Azetidines are important motifs in medicinal chemistry, but there are a limited number of methods for their synthesis. Herein, we present a new method for their modular construction by exploiting the high ring strain associated with azabicyclo[1.1.0]butane. Generation of azabicyclo[1.1.0]butyl lithium followed by its trapping with a boronic ester gives an intermediate boronate complex which, upon N-protonation with acetic acid, undergoes 1,2-migration with cleavage of the central C-N bond to relieve ring strain. The methodology is applicable to primary, secondary, tertiary, aryl and alkenyl boronic esters, and occurs with complete stereospecificity. The homologated azetidinyl boronic esters can be further functionalized through reaction of the N−H azetidine, and through transformation of the boronic ester. The methodology was applied to a short, stereoselective synthesis of the azetidine-containing pharmaceutical, cobimetinib.

The azetidine moiety is ap rivileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after.T owards this goal, we have found that azabicyclo[1.1.0]butyl carbinols,r eadily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain-release reactions upon N-activation. Treatment with trifluoroacetic anhydride or triflic anhydride triggered as emipinacol rearrangement to give keto 1,3,3substituted azetidines.M ore than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups.A lternatively,t reatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates whichg ave spiroepoxya zetidines upon treatment with base.T he electronic nature of the activating agent dictates whichp athwayoperates.

The reactivity of boronate complexes which resemble donor-acceptor cyclopropanes is described. The enantioenriched cyclopropyl boronate complexes were shown to undergo concerted 1,2-metallate rearrangement/ring opening upon activation with a Lewis acid. This method provides atom-efficient access to optically active γ-carbonyl boronic esters in moderate to excellent yields with complete enantiospecificity. Furthermore, a three-component variant of the reaction was established through in-situ alkylation, and the synthetic utility of the products as chiral building blocks was demonstrated.The enantiospecific rearrangement of boronate complexes is an invaluable tool in modern synthetic chemistry as it enables the formation of new C−C and C−X bonds with high levels of stereocontrol. 1,2 Furthermore, the boronic ester is often retained in the product allowing additional transformations to be conducted, including iterative homologations. 2,3 Scheme 1. Examples of leaving group employed in the 1,2metallate rearrangements of boronate complexes

The azetidine moiety is a privileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after. Towards this goal, we have found that azabicyclo[1.1.0]butyl carbinols, readily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain‐release reactions upon N‐activation. Treatment with trifluoroacetic anhydride or triflic anhydride triggered a semipinacol rearrangement to give keto 1,3,3‐substituted azetidines. More than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups. Alternatively, treatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates which gave spiroepoxy azetidines upon treatment with base. The electronic nature of the activating agent dictates which pathway operates.

Introduction The National Hip Fracture Database (NHFD) report that length of stay (LOS) fell (from 19.7 to 16.9 days) in the first year of the COVID-19 pandemic, as patients, families, cares, and staff in health and social care responded to this challenge. This analysis examines trends in Wales where LOS can be profiled very completely as it predominantly remains within a single health board. Method We used data from the NHFD www.nhfd.co.uk to define pre-pandemic LOS (in the year to 1st March 2020) and compare this with the following 18 months. We set figures for all 12 hospitals in Wales against the changes in service organisation which each reported to the NHFD's 2020 Facilities Survey, and against the local incidence of COVID-19 among their hip fracture patients. Results Monthly LOS fell markedly at the pandemic's onset; the national figure falling 8.3 days (from 31.2–22.9 days) between February and June 2020. Overall LOS in Wales fell by 1.6 days across the year as a whole, but this ranged from a fall of 6.3 days in one hospital to a rise of 4.5 days in another. Five hospitals reported a rise in LOS. These hospitals had either never had orthogeriatric support, or lost this to COVID-19 duties, they did not achieve the initial fall in LOS in response to the pandemic, and they reported pressures with ‘outliers’ after the first wave. Unlike other units in Wales they cited problems with workload, particularly in terms of physiotherapy. Discussion NHFD data provide a detailed picture of hospitals’ response to the COVID-19 pandemic, and allow us to examine service factors underpinning their resilience in the face of this challenge. More detailed work should be carried out for the 150 hospitals in England using the same sources of data.