Maltol- and Allomaltol-Derived Oxidopyrylium Ylides: Methyl Substitution Pattern Kinetically Influences [5 + 3] Dimerization versus [5 + 2] Cycloaddition Reactions.

Oxidopyrylium ylides are useful intermediates in synthetic organic chemistry because of their capability of forming structurally complex cycloadducts. They can also self-dimerize via [5 + 3] cycloaddition, which is an oft-reported side reaction that can negatively impact [5 + 2] cycloadduct yields and efficiency. In select instances, these dimers can be synthesized and used as the source of oxidopyrylium ylide, although the generality of this process remains unclear. Thus, how the substitution pattern governs both dimerization and cycloaddition reactions is of fundamental interest to probe factors to regulate them. The following manuscript details our findings that maltol-derived oxidopyrylium ylides (i.e., with ortho methyl substitution relative to oxide) can be trapped prior to dimerization more efficiently than the regioisomeric allomaltol-derived ylide (i.e., with a para methyl substitution relative to oxide). Density functional theory studies provide evidence in support of a sterically (kinetically) controlled mechanism, whereby gauche interactions between appendages of the approaching maltol-derived ylides are privileged by higher barriers for dimerization and thus are readily intercepted by dipolarophiles via [5 + 2] cycloadditions.

Hydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activity.

Hepatitis B virus (HBV) remains a major human pathogen despite the development of both antiviral drugs and a vaccine, in part because the current therapies do not suppress HBV replication far enough to eradicate the virus. Here, we screened 51 troponoid compounds for their ability to suppress HBV RNaseH activity and HBV replication based on the activities of α-hydroxytropolones against HIV RNaseH, with the goal of determining whether the tropolone pharmacophore may be a promising scaffold for anti-HBV drug development. Thirteen compounds inhibited HBV RNaseH, with the best 50% inhibitory concentration (IC50) being 2.3 µM. Similar inhibition patterns were observed against HBV genotype D and C RNaseHs, implying limited genotype specificity. Six of 10 compounds tested against HBV replication in culture suppressed replication via blocking of viral RNaseH activity, with the best 50% effective concentration (EC50) being 0.34 µM. Eighteen compounds inhibited recombinant human RNaseH1, and moderate cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC50]=25 to 79 µM). Therapeutic indexes ranged from 3.8 to 94. Efficient inhibition required an intact α-hydroxytropolone moiety plus one or more short appendages on the tropolone ring, but a wide variety of constituents were permissible. These data indicate that troponoids and specifically α-hydroxytropolones are promising lead candidates for development as anti-HBV drugs, providing that toxicity can be minimized. Potential anti-RNaseH drugs are envisioned to be employed in combination with the existing nucleos(t)ide analogs to suppress HBV replication far enough to block genomic maintenance, with the goal of eradicating infection.