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The use of homogeneous organometallic catalysis for otherwise challenging chemical transformations is a concept that has gained significant interest in recent decades, providing access to a variety of useful chemical products. The catalytic reactivity of transition metals and non-reactive ancillary ligands that bind to the metal center has played an important role in such methods, with notable breakthroughs being Nobel Prize-winning reactions (palladium-catalyzed C-C cross-coupling, 2010). The research compiled in the thesis further develops the themes of ligand design and catalytic applications currently studied in the Stradiotto group. Key ideas throughout the thesis are to establish an understanding of the palladium/Mor-DalPhos catalyst system in ammonia arylation with respect to mechanism and substrate scope, and to expand the reactivity profile of the DalPhos ligand set to more challenging C-N and related cross-coupling processes. The first section describes an examination of the [Pd(cinnamyl)Cl] dimer/Mor-DalPhos catalyst system in C-N cross-coupling employing ammonia to better understand the catalyst formation process and to provide a guide for the development of precatalysts for otherwise challenging room-temperature ammonia monoarylations. Oxidative addition complex [(Mor-DalPhos)Pd(Ph)Cl] proved to be the optimal catalyst for arylation of ammonia at room temperature using aryl halides and tosylates. In the second section, ammonia cross-coupling was extended by applying it in the construction of indole frameworks, for the first time, which gave access to NH-indoles directly from ortho-alkynylbromoarenes. The Pd/JosiPhos was the superior catalyst system in comparison to Pd/Mor-DalPhos for this reaction and further stoichiometric studies revealed the reasons for this may be that the bulky arylalkyne ligand induces loss of ammonia from (Mor-DalPhos)Pd catalytic intermediates, and that catalyst inhibition by the alkyne substrate through irreversible metal binding is also a possible factor prior to the oxidative addition step. The reactivity profile of the DalPhos ligand set was successfully expanded in the third section of the thesis to palladium-catalyzed aminocarbonylation of aryl bromides using a pyridine-derived DalPhos variant (Pyr-DalPhos). Several different aryl and some heteroaryl bromides were accommodated in the coupling reaction with ammonia and carbon monoxide as reagents, providing aryl amide products in synthetically useful yields. The methodology described in the final thesis section demonstrated the use of Mor-DalPhos and [Pd(cinnamyl)Cl] dimer mixtures for gaining access to the first examples of ketone alpha-arylation employing aryl methanesulfonates (mesylates) and expanding the scope of amination reactions involving these non-halide aryl electrophiles to primary alkyl amines for the first time. These transformations featured acetone and methylamine as coupling partners, both of which can be difficult substrates to monoarylate but were found to be coupled with ease in this chemistry.

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Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue results in an intramolecular [2 + 2] cycloaddition to the indole 2,3-double bond. The resultant cyclobutane undergoes spontaneous retro-Mannich fission to produce a spiro[indoline-3,3-pyrrolenine] with relative configuration defined by the orientation of substituents in the transient cyclobutane. The novel tandem intramolecular photocycloaddition- retro-Mannich (TIPCARM) sequence leads to a spiropyrrolidine which is poised to undergo a second retro-Mannich fragmentation [TIPCA(RM)₂] that expels the malonate unit present in the photo substrate and generates transiently an indolenine. The indolenine undergoes rearrangement to a β-carboline which can undergo further rearrangement under oxidizing conditions to an oxindole. Three oxindole natural products, coerulescine, horsfiline and elacomine, were synthesized using this strategy. The TIPCARM strategy was extended to an approach that would encompass the Vinca alkaloids vindorosine and minovine. In this case, the TIPCARM sequence was followed by an intramolecular cyclization that provided tetracyclic ketone 5.86 containing rings A, B, C and D of vindorosine. A tetracyclic intermediate was synthesized which could also provided access to the Vinca alkaloid minovine. / Graduation date: 2012

Οι κυκλινοεξαρτώμενες κινάσες (CDKs) αποτελούν μία οικογένεια κινασών σερίνης/θρεονίνης, η δραστικότητά των οποίων εξαρτάται από την πρόσδεσή τους σε ρυθμιστικές υπομονάδες (κυκλίνες). Οι CDKs διαδραματίζουν καθοριστικό ρόλο στην ομαλή αλληλοδιαδοχή των σταδίων του κυτταρικού κύκλου οδηγώντας σε φυσιολογικό κυτταρικό πολλαπλασιασμό. Ωστόσο, απορρύθμιση της δράσης τους παρατηρείται σε πολλούς καρκινικούς όγκους με συνέπεια να αποτελούν ελκυστικό στόχο για την καταπολέμηση του καρκίνου. Πληθώρα παραγόντων με ανασταλτική δράση έναντι των CDKs έχουν συντεθεί και μερικοί από αυτούς βρίσκονται σε προχωρημένες φάσεις κλινικών δοκιμών. Επιπλέον πρόσφατα πειράματα γενετικής κατέδειξαν την CDK1 ως επαρκή (σε έλειψη των άλλων CDKs) και πιθανά αναγκαία για την ολοκλήρωση του κυτταρικού κύκλου. Στα πλαίσια της παρούσας μελέτης σχεδιάσθηκε και συντέθηκε μια σειρά υποκατεστημένων πυρρολο[2,3-a]καρβαζολίων, σε μία προσπάθεια βελτίωσης των ιδιοτήτων και μελέτης των σχέσων χημικής δομής– βιολογικής δραστικότητας του 2-(αιθοξυκαρβονυλο)-9-χλωρο- πυρρολο[2,3-a]καρβαζολίου , το οποίο πρόσφατα αποδείχθηκε αναστολέας της CDK1. Συγκεκριμένα συντέθηκαν 3-ακυλαμιδο-, 3- αλκυλσουλφοναμιδο- και 3-αμινο-υποκατεστημένα πυρρολο[2,3- a]καρβαζόλια, καθώς και Ν-αλκυλ-υποκατεστημένα πυρρολο[2,3- a]καρβαζολο-2-καρβοξαμίδια. Η σύνθεση των τελικών αυτών προϊόντων στηρίχτηκε στη σύνθεση ενδιαμέσων κατάλληλα υποκατεστημένων 7-κετο- 4,5,6,7-τετραϋδροϊνδολίων, και στην ινδολοποίηση αυτών κατά Fischer με την ο-χλωρο-φαινυλυδραζίνη. Μελετήθηκε η επίδραση των 3-ακυλαμιδο-υποκατεστημένων παραγώγων στη δραστικότητα του συμπλόκου CDK1/κυκλίνη Β. Όλα τα παράγωγα προκάλεσαν σε συγκέντρωση 100 μΜ αναστολή της δραστικότητας της CDK1 σε ποσοστό από 35 έως 75%. Δραστικότερη εμφανίστηκε η ένωση 1a3. / Cyclin dependent kinases (CDKs) are a subgroup of serine/threonine kinases, whose activity depends upon binding to regulatory subunits (cyclins). CDKs have a crucial role in cell cycle progression and proliferation. Deregulation of their activity is a common feature in human tumors; hence, CDKs represent attractive targets for cancer therapy. A plethora of CDK inhibitors have been synthesized and some of them are already in late phases of clinical trials. Furthermore, recent genetic studies have indicated that CDK1 is sufficient (when in absence of other CDKs) and probably essential to drive the cell cycle. Attempting to improve the structural characteristics and study the structure–activity relationships of 9-chloro-2-(ethoxycarbonyl)- pyrrolo[2,3-a]carbazole, which has been proved as a CDK1 inhibitor, this study focused on the design and synthesis of several substituted pyrrolo[2,3-a]carbazole derivatives. Particularly, 3-acylamido-, 3- alkylsulfonamido- and 3-amino-substituted pyrrolo[2,3-a]carbazoles and N-alkyl-substituted pyrrolo[2,3-a]carbazolo-2-carboxamides comprised synthetic targets of the study. The synthesis of the final products was based on the synthesis of appropriately substituted 7-keto-4,5,6,7- tetrahydroindole intermediates which served as building blocks in Fischer indolization reactions with the o-chloro-phenylhydrazine. The effect of the 3-akylamido- substituted derivatives on the CDK1/cyclin B activity was studied. All derivatives proved to inhibit CDK1 activity, in a range of 35 to 75%. Derivative 1a3 proved the most potent inhibitor of CDK1.

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