Abstract
Eighteen (2RS,6RS)-2-(4-methoxyphenyl)-6-(substituted ethyl)dihydro-2H-pyran-4(3H)ones were synthesized via a DDQ-mediated oxidative carbon-hydrogen bond activation reaction. Fourteen of these tetrahydropyrans were substituted with triazoles readily assembled via azide-alkyne click-chemistry reactions. Examples of a linked benzotriazole and pyrazole motif were also prepared. To complement the structural diversity, the alcohol substrates were obtained from stereoselective reductions of the tetrahydropyrone. This library provides rapid access to structurally diverse non-natural compounds to be screened against a variety of biological targets.
Highlights
Natural products and their derivatives continue to provide innovative sources for drug discovery [1,2,3,4]
We describe our diversity-oriented synthesis (DOS) approach to generate a structurally diverse set of triazole-substituted tetrahydropyrans [8,9]
We have recently demonstrated that tetrahydropyrans (THPs) can be formed in high diastereocontrol from benzylic and allylic ethers through a DDQ-mediated (2,3-dichloro-5,6-dicyano1,4-benzoquinone) oxocarbenium ion formation followed by an intramolecular nucleophilic addition [21,22]
Summary
Natural products and their derivatives continue to provide innovative sources for drug discovery [1,2,3,4]. Novel chemical scaffolds (i.e., chemotypes) can provide opportunities to investigate biological targets or pathways that may be inaccessible using only the array of currently known natural products, clinically used compounds, or traditional (hetero)aromatic building blocks In this communication, we describe our diversity-oriented synthesis (DOS) approach to generate a structurally diverse set of triazole-substituted tetrahydropyrans [8,9]. We have recently demonstrated that tetrahydropyrans (THPs) can be formed in high diastereocontrol from benzylic and allylic ethers through a DDQ-mediated (2,3-dichloro-5,6-dicyano1,4-benzoquinone) oxocarbenium ion formation followed by an intramolecular nucleophilic addition [21,22] This versatile methodology is both step [23] and atom[24] efficient, and has been successfully applied to a series of THP-containing natural products [25,26,27,28]. This report will focus on the construction of triazole- (and related heterocyclic) tethered tetrahydropyrones using azide-alkyne ‘click’ chemistry [29,30]
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