Synthesis of Eukaryotic Translation Elongation Inhibitor Lactimidomycin via Zn(II)-Mediated Horner–Wadsworth–Emmons Macrocyclization

Larsen, Brian J.; Sun, Zhankui; Nagorny, Pavel

doi:10.1021/ol401186f

Cited by 26 publications

(14 citation statements)

References 34 publications

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“…Concurrently with our report (vide infra),10 the Kuwahara group described the formal total synthesis of lactimidomycin via macrolactonization of the seco‐acid 19 11. Similar to the Danishefsky and Fürstner approaches, the macrocyclization required the protection of the Δ 2 ‐olefin of 19 via the C2‐phenylselenide.…”

Section: Introductionmentioning

confidence: 82%

Synthesis and Biological Evaluation of Lactimidomycin and Its Analogues

Larsen

Sun

Lachacz

et al. 2015

Chemistry A European J

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The studies culminating in the total synthesis of the glutarimide-containing eukaryote translation elongation inhibitor lactimidomycin are described. The optimized synthetic route features a Zn(II)-mediated intramolecular Horner-Wadsworth-Emmons (HWE) reaction resulting in a highly stereoselective formation of the strained 12-membered macrolactone of lactimidomycin on a 423 mg scale. The presence of the E,Z-diene functionality was found to be key for effective macrocyclizations as a complete removal of these unsaturation units resulted in exclusive formation of the dimer rather than monocyclic enoate. The synthetic route features a late-stage installation of the glutarimide functionality via an asymmetric catalytic Mukaiyama aldol reaction, which allows for a quick generation of lactimidomycin homolog 55 containing two additional carbons in the glutarimide side chain. Similar to lactimidomycin, this analog was found to possess cytotoxicity against MDA-MB-231 breast cancer cells (GI50 =1-3 μM) using in vitro 2D and 3D assays. Although lactimidomycin was found to be the most potent compound in terms of anticancer activity, 55 as well as truncated analogues 50-52 lacking the glutarimide side-chain were found to be significantly less toxic against human mammary epithelial cells.

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Section: Introductionmentioning

confidence: 82%

Synthesis and Biological Evaluation of Lactimidomycin and Its Analogues

Larsen

Sun

Lachacz

et al. 2015

Chemistry A European J

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“…The monomeric macrocyclic product 359a was found to be unstable, easily polymerizing when stored in neat state, most likely because of the high strain present in this structure. 381 Bockmann, Azov, and co-workers have reported the first example of a light-controllable macrocyclization reaction. This method is based in the isomerization of E-and Z-azobenzene producing a significant change in the distances between the terminal −CH 2 − groups.…”

Section: Configurational Preorganizationmentioning

confidence: 99%

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

et al. 2015

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“…Additionally, Nagorny has published a route to lactimidomycin (Scheme B) that utilizes a Suzuki coupling with iodide 69 and boronic acid 70 , followed by oxidation of the primary alcohol and intramolecular HWE coupling to afford the diene 71 . It was envisioned that this strategy would serve to form the strained ring and the enoate double bond in a single step.…”

Section: The Role Of Diverted Total Synthesis In Drug Discoverymentioning

confidence: 99%

Twelve‐membered macrolactones: privileged scaffolds for the development of new therapeutics

Brzozowski

Wuest

2017

Chem Biol Drug Des

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Natural products commonly produced as secondary metabolites of various plants and micro-organisms represent a diverse chemical space of compounds. The diversity of natural products makes them an attractive target for interrogation by both chemists and biologists alike. Indeed, the study of 12-membered macrolactones has already led to the discovery of lead drug compounds and new biological targets, which has motivated the development of diverted total synthetic routes to libraries of analogs. This review explores the discovery, biological characterization, and synthesis of several 12-membered macrolactones, exploiting examples that underscore their importance in the drug discovery field. It is our hope that this review will motivate further interest in this class of natural products, a group of molecules that we think merit the classification of 'privileged scaffolds' within the medicinal chemistry community, to further investigate and develop novel compounds with promising bioactivity. K E Y W O R D Santibiotic, biosynthesis, diverted total synthesis, macrolactone, natural product

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Synthesis of Eukaryotic Translation Elongation Inhibitor Lactimidomycin via Zn(II)-Mediated Horner–Wadsworth–Emmons Macrocyclization

Cited by 26 publications

References 34 publications

Synthesis and Biological Evaluation of Lactimidomycin and Its Analogues

Synthesis and Biological Evaluation of Lactimidomycin and Its Analogues

Macrocyclization Reactions: The Importance of Conformational, Configurational, and Template-Induced Preorganization

Twelve‐membered macrolactones: privileged scaffolds for the development of new therapeutics

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