Highly efficient ortho-fluoro-dimeric cinchona-derived phase-transfer catalysts

Article abstract of DOI:10.1016/S0040-4039(03)00687-7

A series of cinchona alkaloid-derived dimeric quaternary ammonium salts were prepared as chiral phase-transfer catalysts by the introduction of various functional groups on the phenyl ligand. Among them, the 2-F-substituted derivative 21 showed the highes

Full text of DOI:10.1016/S0040-4039(03)00687-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3497–3500
Highly efficient ortho-fluoro-dimeric cinchona-derived
phase-transfer catalysts
Hyeung-geun Park,* Byeong-Seon Jeong, Mi-Sook Yoo, Jeong-Hee Lee, Boon-saeng Park,
Myoung Goo Kim and Sang-sup Jew*
Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
Received 3 February 2003; revised 5 March 2003; accepted 7 March 2003
Abstract—A series of cinchona alkaloid-derived dimeric quaternary ammonium salts were prepared as chiral phase-transfer
catalysts by the introduction of various functional groups on the phenyl ligand. Among them, the 2-F-substituted derivative 21
showed the highest enantioselectivity in the alkylation of the glycine anion equivalent 1 (97 to >99% ee). © 2003 Elsevier Science
Ltd. All rights reserved.
Cinchona alkaloids are popular as chiral sources for
various efficient catalysts, due to their various func-
tional groups, commercial availability, and low cost.
Recently, their N(1)-alkylated ammonium salts were
developed as efficient chiral phase-transfer catalysts.1
Since the first introduction of N(1)-benzylcinchoninium
chloride by the Dolling group,2 the O’Donnell group
elegantly applied the cinchona-derived quaternary
ammonium salts to the catalytic enantioselective syn-
thesis of natural and unnatural a-amino acids via the
asymmetric alkylation of glycinate imine 1 (Fig. 1).3
Figure 2).10 These findings prompted us to investigate
the electronic effect in the dimeric system. In this
communication, we describe the aromatic-F effect in
the alkylation of a glycine anion equivalent involving
cinchona alkaloid-derived dimeric phase-transfer
catalysts.
New dimeric cinchona-derived quaternary ammonium
salts were prepared in two steps from (−)-cinchonidine
(CD) (9–20) or (−)-hydrocinchonidine (HCD) (21) and
the corresponding 1,3-bis(bromomethyl)benzenes, sub-
stituted at the 2- or 5-position with various functional
groups in 85–95% overall yields.7,11 Their catalytic
efficiencies were evaluated by the enantioselective
phase-transfer alkylation, using 5 mol% of catalyst,
N-(diphenylmethylene)glycine tert-butyl ester 1, benzyl
bromide, and 50% aqueous KOH in toluene/chloro-
form (volume ratio=7:3) at 0 or −20°C (Table 1).12
The enantioselective catalytic efficiency was improved
by the increase bulkiness of the N(1)-substituents,
through the replacement of the benzyl group with the
9-anthracenylmethyl group4–6 or the formation of a
dimer (3, 4)7,8 or a trimer (5).9 Recently, we reported
the electronic role of the cinchona alkaloid-derived
phase-transfer catalysts in the alkylation of the glycine
anion equivalent 1, and the unusual aromatic-F effect
in the selectivity.10 Among the various functional
groups substituted on the phenyl ring of N(1)-benzyl-
cinchonidinium bromide, the ortho-fluoro group
increases the enantioselectivity in the alkylation (6–8 in
As shown in Table 1, no significant electronic effect on
the enantioselectivity was observed in the series of
5-substituted derivatives (15–20), except for 18 (entry
11). In the case of the 2-substituted derivatives (9–14,
entries 2–9), the enantioselectivities generally decreased
only in proportion to the bulkiness of the functional
group, not the electronic properties. The bulky sub-
stituents might lead to unfavorable conformations as a
result of the severe steric hindrance. However, the 2-F
catalyst 9 (94% ee) showed enhanced enantioselectivity,
as compared to that of the reference catalyst 3 (90% ee,
entry 1), in accordance with our previous results.10
While the exact mechanistic details of the improvement
in enantioselectivity are not clear at this time, the
Figure 1.
* Corresponding authors.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00687-7

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H. Park et al. / Tetrahedron Letters 44 (2003) 3497–3500
aromatic F might be involved in internal hydrogen
bonding involving water in order to maintain a more
rigid catalyst conformation.10 The corresponding 2-F
catalyst derived from (+)-cinchonine gave (R)-2d in a
slightly lower enantioselectivity (89% ee) compared to 9
at 0°C. In order to improve the catalytic efficiency of 9,
its hydro-derivative (21) was prepared and the catalytic
efficiency was measured. In agreement with the general
tendency, enhanced enantioselectivity was observed
(96% ee at 0°C, entry 14), and the lower reaction
temperature (−20°C) gave even higher enantioselectivity
(98% ee at −20°C, entry 15). Catalyst 21 was chosen for
further investigation with various alkyl halides.12 The
quite high enantioselectivities (97 to >99% ee), shown in
Table 2, indicate that catalyst 21 is a very efficient
phase-transfer catalyst for the enantioselective synthesis
of both natural and unnatural a-amino acids.
In conclusion, a series of meta-dimeric cinchona alka-
loid phase-transfer catalysts were prepared to study the
electronic effect in the catalytic enantioselective phase-
transfer alkylation of the glycine anion equivalent 1.
Among them, only the 2-fluoro substituted catalysts (9,
21) showed greatly enhanced catalytic activities.
Especially, 1,3-bis[O(9)-allylhydrocinchonidinium-N-
methyl]-2-fluorobenzene dibromide 21 is a highly effec-
tive catalyst for the asymmetric phase-transfer
alkylation in the synthesis of chiral a-amino acids.
Applications of 21 to other enantioselective phase-
transfer reactions are currently being investigated.
Figure 2.
Table 1. Enantioselective catalytic phase transfer benzylation of 1a
Entry
Catalyst
Temp. (°C)
Time (h)
% Yieldb
% eec (config.)d
1
2
3
4
5
6
7
8
3
9
0
0
0
0
0
0
0
0
0
0
0
0
0
2
6
6
7
6
5
10
8
10
20
6
91
93
92
90
87
94
90
91
91
85
90
92
89
94
94
90 (S)
94 (S)
74 (S)
67 (S)
55 (S)
78 (S)
30 (S)
86 (S)
88 (S)
89 (S)
66 (S)
88 (S)
87 (S)
96 (S)
98 (S)
10
11
12
13
14
15
16
17
18
19
20
21
21
9
10
11
12
13
14
15
8
10
6
0
−20
8
a The reaction was carried out with 5.0 equiv. of benzyl bromide and 13.0 equiv. of 50% aqueous KOH in the presence of 5.0 mol% of catalyst
in toluene/chloroform (7:3) under the given conditions.
b Isolated yield.
c The enantiopurity was determined by HPLC analysis of the benzylated imine 2d by using a chiral column (Chiralcel OD) with hexanes/2-
propanol (500:2.5) as solvent.
d The absolute configuration was determined by comparison of the HPLC retention time that of an authentic sample, which was synthesized
independently by reported procedures.4–10

H. Park et al. / Tetrahedron Letters 44 (2003) 3497–3500
3499
Table 2. Catalytic enantioselective phase transfer alkylation of 1 with some representative alkyl halides in the presence of 21
(5 mol%)a
a
The reaction conditions were same as Table 1 except reaction temperature and alkyl halides.
b Isolated yield.
c The enantiopurity was determined by HPLC analysis of the alkylated imine 2 by using a chiral column (Chiralcel OD) with hexanes/2-propanol
as solvent.
d The absolute configuration was assigned by the relative retention times of both enantiomers determined previously.4–10
Acknowledgements
quaternary ammonium catalysts that are not derived
from cinchona alkaloids, see: Ooi, T.; Kameda, M.;
Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519.
7. (a) Jew, S.-s.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park,
H.-g. Chem. Commun. 2001, 1244; (b) 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.
8. Very recently, the preparation and application of dimeric
catalysts that incorporate a 9,10-dimethylanthracenyl
bridge was reported by the C. Na´jera group: Chinchilla,
R.; Mazo´n, P.; Na´jera, C. Tetrahedron: Asymmetry 2002,
13, 927.
This work was supported by grant (R01-2002-000-0005-
0) from the Basic Research Program of the KOSEF
(2002).
References
1. (a) Nelson, A. Angew. Chem., Int. Ed. 1999, 38, 1583; (b)
Shioiri, T.; Arai, S. In Stimulating Concepts in Chemistry;
Vogtle, F.; Stoddart, J. F.; Shibasaki, M., Eds.; Wiley-
VCH: Weinheim, 2000; pp. 123–143; (c) O’Donnell, M. J.
In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
VCH: New York, 2000; Chapter 10; (d) O’Donnell, M. J.
Aldrichim. Acta 2001, 34, 3.
9. Park, H.-g.; Jeong, B.-S.; Yoo, M.-S.; Park, M.-k.; Huh,
H.; Jew, S.-s. Tetrahedron Lett. 2001, 42, 4645.
10. Jew, S.-s.; Yoo, M.-S.; Jeong, B.-S.; Park, I. Y.; Park,
H.-g. Org. Lett. 2002, 4, 4245.
2. Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am.
Chem. Soc. 1984, 106, 446.
3. O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem.
Soc. 1989, 111, 2353.
11. All new compounds gave satisfactory analytical and spec-
tral data. Selected data for 21: mp 187°C (decomp.); [h]D25
−135 (c 0.500, CHCl3); IR (KBr) 3399, 2960, 1590 cm−1
;
1H NMR (300 MHz, DMSO-d6); 9.02 (d, J=4.4 Hz, 2H),
8.27 (d, J=8.3 Hz, 2H), 8.14 (d, J=7.6 Hz, 2H), 8.07–
8.02 (m, 2H), 7.90–7.85 (m, 2H), 7.80–7.76 (m, 2H),
7.70–7.63 (m, 3H), 6.48 (s, 2H), 6.14–6.05 (m, 2H), 5.44
(d, J=17.3 Hz, 2H), 5.36 (d, J=12.7 Hz, 2H), 5.25 (d,
J=9.3 Hz, 2H), 4.91 (d, J=12.0 Hz, 2H), 4.35–4.29 (m,
4. Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38,
8595.
5. Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414.
6. For a recent report on the successful enantioselective
monoalkylation of the glycinate imine 1, using chiral

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H. Park et al. / Tetrahedron Letters 44 (2003) 3497–3500
2H), 4.19–4.11 (m, 2H), 4.05–3.99 (m, 4H), 3.65–3.61 (m,
mL). The reaction mixture was then cooled to −20°C, 50%
aqueous KOH (0.25 mL) was added, and the reaction
mixture was stirred at −20°C until the starting material had
been consumed (8 h). The suspension was diluted with ethyl
ether (20 mL), washed with water (2×5 mL), dried over
MgSO4, filtered, and concentrated in vacuo. Purification of
the residue by flash column chromatography afforded the
benzylated imine 2d (61 mg, 94% yield) as a colorless oil.
The enantiomeric excess of 2d was determined by a chiral
HPLC analysis [Chiralcel OD column, hexane:2-
propanol=500:2.5, flow rate=1.0 mL/min, 23°C, u=254
nm, retention times R (minor) 12.2 min, S (major) 22.5 min,
98% ee]. The absolute configuration was determined by
comparison of the HPLC retention times and the [h]D value
with the reported data of an authentic sample.4–10
2H), 3.40–3.31 (m, 4H), 2.28–2.24 (m, 2H), 2.07–2.04 (m,
2H), 2.03–1.96 (m, 2H), 1.87–1.76 (m, 4H), 1.52–1.46 (m,
2H), 1.26–1.20 (m, 4H), 0.68 (t, J=7.2 Hz, 6H); 13C NMR
(75 MHz, CHCl3-d); 149.7, 148.4, 140.6, 193.2, 132.9,
129.9, 128.5, 125.2, 123.9, 118.7, 116.2, 70.1, 65.7, 62.8,
51.5, 35.2, 31.4, 26.3, 25.3, 23.9, 22.5, 22.0, 20.1, 15.1, 14.0,
11.2; MS (FAB): 874 [M-Br]+; HRMS (FAB) calcd for
[C52H63FN4O2Br]+: 874.4118, found: 874.4144.
12. Representative procedure for the catalytic enantioselective
phase-transfer alkylation of 1 in the presence of catalyst 21
(benzylation): Benzyl bromide (0.1 mL, 0.85 mmol) was
added to a mixture of N-(diphenylmethylene)glycine tert-
butyl ester 1 (50 mg, 0.17 mmol) and the chiral catalyst 21
(8.1 mg, 0.0085 mmol) in toluene/chloroform (7:3, 0.75