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

Programmable synthesis of organic cages with reduced symmetry

Integrating symmetry-reducing methods into self-assembly methodology is desirable to efficiently realise the full potential of molecular cages as hosts and catalysts. Although techniques have been explored for metal organic (coordination) cages, rational strategies to develop low symmetry organic cages remain limited. In this article, we describe rules to program the shape and symmetry of organic cage cavities by designing edge pieces that bias the orientation of the amide linkages. We apply the rules to synthesise cages with well-defined cavities, supported by evidence from crystallography, spectroscopy and modelling. Access to low-symmetry, self-assembled organic cages such as those presented, will widen the current bottleneck preventing study of organic enzyme mimics, and provide synthetic tools for novel functional material design

Enzyme-like Acyl Transfer Catalysis in a Bifunctional Organic Cage

Amide-based organic cage cavities are, in principle, ideal enzyme active site mimics. Yet, cage-promoted organocatalysis has remained elusive, in large part due to synthetic accessibility of robust and functional scaffolds. Herein, we report the acyl transfer catalysis properties of robust, hexaamide cages in organic solvent. Cage structural variation reveals that esterification catalysis with an acyl anhydride acyl carrier occurs only in bifunctional cages featuring internal pyridine motifs and two crucial antipodal carboxylic acid groups. H NMR data and X-ray crystallography show that the acyl carrier is rapidly activated inside the cavity as a covalent mixed-anhydride intermediate with an internal hydrogen bond. Michaelis-Menten (saturation) kinetics suggest weak binding ( = 0.16 M) of the alcohol pronucleophile close to the internal anhydride. Finally, activation and delivery of the alcohol to the internal anhydride by the second carboxylic acid group forms ester product and releases the cage catalyst. Eyring analysis indicates a strong enthalpic stabilization of the transition state (5.5 kcal/mol) corresponding to a rate acceleration of 10 over background acylation, and an ordered, associative rate-determining attack by the alcohol, supported by DFT calculations. We conclude that internal bifunctional organocatalysis specific to the cage structural design is responsible for the enhancement over the background reaction. These results pave the way for organic-phase enzyme mimicry in self-assembled cavities with the potential for cavity elaboration to enact selective acylations

A Practical Catalytic Reductive Amination of Carboxylic Acids

We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced

Exploration of the polymorphic solid-state landscape of an amide-linked organic cage using computation and automation

Organic cages can possess complex, functionalised internal cavities that make them promising candidates for synthetic enzyme mimics. Conformationally flexible but chemically robust structures are needed for adaptable guest binding and catalysis, but these rapidly exchanging systems are difficult to resolve in solution. Here, we use inexpensive calculations and high-throughput crystallisation experiments to identify accessible cage conformations for a recently reported organic cage by ‘locking’ them in the solid state. The conformers identified exhibit a range of distances between the carboxylic acid groups in the internal cavity, suggesting adaptability towards binding a wide array of target guest molecules. The complexity of the observed crystal structures goes beyond what is possible with state-of-the-art crystal structure prediction

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

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