Powerful chiral phase-transfer catalysts for the asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids

Article abstract of DOI:10.1002/anie.200462257

The catalytic performance of the chiral phase-transfer catalyst 1 (0.1-0.01 mol%) in the asymmetric alkylation of protected glycine and alanine derivatives exceeds that of existing catalysts. The reaction is used in the enantioselective synthesis of struc

Full text of DOI:10.1002/anie.200462257

Angewandte
Chemie
Asymmetric Synthesis
ering the highly lipophilic nature of 1 and the generation of a
metal enolate in an interfacial layer,[5] such lipophilic 1 (QX)
must move to the interfacial layer to induce a facile exchange
reaction with a metal enolate (Scheme 1). Based on this
Powerful Chiral Phase-Transfer Catalysts for
the Asymmetric Synthesis of a-Alkyl- and
a,a-Dialkyl-a-amino Acids**
Masanori Kitamura, Seiji Shirakawa, and
Keiji Maruoka*
Phase-transfer catalysis (PTC) has been recognized as a
convenient and highly useful tool in academia and industry
because it offers several advantages for practical organic
synthesis, such as operational simplicity, mild reaction con-
ditions in aqueous media, environmental benefits, and suit-
ability for large-scale reactions.[1,2] Also the development of
efficient methods for the preparation of natural and non-
natural a-alkyl- and a,a-dialkyl-a-amino acids, especially in
their enantiomerically pure forms by asymmetric PTC, has
become very important because of their high synthetic
utility.[3,4] Accordingly, several phase-transfer catalysts have
been developed that lead to products with excellent enantio-
selectivities in high yields.[4] However, despite numerous
studies, truly efficient catalytic systems with high enantiose-
lection at very low catalyst loading (e.g., < 0.1 mol%) are still
rare in asymmetric carbon–carbon bond formation, and major
progress in terms of catalyst loading is still desirable for
practical asymmetric synthesis. Since our recently developed,
chiral spiro-type (R,R)- or (S,S)-3,4,5-trifluorophenyl-NAS
bromide 1 shows exceedingly high enantioselectivity in
Scheme 1. Proposed mechanism for the generation of chiral
ammonium enolate.
assumption, our strategy was to replace the rigid binaphthyl
moiety in 1 by flexible straight-chain alkyl groups to furnish a
new catalyst of type 2, which substantially accelerates the
enolate exchange with 2 because of the increasing polarity of
the dialkylammonium moiety. Herein, we report that such a
designer chiral quaternary ammonium salt 2 behaves as a very
powerful chiral phase-transfer catalyst for the highly practi-
cal, enantioselective alkylation of protected-glycine and a-
alkyl-a-amino acid derivatives.
The requisite catalyst (S)-2 can be readily prepared from
the commercially available (S)-1,1’-binaphthyl-2,2’-dicarbox-
ylic acid (3)[6] in a six-step sequence as outlined in Scheme 2.[7]
Scheme 2. a) iPrBr (10 equiv), Bu4N·HSO4 (20 mol%), KF·2H2O (10 equiv),
THF, reflux (95%); b) 1. Mg(TMP)2 (4 equiv), THF, RT; 2. Br2 (8 equiv),
ꢀ788C!RT (91%); c) (3,4,5-F3C6H2)B(OH)2 (2.4 equiv, Pd(OAc)2 (5 mol%),
PPh3 (15 mol%), K2CO3 (3 equiv), DMF, 908C (94%); d) LiAlH4 (3 equiv),
THF, 08C!RT; e) PBr3 (0.5 equiv), THF, 08C (90% from 6); f) R2NH (R=Me,
Et, Bu, C10H21) (1.1 equiv), K2CO3 (2 equiv), CH3CN, reflux (64–99%).
asymmetric alkylation of a-amino acid derivatives,[4d,e,m] our
next target was the design of a very active catalyst. Consid-
[*] M. Kitamura, S. Shirakawa, Prof. K. Maruoka
Department of Chemistry
Thus, (S)-dicarboxylic acid 3 was transformed with iPrBr,
catalytic Bu4N·HSO4, and KF·2H2O to the corresponding
diisopropyl ester 4 in 95% yield. Treatment of 4 with freshly
prepared Mg(TMP)2 (TMP = 2,2,6,6-tetramethylpiperidide)
in THF and subsequent additon of bromine gave rise to (S)-
3,3’-dibromo-1,1’-binaphthyl-2,2’-dicarboxylic ester 5 in 91%
yield. Suzuki–Miyaura cross coupling of 5 with 3,4,5-trifluor-
ophenylboronic acid in the presence of catalytic Pd(OAc)2,
PPh3, and K2CO3 in N,N-dimethylformamide (DMF)
afforded (S)-3,3’-bis(3,4,5-trifluorophenyl)-1,1’-binaphthyl-
2,2’-dicarboxylic ester (6) in 94% yield. Reduction of 6 with
Graduate School of Science, Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan (21 COE on Kyoto University Alliance for
Chemistry). M.K. and S.S. are grateful to the Japanese Society for the
Promotion of Science for Young Scientists for a Research Fellow-
ship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 1549 –1551
DOI: 10.1002/anie.200462257
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Table 1: Catalytic enantioselective phase-transfer alkylation of glycine
derivative 9.[a]
LiAlH4 in THF and subsequent treatment of the resulting
crude alcohol 7 with PBr3 in THF furnished (S)-dibromide 8
in 90% yield. Reaction of 8 with R2NH (R = Me, Et, Bu,
C10H21) and K2CO3 in acetonitrile led to the formation of the
catalyst (S)-2 in yields of 64–99%. The overall yields of (S)-2
from the starting (S)-dicarboxylic acid 3 were 47–72%. The
Entry Catalyst
[mol%]
R’-X
T
t
Yield ee [%]
ꢀ
structure of (S)-2c as a PF6 salt determined by X-ray
[8C] [h] [%][b] (Config)[c]
crystallographic analysis is shown in Figure 1.[8]
1
2
3
(S)-2a (0.05) PhCH2Br
(S)-2b (0.05)
(S)-2c (0.05)
(S)-2c (0.05)
(S)-2c (0.01)
0
0
0
0
0
0
0
0
0
0
0
4
3
2
7
81
98
33 (R)
97 (R)
99 (R)
99 (R)
98 (R)
99 (R)
98 (R)
98 (R)
97 (R)
98 (R)
98 (R)
4[d]
5
12 97
9
4
92
94
6
7
8
9
(S)-2d (0.05)
(S)-2d (0.01)
24 79
=
(S)-2c (0.05) CH2 CHCH2Br
3
5
4
6
87
75
88
83
(S)-2d (0.05)
(S)-2c (0.05) HC CCH2Br
(S)-2d (0.05)
ꢁ
10
11
12
13
(S)-2c (0.05)
0
64 81
67
97 (R)
99 (R)
(S)-2c (0.1)
CH3CH2I[e,f]
ꢀ20
1
[a] Unless otherwise specified, the reaction of 9 (0.3 mmol) was carried
out with 1.2 equivalents of R’X in the presence of catalytic (S)-2 in 50%
aqueous KOH/toluene (volume ratio=1:1) under the given reaction
conditions. [b] Yield of isolated product. [c] Enantiopurity of 10 was
determined by HPLC analysis using a column with a chiral stationary
phase (DAICEL Chiralcel OD) with hexane/isopropanol as the solvent.
[d] Reaction scale=3 mmol. [e] Use of 5 equivalents of alkyl halide and
CsOH·H2O as base. [f] Attempted reaction of 9 with EtI in the presence
of (S)-2c (0.05 mol%) in 50% aqueous KOH/toluene at 08C for 72 hours
gave 10 (R’=Et) in 12% yield with 91% ee.
Figure 1. ORTEP drawing of (S)-2c as a PF6ꢀ salt. PF6ꢀ, solvent, and
hydrogen atoms have been omitted for clarity.
smoothly under mild conditions to furnish the corresponding
a-alkyl-a-amino acids in high yield and excellent enantiose-
lectivity (entry 13).
The chiral efficiency of the phase-transfer catalyst (S)-2
was examined by carrying out asymmetric alkylation of N-
(diphenylmethylene)glycine tert-butyl ester (9; Table 1). (S)-
2a gave a rather disappointing result in terms of reactivity, the
higher homolog (S)-2b was however found to be a very active
phase-transfer catalyst. Indeed, reaction of 9 with benzyl
bromide (1.2 equiv) and 50% aqueous KOH in toluene was
effected in the presence of only 0.05 mol% of catalyst (S)-2b
under argon atmosphere at 08C for 3 hours to furnish the
benzylation product 10 (R’ = CH2Ph) in 81% yield with
excellent enantioselectivity (97% ee) (entry 2). Further accel-
eration of the reaction was observed by using 0.05 mol% of
catalyst (S)-2c (98% yield with 99% ee at 08C for 2 hours)
(entry 3).[9] Even 0.01 mol% of catalyst (S)-2c still gave high
enantioselectivity (98% ee at 08C for 9 hours) (entry 4).
Other selected examples are also listed in Table 1. There
are several characteristic features of these alkylation reac-
tions: 1) In contrast to the existing chiral phase-transfer
catalysts, catalyst (S)-2c exhibited a high catalytic perform-
ance (0.01–0.1 mol%) and demonstrated the remarkable
efficiency and practicality of the present approach towards
the enantioselective synthesis of a-alkyl-a-amino acids.
2) The didecyl analogue (S)-2d exhibited a little less reactivity
to (S)-2c without decreasing enantioselectivity (entries 5 and
6). 3) Not only benzylation and allylation, but also alkylation
of 9 with a simple alkyl halide, such as ethyl iodide, proceeded
The catalyst (S)-2c is, of course, applicable to the
asymmetric alkylation of aldimine Schiff base 11 derived
from d,l-alanine tert-butyl ester (Scheme 3). Thus, reaction of
11 with benzyl bromide (1.2 equiv) and CsOH·H2O (5 equiv)
in toluene in the presence of 0.05 mol% of catalyst (S)-2c
under argon atmosphere at ꢀ208C for 1 hour gave, after
acidic work-up, rise to benzylation product 12 in 63% yield
with 98% ee. Asymmetric allylation and ethylation of 11 was
carried out in a similar manner as described below.
In conclusion, we successfully designed very powerful
chiral phase-transfer catalysts of type 2 to realize a general
Scheme 3. Asymmetric alkylation of Schiff base 11 by using (S)-2c as
catalyst.
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Angewandte
Chemie
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Received: October 10, 2004
Published online: January 31, 2005
Keywords: alkylation · amino acids · enantioselectivity · glycine ·
.
phase-transfer catalysis
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[8] Crystallographic data for (S)-2c as a PF6ꢀ salt: 0.4 ꢄ 0.3 ꢄ 0.2 mm3,
monoclinic, C2, a = 18.70(1), b = 13.80(1), c = 18.176(9) ꢅ, b
= 106.79(5)8, V= 4488(4) ꢅ3, 1calcd = 1.403 gcmꢀ3, Z = 4, 2qmax
= 54.78, m = 0.1383 mmꢀ1, MoKa, l = 0.7107 ꢅ, T= ꢀ1508C. A
total of 20154 reflections were measured. R = 0.068, and Rw
= 0.081 for 11668 observed reflections with I > 3.0s(I). CCDC-
ꢀ
250335 [(S)-2c as a PF6 salt] contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[9] Attempted asymmetric benzylation of 9 with 50% aqueous KOH
in toluene in the presence of 0.05 mol% of catalyst (S,S)-1 under
argon atmosphere at 08C for 24 hours resulted in formation of 10
(R’ = CH2Ph) in only 22% yield with 85% ee.
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