Symmetry breaking and chiral amplification in prebiotic ligation reactions.

The single chirality of biological molecules is a signature of life. Yet, rationalizing how single chirality emerged remains a challenging goal1. Research has commonly focused on initial symmetry breaking and subsequent enantioenrichment of monomer building blocks-sugars and amino acids-that compose the genetic polymers RNA and DNA as well as peptides. If these building blocks are only partially enantioenriched, however, stalling of chain growth may occur, whimsically termed in the case of nucleic acids as "the problem of original syn"2. Here, in studying a new prebiotically plausible route to proteinogenic peptides3-5, we discovered that the reaction favours heterochiral ligation (that is, the ligation of L monomers with D monomers). Although this finding seems problematic for the prebiotic emergence of homochiral L-peptides, we demonstrate, paradoxically, that this heterochiral preference provides a mechanism for enantioenrichment in homochiral chains. Symmetry breaking, chiral amplification and chirality transfer processes occur for all reactants and products in multicomponent competitive reactions even when only one of the molecules in the complex mixture exhibits an imbalance in enantiomer concentrations (non-racemic). Solubility considerations rationalize further chemical purification and enhanced chiral amplification. Experimental data and kinetic modelling support this prebiotically plausible mechanism for the emergence of homochiral biological polymers.

Cobalt-electrocatalytic HAT for functionalization of unsaturated C-C bonds.

The study and application of transition metal hydrides (TMHs) has been an active area of chemical research since the early 1960s1, for energy storage, through the reduction of protons to generate hydrogen2,3, and for organic synthesis, for the functionalization of unsaturated C-C, C-O and C-N bonds4,5. In the former instance, electrochemical means for driving such reactivity has been common place since the 1950s6 but the use of stoichiometric exogenous organic- and metal-based reductants to harness the power of TMHs in synthetic chemistry remains the norm. In particular, cobalt-based TMHs have found widespread use for the derivatization of olefins and alkynes in complex molecule construction, often by a net hydrogen atom transfer (HAT)7. Here we show how an electrocatalytic approach inspired by decades of energy storage research can be made use of in the context of modern organic synthesis. This strategy not only offers benefits in terms of sustainability and efficiency but also enables enhanced chemoselectivity and distinct, tunable reactivity. Ten different reaction manifolds across dozens of substrates are exemplified, along with detailed mechanistic insights into this scalable electrochemical entry into Co-H generation that takes place through a low-valent intermediate.

Prebiotic access to enantioenriched amino acids via peptide-mediated transamination reactions.

The kinetic resolution of racemic amino acids mediated by dipeptides and pyridoxal provides a prebiotically plausible route to enantioenriched proteinogenic amino acids. The enzymatic transamination cycles that are key to modern biochemical formation of enantiopure amino acids may have evolved from this half of the reversible reaction couple. Kinetic resolution of racemic precursors emerges as a general route to enantioenrichment under prebiotic conditions.

Hindered dialkyl ether synthesis with electrogenerated carbocations.

Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions1,2. Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.

Electrochemical borylation of carboxylic acids.

A simple electrochemically mediated method for the conversion of alkyl carboxylic acids to their borylated congeners is presented. This protocol features an undivided cell setup with inexpensive carbon-based electrodes and exhibits a broad substrate scope and scalability in both flow and batch reactors. The use of this method in challenging contexts is exemplified with a modular formal synthesis of jawsamycin, a natural product harboring five cyclopropane rings.

Autocatalytic Models for the Origin of Biological Homochirality.

Autocatalytic models for the emergence of homochirality have been of interest for more than half a century. The sole experimental example of such an amplifying autocatalytic reaction is the Soai reaction. In this review, we trace the history of the theoretical models and the experimental work that led up to the discovery of the remarkable, singular Soai reaction. The experimental and computational studies that have helped to delineate the mechanism of this reaction are discussed in detail. Studies of both the concept of chiral symmetry breaking as well as the subsequent chiral amplification process are discussed. Particular attention is paid to flaws in some of the published models, and suggestions are offered for how such issues might be avoided in future work. The outlook in the search for a prebiotically plausible version of such an amplifying autocatalytic system is presented.

Mechanistic Insight into the Origin of Stereoselectivity in the Ribose-Mediated Strecker Synthesis of Alanine.

Enantioenriched amino acids are produced in a hydrolytic kinetic resolution of racemic aminonitriles mediated by chiral pentose sugars. Experimental kinetic and spectroscopic results combined with DFT computational studies and microkinetic modeling help to identify the nature of the intermediate species and provide insight into the stereoselectivity of their hydrolysis in the prebiotically relevant ribose-alanine system. These studies support a synergistic role for sugars and amino acids in the emergence of homochirality in biological molecules.

Electrochemical Nozaki-Hiyama-Kishi Coupling: Scope, Applications, and Mechanism.

One of the most oft-employed methods for C-C bond formation involving the coupling of vinyl-halides with aldehydes catalyzed by Ni and Cr (Nozaki-Hiyama-Kishi, NHK) has been rendered more practical using an electroreductive manifold. Although early studies pointed to the feasibility of such a process, those precedents were never applied by others due to cumbersome setups and limited scope. Here we show that a carefully optimized electroreductive procedure can enable a more sustainable approach to NHK, even in an asymmetric fashion on highly complex medicinally relevant systems. The e-NHK can even enable non-canonical substrate classes, such as redox-active esters, to participate with low loadings of Cr when conventional chemical techniques fail. A combination of detailed kinetics, cyclic voltammetry, and in situ UV-vis spectroelectrochemistry of these processes illuminates the subtle features of this mechanistically intricate process.

Kinetically guided radical-based synthesis of C(sp3)-C(sp3) linkages on DNA.

DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp3)-C(sp3) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C-C bonds on DNA was studied, which represents a radical-based synthesis in DEL.

Isotopically Directed Symmetry Breaking and Enantioenrichment in Attrition-Enhanced Deracemization.

The evolution of homochirality via attrition-enhanced deracemization (AED) of enantiomorphic solids is carried out using molecules that differ only in the isotopic composition of a phenyl group positioned remote from the chiral center. Enantioenrichment consistently favors the enantiomorph containing a deuterated phenyl group over the protio or 13C version, and the protio version is consistently favored over the 13C version. While these isotopic compounds exhibit identical crystal structures and solubilities, the trend in deracemization correlates with melting points. Understanding the origin of this isotope bias provides fundamental clues about overcoming stochastic behavior to direct the stereochemical outcome in attrition-enhanced deracemization processes. The energy required for breaking symmetry with chiral bias is compared for this near-equilibrium AED process and the far-from-equilibrium Soai autocatalytic reaction. Implications for the origin of biological homochirality are discussed.

Insights into the Role of Transient Chiral Mediators and Pyridone Ligands in Asymmetric Pd-Catalyzed C-H Functionalization.

Mechanistic investigations uncover a novel role for 2-pyridone ligands and interrogate the origin of enantioselectivity in the (+)-norbornene-mediated Pd-catalyzed meta-C(aryl)-H functionalization of diarylmethylamines. Observations from kinetic analysis in concert with in situ 19F NMR monitoring allow us to propose that the pyridone ligand plays a role in enhancing the rate- and enantio-determining insertion of an arylpalladium species into a chiral norbornene derivative. The unprecedented features of 2-pyridone ligands in asymmetric 1,2 migratory insertion, and norbornene as a transient chiral mediator in relay chemistry, provide new insights into this ligand scaffold for future developments in stereoselective transition-metal-catalyzed C-H functionalization.

Utilizing Native Directing Groups: Mechanistic Understanding of a Direct Arylation Leads to Formation of Tetracyclic Heterocycles via Tandem Intermolecular, Intramolecular C-H Activation.

A mechanistic study on a direct arylation using a native picolylamine directing group is reported. Kinetic studies determined the concentration dependence of substrates and catalysts, as well as catalyst degradation, which led to the development of a new set of reaction conditions capable of affording a robust kinetic profile. During reaction optimization, a small impurity was observed, which was determined to be a dual C-H activation product. A second set of conditions were found to flip the selectivity of the C-H activation to form this tetracycle in high yield. A catalytic cycle is proposed for the intermolecular/intramolecular C-H activation pathway.

Water-soluble cavitands promote hydrolyses of long-chain diesters.

Water-soluble, deep cavitands serve as chaperones of long-chain diesters for their selective hydrolysis in aqueous solution. The cavitands bind the diesters in rapidly exchanging, folded J-shape conformations that bury the hydrocarbon chain and expose each ester group in turn to the aqueous medium. The acid hydrolyses in the presence of the cavitand result in enhanced yields of monoacid monoester products. Product distributions indicate a two- to fourfold relative decrease in the hydrolysis rate constant of the second ester caused by the confined space in the cavitand. The rate constant for the first acid hydrolysis step is enhanced approximately 10-fold in the presence of the cavitand, compared with control reactions of the molecules in bulk solution. Hydrolysis under basic conditions (saponification) with the cavitand gave >90% yields of the corresponding monoesters. Under basic conditions the cavitand complex of the monoanion precipitates from solution and prevents further reaction.

Dynamic Ligand Exchange as a Mechanistic Probe in Pd-Catalyzed Enantioselective C-H Functionalization Reactions Using Monoprotected Amino Acid Ligands.

A new tool for probing enantioselective reaction mechanisms is introduced. Monitoring the temporal change in product enantiomeric excess after addition of the opposite enantiomer of the ligand during the reaction provides a means of probing dynamic ligand exchange in enantioselective C-H iodination catalyzed by Pd with monoprotected amino acid ligands (MPAAs). This work has general potential to provide insights about the dynamics of catalyst and ligand molecularity and exchange.

A Role for Pd(IV) in Catalytic Enantioselective C-H Functionalization with Monoprotected Amino Acid Ligands under Mild Conditions.

Kinetic and mechanistic studies of the desymmetrization of benzhydrylamine using Pd/monoprotected amino acid ligands (Pd/MPAA) via C-H functionalization with molecular iodine provide mechanistic insight into the rate-determining step and the oxidation state of Pd in the C-H functionalization step. Enantiomeric excess is strikingly insensitive to temperature from ambient temperature up to over 70 °C, and reaction rate is insensitive to the electronic characteristics of the ligand's benzoyl protecting group. The reaction is highly robust with no evidence of catalyst deactivation. Intriguingly, C-H bond breaking does not occur prior to the addition of I2 to the reaction mixture. Electrochemical experiments demonstrate the viability of oxidative addition of I2 to Pd(II). Together with 19F NMR studies, these observations suggest that iodine oxidizes Pd prior to addition of the amine substrate. This work may lead to a better general understanding of the subtle variations in the reaction mechanisms for C-H functionalization reactions that may be extant for this ligand class depending on substrate, amino acid ligand and protecting group, and reaction conditions.

Potassium tert-Butoxide-Catalyzed Dehydrogenative C-H Silylation of Heteroaromatics: A Combined Experimental and Computational Mechanistic Study.

We recently reported a new method for the direct dehydrogenative C-H silylation of heteroaromatics utilizing Earth-abundant potassium tert-butoxide. Herein we report a systematic experimental and computational mechanistic investigation of this transformation. Our experimental results are consistent with a radical chain mechanism. A trialkylsilyl radical may be initially generated by homolytic cleavage of a weakened Si-H bond of a hypercoordinated silicon species as detected by IR, or by traces of oxygen which can generate a reactive peroxide by reaction with [KOt-Bu]4 as indicated by density functional theory (DFT) calculations. Radical clock and kinetic isotope experiments support a mechanism in which the C-Si bond is formed through silyl radical addition to the heterocycle followed by subsequent ß-hydrogen scission. DFT calculations reveal a reasonable energy profile for a radical mechanism and support the experimentally observed regioselectivity. The silylation reaction is shown to be reversible, with an equilibrium favoring products due to the generation of H2 gas. In situ NMR experiments with deuterated substrates show that H2 is formed by a cross-dehydrogenative mechanism. The stereochemical course at the silicon center was investigated utilizing a 2H-labeled silolane probe; complete scrambling at the silicon center was observed, consistent with a number of possible radical intermediates or hypercoordinate silicates.

Explaining Anomalies in Enamine Catalysis: "Downstream Species" as a New Paradigm for Stereocontrol.

Enantioselective organocatalysis by diarylprolinol ethers is remarkably selective and efficient for a wide range of transformations involving a number of different activation modes, including HOMO activation via enamines. A simple steric model based on facial discrimination in the attack of an enamine on an electrophile has been invoked to rationalize high enantioselectivity. In a number of reactions, however, experimental observations have persistently left us with mechanistic puzzles that fail to fit neatly into this simple picture. Further studies involving both kinetic profiling of reaction networks and NMR spectroscopic characterization of the structures of intermediate species helped us to address these puzzles. This work led to the proposal of a new paradigm for stereocontrol in asymmetric aminocatalysis, demonstrating that the ultimate stereochemical outcome may not, in fact, be determined solely in the stereogenic bond-forming step between enamine and electrophile. The identification of stable species occurring downstream from the addition of an electrophile to an enamine, and the discovery of kinetic features that are diagnostic of the presence of such species, allows development of a new mechanistic framework that reveals a hierarchical selection. Both kinetic and thermodynamic processes associated with downstream intermediates can exert an influence on the ultimate enantioselectivity. Interestingly, the role of these species may be either to enhance or to erode selectivity established at the enamine-electrophile step. The reversibility of steps preceding and subsequent to the stereogenic bond-forming step is an important factor, as are reaction parameters that may stabilize or destabilize intermediates, including the nature of the electrophile counterion and the solvent. These concepts hold implications for the future design and optimization of asymmetric catalytic processes, because such design does not necessarily feature the same parameters at the second hierarchical level as it does at the first. Examples presented to highlight these issues include the conjugate addition of aldehydes to nitroalkenes and the α-chlorination and α-selenylation of aldehdyes using diarylprolinol ether catalysts commonly assumed to follow a steric model for enantioselectivity. While the new paradigm for stereocontrol involving downstream intermediates is developed here for enamine catalysis, the same concepts may hold for other organocatalytic modes of activation.

Necessary conditions for the emergence of homochirality via autocatalytic self-replication.

We analyze a recent proposal for spontaneous mirror symmetry breaking based on the coupling of first-order enantioselective autocatalysis and direct production of the enantiomers that invokes a critical role for intrinsic reaction noise. For isolated systems, the racemic state is the unique stable outcome for both stochastic and deterministic dynamics when the system is in compliance with the constraints dictated by the thermodynamics of chemical reaction processes. In open systems, the racemic outcome also results for both stochastic and deterministic dynamics when driving the autocatalysis unidirectionally by external reagents. Nonracemic states can result in the latter only if the reverse reactions are strictly zero: these are kinetically controlled outcomes for small populations and volumes, and can be simulated by stochastic dynamics. However, the stability of the thermodynamic limit proves that the racemic outcome is the unique stable state for strictly irreversible externally driven autocatalysis. These findings contradict the suggestion that the inhibition requirement of the Frank autocatalytic model for the emergence of homochirality may be relaxed in a noise-induced mechanism.

Cavitands as Reaction Vessels and Blocking Groups for Selective Reactions in Water.

The majority of reactions currently performed in the chemical industry take place in organic solvents, compounds that are generally derived from petrochemicals. To promote chemical processes in water, we examined the use of synthetic, deep water-soluble cavitands in the Staudinger reduction of long-chain aliphatic diazides (C8 , C10 , and C12 ). The diazide substrates are taken up by the cavitand in D2 O in folded, dynamic conformations. The reduction of one azide group to an amine gives a complex in which the substrate is fixed in an unsymmetrical conformation, with the amine terminal exposed and the azide terminal deep and inaccessible within the cavitand. Accordingly, the reduction of the second azide group is inhibited, even with excess phosphine, and good yields of the monofunctionalized products are obtained. In contrast, the reduction of the free diazides in bulk solution yields diamine products.