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

Abstract

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.