Chiral syntheses of 6′-β-fluoroaristeromycin, 6′-β-fluoro-5′-noraristeromycin and aristeromycin

Carbocyclic nucleosides substituted at the C-6′ position are receiving increasing attention. Chiral synthetic accessibility to the biologically promising 6′-β-fluoroaristeromycin is lacking. Its preparation and that of the 5′-nor analogue are described. Along the way, a new method to aristeromycin arose as an outgrowth of a requisite structure proof.     

5′-Noraristeromycin possessing a C-1′ cyclopentyl double bond: a new carbanucleoside structural prototype

Prior to this work only two examples of carbanucleosides possessing a C-1′/C-6′ double bond had been reported and they were minor derivatized side products arising during other targeted syntheses. To develop this structural feature into a new class of potential antiviral agents, the 5′-nor derivative of aristeromycin with such an olefinic structure (6) represents the first example. In this regard, treatment of (1′S,2′S,3′S,4′R,5′S)-6-chloro-9-(2′,3′-isopropylidenedioxy-6′-oxabicyclo[3.1.0]hex-4′-yl)purine (7) with sodium methoxide yielded 6 via an E′₂-like elimination pathway. A convenient way to the C-4′ epimer of 6 (that is, 17) also arose during these studies and is described. Antiviral analysis of 6 and 17 failed to produce any significant activity.     

Isomers of neplanocin A and 2′-deoxyneplanocin A possessing a C-1′/C-6′ double bond

Missing among the unsaturated carbocyclic nucleosides is the 1′,6′-double bond isomer of neplanocin A. A practical synthesis of this compound and its 2′-deoxy derivative is reported from readily accessible cyclopentenols.     

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.     

A short and concise synthesis of isofagomine, homoisofagomine, and 5′-deoxyisofagomine

A short and concise synthesis of isofagomine derivatives via the epoxidation of chiral N-Boc-5-hydroxy-3-piperidene, followed by regioselective epoxide ring opening is described. This constitutes the first reported synthesis of homoisofagomine and the 5′-deoxyisofagomine.     

Novel and efficient syntheses of 3′,5′-diamino derivatives of 2′,3′,5′-trideoxycytidine and 2′,3′,5′-trideoxyadenosine. Protonation behavior of 3′,5′-diaminonucleosides

High yielding synthetic routes to 3′,5′-diamino-2′,3′,5′-trideoxycytidine and 3′,5′-diamino-2′,3′,5′-trideoxyadenosine are described. In addition, the protonation behavior of 3′,5′-diamino-2′,3′,5′-trideoxycytidine, 3′,5′-diamino-2′,3′,5′-trideoxyadenosine, 3′,5′-diamino-3′,5′-dideoxythymidine, and 3′,5′-diamino-2′,3′,5′-trideoxyuridine has been studied by means of pH-metric measurements and NMR spectroscopy. The ionization constants and the sequence of protonation sites have been determined.     

A practical synthetic route to 4′-alkylaristeromycin derivatives: 4′-methylaristeromycin

(−)-(1S,4R)-4-Hydroxy-2-cyclopenten-1-yl acetate provided a convenient entry point for a 16-step chiral preparation of 4′-methylaristeromycin. This procedure is adaptable to a number of carbocyclic nucleosides with a diversity of substitution at C-4′ and C-5′ and a variety of heterocyclic bases.     

Enantiospecific synthesis of 5′,5′,5′-trifluoro-5′-deoxyneplanocin A

(−)-(1S,4R)-4-Hydroxy-2-cyclopenten-1-yl acetate provided a convenient entry point for a 12-step chiral preparation of 5′,5′,5′-trifluoro-5′-deoxyneplanocin A.     

C-4′ Truncated carbocyclic formycin derivatives

Formycin is a naturally occurring C-glycoside (C-nucleoside) that possesses antitumor, antibacterial, antifungal, and antiviral activity. In connection with our ongoing interest in the design and syntheses of C-nucleoside derived antiviral agents this report describes the preparation of carbocyclic formycin and its 7-hydroxy (oxo) analog lacking the C-4′ hydroxylmethylene moiety in racemic form (4 and 6, respectively). An antiviral analysis of (±)-4 did not disclose any activity.     

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.     

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.     

Straightforward synthesis of 3′-deoxy-3′,4′-didehydronucleoside-5′-aldehydes via 2′,3′-O-orthoester group elimination: a simple route to 3′,4′-didehydronucleosides

Straightforward, high-yielding syntheses of 3′-deoxy-3′,4′-didehydronucleoside-5′-aldehydes and 3′-deoxy-3′,4′-didehydronucleosides starting from 2′,3′-O-orthoester derivatives of ribonucleosides are described.     

Synthesis of 4′-substituted 2,2′:6′,2″-terpyridines via a Mitsunobu reaction

Treatment of 2,6-di(pyridin-2-yl)pyridin-4(1H)-one with various appropriately protected ω-substituted primary alcohols or a nucleoside (3,3′-O-diBz-dUrd) in dry THF in the presence of triphenylphosphine and diisopropylazodicarboxylate gives the corresponding 4′-substituted terpyridines in high yield.     

Practical synthesis of adenosine 3′,5′-cyclic monophosphorodithioate

Adenosine 3′,5′-cyclic monophosphorodithioate (cAMPS₂), which has two exocyclic sulfurs directly attached to phosphorus, was synthesized from adenosine phosphoramidite by intramolecular cyclization employing the phosphotriester method as a key step.     

One-step to get 5-azidomethyl-2′-deoxyuridine from 5-hydroxymethyl-2′-deoxyuridine and detection of it through click reaction

Nowadays a few ways to synthesize 5-azidomethyl-2′-deoxyuridine from 5-hydroxymethyl-2′-deoxyuridine have been reported. But none of them was one-step. And many of them need to protect the hydroxyl group on the pentose ring. The detection of 5-hydroxymethyl-2′-deoxyuridine is also very important in many biological processes. However few fluorescence detection strategies have been tried to do this. Herein, we reported a one-step protocol to synthesize 5-azidomethyl-2′-deoxyuridine, which was then used for detecting 5-hydroxymethyl-2′-deoxyuridine through a click reaction.     

New and efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides

A short, efficient synthesis of 5′-amino-5′-(S)-methyl-2′,5′-dideoxynucleosides 1 has been developed through the diastereoselective addition of methylmagnesium bromide or methyllithium to an intermediate tert-butylsulfinimide.     

(+)-Neplanocin F, 2′-fluoroneplanocin, and a 6′-isoneplanocin via a common versatile cyclopentenol precursor

Reductive (diisobutylaluminum hydride) ring opening of an acetal protected cyclopentenol has provided a precursor adaptable to uniquely substituted carbocyclic nucleosides. To illustrate the broad implication of this process the preparation of unnatural (+)-neplanocin F, an ara-like 2′-fluoroneplanocin, and a 6′- isomeric l-like neplanocin analog is described.     

Difluorocarbene chemistry: synthesis of gem-difluorocyclopropenylalkynes and 3,3,3′,3′-tetrafluorobicyclopropyl-1,1′-dienes

A series of gem-difluorocyclopropenylalkynes are easily obtained in good yields by the Sonogashira reaction of 3,3-difluoro-1-iodocyclopropenes with terminal alkynes. Onto these new alkynes addition of difluorocarbene, generated from the decomposition of FSO₂CF₂COOTMS in diglme in the presence of 10 mol% anhydrous NaF at 120 °C, gives 3,3,3′,3′-tetrafluorobicyclopropyl-1,1′-dienes. Acid hydrolysis of gem-difluorocyclopropenylalkynes in refluxing CH₃OH affords the corresponding methoxycarbonylenynes.     

A concise synthesis of 3′-α-fluoro-2′,3′-dideoxyguanosine (FddG) via 3′-α-selective fluorination of 8,2′-thioanhydronucleoside

The antiviral nucleoside 3′-α-fluoro-2′,3′-dideoxyguanosine (FddG) was synthesized via 3′-α-selective fluorination of 8,2′-thioanhydronucleoside as the key step. Desulfurization of 3′-α-fluoro-3′-deoxy-8,2′-thioanhydronucleoside could be achieved by the treatment with Raney Ni in toluene. This method provides a concise route to 3′-α-fluoro-2′,3′-dideoxynucleosides that avoids the use of explosive and expensive SF₄-related fluorinating reagents.     

Uracil ring opening in the reaction of 5-formyl-2′-deoxyuridine with primary alkyl amines

Treatment of 5-formyl-2′-deoxyuridine (f⁵dU) with stoichiometric amounts of strongly nucleophilic, non-hindered primary alkyl amines led to fast and quantitative formation of the corresponding Schiff bases. In the presence of excess amines, novel nucleosides with ring opened pyrimidine bases were formed as a result of the Michael addition of a second amine to the pre-formed imines. In the reaction of f⁵dU with aromatic amines, the formation of Schiff base derivatives was slower and even under prolonged treatment with an excess of amine the uracil ring remained intact.