Seven-component reactions by sequential chemoselective Ugi-Mumm/Ugi-Smiles reactions

Article abstract of DOI:10.1039/b927388c

A seven-component reaction was accomplished by utilizing the different chemoselectivities of the Ugi-Mumm and the Ugi-Smiles reaction. The sequential multicomponent reactions led to highly diverse peptide and glycopeptide like structures.

Full text of DOI:10.1039/b927388c

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Seven-component reactions by sequential chemoselective
Ugi–Mumm/Ugi–Smiles reactionsw
Sebastian Brauch,ab Lars Gabriela and Bernhard Westermann*ab
Received (in Cambridge, UK) 5th January 2010, Accepted 1st March 2010
First published as an Advance Article on the web 19th March 2010
DOI: 10.1039/b927388c
A seven-component reaction was accomplished by utilizing
the different chemoselectivities of the Ugi–Mumm and the
Ugi–Smiles reaction. The sequential multicomponent reactions
led to highly diverse peptide and glycopeptide like structures.
carboxylic acid was changed to an electron poor nitrophenol.
The increased phenol acidity is sufficient to serve as the acidic
building block. In the final, irreversible step, the Smiles
rearrangement leads to the synthesis of N-arylated peptoids
1. In further studies it could be shown that electron poor
aromatic moieties e.g. pyridines and pyrimidines can be used,
too.8
Isonitrile based multicomponent reactions (IMCR’s) have
found numerous applications due to the high degree of
product diversity which can be accomplished in a single
reaction step.1,2 In addition, the Ugi and Passerini reactions
are the best known IMCR’s and have attracted attention due
to the possibility of tandem MCR’s.3 The inherent problem
of side reactions has to be overcome. If a bifunctional,
monoprotected reagent is included, repetitive Ugi reactions
can be carried out, but only after an additional deprotection
step.4 The combination of the Asinger and the Ugi reaction
circumvents these problems, the Asinger product functions as
the imine in the subsequent Ugi reaction.5 If the Ugi reaction
is preceded by a Petasis–Mannich reaction, a seven component
multicomponent reaction can be accomplished leading to
peptoid/peptide substructures.6
In studies using the Ugi protocol for the derivatization of
the nitro caffeic acid derivative 39 we became aware
of competing Ugi–Mumm and Ugi–Smiles reactions
(Scheme 2). Using equimolar amounts of 3 as acid component,
formaldehyde, isopropyl amine and tert-butyl isonitrile, three
products could be identified, the Ugi–Mumm, the Ugi–Smiles
and the Ugi–Mumm/Ugi–Smiles product 4. While studying
this combinatorial effect further, electron poor hydroxy
carboxylic acids 3 and 5–8 and two equivalents each of the other
building blocks (Table 1) were used. Under these conditions
(formaldehyde, isopropyl amine; tert-butyl isonitrile, stirring
overnight at rt), the Ugi–Mumm/Ugi–Smiles product 4a was
formed in 55% yield (entry 1). Considering that eight bonds
are formed, the yield for each bond forming step exceeds
90%. The benzoic acid 5 yields the products 9a–c in 52–68%
(entries 4–6), whereas the nicotinic acid 6 is incorporated in 10
in 25% (entry 7, 85% per bond formed) yield. Limitations can
be observed while using fluoro-substituted benzoic acids 7 and
8, from which only Ugi–Mumm products 12 and 13 were
obtained.
An intriguing extension of the Ugi protocol was published
only recently by El Kaım et al. (Scheme 1).8 Here, the
¨
The high diversity that can be generated by these tandem
multicomponent reactions is exemplified by varying some
components. Most notable with isobutyric aldehyde (entry
3), 4c was formed almost quantitatively. The quantitative
formation of 4c offered the possibility to study the chemo-
selectivity of the two MCR’s. Under controlled conditions,
while adding equimolar amounts of isopropyl amine, iso-
butyric aldehyde and tert-butyl isonitrile, the distribution of
Scheme 1 Ugi–Mumm/Ugi–Smiles reaction.7
a Leibniz-Institute of Plant Biochemistry, Dept. of Bioorganic
Chemistry, Weinberg 3, 06120 Halle, Germany.
E-mail: bwesterm@ipb-halle.de; Fax: +49 345 55821340;
Tel: +49 345 55821309
b Martin-Luther University Halle-Wittenberg, Department of Organic
Chemistry, Kurt-Mothes-Str. 2, 06120 Halle, Germany
w Electronic supplementary information (ESI) available: Experimental
details and spectra. See DOI: 10.1039/b927388c
Scheme
2
Ugi–Mumm/Ugi–Smiles reaction on caffeic acid
derivatives.
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Table 1 Products by isocyanide-based multicomponent reactions
a Mixture of stereoisomers.
the Ugi–Mumm to the Ugi–Smiles was studied. It turned out
that the Ugi–Mumm product 13 is formed in 91%, the
Ugi–Smiles product 14 in only 7% (Scheme 3). The structures
were assigned unambiguously by HMBC experiments.
Based on this considerable degree of chemoselectivity, the
possibility was explored to carry out the reactions sequentially
in one pot, with the Ugi–Mumm reaction first and the
Ugi–Smiles reaction second (Scheme 4).
After adding a first set of Ugi-starting materials (formaldehyde,
isopropyl amine and tert-butyl isonitrile), a second set of
Ugi-components (isobutyric aldehyde, benzyl amine and
n-butyl isonitrile) is added after 24 h, upon which the mixed
Ugi–Mumm/Ugi–Smiles product 15 can be isolated as a
Scheme 3 Competitive experiment of Ugi–Mumm and Ugi–Smiles
reaction.
Scheme 4 Seven-component reactions leading to highly diverse products.
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racemate in 34%, reflecting a 485% yield for each bond
forming step (eight bonds formed). While using 1-b-amino-
GlcNAc as the amine component, the desired glycoconjugate
16 can be isolated as a mixture of diastereomers (3 : 1) in 12%
yield. Most notably, the carbohydrate moiety can be used
without any protecting group.
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The reactions presented here are examples of tandem
Ugi-MCR’s based on the chemoselectivity provided by the
acidic component. This will be utilized inter alia in further
studies concerning the synthesis of highly diverse glyco-
conjugates by easy to carry out protocols.
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This work was supported by a PFI-WGL-Pakt project.
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