Science of Synthesis

Vashchenko, B. V.; Grygorenko, O. O., Science of Synthesis Knowledge Updates, (2021) 3, 243.

General Introduction

While the parent 1,4-dioxane is widely used as a solvent in organic synthesis and is produced in ton quantities, substituted 1,4-dioxanes have also been recognized as useful chemotypes in organic synthesis and drug discovery, with improved pharmacokinetics, solubility, or bioavailability of their derivatives.[‌1‌] This scaffold can be applied for bioisosteric replacement of sp3-enriched carbo- and heterocycles, i.e. piperidine, piperazine, or morpholine, to modify the number and strength of hydrogen-bond acceptors and the overall hydrophilicity of potential drugs. Thus, molecules decorated with a 1,4-dioxane moiety are becoming more attractive for medical purposes, and a significant number of natural products and pharmaceutical agents have been disclosed.[‌2‌–‌6‌] Representative examples include marketed antibiotic spectinomycin (‌1‌),[‌7‌,‌8‌] c-Met kinase inhibitor MK-2461 (‌2‌) with in vivo anticancer activity,[‌9‌] non-receptor tyrosine protein kinase TYK2 inhibitor ‌3‌,[‌10‌] inhibitors ‌4‌ and ‌5‌ of epidermal growth factor activated receptor (EGFR),[‌11‌] muscarinic receptor antagonist ‌6‌,[‌12‌–‌15‌] and bis(1,4-dioxanyl) antiviral agent ‌7‌ (‌Scheme 1‌).[‌16‌]

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References