Zr‐Mediated Hydroboration: Stereoselective Synthesis of Vinyl Boronic Esters.

Wang, Yanong D.; Kimball, Gregory; Prashad, Amar S.; Wang, Yan

doi:10.1002/chin.200613178

Cited by 3 publications

(4 citation statements)

References 1 publication

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“…N-Bocprotected propargylamine 51a 57 was subjected to a hydrozirconation-hydroboration sequence with pinacol borane and Schwartz's reagent to produce the key building block 51b. 58, 59 Suzuki coupling with the corresponding iodo compounds 19a-c gave compounds 52-54. After N-Boc cleavage of the latter with aqueous 4N HCl, the resulting amines were acylated using the trichloroacetyl dibromopyrrole 14a. We next investigated aromatic linkers between our various bicyclic heterocycles and the most active dibromopyrrole structural motif.…”

Section: Scheme 3 Variation Of the East Bicyclementioning

confidence: 99%

From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase

et al. 2021

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Significant inhibition of Aurora B was achieved by the synthesis of simplified fragments of benzosceptrins and oroidin belonging to the marine pyrrole-2-aminoimidazoles metabolites isolated from sponges. Evaluation of kinase inhibition enabled the discovery of a synthetically accessible rigid acetylenic structural analog EL-228 (1), whose structure could be optimized into the potent CJ2-150 (37. Here we present the synthesis of new inhibitors of Aurora B kinase which is an important target for cancer therapy through mitosis regulation. The biologically oriented synthesis yielded several nanomolar inhibitors. The optimized compound CJ2-150 (37) showed a non-ATP competitive allosteric mode of action in a mixed-type inhibition for Aurora B kinase. Molecular docking identified a probable binding mode in the allosteric site "F" and highlighted the key interactions with the protein. We describe the improvement of the inhibitory potency and specificity of the novel scaffold as well as the characterization of the mechanism of action.

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Section: Scheme 3 Variation Of the East Bicyclementioning

confidence: 99%

From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase

et al. 2021

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“…Following Zr-mediated hydroboration 26 of alkyne 26 , the resulting vinylboronic ester 27 was coupled with C1–C11 fragment 2 via a Suzuki coupling. A variety of reaction conditions were screened, but use of Tl 2 CO 3 27 was found to be essential for reaction success, giving the complete C1–C27 framework 28 in 53% yield.…”

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Synthesis of the C1–C27 Fragment of Stambomycin D Validates Modular Polyketide Synthase-Based Stereochemical Assignments

et al. 2021

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The stambomycins are a family of bioactive macrolides isolated from Streptomyces ambofaciens . Aside from two stereocenters installed through cytochrome P450 oxidations, their stereochemistry has been predicted by sequence analysis of the polyketide synthase. We report a synthesis of the C1–C27 fragment of stambomycin D, the spectroscopic data of which correlates well with that of the natural product, further validating predictive sequence analysis as a powerful tool for stereochemical assignment of complex polyketide natural products.

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“…For example, subjection of alkyne 3 (Fig. 2a), bearing an unprotected hydroxy group, to 20 mol % Cp 2 ZrHCl, 4.0 equivalents of pinacolatoborane and 10 mol % Et 3 N (60 °C, 17 h; all are commercially available) 24 followed by routine ester formation furnished diene 1e in 70% overall yield as a single isomer (>98% E ). Treatment of 1e with 5.0 mol % Mo-1 for six hours (vs. 2 h in Fig.…”

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confidence: 99%

“…Twelve- to nineteen-membered unsaturated macrocyclic lactones 4 – 5 and 7 – 8 are additional examples of the sequence that begins with E -selective zirconocene-catalyzed hydroboration 24 of a hydroxy-containing terminal alkyne (Fig. 2a; for synthesis of the precursor to 6 by catalytic protoboryl addition, see below).…”

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Kinetically E-selective macrocyclic ring-closing metathesis

Shen

Nguyen

Koh

et al. 2017

Nature

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Macrocyclic compounds are central to discovery of new drugs but their preparation is often challenging because of the energy barrier required for bringing together and fusing the two ends of an acyclic precursor1. Ring-closing metathesis (RCM) 2,3,4 is a catalytic process that has allowed access to countless biologically active macrocyclic organic molecules even on large scale (up to 200 kilograms)5. The potency of a macrocyclic compound can depend on the stereochemistry of its alkene, or one isomer might be needed for subsequent stereoselective modification (e.g., dihydroxylation6). Still, while kinetically controlled Z-selective RCM reactions have been reported7,8,9,10, the only available olefin metathesis approach for accessing macrocyclic E olefins entails selective removal of the Z component of a stereoisomeric mixture by ethenolysis10, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization, a particularly serious problem when the E alkene is energetically less favored. Here, we show that dienes containing an E-alkenyl–B(pinacolato) group, widely used in catalytic cross-coupling11, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E macrocyclic alkenes. Reactions are promoted by a molybdenum monoaryloxide pyrrolide complex and afford products in up to 73 percent yield and >98:2 E:Z ratio. Utility is highlighted by application to preparation of the twelve-membered ring antibiotic recifeiolide12,13 and the eighteen-membered ring Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor pacritinib14,15 the Z isomer of which has lower potency than the E16. The eighteen-membered ring moiety of pacritinib, a potent in vivo anti-cancer agent in advanced clinical trials for treatment of lymphoma and myelofibrosis, was prepared by an RCM carried out at 20 times higher concentration than when a ruthenium carbene was employed (0.02 vs. 0.001 M; 73% yield, 92% E).

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Zr‐Mediated Hydroboration: Stereoselective Synthesis of Vinyl Boronic Esters.

Cited by 3 publications

References 1 publication

From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase

From Synthetic Simplified Marine Metabolite Analogues to New Selective Allosteric Inhibitor of Aurora B Kinase

Synthesis of the C1–C27 Fragment of Stambomycin D Validates Modular Polyketide Synthase-Based Stereochemical Assignments

Kinetically E-selective macrocyclic ring-closing metathesis

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