Zsuzsanna Sánta

Synthesis of pure methyl [(2S,3R,αR)-1-(3-bromo-4-methoxyphenyl)-3-(α-acetoxy)ethyl-4-oxoazetidin-2-carboxylate] and its enantiomer

Abstract Synthesis of key intermediates leading to 2-iso-oxacephems was carried out starting from l - and d -threonine. As predicted in our previous paper (Tetrahedron Lett. 1995, 36, 8303–8306) all diastereomers of 2-iso-oxacephems can be prepared from the appropriate enantiomers of the amino acid threonine. The absolute configuration of the 2,3- and α-carbon atoms in the β-lactam structure was determined by X-ray crystallographic studies.

Chapter 9 – Computer-Assisted Structure Elucidation in NMR

In NMR spectroscopy, the development of modern computer-assisted structure elucidation (CASE) software tools receives much attention by the worldwide community of chemists and NMR spectroscopists. Whether artificial intelligence can eliminate human error (or even the need for human spectrum-interpretational knowledge) in structure elucidation is certainly an intriguing and important question in its own right and is of particular interest within the conceptual framework of the present book. This chapter addresses this question by examining the capabilities of some relevant software modules from an “anthropic” perspective. The questions of what role these expert systems can play and how they should be handled in a pharmaceutical R&D environment are assessed through a diverse set of structure elucidation problems where Mental Traps could be caught in the act.

Chapter 13 – The Case of an Emotion- and Emotycs-Laden Structure Determination of a Small Synthetic Molecule with an Unexpected Structure

Herein, we disclose the intriguing story of the structural elucidation of an organic molecule that gave a highly unexpected structure in an apparently well-predictable chemical reaction. Due to the interplay of a multitude of misleading and distracting factors, including the fact that the compound had broad NMR signals due to conformational exchange and had the same nominal mass as the expected molecule, in a first (routine) approximation, its structure seemed to correspond to the expected molecule. Only a deeper investigation, initiated by some further unexpected events in relation to this reaction scheme, revealed the true structure of the compound. This story demonstrates how easy it can be to misinterpret experimental data when one subconsciously seeks to confirm expectations (see Trap #29), especially in a time-pressed industrial research environment; it is also a story of the battle between emotycal and rational minds.

NMR Methodological Overview

Abstract Hundreds of NMR experiments (pulse sequences) are currently available to generate spectra providing complementary pieces of structural information that can be used in assembling the 3D structure of small organic molecules. This chapter gives a brief overview of the most common NMR experiments used for that purpose, mainly those appearing in the subsequent chapters of this book. Our primary aim is to give a short description of what each of those experiments can “do,” hopefully serving as a useful reference for the better understanding of the case studies presented later on. In line with the philosophy of this monograph, our discussion is aimed to be accessible to the non-NMR expert, with focus placed on the structural information “revealed” by the particular experiment instead of discussing the spin-physical design or technical implementation of the underlying pulse sequence. All experiments are illustrated with an example, and the possible limitations and interpretational pitfalls (Mental Traps) associated with them will also be outlined.

Attempted Synthesis of Vinca Alkaloids Condensed with Three-Membered Rings

Our successful work for the synthesis of cyclopropanated vinblastine and its derivatives by the Simmons–Smith reaction was followed to build up further three-membered rings into the 14,15-position of the vindoline part of the dimer alkaloid. Halogenated 14,15-cyclopropanovindoline was prepared by reactions with iodoform and bromoform, respectively, in the presence of diethylzinc. Reactions of dichlorocarbene with vindoline resulted in the 10-formyl derivative. Unexpectedly, in the case of the dimer alkaloids vinblastine and vincristine, the rearranged products containing an oxirane ring in the catharanthine part were isolated from the reactions. The attempted epoxidation of vindoline and catharanthine also led to anomalous rearranged products. In the epoxidation reaction of vindoline, an o-quinonoid derivative was obtained, in the course of the epoxidation of catharanthine, a hydroxyindolenine type product and a spiro derivative formed by ring contraction reaction, were isolated. The coupling reaction of vindoline and the spiro derivative obtained in the epoxidation of catharanthine did not result in a bisindole alkaloid. Instead, two surprising vindoline trimers were discovered and characterized by NMR spectroscopy and mass spectrometry.