Fluostatins, benzofluorene-containing aromatic polyketides in the atypical angucycline family, conjugate into dimeric and even trimeric compounds in the post-biosynthesis. The formation of the C–C bond involves a non-enzymatic stereospecific coupling reaction. In this work, the unusual regio- and enantioselectivities were rationalized by density functional theory calculations with the M06-2X (SMD, water)/6–311 + G(d,p)//6–31G(d) method. These DFT calculations reproduce the lowest energy C1-(R)-C10′-(S) coupling pathway observed in a nonenzymatic reaction. Bonding of the reactive carbon atoms (C1 and C10′) of the two reactant molecules maximizes the HOMO–LUMO interactions and Fukui function involving the highest occupied molecular orbital (HOMO) of nucleophile p-QM and lowest unoccupied molecular orbital (LUMO) of electrophile FST₂⁻ anion. In particular, the significant π–π stacking interactions of the low-energy pre-reaction state are retained in the lowest energy pathway for C–C coupling. The distortion/interaction–activation strain analysis indicates that the transition state (TScp-I) of the lowest energy pathway involves the highest stabilizing interactions and small distortion among all possible C–C coupling reactions. One of the two chiral centers generated in this step is lost upon aromatization of the phenol ring in the final difluostatin products. Thus, the π–π stacking interactions between the fluostatin 6-5-6 aromatic ring system play a critical role in the stereoselectivity of the nonenzymatic fluostatin conjugation.

中文翻译：

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了解生物合成后Fluostatin共轭的特定区域和对映体选择性。

非生物古环素家族中的Fluostatins是一种含苯并芴的芳香族聚酮化合物，在生物合成后，会共轭成二聚体甚至三聚体化合物。C–C键的形成涉及非酶立体定向偶联反应。在这项工作中，使用M06-2X（SMD，水）/ 6-311 + G（d，p）// 6-31G（d）方法通过密度泛函理论计算合理化了异常的区域选择性和对映选择性。这些DFT计算重现了在非酶反应中观察到的最低能量C1-（R）-C10'-（S）偶联途径。两个反应物分子的活性碳原子（C1和C10'）的键合使HOMO-LUMO相互作用最大化，并且Fukui功能涉及亲核试剂p-QM的最高占据分子轨道（HOMO）和亲电试剂的最低未占据分子轨道（LUMO） FST₂ ^-阴离子。特别是，低能预反应状态的重要π-π堆积相互作用保留在CC耦合的最低能量路径中。变形/相互作用-活化应变分析表明，在所有可能的C-C偶联反应中，最低能级路径的过渡态（TScp -I）涉及最高的稳定相互作用和较小的变形。在该步骤中产生的两个手性中心之一在最终的双氟他汀产品中苯酚环芳构化后丢失。因此，fluostatin 6-5-6芳香环系统之间的π–π堆积相互作用在非酶促fluostatin结合的立体选择性中起关键作用。