Design of new polyamine-based chiral phase-transfer catalysts for the enantioselective synthesis of phenylalanine

Article abstract of DOI:10.1016/j.tetasy.2004.02.023

Enantiomerically enriched phenylalanine was synthesized by asymmetric benzylation of a glycine Schiff base using polyamine-based chiral phase-transfer catalysts.

Full text of DOI:10.1016/j.tetasy.2004.02.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1243–1245
Design of new polyamine-based chiral phase-transfer catalysts for
the enantioselective synthesis of phenylalanine
Taichi Kano, Shunsuke Konishi, Seiji Shirakawa and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Received 5 February 2004; accepted 24 February 2004
Abstract—Enantiomerically enriched phenylalanine was synthesized by asymmetric benzylation of a glycine Schiff base using
polyamine-based chiral phase-transfer catalysts.
Ó 2004 Elsevier Ltd. All rights reserved.
Catalytic asymmetric synthesis in the efficient produc-
tion of enantiomerically enriched compounds is cur-
rently of considerable interest in organic synthesis, and
as a result a number of chiral metal and nonmetal cat-
alysts have been devised for reaching a useful as well as
practical level of selectivity in recent years.1 The devel-
opment of efficient enantioselective processes utilizing
new chiral catalysts, increasingly requires the rational
design of such catalysts. Among these, the use of phase-
transfer catalysis for the preparation of chiral, non-
racemic organic compounds from prochiral substrates
using enantiomerically pure quaternary ammonium salts
has become a field of growing importance.2 Currently,
cinchona-alkaloid derived chiral phase-transfer cata-
lysts3 and C2-symmetric binaphthyl-modified chiral
spiro-type phase-transfer catalysts4 are the best known
in this area. In addition to these previous endeavors, we
herein report the design of new chiral phase-transfer
catalysts of type 1, based on the use of commercially
available polyamine frameworks with the expectation of
the multiplier effect of chiral auxiliaries as illustrated in
Scheme 1.
A variety of new chiral phase-transfer catalysts 3–10
containing several binaphthyl groups were easily pre-
pared via treatment of the corresponding polyamines
with dibromide (S)-24j in refluxing acetonitrile in
the presence of K2CO3 (Scheme 1, Fig. 1).5 After
simple aqueous work-up (aq NaHCO3), these chiral
phase-transfer catalysts were purified by chromato-
graphy on silica gel, and identified by mass spectro-
metric analysis (ESI). They fall into three categories:
(i) mono-ammonium salts (S)-3–(S)-6 derived from
triamines, (ii) bis-ammonium salts (S)-7 and (S)-8,
Scheme 1.
* Corresponding author. Tel./fax: +81-75-753-4041; e-mail: maruoka@kuchem.kyoto-u.ac.jp
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.023

1244
T. Kano et al. / Tetrahedron: Asymmetry 15 (2004) 1243–1245
nium catalyst (S)-11 derived from dibutylamine gave 14
with an (S)-configuration in 60% yield with 20% ee
(entry 10). Among the chiral mono-ammonium salts,
(S)-5 showed moderate enantioselectivity (50% ee)
(entry 3) when compared to (S)-3, (S)-4, and (S)-6
(entries 1, 2, and 4). Chiral bis-ammonium salt (S)-8,
derived from spermine, exhibited higher enantioselec-
tivity (63% ee) (entry 6). Interestingly, in the case of (S)-
7, an opposite (R)-configuration was obtained (entry 5).
While use of cyclic bis-ammonium salt (S)-9 resulted
in formation of nearly racemic product 14 (entry 8),
the reaction with cyclic tris-ammonium salt (S)-10
predominantly gave the opposite (R)-enantiomer
(entry 9).
Based on the result that using bis-ammonium salt (S)-8
provided the best result for asymmetric benzylation of
13, we optimized the reaction conditions with (S)-8.
Lowering the reaction temperature and using
CsOHÆH2O instead of 50% aqueous KOH, the enantio-
selectivity was increased at the expense of the reaction
rate, with 14 being obtained in 78% yield with 83% ee
(entry 7).
Figure 1.
We have previously shown that asymmetric benzylation
of glycine Schiff base 13 with C2-symmetric binaphthyl-
modified chiral spiro-type phase-transfer catalyst (S,S)-
12 under identical reaction conditions gave (R)-14 (entry
11).4j In contrast, the opposite (S)-configuration was
obtained by using most of polyammonium catalysts
with the (S)-binaphthyl moiety. Therefore, both
enantiomers of 14 can be synthesized by using a single
chiral source.
and (iii) cyclic bis- and tris-ammonium salts (S)-9 and
(S)-10.
We also prepared the simple mono-ammonium salt (S)-
11 in order to examine the effect of the polyamine
framework.
The chiral efficiency of polyamine-based phase-transfer
catalysts (S)-3–(S)-10 was examined by the asymmetric
benzylation of glycine Schiff base 13 with the results
summarized in Table 1. When 13 was treated with
benzyl bromide in the presence of 3 mol % of chiral
catalysts (S)-3–(S)-10 in toluene/50% aqueous KOH (v/v
3:1) at 0 °C under an argon atmosphere, phenylalanine
derivative 14 was obtained in moderate to good yields.
As a controlled experiment, chiral quaternary ammo-
Table 1. Enantioselective benzylation of 13a
Entry
Catalyst
Time (h)
Yield (%)b
Ee (%)c
Configurationd
1
3
4
11
2
51
64
76
81
87
76
78
49
46
60
90
0
32
50
7
––
S
2
3
5
6
S
4
6
10
4
S
5
7
27
63
83
4
R
S
6
8
3
7e
8f
9
8
55
2
S
9
S
10
11
12
50
5
31
20
79
R
S
10
11e
36
R
a Unless otherwise specified, the reaction was carried out with 13 (0.3 mmol) and 1.2 equiv of benzyl bromide in the presence of 3 mol % of 3–12
in 50% aqueous KOH/toluene (v/v 1:3) under the given reaction conditions under argon atmosphere.
b Yield of isolated product.
c Enantiopurity of 14 was determined by HPLC analysis using a chiral column (Daicel Chiralcel OD) with hexane/2-propanol as solvent.
d Absolute configuration of 14 was determined by comparison of the HPLC retention time with the authentic sample independently synthesized by
the reported procedure.4j
e 5 equiv of CsOHÆH2O were used as a base and the reaction was performed at )40 °C.
f 5 equiv of KOH powder were used in the absence of H2O.

T. Kano et al. / Tetrahedron: Asymmetry 15 (2004) 1243–1245
1245
In conclusion, novel polyammonium salts6 containing
several binaphthyl groups have been found to be good
phase-transfer catalysts for the enantioselective synthe-
sis of phenylalanine. The experimental findings show
that the length of methylene chains in the catalysts has a
distinct influence not only on the enantioselectivity, but
also on the absolute configuration.
4. (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
1999, 121, 6519; (b) Ooi, T.; Takeuchi, M.; Kameda, M.;
Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228; (c) Ooi,
T.; Takeuchi, M.; Ohara, D.; Maruoka, K. Synlett. 2001,
1185; (d) Ooi, T.; Takeuchi, M.; Maruoka, K. Synthesis
2001, 1716; (e) Ooi, T.; Uematsu, Y.; Kameda, M.;
Maruoka, K. Angew. Chem., Int. Ed. 2002, 41, 1551; (f)
Maruoka, K. J. Fluorine Chem. 2001, 112, 95; (g) Ooi, T.;
Uematsu, Y.; Maruoka, K. Adv. Synth. Catal. 2002, 344,
288; (h) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K.
Angew. Chem., Int. Ed. 2002, 41, 4542; (i) Ooi, T.; Tayama,
E.; Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 579; (j)
Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
2003, 125, 5139; (k) Hashimoto, T.; Maruoka, K. Tetrahe-
dron Lett. 2003, 44, 3313; (l) Hashimoto, T.; Tanaka, Y.;
Maruoka, K. Tetrahedron: Asymmetry 2003, 14, 1599.
5. Synthesis of chiral bis-ammonium salt (S)-8: To a mixture
of (S)-2 (440 mg, 1.0 mmol) and K2CO3 (249 mg, 1.8 mmol)
in acetonitrile (4 mL) was added spermine (40.5 mg,
0.20 mmol) at room temperature. The mixture was heated
at reflux with stirring for 5 h, and then poured into water.
After extraction with CH2Cl2, the organic extracts were
dried over Na2SO4. Evaporation of solvents and purifica-
tion of the residue by column chromatography on silica gel
(MeOH/CH2Cl2¼1:18 as eluent) afforded chiral bis-ammo-
nium salt (S)-8 (182 mg, 0.12 mmol, 61% yield): IR(film):
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research (No 13853003) from the Ministry of
Education, Culture, Sports, Science, and Technology,
Japan.
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3400, 2960, 2360, 2200, 1466, 1363 cmꢀ1
;
1H NMR
(400 MHz, CDCl3, Me4Si): d 1.77 (br s, 4H, CH2CH2CH2),
2.21 (br s, 4H, CH2CH2CH2), 2.76 (br m, 4H, NCH2CH2),
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ArCH2N), 7.17–7.44 (m, 20H, ArH), 7.52–7.59 (m, 6H,
ArH), 7.73 (d, J ¼ 8:4 Hz, 4H, ArH), 7.91 (d, J ¼ 8:4 Hz,
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58.7, 63.1, 63.2, 125.2, 125.5, 126.3, 126.6, 126.7, 126.8,
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