Synthesis of the 6′-iso analogues of neplanocin A and 5′-homoneplanocin A

An efficient synthesis of 6′-isoneplanocin A and 6′ -isohomoneplanocin A is reported. The key steps in the synthesis include an enyne metathesis and a regioselective oxidation.     

Robust synthesis of enantiopure cyclohexenyl analogues of 2/3-deoxyribose sugars as carbocyclic nucleoside precursors

An expedient synthesis of 2-deoxy (10) and 3-deoxy (11) cyclohexenyl analogues of 2-deoxy and 3-deoxy-d-ribose sugar from commercially available starting materials is reported. Highly efficient enzymatic resolution of the key compound 10 is described using lipase under hydrolytic conditions. The robust methodology applied here will be useful to synthesize cyclohexenyl nucleosides, which possess potent antiviral activity and are capable of gene silencing via RNAi or antisense applications.     

Transition-metal-mediated synthesis of novel carbocyclic nucleoside analogues with antitumoral activity

A diversity-oriented, enantioselective synthesis of new (monoprotected) carbocyclic nucleoside analogues (CNAs) with the nucleobase attached to a 3-hydroxymethyl-4-trialkylsilyloxymethylcyclopent-2-en-1-yl scaffold was developed. As a key intermediate, racemic (5SR,8RS)-8-allyloxy-2-trimethylsilyl-7-oxa-bicyclo[3.3.0]-oct-1-en-3-one was prepared from 1,1-diallyloxy-3-trimethylsilyl-2-propyne in a cobalt-mediated Pauson-Khand reaction. The enantiomerically pure material was obtained through efficient kinetic resolution (selectivity factor s >/= 40 at -78 degrees C) by means of an oxazaborolidine-catalyzed borane reduction (CBS reduction) with catecholborane. The absolute configuration of the resolved products was determined by CD spectroscopy, Mosher ester analysis, and chemical correlation. Subsequent steps involve diastereoselective ketone reduction and fully regio- and diastereoselective introduction of the nucleobase through Pd(0)-catalyzed allylic substitution. The generality of the method was demonstrated by preparation of CNAs in both enantiomeric series with all five natural nucleobases, as well as 5-bromouracil, 5-fluorouracil, and 6-chloropurine. Screening of the various compounds in a cytotoxicity assay with BJAB and ALL tumor cell lines revealed that some of the compounds possess pronounced antitumoral properties (LD50 values down to 9 microM, as determined by lactate dehydrogenase release after 48 h). By measuring DNA fragmentation, it could be shown that the activity results from induction of apoptosis.     

Synthesis of mono- and polyhydroxylated cyclobutane nucleoside analogs

Enantiomerically enriched cyclobutene compounds 13 and 24 are good precursors of several cyclobutane nucleoside analogs. The synthetic ways involve, in the key step, either hydroboration or dihydroxylation.     

An efficient synthesis of (−)-3-deazaaristeromycin

The coupling reaction of 4-chloro-1H-imidazo[4,5-c]pyridine (6-chloro-3-deazapurine) and (3aS,4S,6R,6aR)-tetrahydro-2,2-dimethyl-6-vinyl-3aH-cyclopenta-[d][1,3]dioxo-4-ol under Mitsunobu reaction conditions provides, after three subsequent straightforward reactions, ready access to the highly biologically active (−)-3-deazaaristeromycin. The versatility of this procedure opens access to a diverse pool of 3-deazapurine carbocyclic nucleosides.     

Synthesis of Carbocyclic Pyrimidine Nucleosides Using the Mitsunobu Reaction: O2‐ vs. N1‐Alkylation

The Mitsunobu reaction is an important tool in carbocyclic nucleoside chemistry for the direct coupling of alcohols with heterocyclic bases under mild conditions. Chemical evidences for an unusual competitive O²‐ vs. N¹‐alkylation of 3‐substituted pyrimidines is presented.     

Synthesis of Thymidine,Uridine, and 5‐Methyluridine Nucleolipids: Tools for a Tuned Lipophilization of Oligonucleotides

Three pyrimidine nucleosides, uridine ( 1 ), 5‐methyluridine ( 6 ), and 2′‐deoxythymidine ( 11 ), were converted to amphiphilic nucleolipids. Compounds 1 and 6 were lipophilized by introduction of symmetric ketal moieties with various carbon chain lengths (i.e., 5–17). Two ketal derivatives, 2b and 7a , were additionally further hydrophobized by N(3)‐farnesylation. 2′‐Deoxythymidine was alkylated at N(3) with a cetyl (=hexadecyl) residue, either directly or, after complete orthogonal protection of the sugar OH groups, by Mitsunobu reaction with hexadecan‐1‐ol. Some of the nucleolipids were subsequently converted to their 2‐cyanoethyl phosphoramidites (5′ or 3′), one of which was used for an exemplary synthesis of a lipo‐oligonucleotide. The sequence of this lipo‐oligonucleotide is an encoded manifestation of Pythagoras' law, created with a key table in which the letters of the alphabet, the numbers from 0 to 9 as well as the mostly used mathematical symbols are allocated to a ribonucleic acid triplet of the genetic code.     

Fast identification by FAB-mass spectrometry of building blocks for oligonucleotide synthesis

Negative ion FAB-MS is recommended for the rapid routine identification of monomeric as well as oligomeric building blocks used in the phosphotriester synthesis of DNA fragments.     

Synthesis of Nicotinamide Adenine Dinucleotide (NAD) Analogues with a Sugar Modified Nicotinamide Moiety

The synthesis of nicotinamide adenine dinucleotide (NAD) analogues in which the ribose unit of the nicotinamide moiety is replaced by a hexitol, altritol, and cyclohexenyl sugar mimic is described.     

Synthesis of morpholine nucleoside triphosphates

Triphosphates of all four ribonucleoside derived morpholine subunits were synthesized and characterized by ¹H and ³¹P NMR, UV and mass spectroscopy.     

Synthesis and conformational analysis of a ribo-type cyclohexenyl nucleoside

A straightforward approach to a novel class of ribo-type cyclohexenyl nucleosides is described. An electron-demand Diels-Alder reaction forms the key-step of the chosen synthetic pathway. Although the difference is small, conformational analysis using NMR shows that this nucleoside analogue adopts preferentially an 2H3 conformation (S-type), while the "deoxy" cyclohexenyl analogue has a preference for a C3' endo conformation (N-type). Analyses of the conformational equilibrium reveal that, in the given experimental conditions, the difference between adenosine and its cyclohexenyl congener resides in their different DeltaG values; furthermore, in adenosine, the conformational preference is of enthalpic origin, whereas in the cyclohexenyl congener, the conformational preference is of entropic origin.     

Synthesis of 2′,3′-dideoxy-6′-fluorocarbocyclic nucleosides via Reformatskii-Claisen rearrangement

2′,3′-Dideoxy-6′-fluorocarbocyclic nucleosides, analogues of highly bioactive carbovir and abacavir were synthesized. The notable steps were the incorporation of fluoromethylene group by way of silicon-induced Reformatskii-Claisen rearrangement of allyl bromofluoroacetate, the construction of the carbocyclic ring via ring-closing metathesis (RCM) and the introduction of base by Mitsunobu reaction.     

Synthesis of unnatural 3′-phospha-2′-deoxyfuranose nucleoside analogues

This Letter describes the synthesis of racemic analogues of unnatural 2′-deoxy nucleoside with a phosphorus atom replacing the carbon atom in the 3′-position. A seven-step sequence was developed in racemic series to afford unnatural 3′-phospha-2′-deoxyfuranose nucleosides. The phospha nucleoside analogues were tested against HCV, but did not show any antiviral activity at a 10 μM maximum concentration used for the inhibition assays of analogues 2-T, 2-C and 4-Tα.     

Chemoenzymatic synthesis of novel adenosine carbanucleoside analogues containing a locked 3′-methyl-2′,3′-β-oxirane-fused system

Starting from a readily available enantiopure building block, a straightforward enantioselective approach to 3′-methyl-2′,3′-β-oxirane-fused carbanucleosides bearing adenosine analogues is detailed. The key steps in the syntheses involved a lipase-catalyzed regioselective monoacylation of a diol to obtain the key intermediate and direct coupling of this key intermediate with diversely substituted purine nucleobases under Mitsunobu reaction conditions providing only the N⁹ target molecules.     

Synthesis of a bicyclic double-headed nucleoside

An attempt of preparing a carbocyclic LNA-analogue using different RCM-methods failed. However, a compound with a hemiacetal linker between the C2′ and the C4′-positions was isolated and found to be a suitable substrate for making a conformationally restricted double-headed nucleoside. This contains two uracil nucleobases organized on a bicyclic skeleton and is locked in an N-type conformation.     

Mitsunobu reactions of nucleoside analogs using triisopropyl phosphite-DIAD

Herein, we report the use of triisopropyl phosphite (TIP) as an effective substitute for triphenylphosphine in the Mitsunobu reaction of nucleoside analogs. In addition, the use of triphenyl phosphite as an alternative reagent for the expensive hexamethylphosphorous triamide (HMPT) in the Véliz-Beal bromination protocol is reported.     

Synthesis and evaluation of hexitol nucleoside congeners as ambiguous nucleosides

A series of anhydrohexitol nucleoside congeners was synthesized as ambiguous or so-called universal nucleosides and was evaluated for their hybridization potential and discrimination properties. The 1,5-anhydro-2,3-dideoxy-2-(5-nitroindazol-1-yl)-d-arabino-hexitol 4e showed the lower spread in T_m values upon hybridization to the natural bases, with minimal destabilization, and therefore behaved as a true ambiguous nucleoside.     

Ionic-tag-assisted synthesis of nucleoside triphosphates

We describe an ionic-tag-assisted synthesis of nucleoside triphosphates that combines the advantage of one-pot triphosphate formation and liquid-phase extraction.     

Synthesis of 5-aminothiazoles as building blocks for library synthesis

A convenient route to 4-phenyl-5-aminothiazoles is described, which offers control over substitution at the 2-position. 2-N-Acylglycinamides were dithionated and a subsequent TFAA-mediated cyclisation step was followed by removal of the 5-N-trifluoroacetyl group providing the free amines. Though applicable generally the method was found to be most effective when introducing aromatic substituents at the 2-position, whereupon moderate overall yields of the 5-amino compounds were obtained.