Applications of B-Lactones: Utility of Spiroepoxy-B-Lactones and Development of a Double Diastereoselective Nucleophile Catalyzed, Aldol-Lactonization Process Leading to !-Lactone Fused Carbocycles and Tetrahydrofurans
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Natural products continue to inspire synthetic chemists to develop novel methodologies to provide efficient and expedient syntheses of the target molecules. Haterumalide NA aroused our interest and prompted development of four differing methodologies. Three of the strategies pursued involved use of B-lactone scaffolds as intermediates. Extensions of the nucleophile catalyzed, aldol-lactonization (NCAL) reaction were also pursued and targeted toward alternative natural product targets. The reactivity of the unexpectedly stable strained spirocycle, spiroepoxy-B- lactone, was explored. Spiroepoxy-B-lactones exhibited a wide range of reactivity, but largely rearranged to tetronic acids. The desired reaction manifold remained inaccessible and led to application of the NCAL process to tetrahydrofuran-fused B-lactones. Several tetrahydrofuran-fused B-lactones were prepared, which displayed low diastereoselectivity. The diastereoselectivity could be somewhat improved in a double diastereoselective NCAL process with varied solvent systems, yet the carbocyclic analogues gave much more promising results. The use of carbocycle-fused !-lactones ultimately culminated in a double diastereoselective NCAL process, and overall led to improvements in diastereoselectivities from 1:1-2 up to >19:1. Further expansion of the substrate scope for the NCAL process was studied for application to bridged tricyclic B- lactones, access to carbocycle-fused y-lactones, and towards development of a dynamic kinetic resolution NCAL process. With our interest aimed at haterumalide NA, a modified Negishi cross coupling between zincates and dichloroolefins was also revisited. The stringent anhydrous reaction conditions led to reexamination of initial leads, which provided user-friendly anhydrous conditions by utilizing commercially available anhydrous solvent. However, application was implemented solely to a simplified model system.
double asymmetric synthesis
Negishi cross coupling
Morris, Kay A. (2010). Applications of B-Lactones: Utility of Spiroepoxy-B-Lactones and Development of a Double Diastereoselective Nucleophile Catalyzed, Aldol-Lactonization Process Leading to !-Lactone Fused Carbocycles and Tetrahydrofurans. Doctoral dissertation, Texas A&M University. Available electronically from
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