The rubellins are a family of stereochemically complex anthraquinoid heterodimers containing an unprecedented chemical scaffold. Although the rubellins have been known for over three decades, no total synthesis has been achieved since their discovery. Their topology is characterized by a 6–5–6 fused ring system, five neighboring stereocenters including a quaternary center all in a convoluted core, and an anthraquinone nucleus. The rubellin architecture has been shown to inhibit and reverse the aggregation of tau protein, a therapeutically relevant target for Alzheimer’s disease. Herein, we describe the first stereoselective synthesis of a member of the family, (+)-rubellin C, in 16 steps. Strategic disconnections allow expedient construction of stereochemical and topological intricacy in a short sequence of borylative and transition metal-catalyzed steps.

The [1,2]- and [2,3]-rearrangements of iodonium ylides are synthetically useful reactions for the generation of functionalized α-iodoesters. Allylic iodides are coupled with α-diazoesters in the presence of a copper catalyst and a ligand to generate iodonium ylides, which undergo metal-mediated rearrangements. By fine-tuning the structure of the ligand, we have reversed the regioselectivity of copper-catalyzed reactions of iodonium ylides from [2,3]- to [1,2]-rearrangements with the use of alternate bipyridine ligands. The preference for [1,2]-rearrangements was further improved by using bulky aryl α-diazoester substrates. Several α-iodoesters with a diverse range of functional groups were generated in good yields (up to 88% yield) and high regioselectivities (up to >95:5 regioisomeric ratio). A deuterium-labeled substrate was utilized to gain insight into the mechanism of the reaction.

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We herein report an enantioselective bioreduction of ketones that bear the most frequently used nitrogenheteroaromatics in FDA-approved drugs. Ten varieties of these nitrogen-containing heterocycles were systematically investigated. Eight categories were studied for the first time and seven types were tolerated, significantly expanding the substrate scope of plantmediated reduction. By use of purple carrots in buffered aqueous media with a simplified reaction setup, this biocatalytic transformation was achieved within 48 h at ambient temperature, offering medicinal chemists a pragmatic and scalable tool to access a broad variety of nitrogen-heteroaryl-containing chiral alcohols. With multiple reactive sites, the structurally diverse set of chiral alcohols can be used for library compound preparation, early routescouting activities, and synthesis of other pharmaceutical molecules, favorably accelerating medicinal chemistry campaigns.

This manuscript describes our studies of the class of natural products known as the rubellins, culminating in the total synthesis of (+)-rubellin C. These anthraquinone-based natural products contain a variety of stereochemical and architectural motifs, including a 6-5-6-fused ring system, 5 stereogenic centers, and a central quaternary center. Herein, we report our development of a strategy to target the stereochemically dense core and anthraquinone nucleus, including approaches such as a bifunctional allylboron and vinyl triflate reagent, an anthraquinone benzylic metalation strategy, and a late-stage anthraquinone introduction strategy. Our studies culminate in a successful route to highly functionalized anthraquinone-based natural product scaffolds and a stereoselective total synthesis of (+)-rubellin C. These strategies and outcomes will aid in synthetic planning toward anthraquinonebased natural products of high interest.