A Convenient Synthesis of D-Psicofuranosyl Nucleosides1

Abstract

As part of our studies on the synthesis of conformationally restricted nucleosides of types 1 and 2, where X = CH₂, O or S, we required access to differentially substituted D-psicofuranosyl nucleosides such as 3. As shown in the table, we have developed a convenient approach to such compounds that depends on the direct condensation of the 1,2:3,4-di-O-isopropylidene-β-D-psicofuranose derivative 4 with an appropriate silylated purine or pyrimidine base.² Although the α and β anomers of 3 are formed in a 1:1 ratio, the yields of the β anomers are generally comparable with earlier condensation methods that use psicofuranosyl- halide², 2-benzoates⁴ or 2-nitro derivative⁵. However, the present method has the advantage that the starting sugar 4 is more readily accessible. The precursor 6′-alcohol can be prepared in very large amounts from D-fructose using the method of Prisbe et al.⁴     

Nucleosides VI: A Novel and Convenient Synthesis of Purine S-Cyclonucleosides Via Mitsunobu Reaction

Abstract

Two representative S-cyclonucleosides, 8,5′-anhydro-2′, 3′-O-isopropylidene-8-mercaptoadenosine (3) and 8,2′-anhydro-3′,5′-O-(tetraisopropyldisiloxane-1,3-diyl)-8-mercaptoguanosine (8), were prepared in good yields by dropwise addition of one equivalent each of triphenylphosphine and DEAD in DMF into a mixture of 2′,3′-O-isopropylidene-8-mercaptoadenosine (2) or 3′,5′-O-(tetra-iso-propyldisiloxane-1,3-diyl)-8-mercaptoguanosine (7), respectively, in DMF. Treatment of compound 2 with two equivalents each of triphenylphosphine and DEAD in DMF afforded N-[8,5′-anhydro-2′,3′-O-isopropylidene-8-mercaptopurin-6-yl]triphenylphospha-λ5-azene (4) in 87% yield.     

Stereoselective Approach to the Z-Isomers of Methylenecyclopropane Analogues of Nucleosides: A New Synthesis of Antiviral Synguanol

Stereoselective synthesis of antiviral synguanol (1) is described. Reaction of 6-benzyloxy-2-(dimethylaminomethyleneamino)purine (10) with ethyl (cis,trans)-2-chloro-2-(chloromethyl) cyclopropane-1-carboxylate (2c) under the conditions of alkylation-elimination gave (Z)-6- benzyloxy-2-formylamino-9-[(2-carbethoxycyclopropylidene)methyl]purine (11) but no E,N⁹-isomer. Minor amounts of (Z)-6-benzyloxy-2-formylamino-7-[(2-carbethoxy-cyclopropylidene)methyl]purine (13) were also obtained. Hydrolysis of compounds 11 and 13 in 80% acetic acid afforded (Z)-9-[2-(carbethoxycyclopropylidene)methyl]guanine (14) and (Z)-7-[2-(carbethoxy- cyclopropylidene)methyl]guanine (15). Reduction of 14 furnished synguanol (1). Reaction of N⁴-acetylcytosine (7) with ester 2c led to (Z,E)-1-(2-carbethoxycyclopropropylidenemethyl)cytosine (8, Z/E ratio 6.1:1). Basicity of purine base, lower reactivity of alkylation intermediates as well as interaction of the purine N³ or cytosine O² atoms with the carbonyl group of ester moiety seem to be essential for the observed high stereoselectivity of the alkylation-elimination. The Z-selectivity is interpreted in terms of E1cB mechanism leading to a transitory “cyclic” cyclopropenes which undergo a cyclopropene-methylenecyclopropane rearrangement.     

A Novel and Enantioselective Approach to the Synthesis of Cyclohexane Carbocyclic Nucleosides Starting from (-)-Carvone

Abstract

3,5-dihydroxy-4-(hydroxymethyl)-1-cyclohexanyl adenine has been synthesized starting from (-)-carvone. The adenine base was introduced via Mitsunobu reaction. Conformational analysis showed that the base still adopts the equatorial position at the expence of three axial substituents.     

A New Approach to the Synthesis of Benzothiazole,Benzoxazole, and Pyridine Nucleosides as Potential Antitumor Agents

Abstract

A modified nitrogen and sulfur glycosylation reaction involving benzothiazole benzoxazole and pyridine nucleoside bases with furanose and pyranose sugars are described. Conformational analysis has been studied by homo- and heteronuclear two-dimensional NMR methods (2D DFQ-COSY, HMQC and HMBC). The N and S sites of glycosylation were determined from the ¹H, ¹³C heteronuclear multiple-quantum coherence (HMQC) experiments. All the deprotected nucleosides were tested for their potential antitumor activity.     

Convenient Syntheses of 6-Methylpurine and Related Nucleosides

Abstract

Efficient methods for the synthesis of 6-methylpurine (3), 9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-methylpurine (8), and 6-methyl-9-β-D-ribofuranosylpurine (5) are described. Methodology involving the (Ph₃P)₄Pd catalyzed cross-coupling reaction of CH₃ZnBr with several different 6-chloropurine derivatives is described in high yield. This methodology now provides a facile and high-yielding synthesis of 8, which is needed in significant amounts for studies in cancer gene therapy.     

Enantioselective Synthesis of Carbocyclic Nucleosides by Enzymatic Approach and the Anticancer Activities

Abstract

Enantioselective synthesis of carbocyclic nucleosides, aristereomycin, neplanomycin A and their homologues has been completed by a combination of enzymatic and non-enzymatic procedures starting with a bicyclic meso-diester 2. The study on anticancer activities of them showed that the cytosine homologue exhibits most remarkable activity against L1210 leukemia in mice.     

A Convenient Approach to N-3 Alkylation of 9-Substituted Guanines

Abstract

Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxy-ethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-α]purine 1 directs the benzylation reaction partly into N-4 position to give 3. Cleavage of the third ring of 3 gives 3-benzylacycloguanosine 5, a first 3-aralkilo-9-substituted guanine.     

Synthesis of Cyclobutane Nucleosides

2-(6-Chloropurinyl)-3-benzoyloxymethylcyclobutanone can be prepared by reaction of 6-chloropurine with 3-benzoyloxymethyl-2-bromocyclobutanone. The N-alkylation gave both N-9 and N-7 regioisomers. Both regioisomers upon hydride reduction followed by aminolysis gave the corresponding adenine nucleoside analogues. However, the N-7 series led to the hypoxanthine analogues as byproducts.     

A Convenient Synthesis of Deoxynebularine Phosphoramidite

Abstract

Enzyme catalysis by a cell free preparation from Lactobacillus leichmannii is used to accomplish the transformation of thymidine to deoxynebularine in the presence of purine. The resulting mixture of nucleosides is then converted to their 5′-dimethoxytrityl derivatives which are easily separated using conventional chromatography. Phosphitylation of the 5′-dimethoxytrityl-deoxynebularine then gives the phosphoramidite derivative suitable for incorporation into oligonucleotides.     

Synthesis of D-Fructofuranosylpurine Nucleosides

Abstract

The Mitsunobu reaction has been applied to the formation of purine nucleosides of D-fructofuranose. The use of O-benzyl protection results in a predominance of the β-configuration in these novel compounds and both α- and β-D-fructofuranosyladenine are obtained in stereochemically pure form.     

Selective Synthesis and Application to the Synthesis of (E)-Fluorovinyl Nucleosides

A selective method for synthesizing (E)-fluorovinyl was developed. Novel acyclic (E)-fluorovinyl versions of neplanocin A were designed and selectively synthesized as potential antiviral agents. The condensation of the bromide 7 with the nucleosidic bases (5-FU, C, A, G) and the deprotection afforded the desired acyclic fluorovinyl nucleosides. The synthesized compounds 11, 12, 13, and 16 were evaluated for their antiviral activity. The guanine derivative 16 showed toxicity-dependent anti-HIV-1 activity in MT-4 cells.     

Synthesis of Non-Natural Pyrimidine Nucleosides

Abstract

Two new non-natural nucleosides bearing an amide (8) or an amidine (9) function have been synthesized. Their properties and the geometry of the exocyclic double bond have been studied.     

Synthesis of Some Quinolinium Nucleosides

Abstract

The preparation of a series of quinolinium nucleosides with substituents on the 3-, 4- and 6-position is described.     

Arylamidation of Purine Nucleosides by 2-Acetylalkoxy- Aminofluorene - an Intramolecular Approach to the Synthesis of Nucleoside - Carcinogen Adducts

Abstract

Arylamidation of the guanosine ring at position C-8 by the carcinogen N-2acetylalkoxyaminofluorene was achieved using an intramolecular approach.     

Synthetic Approach to D-Psicofuranosyl Nucleosides and Their 1-Deoxy Analogues

Abstract

The sugar moiety of ketofuranosyl nucleosides derived from D-psicofuranose and 1-deoxy-D-psicofuranose are readily available through nucleophilic addition of D-ribono-1,4 -lactone with lithiated reagents.     

A Novel Route for the Synthesis of Fluorodeoxy Sugars and Nucleosides

Abstract

Ring-fluorination of α- and β-D-pentofuranosides containing free secondary hydroxyl groups by (diethylamino)sulfur trifluoride (DAST) was studied.     

A New Approach to Natural Products Discovery Exemplified by the Identification of Sulfated Nucleosides in Spider Venom

A New Approach to Natural Products Discovery Exemplified by the Identification of Sulfated Nucleosides in Spider Venom@Andrew E. Taggi$Contribution from The Cornell Institute for Research in Chemical Ecology and The Department of Chemistry and Chemical Biology, Baker Laboratory,Cornell UniVersity, Ithaca, New York 14853 @Jerrold Meinwald$Contribution from The Cornell Institute for Research in Chemical Ecology and The Department of Chemistry and Chemical Biology, Baker Lab…     

Asymmetric Synthesis of Cyclopropyl Carbocyclic Nucleosides

Abstract

A number of nucleosides have been synthesized as potential antiviral and antitumor agents.¹ More recently, various dideoxynucleosides have been synthesized and found to be potent anti-HIV agents.² As a part of our drug discovery program for the treatment of HIV and HBV, we have initiated to synthesize cyclopropyl carbocyclic nucleosides as potential antiviral agents. Several papers regarding the synthesis of cyclopropyl carbocyclic nucleosides have appeared in the literature.^3–5 However, they are all reported as racemic mixtures. In this abstract, we wish to report the asymmetric synthesis of cylopropyl carbocyclic nucleosides from optically active common intermediates, 6 and 11.