Trimeric Cinchona alkaloid phase-transfer catalyst: α,α′,α″-tris[O(9)- allylcinchonidinium]mesitylene tribromide

Article abstract of DOI:10.1016/S0040-4039(01)00809-7

A trimeric Cinchona alkaloid ammonium salt, α,α′,α″-tris[O(9)- allylcinchonidinium]mesitylene tribromide has been prepared as a novel phase-transfer catalyst. The catalytic enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl ester using

Full text of DOI:10.1016/S0040-4039(01)00809-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4645–4648
Trimeric Cinchona alkaloid phase-transfer catalyst:
a,a%,a%%-tris[O(9)-allylcinchonidinium]mesitylene tribromide
Hyeung-geun Park,* Byeong-seon Jeong, Mi-sook Yoo, Mi-kyoung Park, Hoon Huh and
Sang-sup Jew*
College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
Received 23 March 2001; revised 10 May 2001; accepted 11 May 2001
Abstract—A trimeric Cinchona alkaloid ammonium salt, a,a%,a%%-tris[O(9)-allylcinchonidinium]mesitylene tribromide has been
prepared as a novel phase-transfer catalyst. The catalytic enantioselective alkylation of N-(diphenylmethylene)glycine tert-butyl
ester using the trimer catalyst showed high enantioselectivity (90–97% ee). © 2001 Elsevier Science Ltd. All rights reserved.
Phase-transfer catalytic reactions have been widely
applied in organic synthesis for the excellent catalytic
efficiency.1 Since the first application of the Cinchona
alkaloid type phase-transfer catalyst (1) for the enan-
tioselective synthesis of a-amino acids by O’Donnell et
al.,2 the development of more efficient catalysts derived
from Cinchona alkaloid has been extensively studied.
Especially, the Lygo and Corey groups independently
developed the efficient Cinchona type phase-transfer
catalysts by replacing the phenyl group of 1 with the
bulkier anthracenyl moiety (2).3,4 Recently, the
Maruoka group developed very efficient non-Cinchona
type catalysts, the C2-symmetric chiral quaternary
ammonium salts prepared from (S)-binaphthol.5
As part of our program toward the development of a
more efficient Cinchona type phase-transfer catalyst, we
introduced bulky environment to the N-benzyl group of
1 by the formation of trimer 3 (Fig. 1). In this commu-
nication, we report the preparation of novel trimeric
a,a%,a%%-tris[O(9)-allylcinchonidinium]mesitylene tribro-
mide 3 and its application to the catalytic enantioselec-
tive alkylation of N-(diphenylmethylene)glycine tert-
butyl ester 5 under mild phase-transfer conditions.
a,a%,a%%-Tris[O(9)-allylcinchonidinium]mesitylene tribro-
mide 3 was prepared in two steps from (−)-cinchonidine
and a,a%,a%%-tribromomesitylene6 4. (−)-Cinchonidine
(3.3 equiv.) and a,a%,a%%-tribromomesitylene were stirred
N
3Br-
Br-
Br-
O
N+
N+
N+
N+
O
O
O
O
N
R
N
R
N
N+
R = H or allyl
R = H or allyl
N
1
2
3
Figure 1.
Keywords: trimeric Cinchona alkaloid ammonium salt; phase-transfer catalyst.
* Corresponding authors.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00809-7

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H. Park et al. / Tetrahedron Letters 42 (2001) 4645–4648
at 100°C in ethanol/DMF/chloroform (volume ratio=
5:6:2)7 for 6 h followed by O(9)-allylation with allyl
bromide and 50% aqueous KOH to give 3 in 92%
overall yield (Scheme 1).8 The enantioselective efficiency
of the trimeric chiral catalyst 3 was evaluated by enan-
tioselective phase-transfer alkylation using 3 mol% of
catalyst 3 along with N-(diphenylmethylene)glycine
tert-butyl ester 5, alkyl halides and 50% aqueous KOH
in toluene/chloroform (volume ratio=7:3) at −20°C for
10–24 h. The enantioselectivities were determined by
chiral HPLC analysis of the alkylated imines 6. The
very high enantioselectivities (S-form, 90–97% ee) are
shown in Table 1. Not only the enantioselectivity but
also the chemical yields are quite high (6b–j, 88–95%)
CD+
Br
N+
a), b)
CD+ =
3Br-
CD+
CD+
Br
O
N
Br
4
3
Scheme 1. Reagents and conditions: (a) (−)-Cinchonidine (3.3 equiv.), EtOH/DMF/CHCl3 (5:6:2), 100°C, 97%; (b) allyl bromide,
50% KOH, CH2Cl2, rt, 95%.
Table 1. Enantioselective catalytic phase-transfer alkylationa

H. Park et al. / Tetrahedron Letters 42 (2001) 4645–4648
4647
Acknowledgements
B
A
CD+
N+
This research was supported by grants of the Research
Institute of Pharmaceutical Sciences in College of Phar-
macy of Seoul National University and Aminogen Co.,
Korea, via the Research Center of New Drug Develop-
ment of Seoul National University.
O
N
+CD
3
References
Figure 2.
1. (a) Makosza, M.; Ludwikow, M. Rocz. Chem. 1965, 39,
1223; (b) Makosza, M.; Serafinowa, B. Rocz. Chem. 1965,
39, 1401, 1595, 1647, 1799, 1805; (c) Makosza, M. Pure
Appl. Chem. 1975, 43, 439; (d) Dolling, U.-H.; Davis, P.;
Grabowski, E. J. J. Am. Chem. Soc. 1984, 106, 446; (e)
Hughes, D. L.; Dolling, U.-H.; Ryan, K. M.; Schoe-
newaldt, E. F.; Grabowski, E. J. J. Org. Chem. 1987, 52,
4745; (f) Masui, M.; Ando, A.; Shioiri, T. Tetrahedron
Lett. 1988, 29, 2835; (g) Nerinckx, W.; Vandewalle, M.
Tetrahedron: Asymmetry 1990, 1, 265; (h) Lee, T. B. K.;
Wong, G. S. K. J. Org. Chem. 1991, 56, 872; (i) Eddine, J.
J.; Cherqaoui, M. Tetrahedron: Asymmetry 1995, 6, 1225;
(j) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Cataly-
sis, 3rd ed.; VCH: Weinheim, 1993; (k) Catalytic Asym-
metric Synthesis, Ojima, I., Ed., VCH: New York, 1993.
2. (a) O’Donnell, M. J.; Benett, W. D.; Wu, S. J. Am. Chem.
Soc. 1989, 111, 2353; (b) Lipkowitz, K. B.; Cavanaugh, M.
W.; Baker, B.; O’Donnell, M. J. J. Org. Chem. 1991, 56,
5181; (c) O’Donnell, M. J.; Wu, S. Tetrahedron: Asymme-
try 1992, 3, 591; (d) O’Donnell, M. J.; Wu, S.; Huffman, J.
C. Tetrahedron 1994, 50, 4507; (e) O’Donnell, M. J. et al.
US Patent 5,554,753, September 10, 1996; (f) O’Donnell,
M. J.; Esikova, I. A.; Mi, A.; Shullenberger, D. F.; Wu, S.
In Phase-Transfer Catalysis; Halpern, M. E., Ed.; ACS
Symposium Series 659; American Chemical Society: Wash-
ington, DC, 1997; Chapter 10; (g) O’Donnell, M. J.;
Delgado, F.; Pottorf, R. Tetrahedron 1999, 55, 6347.
3. (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997,
38, 8595; (b) Lygo, B.; Crosby, J.; Peterson, J. A. Tetra-
hedron Lett. 1999, 40, 1385; (c) Lygo, B. Tetrahedron Lett.
1999, 40, 1389; (d) Lygo, B.; Crosby, J.; Peterson, J. A.
Tetrahedron Lett. 1999, 40, 8671.
except 6a (65%). The alkylated imines 6 could be
further transformed to the corresponding a-amino acids
by acidic hydrolysis via the known procedure.2
It is thought that the high enantioselectivity of 3 is
attributed to the steric hindrance of the counter Cin-
chona unit (CD+) located near the B site as shown in
Fig. 2. Because the direction B is blocked by those two
meta-substituted Cinchona units in 3, the E-enolate of
N-(diphenylmethylene)glycine tert-butyl ester 5 forms
an ion-pair with 3 from the less hindered direction A.
Then, as the re-face of enolate can be effectively
blocked by the formation of the ion-pair, alkyl halide
can approach only the si-face of E-enolate to give the
S-form of 6. The high enantioselectivities indicate that
the trimeric catalyst 3 is a very efficient Cinchona type
phase-transfer catalyst for the synthesis of natural and
unnatural a-amino acids.
In conclusion, we prepared the trimeric Cinchona alka-
loid catalyst 3. The high enantioselective catalytic
efficiency (90–97% ee) and the easy preparation (92% in
two steps) could make 3 a practical phase-transfer
catalyst for the enantioselective synthesis of a-amino
acids.9 The applications of 3 to other asymmetric cata-
lytic reactions are currently being investigated.
General procedure for enantioselective catalytic alkyla-
tion of N-(diphenylmethylene)glycine tert-butyl ester 5
under phase-transfer conditions: To a mixture of N-
(diphenylmethylene)glycine tert-butyl ester 5 (50 mg,
0.17 mmol) and catalyst 3 (8 mg, 0.0085 mmol) in
toluene/chloroform (volume ratio=7:3, 0.75 mL) was
added alkyl halide (0.85 mmol). The reaction mixture
was then cooled (−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.
The suspension was diluted with 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 on silica gel (hex-
ane:EtOAc=50:1) afforded the desired product 6a–j.
The enantioselectivities were determined by chiral
HPLC analysis (DAICEL Chiralcel OD, hexane/2-
propanol, flow rate=0.5 or 1.0 mL/min, 23°C, u=254
nm) The absolute configuration was determined by
comparison of the HPLC retention time with the
authentic sample synthesized by the reported
4. (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc.
1997, 119, 12414; (b) Corey, E. J.; Noe, M. C.; Xu, F.
Tetrahedron Lett. 1998, 39, 5347; (c) Corey, E. J.; Bo, Y.;
Busch-Peterson, J. J. Am. Chem. Soc. 1998, 120, 13000.
5. (a) Ooi, T.; Kaneda, M.; Maruoka, K. J. Am. Chem. Soc.
1999, 121, 6519; (b) Ooi, T.; Takeuchi, M.; Kaneda, M.;
Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228.
6. Spino, C.; Clouston, L. L.; Berg, D. J. Can. J. Chem. 1997,
75, 1047.
7. Baba, N.; Oda, J.; Kawaguchi, M. Agric. Biol. Chem.
1986, 50, 3113.
8. Spectral data for catalyst 3: mp 201°C (decomp.); [h]D23
−128 (c 0.83, CHCl3); IR (KBr) 3437, 2922 cm−1; 1H NMR
(400 MHz, DMSO-d6) l 9.04 (d, J=4.4 Hz, 3H), 8.48 (s,
3H), 8.41 (d, J=8.3 Hz, 3H), 8.16 (d, J=8.3 Hz, 3H),
7.88–7.92 (m, 3H), 7.81–7.85 (m, 3H), 7.73 (d, J=4.4 Hz,
3H), 6.59 (s, 3H), 6.17–6.27 (m, 3H), 5.67–5.78 (m, 3H),
5.50 (d, J=17.2 Hz, 3H), 5.42–5.43 (m, 3H), 5.33–5.38 (m,
6H), 5.14–5.18 (m, 3H), 4.96 (d, J=10.5 Hz, 3H),
procedure.2–4
.

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H. Park et al. / Tetrahedron Letters 42 (2001) 4645–4648
4.51 (dd, J=12.7, 5.2 Hz, 3H), 4.28 (t, J=11.5 Hz, 3H),
59.4, 51.1, 36.9, 26.2, 24.5, 21.6 ppm; MS (FAB): 1279
[M−Br]+; HRMS (FAB) calcd for [C75H87N6O3Br2]+:
1279.5206, found: 1279.5200.
3.95–4.10 (m, 9H), 3.82–3.89 (m, 3H), 3.71–3.78 (m,
3H), 3.05–3.12 (m, 3H), 2.24–2.35 (m, 3H), 1.98–2.10
(m, 6H), 1.83–1.94 (m, 3H), 1.49 (t, J=11.4 Hz, 3H)
ppm; 13C NMR (100 MHz, DMSO-d6) l 150.7, 148.5,
141.7, 141.0, 138.6, 134.8, 130.4, 130.1, 129.7, 128.1,
125.5, 124.4, 120.1, 118.2, 116.6, 72.4, 69.7, 68.6, 63.2,
9. The practicality of our method was confirmed by 1 g
scale reaction (benzylation, entry d in Table 1) shown
the almost similar chemical yield (93%) and enantioselec-
tivity (95% ee) as small scale reaction.
.