Cu-Catalyzed Coupling of Aliphatic Amines with Alkylboronic Esters.

We report a Cu-catalyzed oxidative coupling of aliphatic amines with benzylic and aliphatic boronic esters to give high value alkyl amines, products found widely in applications from medicinal chemistry to materials science. This operationally simple reaction, which can be performed on gram scale, runs under mild conditions and exhibits broad functional group tolerance. The terminal oxidant of the reaction is O2 from the air, avoiding the need for additional chemical oxidants. Investigation into the reaction mechanism suggests that the boronic ester is activated by an aminyl radical, formed through oxidation of the amine by the Cu catalyst, to give a key alkyl radical intermediate. To demonstrate its utility and potential for late-stage functionalization, we showcase the method as the final step in the total synthesis of a TRPV1 antagonist.

Alternative boronic acids in the detection of Mycolactone A/B using the thin layer chromatography (f-TLC) method for diagnosis of Buruli ulcer.

BACKGROUND: Mycobacterium ulcerans is the causative agent of Buruli ulcer. The pathology of M. ulcerans disease has been attributed to the secretion of a potent macrolide cytotoxin known as mycolactone which plays an important role in the virulence of the disease. Mycolactone is a biomarker for the diagnosis of BU that can be detected using the fluorescent-thin layer chromatography (f-TLC) technique. The technique relies on the chemical derivatization of mycolactone A/B with 2-naphthylboronic acid (BA) which acts as a fluorogenic chemosensor. However, background interferences due to co-extracted human tissue lipids, especially with clinical samples coupled with the subjectivity of the method call for an investigation to find an alternative to BA. METHODS: Twenty-six commercially available arylboronic acids were initially screened as alternatives to BA using the f-TLC experiment. UV-vis measurements were also conducted to determine the absorption maximum spectra of mycolactone A/B and myco-boronic acid adducts followed by an investigation of the fluorescence-enhancing ability of the boronate ester formation between mycolactone A/B and our three most promising boronic acids (BA15, BA18, and BA21). LC-MS technique was employed to confirm the adduct formation between mycolactone and boronic acids. Furthermore, a comparative study was conducted between BA18 and BA using 6 Polymerase Chain Reaction (PCR) confirmed BU patient samples. RESULTS: Three of the boronic acids (BA15, BA18, and BA21) produced fluorescent band intensities superior to BA. Complexation studies conducted on thin layer chromatography (TLC) using 0.1 M solution of the three boronic acids and various volumes of 10 ng/µL of synthetic mycolactone ranging from 1 µL - 9 µL corresponding to 10 ng - 90 ng gave similar results with myco-BA18 adduct emerging with the most visibly intense fluorescence bands. UV-vis absorption maxima (λmax) for the free mycolactone A/B was observed at 362 nm, and the values for the adducts myco-BA15, myco-BA18, and myco-BA21 were at 272 nm, 270 nm, and 286 nm respectively. The comparable experimental λmax of 362 nm for mycolactone A/B to the calculated Woodward-Fieser value of 367 nm for the fatty acid side chain of mycolactone A/B demonstrate that even though 2 cyclic boronates were formed, only the boronate of the southern side chain with the chromophore was excited by irradiation at 365 nm. Fluorescence experiments have demonstrated that coupling BA18 to mycolactone A/B along the 1,3-diols remarkably enhanced the fluorescence intensity at 537 nm. High-Resolution Mass Spectrometer (HR-MS) was used to confirm the formation of the myco-BA15 adduct. Finally, f-TLC analysis of patient samples with BA18 gave improved BA18-adduct intensities compared to the original BA-adduct. CONCLUSION: Twenty-six commercially available boronic acids were investigated as alternatives to BA, used in the f-TLC analysis for the diagnosis of BU. Three (3) of them BA15, BA18, and BA21 gave superior fluorescence band intensity profiles. They gave profiles that were easier to interpret after the myco-boronic acid adduct formation and in experiments with clinical samples from patients with BA18 the best. BA18, therefore, has been identified as a potential alternative to BA and could provide a solution to the challenge of background interference of co-extracted human tissue lipids from clinical samples currently associated with the use of BA.

Chan-Lam Amination of Secondary and Tertiary Benzylic Boronic Esters.

We report a Chan-Lam coupling reaction of benzylic and allylic boronic esters with primary and secondary anilines to form valuable alkyl amine products. Both secondary and tertiary boronic esters can be used as coupling partners, with mono-alkylation of the aniline occurring selectively. This is a rare example of a transition-metal-mediated transformation of a tertiary alkylboron reagent. Initial investigation into the reaction mechanism suggests that transmetalation from B to Cu occurs through a single-electron, rather than a two-electron process.

Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aßo-PrPC binding and downstream pathways.

Amyloid ß oligomers (Aßo) are the main toxic species in Alzheimer's disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aßo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aßo binding by a combined 19F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aßo binding to its receptor PrPC in HEK293 cells. They reduced the pFyn levels triggered by Aßo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer's disease pathology, i.e. prion, Aß and Tau, affecting three different pathways through specific binding to Aßo and are, indeed, promising candidates for further development.

Enantioselective Rhodium-Catalyzed Coupling of Arylboronic Acids, 1,3-Enynes, and Imines by Alkenyl-to-Allyl 1,4-Rhodium(I) Migration.

A chiral rhodium complex catalyzes the highly enantioselective coupling of arylboronic acids, 1,3-enynes, and imines to give homoallylic sulfamates. The key step is the generation of allylrhodium(I) species by alkenyl-to-allyl 1,4-rhodium(I) migration.

Arylative Intramolecular Allylation of Ketones with 1,3-Enynes Enabled by Catalytic Alkenyl-to-Allyl 1,4-Rhodium(I) Migration.

Alkenyl-to-allyl 1,4-rhodium(I) migration enables the generation of nucleophilic allylrhodium(I) species by remote C-H activation. This new mode of reactivity was employed in the diastereoselective reaction of arylboron reagents with substrates containing a 1,3-enyne tethered to a ketone, to give products containing three contiguous stereocenters. The products can be obtained in high enantioselectivities using a chiral sulfur-alkene ligand.

Iridium-catalyzed arylative cyclization of alkynones by 1,4-iridium migration.

1,4-Metal migrations enable the remote functionalization of C-H bonds, and have been utilized in a wide variety of valuable synthetic methods. The vast majority of existing examples involve the 1,4-migration of palladium or rhodium. Herein, the stereoselective synthesis of complex polycycles by the iridium-catalyzed arylative cyclization of alkynones with arylboronic acids is described. To our knowledge, these reactions involve the first reported examples of 1,4-iridium migration.

Sterically controlled iodination of arenes via iridium-catalyzed C-H borylation.

A mild method to prepare aryl and heteroaryl iodides by sequential C-H borylation and iodination is reported. The regioselectivity of this process is controlled by steric effects on the C-H borylation step and is complementary to existing methods to form aryl iodides. The iodination of boronic esters has potential for the synthesis of radiolabeled aryl iodides, as demonstrated by the concise synthesis of a potential tracer for SPECT imaging.

Application of the lithiation-borylation reaction to the rapid and enantioselective synthesis of the bisabolane family of sesquiterpenes.

The expedient enantioselective synthesis of 5 bisabolane sesquiterpenes has been achieved using a common, one-pot lithiation-borylation reaction of secondary benzylic carbamates and either protodeboronation or oxidation to give the natural products in fewer than 5 steps, with high yield and >94 : 6 er.

Synthesis, electronic structure, and reactivity of strained nickel-, palladium-, and platinum-bridged [1]ferrocenophanes.

The group 10 bis(phosphine)metalla[1]ferrocenophanes, [{Fe(η(5)-C(5)H(4))(2)}M(Pn-Bu(3))(2)] [M = Ni (4a), Pd (4b), and Pt (4c)], have been prepared by the reaction of Li(2)[Fe(η(5)-C(5)H(4))(2)]·tmeda (5, tmeda = N,N,N',N'-tetramethylethylenediamine) with trans-[MCl(2)(Pn-Bu(3))(2)] [M = Ni (trans-6a) and Pd (trans-6b)] and cis-[PtCl(2)(Pn-Bu(3))(2)] (cis-6c), respectively. Single crystal X-ray diffraction revealed highly tilted, strained structures as characterized by α angles of 28.4° (4a), 24.5° (4b), and 25.2° (4c) and a distorted square planar environment for the group 10 metal center. UV/visible spectroscopy and cyclic voltammetry indicated that all three compounds had smaller HOMO-LUMO gaps and were more electron-rich in nature than ferrocene and other comparable [1]ferrocenophanes. DFT calculations suggested that these differences were principally due to the electron-releasing nature of the M(Pn-Bu(3))(2) metal-ligand fragments. Attempts to induce thermal or anionic ring-opening polymerization of 4a-c were unsuccessful and were complicated by, for example, competing ligand dissociation processes or unfavorable chain propagation. In contrast, these species all reacted rapidly with acids effecting clean extrusion of the bis(phosphine)metal fragment. Carbon monoxide inserted cleanly into one of the palladium-carbon bonds of 4b to afford the ring-expanded, acylated product [{Fe(η(5)-C(5)H(4))(η(5)-C(5)H(4))(CO)}Pd(Pn-Bu(3))(2)] (10). The nickel analogue 4a, however, afforded [Ni(CO)(2)(Pn-Bu(3))(2)] whereas the platinum-bridged complex 4c was inert. Remarkably, all compounds 4a-c were readily oxidized by elemental sulfur to afford the [5,5']bicyclopentadienylidene (pentafulvalene) complexes [{η(4):η(0)-C(5)H(4)(C(5)H(4))}M(Pn-Bu(3))(2)] [M = Ni (11a)] and [(η(2)-C(10)H(8))M(Pn-Bu(3))(2)] [M = Pd (11b) and Pt (11c)] by a formal 4-electron oxidation of the carbocyclic ligands. Compounds 11b and 11c represent the first examples of [5,5']bicyclopentadienylidene as a neutral η(2)-ligand. The relative energies of η(2)-coordination with respect to that of η(4):η(0) bonding were investigated for 11a-c by DFT calculations.