Svetlana B. Tsogoeva

Highly enantioselective addition of ketones to nitroolefins catalyzed by new thiourea–amine bifunctional organocatalysts

A new and effective organocatalytic system: primary amine derived chiral thiourea catalyst and AcOH-H2O additive, which converts different ketones to gamma-nitroketones in high yields (82-99%) and enantioselectivities (90-99%) has been described.

Recent progress in the development of synthetic hybrids of natural or unnatural bioactive compounds for medicinal chemistry.

The present mini-review highlights the recent developments on different classes of synthetic hybrids of natural and/or unnatural bioactive compounds, the utilization of which is very promising, as distinct features of each component can be hybridized and their properties leveraged. Particular stress is put on the respective mode of action and the corresponding rationale behind covalent combinations of various bioactive agents to increase their therapeutic potential, facilitate their administration, to reduce harmful side effects and/or to overcome the problem of multi-drug resistance. This rather recent approach has already found applications in the development of new anti-cancer, anti-Alzheimer, anti-malaria, anti-microbial therapeutics and other novel compounds with unprecedented bioactivity.

Demonstration of "Möbius" aromaticity in planar metallacycles.

Möbius aromaticity, predicted by Edgar Heilbronner in 1964, is a stabilizing effect exhibited by 4n electron fully conjugated cyclic molecules (or transition states) with an odd number of orbital phase inversions. Although it has previously been suggested that this effect might also apply to planar metallacycles in which a transition metal employs a d orbital in delta-type binding mode, only very few examples of stable twisted molecules composed of main group elements are known. We report herein, the first computationally confirmed 4npi aromatic planar metallacyclic examples and their building principles. Aromatic stabilization energy (ASE) of a 8pi metalla-cycloheptatriene [Fe(CH)(6)H(2)], with four doubly occupied pi orbitals and a HOMA value of +0.80 (cf. benzene=+1.0), an NICS(0) value of -8.5 (benzene=-9.8, NICS=nucleus independent chemical shift), and with one phase inversion, is +27.5 kcal mol(-1) (about two-thirds of the value for benzene). In contrast, an unknown non-Möbius 1,4-dimetallabenzene [Fe(2)(CH)(4)H(4)], also with 8pi electrons, and without phase inversions, has an ASE of -4.1 kcal mol(-1) and a NICS(0)=+15.6, indicative of antiaromaticity. Aromaticity of the proposed Möbius aromatic metallacycles is confirmed by using magnetic (NICS(0), NICS(1)(zz), delta(1)H) and geometric (HOMA) aromaticity criteria, planarity, and near equalized C-C bond lengths, bonding analysis (Wiberg bond indices, NBO, and NLMO analysis). The role of wave function boundary conditions (periodic vs. antiperiodic) in chemistry is further stressed, being equivalent to Zimmermans concept of nodal parity for Möbius/Hückel systems.

Assessment of Popular DFT and Semiempirical Molecular Orbital Techniques for Calculating Relative Transition State Energies and Kinetic Product Distributions in Enantioselective Organocatalytic Reactions

The performance of computationally accessible levels of calculation for the transition states of organocatalytic reaction has been assessed. Reference post-Hartree-Fock single point energy calculations were used as standards for the gas-phase Born-Oppenheimer relative energies of pairs of alternative transition states that lead to the two product enantiomers. We show that semiempirical methods cannot even be relied on to yield qualitatively correct results. The geometries (optimized, for instance, with DFT) have a large impact on the results of high-level post-HF calculations, so that it is essential to use an adequate DFT technique and basis set. DFT can yield quantitatively correct results that are consistent with post-HF calculations if functionals that consider dispersion are used. Geometries for large systems show larger errors than those for smaller ones but are treated better by functionals such as M06-2X and w97Bxd that include dispersion implicitly or explicitly. Local correlation techniques introduce errors of comparable magnitude to those given by different levels of geometry optimization. We recommend RICC2/TZVP//M06-2X/TZVP, RI-MP2/TZVP// M06-2X/TZVP, and M06-2X/TZVP// M06-2X/TZVP calculations in that order, depending on the size of the system.

Cytotoxicity of artesunic acid homo- and heterodimer molecules toward sensitive and multidrug-resistant CCRF-CEM leukemia cells.

A novel approach to circumvent multidrug resistance is hybridization of natural products in dimers. We analyzed homodimers of two artesunic acid molecules and heterohybrids of artesunic acid and betulin in human CCRF-CEM and multidrug-resistant P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells. Multidrug-resistant cells were not cross-resistant to the novel compounds. Collateral sensitivity was observed for artesunic acid homodimer. Artesunic acid and artesunic acid homodimer induced G0/G1 cell cycle arrest, apoptosis, and formation of reactive oxygen species.

Asymmetric cycloaddition reactions catalyzed by bifunctional thiourea and squaramide organocatalysts: recent advances

High on the list of challenges in organic chemistry is the development of new efficient chiral catalysts for enantioselective cycloaddition reactions, which are among the most useful processes in chemical synthesis. In the past few decades, various highly enantioselective bifunctional organocatalysts for different versatile cycloaddition reactions have been developed. In most cases, these organocatalytic cycloadditions (e.g. [4 + 2], [3 + 2], formal [3 + 2], formal [3 + 3], formal [5 + 1], [5 + 2], 1,3-dipolar cycloadditions and Tamura cycloaddition) provide the most convenient and economical routes to nitrogen- and oxygen-containing heterocyclic bioactive molecules. This minireview summarizes the recent developments in this field using chiral bifunctional amine-thiourea and amine-squaramide organocatalysts.

Non-heme iron catalysts for epoxidation and aziridination reactions of challenging terminal alkenes: towards sustainability

Through catalytic epoxidation and aziridination of olefins versatile synthetic intermediates and subunits of biologically active compounds and pharmaceuticals –epoxides and aziridines– can be obtained. The focus of this review is on recent advances in the epoxidation and aziridination of challenging terminal alkenes with respect to safety of solvents or reagents used and atom economy aspects, as well as scope and limitations of developed non-heme iron catalysts. The still large research potential for sustainable and environmentally attractive iron-based catalysts in enantioselective epoxide and aziridine synthesis is demonstrated.

Enantioselective epoxidation of electron-deficient olefins: an organocatalytic approach.

Versatile synthetic intermediates--α,β-epoxyketones and α,β-epoxyaldehydes--can be obtained through asymmetric organocatalytic epoxidation of α,β-unsaturated ketones and aldehydes. This Review focuses on some recent advances in these epoxidation reactions with respect to scope and limitations with polyamino acids, phase-transfer catalysts (PTCs), amines, and guanidines as chiral organocatalysts. Furthermore, recent results obtained with chiral peroxides are discussed.

Spontaneous Emergence of Homochirality via Coherently Coupled Antagonistic and Reversible Reaction Cycles

Asymmetric synthesis aims at obtaining enantio-enriched products in stereoselective reactions under a chiral influence. We demonstrate both mathematically and numerically that, even under nominally achiral conditions, fully homochiral steady states can be obtained in open reactive systems by spontaneous mirror-symmetry breaking in the homogenous solution phase when the autocatalytic reaction network is closed in the form of coherently coupled antagonistic reversible reaction cycles which, paradoxically, allow for complete recycling of the reactant. We show that the fully reversible Frank mechanism for spontaneous mirror-symmetry breaking is closely related to the Lotka-Volterra system, which models predator-prey relations in ecosystems. Amplification of total enantiomeric excess and the principle of microscopic reversibility are not in conflict for all conceivable reactions. A viable and widely applicable reaction protocol is introduced and discussed, and it permits the theoretical implications to be applied to practical laboratory examples. Implications for the possible origin of biological homochirality on early earth are discussed.

Novel one-pot process for the synthesis of 1,3-thiazoles via organocatalysed epoxidation of nitro-olefins.

A facile one-pot two-step process for the synthesis of 1,3-thiazole heterocycles via organocatalytic epoxidation of nitro-olefins with the t-BuOOH/DBU system, and subsequent reaction of α-nitro-epoxides with thioamides under mild conditions has been developed.