**1. Introduction**

Tyrosol **1** (4-hydroxyphenethyl alcohol), homovanillyl alcohol **2** (3-hydroxy-4-methoxyphenethyl alcohol) and hydroxytyrosol **3** (3,4-dihydroxyphenethyl alcohol) are low-molecular weight phenols (Figure 1) found mainly in olive mill wastewater, the by-products of the olive oil production [1,2], from which they can be extracted using environmentally and economically sustainable technologies [3,4] and reused according to the circular economy strategy [5].

**Figure 1.** Low-molecular weight phenols found in olive mill wastewater.

They are valuable compounds, displaying a high number of health-promoting effects such as antioxidant, anti-inflammatory and anticancer activity [6,7]. In particular, tyrosol **1** suppresses allergic inflammatory disorders [8], and prevents apoptosis in irradiated keratinocytes [9]. In addition, it is useful to synthetize novel antioxidants [10,11]. Homovanillyl alcohol **2** is a good antioxidant agen<sup>t</sup> [12] and exhibits anti-inflammatory e ffects on human gastric adenocarcinoma cells [13]. In accordance with the theoretical predictions on *ortho*-diphenols [14], hydroxytyrosol **3** is the most powerful antioxidant found in olive oil by-products. In addition, it increases high-density lipoprotein (HDL)-cholesterol, inhibits inflammation, improves endothelial function, decreases tumor growth and metastasis, and protects the central nervous system [15–18]. In our experiment, hydroxytyrosol was synthetized by the 2-iodoxybenzoic acid (IBX) oxidation of tyrosol by safe and eco-friendly procedures [19,20] and used to prepare both hydroxytyrosol-derived compounds [21–23] and poly(vinyl alcohol)-based films with antioxidant activity [24–26].

Despite the remarkable biological properties of these compounds, their applicability as active ingredients in lipophilic foods and cosmetic products requiring solubility in non-aqueous media is limited for the hydrophilic character. With the aim to overcome this limitation, common for almost all phenolic compounds, recently, a growing interest has been devoted to synthesizing lipophilic derivatives. They could be prepared incorporating one or more halogen atoms [27–29] or by introducing di fferent chain lengths [30–40] into the molecular skeleton, avoiding the derivatization of the phenolic moiety to which the biological e ffects, and in particular the antioxidant activity, are attributed.

Among them, tyrosyl, homovanillyl and hydroxytyrosyl esters with di fferent chain lengths proved promising for their beneficial e ffects in non-aqueous media related to their lipophilicity and bioavailability. In particular, antioxidant activity and this relationship with chain length were the objects of many studies. In emulsified systems, the antioxidant activity of alkyl esters is directly related to the chain length: it increases up to a point (C8–C10) and then dramatically decreases [33], revisiting the polar paradox theory [41]. This e ffect, named "the cut-o ff effect", was explained with the surfactant property of lipophilic derivatives. C8–C10 hydroxytyrosyl esters are both the best antioxidants and surfactants [33]. Other studies have shown that esters with medium length chains have comparable or higher antioxidant activity than esters with long chains [42]. Tyrosyl esters were tested as antimicrobial and antileishmanial agents [35] and, recently, their absorption and stability in the intestinal lumen were investigated [43]. This study has demonstrated that lipophilic tyrosol esters were well absorbed by the intestinal lumen, confirming the relevant role of the alkyl chain [43]. Lipophilic hydroxytyrosol esters are good candidates as active ingredients of formulations for the treatment of cutaneous inflammations, permeating through the human stratum corneum and viable epidermis membrane and releasing hydroxytyrosol, which is the antioxidant and anti-inflammatory agen<sup>t</sup> [44].

Based on the literature data, and the need to prepare lipophilic phenolic derivatives for extending their use in food and cosmetic sectors, we planned a simple and low-cost procedure to obtain tyrosyl, homovanillyl and hydroxytyrosyl alkyl esters. Finally, the procedure was applied to hydroxytyrosol-enriched extracts obtained by *Olea europaea* by-products to prepare a panel of lipophilic extracts that are useful for applications where solubility in lipid media is required.

#### **2. Materials and Methods**
