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1.
J Am Chem Soc ; 146(21): 14672-14684, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38743881

RESUMO

Pyridoxal 5'-phosphate (PLP)-dependent enzymes are the most versatile biocatalysts for synthesizing nonproteinogenic amino acids. α,α-Disubstituted quaternary amino acids, such as 1-aminocyclopentane-1-carboxylic acid (cycloleucine), are useful building blocks for pharmaceuticals. In this study, starting with the biosynthesis of fusarilin A, we discovered a family of PLP-dependent enzymes that can facilitate tandem carbon-carbon forming steps to catalyze an overall [3 + 2]-annulation. In the first step, the cycloleucine synthases use SAM as the latent electrophile and an in situ-generated enamine as the nucleophile for γ-substitution. Whereas previously characterized γ-replacement enzymes protonate the resulting α-carbon and release the acyclic amino acid, cycloleucine synthases can catalyze an additional, intramolecular aldol or Mannich reaction with the nucleophilic α-carbon to form the substituted cyclopentane. Overall, the net [3 + 2]-annulation reaction can lead to 2-hydroxy or 2-aminocycloleucine products. These studies further expand the biocatalytic scope of PLP-dependent enzymes.


Assuntos
Fosfato de Piridoxal , Fosfato de Piridoxal/metabolismo , Fosfato de Piridoxal/química , Biocatálise , Estrutura Molecular , Ciclopentanos/química , Ciclopentanos/metabolismo
2.
J Am Chem Soc ; 146(29): 20158-20167, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-38978232

RESUMO

The development of architecturally unique molecular nanocarbons by bottom-up organic synthesis is essential for accessing functional organic materials awaiting technological developments in fields such as energy, electronics, and biomedicine. Herein, we describe the design and synthesis of a triptycene-based three-dimensional (3D) nanocarbon, GFN-1, with geometrical flexibility on account of its three peripheral π-panels being capable of interconverting between two curved conformations. An effective through-space electronic communication among the three π-panels of GFN-1 has been observed in its monocationic radical form, which exhibits an extensively delocalized spin density over the entire 3D π-system as revealed by electron paramagnetic resonance and UV-vis-NIR spectroscopies. The flexible 3D molecular architecture of GFN-1, along with its densely packed superstructures in the presence of fullerenes, is revealed by microcrystal electron diffraction and single-crystal X-ray diffraction, which establish the coexistence of both propeller and tweezer conformations in the solid state. GFN-1 exhibits strong binding affinities for fullerenes, leading to host-guest complexes that display rapid photoinduced electron transfer within a picosecond. The outcomes of this research could pave the way for the utilization of shape and electronically complementary nanocarbons in the construction of functional coassemblies.

3.
Angew Chem Int Ed Engl ; 63(24): e202404290, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38589297

RESUMO

Controlled modulation of electronic and magnetic properties in stimuli-responsive materials provides valuable insights for the design of magnetoelectric or multiferroic devices. This paper demonstrates the modulation of electrical and magnetic properties of a semiconductive, paramagnetic metal-organic framework (MOF) Cu3(C6O6)2 with small gaseous molecules, NH3, H2S, and NO. This study merges chemiresistive and magnetic tests to reveal that the MOF undergoes simultaneous changes in electrical conductance and magnetization that are uniquely modulated by each gas. The features of response, including direction, magnitude, and kinetics, are modulated by the physicochemical properties of the gaseous molecules. This study advances the design of multifunctional materials capable of undergoing simultaneous changes in electrical and magnetic properties in response to chemical stimuli.

4.
Plant J ; 111(4): 995-1014, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35699388

RESUMO

Even subtle modifications in growth conditions elicit acclimation responses affecting the molecular and elemental makeup of organisms, both in the laboratory and in natural habitats. We systematically explored the effect of temperature, pH, nutrient availability, culture density, and access to CO2 and O2 in laboratory-grown algal cultures on growth rate, the ionome, and the ability to accumulate Fe. We found algal cells accumulate Fe in alkaline conditions, even more so when excess Fe is present, coinciding with a reduced growth rate. Using a combination of Fe-specific dyes, X-ray fluorescence microscopy, and NanoSIMS, we show that the alkaline-accumulated Fe was intracellularly sequestered into acidocalcisomes, which are localized towards the periphery of the cells. At high photon flux densities, Zn and Ca specifically over-accumulate, while Zn alone accumulates at low temperatures. The impact of aeration was probed by reducing shaking speeds and changing vessel fill levels; the former increased the Cu quota of cultures, the latter resulted in a reduction in P, Ca, and Mn at low fill levels. Trace element quotas were also affected in the stationary phase, where specifically Fe, Cu, and Zn accumulate. Cu accumulation here depends inversely on the Fe concentration of the medium. Individual laboratory strains accumulate Ca, P, and Cu to different levels. All together, we identified a set of specific changes to growth rate, elemental composition, and the capacity to store Fe in response to subtle differences in culturing conditions of Chlamydomonas, affecting experimental reproducibility. Accordingly, we recommend that these variables be recorded and reported as associated metadata.


Assuntos
Chlamydomonas , Oligoelementos , Reprodutibilidade dos Testes
5.
Nat Chem Biol ; 17(8): 872-877, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34312563

RESUMO

More than 60% of pharmaceuticals are related to natural products (NPs), chemicals produced by living organisms. Despite this, the rate of NP discovery has slowed over the past few decades. In many cases the rate-limiting step in NP discovery is structural characterization. Here we report the use of microcrystal electron diffraction (MicroED), an emerging cryogenic electron microscopy (CryoEM) method, in combination with genome mining to accelerate NP discovery and structural elucidation. As proof of principle we rapidly determine the structure of a new 2-pyridone NP, Py-469, and revise the structure of fischerin, an NP isolated more than 25 years ago, with potent cytotoxicity but hitherto ambiguous structural assignment. This study 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.


Assuntos
Produtos Biológicos/química , Microscopia Crioeletrônica , Modelos Moleculares , Conformação Molecular
6.
J Org Chem ; 88(6): 3403-3408, 2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36820472

RESUMO

The mechanisms of the C-H insertion reactions of vinyl carbocations formed by heterolysis of vinyl trifluoromethanesulfonates (triflates) by catalytic lithiated 1,3-bis[3,5-bis(trifluoromethyl)phenyl]urea (Li+-ureide) have been studied with ωB97X-D density functional theory. The ionization promoted by the Li+-ureide forms a metastable intimate ion pair complex of Li+-ureide-triflate anion and vinyl cation. The relative thermodynamic stabilities of isomeric alkyl cations are impacted by ion-pairing with the Li+-ureide-triflate anion. We show that the C-H insertion reaction of the vinyl cation intermediate is the rate-determining step and explain the effect of the aryl substituents on the formation of the vinyl cation and its C-H insertion reactivity as well as the regioselectivity of C-H activation by the vinyl cation.

7.
Angew Chem Int Ed Engl ; 61(12): e202113972, 2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35029844

RESUMO

The electrochemical generation of vinyl carbocations from alkenyl boronic esters and boronates is reported. Using easy-to-handle nucleophilic fluoride reagents, these intermediates are trapped to form fully substituted vinyl fluorides. Mechanistic studies support the formation of dicoordinated carbocations through sequential single-electron oxidation events. Notably, this electrochemical fluorination features fast reaction times and Lewis acid-free conditions. This transformation provides a complementary method to access vinyl fluorides with simple fluoride salts such as TBAF.

8.
Angew Chem Int Ed Engl ; 61(6): e202113569, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34784436

RESUMO

This paper describes structural elucidation of a layered conductive metal-organic framework (MOF) material Cu3 (C6 O6 )2 by microcrystal electron diffraction with sub-angstrom precision. This insight enables the first identification of an unusual π-stacking interaction in a layered MOF material characterized by an extremely short (2.73 Å) close packing of the ligand arising from pancake bonding and ordered water clusters within pores. Band structure analysis suggests semiconductive properties of the MOF, which are likely related to the localized nature of pancake bonds and the formation of a singlet dimer of the ligand. The spin of CuII within the Kagomé arrangement dominates the paramagnetism of the MOF, leading to strong geometrical magnetic frustration.

9.
J Am Chem Soc ; 143(17): 6578-6585, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33900077

RESUMO

The lomaiviticins are dimeric genotoxic metabolites that contain unusual diazocyclopentadiene functional groups and 2-4 deoxyglycoside residues. Because only 6 of 19 carbon atoms in the monomeric aglycon unit are proton-attached, their structure determination by NMR spectroscopic analysis is difficult. Prior structure elucidation efforts established that the two halves of the lomaiviticins are joined by a single carbon-carbon bond appended to an oxidized cyclohexenone ring. This ring was believed to comprise a 4,5-dihydroxycyclohex-2-ene-1-one. The bridging bond was positioned at C6. This structure proposal has not been tested because no lomaiviticin has been prepared by total chemical synthesis or successfully analyzed by X-ray crystallography. Here, we disclose microED studies which establish that (-)-lomaiviticin C contains a 4,6-dihydroxy-cyclohex-2-ene-1-one residue, that the bridging carbon-carbon bond is located at C5, and that the orientation of the cyclohexenone ring and configuration of the secondary glycoside are reversed, relative to their original assignment. High-field (800 MHz) NMR analysis supports the revised assignment and suggests earlier efforts were misled by a combination of a near-zero 3JH4,H5 coupling constant and a 4JC,H coupling interpreted as a 3JC,H coupling. DFT calculations of the expected 13C chemical shifts and C-H coupling constants provide further robust support for the structure revision. Because the interconversion of lomaiviticins A, B, and C has been demonstrated, these findings apply to each isolate. These studies clarify the structures of this family of metabolites and underscore the power of microED analysis in natural product structure determination.


Assuntos
Fluorenos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Termodinâmica
10.
J Am Chem Soc ; 143(20): 7740-7747, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-33998231

RESUMO

Molecular spur gear dynamics with high gearing fidelity can be achieved through a careful selection of constituent molecular components that favorably position and maintain the two gears in a meshed configuration. Here, we report the synthesis of a new macrocyclic molecular spur gear with a bibenzimidazole stator combined with a second naphthyl bis-gold-phosphine gold complex stator to place two 3-fold symmetric 9,10-diethynyl triptycene cogs at the optimal distance of 8.1 Å for gearing. Micro electron diffraction (µED) analysis confirmed the formation of the macrocyclic structure and the proper alignment of the triptycene cogs. Gearing dynamics in solution are predicted to be extremely fast and, in fact, were too fast to be observed with variable-temperature 1H NMR using CD2Cl2 as the solvent. A combination of molecular dynamics and metadynamics simulations predict that the barriers for gearing and slippage are ca. 4 kcal mol-1 and ca. 9 kcal mol-1, respectively. This system is characterized by enhanced gearing fidelity compared to the acyclic analog. This is achieved by rigidification of the structure, locking the two triptycenes in the preferred gearing distance and orientation.

11.
Angew Chem Int Ed Engl ; 60(5): 2493-2499, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33090649

RESUMO

Solid-state packing plays a defining role in the properties of a molecular organic material, but it is difficult to elucidate in the absence of single crystals that are suitable for X-ray diffraction. Herein, we demonstrate the coupling of divergent synthesis with microcrystal electron diffraction (MicroED) for rapid assessment of solid-state packing motifs, using a class of chiral nanocarbons-expanded helicenes-as a proof of concept. Two highly selective oxidative dearomatizations of a readily accessible helicene provided a divergent route to four electron-deficient analogues containing quinone or quinoxaline units. Crystallization efforts consistently yielded microcrystals that were unsuitable for single-crystal X-ray diffraction, but ideal for MicroED. This technique facilitated the elucidation of solid-state structures of all five compounds with <1.1 Šresolution. The otherwise-inaccessible data revealed a range of notable packing behaviors, including four different space groups, homochirality in a crystal for a helicene with an extremely low enantiomerization barrier, and nanometer scale cavities.

12.
J Am Chem Soc ; 141(23): 9140-9144, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31082208

RESUMO

Here we report the surprising discovery that high-energy vinyl carbocations can be generated under strongly basic conditions, and that they engage in intramolecular sp3 C-H insertion reactions through the catalysis of weakly coordinating anion salts. This approach relies on the unconventional combination of lithium hexamethyldisilazide base and the commercially available catalyst, triphenylmethylium tetrakis(pentafluorophenyl)borate. These reagents form a catalytically active lithium species that enables the application of vinyl cation C-H insertion reactions to heteroatom-containing substrates.


Assuntos
Compostos de Boro/química , Compostos de Lítio/química , Hidrocarbonetos Policíclicos Aromáticos/química , Silanos/química , Compostos de Boro/síntese química , Catálise , Cátions , Eletroquímica , Estrutura Molecular , Hidrocarbonetos Policíclicos Aromáticos/síntese química
13.
Angew Chem Int Ed Engl ; 58(46): 16400-16404, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31313425

RESUMO

Herein we report the discovery of a AuI -DNA hybrid catalyst that is compatible with biological media and whose reactivity can be regulated by small complementary nucleic acid sequences. The development of this catalytic system was enabled by the discovery of a novel AuI -mediated base pair. We found that AuI binds DNA containing C-T mismatches. In the AuI -DNA catalyst's latent state, the AuI ion is sequestered by the mismatch such that it is coordinatively saturated, rendering it catalytically inactive. Upon addition of an RNA or DNA strand that is complementary to the latent catalyst's oligonucleotide backbone, catalytic activity is induced, leading to a sevenfold increase in the formation of a fluorescent product, forged through a AuI -catalyzed hydroamination reaction. Further development of this catalytic system will expand not only the chemical space available to synthetic biological systems but also allow for temporal and spatial control of transition-metal catalysis through gene transcription.


Assuntos
Ouro/química , RNA/química , Aminação , Pareamento Incorreto de Bases , Compostos de Boro/química , Catálise , Ciclização , DNA/química , DNA/metabolismo , Ouro/metabolismo , Hibridização de Ácido Nucleico , RNA/metabolismo , Raios Ultravioleta
14.
Angew Chem Int Ed Engl ; 58(6): 1724-1726, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30548983

RESUMO

Disclosed is a five-step synthesis of (±)-vibralactone, a biologically active terpenoid natural product. A key photochemical valence isomerization of 3-prenyl-pyran-2-one produces both the all-carbon quaternary stereocenter and the ß-lactone at an early stage. Cyclopropanation of the resulting bicyclic ß-lactone produces a strained housane structure that is converted to the natural product through a sequential ring expansion and reduction strategy. This concise and modular route to the natural product provides the shortest total synthesis of (±)-vibralactone reported to date.


Assuntos
Lactonas/síntese química , Lactonas/química , Estrutura Molecular , Estereoisomerismo
15.
Angew Chem Int Ed Engl ; 56(21): 5806-5811, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28418118

RESUMO

A mild, asymmetric Heck-Matsuda reaction of five-, six- and seven-membered ring alkenes and aryl diazonium salts is presented. High yields and enantioselectivities were achieved using Pd0 and chiral anion co-catalysts, the latter functioning as a chiral anion phase-transfer (CAPT) reagent. For certain substrate classes, the chiral anion catalysts were modulated to minimize the formation of undesired by-products. More specifically, BINAM-derived phosphoric acid catalysts were shown to prevent alkene isomerization in cyclopentene and cycloheptene starting materials. DFT(B3LYP-D3) computations revealed that increased product selectivity resulted from a chiral anion dependent lowering of the activation barrier for the desired pathway.


Assuntos
Compostos de Diazônio/química , Ânions , Catálise , Cicloexenos/química , Estrutura Molecular , Transição de Fase , Fenol/química , Estereoisomerismo
16.
J Am Chem Soc ; 137(9): 3213-3216, 2015 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-25723255

RESUMO

A palladium-catalyzed three-component coupling of α-olefins, aryldiazonium salts, and bis(pinacolato)diboron affords direct access to chiral benzylic boronic esters. This process is rendered highly enantioselective using an unprecedented example of cooperative chiral anion phase transfer and transition-metal catalysis.


Assuntos
Alcenos/química , Compostos de Boro/química , Paládio/química , Álcoois/química , Ânions/química , Compostos de Boro/síntese química , Catálise , Técnicas de Química Sintética , Ésteres/química , Espectroscopia de Ressonância Magnética , Estereoisomerismo
17.
J Org Chem ; 79(20): 9740-7, 2014 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-25244187

RESUMO

The total syntheses of basiliolide C and previously unreported epi-basiliolide C are achieved by an Ireland-Claisen/Diels-Alder cascade. The development of a palladium catalyzed cross-coupling of methoxy alkynyl zinc reagents allows for the protecting-group-free syntheses of transtaganolides C and D. Syntheses of transtaganolides C and D are accomplished in a single operation to generate three rings, two all-carbon quaternary centers, and four tertiary stereocenters from a monocyclic, achiral precursor.


Assuntos
Artemisininas/síntese química , Pironas/síntese química , Artemisininas/química , Reação de Cicloadição , Indicadores e Reagentes/química , Estrutura Molecular , Paládio/química , Pironas/química , Estereoisomerismo , Zinco/química
18.
Angew Chem Int Ed Engl ; 53(22): 5600-3, 2014 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-24715416

RESUMO

Herein is reported the first asymmetric utilization of aryldiazonium cations as a source of electrophilic nitrogen. This is achieved through a chiral anion phase-transfer pyrroloindolinization reaction that forms C3-diazenated pyrroloindolines from simple tryptamines and aryldiazonium tetrafluoroborates. The title compounds are obtained in up to 99% yield and 96% ee. The air- and water-tolerant reaction allows electronic and steric diversity of the aryldiazonium electrophile and the tryptamine core.


Assuntos
Indóis/química , Pirróis/química , Ânions/química , Catálise , Cátions/química , Ciclização , Compostos de Diazônio/química , Indóis/síntese química , Estereoisomerismo , Triptaminas/química
19.
Org Lett ; 26(23): 4847-4852, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38842928

RESUMO

We report a catalytic C-O coupling/Claisen cascade reaction enabled by interception of vinyl carbocations with allyl ethers. The reaction utilizes commercially available borate salts as catalysts and is effective at constructing sterically hindered C-C bonds. The reaction mechanism is studied experimentally and computationally to support a charge-accelerated [3,3] rearrangement of a silyloxonium cation. Our reaction is also applied to the highly stereoselective synthesis of fully substituted vinyl ethers.

20.
Org Lett ; 26(33): 6944-6949, 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39116344

RESUMO

Microcrystal electron diffraction (microED) is an emerging technique for rapid crystallographic analysis of small molecule micro- and nanocrystals. In this report, we evaluate the applicability of microED to pharmaceutical compounds through the analysis of 30 samples obtained from the process and medicinal chemistry groups at Amgen Inc. Using only 40 h of microscope time, 15 of 30 crystal structures were elucidated. From these crystal structures, all chiral compounds had the correct absolute stereochemistry assigned by dynamical refinement of continuous rotation electron diffraction data, confirming dynamical refinement as a promising tool for the absolute stereochemistry determination of pharmaceutically relevant compounds.


Assuntos
Nanopartículas , Estereoisomerismo , Estrutura Molecular , Preparações Farmacêuticas/química , Cristalografia por Raios X , Nanopartículas/química , Modelos Moleculares
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