De Novo Asymmetric Synthesis of d- and l-Swainsonine

The enantioselective syntheses of both enantiomers of the indolizidine natural product swainsonine have been achieved in 13 steps from furan. The indolizidine ring system is installed by a one-pot hydrogenolysis of both an azide and an O-Bn group along with an intramolecular reductive amination reaction. The asymmetry of swainsonine was introduced by Noyori reduction of an acylfuran. This route relies upon an Achmatowicz rearrangement, a diastereoselective palladium-catalyzed glycosylation, Luche reduction, and a dihydroxylation reaction

De Novo Asymmetric Synthesis of Anthrax Tetrasaccharide and Related Tetrasaccharide

A de novo asymmetric approach to the natural product anthrax tetrasaccharide 1 and an analogue 2 with an anomeric hexyl azide group has been developed from acetylfuran. The construction of the tetrasaccharide was achieved by a traditional [3 + 1] glycosylation strategy. An iterative diastereoselective palladium-catalyzed glycosylation, Luche reduction, diastereoselective dihydroxylation, and regioselective acylation were employed for the assembly of the l-rhamno-trisaccharide building block. The anthrose building block also required a palladium-catalyzed azide allylation and a triflate inversion to set the gluco-stereochemistry in addition to Luche reduction and dihydroxylation

De Novo Asymmetric Synthesis of Daumone via a Palladium-Catalyzed Glycosylation

The enantioselective syntheses of daumone and two analogues have been achieved in seven to eight steps. This route relies upon a diasteroselective palladium-catalyzed glycosylation reaction for the formation of the anomeric bond. The asymmetry of the sugar and aglycone portion of daumone were introduced by Noyori reduction of an acylfuran and a propargyl ketone. A highly diastereoselective epoxidation and reductive ring opening established the desired C-2 and C-4 stereochemistry of daumone

Formal Total Synthesis of RK-397 via an Asymmetric Hydration and Iterative Allylation Strategy

A formal total synthesis of the oxopentaene macrolide antibiotic RK-397 has been achieved. Nine stereocenters were established by a combination of allylation and our asymmetric hydration reactions and a 1,5-anti-selective aldol reaction. The synthesis proceeded in 19 steps from simple achiral conjugated dienoates

New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Double-Inversion Approach

With sequential use of catalytic asymmetric Cr-mediated coupling reactions, E7389 C14−C35 and halichondrin C14−C38 building blocks have been stereoselectively synthesized. The C19−C20 bond is first formed via the catalytic asymmetric Ni/Cr-mediated coupling, i.e., 8 + 9 → 10 (90%; dr = 22:1), in which vinyl iodide 8 is used as the limiting substrate. The C23−C24 bond is then formed via the catalytic asymmetric Co/Cr-mediated coupling, i.e., 13 + 14 → 4 (82%; dr = 22:1), in which the alkyl−iodide bond in 14 is selectively activated over the vinyl−iodide bond. The catalytic asymmetric Ni/Cr-mediated reaction is employed to couple C14−C26 segment 19 with E7389 C27−C35 segment 20 (91%; dr = >55:1). In this synthesis, the C23−O bond is stereoselectively constructed via a double-inversion process, i.e., 21 → 22, to furnish E7389 C14−C35 building block 22 in 84% yield. The same synthetic sequence has been employed to synthesize halichondrin C14−C38 building block 18b, i.e., 16a + 19 → 18b

De Novo Asymmetric Synthesis of 8a-<i>epi</i>-Swainsonine

An enantioselective and diastereocontrolled approach to 8a-epi-d-swainsonine has been developed from achiral furfural. The key step to this synthesis was a one-pot procedure for the hydrogenolytic removal of two protecting groups and two intramolecular reductive amination reactions. The absolute stereochemistry was introduced by asymmetric Noyori reduction of furfuryl ketone. This route relies on diastereoselective palladium-catalyzed glycosylation to install the anomeric bond, and Luche reduction, diastereoselective dihydroxylation to set up the manno-stereochemistry of the indolizidine precursor

Metabolite Induction of <i>Caenorhabditis elegans</i> Dauer Larvae Arises via Transport in the Pharynx

Caenorhabditis elegans sense natural chemicals in their environment and use them as cues to regulate their development. This investigation probes the mechanism of sensory trafficking by evaluating the processing of fluorescent derivatives of natural products in C. elegans. Fluorescent analogs of daumone, an ascaroside, and apigenin were prepared by total synthesis and evaluated for their ability to induce entry into a nonaging dauer state. Fluorescent imaging detailed the uptake and localization of every labeled compound at each stage of the C. elegans life cycle. Comparative analyses against natural products that did not induce dauer indicated that dauer-triggering natural products accumulated in the cuticle of the pharnyx. Subsequent transport of these molecules to amphid neurons signaled entry into the dauer state. These studies provide cogent evidence supporting the roles of the glycosylated fatty acid daumone and related ascarosides and the ubiquitous plant flavone apigenin as chemical cues regulating C. elegans development

Toolbox Approach to the Search for Effective Ligands for Catalytic Asymmetric Cr-Mediated Coupling Reactions

Chromium catalysts derived from chiral sulfonamides represented by A effect the couplings of aldehydes with vinyl, allyl, or alkyl halides. With three distinct sites for structural modification, A affords access to a structurally diverse pool of chiral sulfonamides. The Cr catalysts derived from these sulfonamides exhibit a broad range of catalyst−substrate matching profiles. A strategy is presented to search for a satisfactory chiral sulfonamide for a given substrate. In order to demonstrate the generality and effectiveness of this approach, five diverse C−C bond-forming cases have been selected from the halichondrin synthesis. For each of the cases, two ligands have been deliberately searched for, to induce the formation of (R)- and (S)-alcohols, respectively, at the arbitrarily chosen efficiency level of “≥80% yield with ≥20:1 stereoselectivity in the presence of ≤20 mol % of a Cr catalyst”. For 9 out of the 10 cases studied, a satisfactory catalyst has been found within this pool of sulfonamides. Even for the remaining case, a Cr catalyst inducing stereoselectivity up to 8:1 has been identified

New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Reductive Cyclization and Oxy-Michael Cyclization Approaches

Cr-mediated coupling reactions are usually achieved with a slight excess of a given nucleophile. To develop a cost-effective use of this process, two different approaches have been studied. The first approach depends on two consecutive catalytic asymmetric Cr-mediated couplings, with use of coupling partners purposely being of unbalanced molecular size and complexity. The second approach rests on the success in identifying the nucleophile, which allows us to achieve the coupling satisfactorily with a 1:1 molar ratio of the coupling partners. The C23−O bond is stereospecifically constructed via reductive cyclization of the oxonium ion, or oxy-Michael cyclization. Both syntheses have a high overall efficiency: E7389 C14−C35 and halichondrin C14−C38 building blocks have been synthesized from the corresponding C27−C35 and C27−C38 aldehydes, respectively, in high overall yields with an excellent stereoselectivity. Because of operational simplicity, the synthesis outlined herein appears to be well suited for scaling

Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy

Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound <b>43</b> (EED226). Guided by X-ray crystallography, compound <b>43</b> was discovered by fragmentation and regrowth of compound <b>7</b>, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of <b>43</b>. Compound <b>43</b> induces robust and sustained tumor regression in EZH2^MUT preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy