Biocatalytic Enantioselective Synthesis of Atropisomers.

Atropisomeric compounds are found extensively as natural products, as ligands for asymmetric transition-metal catalysis, and increasingly as bioactive and pharmaceutically relevant targets. Their enantioselective synthesis is therefore an important ongoing research target. While a vast majority of known atropisomeric structures are (hetero)biaryls, which display hindered rotation around a C-C single bond, our group's long-standing interest in the control of molecular conformation has led to the identification and stereoselective preparation of a variety of other classes of "nonbiaryl" atropisomeric compounds displaying restricted rotation around C-C, C-N, C-O, and C-S single bonds.Biocatalytic transformations are finding increasing application in both academic and industrial contexts as a result of a significant broadening of the range of biocatalytic reactions and sources of enzymes available to the synthetic chemist. In this Account, we summarize the main biocatalytic strategies currently available for the asymmetric synthesis of biaryl, heterobiaryl, and nonbiaryl atropisomers. As is the case with more traditional synthetic approaches to these compounds, most biocatalytic methodologies for the construction of enantioenriched atropisomers follow one of two distinct strategies. The first of these is the direct asymmetric construction of atropisomeric bonds. Synthetically applicable biocatalytic methodologies for this type of transformation are limited, despite the extensive research into the biosynthesis of (hetero)biaryls by oxidative homocoupling or cross-coupling of electron-rich arenes. The second of these is the asymmetric transformation of a molecule in which the bond that will form the axis already exists, and this approach represents the majority of biocatalytic strategies available to the synthetic organic chemist. This strategy encompasses a variety of stereoselective techniques including kinetic resolution (KR), desymmetrization, dynamic kinetic resolution (DKR), and dynamic kinetic asymmetric transformation (DYKAT).Nondynamic kinetic resolution (KR) of conformationally stable biaryl derivatives has provided the earliest and most numerous examples of synthetically useful methodologies for the enantioselective preparation of atropisomeric compounds. Lipases (i.e., enzymes that mediate the formation or hydrolysis of esters) are particularly effective and have attracted broad attention. This success has led researchers to broaden the scope of lipase-mediated transformations to desymmetrization reactions, in addition to a limited number of DKR and DYKAT examples. By contrast, our group has used redox enzymes, including an engineered galactose oxidase (GOase) and commercially available ketoreductases (KREDs), to desymmetrize prochiral atropisomeric diaryl ether and biaryl derivatives. Building on this experience and our long-standing interest in dynamic conformational processes, we later harnessed intramolecular noncovalent interactions to facilitate bond rotation at ambient temperatures, which allowed the development of the efficient DKR of heterobiaryl aldehydes using KREDs. With this Account we provide an overview of the current and prospective biocatalytic strategies available to the synthetic organic chemist for the enantioselective preparation of atropisomeric molecules.

Capacity of patients with brain metastases to make treatment decisions.

OBJECTIVE: The aim of this study was to investigate medical decision-making capacity (MDC) in patients with brain metastases. METHODS: Participants were 41 adults with brain metastases with Karnofsky Performance Status scores of ≥70 who were recruited from an academic medical center and 41 demographically matched controls recruited from the community. We evaluated MDC using the Capacity to Consent to Treatment Instrument and its four clinically relevant consent standards (expressing a treatment choice, appreciation, reasoning, and understanding). Capacity impairment ratings (no impairment, mild/moderate impairment, and severe impairment) on the consent standards were also assigned to each participant with brain metastasis using cutoff scores derived statistically from the performance of the control group. RESULTS: The brain metastasis patient group performed significantly below controls on consent standards of understanding and reasoning. Capacity compromise was defined as performance ≤1.5 standard deviations below the control group mean. Using this definition, approximately 60% of the participants with brain metastases demonstrated capacity compromise on at least one MDC standard. CONCLUSION: When defining capacity compromise as performance ≤1.5 standard deviation below the control group mean, over half of patients with brain metastases have reduced capacity to make treatment decisions. This impairment is demonstrated shortly after initial diagnosis of brain metastases and highlights the importance of routine clinical assessment of MDC following diagnosis of brain metastasis. These results also indicate a need for the development and investigation of interventions to support or improve MDC in this patient population.

Improving the Written Medical Handover.

The handover of large numbers of medical patients, during on call periods when staffing levels are reduced, is a challenge for all acute medical services. At the Royal Cornwall Hospital, a large district general hospital, we identified that foundation doctors were reviewing medical inpatients during weekend on call periods with limited written handover information. We chose to address this problem by developing an intervention, a weekend handover sticker, and piloting it. We used the review of documentation to measure improvement and feedback from users to assess the processes involved. Use of the weekend handover form improved the written communication between weekday and weekend teams. The number of weekend plans documented in the notes increased from 15% to 84% and the provision of a patient summary within the last 7 days increased from 26% to 94%. The feedback from users confirmed it was a useful intervention and 100% (15/15) of doctors and nurses responded positively to the question "Do you think the weekend sticker should be introduced and used at the weekend for all medical patients?" The feedback also identified concerns regarding additional workload for weekday ward staff and this has led to ongoing work to try and ensure that the weekend handover form continues to be used effectively to maintain an improved level of written handover information for on call staff. While we have not included a direct measure of patient care, we hope that by improving the quality of written handover information we are acting to ensure patient information is shared effectively, with likely positive impact on patient care.