The Synthetic and Biological Aspects of Prenylation as the Versatile Tool for Estrogenic Activity Modulation

Abstract

Prenyl group is a ubiquitous structural moiety in natural compounds showing a wide spectrum of different biological activities with potential benefits for human health. This review presents the current knowledge on the prenylation of aromatic compounds such as flavonoids and coumarins. The references to the ‘classical’ methods that encompass Friedel‐Crafts reaction using prenyl alcohol and boron trifluoride, and alkylation with prenyl bromide in the presence of strong bases are given in comparison with the most state‐of‐the‐art prenylation methods. This review highlights the marked advance that has been achieved so far and makes prenyl group installment a versatile tool in the synthesis of drug candidates, natural compounds, and building blocks. Different aspects of prenyl group assembling methods are reported in more than 30 syntheses of natural substances and their analogues. The last part highlights a role of prenylation in flavonoid bioavailability and bioactivity modulation especially regarding their estrogenicity.

8‐Prenylflavanones through Microwave Promoted Tandem Claisen Rearrangement/6‐endo‐trig Cyclization and Cross Metathesis

“…[1,2] Bioactivities of these compounds such as antibacterial and anti-oxidant activity, cytotoxicity and estrogenic activity modulation, have been summarized and discussed in several recent reviews. [3][4][5][6] Prenyl substituents generally increase the bioactivities of flavonoids. This has been attributed to an enhanced membrane permeability, which is caused by the higher lipophilicity compared to the analogous non-prenylated natural products.…”

Prenylcoumarins in One or Two Steps by a Microwave-Promoted Tandem Claisen Rearrangement/Wittig Olefination/Cyclization Sequence

“…The chemical synthesis of C -prenylated coumarins and other phenylpropanoids is often accomplished via thermally induced Claisen rearrangements of either prenyl- or 1,1-dimethylallyl ethers of phenols . While 1,1-dimethylallyl ethers undergo a rearrangement to ortho -prenylated phenols, prenyl ethers react to afford para -prenylated phenols through successive Claisen and Cope rearrangements .…”

“…While 1,1-dimethylallyl ethers undergo a rearrangement to ortho -prenylated phenols, prenyl ethers react to afford para -prenylated phenols through successive Claisen and Cope rearrangements . Many syntheses of C6- or C8-prenylated coumarins start from precursors with a preformed coumarin skeleton and an unprotected hydroxy group, such as umbelliferone, which is first 1,1-dimethylpropargylated, then partially hydrogenated to the 1,1-dimethylallylether, and finally heated to induce a Claisen rearrangement to the prenylated coumarin . To access a wider scope of substitution patterns, it is often advantageous to start from other aromatic compounds and construct the coumarin scaffold during the synthesis.…”

“…2 The chemical synthesis of C-prenylated coumarins and other phenylpropanoids is often accomplished via thermally induced Claisen rearrangements of either prenyl-or 1,1-dimethylallyl ethers of phenols. 21 While 1,1-dimethylallyl ethers undergo a rearrangement to ortho-prenylated phenols, prenyl ethers react to afford para-prenylated phenols through successive Claisen and Cope rearrangements. 22 Many syntheses of C6-or C8prenylated coumarins start from precursors with a preformed coumarin skeleton and an unprotected hydroxy group, such as umbelliferone, which is first 1,1-dimethylpropargylated, then partially hydrogenated to the 1,1-dimethylallylether, and finally heated to induce a Claisen rearrangement to the prenylated coumarin.…”

Prenyl Praxis: A Method for Direct Photocatalytic Defluoroprenylation

“…The prenyl fragment is ubiquitous in a multitude of natural products, and is the fundamental building block of the biodiverse and efficacious terpenoids which present impressive and diverse biological activities. 1 Consequently, the development of prenylation strategies within the context of natural products 2 has been widely studied. 2–3 Many prenylation strategies involve multistep procedures, and one-step prenylation has only been solved for a narrow subset of substrates.…”