Properties of Configurationally Stable Atropoenantiomers in Macrocyclic Natural Products and the Chrysophaentin Family

ConspectusNatural products have played
an indispensable role in the discovery
and development of antibiotics, antineoplastics, and therapeutics
for other diseases. Natural products are unique among all other small
molecules in that they are produced by dedicated enzymatic assembly
lines that are the protein products of biosynthetic gene clusters.
As the products of chiral macromolecules, natural products have distinct
three-dimensional shapes and stereochemistry is often encoded in their
structures through the presence of stereocenters, or in the case of
molecules that lack a stereocenter, the presence of an axis or plane
of chirality. In the latter forms of chirality, if the barrier to
rotation about the chiral axis or chiral plane is sufficiently high,
stable conformers may exist allowing for isolation of discrete conformers,
also known as atropisomers. Importantly, the diverse functions and
biological activities of natural products are contingent upon their
structures, stereochemistry and molecular shape. With continued innovation
in methods for natural products discovery, synthetic chemistry, and
analytical and computational tools, new insights into atropisomerism
in natural products and related scaffolds are being made. As molecular
complexity increases, more than one form of stereoisomerism may exist
in a single compound (for example, point chirality, chiral axes, and
chiral planes), sometimes creating atypical or noncanonical atropisomers,
a term used to distinguish physically noninterconvertable atropisomers
from typical atropisomers.Here we provide an account of the
discovery and unusual structural
and stereochemical features of the chrysophaentins, algal derived
inhibitors of the bacterial cytoskeletal protein FtsZ and its associated
protein partners. Eleven members of the chrysophaentin family have
been discovered to date; seven of these are macrocyclic bis-bibenzyl
ethers wherein the site of the ether linkage yields either a symmetrical
or asymmetrical macrocyclic ring system. The asymmetrical ring system
is highly strained and corresponds to the compounds having the most
potent antimicrobial activity among the family. We review the structure
elucidation and NMR properties that indicate restricted rotation between
axes of two biaryl ethers, and the plane represented by the substituted
2-Z-butene bridge common to all of the macrocycles.
Computational studies that corroborate high barriers to rotation about
one representative plane, on the order of 20+ kcal/mol are presented.
These barriers to rotation fix the conformation of the macrocycle
into a bowl-like structure and suggest that an atropisomer should
exist. Experimental evidence for atropisomerism is presented, consistent
with computational predictions. These properties are discussed in
the context of the total synthesis of 9-dechlorochrysophaenin A and
its ring C isomers. Last, we discuss the implications for the presence
of enantiomers in the biological activity and macrocyclization of
the natural product.