The 'safety-catch' principle in solid-phase linkage strategies and diastereoselective enolate alkylation reactions

The solid-phase synthesis of small molecule libraries can expedite the identification of ligands to biological receptors, and ligands for asymmetric synthesis. The development of general and high yielding methods for solid-phase synthesis is needed to access structurally and functionally diverse libraries. In particular, the development of new linkage strategies for attaching the initial substrates to support is of the utmost importance since the choice of linker dictates the methods that can be employed in a synthesis sequence. When we began our studies, the choice of linkers available for the solid-phase organic synthetic chemist were limited to those employed for peptide and oligonucleotide chemistry. This thesis describes the development and application of new linkage strategies for the preparation of small molecule libraries.;Chapter 1 reviews recent linkage strategies for solid-phase synthesis in which linkers are shown to fulfill important roles in the synthesis and assay of target compounds. Chapter 2 describes our development of a variant of Kenner's arenesufonamide "safety-catch" linker for tethering carboxylic acids to support. We employed the linker for the synthesis of alpha-substituted arylacetic acid derivatives that represent an important class of cyclooxygenase inhibitors and antiinflammatory drugs. The linkage is compatible with a broad range of reaction conditions, yet can be cleaved under mild conditions after a discrete activation step. Carbon-carbon bond-forming reactions, namely, enolate alkylation reactions and Suzuki cross-couplings were employed in the synthesis sequence demonstrating the stability of the linkage towards basic reaction conditions. After an activation step, support-bound compounds were cleaved with nucleophiles to provide target compounds in solution. Chapter 3 describes the development of an N-acylsulfonamide activation method that provides a support-bound active ester equivalent for displacement with a variety of nucleophiles under mild reaction conditions. Chapter 4 describes the development of a second alkanesulfonamide linker that was required to generalize our methods for the loading, activation, and cleavage of alpha-amino acid derivatives. All 20 proteinogenic amino acids when suitably protected can be employed in these methods.;The final chapter describes the development of sulfinamides as dual chiral auxiliaries and linkers for the multi-step solid-phase synthesis of enantioenriched target compounds. Chiral N-acylsulfinamides were shown to facilitate diastereoselective enolate alkylations employing both unreactive and reactive alkylating agents. After an activation step, nucleophilic cleavage provided enantioenriched carboxylic acid, ester, amide, and alcohol target compounds.