Unlocking the C-centered ring-opening of phosphiranium ions for a straightforward entry to functionalized phosphines.

Phosphorus chemistry occupies a pivotal position in contemporary organic chemistry but significant synthetic challenges still endure. In this report, a class of electrophilic phosphiranium salts, bearing fluorinated benzyl quaternizing groups, is introduced for the direct synthesis of diversely ß-functionalized phosphines. We show that, in comparison with regular quaternary phosphiranium salts, these species display the sought balance of excellent stability and high electrophilic reactivity that allow the unlocking of the C-centered ring-opening reactions with different classes of weak nitrogen-, sulfur- and oxygen protic nucleophiles.

2,3-Epoxyamide-alcohols in Domino Reactions: En Route to Molecular Diversity.

The synthesis of polycyclic γ- and δ-lactams bearing up to four contiguous fully controlled stereocenters is presented. For that purpose, we developed an original approach based on the use of 2,3-epoxyamides in domino reactions by taking advantage of the nucleophilic nitrogen atom and electrophilic epoxide. In reaction with enol ethers bearing gem bis-electrophiles on the double bond as Michael acceptors, four different reaction pathways were observed. They all started with a domino oxa-Michael/aza-Michael/epoxide opening sequence and depending on substrates engaged could be followed either by a lactonization or a hemiketalization/retro-aldol cascade. Thus, four original fully-substituted piperidine- or pyrrolidine-2-one scaffolds were selectively synthesized in good to high yields. Moreover, these polycyclic lactams were obtained in high stereo- and chemo-selectively highlighting the efficiency and molecular diversity offered by this new methodology that should offer various synthetic opportunities in the future.

N-Benzyloxyacrylamides as Bisnucleophiles in an Organocatalyzed Domino aza-Michael/Morita-Baylis-Hillman Sequence.

We herein describe a stereoselective organocatalyzed aza-Michael/Morita-Baylis-Hillman domino reaction between readily accessible acrylamides and α,ß-unsaturated carbonyls. This novel, PPh3-promoted atom economic one-pot process features medium to good yields and good stereoselectivity leading to variously substituted piperidin-2-ones bearing an exocyclic olefinic bond, which was shown to be an excellent anchor for further chemical diversification.

Taming the Reactivity of Phosphiranium Salts: Site-Selective C-Centered Ring Opening for Direct Synthesis of Phosphinoethylamines.

Advances in the field of phosphorus chemistry are documented, by revealing the synthetic utility of previously underutilized quaternary phosphiranium salts (QPrS) as three-chain-atom electrophilic building blocks. Notably, control of their challenging C-centered electrophilicity is disclosed with an expedient synthesis of tertiary ß-anilino phosphines as a proof-of-concept.

α-Halogenoacetamides: versatile and efficient tools for the synthesis of complex aza-heterocycles.

This review provides an overview of the applications of α-halogenoacetamides in domino and cycloaddition reactions. α-Halogenoacetamides are versatile building blocks that can lead to a wide variety of complex aza-heterocycles of biological interest when engaged in domino and/or cycloaddition reactions. The reactivity and the reaction conditions involved for these species (solvent, base, etc.) are closely related to the substituent onto the nitrogen atom of the amide: N-alkyl α-halogenoacetamides usually act as formal 1,3-dipoles in domino processes whereas N-alkoxy derivatives often react as real 1,3-dipoles via the formation of aza-oxyallyl cation species. This important modulation of the reactivity of these compounds opens the way to a large panel of reactions and therefore to a large diversity of aza-heterocycles.

Impact of backbone stiffness and hydrophobic chain length of modified xanthan on oil in water emulsion stabilization.

The impact of xanthan chemical modification under both ordered and disordered conformations on oil-in-water (O/W) emulsion stabilization was investigated. While both hydrophobically modified xanthan (HMX) are able to stabilize the O/W interface, a dramatic difference was observed macroscopically. When HMXord (ordered conformation) could produce stable emulsions at concentrations down to 0.2% w/w, HMXdis (disordered conformation) led to unstable systems mostly by creaming whatever the concentration studied. Moreover, in the case of HMXdis, the role of the grafted chain length was investigated and two different behaviors were observed depending on the grafting unit. It was demonstrated that the cornerstone of these emulsion stability was the rheological properties of the continuous phase which was governed by two main factors: the partitioning of HMXdis between the interface and the continuous phase and the viscosifying ability of the polymer, the latter being directly linked to the backbone stiffness.

Hydrophobically modified xanthan: Thickening and surface active agent for highly stable oil in water emulsions.

Oil-in-water (O/W) emulsions were prepared using exclusively a hydrophobically modified xanthan (HMX) under ordered conformation without any surfactant. A series of HMX differing in grafting density were utilized at different concentrations. It was demonstrated that HMX stabilizes O/W emulsions where pristine xanthan do not. Indeed, in some cases, emulsions with HMX proved to be homogeneous and stable over months. Emulsions microstructure and rheological properties were investigated over time as a function of HMX concentration and grafting density in order to determine the mechanisms governing this efficient stability. The higher the HMX concentration is, the better the emulsions stability. However, unexpectedly, increasing the HMX grafting density leads to faster destabilization. The whole set of results demonstrate that the stability of the emulsions against coalescence and creaming is explained by partitioning of HMX molecules between bulk and interface, thus split between viscosifying the aqueous phase and stabilizing the interface.

Chemical modification of xanthan in the ordered and disordered states: An open route for tuning the physico-chemical properties.

The impact of the chain stiffness on physicochemical properties has been studied by chemical modification of xanthan under both ordered and disordered conformations. Corresponding rheological properties were studied and results showed that amphiphilic xanthan exhibited completely different behaviors depending on its conformation during modification. Xanthan, when modified under ordered conformation, exhibits similar behavior to non-modified one, only the chain relaxation being strongly slowed down. Therefore, the high stiffness of xanthan helices does not allow hydrophobic moieties to associate. Oppositely, xanthan modified under its disordered conformation displayed a chemical gel-like behavior without any relaxation of the chain within the studied frequency range nor with temperature, which is unexpected for this length of alkyl chains. These different viscoelastic properties can be correlated to the regioselectivity of the grafting; the latter can be controlled by the conformation of xanthan during modification, thus by the synthesis conditions.

Chemo-, Regio-, and Stereoselective Synthesis of Polysusbtituted Oxazolo[3,2-d][1,4]oxazepin-5(3H)ones via a Domino oxa-Michael/aza-Michael/Williamson Cycloetherification Sequence.

The access to new oxazolo[3,2-d][1,4]oxazepin-5(3H)-ones starting from α-bromoamido alcohols and Michael acceptors under mild conditions is presented. This domino process proved to be chemo-, regio-, and stereoselective and allows the formation of a large diversity of highly functional 7-membered rings in good yields up to 95%. The complete shift of the regioselectivity of the intermediate enolate from a C-C to a C-O bond formation, contrary to the already known alkylations of such ambident nucleophiles, is mostly triggered by steric effects. The last step of the sequence was modeled by DFT giving some important insights for this C-C vs C-O bond shift.

Synthesis of Oxazolidin-4-ones: Domino O-Alkylation/Aza-Michael/Intramolecular Retro-Claisen Condensation.

An original and rapid domino reaction for access to oxazolidin-4-ones is presented. Simply by heating α-bromoamido alcohol in the presence of KNaCO3 and water with readily prepared Michael acceptors, an unprecedented molecular rearrangement is generated. This new methodology enables the hitherto unreported synthesis of functionalized oxazolidin-4-ones. The process was proved to be compatible with a wide variety of substrates, and high regioselectivities were achieved.

Simple access to highly functional bicyclic γ- and δ-lactams: origins of chirality transfer to contiguous tertiary/quaternary stereocenters assessed by DFT.

This paper describes the synthesis of both polysubstituted oxazolo-pyrrolidinones and -piperidinones by a domino process. The methodology is based on the reaction between hydroxyl halogenoamides and Michael acceptors, which leads efficiently to bicyclic lactams. The process is compatible with unsymmetrical electron-withdrawing groups on the Michael acceptor, which allows the formation of two contiguous and fully controlled tertiary and quaternary stereocenters. In the case of tetrasubstituted Michael acceptors, two adjacent quaternary stereocenters are formed in good yield. Starting from (R)-phenylglycinol derived amides results in the formation of enantioenriched bicyclic lactams in low to good yields and with high levels of stereoselectivity, thus greatly increasing the scope and interest of this strategy. The origins of chirality transfer and diastereoselectivity were studied by DFT calculations and have been attributed to a kinetic control in one of the last two steps of the reaction sequence. This selectivity is dependent upon both the substituents on the Michael acceptor and the sodium cation chelation.

Hydrophobically modified xanthan: an amphiphilic but not associative polymer.

Hydrophobic octyl moieties have been grafted in various densities onto the carboxylic acid functions of xanthan under its ordered conformation. The outcoming amphiphilic and associative properties were studied by fluorescence spectroscopy and rheology. Results showed that the conformation of xanthan is not affected by the chemical modification and remains the same as the native one. Additionally, xanthan derivatives do not show any viscoelastic enhancement; nevertheless, their dynamics is strongly slowed down: the higher the grafting density, the slower the relaxation. We proved that hydrophobically modified xanthan, even being amphiphilic, does not exhibit any additional associating properties compared to the unmodified xanthan. The high stiffness of xanthan helices does not allow the derivatives to adopt the organization usually observed for flexible amphiphilic polymers. On the basis of these observations, a model depicting such a singular behavior is proposed.

Synthesis of fluorinated catharanthine analogues and investigation of their biomimetic coupling with vindoline.

The syntheses of 20,20-difluorocatharanthine and congeners, starting from the naturally occurring catharanthine, are reported. The fluorinated catharanthine analogues were investigated as potential precursors to dimeric Vinca alkaloids of the vinflunine family. However, the biomimetic coupling of the fluorinated catharanthine derivatives with vindoline led to unexpected alkaloid structures, the formation of which was rationalized.

Synthesis of highly functionalized pyrrolidines as tunable templates for the direct access to (±)-coerulescine and the tricyclic core of martinellines.

An aza-Michael induced ring closure (aza-MIRC) tandem reaction of benzyl (2-bromoethyl)carbamate with various Michael acceptors is described. The N-Cbz-ß-gem-disubstituted pyrrolidines thus obtained were proved to be versatile intermediates for the rapid access to both martinelline and spirooxindole backbones. An application of this strategy towards an expedient 4 step total synthesis of (±)-coerulescine is also presented.

Domino process optimized via ab initio study for an alternative access to bicyclic lactams.

A totally new acid-free domino process to access highly functionalized bicyclic γ- and δ-lactams starting from commercially available and inexpensive ethoxymethylene derivatives is reported. Mechanisms elucidated by computational calculations led to new reaction conditions that boosted the yields up to 3.5 times higher.

New and expeditious tandem sequence aza-Michael/intramolecular nucleophilic substitution route to substituted gamma-lactams: synthesis of the tricyclic core of (+/-)-martinellines.

A new and highly diastereoselective tandem reaction aza-Michael/intramolecular nucleophilic substitution is presented. This unprecedented tandem reaction between N-substituted alpha-bromoacetamides and Michael acceptors proceeds with good yields and excellent diastereoselectivity to provide the corresponding trisubstituted gamma-lactam systems. An application to the concise synthesis of the tricyclic core of (+/-)-martinelline alkaloids is also described.

A domino N-amidoacylation/aldol-type condensation approach to the synthesis of the topo-I inhibitor Rosettacin and derivatives.

The pot, atom, and step-economic synthesis of Rosettacin topo-I poison and its derivatives has been achieved using a novel domino N-amidoacylation/aldol-type condensation, followed by decarboxylation of the ester function. The key domino procedure simply involves mixing HOBt ester as new reagent with lactam and NaH together in THF or THF/ DMF. The reaction seems to be general and led to suitable N-heterocyclic products in moderate to good yields.

Intermolecular and intramolecular alpha-amidoalkylation reactions using bismuth triflate as the catalyst.

Bismuth(III) triflate was found to promote the formation of stable cyclic N-acyliminium species in remarkable catalytic amounts (1 mol %). The alpha-amidoalkylation process seems to be effective in intermolecular and intramolecular manners leading to alpha-substituted lactams and heterocyclic systems containing azacycles, respectively. By comparing our results with those obtained with the classical Lewis acids as catalysts, it was evidenced clearly that the use of bismuth(III) triflate had been efficient for nearly all alpha-acetoxy lactams we used, except for N-acyliminium precursors bearing a sulfur atom. Also, the process seems to be easy, general, and clean, having diastereoselectivity comparable to protocols using classical Lewis acids and resulting in the formation of polyheterocyclic systems in good to excellent yields (64-99% in acetonitrile as solvent).

Down-regulation of thiamine transporter THTR2 gene expression in breast cancer and its association with resistance to apoptosis.

The recent molecular identification of two thiamine transporters, SLC19A2 (THTR1) and SLC19A3 (THTR2), has provided the opportunity to study thiamine transporter gene expression in human malignancies. We compared RNA levels of both THTR1 and THTR2 in a panel of human breast tumors and corresponding normal tissues. THTR2 RNA levels were down-regulated in breast cancer to 14% of the level found in corresponding normal tissues, while THTR1 levels were unchanged. Both thiamine transport genes were cloned and expressed in a breast cancer cell line to examine the impact of reconstituted thiamine transport gene expression on drug and radiation sensitivity and on resistance to apoptosis. THTR2-transfected breast cancer cells showed a 2.5-fold increase in specific THTR2 activity and a 3-fold increase in cytotoxicity against a bromoacetyl ester derivative of thiamine. Surprisingly, these cells also showed a 3-fold increase in sensitivity to doxorubicin and an increase in sensitivity to ionizing radiation, but no change in sensitivity to methotrexate or paclitaxel. TUNEL assays demonstrate an increase in apoptosis in THTR2-transfected cells exposed to doxorubicin and radiation, and Western blot analysis suggests that apoptosis associated with these cytotoxic stresses is mediated at least in part by a caspase-3-dependent pathway. Therefore, thiamine transporter THTR2 gene expression is down-regulated in breast cancer, which may contribute to resistance to apoptosis in these tumors.