A Mechanistic Rationale for the 9‑Amino(9-deoxy)<i>epi</i> Cinchona Alkaloids Catalyzed Asymmetric Reactions via Iminium Ion Activation of Enones

The 9-amino­(9-deoxy)<i>epi</i> cinchona alkaloids have expanded the synthetic potential of asymmetric aminocatalysis, enabling the highly stereoselective functionalization of a variety of sterically hindered carbonyl compounds. However, there is a lack of basic understanding of the mechanisms of cinchona-based primary aminocatalysis. Herein, we describe how a combination of experimental and theoretical mechanistic studies has revealed the origin of the stereoselectivity of the Friedel–Crafts alkylation of indoles with α,β-unsaturated ketones catalyzed by 9-amino­(9-deoxy)<i>epi</i> quinine. An essential role for the achiral acid cocatalyst is uncovered: upon condensation of the cinchona catalyst with the enone, the resulting covalent imine intermediate and the acid interact to build-up a well-structured ion-pair supramolecular catalytic assembly, which is stabilized by multiple attractive noncovalent interactions. All the components of the assembly cooperatively participate in the stereocontrolling event, with the anion of the achiral acid being the structural element responsible for the π-facial discrimination of the iminium ion intermediate

Unexpected pincer-type coordination (?³-SBS) within a zerovalent platinum metallaboratrane complex

The first structurally characterised zerovalent platinum complex to contain a tridentate pincer-type coordination mode (?3-SBS) is presented, raising further questions concerning the geometries and trans influence of Z-type ligands

Influence of the Solvent and Metal Center on Supramolecular Chirality Induction with Bisporphyrin Tweezer Receptors. Strong Metal Modulation of Effective Molarity Values

We describe the synthesis of a bisporphyrin tweezer receptor <b>1</b>·H₄ and its metalation with Zn­(II) and Rh­(III) cations. We report the thermodynamic characterization of the supramolecular chirality induction process that takes place when the metalated bisporphyrin receptors coordinate to enantiopure 1,2-diaminocyclohexane in two different solvents, toluene and dichloromethane. We also performed a thorough study of several simpler systems that were used as models for the thermodynamic characterization of the more complex bisporphyrin systems. The initial complexation of the chiral diamine with the bisporphyrins produces a 1:1 sandwich complex that opens up to yield a simple 1:2 complex in the presence of excess diamine. The CD spectra associated with the 1:1 and 1:2 complexes of both metalloporphyrins, <b>1</b>·Zn₂ and <b>1</b>·Rh₂, display bisignate Cotton effects when the chirogenesis process is studied in toluene solutions. On the contrary, in dichloromethane solutions, only <b>1</b>·Zn₂ yields CD-active 1:1 and 1:2 complexes, while the 1:2 complex of <b>1</b>·Rh₂ is CD-silent. In both solvents, porphyrin <b>1</b>·Zn₂ features a stoichiometrically controlled chirality inversion process, which is the sign of the Cotton effect of the 1:1 complex is opposite to that of the 1:2 complex. In contrast, porphyrin <b>1</b>·Rh₂ affords 1:1 and 1:2 complexes in toluene solutions with the same sign for their CD couplets. Interestingly, in both solvents, the signs of the CD couplets associated with the 1:1 sandwich complexes of <b>1</b>·Zn₂ and <b>1</b>·Rh₂ are opposite. The amplitudes of the CD couplets are higher for <b>1</b>·Zn₂ than for <b>1</b>·Rh₂. This observation is in agreement with <b>1</b>·Rh₂ having a smaller extinction coefficient than <b>1</b>·Zn₂. We performed DFT-based calculations and assigned molecular structures to the 1:1 and 1:2 complexes that explain the observed signs for their CD couplets. Unexpectedly, the quantification of the thermodynamic stability of the two metallobisporphyrin/diamine 1:1 sandwich complexes revealed the existence of interplay between effective molarity values (EM) and the strength of the intermolecular interaction (<i>K</i>_m; N···Zn or N···Rh) used in their assembly. The EM for the N···Rh­(III) intramolecular interaction is 3 orders of magnitude smaller than that for the N···Zn­(II) interaction, both of which are embedded in the same scaffold of the <b>1</b>·M₂ bisporphyrin receptor

Insight into the Hydrogen Migration Processes Involved in the Formation of Metal–Borane Complexes: Importance of the Third Arm of the Scorpionate Ligand

The reactions of [Ir­(κ³<i>N</i>,<i>N</i>,<i>H</i>-<b>Tai</b>)­(COD)] and [Ir­(κ³<i>N</i>,<i>N</i>,<i>H</i>-^<b>Ph</b><b>Bai</b>)­(COD)] (where <b>Tai</b> = HB­(azaindolyl)₃ and ^<b>Ph</b><b>Bai</b> = Ph­(H)­B­(azaindolyl)₂) with carbon monoxide result in the formation of Z-type iridium–borane complexes supported by 7-azaindole units. Analysis of the reaction mixtures involving the former complex revealed the formation of a single species in solution, [Ir­(η¹-C₈H₁₃)­{κ³<i>N</i>,<i>N</i>,<i>B</i>-B­(azaindolyl)₃}­(CO)₂], as confirmed by NMR spectroscopy. In the case of the ^<b>Ph</b><b>Bai</b> complex, a mixture of species was observed. A postulated mechanism for the formation of the new complexes has been provided, supported by computational studies. Computational studies have also focused on the reaction step involving the migration of hydrogen from boron (in the borohydride group) to the iridium center. These investigations have demonstrated a small energy barrier for the hydrogen migration step (Δ<i>G</i>₂₉₈ = 10.3 kcal mol^–1). Additionally, deuterium labeling of the borohydride units in <b>Tai</b> and ^<b>Ph</b><b>Bai</b> confirmed the final position of the former borohydride hydrogen atom in the resulting complexes. The importance of the “third azaindolyl” unit within these transformations and the difference in reactivity between the two ligands are discussed. The selective coordination properties of this family of metallaboratrane complexes have also been investigated and are discussed herein

Insight into the Hydrogen Migration Processes Involved in the Formation of Metal–Borane Complexes: Importance of the Third Arm of the Scorpionate Ligand

The reactions of [Ir­(κ³<i>N</i>,<i>N</i>,<i>H</i>-<b>Tai</b>)­(COD)] and [Ir­(κ³<i>N</i>,<i>N</i>,<i>H</i>-^<b>Ph</b><b>Bai</b>)­(COD)] (where <b>Tai</b> = HB­(azaindolyl)₃ and ^<b>Ph</b><b>Bai</b> = Ph­(H)­B­(azaindolyl)₂) with carbon monoxide result in the formation of Z-type iridium–borane complexes supported by 7-azaindole units. Analysis of the reaction mixtures involving the former complex revealed the formation of a single species in solution, [Ir­(η¹-C₈H₁₃)­{κ³<i>N</i>,<i>N</i>,<i>B</i>-B­(azaindolyl)₃}­(CO)₂], as confirmed by NMR spectroscopy. In the case of the ^<b>Ph</b><b>Bai</b> complex, a mixture of species was observed. A postulated mechanism for the formation of the new complexes has been provided, supported by computational studies. Computational studies have also focused on the reaction step involving the migration of hydrogen from boron (in the borohydride group) to the iridium center. These investigations have demonstrated a small energy barrier for the hydrogen migration step (Δ<i>G</i>₂₉₈ = 10.3 kcal mol^–1). Additionally, deuterium labeling of the borohydride units in <b>Tai</b> and ^<b>Ph</b><b>Bai</b> confirmed the final position of the former borohydride hydrogen atom in the resulting complexes. The importance of the “third azaindolyl” unit within these transformations and the difference in reactivity between the two ligands are discussed. The selective coordination properties of this family of metallaboratrane complexes have also been investigated and are discussed herein

Unexpectedly High Barriers to M–P Rotation in Tertiary Phobane Complexes: PhobPR Behavior That Is Commensurate with ^tBu₂PR

The four isomers of 9-butylphosphabicyclo[3.3.1]­nonane, <i>s-</i>PhobPBu, where Bu = <i>n</i>-butyl, <i>sec</i>-butyl, isobutyl, <i>tert</i>-butyl, have been prepared. Seven isomers of 9-butylphosphabicyclo[4.2.1]­nonane (<i>a</i>₅<i>-</i>PhobPBu, where Bu = <i>n</i>-butyl, <i>sec</i>-butyl, isobutyl, <i>tert</i>-butyl; <i>a</i>₇<i>-</i>PhobPBu, where Bu = <i>n-</i>butyl, isobutyl, <i>tert</i>-butyl) have been identified in solution; isomerically pure <i>a</i>₅<i>-</i>PhobPBu and <i>a</i>₇<i>-</i>PhobPBu, where Bu = <i>n</i>-butyl, isobutyl, have been isolated. The σ-donor properties of the PhobPBu ligands have been compared using the <i>J</i>_PSe values for the PhobP­(Se)­Bu derivatives. The following complexes have been prepared: <i>trans-</i>[PtCl₂(<i>s-</i>PhobPR)₂] (R = ⁿBu (<b>1a</b>), ⁱBu (<b>1b</b>), ^sBu (<b>1c</b>), ^tBu (<b>1d</b>)); <i>trans-</i>[PtCl₂(<i>a</i>₅<i>-</i>PhobPR)₂] (R = ⁿBu (<b>2a</b>), ⁱBu (<b>2b</b>)); <i>trans-</i>[PtCl₂(<i>a</i>₇<i>-</i>PhobPR)₂] (R = ⁿBu (<b>3a</b>), ⁱBu (<b>3b</b>)); <i>trans-</i>[PdCl₂(<i>s-</i>PhobPR)₂] (R = ⁿBu (<b>4a</b>), ⁱBu (<b>4b</b>)); <i>trans-</i>[PdCl₂(<i>a</i>₅<i>-</i>PhobPR)₂] (R = ⁿBu (<b>5a</b>), ⁱBu (<b>5b</b>)); <i>trans-</i>[PdCl₂(<i>a</i>₇<i>-</i>PhobPR)₂] (R = ⁿBu (<b>6a</b>), ⁱBu (<b>6b</b>)). The crystal structures of <b>1a</b>–<b>4a</b> and <b>1b</b>–<b>6b</b> have been determined, and of the ten structures, eight show an anti conformation with respect to the position of the ligand R groups and two show a syn conformation. Solution variable-temperature ³¹P NMR studies reveal that all of the Pt and Pd complexes are fluxional on the NMR time scale. In each case, two species are present (assigned to be the syn and anti conformers) which interconvert with kinetic barriers in the range 9 to >19 kcal mol^–1. The observed trend is that, the greater the bulk, the higher the barrier. The magnitudes of the barriers to M–P bond rotation for the PhobPR complexes are of the same order as those previously reported for ^tBu₂PR complexes. Rotational profiles have been calculated for the model anionic complexes [PhobPR-PdCl₃]⁻ using DFT, and these faithfully reproduce the trends seen in the NMR studies of <i>trans-</i>[MCl₂(PhobPR)₂]. Rotational profiles have also been calculated for [^tBu₂PR-PdCl₃]⁻, and these show that the greater the bulk of the R group, the lower the rotational barrier: i.e., the opposite of the trend for [PhobPR-PdCl₃]⁻. Calculated structures for the species at the maxima and minima in the M–P rotation energy curves indicate the origin of the restricted rotation. In the case of the PhobPR complexes, it is the rigidity of the bicycle that enforces unfavorable H···Cl clashes involving the Pd–Cl groups with H atoms on the α- or β-carbon in the R substituent and H atoms in 1,3-axial sites within the phosphabicycle

Evaluating the effect of a digital health intervention to enhance physical activity in people with chronic kidney disease (Kidney BEAM): a multicentre, randomised controlled trial in the UK

Background Remote digital health interventions to enhance physical activity provide a potential solution to improve the sedentary behaviour, physical inactivity, and poor health-related quality of life that are typical of chronic conditions, particularly for people with chronic kidney disease. However, there is a need for high-quality evidence to support implementation in clinical practice. The Kidney BEAM trial evaluated the clinical effect of a 12-week physical activity digital health intervention on health-related quality of life. Methods In a single-blind, randomised controlled trial conducted at 11 centres in the UK, adult participants (aged ≥18 years) with chronic kidney disease were recruited and randomly assigned (1:1) to the Kidney BEAM physical activity digital health intervention or a waiting list control group. Randomisation was performed with a web-based system, in randomly permuted blocks of six. Outcome assessors were masked to treatment allocation. The primary outcome was the difference in the Kidney Disease Quality of Life Short Form version 1.3 Mental Component Summary (KDQoL-SF1.3 MCS) between baseline and 12 weeks. The trial was powered to detect a clinically meaningful difference of 3 arbitrary units (AU) in KDQoL-SF1.3 MCS. Outcomes were analysed by an intention-to-treat approach using an analysis of covariance model, with baseline measures and age as covariates. The trial was registered with ClinicalTrials.gov, NCT04872933. Findings Between May 6, 2021, and Oct 30, 2022, 1102 individuals were assessed for eligibility, of whom 340 participants were enrolled and randomly assigned to the Kidney BEAM intervention group (n=173) or the waiting list control group (n=167). 268 participants completed the trial (112 in the Kidney BEAM group and 156 in the waiting list control group). All 340 randomly assigned participants were included in the intention-to treat population. At 12 weeks, there was a significant improvement in KDQoL-SF.13 MCS score in the Kidney BEAM group (from mean 44·6 AU [SD 10·8] at baseline to 47·0 AU [10·6] at 12 weeks) compared with the waiting list control group (from 46·1 AU [10·5] to 45·0 AU [10·1]; between-group difference of 3·1 AU [95% CI 1·8–4·4]; p Interpretation The Kidney BEAM physical activity platform is an efficacious digital health intervention to improve mental health-related quality of life in patients with chronic kidney disease. These findings could facilitate the incorporation of remote digital health interventions into clinical practice and offer a potential intervention worthy of investigation in other chronic conditions.</p