Development of Asymmetric Protonation Reactions for the Synthesis of Indoline Alkaloids

Nitrogen-containing heterocycles, such as indolines and pyrroloindolines, are prevalent in a variety of diverse natural products, many of which exhibit remarkable biological activities. These frameworks have inspired innovative research aimed at discovering novel methods for their stereoselective preparation.

We have developed an enantioselective synthesis of pyrroloindolines based on a formal (3 + 2) cycloaddition of indoles and 2-amidoacrylates. This reaction is promoted by (R)-BINOL•SnCl₄; this complex is a Lewis acid-assisted Brønsted acid that effects a highly face-selective catalyst-controlled protonation of an enolate. Mechanistic studies also determined that the initial product of this reaction is an indolinium ion, which upon aqueous workup undergoes cyclization to the pyrroloindoline.

Based on this result, we investigated alternative nucleophiles to trap the indolinium ion. First, addition of sodium borohydride to the optimized reaction conditions yields indoline-containing amino acid derivatives.

Next, carbon nucleophiles were explored. Indole substrates incorporating a tethered alkene were exposed to the conditions for the formal (3 + 2) cycloaddition, resulting in a conjugate addition/asymmetric protonation/Prins cyclization cascade. In this transformation, the indolinium ion is attacked by the olefin, and the resulting carbocation is quenched by a chloride ion. Zirconium tetrachloride was found to be the optimal Lewis acid. Stoichiometric proton and chloride sources were also found to be crucial for reactivity.

Prediction of Multi-Target Networks of Neuroprotective Compounds with Entropy Indices and Synthesis, Assay, and Theoretical Study of New Asymmetric 1,2-Rasagiline Carbamates

In a multi-target complex network, the links (L-ij) represent the interactions between the drug (d(i)) and the target (t(j)), characterized by different experimental measures (K-i, K-m, IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (c(j)). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%-90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally.

Asymmetric conservation benefits of circle hooks in multispecies billfish recreational fisheries: a synthesis of hook performance and analysis of blue marlin (Makaira nigricans) postrelease survival

We evaluated the conservation benefits of the use of circle hooks compared with standard J hooks in the recreational fishery for Atlantic istiophorid billfishes, noting hooking location and the presence of trauma (bleeding) for 123 blue marlin (Makaira nigricans), 272 white marlin (Kajikia albida), and 132 sailfish (Istiophorus platypterus) caught on natural baits rigged with one of the two hook types. In addition, we used pop-up satellite archival tags (PSATs) to follow the fate of 61 blue marlin caught on natural baits rigged with circle hooks or on a combination of artificial lure and natural bait rigged with J hooks. The frequencies of internal hooking locations and bleeding were significantly lower with circle hooks than with J hooks for each of the three species and were significantly reduced for blue marlin caught on J hooks than for white marlin and sailfish taken on the same hook type. Analysis of the data received from 59 PSATs (two tags released prematurely) indicated no mortalities among the 29 blue marlin caught on circle hooks and two mortalities among the 30 blue marlin caught on J hooks (6.7%). Collectively, the hook location and PSAT data revealed that blue marlin, like white marlin and sailfish, derive substantial conservation benefits from the use of circle hooks, and the negative impacts of J hooks are significantly reduced for blue marlin relative to the other two species.