Development and Scope of the Arene-Fused Domino Michael/Mannich Reaction: Application to the Total Syntheses of <i>Aspidosperma</i> Alkaloids (−)-Aspidospermidine, (−)-Tabersonine, and (−)-Vincadifformine

The development and application of the arene-fused domino Michael/Mannich route to the tetrahydrocarbazole (ABE) core of <i>Aspidosperma</i> alkaloids is described. The scope of this novel transformation was studied in terms of the nucleophilic component (i.e., <i>N</i>-sulfinyl metallodienamine) and the electrophilic component (i.e., Michael acceptor). The successful application of this methodology toward the concise total syntheses of classical indole alkaloids (−)-aspidospermidine, (−)-tabersonine, and (−)-vincadifformine in 10–11 steps, respectively, is also discussed

Domino Michael/Mannich/<i>N</i>‑Alkylation Route to the Tetrahydrocarbazole Framework of Aspidosperma Alkaloids: Concise Total Syntheses of (−)-Aspidospermidine, (−)-Tabersonine, and (−)-Vincadifformine

We report a novel, asymmetric domino Michael/Mannich/<i>N</i>-alkylation sequence for the rapid assembly of the tetrahydrocarbazole framework of <i>Aspidosperma</i> alkaloids. This method was utilized in the concise total syntheses of classical targets (−)-aspidospermidine, (−)-tabersonine, and (−)-vincadifformine in 10 or 11 steps. Additional key steps include ring-closing metathesis to prepare the D-ring and Bosch–Rubiralta spirocyclization to prepare the C-ring

Proposed communication pathways from A2058 to the A752-U2609 and ARM region: the telithromycin pathway (A), G2057 pathway (B), or A2059 pathway (C).

<p>Proposed communication pathways from A2058 to the A752-U2609 and ARM region: the telithromycin pathway (A), G2057 pathway (B), or A2059 pathway (C).</p

Impact of Ribosomal Modification on the Binding of the Antibiotic Telithromycin Using a Combined Grand Canonical Monte Carlo/Molecular Dynamics Simulation Approach

<div><p>Resistance to macrolide antibiotics is conferred by mutation of A2058 to G or methylation by Erm methyltransferases of the exocyclic N6 of A2058 (E. coli numbering) that forms the macrolide binding site in the 50S subunit of the ribosome. Ketolides such as telithromycin mitigate A2058G resistance yet remain susceptible to Erm-based resistance. Molecular details associated with macrolide resistance due to the A2058G mutation and methylation at N6 of A2058 by Erm methyltransferases were investigated using empirical force field-based simulations. To address the buried nature of the macrolide binding site, the number of waters within the pocket was allowed to fluctuate via the use of a Grand Canonical Monte Carlo (GCMC) methodology. The GCMC water insertion/deletion steps were alternated with Molecular Dynamics (MD) simulations to allow for relaxation of the entire system. From this GCMC/MD approach information on the interactions between telithromycin and the 50S ribosome was obtained. In the wild-type (WT) ribosome, the 2′-OH to A2058 N1 hydrogen bond samples short distances with a higher probability, while the effectiveness of telithromycin against the A2058G mutation is explained by a rearrangement of the hydrogen bonding pattern of the 2′-OH to 2058 that maintains the overall antibiotic-ribosome interactions. In both the WT and A2058G mutation there is significant flexibility in telithromycin's imidazole-pyridine side chain (ARM), indicating that entropic effects contribute to the binding affinity. Methylated ribosomes show lower sampling of short 2′-OH to 2058 distances and also demonstrate enhanced G2057-A2058 stacking leading to disrupted A752-U2609 Watson-Crick (WC) interactions as well as hydrogen bonding between telithromycin's ARM and U2609. This information will be of utility in the rational design of novel macrolide analogs with improved activity against methylated A2058 ribosomes.</p></div

The probability distributions for WT, A2058G mutant and methyl modifications of the telithromycin C2-methyl to C2610 C4′ (black), C4-methyl to C2611 C5 (red), and C4-methyl to A2058 C2 (green).

<p>Corresponding crystal structure values are shown as vertical lines using the same color scheme.</p

The number of conformations for WT, A2058G mutant and methyl modifications of (A) COM distances between the base atoms of 2057 and 2058 and (B) angles between planes comprised by 2057 and 2058 base atoms.

<p>The probability distributions for (C) WC G2057 N1 to C2611 N3 distances. The crystal structure values are shown as vertical black lines, while distributions from the GCMC/MD simulations are shown as WT (black), A2058G (red), MAD1 (green), MAD2 (blue), and DMAD (magenta).</p

2D representation of telithromycin and bases within the macrolide binding pocket showing the three biologically relevant telithromycin-ribosome interactions that are the subject of this study: 2′-OH to 2058/2059 hydrogen bonding, stacking between telithromycin's ARM and A752-U2609 WC base pair, and ionic interactions between telithromycin's 3′-protonated dimethylamine and G2505.

<p>Dotted lines represent hydrogen bonding. Hydroxyl groups of the ribose sugars are omitted for clarity.</p

The probability distributions for WT, A2058G mutant and methyl modifications of the (A) WC A752 N1 to U2609 N3 distances, (B) telithromycin imidazole to U2609 N3 distances, (C) distance between the centers of masses of A752-U2609 and telithromycin's imidazole-pyridine (ARM) moiety and (D) angle between the planes defined A752-U2609 and the imidazole-pyridine moieties.

<p>The crystal structure values are shown as a vertical black line, while the distributions from the GCMC/MD simulations are shown as WT (black), A2058G (red), MAD1 (green), MAD2 (blue), and DMAD (magenta).</p

The probability distributions for WT, A2058G mutant and methyl modifications of telithromycin intramolecular distances (A) C3-O to C16-O, (B) C16-O to C6-O, (C) C3-O to C6-O, and (D) C3′-N and C26 as shown in the inset figure.

<p> The crystal structure values are shown as vertical black lines, while distributions are from the GCMC/MD simulations: WT (black), A2058G (red), MAD1 (green), MAD2 (blue), and DMAD (magenta). The probability distributions from telithromycin gas phase simulations without the ribosome are shown in orange.</p

The probability distributions of distances between telithromycin's 3′-protonated dimethylamine and G2505 P for WT, A2058G mutant and methyl modifications.

<p>The crystal structure distance is shown as a vertical black line, while the distributions are from the GCMC/MD simulations: WT (black), A2058G (red), MAD1 (green), MAD2 (blue), and DMAD (magenta).</p