Thailanstatin D

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.

Thailanstatin A has been isolated recently from the fermentation broth of B. thailandensis MSMB43. We describe here an enantioselective convergent synthesis of thailanstatin A methyl ester and evaluation of its splicing activity. Synthesis of both highly functionalized tetrahydropyran rings were carried out from commercially available tri- O-acetyl-d-glucal as the key starting material. Our convergent synthesis involved the synthesis of both tetrahydropyran fragments in a highly stereoselective manner. The fragments were then coupled using cross-metathesis as the key step. The synthesis of the diene subunit included a highly stereoselective Claisen rearrangement, a Cu(I)-mediated conjugate addition of MeLi to set the C-14 methyl stereochemistry, a reductive amination reaction to install the C16-amine functionality, and a Wittig olefination reaction to incorporate the diene unit. The epoxy alcohol subunit was synthesized by a highly selective anomeric allylation, a Peterson olefination, and a vanadium catalyzed epoxidation that installed the epoxide stereoselectively. Cross-metathesis of the olefins provided the methyl ester derivative of thailanstatin A. We have carried out in vitro splicing studies of the methyl ester derivative, which proved to be a potent inhibitor of the spliceosome.

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.