Cyclopeptoids as phase-transfer catalysts for the enantioselective synthesis of α-amino acids

Article abstract of DOI:10.1002/ejoc.201403224

The first application of cyclopeptoids in asymmetric phasetransfer catalysis was examined. A small library of nine alternating N-substituted-glycine and proline hexacyclopeptoids was tested in the enantioselective alkylation of N-(diphenyl-methylene)glyci

Full text of DOI:10.1002/ejoc.201403224

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403224
Cyclopeptoids as Phase-Transfer Catalysts for the Enantioselective Synthesis
of α-Amino Acids
Rosaria Schettini,[a] Brunello Nardone,[a] Francesco De Riccardis,[a] Giorgio Della Sala,*[a]
and Irene Izzo*[a]
Keywords: Organocatalysis / Asymmetric catalysis / Phase-transfer catalysis / Peptidomimetics / Cyclopeptoids
The first application of cyclopeptoids in asymmetric phase-
transfer catalysis was examined. A small library of nine alter-
nating N-substituted-glycine and proline hexacyclopeptoids
was tested in the enantioselective alkylation of N-(diphenyl-
methylene)glycine tert-butyl ester. The presence of an N-ar-
ylmethyl side chain in the catalyst was found to be crucial
for the synthesis of α-amino acids with up to 73%ee.
and biphenyl-modified Maruoka quaternary ammonium
salts.[8,9] Quaternary ammonium salts based on different
chiral scaffolds have rarely gained the status of efficient cat-
alysts.[10–13] An accurate survey of the pertinent literature
shows that, in most cases, the alkylation of glycine ester
derivatives results in modest enantioselectivities.[14] More-
over, thermal lability in the presence of bases/nucleophiles
seriously limits the application of quaternary ammonium
salts for industrial purposes.[15] More stable metal complex-
ing catalysts, such as crown ethers and open-chain poly-
ethers, could offer a valid alternative;[15] however, this type
of catalyst has been poorly investigated in asymmetric
phase-transfer catalysis[16–19] and very few examples are re-
ported for the asymmetric alkylation of glycine derivatives.
In one case, an achiral crown ether was successfully used as
a co-catalyst in the presence of chiral ammonium salts,[20]
whereas more recently, Takizawa and co-workers developed
spiro chiral crown ethers that promoted benzylation with
low to moderate enantioselectivities.[19] In other examples,
different macrocyclic catalysts, such as calixarenes, have
been used merely as scaffolds for anchoring an ammonium
salt group without exploiting potential metal complexing
properties.[21] Considering the vivacity of this intellectual
arena and pondering the well-explored complexation,[22] bi-
layer transport,[23] and phase-transfer catalysis abilities[24]
of cyclopeptoids (cyclic oligomers of N-substituted glyc-
ines),[25] we decided to test them as possible PTCs for the
enantioselective synthesis of amino acids. Compared to
other catalysts, the core structures of which are fixed by
nature or human inventiveness, cyclopeptoids, for their
modular synthesis, have the advantage to display a poten-
tially immense degree of diversity. Moreover, the solid-
phase synthetic approach that we used for their construc-
tion allows quick preparation, no tedious workup/purifica-
tion, and a potentially automated process. These properties
make cyclopeptoids ideal candidates for the exploration of
Introduction
Phase-transfer catalysis is green methodology that is
largely employed in industry and organic synthesis.[1,2] The
preparation of optically active α-amino acids derivatives,
for its simplicity and intrinsic formal elegance, represents
one of the most reliable applications of phase-transfer catal-
ysis.[3] The asymmetric approach introduced by O’Donnell
and co-workers[3d] based on the selective monoalkylation of
benzophenone imines of glycine alkyl esters 1 (Scheme 1)
is paradigmatic and has gained the status of a benchmark
reaction for testing the performance of new phase-transfer
catalysts (PTCs).
Scheme 1. Alkylation of glycine anion equivalents.
Generally, quaternary ammonium salts have been proven
to be the catalysts of choice for such reactions and both
natural and non-natural derivatives have been utilized to
afford products with moderate to excellent enantiomeric ex-
cess values.[2,3] Since their first report in 1989,[4] the Cin-
chona quaternary ammonium salts have been the leading
class of chiral catalysts employed for this reaction and excel-
lent enantioselectivities have been reported by the groups of
O’Donnell,[4] Lygo,[5] and Corey.[6] These results drove sev-
eral groups to test ingeniously modified Cinchona alkaloids
as catalysts.[7] Valid alternatives are the efficient binaphthyl-
[a] Dipartimento di Chimica e Biologia, Università degli Studi di
Salerno,
Via Giovanni Paolo II, 132
E-mail: gdsala@unisa.it
iizzo@unisa.it
http://www.unisa.it/dipartimenti/dip_chimica_e_biologia/index
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403224.
Eur. J. Org. Chem. 2014, 7793–7797
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7793

R. Schettini, B. Nardone, F. De Riccardis, G. Della Sala, I. Izzo
SHORT COMMUNICATION
vast chemical spaces for the discovery of new catalysts. Not- in the selection of the appropriate enantioface of the sub-
withstanding all the reported advantages, and to the best of strate, for example, through the formation of π–π interac-
our knowledge, there is only one example of a peptoid that tions.
has been used in asymmetric catalysis.[26] In this communi-
cation, we report the first example of chiral cyclopeptoids
as PTCs and highlight their potential in asymmetric synthe-
Table 1. Benzylation of N-(diphenylmethylene)glycine tert-butyl es-
ter (7) by using first-generation catalysts.[a]
sis.
Results and Discussions
In our previous investigation, chiral hexameric cyclic
Entry
Catalyst
T [°C]
Yield [%]
ee [%][b,c]
peptoid 3 containing alternating l-proline and N-methoxy-
ethyl glycine residues (Figure 1) showed very high affinity
for alkali metals, and in the solid state, it formed an intri-
guing triple decker Na+ complex.[22b] Taking advantage of
the same synthetic scheme, cyclohexameric peptoids 4–6
(Figure 1) containing l-proline residues were prepared. Li-
pophilicity (benzyl and n-hexyl appendages) or cation affin-
ity (methoxyethyl and methoxyethoxyethyl pendant groups)
dictated the choice of N-alkyl side chains.[24]
1
6
6
6
6
3
4
5
r.t.
r.t.
0
0
0
0
0
29
28
36
54
11
66
36
14 (R)
rac
29 (R)
38 (R)
8 (S)
10 (S)
10 (S)
2[d]
3
4[e]
5[e]
6[e]
7[e]
[a] All reactions were performed in a liquid–liquid system for 20 h
on a 0.08 mmol scale by using 7 (1.0 equiv.), benzyl bromide
(1.2 equiv.), and catalyst (5 mol-%) in toluene (0.8 mL), with 50%
aq. NaOH (0.5 mL), unless otherwise stated. [b] Determined by
HPLC by using a Chiralcel OD-H chiral stationary phase. [c] The
absolute configuration of 8a was determined by comparison of the
HPLC retention time and optical rotation with literature val-
ues.[6,7b] [d] Solid NaOH (3 equiv.) was used. [e] The reaction was
performed under an inert atmosphere after deoxygenation of the
two phases.
To prove the necessity of the base-stable tert-butyl ester
in the glycine substrate, we submitted commercially avail-
able glycine ethyl ester benzophenone imine 1 (R = Et) to
the alkylation conditions developed for 7. However, after
the canonical 20 h reaction (in the presence of catalyst 6),
complete hydrolysis of the ethyl ester was observed.
Moreover, with the purpose of demonstrating the rele-
vance of the peptoid cyclization for the catalytic activity
and enantioselectivity, we performed Cα-alkylation in the
presence of acyclic peptoid 9 (Scheme 2). Although the re-
action proceeded in good yield, the enantioselectivity was
low. This observation served to point out the significance
of the conformational restrictions of the macrocycle in the
facial stereodifferentiation.
Figure 1. First-generation catalysts.
The ability of cyclopeptoids 3–6 to serve as PTCs was
tested in the benzylation of N-(diphenylmethylene)gly-
cine tert-butyl ester (7, Table 1). Initially, the reactions were
performed for 20 h in a toluene/50% NaOH liquid–liquid
biphasic system under aerobic conditions at a catalyst load-
ing of 5 mol-%. The studies started with cyclopeptoid 6.
At room temperature, the (R)-α-amino acid derivative was
obtained with low enantiomeric excess (ee; Table 1, entry 1),
whereas a racemic product was recovered under liquid–solid
conditions (Table 1, entry 2). To improve the low ee ob-
served in the liquid–liquid biphasic system, the reaction was
conducted at 0 °C. As expected, the lower temperature had
a beneficial effect on the enantioselectivity, possibly owing
to a decrease in the conformational flexibility of the catalyst
(Table 1, entry 3). In any case, at both room temperature
and 0 °C, partial decomposition of the starting material was
observed and benzophenone was recovered as a side prod-
uct.[27] For this reason, in a subsequent trial, an inert atmo-
sphere and deoxygenation of the organic and aqueous
phases was performed by taking advantage of anaerobic
conditions (Table 1, entry 4). In this way, both the yield and
the ee were improved. Aliphatic cyclopeptoids 3–5 were
tested under the same conditions (Table 1, entries 5–7). Un-
fortunately, even if the N-methoxyethoxyethyl chain proved
to be beneficial in terms of yield, for all the macrocycles low
ee values resulted. Interestingly, enantioselectivity inversion
Scheme 2. Benzylation of N-(diphenylmethylene)glycine tert-butyl
ester (7) catalyzed by acyclic peptoid 9. Fmoc = 9-fluorenylmeth-
oxycarbonyl.
Considering the promising performance of compound 6
was observed in the presence of these catalysts. This behav- containing the N-benzyl pendant group, it was decided to
ior reveals the decisive role played by the aromatic groups graft the aromatic ring with groups inducing different steric
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Eur. J. Org. Chem. 2014, 7793–7797

Cyclopeptoids in the Enantioselective Synthesis of α-Amino Acids
and electronic effects. In this way, a second generation of Table 2. Benzylation of N-(diphenylmethylene)glycine tert-butyl es-
ter (7) by using second-generation catalysts with different bases and
catalysts was designed and promptly synthesized (see com-
pounds 10–14, Figure 2).
solvents.[a,b]
Entry Cat. Solvent
Base
Yield [%] ee [%][c,d]
1
2
3
4
10 toluene
11 toluene
12 toluene
13 toluene
14 toluene
14 toluene
14 CH2Cl2
14 CHCl3
14 mesitylene
14 o-xylene
14 m-xylene
14 p-xylene
14 chlorobenzene
14 ethyl ether
14 toluene/CHCl3 (7:3) 50% NaOH
14 toluene/CHCl3 (9:1) 50% NaOH
14 toluene/CH2Cl2 (7:3) 50% NaOH
14 toluene
14 toluene
14 toluene
14 toluene
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
7
30 (R)
28 (R)
61 (R)
48 (R)
67 (R)
37 (R)
8 (R)
8 (R)
rac
16 (R)
2 (R)
35 (R)
4 (S)
30 (R)
14 (R)
33 (R)
11 (R)
50 (R)
5 (R)
65
77
53
64
53
38
14
68
51
12
16
63
11
50
54
54
50
7
5
6[e]
7
8
9
10
11
12
13
14
15
16
17
18
19[f]
20[g]
21[f,g]
50% KOH
66% CsOH
CsOH·H2O (s)
CsOH·H2O (s)
86
7
14 (R)
16 (R)
Figure 2. Second-generation catalysts.
[a] All reactions were performed in a liquid–liquid system for 20 h
at 0 °C on a 0.08 mmol scale by using 7 (1.0 equiv.), benzyl bromide
(1.2 equiv.), and catalyst (5 mol-%) in organic solvent (0.8 mL),
with 50% aq. NaOH (0.5 mL), unless otherwise stated. [b] All reac-
tions were performed under an inert atmosphere by deoxygenating
the two phases. [c] Determined by HPLC by using a Chiralcel OD-
H chiral stationary phase. [d] The absolute configuration of 8a was
determined by comparison of the HPLC retention time and optical
rotation with literature values.[6,7b] [e] Toluene (1.6 mL). [f] The re-
action was performed at –20 °C. [g] CsOH·H2O (5.0 equiv.).
All the new macrocycles were used under the best condi-
tions observed for compound 6 (Table 1, entry 4). As can be
seen in Table 2, compounds 10 and 11 containing electron-
withdrawing groups proved to be less efficient, and they
gave lower ee values (Table 2, entries 1 and 2). The steric
hindrance of the 1-naphthyl group on the side chain (cata-
lyst 12; Table 2, entry 3) gave a better ee value and a better
yield. On the other hand, the presence of the weak electron-
donating p-methoxy substituent (catalyst 13; Table 2, en-
try 4) proved to ameliorate only the ee value. Finally, and
to our delight, the ee was improved by using compound
14 containing two methyl groups on the benzyl group, and
although the value was moderate, this result is significant
if compared with those observed for the few macrocyclic
catalysts reported to date.[19] Then, an exhaustive study of
the reaction parameters was performed. The use of more
dilute conditions resulted in a worse performance of cata-
lyst 6 (Table 2, entry 6). An extensive screening of the sol-
vents was performed (Table 2, entries 7–17), and toluene
was the optimal solvent. In addition, some experiments per-
formed with aqueous KOH and CsOH revealed a relevant
effect of the base (Table 2, entries 18 and 19). NaOH gave
a better ee value than the other two hydroxides. Very low
ee values were also obtained with solid CsOH·H2O both at
0 and –20 °C (Table 2, entries 20 and 21).
Table 3. Reaction of N-(diphenylmethylene)glycine tert-butyl ester
(7) with different alkylating agents by using second-generation cat-
alyst 14.[a,b]
Entry RBr
Product Time Yield ee
[h]
[%]
[%][c,d]
1
2
3
4
5
6
benzyl bromide
8a
8b
8c
8d
8e
20
5
64
86
62
62
66
60
53
55
67 (R)
57 (R)
60 (R)
45 (R)
73 (R)
60 (R)
47 (R)
55 (R)
4-nitrobenzyl bromide
4-fluorobenzyl bromide
4-cyanobenzyl bromide
4-methylbenzyl bromide
3,5-dimethylbenzyl bromide 8f
4-(tert-butyl)benzyl bromide 8g
24
45
24
18
24
23
Other alkylating agents were tested to expand the scope
of the alkylation reaction. As shown in Table 3, yields and
ee values were comparable to those obtained with benzyl
bromide (and in some cases were improved). The best ee
value was achieved with 4-methylbenzyl bromide (Table 3,
entry 5).
Finally, we checked the stability of our macrocyclic cata-
lyst to possible base-induced epimerization (conscious of
the strongly basic reaction conditions). After running the
reaction in toluene/50% NaOH we performed an accurate
7
8[e]
allyl bromide
8h
[a] All reactions were performed in a liquid–liquid system for 20 h
at 0 °C on a 0.08 mmol scale by using 7 (1.0 equiv.), benzyl bromide
(1.2 equiv.), and catalyst (5 mol-%) in toluene (0.8 mL), with 50%
aq. NaOH (0.5 mL), unless otherwise stated. [b] All reactions were
performed under an inert atmosphere by deoxygenating the two
phases. [c] Determined by HPLC by using a Chiralcel OD-H chiral
stationary phase. [d] The absolute configurations of products 8a–e,
8g, and 8h were determined by comparison of the HPLC retention
times and optical rotations with literature values[6,7b] and for 8f by
flash chromatography and recovered C3 symmetric cyclo- analogy with known products. [e] Allyl bromide (1.5 equiv.).
Eur. J. Org. Chem. 2014, 7793–7797
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7795

R. Schettini, B. Nardone, F. De Riccardis, G. Della Sala, I. Izzo
SHORT COMMUNICATION
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Conclusions
In conclusion, we reported the first example of the use
of chiral cyclopeptoids in asymmetric phase-transfer cataly-
sis and showed their potential in enantioselective catalysis.
The enantiomeric excess values shown in the alkylation re-
actions of glycine derivative were moderate, but the results
obtained are remarkable considering the very few examples
reported with metal-complexing catalysts. Moreover, these
macrocycles appear to be promising phase-transfer cata-
lysts, as their modular structure and the solid-phase syn-
thetic approach are especially suitable for constructing li-
braries of different compounds for combinatorial catalyst
screening, for instance, by varying the number, the position,
and the nature of each residue.[29] Studies devoted to im-
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Cyclopeptoids in the Enantioselective Synthesis of α-Amino Acids
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[27] The decomposition of a related substrate under aerobic phase-
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[28] For details, see the Supporting Information. The retention time
was the same as that obtained with cyclopeptoid 14.
[29] In this respect, studies are underway by our group to evaluate
the effect of the substitution of proline and N-alkylglycine resi-
dues with different α-amino acids and derivatives.
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Received: September 17, 2014
Published Online: November 10, 2014
Eur. J. Org. Chem. 2014, 7793–7797
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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