Positioning and Configuration of Key Atoms Influence the Topology of [13]-Macrodiolides

Key atoms at specific
positions along the ring govern the shape,
or “topology” of a group of [13]-macrodiolides. Here
we report the synthesis of these macrocycles and their characterization
by functional and structural methods. The [13]-macrodiolides are organized
by three four-atom planar units that help to rigidify them and one
hinge atom that enables the planar units to orient themselves. The
driving force for the organization of the structures is the minimization
of steric strain on groups attached to the key atoms. When the key
atom is a stereocenter, a macrocycle with planar chirality is observed.
An alternative cup-like topology arises when the key atom bears two
alkyl groups. Additionally, the key atoms can work in a coordinated
fashion to guide one topology over another. The synthesis relied on
an acylation-ring closing metathesis sequence. Rigidity was demonstrated
by variable-temperature NMR experiments and diastereoselective epoxidation
reactions. X-ray crystal structures of representative [13]-macrodiolides
served as the basis of the structural observations made. The results
provide a framework for the design of new macrocycles with well-defined
structures as well as for understanding some general principles that
influence the topology of natural product macrocycles.