Cyclopropene cycloadditions with annulated furans: total synthesis of (+)- and (-)-frondosin B and (+)-frondosin A.

The asymmetric total syntheses of the natural products (+)- and (-)-frondosin B and (+)-frondosin A are reported based on a diastereoselective cycloaddition between tetrabromocyclopropene and an annulated furan to provide a highly functionalized common building block. The bridged bicyclic intermediate could be stereo- and chemoselectively manipulated to produce the two structurally distinct members of the frondosins. Both syntheses feature regioselective palladium-coupling reactions and an unprecedented phosphine-mediated ether bridge cleavage. Surprisingly, the planned enantioselective synthesis of frondosin B led to the opposite epimer of the natural product, suggesting an unusual late stage stereoinversion at C8. Frondosin A, but not frondosin B, was shown to have selective antiproliferative activity against several B-cell lines.

Studies on the antiproliferative effects of tropolone derivatives in Jurkat T-lymphocyte cells.

Thujaplicins are tropolone-derived natural products with antiproliferative properties. We recently reported that certain tropolones potently and selectively target histone deacetylases (HDAC) and inhibit the growth of hematological cell lines. Here, we investigated the mechanisms by which these compounds exert their antiproliferative activity in comparison with the pan-selective HDAC inhibitor, vorinostat, using Jurkat T-cell leukemia cells. The tropolones appear to work through a mechanism distinct from vorinostat. These studies suggest that tropolone derivatives may serve as selective epigenetic modulators of hematological cells with potential applications as anti-leukemic or anti-inflammatory agents.

Stereodivergent resolution of oxabicyclic ketones: preparation of key intermediates for platensimycin and other natural products.

An improved methodology for the preparation of enantiopure oxabicyclo[3.2.1]octadienes via a stereodivergent resolution is reported. High catalyst control proximal to the oxabridged stereocenter produces readily separable diastereomers in high yield (>92%) and with excellent optical purity (>95% ee). This resolution strategy is amenable to large-scale preparations, and the utility of the resolution was further demonstrated in the asymmetric preparation of a key intermediate used in the synthesis of the antibiotic (-)-platensimycin.

Continuous Flow-Enabled Synthesis of Bench-Stable Bicyclo[1.1.1]pentane Trifluoroborate Salts and Their Utilization in Metallaphotoredox Cross-Couplings.

Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C(sp2)-C(sp3) cross-coupling of these fragments to afford biaryl isosteres have been scarce. Herein we describe the development of continuous flow-enabled synthesis of bench-stable bicyclo[1.1.1]pentane trifluoroborate salts. Furthermore, we demonstrate the use of metallaphotoredox conditions to enable cross-coupling of these building blocks with complex aryl halide substrates.

Tropolones as lead-like natural products: the development of potent and selective histone deacetylase inhibitors.

Natural products have long been recognized as a rich source of potent therapeutics but further development is often limited by high structural complexity and high molecular weight. In contrast, at the core of the thujaplicins is a lead-like tropolone scaffold characterized by relatively low molecular weight, ample sites for diversification, and metal-binding functionality poised for targeting a range of metalloenzyme drug targets. Here, we describe the development of this underutilized scaffold for the discovery of tropolone derivatives that function as isozyme-selective inhibitors of the validated anticancer drug target, histone deacetylase (HDAC). Several monosubstituted tropolones display remarkable levels of selectivity for HDAC2 and potently inhibit the growth of T-cell lymphocyte cell lines. The tropolones represent a new chemotype of isozyme-selective HDAC inhibitors.