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.

海筒柱胺（Haliclonadiamine）与巴布胺（papuamine）均为双茚烷类海洋天然产物，分离自海绵属（Haliclona sp.）海洋海绵。既往研究报道二者的相对构型仅在8个共享手性中心中的1个存在构型翻转差异。本研究通过X射线晶体衍射术（X-ray crystallography）得到了相反结论：巴布胺的绝对构型为1R,3S,8R,9S,14S,15R,20S,22R，而海筒柱胺的绝对构型为1S,3R,8S,9R,14R,15S,20R,22R。

矛盾的是，二者的电子圆二色谱（Electronic Circular Dichroism, ECD）均呈现负科顿效应（Cotton effect）。X射线晶体衍射分析显示，两种化合物的13元大环核心（13-membered macrocyclic core，包含一个对构型具有重要影响的二烯键（diene））具有相似的构象。在甲醇（MeOH）溶剂化模型下，通过B97x-D/Def2-TZVPP方法计算得到的电子圆二色谱结果证实，二烯键的构型是主导海筒柱胺与巴布胺电子圆二色谱科顿效应的核心因素。

对三个来自不同地理区域的海绵样品开展的额外晶体学与旋光分析表明，这一对天然产物始终以构型相关的配对形式存在。

在讨论相关生物合成途径（biosynthetic pathway）时，必须考虑到在这些海绵属样品中共同发现的生物合成前体（biosynthetic precursor）海筒柱胺C（halichondriamine C）。

综上，本研究证实需要对海筒柱胺的结构进行构型重归属，并提出了一个新的科学问题：海筒柱胺与帕劳胺（palauamine）之间复杂的立体化学关系是如何通过生物合成途径形成的。