Combining C-H functionalisation and flow photochemical heterocyclic metamorphosis (FP-HM) for the synthesis of benzo[1,3]oxazepines

C-H Activation/functionalisation and Flow Photochemical Heterocyclic Metamorphosis (FP-HM) have been combined to synthesize a library of benzo[1,3]oxazepines, a rarely described heterocyclic family. This combined protocol allows a range of arylated products to be made from simple starting materials, and the cheap flow photochemical system has proven effective for rapid synthesis of gram-quantities of benzo[1,3]oxazepines

A steric tethering approach enables palladium-catalysed C-H activation of primary amino alcohols.

Aliphatic primary amines are a class of chemical feedstock essential to the synthesis of higher-order nitrogen-containing molecules, commonly found in biologically active compounds and pharmaceutical agents. New methods for the construction of complex amines remain a continuous challenge to synthetic chemists. Here, we outline a general palladium-catalysed strategy for the functionalization of aliphatic C-H bonds within amino alcohols, an important class of small molecule. Central to this strategy is the temporary conversion of catalytically incompatible primary amino alcohols into hindered secondary amines that are capable of undergoing a sterically promoted palladium-catalysed C-H activation. Furthermore, a hydrogen bond between amine and catalyst intensifies interactions around the palladium and orients the aliphatic amine substituents in an ideal geometry for C-H activation. This catalytic method directly transforms simple, easily accessible amines into highly substituted, functionally concentrated and structurally diverse products, and can streamline the synthesis of biologically important amine-containing molecules.We are grateful to the Marie Curie Foundation (D.P. & J.C.), EPSRC (T.W.G.), the ERC (V.D.), and the ERC and EPSRC for Fellowships (M.J.G.). We are grateful to Adam Smalley for DFT calculations and Yohei Shimidzu for assistance with optimization of the C–H acetoxylation reaction. Mass spectrometry data was acquired at the EPSRC UK National Mass Spectrometry Facility at Swansea University. The authors declare no competing financial interests.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nchem.236

Joint ITC and DFT Study of the Affinity of Some Lewis Bases to HIFP in Solution

HFIP, i.e. 1,1,1,3,3,3-hexafluoropropan-2-ol, was found to be an exceptional medium,[1] either as solvent or co-solvent, that allows many reactions to occur.[2-5] However, the exact role and mode of action of HFIP in various chemical transformations still remains elusive. Despite many reports dealing with water/HFIP complexes, little has been published on other molecular complexes of HFIP as well as on thermochemistry of the formation of such complexes.[6] Within this study the affinity of a series of eight different Lewis bases (3 sulfoxides, 3 Nsp2 pyridine derivatives, 1 aromatic amine, 1 cyclic aliphatic ether) to HFIP (as Lewis acid) is investigated experimentally by Isothermal Titration Calorimetry (ITC) and theoretically using static DFT-D calculations. Measured ITC association enthalpy values ΔHaITC spanned -9.3 kcal/mol - -14 kcal/mol. Computations including a PCM implicit solvation model produced similar exothermicity of association of all studied systems - ΔHa values ranging -8.5 – -12.7 kcal/mol. In general, most of interaction energy is due to the hydrogen bonding and not due to formation of significantly strong halogen bonds. An additional set of calculations combining implicit and explicit solvation by chlorobenzene of the reactants, pointed out the relatively low interference of the solvent with the HFIPbase complexation, which main effect is to slightly enhance the Gibbs energy of the HFIP-Lewis base association. It is speculated that the interactions of bulk HFIP with Lewis bases therefore may significantly intervene in catalytic processes not only via the dynamic miscrostructuration of the medium but also more explicitly by affecting bonds’ polarization at the Lewis bases

Supplementary data for the article: Milovanović, M. R.; Dherbassy, Q.; Wencel‐Delord, J.; Colobert, F.; Zarić, S. D.; Đukić, J.-P. The Affinity of Some Lewis Bases for Hexafluoroisopropanol as a Reference Lewis Acid: An ITC/DFT Study. ChemPhysChem 2020, 21 (18), 2136–2142. https://doi.org/10.1002/cphc.202000560.

Supplementary material for: [https://doi.org/10.1002/cphc.202000560]Related to published version: [https://cherry.chem.bg.ac.rs/handle/123456789/4337]Related to accepted version: [https://cherry.chem.bg.ac.rs/handle/123456789/4339

Cleavage Requirements for Activation of Factor V by Factor Xa

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65728/1/j.1432-1033.1997.00012.x.pd

Rhodium(III)-Catalyzed Dearomatizing (3+2) Annulation of 2-Alkenylphenols and Alkynes

Appropriately substituted 2-alkenylphenols undergo a mild formal [3C+2C] cycloaddition with alkynes when treated with a Rh(III) catalyst and an oxidant. The reaction, which involves the cleavage of the terminal C–H bond of the alkenyl moiety and the dearomatization of the phenol ring, provides a versatile and efficient approach to highly appealing spirocyclic skeletons and occurs with high selectivityWe thank the financial support provided by the Spanish Grants SAF2010-20822-C02 and CSD2007-00006 Consolider Ingenio 2010, the Xunta de Galicia Grants GR2013-041 and EM2013/036, the ERDF, and the European Research Council (Advanced Grant No. 340055). M.G. thanks Xunta de Galicia for a Parga Pondal contractS

Allylic Oxidation of Alkenes Catalyzed by a Copper−Aluminum Mixed Oxide

A strategy for the allylic oxidation of cyclic alkenes with a copper−aluminum mixed oxide as catalyst is presented. The reaction involves the treatment of an alkene with a carboxylic acid employing tert-butyl hydroperoxide as the oxidant. In all cases, the corresponding allylic esters are obtained. When L-proline is employed, the allylic alcohol or ketone is obtained. The oxidation of cyclohexene and valencene has been optimized by design of experiments (DoE) statistical methodology

Switching treatment to cipaglucosidase alfa plus miglustat positively affects patient-reported outcome measures in patients with late-onset Pompe disease

\ua9 The Author(s) 2024.Background: Late-onset Pompe disease (LOPD), a rare autosomal recessive multisystemic disorder, substantially impacts patients’ day-to-day activities, outcomes, and health-related quality of life (HRQoL). The PROPEL trial compared cipaglucosidase alfa plus miglustat (cipa+mig) with alglucosidase alfa plus placebo (alg+pbo) in adult patients with LOPD over 52 weeks and showed improved motor and respiratory function in patients switching treatment from standard-of-care enzyme replacement therapy (ERT) to cipa+mig at baseline. This study evaluated the impact of cipa+mig on patient-reported outcomes (PROs), including HRQoL in ERT-experienced patients, using data from PROPEL. Methods: PROs evaluated included the Subject’s Global Impression of Change (SGIC), Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 20a, PROMIS Fatigue Short Form 8a, Rasch-built Pompe-specific Activity (R-PAct), and European Quality of Life-5 Dimensions 5 Response Levels (EQ-5D-5L). The proportions of responders in the cipa+mig arm and the alg+pbo arm were compared via chi-squared or Fisher’s exact test (patient-level responder analysis), and least squares (LS) mean differences were calculated for change from baseline at Week 52 of the PRO measures (group-level analysis). Results: At Week 52, patient-level SGIC responder and group-level SGIC analyses favored cipa+mig compared with alg+pbo across all SGIC domains (e.g. 90 vs. 59% responders in the cipa+mig vs. the alg+pbo group for SGIC ability to move around; P = 0.0005; and LS mean difference 0.385; P = 0.02). Similarly, PROMIS Physical Function and Fatigue domains numerically favored cipa+mig in both analyses (e.g. 50 vs. 40% responders in the cipa+mig vs. alg+pbo arm for PROMIS Physical Function; P = 0.37; and LS mean difference 3.1; P = 0.11). R-PAct for both treatment groups was similar in the patient-level responder analysis, but numerically favored alg+pbo in the group-level analysis (35% responders in both arms; P = 0.95; and LS mean difference −0.8; P = 0.48). Self-care, usual activities, and depression/anxiety domains of EQ-5D-5L numerically favored cipa+mig in both analyses (e.g. 20 vs. 12% responders in the cipa+mig vs. alg+pbo arm for EQ-5D-5L self-care; P = 0.54; and LS mean difference −0.108; P = 0.52). Conclusions: Overall, switching treatment from alglucosidase alfa to cipa+mig positively impacted PRO measurements during the double-blind period of PROPEL. Trial registration: NCT03729362; Registration date: November 1, 2018; https://clinicaltrials.gov/study/NCT0372936