Synthesis and application of dimeric Cinchona alkaloid phase-transfer catalysts: α,α′-bis[O(9)-allylcinchonidinium]-o, m, or p-xylene dibromide

Article abstract of DOI:10.1039/b102584h

A dimeric Cinchona alkaloid ammonium salt, α,α′-bis[O(9)-allylcinchonidinium]-m-xylene dibromide 4, has been developed as a new efficient phase-transfer catalyst; the catalytic enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester u

Full text of DOI:10.1039/b102584h

Synthesis and application of dimeric Cinchona alkaloid phase-transfer
catalysts: a,aA-bis[O(9)-allylcinchonidinium]-o, m, or p-xylene
dibromide†
Sang-sup Jew,* Byeong-Seon Jeong, Mi-Sook Yoo, Hoon Huh and Hyeung-geun Park*
College of Pharmacy, Seoul National University, Seoul 151-742, Korea. E-mail: ssjew@plaza.snu.ac.kr
Received (in Cambridge, UK) 20th March 2001, Accepted 18th May 2001
First published as an Advance Article on the web 20th June 2001
A dimeric Cinchona alkaloid ammonium salt, a,aA-bis[O(9)-
allylcinchonidinium]-m-xylene dibromide 4, has been devel-
oped as a new efficient phase-transfer catalyst; the catalytic
enantioselective alkylation of N-(diphenylmethylene)gly-
cine tert-butyl ester using 4 provided 7 in a high enantio-
meric excess (90–99% ee).
Although phase-transfer catalytic reactions have been widely
applied in organic synthesis,1,2 asymmetric synthetic reactions
using chiral phase-transfer catalysts have not been extensively
studied as compared to general asymmetric synthetic reactions,
such as asymmetric dihydroxylation,3 asymmetric catalytic
reduction,2 and so on. Since the pioneering work of O’Donnell
et al. (1a),4 the enantioselective alkylation of a prochiral
protected glycine derivative, using Cinchona alkaloid ammo-
nium salts, has become a very attractive method for the
preparation of both natural and unnatural a-amino acids.
Fig. 1
Especially, the Lygo5 and Corey6 groups independently re-
ported the excellent phase-transfer catalysts, N-9-anthracenyl-
methylcinchonidinium chloride (2a) and O(9)-allyl-N-
the high enantioselectivity of 4 is not clear, but it is thought to
be similar to the reported mechanism of 2.6a There are two
possible conformations, 4a and 4b, as shown in Fig. 2. The 4a
conformer seems to be preferred, because of the steric hindrance
between the quinoline and O-allyl moieties and the Cinchona
unit (CD+) in 4b. In addition, the dramatic increase in the
9-anthracenylmethylcinchonidinium
bromide
(2b),
respectively, by replacing the phenyl group of 1 with the bulkier
anthracenyl moiety. Recently, the Maruoka group developed
very efficient non-Cinchona catalysts, the C2-symmetric chiral
quaternary ammonium salts prepared from (S)-binaphthol.7
In connection with the development of Sharpless asymmetric
dihydroxylation, the discovery of ligands with two independent
Cinchona alkaloid units attached to heterocyclic spacers led to
considerable increases in both the enantioselectivity and the
scope of the substrate.3 This dimerization effect prompted us to
develop dimeric Cinchona alkaloid ammonium salts for
enantioselective phase-transfer catalytic reactions. In this
communication, we report the preparation of new dimeric
catalysts, a,aA-bis[O(9)-allylcinchonidinium]-o, m, or p-xylene
dibromides 3–5, and their application to the catalytic enantio-
selective alkylation of N-(diphenylmethylene)glycine tert-butyl
ester 6 under mild phase-transfer conditions (Fig. 1).
Table 1 Enantioselective catalytic phase-transfer alkylation
% eeb
(Config.)c
Entry
Catalyst Temp./°C
Time/h
% yielda
1
2
3
4
5
6
7
8
1b
1b
3
3
4
4
5
5
0
220
0
2
5
3
6
2
5
4
6
92
94
90
88
91
94
92
92
75 (S)
81 (S)
31 (S)
35 (S)
90 (S)
95 (S)
80 (S)
86 (S)
220
Compounds 3–5 were prepared in two steps from cinchoni-
dine and a,aA-dibromo-o, m, or p-xylene, respectively. Cincho-
nidine and a,aA-dibromo-o-, m-, or p-xylene were stirred at
100 °C in EtOH–DMF–CHCl3 (v/v = 2.5+3+1)8 for 6 h
followed by O(9)-allylation with allyl bromide and 50% aq.
KOH, to give the corresponding dimeric Cinchona alkaloid
catalysts 3–5 in 90–92 % overall yields. The enantioselective
efficiency of the prepared catalysts was evaluated by enantio-
selective phase-transfer alkylation using 5 mol% of catalysts
3–5 along with 6, benzyl bromide, and 50% aq. KOH in
0
220
0
220
a Isolated yield of purified material. b Enantiopurity was determined by
HPLC analysis using a chiral column (DAICEL Chiralcel OD). c Absolute
configuration was determined by comparison of the HPLC retention time
with the authentic samples independently synthesized by the reported
procedure.4–7
4f,9
toluene–CHCl3 (v/v = 7+3) at 0 °C or 220 °C for 2–6 h.
Surprisingly, the meta-dimeric catalyst 4‡ showed the highest
enantioselectivity (S-form, 90% ee at 0 °C; 95% ee at 220 °C)
among the three dimeric catalysts 3–5 (Table 1). The order of
enantioselectivity of the three catalysts along with the monomer
catalyst 1b was as follows: meta-dimer (4) > para-dimer (5) 
monomer (1b) ì ortho-dimer (3). The precise mechanism for
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b1/b102584h/
Fig. 2
1244
Chem. Commun., 2001, 1244–1245
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102584h

Table 2 Enantioselective catalytic phase-transfer alkylation
This work was supported by grants from Aminogen Co.,
Korea, via the Research Center of New Drug Development of
Seoul National University and the Research Institute of
Pharmaceutical Sciences in the College of Pharmacy of Seoul
National University.
% eeb
Config.c
Entry
RX
Time/h
% Yielda
Notes and references
a
b
c
CH3I
CH3CH2I
CH3(CH2)4CH2I
3
10
5
72
50
64
90 (S)
92 (S)
99 (S)
‡ All new compounds gave satisfactory analytical and spectral data.
Selected data for 4: mp 181 °C (decomp.); [a]25D 2156 (c 0.320, CHCl3);
IR (KBr) 3437, 2922 cm21; dH (400 MHz, DMSO-d6) 9.03 (d, J = 4.4 Hz,
2 H), 8.35 (d, J = 8.3 Hz, 2 H), 8.15 (d, J = 9.0 Hz, 3 H), 7.97 (d, J = 7.5
Hz, 2 H), 7.90–7.86 (m, 2 H), 7.81–7.76 (m, 3 H), 7.72 (d, J = 4.4 Hz, 2 H),
6.53 (s, 2 H), 6.22–6.16 (m, 2 H), 5.78–5.70 (m, 2 H), 5.49 (d, J = 17.2 Hz,
2 H), 5.37–5.28 (m, 4 H), 5.20–5.14 (m, 4 H), 4.99 (d, J = 10.5 Hz, 2 H),
4.46 (dd, J = 12.5, 5.3 Hz, 2 H), 4.06–4.03 (m, 6 H), 3.82–3.76 (m, 2 H),
3.69–3.64 (m, 2 H), 3.51–3.40 (m, 2 H), 2.84–2.75 (m, 2 H), 2.34–2.26 (m,
2 H), 2.15–2.00 (m, 4 H), 1.92–1.81 (m, 2 H), 1.51–1.42 (m, 2 H); dC (100
MHz, DMSO-d6) 150.6, 148.4, 141.7, 139.3, 138.3, 135.9, 134.6, 130.3,
130.0, 129.9, 128.8, 127.9, 125.4, 124.1, 120.0, 118.0, 116.9, 72.3, 69.7,
68.2, 63.4, 59.3, 51.2, 37.2, 26.3, 24.5, 21.2; MS (ESI): 772 [M]2+; HRMS
(ESI) calcd for [C52H60N4O2]2+: 772.4716, found: 772.4739.
d
e
4
4
86
88
94 (S)
97 (S)
f
3
5
92
94
90 (S)
95 (S)
g
h
i
5
8
87
75
95 (S)
96 (S)
Representative procedure for enantioselective catalytic alkylation of 6
under phase-transfer conditions (benzylation): to a mixture of N-(diphenyl-
methylene)glycine tert-butyl ester 6 (50 mg, 0.17 mmol) and chiral catalyst
4 (8 mg, 0.0085 mmol) in toluene–CHCl3 (v/v = 7+3, 0.75 mL) was added
benzyl bromide (0.1 mL, 0.85 mmol). The reaction mixture was then cooled
(220 °C), 50% aq. KOH (0.25 mL) was added, and the reaction mixture was
stirred at 220 °C until the starting material had been consumed (5 h). The
suspension was diluted with ether (20 mL), washed with water (2 3 5 mL),
dried over MgSO4, filtered and concentrated in vacuo. Purification of the
residue by flash column chromatography on silica gel (hexane+EtOAc =
50+1) afforded the desired product 7g (61 mg, 94% yield) as a colorless oil.
The enantioselectivity was determined by chiral HPLC analysis (DAICEL
j
6
8
5
98
90
96
95 (S)
90 (S)
90 (S)
k
l
a Isolated yield of purified material. b Enantiopurity was determined by
HPLC analysis of the alkylated imine 7 using a chiral column (DAICEL
Chiralcel OD) with hexane–propan-2-ol (500/2 for 7a, 7b, 7g, 7h, 7j, 7k, 7l;
500/1 for 7c, 7d, 7e, 7f; 500/5 for 7i) as solvent. c Absolute configuration
was determined by comparison of the HPLC retention time with the
authentic samples independently synthesized by the reported proce-
dure.4–7
Chiralcel OD, hexane+propan-2-ol = 500+2.5, flow rate = 1.0 ml min21
,
23 °C, l = 254 nm; retention times R (minor) 12.2 min, S (major) 22.5 min,
95% ee). The absolute configuration was determined by comparison of the
HPLC retention time with the authentic sample synthesized by the reported
procedure.4–7
1 (a) E. V. Dehmlow and S. S. Dehmlow, Phase Transfer Catalysis, 3rd
edn., VCH, Weinheim, 1993 and references therein; (b) A. Nelson,
Angew. Chem., Int. Ed., 1999, 38, 1583.
2 I. Ojima, Catalytic Asymmetric Synthesis, 2nd edn., Wiley-VCH, New
York, 2000 and references therein.
enantioselectivity from 1b to 4 implies that the Cinchona unit
(CD+) is located near the B site. Consequently, as the direction
B is sterically hindered by the counter Cinchona unit in 4, the E-
enolate of 6 forms an ion-pair with 4 from the less hindered
direction A. We expect that as the re-face of the enolate can be
effectively blocked by the formation of the ion-pair, the alkyl
halide can approach only the si-face of E-enolate, to give the S-
form. The lack of a difference in the enantioselectivity between
the para-dimer 5 and the monomer 1b implies that the Cinchona
units of the para-dimer 5 do not sterically affect each other. In
the case of the ortho-dimer 3, the severe steric repulsion
between the two Cinchona units may lead to a less efficient
conformation for enantioselectivity. Generally, the lower tem-
perature (220 °C) yielded higher enantioselectivity (Table 1).
Catalyst 4 was chosen for the further investigation of the
enantioselective phase-transfer alkylation with various alkyl
halides. Table 2 indicates the results obtained for the alkylation
of 6 with various alkyl halides, using catalyst 4 under the same
reaction conditions as in Table 1, except for the temperature
(220 °C). The very high enantioselectivities (90–99% ee)
shown in Table 2 indicate that catalyst 4 is a very efficient
enantioselective phase-transfer catalyst for the synthesis of
natural and unnatural a-amino acids.
3 H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem. Rev.,
1994, 94, 2483 and references therein.
4 (a) M. J. O’Donnell, W. D. Benett and S. Wu, J. Am. Chem. Soc., 1989,
111, 2353; (b) K. B. Lipkowitz, M. W. Cavanaugh, B. Baker and M. J.
O’Donnell, J. Org. Chem., 1991, 56, 5181; (c) M. J. O’Donnell and S.
Wu, Tetrahedron: Asymmetry, 1992, 3, 591; (d) M. J. O’Donnell, S. Wu
and J. C. Huffman, Tetrahedron, 1994, 50, 4507; (e) M. J. O’Donnell, S.
Wu, I. Esikova and A. Mi, U.S. Patent 5 554 753, September 10, 1996;
(f) M. J. O’Donnell, I. A. Esikova, A. Mi, D. F. Shullenberger and S. Wu,
in Phase-Transfer Catalysis, ed. M. E. Halpern, ACS Symposium Series
659, American Chemical Society, Washington, DC, 1997, ch. 10; (g)
M. J. O’Donnell, F. Delgado and R. Pottorf, Tetrahedron, 1999, 55,
6347.
5 (a) B. Lygo and P. G. Wainwright, Tetrahedron Lett., 1997, 38, 8595; (b)
B. Lygo, J. Crosby and J. A. Peterson, Tetrahedron Lett., 1999, 40, 1385;
(c) B. Lygo, Tetrahedron Lett., 1999, 40, 1389; (d) B. Lygo, J. Crosby
and J. A. Peterson, Tetrahedron Lett., 1999, 40, 8671; (e) B. Lygo, J.
Crosby, T. R. Lowdon and P. G. Wainwright, Tetrahedron, 2001, 57,
2391; (f) B. Lygo, J. Crosby, T. R. Lowdon, J. A. Peterson and P. G.
Wainwright, Tetrahedron, 2001, 57, 2403.
6 (a) E. J. Corey, F. Xu and M. C. Noe, J. Am. Chem. Soc., 1997, 119,
12414; (b) E. J. Corey, M. C. Noe and F. Xu, Tetrahedron Lett., 1998, 39,
5347; (c) E. J. Corey, Y. Bo and J. Busch-Peterson, J. Am. Chem. Soc.,
1998, 120, 13000.
7 (a) T. Ooi, M. Kameda and K. Maruoka, J. Am. Chem. Soc., 1999, 121,
6519; (b) T. Ooi, M. Takeuchi, M. Kameda and K. Maruoka, J. Am.
Chem. Soc., 2000, 122, 5228.
8 N. Baba, J. Oda and M. Kawaguchi, Agric. Biol. Chem., 1986, 50,
3113.
9 The optimal solvent condition was determined by benzylation of 6 at
220 °C using 4. Toluene–CHCl3 (v/v, 7+3) gave the highest enantiose-
lectivity (95% ee) compared to toluene (87% ee), CH2Cl2 (85% ee),
CHCl3 (90% ee), and toluene–CH2Cl2 (v/v, 7+3, 93% ee).
In conclusion, we prepared the dimeric Cinchona alkaloid
ammonium salt catalysts 3–5 to enhance catalytic efficiency by
the dimerization effect. Among the dimeric catalysts, the meta-
isomer (4) showed the highest catalytic activity (90–99% ee) in
the alkylation of 6. The high catalytic efficiency, the easy
preparation, and the lower preparation cost relative to 2a,b
could make 4 a practical catalyst in industrial synthetic
processes for natural and unnatural chiral a-amino acids.
Applications to other various types of phase-transfer catalytic
reactions using 4 are currently being investigated.
Chem. Commun., 2001, 1244–1245
1245