1,2,3-Triazole-Containing Azamacrocycles from Chiral Triazolopeptoids: Synthesis and Solid-State Studies.

Two new chiral 1,2,3-triazole-containing macrocyclic oligoamides (i. e.: triazolopeptoid 4 and 5) were obtained through solid-phase synthesis of linear precursors followed by high dilution macrocyclization reaction. Theoretical (DFT) and spectroscopic (NMR) studies revealed the intricate interplay between the Nα-chiral side chains and their conformational attitudes. BH3-mediated reduction of the tertiary amide groups of known 1-3 and newly synthesized 4 gave novel azamacrocycles 6-9. Detection of borane complexes of azamacrocycles 6 and 9 (i. e.: 10 and 11), corroborated by X-ray diffraction studies, demonstrated the peculiar properties of 1,2,3-triazole-containing macrorings.

Borane-Trimethylamine Complex: A Versatile Reagent in Organic Synthesis.

Borane-trimethylamine complex (Me3N·BH3; BTM) is the most stable of the amine-borane complexes that are commercially available, and it is cost-effective. It is a valuable reagent in organic chemistry with applications in the reduction of carbonyl groups and carbon-nitrogen double bond reduction, with considerable examples in the reduction of oximes, hydrazones and azines. The transfer hydrogenation of aromatic N-heterocycles and the selective N-monomethylation of primary anilines are further examples of recent applications, whereas the reduction of nitrobenzenes to anilines and the reductive deprotection of N-tritylamines are useful tools in the organic synthesis. Moreover, BTM is the main reagent in the regioselective cleavage of cyclic acetals, a reaction of great importance for carbohydrate chemistry. Recent innovative applications of BTM, such as CO2 utilization as feedstock and radical chemistry by photocatalysis, have extended their usefulness in new reactions. The present review is focused on the applications of borane-trimethylamine complex as a reagent in organic synthesis and has not been covered in previous reviews regarding amine-borane complexes.

Chiral Aminoalcohols and Squaric Acid Amides as Ligands for Asymmetric Borane Reduction of Ketones: Insight to In Situ Formed Catalytic System by DOSY and Multinuclear NMR Experiments.

A series of squaric acid amides (synthesized in 66-99% isolated yields) and a set of chiral aminoalcohols were comparatively studied as ligands in a model reaction of reduction of α-chloroacetophenone with BH3•SMe2. In all cases, the aminoalcohols demonstrated better efficiency (up to 94% ee), while only poor asymmetric induction was achieved with the corresponding squaramides. A mechanistic insight on the in situ formation and stability at room temperature of intermediates generated from ligands and borane as possible precursors of the oxazaborolidine-based catalytic system has been obtained by 1H DOSY and multinuclear 1D and 2D (1H, 10/11B, 13C, 15N) NMR spectroscopy of equimolar mixtures of borane and selected ligands. These results contribute to better understanding the complexity of the processes occurring in the reaction mixture prior to the possible oxazaborolidine formation, which play a crucial role on the degree of enantioselectivity achieved in the borane reduction of α-chloroacetophenone.

Aminopyridine-Borane Complexes as Hydrogen Atom Donor Reagents: Reaction Mechanism and Substrate Selectivity.

Lewis base-borane complexes are shown to be potent hydrogen atom donors in radical chain reduction reactions. Results obtained in 1 H, 11 B, and 13 C NMR measurements and kinetic experiments support a complex reaction mechanism involving the parent borane as well as its initial reaction products as active hydrogen atom donors. Efficient reduction reactions of iodides, bromides, and xanthates in apolar solvents rely on initiator systems generating oxygen-centered radicals under thermal conditions and pyridine-borane complexes carrying solubilizing substituents. In contrast to tin hydride reagents, the pyridine-boranes reduce xanthates faster than the corresponding iodides.

CAAC Boranes. Synthesis and characterization of cyclic (alkyl) (amino) carbene borane complexes from BF3 and BH3.

In situ formation of two cyclic (alkyl) (amino) carbenes (CAACs) followed by addition of BF3•Et2O provided the first two examples of CAAC-BF3 complexes: 1-(2,6-diisopropylphenyl)-3,5,5-trimethyl-3-phenylpyrrolidin-2-ylidene trifluoroborane, and 2-(2,6-diisopropylphenyl)-3,3-dimethyl-2-azaspiro[4.5]decan-1-ylidene trifluoroborane. These CAAC-BF3 complexes are robust compounds that are stable to ambient laboratory conditions and silica gel chromatography. They were characterized by spectroscopy and X-ray crystallography. In contrast, a CAAC complex with borane (BH3) was readily formed in situ according to ¹H and ¹¹B NMR analysis, but did not survive the workup conditions. These results set the stage for further studies of the chemistry of CAAC boranes.

Alkaline Earth Metal-Mediated Highly Iso-selective Ring-Opening Polymerization of rac-Lactide.

Alkaline earth (Ae) metal complexes of the aminophosphine borane ligand are highly active and iso-selective catalysts for the ring-opening polymerization (ROP) of rac-lactide (LA). The polymerization reactions are well controlled and produce polylactides with molecular weights that are precise and narrowly distributed. Kinetic studies reveal that the ROP of rac-LA catalyzed by all Ae metal complexes had a first-order dependency on LA concentration as well as catalyst concentration. A plausible reaction mechanism for Ae metal complex-mediated ROP of rac-LA is discussed, based on controlled kinetic experiments and molecular chain mobility.

Intracellular disulfide reduction by phosphine-borane complexes: Mechanism of action for neuroprotection.

Phosphine-borane complexes are novel cell-permeable drugs that protect neurons from axonal injury in vitro and in vivo. These drugs activate the extracellular signal-regulated kinases 1/2 (ERK1/2) cell survival pathway and are therefore neuroprotective, but do not scavenge superoxide. In order to understand the interaction between superoxide signaling of neuronal death and the action of phosphine-borane complexes, their biochemical activity in cell-free and in vitro assays was studied by electron paramagnetic resonance (EPR) spectrometry and using an intracellular dithiol reporter that becomes fluorescent when its disulfide bond is cleaved. These studies demonstrated that bis(3-propionic acid methyl ester) phenylphosphine-borane complex (PB1) and (3-propionic acid methyl ester) diphenylphosphine-borane complex (PB2) are potent intracellular disulfide reducing agents which are cell permeable. EPR and pharmacological studies demonstrated reducing activity but not scavenging of superoxide. Given that phosphine-borane complexes reduce cell injury from mitochondrial superoxide generation but do not scavenge superoxide, this implies a mechanism where an intracellular superoxide burst induces downstream formation of protein disulfides. The redox-dependent cleavage of the disulfides is therefore a novel mechanism of neuroprotection.

Borane-protected phosphines are redox-active radioprotective agents for endothelial cells.

Exposure to radiation can damage endothelial cells in the irradiated area via the production of reactive oxygen species. We synthesized phosphine-borane complexes that reduce disulfide bonds and had previously been shown to interfere with redox-mediated signaling of cell death. We hypothesized that this class of drugs could interfere with the downstream effects of oxidative stress after irradiation and rescue endothelial cells from radiation damage. Cultured bovine aortic endothelial cells were plated for clonogenic assay prior to exposure to varying doses of irradiation from a (137)Cs irradiator and treated with various concentrations of bis(3-propionic acid methyl ester)phenylphosphine borane complex (PB1) at different time points. The clone-forming ability of the irradiated cells was assessed seven days after irradiation. We compared the radioprotective effects of PB1 with the aminothiol radioprotectant WR1065 and known superoxide scavengers. PB1 significantly protected bovine aortic endothelial cells from radiation damage, particularly when treated both before and after radiation. The radioprotection with 1 µM PB1 corresponded to a dose-reduction factor of 1.24. Radioprotection by PB1 was comparable to the aminothiol WR1065, but was significantly less toxic and required much lower concentrations of drug (1 µM vs. 4 mM, respectively). Superoxide scavengers were not radioprotective in this paradigm, indicating the mechanisms for both loss of clonogenicity and PB1 radioprotection are independent of superoxide signaling. These data demonstrate that PB1 is an effective redox-active radioprotectant for endothelial cells in vitro, and is radioprotective at a concentration approximately 4 orders of magnitude lower than the aminothiol WR1065 with less toxicity.