The manifestations of the retro-Diels Alder reaction in the ground-state structures of a range of cyclopentadiene and cyclohexadiene cycloadducts 9-15 have been investigated by a combination of techniques. These include low-temperature X-ray crystallography, density functional calculations (B3LYP/6-31G(d,p)) on both the ground states and transition states, and the measurement of (13)C-(13)C coupling constants. We have found that the carbon-carbon bonds (labeled bonds a and b), which break in the rDA, are longer in the cycloadducts 9-15 than in their corresponding saturated analogues 9s-15s, which cannot undergo the rDA reaction. The degree of carbon-carbon bond lengthening appears to be related to the reactivity of the cycloadduct, thus the more reactive benzoquinone cycloadducts 5b and 13 have longer carbon-carbon bonds. Those cycloadducts 14 and 15 which are predicted to undergo asynchronous reactions show differing degrees of carbon-carbon bond lengthening, reflecting the differing degrees of bond breaking at the calculated transition states for the rDA.
The early stages of the retro-Diels-Alder reaction are clearly apparent in the structures of the cycloadducts formed between furan or 5-trimethylsilylcyclopentadiene with maleic anhydride and N-methylmaleimide. The degree of lengthening of the C-C bonds that break in this reaction is clearly related to the known reactivity of these cycloadducts toward this reaction. In the structures of the cycloadducts 21 and 22 derived from 2-methoxyfuran, the early stages of an alternative fragmentation reaction are apparent, consistent with the reactivity of these compounds in solution.
Examination of selected cyclohexene derivatives which are fixed into the boat conformation reveals structural deviations from "normal" C-C bond distances consistent with the early stages of the retro Diels-Alder reaction.
Nucleoside analogues have long been recognized as prospects for the discovery of direct acting antivirals (DAAs) to treat hepatitis C virus because they have generally exhibited crossgenotype activity and a high barrier to resistance. C-Nucleosides have the potential for improved metabolism and pharmacokinetic properties over their N-nucleoside counterparts due to the presence of a strong carbon−carbon glycosidic bond and a non-natural heterocyclic base. Three 2′CMe-C-adenosine analogues and two 2′CMe-guanosine analogues were synthesized and evaluated for their anti-HCV efficacy. The nucleotide triphosphates of four of these analogues were found to inhibit the NS5B polymerase, and adenosine analogue 1 was discovered to have excellent pharmacokinetic properties demonstrating the potential of this drug class.
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