New and Efficient Synthesis of Racemic Cyclopent-3-en-1-yl Nucleoside Analogues and Their Derivatives

Abstract

A new, efficient synthesis of racemic cyclopent-3-en-1-yl nucleoside analogues has been developed starting from cyclopentadiene. The key step is the regioselective hydroboration of an intermediately formed mixture of two alkylated cyclopentadienes to give one cyclopentenol. The remaining double bond was further functionalized by hydroboration, epoxidation, cis-hydroxylation and cyclopropanation.Nucleoside analogues have attracted considerable interest due to their important biological activity 1 . Various structural modifications were introduced in both the heterocyclic base and the sugar moiety 2 . In carbocyclic nucleosides the furanose oxygen is replaced by a methylene unit. Such compounds are stable to hydrolysis by phosphorylases that cleave the glycosidic bond in conventional nucleosides. Consequently, carbocyclic nucleosides display enhanced biostability 3 . The removal of the ring oxygen eliminates the anomeric and gauche effects, responsible for forcing the furan system into two distinct conformations 4 . Since the conformation of the five-membered ring is believed to play a critical role in modulating biological activity, the behaviour of nucleosides with a cyclopentane moiety sometimes differs significantly from that of their natural counterparts 5 . Recently, carbocyclic purine analogues such as carbovir 1 6 and the structurally related abacavir 2 7 (Ziagen) were found to be potent inhibitors of HIV reverse

Mitsunobu and Related Reactions: Advances and Applications

“…In addition to what has been discussed in the above sections, a search through SciFinder revealed a few more cases wherein the Mitsunobu reaction has been applied. These include the preparation of (i) 2-substituted 2,3-dihydro-4-quinolones by sulfonamide activated N -alkylation, (ii) entecavir, (iii) cyclic peptolides, (iv) benzothiadiazine dioxide, (v) thymine containing pseudopeptides via N -alkylation by o -Ns activation,(vi) anhydro-nucleosides from cyclization of 6-amino-7H-purine-8(9H)-thione, (vii) 5-{4-[2-(methyl- p -substituted phenylamino)ethoxy]benzyl}thiazolidine-2,4-diones by O -alkylation (ether formation), (viii) furan containing macrolactones, (ix) C(1)−C(7) and C(17)−C(28) subunits of didemnaketal A and B, respectively, , (x) prenylflavanones, (xi) boonein from bisbenzyloxymethyl-substituted bicyclo[2.2.1]ketone, (xii) pseudo-aminosugars, (+)-valienamine and (+)-validamine, (xiii) the monomethyl ether of 1,1′-binaphthol as a precursor for poly(meth)acrylates with a pendant 1,1′-binaphthyl group, (xiv) esters of syn -diisopropyl-1-bromo-2-hydroxy-2-( p -methoxyphenyl)ethylphosphonate, (xv) racemic cyclopent-3-en-1-yl nucleoside analogues, (xvi) pregnane ketols, (xvii) aminopropyl phosphonate nucleosides with purine and pyrimidine bases, (xviii) high glass transition polyimides via etherification for NLO applications, (xix) liquid crystalline aromatic azo compounds (esterification), (xx) peptide nucleic acid monomers based on N -[2-( tert -butoxycarbonylaminomethyl)- trans -4-hydroxy]tetrahydropyrrole acetic acid Me ester, (xxi) chiral liquid crystalline polyacrylates based on l -isoleucine (esterification), (xxii) 20-hydroxyhepoxilins (inversion/rearrangement), (xxiii) α-mercaptomethyl amino acids from α-hydroxymethyl amino acids, (xxiv) β-lactamase hydrolysis resistant penicillin analogues, (xxv) (3 R )-2′3′-dihydro-β,β-caroten-3-ol, (xxvi) deuterium- and tritium-labeled multidrug resistance modulator LY 335979 (etherifcation), (xxvii) acyl glucuronides of R -(−)- and ( S )-(+)-ibuprofen, (xxviii) 2,3-dideoxy-2,3-epimino and 3,4-dideoxy-3,4-epimino derivatives of 1,6-anhydro-β- d -hexopyranoses, (xxix) azaoxamacrobicyclic ligands, (xxx) tetrahydropyrido[2,1- b ]quinazolin-11-ones, (xxxi) reversed imidazole nucleosides, protected (3- N -hydroxyamino-1-alkenyl)phosphonates via BocNHOBoc, (xxxii) poly(etherimide)s with attached NLO moieties, N -(β-phenethyl)- N -triflylvaline ( N -alkylation), and (xxxiv) (−)-cladospolide B …”

A review of methods to synthesise 4′-substituted nucleosides

“…The approaches to 4′-substituted carbocyclic nucleosides include manipulation of an existing nucleoside, use of Grubbs catalyst to cyclise a diene precursor, introduction of the 4′-substituent by stereoselective addition to an enone sugar, and utilisation of chiral auxiliaries to induce stereochemistry at the 4′-position. Shorter racemic syntheses of 4′-substituted carbocyclic nucleosides are noted 46,47 but are not detailed further here. For the general synthesis of carbocyclic nucleosides, and particularly the techniques for coupling the sugar and base unit together, the reader is directed to the recent excellent review by Castillon et al 48…”