Nickel‐Catalyzed Arylboration of Alkenylarenes: Synthesis of Boron‐Substituted Quaternary Carbons and Regiodivergent Reactions

A method for the construction of boron‐substituted quaternary carbons or diarylquaternary carbons by arylboration of highly substituted alkenylarenes is presented. A wide range of alkenes and arylbromides can participate in this reaction thus allowing for a diverse assortment of products to be prepared. In addition, a solvent dependent regiodivergent arylboration of 1,2‐disubstituted alkenylarenes is presented, thus greatly increasing the scope of products that can be accessed.     

Evolution of a forced counter rotating vortex pair for two selected forcing frequencies

In this paper, results from an experimental study of the natural and forced evolution of a pair of counter rotating wing-tip vortices are reported. The vortices were generated using a pair of opposed wing-tips in a wind tunnel and measurements made up to 77 tip-spacings downstream of the models at a chord Reynolds number of 1.3 × 10⁵. The wake was interrogated using 2D particle image velocimetry and the long-wave Crow instability observed. Velocity data were recorded throughout the lifetime of the instability from initial growth through linking, formation of vortex rings and their subsequent decay. Forcing was achieved using pulsed air jets blowing in the span-wise direction from the wing tip and imparting spatially periodic perturbations to the vortices. Forcing at a frequency within the range amplified by the Crow instability was found to enhance the instability growth rate whereas forcing at a frequency outside the amplified range was found to inhibit instability growth. In the latter case the imparted wavelength was observed to die out with a preferred wavelength growing in its place.     

Direct Cyclopropanation of α-Cyano β-Aryl Alkanes by Light-Mediated Single Electron Transfer Between Donor–Acceptor Pairs

Cyclopropanes are traditionally prepared by the formal [2+1] addition of carbene or radical based C1 units to alkenes. In contrast, the one-pot intermolecular cyclopropanation of alkanes by redox active C1 units has remained unrealised. Herein, we achieved this process simply by exposing β-aryl propionitriles and C1 radical precursors (N-oxy esters) to base and blue light. The overall process is redox-neutral and a photocatalyst, whether metal- or organic-based, is not required. Our findings support that single electron transfer (SET) from the α-cyano carbanion of the propionitrile to the N-oxy ester is facilitated by blue-light via their electron donor–acceptor (EDA) complex. The α-cyano carbon radical thus formed can then lose a β-proton to form a π-resonance stabilised radical anion that preferentially couples at the benzylic β-position with a decarboxylated C1 radical unit. This new transition metal-free chemistry tolerates both electron rich and electron deficient (hetero)aryl systems, even sulfide or alkene functionality, to afford a range of cis-aryl/cyano cyclopropanes bearing congested tetrasubstituted quaternary carbons.     

Synthesis of 2-C-methylerythritols and 2-C-methylthreitols via enantiodivergent Sharpless dihydroxylation of trisubstituted olefins

The mevalonate-independent pathway (MIP) is an interesting avenue for antimicrobial lead discovery. Here, we present a unified enantioselective synthesis of all four stereoisomers of 2-C-methyltetrol. These are useful building blocks of many bioactive natural products, including 2-C-methylerythritol phosphate (MEP) of the MIP biosynthetic pathway.     

Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads

We report not only the convergent total synthesis of falcitidin, a natural inhibitor of falcipain-2 from myxobacterium Chitinophaga, but also its diversification into a new antimalarial class of N-acyl tetrapeptides (Acyl-His-Ile-Val-Pro-NH₂). Despite the lack of whole-cell activity of falcitidin itself, our study led to the identification of a trifluoromethyl (CF₃) analogue displaying sub-micromolar IC₅₀ activity against Plasmodium falciparum 3D7 in a standard blood-cell assay, but only when N-tritylated on its histidine (imidazole) residue.     

Relationship between side chain structure and 14-helix stability of beta3-peptides in water

Folded polymers are used in Nature for virtually every vital process. Nonnatural folded polymers, or foldamers, have the potential for similar versatility, and the design and refinement of such molecules is of considerable current interest. Here we report a complete and systematic analysis of the relationship between side chain structure and the 14-helicity of a well-studied class of foldamers, beta(3)-peptides, in water. Our experimental results (1) verify the importance of macrodipole stabilization for maintaining 14-helix structure, (2) provide comprehensive evidence that beta(3)-amino acids branched at the first side chain carbon are 14-helix-stabilizing, (3) suggest a novel role for side chain hydrogen bonding as an additional stabilizing force in beta(3)-peptides containing beta(3)-homoserine or beta(3)-homothreonine, and (4) demonstrate that diverse functionality can be incorporated into a stable 14-helix. Gas- and solution-phase calculations and Monte Carlo simulations recapitulate the experimental trends only in the context of oligomers, yielding insight into the mechanisms behind 14-helix folding. The 14-helix propensities of beta(3)-amino acids differ starkly from the alpha-helix propensities of analogous alpha-amino acids. This contrast informs current models for alpha-helix folding, and suggests that 14-helix folding is governed by different biophysical forces than is alpha-helix folding. The ability to modulate 14-helix structure through side chain choice will assist rational design of 14-helical beta-peptide ligands for macromolecular targets.     

Design of a functional membrane protein by engineering a heme-binding site in glycophorin A

We have designed a functional model membrane protein by engineering a bis-Histidine heme-binding site into a natural membrane protein, glycophorin A (GpA), structurally characterized by the dimerization of a single transmembrane helix. Out of the 32 residues comprising the transmembrane helix of GpA, five amino acids were mutated; the resulting protein, ME1, has been characterized in dodecyl phosphocholin (DPC) micelles by UV-vis, CD spectroscopy, gel electrophoresis, and analytical ultracentrifugation. ME1 binds heme with sub-micromolar affinity and maintains the highly helical secondary structure and dimeric oligomerization state of GpA. The ME1-Heme complex exhibits a redox potential of -128 +/- 2 mV vs SHE, indicating that the heme resides in a hydrophobic environment and is well shielded from the aqueous phase. Moreover, ME1 catalyzes the hydrogen peroxide dependent oxidation of organic substrates such as TMB (2,2',5,5'-tetramethyl-benzidine). This protein may provide a useful framework to investigate how the protein matrix tunes the cofactor properties in membrane proteins.     

Sterically Demanding Oxidative Amidation of α‐Substituted Malononitriles with Amines Using O2

An efficient amidation method between readily available 1,1‐dicyanoalkanes and either chiral or nonchiral amines was realized simply with molecular oxygen and a carbonate base. This oxidative protocol can be applied to both sterically and electronically challenging substrates in a highly chemoselective, practical, and rapid manner. The use of cyclopropyl and thioether substrates support the radical formation of α‐peroxy malononitrile species, which can cyclize to dioxiranes that can monooxygenate malononitrile α‐carbanions to afford activated acyl cyanides capable of reacting with amine nucleophiles.