Synthetic methods that enable simultaneous control over multiple stereogenic centers are desirable for the efficient preparation of pharmaceutical compounds. Herein, we report the discovery and development of a catalyst-mediated asymmetric Michael addition/crystallization–induced diastereomer transformation of broad scope. The sequence controls three stereogenic centers, two of which are stereochemically labile. The configurational instability of 1,3-dicarbonyls and nitroalkanes, typically considered a liability in stereoselective synthesis, is productively leveraged by merging enantioselective Brønsted base organocatalysis and thermodynamic stereocontrol using a single convergent crystallization. The synthesis of useful γ-nitro β-keto amides containing three contiguous stereogenic centers is thus achieved from Michael acceptors containing two prochiral centers.

Progress toward a convergent approach for the enantioselective synthesis of the Veratrum alkaloid jervine is presented. The two requisite fragments were stereoselectively and efficiently fashioned from economical and readily available reagents. Key reactions include (a) a highly diastereoselective Ireland−Claisen rearrangement to establish the necessary cis-relationship between the amine and methyl group on the tetrahydrofuran E-ring; (b) a diastereoselective selenoetherification reaction that enabled the assembly of the D/E oxaspiro[4.5]­decene in the needed configuration; and (c) an enzymatic desymmetrization of an abundant achiral diol en route to a key four-carbon building block as a practical alternative to a protected Roche ester reduction.

Tetrasubstituted stereogenic carbon centers bearing a nitrogen substituent represent important motifs in medicinal chemistry and natural products; therefore, the development of efficient methods for the stereoselective synthesis of this class of compounds continues to be an important problem. This article describes stereoconvergent Henry reactions of γ,γ-disubstituted nitroalkanes to deliver highly functionalized building blocks containing up to five contiguous stereogenic centers including a fully substituted [N]-asymmetric center. Henry reactions of higher order nitroalkanes are often characterized by their reversibility and minimal accompanying thermodynamic stereocontrol. In contrast, mechanistic studies for the present case suggest a scenario in which reversibility is productively leveraged through crystallizationbased stereocontrol, thereby enabling the efficient sequential π-additions of readily accessible starting materials to assemble complex acyclic stereoarrays.

Additions of carbon nucleophiles to racemic α-stereogenic β-oxo acid derivatives that deliver enantiomerically enriched tertiary alcohols are valuable, but uncommon. This article describes stereodivergent Cu-catalyzed borylative cyclizations of racemic β-oxo acid derivatives bearing tethered pro-nucleophilic olefins to deliver highly functionalized cyclopentanols containing four contiguous stereogenic centers. The reported protocol is applicable to a range of β-oxo acid derivatives, and the diastereomeric products are readily isolable by typical chromatographic techniques. α-Stereogenic-β-keto esters are typically thought to have extreme or spontaneous configurational fragility, but mechanistic studies for this system reveal an unusual scenario wherein productive catalysis occurs on the same time scale as background substrate racemization and completely outcompetes on-cycle epimerization, even under the basic conditions of the reaction.

BackgroundMulti-drug resistant superbugs are a serious health threat due to limited treatment options and high mortality rates. Certain superbug strains are now resistant to as many as 36 representative FDA-approved antibiotics, including Colistin and Carbapenem antibiotics, widely considered as the last line of defense against untreatable infections. Nitric oxide (NO) is a diatomic free radical employed by the immune system to eradicate bacteria via oxidative and nitrosative stress. To facilitate storage and controlled release of NO, we have developed NO donor-modified biopolymers based on chitosan, a linear polysaccharide composed of randomly distributed β--linked D-glucosamine and N-acetyl-D-glucosamine. Herein, we report the broad spectrum antibacterial action of low molecular weight (5 kDa) NO-releasing chitosan against Gram-positive and Gram-negative multi-drug-resistant bacterial species, including Klebsiella pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa.MethodsMIC assays were performed using CLSI guidelines in a 96-well plate format. All assays were carried out in triplicate using a two-fold dilution range. The bacterial suspension was then diluted in assay medium to a target concentration of approximately 5 × 105 CFU/mL, after which it was added to all test and growth control wells, and allowed to incubate. Test wells were scored for the lowest NO concentration released from the chitosan to inhibit visual growth of the pathogen. After MIC determination, wells demonstrating inhibition were plated, incubated and resulting colonies counted to determine survival concentration. The lowest concentration of NO to inhibit ≥99.9 % of a given test organism was reported as the MBC. Of note, chitosan alone showed no antibacterial action.ResultsMIC and MBC assays for NO-releasing chitosan against six multi-drug resistant strains are provided below.ConclusionThe properties of the NO-releasing chitosan, including water solubility, make it an excellent drug candidate for treating respiratory infections. Such development is currently underway.Disclosures All authors: No reported disclosures.