Peptide-catalyzed kinetic resolution of planar-chiral metallocenes

Article abstract of DOI:10.1039/c4cc03266g

Kinetic resolution of racemic planar-chiral metallocenes was performed through the conjugate addition of a nucleophile to the enal part of substrates. While no enantiomeric discrimination was found with low-molecular-weight organocatalysts, a properly designed resin-supported peptide catalyzed the reaction in a highly selective manner. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03266g

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Peptide-catalyzed kinetic resolution of
planar-chiral metallocenes†
Midori Akiyama,a Kengo Akagawa,a Hidetake Seinob and Kazuaki Kudo*a
Cite this: Chem. Commun., 2014,
50, 7893
Received 2nd May 2014,
Accepted 23rd May 2014
DOI: 10.1039/c4cc03266g
www.rsc.org/chemcomm
Kinetic resolution of racemic planar-chiral metallocenes was performed with peptide- and peptide-related catalysts, respectively, in which
through the conjugate addition of a nucleophile to the enal part of small catalysts were not effective. Meanwhile, we have developed
substrates. While no enantiomeric discrimination was found with low- a resin-supported peptide catalyst consisting of a turn motif,
molecular-weight organocatalysts, a properly designed resin-supported D-Pro-Aib,11 and a helical part (Fig. 1).12 The N-terminal prolyl residue
peptide catalyzed the reaction in a highly selective manner.
forms the iminium-ion intermediate with an a,b-unsaturated
aldehyde to promote Michael addition of nucleophiles.13 The turn
Planar chirality can be found in the groups of molecules with structure of this peptide plays a key role in enantioselectivity of the
planar structures such as metallocenes, p-ligand complexes, and reaction by covering one face of the peptide-bound substrate. The
cyclophanes, and their enantioselective synthesis is necessary for helical part is indispensable for stabilizing the turn structure.
the applications in chiral chemistry.1 In spite of the recent Because of a fairly large molecular size of the peptide, it is expected
remarkable progress in the field of asymmetric catalysis, the to be applicable for an enantioselective synthesis of planar chiral
development of a versatile method for synthesizing chiral planar compounds. Herein, we report the kinetic resolution of racemic
compounds in a catalytic manner is still a challenging task.2
Planar-chiral ferrocenes represent an important class of chiral supported peptide catalyst.
planar-chiral metallocene derivatives in the presence of a resin-
compounds, and they have been mainly used as the ligands
We first examined the kinetic resolution of racemic
for metal-catalysts3 and organocatalysts.1c,4 Enantioenriched 1,2-disubstituted ferrocene 1a in the 1,4-reduction of the enal part
planar-chiral ferrocenes are usually obtained through the resolution with a Hantzsch ester through the iminium-ion intermediate
of a racemic compound by chiral chromatography,3,4 diastereo- (Table 1).14 The formyl group of this substrate is distant from the
selective transformation with the aid of a chiral directing group,5 ferrocenyl moiety, hence it might be difficult for a low-molecular-
or the reaction with a stoichiometric amount of a chiral reagent.5a–c,6 weight chiral amine catalyst to discriminate the enantiomers. In fact,
There are also some reports for the catalytic asymmetric synthesis of when the reaction was performed using an imidazolidinone catalyst
planar-chiral ferrocenes.5c,7 In most cases, however, the applicability 4 or 5,15 both the recovered starting material 1a and reduced product
of these catalytic reactions is quite limited, and elaborately designed 2a were obtained as racemates (Table 1, entries 1 to 3). In contrast,
substrates are required to attain good enantioselectivity. Because the kinetic resolution took place in the presence of peptide catalyst 6
planar chirality is the nature of the whole shape of a molecule, a to give enantioenriched compounds 1a and 2a with a relative
catalyst with a large-scale asymmetric environment is necessary.
reaction rate (krel) value16 of 4.0 (Table 1, entry 4). The use of peptides
On the other hand, peptide catalysts can provide the large 7 and 8, which lack either the terminal turn structure or the helical
reaction sites suitable for substrate recognition by their specific part resulted in lower krel values (Table 1, entries 5 and 6). This
three-dimensional structures.8 Miller and co-workers9 and indicates the importance of the structural motif of catalyst 6.
Kawabata and co-workers10 have reported regioselective reactions
The fifth amino acid residue from the N-terminus of the
peptide was scanned to achieve higher selectivity because,
according to our previous results,12 the residue is likely to be
a Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku,
Tokyo 153-8505, Japan. E-mail: kkudo@iis.u-tokyo.ac.jp
b Faculty of Education and Human Studies, Akita University, Tegata-Gakuenmachi,
Akita 010-8502, Japan
† Electronic supplementary information (ESI) available: Experimental procedures
and full compound characterization, including NMR spectra and HPLC traces
(PDF). CCDC 996655. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4cc03266g
Fig. 1 Resin-supported peptide catalyst. Aib = 2-aminoisobutyric acid,
AA = amino acid.
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Table 1 Kinetic resolution of a planar-chiral ferrocene through the
reduction of an unsaturated bond
a
b
Entry
Catalyst
1a [% ee]
2a [% ee]
CHPLC [%]
krel
1c,d
2c
4
4
5
6
7
8
o1
o1
o1
27
11
10
o1
o1
o1
51
4
35
11e
42e
3e
35
73
22
1.0
1.0
1.0
4.0
1.2
2.3
3c,d, f
4
5
6
Fig. 2 Plausible mechanism for the kinetic resolution by the peptide
catalyst.
a
Conversion calculated from ees of 1a and 2a (ref. 16a). b Selectivity factor:
c
krel = k(Rp)/k(Sp) (ref. 16). The reaction was performed with 0.5 equiv. of 3
for 3 h. d The reaction was performed in CHCl3. e Determined from
resolution of planar-chiral ferrocene 1a (Fig. 2). The conformation of
the iminium-ion intermediate is considered to be regulated to avoid
the steric repulsion between the iodo group on the cyclopentadienyl
(Cp) ring and the vinylic hydrogen next to the iminium group
(Fig. 2a). For the Sp enantiomer of 1a, both faces of the iminium-
ion intermediate are covered either by the Cp ring or by the peptide
chain with a turn structure (Fig. 2b).12 On the other hand, one face of
the intermediate of the Rp enantiomer is accessible by the reagent,
thus, the reaction proceeds faster than in the case of the Sp isomer.
For the highly selective kinetic resolution, the fifth residue of
the peptide catalyst should prohibit the nucleophilic attack of the
reductant from the upper side of the Sp enantiomer, whereas the
formation of the iminium-ion intermediate with the Rp enantiomer
should not be prevented by the steric repulsion caused by the
Cp ring.
1H NMR spectra of the crude mixture. The hydrochloric acid salt of 5
f
was used.
Table 2 Screening for the 5th residue of the peptide catalyst
a
b
Entry
AA
1a [% ee]
2a [% ee]
CHPLC [%]
krel
1
2
3
4
5
6c
Ala
Nva
Ser(Me)
Hse(Me)
Met
74
45
48
63
70
64
40
61
66
66
61
72
65
43
42
49
53
47
4.9
6.4
7.8
9.2
8.4
Compared to the case with a bulky side chain at the fifth
residue of catalyst 6 (Table 1, entry 4), the introduction of the
linear side chain in the catalyst was considered to be effective
Hse(Me)
11.7
a
b
c
Conversion calculated from ees of 1a and 2a. Selectivity factor. The for this purpose (Table 2, entry 3). Although the role of the
hydrochloric acid salt of a peptide with (Leu-Leu-Aib)3 as the helical
part was used.
oxygen atom is not clear at present, an interaction with the
cationic iminium-ion part might enhance the formation of
the reactive intermediate for the Rp isomer, resulting in the
located around the ferrocenyl part of the iminium-ion intermediate higher selectivity (Table 2, entries 4 and 5).17
(Table 2). The replacement of the fifth tryptophan with alanine
This type of kinetic resolution is potentially extendable to the
increased the selectivity of the reaction (Table 2, entry 1), and reactions with other nucleophiles. Because the Michael addition of
introducing an amino acid with an unbranched alkyl side chain nitromethane to a,b-unsaturated aldehydes is a convenient method
further enhanced the krel value (entry 2). Moreover, the incorpora- for the synthesis of g-amino acid derivatives,18 we employed nitro-
tion of an oxygen or a sulfur atom in the linear side chain was methane as a nucleophile. In the presence of the optimum catalyst 9,
effective to improve the selectivity (Table 2, entries 3 to 5). Among the kinetic resolution proceeded with higher enantioselectivity than
them, the peptide possessing homoserine methyl ether was the in the case with Hantzsch ester 3 (Scheme 1). In this reaction, a new
best for the krel value (Table 2, entry 4). After the optimization of the stereogenic center is created at the b-position of the aldehyde group.
counter anion of the ammonio group of the terminal prolyl residue The configuration of the major product was consistent with the
and the length of the helical part, the krel value of 11.7 was achieved proposed model shown in Fig. 2, in which the addition occurred
(Table 2, entry 6).
from the Re face of the Rp isomer of substrate 1a. The high
On the basis of the preference for the absolute configurations diastereoselectivity of the reaction indicates the well-controlled con-
of the major enantiomers obtained by the peptide-catalyzed formation of the iminium-ion intermediate with regard to the
reaction, we postulated a possible mechanism for the kinetic direction of the ferrocenyl part (Fig. 2a).
7894 | Chem. Commun., 2014, 50, 7893--7896
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Scheme 1 Peptide-catalyzed kinetic resolution through Michael addition
of nitromethane.
Next, the scope of substrates for the kinetic resolution
through the Michael addition of nitromethane by using peptide
9 was examined under optimized reaction conditions (Table 3).
For the planar-chiral ferrocenes with halogen and alkynyl
substituents, both unreacted starting material 1 and product
10 were obtained as highly enantioenriched forms (Table 3,
entries 1 to 8). A shorter reaction time afforded product 10 with
a high ee value (Table 3, entries 1, 3, 5, and 7). Meanwhile, upon
increasing the conversion by elongating the reaction time,
starting material 1 was obtained in a highly enantioselective
manner (Table 3, entries 2, 4, 6, and 8). As to the substrate with
an aromatic group, good enantioselectivity was achieved only
for the product (Table 3, entry 9). In this case, a reaction
conversion could not be increased even in a prolonged reaction
time because of the low solubility of the substrate. In addition
to the ferrocenes, ruthenocenyl substrate 1f could be used in
this catalytic system (Table 3, entries 10 and 11).
Finally, the derivatizations of the obtained materials were
conducted to demonstrate the utility of the present resolution
method (Scheme 2). The Pinnick oxidation of product 10b
followed by an esterification afforded compound 11, which could
be further transformed to amino acid derivative 12 via a
reduction and an N-protection. Because there are only limited
examples for the asymmetric synthesis of amino acid derivatives
with planar chirality,19 this procedure offers a valuable way for
Scheme 2 Transformation into planar-chiral derivatives.
their preparation. Halogen-substituted ferrocenyl compounds
are synthetically useful, because they can easily be transformed
by a coupling reaction.20 The Suzuki–Miyaura reaction with
iodine-containing 1a and p-methoxyphenylboronic acid afforded
coupling product 1e. Alkyl ferrocene 13 could be prepared by the
catalytic hydrogenation of product 10d.
In conclusion, we have successfully shown that the peptide
catalyst is applicable for the kinetic resolution of planar-chiral
metallocenes which cannot be realized by low-molecular-weight
organocatalysts. The use of an amino acid with a sterically less
demanding, heteroatom-containing side chain at an appropriate
position of the peptide sequence was the key for the high
enantioselectivity. Planar chiral ferrocenes could tolerate several
reaction conditions including oxidation and reduction. Further
application of peptide catalysts for synthesizing other planar-
chiral compounds can be expected.
Table 3 Peptide-catalyzed kinetic resolution of planar-chiral metallocenes
This work was financially supported by JSPS KAKENHI
(23550116), and by MEXT KAKENHI (24105506).
Notes and references
1 [% ee
t [h] (% Yield)] (% Yield, d.r.)]
10 [% eea
˜
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1
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1a Fe
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31 (48)
77 (27)
60 (38)
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87 (50)
92 (36, 98:2)
59 (49, 93:7)
89 (25, 97:3)
86 (43, 93:7)
93 (18, 499:o1)
80 (31, 94:6)
83 (37, 88:12)
70 (44, 83:17)
85 (33, 95:5)
87 (27, 92:8)
66 (38, 82:18)
12
8
14
21
36
1-Heptynyl
1-Heptynyl
9
10
11
p-MeOC6H4 10
1f
1f
Ru
Ru
I
I
4
5
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