Self-Regeneration of Chirality with l-Cysteine through 1,3-Dipolar Cycloadditions between Diazoalkanes and Enantiomerically Pure Thiazolines: Experimental and Computational Studies.

Enantiopure 2-thia-4-azabicyclo[3.1.0]hexanes, which can be considered constrained cysteines, have been obtained from l-cysteine by application of the "self-regeneration of chirality" concept. The key intermediates are homochiral thiazolines that can be prepared in multigram scale and react smoothly with a series of diazoalkanes providing Δ1-pyrazolines except for phenyldiazomethane that yield the isomeric Δ2-pyrazolines. Nitrogen extrusion in Δ1-pyrazolines and further reduction of the sulfinyl group yielded the target compounds in good overall yield. Computational studies of the cycloaddition reaction were used for determining the polarity of the process and explaining the observed stereoselectivity. Additional topological studies were employed for determining the influence of noncovalent interactions in the stereochemical course of the reaction, which showed to be a highly asynchronous concerted process.

Computational Mechanistic Study of Thionation of Carbonyl Compounds with Lawesson's Reagent.

The thionation reaction of carbonyl compounds with Lawesson's reagent (LR) has been studied using density functional theory methods and topological analyses. After dissociation of LR, the reaction takes place through a two-step mechanism involving (i) a concerted cycloaddition between one monomer and the carbonyl compound to form a four-membered intermediate and (ii) a cycloreversion leading to the thiocarbonyl derivative and phenyl(thioxo)phosphine oxide. Topological analyses confirmed the concertedness and asynchronicity of the process. The second step is the rate-limiting one, and the whole process resembles the currently accepted mechanism for the lithium salt-free Wittig reaction. No zwitterionic intermediates are formed during the reaction, although stabilizing electrostatic interactions are present in initial stages. Phenyl(thioxo)phosphine oxide formed in the thionation reaction is capable of performing a second thionation, although with energy barriers higher than the first one. The driving force of the thionation reactions is the formation of trimers from the resulting monomers. In agreement with experimental observations, the amides are the most reactive when compared with esters, aldehydes, and ketones and the reaction is slightly influenced by the polarity of the solvent. Whereas for amides and esters substituents have little effect, aldehydes and ketones are influenced by both steric and electronic effects.

Theoretical elucidation of the mechanism of the cycloaddition between nitrone ylides and electron-deficient alkenes.

A full theoretical study of the reaction between a novel type of ylide, i.e. nitrone ylides, and alkenes has been carried out. Both concerted and polar stepwise mechanisms have been considered. Only the zwitterionic mechanism predicts correctly the experimentally observed adducts. Depending on the level of theory, the mechanism moves from concerted to polar stepwise, as demonstrated by the corresponding IRC analyses. The regio- and stereoselectivity of the reaction is well explained for both mono- and disubstituted alkenes. In the case of methyl acrylate a pathway leading to the two diastereoisomers obtained experimentally is predicted. For methyl fumarate a stereospecific mechanism is predicted as a consequence of a C-H···O═C interaction present in a Li-tricoordinated transition structure. The stereospecificity in the reaction with methyl maleate comes from a less hindered coordination around the lithium atom. Calculations with B3LYP and M06-2X functionals indicate that only the latter provides energy values in good agreement with experimental findings.

Stereodivergent approaches to the synthesis of isoxazolidine analogues of alpha-amino acid nucleosides. Total synthesis of isoxazolidinyl deoxypolyoxin C and uracil polyoxin C.

The synthesis of new nucleoside analogues is currently of high interest. We report here full details of a study leading to the synthesis of novel isoxazolidinyl analogues of alpha-amino acid nucleosides. Three different synthetic approaches starting from L-serine have been evaluated for the construction of the isoxazolidine ring. These approaches consisted of Michael addition of N-benzylhydroxylamine to alpha,beta-unsaturated esters, nucleophilic addition of silyl ketene acetals to nitrones and 1, 3-dipolar cycloaddition of nitrones with vinyl acetate. Both Michael addition and nucleophilic addition of enolates could be carried out with stereocontrol at the newly formed stereogenic carbon. The stereocontrol observed in these reactions arises from the protecting group arrangement in the L-serine-derived substrates. Thus, whereas compounds having a diprotected nitrogen led to syn adducts, compounds having a monoprotected nitrogen gave rise to anti adducts. On the other hand, substrates having either a diprotected or monoprotected nitrogen atom led to anti adducts through the cycloaddition route. So, by choosing the appropriate route, isoxazolidinyl analogues having either syn or anti configuration with respect to the glycine unit can be prepared in enantiomerically pure form. The stereoselective synthesis of isoxazolidinyl analogues of deoxypolyoxin C and uracil polyoxin C in both D and L enantiomeric forms using these techniques has been achieved in good yields.

A new entry to glycosylamines.

A new procedure for the introduction of a nitrogen atom into the anomeric centre leading to glycosylamines is described. The new reaction consisting of the condensation of a furanose with a hydroxylamine in the presence of a Lewis acid occurs with a complete degree of diastereoselectivity.

[Bibliometric indicators of production and usage of Archivos de Bronchoneumologia]. / Indicadores bibliométricos de producción y consumo de ARCHIVOS DE BRONCONEUMOLOGIA.

We studied the bibliometric indexes referring to production and scientific output published in ARCHIVOS de BRONCONEUMOLOGIA. All issues published between 1993 and 1994 were studied with the exception of monógraphic or supplementary numbers. For each article we recorded article type, number of authors, authors' place of work, specialty, time until acceptance, time until publication, type of references, language of references, journal and year of references. For each year we calculated the productivity index and the cooperation index, or index of signers per work. We also determined the citation period for references, the Price index, and the insularity index. Productivity index was 1.97 in 1993 and 2.05 in 1994. The cooperation index for the two years reached 4.5 +/- 1.9 (1-10). Authors were widely distributed by provinces and by specialties, although "nuclei" of production could be identified. The citation half-life period was 5.67 years for references in 1993 and 5.94 years in 1994, and the Price index surpassed 40%. The insularity index was very low at 7.76%. In conclusion, the bibliometric indicators for production, readership and obsolescence for the two years analyzed indicate that ARCHIVOS de BRONCONEUMOLOGIA occupies an intermediate position in the ranking of Spanish medical journals.