Development of Enantioselective Methodologies for the Synthesis of Bioactive Small Molecules: A New Route for LNA

In the last few years, particular interest has been showed for molecules that have some effects on living organisms, irrespective of beneficial or not. It concerns of class of compounds that includes a large variety of molecules of relatively small dimensions ( minus 900 Da) characterized by specific biological activities on living organisms. There small molecules can have a variety of biological functions, serving as cell signalling molecules, drugs, pesticides, dyes and in many other roles. These molecules belong to various classes of compounds, as alkaloids, glycosides, lipids, flavonoids, peptides, phenols, terpenes and many others, known as secondary metabolites. For example, Geraniol (1) is a terpene which is present in many essential oils (mainly in rose oil) and it has a rose-like scent; Nicotine (2) is an alkaloid-type molecule and it is responsible for cigarette addiction and Salicin (3) is a glucoside anti-inflammatory agent which is produced by willow bark. A wide variety of organisms including bacteria, fungi, and plants, produce small molecule secondary metabolites also known as natural products, which play a role in cell signalling, pigmentation and in defence against predation. Secondary metabolites are a rich source of biologically active compounds and hence are often used as research tools and leads for drug discovery. Basically, drug design demands the design of shape of molecules and charge to bimolecular target to interact and to bind it. Not only biological activity but also drug like properties is important to design new drug. Ratio between the activity of the active enantiomer (called the eutomer) and that of the enantiomer that is less active (distomer) known as eudismic ratio. The higher is the eudismic ratio; the drug will be more effective. This concept is also applicable for agrochemicals, flavours and fragrances. In the 20th century, pure small molecule was started to use as drug for treatment. After this, there is huge development happened and now small molecules are used to study biological system in chemical genetics. There are three major ways to get enantiopure compounds: one of the common ways is by isolation of desired isomer directly from natural products, another is its synthesis and third is kinetic resolution. For synthesis of enantiopure compounds is generally done by asymmetric synthesis using a chiral base. There are various methods like organocatalysis, enzymatic asymmetric synthesis, etc. The Prof. Marcantoni's group is interested in both asymmetric synthesis and synthesis of biological active compounds. This dissertation discusses the different aspects, as illustrated by the nature of projects; use of methods like organocatalysis and organometallics for synthesis of enantiopure molecule; the new approach to synthesis of biologically active scaffolds. First chapter is focused on asymmetric synthesis of molecule with different methodologies. In this chapter, two projects are discussed, the first part was carried out in Prof. Bartoli G. group at University of Bologna, describes the α-benzoyloxylation of cyclic ketones promoted by primary amine as catalyst. This method was also successfully applied to synthesis of α-oxygenated 1-Indanone derivatives. During draft of this work B. List et al. reported the same kind of reaction but using different reaction condition. The second part was carried out in the Prof. Rovis T. group at Colorado State University, describes about synthesis of alternative route for triazolium salt catalysis for Nheterocyclic carbene. Due to minimal research on synthesis triazolium catalysis in NHCs, we tried to explore that area. The third part describes new methodology for the ring opening of the lactones by means of aminolysis, promoted by CeCl3-NaI system. In this topic we studied effect of steric hindrance on both amines and lactones on the yield of the product. Also presence of water plays crucial role in reaction. This methodology can be applied for synthesis of the Aliskiren, for key step of the lactone ring opening. In fourth topic we discussed the use of Lewis acid promoted benzylation of alcohols. We focused on primary and secondary alcohols for the benzylation, and it is another successful potential application of use of the CeCl3·7H2O as salt. Reaction condition is base free and also solvent free so is quite eco-friendly process. Second chapter describes the total synthesis of functionalized modified nucleoside LNA (Locked Nucleic Acid). As per our knowledge there is no example for synthesis of LNA starting from Adenosine. To fulfil this gap this project is effective.