الفهرس 
titelOnly 14 pages are availabe for public view
 |  | from | 282 |  |  |
| | | from | 282 | | |
Abstract
Recently, macrocyclic synthetic compounds or natural products structures became envogue
due to many potential applications and advantages over small molecular weight
compounds. Macrocycles can target proteins which are difficult to handle by small
molecular weight compounds such as protein-protein interactions (PPIs) due to their large
and flat surface area. Moreover, some macrocycles show enhanced transport properties due
to their chameleon-like behavior in hydrophobic and hydrophilic environments. This
behavior can be triggered by conformational changes induced by a shift between intra- and
intermolecular hydrogen bonding.
A well-known challenge in macrocycle synthesis is the cycle formation over oligo- or
polymerization. Paul Ruggli and Karl Ziegler1
have introduced the high-dilution principle,
according to which low concentrations of the starting acyclic precursor favour cyclization
over chain formation. Another challenge relates to the exploration of the natural
macrocycles for drug discovery since synthesizing such compounds in a timely and diverse
fashion is difficult, especially when a series of molecules for structure-activity relationship
(SAR) elucidation or screening libraries is needed. Moreover, cyclization methods are
required that are working in a general fashion with a wide variety of substrates and
functional groups. Therefore, development of short and efficient synthetic approaches with
only a few steps is necessary.
A number of highly interesting synthetic routes have been developed including rapid
and efficient methodologies such as DNA encoded chemistry, enzyme-catalyzed ring
closures, special classes of structurally ordered macrocycles such as stapled peptides or
accessing peptide macrocycles from genetically encoded polypeptides, which however are
beyond the current assay and have been extensively reviewed elsewhere.2-4 Noteworthy, the
majority of methods focuses on peptide macrocycles. In contrast, multicomponent reaction
chemistry MCR is an excellent technology suitable for the fast and efficient synthesis of
many diverse libraries of macrocycles and also able to generate great levels of molecular
diversity and complexity at low synthetic costs.5
MCRs such as Ugi and Passerini reactions have been used to develop many strategies
towards macrocycle libraries. These reactions are used for macrocyclization directly or to
synthesis linear precursors which can be cyclized whether by MCRs or other procedures.
Already in 1979 Failli and Immer6
for the first time described the use of Ugi MCR for the
one-pot macrocyclization of N, C-terminal unprotected linear hexapeptides. Later many
other groups7-9 contributed to macrocycle synthesis via MCR. Recently, Dömling group
established up-to-now more than 10 different synthetic routes towards variable artificial
macrocycle scaffolds in 1 to maximum 5 sequential steps.
10-16 This gives us a representative
coverage of an interesting and large chemical space of macrocycles with afforda