Conspectus
Macrocyclic
natural products are plentiful in
the bacteria, archaea,
and eukaryote domains of life. For the significant advantages that
they provide to the producing organisms, evolution has learned how
to implement various types of macrocyclization reactions into the
different biosynthetic pathways and how to effect them with remarkable
ease. Mankind greatly benefits from nature’s pool, not least
because naturally occurring macrocycles or derivatives thereof serve
as important drugs for the treatment of many serious ailments.
In stark contrast, macrocyclization reactions are usually perceived
as difficult to accomplish by purely chemical means. While it is true
that ring closure necessarily entails an entropic loss and may result
in the buildup of (considerable) ring strain that must be compensated
for in one way or the other, it is also fair to note tremendous methodological
advances during the last decades that greatly alleviated this traditional
“macrocycle challenge”. It is therefore increasingly
possible to explore the advantages provided by large as well as medium-size
ring systems in a more systematic manner. This venture also holds
the promise of increasing the “chemical space” amenable
to drug development to a considerable extent.
In consideration
of this and other important long-term perspectives,
it is appropriate to revisit the current state of the art. To this
end, a number of vignettes are presented, each of which summarizes
a total synthesis project targeting macrocyclic natural products of
greatly different chemotypes using a variety of transformations to
reach these goals. Although we were occasionally facing “dead
ends”, which are also delineated for the sake of a complete
picture, these case studies illustrate the notion that the formation
of a certain macrocyclic perimeter is (usually) no longer seriously
limiting. In addition to substantial progress in the “classical”
repertoire (macrolactonization and macrolactamization
(pateamine A, spirastrellolide, and belizentrin)), various metal-catalyzed
reactions have arguably led to the greatest leaps forward. Among them,
palladium-catalyzed C–C bond formation (roseophilin and nominal
xestocyclamine A) and, in particular, alkene and alkyne metathesis
stand out (iejimalide, spirastrellolide, enigmazole, ingenamine, and
sinulariadiolide). In some cases, different methods were pursued in
parallel, thus allowing for a critical assessment and comparison.
To the extent that the macrocyclic challenge is vanishing, the
opportunity arises to focus attention on the postmacrocyclization
phase. One may stipulate that a well-designed cyclization precursor
does not only ensure efficient ring closure but also fosters and streamlines
the steps that come after the event. One way to do so is dual (multiple)
use in that the functional groups serving the actual cyclization reaction
also find productive applications downstream from it rather than being
subject to simple defunctionalization. In this context,...