Stereoselective Synthesis of Cyclohexanes via an Iridium Catalyzed (5 + 1) Annulation Strategy.

An iridium catalyzed method for the synthesis of functionalized cyclohexanes from methyl ketones and 1,5-diols is described. This process operates by two sequential hydrogen borrowing reactions, providing direct access to multisubstituted cyclic products with high levels of stereocontrol. This methodology represents a novel (5 + 1) strategy for the stereoselective construction of the cyclohexane core.

Managing emerging mutagenicity risks: Late stage mutagenic impurity control within the atovaquone second generation synthesis.

The mutagenic-impurity control strategy for a second generation manufacturing route to the non-mutagenic antipneumocystic agent atovaquone (2-((1R,4R)-4-(4-chlorophenyl)cyclohexyl)-3-hydroxynaphthalene-1,4-dione) 1 is described. Preliminary assessment highlighted multiple materials of concern which were largely discharged either through returning a negative bacterial mutagenicity assay or through confidence that the impurity would be purged during the downstream processing from when it was first introduced. Additional genotoxicity testing highlighted two materials of concern where initial assessment suggested that testing for these impurities at trace levels within the drug substance would be required. Following a thorough review of process purging detail, spiking and purging experimentation, and an understanding of the process parameters to which they were exposed an ICH M7 Option 4 approach could be justified for their control. The development of two 1H NMR spectroscopy methods for measurement of these impurities is also described as well as a proposed summary table for describing the underlying rationale for ICH M7 control rationales to regulators. This manuscript demonstrates that process purging of potential mutagenic impurities can be realised even when they are introduced in the later stages of a process and highlights the importance of scientific understanding rather than relying on a stage-counting approach.

Hydrogen Borrowing Catalysis with Secondary Alcohols: A New Route for the Generation of ß-Branched Carbonyl Compounds.

A hydrogen borrowing reaction employing secondary alcohols and Ph* (Me5C6) ketones to give ß-branched carbonyl products is described (21 examples). This new C-C bond forming process requires low loadings of [Cp*IrCl2]2, relatively low temperatures, and up to 2.0 equiv of the secondary alcohol. Substrate-induced diastereoselectivity was observed, and this represents the first example of a diastereoselective enolate hydrogen borrowing alkylation. By utilizing the Ph* group, the ß-branched products could be straightforwardly cleaved to the corresponding esters or amides using a retro-Friedel-Crafts reaction. Finally, this protocol was applied to the synthesis of fragrance compound (±)-3-methyl-5-phenylpentanol.

A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies.

The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium-led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions.

Strategic Application and Transformation of ortho-Disubstituted Phenyl and Cyclopropyl Ketones To Expand the Scope of Hydrogen Borrowing Catalysis.

The application of an iridium-catalyzed hydrogen borrowing process to enable the formation of α-branched ketones with higher alcohols is described. In order to facilitate this reaction, ortho-disubstituted phenyl and cyclopropyl ketones were recognized as crucial structural motifs for C-C bond formation. Having optimized the key catalysis step, the ortho-disubstituted phenyl products could be further manipulated by a retro-Friedel-Crafts acylation reaction to produce synthetically useful carboxylic acid derivatives. In contrast, the cyclopropyl ketones underwent homoconjugate addition with several nucleophiles to provide further functionalized branched ketone products.

The development and test-retest reliability of the periodic health evaluation for female athletes (PHE FA) survey.

OBJECTIVES: To develop and assess the test-retest reliability of a survey exploring Australian high-performance female athlete's perspectives toward the periodic health evaluation and their perceived health needs. METHODS: A structured three-phase method for survey development was used to develop the periodic health evaluation for female athletes (PHE FA) survey. Initially, a literature review and gap analysis was performed to identify themes and questions (Phase 1). Survey questions were developed covering demographic information (n = 9); sports-related medical screening (n = 19) and health needs and information (n = 7) (Phase 2). Test-retest reliability of the survey was then assessed (Phase 3). The survey was administered to a purposeful sample of seven high-performance level female athletes who completed the survey, on two separate occasions, 3 weeks apart via Checkbox© survey software (Checkbox Technology Inc., San Francisco, CA). Test-retest reliability was assessed using the intraclass correlation coefficient (ICC). RESULTS: The mean age of the athletes was 29 years (SD 4 years, range 24-34 years). All were able-bodied athletes and 71% participated in team sports. Eighty-six percent of athletes have competed in world championships and 71% were Olympians. The average ICC of all items was 0.998 (95% CI 0.997-0.998, p = 0.000) demonstrating excellent consistency of measures between the two time points.All the athletes preferred a Sport and Exercise Medicine Physician to conduct their PHE and 86% preferred a female doctor. The key topics of interest were pelvic floor health including incontinence (100%); fertility (86%); pregnancy (71%); and mental and emotional wellbeing (71%). Face-to-face education was the preferred option to receive health information. CONCLUSIONS: The PHE FA survey was co-created with an athlete and other key stakeholders. Excellent consistency of measures between the two time points was indicated by the high test-retest reliability of the PHE FA survey. Data collected using the PHE FA survey can contribute to informed evidence-based policies, and processes to support the health and wellbeing of female athletes.