The Prins reaction was the basis to synthesize functionalized alkyl chlorodihydropyran derivatives. The inexpensive, stable, and environmentally friendly FeCl(3) promotes the cyclization. The method represents an efficient and regioselective manner to obtain in a single step chlorovinyl-TMS oxacycles. The in vitro antiproliferative activities of the compounds were examined in the human solid tumor cell lines A2780 (ovarian cancer), SW1573 (non-small cell lung cancer), and WiDr (colon cancer). Overall, the results show an enhancement in the cytotoxicity exhibited by the new analogs when compared to their parental compounds.