A more critical role for silicon in the catalytic Staudinger amidation: silanes as non-innocent reductants

Amides are ubiquitous in organic chemistry and occur in some of the most important natural and non-natural molecules such as peptides, pharmaceuticals and polymers.1 For this reason, amidation reactions are some of the most frequently carried out procedures in chemical synthesis.2 Amidation reactions between azides and carboxylic acid derivatives have found widespread application owing to the fact that they can be deployed in varied and complex reaction media.3,4,5 While many of these methods use carboxylic acid-derived activated esters, the phosphine-mediated amidation reaction between free acids and azides was reported in 1983 by Garcia and co-workers (Scheme 1A).6 The utility of the process is undermined somewhat by the production of triphenylphosphine oxide as a stoichiometric by-product. However, this problem was overcome in 2012 by Ashfeld and co-workers who reported a catalytic, traceless Staudinger ligation reaction (Scheme 1B).7 This process represents a combination of Garcia’s amidation with the work of O’Brien,8 who was the first to demonstrate chemoselective phosphine oxide reduction with phenylsilane in the context of a catalytic Wittig reaction.9–14 Given that the catalytic reaction was constructed on this basis, the authors proposed a catalytic cycle (Scheme 1C) involving two key steps: (a) phosphorus-mediated amidation via an aminophosphonium carboxylate and the reactive N,O-phosphorane; and (b) chemoselective silane-mediated phosphine oxide reduction to return the phosphine catalyst. While these two steps are established as discrete processes, their conflation into a catalytic cycle presents an intriguing chemoselectivity issue, namely the reduction of triphenylphosphine oxide in the presence of reductively labile iminophosphorane, aminophosphonium and N,O-phosphorane intermediates.1

The catalytic Mitsunobu reaction: a critical analysis of the current state-of-the-art

The Mitsunobu reaction is widely regarded as the pre-eminent method for performing nucleophilic substitutions of alcohols with inversion of configuration. However, its applicability to large-scale synthesis is undermined by the fact that alcohol activation occurs at the expense of two stoichiometric reagents – a phosphine and an azodicarboxylate. The ideal Mitsunobu reaction would be sub-stoichiometric in the phosphine and azodicarboxylate species and employ innocuous terminal oxidants and reductants to achieve recycling. This Review article provides a summary and analysis of recent advances towards the development of such catalytic Mitsunobu reactions

Modular Synthesis of α,α-Diaryl α-Amino Esters via Bi(V)-Mediated Arylation/SN2-Displacement of Kukhtin–Ramirez Intermediates

We report a concise and modular approach to α,α-diaryl α-amino esters from readily available α-keto esters. This mild, one-pot protocol proceeds via ketone umpolung, with in situ formation of a Kukhtin–Ramirez intermediate preceding sequential electrophilic arylation by Bi(V) and SN2 displacement by an amine. The methodology is compatible with a wide range of anilines and primary amines - including derivatives of drugs and proteinogenic amino acids - Bi(V) arylating agents, and α-keto ester substrates

Catalytic reductive N-alkylation of amines using carboxylic acids

We report a catalytic reductive alkylation reaction of primary or secondary amines with carboxylic acids. The two-phase process involves silane mediated direct amidation followed by catalytic reduction

Synthesis of 18O-labelled alcohols from unlabelled alcohols

The synthesis of primary, secondary and tertiary 18O-enriched alcohols from readily available 16O-alcohols via a Mitsunobu esterification and hydrolysis is described. The method is further exemplified in the labelling of the active pharmaceutical ingredient, dropropizine and is shown to be tolerant of modern, separation friendly Mitsunobu reagents

From cook to chef: Facilitating the transition from recipe-driven to open-ended research-based undergraduate chemistry lab activities

This paper describes the development of mini-research projects in the third year practical chemistry course at the University of Nottingham for the MSci(Hons) Chemistry degree. The aim of these developments is to bridge the gap between ‘recipe-style’ experiments in the first and second year courses and research projects undertaken in the fourth year or in industry. There is much evidence that, having been given this opportunity to plan and design their own experiment, students exhibit higher-order cognitive skills, which can lead to a more valuable learning experience

Redox-neutral organocatalytic Mitsunobu reactions

Nucleophilic substitution reactions of alcohols are amongst the most fundamental and strategically important transformations in organic chemistry. For over half a century these reactions have been achieved using stoichiometric, and often hazardous, reagents to activate the otherwise unreactive alcohols. Here we demonstrate that a specially designed phosphine oxide promotes nucleophilic substitution reactions of primary and secondary alcohols within a redoxneutral catalysis manifold that produces water as the sole by-product. The scope of the catalytic coupling process encompasses a range of acidic pronucleophiles that allow stereospecific construction of carbon-oxygen and carbon-nitrogen bonds

Ultrasound detection by clupeiform fishes

It has previously been shown that at least one species of fish ~the American shad! in the order clupeiforms ~herrings, shads, and relatives! is able to detect sounds up to 180 kHz. However, it has not been clear whether other members of this order are also able to detect ultrasound. It is now demonstrated, using auditory brainstem response ~ABR!, that at least one additional species, the gulf menhaden ~Brevoortia patronus!, is able to detect ultrasound, while several other species including the bay anchovy ~Anchoa mitchilli!, scaled sardine ~Harengula jaguana!, and Spanish sardine ~Sardinella aurita! only detect sounds to about 4 kHz. ABR is used to confirm ultrasonic hearing in the American shad. The results suggest that ultrasound detection may be limited to one subfamily of clupeiforms, the Alosinae. It is suggested that ultrasound detection involves the utricle of the inner ear and speculate as to why, despite having similar ear structures, only one group may detect ultrasound

Propulsion in a viscoelastic fluid

Flagella beating in complex fluids are significantly influenced by viscoelastic stresses. Relevant examples include the ciliary transport of respiratory airway mucus and the motion of spermatozoa in the mucus-filled female reproductive tract. We consider the simplest model of such propulsion and transport in a complex fluid, a waving sheet of small amplitude free to move in a polymeric fluid with a single relaxation time. We show that, compared to self-propulsion in a Newtonian fluid occurring at a velocity U_N, the sheet swims (or transports fluid) with velocity U / U_N = [1+De^2 (eta_s)/(eta) ]/[1+De^2], where eta_s is the viscosity of the Newtonian solvent, eta is the zero-shear-rate viscosity of the polymeric fluid, and De is the Deborah number for the wave motion, product of the wave frequency by the fluid relaxation time. Similar expressions are derived for the rate of work of the sheet and the mechanical efficiency of the motion. These results are shown to be independent of the particular nonlinear constitutive equations chosen for the fluid, and are valid for both waves of tangential and normal motion. The generalization to more than one relaxation time is also provided. In stark contrast with the Newtonian case, these calculations suggest that transport and locomotion in a non-Newtonian fluid can be conveniently tuned without having to modify the waving gait of the sheet but instead by passively modulating the material properties of the liquid.Comment: 21 pages, 1 figur

Systemic pharmacological treatment of digital ulcers in systemic sclerosis: a systematic literature review

Objective: To evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines. Methods: A systematic literature review of seven databases was performed to identify all original research studies of adult patients with SSc DUs. Randomized controlled trials (RCTs) and prospective longitudinal observational studies (OBSs) were eligible for inclusion. Data were extracted, applying the patient, intervention, comparison, outcome framework, and risk of bias (RoB) was assessed. Due to study heterogeneity, narrative summaries were used to present data. Results: Forty-seven studies that evaluated the treatment efficacy or safety of pharmacological therapies were identified among 4250 references. Data from 18 RCTs of 1927 patients and 29 OBSs of 661 patients, at various RoB (total 2588 patients) showed that i.v. iloprost, phosphodiesterase-5 inhibitors and atorvastatin are effective for the treatment of active DUs. Bosentan reduced the rate of future DUs in two RCTs (moderate RoB) and eight OBSs at low to high RoB. Two small studies (moderate RoB) indicate that Janus kinase inhibitors may be effective for the treatment of active DUs, otherwise there are no data to support the use of immunosuppression or anti-platelet agents in the management of DUs. Conclusion: There are several systemic treatments, across four medication classes, that are effective therapies for the management of SSc DUs. However, a lack of robust data means it is not possible to define the optimal treatment regimen for SSc DUs. The relatively low quality of evidence available has highlighted further areas of research need