Chirality Makes or Breaks Chemically Driven Self-Assembly.

Nature has consistently selected homochiral building blocks from millions of possible diastereomers across diverse biomolecular structures to drive molecular recognition, catalysis and self-assembly. Despite its central role in biology, chirality's influence on chemically driven reaction networks remains unexplored. Here, we demonstrate that chiral aminoacyl phosphate esters, synthetic analogs of biological acylating intermediates, drive self-assembly and reaction pathways, that are modulated purely by their configuration, without the need for changes in functional groups.

Selective peptide bond formation via side chain reactivity and self-assembly of abiotic phosphates.

In the realm of biology, peptide bonds are formed via reactive phosphate-containing intermediates, facilitated by compartmentalized environments that ensure precise coupling and folding. Herein, we use aminoacyl phosphate esters, synthetic counterparts of biological aminoacyl adenylates, that drive selective peptide bond formation through side chain-controlled reactivity and self-assembly. This strategy results in the preferential incorporation of positively charged amino acids from mixtures containing natural and non-natural amino acids during the spontaneous formation of amide bonds in water.

Abiotic Acyl Transfer Cascades Driven by Aminoacyl Phosphate Esters and Self-Assembly.

Biochemical acyl transfer cascades, such as those initiated by the adenylation of carboxylic acids, are central to various biological processes, including protein synthesis and fatty acid metabolism. Designing cascade reactions in aqueous media remains challenging due to the need to control multiple, sequential reactions in a single pot and manage the stability of reactive intermediates. Herein, we developed abiotic cascades using aminoacyl phosphate esters, the synthetic counterparts of biological aminoacyl adenylates, to drive sequential chemical reactions and self-assembly in a single pot.

Guiding Transient Peptide Assemblies with Structural Elements Embedded in Abiotic Phosphate Fuels.

Despite great progress in the construction of non-equilibrium systems, most approaches do not consider the structure of the fuel as a critical element to control the processes. Herein, we show that the amino acid side chains (A, F, Nal) in the structure of abiotic phosphates can direct assembly and reactivity during transient structure formation. The fuels bind covalently to substrates and subsequently influence the structures in the assembly process.

Spontaneous and Selective Peptide Elongation in Water Driven by Aminoacyl Phosphate Esters and Phase Changes.

Nature chose phosphates to activate amino acids, where reactive intermediates and complex machinery drive the construction of polyamides. Outside of biology, the pathways and mechanisms that allow spontaneous and selective peptide elongation in aqueous abiotic systems remain unclear. Herein we work to uncover those pathways by following the systems chemistry of aminoacyl phosphate esters, synthetic counterparts of aminoacyl adenylates.

Annulation of Enals with Carbamoylpropiolates via NHC-Catalyzed Enolate Pathway: Access to Functionalized Maleimides/Iso-maleimides and Synthesis of Aspergillus FH-X-213.

Herein we report the -heterocyclic carbene (NHC)-catalyzed [3 + 2] annulation of α,β-unsaturated aldehydes with carbamoylpropiolates via an unusual enolate pathway leading to the construction of highly functionalized maleimides or isomaleimides. The electronic effect imposed by the alkyl/aryl group present on the amide nitrogen of carbamoylpropiolates plays a crucial role in the selective formation of these important five-membered heterocyclic building blocks. The developed protocol is mild and tolerates a wide range of substituents on both substrates.

Construction of unique SCF-containing building blocks via allylic alkylation of Morita-Baylis-Hillman adducts.

Lewis base-catalyzed allylic alkylation of Morita-Baylis-Hillman adducts with α-SCF3 ketones has been demonstrated. The developed strategy provides efficient access to a series of highly functionalized scaffolds featuring trifluoromethanesufinyl motif on a stereogenic carbon.

Stereoselective construction of deoxy-cruciferane alkaloids by NHC-catalyzed intramolecular annulation of homoenolate with quinazolinone.

Chiral N-heterocyclic carbene (NHC)-catalyzed intramolecular [3 + 2] annulation of enals with an unactivated imine moiety of quinazolinone via formal homoenolate cycloaddition has been demonstrated. It is an excellent approach for stereoselective syntheses of deoxy-cruciferane alkaloids comprising a biologically important pyrroloindoline scaffold. Notably, this is the first report on the NHC-catalyzed asymmetric intramolecular homoenolate annulation with cyclic N-acyl amidine.