Combining chiral elements in asymmetric phase-transfer catalysts: Styrene oxide and chiral α,α-disubstituted pyrroline and piperidine derived structures

Article abstract of DOI:10.1016/j.tetlet.2005.10.141

A new asymmetric phase-transfer catalyst, designed by combining the chiral building blocks styrene oxide and 2,5-dimethylpyrroline, is described. Catalytic testing using standard glycine imino ester alkylations shows good yields and moderate to good enant

Full text of DOI:10.1016/j.tetlet.2005.10.141

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 57–60
Combining chiral elements in asymmetric phase-transfer
catalysts: styrene oxide and chiral a,a-disubstituted pyrroline
and piperidine derived structures
Gregory N. Grover, Walter E. Kowtoniuk and Darren K. MacFarland*
Department of Chemistry, Gettysburg College, 300 North Washington Street, Gettysburg, PA 17325, USA
Received 19 October 2005; accepted 26 October 2005
Available online 21 November 2005
Abstract—A new asymmetric phase-transfer catalyst, designed by combining the chiral building blocks styrene oxide and 2,5-di-
methylpyrroline, is described. Catalytic testing using standard glycine imino ester alkylations shows good yields and moderate to
good enantioselectivities with a surprising change in enantioselectivity over the course of the reaction. Alkylation of the b-hydroxyl
group lead to catalysts with improved selectivity and a larger change in enantioselectivity during the reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Asymmetric phase-transfer catalysis offers a powerful
method for many reactions, including the synthesis of
unnatural amino acids.1–8 Early work focused on
Cinchona derivatives,1–8 though recent reports have
described successes with binaphthyl1–7,9 and other10–14
stereogenic centers. MaroukaÕs state-of-the-art catalyst
now gives remarkable results in a variety of phase-trans-
Figure 1. Catalysts 1a,b, 2a, and 2b.
fer catalyzed reactions, but is limited by a lengthy
synthetic route.
very direct, just two steps from amines prepared by litera-
We now present, a novel design approach in which we
ture methods.
have multiple chiral centers derived from combining dif-
ferent chiral elements.15 We have combined enantiopure
styrene oxide, with chiral, a,a0-disubstituted amines,
2,5-dimethyl pyrroline, and 2,6-dimethylpiperidine;16
2. Results and discussion
following methylation, this yields catalysts with ammo-
Styrene oxide was chosen as a design element for its
nium groups surrounded by three controlled chiral
ready ability to combine with amines, the commercial
centers and a b-hydroxy group (Fig. 1). This provides
availability of both pure enantiomers, and the b-alcohol
left after ring opening. A hydroxyl group in a position to
have an interaction with the substrate in addition to the
electrostatic interaction has been hypothesized to be
important to achieving selectivity dating back to the ori-
ginal Cinchona catalysts.5,8 However, in our results, we
found that the hydroxyl group was converted to an ether
under catalysis conditions (vide infra).
two different influences on the catalyst–substrate inter-
action: the chiral b-alcohol and the chiral a-carbons
on the amine ring. We hope that if the different groups
are properly aligned, they may enhance substrate bind-
ing by working cooperatively, thus providing maximum
enantioselectivity. In addition, our synthetic route is
*
2,5-Dimethylpyrroline and 2,5-dimethylpiperidine were
chosen as the chiral amines because they have chiral
Corresponding author. Tel.: +1 717 337 6260; fax: +1 717 337
6270; e-mail: dmacfarl@gettysburg.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.141

58
G. N. Grover et al. / Tetrahedron Letters 47 (2006) 57–60
centers a to the amine, bringing the asymmetry close to
the ammonium center, which is presumably the primary
point of binding with the enolate intermediate. The
aminesÕ C2 symmetry insures that the ammonium itself
will not be chiral, removing the possibility of additional
uncontrolled stereocenters. Resolution of the racemic
mixture of either amine allows access to both enantio-
mers, which in turn allows access to both diastereomeric
pairs of the catalyst.17,18
Figure 2. Synthetic scheme for catalysts 1 and 2. (i) Ca(OTf)2, MeCN,
reflux 3 days. (ii) MeI, CHCl3, reflux 3 days. Use of (R)-styrene oxide
yields the isomers 1b and 2b.
Combination of the chiral moieties is accomplished by
ring opening of the epoxide with the amine and a
Ca(OTf)2 catalyst (Fig. 2).16 The synthesis is finished
by reaction with MeI.15 Column chromatography easily
separates the quaternized product from any unreacted
starting materials.
After initial catalytic trials showed a dramatic swing in
enantioselectivity over the course of the one-hour reac-
tion time, we devised alkylated catalysts 3–5. Alkylated
catalysts were synthesized under the same conditions
that the catalytic trials were run, namely one hour at
0 °C with a 20-fold excess of alkyl halide (Fig. 3). We
were surprised to have the reaction run to completion
under such mild conditions, even with bulky alkyl
Figure 3. Synthetic scheme for catalysts 3–5.
halides such as 9-(bromomethyl)anthracene, but yields
1
were uniformly good and H NMR spectra showed no
trace of starting material.
Table 1. Results of glycine imino ester alkylation with various alkyl halides at 0 °C
Entry
Catalyst
Alkyl halide
Solvent
Catalyst loading (%)
Time (min)
Enantioselectivity (ee%)a
Completion (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
2a
2a
2a
2a
2b
2b
2b
2b
2-(CH3)BnBr
2-(CH3)BnBr
2-(CH3)BnBr
2-(CH3)BnBr
2-(CH3)BnBr
2-(CH3)BnBr
BnBr
CH2Cl2
CH2Cl2
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
5
5
5
1
1
1
1
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
10
60
10
60
10
60
10
60
10
60
10
60
10
60
20
60
10
60
10
60
10
60
10
60
10
60
10
60
10
60
10
60
10
60
22.4
ꢀ34.7
64.8
ꢀ33.7
ꢀ18.6
21.7
ꢀ0.5
ꢀ5.8
7.0
21.5
12.3
9.8
21.2
8.57
100
11.2
95.2
23.2
67.7
41.9
72.4
2.0
88.2
3.7
84.7
3.1
39.7
68.3
92.8
33.3
88.3
50.8
75.5
18.9
67.9
9.3
38.9
1.4
88.1
9.4
62.1
10.2
63.4
27.3
64.1
6.0
BnBr
9
4-(CH3)BnBr
4-(CH3)BnBr
MeI
MeI
Allyl Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
Allyl Br
18.7
21.9
2-(CH3)BnBr
2-(CH3)BnBr
2-(CH3)BnBr
2-(CH3)BnBr
BnBr
ꢀ11.1
50.3
5.6
49.1
49.4
ꢀ81.0
ꢀ13.0
1.4
BnBr
4-(CH3)BnBr
4-(CH3)BnBr
Allyl Br
Allyl Br
MeI
MeI
BnBr
BnBr
2-(CH3)BnBr
2-(CH3)BnBr
BnBr
BnBr
2-(CH3)BnBr
2-(CH3)BnBr
ꢀ0.5
0.7
ꢀ2.5
38.7
ꢀ23.8
30.5
ꢀ22.6
ꢀ32.1
ꢀ6.2
38.6
ꢀ43.5
58.2
a Enantioselectivity and completion determined by HPLC on a Chiracel OD-H column. Negative enantioselectivities refer to selectivity for the
opposite enantiomer.

G. N. Grover et al. / Tetrahedron Letters 47 (2006) 57–60
59
selectivity swing; quite to the contrary an even larger
swing in enantioselectivity was observed with both the
benzyl (3) and methylnaphthyl (4) derivatives (Table 2,
see entries 1 and 2 or 13 and 14). The 9-methylanthra-
cene derivative 5 showed almost no enantioselectivity,
so correspondingly no swing was observed. The large
size of the anthracenyl group may prohibit close contact
between the catalyst and enolate, removing any pathway
for selectivity.
Figure 4. General scheme for glycine imino ester alkylation.
Catalytic competency was established using standard
literature procedures for the alkylation of glycine imino
ester 6 (Fig. 4).15 Initial results using the hydroxyl cata-
lysts 1a, b, 2a, and 2b showed promising enantioselectiv-
ity, but also a surprising change in enantioselectivity
over time (Table 1). This was not a simple degradation
toward a racemic mixture, but rather a change in prefer-
ence from one product enantiomer to the other. For
example, the enantioselectivity for alkylation with
2-methylbenzyl bromide (entries 3 and 4) at 10 min is
nearly 65% ee, but at 60 min is almost 34% ee for the
opposite enantiomer. While this effect is not observed
for all halides, it is interesting and led us to consider pos-
sible mechanisms.
Perhaps, the change in selectivity could be explained by
the buildup of bromide ion as the reaction progressed.
To test this possibility, we added CsBr (30 equiv) to
the reaction mixture (Table 2, entries 23–26). The shift
in selectivity was indeed muted, but the larger enantio-
selectivity observed at the end of the reaction was not
observed. Thus, the counterion may play a role in the
function of the catalyst, but it is only a contributing
factor.
3. Conclusions
The obvious route for a change in the catalyst is alkyl-
ation of the hydroxyl group, which removes a potential
site for substrate binding and simultaneously changes
the steric environment. The potential of this change
was explored by establishing that alkylation does take
place under catalysis reaction conditions (vide supra).
Thus, compounds 3–5 were synthesized to create a fam-
ily with increasing steric bulk attached to the oxygen
(Fig. 3). However, alkylation did not stop the enantio-
A new design for asymmetric phase-transfer catalysts
has been discussed, and the synthetic scheme and cata-
lytic competency established. In addition to decent
enantioselectivities, an interesting shift in enatioselectiv-
ity during the reaction was observed. Alkylation of the
b-hydroxyl group was established to occur under reac-
tion conditions, but this was not responsible for the
enantioselectivity shift.
Table 2. Results of glycine imino ester alkylation with various alkyl halides at 0 °C using alkylated catalysts 3–5
Entry
Catalyst
Alkyl halide
Solvent
Catalyst loading (%)
Time (min)
Enantioselectivity (ee%)a
Completion (%)
1
2
3
4
5
6
7
8
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
5
5
5
5
4
4
4
4
BnBr
BnBr
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CH2Cl2
Toluene
Toluene
5
5
5
5
5
5
0.5
0.5
0.5
0.5
5
5
5
5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
5
10
60
10
60
10
60
10
120
10
120
10
60
10
60
10
240
10
120
10
120
10
120
10
66.4
ꢀ51.1
39.4
20.8
100
7.15
100
6.1
100
5.1
59.0
2.6
50.6
5.7
83.5
5.4
63.4
0.6
75.0
15.6
59.0
4.5
2-(CH3)BnBr
2-(CH3)BnBr
4-(CH3)BnBr
4-(CH3)BnBr
BnBr
ꢀ58.6
21.4
23.2
ꢀ8.7
BnBr
2.4
9
2-(CH3)BnBr
2-(CH3)BnBr
BnBr
ꢀ14.2
1.6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2.5
BnBr
ꢀ29.1
2-(CH3)BnBr
2-(CH3)BnBr
BnBr
66.7
ꢀ68.9
ꢀ32.0
4.4
BnBr
2-(CH3)BnBr
2-(CH3)BnBr
BnBr
95.4
ꢀ29.8
ꢀ3.5
1.7
BnBr
54.2
4.6
2-(CH3)BnBr
2-(CH3)BnBr
2-(CH3)BnBr–CsBr
2-(CH3)BnBr–CsBr
2-(CH3)BnBr–CsBr
2-(CH3)BnBr–CsBr
ꢀ21.6
6.1
60.2
11.6
100
11.8
100
ꢀ26.4
ꢀ23.0
ꢀ36.9
ꢀ26.5
5
0.5
0.5
60
10
120
a Enantioselectivity and completion determined by HPLC on a Chiracel OD-H column. Negative enantioselectivities refer to selectivity for the
opposite enantiomer.

60
G. N. Grover et al. / Tetrahedron Letters 47 (2006) 57–60
6. Ooi, T.; Takeuchi, M.; Kameda, M.; Marouka, K. J. Am.
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Acknowledgment is made to the Donors of the American
Chemical Society Petroleum Research Fund for support
of this research (Grant #37788-B1), Merck Research
Laboratories, and the Albaugh Fund.
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Included within the supplemental data are detailed
procedures and spectroscopic data. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2005.10.141.
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