Dehydration of alcohols catalyzed by copper(II) sulfate: type II dyotropic reactions and stepwise mechanisms.

Dehydration of alcohols in the presence of copper(II) sulfate has been analyzed computationally. Density functional theory (DFT) calculations on selected alcohols indicate that this reaction can take place via two possible mechanisms: (a) concerted - although asynchronous - type II dyotropic reactions, or (b) stepwise E1-like processes, in which cleavage of the C-O bond occurs in the first step, followed by syn proton elimination. Our calculations show the relationship between the initial alcohol structure and the preferred mechanism, which is a type II dyotropic reaction for primary alcohols, whereas a stepwise process is the favored one when stable carbocation intermediates are energetically accessible. The dehydration of dehydrolinalool (2,7-dimethyl-6-en-1-yn-3-ol, DHL) to yield different alkenes of interest in the fragrance industry is discussed as a case study of its regiochemistry.

Higher-Order Electrocyclizations in Biological and Synthetic Processes.

In general, electrocyclizations follow the Woodward-Hoffmann's rules of conservation of orbital symmetry. These rules have been extensively verified in low-order processes, both in thermal and photochemical reactions, up to eight π-electrons. However, when the number of π-electrons in the system increases, some deviations of that general rules can be found. This focused review highlights the main features of reported higher-order electrocyclizations involving 10, 12, 14, 16 and 18 π-electrons. Some of these examples constitute useful intermediates in the synthesis of biologically active compounds. When computational studies were not included in the reported examples, DFT calculations have been performed to be included in this review. Analysis of the respective pericyclic topologies shows the importance of computational tools for understanding the selectivity observed experimentally.

Organocatalysts Derived from Unnatural α-Amino Acids: Scope and Applications.

The organocatalytic properties of unnatural α-amino acids are reviewed. Post-translational derivatives of natural α-amino acids include 4-hydroxy-l-proline and 4-amino-l-proline scaffolds, and also proline homologues. The activity of synthetic unnatural α-amino acid-based organocatalysts, such as ß-alkyl alanines, alanine-based phosphines, and tert-leucine derivatives, are reviewed herein. The organocatalytic properties of unnatural monocyclic, bicyclic, and tricyclic proline derivatives are also reviewed. Several families of these organocatalysts permit the efficient and stereoselective synthesis of complex natural products. Most of the reviewed organocatalysts accelerate the reported reactions through covalent interactions that raise the HOMO (enamine intermediates) or lower the LUMO (iminium intermediates).

Application of 1,3-Dipolar Reactions between Azomethine Ylides and Alkenes to the Synthesis of Catalysts and Biologically Active Compounds.

The (3+2) cycloaddition between azomethine ylides and alkenes is an efficient, convergent and stereocontrolled method for the synthesis of unnatural pyrrolidine and proline scaffolds. In this review, the application of this reaction to the synthesis of enantiopure organometallic ligands for asymmetric catalysis is presented first. These new EhuPhos ligands can participate in a second generation of 1,3-dipolar reactions that generate an offspring of unnatural proline derivatives that behave as efficient organocatalysts. These densely substituted unnatural l-proline derivatives exhibit distinct features, different to those described for natural l-proline and its derivatives. Finally, several examples of biologically active proline derivatives obtained by means of (3+2) cycloadditions involving azomethine ylides are presented. These applications show the character of privileged structures of these polysubstituted pyrrolidine rings.

Two-State Reactivity of Histone Demethylases Containing Jumonji-C Active Sites: Different Mechanisms for Different Methylation Degrees.

The N-demethylation reactions of N,N,N-trimethylpropan-1-ammonium and N,N-dimethyl- and N-methylpropan-1-aminium cations in the presence of [(AcO)2 (imidazole)2 (H2 O)Fe=O] complex have been studied by density functional theory. These transformations are suitable models for the N-demethylation of tri-, di-, and monomethylated lysine residues of histones in the presence of Jumonji-C containing histone demethylases. It has been found that the N-demethylation reaction is stepwise and occurs on triplet and quintet potential energy hypersurfaces. Both spin states are nearly degenerated and the quantum jump from one state to another has a transition probability close to one. The preferred intrinsic mechanism depends upon the methylation degree. For trimethylated residues the mechanism consists of a proton abstraction from a methyl group followed by a formation of a hydroxymethylaminium intermediate. This mechanism also occurs when dimethylated residues are able to orientate one methyl group towards the Fe=O group of the catalytic site. In contrast, when a N-H group of the substrate is close enough to the Fe=O group, the intrinsically preferred N-demethylation reaction leads to the formation of an iminium intermediate that can be hydrolyzed to form the corresponding N-demethylated product.

Solvent and Substituent Effects in the Periselectivity of the Staudinger Reaction between Ketenes and alpha,beta-Unsaturated Imines. A Theoretical and Experimental Study.

The outcome of the cycloaddition between activated ketenes and alpha,beta-unsaturated imines has been investigated both experimentally and theoretically. Our results indicate that activated monosubstituted ketenes yield exclusively [2 + 2] cycloadducts. Disubstituted activated ketenes yield [2 + 2] and/or [4 + 2] cycloadducts. In one case, an unexpected piperidin-2-one has been obtained, although its relative abundance with respect to the corresponding [2 + 2] or [4 + 2] cycloadducts can be minimized by the proper choice of experimental conditions. The ability of different ab initio and semiempirical methods to account for these results has been tested. The best agreement between theory and experiment is achieved at the MP2/6-31G level of theory, with solvent effects taken into account. The semiempirical hamiltonian AM1, at the RHF level, tends to overestimate the stability of the transition structures leading to six-membered cycloadducts, whereas 3 x 3CI-HE/AM1 and CASSCF(2,2)/6-31G methods tend to overestimate the stability and the biradical character of the transition structures leading to [2 + 2] cycloadducts.