New dimeric anthracenyl-derived Cinchona quaternary ammonium salts as phase-transfer catalysts for the asymmetric synthesis of α-amino acids

Article abstract of DOI:10.1016/S0957-4166(02)00211-2

New dimeric cinchonidine- and cinchonine-derived ammonium salts which incorporate a dimethylanthracenyl bridge have been prepared and used as phase-transfer catalysts in the asymmetric alkylation of N-(diphenylmethylene)glycine esters in good yields and u

Full text of DOI:10.1016/S0957-4166(02)00211-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 927–931
New dimeric anthracenyl-derived Cinchona quaternary
ammonium salts as phase-transfer catalysts for the asymmetric
synthesis of a-amino acids
Rafael Chinchilla, Patricia Mazo´n and Carmen Na´jera*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 26 April 2002; accepted 30 April 2002
Abstract—New dimeric cinchonidine- and cinchonine-derived ammonium salts which incorporate a dimethylanthracenyl bridge
have been prepared and used as phase-transfer catalysts in the asymmetric alkylation of N-(diphenylmethylene)glycine esters in
good yields and up to 90% ee. © 2002 Elsevier Science Ltd. All rights reserved.
The synthesis of optically active naturally occurring
and synthetic a-amino acids using a simple and easily
scalable procedure remains as an important synthetic
challenge.1 Of all the strategies developed, the asym-
metric alkylation of glycine and alanine Schiff bases
using phase-transfer-catalysis (PTC)1p,2 is probably the
most simple, economical and easy to scale up. Thus, the
pioneering work of O’Donnell showed that benzyl
ammonium salts derived from versatile Cinchona alka-
loids,3 such as the cinchonidine-derived 1, were useful
catalysts in the asymmetric alkylation of glycinate
imines.2,4 The results obtained with these catalysts were
improved by Lygo5 and Corey,6 who changed the N-
benzyl substituent to a bulkier 9-methylanthryl group
as shown in catalyst 2. In addition, Merrifield resin-
bound cinchonidine and cinchonine have been
employed as recoverable PTC catalysts.7 Furthermore,
non-Cinchona chiral catalysts, such as spiro ammon-
ium8 and phosphonium salts,9 TADDOL,10 binaphthyl-
derived amines10b,11 and salen–metal complexes12 have
also been used in asymmetric PTC alkylations.
Recently, dimeric13 and trimeric14 quaternary Cinchona
catalysts, derived from o-, m- or p-xylene dibromide 3,
and mesitylene tribromide 4, respectively, have been
employed as chiral PTC catalysts achieving good enan-
tioselectivities. In this context, we envisaged that good
results could be obtained with this type of Cinchona-
derived ammonium salts if a bulkier 9,10-dimethylan-
thryl group was employed as a bridge between the
alkaloid moieties, in analogy to Lygo’s and Corey’s
improvements relative to the monomeric catalysts.
N
+
N
+
O
N
2Br-
O
N
3
N
Br-
X-
3Br-
O
N
N
+
+
N
+
N
OR
OR
+
N
N
O
R = H, allyl, benzyl
R = H, allyl
X = F, Cl, Br
N
O
+
N
1
2
N
* Corresponding author. Tel.: +34-96-5903728; fax: +34-96-5903549;
e-mail: cnajera@ua.es
4
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00211-2

928
R. Chinchilla et al. / Tetrahedron: Asymmetry 13 (2002) 927–931
Thus, dimeric cinchonidine-derived ammonium salt
8a15 was prepared in 85% yield by reaction of 9,10-
di(chloromethyl)anthracene16 5 with cinchonidine 6 (2
equiv.) in EtOH/DMF/CHCl3 at 100°C17 (Scheme 1).
O(9)-Allylation of 8a with allyl bromide in 50%
aqueous KOH afforded the allylated ammonium salt
8b18 in 95% yield. In addition, cinchonine-derived cata-
lyst 919 was prepared in 80% yield following the same
methodology as for 8a but starting from cinchonine 7
(Scheme 1).
the OH group and the quinuclidine system, respectively.
Therefore, only one of the faces is free for coordination
with the formed glycine enolate.
These dimeric cinchonidine-derived ammonium salts 8
and 9 were employed as catalysts in the alkylation
reaction of glycine-derived N-(diphenylmethylene)-
glycine alkyl esters 10 with different halides in a bipha-
sic system formed from a mixture of toluene/CHCl3
and 50% aqueous KOH solution (Table 1). The ees of
the alkylated products 11 were measured by chiral GLC
analysis21 of the corresponding N-trifluoroacetamide
esters.22 The absolute configuration was assigned by the
relative retention times of both enantiomers determined
previously.7b
A PM3-optimized geometry20 for the dication of 8a
(Fig. 1) shows the blocking of the anthryl group of one
of the faces of the tetrahedron formed by the ammo-
nium ion, whereas the other two faces are blocked by
N
2
2 X-
N
OH
+
N
6
OR
+
N
N
RO
8a, R = H, X = Cl
N
Cl
CH2=CHCH2Br
aq KOH
8b, R = allyl, X = Br
N
HO
2 Cl-
Cl
2
N
+
5
N
HO
N+
7
N
OH
N
9
Scheme 1. Preparation of dimeric Cinchona quats.
Figure 1. PM3-optimized geometry for the dication of 8a.

R. Chinchilla et al. / Tetrahedron: Asymmetry 13 (2002) 927–931
Table 1. Enantioselective PTC alkylations
929
Ph
Ph
8 or 9 (5 mol%), 50% aq KOH
R2X
N
CO2R1
N
CO2R1
+
*
toluene/CHCl3
Ph
Ph
R2
10
11
Entry
R1
R2X
Catalyst
Temp. (°C)
Time (h)
Yield (%)a
Ee (%)b
Abs. Config.b
1
2
3
4
5
6
7
8
tBu
tBu
tBu
tBu
iPr
tBu
tBu
tBu
tBu
iPr
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
8a
8a
8a
8a
8a
8b
8b
8b
8b
8b
9
25
0
−20
−30
−20
25
3
6
12
24
9
0.5
1
1
6
3
1
7
15
2
18
2
9
10
2
11
2
–
95
88
75
65
95
98
84
72
98
95
90
85
76
98
90
97
90
60
70
76
67
–
75
86
86
86
89
60
70
80
86
80
73
86
86
78
90
85
84
68
42
70
62
–
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(S)
(S)
(S)
(S)
(R)
(S)
(S)
(S)
(S)
0
−20
−50
−20
25
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
9
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
2-NaphCH2Br
2-NaphCH2Br
8a
8b
8a
8b
9
8a
8b
8a
8b
8a
8b
4-CNC6H4CH2Br
4-CNC6H4CH2Br
4-CNC6H4CH2Br
CH2ꢀCHCH2Br
CH2ꢀCHCH2Br
CHꢁCCH2Br
CHꢁCCH2Br
CH3CH2CH2CH2I
CH3CH2CH2CH2I
11
65
32
(S)
a Isolated crude yield determined by 1H NMR (300 MHz).
b Determined by chiral GLC (Ref. 21).
The alkylation reaction of commercially available
glycine-derived ester 10 (R1=tBu) with benzyl bromide
as electrophile was used as a test reaction. Thus, when
the cinchonidine-derived 8a was employed under PTC
conditions, the reaction showed an ee of the alkylated
product (S)-11 higher when the reaction was performed
at 0°C (86%) than when the reaction was performed at
rt (75%) (Table 1, entries 1 and 2). However, no
influence on the ee was observed when the reaction
temperature was lowered at −20 or −30°C (Table 1,
entries 3 and 4). In contrast, when allylated cin-
chonidine derivative 8b was employed as catalyst, the
influence of the temperature was more remarkable and
the ee of (S)-11 was notably higher at −20°C (80%)
than at rt (60%) or 0°C (70%) (Table 1, entries 6–8),
lowering the temperature to −50°C being necessary to
match the ee achieved using 8a at −20°C (86%) (Table
1, entry 9). In addition, the reaction times using 8b were
considerably lower than when 8a was employed. Inter-
estingly, when the non-commercial isopropyl ester 10
(R1=iPr) was used as starting material,23 the enantiose-
lectivity of (S)-11 was slightly higher or similar than
when using the tert-butyl derivative 10 (R1=tBu), both
employing 8a or 8b (Table 1, entries 5 and 10). When
the cinchonine-derived ammonium salt 9 was used as
PTC catalyst, the enantiomeric alkylated product (R)-
11 was obtained with ees almost identical to when the
pseudoenantiomeric cinchonidine-derived ammonium
salt 8a was used (Table 1, compare entries 11 and 12
with entries 1 and 3).
When other benzylic, allylic and propargylic bromides
were employed as electrophiles using 10 (R1=tBu) as
starting material and a reaction temperature of −20°C,
a similar tendency of higher reactivity and lower enan-
tioselectivity of 8b compared to 8a was observed. Thus,
using 4-bromomethylbenzonitrile as electrophile, a 90%
ee for (S)-11 in 18 h using 8a compared to an 85% ee
in 2 h using 8b was obtained (Table 1, entries 15 and
16). In addition, when a non-activated electrophile such
as n-butyl iodide was used, no reaction was observed
when 8a was used as catalyst, whereas a 65% yield of
the corresponding (S)-11 was obtained using 8b,
although with low ee (Table 1, entries 22 and 23).
It can be concluded that dimeric anthracenyl-derived
Cinchona quaternary ammonium salts are effective cat-
alysts for the enantioselective alkylation of glycine
esters for the synthesis of (S)- and (R)-a-amino acids.
Typical alkylation procedure
A mixture of 10 (0.5 mmol) and the catalyst 8 or 9
(0.025 mmol) in toluene/CHCl3 (7/3 v/v, 2.5 mL) was
cooled (see Table 1) and aqueous 50% solution of KOH
(0.75 mL) was added. The mixture was vigorously
stirred and monitored by GLC. When the reaction was
finished, water (15 mL) was added and the mixture was
extracted with AcOEt (3×15 mL). The organics were
dried (Na2SO4) and evaporated in vacuo.

930
R. Chinchilla et al. / Tetrahedron: Asymmetry 13 (2002) 927–931
G. Tetrahedron 2001, 57, 2391–2402; (f) Lygo, B.;
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We thank the Ministerio de Educacio´n y Ciencia
(MEC) of Spain (DGICYT, research project PB97-
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CHCl3). IR (KBr) w 3396, 2947, 1643, 1585, 1468, 1063,
925, 776, 537 cm−1 1H NMR (300 MHz, DMSO-d6) l
.
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1.21–1.36 (2H, m), 1.71–1.91 (2H, m), 2.12–2.21 (2H, m),
2.68–2.76 (1H, m), 3.36–3.45 (1H, m), 3.54–3.68 (1H, m),
3.84–3.86 (1H, m), 4.44–4.69 (2H, m), 4.99–5.09 (2H, m),
5.68–5.78 (1H, m), 5.98–6.03 (1H, d, J=13.4), 6.58–6.62
(1H, d, J=13.4), 7.09 (1H, s), 7.46 (1H, s), 7.98–7.99 (4H,
m), 8.19–8.22 (1H, d, J=7.3), 8.69–8.71 (1H, d, J=8.5),
8.95–8.98 (1H, d, J=8.5) 9.08–9.10 (1H, d, J=4.9), 9.15–
9.18 (1H, d, J=8.5). 13C NMR (75 MHz, DMSO-d6) l
21.6, 24.6, 25.4, 37.2, 51.3, 54.3, 60.4, 64.9, 67.8, 116.4,
120.4, 124.3, 124.6, 126.0, 126.9, 126.9, 127.2, 129.5,
129.8, 133.0, 133.0, 138.6, 145.8, 147.7, 150.3. MS (ESI)
828 [M−Cl]+.
16. Prepared by bubbling HCl(g) through a solution of
anthracene and paraformaldehyde in dioxane: Miller, M.
W.; Amidon, R. W.; Tawney, P. O. J. Am. Chem. Soc.
1955, 77, 2845–2848.

R. Chinchilla et al. / Tetrahedron: Asymmetry 13 (2002) 927–931
931
17. Baba, N.; Oda, J.; Kawaguchi, M. Agric. Biol. Chem.
1986, 50, 3113–3117.
8.18–8.22 (1H, d, J=8.5), 8.74–8.77 (1H, d, J=7.3), 8.85
(1H, m), 9.08–9.10 (1H, d, J=4.9), 9.15 (1H, m). 13C
NMR (75 MHz, DMSO-d6) l 21.8, 24.5, 26.8, 37.7, 54.7,
55.8, 57.7, 66.9, 68.1, 117.6, 121.4, 125.4, 125.7, 127.7,
127.8, 128.1, 128.3, 130.6, 130.8, 133.9, 134.2, 139.0,
146.6, 148.8, 151.3. MS (ESI) 828 [M−Cl]+.
18. Compound 8b: mp 156°C. [h]2D5 −282 (c 1, CHCl3). IR
(KBr) w 3402, 3073, 2936, 1589, 1515, 1450, 1066, 924,
765 cm−1 1H NMR (300 MHz, DMSO-d6) l 1.43–1.47
.
(1H, m), 1.95 (1H, m), 2.07 (1H, m), 2.21 (1H, m), 2.36
(1H, m), 2.81 (1H, m), 3.56 (2H, m), 3.72–3.80 (1H, m),
3.89–3.99 (3H, m), 4.27–4.30 (2H, m), 4.47–4.63 (2H, m),
4.99–5.07 (1H, m), 5.14–5.31 (1H, m), 5.41–5.53 (1H, m),
5.64–5.82 (1H, m), 5.88–6.10 (1H, m), 6.23–6.36 (1H, m),
6.57–6.62 (1H, d, J=13.4), 7.08 (1H, s), 7.68–7.69 (1H,
m), 7.76–7.97 (3H, m), 8.14–8.24 (1H, m), 8.66 (1H, m),
9.02–9.03 (1H, d, J=4.9), 9.12 (1H, d, J=3.7), 9.23–9.25
(1H, d, J=7.3). 13C NMR (75 MHz, DMSO-d6) l 20.5,
24.5, 25.6, 36.8, 51.5, 54.5, 60.1, 67.5, 69.2, 71.9, 116.5,
117.3, 119.6, 123.4, 124.6, 125.4, 126.1, 127.2, 129.8,
129.9, 132.9, 133.2, 134.0, 137.8, 138.4, 140.9, 141.2,
148.0, 148.1, 150.2. MS (ESI) 952 [M−Br]+.
20. Performed using the PC GAMESS version (Granovsky,
A. A. http://classic.chem.msu.su/gran/gamess/index.html)
of the GAMESS (US) QC package: Schmidt, M. W.;
Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M.
S.; Jensen, J. J.; Koseki, S.; Matsunaga, N.; Nguyen, K.
A.; Su, S.; Windus, T. L.; Dupuis, M.; Montgomery, J.
A. J. Comput. Chem. 1993, 14, 1347–1363.
21. Chirasil-LVal (Chrompack), 1 min 85°C, 2°C/min to
180°C. Reference racemic samples were prepared using
tetrabutylammonium bromide as phase-transfer catalyst.
22. Obtained after HCl(g)/Et2O hydrolysis of the imine and
further reaction with trifluoroacetic anhydride: Oppolzer,
W.; Moretti, R.; Zhou, C. Helv. Chim. Acta 1994, 77,
2363–2380.
19. Compound 9: mp 194°C (decomp.). [h]2D5 +400 (c 0.5,
CHCl3). IR (KBr) w 3389, 3187, 2946, 1636, 1589, 1454,
1
1060, 931, 780, 541 cm−1. H NMR (300 MHz, DMSO-
23. Prepared in 80% overall yield by reaction of glycine with
thionyl chloride in the presence of isopropanol: Patel, R.;
Price, S. J. Org. Chem. 1965, 30, 3575–3576; followed by
treatment of the crude with benzophenone imine: O’Don-
nell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663–
2666.
d6) l 1.66 (2H, m), 1.75 (2H, m), 2.26–2.34 (1H, m),
2.76–2.84 (1H, m), 3.19–3.21 (1H, d, J=6.1), 3.45–3.61
(1H, m), 4.02–4.19 (2H, m), 4.38 (1H, m), 4.51 (1H, m),
5.05–5.10 (1H, m), 5.16–5.19 (1H, d, J=9.8), 5.89–6.01
(1H, m), 6.07–6.11 (1H, d, J=13.4), 6.39–6.44 (1H, d,
J=13.4), 7.00 (1H, s), 7.61 (1H, s), 7.90–7.99 (4H, m)