Characterization of Reactive Organometallic Species via MicroED

Jones, Callum; Asay, Matthew; Kim, Lee Joon; Kleinsasser, Jack F.; Saha, Ambarneil; Fulton, Tyler J.; Berkley, Kevin; Cascio, Duilio; Malyutin, Andrey; Conley, Matthew P.; Stoltz, Brian M.; Lavallo, Vincent; Rodríguez, José A.; Nelson, Hosea M.

doi:10.1021/acscentsci.9b00403

Cited by 48 publications

(39 citation statements)

References 56 publications

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“…Given these challenges, we envisioned that application of the recently reported CryoEM modality MicroED 5 could lead to vertical advances in the field of natural product discovery, as MicroED has recently been demonstrated to provide unambiguous structures from sub-micron-sized crystals of chemical compounds that had failed to yield large crystals suitable for X-ray analysis. 13,14 As an entry into the area, we became interested in a-pyridone containing fungal metabolites.…”

Section: Main Textmentioning

confidence: 99%

Structural Determination of an Orphan Natural Product Using Microcrystal Electron Diffraction and Genome Mining

Kim¹,

Ohashi²,

D³

et al. 2020

Preprint

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<p>More than 60% of pharmaceuticals are related to natural products (NPs), chemicals produced by living organisms.<a></a> Hence, new methods that accelerate natural product discovery are poised to profoundly impact human health. Of the many challenges that remain in natural product discovery, none are as pervasive as structural elucidation, as determination of the molecular structure of a newly discovered natural product can take months, years, or in some cases be altogether unachievable. This challenge can be fueled by lack of sufficient material for spectroscopic analysis, or difficulties in sourcing the producing organism. Even in cases where the analyte is abundant, its physical properties, including molecular structure, can prevent unambiguous structural determination. Here we report the use of microcrystal electron diffraction (MicroED),<a></a> an emerging cryogenic electron microscopy (CryoEM) technique, in combination with genome mining, to address these challenges. As proof-of-principle, we apply these techniques to fischerin (<b>1</b>), an orphan NP isolated more than 30 years ago, with potent cytotoxicity but ambiguous structural assignment.<a></a> We utilize genome mining methods to reconstruct its biosynthetic pathway and highlight the sensitivity of MicroED through the precise determination of the solid-state structure of <b>1</b> from sub-micron thick crystals. This structural solution serves as a powerful demonstration of the synergy of MicroED and synthetic biology in NP discovery, technologies that when taken together will ultimately accelerate the rate at which new drugs are discovered.</p><div><div><p> </p></div></div>

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Section: Main Textmentioning

confidence: 99%

Structural Determination of an Orphan Natural Product Using Microcrystal Electron Diffraction and Genome Mining

Kim¹,

Ohashi²,

D³

et al. 2020

Preprint

Self Cite

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“…The information on the dimeric structure comprising hydrogen bridges was inferred from FTIR, 4,13 solid-state 35 Cl NMR, 14 and structures of related metal complexes, e.g., the dimer [Cp 2 Zr(H)Me] 2 . 15 The structure of Cp 2 Zr(H)Cl (1) has recently been determined by microcrystal electron diffraction (MicroED) analysis, 16 which confirmed the dimeric structure of 1 with hydrogen bridges (Figure 1).…”

Section: Structure and Properties Of Cp 2 Zr(h)clmentioning

confidence: 86%

Are Organozirconium Reagents Applicable in Current Organic Synthesis?

Némethová

Šebesta

2020

Synthesis

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The search for mild, user-friendly, easily accessible, and robust organometallic reagents is an important feature of organometallic chemistry. Ideally, new methodologies employing organometallics should be developed with respect to practical applications in syntheses of target compounds. In this short review, we investigate if organozirconium reagents can fulfill these criteria. Organozirconium compounds are typically generated via in situ hydrozirconation of alkenes or alkynes with the Schwartz reagent. Alkyl and alkenylzirconium reagents have proven to be convenient in conjugate additions, allylic substitutions, cross-coupling reactions, and additions to carbonyls or imines. Furthermore, the Schwartz reagent itself is a useful reducing agent for polar functional groups.1 Introduction2 Synthesis and Generation of the Schwartz Reagent3 Structure and Properties of Cp2Zr(H)Cl4 Reactivity of Organozirconium Reagents4.1 Asymmetric Conjugate Addition4.2 Asymmetric Allylic Alkylations4.3 Desymmetrization Reactions4.4 Cross-Coupling Reactions4.5 1,2-Additions5 Conclusions

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“…DFT geometry optimization of 3 [5b] are well-matched to the experimental data; computed metrics of 1 [5b] reveal a significantly shorter nitrene linkage. This observation is supported by the relative energies computed for singlet and triplet configurations (DEtriplet-singlet = -16.8 kcal•mol -1 ).…”

mentioning

confidence: 90%

“…X-ray and electron diffraction-based experiments are routinely employed to elucidate the chemical structures that are required for the rational design and optimization of small molecule catalysts. 1,2 While crystallography is routinely utilized to examine ligandinduced structural variation in kinetically stable coordination complexes and pre-catalysts, application to the characterization of reactive intermediates, which are intimately involved in the bondmaking and -breaking in catalysis, is typically stymied by the kinetic lability of these species. [3][4][5][6][7] As a result, experimental evaluation of the impact of ligand structure, and coordinating additives present during catalysis, is typically not possible.…”

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confidence: 99%

In Crystallo Snapshots of Rh2-Catalyzed C–H Amination

Das¹,

Wang²,

Trieste³

et al. 2020

Preprint

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<div> <div> <div> <p>Correlation of catalyst structure with activity is foundational to the rational design of transition metal catalysts. While X-ray crystallography routinely provides structural characterization of kinetically stable pre-catalysts and intermediates, experimental elucidation of the structures of reactive intermediates, which are the species intimately engaged in bond-breaking and -making in catalysis, is generally not possible due to the transient nature of these species. Here, we demonstrate in crystallo synthesis of Rh2 nitrenes that participate in catalytic C–H amination, and characterization of these transient intermediates as triplet adducts of Rh2. Further, we observe the impact of coordinating substrate, which is present in excess during catalysis, on the structure of transient Rh2 nitrenes involved in C–H amination. By providing structural characterization of authentic C–H functionalization intermediates, and not kinetically stabilized model complexes, these experiments provide the opportunity to define critical structure-activity relationships. </p> </div> </div> </div>

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Characterization of Reactive Organometallic Species via MicroED

Cited by 48 publications

References 56 publications

Structural Determination of an Orphan Natural Product Using Microcrystal Electron Diffraction and Genome Mining

Structural Determination of an Orphan Natural Product Using Microcrystal Electron Diffraction and Genome Mining

Are Organozirconium Reagents Applicable in Current Organic Synthesis?

In Crystallo Snapshots of Rh2-Catalyzed C–H Amination

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