A New N-Spiro C2-Symmetric Chiral Quaternary Ammonium Bromide Consisting of 4,6-Disubstituted Biphenyl Subunit as an Efficient Chiral Phase-Transfer Catalyst

Article abstract of DOI:10.1055/s-2003-41478

A new N-spiro chiral quaternary ammonium bromide has been designed and assembled from optically active 4,6-disubstituted biphenyl subunits. Its utility as an efficient chiral phase-transfer catalyst has been clearly demonstrated by application to the high

Full text of DOI:10.1055/s-2003-41478

CLUSTER
1931
A New N-Spiro C -Symmetric Chiral Quaternary Ammonium Bromide
2
Consisting of 4,6-Disubstituted Biphenyl Subunit as an Efficient Chiral
Phase-Transfer Catalyst
N
T
-Spiro
C
-Sym
a
metric Chi
k
ra
l
Q
uaterna
a
ry Ammoni
s
um Brom
h
ide i Ooi, Yasushi Kubota, Keiji Maruoka*
2
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Fax +81(75)7534041; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Received 4 June 2003
Ph
Ph
Abstract: A new N-spiro chiral quaternary ammonium bromide has
been designed and assembled from optically active 4,6-
disubstituted biphenyl subunits. Its utility as an efficient chiral
phase-transfer catalyst has been clearly demonstrated by application
to the highly enantioselective alkylation of tert-butyl glycinate
benzophenone Schiff base.
Br
Br
N
N
Key words: chiral quaternary ammonium bromide, biphenyl sub-
unit, glycine ester Schiff base, alkylation, a-amino acids
(R,R)-1a
Ph
Ph
R,R)-1b
(
Since the pioneering study of the Merck group in 1984,1
chiral quaternary ammonium salts readily prepared from
naturally occurring cinchona alkaloid, cinchonine and
cinchonidine have been extensively utilized as a reliable
chiral phase-transfer catalyst for various chemical
transformations including the successful enantioselective
O
O
1
(1 mol%)
N
Ph2C
N
+ RX
Ph2C
OBut
OBut
toluene-50% aq KOH
conditions
H
R
2
3
Scheme 1
2
alkylation of protected glycine derivative 2. It has also
been demonstrated that the introduction of an appropriate
substituent on the central nitrogen atom provides
beneficial effect on the reactivity and selectivity of the
(
volume ratio = 3:1) at 0 °C resulted in clean formation of
the corresponding benzylation product 3 (R = CH Ph) in
9
2
4% isolated yield, and the enantiomeric excess was
3
catalyst. On the other hand, several purely synthetic
determined to be 65% ee (entry 1 in Table 1). Encouraged
by this observation implying the potential of this type of
catalyst, we made a thorough investigation on the effect of
substituent mainly on the selectivity; this eventually
uncovered that use of quaternary ammonium bromide 1b
having dimethylphenylmethyl group on 4,4¢-position of
each biphenyl unit as catalyst under similar conditions led
to significant improvement of the enantioselectivity (94%
chiral quaternary ammonium salts have been elaborated
particularly for the asymmetric synthesis of a-amino acids
under phase-transfer conditions based on the use of
readily available chiral sources such as optically pure 1,1¢-
4
,5
bi-2-naphthol and tartaric acid derivatives. In our
continuous efforts to develop N-spiro type chiral C2-
symmetric quaternary ammonium bromides as designer
5
6
chiral phase-transfer catalysts, we have been interested in
ee, entry 2). Here, the enantioselectivity was further
the possibility of using a chiral biphenyl structure as a
new, easily modifiable subunit for further catalyst
elaboration. In this letter, we wish to report our prelimi-
nary results of this project by introducing a new N-spiro
quaternary ammonium bromide 1 and evaluating its
effectiveness as a chiral phase-transfer catalyst in the
asymmetric alkylation of 2 (Scheme 1).
enhanced to 97% ee by performing the reaction at –20 °C
(
entry 3). As revealed in Table 1, the chiral phase-transfer
catalysis of 1b found a broad scope, and good to excellent
asymmetric inductions were achieved with not only
substituted benzyl bromide but also allylic and
propargylic bromides (entries 4–7). In the reactions with
simple alkyl halides such as ethyl iodide and butyl iodide,
excess alkyl halide and CsOH·H O were employed to
attain sufficient reactivity (entries 8 and 9).
We first prepared simple symmetric N-spiro chiral
quaternary ammonium bromide 1a possessing methyl
groups on 6,6¢-positions for inducing chirality. Initial
evaluation of its catalytic and chiral efficiency in the
asymmetric alkylation of 2 with 1 mol% of 1a and benzyl
bromide (1.2 equiv) in toluene–50% aqueous KOH
2
Based on these results, we further applied catalyst 1b to
5
b
the asymmetric synthesis of a,a-dialkyl-a-amino acids.
Thus, treatment of aldimine Schiff base of alanine tert-
butyl ester with benzyl bromide (1.2 equiv) and
CsOH·H O (5 equiv) in the presence of 1b (1 mol%) in
2
toluene at –20 °C, and subsequent acidic hydrolysis
furnished the desired protected methyl phenylalanine in
82% yield with 95% ee (Scheme 2).
SYNLETT 2003, No. 12, pp 1931–1933
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41478; Art ID: Y00603ST
2
9
.0
9
.2
0
0
3
©
Georg Thieme Verlag Stuttgart · New York

1
932
T. Ooi et al.
CLUSTER
Table 1 Catalytic Enantioselective Phase-Transfer Alkylation of 2a
Conditions Yield (%)b Ee (%)c
A Typical Experimental Procedure is as follows: To a mixture of
2
(74 mg, 0.25 mmol), chiral ammonium bromide 1b (2.4 mg,
Entry RX
0.0025 mmol) and benzyl bromide (36 mL, 0.3 mmol) in toluene
(1.5 mL) was added 50% KOH aq solution (0.5 mL) dropwise at
d
(
config)
0
°C. The reaction mixture was stirred vigorously under argon at-
1e
2
PhCH Br
0, 0.5
0, 6
94
96
90
72
65 (S)
94 (S)
97 (S)
96 (S)
2
mosphere at the same temperature for 6 h. The mixture was then di-
luted with H O and extracted with Et O. The organic extracts were
washed with brine and dried over Na SO . Evaporation of solvents
and purification of the residual oil by column chromatography on
silica gel (Et O/hexane = 1:15 as eluant) gave the alkylation prod-
2
2
PhCH Br
2
2
4
3
PhCH Br
–20, 27
–20, 96
2
2
4
uct 3 (R = CH Ph; 92 mg, 0.24 mmol, 96% yield) as a colorless oil.
The enantiomeric excess was determined by chiral HPLC analysis
2
Br
[
DAICEL CHIRALCEL OD, hexane:2-propanol = 100:1, flow
F
rate = 0.5 mL/min, retention time; 14.8 min (R) and 28.2 min (S)].
5
6
7
Br
–20, 16
–20, 96
–20, 16
93
99
97
97 (S)
85 (S)
96 (S)
Acknowledgment
Ph
Br
This work was partially supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Br
f
8
CH CH I
–20, 4
88
70
86 (S)
82 (S)
3
2
f
9
CH (CH ) I
–20, 5.5
3
2 3
References
a
Unless otherwise specified, the reaction was carried out with 1.2
(
1) (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am.
Chem. Soc. 1984, 106, 446. (b) See also: Bhattacharya, A.;
Dolling, U.-H.; Grabowski, E. J. J.; Karady, S.; Ryan, K. M.;
Weinstock, L. M. Angew. Chem., Int. Ed. Engl. 1986, 25,
equiv of RX in the presence of 1 mol% of 1b in toluene/50% aq KOH
(
volume ratio = 3:1) under the given reaction conditions.
Isolated yield.
Enantiopurity of 3 was determined by HPLC analysis of the alkylat-
b
c
4
76. (c) Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.;
Schoenewaldt, E. F.; Grabowski, E. J. J. J. Org. Chem. 1987,
2, 4745.
ed imine using a chiral column (DAICEL CHIRALCEL OD) with
hexane-2-propanol as solvent.
5
d
Absolute configuration was determined by comparison of the HPLC
(
2) For reviews: (a) O’Donnell, M. J. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Verlag Chemie: New York, 1993,
Chap. 8. (b) Shioiri, T. In Handbook of Phase-Transfer
Catalysis; Sasson, Y.; Neumann, R., Eds.; Blackie
retention time with the authentic sample.
e
With 1a as catalyst.
f
Use of 5 equiv of alkyl halide with CsOH·H O (5 equiv) as base.
2
Academic and Professional: London, 1997, Chap. 14.
(
c) Shioiri, T.; Arai, S. In Stimulating Concepts in
Chemistry; Vogtle, F.; Stoddart, J. F.; Shibasaki, M., Eds.;
Wiley-VCH: Weinheim, 2000, 123. (d) O’Donnell, M. J.
Aldrichimica Acta 2001, 34, 3. (e) Maruoka, K.; Ooi, T.
Chem. Rev. 2003, 103, 3013.
In summary, we have devised a new N-spiro chiral quater-
nary ammonium bromide 1b with 4,6-disubstituted chiral
biphenyl framework, which catalyzed phase-transfer
alkylation of protected glycine derivative 2 with high
enantioselectivity and broad generality. Further, the
catalysis of 1b was found to be applicable to the
asymmetric quaternization of an aldimine Schiff base of
a-alkyl-a-amino acids. This study provides a starting
point for the development of new asymmetric phase-
transfer catalysis based on utilization of the chiral envi-
ronment created by appropriately modified chiral
biphenyl structures.
(3) For representative examples, see: (a) Lygo, B.; Wainwright,
P. G. Tetrahedron Lett. 1997, 38, 8595. (b)Corey, E. J.;Xu,
F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414.
(
c) Jew, S.-S.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park, H.-
G. Chem. Commun. 2001, 1244. (d) Chinchilla, R.; Mazón,
P.; Nájera, C. Tetrahedron: Asymmetry 2002, 13, 927.
(
e) Park, H.-G.; Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park,
M.-K.; Lee, Y.-J.; Kim, M.-J.; Jew, S.-S. Angew. Chem. Int.
Ed. 2002, 41, 3036. (f) Jew, S.-S.; Yoo, M.-S.; Jeong, B.-S.;
Park, Y. II; Park, H.-G. Org. Lett. 2002, 4, 4245.
1
b (1 mol%)
O
O
CsOH•H2O (5 eq) 1 N HCl
H2N
p-Cl-Ph
N
+
2
PhCH Br
OBut
OBut
toluene
THF
Me
–20 °C, 3 h
Ph
Me
82%, 95% ee
Scheme 2
Synlett 2003, No. 12, 1931–1933 © Thieme Stuttgart · New York

CLUSTER
N-Spiro C -Symmetric Chiral Quaternary Ammonium Bromide
1933
2
(
4) 1,1¢-Binaphthyl derivatives: (a) Belokon, Y. N.; Kochetkov,
(5) For our recent contributions, see: (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.; Kameda, M.; Tannai, H.;
Maruoka, K. Tetrahedron Lett. 2000, 41, 8339. (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) Ooi, T.; Takahashi, M.; Doda,
K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640.
(g) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K.
Angew. Chem. Int. Ed. 2002, 41, 4542. (h) Ooi, T.; Tayama,
E.; Maruoka, K. Angew. Chem. Int. Ed. 2003, 42, 579.
K. A.; Churkina, T. D.; Ikonnikov, N. S.; Chesnokov, A. A.;
Larionov, O. V.; Parmar, V. S.; Kumar, R.; Kagan, H. B.
Tetrahedron: Asymmetry 1998, 9, 851. (b) Belokon, Y. N.;
Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.;
Vyskocil, S.; Kagan, H. B. Tetrahedron: Asymmetry 1999,
10, 1723. (c) Tartaric acid derivatives: Shibuguchi, T.;
Fukuta, Y.; Akachi, Y.; Sekine, A.; Ohshima, T.; Shibasaki,
M. Tetrahedron Lett. 2002, 43, 9539. (d) Arai, S.; Tsuji, R.;
Nishida, A. Tetrahedron Lett. 2002, 43, 9535.
(
e) Guanidine derivatives: Kita, T.; Georgieva, A.;
Hashimoto, Y.; Nakata, T.; Nagasawa, K. Angew. Chem. Int.
Ed. 2002, 41, 2832. (f) Nagasawa, K.; Georgieva, A.;
Nakata, T. Tetrahedron 2001, 57, 8959. (g) Metal–salen
complexes: Belokon, Y. N.; North, M.; Kublitski, V. S.;
Ikonnikov, N. S.; Krasik, P. E.; Maleev, V. I. Tetrahedron
Lett. 1999, 40, 6105. (h) Belokon, Y. N.; Davies, R. G.;
North, M. Tetrahedron Lett. 2000, 41, 7245.
2
2
(6) Spectroscopic Characterization of 1b: [a] +156.2 (c
D
1
0.31, CHCl ). H NMR (400 MHz, CDCl ): d = 7.37 (4 H, m,
3
3
Ar-H), 7.21–7.32 (16 H, m, Ar-H), 7.14–7.19 (4 H, m, Ar-
H), 7.04 (4 H, br d, J = 1.6 Hz, Ar-H), 3.87 (4 H, d, J = 13.2
Hz, ArCH ), 3.64 (4 H, d, J = 13.2 Hz, ArCH ), 2.18 (12 H,
2
2
1
3
s, ArCH ), 1.68 (24 H, s, ArCCH ). C NMR (100 MHz,
3
3
CDCl ): d = 150.8, 149.7, 137.5, 135.5, 131.2, 128.2, 127.5,
3
1
2
1
26.7, 126.5, 125.8, 60.3, 42.9, 31.0, 30.5, 20.2. IR (KBr):
963, 2928, 2870, 1740, 1680, 1601, 1495, 1445, 1383,
–
1
364, 1232, 1202, 1097, 1076, 1030, 845, 768, 702 cm .
+
HRMS (ESI-TOF): Calcd for C H N: 902.5659 (M ).
Found: 902.5673 (M ).
6
8
72
+
Synlett 2003, No. 12, 1931–1933 © Thieme Stuttgart · New York