Advances in Organic Synthesis

Protein misfolding is characterized by the inability of proteins to achieve or maintain their bioactive conformation. In addition to protein mutation, intracellular factors such as pH changes, metal ions, and oxidative stress contribute to protein misfolding. To modulate the level of misfolded proteins, different approaches are feasible including the use of pharmacological or chemical chaperones, the activation of degradative pathways and the manipulation of natural folding mechanism. Errors in protein folding are correlated to a broad range of diseases, from common allergies to neurodegenerative diseases, and at the moment, many examples exist of the successful control of protein unfolding that may be used in the therapy of these disorders. This chapter gives an overview on small molecules that can be used to stabilize protein, helping it to achieve near-native conformation and bring back its functions with an emphasis on pharmacological and chemical chaperones.

The present chapter deals with the recent developments in synthetic methodology, process development, and techniques modifications employed in peptides, and proteins synthesis as well as semi-synthesis through solution phase synthesis (SPS), and primarily in the solid phase peptide synthesis (SPPS) method in a variety of sequential, divergent, convergent, and ligation-based strategies. It also dwells upon the physicochemical, stereo-electronic, structural/chemical, and reaction medium's related factors affecting the synthesis, geometric outcomes, purification, and yields of the intended product. The chapter provides recent insights into coupling reagents, linker’s role, and associated feasibilities in handling, solubility issues, and inprocess product’s aggregation during synthesis, purification as well as discusses techniques to resolve these issues with pertinent examples on different sets of ‘difficult’ and long-chain peptides and on diversely-sourced proteins’ syntheses employing various approaches of different kinds for prototypical developments in the field of protein and peptide chemical synthesis.

Bioorthogonal coupling reactions are a powerful tool to create protein conjugates within living systems without interfering with the native biochemical environment. This reaction class has been increasingly utilized over the past few years in the development of new radiopharmaceuticals for medical imaging and radiotherapy. Pretargeting strategies have particularly benefited, where tissue-specific antibodies are first allowed to localize to their target site before a radiolabeled molecule is administered that can covalently bond with the antibody. These radionuclide delivery systems can enhance therapeutic efficacy, reducing radiation exposure and increasing image quality. Current applications of bioorthogonal coupling reactions in pretargeted molecular imaging and radioimmunotherapy will be reviewed.

Xanthenediones, also known as 1,8-dioxo-octahydroxanthenes, are synthetic compounds characterized by the presence of a pyran nucleus fused to two cyclohexen- 2-one rings. They present important biological activities as well as possible technological applications. Typically, xanthenediones are derived from the sequence reaction: Knoevenagel condensation, Michael addition and dehydration. During the cyclization step involved in the preparation of xanthenodiones, the use of a catalyst is required. Within this context, a variety of catalysts has been employed for the synthesis of xanthenediones. It is herein described an overview of catalytic methodologies that have been reported to achieve the preparation of xanthenediones.

In organic synthesis, heterogeneous catalysts have many merits, such as easy separation, cheapness, stabilization, reusability, and environment friendliness. In the past decades, the research on heterogeneous catalysts has made great progress. The particle size of the catalysts reduced from micrometer to nanometer, and further to single atomic level, while the conversion, selectivity and stability increased with reducing the particle size. Especially, in the recent five years, the single atom catalysts have shown excellent stability and high activity in many catalytic reactions, such as CO oxidation, hydrogenation of C=C bonds, oxidation of benzene, hydrogenation of nitroarenes, etc. Single atom catalysts have great potential in organic synthesis due to the combination of the advantages of homogeneous and heterogeneous catalysts. Herein, we will introduce the synthesis and catalytic application of atomically dispersed precious metals (Pd, Pt, Au, Ag, Rh, Ir, Os) or non-precious metals (Fe, Co, Cu, Ni, Mn) anchored onto the framework of supports (e.g. metal, metal oxide, metal hydroxide, graphene, metal organic frameworks and zeolites). The strong interaction between the single atom and support is accompanied by the charge transfer between the metal and support, which leads to a change in the electronic structure, thereby endowing its excellent catalytic performanc