New chiral phase-transfer catalysts possessing a 6,6′-bridged ring on the biphenyl unit: Application to the synthesis of α,α-dialkyl- α-amino acids

Article abstract of DOI:10.1016/j.tetlet.2012.04.127

A new chiral phase-transfer catalyst possessing a 6,6′-bridged ring on the biphenyl unit has been developed for the practical synthesis of α,α-dialkyl-α-amino acids. This catalyst shows very high activity for the asymmetric alkylation of an alanine deriva

Full text of DOI:10.1016/j.tetlet.2012.04.127

Tetrahedron Letters 53 (2012) 3739–3741
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Tetrahedron Letters
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New chiral phase-transfer catalysts possessing a 6,60-bridged ring on the
biphenyl unit: application to the synthesis of a,a-dialkyl-a-amino acids
Yasushi Kubota a, Seiji Shirakawa b, Tsutomu Inoue a, Keiji Maruoka b,
⇑
a Nippon Soda Co., Ltd, 345, Takada, Odawara, Kanagawa 250-0280, Japan
b Laboratory of Synthetic Organic Chemistry and Special Laboratory of Organocatalytic Chemistry, Department of Chemistry, Graduate School of Science, Kyoto University,
Sakyo, Kyoto 606-8502, Japan
a r t i c l e i n f o
a b s t r a c t
A new chiral phase-transfer catalyst possessing a 6,60-bridged ring on the biphenyl unit has been devel-
oped for the practical synthesis of a,a-dialkyl-a-amino acids. This catalyst shows very high activity for
Article history:
Received 13 February 2012
Revised 7 April 2012
Accepted 27 April 2012
Available online 16 May 2012
the asymmetric alkylation of an alanine derivative to give
a
,
a-dialkyl-a-amino acid derivatives with high
enantioselectivities.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Phase-transfer catalysis
Organocatalysis
Amino acids
Alkylations
Asymmetric synthesis
Phase-transfer catalysis (PTC) has been recognized as a power-
ful tool for organic synthesis because of its several advantages (i.e.,
simple procedure, mild reaction conditions with aqueous media
and environmentally benign character, suitability for large-scale
reactions, etc.), which meet the current requirements for practical
organic synthesis.1 Therefore, various types of chiral phase-transfer
catalysts have been developed in recent years and the chiral effi-
ciency of such phase-transfer catalysts was examined by applica-
tion to the asymmetric synthesis of both natural and unnatural
substrate. Herein, we report that chiral phase-transfer catalyst of
type 1, possessing a bridged ring on the biphenyl unit, can be uti-
lized as a practical tool for the asymmetric synthesis of
-amino acids.
a,a-dialkyl-
a
a-alkyl- and
a,a-dialkyl-a
-amino acids.2 In spite of numerous
studies, the search for truly efficient catalytic systems for the syn-
thesis of
a,a-dialkyl-a-amino acids is still in progress in terms of
catalyst loading and reaction conditions.3 We recently developed
highly efficient chiral phase-transfer catalysts for the synthesis of
a
-alkyl-
nely tunable catalyst to improve the activity and enantioselectivity
for the synthesis of -dialkyl- -amino acids. In the course of our
a
-amino acids.4 We were interested in the design of a fi-
The chiral biphenyl core unit was easily prepared as outlined in
a
,a
a
Scheme 1. Thus, p-bromination of commercially available 6-tert-
butyl-m-cresol, followed by oxidative coupling gave the key biphe-
nyl core 3 in good overall yield. Optical resolution of racemic 3
research, the introduction of alkoxy groups to a biphenyl unit pro-
vided successful results in terms of both enantioselectivity and cat-
alyst loading for the synthesis of
a-alkyl-a
-amino acids.4b To
using (R,R)-1,2-diphenylethylenediamine as
a chiral resolving
further improve the catalyst activity and enantioselectivity, we
were interested in the introduction of an alkyl chain bridge of var-
iable length to link the biaryl groups.5 This new catalyst provides a
rigid structure with an appropriate dihedral angle for each
agent was performed quite successfully (88%, >99% ee). Treatment
of (S)-3 with TfOH in toluene gave rise to (S)-5,50-dibromo-6,60-
dimethylbiphenyl-2,20-diol [(S)-4] in 94% yield.
Reaction of (S)-4 with alkyl dihalides in the presence of excess
anhydrous K2CO3 in CH3CN gave compounds 5a–e having C1–C5
bridges linking their biaryl groups (Scheme 2). A series of new
phase-transfer catalysts 6a–e were prepared from 5a–e in a similar
⇑
Corresponding author. Tel./fax: +81 75 753 4041.
E-mail address: maruoka@kuchem.kyoto-u.ac.jp (K. Maruoka).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.127

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Y. Kubota et al. / Tetrahedron Letters 53 (2012) 3739–3741
Scheme 1. Reagents and conditions: (a) NBS (1 equiv), DMF, 92%; (b) CuCl
(10 mol %), TMEDA (15 mol %), O2 (air), CH2Cl2, 56%; (c) (R,R)-1,2-diphenylethylen-
ediamine (0.6 equiv), toluene–hexane, 88%; (d) TfOH (1 equiv), toluene, 94%.
Scheme 3.
Scheme 4.
a,a-dialkyl-a-amino acids. As shown in Table 1, (S)-11 was found
to be an extremely useful catalyst. Catalyst (S)-11 was superior
Scheme 2.
to (S)-12 at 0.02 mol % loading and (S)-13, which is an excellent
catalyst for the preparation of chiral
a
-alkyl-
a
-amino acids,3f,4c un-
manner to the reported method.4 Thus, Suzuki–Miyaura cross cou-
pling6 of (S)-5a–e with an arylboronic acid, ArB(OH)2 [(Ar = 3,5-
(CF3)2–C6H3)] in the presence of a catalytic amount of Pd(OAc)2,
PPh3, and K3PO4 in DMF afforded the corresponding coupled prod-
ucts in good yields. Radical bromination of these resulting coupled
products in benzene and subsequent treatment with Bu2NH fur-
nished (S)-6a–e in high yields.
der low loading conditions (below 0.1 mol %).
Table 1
Effect of phase-transfer catalysts at low catalyst loading
To examine the bridging effect in the catalysts 6a–e, we studied
their application in the asymmetric benzylation of glycine Schiff
base 7. Thus, reaction of 7 with benzyl bromide (1.2 equiv) and
50% aqueous KOH in toluene was carried out in the presence of
1 mol % of (S)-6a–e at 25 °C to furnish benzylation product (R)-8
(Scheme 3). Unexpectedly, there was no catalytic activity with
(S)-6a. However, the enantioselectivity of benzylation product
(R)-8 slightly increased with extension of the bridging chain.
Asymmetric alkylation of 7 in the presence of (S)-6d having a
four-carbon bridge led to formation of (R)-8 in an excellent 94%
yield with 95% ee.
With these results in hand, we applied catalyst (S)-6d to the
asymmetric alkylation of aldimine Schiff base 9 derived from D,L-
alanine tert-butyl ester. Catalyst (S)-6d was found to be quite effec-
tive for the asymmetric quaternization7 of the aldimine Schiff base
9 of alanine tert-butyl ester. As shown in Scheme 4, (S)-6d and its
analogue (S)-114 exhibited high efficiency and selectivity even in
the case of using KOH as the base at room temperature.8,9
Loading/Time
(S)-11
(S)-12
(S)-13
1 mol % (2 h)
82%, 97% ee
89%, 96% ee
85%, 97% ee
—
85%, 97% ee
79%, 95% ee
82%, 97% ee
83%, 97% ee
85%, 97% ee
—
82%, 94% ee
71%, 73% ee
86%, 97% ee
84%, 96% ee
41%, 30% ee
73%, 11% ee
29%, 11% ee
—
0.5 mol % (2 h)
0.1 mol % (20 h)
0.1 mol % (60 h)
0.02 mol % (20 h)
0.01 mol % (40 h)
Prompted by this result, we examined the catalyst loading in or-
der to optimize the catalytic system for the preparation of chiral

Y. Kubota et al. / Tetrahedron Letters 53 (2012) 3739–3741
3741
Table 2
temperature (25 °C) for 20 h. The mixture was then poured into
H2O and extracted with CH2Cl2. The solvents were evaporated,
and the residue was dissolved in THF (5.0 mL). To this solution
was added 1 N HCl (5.0 mL), and the mixture was stirred for 3 h
at room temperature. After evaporation to remove THF, the aque-
ous phase was basified by the addition of solid NaHCO3 and ex-
tracted with EtOAc. The organic extracts were dried over Na2SO4,
and the solvent evaporated. The residue was dissolved in CH2Cl2
(3.0 mL), and to the solution was added benzoyl chloride
(0.30 mmol). After stirring for 1 h at room temperature, aqueous
NH3 was added. The organic materials were extracted with CH2Cl2,
and the organic extracts dried over Na2SO4. Evaporation of the sol-
vent and purification of the residue by column chromatography on
silica gel (EtOAc/hexane as eluent) gave the desired product 10.
Catalytic enantioselective phase-transfer alkylations of alanine derivative 9 catalyzed
by (S)-11a
Entry
1
RX
Yieldb (%)
85
eec (%)
97
PhCH2Br
2
85
95
3
CH2@CHCH2Br
CH„CCH2Br
EtI
86
88
66
96
89
92
References and notes
4
5d,e
1. For reviews on phase-transfer catalysis, see: (a) Dehmlow, E. V.; Dehmlow, S. S.
In Phase Transfer Catalysis, 3rd ed.; VCH: Weinheim, 1993; (b) Starks, C. M.;
Liotta, C. L.; Halpern, M. In Phase-Transfer Catalysis; New York: Chapman & Hall,
1994; (c) Handbook of Phase-Transfer Catalysis; Sasson, Y., Neumann, R., Eds.;
Blackie Academic & Professional: London, 1997; (d) Halpern, M. E., Ed.; Phase-
Transfer Catalysis; ACS Symposium Series 659; American Chemical Society:
Washington DC, 1997.
a
Unless otherwise specified, the reaction was carried out with 1.2 equiv of alkyl
halide in the presence of phase-transfer catalyst (S)-11 (0.02 mol %) in 50% aqueous
KOH/toluene (volume ratio = 1:4) at 25 °C for 20 h.
b
Isolated yield.
Determined by HPLC analysis.
Use of 0.1 mol % of (S)-11.
Use of 5 equiv of alkyl halide.
c
d
2. For recent reviews on asymmetric phase-transfer catalysis, see: (a) O’Donnell,
M. J. Aldrichim. Acta 2001, 34, 3; (b) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103,
3013; (c) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506; (d) Lygo, B.; Andrews, B.
I. Acc. Chem. Res. 2004, 37, 518; (e) Vachon, J.; Lacour, J. Chimia 2006, 60, 266; (f)
Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222; (g) Ooi, T.; Maruoka, K.
Aldrichim. Acta 2007, 40, 77; (h) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107,
5656; (i) Maruoka, K. Org. Process Res. Dev. 2008, 12, 679; (j) Jew, S.-s.; Park, H.-g.
Chem. Commun. 2009, 7090; (k) Maruoka, K. Chem. Rec. 2010, 10, 254.
3. For representative examples, see: (a) O’Donnell, M. J.; Wu, S. Tetrahedron:
Asymmetry 1992, 3, 591; (b) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett.
1999, 40, 8671; (c) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2000, 122, 5228; (d) Jew, S.-s.; Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.; Lee, Y.-J.;
Park, B.-s.; Kim, M. G.; Park, H.-g. J. Org. Chem. 2003, 68, 4514; (e) Ohshima, T.;
Shibuguchi, T.; Fukuta, Y.; Shibasaki, M. Tetrahedron 2004, 60, 7743; (f)
Kitamura, M.; Shirakawa, S.; Maruoka, K. Angew. Chem., Int. Ed. 2005, 44, 1549.
4. (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139; (b) Wang,
Y.-G.; Ueda, M.; Wang, X.; Han, Z.; Maruoka, K. Tetrahedron 2007, 63, 6042; (c)
Kitamura, M.; Shirakawa, S.; Arimura, Y.; Wang, X.; Maruoka, K. Chem. Asian J.
2008, 3, 1702.
e
We further applied catalyst (S)-11 to the asymmetric synthesis
of a,a-dialkyl-a-amino acids with various alkyl halides and repre-
sentative results are listed in Table 2. A remarkable feature of the
catalyst system is that the reaction proceeds under mild reaction
conditions (KOH as base, room temperature) with extremely low
catalyst loading (0.02 mol %).
The origin of the high reactivity of catalyst (S)-11 in comparison
with (S)-13 is ascribed to the stability due to the lower acidity of
the benzylic proton of (S)-11. By fixing the dihedral angle appropri-
ately, the selectivity of (S)-11 increases in contrast to the open-
chain catalysts under the low loading conditions.
In conclusion, we have successfully designed very powerful chi-
ral phase-transfer catalysts (S)-6d and (S)-11 for the synthesis of
5. For a similar approach for the design of chiral ligands, see: (a) Harada, T.; Ueda,
S.; Tuyet, T. M. T.; Inoue, A.; Fujita, K.; Takeuchi, M.; Ogawa, N.; Oku, A.; Shiro, M.
Tetrahedron 1997, 53, 16663; (b) Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J.
Org. Chem. 2000, 65, 6223.
6. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b) Suzuki, A. Angew.
Chem., Int. Ed. 2011, 50, 6723; (c) Suzuki, A.; Yamamoto, Y. Chem. Lett. 2011, 40,
894.
7. Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis;
Christoffers, K., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005.
8. For the alkylation of the aldimine Schiff base 9 of alanine tert-butyl ester, CsOH
a,a
-dialkyl-a-amino acids. These new catalysts are effective for
the practical synthesis of
a
,a
-dialkyl- -amino acids in terms of
a
both high enantioselectivity with low catalyst loading under mild
reaction conditions.
A typical experimental procedure is as follows: To a solution of
alanine derivative 9 (0.25 mmol), alkyl halide (0.30 mmol), and
catalyst (S)-11 (0.00005 mmol, 0.02 mol %) in toluene (2.0 mL)
was added 50% aqueous KOH (0.50 mL) at room temperature
(25 °C). The reaction mixture was stirred vigorously at room
(a relatively expensive base) was often used for the synthesis of
amino acids. See Ref. 3.
a,a-dialkyl-a-
9. A 0.02 mol % loading of (S)-6d provided (R)-10 in lower selectivity (94% ee)
compared with (S)-11 (97% ee) in Table 1.