Cyclohelminthol CPs: Scope and Limitations of Density Functional Theory-Based Structural Elucidation of Natural Products

The effectiveness and limitations
of density functional theory
(DFT) calculations in the structural determination of complexed and
conformationally flexible natural products were demonstrated using
the cyclohelminthols CP-1 (1) CP-2 (2),
CP-3 (3), and CP-4 (4) newly isolated from Helminthosporium velutinum yone96. Prior to DFT calculations,
the structures were tentatively assigned using conventional spectroscopic
analyses. The structures were verified with reference to DFT-derived 13C and 1H NMR chemical shifts, 3JHH and nJCH values, and electronic circular dichroism (ECD) spectra. The 13C chemical shift calculations were very effective for verifying
the ring-structure moieties but less effective for verifying the geometry
of the side chain in which the juncture asymmetric carbon (C-16) was
apart from the ring-structure moiety. However, 1H chemical
shift calculations compensated for the imperfection of the latter.
ECD spectral calculations were used to determine the absolute configurations.
Calculations for virtual simple model molecules enabled us to evaluate
the reliability of the ECD spectral calculation and derive the chiral
torsion responsible for the characteristic Cotton effects.

本研究以从绒状长蠕孢菌（Helminthosporium velutinum yone96）中新分离得到的环蠕孢菌素CP-1（1）、CP-2（2）、CP-3（3）与CP-4（4）为研究对象，验证了密度泛函理论（Density Functional Theory, DFT）计算在络合且构象灵活的天然产物结构鉴定中的有效性与局限性。在开展DFT计算前，研究人员先通过常规光谱分析对各目标化合物的结构进行了初步推定。随后，基于DFT计算得到的13C与1H核磁共振（NMR）化学位移、3JHH及nJCH耦合常数，以及电子圆二色谱（Electronic Circular Dichroism, ECD）光谱，对初步推定的结构完成了验证。其中，13C化学位移计算对环结构片段的验证效果显著，但对于与环结构片段分离的、含连接点手性碳（C-16）的侧链几何构型的验证效果欠佳。不过，1H化学位移计算有效弥补了这一不足。电子圆二色谱计算则被用于确定目标化合物的绝对构型。通过构建虚拟简单模型分子进行计算，本研究得以评估ECD光谱计算的可靠性，并推导得到了与特征科顿效应相关的手性扭转单元。