The development of endo-selective epoxide-opening cascades in water

This tutorial review traces the development of endo-regioselective epoxide-opening reactions in water. Templated, water-promoted epoxide-opening cyclization reactions can offer rapid access to subunits of the ladder polyethers, a fascinating and complex family of natural products. This review may be of interest to those curious about the ladder polyethers and their hypothesized biogenesis, about organic reactions in water, and about the development and application of cascade reactions in organic synthesis

Enantioselective Lewis Base Catalyzed Phosphonyldifluoromethylation of Allylic Fluorides Using C-Silyl Latent Pronucleophile

The first enantioselective phosphonyldifluoromethylation is enabled by the use of diethyl (difluoro(trimethylsilyl)methyl)pho-sphonate reagent as a latent pronuclephile in Lewis base catalyzed substitution of allylic fluorides. The reactions proceed as kinetic resolution to produce both the difluoromethylphosphonate products and the remaining fluorides in good yields and with high stereoselectivity. The use of cinchona based alkaloid catalysts enables the facile synthesis of both enantiomers of the difluoromethylphosphonate products

Enantioselective Lewis base catalysed allylation of picoline- and quinaldine-based latent pronucleophiles†

<jats:p>The concept of latent pronucleophiles enables selective allylation of picolines and quinaldines with allylic fluorides in the presence of Lewis base catalysts. The products are isolated as single regioisomers with good yields and enantioselectivity.</jats:p&gt

Intramolecular Cyclization of Vinyldiazoacetates as a Versatile Route to Substituted Pyrazoles

Vinyldiazo compounds undergo a thermal electrocyclization to form pyrazoles in yields of up to 95%. The reactions are operationally simple, use readily available starting materials, require no intervention of a catalyst, and enable the synthesis of mono-, di- and tri-substituted pyrazoles. With the ability to produce highly substituted pyrazole and the flexibility in installing various types of substituents, this method constitutes a new entry to this valuable heterocyclic scaffold of interest in all branches of chemical industry

Selective C-H Chalcogenation of Thiazoles via Thiazol-2-yl-phosphonium Salts

Thiazoles and benzothiazoles undergo regioselective C2-H chalcogenation via the sequence of thiazole C2-functionalization with phosphines to produce phosphonium salts which in turn react with S- and Se-centered nucleophiles to give products of C2-H chalcogenation and allow for recovery of the starting phosphine. The atom economical sequence proceeds under mild conditions and features broad scope for both the nucleophiles (electron-rich, electron-poor, sterically hindered thiols) and the various substituted benzothiazoles. The access to the substituted medicinally relevant C2-thio benzothiazoles also enables stereoselectivity improvements in the modified Julia olefinations. <br /

Latent Pronucleophiles in Lewis Base Catalysis: Enantioselective Allylation of Silylated Stabilized Carbon Nucleophiles with Allylic Fluorides

Lewis base catalyzed allylations of C-centered nucleophiles have been largely limited to the niche substrates with acidic C-H substituted with C-F bonds at the stabilized carbanionic carbon. Here we report that the concept of latent pronucleophiles serves to overcome these limitations and allow for a variety of common silylated stabilized C-nucleophiles to undergo enantioselective allylations using allylic fluorides. The reactions of silyl enol ethers afford the allylation products in good yields and with high degree of regio / stereoselectivity as well as diastereoselectivity when cyclic silyl enol ethers are used. Further examples of silylated stabilized carbon nucleophiles that undergo efficient allylation speak in favor of the broad applicability of this concept in the arena of C-centered nucleophiles

Robust Synthesis of NIR-Emissive P-Rhodamine Fluorophores

P-rhodamines were accessed by implementing a robust three step sequence consisting of (i) addition of m-metallated anilines to dichlorophosphine oxides, (ii) selective dibromination, and (iii) cyclization of the diaryllithium reagents derived from the dibromides to form the dihydroacridophosphine core of P-rhodamines. A modified route to produce non-symmetric P-rhodamines was additionally developed. A library of the prepared P-rhodamines provides first insight into dependence of fluorophore properties on the structure of P-rhodamines. A P-rhodamine with highest batochromic shifts and quantum yields in the class was identified

Mechanical Compressibility of the Glycosylphosphatidylinositol (GPI) Anchor Backbone Governed by Independent Glycosidic Linkages

About 1% of the human proteome is anchored to the outer leaflet of cell membranes via a class of glycolipids called GPI anchors. In spite of their ubiquity, experimental information about the conformational dynamics of these glycolipids is rather limited. Here, we use a variety of computer simulation techniques to elucidate the conformational flexibility of the Man-α(1→2)-Man-α(1→6)-Man-α(1→4)-GlcNAc-α-OMe tetrasaccharide backbone <b>2</b> that is an essential and invariant part of all GPI-anchors. In addition to the complete tetrasaccharide structure, all disaccharide and trisaccharide subunits of the GPI backbone have been studied as independent moieties. The extended free energy landscape as a function of the corresponding dihedral angles has been determined for each glycosidic linkage relevant for the conformational preferences of the tetrasaccharide backbone (Man-α(1→2)-Man, Man-α(1→6)­Man and Man-α(1→4)-GlcNAc). We compared the free energy landscapes obtained for the same glycosidic linkage within different oligosaccharides. This comparison reveals that the conformational properties of a linkage are primarily determined by its two connecting carbohydrate moieties, just as in the corresponding disaccharide. Furthermore, we can show that the torsions of the different glycosidic linkages within the GPI tetrasaccharide can be considered as statistically independent degrees of freedom. Using this insight, we are able to map the atomistic description to an effective, reduced model and study the response of the tetrasaccharide <b>2</b> to external forces. Even though the backbone assumes essentially a single, extended conformation in the absence of mechanical stress, it can be easily bent by forces of physiological magnitude

Versatility of a Glycosylphosphatidylinositol Fragment in Forming Highly Ordered Polymorphs

Glycosylphosphatidylinositols (GPIs) are often attributed with the ability to associate with the organized membrane microdomains. GPI fragment <b>1</b> forms a highly ordered subgel-phase structure characterized by ordering of both headgroups and alkyl chains in thin layers. While investigating the driving forces behind the formation of these ordered monolayers, we have studied polymorphism of <b>1</b> under different conditions employing surface-sensitive X-ray diffraction methods. Three distinct polymorphs of <b>1</b> (<b>I</b>, <b>II</b>, and <b>III</b>) were identified and characterized by grazing incidence X-ray diffraction. Polymorphs <b>II</b> (a condensed monolayer structure) and <b>III</b> (highly ordered subgel phase) coexist on an 8 M urea solution subphase allowing for a detailed thermodynamic and kinetic analysis of the processes leading to the formation of these polymorphs. They are enantiotropic and can be directly interconverted by changes in temperature or lateral surface pressure. As a consequence, polymorph <b>III</b> nuclei of critical size (or larger) could be formed by density fluctuations in a multicomponent system, and they could continue to exist for a period of time even under conditions that would normally not allow for the nucleation of polymorph <b>III</b>. The processes described here could also lead to the formation of patches of highly ordered structures in a disordered environment of a cell membrane suggesting that GPIs may play a role in the formation of such domains