R-3 Repository :: Browsing by Author "Kürti, László"

Browsing by Author "Kürti, László"

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Antimicrobial activity of a natural compound and analogs against multi-drug-resistant Gram-positive pathogens
(American Society for Microbiology, 2024) Shah, Kush N.; Shah, Parth N.; Agobe, Francesca O.; Lovato, Kaitlyn; Gao, Hongyin; Ogun, Oluwadara; Hoffman, Cason; Yabe-Gill, Marium; Chen, Qingquan; Sweatt, Jordan; Chirra, Bhagath; Muñoz-Medina, Ricardo; Farmer, Delaney E.; Kürti, László; Cannon, Carolyn L.
The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has sparked global concern due to the dwindling availability of effective antibiotics. To increase our treatment options, researchers have investigated naturally occurring antimicrobial compounds and have identified MC21-A (C58), which has potent antimicrobial activity against MRSA. Recently, we have devised total synthesis schemes for C58 and its chloro-analog, C59. Here, we report that both compounds eradicate 90% of the 39 MRSA isolates tested [MIC90 and minimum bactericidal concentration (MBC90)] at lower or comparable concentrations compared to several standard-of-care (SoC) antimicrobials including daptomycin, vancomycin, and linezolid. Furthermore, a stable, water-soluble sodium salt of C59, C59Na, demonstrates antimicrobial activity comparable to C59. C59, unlike vancomycin, kills stationary-phase MRSA in a dose-dependent manner and completely eradicates MRSA biofilms. In contrast to vancomycin, exposing MRSA to sub-MIC concentrations of C59 does not result in the emergence of spontaneous resistance. Similarly, in a multi-step study, C59 demonstrates a low propensity of resistance acquisition when compared to SoC antimicrobials, such as linezolid and clindamycin. Our findings suggest C58, C59, and C59Na are non-toxic to mammalian cells at concentrations that exert antimicrobial activity; the lethal dose at median cell viability (LD50) is at least fivefold higher than the MBC90 in the two mammalian cell lines tested. A morphological examination of the effects of C59 on a MRSA isolate suggests the inhibition of the cell division process as a mechanism of action. Our results demonstrate the potential of this naturally occurring compound and its analogs as non-toxic next-generation antimicrobials to combat MRSA infections
Copper-Catalyzed Synthesis of Hindered Ethers from α-Bromo Carbonyl Compounds
(American Chemical Society, 2018) Zhou, Zhe; Behnke, Nicole Erin; Kürti, László
A catalytic method for the synthesis of sterically hindered ethers and thioethers from α-bromo carbonyl compounds and the corresponding nucleophiles using an inexpensive Cu(I) catalytic system is reported. This facile transformation takes place at ambient temperature and does not require the exclusion of air or moisture; thus, it is well-suited for the functionalization and derivatization of complex organic molecules.
Developing Greener Methods for the Synthesis of Privileged Structural Motifs and Nitrogen Heterocycles
(2021-06-07) Lovato, Kaitlyn; Kürti, László
Efforts towards the development of novel and sustainable methods for the synthesis of privileged scaffolds that are often found in biologically active compounds are described. With the rising interest in green chemistry, the projects highlighted in Part One focused on developing atom economic protocols that minimized the use of transition metal catalysts and eliminated the utilization of harsh/hazardous reaction conditions. In Chapter 1, the investigation of transition metal-free conditions for the α-arylation of activated C(sp3)–H bonds in ester, nitrile, amide, sulfone and diaryl methane substrates is described. The substrate scope of this transformation was thoroughly explored, and a pKa-based reactivity guide was developed. In Chapter 2, the ability for O-cyclopropyl hydroxylamines to function as atom economic, [3,3]-rearrangement precursors for the construction of various classes of heterocycles is presented. An efficient route towards functionalized O-cyclopropyl hydroxylamines and a base-mediated rearrangement protocol for the construction of tetrahydroquinolines are described. Chapter 3 discusses a study conducted in collaboration with Dr. Carolyn Cannon’s group, which reveals naturally occurring biaryl compounds and their structural analogues as potential antimicrobial agents for further investigation. The straightforward synthesis of promising biaryl compounds via an atom economic, organocatalytic and scalable protocol is described. The projects highlighted in Part Two focused on the development of robust methods for the synthesis of nitrogen heterocycles, which are one of the most pervasive structural components in pharmaceutical compounds. Chapter 4 describes a Ti-mediated coupling of oxime ethers and primary alkyl Grignard reagents under Kulinkovich-like conditions to construct previously unreported four-membered nitrogen heterocycles. This work established a one-step protocol for the synthesis of NH-azetidines, which have demonstrated utility in drug discovery and development. In Chapter 5, an investigation into the design and synthesis of a bicyclic scaffold that could function as a next generation para-disubstituted arene molecular mimic is described. A robust protocol for the synthesis of N-substituted bicyclic carbamate scaffolds was developed and these fragments were found to possess comparable substituent geometry to para-disubstituted arenes. This moiety could possess improved aqueous solubility compared to its all-carbon BCP counterpart and has been presented as a promising and novel structural mimic.
Direct and Stereospecific Synthesis of N-H and N-Alkyl Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids
(Wiley, 2017) Ma, Zhiwei; Zhou, Zhe; Kürti, László
A RhII-catalyzed direct and stereospecific N-H- and N-alkyl aziridination of olefins is reported that uses hydroxylamine-O-sulfonic acids as inexpensive, readily available, and nitro group-free aminating reagents. Unactivated olefins, featuring a wide range of functional groups, are converted into the corresponding N-H or N-alkyl aziridines in good to excellent yields. This operationally simple, scalable transformation proceeds efficiently at ambient temperature and is tolerant towards oxygen and trace moisture.
Direct C—H amination and aza-annulation
(2021-05-21) Falck, John R.; Paudyal, Mahesh P.; Kürti, László; Rice University; The Board of Regents of the University of Texas System; United States Patent and Trademark Office
In some aspects, the present disclosure provides methods of aminating an aromatic compound comprising reacting an aminating agent with an aromatic compound in the presence of a rhodium catalyst. In some embodiments, the methods may comprise aminating an aromatic compound which contains multiple different functional groups. The methods described herein may also be used to create bicyclic system comprising reacting an intramolecular aminating agent with an aromatic ring to obtain a second ring containing a nitrogen atom. In another aspect, the methods described herein may also be used to create a cyclic aliphatic cyclic/poly cyclic amine system comprising a reacting an intramolecular aminating agent by insertion into a C(sp3)-H bond.
Dirhodium-catalyzed C-H arene amination using hydroxylamines
(AAAS, 2016) Paudyal, Mahesh P.; Adebesin, Adeniyi Michael; Burt, Scott R.; Ess, Daniel H.; Ma, Zhiwei; Kürti, László; Falck, John R.
Primary and N-alkyl arylamine motifs are key functional groups in pharmaceuticals, agrochemicals, and functional materials, as well as in bioactive natural products. However, there is a dearth of generally applicable methods for the direct replacement of aryl hydrogens with NH2/NH(alkyl) moieties. Here, we present a mild dirhodium-catalyzed C-H amination for conversion of structurally diverse monocyclic and fused aromatics to the corresponding primary and N-alkyl arylamines using NH2/NH(alkyl)-O-(sulfonyl)hydroxylamines as aminating agents; the relatively weak RSO2O-N bond functions as an internal oxidant. The methodology is operationally simple, scalable, and fast at or below ambient temperature, furnishing arylamines in moderate-to-good yields and with good regioselectivity. It can be readily extended to the synthesis of fused N-heterocycles.
Multi-layer 3D chirality: its enantioselective synthesis and aggregation-induced emission
(Oxford University Press, 2021) Zhang, Junliang; Kürti, László
Non-Deprotonative Primary and Secondary Amination of (Hetero)Arylmetals
(American Chemical Society, 2017) Zhou, Zhe; Ma, Zhiwei; Behnke, Nicole Erin; Gao, Hongyin; Kürti, László; BioScience Research Collaborative
Herein we disclose a novel method for the facile transfer of primary (−NH2) and secondary amino groups (−NHR) to heteroaryl- as well as arylcuprates at low temperature without the need for precious metal catalysts, ligands, excess reagents, protecting and/or directing groups. This one-pot transformation allows unprecedented functional group tolerance and it is well-suited for the amination of electron-rich, electron-deficient as well as structurally complex (hetero)arylmetals. In some of the cases, only catalytic amounts of a copper(I) salt is required.
Practical access to axially chiral sulfonamides and biaryl amino phenols via organocatalytic atroposelective N-alkylation
(Springer Nature, 2019) Lu, Shenci; Ng, Shawn Voon Hwee; Lovato, Kaitlyn; Ong, Jun-Yang; Poh, Si Bei; Ng, Xiao Qian; Kürti, László; Zhao, Yu
The importance of axial chirality in enantioselective synthesis has been widely recognized for decades. The practical access to certain structures such as biaryl amino phenols known as NOBINs in enantiopure form, however, still remains a challenge. In drug delivery, the incorporation of axially chiral molecules in systematic screening has also received a great deal of interest in recent years, which calls for innovation and practical synthesis of structurally different axially chiral entities. Herein we present an operationally simple catalytic N-alkylation of sulfonamides using commercially available chiral amine catalysts to deliver two important classes of axially chiral compounds: structurally diverse NOBIN analogs as well as axially chiral N-aryl sulfonamides in excellent enantiopurity. Structurally related chiral sulfonamide has shown great potential in drug molecules but enantioselective synthesis of them has never been accomplished before. The practical catalytic procedures of our methods also bode well for their wide application in enantioselective synthesis.
Practical Organocatalytic Synthesis of Functionalized Non-C2-Symmetrical Atropisomeric Biaryls
(Wiley, 2016) Gao, Hongyin; Xu, Qing-Long; Keene, Craig; Yousufuddin, Muhammed; Ess, Daniel H.; Kürti, László
An organic acid catalyzed direct arylation of aromatic C(sp2)H bonds in phenols and naphthols for the preparation of 1,1′-linked functionalized biaryls was developed. The products are non-C2-symmetrical, atropoisomeric, and represent previously untapped chemical space. Overall this transformation is operationally simple, does not require an external oxidant, is readily scaled up (up to 98 mmol), and the structurally diverse 2,2′-dihydroxy biaryl (i.e., BINOL-type), as well as 2-amino-2′-hydroxy products (i.e., NOBIN-type) are formed with complete regioselectivity. Density-functional calculations suggest that the quinone and imino-quinone monoacetal coupling partners are exclusively arylated at their α-position by an asynchronous [3,3]-sigmatropic rearrangement of a mixed acetal species which is formed in situ under the reaction conditions.
Practical Singly and Doubly Electrophilic Aminating Agents: A New, More Sustainable Platform for Carbon–Nitrogen Bond Formation
(American Chemical Society, 2017) Kattamuri, Padmanabha V.; Yin, Jun; Siriwongsup, Surached; Kwon, Doo-Hyun; Ess, Daniel H.; Li, Qun; Li, Guigen; Yousufuddin, Muhammed; Richardson, Paul F.; Sutton, Scott C.; Kürti, László
Given the importance of amines in a large number of biologically active natural products, active pharmaceutical ingredients, agrochemicals, and functional materials, the development of efficient C–N bond-forming methods with wide substrate scope continues to be at the frontier of research in synthetic organic chemistry. Here, we present a general and fundamentally new synthetic approach for the direct, transition-metal-free preparation of symmetrical and unsymmetrical diaryl-, arylalkyl-, and dialkylamines that relies on the facile single or double addition of readily available C-nucleophiles to the nitrogen atom of bench-stable electrophilic aminating agents. Practical single and double polarity reversal (i.e., umpolung) of the nitrogen atom is achieved using sterically and electronically tunable ketomalonate-derived imines and oximes. Overall, this novel approach represents an operationally simple, scalable, and environmentally friendly alternative to transition-metal-catalyzed C–N cross-coupling methods that are currently used to access structurally diverse secondary amines.
Rapid heteroatom transfer to arylmetals utilizing multifunctional reagent scaffolds
(Springer Nature, 2016) Gao, Hongyin; Zhou, Zhe; Kwon, Doo-Hyun; Coombs, James; Jones, Steven; Behnke, Nicole Erin; Ess, Daniel H.; Kürti, László; BioScience Research Collaborative
Arylmetals are highly valuable carbon nucleophiles that are readily and inexpensively prepared from aryl halides or arenes and widely used on both laboratory and industrial scales to react directly with a wide range of electrophiles. Although C−C bond formation has been a staple of organic synthesis, the direct transfer of primary amino (−NH2) and hydroxyl (−OH) groups to arylmetals in a scalable and environmentally friendly fashion remains a formidable synthetic challenge because of the absence of suitable heteroatom-transfer reagents. Here, we demonstrate the use of bench-stable N−H and N−alkyl oxaziridines derived from readily available terpenoid scaffolds as efficient multifunctional reagents for the direct primary amination and hydroxylation of structurally diverse aryl- and heteroarylmetals. This practical and scalable method provides one-step synthetic access to primary anilines and phenols at low temperature and avoids the use of transition-metal catalysts, ligands and additives, nitrogen-protecting groups, excess reagents and harsh workup conditions.
Symmetry in Cascade Chirality-Transfer Processes: A Catalytic Atroposelective Direct Arylation Approach to BINOL Derivatives
(American Chemical Society, 2016) Wang, Jin-Zheng; Zhou, Jin; Xu, Chang; Sun, Hongbin; Kürti, László; Xu, Qing-Long
Herein we disclose a scalable organocatalytic direct arylation approach for the regio- and atroposelective synthesis of non-C2-symmetric 2,2′-dihydroxy-1,1′-binaphthalenes (BINOLs). In the presence of catalytic amounts of axially chiral phosphoric acids, phenols and naphthols are coupled with iminoquinones via a cascade process that involves sequential aminal formation, sigmatropic rearrangement, and rearomatization to afford enantiomerically enriched BINOL derivatives in good to excellent yields. Our studies suggest that the (local) symmetry of the initially formed aminal intermediate has a dramatic impact on the level of enantioinduction in the final product. Aminals with a plane of symmetry give rise to BINOL derivatives with significantly lower enantiomeric excess than unsymmetrical ones featuring a stereogenic center. Presumably asymmetric induction in the sigmatropic rearrangement step is significantly more challenging than during aminal formation. Sigmatropic rearrangement of the enantiomerically enriched aminal and subsequent rearomatization transfers the central chirality into axial chirality with high fidelity.
trans-Hydroboration–oxidation products in Δ5-steroids via a hydroboration-retro-hydroboration mechanism
(Royal Society of Chemistry, 2020) Hilario-Martínez, J. Ciciolil; Murillo, Fernando; García-Méndez, Jair; Dzib, Eugenia; Sandoval-Ramírez, Jesús; Muñoz-Hernández, Miguel Ángel; Bernès, Sylvain; Kürti, László; Duarte, Fernanda; Merino, Gabriel; Fernández-Herrera, María A.
Herein, we report for the first time a “trans-hydroboration–oxidation product” isolated and characterized under traditional hydroboration–oxidation conditions using cholesterol and diosgenin as substrates. These substrates are excellent starting materials because of the rigidity and different structural environments around the double bond. Further investigations based on experimental evidence, in conjunction with theoretical studies, indicate that the formation of this trans-species occurs via a retro-hydroboration of the major product to generate the corresponding Δ6-structure and the subsequent hydroboration by the β-face. Besides, the corresponding Markovnikov type products have been isolated in synthetically useful yields. The behavior of the reaction under a range of temperatures is also investigated.
Transition metal-free direct dehydrogenative arylation of activated C(sp3)–H bonds: synthetic ambit and DFT reactivity predictions
(Royal Society of Chemistry, 2018) Lovato, Kaitlyn; Guo, Lirong; Xu, Qing-Long; Liu, Fengting; Yousufuddin, Muhammed; Ess, Daniel H.; Kürti, László; Gao, Hongyin
A transition metal-free dehydrogenative method for the direct mono-arylation of a wide range of activated C(sp3)-H bonds has been developed. This operationally simple and environmentally friendly aerobic arylation uses tert-BuOK as the base and nitroarenes as electrophiles to prepare up to gram quantities of structurally diverse sets (>60 examples) of α-arylated esters, amides, nitriles, sulfones and triaryl methanes. DFT calculations provided a predictive model, which states that substrates containing a C(sp3)-H bond with a sufficiently low pK a value should readily undergo arylation. The DFT prediction was confirmed through experimental testing of nearly a dozen substrates containing activated C(sp3)-H bonds. This arylation method was also used in a one-pot protocol to synthesize over twenty compounds containing all-carbon quaternary centers.

Browsing by Author "Kürti, László"

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