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Racemization Studies and Absolute Stereochemistry Determination of Cannabichromene and Development of Cine Substitution of N-Phenylsulfonyl 3-Substituted Indoles


Cannabichromene (CBC) is a cannabinoid of special interest because it has been reported as both scalemic and racemic from Cannabis plants with an unknown absolute stereochemistry. This observation can be explained by the (partial) racemization of the natural, or original, single CBC enantiomer produced through biosynthesis. CBC was resolved chromatographically, and the enantiomer matching the major enantiomer of scalemic CBC isolated from commercially available, naturally derived cannabinoid products was identified. It was determined that CBC racemized rather slowly under laboratory conditions. However, irradiation of CBC with sunlight can lead to facile racemization. Due to unsuccessful attempts of resolving CBC as well as to prevent its potential racemization, CBC was converted to its [2 + 2] cycloaddition product, cannabicyclol (CBL). Natural CBC was determined as the R absolute stereochemistry based on chiroptical data for related natural products and the absolute configuration of a CBL analog determined by X-ray crystallography.

The derivatization of indoles is an important transformation because of the numerous biologically relevant indole-containing compounds. Due to their electron-rich nature, indoles typically behave as nucleophiles in a reaction. However, indoles containing a leaving group on the nitrogen and an electron-withdrawing group on the ring can undergo a cine substitution reaction allowing for C2-functionalization. Pioneering work of Somei showed the cine substitution of N-methoxy 3-formylindole with a variety of oxygen-, nitrogen-, and carbon-centered nucleophiles. However, due to the lack of availability of N-methoxy indoles and challenge of making them, N-sulfonyl indoles were chosen as ideal substrates for cine substitution. The cine substitution of N-phenylsulfonyl 3-substituted indoles with primary alkyl alcohol nucleophiles afforded the desired products in 67 to 88% yield. Formation of side products, for example, 3-substituted indole and sulfonylated nucleophile, can be greatly dependent on the reaction conditions.

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