The sulfone linker in solid-phase organic synthesis: Development of cleavage strategies for the preparation of small molecules

Solid-phase organic synthesis (SPOS) has become a powerful tool in combinatorial chemistry. Linker moieties play a key role in any successful SPOS route as they covalently link the polymeric support and the building block. The ideal linker must readily tether a substrate to the solid support and be stable during various chemical transformations, while at the same time, enable cleavage under specific conditions. Through our efforts, we have successfully demonstrated that a sulfinate-functionalized resin (styrene/1--2% divinyl benzene copolymer beads) can be efficiently prepared and utilized in SPOS. The resulting sulfone linker is shown to be a robust and versatile traceless linker.; In Chapters 1 to 5, various transformations were employed, for examples: S-alkylation, alpha,alpha-dialkylation, SO-2 extrusion, Diels-Alder cycloaddition, Michael addition, 1,3-dipolar cycloaddition, epoxidation and oxirane-ring opening. To liberate our desired molecules from the solid support, new cleavage strategies were developed. In Chapter 1, palladium-catalyzed SN2' sulfinate displacement was performed with resins containing allyl sulfone moieties. The cyclobutylidines were generated with three diversities. By contrast, with resin containing a vinyl sulfone moiety, the specific cleavage protocol was to generate a heterocyclic pyrrole ring with simultaneous cleavage of the sulfone linker. The target molecules---4,5,6,7-tetrahydroisoindole derivatives---were built with two diversities and this work is discussed in Chapter 2.; The third cleavage strategy is oxidation with concomitant beta-elimination of polymer-bound benzenesulfinate. Novel isoxazolocyclobutanones and isoxazolinocyclobutenones (Chapter 3), functionalized alpha,beta-unsaturated ketones (Chapter 4), and 3,5-disubstituted cyclopent-2-ones (Chapter 5) were released from the solid support by this protocol.; The last chapter (Chapter 6) reports the synthesis of unnatural spiroisoxazolinoproline-based amino acids and derivatives. In addition, the key stereoselectivitic 1,3-dipolar cycloadditions with various 4-methylene-1-proline esters were investigated.