Many areas of health-related research are fueled by access to new organic molecules, and the field of organic synthesis is therefore a crucial biomedical discipline. Today, traditional methods of producing organic compounds are being augmented by combinatorial methods that simultaneously make many compounds. The goal of this grant is to develop general new methods for both traditional and combinatorial synthesis that use phase separation techniques for purification. The methods rely on the use of fluorous (highly fluorinated) liquid and solid phases that allow for simple yet very substantive separations. Building on work with fluorous tin reagents over the past granting period, a series of new fluorous phosphines with assorted fluorous tags will be synthesized and extensively studied as both ligands for catalysis and as stoichiometric reagents. In addition, a variety of new fluorous silyl and benzyl protecting groups for oxygen and fluorous carbamate protecting groups for nitrogen will be prepared and studied. The utility of these catalysts, reagents, and protecting groups will be demonstrated in parallel synthesis settings using equipment and instrumentation in the Center for Combinatorial Chemistry. All applications are in the so-called """"""""light fluorous mode,"""""""" where the fluorous tags are relatively small and the separation is by solid-phase extraction over fluorous reverse phase silica, The goal is to produce a new generation of fluorous reagents that mimic their organic parents in terms of reactivity but that are still readily separated from organic compounds. In addition to this focused work, we will pursue new methods to make mixture libraries based on a fluorous tagging approach, and we will introduce and study the first fluorous triphasic reactions. In these areas, the preliminary emphasis is to demonstrate that the new concepts and techniques are viable and to begin to understand them. Focused research towards practical applications will follow in due course. The research is designed to advance fluorous chemistry in both practical and conceptual directions, and thereby increase the level of understanding. In short, the work will help to move the very young field of fluorous chemistry from infancy into childhood.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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University of Pittsburgh
Schools of Arts and Sciences
United States
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Moretti, Jared D; Wang, Xiao; Curran, Dennis P (2012) Minimal fluorous tagging strategy that enables the synthesis of the complete stereoisomer library of SCH725674 macrolactones. J Am Chem Soc 134:7963-70
Gudipati, Venugopal; Curran, Dennis P (2011) Synthesis of C1-C20 and C21-C40 fragments of tetrafibricin. Tetrahedron Lett 52:2254-2257
Moura-Letts, Gustavo; Curran, Dennis P (2007) Selective synthesis of (2Z,4E)-dienyl esters by ene-diene cross metathesis. Org Lett 9:5-8
Du, Wu; Curran, Dennis P; Bevins, Robert L et al. (2002) Synthesis and evaluation of a novel E-ring modified alpha-hydroxy keto ether analogue of camptothecin. Bioorg Med Chem 10:103-10