Design, Synthesis, and Biological Investigation of Thailanstatin A and Spliceostatin D Analogues Containing Tetrahydropyran, Tetrahydrooxazine, and Fluorinated Structural Motifs.

Thailanstatin A and spliceostatin D, two naturally occurring molecules endowed with potent antitumor activities by virtue of their ability to bind and inhibit the function of the spliceosome, and their natural siblings and designed analogues, constitute an appealing family of compounds for further evaluation and optimization as potential drug candidates for cancer therapies. In this article, the design, synthesis, and biological investigation of a number of novel thailanstatin A analogues, including some accommodating 1,1-difluorocyclopropyl and tetrahydrooxazine structural motifs within their structures, are described. Important findings from these studies paving the way for further investigations include the identification of several highly potent compounds for advancement as payloads for antibody-drug conjugates (ADCs) as potential targeted cancer therapies and/or small molecule drugs, either alone or in combination with other anticancer agents.

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.

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,ß,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.

Total Synthesis of Thailanstatin A.

The total synthesis of the spliceosome inhibitor thailanstatin A has been achieved in a longest linear sequence of nine steps from readily available starting materials. A key feature of the developed synthetic strategy is the implementation of a unique, biomimetic asymmetric intramolecular oxa-Michael reaction/hydrogenation sequence that allows diastereodivergent access to highly functionalized tetrahydropyrans, which can be used for the synthesis of designed analogues of this bioactive molecule.

Enantiospecific formal total synthesis of iriomoteolide 3a.

A formal total synthesis of the marine macrolide iriomoteolide 3a is described. Salient features of the synthesis include the elaboration of a ß-keto phosphonate derived from D-(-)-tartaric acid and the extension of a chiral butyrolactone derived from L-glutamic acid. Ring-closing metathesis is employed to construct the macrolactone core of the natural product.