Nonclassical CH−π Supramolecular Interactions in Artemisinic Acid Favor a Single Conformation, Yielding High Diastereoselectivity in the Reduction with Diazene

The
high diastereoselectivity of the hydrogenation of artemisinate
by diazene to form dihydroartemisinate (diastereoselective ratio,
dr, 97:3) necessary for efficient production of artemisin has been
rationalized by state-of-the-art DFT calculations and identification
of the noncovalent interactions by coupled ELF/NCI analysis. Remarkably,
a single conformer of artemisinate is responsible for the high diastereoselectivity
of the reaction. NMR studies confirm the preference for a single conformation
that is found to be identical to that predicted by the calculations.
The calculations and ELF/NCI analyses show that the hydrogenation
of the exocyclic activated CC double bond has a low energy
barrier and that the lowest transition state and the preferred conformation
of free artemisinate develop the same network of weak noncovalent
interactions between the electron donor groups (oxygen and exocyclic
CC double bond) and CH bonds of the cis-decalene
group of the artemisinate, which rationalize the high diastereoselectivity
unusual for a strongly exothermic reaction.

利用二亚胺（diazene）氢化青蒿酸酯（artemisinate）制备双氢青蒿酸酯（dihydroartemisinate）的反应，可实现97:3的非对映体比率（dr），该极高的非对映选择性是高效合成青蒿素（artemisin）的必要前提。本研究通过当前最先进的密度泛函理论（DFT, Density Functional Theory）计算，结合耦合电子定域化函数/非共价相互作用（ELF/NCI, Electron Localization Function/Non-Covalent Interaction）分析对非共价相互作用的表征，对该高选择性的机制进行了合理化阐释。值得注意的是，青蒿酸酯仅需单一构象即可主导该反应的高非对映选择性。核磁共振（NMR, Nuclear Magnetic Resonance）实验证实了单一优势构象的存在，且该构象与理论计算预测的结果完全一致。计算与ELF/NCI分析结果表明，外环活化碳碳双键的氢化反应能垒较低；且自由青蒿酸酯的最低能量过渡态与优势构象，均在电子给体基团（氧原子与外环碳碳双键）与青蒿酸酯顺式十氢萘基团的C-H键之间形成了相同的弱非共价相互作用网络，这一网络合理解释了该强放热反应中反常的高非对映选择性。