Functionalized molecules via MCRs: applications in drug discovery and material science

Abstract

Multicomponent reactions (MCRs) are highly efficient one-pot synthetic approaches for the synthesis of complex and versatile scaffolds. To date, these reactions are considered pillars of medicinal and organic chemistry. Surprisingly, their application in drug discovery and material science is still limited, considering their merits. For example, to the best of our knowledge, MCRs are barely used in material chemistry, particularly towards the synthesis of organic electronic materials such as tetrathiafulvalene (TTF)-based derivatives. In this thesis, exploitation of the MCRs applications in both drug design and material science occurred. Compared with the traditional synthetic protocols, the proposed novel MCR procedures are of higher quality due to the following characteristics: mild conditions, speed, commercially available starting materials, easily scale up approaches and reduced purification steps. In this study, several bioactive and organic electronic materials via MCRs are developed. Herein, five chapters are dealing with the utilization of the MCRs. In summary, more than 160 molecules are obtained and most of these potential adducts are first time synthesized. Chapter 1 deals with numerous functionalized indole tetrazole derivatives resulting via a green, easy and rapid two-step Ugi-tetrazole four component (UT-4CR) procedure from commercially available anilines, aldehydes and TMSN3 in good to excellent yields. Catalytic hydrogenation and additional MCRs are employed to demonstrate the potential of this synthetic protocol. Additionally, this method is gram-scalable and one-pot feasible. Interestingly, an eIF4A3 inhibitor is obtained via this de novo protocol. Chapter 2 exploits the classical Ugi four component reaction (U-4CR) to C2 functionalized indole amides. Excitingly, 20 derivatives are isolated from anilines, glyoxal dimethyl acetal, formic acid and isocyanides via an innovative 2-step protocol in good to excellent yields. These novel indole syntheses have several advantages, such as speed, highly sustainable, mild reaction conditions, low toxicity of the building blocks, high safety standards, broad substrate scope and good yields. This gram-scalable synthetic method is an easier and faster alternative in order to access numerous bioactive molecules. We have exploited all the above by the preparation of 2t, an anti-tuberculosis agent; it has demonstrated excellent features, such as time, amounts of inorganic and organic solvents, process mass intensity (PMI), E-factor and atom economy (AE). Additionally, the SETD2 inhibitor (2r) and another anti-tuberculosis agent (2s) are also obtained simply under our protocol. Chapter 3 presents a library of 45 dibenzothiazepines and benzothiazepines via five different MCRs. Those scaffolds are widely used in biology and material science. Interestingly, most of these polycyclic and rigid dibenzothiapines with high complexity obey to the rule of 5 (Ro5) according to the CSD analysis. In addition, several single crystal structures of these compounds have been solved, offering insights for their potential binding mode. The fluorene structural motif is widely present in numerous natural products and bioactive compounds. This scaffold is a useful candidate in materials science and drug discovery. In Chapter 4, a library of 23 fluorene-fused derivatives is depicted through IMCRs. These novel scaffolds are synthesized by functionalizing a fluorene building block. This work shows the huge potential of the MCRs in the diversity and complexity of fluorene-based compounds. Chapter 5 expands the scope of the MCRs on the functionalization of TTF to obtain numerous electronic adducts. Herein, more than 30 TTF-fused compounds obtained via four different MCRs. In addition, the synthesis of molecules with a D-A or D-π-A system occurred (Scheme 4). This important feature allows an intramolecular charge transfer (ICT) to occur. The single X-ray structure displays a planar character that could help the electron delocalization. What’s more, electronic measurements such as Hall measurement, the energy gap between the HOMO and LUMO, and the measurement of resistance are employed. So far, the applications of the TTF-based derivatives with D-A systems in organic semiconductors and molecular machines fields are limited by the efficient methods. Arguably, the new procedures will build a library of various TTF derivatives and facilitate the rapid development of novel materials.

Στο πρώτο κεφάλαιο της διατριβής συντέθηκαν για πρώτη φορά 2-τετραζολο ινδόλια μέσω της αντίδρασης UT-4CR, τα οποία αποτελούν βιοϊσοστερή των 2-καρβοξυ ινδολίων. Πραγματοποιήθηκαν επιπλέον MCRs και διάφορες δευτερογενείς συνθετικές μετατροπές. Στο δεύτερο κεφάλαιο, εκμεταλλευόμενοι τα ευρήματα της παραπάνω μελέτης, συνθέσαμε επιτυχώς ινδολο αμίδια μέσω της αντίδρασης U-4CR. Η διαδικασία είναι πράσινη και βιώσιμη. Έπειτα (κεφάλαιο 3), πραγματοποιήθηκε η σύνθεση βιβλιοθηκών νέων παραγώγων διβενζοθειαζεπινών και βενζοθιαζινών. Αυτά αποτελούν προνομιούχες δομές και χρησιμοποιούνται ευρέως τόσο στην Φαρμακευτική Χημεία, όσο και στην Χημεία υλικών. Οι ενώσεις αξιολογήθηκαν με υπολογιστικές μελέτες.Στο δεύτερο μέρος της διατριβής (κεφάλαια 4 και 5) πραγματοποιήθηκαν συνθέσεις παραγώγων με έμφαση στις εφαρμογές τους ως ημιαγωγοί. Αναφέρθηκαν συνθέσεις ενώσεων βασιζόμενες στις φλουορενόνες/φλουορένια (κεφάλαιο 4) και TTF (κεφάλαιο 5). Στα τελευταία παράγωγα, πραγματοποιήθηκαν εκτενείς μετρήσεις τόσο σε διάλυμα όσο και σε φιλμ ώστε να αξιολογηθεί η αγωγιμότητά τους. Πάνω από 50 διαφορετικά παράγωγα συντέθηκαν και στα δύο project.