(Photoredox) Organocatalysis in the Emergence of Life: Discovery, Applications, and Molecular Evolution.

ConspectusLife as we know it is built on complex and perfectly interlocking processes that have evolved over millions of years through evolutionary optimization processes. The emergence of life from nonliving matter and the evolution of such highly efficient systems therefore constitute an enormous synthetic and systems chemistry challenge. Advances in supramolecular and systems chemistry are opening new perspectives that provide insights into living and self-sustaining reaction networks as precursors for life. However, the ab initio synthesis of such a system requires the possibility of autonomous optimization of catalytic properties and, consequently, of an evolutionary system at the molecular level. In this Account, we present our discovery of the formation of substituted imidazolidine-4-thiones (photoredox) organocatalysts from simple prebiotic building blocks such as aldehydes and ketones under Strecker reaction conditions with ammonia and cyanides in the presence of hydrogen sulfide. The necessary aldehydes are formed from CO2 and hydrogen under prebiotically plausible meteoritic or volcanic iron-particle catalysis in the atmosphere of the early Earth. Remarkably, the investigated imidazolidine-4-thiones undergo spontaneous resolution by conglomerate crystallization, opening a pathway for symmetry breaking, chiral amplification, and enantioselective organocatalysis. These imidazolidine-4-thiones enable α-alkylations of aldehydes and ketones by photoredox organocatalysis. Therefore, these photoredox organocatalysts are able to modify their aldehyde building blocks, which leads in an evolutionary process to mutated second-generation and third-generation catalysts. In our experimental studies, we found that this mutation can occur not only by new formation of the imidazolidine core structure of the catalyst from modified aldehyde building blocks or by continuous supply from a pool of available building blocks but also by a dynamic exchange of the carbonyl moiety in ring position 2 of the imidazolidine moiety. Remarkably, it can be shown that by incorporating aldehyde building blocks from their environment, the imidazolidine-4-thiones are able to change and adapt to altering environmental conditions without undergoing the entire formation process. The selection of the mutated catalysts is then based on the different catalytic activities in the modification of the aldehyde building blocks and on the catalysis of subsequent processes that can lead to the formation of molecular reaction networks as progenitors for cellular processes. We were able to show that these imidazolidine-4-thiones not only enable α-alkylations but also facilitate other important transformations, such as the selective phosphorylation of nucleosides to nucleotides as a key step leading to the oligomerization to RNA and DNA. It can therefore be expected that evolutionary processes have already taken place on a small molecular level and have thus developed chemical tools that change over time, representing a hidden layer on the path to enzymatically catalyzed biochemical processes.

A Prebiotic Pathway to Nicotinamide Adenine Dinucleotide.

Enzymes play a fundamental role in cellular metabolism. A wide range of enzymes require the presence of complementary coenzymes and cofactors to function properly. While coenzymes are believed to have been part of the last universal ancestor (LUCA) or have been present even earlier, the syntheses of crucial coenzymes like the redox-active coenzymes flavin adenine dinucleotide (FAD) or nicotinamide adenine dinucleotide (NAD+) remain challenging. Here, we present a pathway to NAD+ under prebiotic conditions starting with ammonia, cyanoacetaldehyde, prop-2-ynal and sugar-forming precursors, yielding in situ the nicotinamide riboside. Regioselective phosphorylation and water stable light activated adenosine monophosphate derivatives allow for topographically and irradiation-controlled formation of NAD+. Our findings indicate that NAD+, a coenzyme vital to life, can be formed non-enzymatically from simple organic feedstock molecules via photocatalytic activation under prebiotically plausible early Earth conditions in a continuous process under aqueous conditions.

Dynamic Exchange of Substituents in a Prebiotic Organocatalyst: Initial Steps towards an Evolutionary System.

All evolutionary biological processes lead to a change in heritable traits over successive generations. The responsible genetic information encoded in DNA is altered, selected, and inherited by mutation of the base sequence. While this is well known at the biological level, an evolutionary change at the molecular level of small organic molecules is unknown but represents an important prerequisite for the emergence of life. Here, we present a class of prebiotic imidazolidine-4-thione organocatalysts able to dynamically change their constitution and potentially capable to form an evolutionary system. These catalysts functionalize their building blocks and dynamically adapt to their (self-modified) environment by mutation of their own structure. Depending on the surrounding conditions, they show pronounced and opposing selectivity in their formation. Remarkably, the preferentially formed species can be associated with different catalytic properties, which enable multiple pathways for the transition from abiotic matter to functional biomolecules.

Prebiotically Plausible Organocatalysts Enabling a Selective Photoredox α-Alkylation of Aldehydes on the Early Earth.

Organocatalysis is a powerful approach to extend and (enantio-) selectively modify molecular structures. Adapting this concept to the Early Earth scenario offers a promising solution to explain their evolution into a complex homochiral world. Herein, we present a class of imidazolidine-4-thione organocatalysts, easily accessible from simple molecules available on an Early Earth under highly plausible prebiotic reaction conditions. These imidazolidine-4-thiones are readily formed from mixtures of aldehydes or ketones in presence of ammonia, cyanides and hydrogen sulfide in high selectivity and distinct preference for individual compounds of the resulting catalyst library. These organocatalysts enable the enantioselective α-alkylation of aldehydes under prebiotic conditions and show activities that correlate with the selectivity of their formation. Furthermore, the crystallization of single catalysts as conglomerates opens the pathway for symmetry breaking.