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.

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.

Ru-Catalyzed Enantioselective Hydrogenation of 2-Pyridyl-Substituted Alkenes and Substrate-Mediated H/D Exchange.

A highly efficient and enantioselective asymmetric hydrogenation catalyzed by Ru-DTBM-segphos is reported for a broad range of pyridine-pyrroline tri-substituted alkenes. Kinetic, spectroscopic, and computational studies suggest that addition of H2 is rate-determining and that alkene insertion is the enantio-determining step. These studies also reveal an intriguing Ru-catalyzed H/D exchange process that is facilitated by the substrate at room temperature and low pressure where hydrogenation activity is suppressed. These studies lead to a mechanistic proposal that further defines the roles of hydrogen gas, Ru-H species, and protic solvents in this catalytic system.

Kinetic Rationalization of Nonlinear Effects in Asymmetric Catalytic Cascade Reactions under Curtin-Hammett Conditions.

Observations of nonlinear effects of catalyst enantiopurity on product enantiomeric excess in asymmetric catalysis are often used to infer that more than one catalyst species is involved in one or more reaction steps. We demonstrate here, however, that in the case of asymmetric catalytic cascade reactions, a nonlinear effect may be observed in the absence of any higher order catalyst species or any reaction step involving two catalyst species. We illustrate this concept with an example from a recent report of an organocatalytic enantioselective [10 + 2] stepwise cyclization reaction. The disruption of pre-equilibria (Curtin-Hammett equilibrium) in reversible steps occurring prior to the final irreversible product formation step can result in an alteration of the final product ee from what would be expected based on a linear relationship with the enantiopure catalyst. The treatment accounts for either positive or negative nonlinear effects in systems over a wide range of conditions including "major-minor" kinetics or the more conventional "lock-and-key" kinetics. The mechanistic scenario proposed here may apply generally to other cascade reaction systems exhibiting similar kinetic features and should be considered as a viable alternative model whenever a nonlinear effect is observed in a cascade sequence of reactions.

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.

Kinetic and Thermodynamic Considerations in the Rh-Catalyzed Enantioselective Hydrogenation of 2-Pyridyl-Substituted Alkenes.

The mechanism of asymmetric hydrogenation of 2-pyridyl alkenes catalyzed by chiral Rh-phosphine complexes at ambient temperature is examined using kinetic, spectroscopic, and computational tools. The reaction proceeds with reversible substrate binding followed by rate-determining addition of hydrogen. Substrate binding occurs only through the pyridine nitrogen in contrast to other substrate classes exhibiting stronger substrate direction. The lack of influence of hydrogen pressure on the product enantiomeric excess suggests that a pre-equilibrium in substrate binding is maintained across the pressure range investigated. An off-cycle Rh-hydride species is implicated in the mild catalyst deactivation observed. In contrast to Ru-phosphine-catalyzed reactions of the same substrate class, the stereochemical outcome in this system correlates generally with the relative stability of the E and Z rotamers of the substrate.

In-situ Kinetic Studies of Rh(II)-Catalyzed C-H Functionalization to Achieve High Catalyst Turnover Numbers.

Detailed kinetic studies on the functionalization of unactivated hydrocarbon sp3 C-H bonds by dirhodium-catalyzed reaction of aryldiazoacetates revealed that the C-H functionalization step is rate-determining. The efficiency of this step was increased by using the hydrocarbon as solvent and using donor/acceptor carbenes with an electron-withdrawing substituent on the aryl donor group. The optimum catalyst for these reactions is the tetraphenylphthalimido derivative Rh2(R-TPPTTL)4 and a further beneficial refinement was obtained by using N,N'-dicyclohexylcarbodiimide as an additive. Under the optimum conditions with a catalyst loading of 0.001 mol %, effective enantioselective C-H functionalization (66-97% yield, 83-97% ee) was achieved of cycloalkanes with a range of aryldiazoacetates as long as the aryldiazoacetate was not to sterically demanding. The reaction with cyclohexane using a catalyst loading of 0.0005 mol % could be recharged twice with additional aryldiazoacetate, resulting in an overall dirhodium catalyst turnover number of 580,000.

A P(V) platform for oligonucleotide synthesis.

The promise of gene-based therapies is being realized at an accelerated pace, with more than 155 active clinical trials and multiple U.S. Food and Drug Administration approvals for therapeutic oligonucleotides, by far most of which contain modified phosphate linkages. These unnatural linkages have desirable biological and physical properties but are often accessed with difficulty using phosphoramidite chemistry. We report a flexible and efficient [P(V)]­based platform that can install a wide variety of phosphate linkages at will into oligonucleotides. This approach uses readily accessible reagents and can install not only stereodefined or racemic thiophosphates but any combination of (S, R or rac)­PS with native phosphodiester (PO2) and phosphorodithioate (PS2) linkages into DNA and other modified nucleotide polymers. This platform easily accesses this diversity under a standardized coupling protocol with sustainably prepared, stable P(V) reagents.

Mechanistic Studies of Pd(II)-Catalyzed E/Z Isomerization of Unactivated Alkenes: Evidence for a Monometallic Nucleopalladation Pathway.

Pd(II)-catalyzed E/Z isomerization of alkenes is a common process-yet its mechanism remains largely uncharacterized, particularly with non-conjugated alkenes. In this work, the mechanism of Pd(II)-catalyzed E/Z isomerization of unactivated olefins containing an aminoquinoline-based amide directing group is probed using in situ kinetic analysis, spectroscopic studies, kinetic modeling, and DFT calculations. The directing group allows for stabilization and monitoring of previously undetectable intermediates. Collectively, the data are consistent with isomerization occurring through a monometallic nucleopalladation mechanism.

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.

Prebiotic access to enantioenriched glyceraldehyde mediated by peptides.

A prebiotically plausible route to enantioenriched glyceraldehyde is reported via a kinetic resolution mediated by peptides. The reaction proceeds via a selective reaction between the l-peptide and the l-sugar producing an Amadori rearrangement byproduct and leaving d-glyceraldehyde in excess. Solubility considerations in the synthesis of proline-valine (pro-val) peptides allow nearly enantiopure pro-val to be formed starting from racemic pro and nearly racemic (10%) ee val. (ee = enantiomeric excess = (|d - l|)/(d + l)) Thus enantioenrichment of glyceraldehyde is achieved in a system with minimal initial chiral bias. This work demonstrates synergy between amino acids and sugars in the emergence of biological homochirality.

Chiral lipid bilayers are enantioselectively permeable.

Homochiral membrane bilayers organize biological functions in all domains of life. The membrane's permeability-its key property-correlates with a molecule's lipophilicity, but the role of the membrane's rich and uniform stereochemistry as a permeability determinant is largely ignored in empirical and computational measurements. Here, we describe a new approach to measuring permeation using continuously generated microfluidic droplet interface bilayers (DIBs, generated at a rate of 480 per minute) and benchmark this system by monitoring fluorescent dye DIB permeation over time. Enantioselective permeation of alkyne-labelled amino acids (Ala, Val, Phe, Pro) and dipeptides through a chiral phospholipid bilayer was demonstrated using DIB transport measurements; the biological L enantiomers permeated faster than the D enantiomers (from 1.2-fold to 6-fold for Ala to Pro). Enantioselective permeation both poses a potentially unanticipated criterion for drug design and offers a kinetic mechanism for the abiotic emergence of homochirality via chiral transfer between sugars, amino acids and lipids.

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.

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.

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.

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.

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.

Energy threshold for chiral symmetry breaking in molecular self-replication.

The homochirality of biological molecules (right-handed sugars and left-handed amino acids) is a signature of life. Extensive research has been devoted to understanding how enrichment of one enantiomer over the other might have emerged from a prebiotic world. Here, we use experimental data from the model Soai autocatalytic reaction system to evaluate the energy required for symmetry breaking and chiral amplification in molecular self-replication. One postulate for the source of the original imbalance is the tiny difference in energy between enantiomers due to parity violation in the weak force. We discuss the plausibility of parity violation energy difference coupled with asymmetric autocatalysis as a rationalization for absolute asymmetric synthesis and the origin of the homochirality of biological molecules. Our results allow us to identify the magnitude of the energy imbalance that gives rise to directed symmetry breaking and asymmetric amplification in this autocatalytic system.