A Chemical Reaction Network Drives Complex Population Dynamics in Oscillating Self-Reproducing Vesicles.

We report chemically fueled oscillations of vesicles. The population cycling of vesicles is driven by their self-reproduction and collapse within a biphasic reaction network involving the interplay of molecular and supramolecular events. We studied the oscillations on the molecular and supramolecular scales and tracked vesicle populations in time by interferometric scattering microscopy and dynamic light scattering. Complex supramolecular events were observed during oscillations─including vesicle reproduction, growth, and decomposition─and differences in the number, size, and mass of aggregates can often be observed within and between pulses. This system's dynamic behavior is reminiscent of a reproductive cycle in living cells.

Catalytic Enantioselective Synthesis of 3-Piperidines from Arylboronic Acids and Pyridine.

Piperidines are frequently found in natural products and are of importance to the pharmaceutical industry. A generally useful asymmetric route to enantiomerically enriched 3-substituted piperidines remains elusive. Here we report a cross-coupling approach to enantioenriched 3-piperidines from pyridine- and sp2-hybridized boronic acids. The key step involves a Rh-catalyzed asymmetric reductive Heck reaction of aryl, heteroaryl, or vinyl boronic acids and phenyl pyridine-1(2H)-carboxylate to provide 3-substituted tetrahydropyridines in high yield and excellent enantioselectivity with a wide functional group tolerance. A three-step process involving i) partial reduction of pyridine, ii) Rh-catalyzed asymmetric carbometalation, and then iii) another reduction provides access to a wide variety of enantioenriched 3-piperidines, including clinically used materials such as Preclamol and Niraparib.

Rhodium-Catalyzed Asymmetric Arylation of Cyclobutenone Ketals.

Complex cyclobutanes are important motifs in both bioactive molecules and natural products, yet their enantioselective preparation has not been widely explored. In this work, we describe rhodium-catalyzed enantioselective additions of aryl and vinyl boronic acids to cyclobutenone ketals. This transformation involves enantioselective carbometalation to give cyclobutyl-rhodium intermediates, followed by ß-oxygen elimination to afford enantioenriched enol ethers. Overall, this addition serves as a surrogate for Rh-catalyzed 1,4-additions to cyclobutenone.

Non-stabilized nucleophiles in Cu-catalysed dynamic kinetic asymmetric allylic alkylation.

The development of new reactions forming asymmetric carbon-carbon bonds has enabled chemists to synthesize a broad range of important carbon-containing molecules, including pharmaceutical agents, fragrances and polymers. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. An alternative strategy--dynamic kinetic asymmetric transformation--involves the transformation of a racemic starting material into a single enantiomer product, with greater than 50 per cent maximum yield. The use of stabilized nucleophiles (pKa < 25, where Ka is the acid dissociation constant) in palladium-catalysed asymmetric allylic alkylation reactions has proved to be extremely versatile in these processes. Conversely, the use of non-stabilized nucleophiles in such reactions is difficult and remains a key challenge. Here we report a copper-catalysed dynamic kinetic asymmetric transformation using racemic substrates and alkyl nucleophiles. These nucleophiles have a pKa of ≥50, more than 25 orders of magnitude more basic than the nucleophiles that are typically used in such transformations. Organometallic reagents are generated in situ from alkenes by hydrometallation and give highly enantioenriched products under mild reaction conditions. The method is used to synthesize natural products that possess activity against tuberculosis and leprosy, and an inhibitor of para-aminobenzoate biosynthesis. Mechanistic studies indicate that the reaction proceeds through a rapidly isomerizing intermediate. We anticipate that this approach will be a valuable complement to existing asymmetric catalytic methods.

Coupled Metabolic Cycles Allow Out-of-Equilibrium Autopoietic Vesicle Replication.

We report chemically fuelled out-of-equilibrium self-replicating vesicles based on surfactant formation. We studied the vesicles' autocatalytic formation using UPLC to determine monomer concentration and interferometric scattering microscopy at the nanoparticle level. Unlike related reports of chemically fuelled self-replicating micelles, our vesicular system was too stable to surfactant degradation to be maintained out of equilibrium. The introduction of a catalyst, which introduces a second catalytic cycle into the metabolic network, was used to close the first cycle. This shows how coupled catalytic cycles can create a metabolic network that allows the creation and perseverance of fuel-driven, out-of-equilibrium self-replicating vesicles.

Controlling the Kinetics of Self-Reproducing Micelles by Catalyst Compartmentalization in a Biphasic System.

Compartmentalization of reactions is ubiquitous in biochemistry. Self-reproducing lipids are widely studied as chemical models of compartmentalized biological systems. Here, we explore the effect of catalyst location on copper-catalyzed azide-alkyne cycloadditions which drive the self-reproduction of micelles from phase-separated components. Tuning the hydrophilicity of the copper-ligand complex, so that hydro-phobic or -philic catalysts are used in combination with hydro-philic and -phobic coupling partners, provides a wide range of reactivity patterns. Analysis of the kinetic data shows that reactions with a hydrophobic catalyst are faster than with a hydrophilic catalyst. Diffusion-ordered spectroscopy experiments suggest compartmentalization of the hydrophobic catalyst inside micelles while the hydrophilic catalyst remains in the bulk aqueous phase. The autocatalytic effects observed can be tuned by varying reactant structure and coupling a hydrophilic alkyne and hydrophobic azide results in a more pronounced autocatalytic effect. We propose and test a model that rationalizes the observations in terms of the phase behavior of the reaction components and catalysts.

Visualization of the spontaneous emergence of a complex, dynamic, and autocatalytic system.

Autocatalytic chemical reactions are widely studied as models of biological processes and to better understand the origins of life on Earth. Minimal self-reproducing amphiphiles have been developed in this context and as an approach to de novo "bottom-up" synthetic protocells. How chemicals come together to produce living systems, however, remains poorly understood, despite much experimentation and speculation. Here, we use ultrasensitive label-free optical microscopy to visualize the spontaneous emergence of an autocatalytic system from an aqueous mixture of two chemicals. Quantitative, in situ nanoscale imaging reveals heterogeneous self-reproducing aggregates and enables the real-time visualization of the synthesis of new aggregates at the reactive interface. The aggregates and reactivity patterns observed vary together with differences in the respective environment. This work demonstrates how imaging of chemistry at the nanoscale can provide direct insight into the dynamic evolution of nonequilibrium systems across molecular to microscopic length scales.

Enantio- and Diastereoselective Suzuki-Miyaura Coupling with Racemic Bicycles.

Herein, we describe a rhodium-catalyzed enantio- and diastereoselective Suzuki-Miyaura cross-coupling between racemic fused bicyclic allylic chlorides and boronic acids. The highly stereoselective transformation allows for the coupling of aryl, heteroaryl, and alkenyl boronic acids and gives access to functionalized bicyclic cyclopentenes, which can be converted into other five-membered-ring scaffolds with up to five contiguous stereocenters. Preliminary mechanistic studies suggest that these reactions occur with overall retention of the relative stereochemistry and are enantioconvergent for pseudo-symmetric allylic chloride starting materials. In addition, a bicyclic allylic chloride starting material without pseudo-symmetry undergoes a highly enantioselective regiodivergent reaction.

Mechanistic Studies on a Cu-Catalyzed Asymmetric Allylic Alkylation with Cyclic Racemic Starting Materials.

Mechanistic studies on Cu-catalyzed asymmetric additions of alkylzirconocene nucleophiles to racemic allylic halide electrophiles were conducted using a combination of isotopic labeling, NMR spectroscopy, kinetic modeling, structure-activity relationships, and new reaction development. Kinetic and dynamic NMR spectroscopic studies provided insight into the oligomeric Cu-ligand complexes, which evolve during the course of the reaction to become faster and more highly enantioselective. The Cu-counterions play a role in both selecting different pathways and in racemizing the starting material via formation of an allyl iodide intermediate. We quantify the rate of Cu-catalyzed allyl iodide isomerization and identify a series of conditions under which the formation and racemization of the allyl iodide occurs. We developed reaction conditions where racemic allylic phosphates are suitable substrates using new phosphoramidite ligand D. D also allows highly enantioselective addition to racemic seven-membered-ring allyl chlorides for the first time. 1H and 2H NMR spectroscopy experiments on reactions using allylic phosphates showed the importance of allyl chloride intermediates, which form either by the action of TMSCl or from an adventitious chloride source. Overall these studies support a mechanism where complex oligomeric catalysts both racemize the starting material and select one enantiomer for a highly enantioselective reaction. It is anticipated that this work will enable extension of copper-catalyzed asymmetric reactions and provide understanding on how to develop dynamic kinetic asymmetric transformations more broadly.

High-Power Actuation from Molecular Photoswitches in Enantiomerically Paired Soft Springs.

Motion in plants often relies on dynamic helical systems as seen in coiling tendrils, spasmoneme springs, and the opening of chiral seedpods. Developing nanotechnology that would allow molecular-level phenomena to drive such movements in artificial systems remains a scientific challenge. Herein, we describe a soft device that uses nanoscale information to mimic seedpod opening. The system exploits a fundamental mechanism of stimuli-responsive deformation in plants, namely that inflexible elements with specific orientations are integrated into a stimuli-responsive matrix. The device is operated by isomerization of a light-responsive molecular switch that drives the twisting of strips of liquid-crystal elastomers. The strips twist in opposite directions and work against each other until the pod pops open from stress. This mechanism allows the photoisomerization of molecular switches to stimulate rapid shape changes at the macroscale and thus to maximize actuation power.

Fluorinated Azobenzenes for Shape-Persistent Liquid Crystal Polymer Networks.

Liquid crystal polymer networks respond with an anisotropic deformation to a range of external stimuli. When doped with molecular photoswitches, these materials undergo complex shape modifications under illumination. As the deformations are reversed when irradiation stops, applications where the activated shape is required to have thermal stability have been precluded. Previous attempts to incorporate molecular switches into thermally stable photoisomers were unsuccessful at photogenerating macroscopic shapes that are retained over time. Herein, we show that to preserve photoactivated molecular deformation on the macroscopic scale, it is important not only to engineer the thermal stability of the photoswitch but also to adjust the cross-linking density in the polymer network and to optimize the molecular orientations in the material. Our strategy resulted in materials containing fluorinated azobenzenes that retain their photochemical shape for more than eight days, which constitutes the first demonstration of long-lived photomechanical deformation in liquid-crystal polymer networks.

Barrierless Photoisomerization of 11-cis Retinal Protonated Schiff Base in Solution.

A hallmark of the primary visual event is the barrierless, ultrafast, and efficient 11-cis to all-trans photoisomerization of the retinal protonated Schiff base (RPSB) chromophore. The remarkable reactivity of RPSB in the visual pigment rhodopsin has been attributed to potential energy surface modifications enabled by evolution-optimized chromophore-protein interactions. Here, we use a combined synthetic and ultrafast spectroscopic approach to show that barrierless photoisomerization is an intrinsic property of 11-cis RPSB, suggesting that the protein may merely adjust the ratio between fast reactive and slow unreactive decay channels. These results call for a re-evaluation of our understanding and theoretical description of RPSB photochemistry.

Asymmetric conjugate additions and allylic alkylations using nucleophiles generated by hydro- or carbometallation.

This Minireview discusses catalytic asymmetric conjugate addition and allylic alkylation reactions where the nucleophiles were generated in situ by hydrometallation or carbometallation. This exciting recent trend in asymmetric catalysis promises to expand the range of transformations available for the rapid and selective assembly of complex, functional molecules for both academic and industrial research. This Minireview aims to serve as a reference for studies reported to date and discusses the current state-of-the-art, scope and limitations of these processes.

Novel applications of physical autocatalysis.

The autocatalytic self-reproduction of micelles and vesicles has been studied for several decades. These systems are vital components of certain protocell models and some models for how life may have begun from mixtures of simple chemicals. Here we discuss our recently described autocatalytic systems where self-reproducing micelles are driven by bond-forming reactions. These systems generate increased complexity on both the molecular level, through covalent bond formation, and the supramolecular level, through spontaneous self-assembly into functional aggregates. This provides the conceptual basis for novel studies of the potential roles of self-reproducing lipid aggregates in the prebiotic world.

Copper-catalysed asymmetric allylic alkylation of alkylzirconocenes to racemic 3,6-dihydro-2H-pyrans.

Asymmetric allylic alkylation is a powerful reaction that allows the enantioselective formation of C-C bonds. Here we describe the asymmetric alkylation of alkylzirconium species to racemic 3,6-dihydro-2H-pyrans. Two systems were examined: 3-chloro-3,6-dihydro-2H-pyran using linear optimization (45-93% ee, up to 33% yield, 5 examples) and 3,6-dihydro-2H-pyran-3-yl diethyl phosphate with the assistance of a design of experiments statistical approach (83% ee, 12% yield). (1)H NMR spectroscopy was used to gain insight into the reaction mechanisms.

Synthetic control of retinal photochemistry and photophysics in solution.

Understanding how molecular structure and environment control energy flow in molecules is a requirement for the efficient design of tailor-made photochemistry. Here, we investigate the tunability of the photochemical and photophysical properties of the retinal-protonated Schiff base chromophore in solution. Replacing the n-butylamine Schiff base normally chosen to mimic the saturated linkage found in nature by aromatic amines results in the reproduction of the opsin shift and complete suppression of all isomerization channels. Modification of retinal by directed addition or removal of backbone substituents tunes the overall photoisomerization yield from 0 to 0.55 and the excited state lifetime from 0.4 to 7 ps and activates previously inaccessible reaction channels to form 7-cis and 13-cis products. We observed a clear correlation between the presence of polarizable backbone substituents and photochemical reactivity. Structural changes that increase reaction speed were found to decrease quantum yields, and vice versa, so that excited state lifetime and efficiency are inversely correlated in contrast to the trends observed when comparing retinal photochemistry in protein and solution environments. Our results suggest a simple model where backbone modifications and Schiff base substituents control barrier heights on the excited-state potential energy surface and therefore determine speed, product distribution, and overall yield of the photochemical process.

Chelation enables selectivity control in enantioconvergent Suzuki-Miyaura cross-couplings on acyclic allylic systems.

Asymmetric Suzuki-Miyaura cross-couplings with aryl boronic acids and allylic electrophiles are a powerful method to convert racemic mixtures into enantioenriched products. Currently, enantioconvergent allylic arylations are limited to substrates that are symmetrical about the allylic unit, and the absence of strategies to control regio-, E/Z- and enantioselectivity in acyclic allylic systems is a major restriction. Here, using a system capable of either conjugate addition or allylic arylation, we have discovered the structural features and experimental conditions that allow an acyclic system to undergo chemo- and regioselective, enantioconvergent allylic Suzuki-Miyaura-type arylation. A wide variety of boronic acid coupling partners can be used, and both alkyl and aromatic substituents are tolerated on the allylic unit so that a wide variety of structures can be obtained. Preliminary mechanistic studies reveal that the chelating ability of the ester group is crucial to obtaining high regio- and enantioselectivity. Using this method, we were able to synthesize the natural products (S)-curcumene and (S)-4,7-dimethyl-1-tetralone and the clinically used antidepressant sertraline (Zoloft).

Mechanisms of autocatalysis.

Self-replication is a fundamental concept. The idea of an entity that can repeatedly create more of itself has captured the imagination of many thinkers from von Neumann to Vonnegut. Beyond the sciences and science fiction, autocatalysis has found currency in economics and language theory, and has raised ethical fears memorably summed up by the "gray goo" trope. Autocatalysis is central to the propagation of life and intrinsic to many other biological processes. This includes the modern conception of evolution, which has radically altered humanity's image of itself. Organisms can be thought of as imperfect self-replicators which produce closely-related species, allowing for selection and evolution. Hence, any consideration of self-replication raises one of the most profound questions of all: what is life? Minimal self-replicating systems have been studied with the aim of understanding the principles underlying living systems, allowing us to refine our concepts of biological fitness and chemical stability, self-organization and emergence, and ultimately to discover how chemistry may become biology.

From autocatalysis to survival of the fittest in self-reproducing lipid systems.

Studying autocatalysis - in which molecules catalyse their own formation - might help to explain the emergence of chemical systems that exhibit traits normally associated with biology. When coupled to other processes, autocatalysis can lead to complex systems-level behaviour in apparently simple mixtures. Lipids are an important class of chemicals that appear simple in isolation, but collectively show complex supramolecular and mesoscale dynamics. Here we discuss autocatalytic lipids as a source of extraordinary behaviour such as primitive chemical evolution, chemotaxis, temporally controllable materials and even as supramolecular catalysts for continuous synthesis. We survey the literature since the first examples of lipid autocatalysis and highlight state-of-the-art synthetic systems that emulate life, displaying behaviour such as metabolism and homeostasis, with special consideration for generating structural complexity and out-of-equilibrium models of life. Autocatalytic lipid systems have enormous potential for building complexity from simple components, and connections between physical effects and molecular reactivity are only just beginning to be discovered.

Backbone modification of retinal induces protein-like excited state dynamics in solution.

The drastically different reactivity of the retinal chromophore in solution compared to the protein environment is poorly understood. Here, we show that the addition of a methyl group to the C═C backbone of all-trans retinal protonated Schiff base accelerates the electronic decay in solution making it comparable to the proton pump bacteriorhodopsin. Contrary to the notion that reaction speed and efficiency are linked, we observe a concomitant 50% reduction in the isomerization yield. Our results demonstrate that minimal synthetic engineering of potential energy surfaces based on theoretical predictions can induce drastic changes in electronic dynamics toward those observed in an evolution-optimized protein pocket.