Enantiomeric synthesis of carbocyclic d-4′-C-methylribonucleosides as potential antiviral agents

An efficient synthetic approach for the preparation of enantiomerically pure carbocyclic d-4′-C-methylribonucleosides 3a–f is reported. The key intermediate, d-2,3-O-cyclohexylidene-4-methylcyclopentenone 8, was prepared starting from d-ribose in eight steps via an oxidative rearrangement. Conjugate addition of a catalytic vinylcopper(I) reagent to the α,β-unsaturated ketone 8 yielded cyclopentyl alcohol 10, which bears a quaternary stereogenic carbon at the C4-position. The cyclopentyl alcohol 10 was subsequently coupled with 6-chloropurine or 2-amino-6-chloropurine via an SN2 reaction, followed by a series of functional group transformations and deprotections to furnish purine ribonucleosides 3a–c. Pyrimidine bases were constructed on cyclopentylamine 29 using a linear approach, which furnished the pyrimidine nucleosides 3d–f.

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(3a′S,6a′S)-6′-Methyl-3a′H-spiro[cyclohexane-1,2′-cyclopenta[d][1,3]dioxol]-4′(6a′H)-oneC12H16O3Ee = 100%[α]D27=-35.3 (c 0.97, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3a′S,6a′S)

(3a′S,4′R,6a′S)-4′-Methyl-4′-vinyldihydro-3a′H-spiro[cyclohexane-1,2′-cyclopenta[d][1,3]dioxol]-6′(6a′H)-oneC14H20O3Ee = 100%[α]D27=-209.1 (c 0.76, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3a′S,4′R,6a′S)

(3a′S,4′R,6′S,6a′R)-4′-Methyl-4′-vinyltetrahydro-3′aH-spiro[cyclohexane-1,2′-cyclopenta[d][1,3]dioxol]-6′-olC14H22O3Ee = 100%[α]D26=-9.1 (c 1.46, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3a′S,4′R,6′S,6a′R)

(3a′S,4′R,6′S,6a′R)-4′-((Methoxymethoxy)methyl)-4′-methyltetrahydro-3a′H-spiro[cyclohexane-1,2′-cyclopenta[d][1,3]dioxol]-6′-amineC15H27NO4Ee = 100%[α]D26=+11.3 (c 0.38, EtOAc)Source of chirality: asymmetric synthesisAbsolute configuration: (3a′S,4′R,6′S,6a′R)

(1R,2S,3R,5R)-5-(6-Amino-9H-purin-9-yl)-3-(hydroxymethyl)-3-methylcyclopentane-1,2-diolC12H17N5O3Ee = 100%[α]D24=-29.6 (c 0.32, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2S,3R,5R)

2-Amino-9-((1R,2R,3S,4R)-2,3-dihydroxy-4-(hydroxymethyl)-4-methylcyclopentyl)-1H-purin-6 (9H)-oneC12H17N5O4Ee = 100%[α]D26=-6.45 (c 0.12, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,3S,4R)

9-((1R,2R,3S,4R)-2,3-Dihydroxy-4-(hydroxymethyl)-4-methylcyclopentyl)-1H-purin-6(9H)-oneC12H16N4O4Ee = 100%[α]D27=-37.8 (c 0.25, MeOH–CH2Cl2 1:1)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,3S,4R)

1-((1R,2R,3S,4R)-2,3-Dihydroxy-4-(hydroxymethyl)-4-methylcyclopentyl)-5-methylpyrimidine-2,4(1H,3H)-dioneC12H18N2O5Ee = 100%[α]D27=-81.8 (c 1.40, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,3S,4R)

1-((1R,2R,3S,4R)-2,3-Dihydroxy-4-(hydroxymethyl)-4-methylcyclopentyl)pyrimidine-2,4(1H,3H)-dioneC11H16N2O5Ee = 100%[α]D24=-42.4 (c 0.46, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,3S,4R)

4-Amino-1-((1R,2R,3S,4R)-2,3-dihydroxy-4-(hydroxymethyl)-4-methylcyclopentyl)pyrimidine-2(1H)-oneC11H17N3O4Ee = 100%[α]D26=-39.15 (c 0.51, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2R,3S,4R)