Implementation of micelle-enabled C(sp2)-C(sp3) cross-electrophile coupling in pharmaceutical synthesis.

A sustainable C(sp2)-C(sp3) cross-electrophile coupling was developed between readily available 5-bromophthalide and 1-benzyl-4-iodopiperidine under micellar conditions, leading to a key intermediate of one of our development compounds. Copper was found to play a crucial role as a co-catalyst in this dual catalysis system. The chemistry and process were successfully demonstrated in a kilo scale to deliver sufficient drug substance to the clinical campaigns. This is the first reported scale-up of such a challenging cross-electrophilic coupling that uses an aqueous medium, and not undesirable reprotoxic polar aprotic solvents (e.g. DMF, DMAc, and NMP).

Involuntary Career Changes: A Lonesome Social Experience.

Like any other career process, career changes are influenced by relationships. Moreover, involuntary career changes are a challenging, yet understudied, career transition. Based on a relational perspective of work and careers, we investigated the way people's social environment affects the process and experience of involuntary career changes. Specifically, we aimed to identify the sources of relational influences and to understand how these influences affect career changes. Semi-structured interviews were carried out with 14 adults who were forced to change career because of unemployment or health issues. Through thematic analysis, we identified three sources of relational influences (personal, work, and institutional environment) and three forms of influence that others had on career changes (positive, negative, and ambivalent). These influences manifested at four distinct moments of the process: When participants were leaving their former job, when they were shifting between their former occupation and a new livelihood, when they were exploring new career options, or when they were trying to implement their new career plan. Overall, results suggest that involuntary career changes are deeply shaped by heterogeneous and differentiated relational influences. The effect of the personal environment varied depending on the moment of the career change process. In particular, family and friends tended to be perceived as barriers when it came to shifting from the old to a new occupation and implementing a new career plan. The work environment mostly had a negative effect on the career change experience, suggesting the labor market might be somewhat refractory toward adult career changers. Institutions played a critical role throughout the change process, with support structures often being perceived as inappropriate, but with guidance professionals generally recognizing participants' difficulties. Moreover, diverse forms of ambivalence characterized the identified relational influences, which were sometimes both appreciated and avoided or had ambiguous and fluctuating effects. Finally, although being a fundamentally social experience, involuntary career changes were also characterized by moments of loneliness that reflected the inadequacy of available support and a sense of shame associated with the status of career changer. Study limitations, research perspectives, and practical implications at the labor market, institutional, and individual levels are addressed.

Fostering Research Synergies between Chemists in Swiss Academia and at Novartis.

We present a short overview of the way Novartis chemists interact and collaborate with the academic chemistry community in Switzerland. This article exemplifies a number of collaborations, and illustrates opportunities to foster research synergies between academic and industrial researchers. It also describes established programs available to academic groups, providing them access to Novartis resources and expertise.

A New Dioxazolone for the Synthesis of 1,2-Aminoalcohols via Iridium(III)-Catalyzed C(sp3 )-H Amidation.

Vicinal aminoalcohols are widespread structural motifs in bioactive molecules. We report the development of a new dioxazolone reagent containing a p-nitrophenyldifluoromethyl group, which 1. displays a good safety profile; 2. shows a remarkably high reactivity in the oxime-directed iridium(III)-catalyzed amidation of unactivated C(sp3 )-H bonds; 3. leads to amide products which can be hydrolyzed under mild conditions. The amidation reaction is mild, general and compatible with both primary C-H bonds of tertiary and secondary alcohols, as well as secondary C-H bonds of cyclic secondary alcohols. This method provides an easy access to free 1,2-aminoalcohols after efficient and mild cleavage of the oxime directing group and activated amide.

How Do Spelling, Handwriting Speed, and Handwriting Quality Develop During Primary School? Cross-Classified Growth Curve Analysis of Children's Writing Development.

Aim: Longitudinal studies are rare in the field of writing research, and little is known about the concurrent development of the two transcription skills: spelling and handwriting. This study was designed to provide a comprehensive picture of the development and the longitudinal relations between spelling, handwriting speed, and handwriting quality at the word level. Method: Over a period of 3 years (coh1: Grades 2-4; coh2: Grades 3-5), 117 French-speaking children were assessed on a single-word dictation task. At each testing time, measures of spelling accuracy, handwriting speed, and handwriting quality were collected on 40 words. Words varied in both orthographic and graphic complexity, making it possible to investigate the influence of these levels of complexity on transcription abilities. Results: Linear growth analyses using cross-classified Bayesian structural equation modeling (CC-BSEM) revealed that spelling and speed continued to improve until Grade 5, while handwriting quality reached an early plateau in Grade 2. In the younger cohort, graphic complexity had a significant influence on the pace of development of handwriting speed and on spelling and handwriting quality performance in Grade 2. In the older cohort, a positive relation between spelling and speed and a negative relation between handwriting speed and handwriting quality were found, indicating that fast handwriting is associated with high spelling ability and that fast handwriting is detrimental to handwriting quality. By providing a better understanding of writing development, this study yields innovative findings not only regarding the development of transcription skills but also regarding how spelling, handwriting speed, and handwriting quality can influence each other's performance throughout primary school.

Micelle enabled C(sp2)-C(sp3) cross-electrophile coupling in water via synergistic nickel and copper catalysis.

A robust and sustainable C(sp2)-C(sp3) cross-electrophile coupling was developed via nickel/copper synergistic catalysis under micellar conditions. This protocol provided a general method to access alkylated arenes with good to excellent yields on a very large scale.

Synthesis and Physicochemical Properties of 2-SF5-(Aza)Indoles, a New Family of SF5 Heterocycles.

Structural diversity in heterocyclic chemistry is key to unlocking new properties and modes of action. In this regard, heterocycles embedding emerging fluorinated substituents hold great promise. Herein is described a strategy to access 2-SF5-(aza)indoles for the first time. The sequence relies on the radical addition of SF5Cl to the alkynyl π-system of 2-ethynyl anilines followed by a cyclization reaction. A telescoped sequence is proposed, making this strategy very appealing and reproducible on a gram scale. Downstream functionalizations are also demonstrated, allowing an easy diversification of N- and C3-positions. Ames test, pK a, log P, and differential scanning calorimetry measurements of several fluorinated 2-Rf-indoles are also disclosed. These studies highlight the strategic advantages that a C2-pentafluorosulfanylated motif impart to a privileged scaffold such as an indole.

Interface-rich Aqueous Systems for Sustainable Chemical Synthesis.

Mimicking an enzyme's exquisite activity and selectivity is a long-standing goal for sustainable chemical method development in aqueous media. The use of interface-rich aqueous systems, such as single-chain polymers, micelles and vesicle membranes recently emerged as strategy to emulate the compartmentalization of natural systems. In aqueous solution, aggregates such as micelles or microemulsion droplets are formed, providing reaction environments different from bulk solutions that frequently improve selectivity and accelerate reaction rates for a wide array of chemical transformations. We present here selected examples of interface-rich aqueous systems and discuss the advantages they offer for chemical synthesis. In particular metal-catalyzed cross-coupling reactions are highlighted and future challenges to perform reactions in interface-rich aqueous media are discussed.

Bridging the gap between transition metal- and bio-catalysis via aqueous micellar catalysis.

Previous studies have shown that aqueous solutions of designer surfactants enable a wide variety of valuable transformations in synthetic organic chemistry. Since reactions take place within the inner hydrophobic cores of these tailor-made nanoreactors, and products made therein are in dynamic exchange between micelles through the water, opportunities exist to use enzymes to effect secondary processes. Herein we report that ketone-containing products, formed via initial transition metal-catalyzed reactions based on Pd, Cu, Rh, Fe and Au, can be followed in the same pot by enzymatic reductions mediated by alcohol dehydrogenases. Most noteworthy is the finding that nanomicelles present in the water appear to function not only as a medium for both chemo- and bio-catalysis, but as a reservoir for substrates, products, and catalysts, decreasing noncompetitive enzyme inhibition.

Micelle-Enabled Suzuki-Miyaura Cross-Coupling of Heteroaryl Boronate Esters.

We report a micellar protocol for Suzuki-Miyaura cross-coupling of heteroaryl boronic esters with aryl or heteroaryl halides. The micellar catalysis enables this coupling reaction to run under mild conditions, which avoids the decomposition of heteroaryl boronate esters and allows for high chemoselectivity for cross-coupling reaction with 6-chloropridine-2-boronic ester. The micellar protocol expands the scope of the cross-coupling reaction with challenging heteroaryl boronic esters and complements the existing cross-coupling methods for construction of heterobiaryl building blocks.

Effects of Co-solvents on Reactions Run under Micellar Catalysis Conditions.

The impact of varying percentages of an organic solvent added to reactions run in aqueous nanomicelles as the reaction medium has been investigated. Issues such as rates of reaction, percent conversion, and yield, as well as various practical aspects (e.g., effect on stirring, etc.), are discussed, leading to an operationally simple method for the general improvement of potentially problematic systems across a broad range of reaction types, in particular for reactions run at scale.

Iridium-catalyzed H/D exchange: ligand complexes with improved efficiency and scope.

Hydrogen isotope exchange (HIE) is one of the most attractive tools for the introduction of deuterium or tritium to an organic compound. Herein, iridium complexes with N,P-ligands, highly active catalysts for asymmetric double bond reductions, have been tested for their HIE capabilities. Electron-rich ligands, containing dicyclohexylphosphines or phosphinites, have been identified as excellent ligands for efficient deuterium incorporation. Substrates with strong directing groups, that is, pyridines, ketones, and amides, as well as weak ligating units, such as, nitro, sulfones, and sulfonamides, could be labeled efficiently. With the addition of tris(pentafluorophenyl) borane to the reaction mixture, also highly deactivating nitrile substituents were well tolerated in the reaction. Based on the excellent results obtained with the chiral ThrePhox ligand, a structurally simpler, achiral ligand was developed. The iridium complex containing this ligand, proved to be a powerful catalyst for HIE reactions.

Stereoselective rhodium-catalyzed amination of alkenes.

The first stereoselective rhodium-catalyzed intermolecular aziridination and C-H amination of alkenes to produce chiral carbamate-protected aziridines and allylic amines is described. Good yields and diastereoselectivities were achieved using a readily available chiral N-tosyloxycarbamate and stoichiometric amount of the alkene substrate. Furthermore the protecting group is easy to cleave under mild reaction conditions.

Copper-catalyzed alkene aziridination with N-tosyloxycarbamates.

Pyridine copper complexes were found as active catalysts for the intramolecular aziridination of allylic N-tosyloxycarbamates and the intermolecular aziridination of styrenes with trichloroethyl N-tosyloxycarbamates. Free aziridines were easily obtained by basic deprotection of the trichloroethyl group.

Copper-catalyzed methylenation reaction: total synthesis of (+)-desoxygaliellalactone.

The enantioselective total synthesis of (+)-desoxygaliellalactone was achieved in six steps starting from 4-tert-butyldimethylsilyloxybutanal. This synthesis featured a one-pot copper-catalyzed methylenation-Diels-Alder cyclization. The challenging methylenation of aldehyde 4 was studied under various reaction conditions. Whereas Wittig reaction conditions led to byproducts resulting from decomposition of the sensitive butenolide moiety, the mild copper-catalyzed methylenation reaction produced the desired triene in good yield.