Sustainable Approaches for the Synthesis of Nitrogen and Oxygen Functionalized Small Organic Molecules.

Two important categories of O-functionalized compounds are O-heterocycles and polyphenols. All these two categories are widespread in nature and present as scaffold in many natural compounds. Well-known examples are sugar core of DNA and RNA, Quercitin, Curcumin, Vitamins (especially E and C), Taxol, Dynemicin, and many others; and their biological applications are well-known too (anti-inflammatory, anti- oxidant, antiviral, anticancer and others). The synthesis of O-functionalized compounds has been always an important and crucial research field of organic synthesis and nowadays many methods are reported in literature.[20 - 25] This first chapter is focused on two different projects related together by the O- functionalization of final target products and by the very important biological, antiviral, therapeutical applications that they found or they could find. The aim of first section is to synthesize LNA-Adenosine derivative by linear strategy. The LNA (Locked Nucleic Acid) are very important Nucleic Acid analogues, synthesized for the first time by Iminashi et al. [26] and Wengel et al.[27] respectively in 1997 and 1998, in an independently way. These analogues are very important due to the antisense, antigene, antiviral, and many others bio-applications, overcoming some problems related to employment of not-modified nucleic acids. The topic of the second chapter is the synthesis of a new phenolic compound with potential antiviral activity against Sars-CoV-2. Our purpose is to obtain this new polyphenol through the combination of two intermediates, an alkyne and an aldehyde, obtained from two commercial, cheap and easy available starting material. Natural and synthetic heterocycles has greatly attracted the interest of scientits because of their widely applications in many fields of science: biological, pharmaceutical, synthetical and industrial applications (plastic, solvents, cosmetics, vulcanization accelerators, etc.)[175] Among them, N-heterocycles have always constituted an important synthetic target due to the pharmaceutical and biological superior properties than non-nitrogen containing cycles[175b] and for their wide distribution in many natural bioactive compounds (such as alkaloids).[176] From a statistical analyses it emerges that 59% of FDA-approved small molecule drugs contain at least one of N-heterocycles moieties in which the six- and five-membered are the size-cycles more diffused, although three-, four-, bicyclic-, macrocyclic N-heterocycle scaffolds are present.[177] Moreover, this last class of compounds have shown useful, not only in medicinal fields, but also in metallurgical applications thanks by their ability to chelate first-row transition metals like Mn(II), Zn(II), Fe(II), Cu(II) and for other industrial applications.[178] Nowadays many scientist are focusing on the development of new sustainable synthetic approaches for this class of compounds[175a] given their potential applicability in many science and everyday life aspects. New approaches consist in employment of UV-light (the most sustainable reactions induces, largely applied in organic synthesis); [179] employment of less toxic, environmentally benign and less expensive Lewis Acid catalysts like Zn, Fe, Cu, Ni cores (minimization of waste, time consuming, improved selectivity, often they allow to build complicated structures under mild conditions);[175a], [180] performing the reaction under microwave irradiations;[181] through multicomponent reactions (which implicate time saving, avoid the separation and purification of intermediates, atom- efficent reactions, type reactions used also for the synthesis of pharmaceuticals, drugs and compounds by stereoselective routes);[182] employment of less toxic solvents like ionic liquid;[183] just to cite few examples. This chapter is divided in three sections in which three different N-heterocycle scaffolds are synthesized by new sustainable approaches. The first section is focused on the synthesis of an aza-macrocycle with the purpose to overcome some problems related to the synthesis and enhanced some aspects making them more suitable for green aspects that rule the scientific world today. The aim of second section is the synthesis of a six-membered N-heterocycles (1,2- dihydropyridines) through polycondensation of acyclic precursor using a not expensive and low-toxic Lewis acid like CeCl3 .7H2O, emphasizing kinetic, thermodynamic aspects of condensation process. The last section is divided in two more parts in which: the first one focuses on the synthesis of tetrahydro-β-carboline (very important bioactive compound) using not harmful Brønsted acids like graphene oxide and Amberlyst-15® through the Pictect- Spengler reaction; the second part, instead, reports the first results about the development of a new multi-component Pictect-Spengler reaction promoted by Ce(III)-Lewis Acid for the synthesis of N-substituted tetrahydro-β-carboline.