Chiral chalcogen peptides as ligands for the catalytic enantioselective aryl transfer reaction to aldehydes

Article abstract of DOI:10.1002/ejoc.201000237

A new series of chiral chalcogen peptides were synthesized from, inexpensive and commercially available starting materials. The synthesized compounds were tested as catalysts in the enantioselective arylation of aldehydes by using aryloronic acids as the aryl source. The desired diarylmethanols were obtained in excellent yields and with enantioselectivities up to 91% ee.

Full text of DOI:10.1002/ejoc.201000237

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000237
Chiral Chalcogen Peptides as Ligands for the Catalytic Enantioselective Aryl
Transfer Reaction to Aldehydes
Ricardo S. Schwab,[a] Letiere C. Soares,[a] Luciano Dornelles,[a] Oscar E. D. Rodrigues,*[a]
Márcio W. Paixão,[b] Marcelo Godoi,[c] and Antonio L. Braga*[c]
Keywords: Asymmetric synthesis / Chalcogen peptides / Arylboronic acids / Diarylmethanols / Organozinc reagents /
Selenium
A new series of chiral chalcogen peptides were synthesized
from inexpensive and commercially available starting mate-
rials. The synthesized compounds were tested as catalysts in
the enantioselective arylation of aldehydes by using aryl-
boronic acids as the aryl source. The desired diarylmethanols
were obtained in excellent yields and with enantioselectivi-
ties up to 91% ee.
Introduction
The addition of organometallic reagents to carbonyl
compounds is one of the most important carbon–carbon
bond-forming processes in synthetic organic chemistry.[1]
The enantioselective nature of this reaction provides par-
ticularly useful access to chiral secondary alcohols, which
are important building blocks and ubiquitous subunits
present in many biologically active compounds as well as
in medicinal applications. In this context the asymmetric
arylation of aldehydes in the presence of a chiral ligand has
received special attention[2] since it affords access to chiral
diarylmethanols,[3] which are useful intermediates in the
synthesis of bioactive compounds and natural products.[4]
The application of boronic acids as a nucleophilic aryl
species source, through a boron/zinc[5] exchange, is the most
commonly used protocol to afford the respective diaryl-
methanols. This method allows the exploitation of a broad
range of substituted aryl transfer reagents, since a large
number of arylboronic acids are commercially available.
Another interesting feature of this reaction is that both
enantiomers of a given product can be prepared by using
the same chiral ligand, simply with an appropriate choice
of the reaction partners: arylboronic acid and aldehyde
(Scheme 1).
Scheme 1. Catalytic arylation of aldehydes with arylboronic acids.
Despite the potential usefulness of this protocol, the
asymmetric version of this addition is a dynamic field. The
design of catalysts for the enantioselective addition of or-
ganozinc reagents to aldehydes has been the focus of inten-
sive research. However, only a few efficient catalysts have
been developed for this purpose, and most of them are
based on bidentate compounds. Successful results for the
synthesis of optically active diarylmethanols have been ob-
tained mainly by using chiral β-amino alcohols.[6] Further-
more, the efficient application of ligands bearing organo-
chalcogen moieties are still rare. Recently, the use of chiral
amino sulfides for this purpose has been described, afford-
ing the desired product with high yields and selectivities
(Figure 1).[7]
However, to the best of our knowledge, the application
of chiral selenium-based compounds as catalysts for the
enantioselective addition of PhZnEt to carbonyl com-
pounds is not common, and only the ligand developed by
Bolm et al.[8] has been applied for this purpose (Figure 1).
In addition, peptide-based ligands offer attractive and
practical options in the development of new ligands for
[a] Departamento de Química, Universidade Federal de Santa
Maria,
97105-900 Santa Maria, RS, Brazil
Fax: +55-55-3220-8998
E-mail: rodriguesoed@gmail.com
[b] Departamento de Química, Universidade Federal de São
Carlos,
13565-905 São Carlos, SP, Brazil
[c] Departamento de Química, Universidade Federal de Santa
Catarina,
88040-970 Florianópolis, SC, Brazil
E-mail: albraga@qmc.ufsc.br
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000237.
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Eur. J. Org. Chem. 2010, 3574–3578

Catalytic Enantioselective Aryl Transfer Reaction to Aldehydes
Results and Discussion
Firstly, the N-Boc peptides 1–4 were synthesized in a few
steps with high yields.[9c] The modular nature of chalcogen
peptide ligands was exploited in the systematic alteration of
each structural unit. Initially, we decided to examine the
influence of the R1 group of chalcogeno peptides, while the
R2 and R3 positions were held constant. The compounds
were evaluated as ligands for the enantioselective addition
of PhZnEt to p-tolualdehyde as depicted in the Scheme 2.
Variations in the R1 group showed that it plays an import
role in the enantioselectivity and yield of the reaction. On
analyzing Scheme 2, it is possible to observe that the pep-
tide derived from -selenocysteine derivative 1a, presented
the best performance, affording the desired diarylmethanol
in high yield (94%) and with reasonable enantioselectivity
(46%). Interestingly, by replacing selenium (ligand 1a) with
sulfur (ligand 2a) the optical purity remained, but the yield
dramatically decreased (70%). Thus, based on these results
the greater ability of selenium to act as a ligand, compared
with sulfur, leads us to conclude that the selenium moiety
plays an important role in this reaction.[12] In order to bring
to light this chemical behaviour, we replaced the chalcogen-
Bn group (R1) by an oxygen-Bn or a phenyl group. Thus,
ligands 3a and 4a were tested under the same general proto-
col, affording the desired products, however in only 56 and
66% yield and with 23 and 28% ee, respectively (Scheme 2).
These results suggest that the chalcogen group is an impor-
tant component of the catalyst for this reaction, having con-
siderable influence on the yield and selectivity.
Figure 1. Chiral amino chalcogenides employed as ligands in the
enantioselective arylation of aldehydes.
asymmetric transformations. Peptides are easily prepared,
consist of readily available chiral building blocks and are
modular. They have been extensively applied in asymmetric
organocatalysis.[9] Nevertheless, their applications in the
asymmetric addition of organozinc reagents to carbonyl
compounds has rarely been described.[10]
As part of our growing interest in the development of
new chiral organochalcogen compounds for asymmetric
transformations,[11] we describe herein the application of
this new class of peptides (1–4, Figure 2) as chiral ligands
for the catalytic enantioselective arylation of aromatic alde-
hydes with boronic acids. As far as we are aware these are
the first chalcogen peptides successfully employed to this
aim.
To verify the possibility for steric and electronic refine-
ment in the structure of ligands 1, we performed the depro-
tection of the Boc group (Table 1). The reaction of the chi-
ral peptide 1a with TFA proceeded smoothly at room tem-
perature to give the free amino peptide 1b in good yield.
The ligand 1b showed better performance than 1a in terms
of conversion and enantioselection (Entry 2). This result
might be explained based on the fact that the amine group
possesses a lone pair, and thus it coordinates with the zinc
atom more efficiently than the carbamate moiety.
By extending our studies to other chiral seleno ligands
with variations at the R3 position, we could observe that
the presence of a sterically hindered group was crucial for
a high enantioselectivity. When the gem-diphenyl group was
Figure 2. General design of ligands. AA = amino acid.
Scheme 2. Evaluation of chiral relay ligands in the catalytic arylation of p-tolualdehyde with phenylboronic acid.
Eur. J. Org. Chem. 2010, 3574–3578
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O. E. D. Rodrigues, A. L. Braga et al.
SHORT COMMUNICATION
Table 1. Catalytic arylation of p-tolualdehyde with phenylboronic ever, on decreasing the amount of ligand to 10 mol-% the
acid.[a]
diarylmethanol was obtained with 80% yield and 40% ee
(Entry 5).
With the optimized conditions and having established li-
gand 1b as the most effective one for the asymmetric ad-
dition of arylzinc reagents to aromatic aldehydes, we ex-
tended the scope of our protocol to several aldehydes with
different steric and electronic features (Table 2). In terms
of steric effect, the reaction with 2-tolualdehyde underwent
smooth aryl addition with 91% ee and nearly quantitative
yield (Entry 2). It seems that due to the nearness of the
carbonyl position of the bulky group in the 2-tolualdehyde
to that of 4-tolualdehyde, the transfer of the aryl group oc-
curs with a slightly higher enantiomeric control (Entry 1 vs.
2). A contrasting result was achieved when 2-methoxybenz-
aldehyde was used as the electrophile. In this case a poten-
tial chelating effect between the zinc atom and the methoxy
substituent might be responsible for the decrease in
enantioselectivity (Entry 2 vs. 4). However, the reaction was
not greatly influenced by electronic effects. As shown in
Table 2, electron-donating or -withdrawing groups afforded
the respective products with the same level of enantio-
selectivity (Entries 3 and 5).
Entry Ligand (mol-%)
R2
R3
Yield[b] [%] ee[c,d] [%]
1
2
1a (20)
1b (20)
1b (20)
1b (20)
1b (10)
1c (20)
Boc
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Et
94
97
50
50
80
67
46 (S)
71 (S)
57 (S)
63 (S)
40 (S)
racemic
3[e]
4[f]
5
6
H
[a] Reactions were performed on a 0.5 mmol scale with PhB(OH)2
(2.4 equiv.), Et2Zn (7.2 equiv.) in toluene (first at 60 °C for 15 min,
then at room temperature for 30 min).[14] [b] Isolated yield of the
corresponding product. [c] Enantiomeric excess was determined by
chiral HPLC on a Chiralcel OD-H column. [d] Absolute configura-
tion assigned by correlation to literature data.[15] [e] Reaction was
carried out at 0 °C. [f] 5 mol-% of DiMPEG 1000 was added.
To extend the scope of our methodology and the effi-
ciency of the aryl transfer to aldehydes, we tested different
substituted arylboronic acids. The corresponding com-
pounds were obtained with good yields and with remark-
able enantioselectivities (Entries 7 and 8). For example, the
aryl transfer reaction from (4-methylphenyl)boronic acid to
benzaldehyde occurred with 66% ee (Entry 7). This is an
interesting feature of the methodology employed, since both
enantiomers of a given product can be easily prepared in
good yield and with reasonable enantiomeric excesses by
using the same chiral ligand, simply through the appropri-
ate choice of reaction partners: arylboronic acid and alde-
hyde.
replaced by a gem-diethyl group, total racemization of the
substrate took place (Entry 2 vs. 6). Therefore, steric factors
appear to play a dominant role in determining the enantio-
selectivity in this series of ligands.
We also found that the temperature has a significant in-
fluence on the reaction, and the best result were achieved
at room temperature. When the reaction was performed at
0 °C, the desired product was obtained with lower yield and
enantioselectivity (Entry 2 vs. 3). In order to improve the
enantioselectivity, an additive (DiMPEG)[13] was added,
and again lower enantioselectivity and yield were observed
(Entry 4). These findings may be due to the strong interac-
In order to demonstrate the utility of this method in syn-
tions between DiMPEG and PhZnEt, leading to the deliv- thesizing building blocks for biologically active compounds,
ery of the phenyl group without the influence of a chiral their application to important target molecules is shown in
environment.[7b] We also evaluated the ligand loading; how- Figure 3. The synthesis of a direct precursor for (S)-orphen-
Table 2. Catalytic arylation of aldehydes with arylboronic acids by using ligand 1b.
Entry
Product
Ar1
Ar2
Yield[a] [%]
ee[b,c] [%]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
Ph
Ph
4-CH3C6H4
2-CH3C6H4
4-CH3OC6H4
2-CH3OC6H4
4-ClC6H4
2-ClC6H4
Ph
96
98
85
87
86
94
63
88
71 (S)
91(S)
80 (S)
65 (S)
77 (S)
78 (S)
66 (R)
51 (R)
Ph
5g
5h
4-CH3C6H4
4-ClC6H4
Ph
[a] Isolated yield of the corresponding product. [b] Enantiomeric excess was determined by chiral HPLC analysis. [c] Absolute configura-
tion assigned by correlation to literature data.[15]
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Catalytic Enantioselective Aryl Transfer Reaction to Aldehydes
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Figure 3. Biologically active (S)-orphenadrine.
Conclusions
We have developed a new class of chalcogen-based li-
gands for the enantioselective arylation of aromatic alde-
hydes. This is the first time that seleno peptides have been
applied in the asymmetric arylation of aromatic aldehydes
with good results. The modular synthesis of these ligands
allowed the easy modification of three different sites. In the
presence of chiral ligand 1b, the corresponding diarylmeth-
anols were obtained in excellent yields and with high
enantioselectivities (up to 91% ee).
We believe that the chemistry described herein represents
a new direction for the design of bifunctional, chiral chal-
cogen peptide ligands and their application in asymmetric
catalysis. Intensive research in this area is in progress in our
laboratory.
[6]
Supporting Information (see footnote on the first page of this arti-
cle): General experimental methods and characterization data.
Acknowledgments
The authors gratefully acknowledge Coordenação de Aper-
feiçoamento de Pessoal de Nível Superior (CAPES), Conselho Na-
cional de Desenvolvimento Científico e Tecnológico (CNPq –
INCT Catálise e INCT NANOBIOSIMES) for financial support.
R. S. S. also thanks CAPES for a PhD fellowship. M. W. P.
acknowledges Fundação de Amparo à Pesquisa do Estado de São
Paulo (FAPESP) (grants 2009/07281-0 and 2009/14352-0).
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O. E. D. Rodrigues, A. L. Braga et al.
SHORT COMMUNICATION
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Received: February 21, 2010
Published Online: May 27, 2010
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