A new method for the synthesis of 2,4- and 2,3,4-substituted pyrroles in two or three steps from commercially available ketones and allyl hydroxylamine is described. An iridium-catalyzed isomerization reaction has been developed to convert O-allyl oximes to O-vinyl oximes, which undergo a facile [3,3] rearrangement to form 1,4-imino aldehyde Paal-Knorr intermediates that cyclize to afford the corresponding pyrroles. Optimization and examples of the isomerization and pyrrole formation are discussed.

The regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles has been achieved via [3,3] and [1,3] sigmatropic rearrangements of O-vinyl oximes, respectively. Iridium-catalyzed isomerization of easily prepared O-allyl oximes enables rapid access to O-vinyl oximes. The regioselectivity of pyrrole formation can be controlled by either the identity of the α-substituent or through the addition of an amine base. When enolization is favored, a [3,3] rearrangement followed by a Paal-Knorr cyclization provides a 2,3,4-trisubstituted pyrrole; when enolization is disfavored, a [1,3] rearrangement occurs prior to enolization to produce a 2,3,5-trisubstituted pyrrole after cyclization. Optimization and scope of the O-allyl oxime isomerization and subsequent pyrrole formation are discussed and mechanistic pathways are proposed. Conditions are provided for selecting either the [3,3] rearrangement or the [1,3] rearrangement product with β-ester O-allyl oxime substrates.

Two in two: Dioxygenation of alkenyl boronic acids has been achieved with N-hydroxyphthalimide. The two-step process involves etherification of an alkenyl boronic acid with N-hydroxyphthalimide followed by a [3,3] rearrangement. The dioxygenated product can then be hydrolyzed to form either the corresponding α-hydroxy ketone or the α-benzoyloxy ketone.

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Background Letibotulinumtoxin A (Croma Pharma GmbH, Leobendorf, Austria) is a newly manufactured neurotoxin derived from the C. botulinum strain CBFC26. Objectives To assess efficacy and safety of letibotulinumtoxin A in reducing glabellar line severity (GLS) and to evaluate long term safety and efficacy following repeated injections. Methods In this prospective, randomized, parallel-group, double blind, multicentre, placebo – controlled phase III clinical trial, 355 subjects with moderate to severe glabella frown lines received injections with 20 U of letibotulinumtoxin A or placebo. Glabellar line severity (GLS), onset and duration of effect, time to re-treatment and adverse events were evaluated. Response to treatment was defined as a GLS score of 0 or 1 (assessed by the subject and investigator) and an improvement ≥2 points in GLS score relative to baseline, at week 4 from baseline. Results At 4 weeks, 78.6% of the active treatment subjects where responders (reduction of ≥2 – points on the GLS and GLS of 0 or 1) based on the investigator assessment and 68.8% based on the subject assessment, resulting in a composite responder rate 64.7% for the active treatment group, while it was 0.0% in the placebo group (p < 0.001). The median time to onset of effect was 3.0 days. Time until first re-treatment for the letibotulinumtoxin A group was 127.26 ± 65.6 days. Letibotulinumtoxin A was well tolerated. Conclusions Letibotulinumtoxin A demonstrates high efficacy and a convincing safety profile in the treatment of glabellar lines.

SummaryA Chan–Lam reaction has been used to prepare N-alkenyl-α,β-unsaturated nitrones, which undergo a subsequent thermal rearrangement to the corresponding tri- and tetrasubstituted pyridines. The optimization and scope of these transformations is discussed. Initial mechanistic experiments suggest a reaction pathway involving oxygen transfer followed by cyclization.

Objective The objective of this investigation was to create and validate 5‐point photonumeric scales for the assessment of dynamic crow's feet, static crow's feet, and infraorbital hollows. Material and methods Three novel 5‐point photonumeric scales were created by a medical team. A total of 12 raters from all over the world performed a digital validation, and a total of 5 raters a live validation of the created scale. Results The statistical analysis revealed almost perfect intra‐rater and inter‐rater reliability in the digital validation of the scales for the assessment of static and dynamic crow's feet as well as infraorbital hollows. In the live validation, both crow's feet scales showed almost perfect intra‐rater reliability, while the Croma Infraorbital Hollow Assessment Scale showed substantial intra‐rater reliability. Inter‐rater reliability was substantial for all three scales in the live validation. All three scales, the Croma Dynamic Crow's Feet Assessment Scale, Croma Static Crow's Feet Assessment Scale, and Croma Infraorbital Hollow Assessment Scale, were validated digitally and in a live setting. Conclusion The created scales to assess infraorbital hollowing, dynamic and static crow's feet have been shown to provide substantial to almost perfect agreement in the digital and live validation and can thus be considered as helpful tools in the clinical and research setting. While technical methods and appliances to assess the degrees of severity of age‐dependent features are advancing, validated scales are of great importance due to their ease of use and, as shown by the validations, reliability, and reproducibility.

The synthesis of α-imino aldehydes has been achieved through the thermal [1,3]-rearrangement of O-alkenyl benzophenone oximes. A copper-mediated C-O bond coupling between benzophenone oxime and alkenyl boronic acids provides facile access to the required O-alkenyl oximes and a Horner-Wadsworth-Emmons olefination can be applied to the α-imino aldehyde products to give γ-imino-α,β-unsaturated esters. The scope of the method is described and mechanistic experiments are discussed.