 6921-
6923. Danjo, H.; Tanaka, D.; Hayashi, T.; Uozumi, Y. Tetrahedron 1999,
55, 14341-14352. Uozumi, Y. Danjo, H.; Hayashi, T. Tetrahedron Lett.
1998, 39, 8303-8306.
the remarkable effects of surfactants were demonstrated in
transition metal- and Lewis acid-mediated reactions.9,10 Only
(8) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001,
40, 92-138. Chinchilla, R.; Mazo´n, P.; Na´jera, C. Tetrahedron: Asymmetry
2000, 11, 3277-3281. Belokon, Y. N.; Kochetkov, K. A.; Churkina, T.
D.; Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. V.; Singh, I.; Parmar,
V. S.; Vyskocil, S.; Kagan, H. B. J. Org. Chem. 2000, 65, 7041-7048.
Belokon, Y. N.; Davies, R. G.; North, M. Tetrahedron Lett. 2000, 41, 7245-
7248. Ducry, L.; Diederich, F. HelV. Chim. Acta 1999, 82, 981-1004. Tzalis,
D.; Knochel, P. Tetrahedron Lett. 1999, 40, 3685-3688.
(9) Goedheijt, M. S.; Hanson, B. E.; Reek, J. N. H.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2000, 122, 1650-1657.
Kobayashi, S.; Lam, W. W.-L.; Manabe, K. Tetrahedron Lett. 2000, 41,
6115-6119. Herrmann, W. A.; Kohlpaintner, C. W. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1524-1544.
(13) Sauvagnat, B.; Lamaty, F.; Lazaro, R.; Martinez, J. Tetrahedron
Lett. 2000, 41, 6371-6375. Sauvagnat, B.; Lamaty, F.; Lazaro, R.; Martinez,
J. Tetrahedron Lett. 1998, 39, 821-824.
(14) These surfactants were purchased from Nacalai tesque.
1516
Org. Lett., Vol. 3, No. 10, 2001

Table 2. Enantioselective Benzylation of 1 with Various
PTC’s under Micellar Conditionsa
Table 3. Catalytic Enantioselective Alkylation of 1 with
Several Alkyl Halides in the Presence of 2a and Triton X-100 in
Watera
entry
catalyst
% yieldb
% eec
1
2
3
4
5
2b (R ) H)
2c (R ) Me)
2d (R ) Bn)
4
82
92
89
78
20
84
76
85
72
3
5
a The reaction was carried out with BnBr (2.4 equiv), PTC (1 mol %),
and Triton X-100 (0.5 equiv) in a 1.0 M aqueous KOH (5 equiv) solution
at room temperature. b Isolated yield. c Enantiomeric excess of 3 was
determined by HPLC analysis of the alkylated imine using a chiral column
(DAICEL Chiralcel OD) with hexane/2-propanol as solvent.
was less effective under the micellar conditions, resulting
in a slight decrease of the enantiomeric excess (entry 4). In
contrast with these results, the reaction of 1 with (-)-
TADDOL, which is known as a chiral metal-chelator,8 gave
the racemic product in poor yield (entry 5). From these
results, we selected the allyl ether 2a as the best chiral PTC.
a The reaction was carried out with RX (2.4 equiv), 2a (1 mol %), and
1.0 M aqueous KOH (5 equiv) in the presence of Triton X-100 (0.4 equiv)
at room temperature. b Isolated yield. c Enantiomeric excess of 3 was
determined by HPLC analysis of the alkylated imine using a chiral column
(DAICEL Chiralcel OD) with hexane/2-propanol as solvent. d Absolute
configuration was determined by comparison of the HPLC retention time
with that of an authentic sample. e Not determined.
We finally investigated whether our new method could
be applied to 1 with other electrophiles (Table 3). Indeed,
the alkylation with several arylmethyl bromides and allylic
bromides proceeded smoothly to give rise to the correspond-
ing monoalkylated products 3 in good enantioselectivity (72-
85% ee), even though, in the latter cases, the reaction
required 10 equiv of electrophiles to achieve good chemical
yields (entries 1-7). In contrast to these entries, alkylations
with methyl iodide and ethyl iodide were very sluggish,
resulting in the alkylated products in poor yield or low
enantioselectivity (entries 8 and 9). In any event, the
configurations of the products 3 were the same as those of
products obtained by the liquid-liquid and liquid-solid two-
phase reactions using 2.4-6
organic synthesis in light of the increased demand for
reduction of organic solvents. In addition, the enantiomeric
excess shown here might be further enhanced by using a
more suitably designed PTC.
In conclusion, we have devised a useful and environmen-
tally benign procedure for the catalytic asymmetric alkylation
of the aldimine Schiff base of an amino acid tert-butyl ester
using the micellar system. This method is the first asym-
metric reaction using a micellar system other than the
transition metal-promoted asymmetric reaction. We are now
investigating other applications in nonmetallic catalyst-
promoted asymmetric reactions.
These results suggest that the surfactants only provide a
hydrophobic area for the interaction of the reactants and the
catalyst. The surfactants have no effect on determining the
stereochemistry of the products, despite the fact they are
known as phase-transfer catalysts. The exact role of the
surfactant is not clear at this stage, but because the chiral
PTC would be protected from exposure of the aqueous base
by the incorporation in the PEG moiety of the surfactant,
the asymmetric alkylation in micellar conditions proceeded
effectively with less than 1 mol % of the chiral catalyst 2.
Besides the mild basic conditions and independence of the
substrate solubility in the solvent, the surfactant-aided
asymmetric alkylation may have practical consequences in
Acknowledgment. We are grateful to Professor Keiji
Maruoka and Dr. Takashi Ooi for kindly supplying the
precious chiral catalyst. This work was partially supported
by The Japan Health Sciences Foundation, Mitsubishi
Chemical Corporation Fund, and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports,
and Culture, Japan.
Supporting Information Available: Experimental details
and characterization of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.
OL015829C
Org. Lett., Vol. 3, No. 10, 2001
1517