Stereospecific alkenylidene homologation of organoboronates by SNV reaction.

Concerted nucleophilic substitution, known as SN2 reaction, is a fundamental organic transformation used in synthesis to introduce new functional groups and construct carbon-carbon and carbon-heteroatom bonds1. SN2 reactions typically involve backside attack of a nucleophile to the σ* orbital of a C(sp3)-X bond (X = halogen or other leaving group), resulting in complete inversion of a stereocentre2. By contrast, the corresponding stereoinvertive nucleophilic substitution on electronically unbiased sp2 vinyl electrophiles, namely concerted SNV(σ) reaction, is much rarer, and so far limited to carefully designed substrates mostly in ring-forming processes3,4. Here we show that concerted SNV reactions can be accelerated by a proposed strain-release mechanism in metallated complexes, leading to the development of a general and stereospecific alkenylidene homologation of diverse organoboronates. This method enables the iterative incorporation of multiple alkenylidene units, giving cross-conjugated polyenes that are challenging to prepare otherwise. Further application to the synthesis of bioactive compounds containing multi-substituted alkenes is also demonstrated. Computational studies suggest an unusual SN2-like concerted pathway promoted by diminishing steric strain in the square planar transition state, which explains the high efficiency and stereoinversive feature of this metallate SNV reaction.

Azide-Alkyne Interactions: A Crucial Attractive Force for Their Preorganization for Topochemical Cycloaddition Reaction.

A new class of attractive intermolecular interaction between azide and ethynyl structural entities in a wide range of molecular crystals is reported. This interaction was systematically evaluated by using 11 geometrically different structural motifs that are preorganized to direct a solid-state topochemical azide-alkyne cycloaddition (TAAC) reaction. The supramolecular features of the azide-alkyne interaction were mapped by various crystallographic and quantum chemical approaches. Topological analysis shows the noticeable participation of electron density in the azide⋅⋅⋅alkyne interactions. Interestingly, reorientation of the atomic polarizabilities in vicinal azide and alkyne groups upon interaction in crystals favors soft orbital-guided TAAC reactions. Moreover, various solid-state and gas-phase energy decomposition methods of individual azide⋅⋅⋅alkyne interactions summarize that the strength (varies from -5.7 to -30.1 kJ mol-1 ) is primarily guided by the dispersion forces with a influencing contribution from the electrostatics.

Secondary Structure Tuning of a Pseudoprotein Between ß-Meander and α-Helical Forms in the Solid-State.

Tuning the secondary structure of a protein or polymer in the solid-state is challenging. Here we report the topochemical synthesis of a pseudoprotein and its secondary structure tuning in the solid-state. We designed the dipeptide monomer N3 -Leu-Ala-NH-CH2 -C≡CH (1) for topochemical azide-alkyne cycloaddition (TAAC) polymerization. Dipeptide 1 adopts an anti-parallel ß-sheet-like stacked arrangement in its crystals. Upon heating, the dipeptide undergoes quantitative TAAC polymerization in a crystal-to-crystal fashion yielding large polymers. The reaction occurs between the adjacent monomers in the H-bonded anti-parallel stack, yielding pseudoprotein having a ß-meander structure. When dissolved in methanol, this pseudoprotein changes its secondary structure from ß-meander to α-helical form and it retains the new secondary structure upon desolvation. This work demonstrates a novel paradigm for tuning the secondary structure of a polymer in the solid-state.

Novel Substrates for Kinases Involved in the Biosynthesis of Inositol Pyrophosphates and Their Enhancement of ATPase Activity of a Kinase.

IP6K and PPIP5K are two kinases involved in the synthesis of inositol pyrophosphates. Synthetic analogs or mimics are necessary to understand the substrate specificity of these enzymes and to find molecules that can alter inositol pyrophosphate synthesis. In this context, we synthesized four scyllo-inositol polyphosphates-scyllo-IP5, scyllo-IP6, scyllo-IP7 and Bz-scyllo-IP5-from myo-inositol and studied their activity as substrates for mouse IP6K1 and the catalytic domain of VIP1, the budding yeast variant of PPIP5K. We incubated these scyllo-inositol polyphosphates with these kinases and ATP as the phosphate donor. We tracked enzyme activity by measuring the amount of radiolabeled scyllo-inositol pyrophosphate product formed and the amount of ATP consumed. All scyllo-inositol polyphosphates are substrates for both the kinases but they are weaker than the corresponding myo-inositol phosphate. Our study reveals the importance of axial-hydroxyl/phosphate for IP6K1 substrate recognition. We found that all these derivatives enhance the ATPase activity of VIP1. We found very weak ligand-induced ATPase activity for IP6K1. Benzoyl-scyllo-IP5 was the most potent ligand to induce IP6K1 ATPase activity despite being a weak substrate. This compound could have potential as a competitive inhibitor.

Azide⋠⋠⋠Oxygen Interaction: A Crystal Engineering Tool for Conformational Locking.

We have designed, synthesized, and crystallized 36 compounds, each containing an azide group and an oxygen atom separated by three bonds. Crystal structure analysis revealed that each of these molecules adopts a conformation in which the azide and oxygen groups orient syn to each other with a short O⋅⋅⋅Nß contact. Geometry-optimized structures [using M06-2X/6-311G(d,p) level of theory] also showed the syn conformation in all 36 of these cases, suggesting that this is not merely a crystal packing effect. Quantum topological analysis using Bader's Atoms in Molecules (AIM) theory revealed bond paths and bond critical points (BCP) in these structures suggesting its nature and energetics to be similar to weak hydrogen bonding. The NCI-RDG plot clearly revealed the attractive interaction consisting of electrostatic or dispersive components in all the 36 systems. NBO analysis suggested a weak orbital-relaxation (charge-transfer) contribution of energy for a few (sp2) O-donor systems. Natural population analysis (NPA) and molecular electrostatic potential mapping (MESP) of these crystal structures further revealed the existence of favorable azide-oxygen interaction. A CSD search indicated the frequent and consistent occurrence of this interaction and its role dictating the syn conformation of azide and oxygen in molecules where these groups are separated by 2-4 bonds.