X‑ray Crystallography and Unexpected Chiroptical Properties Reassign the Configuration of Haliclonadiamine

Haliclonadiamine
and papuamine are bis-indane marine natural products
isolated from the marine sponge Haliclona sp. Their
relative structures were previously reported to differ by inversion
at only one of their eight shared stereo­centers. Here X-ray
crystallography shows the opposite to be true: papuamine has a 1R,3S,­8R,9S,­14S,15R,­20S,22R configuration, while haliclona­diamine
has a 1S,3R,­8S,9R,­14R,15S,­20R,22R configuration. Paradoxically
the ECD of each structure displays a negative Cotton effect. X-ray
crystallography reveals the two structures adopt similar conformations
of their 13-membered macrocyclic core that comprises a configurationally
relevant diene. B97x-D/Def2-TZVPP-(MeOH)-calculated ECD supports the
diene configuration with the macrocycle dominating the ECD Cotton
effect for haliclona­diamine and papuamine. Additional crystallographic
and chiroptical analyses of three sponge samples from geographically
distant locations indicate this pair of natural products always exists
as a configurationally related couple. The co-discovery of a biosynthetic
precursor, halichon­driamine C, present in these same Haliclona
samples must be considered when discussing any biosynthetic pathway.
Taken together, this work justifies a reassignment of haliclona­diamine’s
structure and opens the question of how this complex stereo­chemical
relationship between haliclona­diamine and palauamine arises
biosynthetically.