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Abstract: The Claisen-like condensation of a series of 1-arylacetyl-6-acetyl-3,4,7,8-tetramethylglycolurils (Ar = Ph, p-OMeC6H4, and p-Cl[C.sub.6][H.sub.4]) was studied in preparative experiments and by analysis of kinetic data. The reactions proceeded in [...]

Amides that are twisted around the C--N bond show unusual spectroscopy and reactivity when compared with planar amides. The diacyl derivatives of 3,4,7,8-tetramethyl-2,5-dithioglycoluril are intriguing examples of this class, since the crystal structures show that the two acyl groups are twisted by different amounts on either side of the molecule owing to a combination of steric and electronic effects. However, the ¹H NMR spectra in solution at room temperature exhibit only one acyl resonance, so there must be fast interconversion among pairs of equivalent structures of each compound. We have prepared a number of derivatives with different acyl groups, both on the glycoluril framework as well as on its dithio analogue. The chemical exchange in solution was slowed down sufficiently by cooling to see individual sites for only two compounds: the dithiodipivaloyl and the dithiodiadamantyl derivatives. The barriers were estimated at 41 kJ [mol.sup.-1] for the dipivaloyl derivative and 45 kJ [mol.sup.-1] for diadamantyl derivative. The results show that rotation around the twisted amide bond is slowed by both the steric size of the acyl group and the presence of the thioureido group vs. the ureido group in the glycoluril core. In the solid-state 13C NMR spectra, there is no evidence for any dynamics, even for the diacetyl derivative at ambient temperature. Electronic structure calculations predict a geometry for the dipivaloyl derivative very close to that observed in the crystal structure. These results indicate that the crystal confines, but does not distort the molecule. A mechanism for the exchange is proposed. The relevance of these results to the mechanism of Claisen-like condensations in diacylglycolurils is also discussed. Key words: ¹H and [sup.13]C NMR, exchange, dynamics, CP/MAS, solids, line shape analysis, amides, twisted amides, atropisomers, glycoluril. Par comparaison avec les proprietes correspondantes des amides planaires, les proprietes spectroscopiques et la reactivite des amides ayant subi une deformation autour de la liaison C--N presentent des caracteristiques inhabituelles. Les derives diaryles du 3,4,7,8-tetramethyl-2,5-dithioglycouril sent des exemples intriguant de cette classe puisque leurs structures cristallines montrent la presence de deux groupes acyles decales par des angles differents sur chaque cote de la molecule en raison d'une combinaison d'effets sterique et electronique. Toutefois, le spectre RMN du ¹H en solution, a la temperature ambiante ne presente qu'un seul signal de resonance pour un groupe acyle, ce qui implique qu'il se produit une interconversion rapide entre les paires de structures equivalentes de chaque compose. On a prepare un certain hombre de derives avec diffErents groupes acyles, tantdans le squelette du glycoluril que dans son analogue dithio. Le refroidissement des solutions afin de ralentir suffisamment l'Echange chimique en solution ne nous a permis d'observer les sites individuels de deux que dans les cas de deux derives, le dithiodipyvaloyle et le dithiodiadamantyle. On a evalue que les barrieres sent de 41 kJ [mol.sup.-1] pour le derive dipivaloyle et de 45 kJ [mol.sup.-1] pour le derive diadamantyle. Les resultats montrent que la rotation autour de la liaison amide deformee est ralentie tant par la grosseur sterique du groupe acyle que par la presence d'un groupe thioureido vs. le groupe ureido du coeur de glycouril. Dans le spectre RMN du [sup.13]C a l'etat solide, on n'a releve aucune donnee pour quelle que dynamique que ce soit, meme avec le derive diacetyle a la temperature ambiante. Des calculs de structure electronique permettent de predire une geometrie pour le derive dipivaloyle qui ressemble beaucoup a celle observee dans la structure cristalline. Les resultats indiquent que le cristal sert a confiner les molecules sans toutefois les deformer. On propose un mecanisme pour l'echange. On discute aussi de l'interet de ces resultats pour le mecanisme de condensations de type Claisen dans les diacetylglycolurils. Mots cles : RMN du ¹H et [sup.13]C, echange, dynamique, CP/MAS, solides, analyse de la forme des bandes, amides, amides deformes, atropisomeres, glycoluril. [Traduit par la Redaction], Introduction Amides are perhaps the most studied three-atom linkage in chemistry (1, 2). Their central role as the backbone of protein structure provides thousands of different examples of the peptide [...]

Apparent rate constants for the tert-butoxide promoted Claisen-like condensation of a series of [N.sup.1]-acetyl-[N.sup.6]-aroyl-2,5-dithio-3,4,7,8-tetramethylglycolurils (9a-9f) to give [N.sup.1]-(3'-aroyl-3'-oxopropionyl)-2,5-dithio-3,4,7,8-tetramethylglycolurils (10a-10f) were determined by UV spectroscopy. Overall rate accelerations of 3.5- to 18-fold were found relative to the corresponding reactions of the 2,5-dioxo compounds (7a-7f). Analysis of the Hammett plot for 9 and comparison with that for 7 shows that the key C--C bond-forming step, where the enolate of the acetyl group of the substrate attacks the aroyl carbonyl group, is accelerated by the thio substitution. For electron-withdrawing substituents in the aroyl group, the acceleration is sufficient to make this step nonrate limiting: the Hammett ρ value drops from approx. 1.5 for electron-donating groups to 0.27 for electron-withdrawing groups. Deuterium substitution in the acetyl group reduces the rate slightly, a result consistent with a slow but partially reversible first step in which substrate is deprotonated. A similar acceleration and isotope effect are found when diacetyl glycoluril (2) and diacetyl dithio glycoluril (5) are compared. The implications of these results are discussed. Key words: glycoluril, Claisen condensation, kinetics, mechanism. Resume : Faisant appel a la spectroscopie UV, on a determine les constantes de vitesse apparente des condensations de type Claisen, catalysees par l'ion tert-butylate, d'une serie de [N.sup.1]-acetyl-[N.sup.6]-aroyl-2,5-dithio-3,4,7,8-tetramethylglycolurils (9a-9f) conduisant a la formation de [N.sup.1]-(3'-aroyl-3'-oxopropionyl)-2,5-dithio-3,4,7,8-tetramethylglycolurils (10a-10f). On a observe des vitesses globales qui etaient de 3,5 a 18 fois plus rapides que celles des reactions correspondantes avec les composes 2,5-dioxo (7a-7f). Une analyse de la courbe de Hammett pour les composes 9 et une comparaison avec celle des composes 7 montrent que l'etape cle de formation de la liaison C--C, dans laquelle l'enolate du groupe acetyle du substrat attaque le groupe carbonyle de l'aroyle est acceleree par la substitution thio. Pour les substituants electroaffinitaires du groupe aroyle, l'acceleration est suffisante pour que cette etape ne soit plus l'etape cinetiquement determinante: la valeur p de Hammett tombe d'une egale a environ 1,5 pour les groupes electrodonneurs a une valeur de 0,27 pour les groupes electroattracteurs. Une substitution du groupe acetyle par du deuterium reduit legerement la vitesse, un resultat qui est en accord avec une premiere etape lente, mais partiellement reversible, dans laquelle le substrat est deprotone. Une acceleration et un effet isotopique semblable ont aussi ete observes lorsqu'on a compare le diacetylglycoluril (2) et diacetyldithioglycoluril (5). On discute des implications de ces resultats. Mots cles : glycoluril, condensation de Claisen, cinetique, mecanisme. [Traduit par la Redaction], Introduction Auxiliaries are frequently pivotal in the design and execution of stereoselective syntheses (1). For example, the oxazolidinones developed by Evans allow highly diastereoand enantioselective carbon-carbon bond forming reactions, as [...]

Compound 10 (3,4,7,8-tetramethyl-2,5-dithioglycoluril) was converted in two steps to 12a, which contains a malonate and acetate unit attached to N1 and N6, respectively. These two groups are held in proximity in a manner analogous to the loaded ketosynthase domain of polyketide and fatty acid synthases. After cleavage of the methyl ester by pig liver esterase (PLE), a polar intermediate assigned to acid 15 was separated. This material undergoes conversion to acetoacetylglycoluril 18 upon attempted isolation. The overall conversion thus resembles the decarboxylative condensation catalyzed by ketosynthase. Furthermore, isotope labeling and product studies support a mechanism in which decarboxylation of 15 precedes an intramolecular Claisen-like condensation, as it is believed to occur for the ketosynthase enzymic case. The system thus provides a functional chemical model of the key carbon-carbon bond-forming step in fatty acid and polyketide biosynthesis. Key words: biomimetic, decarboxylation, polyketide, esterase, Claisen condensation.

Eight N-acetyl-N-aroyl-glycolurils were prepared and found to undergo efficient tert-butoxide-promoted Claisen-like condensation between the two acyl moieties. The kinetics for formation of each of the N-(aroylacetyl)glycoluril products were monitored by UV spectroscopy. The reactions exhibited pseudo-first-order kinetics in substrate in the presence of excess base. For the parent benzoyl compound the observed first-order rate constant ([k.sub.obs]) was linearly dependent on the concentration of the base, tert-butoxide. A Hammett plot of the resulting apparent second-order rate constants ([k.sub.app]) vs. [sigma] for each of the eight aroyl derivatives was linear and had a positive [rho] value 1.04 [+ or -] 0.04), demonstrating that the substituent on the aromatic ring exerts a significant effect upon the condensation reaction. The corresponding plot for three [D.sub.3]acetyl analogues was also linear, but the slope was reduced by 20% relative to the protonated compounds. The isotope effect ([k.sub.app.sup.H]/[k.sub.app.sup.D]) thus increased from 1.4 (benzoyl) to 2.6 (p-nitrobenzoyl). The results are consistent with a three-step mechanism in which both deprotonation of the acetyl entity and the ensuing nucleophilic attack of the resulting enolate on the benzoyl group are partially rate-determining steps. The tetrahedral intermediate thus produced rapidly collapses to the product. For the [D.sub.3]acetyl benzoyl derivative, exchange of substrate deuterium with solvent hydrogen due to reprotonation of the enolate intermediate occurs at a rate that is similar to that of condensation, but the enolate partitions towards the product when electron withdrawing groups are present in the aroyl ring. Thus, despite the presence of a large excess of co-solvent tert-butanol, the efficiency with which the enolate undergoes condensation remains high. The clean kinetics observed allows further exploration of the details of this intramolecular Claisen-like condensation process. Key words: Claisen condensation, glycoluril, kinetics, Hammett, mechanism.

A simple method for the conversion of glycoluril and several acyl derivatives to the corresponding mono- or dithio derivatives is presented. The novel application of Lawesson's reagent to glycolurils can be extended to N-acylglycolurils. The chemistry of these derivatives are compared in the crossed-Claisen-like condensation with the corresponding oxygen analogue. Results indicate that the thionation offers a more sophisticated and selective template for development of intramolecular crossed-Claisen methodology using the glycoluril template-directed approach.

The effects of a newly discovered antifungal agent, pramanicin, on cytosolic Ca2+ and cell viability of cultured bovine pulmonary artery endothelial cells and on endothelium-dependent relaxation of dog carotid arterial rings were investigated by digital dynamic fluorescence ratio imaging and morphological and contractility studies, respectively. Pramanicin 100 μM, previously shown to cause maximal endothelium-dependent and NO-mediated vascular relaxation, induced a small transient elevation of cytosolic Ca2+ concentration in Ca2+-free medium; subsequent introduction of 1 mM Ca2+ caused a steady, nonsaturating increase of Ca2+, which could be brought down to the basal level by the addition of EGTA. At the single cell level, the elevation of cytosolic Ca2+ initiates from the cell periphery and progresses toward the central region. When added to the plateau phase of phenylephrine-induced contraction, pramanicin induced a slow endothelium-dependent relaxation, which could be reversed with the NO synthase inhibitor, l-NOARG. When preincubated with vascular tissue, pramanicin resulted in an irreversible loss of endothelial function characterized by the lack of carbachol-induced relaxation. Pramanicin caused cell injury characterized by plasmalemmal bleb formation, leading to cell death characterized by Trypan blue staining of the nuclei in cultured vascular endothelial cells in a concentration- and time-dependent manner. Such pramanicin-induced cell death was not associated with Ca2+-mediated or NO-mediated mechanisms. The time course of Ca2+ elevation corresponds with that of pramanicin-induced relaxation of precontracted arterial rings, whereas the time course of endothelial cell death corresponds to that of pramanicin-induced loss of endothelial function as assessed by carbachol-induced relaxation. The pramanicin analogue, PMC-A, a by-product of the biosynthesis of pramanicin, in which the epoxy group is replaced by a C&z.dbnd6;C bond, caused little endothelial-dependent relaxation, but it was able to cause endothelial cell dysfunction, albeit to a lesser extent compared to pramanicin, suggesting a role of the epoxy group in pramanicin for its vasorelaxant effect. [Copyright &y& Elsevier]