RESUMEN

Structurally diverse macrocyclic pyridones can be efficiently synthesized by a rhodium(III)-catalyzed C-H activation/heterocyclization of ω-alkynyl α-substituted acrylic hydroxamates. The use of a O-pivaloyl hydroxamate as directing group was crucial to achieve efficient catalyst turnover in a redox-neutral process.

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Macrocycles are arising considerable interest in medicinal chemistry. With the goal of harnessing C-H activation reactions for the development of efficient macrocyclization processes, the ruthenium(II)-catalyzed cyclization of O-methyl benzhydroxamates possessing an ω-acetylenic chain was investigated to access new structurally diverse macrocyclic isoquinolones. A slow addition of the substrate and the presence of Cu(OAc)2 ⋅H2 O as an additive were crucial for the success of the macrocyclization that features an excellent functional-group compatibility, as illustrated by the successful synthesis of a library of 21 macrocyclic isoquinolones of different ring sizes and substitution patterns. These results contribute to significantly highlight the synthetic interest of C-H activation-mediated processes for the synthesis of new macrocyles incorporating heterocyclic scaffolds of potential interest in medicinal chemistry.

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A simple, efficient and practical metal-free C-H sulfenylation process at the C2 position of non-protected indoles has been developed. 2-Thioindoles were obtained in moderate to high yields using stable and readily available N-(thio)succinimides at room temperature in the presence of TFA.

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A simple, efficient, and practical metal-free C-H sulfenylation of substituted electron-rich arenes has been developed. This method is highly regioselective, and the corresponding aryl sulfides were obtained in moderate to excellent yields from stable and readily accessible N-(alkylthio)- and N-(arylthio)succinimides at room temperature in the presence of TFA.

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With the goal of synthesizing new [n]paracyclophanes, the expansion of the scope of a strategy originally disclosed by Winterfeldt et al., was investigated. This approach involves sequential Diels-Alder/retro-Diels-Alder reactions, the applications of which have been constrained so far to steroid derivatives. An efficient access to new functionalized [9]-, [10]-, and [16]paracyclophanes, including original cage architectures, was developed from readily available building blocks using thermal electrocyclization and a cycloaddition/cycloreversion sequence as the key steps.

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The high diastereoselectivity of the hydrogenation of artemisinate by diazene to form dihydroartemisinate (diastereoselective ratio, dr, 97:3) necessary for efficient production of artemisin has been rationalized by state-of-the-art DFT calculations and identification of the noncovalent interactions by coupled ELF/NCI analysis. Remarkably, a single conformer of artemisinate is responsible for the high diastereoselectivity of the reaction. NMR studies confirm the preference for a single conformation that is found to be identical to that predicted by the calculations. The calculations and ELF/NCI analyses show that the hydrogenation of the exocyclic activated C═C double bond has a low energy barrier and that the lowest transition state and the preferred conformation of free artemisinate develop the same network of weak noncovalent interactions between the electron donor groups (oxygen and exocyclic C═C double bond) and CH bonds of the cis-decalene group of the artemisinate, which rationalize the high diastereoselectivity unusual for a strongly exothermic reaction.

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An iridium-catalyzed hydrogen transfer has been developed in the presence of p-benzoquinone, allowing the synthesis of a diversity of substituted benzofurans, benzothiophenes, and indoles from substituted benzylic alcohols.

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The complex electronic structure and spectroscopic properties of a class of six molecules behaving as near infrared (NIR) fluorescence probes, recently experimentally characterized, are investigated and rationalized using a computational protocol based on Density Functional Theory (DFT) and Time Dependent DFT (TD-DFT). These systems, all belonging to the seminaphthofluorone (SNAFR) series, are characterized by a controlled direction of annulation and regiochemistry of the ionizable moieties significantly tuning the overall absorption and emission features. Experimentally, the overall spectroscopic properties depend both on the pH and on the possible coexistence of different tautomers and regioisomers in solution, thus making the quantitative prediction of their absorption and emission features a challenging task for current ab initio approaches, due to the need for an accurate description of both ground and excited state potential energy landscapes. The results obtained in the present study illustrate the possibility of using a unique computational protocol to describe complex molecular systems in solution not only for the analysis of their intermingled spectroscopic properties but, more interestingly, for the design of new compounds for technological (white emitting dyes) and biological (ratiometric probes) applications.

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As the replacement of a hydrogen atom by a fluorine atom in a compound can have an important impact on its biological properties, the development of methods allowing the introduction of a fluorine atom is of great importance. The scope and limitations of the ring expansion of cyclic 2-hydroxymethyl amines induced by diethylaminosulfur trifluoride (DAST) to produce cyclic ß-fluoro amines was studied as well as the enantioselectivity of the process.

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An in-depth study of the cobalt-catalyzed [2+2+2] cycloaddition between yne-ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal-catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron-deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne-ynamide allows the regioselectivity to be switched toward 3- or 4-aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne-ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3-aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4-aminopyridines arise from an insertion pathway.

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The monoalkylation of acetonitrile by primary alcohols was achieved in a one-pot sequence in the presence of iridium catalysts. A diversity of nitriles has been obtained from aryl- and alkyl-methanols in excellent yield.

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Bimolecular cobalt-catalyzed [2 + 2 + 2] cycloadditions between yne-ynamides and nitriles afford bicyclic 3- or 4-aminopyridines in up to 100% yield. The high regioselectivity observed depends on the substitution pattern at the starting ynamide. Aminopyridines bearing TMS and Ts groups are efficiently deprotected in an orthogonal fashion.

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A methodological study devoted to the Mannich-like multicomponent synthesis of the antiplatelet agent (±)­clopidogrel (7) and the ethyl ester analogue 6 is described. The process involves the formation of 2-chlorophenyl zinc bromide (2) and its subsequent reaction with an alkyl glyoxylate and 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3). We demonstrate that the organozinc reagent 2 also constitutes a very convenient nucleophile for the multicomponent synthesis of the benzylamine core of ticlopidine (9).

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