Dipartimento di Farmacia, Università di Napoli Federico II, Via Montesano 49, 80131 Napoli, Italy.
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale, Largo Donegani 2, 28100 Novara, Italy.
Bioorg Med Chem. 2018 Aug 15;26(15):4532-4536. doi: 10.1016/j.bmc.2018.07.044. Epub 2018 Jul 27.
Electrophilic attack to a double bond, the classic trigger of intramolecular isoprenoid cyclizations, is apparently silent in Cannabis and the diversity of the cannabinome can be ultimately traced to the oxidative cyclization of cannabigerolic acid (CBGA, 1a), a process triggered by the generation of an aromatic electrophilic species. To expand the chemical space of the cannabinoid chemotype, we have investigated an oxidative trigger based on the addition of iodine to the terminal isoprenyl double bond of cannabigerol (CBG, 1b), the decarboxylated and thermally stable version of CBGA (1a). Apart from the predictable product of an iodine-induced cascade cyclization (3), also a pair of unprecedented spiranes named spirocannabigerols (4a,b), derived from the formation of an edge-protonated cyclopropyl cation was also formed, along with a product (5) resulting from the incorporation, in a Friedel-Craft fashion, of the reaction solvent (toluene). Biological evaluation of these compounds on six thermo-transient receptor potential channels (TRPs) showed a remodeling of bioactivity compared to GBC, with emphasis on TRPA1 rather than TRPM8.
亲电试剂攻击双键，这是典型的萜类化合物分子内环化反应的触发因素，但在大麻中这种反应显然是沉默的，大麻素组的多样性最终可以追溯到大麻萜酚酸（CBGA，1a）的氧化环化，这是一个由芳香亲电物种生成引发的过程。为了扩大大麻素化学型的化学空间，我们研究了一种基于碘对大麻二醇（CBG，1b）末端异戊二烯双键加成的氧化触发反应，这是 CBGA（1a）脱羧和热稳定的版本。除了可以预测的碘诱导级联环化产物（3）之外，还形成了一对前所未有的螺旋烷，称为螺环大麻二醇（4a，b），这是通过形成边缘质子化环丙基阳离子形成的，同时还生成了一个产物（5），这是通过傅里德-克拉夫特反应（Friedel-Craft reaction）引入反应溶剂（甲苯）的结果。这些化合物对六个热瞬态受体电位通道（TRPs）的生物评估显示，与 GBC 相比，生物活性发生了重塑，重点是 TRPA1 而不是 TRPM8。
