Effects of Structural Variations on Antibacterial Properties for Conjugated Diynes Generated through Glaser Hay Couplings.

Antibiotic resistance is a growing problem facing global societies today. Many new antibiotics are derivatized versions of already existing antibiotics, which allows for antibiotic resistance to arise. To combat this issue, new antibiotics with different core structures need to be elucidated. Asymmetrical polyacetylenes have been isolated from natural products and they have previously been demonstrated to exhibit antimicrobial and antibacterial activity; however, their synthetic preparation has not made them easily amenable to rapid derivatization for SAR studies. Using a combination of solution and solid-supported chemistries, an array of diynes inspired by a known natural product were prepared and assessed for antibacterial activity. Ultimately, several compounds were identified with improved activity in bacterial viability assays. Moreover, some compounds were discovered that displayed a degree of specificity for E. coli over P. fluorescens and vice versa. These new compounds show promise, and further investigation is needed to pinpoint the specific structural components that elicit biological activity.

Mild, Modular, and Convergent Synthesis of Helical Naphtho[2,1-c]chromenes via a Multistep Cyclization/Aromatization Cascade Sequence.

Tetracyclic 6H-naphtho[2,1-c]chromenes are expeditiously synthesized through a BF3·OEt2-mediated, three-step cascade reaction, creating new central pyran and aromatic rings. The cascade involves the addition of phenol-derived alkynyl substrates to BF3-activated aldehydes followed by alkyne-Prins cyclization, Friedel-Crafts reaction, and final elimination. Aliphatic and electron-deficient aromatic aldehydes afford the products in 50-74% isolated yields, but benzaldehyde and tolualdehyde resulted in lower yields. X-ray analysis of a p-bromophenyl derivative (5aA) shows the two aromatic moieties are twisted by 28° to create a helical backbone.

Electronic effects on a one-pot aromatization cascade involving alkynyl-Prins cyclization, Friedel-Crafts alkylation and dehydration to tricyclic benzo[f]isochromenes.

A three-step domino reaction between 1-aryl-3-hexyne-2,6-diol derivatives and aldehydes is used to construct tricyclic 1,4-dihydro-2H-benzo[f]isochromenes. The cascade is initiated by BF3·OEt2 and involves alkynyl-Prins cyclization, Friedel-Crafts alkenylation, and dehydration/aromatization to create a new, central aromatic ring and eliminate 2 equiv. of water. Electron-donating substituents on the aryl ring of the 1-aryl-3-hexyne-2,6-diols significantly increase overall yields as do electron-rich aldehyde reaction partners. For 2,4-disubstituted 2H-benzo[f]isochromene products, diastereoselectivities in the alkynyl-Prins reaction are ∼1.4 : 1 in favor of the cis-diastereomer. The stereochemistry of one cis-product was verified by X-ray crystallographic analysis and a second structure was also verified by X-ray analysis.

Electrophilic Cyclization of Phenylalkynediols to Naphthyl(aryl)iodonium Triflates with Chelating Hydroxyls: Preparation and X-ray Analyses.

Alkynediols containing one propargylic alcohol as well as a second alcohol, which is propargylic or homopropargylic, react with PhI+CN-OTf (Stang's reagent) or 3,5-(CF3)2C6H3I+CN-OTf to afford naphthyl(aryl)iodonium triflates. The reaction occurs at room temperature over the course of 6-12 h and provides 36-82% yields of microcrystalline solids. Slow diffusion of Et2O into CH3CN solutions of the salts afforded X-ray quality crystals of five compounds with hydroxyl groups forming five- and six-membered chelation complexes with the iodine atom. Crystallizations from larger scale reactions (≥∼0.25 mmol) were generally facile from CH2Cl2.

Atom economical, one-pot, three-reaction cascade to novel tricyclic 2,4-dihydro-1H-benzo[f]isochromenes.

Reaction of 6-methyl-1-phenylhept-3-yne-2,6-diol with various aldehydes under Lewis acid conditions provides an atom economical, two-component cascade reaction sequence to novel 2,4-dihydro-1H-benzo[f]isochromene compounds. Aliphatic aldehydes as well as electron-deficient and -rich aromatic aldehydes can be used.

Bi(OTf)3-, TfOH-, and TMSOTf-mediated, one-pot epoxide rearrangement, addition, and intramolecular silyl-modified Sakurai (ISMS) cascade toward dihydropyrans: comparison of catalysts and role of Bi(OTf)3.

Catalytic quantities of bismuth(III) triflate efficiently initiate the rearrangement of epoxides to aldehydes, which subsequently react with (Z)-δ-hydroxyalkenylsilanes to afford 2,6-disubstituted 3,6-dihydro-2H-pyrans. Isolated yields of desired products using Bi(OTf)(3) were compared with yields obtained when the reactions were run with TfOH and TMSOTf in the presence and absence of several additives. These studies, as well as NMR spectroscopic analyses, indicate an initial Lewis acid/base interaction between Bi(OTf)(3) and substrates providing TfOH in situ.

Synthesis of 2,6-disubstituted dihydropyrans via an efficient BiBr(3)-initiated three component, one-pot cascade.

The rapid synthesis of cis-2,6-disubstituted dihydropyrans is achieved in a three-component, one-pot cascade reaction. BiBr(3)-ediated addition of ketene silyl acetals or silyl enol ethers to beta,gamma-unsaturated cis-4-trimethylsilyl-3-butenal provides a Mukaiyama aldol adduct containing a vinylsilane moiety tethered to a silyl ether. Addition of a second aldehyde initiates a domino sequence involving intermolecular addition followed by an intramolecular silyl-modified Sakurai (ISMS) reaction. Isolated yields of this one-pot reaction vary from 44 to 80% and all compounds were isolated as the cis-diastereomers (10 examples).

BiBr3-initiated tandem addition/silyl-Prins reactions to 2,6-disubstituted dihydropyrans.

A tandem addition/silyl-Prins reaction efficiently affords cis-2,6-disubstituted dihydropyrans (DHPs) using 5 mol % of BiBr3 in CH2Cl2. The reaction occurs between delta-triethylsilyloxyvinyltrimethylsilanes and a variety of aldehydes to give good to excellent isolated yields of DHPs. The diastereoselectivities in the crude products are significantly affected by aldehyde substitution with electron-rich aldehydes, providing 2-3:1 (cis:trans) and neutral (or electron-poor) aldehydes affording dr > or = 19:1 (cis:trans).

Stereoselective construction of cyclic ethers using a tandem two-component etherification: elucidation of the role of bismuth tribromide.

The stereodivergent construction of cyclic ethers remains an important area of synthetic interest, particularly given the ubiquity of C-glycoside derivatives in natural and unnatural pharmacologically important agents. This work describes a series of intramolecular etherification reactions of delta-trialkylsilyloxy aldehydes and ketones using catalytic bismuth tribromide and various trialkylsilyl nucleophiles for the construction of cis- and trans-2,6-di- and trisubstituted tetrahydropyrans. Furthermore, this study provides compelling evidence for the fact that the catalysis may be attributed to the hydrogen bromide and bismuth oxybromide derived from the hydrolysis of bismuth tribromide. The synthetic utility of this protocol is highlighted in the ability to construct adjacent tertiary ethers in a highly stereoselective manner and the development of a sequential two-component cross-coupling followed by reductive etherification process for the expeditious synthesis of nonadjacent tetrahydropyran rings.

Structural and electronic characteristics of thienyl(aryl)iodonium triflates.

A general strategy toward the synthesis of aryliodonium triflate salts has been exploited to afford derivatives that incorporate thiophene and bithiophene components. Both mono- and bis(iodonium) salts have been realized, and a series of bithienyl(aryl)iodonium triflates with increasingly electron-withdrawing substituents on the aryl moiety have been synthesized. X-ray crystallographic analysis of four derivatives (4a, 4b, 6b, and 8c) demonstrates that the solid-state organization of these salts incorporates extensive networks of secondary bonding interactions between the cationic iodonium centers and the triflate counterions. UV-vis spectroscopic analysis shows that the electronic interactions between pendent aryl and heteroaryl groups across the iodonium center can be dictated by substitution. Furthermore, the energy of the HOMO-LUMO gap decreases substantially in weakly or noncoordinating solvents.

(Z)-2-Methylbuten-1-yl(aryl)iodonium trifluoromethanesulfonates containing electron-withdrawing groups on the aryl moiety.

The crystal structures of [(Z)-2-methylbut-1-en-1-yl][4-(trifluoromethyl)phenyl]iodonium trifluoromethanesulfonate, C(12)H(13)F(3)I(+).CF(3)O(3)S(-), (I), (3,5-dichlorophenyl)[(Z)-2-methylbut-1-en-1-yl]iodonium trifluoromethanesulfonate, C(11)H(12)Cl(2)I(+).CF(3)O(3)S(-), (II), and bis[[3,5-bis(trifluoromethyl)phenyl][(Z)-2-methylbut-1-en-1-yl]iodonium] bis(trifluoromethanesulfonate) dichloromethane solvate, 2C(13)H(12)F(6)I(+).2CF(3)O(3)S(-).CH(2)Cl(2), (III), are described. Neither simple acyclic beta,beta-dialkyl-substituted alkenyl(aryl)idonium salts nor a series containing electron-deficient aryl rings have been described prior to this work. Compounds (I)-(III) were found to have distorted square-planar geometries, with each I atom interacting with two trifluoromethanesulfonate counter-ions.