Amino sugars and their glycosides

This thesis describes approaches to the transformation of simple carbohydrates into a polyhydroxylated pyrrolidine and the formation of its glucosides. Chapter one describes the synthesis of the naturally occurring pyrrolidine 2,5-dideoxy-2,5-imino-D-mannitol. Synthesised from di-O-isopropylidene-D-glucose, the key steps are the introduction of nitrogen at C-5 with retention of configuration. Then cyclisation of the nitrogen onto the C-2 position with inversion to form the pyrrolidine ring. Reduction of the aldehyde furnished the polyhydroxylated heterocycle in 3.4% yield over 16 steps. The synthetic compound matched the naturally occurring compound in all respects. Chapter two contains a review of commonly used glycosylation methods. It also describes the glycosylation of di-O-isopropylidene-α-D-glucose as a model system comparing the Koenig-Knorr method to the trichloroacetimidate method using several reaction conditions. Glycosylation of 2,5-dideoxy-2,5-imino-D-mannitol was carried out using the trichloroacetimidate method to synthese all four glucosides. Boron trifluoride etherate and trimethylsilyl trifluoromethanesulphonate were used as catalysts in dichloromethane, diethyl ether and acetonitrile under strictly anhydrous conditions. All four glucosides were prepared 1-O-(αβ-D-glucopyranosyl)-2,5-dideoxy-2,5-imino-D-mannitol and 3-O-(αβ-D-glucopyranosyl)-2,5-dideoxy-2,5-imino-D-mannitol. Biological screening carried out against a wide range of glycosidases and glycosyl transferases indicated that the glucosides showed little inhibition in comparison to 2,5-dideoxy-2,5-imino-D-mannitol. Chapter three describes the isolation and identification of 1-O-(β-D-glucopyranosyl)- 2,5-dideoxy-2,5-imino-D-mannitol from Nephthytis poisonii N.E.Br. a member of the Araceae family found in tropical Africa. Identification was made by comparison with the previously synthesised glucosides of 2,5-dideoxy-2,5-imino-Dmannitol. Investigations of Hyacinthoides non-scriptus (L.) chouard ex Rothm are also discussed. Chapter four describes the synthesis of a diazidolactone that could be used to form a 1,5 disubstituted tetrazole. This would have a second nitrogen functionality in the molecule allowing the possibility of the inclusion of the tetrazole into a peptide sequence. The synthesis was carried out from L-gulono-1,4-lactone. An azido group was introduced selectively at C-2, this unexpectedly occurred with retention of configuration. A second azide was then introduced at C-5, this occurring with the more commonly observed inversion of configuration to afford the 2,5-diazido-2,5-dideoxy-D-manno-1,4-lactone

Studies on the biosynthesis of 1-deoxynojirimycin

1-Deoxynojirimycin (DNJ) is a 1-deoxy-glucose analogue and glucosidase inhibitor which has also been found to inhibit replication of Human Immunodeficiency Virus. It is known to be produced by several strains of Streptomyces lavendulae and in the present study, Streptomyces subrutilus 445 has also been identified as a producer of DNJ and the 1- deoxy-mannose analogue, 1-deoxymannojirimycin (DMJ). DNJ can be assayed in fermentation samples by virtue of its inhibition of pig kidney trehalase, after the removal of the interfering inhibitor no j irimycin by a heat and acid treatment. DNJ and nojirimycin inhibit this trehalase with Ki values of 3.43 x 10-6 and 2.6 x IO-5 M respectively. The production of DNJ in defined media is subject to supression by glucose and phosphate. Addition of ammonium sulphate to the cultures also inhibits DNJ production although it is unclear whether this is purely a supressive effect. Glucose and starch are the best carbon sources and proline the best nitrogen source in defined media containing only one major carbon and one major nitrogen source. Glucose is the biosynthetic precursor to both DNJ and DMJ and a pathway is proposed which involves a glucose to fructose isomerisation, an inversion of the sugar backbone, and an epimerisation of nojirimycin B to nojirimycin

The synthesis of a differentially protected oxygenated pyrroline nitrone and its application in routes to hyacinthacine family alkaloids

Glycosidases are involved in a range of important biological processes. The possibility of blocking or modifying these processes using glycosidase-inhibiting sugar mimics for therapeutic or biotechnological applications has attracted much interest. This may have significance in the treatment of cancer, viral infections, diabetes and obesity. Iminosugars are analogues of mono- or disaccharides where the ring oxygen is replaced by a nitrogen atom. These compounds include polyhydroxylated derivatives of monocyclic structures such as piperidines and pyrrolizidines, and also of bicyclic structures such as indolizidines and pyrrolizidines. Routes to nitrone 190 from L-xylose and D-arabinose were explored and the application of nitrone 190 towards the synthesis to hyacinthacine A1 and hyacinthacine B2 were investigated. The differential protection of the C-3 position of nitrone 190 meant that this position would be selectively deprotected after cycloaddition, liberating the C-1 hydroxyl group (hyacinthacine numbering) as a site for inversion. Inversion of the hydroxyl group would then provide the required stereochemical outcome for hyacinthacines A1 and B2, where the stereochemistry at C-1 and C-2 is ci

Towards the total synthesis of ficellomycin

Chapter One provides a review of the literature relating to the isolation, structure elucidation and biological activity of ficellomycin, a natural product with antibiotic activity. This chapter also provides an overview of published synthetic routes towards ficellomycin and l-azabicyclo[3.1.0]hexanes. Chapter Two describes our synthetic efforts to the l-azabicyclo[3.1.0]hexane core of ficellomycin. Initially, a model system developed in the group with a double cyclisation as key step was optimised. This involved the reduction of a 1,2-azido alcohol, using a solid-supported triphenylphosphine reagent, to an aziridine that undergoes conjugate addition onto a tethered dehydroamino acid in situ. Under these conditions, azido alcohol 94 led to the formation of the four stereoisomeric bicycles 45 alb, 142 alb, in 45% overall yield in a 3: I :5: I ratio. A second approach towards the natural product is also described. This involved the development of a system wherein the C-5 amino substituent is incorporated. Two open chain y-aldehydes 212 and 232, were made in 8 and 10 steps respectively from 168 using a sequence that involved anti-I,4-addition of azide onto 168, formation of Weinreb amides 211 and 231 and their chemoselective reduction as key steps. Reaction of these aldehydes with phosphonate 99 using DBN, produced alkenes 214 and 230 respectively, and exclusively, as the (Z)-isomers. Further stereocontrolled cyclisation to piperidines 220 and 235 possessing the required 38, 58, 6Rstereochemistry was achieved in good yields by hydrogenation using Lindlar's catalyst. We anticipate that these intermediates could be further advanced to the natural product. Chapter Three draws conclusions from the work to date, and discusses future options with respect to the completion of the synthesis to the natural product. Chapter Four contains detailed experimental procedures for the novel compounds described within this thesis

Synthesis and biological evaluation of novel therapeutic candidates for the treatment of infectious and rare diseases

In the current PhD thesis novel synthetic routes were developed for the synthesis of new compounds with the aim to identify therapeutic candidates for the treatment of rare and infectious diseases. Stereoselective synthetic methodologies were herein exploited to obtain compounds with selected features that would improve pharmacological activity and biological selectivity for the target pathogen or host enzymes. Based on the targeted disease for which the compounds have been conceived, this thesis consists of three main sections. The first section has been focused on Cystic Fibrosis (CF), a rare genetic disorder characterized by chronic infection and inflammation of the airways. Herein, the stereoselective synthesis of the unnatural N-Alkyl L-deoxyiminosugars was considered for their application as anti-inflammatory agents in CF. An efficient procedure was developed, involving the use of polymer-supported triphenylphosphine/iodine system (PS-TPP/I2) to prepare the alkyl chains to be assembled on the iminosugar core. Biological assays revealed a very interesting anti-inflammatory properties of these molecules also confirmed in murine models of lung infection. In the second section, the synthesis of novel candidates for the treatment of bacterial infections was reported with the aim to identify alternative therapeutics to face with the serious and global threat of antibacterial resistance. On one hand, N-alkyl D- and L-deoxyiminosugars and their cholesteryl-bearing derivatives were considered in order to evaluate the role of both the chirality and of the lipophilicity on the eventual anti-bacterial activity of these molecules. In this case, a synthetic procedure was finely tuned and the established PS-TPP/I2 activating system was exploited for the conjugation of the iminosugars with the cholesteryl moiety enabling to obtain the target compounds in a solid phase system and in one-pot procedure. On the other hand, a novel synthetic route, as alternative to the existing methods, aimed to the preparation of the corticosteroid anti-inflammatory drug Deflazacort was explored for it repurposing as antibacterial agent. For both classes of compounds, in vitro biological assays revealed a "lead" compound endowed with interesting antibacterial and antibiofilm activity. In the last section the attention has been focused on synthesis of nucleoside analogues for their use in viral diseases. Particularly, two class of sugar modified nucleosides was synthesized, cyclohexenyl nucleosides and piperidinyl nucleosides conceived as selective inhibitors of viral DNA and RNA polymerases. Eventually, propargylated purine nucleosides was prepared with the aim to exploit the potential of NAs for in vivo visualization of viral life cycle

Women in Bioorganic Chemistry

Issues relating to the gender schism and its effect on the career advancement of women in the Academy, especially in the field of STEM disciplines, deserve our attention and the efforts of all the scientific community to mitigate the gender gap. In order to embrace gender equality, recognize the career progression of women, and to celebrate the achievements of women in the field of bioorganic chemistry, we present contributions both from highly renowned female scientists and young female researchers who are in the early stages of their careers. This Special Issue includes fifteen manuscripts, including eleven high-quality research articles and four comprehensive review articles in the area of bioorganic chemistry, published from mid-2020 to early 2022. The scope of this Special Issue covers a wide range of topics at the organic chemistry–biology interface, including the synthesis and derivatization of natural compounds and their analogues, and the investigation of their biological activities in the human health field (for instance as antitumorals, antioxidants and antimicrobial agents), as well as their possible application in the crop protection field as agrochemicals. An example of nanoparticle-based biomaterial is also included. The techniques employed, besides organic synthesis, are in silico studies (docking procedures and molecular modeling), FT-IR spectroscopy, laser diffraction, PET, fluorescence, STD-NMR studies, enzymatic evaluation, experiments on cell lines and in vivo studies on mice

Towards the total synthesis of ficellomycin

Chapter One provides a review of the literature relating to the isolation, structure elucidation and biological activity of ficellomycin, a natural product with antibiotic activity. This chapter also provides an overview of published synthetic routes towards ficellomycin and l-azabicyclo[3.1.0]hexanes. Chapter Two describes our synthetic efforts to the l-azabicyclo[3.1.0]hexane core of ficellomycin. Initially, a model system developed in the group with a double cyclisation as key step was optimised. This involved the reduction of a 1,2-azido alcohol, using a solid-supported triphenylphosphine reagent, to an aziridine that undergoes conjugate addition onto a tethered dehydroamino acid in situ. Under these conditions, azido alcohol 94 led to the formation of the four stereoisomeric bicycles 45 alb, 142 alb, in 45% overall yield in a 3: I :5: I ratio. A second approach towards the natural product is also described. This involved the development of a system wherein the C-5 amino substituent is incorporated. Two open chain y-aldehydes 212 and 232, were made in 8 and 10 steps respectively from 168 using a sequence that involved anti-I,4-addition of azide onto 168, formation of Weinreb amides 211 and 231 and their chemoselective reduction as key steps. Reaction of these aldehydes with phosphonate 99 using DBN, produced alkenes 214 and 230 respectively, and exclusively, as the (Z)-isomers. Further stereocontrolled cyclisation to piperidines 220 and 235 possessing the required 38, 58, 6Rstereochemistry was achieved in good yields by hydrogenation using Lindlar's catalyst. We anticipate that these intermediates could be further advanced to the natural product. Chapter Three draws conclusions from the work to date, and discusses future options with respect to the completion of the synthesis to the natural product. Chapter Four contains detailed experimental procedures for the novel compounds described within this thesis.EThOS - Electronic Theses Online ServiceUniversity of Warwick (UoW)AstraZeneca (AZ)GBUnited Kingdo

Phosphate Tether-Mediated Synthetic Studies- Applications in Natural Products Synthesis.

The focus of this dissertation is the utilization of phosphate tether mediated approaches to synthesize bioactive natural products and their analogs in аn efficient and effective manner. The several salient features, which are inherent to phosphate triesters, include: (i) orthogonal stability under acid conditions, (ii) leaving group ability, (iii) multivalent activation of carbinol centers, (iv) protecting group attributes, and serving as a (v) temporary tether that can be removed under various conditions. Taken collectively various transformations, including chemoselective reductions as well as oxidations of the exocyclic olefin, a diastereoselective cuprate addition and successful cross-metathesis of type I and type II olefins with the exocyclic double bond, all mediated by phosphate tether, have provided the facile synthetic routes towards the synthesis of several natural products. Application of this protocol toward the total synthesis of fostriecin and 8-epi-fostriecin are reported. Fostriecin, an antitumor antibiotic isolated from Streptomyces pulveraceus, is the most selective and potent inhibitor of protein phosphatases 2A and 4, known to-date (IC50s 3.2 nM and 3 nM, respectively). It has been shown to be active against L1210 and P388 leukemia cells in vivo and in vitro against leukemia, lung, breast, and ovarian cancer cells. Synthetic studies related to diastereoselective ring-closing metathesis reaction, regioselective oxidation, diastereoselective Grignard addition and cross metathesis, all mediated by a temporary phosphate tether, have established a scalable route toward the goal of total and analog synthesis of fostriecin and 8-epi-Fostriecin. In addition to the aforementioned transformations, the coupling of orthogonal transformations in a multi-step, one-pot, sequential RCM/CM/H2 process has also allowed for facile synthesis of advanced intermediates en route to the total synthesis of natural products. Application of three step, one-pot, sequential RCM/CM/H2 protocol in a library amenable, efficient and modular synthesis of strictifolione and (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one are also discussed. Both anti-fugal natural products were synthesized in seven linear steps starting from readily available 1,3-anti-diene-diol without incorporating additional protecting groups

Studies towards the total synthesis of (-)-lemonomycin

2006 Spring.Includes bibliographical references.An asymmetric synthesis of the tetracyclic core of (-)-lemonomycin is presented. It features an efficient route towards a highly versatile tetrahydroisoquinoline intermediate, in which a diastereoselective Pictet-Spengler reaction has been developed. In addition, a novel oxidation was discovered in the process of an azomethine ylide cyclization for construction of C and D rings of lemonomycin. An investigation into the mechanism of this novel oxidation has been carried out and the results discussed. The tetracyclic enamide from this process represents a highly functionalized and versatile intermediate. Interestingly, the enamide double bond proved very resistant to reduction and this transformation was fully investigated. More recently, with high-pressure hydrogenation equipment, promising leads towards hydrogenation of this enamide have been uncovered