Base-Catalyzed Phenol-Mannich Condensation of Preformed Cesium Iminodiacetate. The Direct Synthesis of Calcein Blue AM and Related Acyloxymethyl Esters.

A rapid and highly practical one-flask procedure for the positionally selective preparation of (acyloxy)methyl N-(2-hydroxybenzyl)iminodiacetate and related diesters from iminodiacetic acid and phenols is described. The key to this multicomponent phenol-Mannich condensation resides in the use of cesium iminodiacetate as the reaction partner. This protocol has been applied in an unusually direct synthesis of the intracellular fluorescent dye Calcein blue AM, for which scant experimental and spectroscopic data are presently available.

Copper(I)-Catalyzed Cross-Coupling of 1-Bromoalkynes with N-Heterocyclic Organozinc Reagents.

Nitrogen-containing heterocycles represent the majority of FDA-approved small-molecule pharmaceuticals. Herein, we describe a synthetic method to produce saturated N-heterocyclic drug scaffolds with an internal alkyne for elaboration. The treatment of N,N-dimethylhydrazinoalkenes with Et2Zn, followed by a Cu(I)-catalyzed cross-coupling with 1-bromoalkynes, results in piperidines and pyrrolidines with a good yield. Five examples are reported and a proposed mechanism for the Cu(I)-catalyzed cross-coupling is presented.

1,2-Disubstituted Alkenes as Migratory Insertion Participants in Zn(II)-Promoted Metalloamination/Cyclization of N,N-Dimethylhydrazinoalkenes.

Diethylzinc-mediated metalloamination/cyclization of unsaturated N,N-dimethylhydrazines has been extended to the use of 1,2-disubstituted alkenes as N-Zn migratory insertion acceptors. Representative 2-arylethenes and vinylcyclopropanes readily serve as reaction participants in metalloamination/cyclization-allylation cascades.

Divergent Stereocontrolled Synthesis of the Enantiopure Tetracyclic Cores of Asparagamine A and Stemofoline via an Intramolecular 2-Propylidine-1,3-(bis)silane Bicyclization.

A concise and highly diastereoselective synthesis of the polyfused tetracyclic cores of the Stemona alkaloids asparagamine A and stemofoline that relies on a 2-propylidine-1,3-(bis)silane bicyclization onto a enantiodefined pyrrolidine 2,5-di(cation) equivalent derived from l-malic acid is reported. A crucial feature of this divergent synthetic approach involves the solvolysis of a transient and highly labile tertiary-propargylic hydroxylactam trifluoroacetate in the strongly ionizing medium 5 M LiClO4/Et2O. The acyliminium ion generated in this manner undergoes stereospecific interception by the aforementioned (bis)silane nucleophile.

Intramolecular metalloamination of N,N-dimethylhydrazinoalkenes: a versatile method to access functionalized piperidines and pyrrolidines.

Highly diastereoselective metalloamination/cyclization reactions of zinc(II) hydrazides obtained through reaction of diethylzinc with N,N-dimethylhydrazinoalkenes are described. The resulting organozinc intermediates undergo facile allylation and acylation, in situ, to provide the corresponding functionalized piperidines and pyrrolidines.

Efficient Reductions of Dimethylhydrazones using Preformed Primary Amine Boranes.

A convenient method for the reduction of N,N-dimethylhydrazones using amine borane complexes generated in situ is described. It was found that primary amine borane complexes performed exceedingly well at reducing N,N-dimethylhydrazones in as little as 1.1 equivalents, furnishing the corresponding air-sensitive hydrazine products in excellent yields.

Novel Nitro-Heteroaromatic Antimicrobial Agents for the Control and Eradication of Biofilm-Forming Bacteria.

The synthesis and biological activity of several novel nitrothiazole, nitrobenzothiazole, and nitrofuran containing antimicrobial agents for the eradication of biofilm-forming Gram-negative and Gram-positive pathogens is described. Nitazoxanide (NTZ), nitrofurantoin, and furazolidone are commercial antimicrobials which were used as models to show how structural modification improved activity toward planktonic bacteria via minimum inhibitory concentration (MIC) assays and biofilms via minimum biofilm eradication concentration (MBEC) assays. Structure-activity relationship (SAR) studies illustrate the ways in which improvements have been made to the aforementioned antimicrobial agents. It is of particular interest in this regard that the introduction of a chloro substituent at the 5-position of NTZ (analog 1b) resulted in marked activity enhancement, as did the replacement of the 2-acetoxy substituent in the latter compound with a basic amine group (analog 7b). It is also of importance that analog 4a, which is a simple methacrylamide, displayed noteworthy activity against S. epidermidis biofilms. These lead compounds identified to have high activity towards biofilms provide promise as starting points in future pro-drug studies.

Novel phenolic antimicrobials enhanced activity of iminodiacetate prodrugs against biofilm and planktonic bacteria.

Prodrugs are pharmacologically attenuated derivatives of drugs that undergo bioconversion into the active compound once reaching the targeted site, thereby maximizing their efficiency. This strategy has been implemented in pharmaceuticals to overcome obstacles related to absorption, distribution, and metabolism, as well as with intracellular dyes to ensure concentration within cells. In this study, we provide the first examples of a prodrug strategy that can be applied to simple phenolic antimicrobials to increase their potency against mature biofilms. The addition of (acetoxy)methyl iminodiacetate groups increases the otherwise modest potency of simple phenols. Biofilm-forming bacteria exhibit a heightened tolerance toward antimicrobial agents, thereby accentuating the need for new antibiotics as well as those, which incorporate novel delivery strategies to enhance activity toward biofilms.

Sulfenate Esters of Simple Phenols Exhibit Enhanced Activity against Biofilms.

The recalcitrance exhibited by microbial biofilms to conventional disinfectants has motivated the development of new chemical strategies to control and eradicate biofilms. The activities of several small phenolic compounds and their trichloromethylsulfenyl ester derivatives were evaluated against planktonic cells and mature biofilms of Staphylococcus epidermidis and Pseudomonas aeruginosa. Some of the phenolic parent compounds are well-studied constituents of plant essential oils, for example, eugenol, menthol, carvacrol, and thymol. The potency of sulfenate ester derivatives was markedly and consistently increased toward both planktonic cells and biofilms. The mean fold difference between the parent and derivative minimum inhibitory concentration against planktonic cells was 44 for S. epidermidis and 16 for P. aeruginosa. The mean fold difference between the parent and derivative biofilm eradication concentration for 22 tested compounds against both S. epidermidis and P. aeruginosa was 3. This work demonstrates the possibilities of a new class of biofilm-targeting disinfectants deploying a sulfenate ester functional group to increase the antimicrobial potency toward microorganisms in biofilms.

Antimicrobial Activity of Naturally Occurring Phenols and Derivatives Against Biofilm and Planktonic Bacteria.

Biofilm-forming bacteria present formidable challenges across diverse settings, and there is a need for new antimicrobial agents that are both environmentally acceptable and relatively potent against microorganisms in the biofilm state. The antimicrobial activity of three naturally occurring, low molecular weight, phenols, and their derivatives were evaluated against planktonic and biofilm Staphylococcus epidermidis and Pseudomonas aeruginosa. The structure activity relationships of eugenol, thymol, carvacrol, and their corresponding 2- and 4-allyl, 2-methallyl, and 2- and 4-n-propyl derivatives were evaluated. Allyl derivatives showed a consistent increased potency with both killing and inhibiting planktonic cells but they exhibited a decrease in potency against biofilms. This result underscores the importance of using biofilm assays to develop structure-activity relationships when the end target is biofilm.

Synergism among volatile organic compounds resulting in increased antibiosis in Oidium sp.

Oidium sp. has been recovered as an endophyte in Terminalia catappa (tropical chestnut) in Costa Rica. The volatile organic compounds (VOCs) of this organism uniquely and primarily consist of esters of propanoic acid, 2-methyl-, butanoic acid, 2-methyl-, and butanoic acid, 3-methyl-. The VOCs of Oidium sp. are slightly inhibitory to many plant pathogenic fungi. Previous work on the VOCs of Muscodor albus demonstrated that besides esters of small organic acids, a small organic acid and a naphthalene derivative were needed to obtain maximum antibiotic activity. Thus, the addition of exogenous volatile compounds such as isobutyric acid and naphthalene, 1,1'-oxybis caused a dramatic synergistic increase in the antibiotic activity of the VOCs of Oidium sp. against Pythium ultimum. In fact, at elevated concentrations, there was not only 100% inhibition of P. ultimum but killing as well. In addition, a coculture of Muscodor vitigenus (making only naphthalene) and Oidium sp. plus isobutyric acid produced an additive antibiosis effect against P. ultimum. The biological implications of multiple volatile compounds acting to bring about antibiosis in nature are discussed.

Diethylzinc-Mediated Metalloamination-Alkylation of N, N-Dimethylhydrazinoalkenes. Catalysis of C-Zn Alkylation Using Simple Cu(I) Salts.

Metalloamination-alkylation of representative N,N-dimethyl-hydrazinoalkenes has been shown to be effectively catalyzed by CuBr-SMe2, CuCN, and Cul. The current method obviates the use of stoichiometric CuCN(LiCl)2 as a promoter for the electrophilic functionalization event.

Chelating diamide based rate enhancement of intramolecular alkene hydroaminations catalyzed by a neutral Sc(III) complex.

[reaction: see text] Neutral scandium amido complexes are viable catalysts for intramolecular alkene hydroamination. Catalytic activity is strongly coupled to the electronic character of the Sc(III) ligand environment with chelating diamide coordination providing a precatalyst possessing substantially improved activity and superb distereoselectivity in the synthesis of trans-2,5-disubstituted pyrrolidines.

Enantioselective intramolecular alkene hydroaminations catalyzed by yttrium complexes of axially chiral bis(thiolate) ligands.

[structure: see text] A yttrium(III) complex derived from proligand 7c has been shown to be a superior catalyst for enantioselective intramolecular alkene hydroaminations that provide cyclic amines with ee's ranging from 69% to 89%.

Intramolecular alkene hydroaminations catalyzed by a bis(thiophosphinic amidate) Zr(IV) complex.

A neutral Zr(IV) complex has been shown to be an effective precatalyst for intramolecular alkene hydroaminations that provide cyclic amines in good to excellent yields.

Cyclization of 1-bromo-2,7- and 1-bromo-2,8-enynes mediated by indium.

[reaction: see text] The cyclization of 1-bromo-2,7- and 1-bromo-2,8-enynes mediated by indium in DMF produced five- and six-membered cyclic compounds. Although KI was a necessary additive in the cyclization of terminal 1-bromo-2,7-enynes to give the desired products at 25 degrees C, reactions of terminal 1-bromo-2,8-enynes and internal 1-bromo-2,7-enynes with indium proceeded at 100 degrees C in DMF without KI. After cyclizations, subsequent cross-coupling reaction and iodolysis increase the usefulness of this reaction.

Phevalin (aureusimine B) production by Staphylococcus aureus biofilm and impacts on human keratinocyte gene expression.

Staphylococcus aureus biofilms are associated with chronic skin infections and are orders of magnitude more resistant to antimicrobials and host responses. S. aureus contains conserved nonribosomal peptide synthetases that produce the cyclic dipeptides tyrvalin and phevalin (aureusimine A and B, respectively). The biological function of these compounds has been speculated to be involved in virulence factor gene expression in S. aureus, protease inhibition in eukaryotic cells, and interspecies bacterial communication. However, the exact biological role of these compounds is unknown. Here, we report that S. aureus biofilms produce greater amounts of phevalin than their planktonic counterparts. Phevalin had no obvious impact on the extracellular metabolome of S. aureus as measured by high-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance. When administered to human keratinocytes, phevalin had a modest effect on gene expression. However, conditioned medium from S. aureus spiked with phevalin amplified differences in keratinocyte gene expression compared to conditioned medium alone. Phevalin may be exploited as potential biomarker and/or therapeutic target for chronic, S. aureus biofilm-based infections.

On the stereoselective bicyclization of aminodienes catalyzed by chelating diamide complexes of the group 3 metals. A direct comparison of Sc(III) and Y(III) bis(amide)s with an application to the synthesis of alkaloid 195F.

Highly diastereoselective bicyclizations of aminodienes catalyzed by chelating diamide complexes of Sc(III) and Y(III) that lead to pyrrolizidines and indolizidines are described. This bis(annulation) procedure has been utilized in a concise synthesis of the pyrrolizidine alkaloid 195F.

A new and general one-pot synthesis of propargyl alcohols from esters.

Intermediates easily prepared by partial reduction of various esters with LDBBA as a reducing agent smoothly react with lithium acetylides to give propargyl alcohols, without isolation of partial reduction intermediates, in good yields (73-83%).

A stereocontrolled synthesis of (±)-xenovenine via a scandium(III)-catalyzed internal aminodiene bicyclization terminated by a 2-(5-ethyl-2-thienyl)ethenyl group.

A highly diastereoselective binary hydroamination of a 5-amino-1,8-diene containing a 2-(5-ethyl-2-thienyl)ethenyl terminator has been utilized in an efficient synthesis of (±)-xenovenine (1). A pronounced rate enhancement was observed for cyclization onto the 2-(heteroaromatic)ethenyl group in comparison to a simple 1,2-disubstituted alkene.