Structural Studies on Flexible Small Molecules Based on NMR in Oriented Media. Methodology and Application to Natural Products

This thesis describes the development and application of structural elucidation methodologies based on NMR in aligned media. Nuclear magnetic resonance is arguably the most important technique for the structural analysis of organic molecules in solution. In the last decade, Residual Dipolar Coupling (RDC) analysis emerged as a powerful tool for the determination of the three-dimensional structure of organic molecules in solution, complementing and even outperforming the approach based on the classical NMR observables such as NOE or 3J couplings. While application of RDCs to the structural analysis of proteins developed rapidly, their use with “small” molecules (typically organic compounds and natural products with MW < 1000 Da) is still scarce. From the spectroscopic point of view, two features of small molecules pose the main obstacles to the application of RDC to their analysis: the scarcity of observable couplings and the complexity stemming from conformational flexibility in solution. Besides, sample preparation with the optimal degree of alignment is still an issue for most classes of compounds. In this thesis, all these topics are addressed and new experimental and computational advancements are presented. i) Sample preparation. Weak alignment in water and aligning properties of polyacrylamide gels. ii) New observables. Long-range proton–carbon RDCs. iii) Analysis of flexible organic molecules

Self-Sensitized Photooxygenation of 2H-Pyrans: Characterization of Unexpected Products Assisted by Computed Structural Elucidation and Residual Dipolar Couplings

The UVA (350 nm) irradiation of an α-pyran in the presence of oxygen led to the unexpected formation of a tetraoxygenated compound whose structure could not be unambiguously determined on the basis of conventional 1H-13C correlated experiments. 1,1-ADEQUATE (adequate double quantum transfer experiment) and 1,n-ADEQUATE combined with computer-assisted structure elucidation software led to two structural possibilities involving the formation of either an epoxide or an oxetane. Residual dipolar couplings allowed not only the identification of the compound as a spiroepoxide but also the determination of its relative configuration. To account for its formation, we propose a bisepoxide intermediate that, as opposed to most α,β-epoxyketones under irradiation, undergoes O-Cβ cleavage probably due to the presence of an extra oxygen substituent in the β position. 1,2-Acyl migration would then proceed stereoselectively to the final product obtained as a single diastereomer.Fil: Riveira, Martín Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Trigo Mouriño, Pablo. University of Carnegie Mellon; Estados UnidosFil: Troche Pesqueira, Eduardo. University of Carnegie Mellon; Estados Unidos. Universidad de Vigo; EspañaFil: Martin, Gary E.. Merck Research Laboratories; Estados UnidosFil: Navarro Vázquez, Armando. Universidade Federal de Pernambuco; BrasilFil: Mischne, Mirta Paulina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Gil, Roberto R.. University of Carnegie Mellon; Estados Unido

Total Synthesis of Darobactin A

The total synthesis of darobactin A, a recently isolated antibiotic that selectively targets Gram-negative bacteria, has been accomplished in a convergent fashion with a longest linear sequence of 16 steps from ᴅ-Garner’s aldehyde and ʟ-serine. Scalable routes towards three non-canonical amino acids were developed to enable the synthesis. The closure of the bismacrocycle was realized through sequential, halogen-selective Larock indole syntheses, where the proper order of cyclizations proved crucial for the formation of the desired atropisomer of the natural product