Kinetic analysis of copper(I)/feringa-phosphoramidite catalysed AlEt3 1,4-addition to cyclohex-2-en-1-one

ReactIR studies of mixtures of AlEt3 (A) and cyclohex-2-en-1-one (CX) in Et2O indicate immediate formation of the Lewis acid-base complex (CX.A) at -40 oC (K = 12.0 M-1, ΔGo react -1.1 kcal mol-1). Copper(I) catalysts, derived from pre-catalytic Cu(OAc)2 (up to 5 mol- %) and (R,S,S)-P(binaphtholate){N(CHMePh)2} [Feringa’s ligand (L), up to 5 mol-%] convert CX.A (0.04-0.3 M) into its 1,4-addition product enolate (E) within 2000 sec at -40 oC. Kinetic studies (ReactIR and chiral GC) of CX.A, CX and (R)-3-ethylcyclohexanone (P, the H+ quench product of enolate E) show that the true catalyst is formed in the first 300 sec and this subsequently provides P in 82% ee. This true catalyst converts CX.A to E with a rate law [Cu]1.5[L]0.66[CX.A]1 when [L]/[Cu] ≤ 3.5. Above this ligand ratio inhibition by added ligand with order [L]-2.5 is observed. A rate determining step (rds) of Cu3L2(CX.A)2 stoichiometry is shown to be most consistent with the rate law. The presence of the enolate in the active catalyst (Graphical Abstract) best accounts for the reaction’s induction period and molecularity as [E] ≡ [CX.A]. Catalysis proceeds through a ‘shuttling mechanism’ between two C2 symmetry related ground state intermediates. Each turnover consumes one equivalent of CX.A, expels one molecule of E and forms the new Cu-Et bond needed for the next cycle (Graphic Abstract). The observed ligand (L) inhibition and a non-linear ligand Lee effect on the ee of P are all well simulated by the kinetic model. DFT studies [ωB97X-D/SRSC] support coordination of CX.A to the groundstate Cu-trimer and its rapid conversion to E

A proper understanding of Millikan

Ruth Millikan’s teleological theory of mental content is complex and often misunderstood. This paper motivates and clarifies some of the complexities of the theory, and shows that paying careful attention to its details yields answers to a number of common objections to teleological theories, in particular, the problem of novel mental states, the problem of functionally false beliefs, and problems about indeterminacy or multiplicity of function

Toward a simulation approach for alkene ring-closing metathesis : scope and limitations of a model for RCM

A published model for revealing solvent effects on the ring-closing metathesis (RCM) reaction of di-Et diallylmalonate 7 has been evaluated over a wider range of conditions, to assess its suitability for new applications. Unfortunately, the model is too flexible and the published rate consts. do not agree with exptl. studies in the literature. However, by fixing the values of important rate consts. and restricting the concn. ranges studied, useful conclusions can be drawn about the relative rates of RCM of different substrates, precatalyst concn. can be simulated accurately and the effect of precatalyst loading can be anticipated. Progress has also been made toward applying the model to precatalyst evaluation, but further modifications to the model are necessary to achieve much broader aims

TID Tolerance of Popular CubeSat Components

In this paper we report total dose test results of COTS components commonly used on CubeSats. We investigate a variety of analog integrated circuits, a popular microcontroller (PIC24) as well as SD memory card

Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma

Aberrant genetic and epigenetic variations drive malignant transformation and are hallmarks of cancer. Using PCR-free sample preparation we achieved the first in-depth whole genome (hydroxyl)-methylcytosine, single-base-resolution maps from a glioblastoma tumour/margin sample of a patient. Our data provide new insights into how genetic and epigenetic variations are interrelated. In the tumour, global hypermethylation with a depletion of 5-hydroxymethylcytosine was observed. The majority of single nucleotide variations were identified as cytosine-to-thymine deamination products within CpG context, where cytosine was preferentially methylated in the margin. Notably, we observe that cells neighbouring tumour cells display epigenetic alterations characteristic of the tumour itself although genetically they appear “normal”. This shows the potential transfer of epigenetic information between cells that contributes to the intratumour heterogeneity of glioblastoma. Together, our reference (epi)-genome provides a human model system for future studies that aim to explore the link between genetic and epigenetic variations in cancer progression.Cancer Research UK 236 (Grant ID: C14303/A17197), Wellcome Trust (Grant ID: 099232/z/12/z

Bonding in Functionalized Aziridines: Nitrogen-15 and Carbon-13 Studies

Two isomeric pairs of cis- and trans-1-cyclohexyl-2-phenyl-3-benzoylaziridines have been synthesized: (1) with a nitrogen-15 labelled nitrogen, and (2) with carbon-13 labelled ring carbons. The carbon-13 to X (where X=nitrogen-15, carbon-13 or hydrogen-I) spin-spin coupling constants were measured and interpreted in terms of stereoelectronic effects. X-ray crystallographic data (earlier determined for cisand trans-1-cyclohexyl-2-phenyl-3-(p-toluyl)aziridines)1 appear in good agreement with the NMR data. Bonding is discussed for the three-ring itself (NMR studies) and for its substituents (X-ray studies). It is concluded that stereochemical interaction of the Van der Waals type is an important determinant of aziridine bond length. Three-ring to carbonyl hyperconjugation is correlated with stereoelectronic interactions in the trans isomer

Bonding in Functionalized Aziridines: Nitrogen-15 and Carbon-13 Studies

Two isomeric pairs of cis- and trans-1-cyclohexyl-2-phenyl-3-benzoylaziridines have been synthesized: (1) with a nitrogen-15 labelled nitrogen, and (2) with carbon-13 labelled ring carbons. The carbon-13 to X (where X=nitrogen-15, carbon-13 or hydrogen-I) spin-spin coupling constants were measured and interpreted in terms of stereoelectronic effects. X-ray crystallographic data (earlier determined for cisand trans-1-cyclohexyl-2-phenyl-3-(p-toluyl)aziridines)1 appear in good agreement with the NMR data. Bonding is discussed for the three-ring itself (NMR studies) and for its substituents (X-ray studies). It is concluded that stereochemical interaction of the Van der Waals type is an important determinant of aziridine bond length. Three-ring to carbonyl hyperconjugation is correlated with stereoelectronic interactions in the trans isomer

Glioblastoma adaptation traced through decline of an IDH1 clonal driver and macro-evolution of a double-minute chromosome

In a glioblastoma tumour with multi-region sequencing before and after recurrence, we find an IDH1 mutation that is clonal in the primary but lost at recurrence. We also describe the evolution of a double-minute chromosome encoding regulators of the PI3K signalling axis that dominates at recurrence, emphasizing the challenges of an evolving and dynamic oncogenic landscape for precision medicin