Total Syntheses of Thailanstatins A-C, Spliceostatin D, and Analogues Thereof. Stereodivergent Synthesis of Tetrasubstituted Dihydro- and Tetrahydropyrans and Design, Synthesis, Biological Evaluation, and Discovery of Potent Antitumor Agents

摘要

Efficient and selective total syntheses of spliceosome modulating natural products thailanstatins A–C and spliceostatin D are reported. A number of stereoselective methods for the construction of various tetrasubstituted dihydro- and tetrahydropyrans were developed as a prerequisite for the syntheses of these naturally occurring molecules and variations thereof. The pyran-forming reactions utilize a Heck/Saegusa–Ito cascade sequence to generate hydroxy α,β,γ,δ-unsaturated aldehyde precursors followed by a catalyst-controlled oxa-Michael cyclization to furnish tetrasubstituted dihydropyrans with high stereocontrol. Subsequent optimized homogeneous or heterogeneous hydrogenations of these dihydropyran systems afford their tetrahydropyran counterparts, also in a highly stereoselective manner. The synthesized thailanstatins and related analogues were biologically evaluated for their cytotoxic properties, leading to the identification of a number of compounds with exceptionally potent antitumor activities suitable for further development as potential antibody–drug conjugate payloads, single drugs, or drug combinations for cancer therapies. Important structure–activity relationships within the thailanstatin family and structurally related compounds are discussed and are expected to be path-pointing for future studies.