From garden to lab: C-3 chemical modifications of tomatidine unveil broad-spectrum ATP synthase inhibitors to combat bacterial resistance.

Antibiotic resistance is escalating alarmingly worldwide. Bacterial resistance mechanisms are surfacing and proliferating across the globe, jeopardizing our capacity to manage prevalent infectious illnesses. Without drastic measures, we risk entering a post-antibiotic era, where even trivial infections and injuries can cause death again. In this context, we have developed a new class of antibiotics based on tomatidine (TO), a natural product derived from tomato plants, with a novel mode of action by targeting bacterial ATP synthases. The first generation of compounds proved highly specific for small-colony variants (SCVs) of Staphylococcus aureus. However, optimization of this scaffold through extensive structure-activity relationship studies has enabled us to broaden its effectiveness to include both Gram-positive and Gram-negative bacteria. Notably, the results showed that specific C3-modification of TO could improve ATP synthase inhibition and also bypass the outer membrane barrier of Gram-negative bacteria to gain substantial growth inhibition including against multi-resistant strains.

Phenolate-induced intramolecular ring-opening cyclization of N-tosylaziridines: access to functionalized benzoxacycles.

Phenolate-induced, diastereo- and regioselective intramolecular exo-tet ring-opening cyclization of N-tosylaziridines has been achieved for the first time. The N-tosylaziridine substrates bearing a tethered (ortho-(tert-butyldimethylsiloxy))aryl substituent, prepared directly from the corresponding olefins under Sharpless aziridination conditions, furnished functionalized 2,3-dihydrobenzofuran, chroman, and 1-benzoxepane derivatives in excellent yields when treated with tetrabutylammonium fluoride (TBAF) at room temperature. Our ability to synthesize benzoxacycle-based N-tosyl-protected amino alcohols, that are otherwise difficult to obtain by traditional synthetic routes, has opened the door to diversify the chemistry of ß-amino alcohols. We also succesfully performed the Baeyer-Villiger oxidation of a salicylaldehyde ether bearing a tethered N-tosylaziridine moiety with m-CPBA followed by tandem saponification and 6-exo-tet aziridine ring-opening cyclization, furnishing the corresponding trans-3,4-disubstituted-1,4-benzodioxane derivative. Overall, the study has unveiled a new entry to the synthesis of benzoxacycles and has also broadened the impact of aziridines as synthetic building blocks.

Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates.

While the exploitation of the Sharpless asymmetric dihydroxylation as the source of chirality in the synthesis of acyclic molecules and saturated heterocycles has been tremendous, its synthetic utility toward chiral benzo-annulated heterocycles is relatively limited. Thus, in the search for wider applications of Sharpless asymmetric dihydroxylation-derived diols for the synthesis of benzo-annulated heterocycles, we report herein our studies in the asymmetric synthesis of (R)-1-((R)-6-fluorochroman-2-yl)ethane-1,2-diol, (R)-1-((S)-6-fluorochroman-2-yl)ethane-1,2-diol and (S)-6-fluoro-2-((R)-oxiran-2-yl)chroman, which have been used as late-stage intermediates for the asymmetric synthesis of the antihypertensive drug (S,R,R,R)-nebivolol. Noteworthy is that a large number of racemic and asymmetric syntheses of nebivolol and their intermediates have been described in the literature, however, the Sharpless asymmetric dihydroxylation has never been employed as the sole source of chirality for this purpose.

cis-Diastereoselective synthesis of chroman-fused tetralins as B-ring-modified analogues of brazilin.

We have synthesized a series of cis-6a,7,8,12b-tetrahydro-6H-naphtho[2,1-c]chromen-6a-ols as B-ring-modified analogues of (±)-brazilin. A completely regio- and cis-diastereoselective intramolecular Friedel-Crafts epoxy-arene cyclization of 1-tetralone-derived glycidyl ethers catalyzed by Brønsted acids was used as the key step. Our worries concerning the formation of cis-trans product mixtures and their probable conversion to naphthopyran derivatives via dehydration of the tertiary hydroxy group were laid to rest. Additionally, the angular hydroxy group of one of the synthesized products has been reductively removed by a diastereoselective method which should be useful in future for preparing libraries of chroman-fused tetralins with trans-stereochemistry at the ring junction.