Miriam Bru

Supramolecular Control for the Modular Synthesis of Pseudopeptidic Macrocycles through an Anion-Templated Reaction

The anion-templated synthesis of different pseudopeptidic macrocycles has been studied in detail by using a multidisciplinary approach. The reaction between an open-chain pseudopeptidic diamine and the appropriate dialdehyde is highly affected by the presence of the best fitting anionic template. The formation of the corresponding macrocyclic tetraimino-template supramolecular complex is demonstrated by NMR (ROESY and PGSE) and mass spectrometry (ESI-TOF). These supramolecular complexes can be easily reduced to the corresponding more stable tetraamine macrocycles. Accordingly, we have used this reaction to efficiently synthesize a family of new pseudopeptidic macrocycles in a one-pot two-steps anion-templated reductive amination reaction, which comprises a multicomponent macrocyclization through the selective formation of four chemical bonds to yield a unique macrocyclic structure. Different variables like the aliphatic spacer between amino acidic moieties, geometry of the dialdehyde, and structure of the amino acid side chains were thoroughly studied, and their effect in the formation and stability of the supramolecular complexes discussed. The conformational preorganization induced by the template has been monitored by circular dichroism, reflecting the differences observed in the isolated yields, as well as by NMR spectroscopy. This effect has been also supported by molecular modeling. All the experimental and theoretical techniques were strongly consistent and reflected the same trends by comparing the different structural variables introduced in the system.

Nickel‐Catalyzed Direct Carboxylation of Olefins with CO2: One‐Pot Synthesis of α,β‐Unsaturated Carboxylic Acid Salts

The nickel-catalyzed direct carboxylation of alkenes with the cheap and abundantly available C1 building block carbon dioxide (CO2 ) in the presence of a base has been achieved. The one-pot reaction allows for the direct and selective synthesis of a wide range of α,β-unsaturated carboxylates (TON>100, TOF up to 6 h(-1) , TON=turnover number, TOF=turnover frequency). Thus, it is possible, in one step, to synthesize sodium acrylate from ethylene, CO2 , and a sodium salt. Acrylates are industrially important products, the synthesis of which has hitherto required multiple steps.

Structural Diversity in the Self‐Assembly of Pseudopeptidic Macrocycles

The self-assembling abilities of several pseudopeptidic macrocycles have been thoroughly studied both in the solid (SEM, TEM, FTIR) and in solution (NMR, UV, CD, FTIR) states. Detailed microscopy revealed large differences in the morphology of the self-assembling micro/nanostructures depending on the macrocyclic chemical structures. Self-assembly was triggered by the presence of additional methylene groups or by changing from para to meta geometry of the aromatic phenylene backbone moiety. More interestingly, the nature of the side chain also plays a fundamental role in some of the obtained nanostructures, thus producing structures from long fibers to hollow spheres. These nanostructures were obtained in different solvents and on different surfaces, thus implying that the chemical information for the self-assembly is contained in the molecular structure. Dilution NMR studies (chemical shift and self-diffusion rates) suggest the formation of incipient aggregates in solution by a combination of hydrogen-bonding and pi-pi interactions, thus implicating amide and aryl groups, respectively. Electronic spectroscopy further supports the pi-pi interactions because the compounds that lead to fibers show large hypochromic shifts in the UV spectra. Moreover, the fiber-forming macrocycles also showed a more intense CD signature. The hydrogen-bonding interactions within the nanostructures were also characterized by attenuated total-reflectance FTIR spectroscopy, which allowed us to monitor the complete transition from the solution to the dried nanostructure. Overall, we concluded that the self-assembly of this family of pseudopeptidic macrocycles is dictated by a synergic action of hydrogen-bonding and pi-pi interactions. The feasibility and geometrical disposition of these interactions finally render a hierarchical organization, which has been rationalized with a proposal of a model. The understanding of the process at the molecular level has allowed us to prepare hybrid soft materials.

Designed folding of pseudopeptides: the transformation of a configurationally driven preorganization into a stereoselective multicomponent macrocyclization reaction.

The efficient synthesis of large-ring pseudopeptidic macrocycles through a multicomponent [2+2] reductive amination reaction is described. The reaction was entirely governed by the structural information contained in the corresponding open-chain pseudopeptidic bis(amidoamine) precursors, which have a rigid (R,R)-cyclohexane-1,2-diamine moiety. A remarkable match/mismatch relationship between the configurations of the chiral centers of the cyclic diamine and those of the peptidic frame was observed. The macrocyclic tetraimine intermediates have been studied in detail by NMR spectroscopy, circular dichroism (CD), and molecular modeling, and the results support the appropriate preorganization induced by the match combination of the chiral centers. We have also synthesized the corresponding open-chain bis(imine) model compounds. The structural studies (NMR spectroscopy, CD, modeling) of these systems showed an intrinsically lower reactivity of the mismatch combination, even when the product of the reaction was acyclic. In addition, a synergistic effect between the two chiral substructures for the correct folding of the molecules was observed. Finally, X-ray analysis of the HCl salt of one of the macrocycles showed an interesting pattern; the macrocyclic rings stack in columnar aggregates leaving large interstitial channels filled with water-solvated chloride anions.

Crystal structures of the HCl salts of pseudopeptidic macrocycles display “knobs into holes” hydrophobic interactions between aliphatic side chains

The crystal structures of three HCl salts of pseudopeptidic macrocycles show a H-bonding tubular stack of the rings, where the amino acidic side chains (Val, Leu, Ile) display an inter-columnar “knobs into holes” hydrophobic interaction pattern.