Asymmetric one-pot sequential Friedel-Crafts-type alkylation and α-oxyamination catalyzed by a peptide and an enzyme

Article abstract of DOI:10.3762/bjoc.8.152

In the presence of a peptide catalyst and the oxidative enzyme laccase, a one-pot sequential reaction including a Friedel-Crafts-type alkylation of α,β-unsaturated aldehydes followed by an α-oxyamination was realized. The reaction in aqueous solvent to pr

Full text of DOI:10.3762/bjoc.8.152

Asymmetric one-pot sequential Friedel–Crafts-type
alkylation and α-oxyamination catalyzed
by a peptide and an enzyme
Kengo Akagawa, Ryota Umezawa and Kazuaki Kudo*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1333–1337.
Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba,
Meguro-ku, Tokyo 153-8505, Japan
doi:10.3762/bjoc.8.152
Received: 30 May 2012
Accepted: 17 July 2012
Published: 17 August 2012
Email:
Kazuaki Kudo* - kkudo@iis.u-tokyo.ac.jp
* Corresponding author
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
Keywords:
Friedel–Crafts-type alkylation; laccase; one-pot reaction;
organocatalysis; α-oxyamination; resin-supported peptide catalyst
© 2012 Akagawa et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
In the presence of a peptide catalyst and the oxidative enzyme laccase, a one-pot sequential reaction including a Friedel–Crafts-type
alkylation of α,β-unsaturated aldehydes followed by an α-oxyamination was realized. The reaction in aqueous solvent to promote
the enzymatic oxidation, and the use of a peptide catalyst compatible with such conditions, were essential. The present sequential
reaction afforded oxygen-functionalized indole or pyrrole derivatives in a highly enantioselective manner.
Findings
Indole derivatives represent a class of biologically active com- Indoles with an oxygenated stereogenic carbon at the β-pos-
pounds [1-3], and they often have chiral carbon chains attached ition of the ring, such as indolmycin [21,22] and diolmycin
to indole rings. A Friedel–Crafts-type asymmetric alkylation [23], are known as antibiotics (Figure 1). The framework of
(FCAA) to indoles is a versatile method for synthesizing such these compounds could be constructed though the conjugate
chiral indole derivatives. To date, a number of FCAA reactions addition of an indole to α,β-unsaturated aldehydes followed by
by either metal catalysts or organocatalysts have been reported oxygenation at the α-position of the carbonyl group. If such a
[4-11]. Especially because organocatalysts have been demon- sequence can be realized in a one-pot reaction, it would be a
strated to possess a high feasibility for sequential reactions [12- powerful method for the synthesis of oxy-functionalized indole
16], it is expected that a sequential reaction including an derivatives with operational simplicity. To date, there has been
organocatalytic FCAA step could provide highly functionalized no report on the FCAA reaction combined with an α-oxygena-
indole compounds [17-20].
tion of aldehydes [24-29] in a one-pot sequential reaction.
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Beilstein J. Org. Chem. 2012, 8, 1333–1337.
In a one-pot sequential reaction, the compatibility of reaction
conditions in each step is important. Previously, we have
reported a reaction system for the asymmetric α-oxyamination
of aldehydes catalyzed by a peptide and an oxidizing enzyme,
laccase [36,38]. Because the reaction conditions for that system
are mild without employing a strong oxidant, we envisaged that
the sequential FCAA/α-oxygenation could be attained by
adopting the peptide-and-laccase-cocatalyzed oxyamination,
even though indoles are generally prone to be oxidized [39,40].
Figure 1: Oxygen-functionalized indole compounds.
Meanwhile, our group has developed resin-supported peptide By considering that enzymes promote reactions efficiently
catalysts (Figure 2) for several organic reactions in aqueous under aqueous conditions, we thought it necessary to conduct
media [30-37]. Since these catalysts can be applicable for the the one-pot reaction in aqueous media. Therefore, the reaction
FCAA reaction toward α,β-unsaturated aldehydes through sequence shown in Table 1 was first examined in water. After
iminium intermediates [32,37], and an asymmetric α-oxyamina- the FCAA by peptide catalyst 1, the α-oxyamination was
tion of aldehydes via enamines [33], they are expected to be successively performed by adding 2,2,6,6-tetramethylpiperidin-
suitable for a one-pot sequential reaction to make the chiral 1-oxyl (TEMPO) and laccase directly to the reaction mixture.
indoles mentioned above. Herein, we report on an enantioselect- The desired two-step reaction product 4 was obtained with
ive synthesis of oxygenated indole compounds through a one- syn/anti ratio of 75:25, and the ee value of the syn diastereomer
pot sequential FCAA/α-oxyamination catalyzed by the resin- was 96% (Table 1, entry 1). It is noteworthy that the ee of the
supported peptide.
major diastereomer was higher than that of each single reaction
[33,37]. Such enantio-enrichment is generally caused in consec-
utive catalytic asymmetric reactions through the formation of
diastereomeric pairs [17,41]. From the viewpoint of reaction
efficiency, the conversion in each step was low, presumably
because of poor solubility of the substrates in water. Thus, use
of the organic cosolvent THF was examined (Table 1, entries 2
to 5). As a result, the solvent system H2O/THF 2:1 was
regarded as the optimum (Table 1, entry 4). When the reaction
was performed under conditions with a higher content of THF,
Figure 2: Resin-supported peptide catalyst.
Table 1: One-pot sequential Friedel–Crafts-type alkylation/α-oxyamination.
ee [%]b of syn-isomer
(anti-isomer)
entry
solvent
2:3:4a
syn/anti of 4a
1
2
3
4
5
H2O
67:14:19
32:17:51
44:10:46
17:5:78
75:25
73:27
76:24
75:25
–
96 (64)
96 (62)
97 (57)
98 (56)
–
H2O/THF 9:1
H2O/THF 5:1
H2O/THF 2:1
H2O/THF 1:1
15:85:0
aDetermined by 1H NMR spectroscopy of crude mixture. bDetermined by HPLC analysis after being reduced to the corresponding alcohol.
1334

Beilstein J. Org. Chem. 2012, 8, 1333–1337.
such as in the case of H2O/THF 1:1, the peptide/laccase- ical course of the second-step α-oxyamination was determined
catalyzed oxidation did not proceed at all, due to inactivation of mainly by the stereostructure of the peptide catalyst rather than
laccase (Table 1, entry 5). This indicates the importance of by the chirality of the intermediate 3.
water as a solvent for realization of the present sequential reac-
tion.
Finally, other substrates were tested in the present one-pot
sequential reaction system (Table 2). Several substituted indoles
To elucidate the origin of the stereocontrol in the present gave the products with high enantioselectivity (Table 2, entries
sequential reaction, the following control experiment was 1 to 3). As an α,β-unsaturated aldehyde, 3-nitrocinnamaldehyde
conducted. After the first FCAA reaction, peptide catalyst 1 was was also applicable (Table 2, entry 4). Other than indoles, a
removed by filtration and another peptide catalyst 5, which is pyrrole compound could be employed as a starting nucleophile
the enantiomer of 1, was added to promote the α-oxyamination in the sequential FCAA/α-oxyamination (Table 2, entry 5).
(Scheme 1). In this case, the anti-isomer was obtained as a
major diastereomer, and the ee value of the anti-product was In conclusion, the FCAA followed by the asymmetric α-oxyam-
high. The reversal of the diastereoselectivity along with the high ination was realized in a one-pot reaction, by using a peptide
ee of the major diastereomer demonstrates that the stereochem- catalyst and laccase. This sequential reaction afforded the
Scheme 1: Effect of the stereostructure of the peptide catalyst.
Table 2: Examples of the one-pot synthesis of oxygenated heteroaromatic compounds.
ee [%]c of syn-isomer
(anti-isomer)
entry
product
time (h) of first step
yield [%]a
syn/antib
75:25
1
24
59
98 (56)
4
2
24
70
79:21
98 (73)
6
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Beilstein J. Org. Chem. 2012, 8, 1333–1337.
Table 2: Examples of the one-pot synthesis of oxygenated heteroaromatic compounds. (continued)
3
72
57
75:25
98 (55)
7
4
5
36
48
55
51
72:28
70:30
98 (61)
8
9
91 (30)
aIsolated yield. bDetermined by 1H NMR spectroscopy. cDetermined by HPLC analysis after being reduced to the corresponding alcohol.
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