Computational Evidence for Tunneling and a Hidden Intermediate in the Biosynthesis of Tetrahydrocannabinol
Computational Evidence for Tunneling and a Hidden Intermediate in the Biosynthesis of Tetrahydrocannabinol
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DOI：
10.1021/jacs.1c11981
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发表时间：
2022-05-04
影响因子：
15
通讯作者：
Doubleday, Charles
中科院分区：
文献类型：
--
作者：
Greer, Edyta M.;Siev, Victor;Doubleday, Charles
量子隧道计算的反应序列，模拟了大麻酚酸的邻醌方法1到脱羧产物(-)-反式δ 9-四氢大麻酚（THC,3）的转化。这个计算是第一个在这个序列中评估多维隧道的计算。采用POLYRATE和GAUSSRATE，采用B3LYP/6-31G（d,p）计算thc3的形成机制。thc3及其前体上的戊基链被甲基取代，以计算四个不同步骤的隧穿速率：(i)醌类化合物与香叶基1z - ch3的三取代烯烃端基初始diols - alder反应生成2z - ch3，（ii）酸催化的酮-烯醇互变异构，将2rz - ch3转化为4rz - ch3，（iii）羧基旋转化将4rz - ch3转化为4e - ch3，（iv）脱羧化将4e - ch3转化为3- ch3。在293 K时，隧道效应对步骤(i)-(iv)的速率常数的贡献在19% - 76%之间。在步骤（ii）中，零点振动能沿反应路径的不均匀变化在0 K自由能中产生了一个浅最小值。它是一个隐藏的中间体，因为它不是势能表面上的最小值，并且只有当沿着反应路径考虑零点能量时才能检测到。预测的动力学同位素效应将在方便使用的温度下通过实验观察到。这与反应序列的脱羧阶段特别相关，并且由于其在thc3形成中的作用而具有重要意义
Quantum tunneling is computed for a reaction sequence that models the conversion of theortho-quinone methideof cannabigerolic acid1to the decarboxylated product (-)-trans-Delta 9-tetrahydrocannabinol (THC,3). This calculation is thefirst to evaluatemultidimensional tunneling in this sequence. Computations werecarried out with POLYRATE and GAUSSRATE using B3LYP/6-31G(d,p) to examine the mechanism of THC3formation. The pentylchain on THC3and its precursors were replaced with a methyl groupto compute tunneling contributions to the rates of four separate steps:(i) initial Diels-Alder reaction of the quinone methide with thetrisubstituted alkene end-group of the geranyl1Z-CH3to give2Z-CH3,(ii) acid-catalyzed keto-enol tautomerization, which converts2rZ-CH3to4rZ-CH3, (iii) carboxyl rotamerization converting4rZ-CH3to4E-CH3, and (iv) decarboxylation that converts4E-CH3to3-CH3.Tunneling contributions to the rate constants of steps (i)-(iv) are between 19 and 76% at 293 K. In step (ii), nonuniform changes inthe zero-point vibrational energy along the reaction path created a shallow minimum in the 0 K free energy. It is ahidden intermediatebecause it is not a minimum on the potential energy surface and is detectable only when zero-point energy is taken into accountalong the reaction path. Predicted kinetic isotope effects would be experimentally observable at temperatures that are convenient touse. This is particularly relevant in the decarboxylation stage of the reaction sequence and has important implications because of its role in THC3formation