Resveratrol is a compound, which positively influences human health and also extends lifespan through cellular metabolism reorganisation. While resveratrol continues to be the focus of numerous studies, its oligomers are becoming increasingly interesting due to their targeted effects and higher molecular complexity. These oligomers often contain a substituted indane ring, which is a component of many drugs and lead structures. Due to the presence of three or more chiral centres in resveratrol oligomers, the synthesis of stereomerically pure analogues of these compounds is desirable but still challenging.
In the scope of this master’s thesis, we prepared synthetic intermediates of analogues of caraphenol C (library A) and pallidol (library B). For the compounds in library A, we first performed highly selective reductions of 1-indanones with Noyori-Ikariya-type catalysts. The resulting alcohols were then used in Friedel-Crafts alkylation reactions with various aromatic rings. This gave compounds 4a-h, for which we evaluated the selectivity of alkylation by determining the diastereomeric ratio between trans,trans and cis,trans stereomers. For the compounds in library B, we attached a diol with a dibenzopentalene base to the same aromatic rings via Friedel-Crafts alkylation. In this case, we also evaluated the diastereoselectivity of the alkylation reaction by analysing the compounds 4i-n. The purpose of library C was to evaluate the effects of a methoxycarbonyl substituent on the yield and selectivity of the alkylation reaction.
Based on analysis of compounds 4a-h, we found that o-substituted anisole derivatives were the least trans,trans selective. The least diastereoselective reaction occurs with o-bromoanisole (compound 4d), where a significant fraction of the cis,trans product is formed due to the low steric hindrance of the bromine atom in the ortho position and π-π interactions between the aromatic rings. The highest proportion of trans,trans diastereomers is formed in the alkylation of m-cresol (compound 4g), where the methyl group in the meta position is a significant steric hindrance. The compounds from library B consistently exhibit a trans,trans configuration close to or greater than 99%, regardless of the substituents on the aromatic ring, due to the more rigid dibenzopentalene base. For the compounds from library C (compounds 4o and 4p), the absence of a methoxycarbonyl group on the indanol scaffold results in a lower yield for Friedel-Crafts alkylation, but does not significantly affect diastereoselectivity. Biological analysis of analogs of palidol with a reduced number of hydroxyl groups on estrogen receptors α revealed their agonistic activity. Such compounds are potential lead compounds for new anti-osteoporotic drugs.
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