Diversity-Oriented Synthesis of a Library of Substituted Tetrahydropyrones Using Oxidative Carbon-Hydrogen Bond Activation and Click Chemistry.docVIP

Molecules 2011, 16, 3648-3662; doi:10.3390/moleculeOPEN ACCESS molecules ISSN 1420-3049 /journal/molecules Article Diversity-Oriented Synthesis of a Library of Substituted Tetrahydropyrones Using Oxidative Carbon-Hydrogen Bond Activation and Click Chemistry Nilesh Zaware 1, Matthew G. LaPorte 1, Ramy Farid 2, Lei Liu 1, Peter Wipf 1 and Paul E. Floreancig 1,* 1 Department of Chemistry and Center for Chemical Methodologies Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA 2 Schr?dinger, Inc., 120 West 45th Street, New York, NY 10036, USA * Author to whom correspondence should be addressed; E-Mail: florean@; Tel.: ?1 412-624-8727; Fax: ?1 412-624-8611. Received: 9 March 2011 / Accepted: 12 April 2011 / Published: 2 May 2011 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. Keywords: Tetrahydropyran; C-H activation; click-chemistry; diversity-oriented synthesis 1. Introduction Natural products and their derivatives continue to provide innovative sources for drug discovery [1-4]. However, many naturally occurring substrates appear to selectively target more highly connected networks associated with essential biological pathways [5,6]. The aims of the NIH supported Centers for Methodology and Library Design (CMLDs) are to pr