Synthesis of highly functionalized heterocycles employing strain induced diverse reactivity of small ring molecules

Abstract

Chapter 1: A perspective on the emergence of heterocycle synthesis using small ring molecules In the sense of creating a sustainable and sophisticated world for the future generation, the science of molecules and its subdiscipline organic synthesis seek enormous attention in the timeline of advancing the science and society. In this regard, the most excellent organic synthetic chemist, the mother nature inspired a lot to experience its beautiful architectural creation at the molecular level. While the basic understanding of the correlation between the molecular structure and their functions offers to mimic or modify them purposefully or to synthesize new molecules with better properties. It is necessary to mention when we emphasis on nature’s foundation at the molecular structural level, heterocycles are the privileged scaffolds owing to their wide abundance in nature. Heterocycles are predominantly found in drugs, vitamins, biomolecules, natural products, agrochemicals, synthetic pharmaceuticals and many more. Many them exhibit valuable biological activities like antitumor, antibiotic, antimalarial, anti-inflammatory, anti-HIV, antimicrobial, anti-fungal and so forth. Despite these; they are found to have essential applications in material science as well in many forms. Hence, development of facile methods for the synthesis of valuable heterocycles remained one of the most emerging areas to explore even in modern days since its origin. In the beginning section of this chapter, an account of the genesis and the impact of organic synthesis is depicted followed by particular significance of heterocycle synthesis. Also, different strategies for designing heterocycles are discussed employing distinct applications of intrinsic ring strain of small ring molecules. The reactive elements of three different class of small rings (viz donor-acceptor cyclopropane (DAC), aziridine, and oxaziridine) are introduced in the perspective of useful heterocycle synthesis. The utility of this synthetic tool using small rings is also extended with examples of total synthesis. In the end, the aim of the thesis and chapter wise contents are briefly discussed. Chapter 2: Annulation of donor-acceptor cyclopropane and N-tosylaziridinedicarboxylate: one-step synthesis of functionalized 2H-furo[2,3-c]pyrroles Among the various heterocycles, the development of synthetic methods particularly for nitrogen-containing heterocycles reached to an exceptional level of interest over the years. This rise of interest can be attributed with key features of nitrogen-containing heterocycles. They construct the core structural scaffold of many bioactive molecules. Moreover, the nitrogen atom involves in non-bonding interactions to act as a crucial biological linker. The molecular diversity in a heterocyclic molecule arises with the different substituents and with the generation of new stereocenters in the heterocycles. Subsequently, the properties of the new nitrogen-containing heterocycles can be enhanced varying the functional groups as well as generating more number of stereocenters. Introductory chapter revealed the importance of DAC and aziridine as the useful synthons for precious molecules which initiated the “creative art” in mind to design synthetic methodologies for new potent molecules employing them. This chapter reports a novel MgI2-catalyzed annulation between DAC and N-tosylaziridinedicarboxylate to access highly substituted 2H-furo[2,3-c]pyrrole bearing two rings and four stereocenters, including one quaternary carbon stereocenter. The one-step synthetic process for 2H-furo[2,3-c]pyrrole derivatives is of great importance as these molecules are the analogs of a particular class of biologically active compounds like IKM. Among this class of compounds, IKM-159 is most potent and acts as an α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor-selective antagonist with no inhibitory action on kainate (KA) receptors. This work also offers an insight into the mechanism of the annulation process. Chapter 3: Exploration of substituent controlled reactivity of oxaziridine with different donor-acceptor carbon substrates: one-step synthesis of varieties of functionalized N-containing heterocycles A careful study of the exciting annulation of aziridine with DAC to furnish valuable analogs of IKM compounds emerges immense attention to check the possibility of the formation of different other classes of N-containing heterocycles. In this context, we were very much curious to see the reactivity of a particular class of three-membered heterocycle oxaziridine which contains two different heteroatoms. Although oxazirdine is well-known as an electrophilic source of oxygen for varieties of nucleophile like S, P, Se, N, and C- nucleophiles, its feasibility as N-transfer agent is widely unexplored. Furthermore, it can take part in annulation reaction as well to lead numerous heterocycles. As our prime focus was to make an array of different N-containing heterocycles, we designed our methodology with carbon nucleophiles only. This chapter is divided into two separate sections. The first section will demonstrate the development of electrophilic N-transfer ability of oxaziridine with DAC for the one-step synthesis of azetidine molecules. Here, N-substituents played vital role in determining the formation of different cycloadducts. While the second section will further elaborate the scope of N-transfer of oxaziridine with a set of divergent carbon nucleophiles. Overall this chapter represents a comprehensive and systematic study to establish the electrophilic N-transfer role of oxaziridine and thereby to make it as a generalized synthetic tool to access decent three-, four-, and five-membered N-containing heterocycles. Section A: Substituent controlled selective N-transfer of oxaziridine to donor-acceptor cyclopropane: one-step synthesis of functionalized azetidines A distinctive N-substituent controlled electrophilic N-transfer of oxaziridines with donor-acceptor cyclopropanes in the presence of MgI2 is portrayed in this section. The critical aspect of this methodology is that, contrary to earlier reports, the oxaziridine having bulkier N-substituents can also give N-transferred product instead of the O-transferred one. This one-step process resulted into the access of valuable azetidine molecules which have the same structural backbone of various bioactive molecules like mugenic acid, azelnidipine, penaresidin A and so forth. Interestingly, the oxaziridines having α-H containing N-substituents lead to the pyrrolidine derivatives through [3+2] cycloaddition. A mechanistic reasoning for this divergent reactivity is depicted by density functional theory calculations and validated through energy decomposition analysis. Section B: An assessment of the scope and limitations of electrophilic N-transfer of oxaziridine with different 2, 3, and 4-carbon donor-acceptor substrates to furnish diverse N-containing heterocycles The chemistry established in the first section of this chapter explored the new type of reactivity of oxaziridine with DAC. Indeed, the methodology offered a useful protocol for single-step access to valuable azetidine molecules. In this section, we took that opportunity to explore the ability of oxaziridine to transfer the amine functionality to different other donor-acceptor carbon substrates. Our prime focus of this investigation was to survey the scope of N-transfer methodology,for a wide range of carbon substrates and thereby to make it as a generalized synthetic tool. Most importantly, as nitrogen plays the role of the crucial biological linker, it will be an effective technique for the modification of a molecule to get a particular response. Comprehending the applicability of this distinct reactivity of oxaziridine, a series of different donor-acceptor carbon substrates have been examined for the title transformation which helped us to make the conclusive remark on its scopes and limitations. Chapter 4: Organocatalytic activation and chiral induction of donor-acceptor cyclopropane carbaldehyde towards annulation reaction with different dipolarophiles Metal-catalyzed methodologies that are demonstrated in chapter 2 and chapter 3 exhibited the opportunities to make a synthetic design for an array of valuable heterocycles. At the same time, development of organocatalytic methods is highly essential to access those entities. In this aspect, it is noteworthy that the organocatalytic process has several inherent advantages over the metal-catalyzed ones. Organocatalytic reactions are relatively easy to handle owing to their less sensitivity to moisture and air. Regarding cost and toxicity, organocatalysts are more favorable as they are readily available or can be made easily. The major superiority of organocatalysis originates from unique modes of activation that led to the formation of valuable chiral molecules.8 Hence, after making a set N-containing heterocycle, our primary interest was to activate the DAC ring by organocatalyst for annulation reactions. In this chapter, we introduced organocatalytic activation as well as desymmetrization of DAC for annulation reactions. To activate DAC, we modified the acceptor group with an aldehyde. The possibility of annulation reaction with aliphatic aldehydes (bearing α-H) has been tested utilizing the well-known iminium-enamine activation through secondary amine catalyst. Initial attempt to construct a five-membered carbocycle using α-H bearing aliphatic aldehyde eventually followed the well-known aldol condensation pathway that led to the formation of corresponding aldol adduct. Interestingly, although the cyclopropane ring remained intact after this transformation, the aldol adduct was obtained with considerable enantiomeric excess. The enantioselective, organocatalytic [3+3] cycloaddition between cyclopropane carbaldehyde and nitrone is an interesting entry of this chapter which led to one-step synthesis of chiral oxazinane molecule.