Toward Efficient and Stereoselective Aromatic and Dearomative Cope Rearrangements: Experimental and Theoretical Investigations of α-Allyl-α'-Aromatic γ-Lactone Derivatives.

The aromatic Cope rearrangement is an elusive transformation that has been the subject of a limited number of investigations compared to those seemingly close analogues, namely the Cope and aromatic Claisen rearrangement. Herein we report our investigations inspired by moderate success observed in the course of pioneering works. By careful experimental and theoretical investigations, we demonstrate that key substitutions on 1,5-hexadiene scaffold allow fruitful transformations. Especially, efficient functionalisation of the heteroaromatic rings results from the aromatic Cope rearrangement, while highly stereoselective interrupted aromatic Cope rearrangements highlight the formation of chiral compounds through a dearomative process.

Organocatalyzed Asymmetric Allylic Alkylation Enables Synthesis of Chiral γ-Lactones Bearing Vicinal Tertiary and Quaternary Stereocenters.

The synthesis of enantioenriched α-aryl-α'-allyl-γ-butyrolactones bearing vicinal tertiary and quaternary stereocenters through organocatalyzed asymmetric allylic alkylation is reported. The process demonstrated that weakly stabilized enolates derived from α-aryl-γ-butyrolactones can undergo regio-, diastereo-, and enantioselective allylation using the proper activation of Morita-Baylis-Hillman (MBH) carbonates.

cis-Dihydroxylated α-Trifluoromethylated N,O-Acetal from l-Tartaric Acid: Synthesis of Tetrasubstituted Stereocenter via Diastereoselective Pictet-Spengler Cyclization of N-Acyliminium Ions.

The synthesis of cyclic, chiral α-trifluoromethylated N,O-acetals having a protected cis-diol moiety has been readily achieved in two steps from a known bis-Weinreb amide derived from l-tartaric acid. The reaction of O-acetyl analogues of these N,O-acetals with triflic acid in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at 0 °C generated in situ the corresponding electrophilic α-trifluoromethyl N-acyliminium ions that undergo Pictet-Spengler-type cyclizations. After only 10 min of reaction, the original enantiopure aza-tricyclic scaffolds bearing a trifluoromethyl substituent at the bridgehead position were obtained with diastereoselectivities ranging from 75:25 to 97:3.

Broadening the reaction scope of unprotected aldoses via their corresponding nitrones: 1,3-dipolar cycloadditions with alkenes.

Condensation reactions of unprotected tetroses and pentoses with hydroxylamines afforded nitrones, which were easily converted to densely functionalized isoxazolidines in the presence of electron-poor alkenes. The 1,3-dipolar cycloaddition occurred with good facial discrimination of the chiral nitrone but under rather low endo/exo control. Stereochemistry of isomers was ascertained by chemical correlation with known derivatives from the literature. Microwave activation appeared as the most efficient reaction mode, affording the expected adducts within several minutes whereas hours were needed under standard heating. Alternatively, the transformation proved also possible under high pressure conditions by using a hand pump system, avoiding any energy source. Although water could not be used as the solvent, leading to hydrolysis of the nitrone substrate, a large variety of organic solvents proved efficient. The method has potential use in the preparation of non-ionic carbohydrate-based amphiphiles.

Organocatalytic enantioselective allylic alkylation of α-aryl γ-lactones: an approach to densely functionalized quaternary stereocentres.

The asymmetric allylic alkylation (AAA) of α-aryl γ-lactones involving the activation of Morita-Baylis-Hillman (MBH) carbonates by an original chiral Lewis base is reported. A wide range of γ-lactones bearing a quaternary stereocentre was thus obtained in both high yields and high enantiomeric ratios. The direct alkylation by MBH alcohol using in situ activation has been also established. Additionally synthetically useful functional transformations of groups surrounding the quaternary stereocentre have been performed.

Iridium-catalysed asymmetric allylic alkylation of benzofuran γ-lactones followed by heteroaromatic Cope rearrangement: study of an unusual reaction sequence.

The iridium-catalysed asymmetric allylic alkylation of γ-lactones produces an all-carbon quaternary stereocentre substituted by an allyl and a benzofuran. The resulting 1,5-hexadienes were found to be excellent substrates for an unusual heteroaromatic Cope rearrangement. We describe here the first insight into the synthetic outcome of this intriguing reaction sequence.

Synthesis of chiral γ-lactones by one-pot sequential enantioselective organocatalytic michael addition of boronic acids and diastereoselective intramolecular passerini reaction.

The synthesis of α,γ-substituted chiral γ-lactones was quickly achieved in a one pot sequential process. The procedure involves an enantioselective organocatalysed transfer of boronic acid to 5-hydroxyfuran-2(5H)-one, followed by an intramolecular diastereoselective Passerini-type reaction. The methodology was developed and optimized with N-Boc-indole-2-boronic acid giving access to α-indole-γ-substituted lactones in high yields and good diastereoisomeric and enantiomeric ratios. By applying the process to other boronic acids, the synthesis of structurally diversified α,γ-substituted chiral lactones was also achieved in good yields albeit with lower enantioselectivities.

High-resolution and high-sensitivity 2D homonuclear J-resolved NMR spectroscopy.

This paper describes the implementation of the pure absorption ALPESTRE processing of 2D homonuclear J-resolved NMR spectra. The method relies on the computation of the missing information at negative evolution times by means of backward linear prediction. The paper also shows that resolution can be improved by application of time-symmetric apodization functions. The resulting spectra clearly display negative peaks at F(2) chemical shifts that correspond to strong coupling artifacts, thus making it possible to identify them as such. The processing scripts are freely available for downloading, use and modification.

Enantioselective organocatalytic Friedel-Crafts alkylation reaction of indoles with 5-hydroxyfuran-2(5H)-one: access to chiral γ-lactones and γ-lactams via a Ugi 4-center 3-component reaction.

5-Hydroxyfuran-2(5H)-one 1, a readily available renewable resource, was used as an electrophile in the Friedel-Crafts alkylation of indoles catalyzed by a diphenylprolinol silyl ether. Moderate catalyst loading was achieved because of the high reactivity of 5-hydroxyfuran-2(5H)-one 1 in this process. Reduction of the Friedel-Crafts adduct (FC adduct) afforded indoyl lactones in high yield and enantioselectivity. Moreover, the FC adduct was used as a chiral synthon in a diversity-oriented synthesis, as illustrated by its successful engagement in a 4-center 3-component Ugi reaction (U-4C-3CR) to afford chiral five-membered lactams in high yield and enantioselectivity.

Photosensitized addition of isopropanol to furanones in a 365 nm UV-LED microchip.

The DMBP-sensitized addition of isopropanol to furanones was studied in a novel LED-driven microchip reactor. Complete conversions were achieved after just 2.5 to 5 min of irradiation with 6 × 365 nm high-power LEDs. The results were compared to analogous experiments using a conventional batch reactor.

New safety-catch photolabile protecting group.

Photolabile protecting groups have proven their usefulness on many occasions. Their versions as linkers are however less attractive, as robustness and real orthogonality become critical issues. Safety-catch systems, where a preliminary activation phase is necessary, circumvent the problem of premature cleavage. In this work, we introduce a new safety-catch photolabile protecting group, whose cleavage requires the simultaneous presence of light and a chemical promoter.

Neamine dimers targeting the HIV-1 TAR RNA.

Natural aminoglycoside antibiotics, such as neomycin, target bacterial ribosomal RNA. Neomycin also binds strongly to HIV TAR and RRE RNA through the predominant interactions of its neamine core. In the search for antiviral agents targeting multiple binding sites for aminoglycosides in RNA, we report here the synthesis of new neamine dimers and a trimer in which the neamine cores are connected by different linking chains attached at the 4'- and/or 5-positions. Inhibition of TAR-Tat complexation by these oligomers was studied via fluorimetric binding assays performed under two ionic strengths. All dimers strongly inhibit TAR-Tat association, with IC50 values 17-85 times better than the value obtained with neomycin. These results demonstrate that modifying neamine at the 4'- or the 5-position is a promising strategy in the search for antiviral agents.

A peptide nucleic acid-neamine conjugate that targets and cleaves HIV-1 TAR RNA inhibits viral replication.

The neamine part of the aminoglycoside antibiotic neomycin B was conjugated to a 16 mer peptide nucleic acid (PNA) targeting HIV-1 TAR RNA. Attachment of the neamine core allows cellular uptake of the PNA and results in potent inhibition of HIV-1 replication. The polycationic neamine moiety imparts greater solubility to the PNA and also confers a unique RNA cleavage property to the conjugate which is specific to its target site and functional at physiological concentrations of Mg(2+). These properties suggest a potential therapeutic application for this class of compounds.