Evolution of an Efficient and Scalable Nine-Step (Longest Linear Sequence) Synthesis of Zincophorin Methyl Ester

Because of both their synthetically challenging and stereochemically complex structures and their wide range of often clinically relevant biological activities, nonaromatic polyketide natural products have for decades attracted an enormous amount of attention from synthetic chemists and played an important role in the development of modern asymmetric synthesis. Often, such compounds are not available in quantity from natural sources, rendering analogue synthesis and drug development efforts extremely resource-intensive and time-consuming. In this arena, the quest for ever more step-economical and efficient methods and strategies, useful and important goals in their own right, takes on added importance, and the most useful syntheses will combine high levels of step-economy with efficiency and scalability. The nonaromatic polyketide natural product zincophorin methyl ester has attracted significant attention from synthetic chemists due primarily to the historically synthetically challenging C(8)–C(12) all-<i>anti</i> stereopentad. While great progress has been made in the development of new methodologies to more directly address this problem and as a result in the development of more highly step-economical syntheses, a synthesis that combines high levels of step economy with high levels of efficiency and scalability has remained elusive. To address this problem, we have devised a new synthesis of zincophorin methyl ester that proceeds in just nine steps in the longest linear sequence and proceeds in 10% overall yield. Additionally, the scalability and practicability of the route have been demonstrated by performing all of the steps on a meaningful scale. This synthesis thus represents by a significant margin the most step-economical, efficient, and practicable synthesis of this stereochemically complex natural product reported to date, and is well suited to facilitate the synthesis of analogues and medicinal chemistry development efforts in a time- and resource-efficient manner

Synthesis and Evaluation of a Linkable Functional Group-Equipped Analogue of the Epothilones

An approach to the validation of a linker strategy for the epothilone family of microtubule-stabilizing agents is reported. An analogue of epothilone B in which the C(6) methyl group has been replaced with a 4-azidobutyl group has been prepared by total chemical synthesis, and amides derived from the azido group have been shown to retain the activity of the parent compound. These results set the stage for an evaluation of the potential of the epothilones to serve as the drug component of antibody–drug conjugates and other selective tumor cell-targeting conjugates

Nickel-Catalyzed Enantioselective Coupling of Acid Chlorides with α‑Bromobenzoates: An Asymmetric Acyloin Synthesis

The reaction of common acyl-metal species (acyl anion) with aldehydes to furnish acyloins has received much less attention and specifically was restricted to using preformed stoichiometric acyl-metal reagents. Moreover, the (catalytic) enantioselective variants remain unexplored, and the asymmetric synthesis of chiral acyloins has met significant challenges in organic synthesis. Here, we uncover the highly enantioselective coupling of acid chlorides with α-bromobenzoates by nickel catalysis for producing enantioenriched protected α-hydroxy ketones (acyloins, >60 examples) with high enantioselectivities (up to 99% ee). The successful execution of this enantioselective coupling protocol enables the formation of a key ketyl radical from α-bromoalkyl benzoate in situ generated from corresponding aldehyde and acyl bromide, which finally is captured by chiral acyl-Ni species catalytically in situ formed from acyl chlorides, thus avoiding the use of preformed acyl-metal reagents. The synthetic utility of this chemistry is demonstrated in the downstream synthetic elaboration toward a diverse set of synthetically valuable chiral building blocks and biologically active compounds

Asymmetric Catalysis with an Inert Chiral-at-Metal Iridium Complex

The development of a chiral-at-metal iridium­(III) complex for the highly efficient catalytic asymmetric transfer hydrogenation of β,β′-disubstituted nitroalkenes is reported. Catalysis by this inert, rigid metal complex does not involve any direct metal coordination but operates exclusively through weak interactions with functional groups properly arranged in the ligand sphere of the iridium complex. Although the iridium complex relies only on the formation of three hydrogen bonds, it exceeds the performance of most organocatalysts with respect to enantiomeric excess (up to 99% ee) and catalyst loading (down to 0.1 mol %). This work hints at an advantage of structurally complicated rigid scaffolds for non-covalent catalysis, which especially relies on conformationally constrained cooperative interactions between the catalyst and substrates

Asymmetric Catalysis with an Inert Chiral-at-Metal Iridium Complex

The development of a chiral-at-metal iridium­(III) complex for the highly efficient catalytic asymmetric transfer hydrogenation of β,β′-disubstituted nitroalkenes is reported. Catalysis by this inert, rigid metal complex does not involve any direct metal coordination but operates exclusively through weak interactions with functional groups properly arranged in the ligand sphere of the iridium complex. Although the iridium complex relies only on the formation of three hydrogen bonds, it exceeds the performance of most organocatalysts with respect to enantiomeric excess (up to 99% ee) and catalyst loading (down to 0.1 mol %). This work hints at an advantage of structurally complicated rigid scaffolds for non-covalent catalysis, which especially relies on conformationally constrained cooperative interactions between the catalyst and substrates

Asymmetric Catalysis with an Inert Chiral-at-Metal Iridium Complex

The development of a chiral-at-metal iridium­(III) complex for the highly efficient catalytic asymmetric transfer hydrogenation of β,β′-disubstituted nitroalkenes is reported. Catalysis by this inert, rigid metal complex does not involve any direct metal coordination but operates exclusively through weak interactions with functional groups properly arranged in the ligand sphere of the iridium complex. Although the iridium complex relies only on the formation of three hydrogen bonds, it exceeds the performance of most organocatalysts with respect to enantiomeric excess (up to 99% ee) and catalyst loading (down to 0.1 mol %). This work hints at an advantage of structurally complicated rigid scaffolds for non-covalent catalysis, which especially relies on conformationally constrained cooperative interactions between the catalyst and substrates