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Xylose is the optimal substrate for β4GalT7, an essential enzyme in GAG biosynthesis, but analogs act as effective inhibitors.

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reduced reaction time • amenable to gram-scale • simple purification O O N PO N H O HOABSTRACT: Anhydrouridines react with aliphatic amines to give N-alkyl isocytosines, but reported procedures often demand very long reaction times, and can be low-yielding, with narrow scope. A modified procedure for such reactions has been developed, using microwave irradiation, significantly reducing reaction time and allowing facile access to a diverse range of novel nucleosides on gram-scale. The method has been used to prepare a precursor to a novel analogue of lysidine, a naturally occurring iminonucleoside found in t RNA.Non-coded ('unnatural') nucleoside analogues are privileged chemical motifs, possessing a diverse range of biological and clinical properties. Most nucleoside drug candidates contain modified heterocyclic components but modification to the native ribose core can also confer significant biological activity, and 2'-modified nucleosides are found at the heart of marketed antisense oligonucleotide 1 medications, including mipomersen (Kynamro ® , used to treat homozygous familial hypercholesterolemia) and nusinersen (Spinraza ® , for spinal muscular atrophy). 2'-Modified mononucleosides also exhibit biological potency, and arabino-configured nucleosides Cytarabine (ara-C 1, acute myeloid and lymphocytic leukaemias, and lymphomas; Figure 2), Clevudine (2, hepatitis B) and Fludarabine (3, chronic lymphocytic leukaemia, non-Hodgkin lymphoma) are used in the clinic, leading to great interest in methods for synthesis of this class of compound. 2, 3 In addition to therapeutic significance, modified nucleosides are also of great utility as structural probes and as chemical start points for functional synthetic polynucleotides. Arabino-configured antisense systems have been prepared and shown to posses interesting properties, 4 and aminated arabino-isocytosines 4 are also biologically active nucleoside analogues, possessing anti-cancer activity, 5 and as precursors to polynucleotides able to form duplexes with isoG-containing sequences. 6 As part of a research program directed towards synthesis and testing of novel catalytic polynucleotides possessing both modified base and ribose motifs, compounds rarely reported in the literature, we sought a synthetic entry to arabino-configured isocytosines 4.

Abstract:The catalytic synthesis of 3-(2'-glycinoyl)ribose derivatives under mild conditions is described. The key reaction involves silver-catalyzed condensation of isocyanoacetates with 3-ketoriboses.Key words: Catalytic, non-coded amino acids, hybrid peptides, ribonucleoproteins, asymmetric synthesis.Processes involving nucleic acids and proteins dominate the chemistry of biological systems, and synthetic molecules combining the structural features of these two biopolymer classes possess privileged biological properties. As testament to the intrinsic challenge of carrying out synthetic manipulation of nucleosides, there are few methods which are reported to deliver hybrid molecules containing riboside and peptide-like characteristics. Those methods which have been described often feature lynchpin attachment through C-X bonds rather than C-C bonds. i As part of a program of research directed towards the preparation and analysis of riboside-glycine hybrids 1, we have investigated catalytic methods to create C-C bonds between riboses and glycine anion equivalents and we here describe the preliminary data from these studies. Scheme 1. Riboside-glycine hybrids: ambident polymerization monomers.Our target was a riboside-amino acid hybrid which allowed for dual-polymerization strategies; thus monomers 1 could (after appropriate chemical processing) function as building blocks for either synthetic oligonucleotide synthesis (via automated phosphoramidite technology, path A, Scheme 1), or synthetic oligopeptides (path B). The key synthetic challenge to deliver monomers was construction of the 3'-Cα C-C bond highlighted; our studies commenced with preparation and reactions of 3'-ketoribosides 2. We envisaged that olefination with an apposite 2-aminophosphonate (or equivalent reagent), followed by directed reduction would yield our desired ribsoyl glycines (Scheme 2). Thus, 3'-ketouridine and thymines 2a and 2b were prepared and reacted with a range of phosphorusbased carbonyl olefination reagents, but after an exhaustive study of a diverse range of reactions, we concluded that such methodology would not efficiently deliver the desired target products. We therefore turned our attention away from olefination strategies and towards the methodology of Saegusa, ii,iii envisaging Lewis acid-catalyzed reaction of isocyanoacetates with ketoribosides iv as an alternative method to ultimately deliver the target hybrids (Scheme 2). This method not only offered an attractive option of a catalytic rather than stoichiometric process, but also allowed the delivery of a conformation controller in the form of the 3'-hydroxy motif. However, given that ketones are often unpredictable electrophiles in isocyano aldol reactions, 3 this was a challenging ambition. Reactions of ketoribosides 2a and 2b with isocyanoacetate in the presence of substoichiometric Ag(I) salts delivered small amounts of the desired targets, but the product mixture was complex and dominated by depyrimidinated products. After significant at- tempts to optimize the proc...