No abstract

Aquatolide has been reisolated from its natural source, and its structure has been revised on the basis of quantum-chemical NMR calculations, extensive experimental NMR analysis, and crystallography.

It is said that carbon, the most abundant element in organic matter, supplies life’s quantity, whereas nitrogen supplies its quality. It is therefore unsurprising that many natural products that contain basic nitrogens (alkaloids) are coveted for their benefit to human health. However, nitrogen is known to mire many chemical syntheses because of its basicity and susceptibility to oxidation. This challenge may be heightened by the presence of more than one nitrogen atom in a targeted complex alkaloid, but can be met by the selective introduction and removal of functional groups that mitigate basicity, as highlighted herein with the first chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C through 13C feeding studies, supports the existence of a common bicyclo[2.2.2]diazaoctane containing biogenetic precursor to these compounds as has been proposed previously.

N-(5-(2-(5-Chloro-2-methoxyphenylamino)thiazol-4-yl)-4-methylthiazol-2-yl)pivalamide 1 (compound 15Jf) was found previously to correct defective cellular processing of the cystic fibrosis protein ΔF508-CFTR. Eight C4′-C5 C,C-bond-controlling bithiazole analogs of 1 were designed, synthesized, and evaluated to establish that constraining rotation about the bithiazole-tethering has a significant effect on corrector activity. For example, constraining the C4′-C5 bithiazole tether in the s-cis conformation [N-(2-(5-chloro-2-methoxyphenyl-amino)-7,8-dihydro-6H-cyclohepta[1,2-d:3,4-d′]bithiazole-2′-yl)pivalamide; 29] results in improved corrector activity. Heteroatom placement in the bithaizole core is also critical as evidenced by the decisive loss of corrector activity with s-cis constrained N-(2-(5-chloro-2-methoxyphenylamino)-5,6-dihydro-4H-cyclohepta[1,2-d:3,4-d′]bithiazole-2′-yl)pivalamide 33. In addition, computational models were utilized to examine the conformational preferences for select model systems. Following our analysis, the “s-cis locked” cycloheptathiazolothiazole 29 was found to be the most potent bithiazole corrector, with an IC50 of ~450 nM.

In this paper, we describe theoretical studies, using gas-phase quantum chemical calculations, on carbocationic rearrangement pathways leading to the sesquiterpenes sativene, cyclosativene, alpha-ylangene, and beta-ylangene. For all four sesquiterpene natural products, viable pathways are presented, and these are compared both to mechanistic proposals found in the literature, and in certain cases to alternative stereochemical and rearrangement possibilities, thus providing a basis for comparison to experimental results. We find that these four sesquiterpenes likely arise from a common bicyclic intermediate and, furthermore, that the computed pathways are mostly in agreement with previous mechanistic proposals, although the few differences that we have uncovered are significant. Additionally, the potential energy profiles of the pathways are found to be very flat, supporting the notion that following the initial ionization of farnesyl diphosphate, minimal enzymatic intervention may be required for the generation of such sesquiterpenes.

We report the total synthesis of (–)-Nmethylwelwitindolinone C isonitrile, in addition to the total syntheses of the 3-hydroxylated welwitindolinones. Our routes to these elusive natural products feature the strategic use of a deuterium kinetic isotope effect to improve the efficiency of a late-stage nitrene insertion reaction. We also provide a computational prediction for the stereochemical configuration at C3 of the hydroxylated welwitindolinones, which was confirmed by experimental studies.

Mechanistic proposals for the carbocation cas cade reaction leading to the tricyclic sesquiterpene pentalenene are assessed in light of the results of isotopically sensitive branching experiments with the H309A mutant of pentalenene synthase. These experimental results support a mechanism for pentalenene formation involving a 7-protoilludyl cation intermediate that was first predicted using quantum chemical calculations.

1H and 13C NMR computed chemical shifts are determined for eight diastereomers of the originally proposed structure of nobilisitine A, which has recently been shown to be incorrect. On the basis of comparison of the computed chemical shifts with those reported experimentally, we predict that the true structure of nobilisitine A is likely the diastereomer shown here or its enantiomer.