Synthesis of atropisomeric 2,2'-disubstituted-3,3'-quinazolin-4,4'-diones and their application in asymmetric synthesis

This thesis reports all the efforts made in the synthesis of 2,2'-disubstituted-3,3'-quinazolin-4,4'-ones (BiQ), a new class of atropisomeric molecules derived from the 4-quinazolinone scaffold, and their potential application as chiral auxiliaries in asymmetric synthesis. Chapter 1 provides first an overview of axial chirality and atropisomerism and then it reports a review of asymmetric reactions such as Diels-Alder, 1,3-dipolar cycloaddition, epoxydation and cyclopropanation, which have been used in literature as a model for the development of new chiral auxiliaries and chiral ligands. Chapter 2 describes first the synthesis of a series of 2-substituted benzoxazinones and 3-amino-2-substitute-quinazolinones units. Then the successful synthesis of racemic symmetrical and unsymmetrical 2,2'-disubstituted-3,3'-quinazolin-4,4'-ones (BiQ) by condensation of benzoxazinones and aminoquinazolinones units is presented. Chapter 3 presents the design and synthesis of chiral non racemic unsymmetrical and symmetrical biquinazolinones. Once chirality has been introduced via the functionalization of 3-aminoquinazolinone with non-racemic amino acids, the corresponding unsymmetrical biquinazolines were produced using the same methodology previously adopted for the racemic unsymmetrical biquinazolinones. Chapter 4 highlights the unexpected synthesis of 4-isopropyl-3-oxo-l,9a,10- triazaanthracen-9-ones. Full characterization of this new heterocyclic compound is herein reported together with the development of an efficient methodology (good to high yield, no chromatographic purification) for the synthesis of other members of this novel class of compounds. Chapter 5 first presents all the attempts performed for the functionalization of symmetrical 2, 2'-methyl- and 2,2'-ethyl-biquinazolinones via carbanionic chemistry. Lithiation of 2,2'-dimethyl-3,3'-biquinazolinone, and further reaction with aromatic aldehydes led to the corresponding styryl derivates. These compounds were used as a prochiral starting materials in diastereoselective reactions like epoxydation, Diels-Alder, 1,3-dipolar cycloaddition and cyclopropanations in order to assess the efficiency of the biquinazolinones as chiral auxiliaries.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Nucleosided derived antibiotics to fight microbial drug resistance: New utilities for an established class of drugs?

Novel antibiotics are urgently needed to combat the rise of infections due to drug-resistant microorganisms. Numerous natural nucleosides and their synthetically modified analogues have been reported to have moderate to good antibiotic activity against different bacterial and fungal strains. Nucleoside-based compounds target several crucial processes of bacterial and fungal cells such as nucleoside metabolism and cell wall, nucleic acid, and protein biosynthesis. Nucleoside analogues have also been shown to target many other bacterial and fungal cellular processes although these are not well characterized and may therefore represent opportunities to discover new drugs with unique mechanisms of action. In this Perspective, we demonstrate that nucleoside analogues, cornerstones of anticancer and antiviral treatments, also have great potential to be repurposed as antibiotics so that an old drug can learn new tricks

λ5-Phosphorus-Containing α-Diazo Compounds (PCDCs): a valuable tool for accessing phosphorus-functionalized molecules

The compounds characterized by the presence of a λ5-phosphorus functionality at the α-position with respect to the diazo moiety, here referred to as λ5-phosphorus-containing α-diazo compounds (PCDCs), represent a vast class of extremely versatile reagents in organic chemistry and are particularly useful in the preparation of phosphonate- and phosphinoxide-functionalized molecules. Indeed, thanks to the high reactivity of the diazo moiety, PCDCs can be induced to undergo a wide variety of chemical transformations. Among them are carbon–hydrogen, as well as heteroatom–hydrogen insertion reactions, cyclopropanation, ylide formation, Wolff rearrangement, and cycloaddition reactions. PCDCs can be easily prepared from readily accessible precursors by a variety of different methods, such as diazotization, Bamford–Stevens-type elimination, and diazo transfer reactions. This evidence along with their relative stability and manageability make them appealing tools in organic synthesis. This Review aims to demonstrate the ongoing utility of PCDCs in the modern preparation of different classes of phosphorus-containing compounds, phosphonates, in particular. Furthermore, to address the lack of precedent collective papers, this Review also summarizes the methods for PCDCs preparatio

Symmetrical diamidate prodrugs of nucleotide analogues for drug delivery

The use of pronucleotides to circumvent the well-known drawbacks of nucleotide analogs has played a significant role in the area of antiviral and anticancer drug delivery. Several motifs have been designed to mask the negative charges on the phosphorus moiety of either nucleoside monophosphates or nucleoside phosphonates, in order to increase their hydrophobicity and allow entry of the compound into the cell. Among them the bis-amidate analogs, having two identical amino acids as masking groups through a P–N bond, represent a more recent approach for the delivery of nucleotide analogs, endowed with antiviral or anticancer activity. Different synthetic strategies are commonly used for preparing phosphorodiamidates of nucleosides. In this protocol, we would like to focus on the description of the synthetic methodology that in our hand gave the best results using 2′-3′-didehydro-2′-3′-dideoxythymidine (d4T, Stavudine) as model nucleoside. A second strategy for preparing diamidates of nucleoside phosphonates will be reported using {[2-(6-amino-9 H-purin-9-yl)ethoxy]methyl}phosphonic acid (PMEA, adefovir) as model substrate

Synthesis of atropisomeric 2,2'-disubstituted-3,3'-quinazolin-4,4'-diones and their application in asymmetric synthesis

This thesis reports all the efforts made in the synthesis of 2,2'-disubstituted-3,3'-quinazolin-4,4'-ones (BiQ), a new class of atropisomeric molecules derived from the 4-quinazolinone scaffold, and their potential application as chiral auxiliaries in asymmetric synthesis. Chapter 1 provides first an overview of axial chirality and atropisomerism and then it reports a review of asymmetric reactions such as Diels-Alder, 1,3-dipolar cycloaddition, epoxydation and cyclopropanation, which have been used in literature as a model for the development of new chiral auxiliaries and chiral ligands. Chapter 2 describes first the synthesis of a series of 2-substituted benzoxazinones and 3-amino-2-substitute-quinazolinones units. Then the successful synthesis of racemic symmetrical and unsymmetrical 2,2'-disubstituted-3,3'-quinazolin-4,4'-ones (BiQ) by condensation of benzoxazinones and aminoquinazolinones units is presented. Chapter 3 presents the design and synthesis of chiral non racemic unsymmetrical and symmetrical biquinazolinones. Once chirality has been introduced via the functionalization of 3-aminoquinazolinone with non-racemic amino acids, the corresponding unsymmetrical biquinazolines were produced using the same methodology previously adopted for the racemic unsymmetrical biquinazolinones. Chapter 4 highlights the unexpected synthesis of 4-isopropyl-3-oxo-l,9a,10- triazaanthracen-9-ones. Full characterization of this new heterocyclic compound is herein reported together with the development of an efficient methodology (good to high yield, no chromatographic purification) for the synthesis of other members of this novel class of compounds. Chapter 5 first presents all the attempts performed for the functionalization of symmetrical 2, 2'-methyl- and 2,2'-ethyl-biquinazolinones via carbanionic chemistry. Lithiation of 2,2'-dimethyl-3,3'-biquinazolinone, and further reaction with aromatic aldehydes led to the corresponding styryl derivates. These compounds were used as a prochiral starting materials in diastereoselective reactions like epoxydation, Diels-Alder, 1,3-dipolar cycloaddition and cyclopropanations in order to assess the efficiency of the biquinazolinones as chiral auxiliaries

Kinase-independent phosphoramidate S1P1 receptor agonist benzyl ether derivatives

Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P1-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators. Carboxypeptidase, human serum and cell lysate processing experiments were conducted. ProTide BED analogues were found to have an acceptable level of stability in acidic and basic conditions and in vitro metabolic processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research describes the development of an entirely novel family of therapeutic agents

Synthesis of 2‐Acetamido‐1,3,4‐Tri‐O‐Acetyl‐2‐Deoxy‐D‐Mannopyranose ‐6‐Phosphate Prodrugs as potential therapeutic agents

Abstract: Sugar phosphates are emerging as potential therapeutic candidates for certain diseases. However, their high polarity makes them poorly absorbed by the body and their penetration inside the cell is even more difficult without a proper transporter. Amino sugar phosphates (n‐amino‐n‐deoxy‐sugars, carbohydrates in which a hydroxyl group has been replaced with an amine group), such as N‐acetyl‐d‐mannosamine (ManNac)‐6‐phosphate have shown potential as a treatment for a muscular disease called GNE myopathy caused by a deficiency in the production of sialic acid. However, its high polarity leads to poor absorption and consequent high dosage in humans, causing unwanted side effects. Herein, we describe the application of phosphoramidate prodrug chemistry to 1,3,4‐O‐acetylated N‐acetylmannosamine (Ac3ManNAc) to deliver ManNAc‐6‐phosphate (ManNAc‐6‐P), a critical intermediate in sialic acid biosynthesis. Sialic acid deficiency is a hallmark of GNE myopathy, a rare congenital disorder of glycosylation (CDG), caused by mutations in the gene “GNE,” that limit the production of ManNAc‐6‐P. Synthetic methods were developed to provide a library of Ac3ManNAc‐6‐phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Synthesis of 2‐Acetamido‐1,3,4‐tri‐O‐acetyl‐2‐deoxy‐d‐mannopyranose. Basic Protocol 2: Preparation of 3‐acetamido‐6‐((((((S)‐1‐ethoxy‐4‐methyl‐1‐oxo‐pentan‐2‐yl) amino) (phenoxy)phosphoryl) oxy) methyl) tetrahydro‐2H‐pyran‐2,4,5‐triyl triacetate (5). Support Protocol: Preparation of ethyl (chloro(phenoxy)phosphoryl)‐l‐leucinate

Diastereoselective synthesis of P-chirogenic phosphoramidate prodrugs of nucleoside analogues (ProTides) via copper catalysed reaction

The first copper-catalysed diastereoselective synthesis of P-chiral phosphoramidate prodrugs (ProTides) is reported. This procedure allows the synthesis of diastereomeric-enriched mixtures of ProTides. Application of this methodology to the asymmetric phosphorylation of purine and pyrimidine nucleoside analogues is presented

Phosphonoamidate prodrugs of C5-substituted pyrimidine acyclic nucleosides for antiviral therapy

Acyclic nucleoside phosphonates (ANPs) are nowadays one of the key drugs in the treatment of DNA virus and retrovirus infections. In this work, we report the synthesis and antiviral evaluation of phosphonoamidate and diamidates prodrugs of C5-pyrimidine acyclic nucleosides derivatives functionalized with but-2-enyl- chain. In the phosphonoamidate series, the most active compound 15, showed sub-micromolar activity against varicella zoster virus (VZV) (EC50 =0.09-0.5 μM) and μM activity against human cytomegalovirus (HCMV) and herpes simplex virus (HSV). Separation of single diastereoisomers for compound 14, showed that 14b had better anti-herpesvirus activity and no cytotoxicity compared to the diastereoisomeric mixture 14. Very interestingly, phosphonodiamidate 21 showed anti-herpesvirus activity with excellent activity against wild type and thymidine kinase-deficient (TK-) VZV strains (EC50 = 0.47 and 0.2 μM, respectively) and HCMV (EC50 = 3.5-7.2 μM) without any cytotoxicity (CC50 >100)