Manganese(I)-Catalyzed H-P Bond Activation via Metal-Ligand Cooperation

Here we report that chiral Mn(I) complexes are capable of H-P bond activation. This activation mode enables a general method for the hydrophosphination of internal and terminal α,β-unsaturated nitriles. Metal-ligand cooperation, a strategy previously not considered for catalytic H-P bond activation, is at the base of the mechanistic action of the Mn(I)-based catalyst. Our computational studies support a stepwise mechanism for the hydrophosphination and provide insight into the origin of the enantioselectivity

<i>In situ</i> EPR and Raman spectroscopy in the curing of bis-methacrylate-styrene resins

The curing of bis-methacrylate-styrene resins initiated by the cobalt catalyzed decomposition of cumyl hydroperoxide is monitored at ambient temperatures in situ by EPR and Raman spectroscopy. EPR spectroscopy shows the appearance of organic radicals after ca. 1 h from initiation with an increase in intensity from both polystyrene and methacrylate based radical species over a further ca. 2 h period to reach a maximum spin concentration of ca. 2-3 mM. Alkene conversion to polymer was monitored by Raman spectroscopy in real time in situ with EPR spectroscopy and reveals that the appearance of the radical signals is first observed only as the conversion approaches its maximum extent (70% at room temperature), i.e., the resin reaches a glass-like state. The radicals persist for several months on standing at room temperature. Flash frozen samples (77 K) did not show EPR signals within 1 h of initiation. The nature of the radicals responsible for the EPR spectra observed were explored by DFT methods and isotope labelling experiments (D8-styrene) and correspond to radicals of both methacrylate and polystyrene. Combined temperature dependent EPR and Raman spectroscopy shows that conversion increases rapidly upon heating of a cured sample, reaching full conversion at 80 °C with initially little effect on the EPR spectrum. Over time (i.e. subsequent to reaching full conversion of alkene) there was a small but clear increase in the EPR signal due to the methacrylate based radicals and minor decrease in the signal due to the polystyrene based radicals. The appearance of the radical signals as the reaction reaches completion and their absence in samples flash frozen before polymerization has halted, indicate that the observed radicals are non-propagating. The formation of the radicals due to stress within the samples is excluded. Hence, the observed radicals are a representative of the steady state concentration of radicals present in the resin over the entire timespan of the polymerization. The data indicate that the lack of EPR signals is most likely due to experimental aspects, in particular spin saturation, rather than low steady state concentrations of propagating radicals during polymerization.</p

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)

Enantioselective Hydrophosphination of Terminal Alkenyl aza-Heteroarenes

This paper presents the first Mn(I)-catalysed methodology for enantioselective hydrophosphination of terminal alkenyl aza-heteroarenes. The catalyst operates through H-P bond activation, enabling successful hydrophosphination of a diverse range of alkenyl-heteroarenes with high enantioselectivity. The presented protocol addresses the inherently low reactivity and the commonly encountered suboptimal enantioselectivities of these challenging substrates. As an important application we show that this method facilitates the synthesis of a non-symmetric tridentate P,N,P-containing ligand like structure in just two synthetic steps using a single catalytic system.</p

Enantioselective Hydrophosphination of Terminal Alkenyl aza-Heteroarenes

This paper presents the first Mn(I)-catalysed methodology for enantioselective hydrophosphination of terminal alkenyl aza-heteroarenes. The catalyst operates through H-P bond activation, enabling successful hydrophosphination of a diverse range of alkenyl-heteroarenes with high enantioselectivity. The presented protocol addresses the inherently low reactivity and the commonly encountered suboptimal enantioselectivities of these challenging substrates. As an important application we show that this method facilitates the synthesis of a non-symmetric tridentate P,N,P-containing ligand like structure in just two synthetic steps using a single catalytic system.</p

Enantio- and Z-selective synthesis of functionalized alkenes bearing tertiary allylic stereogenic center

Olefins are ubiquitous in biologically active molecules and frequently used as building blocks in chemical transformations. However, although many strategies exist for the synthesis of stereodefined E-olefines, their thermodynamically less stable Z counterparts are substantially more demanding, while access to those bearing an allylic stereocenter with an adjacent reactive functionality remains unsolved altogether. Even the classic Wittig reaction, arguably the most versatile and widely used approach to construct Z-alkenes, falls short for the synthesis of these particularly challenging yet highly useful structural motives. Here, we report a general methodology for Z-selective synthesis of functionalized chiral alkenes that establishes readily available alkene-derived phosphines as an alternative to alkylating reagents in Wittig olefination, thus offering previously unidentified retrosynthetic disconnections for the formation of functionalized disubstituted alkenes. We demonstrate the potential of this method by structural diversification of several bioactive molecules

Manganese(I)-Catalyzed Asymmetric Hydrophosphination of α,β-Unsaturated Carbonyl Derivatives

Here we report catalytic asymmetric hydrophosphination of α,β-unsaturated carbonyl derivatives using a chiral Mn(I) complex as a catalyst. Through H-P bond activation, various phosphine-containing chiral products can be accessed via hydrophosphination of various ketone-, ester-, and carboxamide-based Michael acceptors

Activation of alkyl hydroperoxides by manganese complexes of tmtacn for initiation of radical polymerisation of alkenes

The activation of alkyl hydroperoxides to generate radicals is a key step in the initiation of radical polymerisations in many industrial applications, not least protective coatings. Cobalt soaps (Co(II) alkyl carboxylates) are highly effective catalysts under ambient conditions but viable alternatives based on less scarce catalysts are desirable, with especially iron and manganese catalysts showing potential. Manganese complexes of the ligand N,N′,N″-trimethyl-1,4,7-triazacyclononane (tmtacn) are long established as catalysts for organic oxidations with H2O2, however their reactivity with alkyl hydroperoxides is less studied especially in apolar solvents. Here we show that this family of complexes can be employed as catalysts for the decomposition of alkyl hydroperoxides in apolar solvents such as styrene/methyl methacrylate mixtures and resins based on styrene/bisphenol-A based diglycidyl ether bismethacrylate (BADGE-MA). The progress of alkene polymerisation in crosslinking resins is followed by Raman spectroscopy to establish its dependence on the oxidation state of the manganese catalyst used, as gelation time and onset of autoacceleration are of particular interest for many applications. We show, through reaction progress monitoring with UV/vis absorption and Raman spectroscopy, that the stability of the manganese complexes in the resin mixtures has a substantial effect on curing progress and that the oxidation state of the resting state of the catalyst is most likely Mn(II), in contrast to reactions with H2O2 as oxidant in which the oxidation state of the resting state of catalyst is Mn(III). Manganese complexes of tmtacn are shown to be capable initiators of alkene radical polymerisations, and their rich coordination and redox chemistry means that resin curing kinetics can potentially be tuned more readily than with cobalt alkyl carboxylates.</p

Activation of alkyl hydroperoxides by manganese com plexes of tmtacn for initiation of radical polymerisation of alkenes

The activation of alkyl hydroperoxides to generate radicals is a key step in the initiation of radical polymerisations in many industrial applications, not least protective coatings. Cobalt soaps are highly effective catalysts under ambient conditions but viable alternatives based on less scarce catalysts are desirable, with especially iron and manganese catalysts showing potential. Manganese complexes of the ligand N,N\u27,N"-trimethyl-1,4,7-triazacyclononane (tmtacn) are long established as catalysts for organic oxidations with H2O2, however their reactivity with alkyl hydroperoxides is less studied especially in low- or apolar solvents. Here we show that this family of complexes can be employed as catalysts for the decomposition of alkyl hydroperoxides in apolar solvents such as styrene/methyl methacrylate mixtures and resins based on styrene/bisphenol-A based diglycidyl ether bismethacrylate (BADGE-MA). The progress of alkene polymerisation in crosslinking resins is followed by Raman spectroscopy to establish its dependence on the oxidation state of the manganese catalyst used, as gelation time and onset of autoacceleration are of particular interest for many applications. We show, through reaction progress monitoring with UV/vis absorption and Raman spectroscopy, that the stability of the manganese complexes in the resin mixtures has a substantial effect on curing progress and that the oxidation state of the resting state of the catalyst is most likely Mn(II), in contrast to reactions with H2O2 as oxidant in which the oxidation state of the resting state of catalyst is Mn(III). Manganese complexes of tmtacn are shown to be capable initiators of alkene radical polymerisations, and their rich coordination and redox chemistry means that resin curing kinetics can potentially be tuned more readily than with cobalt soaps