Breaking paracyclophane: the unexpected formation of non-symmetric disubstituted nitro[2.2]metaparacyclophanes.

Substituted [2.2]metaparacyclophanes are amongst the least studied of the simple cyclophanes. This is undoubtedly the result of the lengthy syntheses of these compounds. We report the simple synthesis of a rare example of a non-symmetric [2.2]metaparacyclophane. Treatment of [2.2]paracyclophane under standard nitration conditions gives a mixture of 4-nitro[2.2]paracyclophane, 4-hydroxy-5-nitro[2.2]metaparacyclophane and a cyclohexadienone cyclophane.

Synthesis and Basicity Studies of Quinolino[7,8-h]quinoline Derivatives.

Quinolino[7,8-h]quinoline is a superbasic compound, with a pKaH in acetonitrile greater than that of 1,8-bis(dimethylaminonaphthalene) (DMAN), although its synthesis and the synthesis of its derivatives can be problematic. The use of halogen derivatives 4,9-dichloroquinolino[7,8-h]quinoline (16) and 4,9-dibromoquinolino[7,8-h]quinoline (17) as precursors has granted the formation of a range of substituted quinolinoquinolines. The basicity and other properties of quinolinoquinolines can be modified by the inclusion of suitable functionalities. The experimentally obtained pKaH values of quinolino[7,8-h]quinoline derivatives show that N4,N4,N9,N9-tetraethylquinolino[7,8-h]quinoline-4,9-diamine (26) is more superbasic than quinolino[7,8-h]quinoline. Computationally derived pKaH values of quinolinoquinolines functionalized with dimethylamino (NMe2), 1,1,3,3-tetramethylguanidino (N═C(NMe2)2) or N,N,N',N',N″,N″-hexamethylphosphorimidic triamido (N═P(NMe2)3) groups are significantly greater than those of quinolino[7,8-h]quinoline. Overall, electron-donating functionalities are observed to increase the basicity of the quinolinoquinoline moiety, while the substitution of electron-withdrawing groups lowers the basicity.

The synthesis of planar chiral pseudo-gem aminophosphine pre-ligands based on [2.2]paracyclophane.

The synthesis of three planar chiral pseudo-gem disubstituted [2.2]paracyclophane-derived P,N-pre-ligands is reported along with preliminary results of their activity in the amination of aryl bromides and chlorides. The pseudo-gem aminophosphines were capable of mediating the coupling reaction at a loading of 1 mol%.

The synthesis of substituted amino[2.2]paracyclophanes.

Two methodologies for the formation of substituted amino[2.2]paracyclophane derivatives were developed. The first involves the direct amination of bromo[2.2]paracyclophanes with sodium azide. This permits the synthesis of simple mono- and disubstituted derivatives but fails to give sterically congested pseudo-gem derivatives. A 'one-pot' oxidation-Lossen rearrangement of [2.2]paracyclophane oximes provides access to a range of amino[2.2]paracyclophanes including the most efficient synthesis of the pseudo-gem planar chiral amino acid yet reported.

The concise synthesis and resolution of planar chiral [2.2]paracyclophane oxazolines by C-H activation.

Planar chiral [2.2]paracyclophanes are resolved through the direct C-H arylation of enantiopure oxazolines, providing a convenient route to ligands and chiral materials. Preliminary results show that hydrolysis followed by decarboxylative phosphorylation leads to enantiopure [2.2]paracyclophane derivatives that are otherwise challenging to prepare.

Correlated Transcriptional Responses Provide Insights into the Synergy Mechanisms of the Furazolidone, Vancomycin, and Sodium Deoxycholate Triple Combination in Escherichia coli.

Effective therapeutic options are urgently needed to tackle antibiotic resistance. Furazolidone (FZ), vancomycin (VAN), and sodium deoxycholate (DOC) show promise as their combination can synergistically inhibit the growth of, and kill, multidrug-resistant Gram-negative bacteria that are classified as critical priority by the World Health Organization. Here, we investigated the mechanisms of action and synergy of this drug combination using a transcriptomics approach in the model bacterium Escherichia coli. We show that FZ and DOC elicit highly similar gene perturbations indicative of iron starvation, decreased respiration and metabolism, and translational stress. In contrast, VAN induced envelope stress responses, in agreement with its known role in peptidoglycan synthesis inhibition. FZ induces the SOS response consistent with its DNA-damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables lower dosages and largely mitigates its mutagenic effects. Based on the gene expression changes identified, we propose a synergy mechanism where the combined effects of FZ, VAN, and DOC amplify damage to Gram-negative bacteria while simultaneously suppressing antibiotic resistance mechanisms. IMPORTANCE Synergistic antibiotic combinations are a promising alternative strategy for developing effective therapies for multidrug-resistant bacterial infections. The synergistic combination of the existing antibiotics nitrofurans and vancomycin with sodium deoxycholate shows promise in inhibiting and killing multidrug-resistant Gram-negative bacteria. We examined the mechanism of action and synergy of these three antibacterials and proposed a mechanistic basis for their synergy. Our results highlight much-needed mechanistic information necessary to advance this combination as a potential therapy.

Enantiospecific synthesis of [2.2]paracyclophane-4-thiol and derivatives.

This paper describes a simple route to enantiomerically enriched [2.2]paracyclophane-4-thiol via the stereospecific introduction of a chiral sulfoxide to the [2.2]paracyclophane skeleton. The first synthesis of an enantiomerically enriched planar chiral benzothiazole is also reported.

The enantiospecific synthesis of (+)-monomorine I using a 5-endo-trig cyclisation strategy.

We have developed a general strategy for the synthesis of 2,5-syn disubstituted pyrrolidines that is based on the multi-faceted reactivity of the sulfone moiety and a 5-endo-trig cyclisation. This methodology was applied to the synthesis of indolizidine alkaloid monomorine I. Two factors were key to the success of this endeavour; the first was the choice of nitrogen protecting group whilst the second was the conditions for the final stereoselective amination step. Employing a combination of different protecting groups and an intramolecular reductive amination reaction we were able to prepare (+)-monomorine I in just 11 steps from commercially available D-norleucine in a completely stereoselective manner.

The synthesis of enantiomerically pure 4-substituted [2.2]paracyclophane derivatives by sulfoxide-metal exchange.

A general strategy for the synthesis of enantiomerically pure 4-substituted [2.2]paracyclophanes from a common sulfoxide precursor is described.

Chiral sulfoxides in the enantioselective allylation of aldehydes with allyltrichlorosilane.

The use of chiral sulfoxides as Lewis base catalysts in the allylation of aldehydes with allyltrichlorosilane is reported.

Facile synthesis of planar chiral N-oxides and their use in Lewis base catalysis.

A rapid and versatile method for the preparation of planar chiral [2.2]paracyclophane-derived pyridines and pyridine N-oxides is reported. The potential utility of these compounds in Lewis base catalysis is briefly introduced.

Planar-chiral imidazole-based phosphine ligands derived from [2.2]paracyclophane.

Two planar chiral heteroaryl monophosphines have been synthesised and studied. The phosphines are readily prepared from 4-imidazole[2.2]paracyclophane by selective deprotonation and reaction with the appropriate dialkylchlorophosphines. The planar chiral imidazole was constructed in four steps from readily available [2.2]paracyclophane. The 2-phosphino-N-[2.2]paracyclophanes were active in the Suzuki-Miyaura coupling of aryl bromides and chlorides. Coordination studies indicate P,N-chelation in the solid-state. These studies lay the foundations for asymmetric couplings.

The synthesis of enantiomerically pure [2.2]paracyclophane derivatives.

[2.2]Paracyclophane is a fascinating molecule that offers great potential in a wide range of chemical disciplines. Currently, the synthesis of the majority of enantiomerically pure [2.2]paracyclophane derivatives is based on the resolution of a small number of starting materials or individual resolution procedures are developed for each new compound. The development of more general routes to these valuable compounds via the resolution of a common intermediate is discussed. Ultimately, it would be preferable to synthesise these valuable compounds without recourse to resolution and ideas for this rewarding goal are postulated.

The synthesis and directed ortho-lithiation of 4-tert-butylsulfinyl[2.2]paracyclophane.

The ortho-lithiation of one diastereoisomer of 4-tert-butylsulfinyl[2.2]paracyclophane is the key step to the synthesis of a range of 4,5-disubstituted [2.2]paracyclophane derivatives.