Mechanistic Insights into the Palladium-Catalyzed Aziridination of Aliphatic Amines by C-H Activation.

Detailed kinetic studies and computational investigations have been performed to elucidate the mechanism of a palladium-catalyzed C-H activation aziridination. A theoretical rate law has been derived that matches with experimental observations and has led to an improvement in the reaction conditions. Acetic acid was found to be beneficial in controlling the formation of an off-cycle intermediate, allowing a decrease in catalyst loading and improved yields. Density functional theory (DFT) studies were performed to examine the selectivities observed in the reaction. Evidence for electronic-controlled regioselectivity for the cyclopalladation step was obtained by a distortion-interaction analysis, whereas the aziridination product was justified through dissociation of acetic acid from the palladium(IV) intermediate preceding the product-forming reductive elimination step. The understanding of this reaction mechanism under the synthesis conditions should provide valuable assistance in the comprehension and design of palladium-catalyzed reactions on similar systems.We are grateful to the EPSRC and Pfizer (A.P.S.) for a studentship and the ERC and EPSRC for fellowships (M.J.G.). We are also grateful to Dr Alex Thom and Dr David Pryde (Pfizer) for helpful discussions. The computational work was performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service (http://www.hpc.cam.ac.uk/), provided by Dell Inc. using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England and funding from the Science and Technology Facilities Council. Mass spectrometry data were acquired at the EPSRC UK National Mass Spectrometry Facility at Swansea University.This is the accepted manuscript. The final version is available at http://pubs.acs.org/doi/abs/10.1021/jacs.5b05529

Multicomponent synthesis of tertiary alkylamines by photocatalytic olefin-hydroaminoalkylation.

There is evidence to suggest that increasing the level of saturation (that is, the number of sp3-hybridized carbon atoms) of small molecules can increase their likelihood of success in the drug discovery pipeline1. Owing to their favourable physical properties, alkylamines have become ubiquitous among pharmaceutical agents, small-molecule biological probes and pre-clinical candidates2. Despite their importance, the synthesis of amines is still dominated by two methods: N-alkylation and carbonyl reductive amination3. Therefore, the increasing demand for saturated polar molecules in drug discovery has continued to drive the development of practical catalytic methods for the synthesis of complex alkylamines4-7. In particular, processes that transform accessible feedstocks into sp3-rich architectures provide a strategic advantage in the synthesis of complex alkylamines. Here we report a multicomponent, reductive photocatalytic technology that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involves a visible-light-mediated reduction of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently react with alkenes to form C(sp3)-C(sp3) bonds. The operationally straightforward reaction exhibits broad functional-group tolerance, facilitates the synthesis of drug-like amines that are not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochemical research

Enantioselective and Regiodivergent Copper-Catalyzed Electrophilic Arylation of Allylic Amides with Diaryliodonium Salts.

A catalytic enantioselective and regiodivergent arylation of alkenes is described. Chiral copper(II)bisoxazoline complexes catalyze the addition of diaryliodonium salts to allylic amides in excellent ee. Moreover, the arylation can be controlled by the electronic nature of the diaryliodonium salt enabling the preparation of nonracemic diaryloxazines or β,β'-diaryl enamides.We are grateful to EPSRC, GSK and the University of Cambridge (E.C., H.P.J.M. & M.T.) and the ERC and EPSRC for fellowships (M.J.G.). Mass spectrometry data were acquired at the EPSRC UK National Mass Spectrometry Facility at Swansea University.This is the final version of the article. It first appeared from ACS via http://dx.doi.org/10.1021/jacs.5b0393

A concise and scalable strategy for the total synthesis of dictyodendrin B based on sequential C-H functionalization.

A sequential CH functionalization strategy for the synthesis of the marine alkaloid dictyodendrin B is reported. Our synthesis begins from commercially available 4-bromoindole and involves six direct functionalizations around the heteroarene core as part of a gram-scale strategy towards the natural product.We are grateful to AstraZeneca, Pfizer, and EPSRC (A.K.P., F.O. and R.H.S.) and the ERC and EPSRC for fellowships (M.J.G.).This is the author accepted manuscript. The final version is available from Wiley at http://onlinelibrary.wiley.com/doi/10.1002/anie.201500067/abstract

Trypanosoma cruzi IIc: phylogenetic and phylogeographic insights from sequence and microsatellite analysis and potential impact on emergent Chagas disease.

Trypanosoma cruzi, the etiological agent of Chagas disease, is highly genetically diverse. Numerous lines of evidence point to the existence of six stable genetic lineages or DTUs: TcI, TcIIa, TcIIb, TcIIc, TcIId, and TcIIe. Molecular dating suggests that T. cruzi is likely to have been an endemic infection of neotropical mammalian fauna for many millions of years. Here we have applied a panel of 49 polymorphic microsatellite markers developed from the online T. cruzi genome to document genetic diversity among 53 isolates belonging to TcIIc, a lineage so far recorded almost exclusively in silvatic transmission cycles but increasingly a potential source of human infection. These data are complemented by parallel analysis of sequence variation in a fragment of the glucose-6-phosphate isomerase gene. New isolates confirm that TcIIc is associated with terrestrial transmission cycles and armadillo reservoir hosts, and demonstrate that TcIIc is far more widespread than previously thought, with a distribution at least from Western Venezuela to the Argentine Chaco. We show that TcIIc is truly a discrete T. cruzi lineage, that it could have an ancient origin and that diversity occurs within the terrestrial niche independently of the host species. We also show that spatial structure among TcIIc isolates from its principal host, the armadillo Dasypus novemcinctus, is greater than that among TcI from Didelphis spp. opossums and link this observation to differences in ecology of their respective niches. Homozygosity in TcIIc populations and some linkage indices indicate the possibility of recombination but cannot yet be effectively discriminated from a high genome-wide frequency of gene conversion. Finally, we suggest that the derived TcIIc population genetic data have a vital role in determining the origin of the epidemiologically important hybrid lineages TcIId and TcIIe

Mechanistic investigation into the C(sp3)–H acetoxylation of morpholinones

The study of a selective palladium(II)-catalyzed C(sp3 )–H acetoxylation reaction on a class of cyclic alkyl amines is reported. Computational modelling and kinetic studies were used to provide support for a mechanism involving selective C–O bond formation from a g-aminoalkyl-Pd(IV) intermediate. The C–O bond forming step was computed to occur by a dissociative ionization mechanism followed by an SN2 process involving external acetate attack at the C–Pd(IV) bond. This pathway was computed to be of lowest energy with no competing C–N products observed. Additionally, with a few modifications to reaction conditions, preliminary studies showed that this process could be rendered enantioselective in the presence of a non-racemic BINOL-phosphoric acid

Causality and defect formation in the dynamics of an engineered quantum phase transition in a coupled binary Bose-Einstein condensate

Continuous phase transitions occur in a wide range of physical systems, and provide a context for the study of non-equilibrium dynamics and the formation of topological defects. The Kibble-Zurek (KZ) mechanism predicts the scaling of the resulting density of defects as a function of the quench rate through a critical point, and this can provide an estimate of the critical exponents of a phase transition. In this work we extend our previous study of the miscible-immiscible phase transition of a binary Bose-Einstein condensate (BEC) composed of two hyperfine states in which the spin dynamics are confined to one dimension [J. Sabbatini et al., Phys. Rev. Lett. 107, 230402 (2011)]. The transition is engineered by controlling a Hamiltonian quench of the coupling amplitude of the two hyperfine states, and results in the formation of a random pattern of spatial domains. Using the numerical truncated Wigner phase space method, we show that in a ring BEC the number of domains formed in the phase transitions scales as predicted by the KZ theory. We also consider the same experiment performed with a harmonically trapped BEC, and investigate how the density inhomogeneity modifies the dynamics of the phase transition and the KZ scaling law for the number of domains. We then make use of the symmetry between inhomogeneous phase transitions in anisotropic systems, and an inhomogeneous quench in a homogeneous system, to engineer coupling quenches that allow us to quantify several aspects of inhomogeneous phase transitions. In particular, we quantify the effect of causality in the propagation of the phase transition front on the resulting formation of domain walls, and find indications that the density of defects is determined during the impulse to adiabatic transition after the crossing of the critical point.Comment: 23 pages, 10 figures. Minor corrections, typos, additional referenc

Choice of Moisturiser for Eczema Treatment (COMET):feasibility study of a randomised controlled parallel group trial in children recruited from primary care

OBJECTIVES: To determine the feasibility of a randomised controlled trial of ‘leave on’ emollients for children with eczema. DESIGN: Single-centre, pragmatic, 4-arm, observer-blinded, parallel, randomised feasibility trial. SETTING: General practices in the UK. PARTICIPANTS: Children with eczema aged 1 month to <5 years. OUTCOME MEASURES: Primary outcome—proportion of parents who reported use of the allocated study emollient every day for the duration of follow-up (12 weeks). Other feasibility outcomes—participant recruitment and retention, data collection and completeness and blinding of observers to allocation. INTERVENTIONS: Aveeno lotion, Diprobase cream, Doublebase gel, Hydromol ointment. RESULTS: 197 children were recruited—107 by self-referral (mainly via practice mail-outs) and 90 by inconsultation (clinician consenting and randomising) pathways. Participants recruited inconsultation were younger, had more severe Patient-Oriented Eczema Measure scores and were more likely to withdraw than self-referrals. Parents of 20 (10%) of all the randomised participants reported using the allocated emollient daily for 84 days. The use of other non-study emollients was common. Completeness of data collected by parent-held daily diaries and at monthly study visits was good. Daily diaries were liked (81%) but mainly completed on paper rather than via electronic (‘app’) form. Major costs drivers were general practitioner consultations and eczema-related prescriptions. Observer unblinding was infrequent, and occurred at the baseline or first follow-up visit through accidental disclosure. CONCLUSIONS: It is feasible in a primary care setting to recruit and randomise young children with eczema to emollients, follow them up and collect relevant trial data, while keeping observers blinded to their allocation. However, reported use of emollients (study and others) has design implications for future trials. TRIAL REGISTRATION NUMBER: ISRCTN21828118/EudraCT2013-003001-26

Genome-Scale Multilocus Microsatellite Typing of Trypanosoma cruzi Discrete Typing Unit I Reveals Phylogeographic Structure and Specific Genotypes Linked to Human Infection

Trypanosoma cruzi is the most important parasitic infection in Latin America and is also genetically highly diverse, with at least six discrete typing units (DTUs) reported: Tc I, IIa, IIb, IIc, IId, and IIe. However, the current six-genotype classification is likely to be a poor reflection of the total genetic diversity present in this undeniably ancient parasite. To determine whether epidemiologically important information is “hidden” at the sub-DTU level, we developed a 48-marker panel of polymorphic microsatellite loci to investigate population structure among 135 samples from across the geographic distribution of TcI. This DTU is the major cause of resurgent human disease in northern South America but also occurs in silvatic triatomine vectors and mammalian reservoir hosts throughout the continent. Based on a total dataset of 12,329 alleles, we demonstrate that silvatic TcI populations are extraordinarily genetically diverse, show spatial structuring on a continental scale, and have undergone recent biogeographic expansion into the southern United States of America. Conversely, the majority of human strains sampled are restricted to two distinct groups characterised by a considerable reduction in genetic diversity with respect to isolates from silvatic sources. In Venezuela, most human isolates showed little identity with known local silvatic strains, despite frequent invasion of the domestic setting by infected adult vectors. Multilocus linkage indices indicate predominantly clonal parasite propagation among all populations. However, excess homozygosity among silvatic strains and raised heterozygosity among domestic populations suggest that some level of genetic recombination cannot be ruled out. The epidemiological significance of these findings is discussed