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.

Haliclonadiamine与papuamine均为分离自海洋海绵Haliclona sp.的双茚烷类海洋天然产物。此前已有研究报道，二者的相对结构仅在8个共享手性中心中的1个发生构型反转而存在差异。本研究通过X射线晶体衍射（X-ray crystallography）证实，实际情况恰好相反：papuamine的构型为1R,3S,8R,9S,14S,15R,20S,22R，而haliclonadiamine的构型为1S,3R,8S,9R,14R,15S,20R,22R。令人意外的是，两种化合物的电子圆二色谱（Electron Circular Dichroism, ECD）均呈现负科顿效应。X射线晶体衍射分析显示，二者的13元大环核心（包含一个与构型密切相关的二烯单元）具有相似的构象。基于B97x-D/Def2-TZVPP-(MeOH)方法计算得到的电子圆二色谱结果，验证了该二烯的构型，且大环结构主导了haliclonadiamine与papuamine的ECD科顿效应。对三个采自地理相距遥远区域的海绵样品开展的额外晶体学与手性光学分析表明，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时，必须考虑到在这些Haliclona海绵样品中共同发现的生物合成前体halichondriamine C。综上，本研究证实需要对haliclonadiamine的结构进行重新指认，并提出了一个待解答的问题：haliclonadiamine与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。