László Kürti

Rapid Synthesis of Fused N‐Heterocycles by Transition‐Metal‐Free Electrophilic Amination of Arene CH Bonds

We disclose an efficient and operationally simple protocol for the preparation of fused N-heterocycles starting from readily available 2-nitrobiaryls and PhMgBr under mild conditions. More than two dozen N-heterocycles, including two bioactive natural products, have been synthesized using this method. A stepwise electrophilic aromatic cyclization mechanism was proposed by DFT calculations.

Elusive metal-free primary amination of arylboronic acids: synthetic studies and mechanism by density functional theory.

Herein, we disclose the first metal-free synthesis of primary aromatic amines from arylboronic acids, a reaction that has eluded synthetic chemists for decades. This remarkable transformation affords structurally diverse primary arylamines in good chemical yields, including a variety of halogenated primary anilines that often cannot be prepared via transition-metal-catalyzed amination. The reaction is operationally simple, requires only a slight excess of aminating agent, proceeds under neutral or basic conditions, and, importantly, can be scaled up to provide multigram quantities of primary anilines. Density functional calculations reveal that the most likely mechanism involves a facile 1,2-aryl migration and that the presence of an ortho nitro group in the aminating agent plays a critical role in lowering the free energy barrier of the 1,2-aryl migration step.

Direct stereospecific synthesis of unprotected N-H and N-Me aziridines from olefins.

Unadorned Aziridines Multiple catalytic methods have been developed to make aziridines—strained triangular carbon-nitrogen-carbon rings that function as versatile synthetic intermediates. However, the majority require protection of the nitrogen precursor with a sulfonyl group that is subsequently inconvenient to remove. Jat et al. (p. 61; see the Perspective by Türkmen and Aggarwal) used a hydroxylamine derivative as the nitrogen source together with an established rhodium catalyst to prepare a wide range of unprotected aziridines, with nitrogen bonded simply to hydrogen or a methyl group. A route to triangular carbon-nitrogen rings avoids placement of a hard-to-remove protecting group on the nitrogen precursor. Despite the prevalence of the N-H aziridine motif in bioactive natural products and the clear advantages of this unprotected parent structure over N-protected derivatives as a synthetic building block, no practical methods have emerged for direct synthesis of this compound class from unfunctionalized olefins. Here, we present a mild, versatile method for the direct stereospecific conversion of structurally diverse mono-, di-, tri-, and tetrasubstituted olefins to N-H aziridines using O-(2,4-dinitrophenyl)hydroxylamine (DPH) via homogeneous rhodium catalysis with no external oxidants. This method is operationally simple (i.e., one-pot), scalable, and fast at ambient temperature, furnishing N-H aziridines in good-to-excellent yields. Likewise, N-alkyl aziridines are prepared from N-alkylated DPH derivatives. Quantum-mechanical calculations suggest a plausible Rh-nitrene pathway.

Aerobic, transition-metal-free, direct, and regiospecific mono-α-arylation of ketones: synthesis and mechanism by DFT calculations.

We disclose a facile, aerobic, transition-metal-free, direct, and regiospecific mono-α-arylation of ketones to yield aryl benzyl and (cyclo)alkyl benzyl ketones with substitution patterns that are currently inaccessible or challenging to prepare using conventional methods. The transformation is operationally simple, scalable, and environmentally friendly. There is no need for pre-functionalization (i.e., α-halogenation or silyl enol ether formation) or the use of specialized arylating agents (i.e., diaryliodonium salts). DFT calculations suggest that the in situ-generated enolate undergoes direct C-C bond formation with the nitroarene followed by regioselective O2-mediated C-H oxidation.

Discovery of potent and practical antiangiogenic agents inspired by cortistatin A.

The discovery that cortistatins A and J show noteworthy antiangiogenic activity prompted an investigation of the possibility that simpler and much more easily made compounds based on a steroid core might have useful bioactivity. These studies have led to the development of several potent, water-soluble compounds that may be suitable for local application to treat ocular wet macular degeneration, an important cause of blindness, as well as for treatment of various other angiogenesis-dependent diseases. One of these substances was tested in a mouse retinal angiogenesis model and found to inhibit angiogenesis at a locally administered dose of 500 pmol. Comparison of cell migration data for this and two other synthetic compounds with published data on cortistatin A indicate that they inhibit vascular endothelial growth factor-induced cell migration of human umbilical vein endothelial cells more strongly than cortistatin A.

Origin of Enantioselectivity in the Jacobsen Epoxidation of Olefins

It is proposed that facial selectivity in the Jacobsen epoxidation is determined by electrostatic and steric factors with a two-step pathway involving a carbocationic intermediate.

A Short, Scalable Synthesis of the Carbocyclic Core of the Anti-Angiogenic Cortistatins from (+)-Estrone by B-Ring Expansion

A rapid and scalable synthesis of the carbocyclic core of the potent antiangiogenic natural products, the cortistatins, is presented starting from readily available (+)-estrone. Key steps include a regio- and stereoselective benzylic cyanation and a Demjanov rearrangement.

Dirhodium-catalyzed C-H arene amination using hydroxylamines.

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.

Conformational Energetics of Cationic Backbone Rearrangements in Triterpenoid Biosynthesis Provide an Insight into Enzymatic Control of Product

2,3-( S)-Oxidosqualene (C 30H 50O) serves as a versatile starting point for the remarkable biosynthesis of many isomeric naturally occurring triterpenoids of formula C 30H 50O. These biosyntheses all involve polycyclization via cationic intermediates. The fully cyclized primary products then are converted to various structures by cationic rearrangements involving the polycyclic backbone. The energetics of these rearrangements has been examined by B3LYP 6-31 G* DFT calculations and by ab initio Hartree-Fock calculations at the 6-31G* or 3-21G(*) level. The results have led to the conclusion that the biosynthesis of friedelin, the most drastically rearranged of the pentacyclic triterpenes, involves a complex nonstop process, with no stable intermediates between 2,3-( S)-oxidosqualene and friedelin. It is proposed that this single-reaction biosynthesis consists of pentacyclization to the lupanyl cation followed directly by a sequence of 10 suprafacial 1,2-shifts of carbon and hydrogen, driven by the large exergonicity of the pentacyclization and electrostatic acceleration of the rearrangement steps.

Scalable, transition-metal-free direct oxime O-arylation: rapid access to O-arylhydroxylamines and substituted benzo[b]furans.

O-aryloximes, generated from readily available and inexpensive oximes through transition-metal-free O-arylation, can either be hydrolyzed to O-arylhydroxylamines or conveniently converted to structurally diverse benzo[b]furans through an environmentally benign, one-pot [3,3]-sigmatropic rearrangement/cyclization sequence.