The synthesis of acetoxy-endoperoxyacetal derivatives allowed the formation of functionalized 3,5-disubstituted-1,2dioxolanes through the formation of reactive peroxycarbenium species under Lewis acid mediation. The introduction of a neutral nucleophile such as allylsilanes, silanes, or silyl enol ethers was accomplished with moderate to good yields. The two studied Lewis acids, TiCl4 and SnCl4, gave contrasted results. The higher diastereoselectivity towards the trans diastereomer in experiments with TiCl4 as Lewis acid was explained by a faster degradation of the cis isomer product, conducting generally to lower yields. A rationalization of this result was supported by calculation. about towards one degradation pathway could rationalize why cis-1,2-dioxolanes decompose more easily under treatment with TiCl4.

Herein we report the use of catalytic amount of scandium(III) triflate or indium(III) chloride (with trimethylsilyl chloride) for the functionalization of endoperoxyacetals through Sakurai or Mukaiyama reactions. These catalysts allow milder and more practical conditions than those previously reported with improvements in scope and reproducibility. This method allows a full catalytic sequence from cyclopropanols to produce desired functionalized 1,2‐dioxolanes.

Cyclobutanols undergo an oxidative ring expansion into 1,2-dioxanols by using Co(acac) 2 and triplet oxygen) as radical promoters. The formation of an alkoxy radical drives to the regioselective break of the strained ring with stabilization of a new radical on the most substituted side. The radical traps then oxygen to form 1,2-dioxanols. The reaction is particularly effective on secondary cyclobutanols but can work also on tertiary alcohols. Further acetylation generates peroxycarbenium species under catalytic Lewis acid conditions, which react with neutral nucleophiles. Many original 1,2-dioxanes, which would be difficult to prepare by another method, were then obtained with a preferred 3,6-cis-configuration. This method provides an interesting access to the total synthesis of many natural endoperoxides. File list (3) download file view on ChemRxiv cyclobutanol ring opening ChemRxiv.pdf (1.07 MiB) download file view on ChemRxiv Copy of 1H NMR and 13C NMR spectra.pdf (3.47 MiB) download file view on ChemRxiv Experimental Dioxanes.pdf (1.64 MiB)

Endoperoxides are a source of bioactive compounds which drove to some important anti‐malarial drugs such as artemisinin or arterolane. 1,2‐Dioxolanes drew the attention of many scientists, through the isolation of numerous natural products containing this peroxidized ring structure such as the plakinic acid family or the biosynthetic study of prostaglandins. Thus, a considerable work was reported for the synthesis of such endoperoxides, but mainly applied to the synthesis of 3,3',5,5'‐tetrasubstituted 1,2‐dioxolanes. The recent isolation of new natural products containing a 3,5‐disubstituted dioxolane ring brought our attention on how to specifically prepare such structures. Herein, we tentatively summarize exhaustively all the methods reported for the synthesis of 3,5‐disubstituted 1,2‐dioxolanes. Therefore, nucleophilic substitution with hydrogen peroxide or hydroperoxide, use of electrophilic singlet oxygen, use of triplet oxygen in radical reaction and the chemistry of peroxycarbenium ions will be presented for this purpose.

Endoperoxides are a class of compounds, which is well-known for their antimalarial properties, notably, but few reports exist about 3,5-disubstituted 1,2-dioxolanes. After having designed a new synthetic route for the preparation of these substances, they were evaluated against 4 different agents of infectious diseases, protozoa (Plasmodium, Leishmania) and Fungi (Candida and Aspergillus). Whereas moderate antifungal activity was found for our products, potent antimalarial and antileishmanial activities were observed for a few compounds. The nature of the substituents linked to the endoperoxide ring seems to play an important role in the bioactivities.

The front cover picture, provided by Laurent Ferrié, and co‐workers, is an artistic illustration, using pastel technique, of the functionalization of endoperoxyacetals mediated by mild Lewis acid systems such as InCl3/TMSCl and Sc(OTf)3. Indium and scandium are represented as humanoid workers helping in the cleavage of the acetate bond and bringing the allyl moiety necessary for a Sakurai reaction. The reaction conditions were improved, in comparison to previous reports, allowing an extension of the reagent scope, and more practical conditions. Further details of this work can be found in the Update on pages 1190–1194 (A. Pinet, B. Figadère, L. Ferrié, Adv. Synth. Catal. 2020, 362, 1190–1194; DOI: 10.1002/adsc.201901145).

The spread of antibiotic resistance is an urgent threat to global health that requires new therapeutic approaches. Treatments for pathogenic Gram-negative bacteria are particularly challenging to identify due to the robust OM permeability barrier in these organisms. One strategy is to use antibiotic adjuvants, a class of drugs that have no significant antibacterial activity on their own but can act synergistically with certain antibiotics. Previous studies described the discovery and development of polyaminoisoprenyl molecules as antibiotic adjuvants with an OM effect. In particular, the compound NV716 has been shown to sensitize Pseudomonas aeruginosa to tetracycline antibiotics such as doxycycline. Here, we sought to explore the disruption of OM to sensitize P. aeruginosa to otherwise inactive antimicrobials using a series of tetracycline derivatives in the presence of NV716. We found that OM disruption expands the hydrophobicity threshold consistent with antibacterial activity to include hydrophobic molecules, thereby altering permeation rules in Gram-negative bacteria.