Mechanistic Studies Lead to Dramatically Improved Reaction Conditions for the Cu-Catalyzed Asymmetric Hydroamination of Olefins

Enantioselective copper(I) hydride (CuH)-catalyzed hydroamination has undergone significant development over the past several years. To gain a general understanding of the factors governing these reactions, kinetic and spectroscopic studies were performed on the CuH-catalyzed hydroamination of styrene. Reaction profile analysis, rate order assessment, and Hammett studies indicate that the turnover-limiting step is regeneration of the CuH catalyst by reaction with a silane, with a phosphine-ligated copper(I) benzoate as the catalyst resting state. Spectroscopic, electrospray ionization mass spectrometry, and nonlinear effect studies are consistent with a monomeric active catalyst. With this insight, targeted reagent optimization led to the development of an optimized protocol with an operationally simple setup (ligated copper(II) precatalyst, open to air) and short reaction times (<30 min). This improved protocol is amenable to a diverse range of alkene and alkyne substrate classes.National Institutes of Health (U.S.) (GM58160)National Institutes of Health (U.S.) (GM112197)National Institutes of Health (U.S.) (GM113311

Site-selective C-C modification of proteins at neutral pH using organocatalyst-mediated cross aldol ligations

The bioconjugation of proteins with small molecules has proved an invaluable strategy for probing and perturbing biological mechanisms. The general use of chemical methods for protein functionalisation can be limited however by the requirement for complicated reaction partners to be present in large excess, and harsh conditions which are incompatible with many protein scaffolds. Herein we describe a site-selective organocatalyst-mediated protein aldol ligation (OPAL) that affords stable carbon-carbon linked bioconjugates at neutral pH. OPAL enables rapid modification of proteins using simple aldehyde probes in minimal excess, and is utilised here in the affinity tagging of proteins in cell lysate. Furthermore we demonstrate that the β-hydroxy aldehyde OPAL product can be functionalised again at neutral pH in a tandem organocatalyst-mediated oxime ligation. This tandem strategy is showcased in the ‘chemical mimicry’ of a previously inaccessible natural dual post-translationally modified protein integral to the pathogenesis of the neglected tropical disease Leishmaniasis

Catalytic C(sp3)-H bond activation in tertiary alkylamines.

The development of robust catalytic methods to assemble tertiary alkylamines provides a continual challenge to chemical synthesis. In this regard, transformation of a traditionally unreactive C-H bond, proximal to the nitrogen atom, into a versatile chemical entity would be a powerful strategy for introducing functional complexity to tertiary alkylamines. A practical and selective metal-catalysed C(sp3)-H activation facilitated by the tertiary alkylamine functionality, however, remains an unsolved problem. Here, we report a Pd(II)-catalysed protocol that appends arene feedstocks to tertiary alkylamines via C(sp3)-H functionalization. A simple ligand for Pd(II) orchestrates the C-H activation step in favour of deleterious pathways. The reaction can use both simple and complex starting materials to produce a range of multifaceted γ-aryl tertiary alkylamines and can be rendered enantioselective. The enabling features of this transformation should be attractive to practitioners of synthetic and medicinal chemistry as well as in other areas that use biologically active alkylamines

Accessing nitrosocarbonyl compounds with temporal and spatial control via the photoredox oxidation of N-substituted hydroxylamines

Photoredox catalysis is employed to generate highly reactive acylnitroso species from hydroxamic acid derivatives. The conditions are shown to be comparable to a previously developed transition metal aerobic oxidation and are amenable to a range of transformations including Diels-Alder and ene reactions. This unique application of such an approach gives access to temporal and spatial control in nitroso chemistry

Recognizable languages defined by two-dimensional shift spaces

There are numerous connections between the theory of formal languages and that of symbolic dynamics. In each, the transition from one dimension to two dimensionsis accompanied by much difficulty due in large part to the emptiness problem, which is related to the presence (or lack thereof) of periodic points and is known to be undecidable. Here, we focus on two-dimensional languages that have the property that all blocks allowed by the language can be extended to a configuration of the plane satisfying the structure of the language; for such languages the emptiness problem is not an issue. We first show that dot systems may be associated with two-dimensional languages having this property, so that we might employ these languages as varied examples. We next define a new type of finite automaton and with it, a tool for recognizing two-dimensional strings of data. It is then shown that these automata correctly represent the sofic shift spaces that result from the application of block maps to shifts of finite type. Thereafter, these automataare utilized to investigate properties of transitivity in the two-dimensional languages that they represent. More specifically, new definitions for different types of two-dimensional transitivity are adapted from topological dynamics and then illustrated through the use of dot systems. The appearance of periodic points in the languages represented by these automata is also explored, with a main result being that the existence of a periodic pointis guaranteed under certain conditions. Finally, issues of equivalence are introduced in the two-dimensional setting with regards to formal languages (syntactic monoids) and symbolic dynamics (the follower sets of a graph representing a sofic shift space)

The Direct &#946;-Activation of Aldehydes and Ketones via Photoredox Organocatalysis: Discovery, Scope, and Mechanism

The discovery of activation modes within synthetic chemistry has enabled the development of a myriad of transformations. This thesis details the discovery of a new activation mode that allows for the direct beta-functionalization of carbonyl species, such as aldehydes and ketones, through the synergistic merger of amine and visible light photoredox catalysis. This novel mode of reactivity is particularly attractive for the functionalization of ketones or aldehydes at the beta-position has generally been an elusive transformation. This protocol was successfully executed with electron-deficient benzonitriles to afford beta-aryl ketones and aldehydes with a broad scope for both the aryl and carbonyl coupling partner. The development of an asymmetric variant has yielded promising results; unfortunately, racemization studies have indicated that the beta-aryl product undergoes rapid deprotonation to ablate the stereochemistry set during the stereoselective carbon-carbon bond formation step. Mechanistic studies into this protocol have provided several key insights. Computational studies have aided in recognizing the selective preference for beta-deprotonation over alpha-deprotonation of the enamine radical cation. Similarly, computation has supported radical-radical coupling as the likely mechanism for carbon-carbon bond formation. Electron paramagnetic resonance (EPR) studies have provided evidence for the persistence of the radical anion of 1,4-dicyanobenzene, which also lends support to a radical-radical coupling mechanism. DABCO has also been recognized as an effective electron transfer catalyst through spectroscopic studies, which explains the superiority of this base in the chemical protocol. Lastly, extensive kinetic and isotope labeling experiments indicate that beta-deprotonation of the enamine radical cation is the turnover-limiting step. Together, these results have provided a better fundamental understanding of this complex mechanism