Synthesis of [beta]-heteroaryl propionates via trapping of carbocations with [pi]-nucleophiles, efforts towards the total synthesis of acutumine, and the design, synthesis, and thermodynamics of protein-ligand interactions at the Src SH2 domain

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2013-12

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Abstract

Heterocyclic alcohols were coupled with [pi]-nucleophiles in the presence of trimethylsilyl trifluoromethanesulfonate to provide a variety of substituted [beta]-heteroaryl propionates, including those with contiguous quaternary centers. This reaction also provided [beta]-heteroaryl propionates which were previously inaccessible by known methods by exploiting non-traditional Friedel Crafts reactivity. Good diastereoselectivity was also achieved when a chiral auxiliary was incorporated into the [pi]-nucleophile. Progress towards the synthesis of acutumine, an alkaloid possessing a densely functionalized aza-propellane core, two quaternary centers, and a neopentylic chlorine atom, was pursued. A variety of routes were employed, with some of the key steps explored including a Moore cyclization between dimethyl squarate and protected butyn-3-ols, a SmI₂ mediated ring opening of a densely functionalized dihydroisoquinoline ring, and a Stille reaction to install an key allyl functional handle. The thermodynamics behind the binding affinity of various ligands to the Src SH2 domain was also investigated. A series of four ligands were designed and enantioselectively synthesized in order to compare how differences in the conformations of the ligands affect the thermodynamics of binding. Namely, cyclopropanes were introduced into tetrapeptides to restrict the ligands to their binding conformations. The constricted ligands will then be compared to their appropriate flexible controls via the use of isothermal titration calorimetry (ITC) to determine the thermodynamics differences of binding between the two.

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